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The HBV drug entecavir - effects on HIV-1 replication and resistance.

ABSTRACT: Entecavir, a drug approved by the Food and Drug Administration for the treatment of chronic hepatitis B virus (HBV) infection, is not believed to inhibit replication of human immunodeficiency virus type 1 (HIV-1) at clinically relevant doses. We observed that entecavir led to a consistent 1-log(10) decrease in HIV-1 RNA in three persons with HIV-1 and HBV coinfection, and we obtained supportive in vitro evidence that entecavir is a potent partial inhibitor of HIV-1 replication. Detailed analysis showed that in one of these patients, entecavir monotherapy led to an accumulation of HIV-1 variants with the lamivudine-resistant mutation, M184V. In vitro experiments showed that M184V confers resistance to entecavir. Until more is known about HIV-1-resistance patterns and their selection by entecavir, caution is needed with the use of entecavir in persons with HIV-1 and HBV coinfection who are not receiving fully suppressive antiretroviral regimens.

SUBMITTER: McMahon MA

PROVIDER: S-EPMC3069686 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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The HBV drug entecavir - effects on HIV-1 replication and resistance.

McMahon Moira A MA Jilek Benjamin L BL Brennan Timothy P TP Shen Lin L Zhou Yan Y Wind-Rotolo Megan M Xing Sifei S Bhat Shridhar S Hale Braden B Hegarty Robert R Chong Curtis R CR Liu Jun O JO Siliciano Robert F RF Thio Chloe L CL

The New England journal of medicine 20070601 25

Entecavir, a drug approved by the Food and Drug Administration for the treatment of chronic hepatitis B virus (HBV) infection, is not believed to inhibit replication of human immunodeficiency virus type 1 (HIV-1) at clinically relevant doses. We observed that entecavir led to a consistent 1-log(10) decrease in HIV-1 RNA in three persons with HIV-1 and HBV coinfection, and we obtained supportive in vitro evidence that entecavir is a potent partial inhibitor of HIV-1 replication. Detailed analysis ...[more]

PMID: 17582071

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Project description:We recently reported complex hepatitis B virus (HBV) drug resistant and concomitant vaccine escape hepatitis B surface antigen (HBsAg) variants during human immunodeficiency virus (HIV) co-infection and antiretroviral therapy (ART) exposure in Ethiopia. As a continuation of this report using the HBV positive sera from the same study participants, the current study further analyzed the HBV basal core promoter (BCP)/precore (PC) genes variability in patients with HBV drug resistance (at tyrosine-methionine-aspartate-aspartate (YMDD) reverse transcriptase (RT) motifs) and HIV co-infection in comparison with HBV mono-infected counterparts with no HBV drug resistant gene variants.A total of 143 participants of HBV-HIV co-infected (n = 48), HBV mono-infected blood donors (n = 43) and chronic liver disease (CLD) patients (n = 52) were included in the study. The BCP/PC genome regions responsible for HBeAg expression from the EcoRI site (nucleotides 1653-1959) were sequenced and analyzed for the BCP/PC mutant variants.Among the major mutant variants detected, double BCP mutations (A1762T/G1764A) (25.9%), Kozak sequences mutations (nt1809-1812) (51.7%) and the classical PC mutations such as A1814C/C1816T (15.4%), G1896A (25.2%) and G1862T (44.8%) were predominant mutant variants. The prevalence of the double BCP mutations was significantly lower in HIV co-infected patients (8.3%) compared with HBV mono-infected blood donors (32.6%) and CLD patients (36.5%). However, the Kozak sequences BCP mutations and the majority of PC mutations showed no significant differences among the study groups. Moreover, except for the overall BCP/PC mutant variants, co-prevalence rates of each major BCP/PC mutations and YMDDRT motif associated lamivudine (3TC)/entecavir (ETV) resistance mutations showed no significant differences when compared with the rates of BCP/PC mutations without YMDD RT motif drug resistance gene mutations. Unlike HIV co-infected group, no similar comparison made among HBV mono-infected blood donors and CLD patients since none of them developed the YMDD RT motif associated 3TC/ETV resistance mutations. However, HBV mono-infected blood donors and CLD patients who had no any drug resistance gene variants developed comparable G1862T (60.6% vs. 65.1%) and G1896A (24.2% vs. 11.6%) PC gene mutations.No correlation observed between the BCP/PC genome variability and the YMDD RT motif associated HBV drug resistance gene variants during HIV co-infection. Nevertheless, irrespective of HIV co-infection status, the higher records of the BCP/PC gene variability in this study setting indicate a high risk of potential HBeAg negative chronic HBV infection in Northwest Ethiopia.

Project description:BackgroundPrevious studies have demonstrated the benefits of thymosin alpha-1 (Tα1) in anti-virus, immunological enhancement and anti-inflammation. However, it is controversial about the efficacy and safety of entecavir (ETV) plus Tα1 combination therapy versus ETV monotherapy in cirrhotic patients with hepatitis B virus (HBV) infection.MethodsThe systematic review and meta-analysis of randomized clinical trials (RCTs) were performed to evaluate the efficacy and safety of ETV plus Tα1 combination therapy versus ETV monotherapy in HBV-related patients with cirrhosis. We performed a systematic literature search via PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Journals Database (VIP), and Chinese Biological Medicine database (CBM). Relative risk (RR) and standardized mean difference (SMD) with a fixed- or random- effect model were calculated. Heterogeneity was assessed through a Cochrane Q-test and I2 values.ResultsSeven RCTs involving 1144 subjects were included in the systematic review and meta-analysis. Compared with ETV monotherapy, ETV plus Tα1 combination therapy led to a higher complete response (RR = 1.18; 95% CI, 1.07-1.30). In post treatment for 24 weeks, the HBV DNA undetectable rate and HBeAg loss rate were higher in ETV plus Tα1 group than in ETV alone group (RR = 1.91; 95% CI, 1.56-2.35; RR = 2.05; 95% CI, 1.62-2.60). However, after 48 and 52 weeks of treatment, there was no significant difference between the combination therapy and ETV monotherapy (RR = 1.07; 95% CI, 0.96-1.18; RR = 1.17; 95% CI, 0.89-1.55). At week 52 of treatment, the HBsAg loss rate of ETV plus Tα1 group was no significance with that of ETV alone group (RR = 1.03; 95% CI, 0.15-7.26). In comparison with ETV alone, the some biochemical parameters and liver fibrosis were obviously improved by ETV plus Tα1, and there was significant heterogeneity. In addition, the number of adverse events was significantly reduced by ETV plus Tα1, compared to ETV alone (RR = 0.48; 95% CI, 0.24-0.95).ConclusionsETV plus Tα1 might lead to a higher clinical response and a lower comprehensive adverse reaction rate in HBV-related patients with cirrhosis, compared to ETV alone. However, the whole patients included in this meta-analysis were from Chinese mainland, so that more worldwide RCTs with a larger sample size are needed to verify the current findings.

Dataset Information

The HBV drug entecavir - effects on HIV-1 replication and resistance.

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The HBV drug entecavir - effects on HIV-1 replication and resistance.

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