Study offers clues on which patients may safely stop HBV therapy

Think twice before withdrawing HBV treatment. Not all patients can safely discontinue nucleos(t)ide analogue (NA) therapy as shown in the retrospective RETRACT-B study of patients from Europe, North America, and Asia.

Over half of chronic hepatitis B e antigen (HBeAg)–negative patients who withdrew from NA therapy in the study experienced relapse within 4 years, reported study author Ms Grishma Hirode, a PhD candidate at the University of Toronto in Toronto, Canada at AASLD 2021 – The Liver Meeting.

“Patients do not stabilize after 1 year. They have relapses and these aren’t mild fluctuations,” she continued. “We sought to find out what happened in patients who stopped NA therapy and if there was a way to tell which way they’re going to, and we got the answer clear.”

Hirode and her team examined the long-term virological and biochemical responses in virally suppressed and HBeAg negative patients after NA cessation. The primary outcome was sustained remission after 1 year irrespective of HBV DNA and ALT levels within the first year after NA cessation, with and without HBsAg loss. Sixty-two percent and 29 percent of the patients were on entecavir and tenofovir, respectively, prior to NA cessation. Nine percent were on other therapies.

Within 1 year of HBV treatment cessation, 66 percent had at least one relapse. These patients had relatively high rates of relapse even beyond 1 year. At 2 years, 40 percent had sustained remission (sustained HBV DNA ≤2,000 IU/mL and ALT ≤1.5 x upper limit of normal) without HBsAg loss. At 4 years, only 20 percent remained in sustained remission in the absence of HBsAg loss. This was despite allowing for any HBV DNA and ALT fluctuations. At 4 years, 30 percent remained in sustained remission or achieved HBsAg loss. [AASLD 2021, abstract 22]

There were differences between populations in the subgroup analyses – 28 percent of Asians and 48 percent of Whites had sustained remission or HBsAg loss whereas 20 percent of Asians and 30 percent of Whites experienced sustained remission in the absence of HBsAg loss.

Patients who were HBsAg positive at the initiation of therapy were more likely to have a sustained remission or HBsAg loss (p< 0.05) and to have a sustained remission without HBsAg loss (p<0.05).

At treatment cessation, HBsAg levels below 100 IU/mL were associated with a greater chance of sustained remission or HBsAg loss (p<0.05) and sustained remission without HBsAg loss (p<0.05). Additionally, not having a relapse within the first year after cessation was also associated with a greater chance of sustained remission or HBsAg loss (p<0.05) and sustained remission without HBsAg loss (p<0.05).

“Patients who had profound relapse off therapy may benefit from earlier retreatment for more effective viral suppression and ALT normalization,” said Hirode.

 Flareups and retreatment rates

A separate study in a national cohort in Taiwan lend support to the RETRACT-B findings, showing  high flareups and retreatment rates out to 4 years after discontinuation of oral antiviral treatment in patients with chronic hepatitis B. [AASLD 2021, abstract 23]

Among 10,192 patients, there were a 6.58 percent 4-year cumulative incidence of severe flare-ups (serum ALT levels >5 x the ULN plus serum bilirubin levels >2 mg/dL) after tenofovir or entecavir discontinuation.

The overall incidence of flare-ups was 30.66 percent over 4 years, with a higher risk of flareups associated with older age (p<0.0001), male sex (p<0.0001), cirrhosis (p<0.0001), and a history of hepatic decompensation (p= 0.044).

Meanwhile, the incidence of retreatment at  4 years was 48.74 percent.  The mortality rate subsequent to severe flare was 0.63 percent at 4 years or 0.79 percent if liver transplantation were also accounted for. Risk factors for higher mortality included advanced age (p<0.0001), cirrhosis (p< 0.0001), and hypertension (p=0.029).

“Individual patients and policy-makers should be informed of such risks in the discussion of finite NA therapy,” concluded lead author Dr Yao-Chun Hsu from the I-Shou University in Kaohsiung, Taiwan.

Take-away messages

“The message is the cessation of treatment can benefit some patients,” commented Dr Anna Lok, professor of internal medicine, director of clinical haematology, and assistant dean for clinical research at the University of Michigan in Ann Arbor, Michigan, US. “However, if the goal of treatment withdrawal is to increase the rate of HBsAg loss, only a small percentage of patients would benefit.”

Contrary to studies in Europe, the rates of HBsAg loss in studies with predominantly Asian patients are much lower, she added. “This suggests that withdrawal from medication should be done cautiously, and patients should be monitored for relapse and retreatment,” Lok said.

Which patients might safely stop HBV treatment? Lok said young White patients with a low HBsAg level when treatment is stopped may be good candidates. However, older Asian patients with a high HBsAg titre probably shouldn’t stop therapy as “the chances of relapse are very high whereas the benefit is very low.” Lastly, stopping treatment should never be tried on patients with cirrhosis, she added.