Determining standardized causes of death of infants, children, and adolescents living with HIV in Asia.

OBJECTIVE: To implement a standardized cause of death reporting and review process to systematically disaggregate causes of HIV-related deaths in a cohort of Asian children and adolescents. DESIGN: Death-related data were retrospectively and prospectively assessed in a longitudinal regional cohort study. METHODS: Children under routine HIV care at sites in Cambodia, India, Indonesia, Malaysia, Thailand, and Vietnam between 2008 and 2017 were followed. Causes of death were reported and then independently and centrally reviewed. Predictors were compared using competing risks survival regression analyses. RESULTS: Among 5918 children, 5523 (93%; 52% male) had ever been on combination antiretroviral therapy. Of 371 (6.3%) deaths, 312 (84%) occurred in those with a history of combination antiretroviral therapy (crude all-cause mortality 9.6 per 1000 person-years; total follow-up time 32 361 person-years). In this group, median age at death was 7.0 (2.9-13) years; median CD4 cell count was 73 (16-325) cells/µl. The most common underlying causes of death were pneumonia due to unspecified pathogens (17%), tuberculosis (16%), sepsis (8.0%), and AIDS (6.7%); 12% of causes were unknown. These clinical diagnoses were further grouped into AIDS-related infections (22%) and noninfections (5.8%), and non-AIDS-related infections (47%) and noninfections (11%); with 12% unknown, 2.2% not reviewed. Higher CD4 cell count and better weight-for-age z-score were protective against death. CONCLUSION: Our standardized cause of death assessment provides robust data to inform regional resource allocation for pediatric diagnostic evaluations and prioritization of clinical interventions, and highlight the continued importance of opportunistic and nonopportunistic infections as causes of death in our cohort.

Access to prevention of mother-to-child transmission of HIV along HIV services cascade through integrated active case management in 15 operational districts in Cambodia.

INTRODUCTION: Following the introduction of option B+ in 2013, and with the perspective of eliminating mother-to-child transmission of HIV by 2025, Cambodia has implemented an integrated active case management (IACM) approach since 2014 to improve the notification and follow-up of all HIV-infected cases including pregnant women, and to ensure access to and use of the full prevention of mother-to-child transmission (PMTCT) service package by HIV-infected pregnant women and their HIV-exposed infants. This study aimed to analyse PMTCT cascade data in 15 operational districts (ODs) implementing the IACM approach in Cambodia. METHODS: We analysed PMTCT cohort data from 15 ODs implementing IACM approach between 1 January 2014 and 31 December 2016. We measured key indicators along the PMTCT cascade and compared them to available (cross-sectional) PMTCT indicators during the 2011 to 2013 period. RESULTS: During the period 2014 to 2016, among 938 identified HIV-infected pregnant women, 308 (32.8%) were tested HIV positive during their pregnancy, 9 (1.0%) during labour, while the remaining 621 (66.2%) were women on antiretroviral therapy (ART) who became pregnant. During the study period, 867 (92.4%) of the 938 women received ART during pregnancy and labour. Subsequently, 456 (85.6%) of the 533 HEI born and alive during the study period received 6-week antiretroviral (ARV) prophylaxis, 390 (76.6%) and 396 (77.8%) of the 509 infants aged six weeks or older received cotrimoxazole prophylaxis and HIV-DNA PCR test respectively. Among the 396 HEI who received HIV-DNA PCR test, 7 (1.8%) were found HIV positive. The comparison with cross-sectional PMTCT indicator obtained during the previous 2011 to 2013 period in the same 15 ODs, showed a significant increase in ARV uptake among HIV-infected pregnant women (from 72.3% to 92.4%), in cotrimoxazole uptake (from 41.6% to 73.2%), and in HIV-DNA PCR testing coverage among HEI (from 41.2% to 74.3%). CONCLUSIONS: The implementation of option B+ and IACM may have contributed to the improvement of the PMTCT cascade in Cambodia. However, some gaps in accessing PMTCT services along the HIV cascade persist and need to be addressed.

Use and Outcomes of Antiretroviral Monotherapy and Treatment Interruption in Adolescents With Perinatal HIV Infection in Asia.

PURPOSE: Antiretroviral monotherapy and treatment interruption are potential strategies for perinatally HIV-infected adolescents (PHIVA) who face challenges maintaining effective combination antiretroviral therapy (ART). We assessed the use and outcomes for adolescents receiving monotherapy or undergoing treatment interruption in a regional Asian cohort. METHODS: Regional Asian data (2001-2016) were analyzed to describe PHIVA who experienced ≥2 weeks of lamivudine or emtricitabine monotherapy or treatment interruption and trends in CD4 count and HIV viral load during and after episodes. Survival analyses were used for World Health Organization (WHO) stage III/IV clinical and immunologic event-free survival during monotherapy or treatment interruption, and a Poisson regression to determine factors associated with monotherapy or treatment interruption. RESULTS: Of 3,448 PHIVA, 84 (2.4%) experienced 94 monotherapy episodes, and 147 (4.3%) experienced 174 treatment interruptions. Monotherapy was associated with older age, HIV RNA >400 copies/mL, younger age at ART initiation, and exposure to ≥2 combination ART regimens. Treatment interruption was associated with CD4 count <350 cells/µL, HIV RNA ≥1,000 copies/mL, ART adverse event, and commencing ART age ≥10 years compared with age <3 years. WHO clinical stage III/IV 1-year event-free survival was 96% and 85% for monotherapy and treatment interruption cohorts, respectively. WHO immunologic stage III/IV 1-year event-free survival was 52% for both cohorts. Those who experienced monotherapy or treatment interruption for more than 6 months had worse immunologic and virologic outcomes. CONCLUSIONS: Until challenges of treatment adherence, engagement in care, and combination ART durability/tolerability are met, monotherapy and treatment interruption will lead to poor long-term outcomes.

Emotional and behavioral resilience among children with perinatally acquired HIV in Thailand and Cambodia.

OBJECTIVES: Psychosocial challenges associated with perinatally acquired HIV (PHIV) infection are well known, yet many children infected with HIV since birth demonstrate positive outcomes, referred to as resilience. The purpose of this study was to evaluate emotional-behavioral development and identify salient predictors of resilience among long-term survivors of PHIV. DESIGN: Prospective investigation of children with PHIV compared with demographically similar perinatally HIV-exposed but uninfected (PHEU) and HIV-unexposed, uninfected (HUU) children, all from Thailand and Cambodia. METHODS: The Child Behavior Checklist (CBCL; parent version) was administered at baseline and annual follow-up visits (median follow-up of 3 years) to children age 6-14. Resilience was defined as consistent CBCL scores on the Internalizing, Externalizing or Total Problem T scales within normative ranges (T-scores <60) at every time point. Generalized estimating equations examined CBCL scores over time and logistic models examined demographic, socioeconomic, and cultural predictors of resilience. RESULTS: Participants included 448 children (236 PHIV, 98 PHEU, 114 HUU), with median (interquartile range) age at first evaluation of 7 (6-9) years. Children with PHIV exhibited similar rates of resilience as PHEU and HUU on the Externalizing and Total Problems scales. Resilience on the Internalizing scale was more likely in PHEU (71%) compared with PHIV (59%) or HUU (56%), P = 0.049. Factors associated with resilience in adjusted models included: HIV-exposed but uninfected status, higher household income, Cambodian nationality, female sex, and caregiver type. CONCLUSION: Despite biopsychosocial risks, resilience is observed among PHIV and PHEU children. Further study is needed to understand mechanisms underlying associated factors and intervention priorities.

Impact of the frequency of plasma viral load monitoring on treatment outcomes among children with perinatally acquired HIV.

INTRODUCTION: Recommendations on the optimal frequency of plasma viral load (pVL) monitoring in children living with HIV (CLWH) who are stable on combination antiretroviral therapy (cART) are inconsistent. This study aimed to determine the impact of annual versus semi-annual pVL monitoring on treatment outcomes in Asian CLWH. METHODS: Data on children with perinatally acquired HIV aged <18 years on first-line, non-nucleoside reverse transcriptase inhibitor-based cART with viral suppression (two consecutive pVL <400 copies/mL over a six-month period) were included from a regional cohort study; those exposed to prior mono- or dual antiretroviral treatment were excluded. Frequency of pVL monitoring was determined at the site-level based on the median rate of pVL measurement: annual 0.75 to 1.5, and semi-annual >1.5 tests/patient/year. Treatment failure was defined as virologic failure (two consecutive pVL >1000 copies/mL), change of antiretroviral drug class, or death. Baseline was the date of the second consecutive pVL <400 copies/mL. Competing risk regression models were used to identify predictors of treatment failure. RESULTS: During January 2008 to March 2015, there were 1220 eligible children from 10 sites that performed at least annual pVL monitoring, 1042 (85%) and 178 (15%) were from sites performing annual (n = 6) and semi-annual pVL monitoring (n = 4) respectively. Pre-cART, 675 children (55%) had World Health Organization clinical stage 3 or 4, the median nadir CD4 percentage was 9%, and the median pVL was 5.2 log10 copies/mL. At baseline, the median age was 9.2 years, 64% were on nevirapine-based regimens, the median cART duration was 1.6 years, and the median CD4 percentage was 26%. Over the follow-up period, 258 (25%) CLWH with annual and 40 (23%) with semi-annual pVL monitoring developed treatment failure, corresponding to incidence rates of 5.4 (95% CI: 4.8 to 6.1) and 4.3 (95% CI: 3.1 to 5.8) per 100 patient-years of follow-up respectively (p = 0.27). In multivariable analyses, the frequency of pVL monitoring was not associated with treatment failure (adjusted hazard ratio: 1.12; 95% CI: 0.80 to 1.59). CONCLUSIONS: Annual compared to semi-annual pVL monitoring was not associated with an increased risk of treatment failure in our cohort of virally suppressed children with perinatally acquired HIV on first-line NNRTI-based cART.

Trends in CD4 cell count response to first-line antiretroviral treatment in HIV-positive patients from Asia, 2003-2013: TREAT Asia HIV Observational Database Low Intensity Transfer.

Antiretroviral treatment (ART) guidelines have changed over the past decade, recommending earlier initiation and more tolerable regimens. The study objective was to examine the CD4 response to ART, depending on the year of ART initiation, in HIV-positive patients in the Asia-Pacific. We included HIV-positive adult patients who initiated ART between 2003 and 2013 in our regional cohort from eight urban referral centres in seven countries within Asia. We used mixed-effects linear regression models to evaluate differences in CD4 response by year of ART initiation during 36 months of follow-up, adjusted a priori for other covariates. Overall, 16,962 patients were included. Patients initiating in 2006-9 and 2010-13 had an estimated mean CD4 cell count increase of 8 and 15 cells/µl, respectively, at any given time during the 36-month follow-up, compared to those in 2003-5. The median CD4 cell count at ART initiation also increased from 96 cells/µl in 2003-5 to 173 cells/µl in 2010-13. Our results suggest that the CD4 response to ART is modestly higher for those initiating ART in more recent years. Moreover, fewer patients are presenting with lower absolute CD4 cell counts over time. This is likely to reduce their risk of opportunistic infections and future non-AIDS defining cancers.

Loss to Follow-up Trends in HIV-Positive Patients Receiving Antiretroviral Treatment in Asia From 2003 to 2013.

INTRODUCTION: Over time, there has been a substantial improvement in antiretroviral treatment (ART) programs, including expansion of services and increased patient engagement. We describe time trends in, and factors associated with, loss to follow-up (LTFU) in HIV-positive patients receiving ART in Asia. METHODS: Analysis included HIV-positive adults initiating ART in 2003-2013 at 7 ART programs in Asia. Patients LTFU had not attended the clinic for ≥180 days, had not died, or transferred to another clinic. Patients were censored at recent clinic visit, follow-up to January 2014. We used cumulative incidence to compare LTFU and mortality between years of ART initiation. Factors associated with LTFU were evaluated using a competing risks regression model, adjusted for clinical site. RESULTS: A total of 8305 patients were included. There were 743 patients LTFU and 352 deaths over 26,217 person-years (pys), a crude LTFU, and mortality rate of 2.83 (2.64-3.05) per 100 pys and 1.34 (1.21-1.49) per 100 pys, respectively. At 24 months, the cumulative LTFU incidence increased from 4.3% (2.9%-6.1%) in 2003-05 to 8.1% (7.1%-9.2%) in 2006-09 and then decreased to 6.7% (5.9%-7.5%) in 2010-13. Concurrently, the cumulative mortality incidence decreased from 6.2% (4.5%-8.2%) in 2003-05 to 3.3% (2.8%-3.9%) in 2010-13. The risk of LTFU reduced in 2010-13 compared with 2006-09 (adjusted subhazard ratio = 0.73, 0.69-0.99). CONCLUSIONS: LTFU rates in HIV-positive patients receiving ART in our clinical sites have varied by the year of ART initiation, with rates declining in recent years whereas mortality rates have remained stable. Further increases in site-level resources are likely to contribute to additional reductions in LTFU for patients initiating in subsequent years.