Janssens B, Raleigh B, Soeung S, Akao K, Te V, Gupta J, et al. Effectiveness of highly active antiretroviral therapy in HIV-positive children: evaluation at 12 months in a routine program in Cambodia. Pediatrics 2007 Nov;120(5):e1134-40.
The goal of this study is to describe the clinical, immunologic and virologic outcomes of pediatric patients who have been using highly active antiretroviral therapy (HAART) for more than 12 months in two routine programs in Cambodia.
A cohort study, including a cross-sectional evaluation of virologic status, performed on all children who started HAART between June 2003 and March 2005.
Two district hospitals in Cambodia: Angkor Hospital for Children in Siem Reap province and Takeo District Hospital in Takeo province. The prevalence of HIV in Cambodia was 1.9% in 2003. Antiretroviral therapy has been provided since 2001, and national efforts to prevent mother-to-child transmission began in 2003.
A total of 212 patients started HAART during the study period. All children included in the evaluation were less than 13 years of age and were on HAART for more than 12 months. The mean weight-for-height z score was -1.59 ± standard deviation (SD) 1.08. The median age at start of HAART was 6 years (interquartile range [IQR], 4.2-7.9), and only 7 (3%) children were younger than 18 months. The primary caregivers were biological parents (64%); grandparents (30%); or relatives, neighbors, or orphanages (6%). A total of 76 (36%) of the children were orphans, 8 (10.5%) of whom were cared for in a structured orphanage. The median CD4 percentage before starting HAART in all patients was 6% (IQR, 2.6-13.0), and the median absolute CD4 count for the children older than age 5 years (n=134) was 100 cells/mL (IQR, 22-273). Seven patients were known to have previous ART experience. In January 2006, 193 of the patients were alive and could be included in the cross-sectional virologic evaluation.
The intervention consisted of providing treatment and counseling to children less than 13 years of age who fit the criteria for receiving HAART. Criteria to commence HAART followed national guidelines: HIV-positive status based on results of serology or reverse transcriptase polymerase chain reaction (RT-PCR) testing for children younger than 18 months and CD4 count of <20% for children younger than 5 years or <200 cells/mL for children older than 5 years. The majority of the patients started on a standard first-line regimen of adult, generic fixed-dose combination (FDC) stavudine, lamivudine and nevirapine, as recommended by WHO. Zidovudine and efavirenz were used as alternatives in case of intolerance or interaction with other drugs. Tablets were cut in half to obtain the most appropriate dosages, and for some body weights, nevirapine syrup was added to achieve the correct dosage, according to a standardized drug-dosage table. All patients received at least three HAART-preparation counseling sessions before commencing the treatment. Adherence was not systematically recorded. After commencement of HAART, adherence support was provided by the counselors at a patient's every clinic visit. When feasible, home visits were conducted for patients suspected of needing more social support.
Body weight was measured at every visit. CD4 cell count was measured by flow cytometry at baseline and every 6 months after initiation of HAART. For children who were younger than 5 years, CD4 percentage was used as the standard follow-up indicator; for children older than 5 years, both CD4 percentage and absolute CD4 cell count were used, as recommended by WHO. Between February 2006 and June 2006, viral load measurements by real-time RT-PCR were performed together with routine CD4 tests for all patients who were on HAART for 12 months or more. For patients with an undetectable viral load (<400 copies/mL), a genotype resistance test was done using standard techniques.
The primary outcomes were clinical status/survival, CD4 percentage and CD4 count, viral load, and ART resistance.
Of 212 children who had started HAART before March 2005, 13 had died, 4 were lost to follow-up, and 2 were transferred to another treatment site. According to the survival analysis, 92% and 91% of the children were alive and in care at 12 and 24 months of treatment, respectively. The mean z score increased by 0.81 to -0.78 (SD ±1.17) at 12 months of HAART. Seven patients switched to alternative regimens due to intolerability. The median CD4 percentage gain at 12 months was 17.0% (IQR, 16.3%-30.7%); among children older than 5 years at that time (n=164), the median CD4 cell count gain from baseline was 490 cells/mL. As treated, 156 (81%; 95% CI: 74%-85%) of all 193 patients alive and on HAART for more than 12 months showed an undetectable viral load. In an intention-to-treat analysis, 156 (73.6%; 95% CI: 67.0%-79.0%) of 212 patients who started HAART before March 2005 had an undetectable viral load. Of these, 36 had been on HAART for 24 months, and among this subgroup, 24 (66.6%; 95% CI: 50.0%-80.0%) had an undetectable viral load. Of the 30 children with a viral load of >1,000 copies/mL, 16 (53%) met National Institutes of Heath criteria for immunological failure at the time of viral load testing. In the analysis of baseline characteristics as predictors of virologic failure, being an orphan was found to be statistically significant (risk ratio, 3.8; 95% CI: 1.8-8.0; p=.001). Genotype analysis was successfully performed in 36 of the 37 patients with a detectable viral load, and at least one mutation was found in 34 patients. The most common nucleoside reverse transcriptase inhibitor (NRTI) mutations were M184 (n=26), D67 (n=7), T215 (n=7), and T69 and L210 (n=4). Resistance to lamivudine was found in 27 patients, to zidovudine in 9, to stavudine in 11, to abacavir in 4, to tenofovir in 3 and to didanosine in 3 patients. Non-NRTI resistance was seen in 32 patients. Seven patients developed extensive ART resistance, 5 of whom were known to be ART-experienced prior to enrollment.
The authors conclude that this evaluation provides additional evidence of the effectiveness of integrating HIV/AIDS care with HAART for children in a routine setting. Good virologic suppression and immunologic recovery is achieved by using split adult FDCs. The authors also indicate that viral load monitoring and HIV genotyping are valuable tools for the clinical follow-up of patients and that orphans should receive careful follow-up and extra support.
This cohort study, based on the Newcastle-Ottawa rating system, is of good quality. This study had a few limitations. First, the overall time that patients were taking HAART was relatively short, making it difficult to assess long-term effects. Second, information was not systematically collected on ART experience or adherence to HAART. Third, very few children under the age of 18 months were included in this study because of the unavailability of appropriate diagnostic tools at the clinics to diagnose HIV/AIDS in infants.
The proportion of patients who achieved virologic success is equal to or better than all of the clinical trials in Western settings before 2002.(1) Among the best results cited in the review, three trials are comparable; they report the proportion of patients with a viral load of <400 copies/mL at 48-72 weeks of HAART as 69%, 70% and 87%, respectively, on a population as treated. Only one result is available on an intention-to-treat population, which showed 61% with a viral load <400 copies/mL. Notably, a number of these studies included patients who were not NRTI-naive. The outcomes in this study also generally compare with the published cohort studies in other resource-limited contexts, such as Thailand, Romania and Ivory Coast. (2,3,4) In addition, other studies have found that the use of split adult FDCs of NRTI and HIV-1 non-nucleoside NRTI can achieve good outcomes.(5,6)
Although less than 5% of the estimated 800,000 children in need of ART worldwide are currently receiving it, the number and size of pediatric HAART programs are increasing. This study shows that successful treatment can be achieved for many children in routine, developing settings. The finding of detectable viral loads and resistance in some of the children, however, suggests that more support is needed for adherence, and appropriate strategies must be determined for developing settings, particularly for orphans. Knowledge of prior ART experience is also important in determining appropriate treatment regimens, as children may have been taking inadequate doses from parents or from others on ART. Although this study showed good results with split adult FDC pills, pediatric formulations provide optimal dosing and should be used where available. Additionally, the optimal use of viral load testing in developing settings is not known; it detects treatment failure sooner than CD4 measurements, but CD4 count is a better predictor of disease progression. Further, the optimal time to switch regimens is not clear, especially when the number of regimens available and the amount of funding is limited. Further research in this area, including cost-effectiveness analyses, is needed.
- van Rossum AM, Fraaij PL, de Groot R. Efficacy of highly active antiretroviral therapy in HIV-1 infected children. Lancet Infect Dis 2002 Feb;2(2):93-102. Review.
- Puthanakit T, Oberdorfer A, Akarathum N, Kanjanavanit S, Wannarit P, Sirisanthana T, et al. Efficacy of highly active antiretroviral therapy in HIV-infected children participating in Thailand's National Access to Antiretroviral Program. Clin Infect Dis 2005 Jul 1;41(1):100-7.
- Fassinou P, Elenga N, Rouet F, Laguide R, Kouakoussui KA, Timite M, et al. Highly active antiretroviral therapies among HIV-1-infected children in Abidjan, Côte d'Ivoire. AIDS 2004 Sep 24;18(14):1905-13.
- Kline MW, Matusa RF, Copaciu L, Calles NR, Kline NE, Schwarzwald HL. Comprehensive pediatric human immunodeficiency virus care and treatment in Constanta, Romania: implementation of a program of highly active antiretroviral therapy in a resource-poor setting. Pediatr Infect Dis J 2004 Aug;23(8):695-700.
- Calmy A, Pinoges L, Szumilin E, Zachariah R, Ford N, Ferradini L, et al. Generic fixed-dose combination antiretroviral treatment in resource-poor settings: multicentric observational cohort. AIDS 2006 May 12;20(8):1163-9.
- Chokephaibulkit K, Plipat N, Cressey TR, Frederix K, Phongsamart W, Caparelli E, et al. Pharmacokinetics of nevirapine in HIV-infected children receiving an adult fixed-dose combination of stavudine, lamivudine and nevirapine. AIDS 2005 Sep 23;19(14):1495-9.