Suppressed HIV antibody responses following exposure to antiretrovirals - evidence from PrEP randomized trials and early antiretroviral treatment initiation studies.

BACKGROUND: Exposure to antiretrovirals at or early after HIV acquisition can suppress viral replication and blunt antibody (Ab) responses; a reduced HIV detectability could impact diagnosis and blood donation screening. METHODS: We used three antigen (Ag)/Ab assays and one nucleic acid test (NAT) to analyze samples collected in pre-exposure prophylaxis (PrEP) trials (iPrEx; Partners PrEP) before infection detection by Ab-only rapid diagnostic tests (RDTs), and in early antiretroviral treatment (ART) initiation studies (RV254; SIPP). RESULTS: Reactivity using NAT and Ag/Ab assays in samples collected up to 8 weeks prior to the first reactive RDT from 251 PrEP trials participants varied between 49-61% for active PrEP users and between 27-37% for placebo users. Among RV254 participants, reactivity in Ag/Ab assays was <100% at all timepoints, and lower among those initiating ART earlier. Seroreversions occurred for 29% (16/55), and blood donation screening with NAT and Ag/Ab assays could have missed up to 36% (20/55) of RV254 participants. For SIPP participants, who started ART at later timepoints, Ag/Ab assays identified infections with no evidence of reactivity waning. CONCLUSION: PrEP and early ART initiation can delay or reduce HIV detectability. Considerations for the implementation of NAT and Ag/Ab tests in PrEP/PEP programs relying on Ab-only RDTs should be balanced according to feasibility and public health impact. While blood transfusion services using Ab-only RDTs for HIV screening should adopt higher sensitivity tests, surveillance and further research are needed to determine the need for novel HIV testing algorithms for those already using NAT and Ag/Ab screening assays.

HIV Subtypes and Drug-resistance-associated Mutations in US Blood Donors, 2015-2020.

Background: Monitoring genotypes of HIV infections in blood donors may provide insights into infection trends in the general population. Methods: HIV RNA was extracted from plasma samples of blood donors confirmed as HIV positive by blood screening nucleic acid and antibody tests. HIV genome target regions were amplified using nested real time-polymerase chain reaction followed by next-generation sequencing. Sequences were compared to those in the Los Alamos National Laboratory (LANL) database. Sequences were also assessed for drug resistance mutations (DRM) using the Stanford HIV DRM Database. Results: From available HIV-positive donations collected between 1 September 2015 and 31 December 2020, 563 of 743 (75.8%) were successfully sequenced; 4 were subtype A, 543 subtype B, 5 subtype C, 1 subtype G, 5 circulating recombinant forms (CRF), and 2 were subtype B and D recombinants. Overall, no significant differences between blood donor and available LANL genotypes were found, and the genotypes of newly acquired versus prevalent HIV infections in donors were similar. The proportion of non-B subtypes and CRF remained a small fraction, with no other subtype or CRF representing more than 1% of the total. DRM were identified in 122 (21.6%) samples with protease inhibitor, nucleoside reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitor DRMs identified in 4.9%, 4.6% and 14.0% of samples, respectively. Conclusions: HIV genetic diversity and DRM in blood donors appear representative of circulating HIV infections in the US general population and may provide more information on infection diversity than sequences reported to LANL, particularly for recently transmitted infections.

Detection of Nucleocapsid Antibodies Associated with Primary SARS-CoV-2 Infection in Unvaccinated and Vaccinated Blood Donors.

Nucleocapsid antibody assays can be used to estimate SARS-CoV-2 infection prevalence in regions implementing spike-based COVID-19 vaccines. However, poor sensitivity of nucleocapsid antibody assays in detecting infection after vaccination has been reported. We derived a lower cutoff for identifying previous infections in a large blood donor cohort (N = 142,599) by using the Ortho VITROS Anti-SARS-CoV-2 Total-N Antibody assay, improving sensitivity while maintaining specificity >98%. We validated sensitivity in samples donated after self-reported swab-confirmed infections diagnoses. Sensitivity for first infections in unvaccinated donors was 98.1% (95% CI 98.0-98.2) and for infection after vaccination was 95.6% (95% CI 95.6-95.7) based on the standard cutoff. Regression analysis showed sensitivity was reduced in the Delta compared with Omicron period, in older donors, in asymptomatic infections, <30 days after infection, and for infection after vaccination. The standard Ortho N antibody threshold demonstrated good sensitivity, which was modestly improved with the revised cutoff.

SARS-CoV-2 antibody levels and long COVID occurrence in blood donors.

BACKGROUND: Long COVID is a common condition lacking consensus definition; determinants remain incompletely understood. Characterizing immune profiles associated with long COVID could support the development of preventive and therapeutic strategies. METHODS: We used a survey to investigate blood donors' infection/vaccination history and acute/persistent symptoms following COVID-19. The prevalence of long COVID was evaluated using self-report and an adapted definition from the RECOVER study. We evaluated factors associated with long COVID, focusing on anti-spike and anti-nucleocapsid SARS-CoV-2 antibodies. Lastly, we investigated long COVID clinical subphenotypes using hierarchical clustering. RESULTS: Of 33,610 participants, 16,003 (48%) reported having had COVID-19; 1853 (12%) had self-reported long COVID, 685 (4%) met an adapted RECOVER definition, and 2050 (13%) met at least one definition. Higher anti-nucleocapsid levels measured 12-24 weeks post-infection were associated with higher risk of self-reported and RECOVER long COVID. Higher anti-spike IgG levels measured 12-24 weeks post-infection were associated with lower risk of self-reported long COVID. Higher total anti-spike measured 24-48 weeks post-infection was associated with lower risk of RECOVER long COVID. Cluster analysis identified four clinical subphenotypes; patterns included neurological and psychiatric for cluster 1; neurological and respiratory for cluster 2; multi-systemic for cluster 3; and neurological for cluster 4. DISCUSSION: Long COVID prevalence in blood donors varies depending on the adopted definition. Anti-SARS-CoV-2 antibodies were time-dependently associated with long COVID; higher anti-nucleocapsid levels were associated with higher risk; and higher anti-spike levels were associated with lower risk of long COVID. Different underlying pathophysiologic mechanisms may be associated with distinct clinical subphenotypes.

Comparative Evaluation of Select Serological Assays for Zika Virus Using Blinded Reference Panels.

In response to the 2015 Zika virus (ZIKV) epidemic that occurred in Brazil, numerous commercial serological assays have been developed for clinical and research applications. Diagnosis of recent infection in pregnant women remains challenging. Having standardized, comparative studies of ZIKV tests is important for implementing optimal diagnostic testing and disease surveillance. This is especially important for serology tests used to detect ZIKV infection given that antibodies against ZIKV can cross-react with other arboviruses in the same virus family, such as dengue virus (DENV), yellow fever virus (YFV) and West Nile virus (WNV). We looked at the sensitivity and specificity of tests detecting ZIKV antibodies (IgM, IgG) from multiple manufacturers using panels of samples previously collected with known exposure to ZIKV and other arboviruses. We found that performance of the IgM tests was highly variable, with only one test (Inbios 2.0 IgM capture ELISA) having both high sensitivity and specificity. All IgG tests showed good sensitivity; however, specificity was highly variable, with some assays giving false-positive results on samples infected by another flavivirus. Overall, the results confirmed that accurate ZIKV antibody testing is challenging, especially in specimens from regions endemic for multiple other flaviviruses, and highlight the importance of available and suitable reference samples to evaluate ZIKV diagnostics.

Performance of a rapid recency assay for detection of early HIV infection.

The Asanté HIV-1 Rapid Recency assay's 'verification' line detected HIV infection a median of 18 days later than a nucleic acid detection assay and performed similarly to 19 other existing rapid HIV antibody tests. Pending regulatory approval, the assay could be an option with other rapid tests in national HIV-1 testing algorithms, which would allow collection of HIV recency data as part of a national screening program without requiring additional testing.

The impact of non-disclosure of HIV status and antiretroviral therapy on HIV recency testing and incidence algorithms.

BACKGROUND AND OBJECTIVES: Accurate HIV incidence estimates among blood donors are necessary to assess the effectiveness of programs aimed at limiting transfusion-transmitted HIV. We assessed the impact of undisclosed HIV status and antiretroviral (ARV) use on HIV recency and incidence estimates using increasingly comprehensive recent infection testing algorithms. MATERIALS AND METHODS: Using 2017 donation data from first-time and lapsed donors, we populated four HIV recency algorithms: (1) serology and limiting-antigen avidity testing, (2) with individual donation nucleic amplification testing (ID-NAT) added to Algorithm 1, (3) with viral load added to Algorithm 2 and (4) with ARV testing added to Algorithm 3. Algorithm-specific mean durations of recent infection (MDRI) and false recency rates (FRR) were calculated and used to derive and compare incidence estimates. RESULTS: Compared with Algorithm 4, progressive algorithms misclassified fewer donors as recent: Algorithm 1: 61 (12.1%); Algorithm 2: 14 (2.8%) and Algorithm 3: 3 (0.6%). Algorithm-specific MDRI and FRR values resulted in marginally lower incidence estimates: Algorithm 1: 0.19% per annum (p.a.) (95% confidence interval [CI]: 0.13%-0.26%); Algorithm 2: 0.18% p.a. (95% CI: 0.13%-0.22%); Algorithm 3: 0.17% p.a. (95% CI: 0.13%-0.22%) and Algorithm 4: 0.17% p.a. (95% CI: 0.13%-0.21%). CONCLUSION: We confirmed significant misclassification of recent HIV cases when not including viral load and ARV testing. Context-specific MDRI and FRR resulted in progressively lower incidence estimates but did not fully account for the context-specific variability in incidence modelling. The inclusion of ARV testing, in addition to viral load and ID-NAT testing, did not have a significant impact on incidence estimates.

Associations of Temporal Cardiometabolic Patterns and Incident SARS-CoV-2 Infection Among U.S. Blood Donors With Serologic Evidence of Vaccination.

Introduction: Cardiometabolic diseases are associated with greater COVID-19 severity; however, the influences of cardiometabolic health on SARS-CoV-2 infections after vaccination remain unclear. Our objective was to investigate the associations between temporal blood pressure and total cholesterol patterns and incident SARS-CoV-2 infections among those with serologic evidence of vaccination. Methods: In this prospective cohort of blood donors, blood samples were collected in 2020-2021 and assayed for binding antibodies of SARS-CoV-2 nucleocapsid protein antibody seropositivity. We categorized participants into intraindividual pattern subgroups of blood pressure and total cholesterol (persistently, intermittently, or not elevated [systolic blood pressure <130 mmHg, diastolic blood pressure <80 mmHg, total cholesterol <200 mg/dL]) across the study time points. Results: Among 13,930 donors with 39,736 donations representing 1,127,071 person-days, there were 221 incident SARS-CoV-2 infections among those with serologic evidence of vaccination (1.6%). Intermittent hypertension was associated with greater SARS-CoV-2 infections among those with serologic evidence of vaccination risk (adjusted incidence rate ratio=2.07; 95% CI=1.44, 2.96; p<0.01) than among participants with consistent normotension on the basis of a multivariable Poisson regression. Among men, intermittently elevated total cholesterol (adjusted incidence rate ratio=1.90; 95% CI=1.32, 2.74; p<0.01) and higher BMI at baseline (adjusted hazard ratio=1.44; 95% CI=1.07, 1.93; p=0.01; per 10 units) were associated with greater SARS-CoV-2 infections among those with serologic evidence of vaccination probability; these associations were null among women (both p>0.05). Conclusions: Our findings underscore that the benefits of cardiometabolic health, particularly blood pressure, include a lower risk of SARS-CoV-2 infection after vaccination.

The evolution and interpretation of seroprevalence of SARS-CoV-2 antibodies among South African blood donors from the Beta to Omicron variant-driven waves.

BACKGROUND AND OBJECTIVES: Confirmed COVID-19 diagnoses underestimate the total number of infections. Blood donors can provide representative seroprevalence estimates, which can be leveraged into reasonable estimates of total infection counts and infection fatality rate (IFR). MATERIALS AND METHODS: Blood donors who donated after each of three epidemic waves (Beta, Delta and first Omicron waves) were tested for anti-SARS-CoV-2 nucleocapsid antibodies using the Roche Elecsys anti-SARS-CoV-2 total immunoglobulin assay. Roche Elecsys anti-spike antibody testing was done for the post-Omicron sampling. Prevalence of antibodies was estimated by age, sex, race and province and compared to official case reporting. Province and age group-specific IFRs were estimated using external excess mortality estimates. RESULTS: The nationally weighted anti-nucleocapsid seroprevalence estimates after the Beta, Delta and Omicron waves were 47% (46.2%-48.6%), 71% (68.8%-73.5%) and 87% (85.5%-88.4%), respectively. There was no variation by age and sex, but there were statistically and epidemiologically significant differences by province (except at the latest time point) and race. There was a 13-fold higher seroprevalence than confirmed case counts at the first time point. Age-dependent IFR roughly doubled for every 10 years of age increase over 6 decades from 0.014% in children to 6.793% in octogenarians. CONCLUSION: Discrepancies were found between seroprevalence and confirmed case counts. High seroprevalence rates found among Black African donors can be ascribed to historical inequities. Our IFR estimates were useful in refining previous large disagreements about the severity of the epidemic in South Africa. Blood donor-based serosurveys provided a valuable and efficient way to provide near real-time monitoring of the ongoing SARS-CoV-2 outbreak.

Evidence of HIV incidence reduction in young women, but not in adolescent girls, in KwaZulu-Natal, South Africa.

Objectives: We estimated changes in the HIV incidence from 2013-2018 in Eshowe/Mbongolwane, KwaZulu-Natal, South Africa where Médecins Sans Frontières is engaged in providing HIV testing and care since 2011. Methods: Using data from two cross-sectional household-based surveys conducted in 2013 and 2018, with consenting participants aged 15-59 years, we applied the incidence estimation frameworks of Mahiane et al and Kassanjee et al. Results: In total, 5599 (62.4% women) and 3276 (65.9% women) individuals were included in 2013 and 2018, respectively. We found a mean incidence in women aged 20-29 years of 2.71 cases per 100 person-years (95% confidence interval [CI]: 1.23;4.19) in 2013 and 0.4 cases per 100 person-years (95% CI: 0.0;1.5) in 2018. The incidence in men aged 20-29 years was 1.91 cases per 100 person-years (95% CI: 0.87; 2.93) in 2013 and 0.53 cases per 100 person-years (95% CI: 0.0; 1.4) in 2018. The incidence decline among women aged 15-19 was -0.34 cases per 100 person-years (95% CI: -1.31;0.64). Conclusions: The lack of evidence of incidence decline among adolescent girls is noteworthy and disconcerting. Our findings suggest that large-scale surveys should seriously consider focusing their resources on the core group of women aged 15-19 years.

Evaluation of Ortho VITROS and Roche Elecsys S and NC Immunoassays for SARS-CoV-2 Serosurveillance Applications.

SARS-CoV-2 seroprevalence studies are instrumental in monitoring epidemic activity and require well-characterized, high-throughput assays, and appropriate testing algorithms. The U.S. Nationwide Blood Donor Seroprevalence Study performed monthly cross-sectional serological testing from July 2020 to December 2021, implementing evolving testing algorithms in response to changes in pandemic activity. With high vaccine uptake, anti-Spike (S) reactivity rates reached >80% by May 2021, and the study pivoted from reflex Roche anti-nucleocapsid (NC) testing of Ortho S-reactive specimens to parallel Ortho S/NC testing. We evaluated the performance of the Ortho NC assay as a replacement for the Roche NC assay and compared performance of parallel S/NC testing on both platforms. Qualitative and quantitative agreement of Ortho NC with Roche NC assays was evaluated on preselected S/NC concordant and discordant specimens. All 190 Ortho S+/Roche NC+ specimens were reactive on the Ortho NC assay; 34% of 367 Ortho S+/Roche NC- specimens collected prior to vaccine availability and 43% of 37 Ortho S-/Roche NC+ specimens were reactive on the Ortho NC assay. Performance of parallel S/NC testing using Ortho and Roche platforms was evaluated on 200 specimens collected in 2019 and 3,903 study specimens collected in 2021. All 200 pre-COVID-19 specimens tested negative on the four assays. Cross-platform agreement between Roche and Ortho platforms was 96.4% (3,769/3,903); most discordant results had reactivity close to the cutoffs on the alternate assays. These findings, and higher efficiency and throughput, support the use of parallel S/NC testing on either Roche or Ortho platforms for large serosurveillance studies. IMPORTANCE Seroprevalence studies like the U.S. Nationwide Blood Donor Seroprevalence Study (NBDS) have been critical in monitoring SARS-CoV-2 epidemic activity. These studies rely on serological assays to detect antibodies indicating prior infection. It is critical that the assays and testing algorithms used in seroprevalence studies have adequate performance (high sensitivity, high specificity, ability to discriminate vaccine-induced and infection-induced antibodies, etc.), as well as appropriate characteristics to support large-scale studies, such as high throughput and low cost. In this study we evaluated the performance of Ortho's anti-nucleocapsid assay as a replacement for the Roche anti-nucleocapsid assay and compared performance of parallel anti-spike and anti-nucleocapsid testing on both platforms. These data demonstrate similar performance of the Ortho and Roche anti-nucleocapsid assays and that parallel anti-spike and anti-nucleocapsid testing on either platform could be used for serosurveillance applications.

Estimates of SARS-CoV-2 Seroprevalence and Incidence of Primary SARS-CoV-2 Infections Among Blood Donors, by COVID-19 Vaccination Status - United States, April 2021-September 2022.

Changes in testing behaviors and reporting requirements have hampered the ability to estimate the U.S. SARS-CoV-2 incidence (1). Hybrid immunity (immunity derived from both previous infection and vaccination) has been reported to provide better protection than that from infection or vaccination alone (2). To estimate the incidence of infection and the prevalence of infection- or vaccination-induced antibodies (or both), data from a nationwide, longitudinal cohort of blood donors were analyzed. During the second quarter of 2021 (April-June), an estimated 68.4% of persons aged ≥16 years had infection- or vaccination-induced SARS-CoV-2 antibodies, including 47.5% from vaccination alone, 12.0% from infection alone, and 8.9% from both. By the third quarter of 2022 (July-September), 96.4% had SARS-CoV-2 antibodies from previous infection or vaccination, including 22.6% from infection alone and 26.1% from vaccination alone; 47.7% had hybrid immunity. Prevalence of hybrid immunity was lowest among persons aged ≥65 years (36.9%), the group with the highest risk for severe disease if infected, and was highest among those aged 16-29 years (59.6%). Low prevalence of infection-induced and hybrid immunity among older adults reflects the success of public health infection prevention efforts while also highlighting the importance of older adults staying up to date with recommended COVID-19 vaccination, including at least 1 bivalent dose.*,†.

Standardized evaluation of Zika nucleic acid tests used in clinical settings and blood screening.

Early detection of Zika virus (ZIKV) transmission within geographic regions informs implementation of community mitigation measures such as vector reduction strategies, travel advisories, enhanced surveillance among pregnant women, and possible implementation of blood and organ donor screening or deferral. Standardized, comparative assessments of ZIKV assay and testing lab performance are important to develop optimal approaches to ZIKV diagnostic testing and surveillance. We conducted an expanded blinded panel study to characterize and compare the analytical performance of fifteen diagnostic and blood screening ZIKV NAT assays, including detection among single- and multiplex assays detecting ZIKV, dengue virus (DENV) and chikungunya virus (CHIKV). A 300 member blinded panel was constructed, consisting of 11 serial half-log dilutions ranging from ~104 to 10-1 genome equivalents/mL in 25 replicates each of the Tahitian Asian ZIKV isolate in ZIKV-negative human serum. Additionally, clinical samples from individuals with DENV-like syndrome or suspected ZIKV infection in Brazil were evaluated. The majority of assays demonstrated good specificity. Analytical sensitivities varied 1-2 logs, with a substantially higher limit of detection (LOD) in one outlier. Similar analytical sensitivity for ZIKV RNA detection in singleplex and multiplex assays of the Grifols and ThermoFisher tests were observed. Coefficient of Assay Efficiency (CE), calculated to characterize assays' RNA extraction and amplification efficiency, ranged from 0.13 for the Certest VIASURE multiplex and 0.75 for the Grifols multiplex assays. In general, assays using transcription mediated amplification (TMA) technology had greater CE compared to assays using conventional PCR technology. Donor screening NAT assays were significantly more sensitive than diagnostic RT-qPCR assays, primarily attributable to higher sample input volumes. However, ideal assays to maximize sensitivity and throughput may not be a viable option in all contexts, with other factors such as cost, instrumentation, and regulatory approval status influencing assay availability and selection, particularly in resource constrained settings.

Low rate of detection of SARS-CoV-2 RNA in deceased tissue donors.

Given the possibility for disease transmission, this study was performed to determine whether there is detectable SARS-CoV-2 viral RNA in the blood of deceased tissue donors. A retrospective analysis of blood samples from eligible deceased tissue donors from Oct 2019 through June 2020 was performed. Plasma aliquots were initially tested with a SARS-CoV-2 NAT Assay; positive samples were further tested using an alternate NAT and an antibody assay. The proportion of donors with confirmed RNAemia and 95% confidence intervals were computed. Of donor samples collected in 2019, 894 yielded valid results, with 6 initially positive, none of which confirmed positive by alternate NAT. Of donor samples collected in 2020, 2562 yielded valid initial NAT results, with 21 (0.8%) initially positive. Among those, 3 were confirmed by alternate NAT, 17 were not confirmed, and 1 had an invalid alternate NAT result. The rate of SARS-CoV-2 RNAemia in deceased tissue donors is approximately 1 per 1000, and it is unknown whether this RNAemia reflects the presence of infectious virus. Given these results, the risk of transmission through tissue is thought likely to be low.

Surveillance for Zika, Chikungunya, and Dengue Virus Incidence and RNAemia in Blood Donors at 4 Brazilian Blood Centers During 2016-2019.

BACKGROUND: Except for public health case reports, the incidence of Zika virus (ZIKV), chikungunya virus (CHIKV), and dengue virus (DENV) infection are not available to assess the potential blood transfusion safety threat in Brazil. METHODS: Pools of 6 donation samples (MP6) left over from human immunodeficiency virus, hepatitis B virus, and hepatitis C virus nucleic acid testing were combined to create MP18 pools (3 MP6 pools). Samples were tested using the Grifols triplex ZIKV, CHIKV, and DENV real-time transcription mediated amplification assay to estimate prevalence of RNAemia and incidence, and to compare these results to case reports in São Paulo, Belo Horizonte, Recife, and Rio de Janeiro, from April 2016 through June 2019. RESULTS: ZIKV, CHIKV, and DENV RNAemia were found from donors who donated without overt symptoms of infection that would have led to deferral. The highest RNAemic donation prevalence was 1.2% (95% CI, .8%-1.9%) for DENV in Belo Horizonte in May 2019. Arbovirus infections varied by location and time of year, and were not always aligned with annual arbovirus outbreak seasons in different regions of the country. CONCLUSIONS: Testing donations for arboviruses in Brazil can contribute to public health. Transfusion recipients were likely exposed to ZIKV, CHIKV, and DENV viremic blood components during the study period.

Facilitating Next-Generation Pre-Exposure Prophylaxis Clinical Trials Using HIV Recent Infection Assays: A Consensus Statement from the Forum HIV Prevention Trial Design Project.

Standard-of-care HIV pre-exposure prophylaxis (PrEP) is highly efficacious, but uptake of and persistence on a daily oral pill is low in many settings. Evaluation of alternate PrEP products will require innovation to avoid the unpractically large sample sizes in noninferiority trials. We propose estimating HIV incidence in people not on PrEP as an external counterfactual to which on-PrEP incidence in trial subjects can be compared. HIV recent infection testing algorithms (RITAs), such as the limiting antigen avidity assay plus viral load used on specimens from untreated HIV positive people identified during screening, is one possible approach. Its feasibility is partly dependent on the sample size needed to ensure adequate power, which is impacted by RITA performance, the number of recent infections identified, the expected efficacy of the intervention, and other factors. Screening sample sizes to support detection of an 80% reduction in incidence for 3 key populations are more modest, and comparable to the number of participants in recent phase III PrEP trials. Sample sizes would be significantly larger in populations with lower incidence, where the false recency rate is higher or if PrEP efficacy is expected to be lower. Our proposed counterfactual approach appears to be feasible, offers high statistical power, and is nearly contemporaneous with the on-PrEP population. It will be important to monitor the performance of this approach during new product development for HIV prevention. If successful, it could be a model for preventive HIV vaccines and prevention of other infectious diseases.

Blood Center Testing Allows the Detection and Rapid Treatment of Acute and Recent HIV Infection.

Blood donations in South Africa are tested for HIV RNA using individual donation NAT (ID-NAT), allowing detection and rapid antiretroviral therapy (ART) of acute HIV infections. We enrolled a cohort of acute and recent HIV-infected blood donation candidates in South Africa in 2015-2018, measured HIV antibody, ID-NAT, and recency of infection <195 days (Sedia LAg) at enrollment and initiated early ART. A small cohort of HIV elite controllers was followed without treatment. HIV reservoir measurements included ultrasensitive plasma RNA, cell-associated HIV RNA, and total DNA. Enrollment of 18 Fiebig I-III and 45 Fiebig IV-VI HIV clade C subjects occurred a median of 18 days after index blood donation. ART was administered successfully and compliance with follow-up visits was excellent. There were only minimal differences in HIV reservoir between ART initiation in Fiebig stages I-III vs. IV-VI, but ART noncompliance increased HIV reservoir. In 11 untreated HIV elite controllers, HIV reservoir levels were similar to or higher than those seen in our early treated cohort. National blood services can identify acute HIV cohorts for subsequent HIV cure research studies. Among HIV clade C-infected donors, HIV reservoir differed little by Fiebig stage at treatment initiation, but was smaller than in chronically treated HIV and those with ART noncompliance.

Coronavirus Disease 2019 Vaccine Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2 Infection in the United States Before the Delta- and Omicron-Associated Surges: A Retrospective Cohort Study of Repeat Blood Donors.

BACKGROUND: To inform public health policy, it is critical to monitor coronavirus disease 2019 vaccine effectiveness (VE), including against acquiring infection. METHODS: We estimated VE using self-reported vaccination in a retrospective cohort of repeat blood donors who donated during the first half of 2021, and we demonstrated a viable approach for monitoring VE via serological surveillance. RESULTS: Using Poisson regression, we estimated an overall VE of 88.8% (95% confidence interval, 86.2-91.1), adjusted for demographic covariates and variable baseline risk. CONCLUSIONS: The time since first reporting vaccination, age, race and/or ethnicity, region, and calendar time were statistically significant predictors of incident infection.

The Impact of Early Antiretroviral Treatment (ART) for HIV on the Sensitivity of the Latest Generation of Blood Screening and Point of Care Assays.

INTRODUCTION: Rapid initiation of antiretroviral therapy (ART) in early HIV infection is important to limit seeding of the viral reservoir. A number of studies have shown that if ART is commenced prior to seroconversion, the seroconversion may, or may not, occur. We aimed to assess whether seroreversion or no seroconversion occurs using samples collected during an early treatment study in South Africa. METHODS: We tested 10 longitudinal samples collected over three years from 70 blood donors who initiated ART after detection of acute or early HIV infection during donation screening on fourth- and fifth-generation HIV antibody and RNA assays, and three point of care (POC) rapid tests. Donors were allocated to three treatment groups: (1) very early, (2) early, and (3) later. Longitudinal samples were grouped into time bins post-treatment initiation. RESULTS: On all three high-throughput HIV antibody assays, no clear pattern of declining signal intensity was observed over time after ART initiation in any of the treatment initiation groups and 100% detection was obtained. The Abbott Determine POC assay showed 100% detection at all time points with no seroreversion. However, the Abbott ABON HIV1 and OraSure OraQuick POC assays showed lower proportions of detection in all time bins in the very early treated group, ranging from 50.0% (95% CI: 26.8-73.2%) to 83.1% (95% CI: 64.2-93.0%), and moderate detection rates in the early and later-treated groups. CONCLUSION: While our findings are generally reassuring for HIV detection when high-throughput serological screening assays are used, POC assays may have lower sensitivity for detection of HIV infection after early treatment. Findings are relevant for blood safety and other settings where POC assays are used.

Quantitative interpretation of Sedia LAg Assay test results after HIV diagnosis.

BACKGROUND: Testing for 'recent HIV infection' is common in surveillance, where only population-level estimates (of incidence) are reported. Typically, 'recent infection' is a category, obtained by applying a threshold on an underlying continuous biomarker from some laboratory assay(s). Interpreting the biomarker values obtained for individual subjects, as estimates of the date of infection, has obvious potential applications in the context of studies of early infection, and has also for some years attracted significant interest as an extra component of post-test counselling and treatment initiation. The applicable analyses have typically run aground on the complexity of the full biomarker growth model, which is in principle a non-linear mixed-effects model of unknown structure, the fitting of which seems infeasible from realistically obtainable data. METHODS: It is known that to estimate Mean Duration of Recent Infection (MDRI) at a given value of the recent/non-recent -infection discrimination threshold, one may compress the full biomarker growth model into a relation capturing the probability of a recent test result as a function of time t since infection, given a value of assay threshold h which defines the recent/non-recent discrimination. We demonstrate that the derivative (gradient), with respect to h. of the probability of recent infection, seen as a function of both t and h, is identical to the formal likelihood relevant to Bayesian inference of the time since seroconversion, for a subject yielding an assay result h, at or close to the date of their first positive HIV test. This observation bypasses the need for fitting a complex detailed biomarker growth model. Using publicly available data from the CEPHIA collaboration, we calibrated this likelihood function for the Sedia Lag assay, and performed Bayesian inference on hypothetical infection data. RESULTS: We demonstrate the generation of posteriors for infection date, for patients with various delays between their last negative and first positive HIV test, and a range of LAg assay results (ODn) hypothetically obtained on the date of the first positive result. CONCLUSION: Depending on the last-negative / first-positive interval, there is a range of ODn values that yields posteriors significantly different from the uniform prior one would be left with based merely on interval censoring. Hence, a LAg ODn obtained on the date of, or soon after, diagnosis contains potentially significant information about infection dating. It seems worth analysing other assays with meaningful dynamic range, especially tests already routinely used in primary HIV diagnosis (for example chemiluminescent assays and reader/cartridge lateral flow tests which admit objective variable line intensity readings) which have a sufficient dynamic range that corresponds to a clinically meaningful range of times-since-infection that are worth distinguishing from each other.