No reduction in postnatal death or illness with cotrimoxazole prophylaxis for mothers with HIV

Cotrimoxazole prophylaxis, while safe and well-tolerated, had no significant effect on reducing death or hospital admissions among HIV-infected women followed for one year after having given birth in Zambia, according to Andrew J Nunn and colleagues in a randomised, placebo-controlled trial (TOPAZ) reported in the advance online edition of Tropical Medicine and International Health.

While loss to follow-up was significant (40%), the authors noted a possible benefit to breast-fed babies of women who received cotrimoxazole.

Death rates, before the infants got open-label cotrimoxazole, were 19.5 (95% CI: 12.9 to 29.3) per 100 child-years in the cotrimoxazole arm, compared to 34.5 (95%CI: 24.4 to 48.8) per 100 child-years in the placebo arm, P=0.1.

Bacterial and other opportunistic infections (OIs) continue to account for the high death and disease rate in people with HIV in resource-poor settings where access to antiretroviral therapy remains out of reach for many. HIV is the leading cause of death and disease among women of reproductive age in sub-Saharan Africa. In Zambia, HIV prevalence among pregnant women is reported to be as high as 34%, note the authors.

Little attention has been paid to the prevention of opportunistic infections in HIV-infected pregnant women either before or after birth, they add.

Before ART availability in African countries, and based on the evidence of its efficacy as an effective prophylaxis against bacterial and other opportunistic infections, the World Health Organization (WHO) and UNAIDS in 2000 made a provisional recommendation that cotrimoxazole be given to all adults and children in Africa with symptomatic HIV-1 infection. (Cotrimoxazole prophylaxis is now both widely available and its value in preventing opportunistic infections recognised.)

After careful consideration and review of the existing evidence, the Zambian Ministry of Health – together with the University of Zambia Research and Ethics Committee – agreed to undertake three randomised, placebo-controlled trials looking at cotrimoxazole prophylaxis in HIV infection in children, in adults with tuberculosis and in women after childbirth. The first two showed a significant reduction of all causes of death in those getting cotrimoxazole.

Reporting on the findings from the third trial, the authors note this is the only double-blind, placebo-controlled randomised trial of cotrimoxazole prophylaxis that has been undertaken in HIV-infected women after childbirth in Africa.

From September 2000 to August 2003, 600 postnatal women with HIV at WHO stage 2 or 3 were randomised to receive cotrimoxazole or matching placebo for a year. Follow-up closed in September 2004 when funding became available for those eligible for ARVs to go on to treatment. Primary outcomes were death from any cause, hospital admission and serious adverse events.

Follow-up data was available for 60% (355: 180 on cotrimoxazole and 175 on placebo).

36 women (17 on cotrimoxazole and 19 on placebo) died and an additional 11 (5 on cotrimoxazole and 6 on placebo) were admitted to hospital.

There was no significant difference in the combined event rates between the two treatment arms with 9.4 per 100 women-years in the cotrimoxazole arm (95% CI: 6.2 to 14.3) and 11.4 per 100 women-years in the placebo arm (95% CI: 7.7-16.9): unadjusted HR-0.82, 95% CI: 0.46 to 1.45, P=0.49.

The authors suggest that the relatively small number of deaths is because the women were at an early stage of HIV infection. They add that, in contrast to other studies, there was no measurable mortality benefit for women in the cotrimoxazole arm. They suggest another possibility: “cotrimoxazole prophylaxis for the prevention of HIV-associated OIs selects for resistant pathogens as shown in a study of Kenyan adults.”

The high loss to follow-up (40%) could also explain the lack of effect of cotrimoxazole as well as the lower than anticipated event rate in the placebo group, the authors note. They suggest, in contrast to other studies with good follow-up, this may be because this cohort were not yet immunosuppressed, felt well and did not see the need to attend clinics.

The authors suggest that social pressures may have also played a role. They add that provision of food and refund of transport monies had no effect on follow-up.

The authors note most African countries do not have the resources to provide ART to all. So the critical need for standardised, evidence-based recommendations on preventive measures remains. The development of an overall package of care is in process, they add.

According to WHO, there is clear evidence of the benefits of prophylaxis for both cotrimoxazole and isoniazid preventive therapy, notably in areas where HIV and TB are endemic, yet implementation is a problem.

The authors conclude: ”provision of adequate care through infection-prevention regimens for the large numbers of people affected by HIV remains a daunting task.”