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Combination of tenofovir and lamivudine versus tenofovir after lamivudine failure for therapy of hepatitis B in HIV-coinfection
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AIDS: Volume 20(15) 3 October 2006 p 1951-1954
Schmutz, Guenthera; Nelson, Markb; Lutz, Thomasc; Sheldon, Julied; Bruno, Raffaelee; von Boemmel, Florianf; Hoffmann, Christiang; Rockstroh, Juergenh; Stoehr, Albrechtg; Wolf, Evai; Soriano, Vincentd; Berger, Floriana; Berg, Thomasf; Carlebach, Aminac; Schwarze-Zander, Carolynneh; Schurmann, Dirkf; Jaeger, Hansi; Mauss, Stefana
From the aCenter for HIV and Hepatogastroenterology, Duesseldorf, Germany
bKobler Clinic, Chelsea and Westminster Hospital, London, UK
cHIV-cohort Frankfurt, Germany
dHospital Carlos III, Madrid, Spain
eSan Matteo Hospital, University of Pavia, Italy
fMedizinische Klinik Charite, Berlin, Germany
gInstitute for Interdisciplinary Infectiology and Immunology, Hamburg, Germany
hMed. Klinik I, Universitaetsklinikum Bonn, Germany
iMUC Research, Munich, Germany.
Abstract
Objective: At present sequential monotherapy for chronic hepatitis B with hepatitis B virus (HBV)-polymerase inhibitors is clinical practice. It is unknown to date whether combination therapy with lamivudine plus tenofovir could be superior to sequential therapy with tenofovir after the occurrence of lamivudine resistance.
Methods: We conducted a multicenter, 1: 2 matched pair analysis comparing patients with HBV/HIV-coinfection starting an antiretroviral regimen including tenofovir plus lamivudine with patients who had highly replicative, lamivudine resistant HBe-antigen positive chronic hepatitis B and started with tenofovir as the only active HBV polymerase inhibitor subsequent to lamivudine.
Results: At baseline patients on tenofovir plus lamivudine (n = 25) had a median HBV DNA of 5.9 X 107 copies/ml compared to 1.37 X 108copies/ml in the tenofovir arm (n = 50; P = 0.32). A sustained undetectable HBV DNA < 1000 copies/ml was achieved in 19/25 (76%) patients on tenofovir plus lamivudine and in 42/50 (84%) on tenofovir (P = 0.53). A loss of HBe-antigen was observed in 9/25 (36%) patients on tenofovir plus lamivudine and in 12/50 (24%) patients on tenofovir (P = 0.29). HBs-antigen loss was found in 1/25 (4%) and 3/50 (6%) patients.
Conclusions: In this cohort of HBV/HIV-coinfected individuals, full HBV DNA suppression was achieved in the majority of patients independent of treatment allocation. Loss of HBe- and HBs-antigen was not different between the two study arms. Over a median treatment period of 116 weeks tenofovir was as effective as tenofovir plus lamivudine. Longer treatment periods may be needed to evaluate potential benefits of first-line combination therapy for chronic hepatitis B.
Introduction
Hepatitis B virus (HBV) polymerase inhibitors have changed the treatment of chronic hepatitis B considerably. The drugs are convenient to take and have a favourable toxicity profile making them an attractive alternative to therapy with interferon alpha. However, HBe-antigen or HBs-antigen seroconversion under treatment with HBV polymerase inhibitors need prolonged treatment periods which may be associated with the development of viral resistance and subsequently viral failure. With the approval of lamivudine as the first HBV polymerase inhibitor and the more recent availability of adefovir and tenofovir sequential monotherapy is the clinical reality today. Although combination therapy with HBV polymerase inhibitors may at least theoretically offer stronger antiviral potency and a lower risk of development of viral resistance, the clinical superiority of antiviral combination therapy for chronic hepatitis B has still to be proven [1,2].
Lamivudine is an HBV polymerase inhibitor with good antiviral potency, but a rather quick development of viral resistance particularly in patients where strong viral suppression is not achieved [3,4]. In contrast with lamivudine, HBV resistance to tenofovir is infrequently found during the first years on treatment, making it an attractive candidate for treatment of hepatitis B [5,6]. However, data on the antiviral activity of tenofovir is limited as this drug was primarily approved for HIV treatment and not developed for treatment of chronic hepatitis B [7-10]. In the present analysis combination therapy with lamivudine plus tenofovir was compared to sequential therapy with tenofovir after the occurrence of lamivudine resistance for chronic hepatitis B treatment in HBV/HIV-coinfected patients.
Patients and methods
Patients with HBV/HIV-coinfection were identified by retrospective chart review and prospectively followed thereafter. Two groups of HBV/HIV-coinfected patients were selected for this study. The first group consisted of patients who started a combination of tenofovir and lamivudine as first-line HBV polymerase inhibitor therapy. The second group consisted of patients who had a relapse of HBV DNA (> 100 000 copies/ml) under treatment with lamivudine and subsequently received tenofovir as second line active HBV polymerase inhibitor.
In total a database of 120 patients was accrued. From this database we conducted a multicentre, 1: 2 matched pair analysis comparing the antiviral efficacy of first-line treatment with tenofovir plus lamivudine to sequential therapy with tenofovir after the development of lamivudine failure. Patients were matched according to sex, level of HBV DNA and HBe-antigen status. All patients matched were HBe-antigen positive. The HBV DNA had to be > 100 000 copies/ml. All patients had to be hepatitis C virus-antibody negative.
Genotyping for resistance (Trugene HBV Genotyping, Bayer Diagnostics, Leverkusen, Germany) was performed in 40 of 50 study patients on lamivudine monotherapy before switching to tenofovir. All, but two patients showed resistance mutations against lamivudine e. g., M204V/I, L180M or V173L.
The lower limit of detection of HBV DNA chosen in this study was 1000 copies/ml as this was the least sensitive lower limit of detection from the different HBV DNA assays performed in the local laboratories.
For comparisons of treatment groups nonparametric unpaired Mann-Whitney U-test and Fisher χ2 test were used. The statistical significance level ƒ¿ was 0.05. For statistical analysis software from SPSS was used (SPSS GmbH, Munich, Germany, version 12.0, 2005).
Results
At baseline, patients on tenofovir plus lamivudine (n = 25) had a median HBV DNA of 5.9 X 107 copies/ml (range 1.25 X 105 to 1.5 X 1010 copies/ml) compared to 1.37 X 108 copies/ml (range 1.10 X 105 to 1.14 X 1010 copies/ml) in the tenofovir arm (n = 50; P = 0.32). The median alanine transferase (ALT) level was 78 U/L (range 17-1350 U/L) in the tenofovir plus lamivudine group versus 91 U/L (range 13-759 U/L) in the tenofovir arm (P = 0.54). Median age in the tenofovir plus lamivudine group was 38 years (range, 22-53 years) compared to 43 years (range, 32-68 years) in the tenofovir group (P = 0.01). In the latter group patients had been on lamivudine for a median of 200 weeks (range, 40-364 weeks) before being treated with tenofovir.
The time course of the median HBV DNA level is shown in Fig. 1. After 3 months on treatment, median HBV DNA levels decreased to 140 000 copies/ml in the tenofovir plus lamivudine group compared to 30 000 copies/ml in the tenofovir group (P = 0.21). After 12 months and 24 months on treatment median HBV DNA levels decreased to < 1000 copies/ml in both groups (P = 0.77 and P = 0.86, respectively). An undetectable HBV DNA < 1000 copies/ml during the last two study visits was achieved in 19/25 (76%) patients on tenofovir plus lamivudine and in 42/50 (84%) patients on tenofovir (P = 0.53) (Fig. 2).
Median times on treatment were 129 weeks in the tenofovir plus lamivudine arm (range, 26-206 weeks) and 116 weeks (range, 26-206 weeks) in the tenofovir arm. ALT was normal at the two last study visits in 15/25 (60%) patients on tenofovir plus lamivudine compared to 32/50 (64%) on tenofovir (P = 0.80) (Fig. 2).
A loss of HBe-antigen was observed in 9/25 (36%) patients on tenofovir plus lamivudine and in 12/50 (24%) patients on tenofovir (P = 0.29). HBs-antigen loss was found in 1/25 (4%) and 3/50 (6%) patients, respectively (Fig. 2).
There was no association between HBe-antigen loss and CD4 cell count at baseline. Patients on tenofovir plus lamivudine without HBe-antigen loss had a median of 235 CD4 cells/μl compared to 340 CD4 cells/μl for patients with HBe-antigen loss (P = 0.52). The respective data for patients on tenofovir without HBe-antigen loss were 384 cells/μl and 357 cells/μl for patients with HBe-antigen loss (P = 0.76).
Discussion
After the historical success of antiviral combination therapy for the treatment of HIV-infection antiviral monotherapy is generally considered inferior for the long-term treatment of chronic viral infection. However, in chronic hepatitis B sequential monotherapy remains the clinical reality, due to the drug-by-drug approval process of HBV polymerase inhibitors.
In a clinical trial comparing lamivudine monotherapy to combination therapy with adefovir plus lamivudine no greater antiviral potency was observed during 48 weeks of treatment. However after 48 weeks the development of lamivudine resistant HBV was significantly lower in the combination therapy arm (20% versus 2%) [1]. In contrast, a trial comparing telbivudine with telbivudine plus lamivudine could not detect a difference in antiviral efficacy or development of resistance against telbivudine or lamivudine during 48 weeks [2].
No prospective studies comparing combination therapy with monotherapy for patients on adefovir or tenofovir have been reported to date. This is of particular interest as these nucleotides are more robust against the development of resistance than lamivudine and may be better suited for monotherapy of chronic hepatitis B. In addition, no comparative studies evaluating combination therapy with HBV polymerase inhibitors with an observational period beyond 48 weeks have been published so far.
In this matched-controlled study no marked difference in antiviral efficacy of treatment with tenofovir after the development of lamivudine resistance compared to the first-line combination therapy of tenofovir plus lamivudine was found during a median follow up of about 2 years. With both strategies, the vast majority of patients (93%) showed a viral reduction of at least 3 log10 compared to baseline. Moreover, inhibition of HBV DNA, loss of HBe-antigen and loss of HBs-antigen did not differ between the two study groups. ALT normalized in about 60% of the patients. Of note, all patients were on antiretroviral combination therapy and elevated ALT levels observed despite good suppression of HBV DNA could reflect the hepatotoxicity of some antiretroviral drugs. No patient discontinued therapy with HBV polymerase inhibitors due to adverse events.
Limitations of this partially retrospective study are the small sample size and a potential bias introduced by a higher CD4 cell count in the tenofovir arm due to the study design. However in a statistical analysis the CD4 cell count was not associated with treatment outcomes in this study.
In contrast to HBV monoinfection HBV/HIV coinfected individuals are frequently treated with combinations of HBV polymerase inhibitors as part of their antiretroviral regimen. Most infectious disease specialists consider combination therapy with HBV polymerase inhibitors the superior concept at least for highly replicative chronic hepatitis B. However given the current treatment options cross resistance after viral failure of a combination with tenofovir plus lamivudine or emtricitabine may not leave a second choice of an effective therapy of HBV. Because of this, some experts advocate for sequential monotherapy for the treatment of chronic hepatitis B in particular as most HBV/HIV-coinfected patients may require long-term treatment of their chronic hepatitis B. Sequential monotherapy may leave the option of switching to a non-cross resistant compound from a different class after the development of first viral failure.
In the present study lamivudine was used for sequential monotherapy in HBV/HIV-coinfected individuals due to the lack of other available HBV polymerase inhibitors apart from emtricitabine. Today for sequential monotherapy newer agents such as entecavir or telbivudine will be the more appropriate first- or second-line choice and should replace lamivudine used in this study as first-line monotherapy. Lamivudine suffers from a low genetic barrier to resistance and has demonstrated an inferior viral efficacy compared to entecavir or telbivudine [11,12]. Lamivudine resistance may further induce cross resistance to entecavir or telbivudine decreasing the treatment success with these compounds in second line markedly [11,13]. Thus, if sequential monotherapy rather than combination therapy against HBV is chosen, lamivudine should be avoided if possible. The same may apply for emtricitabine given the similar profile of the two drugs.
In conclusion, these preliminary data show no marked difference between first-line combination therapy of highly replicative chronic hepatitis B with tenofovir plus lamivudine and sequential therapy with tenofovir after the development of lamivudine resistance. However, differences might be seen beyond a treatment period longer than 2 years due to a deferred development of resistance under first-line combination therapy as suggested by the study from Sung and coworkers [1]. Based on our study data trials comparing tenofovir monotherapy with tenofovir based combination therapy will require large patient populations and study durations beyond 2 years.
To further clarify the optimal treatment strategy for chronic hepatitis B in patients with and without HIV-coinfection prospective controlled studies of sufficient size and adequate treatment duration comparing a nucleotide monotherapy with a nucleotide based combination therapy are urgently needed.
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