The Bayesian approach to finding the maximum-tolerated dose in phase I cancer trials is discussed. The suggested approach relies on a realistic dose-toxicity model, allows one to include prior information, and supports clinical decision making by presenting within-trial information in a transparent way. The modeling and decision-making components are flexible enough to be extendable to more complex settings. Critical aspects are emphasized and a comparison with the continual reassessment method (CRM) is performed with data from an actual trial and a simulation study. The comparison revealed similar operating characteristics while avoiding some of the difficulties encountered in the actual trial when applying the CRM.

In the SHCS, HCV infection incidence decreased in IDU, remained stable in HET, and increased 18-fold in MSM in the last 13 years. These observations underscore the need for improved HCV surveillance and prevention among HIV-infected MSM.

Objectives To assess the proportion of patients lost to programme (died, lost to follow-up, transferred-out) between HIV diagnosis and start of antiretroviral therapy (ART) in sub-Saharan Africa, and determine factors associated with loss to programme. Methods Systematic review and meta-analysis. We searched PubMed and EMBASE databases for studies in adults. Outcomes were the percentage of patients dying before starting ART, the percentage lost to follow-up, the percentage with a CD4 cell count, the distribution of first CD4 counts and the percentage of eligible patients starting ART. Data were combined using random-effects meta-analysis. Results 29 studies from sub-Saharan Africa including 148,912 patients were analysed. 6 studies covered the whole period from HIV diagnosis to ART start. Meta-analysis of these studies showed that of 100 patients with a positive HIV test, 72 (95% CI 60–84) had a CD4 cell count measured, 40 (95% CI 26–55) were eligible for ART and 25 (95% CI 13–37) started ART. There was substantial heterogeneity between studies (p<0.0001). Median CD4 cell count at presentation ranged from 154 cells/μl to 274 cells/μl. Patients eligible for ART were less likely to become lost to programme (25% versus 54%, p<0.0001) but eligible patients were more likely to die (11% versus 5%, p<0.0001) than ineligible patients. Loss to programme was higher in men, in patients with low CD4 cell counts and low socio-economic status, and in recent time periods. Conclusions Monitoring and care in the pre-ART time period needs improvement, with greater emphasis on patients not yet eligible for ART.

Objectives To compare outcomes of antiretroviral therapy (ART) in South Africa, where viral load monitoring is routine, with 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 starting 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 multi-state models, measuring time from six months. Findings In South Africa 9.8% (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% (8.5–9.8%) were lost to follow-up and 4.3% (3.9–4.8%) had died. In Malawi and Zambia more patients were on a failing first-line regimen (3.7%, 3.6–3.9%), fewer patients had switched (2.1%, 2.0–2.3%) and more patients were lost (15.3%, 15.0–15.6%) or had died (6.3%, 6.0–6.5%). Median CD4 cell counts were lower in South Africa at start of ART (93 vs. 132 cells/µL, p<0.001) but higher after 3 years (425 vs. 383 cells/µL, p<0.001). The hazard ratio comparing South Africa with Malawi and Zambia, adjusted for age, sex, first-line regimen and CD4 cell count, was 0.58 (95% CI 0.50–0.66) for death and 0.53 (0.48–0.58) for loss to follow-up. Conclusions Over 3 years of ART mortality was lower in South Africa than in Malawi or Zambia. The more favourable outcome in South Africa might be explained by viral load monitoring leading to earlier detection of treatment failure, adherence counselling and timelier switching to second-line ART.

Objectives To describe the CD4 cell count at the start of combination antiretroviral therapy (cART) in low-income (LIC), lower middle-income (LMIC), upper middle-income (UMIC) and high-income (HIC) countries. Methods Patients aged ≥16 years starting cART in a clinic participating in a multi-cohort collaboration spanning six continents (International epidemiological Databases to Evaluate AIDS and ART Cohort Collaboration) were eligible. Multi-level linear regression models were adjusted for age, gender and calendar year; missing CD4 counts were imputed. Findings 379,865 patients from nine LIC, four LMIC, four UMIC and six HIC were included. In LIC the median CD4 cell count at cART initiation increased by 83% from 80 to 145 cells/μl between 2002 and 2009. Corresponding increases in LMIC, UMIC and HIC were from 87 to 155 cells/μl (76% increase), 88 to 135 cells/μl (53%) and 209 to 274 cells/μl (31%). In 2009, compared to LIC, median counts were 13 cells/μl (95% CI -56 to +30) lower in LMIC, 22 cells/μl (-62 to +18) lower in UMIC and 112 /μl (+75 to +149) higher in HIC. They were 23 cells/μl (95% CI +18 to +28) higher in women than men. Median counts were 88 cells/μl (95% CI +35 to +141) higher in countries with an estimated national cART coverage >80%, compared to countries with <40% coverage. Conclusions Median CD4 cell counts at start of cART increased 2000-2009 but remained below 200 cells/μl in LIC and MIC and below 300 cells/μl in HIC. Earlier start of cART will require substantial efforts and resources globally.

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<0.0001). This association remained when adjusting for frequent travelling, contact with foreigners, age, sex, and country of birth (adjusted OR 5.6, 95% CI 1.5–20.8, p = 0.01). Moreover, it became stronger with greater immunosuppression as defined by CD4 T-cell depletion and was not the result of increased social mixing in HIV–infected patients. Our observation was replicated in a second independent panel of 440 M. tuberculosis strains collected during a population-based study in the Canton of Bern between 1991 and 2011. In summary, these findings support a model for TB in which the stable relationship between the human host and its locally adapted M. tuberculosis is disrupted by HIV infection.

Summary 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 <15 years who started ART between January 2001 and December 2006 were included and followed until March 2008. Weight and height were measured at regular intervals from 1 year before to 2 years after the start of ART. Sex- and age-standardized z-scores were calculated for weight-for-age (WAZ) and height-for-age (HAZ). Predictors of growth were identified in multivariable mixed-effect models. Results A total of 497 children started ART and were followed for 972 person-years. Median age (inter-quartile range; IQR) was 8 years (4 to 11 years). Most children were underweight (52% of children), stunted (69%), in advanced clinical stages (94% in WHO stages 3 or 4) and had severe immunodeficiency (77%). After starting ART median (IQR) WAZ and HAZ increased from −2.1 (−2.7 to −1.3) and −2.6 (−3.6 to −1.8) to −1.4 (−2.1 to −0.8) and −1.8 (−2.4 to −1.1) at 24 months, respectively (p<0.001). In multivariable models, baseline WAZ and HAZ scores were the most important determinants of growth trajectories on ART. Conclusions Despite a sustained growth response to ART among children remaining on therapy, normal values were not reached. Interventions leading to earlier HIV diagnosis and initiation of treatment could improve growth response.

Bayesian approaches to the monitoring of group sequential designs have two main advantages compared with classical group sequential designs: first, they facilitate implementation of interim success and futility criteria that are tailored to the subsequent decision making, and second, they allow inclusion of prior information on the treatment difference and on the control group. A general class of Bayesian group sequential designs is presented, where multiple criteria based on the posterior distribution can be defined to reflect clinically meaningful decision criteria on whether to stop or continue the trial at the interim analyses. To evaluate the frequentist operating characteristics of these designs, both simulation methods and numerical integration methods are proposed, as implemented in the corresponding R package gsbDesign. Normal approximations are used to allow fast calculation of these characteristics for various endpoints. The practical implementation of the approach is illustrated with several clinical trial examples from different phases of drug development, with various endpoints, and informative priors.