SEATTLE, WASHINGTON—Bed nets and insecticides form the cornerstone of malaria prevention, with antimalarial drugs being used mainly to treat people who become ill with the disease. The drugs do have some protective effect, but it quickly wanes. Now a study in Uganda suggests that an antiretroviral drug given to HIV-infected children can boost the preventive power of a key malaria drug.
Researchers have long known that in test-tube studies, a class of anti-HIV drugs known as protease inhibitors also cripples the parasites that cause malaria. So a team led by clinicians Diane Havlir of the University of California, San Francisco (UCSF), and Moses Kamya of Makerere University College of Health Sciences in Uganda decided to compare two different cocktails of anti-HIV drugs, only one of which contained protease inhibitors, in HIV-infected children who live in a malarial area of that eastern African country. The results, presented here last week by Makerere University's Jane Achan at the 19th Conference on Retroviruses and Opportunistic Infections, show that one protease inhibitor indeed helped stave off malaria, and it worked by a surprising mechanism.
As Achan explained, the trial in Tororo, Uganda, involved 170 children under 5 who were randomized to receive one of the two combinations of antiretroviral drugs. The group that received a drug cocktail containing the co-formulated protease inhibitors lopinavir and ritonavir had a 41% drop in malaria cases over 2 years compared with the group that received the other antiretroviral cocktail. Further studies showed that the HIV drugs containing protease inhibitors had only a modest direct impact on the malaria parasites. Rather, the success primarily occurred because ritonavir extended the preventive effects of a widely used antimalarial drug, lumefantrine.
"The 41% reduction in clinical malaria episodes is both statistically and clinically significant," says Paula Brentlinger, a clinician at the University of Washington, Seattle, who studies both malaria and HIV in Mozambique. "The fact that it was achieved in one of the most malaria-vulnerable populations in the world is especially heartening." (Other than in pregnancy, research has not shown a convincing link between HIV and malaria susceptibility or severity of disease.)
The researchers teased out the effects of ritonavir by separately analyzing first episodes of malaria and recurrent cases. Children with first episodes were unlikely to have any antimalarial drugs in their bodies at the time of analysis, whereas those who had recurrent cases during the study received an artemether-lumefantrine combination as treatment. When it came to first episodes, the group taking ritonavir had a 29% reduction in malaria cases, which hinted at some effect but was not statistically significant. Recurrent cases in the ritonavir group plummeted by a highly significant 59%. "This is where we really found the dramatic findings," Achan said.
Lumefantrine, unlike artemether, stays in the body for weeks, which provides some protection against malaria. Given that ritonavir blocks cytochrome p450, a liver enzyme that plays a key role in metabolizing drugs, the researchers wondered whether the drug might have extended lumefantrine's preventive effects. Blood samples from the children showed that those receiving ritonavir had nearly fivefold higher levels of lumefantrine 7 days after receiving the antimalarial. "We think that these higher lumefantrine exposures were really what was driving the protection against recurrent episodes of malaria," Achan said.
Carlos "Kent" Campbell, who heads the Malaria Control Program at PATH, a nonprofit organization in Seattle, says bed nets remain the most critical prevention strategy. He also notes that most children who are vulnerable to malaria are not infected with HIV and have no need for antiretrovirals. Yet Campbell says in HIV-infected children, the "unanticipated positive consequences" of ritonavir could have the added benefit of reducing persistent parasitemia caused by malaria, a leading cause of anemia in young children in many African countries. "It's a very interesting finding and could help decide which antiretroviral regimen to use in areas where there's an increased malarial burden," says Campbell, who previously headed the malaria branch at the U.S. Centers for Disease Control and Prevention (CDC).
The current director of CDC's malaria program, S. Patrick Kachur, points out that there have been attempts to use long-acting antimalarials as preventives in specific populations such as pregnant women or people who live in the Sahel and suffer from the disease only during a few months of the year. If ritonavir "potentiates the long tail of lumefantrine," he says, "we certainly want to know."
Aside from the potential impact of these findings in countries double punched by malaria and HIV, the study encourages researchers and clinicians to take a broader view about the effects one drug can have on another. "We always think of drug-drug interactions as something to be avoided, but HIV has taught us the opposite," says Paul Volberding, an HIV/AIDS clinician at UCSF, who did not participate in this study but saw its presentation at the conference. "This is an intriguing first glimpse at one of these interactions."
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