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Background: Published 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 Findings: Children with perinatal HIV aged <18 years initiating cART were followed until their 21st birthday, transfer to adult care, death, loss to follow-up, or last visit up until 31 December 2013. Rates of death and first AIDS-defining events were calculated. Baseline and time-updated risk factors for early/late (≤/>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 <5 years had a CD4 lymphocyte percentage <15% in 1997-2003, which fell to 15% of children in 2011 onwards (p < 0.001). Similarly, 53% and 18% of children ≥5 years had a CD4 count <200 cells/mm3 in 1997-2003 and in 2011 onwards, respectively (p < 0.001). Median follow-up was 5.6 (2.9-8.7) years. Of 94 deaths and 237 first AIDS-defining events, 43 (46%) and 100 (42%) were within 6 months of initiating cART, respectively. Multivariable predictors of early death were: being in the first year of life; residence in Russia, Ukraine, or Thailand; AIDS at cART start; initiating cART on a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen; severe immune suppression; and low BMI-for-age z-score. Current severe immune suppression, low current BMI-for-age z-score, and current viral load >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.Conclusions: In 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. [ABSTRACT FROM AUTHOR]

Background: Data on determinants of long-term disease progression in HIV- infected patients on antiretroviral therapy (ART) are limited in low and middle- income settings. Methods: Effects of current CD4 count, viral load and haemoglobin and diagnosis of AIDS-defining events (ADEs) after start of combination ART (cART) on death and new ADEs were assessed using Poisson regression, in patient aged ≥18 years within a multi-centre cohort in Thailand. Results: Among 1,572 patients, median follow-up from cART initiation was 4.4 (IQR 3.6-6.3) years. The analysis of death was based on 60 events during 6,573 person-years; 30/50 (60%) deaths with underlying cause ascertained were attributable to infections. Analysis of new ADE included 192 events during 5,865 person-years; TB and Pneumocystis jiroveci pneumonia were the most commonly presented first new ADE (35% and 20% of cases, respectively). In multivariable analyses, low current CD4 count after starting cART was the strongest predictor of death and of new ADE. Even at CD4 above 200 cells/mm³, survival improved steadily with CD4, with mortality rare at ≥500 cells/mm³ (rate 1.1 per 1,000 person-years). Haemoglobin had a strong independent effect, while viral load was weakly predictive with poorer prognosis only observed at ≥100,000 copies/ml. Mortality risk increased following diagnosis of ADEs during cART. The decline in mortality rate with duration on cART (from 21.3 per 1,000 person- years within first 6 months to 4.7 per 1,000 person-years at ≥36 months) was accounted for by current CD4 count. Conclusions: Patients with low CD4 count or haemoglobin require more intensive diagnostic and treatment of underlying causes. Maintaining CD4≥500 cells/mm³ minimizes mortality. However, patient monitoring could potentially be relaxed at high CD4 count if resources are limited. Optimal ART monitoring strategies in low-income settings remain a research priority. Better understanding of the aetiology of anaemia in patients on ART could guide prevention and treatment. [ABSTRACT FROM AUTHOR]

Background: Data on determinants of long-term disease progression in HIV-infected patients on antiretroviral therapy (ART) are limited in low and middle-income settings. Methods: Effects of current CD4 count, viral load and haemoglobin and diagnosis of AIDS-defining events (ADEs) after start of combination ART (cART) on death and new ADEs were assessed using Poisson regression, in patient aged ≥18 years within a multi-centre cohort in Thailand. Results: Among 1,572 patients, median follow-up from cART initiation was 4.4 (IQR 3.6–6.3) years. The analysis of death was based on 60 events during 6,573 person-years; 30/50 (60%) deaths with underlying cause ascertained were attributable to infections. Analysis of new ADE included 192 events during 5,865 person-years; TB and Pneumocystis jiroveci pneumonia were the most commonly presented first new ADE (35% and 20% of cases, respectively). In multivariable analyses, low current CD4 count after starting cART was the strongest predictor of death and of new ADE. Even at CD4 above 200 cells/mm3, survival improved steadily with CD4, with mortality rare at ≥500 cells/mm3 (rate 1.1 per 1,000 person-years). Haemoglobin had a strong independent effect, while viral load was weakly predictive with poorer prognosis only observed at ≥100,000 copies/ml. Mortality risk increased following diagnosis of ADEs during cART. The decline in mortality rate with duration on cART (from 21.3 per 1,000 person-years within first 6 months to 4.7 per 1,000 person-years at ≥36 months) was accounted for by current CD4 count. Conclusions: Patients with low CD4 count or haemoglobin require more intensive diagnostic and treatment of underlying causes. Maintaining CD4≥500 cells/mm3 minimizes mortality. However, patient monitoring could potentially be relaxed at high CD4 count if resources are limited. Optimal ART monitoring strategies in low-income settings remain a research priority. Better understanding of the aetiology of anaemia in patients on ART could guide prevention and treatment.

Background: Data are scarce on the long-term clinical outcomes of perinatally HIV-infected children and adolescents receiving antiretroviral therapy (ART) in low/middle-income countries. We assessed the incidence of mortality before (early) and after (late) 6 months of ART and of the composite outcome of new/recurrent AIDS-defining event or death .6 months after ART start (late AIDS/death) and their associated factors. Methods: Study population was perinatally HIV-infected children (≤18 years) initiating ART within the Program for HIV Prevention and Treatment observational cohort (NCT00433030). Factors associated with late AIDS/death were assessed using competing risk regression models accounting for lost to-follow-up and included baseline and time-updated variables. Results: Among 619 children, "early" mortality incidence was 99 deaths per 1000 person-years of follow-up [95% confidence interval (CI): 69 to 142] and "late" mortality 6 per 1000 person-years of follow-up (95% CI: 4 to 9). Of the 553 children alive .6 months after ART initiation, median age at ART initiation was 6.4 years, CD4% 8.2%, and HIV-RNA load 5.1 log10 copies/mL. Thirty-eight (7%) children developed late AIDS/death after median time of 3.3 years: 24 died and 24 experienced new/recurrent AIDS-defining events (10 subsequently died). Factors independently associated with late AIDS/death were current age ≥13 years (adjusted subdistribution hazard ratio 4.9; 95% CI: 2.4 to 10.1), HIV-RNA load always ≥400 copies/mL (12.3; 95% CI: 4.0 to 37.6), BMI-z-score always <-2 SD (13.7; 95% CI: 3.4 to 55.7), and hemoglobin <8 g/dL at least once (4.6; 95% CI: 2.0 to 10.5). Conclusions: After the initial 6 months of ART, being an adolescent, persistent viremia, poor nutritional status, and severe anemia were associated with poor clinical outcomes. This supports the need for novel interventions that target children, particularly adolescents with poor growth and uncontrolled viremia. [ABSTRACT FROM AUTHOR]

Health-related quality of life (HRQL) is an important outcome in HIV/AIDS infection and treatment. However, most existing HIV-HRQL instruments miss important issues (eg, sleeping problems, lipodystrophy). They were developed before highly active antiretroviral therapy (pre-HAART), and in a single language. We sought to develop a contemporary HIV-HRQL instrument (PROQOL-HIV) in multiple languages that accounts for HAART treatment and side effects. This article details the 3-stage content validation phase of PROQOL-HIV.In stage 1, we developed a conceptual model of HIV-HRQL and questionnaire item bank from thematic analysis of 152 patient interviews conducted simultaneously across 9 countries. In stage 2, pilot items were selected by an expert panel to form the pilot instrument. Stage 3 involved linguistic validation and harmonization of selected items to form an equivalent instrument in 9 target languages.Analysis of 3375 pages of interview text revealed 11 underlying themes: general health perception, social relationships, emotions, energy/fatigue, sleep, cognitive functioning, physical and daily activity, coping, future, symptoms, and treatment. Seven issues new to HIV-HRQL measurement were subsumed by these themes: infection fears, future concerns, satisfaction with care, self-esteem problems, sleep problems, work disruption, and treatment issues. Of the 442 theme-related items banked, 70 items met the retention criteria and formed the pilot PROQOL-HIV instrument.HIV patients across 11 countries attributed a wide range of physical, mental, and social issues to their condition, many of which were not measured by existing HIV-HRQL instruments. The pilot PROQOL-HIV instrument captures these issues, is sensitive to sociocultural context, disease stage, and HAART. [ABSTRACT FROM AUTHOR]

Background: A single intrapartum dose of nevirapine for the prevention of mother-to-child transmission of human immunodeficiency virus (HIV) leads to the selection of resistance mutations. Whether there are clinically significant consequences in mothers who are subsequently treated with a nevirapine-containing regimen is unknown. Methods: We randomly assigned 1844 women in Thailand who received zidovudine during the third trimester of pregnancy to receive intrapartum nevirapine or placebo. In the postpartum period, 269 of the women with a CD4 count below 250 cells per cubic millimeter began a nevirapine-containing antiretroviral regimen. Plasma samples were obtained 10 days post partum and analyzed for resistance mutations. Plasma HIV type 1 (HIV-1) RNA was measured before the initiation of therapy and three and six months thereafter. Results: After six months of therapy, the HIV-1 RNA level was less than 50 copies per milliliter in 49 percent of the women who had received intrapartum nevirapine, as compared with 68 percent of the women who had not received intrapartum nevirapine (P=0.03). Resistance mutations to nonnucleoside reverse-transcriptase inhibitors were detectable in blood samples obtained 10 days post partum from 32 percent of the women who had received intrapartum nevirapine; the most frequent mutations were K103N, G190A, and Y181C. Among the women who had received intrapartum nevirapine, viral suppression was achieved at six months in 38 percent of those with resistance mutations and 52 percent of those without resistance mutations (P=0.08). An HIV-1 RNA level at or above the median of 4.53 log10 copies per milliliter before therapy and intrapartum exposure to nevirapine were independently associated with virologic failure. After six months of therapy, there was no significant difference between groups in the CD4 count (P=0.65). Conclusions: Women who received intrapartum nevirapine were less likely to have virologic suppression after six months of postpartum treatment with a nevirapine-containing regimen. Our data suggest the need for strategies to maximize the benefits of both antiretroviral prophylaxis against mother-to-child transmission of HIV and antiretroviral therapy for mothers. N Engl J Med 2004;351:229-40. [ABSTRACT FROM AUTHOR]

Background: Although zidovudine prophylaxis decreases the rate of transmission of the human immunodeficiency virus (HIV) type 1 substantially, a large number of infants still become infected. We hypothesized that the administration, in addition to zidovudine, of a single dose of oral nevirapine to mothers during labor and to neonates would further reduce transmission of HIV. Methods: We conducted a randomized, double-blind trial of three treatment regimens in Thai women who were receiving zidovudine therapy during the third trimester of pregnancy. In one group, mothers and infants received a single dose of nevirapine (nevirapine–nevirapine regimen); in another, mothers and infants received nevirapine and placebo, respectively (nevirapine–placebo regimen); and in the last, mothers and infants received placebo (placebo–placebo regimen). The infants also received one week of zidovudine therapy and were formula-fed. The end point of the study was infection with HIV in the infants, established by virologic testing. Results: Between January 15, 2001, and February 28, 2003, a total of 1844 Thai women were enrolled. At the first interim analysis, the independent data monitoring committee stopped enrollment in the placebo–placebo group. Among women who delivered before the interim analysis, the as-randomized Kaplan–Meier estimates of the transmission rates were 1.1 percent (95 percent confidence interval, 0.3 to 2.2) in the nevirapine–nevirapine group and 6.3 percent (95 percent confidence interval, 3.8 to 8.9) in the placebo–placebo group (P<0.001). The final per-protocol transmission rate in the nevirapine–nevirapine group, 1.9 percent (95 percent confidence interval, 0.9 to 3.0), was not significantly inferior to the rate in the nevirapine–placebo group (2.8 percent; 95 percent confidence interval, 1.5 to 4.1). Nevirapine had an effect within subgroups defined by known risk factors such as viral load and CD4 count. No serious adverse effects were associated with nevirapine therapy. Conclusions: A single dose of nevirapine to the mother, with or without a dose of nevirapine to the infant, added to oral zidovudine prophylaxis starting at 28 weeks' gestation, is highly effective in reducing mother-to-child transmission of HIV. N Engl J Med 2004;351:217-28. [ABSTRACT FROM AUTHOR]