Cotrimoxazole, antiretroviral therapy, and insecticide-treated bednets dramatically reduce the frequency of malaria in Ugandan adults

Giving people HIV cotrimoxazole, antiretroviral therapy (ART), and insecticide-treated bednets (ITBs) reduces the frequency of malaria by 95%, according to a study published in the April 15^th issue of The Lancet. The study, which was run by the United States' Centers for Disease Control (CDC) in Uganda, demonstrated that each intervention contributed something to the preventative effect, reducing the incidence of malaria from a baseline of 50.8 episodes to 2.1 episodes per 100 person years.

Malaria in people with HIV

In regions where it is endemic, malaria is one of the most common and serious conditions among people with HIV. HIV has been linked to a doubling in the incidence of malaria, which in turn, potentially speeds the clinical progression of HIV and the fall of CD4 cell counts. As CD4 cell counts fall, people with HIV become even more susceptible to malaria and to developing more severe forms of the disease.

The basic package of care for people with HIV in Uganda

“Prevention of malaria in HIV-infected people living in endemic areas is increasingly regarded as a part of basic HIV care,” wrote the team of researchers led by Dr. Jonathan Mermin. The CDC has been working in Uganda for several years, exploring what should constitute a basic package of home-based care for people with HIV and their families in sub-Saharan Africa.

A number of potential anti-malaria options have become available over the years, including cotrimoxazole prophylaxis, which has been shown in several studies to reduce the incidence of malaria and mortality in people with HIV, and which is recommended by WHO. In addition, effective ART should theoretically reduce malaria incidence by improving the immune status of people with HIV. Finally, ITBs have been shown to protect against malaria exposure, but their effectiveness in people with HIV has not been determined.

Results

There were 166 episodes of malaria (defined as reported fever and a blood sample indicating the presence of malaria parasites under microscopy) diagnosed during the study, 84 (51%) of these occurred in phase I. Cotrimoxazole prophylaxis lowered malaria incidence by 76% (9.0 cases versus 50.8 cases per 100 person years, incident rate ratio [IRR] 0.24 [0.15-0.38], p

When looking at the additive effects of the intervention, the addition of ART to cotrimoxazole was associated with a 64% fall in malaria incidence, 3.5 vs 9 cases per 100 person-years, IRR 0.36, 95% CI 0.18–0.74, p=0.0056). The effect of ART was similar across the range of CD4 cell counts.

Even though protease inhibitors have been shown to have direct anti-HIV activity, 97% of the participants taking ART in the study were on d4T/3TC plus either nevirapine or efavirenz. "ART probably reduced the frequency of malaria by improving immune function, rather than by direct antimalarial activity," Dr. Mermin stated in a Lancet press release.

Indeed, CD4-cell counts rose by an average of 51 cells/mm³ per μL during the brief (~4 months) of phase III of the study, however, they continued to rise during phase IV (when bednets were added). Thus, it's possible that by restricting the assessment of ART's effect to the relatively brief follow-up of phase III, “we might... have underestimated the effect of ART on the incidence of malaria, since the treatment can take more than a year to achieve its full effect on the immune system,” Mermin and colleagues wrote.

The study

So to assess the effect of ART on the frequency of clinical malaria in people with HIV, as well as the additive effects of cotrimoxazole prophylaxis, ART, and ITBs, the researchers analysed data from two prospective studies, one of cotrimoxazole prophylaxis, and the other of ART in HIV-infected people in rural Uganda.

Together, these studies allowed the researchers to assess of the additive effects of each intervention by looking at the cohort in four sequential phases. In phase I, no specific anti-malaria preventative was offered to the 466 HIV-infected adults who had initially enrolled in the cohort. This phase only lasted for five months but it allowed the researchers to determine the baseline incidence of malaria in this highly endemic setting. In phase II, 399 participants who survived were offered cotrimoxazole prophylaxis. Later, when ART became available in Uganda, 138 of the survivors from the first study clinically eligible for ART were enrolled in phase III (cotrimoxazole prophylaxis and ART), and 897 additional new participants were enrolled to make a total of 1035. During phase IV, 985 of the phase III participants survived and were given ITBs, and 4 more participants were recruited who received ITBs and ART simultaneously.

Baseline characteristics did not differ significantly between phases, except for median CD4 cell counts, which were significantly lower in phases III and IV. Median follow-up for phase II was 532 days; for phase III, it was 126 days and for phase IV (all three interventions), it was 560 days.