Cotrimoxazole prophylaxis for HIV-positive infants aids growth, reduces anaemia

Use of daily cotrimoxazole in untreated HIV-infected infants significantly improved growth and reduced anaemia, Andrew Prendergast and colleagues reported in new findings from an observational analysis of the children enrolled in the Children with Antibiotic Prophylaxis (CHAP) trial published in the April 1 edition of Clinical Infectious Diseases.

The CHAP trial was double-blinded, randomised and placebo-controlled. It took place in Zambia from 2001 until 2003.

The study showed that cotrimoxazole, a cheap, widely available antibiotic, taken daily, reduced death and disease in HIV-infected children across all age groups and CD4 cell counts.

Cotrimoxazole is effective against malaria as well as infections that cause diarrhoea and pneumonia.

While the benefits of cotrimoxazole in HIV-infected adults and children are acknowledged how it works precisely is not well understood. Its chief benefit probably lies in the prevention of bacterial lung infections.

HIV-infected children in sub-Saharan Africa are often underweight and stunted. Malnutrition and anaemia are both independently linked to death in this population.

Weight gain is a crucial component of HIV programmes for infants and children.

So the authors chose to look at whether cotrimoxazole had a specific effect on growth and anaemia in HIV-infected children.

541 HIV-infected children from one to 14 years of age were enrolled at the University Teaching Hospital in Lusaka. 268 children were randomised to get daily cotrimoxazole (240 mg for children under five years of age; 480 mg for children over five years of age) and 273 to get placebo.

Children were followed every month for the first four months, then every two months afterwards.  The trial was stopped early because of the sustained and significant benefits seen in those taking cotrimoxazole.

28% of those taking cotrimoxazole died compared to 42% in the placebo group ( p=0.001).

The mean CD4 cell percentage at baseline was 12.3%. The mean annual change in CD4 cell percentage was +0.14 (95% CI: -.55 to .83) for those taking cotrimoxazole and -0.37% (95% CI: -1.18 to .44) for those on placebo.

Weight and height measurements were available for all 541 children. There was a high baseline prevalence of stunting and underweight. The mean weight-for-age (WAZ) and height-for-age (HAZ) was -2.84 (SD, 1.63) and -3.25 (SD, 1.48), respectively.

Among untreated HIV-infected children taking cotrimoxazole the  weight-for-age decrease was twofold lower and the height-for-age decrease threefold lower compared to children taking placebo.

The difference was statistically significant; the annual change in WAZ (mean -0.15 [95% CI: -.28 to -.03 compared to -.35 (95% CI:-.49 to -.21], heterogeneity, p=.04); and HAZ (men, -0.07 [95% CI: -.15 to .01] compared to -.22[95% CI: -.30 to -.13] heterogeneity, p=.01).

At the time antiretroviral treatment was not publicly available for children in Zambia. So growth among the children in the trial got worse as their HIV disease progressed. The authors suggest that future studies look at whether ART and cotrimoxazole have an additive effect on growth.

Poor growth is the result of many factors and includes an increased rate of infections, poor appetite and difficulty digesting as well as persistent diarrhoea. 

The authors believe that cotrimoxazole affects growth by reducing infections and diarrhoea. They note that cotrimoxazole may lower immune activation in HIV-infected children by lowering intestinal bacteria. The process of microbial translocation, whereby bacteria from the gut get into the blood system, is the primary driver of Immune-activation.

The authors note that microbial translocation is believed to cause malnutrition and stunting in HIV-infected and uninfected children alike. They add that if future studies confirm that cotrimoxazole affects microbial translocation and/or immune activation then it can be used to improve growth in HIV-uninfected children too.

Most of the children had baseline anaemia. However, those taking cotrimoxazole had a four-fold increase in levels of haemoglobin compared to those on placebo. The authors note that anaemia in HIV-infection is due to many factors, the most important of which is a failure to produce red blood cells (erythropoiesis).

It is feasible that cotrimoxazole reduces the levels of cytokines which interfere with the process of erythropoiesis, the authors add.

Policies for cotrimoxazole prophylaxis exist in most countries yet in 2007 only 4% of eligible children got it, the authors note.

The authors conclude “the current study argues for earlier identification of HIV-infected children and more widespread cotrimoxazole use, to reduce morbidity and mortality and to improve growth and anaemia where ART is unavailable. “

Where ART is available its use should be encouraged or continued; it may have an additive effect on nutrition and anaemia as well as reducing mortality as recent findings in adults have shown, they add.

Prendergast A et al. Improved growth and anemia in HIV-infected children taking cotrimoxazole prophylaxis. Clin Inefct Dis 52 (7):953-956, 2011. (Free abstract available here).