Treatment of severe, nonfulminant acute hepatitis B with lamivudine vs placebo: a prospective randomized double‐blinded multicentre trial

Abstract

Acute hepatitis B virus (aHBV) infection can lead to fulminant liver failure, which likely is prevented by early lamivudine therapy. Even nonfulminant but severe acute hepatitis B can lead to significant morbidity and impaired quality of life. Therefore, lamivudine was evaluated in patients with severe aHBV in a placebo-controlled trial. Patients with severe aHBV infection (ALT >10× ULN, bilirubin >85 μm, prothrombin time >50%) were prospectively treated with lamivudine 100 mg/day or with placebo within 8 days after the diagnosis. The primary end point was time to bilirubin <34.2 μm. Secondary end points were time to clear HBsAg and HBV-DNA, development of anti-HBs and normalization of ALT. Eighteen cases were randomized to lamivudine, 17 to placebo. 94% of patients were hospitalized. No individual progressed to hepatic failure; all but one patient achieved the primary end point. Due to smaller than expected patient numbers, all study end points did not become statistically significant between treatment arms. Median time end points [in days] were bilirubin <34.2 μm (26.5 vs 32), ALT normalization (35 vs 48) and HBsAg clearance (48 vs 67) referring to earlier recovery under lamivudine, in contrast to loss of HBV-DNA (62 vs 54) and development of anti-HBs (119 vs 109). In all but two patients (one in every group), HBsAg clearance was reached in the study. Adverse events occurred more frequently during lamivudine therapy, but did not reach statistical significance. Lamivudine may ameliorate severe aHBV infection, but limited patient numbers prevented definite conclusions.

Treatment of fulminant acute Hepatitis B with nucles(t)id analogues is safe and does not lead to secondary chronification of Hepatitis B

“…Accordingly, we were able to show in case series of 6 consecutive patients with ALF due to HBV that the treatment with entecavir remarkably reduced the cell death marker within a few days, leading to a complete recovery in all treated patients [15]. However, in a prospective placebo controlled trial with patients with acute non-fulminant hepatitis B lamivudine treatment did not show a significant advantage towards survival [11]. Another study from China showed an advantage of lamivudine treatment in patients with acute to fulminant hepatitis B only in patients without systemic inflamatoric response syndrome, suggesting the therapy should be started early [16].…”

“…So far, prognostic markers are not established, which may predict who will recover spontaneously and who will control the HBV virus eventually [10]. A randomized trial in severe non-fulminant acute hepatitis B, which tested lamivudine versus placebo, did not show a significant advantage for treatment; however, the numbers were small [11]. Nevertheless, no patient developed liver failure.…”

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection

“…185 The management of acute liver failure and the indication for liver transplantation are discussed in detail in separate EASL CPGs. 151,180 Early NA treatment does not increase the risk of chronicity 181,186 ; in fact, observational data from a multicentre cohort even indicated reduced rates of chronicity, if NA treatment was initiated within 8 weeks of acute hepatitis B presentation in genotype A infected individuals.…”

Antiviral treatment for hepatitis B in infancy: Still an issue for debate

“…Although lamivudine has been used to treat fulminant hepatitis in infancy and severe acute hepatitis B in adults, the efficacy in infants is still controversial due to limited case numbers. 5,6 Well-controlled clinical trials are warranted to explore the efficacy and safety of treatment in those who may benefit from early antiviral treatment. Before such evidence is available, it is still too early to apply antiviral treatment to infants with HBV infection.…”