The effect of declining exposure on T cell-mediated immunity to Plasmodium falciparum - an epidemiological "natural experiment".

BACKGROUND: Naturally acquired immunity to malaria may be lost with lack of exposure. Recent heterogeneous reductions in transmission in parts of Africa mean that large populations of previously protected people may lose their immunity while remaining at risk of infection. METHODS: Using two ethnically similar long-term cohorts of children with historically similar levels of exposure to Plasmodium falciparum who now experience very different levels of exposure, we assessed the effect of decreased parasite exposure on antimalarial immunity. Peripheral blood mononuclear cells (PBMCs) from children in each cohort were stimulated with P. falciparum and their P. falciparum-specific proliferative and cytokine responses were compared. RESULTS: We demonstrate that, while P. falciparum-specific CD4+ T cells are maintained in the absence of exposure, the proliferative capacity of these cells is altered considerably. P. falciparum-specific CD4+ T cells isolated from children previously exposed, but now living in an area of minimal exposure ("historically exposed") proliferate significantly more upon stimulation than cells isolated from children continually exposed to the parasite. Similarly, PBMCs from historically exposed children expressed higher levels of pro-inflammatory cytokines and lower levels of anti-inflammatory cytokines after stimulation with P. falciparum. Notably, we found a significant positive association between duration since last febrile episode and P. falciparum-specific CD4+ T cell proliferation, with more recent febrile episodes associated with lower proliferation. CONCLUSION: Considered in the context of existing knowledge, these data suggest a model explaining how immunity is lost in absence of continuing exposure to P. falciparum.

Outcomes of prevention of mother to child transmission of the human immunodeficiency virus-1 in rural Kenya--a cohort study.

BACKGROUND: Success in prevention of mother-to-child transmission (PMTCT) raises the prospect of eliminating pediatric HIV infection. To achieve global elimination, however, strategies are needed to strengthen PMTCT interventions. This study aimed to determine PMTCT outcomes and identify challenges facing its successful implementation in a rural setting in Kenya. METHODS: A retrospective cohort design was used. Routine demographic and clinical data for infants and mothers enrolling for PMTCT care at a rural hospital in Kenya were analysed. Cox and logistic regression were used to determine factors associated with retention and vertical transmission respectively. RESULTS: Between 2006 and 2012, 1338 infants were enrolled and followed up for PMTCT care with earlier age of enrollment and improved retention observed over time. Mother to child transmission of HIV declined from 19.4 % in 2006 to 8.9 % in 2012 (non-parametric test for trend p = 0.024). From 2009 to 2012, enrolling for care after 6 months of age, adjusted Odds Ratio [aOR]: 23.3 [95 % confidence interval (CI): 8.3-65.4], presence of malnutrition ([aOR]: 2.3 [95 % CI: 1.1-5.2]) and lack of maternal use of highly active antiretroviral therapy (HAART) (aOR: 6.5 [95 % CI: 1.4-29.4]) was associated with increased risk of HIV infection. Infant's older age at enrollment, malnutrition and maternal HAART status, were also associated with drop out from care. Infants who were not actively followed up were more likely to drop out from care (adjusted Hazard Ratio: 6.6 [95 % CI: 2.9-14.6]). DISCUSSION: We report a temporal increase in the proportion of infants enrolling for PMTCT care before 3 months of age, improved retention in PMTCT and a significant reduction in the proportion of infants enrolled who became HIV-infected, emphasizing the benefits of PMTCT. CONCLUSION: A simple set of risk factors at enrollment can identify mother-infant pairs most at risk of infection or drop out for targeted intervention.

Multiple synergistic interactions between atovaquone and antifolates against Plasmodium falciparum in vitro: a rational basis for combination therapy.

The use of synergistic drug combinations for the treatment of drug-resistant malaria is a major strategy to slow the selection and spread of Plasmodium falciparum resistant strains. In order to investigate synergistic compounds, with different modes of action, as alternative candidates for combination therapy, we used standard in vitro P. falciparum cultures and an established synergy testing method to define interactions among dapsone (DDS), atovaquone (ATQ), chlorproguanil (CPG) and its triazine metabolite chlorcycloguanil (CCG). Strong synergy was observed in the combinations DDS/CCG and ATQ/CPG. Multiple combination of these drugs, DDS/CCG/CPG/ATQ also exhibited high synergy although not higher than that of either of the two drug combinations separately. The use of this triple combination DDS/CPG/ATQ, even without an increase in synergy over their double combinations, ATQ/CPG and DDS/CCG, would contribute towards slowing the selection pressure since these drugs act against different targets and would delay the selection of parasites resistant to the three drugs, extending the useful therapeutic life of these valuable compounds.