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Some hepatitis B patients can safely stop antivirals

Liz Highleyman
24 November 2020
Image: lovelypeace/

Many people who take nucleoside/nucleotide antivirals for chronic hepatitis B can safely discontinue treatment, although this usually does not lead to a cure, researchers reported last week at the AASLD virtual Liver Meeting.

Nucleoside/nucleotide analogues such as tenofovir disoproxil fumarate (TDF; Viread), tenofovir alafenamide (TAF; Vemlidy) and entecavir (Baraclude) can keep hepatitis B virus (HBV) replication suppressed indefinitely during treatment. However, few people experience hepatitis B antigen (HBsAg) loss or hepatitis B antibody seroconversion, considered to be a functional cure. People who are hepatitis B 'e' antigen (HBeAg) positive are less likely to be cured.

Treatment guidelines disagree about when it is appropriate to stop treatment. Both AASLD and EASL guidelines state that HBeAg positive patients can consider discontinuation if they experience HBeAg seroconversion and have undetectable HBV DNA for at least six to 12 months, but relapse is common. For HBeAg negative patients, AASLD recommends stopping only after HBsAg loss, while EASL guidelines say treatment can be discontinued after three years in those with viral suppression if close monitoring can be guaranteed.

Prof. Norah Terrault of the University of Southern California and colleagues compared outcomes among chronic hepatitis B patients treated with TDF alone or TDF plus pegylated interferon alfa. About 65% of the participants were men, more than 80% were Asian and the median age was 41 years. About half were HBeAg positive and 7% had liver cirrhosis.

First, 102 participants were randomly assigned to receive TDF monotherapy for 192 weeks, while 99 were assigned to TDF plus pegylated interferon for 24 weeks followed by TDF alone for 168 weeks. At that point, people who had a low viral load (HBV DNA below 1000 IU/ml for the previous 24 weeks) and no cirrhosis were eligible to discontinue TDF; being HBeAg negative was added to the withdrawal criteria partway through the study.

People who experienced severe or prolonged elevation of ALT liver enzyme levels – a marker of liver inflammation – along with elevated bilirubin, high viral load or clinical decompensation after stopping treatment were restarted on TDF monotherapy. Follow-up continued through week 240.

One hundred and five people were eligible to discontinue treatment after 192 weeks, 46 in the TDF group and 55 in the TDF plus pegylated interferon group.

One person (1.0%) treated with TDF alone and four people (4.3%) treated with TDF plus pegylated interferon experienced HBsAg loss by the end of treatment at week 192. Three more people in the monotherapy group and one more in the combination therapy group did so during the withdrawal phase, resulting in similar proportions with HBsAg loss – 4.5% vs 5.7%, respectively – at week 240.

Among those on TDF monotherapy, three of the patients with HBsAg loss had stopped treatment, but one was ineligible for discontinuation. Similarly, four people in the combination therapy arm who experienced HBsAg loss had stopped treatment but one remained on TDF. Among those who stopped treatment, the rates of HBsAg loss were 6.5% in the monotherapy group and 7.3% in the combination therapy group. None of these differences were statistically significant, indicating that adding pegylated interferon did not improve the likelihood of HBsAg loss.

Prof. Terrault also reported that 20 people (41%) who used TDF alone and 27 (61%) in the combination therapy group experienced HBeAg loss. Although the proportion in the combination group was numerically higher, the difference did not reach statistical significance. In both groups, about half maintained a viral load below 20 IU/ml and about 60% had normal ALT at 240 weeks.

At the end of follow-up, 30% of participants in the monotherapy group and 39% in the combination therapy group who stopped treatment were considered to have inactive chronic hepatitis B, with both a low viral load (below 1000 IU/ml) and normal ALT. This was about twice as likely among those who were ineligible for treatment discontinuation and stayed on TDF (63% vs 67%, respectively).

Turning to safety, 24% of participants in the TDF monotherapy group and 31% in the combination therapy group experienced ALT flares. Most flares (70%) in the monotherapy group occurred during the treatment withdrawal phase after TDF was stopped. However, in the combination therapy group, a majority of flares (58%) occurred during the first 24 weeks while participants were still taking pegylated interferon.

In summary, rates of HBsAg loss were similar for people treated with TDF monotherapy or TDF plus pegylated interferon – showing that adding interferon did not improve the odds of a functional cure – but the timing of HBsAg loss differed.

Approximately a third of those eligible for TDF discontinuation met the criteria for inactive chronic hepatitis B, leading the researchers to conclude that "withdrawal of TDF after four years of therapy can be safely achieved in most patients" who meet the criteria for stopping.

In a related study, Dr Hassan Azhari of the University of Calgary and colleagues looked at outcomes in a real-world study of stopping long-term nucleoside/nucleotide analogue therapy.

In this retrospective cohort of 1337 chronic hepatitis B patients, a majority were men and most were Asian. More than 80% were HBeAg negative and had absent or mild liver fibrosis. About 60% were taking TDF and about 35% were taking entecavir, with a median treatment duration of more than six years.

Within this cohort, 47 stopped antivirals while the rest remained on treatment. All who stopped were HBeAg negative and all but one had undetectable viral load at the time of discontinuation. Only one person in this group (2.1%) experienced HBsAg loss, but monitoring is continuing and Dr Azhari suggested more might do so with longer follow-up.

Six patients restarted antivirals due to viral load rebound (above 2000 IU/ml) or ALT flares (more than twice the upper limit of normal). In contrast with prior studies, people who were HBeAg positive prior to initial therapy and those who had been on antivirals longer were more likely to restart treatment. A majority of ALT flares occurred within the first six months after stopping treatment, but some happened later, highlighting the need for ongoing monitoring. None of the participant experienced liver dysfunction and all responded to retreatment.

"Stopping [nucleoside/nucleotide analogues] is feasible in HBeAg negative chronic hepatitis B [patients] with minimal fibrosis and low quantitative HBsAg levels," the researchers concluded.

These findings are in line with those reported at the recent 2020 Digital International Liver Congress. In a German study, 10% of people who stopped antivirals – but none of those who remained on treatment – experienced HBsAg loss during two years of follow-up. In an Australian study, 5% achieved HBsAg loss.

HBsAg loss after nucleoside/nucleotide discontinuation may occur because the resulting increase in viral replication and inflammation flares induce durable immune control of the virus.

Although people who stop antiviral treatment should be carefully monitored and restarted on treatment if ALT levels get too high, Dr Azhari suggested that clinicians may not want to "pull the trigger" and restart antivirals too soon, as these flares can sometimes lead to a functional cure.


Terrault N et al. Randomized trial of 192 weeks of tenofovir with or without peginterferon alfa for the first 24 weeks followed by protocolized withdrawal in adults with chronic hepatitis B. AASLD Liver Meeting, abstract 19, 2020.

Azhari H et al. Real world single center experience on the efficacy of stopping long term nucleos(t)ide analog therapy in patients with chronic hepatitis B. AASLD Liver Meeting, abstract 24, 2020.