Neglected Tropical Diseases, Malaria and HIV/AIDS

An increasing body of evidence indicates that co-infection with the NTDs adversely affects the natural history and progression of malaria and HIV/AIDS (reviewed by Hotez et al, 2006b).

NTDs and Malaria
Several studies (reviewed by Druilhe et al, 2005) point to the increasing severity of clinical malaria that result from helminth coinfection. These studies include findings from Senegal showing enhanced risk or increased incidence of clinical falciparum malaria resulting from either soil-transmitted helminth or schistosome infections, unpublished studies from Malawi showing that women infected with hookworm were at higher risk of having malaria than uninfected women, and studies from Thailand showing increased susceptibility to malaria in patients with soil-transmitted helminth infections. In addition to increased susceptibility to malaria, the helminths, especially hookworm and schistosomiasis, exacerbate the anemia caused by malaria. Studies from Kenya show that the anemia from helminths and malaria can build on each other to produce profound reductions in hemoglobin. Shown in Fig. 4 is the geographic overlap between hookworm and malaria, which is extensive.

To make matters worse, many of these same African populations experience further reductions in hemoglobin because of sickle cell disease and thalassemia, as well as nutritional deficits in iron and folate. The severe anemia resulting from helminth polyparasitism and malaria produces several adverse health consequences among three particularly important African subpopulations: children and pregnant women.

In children, chronic anemia is associated with increased child mortality, and impairments in physical growth, cognitive and motor development, immune function, and school performance. Severe anemia is also a major contributor to mortality from malaria.

In pregnancy, anemia is a leading contributor to maternal morbidity and mortality, and is associated with shock, risk of cardiac failure, decreased ability to work, and adverse perinatal outcomes. In coastal Kenya, malaria was identified as the most important cause of anemia in primigravidae, whereas hookworm attains increased importance among multigravidae. Therefore, women are put at risk by the major consequences of anemia throughout their childbearing years.

NTDs and Intermittent Preventive Therapy (IPT) for Malaria

The studies outlined above have not been conducted in large African populations.   Therefore, there is an urgent need to expand our knowledge base on the interactions between malaria and helminth co-infections by conducting large scale studies in regions of Sub-Saharan Africa with geographic overlap.  Furthermore, there is a similar urgency to examine the impact of NTD control on intermittent preventive therapy (IPT) with antimalarials.  Multiple recent studies in falciparum malaria endemic regions of have shown that malaria chemoprophylaxis with sulfadoxine-pyrethamine (SP) during childhood or during pregnancy substantially improve health outcomes in both child and maternal populations (Greenwood et al, 2005; Greenwood, 2006). 

In children, use of SP or amodioquine at specific times during the first year of life in a program of intermittent preventive therapy in infancy (IPTi) lowers the incidence of malaria and severe anemia without any rebound in clinical malaria the following year (Greenwood et al, 2005).  In addition, in Senegal and Mali, where malaria is seasonal and affects older children, IPT in children (IPTc) during short transmission seasons is also highly effective (Greenwood et al, 2005; Greenwood, 2006).

School-aged children are an important yet understudied population in terms of the health impact of malaria, with some studies indicating that up to 50% of African school-aged children experience an attack of clinical malaria each year (Clarke et al, 2004), and up to 20% of the mortality from malaria occurs in school-aged children (Bundy et al, 2000).  Like helminth infections, malaria also adversely affects cognition and education (Brooker et al, 2000; Fernando et al, 2003).   In pregnancy, IPT (IPTp) protects against maternal anemia and low birthweight, especially in primigravidae and secundigravidae (Greenwood et al, 2005). 

The importance of helminth co-infections in exacerbating malaria in older children (beyond infancy) and in pregnancy, together with evidence that IPT in older children and in pregnant women will greatly reduce morbidity from malaria, suggests that there are multiple opportunities to link NTD control with malaria control. Specifically, studies are needed to:

1. Examine the impact of NTD control with the rapid impact package in older children who are receiving IPTc, particularly in areas with seasonal malaria transmission, and
2. Examine the impact of NTD control with the rapid impact package in pregnant women during their second and third trimester, while they are receiving IPTp.

Among the outcomes to be examined in the IPTc-NTD studies would be health impacts on number of- and clinical severity of malaria attacks, worm burden (fecal egg counts), anemia, and nutritional parameters including weight and height. Cognition and educational studies should also be carried out. Similar outcomes would be examined in the IPTp-NTD studies, additionally studies to examine the health impact on prematurity and birthweight should also be carried out.

Africa Maps: Geographic Overlap of Hookworm and Malaria. Of the estimated 179 million school-aged children living in Sub-Saharan Africa, there are approximately 50 million children with hookworm and 32 million children with both hookworm and falciparum malaria. Upper left: estimated prevalence of hookworm Upper right: risk of falciparum malaria Lower left: overlay of hookworm and falciparum malaria (Simon Brooker, unpublished).

Another body of evidence links helminth coinfections with increased susceptibility to HIV/AIDS or worsening the progression of HIV disease (Fincham et al, 2003). It has been postulated that chronic helminth infections increase the risk of HIV infection, with increased HIV plasma viral load, greater diminution of host T cells, and increased risk of mother-to-child HIV transmission in pregnant women (Fincham et al, 2005; Gallagher et al, 2005).

NTDS AND ANTIRETROVIRAL THERAPY (ART)
Like the existing malaria and helminth co-infection studies, the studies examining the relationship between helminths and HIV/AIDS are similarly of small scale. Therefore, there needs to be large scale studies examining the impact of deworming, administration of the rapid impact package, and other NTD control measures on the clinical course of HIV/AIDS, particularly among adolescents, young adults, and pregnant women.

Among the outcomes to be examined in the ART-NTD studies would be health impacts on host viral load, T cell counts, worm burden (fecal egg counts), and anemia (anemia has been shown to be an independent risk factor for the downward spiral of HIV/AIDS [Hotez et al, 2006b]). Among pregnant women, similar outcomes should be examined but in addition studies to examine the rates of vertical transmission of HIV should be conducted, as well as the health impact on prematurity and birthweight.

The results of the studies in have the potential to profoundly influence health policy and major G8 and U.S. funding initiatives including The Global Fund, PEPFAR, and the President’s Malaria Initiative.