Postural Stability as a Measure of Fall Risk in Older People with and without HIV.

As the number of older people with HIV (PWH) grows, accidental falls and their associated negative health outcomes are of increasing concern. Fall risk can be measured using novel screening tools such as evaluating postural stability using force plate technology. The aims of this study were to test this technology to assess fall risk among older PWH. In a cross-sectional, observational study of people without HIV (PWoH) with a range of fall risk, participants underwent balance assessment using the validated BTrackS balance plate. Postural stability was compared by HIV serostatus. Multivariable linear regressions were used to examine the relationship between postural stability and validated measures of fall risk balance and frailty status. Among 34 PWH and 30 PWoH, all ≥50 years, postural stability was worse among PWH (35.4 cm vs. 28.3 cm, p = .07). In multivariable models, worse postural stability was associated with reporting a fall in the past 6 months (ß = 0.32, p = .004), worse fall efficacy (ß = 0.45, p < .001), and being frail or prefrail (ß = 0.26, p = .027). In multivariable models stratified by HIV serostatus, worse postural stability was significantly associated with worse fall efficacy (ß = 0.53, p < .01) and lower balance confidence (ß = -0.33, p =. 04) among PWH but not PWoH. Among older PWH and PWoH, worse postural stability was associated with validated measures of fall risk, including history of falls and poorer fall efficacy. Assessment of postural sway is a promising objective screening test for fall risk among older PWH.

Risk factors for progression from prediabetes to diabetes among older people with HIV.

OBJECTIVE: Risk factors for progression from prediabetes mellitus (pre-DM) to diabetes mellitus (DM) among people with HIV (PWH) receiving modern antiretroviral therapy (ART) require better characterization. DESIGN: AIDS Clinical Trials Group (ACTG) A5322 (HAILO) was an observational cohort study of PWH ≥40 years old. Participants initiated ART through ACTG randomized clinical trials. METHODS: We used Cox proportional hazards regression models to identify risk factors for development of DM among HAILO participants with pre-DM. RESULTS: Among 1035 HAILO participants, 74 (7%) had pre-DM at entry and another 679 (66%) developed pre-DM during follow-up. Of 753 PWH with pre-DM, 167 (22%) developed DM. In multivariable models, the risk of developing DM was greater with higher BMI, lower CD4 count (≤200 cells/mm 3 ), hypertriglyceridemia, or higher waist circumference at pre-DM diagnosis ( P  < 0.01). CONCLUSION: Rates of pre-DM and progression to DM remain high among virally suppressed PWH receiving modern ART regimens. Traditional risks for DM, such as higher BMI or waist circumference, are associated with increased risk of incident DM among PWH with pre-DM. The association between lower CD4 + and progression to DM suggests a role for advanced immunodeficiency and inflammation. Further investigation of interventions aimed at preventing DM among PWH with pre-DM is needed. Optimizing prevention and treatment for DM may be an intervenable opportunity to improve long-term outcomes for PWH.

Long COVID as a disease of accelerated biological aging: An opportunity to translate geroscience interventions.

It has been four years since long COVID-the protracted consequences that survivors of COVID-19 face-was first described. Yet, this entity continues to devastate the quality of life of an increasing number of COVID-19 survivors without any approved therapy and a paucity of clinical trials addressing its biological root causes. Notably, many of the symptoms of long COVID are typically seen with advancing age. Leveraging this similarity, we posit that Geroscience-which aims to target the biological drivers of aging to prevent age-associated conditions as a group-could offer promising therapeutic avenues for long COVID. Bearing this in mind, this review presents a translational framework for studying long COVID as a state of effectively accelerated biological aging, identifying research gaps and offering recommendations for future preclinical and clinical studies.

Patient and clinician preferences for diabetes management among older adults with co-morbid HIV: A qualitative exploration.

BACKGROUND: Older adults with HIV are at increased risk of developing certain chronic health conditions including type 2 diabetes mellitus (T2DM). As the number and complexity of conditions increases, so do treatment and health care needs. We explored patient and clinician preferences for HIV+T2DM care and perceived solutions to improving care. METHODS: We conducted an exploratory qualitative study comprised of individual in-depth interviews. Participants included English-speaking patients aged 50 and older living with HIV and T2DM and infectious disease (ID) and primary care (PC) clinicians from a large academic health center in Chicago. Thematic analysis drew from the Framework Method. RESULTS: A total of 19 patient and 10 clinician participants were interviewed. Many patients reported seeking HIV and T2DM care from the same clinician; they valued rapport and a 'one-stop-shop'. Others reported having separate clinicians; they valued perceived expertise and specialty care. Nearly all clinicians reported comfort screening for T2DM and initiating first line oral therapy; ID clinicians reported placing referrals for newer, complex therapies. Patients would like educational support for T2DM management; clinicians would like to learn more about newer therapies and easier referral processes. CONCLUSIONS: Patient-centered care includes managing T2DM from a variety of clinical settings for individuals with HIV, yet strategies are needed to better support clinicians. Future research should examine how best to implement these strategies.

A Qualitative Exploration of Perceived Medication Adherence Determinants Conducted Among Older Adults with HIV and Type 2 Diabetes Mellitus.

Background: People living with HIV (PLWH) are at higher risk of developing type 2 diabetes (T2DM). Both chronic conditions require individuals to adhere to medication regimens, yet few studies have sought to explore medication-taking behaviors among individuals with comorbid HIV and T2DM (HIV+T2DM). Objective: This qualitative study sought to: 1) identify and compare perceived determinants of medication adherence for HIV and, separately, for T2DM, and 2) explore how participants prioritize conditions. Methods: Between October 2022 and January 2023, we conducted in-depth interviews with individuals aged 50 or older, living with comorbid HIV+T2DM. Participants were prescribed oral medications to treat their conditions and had recent clinical measures indicating probable challenges with medication adherence. Interviews with consented participants from a large academic health center in the Midwest were conducted remotely. Questions largely drew from the Theoretical Domains Framework (TDF), a widely used implementation science framework. Additional questions explored the prioritization of conditions. Analysis employed the Framework Method and a side-by-side comparison of key determinants of medication adherence by condition. Results: A total of 19 interviews were audio recorded, transcribed, and analyzed. Participants were an average age of 61, mostly male (89.5%), and Non-Hispanic White (47.4%). Although results revealed many commonalities between perceived determinants of medication adherence for HIV and for T2DM, differences relating to two TDF domains were noted: nature of the behavior (taking medications as prescribed), and motivations and goals. Many participants viewed their conditions as equally important, though they suggested T2DM was more difficult to manage, largely due to lifestyle modifications. Conclusion: As individuals with HIV develop chronic conditions, such as T2DM, they may require additional medication adherence support. Attention should be paid to offering support early. Disease perceptions may differ by condition, and as such, one's motivations to take medication as prescribed may also differ by condition.

HIV infection.

The AIDS epidemic has been a global public health issue for more than 40 years and has resulted in ~40 million deaths. AIDS is caused by the retrovirus, HIV-1, which is transmitted via body fluids and secretions. After infection, the virus invades host cells by attaching to CD4 receptors and thereafter one of two major chemokine coreceptors, CCR5 or CXCR4, destroying the host cell, most often a T lymphocyte, as it replicates. If unchecked this can lead to an immune-deficient state and demise over a period of ~2-10 years. The discovery and global roll-out of rapid diagnostics and effective antiretroviral therapy led to a large reduction in mortality and morbidity and to an expanding group of individuals requiring lifelong viral suppressive therapy. Viral suppression eliminates sexual transmission of the virus and greatly improves health outcomes. HIV infection, although still stigmatized, is now a chronic and manageable condition. Ultimate epidemic control will require prevention and treatment to be made available, affordable and accessible for all. Furthermore, the focus should be heavily oriented towards long-term well-being, care for multimorbidity and good quality of life. Intense research efforts continue for therapeutic and/or preventive vaccines, novel immunotherapies and a cure.

Sex-specific associations between plasma interleukin-6 and depression in persons with and without HIV.

Background: Persons with HIV (PWH) have both more frequent depression and higher levels of plasma inflammatory biomarkers compared to persons without HIV (PWoH). Inflammation and depressive symptoms are linked, including in PWH; however, it is unclear whether these associations differ by HIV serostatus and biological sex. Methods: Six plasma inflammatory biomarkers were assessed using samples from PWH and PWoH who participated in six NIH-funded studies through the UCSD HIV Neurobehavioral Research Program (HNRP) from 2011 to 2019. Factor analysis was performed to identify intercorrelated groups of biomarkers. Factors and their components were then examined for relationships with Beck Depression Inventory-II (BDI-II) and modifying effects of sex or HIV serostatus using multivariable linear regression, adjusting for demographics, substance use diagnoses, and relevant co-morbidities. Results: Participants included 150 PWH (age = 48.3 ± 13.1 yr; 88% biologically male) and 138 PWoH (age = 46.3 ± 15.9; 56% male). Two inflammatory factors were identified: Factor 1 loaded on interleukin-6 (IL-6), C-reactive protein (CRP), and D-dimer; Factor 2 loaded on interleukin-8, chemokine C-C ligand 2 (CCL2), and chemokine C-X-C ligand 10 (CXCL10). Sex modified the effect of Factor 1 on BDI-II, with a more positive association for men than women (p = 0.04). No significant association between Factor 2 and BDI-II was found. Of the biomarkers in Factor 1, only IL-6 was significantly associated with BDI-II and was modified by sex (p = 0.003). In sex-stratified analysis, a positive association was found for men (ß = 5.42; 95% confidence interval = [1.32, 9.52]) but not women (ß = -3.88; 95% C.I. = [-11.02, 3.26]). No HIV-related interactions were detected. Interpretation: We identified a depression-associated inflammatory factor present in both PWH and PWoH, consistent with prior studies of PWH only. The association was driven by a correlation between IL-6 and depression exclusively in men, suggesting that the depression-inflammation link differs by sex. Future studies of depression etiology or treatment, including those on persons with HIV, should consider the impact of biological sex in both design and analysis.

Telemedicine and HIV Care Quality Measures During the COVID-19 Pandemic.

BACKGROUND: During the COVID-19 pandemic, telemedicine was adopted to ensure continuity of HIV care. We examined how introducing televisits affected technical quality of care for people with HIV (PWH) during this time. METHODS: PWH receiving HIV care at Howard Brown Health Centers and Northwestern University in Chicago, Illinois were included. HIV care quality indicators were calculated using data extracted from electronic medical records during 4 timepoints every 6 months from March, March 1, 2020 to September 1, 2021. Generalized linear mixed models estimated differences in indicators across timepoints within each site while controlling for multiple observations of individuals. Generalized linear mixed models were also used to compare differences in outcomes among PWH who attended all versus a combination of in-person and televisits versus no televisits across the study time periods. RESULTS: 6447 PWH were included in the analysis. Compared with prepandemic levels, there were significant declines in care utilization and processes of care measures. Measures of HIV virologic suppression, blood pressure control, and HbA1C <7% (in both people with and without diabetes) were stable with no significant differences noted across the study timepoints. Similar trends were observed across all age, race, and sex subgroups. In multivariable models, televisits were not associated with decreased HIV viral suppression. CONCLUSIONS: During the COVID-19 pandemic and rapid implementation of televisits, indicators of care utilization and processes of care decreased compared with prepandemic levels. Among PWH who remained in care, televisits were not associated with worse virologic, blood pressure, and glycemic control in PWH.

Association Between Metformin Use and Cognitive and Physical Function in Persons with HIV and Diabetes.

Older persons with HIV (PWH) experience high rates of cognitive impairment and frailty, and accelerated decline in physical function compared with the general population. Metformin use has been associated with beneficial effects on cognitive and physical function among older adults without HIV. The relationship between metformin use on these outcomes in PWH has not been evaluated. AIDS Clinical Trials Group (ACTG) A5322 is an observational cohort study of older PWH with annual assessments for cognition and frailty, including measures of physical function (e.g., gait speed and grip strength). Participants with diabetes who were prescribed antihyperglycemic medications were included in this analysis to evaluate the association between metformin and functional outcomes. Cross-sectional, longitudinal, and time-to-event models were used to evaluate the relationship between metformin exposure with cognitive, physical function, and frailty outcomes. Ninety-eight PWH met inclusion criteria and were included in at least one model. No significant associations between metformin use, frailty, physical, or cognitive function were noted in unadjusted or adjusted cross-sectional, longitudinal, or time-to-event models (p > .1 for all models). This study is the first to examine the association between metformin use on functional outcomes among older PWH. Although it did not ascertain significant associations between metformin use and functional outcomes, our small sample size, restriction to persons with diabetes, and lack of randomization to metformin therapy were limitations. Larger randomized studies are needed to determine whether metformin use has beneficial effects on cognitive or physical function in PWH. Clinical Trial Registration numbers: 02570672, 04221750, 00620191, and 03733132.

Tecovirimat Use in Ambulatory and Hospitalized Patients With Monkeypox Virus Infection.

ABSTRACT: In this case series of 20 ambulatory and hospitalized adult patients treated for monkeypox virus at a large academic medical center in Chicago, Illinois, tecovirimat use was reserved for those with or at high risk of severe disease, delayed because of logistical and clinical factors, but well tolerated.

Baseline Neurocognitive Impairment (NCI) Is Associated With Incident Frailty but Baseline Frailty Does Not Predict Incident NCI in Older Persons With Human Immunodeficiency Virus (HIV).

BACKGROUND: Neurocognitive impairment (NCI) and frailty are more prevalent among persons with human immunodeficiency virus (HIV, PWH) compared to those without HIV. Frailty and NCI often overlap with one another. Whether frailty precedes declines in neurocognitive function among PWH or vice versa has not been well established. METHODS: AIDS Clinical Trials Group (ACTG) A5322 is an observational cohort study of older PWH. Participants undergo annual assessments for NCI and frailty. ACTG A5322 participants who developed NCI as indexed by tests of impaired executive functioning and processing speed during the first 3 years were compared to persons who maintained normal cognitive function; those who demonstrated resolution of NCI were compared to those who had persistent NCI. Participants were similarly compared by frailty trajectory. We fit multinomial logistic regression models to assess associations between baseline covariates (including NCI) and frailty, and associations between baseline covariates (including frailty) and NCI. RESULTS: In total, 929 participants were included with a median age of 51 years (interquartile range [IQR] 46-56). At study entry, 16% had NCI, and 6% were frail. Over 3 years, 6% of participants developed NCI; 5% developed frailty. NCI was associated with development of frailty (odds ratio [OR] = 2.06; 95% confidence interval [CI] = .94, 4.48; P = .07). Further adjustment for confounding strengthened this association (OR = 2.79; 95% CI = 1.21, 6.43; P = .02). Baseline frailty however was not associated with NCI development. CONCLUSIONS: NCI was associated with increased risk of frailty, but frailty was not associated with development of NCI. These findings suggest that the presence of NCI in PWH should prompt monitoring for the development of frailty and interventions to prevent frailty in this population.

Multidrug resistant Aeromonas infection following medical leech therapy: A case report and development of a joint antimicrobial stewardship and infection prevention protocol.

OBJECTIVE: Aeromonas sp. infections are a recognized complication of medical leech therapy (MLT). In patients requiring MLT, ciprofloxacin or trimethoprim-sulphamethoxazole are commonly used to prevent such nosocomial infections. After a patient at our institution developed a MLT-associated multi-drug resistant (MDR) Aeromonas infection, we developed and evaluated a joint antimicrobial stewardship and infection prevention protocol for MLT at our institution. METHODS: We describe a case of a surgical site infection with MDR Aeromonas following MLT that was resistant to typically prescribed prophylactic antimicrobials, and development of a new leech culture protocol to proactively monitor for antimicrobial resistance among our institution's leech supply. We also report the rates of MLT-associated infections prior to and following implementation of this protocol and the antimicrobial susceptibility profiles detected in leech culture at our institution. RESULTS: Between October 2014 and February 2018, 46 patients received MLT at our institution. Other than the case described in this report, no other instances of MLT-related infections were noted during this time period. Culture results from 22 leeches in six batches since February 2018 showed that all were susceptible to ciprofloxacin, TMP-SMX, and ceftriaxone. Since initiation of a leech culture protocol, no further cases of MLT-associated infections have been reported at our institution. CONCLUSIONS: In light of increasing antimicrobial resistance and the potentially devastating consequences of MLT-associated infections, institutions offering MLT should be aware of these risks and ensure that protocols are in place to minimize infection risks for patients.

Limited correlation between systemic biomarkers and neurocognitive performance before and during HIV treatment.

The AIDS Clinical Trials Group (ACTG) study A5303 investigated the associations between neuropsychological performance (NP) and inflammatory biomarkers in HIV-infected participants. Fifteen NP tests were administered at baseline and week 48 to 233 ART naïve participants randomized to maraviroc- or tenofovir-containing ART. Neurocognition correlated modestly with markers of lymphocyte activation and inflammation pre-ART (percent CD38+/HLA-DR+(CD4+) (r = - 0.22, p = 0.02) and percent CD38+/HLA-DR+(CD8+) (r = - 0.25, p = 0.02)), and with some monocyte subsets during ART (r = 0.25, p = 0.02). Higher interleukin-6 and percent CD38+/HLA-DR+(CD8+) were independently associated with worse severity of HIV-associated neurocognitive disorders (HAND) (p = 0.04 and 0.01, respectively). More studies to identify HAND biomarkers are needed.

Beyond one pill, once daily: current challenges of antiretroviral therapy management in the United States.

Introduction: Modern antiretroviral therapy (ART) has revolutionized HIV treatment. ART regimens are now highly efficacious, well-tolerated, safe, often with one multi-drug pill, once-daily regimens available. However, clinical challenges persist in managing ART in persons with HIV (PWH), such as drug-drug interactions, side effects, pregnancy, co-morbidities, and adherence.Areas Covered: In this review, we discuss the ongoing challenges of ART for adults in the United States. We review the difficulties of initiating ART and maintaining therapy throughout adulthood and discuss new agents and strategies under investigation to address these issues. A PubMed search was utilized to identify relevant publications and guidelines through July 2019.Expert Opinion: Challenges persist in initiation and maintenance of ART. An individual's coexisting medical, social and personal factors must be considered in selecting and continuing ART to ensure safety, tolerability, and efficacy throughout adulthood. Continued development of new therapeutics and novel approaches to ART, such as long acting drugs or dual therapy, are needed to respond to many of these challenges. In addition, future research must address therapeutic disparities for populations historically underrepresented in clinical trials, including women, people aging with HIV, and those with complex comorbidities.

Gait Speed Decline Is Associated with Hemoglobin A1C, Neurocognitive Impairment, and Black Race in Persons with HIV.

Gait speed declines at a faster rate in persons with HIV (PWH) than in the general population but the risk factors associated with this decline are not well understood. In the AIDS Clinical Trials Group (ACTG) A5322 (HAILO, HIV Infection, Aging, and Immune Function Long-term Observational Study), an observational cohort study of PWH ≥40 years of age, those who developed slow gait during the first 3 years of follow-up were compared with persons who maintained normal speed. Associations with demographic and clinical covariates were assessed using multivariable logistic regression. Of 929 participants, 81% were men, 31% Black, and 20% Hispanic. Median age was 51 years [interquartile range (IQR) = 46-56]. At study entry, 92% had plasma HIV RNA <50 copies/mL with median CD4 count 631 cells/mm3 (IQR = 458-840). At study entry, 7% of participants had slow gait, 16% had neurocognitive impairment (NCI), and 12% had diabetes. Over 3 years, 87% maintained normal gait speed, 3% maintained a slow gait, 6% developed a slow gait, and 4% improved from slow to normal gait speed. In multivariable models, hemoglobin A1C (HbA1C) percentage, per one unit increase [odds ratio (OR) = 1.36; 95% confidence interval (CI) = 1.03-1.81; p = .033], NCI (OR = 3.47; 95% CI = 1.57-7.69 p = .002), and black versus white race (OR = 2.45; 95% CI = 1.08-5.59; p = .032) at entry were significantly associated with development of slow gait compared with those maintaining normal gait speed. The association between baseline HbA1C and development of slow gait speed highlights an intervenable target to prevent progression of physical function limitations.

Initial Antiretroviral Therapy in an Integrase Inhibitor Era: Can We Do Better?

With the second-generation integrase inhibitors (dolutegravir and bictegravir) extending the attributes of earlier integrase inhibitors, three-drug regimens containing integrase inhibitors plus two nucleos(t)ide reverse transcriptase inhibitors are now widely recommended for first-line (initial) treatment of human immunodeficiency virus-1 infection. Led by dolutegravir plus lamivudine, two-drug therapy is emerging as a way to reduce antiretroviral therapy cost and adverse effects without compromising treatment options should virologic failure occur. Initial two-drug therapy has limitations, including the relative incompatibility with the coemerging concept of same-day antiretroviral therapy initiation.

"Noncognitive" symptoms of early Alzheimer disease: a longitudinal analysis.

OBJECTIVES: To observe the natural time course of noncognitive symptoms before the onset of symptomatic Alzheimer disease dementia. METHODS: Using the National Alzheimer's Coordinating Center Uniform Data Set from September 2005 to March 2013, data from cognitively normal individuals who were aged 50 years or older at first visit and had subsequent follow-up were analyzed. Survival analyses were used to examine the development of particular symptoms relative to each other on the Neuropsychiatric Inventory Questionnaire (NPI-Q), Functional Activities Questionnaire, and Geriatric Depression Scale, and to compare the development of individual symptoms for persons who did and did not receive a Clinical Dementia Rating (CDR) .0 (indicating abnormal cognition) during the follow-up period. RESULTS: The order of symptom occurrence on the NPI-Q was similar for participants who remained at CDR 0 and for those who received a CDR .0 over the follow-up period, although the time to most NPI-Q symptoms was faster for participants who received a CDR.0 (p, 0.001).With the exception of memory, Geriatric Depression Scale symptoms reported by both CDR groups were similar. CONCLUSIONS: We found a significantly earlier presence of positive symptoms on the NPI-Q in cognitively normal patients who subsequently developed CDR .0. Among participants with no depression symptoms at baseline, results suggest that depressive symptoms may increase with aging regardless of incipient dementia. Such findings begin to delineate the noncognitive course of Alzheimer disease dementia in the preclinical stages. Future research must further elucidate the correlation between noncognitive changes and distinct dementia subtypes.

Plasmodium IspD (2-C-Methyl-D-erythritol 4-Phosphate Cytidyltransferase), an Essential and Druggable Antimalarial Target.

As resistance to current therapies spreads, novel antimalarials are urgently needed. In this work, we examine the potential for therapeutic intervention via the targeting of Plasmodium IspD (2-C-methyl-D-erythritol 4-phosphate cytidyltransferase), the second dedicated enzyme of the essential methylerythritol phosphate (MEP) pathway for isoprenoid biosynthesis. Enzymes of this pathway represent promising therapeutic targets because the pathway is not present in humans. The Malaria Box compound, MMV008138, inhibits Plasmodium falciparum growth, and PfIspD has been proposed as a candidate intracellular target. We find that PfIspD is the sole intracellular target of MMV008138 and characterize the mode of inhibition and target-based resistance, providing chemical validation of this target. Additionally, we find that the Pf ISPD genetic locus is refractory to disruption in malaria parasites, providing independent genetic validation for efforts targeting this enzyme. This work provides compelling support for IspD as a druggable target for the development of additional, much-needed antimalarial agents.