There was a trend towards an improved CD4 cell count and CD4 cell percentage. There were no significant changes in CD8 cell count and the median HIV-1 viral load remained below the limit of detection (Fig. 2). Similarly, CD16/CD56 and CD19 counts remained unchanged.
At 24 weeks, two patients had seroconverted and by 52 weeks, five patients (25%) had seroconverted to HBe-antibody positivity. Three of these five individuals harboured 3TC resistant mutations. No patients experienced any drug-related toxicities or unwanted effects and one patient elected to stop therapy as he wished to discontinue antiretroviral treatment. Serum electrolytes and creatinine remained stable.
The rate of decrease in HBV DNA viral load demonstrated a more rapid initial decline in those individuals who harboured 3TC-resistant mutations compared with those who did not (P = 0.046; one-sided test of variance/central limit theorem; Fig. 3).
This study demonstrates that tenofovir is effective against HBV in HIV-1 infected individuals who have been previously exposed to 3TC and suggests that tenofovir may be used to overcome 3TC resistance.
Anti-HBV efficacy is important in co-infected patients as HIV-1 induced immunosuppression leads to increased HBV replication . We also observed a statistically significant more rapid decline in the slope of HBV DNA decay between those individuals who harboured YMDD mutations and those who did not.
Historically, the development of anti-HIV-1 therapy led to early trials of monotherapy. This resulted in the accumulation of drug resistant mutations and subsequent treatment failure. Similarly, 3TC monotherapy for HBV infection leads to the rapid development of mutants that no longer respond to treatment . This in turn has implications for the clinical outcome of chronic infection including cirrhosis and hepatocellular carcinoma . The use of tenofovir and 3TC as part of a highly active antiretroviral therapy regimen may have superior potency and durability against both HIV-1 and HBV infection.
Adefovir dipivoxil, at a dose of 10 mg daily is active against 3TC-resistant HBV in HIV-1/HBV co-infected individuals . At this dose, no activity against HIV-1 was observed although increased ALT and the development of diabetes were seen. At an HIV-1 treatment dose of either 60 mg or 120 mg daily, nephrotoxicity has been observed in 33% and 42% of patients, respectively . Tenofovir at an HIV-1 treatment dose is active against HBV with no renal toxicity.
The loss of HBeAg in two patients in a relatively short time scale of 24 weeks and in five patients at 1 year is encouraging and should be studied in a larger cohort of patients including HIV-negative HBV-infected individuals. In the largest study using adefovir , two patients out of 35 underwent HBe antigen seroconversion. However, the safety profile of tenofovir is comparable to that of placebo  and we observed no adverse effects. Tenofovir increases the therapeutic options for HIV-1 and HBV co-infection.
Sponsorship: Supported by Gilead UK, Cambridge.
1.Rustgi VK, Hoofnagle JH, Gerin JL, Gelmann EP, Reichert CM, Cooper JN, et al
. Hepatitis B infection in the acquired immunodeficiency syndrome.Ann Intern Med
2.Kane MA. Progress on the control of hepatitis B infection through immunisation.Gut
3.Fact sheets: hepatitis B.
Genva: WHO, October 2000.
4.De Clercq E. Perspectives for the treatment of hepatitis B virus infections.Int J Antimicrob Agents
5.Lok ASF. Chronic hepatitis B.N Engl J Med
6.Lai CL, Chien RN, Leung NWY, Chang TT, Guan R, Tai DI, et al
. A one year trial of lamivudine for chronic hepatitis B.N Engl J Med
7.Dienstag JL, Perrillo RP, Schiff ER, Bartholomew M, Vicarcy C, Rubin M, et al
. A preliminary trial of lamivudine for chronic hepatitis B infection.N Engl J Med
8.Benhamou Y, Katlama C, Lunel F, Coutellier A, Dohin E, Hamm N, et al
. Effects of lamivudine on replication of hepatitis B virus in HIV infected men.Ann Intern Med
9.Benhamou Y, Bochet M, Thibault V, Di Martino V, Caumes E, Bricaire F, et al
. Long term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus infected patients.Hepatology
10.Pillay D, Bartholomeusz A, Cane P, Mutimer D, Schinazi RF, Locarnini S, et al
. Mutations in the hepatitis B virus DNA polymerase associated with antiviral resistance.Int Antiviral News
11.Thibault V, Benhamou Y, Seguret C, Bochet M, Katlama C, Bricaire F, et al
. Hepatitis B virus (HBV) mutations associated with resistance to lamivudine in patients co-infected with HBV and human immunodeficiency virus.J Clin Microbiol
12.Benhamou Y, Bochet M, Thibault V, Calvez V, Fievet MH, Vig P, et al
. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistance hepatitis B virus: an open-label pilot study.Lancet
13.Robbins BL, Srinivas RV, Kim C, Bischofberger N, Fridland A, et al
. Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), bis (isopropyloxymethylcarbonyl) PMPA.Antimicrob Agents Chemother
14.Schooley RT, Ruane P, Myers RA, Beall G, Lampiris H, Berger D, et al
. Tenofovir DF in antiretroviral-experienced patients: results from a 48-weeks, randomised, double-blind study.AIDS
15.Yokota T, Conno K, Chonan E, Mochizuki S, Kojima K, Shigeta S and de Clerq E. Comparitive activities of several nucleoside analogues against duck hepatitis B virus in vitro.Antimicrob Agents Chemother
16.Cooper D, Cheng A, Coakley D, Sayre J, Zhong L, Chen SS, et al
. Anti-HBV activity of tenofovir disoproxil fumarate (TDF) in lamivudine (LAM) experienced HIV/HBV co-infected.Ninth Conference on Retroviruses and Opportunistic Infections
. Seattle, February 2002 [abstract 124].
17.Lopez VA, Bourne EJ, Lutz MW, Condreay LD. Assessment of the COBAS Amplicor HBV Monitor Test for quantitation of serum hepatitis B virus DNA levels.J Clin Microbiol
18.Jardi R, Buti M, Rogriguez-Frias F, Cotrina M, Costas X, Pascual C, et al
. Rapid detection of lamivudine-resistant hepatitis B virus polymerase gene variants.J Virol Methods
19.Jonas MM, Kelley DA, Mizerski J, Badia IB, Areias JA, Schwarz KB, et al
. Clinical trial of lamivudine in children with chronic hepatitis B.N Engl J Med
20.Di Bisceglie AM. Combination therapy for hepatitis B.Gut
21.Kahn J, Lagakos S, Wulfsohn M, Cherng D, Miller M, Cherrington J, et al
. Efficacy and safety of adefovir dipivoxil with anti-retroviral therapy: a randomised controlled trial.JAMA