CD4 count below 300 predicts poorer malaria treatment outcome

HIV-positive people with a CD4 cell count below 300 cells/mm³ have a poorer response to malaria treatment than either HIV-negative people or HIV-positive people with CD4 cell counts above 300 cells/mm³, Zambian and Belgian researchers report in the October 1^st edition of the Journal of Infectious Diseases, now available online.

Although not life-threatening, untreated uncomplicated malaria might result in the impairment of cognitive functions. Treating uncomplicated malaria is therefore a very important public health undertaking. Host immunity also contributes to the clearance of parasites during anti-malarial treatment.

The efficacy of antimalarial treatment might therefore be compromised in patients with impaired immunity. This is a serious public health problem in Sub-Saharan Africa where HIV/malaria co-infections are common and 25.4 million people live with HIV/AIDS (PLWA) and may experience several malaria attacks during the year.

HIV-positive adult Ugandans (Whitworth) and Malawians have been reported to experience more frequent malaria attacks than HIV-1 negative counterparts. Malaria in PLWA increases HIV-1 viral loads and is an important risk factor for HIV-1 transmission to sexual partners and to unborn babies.

The control of malaria in PLWA is thus an important public health imperative. However, there is a conspicuous lack of a clear treatment policy for uncomplicated malaria in PLWA. Studies which address this issue are urgently needed.

Two studies in Ethiopia (Birku) and Uganda (Kamya) have reported on the impact of HIV-1 infection on malaria chemotherapy. There was a delayed clearance of malaria parasites during artemisinin treatment in HIV-1 positive Ethiopian patients. HIV-1 positive adult Ugandans had higher rates of reinfections following antimalarial treatment than HIV-1 negative adults.

Two other studies in Kenya and Malawi reported that HIV-1 infection decreased the efficacy of intermittent preventive treatment with sulfadoxine-pyrimethamine (SP).

These studies underscore the importance of an intact immune system for the efficacy of anti-malarial chemotherapy. The CD4 count is a proxy measure of immunity. However, no study has so far correlated CD4 counts and antimalarial treatment outcome. A team of Zambian and Belgian investigators addressed this question.

The study took place in four periurban health centers in Ndola in Zambia, and involved 971 individuals with malaria (650 HIV-negative and 321 HIV-positive). The subjects were randomised for treatment with either SP or the fixed dose combination artemether-lumefantrine (AL). At enrollment, blood was taken for microscopy for malaria parasites, haemoglobin determination, and CD4 counts; some blood was spotted onto filter membranes for the molecular characterisation (genotyping) of the malaria parasites.

The study subjects were followed up on days 3, 7, 14, 21, 28, and 45 after treatment or at any unscheduled clinic visit for assessing parasitemia, haemoglobin levels on days 14 and 45, and genotyping of parasites in participants who were parasitaemic after day 14. Drug-related adverse events were monitored.

Genotyping to distinguish recrudescence (treatment failure) and reinfections was by the polymerase chain reaction amplification of malaria DNA at two polymorphic P. falciparum genetic marker loci. The primary end-point was genotypically-corrected clinical and parasitological outcome

HIV-1 infection status was not a risk factor for parasitemia or recrudescence. HIV-positive individuals with malaria with a CD4 count 3 had an increased risk of recurrent parasitemia compared with those with a CD4 count > 300 cells/mm³ (relative risk 2.24, p=0.01).

Genotyping showed that recrudescence and reinfection was higher in HIV-positive individuals with CD4 3 than in HIV-positive individuals with CD4 > 300 cells/mm³; however, the difference for reinfection was not statistically significant. Age and treatment regimen had no effect on the relationship between CD4 counts and recrudescence.

Interestingly, the risk for recurrent parasitemia was similar between HIV-positive participants with a CD4 count > 300 cells/mm³ and uninfected participants, thus underscoring the contribution of immunity to the clearance of parasites during chemotherapy. In this study population, a CD4 count > 300 cells/mm³ was a robust proxy measure for immunity.

Serious adverse events (SAE) were observed in only two HIV-positive participants with a CD4 count below 300 cells/mm³. The risk of SAE might therefore be higher in PLWA with a more profound immuno-suppression.

The study provides important insights about antimalarial treatment in PLWA. It might be feasible to stratify PLWA on the basis of CD4 counts and closely follow up those with CD4 counts 3 to monitor and treat recurrent parasitemia and SAE.

This study by Van Geertruyden and colleagues need to be replicated in more African countries with an escalating HIV-1 problem against a background of endemic malaria transmission. Such studies will provide a solid scientific basis for a much-needed treatment policy for malaria in PLWA.

“Our data add to the evidence that HIV-1 infected patients with suppressed immunity represent, next to children and pregnant women, an additional vulnerable group for malaria.”

The authors also warn that, due to inadequate parasite clearance in people with CD4 cell counts below 300, people with advanced HIV disease represent a high-risk group for malarial drug resistance, further compromising malaria control efforts.