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 HIV and Hepatitis.com Coverage of the
XVIII International AIDS Conference
(AIDS 2010)  July 18 - 23, 2010, Vienna, Austria
Does Nevirapine Improve Response to Interferon-based Therapy in HIV/HCV Coinfected Patients?

SUMMARY: Use of an antiretroviral therapy (ART) regimen containing nevirapine (Viramune) was associated with a higher rate of sustained virological response (SVR) to interferon-based therapy among HIV/HCV coinfected patients, according to a study presented last week at the XVIII International AIDS Conference (AIDS 2010) in Vienna. Researchers suggested that nevirapine may improve treatment response by reducing hepatitis C virus (HCV) viral load, but an alternative explanation may be that people taking nevirapine are in better health when starting hepatitis C treatment.

By Liz Highleyman

Past research indicates that HIV/HCV coinfected people tend to have lower rates of response to interferon based therapy compared to those with HCV alone. Some studies have suggested certain nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are associated with poorer response -- perhaps due to drug interactions or intensified side-effects -- but the role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and HIV protease inhibitors has not been well studied and data have been conflicting.

Jose Mira from Valme University Hospital in Seville, Spain, and colleagues assessed the effectiveness of hepatitis C treatment using pegylated interferon plus ribavirin in HIV/HCV coinfected patients taking various antiretroviral regimens.

It has been reported that patients receiving nevirapine-based ART have lower plasma HCV RNA viral load than those treated with protease inhibitors, the investigators noted as background. They suggested, "This fact could have a positive impact on the response to HCV therapy, since a low HCV RNA load is a strong predictor of sustained virological response."

Researchers retrospectively compared the efficacy of first-time hepatitis C treatment in 71 HIV/HCV coinfected individuals taking nevirapine and 94 coinfected patients taking lopinavir/ritonavir (Kaletra) at Spanish hospitals during 2002-2009. All participants also took tenofovir (Viread) plus either lamivudine (3TC, Epivir) or emtricitabine (Emtriva).

About three-quarters of participants were men, the median age was about 41 years, and about 80% had a history of injection drug use. Both groups had well-controlled HIV disease with a baseline CD4 cell count of about 450 cells/mm3.

With regard to HCV status, about 60% in both groups had hard-to-treat HCV genotypes 1 or 4. But participants in the lopinavir/ritonavir arm were significantly more likely than nevirapine recipients to have advanced liver fibrosis > stage F3 (52% vs 21%), cirrhosis (32% vs 6%), and high baseline HCV viral load > 600,000 IU/mL (73% vs 44%).

Participants were treated for chronic hepatitis C using pegylated interferon alpha-2a (Pegasys) or pegylated interferon alpha-2b (PegIntron) plus weight-adjusted ribavirin. Patients with HCV genotype 1 or 4 were treated for 48 weeks while those with genotypes 2 or 3 were treated for 24 weeks. About 90% of participants in both groups reported good ( 80%) adherence. 11% in the lopinavir/ritonavir group and 4% in the nevirapine group used blood cell growth factors to manage anemia or neutropenia. 14% of lopinavir/ritonavir recipients had their doses of pegylated interferon reduced due to toxicities compared with 18% in the nevirapine group; 14% and 10%, respectively, had their ribavirin doses reduced.

Results

Overall, in an intent-to-treat analysis, 56% of participants in the nevirapine arm achieved sustained virological response compared with 37% in the lopinavir/ritonavir arm, a significant difference (P = 0.015).
This was also the case for genotype 1 or 4 patients, but the difference did not reach statistical significance for genotype 2 or 3 patients:
 
Genotype 1 or 4: SVR 43% with nevirapine vs 25% with lopinavir/ritonavir (P = 0.04);
Genotypes 2 or 3: 78% vs 59%, respectively (P = 0.1).
Lack of sustained response was mainly attributable to non-response, occurring in 8% of nevirapine recipients and 23% of lopinavir/ritonavir recipients (P = 0.01).
Other reasons for lack of SVR did not differ significantly between the nevirapine and lopinavir/ritonavir groups:
 
HCV relapse: 17% vs 11%, respectively (P = 0.2);
HCV breakthrough: 7% vs 14%, respectively (P = 0.1);
Treatment discontinuation due to adverse events: 8% vs 10%, respectively (P = 0.8);
Voluntary drop-out: 3% vs 5%, respectively (P = 0.4).
When participants were classified according to baseline HCV RNA, significantly better response with nevirapine was only seen in those with high viral load:
 
HCV RNA < 600,000 IU/mL: SVR 55% with nevirapine vs 53% with lopinavir/ritonavir (P = 0.8);
HCV RNA 600,000 IU/mL: 58% vs 31%, respectively (P = 0.01).
Responses appeared somewhat better in nevirapine recipients with both mild and severe liver fibrosis, but differences again did not reach statistical significance:
 
F0-F2 fibrosis: SVR 47% with nevirapine vs 33% with lopinavir/ritonavir (P = 0.2);
F3-F4 fibrosis: 60% vs 36%, respectively (P = 0.02).
In a multivariate analysis, significant predictors of sustained response included:
 
HCV genotype 2 or 3 (P < 0.001);
Use of nevirapine plus tenofovir plus lamivudine or emtricitabine (P = 0.01);
Taking at least 80% of prescribed hepatitis C therapy, i.e., good adherence and minimal dose reduction (P = 0.01).
HCV viral load and diagnosis of AIDS were not significant factors, however.

Based on these findings, the investigators concluded, "HIV/HCV coinfected patients who receive nevirapine respond better to pegylated interferon plus ribavirin than those individuals receiving lopinavir/ritonavir."

Mira suggested that lower HCV viral load among nevirapine recipients might account for this difference in response rates. Nevirapine suppresses expression of the TNF-alpha receptor more than other antiretroviral drugs, he proposed. This might reduce secretion of TGF-beta, which stimulates HCV replication.

But session moderator Juergen Rockstroh questioned this interpretation. Another potential explanation, he suggested, is that participants taking lopinavir/ritonavir are sicker on average, since ART sequencing often starts with a NNRTI-based regimen and moves to a protease inhibitor regimen as HIV disease progresses. People with more advances HIV disease have reduced immune response to hepatitis C and may have higher levels of inflammation or other factors that contribute to increased HCV viral load and accelerated liver fibrosis progression, both of which can lead to poorer response to interferon.

But Mira disagreed that the study was biased in this way, noting that differences in SVR rates in the nevirapine and lopinavir/ritonavir arms were still seen after adjusting for HCV viral load and liver fibrosis stage.

Valme University Hospital, Seville, Spain; Rocio University Hospital, Seville, Spain; Carlos III Hospital, Madrid, Spain; Germans Trias i Pujol University Hospital, Barcelona, Spain; Clinic Hospital, Barcelona, Spain; Bellvitge University Hospital, Barcelona, Spain; La Princesa University Hospital, Madrid, Spain; Santa Creu i Sant Pau Hospital, Barcelona, Spain; del Mar Hospital, Barcelona, Spain; La Linea Hospital, La Linea de la Concepcion, Spain; Vall d'Hebron University Hospital, Barcelona, Spain; Reina Sofia University Hospital, Cordoba, Spain; General Valencia Hospital, Valencia, Spain.

7/27/10

Reference
J Mira, LF Lopez-Cortes, E Vispo, and others. Concomitant nevirapine therapy is associated with higher efficacy of pegylated interferon plus ribavirin among HIV/hepatitis C virus-coinfected patients. XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23, 2010. Abstract TUAB0101.

 

 

 

 

 

 

 

 

 

 

 



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