iconstar paper   Hepatitis C Articles (HCV)  
Back grey arrow rt.gif
Immediate ART No Better Than Deferred in Asian Kids With Moderate CD4 Loss !
  3rd International Workshop on HIV Pediatrics, July 15-16, 2011, Rome
Mark Mascolini
After 144 weeks of follow-up, immediate antiretroviral therapy (ART) for Thai and Cambodian children over 1 year old and with a starting CD4 percent between 15% and 24% did not improve survival or slow progression to AIDS when compared with deferring therapy until the CD4 percent fell below 15%. Nor did early therapy in the PREDICT trial promote better neurodevelopment. But starting ART sooner prevented two complications--thrombocytopenia and herpes zoster--and promoted faster growth.
In HIV-positive newborns, the randomized CHER trial established that immediate versus deferred ART cut mortality by 76% and HIV progression by 75% [2]. As a result, the World Health Organization (WHO) now recommends immediate ART for all HIV-positive children up to 2 years old regardless of CD4 numbers or WHO clinical stage [3]. But the impact of early versus deferred treatment in older children remained unknown until PREDICT investigators reported their findings at the 3rd International Workshop on HIV Pediatrics in Rome [1]. So guidelines for children over 1 year old rest on results of adult studies.
PREDICT investigators recruited 1- to 12-year-old HIV-positive children with a CD4 percent from 15% to 24% and no antiretroviral experience. The researchers randomized 150 children to start ART immediately and 150 to delay until their CD4 percent dipped below 15% or they had a CDC category C event. Study participants had their CD4 cells measured every 3 months. The primary endpoints were AIDS-free survival and neurodevelopment (as measured by the Berry score) 144 weeks after randomization.
The study group included 180 Thais and 120 Cambodians. Everyone started the same combination--nevirapine, zidovudine, and lamivudine. Most entry traits were similar in the two treatment arms, with average (and standard deviation) age at 6.4 (2.9) years, weight-for-age Z score at -1.32 (1.03), height-for-age Z score at -1.64 (1.32), and CD4 percent at 20% (5%). Median viral load was marginally higher in the immediate group (4.9 log or 80,000 copies) than in the deferred group (4.7 log or 50,000 copies). The deferred arm had a somewhat higher proportion of girls than the immediate arm (64% versus 52%). About one third of children were 1 to 5 years old, while two thirds were older than 5.
Overall trial retention was 97% and did not differ between groups. During follow-up, 69 children (46%) in the deferred group began ART at an average CD4 percent of 13.8%. Only 1 child died during the study, and that child was in the immediate-ART group. Including this death, there were 3 CDC category C events in the immediate arm and 2 in the deferred arm. AIDS-free survival at 144 weeks came to 97.9% in the immediate-treatment group and 98.7% in the deferred-treatment group. Rates of CDC grade C events or death were 7.6 per 1000 person-years in the immediate group and 4.9 per 1000 person-years in the deferred group. At 144 weeks, neurodevelopment as measured by the Berry score was equivalent in the immediate group (84.7) and the deferred group (86.8).
Among secondary endpoints, rates of CDC category B events, hospital admissions, and overall grade 3 or 4 adverse events did not differ significantly between the two study groups. However, the deferred-treatment group had significantly higher rates of newly diagnosed thrombocytopenia (10 versus 1, P = 0.03) and herpes zoster (13 versus 2, P = 0.03). Because of the study design, average CD4 percent at week 144 was significantly higher in the immediate group than in the deferred group (32.7% versus 24.8%, P < 0.001). CD4 gain rates after ART began were similar in the two treatment arms.
Children who started antiretrovirals immediately grew significantly faster than the deferred group (height-for-age Z score -1.43 versus -1.65 at 144 weeks, P = 0.008). And there was a trend toward greater weight gain in the immediate group (weight-for-age Z score -1.10 versus -1.25, P = 0.07).
Pediatricians around the world have much to ponder in these findings. As Pediatrics Workshop cochair Lynne Mofenson (NICHD, NIH) observed, the results are "very controversial since they go against all the adult data."
Several considerations in interpreting the data are clear. First, PREDICT investigator Thanyawee Puthanakit (HIV-NAT, Bangkok) noted that the study population included too few 1- to 3-year-olds to support any firm conclusions for this critical age group. Second, the trial mandated CD4 check-ups every 3 months, an interval probably not realistic for many people in low-income countries, especially for children who live in rural areas far from HIV clinics. Third, by definition all children in PREDICT survived the first year of life without ART and with moderate CD4 loss, so the findings apply only to this group of early survivors with moderate progression.
For 2- to 5-year-olds, WHO now recommends ART for those with a CD4 count at or below 750 or a CD4 percent at or below 25%, whichever is lower, regardless of WHO clinical stage [3]. For children 5 or older, WHO advises starting ART for all with a CD4 count below 350, regardless of WHO clinical stage. US Department of Health and Human Services guidelines recommend ART for 1- to 5-year-olds with a CD4% below 25% regardless or viral load [4]. For children over 5, this panel sets a CD4 count of 350 as the ART-start threshold, regardless of viral load.
1. Puthanakit T, Vonthanak S, Ananworanich J, et al. Randomized clinical trial of immediate versus deferred antiretroviral therapy initiation in children older than one year with moderate immunodeficiency: the PREDICT study (NCT00234091). 3rd International Workshop on HIV Pediatrics. July 15-16, 2011. Rome. Abstract O_01.
2. Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, Jean-Philippe P, McIntyre JA; CHER Study Team. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med. 2008;359:2233-2244. http://www.nejm.org/doi/full/10.1056/NEJMoa0800971,
3. World Health Organization. Antiretroviral therapy for HIV infection in infants and children: towards universal access. 2010 revision. http://www.who.int/hiv/pub/paediatric/infants2010/en/.
4. US Department of Health and Human Services Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. August 16, 2010. http://aidsinfo.nih.gov/contentfiles/PediatricGuidelines.pdf.
  iconpaperstack View Older Articles   Back to Top   www.natap.org