The possibility of safe discontinuation of therapy with nucleos(t)ide analogues (NAs) remains one of the most controversial topics in the management of chronic hepatitis B. Therefore, we systematically reviewed the existing data on NA discontinuation in this setting and tried to identify factors affecting the probability of posttherapy remission. A literature search was performed in order to identify all published studies including patients who discontinued NAs in virological remission (VR) and were followed for 12 months thereafter. Twenty-five studies with 1716 patients were included. The pooled rates of durable VR remission were 51.4%, 39.3%, and 38.2% at 12, 24, and 36 months, respectively, after NA discontinuation, being relatively higher in initially hepatitis B e antigen (HBeAg)-positive patients (62.5%, 53.4%, 51.5%) than HBeAg-negative patients (43.7%, 31.3%, 30.1%) (P 5 0.064). The weighted probability of durable biochemical remission was 65.4%, being numerically higher in HBeAg-positive than HBeAg-negative patients (76.2% versus 56.7%, P 5 0.130). The weighted probability of hepatitis B surface antigen loss was 2.0%. The rates of durable VR did not significantly differ according to the VR definition (hepatitis B virus DNA <200, < 2000, < 20,000 IU/mL) or duration of on-therapy VR in HBeAg-positive patients, but they were significantly higher in studies with HBeAg-negative patients and on-therapy VR > 24 than £ 24 months (VR at 12 months off-NAs: 75.0% versus 35.6%, P 5 0.005). The weighted probability of durable HBeAg seroconversion was 91.9% and 88.0% at 12 and 24 months, respectively, after NA discontinuation without being affected by the duration of on-therapy VR or consolidation therapy (>6 months in all studies). Conclusion: Durable VR seems to be feasible in a substantial proportion of patients who discontinue long-term NA therapy; on-therapy VR > 24 months offers higher chances of off-NA VR in patients with HBeAg-negative chronic hepatitis B. (HEPATOLOGY 2016;63:1481-1492 T reatment against hepatitis B virus (HBV) has dramatically improved over the last 15 years, but HBV eradication remains a rarely attainable target. (1-3) Pegylated interferon-alfa therapy given for a finite duration of usually 48 weeks can achieve sustained off-therapy responses, with almost half of the responders clearing hepatitis B surface antigen (HBsAg) in the long term. However, only 20%-30% of patients with hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis B (CHB) may achieve sustained off-therapy responses after a course of pegylated interferon-alfa. (1)(2)(3) Many patients are reluctant to start treatment with this agent because interferon-alfa may have severe side effects as well as an unfavorable safety profile. Thus, oral antiviral agents, nucleos(t)ide analogues (NAs), represent the main therapeutic option for the majority of CHB patients. (4) Abbreviations: ALT, alanine aminotransferase; BR, biochemical remission; CHB, chronic hepatitis B; CI, confidence interval; HBeAg, hepatitis B e a...

Objective: We aimed to estimate the proportion of post-migration HIV acquisition among HIVpositive migrants in Europe. Design:To reach HIV positive migrants we designed a cross sectional study performed in HIV clinics. Methods:The study was conducted from July 2013-July 2015 in 57 clinics (9 European countries, targeting individuals over 18 years diagnosed in the preceding 5 years and born abroad.Electronic questionnaires supplemented with clinical data were completed in any of 15 languages.Post-migration HIV acquisition was estimated through Bayesian approaches combining extensive information on migration and patients' characteristics. CD4 counts and HIV-RNA trajectories from seroconversion were estimated by bivariate linear mixed models fitted to natural history data. Post-migration acquisition risk factors were investigated with weighted logistic regression. Median time in host countries was 8 years. Post-migration HIV acquisition was 63% (95% CI: 57%-67%); 72% among MSM, 58% and 51% in heterosexual men and women, respectively. Post-migration HIV acquisition was 71% for LAC migrants and 45% for people from SSA. ResultsFactors associated with post-migration HIV acquisition among heterosexual women and MSM were age at migration, length of stay in host country and HIV diagnosis year and among heterosexual men, length of stay in host country, and HIV diagnosis year. Conclusions:A substantial proportion of HIV-positive migrants living in Europe acquired HIV post-migration. This has important implications for European public health policies.

In most HIV-positive individuals, infection time is only known to lie between the time an individual started being at risk for HIV and diagnosis time. However, a more accurate estimate of infection time is very important in certain cases. For example, one of the objectives of the Advancing Migrant Access to Health Services in Europe (aMASE) study was to determine if HIV-positive migrants, diagnosed in Europe, were infected pre- or post-migration. We propose a method to derive subject-specific estimates of unknown infection times using information from HIV biomarkers' measurements, demographic, clinical, and behavioral data. We assume that CD4 cell count (CD4) and HIV-RNA viral load trends after HIV infection follow a bivariate linear mixed model. Using post-diagnosis CD4 and viral load measurements and applying the Bayes' rule, we derived the posterior distribution of the HIV infection time, whereas the prior distribution was informed by AIDS status at diagnosis and behavioral data. Parameters of the CD4-viral load and time-to-AIDS models were estimated using data from a large study of individuals with known HIV infection times (CASCADE). Simulations showed substantial predictive ability (e.g. 84% of the infections were correctly classified as pre- or post-migration). Application to the aMASE study ( n = 2009) showed that 47% of African migrants and 67% to 72% of migrants from other regions were most likely infected post-migration. Applying a Bayesian method based on bivariate modeling of CD4 and viral load, and subject-specific information, we found that the majority of HIV-positive migrants in aMASE were most likely infected after their migration to Europe.

Missing data are common in longitudinal studies. Likelihood-based methods ignoring the missingness mechanism are unbiased provided missingness is at random (MAR);under not-at-random missingness (MNAR), joint modeling is commonly used, often as part of sensitivity analyses. In our motivating example of modeling CD4 count trajectories during untreated HIV infection, CD4 counts are mainly censored due to treatment initiation, with the nature of this mechanism remaining debatable. Here, we evaluate the bias in the disease progression marker's change over time (slope) of a specific class of joint models, termed shared-random-effects-models (SREMs), under MAR drop-out and propose an alternative SREM model. Our proposed model relates drop-out to both the observed marker's data and the corresponding random effects, in contrast to most SREMs, which assume that the marker and the drop-out processes are independent given the random effects. We analytically calculate the asymptotic bias in two SREMs under specific MAR drop-out mechanisms, showing that the bias in marker's slope increases as the drop-out probability increases. The performance of the proposed model, and other commonly used SREMs, is evaluated under specific MAR and MNAR scenarios through simulation studies. Under MAR, the proposed model yields nearly unbiased slope estimates, whereas the other SREMs yield seriously biased estimates. Under MNAR, the proposed model estimates are approximately unbiased, whereas those from the other SREMs are moderately to heavily biased, depending on the parameterization used. The examined models are also fitted to real data and results are compared/discussed in the light of our analytical and simulation-based findings.

Despite data inconsistency and clinical heterogeneity, this systematic review and meta-analysis showed that patients with PMD are at a two-fold higher risk, both during lifetime and in acute phase, of committing a suicidal attempt than patients with non-PMD.