XVIII International AIDS Conference, July 18-23, 2010, Vienna
Mark Mascolini
Compared with people taking a lopinavir (LPV)/ritonavir-based antiretroviral regimen, those taking a nevirapine (NVP)-containing combination were more likely to attain a sustained virologic response (SVR) when treated for hepatitis C virus (HCV) infection with pegylated interferon and ribavirin (PEG-IFN/RBV) [1]. Results must be interpreted cautiously, however, because this is a retrospective cohort study, not a randomized trial, and there were important differences between the lopinavir and nevirapine groups.
Earlier research found that HIV/HCV-coinfected people taking nevirapine had lower HCV loads than people taking an antiretroviral regimen including a protease inhibitor (PI). To see whether nevirapine is also associated with higher SVR rates, Spanish investigators planned this 20-center retrospective study of 71 coinfected adults (43%) taking a nevirapine regimen and 94 (57%) taking lopinavir/ritonavir when they started PEG-IFN/RBV for the first time. Everyone took nevirapine or lopinavir with tenofovir plus either lamivudine or emtricitabine. People took PEG-IFN/RBV for 48 weeks if they had HCV genotype 1 or 4, and for 24 or 48 weeks if they had genotype 2 or 3.
The antiretroviral groups were similar in age (median 42 with nevirapine and 41 with lopinavir), percentage of former injection drug users (76% versus 86%), and body mass index (22..8 versus 23.2 kg/m(2)). Nor did the nevirapine and lopinavir groups differ significantly in initial CD4 count, proportion with HCV genotype 1 or 4, use of PEG-IFN alfa-2a, weight-based RBV dosing, adherence to PEG-IFN/RBV, use of growth factor, or need for PEG-IFN or RBV dose reduction.
But the proportion of men was significantly lower in the nevirapine group (66% versus 81%, P = 0.03), fewer nevirapine takers had fibrosis stage F3 or greater (21% versus 52%, P = 0.001), fewer on nevirapine had cirrhosis (6% versus 32%, P = 0.001), initial HCV load was lower in the nevirapine group (median 5.7 versus 6.1 log IU/mL, P = 0.02), and a significantly lower proportion of people on nevirapine had a starting HCV load over 6 million IU/mL (44% versus 73%, P = 0.001).
In an intention-to-treat analysis, 40 people (56%) taking nevirapine achieved SVR with PEG-IFN/RBV, compared with 35 people (37%) taking lopinavir, a significant difference (P = 0.015). SVR rates were significantly better with nevirapine among people with genotype 1 or 4 (43% versus 25%, P = 0.04). A higher proportion with genotype 2 or 3 had an SVR with nevirapine than with lopinavir (78% versus 59%), though that difference stopped short of statistical significance (P = 0.1). Among people with an initial HCV load at or above 600,000 IU/mL, 58% taking nevirapine and 31% taking lopinavir had an SVR (P = 0.01) (from jules: the numbers of patients were small in this analysis). SVR rates did not differ significantly by liver fibrosis stage (F3-F4, 60% with nevirapine and 36% with lopinavir, P = 0.2).
Among reasons for failure to achieve SVR, nonresponse was the only one to differ in frequency between the nevirapine and lopinavir groups (8% versus 23%, P = 0.01). Rates of viral breakthrough were 7% with nevirapine and 14% with lopinavir (P = 0.1), and the relapse rate were higher with nevirapine (17% versus 11%, P = 0.2).
Multivariate analysis considering numerous factors that may influence SVR determined that three factors independently predicted SVR: a nevirapine regimen (P = 0.01), HCV genotype 2 or 3 (P < 0.001), and greater than 80% adherence to PEG-INF/RBV (P = 0.01). Taking nevirapine rather than lopinavir approximately doubled chances of achieving an SVR in this analysis.
The investigators proposed that lower HCV load with a nevirapine regimen may explain the better response to anti-HCV therapy in people taking a nevirapine-based antiretroviral regimen. They explained that HIV can induce HCV replication through TGF-beta1, which the liver produces in response to proinflammatory cytokines. Research has associated nevirapine with higher decreases in expression of TNF-alpha receptor than are achieved with other antiretrovirals [2], and the Spanish team proposed this might decrease TGF-beta1 secretion in the liver and thereby reduce HCV replication.
Session cochair and HIV/HCV expert Juergen Rockstroh suggested that in a study group of this size, multivariate analysis may not be able to correct for the distinct liver disease progression differences between the nevirapine group and the lopinavir group. He proposed that a matched-pair analysis may afford further insight into the relative value of nevirapine versus lopinavir/ritonavir in people starting PEG-IFN/RBV. Nevirapine must be used with caution in HCV-infected people because liver toxicity is among its best-documented side effects [3,4], especially in the first 10 weeks of therapy.
References
1. Mira JA, Lopez-Cortes LF, Vispo E, et al. Concomitant nevirapine therapy is associated with higher efficacy of pegylated interferon plus ribavirin among HIV/hepatitis C virus-coinfected patients. XVIII International AIDS Conference. July 18-23, 2010. Vienna. Abstract TUAB0101.
2. Virgili N, Fisac C, Martinez E, Ribera E, Gatell JM, Podzamczer D. Proinflammatory cytokine changes in clinically stable, virologically suppressed, HIV-infected patients switching from protease inhibitors to abacavir. J Acquir Immune Defic Syndr. 2009;50:552-553.
3. Macias J, Castellano V, Merchante N, et al. Effect of antiretroviral drugs on liver fibrosis in HIV-infected patients with chronic hepatitis C: harmful impact of nevirapine. AIDS. 2004;18:767-774.
4. Almond LM, Boffito M, Hoggard PG, et al. The relationship between nevirapine plasma concentrations and abnormal liver function tests. AIDS Res Hum Retroviruses. 2004;20:716-722.
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