Protease inhibitor therapy doesn't reduce the risk of malaria for HIV-positive pregnant women

Michael Carter
Published: 17 July 2014

Antiretroviral therapy (ART) based on the protease inhibitor lopinavir/ritonavir (Kaletra) does not reduce the risk of malaria among pregnant women living with HIV, research published in the online edition of the Journal of Infectious Diseases shows.

Previous research had suggested that the protease inhibitor might have a potent anti-malaria activity. However, the present study showed that malaria risk and malaria-associated adverse birth outcomes were similar for women treated with the protease inhibitor and those taking the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (Sustiva or Stocrin).

“In this study, pregnant women were randomised to lopinavir/ritonavir vs efavirenz-based ART to test the hypothesis that a protease inhibitor based ART regimen would be associated with a lower risk of malaria,” explain the authors. “We found there was no difference between the two ART regimens in the risk of placental malaria, the incidence of malaria, the prevalence of asymptomatic parasitemia, and the risk of adverse birth outcomes.”

Malaria during pregnancy is associated with adverse birth outcomes such as spontaneous abortion, premature delivery and low birth weight. The risk of malaria and adverse outcomes is especially severe for pregnant women living with HIV.

Strategies for the prevention of malaria in pregnant women include the use of insecticide-treated bednets and, for women living with HIV, daily prophylaxis with trimethoprim-sulfamethoxazole (TNP-SMX). However, other prevention strategies are urgently required.

Combination antiretroviral therapy is recommended for all pregnant women living with HIV, and there is some evidence this treatment can reduce the risk of malaria. Laboratory studies have shown that protease inhibitors are effective against the malaria parasite. Moreover, a study involving Ugandan school children showed that treatment with an ART regimen based on lopinavir/ritonavir was associated with a 41% reduction in malaria risk compared to therapy based on an NNRTI.

Given these findings, a team of investigators wanted to see if HIV therapy based on lopinavir/ritonavir reduced the risk of malaria during pregnancy compared to NNRTI-based treatment, the current standard of care. They therefore designed a randomised study involving treatment-naive women living with HIV who initiated antiretroviral therapy between weeks 12 and 28 of pregnancy. The women were randomised to take therapy based on lopinavir/ritonavir or efavirenz. The investigators compared the risk of placental malaria up to one year after delivery between the two regimens. Other outcomes included placental malaria diagnosed using histology, adverse birth outcomes, incidence of malaria and the prevalence of asymptomatic malaria parasites.

The study was conducted in the Ugandan region of Tororo where malaria is endemic. A total of 389 women were recruited between 2009 and 2013 and 377 initiated therapy.

Eight weeks after starting HIV therapy, approximately 88% of women had an undetectable viral load. Adherence to HIV therapy was high (97-99%) as was adherence to malaria prophylaxis (98-99%).

Regardless of the testing method used, the prevalence of placental malaria did not differ between lopinavir/ritonavir and efavirenz-based therapy. Placental blood smear identified a prevalence of 4% among women taking efavirenz and 3% among women taking the protease inhibitor. Prevalence was also similar using PCR testing (efavirenz 10% vs lopinavir/ritonavir 7%) and histopathology (efavirenz 29% vs lopinavir/ritonavir 38%).

Rates of adverse birth outcomes were also comparable between the two regimens (efavirenz 28% vs lopinavir/ritonavir 34%).

Lopinavir/ritonavir did not reduce the risk of malaria during or after pregnancy, or the prevalence of asymptomatic malaria parasites.

“New WHO [World Health Organization] guidelines recommending efavirenz-based combination ART for all HIV-infected and breastfeeding women offer the potential of immense benefits in preservation of women’s health and reducing transmission,” comment the investigators. “The main conclusion of this study is that lopinavir/ritonavir did not have sufficient direct antimalarial activity to translate into a clinically meaningful benefit that would support utilizing it in place of efavirenz in highly malaria endemic regions.”

Reference

Natureega P et al. Lopinavir/ritonavir versus efavirenz-based antiretroviral treatment for the prevention of malaria among HIV-infected pregnant women. J Infect Dis, online edition, 2014.