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In May 2011, hepatitis C virus (HCV) protease inhibitors (PIs) were approved by the US Food and Drug Administration to treat persons with genotype 1 chronic hepatitis C virus (HCV) infection, but not those dually infected with human immunodeficiency virus (HIV). Although critical safety and efficacy data are lacking, the availability of the drugs and substantial medical need justify the off-label use of HCV PIs in select HIV/HCV-coinfected persons. Pending results of ongoing investigations, this article represents provisional guidance on the use of HCV PIs in HIV-infected persons.
On 13 May 2011 and 23 May 2011, boceprevir (BOC) and telaprevir (TVR), respectively, were approved by the US Food and Drug Administration to be used with peginterferon and ribavirin for treatment of genotype 1 chronic hepatitis C virus (HCV) infection. Use of these NS3/4A serine protease inhibitors (PIs) with peginterferon and ribavirin improves sustained virologic response by 25%–31% in human immunodeficiency virus (HIV)–uninfected persons [1, 2]. These efficacy data and drug availability raise the question of whether HCV PIs should be used in HIV/HCV-coinfected persons pending final results of ongoing phase 2 and subsequent phase 3 clinical trials of both BOC and TVR. Lacking the relevant data on HIV/HCV-coinfected persons, clinical and policy decisions must be made largely on data from HIV-uninfected persons. The following opinions were provided to the Maryland AIDS Assistance Program and may be useful to others.
In the only data available in the public domain, HIV/HCV-coinfected individuals taking no antiretroviral therapy (ART) with well-controlled HIV infection (n = 13) or taking tenofovir/emtricitabine with either efavirenz (n = 24) or ritonavir-boosted atazanavir (n = 22) were randomized to peginterferon and ribavirin for 48 weeks or TVR plus peginterferon and ribavirin for the first 12 weeks, followed by the continuation of peginterferon and ribavirin for 36 additional weeks . Notably, shortened durations of treatment with response-guided therapy to TVR are not currently being evaluated in HIV/HCV-coinfected patients. Baseline HCV RNA was >800 000 IU/mL for 83%; 69% of patients were white, and only 2 had cirrhosis. Telaprevir was given 750 mg every 7–9 hours with food with ≥20 g of fat (or 1125 mg every 7–9 hours if also taking efavirenz). The proportion of persons with undetectable HCV RNA at week 4 (26 of 38 [68%]) was substantially greater in the TVR arms than with placebo (0 of 22 [0%]). Likewise, at the planned week 12 evaluation, virologic responses were superior in the TVR arm (Figure 1). There were no unexpected adverse events reported through week 12. There were no instances of HIV breakthrough, but 2 patients experienced HCV breakthrough that is typically associated with resistance. In the TVR group, there were more skin and gastrointestinal complaints and 2 patients discontinued due to adverse events (jaundice and anemia). Complete safety and efficacy data to register TVR with peginterferon and ribavirin for use in HIV/HCV-coinfected individuals are not anticipated before 2013.
A phase 2 trial of BOC in combination with peginterferon and ribavirin in HIV/HCV-coinfected persons is ongoing. In this study, 99 HIV/HCV-coinfected patients with stable HIV disease are being treated with an initial 4 weeks of peginterferon plus weight-based ribavirin (lead-in), then randomized 2:1 to the addition of BOC 800 mg every 7–9 hours or placebo to peginterferon alfa and ribavirin for an additional 44 weeks (total therapy, 48 weeks). Subjects were excluded if they were on zidovudine, didanosine, stavudine, efavirenz, etravirine, or nevirapine. Raltegravir and ritonavir-boosted PIs were permitted. An interim analysis was presented for 98 patients (34 placebo and 64 boceprevir) . Baseline HCV RNA was >800 000 IU/mL for 88%; 82% were white; and 5% had cirrhosis. The proportion of persons for whom HCV RNA was undetectable at treatment week 8 (4 weeks of boceprevir vs placebo) was higher in those taking BOC (24 of 64 [37.5%]) than in those taking placebo (5 of 34 [14.7%]) (Figure 2). Likewise, at treatment week 24, HCV was undetectable in 43 of 61 patients (70.5%) in the BOC arm compared with 11 of 32 (34.4%) in the placebo arm. Treatment was discontinued due to an adverse event in 3 (9%) and 9 (14%) of the patients in the placebo and BOC arms, respectively. Complete safety and efficacy data to register BOC with peginterferon and ribavirin for use in HIV/HCV-coinfected individuals are not anticipated before 2013.
Pending more conclusive data and regulatory approval, decisions to use or withhold HCV PIs in HIV/HCV-coinfected persons must take into account multiple related factors. On the one hand, liver fibrosis progression is more rapid and peginterferon and ribavirin treatment is less effective in HIV/HCV-coinfected persons than in those without HIV, and liver transplantation is neither widely available nor highly successful in HIV/HCV-coinfected persons . On the other hand, the safety and efficacy of HCV PIs are largely unproven in HIV/HCV-coinfected persons, data regarding drug-drug interactions are limited, additional anti-HCV medications are being developed, and the price of HCV PIs may add to the cost of the peginterferon and ribavirin treatment regimen. At current cost levels used by the Maryland AIDS Administration and dosing used in phase 2 studies, a full course of BOC would add $51116, while a full course of TVR would add $51 957 or $77 936 (for the additional pill required for coadministration with efavirenz [EFV]). The collective cost of HCV medications could detract from funds available for other medications, and the cost-effectiveness of treatments for HCV has not been rigorously compared with treatments already being supported for HIV.
Until additional data or alternative treatments are available, some experts believe that HCV PIs should be used in combination with peginterferon and ribavirin in certain HIV/HCV-coinfected persons. Since AIDS drug assistance programs will need to consider the provision of HCV PIs alongside other competing priorities, the following interim information was provided by an expert panel in June 2011 to the Maryland AIDS Drug Assistance Program regarding the use of HCV PIs in HIV/HCV-coinfected persons:
Telaprevir is a P-glycoprotein and CYP3A4 substrate and inhibitor . Blood concentrations are reduced by ritonavir-boosted fosamprenavir, darunavir, lopinavir, and, to a lesser extent, atazanavir (Table 1) . Efavirenz also reduces blood concentrations of TVR, an effect that can, in part, be offset by using a higher TVR dose (1125 every 8 hours). TVR use significantly reduces the concentrations of darunavir and fosamprenavir. Boceprevir is primarily metabolized by aldo-keto reductases, and to a lesser extent, may undergo oxidative metabolism and excretion via CYP3A4/5, other complex enzymes, and drug transporters (Table 2) [10, 11]. In healthy volunteers taking both medications, BOC AUC concentrations are decreased 19%, 32%, 45%, with EFV, DRV/r, and LPV/r, respectively.
Likewise, coadministration is associated with a reduction in AUC of ATV, DRV, and LPV of 33%, 43%, 32%, respectively.
Similar to TVR, BOC is an inhibitor of CYP3A4 that increases concentration of substrates such as midazolam, tacrolimus, and atorvastatin.
Approvals of boceprevir and telaprevir for treatment of HCV infection are major advances for the care of persons with chronic genotype 1 HCV infection. Although the medications are not approved by the US Food and Drug Administration for treatment of HIV/HCV-coinfected persons, the benefits of including these medications will outweigh the risks for some individuals. In the future, HIV/HCV-coinfected persons should be included at earlier stages in drug development so that practice guidelines can be based more on data and less on expert opinion.
This research was supported in part by US Public Health Service grants (R01016027 to D. T. and K24DK070528 to K. E. S.).
M. P. has served as an advisor to Roche, Merck, and Vertex. K. E. S. has served as an advisor for Merck, Vertex, Genentech, Bristol-Myers Squibb (BMS), Regulus, GlaxoSmithKline, SciClone, and Boehringer Ingelheim, and has institutionally contracted research associations with Merck/SPRI, Vertex, Genentech, BMS, SciClone, Boehringer Ingelheim, Anadys, and Gilead during the last 12 months. M. S. S. has served as an advisor for Merck, Vertex, Roche, BMS, Boehringer Ingelheim, Pharmasset, Gilead, and Abbott and has institutionally contracted research (paid to Johns Hopkins University) with Merck, Vertex, Roche, BMS, Boehringer Ingelheim, Pharmasset, Gilead, and Abbott. D. T. has served as an advisor for Merck and has received support for National Institutes of Health–funded clinical trials from Merck and Gilead. All other authors report no potential conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.