Correspondence

Resolution of Chronic Hepatitis B after Ritonavir Treatment in an HIV-Infected Patient

N Engl J Med 1999; 340:1765-1766June 3, 1999

Article

To the Editor:

Spontaneous clearance of hepatitis B surface antigen (HBsAg) has been reported in about 5 percent of immunocompetent patients with chronic hepatitis B, but not in patients infected with human immunodeficiency virus (HIV).1 We describe an HIV-infected patient in whom treatment with the HIV-protease inhibitor ritonavir was associated with a flare of his chronic hepatitis B, followed by clearance of the virus and normalization of liver-enzyme levels.

Chronic hepatitis B was diagnosed in 1990 in a 35-year-old asymptomatic HIV-infected patient with a CD4 lymphocyte count of 436×10⁶ cells per liter. The principal laboratory findings during clinical follow-up from 1991 through 1996 were as follows: HBsAg, hepatitis B early antigen (HBeAg), and hepatitis B virus (HBV) DNA (on polymerase-chain-reaction testing); antibodies against HBsAg and HBeAg; negative tests for hepatitis A, C, and delta; and alanine aminotransferase levels of 100 to 200 U per liter. A liver biopsy revealed moderately active chronic hepatitis. A trial of interferon alfa therapy was unsuccessful. Ritonavir was added to the antiretroviral regimen of didanosine and zidovudine; nine weeks later vomiting and hepatomegaly developed, and the serum alanine aminotransferase level increased to 503 U per liter. Antiretroviral therapy was continued. The patient's symptoms resolved within two weeks, and the alanine aminotransferase level returned to normal five months later (Figure 1Figure 1Immunologic, Virologic, and Biochemical Changes in an HIV-Infected Patient with Chronic Hepatitis B before and during Treatment with Ritonavir.), in association with the clearance of HBsAg, HBeAg, and HBV DNA and the appearance of antibodies against HBsAg. During this time, the HIV viral load dropped by an order of 1 log and the CD4 cell count steadily increased (to 384×10⁶ per liter).

Treatment with highly active antiretroviral therapy is paradoxically associated with both an initial flare of some opportunistic infections (mycobacterium and cytomegalovirus) and a lower incidence of these infections afterward.2 In spite of its wide use, only two cases in which highly active antiretroviral therapy has modified the natural evolution of hepatitis B in HIV-infected patients have been described. In both these patients, a clinical flare of hepatitis B occurred shortly after the introduction of ritonavir treatment, followed by complete clearance of HBV in one of them.1,3 It seems likely that similar cases may have been misinterpreted as instances of drug toxicity. Consequently, the development of liver abnormalities after the initiation of highly active antiretroviral therapy may not reflect drug toxicity, and the possibility of a reactivation of chronic hepatitis B should be considered in the differential diagnosis.

Ritonavir does not have direct in vitro activity against HBV.3 As this case report illustrates, the immunologic improvement after the initiation of highly active antiretroviral therapy for HIV infection may also contribute to the control of yet another viral infection in addition to the classic opportunistic ones.

Maria Velasco, M.D.
Aurora Morán, M.D.
María Jesús Téllez, M.D., Ph.D.
Hospital Universitario San Carlos, Madrid 28040, Spain

3 References

1. 1

   Carr A, Cooper DA. Restoration of immunity to chronic hepatitis B infection in HIV-infected patient on protease inhibitor. Lancet 1997;349:995-996
   CrossRef | Web of Science | Medline

2. 2

   Sepkowitz KA. Effect of HAART on natural history of AIDS-related opportunistic disorders. Lancet 1998;351:228-230
   CrossRef | Web of Science | Medline

3. 3

   Mastroianni CM, Trinchieri V, Santopadre P, et al. Acute clinical hepatitis in an HIV-seropositive hepatitis B carrier receiving protease inhibitor therapy. AIDS 1998;12:1939-1940
   Web of Science | Medline

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   Vincent Soriano, Massimo Puoti, Marion Peters, Yves Benhamou, Mark Sulkowski, Fabien Zoulim, Stefan Mauss, Juergen Rockstroh. (2008) Care of HIV patients with chronic hepatitis B: updated recommendations from the HIV-Hepatitis B Virus International Panel. AIDS 22:12, 1399-1410
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   Martyn A French, Patricia Price. (2008) Immune restoration disease complicating antiretroviral therapy in patients with HIV infection: implications and solutions. Future HIV Therapy 2:3, 263-270
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   Yves Benhamou. (2007) Hepatitis B in the HIV-Coinfected Patient. JAIDS Journal of Acquired Immune Deficiency Syndromes 45:Supplement 2, S57-S65
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    C. Manegold, C. Hannoun, A. Wywiol, M. Dietrich, S. Polywka, C. B. Chiwakata, S. Gunther. (2001) Reactivation of Hepatitis B Virus Replication Accompanied by Acute Hepatitis in Patients Receiving Highly Active Antiretroviral Therapy. Clinical Infectious Diseases 32:1, 144-148
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