Treatment of hepatitis B virus (HBV) with lamivudine may not completely suppress viral replication and often fails as a result of lamivudine resistance. Tenofovir is a new HIV inhibitor with further activity against HBV, which was explored in 12 HBV/HIV-co-infected patients with detectable levels of serum HBV-DNA, despite receiving a lamivudine-containing antiretroviral regimen. Lamivudine-resistance mutations were found in HBV from seven patients. HBV-DNA levels dropped a median of 3.78 logs from baseline to 24 weeks. Tenofovir was very effective at reducing HBV-DNA levels in HIV/HBV-co-infected patients carrying either wild-type or lamivudine-resistant viruses.
The main goals of the treatment of hepatitis B virus (HBV) infection are the sustained suppression of HBV replication and a remission of liver disease. Lamivudine is an orally administered nucleoside analogue that inhibits HBV replication, and currently represents the most widely used anti-HBV therapy. However, its effectiveness at decreasing HBV-DNA levels in patients co-infected with HIV seems to be limited [1,2]. Moreover, only a minority of patients achieves HBV seroconversion, even when immune restoration occurs in the setting of potent antiretroviral therapy [1–4]. In addition, whereas longer periods of treatment are associated with higher rates of response, long-term therapy also leads to higher rates of drug resistance (from 14–25% at one year to 52% at 3 years) [2–7]. Although lamivudine-resistant HBV mutants have reduced fitness, and therefore a lower replicative ability, cases of fulminant hepatitis have been reported caused by breakthrough viraemia by these resistant HBV variants [8,9]. Therefore, new therapies are needed for patients, in which lamivudine does not completely suppress viral replication or show a rebound as a result of developing resistance.
Two recent drugs belonging to the nucleotide analogue family (adefovir and tenofovir) have shown in-vitro activity against lamivudine-resistant HBV mutants. Although both drugs exert anti-HIV activity, only tenofovir dixoproxil fumarate (TDF) has recently obtained approval for the treatment of HIV infection . We have explored its anti-HBV activity in HBV/HIV-co-infected patients failing a lamivudine- containing antiretroviral regimen.
Between May 2001 and January 2002, all HIV-infected patients at our institution with positive serum hepatitis B s antigen receiving a lamivudine-containing antiretroviral regimen for at least 24 weeks and showing detectable levels of HBV-DNA were recruited in the study. They began treatment with TDF 300 mg once a day. The main demographics, CD4 lymphocyte counts, and plasma HIV-RNA levels were recorded in all instances. Lamivudine-resistance HBV mutations were examined using a hybridization assay (INNO-LiPA HBV, Innogenetics, Ghent, Belgium). Baseline and follow-up HBV-DNA levels as well as HBV serologies were determined every 12 weeks. Serum HBV-DNA levels were measured using an ultrasensitive quantitative polymerase chain reaction assay (HBV Monitor, Roche Diagnostics, Almere, the Netherlands), which has a lower detection limit of 200 HBV-DNA copies/ml.
Eleven men and one woman with a median age of 41 years were included in the study. Two were former intravenous drug users, eight had acquired HIV and HBV through homosexual contacts, and two through heterosexual relationships. Three subjects were also anti-HCV positive. At baseline, the median (range) CD4 lymphocyte count was 405 (7–1320) cells/mm3, and the median (range) plasma HIV-RNA level was 143 (< 50–289 938) copies/ml. At the time of initiating TDF they had received lamivudine for a median (range) of 84 (24–240) weeks (Table 1).
The median (range) baseline HBV-DNA level was 3.73 × 106 (47.8 × 103–152 × 106) copies/ml. Lamivudine-resistance mutations were found in seven subjects out of 11 examined. Two showed mutations at codon 552, and five showed mutations at positions 552 and 528. In the remaining four individuals, good adherence to the medication was ascertained, which could explain the apparent HBV replication escape, despite a lack of lamivudine resistance mutations. Hepatitis B e antigen was positive at baseline in nine patients. The median time to follow-up was 34 weeks (range 24–48). No side-effects relating to TDF were reported. All patients had a significant decline in HBV-DNA levels, with a median (range) decrease of 3.78 (0.71–5.22) log10 copies/ml from baseline to 24 weeks. The loss of hepatitis B e antiigen was recorded in one subject at 12 weeks; he cleared hepatitis B s antigen at 24 weeks, and has remained with undetectable HBV-DNA levels thereafter (Table 1).
Our preliminary data support the use of TDF to treat chronic hepatitis B in HIV-infected patients failing lamivudine. The decline in HBV-DNA levels achieved within the first 24 weeks of treatment with TDF seems to be comparable with that reported recently by others [11,12]. A median drop in serum HBV-DNA near 4 log10 copies/ml suggests that TDF is quite potent at suppressing the replication of lamivudine-resistant HBV mutants. Moreover, all our patients responded to treatment to a greater or lesser extent. Although these results are very encouraging, further studies including more patients and assessing the durability of the response in the long-term are needed.
TDF is an attractive option for the treatment of HIV/HBV co-infected patients. Although adefovir, the first nucleotide analogue to be developed, has been shown to be effective in the treatment of lamivudine-resistant HBV, renal side-effects preclude its use at the dosage needed for HIV therapy . The good tolerance of TDF, confirmed in the current study, given at doses that effectively suppress both HIV and HBV replication, makes it an ideal drug to treat HBV/HIV co-infection. Given its activity against both HBV and HIV, the next step should be to explore the effectiveness of combination therapy rather than sequential treatment with lamivudine and TDF in individuals with HBV/HIV co-infection.
1.Carton J, Maradona J, Asensi V, Rodríguez M, Martínez A. Lamivudine for chronic hepatitis B and HIV co-infection.AIDS
2.Piroth L, Grappin M, Buisson M, Duong M, Portier H, Chavanet P. Hepatitis B virus seroconversion in HIV-HBV coinfected patients treated with highly active antiretroviral therapy.J Acquir Immune Defic Syndr
3.Puoti M, Airoldi M, Bruno R, Zanini B, Spinetti A, Pezzoli C. Hepatitis B virus co-infection in HIV-infected subjects.AIDS Rev
4.Hoff J, Bani-Sadr F, Gassin M, Raffi F. Evaluation of chronic hepatitis B virus infection in coinfected patients receiving lamivudine as a component of anti-HIV regimens.Clin Infect Dis
5.Benhamou Y, Bochet M, Thibaut V, Di Martino V, Charlotte F, Azria F, et al
. Long-term incidence of hepatitis B virus resistance to lamivudine in HIV-infected patients.Hepatology
6.Wolters L, Niesters H, Hansen B, van der Ende M, Kroon F, Richeter C, et al
. Development of hepatitis B virus resistance for lamivudine in chronic hepatitis B patients co-infected with HIV in a Dutch cohort.J Clin Virol
7.Pillay D, Cane P, Ratcliffe D, Atkins M, Cooper D,for the CAESAR coordinating committee. Evolution of lamivudine- resistant hepatitis B virus and HIV-1 in co-infected individuals: an analysis of the CAESAR study.AIDS
8.Thabut D, Thibault V, Benhamou Y, Bernard B, Aubron-Olivier C, Poynard T, Di Martino V. Successful control of subfulminant hepatitis related to lamivudine-resistant hepatitis B virus in an HIV-infected patient.AIDS
9.Bonacini M, Kurz A, Locarnini S, Ayres A, Gibbs C. Fulminant hepatitis B due to a lamivudine-resistant mutant of HBV in patients coinfected with HIV.Gastroenterology
10.Ying C, De Clercq E, Nicholson W, Furman P, Neyts J. Inhibition of the replication of the DNA polymerase M550V mutation variant of human hepatitis B virus by adefovir, tenofovir, L-FMAU, DAPD, penciclovir and lobucavir.J Viral Hepatol
11.Cooper D, Cheng A, Coakley D, Sayre J, Zhong L, Chen S, et al
. Anti-HBV activity of tenofovir disoproxil fumarate in lamivudine-experienced HIV/HBV coinfected patients.
In: 9th Conference on Retroviruses and Opportunistic Infections
. Seattle, WA, February 2002 [Abstract 124].
12.Benhamou Y, Bochet M, Tubiana R, Poynard T. Tenofovir disoproxil fumarate suppresses lamivudine-resistant HBV replication in patients coinfected with HIV/HBV.
In: 37th Annual Meeting of the European Association for the Study of the Liver
. Madrid, Spain, April 2002 [Abstract 641].
13.Benhamou Y, Bochet M, Thibault V, Calvez V, Fievet M, Vig P, et al
. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study.Lancet