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.