Rapid hepatitis B virus-DNA decay in co-infected HIV-hepatitis B virus 'e-minus' patients with YMDD mutations after 4 weeks of tenofovir therapy.

Abstract

End-stage liver diseases are becoming the most important cause of hospital admission and mortality among HIV-positive patients during the era of highly active antiretroviral therapy in the developed world [1]. Focusing on hepatitis B virus (HBV), HBV and HIV infections share risk factors and HBV–HIV co-infection is quite common. More than 80% of HIV-positive patients have some markers of past or current HBV infection, and 8–11% of them are hepatitis B s antigen (HBsAg) carriers [2]. There are two forms of hepatitis that could be two steps of HBV infection in the same individual: hepatitis B e antigen (HBeAg) positive and HBeAg-negative hepatitis. In southern Europe, 30–80% of patients with chronic hepatitis B are in the HBeAg-negative phase [2]. In patients with HBV infection, HIV co-infection is associated with a higher chronicization rate of acute HBV, higher levels of HBV replication, a lower rate of spontaneous loss of HbeAg or HBsAg, and seroconversion to anti-hepatitis B e and anti-hepatitis B s [2]. The aims of treatment for chronic hepatitis B are to achieve a sustained suppression of HBV replication and remission of liver disease. Lamivudine is an oral nucleoside analogue, active against both HIV and HBV replication. However, HBV resistance to lamivudine occurs in 50–90% of HIV–HBV co-infected patients after 2 and 4 years, at rates higher than in HIV-uninfected individuals and even during treatment with the usual anti-HIV dose of 300 mg daily. The development of the YMDD mutation with long-term lamivudine treatment has apparently not precluded the development of aminotransferase flares with subsequent HBeAg seroconversion. Indeed, the significance of the YMDD mutation on the response to therapy in immune-competent patients has not yet been established. In HBV–HIV-co-infected patients the question is more complex because the imbalance of the immune system could enhance the significance of YMDD mutants in determining HBV exacerbations. Cases of end-stage liver disease during lamivudine treatment have already been reported [3]. Among other anti-HIV nucleoside analogues, tenofovir is able to induce an impressive inhibition of HBV replication in vitro, even in the presence of mutations associated with lamivudine resistance. So far, data on the clinical efficacy of tenofovir on HBV surrogate markers in HIV patients are lacking. We thus tried to determine the effect of tenofovir on the HBV viral load in the first 4 weeks of treatment in patients co-infected with HBV and HIV, carrying the YMDD mutation, recruited in the Italian Tenofovir Expanded Access Program. We selected five patients, whose characteristics are summarized in Table 1. Serum HBV DNA was determined by polymerase chain reaction (Roche Amplicor, lower limit of quantitation 2.6 log10 copies/ml; Roche Diagnostic Systems, Inc., Branchburg, NJ, USA), and the HIV-RNA load by branched DNA. Mutations in the YMDD motif of the HBV-DNA polymerase gene were identified at baseline in all patients.Table 1: Characteristics of the patients.Tenofovir 300 mg once a day was added to the patients’ lamivudine (150 mg twice a day)-containing antiretroviral therapy. Patients were seen at 4-week visits for safety and efficacy evaluations. All patients had YMDD mutant HBV (median duration of resistance 29.6 months; range 11–33 months), five out of five were HBeAg negative/HBeAb-positive and the mean CD4 cell counts and HIV-RNA levels were 207 ± 102 cells/ml and 4.95 ± 5.0 log10 copies/ml, respectively; the mean alanine aminotransferase level was 95 ± 32 IU/l. The baseline characteristics are summarized in Table 1. The mean change in the serum HBV-DNA concentration from baseline (5.11 ± 5.0 log10 copies/ml) was −2.42 log10 copies/ml at week 4. All patients had undetectable HBV-DNA levels at week 4. No alanine aminotransferase flares (at least three times the baseline level) occurred during the first month of of treatment. In general, tenofovir was well tolerated, without other alterations of renal function tests or adverse events. Our preliminary findings showed a rapid slope of HBV viremia after the initiation of tenofovir added to ongoing lamivudine therapy. All patients were failing on lamivudine, carrying the YMDD resistance mutation, and were HBeAg negative and anti-hepatitis B e positive, suggesting that they would have a worse clinical course. A biphasic clearance of HBV DNA has still been demonstrated, with an initial fast phase of viral load decline reflecting the clearance of HBV particles from plasma with a half-life of approximately 24 h, followed by a second slower phase of viral load decline, mirroring the rate-limiting process of the loss of infected cells. These data refer to the use of either lamivudine or adefovir. Our data showed the efficacy of tenofovir in obtaining an early response. These results are very promising, and suggest that a combination therapy for HBV in co-infected patients may become the standard of care in years to come. A large randomized controlled trial, focusing on the durability of response, is needed to determine the strength of this therapeutic option.