Hepatitis C Drug Telaprevir Interacts with Common Antiretroviral Drugs

When Merck’s new hepatitis C drug boceprevir (Victrelis) was approved by the US Food and Drug Administration and European Commission last summer, the company’s stock and reputation got a nice boost from the first of what is expected to be a disease-changing class of drugs-the direct-acting antivirals (DAA’s). Now comes the bad news.

In mid February, Merck warned that when used in combination with ritonavir-boosted protease inhibitors (PIs), boceprevir significantly reduced the effectiveness of those drugs and is less effective itself. Specifically, it reduced the lowest blood levels of ritonavir-boosted atazanavir (Reyataz) and darunavir (Prezista) by 49% and 59% respectively, and the ritonavir/lopinavir combination Kaletra by 43%. There were also large reductions in the average and peak blood concentrations of all three drugs. In addition, Kaletra and ritonavir-boosted darunavir reduced boceprevir blood levels by 45% and 32%, respectively. 

The second approved DAA, telaprevir, has labeling that notes its “safety and efficacy . . . have not been established in patients co-infected with HCV/HIV,” but it appears to be safe when used with ritonavir-boosted atazanavir and efavirenz. 

This is a blow for patients, practitioners and, of course, Merck, given that about a third of those with HIV are co-infected with the hepatitis C virus (HCV). That figure is expected to rise as patients live longer with HIV and as the baby boomers develop complications from previously undiagnosed HCV infection.¹ Co-infected patients already exhibit worse HCV outcomes, with HIV infection increasing the rate of HCV progression to cirrhosis, end-stage liver disease, liver cancer, and death. Co-infected patients also have a 35% increased mortality rate compared to HIV mono-infected patients.^2-4

The drug-drug interaction between boceprevir and ritonavir-boosted antiretrovirals should come as no surprise; even before the new DAA therapies, significant interactions already occurred between ART and anti-HCV drugs, affecting about a third of co-infected patients.^{5, 6}

Articles published as early as 2010 predicted interactions between antiretrovirals and the DAA agents, which are structured similarly to HIV protease inhibitors and likely share a common route of metabolism.⁷ Indeed, laboratory studies found that small concentrations of the HIV drug ritonavir substantially inhibited the metabolism of the DAAs telaprevir (Incivek) and boceprevir, while co-dosing either drug with ritonavir increased the plasma exposure of both HCV compounds. This suggests that both are primarily or exclusively metabolized by CYP3A.^{7, 8} At least two HIV PIs inhibit this enzyme, while several non-nucleoside reverse transcriptase inhibitors are mediated by it.⁷

A week after Merck’s announcement, an international hepatitis C activist group called on regulators and pharmaceutical companies to conduct interaction studies involving HCV/HIV drugs as early as possible.

Until the results of those studies are known, healthcare practitioners who care for co-infected HIV/HCV patients need to tread carefully when introducing the new agents into therapeutic regimens, particularly when using them in conjunction with ritonavir-boosted ART.

References:

1. Ly KN, Xing J, Klevens RM, et al. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med. 2012;156(4):271-278.2. Giordano TP, Kramer JR, Souchek J, et al. Cirrhosis and hepatocellular carcinoma in HIV-infected veterans with and without the hepatitis C virus: a cohort study, 1992-2001. Arch Intern Med. 2004;164(21):2349-2354.3. Martinez-Sierra C, Arizcorreta A, Diaz F, et al. Progression of chronic hepatitis C to liver fibrosis and cirrhosis in patients coinfected with hepatitis C virus and human immunodeficiency virus. Clin Infect Dis. 2003;36(4):491-498.4. Chen TY, Ding EL, Seage Iii GR, et al. Meta-analysis: increased mortality associated with hepatitis C in HIV-infected persons is unrelated to HIV disease progression. Clin Infect Dis. 2009;49(10):1605-1615.5. Evans-Jones JG, Cottle LE, Back DJ, et al. Recognition of risk for clinically significant drug interactions among HIV-infected patients receiving antiretroviral therapy. Clin Infect Dis. 2010;50(10):1419-1421.6. de Maat MM, de Boer A, Koks CH, et al. Evaluation of clinical pharmacist interventions on drug interactions in outpatient pharmaceutical HIV-care. J Clin Pharm Ther. 2004;29(2):121-130.7. Seden K, Back D, Khoo S. New directly acting antivirals for hepatitis C: potential for interaction with antiretrovirals. J Antimicrob Chemother. 2010;65(6):1079-1085.8. Kempf DJ, Klein C, Chen HJ, et al. Pharmacokinetic enhancement of the hepatitis C virus protease inhibitors VX-950 and SCH 503034 by co-dosing with ritonavir. Antivir Chem Chemother. 2007;18(3):163-167.