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The effect of lamivudine on the replication of hepatitis B virus in HIV-infected patients depends on the host immune status (CD4 cell count)
  AIDS 2003; 17(10):1572-1574
Margje Haverkampa. Department of Medicine, Division of Acute Medicine and Infectious Diseases, Utrecht, the Netherlands
We retrospectively analysed the effect of lamivudine on hepatitis B virus (HBV) in HIV-co-infected patients. In this small study we document a CD4 cell-dependent response on HBV replication with lamivudine therapy. In this respect, hepatitis B may be considered an opportunistic infection. Our finding may have important clinical consequences, and large prospective studies are necessary to investigate this further.
Co-infection with hepatitis viruses and HIV-1 is common, because of the shared modes of transmission. Approximately 30% of HIV-infected patients are co-infected with hepatitis C virus. It has been shown that HIV is a risk factor for accelerated hepatitis C virus disease, and liver disease has emerged as a major cause of mortality and morbidity in co-infected patients. Most interest has been focused on co-infection with hepatitis C, but it was recently shown that patients co-infected with HIV-1 and hepatitis B virus (HBV) are also at an increased risk of liver-related mortality, underscoring the importance of the prevention, identification, and comprehensive management of hepatitis B in individuals infected with HIV-1. Among HIV-infected individuals as many as 10% are hepatitis B surface antigen (HBsAg) positive. Chronically infected individuals with HBV replication are at the highest risk of progressive liver disease, leading to cirrhosis, liver failure, and hepatocellular carcinoma. Lamivudine is a well-tolerated reverse transcriptase inhibitor used in anti-HIV therapy and is also an inhibitor of HBV replication. Limited information is available on the effect of lamivudine on chronic hepatitis caused by HBV in HIV-co-infected patients. Benhamou et al. showed in an open-label programme of lamivudine therapy that high doses (600 mg/day or 600 mg/day followed by 300 mg/day) as therapy for HIV led to the prompt inhibition of HBV replication, especially in patients with low HBV-DNA concentrations. However, the emergence of lamivudine-resistant HBV occurred rapidly.
Dore et al, in a retrospective placebo-controlled study, noted at weeks 12 and 52, a median log10 HBV-DNA change of -2.0 and -2.7, respectively, in the lamivudine arms, compared with no reduction among placebo recipients. A trend towards lower alanine aminotransferase (ALT) levels and delayed progression of HIV-1 disease were also seen in the lamivudine arms, compared with the placebo group.
HIV-1 causes immunosuppression associated with a reduced frequency of spontaneous recovery from HBV infection, a higher level of HBV replication, and a higher risk of cirrhosis. Moreover, a recent study showed that HIV co-infection was associated with a poorer response to IFN-[alpha] therapy, more frequent HBV reactivations, and an increased incidence of cirrhosis and cirrhosis-related death in cases with low CD4 cell counts. Therefore, the immune status of the host is of the utmost importance in the pathogenesis, the fate and the reaction to therapy of infections in HIV-co-infected patients, as shown by us previously.
We retrospectively analysed a cohort of HIV-HBV-co-infected patients receiving lamivudine as part of their antiretroviral therapy (150 mg twice a day) to study the effect of the immune status of the host on the outcome of therapy.
Twenty-nine patients who used lamivudine were identified retrospectively as HBsAg positive from the HIV cohort consulting our Division of Infectious Diseases (800 patients). CD4 cell counts, ALT and HBV serology were obtained from the patients' records. The HBV-DNA level was measured quantitatively, using real-time polymerase chain reaction (Taqman; Roche, Basle, Switzerland) with a cut-off of 1000 copies/ml.
We identified 29 HIV-infected patients (3.6%) as HBsAg positive, three women and 26 men (average age 36 years). At the start of therapy 17 out of 29 patients had a CD4 cell count of more than 200 cells/mm3. Fourteen patients of the 29 were hepatitis B e antigen (HBeAg) positive. In the course of therapy, the loss of HBsAg occurred in only two patients, whereas eight out of 14 HBeAg-positive patients (57%) developed anti-hepatitis B e antibodies. At the start and at 6 months of therapy, samples were available for HBV-DNA measurement from 17 patients. Thirteen out of 17 patients (76%) had CD4 cell counts of more 200 cells/mm3. Fifteen out of these 17 patients had replicative chronic HBV infection (HBV DNA > 1000 copies/ml); six out of the 17 patients were HBeAg positive. Considering the whole cohort of 17 patients, the median log HBV-DNA change was -1.3 (P = 0.018) within 6 months of therapy. When we divided the cohort into two arms (CD4 cell counts of less than 200 cells/mm3 or of 200 cells/mm3 or greater), the median log HBV-DNA change was -1.9 in the 200 cells/mm3 or greater arm (P < 0.001; 13 patients). In contrast, the median log HBV-DNA change (+0.77) in the CD4 cell count of less than 200 cells/mm3 arm was not significant (P = 0.543; four patients). This difference between the two groups was significant (P = 0.013). After 6 months of therapy, an HBV-DNA level of nine out of 13 patients (69%) with a CD4 cell count of 200 cells/mm3 or greater was undetectable, compared with two out or four patients in the less than 200 cells/mm3 group. At the end of follow-up (median 33 months), one more patient with a CD4 cell count greater than 200 cells/mm3 had reached this level. Nine out of 13 patients (69.2%) with a CD4 cell count of 200 cells/mm3 or greater had reached a normal serum ALT concentration. Only half of the patients with CD4 cell counts of less than 200 cells/mm3 reached this level.
Our findings highlight the importance of the immune status of the host in the clearance of HBV and the restoration of liver function. This might have important consequences for therapeutic algorithms.
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