Clinical course of lamivudine-resistant HBV infection in renal allograft recipients

Abstract

We have reported that pre-emptive lamivudine therapy based on HBV DNA level markedly reduced liver-related mortality in HBsAg+ renal transplant recipients (RTR). However, the progressive emergence of lamivudine-resistant HBV variants presents a major concern, and yet the natural history of lamivudine-resistant HBV infection in immunosuppressed subjects remains obscure. Since Jan 1996 we have treated 29 of 53 HBsAg+ RTR pre-emptively with lamivudine based on their increasing HBV DNA levels. All the patients had maintenance immunosuppression with low-dose prednisolone and cyclosporin or tacrolimus. All the patients had effective suppression of HBV DNA after treatment. This is a prospective cohort study to examine the clinical course of patients who have developed lamivudine-resistant HBV variants. 14 patients (48.3%) developed lamivudine-resistance with resurgence of HBV DNA during treatment, whereas treatment was successfully withdrawn (i.e. without relapse) after 24.6±11.9 mon in 9 patients (31.0%). The duration of lamivudine therapy and the posttransplant follow-up for the 14 patients were 56.7±12.5 and 97.4±44.9 mon respectively. Lamivudine-resistance emerged after 16.9±7.0 mon (range 10-35) of treatment, with 78.6% within the first 18 mon. Patients with lamivudine-resistant variants showed similar age, gender, baseline eAg status, and post-lamivudine eAg sero-conversion (25.0 vs 33.3%, P=1.00) compared to those who did not develop resistance. Liver biochemistry deteriorated in 11 (78.6%) patients after the emergence of lamivudineresistance, which was transient in 4 (36.4%) but became chronic in 6 (54.5%) patients. The remaining patient developed severe exacerbation, but responded to the addition of famciclovir. Peak HBV DNA after the emergence of resistance was lower (1.26±1.09x109 vs 6.26±12.23x109 copies/ml, P=0.011), while peak ALT was higher (196±117 vs 77±47 iu/l, P=0.005), compared to the respective pre-treatment levels. None of the patients with lamivudine-resistant HBV had liver-related mortality or hepatocellular carcinoma, while the latter affected 2 patients in the other group. We conclude that half of lamivudine-treated HBsAg+ RTR are complicated by drug resistance. Although the subsequent peak HBV DNA is lower than the pre-treatment level, exacerbation of hepatitis is common, and half of these patients develop chronic active hepatitis. Thus, lamivudine-resistant HBV variants will present an escalating clinical problem in immunosuppressed RTR, before the advent of effective therapy.