March 7, 2012
A very significant number of people living with HIV are also living with chronic hepatitis virus infection. Viral hepatitis infection appears to be an ever-increasing cause of morbidity and mortality among coinfected persons. While less common among the people that I care for in Colorado (U.S.), hepatitis C virus (HCV) coinfection will likely have devastating effects in many parts of the world, including Eastern Europe and Central Asia. Until very recently, treatment for viral hepatitis left much to be desired, with a less than optimal side effect profile and even less optimal sustained viral response (SVR) rates.
This situation has led to a relative reluctance among patients and providers alike to widely adopt treatment for viral hepatitis, especially HCV. All of this is changing. This field is the Wild West of drug discovery -- unless one closely follows the major research conferences, it's easy for practicing clinicians to be bewildered and run over by the veritable stampede of clinical studies and findings.
The first two U.S. Food and Drug Administration (FDA)-approved direct-acting antiviral (DAA) agents for HCV, the NS3A/4 protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek), were approved for use in monoinfected HCV genotype 1 patients last year. A significant knowledge gap exists with respect to their safety, effectiveness and drug-drug interaction risk among HCV/HIV-coinfected persons.
Some key findings and my impressions:
Back-to-back presentations by key academic leaders on HCV/HIV treatment give us reason for enthusiasm.
Doug Dieterich from the Mount Sinai School of Medicine in New York presented the results of a phase 2, randomized, placebo-controlled, parallel-group clinical trial of 12 weeks of therapy of telaprevir + pegylated interferon + ribavirin (T/PR) versus placebo followed by 36 weeks of PR (abstract 46). The patient could either be on no antiretroviral therapy or on antiretroviral therapy consisting of either efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC, Atripla) or ritonavir (RTV, Norvir)-boosted atazanavir (ATV, Reyataz) + tenofovir (TDF, Viread) + emtricitabine (FTC, Emtriva) (or lamivudine [3TC, Epivir]). Pharmacokinetic analysis showed no significant interactions between telaprevir and the antiretroviral medications used. The T/PR group had an overall SVR rate of 74% versus 45% for the placebo group. Rash was the most common side effect, seen in about a third of T/PR patients (compared with 23% in the placebo group). Among those patients receiving antiretroviral therapy, there was no HIV RNA breakthrough, suggesting that HCV treatment didn't compromise HIV treatment.
Newly promoted Johns Hopkins University professor Mark Sulkowski presented the analogous 48-week interim results of a study of boceprevir + PR among previously untreated genotype 1 HCV/HIV-coinfected persons (abstract 47). Patients had to have undetectable HIV viral loads and could not be taking an antiretroviral therapy regimen that included an NNRTI, zidovudine (AZT, Retrovir) or didanosine (ddI, Videx). The patients received HCV treatment for 44 weeks. At the end of therapy, 73% versus 32% of the patients achieved a SVR. The tolerability and safety of boceprevir/PR in this study (as was noted in the telaprevir coinfection study) appeared similar to the HCV monoinfected clinical trials, with anemia and neutropenia as the more commonly observed side effects.
One poster presentation (abstract 754) suggests that at least early on-treatment HCV RNA responses to telaprevir are the same in HCV/HIV-coinfected persons as HCV-monoinfected patients.
Drug-drug interactions between the DAA protease inhibitors are an important area of concern and have received recent attention. Last month, investigators from Merck released information that showed significant drug-drug interactions between boceprevir and the ritonavir-boosted HIV protease inhibitors (abstract 771LB). Fortunately, boceprevir does not appear to cause meaningful changes in raltegravir (RAL, Isentress) levels, suggesting a niche for the HIV integrase inhibitor in the treatment of coinfected persons (abstract 772LB). In vitro drug-drug interaction analysis of telaprevir (abstract 756) showed no significant interactions with the HIV protease inhibitors amprenavir (APV, Agenerase), darunavir (TMC114, Prezista) and lopinavir/ritonavir (LPV/r, Kaletra) and minor interactions with atazanavir.
Together, these studies provide some of the first clinical trial evidence suggesting high response rates among HCV genotype 1/HIV-coinfected patients receiving antiretroviral therapy. Providers will need to be mindful of potential drug-drug interactions between HIV and HCV medications. The addition of either HCV protease inhibitor to conventional pegylated interferon/ribavirin therapy significantly improves response rates, even to the difficult to treat HCV genotype 1 and does not appear to be associated with an increased side effect profile or loss of HIV control.
As good as these clinical trial data are, treatment for HCV still appears to require the cumbersome and side-effect-prone pegylated interferon and ribavirin. For many patients, the prospect of interferon-related side effects (never mind the injections) is sufficient reason not to start on therapy. Hence, a tantalizing goal might be an effective interferon-free treatment regimen. Early data on anti-HCV nucleoside therapies from the biotech company Pharmasset have been quite encouraging and the enthusiasm further sparked by Gilead's gigantic US$11 billion purchase of the company.
Late breaking preliminary data of patients from the GS-7977 (also known as PSI-7977) Pharmasset/Gilead ELECTRON study on HCV-monoinfected patients provided further reason for belief in an interferon-free world (abstract 54LB). In this study, HCV-monoinfected patients received the GS-7977 nuke with ribavirin (but no interferon) for 12 weeks. All patients had a rapid viral response by week 4 and all 25 treatment-naive patients achieved a SVR and there was no HIV breakthrough. The treatment seems to be well tolerated. Previous null responders relapsed at the end of GS-7977/ribavirin treatment. The authors speculated that these patients might require longer treatment or a second DAA.
So, the transformation of the treatment of HCV continues. While still early, the data on the treatment of HIV-coinfected persons is very affirmative and likely enough to move forward (carefully) with DAA treatment of those persons who are at risk for liver complications. The future for HCV treatment looks bright and I'm expecting an interferon-free day in the not-so-distant future.
|Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.|