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Tenofovir-Based Rescue Therapy for Advanced Liver Disease in 6 Patients Coinfected with HIV and Hepatitis B Virus and Receiving Lamivudine
BRIEF REPORT
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Clinical Infectious Diseases Jan 2 2008;46
Sonia Gutierrez,1 Silvia Guillemi,1 Natalie Jahnke,1 Valentina Montessori,1,2 P. Richard Harrigan,1,2 and Julio S. G. Montaner1,2
1BC Centre for Excellence in HIV/AIDS, St. Paul's Hospital, and 2Faculty of Medicine, University of British Columbia, Vancouver, Ca
We summarize the clinical history and laboratory results following the introduction of tenofovir among 6 patients coinfected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) who presented with severe liver disease while receiving lamivudine-based highly active antiretroviral therapy. In all cases, the introduction of tenofovir led to a sustained undetectable HBV and HIV loads, with marked clinical and laboratory improvement in liver function. We provide supporting evidence for the role of tenofovir in the management of advanced HBV infection in HIV-positive patients after the development of lamivudine resistance.
Liver disease secondary to chronic viral hepatitis has emerged as a significant cause of morbidity and mortality among persons infected with HIV in the era of HAART [1-3]. Chronic active hepatitis B among HIV-infected subjects has been associated with poorer outcomes, including a high incidence of hepatoma [2], cirrhosis, and cirrhosis-related deaths [4].
Therapeutic options for HIV-infected patients with decompensated hepatitis B virus (HBV)-related liver disease are limited [5]. IFN-ƒ¿ was the first drug approved for the treatment of chronic hepatitis B, but its use is often limited by its toxicity. In addition, it can precipitate liver failure and is contraindicated for patients with decompensated cirrhosis [6]. Lamivudine, commonly used for the treatment of HIV infection [7], is also active against HBV [5, 6]. However, patients coinfected with HIV and HBV who receive lamivudine-based HAART often develop HBV resistance, characterized by the selection of YMDD mutants [7-9]. The emergence of lamivudine-resistant HBV has been associated with progression to acute liver failure [10, 11]. Adefovir, a nucleotide analogue active against HBV, has no anti-HIV activity at the currently recommended doses [12]. In contrast, a new nucleotide analogue, tenofovir, recently approved for the treatment of HIV infection, is also active against HBV, including lamivudine-resistant HBV [7, 13-15]. We describe 6 patients coinfected with HIV and HBV with decompensated liver disease during treatment with lamivudine-based HAART who experienced marked and sustained clinical and virologic improvement following the introduction of tenofovir.
Case report. Patient 1, a 33-year-old man who has sex with men, first received a diagnosis of HIV infection in 1992 (table 1). He also had chronic HBV infection with reactive hepatitis B surface antigen and hepatitis B envelope antigen. His history of prior antiretroviral therapy was extensive and included zidovudine, didanosine, zalcitabine, stavudine, indinavir, lamivudine, ritonavir, and saquinavir. At the time of first referral, he had been receiving lamivudine-based HAART for 3 years. However, his transaminase levels remained elevated, and his level of HBV DNA was > 1.7 x 10-6th copies/mL. The following laboratory values were noted: alanine aminotransferase level, 176 U/L (upper limit of normal, 55 U/L); aspartate aminotransferase level, 353 U/L (upper limit of normal, 45 U/L); bilirubin level, 67 μmol/L (upper limit of normal, 20 μmol/L); international normalized ratio, 1.6 (upper limit of normal, 1.2); and platelet count, 66 G/L (normal range, 150-400 G/L). Furthermore, the presence of jaundice, ascites, and gastrointestinal bleeding caused by decompensated liver disease were noted. HBV DNA genotyping revealed mutations in the YMDD motif at positions M204V/I and L180M, associated with lamivudine resistance [5, 9]. The patient's advanced liver disease was thought to preclude the safe continuation of his HAART regimen; thus, treatment was discontinued, and the patient was referred to our clinic for a second opinion.
At that time, his CD4 cell count was 230 cells/mm3, his plasma HIV RNA level was >100,000 copies/mL, and his HBV DNA level was > 56 x 10-6th copies/mL. A new HAART regimen was begun, including tenofovir, lamivudine, and lopinavir-ritonavir. The patient was also independently evaluated for liver transplantation. He was deemed to be a suitable candidate, provided that he attained a sustained undetectable plasma HIV RNA level, which is a mandatory requirement within the provincial liver transplant program.
As shown in table 1, after a transient increase in transaminase levels after recommencing HAART, liver transaminase levels were substantially lower, and resolution of the ascites was confirmed by ultrasound examination at 10 months. After 45 months of continued therapy, the patient was clinically asymptomatic, with a stable laboratory profile, including the following values: alanine aminotransferase level, 26 U/L (119 at baseline); aspartate aminotransferase level, 39 U/L (212 at baseline); bilirubin level, 22 μmol/L; international normalized ratio, 1.1; platelet count, 123 G/L; and undetectable HBV DNA. Of note, hepatitis B surface antigen was reactive and hepatitis B envelope antigen was nonreactive. The patient's HIV RNA level remained undetectable, and his CD4 cell count was 580 cells/mm3 (CD4 cell percentage, 32%). At this time, the patient was delisted for liver transplantation.
Table 2 summarizes the clinical and laboratory characteristics of 5 additional patients coinfected with HBV and HIV who had advanced liver disease and who were treated with lamivudine or emtricitabine plus tenofovir-based HAART at our clinic. They showed similar sustained clinical, virologic, and biochemical improvement.
Table 2. Summary of laboratory and clinical features of 5 persons coinfected with hepatitis B virus (HBV) and HIV receiving tenofovir-based rescue therapy.
Discussion.
The 6 patients with HIV and HBV coinfection described here showed marked and sustained clinical, virologic, and biochemical improvement following the addition of tenofovir to a lamivudine-based HAART regimen. In all cases, there was reversal of clinical signs of hepatic insufficiency, following sustained undetectable HBV DNA levels and normalization of transaminase levels. Of note, 5 of 6 patients experienced a transient increase in transaminase levels after the initiation of tenofovir-based therapy (data not shown).
Our results expand on those of Benhamou et al. [16], who documented the efficacy of tenofovir in the control of lamivudine-resistant HBV replication among 65 patients coinfected with HBV and HIV, and those of Matthews et al. [17], who described normalization of liver function among 7 cirrhotic patients coinfected with HBV and HIV and treated with tenofovir. Our HBV-HIV-coinfected patients had advanced liver disease and had experienced failure of lamivudine-based therapy. As such, our report provides supporting evidence for the possible role of tenofovir as rescue therapy for HIV-HBV-coinfected patients with advanced decompensated liver disease during treatment with lamivudine. Further studies are necessary to fully characterize the optimal use of tenofovir in dual HIV and HBV infection and advanced liver disease.
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