There is a huge need for improved treatments for hepatitis C, particularly in patients with HIV/HCV coinfection and subgroups thereof (eg, African Americans, those with genotype 1 virus), in whom rates of HCV cure are particularly low with standard therapies. Investigational drugs in new classes, so-called direct antiviral agents (DAAs), given in combination with pegylated interferon and ribavirin, have been shown to improve rates of sustained virologic response (SVR) in HCV-monoinfected patients, and several studies presented at CROI this year provided data on efficacy of new agents (in particular the HCV protease inhibitors telaprevir and boceprevir) in HCV-monoinfected patients.(1),(2) And, importantly, the researchers offered a first glimpse of data on efficacy and safety of telaprevir in HIV/HCV-coinfected persons.(3) This was an interim analysis, examining data only through week 12 (of a planned 48-week treatment course) on 41 patients undergoing treatment in a Phase IIA double-blind study of telaprevir vs placebo, each in combination with peginterferon alfa-2a and ribavirin. Patients had genotype 1 HCV, no previous HCV treatment, and were either a) on no ART with CD4 counts of ≥500 cells/µL and HIV RNA levels of <100,000 copies/mL; or, b) on ART with CD4 counts of ≥300 cells/µL and suppressed HIV. Subjects receiving ART were on either atazanavir/ritonavir or efavirenz with tenofovir/emtricitabine (or lamivudine). Patients within each group were randomized to telaprevir or placebo for the first 12 weeks of therapy, and all were treated with peginterferon alfa-2a and ribavirin (for a planned total of 48 weeks). (In the efavirenz group, the telaprevir dosage was increased to compensate for a known interaction with efavirenz.) The treatment groups were generally well matched at baseline for HCV and HIV factors; the median CD4 count was >500 cells/µL.
By intention-to-treat (ITT) analysis, virologic response rates at weeks 4 and 12 were substantially higher in telaprevir recipients than in controls. At week 4, 70% in the telaprevir groups combined and 5% in the placebo groups combined achieved undetectable HCV RNA levels (rapid virologic response, RVR). At week 12, 68% of telaprevir recipients and 14% of controls had undetectable HCV RNA levels (complete early virologic response, EVR). Of the telaprevir groups, response rates were lower in the atazanavir/ritonavir subgroup at each time point than in either the no-ART or the efavirenz subgroup, though the sample size was small, and conclusions about relative efficacy cannot be made.
HCV virologic failure was seen in 3 telaprevir recipients and 3 placebo recipients (no resistance data were available), and no loss of HIV control was seen in ART recipients. In the no-ART group, a decrease in HIV RNA was seen, consistent with the interferon effect seen in other studies. Median trough concentrations of telaprevir were similar in each ART group and the no-ART group, whereas median trough concentrations of atazanavir, efavirenz, and tenofovir decreased up to 20% in the telaprevir groups, a result that reportedly was similar in placebo groups (data not shown). Telaprevir recipients had higher rates of certain adverse events, including nausea, vomiting, anorexia, fever, pruritus, and rash, compared with controls, but few patients discontinued treatment because of adverse events.
Clinical Bottom Line
RVR and EVR are important predictors of successful HCV treatment (SVR), so it is very promising to see that treatment with telaprevir + peginterferon alfa-2a and ribavirin yields impressively high EVR rates in coinfected genotype 1 patients. SVR results from this study should be presented later this year, and Phase III studies of both telaprevir and boceprevir in HIV/HCV-coinfected patients are under way. These agents are expected to be approved by the U.S. Food and Drug Administration in 2011, and studies of other DAA drugs are in clinical trials.
The availability of these new DAA agents is expected to significantly advance the treatment of HCV in both monoinfected and HIV/HCV-coinfected patients, but many complex treatment issues require study, including basic issues such as length of therapy, the timing and duration of DAA therapy, optimizing outcomes in hard-to-treat patient groups, management of HCV resistance to these agents, and drug-drug interactions. Importantly, both telaprevir and boceprevir appear to have significant interactions with PIs and NNRTIs, via CYP P450 effects, and these have not been well studied. An excellent overview of HCV therapy, titled "New Antiviral Therapies in the Management of HCV Infection," was given by Stefan Zeuzem at the conference, and a webcast of this presentation is available via the CROI website.