Malaria treatment compromised by suppressed immunity in HIV-positive adults

Treatment of uncompromised malaria with the standard first-line regimen of sulphadoxine-pyrimethamine is significantly more likely to be unsuccessful in HIV-positive adults with CD4 cell counts below 200 cells/mm

3, research in Kenya has confirmed.

At present malaria control in HIV-infected people principally entails the drug treatment of uncomplicated malaria. However, five studies in Ethiopia, Uganda, Kenya, Zambia, and Malawi have demonstrated that HIV-1 immunosuppression compromises the efficacy of antimalarial chemotherapy. This is a potential public health calamity in Sub-Saharan Africa where 25.4 million HIV-positive people might have several clinical attacks per year.

The usefulness of CD4 cell count as a proxy measure of immunity for predicting antimalarial treatment efficacy in HIV-positive people needs to be evaluated in different African settings. A study by a team of United States, Canadian, and Kenyan investigators has provided additional insights on the role of CD4 cell counts as an important determinant of sulfadoxine-pyrimethamine efficacy in HIV-positive people.

The study took place in the outpatient clinic of the Siaya District Hospital in western Kenya. Six hundred and twenty (620) participants including 162 HIV-negative adults, 298 HIV-positive adults with a high CD4 cell count (more than 200 cells/mm³), and 159 HIV-positive adults with a low CD4 count (less than 200 cells/mm³) were treated with sulfadoxine-pyrimethamine and followed up in a 28-day World Health Organization (WHO) protocol. At enrolment, blood was taken for HIV testing, malaria parasite counts, haemoglobin determination, and CD4 counts; some blood was spotted onto filter paper for DNA extraction for later genotyping of malaria parasites.

The study participants returned for follow-up visits on days 1-4, 7,14,21, and 28 after treatment for assessment of parasitemia, haemoglobin levels on days 14 and 28, and genotyping of parasites in subjects who were parasitemic after treatment. Genotyping to distinguish recrudescence (treatment failure) and reinfections was by the polymerase chain reaction single strand conformational polymorphism analysis of malaria DNA at a polymorphic P. falciparum genetic marker locus (MSP-2). The primary end-point was treatment failure, either unadjusted or adjusted by PCR.

One hundred and fifteen patients did not complete the study for various reasons. These included 68 individuals withdrawing before the completion of the study, 23 individuals being inappropriately treated, and 24 individuals missing at least one scheduled visit. Common reasons for withdrawal included:

• the patient could not be traced in 68 % of the withdrawals
• spousal refusal (12 %)
• emigration out of the study site (8 %).

The remaining 508 patients (130 HIV-negative adults, 256 HIV-positive adults with a high CD4 cell count, and 122 HIV-positive adults with a low CD4 count) attended all visits and completed the study.

HIV-infected people with malaria with a low CD4 cell count had a significantly higher parasite density, prevalence of fever, and prevalence of anemia than those with a high CD4 cell count or the HIV-negative group. The level of haemoglobin was significantly lower in HIV-infected patients with a low CD4 count by comparison with HIV-infected patients with a high CD4 cell count or the uninfected group.

PCR-adjusted failure rates for the HIV-negative, high CD4, and low CD4 groups were 7.6, 10.6, and 20.5 %, respectively. The low CD4 group demonstrated a higher prevalence of overall treatment failures by comparison with the high CD4 and HIV-negative groups. R-adjusted incidence of reinfections for the HIV-negative, high CD4, and low CD4 groups were 4.3, 6.3, and 11.5 %, respectively. Again, the low CD4 group demonstrated a higher incidence of reinfections by comparison with the high CD4 and uninfected groups. There was no difference in early treatment failure or reinfection rates when the two HIV-infected groups were compared.

Univariate and stratified analyses identified geometric mean parasite density, anaemia, and HIV infection with a CD4 cell count of less than 200 cells/mm³ as significant predictors of treatment failure. Among patients with anemia, there was a significantly higher incidence of PCR-adjusted treatment failure in the low CD4 cell count group than in either the high or uninfected group. In patients without anemia there was no difference in the proportions of patients with treatment failure in the two infected groups.

Drug-related adverse events were monitored but no serious adverse events were observed. Two deaths involving HIV-positive individuals with CD4 cell counts of less than 200 cells/mm³ were more likely due to the progression of HIV disease rather than sulfadoxine-pyrimethamine treatment.

The study by Shah et al. provides additional and important insights about the role of host immunity in determining the efficacy of antimalarial treatment in people living with HIV/AIDS. Specifically, it highlights low CD4 cell counts of less than 200 cells/mm³ as a significant risk factor for sulfadoxine-pyrimethamine treatment failure.

People infected by HIV/AIDS constitute a new vulnerable target group spawned by malaria/HIV interactions in Africa. This calls for an urgent but focused strengthening of malaria control efforts in HIV-positive people. Specifically, prompt diagnosis and treatment of malaria attacks and the use of insecticide-treated bednets and other malaria preventive measures should be part of the healthcare package provided to individuals infected by HIV.