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An open-label study of tenofovir in HIV-1 and Hepatitis B virus co-infected individuals

Nelson, M; Portsmouth, S; Stebbing, J; Atkins, M; Barr, A; Matthews, G; Pillay, Da; Fisher, Mb; Bower, M; Gazzard, B

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From The Chelsea and Westminster Hospital, London, UK; aPHLS, Anti-Viral Susceptibility Unit, University of Birmingham and bRoyal Sussex County Hospital, Brighton, UK.

Correspondence to M. Nelson, The Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK.

Received: 29 October 2002; accepted: 30 October 2002.

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Abstract

Background: Tenofovir is a novel nucleotide analogue recommended for use in HIV-1 infected treatment-experienced patients. Recent data suggest an effect on Hepatitis B virus (HBV) replication. We therefore investigated the use of tenofovir in HIV-1 and HBV co-infected individuals.

Methods: Twenty HIV-1/HBV co-infected patients with a median of 108 weeks lamivudine experience (range, 0–270 weeks) received tenofovir 245 mg daily in addition to or as part of their combination antiretroviral therapy. Their immunologic parameters and HIV-1 RNA and HBV DNA viral loads were followed over a period of 52 weeks. In addition, their HBV DNA polymerase was sequenced at baseline to measure the frequency of YMDD mutations that are associated with lamivudine resistance.

Findings: A significant decrease in HBV DNA viral load (4 × log10) and alanine aminotransferase levels was observed. There were no significant overall differences between the lamivudine-experienced (n = 15) and -naive (n = 5) individuals and tenofovir was well tolerated. Five patients (25%) underwent HBe antigen seroconversion during the study period. Out of the 15 lamivudine-experienced individuals, 10 had YMDD mutations and one had YIDD mutations in HBV DNA.

Interpretation: These results indicate that 52 weeks of tenofovir in addition to antiretroviral therapy is active against HBV, and it appears to overcome lamivudine resistance.

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Introduction

HIV-1 infection is commonly complicated by co-infection with Hepatitis B virus (HBV) [1]. Chronic hepatitis B is a widespread disease affecting more than 350 million people worldwide – approximately 5% of the world's population [2,3]. The two therapies currently licensed for hepatitis B are interferon-α and lamivudine (3TC) [4]. The cytokine interferon-α given subcutaneously results in variable and often unsatisfactory response rates with significant adverse effects [5]. The nucleoside analogue reverse transcriptase inhibitor (NRTI) 3TC is well tolerated and inhibits HBV replication in more than 80% of patients with or without HIV-1 co-infection [6–8]. Emergence of HBV resistance to 3TC occurs in 50% and 90% of HIV-1/HBV co-infected patients after 2 and 4 years of therapy respectively [9]. This is conferred by a mutation in the HBV DNA polymerase gene which entails a substitution of the methionine residue at codon 550 in the YYMD (Tyr-Met-Asp-Asp) motif by either valine or isoleucine [10,11]. The clinical consequences on the course of HBV infection of 3TC resistance in HIV-infected individuals are currently unknown [12].

Tenofovir R-9-(2-phosphonyl-methoxypropyl)adenine is an acyclic nucleotide reverse transcriptase inhibitor [13]. It has a safety profile comparable to placebo and a randomized study has shown dose-related, durable reductions in HIV-1 RNA viral load with activity against NRTI-resistant virus [14].

The in vitro activity of tenofovir against HBV was first demonstrated in 1990 [15] and recent subgroup analyses of HIV-1/HBV co-infected individuals treated with tenofovir showed a reduction in HBV DNA viral load. Patients included in this were 3TC-experienced and harboured YYMD mutations [16]. We therefore wished to study the effects of tenofovir in HIV-1/HBV co-infected patients.

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Methods

From August 2001 to January 2002, 20 HIV-1/HBV co-infected subjects at The Chelsea and Westminster Hospital and Royal Sussex County Hospital, UK were treated with standard antiretroviral therapy as per unit protocol with the addition of 245 mg of tenofovir orally once daily. All were HBe antigen positive. These patients were treated as part of salvage protocols or because of increased HBV DNA despite prolonged use of 3TC.

Patients were followed up in routine HIV clinics at baseline, 4, 12, 24 weeks and then 12 weekly. Hepatitis B serology was performed along with quantitative HBV DNA levels with a baseline detection limit of < 1 × 104 genome equivalents (GEq)/ml [17]. The presence of YYMD mutations was established in baseline blood samples by sequencing of the HBV DNA polymerase [18]. Total lymphocyte and subset analysis was performed using whole blood stained with murine anti-human monoclonal antibodies to CD4, CD8, CD16/56 and CD19 (TetraOne, Beckman Coulter, High Wycombe, UK) and were evaluated on an Epics XL-MCL (Beckman Coulter) flow cytometer. Viral loads in patient plasma was measured using the Quantiplex HIV RNA 3.0 (Chiron bDNA) assay with a lower limit of detection of 50 HIV-1 copies/ml (Chiron Diagnostics, Halstead, UK). These parameters were measured at most clinic visits. Alanine aminotransferase (ALT) and albumin levels were recorded. All individuals gave written informed consent and the study received ethical approval in accordance with the Helsinki declaration.

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Results

All 20 patients were homosexual males and their median age was 43 years (range, 22–52 years). Fifteen out of the 20 patients were 3TC experienced with a median exposure of 138 weeks (range, 8–270 weeks). The median HBV DNA viral load at baseline was 181 500 000 (interquartile range, 47 375 000–755 000 000) GEq/ml. Out of these 15 3TC exposed patients, 11 had mutations at baseline conferring 3TC escape (10 with YMDD and one with YIDD).

Concurrent antiretroviral regimens in addition to tenofovir consisted of: (i) a non-nucleoside reverse transcriptase inhibitor (NNRTI) and two NRTI in nine patients (45%); (ii) three NRTI in three patients (15%); (iii) two NRTI and a boosted protease inhibitor (PI) in two patients (10%); (iv) two PI and two NRTI in two patients (10%); (v) an NNRTI and one NRTI in two patients (10%); (vi) two PI and one NRTI in one patient (5%); and (vii) one PI and three NRTI in the remaining patient (5%). Subgroup analyses contained too few patients to draw useful comparisons although it appeared that there were no significant differences (data not shown).

We observed a median 4 log10 reduction in HBV DNA viral load in the first 24 weeks and a median decrease in ALT from 96 to 43 IU/ml during this time (46% normalized their ALT during the trial). Serum albumin showed a small non-significant increase (Fig. 1). The median in HBV DNA viral load decreased from 126 272 450 GEq/ml to 328 692 during the first 24 weeks. Table 1 demonstrates the percentage of patients with an undetectable HBV load at each time point and the number of patients in the trial who reached this time.

Fig. 1
Fig. 1
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Table 1
Table 1
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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.

Fig. 2
Fig. 2
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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).

Fig. 3
Fig. 3
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Discussion

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 [12]. 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 [19]. This in turn has implications for the clinical outcome of chronic infection including cirrhosis and hepatocellular carcinoma [20]. 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 [12]. 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 [21]. 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 [12], two patients out of 35 underwent HBe antigen seroconversion. However, the safety profile of tenofovir is comparable to that of placebo [14] and we observed no adverse effects. Tenofovir increases the therapeutic options for HIV-1 and HBV co-infection.

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Acknowledgements

Sponsorship: Supported by Gilead UK, Cambridge.

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Keywords:

lamivudine; tenofovir; hepatitis B; HIV-1; antiretroviral therapy; resistance mutation

© 2003 Lippincott Williams & Wilkins, Inc.

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