Aweeka study details impact of HIV drugs on malaria treatment in children
Sub-Saharan Africa is home to a billion people and to overlapping health burdens, including the world’s highest rates of both malaria and HIV infection.
The region’s children are especially hard hit: Those under age five are more susceptible to malaria and accounted for two-thirds of the 438,000 deaths caused by the disease in 2015, according to the World Health Organization (WHO). That is equivalent to a young child dying from the mosquito-borne parasitic disease every two minutes.
At the same time, about three million sub-Saharan children are infected with HIV, accounting for nearly 9 of 10 children with HIV worldwide. The virus damages the immune system, rendering those left untreated even more susceptible to malaria.
While dual treatment of co-infected children is critical, a recently published study co-led by UCSF School of Pharmacy researchers has found that the choice of drugs to treat HIV greatly affects the blood levels and thus the effectiveness of malaria drugs in children due to interactions that affect how their bodies process the medications.
Terms in this article marked with an asterisk (*) are defined here.
ACT: artemisinin-based combination therapy for malaria
ART: antiretroviral therapy for HIV
Pharmacokinetics (PK): how the body processes drugs—including absorption, distribution, metabolism, and excretion
Pharmacodynamics (PD): how drugs affect the body, disease, or infectious agents—including the relationship between dose or drug concentration and effects
Indeed, this first pharmacokinetic*/pharmacodynamic* study of interactions between antiretrovirals and malaria drugs in children found that the WHO’s preferred HIV treatment in those age three and older led to a several-fold reduction in blood concentrations of the most widely used malaria drugs. This, in turn, is associated with about a four times greater risk of recurrent malaria when compared to children receiving a different HIV regimen.
Based on their results, Aweeka and her co-authors—including colleagues at Yale University and those in a long-standing UCSF collaboration with Makerere University in Uganda—assert the need both for close clinical follow-up for recurrent malaria in co-infected children receiving the currently recommended treatments and for the study of new regimens providing greater malaria drug exposure.
The researchers conclude that the need for more effective co-treatments is especially urgent because, in addition to putting children’s lives at risk, such underexposure to antimalarials could contribute to the emergence of more drug-resistant parasites.
Journal Citation: Parikh S, Kajubi R, Huang L, Ssebuliba J, Kiconco S, Gao Q, Li F, Were M, Kakuru A, Achan J, Mwebaza N, Aweeka FT, “Antiretroviral choice for HIV impacts antimalarial exposure and treatment outcomes for Ugandan children,” Clinical Infectious Diseases, Aug. 1, 2016, doi: 10.1093/cid/ciw291
While sub-Saharan malaria and HIV statistics remain daunting, they actually reflect significant improvements resulting from global health efforts.
Between 2000 and 2015, the mortality rate from malaria among African children under age five fell by 71 percent, the WHO reports. In terms of HIV, wider use of antiretroviral drugs during pregnancy has reduced mother-to-infant transmission, and the number of children under age 15 receiving drug therapy more than doubled from 2009 to 2013, reports the agency.
But even as public health efforts seek to greatly increase the percentage of infected sub-Saharan children receiving drug treatments for both diseases—from 16 percent for the most widely used antimalarial regimen and 23 percent for antiretrovirals—the optimal treatment of those co-infected has been uncertain due to drug interactions, as well as differences in how children’s developing bodies process drugs.
Adding to the complexity, both diseases are treated with drug combinations:
- For malaria, WHO guidelines recommend combination therapies in which the drug artemisinin, which rapidly reduces the number of parasites (most commonly Plasmodium falciparum), is given with a longer-acting partner drug. The most widely used regimen combines artemether (a type of artemisinin) with lumefantrine. This is dubbed artemisinin-based combination therapy.
- For HIV, antiretroviral therapy usually combines three drugs that inhibit HIV replication in different ways. This multi-drug approach reduces the potential for resistance—if the virus evades suppression by one drug it may be stopped by another. There are several first-line ART* combinations.
When given concurrently, some antiretrovirals are expected to affect the antimalarials’ metabolism by the body and thus the patients’ overall exposure. This is because antimalarials are acted on by the body’s cytochrome P450 family of drug-metabolizing enzymes and the antiretrovirals are well known to inhibit or enhance these enzymes. In addition, children’s bodies are known to process drugs differently (or are more susceptible to toxicities), so different first-line HIV drug regimens are recommended for different age groups.
A previous study by the UCSF and Makerere researchers had found major differences in the recurrence of malaria in Ugandan children treated for HIV, depending on their antiretroviral regimens. The newly published study looked at a larger group and more intensively analyzed why that is the case.
Aweeka and her co-authors conducted a three-year study (2011 to 2014) in an eastern district of Uganda with high levels of malaria infection. They took blood samples at specific time intervals post-last-dose (measured in hours, days, and weeks) from a total of 370 children (aged six months to eight years) being treated with the standard three-day ACT* regimen for malaria.
While the children in the study were being treated for malaria, the vast majority were also being treated with one of three different regimens for HIV infection. Thus the study’s subjects fell into four groups:
- A group receiving efavirenz-based combination regimen (EFV), the preferred first-line HIV treatment for children three years or older
- A group receiving a lopinavir/ritonavir-based HIV regimen (LPV/r) preferred for children less than three years old but also given to older children
- A group receiving the nevirapine-based therapy for HIV, recommended for children when LPV/r is not feasible
- A control group being treated for malaria and not infected with HIV
At the UCSF Drug Research Unit in San Francisco, which is based in the Department of Clinical Pharmacy and directed by Aweeka, the blood samples from the four groups were analyzed for their concentrations of antimalarial drugs: artemether (a type of artemisinin), its active metabolized form called dihydroartemisinin (DHA), and the longer-acting lumefantrine.
Meanwhile, in Uganda, treatment outcomes were noted for the patients, including whether malaria symptoms recurred within four or six weeks after treatment.
Aweeka and her colleagues found that “selection of antiretroviral therapy has a highly significant impact on antimalarial exposure and clinical outcomes.”
Specifically, EFV-based HIV treatment reduced the blood concentrations over time of all three antimalarial drugs—artemether, its active form DHA, and lumefantrine—up to 3.4-fold compared to the children in the study who were not being treated for HIV. This meant that the children were effectively not receiving the full benefit of their antimalarial regimen.
By contrast, the LPV/r-based HIV therapy had no impact on the rapid-acting artemisinin antimalarial, while its use was associated with doubled blood concentrations of the longer-acting lumefantrine over time, compared to HIV-uninfected children. Specifically, the use of the LPV/r regimen yielded ten times higher levels of the longer-acting lumefantrine a week after the last dose of antimalarials compared to those receiving EFV therapy, since LPV/r impedes metabolism of lumefantrine while EFV enhances it.
The study’s analysis found that the differences in exposure over time to lumefantrine “played a critical role in determining treatment outcomes.” Thus, those children receiving both ACT* and EFV-based HIV therapy had four times greater odds of recurrent malaria within four weeks compared to those on LPV/r HIV treatment.
Notably, these pharmacokinetic* and pharmacodynamic* findings apply particularly, if not solely, to children. The paper by Aweeka et al notes that their initial studies of antiretroviral/antimalairal interactions in healthy adults had underestimated the effect of EFV-based HIV treatment on antimalarial blood levels in children by more than 50 percent, “emphasizing the value of conducting studies directly in the most relevant populations, particularly children who exhibit PK and PD distinctions.”
Given the increased risk to children’s health and survival, as well as the risk for the selection and spread of ACT-resistant parasites due to drug underexposure, the researchers urgently endorsed the study of modified antimalarial dosing. This might mean extending ACT* malaria therapy to five days when a patient is also being treated with EFV-based HIV therapy.
About the School: The UCSF School of Pharmacy is a premier graduate-level academic organization dedicated to improving health through precise therapeutics. It succeeds through innovative research, by educating PharmD health professional and PhD science students, and by caring for the therapeutics needs of patients while exploring innovative new models of patient care. The School was founded in 1872 as the first pharmacy school in the American west. It is an integral part of UC San Francisco, a leading university dedicated to promoting health worldwide.