Raquel Gonzalez and colleagues highlight an urgent need to
                evaluate antimalarials that can be safely administered to
                HIV-infected pregnant women on antiretroviral treatment and
                cotrimoxazole prophylaxis

González, Raquel

Jagoe, George

Menéndez, Clara

Sevene, Esperança Júlia Pires

Slutsker, Laurence

PLoS Medicine

PubMed

Raquel González

Esperança Sevene

George Jagoe

Laurence Slutsker

Clara Menéndez

Crossref

A Public Health Paradox: The Women Most Vulnerable to Malaria Are the Least Protected

Raquel Gonzalez and colleagues highlight an urgent need to evaluate antimalarials that can be safely administered to HIV-infected pregnant women on antiretroviral treatment and cotrimoxazole prophylaxis

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A Public Health Paradox: The Women Most Vulnerable to Malaria Are the Least Protected.

Diposit Digital de la Universitat de Barcelona

A Public Health Paradox: The Women Most Vulnerable to Malaria
                Are the Least Protected

African HIV-infected pregnant women are the most vulnerable population group to malaria infection.

Paradoxically, these women are also the least protected against malaria due to fear of potential interactions between antiretroviral and antimalarial drugs.

Action is urgently needed to evaluate antimalarials that can be safely administered to HIV-infected pregnant women on antiretroviral treatment and cotrimoxazole prophylaxis.Mulheres grávidas africanas infectadas com HIV são o grupo populacional mais vulnerável à infecção por malária.

Paradoxalmente, essas mulheres também são as menos protegidas contra a malária devido ao medo de possíveis interações entre os antirretrovirais e os antimaláricos.

É necessária uma ação urgente para avaliar os antimaláricos que podem ser administrados com segurança a mulheres grávidas infectadas pelo HIV em tratamento anti-retroviral e profilaxia com cotrimoxazol

Sevene, Esperança

Slutske, Laurence

Repositorio UEM (Univ. Eduardo Mondlane)

ESSAYA Public Health Paradox: The Women MostVulnerable to Malaria Are the Least ProtectedRaquel González1,2*, Esperança Sevene2,3, George Jagoe4, Laurence Slutsker5,Clara Menéndez1,21 ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic- Universitat de Barcelona, Barcelona,Spain, 2 Manhiça Health Research Center (CISM), Manhiça, Mozambique, 3 Eduardo Mondlane University,Faculty of Medicine, Maputo, Mozambique, 4 Medicines for Malaria Venture, Geneva, Switzerland,5 Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control andPrevention, Atlanta, Georgia, United States of America* raquel.gonzalez@isglobal.orgWho Are theWomen Most Vulnerable to Malaria?Sub-Saharan Africa (SSA) is considered the be the centre of the global HIV epidemic with thehighest prevalence and incidence of HIV infection globally and where women account forapproximately 57% of all people living with HIV [1]. SSA also concentrates the greatest burdenof malaria. In this region, approximately 30 million pregnancies occur annually in areas ofintense Plasmodium falciparum transmission, and HIV-infected women are known to be themost vulnerable to malaria infection [2,3].For reasons not completely understood, pregnant women are particularly vulnerable tomalaria, with more frequent and higher density infections than nonpregnant women. Malariain pregnancy is associated with significant maternal and infant morbidity and mortality [4]. Ofnote, an estimated 20 million HIV-infected individuals in SSA live in malaria endemic areas,and over 12 million are women of reproductive age [1]. In addition, approximately one millionpregnancies each year are complicated by coinfection with malaria and HIV in SSA [1]. As agroup, women in this region are the most vulnerable to HIV infection due to biological andsociocultural factors [3]. As with malaria, maternal HIV infection increases the risk of miscar-riage, stillbirth, and other adverse birth outcomes [5]. The interaction between the two infec-tions is particularly deleterious in pregnancy. HIV increases the severity of malaria infectionand disease, and malaria infection increases HIV viral load, which in some studies has beenshown to increase the risk of mother-to-child transmission of HIV (MTCT-HIV)[6].Summary Points• African HIV-infected pregnant women are the most vulnerable population group tomalaria infection.• Paradoxically, these women are also the least protected against malaria due to fear ofpotential interactions between antiretroviral and antimalarial drugs.• Action is urgently needed to evaluate antimalarials that can be safely administered toHIV-infected pregnant women on antiretroviral treatment and cotrimoxazoleprophylaxis.PLOSMedicine | DOI:10.1371/journal.pmed.1002014 May 3, 2016 1 / 4a11111OPEN ACCESSCitation: González R, Sevene E, Jagoe G, SlutskerL, Menéndez C (2016) A Public Health Paradox: TheWomen Most Vulnerable to Malaria Are the LeastProtected. PLoS Med 13(5): e1002014. doi:10.1371/journal.pmed.1002014Published: May 3, 2016Copyright: This is an open access article, free of allcopyright, and may be freely reproduced, distributed,transmitted, modified, built upon, or otherwise usedby anyone for any lawful purpose. The work is madeavailable under the Creative Commons CC0 publicdomain dedication.Funding: The authors received no specific fundingfor this work.Competing Interests: The authors have declaredthat no competing interests exist.Abbreviations: ANC, antenatal care; CTXp,cotrimoxazole prophylaxis; IPTp-SP, IntermittentPreventive Treatment with sulfadoxine-pyrimethamine; ITN, insecticide-treated bed net;MTCT-HIV, mother-to-child transmission of HIV; SSA,sub-Saharan Africa.Provenance: Not commissioned; externally peer-reviewedAre Current Malaria Control Strategies Sufficiently Effective forHIV-Infected Pregnant Women?The current WHO recommendation for control of malaria in pregnant women living in stabletransmission areas relies on both the administration of Intermittent Preventive Treatment withsulfadoxine-pyrimethamine (IPTp-SP) beginning as early as possible in the second trimesterand at every scheduled antenatal care (ANC) visit thereafter, along with the use of insecticide-treated bed nets (ITNs) [7]. However, in HIV-infected women, IPTp-SP is contraindicated toavoid the potentially serious drug interactions with concomitant cotrimoxazole prophylaxis(CTXp), which is currently recommended in all HIV-infected pregnant women to preventopportunistic infections [8]. Thus, even though IPTp-SP is a life-saving and highly cost-effec-tive intervention, it cannot be used in the most vulnerable group, HIV-infected women [9,10].Because of the proven antimalarial effect of cotrimoxazole, it has been assumed that CTXpwould provide effective malaria prevention in HIV-infected pregnant women [11]. However,evidence to support this assumption is sparse and requires additional confirmation [12]. Inaddition, programmatic effectiveness of CTXp may be suboptimal due to the challenges ofadherence to a daily regimen of indefinite duration [13]. In a recent study, the addition of anefficacious antimalarial drug (mefloquine) to CTXp in HIV-infected pregnant womenimproved malaria prevention as evidenced by reductions in peripheral parasitemia and placen-tal infection, as well as improvement in overall maternal health with decreased hospital admis-sions [6]. However, mefloquine prophylaxis was not well tolerated, and importantly, was foundto be associated with both an increased maternal HIV viral load at delivery and risk ofMTCT-HIV. In this study, most of the nonobstetric admissions among HIV-infected womenwere due to infectious diseases, which are known to be an important cause of maternal death inthese women [6]. The immunosuppressive effect of malaria is well documented; therefore, theeffective prevention of malaria could help to reduce the risk of opportunistic infections. Theeffect of malaria as a risk factor for death in HIV-infected individuals is increasingly recog-nised, and it has been recently reported among HIV-infected children in Malawi [14].Unfortunately, the assumption that HIV-infected pregnant women are well protectedagainst malaria by CTXp has curtailed evaluation of other drugs for this purpose [15,16]. Ofnote, prevention of MTCT-HIV through lifelong administration of antiretroviral therapy(ART) to HIV-infected pregnant women (termed “option B+”), as well as the recent WHO rec-ommendation to initiate ART for every HIV-infected individual regardless of the CD4 cellcount (“treat all”), should lead to an increase in the survival and therefore number of HIV-infected women of reproductive age [8,17]. This may lead to an increase in the number ofwomen who become pregnant and are exposed to malaria in endemic areas. In this context, thelack of specifically designed studies to evaluate additional malaria prevention strategies in thisspecial population means that the most vulnerable women are also the least protected. Thus,studies are needed in HIV-infected pregnant women in endemic areas in SSA to evaluateimproved malaria prevention tools, including alternative antimalarial drugs. These studiesshould include (or be preceded by) careful assessment of potential pharmacological and safetyinteractions between antimalarial and antiretroviral drugs.What Are the Challenges and theWay Forward?Pregnancy itself increases the complexity of the clinical management of the malaria-HIV coin-fection by reducing the therapeutic options and by altering the function of drug-metabolizingenzymes and drug transporters in a gestational-stage and tissue-specific manner [18,19].Recent pharmacokinetic studies indicate that a significant reduction in systemic exposure tosome antiretroviral and antimalarial drugs may occur when administered concomitantly,PLOSMedicine | DOI:10.1371/journal.pmed.1002014 May 3, 2016 2 / 4raising concerns about an increased risk of treatment failures and/or safety issues [20,21].These disturbing results point to the need for further investigation to evaluate the clinical rele-vance of these drug–drug interactions in pregnancy.More generally, as new policies such as “treat-all” and “option B+” are scaled up, new andcomplex public health challenges may appear due to the increasing number of HIV-infectedpeople who would be exposed to ART. For example, it would be important to implement activepharmacovigilance systems in some sentinel sites to monitor possible drug-related adverseevents, as well as to reinforce the health system to guarantee the sustainability of ART adminis-tration to all HIV-infected individuals and long-term treatment adherence to prevent theappearance of viral mutants of resistance. Moreover, in malaria-endemic areas, HIV-infectedindividuals—in addition to being more likely to receive antimalarial drugs for treatment due totheir increased risk of malaria—may also be receiving these drugs for prevention; examplesinclude seasonal malaria chemoprevention or mass drug administration during malaria elimi-nation efforts. Thus, the problem of malaria–HIV coinfection needs to be revisited to take intoaccount the new context and evolving intervention strategies for both diseases.Author ContributionsWrote the first draft of the manuscript: RG CM. Contributed to the writing of the manuscript:RG ES GJ LS CM. Agree with the manuscript’s results and conclusions: RG ES GJ LS CM. Allauthors have read, and confirm that they meet, ICMJE criteria for authorship.References1. UNAIDS/WHO. Global report: UNAIDS report on the global AIDS Epidemic 2013. WHO Library Cata-loguing-in-Publication Data 2013;UNAIDS(JC2502/1/E).2. Dellicour S, Tatem AJ, Guerra CA, Snow RW, ter Kuile FO. Quantifying the number of pregnancies atrisk of malaria in 2007: a demographic study. PLoS Med. 2010; 7(1):e1000221. Epub 2010/02/04. doi:10.1371/journal.pmed.1000221 PMID: 20126256; PubMed Central PMCID: PMCPMC2811150.3. WHO. HIV in Pregnancy: a review. WHO UNAIDS. 1998. http://www.unaids.org/sites/default/files/media_asset/jc151-hiv-in-pregnancy_en_1.pdf.4. Menendez C, Ferenchick E, Roman E, Bardaji A, Mangiaterra V. Malaria in pregnancy: challenges forcontrol and the need for urgent action. The Lancet Global health. 2015; 3(8):e433–4. Epub 2015/07/19.doi: 10.1016/s2214-109x(15)00041-8 PMID: 26187483.5. 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A public health paradox: the women most vulnerable to malaria are the least protected

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A Public Health Paradox: The Women Most Vulnerable to Malaria Are the Least Protected

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