Scar undone: long-term therapy of hepatitis B.

In recent years, substantial progress has been made in the prevention and control of hepatitis B, a major cause of chronic liver disease, cirrhosis, and liver cancer worldwide. A safe and eff ective hepatitis B virus vaccine was developed in the early 1980s, and its subsequent widespread use resulted in notable decreases in rates of hepatitis B, at least in countries that adopted universal hepatitis B vaccination. Therapies for hepatitis B were developed more recently and are only now showing an eff ect on the burden of this disease. Interferon alfa was approved for this indication in the USA in 1991, but had low effi cacy and was not well tolerated. Oral antiviral agents with activity against hepatitis B were developed in the 1990s. The fi rst three agents approved in the USA (lamivudine in 1998, adefovir in 2002, and telbivudine in 2006) were very well tolerated, and yielded good viral suppression and clinical responses in 1–2 year studies. With more prolonged therapy, however, the effi cacy of these agents was limited by antiviral resistance. These shortcomings seem to be overcome by two newer, more potent antiviral agents—entecavir (approved in 2005) and tenofovir disoproxil fumarate (approved in 2008)— both of which have a high barrier to antiviral resistance. These antiviral agents suppress serum hepatitis B virus DNA to near or below detectable levels, and result in high rates of improvement in both biochemical and histological evidence of disease. Studies show that their long-term use (3–5 years) maintains viral suppression and biochemical improvements. In this issue of The Lancet, Patrick Marcellin and colleagues report that long-term therapy also leads to substantial histological improvements, including decreases in fi brosis and apparent regression of cirrhosis. Such eff ects of long-term antiviral therapy of hepatitis B (and C and D) have been reported previously, but no other report has been as large or convincing. In 489 patients with chronic hepatitis B treated with tenofovir for 4–5 years, 348 underwent repeat liver biopsy. Liver histology showed improvement in infl ammation and necrosis in almost all patients and a decrease in fi brosis in 51% (176 of 348 patients). An impressive fi nding was an apparent regression of cirrhosis in 74% of those with cirrhosis on initial biopsy (71 of 96 patients). Patients without resolution of cirrhosis were more likely to be overweight or obese. Regression of fi brosis, as shown by paired liver biopsies before and after 4 years of therapy, is a strong and convincing endpoint in support of treatment. Nevertheless, histological improvement is a surrogate endpoint for the clinical consequences of cirrhosis: clinical decompensation, death from end-stage liver disease, and hepatocellular carcinoma, the dreaded longterm complication of chronic hepatitis B. In the study from Marcellin and colleagues, these hard endpoints were apparently improved but less well documented than the histological changes. The rate of hepatocellular carcinoma was about 2% (12 cases). Importantly, in patients without hepatocellular carcinoma, none developed hepatic compensation or died of end-stage liver disease. The study did not include an untreated control group for obvious reasons, but historical controls would have predicted higher rates for both outcomes. This study and many others now support the recommendation that patients with chronic hepatitis B receive long-term treatment with a potent oral antiviral agent with a high barrier to resistance. If long-term treatment is recommended, how long should it be continued for, and what criteria should be used to decide when to stop therapy? In patients with HBeAg-positive hepatitis B, guidelines recommend discontinuation of antiviral therapy 6 months after loss of HBeAg. Furthermore, in patients with HBeAg-negative disease, fi ndings from case series have shown that Published Online December 10, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)61721-8