Antiretroviral Therapy Is Effective for Children with HIV in both Wealthy and Resource-Limited Settings

		SUMMARY: Overall mortality and deaths due to opportunistic illness dropped dramatically among U.S. children with HIV after the introduction of highly active antiretroviral therapy (HAART) in the mid-1990s, according to data from a large cohort study. However, the death rate remains 30 times higher than that of uninfected children, largely attributable to non-AIDS-defining infections and organ failure. A related systemic analysis found that among HIV-infected children in resource-limited countries, virological and immunological responses to HAART were similar to those of children in wealthier areas.

By Liz Highleyman

In the first study, published in the January 1, 2009 Journal of Acquired Immune Deficiency Syndromes, investigators with the Pediatric AIDS Clinical Trials Group 219/219C team evaluated changes in the causes and risk factors for death among children with HIV-1 infection.

This multicenter, prospective cohort study enrolled 3553 HIV-infected children and adolescents (up to age 21) between April 1993 and December 2006. The median follow-up period was 5.3 years.

Results

	A total of 298 study participants died during the observation period.
	Death rates decreased significantly between 1994 and 2000, from 7.2 to 0.8 per 100 person-years.
	After 2000, mortality rates remained relatively stable through 2006.
	Over time, the mean age at the time of death roughly doubled, rising from 8.9 years in 1994 to 18.2 years in 2006.
	The most common causes of death were "end-stage AIDS" (48 children, 16%) and pneumonia (41 children, 14%).
	The proportion of deaths due to opportunistic infections (OIs) declined from 37% in 1994-1996 to 24% after 2000.
	While all OI mortality declined during the study period, the decrease was greater for deaths due to Mycobacterium avium complex and cryptosporidiosis.
	In contrast, deaths due to "end-stage AIDS," sepsis (systemic infection), and kidney failure increased.
	After adjusting for other factors, increased risk of death was associated with low CD4 count and presence of AIDS-defining illness at study entry.
	Later birth cohorts and children who initiated HAART were significantly less likely to die than untreated participants (hazard ratio 0.54; P < 0.001).

"Overall death rates declined from 1993 to 2000 but have since stabilized at rates about 30 times higher than for the general U.S. pediatric population," the study authors concluded.

"Deaths due to OIs have declined," they continued, "but non-AIDS-defining infections and multi-organ failure remain major causes of mortality in HIV-1-infected children."

Coauthor Lynne Mofenson noted that while "most HIV-infected children now reach adulthood," it is not yet clear whether they will go on to have a normal lifespan. "Currently, we don't have the means to prevent all the complications of HIV infection," she said.

Resource-limited Settings

As described in the second report, published in the December 15, 2009 issue of Clinical Infectious Diseases, Andrea Ciaranello from Massachusetts General Hospital and colleagues performed a systematic review and meta-analysis of published studies of treatment response among treatment-naive children aged 0-17 years.

The investigators searched the Medline, EMBASE, and LILACS (Latin American and Caribbean Health Sciences Literature) electronic databases and the Cochrane Clinical Trials Register to identify relevant studies conducted in resource-limited countries in Africa, Asia, Latin America, and the Caribbean.

They used this data to calculate pooled estimates of the proportions of children who achieved HIV RNA < 400 copies/mL and CD4 percentage (CD4%) increases after 12 months on treatment (in young children, CD4% is considered a more accurate marker of immune status than absolute CD4 count).

Out of a total of 5928 children who started ART, about 80% did not have viral load data and about 70% were missing CD4% data at 12 months; to approximate an intent-to-treat analysis, children with missing 12-month data were assumed to have HIV RNA > 400 copies/mL and/or no change in CD4%.

Results

	Based on 1097 participants in 9 studies with complete data, the pooled proportion of children with virological suppression was 70%.
	Based on 1839 children in 12 studies with complete data, the pooled CD4% increase was 13.7%.
	In the approximated intent-to-treat analysis, the estimated pooled proportion with HIV RNA < 400 copies/mL decreased to 53%.
	In this type of analysis, the estimated pooled CD4% increase was 8.5%.

These results fall within ranges previously reported from studies of children with HIV in North American and Europe (53%-84% with virological suppression; CD4% gain of 10%-13%).

"Pooled estimates of reported virologic and immunologic benefits after 12 months of ART among HIV-infected children in resource-limited settings are comparable with those observed among children in developed settings," the researchers concluded.

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References

MT Brady, JM Oleske, PL Williams, and others (Pediatric AIDS Clinical Trials Group219/219C Team). Declines in Mortality Rates and Changes in Causes of Death in HIV-1-infected Children During the HAART Era. Journal of Acquired Immune Deficiency Syndromes 53(1): 86-94 (Abstract). January 1, 2009.

AL Ciaranello, Y Chang, AV Margulis, and others. Effectiveness of Pediatric Antiretroviral Therapy in Resource-Limited Settings: A Systematic Review and Meta-analysis. Clinical Infectious Diseases 49(12): 1915-1927 (Abstract).December 15, 2009.