Hepatitis B virus functional cure in persons with HIV: what are the predictors and which novel markers are useful?

Hepatitis B Surface Antigen Loss: Too Little, Too Late and the Challenge for the Future

The royal wedding in chronic hepatitis B: The haves and the have-nots for the combination of pegylated interferon and nucleos(t)ide therapy.

BackgroundThe efficacy of entecavir (ETV) add-on peg-interferon therapy compared with ETV monotherapy in treatment-naïve hepatitis B virus (HBV) patients remains controversial. We investigated whether adding peg-interferon to ongoing ETV treatment leads to a better curative effect or not.MethodsAll patients have been recruited between August 2013 and January 2015 from the Shanghai Public Health Clinical Center and Zhongshan Hospital (China). Eligible HBV patients (n = 144) were randomly divided (1:1) to receive either ETV monotherapy (n = 70) or peg-interferon add-on therapy from week 26 to 52 (n = 74). Patients were followed-up for at least 2 years. Indexes including hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) seroconversion rate, sustained virologic response, transient elastography value, and histological scores were evaluated every 3 months until the end of the study. The rate of patients with HBsAg loss was defined as the primary endpoint criteria.ResultsAt week 26, no patient achieved HBsAg seroconversion in either group. At week 52, one patient in the monotherapy group was HBsAg-negative but there was none in the combination therapy group. The monotherapy group showed significantly better liver function recovery results than the combination therapy group. At week 78, one patient in the combination group had HBsAg seroconverted. At week 104, only three patients in the combination therapy group were HBsAg-negative compared with one patient in monotherapy. The mean alanine aminotransferase and aspartate aminotransferase levels and transient elastography values decreased significantly compared with baseline. Both groups showed a favorable decrease in alpha-fetoprotein (monotherapy: 4.5 [2.8, 7.1] vs. 2.2 [1.8, 3.1] ng/mL, P < 0.001; combination therapy: 5.7 [3.0, 18.8] vs. 3.2 [2.0, 4.3] ng/mL, P < 0.001) and an improved result of liver biopsy examination scores. The combination group showed a better improvement in histology compared with the monotherapy group (mean transient elastography value 6.6 [4.9, 9.8] vs. 7.8 [5.4, 11.1] kPa, P = 0.028). But there was no significant difference in HBsAg conversion rate (1.8% [1/56] vs. 4.1% [3/73], P = 0.809) and HBeAg conversion rate (12.5% [7/56] vs. 11.0% [8/73], P = 0.787), as well as HBV-DNA, sustained virologic response (93.2% vs. 98.5%, P = 0.150) between the two groups.ConclusionsBoth therapies supported liver function recovery and histology improvement. Combination therapy did not show better anti-viral efficacy in HBsAg or HBeAg seroconversion compared with monotherapy. However, combination therapy played a more positive role in reversing hepatic fibrosis compared with monotherapy.Trial registrationClinicalTrials.gov: NCT02849132; https://clinicaltrials.gov/ct2/show/NCT02849132

Relapse of chronic hepatitis B after discontinuation of nucleos(t)ide analogs: Is the glass half full or half empty?

Loss of hepatitis B surface antigen (HBsAg) usually indicates the cure of hepatitis B virus (HBV) infection. In spontaneous hepatitis B e antigen (HBeAg) seroconverters, lower serum HBsAg and HBV DNA levels have been shown to be associated with HBsAg loss over time. However, little is known about their impacts on HBsAg loss in HBeAg-negative patients with limited viral replication. A total of 688 HBeAg-negative patients with baseline serum HBV DNA levels <2000 IU/mL were enrolled in Taiwan. The relationships of HBsAg and HBV DNA levels with subsequent HBsAg loss were investigated. In a mean follow-up of 11.6 years, the average annual rate of HBsAg loss was 1.6%. Baseline HBsAg and HBV DNA levels were inversely associated with subsequent HBsAg loss. When compared to patients who had HBsAg levels >1000 IU/mL, the rates of HBsAg loss were significantly higher in patients with HBsAg levels of 100-999, 10-99, and <10 IU/mL, with hazard ratios of 2.5 (95% confidence interval [CI], 1.6-4.0), 2.8 (95% CI, 1.6-5.0), and 13.2 (95% CI, 8.1-21.5), respectively. Multivariate analysis showed that HBsAg level, but not HBV DNA, remained as an independent factor. The adjusted hazard ratio of HBsAg loss was 13.2 (95% CI, 7.8-22.1) for HBsAg level <10 versus ≥ 1000 IU/mL. When compared to HBV DNA level by receiver operating characteristic curve analysis, HBsAg level served as a better predictor of both 5-year and 10-year HBsAg loss. In HBeAg-negative patients with HBV genotype B or C infection who have HBV DNA level <2000 IU/mL, HBsAg level <10 IU/mL is the strongest predictor of HBsAg loss.

A new role for an old marker, HBsAg

Hepatitis B surface antigen (HBsAg) loss is a milestone that marks the natural history of chronic hepatitis B virus (HBV) infection. Therefore, HBsAg loss is the most desired endpoint in chronic hepatitis B (CHB) but occurs uncommonly.1 Its estimated annual incidence is 0.45–2.38%.2 HBsAg loss is associated with excellent clinical outcomes. Baseline HBsAg, HBV DNA, older age and platelet counts are associated with higher chance of spontaneous HBsAg loss.3-6 And baseline low HBsAg levels is the strongest predictor of spontaneous HBsAg loss compared to other factors.3, 4, 6 Moreover, rates of spontaneous HBsAg loss will be higher along with follow-up.3 The most importance is that spontaneous loss of HBV DNA and HBsAg are important predictors of reduced HCC risk.1, 7 In a recent issue of Aliment Pharmacol Ther, Chen and coworkers8 conducted a case–control study to explore whether there is difference of clinical outcomes between patients with spontaneous and nucleos(t)ide analogue (NAs) treated HBsAg loss. This cohort study was based on 312 CHB patients with spontaneous HBsAg loss and 110 patients with nucleos(t)ide analogue treated HBsAg loss. After a mean follow-up period of 107 months after HBsAg loss, the clinical outcomes (including the incidence of anti-HBs seroconversion, HCC development, overall mortality and variceal bleeding) between patients in the two groups are comparable. Propensity score analysis revealed similar results. This is the first study with long-term follow-up to compare the difference in the clinical outcomes after HBsAg loss between CHB patients with spontaneous and nucleos(t)ide analogue-treated HBsAg loss.8 And this is the main strength of this cohort study. However, the main drawback is the less information about HBV DNA of the included patients. Persistent virus replication and cirrhosis are the two main risk factors of HCC development. HBV covalently closed circular DNA (cccDNA) is responsible for viral persistence. On the other hand, cccDNA is strongly associated with the level of HBV DNA. Therefore, serum HBV DNA, but not HBsAg, reflects the amount of cccDNA and the replication efficiency of HBV in patients with CHB.9 This may explain that HCC can occur in the absence of cirrhosis. Considering the indications of anti-viral therapy with nucleos(t)ide analogues, more patients in the NAs treated group might be with positive or higher HBV DNA than those in the spontaneous HBsAg loss group. Therefore, more patients in the NAs treated group were with cirrhosis (20%) and HCC development (3.6%) than others (7.1% and 0.3%, respectively). Also, patients in the nucleos(t)ide analogues treated group might have higher chance of HCC development in the long run because of the pre-existing fibrosis before and during nucleos(t)ide analogue therapy.8 HBsAg loss was defined as persistent negativity of HBsAg for at least 1 year.8 Patients developed HCC dozens of months after HBsAg loss. The level of HBsAg (or ±) at the time of HCC development was not described. The levels of HBsAg and HBV DNA are connected with necessity of adjuvant anti-viral therapy.10 We applaud Chen and coworkers’ interesting and important work. However, due to the small sample size (especially after propensity score analysis) and limitations of retrospective analysis, more prospective studies with large sample size are warranted to certify these findings. Declaration of personal and funding interests: None.

Hepatitis B surface antigen (HBsAg) loss is a rare event among persons with hepatitis B virus (HBV) monoinfection but seems to happen more frequently in people with HIV (PWH). We assessed the proportion of PWH/HBV coinfection who experienced HBsAg loss during long-term tenofovir-therapy and evaluated its association with quantitative HBsAg (qHBsAg) levels at tenofovir start. All Swiss HIV Cohort Study participants with two or more positive HBsAg measurements more than 6 months apart, and at least 4 years of tenofovir-containing antiretroviral therapy (ART), were considered. Our main outcomes were the loss of HBsAg during the first 2 years of tenofovir therapy and until the last available follow-up. We explored the association between qHBsAg levels at tenofovir start and HBsAg loss using multivariable logistic regression adjusted for potential confounders. A total of 272 PWH and HBV coinfection were included. Median age was 41 years (IQR 36-46) and 81% (221) were men. At tenofovir start, 62% (169/272) received prior HBV active therapy, 49% (110/224) were hepatitis B e antigen (HBeAg)-positive, 82% (222/272) had detectable HBV DNA (median 4.0 log10 IU/mL, IQR 2.1-7.5) and 19% (46/242) had low qHBsAg, defined as <1000 IU/mL. HBsAg loss was observed in 7% (19/272) of participants during the first 2 years of tenofovir-containing ART and in 16% (43/272) after a median follow-up time of 8.4 years (IQR 2.6-15.8). At the last follow-up, 59% (16/27) of those with HBsAg loss had seroconverted for detectable anti-HBs antibodies. In multivariable analyses, low qHBsAg at tenofovir start (OR 5.3, 95% CI 1.6-17.8) was a significant predictor of HBsAg loss. We found high rates of HBsAg loss in PWH and HBV coinfection on long-term tenofovir-containing ART, most of whom had low qHBsAg at tenofovir start.

Loss of hepatitis B surface antigen (HBsAg) usually indicates that hepatitis B virus (HBV) infection has been cured. However, little is known about factors predicting HBsAg loss in patients who spontaneously clear hepatitis B e antigen (HBeAg). We studied 390 Taiwanese HBeAg-positive patients with chronic hepatitis who had spontaneously cleared HBeAg (seroconversion) during follow-up. Serum levels of HBV DNA and HBsAg were determined 1 year after HBeAg seroconversion, and their relationships with subsequent HBsAg loss were investigated. In a mean follow-up of 7.4 years, the average annual rate of HBsAg loss was 0.62%. Serum levels of HBsAg and HBV DNA were inversely associated with HBsAg loss in a dose-response manner. Compared with patients with HBsAg levels ≥1000 IU/mL, the HBsAg loss rate was higher for those with HBsAg levels of 100 to 999 and <100 IU/mL, with hazard ratios of 4.4 (95% confidence interval, 1.1-17.0) and 24.3 (8.7-67.5), respectively. Among those who underwent HBsAg loss within 6 years of follow-up, serum HBsAg levels were a better predictor than HBV DNA levels by receiver operating characteristic curve analysis (area under the receiver operating characteristic curve, 0.90 vs 0.69; P = .012); an HBsAg level <100 IU/mL predicted HBsAg loss within 6 years with a diagnostic accuracy of 91.5%, sensitivity of 83.3%, specificity of 92.1%, positive predictive value of 45.5%, and negative predictive value of 98.6% in patients with an HBV DNA level <200 IU/mL. Low serum levels of HBsAg, alone or in combination with HBV DNA levels, 1 year after HBeAg seroconversion can predict HBsAg loss in patients with HBV genotype B or C infection.

Background An effective therapeutic strategy for hepatis B virus (HBV) cure remains an urgent unmet need. We aimed to define the incidence, kinetics, and predictors of hepatitis B surface antigen (HBsAg) loss in people with HIV and HBV (PWH-HBV) following HBV-active antiretroviral therapy (ART) in PWH-HBV in Asia. Methods 97 PWH-HBV commencing HBV-active ART were recruited prospectively in Thailand (n = 94) and Malaysia (n = 3), then followed for 24 months. Time to HBV serology change was calculated. Univariate associations between baseline characteristics and HBsAg loss were examined using the Mann-Whitney or chi-square tests. Multivariable analysis was undertaken using Cox regression. Results Twenty-one individuals (22%) lost HBsAg during follow-up (11.7 per 100 person-years), 14 of whom gained anti-HBs. Twenty-two of 61 (36.1%) individuals who were hepatitis B “e” antigen (HBeAg) positive at baseline lost HBeAg over the study, 15 of whom gained anti-HBe. Most individuals lost HBsAg and HBeAg by the month 12 study visit (81% and 63.6%, respectively), with median times of 5.8 and 12.0 months to HBsAg and HBeAg loss, respectively. Univariate analysis showed baseline characteristics associated with HBsAg loss were higher alanine aminotransferase (ALT; P = .005), tenofovir alafenamide (TAF)–containing ART regimen (P = .025), younger age (P = .040), lower liver stiffness (P = .010), and quantitative HBsAg &amp;lt; log10 2.0 IU/mL (P = .001). All 5 factors remained significant in a Cox regression analysis that adjusted for baseline CD4 count. Conclusions High HBsAg loss rates occur in PWH and HBV early after commencing ART. Our study suggests that TAF-containing ART regimens may be preferable as first-line therapy in HIV-HBV coinfection.

Early Serum HBsAg Kinetics as Predictor of HBsAg Loss in Patients with HBeAg-Negative Chronic Hepatitis B after Treatment with Pegylated Interferonα-2a.

CLINICAL CURE OF A CHRONIC HEPATITIS B PATIENT WITH NORMAL SERUM ALANINE AMINOTRANSFERASE TREATED WITH PEGYLATED INTERFERON ALFA-2A: A CASE REPORT.

The study investigated the role of hepatitis B core-related antigen (HBcrAg) in hepatitis B virus (HBV) relapse after stopping tenofovir disoproxil fumarate (TDF) in HBeAg-negative patients. A total of 185 HBeAg-negative patients without cirrhosis who had stopped TDF treatment for at least 6months were recruited. All patients fulfilled the stopping criteria proposed by the Asian Pacific Association for the Study of the Liver 2012. The 3-year cumulative incidences of virological relapse, clinical relapse, and hepatitis B surface antigen (HBsAg) loss were 72, 60.1 and 14.5%, respectively. End-of-treatment (EOT) HBsAg level was an independent predictor of virological relapse (hazard ratio (HR): 2.263; 95% confidence interval (CI): 1.779-2.887), clinical relapse (HR 1.773; 95% CI 1.367-2.298), and HBsAg loss (HR 0.179; 95% CI 0.096-0.335). Among patients who had HBsAg < 100 and ≥ 100IU/mL, the 3-year virological relapse rates were 37.4% and 85.3% (p < 0.001), clinical relapse rates were 30.3 and 71.7% (p < 0.001), and HBsAg loss rates were 40.6 and 2.6% (p < 0.001), respectively. Among the 53 patients with EOT HBsAg level < 100IU/mL, the 3-year virological relapse rates in patients with baseline HBcrAg levels < 4.7 and ≥ 4.7 log10 U/mL were 20.3 and 60.4% (p = 0.003), and the clinical relapse rates were 10.3 and 59.5% (p < 0.001) respectively. Additionally, the 3-year HBsAg loss rates in patients with baseline HBcrAg ≤ 3 and > 3 log10 U/mL were 42.9 and 7.9% (p < 0.001). The combination of EOT HBsAg and baseline HBcrAg levels could further reduce the risk of HBV relapse after stopping TDF therapy in HBeAg-negative patients.

Historic and current hepatitis B viral DNA and quantitative HBsAg level are not associated with cirrhosis in non-Asian women with chronic hepatitis B

We investigated the incidence and predictors of post-treatment hepatitis B virus (HBV) relapse and hepatitis B surface antigen (HBsAg) loss. After cessation of nucleoside analogue (NA) treatment in hepatitis B e antigen (HBeAg)-negative patients with cirrhosis. The rates of HBsAg loss and hepatocellular carcinoma (HCC) development in HBeAg-negative patients with cirrhosis who continued NA treatment were compared with those who discontinued treatment. Patients with compensated cirrhosis who had discontinued NA treatment for at least 12months (discontinuing group; n=73) and patients who continued entecavir treatment for at least 4years (continuing group; n=158) were recruited. Serum HBsAg levels were analysed at the end of treatment (discontinuing group) or at 2.5-3years of treatment (continuing group). In the discontinuing group, the 6-year cumulative incidence of post-treatment virological relapse and HBsAg loss were 56.3% and 46.7%, respectively. The end-of-treatment HBsAg level of 300IU/mL was a cut-off value for subsequent post-treatment HBsAg loss and sustained response. In the continuing group, HBsAg loss occurred in five of 158 patients. Cox regression analysis showed that HBsAg levels in the discontinuing group were independent predictors for HBsAg loss in all patients and 104 propensity score (PS)-matched patients. There was no significant difference in HCC development between the groups in all patients and 104 PS-matched patients. Two patients experienced post-treatment alanine aminotransferase flare with hepatic decompensation, and neither of them died after retreatment. In conclusion, HBeAg-negative patients with cirrhosis who discontinued NA treatment might have a higher rate of HBsAg loss and their risk of developing HCC did not increase compared with those who continued entecavir treatment.