Dear Dr. Mossman,

At the multispecialty hospital where I work, administrators refer to patients as “customers” and tell us that, by improving “the customer experience,” we can reduce complaints and avoid malpractice suits. This business lingo offends me. Doesn’t providing good care do more to prevent malpractice claims than calling sick patients “customers”?

Submitted by “Dr. H”

“All words are pegs to hang ideas on.” As was true when Reverend Henry Ward Beecher uttered this phrase in the 19th century,¹ names affect how we relate to and feel about people. Many doctors don’t think of themselves as “selling” services, and they find calling patients “customers” distasteful.

But for at least 4 decades, mental health professionals themselves have used a “customer approach” to think about certain aspects of psychiatrist–patient encounters.² More pertinent to Dr. H’s questions, many attorneys who advise physicians are convinced that giving patients a satisfying “customer experience” is a sound strategy for reducing the risk of malpractice litigation.³

If the attorneys are right, taking a customer service perspective can lower the likelihood that psychiatrists will be sued. To understand why, this article looks at:
   • terms for referring to health care recipients
   • the feelings those terms generate
   • how the “customer service” perspective has become a malpractice prevention
      strategy.

Off-putting connotations

All the currently used ways of referring to persons served by doctors have off-putting features.

The word “patient” dates back to the 14th century and comes from Latin present
participles of pati, “to suffer.” Although Alpha Omega Alpha’s motto—“be worthy
to serve the suffering”⁴—expresses doctors’ commitment to help others, “patient”
carries emotional baggage. A “patient” is “a sick individual” who seeks treatment
from a physician,⁵ a circumstance that most people (including doctors) find unpleasant and hope is only temporary. The adjective “patient” means “bearing pains or trials calmly or without complaint” and “manifesting forbearance under provocation or strain,”⁵ phrases associated with passivity, deference, and a long wait to see the doctor.

Because “patient” evokes notions of helplessness and need for direction, non-medical psychotherapists often use “client” to designate care recipients. “Client” has the same Latin root as “to lean” and refers to someone “under the protection of another.” More pertinent to discussions of mental health care, a “client” also is “a person who pays a professional person or organization for services” or “a customer.”⁵ The latter definition explains what makes “client” feel wrong to medical practitioners, who regard those they treat as deserving more compassion and sacrifice than someone who simply purchases professional services.

“Consumer,” a word of French origin derived from the Latin consumere (“to take
up”), refers to “a person who buys goods and services.”⁵ If “consumers” are buyers, then those from whom they make purchases are merchants or sellers. Western marketplace concepts often regard consumers as sovereign judges of their needs, and the role of commodity producers is to try to satisfy those needs.⁶

The problem with viewing health care recipients this way is that sellers don’t caution customers about buying things when only principles of supply-and-demand govern exchange relationships.⁷ Quite the contrary: producers sometimes promote their products through “advertising [that] distorts reality and creates artificial needs to make profit for a firm.”⁸ If physicians behave this way, however, they get criticism and deserve it.

A “customer” in 15th-century Middle English was a tax collector, but in modern
usage, a customer is someone who, like a consumer, “purchases some commodity or service.”⁵ By the early 20th century, “customer” became associated with notions of empowerment embodied in the merchants’ credo, “The customer is always right.”⁹ Chronic illnesses often require self-management and collaboration with those labeled the “givers” and “recipients” of medical care. Research shows that “patients are more trusting of, and committed to, physicians who adopt an empowering communication style with them,” which suggests “that empowering
patients presents a means to improve the patient–physician relationship.”¹⁰

Feelings about names

People have strong feelings about what they are called. In opposing calling patients “consumers,” Nobel Prize-winning economist Paul Krugman explains: “Medical care is an area in which crucial decisions—life and death decisions—must be made; yet making those decisions intelligently requires a vast amount of specialized knowledge; and often those decisions must also be made under conditions in which the patient …needs action immediately, with no time for discussion, let alone comparison shopping. …That’s why doctors have traditionally…been expected to behave according to higher standards than the average professional…The idea that all this can be reduced to money—that doctors are just people selling services to consumers of health care—is, well, sickening.”¹¹

Less famous recipients of nonpsychiatric medical services also prefer being called
“patients” over “clients” or “consumers.”^12-14 Recipients of mental health services have a different view, however. In some surveys, “patient” gets a plurality or majority of service recipients’ votes,^15,16 but in others, recipients prefer to be called “clients” or other terms.^17,18 Of note, people who prefer being called “patients” tend to strongly dislike being called “clients.”¹⁹ On the professional
side, psychiatrists—along with other physicians—prefer to speak of treating “patients” and to criticize letting economic phrases infect medical discourse.^20-22

Names: A practical difference?

Does what psychiatrists call those they serve make any practical difference? Perhaps not, but evidence suggests that the attitudes that doctors take toward patients affects economic success and malpractice risk.

When they have choices about where they can seek health care, medical patients value physicians’ competence, but they also consider nonclinical factors such as family members’ opinions and convenience.²³ Knowing this, the federal government’s Centers for Medicare & Medicaid Services publishes results from its Hospital Consumer Assessment of Healthcare Providers and Systems to “create incentives for hospitals to improve their quality of care.”²⁴

Nonclinical factors play a big part in patients’ decisions about suing their doctors, too. Many malpractice claims turn out to be groundless in the sense that they do not involve medical errors,²⁵ and most errors that result in injury do not lead to malpractice suits.²⁶

What explains this disparity? Often when a lawsuit is filed, whatever injury may have occurred is coupled with an aggravating factor, such as a communication gaffe,²⁷ a physician’s domineering tone of voice,²⁸ or failure to acknowledge error.²⁹ The lower a physician’s patient satisfaction ratings, the higher the physician’s likelihood of receiving complaints and getting sued for malpractice.^30,31

These kinds of considerations probably lie behind the recommendation of one hospital manager to doctors: “Continue to call them patients but treat them like
customers.”³² More insights into this view come from responses solicited from Yale
students, staff members, and alumni about whether it seems preferable to be a “patient” or a “customer” (Box).³³

Bottom Line

When patients get injured during medical care, evidence suggests that how they feel about their doctors makes a big difference in whether they decide to file suit. If you’re like most psychiatrists, you prefer to call persons whom you treat “patients.” But watching and improving the things that affect your patients’ “customer experience” may help you avoid malpractice litigation.

Related Resource
• Goldhill D. To fix healthcare, turn patients into customers. Bloomberg Personal Finance. www.bloomberg.com/news/2013-01-03/to-fix-health-care-turn-patients-intocustomers.html.

Disclosure
Dr. Mossman reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dear Dr. Mossman,

At the multispecialty hospital where I work, administrators refer to patients as “customers” and tell us that, by improving “the customer experience,” we can reduce complaints and avoid malpractice suits. This business lingo offends me. Doesn’t providing good care do more to prevent malpractice claims than calling sick patients “customers”?

Submitted by “Dr. H”

“All words are pegs to hang ideas on.” As was true when Reverend Henry Ward Beecher uttered this phrase in the 19th century,¹ names affect how we relate to and feel about people. Many doctors don’t think of themselves as “selling” services, and they find calling patients “customers” distasteful.

But for at least 4 decades, mental health professionals themselves have used a “customer approach” to think about certain aspects of psychiatrist–patient encounters.² More pertinent to Dr. H’s questions, many attorneys who advise physicians are convinced that giving patients a satisfying “customer experience” is a sound strategy for reducing the risk of malpractice litigation.³

If the attorneys are right, taking a customer service perspective can lower the likelihood that psychiatrists will be sued. To understand why, this article looks at:
   • terms for referring to health care recipients
   • the feelings those terms generate
   • how the “customer service” perspective has become a malpractice prevention
      strategy.

Off-putting connotations

All the currently used ways of referring to persons served by doctors have off-putting features.

The word “patient” dates back to the 14th century and comes from Latin present
participles of pati, “to suffer.” Although Alpha Omega Alpha’s motto—“be worthy
to serve the suffering”⁴—expresses doctors’ commitment to help others, “patient”
carries emotional baggage. A “patient” is “a sick individual” who seeks treatment
from a physician,⁵ a circumstance that most people (including doctors) find unpleasant and hope is only temporary. The adjective “patient” means “bearing pains or trials calmly or without complaint” and “manifesting forbearance under provocation or strain,”⁵ phrases associated with passivity, deference, and a long wait to see the doctor.

Because “patient” evokes notions of helplessness and need for direction, non-medical psychotherapists often use “client” to designate care recipients. “Client” has the same Latin root as “to lean” and refers to someone “under the protection of another.” More pertinent to discussions of mental health care, a “client” also is “a person who pays a professional person or organization for services” or “a customer.”⁵ The latter definition explains what makes “client” feel wrong to medical practitioners, who regard those they treat as deserving more compassion and sacrifice than someone who simply purchases professional services.

“Consumer,” a word of French origin derived from the Latin consumere (“to take
up”), refers to “a person who buys goods and services.”⁵ If “consumers” are buyers, then those from whom they make purchases are merchants or sellers. Western marketplace concepts often regard consumers as sovereign judges of their needs, and the role of commodity producers is to try to satisfy those needs.⁶

The problem with viewing health care recipients this way is that sellers don’t caution customers about buying things when only principles of supply-and-demand govern exchange relationships.⁷ Quite the contrary: producers sometimes promote their products through “advertising [that] distorts reality and creates artificial needs to make profit for a firm.”⁸ If physicians behave this way, however, they get criticism and deserve it.

A “customer” in 15th-century Middle English was a tax collector, but in modern
usage, a customer is someone who, like a consumer, “purchases some commodity or service.”⁵ By the early 20th century, “customer” became associated with notions of empowerment embodied in the merchants’ credo, “The customer is always right.”⁹ Chronic illnesses often require self-management and collaboration with those labeled the “givers” and “recipients” of medical care. Research shows that “patients are more trusting of, and committed to, physicians who adopt an empowering communication style with them,” which suggests “that empowering
patients presents a means to improve the patient–physician relationship.”¹⁰

Feelings about names

People have strong feelings about what they are called. In opposing calling patients “consumers,” Nobel Prize-winning economist Paul Krugman explains: “Medical care is an area in which crucial decisions—life and death decisions—must be made; yet making those decisions intelligently requires a vast amount of specialized knowledge; and often those decisions must also be made under conditions in which the patient …needs action immediately, with no time for discussion, let alone comparison shopping. …That’s why doctors have traditionally…been expected to behave according to higher standards than the average professional…The idea that all this can be reduced to money—that doctors are just people selling services to consumers of health care—is, well, sickening.”¹¹

Less famous recipients of nonpsychiatric medical services also prefer being called
“patients” over “clients” or “consumers.”^12-14 Recipients of mental health services have a different view, however. In some surveys, “patient” gets a plurality or majority of service recipients’ votes,^15,16 but in others, recipients prefer to be called “clients” or other terms.^17,18 Of note, people who prefer being called “patients” tend to strongly dislike being called “clients.”¹⁹ On the professional
side, psychiatrists—along with other physicians—prefer to speak of treating “patients” and to criticize letting economic phrases infect medical discourse.^20-22

Names: A practical difference?

Does what psychiatrists call those they serve make any practical difference? Perhaps not, but evidence suggests that the attitudes that doctors take toward patients affects economic success and malpractice risk.

When they have choices about where they can seek health care, medical patients value physicians’ competence, but they also consider nonclinical factors such as family members’ opinions and convenience.²³ Knowing this, the federal government’s Centers for Medicare & Medicaid Services publishes results from its Hospital Consumer Assessment of Healthcare Providers and Systems to “create incentives for hospitals to improve their quality of care.”²⁴

Nonclinical factors play a big part in patients’ decisions about suing their doctors, too. Many malpractice claims turn out to be groundless in the sense that they do not involve medical errors,²⁵ and most errors that result in injury do not lead to malpractice suits.²⁶

What explains this disparity? Often when a lawsuit is filed, whatever injury may have occurred is coupled with an aggravating factor, such as a communication gaffe,²⁷ a physician’s domineering tone of voice,²⁸ or failure to acknowledge error.²⁹ The lower a physician’s patient satisfaction ratings, the higher the physician’s likelihood of receiving complaints and getting sued for malpractice.^30,31

These kinds of considerations probably lie behind the recommendation of one hospital manager to doctors: “Continue to call them patients but treat them like
customers.”³² More insights into this view come from responses solicited from Yale
students, staff members, and alumni about whether it seems preferable to be a “patient” or a “customer” (Box).³³

Bottom Line

When patients get injured during medical care, evidence suggests that how they feel about their doctors makes a big difference in whether they decide to file suit. If you’re like most psychiatrists, you prefer to call persons whom you treat “patients.” But watching and improving the things that affect your patients’ “customer experience” may help you avoid malpractice litigation.

Related Resource
• Goldhill D. To fix healthcare, turn patients into customers. Bloomberg Personal Finance. www.bloomberg.com/news/2013-01-03/to-fix-health-care-turn-patients-intocustomers.html.

Disclosure
Dr. Mossman reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dear Dr. Mossman,

At the multispecialty hospital where I work, administrators refer to patients as “customers” and tell us that, by improving “the customer experience,” we can reduce complaints and avoid malpractice suits. This business lingo offends me. Doesn’t providing good care do more to prevent malpractice claims than calling sick patients “customers”?

Submitted by “Dr. H”

“All words are pegs to hang ideas on.” As was true when Reverend Henry Ward Beecher uttered this phrase in the 19th century,¹ names affect how we relate to and feel about people. Many doctors don’t think of themselves as “selling” services, and they find calling patients “customers” distasteful.

But for at least 4 decades, mental health professionals themselves have used a “customer approach” to think about certain aspects of psychiatrist–patient encounters.² More pertinent to Dr. H’s questions, many attorneys who advise physicians are convinced that giving patients a satisfying “customer experience” is a sound strategy for reducing the risk of malpractice litigation.³

If the attorneys are right, taking a customer service perspective can lower the likelihood that psychiatrists will be sued. To understand why, this article looks at:
   • terms for referring to health care recipients
   • the feelings those terms generate
   • how the “customer service” perspective has become a malpractice prevention
      strategy.

Off-putting connotations

All the currently used ways of referring to persons served by doctors have off-putting features.

The word “patient” dates back to the 14th century and comes from Latin present
participles of pati, “to suffer.” Although Alpha Omega Alpha’s motto—“be worthy
to serve the suffering”⁴—expresses doctors’ commitment to help others, “patient”
carries emotional baggage. A “patient” is “a sick individual” who seeks treatment
from a physician,⁵ a circumstance that most people (including doctors) find unpleasant and hope is only temporary. The adjective “patient” means “bearing pains or trials calmly or without complaint” and “manifesting forbearance under provocation or strain,”⁵ phrases associated with passivity, deference, and a long wait to see the doctor.

Because “patient” evokes notions of helplessness and need for direction, non-medical psychotherapists often use “client” to designate care recipients. “Client” has the same Latin root as “to lean” and refers to someone “under the protection of another.” More pertinent to discussions of mental health care, a “client” also is “a person who pays a professional person or organization for services” or “a customer.”⁵ The latter definition explains what makes “client” feel wrong to medical practitioners, who regard those they treat as deserving more compassion and sacrifice than someone who simply purchases professional services.

“Consumer,” a word of French origin derived from the Latin consumere (“to take
up”), refers to “a person who buys goods and services.”⁵ If “consumers” are buyers, then those from whom they make purchases are merchants or sellers. Western marketplace concepts often regard consumers as sovereign judges of their needs, and the role of commodity producers is to try to satisfy those needs.⁶

The problem with viewing health care recipients this way is that sellers don’t caution customers about buying things when only principles of supply-and-demand govern exchange relationships.⁷ Quite the contrary: producers sometimes promote their products through “advertising [that] distorts reality and creates artificial needs to make profit for a firm.”⁸ If physicians behave this way, however, they get criticism and deserve it.

A “customer” in 15th-century Middle English was a tax collector, but in modern
usage, a customer is someone who, like a consumer, “purchases some commodity or service.”⁵ By the early 20th century, “customer” became associated with notions of empowerment embodied in the merchants’ credo, “The customer is always right.”⁹ Chronic illnesses often require self-management and collaboration with those labeled the “givers” and “recipients” of medical care. Research shows that “patients are more trusting of, and committed to, physicians who adopt an empowering communication style with them,” which suggests “that empowering
patients presents a means to improve the patient–physician relationship.”¹⁰

Feelings about names

People have strong feelings about what they are called. In opposing calling patients “consumers,” Nobel Prize-winning economist Paul Krugman explains: “Medical care is an area in which crucial decisions—life and death decisions—must be made; yet making those decisions intelligently requires a vast amount of specialized knowledge; and often those decisions must also be made under conditions in which the patient …needs action immediately, with no time for discussion, let alone comparison shopping. …That’s why doctors have traditionally…been expected to behave according to higher standards than the average professional…The idea that all this can be reduced to money—that doctors are just people selling services to consumers of health care—is, well, sickening.”¹¹

Less famous recipients of nonpsychiatric medical services also prefer being called
“patients” over “clients” or “consumers.”^12-14 Recipients of mental health services have a different view, however. In some surveys, “patient” gets a plurality or majority of service recipients’ votes,^15,16 but in others, recipients prefer to be called “clients” or other terms.^17,18 Of note, people who prefer being called “patients” tend to strongly dislike being called “clients.”¹⁹ On the professional
side, psychiatrists—along with other physicians—prefer to speak of treating “patients” and to criticize letting economic phrases infect medical discourse.^20-22

Names: A practical difference?

Does what psychiatrists call those they serve make any practical difference? Perhaps not, but evidence suggests that the attitudes that doctors take toward patients affects economic success and malpractice risk.

When they have choices about where they can seek health care, medical patients value physicians’ competence, but they also consider nonclinical factors such as family members’ opinions and convenience.²³ Knowing this, the federal government’s Centers for Medicare & Medicaid Services publishes results from its Hospital Consumer Assessment of Healthcare Providers and Systems to “create incentives for hospitals to improve their quality of care.”²⁴

Nonclinical factors play a big part in patients’ decisions about suing their doctors, too. Many malpractice claims turn out to be groundless in the sense that they do not involve medical errors,²⁵ and most errors that result in injury do not lead to malpractice suits.²⁶

What explains this disparity? Often when a lawsuit is filed, whatever injury may have occurred is coupled with an aggravating factor, such as a communication gaffe,²⁷ a physician’s domineering tone of voice,²⁸ or failure to acknowledge error.²⁹ The lower a physician’s patient satisfaction ratings, the higher the physician’s likelihood of receiving complaints and getting sued for malpractice.^30,31

These kinds of considerations probably lie behind the recommendation of one hospital manager to doctors: “Continue to call them patients but treat them like
customers.”³² More insights into this view come from responses solicited from Yale
students, staff members, and alumni about whether it seems preferable to be a “patient” or a “customer” (Box).³³

Bottom Line

When patients get injured during medical care, evidence suggests that how they feel about their doctors makes a big difference in whether they decide to file suit. If you’re like most psychiatrists, you prefer to call persons whom you treat “patients.” But watching and improving the things that affect your patients’ “customer experience” may help you avoid malpractice litigation.

Related Resource
• Goldhill D. To fix healthcare, turn patients into customers. Bloomberg Personal Finance. www.bloomberg.com/news/2013-01-03/to-fix-health-care-turn-patients-intocustomers.html.

Disclosure
Dr. Mossman reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Neuropsychological evaluation, consisting of a thorough examination of cognitive and behavioral functioning, can make an invaluable contribution to the care of psychiatric patients. Through the vehicle of standardized measures of abilities, patients’ cognitive strengths and weaknesses can be elucidated—revealing potential areas for further interventions or to explain impediments to treatment. A licensed clinical psychologist provides this service.

You, as a consumer of reported findings, can use the results to inform your diagnosis and treatment plan. Recommendations from the neuropsychologist often address dispositional planning, cognitive intervention, psychiatric intervention, and work and school accommodations.


Probing the brain−behavior relationship

Neuropsychology is a subspecialty of clinical psychology that is focused on understanding the brain–behavior relationship. Drawing information from multiple disciplines, including psychiatry and neurology, neuropsychology seeks to uncover the cognitive, behavioral, and emotional difficulties that can result from known or suspected brain dysfunction. Increasingly, to protect the public and referral sources, clinical psychologists who perform neuropsychological testing demonstrate their competence through board certification (eg, the American Board of Clinical Neuropsychology).

How is testing conducted? Evaluations comprise measures that are standardized, scored objectively, and have established psychometric properties. Testing can performed on an outpatient or inpatient basis; the duration of testing depends on the question for which the referring practitioner seeks an answer.

Measures typically are administered by paper and pencil, although computer-based
assessments are increasingly being employed. Because of the influence of demographic variables (age, sex, years of education, race), scores are compared with normative samples that resemble those of the patient’s background as closely as possible.

A thorough clinical interview with the patient, a collateral interview with caregivers
and family, and review of relevant medical records are crucial parts of the assessment. Multiple areas of cognition are assessed:
   • intelligence
   • academic functioning
   • attention
   • working memory
   • speed of processing
   • learning and memory
   • visual spatial skills
   • fine motor skills
   • executive functioning.

Essentially, the evaluation speaks to a patient’s neurocognitive functioning and cerebral integrity.

How are results scored? Interpretation of test scores is contingent on expectations of how a patient should perform in the absence of neurologic or psychiatric illness (ie, based on normative data and performancebased estimates of premorbid functioning).¹ The overall pattern of intact scores and deficit scores can be used to form specific impressions about a diagnosis, cognitive strengths and weaknesses, and strategies for intervention.

Personality testing. In addition to the cognitive aspect of the evaluation, personality measures are incorporated when relevant to the referral question or presenting concern.

Personality tests can be broadly divided into objective and projective measures.
Objective personality measures, such as the Minnesota Multiphasic Personality
Inventory-Second Edition, require the examinee to respond to a set of items as
true or false or on a Likert-type scale from strongly agree to disagree. Responses are then scored in standardized fashion, making comparisons to normative data, which are then analyzed to determine the extent to which the examinee experiences psychiatric symptoms.

As part of testing, patients’ responses to ambiguous or unstructured standard
stimuli—such as a series of drawings, abstract patterns, or incomplete sentences—
are analyzed to determine underlying personality traits, feelings, and attitudes.
Classic examples of these measures include the Rorschach Test and the Thematic
Apperception Test.

Personality measures and psychiatric testing are designed to answer questions
related to patients’ emotional status. These measures assess psychiatric symptoms and diagnoses, whereas neuropsychological measures provide an understanding of patients’ cognitive assets and limitations.

7 Common questions about neuropsychological testing

1 Will my patient’s insurance cover these assessments? The question is common from practitioners who are considering requesting an assessment for a patient. The short answer is “Yes.”

Most payers follow Medicare guidelines for reimbursement of neuropsychological
testing; if testing is determined to be medically necessary, insurance companies often cover the assessment. Medicaid also pays for psychometric testing services. Neuropsychologists who have a hospital-based practice typically include patients
with all types of insurance coverage. For example, 40% of patients seen in a hospital are covered by Medicare or Medicaid.²

A caveat: Local intermediaries interpret policies and procedures in different ways,
so there is variability in coverage by geographic region. That is why it is crucial
for neuropsychologists to obtain preauthorization, as would be the case with other medical procedures and services sought by referral.

Last, insurance companies do not pay for assessment of a learning disability. The
rationale typically offered for this lack of coverage? The assessment is for academic, not medical, purposes. In such a situation, patients and their families are offered a private-pay option.

2 What are the indications for neuropsychological assessment? Psychiatric practitioners are one of the top medical specialties that refer their patients for neuropsychological testing.³ This is because many patients with a psychiatric or
neurologic disorder experience changes in cognition, mood, and personality. Such
changes can range in severity from subtle to dramatic, and might reflect an underlying disease state or a side effect of medication or other treatment. Whatever the nature of a patient’s problem, careful assessment might help elucidate specific areas with which he (she) is struggling—so that you can better target your interventions. Table 1 lists common reasons for referring a patient for neuropsychological evaluation. Throughout this discussion, we describe examples of clinical situations in which neuropsychological testing is useful for establishing a differential diagnosis and dispositional planning.

3 How does neuropsychological testing help with the differential diagnosis? As an example, one area in which cognitive testing can be beneficial is in geriatric psychiatry.Dementia. Aging often is accompanied by a normal decline in memory and other cognitive functions. But because subtle changes in memory and cognition also canbe the sign of a progressive cognitive disorder, differentiating normal aging from early dementia is essential. Table 2 summarizes typical changes in cognition with aging.

Neuropsychologists, through knowledge of psychometric testing and the brain−behavior relationship, can help you detect dementia and plan treatment early. To determine if cognitive changes are progressive, patients might undergo re-evaluation—typically, every 6 to 12 months—to ascertain if changes have occurred. Mood disorders. Neuropsychological evaluation can be useful in building a differential diagnosis when determining whether cognitive symptoms are attributable to a mood disorder or a medical illness. Cognitive deficits associated with an affective disturbance generally include impairments in attention, memory, and executive functioning.⁴ The severity of deficits has been linked to severity of illness. When patients with a mood disorder demonstrate localizing impairments or those of greater severity than expected, suspicion arises that another cause likely better explains those deficits, and further medical testing then is often recommended. Medical procedures. Increasingly, neuropsychological assessment is used to assist in determining the appropriateness of medical procedures. For example, neurosurgical patients being considered for deep brain stimulation, brain tumor resectioning, and epilepsy surgery often are referred for preoperative and postoperative testing. Treating clinicians need an understanding of current cognitive status, localization of functioning, and psychological status to make appropriate decisions about a patient’s candidacy for one of these procedures,and to understand associated risk.

4 How is neuropsychological testing used for dispositional planning? The
results of cognitive and psychological testing have implications for dispositional
planning for patients who are receiving psychiatric care. The primary issue often is
to determine the patient’s level of independence and ability to make decisions about his affairs.⁵

Neuropsychological testing can help determine if cognitive deficits limit aspects of functional independence—for example, can the patient live alone, or must he live with family or in a residential care facility? Generally, the greater the cognitive impairment, the more supervision and assistance are required. This relationship between cognitive ability and independence in activities of daily living has been demonstrated in many groups of psychiatric patients, including older adults with dementia,⁶ patients with schizophrenia,⁷ and those with bipolar disorder.⁸

Specific recommendations can be made regarding management of finances, administering medications, and driving. To formulate an appropriate dispositional plan, the referring psychiatrist might integrate recommendations from the neuropsychological assessment with findings of other evaluations and with information that has been collected about the patient.

5 Can neuropsychological testing be used to refer a patient for neurological and cognitive rehabilitation? Yes. The neuropsychologist is singularly qualified to make recommendations about a range of interventions for cognitive deficits that have been identified on formal testing.

Typically, recommendations for addressing cognitive deficits involve rehabilitation
focused on development and use of compensatory strategies and modification to promote brain health.^9,10 Rehabilitation therapy typically is aimed at increasing functioning independence and reducing physical and cognitive deficits associated
with illness (eg, traumatic brain injury [TBI], stroke, orthopedic injury, debility).

Patients who have a TBI or who have had a stroke often have comorbid psychiatric problems, including mood and anxiety disorders, that can exacerbate deficits and impede engagement in rehabilitation. The neuropsychological evaluation can determine if this is the case and if psychiatric consultation is warranted to assist with managing symptoms.

Premorbid psychiatric illness can affect rehabilitation. Formal neuropsychological testing can assist with parsing out deficits associated with new-onset illness compared with premorbid psychiatric problems. The evaluation of a patient before he begins rehabilitation also can be compared with evaluations made during treatment and after discharge to 1) assess for changes and 2) update recommendations about management.

Recommendations about cognitive interventions might include specific compensatory strategies to address areas of weakness and capitalize on strengths. Such strategies can include using internal mnemonics, such as visual imagery (ie, using a visual image to help encode verbal information) or semantic elaboration (using semantic cues to aid in encoding and recall of information). Methods can help train patients to capitalize on areas of stronger cognitive functioning in compensating for their weaknesses; an example is the spaced-retrieval technique, which relies on repetition of information that is to be learned over time.¹¹

Perhaps the most practical strategies for addressing areas of weakness are nonmnemonic-based external memory aids, such as diaries, notebooks, calendars, alarms, and lists.¹² For example, for a patient with a TBI who has impaired memory, recommendations might include using written notes or a calendar system; using a pillbox for medication management; and using labels to promote structure and consistency in the home. These strategies are meant to promote increased independence and to minimize the effect of cognitive deficits on daily functioning.   

Recommended strategies can include lifestyle changes to promote improved cognitive functioning and overall health, such as:
   • sleep hygiene, to reduce the effects of fatigue
   • encouraging the patient to adhere to a diet, take prescribed medications, and  follow up with his health care providers
   • developing cognitive and physical exercise routines.

In addition, a patient who has had a stroke or who have a TBI might benefit from psychotherapy or referral to a group program or community resources to help cope with the effects of illness.¹³

6 How does neuropsychological testing help determine the appropriate psychiatric intervention for a patient? Results of neuropsychological testing can help determine appropriate interventions for a psychiatric condition that might be the principal factor affecting the patient’s functioning.

Concerning psychoactive medications, consider the following:

Mood and anxiety disorders. Neuropsychological measures can help substantiate the need for pharmacotherapy in a comorbid mood or anxiety disorder in a patient who has a neurologic illness, such as stroke or TBI.

ADHD. In a patient who has attentiondeficit/hyperactivity disorder (ADHD), results of cognitive testing might help determine if attention issues undermine daily functioning. Testing provides information beyond rating scale scores to justify diagnosis and psychopharmacotherapy.¹⁴

Dementia. Geriatric patients who have dementia often have coexisting behavioral and mood changes that, once evaluated, might improve with pharmacotherapy.

Other areas. Cognitive side effects of medications can be monitored by conducting testing before and after medication is started. The evaluation can address the patient’s ability to engage in psychotherapeutic interventions. Patients who have severe cognitive deficits might have greater difficulty engaging in psychotherapy, compared with patients who have less severe, or no, cognitive
impairment.¹⁵

7 Does neuropsychological testing help patients make return-to-work
and return-to-school decisions? Yes. Cognitive and psychiatric functioning have
implications for decisions about occupational and academic pursuits.

Patients who have severe cognitive or psychiatric symptoms might be or might not be able to maintain gainful employment or participate in school. Testing can help 1) document and justify disability and 2) establish recommendations about disability status. Those whose cognitive impairments or psychiatric symptoms are less severe might benefit from neuropsychological testing so that recommendations can be made regarding accommodations at work or in school, such as:
   • reduced work or school schedule
   • reduced level of occupational or academic demand
   • change in supervision or evaluation procedures by employer or school.

Cognitive strengths and weaknesses can be used to help a patient devise and implement compensatory strategies at work or school, such as:
   • note-taking
   • audio recording of meetings and lectures
   • using a calendar.

Patients sometimes benefit from formal vocational rehabilitation services to facilitate finding appropriate employment, returning to employment, and implementing workplace accommodations.


In conclusion

Neuropsychological evaluation, typically covered by health insurance, provides the
referring clinician with objective information about patients’ cognitive assets and limitations. In turn, this information can help you make a diagnosis and plan
treatment.

Unlike psychological testing, in which the patient is assessed for psychiatric
symptoms and conditions, neuropsychological measures offer insight into such
abilities as attention, memory, and reasoning. Neuropsychological evaluations also
can add insight to your determination of the cause of symptoms, thereby influencing decisions about medical therapy.

Last, these evaluations can aid with decision-making about dispositional planning
and whether adjunctive services, such as rehabilitation, would be of benefit.


Bottom Line

Neuropsychological assessments are a useful consultation to consider for patients
in a psychiatric setting. These evaluations can aid you in building and narrowing the differential diagnosis; identifying patients’ strengths and weakness; and making informed recommendations about functional independence.

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Neuropsychological evaluation, consisting of a thorough examination of cognitive and behavioral functioning, can make an invaluable contribution to the care of psychiatric patients. Through the vehicle of standardized measures of abilities, patients’ cognitive strengths and weaknesses can be elucidated—revealing potential areas for further interventions or to explain impediments to treatment. A licensed clinical psychologist provides this service.

You, as a consumer of reported findings, can use the results to inform your diagnosis and treatment plan. Recommendations from the neuropsychologist often address dispositional planning, cognitive intervention, psychiatric intervention, and work and school accommodations.


Probing the brain−behavior relationship

Neuropsychology is a subspecialty of clinical psychology that is focused on understanding the brain–behavior relationship. Drawing information from multiple disciplines, including psychiatry and neurology, neuropsychology seeks to uncover the cognitive, behavioral, and emotional difficulties that can result from known or suspected brain dysfunction. Increasingly, to protect the public and referral sources, clinical psychologists who perform neuropsychological testing demonstrate their competence through board certification (eg, the American Board of Clinical Neuropsychology).

How is testing conducted? Evaluations comprise measures that are standardized, scored objectively, and have established psychometric properties. Testing can performed on an outpatient or inpatient basis; the duration of testing depends on the question for which the referring practitioner seeks an answer.

Measures typically are administered by paper and pencil, although computer-based
assessments are increasingly being employed. Because of the influence of demographic variables (age, sex, years of education, race), scores are compared with normative samples that resemble those of the patient’s background as closely as possible.

A thorough clinical interview with the patient, a collateral interview with caregivers
and family, and review of relevant medical records are crucial parts of the assessment. Multiple areas of cognition are assessed:
   • intelligence
   • academic functioning
   • attention
   • working memory
   • speed of processing
   • learning and memory
   • visual spatial skills
   • fine motor skills
   • executive functioning.

Essentially, the evaluation speaks to a patient’s neurocognitive functioning and cerebral integrity.

How are results scored? Interpretation of test scores is contingent on expectations of how a patient should perform in the absence of neurologic or psychiatric illness (ie, based on normative data and performancebased estimates of premorbid functioning).¹ The overall pattern of intact scores and deficit scores can be used to form specific impressions about a diagnosis, cognitive strengths and weaknesses, and strategies for intervention.

Personality testing. In addition to the cognitive aspect of the evaluation, personality measures are incorporated when relevant to the referral question or presenting concern.

Personality tests can be broadly divided into objective and projective measures.
Objective personality measures, such as the Minnesota Multiphasic Personality
Inventory-Second Edition, require the examinee to respond to a set of items as
true or false or on a Likert-type scale from strongly agree to disagree. Responses are then scored in standardized fashion, making comparisons to normative data, which are then analyzed to determine the extent to which the examinee experiences psychiatric symptoms.

As part of testing, patients’ responses to ambiguous or unstructured standard
stimuli—such as a series of drawings, abstract patterns, or incomplete sentences—
are analyzed to determine underlying personality traits, feelings, and attitudes.
Classic examples of these measures include the Rorschach Test and the Thematic
Apperception Test.

Personality measures and psychiatric testing are designed to answer questions
related to patients’ emotional status. These measures assess psychiatric symptoms and diagnoses, whereas neuropsychological measures provide an understanding of patients’ cognitive assets and limitations.

7 Common questions about neuropsychological testing

1 Will my patient’s insurance cover these assessments? The question is common from practitioners who are considering requesting an assessment for a patient. The short answer is “Yes.”

Most payers follow Medicare guidelines for reimbursement of neuropsychological
testing; if testing is determined to be medically necessary, insurance companies often cover the assessment. Medicaid also pays for psychometric testing services. Neuropsychologists who have a hospital-based practice typically include patients
with all types of insurance coverage. For example, 40% of patients seen in a hospital are covered by Medicare or Medicaid.²

A caveat: Local intermediaries interpret policies and procedures in different ways,
so there is variability in coverage by geographic region. That is why it is crucial
for neuropsychologists to obtain preauthorization, as would be the case with other medical procedures and services sought by referral.

Last, insurance companies do not pay for assessment of a learning disability. The
rationale typically offered for this lack of coverage? The assessment is for academic, not medical, purposes. In such a situation, patients and their families are offered a private-pay option.

2 What are the indications for neuropsychological assessment? Psychiatric practitioners are one of the top medical specialties that refer their patients for neuropsychological testing.³ This is because many patients with a psychiatric or
neurologic disorder experience changes in cognition, mood, and personality. Such
changes can range in severity from subtle to dramatic, and might reflect an underlying disease state or a side effect of medication or other treatment. Whatever the nature of a patient’s problem, careful assessment might help elucidate specific areas with which he (she) is struggling—so that you can better target your interventions. Table 1 lists common reasons for referring a patient for neuropsychological evaluation. Throughout this discussion, we describe examples of clinical situations in which neuropsychological testing is useful for establishing a differential diagnosis and dispositional planning.

3 How does neuropsychological testing help with the differential diagnosis? As an example, one area in which cognitive testing can be beneficial is in geriatric psychiatry.Dementia. Aging often is accompanied by a normal decline in memory and other cognitive functions. But because subtle changes in memory and cognition also canbe the sign of a progressive cognitive disorder, differentiating normal aging from early dementia is essential. Table 2 summarizes typical changes in cognition with aging.

Neuropsychologists, through knowledge of psychometric testing and the brain−behavior relationship, can help you detect dementia and plan treatment early. To determine if cognitive changes are progressive, patients might undergo re-evaluation—typically, every 6 to 12 months—to ascertain if changes have occurred. Mood disorders. Neuropsychological evaluation can be useful in building a differential diagnosis when determining whether cognitive symptoms are attributable to a mood disorder or a medical illness. Cognitive deficits associated with an affective disturbance generally include impairments in attention, memory, and executive functioning.⁴ The severity of deficits has been linked to severity of illness. When patients with a mood disorder demonstrate localizing impairments or those of greater severity than expected, suspicion arises that another cause likely better explains those deficits, and further medical testing then is often recommended. Medical procedures. Increasingly, neuropsychological assessment is used to assist in determining the appropriateness of medical procedures. For example, neurosurgical patients being considered for deep brain stimulation, brain tumor resectioning, and epilepsy surgery often are referred for preoperative and postoperative testing. Treating clinicians need an understanding of current cognitive status, localization of functioning, and psychological status to make appropriate decisions about a patient’s candidacy for one of these procedures,and to understand associated risk.

4 How is neuropsychological testing used for dispositional planning? The
results of cognitive and psychological testing have implications for dispositional
planning for patients who are receiving psychiatric care. The primary issue often is
to determine the patient’s level of independence and ability to make decisions about his affairs.⁵

Neuropsychological testing can help determine if cognitive deficits limit aspects of functional independence—for example, can the patient live alone, or must he live with family or in a residential care facility? Generally, the greater the cognitive impairment, the more supervision and assistance are required. This relationship between cognitive ability and independence in activities of daily living has been demonstrated in many groups of psychiatric patients, including older adults with dementia,⁶ patients with schizophrenia,⁷ and those with bipolar disorder.⁸

Specific recommendations can be made regarding management of finances, administering medications, and driving. To formulate an appropriate dispositional plan, the referring psychiatrist might integrate recommendations from the neuropsychological assessment with findings of other evaluations and with information that has been collected about the patient.

5 Can neuropsychological testing be used to refer a patient for neurological and cognitive rehabilitation? Yes. The neuropsychologist is singularly qualified to make recommendations about a range of interventions for cognitive deficits that have been identified on formal testing.

Typically, recommendations for addressing cognitive deficits involve rehabilitation
focused on development and use of compensatory strategies and modification to promote brain health.^9,10 Rehabilitation therapy typically is aimed at increasing functioning independence and reducing physical and cognitive deficits associated
with illness (eg, traumatic brain injury [TBI], stroke, orthopedic injury, debility).

Patients who have a TBI or who have had a stroke often have comorbid psychiatric problems, including mood and anxiety disorders, that can exacerbate deficits and impede engagement in rehabilitation. The neuropsychological evaluation can determine if this is the case and if psychiatric consultation is warranted to assist with managing symptoms.

Premorbid psychiatric illness can affect rehabilitation. Formal neuropsychological testing can assist with parsing out deficits associated with new-onset illness compared with premorbid psychiatric problems. The evaluation of a patient before he begins rehabilitation also can be compared with evaluations made during treatment and after discharge to 1) assess for changes and 2) update recommendations about management.

Recommendations about cognitive interventions might include specific compensatory strategies to address areas of weakness and capitalize on strengths. Such strategies can include using internal mnemonics, such as visual imagery (ie, using a visual image to help encode verbal information) or semantic elaboration (using semantic cues to aid in encoding and recall of information). Methods can help train patients to capitalize on areas of stronger cognitive functioning in compensating for their weaknesses; an example is the spaced-retrieval technique, which relies on repetition of information that is to be learned over time.¹¹

Perhaps the most practical strategies for addressing areas of weakness are nonmnemonic-based external memory aids, such as diaries, notebooks, calendars, alarms, and lists.¹² For example, for a patient with a TBI who has impaired memory, recommendations might include using written notes or a calendar system; using a pillbox for medication management; and using labels to promote structure and consistency in the home. These strategies are meant to promote increased independence and to minimize the effect of cognitive deficits on daily functioning.   

Recommended strategies can include lifestyle changes to promote improved cognitive functioning and overall health, such as:
   • sleep hygiene, to reduce the effects of fatigue
   • encouraging the patient to adhere to a diet, take prescribed medications, and  follow up with his health care providers
   • developing cognitive and physical exercise routines.

In addition, a patient who has had a stroke or who have a TBI might benefit from psychotherapy or referral to a group program or community resources to help cope with the effects of illness.¹³

6 How does neuropsychological testing help determine the appropriate psychiatric intervention for a patient? Results of neuropsychological testing can help determine appropriate interventions for a psychiatric condition that might be the principal factor affecting the patient’s functioning.

Concerning psychoactive medications, consider the following:

Mood and anxiety disorders. Neuropsychological measures can help substantiate the need for pharmacotherapy in a comorbid mood or anxiety disorder in a patient who has a neurologic illness, such as stroke or TBI.

ADHD. In a patient who has attentiondeficit/hyperactivity disorder (ADHD), results of cognitive testing might help determine if attention issues undermine daily functioning. Testing provides information beyond rating scale scores to justify diagnosis and psychopharmacotherapy.¹⁴

Dementia. Geriatric patients who have dementia often have coexisting behavioral and mood changes that, once evaluated, might improve with pharmacotherapy.

Other areas. Cognitive side effects of medications can be monitored by conducting testing before and after medication is started. The evaluation can address the patient’s ability to engage in psychotherapeutic interventions. Patients who have severe cognitive deficits might have greater difficulty engaging in psychotherapy, compared with patients who have less severe, or no, cognitive
impairment.¹⁵

7 Does neuropsychological testing help patients make return-to-work
and return-to-school decisions? Yes. Cognitive and psychiatric functioning have
implications for decisions about occupational and academic pursuits.

Patients who have severe cognitive or psychiatric symptoms might be or might not be able to maintain gainful employment or participate in school. Testing can help 1) document and justify disability and 2) establish recommendations about disability status. Those whose cognitive impairments or psychiatric symptoms are less severe might benefit from neuropsychological testing so that recommendations can be made regarding accommodations at work or in school, such as:
   • reduced work or school schedule
   • reduced level of occupational or academic demand
   • change in supervision or evaluation procedures by employer or school.

Cognitive strengths and weaknesses can be used to help a patient devise and implement compensatory strategies at work or school, such as:
   • note-taking
   • audio recording of meetings and lectures
   • using a calendar.

Patients sometimes benefit from formal vocational rehabilitation services to facilitate finding appropriate employment, returning to employment, and implementing workplace accommodations.


In conclusion

Neuropsychological evaluation, typically covered by health insurance, provides the
referring clinician with objective information about patients’ cognitive assets and limitations. In turn, this information can help you make a diagnosis and plan
treatment.

Unlike psychological testing, in which the patient is assessed for psychiatric
symptoms and conditions, neuropsychological measures offer insight into such
abilities as attention, memory, and reasoning. Neuropsychological evaluations also
can add insight to your determination of the cause of symptoms, thereby influencing decisions about medical therapy.

Last, these evaluations can aid with decision-making about dispositional planning
and whether adjunctive services, such as rehabilitation, would be of benefit.


Bottom Line

Neuropsychological assessments are a useful consultation to consider for patients
in a psychiatric setting. These evaluations can aid you in building and narrowing the differential diagnosis; identifying patients’ strengths and weakness; and making informed recommendations about functional independence.

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Neuropsychological evaluation, consisting of a thorough examination of cognitive and behavioral functioning, can make an invaluable contribution to the care of psychiatric patients. Through the vehicle of standardized measures of abilities, patients’ cognitive strengths and weaknesses can be elucidated—revealing potential areas for further interventions or to explain impediments to treatment. A licensed clinical psychologist provides this service.

You, as a consumer of reported findings, can use the results to inform your diagnosis and treatment plan. Recommendations from the neuropsychologist often address dispositional planning, cognitive intervention, psychiatric intervention, and work and school accommodations.


Probing the brain−behavior relationship

Neuropsychology is a subspecialty of clinical psychology that is focused on understanding the brain–behavior relationship. Drawing information from multiple disciplines, including psychiatry and neurology, neuropsychology seeks to uncover the cognitive, behavioral, and emotional difficulties that can result from known or suspected brain dysfunction. Increasingly, to protect the public and referral sources, clinical psychologists who perform neuropsychological testing demonstrate their competence through board certification (eg, the American Board of Clinical Neuropsychology).

How is testing conducted? Evaluations comprise measures that are standardized, scored objectively, and have established psychometric properties. Testing can performed on an outpatient or inpatient basis; the duration of testing depends on the question for which the referring practitioner seeks an answer.

Measures typically are administered by paper and pencil, although computer-based
assessments are increasingly being employed. Because of the influence of demographic variables (age, sex, years of education, race), scores are compared with normative samples that resemble those of the patient’s background as closely as possible.

A thorough clinical interview with the patient, a collateral interview with caregivers
and family, and review of relevant medical records are crucial parts of the assessment. Multiple areas of cognition are assessed:
   • intelligence
   • academic functioning
   • attention
   • working memory
   • speed of processing
   • learning and memory
   • visual spatial skills
   • fine motor skills
   • executive functioning.

Essentially, the evaluation speaks to a patient’s neurocognitive functioning and cerebral integrity.

How are results scored? Interpretation of test scores is contingent on expectations of how a patient should perform in the absence of neurologic or psychiatric illness (ie, based on normative data and performancebased estimates of premorbid functioning).¹ The overall pattern of intact scores and deficit scores can be used to form specific impressions about a diagnosis, cognitive strengths and weaknesses, and strategies for intervention.

Personality testing. In addition to the cognitive aspect of the evaluation, personality measures are incorporated when relevant to the referral question or presenting concern.

Personality tests can be broadly divided into objective and projective measures.
Objective personality measures, such as the Minnesota Multiphasic Personality
Inventory-Second Edition, require the examinee to respond to a set of items as
true or false or on a Likert-type scale from strongly agree to disagree. Responses are then scored in standardized fashion, making comparisons to normative data, which are then analyzed to determine the extent to which the examinee experiences psychiatric symptoms.

As part of testing, patients’ responses to ambiguous or unstructured standard
stimuli—such as a series of drawings, abstract patterns, or incomplete sentences—
are analyzed to determine underlying personality traits, feelings, and attitudes.
Classic examples of these measures include the Rorschach Test and the Thematic
Apperception Test.

Personality measures and psychiatric testing are designed to answer questions
related to patients’ emotional status. These measures assess psychiatric symptoms and diagnoses, whereas neuropsychological measures provide an understanding of patients’ cognitive assets and limitations.

7 Common questions about neuropsychological testing

1 Will my patient’s insurance cover these assessments? The question is common from practitioners who are considering requesting an assessment for a patient. The short answer is “Yes.”

Most payers follow Medicare guidelines for reimbursement of neuropsychological
testing; if testing is determined to be medically necessary, insurance companies often cover the assessment. Medicaid also pays for psychometric testing services. Neuropsychologists who have a hospital-based practice typically include patients
with all types of insurance coverage. For example, 40% of patients seen in a hospital are covered by Medicare or Medicaid.²

A caveat: Local intermediaries interpret policies and procedures in different ways,
so there is variability in coverage by geographic region. That is why it is crucial
for neuropsychologists to obtain preauthorization, as would be the case with other medical procedures and services sought by referral.

Last, insurance companies do not pay for assessment of a learning disability. The
rationale typically offered for this lack of coverage? The assessment is for academic, not medical, purposes. In such a situation, patients and their families are offered a private-pay option.

2 What are the indications for neuropsychological assessment? Psychiatric practitioners are one of the top medical specialties that refer their patients for neuropsychological testing.³ This is because many patients with a psychiatric or
neurologic disorder experience changes in cognition, mood, and personality. Such
changes can range in severity from subtle to dramatic, and might reflect an underlying disease state or a side effect of medication or other treatment. Whatever the nature of a patient’s problem, careful assessment might help elucidate specific areas with which he (she) is struggling—so that you can better target your interventions. Table 1 lists common reasons for referring a patient for neuropsychological evaluation. Throughout this discussion, we describe examples of clinical situations in which neuropsychological testing is useful for establishing a differential diagnosis and dispositional planning.

3 How does neuropsychological testing help with the differential diagnosis? As an example, one area in which cognitive testing can be beneficial is in geriatric psychiatry.Dementia. Aging often is accompanied by a normal decline in memory and other cognitive functions. But because subtle changes in memory and cognition also canbe the sign of a progressive cognitive disorder, differentiating normal aging from early dementia is essential. Table 2 summarizes typical changes in cognition with aging.

Neuropsychologists, through knowledge of psychometric testing and the brain−behavior relationship, can help you detect dementia and plan treatment early. To determine if cognitive changes are progressive, patients might undergo re-evaluation—typically, every 6 to 12 months—to ascertain if changes have occurred. Mood disorders. Neuropsychological evaluation can be useful in building a differential diagnosis when determining whether cognitive symptoms are attributable to a mood disorder or a medical illness. Cognitive deficits associated with an affective disturbance generally include impairments in attention, memory, and executive functioning.⁴ The severity of deficits has been linked to severity of illness. When patients with a mood disorder demonstrate localizing impairments or those of greater severity than expected, suspicion arises that another cause likely better explains those deficits, and further medical testing then is often recommended. Medical procedures. Increasingly, neuropsychological assessment is used to assist in determining the appropriateness of medical procedures. For example, neurosurgical patients being considered for deep brain stimulation, brain tumor resectioning, and epilepsy surgery often are referred for preoperative and postoperative testing. Treating clinicians need an understanding of current cognitive status, localization of functioning, and psychological status to make appropriate decisions about a patient’s candidacy for one of these procedures,and to understand associated risk.

4 How is neuropsychological testing used for dispositional planning? The
results of cognitive and psychological testing have implications for dispositional
planning for patients who are receiving psychiatric care. The primary issue often is
to determine the patient’s level of independence and ability to make decisions about his affairs.⁵

Neuropsychological testing can help determine if cognitive deficits limit aspects of functional independence—for example, can the patient live alone, or must he live with family or in a residential care facility? Generally, the greater the cognitive impairment, the more supervision and assistance are required. This relationship between cognitive ability and independence in activities of daily living has been demonstrated in many groups of psychiatric patients, including older adults with dementia,⁶ patients with schizophrenia,⁷ and those with bipolar disorder.⁸

Specific recommendations can be made regarding management of finances, administering medications, and driving. To formulate an appropriate dispositional plan, the referring psychiatrist might integrate recommendations from the neuropsychological assessment with findings of other evaluations and with information that has been collected about the patient.

5 Can neuropsychological testing be used to refer a patient for neurological and cognitive rehabilitation? Yes. The neuropsychologist is singularly qualified to make recommendations about a range of interventions for cognitive deficits that have been identified on formal testing.

Typically, recommendations for addressing cognitive deficits involve rehabilitation
focused on development and use of compensatory strategies and modification to promote brain health.^9,10 Rehabilitation therapy typically is aimed at increasing functioning independence and reducing physical and cognitive deficits associated
with illness (eg, traumatic brain injury [TBI], stroke, orthopedic injury, debility).

Patients who have a TBI or who have had a stroke often have comorbid psychiatric problems, including mood and anxiety disorders, that can exacerbate deficits and impede engagement in rehabilitation. The neuropsychological evaluation can determine if this is the case and if psychiatric consultation is warranted to assist with managing symptoms.

Premorbid psychiatric illness can affect rehabilitation. Formal neuropsychological testing can assist with parsing out deficits associated with new-onset illness compared with premorbid psychiatric problems. The evaluation of a patient before he begins rehabilitation also can be compared with evaluations made during treatment and after discharge to 1) assess for changes and 2) update recommendations about management.

Recommendations about cognitive interventions might include specific compensatory strategies to address areas of weakness and capitalize on strengths. Such strategies can include using internal mnemonics, such as visual imagery (ie, using a visual image to help encode verbal information) or semantic elaboration (using semantic cues to aid in encoding and recall of information). Methods can help train patients to capitalize on areas of stronger cognitive functioning in compensating for their weaknesses; an example is the spaced-retrieval technique, which relies on repetition of information that is to be learned over time.¹¹

Perhaps the most practical strategies for addressing areas of weakness are nonmnemonic-based external memory aids, such as diaries, notebooks, calendars, alarms, and lists.¹² For example, for a patient with a TBI who has impaired memory, recommendations might include using written notes or a calendar system; using a pillbox for medication management; and using labels to promote structure and consistency in the home. These strategies are meant to promote increased independence and to minimize the effect of cognitive deficits on daily functioning.   

Recommended strategies can include lifestyle changes to promote improved cognitive functioning and overall health, such as:
   • sleep hygiene, to reduce the effects of fatigue
   • encouraging the patient to adhere to a diet, take prescribed medications, and  follow up with his health care providers
   • developing cognitive and physical exercise routines.

In addition, a patient who has had a stroke or who have a TBI might benefit from psychotherapy or referral to a group program or community resources to help cope with the effects of illness.¹³

6 How does neuropsychological testing help determine the appropriate psychiatric intervention for a patient? Results of neuropsychological testing can help determine appropriate interventions for a psychiatric condition that might be the principal factor affecting the patient’s functioning.

Concerning psychoactive medications, consider the following:

Mood and anxiety disorders. Neuropsychological measures can help substantiate the need for pharmacotherapy in a comorbid mood or anxiety disorder in a patient who has a neurologic illness, such as stroke or TBI.

ADHD. In a patient who has attentiondeficit/hyperactivity disorder (ADHD), results of cognitive testing might help determine if attention issues undermine daily functioning. Testing provides information beyond rating scale scores to justify diagnosis and psychopharmacotherapy.¹⁴

Dementia. Geriatric patients who have dementia often have coexisting behavioral and mood changes that, once evaluated, might improve with pharmacotherapy.

Other areas. Cognitive side effects of medications can be monitored by conducting testing before and after medication is started. The evaluation can address the patient’s ability to engage in psychotherapeutic interventions. Patients who have severe cognitive deficits might have greater difficulty engaging in psychotherapy, compared with patients who have less severe, or no, cognitive
impairment.¹⁵

7 Does neuropsychological testing help patients make return-to-work
and return-to-school decisions? Yes. Cognitive and psychiatric functioning have
implications for decisions about occupational and academic pursuits.

Patients who have severe cognitive or psychiatric symptoms might be or might not be able to maintain gainful employment or participate in school. Testing can help 1) document and justify disability and 2) establish recommendations about disability status. Those whose cognitive impairments or psychiatric symptoms are less severe might benefit from neuropsychological testing so that recommendations can be made regarding accommodations at work or in school, such as:
   • reduced work or school schedule
   • reduced level of occupational or academic demand
   • change in supervision or evaluation procedures by employer or school.

Cognitive strengths and weaknesses can be used to help a patient devise and implement compensatory strategies at work or school, such as:
   • note-taking
   • audio recording of meetings and lectures
   • using a calendar.

Patients sometimes benefit from formal vocational rehabilitation services to facilitate finding appropriate employment, returning to employment, and implementing workplace accommodations.


In conclusion

Neuropsychological evaluation, typically covered by health insurance, provides the
referring clinician with objective information about patients’ cognitive assets and limitations. In turn, this information can help you make a diagnosis and plan
treatment.

Unlike psychological testing, in which the patient is assessed for psychiatric
symptoms and conditions, neuropsychological measures offer insight into such
abilities as attention, memory, and reasoning. Neuropsychological evaluations also
can add insight to your determination of the cause of symptoms, thereby influencing decisions about medical therapy.

Last, these evaluations can aid with decision-making about dispositional planning
and whether adjunctive services, such as rehabilitation, would be of benefit.


Bottom Line

Neuropsychological assessments are a useful consultation to consider for patients
in a psychiatric setting. These evaluations can aid you in building and narrowing the differential diagnosis; identifying patients’ strengths and weakness; and making informed recommendations about functional independence.

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

A 68-year-old woman presented with a 5-day history of extensive pruritic purpuric skin lesions of varying sizes on her trunk and extremities (FIGURE 1A and 1B). In addition, the patient had a few nonblanching, erythematous macules on her extremities.

The patient had no neurological complaints and her family history was negative for a similar condition. We performed a punch biopsy.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Churg-Strauss syndrome (CSS)—also known as allergic granulomatosis and angiitis—is a rare multisystemic vasculitis of small- to medium-sized vessels characterized by asthma, chronic rhinosinusitis, and prominent peripheral blood eosinophilia.^1,2 Mean diagnosis age is 50 years with no gender predilection.² Any organ system can be affected, although the lungs are most commonly involved, followed by the skin.^1,2

The most common skin finding is palpable purpura on the lower extremities.Based on criteria from the American College of Rheumatology, the diagnosis of CSS can be made if 4 of the following 6 criteria are met: (1) asthma, (2) eosinophilia >10% on a differential white blood cell (WBC) count, (3) paranasal sinus abnormalities, (4) a transient pulmonary infiltrate detected on chest x-ray, (5) mono- or polyneuropathy, and (6) a biopsy specimen showing extravascular accumulation of eosinophils.²

Skin biopsy specimen from our patient showed leukocytoclastic vasculitis with prominent tissue eosinophilia. Laboratory studies showed an elevated WBC count of 12,300/mcL (reference range, 4500-11,000/mcL), and eosinophilia of 40% (reference range, 1%-4%). A serologic test for perinuclear pattern antineutrophil cytoplasmic antibodies (p-ANCA) was positive. (More on this in a moment.) Radiography of the chest showed transient pulmonary infiltrates.

Based on the clinical and laboratory findings, the patient was positive for 4 of 6 criteria and given a diagnosis of CSS.

What we know—and don’t know—about CSS

The exact etiopathogenesis of CSS is unknown.^2-4 Although ANCAs are detected in about 40% to 60% of CSS patients, it is not yet known whether ANCAs have a pathogenic role.^2-3 Abnormalities in immunologic function also occur, including heightened Th1 and Th2 lymphocyte function, increased recruitment of eosinophils, and decreased eosinophil apoptosis. Genetic factors, including certain interleukin-10 polymorphisms and HLA classes such as HLA-DRB4, may also contribute to CSS pathogenesis.⁴

Three distinct sequential phases have been described, although these are not always clearly distinguishable.^2,5
• The first is the prodromal or allergic phase, which is characterized by the onset of asthma later in life in patients with no family history of atopy. There may or may not be an associated allergic rhinitis.
• In the eosinophilic phase, peripheral blood eosinophilia and eosinophilic infiltration of multiple organs (especially the lungs and gastrointestinal [GI] tract) occur.
• The vasculitis phase is characterized by life-threatening systemic vasculitis of the small and medium vessels that is often associated with vascular and extravascular granulomatosis.

Cutaneous and extracutaneous findings

One-half to two-thirds of patients with CSS have cutaneous manifestations that typically present in the vasculitis phase.^2,5 The most common skin finding is palpable purpura on the lower extremities. Macular or papular erythematous eruption, urticaria, subcutaneous skin-colored or erythematous nodules, livedo reticularis, and erythema multiforme–like eruption may also be seen.^2,5,6 Skin biopsies will show numerous eosinophils with either leukocytoclastic vasculitis or extravascular necrotizing granuloma.⁵

Extracutaneous manifestations of CSS include renal, cardiac, GI tract, and nervous system involvement.^2,7

To identify patients with a poor prognosis, the 5-factor score (FFS) can be used. This score assigns 1 point each to GI tract involvement, renal insufficiency, proteinuria, central nervous system involvement, and cardiomyopathy.⁷ CSS patients with an FFS ≥2 have a considerably greater risk of mortality.⁷

Treatment involves corticosteroids

Systemic corticosteroids (prednisone, 1 mg/kg/day) are the primary treatment for patients with CSS; most patients improve dramatically with therapy.² Adjunctive therapy with immunosuppressive agents such as cyclophosphamide, methotrexate (10-15 mg per week), chlorambucil, or azathioprine may be needed if a patient does not respond adequately to steroids alone.²

Prednisone for our patient

We started our patient on prednisone 1 mg/kg/d. Her skin lesions resolved and subsequent laboratory tests, including eosinophil counts, normalized. Prednisone therapy was gradually tapered over several months to attain the lowest dose required for control of symptoms—in this case, 5 mg/d.

CORRESPONDENCE
Ossama Abbas, MD, Associate Professor, Department of Dermatology, American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Beirut, Lebanon; ossamaabbas2003@yahoo.com

A 68-year-old woman presented with a 5-day history of extensive pruritic purpuric skin lesions of varying sizes on her trunk and extremities (FIGURE 1A and 1B). In addition, the patient had a few nonblanching, erythematous macules on her extremities.

The patient had no neurological complaints and her family history was negative for a similar condition. We performed a punch biopsy.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Churg-Strauss syndrome (CSS)—also known as allergic granulomatosis and angiitis—is a rare multisystemic vasculitis of small- to medium-sized vessels characterized by asthma, chronic rhinosinusitis, and prominent peripheral blood eosinophilia.^1,2 Mean diagnosis age is 50 years with no gender predilection.² Any organ system can be affected, although the lungs are most commonly involved, followed by the skin.^1,2

The most common skin finding is palpable purpura on the lower extremities.Based on criteria from the American College of Rheumatology, the diagnosis of CSS can be made if 4 of the following 6 criteria are met: (1) asthma, (2) eosinophilia >10% on a differential white blood cell (WBC) count, (3) paranasal sinus abnormalities, (4) a transient pulmonary infiltrate detected on chest x-ray, (5) mono- or polyneuropathy, and (6) a biopsy specimen showing extravascular accumulation of eosinophils.²

Skin biopsy specimen from our patient showed leukocytoclastic vasculitis with prominent tissue eosinophilia. Laboratory studies showed an elevated WBC count of 12,300/mcL (reference range, 4500-11,000/mcL), and eosinophilia of 40% (reference range, 1%-4%). A serologic test for perinuclear pattern antineutrophil cytoplasmic antibodies (p-ANCA) was positive. (More on this in a moment.) Radiography of the chest showed transient pulmonary infiltrates.

Based on the clinical and laboratory findings, the patient was positive for 4 of 6 criteria and given a diagnosis of CSS.

What we know—and don’t know—about CSS

The exact etiopathogenesis of CSS is unknown.^2-4 Although ANCAs are detected in about 40% to 60% of CSS patients, it is not yet known whether ANCAs have a pathogenic role.^2-3 Abnormalities in immunologic function also occur, including heightened Th1 and Th2 lymphocyte function, increased recruitment of eosinophils, and decreased eosinophil apoptosis. Genetic factors, including certain interleukin-10 polymorphisms and HLA classes such as HLA-DRB4, may also contribute to CSS pathogenesis.⁴

Three distinct sequential phases have been described, although these are not always clearly distinguishable.^2,5
• The first is the prodromal or allergic phase, which is characterized by the onset of asthma later in life in patients with no family history of atopy. There may or may not be an associated allergic rhinitis.
• In the eosinophilic phase, peripheral blood eosinophilia and eosinophilic infiltration of multiple organs (especially the lungs and gastrointestinal [GI] tract) occur.
• The vasculitis phase is characterized by life-threatening systemic vasculitis of the small and medium vessels that is often associated with vascular and extravascular granulomatosis.

Cutaneous and extracutaneous findings

One-half to two-thirds of patients with CSS have cutaneous manifestations that typically present in the vasculitis phase.^2,5 The most common skin finding is palpable purpura on the lower extremities. Macular or papular erythematous eruption, urticaria, subcutaneous skin-colored or erythematous nodules, livedo reticularis, and erythema multiforme–like eruption may also be seen.^2,5,6 Skin biopsies will show numerous eosinophils with either leukocytoclastic vasculitis or extravascular necrotizing granuloma.⁵

Extracutaneous manifestations of CSS include renal, cardiac, GI tract, and nervous system involvement.^2,7

To identify patients with a poor prognosis, the 5-factor score (FFS) can be used. This score assigns 1 point each to GI tract involvement, renal insufficiency, proteinuria, central nervous system involvement, and cardiomyopathy.⁷ CSS patients with an FFS ≥2 have a considerably greater risk of mortality.⁷

Treatment involves corticosteroids

Systemic corticosteroids (prednisone, 1 mg/kg/day) are the primary treatment for patients with CSS; most patients improve dramatically with therapy.² Adjunctive therapy with immunosuppressive agents such as cyclophosphamide, methotrexate (10-15 mg per week), chlorambucil, or azathioprine may be needed if a patient does not respond adequately to steroids alone.²

Prednisone for our patient

We started our patient on prednisone 1 mg/kg/d. Her skin lesions resolved and subsequent laboratory tests, including eosinophil counts, normalized. Prednisone therapy was gradually tapered over several months to attain the lowest dose required for control of symptoms—in this case, 5 mg/d.

CORRESPONDENCE
Ossama Abbas, MD, Associate Professor, Department of Dermatology, American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Beirut, Lebanon; ossamaabbas2003@yahoo.com

A 68-year-old woman presented with a 5-day history of extensive pruritic purpuric skin lesions of varying sizes on her trunk and extremities (FIGURE 1A and 1B). In addition, the patient had a few nonblanching, erythematous macules on her extremities.

The patient had no neurological complaints and her family history was negative for a similar condition. We performed a punch biopsy.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Churg-Strauss syndrome (CSS)—also known as allergic granulomatosis and angiitis—is a rare multisystemic vasculitis of small- to medium-sized vessels characterized by asthma, chronic rhinosinusitis, and prominent peripheral blood eosinophilia.^1,2 Mean diagnosis age is 50 years with no gender predilection.² Any organ system can be affected, although the lungs are most commonly involved, followed by the skin.^1,2

The most common skin finding is palpable purpura on the lower extremities.Based on criteria from the American College of Rheumatology, the diagnosis of CSS can be made if 4 of the following 6 criteria are met: (1) asthma, (2) eosinophilia >10% on a differential white blood cell (WBC) count, (3) paranasal sinus abnormalities, (4) a transient pulmonary infiltrate detected on chest x-ray, (5) mono- or polyneuropathy, and (6) a biopsy specimen showing extravascular accumulation of eosinophils.²

Skin biopsy specimen from our patient showed leukocytoclastic vasculitis with prominent tissue eosinophilia. Laboratory studies showed an elevated WBC count of 12,300/mcL (reference range, 4500-11,000/mcL), and eosinophilia of 40% (reference range, 1%-4%). A serologic test for perinuclear pattern antineutrophil cytoplasmic antibodies (p-ANCA) was positive. (More on this in a moment.) Radiography of the chest showed transient pulmonary infiltrates.

Based on the clinical and laboratory findings, the patient was positive for 4 of 6 criteria and given a diagnosis of CSS.

What we know—and don’t know—about CSS

The exact etiopathogenesis of CSS is unknown.^2-4 Although ANCAs are detected in about 40% to 60% of CSS patients, it is not yet known whether ANCAs have a pathogenic role.^2-3 Abnormalities in immunologic function also occur, including heightened Th1 and Th2 lymphocyte function, increased recruitment of eosinophils, and decreased eosinophil apoptosis. Genetic factors, including certain interleukin-10 polymorphisms and HLA classes such as HLA-DRB4, may also contribute to CSS pathogenesis.⁴

Three distinct sequential phases have been described, although these are not always clearly distinguishable.^2,5
• The first is the prodromal or allergic phase, which is characterized by the onset of asthma later in life in patients with no family history of atopy. There may or may not be an associated allergic rhinitis.
• In the eosinophilic phase, peripheral blood eosinophilia and eosinophilic infiltration of multiple organs (especially the lungs and gastrointestinal [GI] tract) occur.
• The vasculitis phase is characterized by life-threatening systemic vasculitis of the small and medium vessels that is often associated with vascular and extravascular granulomatosis.

Cutaneous and extracutaneous findings

One-half to two-thirds of patients with CSS have cutaneous manifestations that typically present in the vasculitis phase.^2,5 The most common skin finding is palpable purpura on the lower extremities. Macular or papular erythematous eruption, urticaria, subcutaneous skin-colored or erythematous nodules, livedo reticularis, and erythema multiforme–like eruption may also be seen.^2,5,6 Skin biopsies will show numerous eosinophils with either leukocytoclastic vasculitis or extravascular necrotizing granuloma.⁵

Extracutaneous manifestations of CSS include renal, cardiac, GI tract, and nervous system involvement.^2,7

To identify patients with a poor prognosis, the 5-factor score (FFS) can be used. This score assigns 1 point each to GI tract involvement, renal insufficiency, proteinuria, central nervous system involvement, and cardiomyopathy.⁷ CSS patients with an FFS ≥2 have a considerably greater risk of mortality.⁷

Treatment involves corticosteroids

Systemic corticosteroids (prednisone, 1 mg/kg/day) are the primary treatment for patients with CSS; most patients improve dramatically with therapy.² Adjunctive therapy with immunosuppressive agents such as cyclophosphamide, methotrexate (10-15 mg per week), chlorambucil, or azathioprine may be needed if a patient does not respond adequately to steroids alone.²

Prednisone for our patient

We started our patient on prednisone 1 mg/kg/d. Her skin lesions resolved and subsequent laboratory tests, including eosinophil counts, normalized. Prednisone therapy was gradually tapered over several months to attain the lowest dose required for control of symptoms—in this case, 5 mg/d.

CORRESPONDENCE
Ossama Abbas, MD, Associate Professor, Department of Dermatology, American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Beirut, Lebanon; ossamaabbas2003@yahoo.com

The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) released several new immunization recommendations in 2013, and they pertain to special populations: infants at high risk for meningococcal disease who could benefit from a new vaccine; children ages 2 to 16 years who may now receive the Japanese encephalitis (JE) vaccine if traveling to Asia; and children and adolescents at high risk for Streptococcus pneumoniae infections who should receive the 13-valent pneumococcal conjugate vaccine (PCV13).

New meningococcal vaccine for high-risk infants

A third vaccine against meningococcal disease, Menveo (Novartis), has been approved for use in high-risk infants ages 2 to 23 months—those with complement deficiencies or functional or anatomic asplenia, those involved in an institutional or community outbreak of meningococcal disease, and those traveling to a meningococcal-endemic area (eg, the meningitis belt of Africa). The 3 vaccines approved for use in infants (TABLE 1) vary in indications and use for travel.¹ Keep in mind that vaccination against meningococcal disease is not recommended for routine use in infants because of the low prevalence of disease and a predominance of meningococcal type B, which is not prevented by any of the current vaccines.²

Japanese encephalitis vaccine approved for children, adolescents

Since 2009, a vaccine of inactivated JE virus derived from Vero cell culture (Ixiaro, manufactured by Intercell Biomedical and distributed by Norvartis) has been available in the United States for adults ≥17 years who travel during JE virus transmission season to parts of Asia where the virus is endemic. In May 2013, the US Food and Drug Administration licensed the JE vaccine for use in children ages 2 to 16 years, and in June 2013, ACIP recommended it for those in this age group for the same indications as adults.³

Individuals at high risk are those likely to visit rural areas where the virus is prevalent. The vaccine is not recommended for short-term travelers who will confine their visit to urban areas or who will refrain from traveling during the JE transmission season. The CDC travel Web site describes the geographic areas where the JE virus can be found and the timing of the JE season (http://wwwnc.cdc.gov/travel/diseases/japanese-encephalitis; see “Who is at risk?”). Use of the vaccine will be uncommon, and most of those who will receive it will need to visit a travel clinic or local health department. A primary series is 2 doses, given 28 days apart.

Pneumococcal vaccine for high-risk children up to age 18

ACIP now recommends the use of both PCV13 and 23-valent pneumococcal polysaccharide vaccine (PPSV23) in children ages 6 to 18 years who have not been vaccinated with these products and who have certain immunocompromising conditions, functional or anatomic asplenia (including those with sickle cell disease), cerebrospinal fluid leaks, or cochlear implants (TABLE 2).⁴ PPSV23 alone is recommended for those in this age group with chronic heart, lung, or liver disease or diabetes, and for those who smoke. The recommendation is complicated because those with asplenia or immunocompromising conditions should receive 2 doses of PPSV23 at least 5 years apart (TABLE 2). PCV13 is indicated even if the patient was previously fully immunized with 7-valent pneumococcal conjugate vaccine.

While invasive pneumococcal disease rates have fallen overall, patients with high-risk conditions still have high relative risk.Ideally, all children for whom PCV13 is indicated would receive a full vaccine series as infants, and at 2, 4, 6, and 12 to 15 months of age. Those with chronic medical conditions and immunocompromising conditions should additionally receive PPSV23 at age 2 years, and again 5 years later if they have asplenia or an immunocompromising condition.⁵ However, some of these children will remain unimmunized; others can become underimmunized if they acquire a condition that heightens their risk for pneumococcal disease. Both situations make necessary the new recommendation for those ages 6 to 18 years. For those who have received neither vaccine, the recommended sequence is to receive PCV13 first, followed by PPSV23 at least 8 weeks later.

Pneumococcal vaccine recommendations are now uniform for those ages 6 to 64 years with chronic medical conditions and immunocompromising conditions.^2,6 All those ≥65 should receive PPSV23, even if they have received 2 previous doses. At least 5 years should have passed from a previous PPSV23 dose. This is the only scenario in which a third dose of PPSV23 is recommended.

Universal use of pneumococcal vaccines has markedly reduced invasive pneumococcal disease nationally in vaccinated and unvaccinated individuals.5 While invasive pneumococcal disease rates have fallen overall, patients with high-risk conditions still have a high relative risk. The incidence rates (cases per 100,000) for children with hematologic malignancies were estimated at 1282 (rate ratio [RR], compared with children without this condition, of 822); 197 for those with HIV infection (RR=122), and 56 for those with sickle cell disease (RR=27).⁴

As the incidence of antibiotic resistance increases, the primary prevention of bacterial infections becomes more significant. It is of both public health and individual importance that those who develop conditions placing them at increased risk for pneumococcal disease or complications from pneumococcal infection receive recommended pneumococcal vaccines.

The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) released several new immunization recommendations in 2013, and they pertain to special populations: infants at high risk for meningococcal disease who could benefit from a new vaccine; children ages 2 to 16 years who may now receive the Japanese encephalitis (JE) vaccine if traveling to Asia; and children and adolescents at high risk for Streptococcus pneumoniae infections who should receive the 13-valent pneumococcal conjugate vaccine (PCV13).

New meningococcal vaccine for high-risk infants

A third vaccine against meningococcal disease, Menveo (Novartis), has been approved for use in high-risk infants ages 2 to 23 months—those with complement deficiencies or functional or anatomic asplenia, those involved in an institutional or community outbreak of meningococcal disease, and those traveling to a meningococcal-endemic area (eg, the meningitis belt of Africa). The 3 vaccines approved for use in infants (TABLE 1) vary in indications and use for travel.¹ Keep in mind that vaccination against meningococcal disease is not recommended for routine use in infants because of the low prevalence of disease and a predominance of meningococcal type B, which is not prevented by any of the current vaccines.²

Japanese encephalitis vaccine approved for children, adolescents

Since 2009, a vaccine of inactivated JE virus derived from Vero cell culture (Ixiaro, manufactured by Intercell Biomedical and distributed by Norvartis) has been available in the United States for adults ≥17 years who travel during JE virus transmission season to parts of Asia where the virus is endemic. In May 2013, the US Food and Drug Administration licensed the JE vaccine for use in children ages 2 to 16 years, and in June 2013, ACIP recommended it for those in this age group for the same indications as adults.³

Individuals at high risk are those likely to visit rural areas where the virus is prevalent. The vaccine is not recommended for short-term travelers who will confine their visit to urban areas or who will refrain from traveling during the JE transmission season. The CDC travel Web site describes the geographic areas where the JE virus can be found and the timing of the JE season (http://wwwnc.cdc.gov/travel/diseases/japanese-encephalitis; see “Who is at risk?”). Use of the vaccine will be uncommon, and most of those who will receive it will need to visit a travel clinic or local health department. A primary series is 2 doses, given 28 days apart.

Pneumococcal vaccine for high-risk children up to age 18

ACIP now recommends the use of both PCV13 and 23-valent pneumococcal polysaccharide vaccine (PPSV23) in children ages 6 to 18 years who have not been vaccinated with these products and who have certain immunocompromising conditions, functional or anatomic asplenia (including those with sickle cell disease), cerebrospinal fluid leaks, or cochlear implants (TABLE 2).⁴ PPSV23 alone is recommended for those in this age group with chronic heart, lung, or liver disease or diabetes, and for those who smoke. The recommendation is complicated because those with asplenia or immunocompromising conditions should receive 2 doses of PPSV23 at least 5 years apart (TABLE 2). PCV13 is indicated even if the patient was previously fully immunized with 7-valent pneumococcal conjugate vaccine.

While invasive pneumococcal disease rates have fallen overall, patients with high-risk conditions still have high relative risk.Ideally, all children for whom PCV13 is indicated would receive a full vaccine series as infants, and at 2, 4, 6, and 12 to 15 months of age. Those with chronic medical conditions and immunocompromising conditions should additionally receive PPSV23 at age 2 years, and again 5 years later if they have asplenia or an immunocompromising condition.⁵ However, some of these children will remain unimmunized; others can become underimmunized if they acquire a condition that heightens their risk for pneumococcal disease. Both situations make necessary the new recommendation for those ages 6 to 18 years. For those who have received neither vaccine, the recommended sequence is to receive PCV13 first, followed by PPSV23 at least 8 weeks later.

Pneumococcal vaccine recommendations are now uniform for those ages 6 to 64 years with chronic medical conditions and immunocompromising conditions.^2,6 All those ≥65 should receive PPSV23, even if they have received 2 previous doses. At least 5 years should have passed from a previous PPSV23 dose. This is the only scenario in which a third dose of PPSV23 is recommended.

Universal use of pneumococcal vaccines has markedly reduced invasive pneumococcal disease nationally in vaccinated and unvaccinated individuals.5 While invasive pneumococcal disease rates have fallen overall, patients with high-risk conditions still have a high relative risk. The incidence rates (cases per 100,000) for children with hematologic malignancies were estimated at 1282 (rate ratio [RR], compared with children without this condition, of 822); 197 for those with HIV infection (RR=122), and 56 for those with sickle cell disease (RR=27).⁴

As the incidence of antibiotic resistance increases, the primary prevention of bacterial infections becomes more significant. It is of both public health and individual importance that those who develop conditions placing them at increased risk for pneumococcal disease or complications from pneumococcal infection receive recommended pneumococcal vaccines.

The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) released several new immunization recommendations in 2013, and they pertain to special populations: infants at high risk for meningococcal disease who could benefit from a new vaccine; children ages 2 to 16 years who may now receive the Japanese encephalitis (JE) vaccine if traveling to Asia; and children and adolescents at high risk for Streptococcus pneumoniae infections who should receive the 13-valent pneumococcal conjugate vaccine (PCV13).

New meningococcal vaccine for high-risk infants

A third vaccine against meningococcal disease, Menveo (Novartis), has been approved for use in high-risk infants ages 2 to 23 months—those with complement deficiencies or functional or anatomic asplenia, those involved in an institutional or community outbreak of meningococcal disease, and those traveling to a meningococcal-endemic area (eg, the meningitis belt of Africa). The 3 vaccines approved for use in infants (TABLE 1) vary in indications and use for travel.¹ Keep in mind that vaccination against meningococcal disease is not recommended for routine use in infants because of the low prevalence of disease and a predominance of meningococcal type B, which is not prevented by any of the current vaccines.²

Japanese encephalitis vaccine approved for children, adolescents

Since 2009, a vaccine of inactivated JE virus derived from Vero cell culture (Ixiaro, manufactured by Intercell Biomedical and distributed by Norvartis) has been available in the United States for adults ≥17 years who travel during JE virus transmission season to parts of Asia where the virus is endemic. In May 2013, the US Food and Drug Administration licensed the JE vaccine for use in children ages 2 to 16 years, and in June 2013, ACIP recommended it for those in this age group for the same indications as adults.³

Individuals at high risk are those likely to visit rural areas where the virus is prevalent. The vaccine is not recommended for short-term travelers who will confine their visit to urban areas or who will refrain from traveling during the JE transmission season. The CDC travel Web site describes the geographic areas where the JE virus can be found and the timing of the JE season (http://wwwnc.cdc.gov/travel/diseases/japanese-encephalitis; see “Who is at risk?”). Use of the vaccine will be uncommon, and most of those who will receive it will need to visit a travel clinic or local health department. A primary series is 2 doses, given 28 days apart.

Pneumococcal vaccine for high-risk children up to age 18

ACIP now recommends the use of both PCV13 and 23-valent pneumococcal polysaccharide vaccine (PPSV23) in children ages 6 to 18 years who have not been vaccinated with these products and who have certain immunocompromising conditions, functional or anatomic asplenia (including those with sickle cell disease), cerebrospinal fluid leaks, or cochlear implants (TABLE 2).⁴ PPSV23 alone is recommended for those in this age group with chronic heart, lung, or liver disease or diabetes, and for those who smoke. The recommendation is complicated because those with asplenia or immunocompromising conditions should receive 2 doses of PPSV23 at least 5 years apart (TABLE 2). PCV13 is indicated even if the patient was previously fully immunized with 7-valent pneumococcal conjugate vaccine.

While invasive pneumococcal disease rates have fallen overall, patients with high-risk conditions still have high relative risk.Ideally, all children for whom PCV13 is indicated would receive a full vaccine series as infants, and at 2, 4, 6, and 12 to 15 months of age. Those with chronic medical conditions and immunocompromising conditions should additionally receive PPSV23 at age 2 years, and again 5 years later if they have asplenia or an immunocompromising condition.⁵ However, some of these children will remain unimmunized; others can become underimmunized if they acquire a condition that heightens their risk for pneumococcal disease. Both situations make necessary the new recommendation for those ages 6 to 18 years. For those who have received neither vaccine, the recommended sequence is to receive PCV13 first, followed by PPSV23 at least 8 weeks later.

Pneumococcal vaccine recommendations are now uniform for those ages 6 to 64 years with chronic medical conditions and immunocompromising conditions.^2,6 All those ≥65 should receive PPSV23, even if they have received 2 previous doses. At least 5 years should have passed from a previous PPSV23 dose. This is the only scenario in which a third dose of PPSV23 is recommended.

Universal use of pneumococcal vaccines has markedly reduced invasive pneumococcal disease nationally in vaccinated and unvaccinated individuals.5 While invasive pneumococcal disease rates have fallen overall, patients with high-risk conditions still have a high relative risk. The incidence rates (cases per 100,000) for children with hematologic malignancies were estimated at 1282 (rate ratio [RR], compared with children without this condition, of 822); 197 for those with HIV infection (RR=122), and 56 for those with sickle cell disease (RR=27).⁴

As the incidence of antibiotic resistance increases, the primary prevention of bacterial infections becomes more significant. It is of both public health and individual importance that those who develop conditions placing them at increased risk for pneumococcal disease or complications from pneumococcal infection receive recommended pneumococcal vaccines.

To the Editor: In the December 2013 Cleveland Clinic Journal of Medicine, Tehrani and Seto provide a review of the updated definitions of myocardial infarction (MI).¹ A key concept incorporated into the structured definitions is that cardiac biomarkers must be interpreted in a clinical context.² This in turn helps better align the laboratory and clinical findings with the pathophysiologic processes.

However, there is another dimension to the definitions that is sometimes overlooked and requires careful attention: translation of the definitions into codes and comparable databases. Accurate and consistent coding according to the International Statistical Classification of Diseases, ninth edition (ICD-9), and the ICD-10 is critically vital to the appropriate analysis of data, research, quality measurement, and reimbursement of services related to MI. Unfortunately, there is no straightforward translation of the definitions into ICD-9 codes, and the challenge is further confounded when it comes to ICD-10, which will be implemented in October 2014.

The ICD-10-CM Index to Diseases does not yet recognize this nomenclature. ST-elevation MI is the default for the unspecified term “acute MI.” Non-ST-elevation MI requires more explicit documentation and is classified based on whether it occurs during or after a variety of procedures. Type 2 MI is particularly challenging because of the several possible ways to code the condition—for example, as acute subendocardial MI (I21.4), demand ischemia (I24.8), or acute MI, unspecified (I21.9). Coding guidelines are assumed to standardize the approach to coding these conditions, but there is no guarantee that comparability of the data will endure biases of code assignment. Although extreme precision in disease capture by coding may not exist, other clinical conditions have better correlations with coding classifications, such as stages of chronic kidney disease ranging from stage 1 through end-stage renal disease (N18.1 through N18.6). Furthermore, ICD-10 codes are insufficient to clearly distinguish the type of acute MI.³

While the concept of acute MI applies when the stated date of onset is less than 8 weeks in ICD-9,⁴ it changes to 4 weeks in ICD-10. “Acute” can reference an initial or a subsequent MI in ICD-10, but it does not define the time frame of the MI.⁵ This is different than in ICD-9, where the concept of “subsequent” refers to a “subsequent episode of care.”

On the surface, these variations may not seem significant. However, the discriminatory efforts to better define a patient’s clinical condition using the new definitions may get diluted by the challenges of the coding process. The implications on comparability of quality metrics and reporting are not to be underestimated and need to be assessed on a national level.

To the Editor: In the December 2013 Cleveland Clinic Journal of Medicine, Tehrani and Seto provide a review of the updated definitions of myocardial infarction (MI).¹ A key concept incorporated into the structured definitions is that cardiac biomarkers must be interpreted in a clinical context.² This in turn helps better align the laboratory and clinical findings with the pathophysiologic processes.

However, there is another dimension to the definitions that is sometimes overlooked and requires careful attention: translation of the definitions into codes and comparable databases. Accurate and consistent coding according to the International Statistical Classification of Diseases, ninth edition (ICD-9), and the ICD-10 is critically vital to the appropriate analysis of data, research, quality measurement, and reimbursement of services related to MI. Unfortunately, there is no straightforward translation of the definitions into ICD-9 codes, and the challenge is further confounded when it comes to ICD-10, which will be implemented in October 2014.

The ICD-10-CM Index to Diseases does not yet recognize this nomenclature. ST-elevation MI is the default for the unspecified term “acute MI.” Non-ST-elevation MI requires more explicit documentation and is classified based on whether it occurs during or after a variety of procedures. Type 2 MI is particularly challenging because of the several possible ways to code the condition—for example, as acute subendocardial MI (I21.4), demand ischemia (I24.8), or acute MI, unspecified (I21.9). Coding guidelines are assumed to standardize the approach to coding these conditions, but there is no guarantee that comparability of the data will endure biases of code assignment. Although extreme precision in disease capture by coding may not exist, other clinical conditions have better correlations with coding classifications, such as stages of chronic kidney disease ranging from stage 1 through end-stage renal disease (N18.1 through N18.6). Furthermore, ICD-10 codes are insufficient to clearly distinguish the type of acute MI.³

While the concept of acute MI applies when the stated date of onset is less than 8 weeks in ICD-9,⁴ it changes to 4 weeks in ICD-10. “Acute” can reference an initial or a subsequent MI in ICD-10, but it does not define the time frame of the MI.⁵ This is different than in ICD-9, where the concept of “subsequent” refers to a “subsequent episode of care.”

On the surface, these variations may not seem significant. However, the discriminatory efforts to better define a patient’s clinical condition using the new definitions may get diluted by the challenges of the coding process. The implications on comparability of quality metrics and reporting are not to be underestimated and need to be assessed on a national level.

To the Editor: In the December 2013 Cleveland Clinic Journal of Medicine, Tehrani and Seto provide a review of the updated definitions of myocardial infarction (MI).¹ A key concept incorporated into the structured definitions is that cardiac biomarkers must be interpreted in a clinical context.² This in turn helps better align the laboratory and clinical findings with the pathophysiologic processes.

However, there is another dimension to the definitions that is sometimes overlooked and requires careful attention: translation of the definitions into codes and comparable databases. Accurate and consistent coding according to the International Statistical Classification of Diseases, ninth edition (ICD-9), and the ICD-10 is critically vital to the appropriate analysis of data, research, quality measurement, and reimbursement of services related to MI. Unfortunately, there is no straightforward translation of the definitions into ICD-9 codes, and the challenge is further confounded when it comes to ICD-10, which will be implemented in October 2014.

The ICD-10-CM Index to Diseases does not yet recognize this nomenclature. ST-elevation MI is the default for the unspecified term “acute MI.” Non-ST-elevation MI requires more explicit documentation and is classified based on whether it occurs during or after a variety of procedures. Type 2 MI is particularly challenging because of the several possible ways to code the condition—for example, as acute subendocardial MI (I21.4), demand ischemia (I24.8), or acute MI, unspecified (I21.9). Coding guidelines are assumed to standardize the approach to coding these conditions, but there is no guarantee that comparability of the data will endure biases of code assignment. Although extreme precision in disease capture by coding may not exist, other clinical conditions have better correlations with coding classifications, such as stages of chronic kidney disease ranging from stage 1 through end-stage renal disease (N18.1 through N18.6). Furthermore, ICD-10 codes are insufficient to clearly distinguish the type of acute MI.³

While the concept of acute MI applies when the stated date of onset is less than 8 weeks in ICD-9,⁴ it changes to 4 weeks in ICD-10. “Acute” can reference an initial or a subsequent MI in ICD-10, but it does not define the time frame of the MI.⁵ This is different than in ICD-9, where the concept of “subsequent” refers to a “subsequent episode of care.”

On the surface, these variations may not seem significant. However, the discriminatory efforts to better define a patient’s clinical condition using the new definitions may get diluted by the challenges of the coding process. The implications on comparability of quality metrics and reporting are not to be underestimated and need to be assessed on a national level.

In Reply: We thank Dr. Antonios for his comments regarding the current shortcomings of the ICD-9 and ICD-10 coding systems in describing the acute MI types as defined in the universal definition. We share his concern that accurate and consistent coding of MIs may be difficult when the definition of MI changes over a short period of time. Such changes create a disconnect not only between our clinical terminology and coding systems, but also potentially between our conventional sense of a “heart attack” as an acute coronary syndrome or a clinically significant infarction rather than a small troponin elevation from demand ischemia. This has consequences not only for quality measures and reporting, but also for clinical research trials and clinical care. This is exemplified by reports of recent trials that were possibly prematurely discontinued, as the use of troponin thresholds may conflate large MIs with clinically insignificant ones.¹

Recently, the Society for Cardiovascular Angiography and Interventions published a new definition of “clinically relevant” MI after revascularization.² Rather than relying on troponins, which are elevated in as many as 24.3% of uncomplicated percutaneous coronary interventions and in 42% to 82% of uncomplicated coronary artery bypass grafting procedures (based on the 2007 universal definition), they point to extensive literature documenting that only patients with elevated creatine kinase MB more than 10 times the upper limit of normal after revascularization have a worsened prognosis. We favor this clinically relevant MI definition for post-revascularization MI. We also favor the use of creatine kinase MB as a less sensitive but more specific confirmatory marker for acute coronary syndromes (type 1) or clinically significant supply-demand (type 2) MI, when the symptoms or electrocardiographic signs are nondiagnostic, as they often are.³ However, until there is a consensus around a single definition, clinicians are effectively walking around a Tower of Babel and must take care to be specific when documenting an MI.

In Reply: We thank Dr. Antonios for his comments regarding the current shortcomings of the ICD-9 and ICD-10 coding systems in describing the acute MI types as defined in the universal definition. We share his concern that accurate and consistent coding of MIs may be difficult when the definition of MI changes over a short period of time. Such changes create a disconnect not only between our clinical terminology and coding systems, but also potentially between our conventional sense of a “heart attack” as an acute coronary syndrome or a clinically significant infarction rather than a small troponin elevation from demand ischemia. This has consequences not only for quality measures and reporting, but also for clinical research trials and clinical care. This is exemplified by reports of recent trials that were possibly prematurely discontinued, as the use of troponin thresholds may conflate large MIs with clinically insignificant ones.¹

Recently, the Society for Cardiovascular Angiography and Interventions published a new definition of “clinically relevant” MI after revascularization.² Rather than relying on troponins, which are elevated in as many as 24.3% of uncomplicated percutaneous coronary interventions and in 42% to 82% of uncomplicated coronary artery bypass grafting procedures (based on the 2007 universal definition), they point to extensive literature documenting that only patients with elevated creatine kinase MB more than 10 times the upper limit of normal after revascularization have a worsened prognosis. We favor this clinically relevant MI definition for post-revascularization MI. We also favor the use of creatine kinase MB as a less sensitive but more specific confirmatory marker for acute coronary syndromes (type 1) or clinically significant supply-demand (type 2) MI, when the symptoms or electrocardiographic signs are nondiagnostic, as they often are.³ However, until there is a consensus around a single definition, clinicians are effectively walking around a Tower of Babel and must take care to be specific when documenting an MI.

In Reply: We thank Dr. Antonios for his comments regarding the current shortcomings of the ICD-9 and ICD-10 coding systems in describing the acute MI types as defined in the universal definition. We share his concern that accurate and consistent coding of MIs may be difficult when the definition of MI changes over a short period of time. Such changes create a disconnect not only between our clinical terminology and coding systems, but also potentially between our conventional sense of a “heart attack” as an acute coronary syndrome or a clinically significant infarction rather than a small troponin elevation from demand ischemia. This has consequences not only for quality measures and reporting, but also for clinical research trials and clinical care. This is exemplified by reports of recent trials that were possibly prematurely discontinued, as the use of troponin thresholds may conflate large MIs with clinically insignificant ones.¹

Recently, the Society for Cardiovascular Angiography and Interventions published a new definition of “clinically relevant” MI after revascularization.² Rather than relying on troponins, which are elevated in as many as 24.3% of uncomplicated percutaneous coronary interventions and in 42% to 82% of uncomplicated coronary artery bypass grafting procedures (based on the 2007 universal definition), they point to extensive literature documenting that only patients with elevated creatine kinase MB more than 10 times the upper limit of normal after revascularization have a worsened prognosis. We favor this clinically relevant MI definition for post-revascularization MI. We also favor the use of creatine kinase MB as a less sensitive but more specific confirmatory marker for acute coronary syndromes (type 1) or clinically significant supply-demand (type 2) MI, when the symptoms or electrocardiographic signs are nondiagnostic, as they often are.³ However, until there is a consensus around a single definition, clinicians are effectively walking around a Tower of Babel and must take care to be specific when documenting an MI.

To the Editor: Dr. Li and colleagues provide a well-written article about what is generally believed regarding myasthenia gravis (MG). However, like most reviews, it perpetuates the myths surrounding current medical practice, resulting in delays in diagnosis, treatment initiation, and insurance approval and reimbursement, and therefore increased morbidity and mortality. Stricter statistical and editorial review is needed and what is known and unknown clearly stated. Patients, in particular those of us who are physicians ourselves, recognize that this is no academic quibble.

Myasthenia gravis was a clinical diagnosis until blood tests began to pick up antibodies. If the blood tests have to be positive to diagnose MG, then everyone diagnosed with MG will have positive blood tests. If the muscle studies have to show particular abnormalities to diagnose MG, then everyone diagnosed with MG will have those abnormalities. It makes doctors more comfortable to have these evidences of their understanding verified, but it does not help any of the patients who do not meet the testing criteria but have the clinical findings.

We know, in contrast to what was thought a number of years ago, that there are “seronegative” patients with clinical evidence of myasthenia who are antibody-positive. For those who are MuSK-positive, their problem is now well described, and although it affects a different part of the neuromuscular junction, it remains under the MG umbrella. We also know there are other antibodies, for which we have no commercial tests, in patients with symptoms of MG who respond to treatment for autoimmune problems. This article is relatively dismissive of the clinical validity of those antibodies, and certainly a degree of skepticism is a good thing as long as the patients remain diagnosed and treated.

It is of more than academic interest that these misconceptions and prejudices be recognized. At the very least, editorial boards should insist that statistics in papers reflect the diagnostic skills of the authors. If over 95% of an author’s diagnosed patients are seropositive, then one can suspect there is heavy reliance on blood studies for diagnosis, and rejection of those who do not meet those criteria. The statistics should read “over 95% of patients we diagnose with MG have positive blood studies” rather than “over 95% of patients with MG have positive blood studies.” Dismissing a significant portion of a patient population will also affect treatment statistics, which then should read that “for those who meet this criteria, _—% will respond to…”

If patients meet clinical criteria for the diagnosis of MG and a large percentage do not have positive serology, then more research needs to be done into their particular autoimmune problems, and better testing may become commercially viable. Recognizing the problem will lead to better clinical diagnosis and treatment, and strict diagnostic criteria would permit their inclusion in studies. For many of us this would create a more open and questioning atmosphere as to our understanding of the spectrum of autoimmune myasthenia and the ability and willingness to diagnose and treat “seronegative” autoimmune myasthenia when we see it.

To the Editor: Dr. Li and colleagues provide a well-written article about what is generally believed regarding myasthenia gravis (MG). However, like most reviews, it perpetuates the myths surrounding current medical practice, resulting in delays in diagnosis, treatment initiation, and insurance approval and reimbursement, and therefore increased morbidity and mortality. Stricter statistical and editorial review is needed and what is known and unknown clearly stated. Patients, in particular those of us who are physicians ourselves, recognize that this is no academic quibble.

Myasthenia gravis was a clinical diagnosis until blood tests began to pick up antibodies. If the blood tests have to be positive to diagnose MG, then everyone diagnosed with MG will have positive blood tests. If the muscle studies have to show particular abnormalities to diagnose MG, then everyone diagnosed with MG will have those abnormalities. It makes doctors more comfortable to have these evidences of their understanding verified, but it does not help any of the patients who do not meet the testing criteria but have the clinical findings.

We know, in contrast to what was thought a number of years ago, that there are “seronegative” patients with clinical evidence of myasthenia who are antibody-positive. For those who are MuSK-positive, their problem is now well described, and although it affects a different part of the neuromuscular junction, it remains under the MG umbrella. We also know there are other antibodies, for which we have no commercial tests, in patients with symptoms of MG who respond to treatment for autoimmune problems. This article is relatively dismissive of the clinical validity of those antibodies, and certainly a degree of skepticism is a good thing as long as the patients remain diagnosed and treated.

It is of more than academic interest that these misconceptions and prejudices be recognized. At the very least, editorial boards should insist that statistics in papers reflect the diagnostic skills of the authors. If over 95% of an author’s diagnosed patients are seropositive, then one can suspect there is heavy reliance on blood studies for diagnosis, and rejection of those who do not meet those criteria. The statistics should read “over 95% of patients we diagnose with MG have positive blood studies” rather than “over 95% of patients with MG have positive blood studies.” Dismissing a significant portion of a patient population will also affect treatment statistics, which then should read that “for those who meet this criteria, _—% will respond to…”

If patients meet clinical criteria for the diagnosis of MG and a large percentage do not have positive serology, then more research needs to be done into their particular autoimmune problems, and better testing may become commercially viable. Recognizing the problem will lead to better clinical diagnosis and treatment, and strict diagnostic criteria would permit their inclusion in studies. For many of us this would create a more open and questioning atmosphere as to our understanding of the spectrum of autoimmune myasthenia and the ability and willingness to diagnose and treat “seronegative” autoimmune myasthenia when we see it.

To the Editor: Dr. Li and colleagues provide a well-written article about what is generally believed regarding myasthenia gravis (MG). However, like most reviews, it perpetuates the myths surrounding current medical practice, resulting in delays in diagnosis, treatment initiation, and insurance approval and reimbursement, and therefore increased morbidity and mortality. Stricter statistical and editorial review is needed and what is known and unknown clearly stated. Patients, in particular those of us who are physicians ourselves, recognize that this is no academic quibble.

Myasthenia gravis was a clinical diagnosis until blood tests began to pick up antibodies. If the blood tests have to be positive to diagnose MG, then everyone diagnosed with MG will have positive blood tests. If the muscle studies have to show particular abnormalities to diagnose MG, then everyone diagnosed with MG will have those abnormalities. It makes doctors more comfortable to have these evidences of their understanding verified, but it does not help any of the patients who do not meet the testing criteria but have the clinical findings.

We know, in contrast to what was thought a number of years ago, that there are “seronegative” patients with clinical evidence of myasthenia who are antibody-positive. For those who are MuSK-positive, their problem is now well described, and although it affects a different part of the neuromuscular junction, it remains under the MG umbrella. We also know there are other antibodies, for which we have no commercial tests, in patients with symptoms of MG who respond to treatment for autoimmune problems. This article is relatively dismissive of the clinical validity of those antibodies, and certainly a degree of skepticism is a good thing as long as the patients remain diagnosed and treated.

It is of more than academic interest that these misconceptions and prejudices be recognized. At the very least, editorial boards should insist that statistics in papers reflect the diagnostic skills of the authors. If over 95% of an author’s diagnosed patients are seropositive, then one can suspect there is heavy reliance on blood studies for diagnosis, and rejection of those who do not meet those criteria. The statistics should read “over 95% of patients we diagnose with MG have positive blood studies” rather than “over 95% of patients with MG have positive blood studies.” Dismissing a significant portion of a patient population will also affect treatment statistics, which then should read that “for those who meet this criteria, _—% will respond to…”

If patients meet clinical criteria for the diagnosis of MG and a large percentage do not have positive serology, then more research needs to be done into their particular autoimmune problems, and better testing may become commercially viable. Recognizing the problem will lead to better clinical diagnosis and treatment, and strict diagnostic criteria would permit their inclusion in studies. For many of us this would create a more open and questioning atmosphere as to our understanding of the spectrum of autoimmune myasthenia and the ability and willingness to diagnose and treat “seronegative” autoimmune myasthenia when we see it.

In Reply: We appreciate Dr. Keiter’s comments. We agree that myasthenia gravis, like most medical disorders, rests on clinical diagnosis. We have patients we treat for myasthenia gravis in the absence of the typical serological confirmation. A very few of these patients with restricted oculobulbar symptoms may also have normal single-fiber EMG studies. In this situation, the decision to treat an individual for myasthenia gravis must rest on the physician’s clinical judgment, but also on the patient’s understanding that the condition does not have the diagnostic support often seen. The decision to treat with medications that have potential severe side effects requires the patient’s understanding of the context in which the diagnosis is being made and the specific treatment is being suggested.

In Reply: We appreciate Dr. Keiter’s comments. We agree that myasthenia gravis, like most medical disorders, rests on clinical diagnosis. We have patients we treat for myasthenia gravis in the absence of the typical serological confirmation. A very few of these patients with restricted oculobulbar symptoms may also have normal single-fiber EMG studies. In this situation, the decision to treat an individual for myasthenia gravis must rest on the physician’s clinical judgment, but also on the patient’s understanding that the condition does not have the diagnostic support often seen. The decision to treat with medications that have potential severe side effects requires the patient’s understanding of the context in which the diagnosis is being made and the specific treatment is being suggested.

In Reply: We appreciate Dr. Keiter’s comments. We agree that myasthenia gravis, like most medical disorders, rests on clinical diagnosis. We have patients we treat for myasthenia gravis in the absence of the typical serological confirmation. A very few of these patients with restricted oculobulbar symptoms may also have normal single-fiber EMG studies. In this situation, the decision to treat an individual for myasthenia gravis must rest on the physician’s clinical judgment, but also on the patient’s understanding that the condition does not have the diagnostic support often seen. The decision to treat with medications that have potential severe side effects requires the patient’s understanding of the context in which the diagnosis is being made and the specific treatment is being suggested.

Scientists say they’ve created a synthetic form of low-molecular-weight heparin (LMWH) that is both reversible and safe for patients with poor kidney function.

In the event of uncontrolled bleeding, this synthetic heparin can be reversed by an existing drug.

And the LMWH is cleared by the liver rather than the kidneys.

The team described their creation of the drug in Nature Chemical Biology.

“When doctors talk to me about the kind of heparin they want to use during and after surgery, they want it reversible, and they want it to not go through the kidneys,” said study author Jian Liu, PhD, of the University of North Carolina, Chapel Hill.

Dr Liu noted that up to 5% of patients receiving heparin experience some form of uncontrolled bleeding. Patients receiving unfractionated heparin are in less danger because there is an existing FDA-approved antidote available, protamine.

But protamine is not as effective in reversing LMWH. So Dr Liu and his colleagues tweaked the drug’s molecular structure so that protamine is able to deactivate LMWH.

The team used a chemo-enzymatic process to synthesize the LMWH, an approach they developed in research on a simpler anticoagulant published in Science in 2011. Synthesizing the LMWH allowed them to make improvements on the animal-derived form of the drug.

That form of LMWH is cleared from the body by the kidneys, which can make it unsuitable for patients with a weakened renal system. So the researchers made changes that allowed their LMWH to bind to receptors that clear it through the liver.

“If a person’s kidneys aren’t effectively clearing heparin from the blood, the drug stays active in the body for longer than expected,” said study author Nigel Key, MB ChB, also of the University of North Carolina.

“That can represent a potentially dangerous situation for the physician, pharmacist, and patient.”

LMWH did prove dangerous in 2008, when more than 80 people died and hundreds of others suffered adverse reactions to the drug. Authorities linked the problems to a contaminant in raw natural heparin from China.

“Whenever you mix the food chain and the drug chain together, you end up with potential for disaster,” said study author Robert Linhardt, PhD, of the Rensselaer Polytechnic Institute in Troy, New York.

“Whether it comes from contamination, adulteration, impurities like viruses or prions—any of those possibilities are much more likely when you make something in an uncontrolled environment. This is a drug that millions of people rely upon, and it’s important to develop a safe, synthetic alternative to the current supply chain.”

LMWH makes up more than half the US market for heparin. The researchers said the new version they created is a safe, economically viable alternative to the existing animal-derived supply.

“The pig stuff has served us well for 50 years and is very inexpensive, but if we cannot control the supply chain, we cannot ensure the safety of the drug,” Dr Liu said. “I am working for the day when synthetic heparin can be brewed in large laboratories at a low cost.”

Scientists say they’ve created a synthetic form of low-molecular-weight heparin (LMWH) that is both reversible and safe for patients with poor kidney function.

In the event of uncontrolled bleeding, this synthetic heparin can be reversed by an existing drug.

And the LMWH is cleared by the liver rather than the kidneys.

The team described their creation of the drug in Nature Chemical Biology.

“When doctors talk to me about the kind of heparin they want to use during and after surgery, they want it reversible, and they want it to not go through the kidneys,” said study author Jian Liu, PhD, of the University of North Carolina, Chapel Hill.

Dr Liu noted that up to 5% of patients receiving heparin experience some form of uncontrolled bleeding. Patients receiving unfractionated heparin are in less danger because there is an existing FDA-approved antidote available, protamine.

But protamine is not as effective in reversing LMWH. So Dr Liu and his colleagues tweaked the drug’s molecular structure so that protamine is able to deactivate LMWH.

The team used a chemo-enzymatic process to synthesize the LMWH, an approach they developed in research on a simpler anticoagulant published in Science in 2011. Synthesizing the LMWH allowed them to make improvements on the animal-derived form of the drug.

That form of LMWH is cleared from the body by the kidneys, which can make it unsuitable for patients with a weakened renal system. So the researchers made changes that allowed their LMWH to bind to receptors that clear it through the liver.

“If a person’s kidneys aren’t effectively clearing heparin from the blood, the drug stays active in the body for longer than expected,” said study author Nigel Key, MB ChB, also of the University of North Carolina.

“That can represent a potentially dangerous situation for the physician, pharmacist, and patient.”

LMWH did prove dangerous in 2008, when more than 80 people died and hundreds of others suffered adverse reactions to the drug. Authorities linked the problems to a contaminant in raw natural heparin from China.

“Whenever you mix the food chain and the drug chain together, you end up with potential for disaster,” said study author Robert Linhardt, PhD, of the Rensselaer Polytechnic Institute in Troy, New York.

“Whether it comes from contamination, adulteration, impurities like viruses or prions—any of those possibilities are much more likely when you make something in an uncontrolled environment. This is a drug that millions of people rely upon, and it’s important to develop a safe, synthetic alternative to the current supply chain.”

LMWH makes up more than half the US market for heparin. The researchers said the new version they created is a safe, economically viable alternative to the existing animal-derived supply.

“The pig stuff has served us well for 50 years and is very inexpensive, but if we cannot control the supply chain, we cannot ensure the safety of the drug,” Dr Liu said. “I am working for the day when synthetic heparin can be brewed in large laboratories at a low cost.”

Scientists say they’ve created a synthetic form of low-molecular-weight heparin (LMWH) that is both reversible and safe for patients with poor kidney function.

In the event of uncontrolled bleeding, this synthetic heparin can be reversed by an existing drug.

And the LMWH is cleared by the liver rather than the kidneys.

The team described their creation of the drug in Nature Chemical Biology.

“When doctors talk to me about the kind of heparin they want to use during and after surgery, they want it reversible, and they want it to not go through the kidneys,” said study author Jian Liu, PhD, of the University of North Carolina, Chapel Hill.

Dr Liu noted that up to 5% of patients receiving heparin experience some form of uncontrolled bleeding. Patients receiving unfractionated heparin are in less danger because there is an existing FDA-approved antidote available, protamine.

But protamine is not as effective in reversing LMWH. So Dr Liu and his colleagues tweaked the drug’s molecular structure so that protamine is able to deactivate LMWH.

The team used a chemo-enzymatic process to synthesize the LMWH, an approach they developed in research on a simpler anticoagulant published in Science in 2011. Synthesizing the LMWH allowed them to make improvements on the animal-derived form of the drug.

That form of LMWH is cleared from the body by the kidneys, which can make it unsuitable for patients with a weakened renal system. So the researchers made changes that allowed their LMWH to bind to receptors that clear it through the liver.

“If a person’s kidneys aren’t effectively clearing heparin from the blood, the drug stays active in the body for longer than expected,” said study author Nigel Key, MB ChB, also of the University of North Carolina.

“That can represent a potentially dangerous situation for the physician, pharmacist, and patient.”

LMWH did prove dangerous in 2008, when more than 80 people died and hundreds of others suffered adverse reactions to the drug. Authorities linked the problems to a contaminant in raw natural heparin from China.

“Whenever you mix the food chain and the drug chain together, you end up with potential for disaster,” said study author Robert Linhardt, PhD, of the Rensselaer Polytechnic Institute in Troy, New York.

“Whether it comes from contamination, adulteration, impurities like viruses or prions—any of those possibilities are much more likely when you make something in an uncontrolled environment. This is a drug that millions of people rely upon, and it’s important to develop a safe, synthetic alternative to the current supply chain.”

LMWH makes up more than half the US market for heparin. The researchers said the new version they created is a safe, economically viable alternative to the existing animal-derived supply.

“The pig stuff has served us well for 50 years and is very inexpensive, but if we cannot control the supply chain, we cannot ensure the safety of the drug,” Dr Liu said. “I am working for the day when synthetic heparin can be brewed in large laboratories at a low cost.”

In late 2013, the US Food and Drug Administration (FDA) approved sofosbuvir and simeprevir, the newest direct-acting antiviral agents for treating chronic hepatitis C virus (HCV) infection. Multiple clinical trials have demonstrated dramatically improved treatment outcomes with these agents, opening the door to all-oral regimens or interferon-free regimens as the future standard of care for HCV.

See related editorial

In this article, we discuss the results of the trials that established the efficacy and safety of sofosbuvir and simeprevir and led to their FDA approval. We also summarize the importance of these agents and evaluate other direct-acting antivirals currently in the pipeline for HCV treatment.

HCV IS A RISING PROBLEM

Chronic HCV infection is a major clinical and public health problem, with the estimated number of people infected exceeding 170 million worldwide, including 3.2 million in the United States.¹ It is a leading cause of cirrhosis, and its complications include hepatocellular carcinoma and liver failure. Cirrhosis due to HCV remains the leading indication for liver transplantation in the United States, accounting for nearly 40% of liver transplants in adults.²

The clinical impact of HCV will only continue to escalate, and in parallel, so will the cost to society. Models suggest that HCV-related deaths will double between 2010 and 2019, and considering only direct medical costs, the projected financial burden of treating HCV-related disease during this interval is estimated at between $6.5 and $13.6 billion.³

AN RNA VIRUS WITH SIX GENOTYPES

HCV, first identified in 1989, is an enveloped, single-stranded RNA flavivirus of the Hepacivirus genus measuring 50 to 60 nm in diameter.⁴ There are six viral genotypes, with genotype 1 being the most common in the United States and traditionally the most difficult to treat.

Once inside the host cell, the virus releases its RNA strand, which is translated into a single polyprotein of about 3,000 amino acids. This large molecule is then cleaved by proteases into several domains: three structural proteins (C, E1, and E2), a small protein called p7, and six nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) (Figure 1).⁵ These nonstructural proteins enable the virus to replicate.

GOAL OF TREATING HCV: A SUSTAINED VIROLOGIC RESPONSE

The aim of HCV treatment is to achieve a sustained virologic response, defined as having no detectable viral RNA after completion of antiviral therapy. This is associated with substantially better clinical outcomes, lower rates of liver-related morbidity and all-cause mortality, and stabilization of or even improvement in liver histology.^6,7 This end point has traditionally been assessed at 6 months after the end of therapy, but recent data suggest the rates at 12 weeks are essentially equivalent.

Table 1 summarizes the patterns of virologic response in treating HCV infection.

Interferon plus ribavirin: The standard of care for many years

HCV treatment has evolved over the past 20 years. Before 2011, the standard of care was a combination of interferon alfa-polyethylene glycol (peg-interferon), given as a weekly injection, and oral ribavirin. Neither drug has specific antiviral activity, and when they are used together they result in a sustained virologic response in fewer than 50% of patients with HCV genotype 1 and, at best, in 70% to 80% of patients with other genotypes.⁸

Nearly all patients receiving interferon experience side effects, which can be serious. Fatigue and flu-like symptoms are common, and the drug can also cause psychiatric symptoms (including depression or psychosis), weight loss, seizures, peripheral neuropathy, and bone marrow suppression. Ribavirin causes hemolysis and skin complications and is teratogenic.⁹

An important bit of information to know when using interferon is the patient’s IL28B genotype. This refers to a single-nucleotide polymorphism (C or T) on chromosome 19q13 (rs12979860) upstream of the IL28B gene encoding for interferon lambda-3. It is strongly associated with responsiveness to interferon: patients with the IL28B CC genotype have a much better chance of a sustained virologic response with interferon than do patients with CT or TT.

In May 2011, the FDA approved the NS3/4A protease inhibitors boceprevir and telaprevir for treating HCV genotype 1, marking the beginning of the era of direct-acting antiviral agents.¹⁰ When these drugs are used in combination with peg-interferon alfa and ribavirin, up to 75% of patients with HCV genotype 1 who have had no previous treatment achieve a sustained virologic response.

But despite greatly improving the response rate, these first-generation protease inhibitors have substantial limitations. Twenty-five percent of patients with HCV genotype 1 who have received no previous treatment and 71% of patients who did not respond to previous treatment will not achieve a sustained virologic response with these agents.¹¹ Further, they are effective only against HCV genotype 1, being highly specific for the amino acid target sequence of the NS3 region.

Also, they must be used in combination with interferon alfa and ribavirin because the virus needs to mutate only a little—a few amino-acid substitutions—to gain resistance to them.¹² Therefore, patients are still exposed to interferon and ribavirin, with their toxicity. In addition, dysgeusia is seen with boceprevir, rash with telaprevir, and anemia with both.^13,14

Finally, serious drug-drug interactions prompted the FDA to impose warnings for the use of these agents with other medications that interact with CYP3A4, the principal enzyme responsible for their metabolism. Thus, these significant adverse effects dampen the enthusiasm of patients contemplating a long course of treatment with these agents.

The need to improve the rate of sustained virologic response, shorten the duration of treatment, avoid serious side effects, improve efficacy in treating patients infected with genotypes other than 1, and, importantly, eliminate the need for interferon alfa and its serious adverse effects have driven the development of new direct-acting antiviral agents, including the two newly FDA-approved drugs, sofosbuvir and simeprevir.

SOFOSBUVIR: A POLYMERASE INHIBITOR

Sofosbuvir is a uridine nucleotide analogue that selectively inhibits the HCV NS5B RNA-dependent RNA polymerase (Figure 1). It targets the highly conserved nucleotide-binding pocket of this enzyme and functions as a chain terminator.¹⁵ While the protease inhibitors are genotype-dependent, inhibition of the highly conserved viral polymerase has an impact that spans genotypes.

Early clinical trials of sofosbuvir

Sofosbuvir has been tested in combination with interferon alfa and ribavirin, as well as in interferon-free regimens (Table 2).^16–20

Rodriguez-Torres et al,¹⁵

• 56% with sofosbuvir 100 mg, peg-interferon, and ribavirin
• 83% with sofosbuvir 200 mg, peg-interferon, and ribavirin
• 80% with sofosbuvir 400 mg, peg-interferon, and ribavirin
• 43% with peg-interferon and ribavirin alone.

The ATOMIC trial¹⁶ tested the efficacy and safety of sofosbuvir in combination with peg-interferon and ribavirin in patients with HCV genotype 1, 4, or 6, without cirrhosis, who had not received any previous treatment. Patients with HCV genotype 1 were randomized to three treatments:

• Sofosbuvir 400 mg orally once daily plus peg-interferon and ribavirin for 12 weeks
• The same regimen, but for 24 weeks
• Sofosbuvir plus peg-interferon and ribavirin for 12 weeks, followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin.

The rates of sustained virologic response were very high and were not significantly different among the three groups: 89%, 89%, and 87%, respectively. Patients who were able to complete a full course of therapy achieved even higher rates of sustained virologic response, ranging from 96% to 98%. The likelihood of response was not adversely affected by the usual markers of a poorer prognosis, such as a high viral load (≥ 800,000 IU/mL) or a non-CC IL28B genotype. Although patients with cirrhosis (another predictor of no response) were excluded from this study, the presence of bridging fibrosis did not seem to affect the rate of sustained virologic response. The results in patients with genotypes other than 1 were very encouraging, but the small number of patients enrolled precluded drawing firm conclusions in this group.

Important implications of the ATOMIC trial include the following:

There is no benefit in prolonging treatment with sofosbuvir beyond 12 weeks, since adverse events increased without any improvement in the rate of sustained virologic response.

There is a very low likelihood of developing viral resistance or mutation when using sofosbuvir.

There is no role for response-guided therapy, a concept used with protease inhibitor-based regimens in which patients who have complete clearance of the virus within the first 4 weeks of treatment (a rapid virologic response) and remain clear through 12 weeks of treatment (an extended rapid viral response) can be treated for a shorter duration without decreasing the likelihood of a sustained virologic response.

Lawitz et al¹⁷ conducted a randomized double-blind phase 2 trial to evaluate the effect of sofosbuvir dosing on response in noncirrhotic, previously untreated patients with HCV genotype 1, 2, or 3. Patients with HCV genotype 1 were randomized to one of three treatment groups in a 2:2:1 ratio: sofosbuvir 200 mg orally once daily, sofosbuvir 400 mg orally once daily, or placebo, all for 12 weeks in combination with peg-interferon (180 μg weekly) and ribavirin in a dosage based on weight. Depending on the viral response, patients continued peg-interferon and ribavirin for an additional 12 weeks if they achieved an extended rapid viral response, or 36 weeks if they did not achieve an extended rapid virologic response, and in all patients who received placebo. Patients with HCV genotype 2 or 3 were given sofosbuvir 400 mg once daily in combination with interferon and ribavirin for 12 weeks.

As in the ATOMIC trial, all patients treated with sofosbuvir had a very rapid reduction in viral load: 98% of patients with genotype 1 developed a rapid virologic response, and therefore almost all were eligible for the shorter treatment course of 24 weeks.¹⁷ The latter finding again suggested that response-guided treatment is not relevant with sofosbuvir-based regimens.

Very high rates of sustained virologic response were seen: 90% in patients with genotype 1 treated with sofosbuvir 200 mg, 91% in those with genotype 1 treated with 400 mg, and 92% in those with genotype 2 or 3. Although 6% of patients in the 200-mg group had virologic breakthrough after completing sofosbuvir treatment, no virologic breakthrough was observed in the 400-mg group, suggesting that the 400-mg dose might suppress the virus more effectively.¹⁷

The ELECTRON trial¹⁸ was a phase 2 study designed to evaluate the efficacy and safety of sofosbuvir and ribavirin in interferon-sparing and interferon-free regimens in patients with HCV genotype 1, 2, or 3 infection. Sofosbuvir was tested with peg-interferon and ribavirin, with ribavirin alone, and as monotherapy in previously untreated patients with genotype 2 or 3. A small number of patients with genotype 1 who were previously untreated and who were previously nonresponders were also treated with sofosbuvir and ribavirin.

All patients had a rapid virologic response, and viral suppression was sustained through the end of treatment. All patients with genotype 2 or 3 treated with double therapy (sofosbuvir and ribavirin) or triple therapy (sofosbuvir, peg-interferon, and ribavirin) achieved a sustained virologic response, compared with only 60% of patients treated with sofosbuvir monotherapy. The monotherapy group had an equal number of relapsers among those with genotype 2 or 3. Of the genotype 1 patients treated with sofosbuvir and ribavirin, 84% of those previously untreated developed a sustained virologic response, whereas only 10% of the previous nonresponders did.

The NEUTRINO trial¹⁹ studied the efficacy and safety of sofosbuvir in previously untreated patients with HCV genotype 1, 4, 5, or 6. In this phase 3 open-label study, all patients received sofosbuvir plus peg-interferon and weight-based ribavirin therapy for 12 weeks. Of the patients enrolled, 89% had genotype 1, while 9% had genotype 4 and 2% had genotype 5 or 6. Overall, 17% of the patients had cirrhosis.

The viral load rapidly decreased in all patients treated with sofosbuvir irrespective of the HCV genotype, IL28B status, race, or the presence or absence of cirrhosis. Ninety-nine percent of patients with genotype 1, 4, 5, or 6 achieved a rapid virologic response, and 90% achieved a sustained virologic response at 12 weeks after completion of treatment with sofosbuvir and ribavirin. Patients with cirrhosis had a slightly lower rate of sustained virologic response (80%, compared with 92% in patients without cirrhosis). Also, patients with non-CC IL28B genotypes had a lower rate of sustained virologic response (87% in non-CC allele vs 98% in patients with the favorable CC allele).

The FISSION trial¹⁹ recruited previously untreated patients with genotype 2 or 3 and randomized them to therapy with either sofosbuvir plus ribavirin in a weight-based dose for 12 weeks, or 24 weeks of interferon and ribavirin. In this study, 20% of patients in each treatment group had cirrhosis.

As in the NEUTRINO trial, the viral load rapidly decreased in all patients treated with sofosbuvir irrespective of HCV genotype, IL28B status, race, or the presence or absence of cirrhosis. Here, 100% of patients with genotype 2 or 3 who were treated with sofosbuvir and ribavirin achieved a rapid virologic response. Differences in outcome emerged based on genotype: 97% of those with genotype 2 and 56% of those with genotype 3 achieved a sustained virologic response. The overall rate was 67%, which was not different from patients treated with peg-interferon and ribavirin. In the subgroup of patients with cirrhosis, 47% of those treated with sofosbuvir and ribavirin achieved a sustained virologic response, vs 38% of those who received peg-interferon plus ribavirin.

In both the NEUTRINO and FISSION trials, few patients discontinued treatment, with higher rates of most adverse events occurring in patients treated with peg-interferon and ribavirin.

POSITRON,²⁰ a phase 3 clinical trial, tested sofosbuvir in patients with HCV genotype 2 or 3 who were ineligible for peg-interferon, unwilling to take peg-interferon, or unable to tolerate peg-interferon (mainly because of clinically significant psychiatric disorders). Patients were randomized to two treatment groups for 12 weeks: sofosbuvir plus ribavirin, or placebo. About 50% of patients had HCV genotype 3, and 16% had cirrhosis.

The overall rate of sustained virologic response at 12 weeks after treatment was 78% in the sofosbuvir-and-ribavirin group (93% in genotype 2 patients and 61% in genotype 3 patients). Again, cirrhosis was associated with a lower rate of sustained virologic response (61% of patients with cirrhosis achieved a sustained virologic response vs 81% of patients without cirrhosis). None of the sofosbuvir-treated patients had virologic failure while on treatment.

FUSION,²⁰ another phase 3 trial, evaluated sofosbuvir in patients infected with HCV genotype 2 or 3 for whom interferon-based treatment had failed. They were randomized to either 12 weeks or 16 weeks of sofosbuvir and weight-based ribavirin treatment. About 60% of patients had HCV genotype 3, and 34% had cirrhosis.

The overall sustained virologic response rate was 50% in the patients treated for 12 weeks and 73% in those treated for 16 weeks: specifically, 86% of patients with genotype 2 achieved a sustained virologic response at 12 weeks and 94% at 16 weeks, whereas in those with genotype 3 the rates were 30% at 12 weeks and 62% at 16 weeks.

Cirrhosis was again a predictor of lack of response to sofosbuvir. In the group treated for 12 weeks, 31% of those with cirrhosis achieved a sustained virologic response compared with 61% in those without cirrhosis. In the group treated for 16 weeks, 61% of those with cirrhosis achieved a sustained virologic response compared with 76% in those without cirrhosis.

In both the POSITRON and FUSION trials, relapse accounted for all treatment failures, and no virologic resistance was detected in patients who did not have a sustained virologic response. The investigators concluded that 12 weeks of treatment with sofosbuvir and ribavirin can be effective for HCV genotype 2 infection, but extending the treatment to 16 weeks may be beneficial for genotype 3. This may be especially important in patients with cirrhosis or those who did not have a response to peg-interferon-based treatment.

VALENCE,²¹ an ongoing phase 3 trial in Europe, is assessing the safety and efficacy of sofosbuvir 400 mg once daily and weight-based ribavirin in patients with HCV genotype 2 or 3. Eighty-five percent of the trial participants have received previous treatment, and 21% have cirrhosis. Patients were originally randomized in a 4:1 ratio to receive sofosbuvir plus ribavirin for 12 weeks or matching placebo, but as a result of emerging data suggesting that patients with genotype 3 would benefit from more than 12 weeks of treatment, the study was subsequently amended to extend treatment to 24 weeks for patients with genotype 3.

Overall rates of sustained virologic response were 93% in patients with genotype 2 and 85% in patients with genotype 3. In previously treated patients with genotype 2 who were treated for 12 weeks, the rates of sustained virologic response were 91% in those without cirrhosis vs 88% in those with cirrhosis. In previously treated patients with genotype 3, the rates in those treated for 24 weeks were 87% in patients without cirrhosis vs 60% with cirrhosis. The safety profile was consistent with that of ribavirin.

Side effects of sofosbuvir

In clinical trials, side effects occurred most often when sofosbuvir was combined with interferon and ribavirin and were consistent with the known side effects of the latter two agents. The most frequently reported side effects included fatigue, insomnia, nausea, rash, anemia, headache, and arthralgia, with most of these adverse events rated by treating clinicians as being mild in severity.^15,20

In the ATOMIC trial, the most common events leading to drug discontinuation were anemia and neutropenia, both associated with interferon and ribavirin. Patients receiving sofosbuvir monotherapy after 12 weeks of triple therapy showed rapid improvement in hemoglobin levels and neutrophil counts, indicating that hematologic abnormalities attributed solely to sofosbuvir are minimal. In the FISSION trial, the incidence of adverse events was consistently lower in those receiving sofosbuvir-ribavirin than in patients receiving interferon-ribavirin without sofosbuvir.¹⁹

In the POSITRON trial, discontinuation of sofosbuvir because of adverse events was uncommon, and there were no differences in the incidence of adverse events and laboratory abnormalities between patients with and without cirrhosis when they received sofosbuvir and ribavirin.²⁰

Sofosbuvir dosage and indications

Sofosbuvir is approved in an oral dose of 400 mg once daily in combination with ribavirin for patients infected with HCV genotype 2 or 3 and in combination with ribavirin and interferon alfa in patients infected with HCV genotype 1 or 4 (Table 3). It could be considered for HCV genotype 1 in combination with ribavirin alone for 24 weeks in patients who are ineligible for interferon.

Sofosbuvir is also recommended in combination with ribavirin in HCV-infected patients with hepatocellular carcinoma who are awaiting liver transplantation, for up to 48 weeks or until they receive a transplant, to prevent posttransplant reinfection with HCV.

A course of therapy is expected to cost about $84,000, which is significantly more than the cost of previous triple therapy (peg-interferon, ribavirin, and either boceprevir or telaprevir).²² This high cost will undoubtedly lead to less widespread use in developing countries, and potentially even in the United States. As newer direct-acting antiviral agents become available, the price will likely come down, enhancing access to these drugs.

SIMEPREVIR: A SECOND-GENERATION PROTEASE INHIBITOR

Telaprevir and boceprevir are NS3/A4 protease inhibitors that belong to the alfa-ketoamid derivative class. Simeprevir belongs to the macrocyclic class and has a different way of binding to the target enzyme.²³ Like sofosbuvir, simeprevir was recently approved by the FDA for the treatment of HCV genotype 1.

The therapeutic efficacy of simeprevir has been tested in several clinical trials (Table 4), including QUEST-1²⁴ and QUEST-2²⁵ (in previously untreated patients), PROMISE²⁶ (in prior relapsers), and ASPIRE²⁷ (in prior partial and null responders). Results from these trials showed high overall rates of sustained virologic response with triple therapy (ie, simeprevir combined with peg-interferon and ribavirin). It was generally well tolerated, and most adverse events reported during 12 weeks of treatment were of mild to moderate severity.

In QUEST-1 and QUEST-2, both double-blind phase 3 clinical trials, previously untreated patients infected with HCV genotype 1 were randomized in a 2:1 ratio to receive either simeprevir 150 mg daily or placebo for 12 weeks; both groups also received peg-interferon and ribavirin. Patients then received peg-interferon and ribavirin alone for 12 or 36 weeks in the simeprevir group (based on response) and for 36 weeks in the placebo group.

The overall rate of sustained virologic response at 12 weeks was 80% in the simeprevir group (75% in those with genotype 1a and 85% in those with genotype 1b) vs 50% in the placebo group (receiving peg-interferon and ribavirin alone).^24,25

PROMISE,²⁶ another double-blind randomized phase 3 clinical trial, evaluated simeprevir in patients with HCV genotype 1 who relapsed after previous interferon-based therapy. It had a similar design to QUEST-1 and QUEST-2, and 15% of all patients had cirrhosis.

The overall sustained virologic response rate at 12 weeks after treatment was 79% in the simeprevir group (70% in patients with genotype 1a and 86% in those with genotype 1b) vs 37% in the placebo group. Rates were similar in patients with absent to moderate fibrosis (82%), advanced fibrosis (73%), or cirrhosis (74%).

ASPIRE.²⁷ Simeprevir efficacy in patients with HCV genotype 1 for whom previous therapy with peg-interferon and ribavirin had failed was tested in ASPIRE, a double-blind randomized phase 2 clinical trial. Patients were randomized to receive simeprevir (either 100 mg or 150 mg daily) for 12, 24, or 48 weeks in combination with 48 weeks of peg-interferon and ribavirin, or placebo plus peg-interferon and ribavirin for 48 weeks.

The primary end point was the rate of sustained virologic response at 24 weeks. Overall, rates were 61% to 80% for the simeprevir treatment groups compared with 23% with placebo, regardless of prior response to peg-interferon and ribavirin. By subgroup, rates were:

• 77% to 89% with simeprevir vs 37% with placebo in prior relapsers
• 48% to 86% with simeprevir vs 9% with placebo in prior partial responders
• 38% to 59% with placebo vs 19% for prior nonresponders.

The best rates of sustained viral response at 24 weeks were in the groups that received simeprevir 150 mg daily: 85% in prior relapsers, 75% in prior partial responders, and 51% in prior nonresponders.

Simeprevir vs other direct-acting antiviral drugs

Advantages of simeprevir over the earlier protease inhibitors include once-daily dosing, a lower rate of adverse events (the most common being fatigue, headache, rash, photosensitivity, and pruritus), a lower likelihood of discontinuation because of adverse events, and fewer drug-drug interactions (since it is a weak inhibitor of the CYP3A4 enzyme).

Unlike sofosbuvir, simeprevir was FDA-approved only for HCV genotype 1 and in combination with interferon alfa and ribavirin. Compared with sofosbuvir, the treatment duration with simeprevir regimens is longer overall (interferon alfa and ribavirin are given for 12 weeks in sofosbuvir-based regimens vs 24 to 48 weeks with simeprevir). As with sofosbuvir, the estimated cost of simeprevir is high, about $66,000 for a 12-week course.

Simeprevir dosage and indications

Simeprevir was approved at an oral dose of 150 mg once daily in combination with ribavirin and interferon alfa in patients with HCV genotype 1 (Table 5).

The approved regimens for simeprevir are fixed in total duration based on the patient’s treatment history. Specifically, all patients receive the drug in combination with peg-interferon and ribavirin for 12 weeks. Then, previously untreated patients and prior relapsers continue to receive peg-interferon and ribavirin alone for another 12 weeks, and those with a partial or null response continue with these drugs for another 36 weeks.

Patients infected with HCV genotype 1a should be screened for the NS3 Q80K polymorphism at baseline, as it has been associated with substantially reduced response to simeprevir.

Sofosbuvir and simeprevir in combination

The COSMOS trial.²⁸ Given their differences in mechanism of action, sofosbuvir and simeprevir are being tested in combination. The COSMOS trial is an ongoing phase 2 randomized open-label study investigating the efficacy and safety of simeprevir and sofosbuvir in combination with and without ribavirin in patients with HCV genotype 1, including nonresponders and those with cirrhosis. Early results are promising, with very high rates of sustained virologic response with the sofosbuvir-simeprevir combination (93% to 100%) and indicate that the addition of ribavirin might not be needed to achieve sustained virologic response in this patient population.

THE FUTURE

The emergence of all-oral regimens for HCV treatment with increasingly sophisticated agents such as sofosbuvir and simeprevir will dramatically alter the management of HCV patients. In view of the improvement in sustained virologic response rates with these treatments, and since most HCV-infected persons have no symptoms, the US Centers for Disease Control and Prevention²⁹ recently recommended one-time testing of the cohort in which the prevalence of HCV infection is highest: all persons born between 1945 and 1965. This undoubtedly will increase the detection of this infection—and the number of new patients expecting treatment.

Future drugs promise further improvements (Table 6).^30–35 Advances in knowledge of the HCV molecular structure have led to the development of numerous direct-acting antiviral agents with very specific viral targets. A second wave of protease inhibitors and of nucleoside and nonnucleoside polymerase inhibitors will soon be available. Inhibitors of NS5A (a protein important in the assembly of the viral replication complex) such as daclatasvir and ledipasvir, are currently in phase 3 clinical trials. Other viral proteins involved in assembly of the virus, including the core protein and p7, are being explored as drug targets. In addition, inhibiting host targets such as cyclophilin A and miR122 has gained traction recently, with specific agents currently in phase 2 and 3 clinical trials.

Factors that previously were major determinants of response to treatment, such as IL28B genotype, viral load, race, age, extent of fibrosis, and genotype 1 subtypes, will become much less important with the introduction of highly potent direct-acting antiviral agents.

Many all-oral combinations are being evaluated in clinical trials. For example, the open-label, phase 2 LONESTAR trial tested the utility of combining sofosbuvir and ledipasvir (an NS5A inhibitor) with and without ribavirin for 8 or 12 weeks in previously untreated patients with HCV genotype 1, and for 12 weeks in patients with HCV genotype 1 who did not achieve a sustained virologic response after receiving a protease inhibitor-based regimen (half of whom had compensated cirrhosis).³⁶ Sustained virologic response rates were very high (95% to 100%) in both previously treated and previously untreated patients, including those with cirrhosis. Similar rates were achieved by the 8-week and 12-week groups in noncirrhotic patients who had not been previously treated for HCV. The typical hematologic abnormalities associated with interferon were not observed except for mild anemia in patients who received ribavirin. These results suggest that the combination of sofosbuvir and ledipasvir could offer a very effective, short, all-oral treatment for patients with HCV genotype 1, including those with cirrhosis, who up to now have been difficult to treat.

Challenges remaining

The success of sofosbuvir and simeprevir paves the way for interferon-free regimens.³⁷ For a long time, the treatment of HCV infection required close monitoring of patients while managing the side effects of interferon, but the current and emerging direct-acting antiviral agents will soon change this practice. Given the synergistic effects of combination therapy—targeting the virus at multiple locations, decreasing the likelihood of drug resistance, and improving efficacy—combination regimens seem to be the optimal solution to the HCV epidemic. Lower risk of side effects and shorter treatment duration will definitely improve the acceptance of any new regimen. New agents that act against conserved viral targets, thereby yielding activity across multiple genotypes, will be advantageous as well. Table 7 compares the rates of sustained virologic response of the different currently approved HCV treatment regimens.

Clinical challenges remain, including the management of special patient populations for whom data are still limited. These include patients with cirrhosis, chronic kidney disease, renal failure, and concurrent infection with human immunodeficiency virus, and patients who have undergone solid organ transplantation. Clinical trials are under way to evaluate the treatment options for these patients, who will likely need to wait for the emergence of additional agents before dramatic improvement in sustained virologic response rates may be expected.38

As the treatment of HCV becomes simpler, safer, and more effective, primary care physicians will increasingly be expected to manage it. Difficult-to-treat patients, including the special populations above, will require specialist management and individualized treatment regimens, at least until better therapies are available. The high projected cost of the new agents may limit access, at least initially. However, the dramatic improvement in sustained virologic response rates and all that that implies in terms of decreased risk of advanced liver disease and its complications will undoubtedly make these therapies cost-effective.³⁹

In late 2013, the US Food and Drug Administration (FDA) approved sofosbuvir and simeprevir, the newest direct-acting antiviral agents for treating chronic hepatitis C virus (HCV) infection. Multiple clinical trials have demonstrated dramatically improved treatment outcomes with these agents, opening the door to all-oral regimens or interferon-free regimens as the future standard of care for HCV.

See related editorial

In this article, we discuss the results of the trials that established the efficacy and safety of sofosbuvir and simeprevir and led to their FDA approval. We also summarize the importance of these agents and evaluate other direct-acting antivirals currently in the pipeline for HCV treatment.

HCV IS A RISING PROBLEM

Chronic HCV infection is a major clinical and public health problem, with the estimated number of people infected exceeding 170 million worldwide, including 3.2 million in the United States.¹ It is a leading cause of cirrhosis, and its complications include hepatocellular carcinoma and liver failure. Cirrhosis due to HCV remains the leading indication for liver transplantation in the United States, accounting for nearly 40% of liver transplants in adults.²

The clinical impact of HCV will only continue to escalate, and in parallel, so will the cost to society. Models suggest that HCV-related deaths will double between 2010 and 2019, and considering only direct medical costs, the projected financial burden of treating HCV-related disease during this interval is estimated at between $6.5 and $13.6 billion.³

AN RNA VIRUS WITH SIX GENOTYPES

HCV, first identified in 1989, is an enveloped, single-stranded RNA flavivirus of the Hepacivirus genus measuring 50 to 60 nm in diameter.⁴ There are six viral genotypes, with genotype 1 being the most common in the United States and traditionally the most difficult to treat.

Once inside the host cell, the virus releases its RNA strand, which is translated into a single polyprotein of about 3,000 amino acids. This large molecule is then cleaved by proteases into several domains: three structural proteins (C, E1, and E2), a small protein called p7, and six nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) (Figure 1).⁵ These nonstructural proteins enable the virus to replicate.

GOAL OF TREATING HCV: A SUSTAINED VIROLOGIC RESPONSE

The aim of HCV treatment is to achieve a sustained virologic response, defined as having no detectable viral RNA after completion of antiviral therapy. This is associated with substantially better clinical outcomes, lower rates of liver-related morbidity and all-cause mortality, and stabilization of or even improvement in liver histology.^6,7 This end point has traditionally been assessed at 6 months after the end of therapy, but recent data suggest the rates at 12 weeks are essentially equivalent.

Table 1 summarizes the patterns of virologic response in treating HCV infection.

Interferon plus ribavirin: The standard of care for many years

HCV treatment has evolved over the past 20 years. Before 2011, the standard of care was a combination of interferon alfa-polyethylene glycol (peg-interferon), given as a weekly injection, and oral ribavirin. Neither drug has specific antiviral activity, and when they are used together they result in a sustained virologic response in fewer than 50% of patients with HCV genotype 1 and, at best, in 70% to 80% of patients with other genotypes.⁸

Nearly all patients receiving interferon experience side effects, which can be serious. Fatigue and flu-like symptoms are common, and the drug can also cause psychiatric symptoms (including depression or psychosis), weight loss, seizures, peripheral neuropathy, and bone marrow suppression. Ribavirin causes hemolysis and skin complications and is teratogenic.⁹

An important bit of information to know when using interferon is the patient’s IL28B genotype. This refers to a single-nucleotide polymorphism (C or T) on chromosome 19q13 (rs12979860) upstream of the IL28B gene encoding for interferon lambda-3. It is strongly associated with responsiveness to interferon: patients with the IL28B CC genotype have a much better chance of a sustained virologic response with interferon than do patients with CT or TT.

In May 2011, the FDA approved the NS3/4A protease inhibitors boceprevir and telaprevir for treating HCV genotype 1, marking the beginning of the era of direct-acting antiviral agents.¹⁰ When these drugs are used in combination with peg-interferon alfa and ribavirin, up to 75% of patients with HCV genotype 1 who have had no previous treatment achieve a sustained virologic response.

But despite greatly improving the response rate, these first-generation protease inhibitors have substantial limitations. Twenty-five percent of patients with HCV genotype 1 who have received no previous treatment and 71% of patients who did not respond to previous treatment will not achieve a sustained virologic response with these agents.¹¹ Further, they are effective only against HCV genotype 1, being highly specific for the amino acid target sequence of the NS3 region.

Also, they must be used in combination with interferon alfa and ribavirin because the virus needs to mutate only a little—a few amino-acid substitutions—to gain resistance to them.¹² Therefore, patients are still exposed to interferon and ribavirin, with their toxicity. In addition, dysgeusia is seen with boceprevir, rash with telaprevir, and anemia with both.^13,14

Finally, serious drug-drug interactions prompted the FDA to impose warnings for the use of these agents with other medications that interact with CYP3A4, the principal enzyme responsible for their metabolism. Thus, these significant adverse effects dampen the enthusiasm of patients contemplating a long course of treatment with these agents.

The need to improve the rate of sustained virologic response, shorten the duration of treatment, avoid serious side effects, improve efficacy in treating patients infected with genotypes other than 1, and, importantly, eliminate the need for interferon alfa and its serious adverse effects have driven the development of new direct-acting antiviral agents, including the two newly FDA-approved drugs, sofosbuvir and simeprevir.

SOFOSBUVIR: A POLYMERASE INHIBITOR

Sofosbuvir is a uridine nucleotide analogue that selectively inhibits the HCV NS5B RNA-dependent RNA polymerase (Figure 1). It targets the highly conserved nucleotide-binding pocket of this enzyme and functions as a chain terminator.¹⁵ While the protease inhibitors are genotype-dependent, inhibition of the highly conserved viral polymerase has an impact that spans genotypes.

Early clinical trials of sofosbuvir

Sofosbuvir has been tested in combination with interferon alfa and ribavirin, as well as in interferon-free regimens (Table 2).^16–20

Rodriguez-Torres et al,¹⁵

• 56% with sofosbuvir 100 mg, peg-interferon, and ribavirin
• 83% with sofosbuvir 200 mg, peg-interferon, and ribavirin
• 80% with sofosbuvir 400 mg, peg-interferon, and ribavirin
• 43% with peg-interferon and ribavirin alone.

The ATOMIC trial¹⁶ tested the efficacy and safety of sofosbuvir in combination with peg-interferon and ribavirin in patients with HCV genotype 1, 4, or 6, without cirrhosis, who had not received any previous treatment. Patients with HCV genotype 1 were randomized to three treatments:

• Sofosbuvir 400 mg orally once daily plus peg-interferon and ribavirin for 12 weeks
• The same regimen, but for 24 weeks
• Sofosbuvir plus peg-interferon and ribavirin for 12 weeks, followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin.

The rates of sustained virologic response were very high and were not significantly different among the three groups: 89%, 89%, and 87%, respectively. Patients who were able to complete a full course of therapy achieved even higher rates of sustained virologic response, ranging from 96% to 98%. The likelihood of response was not adversely affected by the usual markers of a poorer prognosis, such as a high viral load (≥ 800,000 IU/mL) or a non-CC IL28B genotype. Although patients with cirrhosis (another predictor of no response) were excluded from this study, the presence of bridging fibrosis did not seem to affect the rate of sustained virologic response. The results in patients with genotypes other than 1 were very encouraging, but the small number of patients enrolled precluded drawing firm conclusions in this group.

Important implications of the ATOMIC trial include the following:

There is no benefit in prolonging treatment with sofosbuvir beyond 12 weeks, since adverse events increased without any improvement in the rate of sustained virologic response.

There is a very low likelihood of developing viral resistance or mutation when using sofosbuvir.

There is no role for response-guided therapy, a concept used with protease inhibitor-based regimens in which patients who have complete clearance of the virus within the first 4 weeks of treatment (a rapid virologic response) and remain clear through 12 weeks of treatment (an extended rapid viral response) can be treated for a shorter duration without decreasing the likelihood of a sustained virologic response.

Lawitz et al¹⁷ conducted a randomized double-blind phase 2 trial to evaluate the effect of sofosbuvir dosing on response in noncirrhotic, previously untreated patients with HCV genotype 1, 2, or 3. Patients with HCV genotype 1 were randomized to one of three treatment groups in a 2:2:1 ratio: sofosbuvir 200 mg orally once daily, sofosbuvir 400 mg orally once daily, or placebo, all for 12 weeks in combination with peg-interferon (180 μg weekly) and ribavirin in a dosage based on weight. Depending on the viral response, patients continued peg-interferon and ribavirin for an additional 12 weeks if they achieved an extended rapid viral response, or 36 weeks if they did not achieve an extended rapid virologic response, and in all patients who received placebo. Patients with HCV genotype 2 or 3 were given sofosbuvir 400 mg once daily in combination with interferon and ribavirin for 12 weeks.

As in the ATOMIC trial, all patients treated with sofosbuvir had a very rapid reduction in viral load: 98% of patients with genotype 1 developed a rapid virologic response, and therefore almost all were eligible for the shorter treatment course of 24 weeks.¹⁷ The latter finding again suggested that response-guided treatment is not relevant with sofosbuvir-based regimens.

Very high rates of sustained virologic response were seen: 90% in patients with genotype 1 treated with sofosbuvir 200 mg, 91% in those with genotype 1 treated with 400 mg, and 92% in those with genotype 2 or 3. Although 6% of patients in the 200-mg group had virologic breakthrough after completing sofosbuvir treatment, no virologic breakthrough was observed in the 400-mg group, suggesting that the 400-mg dose might suppress the virus more effectively.¹⁷

The ELECTRON trial¹⁸ was a phase 2 study designed to evaluate the efficacy and safety of sofosbuvir and ribavirin in interferon-sparing and interferon-free regimens in patients with HCV genotype 1, 2, or 3 infection. Sofosbuvir was tested with peg-interferon and ribavirin, with ribavirin alone, and as monotherapy in previously untreated patients with genotype 2 or 3. A small number of patients with genotype 1 who were previously untreated and who were previously nonresponders were also treated with sofosbuvir and ribavirin.

All patients had a rapid virologic response, and viral suppression was sustained through the end of treatment. All patients with genotype 2 or 3 treated with double therapy (sofosbuvir and ribavirin) or triple therapy (sofosbuvir, peg-interferon, and ribavirin) achieved a sustained virologic response, compared with only 60% of patients treated with sofosbuvir monotherapy. The monotherapy group had an equal number of relapsers among those with genotype 2 or 3. Of the genotype 1 patients treated with sofosbuvir and ribavirin, 84% of those previously untreated developed a sustained virologic response, whereas only 10% of the previous nonresponders did.

The NEUTRINO trial¹⁹ studied the efficacy and safety of sofosbuvir in previously untreated patients with HCV genotype 1, 4, 5, or 6. In this phase 3 open-label study, all patients received sofosbuvir plus peg-interferon and weight-based ribavirin therapy for 12 weeks. Of the patients enrolled, 89% had genotype 1, while 9% had genotype 4 and 2% had genotype 5 or 6. Overall, 17% of the patients had cirrhosis.

The viral load rapidly decreased in all patients treated with sofosbuvir irrespective of the HCV genotype, IL28B status, race, or the presence or absence of cirrhosis. Ninety-nine percent of patients with genotype 1, 4, 5, or 6 achieved a rapid virologic response, and 90% achieved a sustained virologic response at 12 weeks after completion of treatment with sofosbuvir and ribavirin. Patients with cirrhosis had a slightly lower rate of sustained virologic response (80%, compared with 92% in patients without cirrhosis). Also, patients with non-CC IL28B genotypes had a lower rate of sustained virologic response (87% in non-CC allele vs 98% in patients with the favorable CC allele).

The FISSION trial¹⁹ recruited previously untreated patients with genotype 2 or 3 and randomized them to therapy with either sofosbuvir plus ribavirin in a weight-based dose for 12 weeks, or 24 weeks of interferon and ribavirin. In this study, 20% of patients in each treatment group had cirrhosis.

As in the NEUTRINO trial, the viral load rapidly decreased in all patients treated with sofosbuvir irrespective of HCV genotype, IL28B status, race, or the presence or absence of cirrhosis. Here, 100% of patients with genotype 2 or 3 who were treated with sofosbuvir and ribavirin achieved a rapid virologic response. Differences in outcome emerged based on genotype: 97% of those with genotype 2 and 56% of those with genotype 3 achieved a sustained virologic response. The overall rate was 67%, which was not different from patients treated with peg-interferon and ribavirin. In the subgroup of patients with cirrhosis, 47% of those treated with sofosbuvir and ribavirin achieved a sustained virologic response, vs 38% of those who received peg-interferon plus ribavirin.

In both the NEUTRINO and FISSION trials, few patients discontinued treatment, with higher rates of most adverse events occurring in patients treated with peg-interferon and ribavirin.

POSITRON,²⁰ a phase 3 clinical trial, tested sofosbuvir in patients with HCV genotype 2 or 3 who were ineligible for peg-interferon, unwilling to take peg-interferon, or unable to tolerate peg-interferon (mainly because of clinically significant psychiatric disorders). Patients were randomized to two treatment groups for 12 weeks: sofosbuvir plus ribavirin, or placebo. About 50% of patients had HCV genotype 3, and 16% had cirrhosis.

The overall rate of sustained virologic response at 12 weeks after treatment was 78% in the sofosbuvir-and-ribavirin group (93% in genotype 2 patients and 61% in genotype 3 patients). Again, cirrhosis was associated with a lower rate of sustained virologic response (61% of patients with cirrhosis achieved a sustained virologic response vs 81% of patients without cirrhosis). None of the sofosbuvir-treated patients had virologic failure while on treatment.

FUSION,²⁰ another phase 3 trial, evaluated sofosbuvir in patients infected with HCV genotype 2 or 3 for whom interferon-based treatment had failed. They were randomized to either 12 weeks or 16 weeks of sofosbuvir and weight-based ribavirin treatment. About 60% of patients had HCV genotype 3, and 34% had cirrhosis.

The overall sustained virologic response rate was 50% in the patients treated for 12 weeks and 73% in those treated for 16 weeks: specifically, 86% of patients with genotype 2 achieved a sustained virologic response at 12 weeks and 94% at 16 weeks, whereas in those with genotype 3 the rates were 30% at 12 weeks and 62% at 16 weeks.

Cirrhosis was again a predictor of lack of response to sofosbuvir. In the group treated for 12 weeks, 31% of those with cirrhosis achieved a sustained virologic response compared with 61% in those without cirrhosis. In the group treated for 16 weeks, 61% of those with cirrhosis achieved a sustained virologic response compared with 76% in those without cirrhosis.

In both the POSITRON and FUSION trials, relapse accounted for all treatment failures, and no virologic resistance was detected in patients who did not have a sustained virologic response. The investigators concluded that 12 weeks of treatment with sofosbuvir and ribavirin can be effective for HCV genotype 2 infection, but extending the treatment to 16 weeks may be beneficial for genotype 3. This may be especially important in patients with cirrhosis or those who did not have a response to peg-interferon-based treatment.

VALENCE,²¹ an ongoing phase 3 trial in Europe, is assessing the safety and efficacy of sofosbuvir 400 mg once daily and weight-based ribavirin in patients with HCV genotype 2 or 3. Eighty-five percent of the trial participants have received previous treatment, and 21% have cirrhosis. Patients were originally randomized in a 4:1 ratio to receive sofosbuvir plus ribavirin for 12 weeks or matching placebo, but as a result of emerging data suggesting that patients with genotype 3 would benefit from more than 12 weeks of treatment, the study was subsequently amended to extend treatment to 24 weeks for patients with genotype 3.

Overall rates of sustained virologic response were 93% in patients with genotype 2 and 85% in patients with genotype 3. In previously treated patients with genotype 2 who were treated for 12 weeks, the rates of sustained virologic response were 91% in those without cirrhosis vs 88% in those with cirrhosis. In previously treated patients with genotype 3, the rates in those treated for 24 weeks were 87% in patients without cirrhosis vs 60% with cirrhosis. The safety profile was consistent with that of ribavirin.

Side effects of sofosbuvir

In clinical trials, side effects occurred most often when sofosbuvir was combined with interferon and ribavirin and were consistent with the known side effects of the latter two agents. The most frequently reported side effects included fatigue, insomnia, nausea, rash, anemia, headache, and arthralgia, with most of these adverse events rated by treating clinicians as being mild in severity.^15,20

In the ATOMIC trial, the most common events leading to drug discontinuation were anemia and neutropenia, both associated with interferon and ribavirin. Patients receiving sofosbuvir monotherapy after 12 weeks of triple therapy showed rapid improvement in hemoglobin levels and neutrophil counts, indicating that hematologic abnormalities attributed solely to sofosbuvir are minimal. In the FISSION trial, the incidence of adverse events was consistently lower in those receiving sofosbuvir-ribavirin than in patients receiving interferon-ribavirin without sofosbuvir.¹⁹

In the POSITRON trial, discontinuation of sofosbuvir because of adverse events was uncommon, and there were no differences in the incidence of adverse events and laboratory abnormalities between patients with and without cirrhosis when they received sofosbuvir and ribavirin.²⁰

Sofosbuvir dosage and indications

Sofosbuvir is approved in an oral dose of 400 mg once daily in combination with ribavirin for patients infected with HCV genotype 2 or 3 and in combination with ribavirin and interferon alfa in patients infected with HCV genotype 1 or 4 (Table 3). It could be considered for HCV genotype 1 in combination with ribavirin alone for 24 weeks in patients who are ineligible for interferon.

Sofosbuvir is also recommended in combination with ribavirin in HCV-infected patients with hepatocellular carcinoma who are awaiting liver transplantation, for up to 48 weeks or until they receive a transplant, to prevent posttransplant reinfection with HCV.

A course of therapy is expected to cost about $84,000, which is significantly more than the cost of previous triple therapy (peg-interferon, ribavirin, and either boceprevir or telaprevir).²² This high cost will undoubtedly lead to less widespread use in developing countries, and potentially even in the United States. As newer direct-acting antiviral agents become available, the price will likely come down, enhancing access to these drugs.

SIMEPREVIR: A SECOND-GENERATION PROTEASE INHIBITOR

Telaprevir and boceprevir are NS3/A4 protease inhibitors that belong to the alfa-ketoamid derivative class. Simeprevir belongs to the macrocyclic class and has a different way of binding to the target enzyme.²³ Like sofosbuvir, simeprevir was recently approved by the FDA for the treatment of HCV genotype 1.

The therapeutic efficacy of simeprevir has been tested in several clinical trials (Table 4), including QUEST-1²⁴ and QUEST-2²⁵ (in previously untreated patients), PROMISE²⁶ (in prior relapsers), and ASPIRE²⁷ (in prior partial and null responders). Results from these trials showed high overall rates of sustained virologic response with triple therapy (ie, simeprevir combined with peg-interferon and ribavirin). It was generally well tolerated, and most adverse events reported during 12 weeks of treatment were of mild to moderate severity.

In QUEST-1 and QUEST-2, both double-blind phase 3 clinical trials, previously untreated patients infected with HCV genotype 1 were randomized in a 2:1 ratio to receive either simeprevir 150 mg daily or placebo for 12 weeks; both groups also received peg-interferon and ribavirin. Patients then received peg-interferon and ribavirin alone for 12 or 36 weeks in the simeprevir group (based on response) and for 36 weeks in the placebo group.

The overall rate of sustained virologic response at 12 weeks was 80% in the simeprevir group (75% in those with genotype 1a and 85% in those with genotype 1b) vs 50% in the placebo group (receiving peg-interferon and ribavirin alone).^24,25

PROMISE,²⁶ another double-blind randomized phase 3 clinical trial, evaluated simeprevir in patients with HCV genotype 1 who relapsed after previous interferon-based therapy. It had a similar design to QUEST-1 and QUEST-2, and 15% of all patients had cirrhosis.

The overall sustained virologic response rate at 12 weeks after treatment was 79% in the simeprevir group (70% in patients with genotype 1a and 86% in those with genotype 1b) vs 37% in the placebo group. Rates were similar in patients with absent to moderate fibrosis (82%), advanced fibrosis (73%), or cirrhosis (74%).

ASPIRE.²⁷ Simeprevir efficacy in patients with HCV genotype 1 for whom previous therapy with peg-interferon and ribavirin had failed was tested in ASPIRE, a double-blind randomized phase 2 clinical trial. Patients were randomized to receive simeprevir (either 100 mg or 150 mg daily) for 12, 24, or 48 weeks in combination with 48 weeks of peg-interferon and ribavirin, or placebo plus peg-interferon and ribavirin for 48 weeks.

The primary end point was the rate of sustained virologic response at 24 weeks. Overall, rates were 61% to 80% for the simeprevir treatment groups compared with 23% with placebo, regardless of prior response to peg-interferon and ribavirin. By subgroup, rates were:

• 77% to 89% with simeprevir vs 37% with placebo in prior relapsers
• 48% to 86% with simeprevir vs 9% with placebo in prior partial responders
• 38% to 59% with placebo vs 19% for prior nonresponders.

The best rates of sustained viral response at 24 weeks were in the groups that received simeprevir 150 mg daily: 85% in prior relapsers, 75% in prior partial responders, and 51% in prior nonresponders.

Simeprevir vs other direct-acting antiviral drugs

Advantages of simeprevir over the earlier protease inhibitors include once-daily dosing, a lower rate of adverse events (the most common being fatigue, headache, rash, photosensitivity, and pruritus), a lower likelihood of discontinuation because of adverse events, and fewer drug-drug interactions (since it is a weak inhibitor of the CYP3A4 enzyme).

Unlike sofosbuvir, simeprevir was FDA-approved only for HCV genotype 1 and in combination with interferon alfa and ribavirin. Compared with sofosbuvir, the treatment duration with simeprevir regimens is longer overall (interferon alfa and ribavirin are given for 12 weeks in sofosbuvir-based regimens vs 24 to 48 weeks with simeprevir). As with sofosbuvir, the estimated cost of simeprevir is high, about $66,000 for a 12-week course.

Simeprevir dosage and indications

Simeprevir was approved at an oral dose of 150 mg once daily in combination with ribavirin and interferon alfa in patients with HCV genotype 1 (Table 5).

The approved regimens for simeprevir are fixed in total duration based on the patient’s treatment history. Specifically, all patients receive the drug in combination with peg-interferon and ribavirin for 12 weeks. Then, previously untreated patients and prior relapsers continue to receive peg-interferon and ribavirin alone for another 12 weeks, and those with a partial or null response continue with these drugs for another 36 weeks.

Patients infected with HCV genotype 1a should be screened for the NS3 Q80K polymorphism at baseline, as it has been associated with substantially reduced response to simeprevir.

Sofosbuvir and simeprevir in combination

The COSMOS trial.²⁸ Given their differences in mechanism of action, sofosbuvir and simeprevir are being tested in combination. The COSMOS trial is an ongoing phase 2 randomized open-label study investigating the efficacy and safety of simeprevir and sofosbuvir in combination with and without ribavirin in patients with HCV genotype 1, including nonresponders and those with cirrhosis. Early results are promising, with very high rates of sustained virologic response with the sofosbuvir-simeprevir combination (93% to 100%) and indicate that the addition of ribavirin might not be needed to achieve sustained virologic response in this patient population.

THE FUTURE

The emergence of all-oral regimens for HCV treatment with increasingly sophisticated agents such as sofosbuvir and simeprevir will dramatically alter the management of HCV patients. In view of the improvement in sustained virologic response rates with these treatments, and since most HCV-infected persons have no symptoms, the US Centers for Disease Control and Prevention²⁹ recently recommended one-time testing of the cohort in which the prevalence of HCV infection is highest: all persons born between 1945 and 1965. This undoubtedly will increase the detection of this infection—and the number of new patients expecting treatment.

Future drugs promise further improvements (Table 6).^30–35 Advances in knowledge of the HCV molecular structure have led to the development of numerous direct-acting antiviral agents with very specific viral targets. A second wave of protease inhibitors and of nucleoside and nonnucleoside polymerase inhibitors will soon be available. Inhibitors of NS5A (a protein important in the assembly of the viral replication complex) such as daclatasvir and ledipasvir, are currently in phase 3 clinical trials. Other viral proteins involved in assembly of the virus, including the core protein and p7, are being explored as drug targets. In addition, inhibiting host targets such as cyclophilin A and miR122 has gained traction recently, with specific agents currently in phase 2 and 3 clinical trials.

Factors that previously were major determinants of response to treatment, such as IL28B genotype, viral load, race, age, extent of fibrosis, and genotype 1 subtypes, will become much less important with the introduction of highly potent direct-acting antiviral agents.

Many all-oral combinations are being evaluated in clinical trials. For example, the open-label, phase 2 LONESTAR trial tested the utility of combining sofosbuvir and ledipasvir (an NS5A inhibitor) with and without ribavirin for 8 or 12 weeks in previously untreated patients with HCV genotype 1, and for 12 weeks in patients with HCV genotype 1 who did not achieve a sustained virologic response after receiving a protease inhibitor-based regimen (half of whom had compensated cirrhosis).³⁶ Sustained virologic response rates were very high (95% to 100%) in both previously treated and previously untreated patients, including those with cirrhosis. Similar rates were achieved by the 8-week and 12-week groups in noncirrhotic patients who had not been previously treated for HCV. The typical hematologic abnormalities associated with interferon were not observed except for mild anemia in patients who received ribavirin. These results suggest that the combination of sofosbuvir and ledipasvir could offer a very effective, short, all-oral treatment for patients with HCV genotype 1, including those with cirrhosis, who up to now have been difficult to treat.

Challenges remaining

The success of sofosbuvir and simeprevir paves the way for interferon-free regimens.³⁷ For a long time, the treatment of HCV infection required close monitoring of patients while managing the side effects of interferon, but the current and emerging direct-acting antiviral agents will soon change this practice. Given the synergistic effects of combination therapy—targeting the virus at multiple locations, decreasing the likelihood of drug resistance, and improving efficacy—combination regimens seem to be the optimal solution to the HCV epidemic. Lower risk of side effects and shorter treatment duration will definitely improve the acceptance of any new regimen. New agents that act against conserved viral targets, thereby yielding activity across multiple genotypes, will be advantageous as well. Table 7 compares the rates of sustained virologic response of the different currently approved HCV treatment regimens.

Clinical challenges remain, including the management of special patient populations for whom data are still limited. These include patients with cirrhosis, chronic kidney disease, renal failure, and concurrent infection with human immunodeficiency virus, and patients who have undergone solid organ transplantation. Clinical trials are under way to evaluate the treatment options for these patients, who will likely need to wait for the emergence of additional agents before dramatic improvement in sustained virologic response rates may be expected.38

As the treatment of HCV becomes simpler, safer, and more effective, primary care physicians will increasingly be expected to manage it. Difficult-to-treat patients, including the special populations above, will require specialist management and individualized treatment regimens, at least until better therapies are available. The high projected cost of the new agents may limit access, at least initially. However, the dramatic improvement in sustained virologic response rates and all that that implies in terms of decreased risk of advanced liver disease and its complications will undoubtedly make these therapies cost-effective.³⁹

In late 2013, the US Food and Drug Administration (FDA) approved sofosbuvir and simeprevir, the newest direct-acting antiviral agents for treating chronic hepatitis C virus (HCV) infection. Multiple clinical trials have demonstrated dramatically improved treatment outcomes with these agents, opening the door to all-oral regimens or interferon-free regimens as the future standard of care for HCV.

See related editorial

In this article, we discuss the results of the trials that established the efficacy and safety of sofosbuvir and simeprevir and led to their FDA approval. We also summarize the importance of these agents and evaluate other direct-acting antivirals currently in the pipeline for HCV treatment.

HCV IS A RISING PROBLEM

Chronic HCV infection is a major clinical and public health problem, with the estimated number of people infected exceeding 170 million worldwide, including 3.2 million in the United States.¹ It is a leading cause of cirrhosis, and its complications include hepatocellular carcinoma and liver failure. Cirrhosis due to HCV remains the leading indication for liver transplantation in the United States, accounting for nearly 40% of liver transplants in adults.²

The clinical impact of HCV will only continue to escalate, and in parallel, so will the cost to society. Models suggest that HCV-related deaths will double between 2010 and 2019, and considering only direct medical costs, the projected financial burden of treating HCV-related disease during this interval is estimated at between $6.5 and $13.6 billion.³

AN RNA VIRUS WITH SIX GENOTYPES

HCV, first identified in 1989, is an enveloped, single-stranded RNA flavivirus of the Hepacivirus genus measuring 50 to 60 nm in diameter.⁴ There are six viral genotypes, with genotype 1 being the most common in the United States and traditionally the most difficult to treat.

Once inside the host cell, the virus releases its RNA strand, which is translated into a single polyprotein of about 3,000 amino acids. This large molecule is then cleaved by proteases into several domains: three structural proteins (C, E1, and E2), a small protein called p7, and six nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) (Figure 1).⁵ These nonstructural proteins enable the virus to replicate.

GOAL OF TREATING HCV: A SUSTAINED VIROLOGIC RESPONSE

The aim of HCV treatment is to achieve a sustained virologic response, defined as having no detectable viral RNA after completion of antiviral therapy. This is associated with substantially better clinical outcomes, lower rates of liver-related morbidity and all-cause mortality, and stabilization of or even improvement in liver histology.^6,7 This end point has traditionally been assessed at 6 months after the end of therapy, but recent data suggest the rates at 12 weeks are essentially equivalent.

Table 1 summarizes the patterns of virologic response in treating HCV infection.

Interferon plus ribavirin: The standard of care for many years

HCV treatment has evolved over the past 20 years. Before 2011, the standard of care was a combination of interferon alfa-polyethylene glycol (peg-interferon), given as a weekly injection, and oral ribavirin. Neither drug has specific antiviral activity, and when they are used together they result in a sustained virologic response in fewer than 50% of patients with HCV genotype 1 and, at best, in 70% to 80% of patients with other genotypes.⁸

Nearly all patients receiving interferon experience side effects, which can be serious. Fatigue and flu-like symptoms are common, and the drug can also cause psychiatric symptoms (including depression or psychosis), weight loss, seizures, peripheral neuropathy, and bone marrow suppression. Ribavirin causes hemolysis and skin complications and is teratogenic.⁹

An important bit of information to know when using interferon is the patient’s IL28B genotype. This refers to a single-nucleotide polymorphism (C or T) on chromosome 19q13 (rs12979860) upstream of the IL28B gene encoding for interferon lambda-3. It is strongly associated with responsiveness to interferon: patients with the IL28B CC genotype have a much better chance of a sustained virologic response with interferon than do patients with CT or TT.

In May 2011, the FDA approved the NS3/4A protease inhibitors boceprevir and telaprevir for treating HCV genotype 1, marking the beginning of the era of direct-acting antiviral agents.¹⁰ When these drugs are used in combination with peg-interferon alfa and ribavirin, up to 75% of patients with HCV genotype 1 who have had no previous treatment achieve a sustained virologic response.

But despite greatly improving the response rate, these first-generation protease inhibitors have substantial limitations. Twenty-five percent of patients with HCV genotype 1 who have received no previous treatment and 71% of patients who did not respond to previous treatment will not achieve a sustained virologic response with these agents.¹¹ Further, they are effective only against HCV genotype 1, being highly specific for the amino acid target sequence of the NS3 region.

Also, they must be used in combination with interferon alfa and ribavirin because the virus needs to mutate only a little—a few amino-acid substitutions—to gain resistance to them.¹² Therefore, patients are still exposed to interferon and ribavirin, with their toxicity. In addition, dysgeusia is seen with boceprevir, rash with telaprevir, and anemia with both.^13,14

Finally, serious drug-drug interactions prompted the FDA to impose warnings for the use of these agents with other medications that interact with CYP3A4, the principal enzyme responsible for their metabolism. Thus, these significant adverse effects dampen the enthusiasm of patients contemplating a long course of treatment with these agents.

The need to improve the rate of sustained virologic response, shorten the duration of treatment, avoid serious side effects, improve efficacy in treating patients infected with genotypes other than 1, and, importantly, eliminate the need for interferon alfa and its serious adverse effects have driven the development of new direct-acting antiviral agents, including the two newly FDA-approved drugs, sofosbuvir and simeprevir.

SOFOSBUVIR: A POLYMERASE INHIBITOR

Sofosbuvir is a uridine nucleotide analogue that selectively inhibits the HCV NS5B RNA-dependent RNA polymerase (Figure 1). It targets the highly conserved nucleotide-binding pocket of this enzyme and functions as a chain terminator.¹⁵ While the protease inhibitors are genotype-dependent, inhibition of the highly conserved viral polymerase has an impact that spans genotypes.

Early clinical trials of sofosbuvir

Sofosbuvir has been tested in combination with interferon alfa and ribavirin, as well as in interferon-free regimens (Table 2).^16–20

Rodriguez-Torres et al,¹⁵

• 56% with sofosbuvir 100 mg, peg-interferon, and ribavirin
• 83% with sofosbuvir 200 mg, peg-interferon, and ribavirin
• 80% with sofosbuvir 400 mg, peg-interferon, and ribavirin
• 43% with peg-interferon and ribavirin alone.

The ATOMIC trial¹⁶ tested the efficacy and safety of sofosbuvir in combination with peg-interferon and ribavirin in patients with HCV genotype 1, 4, or 6, without cirrhosis, who had not received any previous treatment. Patients with HCV genotype 1 were randomized to three treatments:

• Sofosbuvir 400 mg orally once daily plus peg-interferon and ribavirin for 12 weeks
• The same regimen, but for 24 weeks
• Sofosbuvir plus peg-interferon and ribavirin for 12 weeks, followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin.

The rates of sustained virologic response were very high and were not significantly different among the three groups: 89%, 89%, and 87%, respectively. Patients who were able to complete a full course of therapy achieved even higher rates of sustained virologic response, ranging from 96% to 98%. The likelihood of response was not adversely affected by the usual markers of a poorer prognosis, such as a high viral load (≥ 800,000 IU/mL) or a non-CC IL28B genotype. Although patients with cirrhosis (another predictor of no response) were excluded from this study, the presence of bridging fibrosis did not seem to affect the rate of sustained virologic response. The results in patients with genotypes other than 1 were very encouraging, but the small number of patients enrolled precluded drawing firm conclusions in this group.

Important implications of the ATOMIC trial include the following:

There is no benefit in prolonging treatment with sofosbuvir beyond 12 weeks, since adverse events increased without any improvement in the rate of sustained virologic response.

There is a very low likelihood of developing viral resistance or mutation when using sofosbuvir.

There is no role for response-guided therapy, a concept used with protease inhibitor-based regimens in which patients who have complete clearance of the virus within the first 4 weeks of treatment (a rapid virologic response) and remain clear through 12 weeks of treatment (an extended rapid viral response) can be treated for a shorter duration without decreasing the likelihood of a sustained virologic response.

Lawitz et al¹⁷ conducted a randomized double-blind phase 2 trial to evaluate the effect of sofosbuvir dosing on response in noncirrhotic, previously untreated patients with HCV genotype 1, 2, or 3. Patients with HCV genotype 1 were randomized to one of three treatment groups in a 2:2:1 ratio: sofosbuvir 200 mg orally once daily, sofosbuvir 400 mg orally once daily, or placebo, all for 12 weeks in combination with peg-interferon (180 μg weekly) and ribavirin in a dosage based on weight. Depending on the viral response, patients continued peg-interferon and ribavirin for an additional 12 weeks if they achieved an extended rapid viral response, or 36 weeks if they did not achieve an extended rapid virologic response, and in all patients who received placebo. Patients with HCV genotype 2 or 3 were given sofosbuvir 400 mg once daily in combination with interferon and ribavirin for 12 weeks.

As in the ATOMIC trial, all patients treated with sofosbuvir had a very rapid reduction in viral load: 98% of patients with genotype 1 developed a rapid virologic response, and therefore almost all were eligible for the shorter treatment course of 24 weeks.¹⁷ The latter finding again suggested that response-guided treatment is not relevant with sofosbuvir-based regimens.

Very high rates of sustained virologic response were seen: 90% in patients with genotype 1 treated with sofosbuvir 200 mg, 91% in those with genotype 1 treated with 400 mg, and 92% in those with genotype 2 or 3. Although 6% of patients in the 200-mg group had virologic breakthrough after completing sofosbuvir treatment, no virologic breakthrough was observed in the 400-mg group, suggesting that the 400-mg dose might suppress the virus more effectively.¹⁷

The ELECTRON trial¹⁸ was a phase 2 study designed to evaluate the efficacy and safety of sofosbuvir and ribavirin in interferon-sparing and interferon-free regimens in patients with HCV genotype 1, 2, or 3 infection. Sofosbuvir was tested with peg-interferon and ribavirin, with ribavirin alone, and as monotherapy in previously untreated patients with genotype 2 or 3. A small number of patients with genotype 1 who were previously untreated and who were previously nonresponders were also treated with sofosbuvir and ribavirin.

All patients had a rapid virologic response, and viral suppression was sustained through the end of treatment. All patients with genotype 2 or 3 treated with double therapy (sofosbuvir and ribavirin) or triple therapy (sofosbuvir, peg-interferon, and ribavirin) achieved a sustained virologic response, compared with only 60% of patients treated with sofosbuvir monotherapy. The monotherapy group had an equal number of relapsers among those with genotype 2 or 3. Of the genotype 1 patients treated with sofosbuvir and ribavirin, 84% of those previously untreated developed a sustained virologic response, whereas only 10% of the previous nonresponders did.

The NEUTRINO trial¹⁹ studied the efficacy and safety of sofosbuvir in previously untreated patients with HCV genotype 1, 4, 5, or 6. In this phase 3 open-label study, all patients received sofosbuvir plus peg-interferon and weight-based ribavirin therapy for 12 weeks. Of the patients enrolled, 89% had genotype 1, while 9% had genotype 4 and 2% had genotype 5 or 6. Overall, 17% of the patients had cirrhosis.

The viral load rapidly decreased in all patients treated with sofosbuvir irrespective of the HCV genotype, IL28B status, race, or the presence or absence of cirrhosis. Ninety-nine percent of patients with genotype 1, 4, 5, or 6 achieved a rapid virologic response, and 90% achieved a sustained virologic response at 12 weeks after completion of treatment with sofosbuvir and ribavirin. Patients with cirrhosis had a slightly lower rate of sustained virologic response (80%, compared with 92% in patients without cirrhosis). Also, patients with non-CC IL28B genotypes had a lower rate of sustained virologic response (87% in non-CC allele vs 98% in patients with the favorable CC allele).

The FISSION trial¹⁹ recruited previously untreated patients with genotype 2 or 3 and randomized them to therapy with either sofosbuvir plus ribavirin in a weight-based dose for 12 weeks, or 24 weeks of interferon and ribavirin. In this study, 20% of patients in each treatment group had cirrhosis.

As in the NEUTRINO trial, the viral load rapidly decreased in all patients treated with sofosbuvir irrespective of HCV genotype, IL28B status, race, or the presence or absence of cirrhosis. Here, 100% of patients with genotype 2 or 3 who were treated with sofosbuvir and ribavirin achieved a rapid virologic response. Differences in outcome emerged based on genotype: 97% of those with genotype 2 and 56% of those with genotype 3 achieved a sustained virologic response. The overall rate was 67%, which was not different from patients treated with peg-interferon and ribavirin. In the subgroup of patients with cirrhosis, 47% of those treated with sofosbuvir and ribavirin achieved a sustained virologic response, vs 38% of those who received peg-interferon plus ribavirin.

In both the NEUTRINO and FISSION trials, few patients discontinued treatment, with higher rates of most adverse events occurring in patients treated with peg-interferon and ribavirin.

POSITRON,²⁰ a phase 3 clinical trial, tested sofosbuvir in patients with HCV genotype 2 or 3 who were ineligible for peg-interferon, unwilling to take peg-interferon, or unable to tolerate peg-interferon (mainly because of clinically significant psychiatric disorders). Patients were randomized to two treatment groups for 12 weeks: sofosbuvir plus ribavirin, or placebo. About 50% of patients had HCV genotype 3, and 16% had cirrhosis.

The overall rate of sustained virologic response at 12 weeks after treatment was 78% in the sofosbuvir-and-ribavirin group (93% in genotype 2 patients and 61% in genotype 3 patients). Again, cirrhosis was associated with a lower rate of sustained virologic response (61% of patients with cirrhosis achieved a sustained virologic response vs 81% of patients without cirrhosis). None of the sofosbuvir-treated patients had virologic failure while on treatment.

FUSION,²⁰ another phase 3 trial, evaluated sofosbuvir in patients infected with HCV genotype 2 or 3 for whom interferon-based treatment had failed. They were randomized to either 12 weeks or 16 weeks of sofosbuvir and weight-based ribavirin treatment. About 60% of patients had HCV genotype 3, and 34% had cirrhosis.

The overall sustained virologic response rate was 50% in the patients treated for 12 weeks and 73% in those treated for 16 weeks: specifically, 86% of patients with genotype 2 achieved a sustained virologic response at 12 weeks and 94% at 16 weeks, whereas in those with genotype 3 the rates were 30% at 12 weeks and 62% at 16 weeks.

Cirrhosis was again a predictor of lack of response to sofosbuvir. In the group treated for 12 weeks, 31% of those with cirrhosis achieved a sustained virologic response compared with 61% in those without cirrhosis. In the group treated for 16 weeks, 61% of those with cirrhosis achieved a sustained virologic response compared with 76% in those without cirrhosis.

In both the POSITRON and FUSION trials, relapse accounted for all treatment failures, and no virologic resistance was detected in patients who did not have a sustained virologic response. The investigators concluded that 12 weeks of treatment with sofosbuvir and ribavirin can be effective for HCV genotype 2 infection, but extending the treatment to 16 weeks may be beneficial for genotype 3. This may be especially important in patients with cirrhosis or those who did not have a response to peg-interferon-based treatment.

VALENCE,²¹ an ongoing phase 3 trial in Europe, is assessing the safety and efficacy of sofosbuvir 400 mg once daily and weight-based ribavirin in patients with HCV genotype 2 or 3. Eighty-five percent of the trial participants have received previous treatment, and 21% have cirrhosis. Patients were originally randomized in a 4:1 ratio to receive sofosbuvir plus ribavirin for 12 weeks or matching placebo, but as a result of emerging data suggesting that patients with genotype 3 would benefit from more than 12 weeks of treatment, the study was subsequently amended to extend treatment to 24 weeks for patients with genotype 3.

Overall rates of sustained virologic response were 93% in patients with genotype 2 and 85% in patients with genotype 3. In previously treated patients with genotype 2 who were treated for 12 weeks, the rates of sustained virologic response were 91% in those without cirrhosis vs 88% in those with cirrhosis. In previously treated patients with genotype 3, the rates in those treated for 24 weeks were 87% in patients without cirrhosis vs 60% with cirrhosis. The safety profile was consistent with that of ribavirin.

Side effects of sofosbuvir

In clinical trials, side effects occurred most often when sofosbuvir was combined with interferon and ribavirin and were consistent with the known side effects of the latter two agents. The most frequently reported side effects included fatigue, insomnia, nausea, rash, anemia, headache, and arthralgia, with most of these adverse events rated by treating clinicians as being mild in severity.^15,20

In the ATOMIC trial, the most common events leading to drug discontinuation were anemia and neutropenia, both associated with interferon and ribavirin. Patients receiving sofosbuvir monotherapy after 12 weeks of triple therapy showed rapid improvement in hemoglobin levels and neutrophil counts, indicating that hematologic abnormalities attributed solely to sofosbuvir are minimal. In the FISSION trial, the incidence of adverse events was consistently lower in those receiving sofosbuvir-ribavirin than in patients receiving interferon-ribavirin without sofosbuvir.¹⁹

In the POSITRON trial, discontinuation of sofosbuvir because of adverse events was uncommon, and there were no differences in the incidence of adverse events and laboratory abnormalities between patients with and without cirrhosis when they received sofosbuvir and ribavirin.²⁰

Sofosbuvir dosage and indications

Sofosbuvir is approved in an oral dose of 400 mg once daily in combination with ribavirin for patients infected with HCV genotype 2 or 3 and in combination with ribavirin and interferon alfa in patients infected with HCV genotype 1 or 4 (Table 3). It could be considered for HCV genotype 1 in combination with ribavirin alone for 24 weeks in patients who are ineligible for interferon.

Sofosbuvir is also recommended in combination with ribavirin in HCV-infected patients with hepatocellular carcinoma who are awaiting liver transplantation, for up to 48 weeks or until they receive a transplant, to prevent posttransplant reinfection with HCV.

A course of therapy is expected to cost about $84,000, which is significantly more than the cost of previous triple therapy (peg-interferon, ribavirin, and either boceprevir or telaprevir).²² This high cost will undoubtedly lead to less widespread use in developing countries, and potentially even in the United States. As newer direct-acting antiviral agents become available, the price will likely come down, enhancing access to these drugs.

SIMEPREVIR: A SECOND-GENERATION PROTEASE INHIBITOR

Telaprevir and boceprevir are NS3/A4 protease inhibitors that belong to the alfa-ketoamid derivative class. Simeprevir belongs to the macrocyclic class and has a different way of binding to the target enzyme.²³ Like sofosbuvir, simeprevir was recently approved by the FDA for the treatment of HCV genotype 1.

The therapeutic efficacy of simeprevir has been tested in several clinical trials (Table 4), including QUEST-1²⁴ and QUEST-2²⁵ (in previously untreated patients), PROMISE²⁶ (in prior relapsers), and ASPIRE²⁷ (in prior partial and null responders). Results from these trials showed high overall rates of sustained virologic response with triple therapy (ie, simeprevir combined with peg-interferon and ribavirin). It was generally well tolerated, and most adverse events reported during 12 weeks of treatment were of mild to moderate severity.

In QUEST-1 and QUEST-2, both double-blind phase 3 clinical trials, previously untreated patients infected with HCV genotype 1 were randomized in a 2:1 ratio to receive either simeprevir 150 mg daily or placebo for 12 weeks; both groups also received peg-interferon and ribavirin. Patients then received peg-interferon and ribavirin alone for 12 or 36 weeks in the simeprevir group (based on response) and for 36 weeks in the placebo group.

The overall rate of sustained virologic response at 12 weeks was 80% in the simeprevir group (75% in those with genotype 1a and 85% in those with genotype 1b) vs 50% in the placebo group (receiving peg-interferon and ribavirin alone).^24,25

PROMISE,²⁶ another double-blind randomized phase 3 clinical trial, evaluated simeprevir in patients with HCV genotype 1 who relapsed after previous interferon-based therapy. It had a similar design to QUEST-1 and QUEST-2, and 15% of all patients had cirrhosis.

The overall sustained virologic response rate at 12 weeks after treatment was 79% in the simeprevir group (70% in patients with genotype 1a and 86% in those with genotype 1b) vs 37% in the placebo group. Rates were similar in patients with absent to moderate fibrosis (82%), advanced fibrosis (73%), or cirrhosis (74%).

ASPIRE.²⁷ Simeprevir efficacy in patients with HCV genotype 1 for whom previous therapy with peg-interferon and ribavirin had failed was tested in ASPIRE, a double-blind randomized phase 2 clinical trial. Patients were randomized to receive simeprevir (either 100 mg or 150 mg daily) for 12, 24, or 48 weeks in combination with 48 weeks of peg-interferon and ribavirin, or placebo plus peg-interferon and ribavirin for 48 weeks.

The primary end point was the rate of sustained virologic response at 24 weeks. Overall, rates were 61% to 80% for the simeprevir treatment groups compared with 23% with placebo, regardless of prior response to peg-interferon and ribavirin. By subgroup, rates were:

• 77% to 89% with simeprevir vs 37% with placebo in prior relapsers
• 48% to 86% with simeprevir vs 9% with placebo in prior partial responders
• 38% to 59% with placebo vs 19% for prior nonresponders.

The best rates of sustained viral response at 24 weeks were in the groups that received simeprevir 150 mg daily: 85% in prior relapsers, 75% in prior partial responders, and 51% in prior nonresponders.

Simeprevir vs other direct-acting antiviral drugs

Advantages of simeprevir over the earlier protease inhibitors include once-daily dosing, a lower rate of adverse events (the most common being fatigue, headache, rash, photosensitivity, and pruritus), a lower likelihood of discontinuation because of adverse events, and fewer drug-drug interactions (since it is a weak inhibitor of the CYP3A4 enzyme).

Unlike sofosbuvir, simeprevir was FDA-approved only for HCV genotype 1 and in combination with interferon alfa and ribavirin. Compared with sofosbuvir, the treatment duration with simeprevir regimens is longer overall (interferon alfa and ribavirin are given for 12 weeks in sofosbuvir-based regimens vs 24 to 48 weeks with simeprevir). As with sofosbuvir, the estimated cost of simeprevir is high, about $66,000 for a 12-week course.

Simeprevir dosage and indications

Simeprevir was approved at an oral dose of 150 mg once daily in combination with ribavirin and interferon alfa in patients with HCV genotype 1 (Table 5).

The approved regimens for simeprevir are fixed in total duration based on the patient’s treatment history. Specifically, all patients receive the drug in combination with peg-interferon and ribavirin for 12 weeks. Then, previously untreated patients and prior relapsers continue to receive peg-interferon and ribavirin alone for another 12 weeks, and those with a partial or null response continue with these drugs for another 36 weeks.

Patients infected with HCV genotype 1a should be screened for the NS3 Q80K polymorphism at baseline, as it has been associated with substantially reduced response to simeprevir.

Sofosbuvir and simeprevir in combination

The COSMOS trial.²⁸ Given their differences in mechanism of action, sofosbuvir and simeprevir are being tested in combination. The COSMOS trial is an ongoing phase 2 randomized open-label study investigating the efficacy and safety of simeprevir and sofosbuvir in combination with and without ribavirin in patients with HCV genotype 1, including nonresponders and those with cirrhosis. Early results are promising, with very high rates of sustained virologic response with the sofosbuvir-simeprevir combination (93% to 100%) and indicate that the addition of ribavirin might not be needed to achieve sustained virologic response in this patient population.

THE FUTURE

The emergence of all-oral regimens for HCV treatment with increasingly sophisticated agents such as sofosbuvir and simeprevir will dramatically alter the management of HCV patients. In view of the improvement in sustained virologic response rates with these treatments, and since most HCV-infected persons have no symptoms, the US Centers for Disease Control and Prevention²⁹ recently recommended one-time testing of the cohort in which the prevalence of HCV infection is highest: all persons born between 1945 and 1965. This undoubtedly will increase the detection of this infection—and the number of new patients expecting treatment.

Future drugs promise further improvements (Table 6).^30–35 Advances in knowledge of the HCV molecular structure have led to the development of numerous direct-acting antiviral agents with very specific viral targets. A second wave of protease inhibitors and of nucleoside and nonnucleoside polymerase inhibitors will soon be available. Inhibitors of NS5A (a protein important in the assembly of the viral replication complex) such as daclatasvir and ledipasvir, are currently in phase 3 clinical trials. Other viral proteins involved in assembly of the virus, including the core protein and p7, are being explored as drug targets. In addition, inhibiting host targets such as cyclophilin A and miR122 has gained traction recently, with specific agents currently in phase 2 and 3 clinical trials.

Factors that previously were major determinants of response to treatment, such as IL28B genotype, viral load, race, age, extent of fibrosis, and genotype 1 subtypes, will become much less important with the introduction of highly potent direct-acting antiviral agents.

Many all-oral combinations are being evaluated in clinical trials. For example, the open-label, phase 2 LONESTAR trial tested the utility of combining sofosbuvir and ledipasvir (an NS5A inhibitor) with and without ribavirin for 8 or 12 weeks in previously untreated patients with HCV genotype 1, and for 12 weeks in patients with HCV genotype 1 who did not achieve a sustained virologic response after receiving a protease inhibitor-based regimen (half of whom had compensated cirrhosis).³⁶ Sustained virologic response rates were very high (95% to 100%) in both previously treated and previously untreated patients, including those with cirrhosis. Similar rates were achieved by the 8-week and 12-week groups in noncirrhotic patients who had not been previously treated for HCV. The typical hematologic abnormalities associated with interferon were not observed except for mild anemia in patients who received ribavirin. These results suggest that the combination of sofosbuvir and ledipasvir could offer a very effective, short, all-oral treatment for patients with HCV genotype 1, including those with cirrhosis, who up to now have been difficult to treat.

Challenges remaining

The success of sofosbuvir and simeprevir paves the way for interferon-free regimens.³⁷ For a long time, the treatment of HCV infection required close monitoring of patients while managing the side effects of interferon, but the current and emerging direct-acting antiviral agents will soon change this practice. Given the synergistic effects of combination therapy—targeting the virus at multiple locations, decreasing the likelihood of drug resistance, and improving efficacy—combination regimens seem to be the optimal solution to the HCV epidemic. Lower risk of side effects and shorter treatment duration will definitely improve the acceptance of any new regimen. New agents that act against conserved viral targets, thereby yielding activity across multiple genotypes, will be advantageous as well. Table 7 compares the rates of sustained virologic response of the different currently approved HCV treatment regimens.

Clinical challenges remain, including the management of special patient populations for whom data are still limited. These include patients with cirrhosis, chronic kidney disease, renal failure, and concurrent infection with human immunodeficiency virus, and patients who have undergone solid organ transplantation. Clinical trials are under way to evaluate the treatment options for these patients, who will likely need to wait for the emergence of additional agents before dramatic improvement in sustained virologic response rates may be expected.38

As the treatment of HCV becomes simpler, safer, and more effective, primary care physicians will increasingly be expected to manage it. Difficult-to-treat patients, including the special populations above, will require specialist management and individualized treatment regimens, at least until better therapies are available. The high projected cost of the new agents may limit access, at least initially. However, the dramatic improvement in sustained virologic response rates and all that that implies in terms of decreased risk of advanced liver disease and its complications will undoubtedly make these therapies cost-effective.³⁹