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Nucleos(t)ide analogue withdrawal in chronic hepatitis B patients leads to limited sustained remission in the absence of HBsAg loss: results from the RETRACT-B study
Sustained HBV Remission in Only 20% 4 Years After Nucs Stop Without HBsAg Loss
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AASLD, The Liver Meeting, November 12-15, 2021
Mark Mascolini
Only 20% of people who stopped nucleos(t)ide analogs (Nucs) for chronic HBV infection had sustained remission for 4 years without hepatitis B surface antigen (HBsAg) loss [1]. In this 945-person RETRACT-B study analysis, at 4 years 30% either lost HBsAg (which indicates current HBV infection) or remained in sustained remission.
Although contemporary Nucs have proved effective in managing chronic HBV infection, RETRACT-B investigators noted, functional cure or HBsAg loss is rare when therapy continues. Because HBsAg loss occurs more often after Nuc withdrawal than during continuing therapy, some authorities advocate stopping Nucs as a therapeutic alternative. But stopping Nucs can lead to severe HBV reactivation flares that may result in hepatic decompensation or death. And HBV suppression may be harder to maintain during off-therapy periods without HBsAg loss than during continuing therapy.
To explore long-term responses after Nucs stop in people with chronic HBV infection-especially in those who do not lose HBsAg-RETRACT-B researchers focused on Nuc-stoppers negative for HBeAg (which indicates ongoing HBV replication) when they halted therapy. The protocol allowed participants to have variable HBV DNA and alanine aminotransferase (ALT) levels within the first year of stopping treatment because HBV DNA and ALT almost always jump after Nuc therapy stops. After excluding people with HBsAg loss, retreatment, and other clinical events during the first year of stopping treatment, the researchers ended up with a study contingent of 945 people.
The primary outcome of this analysis was sustained HBV remission after 1 year of stopping therapy, regardless of HBV DNA and ALT levels in that first year, with or without HBsAg loss. The RETRACT-B team defined sustained remission as sustained HBV DNA at or below 2000 IU/mL and ALT at or below 1.5 times the upper limit of normal (ULN). Virologic relapse meant HBV DNA above 2000 IU/mL. Biochemical relapse was ALT above 1.5 times ULN. And clinical relapse meant HBV DNA above 2000 IU/mL and ALT above 1.5 times ULN. Participating centers included several throughout Europe, Taiwan, and Hong Kong, and one in Canada.
The 945 study participants averaged 53 years in age when they stopped therapy, 72% were men, 91% Asian, and 9% white or another race. Most people, 62%, had taken entecavir, 29% tenofovir, and 9% another Nuc for a median duration of 3 years. Most people, 84%, started therapy HBsAg negative, and 11% had cirrhosis when they stopped. HBsAg level when treatment stopped averaged 2.6 log10 IU/mL. During follow-up participants made a median of 9 visits, averaging 4 months between visits.
Within the first year after stopping therapy, 66% of participants had at least one relapse, 57% had a virologic relapse, 36% a biochemical relapse, and 24% a clinical relapse. Two years after treatment stopped, 40% had sustained remission without HBsAg loss, 4% had HBsAg loss, and 44% had sustained remission or HBsAg loss. At 4 years those percentages were 20%, 10%, and 30%.
The RETRACT-B investigators reported the following subgroup proportions at 4 years (1) with sustained remission without HBsAg loss and (2) with sustained remission or HBsAg loss:
- Age less than 50 vs older: (1) 24% vs 19%, (2) 30% vs 30%
- Male vs female: (1) 21% vs 21%, (2) 31% vs 27%
- Stopped tenofovir vs entecavir: (1) 21% vs 21%, (2) 32% vs 29%
- White vs Asian: (1) 30% vs 20%, (2) 48% vs 28%
- HBeAg+ vs HBeAg- at start of therapy: (1) 31% vs 19%, (2) 36% vs 28%
- HBsAg below 100 vs higher when Nuc stopped: (1) 24% vs 20%, (2) 58% vs 24%
- No relapse vs any relapse within 1 year: (1) 37% vs 13%, (2) 50% vs 19%
From 1 to 4 years after treatment stopped, virologic relapse rates among people with HBV DNA above 2000 IU/mL were 65% for relapses above 2000 IU/mL and 44% for relapses above 20,000 IU/mL. (Average maximum HBV DNA was 5.1 log10 IU/mL.) At 1 to 4 years among people with ALT above 1.5 times ULN, biochemical relapse rates were 49% for ALT above 1.5 times ULN, 43% for ALT above 2 times ULN, and 16% for ALT above 5 times ULN. (Median maximum ALT was 3.0 times ULN.) From 1 to 4 years after treatment stopped, 41% had a clinical relapse and 35% resumed treatment.
RELAPSE-B investigators concluded that 4 years after Nucs stopped only 20% of HBV patients remained in remission without HBsAg loss, while 30% remained in remission or achieved HBsAg loss. Groups with higher rates of sustained remission were whites versus Asians, those starting Nuc therapy positive for HBeAg, and those with an HBsAg level below 100 IU/mL when Nuc therapy stopped.
Most RETRACT-B participants who stayed off Nuc therapy, the researchers noted, "had profound relapses and thus may have benefitted from earlier retreatment for more effective viral suppression and ALT normalization."
Reference
1. Hirode G, Hansen BE, Chen CH, et al. Nucleos(t)ide analogue withdrawal in chronic hepatitis B patients leads to limited sustained remission in the absence of HBsAg loss: results from the RETRACT-B study. AASLD, The Liver Meeting, November 12-15, 2021. Parallel session 1: Advances with Approved HBV Therapies.
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