Malaria burden in a birth cohort of HIV-exposed uninfected Ugandan infants living in a high malaria transmission setting

Abel Kakuru, Paul Natureeba, Mary K Muhindo, Tamara D Clark, Diane V Havlir, Deborah Cohan, Grant Dorsey, Moses R Kamya, Theodore Ruel, Abel Kakuru, Paul Natureeba, Mary K Muhindo, Tamara D Clark, Diane V Havlir, Deborah Cohan, Grant Dorsey, Moses R Kamya, Theodore Ruel

Abstract

Background: HIV-exposed, uninfected (HEU) infants suffer high morbidity and mortality in the first year of life compared to HIV-unexposed, uninfected (HUU) infants, but accurate data on the contribution of malaria are limited.

Methods: The incidence of febrile illnesses and malaria were evaluated in a birth cohort of HEU infants. Infants were prescribed daily trimethoprim-sulfamethoxazole (TS) prophylaxis from 6 weeks of age until exclusion of HIV-infection after cessation of breastfeeding. Infants were followed for all illnesses using passive surveillance and routine blood smears were done monthly. Malaria was diagnosed as a positive blood smear plus fever. Placental malaria was determined by histopathology, placental blood smear and PCR. Risk factors for time to first episode of malaria were assessed using a Cox proportional hazards model. Malaria incidence among HEU infants aged 6-12 months was compared to that in other cohorts of HEU and HUU infants from the same region.

Results: Among 361 HEU infants enrolled, 248 completed 12 months of follow-up resulting in 1562 episodes of febrile illness and 253 episodes of malaria after 305 person-years of follow-up. The incidence of febrile illness was 5.12 episodes per person-year (PPY), ranging from 4.13 episodes PPY in the first 4 months of life to 5.71 episodes PPY between 5 and 12 months of age. The overall malaria incidence was 0.83 episodes per person-year (PPY), increasing from 0.03 episodes PPY in the first 2 months of life to 2.00 episodes PPY between 11 and 12 months of age. There were no episodes of complicated malaria. The prevalence of asymptomatic parasitaemia was 1.2 % (19 of 1568 routine smears positive). Infants born to mothers with parasites detected from placental blood smears were at higher risk of malaria (hazard ratio = 4.51, P < 0.001). HEU infants in this study had a 2.4- to 3.5-fold lower incidence of malaria compared to HUU infants in other cohort studies from the same area.

Conclusion: The burden of malaria in this birth cohort of HEU infants living in a high-transmission setting and taking daily TS prophylaxis was relatively low. Alternative etiologies of fever should be considered in HEU-infants taking daily TS prophylaxis who present with fever. Trial Registration NCT00993031, registered 8 October, 2009.

Keywords: HIV-exposed uninfected infants; Malaria; Placental malaria.

Figures

Fig. 1
Fig. 1
Study profile
Fig. 2
Fig. 2
Incidence of febrile illnesses and malaria by age category
Fig. 3
Fig. 3
Risk of malaria over the first year of life, by placental malaria category

References

    1. Afran L, Garcia Knight M, Nduati E, Urban BC, Heyderman RS, Rowland-Jones SL. HIV-exposed uninfected children: a growing population with a vulnerable immune system? Clin Exp Immunol. 2014;176:11–22. doi: 10.1111/cei.12251.
    1. Koyanagi A, Humphrey JH, Ntozini R, Nathoo K, Moulton LH, Iliff P, et al. Morbidity among human immunodeficiency virus-exposed but uninfected, human immunodeficiency virus-infected, and human immunodeficiency virus-unexposed infants in Zimbabwe before availability of highly active antiretroviral therapy. Pediatr Infect Dis J. 2011;30:45–51. doi: 10.1097/INF.0b013e3181ecbf7e.
    1. Brahmbhatt H, Kigozi G, Wabwire-Mangen F, Serwadda D, Lutalo T, Nalugoda F, et al. Mortality in HIV-infected and uninfected children of HIV-infected and uninfected mothers in rural Uganda. J Acquir Immune Defic Syndr. 1999;2006(41):504–508.
    1. Marinda E, Humphrey JH, Iliff PJ, Mutasa K, Nathoo KJ, Piwoz EG, et al. Child mortality according to maternal and infant HIV status in Zimbabwe. Pediatr Infect Dis J. 2007;26:519–526. doi: 10.1097/01.inf.0000264527.69954.4c.
    1. Landes M, van Lettow M, Chan AK, Mayuni I, Schouten EJ, Bedell RA. Mortality and health outcomes of HIV-exposed and unexposed children in a PMTCT cohort in Malawi. PLoS ONE. 2012;7:e47337. doi: 10.1371/journal.pone.0047337.
    1. Shapiro RL, Lockman S. Mortality among HIV-exposed infants: the first and final frontier. Clin Infect Dis. 2010;50:445–447. doi: 10.1086/649887.
    1. Slogrove A, Reikie B, Naidoo S, De Beer C, Ho K, Cotton M, et al. HIV-exposed uninfected infants are at increased risk for severe infections in the first year of life. J Trop Pediatr. 2012;58:505–508. doi: 10.1093/tropej/fms019.
    1. World Health Organization. Guidelines on post-exposure prophylaxis for HIV and the use of co-trimoxazole prophylaxis for HIV-related infections among adults, adolescents and children. Geneva: World Health Organization; 2014. .
    1. Kamya MR, Kapisi J, Bigira V, Clark TD, Kinara S, Mwangwa F, et al. Efficacy and safety of three regimens for the prevention of malaria in young HIV-exposed Ugandan children: a randomized controlled trial. AIDS. 2014;28:2701–2709. doi: 10.1097/QAD.0000000000000497.
    1. Bigira V, Kapisi J, Clark TD, Kinara S, Mwangwa F, Muhindo MK, et al. Protective efficacy and safety of three antimalarial regimens for the prevention of malaria in young Ugandan children: a randomized controlled trial. PLoS Med. 2014;11:e1001689. doi: 10.1371/journal.pmed.1001689.
    1. Homsy J, Dorsey G, Arinaitwe E, Wanzira H, Kakuru A, Bigira V, et al. Protective efficacy of prolonged co-trimoxazole prophylaxis in HIV-exposed children up to age 4 years for the prevention of malaria in Uganda: a randomised controlled open-label trial. Lancet Glob Health. 2014;2:e727–e736. doi: 10.1016/S2214-109X(14)70329-8.
    1. Sandison TG, Homsy J, Arinaitwe E, Wanzira H, Kakuru A, Bigira V, et al. Protective efficacy of co-trimoxazole prophylaxis against malaria in HIV exposed children in rural Uganda: a randomised clinical trial. BMJ. 2011;342:d1617. doi: 10.1136/bmj.d1617.
    1. Natureeba P, Ades V, Luwedde F, Mwesigwa J, Plenty A, Okong P, et al. Lopinavir/ritonavir-based antiretroviral treatment (ART) versus efavirenz-based ART for the prevention of malaria among HIV-infected pregnant women. J Infect Dis. 2014;210:1938–1945. doi: 10.1093/infdis/jiu346.
    1. Kamya MR, Arinaitwe E, Wanzira H, Katureebe A, Barusya C, Kigozi SP, et al. Malaria transmission, infection, and disease at three sites with varied transmission intensity in Uganda: implications for malaria control. Am J Trop Med Hyg. 2015;92:903–912. doi: 10.4269/ajtmh.14-0312.
    1. Snounou G, Viriyakosol S, Jarra W, Thaithong S, Brown KN. Identification of the four human malaria parasite species in field samples by the polymerase chain reaction and detection of a high prevalence of mixed infections. Mol Biochem Parasitol. 1993;58:283–292. doi: 10.1016/0166-6851(93)90050-8.
    1. Kourtis AP, Wiener J, Kayira D, Chasela C, Ellington SR, Hyde L, et al. Health outcomes of HIV-exposed uninfected African infants. AIDS. 2013;27:749–759. doi: 10.1097/QAD.0b013e32835ca29f.
    1. Davis NL, Barnett EJ, Miller WC, Dow A, Chasela CS, Hudgens MG, et al. Impact of daily cotrimoxazole on clinical malaria and asymptomatic parasitemias in HIV-exposed uninfected infants. Clin Infect Dis. 2015;61:368–374. doi: 10.1093/cid/civ309.
    1. Snow RW, Nahlen B, Palmer A, Donnelly CA, Gupta S, Marsh K. Risk of severe malaria among African infants: direct evidence of clinical protection during early infancy. J Infect Dis. 1998;177:819–822. doi: 10.1086/517818.
    1. Sehgal VM, Siddjiqui WA, Alpers MP. A seroepidemiological study to evaluate the role of passive maternal immunity to malaria in infants. Trans R Soc Trop Med Hyg. 1989;83(Suppl):105–106. doi: 10.1016/0035-9203(89)90616-0.
    1. Hviid L, Staalsoe T. Malaria immunity in infants: a special case of a general phenomenon? Trends Parasitol. 2004;20:66–72. doi: 10.1016/j.pt.2003.11.009.
    1. Pasvol G, Weatherall DJ, Wilson RJ. Effects of foetal haemoglobin on susceptibility of red cells to Plasmodium falciparum. Nature. 1977;270:171–173. doi: 10.1038/270171a0.
    1. Riboflavin deficiency inhibits multiplication of malarial parasites Nutr Rev. 1984;42:195–196.
    1. Mbeye NM, ter Kuile FO, Davies M-A, Phiri KS, Egger M, Wandeler G, et al. Cotrimoxazole prophylactic treatment prevents malaria in children in sub-Saharan Africa: systematic review and meta-analysis. Trop Med Int Health. 2014;19:1057–1067. doi: 10.1111/tmi.12352.
    1. Le Port A, Watier L, Cottrell G, Ouédraogo S, Dechavanne C, Pierrat C, et al. Infections in infants during the first 12 months of life: role of placental malaria and environmental factors. PLoS ONE. 2011;6:e27516. doi: 10.1371/journal.pone.0027516.
    1. Schwarz NG, Adegnika AA, Breitling LP, Gabor J, Agnandji ST, Newman RD, et al. Placental malaria increases malaria risk in the first 30 months of life. Clin Infect Dis. 2008;47:1017–1025. doi: 10.1086/591968.
    1. Mutabingwa TK, Bolla MC, Li J-L, Domingo GJ, Li X, Fried M, et al. Maternal malaria and gravidity interact to modify infant susceptibility to malaria. PLoS Med. 2005;2:e407. doi: 10.1371/journal.pmed.0020407.
    1. Hesran JYL, Cot M, Personne P, Fievet N, Dubois B, Beyeme M, et al. Maternal placental infection with Plasmodium falciparum and malaria morbidity during the first 2 years of life. Am J Epidemiol. 1997;146:826–831. doi: 10.1093/oxfordjournals.aje.a009200.
    1. Asante KP, Owusu-Agyei S, Cairns M, Dodoo D, Boamah EA, Gyasi R, et al. Placental malaria and the risk of malaria in infants in a high malaria transmission area in Ghana: a prospective cohort study. J Infect Dis. 2013;208:1504–1513. doi: 10.1093/infdis/jit366.
    1. Similar mortality with cotrimoxazole vs placebo in HIV-exposed uninfected children | CROI Conference. Boston Massachusetts, February 22–25, 2016; abstract no: 37 .

Source: PubMed

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