A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B

The University of Calgary, Calgary, Alberta, Canada
Archives of Internal Medicine (Impact Factor: 17.33). 01/2006; 166(1):49-56. DOI: 10.1001/archinte.166.1.49
Source: PubMed


Emtricitabine is a nucleoside analogue approved for treatment of human immunodeficiency virus 1 with clinical activity against hepatitis B virus (HBV).
To compare the safety and efficacy of emtricitabine with placebo in patients with HBV, we conducted a randomized (2:1), double-blind study at 34 sites in North America, Asia, and Europe that enrolled adults between November 2000 and July 2002 who had chronic HBV infection but had never been exposed to nucleoside or nucleotide treatment. Each patient received either 200 mg of emtricitabine (n=167) or placebo (n=81) once daily for 48 weeks and underwent a pretreatment and end-of-treatment liver biopsy. Histologic improvement was defined as a 2-point reduction in Knodell necroinflammatory score with no worsening in fibrosis.
At the end of treatment, 103 (62%) of 167 patients receiving active treatment had improved liver histologic findings vs 20 (25%) of 81 receiving placebo (P<.001), with significance demonstrated in subgroups positive (P<.001) and negative (P=.002) for hepatitis Be (HBe) antigen. Serum HBV DNA readings showed less than 400 copies/mL in 91 (54%) of 167 patients in the emtricitabine group vs 2 (2%) of 81 in the placebo group (P<.001); alanine aminotransferase levels were normal in 65% (109/167) vs 25% (20/81), respectively (P<.001). At week 48, 20 (13%) of 159 patients in the emtricitabine group with HBV DNA measured at the end of treatment had detectable virus with resistance mutations (95% confidence interval, 8%-18%). The rate of seroconversion to anti-HBe (12%) and HBe antigen loss were not different between arms. The safety profile of emtricitabine during treatment was similar to that of placebo. Posttreatment exacerbation of HBV infection developed in 23% of emtricitabine-treated patients.
In patients with chronic HBV, both positive and negative for HBe antigen, 48 weeks of emtricitabine treatment resulted in significant histologic, virologic, and biochemical improvement.

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    • "WHO guidelines also define the clinical contraindications of PrEP with caution (Graham et al. 2007). Another major side-effect was hepatic flare (Lim et al. 2006, van Bommel et al. 2004). Prior research indicated that 23% patients might have post-treatment exacerbation of hepatitis-B infection (Mondou et al. 2005). "
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    • "In contrast, in the emtricitabine monotherapy trial, resistance occurred in 13% at 48 weeks [26], reminiscent of, if not quite matching, resistance rates with lamivudine . Thus, although once again the relatively small number of patients precludes any notion of complete protection against resistance, this study provides another important indication that for drugs with a low genetic barrier to resistance, the concomitant administration of a HBV drug with a higher genetic barrier can prevent resistance to the former. "
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    • ". Unfortunately, however, the HBV polymerase mutations responsible for lamivudine resistance emerge rapidly in coinfected patients, with resistance occurring in up to 20% per year [45]. Emtricitabine suppresses HBV DNA [47] similar to the effect of lamivudine in HBV-monoinfected patients, has the same pattern of resistance mutations as lamivudine, and is considered interchangeable with lamivudine for the treatment of HIV [48] [49]. Because of the poor resistance profiles and the risk of severe hepatitis B flares with emergent resistance [45] [46] [50], lamivudine and emtricitabine monotherapy against HBV should be absolutely avoided in HBV/HIV-coinfected patients except where economic or regulatory constraints limit tenofovir's use. "
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