Charlebois ED, Ruel TD, Gasasira AF, et al. Short-term risk of HIV disease progression and death in Ugandan children not eligible for antiretroviral therapy. J Acquir Immune Defic Syndr. 2010 Jun 29.
World Health Organization (WHO) guidelines recommend antiretroviral therapy (ART) for all HIV-infected children under one year of age and for older children who meet clinical or age-specific CD4 and viral load criteria.(1, 2) Little is known about disease progression in children not yet eligible for ART in resource-constrained areas.
To assess the risk and predictors of short-term disease progression in children not currently eligible for ART
Pediatric HIV clinic, Kampala, Uganda
HIV-infected, ART-naïve children aged 1-10 years and weight >5 kg
WHO clinical stage 3 or 4 event, age-specific CD4 threshold for ART-initiation, or death
Data for this analysis were obtained from the Children with HIV and Malaria Project. Children were enrolled from October 2005 through August 2006. Children who met criteria for ART were treated according to Uganda and WHO criteria. All medical conditions (HIV-related or other) were evaluated and treated according to standard protocols. Parents agreed not to provide medications to their children other than those prescribed at the clinic. All participants were given cotrimoxazole prophylaxis and insecticide-treated bed nets.
Complete blood counts, plasma HIV RNA level, and CD4 cell counts and percentages were measured every 12
weeks. Levels of T cell activation (defined as percentage of CD4 and CD8 cells expressing both CD38 and HLADR)
were measured one time for each participant within a median of 84 days of enrollment.
There were 192 children included in the analysis. Their median age was 6.4 years, and 43% were
male. The mean baseline CD4 percentage was 24% (range 8%-46%) and mean log10 HIV RNA copies/mL was
5.0 (range undetectable to >6.0 log10 copies/mL).
A total of 37 children (19%) progressed to stage 3 or 4 disease, died, or reached the CD4 level to initiate ART
after a median of 605 days of follow-up per child (interquartile ratio 280-700). Among the children who
progressed significantly, more were aged 1-3 years and had lower mean CD4 count percentage and hemoglobin
levels and higher viral loads and CD4 and CD8 activation levels.
The independent predictors of disease progression were CD4 percentage (hazard ratio [HR] 2.0% per 10%
decrease, P=0.013), HIV RNA level (HR 1.8, P=0.034), and age less than three years (HR =3.0, P=0.008).
Factors that were predictive of progression-free survival were baseline HIV RNA .100,000/mL (P=0.03) and a
combination of RNA .100,000/mL and CD4 percentage <25% at baseline (P=0.01). The CD4 percentage <25%
alone as a dichotomy was not predictive (P=0.15). Among children with levels of HIV RNA >100,000 copies/mL
and CD4 percentage <25%, 11% and 15% progressed within one and two years, respectively. In contrast,
among children with levels of HIV RNA >100,000 copies/mL and CD4% <25%, 29%, and 34% progressed within
one and two years, respectively.
HIV-infected children who are in care, but not eligible for ART, will experience disease progression.
The study population is likely to be representative of HIV-infected children in care in resource-constrained areas; HIV and other laboratory markers were appropriately documented at baseline and follow-up. The ascertainment of outcomes at baseline and follow-up were acceptable. Loss to follow-up was accounted for and small. There are two important limitations: the study was small and by its design included only children who survived earlier mortality from HIV and other diseases.
This study supports others in which HIV viral load and CD4% are strong predictors of short-term disease progression(3, 4) and mortality.(4, 5) This study demonstrated that a substantial proportion of children experienced a clinical stage 3 or 4 event, died, or had declines in CD4 cells to the threshold level for ART initiation. The study draws into question the need to revise current treatment recommendations towards earlier initiation of ART in children as the WHO did in its treatment recommendations for HIV-infected infants. However, there remains a need for additional data with which to assess current treatment guidelines.
- WHO. Report of the WHO Technical Reference Group. Paper presented at: Paediatric HIV/ART Care Guideline Group Meeting; April 10-11, 2008; WHO Headquarters, Geneva, Switzerland.
- Antiretroviral therapy of HIV infection in infants and children in resource-limited settings: towards universal access. Geneva, Switzerland: World Health Organization; 2006.
- Palumbo PE, Raskino C, Fiscus S, et al. Predictive value of quantitative plasma HIV RNA and CD4+ lymphocyte count in HIV-infected infants and children. JAMA. 1998;279:756-761.
- HIV Paediatric Prognostic Markers Collaborative Study G. Short-term risk of disease progression in HIV-1-infected children receiving no antiretroviral therapy or zidovudine monotherapy: a meta-analysis. Lancet. 2003;362:1605-1611.
- Mofenson LM, Korelitz J, Meyer WA III, et al. The relationship between serum human immunodeficiency virus type 1 (HIV-1) RNA level, CD4 lymphocyte percent, and long-term mortality risk in HIV-1-infected children. National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group. J Infect Dis. 1997;175:1029-1038.