Browsing by Author "Welte, Alex"

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    Age-disparity, sexual connectedness and HIV infection in disadvantaged communities around Cape Town, South Africa: A study protocol
    (BioMed Central Ltd, 2011) Delva, Wim; Beauclair, Roxanne; Welte, Alex; Vansteelandt, Stijn; Hens, Niel; Aerts, Marc; Du Toit, Elizabeth; Beyers, Nulda; Temmerman, Marleen
    Abstract: Background Crucial connections between sexual network structure and the distribution of HIV remain inadequately understood, especially in regard to the role of concurrency and age disparity in relationships, and how these network characteristics correlate with each other and other risk factors. Social desirability bias and inaccurate recall are obstacles to obtaining valid, detailed information about sexual behaviour and relationship histories. Therefore, this study aims to use novel research methods in order to determine whether HIV status is associated with age-disparity and sexual connectedness as well as establish the primary behavioural and socio-demographic predictors of the egocentric and community sexual network structures. Method/Design We will conduct a cross-sectional survey that uses a questionnaire exploring one-year sexual histories, with a focus on timing and age disparity of relationships, as well as other risk factors such as unprotected intercourse and the use of alcohol and recreational drugs. The questionnaire will be administered in a safe and confidential mobile interview space, using audio computer-assisted self-interview (ACASI) technology on touch screen computers. The ACASI features a choice of languages and visual feedback of temporal information. The survey will be administered in three peri-urban disadvantaged communities in the greater Cape Town area with a high burden of HIV. The study communities participated in a previous TB/HIV study, from which HIV test results will be anonymously linked to the survey dataset. Statistical analyses of the data will include descriptive statistics, linear mixed-effects models for the inter- and intra-subject variability in the age difference between sexual partners, survival analysis for correlated event times to model concurrency patterns, and logistic regression for association of HIV status with age disparity and sexual connectedness. Discussion This study design is intended to facilitate more accurate recall of sensitive sexual history data and has the potential to provide substantial insights into the relationship between key sexual network attributes and additional risk factors for HIV infection. This will help to inform the design of context-specific HIV prevention programmes.
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    Birth outcomes following antiretroviral exposure during pregnancy : initial results from a pregnancy exposure registry in South Africa
    (AOSIS, 2019) Mehta, Ushma C.; Van Schalkwyk, Cari; Naidoo, Prineetha; Ramkissoon, Arthi; Mhlongo, Otty; Maharaj, Niren R.; Naidoo, Niree; Fieggen, Karen; Urban, Michael F.; Krog, Shaun; Welte, Alex; Dheda, Mukesh; Pillay, Yogan; Moran, Neil F.
    Background: In 2013, a pregnancy exposure registry and birth defects surveillance (PER/BDS) system was initiated in eThekwini District, KwaZulu-Natal (KZN), to assess the impact of antiretroviral treatment (ART) on birth outcomes. Objectives: At the end of the first year, we assessed the risk of major congenital malformations (CM) and other adverse birth outcomes (ABOs) detected at birth, in children born to women exposed to ART during pregnancy. Method: Data were collected from women who delivered at Prince Mshiyeni Memorial Hospital, Durban, from 07 October 2013 to 06 October 2014, using medicine exposure histories and birth outcomes from maternal interviews, clinical records and neonatal surface examination. Singleton births exposed to only one ART regimen were included in bivariable analysis for CM risk and multivariate risk analysis for ABO risk. Results: Data were collected from 10 417 women with 10 517 birth outcomes (4013 [38.5%] HIV-infected). Congenital malformations rates in births exposed to Efavirenz during the first trimester (T1) (RR 0.87 [95% CI 0.12–6.4; p = 0.895]) were similar to births not exposed to ART during T1. However, T1 exposure to Nevirapine was associated with the increased risk of CM (RR 9.28 [95% CI 2.3–37.9; p = 0.002]) when compared to the same group. Other ABOs were more frequent in the combination of HIV/ART-exposed births compared to HIV-unexposed births (29.9% vs. 26.0%, adjusted RR 1.23 [1.14–1.31; p < 0.001]). Conclusion: No association between T1 use of EFV-based ART regimens and CM was observed. Associations between T1 NVP-based ART regimen and CM need further investigation. HIV- and ART-exposed infants had more ABOs compared to HIV-unexposed infants.
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    A comparison of biomarker based incidence estimators
    (Public Library of Science (PLOS), 2009-10) McWalter, Thomas A.; Welte, Alex
    Background: Cross-sectional surveys utilizing biomarkers that test for recent infection provide a convenient and cost effective way to estimate HIV incidence. In particular, the BED assay has been developed for this purpose. Controversy surrounding the way in which false positive results from the biomarker should be handled has lead to a number of different estimators that account for imperfect specificity. We compare the estimators proposed by McDougal et al., Hargrove et al. and McWalter & Welte. Methodology/Principal Findings: The three estimators are analyzed and compared. An identity showing a relationship between the calibration parameters in the McDougal methodology is shown. When the three estimators are tested under a steady state epidemic, which includes individuals who fail to progress on the biomarker, only the McWalter/ Welte method recovers an unbiased result. Conclusions/Significance: Our analysis shows that the McDougal estimator can be reduced to a formula that only requires calibration of a mean window period and a long-term specificity. This allows simpler calibration techniques to be used and shows that all three estimators can be expressed using the same set of parameters. The McWalter/Welte method is applicable under the least restrictive assumptions and is the least prone to bias of the methods reviewed. © 2009 McWalter, Welte.
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    Comparison of cross-sectional HIV incidence assay results from dried blood spots and plasma
    (Public Library of Science, 2017-02-23) Schlusser, Katherine E.; Pilcher, Christopher; Kallas, Esper G.; Santos, Breno R.; Deeks, Steven G.; Facente, Shelley; Keating, Sheila M.; Busch, Michael P.; Murphy, Gary; Welte, Alex; Quinn, Thomas; Eshleman, Susan H.; Laeyendecker, Oliver
    Background: Assays have been developed for cross-sectional HIV incidence estimation using plasma samples. Large scale surveillance programs are planned using dried blood spot (DBS) specimens for incidence assessment. However, limited information exists on the performance of HIV cross-sectional incidence assays using DBS. Methods: The assays evaluated were: Maxim HIV-1 Limiting Antigen Avidity EIA (LAg-Avidity), Sedia HIV-1 BED-Capture EIA (BED-CEIA), and CDC modified BioRad HIV-1/2 Plus O Avidity-based Assay (CDC-BioRad Avidity) using pre-determined cutoff values. 100 matched HIV-1 positive plasma and DBS samples, with known duration of infection, from the Consortium for the Evaluation and Performance of HIV Incidence Assays repository were tested. All assays were run in duplicate. To examine the degree of variability within and between results for each sample type, both categorical and continuous results were analyzed. Associations were assessed with Bland Altman, R2 values and Cohen’s kappa coefficient (ĸ). Results: Intra-assay variability using the same sample type was similar for all assays (R2 0.96 to 1.00). The R2 values comparing DBS and plasma results for LAg-Avidity, BED-CEIA, and CDC-BioRad Avidity were 0.96, 0.94, and 0.84, respectively. The concordance and ĸ values between DBS and plasma for all three assays were >87% and >0.64, respectively. The Bland-Altman analysis showed significant differences between plasma and DBS samples. For all three assays, a higher number of samples were classified as recent infections using DBS samples. Conclusions: DBS and plasma sample results were highly correlated. However, when compared to plasma, each assay performed somewhat differently in DBS at the lower and higher ends of the dynamic range. DBS samples were more likely to be classified as recently infected by all three assays, which may lead to overestimation of incidence in surveys using performance criteria derived for plasma samples.
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    Computational analysis of antibody dynamics identifies recent HIV-1 infection
    (American Society for Clinical Investigation, 2018) Seaton, Kelly E.; Vandergrift, Nathan A.; Deal, Aaron W.; Rountree, Wes; Bainbridge, John; Grebe, Eduard; Anderson, David A.; Sawant, Sheetal; Shen, Xiaoying; Yates, Nicole L.; Denny, Thomas N.; Liao, Hua-Xin; Haynes, Barton F.; Robb, Merlin L.; Parkin, Neil; Santos, Breno R.; Garrett, Nigel; Price, Matthew A.; Naniche, Denise; Duerr, Ann C.; The CEPHIA group; Keating, Sheila; Hampton, Dylan; Facente, Shelley; Marson, Kara; Welte, Alex; Pilcher, Christopher D.; Cohen, Myron S.; Tomaras, Georgia D.
    Accurate HIV-1 incidence estimation is critical to the success of HIV-1 prevention strategies. Current assays are limited by high false recent rates (FRRs) in certain populations and a short mean duration of recent infection (MDRI). Dynamic early HIV-1 antibody response kinetics were harnessed to identify biomarkers for improved incidence assays. We conducted retrospective analyses on circulating antibodies from known recent and longstanding infections and evaluated binding and avidity measurements of Env and non-Env antigens and multiple antibody forms (i.e., IgG, IgA, IgG3, IgG4, dIgA, and IgM) in a diverse panel of 164 HIV-1–infected participants (clades A, B, C). Discriminant function analysis identified an optimal set of measurements that were subsequently evaluated in a 324-specimen blinded biomarker validation panel. These biomarkers included clade C gp140 IgG3, transmitted/founder clade C gp140 IgG4 avidity, clade B gp140 IgG4 avidity, and gp41 immunodominant region IgG avidity. MDRI was estimated at 215 day or alternatively, 267 days. FRRs in untreated and treated subjects were 5.0% and 3.6%, respectively. Thus, computational analysis of dynamic HIV-1 antibody isotype and antigen interactions during infection enabled design of a promising HIV-1 recency assay for improved cross-sectional incidence estimation.
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    Cost-effectiveness of different strategies to monitor adults on antiretroviral treatment : a combined analysis of three mathematical models
    (Elsevier, 2014-01) Keebler, Daniel; Revill, Paul; Braithwaite, Scott; Phillips, Andrew; Blaser, Nello; Borquez, Annick; Cambiano, Valentina; Ciaranello, Andrea; Estill, Janne; Gray, Richard; Hill, Andrew; Keiser, Olivia; Kessler, Jason; Menzies, Nicolas A.; Nucifora, Kimberly A.; Vizcaya, Luisa Salazar; Walker, Simon; Welte, Alex; Easterbrook, Philippa; Doherty, Meg; Hirnschall, Gottfried; Hallett, Timothy B.
    Background WHO's 2013 revisions to its Consolidated Guidelines on antiretroviral drugs recommend routine viral load monitoring, rather than clinical or immunological monitoring, as the preferred monitoring approach on the basis of clinical evidence. However, HIV programmes in resource-limited settings require guidance on the most cost-effective use of resources in view of other competing priorities such as expansion of antiretroviral therapy coverage. We assessed the cost-effectiveness of alternative patient monitoring strategies. Methods We evaluated a range of monitoring strategies, including clinical, CD4 cell count, and viral load monitoring, alone and together, at different frequencies and with different criteria for switching to second-line therapies. We used three independently constructed and validated models simultaneously. We estimated costs on the basis of resource use projected in the models and associated unit costs; we quantified impact as disability-adjusted life years (DALYs) averted. We compared alternatives using incremental cost-effectiveness analysis. Findings All models show that clinical monitoring delivers significant benefit compared with a hypothetical baseline scenario with no monitoring or switching. Regular CD4 cell count monitoring confers a benefit over clinical monitoring alone, at an incremental cost that makes it affordable in more settings than viral load monitoring, which is currently more expensive. Viral load monitoring without CD4 cell count every 6–12 months provides the greatest reductions in morbidity and mortality, but incurs a high cost per DALY averted, resulting in lost opportunities to generate health gains if implemented instead of increasing antiretroviral therapy coverage or expanding antiretroviral therapy eligibility. Interpretation The priority for HIV programmes should be to expand antiretroviral therapy coverage, firstly at CD4 cell count lower than 350 cells per μL, and then at a CD4 cell count lower than 500 cells per μL, using lower-cost clinical or CD4 monitoring. At current costs, viral load monitoring should be considered only after high antiretroviral therapy coverage has been achieved. Point-of-care technologies and other factors reducing costs might make viral load monitoring more affordable in future.
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    Cost-effectiveness of Xpert MTB/RIF and investing in health care in Africa
    (Elsevier, 2014-10) Dheda, Keertan; Theron, Grant; Welte, Alex
    The Xpert MTB/RIF assay is an accurate test for the diagnosis of tuberculosis when an adequate sputum sample can be obtained; even in smear-negative tuberculosis the sensitivity is about 67%.1, 2 Although the assay turnaround time is under 2 h, depending on the health-care setting, time to tuberculosis treatment can be 2 weeks or more in a substantial number of patients.3 The technology has now been endorsed by WHO as a frontline test for tuberculosis in populations where there is a high incidence of HIV.4 Indeed, several countries in Africa are rolling out Xpert MTB/RIF.5 However, for expanded and sustained uptake, governments and policy makers require information about the cost-effectiveness of the technology to allow for appropriate planning and allocation of health-care resources. Cost-effectiveness must be balanced against affordability and sustainability. Thus, although the diagnostic accuracy of the technique is not in doubt, questions remain about the cost-effectiveness of the technology given that the overall number of patients treated for tuberculosis can remain unchanged6 and given the high rates of empirical treatment in resource-poor health-care settings.7
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    Evaluating audio computer assisted self-interviews in urban south African communities : evidence for good suitability and reduced social desirability bias of a cross-sectional survey on sexual behaviour
    (BioMed Central, 2013-01) Beauclair, Roxanne; Meng, Fei; Deprez, Nele; Temmerman, Marleen; Welte, Alex; Hens, Niel; Delva, Wim
    Abstract: Efficient HIV prevention requires accurate identification of individuals with risky sexual behaviour. However, self-reported data from sexual behaviour surveys are prone to social desirability bias (SDB). Audio Computer-Assisted Self-Interviewing (ACASI) has been suggested as an alternative to face-to-face interviewing (FTFI), because it may promote interview privacy and reduce SDB. However, little is known about the suitability and accuracy of ACASI in urban communities with high HIV prevalence in South Africa. To test this, we conducted a sexual behaviour survey in Cape Town, South Africa, using ACASI methods. Methods Participants (n = 878) answered questions about their sexual relationships on a touch screen computer in a private mobile office. We included questions at the end of the ACASI survey that were used to assess participants’ perceived ease of use, privacy, and truthfulness. Univariate logistic regression models, supported by multivariate models, were applied to identify groups of people who had adverse interviewing experiences. Further, we constructed male–female ratios of self-reported sexual behaviours as indicators of SDB. We used these indicators to compare SDB in our survey and in recent FTFI-based Demographic and Health Surveys (DHSs) from Lesotho, Swaziland, and Zimbabwe. Results Most participants found our methods easy to use (85.9%), perceived privacy (96.3%) and preferred ACASI to other modes of inquiry (82.5%) when reporting on sexual behaviours. Unemployed participants and those in the 40–70 year old age group were the least likely to find our methods easy to use (OR 0.69; 95% CI: 0.47–1.01 and OR 0.37; 95% CI: 0.23–0.58, respectively). In our survey, the male–female ratio for reporting >2 sexual partners in the past year, a concurrent relationship in the past year, and > 2 sexual partners in a lifetime was 3.4, 2.6, and 1.2, respectively— far lower than the ratios observed in the Demographic and Health Surveys. Conclusions Our analysis suggests that most participants in our survey found the ACASI modality to be acceptable, private, and user-friendly. Moreover, our results indicate lower SDB than in FTFI techniques. Targeting older and unemployed participants for ACASI training prior to taking the survey may help to improve their perception of ease and privacy.
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    HIV incidence in rural South Africa : comparison of estimates from longitudinal surveillance and cross-sectional cBED assay testing
    (Public Library of Science (PLOS), 2008-04) Barnighausen, Till; Wallrauch, Claudia; Welte, Alex; McWalter, Thomas A.; Mbizana, Nhlanhla; Viljoen, Johannes; Graham, Natalie; Tanser, Frank; Puren, Adrian; Newell, Marie-Louise
    Background: The BED IgG-Capture Enzyme Immunoassay (cBED assay), a test of recent HIV infection, has been used to estimate HIV incidence in cross-sectional HIV surveys. However, there has been concern that the assay overestimates HIV incidence to an unknown extent because it falsely classifies some individuals with non-recent HIV infections as recently infected. We used data from a longitudinal HIV surveillance in rural South Africa to measure the fraction of people with nonrecent HIV infection who are falsely classified as recently HIV-infected by the cBED assay (the long-term false-positive ratio (FPR)) and compared cBED assay-based HIV incidence estimates to longitudinally measured HIV incidence. Methodology/Principal Findings: We measured the long-term FPR in individuals with two positive HIV tests (in the HIV surveillance, 2003-2006) more than 306 days apart (sample size n = 1,065). We implemented four different formulae to calculate HIV incidence using cBED assay testing (n = 11,755) and obtained confidence intervals (CIs) by directly calculating the central 95th percentile of incidence values. We observed 4,869 individuals over 7,685 person-years for longitudinal HIV incidence estimation. The long-term FPR was 0.0169 (95% CI 0.0100-0.0266). Using this FPR, the cross-sectional cBED-based HIV incidence estimates (per 100 people per year) varied between 3.03 (95% CI 2.44-3.63) and 3.19 (95% CI 2.57-3.82), depending on the incidence formula. Using a long-term FPR of 0.0560 based on previous studies, HIV incidence estimates varied between 0.65 (95% CI 0.00-1.32) and 0.71 (95% CI 0.00-1.43). The longitudinally measured HIV incidence was 3.09 per 100 people per year (95% CI 2.69-3.52), after adjustment to the sex-age distribution of the sample used in cBED assay-based estimation. Conclusions/Significance: In a rural community in South Africa with high HIV prevalence, the long-term FPR of the cBED assay is substantially lower than previous estimates. The cBED assay performs well in HIV incidence estimation if the locally measured long-term FPR is used, but significantly underestimates incidence when a FPR estimate based on previous studies in other settings is used. © 2008 Bärnighausen et al.
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    HIV treatment as prevention : principles of good HIV epidemiology modelling for public health decision- making in all modes of prevention and evaluation
    (Public Library of Science (PLOS), 2012-07) Delva, Wim; Wilson, David P.; Abu-Raddad, Laith; Gorgens, Marelize; Wilson, David; Hallett, Timothy B.; Welte, Alex
    Public health responses to HIV epidemics have long relied on epidemiological modelling analyses to help prospectively project and retrospectively estimate the impact, cost-effectiveness, affordability, and investment returns of interventions, and to help plan the design of evaluations. But translating model output into policy decisions and implementation on the ground is challenged by the differences in background and expectations of modellers and decision-makers. As part of the PLoS Medicine Collection ‘‘Investigating the Impact of Treatment on New HIV Infections’’—which focuses on the contribution of modelling to current issues in HIV prevention—we present here principles of ‘‘best practice’’ for the construction, reporting, and interpretation of HIV epidemiological models for public health decision-making on all aspects of HIV. Aimed at both those who conduct modelling research and those who use modelling results, we hope that the principles described here will become a shared resource that facilitates constructive discussions about the policy implications that emerge from HIV epidemiology modelling results, and that promotes joint understanding between modellers and decision-makers about when modelling is useful as a tool in quantifying HIV epidemiological outcomes and improving prevention programming.
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    Incidence of TB and HIV in prospectively followed household contacts of TB index patients in South Africa
    (PLoS, 2014-04) Van Schalkwyk, Cari; Variava, Ebrahim; Shapiro, Adrienne E.; Rakgokong, Modiehi; Masonoke, Katlego; Lebina, Limakatso; Welte, Alex; Martinson, Neil
    Objective: To report the incidence rates of TB and HIV in household contacts of index patients diagnosed with TB. Design: A prospective cohort study in the Matlosana sub-district of North West Province, South Africa. Methods: Contacts of index TB patients received TB and HIV testing after counseling at their first household visit and were then followed up a year later, in 2010. TB or HIV diagnoses that occurred during the period were determined. Results: For 2,377 household contacts, the overall observed TB incidence rate was 1.3 per 100 person years (95% CI 0.9–1.9/100py) and TB incidence for individuals who were HIV-infected and HIV seronegative at baseline was 5.4/100py (95% CI 2.9–9.0/100py) and 0.7/100py (95% CI 0.3–1.4/100py), respectively. The overall HIV incidence rate was 2.2/100py (95% CI 1.3–8.4/100py). Conclusions: In the year following a household case finding visit when household contacts were tested for TB and HIV, the incidence rate of both active TB and HIV infection was found to be extremely high. Clearly, implementing proven strategies to prevent HIV acquisition and preventing TB transmission and progression to disease remains a priority in settings such as South Africa.
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    Infection staging and incidence surveillance applications of high dynamic range diagnostic immuno-assay platforms
    (Wolters Kluwer, 2017-12) Grebe, Eduard; Welte, Alex; Hall, Jake; Keating, Sheila; Facente, Shelley; Marson, Kara; Martin, Jeffrey; Little, Susan; Price, Matthew; Kallas, Esper; Busch, Michael; Pilcher, Christopher; Murphy, Gary; Consortium for the Evaluation and Performance of HIV Incidence Assays (CEPHIA); South African Centre for Epidemiological Modelling and Analysis (SACEMA)
    Background: Custom HIV staging assays, including the Sedia HIV-1 Limiting Antigen (LAg) Avidity EIA and avidity modifications of the Ortho VITROS anti-HIV-1+2 and Abbott ARCHITECT HIV Ag/Ab Combo assays, are used to identify “recent” infections in clinical settings and for cross-sectional HIV incidence estimation. However, the high dynamic range of chemiluminescent platforms allows differentiating recent and long-standing infection on signal intensity, and this raises the prospect of using unmodified diagnostic assays for infection timing and surveillance applications. Methods: We tested a panel of 2500 well-characterized specimens with estimable duration of HIV infection with the 3 assays and the unmodified ARCHITECT. Regression models were used to estimate mean durations of recent infection (MDRIs), contextspecific false-recent rates (FRRs) and correlation between diagnostic signal intensity and LAg measurements. Hypothetical epidemiological scenarios were constructed to evaluate utility in surveillance applications. Results: Over a range of MDRIs (reflecting recency discrimination thresholds), a diluted ARCHITECT-based RITA produced lower FRRs than the VITROS platform (FRR z 0.5% and 1.5%, respectively at MDRI z 200 days), and the unmodified diagnostic ARCHITECT produces incidence estimates with comparable precision to LAg (relative SE z 17.5% and 15%, respectively at MDRIz 200 days). ARCHITECT S/CO measurements were highly correlated with LAg optical density measurements (r = 0.80), and values below 200 are strongly predictive of LAg recency and duration of infection less than 1 year. Conclusions: Low quantitative measurements from the unmodified ARCHITECT obviate the need for additional recency testing, and its use is feasible in clinical staging and incidence surveillance applications.
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    Interpreting HIV diagnostic histories into infection time estimates : analytical framework and online tool
    (BMC (part of Springer Nature), 2019-10-26) Grebe, Eduard; Facente, Shelley N.; Bingham, Jeremy; Pilcher, Christopher D.; Powrie, Andrew; Gerber, Jarryd; Priede, Gareth; Chibawara, Trust; Busch, Michael P.; Murphy, Gary; Kassanjee, Reshma; Welte, Alex
    Background: It is frequently of epidemiological and/or clinical interest to estimate the date of HIV infection or time-since-infection of individuals. Yet, for over 15 years, the only widely-referenced infection dating algorithm that utilises diagnostic testing data to estimate time-since-infection has been the ‘Fiebig staging’ system. This defines a number of stages of early HIV infection through various standard combinations of contemporaneous discordant diagnostic results using tests of different sensitivity. To develop a new, more nuanced infection dating algorithm, we generalised the Fiebig approach to accommodate positive and negative diagnostic results generated on the same or different dates, and arbitrary current or future tests – as long as the test sensitivity is known. For this purpose, test sensitivity is the probability of a positive result as a function of time since infection. Methods: The present work outlines the analytical framework for infection date estimation using subject-level diagnostic testing histories, and data on test sensitivity. We introduce a publicly-available online HIV infection dating tool that implements this estimation method, bringing together 1) curatorship of HIV test performance data, and 2) infection date estimation functionality, to calculate plausible intervals within which infection likely became detectable for each individual. The midpoints of these intervals are interpreted as infection time ‘point estimates’ and referred to as Estimated Dates of Detectable Infection (EDDIs). The tool is designed for easy bulk processing of information (as may be appropriate for research studies) but can also be used for individual patients (such as in clinical practice). Results: In many settings, including most research studies, detailed diagnostic testing data are routinely recorded, and can provide reasonably precise estimates of the timing of HIV infection. We present a simple logic to the interpretation of diagnostic testing histories into infection time estimates, either as a point estimate (EDDI) or an interval (earliest plausible to latest plausible dates of detectable infection), along with a publicly-accessible online tool that supports wide application of this logic. Conclusions: This tool, available at https://tools.incidence-estimation.org/idt/, is readily updatable as test technology evolves, given the simple architecture of the system and its nature as an open source project.
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    Modelling the human immunodeficiency virus (HIV) epidemic : a review of the substance and role of models in South Africa
    (Medpharm Publications, 2018) Geffen, Nathan; Welte, Alex
    We review key mathematical models of the South African human immunodeficiency virus (HIV) epidemic from the early 1990s onwards. In our descriptions, we sometimes differentiate between the concepts of a model world and its mathematical or computational implementation. The model world is the conceptual realm in which we explicitly declare the rules – usually some simplification of ‘real world’ processes as we understand them. Computing details of informative scenarios in these model worlds is a task requiring specialist knowledge, but all other aspects of the modelling process, from describing the model world to identifying the scenarios and interpreting model outputs, should be understandable to anyone with an interest in the epidemic.
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    Morbidity and mortality up to 5 years post tuberculosis treatment in South Africa : a pilot study
    (Elsevier, 2019) Osman, Muhammad; Welte, Alex; Dunbar, Rory; Brown, Rosemary; Hoddinott, Graeme; Hesseling, Anneke C.; Marx, Florian M.
    Background: A high risk of tuberculosis (TB), chronic lung disease, and mortality have been reported among people with a history of previous TB treatment, but data from high-incidence settings remain limited. The aim of this study was to characterize general morbidity and mortality among adults who had successfully completed TB treatment in the past 5 years in a high-incidence setting in South Africa. Methods: Adults ( 18 years) who had completed treatment for pulmonary TB between 2013 and 2017 were randomly selected from TB treatment registers. Household visits were conducted to locate and interview former TB (FTB) patients, and bacteriological testing for TB was offered. Additional data sources were used to ascertain the vitality status of FTB patients who could not be located. Results: Addresses were located for 200 of the 223 FTB patients sampled and 89 FTB patients were contacted of whom 51 agreed to be interviewed. Approximately half reported persistent respiratory symptoms, such as shortness of breath and wheezing, and repeated lung infections. One (3.6%) of 28 patients who provided a sputum sample had culture-positive TB and another two were currently on re-treatment for TB. Fifteen deaths post treatment were ascertained, resulting in a standardized mortality ratio of 3.8 (95% confidence interval 2.3–6.3) after successful TB treatment relative to the general population. Conclusions: In this high-incidence setting, locating and interviewing FTB patients was challenging. The study findings are consistent with a high rate of respiratory disease, including recurrent TB, and substantially elevated mortality among FTB patients.
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    Mortality during tuberculosis treatment in South Africa using an 8-year analysis of the national tuberculosis treatment register
    (Nature, 2021-08) Osman, Muhammad; Van Schalkwyk, Cari; Naidoo, Pren; Seddon, James A.; Dunbare, Rory; Dlamini, Sicelo S.; Welte, Alex; Hesseling, Anneke C.; Claassens, Mareli M.
    In 2011, the South African HIV treatment eligibility criteria were expanded to allow all tuberculosis (TB) patients lifelong ART. The impact of this change on TB mortality in South Africa is not known. We evaluated mortality in all adults (≥ 15 years old) treated for drug-susceptible TB in South Africa between 2009 and 2016. Using a Cox regression model, we quantified risk factors for mortality during TB treatment and present standardised mortality ratios (SMR) stratified by year, age, sex, and HIV status. During the study period, 8.6% (219,618/2,551,058) of adults on TB treatment died. Older age, male sex, previous TB treatment and HIV infection (with or without the use of ART) were associated with increased hazard of mortality. There was a 19% reduction in hazard of mortality amongst all TB patients between 2009 and 2016 (adjusted hazard ratio: 0.81 95%CI 0.80–0.83). The highest SMR was in 15–24-year-old women, more than double that of men (42.3 in 2016). Between 2009 and 2016, the SMR for HIV-positive TB patients increased, from 9.0 to 19.6 in women, and 7.0 to 10.6 in men. In South Africa, case fatality during TB treatment is decreasing and further interventions to address specific risk factors for TB mortality are required. Young women (15–24-year-olds) with TB experience a disproportionate burden of mortality and interventions targeting this age-group are needed.
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    Performance comparison of the Maxim and Sedia Limiting Antigen Avidity assays for HIV incidence surveillance
    (Public Library of Science, 2019-07-26) Sempa, Joseph B.; Welte, Alex; Busch, Michael P.; Hall, Jake; Hampton, Dylan; Facente, Shelley N.; Keating, Sheila M.; Marson, Kara; Parkin, Neil; Pilcher, Christopher D.; Murphy, Gary; Grebe, Eduard
    Background: Two manufacturers, Maxim Biomedical and Sedia Biosciences Corporation, supply CDC-approved versions of the HIV-1 Limiting Antigen Avidity EIA (LAg) for detecting ‘recent’ HIV infection in cross-sectional incidence estimation. This study assesses and compares the performance of the two assays for incidence surveillance. Methods: We ran both assays on a panel of 2,500 well-characterized HIV-1-infected specimens. We analysed concordance of assay results, assessed reproducibility using repeat testing and estimated mean durations of recent infection (MDRIs) and false-recent rates (FRRs) for a range of normalized optical density (ODn) thresholds, alone and in combination with viral load thresholds. We defined three hypothetical surveillance scenarios, similar to the Kenyan and South African epidemics, and a concentrated epidemic. These scenarios allowed us to evaluate the precision of incidence estimates obtained by means of various recent infection testing algorithms (RITAs) based on each of the two assays. Results: The Maxim assay produced lower ODn values than the Sedia assay on average, largely as a result of higher calibrator readings (mean OD of 0.749 vs. 0.643), with correlation of normalized readings lower (R2 = 0.908 vs. R2 = 0.938). Reproducibility on blinded control specimens was slightly better for Maxim. The MDRI of a Maxim-based algorithm at the ‘standard’ threshold (ODn ≤1.5 & VL >1,000) was 201 days (95% CI: 180,223) and for Sedia 171 (152,191). The difference Differences in MDRI were estimated at 32.7 (22.9,42.8) and 30.9 days (21.7,40.7) for the two algorithms, respectively. Commensurately, the Maxim algorithm had a higher FRR in treatment-naive subjects (1.7% vs. 1.1%). The two assays produced similar precision of incidence estimates in the three surveillance scenarios. Conclusions: Differences between the assays can be primarily attributed to the calibrators supplied by the manufacturers. Performance for surveillance was extremely similar, although different thresholds were optimal (i.e. produced the lowest variance of incidence estimates) and at any given ODn threshold, different estimates of MDRI and FRR were obtained. The two assays cannot be treated as interchangeable: assay and algorithm-specific performance characteristic estimates must be used for survey planning and incidence estimation.
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    Pooled PCR testing of dried blood spots for infant HIV diagnosis is cost efficient and accurate
    (BMC (part of Springer Nature), 2019) Van Schalkwyk, Cari; Maritz, Jean; Van Zyl, Gert U.; Preiser, Wolfgang; Welte, Alex
    Background: Access to qualitative HIV PCRs for early infant diagnosis (EID) is restricted in resource-limited settings due to cost. We hypothesised that pooling of dried blood spots (DBS), defined as combining multiple patient samples in a single test with subsequent individual testing of positive pools, would be cost saving while retaining clinical accuracy compared to individual patient testing. Methods: Cost savings: A model was developed to simulate reagent and consumable cost saving of pooled compared to individual sample testing. Daily sample/result data of a public health laboratory in South Africa were used to illustrate outputs from the model. Samples were randomly allocated to pools and the process was repeated 1000 times to measure variation in estimates due to this stochasticity. Clinical accuracy: 1170 patient samples were tested using the Roche CAP/CTM Qual assay in pools of five 50 μl DBS. Negative pools comprised DBS previously tested in single reactions; positive pools included 1 positive sample. Results: Pooling would have saved 64% of laboratory costs in 2015. The model is published as an R-based web tool, into which the user enters sample/positivity estimates and workflow management parameters to obtain cost saving estimates at an optimal pool size. Sensitivity of pooled testing was 98.8% overall; 100% for strongly reactive pools. One pool tested false positive which would not impact clinical specificity as individual patient testing is performed prior to reporting. Conclusions: Pooled PCR testing for EID remains accurate and dramatically reduces costs in settings with moderate to low prevalence rates and sufficient sample numbers.
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    Population-level HIV incidence estimates using a combination of synthetic cohort and recency biomarker approaches in KwaZulu-Natal, South Africa
    (Public Library of Science, 2018-09-13) Grebe, Eduard; Welte, Alex; Johnson, Leigh F.; Van Cutsem, Gilles; Adrian Puren, Adrian; Ellman, Tom; Etard, Jean-Francois; Consortium for the Evaluation and Performance of HIV Incidence Assays; Huerga, Helena
    Introduction: There is a notable absence of consensus on how to generate estimates of population-level incidence. Incidence is a considerably more sensitive indicator of epidemiological trends than prevalence, but is harder to estimate. We used a novel hybrid method to estimate HIV incidence by age and sex in a rural district of KwaZulu-Natal, South Africa. Methods: Our novel method uses an ‘optimal weighting’ of estimates based on an implementation of a particular ‘synthetic cohort’ approach (interpreting the age/time structure of prevalence, in conjunction with estimates of excess mortality) and biomarkers of ‘recent infection’ (combining Lag-Avidity, Bio-Rad Avidity and viral load results to define recent infection, and adapting the method for age-specific incidence estimation). Data were obtained from a population-based cross-sectional HIV survey conducted in Mbongolwane and Eshowe health service areas in 2013. Results: Using the combined method, we find that age-specific HIV incidence in females rose rapidly during adolescence, from 1.33 cases/100 person-years (95% CI: 0.98,1.67) at age 15 to a peak of 5.01/100PY (4.14,5.87) at age 23. In males, incidence was lower, 0.34/100PY (0.00-0.74) at age 15, and rose later, peaking at 3.86/100PY (2.52-5.20) at age 30. Susceptible population-weighted average incidence in females aged 15-29 was estimated at 3.84/100PY (3.36-4.40), in males aged 15-29 at 1.28/100PY (0.68-1.50) and in all individuals aged 15-29 at 2.55/100PY (2.09-2.76). Using the conventional recency biomarker approach, we estimated HIV incidence among females aged 15-29 at 2.99/100PY (1.79-4.36), among males aged 15-29 at 0.87/100PY (0.22-1.60) and among all individuals aged 15-59 at 1.66/100PY (1.13-2.27). Discussion: HIV incidence was very high in women aged 15-30, peaking in the early 20s. Men had lower incidence, which peaked at age 30. The estimates obtained from the hybrid method are more informative than those produced by conventional analysis of biomarker data, and represents a more optimal use of available data than either the age-continuous biomarker or synthetic cohort methods alone. The method is mainly useful at younger ages, where excess mortality is low and uncertainty in the synthetic cohort estimates is reasonably small. Conclusion: Application of this method to large-scale population-based HIV prevalence surveys is likely to result in improved incidence surveillance over methods currently in wide use. Reasonably accurate and precise age-specific estimates of incidence are important to target better prevention, diagnosis and care strategies.
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    Recalibration of the limiting antigen avidity EIA to determine mean duration of recent infection in divergent HIV-1 subtypes
    (Public Library of Science, 2015) Duong, Yen T.; Kassanjee, Reshma; Welte, Alex; Morgan, Meade; De, Anindya; Dobbs, Trudy; Rottinghaus, Erin; Nkengasong, John; Kittinunvorakoon, Chonticha; Raengsakulrach, Boonyos; Martin, Michael; Choopanya, Kachit; Vanichseni, Suphak; Jiang, Yan; Qiu, Maofeng; Yu, Haiying; Hao, Yan; Shah, Neha; Le, Linh-Vi; Kim, Andrea A.; Nguyen, Tuan Anh; Ampofo, William; Parekh, Bharat S.; Curlin, Marcel E.
    Background: Mean duration of recent infection (MDRI) and misclassification of long-term HIV-1 infections, as proportion false recent (PFR), are critical parameters for laboratory-based assays for estimating HIV-1 incidence. Recent review of the data by us and others indicated that MDRI of LAg-Avidity EIA estimated previously required recalibration. We present here results of recalibration efforts using >250 seroconversion panels and multiple statistical methods to ensure accuracy and consensus. Methods: A total of 2737 longitudinal specimens collected from 259 seroconverting individuals infected with diverse HIV-1 subtypes were tested with the LAg-Avidity EIA as previously described. Data were analyzed for determination of MDRI at ODn cutoffs of 1.0 to 2.0 using 7 statistical approaches and sub-analyzed by HIV-1 subtypes. In addition, 3740 specimens from individuals with infection >1 year, including 488 from patients with AIDS, were tested for PFR at varying cutoffs. Results: Using different statistical methods, MDRI values ranged from 88–94 days at cutoff ODn = 1.0 to 177–183 days at ODn = 2.0. The MDRI values were similar by different methods suggesting coherence of different approaches. Testing for misclassification among long-term infections indicated that overall PFRs were 0.6% to 2.5% at increasing cutoffs of 1.0 to 2.0, respectively. Balancing the need for a longer MDRI and smaller PFR (<2.0%) suggests that a cutoff ODn = 1.5, corresponding to an MDRI of 130 days should be used for cross-sectional application. The MDRI varied among subtypes from 109 days (subtype A&D) to 152 days (subtype C). Conclusions: Based on the new data and revised analysis, we recommend an ODn cutoff = 1.5 to classify recent and long-term infections, corresponding to an MDRI of 130 days (118–142). Determination of revised parameters for estimation of HIV-1 incidence should facilitate application of the LAg-Avidity EIA for worldwide use