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Professor of Gastroenterology
Director, Division of Gastroenterology and Hepatology
IRCCS Ca Granda Policlinico Hospital
University of Milan
Pietro Lampertico, MD, PhD, has disclosed that he has received consulting fees from AbbVie, Eiger, Gilead Sciences, Janssen, MSD, MYR, and Roche.
Oral therapy with nucleos(t)ide analogues (NAs) for patients with chronic HBV infection prevents progression to cirrhosis and clinical decompensation and reduces the hepatocellular carcinoma risk by approximately 50%. It is effective, safe, and accessible to most patients. However, NA therapy requires long-term administration, and the disadvantages of continuous therapy include the risk of developing drug resistance, safety, cost, adherence, and the need for continued monitoring.
Stopping Rules for NA Therapy
The best and safest stopping rule for NA therapy, even in patients with compensated cirrhosis, is a “functional cure,” which is defined as HBsAg loss with or without seroconversion. HBsAg loss is a sign of immune control and is associated with silencing of covalently closed circular (ccc) DNA and/or a decreased number of infected liver cells. However, this endpoint is achieved in < 5% of patients over 10 years of NA therapy.
Strategies to Increase the Rate of HBsAg Loss
Strategies to foster HBsAg loss in NA-treated patients have been explored. One option would be to continue oral therapy as HBsAg levels decline. Typically, HBsAg levels decrease < 0.1 log IU/mL per year. Several studies have shown that peginterferon, either as an add-on or switch strategy, may increase functional cure rates in select patients with low HBsAg levels. Ongoing studies suggest that new antivirals targeting cccDNA, HBsAg production, or HBsAg export may contribute to accelerated HBsAg loss, even with a short-term, finite treatment course. Last but not least, stopping NA before HBsAg loss has been recently advocated as a possible alternative strategy.
Outcomes of NA Discontinuation Before HBsAg Loss
International guidelines provide recommendations on stopping NA therapy before HBsAg loss in selected HBeAg-positive and HBeAg-negative patients. HBeAg seroconversion and consolidation of response are required in HBeAg-positive patients. In HBeAg-negative patients, discontinuation of NA therapy in selected patients may be considered if no evidence of cirrhosis was present at the start of NA therapy, if the patient achieved long-term (≥ 3 years) virologic suppression, and if the patient can guarantee close posttherapy monitoring.
Recent retrospective and prospective studies demonstrated that stopping NA before HBsAg loss results in the following: a rebound in HBV DNA; an increase in ALT levels in many cases; ALT flares that can be severe and life-threatening in some cases; and loss of HBsAg in some cases. In some patients, clearance of HBsAg can follow an ALT flare. The rates of HBsAg loss in different studies vary from 1% in a cohort of Asian Canadian patients to up to 20% in a study of HBeAg-negative patients in Europe. Viral and liver parameters must be closely monitored for at least 6 months after NA withdrawal, so patients’ compliance with blood tests every 2 weeks is essential.
Reasons for NA Discontinuation Before HBsAg Loss
From my perspective, the most important question is not “if” NA can be discontinued before HBsAg loss but “why” doctors may want to pursue this strategy. If the goal is sustained long-term undetectable HBV DNA off therapy to reduce hepatocellular carcinoma risk, NA should not be discontinued. Only 30% of the patients will achieve a clinical/virologic profile of an inactive carrier, now referred to as HBeAg-negative chronic infection.
If HBsAg loss is the target, this may be achieved in some patients with discontinuation of NA therapy, but most patients will not reach this goal. In addition, approximately 40% of patients who discontinue NA therapy will have to resume antiviral therapy because of hepatitis reactivation.
In conclusion, a “one-size-fits-all” strategy cannot be used to determine if and when to discontinue NA therapy. Doctors should weigh the advantages and disadvantages of continuing or discontinuing NA therapy before HBsAg loss, and after thoughtful discussion with the patient, a recommendation can be made.
What are your thoughts on the arguments for and against NA discontinuation in patients before HBsAg loss? Please share your insights in the comment section.