Effect of depression treatment on health behaviors and cardiovascular risk factors in primary care patients with depression and elevated cardiovascular risk: data from the eIMPACT trial.

BACKGROUND: Depression is an independent risk factor for cardiovascular disease (CVD), but it is unknown if successful depression treatment reduces CVD risk. METHODS: Using eIMPACT trial data, we examined the effect of modernized collaborative care for depression on indicators of CVD risk. A total of 216 primary care patients with depression and elevated CVD risk were randomized to 12 months of the eIMPACT intervention (internet cognitive-behavioral therapy [CBT], telephonic CBT, and select antidepressant medications) or usual primary care. CVD-relevant health behaviors (self-reported CVD prevention medication adherence, sedentary behavior, and sleep quality) and traditional CVD risk factors (blood pressure and lipid fractions) were assessed over 12 months. Incident CVD events were tracked over four years using a statewide health information exchange. RESULTS: The intervention group exhibited greater improvement in depressive symptoms (p < 0.01) and sleep quality (p < 0.01) than the usual care group, but there was no intervention effect on systolic blood pressure (p = 0.36), low-density lipoprotein cholesterol (p = 0.38), high-density lipoprotein cholesterol (p = 0.79), triglycerides (p = 0.76), CVD prevention medication adherence (p = 0.64), or sedentary behavior (p = 0.57). There was an intervention effect on diastolic blood pressure that favored the usual care group (p = 0.02). The likelihood of an incident CVD event did not differ between the intervention (13/107, 12.1%) and usual care (9/109, 8.3%) groups (p = 0.39). CONCLUSIONS: Successful depression treatment alone is not sufficient to lower the heightened CVD risk of people with depression. Alternative approaches are needed. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02458690.

Immune checkpoints and pancreatic beta cell dysfunction in HIV.

We explored the impact of immune dysregulation on pancreatic beta cell injury in HIV patients. Analyzing 105 participant samples, we observed lower IL-21 levels and elevated immune checkpoint levels (e.g. PD-1, CD27+, CD40+) in untreated HIV patients. Notably, soluble TIM-3 correlated positively with improved beta cell function and inversely with beta cell stress, suggesting its potential role in beta cell protection in untreated HIV.

Depressive symptom clusters and biomarkers of monocyte activation, inflammation, and coagulation in people with HIV and depression.

We assess associations of somatic and cognitive/affective depressive symptom clusters with monocyte activation (soluble (s)CD14, sCD163), systemic inflammation (interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP)), and coagulation (D-dimer, fibrinogen) in people with HIV (PWH) on suppressive antiretroviral therapy with depression. Utilizing baseline data from a randomized controlled trial, we found no significant associations in linear regression models examining individual depressive symptom clusters; however, models examining both clusters simultaneously showed that the somatic cluster was positively associated with inflammation biomarkers, while the cognitive/affective cluster was negatively associated with inflammation and coagulation biomarkers (suggesting a cooperative suppression effect). Our findings indicate a differential association with depressive symptom clusters and biological mechanisms underlying cardiovascular disease (CVD) in HIV, which may be driven by unique components of each depressive symptom cluster. This line of research could identify subgroups of PWH with depression at elevated CVD risk needing early CVD prevention approaches. Supported by R01 HL126557.

Remdesivir for Treatment of COVID-19 Requiring Oxygen Support: A Cross-Study Comparison from Two Large, Open-Label Studies.

BACKGROUND: Remdesivir, an RNA-polymerase prodrug inhibitor approved for treatment of COVID-19, shortens recovery time and improves clinical outcomes. This prespecified analysis compared remdesivir plus standard-of-care (SOC) with SOC alone in adults hospitalized with COVID-19 requiring oxygen support in the early stage of the pandemic. METHODS: Data for 10-day remdesivir treatment plus SOC from the extension phase of an open-label study (NCT04292899) were compared with real-world, retrospective data on SOC alone (EUPAS34303). Both studies included patients aged ≥18 years hospitalized with SARS-CoV-2 up to 30 May 2020, with oxygen saturation ≤94%, on room air or supplemental oxygen (all forms), and with pulmonary infiltrates. Propensity score weighting was used to balance patient demographics and clinical characteristics across treatment groups. The primary endpoint was time to all-cause mortality or end of study (day 28). Time-to-discharge, with a 10-day landmark to account for duration of remdesivir treatment, was a secondary endpoint. RESULTS: 1974 patients treated with remdesivir plus SOC, and 1426 with SOC alone, were included after weighting. Remdesivir significantly reduced mortality versus SOC (hazard ratio [HR]: 0.46, 95% confidence interval: 0.39-0.54). This association was observed at each oxygen support level, with the lowest HR for patients on low-flow oxygen. Remdesivir significantly increased the likelihood of discharge at day 28 versus SOC in the 10-day landmark analysis (HR: 1.64; 95% confidence interval: 1.43-1.87). CONCLUSIONS: Remdesivir plus early-2020 SOC was associated with a 54% lower mortality risk and shorter hospital stays compared with SOC alone in patients hospitalized with COVID-19 requiring oxygen support. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT04292899 and EUPAS34303.

Preswitch Regimens Influence the Rate of Weight Gain After Switch to Tenofovir Disoproxil Fumarate, Lamivudine, and Dolutegravir (TLD): Study From an East African Cohort.

Background: Switching from non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens to dolutegravir (DTG) has been associated with greater weight gain. Methods: We conducted our analysis using a longitudinal cohort of people with HIV (PWH) in Western Kenya. We evaluated changes in the rate of weight gain among treatment-experienced, virally suppressed PWH who switched from NNRTI to tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD). We modeled the weights pre- and postswitch using a 2-phase model with linear trend preswitch and an inverted exponential function postswitch. We estimated an 18-month excess weight gain by comparing the projected weight with that expected using the preswitch rate. Results: A total of 18 662 individuals were included in our analysis, with 55% switching from efavirenz (EFV) and 45% from nevirapine (NVP). Of the studied individuals, 51% were female, and the median age and body mass index (BMI) were 51 years and 22 kg/m2, respectively. For the overall population, the rate of weight gain increased from 0.47 kg/year preswitch to 0.77 kg/year, with higher increases for females (0.57 kg/year to 0.96 kg/year) than males (0.34 kg/year to 0.62 kg/year). The rate of weight gain for individuals switching from EFV-based regimens significantly increased from 0.57 kg/year preswitch to 1.11 kg/year postswitch but remained stable at 0.35 kg/year preswitch vs 0.32 kg/year postswitch for individuals switching from NVP-based regimens. Conclusions: Switching from NNRTI-based regimens to TLD is associated with a modest increase in the rate of weight gain, with the preswitch NNRTI being the key determinant of the amount of weight gain experienced postswitch.

The INGENIOUS trial: Impact of pharmacogenetic testing on adverse events in a pragmatic clinical trial.

Adverse drug events (ADEs) account for a significant mortality, morbidity, and cost burden. Pharmacogenetic testing has the potential to reduce ADEs and inefficacy. The objective of this INGENIOUS trial (NCT02297126) analysis was to determine whether conducting and reporting pharmacogenetic panel testing impacts ADE frequency. The trial was a pragmatic, randomized controlled clinical trial, adapted as a propensity matched analysis in individuals (N = 2612) receiving a new prescription for one or more of 26 pharmacogenetic-actionable drugs across a community safety-net and academic health system. The intervention was a pharmacogenetic testing panel for 26 drugs with dosage and selection recommendations returned to the health record. The primary outcome was occurrence of ADEs within 1 year, according to modified Common Terminology Criteria for Adverse Events (CTCAE). In the propensity-matched analysis, 16.1% of individuals experienced any ADE within 1-year. Serious ADEs (CTCAE level ≥ 3) occurred in 3.2% of individuals. When combining all 26 drugs, no significant difference was observed between the pharmacogenetic testing and control arms for any ADE (Odds ratio 0.96, 95% CI: 0.78-1.18), serious ADEs (OR: 0.91, 95% CI: 0.58-1.40), or mortality (OR: 0.60, 95% CI: 0.28-1.21). However, sub-group analyses revealed a reduction in serious ADEs and death in individuals who underwent pharmacogenotyping for aripiprazole and serotonin or serotonin-norepinephrine reuptake inhibitors (OR 0.34, 95% CI: 0.12-0.85). In conclusion, no change in overall ADEs was observed after pharmacogenetic testing. However, limitations incurred during INGENIOUS likely affected the results. Future studies may consider preemptive, rather than reactive, pharmacogenetic panel testing.

Cryptococcal Meningitis in Young, Immunocompetent Patients: A Single-Center Retrospective Case Series and Review of the Literature.

Background: Cryptococcal meningitis is an uncommon but serious infection with high mortality and morbidity. Classically described in immunocompromised patients, including those with solid organ transplants or HIV/AIDS, cryptococcosis has also been reported in young and otherwise healthy patients, albeit rarely. Methods: We retrospectively searched for all cases of cryptococcal meningitis in young (≤50 years) and previously healthy patients with no known immunocompromising conditions from January 2015 to January 2022 at Indiana University Health (IU Health). Additionally, a PubMed literature review was performed with the keywords "cryptococcal meningitis" and "immunocompetent" from January 1988 to January 2022. Clinical courses, including outcomes and treatment regimens, were evaluated. Results: We identified 4 local cases of cryptococcal meningitis in otherwise healthy patients age ≤50 years. Three cases were due to Cryptococcus neoformans, with 1 experiencing a postinfectious inflammatory response syndrome (PIIRS). The PubMed search identified 51 additional cases, with 32 (63%) being caused by Cryptococcus neoformans and 8 (17%) by Cryptococcus gattii. Of the 51 cases, only 2 resulted in death directly due to cryptococcosis. Fifteen (29%) had PIIRS, with steroid treatment documented in 11 of 15. Antifungal induction regimens and duration were varied but predominately consisted of amphotericin and flucytosine, with a mean induction duration of 5.0 weeks. Conclusions: Cryptococcal meningitis in young, previously healthy patients is likely under-recognized. PIIRS (akin to immune reconstitution inflammatory syndrome observed in HIV/AIDS) with prolonged recovery should be of concern. Determining risk factors for cryptococcosis in these patients remains elusive.

Effect of modernized collaborative care for depression on depressive symptoms and cardiovascular disease risk biomarkers: eIMPACT randomized controlled trial.

Although depression is a risk and prognostic factor for cardiovascular disease (CVD), clinical trials treating depression in patients with CVD have not demonstrated cardiovascular benefits. We proposed a novel explanation for the null results for CVD-related outcomes: the late timing of depression treatment in the natural history of CVD. Our objective was to determine whether successful depression treatment before, versus after, clinical CVD onset reduces CVD risk in depression. We conducted a single-center, parallel-group, assessor-blinded randomized controlled trial. Primary care patients with depression and elevated CVD risk from a safety net healthcare system (N = 216, Mage = 59 years, 78% female, 50% Black, 46% with income <$10,000/year) were randomized to 12 months of the eIMPACT intervention (modernized collaborative care involving internet cognitive-behavioral therapy [CBT], telephonic CBT, and/or select antidepressants) or usual primary care for depression (primary care providers supported by embedded behavioral health clinicians and psychiatrists). Outcomes were depressive symptoms and CVD risk biomarkers at 12 months. Intervention participants, versus usual care participants, exhibited moderate-to-large (Hedges' g = -0.65, p < 0.01) improvements in depressive symptoms. Clinical response data yielded similar results - 43% of intervention participants, versus 17% of usual care participants, had a ≥ 50% reduction in depressive symptoms (OR = 3.73, 95% CI: 1.93-7.21, p < 0.01). However, no treatment group differences were observed for the CVD risk biomarkers - i.e., brachial flow-mediated dilation, high-frequency heart rate variability, interleukin-6, high-sensitivity C-reactive protein, ß-thromboglobulin, and platelet factor 4 (Hedges' gs = -0.23 to 0.02, ps ≥ 0.09). Our modernized collaborative care intervention - which harnessed technology to maximize access and minimize resources - produced clinically meaningful improvements in depressive symptoms. However, successful depression treatment did not lower CVD risk biomarkers. Our findings indicate that depression treatment alone may not be sufficient to reduce the excess CVD risk of people with depression and that alternative approaches are needed. In addition, our effective intervention highlights the utility of eHealth interventions and centralized, remote treatment delivery in safety net clinical settings and could inform contemporary integrated care approaches. Trial Registration:ClinicalTrials.gov Identifier: NCT02458690.

Non-alcoholic fatty liver disease is not associated with impairment in health-related quality of life in virally suppressed persons with human immune deficiency virus.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in persons with HIV (PWH) (HIV-NAFLD). It is unknown if HIV-NAFLD is associated with impairment in health-related quality of life (HRQOL). We examined HRQOL in PWH with and without NAFLD, compared HRQOL in HIV- versus primary NAFLD, and determined factors associated with HRQOL in these groups. Prospectively enrolled 200 PWH and 474 participants with primary NAFLD completed the Rand SF-36 assessment which measures 8 domains of HRQOL. Individual domain scores were used to create composite physical and mental component summary scores. Univariate and multivariate analyses determined variables associated with HRQOL in PWH and in HIV- and primary NAFLD. In PWH, 48% had HIV-NAFLD, 10.2% had clinically significant fibrosis, 99.5% were on antiretroviral therapy, and 96.5% had HIV RNA <200 copies/ml. There was no difference in HRQOL in PWH with or without NAFLD. Diabetes, non-Hispanic ethnicity, and nadir CD4 counts were independently associated with impaired HRQOL in PWH. In HIV-NAFLD, HRQOL did not differ between participants with or without clinically significant fibrosis. Participants with HIV-NAFLD compared to those with primary NAFLD were less frequently cisgender females, White, more frequently Hispanic, had lower BMI and lower frequency of obesity and diabetes. HRQOL of individuals with HIV-NAFLD was not significantly different from those with primary NAFLD. In conclusion, in virally suppressed PWH, HRQOL is not different between participants with or without HIV-NAFLD. HRQOL is not different between HIV-NAFLD and primary NAFLD.

Burden of fatty liver and hepatic fibrosis in persons with HIV: A diverse cross-sectional US multicenter study.

BACKGROUND AIMS: The current prevalence of fatty liver disease (FLD) due to alcohol-associated (AFLD) and nonalcoholic (NAFLD) origins in US persons with HIV (PWH) is not well defined. We prospectively evaluated the burden of FLD and hepatic fibrosis in a diverse cohort of PWH. APPROACH RESULTS: Consenting participants in outpatient HIV clinics in 3 centers in the US underwent detailed phenotyping, including liver ultrasound and vibration-controlled transient elastography for controlled attenuation parameter and liver stiffness measurement. The prevalence of AFLD, NAFLD, and clinically significant and advanced fibrosis was determined. Univariate and multivariate logistic regression models were used to evaluate factors associated with the risk of NAFLD. Of 342 participants, 95.6% were on antiretroviral therapy, 93.9% had adequate viral suppression, 48.7% (95% CI 43%-54%) had steatosis by ultrasound, and 50.6% (95% CI 45%-56%) had steatosis by controlled attenuation parameter ≥263 dB/m. NAFLD accounted for 90% of FLD. In multivariable analysis, old age, higher body mass index, diabetes, and higher alanine aminotransferase, but not antiretroviral therapy or CD4 + cell count, were independently associated with increased NAFLD risk. In all PWH with fatty liver, the frequency of liver stiffness measurement 8-12 kPa was 13.9% (95% CI 9%-20%) and ≥12 kPa 6.4% (95% CI 3%-11%), with a similar frequency of these liver stiffness measurement cutoffs in NAFLD. CONCLUSIONS: Nearly half of the virally-suppressed PWH have FLD, 90% of which is due to NAFLD. A fifth of the PWH with FLD has clinically significant fibrosis, and 6% have advanced fibrosis. These data lend support to systematic screening for high-risk NAFLD in PWH.