Comparison of accuracy of HIV diagnosis between rapid HIV test kits conducted in non-laboratory settings and laboratory-based methods in South Africa

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Doctor of Philosophy Johannesburg, 2016Introduction South Africa has the largest absolute number of individuals living with human immuno-deficiency virus (HIV) in the world. The quality assurance (QA) of HIV rapid diagnostic tests (RDT) has not kept pace with the rate of expanded testing and utilisation of RDT. This has made it difficult to assess the accuracy of testing. In South Africa HIV counselling and testing (HCT) and the use of HIV RDT is the point of entry to HIV prevention, management, care, treatment and support. HCT in public health facilities is delivered mainly through rapid testing by nonprofessional staff. Implementation of QA processes is crucial for accurate diagnosis of HIV. However, accuracy of HCT using rapid test kits in non-laboratory settings in South Africa will remain a challenge unless there is evidence that nonlaboratory rapid HIV testing results are as reliable as the laboratory-based enzyme immunoassays. This study aimed to determine the accuracy of HIV RDT in the context of an intervention. The objectives of the study were: i. To assess the sensitivity and specificity of rapid test kits in two provinces; ii. To assess the sensitivity and specificity of rapid test kits between the two provinces and New Start nongovernmental organisation (NGO) which implemented a more comprehensive quality management system (QMS); iii. To assess the accuracy of HIV RDT in the two provinces; iv. To assess the accuracy of HIV RDT between the two provinces and New Start sites. The hypothesis was ‘the accuracy of HIV diagnosis using HIV RDT kits in nonlaboratory settings in which an intervention has been introduced (internal quality control), also known as IQC, will not be different compared to settings that do not utilize IQC’. Methods In South Africa, the current laboratory-based gold standard for diagnosis of HIV infection in adults in the public sector as recommended by the National Health Laboratory Services (NHLS) Virology expert committee is a serial 2-test algorithm. Thus, a reactive enzyme immunoassay (EIA) test result must be confirmed by a second confirmatory EIA that must be different in terms of antigens and technology. The Expert Committee recommendation is that positive results should be confirmed by a separate sample 14 days later. In the case of HIV rapid testing the national HIV counselling and testing (HCT) policy, 2010, similarly recommends a serial 2-test algorithm for diagnosis where a reactive screening test is confirmed by a different confirmatory test. If the confirmatory test is reactive the diagnosis is positive. If test 1 is non-reactive then the diagnosis is negative. In case of discrepant results an enzyme-linked immunosorbent assay (ELISA) test was recommended as a tiebreaker. A new HIV testing services (HTS) policy was approved in South Africa in 2016 and it further recommended that the first time discrepant results are found, the counsellor must repeat the algorithm and if on repeat, the results are still discrepant, then reflex testing is recommended where the blood (whole blood) of a client is taken to the laboratory for ELISA (NDOH, 2016).This algorithm has replaced the use of Western Blot is South Africa. The rationale for the change was based on the sensitivity and specificity of 3rd and 4th generation ELISAs, workload, costs and expertise. With the introduction of the 3rd and latterly 4th generation EIA tests the above algorithm is in use in South Africa and has replaced the use of the Western blot as a confirmatory test. The rationale for the change is based on earlier detection of HIV infection, workload, costs and expertise. Further developments for a diagnostic algorithm include the use of a fourth generation test and if reactive to use a HIV-1 and HIV-2 discriminatory test and HIV viral load. This study was cross-sectional and compared the performance of HIV RDT in selected sites in Limpopo province that had introduced an intervention viz., an internal quality control (IQC) as part of quality management system (QMS) implementation, and compared to Mpumalanga province that had not introduced the IQC and performed limited QMS activities. The sample size calculated for the study was N = 717. IQC is an independent internal quality control that is used to check that an analytical phase or test precision is optimal. The introduction of routine QMS in Limpopo was through implementation of IQC supported by appropriate training and certification of implementers. IQC was implemented routinely as part of the provincial QA initiatives with the aim of supporting the implementation of HIV RDT in non- laboratory settings. There are other QA measures that may be implemented to support HIV RDT programmes including external quality assessment (EQA) such as proficiency testing (PT) which is a tool used to assess the testing process independently. EQA implementation was however not part of the Limpopo (LP) QMS implementation. Six high volume testing sites comprising of 3 hospitals and 3 clinics were selected per province. This was to avoid the risk of not meeting the required number of participants due to refusals, lack of results and challenges with reporting. In order to mitigate risk, the study was oversampled, where a total of 457 participants from the LP sites were enrolled in the study and results were analysed and compared to those of 361 participants from the Mpumalanga (MP) sites resulting in a total sample size of 818. The analyses included demographics, performance of RT as measured by the number of discordant results, reliability and validity of rapid tests RT as measured by the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) results. The data between Limpopo and Mpumalanga were further analysed together with the data from selected sites from a non-governmental organisation (NGO) called New Start and the performance, reliability and validity of the HIV test results were compared. The main role of New Start was to offer HCT in support of the government priorities and it implemented several different QMS measures for HIV rapid testing, namely, IQC, EQA, PT and re-testing, training for implementers, development and implementation of standard operating procedures (SOPs), and ensuring that all commodities were stored under appropriate conditions including temperature monitoring. In order to determine the validity and reliability of HIV RDT against the gold standard ELISA in Limpopo, Mpumalanga and New Start sites, the rate of discordance, the sensitivity, specificity, PPV and NPV were determined. Logistic regression models were constructed to assess the association between the interventions in the provinces. Crude and adjusted odds ratios were used as a measure of association between exposure and outcome and a 95% precision of estimate was used to ascertain statistical significance. Exposure factors with p<0.05 were considered statistically significant. Results A total of 947 attendees for HCT services in selected sites in Mpumalanga and Limpopo provinces between August and April 2012, were screened and of these, 818 were enrolled into the study according to the study inclusion criteria. There was no significant difference (p=0.05) between the number of participants enrolled in Limpopo (457) as compared to Mpumalanga (361) though Limpopo enrolled more participants than Mpumalanga. All available data from New Start sites for the period 2008 was analysed. The gender, rate of discordance and HIV positivity rate were significantly different between the two provinces (p<0.05). The study showed that the laboratory-based HIV prevalence rate in each setting was 22.9% in Limpopo, 26% in Mpumalanga and 11% in New Start sites. The prevalence rates reported by Shisana, 2014, were 21.8% for Mpumalanga and 13.9% for Limpopo. The rate of discordant HIV test results between the 2 provinces and New Start sites was also measured where discordant results were defined as those that were different between HIV rapid test and the ELISA test. The rate of discordant HIV test results was 5.9% (27) in Limpopo, 11.0% (40) in Mpumalanga p= 0.010 and 1.4% (68) in New Start sites. False negative results accounted for all the discordant results. Logistic regression models were used to estimate the Odds Ratio (OR) and the 95% confidence interval of the association between implementation of QA programme and the HIV test accuracy or the HIV discordance rate. Facilities without a QA intervention programme had an approximately 2-fold increased odds of HIV test discordance compared to facilities with a QA programme in place (crude OR 1.86, 95% CI: 1.10 – 3.12 and adjusted OR 1.90, 95% CI:1.08 - 3.30). This association was statistically significant. The sex and age of the participants was not associated with discordance rate. The sensitivities of the HIV RDT in Limpopo, Mpumalanga and New Start sites were 86% (CI: 83.9-89.4), 72% (CI: 64.2-79.0) and 98% (CI: 97.6-98.4) respectively. In this study, specificity ranged within 99% (CI: 98.9-99.9) in all sites (Provinces and New Start sites). The PPV in Limpopo, Mpumalanga and New Start sites were 98% (CI: 93.2-99.6), 97% (CI: 91.0-99.2) and 93% (CI: 92.3-93.7) respectively, The NPV results in Limpopo were 93% (90.5-95.2), Mpumalanga at 86% (CI:81.3-90.7). For New Start sites, the NPV was 99.6% (CI: 99.4-99.8). The sensitivities and specificities of the sites were used at a national prevalence rate of 18.8% to determine the national PPV and NPV and these were found to be 100% (CI: 100-100) and 91.3% (CI: 89.04-92.96) respectively. Discussion In all three settings the World health Organisation (WHO) recommended sensitivity (>99%) and specificity (>98%) were not met. There was a gradient of sensitivities and specificities that was associated with the extent of QA implementation. Thus, New Start sites with a more extensive set of QA activities had the highest sensitivity; LP with introduction of IQC, had an intermediate sensitivity and MP the lowest. Despite the introduction of an intervention LP was not able to meet the required level of QA implementation compared to New Start. Increased discordance was associated with the extent of implementation of QA as shown by the results of the logistic regression model (crude and adjusted). In this study there was a decline in sensitivity that resulted in some false negative results. To a lesser extent, some false positive results were also identified in New Start sites. In the case of LP and MP the potential contributory factors to false negative results xi would include the extent of QA implementation and training. Further evidence of the relative poor implementation would include the M&E assessments and in the course of the study there lost results, poorly taken and missing specimens that led to data being excluded. Conclusion On the basis of these results, it is concluded that implementation of quality assurance measures is critical to ensure correct diagnosis of rapid HIV testing. Furthermore, implementation of a combination of aspects of QA is urgently required including training of all implementing staff on quality assurance of rapid HIV testing, monitoring and evaluation to assess kit performance through IQC and PT, as well as implementation of the current South African HIV testing Services (HTS) Policy. All PT methods should be explored for implementation and training and certification of implementers must be ensured.MT201

Geometric induction of bone formation

Student Number : 9501020M - M Sc dissertation - School of Clinical Medicine - Faculty of Health SciencesAn exciting and novel concept of tissue engineering and morphogenesis is the generation of bone by the implantation of smart biomaterials that in their own right can induce a desired and specific morphogenetic response from the host tissues without the addition of exogenously applied bone morphogenetic and osteogenic proteins

Provider-initiated counselling and testing (PICT): An overview

South Africa has the highest number of people living with HIV in the world. Despite this, many South Africans do not know their HIV status and uptake of voluntary counselling and testing (VCT) has been suboptimal. In clinical settings there are many missed opportunities for HIV diagnosis as most patients are not routinely offered HIV counselling and testing (HCT). Provider-initiated counselling and testing (PICT) has been introduced to ensure that HCT becomes the standard of care in all consultations with health providers. PICT promotes universal access to prevention, care and treatment services for all clients by increasing the utilisation and acceptance of HCT services. This article outlines the rationale for PICT as well providing an overview of the implementation protocol that will equip health care providers with the knowledge required to integrate HCT into routine medical care

The cost effectiveness and optimal configuration of HIV self-test distribution in South Africa: a model analysis.

BACKGROUND: HIV self-testing (HIVST) has been shown to be acceptable, feasible and effective in increasing HIV testing uptake. Novel testing strategies are critical to achieving the UNAIDS target of 95% HIV-positive diagnosis by 2025 in South Africa and globally. METHODS: We modelled the impact of six HIVST kit distribution modalities (community fixed-point, taxi ranks, workplace, partners of primary healthcare (PHC) antiretroviral therapy (ART) patients), partners of pregnant women, primary PHC distribution) in South Africa over 20 years (2020-2039), using data collected alongside the Self-Testing AfRica Initiative. We modelled two annual distribution scenarios: (A) 1 million HIVST kits (current) or (B) up to 6.7 million kits. Incremental economic costs (2019 US$) were estimated from the provider perspective; assumptions on uptake and screening positivity were based on surveys of a subset of kit recipients and modelled using the Thembisa model. Cost-effectiveness of each distribution modality compared with the status-quo distribution configuration was estimated as cost per life year saved (estimated from life years lost due to AIDS) and optimised using a fractional factorial design. RESULTS: The largest impact resulted from secondary HIVST distribution to partners of ART patients at PHC (life years saved (LYS): 119 000 (scenario A); 393 000 (scenario B)). However, it was one of the least cost-effective modalities (A:$1394/LYS; B: $4162/LYS). Workplace distribution was cost-saving ($52-$76 million) and predicted to have a moderate epidemic impact (A: 40 000 LYS; B: 156 000 LYS). An optimised scale-up to 6.7 million tests would result in an almost threefold increase in LYS compared with a scale-up of status-quo distribution (216 000 vs 75 000 LYS). CONCLUSION: Optimisation-informed distribution has the potential to vastly improve the impact of HIVST. Using this approach, HIVST can play a key role in improving the long-term health impact of investment in HIVST

Southern African HIV Clinicians Society 2022 guideline for the management of sexually transmitted infections : moving towards best practice

Sexually transmitted infections (STIs) are among the most common acute conditions worldwide with sub-Saharan Africa ranking among the regions with the highest burdens globally. Adolescent girls and young women (AGYW), people living with HIV (PLHIV), pregnant women, and key and vulnerable populations are disproportionally affected by STIs. The social determinants of health, gender inequality, and STI-associated stigma and discrimination (at both the community and facility level) are important contributors to the sustained high burden of infection.http://www.sajhivmed.org.za/index.php/hivmeddm2022Medical Microbiolog

The cost and intermediary cost-effectiveness of oral HIV self-test kit distribution across 11 distribution models in South Africa.

BACKGROUND: Countries around the world seek innovative ways of closing their remaining gaps towards the target of 95% of people living with HIV (PLHIV) knowing their status by 2030. Offering kits allowing HIV self-testing (HIVST) in private might help close these gaps. METHODS: We analysed the cost, use and linkage to onward care of 11 HIVST kit distribution models alongside the Self-Testing AfRica Initiative's distribution of 2.2 million HIVST kits in South Africa in 2018/2019. Outcomes were based on telephonic surveys of 4% of recipients; costs on a combination of micro-costing, time-and-motion and expenditure analysis. Costs were calculated from the provider perspective in 2019 US$, as incremental costs in integrated and full costs in standalone models. RESULTS: HIV positivity among kit recipients was 4$4.87 (sex worker model) and $18.07 (mobile integration model), with differences largely driven by kit volumes. HIVST kit costs (at$2.88 per kit) and personnel costs were the largest cost items throughout. Average costs per outcome increased along the care cascade, with the sex worker network model being the most cost-effective model across metrics used (cost per kit distributed/recipient screening positive/confirmed positive/initiating ART). Cost per person confirmed positive for HIVST was higher than standard HIV testing. CONCLUSION: HIV self-test distribution models in South Africa varied widely along four characteristics: distribution volume, HIV positivity, linkage to care and cost. Volume was highest in models that targeted public spaces with high footfall (flexible community, fixed point and transport hub distribution), followed by workplace models. Transport hub, workplace and sex worker models distributed kits in the least costly way. Distribution via index cases at facility as well as sex worker network distribution identified the highest number of PLHIV at lowest cost

Optimizing HIV retesting during pregnancy and postpartum in four countries: a cost-effectiveness analysis.

INTRODUCTION: HIV retesting during late pregnancy and breastfeeding can help detect new maternal infections and prevent mother-to-child HIV transmission (MTCT), but the optimal timing and cost-effectiveness of maternal retesting remain uncertain. METHODS: We constructed deterministic models to assess the health and economic impact of maternal HIV retesting on a hypothetical population of pregnant women, following initial testing in pregnancy, on MTCT in four countries: South Africa and Kenya (high/intermediate HIV prevalence), and Colombia and Ukraine (low HIV prevalence). We evaluated six scenarios with varying retesting frequencies from late in antenatal care (ANC) through nine months postpartum. We compared strategies using incremental cost-effectiveness ratios (ICERs) over a 20-year time horizon using country-specific thresholds. RESULTS: We found maternal retesting once in late ANC with catch-up testing through six weeks postpartum was cost-effective in Kenya (ICER = $166 per DALY averted) and South Africa (ICER=$289 per DALY averted). This strategy prevented 19% (Kenya) and 12% (South Africa) of infant HIV infections. Adding one or two additional retests postpartum provided smaller benefits (1 to 2 percentage point increase in infections averted versus one retest). Adding three retests during the postpartum period averted additional infections (1 to 3 percentage point increase in infections averted versus one retest) but ICERs ($7639 and in Kenya and$11 985 in South Africa) greatly exceeded the cost-effectiveness thresholds. In Colombia and Ukraine, all retesting strategies exceeded the cost-effectiveness threshold and prevented few infant infections (up to 31 and 5 infections, respectively). CONCLUSIONS: In high HIV burden settings with MTCT rates similar to those seen in Kenya and South Africa, HIV retesting once in late ANC, with subsequent intervention, is the most cost-effective strategy for preventing infant HIV infections. In these settings, two HIV retests postpartum marginally reduced MTCT and were less costly than adding three retests. Retesting in low-burden settings with MTCT rates similar to Colombia and Ukraine was not cost-effective at any time point due to very low HIV prevalence and limited breastfeeding

Cost-effectiveness of dual maternal HIV and syphilis testing strategies in high and low HIV prevalence countries: a modelling study.

BACKGROUND: Dual HIV and syphilis testing might help to prevent mother-to-child transmission (MTCT) of HIV and syphilis through increased case detection and treatment. We aimed to model and assess the cost-effectiveness of dual testing during antenatal care in four countries with varying HIV and syphilis prevalence. METHODS: In this modelling study, we developed Markov models of HIV and syphilis in pregnant women to estimate costs and infant health outcomes of maternal testing at the first antenatal care visit with individual HIV and syphilis tests (base case) and at the first antenatal care visit with a dual rapid diagnostic test (scenario one). We additionally evaluated retesting during late antenatal care and at delivery with either individual tests (scenario two) or a dual rapid diagnosis test (scenario three). We modelled four countries: South Africa, Kenya, Colombia, and Ukraine. Strategies with an incremental cost-effectiveness ratio (ICER) less than the country-specific cost-effectiveness threshold (US$500 in Kenya,$750 in South Africa, $3000 in Colombia, and$1000 in Ukraine) per disability-adjusted life-year averted were considered cost-effective. FINDINGS: Routinely offering testing at the first antenatal care visit with a dual rapid diagnosis test was cost-saving compared with the base case in all four countries (ICER: -$26 in Kenya,-$559 in South Africa, -$844 in Colombia, and -$454 in Ukraine). Retesting during late antenatal care with a dual rapid diagnostic test (scenario three) was cost-effective compared with scenario one in all four countries (ICER: $270 in Kenya,$260 in South Africa, $2207 in Colombia, and$205 in Ukraine). INTERPRETATION: Incorporating dual rapid diagnostic tests in antenatal care can be cost-saving across countries with varying HIV prevalence. Countries should consider incorporating dual HIV and syphilis rapid diagnostic tests as the first test in antenatal care to support efforts to eliminate MTCT of HIV and syphilis. FUNDING: WHO, US Agency for International Development, and the Bill & Melinda Gates Foundation

Cost-effectiveness of voluntary medical male circumcision for HIV prevention across sub-Saharan Africa : results from five independent models

BACKGROUND: Voluntary medical male circumcision (VMMC) has been a recommended HIV prevention strategy in sub-Saharan Africa since 2007, particularly in countries with high HIV prevalence. However, given the scale-up of antiretroviral therapy programmes, it is not clear whether VMMC still represents a cost-effective use of scarce HIV programme resources. METHODS: Using five existing well described HIV mathematical models, we compared continuation of VMMC for 5 years in men aged 15 years and older to no further VMMC in South Africa, Malawi, and Zimbabwe and across a range of setting scenarios in sub-Saharan Africa. Outputs were based on a 50-year time horizon, VMMC cost was assumed to be US$90, and a cost-effectiveness threshold of US$500 was used. FINDINGS: In South Africa and Malawi, the continuation of VMMC for 5 years resulted in cost savings and health benefits (infections and disability-adjusted life-years averted) according to all models. Of the two models modelling Zimbabwe, the continuation of VMMC for 5 years resulted in cost savings and health benefits by one model but was not as cost-effective according to the other model. Continuation of VMMC was cost-effective in 68% of setting scenarios across sub-Saharan Africa. VMMC was more likely to be cost-effective in modelled settings with higher HIV incidence; VMMC was cost-effective in 62% of settings with HIV incidence of less than 0·1 per 100 person-years in men aged 15-49 years, increasing to 95% with HIV incidence greater than 1·0 per 100 person-years. INTERPRETATION: VMMC remains a cost-effective, often cost-saving, prevention intervention in sub-Saharan Africa for at least the next 5 years. FUNDING: Bill & Melinda Gates Foundation for the HIV Modelling Consortium

Cost-effectiveness of easy-access, risk-informed oral pre-exposure prophylaxis in HIV epidemics in sub-Saharan Africa: a modelling study.

BACKGROUND: Approaches that allow easy access to pre-exposure prophylaxis (PrEP), such as over-the-counter provision at pharmacies, could facilitate risk-informed PrEP use and lead to lower HIV incidence, but their cost-effectiveness is unknown. We aimed to evaluate conditions under which risk-informed PrEP use is cost-effective. METHODS: We applied a mathematical model of HIV transmission to simulate 3000 setting-scenarios reflecting a range of epidemiological characteristics of communities in sub-Saharan Africa. The prevalence of HIV viral load greater than 1000 copies per mL among all adults (HIV positive and negative) varied from 1·1% to 7·4% (90% range). We hypothesised that if PrEP was made easily available without restriction and with education regarding its use, women and men would use PrEP, with sufficient daily adherence, during so-called seasons of risk (ie, periods in which individuals are at risk of acquiring infection). We refer to this as risk-informed PrEP. For each setting-scenario, we considered the situation in mid-2021 and performed a pairwise comparison of the outcomes of two policies: immediate PrEP scale-up and then continuation for 50 years, and no PrEP. We estimated the relationship between epidemic and programme characteristics and cost-effectiveness of PrEP availability to all during seasons of risk. For our base-case analysis, we assumed a 3-monthly PrEP cost of US$29 (drug$11, HIV test $4, and$14 for additional costs necessary to facilitate education and access), a cost-effectiveness threshold of $500 per disability-adjusted life-year (DALY) averted, an annual discount rate of 3$100 per DALY averted, a discount rate of 7% per annum, the use of PrEP outside of seasons of risk, and reduced uptake of risk-informed PrEP. FINDINGS: In the context of PrEP scale-up such that 66% (90% range across setting-scenarios 46-81) of HIV-negative people with at least one non-primary condomless sex partner take PrEP in any given period, resulting in 2·6% (0·9-6·0) of all HIV negative adults taking PrEP at any given time, risk-informed PrEP was predicted to reduce HIV incidence by 49% (23-78) over 50 years compared with no PrEP. PrEP was cost-effective in 71% of all setting-scenarios, and cost-effective in 76% of setting-scenarios with prevalence of HIV viral load greater than 1000 copies per mL among all adults higher than 2%. In sensitivity analyses with a $100 per DALY averted cost-effectiveness threshold, a 7% per year discount rate, or with PrEP use that was less well risk-informed than in our base case, PrEP was less likely to be cost-effective, but generally remained cost-effective if the prevalence of HIV viral load greater than 1000 copies per mL among all adults was higher than 3%. In sensitivity analyses based on additional setting-scenarios in which risk-informed PrEP was less extensively used, the HIV incidence reduction was smaller, but the cost-effectiveness of risk-informed PrEP was undiminished. INTERPRETATION: Under the assumption that making PrEP easily accessible for all adults in sub-Saharan Africa in the context of community education leads to risk-informed use, PrEP is likely to be cost-effective in settings with prevalence of HIV viral load greater than 1000 copies per mL among all adults higher than 2%, suggesting the need for implementation of such approaches, with ongoing evaluation. FUNDING: US Agency for International Development, US President's Emergency Plan for AIDS Relief, and Bill & Melinda Gates Foundation