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BackgroundGlobally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia.Methods and findingsThrough the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria.ConclusionTo our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.

BackgroundPublished estimates of mortality and progression to AIDS as children with HIV approach adulthood are limited. We describe rates and risk factors for death and AIDS-defining events in children and adolescents after initiation of combination antiretroviral therapy (cART) in 17 middle- and high-income countries, including some in Western and Central Europe (W&CE), Eastern Europe (Russia and Ukraine), and Thailand.Methods and findingsChildren with perinatal HIV aged 6 months of cART) death and progression to AIDS were assessed. Of 3,526 children included, 32% were from the United Kingdom or Ireland, 30% from elsewhere in W&CE, 18% from Russia or Ukraine, and 20% from Thailand. At cART initiation, median age was 5.2 (IQR 1.4-9.3) years; 35% of children aged 400 c/mL predicted late death. Predictors of early and late progression to AIDS were similar. Study limitations include incomplete recording of US Centers for Disease Control (CDC) disease stage B events and serious adverse events in some countries; events that were distributed over a long time period, and that we lacked power to analyse trends in patterns and causes of death over time.ConclusionsIn our study, 3,526 children and adolescents with perinatal HIV infection initiated antiretroviral therapy (ART) in countries in Europe and Thailand. We observed that over 40% of deaths occurred ≤6 months after cART initiation. Greater early mortality risk in infants, as compared to older children, and in Russia, Ukraine, or Thailand as compared to W&CE, raises concern. Current severe immune suppression, being underweight, and unsuppressed viral load were associated with a higher risk of death at >6 months after initiation of cART.

BackgroundThe study aimed to assess the feasibility of conducting large scale HIV prevention clinical trials in Mozambique by measuring HIV prevalence and incidence among women of reproductive age. This paper describes the baseline socio-demographic characteristics of the Mozambique Microbicides Development Programme (MDP) feasibility cohort, baseline prevalence of HIV and other STIs, and HIV incidence.MethodsThe Mozambique MDP feasibility study was conducted from September 2007 to August 2009 in urban Mavalane and rural Manhiça, in Southern Mozambique. Sexually active, HIV negative women aged 18 years and above were recruited to attend the study clinic every 4 weeks for a total of 40 weeks. At baseline, we collected demographic and sexual behaviour data, samples to test for sexually transmitted infections (STI) and conducted HIV rapid testing. STI and HIV testing were repeated at clinical follow-up visits. We describe HIV prevalence of women at screening, the demographic, behavioural and clinical characteristics of women at enrolment, and HIV incidence during follow-up.ResultsWe screened 793 women (369 at Mavalane and 424 at Manhiça) and enrolled 505 eligible women (254 at Mavalane and 251 at Manhiça). Overall HIV prevalence at screening was 17%; 10% at Mavalane and 22% at Manhiça. Women screened at Manhiça were twice as likely as women screened at Mavalane to be HIV positive and HIV positive status was associated with younger age (18-34), lower educational level, not using a reliable method of contraception and being Zionist compared to other Christian religions. At enrolment contraceptive use was low in both clinics at 19% in Mavalane and 21% in Manhiça, as was reported condom use at last sex act at 48% in Mavalane and 25% in Manhiça. At enrolment, 8% of women tested positive for Trichomonas vaginalis, 2% for Neisseria gonorrhoeae, 4% for Chlamydia trachomatis and 46% for bacterial vaginosis. In Manhiça, 8% of women had active syphilis at screening. HIV incidence was 4.3 per 100 person years at Mavalane and 9.2 per 100 person years at Manhiça.ConclusionsWe demonstrated the ability to recruit a cohort of women at risk of HIV who were willing to participate in clinical research. The high HIV incidence necessitates additional action around HIV prevention for women and offers opportunities to evaluate the impact of available prevention options, such as treatment as prevention and oral PrEP. The high HIV incidence and STI prevalence also offers opportunities to evaluate the added benefit of potential prevention options such as new formulations of oral PrEP, vaginal microbicides (also called topical PrEP), vaccines, and multi-purpose technologies for HIV, STIs and contraception.

[This corrects the article DOI: 10.1371/journal.pone.0137834.].

BackgroundMajor protease mutations are rarely observed following failure with protease inhibitors (PI), and other viral determinants of failure to PI are poorly understood. We therefore characterized Gag-Protease phenotypic susceptibility in subtype A and D viruses circulating in East Africa following viral rebound on PIs.MethodsSamples from baseline and treatment failure in patients enrolled in the second line LPV/r trial SARA underwent phenotypic susceptibility testing. Data were expressed as fold-change in susceptibility relative to a LPV-susceptible reference strain.ResultsWe cloned 48 Gag-Protease containing sequences from seven individuals and performed drug resistance phenotyping from pre-PI and treatment failure timepoints in seven patients. For the six patients where major protease inhibitor resistance mutations did not emerge, mean fold-change EC50 to LPV was 4.07 fold (95% CI, 2.08-6.07) at the pre-PI timepoint. Following viral failure the mean fold-change in EC50 to LPV was 4.25 fold (95% CI, 1.39-7.11, p = 0.91). All viruses remained susceptible to DRV. In our assay system, the major PI resistance mutation I84V, which emerged in one individual, conferred a 10.5-fold reduction in LPV susceptibility. One of the six patients exhibited a significant reduction in susceptibility between pre-PI and failure timepoints (from 4.7 fold to 9.6 fold) in the absence of known major mutations in protease, but associated with changes in Gag: V7I, G49D, R69Q, A120D, Q127K, N375S and I462S. Phylogenetic analysis provided evidence of the emergence of genetically distinct viruses at the time of treatment failure, indicating ongoing viral evolution in Gag-protease under PI pressure.ConclusionsHere we observe in one patient the development of significantly reduced susceptibility conferred by changes in Gag which may have contributed to treatment failure on a protease inhibitor containing regimen. Further phenotype-genotype studies are required to elucidate genetic determinants of protease inhibitor failure in those who fail without traditional resistance mutations whilst PI use is being scaled up globally.

Guidance is needed on best medical management for advanced HIV disease with multidrug resistance (MDR) and limited retreatment options. We assessed two novel antiretroviral (ARV) treatment approaches in this setting.We conducted a 2×2 factorial randomized open label controlled trial in patients with a CD4 count≤300 cells/µl who had ARV treatment (ART) failure requiring retreatment, to two options (a) re-treatment with either standard (≤4 ARVs) or intensive (≥5 ARVs) ART and b) either treatment starting immediately or after a 12-week monitored ART interruption. Primary outcome was time to developing a first AIDS-defining event (ADE) or death from any cause. Analysis was by intention to treat. From 2001 to 2006, 368 patients were randomized. At baseline, mean age was 48 years, 2% were women, median CD4 count was 106/µl, mean viral load was 4.74 log(10) copies/ml, and 59% had a prior AIDS diagnosis. Median follow-up was 4.0 years in 1249 person-years of observation. There were no statistically significant differences in the primary composite outcome of ADE or death between re-treatment options of standard versus intensive ART (hazard ratio 1.17; CI 0.86-1.59), or between immediate retreatment initiation versus interruption before re-treatment (hazard ratio 0.93; CI 0.68-1.30), or in the rate of non-HIV associated serious adverse events between re-treatment options.We did not observe clinical benefit or harm assessed by the primary outcome in this largest and longest trial exploring both ART interruption and intensification in advanced MDR HIV infection with poor retreatment options.Clinicaltrials.gov NCT00050089.