Fiebig Stage Research Articles

Clones of infected cells arise early in HIV-infected individuals.

In HIV-infected individuals on long-term antiretroviral therapy (ART), more than 40% of the infected cells are in clones. Although most HIV proviruses present in individuals on long-term ART are defective, including those in clonally expanded cells, there is increasing evidence that clones carrying replication-competent proviruses are common in patients on long-term ART and form part of the HIV reservoir that makes it impossible to cure HIV infection with current ART alone. Given the importance of clonal expansion in HIV persistence, we determined how soon after HIV acquisition infected clones can grow large enough to be detected (clones larger than ca. 1 × 105 cells). We studied 12 individuals sampled in early HIV infection (Fiebig stage III-V/VI) and 5 who were chronically infected. The recently infected individuals were started on ART at or near the time of diagnosis. We isolated more than 6,500 independent integration sites from peripheral blood mononuclear cells before ART was initiated and after 0.5-18 years of suppressive ART. Some infected clones could be detected approximately 4 weeks after HIV infection and some of these clones persisted for years. The results help to explain how the reservoir is established early and persists for years.

Estimation of the Seroconversion Duration of HIV-1 Antibodies in Individuals With Recent Infection in China.

The identification of recent HIV-1 infection is clinically important for the effective treatment and prevention of transmission. However, the window period for seroconversion with respect to various HIV-1 antibodies is not well characterized. In addition, the routine HIV testing algorithms are not particularly appropriate for the identification of recent HIV-1 infection. In this study, we enrolled individuals who showed seroconversion from negative Western blot (WB) or indeterminate WB results and analyzed the window periods for appearance of HIV-1 antibodies. A total of 10,934 individuals with suspected HIV infection were tested by Wuhan CDC between 2012 and 2017; of these, 40 individuals with initial negative WB and 102 individuals with initial indeterminate WB who showed positive WB results within 100 days were included in the analysis. The mean time for seroconversion was 43.90 (95% confidence interval [CI]: 37.30–50.50) days and 42.15 (95% CI: 37.99–46.30) days, respectively. The time duration for p31 seroconversion among people with negative WB and indeterminate WB was 58.11 (95% CI, 44.30–71.92) days and 51.91 (95% CI, 44.55–59.28) days, respectively, both of which were significantly longer (p = 0.0169) than those in people without p31 seroconversion. A similar difference was observed with respect to p66 seroconversion, with a window time of 53.53 (95% CI, 43.54–63.52) days and 47.87 (95% CI, 43.16–52.57) days among people with negative WB and indeterminate WB, respectively. These data suggest that HIV-1 antibody p66, like p31, may serve as a potential serological marker for distinguishing Fiebig stage V and stage VI at day 70 post-infection.

Impact of Early Antiretroviral Therapy on Detection of Cell-Associated HIV-1 Nucleic Acid in Blood by the Roche Cobas TaqMan Test.

The Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 test, v2.0 (the CAP/CTM assay), was used to quantify cell-associated HIV-1 (CAH) nucleic acid in peripheral blood mononuclear cells (PBMC) from well-characterized clinical specimens from HIV-1-infected individuals on antiretroviral therapy (ART). Chronically infected individuals on ART with no detectable plasma HIV-1 RNA demonstrated average CAH burdens of 3.2 HIV-1 log10 copies/million cells. Assay sensitivity and specificity were 98.9% and 100%, respectively, with the positive and negative predictive values being 100% and 98.6%, respectively. The CAH burden was also measured at weeks 0, 1, 2, 8, and 60 in 37 participants (RV254/SEARCH010, Bangkok, Thailand) stratified by Fiebig stage (Fiebig stage I [FI] to FVI) at ART initiation. Prior to ART initiation, the average CAH burden was 1.4, 4.1, and 3.6 log10 copies/million PBMCs for individuals who initiated ART at FI, FII, and FIII to FVI, respectively. Initiation of ART resulted in a rapid decline of CAH in all individuals, with the greatest decrease being observed in individuals who initiated ART at FI to FIII. By week 60, 100% (FI), 71.8% (FII/FIII), and 20.5% (FIV to FVI) of samples from individuals initiating treatment were at or near the limit of quantitation. Residual CAH was detectable at 60 weeks in most individuals who initiated ART at later stages (FIV to FVI) and averaged 1.9 ± 0.7 log10 copies/million PBMCs. The modified Roche CAP/CTM assay provides a convenient, standardized approach to measure residual HIV in blood and may be useful for monitoring patients under therapy or those participating in HIV remission studies.

Safety and efficacy of VRC01 broadly neutralising antibodies in adults with acutely treated HIV (RV397): a phase 2, randomised, double-blind, placebo-controlled trial

HIV-1-specific broadly neutralising antibodies such as VRC01 could promote HIV remission by halting viral replication and clearing infected cells. We investigated whether VRC01 could promote sustained viral control off antiretroviral therapy (ART) in adults who initiated ART during acute HIV infection. We did a randomised, double-blind, placebo-controlled trial at the Thai Red Cross AIDS Research Centre in Bangkok, Thailand. Eligible participants were aged 20-50 years, had initiated ART during acute infection (ie, Fiebig stages I-III), had been taking ART for more than 24 months, had fewer than 50 HIV-1 RNA copies per mL on three consecutive measurements, had more than 400 CD4 cells per μL, had fewer than ten copies of integrated HIV-1 DNA per 106 peripheral blood mononuclear cells, and were in generally good health. Eligible participants were randomly assigned (3:1) based on computer-generated lists with a blocking factor of 4 to receive VRC01 (40 mg/kg) or placebo (saline) intravenously every 3 weeks for up to 24 weeks during analytic interruption of ART, followed by continued observation off all therapies. Randomisation was stratified by Fiebig stage (I vs II vs III) at HIV diagnosis. Participants were monitored closely and resumed ART if 1000 or more HIV-1 RNA copies were detected per mL of plasma. The primary outcomes were the frequency of serious adverse events and the proportion of participants with fewer than 50 HIV-1 RNA copies per mL 24 weeks after treatment interruption. Efficacy analyses included all participants who received at least one full dose of study product, and safety analyses included all participants exposed to any study product. The trial was registered with ClinicalTrials.gov, number NCT02664415. This trial is completed. Between Aug 8, 2016, and Jan 9, 2017, 19 men were randomly assigned, 14 to the VRC01 group and five to the placebo group. One participant in the VRC01 group received a partial infusion without undergoing treatment interruption. The other 18 participants all received at least one full study infusion and underwent ART interruption. No serious adverse events were reported in either group. Only one participant in the VRC01 group achieved the primary efficacy endpoint of viral suppression 24 weeks after ART interruption. The other 17 restarted ART because of a confirmed recording of 1000 or more HIV-1 RNA copies per mL before 24 weeks. VRC01 monotherapy in individuals who initiated ART during acute HIV infection was well tolerated but did not significantly increase the number of participants with viral suppression 24 weeks after ART interruption. Further development of VRC01 and other immunotherapies for HIV will probably occur as part of combination regimens that include several treatments directed against unique therapeutic targets. US Department of the Army, US National Institutes of Health, and the Thai Red Cross AIDS Research Centre.

Acute HIV Infection in Youth: Protocol for the Adolescent Trials Network 147 (ATN147) Comprehensive Adolescent Research and Engagement Studies (CARES) Study.

BackgroundEarly treatment studies have shown that prompt treatment of HIV with combination antiretroviral therapy (cART) can limit the size of latent viral reservoirs, thereby providing clinical and public health benefits. Studies have demonstrated that adolescents have a greater capacity for immune reconstitution than adults. Nevertheless, adolescents who acquired HIV through sexual transmission have not been included in early treatment studies because of challenges in identification and adherence to cART.ObjectiveThis study aimed to identify and promptly treat with cART youth aged 12 to 24 years in Los Angeles and New Orleans who have acute, recent, or established HIV infection, as determined by Fiebig stages 1 to 6 determined by viral RNA polymerase chain reaction, p24 antigen presence, and HIV-1 antigen Western blot. The protocol recommends treatment on the day of diagnosis when feasible. Surveillance and dedicated behavioral strategies are used to retain them in care and optimize adherence. Through serial follow-up, HIV biomarkers and response to antiretroviral therapy (ART) are assessed. The study aims to assess viral dynamics, decay and persistence of viral reservoirs over time, and correlate these data with the duration of viral suppression.MethodsA total of 72 youth (36 acutely infected and 36 treatment naïve controls) are enrolled across clinical sites using a current community-based strategy and direct referrals. Youth are prescribed ART according to the standard of care HIV-1 management guidelines and followed for a period of 2 years. Assessments are conducted at specific time points throughout these 2 years of follow-up for monitoring of adherence to ART, viral load, magnitude of HIV reservoirs, and presence of coinfections.ResultsThe study began enrolling youth in July 2017 across study sites in Los Angeles and New Orleans. As of September 30, 2018, a total of 37 youth were enrolled, 12 with recently acquired, 16 with established HIV infection as determined by Fiebig staging, and 9 pending determination of Fiebig status. Recruitment and enrollment are ongoing.ConclusionsWe hypothesize that the size of the HIV reservoir and immune activation markers will be different across groups treated with cART, that is, those with acute or recent HIV infection and those with established infection. Adolescents treated early who are virally suppressed will have diminished HIV reservoirs than those with established infection. These youth may be potential candidates for a possible HIV vaccine and additional HIV remission intervention trials. Our study will inform future studies of viral remission strategies.International Registered Report Identifier (IRRID)DERR1-10.2196/10807

560. Immune Recovery of Acute HIV-Treated Patients Is Characterized by an Increase in Immune Senescence

BackgroundARV treatment (ART) administered during acute HIV-infection presents several immunological benefits leading to a better CD4+ T-cell recovery and a diminished HIV reservoir.MethodsPatients with acute HIV-infection, enrolled in the VIHIA cohort, had blood samples taken at diagnosis and at 2, 6 and 12 months after ART initiation. Flow-cytometry analysis was performed in fresh whole blood. Naïve-(Nv), central memory (CM), effector memory (EM) and terminally differentiated T-cells (TMRA), as well as activation markers were defined using CD3, CD4, CD8, CD45RA, CCR7, CD38, CD31 and HLA-DR markers. CD28 and CD57 were used to identify immunosenescent cells. Fox-P3, CD 25, CD127 and CD45RA were used to identify Regulatory T cells (Treg) and their subsets. To assess changes over time, Wilcoxon-matched-pairs signed rank test was used for each value between baseline and months 2 and 12 independently.ResultsFour patients were diagnosed at Fiebig stage II; 5 patients at Fiebig stage III, 24 patients at stage IV and 5 patients in stage V. All patients received treatment within the first 24 hours of HIV diagnosis. Only 13 patients had flow-cytometry data at baseline and 1 year of follow-up. All subjects were MSM with a mean age of 32 y.o. Mean CD4+ T-cell count was 439 cells/μL and mean viral load was 1.2 million copies/mL (23,379–10 × 106 copies/mL) at baseline. The change in T-cell differentiation patterns at 0 and 12 months is shown in Figure 1. Activation markers decreased in all studied subsets at 2 months and furthermore at 12 months. Total T-regs increased from 5.1% to 7.8% at 1 year of follow-up (Figure 2). Immunosenescence markers increased steadily throughout the study in all T-cell subsets, being statistically significant in the total T-cell CD8 population at 12 months of follow-up (Figure 3) unrelated to Fiebig stage.ConclusionIt has been hypothesized that early ART decreases T-cell immunosenescence; however, in our cohort despite treatment during acute HIV, we observed that at 1 year follow-up immunosenescence markers increased despite a decrease in immune activation and a recovery of T-cell subsets. Disclosures All authors: No reported disclosures.

Neutralization Sensitivity of a Novel HIV-1 CRF01_AE Panel of Infectious Molecular Clones.

HIV-1 CRF01_AE is dominant in Thailand where RV144 vaccine trial was conducted. To study immune correlates of protection in ongoing trials, CRF01_AE-derived reagents are essential. Here, we present a panel of 14 HIV-1 infectious molecular clones (IMCs) identified from different stages of infection and characterization of their neutralization sensitivity using 2 standard assays. One full-length IMC was constructed using a transmitted-founder virus to express Renilla luciferase (LucR) reporter gene and full-length envelopes (envs) of exogenous HIV-1. A panel of IMCs was generated, expressing envs of viruses from acute (Fiebig stages I/II and I-IV) and chronic (>Fiebig VI) infection. Neutralization assays were performed using TZM-bl or A3R5 cell lines, and sera or monoclonal antibodies (mAbs). Wilcoxon matched-paired test was used to assess neutralization differences between assays and reagents; correlation coefficients were evaluated by linear regression. Neutralization potency observed was significantly higher in the A3R5 assay when testing mAbs and serum pools (P < 0.0001); the stage of infection from which env was derived did not associate with IMC neutralization sensitivity. Neutralization values from A3R5 and TZM-bl assays were strongly correlated when mAbs were tested (R = 0.7, P < 0.0001), but a weaker association was seen with serum pools (R = 0.17, P = 0.03). This novel panel of CRF01_AE reporter IMC is useful for assessing vaccine-induced neutralizing antibodies in multiple assays, including those using primary cell targets. The significant differences in TZM-bl and A3R5 neutralization sensitivity, as well as the poor association when using polyclonal sera indicates the need for caution in choosing one specific platform.

HIV-1 RNA testing of pooled dried blood spots is feasible to diagnose acute HIV infection in resource limited settings

Objectives:Rapid human immunodeficiency virus (HIV) antibody tests, routinely used for diagnosis in adults and older children in resource-limited settings (RLS), do not detect early HIV infections prior to seroconversion or when antibody levels are still low. Nucleic acid amplification to detect HIV-1 RNA is the most sensitive method for acute HIV infection diagnosis, but is costly. We therefore investigated HIV- 1 RNA testing of pooled dried blood spots (DBS) to diagnose acute HIV infection.Design:Laboratory-based investigation.Methods:DBS were collected from HIV-1 Voluntary Counselling and Testing (HVCT) clients who tested negative on the Advanced QualityTM HIV antibody rapid test. DBS samples from five participants were pooled and tested on the COBAS AmpliPrep/COBAS TaqMan HIV-1 (CAP/CTM) Test v2. Individual DBS were tested when pools tested positive ( 200 RNA copies/ml). Acute infection was confirmed by HIV viral load testing, two fourth-generation HIV serological assays, and Geenius™ HIV 1/2 Assay for antibody band identification.Results:Of 482 participants who were tested, one (0.2%) had acute. HIV infection: Fourth generation serology was low-level positive, the plasma HIV viral load was 15 929 HIV-1 RNA copies/ml, gp160 and gp41 antibody bands were positive and the p31 band was negative, indicating a Fiebig Stage 5 infection.Conclusions: Pooled DBS HIV-1 RNA testing is efficient compared to individual testing for acute HIV infection diagnosis. Early identification of participants with acute HIV infection facilitates immediate initiation of antiretroviral therapy to improve immune recovery and prevent transmission to others.

No Time to Delay! Fiebig Stages and Referral in Acute HIV infection: Seattle Primary Infection Program Experience.

There has been increasing recognition of the importance of diagnosing individuals during the earliest stages of human immunodeficiency virus (HIV) infection. Sera from individuals referred to a primary HIV infection research program were screened using the IgG-sensitive Vironostika HIV-1 Microelisa System, IgG/IgM-sensitive GS HIV-1/HIV-2 Plus O antibody enzyme immunoassay (EIA), or Abbott ARCHITECT HIV antigen (Ag)/antibody (Ab) Combo assay and confirmed by the Bio-Rad Multispot and Western blot. A subset of participants was co-enrolled in a study designed to compare the ability of point-of-care tests to detect early infection. We calculated time within primary infection laboratory stages using actual observed transitions and with an expectation-maximization algorithm. Three hundred and sixty participants contributed data to this analysis. Of 123 persons referred with EIA-negative/RNA-positive test results (Fiebig stage I-II) or for concern for symptoms, 24 (20%) were still in stages I-II, and 99 (80%) were in stages III or later at their screening visit. Participants were estimated to spend a median of 13.5 days in stages I and II, 2.3 days in stage III, and 7.8 days in stage IV. OraQuick performed on oral fluids detected 53% of 17 participants in stage V. The durations of stages we observed are consistent with previous publications. Most persons referred for research no longer had acute infection at their first visit. Programs wishing to identify persons in the very earliest stages of infection need to expedite referrals or develop targeted screening programs.

Distribution of Human Immunodeficiency Virus (HIV) Ribonucleic Acid in Cerebrospinal Fluid and Blood Is Linked to CD4/CD8 Ratio During Acute HIV.

Human immunodeficiency virus (HIV) ribonucleic acid (RNA) levels in the plasma and cerebrospinal fluid (CSF) are correlated in chronic HIV infection, but their dynamics have not been characterized during acute infection. This study analyzed predictors of CSF HIV RNA and relative degree of CNS viral transmigration expressed as plasma minus CSF HIV log10 RNA (PCratio) during untreated acute HIV infection. Cerebrospinal fluid immune markers were compared between groups with different PCratio. One hundred seventeen mostly male (97%) participants in the RV254 cohort in Bangkok, Thailand, had a median age of 28 years and an estimated median 18 days duration of infection; 43 (37%) were Fiebig stages I/II. Twenty-seven (23%) had CSF HIV RNA <80 copies/mL. Those with quantifiable levels (n = 90) had median CSF HIV RNA and PCratio of 3.76 and 2.36 log10 copies/mL, respectively. Human immunodeficiency virus RNA peaked at Fiebig III in plasma and Fiebig IV in CSF. In multivariable analyses, plasma HIV RNA and CD4/CD8 ratio independently correlated with CSF HIV RNA (P < .001), whereas CD4/CD8 ratio predicted PCratio (P = .018). Participants with PCratio <1 had higher CSF neopterin, soluble (s)CD163, interleukin-6, and sCD14 levels (all P < .05). CD4/CD8 ratio independently correlated with CSF HIV RNA and PCratio, suggesting that immune responses modulate central nervous system viral entry at early infection.

Acute Retroviral Syndrome Is Associated With High Viral Burden, CD4 Depletion, and Immune Activation in Systemic and Tissue Compartments.

Many individuals with acute human immunodeficiency virus infection (AHI) experience acute retroviral syndrome (ARS), which is associated with adverse long-term clinical outcomes. Participants presenting for voluntary human immunodeficiency virus (HIV) testing were enrolled during AHI in Bangkok, Thailand. ARS was defined by ≥3 qualifying signs/symptoms. HIV burden, immunophenotypes, and biomarkers were stratified by ARS diagnosis at enrollment and after up to 96 weeks of antiretroviral therapy (ART). From 212382 samples screened, 430 participants were enrolled during AHI, including 335 (78%) with ARS. Median age was 26 years and 416 (97%) were men. Sixty (14%) underwent sigmoid biopsy and 105 (24%) underwent lumbar puncture during AHI. Common symptoms included fever (93%), fatigue (79%), pharyngitis (67%), and headache (64%). Compared to those without ARS, participants with ARS were in later Fiebig stages with higher HIV RNA in blood, colon, and cerebrospinal fluid; higher total HIV DNA in blood; CD4 depletion in blood and colon; and elevated plasma tumor necrosis factor alpha (TNF-α), C-reactive protein, and D-dimer (all P < .05). Subgroup analyses of Fiebig I/II participants (95 with ARS, 69 without) demonstrated similar findings. After 96 weeks of ART, TNF-α and interleukin 6 were elevated in the ARS group (P < .05) but other biomarkers equilibrated. ARS was associated with high viral burden, CD4 depletion, and immune activation across multiple body compartments during AHI and prior to ART. Persistent inflammation despite suppressive ART could contribute to increased morbidity in individuals who experience ARS.

Detection and treatment of Fiebig stage I HIV-1 infection in young at-risk women in South Africa: a prospective cohort study

HIV incidence among young women in sub-Saharan Africa remains high and their inclusion in vaccine and cure efforts is crucial. We aimed to establish a cohort of young women detected during Fiebig stage I acute HIV infection in whom treatment was initiated immediately after diagnosis to advance research in this high-risk group. 945 women aged 18-23 years in KwaZulu-Natal, South Africa, who were HIV uninfected and sexually active consented to HIV-1 RNA testing twice a week and biological sampling and risk assessment every 3 months during participation in a 48-96 week life-skills and job-readiness programme. We analysed the effect of immediate combination antiretroviral therapy (ART) on viraemia and immune responses, sexual risk behaviour, and the effect of the socioeconomic intervention. 42 women were diagnosed with acute HIV infection between Dec 1, 2012, and June 30, 2016, (incidence 8·2 per 100 person-years, 95% CI 5·9-11·1), of whom 36 (86%) were diagnosed in Fiebig stage I infection with a median initial viral load of 2·97 log10 copies per mL (IQR 2·42-3·85). 23 of these 36 women started ART at a median of 1 day (1-1) after detection, which limited the median peak viral load to 4·22 log10 copies per mL (3·27-4·83) and the CD4 nadir to 685 cells per μL (561-802). ART also suppressed viral load (to <20 copies per mL) within a median of 16 days (12-26) and, in 20 (87%) of 23 women, prevented seroconversion, as shown with western blotting. 385 women completed the 48 week socioeconomic intervention, of whom 231 were followed up for 1 year. 202 (87%) of these 231 women were placed in jobs, returned to school, or started a business. Frequent HIV screening combined with a socioeconomic intervention facilitated sampling and risk assessment before and after infection. In addition to detection of acute infection and immediate treatment, we established a cohort optimised for prevention and cure research. Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases, International AIDS Vaccine Initiative, Wellcome Trust, Howard Hughes Medical Institute.

Plasma CXCL13 but Not B Cell Frequencies in Acute HIV Infection Predicts Emergence of Cross-Neutralizing Antibodies.

Immunological events in acute HIV-1 infection before peak viremia (hyperacute phase) may contribute to the development of broadly cross-neutralizing antibodies. Here, we used pre-infection and acute-infection peripheral blood mononuclear cells and plasma samples from 22 women, including 10 who initiated antiretroviral treatment in Fiebig stages I–V of acute infection to study B cell subsets and B-cell associated cytokines (BAFF and CXCL13) kinetics for up to ~90 days post detection of plasma viremia. Frequencies of B cell subsets were defined by flow cytometry while plasma cytokine levels were measured by ELISA. We observed a rapid but transient increase in exhausted tissue-like memory, activated memory, and plasmablast B cells accompanied by decline in resting memory cells in untreated, but not treated women. B cell subset frequencies in untreated women positively correlated with viral loads but did not predict emergence of cross-neutralizing antibodies measured 12 months post detection of plasma viremia. Plasma BAFF and CXCL13 levels increased only in untreated women, but their levels did not correlate with viral loads. Importantly, early CXCL13 but not BAFF levels predicted the later emergence of detectable cross-neutralizing antibodies at 12 months post detection of plasma viremia. Thus, hyperacute HIV-1 infection is associated with B cell subset changes, which do not predict emergence of cross-neutralizing antibodies. However, plasma CXCL13 levels during hyperacute infection predicted the subsequent emergence of cross-neutralizing antibodies, providing a potential biomarker for the evaluation of vaccines designed to elicit cross-neutralizing activity or for natural infection studies to explore mechanisms underlying development of neutralizing antibodies.

The effect of oral preexposure prophylaxis on the progression of HIV-1 seroconversion.

To investigate whether oral preexposure prophylaxis (PrEP) alters timing and patterns of seroconversion when PrEP use continues after HIV-1 infection. Retrospective testing of the timing of Fiebig stage HIV-1 seroconversion in the Partners PrEP Study, a randomized placebo-controlled clinical trial of PrEP conducted in Kenya and Uganda. Specimens from 138 seroconverters were collected every 3 months and when HIV-1 infection was suspected based on monthly rapid HIV-1 tests. Progression of seroconversion was compared between randomized groups (PrEP versus placebo) and per-protocol groups (placebo versus PrEP participants with detectable tenofovir during the seroconversion period) using laboratory assessment of Fiebig stage. Delay in site-detection of seroconversion and association with PrEP drug-regimen resistant virus were assessed using logistic regression. Analysis of time to each Fiebig stage used maximum likelihood estimation with a parametric model to accommodate the varying lengths of HIV-infection intervals. There was a significant increase in delayed site detection of infection associated with PrEP (odds ratio = 3.49, P = 0.044). Delay in detection was not associated with increased risk of resistance in the PrEP arm (odds ratio = 0.93, P = 0.95). Estimated time to each Fiebig stage was elongated in seroconverters with evidence of ongoing PrEP use, significantly for only Stage 5 (28 versus 17 days, P = 0.05). Adjusted for Fiebig stage, viral RNA was ∼2/3 log lower in those assigned to PrEP compared with placebo; no differences were found in Architect signal to cut-off at any stage. Ongoing PrEP use in seroconverters may delay detection of infection and elongate seroconversion, although the delay does not increase risk of resistance.

Sensitivity of the STAT-VIEW rapid self-test and implications for use during acute HIV infection

ObjectivesHIV testing is an important step towards diminishing incident infections. Rapid self-tests whose use is becoming more common in France could help increase access to testing, yet could fail to...

Staging of recent HIV-1 infection using Geenius rapid confirmatory assay compared to INNO-LIA, New Lav and Blot 2.2 assays

BackgroundBesides confirmation of HIV seropositivity, Western Blot (WB) assays play an important role for identification of recent infection based on incomplete antibody reactivity and lack of p31 band. ObjectivesWe evaluated the capacities of the Geenius™ HIV1/2 Confirmatory Assay (Bio-Rad), a new generation rapid confirmatory assay based on immune-chromatography and automated reading, for staging of HIV-1 infection. Study designSixteen samples collected during early HIV-1 infections (Fiebig stage III–VI) were tested using the Geenius assay, and compared to HIV Blot 2.2 WB assay (MP Diagnostics), New Lav Blot I WB assay (Bio-Rad) and INNO-LIA™ HIV I/II Score Dot Blot assay (Fujirebio). Results obtained with Geenius and INNO LIA in 47 newly diagnosed chronic HIV-1 infections were also compared. ResultsThe p24 band was less frequently detected in early HIV-1 infections using the Geenius (3/16) compared to the New Lav (15/16, p<0.0001), INNO-LIA (13/16, p=0.0011), and Blot 2.2 (13/16, p=0.0011). Testing samples collected during chronic infection allowed to confirm that p31 band and complete Gag, Pol, Env profiles were less frequently observed using the Geenius assay compared to the INNO LIA assay (p=0.027 for p31, and p=0.0015 for complete profile). ConclusionsThe Geenius assay is a simple and rapid test showing a high sensitivity to detect Env bands and to confirm HIV-1 seropositivity during the early phases of infection. However, this test is less suitable for distinguishing between later stages of acute and chronic infections because of a reduced sensitivity to detect the p31 and p24 bands compared to INNO LIA and New Lav assays.

Neurological involvement in patients with acute/recent HIV-1 infection. A case-control study.

Primary HIV-1 infection is a relevant period for its virological and epidemiological consequences. Most patients present a symptomatic disease that can be potentially serious, but neurological involvement during primary HIV-1 infection has been poorly studied. The aim of this study was to describe the characteristics and outcomes of primary HIV-1 infection patients presenting neurological symptoms and to compare them with primary HIV-1 infection patients without neurological involvement. Retrospective case-control study (1:3) comparing primary HIV-1 infection patients with and without neurological involvement enrolled in the Acute/Recent Hospital Clinic PHI Cohort between 1997 and 2016. Matching criteria included age (±10years), gender, year of diagnosis (±4years), and Fiebig stage. The conditional logit model was used for comparisons. Fourteen out of 463 patients (3.02%) enrolled in the Acute/Recent Hospital Clinic PHI Cohort between 1997 and 2016 presented neurological symptoms. 28.5% of cases presented as meningitis and 71.5% as meningoencephalitis. Cerebrospinal fluid showed non-specific findings, including pleocytosis with lymphocyte predominance and increased protein levels. All cases required hospitalisation, whereas only 19% of the controls did. No other pathogen was identified in any case, but five patients initiated empirically antimicrobial treatment for other aetiologies until diagnosis was confirmed. CD4/CD8 ratio was significantly lower (p=0.039) and plasmatic viral load significantly higher in the case group, compared to controls (p=0.028). Risk factors, HIV-1 tropism, subtype distribution, and prescribed ART regimens were comparable between cases and controls. After 6months on ART, 92% of cases had undetectable viral load, similar to controls, and CD4/CD8 ratio became also comparable between groups. All cases recovered rapidly with ART and were discharged without sequels. Neurological involvement during primary HIV-1 infection is unusual but serious, always requiring hospitalisation. Diagnosis is difficult because of the wide range of symptoms and similarities with other viral aetiologies. Neurological manifestations during primary HIV-1 infection are associated with a lower CD4/CD8 ratio and with a higher viral load than controls. Immediate ART initiation and rapid viral load decrease are required, allowing complete clinical recovery.

A-102 Impact of treatment in Fiebig Stage I on HIV-specific immune responses

A-102 Impact of treatment in Fiebig Stage I on HIV-specific immune responses

Viral kinetics in untreated versus treated acute HIV infection in prospective cohort studies in Thailand.

Introduction: The extent of viral replication during acute HIV infection (AHI) influences HIV disease progression. However, information comparing viral load (VL) kinetics with and without antiretroviral therapy (ART) in AHI is limited. The knowledge gained could inform preventive strategies aimed at reducing VL during AHI and therapeutic strategies to alter the viral kinetics that may enhance the likelihood of achieving HIV remission.Methods: The analysis utilized VL data captured during the first year of HIV infection from two studies in Thailand: the RV217 study (untreated AHI, 30 participants and 412 visits) and the RV254 study (treated AHI, 235 participants and 2803 visits). Fiebig stages were I/II (HIV RNA+, HIV IgM−) and Fiebig III/IV (HIV IgM+, Western blot-/indeterminate). Data were modelled utilizing spline effects within a linear mixed model, with a random intercept and slope to allow for between-subject variability and adjustment for the differences in variability between studies. The number of knots in the quadratic spline basis functions was determined by comparing models with differing numbers of knots via the Akaike Information Criterion. Models were fit using PROC GLIMMIX in SAS v9.3.Results: At enrolment, there were 24 Fiebig I/II and 6 Fiebig III/IV individuals in the untreated group and 137 Fiebig I/II and 98 Fiebig III/IV individuals in the treated group. Overall, the median age was 27.5 years old, most were male (89%), and CRF01_AE was the most common HIV clade (76%). By day 12 (4 days after ART in RV254), the untreated group had a 2.7-fold higher predicted mean VL level compared to those treated (predicted log VL 6.19 for RV217 and 5.76 for RV254, p = 0.05). These differences increased to 135-fold by day 30 (predicted log VL 4.89 for RV217 and 2.76 for RV254) and 1148-fold by day 120 (predicted log VL 4.68 for RV217 and 1.63 for RV254) (p < 0.0001 for both) until both curves were similarly flat at about day 150 (p = 0.17 between days 150 and 160). The VL trajectories were significantly different between Fiebig I/II and Fiebig III/IV participants when comparing the two groups and within the treated group (p < 0.001 for both).Conclusions: Initiating ART in AHI dramatically changed the trajectory of VL very early in the course of infection that could have implications for reducing transmission potential and enhancing responses to future HIV remission strategies. There is an urgency of initiating ART when acute infection is identified. New and inexpensive strategies to engage and test individuals at high risk for HIV as well as immediate treatment access will be needed to improve the treatment of acute infection globally.Clinical Trial Number: NCT00796146 and NCT00796263

Impact of early cART in the gut during acute HIV infection.

Early after HIV infection there is substantial depletion of CD4+ T cells in the gastrointestinal (GI) tract lamina propria (LP), with associated epithelial barrier damage, leading to microbial translocation and systemic inflammation and immune activation. In this study, we analyzed these early events in the GI tract in a cohort of Thai acute HIV-infected patients and determined the effect of early combination antiretroviral treatment (cART). HIV-uninfected and chronically and acutely HIV-infected patients at different Fiebig stages (I-V) underwent colonic biopsies and then received cART. Immunohistochemistry and quantitative image analysis were performed on cross-sectional and longitudinal colon biopsy specimens (day 0 to week 96) to measure GI tract damage (infiltration of polymorphonuclear cells), inflammation (M×1, TNF-α), immune activation (Ki-67), and the CD4+ T cell population in the LP. The magnitude of GI tract damage, immune activation, and inflammation was significantly increased, with significantly depleted CD4+ T cells in the LP in all acutely infected groups prior to cART compared with HIV-uninfected control participants. While most patients treated during acute infection resolved GI tract inflammation and immune activation back to baseline levels after 24 weeks of cART, most acutely infected participants did not restore their CD4+ T cells after 96 weeks of cART.