A Case for Treating High Hepatitis B DNA Levels before Starting HIV Therapy

Although many individuals are infected with both HIV and the hepatitis B virus (HBV), this issue has received less attention than HIV-hepatitis C virus (HCV) coinfection.

In a letter in the November 28, 2006 issue of AIDS, Jason Baker, David Boulware, and Paul Bohjanen from the University of Minnesota at Minneapolis made the case for providing hepatitis B treatment for coinfected patients with high HBV viral loads before initiating antiretroviral therapy for HIV.

Despite the overall effectiveness of antiretroviral therapy, they explained, "some patients experience paradoxical worsening, a complication termed 'immune reconstitution inflammatory syndrome' (IRIS)." Immune-mediated damage to HBV-infected hepatocytes (liver cells) is often reduced in patients with HIV-related immunosuppression, but the restoration of anti-HBV immune responses with antiretroviral therapy can cause acute liver inflammation.

The authors described a case of suspected immune reconstitution hepatitis after the initiation of drugs active against both HIV and HBV, which include 3TC (lamivudine; Epivir), emtricitabine (Emtriva), and tenofovir DF (Viread). They proposed that, "the high HBV antigen burden present during immune reconstitution caused this complication, and that HBV treatment before initiating HIV therapy may have prevented IRIS."

Case Study

The patient was a 43-year-old man with HIV and chronic HBV infection, a CD4 cell count of 85 cells/mm3, and an HIV viral load of 41,800 copies/mL. He presented after being off antiretroviral therapy for 4 years. He had previously been treated with 3TC, AZT (Retrovir), ddC (Hivid), d4T (Zerit), nelfinavir (Viracept), saquinavir (Invirase), and efavirenz (Sustiva).

Initial laboratory evaluation revealed that he was HBV surface antigen positive, core antibody positive, and early antibody positive. His albumin was 4.3 g/dL, bilirubin 0.3 mg/dL, AST 59 U/L, ALT 82 U/:, and creatinine 0.95 mg/dL. His plasma HBV DNA level was more than 1,000,000,000 copies/mL by Cobas TaqMan.

Upon reinitiating care in 2005, the man was started on tenofovir, emtricitabine, abacavir (Ziagen), atazanavir (Reyataz), and ritonavir (Norvir). Four weeks after restarting antiretroviral therapy, he was doing well clinically, his HIV viral load had fallen to 193 copies/mL, and his liver enzyme levels were unchanged (AST 57 U/L; ALT 84 U/L).

After 8 weeks, however, he returned to the clinic with jaundice, dark urine, and abdominal pain. A laboratory evaluation revealed acute hepatitis, with AST of 1289 U/L, ALT of 2409 U/L, bilirubin of 2.2 mg/dL, alkaline phosphatase of 292 U/L, gamma-glutamyl transferase (GGT) of 137 U/L, and international normalized ratio of 1.2. He denied taking other medications or drinking alcohol, and showed no evidence of infection with hepatitis A, C, or D, cytomegalovirus, Epstein-Barr virus, or herpes simplex virus.

At this time, his HBV DNA level had decreased by 3.5 logs to 334,000 copies/mL. His HIV RNA was below 50 copies/mL, and his CD4 cell count had doubled to 152 cells/mm3.

Resolution

The man's antiretroviral medications were discontinued, and 3TC and entecavir (Baraclude) were started for HBV treatment (although it was assumed, based on his treatment history, that he had 3TC-resistant HBV). On this regimen, his liver enzyme levels normalized (AST and ALT both 43 U/L) and complete HBV suppression occurred (< 200 copies/mL).

After 3 months, 3TC and entecavir were discontinued and he resumed his previous HAART regimen. Over the next 3 months, his HIV viral load again became undetectable and his CD4 count rose to 143 cells/mm3. In addition, his HBV DNA remained suppressed and his AST and ALT levels remained normal (both 30 U/L).

Discussion

"This patient with HIV-HBV coinfection suffered an acute exacerbation of hepatitis 8 weeks after starting potent therapy against HIV and HBV, despite a rapid virological response," the authors concluded. "After full suppression of his HBV DNA, he had no further complications upon re-initiation of the identical antiretroviral therapy regimen."

"The steady decline in HBV DNA, lack of evidence of drug toxicity, and timing with immune reconstitution all strongly suggest IRIS as the overriding explanation," they continued. "The high HBV antigen burden in the setting of improved immunity was probably responsible for his hepatitis. Perhaps full HBV suppression before ART initiation could have prevented IRIS."

"IRIS is hypothesized to arise from the restoration of pathogen-specific immune responses, so it follows that the antigen burden may predict the risk of IRIS," they wrote. "Entecavir, an effective anti-HBV therapy without overlapping anti-HIV activity, can decrease the HBV antigen burden without developing HIV resistance. Among those with high HBV viral loads, controlling HBV infection with HBV-specific agents, such as entecavir, before initiating anti-HIV therapy may prevent IRIS-induced hepatitis."

12/05/06

Reference
J V Baker, D R Boulware, P R Bohjanen. A case for treating high hepatitis B DNA levels before starting HIV therapy [Correspondence]. AIDS 20(18): 2402-2403. November 28, 2006.