Hepatitis B surface antigen seroclearance is uncommon but durable in the long run

Seroclearance of HBsAg is considered the functional cure of chronic hepatitis B, resulting in a favorable clinical outcome and minimal risk of developing HCC and hepatic decompensation.1 Previous meta-analysis suggested that HBsAg seroclearance is durable with a low rate of HBsAg seroreversion of 6.2% at a median of 4.7 years2; however, long-term follow-up data are scarce. Also, most of the available studies are based on clinic or hospital settings which may include patients with a more severe chronic liver disease. Findings based on a population-screening cohort remain limited. In Hepatology this month, Bruden et al3 report the results of a retrospective cohort study of Alaskan Native patients with chronic HBV infection whose rate and durability of HBsAg seroclearance were studied during their long-term follow-up. A notable feature of this study is the inclusion of persons with chronic HBV infection identified through a population-based screening conducted in Alaska between 1982 and 1987. The original screening included 53,000 Alaska Native individuals, which accounted for 70% of the population and 90% of those residing in the HBV endemic area of Alaska. Among those screened, 1680 (3.2%) were diagnosed with chronic HBV infection by positive HBsAg for at least 6 months and 1079 of them provided consent to be followed up (average duration of 33 y, with a median of 37 available HBsAg results). At the time of screening, only HBsAg, HBsAb, and HBcAb were available. Subsequently, the virologic characterization was completed by testing stored baseline serum samples for HBeAg, antibody to HBeAg, HBV genotype, and HBV DNA. Throughout the follow-up period, 945 (87.6%) remained treatment naïve, suggesting that most of them had absent or mild signs of liver disease. During follow-up, 260 of the 1079 (24%) successfully cleared HBsAg at a median age of 44.5 years, with an annual incidence rate of 0.82%. This is in line with a previous meta-analysis suggesting around 1% of annual HBsAg seroclearance rate.4 At variance with previous studies,4,5 the HBsAg clearance rate was linear over time, with a cumulative rate of HBsAg loss of 17.3% and 25.9% at 25 and 35 years of follow-up, respectively. Considering the young age of the cohort at the study entry (20 y) and the higher HBsAg loss rate in individuals older than 40 years at baseline, as suggested by the authors, the HBsAg clearance rate could increase with the cohort's aging. Accordingly, in the studies where the HBsAg clearance rates were not linear and increased over time, the mean age of the cohorts was older (35.6 and 45 y, respectively).4,5 Consistently with previous studies,4–6 the annual incidence of HBsAg seroclearance was the highest (1.07%) in HBeAg-negative as compared to HBeAg-positive individuals who seroconverted during follow-up (0.56%), and those who remained HBeAg positive or had fluctuating HBeAg status during follow-up (0.25%). This finding together with the higher HBsAg clearance rates in persons with HBV DNA serum levels <100 IU/mL compared to those with viremia ≥10,000 IU/mL (0.57% vs. 0.25%, p=0.04) and the lower rates in patients with cirrhosis (0.36% vs. 0.88 per person-year, p<0.001) suggests that HBsAg clearance occurs more frequently in HBV-infected individuals who achieved an early control of HBV infection with transition to the HBeAg-negative phase and a shorter duration of HBV-associated liver disease. The most prevalent HBV genotype in the cohort was genotype D, which sustained the infection in half of the patients; whereas the other HBV genotypes were genotype A2 (13%), B6 (3%), C2 (6%), F (17%), and undetermined (10%). As an intriguing novelty, the study provides evidence that individuals infected by genotypes D and F were 1.9 (95% CI: 1.2, 3.0) and 2.0 (95% CI: 1.2, 3.3) more likely to clear HBsAg than those infected by genotype A, while the clearance rate of genotypes B and C did not differ from that of genotype A. The role of HBV genotypes in HBsAg clearance remains to be further investigated, as a recent meta-analysis of 34 studies (42,588 patients and 3194 seroclearance events) did not find any significant difference among the different genotypes.4 By converse, HBsAg clearance after nucleos(t)ide analogues discontinuation was reported to be influenced by the infecting HBV genotype, with higher rates in genotypes A and D.7 However, in most of the previous studies, ethnicity was a potential confounding factor, whereas this is not the case in the current cohort where only Alaska Native persons were enrolled. Thus, this unusual condition, where all the major genotypes are present in a homogeneous ethnic group could contribute to a better understanding of the exclusive role of HBV genotypes on the outcome of HBV infection and disease. Actually, the authors show that the age at which 50% of their cases cleared HBeAg was <20 years for individuals infected with genotypes A, B, D, and F and >40 years in those infected by genotype C.3 An accurate definition of the different phases of HBV infection in the subgroup of carriers infected with different genotypes would have granted a more appropriate analysis of the HBV genotype impact on the incidence rate of HBsAg seroclearance and helped to address the potential role of confounding factors such as the mode of HBV transmission, ethnicity, and stage of liver disease. Unluckily a major drawback of the study is the lack of an accurate definition of the different phases of HBV infection in the cohort. A peculiarity of this cohort is the presence of a significant proportion of patients with HBV genotype F, which is the most common genotype in South and Central America but is underrepresented in most of the studies, from Asian-Pacific regions, Europe, and the North America, where HBV genotypes A, B, C, and D are predominant. A previous study from the same cohort of Alaskan Natives suggested that genotype F infection has the highest risk of developing HCC among all the 5 genotypes, with a significant proportion of patients with HBV genotype F developing HCC at a younger age.8 In the current study, Bruden et al observed a higher rate of HBsAg clearance in individuals infected by genotype F; however, among the 4 patients who developed HCC at a mean of 5 years after HBsAg seroclearance, all had HBV genotype F. The finding might suggest that patients with HBV genotype F may still carry a non-negligible risk of HCC even after HBsAg seroclearance. Further information on the age of HBsAg seroclearance, gender, and the presence of cirrhosis would be helpful to better understand the underlying risk of HCC in these patients despite HBsAg seroclearance and to define appropriately tailored surveillance programs.9 At variance with previous reports, in the current study, the HCC rate following HBsAg seroclearance was comparable to that prior HBsAg loss (98.6 vs. 124.7 cases per 100,000 person-years). Actually, the overall rates appear low and comparable to those reported in the setting of inactive carriers; nevertheless, an accurate characterization of patients who developed HCC would be useful to better understand the role played not only by virologic factors but also by the age at the time of HBsAg loss, the presence of cofactors, and the stage of liver disease. Finally, another relevant piece of knowledge provided by Bruden et al's study is the evidence of the high rate of long-term durability of HBsAg seroclearance. Among 260 individuals who achieved HBsAg seroclearance, 249 (96%) remained HBsAg negative after a median follow-up of 13 years3 and 77% of them had persistently detectable HBsAb. Interestingly, also the 11 persons who had ≥2 transient positive HBsAg-positive results ended the follow-up with ≥1 negative HBsAg result. After HBsAg clearance, transient detection of HBV DNA levels ≥100 IU/mL was reported in 26 (11%) of the 239 persons whose viremia was tested, but HBV DNA was undetectable in all cases at the end of follow-up. These findings suggest that an effective and durable control of HBV infection can be achieved, at least in the setting of spontaneous HBsAg clearance. Actually, in this cohort, only 9 (3.5%) patients cleared HBsAg after antiviral treatment; thus, data regarding the long-term durability of treatment-induced HBsAg seroclearance, at least when nucleos(t)ide analogues are considered, remain inconsistent. In conclusion, Bruden et al studying their cohort of HBV-infected persons, who were identified by population screening in the Alaskan Native population, confirmed previous studies about the relatively low rate of HBsAg seroclearance, but showed its long-term durability during a median follow-up of 13.1 years after HBsAg loss. Temporary reappearance of HBsAg or HBV DNA may occur in a minority of cases, without being the hallmark of the recurrence of an overt infection. The major intriguing and unsolved issue raised by the study is the role of HBV genotypes not only in the setting of HBsAg seroclearance but also in HCC development: whether its importance is greater than that of ethnicity, mode of HBV infection, and cofactors of liver disease remained to be answered.