Treatment Paradigm for Chronic HBV in Flux

Bruce Jancin

April 02, 2021

These days deciding when to stop targeted treatment for chronic hepatitis B is a bigger challenge than knowing when to start, Norah A. Terrault, MD, MPH, observed at the Gastroenterology Updates, IBD, Liver Disease Conference.

That's because the treatment paradigm is in flux. The strategy is shifting from achieving hepatitis B virus (HBV) DNA suppression through indefinite use of nucleoside analogues to striving for functional cure, which means eliminating hepatitis B surface antigen (HBsAg) and sustained inactive chronic hepatitis B off therapy. It's a goal that recognizes that, while suppression is worthwhile because it reduces a patient's risk of hepatocellular carcinoma, HBsAg clearance is better because it's associated with an even lower risk of the malignancy, explained Terrault, professor of medicine and chief of gastroenterology and liver diseases at the University of Southern California, Los Angeles.

The current strategy in patients who are hepatitis B e antigen (HBeAg) positive at the outset is to treat with a nucleoside analogue until seroconversion, followed by a further year or more of consolidation therapy then treatment withdrawal. It's a rational approach whose primary benefit is it allows identification of the roughly 50% of patients who can remain off treatment with inactive chronic hepatitis B. The other 50% – those who experience clinical relapse – will need retreatment.

Factors predictive of increased likelihood of a sustained off-treatment response include age younger than 40 years at the time of seroconversion, more than 1 year of consolidation therapy, and undetectable HBV DNA at cessation of treatment.

"In my own practice now, I actually extend the consolidation period for 2 years before I consider stopping, and I really favor doing a trial of stopping treatment in those who are younger," Terrault said.

The biggest change in thinking involves the duration of therapy in patients who are HBeAg negative. The strategy has been to treat indefinitely unless there is a compelling reason to stop, such as toxicity, cost, or patient preference. However, it has now been demonstrated in at least nine published studies that withdrawal of therapy has a favorable immunologic effect in noncirrhotic patients with HBeAg-negative chronic hepatitis B who have been HBV DNA negative on nucleoside analogues for at least 3 years. This trial off therapy can bring major benefits because roughly 50% of patients will have sustained inactive chronic hepatitis B off-treatment and 20% of patients will become HbsAg negative with functional cure at 3-5 years of follow-up.

"This is what's impressive: that 20% of patients have lost surface antigen, because if you continue HbeAg-negative patients on nucleoside analogue therapy, essentially none of them lose surface antigen. This is an impressive number, and you're also able to identify about 50% of patients who didn't need to be on treatment because they now have immune control and can remain inactive carriers off treatment," the gastroenterologist commented.

Treatment withdrawal in HBeAg-negative patients usually is followed by disease flares 8-12 weeks later because of host immune clearance, and therein lies a problem.

"The challenge with the withdrawal strategy is these flares that appear to be necessary and important, can be good or bad, and we're really not very good at predicting what the flare is going to look like and how severe it's going to be," according to Terrault, first author of the current American Association for the Study of Liver Diseases guidance on prevention, diagnosis, and treatment of chronic hepatitis B.

The good flares are accompanied by a reductions in HBV DNA and viral proteins, loss of HbsAg, and preserved liver function. The bad flares entail excessive host immune clearance leading to liver dysfunction or failure, with no reduction in viral proteins. The search is on for predictors of response to treatment withdrawal in HbeAg-negative patients. Potential differences in outcomes with the three available nucleoside analogues are being looked at, as are duration of viral suppression on treatment and differences in patient characteristics. A low quantitative HbsAg level at the time of drug withdrawal may also be important as a predictor of a higher likelihood of HBsAg loss over time off treatment.

"The studies that have been done are basically withdrawing everyone and then seeing what happens. I think we want to have a more refined approach," she said.

This is an unfolding story. The encouraging news is that the drug development pipeline is rich with agents with a variety of mechanisms aimed at achieving HbsAg loss with finite therapy. Some of the studies are now in phase 2 and 3.

"We should be extremely excited," Terrault said. "I think in the future we're very likely to have curative therapies in a much greater proportion of our patients."

When to Start Nucleoside Analogues

Three antiviral oral nucleoside analogues are available as preferred therapies for chronic HBV: entecavir (Baraclude), tenofovir alafenamide (Vemlidy), and tenofovir disoproxil (Viread). All three provide high antiviral efficacy and low risk for resistance. The treatment goal is to prevent disease progression and HBV complications, including hepatocellular carcinoma, in individuals with active chronic hepatitis B.

The major liver disease medical societies differ only slightly on the criteria for starting treatment. Broadly, they recommend starting therapy in all patients with cirrhosis, as well as in patients without cirrhosis who have both a serum ALT level more than twice the upper limit of normal and elevated HBV DNA levels. The treatment threshold for HBV DNA levels is higher in patients who are HBeAg positive than it is for patients who are HBeAg negative; for example, the American Association for the Study of Liver Diseases recommends that an HbeAg-positive patient should have a HBV DNA titer greater than 20,000 IU/mL, which is a level 10 times higher than the group's treatment threshold in HBeAg-negative patients. However, these thresholds are intended as guidance, not absolute rules, Terrault emphasized. Nearly 40% of patients don't meet the dual ALT and HBV DNA thresholds, and serial monitoring of such patients for 6-12 months is recommended because they may be in transition.

The choice of nucleoside analogue is largely based on comorbidities. Any of the three preferred antivirals can be used when there are none. Tenofovir disoproxil is preferred in pregnancy because of its safety profile in that setting. In patients who are aged over 60 years or have bone disease or renal impairment, tenofovir alafenamide and entecavir are preferred. Entecavir should be avoided in favor of either form of tenofovir in patients who are HIV positive or have prior exposure to lamivudine.

Regarding treatment with these drugs, the recommendations target those whose liver disease is being driven by active HBV rather than fatty liver disease or some other cause. That's the reason for the reserving treatment for patients with both high HBV DNA and high serum ALT.

"There's definitely a camp that feels these are safe drugs, easy to use, and we should treat more people. I have to say I'm not hanging out in that camp. I still feel we should do targeted treatment, especially since there are many new drugs coming where we're going to be able to offer cure to more people. So I feel like putting everybody on suppressive therapy isn't the answer," she said.

Terrault receives research grants from and/or serves as a consultant to numerous pharmaceutical companies.

This article originally appeared on, part of the Medscape Professional Network.


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