Kinetics of hepatitis B virus replication in anti-HBc positive/HBsAg-negative people with HIV switching to tenofovir sparing therapy.

To unravel the still unexplored HBV-replicative kinetics in anti-HBc-positive/HBsAg-negative people-with-HIV (PWH) suspending tenofovir disoproxil-fumarate/tenofovir-alafenamide (TDF/TAF). A total of 101 anti-HBc-positive/HBsAg-negative PWH switching to TDF/TAF-sparing therapy were included. Serum HBV-DNA and HBV-RNA were quantified by droplet-digital-PCR at switching (T0), within 12 months (T1) and 12-24 months postswitch (T2). At T0, 33.7% had cryptic HBV-DNA (undetected by commercial assays, median [interquartile range (IQR)]: 2 [1-5] IU/mL) and 22% were positive to HBV-RNA alone (median [IQR]: 4 [3-4] IU/mL), indicating an active HBV-reservoir despite HBsAg-negativity and TDF/TAF-pressure. Notably, anti-HBs-titer <100 mIU/mL independently correlated with cryptic HBV-DNA at T0 (OR [95% CI]: 2.6 [1.02-6.5], P = 0.04). After TDF/TAF-withdrawal, the rate of PWH achieving HBV-DNA >10 IU/mL increased from 12.9% at T1 to 42.6% at T2 (P < 0.0001). Likewise, a rise from 2 to 11% was observed for HBV-DNA >100 IU/mL (P = 0.02); median (IQR) HBV-DNA: 579 (425-770) IU/mL. Notably, HBV-DNA >10 IU/mL at T2 occurred in 70% of PWH with cryptic HBV-DNA, in 38.5% with HBV-RNA alone and in 25% negative to both HBV-markers at T0 (P = 0.01). Cryptic HBV-DNA at T0 and lower nadir CD4+ T-cell-count independently predicted HBV-DNA >10 IU/mL at T2 (OR [95% CI]: 8.2 [1.7-40.6], P = 0.01; OR [95% CI]: 8.1 [1.3-52.1], P = 0.03). Lastly, persistent HBV-DNA positivity was independently associated with a reduced CD4+ T-cell recovery at T2 (OR [95% CI]: 0.07 [0.01-0.77], P = 0.03). This study underlines the importance to regularly monitor anti-HBc-positive/HBsAg-negative PWH undergoing TDF/TAF-sparing regimen and the role of highly-sensitive HBV markers in optimizing their management.

Salpini R ，D'Anna S ，Alkhatib M ，Piermatteo L ，Tavelli A ，Benedetti L ，Quiros Roldan E ，Cingolani A ，Papalini C ，Carrara S ，Malagnino V ，Puoti M ，Sarmati L ，Ceccherini-Silberstein F ，Perno CF ，Monforte AD ，Svicher V ... -  《-》

[Analysis of the clinical characteristics of HBeAg-negative chronic HBV infection in indeterminate phase with a low viral load].

Zhou LL ，Bai XX ，Dong B ，Xin JJ ，Xu GH ，Liu N ... -  《-》

Hepatitis B virus (HBV) viremia despite tenofovir disoproxil fumarate-containing antiretroviral therapy in persons with HBV/HIV coinfection.

The goal of treatment of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection is suppression of both viruses; yet incomplete HBV suppression on tenofovir (TFV) disoproxil fumarate (TDF)-based antiretroviral therapy (ART) is common. This study investigated TFV resistance-associated mutations (RAMs) in individuals with HBV/HIV coinfection with viremia on TDF/lamivudine (3TC)-containing ART. Samples from individuals with HBV DNA levels ≥20 IU/mL in a cross-sectional study of 138 persons with HBV/HIV coinfection in Ghana were analyzed in the present study. HBV was sequenced for RAM analysis. TFV-diphosphate (TFV-DP) concentration in peripheral blood mononuclear cells (PBMCs) was used to assess ART adherence level. Nine of 138 participants (6.5 %) had detectable HBV DNA levels ≥20 IU/mL while on ART. Seven of the nine participants had TFV-DP concentrations commensurate with 7 doses per week, and six had suppressed HIV RNA. Phylogenetic analysis revealed that eight sequences were HBV genotype E, with one genotype E/A recombinant. Ten previously-reported TFV RAMs were present in the study samples; eight were wild-type for HBV genotype E. The non-genotype-E-wild-type point mutations M267L and K333Q were found in two and one patients, respectively. No 3TC RAMs were found. HBV viremia despite high adherence to TDF/3TC-based ART may be associated with the presence of TFV RAMs. These findings highlight the need for enhanced resistance monitoring and further research to examine the clinical significance of reported TFV RAMs. Individuals with HBV/HIV coinfection and TFV resistance on TDF-based ART may need alternative treatment strategies.

Ryan P ，Odegard E ，Meeds H ，Lartey M ，Ganu VJ ，Tachi K ，Yang H ，Ojewale O ，Boamah I ，Obo-Akwa A ，Antwi K ，Anderson PL ，Blackard JT ，Kwara A ... -  《-》

Switching to tenofovir alafenamide in patients with virologically suppressed chronic hepatitis B and renal or hepatic impairment: final week 96 results from an open-label, multicentre, phase 2 study.

Phase 3 studies in patients with chronic hepatitis B have shown tenofovir alafenamide to have non-inferior efficacy to tenofovir disoproxil fumarate, with improved renal and bone safety. We conducted this study to evaluate the safety and efficacy of switching to tenofovir alafenamide in participants with chronic hepatitis B and renal or hepatic impairment. This open-label, multicentre, phase 2 study was done in eight countries or territories at 30 sites. We recruited adults (≥18 years) with chronic hepatitis B who were virally suppressed on nucleoside or nucleotide analogues and had renal impairment (part A: moderate or severe in cohort 1 [estimated glomerular filtration rate by the Cockcroft-Gault formula (eGFRCG) 15-59 mL/min] or end-stage renal disease [eGFRCG <15 mL/min] on haemodialysis in cohort 2) or hepatic impairment including decompensation (part B: Child-Turcotte-Pugh score 7-12). Participants switched to 25 mg of tenofovir alafenamide given orally once daily for 96 weeks. The primary endpoint was the proportion of participants with viral suppression (HBV DNA <20 IU/mL) at week 24 by missing-equals-failure analysis. Efficacy (full analysis set) and safety (safety analysis set) analyses included all enrolled participants who received at least one dose of the study drug. Week 96 safety was assessed, including renal and bone parameters. This trial is registered at ClinicalTrials.gov, NCT03180619, and is completed. 124 participants (93 in part A [78 in cohort 1 and 15 in cohort 2] and 31 in part B) were enrolled between Aug 11, 2017, and Oct 17, 2018, and included in the full and safety analysis sets. 106 (85%) participants completed the study. There were 69 (74%) men and 24 (26%) women in part A and 21 (68%) men and ten (32%) women in part B. At week 24, 91 (97·8%, 95% CI 92·4 to 99·7) of 93 individuals in part A (76 [97·4%, 91·0 to 99·7] of 78 in cohort 1 and 15 [100·0%, 78·2 to 100·0] of 15 in cohort 2) and 31 (100·0%, 88·8 to 100·0) in part B had HBV DNA of less than 20 IU/mL. By week 96, the most common adverse event was upper respiratory tract infection, which occurred in 14 (15%) participants in part A and in six (19%) participants in part B. Serious adverse events occurred in 20 (22%) part A participants and in ten (32%) part B participants; none were related to treatment. No treatment-related deaths occurred. At week 96, median change in estimated glomerular filtration rate (Cockcroft-Gault method) was 1·0 mL/min (IQR -2·8 to 4·5) in cohort 1 and -2·4 mL/min (-11·4 to 10·7) in part B. Mean changes in spine and hip bone mineral density were 1·02% (SD 4·44) and 0·20% (3·25) in part A and -0·25% (3·91) and 0·28% (3·25) in part B. Tenofovir alafenamide might offer continued antiviral efficacy and a favourable safety profile for patients with renal or hepatic impairment and chronic hepatitis B switching from tenofovir disoproxil fumarate or other antivirals. Gilead Sciences.

Janssen HLA ，Lim YS ，Lampertico P ，Heo J ，Chen CY ，Fournier C ，Tsang TYO ，Bae H ，Chen CH ，Coffin CS ，Ahn SH ，Trinh H ，Flaherty JF ，Abramov F ，Zhao Y ，Liu Y ，Lau A ，German P ，Chuang WL ，Agarwal K ，Gane E ... -  《The Lancet Gastroenterology &amp; Hepatology》

Misuse of the Lower Limit of Detection in HBV DNA Testing and Anti-HBe Positive Status Will Significantly Impact the Diagnosis of Occult HBV Infection.

The diagnosis of occult hepatitis B virus (HBV) infection (OBI) is influenced by factors such as the lower limit of detection (LOD) of the HBV DNA test. However, in clinical practice and scientific research, the lower limit of quantification (LOQ) is often misused as the LOD. This study aims to investigate the impact of misuse of the LOD of the HBV DNA test on the detection rate of OBI, as well as the risk factors for OBI. Four hundred twelve patients who were HBsAg-negative and had undergone high-sensitivity HBV DNA testing were included in this study. HBV DNA was detected using the Cobas 6800 System with an LOD of 2.4 IU/mL and an LOQ of 10 IU/mL. The effect of using the LOQ as the LOD on the detection rate of OBI was compared, and univariate and multivariate logistic regression analyses were used to explore the risk factors for OBI. (1) Of the 412 patients, 63.3% (n = 261) were male, with a median age of 47 (range 34-55) years. A total of 473 HBV DNA test results were obtained, with 366 individuals undergoing only one HBV DNA test and the remaining 46 patients undergoing 2 to 5 HBV DNA tests (resulting in a total of 107 test results). (2) Considering only the first HBV DNA test result, the detection rate of OBI was 4.1% (17/412). However, when the LOQ (10 IU/mL) was used as the LOD, the detection rate of OBI was only 1.5% (6/412) (p < 0.001). (3) Univariate analysis showed that there were statistically significant differences in age, anti-HBe positivity rate and anti-HBc positivity rate between OBI and non-OBI individuals (p < 0.05). Multivariate regression analysis showed that anti-HBe positivity was an independent risk factor for OBI in this study (odds ratio [OR] = 3.807, 95% confidence interval [CI]: 1.065-13.617, p = 0.040), while anti-HBs positivity was a protective factor against OBI (OR = 0.271, 95% CI: 0.093-0.787, p = 0.016). (4) Among the 46 patients who underwent repeated testing, a total of seven individuals were found to be HBV DNA-positive in the first test, and six individuals tested positive for HBV DNA one or more times in subsequent tests. When OBI was confirmed by ≥ 1 out of 1-5 tests with detectable HBV DNA, the detection rate of OBI in this study could increase from 4.1% to 5.6%. The detection rate of OBI among HBsAg-negative adult patients attending hepatology departments in this region is 4.1%. Misusing the LOQ as LOD can significantly decrease the detection rate of OBI. The presence of anti-HBe positivity and undergoing multiple HBV DNA tests can lead to a significant increase in the detection rate of OBI.

Wang B ，Wang X ，Xiao L ，Xian J ... -  《-》