Inhaled bronchodilators are central for the treatment of chronic obstructive pulmonary disease (COPD), as they can provide symptom relief and reduce the frequency and severity of exacerbations while improving health status and exercise tolerance. In 2017, glycopyrrolate (GLY) delivered via the eFlow® closed system (CS) nebulizer (nebulized GLY; 25 µg twice daily), was approved by the US Food and Drug Administration for maintenance treatment of moderate-to-very-severe COPD. This approval was based largely on results from the replicate, placebo-controlled, Phase III clinical trials- GOLDEN 3 and 4. In this review, we summarize key findings from secondary analyses of the GOLDEN 3 and 4 studies, and provide a comprehensive overview that may assist both pulmonologists and primary-care providers in their treatment decisions. Comorbidities are common among patients with COPD in clinical practice and may impact bronchodilator efficacy. This review highlights outcomes among subpopulations of patients with comorbidities (e.g., anxiety/depression, cardiovascular disease), and their impact on the efficacy of nebulized GLY. In addition, the efficacy and safety of nebulized GLY across various demographics (e.g., age, gender) and baseline disease characteristics (e.g., disease severity, rescue medication use) are discussed. Real-world outcomes with nebulized GLY, including device satisfaction, healthcare resource utilization, and exacerbations, are also presented. These secondary analyses and real-world data complement the primary results with nebulized GLY from Phase III studies and support the need for the inclusion of patients representative of real-world clinical practice in RCTs. In addition, these data suggest that RCTs for COPD therapies should be complemented with real-world observational studies.

Background

Smoking is a major risk factor for COPD and may impact the efficacy of COPD treatments; however, a large proportion of COPD patients continue to smoke following diagnosis.

Methods

This post-hoc analysis of pooled data from the replicate 12-week, placebo-controlled GEM1 and GEM2 studies assessed the impact of smoking status on the efficacy and safety of glycopyrrolate 15.6 μg twice daily vs placebo in patients with moderate-to-severe COPD. Data from 867 patients enrolled in GEM1 and GEM2 were pooled for analysis and grouped by smoking status (57% current smokers, 43% ex-smokers). Forced expiratory volume in 1 s (FEV₁) area under the curve from 0 to 12 h, trough FEV₁, forced vital capacity, St George's Respiratory Questionnaire (SGRQ) total score, COPD assessment test (CAT) score, transition dyspnea index (TDI) focal score, daily symptom scores, and rescue medication use were assessed in current smokers and ex-smokers. Incidences of adverse events (AEs) and serious AEs (SAEs) were also assessed.

Results

Treatment with glycopyrrolate resulted in significant improvements in all lung function measures, independent of smoking status. In both current and ex-smokers, changes from baseline in trough FEV₁ were less marked in patients taking inhaled corticosteroids (ICS) than those not receiving ICS. Changes from baseline in SGRQ total score and rescue medication use were significantly greater with glycopyrrolate compared with placebo, regardless of smoking status. Changes in the CAT score, TDI focal score, and daily symptom scores significantly improved versus placebo, but only in current smokers. Improvements in patient-reported outcomes (PROs) with glycopyrrolate relative to placebo were numerically greater in current smokers than ex-smokers. The incidences of AEs and SAEs were similar regardless of smoking status.

Conclusions

In this post-hoc analysis of GEM1 and GEM2, glycopyrrolate use led to significant improvements in lung function, independent of baseline smoking status; improvements were less marked among patients receiving background ICS, regardless of baseline smoking status. Improvements in PROs were greater with glycopyrrolate than placebo, and the magnitude of changes was numerically greater among current smokers. The safety profile of glycopyrrolate was comparable between current smokers and ex-smokers.

Stigma towards trans women in Nepal creates individual and system-level risks for HIV. A critical protective factor is access to HIV prevention. Research is needed to determine the impact of stigma on HIV testing among trans women in Nepal. We conducted a secondary analysis of data collected using respondent driven sampling in 2019 on HIV risk among trans women in Nepal. Data analysis was restricted to trans women who were HIV negative at testing through the parent study. Descriptive statistics, tests for bivariable associations between HIV testing and stigma variables, and binomial Poisson regression were conducted to examine HIV testing outcomes. There were 173 participants who tested negative for HIV in our sample. The majority were under age 35 (59%) and most had a grade school education or less (64.7%). No trans women were homeless and most rented a room (70.5%) or owned their home (19.7%). The majority were currently sex workers (57.8%). Almost all HIV-negative trans women had ever been tested for HIV (90.8%), but only 53.5% in the last 3 months. The most frequently cited reason for not having been tested was thinking they were at low risk for HIV (40.9%) and being afraid of receiving a positive test result (22.7%). HIV and anti-trans stigma were high across most measures, including that almost all (94.2%) believed that most people in Nepal would discriminate against people with HIV. And most participants thought trans women were not accepted in Nepali Society (65.9%). Most participants also reported high social support (70.5%). Social cohesion among participants varied, with most experiencing medium (41.6%) or high (33.5%) social cohesion. Just over half had high social participation (55.5%). Participants who reported current sex work had lower prevalence of not testing for HIV in the last 3 months (prevalence ratio, PR = 0.54, 95% confidence interval, 95%CI = 0.32-0.92, p = 0.02). Every one-unit increase in social cohesion was associated with 1.05 times the prevalence of not testing for HIV in the last 3 months (95%CI = 1.01-1.09, p-value = 0.02). Trans women who did sex work were more likely to be HIV tested while those who were more socially connected to peers were less likely to have recently been tested for HIV. HIV stigma may result in fear of social rejection from peers if one tests positive. Interventions that focus on addressing stigma within trans women's social networks and strategies to mitigate HIV stigma in society may result in increased frequency of HIV testing among trans women in Nepal.

Background

Transgender women (trans women) in Nepal are underserved in the HIV response. Data are needed to determine the HIV prevalence disaggregated from other key populations and to identify the particular risks faced by this community. Trans women are marginalized around the world and research is also needed to determine the impact of stigma on HIV risk to inform trans-specific interventions.

Methods

In 2019, we conducted the first population-based HIV behavioral surveillance study of trans women disaggregated from other key populations using respondent driven sampling (RDS). We estimated the HIV prevalence for trans women, and bivariate and multivariate Poisson binomial regression models were constructed to examine the relationship between HIV risk and stigma.

Results

Trans women participants (N = 200) had a mean age of 33 years old (SD = 10.96). We found a weighted HIV prevalence of 11.3% (95% CI 6·82% - 18·13). We found that depression and anxiety (aPR 0.81; 95% CI 0.67-0.97; p = 0·02) and current engagement in sex work (aPR 1.31; 95% CI 1.01-1.71; p = 0·046) were significantly associated with greater prevalence of condomless receptive anal intercourse. We found that experienced stigma of ever being verbally abused due to gender identity was significantly associated with lower prevalence of depression and anxiety (aPR 0.42; 95% CI 0.20-0.87; p = 0·002). Feeling unaccepted in Nepali society and believing people thought they were a criminal because of their trans identity was significantly associated greater prevalence of current sex work (aPR 1.36; 95% CI 1.03-1.78; p = 0·03; aPR 1.45; 95% CI 1.03-2.07; p = 0.04). Every measure of experienced stigma assessed was significantly associated with greater prevalence of current engagement in sex work.

Conclusions

Trans women are highly stigmatized in Nepal, leading to individual and systems factors that impact their risk for HIV. Interventions are needed that support the economic and mental wellbeing of trans women to prevent their heighted risk of HIV from stigma.

Depression is a common illness in people with HIV (PWH) and is associated with substantial morbidity and mortality. The mechanisms that underpin depression in PWH remain incompletely elucidated, and more research is therefore needed to develop effective treatments. One hypothesis is that neurotransmitter levels may be altered. These levels could be influenced by the chronic inflammation and viral persistence that occurs in PWH. We examined a panel of cerebrospinal fluid (CSF) neurotransmitters in PWH on suppressive antiretroviral therapy (ART), many of whom had a current depression diagnosis. CSF monoamine neurotransmitters and their metabolites were measured from participants in studies at the Emory Center for AIDS Research (CFAR). Only participants on stable ART with suppressed HIV RNA from both plasma and CSF were analyzed. Neurotransmitter levels were measured with high-performance liquid chromatography (HPLC). Neurotransmitters and their metabolites included dopamine (DA), homovanillic acid (HVA, a major metabolite of dopamine), serotonin (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA, a major metabolite of serotonin), and 4-hydroxy-3-methoxyphenylglycol (MHPG, a major metabolite of norepinephrine). Multivariable logistic regression was used to evaluate factors associated with depression. There were 79 PWH with plasma and CSF HIV RNA levels < 200 copies/mL at the time of the visit, and 25 (31.6%) carried a current diagnosis of depression. Participants with depression were significantly older (median age 53 years versus 47 years, P = 0.014) and were significantly less likely to be African American (48.0% versus 77.8%, P = 0.008). Participants with depression had significantly lower dopamine levels (median 0.49 ng/mL versus 0.62 ng/mL, P = 0.03) and significantly lower 5-HIAA levels (median 12.57 ng/mL versus 15.41 ng/mL, P = 0.015). Dopamine and 5-HIAA were highly correlated. In the multivariable logistic regression models, lower 5-HIAA was significantly associated with the depression diagnosis when accounting for other significant demographic factors. The associations between lower 5-HIAA, lower dopamine, and depression in PWH suggest that altered neurotransmission may contribute to these comorbid conditions. However, the effects of antidepressants on neurotransmitters cannot be ruled out as a factor in the 5-HIAA results.