HBV: Rethink the Free Pass for Immune-Tolerant Patients

M. Alexander Otto

February 27, 2020

EXPERT ANALYSIS FROM GUILD 2020

MAUI, HAWAII – There might well be a cure for hepatitis B in coming years, just like there is now for hepatitis C, according to Norah Terrault, MD, chief of the division of GI and liver at the University of Southern California, Los Angeles.

"We are going to have a laundry list of new drugs" that are in the pipeline now. Phase 2 results "look encouraging. You will hear much more about this in the years ahead," said Dr. Terrault, lead author of the 2018 American Association for the Study of Liver Diseases (AASLD) hepatitis B guidance.

For now, though, the field is largely limited to the nucleoside analogues tenofovir and entecavir. Treatment is often indefinite because, although hepatitis B virus (HBV) e-antigen is cleared, it usually doesn't clear the HBV surface antigen, which is linked to liver cancer. "Even with e-antigen–negative patients, we feel that indefinite therapy is really the way to go," Dr. Terrault said at the Gastroenterology Updates, IBD, Liver Disease Conference.

One of the biggest problems with that strategy is what to do when HBV does not seem to be much of a problem for carriers. Such patients are referred to as immune tolerant.

A newly recognized cancer risk

Immune tolerant patients tend to be young and have extremely high viral loads but no apparent ill effects, with normal ALT levels, normal histology, and no sign of cirrhosis. Although the AASLD recommends not treating these patients until they are 40 years old, waiting makes people nervous. "You have a hammer, you want to hit a nail," Dr. Terrault said.

A recent review (Gut. 2018 May;67[5]:945-52) suggests that hitting the nail might be the way to go. South Korean investigators found that 413 untreated immune tolerate patients with a mean age of 38 years had more than twice the risk of liver cancer over 10 years than did almost 1,500 treated patients with active disease.

The study investigators concluded that "unnecessary deaths could be prevented through earlier antiviral intervention in select [immune tolerate] patients."

This finding is one reason "we [AASLD] are rethinking the mantra of not treating the immune tolerant. There is a group that is transitioning" to active disease. "I'm thinking we should really [lower] the age cutoff" to 30 years, as some other groups [European Association for the Study of the Liver and Asian Pacific Association for the Study of the Liver] have done, plus "patients feel really good when they know the virus is controlled, and so do physicians," Dr. Terrault said.

Entecavir versus tenofovir

Meanwhile, recent studies have raised the question of whether tenofovir is better than entecavir at preventing liver cancer.

A JAMA Oncology (JAMA Oncol. 2019 Jan 1;5[1]:30-6) study of some 25,000 patients in South Korea found a 32% lower risk of liver cancer when they were treated with tenofovir instead of entecavir. "This led to a lot of concern that maybe we should be moving all our patients to tenofovir," she said.

Another study, a meta-analysis published earlier this year (Hepatol Int. 2020 Jan;14[1]:105-14), confirmed the difference in cancer risk when it combined those findings with other research. After adjustment for potential confounders, including disease stage and length of follow-up, "the difference disappeared" (hazard ration, 0.87; 95% confidence interval, 0.73-1.04), authors of the meta-analysis reported.

Study patients who received entecavir tended to be "treated many years ago and tended to have more severe [baseline] disease," Dr. Terrault said.

So "while we see this difference, there's not enough data yet for us to make a recommendation for our patients to switch from" entecavir to tenofovir. "Until a randomized controlled trial is done, this may remain an issue," she said.

A drug holiday?

Dr. Terrault also reviewed research that suggests nucleoside analogue treatment can be stopped in e-antigen–negative patients after at least 3 years.

"The evidence is increasing that a finite NA [nucleoside analogue] treatment approach leads to higher HBsAg [hepatitis B surface antigen] loss rates, compared with the current long-term NA strategy, and can be considered a rational strategy to induce a functional cure in selected HBeAg-negative patients without cirrhosis who are willing to comply with close follow-up monitoring. ... The current observed functional cure rates" – perhaps about 40% – "would be well worth the effort," editorialists commenting on the research concluded (Hepatology. 2018 Aug;68[2]:397-400).

It's an interesting idea, Dr. Terrault said, but the virus will flare 8-12 weeks after treatment withdrawal, which is why it shouldn't be considered in patients with cirrhosis.

Dr. Terrault is a consultant for AbbVie, Merck, Gilead, and other companies and disclosed grants from those companies and others.

This story originally appeared on MDedge.com.

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