Weight Gain After Antiretroviral Therapy Initiation and Subsequent Risk of Metabolic and Cardiovascular Disease.

BACKGROUND: Weight gain following initiation of antiretroviral therapy (ART) is common. We assessed the impact of changes in weight in the year following ART initiation with subsequent cardiometabolic disease among AIDS Clinical Trials Group (ACTG) participants. METHODS: Linear regression models were fit to examine the association between change in weight/waist circumference (WC) in weeks 0-48 and change in metabolic parameters in weeks 0-48 and 48-96. Cox proportional hazard models were fit to examine the association between changes in weight/WC in weeks 0-48 and diabetes mellitus (DM), metabolic syndrome, or cardiometabolic and cardiovascular events after week 48. RESULTS: Participants (N = 2624) were primarily male (81%) and non-White (60%). Mean weight gain from 0-48 weeks was 3.6 kg (SD 7.3); 130 participants developed DM; 360 metabolic syndrome; 424 any cardiometabolic event; 28 any cardiovascular event, over 480 weeks of follow-up. In adjusted models, total cholesterol increased by 0.63 mg/dL (95% confidence interval [CI] [.38, .089]) and LDL by 0.39 mg/dL (0.19, 0.59) per 1 kg increase in weight from weeks 0 to48. Participants who experienced >10% weight gain (vs -5% to 5%) had an increased risk of DM (hazard ratio [HR] 2.01, 95% CI [1.30, 3.08]), metabolic syndrome (HR 2.24, 95% CI [1.55, 2.62]), and cardiometabolic outcomes (HR 1.54, 95% CI [1.22, 1.95]). Participants who lost more than 5% of their baseline weight had a lower risk of incident metabolic syndrome (HR 0.67, 95% CI [0.42, 1.07]). Trends for WC were similar. CONCLUSIONS: Weight and body composition changes in the first year following ART initiation are associated with contemporaneous changes in metabolic parameters and subsequent cardiometabolic disease.

Pharmacogenetics of weight gain following switch from efavirenz- to integrase inhibitor-containing regimens.

BACKGROUND: Excessive weight gain affects some persons with HIV after switching to integrase strand transfer inhibitor (INSTI)-containing antiretroviral therapy (ART). We studied associations between CYP2B6 genotype and weight gain after ART switch among ACTG A5001 and A5322 participants. METHODS: Eligible participants switched from efavirenz- to INSTI-containing ART, had genotype data, and had weight data at least once from 4 weeks to 2 years post-switch. Multivariable linear mixed effects models adjusted for race/ethnicity, CD4, age, BMI and INSTI type assessed relationships between CYP2B6 genotype and estimated differences in weight change. RESULTS: A total of 159 eligible participants switched ART from 2007 to 2019, of whom 138 had plasma HIV-1 RNA < 200 copies/mL (65 CYP2B6 normal, 56 intermediate, 17 poor metabolizers). Among participants with switch HIV-1 RNA < 200 copies/mL, weight increased in all 3 CYP2B6 groups. The rate of weight gain was greater in CYP2B6 poor than in CYP2B6 normal metabolizers overall, and within 9 subgroups (male, female, White, Black, Hispanic, dolutegravir, elvitegravir, raltegravir, and TDF in the pre-switch regimen); only in Hispanic and elvitegravir subgroups were these associations statistically significant ( P  < 0.05). Compared to normal metabolizers, CYP2B6 intermediate status was not consistently associated with weight gain. CONCLUSION: CYP2B6 poor metabolizer genotype was associated with greater weight gain after switch from efavirenz- to INSTI-containing ART, but results were inconsistent. Weight gain in this setting is likely complex and multifactorial.

Call to Action: Prioritizing the Use of Inclusive, Nonstigmatizing Language in Scientific Communications.

The language we use in our scientific communications can either empower or stigmatize the people we study and care for. Clinical Infectious Diseases is committed to prioritizing the use of inclusive, nonstigmatizing language in published manuscripts. We hereby call upon submitting authors, reviewers, and editors to do the same.

Changes in Body Mass Index with Longer-term Integrase Inhibitor Use: A Longitudinal Analysis of Data from the Randomized Trial to Prevent Vascular Events in Human Immunodeficiency Virus (REPRIEVE).

Over 2-years of follow-up, integrase strand transfer inhibitor (INSTI)-use was associated with weight gain among those on an INSTI <2 years at entry (+0.27 kg/m2/year; 95% confidence interval [CI], .22 to .33 vs +0.17 kg/m2/year; 95% CI, .12 to .23; P = .01), but not those on an entry INSTI >2 years.

Movement-related beta and gamma oscillations indicate parallels and disparities between Alzheimer's disease and HIV-associated neurocognitive disorder.

People with HIV (PWH) often develop HIV-related neurological impairments known as HIV-associated neurocognitive disorder (HAND), but cognitive dysfunction in older PWH may also be due to age-related disorders such as Alzheimer's disease (AD). Discerning these two conditions is challenging since the specific neural characteristics are not well understood and limited studies have probed HAND and AD spectrum (ADS) directly. We examined the neural dynamics underlying motor processing during cognitive interference using magnetoencephalography (MEG) in 22 biomarker-confirmed patients on the ADS, 22 older participants diagnosed with HAND, and 30 healthy aging controls. MEG data were transformed into the time-frequency domain to examine movement-related oscillatory activity and the impact of cognitive interference on distinct stages of motor programming. Both cognitively impaired groups (ADS/HAND) performed significantly worse on the task (e.g., less accurate and slower reaction time) and exhibited reductions in frontal and cerebellar beta and parietal gamma activity relative to controls. Disease-specific aberrations were also detected such that those with HAND exhibited weaker gamma interference effects than those on the ADS in frontoparietal and motor areas. Additionally, temporally distinct beta interference effects were identified, with ADS participants exhibiting stronger beta interference activity in the temporal cortex during motor planning, along with weaker beta interference oscillations dispersed across frontoparietal and cerebellar cortices during movement execution relative to those with HAND. These results indicate both overlapping and distinct neurophysiological aberrations in those with ADS disorders or HAND in key motor and top-down cognitive processing regions during cognitive interference and provide new evidence for distinct neuropathology.

Resting state network connectivity alterations in HIV: Parallels with aging.

The increasing incidence of age-related comorbidities in people with HIV (PWH) has led to accelerated aging theories. Functional neuroimaging research, including functional connectivity (FC) using resting-state functional magnetic resonance imaging (rs-fMRI), has identified neural aberrations related to HIV infection. Yet little is known about the relationship between aging and resting-state FC in PWH. This study included 86 virally suppressed PWH and 99 demographically matched controls spanning 22-72 years old who underwent rs-fMRI. The independent and interactive effects of HIV and aging on FC were investigated both within- and between-network using a 7-network atlas. The relationship between HIV-related cognitive deficits and FC was also examined. We also conducted network-based statistical analyses using a brain anatomical atlas (n = 512 regions) to ensure similar results across independent approaches. We found independent effects of age and HIV in between-network FC. The age-related increases in FC were widespread, while PWH displayed further increases above and beyond aging, particularly between-network FC of the default-mode and executive control networks. The results were overall similar using the regional approach. Since both HIV infection and aging are associated with independent increases in between-network FC, HIV infection may be associated with a reorganization of the major brain networks and their functional interactions in a manner similar to aging.

Mitochondrial redox environments predict sensorimotor brain-behavior dynamics in adults with HIV.

Despite virologic suppression, people living with HIV (PLWH) remain at risk for developing cognitive impairment, with aberrations in motor control being a predominant symptom leading to functional dependencies in later life. While the neuroanatomical bases of motor dysfunction have recently been illuminated, the underlying molecular processes remain poorly understood. Herein, we evaluate the predictive capacity of the mitochondrial redox environment on sensorimotor brain-behavior dynamics in 40 virally-suppressed PLWH and 40 demographically-matched controls using structural equation modeling. We used state-of-the-art approaches, including Seahorse Analyzer of mitochondrial function, electron paramagnetic resonance spectroscopy to measure superoxide levels, antioxidant activity assays and dynamic magnetoencephalographic imaging to quantify sensorimotor oscillatory dynamics. We observed differential modulation of sensorimotor brain-behavior relationships by superoxide and hydrogen peroxide-sensitive features of the redox environment in PLWH, while only superoxide-sensitive features were related to optimal oscillatory response profiles and better motor performance in controls. Moreover, these divergent pathways may be attributable to immediate, separable mechanisms of action within the redox environment seen in PLWH, as evidenced by mediation analyses. These findings suggest that mitochondrial redox parameters are important modulators of healthy and pathological oscillations in motor systems and behavior, serving as potential targets for remedying HIV-related cognitive-motor dysfunction in the future.

Geographical Differences in the Self-Reported Functional Impairment of People With Human Immunodeficiency Virus (HIV) and Associations With Cardiometabolic Risk.

BACKGROUND: We sought to explore multinational differences in functional status by global burden of disease (GBD) regions in the REPRIEVE cohort. METHODS: REPRIEVE is a prospective, double-blind, randomized, placebo-controlled, multicenter, phase III primary cardiovascular prevention study of pitavastatin calcium vs placebo among people with human immunodeficiency virus (HIV, PWH) ages 40-75 on antiretroviral therapy (ART). GBD super regions were defined using World Health Organization classifications. Participants were categorized by impairment on the Duke Activity Status Instrument (DASI: none, some, moderate, severe). Logistic regression models examined risk factors and GBD regions associated with functional impairment. The association between functional impairment and cardiometabolic risk was also explored. RESULTS: Of 7736 participants, the majority were from high-income countries (n = 4065), were male (65%), and had received ART for ≥ 10 years. The median DASI score was 58.2 (interquartile range [IQR] 50.2, 58.2); 36% reported at least some impairment. In adjusted analyses, functional impairment was significantly more frequent among participants from Southeast/East Asia. Other factors associated with greater impairment included female sex, Black race, older age, current/former smoking, higher body mass index, use of ART for ≥ 10 years, and select ART regimens; differences were seen in risks across GBD regions. Functional impairment was associated with increased cardiometabolic risk. CONCLUSIONS: Over 1/3 of middle-aged and older PWH in a global cohort across diverse GBD regions demonstrate functional impairments. The associations between DASI and cardiometabolic risk suggest that a measure of functional status may improve risk prediction; these longitudinal associations will be further investigated over REPRIEVE trial follow-up.

Low Rates of Lung Cancer Screening Referrals in Patients With Human Immunodeficiency Virus: A Correlational Study.

People living with HIV (PLWH) have an increased risk of lung cancer compared to the general population. In 2013, the United States Preventive Services Task Force (USPSTF) released their lung cancer screening (LCS) guidelines. However, the impact of these guidelines has not been well established in PLWH. The objective of this retrospective descriptive study is to evaluate the frequency of lung cancer screening referrals and factors associated with LCS referrals using the 2013 USPSTF screening guidelines in at-risk PLWH. We collected demographic and clinical information on PLWH from electronic medical records from July 2016 to July 2018. Descriptive statistics, chi-square tests, t-tests, Wilcoxon rank sum tests, and Fisher's exact tests were used for analysis. Only 14% of patients who met 2013 USPSTF screening guidelines were referred for screening. Patients who received a referral were more likely to have received tobacco cessation counseling. Patients who received and completed a referral were more likely to have hepatitis C infection. Quality improvement strategies are needed to improve rates of LCS in PLWH.

The Association Between Weight Gain, Sex, and Immune Activation Following the Initiation of Antiretroviral Therapy.

BACKGROUND: Immune activation persists despite suppressive antiretroviral therapy (ART) and may be affected by sex or body composition. We explored these relationships in a subset of participants who initiated ART in two large randomized trials. METHODS: Purposeful sampling selected participants who achieved virologic suppression on ART and either maintained weight within ± 0.5 kg/m2 or gained 2.6-6.4 kg/m2 from baseline to 96 weeks. We measured 7 markers of inflammation and immune activation at weeks 0 and 96. Multivariable linear regression explored associations of weight gain, sex, and pre-ART BMI with pre-ART and changes in biomarker concentrations. RESULTS: 340 participants were selected; median pre-ART age 42 years, CD4+ cell count 273 cells/mm3, HIV-1 RNA 4.7 log10 copies/mL; 49% were women, 33% white, 42% black, and 24% Hispanic. Among participants with a normal pre-ART BMI, higher pre-ART levels of IL-6, sTNF-RI and RII, CXCL-10, sCD163 and hsCRP were associated with weight gain. Association of weight gain with week 96 changes of these biomarkers differed by sex; women who gained weight had smaller declines in most measured biomarkers compared to men who gained. CONCLUSIONS: Among women, weight gain is associated with attenuated decline in several immune activation markers following ART initiation. Clinical Trials Registration. NCT00811954 and NCT00811954.

Neighborhood Deprivation and Racial/Ethnic Disparities in Human Immunodeficiency Virus Viral Suppression: A Single-center, Cross-sectional Study in the United States Midwest.

Combating disparities is a crucial goal of ongoing efforts to end the human immunodeficiency virus (HIV) epidemic. In a multivariable analysis of a cohort in the Midwestern United States, racial/ethnic disparities in HIV viral suppression were no longer robust after accounting for other sociodemographic factors. Neighborhood deprivation and low income were independently inversely associated with viral suppression.

Successful application of pharmacogenomic testing in the evaluation and management of a patient with human immunodeficiency virus and disseminated histoplasmosis.

OBJECTIVES: To demonstrate the successful use of pharmacogenomic testing to specifically tailor antifungal treatment to the phenotype of a patient with human immunodeficiency virus (HIV) and disseminated histoplasmosis who had clinical progression while on itraconazole and subsequently had insufficient therapeutic drug levels of voriconazole. CASE SUMMARY: We present the case of a patient with HIV and disseminated histoplasmosis with a persistently elevated serum Histoplasma capsulatum antigen and subtherapeutic levels of voriconazole. Pharmacogenomic testing revealed he was a CYP2C19 rapid metabolizer, thus explaining his persistent, subtherapeutic levels of voriconazole and prompting a change in therapy. PRACTICE IMPLICATIONS: Our case illustrates the importance of pharmacogenomic testing as a tool to evaluate subtherapeutic itraconazole or voriconazole levels, especially in patients with failed clinical or Histoplasmosis Ag response despite reporting full adherence to prescribed therapy.

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.

Plasma and intracellular pharmacokinetics of tenofovir disoproxil fumarate and emtricitabine in transgender women receiving feminizing hormone therapy.

BACKGROUND: Transwomen have an increased risk of HIV acquisition compared with other adults. Drug-drug interactions between pre-exposure prophylaxis (PrEP) and gender-affirming therapy are cited as a reason for poor PrEP uptake among transwomen. We evaluated plasma tenofovir and emtricitabine pharmacokinetics and their active intracellular anabolites, tenofovir-diphosphate and emtricitabine-triphosphate, in transwomen receiving feminizing hormones. METHODS: We enrolled HIV-negative transwomen (≥19 years) not receiving PrEP. Participants took oral tenofovir disoproxil fumarate/emtricitabine 300/200 mg daily for 14 days. Plasma was collected at 0 h (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 and 12 h on day 14 post-tenofovir disoproxil fumarate/emtricitabine dose. The plasma AUC0-24 was calculated using the trapezoidal rule and compared with historical HIV-negative cisgender adults as geometric mean ratios (GMRs, 90% CI). Secondarily, tenofovir-diphosphate and emtricitabine-triphosphate from PBMCs collected at 0 h and 12 h were reported descriptively as geometric means (90% CI). Clinical trials registration: NCT03270969. RESULTS: Among 15 transwomen (mean age 32 years), geometric mean tenofovir and emtricitabine plasma AUC0-24 were lower compared with controls: tenofovir, 2.10 versus 2.76 mg·h/L, GMR 0.76 (0.65-0.90), P = 0.01; emtricitabine, 9.15 versus 10.64 mg·h/L, GMR 0.86 (0.75-0.98), P = 0.07. Tenofovir-diphosphate and emtricitabine-triphosphate concentrations were higher than previously reported in the literature: 167.1 (146.6-190.5) fmol/106 cells and 15.4 (13.8-17.3) pmol/106 cells, respectively. CONCLUSIONS: We observed lower plasma tenofovir and emtricitabine concentrations in transwomen compared with historical cisgender adults, yet intracellular tenofovir-diphosphate and emtricitabine-triphosphate concentrations were higher than previously reported in PBMCs. Understanding the differences of PrEP pharmacokinetics in plasma and tissue compartments and the resultant impact on efficacy remains important for transwomen.

Uveomeningeal syndrome in a healthy, young male: an unusual presentation of West Nile virus.

West Nile virus (WNV) is an RNA flavivirus transmitted through a mosquito vector. In 2018 Nebraska reported 242 cases, the highest incidence of WNV since 2003. This included 119 neuroinvasive cases (49%) and 11 deaths (4.5%) (DHHS 2018). Clinical presentation ranges from uncomplicated symptoms including fever, headache, and myalgias to neuroinvasive disease characterized by meningoencephalitis, flaccid paralysis, and other neurologic manifestations. Neuroinvasive WNV usually occurs in elderly and immunocompromised individuals, and ocular involvement is often not detected until later in the disease course. We describe a case of neuroinvasive WNV presenting with uveomeningitis in a young and otherwise healthy patient.

A pharmacist-led medication switch protocol in an academic HIV clinic: patient knowledge and satisfaction.

BACKGROUND: Tenofovir alafenamide (TAF) is associated with less renal and bone toxicity compared with tenofovir disoproxil (TDF). TAF's recent FDA approval has spurred HIV providers to consider switching antiretroviral therapy (ART) regimens containing TDF to TAF to minimize long term risks. Patient views on the process of such medication switches have not been explored. METHODS: Patients taking elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) following the Food and Drug Administration's (FDA) approval of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) received medication education from an HIV pharmacist prior to switching to the tenofovir alafenamide (TAF) formulation. Patients were asked to complete a cross-sectional survey assessing satisfaction with the switch process and knowledge about the new medication 4 to 8 weeks post-switch. RESULTS: Sixty five patients completed the switch and 57 (88%) completed a follow-up survey. Most (86%) reported understanding why the switch was made, while 91% correctly identified that TAF is associated with reduced renal toxicity, and 73% correctly identified that TAF is associated with reduced bone toxicity. No statistically significant difference was found in satisfaction with or understanding of why the medication switch was made when assessed by sex, age, race, or education, but there was a trend toward significance in the distribution of answers based on education level with those with a high school diploma, General Educational Development (GED) or less being more likely to be satisfied with the medication switch (p = 0.074). CONCLUSIONS: Education from an ambulatory clinic-based HIV pharmacist resulted in high rates of patient satisfaction and understanding of the switch from TDF to TAF-containing ART.

Clinical markers of HIV predict redox-regulated neural and behavioral function in the sensorimotor system.

Even in the modern era of combination antiretroviral therapy, aberrations in motor control remain a predominant symptom contributing to age-related functional dependencies (e.g., neurocognitive impairment) in people with HIV (PWH). While recent evidence implicates aberrant mitochondrial redox environments in the modulation of neural oscillatory activity serving motor control in PWH, the contribution of important clinical and demographic factors on this bioenergetic-neural-behavioral pathway is unknown. Herein, we evaluate the predictive capacity of clinical metrics pertinent to HIV (e.g., CD4 nadir, time with viremia) and age on mitochondrial redox-regulated sensorimotor brain-behavior dynamics in 69 virally-suppressed PWH. We used state-of-the-art systems biology and neuroscience approaches, including Seahorse analyzer of mitochondrial energetics, EPR spectroscopy of intracellular oxidant levels, antioxidant activity assays pertinent to superoxide and hydrogen peroxide (H2O2) redox environments, and magnetoencephalographic (MEG) imaging to quantify sensorimotor oscillatory dynamics. Our results demonstrate differential effects of redox systems on the neural dynamics serving motor function in PWH. In addition, measures of immune stability and duration of compromise due to HIV had dissociable effects on this pathway, above and beyond the effects of age alone. Moreover, peripheral measures of antioxidant activity (i.e., superoxide dismutase) fully mediated the relationship between immune stability and current behavioral performance, indicative of persistent oxidative environments serving motor control in the presence of virologic suppression. Taken together, our data suggest that disease-related factors, in particular, are stronger predictors of current redox, neural and behavioral profiles serving motor function, which may serve as effective targets for alleviating HIV-specific alterations in cognitive-motor function in the future.

Acceptability, Feasibility, and Appropriateness of Implementation of Long-acting Injectable Antiretrovirals: A National Survey of Ryan White Clinics in the United States.

Background: The approval of long-acting injectable cabotegravir/rilpivirine (LAI CAB/RPV) heightened the urgency of ensuring effective implementation. Our study assesses readiness and barriers to implement LAI CAB/RPV across Ryan White-funded clinics in the United States. Methods: We conducted a cross-sectional survey between December 2020 and January 2021 using validated 4-item measures: acceptability of intervention measure (AIM), intervention appropriateness measure (IAM), and feasibility of intervention measure (FIM). Associations between measures and clinic characteristics were evaluated via Spearman rank correlations. A 5-point Likert scale ranked potential barriers of implementation responses. Open-ended questions were analyzed through a thematic approach. Results: Of 270 clinics, 44 (16%) completed the survey: 38% federally qualified health centers, 36% academic, 20% community-based organizations, 14% hospital outpatient, and 9% nonprofit. Means (SD; range) were as follows: AIM, 17.6 (2.4; 12-20); IAM, 17.6 (2.4; 13-20); and FIM, 16.8 (2.9; 7-20). Twenty percent were not at all ready to implement LAI CAB/RPV, and 52% were slightly or somewhat ready. There was a significant association between AIM and the proportion of Medicaid patients (AIM, rho = 0.312, P = .050). Community-based organizations scored the highest readiness measures (mean [SD]: AIM, 19.50 [1.41]; IAM, 19.25 [1.49]; FIM, 19.13 [1.36]) as compared with other clinics. Implementation barriers were cost and patients' nonadherence to visits. Conclusions: There is variability of readiness yet high levels of perceived acceptability and appropriateness of implementing LAI CAB/RPV among Ryan White clinics, necessitating tailored interventions for successful implementation. A special focus on addressing the barriers of adherence and the cost of implementation is needed.