Tammy H. Cummings

Innate immune signaling through inflammasome activation has been implicated in the pathogenesis of multiple sclerosis (MS). We previously demonstrated that nucleoside reverse transcriptase inhibitors (NRTIs), drugs approved to treat HIV and hepatitis B virus infections, and kamuvudines, safer NRTI derivatives, both inhibit inflammasome activation. Here, we report that in the experimental autoimmune encephalitis mouse model of MS, treatment with kamuvudine-9 (K-9), an NRTI derivative with an enhanced safety profile, prevented further neurological deficits and reversed preexisting paralysis and vision loss. K-9 promoted myelin and axonal preservation in the mouse spinal cord and abolished the increase in serum neurofilament light (NfL) chain. K-9 disrupted interactions between nucleotide-binding domain leucine-rich repeat (NLR) pyrin domain-containing protein 3 (NLRP3) and NIMA-related kinase 7 (NEK7) and between NLRP3 and NLR CARD domain containing 4 (NLRC4), inhibiting dual inflammasome activation. K-9 also exhibited appropriate safety and pharmacokinetic characteristics and biodistribution. In three distinct human cohorts, there was a lower incidence of MS in those individuals receiving NRTIs for HIV infection, preexposure prophylaxis for HIV, or hepatitis B virus infection. NRTI use was also associated with a reduction in relapse rate in individuals with MS. These findings provide a rationale for further investigating K-9 for treating MS.

Background: As people with HIV (PWH) live longer because of effective antiretroviral therapy, age-related comorbidities—including cognitive impairment—are increasingly prevalent. HIV-associated neurocognitive disorders (HAND) remain a major cause of morbidity. In prior work, we identified an association between blood–brain barrier (BBB)–penetrant angiotensin-converting enzyme inhibitors (ACEi) and reduced risk of dementia in PWH. We are now expanding our work and methodology to more the effects of BBB ACEi on the risk of HAND. Methods: Using the Veterans Affairs Informatics and Computing Infrastructure, we conducted a retrospective cohort study to evaluate the association between BBB ACEi exposure and incident HAND among PWH. We used natural language processing to identify clinically documented HAND cases—including HIV-associated dementia, mild neurocognitive disorder, and asymptomatic neurocognitive impairment—from unstructured electronic medical notes. Eligible patients initiated ACEi therapy after HIV diagnosis between 2000 and 2024. Cox proportional hazards models, propensity score matching, and inverse probability treatment weighting were used to estimate adjusted hazard ratios. Results: Among 10,512 eligible PWH, 10,110 were exposed to BBB ACEi and 402 to non-BBB ACEi. In the unmatched cohort, HAND incidence was similar between groups (5.13% vs. 5.47%). However, after propensity score matching (n = 349 per group), BBB ACEi exposure was associated with a significantly lower risk of HAND (hazard ratio = 0.401; 95% confidence interval: 0.175–0.917). Conclusions: BBB-penetrant ACEi were associated with a reduced risk of incident HAND in a propensity score–matched cohort of PWH. These findings support further investigation into repurposing centrally acting ACEi as a potential neuroprotective strategy in the HIV population.

Background: This study evaluated clinical and economic outcomes associated with antiretroviral therapy (ART) resistance among people with HIV (PWH) within a nationally representative database. Methods: Retrospective claims data were extracted from the Veterans Affairs Informatics and Computing Infrastructure. PWH receiving testing for resistance-associated mutations (RAMs) between 2003 and 2023 were categorized as resistant if they had ≥1 documented RAM in integrase strand transfer inhibitor, protease inhibitor, or reverse transcriptase genes. Results: Among 7746 veterans with interpretable resistance tests, 1875 had no detectable resistance, 4466 had ≥1 major or minor RAM (any RAM), and 1405 had ≥1 major RAM. The median CD4 count was highest for those without RAMs (357 cells/mm3) and lowest for those with major RAMs (285 cells/mm3). Opportunistic infections during the 1-year follow-up were present in 3.8% without RAMs as compared with >5% for both RAM groups. Hospitalizations were more frequent in the major RAM and any RAM cohorts vs the no resistance cohort (P < .001 for both). Total all-cause costs averaged $45 476 for those without RAMs as compared with $49 945 for those with any RAM and $48 392 for those with a major RAM. Among PWH initiating ART after resistance testing (n = 3522), those without RAMs had the longest persistence, while those with RAMs had shorter persistence (P < .0001). PWH prescribed ART at the time of resistance testing who had RAMs were most likely to switch to a regimen based on an integrase strand transfer inhibitor or protease inhibitor. Conclusions: In this real-world analysis, PWH with detectable resistance had lower CD4 counts, more frequent hospitalizations and opportunistic infections, greater economic costs, and increased discontinuation of ART.

Aim: To compare the safety and efficacy of antidepressants (AD) among older adults with major depressive disorder (MDD) by assessing treatment change, augmentation and hospitalization rates. Methods: This retrospective study analyzed data from the Veterans Affairs (VA) database, including 142,138 patients aged ≥60 years diagnosed with MDD. Patients prescribed bupropion, citalopram, duloxetine, escitalopram, fluoxetine, mirtazapine, paroxetine, sertraline, or venlafaxine were included. Outcomes were treatment change, augmentation and hospitalization rates. Hazard ratios (aHRs) were calculated using sertraline as the reference. Results: Of the patients, 39.6% required augmentation, 18.1% changed antidepressant treatment and 13.3% were hospitalized. The corresponding incidence rate was 544, 124 and 122 events per 1000 person-years. Compared with sertraline, mirtazapine users had the highest AD change risk (aHR 1.34, 95% CI: 1.29–1.40), while duloxetine users had the lowest (aHR 0.87, 95% CI: 0.83–0.92). Duloxetine also had the lowest augmentation risk (aHR 0.89, 95% CI: 0.86–0.92). Mirtazapine users also had the highest risks of augmentation (aHR 1.15, 95% CI: 1.12–1.18) and hospitalization (aHR 1.14, 95% CI: 1.07–1.23). Bupropion had the lowest hospitalization risk (aHR 0.77, 95% CI: 0.71–0.84). Conclusion: Antidepressant choice significantly influences treatment outcomes in older adults with MDD. Duloxetine demonstrated the best profile with the lowest risks of AD change and augmentation, while mirtazapine posed the highest risks of all three outcomes. Personalized treatment strategies are crucial to improving outcomes in this population.

More than one million people in the United States and over 38 million people worldwide are living with human immunodeficiency virus (HIV) infection. Antiretroviral therapy (ART) greatly improves the health of people living with HIV (PLWH); however, the increased life longevity of PLWH has revealed consequences of HIV-associated comorbidities. HIV can enter the brain and cause inflammation even in individuals with well-controlled HIV infection. The quality of life for PLWH can be compromised by cognitive deficits and memory loss, termed HIV-associated neurological disorders (HAND). HIV-associated dementia is a related but distinct diagnosis. Common causes of dementia in PLWH are similar to the general population and can affect cognition. There is an urgent need to identify treatments for the aging PWLH population. We previously developed AI-based biomedical literature mining systems to uncover a potential novel connection between HAND the renin-angiotensin system (RAAS), which is a pharmacological target for hypertension. RAAS-targeting anti-hypertensives are gaining attention for their protective benefits in several neurocognitive disorders. To our knowledge, the effect of RAAS-targeting drugs on the cognition of PLWH development of dementia has not previously been analyzed. We hypothesized that exposure to angiotensin-converting enzyme inhibitors (ACEi) that cross the blood brain barrier (BBB) reduces the risk/occurrence of dementia in PLWH. We report a retrospective cohort study of electronic health records (EHRs) to examine the proposed hypothesis using data from the United States Department of Veterans Affairs, in which a primary outcome of dementia was measured in controlled cohorts of patients exposed to BBB-penetrant ACEi versus those unexposed to BBB-penetrant ACEi. The results reveal a statistically significant reduction in dementia diagnosis for PLWH exposed to BBB-penetrant ACEi. These results suggest there is a potential protective effect of BBB ACE inhibitor exposure against dementia in PLWH that warrants further investigation.

Oral factor Xa (FXa) inhibitors significantly reduce incidence of stroke and thromboembolic events in patients with atrial fibrillation or venous thromboembolism. Due to various factors and the lack of a randomized controlled trial comparing andexanet alfa to usual care, non-specific replacement agents including 4 F-PCC are still used off-label for FXa inhibitor bleed management. Clinical and mortality data were extracted from the inpatient medical data and Veteran Affairs (VA) vital status files over the time of March 2014 through December 2020. Propensity score-weighted models were used for this retrospective cohort study using data from the Veterans Affairs Informatics and Computing Infrastructure (VINCI). The study included 255 patients (85-andexanet alfa and 170-4 F-PCC) exposed to an oral factor Xa inhibitor and hospitalized with an acute major, gastrointestinal (GI), intracranial (ICH) or other bleed. In-hospital mortality was significantly lower in the andexanet alfa cohort compared to the 4 F-PCC cohort (10.6% vs. 25.3%, p = 0.01). Propensity score–weighted Cox models reveal a 69% lower hazard of in-hospital mortality for those treated with andexanet alfa (HR 0.31, 95% CI 0.14–0.71) compared to those treated with 4 F-PCC. Additionally, those treated with andexanet alfa had a lower 30-day mortality rate and lower 30-day hazard of mortality in the weighted Cox model (20.0% vs. 32.4%, p = 0.039; HR 0.54, 95% CI 0.30–0.98) compared to those treated with 4 F-PCC. Among 255 US veterans with major bleeding in the presence of an oral factor Xa inhibitor, treatment with andexanet alfa was associated with lower in-hospital and 30-day mortality than treatment with 4 F-PCC.

Checkpoint inhibitors can be a highly effective antitumor therapy but only to a subset of patients, presumably due to immunotherapy resistance. Fluoxetine was recently revealed to inhibit the NLRP3 inflammasome, and NLRP3 inhibition could serve as a target for immunotherapy resistance. Therefore, we evaluated the overall survival (OS) in patients with cancer receiving checkpoint inhibitors combined with fluoxetine. A cohort study was conducted among patients diagnosed with lung, throat (pharynx or larynx), skin, or kidney/urinary cancer treated with checkpoint inhibitor therapy. Utilizing the Veterans Affairs Informatics and Computing Infrastructure, patients were retrospectively evaluated during the period from October 2015 to June 2021. The primary outcome was overall survival (OS). Patients were followed until death or the end of the study period. There were 2316 patients evaluated, including 34 patients who were exposed to checkpoint inhibitors and fluoxetine. Propensity score weighted Cox proportional hazards demonstrated a better OS in fluoxetine-exposed patients than unexposed (HR: 0.59, 95% CI 0.371–0.936). This cohort study among cancer patients treated with checkpoint inhibitor therapy showed a significant improvement in the OS when fluoxetine was used. Because of this study’s potential for selection bias, randomized trials are needed to assess the efficacy of the association of fluoxetine or another anti-NLRP3 drug to checkpoint inhibitor therapy.

Medicare Annual Wellness Visits (AWVs) are annual appointments with the primary care team to prepare personalized prevention plans and focus on gaps in care. Although beneficial, AWVs are often difficult for providers to schedule and complete due to the increased time commitments compared to other visits. The purpose of this study was to assess the clinical, economic and patient-level value of newly implemented pharmacist-led AWVs within a rural Federally Qualified Health Center (FQHC). This retrospective, cohort study included patients who completed an AWV between 1 October 2021, and 14 February 2022. The primary objective was to compare the per clinician rate of completed AWVs between pharmacists and providers. The secondary objectives were to compare revenue generated, interventions made, and patient satisfaction between pharmacist- and provider-led AWVs. During the study period, nine providers completed 139 AWVs (15.4/provider) and two pharmacists completed 116 AWVs (58/pharmacist). Proportions of interventions ordered among those due in eligible patients were similar between pharmacists and providers (47.6% vs. 44.5%; p = 0.356). Patient satisfaction was overall positive with no difference between groups. Pharmacist-led AWVs increased completion of AWVs by 83% over a 20-week period, including significantly more initial, compared to subsequent, AWVs than providers. Sustainability of pharmacist-led AWVs at this FQHC is supported by study outcomes.

Background: Clostridioides difficile (C. difficile) infection (CDI) is strongly associated with inflammation and has the potential to cause recurrent infections. Pre-clinical data suggest that melatonin has beneficial effects in the gastrointestinal tract due to its anti-inflammatory and antibacterial properties. This analysis examines the association between melatonin and the risk of recurrent CDI. Methods: A retrospective cohort study was conducted among patients with an inpatient diagnosis of CDI along with a positive C. difficile polymerase chain reaction (PCR) or enzyme immunoassay (EIA) test result. Patients were followed until the first study end point (death) or the first instance of recurrent infection. Propensity-score weighting was utilized accounting for confounding factors and weighted Cox models were estimated. Results: A total of 24,782 patients met the inclusion criteria, consisting of 3457 patients exposed to melatonin and 21,325 patients with no melatonin exposure. The results demonstrate that those exposed to melatonin were associated with a 21.6% lower risk of recurrent CDI compared to patients without melatonin exposure (HR = 0.784; 95% CI = 0.674–0.912). Conclusion: Our results demonstrate a decreased rate of recurrent CDI in patients exposed to melatonin. Further research on melatonin as an antimicrobial adjuvant and anti-inflammatory is warranted for the management of recurrent CDI.