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BackgroundDried plasma spot specimens may be a viable alternative to traditional liquid plasma in field settings, but the diagnostic accuracy is not well understood.MethodsStandard databases (PubMed and Medline), conferences, and gray literature were searched until January 2019. The quality of evidence was evaluated using the Standards for Reporting Studies of Diagnostic Accuracy and Quality Assessment of Diagnostic Accuracy Studies-2 criteria. We used univariate and bivariate random effects models to determine misclassification, sensitivity, and specificity across multiple thresholds, overall and for each viral load technology, and to account for between-study variation.ResultsWe identified 23 studies for inclusion in the systematic review that compared the diagnostic accuracy of dried plasma spots with that of plasma. Primary data from 16 of the 23 studies were shared and included in the meta-analysis, representing 18 countries, totaling 1847 paired dried plasma spot:plasma data points. The mean bias of dried plasma spot specimens compared with that of plasma was 0.28 log10 copies/mL, whereas the difference in median viral load was 2.25 log10 copies/mL. More dried plasma spot values were undetectable compared with plasma values (43.6% vs. 29.8%). Analyzing all technologies together, the sensitivity and specificity of dried plasma spot specimens were >92% across all treatment failure thresholds compared and total misclassification

Overview One of the main challenges in an emerging pathogen outbreak is the availability of and access to reliable laboratory diagnostic tests for timely and accurate confirmation of the disease [...]

1 | INTRODUCTION Gaps remain in coverage of early infant diagnosis (EID) of HIV (estimated at 60% globally in 2019) [1], and delays in result delivery can lead to loss-to-follow-up [...], Introduction: Point-of-care (POC) early infant diagnosis (EID) testing has been shown to dramatically decrease turnaround times from sample collection to caregiver result receipt and time to ART initiation for HIV-positive infants compared to centralized laboratory testing. As governments in sub-Saharan Africa implement POC EID technologies, we report on the feasibility and effectiveness of POC EID testing and the impact of same-day result delivery on rapid ART initiation within nationa programmes across six countries. Methods: This pre-/post-evaluation compared centralized laboratory-based (pre) with POC (post) EID testing in 52 facilities across Cameroon, Democratic Republic of Congo, Ethiopia, Kenya, Senegal and Zimbabwe between April 2017 and October 2019 (country-dependent). Data were collected retrospectively from routine records at health facilities for all infants tested under two years of age. Hazard ratios and 95% confidence intervals were calculated to compare time-to-event outcomes, visualized with Kaplan--Meier curves, and the Somers' D test was used to compare continuous outcomes. Results: Data were collected for 2892 EID tests conducted on centralized laboratory-based platforms and 4610 EID tests on POC devices with 127 (4%) and 192 (4%) HIV-positive infants identified, respectively. POC EID significantly reduced the time from sample collection to caregiver result receipt (POC median: 0 days, IQR: 0 to 0 vs. centralized: 35 days, IQR: 26 to 56) and time from sample collection to ART initiation for HIV-positive infants (POC median: 1 day, IQR: 0 to 7 vs. centralized: 39 days, IQR: 26 to 57). With POC testing, 72% of infants received results on the same day as sample collection; HIV-positive infants with a same-day diagnosis had six times the rate of ART initiation compared to those diagnosed one or more days after sample collection (HR: 6.39; 95% CI: 3.44 to 11.85). Conclusions: Same-day diagnosis and treatment initiation for infants is possible with POC EID within routine government-led and -supported public sector healthcare facilities in resource-limited settings. Given that POC EID allows for rapid ART initiation, aligning to the World Health Organization's recommendation of ART initiation within seven days, its use in public sector programmes has the potential to reduce overall mortality for infants with HIV through early treatment initiation. Keywords: point of care; early infant diagnosis; Africa; ART initiation; turnaround times

1 | INTRODUCTION HIV viral load (VL) monitoring is recommended by the World Health Organization (WHO) to confirm viral suppression and to take action if a patient has an elevated [...], Introduction: In many low- and middle-income countries, HIV viral load (VL) testing occurs at centralized laboratories and time-to-result-delivery is lengthy, preventing timely monitoring of HIV treatment adherence. Near point-of-care (POC) devices, which are placed within health facility laboratories rather than clinics themselves (i.e. "true" POC), can offer VL in conjunction with centralized laboratories to expedite clinical decision making and improve outcomes, especially for patients at high risk of treatment failure. We assessed impacts of near-POC VL testing on result receipt and clinical action in public sector programmes in Cameroon, Democratic Republic of Congo, Kenya, Malawi, Senegal, Tanzania and Zimbabwe. Methods: Routine health data were collected retrospectively after introducing near-POC VL testing at 57 public sector health facilities (2017 to 2019, country-dependent). Where possible, key indicators were compared to data from patients receiving centralized laboratory testing using hazard ratios and the Somers' D test. Results: Data were collected from 6795 tests conducted on near-POC and 17614 tests on centralized laboratory-based platforms. Thirty-one percent (2062/6694) of near-POC tests were conducted for high-risk populations: pregnant and breastfeeding women, children and those with suspected failure. Compared to conventional testing, near-POC improved the median time from sample collection to return of results to patient [six vs. sixty-eight days, effect size: -32.2%; 95% CI: -41.0% to -23.4%] and to clinical action for individuals with an elevated HIV VL [three vs. fourty-nine days, effect size: -35.4%; 95% CI: -46.0% to -24.8%]. Near-POC VL results were two times more likely to be returned to the patient within 90 days compared to centralized tests [50% (1781/3594) vs. 27% (4172/15271); aHR: 2.22, 95% CI: 2.05 to 2.39]. Thirty-seven percent (340/925) of patients with an elevated near-POC HIV VL result had documented clinical follow-up actions within 30 days compared to 7% (167/2276) for centralized testing. Conclusions: Near-POC VL testing enabled rapid test result delivery for high-risk populations and led to significant improvements in the timeliness of patient result receipt compared to centralized testing. While there was some improvement in time-to-clinical action with near-POC VL testing, major gaps remained. Strengthening of systems supporting the utilization of results for patient management are needed to truly capitalize on the benefits of decentralized testing. Keywords: point of care; viral load monitoring; Africa; viral suppression

1 | INTRODUCTION In 2019, more than 1.2 million infants were born to women with HIV worldwide and 150,000 acquired HIV [1]. Prompt diagnosis and treatment are critical to the [...], Introduction: Uptake of early infant HIV diagnosis (EID) varies widely across sub-Saharan African settings. We evaluated the potential clinical impact and cost-effectiveness of universal maternal HIV screening at infant immunization visits, with referra to EID and maternal antiretroviral therapy (ART) initiation. Methods: Using the CEPAC-Pediatric model, we compared two strategies for infants born in 2017 in Cote d'Ivoire (CI), South Africa (SA), and Zimbabwe: (1) existing EID programmes offering six-week nucleic acid testing (NAT) for infants with known HIV exposure (EID), and (2) EID plus universal maternal HIV screening at six-week infant immunization visits, leading to referral for infant NAT and maternal ART initiation (screen-and-test). Model inputs included published Ivoirian/South African/Zimbabwean data: maternal HIV prevalence (4.8/30.8/16.1%), current uptake of EID (40/95/65%) and six-week immunization attendance (99/74/94%). Referral rates for infant NAT and maternal ART initiation after screen-and-test were 80%. Costs included NAT ($24/infant), maternal screening ($10/mother-infant pair), ART ($5 to 31/month) and HIV care ($15 to 190/month). Model outcomes included mother-to-child transmission of HIV (MTCT) among HIV-exposed infants, and life expectancy (LE) and mean lifetime per-person costs for children with HIV (CWH) and all children born in 2017. We calculated incremental cost-effectiveness ratios (ICERs) using discounted (3%/year) lifetime costs and LE for all children. We considered two cost-effectiveness thresholds in each country: (1) the per-capita GDP ($1720/6380/2150) per year-of-life saved (YLS), and (2) the CEPAC-generated ICER of offering 2 versus 1 lifetime ART regimens (e.g. offering second-line ART; $520/500/580/YLS). Results: With EID, projected six-week MTCT was 9.3% (CI), 4.2% (SA) and 5.2% (Zimbabwe). Screen-and-test decreased total MTCT by 0.2% to 0.5%, improved LE by 2.0 to 3.5 years for CWH and 0.03 to 0.07 years for all children, and increased discounted costs by $17 to 22/child (all children). The ICER of screen-and-test compared to EID was $1340/YLS (CI), $650/YLS (SA) and $670/YLS (Zimbabwe), below the per-capita GDP but above the ICER of 2 versus 1 lifetime ART regimens in all countries. Conclusions: Universal maternal HIV screening at immunization visits with referral to EID and maternal ART initiation may reduce MTCT, improve paediatric LE, and be of comparable value to current HIV-related interventions in high maternal HIV prevalence settings like SA and Zimbabwe. Keywords: Early infant diagnosis; HIV; paediatric HIV testing; HIV-exposed infants; immunization; prevention of mother-to-child HIV transmission

In 2021, there were more than 150,000 new HIV infections among children; however, only 52% of children living with HIV were on antiretroviral treatment (ART) [1]. Untreated infants and young [...]

Author(s): Lara Vojnov 1,*, Sergio Carmona 2, Clement Zeh 3, Jessica Markby 4, Debrah Boeras 3, Marta R. Prescott 1, Anthony L. H. Mayne 5, Souleymane Sawadogo 6, Christiane Adje-Toure [...], Background Accurate routine HIV viral load testing is essential for assessing the efficacy of antiretroviral treatment (ART) regimens and the emergence of drug resistance. While the use of plasma specimens is the standard for viral load testing, its use is restricted by the limited ambient temperature stability of viral load biomarkers in whole blood and plasma during storage and transportation and the limited cold chain available between many health care facilities in resource-limited settings. Alternative specimen types and technologies, such as dried blood spots, may address these issues and increase access to viral load testing; however, their technical performance is unclear. To address this, we conducted a meta-analysis comparing viral load results from paired dried blood spot and plasma specimens analyzed with commonly used viral load testing technologies. Methods and findings Standard databases, conferences, and gray literature were searched in 2013 and 2018. Nearly all studies identified (60) were conducted between 2007 and 2018. Data from 40 of the 60 studies were included in the meta-analysis, which accounted for a total of 10,871 paired dried blood spot:plasma data points. We used random effects models to determine the bias, accuracy, precision, and misclassification for each viral load technology and to account for between-study variation. Dried blood spot specimens produced consistently higher mean viral loads across all technologies when compared to plasma specimens. However, when used to identify virological failure, each technology compared best to plasma at a threshold of 1,000 copies/ml, the present World Health Organization recommended virological failure threshold. Some heterogeneity existed between technologies; however, 5 technologies had a sensitivity greater than 95%. Furthermore, 5 technologies had a specificity greater than 85% yet 2 technologies had a specificity less than 60% using a treatment failure threshold of 1,000 copies/ml. The study's main limitation was the direct applicability of findings as nearly all studies to date used dried blood spot samples prepared in laboratories using precision pipetting that resulted in consistent input volumes. Conclusions This analysis provides evidence to support the implementation and scale-up of dried blood spot specimens for viral load testing using the same 1,000 copies/ml virological failure threshold as used with plasma specimens. This may support improved access to viral load testing in resource-limited settings lacking the required infrastructure and cold chain storage for testing with plasma specimens.

1 | INTRODUCTION Although significant increases in early infant diagnosis (EID) testing coverage has occurred globally in the past ten years, only approximately 50% of HIV-exposed infants received an EID [...], Introduction: Viral load testing is essential to manage HIV disease, especially in infants and children. Early infant diagnosis (EID) is performed using nucleic-acid testing in children under 18 months. Resource-limited health systems face severe chalenges to scale-up both viral load and EID to unprecedented levels. Streamlining laboratory systems would be beneficial to improve access to quality testing and to increase efficiency of antiretroviral treatment programmes. We evaluated the performance of viral load testing to serve as an EID assay in children younger than 18 months. Methods: This study was an observational, prospective study, including children between one and 18 months of age who were born to HIV-positive mothers in 134 health facilities in Maputo City and Maputo Province, Mozambique. Dried blood spot specimens from heel or toe pricks were collected between January and April 2018, processed using SPEX buffer for both assays, and tested for routine EID and viral load testing using the Roche CAP/CTM HIV-1 Qualitative v2 and Roche CAP/CTM HIV-1 Quantitative v2 assays respectively. The sensitivity, specificity and positive and negative predictive values were estimated using the EID results as the reference standard. Results: A total of 1021 infants were included in the study, of which 47% were female. Over 95% of mothers and children were on antiretroviral treatment or received antiretroviral prophylaxis respectively. The sensitivity and specificity of using the viral load assay to detect infection were 100% (95% CI: 96.2 to 100%) and 99.9% (95% CI: 99.4 to 100%). The positive and negative predictive values were 99.0% (95% CI: 94.3 to 100%) and 100% (95% CI: 99.6 to 100%). The McNemar's test was 1.000 and Cohen's kappa was 0.994. Conclusions: The comparable performance suggests that viral load assays can be used as an infant diagnostic assay. Infants with either low levels of viraemia or high cycle threshold values should be repeat tested to ensure the result is truly positive prior to treatment initiation, regardless of assay used. Viral load assays could replace traditional EID testing, substantially streamlining molecular laboratory services for children and lowering costs, with the additional advantage of providing baseline viral load results for antiretroviral treatment management. Keywords: diagnostics; paediatrics; testing; virology; LMIC; Africa; viral load monitoring Additional information may be found under the Supporting Information tab for this article.

1 | INTRODUCTION Guidelines for antiretroviral therapy in resource-limited settings recommend enhanced adherence counselling following a first elevated viral load [1]. This approach helps programme managers and clinicians to discriminate [...], Introduction: Guidelines for antiretroviral therapy recommend enhanced adherence counselling be provided to individuals with an initial elevated viral load before making a decision whether to switch antiretroviral regimen. We undertook this systematic review to estimate the proportion of patients with an initial elevated viral load who resuppress following enhanced adherence counselling. Methods: Two databases and two conference abstract sites were searched from January 2012 to October 2019 for studies reporting the number of patients with an elevated viral load whose viral load was undetectable when subsequently assessed. Data were pooled using random effects meta-analysis. Results: Fifty-eight studies reported outcomes of 45,720 viraemic patients, mostly from Africa (48 studies), and among patients on first-line antiretroviral therapy (43 studies). Almost half (46.1%, 95% CI 42.6% to 49.5%) of patients with an initial elevated viral load resuppressed following an enhanced adherence intervention. Of those on first-line ART with confirmed virological failure (6280 patients, 21 studies), only 53.4% (40.1% to 66.8%) were appropriately switched to a different regimen. Resuppression was higher among studies that provided details of adherence support. The proportion resuppressing was lower among children (31.2%, 21.1% to 41.3%) and adolescents (40.4%, 15.7% to 65.2%) compared to adults (50.4%, 42.6% to 58.3%). No important differences were observed by date of study publication, gender, viral failure threshold, publication status, time between viral loads or treatment regimen. Information on resistance testing among people with an elevated viral load was inconsistently reported. Conclusions: The findings of this review suggest that in settings with limited resources, current guideline recommendations to provide enhanced adherence counselling can result in resuppression of a substantial number of these patients, avoiding unnecessary drug regimen changes. Appropriate action on viral load results is limited across a range of settings, highlighting the importance of viral load cascade analyses to identify gaps and focus quality improvement to ensure that action is taken on the results of viral load testing. Keywords: adherence; enhanced adherence counselling; elevated viral load; viral suppression; viral resuppression

Author(s): Nathan Ford 1,*, Ingrid Eshun-Wilson 2, Wole Ameyan 1, Morkor Newman 1, Lara Vojnov 1, Meg Doherty 1, Elvin Geng 2 Summary points Improvements in HIV service delivery are [...]

1 INTRODUCTIONSince 2013, when the World Health Organization strongly recommended the use of HIV viral load (VL) testing to monitor viral suppression in persons on antiretroviral therapy (ART) in low [...], Introduction: The scale-up of effective HIV viral load (VL) testing is an urgent public health priority. Implementation of testing is supported by the availability of accurate, nucleic acid based laboratory and point-of-care (POC) VL technologies and strong WHO guidance recommending routine testing to identify treatment failure. However, test implementation faces challenges related to the developing health systems in many low-resource countries. The purpose of this commentary is to review the challenges and solutions from the large-scale implementation of other diagnostic tests, namely nucleic-acid based early infant HIV diagnosis (EID) and CD4 testing, and identify key lessons to inform the scale-up of VL.Discussion: Experience with EID and CD4 testing provides many key lessons to inform VL implementation and may enable more effective and rapid scale-up. The primary lessons from earlier implementation efforts are to strengthen linkage to clinica care after testing, and to improve the efficiency of testing. Opportunities to improve linkage include data systems to support the follow-up of patients through the cascade of care and test delivery, rapid sample referral networks, and POC tests. Opportunities to increase testing efficiency include improvements to procurement and supply chain practices, well connected tiered aboratory networks with rational deployment of test capacity across different levels of health services, routine resource mapping and mobilization to ensure adequate resources for testing programs, and improved operational and quality management of testing services. If applied to VL testing programs, these approaches could help improve the impact of VL on ART failure management and patient outcomes, reduce overall costs and help ensure the sustainable access to reduced pricing for test commodities, as well as improve supportive health systems such as efficient, and more rigorous quality assurance. These lessons draw from traditional laboratory practices as well as fields such as logistics, operations management and business.Conclusions: The lessons and innovations from large-scale EID and CD4 programs described here can be adapted to inform more effective scale-up approaches for VL. They demonstrate that an integrated approach to health system strengthening focusing on key levers for test access such as data systems, supply efficiencies and network management. They also highlight the challenges with implementation and the need for more innovative approaches and effective partnerships to achieve equitable and cost-effective test access.Keywords: HIV; viral load; early infant diagnosis; EID; CD4 implementation

Author(s): Peter D. Ehrenkranz 1,*, Solange L. Baptiste 2, Helen Bygrave 3, Tom Ellman 4, Naoko Doi 5, Anna Grimsrud 6, Andreas Jahn 7, Thokozani Kalua 7, Rose Kolola Nyirenda [...]

Background We compared the cost-effectiveness of pediatric provider–initiated HIV testing and counseling (PITC) vs no PITC in a range of clinical care settings in South Africa. Methods We used the Cost-Effectiveness of Preventing AIDS Complications Pediatric model to simulate a cohort of children, aged 2–10 years, presenting for care in 4 settings (outpatient, malnutrition, inpatient, tuberculosis clinic) with varying prevalence of undiagnosed HIV (1.0%, 15.0%, 17.5%, 50.0%, respectively). We compared "PITC" (routine testing offered to all patients; 97% acceptance and 71% linkage to care after HIV diagnosis) with no PITC. Model outcomes included life expectancy, lifetime costs, and incremental cost-effectiveness ratios (ICERs) from the health care system perspective and the proportion of children with HIV (CWH) diagnosed, on antiretroviral therapy (ART), and virally suppressed. We assumed a threshold of $3200/year of life saved (YLS) to determine cost-effectiveness. Sensitivity analyses varied the age distribution of children seeking care and costs for PITC, HIV care, and ART. Results PITC improved the proportion of CWH diagnosed (45.2% to 83.2%), on ART (40.8% to 80.4%), and virally suppressed (32.6% to 63.7%) at 1 year in all settings. PITC increased life expectancy by 0.1–0.7 years for children seeking care (including those with and without HIV). In all settings, the ICER of PITC vs no PITC was very similar, ranging from $710 to $1240/YLS. PITC remained cost-effective unless undiagnosed HIV prevalence was <0.2%. Conclusions Routine testing improves HIV clinical outcomes and is cost-effective in South Africa if the prevalence of undiagnosed HIV among children exceeds 0.2%. These findings support current recommendations for PITC in outpatient, inpatient, tuberculosis, and malnutrition clinical settings. [ABSTRACT FROM AUTHOR]

Introduction The ambitious new global targets to identify 90% of all people living with HIV, treat 90% of those identified as infected and achieve virologic suppression in 90% of treated [...], Introduction: Despite significant gains in access to early infant diagnosis (EID) over the past decade, most HIV?exposed infants still do not get tested for HIV in the first two months of life. For those who are tested, the long turnaround time between when the sample is drawn and when the results are returned leads to a high rate of loss to follow?up, which in turn means that few infected infants start antiretroviral treatment. Consequently, there continues to be high mortality from perinatally acquired HIV, and the ambitious goals of 90% of infected children identified, 90% of identified children treated and 90% of treated children with sustained virologic suppression by 2020 seem far beyond our reach. The objective of this commentary is to review recent advances in the field of HIV diagnosis in infants and describe how these advances may overcome long?standing barriers to access to testing and treatment. Discussion: Several innovative approaches to EID have recently been described. These include point?of?care testing, use of SMS printers to connect the central laboratory and the health facility through a mobile phone network, expanding paediatric testing to other entry points where children access the health system and testing HIV?exposed infants at birth as a rapid way to identify in utero infection. Each of these interventions is discussed here, together with the opportunities and challenges associated with scale?up. Point?of?care testing has the potential to provide immediate results but is less cost?effective in settings where test volumes are low. Virological testing at birth has been piloted in some countries to identify those infants who need urgent treatment, but a negative test at birth does not obviate the need for additional testing at six weeks. Routine testing of infants in child health settings is a useful strategy to identify exposed and infected children whose mothers were not enrolled in programmes for the prevention of mother?to?child transmission. Facility?based SMS printers speed up the return of laboratory results and may be of value for other testing services apart from HIV infant diagnosis. Conclusions: New tools and strategies for HIV infant diagnosis could have a significant positive impact on the identification and retention of HIV?infected infants. In order to be most effective, national programmes should carefully consider which ideas to implement and how best to integrate novel strategies into existing systems. There is no single solution that will work everywhere. Rather, a number of approaches need to be considered and should be linked in order to achieve the greatest impact on the continuum of care from testing to treatment.