A short-course of co-trimoxazole prophylaxis, commonly used to prevent and treat a number of AIDS-defining infections, provides almost 100% protection against malaria and does not cause resistance to the anti-malarial drug sulfadoxine-pyrimethamine, according to research conducted in Mali and published in the November 15th edition of the Journal of Infectious Diseases.
Co-trimoxazole has been shown to reduce death and illness in HIV-positive individuals with weakened immune systems and prophylaxis and it is recommended in resource-limited settings by UNAIDS for all HIV-positive individuals with a CD4 cell count below 500 cells/mm3, and all infants born to HIV-positive mothers. However, co-trimoxazole and sulfadoxine-pyrimethamine work in similar ways and and concerns have been expressed that the widespread use of co-trimoxazole would increase the prevalence of malaria parasites resistant to sulfadoxine-pyrimethamine. A study published last month found that co-trimoxazale reduced the incidence of malaria amongst HIV-positive Malawians, however another study conducted in Malawi, and published in the summer, found that most AIDS-related opportunistic infections which could be prevented by co-trimoxazole were rare, and malaria with reduced sensitivity to co-trimoxazole was widespread, with concerns expressed that co-trimonxazole prophylaxis for HIV-positive individuals may have more risks than benefits.
These concerns may, however, be unfounded. “In light of the results of the present study and the clear evidence that [co-trimoxazole] prophylaxis prevents death in persons living with HIV/AIDS in a variety of African settings, it is evident that concerns about the spread of sulfadoxine-pyrimethamine resistance do not justify further delays in the implementation of co-trimoxazole prophylaxis”, write the investigators.
Investigators designed a randomised, open-label study which recruited a total of 240 children aged between 5 and 15 years in Mali. The primary outcome of the study was to test the theory that prophylaxis with co-trimoxazole decreases the efficacy of sulfadoxine-pyrimethamine treatment for malaria. The secondary objective was to see if treatment with co-trimoxazole promotes the emergence of malaria parasites with resistance.
Children in the control arm received prophylactic injections of co-trimoxazole (consisting of trimethoprim 150mg/m2 and sulfamethoxazole 750mg/m2) on three successive days for twelve weeks. (An earlier trial conducted in Zambia examining the safety and efficacy of co-trimoxazole prophylaxis in HIV-positive children provided an oral dose consisting of 240 mg [5 ml suspension] co-trimoxazole daily for children under five, and those older than 5 years 480 mg [10 ml]). All the children were monitored for clinical symptoms of malaria and had blood samples analysed to see if they had asymptomatic malaria.
The children had a mean age of ten years and were randomised on a 2:1 basis into a treatment or a control arm. Children in the control arm received prophylactic injections of co-trimoxazole on three successive days each week for twelve weeks. At baseline, blood tests indicated that 20% of the children in the treatment arm and 16% of children in the control group were infected with the malaria parasite.
Follow-up was for a mean of 11.8 weeks in the treatment arm and 11.7 weeks in the control arm. Just one case of clinical malaria occurred during 1890 person weeks of follow-up in the treatment arm. By comparison, 72 cases of malaria occurred during 681 person weeks of follow-up in the control arm.
“The prophylactic efficacy of [co-trimoxazole] against uncomplicated malaria was 99.5%”, write the investigators.
Asymptomatic malaria was found in three out of 466 blood samples obtained from children in the prophylaxis arm and 43 out of 231 blood samples from children in the control arm. Co-trimoxazole therefore had a 97% efficacy against asymptomatic malaria.
The investigators also found that the children in the treatment arm had fewer gastrointestinal illnesses and required fewer prescription medications than children in the control group. They also found that co-trimoxazole prophylaxis appeared to increase levels of haemoglobin leading to a lower incidence of anaemia in the treatment arm.
Only one severe adverse event was seen in the co-trimoxazole arm. This was a case of acute hepatitis which occurred three days after the first dose of co-trimoxazole. The child showed evidence of infection with hepatitis A virus and hepatitis B virus.
A similar pattern of malaria parasite resistance was observed in the treatment and control arms.
Thera MA et al. Impact of trimethoprim-sulfamethoxazole prophylaxis on falciparum malaria infection and disease. J Infect Dis 192: 1823 - 1829, 2005.