New protease inhibitors showing promise for HIV/HCV coinfection

  • August 28, 2013

This is an exciting time in the treatment of chronic hepatitis C virus infections. As opposed to the antibiotic pipeline, there are a number of new antiviral agents for treatment of hepatitis C in development that may transform the way these patients are treated.

Chronic infection with HCV has emerged as a major cause of morbidity and mortality in those living with HIV infection. Approximately 15% to 30% of patients with HIV in the United States are estimated to be coinfected with HIV and HCV. All patients with HIV/HCV coinfection should be evaluated for HCV therapy because of the more rapid progression of liver disease in those with HCV alone, and because the successful treatment of HCV may also reduce the risk for hepatotoxicity from the use of HAART in these patients.

Jeff Brock

The treatment for HCV has become increasingly successful, but it is complex, particularly in the HIV coinfected patient who is often on multiple medications and has other barriers to care. Treatment of both HIV and HCV is feasible, although it can be complicated because of the high pill burden, drug interactions and overlapping adverse effects that require careful monitoring.

Available treatment options

The currently available treatment regimens for HCV leave much to be desired. They have poor safety profiles, tolerability issues and low success rates, particularly in the HIV/HCV coinfected patients. While the treatment of HIV has led to reduced mortality during the past 15 years, the treatment of HCV has essentially remained unchanged with pegylated interferon alfa plus ribavirin (PegIFN/RBV).

PegIFN/RBV is recommended for those HIV/HCV coinfected patients who are at the greatest risk for developing liver disease. Pegylated interferon has covalently bound molecules of polyethylene glycol that slow the metabolism of interferon, which permits a weekly dosing schedule, increased serum levels, and improved activity against HCV. The primary goal in HCV treatment is to achieve a sustained viral response, which is defined as an undetectable HCV RNA 24 weeks after the end of therapy. HCV treatment in HIV/HCV coinfected patients is complicated by low rates of treatment initiation, higher rates of contraindications to the medications and a low sustained virologic response in those who are treated for HCV.

The two newest agents available are boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex Pharmaceuticals), which are protease inhibitors specific for HCV. They were approved in the United States and Europe in 2011 for use in combination with PegIFN/RBV among HIV-negative patients with HCV genotype-1 infection only. The approval was based on randomized trials demonstrating that patients achieved a greater sustained viral response with triple therapy compared with standard dual therapy in those who were either treatment-naive or were treated previously, but were nonresponders. Despite not being FDA-approved for treatment of HIV/HCV coinfected patients, use of these agents in this patient population is evolving because of the disappointing success with standard treatment.

Evolving therapies for HIV/HCV

A newly published controlled trial conducted by Sulkowski and colleagues randomly assigned 60 patients with HIV and HCV genotype-1 infection to 12 weeks of pegylated interferon alfa-2a and ribavirin, plus either placebo or telaprevir, followed by 36 weeks of peginterferon with ribavirin. After 4 weeks of therapy, 68% of the patients in the telaprevir group had undetectable HCV RNA, whereas 0% of those in the control arm had this response. The sustained viral response was achieved in 74% of patients in the telaprevir treatment group vs. 45% of those in the control group. Reported adverse effects were more common with telaprevir-treated patients, specifically pruritus, dizziness, headache, nausea, rash and anemia. Telaprevir is a substrate and an inhibitor of CYP3A4 and p-glycoprotein enzymes, so interactions with antiretrovirals metabolized by these pathways may occur.

Drug interactions possible

To date, there is less published data available for treatment of HIV/HCV coinfected patients with boceprevir. A phase 2a study was presented at the 19th CROI meeting comparing boceprevir or placebo combined with PegIFN/RBV for the treatment of chronic HCV genotype-1 infection in adults. Ninety-eight patients were given 4 weeks of lead-in treatment with PegIFN/RBV, followed by 44 weeks of combination therapy of boceprevir 800 mg every 8 hours, plus PegIFN/RBV. Patients assigned efavirenz (Sustiva, Bristol-Myers Squibb) or other non-nucleoside reverse transcriptase inhibitors were not enrolled based on previous drug interaction studies.

The sustained viral response at week 12 was higher in the boceprevir treatment group (67.7%) compared with PegIFN/RBV alone (26.5%). Reported adverse effects were common among patients who received boceprevir, with a greater frequency of anemia, neutropenia, pyrexia, decreased appetite, diarrhea, vomiting, and taste disturbances. Boceprevir is metabolized by aldo-keto reductase, but it is also a substrate and inhibitor of CYP3A4/5 and p-glycoprotein enzymes, so drug-drug interactions may occur. When boceprevir is administered with efavirenz, and ritonavir-boosted regimens of atazanavir, darunavir (Prezista, Janssen Therapeutics), lopinavir and raltegravir (Isentress, Merck), bidirectional interactions occur, so concomitant use is not recommended. If patients are taking an HIV protease inhibitor along with boceprevir, then consideration should be given to changing the HIV protease inhibitor or efavirenz to raltegravir.

Telaprevir and boceprevir are the first generation of direct-acting antiviral agents that have improved the sustained viral response for HCV genotype-1 infections. However, PegIFN/RBV treatment is still required. Although use of telaprevir or boceprevir in the HIV/HCV coinfected patient would be considered off-label, consideration should be given to utilizing these agents when HCV treatment is desired because the current evidence shows a substantial improvement in treatment success.

However, use of these medications along with PegIFN/RBV presents several challenges such as substantial side effects, drug-drug interactions and increased costs. There are several direct-acting antiviral agents in the pipeline that will likely yield higher sustained viral response, shorter treatment durations, lower pill burden and improved safety profiles. Until they are available, careful selection of patients who may benefit from a HCV-specific protease inhibitor may help improve the outcomes of the HIV/HCV infected patient.

- By Jeff Brock, PharmD

References:

Ghany MG. Hepatology. 2011;54:1433-1444.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.
Sulkowski MS. Ann Intern Med. 2013;159:86-96.
Sulkowski MS. J Infect Dis. 2013;207(suppl 1):s26-s32.

Disclosure: Brock reports no relevant financial disclosures.