Alex Welte

Male Circumcision for HIV Prevention in High HIV Prevalence Settings: What Can Mathematical Modelling Contribute to Informed Decision Making?

Experts from UNAIDS, WHO, and the South African Centre for Epidemiological Modelling report their review of mathematical models estimating the impact of male circumcision on HIV incidence in high HIV prevalence settings

Beyond detuning: 10 years of progress and new challenges in the development and application of assays for HIV incidence estimation.

In the ongoing battle against HIV/AIDS, it is critical that we are able to measure and monitor HIV incidence, that is the number of new infections during a period of time, usually expressed as number of infections/person-years of observation or as an annual percentage of the population that acquire infection. Knowledge of HIV incidence is necessary to understand transmission patterns; to provide a rational basis for targeting prevention efforts; to evaluate interventions to reduce transmission; and to predict or project the burden of HIV infection in different demographic and risk populations. Reliable information on HIV incidence is especially important to support prevention programs in the low-income and middleincome countries that continue to bear a disproportionate share of the global burden of the HIVepidemic. Improved estimates of HIV incidence are essential to evaluate

HIV incidence in rural South Africa: comparison of estimates from longitudinal surveillance and cross-sectional cBED assay testing.

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 non-recent 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.

Independent assessment of candidate HIV incidence assays on specimens in the CEPHIA repository

Objective:Cross-sectional HIV incidence surveillance, using assays that distinguish ‘recent’ from ‘nonrecent’ infections, has been hampered by inadequate performance and characterization of incidence assays. In this study, the Consortium for the Evaluation and Performance of HIV Incidence Assays presents results of the first independent evaluation of five incidence assays (BED, Limiting Antigen Avidity, Less-sensitive Vitros, Vitros Avidity and BioRad Avidity). Design:A large repository of diverse specimens from HIV-positive patients was established, multiple assays were run on 2500 selected specimens, and data were analyzed to estimate assay characteristics relevant for incidence surveillance. Methods:The mean duration of recent infection (MDRI, average time ‘recent’ while infected for less than some time cut-off T) was estimated from longitudinal data on seroconverters by regression. The false-recent rate (FRR, probability of testing ‘recent’ when infected for longer than T) was explored by measuring the proportions of ‘recent’ results in various subsets of patients. Results:Assays continue to fail to attain the simultaneously large MDRI and small FRR demanded by existing performance guidelines. All assays produce high FRRs amongst virally suppressed patients (>40%), including elite controllers and treated patients. Conclusions:Results from this first independent evaluation provide valuable information about the current performance of assays, and suggest the need for further optimization. Variation of ‘recent’/‘nonrecent’ thresholds and the use of multiple antibody-maturation assays, as well as other biomarkers, can now be explored, using the rich data generated by the Consortium for the Evaluation and Performance of HIV Incidence Assays. Consistently high FRRs amongst those virally suppressed suggest that viral load will be a particularly valuable supplementary marker. Video abstract:http://links.lww.com/QAD/A569

Significantly diminished long-term specificity of the BED capture enzyme immunoassay among patients with HIV-1 with very low CD4 counts and those on antiretroviral therapy.

Objective:To estimate the proportion who test as recent infections by the BED capture enzyme immunoassay (BED) among patients about to commence, and those receiving, antiretroviral therapy. Design:Cryopreserved plasma samples from HIV patients on the national antiretroviral treatment (ART) rollout program at Tygerberg Hospital HIV clinic, South Africa, were tested using the BED assay. Participants:Five hundred five patients qualifying for ART were included in this study. Method:All plasma samples from each patient were tested by BED. Basic demographic data, HIV-1 viral load, and CD4 count results were obtained from the laboratory database. Main Outcome:The proportion presenting as false recently infected is reported. Results:Among patients, with presumed long-term HIV-1 infections, about to commence ART, 11.2% [95% confidence interval (CI): 8.3 to 14.5%] tested recent by BED. The proportion was higher among patients with CD4 counts <50 cells per microliter [odds ratio 2.63, 95% CI: 1.39 to 5.00] and log10 HIV-1 viral load less than 4 [odds ratio 3.03, 95% CI: 1.05 to 9.09]. Proportions testing false recent increased from 11.2% before ART to 17%, 25%, 38%, and 56% at 0.5, 1, 1.5, and 2 years, respectively, after ART initiation. Conclusions:If the BED method is to be used for the accurate estimation of HIV incidence from cross-sectional surveys, it will be essential, before other statistical adjustment methods, to identify, at least, all cases who are on ART and all those with CD4 counts < 50 cells per microliter. The more general remaining problem is the unequivocal identification of all persons with long-term HIV infections.

HIV treatment as prevention : models, data, and questions-towards evidence-based decision-making

Antiretroviral therapy (ART) for those infected with HIV can prevent onward transmission of infection, but biological efficacy alone is not enough to guide policy decisions about the role of ART in reducing HIV incidence. Epidemiology, economics, demography, statistics, biology, and mathematical modelling will be central in framing key decisions in the optimal use of ART. PLoS Medicine, with the HIV Modelling Consortium, has commissioned a set of articles that examine different aspects of HIV treatment as prevention with a forward-looking research agenda. Interlocking themes across these articles are discussed in this introduction. We hope that this article, and others in the collection, will provide a foundation upon which greater collaborations between disciplines will be formed, and will afford deeper insights into the key factors involved, to help strengthen the support for evidence-based decision-making in HIV prevention.

A New General Biomarker-based Incidence Estimator

Background: Estimating disease incidence from cross-sectional surveys, using biomarkers for “recent” infection, has attracted much interest. Despite widespread applications to HIV, there is currently no consensus on the correct handling of biomarker results classifying persons as “recently” infected long after the infections occurred. Methods: We derive a general expression for a weighted average of recent incidence that—unlike previous estimators—requires no particular assumption about recent infection biomarker dynamics or about the demographic and epidemiologic context. This is possible through the introduction of an explicit timescale T that truncates the period of averaging implied by the estimator. Results: The recent infection test dynamics can be summarized into 2 parameters, similar to those appearing in previous estimators: a mean duration of recent infection and a false-recent rate. We identify a number of dimensionless parameters that capture the bias that arises from working with tractable forms of the resulting estimator and elucidate the utility of the incidence estimator in terms of the performance of the recency test and the population state. Estimation of test characteristics and incidence is demonstrated using simulated data. The observed confidence interval coverage of the test characteristics and incidence is within 1% of intended coverage. Conclusions: Biomarker-based incidence estimation can be consistently adapted to a general context without the strong assumptions of previous work about biomarker dynamics and epidemiologic and demographic history.

HIV incidence estimation using the BED capture enzyme immunoassay: systematic review and sensitivity analysis.

Background: HIV incidence estimates are essential for understanding the evolution of the HIV epidemic and the impact of interventions. Tests for recent HIV infection allow incidence estimation based on a single cross-sectional survey. The BED IgG-Capture Enzyme Immunoassay (BED assay) is a commercially available and widely used test for recent HIV infection. Methods: In a systematic literature search for BED assay studies, we identified 1181 unique studies, 1138 of which were excluded based on titles or abstracts. We conducted reviews of the 43 remaining publications and a further 23 studies identified on conference Web sites or by colleagues. Thirty-nine articles were included in the final review. We investigated the sensitivity of incidence values to various estimation methods and parameter choices. Results: BED assay surveys have been conducted on 5 continents in general populations and high-risk groups, using 1 or more of 10 distinct incidence formulae. Most studies used estimators that do not account for assay imperfection. Those studies that correct for assay imperfection commonly do not use locally valid assay parameters. Incidence estimates were very sensitive to methodological and parameter choices. Most confidence intervals provided good assessment of uncertainty due to counting error, but only a few incorporated parameter uncertainty. Conclusions: BED assay surveys can produce valid HIV incidence estimates, but many studies have not sufficiently accounted for assay imperfection. Future studies should (1) report all information necessary for incidence point and uncertainty estimation, (2) use an unbiased estimator with locally valid assay calibration parameters, and (3) compute confidence intervals that take into account parameter uncertainty.

Treatment as prevention: preparing the way

Potent antiretroviral therapy (ART) reduces mortality and morbidity in people living with HIV by reducing viral load and allowing their immune systems to recover. The reduction in viral load soon after starting ART has led to the hypothesis that early and widespread ART could prevent onward transmission and therefore eliminate the HIV epidemic in the long term. While several authors have argued that it is feasible to use HIV treatment as prevention (TasP), provided treatment is started sufficiently early, others have reasonably drawn attention to the many operational difficulties that will need to be overcome if the strategy is to succeed in reducing HIV transmission. Furthermore, international public health policy must be based on more than theoretical studies, no matter how appealing. Community randomized controlled trials provide the gold standard for testing the extent to which early treatment reduces incidence, but much still needs to be understood and the immediate need is for operational studies to explore the practical feasibility of this approach. Here, we examine some of the issues to be addressed, the obstacles to be overcome, and strategies that may be necessary if TasP is to be effective. Studies of this kind will provide valuable information for the design of large-scale trials, as well as essential information that will be needed if early treatment is to be incorporated into public health policy.

Relating recent infection prevalence to incidence with a sub-population of assay non-progressors

We present a new analysis of relationships between disease incidence and the prevalence of an experimentally defined state of ‘recent infection’. This leads to a clean separation between biological parameters (properties of disease progression as reflected in a test for recent infection), which need to be calibrated, and epidemiological state variables, which are estimated in a cross-sectional survey. The framework takes into account the possibility that details of the assay and host/pathogen chemistry leave a (knowable) fraction of the population in the recent category for all times. This systematically addresses an issue which is the source of some controversy about the appropriate use of the BED assay for defining recent HIV infection. The analysis is, however, applicable to any assay that forms the basis of a test for recent infection. Analysis of relative contributions of error arising variously from statistical considerations and simplifications of general expressions indicate that statistical error dominates heavily over methodological bias for realistic epidemiological and biological scenarios.