Publications by authors named "Revathy Nallusamy"

37 Publications

A single-center pilot study in Malaysia on the clinical utility of whole-exome sequencing for inborn errors of immunity.

Clin Exp Immunol 2021 Jun 1. Epub 2021 Jun 1.

Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.

Primary immunodeficiency diseases refer to inborn errors of immunity (IEI) that affect the normal development and function of the immune system. The phenotypical and genetic heterogeneity of IEI have made their diagnosis challenging. Hence, whole-exome sequencing (WES) was employed in this pilot study to identify the genetic etiology of 30 pediatric patients clinically diagnosed with IEI. The potential causative variants identified by WES were validated using Sanger sequencing. Genetic diagnosis was attained in 46.7% (14 of 30) of the patients and categorized into autoinflammatory disorders (n = 3), diseases of immune dysregulation (n = 3), defects in intrinsic and innate immunity (n = 3), predominantly antibody deficiencies (n = 2), combined immunodeficiencies with associated and syndromic features (n = 2) and immunodeficiencies affecting cellular and humoral immunity (n = 1). Of the 15 genetic variants identified, two were novel variants. Genetic findings differed from the provisional clinical diagnoses in seven cases (50.0%). This study showed that WES enhances the capacity to diagnose IEI, allowing more patients to receive appropriate therapy and disease management.
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http://dx.doi.org/10.1111/cei.13626DOI Listing
June 2021

Atypical Presentation of Severe Fungal Necrotizing Fasciitis in a Patient with X-Linked Agammaglobulinemia.

J Clin Immunol 2021 Aug 13;41(6):1178-1186. Epub 2021 Mar 13.

Primary Immunodeficiency Unit, Allergy and Immunology Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health, Selangor, Malaysia.

X-linked agammaglobulinemia is a rare primary immunodeficiency due to a BTK mutation. The patients are characteristically deficient in peripheral B cells and serum immunoglobulins. While they are susceptible to infections caused by bacteria, enteroviruses, and parasites, fungal infections are uncommon in XLA patients. Here, we report a boy of Malay ethnicity who suffered from recurrent upper respiratory tract infections and severe progressive necrotizing fasciitis caused by Saksenaea erythrospora. Immunological tests showed a B cell deficiency and hypogammaglobulinemia. Whole-exome sequencing identified a dinucleotide deletion (c.1580_1581del) in BTK, confirmed by Sanger sequencing and predicted to be disease causing by in silico functional prediction tools (Varsome and MutationTaster2) but was absent in the gnomAD database. This mutation resulted in a frameshift and premature termination (p.C527fs), which disrupted the protein structure. The mother was heterozygous at the mutation site, confirming her carrier status. Flow cytometric analysis of monocyte BTK expression showed it to be absent in the patient and bimodal in the mother. This study describes a novel BTK mutation in a defined hotspot and an atypical fungal phenotype in XLA. Further studies are required to understand the pathogenesis of fungal infection in XLA.
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http://dx.doi.org/10.1007/s10875-021-01017-3DOI Listing
August 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

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

AIDS 2020 08;34(10):1527-1537

The Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia.

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.
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http://dx.doi.org/10.1097/QAD.0000000000002583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487212PMC
August 2020

A novel de novo NLRC4 mutation reinforces the likely pathogenicity of specific LRR domain mutation.

Clin Immunol 2020 02 20;211:108328. Epub 2019 Dec 20.

Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia; Centre of Research in Systems Biology, Structural Bioinformatics and Human Digital Imaging (CRYSTAL), University of Malaya, Kuala Lumpur, Malaysia. Electronic address:

Autoinflammatory disorders are characterized by dysregulated innate immune response, resulting in recurrent uncontrolled systemic inflammation and fever. Gain-of-function mutations in NLRC4 have been described to cause a range of autoinflammatory disorders. We report a twelve-year-old Malay girl with recurrent fever, skin erythema, and inflammatory arthritis. Whole exome sequencing and subsequent bidirectional Sanger sequencing identified a heterozygous missense mutation in NLRC4 (NM_001199138: c.1970A > T). This variant was predicted to be damaging in silico, was absent in public and local databases and occurred in a highly conserved residue in the leucine-rich repeat (LRR) domain. Cytokine analysis showed extremely high serum IL-18 and IL-18/CXCL9 ratio, consistent with other NLRC4-MAS patients. In summary, we identified the first patient with a novel de novo heterozygous NLRC4 gene mutation contributing to autoinflammatory disease in Malaysia. Our findings reinforce the likely pathogenicity of specific LRR domain mutations in NLRC4 and expand the clinical spectrum of NLRC4 mutations.
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http://dx.doi.org/10.1016/j.clim.2019.108328DOI Listing
February 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

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

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

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

Impact of a new aggressive nutrition policy incorporating early introduction of parenteral nutrition and mother's own milk on growth of preterm infants.

World J Pediatr 2016 Nov 10;12(4):450-454. Epub 2016 Jun 10.

Department of Pediatrics, Penang Hospital, Penang, Malaysia.

Background: Most of the evidence on early feeding of preterm infants was derived from high income settings, it is equally important to evaluate whether it can be successfully implemented into less resourced settings. This study aimed to compare growth and feeding of preterm infants before and after the introduction of a new aggressive feeding policy in Penang Hospital, a tertiary referral hospital in a middle income country.

Methods: The new aggressive feeding policy was developed mainly from Cochrane review evidence, using early parenteral and enteral nutrition with standardized breastfeeding counselling aimed at empowering mothers to provide early expressed milk. A total of 80 preterm babies (34 weeks and below) discharged from NICU were included (40 pre- and 40 post-intervention). Pre and post-intervention data were compared. The primary outcome was growth at day 7, 14, 21 and at discharge and secondary outcomes were time to full oral feeding, breastfeeding rates, and adverse events.

Results: Complete data were available for all babies to discharge. One baby was discharged prior to day 14 and 10 babies before day 21, so growth data for these babies were unavailable. Baseline data were similar in the two groups. There was no significant weight difference at 7, 14, 21 days and at discharge. More post-intervention babies were breastfed at discharge than pre-intervention babies (21 vs. 8, P=0.005). Nosocomial infection (11 vs. 4, P=0.045), and blood transfusion were significantly lower in the postintervention babies than in the pre-intervention babies (31 vs. 13, P=0.01). The post-intervention babies were more likely to achieve shorter median days (interquartile range) to full oral feeding [11 (6) days vs. 13 (11) days, P=0.058] and with lower number affecting necrotising enterocolitis (0 vs. 5, P=0.055).

Conclusion: Early aggressive parenteral nutrition and early provision of mother's milk did not result in improved growth as evidenced by weight gain at discharge. However we found more breastfeeding babies, lower nosocomial infection and transfusion rates. Our findings suggest that implementing a more aggressive feeding policy supported by high level scientific evidence is able to improve important outcomes.
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http://dx.doi.org/10.1007/s12519-016-0037-7DOI Listing
November 2016

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

Hand hygiene compliance in Penang, Malaysia: Human audits versus product usage.

Am J Infect Control 2016 06 17;44(6):e95-7. Epub 2016 Feb 17.

School of Public Health and Community Medicine, UNSW Medicine, Sydney, NSW, Australia. Electronic address:

Hand hygiene auditing is mandatory for all Malaysian public hospitals; nonetheless, the burden of auditing is impacting the support and sustainability of the program. We report an alternative method to routinely measure hand hygiene compliance with the aim to test whether alcohol-based handrub purchase data could be used as a proxy for usage because human auditing has decreased validity and reliability inherent in the methodology.
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http://dx.doi.org/10.1016/j.ajic.2015.12.031DOI Listing
June 2016

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

Final Height and Associated Factors in Perinatally HIV-infected Asian Adolescents.

Pediatr Infect Dis J 2016 Feb;35(2):201-4

From the *HIV-NAT, the Thai Red Cross AIDS Research Centre, Bangkok, Thailand; †The Kirby Institute, University of New South Wales, Sydney, Australia; ‡Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand; §Department of Pediatrics, Siriraj Hospital, Mahidol University, Bangkok, Thailand; ¶Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand; ‖Division of Infectious Diseases, Department of Pediatrics, Khon Kaen University, Khon Kaen, Thailand; **Research Unit, National Centre for HIV/AIDS, Dermatology and STDs, Phnom Penh, Cambodia; ††Department of Public Health, University of Health Sciences, Phnom Penh, Cambodia; ‡‡Pediatric TB/HIV/AIDS Care Department, National Pediatric Hospital, Phnom Penh, Cambodia; §§YR Gaitonde Centre for AIDS Research and Education, Chennai, India; ¶¶Department of Pediatrics, Penang Hospital, Penang, Malaysia; ‖‖Infectious Disease Department, National Hospital of Pediatrics, Hanoi, Vietnam; ***Department of Pediatrics, Hospital Raja Perempuan Zainab II, Kelantan, Malaysia; †††TREAT Asia/amfAR, The Foundation for AIDS Research, Bangkok, Thailand; and ‡‡‡Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

We analyzed final height of 273 perinatally HIV-infected Asian adolescents older than 18 years at their last clinic visit. By the World Health Organization child growth reference, 30% were stunted, but by the Thai child growth reference, 19% were stunted. Half of those who were stunted at antiretroviral therapy initiation remained stunted over time. Being male and having a low baseline height-for-age Z score of less than -1.0 were associated with low final height Z score.
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http://dx.doi.org/10.1097/INF.0000000000000961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712093PMC
February 2016

Tuberculosis in Pediatric Antiretroviral Therapy Programs in Low- and Middle-Income Countries: Diagnosis and Screening Practices.

J Pediatric Infect Dis Soc 2015 Mar 28;4(1):30-8. Epub 2014 Mar 28.

Institute of Social and Preventive Medicine (ISPM), University of Bern, Switzerland Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Switzerland.

Background: The global burden of childhood tuberculosis (TB) is estimated to be 0.5 million new cases per year. Human immunodeficiency virus (HIV)-infected children are at high risk for TB. Diagnosis of TB in HIV-infected children remains a major challenge.

Methods: We describe TB diagnosis and screening practices of pediatric antiretroviral treatment (ART) programs in Africa, Asia, the Caribbean, and Central and South America. We used web-based questionnaires to collect data on ART programs and patients seen from March to July 2012. Forty-three ART programs treating children in 23 countries participated in the study.

Results: Sputum microscopy and chest Radiograph were available at all programs, mycobacterial culture in 40 (93%) sites, gastric aspiration in 27 (63%), induced sputum in 23 (54%), and Xpert MTB/RIF in 16 (37%) sites. Screening practices to exclude active TB before starting ART included contact history in 41 sites (84%), symptom screening in 38 (88%), and chest Radiograph in 34 sites (79%). The use of diagnostic tools was examined among 146 children diagnosed with TB during the study period. Chest Radiograph was used in 125 (86%) children, sputum microscopy in 76 (52%), induced sputum microscopy in 38 (26%), gastric aspirate microscopy in 35 (24%), culture in 25 (17%), and Xpert MTB/RIF in 11 (8%) children.

Conclusions: Induced sputum and Xpert MTB/RIF were infrequently available to diagnose childhood TB, and screening was largely based on symptom identification. There is an urgent need to improve the capacity of ART programs in low- and middle-income countries to exclude and diagnose TB in HIV-infected children.
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http://dx.doi.org/10.1093/jpids/piu020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654358PMC
March 2015

Prevalence and incidence of liver dysfunction and assessment of biomarkers of liver disease in HIV-infected Asian children.

Pediatr Infect Dis J 2015 Jun;34(6):e153-8

*Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand; †HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand; ‡TB/HIV Department, National Pediatric Hospital, Phnom Penh, Cambodia; §The Kirby Institute, University of New South Wales, Sydney, Australia; ¶Department of Child Health, Sanglah Hospital, Udayana University, Bali, Indonesia; ‖Infectious Disease Department, National Hospital of Pediatrics, Hanoi, Vietnam; **Research Unit, National Center for HIV/AIDS, Dermatology and STDs, Social Health Clinic, Phnom Penh, Cambodia; ††Faculty of Medicine, University of Health Sciences, Phnom Penh, Cambodia; ‡‡Department of Pediatrics, Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand; §§Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; ¶¶Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; ‖‖Infectious Disease Department, Children's Hospital 1, Ho Chi Minh City, Vietnam; ***Infectious Disease Department, Children's Hospital 2, Ho Chi Minh City, Vietnam; †††Y.R. Gaitonde Centre for AIDS Research and Education (YRG CARE), Chennai, India; ‡‡‡Department of Pediatrics, Hospital Raja Perempuan Zainab II, Kelantan, Malaysia; §§§Pediatric Institute, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; ¶¶¶Pediatric Allergy-Immunology Division, Cipto Mangunkusumo General Hospital, Jakarta, Indonesia; ‖‖‖Department of Pediatrics, Hospital Likas, Kota Kinabalu, Malaysia; ****Department of Pediatrics, Penang Hospital, Penang, Malaysia; and ††††TREAT Asia/amfAR-The Foundation for AIDS Research, Bangkok, Thailand.

Background: We determined the prevalence and incidence of liver dysfunction before and after initiation of combination antiretroviral therapy (cART) in the TREAT Asia Pediatric HIV Observational Database.

Methods: Data from children initiated on cART between 2 and 18 years of age with baseline alanine aminotransferase (ALT) available before and at least once after cART initiation in TREAT Asia Pediatric HIV Observational Database between 2008 and 2012 were analyzed. Prevalence and incidence of liver dysfunction and biomarkers including the aspartate aminotransferase to platelet ratio index and FIB4 index (a noninvasive panel to stage liver disease) were assessed.

Results: Data from 1930 children were included. Their median age was 6.9 years; 49% were male; 98% were perinatally infected and 94% were initiated on non-nucleoside reverse transcriptase-based cART regimens. Before cART, the prevalence of ALT ≥3 times the upper limit of normal (×ULN) was 5.8%. There were 8.5% of children with aspartate aminotransferase to platelet ratio index >1.5 (suggestive of liver fibrosis) and 2.7% with FIB4 index >1.3 (predictive of possible cirrhosis). Among the 1143 cases with normal baseline ALT (≤1×ULN), the incidence of ALT 3×ULN after cART was 1.19 of 1000 person-months (95% confidence interval: 0.93-1.51). Two of 350 with available tests (0.6%) met Hy's law (ALT >3×ULN and total bilirubin >2×ULN). By multivariate analysis, baseline hemoglobin <7.5 g/dL was a predictor of ALT >3×ULN, whereas age 5-9 years at cART initiation was protective for liver dysfunction.

Conclusions: We demonstrated a low prevalence and incidence of liver dysfunction before and after cART initiation in children with normal baseline chemistries. In this population facing life-long cART, prospective surveillance for emergence of liver disease is warranted.
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http://dx.doi.org/10.1097/INF.0000000000000693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435819PMC
June 2015

The long-term outcomes of antiretroviral treatment initiated with mono or dual nucleoside reverse transcriptase inhibitors in HIV-1-infected children: an Asian observational study.

J Virus Erad 2015;1(3):192-195. Epub 2015 Jun 30.

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

After a median of 115.9 months of follow-up, 90% of 206 HIV-1-infected children in a cohort in Asia who initiated antiretroviral treatment (ART) with mono or dual nucleoside reverse transcriptase inhibitors were alive and had comparable immunological and virological outcomes as compared to the 1,915 children who had started with highly active antiretroviral regimens. However, these children had higher rates of treatment-related adverse events, opportunistic infections, and cumulative mortality, and were more likely to require protease inhibitor-containing regimens or other more novel ART-based regimens.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827263PMC
June 2015

Outcomes of human immunodeficiency virus-infected children after anti-retroviral therapy in Malaysia.

J Paediatr Child Health 2015 Feb 20;51(2):204-8. Epub 2014 Aug 20.

Department of Paediatrics, Hospital Likas, Kota Kinabalu, Malaysia.

Aims: To describe outcome and examine factors associated with mortality among human immunodeficiency virus (HIV)-infected children in Malaysia after anti-retroviral therapy (ART).

Methods: Retrospective and prospective data collected through March 2009 from children in four different states in Malaysia enrolled in TREAT Asia's Pediatric HIV Observational Database were analysed.

Results: Of 347 children in the cohort, only 278 (80.1%) were commenced on ART. The median CD4 count and median age at baseline prior to ART was 272 cells/μL and 4.2 years (interquartile range (IQR): 1.4, 7.4 years), respectively. The median duration of follow-up was 3.7 years (IQR: 1.8, 6.0) with 32 deaths giving a crude mortality rate of 2.86 per 100 child-years. The mortality rate highest in the first 6 months of ART was 10.62 per 100 child-years and declined to 1.83 per 100 child-years thereafter. On univariate analyses, only baseline median CD4 percentage, weight for age z score, height for age z score and anaemia were significantly associated with mortality. Upon including all four of these predictors into a single multivariate model, only weight for age z score remained statistically significantly predictive of mortality.

Conclusions: Children commenced on ART had high mortality in the first 6 months especially in those with low CD4 percentage, wasting and anaemia. Poor nutritional status is an important independent predictor of mortality in this study. Besides initiating ART therapy, nutritional support and intervention must receive the utmost attention.
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http://dx.doi.org/10.1111/jpc.12712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412847PMC
February 2015

Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial.

Lancet 2014 Oct 10;384(9951):1358-65. Epub 2014 Jul 10.

Sanofi Pasteur, Singapore, Singapore.

Background: An estimated 100 million people have symptomatic dengue infection every year. This is the first report of a phase 3 vaccine efficacy trial of a candidate dengue vaccine. We aimed to assess the efficacy of the CYD dengue vaccine against symptomatic, virologically confirmed dengue in children.

Methods: We did an observer-masked, randomised controlled, multicentre, phase 3 trial in five countries in the Asia-Pacific region. Between June 3, and Dec 1, 2011, healthy children aged 2-14 years were randomly assigned (2:1), by computer-generated permuted blocks of six with an interactive voice or web response system, to receive three injections of a recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV), or placebo, at months 0, 6, and 12. Randomisation was stratified by age and site. Participants were followed up until month 25. Trial staff responsible for the preparation and administration of injections were unmasked to group allocation, but were not included in the follow-up of the participants; allocation was concealed from the study sponsor, investigators, and parents and guardians. Our primary objective was to assess protective efficacy against symptomatic, virologically confirmed dengue, irrespective of disease severity or serotype, that took place more than 28 days after the third injection. The primary endpoint was for the lower bound of the 95% CI of vaccine efficacy to be greater than 25%. Analysis was by intention to treat and per procotol. This trial is registered with ClinicalTrials.gov, number NCT01373281.

Findings: We randomly assigned 10,275 children to receive either vaccine (n=6851) or placebo (n=3424), of whom 6710 (98%) and 3350 (98%), respectively, were included in the primary analysis. 250 cases of virologically confirmed dengue took place more than 28 days after the third injection (117 [47%] in the vaccine group and 133 [53%] in the control group). The primary endpoint was achieved with 56·5% (95% CI 43·8-66·4) efficacy. We recorded 647 serious adverse events (402 [62%] in the vaccine group and 245 [38%] in the control group). 54 (1%) children in the vaccine group and 33 (1%) of those in the control group had serious adverse events that happened within 28 days of vaccination. Serious adverse events were consistent with medical disorders in this age group and were mainly infections and injuries.

Interpretation: Our findings show that dengue vaccine is efficacious when given as three injections at months 0, 6, and 12 to children aged 2-14 years in endemic areas in Asia, and has a good safety profile. Vaccination could reduce the incidence of symptomatic infection and hospital admission and has the potential to provide an important public health benefit.

Funding: Sanofi Pasteur.
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http://dx.doi.org/10.1016/S0140-6736(14)61060-6DOI Listing
October 2014

Weight as predictors of clinical progression and treatment failure: results from the TREAT Asia Pediatric HIV Observational Database.

J Acquir Immune Defic Syndr 2014 Sep;67(1):71-6

*The Kirby Institute, Faculty of Medicine, University of New South Wales, Sydney, Australia; †TREAT Asia/amfAR-The Foundation for AIDS Research, Bangkok, Thailand; ‡Programs for HIV Prevention and Treatment, Institut de Recherche pour le Développement, France, and Chiang Mai University, Chiang Mai, Thailand; §YR Gaitonde Centre for AIDS Research and Education, Chennai, India; ‖Infectious Disease Department, Children's Hospital 2, Ho Chi Minh City, Vietnam; ¶Infectious Disease Department, National Hospital of Pediatrics, Hanoi, Vietnam; #Pediatric Department, Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand; **Pediatric Department , Khon Kaen University, Khon Kaen, Thailand; ††Pediatric Department , Siriraj Hospital, Mahidol University, Bangkok, Thailand; ‡‡Infectious Disease Department, Children's Hospital 1, Ho Chi Minh City, Vietnam; §§Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; ‖‖TB/HIV Department, National Pediatric Hospital, Phnom Penh, Cambodia; ¶¶Research Unit, National Centre for HIV/AIDS, Dermatology and STDs, Phnom Penh, Cambodia; ##HIV-NAT/Thai Red Cross AIDS Research Centre, Bangkok, Thailand; ***Department of Pediatrics, Hospital Raja Perempuan Zainab II, Kelantan, Malaysia; †††Pediatric Allergy-Immunology Division, Cipto Mangunkusumo General Hospital, Jakarta, Indonesia; ‡‡‡Pediatric Institute, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; §§§Department of Pediatrics, Hospital Likas, Kota Kinabalu, Malaysia; ‖‖‖Department of Pediatrics, Penang Hospital, Penang, Malaysia; and ¶¶¶Allergy-Immunology Division, Sanglah Hospital, Udayana University, Bali, Indonesia.

Objective: To evaluate the value of time-updated weight and height in predicting clinical progression, and immunological and virological failure in children receiving combination antiretroviral therapy (cART).

Methods: We used Cox regression to analyze data of a cohort of Asian children.

Results: A total of 2608 children were included; median age at cART was 5.7 years. Time-updated weight for age z score < -3 was associated with mortality (P < 0.001) independent of CD4% and < -2 was associated with immunological failure (P ≤ 0.03) independent of age at cART.

Conclusions: Weight monitoring provides useful data to inform clinical management of children on cART in resource-limited settings.
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http://dx.doi.org/10.1097/QAI.0000000000000227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134392PMC
September 2014

Characterizing HIV manifestations and treatment outcomes of perinatally infected adolescents in Asia.

Pediatr Infect Dis J 2014 Mar;33(3):291-4

From the *Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; †Biostatistics and Databases Program, The Kirby Institute, Faculty of Medicine, The University of New South Wales, Sydney, Australia; ‡Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; §Penang Hospital, Penang, Malaysia; ¶HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok; ‖Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand; **National Hospital of Pediatrics, Hanoi, Vietnam; ††National Centre for HIV/AIDS Dermatology and STDs, Phnom Penh, Cambodia; ‡‡YR Gaitonde Centre for AIDS Research and Education, Chennai, India; §§Khon Kaen University, Khon Kaen, Thailand; ¶¶Children's Hospital 2, Ho Chi Minh City, Vietnam; ‖‖Cipto Mangunkusumo General Hospital, Jakarta, Indonesia; ***Hospital Raja Perempuan Zainab II, Kelantan; †††Pediatric Institute, Hospital Kuala Lumpur, Kuala Lumpur; ‡‡‡Hospital Likas, Kota Kinabalu, Malaysia; §§§Children's Hospital 1, Ho Chi Minh City, Vietnam; ¶¶¶Sanglah Hospital, Udayana University, Bali, Indonesia; and ‖‖‖TREAT Asia/amfAR - The Foundation for AIDS Research, Bangkok, Thailand.

Background: More perinatally HIV-infected children in Asia are reaching adolescence.

Methods: We analyzed data from July 1991 to March 2011 reported by 18 clinics in 6 countries of children age >12 years.

Results: Of 1254 adolescents, 33 (2.6%) died, and 52 (4.1%) were lost to follow-up within 2.4-year (3566 person-years) median follow-up period. Of 1061 adolescents under active follow-up, 485 (46%) were male, median (interquartile range) age was 14.7 (13.3-16.4) years, 73% had lost a parent(s), 93% attended school and 62% were aware of their HIV status. At the most recent evaluation, 93% were receiving highly active antiretroviral therapy, 71% (N = 737/1035) had CD4 ≥ 500 cells/mm(3) and 87% (N = 718/830) had viral load (VL) <400 copies/mL. Current CD4 ≥ 200 cells/mm(3), no previous World Health Organization stage 3 or 4 and being on a first-line regimen were independently associated with recent VL <400 copies/mL. Current age <15 years, VL <400 copies/mL, CD4 15-24% (vs. <10%) at antiretroviral therapy initiation, no previous World Health Organization stage 3 or 4 and antiretroviral therapy duration of ≥ 1 year were associated with recent CD4 ≥ 500 cells/mm(3). Primary causes of death after age 12 were opportunistic infections (N = 15/33) and other AIDS- or treatment-related conditions (N = 9/33). Those at age 12 with CD4 <200 versus ≥ 500 cells/mm and those with VL ≥ 10,000 versus <10,000 copies/mL were 17.4 and 4.76 times more likely to die in adolescence, respectively.

Conclusion: Adolescents in this cohort have been successfully maintained in HIV care. Initiating treatment at earlier stages of disease was associated with immune recovery and virologic suppression during adolescence.
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http://dx.doi.org/10.1097/INF.0b013e3182a18223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922889PMC
March 2014

Dengue and other common causes of acute febrile illness in Asia: an active surveillance study in children.

PLoS Negl Trop Dis 2013 25;7(7):e2331. Epub 2013 Jul 25.

Research Institute for Tropical Medicine, Muntinlupa City, Philippines.

Background: Common causes of acute febrile illness in tropical countries have similar symptoms, which often mimic those of dengue. Accurate clinical diagnosis can be difficult without laboratory confirmation and disease burden is generally under-reported. Accurate, population-based, laboratory-confirmed incidence data on dengue and other causes of acute fever in dengue-endemic Asian countries are needed.

Methods And Principal Findings: This prospective, multicenter, active fever surveillance, cohort study was conducted in selected centers in Indonesia, Malaysia, Philippines, Thailand and Vietnam to determine the incidence density of acute febrile episodes (≥ 38 °C for ≥ 2 days) in 1,500 healthy children aged 2-14 years, followed for a mean 237 days. Causes of fever were assessed by testing acute and convalescent sera from febrile participants for dengue, chikungunya, hepatitis A, influenza A, leptospirosis, rickettsia, and Salmonella Typhi. Overall, 289 participants had acute fever, an incidence density of 33.6 per 100 person-years (95% CI: 30.0; 37.8); 57% were IgM-positive for at least one of these diseases. The most common causes of fever by IgM ELISA were chikungunya (in 35.0% of in febrile participants) and S. Typhi (in 29.4%). The overall incidence density of dengue per 100 person-years was 3.4 by nonstructural protein 1 (NS1) antigen positivity (95% CI: 2.4; 4.8) and 7.3 (95% CI: 5.7; 9.2) by serology. Dengue was diagnosed in 11.4% (95% CI: 8.0; 15.7) and 23.9% (95% CI: 19.1; 29.2) of febrile participants by NS1 positivity and serology, respectively. Of the febrile episodes not clinically diagnosed as dengue, 5.3% were dengue-positive by NS1 antigen testing and 16.0% were dengue-positive by serology.

Conclusions: During the study period, the most common identified causes of pediatric acute febrile illness among the seven tested for were chikungunya, S. Typhi and dengue. Not all dengue cases were clinically diagnosed; laboratory confirmation is essential to refine disease burden estimates.
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http://dx.doi.org/10.1371/journal.pntd.0002331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723539PMC
February 2014

X-linked chronic granulomatous disease in a male child with an X-CGD carrier, Klinefelter brother.

Asian Pac J Allergy Immunol 2013 Jun;31(2):167-72

Institute for Medical Research, Jalan Pahang, Kuala Lumpur, Malaysia.

Background: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency (PID) caused by a dysfunctional respiratory burst enzyme NADPH-oxidase. The concurrence of Klinefelter's Syndrome (KS) and CGD would be extremely rare.

Objective: We describe the study of a family where the youngest male child had X-linked CGD (X-CGD) while his older brother was both an X-CGD carrier and a Klinefelter.

Methods: Flow cytometry was used to study respiratory burst and gp91-phox expression, while genetic investigation was done by RT-PCR, PCR and X-chromosome short tandem repeat (X-STR) analysis.

Results: The Dihydrorhodamine (DHR) assay showed the patient's neutrophils failed to produce a respiratory burst, while both the mother and an older brother showed a bimodal response. gp91-phox expression was absent in the patient's neutrophils, and bimodal in the mother's and brother's neutrophils. The patient's cDNA showed a C>T change at nucleotide 676 of the CYBB gene. The same change was seen in the patient's gDNA, while the brother and mother were heterozygous, with C and T, in this position. The c.676C>T is a nonsense mutation that leads to premature termination of the gp91-phox protein. The brother karyotyped as 47, XXY and X chromosome analysis showed that he had inherited both his mother's X chromosomes.

Conclusions: This study showed that the patient had gp91-phox deficient CGD while his older brother was a CGD carrier and a Klinefelter, who had inherited both his mother's X chromosomes. This is the first report of such a concurrence in an individual, and argues for family members to be included in PID studies.
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http://dx.doi.org/10.12932/AP0274.31.2.2013DOI Listing
June 2013
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