LAMIVUDINE INHIBITS HEPATITIS B VIRUS REPLICATION IN KIDNEY GRAFT RECIPIENTS

Abstract

Renal graft recipients with hepatitis B virus (HBV) infection are at increased risk of fatal outcome when they have serological evidence of active viral replication, such as HBV DNA and/or hepatitis B e antigen (HBeAg) in the serum (1). Interferon-α therapy is precluded in such cases by its attendant high risk of severe graft rejection(2,3). Rostaing and co-workers(4) now report the benefits of lamivudine in six renal graft recipients with active HBV replication. Lamivudine, a new nucleoside analog, inhibits HBV replication in patients infected by HBV (5,6) and prevents HBV recurrence after liver transplantation(7,8). In the six reported patients, HBV DNA cleared rapidly from the serum, whereas elevated alanine aminotransferase(ALT) levels in five cases promptly returned to normal. Unfortunately, withdrawal of the drug in four patients after 6 months resulted in a prompt biochemical and virological relapse. The rarity of such reports prompted us to report our experience with an additional four cases of kidney graft recipients with severe HBV infection who were given 100 mg of lamivudine daily. We extend the observations of Rostaing et al., as our follow-up period was longer (range, 15-21 months), and illustrate two potential drawbacks of the therapy, i.e., a major flare-up of the liver disease after inadvertent withdrawal of treatment and the emergence of a resistance to the drug in another patient. The four male patients, aged 52 years (range, 44-62 years), had maintained their transplants for an average period of 13 years (range, 0.5-21 years)(second transplantation in one patient). Maintenance immunosuppression at the time of lamivudine onset consisted of prednisolone and cyclosporine in three patients and prednisolone and azathioprine in one patient(Table 1). They were known to be hepatitis B surface antigen (HBsAg)-positive for an average of 20 years (range, 15-23 years); HBV status at lamivudine onset was HBsAg (n=4), HBeAg (n=1), hepatitis B core antibody (HBcAb) (n=4), and hepatitis B e antibody (HBeAb)(n=3) (Abbott Laboratories). HBV DNA (detection limit of 1.5 pg/ml; Abbott hepatitis B viral DNA, Abbott Laboratories) was detected in the serum of all patients. None of them had anti-hepatitis C virus antibody (ELISA-III, Abbott Laboratories). All had severe impairment of liver function, as assessed by a very low level on the aminopyrine breath test (mean value at beginning of therapy: 1.10% [range, 0.37-1.46%; normal value: 2.8%]). A transjugular liver biopsy performed in three patients demonstrated severe liver cirrhosis (n=1), chronic aggressive hepatitis (n=1), and a normal HBsAg carrier status (n=1) (Table 1).Table 1: Individual characteristicsAs shown in Figure 1, lamivudine promptly reduced the HBV DNA serum concentration in all patients; the other HBV markers remained unchanged. Within 6 months of therapy, ALT levels normalized in all patients (from an average of 78.5±76.7 IU/L [median ± SEM] to 20±5.2 IU/L; normal value: 5-32 IU/L). The aminopyrine breath test, repeated in two patients after 12 and 18 months of treatment, increased from 1.11% and 0.37% to 1.74% and 0.77%, respectively. The serum creatinine level (median ± SEM) rose slightly in all patients, from 1.73±0.16 mg/dl at baseline to 1.89±0.17 mg/dl at 6 months and 1.90±0.07 mg/dl (n=3) at 12 months. Cyclosporine trough levels remained unchanged. No adverse effect of lamivudine was reported. Patients 2 and 3 are currently doing well 21 and 16 months after onset of treatment. In patient 1, both ALT and HBV DNA levels rose sharply between 9 and 12 months of treatment (Fig. 1). He subsequently developed severe hepatic failure and eventually died after surgery for massive hemochesia 17 months after lamivudine onset. A mutation in the YMDD locus of the HBV polymerase gene (9-11) was thereafter demonstrated. In patient 4, lamivudine was inadvertently withdrawn after aortic dissection surgery. Severe transient hepatic encephalopathy occurred. Despite the fact that lamivudine was resumed after 10 days of interruption, ALT levels rose from 31 to 545 IU/L and the HBV DNA level sharply increased(see Fig. 1). The branched DNA concentration (detection limit of 0.7 mEq/ml; Chiron Corp.), which was 2004 mEq/ml at lamivudine resumption and 7359 mEq/ml 19 days later, has decreased to 927.5 mEq/ml. Unfortunately, the patient developed hepatic encephalopathy and liver failure, and he eventually died.Fig. 1: HBV DNA levels.We therefore confirm that in kidney graft recipients with sever HBV infection, lamivudine effectively inhibits HBV replication with an attendant improvement of liver tests. This effect was observed despite the continuation of maintenance immunosuppression. A severe flare-up of the hepatitis, however, was observed in two patients during follow-up. In one of them, the flare-up was caused by the emergence of a resistance to the drug after less than 12 months of treatment; in the other patient, the flare-up followed lamivudine withdrawal. Both findings have previously been reported(4,5,8-11). The latter complication suggests that once started, lamivudine treatment should not be withdrawn. Given the unfavorable prognosis of chronic HBV infection in kidney graft recipients, the advent of a drug able to inhibit HBV replication is welcome. Together with the data of Rostaing and co-workers, our data are sufficiently encouraging for a larger study of the effect of lamivudine in HBV DNA-positive kidney graft recipients to be undertaken. This study should be reserved for patients with advanced HBV liver disease, since lamivudine is likely to be a lifetime therapy. The risk of resistance to the drug with its attendant effect on the course of liver disease should be evaluated in the long-term. Eric Goffin Yves Horsmans Chantal Cornu Jean-Paul Squifflet Yves Pirson Departments of Nephrology, Hepatology, Virology, and Renal Transplantation; Louvain Medical School; Hôpital Saint-Luc; 1200 Brussels, Belgium