Impact of antiretroviral treatment on height evolution of HIV infected children.

BACKGROUND: Antiretroviral treatment (ART) has been shown to have a beneficial effect on the weight evolution but its effect on height remains unclear. We described patterns of height evolution and identified predictors of catch-up growth in HIV-infected children on ART. METHODS: To describe the height evolution from birth to adulthood, we developed a nonlinear mixed effect model using data from perinatally HIV-infected children who initiated ART from 1999 to 2013 in a prospective cohort study in Thailand. The main covariates of interest were: sex, ART regimen (dual nucleoside reverse-transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor (NNRTI)-, or protease inhibitor (PI)-based), baseline CD4 percentage, HIV-RNA load and CDC HIV Classification stage and occurrence of AIDS-defining events. RESULTS: A total 477 children (43% boys) contributed 18,596 height measurements over a median duration of 6.3 years on ART (interquartile range, 3.0 to 8.3). At ART initiation, median age was 6.2 years (1.8 to 9.6), 16% of children were underweight (weight-for-age z-score < - 2), 49% presented stunting (height-for-age z-score < - 2), and 7% wasting (weight-for-height z-score < - 2). The most frequent regimen at ART initiation was NNRTI-based (79%). A model with 4 components, birth length and 3 exponential functions of age accounting for the 3 growth phases was developed and show that the height-growth velocity was inversely associated with the age at ART initiation, the adult height was significantly lower in those who had experienced at least one AIDS-defining event while, as expected, the model found that adult height in females was lower than in males. Age at ART initiation, type of ART regimen, CDC stage, CD4 percentages, and HIV-RNA load were not associated with the final height. CONCLUSIONS: The younger the children at ART initiation, the greater the effect on height-growth velocity, supporting the World Health Organization's recommendation to start ART as early as possible. However, final adult height was not linked to the age at ART initiation.

Incidence and risk factors of loss to follow-up among HIV-infected children in an antiretroviral treatment program.

INTRODUCTION: The success of antiretroviral treatment (ART) programs can be compromised by high rates of patient loss to follow-up (LTFU). We assessed the incidence and risk factors of LTFU in a large cohort of HIV-infected children receiving ART in Thailand. METHODS: All children participating in a multicenter cohort (NCT00433030) between 1999 and 2014 were included. The date of LTFU was 9 months after the last contact date. ART interruption was defined as ART discontinuation for more than 7 days followed by resumption of treatment. Baseline and time-dependent risk factors associated with LTFU were identified using Fine and Gray competing risk regression models with death or referral to another hospital as competing events. RESULTS: Of 873 children who were followed during a median of 8.6 years (interquartile range 4.5-10.6), 196 were LTFU, 73 died, and 195 referred. The cumulative incidence of LTFU was 2.9% at 1 year, 7.3% at 5 years and 22.2% at 10 years. Children aged 13 years and more had a 3-fold higher risk (95% confidence interval 2.06-4.78) of LTFU than those younger. Children who had interrupted ART within the previous year had a 2.5-fold higher risk (1.12-5.91) than those who had not. The risk of LTFU was lower in children stunted (height-for-age Z-scores <-2 SD) (0.42-0.96) or underweight (weight-for-age Z-scores <-2 SD) (0.24-0.97). CONCLUSION: Adolescence, ART interruption and absence of growth deficit were associated with LTFU. These may be warnings that should draw clinicians' attention and possibly trigger specific interventions. Children with no significant growth retardation may also be at risk of LTFU.

"Enhanced acquisition of antibiotic-resistant intestinal E. coli during the first year of life assessed in a prospective cohort study".

Background: Increasing bacterial resistance to antibiotics is a serious problem worldwide. We sought to record the acquisition of antibiotic-resistant Escherichia coli (E. coli) in healthy infants in Northern Thailand and investigated potential determinants. Methods: Stool samples from 142 infants after birth, at ages 2wk, 2mo, 4 to 6mo, and 1y, and parent stool samples were screened for E. coli resistance to tetracycline, ampicillin, co-trimoxazole, and cefazoline by culture, and isolates were further investigated for multiresistance by disc diffusion method. Pulsed-field gel electrophoresis was performed to identify persistent and transmitted strains. Genetic comparison of resistant and transmitted strains was done by multilocus sequence typing (MLST) and strains were further investigated for extra- and intra-intestinal virulence factors by multiplex PCR. Results: Forty-seven (33%) neonatal meconium samples contained resistant E. coli. Prevalence increased continuously: After 1y, resistance proportion (tetracycline 80%, ampicillin 72%, co-trimoxazole 66%, cefazoline 35%) almost matched those in parents. In 8 infants (6%), identical E. coli strains were found in at least 3 sampling time points (suggesting persistence). Transmission of resistant E. coli from parents to child was observed in only 8 families. MLST showed high diversity. We could not identify any virulence genes or factors associated with persistence, or transmission of resistant E. coli. Full-term, vaginal birth and birth in rural hospital were identified as risk factors for early childhood colonization with resistant E. coli. Conclusion: One third of healthy Thai neonates harboured antibiotic-resistant E. coli in meconium. The proportion of resistant E. coli increased during the first year of life almost reaching the value in adults. We hypothesize that enhancement of infection control measures and cautious use of antibiotics may help to control further increase of resistance.

Hospitalization and mortality among HIV-infected children after receiving highly active antiretroviral therapy.

BACKGROUND: Pediatric antiretroviral therapy programs have recently been implemented in resource-limited settings. Their impact in a prospective cohort is not well documented. The aim of this study was to evaluate the rates and causes of hospitalization and mortality among human immunodeficiency virus (HIV)-infected Thai children after receiving highly active antiretroviral therapy (HAART). METHODS: Children who started receiving HAART from August 2002 to March 2005 were prospectively observed. The patients included in the study were antiretroviral-naive HIV-infected children who had CD4 cell percentages < or =15% before treatment. All patients were observed for at least 48 weeks. RESULTS: One hundred ninety-two children were included. The mean age at HAART initiation was 7.6 years (range, 0.4-14.8 years). At baseline, the mean CD4 cell percentage (+/-SD) was 5.2%+/-4.9%, and the mean plasma HIV RNA level (+/-SD) was 5.4+/-0.5 log(10) copies/mL. Sixty-seven children (35%) were hospitalized a total of 108 times. The hospitalization rate decreased from 30.7% during the first 24-week period to 2.0% during weeks 120-144 after initiation of HAART. Fifty-nine hospital admissions (54.6%) occurred during the first 24 weeks of HAART. Causes of hospitalization were pneumonia and other bacterial infections (61.7%), immune reconstitution syndrome (23.4%), noninfectious illness (6.5%), opportunistic infection (5.6%), and drug-related events (2.8%). The mortality rate decreased from 5.7% in the first 24 weeks to 0%-0.6% in the subsequent 24-week intervals. CONCLUSION: Hospitalization and mortality rates significantly decreased among HIV-infected children receiving HAART. Most hospitalizations and deaths occurred during the first 24 weeks of HAART.

Sustained immunologic and virologic efficacy after four years of highly active antiretroviral therapy in human immunodeficiency virus infected children in Thailand.

We report the long-term efficacy of highly active antiretroviral therapy (HAART) in 107 antiretroviral-naive human immunodeficiency virus (HIV)-infected Thai children. In an intention-to-treat analysis, 70% of the children had undetectable HIV RNA titers after 192 weeks of HAART. The mean CD4 cell percentage increased from 5.3% to 26.6%. HAART is effective for HIV-infected children in this resource-poor setting despite initiation of treatment in the advanced stage of disease.

Immune reconstitution syndrome after highly active antiretroviral therapy in human immunodeficiency virus-infected thai children.

BACKGROUND: There is little information about the immune reconstitution syndrome (IRS) in children, especially from resource-poor countries. OBJECTIVE: To determine the incidence and spectrum of IRS in advanced stage human immunodeficiency virus (HIV)-infected children after initiation of highly active antiretroviral therapy (HAART). METHODS: Between May 2002 and April 2004, 153 symptomatic HIV-infected children who had CD4 lymphocyte percentage < or =15% initiated HAART in a national antiretroviral drug access program. All patients were followed for 48 weeks. In this study, IRS was defined as a disease event caused by microorganisms or conditions previously reported to be associated with IRS in patients having immunologic and/or virologic response to HAART. RESULTS: The incidence of IRS was 19% (95% confidence interval, 13.1-26.1). The median time of onset was 4 weeks after start of HAART (range, 2-31). There were 32 episodes of IRS, including 14 caused by mycobacterial organisms, 7 by varicella-zoster virus, 7 by herpes simplex virus, 3 by Cryptococcus neoformans and 1 episode of Guillain-Barré syndrome. Patients who had IRS develop had lower baseline CD4 lymphocyte percentages compared with those who did not (P = 0.02). CONCLUSIONS: IRS is common among HIV-infected children who received HAART in their advanced stage of disease. Educational programs for patients and health care workers on recognizing and treating these conditions should be integrated into antiretroviral treatment access programs.

Immune reconstitution syndrome from nontuberculous mycobacterial infection after initiation of antiretroviral therapy in children with HIV infection.

The immune reconstitution syndrome caused by nontuberculous mycobacterial (NTM) infection is reported in 9 of 153 HIV-infected children 2 to 26 weeks after initiation of antiretroviral therapy. The clinical syndrome included fever and dyspnea (2 children), fever and abdominal pain (3), subcutaneous nodules or suppurative lymphadenitis (4). The causative species were Mycobacterium avium (4), Mycobacterium scrofulaceum (3), Mycobacterium kansasii (1) and Mycobacterium simiae (1).

Efficacy of highly active antiretroviral therapy in HIV-infected children participating in Thailand's National Access to Antiretroviral Program.

BACKGROUND: Programs for access to antiretroviral treatment were only recently implemented in developing countries. This study aimed to describe the effect of highly active antiretroviral therapy (HAART) in treating human immunodeficiency virus (HIV)-infected children in Thailand's National Access to Antiretroviral Program for People Living with HIV/AIDS. METHODS: From August 2002 to July 2003, a total of 107 children were enrolled in the study. They received HAART consisting of either nevirapine or efavirenz, together with lamivudine and stavudine. Generic drugs and/or adult formulations were used. CD4 lymphocyte count, plasma HIV RNA level, and weight-for-age and height-for-age z scores were measured before, 2 months after, and every 6 months after initiation of HAART. A genotypic resistance assay was performed for patients with poor virological response. RESULTS: The mean age of the patients was 7.7 years (range, 2.1-13.8 years). At baseline, the median CD4 cell percentage was 3%, and the plasma HIV RNA level was 5.4 log10 copies/mL. Four patients died from HIV-related illness. After 72 weeks of HAART, the median CD4 cell percentage was 21%, and 76% of patients had HIV RNA levels of < 50 copies/mL. The mean weight-for-age and height-for-age z scores increased from -1.9 to -1.3 (P < .0001) and from -2.3 to -2.0 (P < .0001), respectively. The percentage of patients who took > or = 95% of prescribed medications during the interval between every follow-up visit was 86% For patients with suboptimal virological response, the most common resistance mutations among HIV isolates were associated with lamivudine and with nonnucleoside reverse-transcriptase inhibitors. CONCLUSION: In this resource-limited setting, HAART is safe and effective for HIV-infected children despite initiation of treatment during the advanced stage of disease. The use of generic and nonpediatric drug formulations is feasible.

Risk of first-line antiretroviral therapy failure in HIV-infected Thai children and adolescents.

BACKGROUND: Adolescence may affect adherence and response to highly active antiretroviral therapy (HAART). Limited data are available regarding the long-term treatment outcomes of perinatal HIV-infected adolescents. METHODS: Data from perinatally acquired HIV-infected Thai children who started first-line nonnucleoside analog-based HAART before 18 years of age and treated for ≥24 weeks were analyzed. Children were categorized by age at HAART initiation; age<3 years, 3-9 years, early adolescence (10-13 years) and middle adolescence (14-16 years). CD4 and HIV-RNA were monitored every 6-12 months. Virologic failure (VF) was defined as HIV-RNA≥1000 copies/mL after ≥24 weeks of HAART. RESULTS: Of 840 children, 68% were in pre-adolescence. Median baseline CD4% was 7.9%. Use of nevirapine versus efavirenz was 77:23%. Median duration of nonnucleoside reverse transcriptase inhibitor-based HAART was 5.6 years. No differences between groups were observed for rate of HIV-RNA<50 copies/mL (68%, P=0.18) and rate of VF (28%, P=0.82), median time to VF (22 months, P=0.13). Incidence of VF per 100 child-year in children age<3 years, 3-9 years, early adolescence and middle adolescence were 7.9, 4.7, 7.4 and 10.8, respectively (P=0.012). Median adherence by pill count was 97.3% (P=0.23). By multivariate analysis, predictors for VF were age at HAART initiation of <3 years (HR: 1.73, 95% CI: 1.18-2.55), age 10-16 years (HR: 1.47, 95% CI: 1.09-1.97), and nevirapine use (HR: 1.63, 95% CI: 1.14-2.32). CONCLUSIONS: VF rates were observed in one-third of long-term treated Thai children on first-line HAART. Age 3-9 years at HAART initiation was associated with less VF compared with those younger or older, whereas children who used nevirapine had higher VF.

Long-term outcomes of HIV-infected children in Thailand: the Thailand Pediatric HIV Observational Database.

OBJECTIVE: To describe the outcomes of antiretroviral therapy (ART) in a large cohort of HIV-infected children in Thailand. METHODS: The data were obtained from four collaborative referral sites around the country. Data from 2008 to March 2011 were collected prospectively, and data before 2008 were collected retrospectively. RESULTS: Of the 1139 children, 599 (52.6%) were female, and the duration of ART was a median 2.9 years (interquartile range (IQR) 3.3-5.5 years). At ART initiation, the median age was 7.1 years (IQR 3.4-10.0 years), CD4 percentage was 9.0% (IQR 3.0-17.0%), and 61.3% were in World Health Organization (WHO) stage 3 or 4. Seventy-four percent were initiated on an NNRTI-based regimen. The death and lost to follow-up rates were 1.3 (95% confidence interval (CI) 1.1-1.6) and 2.2 (95% CI 1.6-2.6)/100 patient-years of follow-up, respectively. At the last clinic visit of 919 children, the median CD4 percentage was 27.0% (IQR 23.0-32.0%) and 80.2% had HIV-RNA <40 copies/ml. WHO stage 1 or 2 at ART initiation was associated with having a viral load <40 copies/ml (p < 0.002), and baseline CD4 ≥15% and starting with a three-drug regimen were associated with achieving CD4 ≥25% (p<0.001). CONCLUSIONS: Although most children initiated ART at low CD4 levels, the majority achieved immune reconstitution and long-term virological control. Earlier treatment may improve these outcomes.