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.
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.