Norman L. Beatty, MD

From the University of Florida College of Medicine, Division of Infectious Diseases and Global Medicine, Gainesville, FL.

Abstract

• Objective: To review current reports on atypical manifestations of coronavirus disease 2019 (COVID-19).
• Methods: Review of the literature.
• Results: Evidence regarding atypical features of COVID-19 is accumulating. SARS-CoV-2 can infect human cells that express the angiotensin-converting enzyme 2 receptor, which would allow for a broad spectrum of illnesses affecting the renal, cardiac, and gastrointestinal organ systems. Neurologic, cutaneous, and musculoskeletal manifestations have also been reported. The potential for SARS-CoV-2 to induce a hypercoagulable state provides another avenue for the virus to indirectly damage various organ systems, as evidenced by reports of cerebrovascular disease, myocardial injury, and a chilblain-like rash in patients with COVID-19.
• Conclusion: Because the signs and symptoms of COVID-19 may occur with varying frequency across populations, it is important to keep differentials broad when assessing patients with a clinical illness that may indeed be COVID-19.

Keywords: coronavirus; severe acute respiratory syndrome coronavirus-2; SARS-CoV-2; pandemic.

Coronavirus disease 2019 (COVID-19), the syndrome caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was first reported in Wuhan, China, in early December 2019.¹ Since then, the virus has spread quickly around the world, with the World Health Organization (WHO) declaring the coronavirus outbreak a global pandemic on March 11, 2020. As of May 21, 2020, more than 5,000,000 cases of COVID-19 have been confirmed, and more than 328,000 deaths related to COVID-19 have been reported globally.² These numbers are expected to increase, due to the reproduction number (R0) of SARS-CoV-2. R0 represents the number of new infections generated by an infectious person in a totally naïve population.³ The WHO estimates that the R0 of SARS-CoV-2 is 1.95, with other estimates ranging from 1.4 to 6.49.³ To control the pathogen, the R0 needs to be brought under a value of 1.

A fundamental tool in lowering the R0 is prompt testing and isolation of those who display signs and symptoms of infection. SARS-CoV-2 is still a novel pathogen about which we know relatively little. The common symptoms of COVID-19 are now well known—including fever, fatigue, anorexia, cough, and shortness of breath—but atypical manifestations of this viral continue to be reported and described. To help clinicians across specialties and settings identify patients with possible infection, we have summarized findings from current reports on COVID-19 manifestations involving the renal, cardiac, gastrointestinal (GI), and other organ systems.

Renal

During the 2003 SARS-CoV-1 outbreak, acute kidney injury (AKI) was an uncommon complication of the infection, but early reports suggest that AKI may occur more commonly with COVID-19.⁴ In a study of 193 patients with laboratory-confirmed COVID-19 treated in 3 Chinese hospitals, 59% presented with proteinuria, 44% with hematuria, 14% with increased blood urea nitrogen, and 10% with increased levels of serum creatinine.⁴ These markers, indicative of AKI, may be associated with increased mortality. Among this cohort, those with AKI had a mortality risk 5.3 times higher than those who did not have AKI.⁴ The pathophysiology of renal disease in COVID-19 may be related to dehydration or inflammatory mediators, causing decreased renal perfusion and cytokine storm, but evidence also suggests that SARS-CoV-2 is able to directly infect kidney cells.⁵ The virus infects cells by using angiotensin-converting enzyme 2 (ACE2) on the cell membrane as a cell entry receptor; ACE2 is expressed on the kidney, heart, and GI cells, and this may allow SARS-CoV-2 to directly infect and damage these organs. Other potential mechanisms of renal injury include overproduction of proinflammatory cytokines and administration of nephrotoxic drugs. No matter the mechanism, however, increased serum creatinine and blood urea nitrogen correlate with an increased likelihood of requiring intensive care unit (ICU) admission.⁶ Therefore, clinicians should carefully monitor renal function in patients with COVID-19.

Cardiac

In a report of 138 Chinese patients hospitalized for COVID-19, 36 required ICU admission: 44.4% of these had arrhythmias and 22.2% had developed acute cardiac injury.⁶ In addition, the cardiac cell injury biomarker troponin I was more likely to be elevated in ICU patients.⁶ A study of 21 patients admitted to the ICU in Washington State found elevated levels of brain natriuretic peptide.⁷ These biomarkers reflect the presence of myocardial stress, but do not necessarily indicate direct myocardial infection. Case reports of fulminant myocarditis in those with COVID-19 have begun to surface, however.^8,9 An examination of 68 deaths in persons with COVID-19 concluded that 7% were caused by myocarditis with circulatory failure.¹⁰

The pathophysiology of myocardial injury in COVID-19 is likely multifactorial. This includes increased inflammatory mediators, hypoxemia, and metabolic changes that can directly damage myocardial tissue. These factors can also exacerbate comorbid conditions, such as coronary artery disease, leading to ischemia and dysfunction of preexisting electrical conduction abnormalities. However, pathologic evidence of myocarditis and the presence of the ACE2 receptor, which may be a mediator of cardiac function, on cardiac muscle cells suggest that SARS-CoV-2 is capable of directly infecting and damaging myocardial cells. Other proposed mechanisms include infection-mediated downregulation of ACE2, causing cardiac dysfunction, or thrombus formation.¹¹ Although respiratory failure is the most common source of advanced illness in COVID-19 patients, myocarditis and arrhythmias can be life-threatening manifestations of the disease.

Gastrointestinal

As noted, ACE2 is expressed in the GI tract. In 73 patients hospitalized for COVID-19, 53.4% tested positive for SARS-CoV-2 RNA in stool, and 23.4% continued to have RNA-positive stool samples even after their respiratory samples tested negative.¹² These findings suggest the potential for SARS-CoV-2 to spread through fecal-oral transmission in those who are asymptomatic, pre-symptomatic, or symptomatic. This mode of transmission has yet to be determined conclusively, and more research is needed. However, GI symptoms have been reported in persons with COVID-19. Among 138 hospitalized patients, 10.1% had complaints of diarrhea and nausea and 3.6% reported vomiting.⁶ Those who reported nausea and diarrhea noted that they developed these symptoms 1 to 2 days before they developed fever.⁶ Also, among a cohort of 1099 Chinese patients with COVID-19, 3.8% complained of diarrhea.¹³ Although diarrhea does not occur in a majority of patients, GI complaints, such as nausea, vomiting, or diarrhea, should raise clinical suspicion for COVID-19, and in known areas of active transmission, testing of patients with GI symptoms is likely warranted.

Ocular

Ocular manifestations of COVID-19 are now being described, and should be taken into consideration when examining a patient. In a study of 38 patients with COVID-19 from Hubei province, China, 31.6% had ocular findings consistent with conjunctivitis, including conjunctival hyperemia, chemosis, epiphora, and increased ocular secretions.¹⁴ SARS-CoV-2 was detected in conjunctival and nasopharyngeal samples in 2 patients from this cohort. Conjunctival congestion was reported in a cohort of 1099 patients with COVID-19 treated at multiple centers throughout China, but at a much lower incidence, approximately 0.8%.¹³ Because SARS-CoV-2 can cause conjunctival disease and has been detected in samples from the external surface of the eye, it appears the virus is transmissible from tears or contact with the eye itself.

Neurologic

Common reported neurologic symptoms include dizziness, headache, impaired consciousness, ataxia, and cerebrovascular events. In a cohort of 214 patients from Wuhan, China, 36.4% had some form of neurological insult.¹⁵ These symptoms were more common in those with severe illness (P = 0.02).¹⁵ Two interesting neurologic symptoms that have been described are anosmia (loss of smell) and ageusia (loss of taste), which are being found primarily in tandem. It is still unclear how many people with COVID-19 are experiencing these symptoms, but a report from Italy estimates 19.4% of 320 patients examined had chemosensory dysfunction.¹⁶ The aforementioned report from Wuhan, China, found that 5.1% had anosmia and 5.6% had ageusia.¹⁵ The presence of anosmia/ageusia in some patients suggests that SARS-CoV-2 may enter the central nervous system (CNS) through a retrograde neuronal route.¹⁵ In addition, a case report from Japan described a 24-year-old man who presented with meningitis/encephalitis and had SARS-CoV-2 RNA present in his cerebrospinal fluid, showing that SARS-CoV-2 can penetrate into the CNS.¹⁷

SARS-CoV-2 may also have an association with Guillain–Barré syndrome, as this condition was reported in 5 patients from 3 hospitals in Northern Italy.¹⁸ The symptoms of Guillain–Barré syndrome presented 5 to 10 days after the typical COVID-19 symptoms, and evolved over 36 hours to 4 days afterwards. Four of the 5 patients experienced flaccid tetraparesis or tetraplegia, and 3 required mechanical ventilation.¹⁸

Another possible cause of neurologic injury in COVID-19 is damage to endothelial cells in cerebral blood vessels, causing thrombus formation and possibly increasing the risk of acute ischemic stroke.^15,19 Supporting this mechanism of injury, significantly lower platelet counts were noted in patients with CNS symptoms (P = 0.005).¹⁵ Other hematological impacts of COVID-19 have been reported, particularly hypercoagulability, as evidenced by elevated D-dimer levels.^13,20 This hypercoagulable state is linked to overproduction of proinflammatory cytokines (cytokine storm), leading to dysregulation of coagulation pathways and reduced concentrations of anticoagulants, such as protein C, antithrombin III, and tissue factor pathway inhibitor.²¹

Cutaneous

Cutaneous findings emerging in persons with COVID-19 demonstrate features of small-vessel and capillary occlusion, including erythematous skin eruptions and petechial rash. One report from Italy noted that 20.4% of patients with COVID-19 (n = 88) had a cutaneous finding, with a cutaneous manifestation developing in 8 at the onset of illness and in 10 following hospital admission.²² Fourteen patients had an erythematous rash, primarily on the trunk, with 3 patients having a diffuse urticarial appearing rash, and 1 patient developing vesicles.²² The severity of illness did not appear to correlate with the cutaneous manifestation, and the lesions healed within a few days.

One case report described a patient from Bangkok who was thought to be suffering from dengue fever, but was found to have SARS-CoV-2 infection. He initially presented with skin rash and petechiae, and later developed respiratory disease.²³

Other dermatologic findings of COVID-19 resemble chilblains disease, colloquially referred to as “COVID toes.” Two women, 27 and 35 years old, presented to a dermatology clinic in Qatar with a chief complaint of skin rash, described as red-purple papules on the dorsal aspects of the fingers bilaterally.²² Both patients had an unremarkable medical and drug history, but recent travel to the United Kingdom dictated SARS-CoV-2 screening, which was positive.²⁴ An Italian case report describes a 23-year-old man who tested positive for SARS-CoV-2 and had violaceous plaques on an erythematous background on his feet, without any lesions on his hands.²⁵ Since chilblains is less common in the warmer months and these events correspond with the COVID-19 pandemic, SARS-CoV-2 infection is the suspected etiology. The pathophysiology of these lesions is unclear, and more research is needed. As more data become available, we may see cutaneous manifestations in patients with COVID-19 similar to those commonly reported with other viral infectious processes.

Musculoskeletal

Of 138 patients hospitalized in Wuhan, China, for COVID-19, 34.8% presented with myalgia; the presence of myalgia does not appear to be correlated with an increased likelihood of ICU admission.⁶ Myalgia or arthralgia was also reported in 14.9% among the cohort of 1099 COVID-19 patients in China.¹³ These musculoskeletal symptoms are described among large muscle groups found in the extremities, trunk, and back, and should raise suspicion in patients who present with other signs and symptoms concerning for COVID-19.

Evidence regarding atypical features of COVID-19 is accumulating. SARS-CoV-2 can infect a human cells that express the ACE2 receptor, which would allow for a broad spectrum of illnesses. The potential for SARS-CoV-2 to induce a hypercoagulable state allows it to indirectly damage various organ systems,²⁰ leading to cerebrovascular disease, myocardial injury, and a chilblain-like rash. Clinicians must be aware of these unique features, as early recognition of persons who present with COVID-19 will allow for prompt testing, institution of infection control and isolation practices, and treatment, as needed, among those infected. Also, this is a pandemic involving a novel virus affecting different populations throughout the world, and these signs and symptoms may occur with varying frequency across populations. Therefore, it is important to keep differentials broad when assessing patients with a clinical illness that may indeed be COVID-19.

Corresponding author: Norman L. Beatty, MD, norman.beatty@medicine.ufl.edu.

Financial disclosures: None.

From the University of Florida College of Medicine, Division of Infectious Diseases and Global Medicine, Gainesville, FL.

Abstract

• Objective: To review current reports on atypical manifestations of coronavirus disease 2019 (COVID-19).
• Methods: Review of the literature.
• Results: Evidence regarding atypical features of COVID-19 is accumulating. SARS-CoV-2 can infect human cells that express the angiotensin-converting enzyme 2 receptor, which would allow for a broad spectrum of illnesses affecting the renal, cardiac, and gastrointestinal organ systems. Neurologic, cutaneous, and musculoskeletal manifestations have also been reported. The potential for SARS-CoV-2 to induce a hypercoagulable state provides another avenue for the virus to indirectly damage various organ systems, as evidenced by reports of cerebrovascular disease, myocardial injury, and a chilblain-like rash in patients with COVID-19.
• Conclusion: Because the signs and symptoms of COVID-19 may occur with varying frequency across populations, it is important to keep differentials broad when assessing patients with a clinical illness that may indeed be COVID-19.

Keywords: coronavirus; severe acute respiratory syndrome coronavirus-2; SARS-CoV-2; pandemic.

Coronavirus disease 2019 (COVID-19), the syndrome caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was first reported in Wuhan, China, in early December 2019.¹ Since then, the virus has spread quickly around the world, with the World Health Organization (WHO) declaring the coronavirus outbreak a global pandemic on March 11, 2020. As of May 21, 2020, more than 5,000,000 cases of COVID-19 have been confirmed, and more than 328,000 deaths related to COVID-19 have been reported globally.² These numbers are expected to increase, due to the reproduction number (R0) of SARS-CoV-2. R0 represents the number of new infections generated by an infectious person in a totally naïve population.³ The WHO estimates that the R0 of SARS-CoV-2 is 1.95, with other estimates ranging from 1.4 to 6.49.³ To control the pathogen, the R0 needs to be brought under a value of 1.

A fundamental tool in lowering the R0 is prompt testing and isolation of those who display signs and symptoms of infection. SARS-CoV-2 is still a novel pathogen about which we know relatively little. The common symptoms of COVID-19 are now well known—including fever, fatigue, anorexia, cough, and shortness of breath—but atypical manifestations of this viral continue to be reported and described. To help clinicians across specialties and settings identify patients with possible infection, we have summarized findings from current reports on COVID-19 manifestations involving the renal, cardiac, gastrointestinal (GI), and other organ systems.

Renal

During the 2003 SARS-CoV-1 outbreak, acute kidney injury (AKI) was an uncommon complication of the infection, but early reports suggest that AKI may occur more commonly with COVID-19.⁴ In a study of 193 patients with laboratory-confirmed COVID-19 treated in 3 Chinese hospitals, 59% presented with proteinuria, 44% with hematuria, 14% with increased blood urea nitrogen, and 10% with increased levels of serum creatinine.⁴ These markers, indicative of AKI, may be associated with increased mortality. Among this cohort, those with AKI had a mortality risk 5.3 times higher than those who did not have AKI.⁴ The pathophysiology of renal disease in COVID-19 may be related to dehydration or inflammatory mediators, causing decreased renal perfusion and cytokine storm, but evidence also suggests that SARS-CoV-2 is able to directly infect kidney cells.⁵ The virus infects cells by using angiotensin-converting enzyme 2 (ACE2) on the cell membrane as a cell entry receptor; ACE2 is expressed on the kidney, heart, and GI cells, and this may allow SARS-CoV-2 to directly infect and damage these organs. Other potential mechanisms of renal injury include overproduction of proinflammatory cytokines and administration of nephrotoxic drugs. No matter the mechanism, however, increased serum creatinine and blood urea nitrogen correlate with an increased likelihood of requiring intensive care unit (ICU) admission.⁶ Therefore, clinicians should carefully monitor renal function in patients with COVID-19.

Cardiac

In a report of 138 Chinese patients hospitalized for COVID-19, 36 required ICU admission: 44.4% of these had arrhythmias and 22.2% had developed acute cardiac injury.⁶ In addition, the cardiac cell injury biomarker troponin I was more likely to be elevated in ICU patients.⁶ A study of 21 patients admitted to the ICU in Washington State found elevated levels of brain natriuretic peptide.⁷ These biomarkers reflect the presence of myocardial stress, but do not necessarily indicate direct myocardial infection. Case reports of fulminant myocarditis in those with COVID-19 have begun to surface, however.^8,9 An examination of 68 deaths in persons with COVID-19 concluded that 7% were caused by myocarditis with circulatory failure.¹⁰

The pathophysiology of myocardial injury in COVID-19 is likely multifactorial. This includes increased inflammatory mediators, hypoxemia, and metabolic changes that can directly damage myocardial tissue. These factors can also exacerbate comorbid conditions, such as coronary artery disease, leading to ischemia and dysfunction of preexisting electrical conduction abnormalities. However, pathologic evidence of myocarditis and the presence of the ACE2 receptor, which may be a mediator of cardiac function, on cardiac muscle cells suggest that SARS-CoV-2 is capable of directly infecting and damaging myocardial cells. Other proposed mechanisms include infection-mediated downregulation of ACE2, causing cardiac dysfunction, or thrombus formation.¹¹ Although respiratory failure is the most common source of advanced illness in COVID-19 patients, myocarditis and arrhythmias can be life-threatening manifestations of the disease.

Gastrointestinal

As noted, ACE2 is expressed in the GI tract. In 73 patients hospitalized for COVID-19, 53.4% tested positive for SARS-CoV-2 RNA in stool, and 23.4% continued to have RNA-positive stool samples even after their respiratory samples tested negative.¹² These findings suggest the potential for SARS-CoV-2 to spread through fecal-oral transmission in those who are asymptomatic, pre-symptomatic, or symptomatic. This mode of transmission has yet to be determined conclusively, and more research is needed. However, GI symptoms have been reported in persons with COVID-19. Among 138 hospitalized patients, 10.1% had complaints of diarrhea and nausea and 3.6% reported vomiting.⁶ Those who reported nausea and diarrhea noted that they developed these symptoms 1 to 2 days before they developed fever.⁶ Also, among a cohort of 1099 Chinese patients with COVID-19, 3.8% complained of diarrhea.¹³ Although diarrhea does not occur in a majority of patients, GI complaints, such as nausea, vomiting, or diarrhea, should raise clinical suspicion for COVID-19, and in known areas of active transmission, testing of patients with GI symptoms is likely warranted.

Ocular

Ocular manifestations of COVID-19 are now being described, and should be taken into consideration when examining a patient. In a study of 38 patients with COVID-19 from Hubei province, China, 31.6% had ocular findings consistent with conjunctivitis, including conjunctival hyperemia, chemosis, epiphora, and increased ocular secretions.¹⁴ SARS-CoV-2 was detected in conjunctival and nasopharyngeal samples in 2 patients from this cohort. Conjunctival congestion was reported in a cohort of 1099 patients with COVID-19 treated at multiple centers throughout China, but at a much lower incidence, approximately 0.8%.¹³ Because SARS-CoV-2 can cause conjunctival disease and has been detected in samples from the external surface of the eye, it appears the virus is transmissible from tears or contact with the eye itself.

Neurologic

Common reported neurologic symptoms include dizziness, headache, impaired consciousness, ataxia, and cerebrovascular events. In a cohort of 214 patients from Wuhan, China, 36.4% had some form of neurological insult.¹⁵ These symptoms were more common in those with severe illness (P = 0.02).¹⁵ Two interesting neurologic symptoms that have been described are anosmia (loss of smell) and ageusia (loss of taste), which are being found primarily in tandem. It is still unclear how many people with COVID-19 are experiencing these symptoms, but a report from Italy estimates 19.4% of 320 patients examined had chemosensory dysfunction.¹⁶ The aforementioned report from Wuhan, China, found that 5.1% had anosmia and 5.6% had ageusia.¹⁵ The presence of anosmia/ageusia in some patients suggests that SARS-CoV-2 may enter the central nervous system (CNS) through a retrograde neuronal route.¹⁵ In addition, a case report from Japan described a 24-year-old man who presented with meningitis/encephalitis and had SARS-CoV-2 RNA present in his cerebrospinal fluid, showing that SARS-CoV-2 can penetrate into the CNS.¹⁷

SARS-CoV-2 may also have an association with Guillain–Barré syndrome, as this condition was reported in 5 patients from 3 hospitals in Northern Italy.¹⁸ The symptoms of Guillain–Barré syndrome presented 5 to 10 days after the typical COVID-19 symptoms, and evolved over 36 hours to 4 days afterwards. Four of the 5 patients experienced flaccid tetraparesis or tetraplegia, and 3 required mechanical ventilation.¹⁸

Another possible cause of neurologic injury in COVID-19 is damage to endothelial cells in cerebral blood vessels, causing thrombus formation and possibly increasing the risk of acute ischemic stroke.^15,19 Supporting this mechanism of injury, significantly lower platelet counts were noted in patients with CNS symptoms (P = 0.005).¹⁵ Other hematological impacts of COVID-19 have been reported, particularly hypercoagulability, as evidenced by elevated D-dimer levels.^13,20 This hypercoagulable state is linked to overproduction of proinflammatory cytokines (cytokine storm), leading to dysregulation of coagulation pathways and reduced concentrations of anticoagulants, such as protein C, antithrombin III, and tissue factor pathway inhibitor.²¹

Cutaneous

Cutaneous findings emerging in persons with COVID-19 demonstrate features of small-vessel and capillary occlusion, including erythematous skin eruptions and petechial rash. One report from Italy noted that 20.4% of patients with COVID-19 (n = 88) had a cutaneous finding, with a cutaneous manifestation developing in 8 at the onset of illness and in 10 following hospital admission.²² Fourteen patients had an erythematous rash, primarily on the trunk, with 3 patients having a diffuse urticarial appearing rash, and 1 patient developing vesicles.²² The severity of illness did not appear to correlate with the cutaneous manifestation, and the lesions healed within a few days.

One case report described a patient from Bangkok who was thought to be suffering from dengue fever, but was found to have SARS-CoV-2 infection. He initially presented with skin rash and petechiae, and later developed respiratory disease.²³

Other dermatologic findings of COVID-19 resemble chilblains disease, colloquially referred to as “COVID toes.” Two women, 27 and 35 years old, presented to a dermatology clinic in Qatar with a chief complaint of skin rash, described as red-purple papules on the dorsal aspects of the fingers bilaterally.²² Both patients had an unremarkable medical and drug history, but recent travel to the United Kingdom dictated SARS-CoV-2 screening, which was positive.²⁴ An Italian case report describes a 23-year-old man who tested positive for SARS-CoV-2 and had violaceous plaques on an erythematous background on his feet, without any lesions on his hands.²⁵ Since chilblains is less common in the warmer months and these events correspond with the COVID-19 pandemic, SARS-CoV-2 infection is the suspected etiology. The pathophysiology of these lesions is unclear, and more research is needed. As more data become available, we may see cutaneous manifestations in patients with COVID-19 similar to those commonly reported with other viral infectious processes.

Musculoskeletal

Of 138 patients hospitalized in Wuhan, China, for COVID-19, 34.8% presented with myalgia; the presence of myalgia does not appear to be correlated with an increased likelihood of ICU admission.⁶ Myalgia or arthralgia was also reported in 14.9% among the cohort of 1099 COVID-19 patients in China.¹³ These musculoskeletal symptoms are described among large muscle groups found in the extremities, trunk, and back, and should raise suspicion in patients who present with other signs and symptoms concerning for COVID-19.

Evidence regarding atypical features of COVID-19 is accumulating. SARS-CoV-2 can infect a human cells that express the ACE2 receptor, which would allow for a broad spectrum of illnesses. The potential for SARS-CoV-2 to induce a hypercoagulable state allows it to indirectly damage various organ systems,²⁰ leading to cerebrovascular disease, myocardial injury, and a chilblain-like rash. Clinicians must be aware of these unique features, as early recognition of persons who present with COVID-19 will allow for prompt testing, institution of infection control and isolation practices, and treatment, as needed, among those infected. Also, this is a pandemic involving a novel virus affecting different populations throughout the world, and these signs and symptoms may occur with varying frequency across populations. Therefore, it is important to keep differentials broad when assessing patients with a clinical illness that may indeed be COVID-19.

Corresponding author: Norman L. Beatty, MD, norman.beatty@medicine.ufl.edu.

Financial disclosures: None.

From the University of Florida College of Medicine, Division of Infectious Diseases and Global Medicine, Gainesville, FL.

Abstract

• Objective: To review current reports on atypical manifestations of coronavirus disease 2019 (COVID-19).
• Methods: Review of the literature.
• Results: Evidence regarding atypical features of COVID-19 is accumulating. SARS-CoV-2 can infect human cells that express the angiotensin-converting enzyme 2 receptor, which would allow for a broad spectrum of illnesses affecting the renal, cardiac, and gastrointestinal organ systems. Neurologic, cutaneous, and musculoskeletal manifestations have also been reported. The potential for SARS-CoV-2 to induce a hypercoagulable state provides another avenue for the virus to indirectly damage various organ systems, as evidenced by reports of cerebrovascular disease, myocardial injury, and a chilblain-like rash in patients with COVID-19.
• Conclusion: Because the signs and symptoms of COVID-19 may occur with varying frequency across populations, it is important to keep differentials broad when assessing patients with a clinical illness that may indeed be COVID-19.

Keywords: coronavirus; severe acute respiratory syndrome coronavirus-2; SARS-CoV-2; pandemic.

Coronavirus disease 2019 (COVID-19), the syndrome caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was first reported in Wuhan, China, in early December 2019.¹ Since then, the virus has spread quickly around the world, with the World Health Organization (WHO) declaring the coronavirus outbreak a global pandemic on March 11, 2020. As of May 21, 2020, more than 5,000,000 cases of COVID-19 have been confirmed, and more than 328,000 deaths related to COVID-19 have been reported globally.² These numbers are expected to increase, due to the reproduction number (R0) of SARS-CoV-2. R0 represents the number of new infections generated by an infectious person in a totally naïve population.³ The WHO estimates that the R0 of SARS-CoV-2 is 1.95, with other estimates ranging from 1.4 to 6.49.³ To control the pathogen, the R0 needs to be brought under a value of 1.

A fundamental tool in lowering the R0 is prompt testing and isolation of those who display signs and symptoms of infection. SARS-CoV-2 is still a novel pathogen about which we know relatively little. The common symptoms of COVID-19 are now well known—including fever, fatigue, anorexia, cough, and shortness of breath—but atypical manifestations of this viral continue to be reported and described. To help clinicians across specialties and settings identify patients with possible infection, we have summarized findings from current reports on COVID-19 manifestations involving the renal, cardiac, gastrointestinal (GI), and other organ systems.

Renal

During the 2003 SARS-CoV-1 outbreak, acute kidney injury (AKI) was an uncommon complication of the infection, but early reports suggest that AKI may occur more commonly with COVID-19.⁴ In a study of 193 patients with laboratory-confirmed COVID-19 treated in 3 Chinese hospitals, 59% presented with proteinuria, 44% with hematuria, 14% with increased blood urea nitrogen, and 10% with increased levels of serum creatinine.⁴ These markers, indicative of AKI, may be associated with increased mortality. Among this cohort, those with AKI had a mortality risk 5.3 times higher than those who did not have AKI.⁴ The pathophysiology of renal disease in COVID-19 may be related to dehydration or inflammatory mediators, causing decreased renal perfusion and cytokine storm, but evidence also suggests that SARS-CoV-2 is able to directly infect kidney cells.⁵ The virus infects cells by using angiotensin-converting enzyme 2 (ACE2) on the cell membrane as a cell entry receptor; ACE2 is expressed on the kidney, heart, and GI cells, and this may allow SARS-CoV-2 to directly infect and damage these organs. Other potential mechanisms of renal injury include overproduction of proinflammatory cytokines and administration of nephrotoxic drugs. No matter the mechanism, however, increased serum creatinine and blood urea nitrogen correlate with an increased likelihood of requiring intensive care unit (ICU) admission.⁶ Therefore, clinicians should carefully monitor renal function in patients with COVID-19.

Cardiac

In a report of 138 Chinese patients hospitalized for COVID-19, 36 required ICU admission: 44.4% of these had arrhythmias and 22.2% had developed acute cardiac injury.⁶ In addition, the cardiac cell injury biomarker troponin I was more likely to be elevated in ICU patients.⁶ A study of 21 patients admitted to the ICU in Washington State found elevated levels of brain natriuretic peptide.⁷ These biomarkers reflect the presence of myocardial stress, but do not necessarily indicate direct myocardial infection. Case reports of fulminant myocarditis in those with COVID-19 have begun to surface, however.^8,9 An examination of 68 deaths in persons with COVID-19 concluded that 7% were caused by myocarditis with circulatory failure.¹⁰

The pathophysiology of myocardial injury in COVID-19 is likely multifactorial. This includes increased inflammatory mediators, hypoxemia, and metabolic changes that can directly damage myocardial tissue. These factors can also exacerbate comorbid conditions, such as coronary artery disease, leading to ischemia and dysfunction of preexisting electrical conduction abnormalities. However, pathologic evidence of myocarditis and the presence of the ACE2 receptor, which may be a mediator of cardiac function, on cardiac muscle cells suggest that SARS-CoV-2 is capable of directly infecting and damaging myocardial cells. Other proposed mechanisms include infection-mediated downregulation of ACE2, causing cardiac dysfunction, or thrombus formation.¹¹ Although respiratory failure is the most common source of advanced illness in COVID-19 patients, myocarditis and arrhythmias can be life-threatening manifestations of the disease.

Gastrointestinal

As noted, ACE2 is expressed in the GI tract. In 73 patients hospitalized for COVID-19, 53.4% tested positive for SARS-CoV-2 RNA in stool, and 23.4% continued to have RNA-positive stool samples even after their respiratory samples tested negative.¹² These findings suggest the potential for SARS-CoV-2 to spread through fecal-oral transmission in those who are asymptomatic, pre-symptomatic, or symptomatic. This mode of transmission has yet to be determined conclusively, and more research is needed. However, GI symptoms have been reported in persons with COVID-19. Among 138 hospitalized patients, 10.1% had complaints of diarrhea and nausea and 3.6% reported vomiting.⁶ Those who reported nausea and diarrhea noted that they developed these symptoms 1 to 2 days before they developed fever.⁶ Also, among a cohort of 1099 Chinese patients with COVID-19, 3.8% complained of diarrhea.¹³ Although diarrhea does not occur in a majority of patients, GI complaints, such as nausea, vomiting, or diarrhea, should raise clinical suspicion for COVID-19, and in known areas of active transmission, testing of patients with GI symptoms is likely warranted.

Ocular

Ocular manifestations of COVID-19 are now being described, and should be taken into consideration when examining a patient. In a study of 38 patients with COVID-19 from Hubei province, China, 31.6% had ocular findings consistent with conjunctivitis, including conjunctival hyperemia, chemosis, epiphora, and increased ocular secretions.¹⁴ SARS-CoV-2 was detected in conjunctival and nasopharyngeal samples in 2 patients from this cohort. Conjunctival congestion was reported in a cohort of 1099 patients with COVID-19 treated at multiple centers throughout China, but at a much lower incidence, approximately 0.8%.¹³ Because SARS-CoV-2 can cause conjunctival disease and has been detected in samples from the external surface of the eye, it appears the virus is transmissible from tears or contact with the eye itself.

Neurologic

Common reported neurologic symptoms include dizziness, headache, impaired consciousness, ataxia, and cerebrovascular events. In a cohort of 214 patients from Wuhan, China, 36.4% had some form of neurological insult.¹⁵ These symptoms were more common in those with severe illness (P = 0.02).¹⁵ Two interesting neurologic symptoms that have been described are anosmia (loss of smell) and ageusia (loss of taste), which are being found primarily in tandem. It is still unclear how many people with COVID-19 are experiencing these symptoms, but a report from Italy estimates 19.4% of 320 patients examined had chemosensory dysfunction.¹⁶ The aforementioned report from Wuhan, China, found that 5.1% had anosmia and 5.6% had ageusia.¹⁵ The presence of anosmia/ageusia in some patients suggests that SARS-CoV-2 may enter the central nervous system (CNS) through a retrograde neuronal route.¹⁵ In addition, a case report from Japan described a 24-year-old man who presented with meningitis/encephalitis and had SARS-CoV-2 RNA present in his cerebrospinal fluid, showing that SARS-CoV-2 can penetrate into the CNS.¹⁷

SARS-CoV-2 may also have an association with Guillain–Barré syndrome, as this condition was reported in 5 patients from 3 hospitals in Northern Italy.¹⁸ The symptoms of Guillain–Barré syndrome presented 5 to 10 days after the typical COVID-19 symptoms, and evolved over 36 hours to 4 days afterwards. Four of the 5 patients experienced flaccid tetraparesis or tetraplegia, and 3 required mechanical ventilation.¹⁸

Another possible cause of neurologic injury in COVID-19 is damage to endothelial cells in cerebral blood vessels, causing thrombus formation and possibly increasing the risk of acute ischemic stroke.^15,19 Supporting this mechanism of injury, significantly lower platelet counts were noted in patients with CNS symptoms (P = 0.005).¹⁵ Other hematological impacts of COVID-19 have been reported, particularly hypercoagulability, as evidenced by elevated D-dimer levels.^13,20 This hypercoagulable state is linked to overproduction of proinflammatory cytokines (cytokine storm), leading to dysregulation of coagulation pathways and reduced concentrations of anticoagulants, such as protein C, antithrombin III, and tissue factor pathway inhibitor.²¹

Cutaneous

Cutaneous findings emerging in persons with COVID-19 demonstrate features of small-vessel and capillary occlusion, including erythematous skin eruptions and petechial rash. One report from Italy noted that 20.4% of patients with COVID-19 (n = 88) had a cutaneous finding, with a cutaneous manifestation developing in 8 at the onset of illness and in 10 following hospital admission.²² Fourteen patients had an erythematous rash, primarily on the trunk, with 3 patients having a diffuse urticarial appearing rash, and 1 patient developing vesicles.²² The severity of illness did not appear to correlate with the cutaneous manifestation, and the lesions healed within a few days.

One case report described a patient from Bangkok who was thought to be suffering from dengue fever, but was found to have SARS-CoV-2 infection. He initially presented with skin rash and petechiae, and later developed respiratory disease.²³

Other dermatologic findings of COVID-19 resemble chilblains disease, colloquially referred to as “COVID toes.” Two women, 27 and 35 years old, presented to a dermatology clinic in Qatar with a chief complaint of skin rash, described as red-purple papules on the dorsal aspects of the fingers bilaterally.²² Both patients had an unremarkable medical and drug history, but recent travel to the United Kingdom dictated SARS-CoV-2 screening, which was positive.²⁴ An Italian case report describes a 23-year-old man who tested positive for SARS-CoV-2 and had violaceous plaques on an erythematous background on his feet, without any lesions on his hands.²⁵ Since chilblains is less common in the warmer months and these events correspond with the COVID-19 pandemic, SARS-CoV-2 infection is the suspected etiology. The pathophysiology of these lesions is unclear, and more research is needed. As more data become available, we may see cutaneous manifestations in patients with COVID-19 similar to those commonly reported with other viral infectious processes.

Musculoskeletal

Of 138 patients hospitalized in Wuhan, China, for COVID-19, 34.8% presented with myalgia; the presence of myalgia does not appear to be correlated with an increased likelihood of ICU admission.⁶ Myalgia or arthralgia was also reported in 14.9% among the cohort of 1099 COVID-19 patients in China.¹³ These musculoskeletal symptoms are described among large muscle groups found in the extremities, trunk, and back, and should raise suspicion in patients who present with other signs and symptoms concerning for COVID-19.

Evidence regarding atypical features of COVID-19 is accumulating. SARS-CoV-2 can infect a human cells that express the ACE2 receptor, which would allow for a broad spectrum of illnesses. The potential for SARS-CoV-2 to induce a hypercoagulable state allows it to indirectly damage various organ systems,²⁰ leading to cerebrovascular disease, myocardial injury, and a chilblain-like rash. Clinicians must be aware of these unique features, as early recognition of persons who present with COVID-19 will allow for prompt testing, institution of infection control and isolation practices, and treatment, as needed, among those infected. Also, this is a pandemic involving a novel virus affecting different populations throughout the world, and these signs and symptoms may occur with varying frequency across populations. Therefore, it is important to keep differentials broad when assessing patients with a clinical illness that may indeed be COVID-19.

Corresponding author: Norman L. Beatty, MD, norman.beatty@medicine.ufl.edu.

Financial disclosures: None.

Study Overview

Objective. To evaluate the effect of changing from tenofovir disoproxil fumarate (TDF) –containing antiretroviral therapy (ART) to tenofovir alafenamide (TAF) –containing ART in patients ages 60 years and older living with HIV.

Design. Prospective, open-label, multicenter, randomized controlled trial.

Setting and participants. The study was completed across 36 European centers over 48 weeks. Patients were enrolled from December 12, 2015, to March 21, 2018, and were eligible to participate if they were diagnosed with HIV-1; virologically suppressed to < 50 copies/mL; on a TDF-containing ART regimen; and ≥ 60 years of age.

Intervention. Participants (n = 167) were randomly assigned in a 2:1 ratio to ART with TAF (10 mg), elvitegravir (EVG; 150 mg), cobicistat (COB; 150 mg), and emtricitabine (FTC; 200 mg) or to continued therapy with a TDF-containing ART regimen (300 mg TDF).

Main outcome measures. Primary outcome measures were the change in spine and hip bone mineral density from baseline at week 48. Secondary outcome measures included bone mineral density changes from baseline at week 24, HIV viral suppression and change in CD4 count at weeks 24 and 48, and the assessment of safety and tolerability of each ART regimen until week 48.

Main results. At 48 weeks, patients (n = 111) in the TAF+EVG+COB+FTC group had a mean 2.24% (SD, 3.27) increase in spine bone mineral density, while those in the TDF-containing group (n = 56) had a mean 0.10% decrease (SD, 3.39), a difference of 2.43% (95% confidence interval [CI], 1.34-3.52; P < 0.0001). In addition, at 48 weeks patients in the TAF+EVG+COB+FTC group had a mean 1.33% increase (SD, 2.20) in hip bone mineral density, as compared with a mean 0.73% decrease (SD, 3.21) in the TDF-containing group, a difference of 2.04% (95% CI, 1.17-2.90; P < 0.0001).

Similar results were seen in spine and hip bone mineral density in the TAF+EVG+COB+FTC group at week 24, with increases of 1.75% (P = 0.00080) and 1.35% (P = 0.00040), respectively. Both treatment groups maintained high virologic suppression. The TAF+EVG+COB+FTC group maintained 94.5% virologic suppression at week 24 and 93.6% at week 48, as compared with virologic suppression of 100% and 94.5% at weeks 24 and 48, respectively, in the TDF-containing group. However, the TAF+EVG+COB+FTC group had an increase in CD4 count from baseline (56 cells/µL), with no real change in the TDF-containing group (–1 cell/µL). Patients in the TAF+EVG+COB+FTC group had a mean 27.8 mg/g decrease in urine albumin-to-creatinine ratio (UACR) versus a 7.7 mg/g decrease in the TDF-containing group (P = 0.0042). In addition, patients in the TAF+EVG+COB+FTC group had a mean 49.8 mg/g decrease in urine protein-to-creatinine ratio (UPCR) versus a 3.8 mg/g decrease in the TDF-containing group (P = 0.0042).

Conclusion. Patients 60 years of age or older living with virologically suppressed HIV may benefit from improved bone mineral density by switching from a TDF-containing ART regimen to a TAF-containing regimen after 48 weeks, which, in turn, may help to reduce the risk for osteoporosis. Patients who were switched to a TAF-containing regimen also had favorable improvements in UACR and UPCR, which could indicate better renal function.

Commentary

The Centers for Disease Control and Prevention estimated that in 2018 nearly half of those living with HIV in the United States were older than 50 years.¹ Today, the life expectancy of patients living with HIV on ART in developed countries is similar to that of patients not living with HIV. A meta-analysis published in 2017 estimated that patients diagnosed with HIV at age 20 beginning ART have a life expectancy of 63 years, and another study estimated that life expectancy in such patients is 89.1% of that of the general population in Canada.^2,3 Overall, most people living with HIV infection are aging and at risk for medical conditions similar to persons without HIV disease. However, rates of osteoporosis in elderly patients with HIV are estimated to be 3 times greater than rates in persons without HIV.⁴ As a result, it is becoming increasingly important to find ways to decrease the risk of osteoporosis in these patients.

ART typically includes a nucleoside reverse transcriptase inhibitor (NRTI) combination and a third agent, such as an integrase strand inhibitor. Tenofovir is a commonly used backbone NRTI that comes in 2 forms, TDF (tenofovir disoproxil fumarate) and TAF (tenofovir alafenamide). Both are prodrugs that are converted to tenofovir diphosphate. TDF specifically is associated with an increased risk of bone loss and nephrotoxicity. The loss in bone mineral density is most similar to the bone loss seen with oral glucocorticoids.⁵ TDF has been shown to increase plasma levels of RANKL and tumor necrosis factor-α, leading to increased bone resorption.⁶ The long-term effects of TDF- versus TAF-containing ART on bone mineral density have, to our knowledge, not been compared previously in a randomized control study. The significance of demonstrating an increase in bone mineral density in the prevention of osteoporotic bone fracture in people living with HIV is less clear. A long-term cohort study completed in Japan looking at patients on TDF showed an increased risk of bone fractures in both older postmenopausal women and younger men.⁷ However, a retrospective cohort study looking at 1981 patients with HIV found no association between bone fractures and TDF.⁸

This randomized controlled trial used appropriate methods to measure the reported primary and secondary endpoints; however, it would be of benefit to continue following these patients to measure their true long-term risk of osteoporosis-related complications. In terms of the study’s secondary endpoints, it is notable that the patients maintained HIV viral suppression after the switch and CD4 counts remained stable (with a slight increase observed in the TAF-containing ART cohort).

In regard to the patient’s renal function, patients in the TAF group had significantly improved UACR and UPCR, which likely reflects improved glomerular filtration. Improved renal function is also increasingly important for patients with HIV, as up to 48.5% have some form of chronic kidney disease.⁹

This study shows that making the switch from TDF- to TAF-containing ART can lead to improved bone mineral density. We can extrapolate that switching may lead to a decreased risk of osteoporosis and osteoporosis-related complications, such as bone fracture, but this needs to be investigated in more detail. As demonstrated in this study, switching from a TDF- to a TAF-containing regimen can also lead to improved renal function while maintaining HIV viral suppression and CD4 counts.

Unfortunately, the regimen selected with TAF in this study (elvitegravir, cobicistat, and emtricitabine) includes cobicistat, which is no longer recommended as initial therapy due to its risk of drug-drug interactions, and elvitegravir, which has a lower barrier to resistance than other integrase strand inhibitors.^10,11 The United States Department of Health and Human Services guidelines and the International Antiviral Society-USA Panel suggest using several other TAF-containing regimens for beginning or even switching therapy in older patients.^10,11

When choosing between either a TAF- or a TDF-containing regimen to treat HIV infection in older patients, increasing evidence shows that using a TAF-containing ART regimen may be more beneficial for people living and aging with virologically suppressed HIV infection.

–Sean P. Bliven, and Norman L. Beatty, MD, University of Florida College of Medicine, Division of Infectious Diseases and Global Medicine, Gainesville, FL

Study Overview

Objective. To evaluate the effect of changing from tenofovir disoproxil fumarate (TDF) –containing antiretroviral therapy (ART) to tenofovir alafenamide (TAF) –containing ART in patients ages 60 years and older living with HIV.

Design. Prospective, open-label, multicenter, randomized controlled trial.

Setting and participants. The study was completed across 36 European centers over 48 weeks. Patients were enrolled from December 12, 2015, to March 21, 2018, and were eligible to participate if they were diagnosed with HIV-1; virologically suppressed to < 50 copies/mL; on a TDF-containing ART regimen; and ≥ 60 years of age.

Intervention. Participants (n = 167) were randomly assigned in a 2:1 ratio to ART with TAF (10 mg), elvitegravir (EVG; 150 mg), cobicistat (COB; 150 mg), and emtricitabine (FTC; 200 mg) or to continued therapy with a TDF-containing ART regimen (300 mg TDF).

Main outcome measures. Primary outcome measures were the change in spine and hip bone mineral density from baseline at week 48. Secondary outcome measures included bone mineral density changes from baseline at week 24, HIV viral suppression and change in CD4 count at weeks 24 and 48, and the assessment of safety and tolerability of each ART regimen until week 48.

Main results. At 48 weeks, patients (n = 111) in the TAF+EVG+COB+FTC group had a mean 2.24% (SD, 3.27) increase in spine bone mineral density, while those in the TDF-containing group (n = 56) had a mean 0.10% decrease (SD, 3.39), a difference of 2.43% (95% confidence interval [CI], 1.34-3.52; P < 0.0001). In addition, at 48 weeks patients in the TAF+EVG+COB+FTC group had a mean 1.33% increase (SD, 2.20) in hip bone mineral density, as compared with a mean 0.73% decrease (SD, 3.21) in the TDF-containing group, a difference of 2.04% (95% CI, 1.17-2.90; P < 0.0001).

Similar results were seen in spine and hip bone mineral density in the TAF+EVG+COB+FTC group at week 24, with increases of 1.75% (P = 0.00080) and 1.35% (P = 0.00040), respectively. Both treatment groups maintained high virologic suppression. The TAF+EVG+COB+FTC group maintained 94.5% virologic suppression at week 24 and 93.6% at week 48, as compared with virologic suppression of 100% and 94.5% at weeks 24 and 48, respectively, in the TDF-containing group. However, the TAF+EVG+COB+FTC group had an increase in CD4 count from baseline (56 cells/µL), with no real change in the TDF-containing group (–1 cell/µL). Patients in the TAF+EVG+COB+FTC group had a mean 27.8 mg/g decrease in urine albumin-to-creatinine ratio (UACR) versus a 7.7 mg/g decrease in the TDF-containing group (P = 0.0042). In addition, patients in the TAF+EVG+COB+FTC group had a mean 49.8 mg/g decrease in urine protein-to-creatinine ratio (UPCR) versus a 3.8 mg/g decrease in the TDF-containing group (P = 0.0042).

Conclusion. Patients 60 years of age or older living with virologically suppressed HIV may benefit from improved bone mineral density by switching from a TDF-containing ART regimen to a TAF-containing regimen after 48 weeks, which, in turn, may help to reduce the risk for osteoporosis. Patients who were switched to a TAF-containing regimen also had favorable improvements in UACR and UPCR, which could indicate better renal function.

Commentary

The Centers for Disease Control and Prevention estimated that in 2018 nearly half of those living with HIV in the United States were older than 50 years.¹ Today, the life expectancy of patients living with HIV on ART in developed countries is similar to that of patients not living with HIV. A meta-analysis published in 2017 estimated that patients diagnosed with HIV at age 20 beginning ART have a life expectancy of 63 years, and another study estimated that life expectancy in such patients is 89.1% of that of the general population in Canada.^2,3 Overall, most people living with HIV infection are aging and at risk for medical conditions similar to persons without HIV disease. However, rates of osteoporosis in elderly patients with HIV are estimated to be 3 times greater than rates in persons without HIV.⁴ As a result, it is becoming increasingly important to find ways to decrease the risk of osteoporosis in these patients.

ART typically includes a nucleoside reverse transcriptase inhibitor (NRTI) combination and a third agent, such as an integrase strand inhibitor. Tenofovir is a commonly used backbone NRTI that comes in 2 forms, TDF (tenofovir disoproxil fumarate) and TAF (tenofovir alafenamide). Both are prodrugs that are converted to tenofovir diphosphate. TDF specifically is associated with an increased risk of bone loss and nephrotoxicity. The loss in bone mineral density is most similar to the bone loss seen with oral glucocorticoids.⁵ TDF has been shown to increase plasma levels of RANKL and tumor necrosis factor-α, leading to increased bone resorption.⁶ The long-term effects of TDF- versus TAF-containing ART on bone mineral density have, to our knowledge, not been compared previously in a randomized control study. The significance of demonstrating an increase in bone mineral density in the prevention of osteoporotic bone fracture in people living with HIV is less clear. A long-term cohort study completed in Japan looking at patients on TDF showed an increased risk of bone fractures in both older postmenopausal women and younger men.⁷ However, a retrospective cohort study looking at 1981 patients with HIV found no association between bone fractures and TDF.⁸

This randomized controlled trial used appropriate methods to measure the reported primary and secondary endpoints; however, it would be of benefit to continue following these patients to measure their true long-term risk of osteoporosis-related complications. In terms of the study’s secondary endpoints, it is notable that the patients maintained HIV viral suppression after the switch and CD4 counts remained stable (with a slight increase observed in the TAF-containing ART cohort).

In regard to the patient’s renal function, patients in the TAF group had significantly improved UACR and UPCR, which likely reflects improved glomerular filtration. Improved renal function is also increasingly important for patients with HIV, as up to 48.5% have some form of chronic kidney disease.⁹

This study shows that making the switch from TDF- to TAF-containing ART can lead to improved bone mineral density. We can extrapolate that switching may lead to a decreased risk of osteoporosis and osteoporosis-related complications, such as bone fracture, but this needs to be investigated in more detail. As demonstrated in this study, switching from a TDF- to a TAF-containing regimen can also lead to improved renal function while maintaining HIV viral suppression and CD4 counts.

Unfortunately, the regimen selected with TAF in this study (elvitegravir, cobicistat, and emtricitabine) includes cobicistat, which is no longer recommended as initial therapy due to its risk of drug-drug interactions, and elvitegravir, which has a lower barrier to resistance than other integrase strand inhibitors.^10,11 The United States Department of Health and Human Services guidelines and the International Antiviral Society-USA Panel suggest using several other TAF-containing regimens for beginning or even switching therapy in older patients.^10,11

When choosing between either a TAF- or a TDF-containing regimen to treat HIV infection in older patients, increasing evidence shows that using a TAF-containing ART regimen may be more beneficial for people living and aging with virologically suppressed HIV infection.

–Sean P. Bliven, and Norman L. Beatty, MD, University of Florida College of Medicine, Division of Infectious Diseases and Global Medicine, Gainesville, FL

Study Overview

Objective. To evaluate the effect of changing from tenofovir disoproxil fumarate (TDF) –containing antiretroviral therapy (ART) to tenofovir alafenamide (TAF) –containing ART in patients ages 60 years and older living with HIV.

Design. Prospective, open-label, multicenter, randomized controlled trial.

Setting and participants. The study was completed across 36 European centers over 48 weeks. Patients were enrolled from December 12, 2015, to March 21, 2018, and were eligible to participate if they were diagnosed with HIV-1; virologically suppressed to < 50 copies/mL; on a TDF-containing ART regimen; and ≥ 60 years of age.

Intervention. Participants (n = 167) were randomly assigned in a 2:1 ratio to ART with TAF (10 mg), elvitegravir (EVG; 150 mg), cobicistat (COB; 150 mg), and emtricitabine (FTC; 200 mg) or to continued therapy with a TDF-containing ART regimen (300 mg TDF).

Main outcome measures. Primary outcome measures were the change in spine and hip bone mineral density from baseline at week 48. Secondary outcome measures included bone mineral density changes from baseline at week 24, HIV viral suppression and change in CD4 count at weeks 24 and 48, and the assessment of safety and tolerability of each ART regimen until week 48.

Main results. At 48 weeks, patients (n = 111) in the TAF+EVG+COB+FTC group had a mean 2.24% (SD, 3.27) increase in spine bone mineral density, while those in the TDF-containing group (n = 56) had a mean 0.10% decrease (SD, 3.39), a difference of 2.43% (95% confidence interval [CI], 1.34-3.52; P < 0.0001). In addition, at 48 weeks patients in the TAF+EVG+COB+FTC group had a mean 1.33% increase (SD, 2.20) in hip bone mineral density, as compared with a mean 0.73% decrease (SD, 3.21) in the TDF-containing group, a difference of 2.04% (95% CI, 1.17-2.90; P < 0.0001).

Similar results were seen in spine and hip bone mineral density in the TAF+EVG+COB+FTC group at week 24, with increases of 1.75% (P = 0.00080) and 1.35% (P = 0.00040), respectively. Both treatment groups maintained high virologic suppression. The TAF+EVG+COB+FTC group maintained 94.5% virologic suppression at week 24 and 93.6% at week 48, as compared with virologic suppression of 100% and 94.5% at weeks 24 and 48, respectively, in the TDF-containing group. However, the TAF+EVG+COB+FTC group had an increase in CD4 count from baseline (56 cells/µL), with no real change in the TDF-containing group (–1 cell/µL). Patients in the TAF+EVG+COB+FTC group had a mean 27.8 mg/g decrease in urine albumin-to-creatinine ratio (UACR) versus a 7.7 mg/g decrease in the TDF-containing group (P = 0.0042). In addition, patients in the TAF+EVG+COB+FTC group had a mean 49.8 mg/g decrease in urine protein-to-creatinine ratio (UPCR) versus a 3.8 mg/g decrease in the TDF-containing group (P = 0.0042).

Conclusion. Patients 60 years of age or older living with virologically suppressed HIV may benefit from improved bone mineral density by switching from a TDF-containing ART regimen to a TAF-containing regimen after 48 weeks, which, in turn, may help to reduce the risk for osteoporosis. Patients who were switched to a TAF-containing regimen also had favorable improvements in UACR and UPCR, which could indicate better renal function.

Commentary

The Centers for Disease Control and Prevention estimated that in 2018 nearly half of those living with HIV in the United States were older than 50 years.¹ Today, the life expectancy of patients living with HIV on ART in developed countries is similar to that of patients not living with HIV. A meta-analysis published in 2017 estimated that patients diagnosed with HIV at age 20 beginning ART have a life expectancy of 63 years, and another study estimated that life expectancy in such patients is 89.1% of that of the general population in Canada.^2,3 Overall, most people living with HIV infection are aging and at risk for medical conditions similar to persons without HIV disease. However, rates of osteoporosis in elderly patients with HIV are estimated to be 3 times greater than rates in persons without HIV.⁴ As a result, it is becoming increasingly important to find ways to decrease the risk of osteoporosis in these patients.

ART typically includes a nucleoside reverse transcriptase inhibitor (NRTI) combination and a third agent, such as an integrase strand inhibitor. Tenofovir is a commonly used backbone NRTI that comes in 2 forms, TDF (tenofovir disoproxil fumarate) and TAF (tenofovir alafenamide). Both are prodrugs that are converted to tenofovir diphosphate. TDF specifically is associated with an increased risk of bone loss and nephrotoxicity. The loss in bone mineral density is most similar to the bone loss seen with oral glucocorticoids.⁵ TDF has been shown to increase plasma levels of RANKL and tumor necrosis factor-α, leading to increased bone resorption.⁶ The long-term effects of TDF- versus TAF-containing ART on bone mineral density have, to our knowledge, not been compared previously in a randomized control study. The significance of demonstrating an increase in bone mineral density in the prevention of osteoporotic bone fracture in people living with HIV is less clear. A long-term cohort study completed in Japan looking at patients on TDF showed an increased risk of bone fractures in both older postmenopausal women and younger men.⁷ However, a retrospective cohort study looking at 1981 patients with HIV found no association between bone fractures and TDF.⁸

This randomized controlled trial used appropriate methods to measure the reported primary and secondary endpoints; however, it would be of benefit to continue following these patients to measure their true long-term risk of osteoporosis-related complications. In terms of the study’s secondary endpoints, it is notable that the patients maintained HIV viral suppression after the switch and CD4 counts remained stable (with a slight increase observed in the TAF-containing ART cohort).

In regard to the patient’s renal function, patients in the TAF group had significantly improved UACR and UPCR, which likely reflects improved glomerular filtration. Improved renal function is also increasingly important for patients with HIV, as up to 48.5% have some form of chronic kidney disease.⁹

This study shows that making the switch from TDF- to TAF-containing ART can lead to improved bone mineral density. We can extrapolate that switching may lead to a decreased risk of osteoporosis and osteoporosis-related complications, such as bone fracture, but this needs to be investigated in more detail. As demonstrated in this study, switching from a TDF- to a TAF-containing regimen can also lead to improved renal function while maintaining HIV viral suppression and CD4 counts.

Unfortunately, the regimen selected with TAF in this study (elvitegravir, cobicistat, and emtricitabine) includes cobicistat, which is no longer recommended as initial therapy due to its risk of drug-drug interactions, and elvitegravir, which has a lower barrier to resistance than other integrase strand inhibitors.^10,11 The United States Department of Health and Human Services guidelines and the International Antiviral Society-USA Panel suggest using several other TAF-containing regimens for beginning or even switching therapy in older patients.^10,11

When choosing between either a TAF- or a TDF-containing regimen to treat HIV infection in older patients, increasing evidence shows that using a TAF-containing ART regimen may be more beneficial for people living and aging with virologically suppressed HIV infection.

–Sean P. Bliven, and Norman L. Beatty, MD, University of Florida College of Medicine, Division of Infectious Diseases and Global Medicine, Gainesville, FL

Study Overview

Objective. To evaluate the efficacy and safety of a once-daily 2-drug antiretroviral (ARV) regimen, dolutegravir plus lamivudine, for the treatment of HIV-1 infection in adults naive to antiretroviral therapy (ART).

Design. GEMINI-1 and GEMINI-2 were 2 identically designed multicenter, double-blind, randomized, noninferiority, phase 3 clinical trials conducted between July 18, 2016 and March 31, 2017. Participants were stratified to receive 1 of 2 once-daily HIV regimens: the study regimen, consisting of once-daily dolutegravir 50 mg plus lamivudine 300 mg, or the standard-of-care regimen, consisting of once-daily dolutegravir 50 mg plus tenofovir disoproxil fumarate (TDF) 300 mg plus emtricitabine 200 mg. While this article presents results at week 48, both trials are scheduled to evaluate participants up to week 148 in an attempt to evaluate long-term efficacy and safety.

Setting and participants. Eligible participants had to be aged 18 years or older with treatment-naive HIV-1 infection. Women were eligible if they were not (1) pregnant, (2) lactating, or (3) of reproductive potential, defined by various means, including tubal ligation, hysterectomy, postmenopausal, and the use of highly effective contraception. Initially, eligibility screening restricted participation to those with viral loads between 1000 and 100,000 copies/mL. However, the upper limit was later increased to 500,000 copies/mL based on an independent review of results from other clinical trials^1,2 evaluating dual therapy with dolutegravir and lamivudine, which indicated efficacy in patients with viral loads up to 500,000.^3-5

Notable exclusion criteria included: (1) major mutations to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors; (2) evidence of hepatitis B infection; (3) hepatitis C infection with anticipation of initiating treatment within 48 weeks of study enrollment; and (4) stage 3 HIV disease, per Centers for Disease Control and Prevention criteria, with the exception of cutaneous Kaposi sarcoma and CD4 cell counts < 200 cells/mL.

Main outcome measures. The primary endpoint was demonstration of noninferiority of the 2-drug ARV regimen through assessment of the proportion of participants who achieved virologic suppression at week 48 in the intent-to-treat-exposed population. For the purposes of this study, virologic suppression was defined as having fewer than 50 copies of HIV-1 RNA per mL at week 48. For evaluation of safety and toxicity concerns, renal and bone biomarkers were assessed at study entry and at weeks 24 and 48. In addition, participants who met virological withdrawal criteria were evaluated for integrase strand transfer inhibitor mutations. Virological withdrawal was defined as the presence of 1 of the following: (1) HIV RNA > 200 copies/mL at week 24, (2) HIV RNA > 200 copies/mL after previous HIV RNA < 200 copies/mL (confirmed rebound), and (3) a < 1 log₁₀ copies/mL decrease from baseline (unless already < 200 copies/mL).

Main results. GEMINI-1 and GEMINI-2 randomized a combined total of 1441 participants to receive either the once-daily 2-drug ARV regimen (dolutegravir and lamivudine, n = 719) or the once-daily 3-drug ARV regimen (dolutegravir, TDF, and emtricitabine, n = 722). Of the 533 participants who did not meet inclusion criteria, the predominant reasons for exclusion were either having preexisting major viral resistance mutations (n = 246) or viral loads outside the range of 1000 to 500,000 copies/mL (n = 133).

Baseline demographic and clinical characteristics were similar between both groups. The median age was 33 years (10% were over 50 years of age), and participants were mostly male (85%) and white (68%). Baseline HIV RNA counts of > 100,000 copies/mL were found in 293 participants (20%), and 188 (8%) participants had CD4 counts of ≤ 200 cells/mL.

Noninferiority of the once-daily 2-drug versus the once-daily 3-drug ARV regimen was demonstrated in both the GEMINI-1 and GEMINI-2 trials for the intent-to-treat-exposed population. In GEMINI-1, 90% (n = 320) in the 2-drug ARV group achieved virologic suppression at week 48 compared to 93% (n = 332) in the 3-drug ARV group (no statistically significant difference). In GEMINI-2, 93% (n =335 ) in the 2-drug ARV group achieved virologic suppression at week 48 compared to 94% (n = 337) in the 3-drug ARV group (no statistically significant difference).

A subgroup analysis found no significant impact of baseline HIV RNA (> 100,000 compared to ≤ 100,000 copies/mL) on achieving virologic suppression at week 48. However, a subgroup analysis did find that participants with CD4 counts < 200 copies/mL had a reduced response in the once-daily 2-drug versus 3-drug ARV regimen for achieving virologic response at week 48 (79% versus 93%, respectively).

Overall, 10 participants met virological withdrawal criteria during the study period, and 4 of these were on the 2-drug ARV regimen. For these 10 participants, genotypic testing did not find emergence of resistance to either nucleoside reverse transcriptase or integrase strand transfer inhibitors.

Regarding renal biomarkers, increases of both serum creatinine and urinary excretion of protein creatinine were significantly greater in the 3-drug ARV group. Also, biomarkers indicating increased bone turnover were elevated in both groups, but the degree of elevation was significantly lower in the 2-drug ARV regimen cohort. It is unclear whether these findings reflect an increased or decreased risk of developing osteopenia or osteoporosis in the 2 study groups.

Conclusion. The once-daily 2-drug ARV regimen dolutegravir and lamivudine is noninferior to the guideline-recommended once-daily 3-drug ARV regimen dolutegravir, TDF, and emtricitabine at achieving viral suppression in ART-naive HIV-1 infected individuals with HIV RNA counts < 500,000 copies/mL. However, the efficacy of this ARV regimen may be compromised in individuals with CD4 counts < 200 cells/mL.

Currently, the mainstay of HIV pharmacotherapy is a 3-drug regimen consisting of 2 nucleoside reverse transcriptase inhibitors in combination with 1 drug from another class, with an integrase strand transfer inhibitor being the preferred third drug.⁶ Despite the improved tolerability of contemporary ARVs, there remains concern among HIV practitioners regarding potential toxicities associated with cumulative drug exposure, specifically related to nucleoside reverse transcriptase inhibitors. As a result, there has been much interest in evaluating 2-drug ARV regimens for HIV treatment in order to reduce overall drug exposure.^7-10

The 48-week results of the GEMINI-1 and GEMINI-2 trials, published in early 2019, further expand our understanding regarding the efficacy and safety of 2-drug regimens in HIV treatment. These identically designed studies evaluated once-daily dolutegravir and lamivudine for HIV in a treatment-naive population. This goes a step further than the SWORD-1 and SWORD-2 trials, which evaluated once-daily dolutegravir and rilpivirine as a step-down therapy for virologically suppressed individuals and led to the U.S. Food and Drug Administration (FDA) approval of the single-tablet combination regimen dolutegravir/rilpivirine (Juluca).¹⁰ Therefore, whereas the SWORD trials evaluated a 2-drug regimen for maintenance of virologic suppression, the GEMINI trials assessed whether a 2-drug regimen can both achieve and maintain virologic suppression.

The results of the GEMINI trials are promising for a future direction in HIV care. The rates of virologic suppression achieved in these trials are comparable to those seen in the SWORD trials.¹⁰ Furthermore, the virologic response seen in the GEMINI trials is comparable to that seen in similar trials that evaluated a 3-drug ARV regimen consisting of an integrase strand transfer inhibitor–based backbone in ART-naive individuals.^11,12

A major confounder to the design of this trial was that it included TDF as one of the components in the comparator arm, an agent that has already been demonstrated to have detrimental effects on both renal and bone health.^13,14 Additionally, the bone biomarker results were inconclusive, and the agents’ effects on bone would have been better demonstrated through bone mineral density testing, as had been done in prior trials.

Applications for Clinical Practice

Given the recent FDA approval of the single-tablet combination regimen dolutegravir and lamivudine (Dovato), this once-daily 2-drug ARV regimen will begin making its way into clinical practice for certain patients. Prior to starting this regimen, hepatitis B infection first must be ruled out due to poor efficacy of lamivudine monotherapy for management of chronic hepatitis B infection.¹⁵ Additionally, baseline genotype testing should be performed prior to starting this ART given that approximately 10% of newly diagnosed HIV patients have baseline resistance mutations.¹⁶ Obtaining rapid genotype testing may be difficult to accomplish in low-resource settings where such testing is not readily available. Finally, this approach may not be applicable to those presenting with acute HIV infection, in whom viral loads are often in the millions of copies per mL. It is likely that dolutegravir/lamivudine could assume a role similar to that of dolutegravir/rilpivirine, in which patients who present with acute HIV step down to a 2-drug regimen once their viral loads have either dropped below 500,000 copies/mL or have already been suppressed.

—Evan K. Mallory, PharmD, Banner-University Medical Center Tucson, and Norman L. Beatty, MD, University of Arizona College of Medicine, Tucson, AZ

Study Overview

Objective. To evaluate the efficacy and safety of a once-daily 2-drug antiretroviral (ARV) regimen, dolutegravir plus lamivudine, for the treatment of HIV-1 infection in adults naive to antiretroviral therapy (ART).

Design. GEMINI-1 and GEMINI-2 were 2 identically designed multicenter, double-blind, randomized, noninferiority, phase 3 clinical trials conducted between July 18, 2016 and March 31, 2017. Participants were stratified to receive 1 of 2 once-daily HIV regimens: the study regimen, consisting of once-daily dolutegravir 50 mg plus lamivudine 300 mg, or the standard-of-care regimen, consisting of once-daily dolutegravir 50 mg plus tenofovir disoproxil fumarate (TDF) 300 mg plus emtricitabine 200 mg. While this article presents results at week 48, both trials are scheduled to evaluate participants up to week 148 in an attempt to evaluate long-term efficacy and safety.

Setting and participants. Eligible participants had to be aged 18 years or older with treatment-naive HIV-1 infection. Women were eligible if they were not (1) pregnant, (2) lactating, or (3) of reproductive potential, defined by various means, including tubal ligation, hysterectomy, postmenopausal, and the use of highly effective contraception. Initially, eligibility screening restricted participation to those with viral loads between 1000 and 100,000 copies/mL. However, the upper limit was later increased to 500,000 copies/mL based on an independent review of results from other clinical trials^1,2 evaluating dual therapy with dolutegravir and lamivudine, which indicated efficacy in patients with viral loads up to 500,000.^3-5

Notable exclusion criteria included: (1) major mutations to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors; (2) evidence of hepatitis B infection; (3) hepatitis C infection with anticipation of initiating treatment within 48 weeks of study enrollment; and (4) stage 3 HIV disease, per Centers for Disease Control and Prevention criteria, with the exception of cutaneous Kaposi sarcoma and CD4 cell counts < 200 cells/mL.

Main outcome measures. The primary endpoint was demonstration of noninferiority of the 2-drug ARV regimen through assessment of the proportion of participants who achieved virologic suppression at week 48 in the intent-to-treat-exposed population. For the purposes of this study, virologic suppression was defined as having fewer than 50 copies of HIV-1 RNA per mL at week 48. For evaluation of safety and toxicity concerns, renal and bone biomarkers were assessed at study entry and at weeks 24 and 48. In addition, participants who met virological withdrawal criteria were evaluated for integrase strand transfer inhibitor mutations. Virological withdrawal was defined as the presence of 1 of the following: (1) HIV RNA > 200 copies/mL at week 24, (2) HIV RNA > 200 copies/mL after previous HIV RNA < 200 copies/mL (confirmed rebound), and (3) a < 1 log₁₀ copies/mL decrease from baseline (unless already < 200 copies/mL).

Main results. GEMINI-1 and GEMINI-2 randomized a combined total of 1441 participants to receive either the once-daily 2-drug ARV regimen (dolutegravir and lamivudine, n = 719) or the once-daily 3-drug ARV regimen (dolutegravir, TDF, and emtricitabine, n = 722). Of the 533 participants who did not meet inclusion criteria, the predominant reasons for exclusion were either having preexisting major viral resistance mutations (n = 246) or viral loads outside the range of 1000 to 500,000 copies/mL (n = 133).

Baseline demographic and clinical characteristics were similar between both groups. The median age was 33 years (10% were over 50 years of age), and participants were mostly male (85%) and white (68%). Baseline HIV RNA counts of > 100,000 copies/mL were found in 293 participants (20%), and 188 (8%) participants had CD4 counts of ≤ 200 cells/mL.

Noninferiority of the once-daily 2-drug versus the once-daily 3-drug ARV regimen was demonstrated in both the GEMINI-1 and GEMINI-2 trials for the intent-to-treat-exposed population. In GEMINI-1, 90% (n = 320) in the 2-drug ARV group achieved virologic suppression at week 48 compared to 93% (n = 332) in the 3-drug ARV group (no statistically significant difference). In GEMINI-2, 93% (n =335 ) in the 2-drug ARV group achieved virologic suppression at week 48 compared to 94% (n = 337) in the 3-drug ARV group (no statistically significant difference).

A subgroup analysis found no significant impact of baseline HIV RNA (> 100,000 compared to ≤ 100,000 copies/mL) on achieving virologic suppression at week 48. However, a subgroup analysis did find that participants with CD4 counts < 200 copies/mL had a reduced response in the once-daily 2-drug versus 3-drug ARV regimen for achieving virologic response at week 48 (79% versus 93%, respectively).

Overall, 10 participants met virological withdrawal criteria during the study period, and 4 of these were on the 2-drug ARV regimen. For these 10 participants, genotypic testing did not find emergence of resistance to either nucleoside reverse transcriptase or integrase strand transfer inhibitors.

Regarding renal biomarkers, increases of both serum creatinine and urinary excretion of protein creatinine were significantly greater in the 3-drug ARV group. Also, biomarkers indicating increased bone turnover were elevated in both groups, but the degree of elevation was significantly lower in the 2-drug ARV regimen cohort. It is unclear whether these findings reflect an increased or decreased risk of developing osteopenia or osteoporosis in the 2 study groups.

Conclusion. The once-daily 2-drug ARV regimen dolutegravir and lamivudine is noninferior to the guideline-recommended once-daily 3-drug ARV regimen dolutegravir, TDF, and emtricitabine at achieving viral suppression in ART-naive HIV-1 infected individuals with HIV RNA counts < 500,000 copies/mL. However, the efficacy of this ARV regimen may be compromised in individuals with CD4 counts < 200 cells/mL.

Currently, the mainstay of HIV pharmacotherapy is a 3-drug regimen consisting of 2 nucleoside reverse transcriptase inhibitors in combination with 1 drug from another class, with an integrase strand transfer inhibitor being the preferred third drug.⁶ Despite the improved tolerability of contemporary ARVs, there remains concern among HIV practitioners regarding potential toxicities associated with cumulative drug exposure, specifically related to nucleoside reverse transcriptase inhibitors. As a result, there has been much interest in evaluating 2-drug ARV regimens for HIV treatment in order to reduce overall drug exposure.^7-10

The 48-week results of the GEMINI-1 and GEMINI-2 trials, published in early 2019, further expand our understanding regarding the efficacy and safety of 2-drug regimens in HIV treatment. These identically designed studies evaluated once-daily dolutegravir and lamivudine for HIV in a treatment-naive population. This goes a step further than the SWORD-1 and SWORD-2 trials, which evaluated once-daily dolutegravir and rilpivirine as a step-down therapy for virologically suppressed individuals and led to the U.S. Food and Drug Administration (FDA) approval of the single-tablet combination regimen dolutegravir/rilpivirine (Juluca).¹⁰ Therefore, whereas the SWORD trials evaluated a 2-drug regimen for maintenance of virologic suppression, the GEMINI trials assessed whether a 2-drug regimen can both achieve and maintain virologic suppression.

The results of the GEMINI trials are promising for a future direction in HIV care. The rates of virologic suppression achieved in these trials are comparable to those seen in the SWORD trials.¹⁰ Furthermore, the virologic response seen in the GEMINI trials is comparable to that seen in similar trials that evaluated a 3-drug ARV regimen consisting of an integrase strand transfer inhibitor–based backbone in ART-naive individuals.^11,12

A major confounder to the design of this trial was that it included TDF as one of the components in the comparator arm, an agent that has already been demonstrated to have detrimental effects on both renal and bone health.^13,14 Additionally, the bone biomarker results were inconclusive, and the agents’ effects on bone would have been better demonstrated through bone mineral density testing, as had been done in prior trials.

Applications for Clinical Practice

Given the recent FDA approval of the single-tablet combination regimen dolutegravir and lamivudine (Dovato), this once-daily 2-drug ARV regimen will begin making its way into clinical practice for certain patients. Prior to starting this regimen, hepatitis B infection first must be ruled out due to poor efficacy of lamivudine monotherapy for management of chronic hepatitis B infection.¹⁵ Additionally, baseline genotype testing should be performed prior to starting this ART given that approximately 10% of newly diagnosed HIV patients have baseline resistance mutations.¹⁶ Obtaining rapid genotype testing may be difficult to accomplish in low-resource settings where such testing is not readily available. Finally, this approach may not be applicable to those presenting with acute HIV infection, in whom viral loads are often in the millions of copies per mL. It is likely that dolutegravir/lamivudine could assume a role similar to that of dolutegravir/rilpivirine, in which patients who present with acute HIV step down to a 2-drug regimen once their viral loads have either dropped below 500,000 copies/mL or have already been suppressed.

—Evan K. Mallory, PharmD, Banner-University Medical Center Tucson, and Norman L. Beatty, MD, University of Arizona College of Medicine, Tucson, AZ

Study Overview

Objective. To evaluate the efficacy and safety of a once-daily 2-drug antiretroviral (ARV) regimen, dolutegravir plus lamivudine, for the treatment of HIV-1 infection in adults naive to antiretroviral therapy (ART).

Design. GEMINI-1 and GEMINI-2 were 2 identically designed multicenter, double-blind, randomized, noninferiority, phase 3 clinical trials conducted between July 18, 2016 and March 31, 2017. Participants were stratified to receive 1 of 2 once-daily HIV regimens: the study regimen, consisting of once-daily dolutegravir 50 mg plus lamivudine 300 mg, or the standard-of-care regimen, consisting of once-daily dolutegravir 50 mg plus tenofovir disoproxil fumarate (TDF) 300 mg plus emtricitabine 200 mg. While this article presents results at week 48, both trials are scheduled to evaluate participants up to week 148 in an attempt to evaluate long-term efficacy and safety.

Setting and participants. Eligible participants had to be aged 18 years or older with treatment-naive HIV-1 infection. Women were eligible if they were not (1) pregnant, (2) lactating, or (3) of reproductive potential, defined by various means, including tubal ligation, hysterectomy, postmenopausal, and the use of highly effective contraception. Initially, eligibility screening restricted participation to those with viral loads between 1000 and 100,000 copies/mL. However, the upper limit was later increased to 500,000 copies/mL based on an independent review of results from other clinical trials^1,2 evaluating dual therapy with dolutegravir and lamivudine, which indicated efficacy in patients with viral loads up to 500,000.^3-5

Notable exclusion criteria included: (1) major mutations to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors; (2) evidence of hepatitis B infection; (3) hepatitis C infection with anticipation of initiating treatment within 48 weeks of study enrollment; and (4) stage 3 HIV disease, per Centers for Disease Control and Prevention criteria, with the exception of cutaneous Kaposi sarcoma and CD4 cell counts < 200 cells/mL.

Main outcome measures. The primary endpoint was demonstration of noninferiority of the 2-drug ARV regimen through assessment of the proportion of participants who achieved virologic suppression at week 48 in the intent-to-treat-exposed population. For the purposes of this study, virologic suppression was defined as having fewer than 50 copies of HIV-1 RNA per mL at week 48. For evaluation of safety and toxicity concerns, renal and bone biomarkers were assessed at study entry and at weeks 24 and 48. In addition, participants who met virological withdrawal criteria were evaluated for integrase strand transfer inhibitor mutations. Virological withdrawal was defined as the presence of 1 of the following: (1) HIV RNA > 200 copies/mL at week 24, (2) HIV RNA > 200 copies/mL after previous HIV RNA < 200 copies/mL (confirmed rebound), and (3) a < 1 log₁₀ copies/mL decrease from baseline (unless already < 200 copies/mL).

Main results. GEMINI-1 and GEMINI-2 randomized a combined total of 1441 participants to receive either the once-daily 2-drug ARV regimen (dolutegravir and lamivudine, n = 719) or the once-daily 3-drug ARV regimen (dolutegravir, TDF, and emtricitabine, n = 722). Of the 533 participants who did not meet inclusion criteria, the predominant reasons for exclusion were either having preexisting major viral resistance mutations (n = 246) or viral loads outside the range of 1000 to 500,000 copies/mL (n = 133).

Baseline demographic and clinical characteristics were similar between both groups. The median age was 33 years (10% were over 50 years of age), and participants were mostly male (85%) and white (68%). Baseline HIV RNA counts of > 100,000 copies/mL were found in 293 participants (20%), and 188 (8%) participants had CD4 counts of ≤ 200 cells/mL.

Noninferiority of the once-daily 2-drug versus the once-daily 3-drug ARV regimen was demonstrated in both the GEMINI-1 and GEMINI-2 trials for the intent-to-treat-exposed population. In GEMINI-1, 90% (n = 320) in the 2-drug ARV group achieved virologic suppression at week 48 compared to 93% (n = 332) in the 3-drug ARV group (no statistically significant difference). In GEMINI-2, 93% (n =335 ) in the 2-drug ARV group achieved virologic suppression at week 48 compared to 94% (n = 337) in the 3-drug ARV group (no statistically significant difference).

A subgroup analysis found no significant impact of baseline HIV RNA (> 100,000 compared to ≤ 100,000 copies/mL) on achieving virologic suppression at week 48. However, a subgroup analysis did find that participants with CD4 counts < 200 copies/mL had a reduced response in the once-daily 2-drug versus 3-drug ARV regimen for achieving virologic response at week 48 (79% versus 93%, respectively).

Overall, 10 participants met virological withdrawal criteria during the study period, and 4 of these were on the 2-drug ARV regimen. For these 10 participants, genotypic testing did not find emergence of resistance to either nucleoside reverse transcriptase or integrase strand transfer inhibitors.

Regarding renal biomarkers, increases of both serum creatinine and urinary excretion of protein creatinine were significantly greater in the 3-drug ARV group. Also, biomarkers indicating increased bone turnover were elevated in both groups, but the degree of elevation was significantly lower in the 2-drug ARV regimen cohort. It is unclear whether these findings reflect an increased or decreased risk of developing osteopenia or osteoporosis in the 2 study groups.

Conclusion. The once-daily 2-drug ARV regimen dolutegravir and lamivudine is noninferior to the guideline-recommended once-daily 3-drug ARV regimen dolutegravir, TDF, and emtricitabine at achieving viral suppression in ART-naive HIV-1 infected individuals with HIV RNA counts < 500,000 copies/mL. However, the efficacy of this ARV regimen may be compromised in individuals with CD4 counts < 200 cells/mL.

Currently, the mainstay of HIV pharmacotherapy is a 3-drug regimen consisting of 2 nucleoside reverse transcriptase inhibitors in combination with 1 drug from another class, with an integrase strand transfer inhibitor being the preferred third drug.⁶ Despite the improved tolerability of contemporary ARVs, there remains concern among HIV practitioners regarding potential toxicities associated with cumulative drug exposure, specifically related to nucleoside reverse transcriptase inhibitors. As a result, there has been much interest in evaluating 2-drug ARV regimens for HIV treatment in order to reduce overall drug exposure.^7-10

The 48-week results of the GEMINI-1 and GEMINI-2 trials, published in early 2019, further expand our understanding regarding the efficacy and safety of 2-drug regimens in HIV treatment. These identically designed studies evaluated once-daily dolutegravir and lamivudine for HIV in a treatment-naive population. This goes a step further than the SWORD-1 and SWORD-2 trials, which evaluated once-daily dolutegravir and rilpivirine as a step-down therapy for virologically suppressed individuals and led to the U.S. Food and Drug Administration (FDA) approval of the single-tablet combination regimen dolutegravir/rilpivirine (Juluca).¹⁰ Therefore, whereas the SWORD trials evaluated a 2-drug regimen for maintenance of virologic suppression, the GEMINI trials assessed whether a 2-drug regimen can both achieve and maintain virologic suppression.

The results of the GEMINI trials are promising for a future direction in HIV care. The rates of virologic suppression achieved in these trials are comparable to those seen in the SWORD trials.¹⁰ Furthermore, the virologic response seen in the GEMINI trials is comparable to that seen in similar trials that evaluated a 3-drug ARV regimen consisting of an integrase strand transfer inhibitor–based backbone in ART-naive individuals.^11,12

A major confounder to the design of this trial was that it included TDF as one of the components in the comparator arm, an agent that has already been demonstrated to have detrimental effects on both renal and bone health.^13,14 Additionally, the bone biomarker results were inconclusive, and the agents’ effects on bone would have been better demonstrated through bone mineral density testing, as had been done in prior trials.

Applications for Clinical Practice

Given the recent FDA approval of the single-tablet combination regimen dolutegravir and lamivudine (Dovato), this once-daily 2-drug ARV regimen will begin making its way into clinical practice for certain patients. Prior to starting this regimen, hepatitis B infection first must be ruled out due to poor efficacy of lamivudine monotherapy for management of chronic hepatitis B infection.¹⁵ Additionally, baseline genotype testing should be performed prior to starting this ART given that approximately 10% of newly diagnosed HIV patients have baseline resistance mutations.¹⁶ Obtaining rapid genotype testing may be difficult to accomplish in low-resource settings where such testing is not readily available. Finally, this approach may not be applicable to those presenting with acute HIV infection, in whom viral loads are often in the millions of copies per mL. It is likely that dolutegravir/lamivudine could assume a role similar to that of dolutegravir/rilpivirine, in which patients who present with acute HIV step down to a 2-drug regimen once their viral loads have either dropped below 500,000 copies/mL or have already been suppressed.

—Evan K. Mallory, PharmD, Banner-University Medical Center Tucson, and Norman L. Beatty, MD, University of Arizona College of Medicine, Tucson, AZ