Linda Aurpibul

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.

Response to Measles, Mumps, and Rubella Revaccination in HIV-Infected Children with Immune Recovery after Highly Active Antiretroviral Therapy

BACKGROUND The low prevalence of measles antibody in human immunodeficiency virus (HIV)-infected children after immune recovery as a result of highly active antiretroviral therapy increases the risk of morbidity and mortality from disease. The objective of our study was to evaluate the efficacy and safety of revaccination with measles, mumps, and rubella (MMR) vaccine in HIV-infected children with immune recovery. METHODS Inclusion criteria were (1) HIV-infected children aged >5 years, (2) a nadir CD4 lymphocyte percentage <or=15%, (3) immune recovery (defined as a CD4 lymphocyte percentage >15% for >or=3 months after highly active antiretroviral therapy), and (4) no protective antibody against measles. Each child received 1 dose of MMR vaccine, and antibodies were measured at 4 and 24 weeks after vaccination. Protective antibodies were defined as an antimeasles immunoglobulin G (IgG) level >or=320 mIU/mL, an antimumps IgG titer >1:500, and an antirubella IgG level >10 IU/mL. RESULTS There were 51 participants. The mean age (+/- standard deviation) was 10.2 +/- 2.5 years. Prior to revaccination, 28 participants (55%) had baseline protective antibody to mumps, and 11 (20%) had baseline protective antibody to rubella. The prevalence of protective antibody at 4 weeks was 90%, 100%, and 78% for measles, rubella, and mumps, respectively, and then slightly decreased to 80%, 94%, and 61%, respectively, at 24 weeks after revaccination. No serious adverse reactions were attributed to revaccination. CONCLUSIONS The majority of HIV-infected children with immune recovery can develop protective antibodies after MMR revaccination. Revaccination with MMR vaccine in HIV-infected children with immune recovery should be considered to ensure individual immunity and limit the spread of disease.

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.

Poor Cognitive Functioning of School-Aged Children in Thailand with Perinatally Acquired HIV Infection Taking Antiretroviral Therapy

Neurocognitive outcome is an essential aspect of treatment for HIV-infected children. This study is aimed at assessing cognitive functioning in school-aged HIV-infected children and the change after receiving antiretroviral therapy (ART). We conducted a prospective cohort study of HIV-infected Thai children from 6-12 years of age compared with HIV-affected (children of HIV-positive mothers who were not infected with HIV), and normal control groups. Wechsler Intelligence Scale for Children-III (WISC-III) was administered at enrollment and 30 months of follow-up. Semistructured interviews of primary caregivers were performed. From April to October 2003, 121 children were enrolled; 39 HIV-infected, 40 HIV-affected, and 42 control children with a median age of 9.3 years. The HIV-infected group had a mean (standard deviation [SD]) CD4 percentage of 13.8% (5.3), 87% of whom had been receiving ART for a median of 35 weeks. At the first cognitive assessment, the mean (SD) of full-scale intelligence quotient (FSIQ) was 79 (13) and 88 (10) among HIV-infected and HIV-affected children, which was statistically lower than that of the control group at 96 (13; p < 0.01). The proportion of children with average intelligence level (FSIQ > 90) among 3 groups were 21%, 49%, and 76%, respectively (p < 0.01). At 30 months of follow-up, the HIV-infected group had a mean (SD) CD4 percentage of 25.6% (5.6); 77% had undetectable viral load. The mean (SD) FSIQ of children among three groups were 75 (12), 85 (12), and 91 (12), respectively. Compared with the baseline assessment, the verbal scale score significantly decreased in all groups, including the controls, whereas the performance scales did not change. In conclusion, school-aged HIV-infected children have lower cognitive function than HIV-affected and normal children. Cognitive function was not improved after receiving ART. Further study to address whether early ART can preserve cognitive functioning among HIV-infected children should be explored.

Outcomes of antiretroviral therapy in children in Asia and Africa: a comparative analysis of the IeDEA pediatric multiregional collaboration.

Background:We investigated 18-month incidence and determinants of death and loss to follow-up of children after antiretroviral therapy (ART) initiation in a multiregional collaboration in lower-income countries. Methods:HIV-infected children (positive polymerase chain reaction <18 months or positive serology ≥18 months) from International Epidemiologic Databases to Evaluate AIDS cohorts, <16 years, initiating ART were eligible. A competing risk regression model was used to analyze the independent risk of 2 failure types: death and loss to follow-up (>6 months). Findings:Data on 13,611 children, from Asia (N = 1454), East Africa (N = 3114), Southern Africa (N = 6212), and West Africa (N = 2881) contributed 20,417 person-years of follow-up. At 18 months, the adjusted risk of death was 4.3% in East Africa, 5.4% in Asia, 5.7% in Southern Africa, and 7.4% in West Africa (P = 0.01). Age < 24 months, World Health Organization stage 4, CD4 < 10%, attending a private sector clinic, larger cohort size, and living in West Africa were independently associated with poorer survival. The adjusted risk of loss to follow-up was 4.1% in Asia, 9.0% in Southern Africa, 14.0% in East Africa, and 21.8% in West Africa (P < 0.01). Age < 12 months, nonnucleoside reverse transcriptase inhibitor I–based ART regimen, World Health Organization stage 4 at ART start, ART initiation after 2005, attending a public sector or a nonurban clinic, having to pay for laboratory tests or antiretroviral drugs, larger cohort size, and living in East Africa or West Africa were significantly associated with higher loss to follow-up. Conclusions:Findings differed substantially across regions but raise overall concerns about delayed ART start, low access to free HIV services for children, and increased workload on program retention in lower-income countries. Universal free access to ART services and innovative approaches are urgently needed to improve pediatric outcomes at the program level.

Neurodevelopmental outcomes in HIV-exposed-uninfected children versus those not exposed to HIV

Human immunodeficiency virus (HIV)-negative children born to HIV-infected mothers may exhibit differences in neurodevelopment (ND) compared to age- and gender-matched controls whose lives have not been affected by HIV. This could occur due to exposure to HIV and antiretroviral agents in utero and perinatally, or differences in the environment in which they grow up. This study assessed neurodevelopmental outcomes in HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU) children enrolled as controls in a multicenter ND study from Thailand and Cambodia. One hundred sixty HEU and 167 HUU children completed a neurodevelopmental assessment using the Beery Visual Motor Integration (VMI) test, Color Trails, Perdue Pegboard, and Child Behavior Checklist (CBCL). Thai children (n = 202) also completed the Wechsler Intelligence Scale (IQ) and Stanford-Binet II memory tests. In analyses adjusted for caregiver education, parent as caregiver, household income, age, and ethnicity, statistically significant lower scores were seen on verbal IQ (VIQ), full-scale IQ (FSIQ), and Binet Bead Memory among HEU compared to HUU. The mean (95% CI) differences were −6.13 (−10.3 to −1.96), p = 0.004; −4.57 (−8.80 to −0.35), p = 0.03; and −3.72 (−6.57 to −0.88), p = 0.01 for VIQ, FSIQ, and Binet Bead Memory, respectively. We observed no significant differences in performance IQ, other Binet memory domains, Color Trail, Perdue Pegboard, Beery VMI, or CBCL test scores. We conclude that HEU children evidence reductions in some neurodevelopmental outcomes compared to HUU; however, these differences are small and it remains unclear to what extent they have immediate and long-term clinical significance.

Prevalence of protective antibody against measles in HIV-infected children with immune recovery after highly active antiretroviral therapy.

This study was conducted to determine the prevalence of measles‐protective antibody in HIV‐infected children with immune recovery after highly active antiretroviral therapy (HAART).

Survival of HIV-Infected Children: A Cohort Study From the Asia-Pacific Region

Background:Combination antiretroviral therapy (ART) has been used for HIV-infected children in many Asian countries since 2002. This study describes survival outcomes among HIV-infected children in a multicenter regional cohort in Asia. Patients and Methods:Retrospective and prospective data collected through March 2009 from children in 5 countries enrolled in TREAT Asias Pediatric HIV Observational Database were analysed. Multivariate Cox proportional hazard models were used to assess factors associated with mortality in children who received ART. Results:Among 2280 children, 1752 (77%) had received ART. During a median follow-up of 3.1 years after ART, 115 (6.6%) deaths occurred, giving a crude mortality rate of 1.9 per 100 child-years [95% confidence interval (CI): 1.6 to 2.4]. The mortality rate was highest in the first 3 months of ART (10.2 per 100 child-years; 95% CI: 7.5 to 13.7) and declined after 12 months (0.9 per 100 child-years; 95% CI: 0.7 to 1.3). Those with a low recent CD4 percentage, who started ART with lower baseline weight-for-age Z score, or with WHO clinical stage 4 had an increased risk of death. Of 528 (23%) children who never received ART, 36 (6.8%) died after presenting to care, giving a crude mortality rate of 4.1 per 100 child-years (95% CI: 3.0 to 5.7), with a lost-to-program rate of 31.5 per 100 child-years (95% CI: 28.0 to 35.5). Conclusions:The high mortality during the first 3 months of ART and in those with low CD4 percentage support the implementation of early diagnosis and ART initiation.

Pharmacokinetics and safety of a new paediatric fixed-dose combination of zidovudine/lamivudine/nevirapine in HIV-infected children.

BACKGROUND Alternatives to the available stavudine-containing paediatric fixed-dose combination (FDC) tablets are rapidly needed due to concerns regarding the cumulative toxicity of long-term stavudine exposure. We report the bioavailability and short-term safety of a novel paediatric FDC tablet of zidovudine (ZDV)/lamivudine (3TC)/nevirapine (NVP; 30/15/28 mg) in HIV-infected children. METHODS In this Phase I/II open-label pharmacokinetic study, 42 children weighing 6-30 kg treated with NVP-based HAART for ≥4 weeks were randomized to receive the FDC tablets (GPO-VIR Z30) or the liquid formulations. Dosing was weight-based. Intensive 12-h blood sampling was performed after 2 weeks; subjects then crossed-over to the alternate formulation at equal doses and sampling repeated 2 weeks later. Pharmacokinetic parameters were determined by non-compartmental analysis. Buccal-swab samples were collected for cytochrome P450 (CYP)2B6 polymorphism analysis. RESULTS With the FDC tablet, the geometric mean (90% CI) area under the curve (AUC) for ZDV, 3TC and NVP was 1.58 (1.49-1.68), 7.78 (7.38-8.19) and 68.88 (62.13-76.36) μg•h/ml, respectively. Rules for NVP therapeutic inadequacy were defined a priori, and despite lower NVP exposure with the tablet (P<0.001), the levels remained therapeutically adequate. ZDV AUC was similar between formulations. 3TC exposure was significantly higher with the tablet but comparable to historical data in adults and children taking branded tablets. While receiving the tablet, NVP AUC in children with CYP2B 516 GG (45%), GT (45%) and TT (10%) genotypes were 67.0, 74.5 and 106.4 μg•h/ml, respectively (P=0.04). CONCLUSIONS Disparities in drug exposure between formulations were observed; however, the FDC tablet delivered therapeutically adequate exposures of each drug and could well play an important role in simplifying antiretroviral treatment for children.

Persistence of Measles, Mumps, and Rubella Protective Antibodies 3 Years after Revaccination in HIV-Infected Children Receiving Antiretroviral Therapy

Three years after measles, mumps, and rubella revaccination in 38 human immunodeficiency virus-infected children who had achieved immune recovery after antiretroviral therapy, the prevalence of protective antibody levels was 85% for measles, 61% for mumps, and 79% for rubella, compared with 88%, 84%, and 100%, respectively, 1 month after revaccination.