Search

Background: Existing studies have suggested decreased adherence and rebound in mortality in perinatally HIV-infected adolescents receiving antiretroviral therapy (ART) as compared to adults and young children. Methods: We used both quantitative and qualitative approaches to identify factors influencing adherence among perinatally infected adolescents in Thailand. We analyzed data from 568 pairs of perinatally infected adolescents (aged 12–19) and their primary caregivers in the Teens Living With Antiretrovirals (TEEWA) study, a cross-sectional survey conducted in 2010–2012. We also conducted 12 in-depth interviews in 2014 with infected adolescents or their primary caregivers to elicit experiences of living with long-term ART. Results: From the quantitative analysis, a total of 275 (48.4%) adolescents had evidence of suboptimal adherence based on this composite outcome: adolescents self-reported missing doses in the past 7 days, caregiver rating of overall adherence as suboptimal, or latest HIV-RNA viral load ≥1000 copies/ml. In multivariate logistic regression analysis, younger age, having grandparents or extended family members as the primary caregiver, caregiver-assessed poor intellectual ability, having a boy/girlfriend, frequent online chatting, self-reported unhappiness and easiness in asking doctors questions were significantly associated with suboptimal adherence. From the in-depth interviews, tensed relationships with caregivers, forgetfulness due to busy schedules, and fear of disclosing HIV status to others, especially boy/girlfriends, were important contributors to suboptimal adherence. Social and emotional support and counseling from peer group was consistently reported as a strong adherence-promoting factor. Conclusion: Our findings highlight unique barriers of ART adherence among the perinatally infected adolescents. Future interventions should be targeted at helping adolescents to improve interpersonal relationships and build adaptive skills in recognizing and addressing challenging situations related to ART taking.

Background: Human immunodeficiency virus (HIV)–infected pregnant women increasingly receive antiretroviral therapy (ART) to prevent mother-to-child transmission (PMTCT). Studies suggest HIV-exposed uninfected (HEU) children face higher mortality than HIV-unexposed children, but most evidence relates to the pre-ART era, breastfeeding of limited duration, and considerable maternal mortality. Maternal ART and prolonged breastfeeding while on ART may improve survival, although this has not been reliably quantified. Methods: Individual data on 19 219 HEU children from 21 PMTCT trials/cohorts undertaken from 1995 to 2015 in Africa and Asia were pooled to estimate the association between 24-month mortality and maternal/infant factors, using random-effects Cox proportional hazards models. Adjusted attributable fractions of risks computed using the predict function in the R package “frailtypack” were used to estimate the relative contribution of risk factors to overall mortality. Results: Cumulative incidence of death was 5.5% (95% confidence interval, 5.1–5.9) by age 24 months. Low birth weight (LBW <2500 g, adjusted hazard ratio (aHR, 2.9), no breastfeeding (aHR, 2.5), and maternal death (aHR, 11.1) were significantly associated with increased mortality. Maternal ART (aHR, 0.5) was significantly associated with lower mortality. At the population level, LBW accounted for 16.2% of 24-month mortality, never breastfeeding for 10.8%, mother not receiving ART for 45.6%, and maternal death for 4.3%; combined, these factors explained 63.6% of deaths by age 24 months. Conclusions: Survival of HEU children could be substantially improved if public health practices provided all HIV-infected mothers with ART and supported optimal infant feeding and care for LBW neonates.

: Using a randomized controlled trial, Marc Lallemant and colleagues ask if a CD4-based monitoring and treatment switching strategy provides a similar clinical outcome compared to the standard viral load-based strategy for adults with HIV in Thailand. Please see later in the article for the Editors' Summary [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]

Thailand has been severely affected by AIDS/HIV. The epidemic has undermined the health of the population of working age, placing stress on intergenerational relations and threatening the social fabric. Older people in families affected by the disease, although not the main victims, have experienced major changes in relationships with their adult children and grandchildren. However, the availability of antiretrovirals has transformed HIV infection from a lethal to a chronic disease. Intergenerational relationships are analysed with data from a quantitative survey of HIV-infected adults currently receiving antiretroviral treatment in Northern Thailand. The introduction of antiretroviral treatment has eased the pressure on families. Where HIV-infected adults are more dependent on their older parents, it is because they are single and childless or single parents. While ageing parents remain a source of support for their adult children, the introduction of antiretroviral treatment has radically changed the prospects for HIV-infected adults and their regained health allows them to work, take care of their family and fulfil their filial duties as expected in Thai society. If Thailand's original aim in introducing health policies in this area was to curtail the HIV epidemic, its positive impact on intergenerational relations is an additional benefit. [ABSTRACT FROM AUTHOR]

Objectives: To respond to the primary safety objective of the Perinatal HIV Prevention Trial 1 (PHPT-1) by studying the evolution of haematological parameters according to zidovudine exposure duration in HIV-1--infected pregnant women. Design: Multicenter, randomized, double-blind, controlled trial of different durations of zidovudine prophylaxis. Setting: 27 hospitals in Thailand. Participants: 1,436 HIV-infected pregnant women in PHPT-1. Intervention: Zidovudine prophylaxis initiation at 28 or 35 wk gestation. Outcome measures: Haemoglobin level, leucocytes, total lymphocyte counts, and absolute neutrophil counts were measured at 26, 32, and 35 wk and at delivery. The evolution of haematological parameters was estimated between 26 and 35 wk (zidovudine/placebo) and between 35 wk and delivery to compare a long versus short zidovudine exposure. For each parameter, linear mixed models were adjusted on baseline sociodemographic variables, HIV clinical stage, CD4 count, and viral load. Results: Between 26 and 35 wk, haemoglobin, leucocytes, and absolute neutrophil counts decreased in zidovudine-exposed compared to unexposed women (mean difference [95% Cl] -0.4 [-0.5 to -0.3], -423 [-703 to -142], -485 [-757 to -213], respectively). However, between 35 wk and delivery, the haematological parameters increased faster in women exposed to long rather than short durations of zidovudine (0.1 [0.0 to 0.1]; 105 [18 to 191]; 147 [59 to 234], respectively). At delivery, the differences were not statistically significant, except for mean haemoglobin level, which remained slightly lower in the long zidovudine treatment group (difference: 0.2 g/dl). Zidovudine had no negative impact on the absolute lymphocyte counts. Conclusion: Zidovudine initiated at 28 wk gestation rather than 35 wk had a transient negative impact on the evolution of haematological parameters, which was largely reversed by delivery despite continuation of zidovudine. This result provides reassurance about the safety of early initiation of zidovudine prophylaxis during pregnancy to maximize prevention of perinatal HIV. [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.

Introduction: Infants born to women living with HIV initiating combination antiretroviral therapy (cART) late in pregnancy are at high risk of intrapartum infection. Mother/infant perinatal antiretroviral intensification may substantially reduce this risk., Methods: In this single-arm Bayesian trial, pregnant women with HIV receiving standard of care antiretroviral prophylaxis in Thailand (maternal antenatal lopinavir-based cART; nonbreastfed infants 4 weeks' postnatal zidovudine) were offered "antiretroviral intensification" (labor single-dose nevirapine plus infant zidovudine-lamivudine-nevirapine for 2 weeks followed by zidovudine-lamivudine for 2 weeks) if their antenatal cART was initiated ≤8 weeks before delivery. A negative birth HIV-DNA polymerase chain reaction (PCR) followed by a confirmed positive PCR defined intrapartum transmission. Before study initiation, we modeled intrapartum transmission probabilities using data from 3738 mother/infant pairs enrolled in our previous trials in Thailand using a logistic model, with perinatal maternal/infant antiretroviral regimen and predicted viral load at delivery as main covariates. Using the characteristics of the women enrolled who received intensification, prior intrapartum transmission probabilities (credibility intervals) with/without intensification were estimated. After including the transmission data observed in the current study, the corresponding Bayesian posterior transmission probability was derived., Results: No intrapartum transmission of HIV was observed among the 88 mother/infant pairs receiving intensification. The estimated intrapartum transmission probability was 2·2% (95% credibility interval 0·5-6·1) without intensification versus 0·3% (0·0-1·6) with intensification. The probability of superiority of intensification over standard of care was 94·4%. Antiretroviral intensification appeared safe., Conclusion: Mother/infant antiretroviral intensification was effective in preventing intrapartum transmission of HIV in pregnant women receiving ≤8 weeks antepartum cART.

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.

Background: Nevirapine (NVP) is a key component of antiretroviral prophylaxis and treatment for neonates. We evaluated current World Health Organization (WHO) weight-band NVP prophylactic dosing recommendations and investigated optimal therapeutic NVP dosing for neonates., Methods: The PHPT-5 study in Thailand assessed the efficacy of "Perinatal Antiretroviral Intensification" to prevent mother-to-child transmission of HIV in women with <8 weeks of antiretroviral treatment before delivery (NCT01511237). Infants received a 2-week course of zidovudine/lamivudine/NVP (NVP syrup/once daily: 2 mg/kg for 7 days; then 4 mg/kg for 7 days). Infant samples were assessed during the first 2 weeks of life. NVP population pharmacokinetics (PK) parameters were estimated using nonlinear mixed-effects models. Simulations were performed to estimate the probability of achieving target NVP trough concentrations for prophylaxis (>0.10 mg/L) and for therapeutic efficacy (>3.0 mg/L) using different infant dosing strategies., Results: Sixty infants (55% male) were included. At birth, median (range) weight was 2.9 (2.3-3.6) kg. NVP concentrations were best described by a 1-compartment PK model. Infant weight and postnatal age influenced NVP PK parameters. Based on simulations for a 3-kg infant, ≥92% would have an NVP trough >0.1 mg/L after 48 hours through 2 weeks using the PHPT-5 and WHO-dosing regimens. For NVP-based therapy, a 6-mg/kg twice daily dose produced a trough >3.0 mg/L in 87% of infants at 48 hours and 80% at 2 weeks., Conclusion: WHO weight-band prophylactic guidelines achieved target concentrations. Starting NVP 6 mg/kg twice daily from birth is expected to achieve therapeutic concentrations during the first 2 weeks of life.

Background: Use of several antiretrovirals (ARVs) has been shown to be associated with a higher risk of diabetes in HIV-infected adults. We estimated the incidence of new-onset diabetes and assessed the association between individual ARVs and ARV combinations, and diabetes in a large cohort in Thailand., Methods: We selected all HIV-1-infected, nondiabetic, antiretroviral-naive adults enrolled in the Program for HIV Prevention and Treatment cohort (NCT00433030) between January 2000 and December 2011. Diabetes was defined as confirmed fasting plasma glucose ≥ 126 mg/dL or random plasma glucose ≥ 2 00 mg/dL. Incidence was the number of cases divided by the total number of person-years of follow-up. Association between ARVs and ARV combinations, and new-onset diabetes was assessed using Cox proportional hazards models., Results: Overall, 1594 HIV-infected patients (76% female) were included. Median age at antiretroviral therapy initiation was 32.5 years. The incidence rate of diabetes was 5.0 per 1000 person-years of follow-up (95% confidence interval: 3.8 to 6.6) (53 cases). In analyses adjusted for potential confounders, exposure to stavudine + didanosine [adjusted hazard ratio (aHR) = 3.9; P = 0.001] and cumulative exposure ≥ 1 year to zidovudine (aHR = 2.3 vs. no exposure; P = 0.009) were associated with a higher risk of diabetes. Conversely, cumulative exposure ≥ 1 year to tenofovir (aHR = 0.4 vs. no exposure; P = 0.02) and emtricitabine (aHR = 0.4 vs. no exposure; P = 0.03) were associated with a lower risk., Conclusions: The incidence of diabetes in this predominantly female, young, lean population was relatively low. Although stavudine and didanosine have now been phased out in most antiretroviral therapy programs, our analysis suggests a higher risk of diabetes with zidovudine, frequently prescribed today in resource-limited settings.

Background: As antiretroviral treatment (ART) programs mature, data on drug utilization and costs are needed to assess durability of treatments and inform program planning., Methods: Children initiating ART were followed up in an observational cohort in Thailand. Treatment histories from 1999 to 2009 were reviewed. Treatment changes were categorized as: drug substitution (within class), switch across drug class (non nucleoside reverse-transcriptase inhibitors (NNRTI) to/from protease inhibitor (PI)), and to salvage therapy (dual PI or PI and NNRTI). Antiretroviral drug costs were calculated in 6-month cycles (US$ 2009 prices). Predictors of high drug cost including characteristics at start of ART (baseline), initial regimen, treatment change, and duration on ART were assessed using mixed-effects regression models., Results: Five hundred seven children initiated ART with a median 54 (interquartile range, 36-72) months of follow-up. Fifty-two percent had a drug substitution, 21% switched across class, and 2% to salvage therapy. When allowing for drug substitution, 78% remained on their initial regimen. Mean drug cost increased from $251 to $428 per child per year in the first and fifth year of therapy, respectively. PI-based and salvage regimens accounted for 16% and 2% of treatments prescribed and 33% and 5% of total costs, respectively. Predictors of high cost include baseline age ≥ 8 years, non nevirapine-based initial regimen, switch across drug class, and to salvage regimen (P < 0.005)., Conclusions: At 5 years, 21% of children switched across drug class and 2% received salvage therapy. The mean drug cost increased by 70%. Access to affordable second- and third-line drugs is essential for the sustainability of treatment programs.

Objectives: This study reports the psychometric validation of a new HIV/AIDS-specific health-related quality of life (HRQL) questionnaire, the Patient Reported Outcomes Quality of Life-HIV. The instrument was developed simultaneously across Europe, North and South America, Africa, Asia, and Australia to assess multidimensional quality of life impairments in the era of highly active antiretroviral therapy., Method: A cross-sectional study was performed in 8 countries. The pilot 70-item questionnaire was co-administered with the HIV symptoms index, the EQ-5D and Medical Outcomes Study-HIV questionnaires. Demographic and biomedical data were collected. After item analysis and reduction, convergent discriminant concurrent validity and known-group validity were examined. Internal consistency and reliability scores were assessed using Cronbach alpha and intraclass correlation., Results: The final sample of 791 patients was composed of 64% males (median age: 41 years, HIV diagnosis = 5 years), 13.8% were treatment naive. Item reduction yielded a 43-item form surveying 8 dimensions and 1 global health item that showed good convergent and discriminant validity and reliability (98% scaling success; Cronbach alphas 0.77-0.89). Correlations with EQ-5D and Medical Outcomes Study-HIV complied with concurrent validity expectations; likewise, correlations against the number of self-reported symptoms and depression showed good support for criterion validity. A test-retest study on French patients (n = 34) showed temporal stability (intraclass correlation coefficient = 0.86). Significant and meaningful differences of HRQL scores between countries were found., Conclusions: The Patient Reported Outcomes Quality of Life-HIV questionnaire is a valid and reliable instrument for assessing HRQL specific to HIV disease in different cultures and healthcare systems.

Objectives: 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., Methods: 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., Results: 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., Conclusions: 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.

Objective: To compare family reports of pregnancy status in deceased women with a biological assessment of pregnancy using a post-mortem beta-HCG test., Method: We investigated the deaths of females of reproductive age registered at the Pointe Noire morgue from June 30 to October 18, 2001. A physician interviewed relatives about the circumstances of death, in particular whether the woman had been pregnant at the time of death, and whether she had delivered or had an abortion (induced or spontaneous) within the past 6 weeks. The bodies were then examined and blood samples taken for beta-HCG testing., Results: Among 368 deaths of women of reproductive age registered, 34 deaths were identified as pregnancy-related: 23 by both the family interview and the beta-HCG test, five by beta-HCG test only and six were beta-HCG negative but the family had reported a recent delivery., Conclusion: In this setting, the approach based on family reports underestimates mortality during pregnancy by 24% and mortality during pregnancy or within 6 weeks postpartum by 15%.

Objectives: The extent to which HIV affects pregnancy-related mortality in countries with high HIV/AIDS and maternal mortality is poorly understood. The objectives of this study were to investigate the mortality of women of reproductive age by both HIV and pregnancy status, and quantify the excess mortality attributable to HIV during pregnancy in Pointe Noire, Congo., Design: Prospective mortuary investigation of all deaths in women aged 15-44 years, during 112 consecutive days., Methods: Mortality rates by HIV and pregnancy were computed. During the study period, 378 corpses were examined, blood was tested for HIV and pregnancy, relatives were interviewed and hospital files were reviewed. Denominators were obtained from a census with women-years assigned to pregnancy and/or HIV based on levels of fertility and HIV prevalence in the city., Results: The mortality rate was 32 times higher [95% confidence interval (CI), 25-39] among HIV-positive than among HIV-negative women. The relative increase in mortality associated with HIV was much higher in non-pregnant [rate ratio (RR), 41; 95% CI, 32-52] than in pregnant women (RR, 4; 95% CI, 2-9). Among HIV-positive women, pregnancy appeared to confer a survival benefit., Conclusion: These findings have important implications for the interpretation of trends in maternal mortality in the context of HIV. The apparent survival benefit of pregnant HIV-positive women is largely due to their low fertility in the latest stage of the disease. As the HIV epidemic matures and more women become severely ill, any potential adverse effects associated with HIV and pregnancy may be increasingly offset by selection effects, and maternal mortality may not increase further.