Evaluation of multi-assay algorithms for identifying individuals with recent HIV infection: HPTN 071 (PopART)

Background Assays and multi-assay algorithms (MAAs) have been developed for population-level cross-sectional HIV incidence estimation. These algorithms use a combination of serologic and/or non-serologic biomarkers to assess the duration of infection. We evaluated the performance of four MAAs for individual-level recency assessments. Methods Samples were obtained from 220 seroconverters (infected <1 year) and 4,396 non-seroconverters (infected >1 year) enrolled in an HIV prevention trial (HPTN 071 [PopART]); 28.6% of the seroconverters and 73.4% of the non-seroconverters had HIV viral loads ≤400 copies/mL. Samples were tested with two laboratory-based assays (LAg-Avidity, JHU BioRad-Avidity) and a point-of-care assay (rapid LAg). The four MAAs included different combinations of these assays and HIV viral load. Seroconverters on antiretroviral treatment (ART) were identified using a qualitative multi-drug assay. Results The MAAs identified between 54 and 100 (25% to 46%) of the seroconverters as recently-infected. The false recent rate of the MAAs for infections >2 years duration ranged from 0.2%-1.3%. The MAAs classified different overlapping groups of individuals as recent vs. non-recent. Only 32 (15%) of the 220 seroconverters were classified as recent by all four MAAs. Viral suppression impacted the performance of the two LAg-based assays. LAg-Avidity assay values were also lower for seroconverters who were virally suppressed on ART compared to those with natural viral suppression. Conclusions The four MAAs evaluated varied in sensitivity and specificity for identifying persons infected <1 year as recently infected and classified different groups of seroconverters as recently infected. Sensitivity was low for all four MAAs. These performance issues should be considered if these methods are used for individual-level recency assessments.

Estimating real snakebite incidence in Colombia by using mathematical modelling and statistical inference.

Snakebite envenoming is a Neglected Tropical Disease affecting mainly deprived populations. Its burden is normally underestimated because patients prefer to seek for traditional medicine. Thus, applying strategies to optimize disease' management and treatment delivery is difficult. We propose a framework to estimate snakebite incidence at a fine political scale based on available data, testing it in Colombia. First, we produced snakebite fine-scale risk maps based on the most medically important venomous snake species (Bothrops asper and B. atrox). We validated them with reported data in the country. Then, we proposed a generalized mixed effect model that estimates total incidence based on produced risk maps, poverty indexes, and an accessibility score that reflects the struggle to reach a medical center. Finally, we calibrated our model with national snakebite reported data from 2010 to 2019 using a Markov chain Monte Carlo (MCMC) algorithm and estimated underreporting based on the total incidence estimation. Our results suggest that 10.3% of total snakebite cases are not reported in Colombia and do not seek medical attention. The Orinoco and Amazonian regions (east of Colombia) share a high snakebite risk with a high underreporting. Our work highlights the importance of multidisciplinary approaches to face snakebite.

Rapid incidence estimation from SARS-CoV-2 genomes reveals decreased case detection in Europe during summer 2020

By October 2021, 230 million SARS-CoV-2 diagnoses have been reported. Yet, a considerable proportion of cases remains undetected. Here, we propose GInPipe, a method that rapidly reconstructs SARS-CoV-2 incidence profiles solely from publicly available, time-stamped viral genomes. We validate GInPipe against simulated outbreaks and elaborate phylodynamic analyses. Using available sequence data, we reconstruct incidence histories for Denmark, Scotland, Switzerland, and Victoria (Australia) and demonstrate, how to use the method to investigate the effects of changing testing policies on case ascertainment. Specifically, we find that under-reporting was highest during summer 2020 in Europe, coinciding with more liberal testing policies at times of low testing capacities. Due to the increased use of real-time sequencing, it is envisaged that GInPipe can complement established surveillance tools to monitor the SARS-CoV-2 pandemic. In post-pandemic times, when diagnostic efforts are decreasing, GInPipe may facilitate the detection of hidden infection dynamics.

Smoothing age/time structure of HIV prevalence, for optimal use in synthetic cohort based incidence estimation

Population-based surveys which ascertain HIV status are conducted in heavily affected countries, with the estimation of incidence being a primary goal. Numerous methods exist under the umbrella of ‘synthetic cohort analysis’, by which we mean estimating incidence from the age/time structure of prevalence (given knowledge on mortality). However, not enough attention has been given to how serostatus data is ‘smoothed’ into a time/age-dependent prevalence, so as to optimise the estimation of incidence.To support this and other related investigations, we developed a comprehensive simulation environment in which we simulate age/time structured SI type epidemics and surveys. Scenarios are flexibly defined by demographic rates (fertility, incidence and mortality – dependent, as appropriate, on age, time, and time-since-infection) without any reference to underlying causative processes/parameters. Primarily using 1) a simulated epidemiological scenario inspired by what is seen in the hyper-endemic HIV affected regions, and 2) pairs of cross-sectional surveys, we explored A) options for extracting the age/time structure of prevalence so as to optimise the use of the formal incidence estimation framework of Mahiane et al, and B) aspects of survey design such as the interaction of epidemic details, sample-size/sampling-density and inter-survey interval.Much as in our companion piece which crucially investigated the use of ‘recent infection’ (whereas the present analysis hinges fundamentally on the estimation of the prevalence gradient) we propose a ‘one size fits most’ process for conducting ‘synthetic cohort’ analyses of large population survey data sets, for HIV incidence estimation: fitting a generalised linear model for prevalence, separately for each age/time point where an incidence estimate is desired, using a ‘moving window’ data inclusion rule. Overall, even in very high incidence settings, sampling density requirements are onerous.The general default approach we propose for fitting HIV prevalence to data as a function of age and time appears to be broadly stable over various epidemiological stages. Particular scenarios of interest, and the applicable options for survey design and analysis, can readily be more closely investigated using our approach. We note that it is often unrealistic to expect even large household based surveys to provide meaningful incidence estimates outside of priority groups like young women, where incidence is often particularly high.

Smoothing age/time structure of HIV prevalence, for optimal use in synthetic cohort based incidence estimation

BackgroundPopulation-based surveys which ascertain HIV status are conducted in heavily affected countries, with the estimation of incidence being a primary goal. Numerous methods exist under the umbrella of ‘synthetic cohort analysis’, by which we mean estimating incidence from the age/time structure of prevalence (given knowledge on mortality). However, not enough attention has been given to how serostatus data is ‘smoothed’ into a time/age-dependent prevalence, so as to optimise the estimation of incidence.MethodsTo support this and other related investigations, we developed a comprehensive simulation environment in which we simulate age/time structured SI type epidemics and surveys. Scenarios are flexibly defined by demographic rates (fertility, incidence and mortality – dependent, as appropriate, on age, time, and time-since-infection) without any reference to underlying causative processes/parameters. Primarily using 1) a simulated epidemiological scenario inspired by what is seen in the hyper-endemic HIV affected regions, and 2) pairs of cross-sectional surveys, we explored A) options for extracting the age/time structure of prevalence so as to optimise the use of the formal incidence estimation framework of Mahiane et al, and B) aspects of survey design such as the interaction of epidemic details, sample-size/sampling-density and inter-survey interval.ResultsMuch as in our companion piece which crucially investigated the use of ‘recent infection’ (whereas the present analysis hinges fundamentally on the estimation of the prevalence gradient) we propose a ‘one size fits most’ process for conducting ‘synthetic cohort’ analyses of large population survey data sets, for HIV incidence estimation: fitting a generalised linear model for prevalence, separately for each age/time point where an incidence estimate is desired, using a ‘moving window’ data inclusion rule. Overall, even in very high incidence settings, sampling density requirements are onerous.ConclusionThe general default approach we propose for fitting HIV prevalence to data as a function of age and time appears to be broadly stable over various epidemiological stages. Particular scenarios of interest, and the applicable options for survey design and analysis, can readily be more closely investigated using our approach. We note that it is often unrealistic to expect even large household based surveys to provide meaningful incidence estimates outside of priority groups like young women, where incidence is often particularly high.

Optimal accounting for age and time structure of HIV incidence estimates based on cross-sectional survey data with ascertainment of ‘recent infection’

BackgroundMany surveys have attempted to estimate HIV incidence from cross-sectional data which includes ascertainment of ‘recent infection’, but the inevitable age and time structure of this data has never been systematically explored – no doubt partly because statistical precision in such estimates is often insufficient to allow for satisfactory disaggregation. Given the non-trivial age structure of HIV incidence and prevalence, and the enormous investments that have been made in such data sets, it is important to understand effective ways to extract valid age structure from these precious data sets. MethodsUsing a comprehensive demographic/epidemiological simulation platform developed for this, and some wider, purposes (documented in more detail separately) we simulated a complex ‘South Africa inspired’ HIV epidemic, with explicitly specified 1) age/time dependent incidence, 2) age/time dependent mortality for uninfected individuals, and 3) age/time/time-since-infection dependent mortality for infected individuals. In this simulated world, we conducted cross-sectional surveys at various times, and applied variants of the recent infection based incidence estimation methodology of Kassanjee et al. We analysed in considerable detail how to smooth, and average over, the age structure in these surveys to produce the incidence estimates, paying attention to the fundamental trade-off between bias and statistical error.ResultsWe summarise our detailed observations about incidence estimates, generated by various age smoothing or age disaggregation procedures, into a straightforward fully specified ‘one size fits most’ algorithm for processing the survey data into age-specific incidence estimates: 1) generalised linear regression to turn observations into ‘prevalence’ of ‘infection’ and ‘recent infection’ (logit, and complementary log log, link functions, respectively; fitting coefficients of up to cubic terms in age/time); 2) a ‘moving window’ data inclusion recipe which handles each age/time point of interest separately; 3) post hoc age averaging of resulting pseudo continuously fitted incidence; 4) bootstrapping as a generic variance/significance estimation procedure.ConclusionsAs far as we are aware, this is the first analysis of several fine details of how age structure in cross-sectional surveys interacts with recency-based incidence estimation. Our proposed default estimation procedure generates incidence estimates with negligible bias and near-optimal precision, and can be readily applied to complex survey data sets by any group in possession of such data. Our code is available, in part freely through the R computing platform, and in part upon request.

Optimal accounting for age and time structure of HIV incidence estimates based on cross-sectional survey data with ascertainment of ‘recent infection’

BackgroundMany surveys have attempted to estimate HIV incidence from cross-sectional data which includes ascertainment of ‘recent infection’, but the inevitable age and time structure of this data has never been systematically explored – no doubt partly because statistical precision in such estimates is often insufficient to allow for satisfactory disaggregation. Given the non-trivial age structure of HIV incidence and prevalence, and the enormous investments that have been made in such data sets, it is important to understand effective ways to extract valid age structure from these precious data sets. MethodsUsing a comprehensive demographic/epidemiological simulation platform developed for this, and some wider, purposes (documented in more detail separately) we simulated a complex ‘South Africa inspired’ HIV epidemic, with explicitly specified 1) age/time dependent incidence, 2) age/time dependent mortality for uninfected individuals, and 3) age/time/time-since-infection dependent mortality for infected individuals. In this simulated world, we conducted cross-sectional surveys at various times, and applied variants of the recent infection based incidence estimation methodology of Kassanjee et al. We analysed in considerable detail how to smooth, and average over, the age structure in these surveys to produce the incidence estimates, paying attention to the fundamental trade-off between bias and statistical error.ResultsWe summarise our detailed observations about incidence estimates, generated by various age smoothing or age disaggregation procedures, into a straightforward fully specified ‘one size fits most’ algorithm for processing the survey data into age-specific incidence estimates: 1) generalised linear regression to turn observations into ‘prevalence’ of ‘infection’ and ‘recent infection’ (logit, and complementary log log, link functions, respectively; fitting coefficients of up to cubic terms in age/time); 2) a ‘moving window’ data inclusion recipe which handles each age/time point of interest separately; 3) post hoc age averaging of resulting pseudo continuously fitted incidence; 4) bootstrapping as a generic variance/significance estimation procedure.ConclusionsAs far as we are aware, this is the first analysis of several fine details of how age structure in cross-sectional surveys interacts with recency-based incidence estimation. Our proposed default estimation procedure generates incidence estimates with negligible bias and near-optimal precision, and can be readily applied to complex survey data sets by any group in possession of such data. Our code is available, in part freely through the R computing platform, and in part upon request.

Use of HIV Recency Assays for HIV Incidence Estimation and Non-Incidence Surveillance Use Cases: A systematic review

ABSTRACTIntroductionHIV assays designed to detect recent infection, also known as “recency assays,” are often used to estimate HIV incidence in a specific country, region, or subpopulation, alone or as part of recent infection testing algorithms (RITAs). Recently, many countries and organizations have become interested in using recency assays within case surveillance systems and routine HIV testing services, and in measuring other indicators beyond incidence, generally referred to as “non-incidence surveillance use cases.”MethodsTo identify best methodological and field implementation practices for the use of recency assays to estimate HIV incidence and trends in recent infections for key populations or specific geographic areas, we undertook: 1) a global Call for Information released from WHO/UNAIDS; and 2) a systematic review of the literature to: (a) assess the field performance characteristics of commercially available recency assays, (b) understand the use of recency testing for surveillance in programmatic and laboratory settings, and (c) review methodologies for implementing recency testing for both incidence estimation and non-incidence use cases.Results and discussionAmong the 90 documents ultimately reviewed, 65 (88%) focused on assay/algorithm performance or methodological descriptions, with high-quality evidence of accurate age- and sex- disaggregated HIV incidence estimation at national or regional levels in general population settings, but not at finer geographic levels for prevention prioritization. The remaining 25 documents described field-derived incidence (n=14) and non-incidence (n=11) use cases, including integrating RITAs into routine surveillance and assisting with molecular genetic analyses, but evidence was generally weaker or only reported on what was done, without validation data or findings related to effectiveness of recency assays when used for these purposes.ConclusionsHIV recency assays have been widely validated for estimating HIV incidence in age- and sex-specific populations at national and sub-national regional levels; however, there was a lack of evidence validating the accuracy and effectiveness of using recency assays for non-incidence surveillance use cases. The evidence identified through this review will be used in forthcoming technical guidance on the use of HIV recency assays for surveillance use cases by WHO and UNAIDS; further evidence on methodologies and effectiveness of non-incidence use cases is needed.