Search

Objective: Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) remain prevalent despite viral suppression on antiretroviral therapy (ART). Vascular disease contributes to HAND, but peripheral markers that distinguish vascular cognitive impairment (VCI) from HIV-related etiologies remain unclear., Design: Cross-sectional study of vascular injury, inflammation, and central nervous system (CNS) injury markers in relation to HAND., Methods: Vascular injury (VCAM-1, ICAM-1, CRP), inflammation (IFN-γ, IL-1β, IL-6, IL-8, IL-15, IP-10, MCP-1, VEGF-A), and CNS injury (NFL, total Tau, GFAP, YKL-40) markers were measured in plasma and CSF from 248 individuals (143 HIV+ on suppressive ART and 105 HIV- controls)., Results: Median age was 53 years, median CD4 + cell count, and duration of HIV infection were 505 cells/μl and 16 years, respectively. Vascular injury, inflammation, and CNS injury markers were increased in HIV+ compared with HIV- individuals ( P < 0.05). HAND was associated with increased plasma VCAM-1, ICAM-1, and YKL-40 ( P  < 0.01) and vascular disease ( P  = 0.004). In contrast, inflammation markers had no significant association with HAND. Vascular injury markers were associated with lower neurocognitive T scores in age-adjusted models ( P  < 0.01). Furthermore, plasma VCAM-1 correlated with NFL ( r  = 0.29, P  = 0.003). Biomarker clustering separated HAND into three clusters: two clusters with high prevalence of vascular disease, elevated VCAM-1 and NFL, and distinctive inflammation profiles (CRP/ICAM-1/YKL-40 or IL-6/IL-8/IL-15/MCP-1), and one cluster with no distinctive biomarker elevations., Conclusions: Vascular injury markers are more closely related to HAND and CNS injury in PWH on suppressive ART than inflammation markers and may help to distinguish relative contributions of VCI to HAND., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: People with HIV (PWH) have increased frailty risk at younger ages compared with the general population. Multimorbidity is associated with frailty, yet effects of specific comorbidities on transition to frailty in PWH are unknown., Setting: Prospective study of 219 PWH age 45 years or older in the National NeuroAIDS Tissue Consortium., Methods: Frailty status was categorized using Fried frailty phenotype criteria. Comorbidities [bone disease, cardiovascular disease, cerebrovascular disease, liver disease, renal disease, diabetes, chronic obstructive pulmonary disease (COPD), hypertension, obesity, cancers, neuropsychiatric conditions] were assessed from longitudinal data. Associations between baseline comorbidities and transition to frailty within 30 months were analyzed using Kaplan-Meier and Cox regression models. Grip strength was assessed using mixed-effects models., Results: At baseline, the median age was 61 years, 73% were male 98% were on antiretroviral therapy, 29% had ≥3 comorbidities, 27% were robust, and 73% were pre-frail. Cerebrovascular disease, diabetes, and COPD were independent predictors of transition to frailty within 30 months in models adjusted for age, sex, and multimorbidity (≥3 additional comorbidities) [hazard ratios (95% confidence intervals) 2.52 (1.29 to 4.93), 2.31 (1.12 to 4.76), and 1.82 (0.95 to 3.48), respectively]. Furthermore, cerebrovascular disease, diabetes, COPD, or liver disease co-occurring with multimorbidity was associated with substantially increased frailty hazards compared with multimorbidity alone (hazard ratios 4.75-7.46). Cerebrovascular disease was associated with decreased baseline grip strength (P = 0.0001), whereas multimorbidity, diabetes, and COPD were associated with declining grip strength (P < 0.10)., Conclusions: In older PWH, cerebrovascular disease, diabetes, COPD, or liver disease co-occurring with multimorbidity is associated with substantially increased risk of becoming frail within 30 months. Interventions targeting these comorbidities may ameliorate frailty and age-related functional decline in PWH., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: People with HIV (PWH) have increased prevalence of multimorbidity and frailty at younger ages compared with the general population. This study investigated individual and combinatorial effects of neuropsychiatric and medical comorbidities as predictors of frailty in PWH., Design: Analysis of data from the National NeuroAIDS Tissue Consortium, a longitudinal observational cohort., Methods: Five hundred and twenty-four PWH over age 40 years were classified using Fried's Frailty criteria. Twelve comorbidities were documented from longitudinal data and associations between individual and co-occurring comorbidities with frailty were assessed using weighted network and logistic regression analyses., Results: At frailty assessment between 2015 and 2020, median age was 61 years, 76% were men, 94% were on antiretroviral therapy (ART), 73% had two or more comorbidities, 24% were frail, and 52% were prefrail. Among individual comorbidities, highest odds of frailty were in participants with depressive symptoms [adjusted odds ratio (aOR), 95% confidence interval (CI) 3.48 (2.22-5.46)], followed by bone disease and chronic obstructive pulmonary disease (COPD) [2.47 (1.28-4.72) and 2.13 (1.36-3.34), respectively]. Among co-occurring comorbidities, highest odds of frailty were in participants having depressive symptoms with diabetes, hypertension, or obesity [aORs (95% CIs) 5.29 (2.32-12.08), 5.21 (2.65-10.40), 4.85 (2.39-9.95), respectively], cognitive impairment with diabetes or renal disease [2.81 (1.38-5.68) and 2.53 (1.26-5.03), respectively], renal disease with cardiovascular disease [2.81 (1.32-6.01)], and diabetes with obesity [2.76 (1.39-5.45)]., Conclusion: Co-occurrence of depressive symptoms, cognitive impairment, diabetes, or renal disease with other medical conditions substantially increases odds of frailty in older PWH. Identifying and treating these comorbidities may help to reduce functional decline with aging in PWH., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The number of people living with HIV infection has been increasing globally. Administration of antiretroviral therapy is effective in controlling the infection for most patients and, as a consequence, people living with HIV (PLWH) now often have a long life expectancy. However, their risk of developing cancer - most notably virus-related cancers - has been increasing. To date, few studies have assessed the risk of genitourinary cancers in PLWH, and robust scientific data on their treatment-related outcomes are lacking. Previous studies have noted that PLWH are at a reduced risk of prostate cancer; however, low adoption and/or availability of prostate cancer screening among these patients might be confounding the validity of this finding. In genitourinary cancers, advanced stage at diagnosis and reduced cancer-specific mortality have been reported in PLWH. These data likely reflect, at least in part, the inequity of health care access for PLWH. Notably, systemic chemotherapy and/or radiotherapy could decrease total CD4 + cell counts, which could, therefore, increase the risk of morbidity and mortality from cancer treatments in PLWH. Immune checkpoint inhibitors have become the therapeutic backbone for many advanced malignancies in the general population; however, most studies validating their efficacy have excluded PLWH owing to concerns of severe adverse effects from immune checkpoint inhibitors themselves and/or related to their immunosuppressed status. To our knowledge, no genitourinary cancer survivorship programme exists that specifically caters to the needs of PLWH. By including PLWH in ongoing cancer trials, we can gain invaluable insights that will help to improve cancer care specifically for PLWH., (© 2024. Springer Nature Limited.)

Objective(s): HIV-positive individuals have elevated rates of anal squamous cell carcinoma (SCC), and sexually transmitted infections with its causative agent, high-risk human papillomavirus, and other oncoviruses including hepatitis B virus (HBV). HBV infection can cause liver cancer, and has been associated with increased risk of some extra-hepatic cancers including biliary tract cancer, pancreatic cancer, and non-Hodgkin lymphoma. Whether HBV is associated with anal SCC risk is unknown., Design: Prospective study of anal SCC risk in HIV-positive and HIV-negative MSM in the Multicenter AIDS Cohort Study from 1984 to 2014., Methods: Poisson regression models were used to examine the association between past or current HBV infection (positive tests for HBV core antibodies, surface antigen, and/or DNA) and anal SCC risk., Results: We observed 53 cases of anal SCC among 5298 participants with 79 334 person-years follow-up. Among HIV-positive men, past or current HBV infection was associated with anal SCC risk in models adjusted for age, CD4+ cell counts, HAART use, and other risk factors [incidence rate ratio (IRR), 95% confidence interval 3.15, 1.27-7.82]. Additional risk factors included immunological parameters 1 and 6 years prior to diagnosis (IRR, 95% confidence interval 2.45, 1.31-4.58 and 2.44, 1.3-4.59 for CD4+ cell counts <500 cells/μl; 2.43, 1.34-4.42 and 2.77, 1.5-5.11 for CD4+ : CD8+ ratios <0.5, respectively). Among HIV-negative men, IRR for prior HBV and anal SCC risk was similar, but NS due to small number of cases., Conclusion: HIV-positive MSM with prior HBV infection have increased anal SCC risk. This population may benefit from screening.

Objective: HIV and Epstein-Barr virus (EBV) co-infection has been linked to increased immune activation and larger HIV reservoir. We assessed whether anti-EBV humoral responses are associated with increased cerebrospinal fluid (CSF) inflammation and with neurocognitive impairment (NCI) in people with HIV (PWH)., Design: Cross-sectional analysis in 123 EBV-seropositive PWH either on antiretroviral therapy ( n  = 70) or not., Methods: Serum and CSF anti-EBV viral capsid antigen immunoglobulin G (anti-EVI) and CSF EBV DNA were measured by commercial immunoassay and RT-PCR. Seventy-eight participants without neurological confounding factors underwent neurocognitive assessment (Global Deficit Score, GDS). CSF total tau and 181-phosphorylated-tau (ptau) were measured by immunoassays together with biomarkers of blood-brain barrier (BBB) integrity, immune activation, astrocytosis, and intrathecal synthesis. Logistic and linear regressions and moderation analysis were used to investigate the relationships between CSF anti-EVI, GDS, and biomarkers., Results: Twenty-one (17.1%) and 22 participants (17.9%) had detectable CSF anti-EVI (10.5-416.0 U/ml) and CSF EBV DNA (25-971 copies/ml). After adjusting for BBB integrity, age, and clinical factors, the presence of CSF anti-EVI was only associated with serum levels of anti-EVI, and not with CSF EBV DNA. CSF anti-EVI, tau and ptau showed reciprocal interactions affecting their associations with GDS. After adjusting for demographics and clinical parameters, higher CSF anti-EVI levels were associated with worse GDS (aβ 0.45, P  < 0.001), and CSF levels of tau and ptau had a moderation effect on the strength of this association (models' P  < 0.001)., Conclusion: Humoral immune responses against EBV within the central nervous system may contribute to NCI in PWH through mechanisms that involve neuronal injury., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cerebrospinal fluid (CSF) viral escape occurs in 4%-20% of human immunodeficiency virus (HIV)-infected adults, yet the impact of antiretroviral therapy (ART) on CSF escape is unclear., Methods: A prospective study of 1063 participants with baseline plasma viral load (VL) ≤400 copies/mL between 2005 and 2016. The odds ratio (OR) for ART regimens (protease inhibitor with nucleoside reverse transcriptase inhibitor [PI + NRTI] vs other ART) and CSF escape was estimated using mixed-effects models., Results: Baseline mean age was 46 years, median plasma VL, and CD4 count were 50 copies/mL, and 424 cells/μL, respectively. During median follow-up of 4.4 years, CSF escape occurred in 77 participants (7.2%). PI + NRTI use was an independent predictor of CSF escape (OR, 3.1; 95% confidence interval, 1.8-5.0) in adjusted analyses and models restricted to plasma VL ≤50 copies/mL (P < .001). Regimens that contained atazanavir (ATV) were a stronger predictor of CSF viral escape than non-ATV PI + NRTI regimens. Plasma and CSF M184V/I combined with thymidine-analog mutations were more frequent in CSF escape vs no escape (23% vs 2.3%). Genotypic susceptibility score-adjusted central nervous system (CNS) penetration-effectiveness (CPE) values were calculated for CSF escape with M184V/I mutations (n = 34). Adjusted CPE values were low (<5) for CSF in 27 (79%), indicating suboptimal CNS drug availability., Conclusions: PI + NRTI regimens are independent predictors of CSF escape in HIV-infected adults. Reduced CNS ART bioavailability may predispose to CSF escape in patients with M184V/I mutations.

Objectives: Chemokine receptor CCR5 is the principal co-receptor for entry of M-tropic HIV virus into immune cells. It is expressed in the central nervous system and may contribute to neuro-inflammation. The CCR5 antagonist maraviroc (MVC) has been suggested to improve HIV-associated neurocognitive impairment (NCI)., Design: A double-blind, placebo-controlled, 48-week, randomized study of MVC vs. placebo in people with HIV (PWH) on stable antiretroviral therapy (ART) for more than one year in Hawaii and Puerto Rico with plasma HIV RNA less than 50 copies/ml and at least mild NCI defined as an overall or domain-specific neuropsychological z (NPZ) score less than -0.5., Methods: Study participants were randomized 2 : 1 to intensification of ART with MVC vs. placebo. The primary endpoint was change in global and domain-specific NPZ modeled from study entry to week 48. Covariate adjusted treatment comparisons of average changes in cognitive outcome were performed using winsorized NPZ data. Monocyte subset frequencies and chemokine expression as well as plasma biomarker levels were assessed., Results: Forty-nine participants were enrolled with 32 individuals randomized to MVC intensification and 17 to placebo. At baseline, worse NPZ scores were seen in the MVC arm. Comparison of 48-week NPZ change by arm revealed no differences except for a modest improvement in the Learning and Memory domain in the MVC arm, which did not survive multiplicity correction. No significant changes between arms were seen in immunologic parameters., Conclusion: This randomized controlled study found no definitive evidence in favor of MVC intensification among PWH with mild cognitive difficulties., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Marijuana use is prevalent among persons infected with human immunodeficiency virus (HIV), but its long-term effects on HIV disease progression and comorbidities are unknown., Methods: In this prospective study of 558 HIV-infected men enrolled in the Multicenter AIDS Cohort Study between 1990 and 2010, there were 182 HIV seroconverters and 376 with viral suppression on combination antiretroviral therapy (ART). Associations between heavy marijuana use and HIV disease markers or white blood cell (WBC) count were examined using mixed-effects and linear regression models. Effects of marijuana use on cardiovascular (CV) events and other endpoints were estimated using Kaplan-Meier and logistic regression analyses., Results: The median baseline age of participants was 41, 66% were white, 79% had education >12 years, and 20% reported heavy marijuana use at ≥50% of biannual visits during follow-up. Long-term heavy marijuana use showed no significant associations with viral load, CD4 counts, AIDS, cancer, or mortality in both cohorts but was independently associated with increased CV events between ages 40-60 after adjusting for age, tobacco smoking, viral load, and traditional risk factors (odds ratio [OR], 2.5; 95% confidence interval [CI] 1.3, 5.1). Marijuana and tobacco use were each independently associated with higher WBC counts in adjusted models (P < .01); the highest quartile of WBC counts (≥6500 cells/µL) was associated with increased CV events (OR 4.3; 95% CI, 1.5, 12.9)., Conclusions: Heavy marijuana use is a risk factor for CV disease in HIV-infected men ages 40-60, independent of tobacco smoking and traditional risk factors., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.)

Purpose: African American men have the highest incidence of prostate cancer among ethnic groups, and racial disparity is highest in younger men. Prostate cancer prevalence is rising in HIV-infected men due to improved survival on antiretroviral therapies, yet little is known about racial differences in prostate cancer risk by HIV-infection status and age., Methods: This is a prospective cohort study of prostate cancer risk in 2,800 HIV-infected and -uninfected men who have sex with men (MSM) aged 40-70 years (22% African American) who were enrolled in the multicenter AIDS cohort study from 1996 to 2010. Poisson regression models were used to examine associations between race and HIV-infection status and prostate cancer risk among men aged 40-70, 40-55, and 56-70 years., Results: Among men aged 40-70 years, incidence rates (IR) per 100,000 person-years were 169 among all men and 276 among African American HIV-infected men. Prostate cancer risk was similar by HIV-infection status (IRR 1.0, 95% CI 0.55-1.82), but nearly threefold higher in African Americans compared to non-African Americans in adjusted models (IRRs 2.66 and 3.22, 95% CIs 1.36-5.18 and 1.27-8.16 for all or HIV-infected men, respectively). Racial disparity in prostate cancer risk was greatest in African American men aged 40-55 years (adjusted IRR 3.31, 95% CI 1.19-9.22). Prostate cancer risk showed associations with family history of prostate cancer (p = 0.001), but not heavy smoking, androgen supplement use, or HIV-related factors., Conclusions: Among MSM, African American HIV-positive and HIV-negative men aged 40-55 years have threefold increased risk of young-onset prostate cancer compared to non-African American men, highlighting the need to make informed decisions about screening in this population.

Background: Changes in white matter (WM) underlie the neurocognitive damages induced by a human immunodeficiency virus (HIV) infection. This study aimed to examine using a bundle-associated fixel-based analysis (FBA) pipeline for investigating the microstructural and macrostructural alterations in the WM of the brain of HIV patients., Methods: This study collected 93 HIV infected patients and 45 age/education/handedness matched healthy controls (HCs) at the Beijing Youan Hospital between January 1, 2016 and December 30, 2016.All HIV patients underwent neurocognitive evaluation and laboratory testing followed by magnetic resonance imaging (MRI) scanning. In order to detect the bundle-wise WM abnormalities accurately, a specific WM bundle template with 56 tracts of interest was firstly generated by an automated fiber clustering method using a subset of subjects. Fixel-based analysis was used to investigate bundle-wise differences between HIV patients and HCs in three perspectives: fiber density (FD), fiber cross-section (FC), and fiber density and cross-section (FDC). The between-group differences were detected by a two-sample t -test with the false discovery rate (FDR) correction ( P <0.05). Furthermore, the covarying relationship in FD, FC and FDC between any pair of bundles was also accessed by the constructed covariance networks, which was subsequently compared between HIV and HCs via permutation t -tests. The correlations between abnormal WM metrics and the cognitive functions of HIV patients were explored via partial correlation analysis after controlling age and gender., Results: Among FD, FC and FDC, FD was the only metric that showed significant bundle-wise alterations in HIV patients compared to HCs. Increased FD values were observed in the bilateral fronto pontine tract, corona radiata frontal, left arcuate fasciculus, left corona radiata parietal, left superior longitudinal fasciculus III, and right superficial frontal parietal (SFP) (all FDR P <0.05). In bundle-wise covariance network, HIV patients displayed decreased FD and increased FC covarying patterns in comparison to HC ( P <0.05) , especially between associated pathways. Finally, the FCs of several tracts exhibited a significant correlation with language and attention-related functions., Conclusions: Our study demonstrated the utility of FBA on detecting the WM alterations related to HIV infection. The bundle-wise FBA method provides a new perspective for investigating HIV-induced microstructural and macrostructural WM-related changes, which may help to understand cognitive dysfunction in HIV patients thoroughly., (Copyright © 2023 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Background: Men who have sex with men (MSM) are at high risk for oral human papillomavirus (HPV infection). There are no specific screening guidelines to facilitate the identification of people at risk for oral HPV infection. We aimed to estimate the prevalence of oral high-risk HPV and create a risk score to identify MSM at higher risk for prevalent oral HPV., Methods: We collected baseline data from a clinical trial from a subsample of 500 MSM attending sexually transmitted disease treatment clinics; they provided an oral gargle sample for high-risk HPV detection. We calculated oral high-risk HPV prevalence and 95% confidence intervals (CIs), used a logistic regression model to identify factors associated with high-risk HPV infection, and created a risk score., Results: The prevalence of any oral high-risk HPV among MSM was 11.1% (95% CI: 8.6-14.2), with a higher prevalence observed among men living with HIV (14.8%). Factors independently associated with oral high-risk HPV were age ≥40 years (OR = 2.71, 95% CI: 1.28-5.73 compared to <40 years), being HIV-positive with CD4 count 200-499 (OR = 2.76, 95% CI: 1.34-5.65 compared to HIV-negative), and recent recreational use of vasodilators (poppers/sildenafil) (OR = 2.02, 95% CI: 1.02-2.97). The risk score had good discriminatory power (AUC = 0.70, 95% CI: 0.63-0.77)., Conclusions: MSM have specific predictors for prevalent oral high-risk HPV, and a risk score could be used by clinicians to target men with vaccine recommendations and counseling, and identify those who could benefit from primary interventions given the available resources, or for referral to dental services for follow-up when available., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Two in every five patients with active tuberculosis (TB) remain undiagnosed or unreported. Therefore community-based, active case-finding strategies require urgent implementation. However, whether point-of-care (POC), portable battery-operated, molecular diagnostic tools deployed at a community level, compared with conventionally used POC smear microscopy, can shorten time-to-treatment initiation, thus potentially curtailing transmission, remains unclear. To clarify this issue, we performed an open-label, randomized controlled trial in periurban informal settlements of Cape Town, South Africa, where we TB symptom screened 5,274 individuals using a community-based scalable mobile clinic. Some 584 individuals with HIV infection or symptoms of TB underwent targeted diagnostic screening and were randomized (1:1) to same-day smear microscopy (n = 296) or on-site DNA-based molecular diagnosis (n = 288; GeneXpert). The primary aim was to compare time to TB treatment initiation between the arms. Secondary aims included feasibility and detection of probably infectious people. Of participants who underwent targeted screening, 9.9% (58 of 584) had culture-confirmed TB. Time-to-treatment initiation occurred significantly earlier in the Xpert versus the smear-microscopy arm (8 versus 41 d, P = 0.002). However, overall, Xpert detected only 52% of individuals with culture-positive TB. Notably, Xpert detected almost all of the probably infectious patients compared with smear microscopy (94.1% versus 23.5%, P = <0.001). Xpert was associated with a shorter median time to treatment of probably infectious patients (7 versus 24 d, P = 0.02) and a greater proportion of infectious patients were on treatment at 60 d compared with the probably noninfectious patients (76.5% versus 38.2%, P < 0.01). Overall, a greater proportion of POC Xpert-positive participants were on treatment at 60 d compared with all culture-positive participants (100% versus 46.5%, P < 0.01). These findings challenge the traditional paradigm of a passive case-finding, public health strategy and argues for the implementation of portable DNA-based diagnosis with linkage to care as a community-oriented, transmission-interruption strategy. The study was registered with the South African National Clinical Trials Registry (application ID 4367; DOH-27-0317-5367) and ClinicalTrials.gov (NCT03168945)., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) affect approximately half of people living with HIV despite viral suppression with antiretroviral therapies and represent a major cause of morbidity. HAND affects activities of daily living including driving, using the Internet and, importantly, maintaining drug adherence. Whilst viral suppression with antiretroviral therapies (ART) has reduced the incidence of severe dementia, mild neurocognitive impairments continue to remain prevalent. The neuropathogenesis of HAND in the context of viral suppression remains ill-defined, but underlying neuroinflammation is likely central and driven by a combination of chronic intermittent low-level replication of whole virus or viral components, latent HIV infection, peripheral inflammation possibly from a disturbed gut microbiome or chronic cellular dysfunction in the central nervous system. HAND is optimally diagnosed by clinical assessment with imaging and neuropsychological testing, which can be difficult to perform in resource-limited settings. Thus, the identification of biomarkers of disease is a key focus of the field. In this chapter, recent advances in the pathogenesis of HAND and biomarkers that may aid its diagnosis and treatment will be discussed., (© 2020. Springer Nature Switzerland AG.)

Neurocognitive impairment caused by chronic human immunodeficiency virus (HIV) infection is a growing concern. In this chapter we discuss the inflammatory mechanisms underlying the pathology of asymptomatic and mild neurocognitive impairment in the context of antiretroviral therapy. We discuss the role of HIV, viral proteins, and virally infected cells on the development of neuroinflammation and the effect of viral proteins on the cells of the central nervous system.We examine how these collective factors result in an inflammatory context that triggers the development of neurocognitive impairment in HIV. We assess the contribution of antiretrovirals and drugs of abuse, including methamphetamine, cannabis, and opioids, to the neurotoxic and neuroinflammatory milieu that leads to the development of neurocognitive impairment in HIV-infected individuals. We also examined circulating biomarkers, NF-L, sCD163, and sCD14, pertinent to identifying changes in the CNS that could indicate real-time changes in patient physiology. Lastly, we discuss future studies, such as exosomes and the microbiome, which could play a role in the HIV-induced neuroinflammation that eventually manifests as cognitive impairment., (© 2019. Springer Nature Switzerland AG.)

The prevalence of cognitive impairment or learning difficulties in HIV-infected children is high despite access to antiretroviral treatment (ART). Several biological mechanisms, including latent HIV reservoir persistence in the brain, local inflammation within the central nervous system (CNS), disruption of neuronal function and integrity, and ongoing infiltration of activated HIV target cells to the CNS during brain development, may each dampen efficacy of ART. Development of therapeutics to target these mechanisms will be crucial, and potential candidates may include chemokine receptor antagonists. Separately, psychosocial approaches to support caregiving may leverage neuroplasticity and support brain development during critical developmental windows in spite of perinatal HIV infection. Multipronged approaches that encompass both approaches are crucial for optimizing neurodevelopmental outcomes in these extraordinarily vulnerable children. Dynamic neuropsychological assessments, such as what can be obtained with the use of computerized cognitive games intervention, may prove more sensitive to the brain/behavior benefits of ART. Dynamic neuropsychological outcomes, neuroinflammatory biomarkers, and brain development neuroprotective factors (BDNFs) may each be used to evaluate brain/behavior integrity of children in response to new treatment options., (© 2019. Springer Nature Switzerland AG.)

Background: People living with HIV are at risk for anal dysplasia/cancer. Screening/surveillance is costly and burdensome, and the frequency is not evidence based. Objective markers of increased risk of anal carcinogenesis are needed to tailor screening/surveillance. Low CD4/CD8 ratio is associated with increased overall cancer risk in people living with HIV but has yet to be examined for quantifying anal cancer risk., Objective: We hypothesized that low CD4/CD8 ratios correlate with increased risk for high-grade anal dysplasia and cancer., Design: This is a single-institution, retrospective review of people living with HIV from 2002 to 2018., Setting: This study was conducted at the University of Wisconsin School of Medicine and Public Health., Patients: Patients with advanced disease (high-grade anal dysplasia and/or anal cancer) were compared with patients with negative anal cytology., Main Outcome Measures: The independent variables were lowest (nadir) CD4/CD8 and CD4/CD8 nearest to screening/diagnosis. Logistic regression modeling was used to estimate the adjusted odds of advanced disease., Results: A total of 377 people living with HIV were examined: 266 with negative cytology and 111 with advanced disease (16 cancer, 95 high-grade anal dysplasia). Mean nadir ratio and mean nearest ratio were lower in patients with advanced disease than in those with negative screening (0.26 vs 0.47 (p < 0.001) and 0.61 vs 0.87 (p < 0.001)). In adjusted analyses, increase in nadir ratio or nearest ratio of 1 unit conferred decreased risk of advanced disease (OR, 0.10; 95% CI, 0.02-0.45; p = 0.002) and (OR, 0.31; 95% CI, 0.12-0.83; p = 0.02). The optimal threshold for using CD4/CD8 ratio as a risk factor for advanced disease was 0.47 for nadir ratio (sensitivity 0.59 and specificity 0.91) and 0.95 for nearest ratio (sensitivity 0.56 and specificity 0.92)., Limitations: This is a retrospective, single-institution study., Conclusions: Low CD4/CD8 ratio confers additional risk of high-grade anal dysplasia and anal cancer beyond the diagnosis of HIV, even when adjusting for known risks factors of anal cancer. Our data suggest that the CD4/CD8 ratio may be able to help identify people living with HIV who are at higher risk of anal cancer development. See Video Abstract at http://links.lww.com/DCR/B336. LA RELACIÓN CD4 / CD8 COMO UN MARCADOR NOVEDOSO PARA EL AUMENTO DEL RIESGO DE DISPLASIA ANAL DE ALTO GRADO Y CÁNCER ANAL EN PACIENTES VIH+: UN ESTUDIO DE COHORTE RETROSPECTIVO: Las personas que viven con el virus de la inmunodeficiencia humana están en riesgo de displasia / cáncer anal. La detección / vigilancia es costosa, laboriosa y la frecuencia no se basa en evidencias. Se necesitan marcadores objetivos de mayor riesgo de carcinogénesis anal para adaptar la detección / vigilancia. La relación baja de CD4 / CD8 se asocia con un mayor riesgo general de cáncer en personas que viven con el virus de inmunodeficiencia humana, pero aún no se ha examinado para cuantificar el riesgo de cáncer anal.Hicimos la hipotesis de que la relación baja de CD4 / CD8 se correlacionan con un mayor riesgo de displasia anal de alto grado y cáncer.Revisión retrospectiva de una sola institución de personas que viven con el virus de la inmunodeficiencia humana desde 2002 hasta 2018.Facultad de Medicina y Salud Pública de la Universidad de Wisconsin.Los pacientes con enfermedad avanzada (displasia anal de alto grado y / o cáncer anal) se compararon con pacientes con citología anal negativa.Las variables independientes más bajas fueron (nadir) CD4 / CD8 y la relación CD4 / CD8 más cercanas a la detección / diagnóstico. Se utilizó el modelo de regresión logística para estimar las probabilidades ajustadas de enfermedad avanzada.Se examinaron un total de 377 personas que viven con el virus de inmunodeficiencia humana, 266 con citología negativa y 111 con enfermedad avanzada (16 cáncer, 95 displasia anal de alto grado). La tasa nadir y la tasa media más cercana fueron más bajas en pacientes con enfermedad avanzada vs. aquellos con cribado negativo (0.26 v. 0.47 (p <0.001) y 0.61 v. 0.87 (p <0.001), respectivamente. En los análisis ajustados, el aumento en la tasa nadir o la tasa más cercana a una unidad confirió una disminución del riesgo de enfermedad avanzada (OR de 0,10 (IC del 95%: 0,02, 0,45, p = 0,002)) y (OR 0,31 (IC del 95%: 0,12, 0,83, p = 0.02)), respectivamente. El umbral óptimo para usar la relacion CD4 / CD8 como factor de riesgo de enfermedad avanzada fue 0,47 para la tasa nadir (sensibilidad 0,59 y especificidad 0,91) y 0,95 para la tasa más cercana (sensibilidad 0,56 y especificidad 0,92).Este es un estudio retrospectivo de una sola institución.La baja relación CD4 / CD8 confiere un riesgo adicional de displasia anal de alto grado y cáncer anal más allá del diagnóstico del virus de inmunodeficiencia humana, incluso cuando se ajustan los factores de riesgo conocidos de cáncer anal. Nuestros datos sugieren que la relación CD4/CD8 puede ayudar a identificar a las personas que viven con el virus de inmunodeficiencia humana que tienen un mayor riesgo de desarrollar cáncer anal. Consulte Video Resumen en http://links.lww.com/DCR/B336.

Purpose of Review: As people living with human immunodeficiency virus (HIV, PLWH) age, aging-related comorbidities have come into focus as major challenges to their overall health. In this review, an in-depth overview of the two most commonly encountered chronic lung diseases in PLWH, chronic obstructive pulmonary disease (COPD) and lung cancer, is provided., Recent Findings: The risk for both COPD and lung cancer remains significantly higher in PLWH compared to the HIV-uninfected population, although fortunately rates of lung cancer appear to be declining over the last two decades. Outcomes for PLWH with these conditions, though, continue to be poor with worse survival rates in comparison to the general population. PLWH still face major barriers in accessing care for these conditions, including a higher likelihood of being underdiagnosed with COPD and a lower likelihood of being referred for lung cancer screening or treatment. A lack of evidence for optimal treatment strategies for both COPD and lung cancer still hampers the care of PLWH with these conditions., Summary: COPD and lung cancer represent substantial burdens of disease in PLWH. Improved access to standard-of-care screening and treatment and greater investigation into therapeutic responses specifically in this population are recommended., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: The role of cardiometabolic diseases (CMDs) on physical health-related quality of life (P-HRQoL) and quality of sleep was examined among 261 PLWH ≥40 years, recruited from a university-affiliated HIV clinic in the Deep U.S. South. Using a cross-sectional study design, participants completed the Medical Outcomes Study HIV Health Survey (MOS-HIV; P-HRQoL) and Pittsburgh Sleep Quality Index. The overall prevalence of self-reporting ≥1 CMD was 64.4%. P-HRQoL scores were lower in PLWH with ≥1 CMD compared with those with no CMDs (45.53 ± 11.54 vs. 49.67 ± 10.77, p <.01). Poor sleep quality was higher among participants with ≥1 CMD compared with those with no CMDs (9.28 ± 4.42 vs. 7.26 ± 4.17, p <.01). Each additional CMD resulted in a 1.83-point decrease in P-HRQoL and 0.74-point increase in poor sleep quality scores. Interventions that focus on targeting these quality-of-life domains in PLWH with CMDs are needed., (Copyright © 2022 Association of Nurses in AIDS Care.)

Objective: Depression, substance use disorders, and other neuropsychiatric comorbidities are common in people with HIV (PWH), but the underlying mechanisms are not sufficiently understood. HIV-induced damage to the gastrointestinal tract potentiates residual immune dysregulation in PWH receiving effective antiretroviral therapy. However, few studies among PWH have examined the relevance of microbiome-gut-brain axis: bidirectional crosstalk between the gastrointestinal tract, immune system, and central nervous system., Methods: A narrative review was conducted to integrate findings from 159 articles relevant to psychoneuroimmunology (PNI) and microbiome-gut-brain axis research in PWH., Results: Early PNI studies demonstrated that neuroendocrine signaling via the hypothalamic-pituitary-adrenal axis and autonomic nervous system could partially account for the associations of psychological factors with clinical HIV progression. This review highlights the need for PNI studies examining the mechanistic relevance of the gut microbiota for residual immune dysregulation, tryptophan catabolism, and oxytocin release as key biological determinants of neuropsychiatric comorbidities in PWH (i.e., body-to-mind pathways). It also underscores the continued relevance of neuroendocrine signaling via the hypothalamic-pituitary-adrenal axis, autonomic nervous system, and oxytocin release in modifying microbiome-gut-brain axis functioning (i.e., mind-to-body pathways)., Conclusions: Advancing our understanding of PNI and microbiome-gut-brain axis pathways relevant to depression, substance use disorders, and other neuropsychiatric comorbidities in PWH can guide the development of novel biobehavioral interventions to optimize health outcomes. Recommendations are provided for biobehavioral and neurobehavioral research investigating bidirectional PNI and microbiome-gut-brain axis pathways among PWH in the modern antiretroviral therapy era., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Psychosomatic Society.)

Objectives: The aim of this study was to assess the impact of hepatitis B virus (HBV) infection on non-liver malignancies in people living with HIV (PLWH)., Methods: All persons aged ≥ 18 years with known hepatitis B virus (HBV) surface antigen (HBsAg) status after the latest of 1 January 2001 and enrolment in the EuroSIDA cohort (baseline) were included in the study; persons were categorized as HBV positive or negative using the latest HBsAg test and followed to their first diagnosis of nonliver malignancy or their last visit., Results: Of 17 485 PLWH included in the study, 1269 (7.2%) were HBV positive at baseline. During 151 766 person-years of follow-up (PYFU), there were 1298 nonliver malignancies, 1199 in those currently HBV negative [incidence rate (IR) 8.42/1000 PYFU; 95% confidence interval (CI) 7.94-8.90/1000 PYFU] and 99 in those HBV positive (IR 10.54/1000 PYFU; 95% CI 8.47-12.62/1000 PYFU). After adjustment for baseline confounders, there was a significantly increased incidence of nonliver malignancies in HBV-positive versus HBV-negative individuals [adjusted incidence rate ratio (aIRR) 1.23; 95% CI 1.00-1.51]. Compared to HBV-negative individuals, HBsAg-positive/HBV-DNA-positive individuals had significantly increased incidences of nonliver malignancies (aIRR 1.37; 95% CI 1.00-1.89) and NHL (aIRR 2.57; 95% CI 1.16-5.68). There was no significant association between HBV and lung or anal cancer., Conclusions: We found increased rates of nonliver malignancies in HBsAg-positive participants, the increases being most pronounced in those who were HBV DNA positive and for NHL. If confirmed, these results may have implications for increased cancer screening in HIV-positive subjects with chronic HBV infection., (© 2021 British HIV Association.)

Background: Anal squamous cell carcinoma is rare, in general, but considerably higher in HIV-infected men who have sex with men. There is no consensus on the screening of at-risk populations., Objective: This study aimed to determine the incidence rates of anal squamous cell carcinoma and the efficacy of a screening program., Design: This is a cohort study (SeVIHanal/NCT03713229)., Setting: This study was conducted at an HIV outpatient clinic in Seville, Spain., Patients: From 2004 to 2017, all patients with at least 1 follow-up visit were analyzed (follow-up group), including a subgroup of men who have sex with men who participated in a specialized program for screening and treating anal neoplasia (SCAN group) from 2011 onward., Main Outcome Measures: The primary outcome measure was the incidence rate of anal squamous cell carcinoma., Results: Of the 3878 people living with HIV included in the follow-up group, 897 were transferred to the SCAN group; 1584 (41%) were men who have sex with men. Total follow-up was 29,228 person-years with an overall incidence rate for anal squamous cell carcinoma of 68.4/100,000 person-years (95% CI, 46.7-97.4). The changes in the incidence rate/100,000 person-years (95% CI) over time was 20.7 (3.40-80.5) for 2004 to 2006, 37.3 (13.4-87.3) for 2007 to 2010, and 97.8 (63.8-144.9) for 2011 to 2017 (p < 0.001). The strongest impact on the incidence of anal squamous cell carcinoma was made by the lack of immune restoration (adjusted incidence rate ratio (95% CI): 6.59 (4.24-10); p < 0.001), the Centers for Disease Control and Prevention category C (adjusted incidence rate ratio (95% CI): 7.49 (5.69-9.85); p < 0.001), and non-men who have sex with men (adjusted incidence rate ratio (95% CI): 0.07 (0.05-0.10); p < 0.001) in a Poisson analysis. From 2010 to 2017, incidence rates (95% CI) of anal squamous cell carcinoma within the SCAN group and the men who have sex with men of the follow-up group were 95.7 (39.6-202) and 201 (101-386)/100,000 person-years (adjusted incidence rate ratio (95% CI): 0.30 (0.23-0.39); p<0.001). The incidence rate ratio (95% CI) including non-men who have sex with men in the follow-up group was 0.87 (0.69-1.11); p = 0.269., Limitations: Adherence to the visits could not be quantified., Conclusion: Incidence rates of anal squamous cell carcinoma in people living with HIV increased significantly from 2004 to 2017, especially in men who have sex with men who were not being screened. Participation in the SCAN program significantly reduced the incidence of anal squamous cell carcinoma in men who have sex with men, in whom focus should be placed, especially on those presenting with Centers for Disease Control and Prevention category C and advanced immune suppression. See Video Abstract at http://links.lww.com/DCR/B734., Tasa De Incidencia Y Factores De Riesgo Del Carcinoma Anal a Clulas Escamosas En Una Cohorte De Personas Que Viven Con El Vih De a Implementacin De Un Programa De Deteccin: ANTECEDENTES:El carcinoma anal a células escamosas es generalmente raro, pero considerablemente más alto en hombres infectados por el VIH que tienen relaciones sexuales con hombres. No hay consenso sobre el cribado de poblaciones en riesgo.OBJETIVO:Este estudio tuvo como objetivo determinar las tasas de incidencia del carcinoma anal a células escamosas y la eficacia de un programa de detección.DISEÑO:Estudio de cohorte (SeVIHanal / NCT03713229).AJUSTE:Clínica ambulatoria de VIH en Sevilla, España.PACIENTES:De 2004 a 2017, se analizaron todos los pacientes con al menos una visita de seguimiento (grupo F / U), incluido un subgrupo de hombres que tenían relaciones sexuales con hombres que participaron en un programa especializado de cribado y tratamiento de neoplasias anales (SCAN-group) a partir de 2011.PRINCIPALES MEDIDAS DE RESULTADO:Tasas de incidencia del carcinoma anal a células escamosas.RESULTADOS:De las 3878 personas que viven con el VIH incluidas en el grupo F / U, 897 fueron transferidas al grupo SCAN, 1584 (41%) eran hombres que tenían relaciones sexuales con hombres. El seguimiento total fue de 29228 personas-año con una tasa de incidencia general de carcinoma anal a células escamosas de 68,4 / 100000 personas-año [intervalo de confianza del 95%: 46,7-97,4]. El cambio en las tasas de incidencia / 100000 personas-año (intervalo de confianza del 95%) a lo largo del tiempo fue 20,7 (3,40-80,5) para 2004-2006, 37,3 (13,4-87,3) para 2007-2010 y 97,8 (63,8-144,9) para 2011-2017, p <0,001. El impacto más fuerte en la incidencia del carcinoma a células escamosas anal fue la falta de restauración inmunológica [índice de tasa de incidencia ajustado (intervalo de confianza del 95%): 6,59 (4,24-10); p <0,001], categoría C de los Centros de Control de Enfermedades [índice de tasa de incidencia ajustado (intervalo de confianza del 95%): 7,49 (5,69-9,85); p <0,001] y no hombres que tenían relaciones sexuales con hombres [razón de tasa de incidencia ajustada (intervalo de confianza del 95%): 0,07 (0,05-0,10); p <0,001] en el análisis de Poisson. Desde 2010-2017, las tasas de incidencia (intervalo de confianza del 95%) de carcinoma anal a células escamosas dentro del grupo SCAN y los hombres que tienen relaciones sexuales con hombres del grupo F / U fueron 95,7 (39,6-202) y 201 (101- 386) / 100000 personas-año [razón de tasa de incidencia ajustada (intervalo de confianza del 95%): 0,30 (0,23-0,39); p <0,001]. La razón de la tasa de incidencia (intervalo de confianza del 95%), incluidos los no hombres que tenían relaciones sexuales con hombres en F / U, fue de 0,87 [0,69-1,11); p = 0,269].LIMITACIONES:No se pudo cuantificar la adherencia a las visitas.CONCLUSIÓNES:La tasa de incidencia del carcinoma anal a células escamosas en personas que viven con el VIH aumentó significativamente de 2004 a 2017, especialmente en hombres que tenían relaciones sexuales con hombres que no se someten a pruebas de detección. La participación en el programa SCAN redujo significativamente la incidencia de carcinoma anal a células escamosas en hombres que tenían relaciones sexuales con hombres, en quienes se debe prestar una especial atención, sobre todo en aquellos que se presentan en la categoría C de los Centros de Control de Enfermedades con inmunodeficiencia avanzada. Consulte Video Resumen en http://links.lww.com/DCR/B734., (Copyright © The ASCRS 2021.)

Objective: To characterize the clinical, laboratory and radiological characteristics of persons with HIV (PWH) presenting with cerebrospinal fluid (CSF) HIV RNA escape., Design: Retrospective case review of PWH presenting with symptomatic CSF HIV RNA escape at seven tertiary HIV clinical sites in the United Kingdom and Italy., Method: PWH with symptomatic CSF HIV RNA escape episodes were identified and data obtained from medical records. CSF HIV RNA escape was defined as quantifiable CSF HIV RNA in unquantifiable plasma HIV RNA or CSF HIV RNA greater than plasma HIV RNA in cases where plasma HIV RNA was quantifiable. The onset of clinical symptoms was classified as acute (<2 weeks-6 months), or chronic (>6 months) and differences in presentation in those with CSF HIV RNA below and above 1000 copies/ml determined., Results: We identified 106 PWH with CSF HIV RNA escape (65 male); 68 (64%) PWH had acute presentations and 38 (36%) had chronic presentations. Cognitive decline (n = 54; 50.9%), confusion (n = 20; 18.9%) and headache (n = 28; 26.4%) were the most common presentations, with cognitive decline being more common in PWH who presented chronically compared with PWH who presented acutely (73.7% vs. 35.3%, P = 0.0002). Sixty PWH had CSF HIV RNA at least 1000 copies/ml and presented more frequently with confusion (n = 15/60; 25.0%) compared with PWH with CSF HIV RNA less than 1000 copies/ml at presentation (n = 5/46; 10.9%; P = 0.03)., Conclusion: Cognitive decline, confusion and headache are the most frequent presenting symptoms of CSF HIV RNA escape and their relative frequency varied according to symptom onset and CSF HIV RNA concentration., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Although previous studies have shown a decreased incidence of prostate cancer in men with HIV/AIDS, the consensus has not been reached. Our aim is to conduct a systematic review and meta-analysis to assess the risk of prostate cancer among people with HIV/AIDS., Methods: We systematically searched PubMed, Web of Science, Embase, and Cochrane Library until March 2020. Cohort studies were included if they compared the prostate cancer risk between people with HIV/AIDS and uninfected controls or the general population. The summary standardized incidence ratio (SIR) and 95% confidence interval (CI) were calculated using a random-effects model., Results: A total of 27 studies were included for analysis, with more than 2780 males with HIV/AIDS developing prostate cancer. The results showed that HIV infection was associated with a decreased risk of prostate cancer incidence (SIR, 0.76; 95% CI, 0.64-0.91; P = 0.003), with significant heterogeneity (P < 0.001; I 2  = 91.6%). A range of sensitivity analyzes did not significantly change the results., Conclusions: Our study shows that people with HIV/AIDS have a lower incidence of prostate cancer compared with the general population. However, significant heterogeneity exists among the included studies. Further prospective studies with better designs are needed to elucidate the association between HIV infection and prostate cancer.

Objectives: The relationship between marijuana use and markers of chronic lung disease in people living with HIV (PLWH) is poorly understood., Methods: We performed a cross-sectional analysis of the Examinations of HIV-Associated Lung Emphysema (EXHALE) study, including 162 HIV-positive patients and 138 participants without HIV. We modelled marijuana exposure as: (i) current daily or weekly marijuana smoking vs. monthly or less often; or (ii) cumulative marijuana smoking (joint-years). Linear and logistic regression estimated associations between marijuana exposure and markers of lung disease, adjusted for tobacco smoking and other factors., Results: In PLWH, current daily or weekly marijuana use was associated with a larger forced vital capacity (FVC), larger total lung capacity and increased odds of radiographic emphysema compared with marijuana non-smokers in adjusted models; these associations were not statistically significant in participants without HIV. Marijuana joint-years were associated with higher forced expiratory volume in 1 s and FVC in PLWH but not with emphysema., Conclusions: In PLWH, marijuana smoking was associated with higher lung volumes and potentially with radiographic emphysema. No consistently negative associations were observed between marijuana and measures of chronic lung health., (© 2020 British HIV Association.)

Objective: Aim of this study was to compare cerebrospinal fluid (CSF) virological control, biomarkers and neurocognition of neurologically symptomatic patients on dual antiretroviral therapies (dual therapy) vs. 2 nucleoside reverse transcriptase inhibitors-based three-drug regimens (triple therapy)., Design: Retrospective monocentric cross-sectional study., Methods: We analysed data from people living with HIV undergoing lumbar puncture for clinical/research reasons with plasma HIV-RNA less than 200 copies/ml and neurological/neurocognitive symptoms without significant contributing comorbidities. We measured CSF HIV-RNA, inflammation, blood-brain barrier integrity, neuronal damage and astrocytosis biomarkers (five biomarkers by ELISA and five indices by immunoturbidimetry) and recorded the neurocognitive performance (14 tests). CSF escape was defined as any case of CSF HIV-RNA 0.5 Log10 higher than viraemia or any case of detectable CSF HIV-RNA coupled with undetectable viraemia., Results: A total of 78 patients on triple therapy and 19 on dual therapy were included. Overall, 75.3% male, median age 51 years (46-58), current CD4 count 545 cells/μl (349-735), time on current regimens 18 months (8-29), but length of plasma suppression 32 months (14-94). The two groups did not differ in terms of HIV-associated neurological diagnoses, demographic and viro-immunological features. Undetectable CSF HIV-RNA (73.7% in dual therapy vs. 78.2% in triple therapy, p.67) and CSF escape (21.1% in dual therapy vs. 19.2% in triple therapy, p.86) did not differ. No difference was observed in depression, anxiety, neurocognition (in 63 participants) nor in any tested biomarker., Conclusion: In people living with HIV with neurological/neurocognitive symptoms, peripherally effective dual therapy can show CSF virosuppression, inflammation, neuronal and astrocyte integrity and neurocognition comparable to triple therapy.

Background: Mononuclear cells play key roles in the pathogenesis of HIV-associated neurocognitive disorders (HAND). Limited studies have looked at the association of markers of monocyte activation with HAND in Africa. We examined this association among HIV-1-infected patients in Nigeria., Method: A total of 190 HIV-infected treatment-naive participants with immune marker data were included in this cross-sectional study. Plasma levels of soluble CD14 (sCD14), soluble CD163, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), and neopterin were measured. Demographically adjusted T scores obtained from a 7-domain neuropsychological test battery were generated, and functional status was assessed using activities of daily living questionnaire. Participants were classified as unimpaired, having asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), or HIV-associated dementia (HAD) in line with the "Frascati" criteria., Results: Thirty-two participants (16.8%) had ANI, 14 (7.4%) had MND, whereas none had HAD. In multivariable linear regression analyses, after adjusting for age, gender, education, CD4 count, and viral load, mean levels of sCD14 were higher among those with ANI and MND as compared with the unimpaired (P = 0.033 and 0.023, respectively). Similarly, the mean level of MCP-1 was greater among those with HAND as compared with the unimpaired (P = 0.047). There were also trends for higher levels of sCD163 and TNF-α among females with MND in univariable analyses., Conclusions: Levels of monocyte activation markers correlate with the severity of impairment among individuals with HAND. The mechanisms that underlie these effects and the potential role of gender require further study.

Purpose of Review: To summarize the state of chronic, treated HIV infection and its contribution to accelerated aging, and to evaluate recent research relevant to the study and treatment of aging and senescence., Recent Findings: Chronic treated HIV-1 infection is associated with significant risk of end-organ impairment, non-AIDS-associated malignancies, and accelerated physiologic aging. Coupled with the chronologic aging of the HIV-1-positive population, the development of therapies that target these processes is of great clinical importance. Age-related diseases are partly the result of cellular senescence. Both immune and nonimmune cell subsets are thought to mediate this senescent phenotype, a state of stable cell cycle arrest characterized by sustained release of pro-inflammatory mediators. Recent research in the field of aging has identified a number of 'senotherapeutics' to combat aging-related diseases, pharmacologic agents that act either by selectively promoting the death of senescent cells ('senolytics') or modifying senescent phenotype ('senomorphics')., Summary: Senescence is a hallmark of aging-related diseases that is characterized by stable cell cycle arrest and chronic inflammation. Chronic HIV-1 infection predisposes patients to aging-related illnesses and is similarly marked by a senescence-like phenotype. A better understanding of the role of HIV-1 in aging will inform the development of therapeutics aimed at eliminating senescent cells that drive accelerated physiologic aging.

Atherosclerotic vascular disease disproportionately affects persons living with HIV (PLWH) compared to those without. The reasons for the excess risk include dysregulated immune response and inflammation related to HIV infection itself, comorbid conditions, and co-infections. Here, we review an updated understanding of immune and inflammatory pathways underlying atherosclerosis in PLWH, including effects of viral products, soluble mediators and chemokines, innate and adaptive immune cells, and important co-infections. We also present potential therapeutic targets which may reduce cardiovascular risk in PLWH. [ABSTRACT FROM AUTHOR]

Although treatable with antiretroviral therapy, HIV infection persists in people living with HIV (PLWH). It is well known that the HIV virus finds refuge in places for which antiretroviral medications do not reach therapeutic levels, mainly the CNS. It is clear that as PLWH age, the likelihood of developing HIV-associated neurological deficits increases. At the biochemical level neurological dysfunction is the manifestation of altered cellular function and ineffective intercellular communication. In this review, we examine how intercellular signaling in the brain is disrupted in the context of HIV. Specifically, the concept of how the blood-brain barrier can be a convergence point for crosstalk, is explored. Crosstalk between the cells of the neurovascular unit (NVU) (endothelium, pericytes, astrocytes, microglia and neurons) is critical for maintaining proper brain function. In fact, the NVU allows for rapid matching of neuronal metabolic needs, regulation of blood-brain barrier (BBB) dynamics for nutrient transport and changes to the level of immunosurveillance. This review invites the reader to conceptually consider the BBB as a router or convergence point for NVU crosstalk, to facilitate a better understanding of the intricate signaling events that underpin the function of the NVU during HIV associated neuropathology. [ABSTRACT FROM AUTHOR]

Although antiretroviral therapy (ART) can suppress peripheral HIV, patients still suffer from neuroHIV due to insufficient levels of ART drugs in the brain. Hence, this study focuses on developing a poly lactic-co-glycolic acid (PLGA) nanoparticle-based ART drug delivery system for darunavir (DRV) using an intranasal route that can overcome the limitation of drug metabolic stability and blood–brain barrier (BBB) permeability. The physicochemical properties of PLGA-DRV were characterized. The results indicated that PLGA-DRV formulation inhibits HIV replication in U1 macrophages directly and in the presence of the BBB without inducing cytotoxicity. However, the PLGA-DRV did not inhibit HIV replication more than DRV alone. Notably, the total antioxidant capacity remained unchanged upon treatment with both DRV or PLGA-DRV in U1 cells. Compared to DRV alone, PLGA-DRV further decreased reactive oxygen species, suggesting a decrease in oxidative stress by the formulation. Oxidative stress is generally increased by HIV infection, leading to increased inflammation. Although the PLGA-DRV formulation did not further reduce the inflammatory response, the formulation did not provoke an inflammatory response in HIV-infected U1 macrophages. As expected, in vitro experiments showed higher DRV permeability by PLGA-DRV than DRV alone to U1 macrophages. Importantly, in vivo experiments, especially using intranasal administration of PLGA-DRV in wild-type mice, demonstrated a significant increase in the brain-to-plasma ratio of DRV compared to the free DRV. Overall, findings from this study attest to the potential of the PLGA-DRV nanoformulation in reducing HIV pathogenesis in macrophages and enhancing drug delivery to the brain, offering a promising avenue for treating HIV-related neurological disorders. [ABSTRACT FROM AUTHOR]

HIV establishes a viral reservoir in the CNS despite viral suppression in the blood on antiretroviral therapy (ART). In a minority of people with HIV (PWH), HIV RNA is detectable in CSF when HIV RNA in plasma is undetectable or HIV RNA levels are higher in CSF compared with plasma, an event termed CSF viral escape that can occur with or without neurological symptoms. Asymptomatic CSF viral escape occurs in 3–20% of PWH on ART, yet associated biomarkers are unclear. To identify biomarkers associated with asymptomatic CSF viral escape, we performed a matched group study of PWH on ART with vs. without CSF viral escape (n = 10 and n = 60, respectively, matched for age, duration of HIV infection, nadir CD4 count, and ART regimen) and 50 HIV-negative controls. PWH were on 3 or more ART drugs for >1 year, and the group with no CSF viral escape was suppressed below 50 copies/mL in plasma and CSF. Biomarkers of inflammation (IFN-γ, IL-1β, IL-6, IL-8, IL-15, IP-10, MCP-1, VEGF), cell adhesion (ICAM-1, VCAM-1), CNS injury (NFL), and glial activation (GFAP, YKL-40) were measured in paired plasma and CSF using the Meso Scale Discovery platform. PWH with vs. without CSF viral escape had more individuals (40%) with a plasma viral load (VL) > 50 copies/mL, higher CSF VL (median 156 vs. 40 copies/mL; p < 0.0001), lower CD4 count (318 vs. 512; p = 0.045), and higher CSF WBC (median [IQR] 4 [0–22] vs. 2 [0–4] cells/µL; p = 0.15) but similar proportions with HIV-associated neurocognitive disorders (HAND) (50% vs. 47%). CSF viral escape was associated with increased IL-1β, IFN-γ, IP-10, ICAM-1, and VCAM-1 in CSF but not plasma; IP-10 had the strongest association (p = 0.0008). CSF VL and WBC correlated with IFN-γ, IP-10, ICAM-1, and VCAM-1 (p < 0.05). Although markers of CNS injury showed no significant association with asymptomatic CSF viral escape, CSF YKL-40 correlated positively with CSF IL-1β (p = 0.003), IFN-γ (p = 0.0008), IP-10 (p < 0.0001), and NFL (p = 0.06) and negatively with neurocognitive T scores (p = 0.02). These findings identify CSF inflammation and glial activation markers that may serve as surrogate measures of HIV persistence in the CNS for future studies on therapeutics targeting the CNS reservoir. [ABSTRACT FROM AUTHOR]

The intestinal barrier has the daunting task of allowing nutrient absorption while limiting the entry of microbial products into the systemic circulation. HIV infection disrupts the intestinal barrier and increases intestinal permeability, leading to microbial product translocation. Convergent evidence has shown that gut damage and an enhanced level of microbial translocation contribute to the enhanced immune activation, the risk of non-AIDS comorbidity, and mortality in people living with HIV (PLWH). Gut biopsy procedures are invasive, and are not appropriate or feasible in large populations, even though they are the gold standard for intestinal barrier investigation. Thus, validated biomarkers that measure the degree of intestinal barrier damage and microbial translocation are needed in PLWH. Hematological biomarkers represent an objective indication of specific medical conditions and/or their severity, and should be able to be measured accurately and reproducibly via easily available and standardized blood tests. Several plasma biomarkers of intestinal damage, i.e., intestinal fatty acid-binding protein (I-FABP), zonulin, and regenerating islet-derived protein-3a (REG3α), and biomarkers of microbial translocation, such as lipopolysaccharide (LPS) and (1,3)-β-D-Glucan (BDG) have been used as markers of risk for developing non-AIDS comorbidities in cross sectional analyses and clinical trials, including those aiming at repair of gut damage. In this review, we critically discuss the value of different biomarkers for the estimation of gut permeability levels, paving the way towards developing validated diagnostic and therapeutic strategies to repair gut epithelial damage and to improve overall disease outcomes in PLWH. [ABSTRACT FROM AUTHOR]

In the last decade, studies in persons with HIV (PWH) on antiretroviral therapy (ART) have shed light on the significance of persistently high CD8 counts and low CD4/CD8 ratios. A low CD4/CD8 ratio reflects increased immune activation and is associated with an increased risk of severe non-AIDS events. As a result, many clinicians now believe that the CD4/CD8 ratio can help in HIV monitoring, and many researchers now report it as an efficacy marker in interventional studies. However, the topic is more complex. Recent studies have not yielded unanimous conclusions on the ability of the CD4/CD8 ratio to predict adverse outcomes, and only some clinical guidelines recommend monitoring it. Knowledge gaps remain on the best cutoff points, associated clinical events, effects of treatments, and how the CD4/CD8 ratio could improve decision making in the clinic. Here, we critically review the literature, identify knowledge gaps, and discuss the role of the CD4/CD8 ratio as a marker for HIV monitoring. [ABSTRACT FROM AUTHOR]

We recently reveal that anti-CD4 autoantibodies contribute to blunted CD4+ T cell reconstitution in HIV+ individuals on antiretroviral therapy (ART). Cocaine use is common among HIV+ individuals and is associated with accelerated disease progression. However, the mechanisms underlying cocaine-induced immune perturbations remain obscure. We evaluated plasma levels of anti-CD4 IgG and markers of microbial translocation, as well as B-cell gene expression profiles and activation in HIV+ chronic cocaine users and non-users on suppressive ART, as well as uninfected controls. Plasma purified anti-CD4 IgGs were assessed for antibody-dependent cytotoxicity (ADCC). HIV+ cocaine users had increased plasma levels of anti-CD4 IgGs, lipopolysaccharide (LPS), and soluble CD14 (sCD14) versus non-users. An inverse correlation was observed in cocaine users, but not non-drug users. Anti-CD4 IgGs from HIV+ cocaine users mediated CD4+ T cell death through ADCC in vitro. B cells from HIV+ cocaine users exhibited activation signaling pathways and activation (cycling and TLR4 expression) related to microbial translocation versus non-users. This study improves our understanding of cocaine associated B cell perturbations and immune failure and the new appreciation for autoreactive B cells as novel therapeutic targets. [ABSTRACT FROM AUTHOR]

The balance of microbial communities in the gut is extremely important for normal physiological function. Disruption of the balance is often associated with various disorders and diseases. Both HIV infection and cocaine use are known to change the gut microbiota and the epithelial barrier integrity, which contribute to inflammation and immune activation. Our recent study shows that Tat expression and cocaine exposure result in changes of genome-wide DNA methylation and gene expression and lead to worsen the learning and memory impairments. In the current study, we extended the study to determine effects of Tat and cocaine on the gut microbiota composition. We found that both Tat expression and cocaine exposure increased Alteromonadaceae in 6-month-old female/male mice. In addition, we found that Tat, cocaine, or both increased Alteromonadaceae, Bacteroidaceae, Cyanobiaceae, Erysipelotrichaceae, and Muribaculaceae but decreased Clostridiales_vadinBB60_group, Desulfovibrionaceae, Helicobacteraceae, Lachnospiraceae, and Ruminococcaceae in 12-month-old female mice. Lastly, we analyzed changes of metabolic pathways and found that Tat decreased energy metabolism and nucleotide metabolism, and increased lipid metabolism and metabolism of other amino acids while cocaine increased lipid metabolism in 12-month-old female mice. These results demonstrated that Tat expression and cocaine exposure resulted in significant changes of the gut microbiota in an age- and sex-dependent manner and provide additional evidence to support the bidirectional gut–brain axis hypothesis. [ABSTRACT FROM AUTHOR]

This review outlines the neuropathogenesis of HIV, from initial HIV entry into the central nervous system (CNS) to chronic infection, focusing on key advancements in the last 5 years. Discoveries regarding acute HIV infection reveal timing and mechanisms of early HIV entry and replication in the CNS, early inflammatory responses, and establishment of genetically distinct viral reservoirs in the brain. Recent studies additionally explore how chronic HIV infection is maintained in the CNS, examining how the virus remains in a latent "hidden" state in diverse cells in the brain, and how this leads to sustained pathological inflammatory responses. Despite viral suppression with antiretroviral therapy, HIV can persist and even replicate in the CNS, and associate with ongoing neuropathology including CD8 + T-lymphocyte mediated encephalitis. Crucial investigation to advance our understanding of the immune mechanisms that both control viral infection and lead to pathological consequences in the brain is necessary to develop treatments to optimize long-term neurologic health in people living with HIV. [ABSTRACT FROM AUTHOR]

Human Immunodeficiency virus (HIV)-associated neurocognitive disorders are a major burden for people living with HIV whose viremia is stably suppressed with antiretroviral therapy. The pathogenesis of disease is likely multifaceted, with contributions from viral reservoirs including the brain, chronic and systemic inflammation, and traditional risk factors including drug use. Elucidating the effects of each element on disease pathogenesis is near impossible in human clinical or ex vivo studies, facilitating the need for robust and accurate non-human primate models. In this review, we describe the major non-human primate models of neuroHIV infection, their use to study the acute, chronic, and virally suppressed infection of the brain, and novel therapies targeting brain reservoirs and inflammation. [ABSTRACT FROM AUTHOR]

Background: Thanks to direct-acting antivirals, hepatitis C virus (HCV) infection can be cured, with similar rates in HCV-infected and HIV–HCV co-infected patients. HCV cure is likely to foster behavioral changes in psychoactive substance use, which is highly prevalent in people living with HIV (PLWH). Cannabis is one substance that is very commonly used by PLWH, sometimes for therapeutic purposes. We aimed to identify correlates of cannabis use reduction following HCV cure in HIV–HCV co-infected cannabis users and to characterize persons who reduced their use. Methods: We used data collected on HCV-cured cannabis users in a cross-sectional survey nested in the ANRS CO13 HEPAVIH cohort of HIV–HCV co-infected patients, to perform logistic regression, with post-HCV cure cannabis reduction as the outcome, and socio-behavioral characteristics as potential correlates. We also characterized the study sample by comparing post-cure substance use behaviors between those who reduced their cannabis use and those who did not. Results: Among 140 HIV-infected cannabis users, 50 and 5 had reduced and increased their use, respectively, while 85 had not changed their use since HCV cure. Cannabis use reduction was significantly associated with tobacco use reduction, a decrease in fatigue level, paying more attention to one's dietary habits since HCV cure, and pre-HCV cure alcohol abstinence (p = 0.063 for alcohol use reduction). Conclusions: Among PLWH using cannabis, post-HCV cure cannabis reduction was associated with tobacco use reduction, improved well-being, and adoption of healthy behaviors. The management of addictive behaviors should therefore be encouraged during HCV treatment. [ABSTRACT FROM AUTHOR]

The HIV co-receptors, CCR5 and CXCR4, are necessary for HIV entry into target cells, interacting with the HIV envelope protein, gp120, to initiate several signaling cascades thought to be important to the entry process. Co-receptor signaling may also promote the development of neuroHIV by contributing to both persistent neuroinflammation and indirect neurotoxicity. But despite the critical importance of CXCR4 and CCR5 signaling to HIV pathogenesis, there is only one therapeutic (the CCR5 inhibitor Maraviroc) that targets these receptors. Moreover, our understanding of co-receptor signaling in the specific context of neuroHIV is relatively poor. Research into co-receptor signaling has largely stalled in the past decade, possibly owing to the complexity of the signaling cascades and functions mediated by these receptors. Examining the many signaling pathways triggered by co-receptor activation has been challenging due to the lack of specific molecular tools targeting many of the proteins involved in these pathways and the wide array of model systems used across these experiments. Studies examining the impact of co-receptor signaling on HIV neuropathogenesis often show activation of multiple overlapping pathways by similar stimuli, leading to contradictory data on the effects of co-receptor activation. To address this, we will broadly review HIV infection and neuropathogenesis, examine different co-receptor mediated signaling pathways and functions, then discuss the HIV mediated signaling and the differences between activation induced by HIV and cognate ligands. We will assess the specific effects of co-receptor activation on neuropathogenesis, focusing on neuroinflammation. We will also explore how the use of substances of abuse, which are highly prevalent in people living with HIV, can exacerbate the neuropathogenic effects of co-receptor signaling. Finally, we will discuss the current state of therapeutics targeting co-receptors, highlighting challenges the field has faced and areas in which research into co-receptor signaling would yield the most therapeutic benefit in the context of HIV infection. This discussion will provide a comprehensive overview of what is known and what remains to be explored in regard to co-receptor signaling and HIV infection, and will emphasize the potential value of HIV co-receptors as a target for future therapeutic development. [ABSTRACT FROM AUTHOR]

Background Pregnant women with HIV (PWWH) have high postpartum morbidity and mortality from infections like tuberculosis. Immunologic changes during pregnancy and postpartum periods may contribute to these risks, particularly the immunoregulatory kynurenine pathway of tryptophan catabolism, which contributes to both HIV and tuberculosis pathogenesis and increases in the early postpartum period. Methods Women with HIV initiating antiretroviral therapy (ART) in the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort who were pregnant at enrollment or became pregnant during observation were studied (n = 54). Plasma kynurenine/tryptophan (KT) ratio, soluble CD14 (sCD14), sCD163, sCD27, interferon-inducible protein 10 (IP-10), D-dimer, interleukin-6, and intestinal fatty-acid binding protein levels were assessed through the first year of ART and at 3-month intervals throughout pregnancy and 1 year postpartum. Biomarker changes were assessed with linear mixed models adjusted for ART duration. Hemoglobin concentration changes were used to estimate pregnancy-related changes in plasma volume. Results The median pre-ART CD4 count was 134. D-dimer increased through the third trimester before returning to baseline postpartum, while most other biomarkers declined significantly during pregnancy, beyond what would be expected from pregnancy-associated plasma volume expansion. IP-10 and sCD14 remained suppressed for at least 12 months postpartum. KT ratio was the only biomarker that increased above prepregnancy baseline postpartum (mean + 30%; P  < .001) and remained higher than baseline for ≥9 months (P  ≤ .045 for all time points). Conclusions Several immune activation markers decline during pregnancy and remain suppressed postpartum, but the kynurenine pathway of tryptophan catabolism increases above baseline for ≥9 months postpartum. The mechanisms underlying postpartum kynurenine pathway activity are incompletely understood but may contribute to increased tuberculosis risk in this setting. [ABSTRACT FROM AUTHOR]

Background: Despite early antiretroviral therapy (ART), ART-suppressed people with human immunodeficiency virus (HIV) (PWH) remain at higher risk for infections and infection-related cancers than the general population. The immunologic pathways that remain abnormal in this setting, potentially contributing to these complications, are unclear.Methods: ART-suppressed PWH and HIV-negative controls, all cytomegalovirus seropositive and enriched for HIV risk factors, were sampled from an influenza vaccine responsiveness study. PWH were stratified by timing of ART initiation (within 6 months of infection [early ART] vs later) and nadir CD4+ T-cell count among later initiators. Between-group differences in kynurenine-tryptophan (KT) ratio, interferon-inducible protein 10, soluble CD14 and CD163, soluble tumor necrosis factor receptor 2, interleukin 6, and soluble urokinase plasminogen activator receptor were assessed after confounder adjustment.Results: Most participants (92%) were male, reflecting the demographics of early-ART initiators in San Francisco. Most biomarkers were higher among later-ART initiators. Participants in the early-ART group achieved near-normal soluble tumor necrosis factor receptor 2, interleukin 6, and soluble urokinase plasminogen activator receptor levels, but substantially higher KT ratio than those without HIV after confounder adjustment (P = .008). Soluble CD14, soluble CD163, and interferon-inducible protein 10 trended similarly.Conclusions: While early-ART initiators restore near-normal levels of many inflammatory markers, the kynurenine pathway of tryptophan catabolism remains abnormally high. Because this pathway confers adaptive immune defects and predicts tuberculosis and cancer progression, this it may contribute to persistent risks of these complications in this setting. [ABSTRACT FROM AUTHOR]

Central nervous system dysfunction, associated with human immunodeficiency virus (HIV) infection, remains a significant clinical concern, affecting at least 50% of infected people. Imbalances in cytokine expression levels have been linked to HIV-associated neurocognitive disorders. The aim of this study was to evaluate plasma cytokine levels as predictor neurocognitive impairment in HIV infection using a multiplex profiling kit. Stepwise regression model was used to identify cytokine biomarkers of overall and domain-specific cognitive performance. Higher interleukin (IL)-2 (β = 0.04; P = 0.001) and eotaxin (β = 0.01; P = 0.017) were predictors of global neurocognitive, whereas higher IL-5 (β = 0.005; P = 0.007) was negative predictor of global cognitive deficit. IL-2 was a negative predictor of most cognitive domain functions, including recall (β = 0.24; P = 0.005), recognition (β = 0.04; P = 0.026), mental control (β = 0.38; P = 0.005), symbol search (β = −0.55; P = 0.001), and digital symbol (β = −0.79; P = 0.019). IL-6 was associated with 3 impaired domains, mental processing (β = −0.468; P = 0.027), recognition (β = −0.044; P = 0.012), and learning (β = 0.02668; P = 0.020) These results show that plasma cytokines/chemokines may serve as markers of neurocognitive impairment in HIV infection. [ABSTRACT FROM AUTHOR]

Introduction: Amidst unfavorable effects of alcohol and other substances on the course and outcomes of human immunodeficiency virus (HIV) infection, this study aimed at identifying patterns of alcohol and substance usage and their association with gender and presence of psychological distress among people living with HIV/acquired immunodeficiency syndrome (AIDS) (PLWHA). Material and methods: Using a cross-sectional survey, questionnaires with socio-demographic variables, Kessler psychological distress (K-10), and the condensed alcohol, smoking, and substance involvement screening test (ASSIST) were administered to PLWHA attending HIV clinic at the State University Teaching Hospital, Ado-Ekiti, Nigeria. Lifetime and current substance use as well as levels of risky use of alcohol and other substances were determined, and their relationship with gender and psychological distress were verified using bivariate statistics. Results: Among 297 participants, the majority were females (72.0%), with mean age of 37.49 years (SD = 10.02). Lifetime and current prevalence were alcohol 62.6% and 37.0%; cannabis 6.1% and 2.7%; nicotine 14.8% and 6.1%; and sedatives 43.1% and 15.4%, respectively. Males were more likely to drink alcohol, use cannabis, and smoke cigarettes than their female counterparts (p < 0.001). Those who were current sedatives users were more likely to be experiencing psychological distress (p = 0.023). Conclusions: Despite the negative effect of alcohol on the course and outcomes of HIV infection, a higher proportion of the participants had a history of lifetime and current alcohol and other substance use, with the majority of current substance users being a moderate- to high-risk users. Interventions aimed at reducing excessive substance use are needed to optimize treatment outcomes. [ABSTRACT FROM AUTHOR]

Background The rapid plasma reagin (RPR) assay is commonly used as a surrogate marker of infectious syphilis, but is non-specific, slow to change and variable in its rate of decline post treatment.Methods: Within an urban sexual health service testing predominantly men who have sex with men, a file review of RPR changes was undertaken in all subjects who had a dilution level of ≥1:4, between January 2015 to the end of December 2018.Results: Overall, 248 cases of infectious syphilis were identified in 215 subjects (165 HIV seropositive, 50 HIV seronegative). Among unique-subject cases with follow-up RPR recorded, seroreversion to a non-reactive titre was achieved in only 42.3% (71/168) cases at a median of 235 days (interquartile range: 138-348 days) and was significantly less likely if patients had HIV infection (P = 0.02), late latent syphilis (P = 0.003) or a subsequent syphilis infection (P < 0.0001). Having HIV infection (P = 0.03) or a subsequent episode of syphilis (P = 0.01) were associated with a lower likelihood of documented cure.Conclusions: The slow decay in RPR titres post therapy and the inability of a significant number of subjects to achieve a non-reactive result over time makes RPR a poor test for assessing the adequacy of treatment or in diagnosing re-infection, especially in populations having repeated and frequent risk exposures. As the number of syphilis cases continue to climb, better tests that accurately assess pathogen presence are urgently needed. [ABSTRACT FROM AUTHOR]

The chemokine system mediates acute inflammation by driving leukocyte migration to damaged or infected tissues. However, elevated expression of chemokines and their receptors can contribute to chronic inflammation and malignancy. Thus, great effort has been taken to target these molecules. The first hint of the druggability of the chemokine system was derived from the role of chemokine receptors in HIV infection. CCR5 and CXCR4 function as essential co-receptors for HIV entry, with the former accounting for most new HIV infections worldwide. Not by chance, an anti-CCR5 compound, maraviroc, was the first FDA-approved chemokine receptor-targeting drug. CCR5, by directing leukocytes to sites of inflammation and regulating their activation, also represents an important player in the inflammatory response. This function is shared with CCR2 and its selective ligand CCL2, which constitute the primary chemokine axis driving the recruitment of monocytes/macrophages to inflammatory sites. Both receptors are indeed involved in the pathogenesis of several immune-mediated diseases, and dual CCR5/CCR2 targeting is emerging as a more efficacious strategy than targeting either receptor alone in the treatment of complex human disorders. In this review, we focus on the distinctive and complementary contributions of CCR5 and CCR2/CCL2 in HIV infection, multiple sclerosis, liver fibrosis and associated hepatocellular carcinoma. The emerging therapeutic approaches based on the inhibition of these chemokine axes are highlighted. [ABSTRACT FROM AUTHOR]

Background Dipeptidyl peptidase-4 (DPP-4) inhibitors have pleotropic anti-inflammatory and immune regulatory effects in addition to glucoregulation. We evaluated inflammation and immune markers in suppressed human immunodeficiency virus (HIV) infection during treatment with the DPP-4 inhibitor sitagliptin. Methods Virologically suppressed adults with HIV without diabetes on stable antiretroviral therapy (ART) with ≥100/μL CD4 cells were randomized to 16 weeks of sitagliptin 100 mg/day vs placebo in a multicenter trial. The primary endpoint was the change in plasma soluble CD14 (sCD14) from baseline to week 15–16. Results Ninety participants were randomized, and 42 from each arm were included in per-protocol analyses. Participants were 45% non-Hispanic white, 38% non-Hispanic black, and 15% Hispanic, with a median age of 51 years; 83% were male; and the median CD4 count was 602 cells/μL. At week 15–16, there was no difference in sCD14 change between the 2 arms (P =.69). Relative to placebo, the sitagliptin arm had 47% greater decline in CXCL10 (95% confidence interval, –57% to –35%) at week 15 (P <.001). There were no significant between-arm differences in other soluble biomarkers, total CD4 and CD8 counts, or markers of lymphocyte or monocyte activation. Sitagliptin was well tolerated. Conclusions Sixteen weeks of sitagliptin had no effect on sCD14 levels in virologically suppressed participants with HIV. CXCL10, a chemokine involved in atherogenesis that predicts non-AIDS events during ART, declined markedly with sitagliptin. This suggests that DPP-4 inhibition has the potential to reduce cardiovascular morbidity in treated HIV infection. Clinical Trials Registration NCT01426438. [ABSTRACT FROM AUTHOR]

A major obstacle to HIV eradication is the presence of infected cells that persist despite suppressive antiretroviral therapy (ART). HIV largely resides outside of the peripheral circulation, and thus, numerous anatomical and lymphoid compartments that have the capacity to harbor HIV are inaccessible to routine sampling. As a result, there is a limited understanding of the tissue burden of HIV infection or anatomical distribution of HIV transcriptional and translational activity. Novel, non-invasive, in vivo methods are urgently needed to address this fundamental gap in knowledge. In this review, we discuss past and current nuclear imaging approaches that have been applied to HIV infection with an emphasis on current strategies to implement positron emission tomography (PET)-based imaging to directly visualize and characterize whole-body HIV burden. These imaging approaches have various limitations, such as the potential for limited PET sensitivity and specificity in the setting of ART suppression or low viral burden. However, recent advances in high-sensitivity, total-body PET imaging platforms and development of new radiotracer technologies that may enhance anatomical penetration of target-specific tracer molecules are discussed. Potential strategies to image non-viral markers of HIV tissue burden or focal immune perturbation are also addressed. Overall, emerging nuclear imaging techniques and platforms may play an important role in the development of novel therapeutic and HIV reservoir eradication strategies. [ABSTRACT FROM AUTHOR]