HIV-positive children have greatly increased risk of neutropenia during artesunate / amodiaquine malaria treatment

HIV-infected Uganda children had over seven times the risk of neutrophil depletion (neutropenia) while receiving antimalarial treatment compared to Ugandan children who were not HIV-1-infected, according to the findings of a longitudinal study published in the April 1^st edition of Clinical Infectious Diseases.

In HIV-infected children, antiretroviral drug treatment (ART) increased the risk of neutropenia by almost threefold, and the neutropenia in turn increased the risk of pneumonia. The authors and an accompanying editorial recommend an urgent evaluation of alternative antimalarial treatment options for HIV-infected patients.

Neutrophils constitute a critical component of the body’s defense system for warding off bacterial infections. Neutrophil depletion therefore leaves the patient vulnerable to a legion of bacterial infections.

Malaria kills an estimated 1-2 million children every year in sub-Saharan Africa. The mainstay of malaria control is chemotherapy. Unfortunately, chloroquine and sulfadoxine-pyrimethamine, the most affordable and available antimalarial drugs in Africa, have become obsolete because of the emergence of drug-resistant malaria parasites.

In the event, most African countries including Uganda have adopted artemisinin-based combination therapies (ACT) for the treatment of uncomplicated malaria. Artesunate plus amodiaquine (AS-AQ) is one such ACT which is recommended by the World Health Organization (WHO). There are also concerted national efforts in Africa to increase access to ART for HIV-infected patients.

Malaria and HIV co-exist in sub-Saharan Africa and each infection affects the clinical course of the other. All HIV-infected patients receive daily trimethoprim-sulfamethoxazole (TMX, or cotrimoxazole) prophylaxis in addition to ART. With the greater access to ACT and ART by malaria and AIDS patients, there is increasing concern about hitherto unknown drug interactions between ACT, ART, and TMX that might significantly compromise the quality of life of HIV/AIDS patients.

There is a paucity of studies which have addressed the safety and efficacy of ACT such as AS-AQ among HIV–infected patients. In order to address this issue, a team of Ugandan and US investigators compared the efficacy and safety of AS-AQ for the treatment of uncomplicated malaria in HIV-infected and HIV-uninfected Ugandan children.

The study sites were a malaria clinic and a paediatric HIV clinic in Kampala. The study subjects were 601 HIV-uninfected children recruited between November 2004 and April 2005 and 300 HIV-infected children enrolled in a paediatric HIV clinic between October 2005 and August 2006.

Among the HIV-uninfected children, 134 received AS-AQ whenever they had a malaria attack over 29 months of follow-up. HIV-infected children received TMX prophylaxis and ART in accordance with national guidelines and 26 HIV-infected children received AS-AQ during malaria episodes over an 18-month follow up.

Malaria treatment outcomes were assessed using standardized guidelines. Complete blood cell counts and liver enzyme (ALT) levels were assessed on the day of malaria diagnosis and after 14 days. Malaria treatment was highly efficacious in both the HIV-infected and HIV-uninfected cohorts (28-day risk of parasite persistence or recrudescence, 0% and 3.6%, respectively). Surprisingly, there was a trend towards increased risk of recurrent malaria among the HIV-uninfected children (2.9% vs. 13.2%; P=0.08).

While baseline neutrophil counts in all subjects were normal, the incidence of neutropenia occurring 14 days after the initiation of treatment with AS-AQ was higher among HIV-infected children than among HIV-uninfected children (45% vs. 6%; P <.001 all="" but16="" cells="" children="" count="" episodes="" hiv-infected="" hiv-uninfected="" in="" life-threatening="" mild="" moderate="" neutropenia="" of="" or="" severe="" severity="" the="" to="" was="" were="">3).

Of the 12 HIV-infected children who received ART and AS-AQ, 11 were on zidovudine (AZT). The risk of neutropenia in these children was significantly higher than among those who did not receive ART (75% vs. 26%; P=.001). The risk of pneumonia was greater among neutropenic patients who received AS-AQ than in control subjects.

There is evidence of an independent association between neutropenia and treatment with each of the drugs TMX, ART, and AQ. This has raised safety concerns about possible adverse interactions between these drugs in patients with both malaria and HIV.

These findings provide the first strong evidence that these drug interactions might exacerbate neutropenia in HIV-infected Ugandan children.

The results also come at a time when many African countries are striving to increase access to both ACT and ART for the treatment of malaria and AIDS patients, respectively. Although the findings suggest an urgent need for alternative antimalarial drugs and ART for the care of HIV-infected patients, the accompanying editorial urges caution against abandoning AQ without a more profound understanding the mechanisms of the reported neutrophil depletion.