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Stopping antivirals may offer a chance for a hepatitis B cure

Liz Highleyman
06 September 2020
Florian van Bömmel, University Hospital Leipzig, speaking to the Digital International LIver Congress.

Discontinuation of long-term nucleoside/nucleotide antiviral treatment for hepatitis B can allow some people to achieve a cure, according to a pair of presentations last week at the 2020 Digital International Liver Congress. This may happen because the flares of viral replication and inflammation that can occur when the drugs are stopped induces durable immune control of the virus.

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 during treatment, but they seldom lead to a cure. Very few people experience hepatitis B antigen (HBsAg) loss or hepatitis B antibody seroconversion using antivirals alone, and guidelines recommend indefinite treatment.

Prof. Florian van Bömmel of University Hospital Leipzig in Germany and colleagues evaluated the effect of nucleoside/nucleotide discontinuation in the Stop-NUC trial.



Partial recovery from an illness, an alternative word for regression.

The study included 158 people with hepatitis B 'e' antigen (HBeAg) negative chronic HBV infection who had viral load suppression below 1000 IU/ml for at least four years while taking TDF, entecavir, lamivudine (Epivir) or telbivudine (Sebivo). Just over 60% were men, about 80% were white and the median age was 52 years.

At study entry, they had normal ALT liver enzyme levels and none had yet progressed to advanced fibrosis or cirrhosis. People with liver cancer, those with HIV, hepatitis C or hepatitis D co-infection and those who drank heavily were excluded.

Participants were randomly assigned to either stop or continue antiviral treatment. Follow-up continued for 96 weeks

During follow-up, all patients who stopped antivirals experienced viral load flares, with HBV DNA exceeding 20 IU/ml. However, in some cases these were transient and patients went on to re-suppress the virus without the drugs. At 96 weeks, 18% of participants who stopped antivirals had viral suppression.

Resurgence of viral replication was associated with rising ALT levels, an indicator of inflammation. ALT flares were observed in about a third of people who stopped antivirals, but in most cases ALT normalised even in the absence of treatment. At 96 weeks, 77% of people who stopped antivirals had ALT levels within the normal range. The researchers determined that 41% of those who stopped treatment were in 'sustained remission', defined as having both HBV DNA below 2000 IU/ml and normal ALT.

No one who stopped treatment experienced serious adverse events related to nucleoside/nucleotide discontinuation, van Bömmel reported.

Eight people (10%) who stopped antivirals – but none of those who remained on treatment – experienced HBsAg loss by week 96. This happened more often in those with low HBsAg levels (below 1000 IU/ml) at baseline: 28% of these individuals experienced HBsAg loss.

HBsAg loss occurred throughout the follow-up period, with some people having a steep decline soon after stopping treatment and others having a slow, steady decrease, van Bömmel said. The study authors mentioned in their abstract (though not in the presentation) that six people (8%) achieved seroconversion, considered a higher bar to reach.

Eleven people (14%) restarted treatment because of severe or persistent liver enzyme elevation, high viral load or their physician's decision. But two-thirds (68%) had no indication for treatment according to current EASL recommendations.

"This first large-scale randomised study demonstrates the potential of discontinuation of long-term [nucleoside/nucleotide] treatment for induction of durable control and functional cure in patients with HBeAg chronic hepatitis B," the researchers concluded.

Another study by Dr Samuel Hall of St Vincent’s Hospital in Melbourne and colleagues also looked at changes in HBsAg levels after nucleoside/nucleotide discontinuation in a mostly Asian but otherwise similar population.

The NA-STOP trial included people with viral suppression for at least 18 months. Most were taking TDF or entecavir. This study will also continue for 96 weeks; Hall presented interim results for 107 people followed through week 48.

Here too, everyone who discontinued treatment experienced viral reactivation. Further, 42% saw their ALT rise to more than twice the upper limit of normal and 21% had spikes to more than 10 times the upper limit. Both viral relapse and ALT flares occurred earlier in people who stopped TDF compared with those who stopped entecavir.

Five people (5%) experienced HBsAg loss. Again, this was more likely to occur in people with lower HBsAg levels at baseline.

Hall described two patterns: "good flares" (seen in five patients), which involved early steep but brief rises in HBV DNA and ALT and profound reduction in HBsAg levels, and "bad flares" (seen in 21 patients), which involved smaller but more persistent viral load increases, persistent or recurrent ALT elevation and little decline in HBsAg levels.

Twelve people (11%) restarted treatment due to elevated viral load and ALT. But a majority did not meet the traditional start criteria after 48 week off treatment, with 41% having HBV DNA below 2000 IU/ml and 72% having near-normal ALT.

"The data to date support a place for treatment withdrawal in selected patients on long-term [nucleoside/nucleotide analogue] therapy," the researchers concluded.

Van Bömmel noted that more than two years of follow-up will be needed to assess the effects of antiviral discontinuation, as some people experienced HBsAg only late in the Stop-NUC study. With further follow-up, more people in the NA-Stop study may achieve HBsAg loss as well.

Van Bömmel cautioned that ALT flares occurred even during the second year after stopping antivirals, so long-term monitoring is necessary.


Van BömmelF et al. Response to discontinuation of long-term nucleos(t)ide analogue treatment in HBeAg negative patients: Results of the Stop-NUC trial. Journal of Hepatology, supplement 1 [International Liver Congress], LBO06, S118, 2020.

Hall S et al. A prospective study of nucleot(s)ide analogue discontinuation in non-cirrhotic HBeAg-negative chronic hepatitis B patients: interim analysis at week 48 demonstrates profound reductions of HBsAg associated with ALT flare. Journal of Hepatology, supplement 1 [International Liver Congress], AS095, S69, 2020.