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Johannesburg, South Africa

Wallis R.S.,The Aurum Institute
Frontiers in Microbiology | Year: 2016

The natural history of human infection with Mycobacterium tuberculosis (Mtb) is highly variable, as is the response to treatment of active tuberculosis. There is presently no direct means to identify individuals in whom Mtb infection has been eradicated, whether by a bactericidal immune response or sterilizing antimicrobial chemotherapy. Mathematical models can assist in such circumstances by measuring or predicting events that cannot be directly observed. The 3 models discussed in this review illustrate instances in which mathematical models were used to identify individuals with innate resistance to Mtb infection, determine the etiologic mechanism of tuberculosis in patients treated with tumor necrosis factor blockers, and predict the risk of relapse in persons undergoing tuberculosis treatment. These examples illustrate the power of various types of mathematic models to increase knowledge and thereby inform interventions in the present global tuberculosis epidemic. © 2016 Wallis. Source


Noguchi L.M.,Johns Hopkins University | Hillier S.L.,University of Washington | Hillier S.L.,University of Pittsburgh | Bunge K.,University of Washington | And 11 more authors.
The Lancet HIV | Year: 2015

Background Several observational studies have reported that HIV-1 acquisition seems to be higher in women who use depot medroxyprogesterone acetate (DMPA) than in those who do not use hormonal contraception. We aimed to assess whether two injectable progestin-only contraceptives, DMPA and norethisterone enanthate (NET-EN), confer diff erent risks of HIV-1 acquisition. Methods We included data from South African women who used injectable contraception while participating in the VOICE study, a multisite, randomised, placebo-controlled trial that investigated the safety and effi cacy of three formulations of tenofovir for prevention of HIV-1 infection in women between Sept 9, 2009, and Aug 13, 2012. Women were assessed monthly for contraceptive use and incident infection. We estimated the diff erence in incident HIV-1 infection between DMPA and NET-EN users by Cox proportional hazards regression analyses in this prospective cohort. The VOICE trial is registered with ClinicalTrials.gov, NCT00705679. Findings 3141 South African women using injectable contraception were included in the present analysis: 1788 (56 9%) solely used DMPA, 1097 (34 9%) solely used NET-EN, and 256 (8 2%) used both injectable types at diff erent times during follow-up. During 2733 7 person-years of follow-up, 207 incident HIV-1 infections occurred (incidence 7 57 per 100 person-years, 95% CI 6 61-8 68). Risk of HIV-1 acquisition was higher among DMPA users (incidence 8 62 per 100 person-years, 95% CI 7 35-10 11) than among NET-EN users (5 67 per 100 person-years, 4 35-7 38; hazard ratio 1 53, 95% CI 1 12-2 08; p=0 007). This association persisted when adjusted for potential confounding variables (adjusted hazard ratio [aHR] 1 41, 95% CI 1 06-1 89; p=0 02). Among women seropositive for herpes simplex virus type 2 (HSV-2) at enrolment, the aHR was 2 02 (95% CI 1 26-3 24) compared with 1 09 (0 78-1 52) for HSV-2-seronegative women (Pinteraction=0 07). Interpretation Although moderate associations in observational analyses should be interpreted with caution, these fi ndings suggest that NET-EN might be an alternative injectable drug with a lower HIV risk than DMPA in high HIV-1 incidence settings where NET-EN is available. Source


Latka M.H.,The Aurum Institute | Fielding K.,London School of Hygiene and Tropical Medicine | Gray G.E.,University of Witwatersrand | Bekker L.-G.,University of Cape Town | And 10 more authors.
PLoS ONE | Year: 2012

Background: HIV prevention trials are increasingly being conducted in sub-Saharan Africa. Women at risk for HIV are also at risk of pregnancy. To maximize safety, women agree to avoid pregnancy during trials, yet pregnancies occur. Using data from the HVTN 503/"Phambili" vaccine trial, we report pregnancy incidence during and after the vaccination period and identify factors, measured at screening, associated with incident pregnancy. Methods: To enrol in the trial, women agreed and were supported to avoid pregnancy until 1 month after their third and final vaccination ("vaccination period"), corresponding to the first 7 months of follow-up. Unsterilized women, pooled across study arms, were analyzed. Poisson regression compared pregnancy rates during and after the vaccination period. Cox proportional hazards regression identified associations with first pregnancy. Results: Among 352 women (median age 23 yrs; median follow-up 1.5 yrs), pregnancy incidence was 9.6/100 women-years overall and 6.8/100 w-yrs and 11.3/100 w-yrs during and after the vaccination period, respectively [Rate Ratio = 0.60 (0.32-1.14), p = 0.10]. In multivariable analysis, pregnancy was reduced among women who: enrolled at sites providing contraception on-site [HR = 0.43, 95% CI (0.22-0.86)]; entered the trial as injectable contraceptive users [HR = 0.37 (0.21-0.67)] or as consistent condom users (trend) [HR = 0.54 (0.28-1.04)]. Compared with women with a single partner of HIV-unknown status, pregnancy rates were increased among women with: a single partner whose status was HIV-negative [HR = 2.34(1.16-4.73)] and; 2 partners both of HIV-unknown status [HR = 4.42(1.59-12.29)]. Women with 2 more of these risk factors: marijuana use, heavy drinking, or use of either during sex, had increased pregnancy incidence [HR = 2.66 (1.24-5.72)]. Conclusions: It is possible to screen South African women for pregnancy risk at trial entry. Providing injectable contraception for free on-site and supporting consistent condom use may reduce incident pregnancy. Screening should determine the substance use, partnering, and HIV status of both members of the couple for both pregnancy and HIV prevention. Trial Registration: SA National Health Research Database DOH-27-0207-1539; Clinicaltrials.gov NCT00413725. © 2012 Latka et al. Source


Meyer-Rath G.,London School of Hygiene and Tropical Medicine | Meyer-Rath G.,Boston University | Meyer-Rath G.,University of Witwatersrand | Pienaar J.,Anglo American | And 7 more authors.
PLoS Medicine | Year: 2015

Background: HIV impacts heavily on the operating costs of companies in sub-Saharan Africa, with many companies now providing antiretroviral therapy (ART) programmes in the workplace. A full cost–benefit analysis of workplace ART provision has not been conducted using primary data. We developed a dynamic health-state transition model to estimate the economic impact of HIV and the cost–benefit of ART provision in a mining company in South Africa between 2003 and 2022. Methods and Findings: A dynamic health-state transition model, called the Workplace Impact Model (WIM), was parameterised with workplace data on workforce size, composition, turnover, HIV incidence, and CD4 cell count development. Bottom-up cost analyses from the employer perspective supplied data on inpatient and outpatient resource utilisation and the costs of absenteeism and replacement of sick workers. The model was fitted to workforce HIV prevalence and separation data while incorporating parameter uncertainty; univariate sensitivity analyses were used to assess the robustness of the model findings. As ART coverage increases from 10% to 97% of eligible employees, increases in survival and retention of HIV-positive employees and associated reductions in absenteeism and benefit payments lead to cost savings compared to a scenario of no treatment provision, with the annual cost of HIV to the company decreasing by 5% (90% credibility interval [CrI] 2%–8%) and the mean cost per HIV-positive employee decreasing by 14% (90% CrI 7%–19%) by 2022. This translates into an average saving of US$950,215 (90% CrI US$220,879–US$1.6 million) per year; 80% of these cost savings are due to reductions in benefit payments and inpatient care costs. Although findings are sensitive to assumptions regarding incidence and absenteeism, ART is cost-saving under considerable parameter uncertainty and in all tested scenarios, including when prevalence is reduced to 1%—except when no benefits were paid out to employees leaving the workforce and when absenteeism rates were half of what data suggested. Scaling up ART further through a universal test and treat strategy doubles savings; incorporating ART for family members reduces savings but is still marginally cost-saving compared to no treatment. Our analysis was limited to the direct cost of HIV to companies and did not examine the impact of HIV prevention policies on the miners or their families, and a few model inputs were based on limited data, though in sensitivity analysis our results were found to be robust to changes to these inputs along plausible ranges. Conclusions: Workplace ART provision can be cost-saving for companies in high HIV prevalence settings due to reductions in healthcare costs, absenteeism, and staff turnover. Company-sponsored HIV counselling and voluntary testing with ensuing treatment of all HIV-positive employees and family members should be implemented universally at workplaces in countries with high HIV prevalence. © 2015 Meyer-Rath et al. Source


Velen K.,The Aurum Institute | Lewis J.J.,The Aurum Institute | Lewis J.J.,London School of Hygiene and Tropical Medicine | Charalambous S.,The Aurum Institute | And 5 more authors.
PLoS ONE | Year: 2013

Background:Tenofovir (TDF) is part of the WHO recommended first-line antiretroviral therapy (ART); however, there are limited data comparing TDF to other nucleoside reverse transcriptase inhibitors in resource-limited-settings. Using a routine workplace and community-based ART cohort in South Africa, we assessed single drug substitution, HIV RNA suppression, CD4 count increase, loss-from-care, and mortality between TDF, stavudine (d4T) 30 mg dose, and zidovudine (AZT).Methods:In a prospective cohort study we included ART naïve patients aged ≥17 years-old who initiated ART containing TDF, d4T, or AZT between 2007 and 2009. For analysis of single drug substitutions we used a competing-risks time-to-event analysis; for loss-from-care, mixed-effect Poisson modeling; for HIV RNA suppression, competing-risks logistic regression; for CD4 count slope, mixed-effects linear regression; and for mortality, proportional hazards modeling.Results:Of 6,196 patients, the initial drug was TDF for 665 (11%), d4T for 4,179 (68%), and AZT for 1,352 (22%). During the first 6 months of ART, the adjusted hazard ratio for a single drug substitution was 2.3 for d4T (95% confidence interval [CI]: 0.27, 19) and 5.2 for AZT (95% CI: 1.1, 23), compared to TDF; whereas, after 6 months, it was 10 (95% CI: 5.8, 18) and 4.4 (95% CI: 2.5, 7.8) for d4T and AZT, respectively. Virologic suppression was similar by agent; however, CD4 count rise was lowest for AZT. The adjusted hazard ratio for loss-from-care, when compared to TDF, was 1.5 (95% CI: 1.1, 1.9) for d4T and 1.2 (95% CI: 1.1, 1.4) for AZT. The adjusted hazard ratio for mortality, when compared to TDF, was 2.7 (95% CI: 2.0, 3.5) and 1.4 (95% CI: 1.3, 1.5) and for d4T and AZT, respectively.Discussion:In routine care, TDF appeared to perform better than either d4T or AZT, most notably with less drug substitution and mortality than for either other agent. © 2013 Velen et al. Source

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