Antiretroviral Therapy Era Research Articles

Severity and Number of Substances Used are Independently Associated with Antiretroviral Therapy Adherence Over Time among People with HIV in the Current Treatment Era.

Substance use is associated with decreased antiretroviral therapy (ART) adherence among people with HIV (PWH). Adherence plays a significant role in mediating the negative effects of substance use on HIV suppression and is a principal modifiable patient-level factor in improving HIV suppression and reducing ART drug resistance. Understanding substance use and ART adherence, particularly with rapidly changing substance use epidemiology and ART regimens, is vital to improving HIV care. Among 10,557 PWH (2010-2021) from 8 academic clinical sites nationally we examined longitudinal associations of substance use severity and number of substances used (measured using AUDIT-C and modified ASSIST) with patient-reported ART adherence (visual analog scale). Alcohol (68% any use, 18% unhealthy use [AUDIT-C > 4 men, > 3 women]), marijuana (33%), and methamphetamine (9%) use were most reported. Polysubstance use was common (32%). Both higher severity substance use and higher number of substances used were associated with lower ART adherence. Severity of methamphetamine use had the strongest dose-response association with ART adherence (low severity [ASSIST 1-3]: -3.05%, 95% CI: -4.23%, -1.87%; moderate [ASSIST 4-26]: -6.20%, 95% CI: -7.08%, -5.33%; high [ASSIST > 26]: -10.77%, 95% CI: -12.76%, -8.78%). Severe substance use, especially methamphetamine, and higher number of illicit drugs used were associated with declines in adherence at levels that were likely clinically meaningful in the modern era of ART. Findings support integrating substance use care with HIV care and potential benefits of harm reduction strategies for improving adherence such as encouraging lower levels of substance use and fewer number of substances used.

Reduction of aortic stiffness in newly diagnosed persons with HIV-infection: modifiable vascular dysfunction after antiretroviral therapy?

Abstract Background People living with HIV (PLWH) are at an increased risk of cardiovascular disease (CVD), which is underestimated by contemporary risk stratification systems[1]. Subclinical cardiovascular abnormalities may be present at the time of HIV diagnosis and serve as potential substrate for future CVD. Aortic stiffness, as measured with pulse wave velocity (PWV), is a validated predictor of CVD [2,3] and has been shown to be elevated in PLWH at the time of HIV diagnosis compared to HIV-uninfected persons[4]. Purpose To prospectively assess the influence of contemporary antiretroviral therapy (ART) on aortic stiffness in a group of newly diagnosed PLWH in a low- to middle-income setting. Methods A group of ART naïve PLWH with modest cardiovascular risk and free from known CVD, was recruited at the time of HIV diagnosis from the Western Cape Province of South Africa. Aortic stiffness was measured using carotid-femoral PWV on a commercially available device that simultaneously measured the carotid and femoral waveforms on a supine patient in a temperature-controlled room utilising established methodology[4]. The algorithmically-calculated time delay between the upstroke of the carotid and femoral wave-forms provided the transit time (TT). Carotid femoral path distance (path length) was measured using surface anatomy. PWV was calculated as direct path length divided by TT. Aortic distensibility was expressed according to the Bramwell-Hill equation as 3.57/PWV(squared)[5]. ART was initiated and PWV was re-evaluated 9 months later. Results Seventy-three participants completed follow-up and were included. The cohort was relatively young (mean age 32±7 years) with good female representation (n=33, 45%). Most received tenofovir/lamivudine/dolutegravir (n=71, 97%) Half of the group smoked cigarettes. Two participants were controlled hypertensives, and two participants had metabolic syndrome. A significant decrease in PWV (with scaling factor of 0.8) was observed at 9 months of ART (5.93 ±1.0 vs. 5.69 ±1.0 m/s; p=0.01). Aortic distensibility increased significantly as well (0.20 [IQR: 0.16 to 0.26] vs. 0.21 [IQR: 0.19 to 0.27] mmHg-1; p=0.02). Conclusion Improvement in aortic stiffness was observed in a group of newly diagnosed PLWH after 9 months of ART-initiation. This provides evidence of a modifiable component of vascular dysfunction and, in turn, cardiovascular risk with the use of contemporary ART at 9 months. It is unknown if this effect will be sustained long-term. The use of aortic stiffness (alone or in combination with other parameters) as a predictor of cardiovascular outcomes in the ART era requires further study.Abstract figureAbstract table

High Clinical Burden of Cryptosporidium spp. in Adult Patients with Acquired Immunodeficiency in Ghana

There is a paucity of information on the prevalence, risk factors, and clinical correlates of people living with HIV (PLWH) who are co-infected with Cryptosporidium spp. in the post-combined antiretroviral therapy era in Ghana. To provide such data, in this observational study, stool samples of 640 HIV-positive and 83 HIV-negative individuals in Ghana were screened for Cryptosporidium spp. Additionally, sociodemographic parameters, clinical symptoms, medication intake, and immunological parameters were assessed. The prevalence of Cryptosporidium spp. was 11.8% (n = 73) in HIV-positive and 1.2% (n = 1) in HIV-negative participants (p < 0.001). Within the group of HIV-positive participants, the prevalence reached 26.0% in patients with CD4+ T cell counts below 200 cells/µL and 46.2% in the subgroup with CD4+ T cell counts below 50 cells/µL. The frequencies of the clinical manifestation of weight loss and gastrointestinal symptoms were significantly higher in patients with Cryptosporidium spp. compared to those without co-infection (45.8% vs. 21.4%, p < 0.001 and 22.2% vs. 12.2%, p = 0.031, respectively). In the modern post-cART era, the acquisition of Cryptosporidium spp. among PLWH in Ghana is driven largely by the degree of immunosuppression. Access to cART and screening for Cryptosporidium spp. as part of routine care might help control and reduce the burden of the infection.

Lenacapavir: Playing the Long Game in the New Era of Antiretrovirals.

The mainstay of antiretroviral therapy (ART) has been combination oral therapy. While oral ART is highly effective, nonadherence remains a chief concern. Addressing this concern in recent years is the emergence of long-acting antiretrovirals for the treatment and prevention of HIV-1 infection. The most recently approved long-acting antiretroviral is the first-in-class capsid inhibitor lenacapavir (LEN) for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. Due to its biannual subcutaneous dosing scheme to inhibit the HIV-1 capsid, LEN exhibits unique pharmacokinetics and reinforces an evolving era of ART. In this review, we evaluate published and accepted research articles, conference proceedings, and clinical trial records to provide a comprehensive overview of LEN for treatment and preliminary data for the prevention of HIV-1 infection. These data include clinical trials outcomes, in vitro and in vivo resistance profiles, and preclinical data supporting downstream indications. We also discuss the unique clinical pharmacology of LEN with the goal of serving as a resource toward subsequent physiologically based, population-based, and other miscellaneous pharmacometric-focused analyses. Given the dynamic nature of the HIV treatment and prevention research fields, we also discuss ongoing studies related to LEN for treatment-naïve adults and for prevention. Lastly, we discuss important pharmacologic gaps in special populations, drug-drug interactions, and at the sites of action germane to HIV treatment and prevention. The information discussed in this review will provide knowledge and understanding of the unique pharmacologic properties of LEN to assist clinicians and researchers as they navigate the dynamic HIV research landscape.

Expert Consensus Statement on an Updated Definition of Unintended Weight Loss Among Persons With Human Immunodeficiency Virus in the Modern Treatment Era.

The era of modern antiretroviral therapy (ART) has markedly improved health and survival among persons with human immunodeficiency virus (HIV) (PWH). In the pre-ART era, wasting was associated with HIV disease progression to acquired immunodeficiency syndrome and death. Effective ART has reduced the prevalence and incidence of this pre-ART form of HIV-associated wasting. However, a subgroup of ART-treated virally suppressed PWH continue to lose weight, often accompanied by aging-related comorbidities and/or functional deficits. For this subgroup of patients, the older definition of HIV-associated wasting (HIVAW) cannot and should not be applied. An expert panel comprising the authors of this white paper convened to review the existing definition of HIVAW and to create an updated definition that they termed HIV-associated weight loss, based on clinically defined parameters among contemporary PWH receiving ART. Here, clinical features and laboratory biomarkers associated with HIV-associated weight loss are reviewed and approaches to screening and treatment are considered. Available management approaches, including the use of current US Food and Drug Administration-approved medications for HIVAW and other available therapies are discussed. The expert panel also identified knowledge gaps and provided recommendations for clinicians, payers, and researchers.

Evaluation of Viral Suppression in Paediatric Populations: Implications for the Transition to Dolutegravir-Based Regimens in Cameroon: The CIPHER-ADOLA Study.

Mortality in children accounts for 15% of all AIDS-related deaths globally, with a higher burden among Cameroonian children (25%), likely driven by poor virological response. We sought to evaluate viral suppression (VS) and its determinants in a nationally representative paediatric and young adult population receiving antiretroviral therapy (ART). A cross-sectional and multicentric study was conducted among Cameroonian children (<10 years), adolescents (10-19 years) and young adults (20-24 years). Data were collected from the databases of nine reference laboratories from December 2023 to March 2024. A conditional backward stepwise regression model was built to assess the predictors of VS, defined as a viral load (VL) <1000 HIV-RNA copies/mL. Overall, 7558 individuals (females: 73.2%) were analysed. Regarding the ART regimen, 17% of children, 80% of adolescents and 83% of young adults transitioned to dolutegravir (DTG)-based regimens. Overall VS was 82.3%, with 67.3% (<10 years), 80.5% (10-19 years) and 86.5% (20-24 years), and p < 0.001. VS was 85.1% on a DTG-based regimen versus 80.0% on efavirenz/nevirapine and 65.6% on lopinavir/ritonavir or atazanavir/ritonavir. VS was higher in females versus males (85.8% versus 78.2%, p < 0.001). The VS rate remained stable around 85% at 12 and 24 months but dropped to about 80% at 36 months after ART initiation, p < 0.009. Independent predictors of non-VS were younger age, longer ART duration (>36 months), backbone drug (non-TDF/3TC) and anchor drug (non-DTG based). In this Cameroonian paediatric population with varying levels of transition to DTG, overall VS remains below the 95% targets. Predictors of non-VS are younger age, non-TDF/3TC- and non-DTG-based regimens. Thus, efforts toward eliminating paediatric AIDS should prioritise the transition to a DTG-based regimen in this new ART era.

Immune Characteristics and Immunotherapy of HIV-Associated Lymphoma.

In the era of antiretroviral therapy (ART), mortality among people living with the human immunodeficiency virus (HIV) has significantly decreased, yet the population of people living with HIV remains substantial. Among people living with HIV (PLWH), HIV-associated lymphoma (HAL) has surpassed Kaposi's sarcoma to become the most common tumor in this population in developed countries. However, there remains a dearth of comprehensive and systematic understanding regarding HIV-associated lymphomas. This review aims to shed light on the changes in the immune system among PLWH and the characteristics of the immune microenvironment in HIV-associated lymphoma, with a specific focus on the immune system's role in these individuals. Additionally, it seeks to explore recent advancements in immunotherapy for the treatment of HIV-associated lymphoma, intending to enhance strategies for immunotherapy in this specific population.

Experience of practical use of enterosorbents in the treatment of HIV-infected children with diarrhea syndrome

Despite advances in antiretroviral therapy (ART), diarrhea is common among people living with HIV (PLHIV) and negatively impacts quality of life. Although diarrheal diseases caused by opportunistic infections have decreased in the ART era, the overall prevalence of diarrhea remains unchanged, estimated at 28% to 60% of PLHIV.The aim of the study: to conduct a comparative assessment of the clinical efficacy of enterosorbents in the treatment of diarrheal syndrome in children with HIV infection.Materials and methods. The study material included 80 HIV-infected children who experienced acute infectious diarrhea aged 5 to 14 years. The main group included 40 children who received enterosgel, 2 times 1 tablespoon included in the traditional treatment regimen, and the control group included 40 children who received the drug lactofiltrum against the background of traditional therapy, 1 tablet 3 times a day. The duration of treatment was 10 days.Results and discussion. During the treatment of acute diarrhea in children with HIV infection with Enterosgel, a significant decrease in the daily amount and in the duration of diarrhea was observed, which leads to a noticeable loss of signs of dehydration (P&lt;0.05). Elimination of acute diarrhea in children with HIV infection may also have eliminated the underlying intoxication syndrome due to the underlying and burning disease, which may lead to a reduction in health care costs and socioeconomic burden.Conclusion. During the treatment of acute diarrhea in children with HIV infection with Enterosgel, a decrease in the daily amount and in the duration of diarrhea is reliably observed, which leads to a significant disappearance of signs of dehydration (р&lt;0.05).

Cancer risk among people living with Human Immunodeficiency Virus (HIV) in Rwanda from 2007 to 2018.

Assessing the risk of cancer among people living with HIV (PLHIV) in the current era of antiretroviral therapy (ART) is crucial, given their increased susceptibility to many types of cancer and prolonged survival due to ART exposure. Our study aims to compare the association between HIV infection and specific cancer sites in Rwanda. Population-based cancer registry data were used to identify cancer cases in both PLHIV and HIV-negative persons. A probabilistic record linkage approach between the HIV and cancer registries was used to supplement HIV status ascertainment in the cancer registry. Associations between HIV infection and different cancer types were evaluated using unconditional logistic regression models. We performed several sensitivity analyses to assess the robustness of our findings and to evaluate the potential impact of different assumptions on our results. From 2007 to 2018, the cancer registry recorded 17,679 cases, of which 7% were diagnosed among PLHIV. We found significant associations between HIV infection and Kaposi's Sarcoma (KS) (adjusted odds ratio [OR]: 29.1, 95% CI: 23.2-36.6), non-Hodgkin lymphoma (NHL) (1.6, 1.3-2.0), Hodgkin lymphoma (HL) (1.6, 1.1-2.4), cervical (2.3, 2.0-2.7), vulvar (4.0, 2.5-6.5), penile (3.0, 2.0-4.5), and eye cancers (2.2, 1.6-3.0). Men living with HIV had a higher risk of anal cancer (3.1, 1.0-9.5) than men without HIV, but women living with HIV did not have higher risk than women without HIV (1.0, 0.2-4.3). Our study found that in an era of expanded ART coverage in Rwanda, HIV is associated with a broad range of cancers, particularly those linked to viral infections.

Community-acquired pneumonia in people with Human Immunodeficiency Virus (HIV) during the current era of effective antiretroviral therapy: A multi-center retrospective cohort study.

It is unclear if Human Immunodeficiency Virus (HIV) infection affects the prognosis for community acquired pneumonia (CAP) in the current era of effective anti-retroviral therapy. In this multi-center retrospective cohort study of patients admitted for CAP, we compared the in-hospital mortality rate between people with HIV (PWH) and people without HIV. The study included consecutive patients admitted with a diagnosis of CAP across 31 hospitals in Ontario, Canada from 2015 to 2022. HIV infection was based on discharge diagnoses and anti-retroviral prescription. The primary outcome was in-hospital mortality. Competing risk models were used to describe time to death in hospital or discharge. Potential confounders were balanced using overlap weighting of propensity scores. Of 82,822 patients admitted with CAP, 1,518 (1.8%) patients had a diagnosis of HIV. PWH were more likely to be younger, be male and have less comorbidities. In hospital, 67 (4.4%) PWH and 6,873 (8.5%) people without HIV died. HIV status had an adjusted sub-distribution hazard ratio (sHR) of 1.02 (95% CI 0.80-1.31 P=0.8440) for dying in hospital. Of 1,518 PWH, 440 (29.0%) patients had a diagnosis of acquired immunodeficiency syndrome (AIDS). AIDS diagnosis had an adjusted sHR of 3.04 (95% CI 1.69-5.45 P=0.0002) for dying in hospital compared to HIV without AIDS. People with and without HIV admitted for CAP had a similar in-hospital mortality rate. For PWH, AIDS significantly increased the mortality risk. HIV infection by itself without AIDS should not be considered a poor prognostic factor for CAP.

Infective endocarditis in HIV-infected patients. Analysis of a national cohort

Background There is limited recent evidence about infective endocarditis (IE) in HIV-infected patients. Our aim was to compare IE according to HIV infection presence. Methods Consecutive inclusion of IE patients at 46 Spanish hospitals between 2008 and 2021. Results From 5667 patients, 99 were HIV-infected (1·7%; 50 intravenous drugs users). Compared to patients without HIV, HIV-infected patients were more frequently male (84% vs. 67%), had younger median age (46 vs. 69 years), and less comorbidities, except liver disease (52% vs. 9%) and intravenous drug use (51% vs. 1%). They had more common tricuspid location (36% vs. 5%) and community-acquired IE (82% vs. 63%), vascular (29% vs. 17%) and cutaneous (22% vs. 7%) foci of infection, and Staphylococcus aureus aetiology (46% vs. 22%). Vegetations (84% vs. 72%), vascular phenomena (17% vs. 9%), splenomegaly (30% vs. 11%), and embolisation (41% vs 21%) were also more common. Surgical indication and surgery were less frequent in HIV-infected patients (54% vs 67%, 28% vs 47%, respectively). Median CD4 count in HIV-infected patients was 318 cells/mm3. In-hospital mortality (23% vs. 26%) and one-year mortality (25% vs. 32%) were similar in both groups. HIV infection was not independently associated with in-hospital (odds ratio 1·1, 95% CI 0·6–1·9) nor one-year mortality (hazard ratio 0·8, 95% CI 0·4–1·3). Conclusions In the combined antiretroviral therapy era, less than 2% of IE patients have HIV infection. HIV-infected patients have a different clinical profile than those without HIV, but the presence of HIV does not seem to impact on IE prognosis.

Palliative care considerations for the older adults with HIV/AIDS: a clinical practice review.

Human immunodeficiency virus (HIV) has historically been viewed as a terminal condition affecting younger populations, however, with advancements in antiretroviral therapy (ART) and better healthcare provisions, people with HIV are now living longer than ever before. This shift has highlighted the need to readdress the end-of-life care needs of patients aging with HIV. People aging with HIV face a double burden. Aging itself comes with an array of health challenges, including cognitive decline, frailty, and increased susceptibility to chronic illnesses. Despite effective management with ART, HIV is associated with ongoing inflammation, and may accelerate aging processes, increasing the risk of certain cancers and comorbidities, as well as an increased risk of cardiovascular disease. The stigma surrounding HIV, though diminished over the years, still lingers. People living with HIV have experienced decades of intersecting stigmatized identities in the context of social isolation, leading to potential psychological challenges like depression, anxiety, and loneliness, all of which may be amplified by aging. Addressing these emotional and social needs is as crucial as managing their physical health. The integration of primary palliative care into geriatric practice is crucial, as it improves the quality of life for older patients with chronic illnesses, life-limiting conditions. This is particularly relevant for aging individuals with HIV, who often face complex medical needs and multiple comorbidities. Primary palliative care is the basic, integrated palliative care support provided by non-specialists as part of routine care, while specialist palliative care involves more complex and specialized support from a team with specific training in palliative care. Incorporating palliative care principles enables geriatric healthcare providers to address these comprehensive needs more effectively. This approach encompasses not only physical symptom management but also the emotional well-being of patients. It aids in advanced care planning and decision-making that resonate with the patients' values and goals. Ultimately, this integrated approach leads to improved patient outcomes and a higher quality of care. This review delves into the unique considerations and challenges of providing palliative care to people aging with HIV, recognizing the interplay of age and HIV in the era of modern ART.

Long-acting injection therapies: New opportunities and challenges

Since the development of an effective antiretroviral therapy (ART) in 1996, substantial progress has been made in terms of efficacy, safety and ease of use. While at the beginning of the ART era the foremost goal necessarily was patient survival, over time it has become increasingly possible to shift the focus towards aspects of patient's quality of life. The latest developments are the long-acting injection therapies (LAI), foregoing for the first time the necessity to take pills. The only available injection therapy so far comprises 2 intramuscular injections every 2 months, with 3 ml of Cabotegravir 600 mg and 3 ml of Rilpivirine 900 mg being injected, respectively. Through this, patient's needs that were hitherto precluded from consideration could be addressed. These needs are inextricably linked to the stigmata people living with HIV (PLWH) are still confronted with on a daily basis. LAI have the potential to relieve PLWH of some of the heavy psychological burdens associated with the continued stigmatization. However, as a new therapy, new challenges need to be considered the use of LAI.

CD4 nadir and neurocognitive trajectories in people living with HIV.

Human immunodeficiency virus-associated neurocognitive disorders persist in the combination antiretroviral therapy era. CD4 nadir is a well-established predictor of cognition cross-sectionally, but its impact on longitudinal neurocognitive (NC) trajectories is unclear. The few studies on this topic examined trajectories of global cognition, rather than specific NC domains. The current study examined CD4 nadir in relation to domain-specific NC decline. 132 HIV + adults from the Temple/Drexel Comprehensive NeuroHIV Center, Clinical and Translational Research Support Core Cohort were administered comprehensive NC assessments longitudinally, with last visit occurring an average of 12years after CD4 nadir. Linear mixed models were used to examine CD4 nadir in relation to longitudinal NC trajectories in three empirically identified NC domains: speed/executive function (S/EF), visuospatial memory (VM), and verbal fluency (VF). CD4 nadir was associated with change in VF (p = 0.020), but not with S/EF or VM. Specifically, those with CD4 nadir < 200 demonstrated increasing VF over time (p = .002), whereas those with CD4 nadir > 200 demonstrated stable VF (p = .568), though these differing trajectories may partly reflect regression to the mean or differential practice effect. CD4 dynamics over time were analyzed as potential mechanisms for the identified associations, with mixed findings. While low CD4 nadir has been associated with weaker neurocognition among people living with HIV, the results of this study suggest that low CD4 nadir is not associated with ongoing decline a decade later. Nadir-related deficits in VF may be stable or even improve over time, possibly reflecting the beneficial cognitive effects of long-term treatment and immune reconstitution.

The impact of HIV and CD4 count stratification on all cause mortality for adenocarcinoma and squamous cell lung cancers in the antiretroviral therapy era: Analysis of National Veterans Affairs and Kaiser Permanente Northern cohorts.

8070 Background: Since the widespread introduction of antiretroviral therapy (ART), people living with HIV (PWH) have experienced substantially decreased morbidity and mortality. However, PWH are at higher risk for lung cancer and have decreased cancer survival rates compared to people without HIV (PWoH). Few studies have evaluated histology-specific lung cancer survival by stage and HIV immune control. Methods: A retrospective cohort study was conducted with newly diagnosed non-small cell lung cancer (NSCLC), including PWH with PWoH, identified between 2008 and 2020 from the US Department of Veterans Affairs and Kaiser Permanente, California. Adjusted hazard ratios for 5-year survival by CD4 count (≥ 500 cells/mm3, &lt;500 cells/mm3, ref: PwOH) were estimated using Cox models stratified by subtype (adenocarcinoma, squamous) and TNM (I, II/III, IV) stage. Results: This cohort consisted of 562 PWH (53% adenocarcinoma, 33% squamous cell) and 91,370 PWoH (52% adenocarcinoma, 33% squamous cell, 15% not specified). The PWH cohort tended to be younger (62 vs. 69 years), male (97% vs. 83%), and non-Hispanic Black race (48% vs. 14%), compared to PWoH. Among PWH, 41% had CD4 ≥500 cells/mm3, 59% had CD4 &lt;500 cells/mm3 . The median survival in years for PWoH, PWH CD4 count ≥500 cell/mm3and &lt;500 cells/mm3 were: 2.4 ±0.10, 2.3 ± 0.17, 2.0±0.17, respectively for adenocarcinoma, and 2.1±0.01, 2.3±0.21, 1.6±0.17 respectively for squamous cell carcinoma. The table shows the adjusted HR for all-cause mortality for Adenocarcinoma and Squamous Cell Carcinoma comparing PWH ≥500 and PWH&lt;500 to PWoH (as reference) stratified by stage. Conclusions: Although it is well known that low CD counts (&lt;200) are associated with poor cancer outcomes, higher CD4 counts (CD&lt;500) at the time of lung cancer diagnosis may still play a role in the treatment outcomes of NSCLC. PWH who have CD4 counts ≥500 appear to have similar survival compared to PWoH, but CD4&lt;500, those with (vs. without) HIV have higher rates of mortality for both adenocarcinoma and squamous cell histologies. Adjusted hazard ratios (HR)* with 95% confidence intervals (CI) for 5-year all-cause-mortality associated with HIV by CD4 count (reference: PWoH), across Adenocarcinoma and Squamous Cell Cancer histology and baseline cancer stage. [Table: see text]

Acquired Immunodeficiency Syndrome Cholangiopathy in the Highly Active Antiretroviral Therapy Era

Acquired Immunodeficiency Syndrome Cholangiopathy in the Highly Active Antiretroviral Therapy Era

Extracellular vesicles produced by HIV-1 Nef-expressing cells induce myelin impairment and oligodendrocyte damage in the mouse central nervous system

HIV-associated neurocognitive disorders (HAND) are a spectrum of cognitive impairments that continue to affect approximately half of all HIV-positive individuals despite effective viral suppression through antiretroviral therapy (ART). White matter pathologies have persisted in the ART era, and the degree of white matter damage correlates with the degree of neurocognitive impairment in patients with HAND. The HIV protein Nef has been implicated in HAND pathogenesis, but its effect on white matter damage has not been well characterized. Here, utilizing in vivo, ex vivo, and in vitro methods, we demonstrate that Nef-containing extracellular vesicles (Nef EVs) disrupt myelin sheaths and inflict damage upon oligodendrocytes within the murine central nervous system. Intracranial injection of Nef EVs leads to reduced myelin basic protein (MBP) staining and a decreased number of CC1 + oligodendrocytes in the corpus callosum. Moreover, cerebellar slice cultures treated with Nef EVs exhibit diminished MBP expression and increased presence of unmyelinated axons. Primary mixed brain cultures and enriched oligodendrocyte precursor cell cultures exposed to Nef EVs display a decreased number of O4 + cells, indicative of oligodendrocyte impairment. These findings underscore the potential contribution of Nef EV-mediated damage to oligodendrocytes and myelin maintenance in the pathogenesis of HAND.

Longitudinal Analysis of Overlapping Psychosocial Factors Predicting Incident Hospitalization Among Mixed HIV Serostatus Men who have Sex with Men in the Multicenter AIDS Cohort Study.

Men who have sex with men (MSM) are at increased risk for certain types of chronic diseases and mental health problems. Despite having extended survival in the highly active antiretroviral therapy (HAART) era, MSM living with HIV contend with aging-related diseases and complications with treatment. Consequent hospitalizations incur high costs, fear, low quality of life, and frailty. Unlike heterosexual men, MSM experience more structural violence and "syndemics" of psychosocial factors that not only accelerate HIV acquisition and transmission risk but also may increase morbidity, leading to greater rates of hospitalization. We aim to examine the impact of "syndemic" psychosocial factors on the incidence of hospitalization among geographically diverse MSM in the US. Participants were 1760 MSM from the Multicenter AIDS Cohort Study (MACS) between 2004 and 2019. We examined the relationship between six psychosocial factors (depression, stimulant use, smoking, heroin use, childhood sexual abuse, and intimate partner violence) and incident hospitalization (admission to a hospital for treatment). We found a positive dose-response relationship between the number of syndemic factors and hospitalization. MSM reporting five or more syndemic factors had over twice the risk of hospitalization compared to MSM without syndemic factors [aRR = 2.14 (95% CI = 1.56, 2.94)]. Psychosocial factors synergistically increased hospitalizations over time. The positive dose-response relationship between the number of syndemic factors and hospitalization and the synergistic effects of these factors underscore the need for interventions that disentangle the syndemics to reduce hospitalization and related costs and improve the quality of life among MSM.

Cognitive impairment in children and adolescents living with perinatal HIV disease in the ART era: a meta-analysis

Despite improved survival and overall health outcomes from modern antiretroviral therapy (ART), children and adolescents living with HIV are facing pervasive impairments in neurodevelopment including cognitive impairment, but there remains a lack of consensus on the cognitive domains that are affected in those children and adolescents. The objective of this meta-analysis was to evaluate the impact of perinatal HIV-infection on executive function, working memory, and speed of information processing in the ART era. The PubMed database was searched for studies published between 1997 and 2024, plus additional search with the ScienceDirect, bioRxiv, and medRxiv databases. A meta-analysis was conducted on thirty-five studies published between 2012 and 2023 that encompassed a total of 4066 perinatally-infected HIV patients, 2349 HIV-exposed uninfected (HEU) controls, and 2466 HIV-unexposed, uninfected (HUU) controls. Performance scores on executive function, working memory, and processing speed were pooled using random-effects meta-analysis. Compared to HEU and HUU controls, perinatally HIV-infected children and adolescents presented with significant impairments in processing speed (Hedges g=-0.64, p<0.00001), working memory (Hedges g=-0.69, p<0.00001), and to a lesser degree, executive function (Hedges g=-0.35, p=0.02). Meta-regression analysis suggested that the effect estimate of processing speed impairment negatively correlated with Gross National Income (GNI) per capita of the study countries (CALHIV vs HUU, p=0.0016; CALHIV vs HEU, p=0.0019), even though HIV-infected cases were compared to sociodemographically matched HUU controls from the same countries. Sub-group meta-analyses with participants from high-income or low-/middle-income countries provided further evidence suggesting that the performance gap between HIV-infected cases and HUU/HEU controls may be larger in low-/middle-income countries than high-income countries. In the ART era, cognitive impairment (especially reduced processing speed and working memory) persists in children and adolescents living with HIV. These impairments may be more pronounced among those children and adolescents living with HIV in low-income countries, suggesting that there may be global health inequities in treatment outcomes with perinatal HIV-infection. However, meta-analysis and meta-regression analysis have their limitations, which calls for future collaborative multi-country international studies to directly investigate this important topic. Nevertheless, there is an unmet need to assure equity in timely assessments and interventions to optimize neurocognitive development and outcomes among children and adolescents with perinatal HIV globally. This research was supported in part by NIH R01MH108466, NIH R56NS124422, and NIH R01NS124422.

Transactivator of Transcription (Tat)-Induced Neuroinflammation as a Key Pathway in Neuronal Dysfunction: A Scoping Review.

The activity of HIV-1 and its viral proteins within the central nervous system (CNS) is responsible for a wide array of neuropathological effects, resulting in a spectrum of neurocognitive deficits defined as HIV-associated neurocognitive disorders (HAND). Amongst the various viral proteins, the transactivator of transcription (Tat) remains detectable even with effective antiretroviral therapy (ART) and suppressed viremia, highlighting the significance of this protein in the modern ART era. Tat has been extensively researched in both fundamental and clinical settings due to its role in neuroinflammation, neuronal damage, and neurocognitive impairment amongst people living with HIV (PLHIV). To date, numerous fundamental studies have explored Tat-induced neuroinflammation. However, there is no clear consensus on the most frequently studied inflammatory markers or the consistency in the levels of these Tat-induced inflammatory marker levels across different studies. Therefore, we conducted a scoping review of studies investigating Tat-induced neuroinflammation. We conducted searches in PubMed, Scopus, and Web of Science databases using a search protocol tailored specifically to adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for scoping reviews (PRISMA-ScR) guidelines. From the 22 included studies, findings suggest that the HIV-1 Tat protein amplifies levels of neuroinflammatory markers. Amongst the vast array of inflammatory markers explored in the included studies, consistent results point to higher levels of CCL2, IL-6, IL-8, and TNF-α in primary cells and cell lines exposed to or transfected with HIV-1 Tat. These markers are regulated by key inflammatory pathways, such as the extracellularsignal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol 3-kinase (PI3K) pathway, the p38 MAPK pathway, and nuclear factor-kB (NF-kB). Furthermore, Tat has been shown to induce neuronal apoptosis, both directly and indirectly. With regards to study designs, utilizing full-length Tat101 at concentrations ranging from 100 to 1000 ng/ml and durations of 24 and 48 h appears optimal for investigating Tat-induced neuroinflammation. In this context, we highlight specific inflammatory markers and pathways that are potentially pivotal in Tat-induced neuroinflammation and subsequent neuronal damage. A deeper investigation into these markers and pathways is crucial to better understand their roles in the development of HAND.