3TC resistance leads to hepatitis B flare

Doctors in Melbourne, Australia, report a severe and prolonged flare of hepatitis B in an HIV-HBV co-infected patient, which they believe was caused by the emergence of 3TC-resistant HBV together with a strong and prolonged HBV-specific CD8 T cell response.

The patient was a 40-year-old man diagnosed with HIV and HBV in 1998; treatment with d4T, 3TC and nevirapine was commenced. However, after three months the HIV load remained high and the regimen was changed to AZT, ddI and nelfinavir. The viral load then fell to less than 50 copies/ml. Eighteen months after the initial diagnosis, the man was referred for management of severe hepatitis.

Sequencing of the HBV genome isolated from the patient’s serum did not identify compensatory mutations in the HBV polymerase that may have restored viral replication. “However, a strong HBV-specific CD8 T-cell response was identified and may have resulted in the severe hepatitis,” write Theo Gouskos and colleagues in the journal AIDS.

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This case report adds to the increasing body of literature on the dangers of lamivudine montherapy for the treatment of HBV in HBV/HIV co-infection. Other studies have reported around 90% lamivudine resistance by four years in HBV/HIV co-infected patients. Although not all ‘YMDD’ mutants have increased replicative capacity, this may occur in some cases where further compensatory mutations develop.

As demonstrated here, the mechanism of the flare is multifactorial, and an immune restoration phenomenon resulting from the HAART in the presence of replicating HBV (even at low levels) may be enough.

Current BHIVA guidelines suggest considering a HAART regimen that includes tenofovir and lamivudine for patients with viraemic HBV/HIV co-infection. This should prevent the emergence of lamivudine-resistance mutations in HBV.

Gouskos T, Wightman, F, Chang J et al. Severe hepatitis and prolonged hepatitis B virus-specific CD8 T-cell response after selection of hepatitis B virus YMDD variant in an HIV/hepatitis B virus coinfected patient. AIDS 2004, Vol 18 No 12, 1734-7.