Standard HIV drug used in Africa may spawn resistance to a first-line malaria drug

Oct 1, 2001 (CIDRAP News) – Researchers from the University of Maryland School of Medicine have reported laboratory evidence of Plasmodium falciparum cross-resistance between trimethoprim-sulfamethoxazole, one of the standard treatments for HIV patients in Africa, and sulfadoxine-pyrimethamine, the first-line antimalarial drug in parts of Africa. The findings suggest that African HI patients who take trimethoprim-sulfamethoxazole (co-trimoxazole) to prevent opportunistic infections could be left with no effective treatment if they contract malaria, the researchers state in a research letter in the Sept 29 issue of The Lancet.

"People taking trimethoprim-sulfamethoxazole prophylaxis while concurrently infected with HIV and P falciparum may not respond to sulfadoxine-pyrimethamine, incurring an increased risk of severe disease and death," states the report by Jayasree K. Iyer and colleagues. In countries where pyrimethamine is the first-line antimalaria drug, chloroquine resistance is also common, and other drugs are too expensive or poorly tolerated, they write.

Certain point (amino-acid position) mutations in P falciparum dihydrofolate reductase (DHFR) confer resistance to pyrimethamine, the article explains. If co-trimoxazole selects for these mutations, co-trimoxazole prophylaxis may promote the development of P falciparum resistance to pyrimethamine in areas where HIV infection and malaria are both common. The authors looked for cross-resistance in naturally occurring and genetically engineered P falciparum strains with known DHFR point mutations. A yeast expression system was used to quantify resistance in the synthetic strains. For the natural strains, a standard growth assay was used to measure susceptibility, and the results were confirmed with the yeast expression system. The authors determined the 50% inhibitory concentrations (IC50) of the drugs for each strain and then divided those values by the corresponding IC50 for wild-type P falciparum to calculate the relative resistance.

The results showed cross-resistance in five of the six naturally occurring strains and both of the synthetic alleles tested. On this basis, the authors recommend that clinical studies be done in Africa to test the effect of co-trimoxazole prophylaxis on the efficacy of pyrimethamine. "Until these studies are done, we recommend using alternative therapies for treating malaria in people taking trimethoprim-sulfamethoxazole," they conclude.

In an accompanying commentary article, Xavier Anglaret of Universite Victor Segalen Bordeaux in Bordeaux, France, suggests that the findings are not sufficient grounds for abandoning the use of co-trimoxazole prophylaxis in Africa. "Although improving knowledge about molecular mechanisms of cross-resistance is an important step in understanding the process, it remains difficult to have a clear idea of the specific risk induced by co-trimoxazole prophylaxis in sub-Saharan Africa, where co-trimoxazole and sulfadoxine-pyrimethamine are already widely prescribed for curative use," he writes. To evaluate the resistance risk posed by prophylactic use of co-trimoxazole, "the effect of the current curative use of co-trimoxazole and other sulphonamides on the development of resistance has to be assessed first."

Anglaret notes that UNAIDS and the World Health Organization recommended in 2000 that prophylactic co-trimoxazole be included in a "minimum package" of care for Africans with HIV or AIDS, and that the treatment be monitored for efficacy and side effects. The efficacy of pyrimethamine for malaria should also be monitored, but the risks inherent in withholding co-trimoxazole prophylaxis outweigh the risk of co-trimoxazole-induced resistance, he asserts.

Iyer JK, Milhous WK, Cortese JF, et al. Plasmodium falciparum cross-resistance between trimethoprim and pyrimethamine. Lancet 2001;358(9287):1066-7
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Anglaret X. Trimethoprim-sulfamethoxazole prophylaxis in sub-Saharan Africa. Lancet 2001;358(9287):
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