The risk of sexual transmission of HIV in individuals with low-level HIV viraemia: a systematic review.

BACKGROUND: The risk of sexual transmission of HIV from individuals with low-level HIV viraemia receiving antiretroviral therapy (ART) has important public health implications, especially in resource-limited settings that use alternatives to plasma-based viral load testing. This Article summarises the evidence related to sexual transmission of HIV at varying HIV viral load levels to inform messaging for people living with HIV, their partners, their health-care providers, and the wider public. METHODS: We conducted a systematic review and searched PubMed, MEDLINE, Cochrane Central Register of Controlled Trials, Embase, Conference Proceedings Citation Index-Science, and WHO Global Index Medicus, for work published from Jan 1, 2010 to Nov 17, 2022. Studies were included if they pertained to sexual transmission between serodiscordant couples at various levels of viraemia, the science behind undetectable=untransmittable, or the public health impact of low-level viraemia. Studies were excluded if they did not specify viral load thresholds or a definition for low-level viraemia or did not provide quantitative viral load information for transmission outcomes. Reviews, non-research letters, commentaries, and editorials were excluded. Risk of bias was evaluated using the ROBINS-I framework. Data were extracted and summarised with a focus on HIV sexual transmission at varying HIV viral loads. FINDINGS: 244 studies were identified and eight were included in the analysis, comprising 7762 serodiscordant couples across 25 countries. The certainty of evidence was moderate; the risk of bias was low. Three studies showed no HIV transmission when the partner living with HIV had a viral load less than 200 copies per mL. Across the remaining four prospective studies, there were 323 transmission events; none were in patients considered stably suppressed on ART. Among all studies there were two cases of transmission when the index patient's (ie, patient with previously diagnosed HIV infection) most recent viral load was less than 1000 copies per mL. However, interpretation of both cases was complicated by long intervals (ie, 50 days and 53 days) between the transmission date and the most recent index viral load result. INTERPRETATION: There is almost zero risk of sexual transmission of HIV with viral loads of less than 1000 copies per mL. These data provide a powerful opportunity to destigmatise HIV and promote adherence to ART through dissemination of this positive public health message. These findings can also promote access to viral load testing in resource-limited settings for all people living with HIV by facilitating uptake of alternative sample types and technologies. FUNDING: Bill & Melinda Gates Foundation.

The clinical effect of point-of-care HIV diagnosis in infants: a systematic review and meta-analysis.

BACKGROUND: Timely diagnosis and treatment of HIV is crucial in HIV-exposed infants to prevent the high rates of mortality seen during the first 2 years of life if HIV is untreated. However, challenges with sample transportation, testing, and result delivery to caregivers have led to long delays in treatment initiation. We aimed to compare the clinical effect of point-of-care HIV testing versus laboratory-based testing (standard of care) in HIV-exposed infants. METHODS: We did a systematic review and meta-analysis and searched PubMed, MEDLINE, Cochrane Central Register of Controlled Trials, Embase, Conference Proceedings Citation Index-Science, and WHO Global Index Medicus, from Jan 1, 2014, to Aug 31, 2020. Studies were included if they pertained to the use of point-of-care nucleic acid testing for infant HIV diagnosis, had a laboratory-based nucleic acid test as the comparator or standard of care against the index test (same-day point-of-care testing), evaluated clinical outcomes when point-of-care testing was used, and included HIV-exposed infants aged younger than 2 years. Studies were excluded if they did not use a laboratory-based comparator, a nucleic acid test that had been approved by a stringent regulatory authority, or diagnostic-accuracy or performance evaluations (eg, no clinical outcomes included). Reviews, non-research letters, commentaries, and editorials were also excluded. The risk of bias was evaluated using the ROBINS-I framework. Data were extracted from published reports. Data from all studies were analysed using frequency statistics to describe the overall populations evaluated and their results. Key outcomes were time to result delivery and antiretroviral therapy initiation, and proportion of HIV-positive infants initiated on antiretroviral therapy within 60 days after sample collection. FINDINGS: 164 studies were identified by the search and seven were included in the analysis, comprising 37 377 infants in total across 15 countries, including 25 170 (67%) who had point-of-care HIV testing and 12 207 (33%) who had standard-of-care testing. The certainty of evidence was high. Same-day point-of-care testing led to a significantly shorter time between sample collection and result delivery to caregivers compared with standard-of-care testing (median 0 days [95% CI 0-0] vs 35 days [35-37]). Time from sample collection to antiretroviral therapy initiation in infants found to be HIV-positive was significantly lower with point-of-care testing compared with standard of care (median 0 days [95% CI 0-1] vs 40 days [36-44]). When each study's result was weighted equally, 90·3% (95% CI 76·7-96·5) of HIV-positive infants diagnosed using point-of-care testing had started antiretroviral therapy within 60 days of sample collection, compared with only 51·6% (27·1-75·7) who had standard-of-care testing (odds ratio 8·74 [95% CI 6·6-11·6]; p<0·0001). INTERPRETATION: Overall, the certainty of the evidence in this analysis was rated as high for the primary outcomes related to result delivery and treatment initiation, with no serious risk of bias, inconsistency, indirectness, or imprecision. In HIV-exposed infants, same-day point-of-care HIV testing was associated with significantly improved time to result delivery, time to antiretroviral therapy initiation, and proportion of HIV-positive infants starting antiretroviral therapy within 60 days compared with standard of care. FUNDING: The Bill & Melinda Gates Foundation.

Role of viral suppression in HIV treatment and prevention and its potential in addressing harmful laws and discrimination.

The World Health Organization's (WHO) global public health mandate includes a focus on expanding access to HIV testing, antiretroviral therapy (ART) and treatment monitoring to improve the clinical management of HIV, achieve sustained viral suppression, and prevent HIV-related incidence, morbidity, and mortality. This article documents key moments in research and WHO policies that have informed how ART is applied within HIV programs, including as a prevention tool with the potential to support efforts to address HIV-related discrimination. For more than 20years, WHO has promoted the benefits of HIV treatment including as part of the approach to prevent the mother-to-child transmission (vertical transmission) of HIV. WHO guidance has followed, and continues to follow, the evolving evidence. In 2023, WHO continues to clarify that there is zero risk of sexual HIV transmission when a person living with HIV has an undetectable viral load and an almost zero or negligible risk of sexual transmission when a person living with HIV has a viral load of ≤1000copies/mL - helping to evolve the focus of community campaigns and health worker training to include a focus on 'virally suppressed' while also continuing to emphasise the ultimate goal of achieving an undetectable viral load. This evolution does two things: first, it strongly reasserts the evidence around there being no chance of transmission if a person has an undetectable viral load; and second, it provides an extremely strong degree of confidence that, similarly, individuals who are virally suppressed will not pass on the virus sexually. WHO is now encouraging positive and clear messaging to highlight that the consistent use of ART prevents onwards HIV transmission.

The performance of using dried blood spot specimens for HIV-1 viral load testing: A systematic review and meta-analysis.

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 treatment failure, each technology compared best to plasma at a threshold of 1,000 copies/ml, the present World Health Organization recommended treatment 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 treatment 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.

Integrated use of laboratory services for multiple infectious diseases in the WHO European Region during the COVID-19 pandemic and beyond.

Technical advances in diagnostic techniques have permitted the possibility of multi-disease-based approaches for diagnosis and treatment monitoring of several infectious diseases, including tuberculosis (TB), human immunodeficiency virus (HIV), viral hepatitis and sexually transmitted infections (STI). However, in many countries, diagnosis and monitoring, as well as disease response programs, still operate as vertical systems, potentially causing delay in diagnosis and burden to patients and preventing the optimal use of available resources. With countries facing both human and financial resource constraints, during the COVID-19 pandemic even more than before, it is important that available resources are used as efficiently as possible, potential synergies are leveraged to maximise benefit for patients, continued provision of essential health services is ensured. For the infectious diseases, TB, HIV, hepatitis C (HCV) and STI, sharing devices and integrated services starting with rapid, quality-assured, and complete diagnostic services is beneficial for the continued development of adequate, efficient and effective treatment strategies. Here we explore the current and future potential (as well as some concerns), importance, implications and necessary implementation steps for the use of platforms for multi-disease testing for TB, HIV, HCV, STI and potentially other infectious diseases, including emerging pathogens, using the example of the COVID-19 pandemic.

Future directions for HIV service delivery research: Research gaps identified through WHO guideline development.

Nathan Ford and co-authors discuss the systematic identification of research gaps in improving HIV service delivery.

Sustainable HIV treatment in Africa through viral-load-informed differentiated care.

There are inefficiencies in current approaches to monitoring patients on antiretroviral therapy in sub-Saharan Africa. Patients typically attend clinics every 1 to 3 months for clinical assessment. The clinic costs are comparable with the costs of the drugs themselves and CD4 counts are measured every 6 months, but patients are rarely switched to second-line therapies. To ensure sustainability of treatment programmes, a transition to more cost-effective delivery of antiretroviral therapy is needed. In contrast to the CD4 count, measurement of the level of HIV RNA in plasma (the viral load) provides a direct measure of the current treatment effect. Viral-load-informed differentiated care is a means of tailoring care so that those with suppressed viral load visit the clinic less frequently and attention is focussed on those with unsuppressed viral load to promote adherence and timely switching to a second-line regimen. The most feasible approach to measuring viral load in many countries is to collect dried blood spot samples for testing in regional laboratories; however, there have been concerns over the sensitivity and specificity of this approach to define treatment failure and the delay in returning results to the clinic. We use modelling to synthesize evidence and evaluate the cost-effectiveness of viral-load-informed differentiated care, accounting for limitations of dried blood sample testing. We find that viral-load-informed differentiated care using dried blood sample testing is cost-effective and is a recommended strategy for patient monitoring, although further empirical evidence as the approach is rolled out would be of value. We also explore the potential benefits of point-of-care viral load tests that may become available in the future.

The missed potential of CD4 and viral load testing to improve clinical outcomes for people living with HIV in lower-resource settings.

In a Policy Forum, Peter Ehrenkranz and colleagues discuss the contribution of CD4 and viral load testing to outcomes for people with HIV in low- and middle-income countries.

Managing Advanced HIV Disease in a Public Health Approach.

In 2017, the World Health Organization (WHO) published guidelines for the management of advanced human immunodeficiency virus (HIV) disease within a public health approach. Recent data suggest that more than a third of people starting antiretroviral therapy (ART) do so with advanced HIV disease, and an increasing number of patients re-present to care at an advanced stage of HIV disease following a period of disengagement from care. These guidelines recommend a standardized package of care for adults, adolescents, and children, based on the leading causes of morbidity and mortality: tuberculosis, severe bacterial infections, cryptococcal meningitis, toxoplasmosis, and Pneumocystis jirovecii pneumonia. A package of targeted interventions to reduce mortality and morbidity was recommended, based on results of 2 recent randomized trials that both showed a mortality reduction associated with delivery of a simplified intervention package. Taking these results and existing recommendations into consideration, WHO recommends that a package of care be offered to those presenting with advanced HIV disease; depending on age and CD4 cell count, the package may include opportunistic infection screening and prophylaxis, including fluconazole preemptive therapy for those who are cryptococcal antigen positive and without evidence of meningitis. Rapid ART initiation and intensified adherence interventions should also be proposed to everyone presenting with advanced HIV disease.

Significant Patient Impact Observed Upon Implementation of Point-of-Care Early Infant Diagnosis Technologies in an Observational Study in Malawi.

Background: In Malawi in 2014, <20% of human immunodeficiency virus (HIV)-exposed infants received an early infant diagnosis (EID) test in the first 2 months of life and only 30% of HIV-infected children were on antiretroviral therapy (ART). We sought to understand the potential patient impact of improving timely infant diagnosis and treatment initiation through implementation of point-of-care (POC) EID technologies in Malawi. Methods: In this observational study, POC EID technologies were introduced into routine services at 7 health facilities across Malawi in September 2015. The primary outcome was the proportion of HIV-infected infants initiating ART within 60 days of sample collection in the POC arm compared to the baseline arm with conventional laboratory-based EID testing. Results: The time from sample collection to result received by the patient decreased significantly from 56 days (interquartile range [IQR], 30-81 days) in the baseline arm to <1 day in the POC arm (P < .001). Of the HIV-infected infants, the time between sample collection and ART initiation was reduced from 38 days (IQR, 30-54 days) in the baseline arm to <1 day (IQR, 0-1 day) in the POC arm (P = .019). Furthermore, the proportion of HIV-infected infants initiated on ART within 60 days of sample collection increased significantly from 41.9% to 91.1% after the introduction of POC (adjusted risk ratio, 2.28; P < .001). Conclusions: ART initiation rates were significantly improved with the implementation of same-day POC EID testing compared with referred, longer-turnaround laboratory-based testing.

Evaluation of the Whole-Blood Alere Q NAT Point-of-Care RNA Assay for HIV-1 Viral Load Monitoring in a Primary Health Care Setting in Mozambique.

Viral load testing is the WHO-recommended monitoring assay for patients on HIV antiretroviral therapy (ART). Point-of-care (POC) assays may help improve access to viral load testing in resource-limited settings. We compared the performance of the Alere Q NAT POC viral load technology (Alere Technologies, Jena, Germany), measuring total HIV RNA using finger prick capillary whole-blood samples collected in a periurban health center, with that of a laboratory-based plasma RNA test (Roche Cobas Ampliprep/Cobas TaqMan v2) conducted on matched venous blood samples. The whole-blood Alere Q NAT POC assay produced results with a bias of 0.8593 log copy/ml compared to the laboratory-based plasma assay. However, at above 10,000 copies/ml, the bias was 0.07 log copy/ml. Using the WHO-recommended threshold to determine ART failure of 1,000 copies/ml, the sensitivity and specificity of the whole-blood Alere Q NAT POC assay were 96.83% and 47.80%, respectively. A cutoff of 10,000 copies/ml of whole blood with the Alere Q NAT POC assay appears to be a better predictor of ART failure threshold (1,000 copies/ml of plasma), with a sensitivity of 84.0% and specificity of 90.3%. The precision of the whole-blood Alere Q NAT POC assay was comparable to that observed with the laboratory technology (5.4% versus 7.5%) between detectable paired samples. HIV POC viral load testing is feasible at the primary health care level. Further research on the value of whole-blood viral load to monitor antiretroviral therapy is warranted.

A meta-analysis of the performance of the Pima™ CD4 for point of care testing.

BACKGROUND: The Alere point-of-care (POC) Pima™ CD4 analyzer allows for decentralized testing and expansion to testing antiretroviral therapy (ART) eligibility. A consortium conducted a pooled multi-data technical performance analysis of the Pima CD4. METHODS: Primary data (11,803 paired observations) comprised 22 independent studies between 2009-2012 from the Caribbean, Asia, Sub-Saharan Africa, USA and Europe, using 6 laboratory-based reference technologies. Data were analyzed as categorical (including binary) and numerical (absolute) observations using a bivariate and/or univariate random effects model when appropriate. RESULTS: At a median reference CD4 of 383 cells/µl the mean Pima CD4 bias is -23 cells/µl (average bias across all CD4 ranges is 10 % for venous and 15% for capillary testing). Sensitivity of the Pima CD4 is 93% (95% confidence interval [CI] 91.4% - 94.9%) at 350 cells/µl and 96% (CI 95.2% - 96.9%) at 500 cells/µl, with no significant difference between venous and capillary testing. Sensitivity reduced to 86% (CI 82% - 89%) at 100 cells/µl (for Cryptococcal antigen (CrAg) screening), with a significant difference between venous (88%, CI: 85% - 91%) and capillary (79%, CI: 73% - 84%) testing. Total CD4 misclassification is 2.3% cases at 100 cells/µl, 11.0% at 350 cells/µl and 9.5 % at 500 cells/µl, due to higher false positive rates which resulted in more patients identified for treatment. This increased by 1.2%, 2.8% and 1.8%, respectively, for capillary testing. There was no difference in Pima CD4 misclassification between the meta-analysis data and a population subset of HIV+ ART naïve individuals, nor in misclassification among operator cadres. The Pima CD4 was most similar to Beckman Coulter PanLeucogated CD4, Becton Dickinson FACSCalibur and FACSCount, and less similar to Partec CyFlow reference technologies. CONCLUSIONS: The Pima CD4 may be recommended using venous-derived specimens for screening (100 cells/µl) for reflex CrAg screening and for HIV ART eligibility at 350 cells/µl and 500 cells/µl thresholds using both capillary and venous derived specimens. These meta-analysis findings add to the knowledge of acceptance criteria of the Pima CD4 and future POC tests, but implementation and impact will require full costing analysis.

The majority of freshly sorted simian immunodeficiency virus (SIV)-specific CD8(+) T cells cannot suppress viral replication in SIV-infected macrophages.

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) primarily infect activated CD4(+) T cells but can infect macrophages. Surprisingly, ex vivo tetramer-sorted SIV-specific CD8(+) T cells that eliminated and suppressed viral replication in SIV-infected CD4(+) T cells failed to do so in SIV-infected macrophages. It is possible, therefore, that while AIDS virus-infected macrophages constitute only a small percentage of all virus-infected cells, they may be relatively resistant to CD8(+) T cell-mediated lysis and continue to produce virus over long periods of time.

Cost-effectiveness of point-of-care versus centralised, laboratory-based nucleic acid testing for diagnosis of HIV in infants: a systematic review of modelling studies.

BACKGROUND: Point-of-care (POC) nucleic acid testing for diagnosis of HIV in infants facilitates earlier initiation of antiretroviral therapy (ART) than with centralised (standard-of-care, SOC) testing, but can be more expensive. We evaluated cost-effectiveness data from mathematical models comparing POC with SOC to provide global policy guidance. METHODS: In this systematic review of modelling studies, we searched PubMed, MEDLINE, Embase, the National Health Service Economic Evaluation Database, Econlit, and conference abstracts, combining terms for "HIV" + "infant"/"early infant diagnosis" + "point-of-care" + "cost-effectiveness" + "mathematical models", without restrictions from database inception to July 15, 2022. We selected reports of mathematical cost-effectiveness models comparing POC with SOC for HIV diagnosis in infants younger than 18 months. Titles and abstracts were independently reviewed, with full-text review for qualifying articles. We extracted data on health and economic outcomes and incremental cost-effectiveness ratios (ICERs) for narrative synthesis. The primary outcomes of interest were ICERs (comparing POC with SOC) for ART initiation and survival of children living with HIV. FINDINGS: Our search identified 75 records through database search. 13 duplicates were excluded, leaving 62 non-duplicate articles. 57 records were excluded and five were reviewed in full text. One article was excluded as it was not a modelling study, and four qualifying studies were included in the review. These four reports were from two mathematical models from two independent modelling groups. Two reports used the Johns Hopkins model to compare POC with SOC for repeat early infant diagnosis testing in the first 6 months in sub-Saharan Africa (first report, simulation of 25 000 children) and Zambia (second report, simulation of 7500 children). In the base scenario, POC versus SOC increased probability of ART initiation within 60 days of testing from 19% to 82% (ICER per additional ART initiation range US$430-1097; 9-month cost horizon) in the first report; and from 28% to 81% in the second ($23-1609, 5-year cost horizon). Two reports compared POC with SOC for testing at 6 weeks in Zimbabwe using the Cost-Effectiveness of Preventing AIDS Complications-Paediatric model (simulation of 30 million children; lifetime horizon). POC increased life expectancy and was considered cost-effective compared with SOC (ICER $711-850 per year of life saved in HIV-exposed children). Results were robust throughout sensitivity and scenario analyses. In most scenarios, platform cost-sharing (co-use with other programmes) resulted in POC being cost-saving compared with SOC. INTERPRETATION: Four reports from two different models suggest that POC is a cost-effective and potentially cost-saving strategy for upscaling of early infant testing compared with SOC. FUNDING: Bill & Melinda Gates Foundation, Unitaid, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, WHO, and Massachusetts General Hospital Research Scholars.

HIV viral load assays when used with whole blood perform well as a diagnostic assay for infants.

OBJECTIVE: Over the past several years, only approximately 50% of HIV-exposed infants received an early infant diagnosis test within the first two months of life. While high attrition and mortality account for some of the shortcomings in identifying HIV-infected infants early and putting them on life-saving treatment, fragmented and challenging laboratory systems are an added barrier. We sought to determine the accuracy of using HIV viral load assays for infant diagnosis of HIV. METHODS: We enrolled 866 Ugandan infants between March-April 2018 for this study after initial laboratory diagnosis. The median age was seven months, while 33% of infants were less than three months of age. Study testing was done using either the Roche or Abbott molecular technologies at the Central Public Health Laboratory. Dried blood spot samples were prepared according to manufacturer-recommended protocols for both the qualitative and quantitative assays. Viral load test samples for the Roche assay were processed using two different buffers: phosphate-buffered saline (PBS: free virus elution viral load protocol [FVE]) and Sample Pre-Extraction Reagent (SPEX: qualitative buffer). Dried blood spot samples were processed for both assays on the Abbott using the manufacturer's standard infant diagnosis protocol. All infants received a qualitative test for clinical management and additional paired quantitative tests. RESULTS: 858 infants were included in the analysis, of which 50% were female. Over 75% of mothers received antiretroviral therapy, while approximately 65% of infants received infant prophylaxis. The Roche SPEX and Abbott technologies had high sensitivity (>95%) and specificity (>98%). The Roche FVE had lower sensitivity (85%) and viral load values. CONCLUSIONS: To simplify and streamline laboratory practices, HIV viral load may be used to diagnose HIV infection in infants, particularly using the Roche SPEX and Abbott technologies.

Cost-effectiveness of Routine Provider-Initiated Testing and Counseling for Children With Undiagnosed HIV in South Africa.

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.

Diagnostic Accuracy of Dried Plasma Spot Specimens for HIV-1 Viral Load Testing: A Systematic Review and Meta-analysis.

BACKGROUND: Dried plasma spot specimens may be a viable alternative to traditional liquid plasma in field settings, but the diagnostic accuracy is not well understood. METHODS: Standard 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. RESULTS: We 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 <5.4% across all treatment failure thresholds compared. Some technologies had lower sensitivity or specificity; however, the results were typically consistent across treatment failure thresholds. DISCUSSION: Overall, dried plasma spot specimens performed relatively well compared with plasma with sensitivity and specificity values greater than 90% and misclassification rates less than 10% across all treatment failure thresholds reviewed.

Effective simian immunodeficiency virus-specific CD8+ T cells lack an easily detectable, shared characteristic.

The immune correlates of human/simian immunodeficiency virus control remain elusive. While CD8(+) T lymphocytes likely play a major role in reducing peak viremia and maintaining viral control in the chronic phase, the relative antiviral efficacy of individual virus-specific effector populations is unknown. Conventional assays measure cytokine secretion of virus-specific CD8(+) T cells after cognate peptide recognition. Cytokine secretion, however, does not always directly translate into antiviral efficacy. Recently developed suppression assays assess the efficiency of virus-specific CD8(+) T cells to control viral replication, but these assays often use cell lines or clones. We therefore designed a novel virus production assay to test the ability of freshly ex vivo-sorted simian immunodeficiency virus (SIV)-specific CD8(+) T cells to suppress viral replication from SIVmac239-infected CD4(+) T cells. Using this assay, we established an antiviral hierarchy when we compared CD8(+) T cells specific for 12 different epitopes. Antiviral efficacy was unrelated to the disease status of each animal, the protein from which the tested epitopes were derived, or the major histocompatibility complex (MHC) class I restriction of the tested epitopes. Additionally, there was no correlation with the ability to suppress viral replication and epitope avidity, epitope affinity, CD8(+) T-cell cytokine multifunctionality, the percentage of central and effector memory cell populations, or the expression of PD-1. The ability of virus-specific CD8(+) T cells to suppress viral replication therefore cannot be determined using conventional assays. Our results suggest that a single definitive correlate of immune control may not exist; rather, a successful CD8(+) T-cell response may be comprised of several factors.

Recombinant yellow fever vaccine virus 17D expressing simian immunodeficiency virus SIVmac239 gag induces SIV-specific CD8+ T-cell responses in rhesus macaques.

Here we describe a novel vaccine vector for expressing human immunodeficiency virus (HIV) antigens. We show that recombinant attenuated yellow fever vaccine virus 17D expressing simian immunodeficiency virus SIVmac239 Gag sequences can be used as a vector to generate SIV-specific CD8(+) T-cell responses in the rhesus macaque. Priming with recombinant BCG expressing SIV antigens increased the frequency of these SIV-specific CD8(+) T-cell responses after recombinant YF17D boosting. These recombinant YF17D-induced SIV-specific CD8(+) T cells secreted several cytokines, were largely effector memory T cells, and suppressed viral replication in CD4(+) T cells.

Reversion of CTL escape-variant immunodeficiency viruses in vivo.

Engendering cytotoxic T-lymphocyte (CTL) responses is likely to be an important goal of HIV vaccines. However, CTLs select for viral variants that escape immune detection. Maintenance of such escape variants in human populations could pose an obstacle to HIV vaccine development. We first observed that escape mutations in a heterogeneous simian immunodeficiency virus (SIV) isolate were lost upon passage to new animals. We therefore infected macaques with a cloned SIV bearing escape mutations in three immunodominant CTL epitopes, and followed viral evolution after infection. Here we show that each mutant epitope sequence continued to evolve in vivo, often re-establishing the original, CTL-susceptible sequence. We conclude that escape from CTL responses may exact a cost to viral fitness. In the absence of selective pressure upon transmission to new hosts, these original escape mutations can be lost. This suggests that some HIV CTL epitopes will be maintained in human populations.