HIV-negative Adults Research Articles

Urine lipoarabinomannan concentrations among HIV-negative adults with pulmonary or extrapulmonary tuberculosis disease in Vietnam.

Lipoarabinomannan (LAM) is a promising target biomarker for diagnosing subclinical and clinical tuberculosis (TB). Urine LAM (uLAM) testing using rapid diagnostic tests (RDTs) has been approved for people living with HIV (PLWH), however there is limited data regarding uLAM levels in HIV-negative (HIV-ve) adults with clinical TB. We conducted a clinical study of adults presenting with clinical TB-related symptoms at the National Lung Hospital in Hanoi, Vietnam. The uLAM concentrations were measured using electrochemiluminescent (ECL) immunoassays and compared to a microbiological reference standard (MRS) using GeneXpert Ultra and TB culture testing. Estimated uLAM concentrations above plate specific calculated limit of detection (LOD) were considered uLAM positive. Additional microbiological testing was conducted for possible extrapulmonary TB (EPTB). Among 745 participants enrolled, 335 (44.9%) participants with presumptive pulmonary TB (PTB) and 6 (11.3%) participants with presumptive EPTB had confirmed TB disease. Overall, the S/A antibody pair had a sensitivity of 39% (95% Confidence Interval [CI] 0.33, 0.44) and a specificity of 97% (95% CI 0.96, 0.99) compared to the MRS. The F/A antibody pair had a sensitivity of 41% (95% CI 0.35, 0.47) and a specificity of 79% (95% CI 0.75, 0.84). S/A provided greater discriminatory ability compared to F/A for both individuals with presumptive PTB (AUROC: 0.74 vs 0.63, p<0.0001) and presumptive EPTB (0.76 vs 0.54, p = 0.045) when using the MRS. Among HIV-ve participants in an adult cohort in Vietnam, the concentrations of uLAM remained relatively low for people with clinical TB, which may present challenges for improving RDT sensitivity.

Predictors of HIV seroconversion in Botswana: machine learning analysis in a representative, population-based HIV incidence cohort.

To identify predictors of HIV acquisition in Botswana. We applied machine learning approaches to identify HIV risk predictors using existing data from a large, well-characterized HIV incidence cohort. We applied machine learning (randomForestSRC) to analyze data from a large population-based HIV incidence cohort enrolled in a cluster-randomized HIV prevention trial in 30 communities across Botswana. We sought to identify the most important risk factors for HIV acquisition, starting with 110 potential predictors. During a median 29-month follow-up of 8,551 HIV-negative adults, 147 (1.7%) acquired HIV. Our machine learning analysis found that for females, the most important variables for predicting HIV acquisition were the use of injectable hormonal contraception, frequency of sex in the prior 3 months with the most recent partner and residing in a community with HIV prevalence of 29% or higher. For the small proportion (0.3%) of females who had all three risk factors, their estimated probability of acquiring HIV during 29 months of follow-up was 34% (approximate annual incidence of 14%). For males, non-long-term relationships with the most recent partner and community HIV prevalence of 34% or higher were the most important HIV risk predictors. The 6% of males who had both risk factors had a 5.1% probability of acquiring HIV during the follow-up period (approximate annual incidence of 2.1%). Machine learning approaches allowed us to analyze a large number of variables to efficiently identify key factors strongly predictive of HIV risk. These factors could help target HIV prevention interventions in Botswana. NCT01965470.

The impact of COVID-19 on sexual risk behaviour for HIV acquisition in east Zimbabwe: An observational study.

The Covid-19 pandemic and associated restrictions have the potential to alter sexual risk behaviours for HIV acquisition with important implications for HIV prevention programmes in sub-Saharan Africa. To date, no large-scale data have been published to substantiate hypothesised changes in sexual risk behaviours. We used longitudinal survey data to assess the impact of Covid-19 on sexual risk behaviours in east Zimbabwe. Data on sexual behaviours in HIV-negative adults aged 15-54 years were collected in two rounds of a general population open-cohort survey conducted in Manicaland, Zimbabwe shortly before (July 2018 to December 2019; N = 7316) and several months into the Covid-19 epidemic (February to July 2021; N = 6356). Descriptive statistics and logistic regression models of serial cross-sectional and prospective cohort data were used to assess changes in sexual risk behaviours. The proportion of females aged 15-19 years reporting sexual debut declined from 29.7% before Covid-19 to 20.3% during Covid-19 (adjusted odds ratio (AOR) = 0.49, 95% confidence interval (95% CI), 0.38-0.63). Fewer sexually-active females reported multiple sexual partners during Covid-19 (3.35% versus 6.07%; AOR = 0.55, 95% CI, 0.43-0.72). No population-level changes in male behaviour between survey rounds were recorded but the cohort analysis revealed a complex pattern of behaviour change with HIV risk behaviours increasing for some individuals and decreasing for others. Overall HIV risk behaviours remained high in a sub-Saharan African population with a generalised HIV epidemic over a period of Covid-19 lockdowns when movements and social contacts were restricted.

Autoantibodies Neutralizing GM-CSF in HIV-Negative Colombian Patients Infected with Cryptococcus gattii and C. neoformans

BackgroundCryptococcosis is a life-threatening disease caused by Cryptococcus neoformans or C. gattii. Neutralizing autoantibodies (auto-Abs) against granulocyte-macrophage colony-stimulating factor (GM-CSF) in otherwise healthy adults with cryptococcal meningitis have been described since 2013. We searched for neutralizing auto-Abs in sera collected from Colombian patients with non-HIV-associated cryptococcosis in a retrospective national cohort from 1997 to 2016.MethodsWe reviewed clinical and laboratory records and assessed the presence of neutralizing auto-Abs against GM-CSF in 30 HIV negative adults with cryptococcosis (13 caused by C. gattii and 17 caused by C. neoformans).ResultsWe detected neutralizing auto-Abs against GM-CSF in the sera of 10 out of 13 (77%) patients infected with C. gattii and one out of 17 (6%) patients infected with C. neoformans.ConclusionsWe report eleven Colombian patients diagnosed with cryptococcosis who had auto-Abs that neutralize GM-CSF. Among these patients, ten were infected with C. gattii and only one with C. neoformans.

Safety and Immunogenicity of a DNA Vaccine With Subtype C gp120 Protein Adjuvanted With MF59 or AS01B: A Phase 1/2a HIV-1 Vaccine Trial.

An effective vaccine is required to end the HIV pandemic. We evaluated the safety and immunogenicity of a DNA (DNA-HIV-PT123) vaccine with low- or high-dose bivalent (TV1.C and 1086.C glycoprotein 120) subtype C envelope protein combinations, adjuvanted with MF59 or AS01B. HIV Vaccine Trials Network (HVTN)108 was a randomized, placebo-controlled, double-blind, phase 1/2a trial conducted in the United States and South Africa. HIV-negative adults were randomly assigned to 1 of 7 intervention arms or placebo to assess DNA prime with DNA/protein/adjuvant boosts, DNA/protein/adjuvant co-administration, and low-dose protein/adjuvant regimens. HVTN111 trial participants who received an identical regimen were also included. Outcomes included safety and immunogenicity 2 weeks and 6 months after final vaccination. From June 2016 to July 2018, 400 participants were enrolled (N = 334 HVTN108, N = 66 HVTN111); 370 received vaccine and 30 received placebo. There were 48 grade 3 and 3 grade 4 reactogenicity events among 39/400 (9.8%) participants, and 32 mild/moderate-related adverse events in 23/400 (5.8%) participants. All intervention groups demonstrated high IgG response rates (>89%) and high magnitudes to HIV-1 Env gp120 and gp140 proteins; response rates for AS01B-adjuvanted groups approached 100%. V1V2 IgG magnitude, Fc-mediated functions, IgG3 Env response rates, and CD4+ T-cell response magnitudes and rates were higher in the AS01B-adjuvanted groups. The AS01B-adjuvanted low-dose protein elicited greater IgG responses than the higher protein dose. The vaccine regimens were generally well tolerated. Co-administration of DNA with AS01B-adjuvanted bivalent Env gp120 elicited the strongest humoral responses; AS01B-adjuvanted regimens elicited stronger CD4+ T-cell responses, justifying further evaluation.ClinicalTrials.gov registration: NCT02915016, registered 26 September 2016.

Rapid decrease in IL-1Ra and IP-10 plasma levels following tuberculosis treatment initiation

ObjectivesMonitoring tools that could provide quick predictions of tuberculosis (TB) treatment outcomes are urgently needed. Here, we assessed whether the evolution of selected biomarkers of innate immunity may help monitoring TB treatment response within 2 weeks of treatment initiation. MethodsANRS12394-LILAC-TB was a proof-of-concept prospective study: adults with a rifampicin-susceptible TB who are HIV-negative and HIV-infected documented by a positive Xpert MTB/RIF test were enrolled in Cambodia and Côte d'Ivoire. Plasma concentrations of interleukin-1 receptor antagonist (IL-1Ra), interferon-γ–induced protein-10 and clusters of differentiation (CD) (scavenging CD163) were measured by commercial enzyme-linked immunosorbent assay kits. A Wilcoxon test for paired data was used for longitudinal comparisons. ResultsA total of 55 patients were enrolled (women: 31%, median age: 37 years; median CD4 count in the 10 of 13 participants with HIV: 53 cells/mm3). Overall, 83% were considered in TB treatment success. Compared with baseline, the IL-1Ra plasma levels significantly decreased as soon as week (W) 1, independent of HIV status (−71% in HIV-positive vs −33% in HIV-negative; P <0.001). The IP-10 plasma levels significantly decreased at W1 and W2 compared with baseline (P <0.0001); however, that decrease was less marked in participants with HIV. ConclusionsOur findings suggest that measuring IL-1Ra plasma levels with a standard enzyme-linked immunosorbent assay technique at baseline and then 1 week after TB treatment onset could help clinicians to quickly assess TB treatment response.

The Trends and Risk Factors of AIDS-Defining Cancers and Non-AIDS-Defining Cancers in Adults Living with and without HIV: A Narrative Review.

People living with HIV (PLHIV) are at a high-risk of developing AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs). This review is aimed at exploring available evidence regarding the trends of ADCs and NADCs and the associated risk factors among adult PLHIV. We conducted a comprehensive search of PubMed, Web of Science, and EBSCO host databases to identify articles published between 2010 and 2023 that reported incidence and mortality rates of cancer, including ADCs and NADCs among PLHIV. We compared trends and rates in PLHIV with HIV-negative adults and further assessed related risk factors. A total of 1886 potentially eligible articles were screened, and of these, 36 were included in this study. More than 50% (n = 20) of these were based in high-income countries. Seventeen studies reported a higher prevalence of NADCs compared to ADCs, with twelve of these conducted in high-income countries. Conversely, eight out of twelve studies reporting a higher prevalence of ADCs versus NADCs were from low-and-middle and upper-middle-income countries. Ten studies indicated a higher incidence of ADCs (6 studies) and NADCs (4 studies) among PLHIV compared to HIV-negative individuals. In contrast, only two studies observed an increase in NADCs among the HIV-negative population. In comparing mortality, seven out of nine studies showed elevated NADC-related deaths compared to ADCs. The main risk factors identified for any cancer, NADCs, and related mortality were advancing age, and longer duration of HIV infection, while lower CD4 cell counts (<200 cells/μl), was associated with both ADC and NADC occurrences. Chronic HIV infection combined with advancing age in PLHIV taking antiretroviral therapy appears to have contributed to increasing cancer burden, particularly the incidence of NADCs and associated mortality. These findings stress the importance of screening for high-risk cancers among PLHIV for early detection and treatment to ensure improved outcomes.

Th1 cell immune response in Talaromyces marneffei infection with anti-interferon-γ autoantibody syndrome.

Anti-interferon-γ autoantibody (AIGA) syndrome may be the basis of disseminated Talaromyces marneffei infection in human immunodeficiency virus (HIV)-negative adults. However, the pathogenesis of Th1 cell immunity in T. marneffei infection with AIGA syndrome is unknown. A multicenter study of HIV-negative individuals with T. marneffei infection was conducted between September 2018 and September 2020 in Guangdong and Guangxi, China. Patients were divided into AIGA-positive (AP) and AIGA-negative (AN) groups according to the AIGA titer and neutralizing activity. The relationship between AIGA syndrome and Th1 immune deficiency was investigated by using AP patient serum and purification of AIGA. Fifty-five HIV-negative adults with disseminated T. marneffei infection who were otherwise healthy were included. The prevalence of AIGA positivity was 83.6%. Based on their AIGA status, 46 and 9 patients were assigned to the AP and AN groups, respectively. The levels of Th1 cells, IFN-γ, and T-bet were higher in T. marneffei-infected patients than in healthy controls. However, the levels of CD4+ T-cell STAT-1 phosphorylation (pSTAT1) and Th1 cells were lower in the AP group than in the AN group. Both the serum of patients with AIGA syndrome and the AIGA purified from the serum of patients with AIGA syndrome could reduce CD4+ T-cell pSTAT1, Th1 cell differentiation and T-bet mRNA, and protein expression. The Th1 cell immune response plays a pivotal role in defense against T. marneffei infection in HIV-negative patients. Inhibition of the Th1 cell immune response may be an important pathological effect of AIGA syndrome.IMPORTANCEThe pathogenesis of Th1 cell immunity in Talaromyces marneffei infection with anti-interferon-γ autoantibody (AIGA) syndrome is unknown. This is an interesting study addressing an important knowledge gap regarding the pathogenesis of T. marneffei in non-HIV positive patients; in particular patients with AIGA. The finding of the Th1 cell immune response plays a pivotal role in defense against T. marneffei infection in HIV-negative patients, and inhibition of the Th1 cell immune response may be an important pathological effect of AIGA syndrome, which presented in this research could help bridge the current knowledge gap.

Distinctive antibody responses to Mycobacterium tuberculosis in pulmonary and brain infection.

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains a global health burden. While M. tuberculosis is primarily a respiratory pathogen, it can spread to other organs, including the brain and meninges, causing TB meningitis (TBM). However, little is known about the immunological mechanisms that lead to differential disease across organs. Attention has focused on differences in T cell responses in the control of M. tuberculosis in the lungs, but emerging data point to a role for antibodies, as both biomarkers of disease control and as antimicrobial molecules. Given an increasing appreciation for compartmentalized antibody responses across the blood-brain barrier, here we characterized the antibody profiles across the blood and brain compartments in TBM and determined whether M. tuberculosis-specific humoral immune responses differed between M. tuberculosis infection of the lung (pulmonary TB) and TBM. Using a high throughput systems serology approach, we deeply profiled the antibody responses against 10 different M. tuberculosis antigens, including lipoarabinomannan (LAM) and purified protein derivative (PPD), in HIV-negative adults with pulmonary TB (n = 10) versus TBM (n = 60). Antibody studies included analysis of immunoglobulin isotypes (IgG, IgM, IgA) and subclass levels (IgG1-4) and the capacity of M. tuberculosis-specific antibodies to bind to Fc receptors or C1q and to activate innate immune effector functions (complement and natural killer cell activation; monocyte or neutrophil phagocytosis). Machine learning methods were applied to characterize serum and CSF responses in TBM, identify prognostic factors associated with disease severity, and define the key antibody features that distinguish TBM from pulmonary TB. In individuals with TBM, we identified CSF-specific antibody profiles that marked a unique and compartmentalized humoral response against M. tuberculosis, characterized by an enrichment of M. tuberculosis-specific antibodies able to robustly activate complement and drive phagocytosis by monocytes and neutrophils, all of which were associated with milder TBM severity at presentation. Moreover, individuals with TBM exhibited M. tuberculosis-specific antibodies in the serum with an increased capacity to activate phagocytosis by monocytes, compared with individuals with pulmonary TB, despite having lower IgG titres and Fcγ receptor-binding capacity. Collectively, these data point to functionally divergent humoral responses depending on the site of infection (i.e. lungs versus brain) and demonstrate a highly compartmentalized M. tuberculosis-specific antibody response within the CSF in TBM. Moreover, our results suggest that phagocytosis- and complement-mediating antibodies may promote attenuated neuropathology and milder TBM disease.

Oxidative stress, microparticles, and E-selectin do not depend on HIV suppression.

Oxidative stress and inflammation are considered predictors of diseases associated with aging. Markers of oxidative stress, inflammation, and endothelial activation were investigated in people with HIV on antiretroviral treatment to determine whether they had an immunosenescent phenotype that might predispose to the development of premature age-related diseases. This study was conducted on 213 subjects with HIV. The control groups consisted of healthy HIV-negative adults. The level of oxidative stress was measured by assessing the production of malondialdehyde levels, which were detected by thiobarbituric acid reactive substance (TBARS) assay. The level of microparticles indicated the presence of inflammation and endothelial activation was measured by E-selectin levels. Significant differences were determined by appropriate statistical tests, depending on the distribution of variables. Relationships between continuous variables were quantified using Spearman's rank correlation coefficient. TBARS, and microparticle and E-selectin levels were significantly higher in untreated and treated subjects with HIV compared with HIV-negative controls (P<0.001). The levels of the investigated markers were not significantly different between untreated and treated patients and no significant correlation of these markers was found with CD4+ count, CD4+/CD8+ ratio, and the number of HIV-1 RNA copies. Elevated markers of oxidative stress, inflammatory and endothelial activation were independent of the virologic and immunologic status of people with HIV. These results support the hypothesis that residual viremia in cellular reservoirs of various tissues is a key factor related to the premature aging of the immune system and predisposition to the premature development of diseases associated with aging.

Isolated Extra-Pulmonary Tuberculosis in ENT: A Commonly Missed Diagnosis.

Tuberculosis (TB) constitutes 15-20% of TB cases in general practice among HIV-negative adults in India. The head and neck region provides an impressive field of research because of its varied presentations and different sites of involvement. TB may often mimic malignancy and is misdiagnosed, which leads to an unnecessary delay in diagnosis. Through this study, we aim to draw focus on the various ways in which isolated extrapulmonary TB manifests in today's clinical practice in the head and neck region. Prospective analysis of 60 patients diagnosed with TB in a simple random sampling over 1year. The period of study was from July 2022 to June 2023. All those patients who presented to the ENT OPD of Civil Hospital of Asarwa. Patients with complete clinical data were included in the study. In our study patients in the 3rd and 4th decade of life were most commonly affected and a male preponderance of the disease was seen. The most common presentation of EPTB in the head and neck region is cervical lymphadenitis, followed by tuberculous otitis media and laryngeal TB. Each of these has a characteristic clinical presentation that helps to identify this disease. Fine needle aspiration cytology is a very efficient cytopathological examination method that helps in the diagnosis of the disease. Special care should be taken in patients in whom other routine conventional medical and surgical therapy fail to show the desired outcome. Special care and a high degree of suspicion are needed to diagnose extrapulmonary TB. Once rightly diagnosed, it will prevent the progression of the disease and its complications.

Oral health-related quality of life among people living with HIV and HIV-negative adults in Kigali, Rwanda: a comparative cross-sectional study

BackgroundAssessing health-related quality of life has become integral to people living with HIV (PLHIV) follow-up. However, there is a lack of data regarding the impact of oral health on quality of life, known as Oral health-related quality of life (OHRQoL) among PLHIV compared to HIV-negative individuals in Rwanda.AimThe study aimed to assess OHRQoL among PLHIV compared to HIV-negative counterparts in Kigali, Rwanda.MethodsThe Oral Health Impact Profile short version (OHIP-14) questionnaire was interviewer-administered to 200 PLHIV and 200 HIV-negative adults (≥ 18 years old) at an HIV clinic of Kigali Teaching Hospital (CHUK). Socio-demographic characteristics, including age, sex, occupation, and socioeconomic status (SES) of participants, were collected using a survey questionnaire. A 4-point Likert scale was used to assess the frequency of oral impacts for all 14 items within 7 domains of the OHIP tool. The descriptive statistics were used to see frequencies and percentages of OHRQoL among PLHIV and HIV-negative persons, respectively. The Chi-square test was used to determine the association of OHRQoL with caries (DMFT) and periodontal disease (CPITN) among PLHIV compared to HIV-negative individuals.ResultsThe results revealed a higher prevalence of PLHIV with poor OHRQoL than HIV-negative individuals in 5 domains and almost all items of OHIP-14 except for the OHIP 3 (found it uncomfortable to eat any foods because of problems with teeth or mouth) and OHIP-14 (being totally unable to function because of problems with teeth or mouth). The findings showed statistically significant results (p ≤ 0.05) for the OHIP1 item “trouble pronouncing any word,” with a prevalence of 2.5% (n = 11) and 2.25% (n = 9) in PLHIV and HIV-negative, respectively. Also, PLHIV had a significantly higher prevalence, 2.75% (n = 11) for the OHIP 13 item “life not satisfying due to teeth and mouth problems compared to HIV-negative individuals 2% (8) p ≤ 0.05. Moreover, dental caries was significantly associated with poor OHRQoL among PLHIV and HIV-negative adults and for all 14 items of the OHIP tool. Periodontal disease was not significantly associated with OHRQoL among PLHIV and HIV-negative adults.ConclusionThis study revealed poor OHRQoL among PLHIV compared to HIV-negative adults. There is a need for further longitudinal studies to investigate the OHRQoL in Rwanda, especially among PLHIV. It is essential to include oral health care as one of the components of the medical health care programs for PLHIV in Rwanda.

Feasibility and assessment of a comprehensive emergency department-based intervention for patients at risk of HIV.

Behavioral factors increase the risk of contracting HIV. A comprehensive prevention services (CPS) intervention includes risk assessment and referral for those with confirmed risk. This project sought to assess the feasibility of an emergency department (ED)-based CPS program. A prospective cross-sectional assessment was conducted from October, 2021 through May, 2023, at a single ED in Birmingham, Alabama. Either of two screening methods were subjected to HIV negative adults: 1) manual chief complaint review or 2) objective electronic medical record (EMR) query. Manual and EMR screening methods considered sexually transmitted infections (STIs) or a positive urine drug test (to observe for commonly injectable drugs) within 12 months of current ED visit. Identified patients were approached in the ED (manual review) or via phone (EMR alert). Persons confirmed at risk for HIV following engagement questionnaire completion were made aware of their risk and offered referral to local CPS clinics. Primary outcome was CPS linkage. Descriptive analysis was performed. Of 184 patients approached, 147 agreed to engagement (79.9%), 117 in-person and 30 via phone; 125 (85.1%) were confirmed at risk for HIV; majority were white (66.4%), male (63.2%), between the ages of 30 and 49 (64.8%), uninsured (78.4%), and without a primary care provider (93.6%). Sexual behavior was identified as a recent (within six months) risk factor in 97 (77.6%) patients. Injection drug use was identified as a recent (within six months) risk factor in 71 (56.8%) patients. Fifty-four (43.2%) expressed interest in obtaining CPS follow-up. To-date, ten patients (18.5%) have connected with a CPS counsellor via phone and five (9.3%) have had a subsequent follow-up appointment to discuss CPS with a medical provider. Thirty at-risk patients (24.0%) received ED-initiated buprenorphine/naloxone. Targeted screening tools can aid in the identification of persons at risk for HIV in the ED; further, subsequent engagement and CPS implementation amongst this cohort is feasible. CPS clinic linkage may be challenging however, a CPS definition inclusive of ED-initiated medication for opioid use disorder, may offer opportunity for increased uptake.

2541. Steady-state PK of Fixed Dose Dolutegravir+Rilpivirine in Hemodialysis

Abstract Background Fixed dose combination (FDC) dolutegravir (DTG) plus rilpivirine (RPV) is an approved antiretroviral treatment regimen for people with HIV. The steady-state PK of FDC DTG+RPV in those requiring hemodialysis (HD) has not been previously studied. Methods We performed a single-center, prospective evaluation of the steady-state PK of FDC DTG (50mg)+RPV(25mg) in HIV-negative adults either requiring HD (n=4; 2 men, 2 women) or with normal renal function, defined as CrCl ≥ 75mL/min (n=2; 1 man, 1 woman). All participants received DTG+RPV daily for 10-14 days with food before undergoing an intensive 24-hour PK evaluation (performed between dialysis days for those requiring HD). Plasma drug and metabolite concentrations were measured using a validated LC/MS/MS assay method (QTRAP 6500+LC-MS/MS system) with turboelectrospray source operating in both positive (confirmation) and negative (quantification) modes. We did not evaluate dialysis extraction of DTG+RPV. Descriptive PK parameters were calculated. Results No participant experienced serious or grade 3-4 adverse events; there were no study discontinuations. The 4 HD and 2 normal renal function participants were of similar ages (range, 50-60 vs 53-58 years) and BMI (range, 18.5-28.2 vs 20.3-24.0 kg/m2). The Table shows the PK parameters assessed in the study population for circulating plasma DTG, DTG-glucuronide (DTG’s primary metabolite), and RPV. Conclusion In this study, HD did not lead to clinically appreciable differential exposures to DTG and RPV; the markedly increased exposure to DTG-glucoranide (which is considered inert) in HD suggests increased UGT1A1 activation. All participants maintained exposures throughout the dosing interval greater than the reported IC90 efficacy values for DTG (64ng/mL) and RPV (12ng/mL). These data suggest no dosing modifications are needed for the FDC DTG+RPV regimen in HD. Disclosures Samir K. Gupta, MD, Gilead Sciences: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support Allon Friedman, MD, Eli Lilly: Advisor/Consultant|Eli Lilly: Stocks/Bonds|GI Dynamics: Advisor/Consultant|Gila Therapeutics: Advisor/Consultant

Appropriate usage of post-exposure prophylaxis-in-pocket for HIV prevention by individuals with low-frequency exposures.

PEP-In-Pocket (Post-Exposure Prophylaxis-In-Pocket, or "PIP") is a biobehavioural HIV prevention strategy wherein patients are proactively identified and given a prescription for HIV post-exposure prophylaxis (PEP) medications to self-initiate in case of high-risk exposures. We evaluated this strategy in a prospective observational study at two hospital-based clinics in Toronto, Canada. HIV-negative adults using PIP underwent chart review and completed quarterly electronic questionnaires over 12months. The primary objective was to quantify appropriate PIP initiation, defined as starting PIP within 72h of a high-risk exposure. Secondary objectives were to quantify HIV seroconversions, changes in sexual risk behaviour, sexual satisfaction, and satisfaction with the PIP strategy. From 11/2017 to 02/2020, 43 participants enrolled and completed ≥1 questionnaire. PIP was self-initiated on 27 occasions by 15 participants, of which 24 uses (89%) were appropriate, 2 were unnecessary, and 1 was for an unknown exposure. Chart review identified no inappropriate non-use. Over 32 person-years of testing follow-up, we observed zero HIV seroconversions. Sexual risk declined modestly over follow-up, with a HIRI-MSM (HIV Incidence Risk Index for MSM) change of -0.39 (95% CI = -0.58, -0.21 per 3months, p < .001). Sexual satisfaction was stable over time. At 12months, 31 (72%) remained on PIP, 8 (19%) had transitioned to pre-exposure prophylaxis and 4 (9%) were lost-to-follow-up. Among participants who remained on PIP and completed questionnaires at 12months, 24/25 (96%) strongly/somewhat agreed that PIP decreased their anxiety about contracting HIV and 25/25 (100%) strongly/somewhat agreed that they would recommend PIP to a friend. PIP is a feasible HIV prevention strategy in carefully selected individuals at modest HIV risk.

Are people living with HIV have a low vulnerability to omicron variant infection: results from a cross-sectional study in China

BackgroundA surge of more than 80 million Omicron variant infected cases was reported in China less than a month after the "zero COVID" strategy ended on December 7, 2022. In this circumstance, whether people living with HIV (PLWH) in China experience a similar risk is not clear.MethodsA cross-sectional study was conducted in the Wuchang District of Wuhan between December 20, 2022, and January 18, 2023 through a self-administered online survey. PLWH and HIV-negative people aged ≥ 18 years old who volunteered for this survey were eligible. The prevalence of Omicron variant infection between PLWH and HIV-negative people was compared, and the factors associated with the Omicron variant infection among PLWH and HIV-negative people were further evaluated, respectively.ResultsIn total, 890 PLWH and 1,364 HIV-negative adults from Wuchang District were enrolled. Among these participants, 690 PLWH (77.5%) and 1163 HIV-negative people (85.3%) reported SARS-CoV-2 infection. Gender, chronic disease conditions, and COVID-19 vaccination status significantly differed between the two groups. After adjusting gender, age, comorbidities, and COVID-19 vaccination status, the risk of SARS-CoV-2 infection among PLWH was significantly lower than among HIV-negative people (aOR 0.56, 95%CI 0.42–0.76). Multivariable logistic regression analysis showed that PLWH with older age and detectable HIV-viral load (HIV-VL) had decreased risk of SARS-CoV-2 infection (aOR 0.98, 95%CI 0.96–0.99; aOR 0.59, 95%CI 0.36–0.97). Compared with PLWH receiving one/two doses of COVID-19 vaccines, no significant differences in the risk of SARS-CoV-2 infection were observed among PLWH receiving three doses of inactivated vaccines and four doses of vaccines (three doses of inactivated vaccines plus one dose of inhaled recombinant adenovirus type 5 (AD5)-vectored vaccine). Among HIV-negative people, those receiving four doses of COVID-19 vaccines had a lower risk of SARS-CoV-2 infection than those receiving one/two doses (aOR 0.14, 95%CI 0.08–0.25).ConclusionsOur study proves that PLWH have a lower risk of Omicron variant infection than HIV-negative people. However, even PLWH with younger age and virological suppression should strengthen the prevention against SARS-CoV-2 infection. Three doses of inactivated vaccines plus one dose of inhaled recombinant AD5-vectored COVID-19 vaccine may provide better protection for HIV-negative people.

3 The Relationship Between Apolipoprotein-E4 Genotype, Memory, and the Medial Temporal Lobe and How These Relationships Vary by Race in Middle-Aged Persons with HIV

Objective:Many people with HIV (PWH) are at risk for age-related neurodegenerative disorders such as Alzheimer’s disease (AD). Studies on the association between cognition, neuroimaging outcomes, and the Apolipoprotein E4 (APOE4) genotype, which is associated with greater risk of AD, have yielded mixed results in PWH; however, many of these studies have examined a wide age range of PWH and have not examined APOE by race interactions that are observed in HIV-negative older adults. Thus, we examined how APOE status relates to cognition and medial temporal lobe (MTL) structures (implicated in AD pathogenesis) in mid- to older-aged PWH. In exploratory analyses, we also examined race (African American (AA)/Black and non-Hispanic (NH) White) by APOE status interactions on cognition and MTL structures.Participants and Methods:The analysis included 88 PWH between the ages of 45 and 68 (mean age=51±5.9 years; 86% male; 51% AA/Black, 38% NH-White, 9% Hispanic/Latinx, 2% other) from the CNS HIV Antiretroviral Therapy Effects Research multi-site study. Participants underwent APOE genotyping, neuropsychological testing, and structural MRI; APOE groups were defined as APOE4+ (at least one APOE4 allele) and APOE4- (no APOE4 alleles). Eighty-nine percent of participants were on antiretroviral therapy, 74% had undetectable plasma HIV RNA (&lt;50 copies/ml), and 25% were APOE4+ (32% AA/Black/15% NH-White). Neuropsychological testing assessed seven domains, and demographically-corrected T-scores were calculated. FreeSurfer 7.1.1 was used to measure MTL structures (hippocampal volume, entorhinal cortex thickness, and parahippocampal thickness) and the effect of scanner was regressed out prior to analyses. Multivariable linear regressions tested the association between APOE status and cognitive and imaging outcomes. Models examining cognition covaried for comorbid conditions and HIV disease characteristics related to global cognition (i.e., AIDS status, lifetime methamphetamine use disorder). Models examining the MTL covaried for age, sex, andrelevant imaging covariates (i.e., intracranial volume or mean cortical thickness).Results:APOE4+ carriers had worse learning (ß=-0.27, p=.01) and delayed recall (ß=-0.25, p=.02) compared to the APOE4- group, but APOE status was not significantly associated with any other domain (ps&gt;0.24). APOE4+ status was also associated with thinner entorhinal cortex (ß=-0.24, p=.02). APOE status was not significantly associated with hippocampal volume (ß=-0.08, p=0.32) or parahippocampal thickness (ß=-0.18, p=.08). Lastly, race interacted with APOE status such that the negative association between APOE4+ status and cognition was stronger in NH-White PWH as compared to AA/Black PWH in learning, delayed recall, and verbal fluency (ps&lt;0.05). There were no APOE by race interactions for any MTL structures (ps&gt;0.10).Conclusions:Findings suggest that APOE4 carrier status is associated with worse episodic memory and thinner entorhinal cortex in mid- to older-aged PWH. While APOE4+ groups were small, we found that APOE4 carrier status had a larger association with cognition in NH-White PWH as compared to AA/Black PWH, consistent with studies demonstrating an attenuated effect of APOE4 in older AA/Black HIV-negative older adults. These findings further highlight the importance of recruiting diverse samples and suggest exploring other genetic markers (e.g., ABCA7) that may be more predictive of AD in some races to better understand AD risk in diverse groups of PWH.

Attitudes and Intentions toward Use of HIV Pre-Exposure Prophylaxis (PrEP) among Adults Receiving Treatment for Opioid Use

Background: Although pre-exposure prophylaxis (PrEP) prevents HIV, little is known about PrEP awareness and factors associated with intention to take PrEP among people with opioid use disorder (OUD). Methods: HIV-negative adults recruited from an outpatient treatment program in Cincinnati, Ohio completed self-administered surveys. Items derived from literature and health behavioral theory included demographics, sexual and drug use behaviors, HIV prevention practices, PrEP knowledge, and attitudes toward PrEP. Primary outcomes were 1) intention to ask a clinician about PrEP and 2) intention to accept PrEP if recommended by a clinician. Outcomes were dichotomized into higher vs. lower intention for analyses in logistic regression models. Results: Among 198 participants, 60.3% reported past injection drug use. Among 58 participants (29.3%) meeting criteria for PrEP, 24% were aware of PrEP, 15.5% had discussed it with a clinician, and 5% had taken it. Factors associated with intention to ask a clinician about PrEP included being somewhat confident about consistent condom use (p < 0.01), motivation to comply with normative beliefs (p < 0.01), and reporting that PrEP fits very well (p < 0.01) and is easy to fit (p < 0.01) into current prevention practices. Factors associated with intention to accept PrEP if recommended by a clinician included motivation to comply with normative beliefs (p < 0.01) and PrEP being easy to fit into current prevention practices (p < 0.01). Conclusion: Among participants meeting indications for PrEP, only 24% were aware of it and few had taken it. Interventions that normalize PrEP and target incorporating PrEP into current prevention practices may improve uptake among individuals with OUD.

From simple to complex: Protein-based biomarker discovery in tuberculosis.

Tuberculosis (TB) is a deadly infectious disease that affects millions of people globally. TB proteomics signature discovery has been a rapidly growing area of research that aims to identify protein biomarkers for the early detection, diagnosis, and treatment monitoring of TB. In this review, we have highlighted recent advances in this field and how it is moving from the study of single proteins to high-throughput profiling and from only using proteomics to include additional types of data in multi-omics studies. We have further covered the different sample types and experimental technologies used in TB proteomics signature discovery, focusing on studies of HIV-negative adults. The published signatures were defined as either coming from hypothesis-based protein targeting or from unbiased discovery approaches. The methodological approaches influenced the type of proteins identified and were associated with the circulating protein abundance. However, both approaches largely identified proteins involved in similar biological pathways, including acute-phase responses and T-helper type 1 and type 17 responses. By analysing the frequency of proteins in the different signatures, we could also highlight potential robust biomarker candidates. Finally, we discuss the potential value of integration of multi-omics data and the importance of control cohorts and signature validation.

Comparison of the Fecal Bacteriome of HIV-Positive and HIV-Negative Older Adults.

HIV infection is considered a scenario of accelerated aging. Previous studies have suggested a link between aging, frailty, and gut dysbiosis, but there is a knowledge gap regarding the HIV population. Our objective was to compare the fecal bacteriome of older people with HIV (PWH) and non-HIV controls, and to assess potential links between gut dysbiosis and frailty. A total of 36 fecal samples (24 from PWH and 12 from non-HIV controls) were submitted to a metataxonomic analysis targeting the V3-V4 hypervariable region of the 16S rRNA gene. High-quality reads were assembled and classified into operational taxonomic units. Alpha diversity, assessed using the Shannon index, was higher in the control group than in the HIV group (p < 0.05). The relative abundance of the genus Blautia was higher in the HIV group (p < 0.001). The presence of Blautia was also higher in PWH with depression (p = 0.004), whereas the opposite was observed for the genus Bifidobacterium (p = 0.004). Our study shows shifts in the composition of the PWH bacteriome when compared to that of healthy controls. To our knowledge, this is the first study suggesting a potential link between depression and gut dysbiosis in the HIV population.