Publications by authors named "Rawiwan Hansudewechakul"

68 Publications

Increased Burden of Concordant and Sequential Anogenital Human Papillomavirus Infections Among Asian Young Adult Women With Perinatally Acquired HIV Compared With HIV-Negative Peers.

Sex Transm Dis 2021 Mar;48(3):200-205

Department of Global Health, Amsterdam University Medical Centers, University of Amsterdam, and Amsterdam Institute for Global Health and Development.

Background: Youth with perinatally acquired HIV (YPHIV) are at higher risk for anogenital human papillomavirus (HPV) infection.

Methods: We enrolled a cohort of YPHIV and HIV-negative youth in Thailand and Vietnam, matched by age and lifetime sex partners, and followed them up for 144 weeks (to 2017). Participants had annual pelvic examinations with samples taken for HPV genotyping. Concordant infection was simultaneous HPV detection in multiple anogenital compartments (cervical, vaginal, anal); sequential infection was when the same type was found in successive compartments (cervicovaginal to/from anal). Generalized estimating equations were used to assess factors associated with concordant infection, and Cox regression was used to assess factors associated with sequential infection.

Results: A total of 93 YPHIV and 99 HIV-negative women were enrolled, with a median age of 19 years (interquartile range, 18-20 years). High-risk anogenital HPV infection was ever detected in 76 (82%) YPHIV and 66 (67%) HIV-negative youth during follow-up. Concordant anogenital high-risk HPV infection was found in 62 (66%) YPHIV versus 44 (34%) HIV-negative youth. Sequential cervicovaginal to anal high-risk HPV infection occurred in 20 YPHIV versus 5 HIV-negative youth, with an incidence rate of 9.76 (6.30-15.13) versus 2.24 (0.93-5.38) per 100 person-years. Anal to cervicovaginal infection occurred in 4 YPHIV versus 0 HIV-negative women, with an incidence rate of 1.78 (0.67-4.75) per 100 person-years. Perinatally acquired HIV was the one factor independently associated with both concordant and sequential high-risk HPV infection.

Conclusions: Children and adolescents with perinatally acquired HIV should be prioritized for HPV vaccination, and cervical cancer screening should be part of routine HIV care for sexually active YPHIV.
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http://dx.doi.org/10.1097/OLQ.0000000000001294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867588PMC
March 2021

Impact of low-level viraemia on virological failure among Asian children with perinatally acquired HIV on first-line combination antiretroviral treatment: a multicentre, retrospective cohort study.

J Int AIDS Soc 2020 07;23(7):e25550

Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand.

Introduction: The clinical relevance of low-level viraemia (LLV) and virological outcomes among children living with HIV (CLHIV) remains controversial. This study aimed to determine the impact of LLV on virological failure (VF) among Asian CLHIV on first-line combination antiretroviral therapy (cART).

Methods: CLHIV aged <18 years, who were on first-line cART for ≥12 months, and had virological suppression (two consecutive plasma viral load [pVL] <50 copies/mL) were included. Those who started treatment with mono/dual antiretroviral therapy, had a history of treatment interruption >14 days, or received treatment and care at sites with a pVL lower limit of detection >50 copies/mL were excluded. LLV was defined as a pVL 50 to 1000 copies/mL, and VF as a single pVL >1000 copies/mL. Baseline was the time of the second pVL < 50 copies/mL. Cox proportional hazards models were performed to assess the association between LLV and VF.

Results: From January 2008 to September 2016, 508 CLHIV (55% female) were eligible for the study. At baseline, the median age was 9.6 (IQR: 7.0 to 12.3) years, cART duration was 1.4 (IQR: 1.3 to 1.8) years, 97% of CLHIV were on non-nucleoside reverse transcriptase inhibitor-based regimens, and the median CD4 was 25% (IQR: 20% to 30%). Over a median follow-up time of 6.0 (IQR: 3.1 to 8.9) years from baseline, 86 CLHIV (17%) had ever experienced LLV, of whom 32 (37%) had multiple LLV episodes. Female sex, living in Malaysia (compared to Cambodia), having family members other than biological parents/grandparents as a primary caregiver, and baseline CD4 < 25% increased risk of LLV. Overall, 115 children (23%) developed VF, corresponding to a rate of 4.0 (95%CI: 3.4 to 4.9) per 100 person-years of follow-up (PYFU). VF was greater among children who had ever experienced LLV compared with those who maintained virological suppression throughout the study period (8.9 vs. 3.3 per 100 PYFU; p < 0.001). In multivariable analyses, ever experiencing LLV was associated with increased risk of subsequent VF (adjusted hazard ratio: 3.01; 95%CI: 1.97 to 4.60).

Conclusions: LLV increased the risk of subsequent VF among Asian CLHIV who had previously been suppressed on first-line cART. Adherence interventions and additional targeted pVL monitoring may be warranted among children with LLV to facilitate early detection of VF.
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http://dx.doi.org/10.1002/jia2.25550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338042PMC
July 2020

Continuous prophylactic ARV/ART since birth reduces seeding and persistence of the viral reservoir in vertically HIV-infected children.

Clin Infect Dis 2020 Jun 5. Epub 2020 Jun 5.

Centre de Recherche du CHUM and department of microbiology, infectiology and immunology, Université de Montréal, Canada.

Background: Early antiretroviral therapy (ART) restricts the size of the HIV reservoir in infants. However, whether antiretroviral (ARV) prophylaxis given to exposed vertically infected children exerts similar effects remains unknown.

Methods: We measured total and integrated HIV DNA, as well as the frequency of CD4 T-cells producing multiply-spliced RNA (msRNA) after stimulation (inducible reservoir) in vertically-infected Thai infants. Eighty-five infants were followed longitudinally for up to three years. We compared the size of the reservoir in children who received continuous prophylactic ARV since birth versus those who never received or discontinued prophylaxis before initiating ART. We used samples from a cross-sectional cohort of 37 Thai children who had initiated ART within 6 months of life to validate our findings.

Results: Before ART, levels of HIV DNA and the frequencies of cells producing msRNA were significantly lower in infants who received continuous prophylactic ARV since birth compared to those in whom prophylactic ARV was discontinued or never initiated (p<0.020 and p<0.001, respectively). Upon ART initiation, total and integrated HIV DNA levels decayed significantly in both groups (<0.01 in all cases). Interestingly, the initial differences in the frequencies of infected cells persisted during three years on ART. The beneficial effect of prophylaxis on the size of the HIV reservoir was confirmed in the cross-sectional study. Importantly, no differences were observed between children who discontinued prophylactic ARV before starting ART and those who delayed ART initiation without receiving prior prophylaxis.

Conclusions: Neonatal prophylactic ARV with direct transition to ART durably limits the size of the HIV reservoir.
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http://dx.doi.org/10.1093/cid/ciaa718DOI Listing
June 2020

Prevalence of High-risk Nonavalent Vaccine-type Human Papillomavirus Infection Among Unvaccinated, Sexually Active Asian Female Adolescents With and Without Perinatally Acquired HIV Infection.

Pediatr Infect Dis J 2020 07;39(7):615-619

From the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Background: We studied the prevalence of 7, high-risk human papillomavirus (HPV) types in the nonavalent vaccine (HRVT-7: HPV 16, 18, 31, 33, 45, 52, 58) among vaccine-naïve, sexually active Asian female adolescents with and without perinatally acquired HIV infection (PHIV).

Methods: PHIV female adolescents 12-24 years of age and HIV-uninfected controls matched by age and number of lifetime sex partners were enrolled in a 3-year observational cohort study in Thailand and Vietnam. Samples from the oral cavity, anus, cervix and vagina were collected for HRVT-7 HPV genotyping, and serum collected for HPV 16 and 18 antibody testing. Baseline data were analyzed using multivariable logistic regression.

Results: We included 93 PHIV (median CD4 593 cells/mm, 62% with HIV RNA suppression) and 99 HIV-uninfected adolescents (median lifetime sex partners 2). The overall prevalence of HRVT-7 infection was 53% in PHIV and 49% in HIV-uninfected adolescents (P = 0.66). Cervical HRVT-7 DNA was detected more frequently in PHIV than HIV-uninfected adolescents (37% vs. 23%, P = 0.04). Overall, more lifetime partners [≥3 vs. 1; odds ratio (OR) 2.99 (1.38-6.51), P = 0.02] and having other sexually transmitted infections [OR 3.30 (1.51-7.21), P = 0.003] increased the risk of HRVT-7 infection and/or positive HPV 16/18 antibodies; while detectable HIV RNA [OR 2.78 (1.05-7.36), P = 0.04] increased the risk among PHIV adolescents.

Conclusions: Half of sexually active Asian female adolescents, regardless of HIV infection, had already acquired HRVT-7 infection. This underscores the need for earlier access to HPV vaccine in the region.
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http://dx.doi.org/10.1097/INF.0000000000002659DOI Listing
July 2020

Implementation of an active case management network to identify HIV-positive infants and accelerate the initiation of antiretroviral therapy, Thailand 2015 to 2018.

J Int AIDS Soc 2020 02;23(2):e25450

Bureau of AIDS, TB and STIs, Ministry of Public Health, Nonthaburi, Thailand.

Introduction: Early initiation of antiretroviral therapy (ART) can reduce HIV-related morbidity and mortality in HIV-positive infants. We implemented an Active Case Management Network to promote early ART initiation Aiming for Cure (ACC) in August 2014. We describe ACC implementation, early infant diagnosis (EID) coverage and ART initiation during August 2014 to July 2018 compared with a national EID survey during October 2007 to September 2011 (pre-ACC).

Methods: Thailand's 2014 HIV Treatment Guidelines recommend that HIV-exposed infants have HIV polymerase chain reaction (PCR) testing at birth, one month and at two to four months. Testing is done at 14 national HIV PCR laboratories. When an HIV-positive infant (HIV PCR+) is identified, PCR laboratory staff send the result to the hospital staff responsible for the infant's care and to the national laboratory case manager (CM). As part of ACC, the national laboratory CM alerts a regional CM who contacts the hospital staff caring for the infant to offer technical support with ART initiation and ART adherence. CMs enter clinical, demographic and laboratory data into the national ACC database. We analysed the ACC data from August 2014 to July 2018 to assess the ACC's impact on EID coverage, ART initiation and time-to-ART initiation.

Results: The uptake of EID increased from 64% (pre-ACC) to >95% in 2018 (ACC). The number of HIV-positive infants born declined from 429 cases (pre-ACC) to 267 cases (ACC). Median age at the first-positive PCR declined from 75 days (pre-ACC) to 60 days (ACC); P < 0.001. Among 429 infants diagnosed before ACC was started, 241 (56%) received ART; during ACC, 235 (88%) of 267 HIV-positive infants received ART. The median age at ART initiation declined from 282 days before ACC to 83 days during ACC (P < 0.001) and the median time from blood collection to ART initiation declined from 168 days before ACC to 23 days during ACC (P < 0.001).

Conclusions: An innovative case management network (ACC) has been established in Thailand and results suggest that the network is promoting EID and early ART initiation. The ACC model, using case-managed PCR notification and follow-up, may speed ART initiation in other settings.
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http://dx.doi.org/10.1002/jia2.25450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046526PMC
February 2020

Incidence and Persistence of High-risk Anogenital Human Papillomavirus Infection Among Female Youth With and Without Perinatally Acquired Human Immunodefiency Virus Infection: A 3-year Observational Cohort Study.

Clin Infect Dis 2020 11;71(8):e270-e280

TREAT Asia/amfAR - The Foundation for AIDS Research, Bangkok, Thailand.

Background: Female youth with perinatally acquired human immunodeficiency virus (PHIV) may be at higher risk than uninfected youth for persistent anogenital human papillomavirus (HPV) infection, due to prolonged immunodeficiency.

Methods: A 3-year cohort study was conducted between 2013 and 2017 among Thai and Vietnamese PHIV and HIV-uninfected females 12-24 years, matched by age group and number of lifetime sexual partners. For HPV genotyping, cervical and anal samples were obtained at baseline and annually. Vaginal samples were collected at baseline and every 6 months. Factors associated with high-risk HPV (HR-HPV) persistence and incidence were assessed.

Results: We enrolled 93 PHIV and 99 HIV-uninfected females. Median age was 19 (interquartile range [IQR] 18-20) years. For the 7 HR-HPV types (16, 18, 31, 33, 45, 52, 58) in the nonavalent HPV vaccine, PHIV had significantly higher incidence (P = .03) and persistence (P = .01) than HIV-uninfected youth over a 3-year period. Having HIV (adjusted hazard ratio [aHR] 2.1, 95% confidence interval [CI] 1.1-3.9) and ever using illegal substances (aHR 4.8, 95% CI 1.8-13.0) were associated with incident 7 HR-HPV infections. HIV-positive status (adjusted prevalence ratio [aPR] 2.2, 95% CI 1.5-3.2), recent alcohol use (aPR 1.75, 95% CI 1.2-2.5), and higher number of lifetime partners (aPR 2.0, 95% CI 1.4-3.1, for 3-5 partners; aPR 1.93, 95% CI 1.2-3.2, for ≥6 partners) were significantly associated with persistent 7 HR-HPV infections.

Conclusions: Female PHIV were at higher risk of having anogenital HR-HPV acquisition and persistence. Primary and secondary prevention programs for HPV infection and HPV-related diseases should be prioritized for PHIV children and youth.
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http://dx.doi.org/10.1093/cid/ciz1143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755021PMC
November 2020

Dual Analysis of Loss to Follow-up for Perinatally HIV-Infected Adolescents Receiving Combination Antiretroviral Therapy in Asia.

J Acquir Immune Defic Syndr 2019 12;82(5):431-438

The Kirby Institute, UNSW Australia, Sydney, Australia.

Background: Perinatally HIV-infected adolescents (PHIVA) are an expanding population vulnerable to loss to follow-up (LTFU). Understanding the epidemiology and factors for LTFU is complicated by varying LTFU definitions.

Setting: Asian regional cohort incorporating 16 pediatric HIV services across 6 countries.

Methods: Data from PHIVA (aged 10-19 years) who received combination antiretroviral therapy 2007-2016 were used to analyze LTFU through (1) an International epidemiology Databases to Evaluate AIDS (IeDEA) method that determined LTFU as >90 days late for an estimated next scheduled appointment without returning to care and (2) the absence of patient-level data for >365 days before the last data transfer from clinic sites. Descriptive analyses and competing-risk survival and regression analyses were used to evaluate LTFU epidemiology and associated factors when analyzed using each method.

Results: Of 3509 included PHIVA, 275 (7.8%) met IeDEA and 149 (4.3%) met 365-day absence LTFU criteria. Cumulative incidence of LTFU was 19.9% and 11.8% using IeDEA and 365-day absence criteria, respectively. Risk factors for LTFU across both criteria included the following: age at combination antiretroviral therapy initiation <5 years compared with age ≥5 years, rural clinic settings compared with urban clinic settings, and high viral loads compared with undetectable viral loads. Age 10-14 years compared with age 15-19 years was another risk factor identified using 365-day absence criteria but not IeDEA LTFU criteria.

Conclusions: Between 12% and 20% of PHIVA were determined LTFU with treatment fatigue and rural treatment settings consistent risk factors. Better tracking of adolescents is required to provide a definitive understanding of LTFU and optimize evidence-based models of care.
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http://dx.doi.org/10.1097/QAI.0000000000002184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857712PMC
December 2019

Peritransition Outcomes of Southeast Asian Adolescents and Young Adults With HIV Transferring From Pediatric to Adult Care.

J Adolesc Health 2020 01 15;66(1):92-99. Epub 2019 Oct 15.

HIV-NAT, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Purpose: The aim of this article was to study the clinical and social outcomes of health care transition among Asian adolescents and young adults with HIV (AYHIV).

Methods: AYHIV who transferred from a pediatric to an adult clinic within the past year across five sites in Malaysia, Thailand, and Vietnam had clinical and laboratory evaluations and completed questionnaires about their health, socioeconomic factors, and transition experiences. Multiple logistic regression was used to assess associations with HIV viremia.

Results: Of 93 AYHIV enrolled between June 2016 and April 2017, 56% were female, 87% acquired HIV through perinatal exposure, median age was 20 years (interquartile range [IQR] 18.5-21). Two-thirds were in a formal education program, 43% were employed, 43% of females and 35% of males were sexually active. Median lifetime antiretroviral therapy duration was 6.2 years (IQR 3.3-10.7); 45% had received second-line therapy. Median CD4 was 601 cells/mm (IQR 477-800); 82% had HIV-RNA <40 copies/mL. Being in a relationship, a shorter posttransition duration, self-reported adherence of ≥95%, and higher CD4 were inversely associated with HIV viremia. Half felt very prepared for the transfer to adult care, and 20% frequently and 43% sometimes still met with pediatric providers. Two-thirds reported needing to keep their HIV a secret, and 23%-38% reported never or rarely having someone to discuss problems with.

Conclusions: Asian AYHIV in our cohort were concerned about the negative social impact of having and disclosing HIV, and one-third lacked people they could trust with their personal problems, which could have negative implications for their ability to navigate adult life.
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http://dx.doi.org/10.1016/j.jadohealth.2019.07.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928413PMC
January 2020

Trajectory Analysis of Cognitive Outcomes in Children With Perinatal HIV.

Pediatr Infect Dis J 2019 10;38(10):1038-1044

Missouri Institute of Mental Health, University of Missouri-St. Louis, St. Louis, Missouri.

Background: Children with perinatal HIV (pHIV) may display distinct long-term cognitive phenotypes. We used group-based trajectory modeling to identify clusters of children with pHIV after similar developmental trajectories and predictors of belonging to select cognitive trajectory groups.

Methods: Participants included children, 4-17 years of age, with pHIV in Thailand and Cambodia. Cognitive measures included translated versions of Intelligence Quotient tests, Color Trails Tests and Beery-Buktenica Developmental Test of Visual-Motor Integration conducted semiannually over 3-6 years. The best fit of trajectory groups was determined using maximum likelihood estimation. Multivariate logistic regression identified baseline factors associated with belonging to the lowest scoring trajectory group.

Results: Group-based trajectory analyses revealed a 3-cluster classification for each cognitive test, labeled as high, medium and low scoring groups. Most trajectory group scores remained stable across age. Verbal IQ declined in all 3 trajectory groups and the high scoring group for Children's Color Trails Test 1 and 2 showed an increase in scores across age. Children in the lowest scoring trajectory group were more likely to present at an older age and report lower household income.

Conclusions: Group-based trajectory modeling succinctly classifies cohort heterogeneity in cognitive outcomes in pHIV. Most trajectories remained stable across age suggesting that cognitive potential is likely determined at an early age with the exception of a small subgroup of children who displayed developmental gains in select cognitive domains and may represent those with better cognitive reserve. Poverty and longer duration of untreated HIV may predispose children with pHIV to suboptimal cognitive development.
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http://dx.doi.org/10.1097/INF.0000000000002427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776249PMC
October 2019

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

J Adolesc Health 2019 11 5;65(5):651-659. Epub 2019 Aug 5.

Kirby Institute, University of New South Wales Sydney, New South Wales, Australia.

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.
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http://dx.doi.org/10.1016/j.jadohealth.2019.05.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007807PMC
November 2019

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

J Int AIDS Soc 2019 06;22(6):e25312

Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand.

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 log 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.
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http://dx.doi.org/10.1002/jia2.25312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556679PMC
June 2019

A Longitudinal Study of Behavioral Risk, Adherence, and Virologic Control in Adolescents Living With HIV in Asia.

J Acquir Immune Defic Syndr 2019 06;81(2):e28-e38

The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), The Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

Background: Adolescents living with HIV (ALHIV) have poorer adherence and clinical outcomes than adults. We conducted a study to assess behavioral risks and antiretroviral therapy outcomes among ALHIV in Asia.

Methods: A prospective cohort study among ALHIV and matched HIV-uninfected controls aged 12-18 years was conducted at 9 sites in Malaysia, Thailand, and Vietnam from July 2013 to March 2017. Participants completed an audio computer-assisted self-interview at weeks 0, 48, 96, and 144. Virologic failure (VF) was defined as ≥1 viral load (VL) measurement >1000 copies/mL. Generalized estimating equations were used to identify predictors for VF.

Results: Of 250 ALHIV and 59 HIV-uninfected controls, 58% were Thai and 51% females. The median age was 14 years at enrollment; 93% of ALHIV were perinatally infected. At week 144, 66% of ALHIV were orphans vs. 28% of controls (P < 0.01); similar proportions of ALHIV and controls drank alcohol (58% vs. 65%), used inhalants (1% vs. 2%), had been sexually active (31% vs. 21%), and consistently used condoms (42% vs. 44%). Of the 73% of ALHIV with week 144 VL testing, median log VL was 1.60 (interquartile range 1.30-1.70) and 19% had VF. Over 70% of ALHIV had not disclosed their HIV status. Self-reported adherence ≥95% was 60% at week 144. Smoking cigarettes, >1 sexual partner, and living with nonparent relatives, a partner or alone, were associated with VF at any time.

Conclusions: The subset of ALHIV with poorer adherence and VF require comprehensive interventions that address sexual risk, substance use, and HIV-status disclosure.
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http://dx.doi.org/10.1097/QAI.0000000000002008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522277PMC
June 2019

Early and Late Virologic Failure After Virologic Suppression in HIV-Infected Asian Children and Adolescents.

J Acquir Immune Defic Syndr 2019 03;80(3):308-315

Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.

Background: Virologic failure is a major threat to maintaining effective combination antiretroviral therapy, especially for children in need of lifelong treatment. With efforts to expand access to HIV viral load testing, our understanding of pediatric virologic failure is evolving.

Setting: An Asian cohort in 16 pediatric HIV services across 6 countries.

Methods: From 2005 to 2014, patients younger than 20 years who achieved virologic suppression and had subsequent viral load testing were included. Early virologic failure was defined as a HIV RNA ≥1000 copies per milliliter within 12 months of virologic suppression, and late virologic as a HIV RNA ≥1000 copies per milliliter after 12 months following virologic suppression. Characteristics at combination antiretroviral therapy initiation and virologic suppression were described, and a competing risk time-to-event analysis was used to determine cumulative incidence of virologic failure and factors at virologic suppression associated with early and late virologic failure.

Results: Of 1105 included in the analysis, 182 (17.9%) experienced virologic failure. The median age at virologic suppression was 6.9 years, and the median time to virologic failure was 24.6 months after virologic suppression. The incidence rate for a first virologic failure event was 3.3 per 100 person-years. Factors at virologic suppression associated with late virologic failure included older age, mostly rural clinic setting, tuberculosis, protease inhibitor-based regimens, and early virologic failure. No risk factors were identified for early virologic failure.

Conclusions: Around 1 in 5 experienced virologic failure in our cohort after achieving virologic suppression. Targeted interventions to manage complex treatment scenarios, including adolescents, tuberculosis coinfection, and those with poor virologic control are required.
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http://dx.doi.org/10.1097/QAI.0000000000001921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952284PMC
March 2019

Disease- and Treatment-related Morbidity in Adolescents With Perinatal HIV Infection in Asia.

Pediatr Infect Dis J 2019 03;38(3):287-292

From the The Kirby Institute, UNSW, Sydney, Australia.

Background: Perinatally HIV-infected adolescents (PHIVA) are exposed to a chronic systemic infection and long-term antiretroviral therapy (ART), leaving them susceptible to morbidities associated with inflammation, immunodeficiency and drug toxicity.

Methods: Data collected 2001 to 2016 from PHIVA 10-19 years of age within a regional Asian cohort were analyzed using competing risk time-to-event and Poisson regression analyses to describe the nature and incidence of morbidity events and hospitalizations and identify factors associated with disease-related, treatment-related and overall morbidity. Morbidity was defined according to World Health Organization clinical staging criteria and U.S. National Institutes of Health Division of AIDS criteria.

Results: A total 3,448 PHIVA contributed 17,778 person-years. Median age at HIV diagnosis was 5.5 years, and ART initiation was 6.9 years. There were 2,562 morbidity events and 307 hospitalizations. Cumulative incidence for any morbidity was 51.7%, and hospitalization was 10.0%. Early adolescence was dominated by disease-related infectious morbidity, with a trend toward noninfectious and treatment-related morbidity in later adolescence. Higher overall morbidity rates were associated with a CD4 count <350 cells/µL, HIV viral load ≥10,000 copies/mL and experiencing prior morbidity at age <10 years. Lower overall morbidity rates were found for those 15-19 years of age compared with 10-14 years and those who initiated ART at age 5-9 years compared with <5 or ≥10 years.

Conclusions: Half of our PHIVA cohort experienced a morbidity event, with a trend from disease-related infectious events to treatment-related and noninfectious events as PHIVA age. ART initiation to prevent immune system damage, optimize virologic control and minimize childhood morbidity are key to limiting adolescent morbidity.
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http://dx.doi.org/10.1097/INF.0000000000002208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375771PMC
March 2019

Seroprevalence of Hepatitis B Among HIV-infected Children and Adolescents Receiving Antiretroviral Therapy in the TREAT Asia Pediatric HIV Observational Database.

Pediatr Infect Dis J 2018 08;37(8):788-793

Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.

Background: Hepatitis B (HBV)-HIV coinfection is associated with liver inflammation, which can progress to liver fibrosis/cirrhosis and hepatocellular carcinoma. We determined HBV seroprevalence in children and adolescents participating in the TREAT Asia Pediatric HIV Observational Database.

Methods: A multisite cross-sectional study was conducted in HIV-infected patients currently <25 years old receiving antiretroviral treatment (ART) who had HBV surface antigen (HBsAg), or HBV surface antibody (anti-HBs) or HBV core antibody (anti-HBc) tested during 2012-2013. HBV coinfection was defined as having either a positive HBsAg test or being anti-HBc positive and anti-HBs negative, reflective of past HBV infection. HBV seroprotection was defined as having a positive anti-HBs test.

Results: A total of 3380 patients from 6 countries (Vietnam, Thailand, Cambodia, Malaysia, Indonesia and India) were included. The current median (interquartile range) age was 11.2 (7.8-15.1) years. Of the 2755 patients (81.5%) with HBsAg testing, 130 (4.7%) were positive. Of 1558 (46%) with anti-HBc testing, 77 (4.9%) were positive. Thirteen of 1037 patients with all 3 tests were anti-HBc positive and HBsAg and anti-HBs negative. One child was positive for anti-HBc and negative for anti-HBs but did not have HBsAg tested. The prevalence of HBV coinfection was 144/2759 (5.2%) (95% confidence interval: 4.4-6.1). Of 1093 patients (32%) with anti-HBs testing, 257 (23.5%; confidence interval: 21.0-26.0) had positive tests representing HBV seroprotection.

Conclusions: The estimated prevalence of HBV coinfection in this cohort of Asian HIV-infected children and adolescents on ART was 5.2%. The majority of children and adolescents tested in this cohort (76.5%) did not have protective HBV antibody. The finding supports HBV screening of HIV-infected children and adolescents to guide revaccination, the use of ART with anti-HBV activity and future monitoring.
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http://dx.doi.org/10.1097/INF.0000000000001901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097529PMC
August 2018

Characteristics, mortality and outcomes at transition for adolescents with perinatal HIV infection in Asia.

AIDS 2018 07;32(12):1689-1697

Pediatric Institute, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia.

Objectives: The aim of this study was to describe characteristics of perinatally HIV-infected adolescents (PHIVAs), factors associated with mortality, and outcomes at transition.

Design: Ongoing observational database collating clinical data on HIV-infected children and adolescents in Asia.

Methods: Data from 2001 to 2016 relating to adolescents (10-19 years) with perinatal HIV infection were analysed to describe characteristics at adolescent entry and transition and combination antiretroviral therapy (cART) regimens across adolescence. A competing risk regression analysis was used to determine characteristics at adolescent entry associated with mortality. Outcomes at transition were compared on the basis of age at cART initiation.

Results: Of 3448 PHIVA, 644 had reached transition. Median age at HIV diagnosis was 5.5 years, cART initiation 7.2 years and transition 17.9 years. At adolescent entry, 35.0% had CD4+ cell count less than 500 cells/μl and 51.1% had experienced a WHO stage III/IV clinical event. At transition, 38.9% had CD4+ cell count less than 500 copies/ml, and 53.4% had experienced a WHO stage III/IV clinical event. Mortality rate was 0.71 per 100 person-years, with HIV RNA ≥1000 copies/ml, CD4+ cell count less than 500 cells/μl, height-for-age or weight-for-age z-score less than -2, history of a WHO stage III/IV clinical event or hospitalization and at least second cART associated with mortality. For transitioning PHIVA, those who commenced cART age less than 5 years had better virologic and immunologic outcomes, though were more likely to be on at least second cART.

Conclusion: Delayed HIV diagnosis and cART initiation resulted in considerable morbidity and poor immune status by adolescent entry. Durable first-line cART regimens to optimize disease control are key to minimizing mortality. Early cART initiation provides the best virologic and immunologic outcomes at transition.
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http://dx.doi.org/10.1097/QAD.0000000000001883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084456PMC
July 2018

Risk Factors for Human Papillomavirus Infection and Abnormal Cervical Cytology Among Perinatally Human Immunodeficiency Virus-Infected and Uninfected Asian Youth.

Clin Infect Dis 2018 08;67(4):606-613

Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

Background: Infection with high-risk human papillomavirus (HR-HPV) may be higher in perinatally human immunodeficiency virus (HIV)-infected (PHIV) than HIV-uninfected (HU) adolescents because of long-standing immune deficiency.

Methods: PHIV and HU females aged 12-24 years in Thailand and Vietnam were matched by age group and lifetime sexual partners. At enrollment, blood, cervical, vaginal, anal, and oral samples were obtained for HPV-related testing. The Wilcoxon and Fisher exact tests were used for univariate and logistic regression for multivariate analyses.

Results: Ninety-three PHIV and 99 HU adolescents (median age 19 [18-20] years) were enrolled (June 2013-July 2015). Among PHIV, 94% were currently receiving antiretroviral therapy, median CD4 count was 593 (392-808) cells/mm3, and 62% had a viral load <40 copies/mL. Across anogenital compartments, PHIV had higher rates of any HPV detected (80% vs 60%; P = .003) and any HR-HPV (60% vs 43%, P = .02). Higher proportions of PHIV had abnormal Pap smears (eg, atypical squamous cells of unknown significance [ASC-US], 12% vs 14%; low-grade squamous intraepithelial neoplastic lesions, 19% vs 1%). After adjusting for ever being pregnant and asymptomatic sexually transmitted infections (STI) at enrollment, PHIV were more likely to have HR-HPV than HU (odds ratio, 2.02; 95% confidence interval, 1.09-3.77; P = .03).

Conclusions: Perinatal HIV infection was associated with a higher risk of HR-HPV and abnormal cervical cytology. Our results underscore the need for HPV vaccination for PHIV adolescents and for prevention and screening programs for HPV and other STIs.
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http://dx.doi.org/10.1093/cid/ciy144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190885PMC
August 2018

Adherence to antiretroviral therapy, stigma and behavioral risk factors in HIV-infected adolescents in Asia.

AIDS Care 2018 06 16;30(6):727-733. Epub 2018 Jan 16.

b TREAT Asia/amfAR-The Foundation for AIDS Research , Bangkok , Thailand.

We studied behavioral risks among HIV-infected and uninfected adolescents using an audio computer-assisted self-interview. A prospective cohort study was initiated between 2013 and 2014 in Malaysia, Thailand, and Vietnam. HIV-infected adolescents were matched to uninfected adolescents (4:1) by sex and age group (12-14 and 15-18 years). We enrolled 250 HIV-infected (48% male; median age 14.5 years; 93% perinatally infected) and 59 uninfected (51% male; median age 14.1 years) adolescents. At enrollment, HIV-infected adolescents were on antiretroviral therapy (ART) for a median (IQR) of 7.5 (4.7-10.2) years, and 14% had HIV-RNA >1000 copies/mL; 19% reported adherence <80%. Eighty-four (34%) HIV-infected and 26 (44%) uninfected adolescents reported having ever smoked cigarettes or drunk alcohol (p = 0.13); 10% of HIV-infected and 17% of uninfected adolescents reported having initiated sexual activity; 6 of the HIV-infected adolescents had HIV-RNA >1000 copies/mL. Risk behaviors were common among adolescents, with few differences between those with and without HIV.
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http://dx.doi.org/10.1080/09540121.2018.1425363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912939PMC
June 2018

Structural Neuroimaging and Neuropsychologic Signatures in Children With Vertically Acquired HIV.

Pediatr Infect Dis J 2018 07;37(7):662-668

HIV Netherlands Australia Thailand (HIV-NAT) Research Collaboration, Thai Red Cross AIDS Research Center, Bangkok, Thailand.

Background: Children with vertically acquired HIV exhibit persistent cognitive impairments, yet the corresponding neuroimaging signature of vertical infection remains unclear.

Methods: Fifty healthy control children and 51 vertically infected children were included in the study. The HIV-infected group consisted of survivors who had not received antiretroviral therapy at birth. The HIV-infected group averaged 11.4 (2.5) years of age, with a median CD4 count of 683 cells/mm(3). Most (71%) of the HIV-infected children were on antiretroviral therapy for a median of 34 months (range: 33-42) with HIV RNA <40 copies/mL in 89% of the sample. The HIV-uninfected group averaged 10.6 (2.6) years of age. Magnetic resonance imaging was acquired to determine volumes of the caudate, putamen, thalamus, pallidum, hippocampus, nucleus accumbens, total white matter, total gray matter and cortical gray matter. Correlational analyses examined the degree of shared variance between brain volumes and both cognitive performances and laboratory markers of disease activity (T cells and plasma viral load).

Results: HIV-infected children exhibited larger volumes of the caudate, nucleus accumbens, total gray matter and cortical gray matter when compared with the controls. Volumetric differences were predominately evident in children under 12 years of age. HIV-infected children performed worse than controls on most neuropsychologic tests, though neither cognitive performances nor laboratory markers corresponded to brain volumes in the HIV-infected children.

Conclusions: Outcomes of the present study suggest abnormal brain maturation among HIV-infected pediatric survivors. Longitudinal studies of brain integrity and related resilience factors are needed to determine the impact of neuroimaging abnormalities on psychosocial function in pediatric HIV.
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http://dx.doi.org/10.1097/INF.0000000000001852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984109PMC
July 2018

Treatment Outcomes of Third-line Antiretroviral Regimens in HIV-infected Thai Adolescents.

Pediatr Infect Dis J 2017 Oct;36(10):967-972

From the *The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), The Thai Red Cross AIDS Research Centre, Bangkok, Thailand; †Division of Infectious Diseases, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; ‡Bamrasnaradura Infectious Diseases Institute, Nonthaburi, Thailand; §Nakornping Hospital, Chiang Mai, Thailand; ¶Division of Infectious Diseases, Department of Pediatrics, Khon Kaen University, Khon Kaen, Thailand; ‖Prapokklao Hospital, Chantaburi, Thailand; **Surin Hospital, Surin, Thailand; ††Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand; ‡‡The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia; §§Department of Global Health, Academic Medical Center, University of Amsterdam, Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands; ¶¶Division of Infectious Diseases, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; and ‖‖The University of Amsterdam, Amsterdam, The Netherlands.

Background: Efficacy and safety data of third-line antiretroviral (ARV) regimens in adolescents are limited.

Methodology: This study enrolled HIV-infected Thais who were treated with third-line regimens consisting of darunavir/ritonavir (DRV/r), etravirine (ETR), tipranavir/ritonavir or raltegravir.

Results: Fifty-four adolescents 2-17 years of age were enrolled from 8 sites and followed for 48 weeks. Reasons for switch were second-line failure (n = 44) and toxicity to second-line regimens (n = 10). At switching to third-line ARV, the median age (interquartile range) was 14.3 (12.4-15.4) years. Genotypes at time of second-line failure (n = 44) were M184V (77%), ≥4 thymidine analogue mutations (25%), non-nucleoside reverse transcriptase inhibitor-resistant associated mutation (RAM) (80%), ETR-RAM score ≥4 (14%), any lopinavir-RAM (59%) and ≥1 major DRV-RAM (41%). The third-line regimens had a median of 4 (min-max, 4-6) drugs and included ETR/DRV/r (43%), DRV/r (33%), ETR (17%), tipranavir/ritonavir (2%) or raltegravir/DRV/r/ (4%). The median CD4 (interquartile range) increased from 16% (12-21) at third-line switch to 21% (18-25) and 410 (172-682) to 607 (428-742) cells/mm at 48 weeks (P < 0.001). HIV RNA declined from 3.9 (2.9-4.9) to 1.6 (1.6-3.0) log10 copies/mL (P < 0.001) and 33/50 (66%) had levels <50 copies/mL at 48 weeks. Seventeen (31%) had HIV-RNA ≥1000 copies/mL; about half due to poor adherence; genotyping in 13 of these adolescents revealed ETR-RAM score ≥4 in 2 (15%) and ≥1 major DRV-RAM in 7 (54%).

Conclusions: Third-line ARV therapy was well tolerated and resulted in virologic suppression in 70% of adolescents at 1 year. Poor adherence and limited ARV options are major problems in the long-term management of adolescents with HIV.
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http://dx.doi.org/10.1097/INF.0000000000001638DOI Listing
October 2017

Incidence of Postsuppression Virologic Rebound in Perinatally HIV-Infected Asian Adolescents on Stable Combination Antiretroviral Therapy.

J Adolesc Health 2017 Jul 24;61(1):91-98. Epub 2017 Mar 24.

Faculty of Medicine, The Kirby Institute, UNSW Australia, Sydney, Australia.

Purpose: To assess the incidence and predictors of postsuppression virologic rebound (VR) among adolescents on stable combination antiretroviral therapy in Asia.

Methods: Perinatally HIV-infected Asian adolescents (10-19 years) with documented virologic suppression (two consecutive viral loads [VLs] <400 copies/mL ≥6 months apart) were included. Baseline was the date of the first VL <400 copies/mL at age ≥10 years or the 10th birthday for those with prior suppression. Cox proportional hazards models were used to identify predictors of postsuppression VR (VL >1,000 copies/mL).

Results: Of 1,379 eligible adolescents, 47% were males. At baseline, 22% were receiving protease inhibitor-containing regimens; median CD4 cell count (interquartile range [IQR]) was 685 (448-937) cells/mm; 2% had preadolescent virologic failure (VF) before subsequent suppression. During adolescence, 180 individuals (13%) experienced postsuppression VR at a rate of 3.4 (95% confidence interval: 2.9-3.9) per 100 person-years, which was consistent over time. Median time to VR during adolescence (IQR) was 3.3 (2.1-4.8) years. Wasting (weight-for-age z-score <-2.5), being raised by grandparents, receiving second-line protease inhibitor-based regimens, starting combination antiretroviral therapy after 2005, and having preadolescent VF were independent predictors of adolescent VR. At VR, median age, CD4 cell count, and VL (IQR) were 14.8 (13.2-16.4) years, 507 (325-723) cells/mm, and 4.1 (3.5-4.7) log copies/mL, respectively.

Conclusions: A modest and consistent incidence of postsuppression VR was documented during adolescence in our cohort. Having poor weight, receiving second-line regimens, and prior VF were associated with an increased VR rate. Adolescents at higher risk of VR may benefit from more intensive VL monitoring to enhance adherence management.
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http://dx.doi.org/10.1016/j.jadohealth.2017.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5483211PMC
July 2017

HIV-infected children in the Asia-Pacific region with baseline severe anemia: antiretroviral therapy and outcomes.

Asian Biomed (Res Rev News) 2016 Jun;10(3):229-234

The Kirby Institute, University of New South Wales, Sydney, NSW 2052, Australia.

Background: Severe anemia is common among children infected with human immunodeficiency virus (HIV). The choice of antiretroviral (ART) regimen needs careful consideration. No information is available regarding the initial ART regimens used in the Asia-Pacific region and the rate of switch of ART regimens in HIV-infected children with severe anemia.

Objectives: To study the initial ART regimens and the rate of switch of ART regimens used during the first 36 months in HIV-infected children with severe anemia and to evaluate their clinical and laboratory outcomes.

Methods: We analyzed regional cohort data of 130 Asian children aged <18 years with baseline severe anemia (hemoglobin <7.5 g/dl) who started antiretroviral therapy (ART) between January 2003 and September 2013.

Results: At ART initiation, median age was 3.5 years old (interquartile range (IQR) 1.7 to 6.3) and median hemoglobin was 6.7 g/dL (IQR 5.9-7.1, range 3.0-7.4). Initial ART regimens included stavudine (85.4%), zidovudine (13.8%), and abacavir (0.8%). In 81 children with available hemoglobin data after 6 months of ART, 90% recovered from severe anemia with a median hemoglobin of 10.7 g/dL (IQR 9.6-11.7, range 4.4-13.5). Those starting AZT-based ART had a mortality rate of 10.8 (95% confidence interval (CI) 4.8-23.9) per 100 patient-years compared to 2.7 (95% CI 1.6-4.6) per 100 patient-years among those who started d4T-based ART.

Conclusions: With the phase-out of stavudine, age-appropriate non-zidovudine options are needed for younger Asian children with severe anemia.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321077PMC
June 2016

Response to Tenofovir Among Lamivudine-experienced Hepatitis B and HIV-coinfected Adolescents.

Pediatr Infect Dis J 2017 04;36(4):401-404

From the *Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand; †Division of Infectious Diseases, Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; ‡Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand: §Nakornping Hospital, Chiang Mai, Thailand; ¶The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), the Thai Red Cross AIDS Research, Bangkok, Thailand; and ‖Department of Pediatrics, Faculty of Medicine, and Research Unit in Pediatric Infectious Diseases and Vaccines, Chulalongkorn University, Bangkok, Thailand.

We determined hepatitis B virus (HBV) suppression rates among 18 lamivudine (3TC)-experienced HBV-human immunodeficiency virus-coinfected adolescents after treatment with tenofovir disoproxil fumurate (TDF). At TDF initiation, their median age was 17.6 years, and duration of 3TC exposure was 7.3 years. Eleven patients (61%) achieved HBV DNA <60 IU/mL after 48 weeks on TDF and 3TC which was similar to adult studies, although hepatitis B surface antigen loss or hepatitis B envelope antigen seroconversion did not occur.
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http://dx.doi.org/10.1097/INF.0000000000001491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348266PMC
April 2017

Short Communication: Impact of Viral Load Use on Treatment Switch in Perinatally HIV-Infected Children in Asia.

AIDS Res Hum Retroviruses 2017 03 31;33(3):230-233. Epub 2016 Oct 31.

17 TREAT Asia/amfAR-The Foundation for AIDS Research , Bangkok, Thailand .

We sought to assess the impact of routine HIV viral load (VL) monitoring on the incidence of switching from a first- to a second-line antiretroviral therapy (ART) regimen, and to describe factors associated with switch. Data from a regional cohort of 16 clinical programs in six Asian countries were analyzed. Second-line switch was defined as a change from a non-nucleoside reverse transcriptase inhibitor (NNRTI) to a protease inhibitor (PI) or vice versa, and ≥1 of the following: (1) reported treatment failure by local criteria, (2) switch of ≥1 additional drug, or (3) a preceding HIV VL ≥1,000 copies/ml. Routine VL was having ≥1 test after ≥24 weeks of ART and ≥1 time/year thereafter. Factors associated with time to switch were evaluated with death and loss to follow-up as competing risks. A total of 2,398 children were included in this analysis. At ART initiation, the median (interquartile range) age was 6.0 (3.3-8.9) years, more than half had WHO stage 3 or 4, the median CD4 was 189 (47-456) cells/mm, 93% were on NNRTI-based first-line ART, and 34% had routine VL monitoring. Treatment switch occurred in 17.6% of patients, at a median of 35 (22-49) months. After adjusting for country, sex, first ART regimen, and CD4% at ART initiation, children with routine VL monitoring were 1.46 (95% confidence interval 1.11-1.93) times more likely to be switched (p = .007). Scale-up of VL testing will lead to earlier identification of treatment failure, and it can help guide earlier switches to prevent resistance.
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http://dx.doi.org/10.1089/AID.2016.0039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333561PMC
March 2017

Impact of orphan status on HIV treatment outcomes and retention in care of children and adolescents in Asia.

J Virus Erad 2016 Oct 5;2(4):227-231. Epub 2016 Oct 5.

TREAT Asia/amfAR - The Foundation for AIDS Research , Bangkok , Thailand .

An analysis of the impact of orphanhood at antiretroviral therapy (ART) initiation on HIV outcomes in Asia included 4300 children; 51% were male. At ART initiation, 1805 (42%) were non-orphans (median age: 3 years), 1437 (33%) were single orphans (6 years) and 1058 (25%) were double orphans (7 years). Ten-year post-ART survival was 93.4-95.2% across orphan categories. Clinic transfers were higher among single and double orphans than non-orphans (41% 11%, <0.001). On multivariate analysis, children ≥3 years at ART initiation (hazard ratio 1.58 <3 years, 95% confidence interval: 1.11-2.24) were more likely to be lost to follow-up. Although post-ART mortality and retention did not differ by orphan status, orphans were at greater risk of starting ART at older ages, and with more severe immunosuppression and poorer growth.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075350PMC
October 2016

Early Height and Weight Changes in Children Using Cotrimoxazole Prophylaxis With Antiretroviral Therapy.

Clin Infect Dis 2016 11 28;63(9):1236-1244. Epub 2016 Jul 28.

The Kirby Institute, University of New South Wales, Sydney, Australia.

Background: The growth benefits of cotrimoxazole during early antiretroviral therapy (ART) are not well characterized.

Methods: Individuals enrolled in the Therapeutics Research, Education, and AIDS Training in Asia Pediatric HIV Observational Database were included if they started ART at ages 1 month-14 years and had both height and weight measurements available at ART initiation (baseline). Generalized estimating equations were used to identify factors associated with change in height-for-age z-score (HAZ), follow-up HAZ ≥ -2, change in weight-for-age z-score (WAZ), and follow-up WAZ ≥ -2.

Results: A total of 3217 children were eligible for analysis. The adjusted mean change in HAZ among cotrimoxazole and non-cotrimoxazole users did not differ significantly over the first 24 months of ART. In children who were stunted (HAZ < -2) at baseline, cotrimoxazole use was not associated with a follow-up HAZ ≥ -2. The adjusted mean change in WAZ among children with a baseline CD4 percentage (CD4%) >25% became significantly different between cotrimoxazole and non-cotrimoxazole users after 6 months of ART and remained significant after 24 months (overall P < .01). Similar changes in WAZ were observed in those with a baseline CD4% between 10% and 24% (overall P < .01). Cotrimoxazole use was not associated with a significant difference in follow-up WAZ in children with a baseline CD4% <10%. In those underweight (WAZ < -2) at baseline, cotrimoxazole use was associated with a follow-up WAZ ≥ -2 (adjusted odds ratio, 1.70 vs not using cotrimoxazole [95% confidence interval, 1.28-2.25], P < .01). This association was driven by children with a baseline CD4% ≥10%.

Conclusions: Cotrimoxazole use is associated with benefits to WAZ but not HAZ during early ART in Asian children.
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http://dx.doi.org/10.1093/cid/ciw514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064162PMC
November 2016

Low Risk of CD4 Decline After Immune Recovery in Human Immunodeficiency Virus-Infected Children With Viral Suppression.

J Pediatric Infect Dis Soc 2017 Jun;6(2):173-177

Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Background.: Regular CD4 count testing is often used to monitor antiretroviral therapy efficacy. However, this practice may be redundant in children with a suppressed human immunodeficiency virus (HIV) viral load.

Methods: Study end points were as follows: (1) a CD4 count <200 cells/mm3 followed by a CD4 count ≥200 cells/mm3 (transient CD4 <200); (2) CD4 count <200 cells/mm3 confirmed within 6 months (confirmed CD4 <200); and (3) a new or recurrent World Health Organization (WHO) stage 3 or 4 illness (clinical failure). Kaplan-Meier curves and Cox regression were used to evaluate rates and predictors of transient CD4 <200, confirmed CD4 <200, and clinical failure among virally suppressed children aged 5-15 years who were enrolled in the TREAT Asia Pediatric HIV Observational Database.

Results: Data from 967 children were included in the analysis. At the time of confirmed viral suppression, median age was 10.2 years, 50.4% of children were female, and 95.4% were perinatally infected with HIV. Median CD4 cell count was 837 cells/mm3, and 54.8% of children were classified as having WHO stage 3 or 4 disease. In total, 18 transient CD4 <200 events, 2 confirmed CD4 <200 events, and10 clinical failures occurred at rates of 0.73 (95% confidence interval [95% CI], 0.46-1.16), 0.08 (95% CI, 0.02-0.32), and 0.40 (95% CI, 0.22-0.75) events per 100 patient-years, respectively. CD4 <500 cells/mm3 at the time of viral suppression confirmation was associated with higher rates of both CD4 outcomes.

Conclusions: Regular CD4 testing may be unnecessary for virally suppressed children aged 5-15 years with CD4 ≥500 cells/mm3.
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http://dx.doi.org/10.1093/jpids/piw031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251660PMC
June 2017

Antiretroviral Therapy in Severely Malnourished, HIV-infected Children in Asia.

Pediatr Infect Dis J 2016 May;35(5):e144-51

From the *The Kirby Institute, UNSW Australia, Sydney, Australia; †Department of Pediatrics, Faculty of Medicine, Chiang Mai University and Research Institute for Health Sciences, Chiang Mai, Thailand; ‡Cipto Mangunkusumo General Hospital, Jakarta, Indonesia; §Hospital Likas, Kota Kinabalu, Malaysia; ¶Division of Infectious Diseases, Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; ‖National Centre for HIV/AIDS Dermatology and STDs, Phnom Penh, Cambodia; **Children's Hospital 1, Ho Chi Minh City, Vietnam; ††Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand; ‡‡National Hospital of Pediatrics, Hanoi, Vietnam; §§Children's Hospital 2, Ho Chi Minh City, Vietnam; ¶¶HIV-NAT, the Thai Red Cross AIDS Research Centre, Bangkok, Thailand; ‖‖Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; ***Hospital Raja Perempuan Zainab II, Kelantan, Malaysia; †††YRGCARE Medical Centre, CART CRS, Chennai, India; ‡‡‡Sanglah Hospital, Udayana University, Bali, Indonesia; §§§Pediatric Institute, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; and ¶¶¶Members of TREAT Asia Pediatric HIV Observational Database are listed in Appendix.

Background: Information on antiretroviral therapy (ART) use in HIV-infected children with severe malnutrition (SM) is lacking. We investigated long-term ART outcomes in this population.

Methods: Children enrolled in the TREAT Asia Pediatric HIV Observational Database who had SM (weight-for-height or body mass index-for-age Z score less than -3) at ART initiation were analyzed. Generalized estimating equations were used to investigate poor weight recovery (weight-for-age Z score less than -3) and poor CD4% recovery (CD4% <25), and competing risk regression was used to analyze mortality and toxicity-associated treatment modification.

Results: Three hundred fifty-five (11.9%) of 2993 children starting ART had SM. Their median weight-for-age Z score increased from -5.6 at ART initiation to -2.3 after 36 months. Not using trimethoprim-sulfamethoxazole prophylaxis at baseline was associated with poor weight recovery [odds ratio: 2.49 vs. using; 95% confidence interval (CI): 1.66-3.74; P < 0.001]. Median CD4% increased from 3.0 at ART initiation to 27.2 after 36 months, and 56 (15.3%) children died during follow-up. More profound SM was associated with poor CD4% recovery (odds ratio: 1.78 for Z score less than -4.5 vs. -3.5 to less than -3.0; 95% CI: 1.08-2.92; P = 0.023) and mortality (hazard ratio: 2.57 for Z score less than -4.5 vs. -3.5 to less than -3.0; 95% CI: 1.24-5.33; P = 0.011). Twenty-two toxicity-associated ART modifications occurred at a rate of 2.4 per 100 patient-years, and rates did not differ by malnutrition severity.

Conclusion: Trimethoprim-sulfamethoxazole prophylaxis is important for the recovery of weight-for-age in severely malnourished children starting ART. The extent of SM does not impede weight-for-age recovery or antiretroviral tolerability, but CD4% response is compromised in children with a very low weight-for-height/body mass index-for-age Z score, which may contribute to their high rate of mortality.
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http://dx.doi.org/10.1097/INF.0000000000001074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4829479PMC
May 2016

Soluble CD163 and monocyte populations in response to antiretroviral therapy and in relationship with neuropsychological testing among HIV-infected children.

J Virus Erad 2015;1(3):196-202. Epub 2015 Jun 30.

HIV Netherlands Australia Thailand (HIV-NAT) Research Collaboration, Thai Red Cross AIDS Research Center, Bangkok, Thailand; Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Background: Monocytes play a central role in HIV neuropathogenesis, but there are limited data on monocyte subsets and markers of monocyte activation in perinatally HIV-infected children.

Objective: To determine the relationship between monocyte subsets, the sCD163 monocyte activation marker, and neuropsychological performance among perinatally HIV-infected children initiating antiretroviral therapy (ART).

Methods: ART-naïve children from the PREDICT study were categorised into two groups: those on ART for ≥24 weeks (ART group, =201) and those untreated (no ART group, =79). This analysis used data from the baseline and week 144 including sCD163 and frequencies of activated monocytes (CD14+/CD16+/HLA-DR+), perivascular monocytes (CD14+/CD16+/CD163+ and CD14low/CD16+/CD163+), and neuropsychological testing scores: Verbal and Performance Intelligence Quotient (VIQ and PIQ), Beery Visuomotor Integration (VMI) and Children's Color Trails 2 (CT2).

Results: Baseline demographic and HIV disease parameters were similar between groups. The median age was 6 years, CD4 was 20% (620 cells/mm), and HIV RNA was 4.8 log. By week 144, the ART the no ART group had significantly higher CD4 (938 552 cells/mm) and lower HIV RNA (1.6 4.38 log copies/mL, <0.05). sCD163 declined in the ART no ART group (median changes -2533 -159 ng/mL, <0.0001). Frequencies of all monocyte subsets declined in the treated but not the untreated group ( <0.05). Higher CD14+/CD16+/HLA-DR+ percentage was associated with higher VIQ, Beery VMI and CT2 scores. Higher percentages of CD14+/CD16+/CD163+ and CD14low/CD16+/CD163+ were associated with higher CT2 and VIQ, respectively.

Conclusion: ART significantly reduced sCD163 levels and frequencies of activated and perivascular monocytes. Higher frequencies of these cells correlated with better neuropsychological performance suggesting a protective role of monocyte-macrophage immune activation in perinatal HIV infection in terms of neuropsychological function.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729380PMC
June 2015

Non-Nucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy in Perinatally HIV-Infected, Treatment-Naïve Adolescents in Asia.

J Adolesc Health 2016 Apr 20;58(4):451-459. Epub 2016 Jan 20.

Faculty of Medicine, The Kirby Institute, UNSW Australia, Sydney, New South Wales, Australia.

Purpose: About a third of untreated, perinatally HIV-infected children reach adolescence. We evaluated the durability and effectiveness of non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) in this population.

Methods: Data from perinatally HIV-infected, antiretroviral-naïve patients initiated on NNRTI-based ART aged 10-19 years who had ≥6 months of follow-up were analyzed. Competing risk regression was used to assess predictors of NNRTI substitution and clinical failure (World Health Organization Stage 3/4 event or death). Viral suppression was defined as a viral load <400 copies/mL.

Results: Data from 534 adolescents met our inclusion criteria (56.2% female; median age at treatment initiation 11.8 years). After 5 years of treatment, median height-for-age z score increased from -2.3 to -1.6, and median CD4+ cell count increased from 131 to 580 cells/mm(3). The proportion of patients with viral suppression after 6 months was 87.6% and remained >80% up to 5 years of follow-up. NNRTI substitution and clinical failure occurred at rates of 4.9 and 1.4 events per 100 patient-years, respectively. Not using cotrimoxazole prophylaxis at ART initiation was associated with NNRTI substitution (hazard ratio [HR], 1.5 vs. using; 95% confidence interval [CI] = 1.0-2.2; p = .05). Baseline CD4+ count ≤200 cells/mm(3) (HR, 3.3 vs. >200; 95% CI = 1.2-8.9; p = .02) and not using cotrimoxazole prophylaxis at ART initiation (HR, 2.1 vs. using; 95% CI = 1.0-4.6; p = .05) were both associated with clinical failure.

Conclusions: Despite late ART initiation, adolescents achieved good rates of catch-up growth, CD4+ count recovery, and virological suppression. Earlier ART initiation and routine cotrimoxazole prophylaxis in this population may help to reduce current rates of NNRTI substitution and clinical failure.
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http://dx.doi.org/10.1016/j.jadohealth.2015.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808326PMC
April 2016