Summary: limitations of current therapies

Guideline-preferred nucleos(t)ide analogues suppress HBV DNA but are given long term: the AASLD 2018 guidance suggests “indefinite antiviral therapy for adults with HBeAg-negative, immune-active CHB”, and the WHO 2024 guideline states that “Antiviral therapy is lifelong.” A meta-analysis of 34 studies reported a pooled annual HBsAg seroclearance rate of 1.02%, and 8-year tenofovir alafenamide data show HBsAg loss in 2% to 3% of participants. In the PAGE-B cohort of 1,644 Caucasian patients treated with entecavir or tenofovir, the 10- and 15-year cumulative incidences of HCC were 10.9% and 13.2%. In a cohort of 6696 patients receiving long-term nucleos(t)ide analogue therapy, the discontinuation probability was 29.4% at 12 months and 55.6% at 5 years. Peginterferon is a finite alternative with higher HBsAg loss than nucleos(t)ide analogues, but the AASLD/IDSA guideline states that it “is rarely used, given its limitations of applicability, safety and tolerability”.

Indefinite duration of nucleos(t)ide analogue therapy

“The AASLD suggests indefinite antiviral therapy for adults with HBeAg-negative, immune-active CHB unless there is a compelling rationale for treatment discontinuation” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“A decision to discontinue therapy for HBeAg-negative adults without cirrhosis requires careful consideration of risks and benefits for health outcomes, including the following: (i) risk for virological relapse, hepatic decompensation, liver cancer, and death; (ii) burden of continued antiviral therapy, financial concerns associated with medication costs and long-term monitoring, adherence, and potential for drug resistance with treatment interruptions; and (iii) patient and provider preferences.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote

“Available treatments for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B are associated with poor sustained responses. As a result, nucleoside and nucleotide analogues are typically continued indefinitely, a strategy associated with the risk of resistance and unknown long-term safety implications.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote

Current therapies are not curative

“Current therapies (pegylated interferon alfa [pegIFNa] and nucleos(t)ide analogues [NAs]) are not curative due to persistence of covalently closed circular DNA (cccDNA), a stable, non-integrated form of viral DNA located in the hepatocyte nucleus, as well as HBV DNA that is directly integrated into the host genome.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote

“Although treatment is not considered curative, antiviral treatment, monitoring, and liver cancer surveillance can reduce morbidity and mortality.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote

Low HBsAg loss on nucleos(t)ide analogues: pivotal and long-term trial data

Regimen and duration	HBeAg-positive	HBeAg-negative
Entecavir, 48 weeks	“HBsAg loss: 2%”	“HBsAg loss: <1%”
Tenofovir disoproxil fumarate, 96 weeks	“HBsAg loss: 1%”	“HBsAg loss:0%”
Tenofovir alafenamide, 96 weeks	“HBsAg loss: 1%”	“HBsAg loss:<1%”
Tenofovir alafenamide, 5 years	“HBsAg loss: 0.8%”	“HBsAg loss:1.2%”

“Low rates of HBsAg loss on NA treatment are ascribed to the limited effect of NAs on the cccDNA template and to the significant contribution of HBV integration to HBsAg production, especially in HBeAg-negative individuals.” (opens the source at this quote in a new tab)
“Achieving functional cure (HBsAg loss) remains rare with current therapies. The prospect of effective finite treatments is highly appealing, particularly given the challenges associated with the strict adherence required for prolonged NA therapy, especially for young patients. Thus, there is an unmet need for curative therapies.” (opens the source at this quote in a new tab)

“Annual rates of spontaneous and on-treatment NA-related HBsAg loss remain very low (~0.5-1%).” (opens the source at this quote in a new tab)
“Increasingly, there is emphasis on the achievement of HBsAg loss as the desired endpoint for treatment (functional cure), because of its association with reduction in clinical outcomes and long-term durability, though it is recognized that functional cure is infrequent with current approved therapies, albeit higher with peginterferon than for NAs.” (opens the source at this quote in a new tab)

Residual hepatocellular carcinoma risk during long-term nucleos(t)ide analogue therapy

“Of 1,644 patients, 903 were followed beyond year 10 (mean:14 ± 2 years). The 10- and 15-year cumulative incidences of HCC were 10.9% and 13.2%, respectively. The HCC IR was 1.25 before year 10 and 0.55/100 PYs after year 10 (p <0.001), with similar findings after inverse probability weighting.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote
“Despite >10 years of NA therapy, patients with CHB remain at risk of HCC, although the incidence rate declines significantly. HCC remains the main determinant of mortality.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote

“Nevertheless, a risk of adverse liver-related outcomes remains despite HBV DNA suppression, and this risk can be mitigated by achieving HBsAg loss.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote

Persistence and adherence with long-term nucleos(t)ide analogue therapy: U.S. claims data

“In total, 6696 patients met the study eligibility criteria.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Overall, 40.6% of patients discontinued treatment; discontinuation probability was 29.4% at 12 months and 55.6% at 5 years. Of those who discontinued, 45.7% restarted during the study period. Mean adherence (proportion of days covered [PDC]) was 0.91, and 86.5% of participants had a PDC ≥ 80%.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote

“An inception cohort of 564 patients (24%), without a NA prescription in the 6 months pre-index period and at least 2 years of follow-up, was created. Persistence among the inception cohort was 29% for first year and 14% for first 2 years.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote

Peginterferon tolerability and response variability

“The variable response rates and unfavourable safety profile of PEG-IFNα treatment are major drawbacks that limit patients' eligibility or prompt patients to decline this treatment option.” (opens the source at this quote in a new tab)
“Despite the slightly higher HBeAg/anti-HBe seroconversion rates, the overall rate of HBsAg loss after PEG-IFNα therapy is still low.” (opens the source at this quote in a new tab)

Relapse risk with finite nucleos(t)ide analogue therapy

“Discontinuation increases HBsAg loss but carries a substantial risk of virological relapse and clinical flares.” (opens the source at this quote in a new tab)