Co-trimoxazole reduces risk of death for children in Zambia, should be given to all children with HIV symptoms, say researchers

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A large randomised study of co-trimoxazole prophylaxis in Zambian children with HIV infection has shown that daily treatment with the drug almost halved the risk of death over a median follow-up period of 19 months. The researchers recommend that all children with symptoms of HIV infection in resource-limited settings should receive the drug. UNICEF today described the study as a “major breakthrough [that] has the potential to save the lives of hundreds of thousands of children each year".

Although co-trimoxazole prophylaxis is already recommended for children for CD4 cell percentages less than 15 in resource-limited settings, concerns have been expressed about its effectiveness due to high levels of bacterial resistance to the drug in many regions. This study is the first to test its use in children in a region with high background levels of co-trimoxazole resistance, and is the longest running study of co-trimoxazole prophylaxis yet reported from a developing country setting.

The Children with HIV Antibiotic Prophylaxis trial (CHAP) was sponsored by the UK’s Department for International Development and recruited 534 children with symptomatic HIV infection aged six months to five years of age in Zambia. The study’s recruitment criteria were later extended to include all children up to the age of 15 as the number of diagnoses increased at the University Teaching Hospital in Lusaka.

Glossary

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

Pneumocystis carinii pneumonia (PCP)

Pneumocystis carinii pneumonia is a form of pneumonia that is an AIDS defining illness.

p-value

The result of a statistical test which tells us whether the results of a study are likely to be due to chance and would not be confirmed if the study was repeated. All p-values are between 0 and 1; the most reliable studies have p-values very close to 0. A p-value of 0.001 means that there is a 1 in 1000 probability that the results are due to chance and do not reflect a real difference. A p-value of 0.05 means there is a 1 in 20 probability that the results are due to chance. When a p-value is 0.05 or below, the result is considered to be ‘statistically significant’. Confidence intervals give similar information to p-values but are easier to interpret. 

pneumonia

Any lung infection that causes inflammation. The infecting organism may be bacteria (such as Streptococcus pneumoniae), a virus (such as influenza), a fungus (such as Pneumocystis pneumonia or PCP) or something else. The disease is sometimes characterised by where the infection was acquired: in the community, in hospital or in a nursing home.

rash

A rash is an area of irritated or swollen skin, affecting its colour, appearance, or texture. It may be localised in one part of the body or affect all the skin. Rashes are usually caused by inflammation of the skin, which can have many causes, including an allergic reaction to a medicine.

The study excluded children with opportunistic infections or a history of allergy to the study drug. It recruited children with symptoms suggestive of advanced HIV disease such as candidiasis, lymphadenopathy, recurrent pneumonia and failure to thrive. All children were tested for HIV antibodies and children younger than 18 months with HIV antibodies were treated presumptively. This approach, say the authors, reflects the real life situation in Africa where more sophisticated tests that can distinguish between maternal antibodies and genuine HIV infection in a young child are not available.

Children were randomised to receive co-trimoxazole or placebo. Children younger than 5 years received 240 mg (5 mL suspension) co-trimoxazole daily, and those older than 5 years 480 mg (10 mL), or matching placebo.

At baseline almost three-quarters of children had already been in hospital at least once, 43% had been diagnosed with candida and 28% with bacterial infections. Of 393 children who received CD4 cell tests, 69% had CD4 cell percentages below 15.

In October, 2003, the data and safety monitoring committee recommended early stopping of the trial when it became apparent that there was a significant benefit to co-trimoxazole treatment.

After median follow-up of 19 months, 74 (28%) children in the co-trimoxazole group and 112 (42%) in the placebo group had died (hazard ratio [HR] 0.57, p=0.0002), amounting to a 43% reduction in the risk of death. This benefit applied in children followed up beyond 12 months (n=320, HR 0.48 [0.27–0.84]) and across all ages and baseline CD4 counts.

Sixteen (6%) children in the co-trimoxazole group had grade 3 or 4 adverse events compared with 18 (7%) in the placebo group. These events included rash (one placebo), and a neutrophil count on one occasion less than 0.5 109/L (16 [6%] co-trimoxazole vs seven [3%] placebo, p=0.06).

The authors say that they are not certain why cotrimoxazole reduced the death rate in this study. Although the drug is recommended as prophylaxis against pneumocystis carinii pneumonia (PCP), no cases of infection could be confirmed in children and the benefit was not confined to the children with the lowest CD4 cell counts, as would be expected if the chief benefit of treatment related to a reduction in the incidence of PCP. Further analysis is needed, say the investigators, to determine why the treatment was effective.

Nevertheless, the authors confidently conclude: “We believe, therefore, that our results can be generalised to a policy that could be applied universally to children with clinical features of HIV infection in Africa: all should receive co-trimoxazole prophylaxis irrespective of age and CD4 count.”

“The results of this trial should provide an impetus to provide clinical care with co-trimoxazole prophylaxis

and nutritional support, irrespective of levels of resistance to this drug. Whether it would continue to add benefit to children also taking antiretroviral therapy in areas of high background rates of infection remains to be seen.”

HIV & AIDS Treatment in Practice

The implications of these study findings for treatment practice in resource-limited settings will be discussed in detail in a forthcoming issue of NAM's electronic newsletter on HIV treatment in developing countries, HIV & AIDS Treatment in Practice. To subscribe to the newsletter, click here.

References

Chintu C et al. Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a double-blind randomised placebo-controlled trial. The Lancet 364: 1865-71, 2004.