Polypharmacy Is Associated With Slow Gait Speed and Recurrent Falls in Older People With HIV.

BACKGROUND: Older people with human immunodeficiency virus (HIV, PWH) are prone to using multiple medications due to higher rates of medical comorbidities and the use of antiretroviral therapy (ART). We assessed the prevalence and clinical impact of polypharmacy among PWH. METHODS: We leveraged clinical data from the AIDS Clinical Trials Group A5322 study "Long-Term Follow-up of Older HIV-infected Adults: Addressing Issues of Aging, HIV Infection and Inflammation" (HAILO). We included PWH aged ≥40 years with plasma HIV RNA levels <200 copies/µL. We assessed the relationship between polypharmacy (defined as the use of 5 or more prescription medications, excluding ART) and hyperpolypharmacy (defined as the use of 10 or more prescription medications, excluding ART) with slow gait speed (less than 1 meter/second) and falls, including recurrent falls. RESULTS: Excluding ART, 24% of study participants had polypharmacy and 4% had hyperpolypharmacy. Polypharmacy was more common in women (30%) than men (23%). Participants with polypharmacy had a higher risk of slow gait speed (odds ratio [OR] = 1.78; 95% confidence interval [CI] = 1.27-2.50) and increased risk of recurrent falls (OR = 2.12; 95% CI = 1.06-4.23). The risk for recurrent falls was further increased in those with hyperpolypharmacy compared with those without polypharmacy (OR = 3.46; 95% CI = 1.32-9.12). CONCLUSIONS: In this large, mixed-sex cohort of PWH aged ≥40 years, polypharmacy was associated with slow gait speed and recurrent falls, even after accounting for medical comorbidities, alcohol use, substance use, and other factors. These results highlight the need for increased focus on identifying and managing polypharmacy and hyperpolypharmacy in PWH.

Liver Inflammation Is Common and Linked to Metabolic Derangements in Persons With Treated Human Immunodeficiency Virus (HIV).

BACKGROUND: We sought to characterize in people with human immunodeficiency virus (PWH) the potential etiologies of elevated alanine aminotransferase (ALT) levels, which are common and often unexplained. METHODS: Participants from the longitudinal observational AIDS Clinical Trials Group HAILO cohort without a history of hepatitis C virus (HCV) or hepatitis B virus (HBV) infection nor reported heavy alcohol use were included. Clinical and demographic characteristics, including medication use, the hepatic steatosis index (HSI), and metabolic syndrome (MetS) were compared between participants with and without ALT elevation. RESULTS: Six hundred sixty-two participants were included; 444 (67%) had ≥1 and 229 (35%) ≥2 consecutive ALT elevations during a median of 4.0 years of follow-up. HSI and Hispanic or other (non-White or Black) race/ethnicity were consistently associated with higher odds of abnormal ALT (odds ratio [OR] 1.1 for HSI as a continuous variable, OR 1.9-2.8 for Hispanic/other race/ethnicity for ≥1 or ≥2 ALT elevations); older age and current smoking were associated with lower odds of abnormal ALT. Associations with metabolic disease, as well as with incident HBV and HCV infection, were strengthened by restricting outcomes to persistent and higher degrees of ALT elevation. CONCLUSIONS: ALT elevation was common in this cohort of PWH and associated with metabolic disease and hepatic steatosis markers. Nonalcoholic fatty liver disease is likely a common cause of liver inflammation in PWH receiving suppressive antiretrovirals, deserving targeted diagnosis and intervention.

Effect of Clonal Hematopoiesis on Cardiovascular Disease in People Living with HIV.

Hematopoietic stem cells (HSCs) with age-associated somatic mutations that disproportionally contribute to hematopoiesis generate the condition known as clonal hematopoiesis (CH). While CH conveys increased risk of hematologic cancer, there is also strong association between CH and cardiovascular disease (CVD). Accumulating evidence suggests that inflammation mechanistically links CH to CVD, and we hypothesized that CH may be a predictive biomarker of CVD in conditions of chronic inflammation. One such patient population comprises people living with HIV (PLWH) who also have substantially increased incidences of CVD and CH . We studied the association between CH and CVD in PLWH using samples from ACTG Study A5001 (or ALLRT), a prospective clinical trial of HIV-infected persons with long-term follow-up. We observed a positive association between CH and CVD in PLWH independent of traditional CVD risk factors. Moreover, in CVD cases, the CH clone was identifiable in the blood years before CVD diagnosis, unlike in PLWH with CH who did not have CVD. With the life span of PLWH increasing because of advances in treatment, our results indicate that the presence of CH and its clonal dynamics could be used as a prognostic biomarker of the risk for CVD in PLWH.

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.

Plasma Citrate and Succinate Are Associated With Neurocognitive Impairment in Older People With HIV.

BACKGROUND: Neurocognitive impairment (NCI) is associated with monocyte activation in people with HIV (PWH). Activated monocytes increase glycolysis, reduce oxidative phosphorylation, and accumulate citrate and succinate, tricarboxylic acid (TCA) cycle metabolites that promote inflammation-this metabolic shift may contribute to NCI and slowed gait speed in PWH. METHODS: Plasma citrate and succinate were assayed by liquid chromatography-mass spectrometry from 957 participants upon entry to a multicenter, prospective cohort of older PWH. Logistic, linear, and mixed-effects linear regression models were used to examine associations between entry/baseline TCA cycle metabolites and cross-sectional and longitudinal NCI, neuropsychological test scores (NPZ-4), and gait speed. RESULTS: Median age was 51 (range 40-78) years. Each 1 standard deviation (SD) citrate increment was associated with 1.18 higher odds of prevalent NCI at baseline (P = .03), 0.07 SD lower time-updated NPZ-4 score (P = .01), and 0.02 m/s slower time-updated gait speed (P < .0001). Age accentuated these effects. In the oldest age-quartile, higher citrate was associated with 1.64 higher odds of prevalent NCI, 0.17 SD lower NPZ-4, and 0.04 m/s slower gait speed (P ≤ .01 for each). Similar associations were apparent with succinate in the oldest age-quintile, but not with gait speed. In participants without NCI at entry, higher citrate predicted a faster rate of neurocognitive decline. CONCLUSIONS: Higher plasma citrate and succinate are associated with worse cross-sectional and longitudinal measures of neurocognitive function and gait speed that are age-dependent, supporting the importance of altered bioenergetic metabolism in the pathogenesis of NCI in older PWH.

Risk Factors for Weight Gain Following Switch to Integrase Inhibitor-Based Antiretroviral Therapy.

BACKGROUND: Treatment initiation with integrase strand transfer inhibitors (INSTIs) has been associated with excess weight gain. Whether similar gains are seen after switch to INSTIs among virologically suppressed persons is less clear. We assessed pre/post-INSTI weight changes from AIDS Clinical Trials Group participants (A5001 and A5322). METHODS: Participants who were in follow-up from 1997-2017 and switched to INSTI-based antiretroviral regimens were included. Piecewise linear mixed-effects models adjusting for age, sex, race/ethnicity, baseline BMI, nadir and current CD4+ T-cell count, smoking, diabetes and follow-up time with suppressed HIV-1 RNA examined weight and waist circumference change before and after first switch to INSTIs. Linear spline models with a single knot at time of switch accounted for nonlinear trends. RESULTS: The 972 participants who switched to INSTIs were 81% male and 50% nonwhite with a median age at switch of 50 years, CD4+ T-cell count 512 cells/µL, and BMI 26.4 kg/m2. Restricting to persons with suppressed HIV-1 RNA at switch (n = 691), women, blacks, and persons ≥60 years experienced greater weight gain in the 2 years after versus before switch. In adjusted models, white or black race, age ≥60, and BMI ≥30 kg/m2 at switch were associated with greater weight gain following switch among women; age ≥60 was the greatest risk factor among men. Trends for waist circumference were similar. CONCLUSIONS: Yearly weight gain increased following switch to INSTIs, particularly for women, blacks, and persons aged ≥60. Concomitant increases in waist circumference suggest that this weight gain is associated with an increase in fat mass.

Mitochondrial DNA Haplogroups and Frailty in Adults Living with HIV.

Mitochondrial DNA (mtDNA) haplogroup has been associated with disease risk and longevity. Among persons with HIV (PWH), mtDNA haplogroup has been associated with AIDS progression, neuropathy, cognitive impairment, and gait speed decline. We sought to determine whether haplogroup is associated with frailty and its components among older PWH. A cross-sectional analysis was performed of AIDS Clinical Trials Group A5322 (HAILO) participants with available genome-wide genotype and frailty assessments. Multivariable logistic regression models adjusted for age, gender, education, smoking, hepatitis C, and prior use of didanosine/stavudine. Among 634 participants, 81% were male, 49% non-Hispanic white, 31% non-Hispanic black, and 20% Hispanic. Mean age was 51.0 (standard deviation 7.5) years and median nadir CD4 count was 212 (interquartile range 72, 324) cells/µL; 6% were frail, 7% had slow gait, and 21% weak grip. H haplogroup participants were more likely to be frail/prefrail (p = .064), have slow gait (p = .09), or weak grip (p = .017) compared with non-H haplogroup participants (not all comparisons reached statistical significance). In adjusted analyses, PWH with haplogroup H had a greater odds of being frail versus nonfrail [odds ratio (OR) 4.0 (95% confidence interval 1.0-15.4)] and having weak grip [OR 2.1 (1.1, 4.1)], but not slow gait [OR 1.6 (0.5, 5.0)] compared with non-H haplogroup. Among black and Hispanic participants, haplogroup was not significantly associated with frailty, grip, or gait. Among antiretroviral therapy (ART)-treated PWH, mtDNA haplogroup H was independently associated with weak grip and frailty. This association could represent a mechanism of weakness and frailty in the setting of HIV and ART.

Metformin reduces prostate cancer risk among men with benign prostatic hyperplasia: A nationwide population-based cohort study.

Benign Prostate Hyperplasia (BPH) has been associated with prostate cancer prevalent among men after 50 years of age, however, it is unclear whether the antidiabetic drug, metformin, can reduce prostate cancer for men with BPH. The insurance claims data of men aged 50 years or older, with both type 2 diabetes mellitus (T2DM) and BPH diagnosed from 1997 to 2007 were analyzed. Individuals were followed up for at least 5 years. We identified 2906 and 2906 patients as the metformin cohort and nonmetformin cohort, respectively. The Cox method analysis showed that the metformin cohort had an adjusted hazard ratio (aHR) of 0.69 (95% confidence interval [CI] = 0.49-0.96, P = 0.0298) for prostate cancer, compared to the nonmetformin cohort after controlling for age, traditional Chinese medicine (TCM) use, prostate specific antigen, and Charlson comorbidity index. Patients using TCM for BPH (per 6 months) also had an aHR of 0.41 (95% CI = 0.24-0.69; P = 0.0009). In conclusion, both metformin medication and TCM use could be associated with reduced risk of prostate cancer for men with BPH and diabetes.

Impact of aging on neurocognitive performance in previously antiretroviral-naive HIV-infected individuals on their first suppressive regimen.

BACKGROUND: Despite treatment with virologically suppressive antiretroviral therapy (ART), neurocognitive impairment may persist or develop de novo in aging HIV-infected individuals. We evaluated advancing age as a predictor of neurocognitive impairment in a large cohort of previously ART-naive individuals on long-term ART. DESIGN: The AIDS Clinical Trials Group Longitudinal Linked Randomized Trials was a prospective cohort study of HIV-infected individuals originally enrolled in randomized ART trials. This analysis examined neurocognitive outcomes at least 2 years after ART initiation. METHODS: All participants underwent annual neurocognitive testing consisting of Trail making A and B, the wechsler adult intelligence scale-revised Digit Symbol and Hopkins Verbal Learning Tests. Uni and multivariable repeated measures regression models evaluated factors associated with neurocognitive performance. Predictors at parent study entry (ART naive) included entry demographics, smoking, injection drug use, hepatitis B surface antigen, hepatitis C virus serostatus, history of stroke, ART regimen type, pre-ART nadir CD4 cell count, and plasma viral load and as well as time-updated plasma viral load and CD4 cell count. RESULTS: The cohort comprised 3313 individuals with median pre-ART age of 38 years, 20% women; 36% Black, non-Hispanic; 22% Hispanic. Virologic suppression was maintained at 91% of follow-up visits. Neurocognitive performance improved with years of ART. After adjusting for the expected effects of age using norms from HIV-negative individuals, the odds of neurocognitive impairment at follow-up visits among the HIV infected increased by nearly 20% for each decade of advancing age. CONCLUSION: Despite continued virologic suppression and neurocognitive improvement in the cohort as a whole, older individuals were more likely to have neurocognitive impairment than younger individuals.

Association Between Frailty and Components of the Frailty Phenotype With Modifiable Risk Factors and Antiretroviral Therapy.

The impact of antiretroviral therapy (ART) on frailty among human immunodeficiency virus (HIV)-infected adults has not been well described. HIV-infected participants aged ≥40 years with initial ART receipt through a randomized, controlled AIDS Clinical Trials Group trial completed a frailty assessment. Ordinal logistic regression models examined factors associated with frailty. Of 1016 participants, 6% were frail, and 38% were prefrail. Frailty was associated with lower education, older age, Medicare/Medicaid, initial efavirenz, smoking, obesity, and neurocognitive impairment; physical activity and alcohol use were protective. The associations with ART require further investigation, and associations between frailty and modifiable factors provide targets for future interventions.

Disability Among Middle-Aged and Older Persons With Human Immunodeficiency Virus Infection.

BACKGROUND: Older human immunodeficiency virus (HIV)-infected adults may experience higher rates of frailty and disability than the general population. Improved understanding of the prevalence, risk factors, and types of impairment can better inform providers and the healthcare system. METHODS: HIV-infected participants within the AIDS Clinical Trials Group A5322 HAILO study self-reported disability by the Lawton-Brody Instrumental Activities of Daily Living (IADL) Questionnaire. Frailty was measured by 4-m walk time, grip strength, self-reported weight loss, exhaustion, and low activity. Logistic regression models identified characteristics associated with any IADL impairment. Agreement between IADL impairment and frailty was assessed using the weighted kappa statistic. RESULTS: Of 1015 participants, the median age was 51 years, 15% were aged ≥60 years, 19% were female, 29% black, and 20% Hispanic. At least 1 IADL impairment was reported in 18% of participants, most commonly with housekeeping (48%) and transportation (36%) and least commonly with medication management (5%). In multivariable models, greater disability was significantly associated with neurocognitive impairment, lower education, Medicare/Medicaid insurance (vs private/other coverage), smoking, and low physical activity. Although a greater proportion of frail participants had IADL impairment (52%) compared to non-frail (11%) persons, agreement was poor (weighted kappa <0.18, 95% confidence interval, 0.13, 0.23). CONCLUSION: IADL disability occurs frequently among middle-aged and older HIV-infected adults on effective antiretroviral therapy. Potentially modifiable risk factors (smoking, physical activity) provide targets for interventions to maintain independent living. Systematic recognition of persons at greater risk for disability can facilitate connection to resources that may help preserve independence.

Proteinuria is associated with neurocognitive impairment in antiretroviral therapy treated HIV-infected individuals.

BACKGROUND: Proteinuria is a marker of vascular dysfunction that predicted increased cardiovascular mortality and is associated with neurocognitive impairment (NCI) in population-based studies. We examined associations between proteinuria and HIV-associated NCI. METHODS: Multivariable logistic regression was used to examine associations between NCI at the first neurocognitive assessment (baseline) and simultaneous, clinically significant proteinuria [as random spot urine protein-to-creatinine ratios (UP/Cr) ≥200 mg/g] in a prospective multicenter observational cohort study. Generalized estimating equations were used to examine associations between baseline proteinuria and subsequent NCI among subjects without NCI at baseline. NCI was defined as a Z-score, derived from the combination of normalized scores from the Trailmaking A and B and the Wechsler Adult Intelligence Scale-Revised Digit Symbol tests. RESULTS: A total of 1972 subjects were included in this analysis. Baseline proteinuria was associated with increased odds of NCI [odds ratio (OR): 1.41, 95% confidence interval (CI): 1.08 to 1.85; P = 0.01] and with subsequent NCI among subjects without NCI at baseline (OR: 1.39, 95% CI: 1.01 to 1.93; P = 0.046) in multivariable models adjusted for risk factors and potential confounders. Similar associations were evident when these analyses were limited to visits at which time study subjects maintained plasma HIV RNA levels <200 copies per milliliter. CONCLUSIONS: The association between proteinuria and NCI observed in this study adds to a growing body of evidence implicating contributions by vascular disease to NCI in antiretroviral treated individuals. Studies examining interventions that improve vascular function are warranted.