Towards more accurate HIV testing in sub‐Saharan Africa: a multi‐site evaluation of HIV RDTs and risk factors for false positives

Introduction : Although individual HIV rapid diagnostic tests (RDTs) show good performance in evaluations conducted by WHO, reports from several African countries highlight potentially significant performance issues. Despite widespread use of RDTs for HIV diagnosis in resource‐constrained settings, there has been no systematic, head‐to‐head evaluation of their accuracy with specimens from diverse settings across sub‐Saharan Africa. We conducted a standardized, centralized evaluation of eight HIV RDTs and two simple confirmatory assays at a WHO collaborating centre for evaluation of HIV diagnostics using specimens from six sites in five sub‐Saharan African countries. Methods : Specimens were transported to the Institute of Tropical Medicine (ITM), Antwerp, Belgium for testing. The tests were evaluated by comparing their results to a state‐of‐the‐art reference algorithm to estimate sensitivity, specificity and predictive values. Results : 2785 samples collected from August 2011 to January 2015 were tested at ITM. All RDTs showed very high sensitivity, from 98.8% for First Response HIV Card Test 1–2.0 to 100% for Determine HIV 1/2, Genie Fast, SD Bioline HIV 1/2 3.0 and INSTI HIV‐1/HIV‐2 Antibody Test kit. Specificity ranged from 90.4% for First Response to 99.7% for HIV 1/2 STAT‐PAK with wide variation based on the geographical origin of specimens. Multivariate analysis showed several factors were associated with false‐positive results, including gender, provider‐initiated testing and the geographical origin of specimens. For simple confirmatory assays, the total sensitivity and specificity was 100% and 98.8% for ImmunoComb II HIV 12 CombFirm (ImmunoComb) and 99.7% and 98.4% for Geenius HIV 1/2 with indeterminate rates of 8.9% and 9.4%. Conclusions : In this first systematic head‐to‐head evaluation of the most widely used RDTs, individual RDTs performed more poorly than in the WHO evaluations: only one test met the recommended thresholds for RDTs of ≥99% sensitivity and ≥98% specificity. By performing all tests in a centralized setting, we show that these differences in performance cannot be attributed to study procedure, end‐user variation, storage conditions, or other methodological factors. These results highlight the existence of geographical and population differences in individual HIV RDT performance and underscore the challenges of designing locally validated algorithms that meet the latest WHO‐recommended thresholds.     

A Commitment to HIV Diagnostic Accuracy – a comment on “Towards more accurate HIV testing in sub‐Saharan Africa: a multi‐site evaluation of HIV RDTs and risk factors for false positives” and “HIV misdiagnosis in sub‐Saharan Africa: a performance of diagnostic algorithms at six testing sites”

As part of the global response to the HIV/AIDS epidemic, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) is committed to the provision of high‐quality services and ensuring testing accuracy. Two recently published papers focusing on HIV testing and misdiagnosis in sub‐Saharan Africa by Kosack et al. report on evaluations of HIV rapid diagnostic tests (RDTs) and found lower than expected specificity and sensitivity on some tests when used in certain geographic locations. The magnitude of PEPFAR's global HIV response has been possible due to the extensive use of RDTs, which have made HIV diagnosis accessible all over the world. We take the opportunity to address concerns raised about the potential implications that these findings could have on real‐world HIV testing accuracy. PEPFAR supported countries adhere to the normative guidance by World Health Organization (WHO) supporting algorithms which require sequential positive tests for diagnostic accuracy. An analysis of Médecins Sans Frontières (MSF) RDT site‐specific data applied to PEPFAR in‐country protocols demonstrate a variation in the diagnostic accuracy of the testing algorithms, but with a very small population‐level effect. The data demonstrate, with the use of these algorithms, that the RDT outcomes found in the study by Kosack et al. would be largely mitigated and would not be expected to have a significant impact on diagnostic accuracy and overall programming in most countries. Avoiding any misdiagnosis is a priority for PEPFAR, and it remains vital to gain a deeper understanding of the causes and the extent of diagnostic errors and any misclassification. Extensive quality control mechanisms and continued research are essential. With a focus on epidemic control and ensuring diagnostic accuracy, PEPFAR recommends that all countries use WHO pre‐qualified RDTs within the recommended strategies and algorithms for HIV testing. We also support validation of HIV testing algorithms using in‐country specimens to determine optimal performance, and the reverification testing of all people diagnosed with HIV prior to starting treatment as an essential quality assurance measure.     

Comparative assessment of five trials of universal HIV testing and treatment in sub‐Saharan Africa

Design

Universal voluntary HIV counselling and testing followed by prompt initiation of antiretroviral therapy (ART) for all those diagnosed HIV‐infected (universal test and treat, UTT) is now a global health standard. However, its population‐level impact, feasibility and cost remain unknown. Five community‐based trials have been implemented in sub‐Saharan Africa to measure the effects of various UTT strategies at population level: BCPP/YaTsie in Botswana, MaxART in Swaziland, HPTN 071 (PopART) in South Africa and Zambia, SEARCH in Uganda and Kenya and ANRS 12249 TasP in South Africa. This report describes and contrasts the contexts, research methodologies, intervention packages, themes explored, evolution of study designs and interventions related to each of these five UTT trials.

Methods

We conducted a comparative assessment of the five trials using data extracted from study protocols and collected during baseline studies, with additional input from study investigators. We organized differences and commonalities across the trials in five categories: trial contexts, research designs, intervention packages, trial themes and adaptations.

Results

All performed in the context of generalized HIV epidemics, the trials highly differ in their social, demographic, economic, political and health systems settings. They share the common aim of assessing the impact of UTT on the HIV epidemic but differ in methodological aspects such as study design and eligibility criteria for trial populations. In addition to universal ART initiation, the trials deliver a wide range of biomedical, behavioural and structural interventions as part of their UTT strategies. The five studies explore common issues, including the uptake rates of the trial services and individual health outcomes. All trials have adapted since their initiation to the evolving political, economic and public health contexts, including adopting the successive national recommendations for ART initiation.

Conclusions

We found substantial commonalities but also differences between the five UTT trials in their design, conduct and multidisciplinary outputs. As empirical literature on how UTT may improve efficiency and quality of HIV care at population level is still scarce, this article provides a foundation for more collaborative research on UTT and supports evidence‐based decision making for HIV care in country and internationally.

     

Scaling a waterfall: a meta‐ethnography of adolescent progression through the stages of HIV care in sub‐Saharan Africa

Introduction : Observational studies have shown considerable attrition among adolescents living with HIV across the “cascade” of HIV care in sub‐Saharan Africa, leading to higher mortality rates compared to HIV‐infected adults or children. We synthesized evidence from qualitative studies on factors that promote or undermine engagement with HIV services among adolescents living with HIV in sub‐Saharan Africa. Methods : We systematically searched five databases for studies published between 2005 and 2016 that met pre‐defined inclusion criteria. We used a meta‐ethnographic approach to identify first, second and third order constructs from eligible studies, and applied a socio‐ecological framework to situate our results across different levels of influence, and in relation to each stage of the HIV cascade. Results and discussion : We identified 3089 citations, of which 24 articles were eligible for inclusion. Of these, 17 were from Southern Africa while 11 were from Eastern Africa. 6 explored issues related to HIV testing, 11 explored treatment adherence, and 7 covered multiple stages of the cascade. Twelve third‐order constructs emerged to explain adolescents' engagement in HIV care. Stigma was the most salient factor impeding adolescents' interactions with HIV care over the past decade. Self‐efficacy to adapt to life with HIV and support from family or social networks were critical enablers supporting uptake and retention in HIV care and treatment programmes. Provision of adolescent‐friendly services and health systems issues, such as the availability of efficient, confidential and comfortable services, were also reported to drive sustained care engagement. Individual‐level factors, including past illness experiences, identifying mechanisms to manage pill‐taking in social situations, financial (in)stability and the presence/absence of future aspirations also shaped adolescents HIV care engagement. Conclusions : Adolescents' initial and ongoing use of HIV care was frequently undermined by individual‐level issues; although family, community and health systems factors played important roles. Interventions should prioritise addressing psychosocial issues among adolescents to promote individual‐level engagement with HIV care, and ultimately reduce mortality. Further research should explore issues relating to care linkage and ART initiation in different settings, particularly as “test and treat” policies are scaled up.     

Reviewing independent access to HIV testing,counselling and treatment for adolescents in HIV‐specific laws in sub‐Saharan Africa: implications for the HIV response

Introduction : AIDS is a leading cause of death among adolescents in sub‐Saharan Africa. Yet, legal, policy and social barriers continue to restrict their access to HIV services. In recent years, access to independent HIV testing and treatment for adolescents has gained increased attention. The 2013 WHO Guidance on HIV testing and counselling and care for adolescents living with HIV (WHO Guidance) calls for reviewing legal and regulatory frameworks to facilitate adolescents’ access to comprehensive HIV services. As of 31 March 2017, some 28 countries in sub‐Saharan Africa have adopted HIV‐specific legislation. But there is limited understanding of the provisions of these laws on access to HIV services for adolescents and their implication on efforts to scale up HIV prevention, testing, treatment and care among this population. Methods : A desk review of 28 HIV‐specific laws in sub‐Saharan Africa complemented with the review of HIV testing policies in four countries using human rights norms and key public health recommendations from the 2013 WHO Guidance. These recommendations call on countries to (i) lower the age of consent to HIV testing and counselling and allow mature adolescents who have not reached the age of consent to independently access HIV testing, (ii) ensure access to HIV counselling for adolescents, (iii) protect the confidentiality of adolescents living with HIV and (iv) facilitate access to HIV treatment for adolescents living with HIV. Results : Most HIV‐specific laws fail to take into account human rights principles and public health recommendations for facilitating adolescents’ access to HIV services. None of the countries with HIV‐specific laws has adopted all four recommendations for access to HIV services for adolescents. Discrepancies exist between HIV laws and national policy documents. Inadequate and conflicting provisions in HIV laws are likely to hinder access to HIV testing, counselling and treatment for adolescents. Conclusions : Efforts to end legal barriers to access to HIV services for adolescents in sub‐Saharan Africa should address HIV‐specific laws. Restrictive provisions in these laws should be reformed, and their protective norms effectively implemented including by translating them into national policies and ensuring sensitization and training of healthcare workers and communities. This study reiterates the need for action in all countries across Africa and beyond to review their laws and policies to create an enabling environment to accelerate access to HIV prevention, testing and treatment services for adolescents.     

Declining HIV incidence in sub‐Saharan Africa: a systematic review and meta‐analysis of empiric data

IntroductionUNAIDS models suggest HIV incidence is declining in sub‐Saharan Africa. The objective of this study was to assess whether modelled trends are supported by empirical evidence.MethodsWe conducted a systematic review and meta‐analysis of adult HIV incidence data from sub‐Saharan Africa by searching Embase, Scopus, PubMed and OVID databases and technical reports published between 1 January 2010 and 23 July 2019. We included prospective and cross‐sectional studies that directly measured incidence from blood samples. Incidence data were abstracted according to population risk group, geographic location, sex, intervention arm and calendar period. Weighted regression models were used to assess incidence trends across general population studies by sex. We also identified studies reporting greater than or equal to three incidence measurements since 2010 and assessed trends within them.ResultsTotal 291 studies, including 22 sub‐Saharan African countries, met inclusion criteria. Most studies were conducted in South Africa (n = 102), Uganda (n = 46) and Kenya (n = 41); there were 26 countries with no published incidence data, most in western and central Africa. Data were most commonly derived from prospective observational studies (n = 163; 56%) and from geographically defined populations with limited demographic or risk‐based enrolment criteria other than age (i.e., general population studies; n = 151; 52%). Across general population studies, average annual incidence declines since 2010 were 0.12/100 person‐years (95% CI: 0.06–0.18; p = 0.001) among men and 0.10/100 person‐years (95% CI: −0.02–0.22; p = 0.093) among women in eastern Africa, and 0.25/100 person‐years (95% CI: 0.17–034; p < 0.0001) among men and 0.42/100 person‐years (95% CI: 0.23–0.62; p = 0.0002) among women in southern Africa. In nine of 10 studies with multiple measurements, incidence declined over time, including in two studies of key populations. Across all population risk groups, the highest HIV incidence estimates were observed among men who have sex with men, with rates ranging from 1.0 to 15.4/100 person‐years. Within general population studies, incidence was typically higher in women than men with a median female‐to‐male incidence rate ratio of 1.47 (IQR: 1.11 to 1.83) with evidence of a growing sex disparity over time.ConclusionsEmpirical incidence data show the rate of new HIV infections is declining in eastern and southern Africa. However, recent incidence data are non‐existent or very limited for many countries and key populations.     

Adherence to antiretroviral therapy for HIV in sub‐Saharan Africa and Asia: a comparative analysis of two regional cohorts

Introduction : Our understanding of how to achieve optimal long‐term adherence to antiretroviral therapy (ART) in settings where the burden of HIV disease is highest remains limited. We compared levels and determinants of adherence over time between HIV‐positive persons receiving ART who were enrolled in a bi‐regional cohort in sub‐Saharan Africa and Asia. Methods : This multicentre prospective study of adults starting first‐line ART assessed patient‐reported adherence at follow‐up clinic visits using a 30‐day visual analogue scale. Determinants of suboptimal adherence (<95%) were assessed for six‐month intervals, using generalized estimating equations multivariable logistic regression with multiple imputations. Region of residence (Africa vs. Asia) was assessed as a potential effect modifier. Results : Of 13,001 adherence assessments in 3934 participants during the first 24 months of ART, 6.4% (837) were suboptimal, with 7.3% (619/8484) in the African cohort versus 4.8% (218/4517) in the Asian cohort (p < 0.001). In the African cohort, determinants of suboptimal adherence were male sex (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.06–1.53; p = 0.009), younger age (OR 0.8 per 10 year increase; 0.8–0.9; p = 0.003), use of concomitant medication (OR 1.8, 1.0–3.2; p = 0.044) and attending a public facility (OR 1.3, 95% CI 1.1–1.7; p = 0.004). In the Asian cohort, adherence was higher in men who have sex with men (OR for suboptimal adherence 0.6, 95% CI 0.4–0.9; p = 0.029) and lower in injecting drug users (OR for suboptimal adherence 1.6, 95% CI 0.9–2.6; p = 0.075), compared to heterosexuals. Risk of suboptimal adherence decreased with longer ART duration in both regions. Participants in low‐ and lower‐middle‐income countries had a higher risk of suboptimal adherence (OR 1.6, 1.3–2.0; p < 0.001), compared to those in upper‐middle or high‐income countries. Suboptimal adherence was strongly associated with virological failure, in Africa (OR 5.8, 95% CI 4.3–7.7; p < 0.001) and Asia (OR 9.0, 95% CI 5.0–16.2; p < 0.001). Patient‐reported adherence barriers among African participants included scheduling demands, drug stockouts, forgetfulness, sickness or adverse events, stigma or depression, regimen complexity and pill burden. Conclusions : Psychosocial factors and health system resources may explain regional differences. Adherence‐enhancing interventions should address patient‐reported barriers tailored to local settings, prioritizing the first years of ART.     

Male circumcision for HIV prevention: current evidence and implementation in sub‐Saharan Africa

Heterosexual exposure accounts for most HIV transmission in sub‐Saharan Africa, and this mode, as a proportion of new infections, is escalating globally. The scientific evidence accumulated over more than 20 years shows that among the strategies advocated during this period for HIV prevention, male circumcision is one of, if not, the most efficacious epidemiologically, as well as cost‐wise. Despite this, and recommendation of the procedure by global policy makers, national implementation has been slow. Additionally, some are not convinced of the protective effect of male circumcision and there are also reports, unsupported by evidence, that non‐sex‐related drivers play a major role in HIV transmission in sub‐Saharan Africa. Here, we provide a critical evaluation of the state of the current evidence for male circumcision in reducing HIV infection in light of established transmission drivers, provide an update on programmes now in place in this region, and explain why policies based on established scientific evidence should be prioritized. We conclude that the evidence supports the need to accelerate the implementation of medical male circumcision programmes for HIV prevention in generalized heterosexual epidemics, as well as in countering the growing heterosexual transmission in countries where HIV prevalence is presently low.     

Examining the effects of HIV self‐testing compared to standard HIV testing services: a systematic review and meta‐analysis

Introduction : HIV self‐testing (HIVST) is a discreet and convenient way to reach people with HIV who do not know their status, including many who may not otherwise test. To inform World Health Organization (WHO) guidance, we assessed the effect of HIVST on uptake and frequency of testing, as well as identification of HIV‐positive persons, linkage to care, social harm, and risk behaviour. Methods : We systematically searched for studies comparing HIVST to standard HIV testing until 1 June 2016. Meta‐analyses of studies reporting comparable outcomes were conducted using a random‐effects model for relative risks (RR) and 95% confidence intervals. The quality of evidence was evaluated using GRADE. Results : After screening 638 citations, we identified five randomized controlled trials (RCTs) comparing HIVST to standard HIV testing services among 4,145 total participants from four countries. All offered free oral‐fluid rapid tests for HIVST and were among men. Meta‐analysis of three RCTs showed HIVST doubled uptake of testing among men (RR = 2.12; 95% CI: 1.51, 2.98). Meta‐analysis of two RCTs among men who have sex with men showed frequency of testing nearly doubled (Rate ratio = 1.88; 95% CI: 1.17; 3.01), resulting in two more tests in a 12–15‐month period (Mean difference = 2.13; 95% CI: 1.59, 2.66). Meta‐analysis of two RCTs showed HIVST also doubled the likelihood of an HIV‐positive diagnosis (RR = 2.02; 95% CI: 0.37, 10.76, 5.32). Across all RCTs, there was no indication of harm attributable to HIVST and potential increases in risk‐taking behaviour appeared to be minimal. Conclusions : HIVST is associated with increased uptake and frequency of testing in RCTs. Such increases, particularly among those at risk who may not otherwise test, will likely identify more HIV‐positive individuals as compared to standard testing services alone. However, further research on how to support linkage to confirmatory testing, prevention, treatment and care services is needed. WHO now recommends HIVST as an additional HIV testing approach.