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Hepatitis B virus (HBV) infection is a major cause of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients worldwide. It is unclear whether HIV-related outcomes are affected by HBV coinfection. We compared virological suppression and immunological recovery during antiretroviral therapy (ART) of patients of different HBV serological status in the Swiss HIV Cohort Study. CD4 cell recovery during ART was significantly impaired in hepatitis B surface antigen-positive patients and in those with anti-hepatitis B core antigen alone compared with HBV-uninfected patients, despite similar virological efficacy of ART. CD4 increase in patients with resolved HBV infection was similar to that in HBV-uninfected individuals

OBJECTIVES To identify factors associated with discrepant outcome reporting in randomized drug trials. STUDY DESIGN AND SETTING Cohort study of protocols submitted to a Swiss ethics committee 1988-1998: 227 protocols and amendments were compared with 333 matching articles published during 1990-2008. Discrepant reporting was defined as addition, omission, or reclassification of outcomes. RESULTS Overall, 870 of 2,966 unique outcomes were reported discrepantly (29.3%). Among protocol-defined primary outcomes, 6.9% were not reported (19 of 274), whereas 10.4% of reported outcomes (30 of 288) were not defined in the protocol. Corresponding percentages for secondary outcomes were 19.0% (284 of 1,495) and 14.1% (334 of 2,375). Discrepant reporting was more likely if P values were

OBJECTIVES Zidovudine (ZDV) is recommended for first-line antiretroviral therapy (ART) in resource-limited settings. ZDV may, however, lead to anemia and impaired immunological response. We compared CD4+ cell counts over 5 years between patients starting ART with and without ZDV in southern Africa. DESIGN Cohort study. METHODS Patients aged at least 16 years who started first-line ART in South Africa, Botswana, Zambia, or Lesotho were included. We used linear mixed-effect models to compare CD4+ cell count trajectories between patients on ZDV-containing regimens and patients on other regimens, censoring follow-up at first treatment change. Impaired immunological recovery, defined as a CD4+ cell count below 100 cells/μl at 1 year, was assessed in logistic regression. Analyses were adjusted for baseline CD4+ cell count and hemoglobin level, age, sex, type of regimen, viral load monitoring, and calendar year. RESULTS A total of 72,597 patients starting ART, including 19,758 (27.2%) on ZDV, were analyzed. Patients on ZDV had higher CD4+ cell counts (150 vs.128 cells/μl) and hemoglobin level (12.0 vs. 11.0 g/dl) at baseline, and were less likely to be women than those on other regimens. Adjusted differences in CD4+ cell counts between regimens containing and not containing ZDV were -16 cells/μl [95% confidence interval (CI) -18 to -14] at 1 year and -56 cells/μl (95% CI -59 to -52) at 5 years. Impaired immunological recovery was more likely with ZDV compared to other regimens (odds ratio 1.40, 95% CI 1.22-1.61). CONCLUSION In southern Africa, ZDV is associated with inferior immunological recovery compared to other backbones. Replacing ZDV with another nucleoside reverse transcriptase inhibitor could avoid unnecessary switches to second-line ART.

BACKGROUND: Hepatitis C virus (HCV) infection has a growing impact on morbidity and mortality in patients infected with human immunodeficiency virus (HIV). We assessed trends in HCV incidence in the different HIV transmission groups in the Swiss HIV Cohort Study (SHCS). METHODS: HCV infection incidence was assessed from 1998, when routine serial HCV screening was introduced in the SHCS, until 2011. All HCV-seronegative patients with at least 1 follow-up serology were included. Incidence rates (IRs) of HCV infections were compared between men who have sex with men (MSM), injection drug users (IDU), and heterosexuals (HET). RESULTS: HCV incidence was assessed in 3333 MSM, 123 IDU, and 3078 HET with a negative HCV serology at baseline. Over 23 707 person-years (py) for MSM, 733 py for IDU, and 20 752 py for HET, 101 (3%), 41 (33%), and 25 (1%) of patients seroconverted, respectively. The IR of HCV infections in MSM increased from 0.23 (95% credible interval [CrI], .08-.54) per 100 py in 1998 to 4.09 (95% CrI, 2.57-6.18) in 2011. The IR decreased in IDU and remained

Objective To provide estimates of mortality among HIV-infected patients starting combination antiretroviral therapy. Methods We report on the death rates from 122 925 adult HIV-infected patients aged 15 years or older from East, Southern and West Africa, Asia Pacific and Latin America. We use two methods to adjust for biases in mortality estimation resulting from loss from follow-up, based on double-sampling methods applied to patient outreach (Kenya) and linkage with vital registries (South Africa), and apply these to mortality estimates in the other three regions. Age, gender and CD4 count at the initiation of therapy were the factors considered as predictors of mortality at 6, 12, 24 and >24 months after the start of treatment. Results Patient mortality was high during the first 6 months after therapy for all patient subgroups and exceeded 40 per 100 patient years among patients who started treatment at low CD4 count. This trend was seen regardless of region, demographic or disease-related risk factor. Mortality was under-reported by up to or exceeding 100% when comparing estimates obtained from passive monitoring of patient vital status. Conclusions Despite advances in antiretroviral treatment coverage many patients start treatment at very low CD4 counts and experience significant mortality during the first 6 months after treatment initiation. Active patient tracing and linkage with vital registries are critical in adjusting estimates of mortality, particularly in low- and middle-income settings.

Objetivo: La desnutrición es común entre niños infectados con VIH en África y es un indicador para iniciar tratamiento antirretroviral (TAR). Hemos examinado el estado antropométrico en respuesta al TAR en niños tratados en una clínica del sector público de Malawi. Métodos: Todos los niños, Objective Malnutrition is common in HIV-infected children in Africa and an indication for antiretroviral treatment (ART). We examined anthropometric status and response to ART in children treated at a large public-sector clinic in Malawi. Methods All children aged, Objectif: La malnutrition est fréquente chez les enfants infectés par le VIH en Afrique et est une indication pour le traitement antirétroviral (ART). Nous avons examiné le statut anthropométrique et la réponse au traitement ART chez les enfants dans une grande clinique du secteur publique au Malawi. Méthodes: Tous les enfants âgés de < 15 ans qui ont commencé l’ART entre janvier 2001 et décembre 2006 ont été inclus et suivis jusqu’en mars 2008. Le poids et taille ont été mesurés à intervalles réguliers à partir de 1 an avant à 2 ans après le début de l’ART. Les scores Z normalisés selon le sexe et l’âge ont été calculés pour le poids pour l’âge (WAZ) et la taille pour l’âge (HAZ). Les prédicteurs de la croissance ont été identifiés dans des modèles multivariés à effets mixtes. Résultats: Un total de 497 enfants ont commencé l’ART et ont été suivis pendant 972 personnes-années. L’âge médian (intervalle interquartile; IQR) était de 8 ans (4 à 11 ans). La plupart (52%) des enfants souffraient d’insuffisance pondérale, d’un retard de croissance (69%), étaient aux stades cliniques avancés (94% aux stades OMS 3 ou 4) et avaient une immunodéficience sévère (77%). Après le commencement de l’ART, le WAZ (IQR) et HAZ médians ont augmenté, passant de -2,1 (-2,7 à -1,3) et -2,6 (-3,6 à -1.8) à -1,4 (-2,1 à -0,8) et -1,8 (-2,4 à -1.1) au 24ème mois, respectivement (p

BACKGROUND There is debate over using tenofovir or zidovudine alongside lamivudine in second-line antiretroviral therapy (ART) following stavudine failure. We analyzed outcomes in cohorts from South Africa, Zambia and Zimbabwe METHODS: Patients aged ≥16 years who switched from a first-line regimen including stavudine to a ritonavir-boosted lopinavir-based second-line regimen with lamivudine or emtricitabine and zidovudine or tenofovir in seven ART programs in southern Africa were included. We estimated the causal effect of receiving tenofovir or zidovudine on mortality and virological failure using Cox proportional hazards marginal structural models. Its parameters were estimated using inverse probability of treatment weights. Baseline characteristics were age, sex, calendar year and country. CD4 cell count, creatinine and hemoglobin levels were included as time-dependent confounders. RESULTS 1,256 patients on second-line ART, including 958 on tenofovir, were analyzed. Patients on tenofovir were more likely to have switched to second-line ART in recent years, spent more time on first-line ART (33 vs. 24 months) and had lower CD4 cell counts (172 vs. 341 cells/μl) at initiation of second-line ART. The adjusted hazard ratio comparing tenofovir with zidovudine was 1.00 (95% confidence interval 0.59-1.68) for virologic failure and 1.40 (0.57-3.41) for death. CONCLUSIONS We did not find any difference in treatment outcomes between patients on tenofovir or zidovudine; however, the precision of our estimates was limited. There is an urgent need for randomized trials to inform second-line ART strategies in resource-limited settings.

The two-way plot is a well-known tool to visualize the fit of a two-way table. An additive fit can be represented by two sets of parallel traces, whose intersection ordinates equal the fitted values. Based on linear traces, a variety of other two-way plots were investigated recently. In this work we present two-way plots based on general traces. We show that the resulting fits equal the ones using linear traces. Hence, we also study mixed traces: hyperbolic ones to represent the columns and linear ones to represent the rows of a two-way table.

BACKGROUND There is limited evidence on the optimal timing of antiretroviral therapy (ART) initiation in children 2-5 y of age. We conducted a causal modelling analysis using the International Epidemiologic Databases to Evaluate AIDS-Southern Africa (IeDEA-SA) collaborative dataset to determine the difference in mortality when starting ART in children aged 2-5 y immediately (irrespective of CD4 criteria), as recommended in the World Health Organization (WHO) 2013 guidelines, compared to deferring to lower CD4 thresholds, for example, the WHO 2010 recommended threshold of CD4 count

The phylogeographic population structure of Mycobacterium tuberculosis suggests local adaptation to sympatric human populations. We hypothesized that HIV infection, which induces immunodeficiency, will alter the sympatric relationship between M. tuberculosis and its human host. To test this hypothesis, we performed a nine-year nation-wide molecular-epidemiological study of HIV-infected and HIV-negative patients with tuberculosis (TB) between 2000 and 2008 in Switzerland. We analyzed 518 TB patients of whom 112 (21.6%) were HIV-infected and 233 (45.0%) were born in Europe. We found that among European-born TB patients, recent transmission was more likely to occur in sympatric compared to allopatric host-pathogen combinations (adjusted odds ratio [OR] 7.5, 95% confidence interval [95% CI] 1.21-infinity, p = 0.03). HIV infection was significantly associated with TB caused by an allopatric (as opposed to sympatric) M. tuberculosis lineage (OR 7.0, 95% CI 2.5-19.1, p

Objectives: To compare outcomes of antiretroviral therapy (ART) in South Africa, where viral load monitoring is routine, with those in Malawi and Zambia, where monitoring is based on CD4 cell counts. Methods: We included 18 706 adult patients starting ART in South Africa and 80 937 patients in Zambia or Malawi. We examined CD4 responses in models for repeated measures and the probability of switching to second-line regimens, mortality and loss to follow-up in multistate models, measuring time from 6 months. Results: In South Africa, 9.8% [95% confidence interval (CI) 9.1–10.5] had switched at 3 years, 1.3% (95% CI 0.9–1.6) remained on failing first-line regimens, 9.2% (95% CI 8.5–9.8) were lost to follow-up and 4.3% (95% CI 3.9–4.8) had died. In Malawi and Zambia, more patients were on a failing first-line regimen [3.7% (95% CI 3.6–3.9], fewer patients had switched [2.1% (95% CI 2.0–2.3)] and more patients were lost to follow-up [15.3% (95% CI 15.0–15.6)] or had died [6.3% (95% CI 6.0–6.5)]. Median CD4 cell counts were lower in South Africa at the start of ART (93 vs. 132 cells/μl; P

The standard Kalman filter is a powerful and widely used tool to perform prediction, filtering and smoothing in the fields of linear Gaussian state-space models. In its standard setting it has a simple recursive form which implies high computational efficiency. As the latter is essentially a least squares procedure optimality properties can be derived easily. These characteristics of the standard Kalman filter depend strongly on distributional and linearity assumptions of the model. If we consider nonlinear non-Gaussian state-space models all these properties and characteristics are no longer valid. Consequently there are different approaches on the robustification of the Kalman filter. One is based on the the ideas of minimax problems and influence curves. Others use numerical integration and Monte Carlo methods. Herein we propose a new filter by implementing a method of numerical integration, called scrambled net quadrature, which consists of a mixture of Monte Carlo methods and quasi-Monte Carlo methods, providing an integration error of order of magnitude $N^{-3/2}\log(N)^{(r-1)/2}$ in probability, where $r$ denotes dimension. We show that the point-wise bias of the posterior density estimate is of order of magnitude $N^{-3}\log(N)^{r-1}$ but grows linearly with time.

Mortality in patients starting antiretroviral therapy (ART) is higher in Malawi and Zambia than in South Africa. We examined whether different monitoring of ART (viral load [VL] in South Africa and CD4 count in Malawi and Zambia) could explain this mortality difference.

In time series analysis state-space models provide a wide and flexible class. The basic idea is to describe an unobservable phenomenon of interest on the basis of noisy data. The first constituent of such a model is the so-called state equation, which characterises the unobserved state of the system. The second part is the so-called observation equation, which describes the observable variables as a function of the unobserved state. The purpose of the analysis of state-space models is to infer the relevant properties of the unobserved phenomenon from the observed data. A powerful tool to do so in the linear Gaussian setting is the Kalman filter. It provides a simple recursive computational scheme for the conditional expectation of the unobserved state given the observed data. However, since the Kalman filter is is linear in the data it is sensitive to outlying observations. A certain robustness of the procedure can easily be achieved by abandoning the Gaussianity assumption. On the other hand, the assumption of linearity is frequently found to be inadequate in practical situations and therefore needs to be generalised as well. However, without linearity and Gaussianity the simple recursive formulae of the Kalman filter are lost and the recursive computation of the conditional expectation must be replaced by approximations of ratios of high dimensional integral. Numerical and Monte Carlo integration techniques have been proposed for this purpose. The former yield powerful tools in low dimensional problems but suffer in high dimensional settings from the resulting computational burden. On the other hand Monte Carlo integration techniques lead to so-called particle filters, which provide computationally attractive tools even applicable in high dimensional problems. Although particle filters have some appealing properties they are not entirely convincing: the approximation error is relatively large; outliers may significantly affect the computational efficiency and in practical situations it is often very difficult to tune them adequately. Hence, we propose to adopt another integration method, the so-called scrambled net integration – a hybrid of numerical and Monte Carlo integration techniques. For the non-iterative approximation of integrals, this method has been proven to be often much more accurate than Monte Carlo methods as well as to deal well with the computational burden in high dimensions. We implement scrambled net integration in the general Kalman recursions and derive new prediction, filtering and smoothing algorithms. Further, we show that the approximation error remains stable during iterations and that the accuracy of the resulting state estimates is higher than that of particle filters. The resulting algorithms are more robust than the particle filter algorithm since their computational complexity is not influenced by outlying observations. In addition, we prove a central limit theorem for the estimator of the filter's expectation. Scrambled nets can also be used for hyper-parameter estimation since the likelihood of a general state-space model is a byproduct of the general Kalman recursions. They not only provide an approximation to the likelihood function but also a suitable grid over which it is maximised. The resulting estimation procedure is particularly attractive when dealing with high dimensional hyper-parameter spaces. Finally, one of the main difficulties when studying the properties of an unobserved phenomenon is designing a good general state-space model. Besides the determination of state and observation equations the problem of choosing appropriate noise distributions is crucial since they express the inherent uncertainty of the model used. From a practical point of view it is frequently completely unclear how to choose these noise distributions. Rather than relying on an uneducated guess of a single distributional model we propose to use several fundamentally different distributions and derive an adaptive filter providing a data-driven approach, which is naturally robust with respect to deviations from a distributional model.