Comment on the Controversy in Guidelines of HBV Concurrent

Jian Sun  Nanfang Hospital, Nanfang Medical University, Guangzhou, China

In the afternoon of 14 Feb, there was a concurrent session of the topic about the controversy in guidelines of HBV. There were mainly two topics. One was whether we should treat patients with low ALT and the other was whether nucleos(t)ide analogs treatment can be stopped.

The first debate about whether we should treat patients with low ALT was between Professor Nancy W.Y. Leung from HK and Professor Wan-Cheng Chow from Sigapore. Professor Chow is on the con side about starting treatment for low ALT, as recent guidelines on management of chronic hepatitis B (including guidelines of AASLD, APASL and EASL, et al.) all recommend that antiviral treatment should mainly be prescribed to patients with raised ALT. And there are data show that antiviral treatment in patients with normal ALT is not as effective as that in patients with raised ALT.

However, Professor Leung gave some supportive reasons for the treatment in patients with low ALT. (1)ALT in blood may fluctuate and monitoring interval of 3 to 6 months may not detect the raised ALT. (2)The “normal” ALT used in different laboratories is above the new suggested normal of 30 IU/L for males and 19 IU/L for females. (3)Recent data indicates that patients with “persistent” low or normal ALT have significant liver diseases. (4)For patients ≥40 years old, prolonged duration of viraemia even with normal ALT exposes them to higher risk of fibrosis progression and hepatocellular carcinoma development. (5)In HBeAg-negative patients, ALT may be even more difficult to monitor. (6)In patients with advanced fibrosis or cirrhosis, ALT may be not enough to reflect diseases progression.

Whether or not we treat patients with normal ALT, we should give patients a thorough evaluation. During the treatment of chronic hepatitis B patients, ALT is not the only indication for antiviral treatment. As mentioned in the 2008 APASL consensus statement on the management of chronic hepatitis B, careful assessment on an individual basis and the therapy should be tailored for individual needs.

The debate on the topic whether nucleos(t)ide analogs can be stopped was between Professor Jidong Jia from China and Professor Eugene R. Schiff from the United States. Professor Jia was on the pro side of the debate and Professor Schiff was on the con side.

In the opinion of Professor Jia, chronic hepatitis B is an infectious disease, not a genetic disease; life-long therapy is not theoretically required. Also there are data supporting the definite duration of nucleos(t)ide analogs treatment. The first is the treatment of patients with refractory course or severe clinical manifestations. In those patients, when clinical and virological response is achieved, antiviral treatment can be stopped. The second is nucleos(t)-ide analogs in the prophylaxis of HBV reactivation in patients receiving immune suppressive therapy. In those patients, NAs can also be stopped in most patients 6 weeks to 6 months after the completion of immune suppressive therapy. About this problem, the 2007 AASLD guideline has different recommendations for patients with different baseline HBV DNA. According to the AASLD guideline, patients with baseline HBV DNA <2 000 IU/ml level should continue treatment for 6 months after completion of chemotherapy or immunosuppressive therapy. Patients with high baseline HBV DNA (>2 000 IU/ml) level should continue treatment until they reach treatment endpoints as in immunocompetent patients. The third is for HBeAg-positive patients, once the HBV DNA is suppressed for an extended period of time and HBeAg seroconversion has been achieved, NAs can be stopped after 6 months of consolidation and in over 80% of these patients, the HBeAg seroconversion is stable for least one year. The fourth is for HBeAg-negative patients, current data shows that most patients may relapse after NAs treatment were stopped. But according to recent guidelines, there are data showing that for HBeAg-negative patients, when virological response and ALT normalization are achieved, prolonged consolidation treatment may bring more sustained response. So, NAs can be stopped at least for some HBeAg-negative patients. In professor Jia’s opinion, patient selection is important for the treatment response and also the treatment duration. For HBeAg-positive patients, HBeAg seroconversion is important for sustained response after NAs treatment. HBeAg seroconversion rate and their durability are determined by host factors such as age, gender, route of HBV infection, immune status and liver disease activity, and virological profiles such as genotypes and gene mutations. Therefore, clinicians should clearly understand all these baseline factors and carefully weigh these variables in deciding whether to treat a patient, what to use and for how long to treat. For patients of young age, HBeAg-positive, HBV genotype A or B, high liver diseases activity (higher ALT and/or active necroinflammation in histology) and without cirrhosis, the HBeAg seroconversion rate is high and NAs can be stopped after a 6 months of consolidation.

In Professor Schiff’s opinion, the reasons for not stopping NAs treatments are: first, though current data shows that for HBeAg-positive patients, once the HBV DNA is suppressed for an extended period of time and HBeAg seroconversion has been achieved, NAs can be stopped after an 6 months of consolidation and in over 80% of these patients, and the HBeAg seroconversion is stable for least one year. There is a lack of long term data supporting true durability and many of these patients continue to have detectable HBV DNA, albeit low viral levels. In addition, chronic HBeAg-negative hepatitis patients notoriously relapse when treatment is stopped even after years of HBV DNA negativity on therapy. Also, if the patient has underlying cirrhosis or is at high risk for hepatocellular carcinoma,NAs treatment cannot be stopped and those patients might need life-long therapy.

Besides, there are supportive reasons for long-term and even life-long NAs therapy. There is progress in NAs: more recently licensed drugs such as entecavir and tenofovir are very robust and the rate of evolving resistant mutations thus far is very low. Rapid attainment of HBV DNA negativity documented with sensitive assays is much less likely to result in clinically significant viral breakthrough among compliant patients. That makes long-term NAs therapy an available choice. Also, there are many examples of diseases that require long-term indefinite therapy, e.g. hypercholesterolemia, hypertension, and glucose intolerance. The primary limitation in long term antiviral therapy for HBV is cost. Long-term treatment is costly and fraught with compliance problems but the advantages of long-term treatment outweigh the risk of discontinuing therapy.

The debate between Professor Schiff and Professor Jia brought us insight into the current state of NAs therapy. If we review the current guidelines of management of chronic hepatitis B, we can find that for NAs treatment of HBeAg-positive chronic hepatitis B patients, the guidelines have a consensus of definite duration, that is to say that there are indications for when to stop treatment. But for treatment of HBeAg negative patients, the AASLD and EASL guideline present no indications for when to stop treatment. Guidelines of APASL recommend that treatment discontinuation can be considered if undetectable HBV-DNA has been documented on three separate occasions 6 months apart. To understand the controversy between guidelines is to understand the nature of evidence based medicine. The controversy indicate there are still not enough data on those topics.