Does nevirapine improve hepatitis C treatment outcomes in HIV/HCV co-infected individuals?

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HIV/hepatitis C (HCV) co-infected people who included nevirapine (Viramune) in their antiretroviral therapy (ART) regimen were more likely to achieve sustained response to interferon-based therapy for chronic hepatitis C, according to a Spanish study presented on Tuesday at the Eighteenth International AIDS Conference in Vienna.

The researchers suggested nevirapine may lower HCV viral load and thereby improve treatment response, but an alternative explanation is that people who are prescribed this drug are less sick at the outset, and therefore more likely to respond to HCV treatment in any case.

Jose Mira, from Valme University Hospital in Seville, and colleagues evaluated the effectiveness of chronic hepatitis C treatment using pegylated interferon plus ribavirin in HIV/HCV co-infected patients using different antiretroviral regimens.

Glossary

pegylated interferon

Pegylated interferon, also known as peginterferon, is a chemically modified form of the standard interferon, sometimes used to treat hepatitis B and C. The difference between interferon and peginterferon is the PEG, which stands for a molecule called polyethylene glycol. The PEG does nothing to fight the virus. But by attaching it to the interferon (which does fight the virus), the interferon will stay in the blood much longer. 

sustained virological response (SVR)

The continued, long-term suppression of a virus as a result of treatment. In hepatitis C, refers to undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 12 or 24 weeks after ending treatment and is considered to be a cure (SVR12 or SVR24).

fibrosis

Scarring of the liver – the development of hard, fibrous tissue. See also ‘cirrhosis’, which is more severe scarring.

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

inflammation

The general term for the body’s response to injury, including injury by an infection. The acute phase (with fever, swollen glands, sore throat, headaches, etc.) is a sign that the immune system has been triggered by a signal announcing the infection. But chronic (or persisting) inflammation, even at low grade, is problematic, as it is associated in the long term to many conditions such as heart disease or cancer. The best treatment of HIV-inflammation is antiretroviral therapy.

Prior research suggested that certain nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) used to treat HIV are associated with poorer response to interferon, perhaps due to drug interactions or intensified side-effects.

The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and HIV protease inhibitors is less well studied, and what research there is has produced conflicting findings. A study called RIBAVIC, for example, found that use of HIV protease inhibitors was associated with less successful hepatitis C treatment, but others have not seen a similar link.

Some reports suggest that co-infected patients on nevirapine-based ART have lower plasma HCV RNA levels than those treating their HIV with a protease inhibitor or an alternative NNRTI, efavirenz (Sustiva, Stocrin). Lower HCV viral load, in turn, is a predictor of better hepatitis C treatment outcomes.

Mira's team retrospectively compared the efficacy of hepatitis C treatment between 71 HIV/HCV co-infected individuals taking nevirapine and 94 taking lopinavir/ritonavir (Kaletra) at hospitals in Spain between 2002 and 2009. All participants rounded out their ART regimens with tenofovir (Viread) plus either 3TC (Epivir) or emtricitabine (Emtriva).

Baseline demographic factors were similar in both study arms. About three-quarters of participants were men, the median age was just over 40 years, and about 80% had a history of injecting drug use. Both groups had well-controlled HIV disease with a CD4 cell count of approximately 450 cells/mm3. About 60% in both groups had hard-to-treat HCV genotypes 1 or 4.

But significantly more participants in the lopinavir/ritonavir group had advanced liver fibrosis (stage F3 or greater; 52 vs 21%) and high baseline HCV viral load (> 600,000 IU/ml; 73 vs 44%).

Participants were treated for chronic hepatitis C for the first time using a standard regimen of pegylated interferon (Pegasys or PegIntron) plus weight-adjusted ribavirin. People with HCV genotypes 1 or 4 were treated for 48 weeks, whilst those with the more responsive genotypes 2 or 3 completed treatment after 24 weeks. About 90% of participants in both groups reported good adherence. They were permitted to use blood cell growth factors to manage the side-effects of neutropenia due to interferon and anaemia caused by ribavirin.

People taking nevirapine were significantly more likely than those taking lopinavir/ritonavir to achieve sustained virological response (SVR), or continued undetectable HCV viral load six months after finishing treatment. In an intent-to-treat analysis, overall SVR rates were 56 vs 37%, respectively (43 vs 25% for patients with genotypes 1 or 4; 78 vs 59% for those with genotypes 2 or 3).

Lack of SVR was mainly attributable to non-response, occurring in 8% of nevirapine recipients and with 23% of lopinavir/ritonavir recipients. Rates of relapse, viral breakthrough and discontinuation due to adverse events were similar in both arms.

When participants were classified according to viral load, however, divergent response associated with antiretroviral drug choice was only apparent amongst participants with high HCV viral load.

The researchers concluded that HIV/HCV co-infected people who use nevirapine for ART respond better to pegylated interferon plus ribavirin than those who use lopinavir/ritonavir. Mira proposed that the lower HCV viral load levels seen in nevirapine users might account for this difference in response rates.

Session moderator Jürgen Rockstroh called this interpretation into question, however. Whilst Mira credited nevirapine with lowering HCV viral load, another possible explanation is that participants taking lopinavir/ritonavir may be sicker on average, because traditional ART sequencing starts with a NNRTI-based regimen and moves on to protease-based therapy as HIV disease progresses.

People at later stages of HIV disease may have reduced immune response to hepatitis C and higher levels of inflammation or other factors that contribute to increased HCV viral load and accelerated liver fibrosis progression – both of which predict poorer response to interferon.

But Mira disagreed that the study was biased in this way, noting that differences in interferon response between nevirapine and lopinavir/ritonavir recipients was still apparent after adjusting for HCV viral load and extent of liver fibrosis.

Further information

Jose A Mira's presentation and related abstract is available on the official conference website.

References

Mira J et al. Concomitant nevirapine therapy is associated with higher efficacy of pegylated interferon plus ribavirin among HIV/hepatitis C virus-coinfected patients. Eighteenth International AIDS Conference, Vienna, abstract TUAB0101, 2010.