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BackgroundWhen a clinical treatment fails or shows suboptimal results, the question of when to switch to another treatment arises. Treatment switching strategies are often dynamic because the time of switching depends on the evolution of an individual's time-varying covariates. Dynamic strategies can be directly compared in randomized trials. For example, HIV-infected individuals receiving antiretroviral therapy could be randomized to switching therapy within 90 days of HIV-1 RNA crossing above a threshold of either 400 copies/ml (tight-control strategy) or 1000 copies/ml (loose-control strategy).MethodsWe review an approach to emulate a randomized trial of dynamic switching strategies using observational data from the Antiretroviral Therapy Cohort Collaboration, the Centers for AIDS Research Network of Integrated Clinical Systems and the HIV-CAUSAL Collaboration. We estimated the comparative effect of tight-control vs. loose-control strategies on death and AIDS or death via inverse-probability weighting.ResultsOf 43 803 individuals who initiated an eligible antiretroviral therapy regimen in 2002 or later, 2001 met the baseline inclusion criteria for the mortality analysis and 1641 for the AIDS or death analysis. There were 21 deaths and 33 AIDS or death events in the tight-control group, and 28 deaths and 41 AIDS or death events in the loose-control group. Compared with tight control, the adjusted hazard ratios (95% confidence interval) for loose control were 1.10 (0.73, 1.66) for death, and 1.04 (0.86, 1.27) for AIDS or death.ConclusionsAlthough our effective sample sizes were small and our estimates imprecise, the described methodological approach can serve as an example for future analyses.

Introduction: HIV-1 infection leads to chronic inflammation and to an increased risk of non-AIDS mortality. Our objective was to determine whether AIDS-defining events (ADEs) were associated with increased overall and cause-specific non-AIDS related mortality after antiretroviral therapy (ART) initiation. Methods: We included HIV treatment-naive adults from the Antiretroviral Therapy Cohort Collaboration (ART-CC) who initiated ART from 1996 to 2014. Causes of death were assigned using the Coding Causes of Death in HIV (CoDe) protocol. The adjusted hazard ratio (aHR) for overall and cause-specific non-AIDS mortality among those with an ADE (all ADEs, tuberculosis (TB), Pneumocystis jiroveci pneumonia (PJP), and non-Hodgkin's lymphoma (NHL)) compared to those without an ADE was estimated using a marginal structural model. Results: The adjusted hazard of overall non-AIDS mortality was higher among those with any ADE compared to those without any ADE (aHR 2.21, 95% confidence interval (CI) 2.00 to 2.43). The adjusted hazard of each of the cause-specific non-AIDS related deaths were higher among those with any ADE compared to those without, except metabolic deaths (malignancy aHR 2.59 (95% CI 2.13 to 3.14), accident/suicide/overdose aHR 1.37 (95% CI 1.05 to 1.79), cardiovascular aHR 1.95 (95% CI 1.54 to 2.48), infection aHR (95% CI 1.68 to 2.81), hepatic aHR 2.09 (95% CI 1.61 to 2.72), respiratory aHR 4.28 (95% CI 2.67 to 6.88), renal aHR 5.81 (95% CI 2.69 to 12.56) and central nervous aHR 1.53 (95% CI 1.18 to 5.44)). The risk of overall and cause-specific non-AIDS mortality differed depending on the specific ADE of interest (TB, PJP, NHL). Conclusions: In this large multi-centre cohort collaboration with standardized assignment of causes of death, non-AIDS mortality was twice as high among patients with an ADE compared to without an ADE. However, non-AIDS related mortality after an ADE depended on the ADE of interest. Although there may be unmeasured confounders, these findings suggest that a common pathway may be independently driving both ADEs and NADE mortality. While prevention of ADEs may reduce subsequent death due to NADEs following ART initiation, modification of risk factors for NADE mortality remains important after ADE survival. Keywords: AIDS-defining events; non-AIDS mortality; tuberculosis; Pneumocystis jiroveci pneumonia; non-Hodgkin's lymphoma; marginal structural model, 1 | INTRODUCTION In the era of antiretroviral therapy (ART), there have been striking decreases in acquired immune deficiency syndrome (AIDS)-related mortality [1-3] and prolongation of life expectancy [4-7] for [...]

It is important to account for timing of puberty when studying the adolescent brain and cognition. The use of classical methods for assessing pubertal status may not be feasible in some studies, especially in male adolescents. Using data from a sample of 478 males from a longitudinal birth cohort, we describe the calculations of three independent height-based markers of pubertal timing: Age at Peak Height Velocity (APHV), Height Difference in Standard Deviations (HDSDS), and Percent Achieved of Adult Stature (PAAS). These markers correlate well with each other. In a separate cross-sectional study, we show that the PAAS marker correlates well with testosterone levels and self-reported pubertal-stage scores. We conclude by discussing key considerations for investigators when drawing upon these methods of assessing pubertal timing.

Background Substantial reductions in adult mortality have been observed in South Africa since the mid-2000s, but there has been no formal evaluation of how much of this decline is attributable to the scale-up of antiretroviral treatment (ART), as previous models have not been calibrated to vital registration data. We developed a deterministic mathematical model to simulate the mortality trends that would have been expected in the absence of ART, and with earlier introduction of ART. Methods and findings Model estimates of mortality rates in ART patients were obtained from the International Epidemiology Databases to Evaluate AIDS-Southern Africa (IeDEA-SA) collaboration. The model was calibrated to HIV prevalence data (1997-2013) and mortality data from the South African vital registration system (1997-2014), using a Bayesian approach. In the 1985-2014 period, 2.70 million adult HIV-related deaths occurred in South Africa. Adult HIV deaths peaked at 231,000 per annum in 2006 and declined to 95,000 in 2014, a reduction of 74.7% (95% CI: 73.3%-76.1%) compared to the scenario without ART. However, HIV mortality in 2014 was estimated to be 69% (95% CI: 46%-97%) higher in 2014 (161,000) if the model was calibrated only to HIV prevalence data. In the 2000-2014 period, the South African ART programme is estimated to have reduced the cumulative number of HIV deaths in adults by 1.72 million (95% CI: 1.58 million-1.84 million) and to have saved 6.15 million life years in adults (95% CI: 5.52 million-6.69 million). This compares with a potential saving of 8.80 million (95% CI: 7.90 million-9.59 million) life years that might have been achieved if South Africa had moved swiftly to implement WHO guidelines (2004-2013) and had achieved high levels of ART uptake in HIV-diagnosed individuals from 2004 onwards. The model is limited by its reliance on all-cause mortality data, given the lack of reliable cause-of-death reporting, and also does not allow for changes over time in tuberculosis control programmes and ART effectiveness. Conclusions ART has had a dramatic impact on adult mortality in South Africa, but delays in the rollout of ART, especially in the early stages of the ART programme, have contributed to substantial loss of life. This is the first study to our knowledge to calibrate a model of ART impact to population-level recorded death data in Africa; models that are not calibrated to population-level death data may overestimate HIV-related mortality., Author(s): Leigh F. Johnson 1,*, Margaret T. May 2, Rob E. Dorrington 3, Morna Cornell 1, Andrew Boulle 1, Matthias Egger 1,4, Mary-Ann Davies 1 Introduction Substantial declines in adult [...]

Introduction: Response to antiretroviral therapy (ART) among individuals infected with HIV-2 is poorly described. We compared the immunological response among patients treated with three nucleoside reverse-transcriptase inhibitors (NRTIs) to boosted protease inhibitor (PI) and unboosted PI-based regimens in West Africa. Methods: This prospective cohort study enrolled treatment-naive HIV-2-infected patients within the International Epidemiological Databases to Evaluate AIDS collaboration in West Africa. We used mixed models to compare the CD4 count response to treatment over 12 months between regimens. Results: Of 422 HIV-2-infected patients, 285 (67.5%) were treated with a boosted PI-based regimen, 104 (24.6%) with an unboosted PI-based regimen and 33 (7.8%) with three NRTIs. Treatment groups were comparable with regard to gender (54.5% female) and median age at ART initiation (45.3 years; interquartile range 38.3 to 51.8).Treatment groups differed by clinical stage (21.2%, 16.8% and 17.3% at CDC Stage C or World Health Organization Stage IV for the triple NRTI, boosted PI and unboosted PI groups, respectively, p =0.02), median length of follow-up (12.9,17.7 and 44.0 months for the triple NRTI, the boosted PI and the unboosted PI groups, respectively, p Conclusions: In this observational study using African data, boosted PI-containing regimens had better immunological response compared to triple NRTI combinations and unboosted PI-based regimens at 12 months. A randomized clinical trial is still required to determine the best initial regimen for treating HIV-2 infected patients. Keywords: HIV-2; immunological response; antiretroviral treatment; linear mixed models; West Africa., Introduction Between one and two million people are estimated to be living with HIV-2 infection in West Africa [1], the region that is the epicentre of the HIV-2 epidemic, with [...]