Triple Therapy Boosts HCV Response After Transplant



BOSTON – Liver transplant recipients with hepatitis C virus infection who underwent triple-drug therapy achieved a high extended rapid virologic response rate but often contended with treatment complications in a retrospective multicenter cohort study.

The extended rapid virologic response (eRVR) rate seen in 57% of patients was "encouraging, given a very difficult-to-cure population," Dr. James R. Burton, Jr., said at the annual meeting of the American Association for the Study of Liver Diseases. He noted, however, that it’s not clear if the encouraging eRVR rate will predict sustained virologic response (SVR) as it does in non-liver transplant patients.

Dr. James R. Burton, Jr.

The use of peginteferon plus ribavirin in liver transplant recipients with hepatitis C virus infection has an SVR of only 30%. While triple therapy with peginterferon, ribavirin, and a protease inhibitor (boceprevir or telaprevir) has significantly improved rates of SVR in patients infected with genotype 1 hepatitis C virus, its safety and efficacy in liver transplant recipients is unknown, said Dr. Burton, medical director of liver transplantation at the University of Colorado Hospital, Aurora.

With 101 patients, the five-center study is the largest involving triple therapy in liver transplant recipients with hepatitis C virus infection.

Telaprevir was the protease inhibitor used most often in patients (90% vs. 10% with boceprevir). Nearly all patients (96%) had a lead-in treatment phase with peginterferon plus ribavirin. A minority of patients (14%) had an extended lead-in phase of at least 90 days (median of 189 days) and were excluded from efficacy, but not safety, analyses. The other patients had a lead-in lasting a median of 29 days. The patients with a long lead-in phase had a median of 398 total treatment days, compared with a median of 154 days for those with a shorter lead-in time.

The efficacy study population involved genotype 1–infected patients (54% genotype 1a, 39% 1b, and 7% mixed) from five medical centers. Most patients were men (76%); they had a median age of 58 years and a median duration of 54 months from their liver transplant to starting a protease inhibitor. An unfavorable IL28B genotype was found in 69% of 45 patients tested. In the 60% of patients who had undergone previous antiviral therapy, 29% had a partial response. On liver biopsy, another 47% of patients had either bridging fibrosis or cirrhosis.

The immunosuppressive agents used by the patients included cyclosporine (66%) and tacrolimus (23%). A small percentage did not receive a calcineurin inhibitor or rapamycin. Another 27% were taking corticosteroids, and 72% were taking mycophenolate mofetil or mycophenolic acid.

On treatment, the percentage of patients who had an HCV RNA level less than the limit of detection increased from 55% at 4 weeks to 63% at 8 weeks. At 12 weeks the percentage was 71%. An eRVR, defined as negative HCV RNA tests at 4 and 12 weeks, occurred in 57%. An eRVR occurred significantly more often among patients who had at least a 1 log drop in HCV RNA levels during the lead-in phase than did those with less than a 1 log drop (76% vs. 35%).

Overall, 12% of patients experienced virologic breakthrough, and treatment was stopped. This occurred more often among those with a long lead-in vs. those with a short lead-in (21% vs. 10%, respectively). Another 14% discontinued treatment early because of an adverse event; discontinuations occurred more often among patients with a long lead-in (40% vs. 11%).

Protease inhibitors are known to inhibit the metabolism of calcineurin inhibitors, which was reflected in the study by the need to reduce the median daily doses of cyclosporine (from 200 mg to 50 mg) and tacrolimus (from 1.0 mg to 0.06 mg) after protease inhibitor therapy began.

Many patients (49%) required blood transfusions during triple therapy. During the first 16 weeks of therapy, these patients used a median of 2.5 units. The majority of patients (86%) used growth factors, including granulocyte-colony stimulating factor in 44% and erythropoietin in 79%. Medication dose reductions were most frequent for ribavirin (in 78%). A total of 7% were hospitalized for anemia, Dr. Burton said.

Renal insufficiency, defined as an increase in creatinine of greater than 0.5 mg/dL from baseline, developed in 32%. Of two rejection episodes in the study, one involved a patient coming off a protease inhibitor.

Dr. Burton suggested that future studies should focus on identifying predictors for nonresponse to avoid unnecessary treatment and associated toxicities such as complications of anemia and adverse events related to significant protease inhibitor–calcineurin inhibitor interactions, such as worsening renal function and graft rejection when transitioning off a protease inhibitor.


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