Search

Objective: To assess whether quantified hepatitis B core-related antigen (qHBcrAg) is a surrogate marker of intrahepatic replication in HIV and hepatitis B virus (HBV) coinfection., Design: Cross-sectional study of 31 HIV-HBV-infected patients (total liver biopsies, n = 38) from a well defined cohort., Methods: Spearman's rank correlation coefficients were calculated between qHBcrAg and intrahepatic markers of HBV replication [total intrahepatic-DNA, covalently closed circular (ccc) DNA, cccDNA : total intrahepatic-DNA ratio]., Results: At biopsy, 22 (71.0%) patients were hepatitis B 'e' antigen (HBeAg)-positive, 22 (71.0%) had detectable plasma HBV-DNA, and 17 (54.8%) were treated with tenofovir. Median levels (interquartile range) of intrahepatic markers were as follows: HBV cccDNA (n = 34), 0.26 copies/cell (0.4-2.89); total intrahepatic-DNA (n = 38), 2.38 copies/cell (0.58-207.9), and cccDNA : total intrahepatic-DNA ratio (n = 34), 0.05 (interquartile range = 0.01-0.12). There was a significantly strong correlation between qHBcrAg and cccDNA in all patients (Rho = 0.65, P < 0.001), while a moderate correlation was observed between qHBcrAg and total intrahepatic-DNA (Rho = 0.57, P < 0.001) or cccDNA : total intrahepatic-DNA ratio (Rho = -0.45, P = 0.01). Similar findings were observed for HBeAg-positive patients and those with detectable HBV-DNA, with the exception of qHBcrAg and cccDNA or cccDNA : total intrahepatic-DNA ratio. In contrast, no significant correlation between qHBcrAg and any intrahepatic marker was observed in HBeAg-negative patients or those with undetectable HBV-DNA. No significant difference was observed in median qHBcrAg levels across liver fibrosis stages (P = 0.5)., Conclusion: qHBcrAg is a potential surrogate marker of cccDNA in HIV-HBV coinfected patients, yet might be less useful with undetectable serum HBV-DNA or HBeAg-negative status. Whether qHBcrAg provides further clinical utility compared with other serological markers remains debatable.

Introduction: Infection with hepatitis B virus (HBV) genotype G has been associated with increased liver fibrosis levels compared with other genotypes in cross-sectional studies, yet its role in fibrosis evolution remains to be established., Methods: In this prospective cohort study, 158 human immunodeficiency virus (HIV)-HBV coinfected patients had available HBV genotyping at baseline. Liver fibrosis was assessed at baseline and every 6 to 12 months by the FibroTest (BioPredictive, Paris, France). Risk factors for fibrosis regression (F3-F4 to F0-F1-F2) and progression (F0-F1-F2 to F3-F4) between baseline and end of follow-up were evaluated., Results: Most patients were male (88.6%) with a median age of 39 years. HBV genotype A was more prevalent compared with other HBV genotypes (62.7% vs D = 10.8%, E = 10.8%, and G = 15.8%). Patients were followed up for a median of 83 months (IQR = 37-97). In the 43 (27.2%) patients with F3-F4 baseline liver fibrosis, 7 (16.2%) regressed to F0-F1-F2 fibrosis at the last follow-up visit. In the 115 (72.8%) with F0-F1-F2 fibrosis at baseline, 19 (16.5%) progressed to F3-F4 fibrosis at last visit. In multivariable analysis, fibrosis progression was independently associated with older age (P <0.005), baseline CD4+ cell count less than 350/mm 3 ( P <0.01), longer antiretroviral therapy duration ( P <0.03), and HBV genotype G infection (vs non-G, P <0.01). When examining averages over time, the rate of FibroTest increase was faster in genotype G vs non-G-infected patients with baseline F0-F1-F2 fibrosis ( P for interaction = 0.002)., Conclusion: In HIV-HBV coinfected patients, HBV genotype G is an independent risk factor for liver fibrosis progression as determined by noninvasive markers. HBV genotype G-infected patients with low initial liver fibrosis levels may require more careful monitoring., (© 2018 Wiley Periodicals, Inc.)

The precore (pc) W28* mutation arises from immune-selective pressures during the hepatitis B "e" antigen (HBeAg)-positive phase of chronic hepatitis B virus (HBV) infection and has been linked to severe liver-related morbidity. Here, we examined the determinants of harboring this mutation and its rate of emergence in treated patients co-infected with human immunodeficiency virus (HIV) and HBV. In a three-year prospective cohort of 165 HIV-HBV co-infected patients, pcW28* mutation was determined via DNA-chip during yearly sampling. In a subgroup with liver biopsies, HBV covalently-closed circular (ccc)-DNA and total intrahepatic (IH)-DNA were quantified by real-time PCR. From respective inclusion to year-3 visits, median HBV-DNA levels decreased (5.88 log 10 IU/mL to <1.78 log 10 IU/mL, p < 0.001) and tenofovir-use increased (15.8%-71.4%, p < 0.001). At baseline, 47 of 162 (29.0%) patients had the pcW28* mutation and were more frequently HBeAg-negative (adjusted-OR = 4.37, 95%CI = 1.76-10.86) and had non-A HBV genotypes (adjusted-OR = 9.14, 95%CI = 4.05-20.66). No association with HIV-related factors was observed. In 114 patients without baseline mutation and available data, four developed incident pcW28* mutation by the end of follow-up (cumulative 3.5%, 95%CI = 1.3-9.1%). In the 32 patients with liver biopsies, 10 (31.3%) patients harboring the pcW28* mutation had significantly lower adjusted mean cccDNA (0.05 versus without = 0.43 copies/cell, p < 0.001) and total IH-DNA levels (2.31 versus without = 18.59 copies/cell, p = 0.006). In conclusion, the pcW28* mutation infrequently appeared in this co-infected study population with increased use of potent antivirals and suppressed levels of circulating virus., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Unlabelled: Anti-hepatitis B virus (HBV) nucleos(t)ides analogs (NA) exert selective pressures on polymerase (pol) and surface (S) genes, inducing treatment resistance and increasing the risk of vaccine escape mutants. The rate of emergence for these mutations is largely unknown in patients coinfected with human immunodeficiency virus (HIV) and HBV undergoing dual-active therapy. In a 3-year, repeat-sampling, prospective cohort study, HBV viral genome sequences of 171 HIV-HBV coinfected patients, presenting with HBV viremia for at least one visit, were analyzed every 12 months via DNA chip. Logistic and Cox proportional hazard models were used to determine risk factors specifically for S gene mutations at baseline and during follow-up, respectively. HBV-DNA levels >190 IU/mL substantially decreased from 91.8% at inclusion to 40.3% at month 36 (P < 0.001), while lamivudine (LAM) or emtricitabine (FTC) use remained steady (71.9%) and tenofovir (TDF) use expanded (month 0, 17.5%; month 36, 66.7%; P < 0.001). The largest increase of any mutation class was observed in l-nucleoside-associated pol gene/antiviral-associated S gene mutations (cumulative incidence at the end of follow-up, 17.5%) followed by alkyl phosphonate-associated pol-gene (7.4%), immune-associated S gene (specifically any amino acid change at positions s120/s145, 6.4%), and d-cyclopentane-associated pol-gene mutations (2.4%). Incidence of l-nucleoside-associated pol-gene/antiviral-associated S gene mutations was significantly associated with concomitant LAM therapy (adjusted hazard ratio [HR], 4.61; 95% confidence interval [CI], 1.36-15.56), but inversely associated with TDF use (adjusted HR/month, 0.94; 95% CI,0.89-0.98). Cumulative duration of TDF was significantly associated with a reduction in the occurrence of immune-associated S gene mutations (HR/month, 0.88; 95% CI, 0.79-0.98). No major liver-related complications (e.g., fulminant hepatitis, decompensated liver, and hepatocellular carcinoma) were observed in patients with incident mutations., Conclusion: Vaccine escape mutants selected by NA exposure were frequent and steadily increasing during follow-up. Although the high antiviral potency of TDF can mitigate incident mutations, other antiviral options are limited in this respect. The public health implications of their transmission need to be addressed., (Copyright © 2013 by the American Association for the Study of Liver Diseases.)

Background: Characteristics and factors influencing viral decay under tenofovir (TDF) and adefovir (ADV) need to be determined in HIV-HBV-coinfected patients., Methods: This open-label study compared the HBV dynamics in 85 HIV-HBV-coinfected patients initiating an antiretroviral regimen, either including TDF or associated with ADV. The first 6-month change in viral load was analysed using mixed linear models. The adjusted hazards ratio, comparing the rates of undetectable HBV DNA between treatments, was calculated using a Cox proportional hazard model., Results: The HBV DNA decay, adjusted for baseline HBV viral load was more pronounced in patients treated with TDF than with ADV at 12 months (66% versus 53%, P=0.0001). Patients in the TDF group presented a steeper slope of decline at 1.1 (95% confidence interval [CI] 0.9-1.3), compared with 0.8 (95% CI 0.6-1.0) in the ADV group (P=0.036). The mean time to HBV DNA undetectability was 19.3 months (95% CI 16.7-22.0) with TDF and 25.9 months (95% CI 21.1-30.7) with ADV. When adjusted for hepatitis B virus e antigen, HBV DNA and alanine aminotransferase levels at baseline, the influence of treatment on time to HBV DNA undetectability remained in favour of TDF versus ADV (hazard ratio=2.79, 95% CI 1.05-7.40, P=0.039), Conclusions: TDF influenced more strongly the early-phase HBV DNA kinetics than ADV. This is associated with a sustained antiviral activity in the TDF group, in which patients reached the threshold of HBV undetectability at a faster rate and in a larger proportion than those taking ADV.

Background In individuals living with human immunodeficiency virus (HIV) and hepatitis B virus (HBV), widespread tenofovir (TDF)–containing antiretroviral therapy (ART) has led to substantial decreases in HBV-DNA and HIV-RNA detection. However, the links between viral replication, liver fibrosis, and mortality remain unclear. Methods A total of 300 individuals living with HIV-HBV and undergoing ART were prospectively followed. Virological and clinical data were obtained at baseline and every 6–12 months. We quantified the associations between HBV-DNA, HIV-RNA, and liver fibrosis with risk of all-cause mortality using a joint longitudinal survival model. Viral detection, viral loads, and time-averaged cumulative viral loads of HIV and HBV were modeled as 3 separate exposures. Results During a median of 10.5 years (interquartile range, 4.0–14.6), the proportion undergoing TDF-containing ART (baseline = 18.7%, end of follow-up = 79.1%) and with undetectable HBV-DNA (baseline = 36.7%, end of follow-up = 94.8%) substantially increased. 42 participants died (incidence rate = 1.30/100 person-years, 95% confidence interval [CI] =.96–1.76). The leading causes of death were non-AIDS/non–liver-related malignancies (28.6%), followed by liver-related (16.7%), AIDS-related (16.7%), and other (16.7%). All-cause mortality was associated with HBV-DNA viral load (adjusted hazards ratio [aHR] per log10 IU/mL = 1.41, 95% CI = 1.04–1.93, P = .03) or time-averaged cumulative HBV-DNA (aHR per log10 copy-years = 1.37, 95% CI = 1.03–1.83, P = .03), but not undetectable HBV-DNA. Advanced liver fibrosis at baseline was also associated with increased mortality rates (aHR = 2.35, 95% CI = 1.16–4.76, P  = .02). No significant association between HIV-RNA replication and mortality was observed. Conclusions Concurrent and historical HBV replication and liver fibrosis are important drivers of all-cause mortality in largely TDF-treated individuals living with HIV-HBV, despite one-fifth of deaths being liver-related. HBV-DNA and liver fibrosis remain important prognostic indicators for this patient population. [ABSTRACT FROM AUTHOR]

Background & Aims: Data on liver fibrosis evolution and its involvement in liver‐related morbidity are scarce in individuals with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) co‐infection during treatment. We identified profiles of liver fibrosis evolution in coinfected patients undergoing tenofovir (TDF). Methods: We included 169 HIV‐HBV‐coinfected patients on TDF‐based antiretroviral therapy. Virological and clinical data were obtained at TDF‐initiation and every 6‐12 months. From data on non‐invasive liver fibrosis assessments collected yearly (FibroTest®), we established clusters of individuals with similar liver fibrosis evolution using group‐based trajectory models. Results: Four profiles of liver fibrosis evolution were established from a median follow‐up of 7.6 years (IQR = 3.1‐13.1): low fibrosis with no progression (29.6%, profile A), low fibrosis with progression (22.5%, profile B), moderate fibrosis with high fluctuation (39.6%, profile C), and cirrhosis with no regression (8.3%, profile D). When compared to profile A, baseline HBeAg‐positive status was associated with profiles B (P =.007) and C (P =.004), older age with profiles C (P <.001) and D (P =.001), exposure to second‐generation protease inhibitors with profile C (P =.004), and CD4+ <500/mm3 at the last visit with profiles C (P =.02) and D (P =.002). Incident liver‐related events occurred in profiles other than A (B, n = 1/38; C, n = 6/67; D, n = 3/14) and all five cases of hepatocellular carcinoma occurred in profiles C (n = 2) and D (n = 3). Conclusions: TDF‐treated HIV‐HBV coinfected individuals do not seem to benefit from comparable levels of liver fibrosis regression as in HBV mono‐infection. Liver‐related morbidity occurs mainly in those with fluctuating or consistently high fibrosis levels. [ABSTRACT FROM AUTHOR]

Objectives: To determine the extent of hepatitis B virus (HBV) suppression and its association with seroclearance of hepatitis 'e' antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in HIV/HBV-coinfected patients undergoing long-term tenofovir-based antiretroviral therapy (ART).Methods: We prospectively followed 165 HIV/HBV-coinfected patients undergoing tenofovir-based ART. Serum HBV-DNA viral loads and HBeAg and HBsAg status were obtained at tenofovir initiation and every 6-12 months. We calculated the proportion achieving virological response (VR, <60 IU/mL) during follow-up. We also calculated rates of HBeAg- and HBsAg-seroclearance, which were compared between those who achieved versus never achieved VR during follow-up using an Exact binomial test.Results: During a median 8.1 years (IQR = 4.0-13.2) of tenofovir treatment, 152 (92.1%) patients were able to achieve VR and 13 (7.9%) never achieved VR (median HBV-DNA at the end of follow-up = 608 IU/mL, range = 67-52 400 000). The prevalence of individuals with detectable HBV-DNA (≥60 IU/mL) decreased during tenofovir treatment: 15.1% (n = 14/93) at 5 years, 3.2% (n = 2/62) at 10 years and, 3.2% (n = 1/31) at 15 years. 44/96 HBeAg-positive patients (6.15/100 person-years) had HBeAg-seroclearance and 13/165 patients overall (0.87/100 person-years) had HBsAg-seroclearance. No difference in HBeAg-seroclearance was observed between those who achieved versus never achieved VR (7.4 versus 3.7/100 person-years, P = 0.33), while HBsAg-seroclearance was only observed in those with VR (1.0 versus 0/100 person-years, P = 0.49; respectively). Individuals with VR also had a higher frequency of undetectable HIV-RNA during treatment (P < 0.001).Conclusions: During long-term tenofovir-based ART for HIV/HBV coinfection, persistent HBV viraemia is apparent, but becomes less frequent over time. HBsAg-seroclearance only occurred in those with full HBV and relatively high HIV suppression. [ABSTRACT FROM AUTHOR]

Background Quantitative hepatitis B core-related antigen (qHBcrAg) or antihepatitis B core antibody (qAnti-HBc) could be useful in monitoring liver fibrosis evolution during chronic hepatitis B virus (HBV) infection, yet it has not been assessed in human immunodeficiency virus (HIV)-HBV-coinfected patients undergoing treatment with tenofovir (TDF). Methods One hundred fifty-four HIV-HBV-infected patients initiating a TDF-containing antiretroviral regimen were prospectively followed. The qHBcrAg and qAnti-HBc and liver fibrosis assessment were collected every 6–12 months during TDF. Hazard ratios (HRs) assessing the association between qHBcrAg/qAnti-HBc and transitions from none/mild/significant fibrosis to advanced fibrosis/cirrhosis (progression) and from advanced fibrosis/cirrhosis to none/mild/significant fibrosis (regression) were estimated using a time-homogeneous Markov model. Results At baseline, advanced liver fibrosis/cirrhosis was observed in 40 (26%) patients. During a median follow-up of 48 months (interquartile range, 31–90), 38 transitions of progression (IR = 7/100 person-years) and 34 transitions of regression (IR = 6/100 person-years) were observed. Baseline levels of qHBcrAg and qAnti-HBc were not associated with liver fibrosis progression (adjusted-HR per log10 U/mL = 1.07, 95% confidence interval [CI] = 0.93–1.24; adjusted-HR per log10 Paul-Ehrlich-Institute [PEI] U/mL = 0.85, 95% CI = 0.70–1.04, respectively) or regression (adjusted-HR per log10 U/mL = 1.17, 95% CI = 0.95–1.46; adjusted-HR per log10 PEI U/mL = 0.97, 95% CI = 0.78–1.22, respectively) after adjusting for age, gender, duration of antiretroviral therapy, protease inhibitor-containing antiretroviral therapy, and CD4+/CD8+ ratio. Nevertheless, changes from the previous visit of qAnti-HBc levels were associated with liver fibrosis regression (adjusted-HR per log10 PEIU/mL change = 5.46, 95% CI = 1.56–19.16). Conclusions Baseline qHBcrAg and qAnti-HBc levels are not associated with liver fibrosis evolution in TDF-treated HIV-HBV coinfected patients. The link between changes in qAnti-HBc levels during follow-up and liver fibrosis regression merits further study. [ABSTRACT FROM AUTHOR]

Introduction: Long-term tenofovir disoproxil fumarate (TDF) use has been associated with significant regression of liver fibrosis during hepatitis B virus (HBV) mono-infection, yet little is known during HIV-HBV coinfection. The aim of this study was to evaluate the evolution of liver fibrosis and its determinants in TDF-treated coinfected patients. Methods: In this prospective cohort study, 167 HIV-HBV-infected patients initiating TDF-containing antiretroviral therapy were included. Fibrosis was assessed using the FibroTest® at baseline and every six to twelve months. Risk factors for fibrosis progression (F0-F1-F2 to F3-F4) and regression (F3-F4 to F0-F1-F2) were evaluated. Results: At baseline, 134 (80.2%) patients had detectable HBV-DNA (median = 4.93 log10 IU/mL, IQR = 2.94-7.15) and 104 (62.3%) had hepatitis B "e" antigen-positive serology. Median follow-up was sixty months (IQR = 36-93). In the 47 (28.1%) patients with F3-F4 baseline fibrosis, 7/47 (14.9%) regressed to F0-F1-F2 at last follow-up visit. Fibrosis regression was significantly associated with higher CD4+ cell counts (P = 0.009) and lower fasting triglyceride levels (P = 0.007) at TDF-initiation. In the 120 (71.9%) patients with F0-F1-F2-baseline fibrosis, 20/120 (16.7%) progressed to F3-F4 at last follow-up visit. Fibrosis progression was associated with male gender (P = 0.01), older age (P = 0.001), from low/moderate HBV-endemic country (P = 0.007), lower nadir CD4+ cell count (P = 0.03), higher fasting glycaemia (P = 0.03) and anaemia (P = 0.004) at TDF-initiation. Control of HBV replication at end of follow-up was extensive (88.1%), while no HBV-related factors emerged as predictors of progression/regression. Incidence of severe liver-related events was low (n = 4, rate = 0.5/100 person-years). Conclusions: Liver fibrosis levels are stable for most coinfected patients undergoing TDF, despite control of HBV replication. Nevertheless, a concerning amount of liver fibrosis progression did occur, which could be partly explained by metabolic abnormalities and past severe immunosuppression and requires further evaluation. [ABSTRACT FROM AUTHOR]

Accurate laboratory confirmation for Hepatitis B diagnosis and monitoring are crucial. Recently an ultrasensitive immunoassay test, the HBsAg Next (HBsAgNx), has been reported approximately eight times more sensitive than current HBsAg assays. The aim of our study was to assess the analytical performances of this new test. 253 clinical samples from Saint Louis University Hospital were analyzed, splitted into four panels: (1) routine prospectively screening serums (n = 196), (2) retrospective serum samples before HBV reactivation (HBV-R) (n = 18), (3) occult HBV infection (OBI) (n = 10) and (4) a selection of wild type HBV genotypes (n = 29) Panel 1, showed robust agreement with the HBsAg Qualitative II (HBsAgQII) assay (Cohen's kappa = 0.83). Despite this agreement, 7 false positive with the HBsAgQII assay were found negative with HBsAgNx. One OBI was detected only with HBsAgNx. Panel 2 showed potential time savings in diagnosing HBV-R using HBsAgNx among 4/18 HBsAg positives samples. Panel 3 highlighted the ability of HBsAgNx to detect HBsAg in OBI patients defined by negative for HBsAg with HBsAgQII assay and positive for HBV DNA. Furthermore, the HBsAgNx assay detected all different genotypes. The study highlights the effectiveness of the HBsAgNx assay, showing its performance. It excels in detecting weakly positive samples and addressing challenging cases. HBsAgNx assay demonstrates promising analytical performances, with improved sensitivity and specificity compared to standard HBsAgQII assay, able to detect all genotypes. Its potential impact on early detecting and monitoring reactivations, and occult infections could be very useful in clinical practice. [ABSTRACT FROM AUTHOR]

Background & Aims In the presence of highly-potent antivirals, persistence of hepatitis B virus (HBV) is most well-characterized by covalently-closed circular DNA (cccDNA) and total intrahepatic DNA (IH-DNA). We sought to determine how antiviral therapy could affect their levels during human immunodeficiency virus (HIV)-HBV co-infection. Methods Sixty co-infected patients from a well-defined cohort with ⩾1 liver biopsy were studied. HBV cccDNA and total IH-DNA were extracted from biopsies and quantified by real-time PCR. Factors associated with intrahepatic viral load were determined using mixed-effect linear regression and half-life viral kinetics during reconstructed follow-up using non-linear exponential decay models. Results At biopsy, 35 (58.3%) patients were hepatitis B “e” antigen (HBeAg)-positive and 33 (55.0%) had detectable plasma HBV-DNA (median = 4.58 log 10 IU/ml, IQR = 2.95–7.43). Overall, median cccDNA was −0.95 log 10 copies/cell (IQR = −1.70, −0.17) and total IH-DNA was 0.27 log 10 copies/cell (IQR = −0.39, 2.00). In multivariable analysis, significantly lower levels of cccDNA and total IH-DNA were observed in patients with HBeAg-negative serology, nadir CD4 + cell counts >250/mm 3 , and longer cumulative TDF-duration, but not lamivudine- or adefovir-duration. In post-hoc analysis using reconstructed TDF-duration (median 29.6 months, IQR = 15.0–36.1, n = 31), average half-life of cccDNA was estimated at 9.2 months (HBeAg-positive = 8.6, HBeAg-negative = 26.2) and total IH DNA at 5.8 months (HBeAg-positive = 1.3, HBeAg-negative = 13.6). Intrahepatic viral loads remained detectable for all patients, even with prolonged TDF-exposure. Conclusions In co-infection, TDF-use is associated with lower levels of HBV replication intermediates and cccDNA. Slow decay of intrahepatic viral loads underscores that TDF is unable to completely block intracellular viral DNA synthesis, which possibly accounts for continuous replenishment of the cccDNA pool. Lay summary Chronic hepatitis B virus (HBV) is a persistent infection, while the only real way of knowing the extent of this persistence is through measuring levels of virus in the liver. In this study, we examine levels of HBV in the liver among patients with both HBV and human immunodeficiency virus, or HIV, infection. It would appear that the currently available medication, namely “tenofovir”, works well to decrease virus levels in the liver, but it remains at low levels despite long periods of treatment. [ABSTRACT FROM AUTHOR]