Anders Boyd

HIV/hepatitis B virus co-infection: current challenges and new strategies

Chronic hepatitis B virus (HBV) infection, which affects 7%-10% of HIV-infected patients, is associated with an increased frequency of AIDS-related and non-AIDS-related clinical endpoints, such as end-stage liver diseases including cirrhosis and hepatocellular carcinoma. Broad access to a very efficient antiviral therapy containing nucleos(t)ide analogues with dual activity against HBV and HIV reverse transcriptases has initiated a transition in the paradigm of HBV control in the context of HIV-induced immunosuppression. The control of viral replication is not currently such a problem, but preventing the emergence of HBV polymerase and surface gene mutants after prolonged exposure to nucleos(t)ides and their consequences in terms of HBV vaccine escape are the next long-term challenges. Another challenge is the prevention of end-stage liver disease in an ageing population, in whom non-invasive markers of liver fibrosis, although used more frequently as a substitute for liver biopsy, are not the panacea. Finally, access to prevention, diagnosis, care and treatment of HBV infection remains a major issue in developing countries, including most regions of Africa and Asia, where HBV is endemic and the epidemic of HIV infection is still thriving.

Performance of rapid tests for detection of HBsAg and anti-HBsAb in a large cohort, France

BACKGROUND & AIMS The systematic use of rapid tests performed at points-of-care may facilitate hepatitis B virus (HBV) screening and substantially increase HBV infection awareness. The aim of this study was to evaluate the effectiveness of such tests for HBsAg and anti-HBsAb detection among individuals visiting a variety of healthcare centers located in a low HBV-prevalent area. METHODS Three rapid tests for hepatitis B surface antigen (HBsAg) detection (VIKIA, Determine and Quick Profile) and one test for anti-hepatitis B surface antibody (anti-HBsAb) detection (Quick Profile) were evaluated in comparison to ELISA serology. Sensitivity (Se), specificity (Sp), positive and negative predictive values (PPV and NPV, respectively) and area under the ROC curve were used to estimate test performance. Non-inferiority criteria of the joint Se, Sp were set at 0.80, 0.95. RESULTS Among the 3956 subjects screened, 85 (2.1%) were HBsAg-positive and 2225 (56.5%) had a protective anti-HBsAb titer. Test Se and Sp (lower bound of 97.5% CI) were as follows: 96.5% (89.0%), 99.9% (99.8%) for Vikia; 93.6% (80.7%), 100.0% (99.8%) for Determine; and 90.5% (80.8%), 99.7% (99.5%) for Quick Profile; with all three tests achieving minimal non-inferiority criteria. False negatives were typically observed in inactive HBsAg carriers. The anti-HBsAb Quick Profile test had excellent specificity (97.8%) and PPV (97.8%) albeit low sensitivity (58.3%), thus failing to establish non-inferiority. CONCLUSIONS All three HBsAg rapid tests could be considered ideal for HBV screening in low HBV-prevalent countries, given the ease of use, rapidity, and high classification probabilities. The anti-HBsAb Quick Profile could be considered reliable only for positive tests.

Kinetics of hepatitis B surface and envelope antigen and prediction of treatment response to tenofovir in antiretroviral-experienced HIV-hepatitis B virus-infected patients.

Objective:Hepatitis B surface (HBsAg) and envelope (HBeAg) antigen loss are the primary goals of treating chronic hepatitis B virus (HBV). Although their quantification is useful for other antivirals, such has not been the case with tenofovir disoproxil fumarate (TDF), particularly in HIV infection. Design:Prospective, multicenter, cohort study in 143 antiretroviral-experienced HIV–HBV-co-infected patients initiating TDF. Methods:HBsAg (IU/ml) and HBeAg levels (S/CO) were measured every 6 months. HBsAg and HBeAg decline (&Dgr;) were assessed by mixed-effect linear models. Quantification criteria were used to assess predictability of antigen loss with time-dependent receiver operating characteristic curves. Results:After a median follow-up of 30.3 months, cumulative incidence rate of HBsAg loss was 4.0% (n = 4) in the entire study population and HBeAg loss was 21.0% (n = 17) in the 96 HBeAg-positive patients. &Dgr;HBsAg was steady during follow-up (HBeAg-positive: −0.027; HBeAg-negative: −0.017 log10 IU/ml per month), whereas &Dgr;HBeAg ratio was strongly biphasic (−27.1 S/CO per month before and −6.5 S/CO per month after 18 months). Baseline HBeAg and &Dgr;HBeAg were significantly different in patients harboring precore mutations (P < 0.01), whereas both &Dgr;HBsAg and &Dgr;HBeAg were significantly slower among HBeAg-positive patients with CD4+ T-cell count less than 350 cells/&mgr;l (P < 0.05). HBeAg-ratio of 10 S/CO or less at 12 months of therapy was the optimal marker of HBeAg loss, with high sensitivity (0.82) and specificity (0.84) at 36 months. In patients with HBsAg loss, three of four (75.0%) patients had a baseline level of HBsAg of 400 IU/ml or less. Conclusion:During TDF treatment, HIV-induced immunosuppression and HBV genetic variability are associated with differences in HBsAg and HBeAg decline among antiretroviral-experienced, co-infected patients. Considering the decline of HBsAg level is slow, further evaluation is needed to determine its role as a marker of therapeutic efficacy.

Gender differences in mental disorders and suicidality in Europe: Results from a large cross-sectional population-based study

INTRODUCTION When evaluating gender differences in mental disorders and suicidality, specifically between European countries, studies are sparse and frequently hindered by methodological issues, such as the limited items evaluated and inconsistent sampling designs. METHODS In ten European countries participating in the World Mental Health Survey Initiative, lifetime internalizing and externalizing disorders and suicidality were assessed among 37,289 respondents. Disorders were classified using DMS-IV criteria. Odds ratios (OR) for gender differences were calculated using logistic regression, while trends across age-groups were tested via gender × age interaction. RESULTS Within countries, prevalence of any lifetime internalizing disorder ranged from 10.8% to 44.5% among women and 5.9% to 26.5% among men, with women having consistently higher odds than men (OR range: 1.52-2.73). Prevalence of any lifetime externalizing disorders ranged from 0.2% to 6.6% among women and 2.2% to 22.4% among men, with women having consistently lower odds than men (OR range: 0.05-0.35). Any lifetime suicide attempt was found in 0.8-5.4% of women and 0.3-2.4% of men, showing inconsistent relative gender-differences across countries (OR range: 0.77-4.72). Significant effects in gender OR across age-groups were not observed for any internalizing disorder or suicide attempt, yet were present for any externalizing disorder in France (p = 0.01), the Netherlands (p = 0.05), and Spain (p = 0.02). LIMITATIONS Mental disorders were assessed with the CIDI 3.0 and not psychiatric evaluations. Suicidality does not fully represent more important clinical events, such as suicide mortality. CONCLUSIONS Consistent across European countries, internalizing disorders are more common among women and externalizing disorders among men, whereas gender differences in suicidality varied.

High incidence of treatment-induced and vaccine-escape hepatitis B virus mutants among human immunodeficiency virus/hepatitis B–infected patients

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. (Hepatology 2013;53:912–922)

Persistent viremia in human immunodeficiency virus/hepatitis B coinfected patients undergoing long‐term tenofovir: Virological and clinical implications

Tenofovir (TDF) is considered the ideal treatment for patients coinfected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV). However, certain coinfected patients exhibit incomplete viral suppression, with persistent, and sometimes transient, bouts of HBV replication. The reasons for this, including clinical effect, are unclear. A total of 111 HIV‐HBV‐infected patients undergoing TDF‐containing antiretroviral therapy were prospectively followed. Serum HBV‐DNA viral load, hepatitis surface (HBsAg) and e antigen (HBeAg) status were obtained at baseline and every 6‐12 months. Amino acid (aa) changes on the polymerase gene were assessed using direct sequencing after nested polymerase chain reaction in patients with persistent viremia (PV). After a median of 74.7 months (interquartile range: 33.4‐94.7), virological response (VR; <60 IU/mL) occurred in 96 of 111 (86.5%) patients. Of these, 86 of 96 (89.6%) remained completely undetectable during follow‐up (stabilized VR). The remaining 10 of 96 (10.4%) patients had a transient blip of detectable HBV‐DNA (transient PV), during which time 9 of 9 (100%) with available samples had detectable plasma TDF. Low‐level PV (LL‐PV; 61‐2,000 IU/mL) was observed in 11 of 111 (9.9%) patients, the majority of which had detectable plasma TDF (8 of 9; 88.9%). High‐level PV (>2,000 IU/mL) was rare (4 of 111; 3.6%) and was associated with nonadherence. At TDF initiation, patients with stabilized VR had significantly higher nadir CD4+ count, compared to those with transient PV (P = 0.006) or LL‐PV (P = 0.04). No consistent aa changes, other than those associated with lamivudine resistance, were observed in patients with persistent viremia. Importantly, HBeAg loss, HBeAg seroconversion, and HBsAg loss only occurred in patients with stabilized VR. Two patients with stabilized VR developed hepatocellular carcinoma and 2 with LL PV died, 1 of a liver‐related cause. Conclusion: Suboptimal HBV control during TDF treatment has a negative effect on serological outcomes, but not necessarily clinical events. Immunoregulation may provide more insight into this phenomenon. (Hepatology 2014;60:497–507)

Simultaneous Human Immunodeficiency Virus-Hepatitis B-Hepatitis C Point-of-Care Tests Improve Outcomes in Linkage-to-Care: Results of a Randomized Control Trial in Persons Without Healthcare Coverage.

In this randomized-control trial, conducted at a free clinic in France for predominately immigrant populations without healthcare, we demonstrate that simultaneous HIV/HBV/HCV point-of-care rapid testing improves screening outcomes. Increased awareness of infection status likely helped link these patients to care.

Are there gender differences in service use for mental disorders across countries in the European Union? Results from the EU-World Mental Health survey

Background Women are more likely than men to use mental healthcare (MHC) due to differences in the types of problems and help-seeking behaviours. The consistency of this relationship across European countries, whose MHC organisation differs substantially, is unknown. Methods Lifetime MHC-use and the type of MHC provider were assessed in 37 289 participants from the EU-World Mental Health (EU-WMH) survey, including 10 European countries (Northern Ireland, The Netherlands, Belgium, Germany, France, Spain, Italy, Portugal, Bulgaria and Romania). Lifetime mood/anxiety disorders (DSM-IV) and severity were evaluated using the CIDI V.3.0. Results MHC use was significantly higher for women than men in every country except for Romania (overall OR=1.80, 95% CI1.64 to 1.98), while remaining so after adjusting for socioeconomic characteristics (age, income level, employment status, education, marital status; adjusted OR=1.87, 95% CI 1.69 to 2.06) and country-level indicators (MHC provision, private household out-of-pocket expenditure, and Gender Gap Index; adjusted OR=1.89, 95% CI 1.71 to 2.08). Compared with men, women were also more likely to consult general practitioners (GP) versus specialised MHC (OR=1.32, 95% CI 1.12 to 1.56) with high between-country variability. In participants with mood disorder, the gender relationship in MHC use and type of MHC did not change. Conversely, in participants with anxiety disorder, no significant gender relationship in MHC use was observed (adjusted OR=1.21, 95% CI 0.99 to 1.47). Finally, men with severe mental health problems had a significantly higher odds of MHC use (OR=14.70) when compared with women with similar levels (OR=8.95, p for interaction=0.03) after adjusting for socioeconomic characteristics and country-level indicators. Conclusions Women use MHC and GPs more frequently than men, yet this depends on the type and severity of mental health problems.

Liver fibrosis changes in HIV-HBV-coinfected patients: clinical, biochemical and histological effect of long-term tenofovir disoproxil fumarate use.

BACKGROUND Data on liver fibrosis evolution in HIV-HBV-coinfected patients treated with tenofovir disoproxil fumarate (TDF) are scarce. The effect of TDF on liver fibrosis in 148 HIV-HBV-coinfected patients was prospectively evaluated using Fibrometer∆ scores and liver biopsies in a subset of patients. METHODS The mean change from baseline (Δ) in Fibrometer score was modelled using a generalized estimating equation. Homogeneous continuous-time Markov models were used to study risk factors for regression or progression of liver fibrosis. RESULTS Median follow-up of patients treated with TDF was 29.5 months (25th-75th percentile 20.9-38.1). The distribution of scored fibrosis at TDF initiation was F0-F1 n=65, F2 n=37 and F3-F4 n=46. In patients with a baseline fibrosis score of F3-F4, Fibrometer score decreased with a triphasic shape (Fibrometer Δ at 12, 24 and 36 months after TDF initiation was -0.079, -0.069 and -0.102, respectively). Despite duration on TDF, higher fibrosis scores were noted in F3-F4 patients with high HBV viral load and HDV coinfection, and in F0-F2 patients who had high HBV viral load and low CD4(+) T-cell count. Progression in fibrosis score over time was influenced by age, alcohol consumption, low CD4(+) T-cell count and HCV coinfection, whereas HDV coinfection and longer duration of HBV infection prevented fibrosis regression. No influence of antiretrovirals other than TDF was found. CONCLUSIONS The use of TDF in HIV-HBV-coinfected patients led to a decrease in liver fibrosis score in patients with advanced fibrosis or cirrhosis. Sustainability of its direct antiviral and indirect antifibrotic effects on the liver need to be studied further.

Parental Smoking in the Vicinity of Children and Tobacco Control Policies in the European Region

Objective To ascertain patterns of parental smoking in the vicinity of children in Eastern and Western Europe and their relation to Tobacco Control Scale (TCS) scores. Methods Data on parental smoking patterns were obtained from the School Child Mental Health Europe (SCMHE), a 2010 cross-sectional survey of 5141 school children aged 6 to 11 years and their parents in six countries: Germany, Netherlands, Lithuania, Romania, Bulgaria and Turkey ranked by TCS into three level categories toward tobacco control policies. Results A slightly higher proportion of Eastern compared to Western European mothers (42.4 vs. 35.1%) were currently smoking in but the difference was not statistically significant after adjusting for maternal age and maternal educational attainment. About a fifth (19.3%) and a tenth (10.0%) of Eastern and Western European mothers, respectively, smoked in the vicinity of their children, and the difference was significant even after adjustment for potential confounders (p<0.001). Parents with the highest educational attainment were significantly less likely to smoke in the vicinity of their children than those with the lowest attainment. After control of these covariates lax tobacco control policies, compared to intermediate policies, were associated with a 50% increase in the likelihood of maternal smoking in the vicinity of children adjusted odds ratio (AOR) = 1.52 and 1.64. Among fathers, however, the relationship with paternal smoking and TCS seems more complex since strict policy increases the risk as well AOR = 1,40. Only one country, however belongs to the strict group. Significance Tobacco control policies seem to have influenced maternal smoking behaviors overall to a limited degree and smoking in the vicinity of children to a much greater degree. Children living in European countries with lax tobacco control policies are more likely to be exposed to second hand smoking from maternal and paternal smoking.