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Gaborone, Botswana

Mutapi F.,University of Edinburgh | Rujeni N.,University of Edinburgh | Bourke C.,University of Edinburgh | Mitchell K.,University of Edinburgh | And 6 more authors.
PLoS Neglected Tropical Diseases

Background: Morbidity due to schistosomiasis is currently controlled by treatment of schistosome infected people with the antihelminthic drug praziquantel (PZQ). Children aged up to 5 years are currently excluded from schistosome control programmes largely due to the lack of PZQ safety data in this age group. This study investigated the safety and efficacy of PZQ treatment in such children. Methods: Zimbabwean children aged 1-5 years (n = 104) were treated with PZQ tablets and side effects were assessed by questionnaire administered to their caregivers within 24 hours of taking PZQ. Treatment efficacy was determined 6 weeks after PZQ administration through schistosome egg counts in urine. The change in infection levels in the children 1-5 years old (n = 100) was compared to that in 6-10 year old children (n = 435). Principal Findings: Pre-treatment S. haematobium infection intensity in 1-5 year olds was 14.6 eggs/10 ml urine and prevalence was 21%. Of the 104 children, 3.8% reported side effects within 24 hours of taking PZQ treatment. These were stomach ache, loss of appetite, lethargy and inflammation of the face and body. PZQ treatment significantly reduced schistosome infection levels in 1-5 year olds with an egg reduction rate (ERR) of 99% and cure rate (CR) of 92%. This was comparable to the efficacy of praziquantel in 6-10 year olds where ERR was 96% and CR was 67%. Interpretation/Significance: PZQ treatment is as safe and efficacious in children aged 1-5 years as it is in older children aged 6-10 years in whom PZQ is the drug of choice for control of schistosome infections. © 2011 Mutapi et al. Source

Mutapi F.,University of Edinburgh | Imai N.,University of Edinburgh | Nausch N.,University of Edinburgh | Bourke C.D.,University of Edinburgh | And 8 more authors.

In animal experimental models, parasitic helminth infections can protect the host from auto-immune diseases. We conducted a population-scale human study investigating the relationship between helminth parasitism and auto-reactive antibodies and the subsequent effect of anti-helminthic treatment on this relationship. Levels of antinuclear antibodies (ANA) and plasma IL-10 were measured by enzyme linked immunosorbent assay in 613 Zimbabweans (aged 2-86 years) naturally exposed to the blood fluke Schistosoma haematobium. ANA levels were related to schistosome infection intensity and systemic IL-10 levels. All participants were offered treatment with the anti-helminthic drug praziquantel and 102 treated schoolchildren (5-16 years) were followed up 6 months post-antihelminthic treatment. ANA levels were inversely associated with current infection intensity but were independent of host age, sex and HIV status. Furthermore, after allowing for the confounding effects of schistosome infection intensity, ANA levels were inversely associated with systemic levels of IL-10. ANA levels increased significantly 6 months after anti-helminthic treatment. Our study shows that ANA levels are attenuated in helminth-infected humans and that anti-helminthic treatment of helminth-infected people can significantly increase ANA levels. The implications of these findings are relevant for understanding both the aetiology of immune disorders mediated by auto-reactive antibodies and in predicting the long-term consequences of large-scale schistosomiasis control programs. © 2011 Mutapi et al. Source

Rowley C.F.,Beth Israel Deaconess Medical Center | Rowley C.F.,Harvard University | Rowley C.F.,Botswana Harvard AIDS Institute
Clinical Infectious Diseases

CD4 counts and human immunodeficiency virus (HIV) load testing are essential components of HIV care, and making these tests available in resource-limited settings is critical to the roll-out of HIV treatment globally. Until recently, the evidence supporting the importance of laboratory monitoring in resource-limited settings was lacking, but there is now a consensus emerging that testing should become routine to ensure the longevity of treatment programs. Low-cost, point-of-care testing offers the potential to fill this role as it potentially improves all aspects of HIV care, ranging from the diagnosis and staging of HIV infection in both infants and adults to monitoring for treatment failure once antiretroviral therapy has been initiated. It is imperative for low-cost solutions to become a reality, but it is equally imperative that close scrutiny be given to each new device that hits the market to ensure they perform optimally in all settings. © 2013 The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. Source

Grinsztejn B.,Institute Pesquisa Clinica Evandro Chagas | Hosseinipour M.C.,University of North Carolina at Chapel Hill | Ribaudo H.J.,Harvard University | Swindells S.,University of Nebraska Medical Center | And 26 more authors.
The Lancet Infectious Diseases

Background: Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes. Methods: The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00074581. Findings: 1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373-522) cells per μL in patients assigned to the early treatment group and 428 (357-522) cells per μL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197-249) cells per μL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0·73, 95% CI 0·52-1·03; p=0·074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0·64, 0·43-0·96; p=0·031), tuberculosis developed in 17 versus 34 patients, respectively (0·49, 0·28-0·89, p=0·018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24·9 per 100 person-years, 95% CI 22·5-27·5) versus 585 in the delayed treatment group (29·2 per 100 person-years, 26·5-32·1; p=0·025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group. Interpretation: Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment. Funding: US National Institute of Allergy and Infectious Diseases. © 2014 Elsevier Ltd. Source

Novitsky V.,Harvard University | Wang R.,Harvard University | Rossenkhan R.,Botswana Harvard AIDS Institute | Rossenkhan R.,University of Botswana | And 2 more authors.
Infection, Genetics and Evolution

Background: HIV-1 nucleotide substitution rates are central for understanding the evolution of HIV-1. Their accurate estimation is critical for analysis of viral dynamics, identification of divergence time of HIV variants, inference of HIV transmission clusters, and modeling of viral evolution. Methods: Intra-patient nucleotide substitution rates in HIV-1C gag and env gp120 V1C5 were analyzed in a longitudinal cohort of 32 individuals infected with a single viral variant. Viral quasispecies were derived by single genome amplification/sequencing from serially sampled blood specimens collected at median (IQR) of 5 (4-6) times per subject from enrollment (during Fiebig stages II to V) over a median (IQR) of 417 (351-471) days post-seroconversion (p/s). HIV-1C evolutionary rates were estimated by BEAST v.1.7 using a relaxed lognormal molecular clock model. The effect of antiretroviral therapy (ART) on substitution rates in gag and env was assessed in a subset of six individuals who started ARV therapy during the follow-up period. Results: During primary HIV-1C infection, the intra-patient substitution rates were estimated at a median (IQR) of 5.22E-03 (3.28E-03-7.55E-03) substitutions per site per year of infection within gag, and 1.58E-02 (9.99E-03-2.04E-02) substitutions per site per year within env gp120 V1C5. The substitution rates in env gp120 V1C5 were higher than in gag (p < 0.001, Wilcoxon signed rank test). The median (IQR) relative rates of evolution at codon positions 1, 2, and 3 were 0.73 (0.48-0.84), 0.67 (0.52-0.86), and 1.54 (1.21-1.71) in gag, and 1.01 (0.86-1.15), 1.05 (0.99-1.21), and 0.86 (0.67-0.94) in env gp120 V1C5, respectively. A first to the third position codon rate ratio >1.0 within env was found in 25 (78.1%) cases, but only in 4 (12.5%) cases in gag, while a second to the third position codon rate ratio >1.0 in env was observed in 26 (81.3%) cases, but in gag only in 2 (6.3%) cases (p < 0.001 for both comparisons, Fisher's exact test). No ART effect on substitution rates in gag and env was found, at least within the first 3-4 months after ART initiation. Individuals with early viral set point ≥4.0 log10 copies/ml had higher substitution rates in env gp120 V1C5 (median (IQR) 1.88E-02 (1.54E-02-2.46E-02) vs. 1.04E (7.24E-03-1.55E-02) substitutions per site per year; p = 0.017, Mann-Whitney sum rank test), while individuals with early viral set point ≥3.0 log10 copies/ml had higher substitution rates in gag (median (IQR) 5.66E-03 (3.45E-03-7.94E-03) vs. 1.78E-03 (4.57E-04-5.15E-03); p = 0.028; Mann-Whitney sum rank test). Conclusions: The results suggest that in primary HIV-1C infection, (1) intra-host evolutionary rates in env gp120 V1C5 are about 3-fold higher than in gag; (2) selection pressure in env is more frequent than in gag; (3) initiation of ART does not change substitution rates in HIV-1C env or gag, at least within the first 3-4 months after starting ART; and (4) intra-host evolutionary rates in gag and env gp120 V1C5 are higher in individuals with elevated levels of early viral set point. © 2013 Elsevier B.V. All rights reserved. Source

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