Daily cotrimoxazole preferable to intermittent preventative therapy inHIV-infected children

Polly Clayden, HIV i-Base

WHO recommends daily cotrimoxazole preventative therapy (CPT) for infants and children. US guidelines recommend either daily or three days a week. Adult studies suggest that thrice-weekly CPT is as effective as daily but with a decrease in side effects and an increase in tolerability. The optimum frequency for CPT in children has not been determined.

A paper, published in AIDS, by Heather Zar and colleagues, reported results from a South African study of children randomised to receive either daily or thrice-weekly CPT.

The study looked at mortality, bacterial infections, hospitalisation and adverse events.

A total of 339 children, attending, either Red Cross War Memorial Children’s Hospital, University of Cape Town or Tygerberg Hospital at Stellenbosch University, aged eight months and above were enrolled. Of these, 10 tested negative and five were lost to follow up within a month from randomisation.

The study, which commenced in December 2002, originally had a factorial design and compared both three times weekly CPT vs daily CPT, and isoniazid (INH) vs. placebo. The placebo arm was stopped in May 2004, on the advice of the DSMB, and all children were switched to INH. INH was then discontinued in December 2007 as most children were receiving HAART. The investigators continued to study three times weekly CPT vs daily CPT. Results are from this investigation from January 2003 through December 2007.

Of the 324 children, 165 (50.9%) were randomised to receive intermittent therapy and 159 to daily therapy. They were a median age of 23 months (IQR 9.5-48.6 months). Almost one third (30.3%) were less than 12 months of age. The majority (88.6%) were symptomatic and the median CD4 percentage was 20%. At enrolment 8.6% of children were receiving HAART, and 63.9% received it during the study. Malnutrition was common. Baseline characteristics were similar in both groups.

Overall 9% of children were lost to of which 57% were in the group receiving daily CPT. An additional 24% withdrew from the study, 13% from the daily group, mostly due to logistics. Median follow up was 1.97 years (IQR 1.3-3.3 years) vs 1.92 years (IQR 0.5-3.29 years), p=0.37, in the intermittent and daily groups respectively. The investigators reported excellent adherence in both groups.

They found similar mortality rates in both groups: 24/165 (14.5%) vs 29/159 (18.2%) deaths in the intermittent and daily groups respectively, HR 0.75 (95% CI, 0.44-1.29), p=0.3. The difference in the cumulative survival proportions estimated at one year was 0.04 (90% CI -0.03- 0.10). Therefore thrice weekly was defined as non inferior to daily CPT as the CI for difference included zero and exceeded the predefined delta of -0.1 at one year of follow up. The choice of inferiority margin was based on expert opinion.

Infants had a six-fold higher incidence of death compared to children greater than one year of age (20 vs 3.6 per 100 child years), IRR 5.91 (95% CI 3.3-11.2) p<0.0001.

Causes of death were similar in both groups. Overall this was, 32% sepsis, 25% pneumonia and 15% diarrhoea.

However intermittent CPT was associated with a two increased incidence of bacteraemia, IR 9.6 vs 4.07 per 100 child years, IRR 2.36 (95% CI 1.21-4.87), p=0.006.

Additionally children receiving intermittent IPT spent significantly more days in hospital than those receiving daily, 228.5 vs 198.5 days per 100 child years, IRR 1.15 (95% CI 1.04-1.28), p=0.004. The admission rate was similar between the two groups.

Toxicity was similar in both groups, with an overall incidence of 6.8 grade 3 or 4 events per 100 child years (46 events; 25 intermittent, 21 daily).

The investigators concluded that their results support the current WHO recommendations of daily CPT for infants and children. They acknowledge that their
results may not apply to settings with different burdens of bacterial disease. They wrote: “Widespread implementation of CPT is needed in areas of sub-Saharan Africa where this intervention is not available.”

Ref: Zar HJ et al. A randomised controlled trial of intermittent compared to daily cotrimoxazole therapy in HIV-infected children. AIDS 2010, volume 24:

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