Puthanakit T, Saphonn V, Ananworanich J, Kosalaraksa P, Hansudewechakul R, Vibol U, et al. Early versus deferred antiretroviral therapy for children older than 1 year infected with HIV (PREDICT): a multicentre, randomised, open-label trial. Lancet Infect Dis. 2012 Oct 8. pii: S1473-3099(12)70242-6. doi: 10.1016/S1473-3099(12)70242-6.
To determine the optimum time to start antiretroviral therapy (ART) in HIV-infected children who have survived past their first year of age without treatment.
Nine tertiary referral hospitals or research sites in the Comprehensive International Program for Research in AIDS (CIPRA) Thailand and Cambodia Network.
Randomized controlled trial.
HIV-infected children aged 1- 12 years, with moderate immunosuppression (CD4 percentage of 15% to 24%), no history of AIDS illness, and no previous ART (except exposure through prevention of mother-to-child HIV transmission efforts).
AIDS-free survival. Neurodevelopmental outcomes were assessed in a substudy with the Beery visual motor integration (VMI) test. Other secondary outcomes included ART adherence, rates of hospital admission, changes in CD4 percentage and growth, toxicity related to antiretroviral therapy, and cumulative proportions of children with virologic failure.
Participants were randomly allocated (1:1) to early ART (for children with a CD4 percentage of 15% to 24%) or deferred treatment (started after a decline in CD4 percentage to <15% or development of US Centers for Disease Control and Prevention (CDC) category C events.(1) Immunological criteria for ART initiation in children aged 1-3 years were subsequently modified to CD4 percentages of less than 20%, due to changes in WHO and country guidelines.
First-line ART was zidovudine (ZDV), lamivudine (3TC), and nevirapine (NVP). In children with previous NVP exposure, a protease inhibitor (lopinavir-ritonavir [LPV/r] or, until September 2007, nelfinavir [NFV]) was substituted. Abacavir (ABC) was substituted for ZDV in children with grade 3 or 4 hematological toxicity.(2) Efavirenz (EFV), LPV/r or NFV was substituted for NVP in some children with NVP hypersensitivity. Children needing tuberculosis treatment received ZDV, 3TC, and ABC. Investigators defined virologic failure as HIV RNA of >1000 copies/mL after six months or more of treatment. Second-line ART was based on genotypic resistance testing.
Children in the early treatment group were seen at clinical research sites at two, four, eight and 12 weeks and every 12 weeks thereafter; children in the deferred treatment group were seen at clinical research sites at eight weeks, 12 weeks and every 12 weeks thereafter. Investigators performed clinical assessments, including for toxicity or HIV-related events, at every visit; they did complete blood counts and measured CD4 percentages, cell counts, serum electrolytes and alanine transaminase concentrations every 12 weeks. They also assessed plasma HIV RNA and did Beery VMI tests every 24 weeks and used adherence questionnaires and pill counts to assess ART adherence.
Between March 2006 and September 2008, researchers screened 455 Thai and Cambodian children; 155 were excluded before randomization, primarily for having CD4 percentages above or below the pre-specified thresholds. One hundred fifty children were randomized to early treatment, and 150 to deferred treatment. One child in the early treatment group withdrew before treatment and was excluded from analyses. At baseline, CD4 percentages and cell counts were comparable between the groups, at an overall median of 20% (interquartile range [IQR] 17% to 23%) and 619 cells/µL (IQR 437 to 850 cells/µL). Age group distribution, gender, country of origin, Z-scores and baseline clinical characteristics were also similar, though there was a somewhat higher percentage of girls in the deferred treatment group (n=96, 64%; vs. n=77, 52%). The median age overall was 6.5 years (IQR 3.9 to 8.4 years)
By the end of the study period in May 2011, 69 (46%) children in the deferred treatment group had initiated ART, The mean CD4 percentage at initiation in the deferred treatment group was 13.8% (standard deviation [SD] 2.8%); the mean CD4 cell count was 591 cells/µL (SD 508 cells/µL) in 17 children under five years old and 309 cells /µL (SD 141 cells/µL) in 52 children aged five or older.
In the early treatment group, children received ART for 99% of the total study period, compared with 25% in the deferred treatment group. Nearly all children in both treatment groups were alive and had high AIDS-free survival at week 144. In an intention-to-treat analysis, AIDS-free survival rates at week 144 were 97.9% (95% confidence interval [CI], 93.7% to 99.3%) in the early treatment group and 98.7% (95% CI 94.7% to 99.7%) in the deferred treatment group (p=0.6). The incidence rate ratio (iRR) of CDC category C events per 1000 person-years of follow-up was 7.6 (95% CI 2.5 to 23.6) in the early treatment group and 4.9 (95% CI 1.2 to 19.7) in the deferred treatment group (adjusted hazard ratio [aHR] 0.8, 95% CI 0.1 to 4.6, p=0.8). Only five children experienced CDC category C events, three from the early treatment group and two from the deferred treatment group. HIV-associated hospital admissions were higher in the early treatment group (14 admissions vs. 9), but six of the early treatment group's admissions were for one child. This child was admitted six times for pneumonia, and subsequently died. This was also the only death during the study period. The incidence of CDC category B events was somewhat lower in the early treatment group, iRR 88 per 1000 person-years (95% CI 61 to 122) vs. iRR 110 per 1000 person-years (95% CI 80 to 147) in the deferred treatment group.
For children with ≥48 weeks of antiretroviral therapy, 121 (81%) of 149 in the early treatment group and 47 (85%) of 55 in the deferred treatment group had HIV RNA <50 copies/mL and remained on first-line ART (absolute difference -4%, 95% CI -15 to 7, p=0.5). Cumulatively, 13 (9%) children in the early treatment group and four (6%) of 69 in the deferred treatment group who started ART switched to second-line ART regimens (p=0.59).
Adherence to ART was good in both groups, with >95% adherence reported by 88% in the early treatment group and 90% those on ART in the deferred treatment group.
Children in the early treatment group had similar weight gain but better height gain than did those in the deferred treatment group. The mean height gain per year was 5.4 centimeters (SD 1.4 cm) in the early treatment group and 4.9 centimeters (SD 1.2 cm) in the deferred treatment group (absolute difference -0.5, 95% CI -0.8 to -0.2, p=0.001). The mean height-for-age Z score at week 144 was -1.45 (SD 1.30) in the early and -1.67 (SD 1.14) in the deferred treatment group (mean difference -0.22, 95% CI -0.38 to -0.08, p=0.003).
Because the neurodevelopment substudy was phased in after the main study had started, researchers only did baseline Beery VMI assessments in 39 children in the early treatment group (mean 81.5, SD 17.2) and 32 children in the deferred treatment group (mean 87.1, SD 14.4). At week 144, the standardized Beery VMI score in 132 children in the early treatment group was 85.2 (SD 13.8), compared with 86.6 (14.0) for 140 children in the deferred treatment group (absolute difference 1.4, 95% CI -1.89 to 4.77, p=0.4). Distribution of age, sex, and treatment group did not differ for children completing the baseline assessment from those who did not complete the assessment. For the 71 children who had a baseline assessment, the mean difference in Beery standard score change from baseline from week 0 to week 144 between the early and the deferred arms was -4.37 (95% CI -12.00 to 3.26; p=0.26).
In analyses adjusted for sex and baseline age, treatment groups did not differ for rates of CDC category B and C events, hospital admissions, CD4 percentage recovery on ART, undetectable plasma HIV RNA after ≥48 weeks on ART, and Beery VMI score.
The authors conclude that AIDS-free survival in both treatment groups was high, and that this low event rate means that their study was underpowered to detect differences between early and deferred ART initiation. Additional follow-up of study participants or future studies are needed to answer this clinical question.
The overall risk of bias in this trial is low. Randomization was performed by an independent biostatistician working at the trial's coordinating center, using a computer program. Allocation concealment was adequate. Blinding was not possible. Attrition and loss to follow-up are adequately accounted for. The trial compares favorably to its registration document.(3)
This trial's findings differ from those of the Children with HIV Early Antiretroviral Therapy (CHER) trial,(4) which showed that early ART reduced mortality by 76% in HIV-infected infants aged <12 weeks, compared to deferred ART. However, the CHER children were much younger. Children surviving their first year of life without antiretroviral therapy, as in the current study, may represent a group of children with slow HIV disease progression. Also, this trial was conducted in Cambodia and Thailand, and its findings might not be applicable to the generalized epidemic settings of sub-Saharan Africa where routine CD4 percentage monitoring is often not available and the burden of disease and malnutrition may be higher.
Clinicians should follow current World Health Organization guidelines on ART for children and infants.(5) New guidance is expected to be released in mid-2013.
- US Department of Health and Human Services. Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR Morb Mortal Wkly Rep 1994; 43: 1-10.
- US National Institutes of Health (NIH), Division of AIDS (DAIDS). Table for grading the severity of adult and pediatric adverse events (2004). [accessed 20 October 2012]
- When to Start Anti-HIV Drugs in Children Infected With HIV (The PREDICT Study). ClinicalTrials.gov Identifier: NCT00234091. [accessed 20 October 2012]
- Early antiretroviral therapy and mortality among HIV-infected infants. Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, Jean-Philippe P, McIntyre JA; CHER Study Team. N Engl J Med. 2008 Nov 20;359(21):2233-44.
- World Health Organization (WHO). Antiretroviral therapy for HIV infection in infants and children: Towards universal access. Recommendations for a public health approach. 2010 revision. [accessed 20 October 2012]