Modern Antiretroviral Therapy Era Research Articles

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.

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

AbstractThe 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 extracellular signal-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.

Incident HIV-Associated Wasting/Low Weight Is Associated with Nearly Doubled Mortality Risk in the Modern ART Era.

HIV-associated wasting (HIVAW) is an underappreciated AIDS-defining illness, despite highly effective antiretroviral therapy (ART). We (a) assessed the association between incident HIVAW/low weight and all-cause mortality and (b) described virologic outcomes after people with HIV (PWH) experienced HIVAW/low weight while on ART. In the Observational Pharmaco-Epidemiology Research & Analysis (OPERA®) cohort, PWH without prior HIVAW/low weight who were active in care in 2016-2020 were followed through the first of the following censoring events: death, loss to follow-up, or study end (October 31, 2021). HIVAW/low weight was a diagnosis of wasting or low body mass index (BMI)/underweight or a BMI measurement <20 kg/m2. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between time-dependent HIVAW/low weight and mortality were estimated with extended Cox regression models. Over a median follow-up of 45 months (interquartile range: 27, 65), there were 4,755 (8%) cases of HIVAW/low weight and 1,354 (2%) deaths among 62,314 PWH. PWH who experienced HIVAW/low weight had a significantly higher risk of death than those who did not (HR: 1.96; 95% CI: 1.68, 2.27) after adjusting for age, race, ethnicity, and changes in viral load (VL) and Veterans Aging Cohort Study Mortality Index scores over follow-up. Among 4,572 PWH on ART at HIVAW/low weight, 68% were suppressed (VL of <200 copies/mL); subsequent virologic failure was uncommon (7%). Among viremic PWH, 70% and 60% achieved suppression and undetectability (VL of <50 copies/mL), respectively, over follow-up. HIVAW remains a challenge for some PWH. Particular attention needs to be paid to HIVAW/low weight and virologic control to restore health and potentially reduce the risk of death.

Survival and prognostic factors of progressive multifocal leukoencephalopathy in people living with HIV in modern ART era.

The incidence of progressive multifocal leukoencephalopathy (PML) in people living with HIV (PLWH) is 2%-4%. Currently, there is no effective therapeutic strategy for the treatment of PML in PLWH, resulting in a mortality of up to 50%. This study aimed to identify risk factors of death and prognostic markers in people living with HIV with PML. A retrospective cohort study of AIDS-related PML individuals was conducted from January 1, 2015, to October 1, 2022, in Shanghai, China. PLWH who were diagnosed with PML for the first time were included. Kaplan-Meier curve and Cox regression were used to analyze the survival and its predictors. Levels of inflammatory markers and immune checkpoint inhibitors in blood and cerebrospinal fluid (CSF) were measured in the prestored samples using bead-based multiplex assay Indolamine 2,3-dioxygenase was determined using ELISA. Twenty of 71 subjects had initiated antiretroviral therapy (ART) before PML onset and no patients discontinued ART during this period. In total, 34 patients (47.9%) had opportunistic infections (OIs), the median CD4+ T cell count was 73.0 (33.0-149.0) cells/μL. The estimated probability of survival at six months was 78% (95% confidential intervals [CIs]:0.63-0.85). OIs, low CD4+ T cell count were associated with lower estimated six-month survival (hazard ratio 8.01, 95% CIs: 1.80-35.00, P=0.006 and 5.01, 95% CIs:1.57-16.03, p=0.007). Indolamine 2,3-dioxygenase activity in CSF of non-survivors group were higher than survivors group (p<0.05). The survival rate of AIDS-related PML in the modern ART era was higher than the survival rate a decade ago. Low CD4+T cell count, OIs, were all associated with death of individuals with AIDS-related PML. The role of IDO in AIDS-related PML warrant further investigation.

HIV Infection and 90-Day Stroke Outcomes in Uganda: A Prospective Observational Cohort Study.

Little is known about the impact of HIV infection on the clinical presentation and outcomes after stroke in the modern antiretroviral therapy (ART) era. We aimed to compare stroke characteristics and outcomes between persons with HIV (PWH) and without HIV (PWOH) presenting with stroke in Uganda. We conducted a matched cohort study at Mulago National Referral Hospital and Mbarara Regional Referral Hospital between January 2018 and November 2020. We enrolled consecutive PWH presenting with CT-confirmed acute or subacute stroke (symptom onset ≤14 days) and matched them by sex and stroke type to 2 consecutive available PWOH admitted to the same hospital. We obtained baseline clinical data and followed participants for 90 days from the day of clinical presentation. We compared stroke severity (defined by the NIH stroke scale [NIHSS]) and 90-day all-cause mortality and morbidity (using the modified Rankin Scale [mRS]) by HIV serostatus with and without adjustment for confounders. We enrolled 105 PWH and 157 PWOH with stroke. PWH were younger (mean [SD] age 49 [14] vs 59 [16] years, p < 0.001), and nearly 80% (82/105) were on ART for a median of 5 years and a median CD4 count of 214 cells/uL (interquartile range 140, 337). Compared with PWOH, PWH presented with a 3-point lower median NIHSS (16 vs 19, p = 0.011), a 20% lower proportion of all-cause mortality at 90 days (p = 0.001), and had less disability at 90 days (median mRS 4 vs 5, p = 0.004). Age and NIHSS-adjusted odds ratio of 90-day all-cause mortality in PWH compared with PWOH was 0.45 (95% CI 0.22-0.96, p = 0.037). In the modern ART era, PWH with acute stroke in Uganda present with modest stroke and are significantly less likely to die within 90 days than PWOH. This potentially reflects the protective effects of ART, enhanced health care access, and their younger age at stroke presentation.

Viral protein R (Vpr)-induced neuroinflammation and its potential contribution to neuronal dysfunction: a scoping review

HIV-associated neurocognitive disorders (HAND) are the result of the activity of HIV-1 within the central nervous system (CNS). While the introduction of antiretroviral therapy (ART) has significantly reduced the occurrence of severe cases of HAND, milder cases still persist. The persistence of HAND in the modern ART era has been linked to a chronic dysregulated inflammatory profile. There is increasing evidence suggesting a potential role of Viral protein R (Vpr) in dysregulating the neuroinflammatory processes in people living with HIV (PLHIV), which may contribute to the development of HAND. Since the role of Vpr in neuroinflammatory mechanisms has not been clearly defined, we conducted a scoping review of fundamental research studies on this topic. The review aimed to assess the size and scope of available research literature on this topic and provide commentary on whether Vpr contributes to neuroinflammation, as highlighted in fundamental studies. Based on the specified selection criteria, 10 studies (6 of which were cell culture-based and 4 that included both animal and cell culture experiments) were eligible for inclusion. The main findings were that (1) Vpr can increase neuroinflammatory markers, with studies consistently reporting higher levels of TNF-α and IL-8, (2) Vpr induces (neuro)inflammation via specific pathways, including the PI3K/AKT, p38-MAPk, JNK-SAPK and Sur1-Trpm4 channels in astrocytes and the p38 and JNK-SAPK in myeloid cells, and (3) Vpr-specific protein amino acid signatures (73R, 77R and 80A) may play an important role in exacerbating neuroinflammation and the neuropathophysiology of HAND. Therefore, Vpr should be investigated for its potential contribution to neuroinflammation in the development of HAND.

CD4+ T lymphocyte recovery in the modern antiretroviral therapy era: Toward a new threshold for defining immunological non-responders

IntroductionDespite the high level of efficacy of modern antiretroviral therapy (ART) in reducing HIV viremia and the control of viral replication, some people living with HIV (PLWH) do not recover their CD4+ T cell count.MethodsTo evaluate the frequency and predictive factors of discordant immune responses, we performed a retrospective cohort study of 324 antiretroviral-naïve PLWH who initiated first-line ART between 2008 and 2018 and maintained HIV RNA &amp;lt; 50 copies/ml during 36 months of follow-up. PLWH were defined as immunological non-responders (INRs) when CD4+ T cell count was &amp;lt; 20% compared with baseline (INR20%), or &amp;lt; 500 cells/mm3 (INR500) or &amp;lt; 200 cells/mm3 (INR200) at 36 months.ResultsThe prevalence of INR20%, INR500, and INR200 was 12.5%, 34.6%, and 1.5%, respectively. After adjustment for possible confounders, CD4 nadir showed a significant association with all INR definitions, with lower values predicting INR500 (aOR 0.98, 95% CI 0.98–0.99, p &amp;lt; 0.001) and INR200 (aOR 0.98, 95% CI 0.95–1.01, p = 0.096). Moreover, a higher baseline CD4/CD8 ratio was inversely related to the probability of being INR500 (OR 0.03, 95% CI 0.01–0.12, p &amp;lt; 0.001) and INR200 (OR 0.002, 95% CI 18–7–67.72, p = 0.255). By contrast, INR20% had a higher CD4 nadir and CD4/CD8 ratio than other INRs, suggesting the identification of an heterogenous population with such definition.DiscussionThe present study highlights how INR200 has become rare in the contemporary ART era, and about one-third of PLWH meet the criteria for INR500. Overcoming the threshold of 500 CD4/mm3 could be an appropriate definition of immune response, in contrast with the older definitions of INR200 and INR20%. Early diagnosis and rapid treatment initiation, before CD4 counts and the CD4/CD8 ratio begin to decline, are critical for achieving an optimal immune response.

441. Association between Incident HIV-Associated Wasting/Low Weight and All-Cause Mortality in the OPERA® Cohort

Abstract Background HIV-associated wasting (i.e., progressive, involuntary weight loss with both fat and lean tissue loss; HIVAW) is an under-appreciated AIDS-defining illness; the 2012-2018 period prevalence was reported as 18% in a recent claims study in the United States. We aimed to assess the association between incident HIVAW/low weight and all-cause mortality in the era of modern combination antiretroviral therapy (ART). Methods In the Observational Pharmaco-Epidemiology Research &amp; Analysis (OPERA®) cohort, PWH without (a) any prior HIVAW/low weight, (b) malignancy within 3 years, and (c) opportunistic infection within 1 year who were active in care between 2016 and 2020 were followed through death, loss to follow-up, or study end (31OCT2021). HIVAW/low weight included a wasting or low BMI/underweight diagnosis (ICD codes, title search) or BMI &amp;lt; 20 kg/m2. Hazard ratios (HR) and 95% confidence intervals (CI) for the association between time-dependent incident HIVAW/low weight (exposure) and all-cause mortality (outcome) were estimated with extended Cox regression models. The adjusted model included age at baseline, race, ethnicity, and time-dependent covariates (log10 viral load, Veterans Aging Cohort Study [VACS] Mortality Index score). Viral load and VACS score were included as surrogate markers for ART use and comorbidities, respectively. Linear and quadratic terms of continuous variables were included. Results Of 67,119 PWH without prior HIVAW/low weight in OPERA®, 62,314 (93%) PWH had non-missing covariate data and were included in the models; baseline characteristics did not differ between the full and model study populations (Table 1). Over a median follow-up of 45 months (interquartile range: 27, 65), there were 4,755 (8%) cases of incident HIVAW/low weight and 1,354 (2%) deaths. In the adjusted model, PWH who experienced incident HIVAW/low weight had a significantly increased risk of death over follow-up than those who did not experience HIVAW/low weight (HR: 1.96; 95% CI: 1.68, 2.27) (Table 2). Conclusion In this analysis of 62,314 PWH in care, incident HIVAW/low weight was associated with twice the risk for all-cause mortality in the modern ART era. Particular attention needs to be paid to HIVAW/low weight among PWH to restore health and potentially reduce the risk of death. Disclosures Rachel P. Weber, PhD, AIDS Healthcare Foundation: Client of my employer|EMD Serono: Client of my employer|Gilead Sciences: Client of my employer|Janssen: Client of my employer|Merck &amp; Co.: Client of my employer|TheraTechnologies: Client of my employer|ViiV Healthcare: Client of my employer Laurence Brunet, PhD, AIDS Healthcare Foundation: Client of my employer|EMD Serono: Client of my employer|Gilead Sciences: Client of my employer|Janssen: Client of my employer|Merck &amp; Co: Client of my employer|TheraTechnologies: Client of my employer|ViiV Healthcare: Client of my employer Javeed Siddiqui, MD, MPH, Abbvie: Advisor/Consultant|Abbvie: Honoraria|Cumberland pharmaceuticals: Advisor/Consultant|Cumberland pharmaceuticals: Honoraria|EMD serono: Advisor/Consultant|EMD serono: Honoraria|Merck: Advisor/Consultant|Merck: Honoraria Javeed Siddiqui, MD, MPH, Abbvie: Advisor/Consultant|Abbvie: Honoraria|Cumberland pharmaceuticals: Advisor/Consultant|Cumberland pharmaceuticals: Honoraria|EMD serono: Advisor/Consultant|EMD serono: Honoraria|Merck: Advisor/Consultant|Merck: Honoraria Michael Harbour, MD, MPH, FACP, EMD Serono: Employee Amy L. Phillips, PharmD, EMD Serono, Inc.: Employment Brooke Hayward, SM, MBA, EMD Serono, Inc.: Employee Jennifer S. Fusco, BS, AIDS Healthcare Foundation: Client of my employer|EMD Serono: Client of my employer|Gilead Sciences: Client of my employer|Janssen: Client of my employer|Merck &amp; Co.: Client of my employer|TheraTechnologies: Client of my employer|ViiV Healthcare: Client of my employer Ricky K. Hsu, MD, Gilead: Honoraria|Merck: Honoraria|ViiV: Advisor/Consultant|ViiV: Grant/Research Support|ViiV: Honoraria Gregory P. Fusco, MD, MPH, AIDS Healthcare Foundation: Client of employer|EMD: Grant/Research Support|Gilead Sciences: Client of employer|Janssen: Client of employer|Merck &amp; Co.: Client of employer|Theratechnologies: Client of employer|ViiV Healthcare: Client of employer.

Abstract 15540: Single Cell Transcriptional-Epigenetic Profiling and Sub-Cellular Proteomics Demonstrate That HIV-Nef Extracellular Vesicles Modulate Human Macrophage Heterogeneity to Promote Atherosclerosis

Background: In the era of modern Anti-Retroviral Therapy, people living with HIV continue to remain at a higher risk than the general population for cardiovascular diseases including atherosclerosis. We hypothesized that circulating extracellular vesicles (EV) containing HIV-Nef protein promote inflammation by switching the pattern of macrophage heterogeneity towards a pro-inflammatory state that underlies cardiovascular disease. Methods &amp; Results: Human primary macrophages were stimulated with EV engineered to contain HIV-Nef. Macrophage heterogeneity was characterized by simultaneous single cell mRNA-seq and single cell ATAC-seq integrated with WNN mapping in 50,931 cells. Among 16 clusters (Fig. A), pseudotime (Slingshot), gene regulatory (DoRothEA and SCENIC) and transcription factor motif accessibility (ChromVar) analyses demonstrated that HIV-Nef regulates 3 inflammatory clusters as gauged by differentially active and accessible transcription factors, e.g., JUN, YY1 and STAT1. Sub-cellular proteomics identified differentially abundant proteins associated with DNA (662 proteins), nucleus (261), cytosol (461), cell surface (72) and EV (132). Pathway enrichment analysis of these proteins revealed changes in biological processes in immune responses, cytoskeletal regulation, and metabolism. Functional phenotyping showed HIV-Nef shifts macrophages towards a pro-inflammatory phenotype by suppressing atheroprotective efferocytosis, promoting chemotaxis and altering metabolic state. Furthermore, short-term injection of HIV-Nef EV into WT mice induced inflammatory chemokine secretion, while long-term injection into Ldlr -/- mice enhanced atherogenesis (Fig.B). Conclusions: Persistent Nef in EV of HIV survivors may modulate macrophage heterogeneity to promote chronic inflammation. These findings may help identify patients at risk for cardiovascular complications and develop novel atheroprotective therapies.

The economic burden of HIV-associated wasting in the era of modern antiretroviral therapy.

BACKGROUND: HIV-associated wasting (HIVAW) is associated with increased morbidity and mortality in people living with HIV (PWH). Evaluating health care resource utilization and cost predictors of HIVAW is important in understanding the overall economic burden of the disease. OBJECTIVE: To evaluate the economic burden and cost predictors associated with HIVAW. METHODS: This analysis of the IBM MarketScan Commercial, Medicare Supplemental, and Medicaid databases included members with a claim for HIV (using International Classification of Diseases, Ninth Revision and Tenth Revision, Clinical Modification codes) between July 2012 and September 2018, with the HIV index date defined as the first HIV diagnosis claim in the dataset. PWH were excluded if they were aged less than 18 years, had any malignancy claim, or had less than 6 months of enrollment data pre-HIV or post-HIV index date. Members were defined as having HIVAW using an algorithm of claims for weight loss-related diagnoses, appetite stimulant or nontestosterone anabolic agents, or enteral/parenteral nutrition at any time post-HIV index. Taking antiretroviral therapy (ART) was defined as having at least 1 pharmacy claim of any ART 12 months post-HIV index. Total all-cause costs were calculated as the sum of payments for hospitalizations, emergency department visits, outpatient visits, and pharmacy use. A multivariate generalized linear model with log-link and γ distribution was used to estimate the impact of HIVAW predictors of total all-cause costs. RESULTS: Among 42,587 members with HIV included in the study (64.6% male; mean age: 44 years; 67.5% insured with Medicaid; and 63.9% taking ART), the overall prevalence of HIVAW was 18.3% during the study period. HIVAW prevalence was 17.9% for those taking ART and 19.1% for those not taking ART. Prevalence by payer type was 7.5% for Commercial ± Medicare Supplemental and 23.5% for Medicaid. Members with HIVAW had more comorbidities and opportunistic infections compared with members without HIVAW. Members with HIVAW were also more than twice as likely to be hospitalized (71.1% vs 32.1%) and had 5 times the number of hospitalizations (1.0 vs 0.2) and twice the number of emergency department visits (3.0 vs 1.3) per year post-index compared with members without HIVAW (P < 0.01). HIVAW was associated with 1.3-times-higher mean annualized total all-cause costs per member (95% CI = 1.26-1.36). CONCLUSIONS: HIVAW remains prevalent despite advances in ART and is associated with additional health care resource utilization and costs. Further research is needed to better understand the relationship between HIVAW and comorbidity burden and ART utilization and payer types. DISCLOSURES: This study was sponsored by EMD Serono, Inc., Rockland, MA, USA (CrossRef Funder ID: 10.13039/100004755). Dr Siddiqui has received consulting and speaking fees from AbbVie, BioFire, Cumberland, EMD Serono, Inc., Rockland, MA, USA, and Merck. Dr Samuel, Ms Hayward, Ms Wirka, Dr Phillips, and Dr Harbour are employees of EMD Serono, Inc., Rockland, MA, USA. Drs Deering and Harshaw are employees of EPI-Q, Inc., which received payment from EMD Serono, Inc., Rockland, MA, USA, for the development and execution of this study.

The Interaction of HIV With Mental Health in the Modern Antiretroviral Therapy Era.

ABSTRACTPeople with HIV (PWH) receiving effective antiretroviral therapy (ART) continue to display residual immune dysregulation that amplifies the risk for neuropsychiatric comorbidities. At the same time, PWH commonly experience intersectional stigma and other psychosocial stressors that are linked to neuroendocrine stress responses, potentiate residual immune dysregulation, and alter other biobehavioral processes relevant to health outcomes. This special issue of Psychosomatic Medicine seeks to advance our understanding of the intersection of HIV with mental health in the modern ART era. Several articles cover topics related to the prevalence and treatment of psychiatric comorbidities among PWH such as depression, suicidality, and substance use disorders. Other articles delineate biobehavioral mechanisms relevant to mental health in PWH such as inflammation, immune activation, neuroendocrine signaling, cellular aging, the microbiome-gut-brain axis, and neurobehavioral processes. Collectively, the articles in this special issue highlight the continued importance of biobehavioral and neurobehavioral mental health research in the modern ART era.

Suicidality Among People Living With HIV From 2010 to 2021: A Systematic Review and a Meta-regression.

ABSTRACTObjectiveThe association between human immunodeficiency virus (HIV)/AIDS and suicidality is not well understood, partly because of variability in results. This meta-analysis aimed to investigate the predictive value of HIV/acquired immune deficiency syndrome for incident suicidality.MethodsA literature review was conducted of articles published between January 1, 2010, and October 31, 2021. The following databases were searched: Embase, MEDLINE, CINAHL, Web of Science, and Scopus. The search terms included human immunodeficiency virus (HIV), suicidal behavior, auto mutilation, and self-injurious behavior. Observational studies were screened following a registered protocol, and eligible ones were meta-analyzed and followed by meta-regression.ResultsA total of 43 studies were included in this systematic review, and a meta-regression included 170,234 participants. The pooled prevalence estimates of suicidal ideation, attempted suicide, and deaths by suicide were 22.3%, 9.6%, and 1.7%, respectively. The following significant risk factors for suicide ideation were found: substance use, depression, low quality of life, low social support, without HIV status disclosure, living alone, low level of memory problems, family history of suicide, and stage III of HIV. Risk factors for suicide attempts were depression and family history of suicide. An elevated risk for suicide-related death was found for people living with HIV (PLHIV) who had a psychiatric disorder and in studies conducted in hospital-based settings (versus national database studies or HIV clinic settings).ConclusionsThe risk of suicidality is high among PLHIV within all six World Health Organization regions during the modern antiretroviral therapy era. Assessment of socioeconomic and psychological factors is recommended for further management to prevent suicide among PLHIV. The present findings are useful for design of intervention protocols and development of clinical practice guidelines intended to manage the well-being of PLHIV worldwide.

Through the Looking-Glass: Psychoneuroimmunology and the Microbiome-Gut-Brain Axis in the Modern Antiretroviral Therapy Era.

ABSTRACTObjectiveDepression, 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.MethodsA narrative review was conducted to integrate findings from 159 articles relevant to psychoneuroimmunology (PNI) and microbiome-gut-brain axis research in PWH.ResultsEarly 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).ConclusionsAdvancing 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.

Seropositivity, Risks, and Morbidity From Varicella-Zoster Virus Infections in an Adult PWH Cohort From 2000-2020.

BackgroundVaricella-zoster virus (VZV) infection disproportionately affects people with HIV (PWH), primarily presenting as herpes zoster. However, VZV seroprevalence, its association with zoster, and clinical outcomes remain understudied in era of modern antiretroviral therapy (ART). We assessed VZV seroprevalence, rates of VZV illness, and associated health care costs in a large cohort of PWH over 20 years.MethodsWe performed retrospective chart reviews of patients followed at a regional HIV clinic from January 1, 2000, to December 31, 2020. Serological, immunization, clinical, and costing data were extracted from in-house databases. VZV-related inpatient admissions, emergency department (ED), and urgent care (UC) visits were identified using relevant International Classification of Disease (ICD-10) codes and validated where possible by 2 physicians. Health care utilization costs were adjusted to 2020 Canadian dollars.ResultsOf 3006 PWH, VZV serology was available for 2628; of these, 2503 (95.2%) were seropositive. Only 39% of known seronegative patients were subsequently immunized for varicella. During 29 768 years of patient follow-up, 38 hospitalizations and 138 ED/UC visits due to VZV infection were identified. Most occurred in VZV-seropositive PWH <50 years of age (82%) who were unimmunized (99.2%) and not on ART (64.8%). Nearly 25% of hospitalizations were due to laboratory-confirmed VZV meningitis/encephalitis. The average admission cost was CDN$33 001; the total measured cost of VZV illness was CDN$1 258 718.ConclusionsDespite ART and vaccines for chickenpox and shingles, VZV still caused significant costs and morbidity for PWH, occurring at younger ages and often as encephalitis/meningitis. Supporting ART adherence may reduce VZV illness and hospitalization costs in PWH, and the cost-effectiveness of expanding shingles vaccine use warrants further study.

Outcomes of Cervical Cancer in HIV-Positive Women Treated With Radiotherapy at a Tertiary Care Center in India.

PURPOSEThere are limited data on management of cervical cancer in women living with HIV in the modern antiretroviral therapy era. The study aimed to evaluate outcomes and toxicities of these patients treated with radiotherapy.MATERIALS AND METHODSA retrospective analysis of HIV-positive cervical cancer patients treated with radiotherapy between 2011 and 2018 was conducted at a tertiary care center in India.RESULTSEighty-two HIV-positive cervical cancer patients treated with radiotherapy were identified. Their median age was 45 years. Seventy-four (90%) patients received radiotherapy with curative-intent and eight patients received palliative radiotherapy. Median CD4 count at the start of treatment was 342 cells/mm3 (interquartile range: 241-531). Among patients planned for definitive radiotherapy, concurrent cisplatin was planned in 52 (70%) patients with a median of four chemotherapy cycles, and 81% (n = 60) patients received brachytherapy. Among patients who received brachytherapy, the median prescription dose was 80 Gy. Seventy-seven patients completed their prescribed treatment. At a median follow-up of 37 months, 3-year disease-free survival of patients planned with curative-intent was 54%. On multivariate analysis, treatment completion was associated with favorable disease-free survival. Grade III/IV acute gastrointestinal toxicity was seen in five (6.8%) patients, whereas 30% patients had grade III/IV acute hematologic toxicity. All these patients completed their planned radiotherapy with good supportive care.CONCLUSIONStandard treatment of chemoradiation should be planned in women living with HIV with well-managed HIV presenting with locally advanced cervical cancer. Our study highlights the need for optimal management of these patients by a multidisciplinary team with intensive supportive care to ensure completion of planned treatment to achieve better outcomes.

Comparative outcomes for mature T-cell and NK/T-cell lymphomas in people with and without HIV and to AIDS-defining lymphomas

AbstractThere are no studies comparing the prognosis for mature T-cell lymphoma (TCL) in people with HIV (PWH) to people without HIV (PWoH) and to AIDS-defining B-cell lymphomas (A-BCLs) in the modern antiretroviral therapy era. North American AIDS Cohort Collaboration on Research and Design and Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment are cohorts that enroll patients diagnosed with HIV and TCL, respectively. In our study, 52, 64, 101, 500, and 246 PWH with histologic confirmation of TCL, primary central nervous system lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma (DLBCL), and Hodgkin's lymphoma (HL), respectively, and 450 TCLs without HIV were eligible for analysis. At the time of TCL diagnosis, anaplastic large-cell lymphoma (ALCL) was the most common TCL subtype within PWH. Although PWH with TCL diagnosed between 1996 and 2009 experienced a low 5-year survival probability at 0.23 (95% confidence interval [CI]: 0.13, 0.41), we observed a marked improvement in their survival when diagnosed between 2010 and 2016 (0.69; 95% CI: 0.48, 1; P = .04) in contrast to TCLs among PWoH (0.45; 95% CI: 0.41, 0.51; P = .53). Similarly, PWH with ALCLs diagnosed between 1996 and 2009 were associated with a conspicuously inferior 5-year survival probability (0.17; 95% CI: 0.07, 0.42) and consistently lagged behind A-BCL subtypes such as Burkitt's (0.43; 95% CI:0.33, 0.57; P = .09) and DLBCL (0.17; 95% CI: 0.06, 0.46; P = .11) and behind HL (0.57; 95% CI: 0.50, 0.65; P < .0001). Despite a small number, those diagnosed between 2010 and 2016 experienced a remarkable improvement in survival (0.67; 95% CI: 0.3, 1) in comparison with PWoH (0.76; 95% CI: 0.66, 0.87; P = .58). Thus, our analysis confirms improved overall survival for aggressive B- and T-cell malignancies among PWH in the last decade.

The incidence of and risk factors for hospitalized acute kidney injury among people living with HIV on antiretroviral treatment.

The epidemiology of hospitalized acute kidney injury (AKI) among people living with HIV (PLWH) in the era of modern antiretroviral therapy (ART) for all PLWH is not well characterized. We evaluated the incidence of and risk factors for hospitalized AKI from 2005 to 2015 among PLWH on ART. We conducted a retrospective analysis of PLWH from the Johns Hopkins HIV Clinical Cohort. We defined hospitalized AKI as a rise of ≥0.3mg/dL in serum creatinine (SCr) within any 48-h period or a 50% increase in SCr from baseline and assessed associations of risk factors with incident AKI using multivariate Cox regression models. Most participants (75%) were black, 34% were female, and the mean age was 43years. The incidence of AKI fluctuated annually, peaking at 40 per 1000 person-years (PY) [95% confidence interval (CI) 22-69 per 1000 PY] in 2007, and reached a nadir of 20 per 1000 PY (95% CI 11-34 per 1000 PY) in 2010. There was no significant temporal trend (-3.3% change per year; 95% CI -8.6 to 2.3%; P=0.24). After multivariable adjustment, characteristics independently associated with AKI included black race [hazard ratio (HR) 2.44; 95% CI 1.42-4.20], hypertension (HR 1.62; 95% CI 1.09-2.38), dipstick proteinuria >1 (HR 1.86; 95% CI 1.07-3.23), a history of AIDS (HR 1.82; 95% CI 1.29-2.56), CD4 count <200 cells/µL (HR 1.46; 95% CI 1.02-2.07), and lower serum albumin (HR 1.73 per 1g/dL decrease; 95% CI 1.02-2.07). In this contemporary cohort of PLWH, the annual incidence of first AKI fluctuated during the study period. Attention to modifiable AKI risk factors and social determinants of health may further reduce AKI incidence among PLWH.

Impact of Direct-Acting Antivirals on the Outcome of HIV/HCV Coinfected Patients with Non-Hodgkin Lymphomas in the Modern Anti-Retroviral Therapy Era: A Retrospective Multicenter Study of 74 Cases

Impact of Direct-Acting Antivirals on the Outcome of HIV/HCV Coinfected Patients with Non-Hodgkin Lymphomas in the Modern Anti-Retroviral Therapy Era: A Retrospective Multicenter Study of 74 Cases

Cause of hospitalization and death in the antiretroviral era in Sub-Saharan Africa published 2008-2018: A systematic review.

Background:Worldwide despite the availability of antiretroviral therapy, human immunodeficiency virus/acquired immunodeficiency syndrome still causes morbidity and mortality among patients. In Sub-Saharan Africa, human immunodeficiency virus/acquired immunodeficiency syndrome remains a major public health concern. The aim of this study was to identify the causes of morbidity and mortality in the modern antiretroviral therapy era in Sub-Saharan Africa.Methods:We conducted a systematic review according to the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. We searched relevant studies from 3 databases which are Google Scholar, PubMed, and CINAHL. Two review authors independently screened titles, abstracts, and full-text articles in duplicate, extracted data, and assessed bias. Discrepancies were resolved by discussion or arbitration of a third review author. R software version 3.6.2 was used to analyze the data. Maximum values were used in order to show which disease was mostly spread out by looking at the highest prevalence reported. This systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO).Results:A total of 409 articles were obtained from the database search, finally 12 articles met the inclusion criteria and were eligible for data extraction. Among them, 3 were conducted in Nigeria, 2 were conducted in Uganda, 3 were conducted in South Africa, 1 in Gabon, 1 in Ethiopia, 1 in Ghana, and 1 in Burkina Faso. In most of the included studies, tuberculosis was the leading cause of hospitalization which accounted for between 18% and 40.7% and it was also the leading cause of death and accounted for between 16% and 44.3%, except in 1 which reported anemia as the leading cause of hospitalization and in 2 which reported wasting syndrome and meningitis respectively as the leading causes of death. Opportunistic malignancies accounted between for 1.8% to 5% of hospitalization and 1.2% to 9.8% of deaths.Conclusions:Tuberculosis is the commonest cause of hospitalization and death in Sub-Saharan Africa, but it is always followed by other infectious disease and other non-AIDS related causes.

HIV-associated wasting prevalence in the era of modern antiretroviral therapy.

Objective:To understand the prevalence of HIV-associated wasting (HIVAW) in the United States.Design:Medical and pharmacy claims study using IBM MarketScan Commercial, Medicare Supplemental and Medicaid Databases.Methods:Study period: July 2012–September 2018 (first HIV diagnosis claim = HIV index date). People with HIV (PWH) were excluded if they were aged less than 18 years, had any malignancy claim or had less than 6 months of enrollment data pre or post-HIV index date. HIVAW was defined by proxy using claims for weight loss–related diagnoses, appetite stimulant/nontestosterone anabolic agents or enteral/parenteral nutrition. Prevalence was reported cumulatively, by insurance type and antiretroviral therapy (ART) pharmacy claims (defined as ≥1 pharmacy claim of any ART within 12 months post-HIV index date). Statistical analysis assessed factors potentially associated with HIVAW.Results:The study population comprised 42 587 PWH (64.6% male, mean age 44 years, 67.5% on Medicaid, 63.9% on ART). Cumulative HIVAW prevalence (2012–2018) was 18.3% (n = 7804) for all PWH (17.9% on ART, 19.1% not on ART). HIVAW prevalence by payer was 7.5% for Commercial and Medicare Supplemental and 23.5% for Medicaid. The strongest associations with the likelihood of meeting the definition of HIVAW were for individuals with Medicaid and hospitalization(s) post-HIV index date; race and ART status were not associated.Conclusions:Findings suggest HIVAW remains prevalent in PWH. ART use was not found to be associated with HIVAW. HIVAW was highest among those with Medicaid coverage or any hospitalization(s). Further research is needed to better understand additional factors associated with and contributing to HIVAW.