Delayed acquisition of Plasmodium falciparum antigen-specific CD4(+) T cell responses in HIV-exposed uninfected Malawian children receiving daily cotrimoxazole prophylaxis.

BACKGROUND: Cotrimoxazole (CTX) prophylaxis, recommended in HIV-exposed uninfected (HEU) children primarily against HIV-related opportunistic infections, has been shown to have some efficacy against Plasmodium falciparum malaria. The effects of CTX prophylaxis on the acquisition of P. falciparum antigen specific CD4(+) T cells-mediated immunity in HEU children is still not fully understood. METHODS: Peripheral blood was collected from HEU and HIV-unexposed uninfected (HUU) children at 6, 12 and 18 months of age. Proportion of CD4(+) T cells subsets were determined by immunophenotyping. P. falciparum antigen-specific CD4(+) T cells responses were measured by intracellular cytokine staining assay. RESULTS: There were no differences in the proportions of naïve, effector and memory CD4(+) T cell subsets between HEU and HUU children at all ages. There was a trend showing acquisition of P. falciparum-specific IFN-γ and TNF-producing CD4(+) T cells with age in both HUU and HEU children. There was, however, lower frequency of P. falciparum-specific IFN-γ-producing CD4(+) T cells in HEU compared to HUU at 6 and 12 months, which normalized 6 months after stopping CTX prophylaxis. CONCLUSION: The results demonstrate that there is delayed acquisition of P. falciparum-specific IFN-γ-producing CD4(+) T cells in HEU children on daily cotrimoxazole prophylaxis, which is evident at 6 and 12 months of age in comparison to HUU age-matched controls. However, whether this delayed acquisition of P. falciparum-specific IFN-γ-producing CD4(+) T cells leads to higher risk to malaria disease remains unknown and warrants further investigation.

The effects of shifting tasks from pharmacy to non-pharmacy personnel for providing antiretroviral therapy to people living with HIV: a systematic review protocol.

INTRODUCTION: Shifting selected antiretroviral therapy (ART) tasks from specialised healthcare workers to those with shorter or less formal training has been implemented in resource-limited settings to alleviate critical shortages of human resources for health. However, the specifics of shifting ART dispensing from pharmacy to non-pharmacy personnel have not been addressed in a systematic review, although this can potentially increase access to ART. We will assess the effects of shifting dispensing and distribution of ART and adherence assessment from pharmacy to non-pharmacy personnel in low and middle-income countries. METHODS AND ANALYSIS: We will search PubMed, CENTRAL, EMBASE, WHO Global Health Library and relevant grey literature for eligible controlled trials. Two authors will screen the search output, select eligible studies, assess risk of bias and extract data from included studies, resolving discrepancies by discussion and consensus. We will perform meta-analysis using both fixed and random effects models, investigate clinical and statistical heterogeneity, and assess our confidence in the overall evidence using standard Cochrane methods, including GRADE. ETHICS AND DISSEMINATION: Only secondary data will be included in this review and ethics approval is not required. We will disseminate the review findings in various scientific fora, including peer-reviewed journals. The findings may help to inform policy makers in defining the scope of work of healthcare workers, and global recommendations for shifting the dispensing and distribution of ART from pharmacy to non-pharmacy personnel. TRIAL REGISTRATION NUMBER: CRD42015017034.

Proportions of CD4+, CD8+ and B cell subsets are not affected by exposure to HIV or to Cotrimoxazole prophylaxis in Malawian HIV-uninfected but exposed children.

BACKGROUND: As a result of successful PMTCT programs, children born from HIV-infected mothers are now effectively protected from contracting the infection. However, it is not well known whether in utero exposure to the virus and the subsequent exposure to Cotrimoxazole (CTX) prophylaxis affect the cell mediated immune system of the children. This observational prospective study was aimed at determining how CD4(+) T, CD8(+) T and B cell subsets varied in HIV-exposed but uninfected (HEU) children at different ages. METHODS: We recruited HEU and HIV-unexposed and uninfected (HUU) children from 6 months of age and followed them up until they were 18 months old. HEU children received daily CTX prophylaxis beginning at 6 weeks of age until when 12 months of age. Venous blood samples were collected 6 monthly and analysed for different subsets of CD8(+) T, B cells and totalCD4(+) T cells. RESULTS: At 6 months of age, HEU children had a lower percentage of total CD4(+) T cells compared to HUU children and a lower proportion of naïve CD8(+) T cells but higher percentage of effector memory CD8(+) T cells compared to HUU children. HEU and HUU children had similar proportions of all B cell subsets at all ages. CONCLUSIONS: The study showed that the subtle variations in CD4(+) and CD8(+) T cell subsets observed at 6 months do not last beyond 12 months of age, suggesting that HEU children have a robust cell-mediated immune system during first year of life. TRIAL REGISTRATION: This article report is not based on results of a controlled health-care intervention.

Cotrimoxazole prophylactic treatment prevents malaria in children in sub-Saharan Africa: systematic review and meta-analysis.

OBJECTIVES: Cotrimoxazole prophylactic treatment (CPT) prevents opportunistic infections in HIV-infected or HIV-exposed children, but estimates of the effectiveness in preventing malaria vary. We reviewed studies that examined the effect of CPT on incidence of malaria in children in sub-Saharan Africa. METHODS: We searched PubMed and EMBASE for randomised controlled trials (RCTs) and cohort studies on the effect of CPT on incidence of malaria and mortality in children and extracted data on the prevalence of sulphadoxine-pyrimethamine resistance-conferring point mutations. Incidence rate ratios (IRR) from individual studies were combined using random effects meta-analysis; confounder-adjusted estimates were used for cohort studies. The importance of resistance was examined in meta-regression analyses. RESULTS: Three RCTs and four cohort studies with 5039 children (1692 HIV-exposed; 2800 HIV-uninfected; 1486 HIV-infected) were included. Children on CPT were less likely to develop clinical malaria episodes than those without prophylaxis (combined IRR 0.37, 95% confidence interval: 0.21-0.66), but there was substantial between-study heterogeneity (I-squared = 94%, P < 0.001). The protective efficacy of CPT was highest in an RCT from Mali, where the prevalence of antifolate resistant plasmodia was low. In meta-regression analyses, there was some evidence that the efficacy of CPT declined with increasing levels of resistance. Mortality was reduced with CPT in an RCT from Zambia, but not in a cohort study from Côte d'Ivoire. CONCLUSIONS: Cotrimoxazole prophylactic treatment reduces incidence of malaria and mortality in children in sub-Saharan Africa, but study designs, settings and results were heterogeneous. CPT appears to be beneficial for HIV-infected and HIV-exposed as well as HIV-uninfected children.