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Reactivation of HBV replication in HIV-HBV infected patients

      To the Editor:
      In immunocompetent patients with isolated hepatitis B core antibody (anti-HBc), hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is detected by polymerase chain reaction (PCR) in about 10% of cases and HBV reactivation is rare (
      • Grob P.
      • Jilg W.
      • Bornhak H.
      • et al.
      Serological pattern “anti-HBc alone:” report on a workshop.
      ). However, in patients coinfected with human immunodeficiency virus (HIV), HBV DNA is intermittently detected in more than 85% of patients (
      • Hofer M.
      • Joller-Jemelka H.I.
      • Grob P.J.
      • et al.
      Frequent chronic hepatitis B virus infection in HIV-infected patients positive for antibody to hepatitis B core antigen only.
      ). We report 2 patients with HIV infection and isolated anti-HBc who developed acute replicative hepatitis B despite having a negative HBV DNA test before hepatitis B reactivation.
      Patient 1 was a 42-year-old man who had HIV infection since 1987, Centers for Disease Control and Prevention (CDC) stage B disease, and isolated anti-HBc since 1995. The test results for hepatitis B surface antigen (HBsAg) and its antibody (anti-HBs), and hepatitis B e antigen (HBeAg) and its antibody (anti-HBe), were negative. Liver enzyme levels were normal. In November 1996, treatment with stavudine and lamivudine was started. One month later, he presented with elevated alanine aminotransferase levels (1208 U/L; normal, 6 to 40 U/L). HBsAg was detected for the first time. Tests for anti-HBc immunoglobulin (Ig) M and anti-HBe were positive. HBV DNA level was 3.8 log copies/mL. Serologic tests for hepatitis A, C, and D, and hepatitis C virus (HCV) ribonucleic acid (RNA), were negative. There was an increase in CD4+ lymphocytes from 290 to 350/mm3, and HIV RNA level dropped from 4.8 log copies/mL to <500 copies/mL. Antiretroviral treatment was maintained, and liver enzyme levels returned to normal within 2 months. HBV DNA became undetectable (lower detection limit <1000 copies/mL) after 3 months of lamivudine treatment. Retrospectively, HBV DNA was undetectable (lower detection limit <1000 copies/mL) 11 months before the start of antiretroviral treatment.
      Patient 2 was a 45-year-old woman with HIV infection since 1994, CDC stage B disease, and isolated anti-HBc since 1997. Antibodies to HCV and HCV RNA were positive. Since 1998, she had been taking stavudine, lamivudine, and nevirapine. In December 2000, she was admitted for jaundice, ascites, and elevated liver enzyme levels. Tests for HBsAg, anti-HBc IgM, and HBeAg were positive. HBV DNA level was 4.2 log copies/mL. Test for HCV RNA was negative. The CD4 count was 118 cells/mm3 and plasma HIV RNA level was 6.3 log copies/mL. Two months later, therapy with zidovudine and lamivudine was reintroduced. HBV DNA levels dropped rapidly to undetectable levels, and anti-HBe was present. Retrospectively, HBV DNA was undetectable (lower detection limit <1000 copies/mL) 3 years and 1 year before liver decompensation.
      Transmission of HBV infection from blood and organ donors with isolated anti-HBc was not detected by DNA amplification in most reports (
      • Brechot C.
      • Thiers V.
      • Kremsdorf D.
      • et al.
      Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen clinically significant or purely “occult”?.
      ,
      • Allain J.P.
      • Hewitt P.E.
      • Tedder R.S.
      • et al.
      anti-HBc Screening Study Group
      Evidence that anti-HBc but not HBV DNA testing may prevent some HBV transmission by transfusion.
      ). Yet it has been observed that some liver transplant recipients developed acute HBV infection even when the donor was negative for HBsAg, or positive for anti-HBc alone or for both anti-HBc and anti-HBs. Indeed, at the Digestive Disease Week 2000, Marusawa et al reported detecting HBV DNA in liver samples from 24 of 32 healthy, related liver donors with negative tests for HBV antigens and genomes, a normal alanine aminotransferase test, and anti-HBc. The detected HBV genomes included covalently closed circular DNA and pregenomic RNA, the replication intermediate of HBV. In our 2 patients, HBV DNA was also undetectable by PCR in blood serum before hepatitis B reactivation, the alanine aminotransferase test was normal, and anti-HBc was the only marker of HBV infection.
      In HIV-positive patients, hepatitis B reactivation has been reported in patients who were positive for HBsAg and who had recovered fully from HBV infection and developed anti-HBs (
      • Manegold C.
      • Hannoun C.
      • Wywiol A.
      • et al.
      Reactivation of hepatitis B virus replication accompanied by acute hepatitis in patients receiving highly active antiretroviral therapy.
      ). Patients with isolated anti-HBc, even with a negative HBV DNA test, are also at risk of sudden HBV reactivation and subsequent severe hepatic failure.

      References

        • Grob P.
        • Jilg W.
        • Bornhak H.
        • et al.
        Serological pattern “anti-HBc alone:”.
        J Med Virol. 2000; 62: 450-455
        • Hofer M.
        • Joller-Jemelka H.I.
        • Grob P.J.
        • et al.
        Frequent chronic hepatitis B virus infection in HIV-infected patients positive for antibody to hepatitis B core antigen only.
        Eur J Clin Microbiol Infect Dis. 1998; 17: 6-13
        • Brechot C.
        • Thiers V.
        • Kremsdorf D.
        • et al.
        Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen.
        Hepatology. 2001; 34: 194-203
        • Allain J.P.
        • Hewitt P.E.
        • Tedder R.S.
        • et al.
        • anti-HBc Screening Study Group
        Evidence that anti-HBc but not HBV DNA testing may prevent some HBV transmission by transfusion.
        Br J Haematol. 1999; 107: 186-195
        • Manegold C.
        • Hannoun C.
        • Wywiol A.
        • et al.
        Reactivation of hepatitis B virus replication accompanied by acute hepatitis in patients receiving highly active antiretroviral therapy.
        Clin Infect Dis. 2001; 32: 144-148