Date Published: October 26, 2011
Publisher: BioMed Central
Author(s): Torsak Bunupuradah, Thanyawee Puthanakit, Pope Kosalaraksa, Stephen Kerr, Pitch Boonrak, Wasana Prasitsuebsai, Pagakrong Lumbiganon, Tawan Mengthaisong, Chayapa Phasomsap, Chitsanu Pancharoen, Kiat Ruxrungtham, Jintanat Ananworanich.
There are limited data of immunologic and virologic failure in Asian HIV-infected children using non-nucleoside reverse transcriptase inhibitor (NNRTI)-based highly active antiretroviral therapy (HAART). We examined the incidence rate of immunologic failure (IF) and virologic failure (VF) and the accuracy of using IF to predict VF in Thai HIV-infected children using first-line NNRTI-based HAART.
Antiretroviral (ART)-naïve HIV-infected children from 2 prospective cohorts treated with NNRTI-based HAART during 2001-2008 were included. CD4 counts were performed every 12 weeks and plasma HIV-RNA measured every 24 weeks. Immune recovery was defined as CD4%≥25%. IF was defined as persistent decline of ≥5% in CD4% in children with CD4%<15% at baseline or decrease in CD4 count ≥30% from baseline. VF was defined as HIV-RNA>1,000 copies/ml after at least 24 weeks of HAART. Clinical and laboratory parameter changes were assessed using a paired t-test, and a time to event approach was used to assess predictors of VF. Sensitivity and specificity of IF were calculated against VF.
107 ART-naive HIV-infected children were included, 52% female, % CDC clinical classification N:A:B:C 4:44:30:22%. Baseline data were median (IQR) age 6.2 (4.2-8.9) years, CD4% 7 (3-15), HIV-RNA 5.0 (4.9-5.5) log10copies/ml. Nevirapine (NVP) and efavirenz (EFV)-based HAART were started in 70% and 30%, respectively.
Immunologic failure, as defined here, had low sensitivity compared to VF and should not be recommended to detect treatment failure. Plasma HIV-RNA should be performed twice, at weeks 24 and 48, to detect early treatment failure.
Clinicaltrials.gov identification number NCT00476606
Over 140,000 children in South and Southeast Asia are living with HIV . Treatment with highly active antiretroviral therapy (HAART) has increased the life expectancy of HIV-infected children [2-6]. Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART is commonly prescribed as the first-line regimen in resource-limited settings [2-8]. In Thailand, the majority of HIV-infected individuals have HIV-1 subtype CRF01_AE . A national program has provided free HAART since 2004 [2,3].
Data from HIV-infected children who were enrolled in 2 prospective cohorts at the HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), the Thai Red Cross AIDS Research Centre, Bangkok and Khon Kaen University, Khon Kaen, Thailand from December 2001 to March 2008 were used. The inclusion criteria for this study were HIV-infected children aged 1-18 years at enrolment who were antiretroviral therapy (ART) naïve before initiating first-line NNRTI-based HAART. The criteria to start HAART in these HIV-infected children followed WHO 2006 guidelines  and Thai 2008 guidelines ; CDC clinical classification C, or CD4% <20% in children aged < 3 years, or CD4%<15% in children aged ≥ 3 years [14,15]. The ART regimen and dosages were calculated according to a child's body weight or body surface area according to recommendations in the WHO 2006 guidelines  and Thai 2008 guidelines . Adherence counselling was performed at each visit according to standard practice. The self-report adherence questionnaires were completed by caregivers at every visit. The missing doses in the last 3 days or missing > 15 doses since last visit were defined as poor adherence.
One hundred and seven HIV-infected children were included in the analysis. The median (IQR) age was 6.2 (4.2-8.9) years, 52.3% were female. Zidovudine (AZT), and stavudine (d4T) were used in 60.4% and 39.6%, respectively. All used lamivudine (3TC). Nevirapine (NVP) and efavirenz (EFV)-based HAART were prescribed 70% and 30%, respectively. The median (IQR) baseline CD4% and HIV-RNA were 7 (3-15) and 5.0 (4.9-5.5) log10 copies/ml (Table 1).
At 96 weeks after NNRTI-based HAART initiation, HIV-infected children had significant improvement of growth, hemoglobin, CD4%, and CD4 count. Only 1 child experienced IF. VF mostly occurred within the first 24 weeks of NNRTI-based HAART but a quarter developed failure between 24 to 48 weeks. To detect early treatment failure, having two HIV-RNA monitorings within the first year, at weeks 24 and 48, would be ideal. Low sensitivity of IF to predict VF was found.
In summary, NNRTI-based HAART has shown significant improvement of clinical, immunologic and virologic outcomes. At 96 weeks, 75% of children had suppressed plasma HIV-RNA and 89% had immune recovery. Almost all of VF occurred in the first year after HAART initiation. Immunologic failure had low sensitivity and should not be relied on as a monitoring for treatment failure. Plasma HIV-RNA should be performed once, and preferably twice, in the first year after NNRTI-based HAART to detect early treatment failure, and subsequently once a year if feasible as a routine monitoring for all on HAART.
All authors declare no conflict of interest and that member of their immediate families do not have a financial interest in or arrangement with any commercial organization that may have a direct interest in the subject matter of this article.
TB, TP, PK, and JA designed the study, collected data, wrote the first draft, reviewed and commented draft of manuscript before submission. WP, PL, CPa, and KR designed the study, collected data, reviewed and commented draft of manuscript before submission. SK, PB analyzed, reviewed and commented draft of manuscript before submission. TM and CPh collected data, reviewed and commented draft of manuscript before submission. All authors have read and approved the final manuscript.