Abstract
Introduction
Smoking cessation rates in people with HIV (PWH) are lower than in the general population, even when evidence-based treatments are used. This 16-week study examined the feasibility, acceptability, and preliminary efficacy of preloading with nicotine replacement therapy (NRT) in PWH to improve cessation outcomes.
Methods
Forty-nine participants were randomized to nicotine patch preloading (NRT-P) for 3 weeks prior to the target quit date (TQD) or standard treatment with no preloading (ST). All participants received combination NRT for 8 weeks at TQD, with five sessions of behavioral counseling. At week 16, biochemically verified 7-day point-prevalence abstinence was assessed.
Results
Mean preloading patch days was 19.7 (out of 21 days; SD 2.7), indicating excellent acceptability. Mean patch days post-TQD (out of 56 days) was 47.4 (SD = 13.2) in NRT-P and 32.7 (SD = 21.8) in ST (t = −2.48, p = .01). At week 16 there was no group difference in week 16 point-prevalence abstinence, but NRT-P participants smoked significantly fewer cigarettes per week (10.1 [SD 14.7] vs. 47.2 [SD 67.6]) and had lower carbon monoxide levels (5.22 [SD 3.6] vs. 10.89 [SD 11.3], p = .04) compared to ST participants. Cessation self-efficacy increased significantly over time in the NRT-P condition only.
Conclusions
NRT preloading is feasible and acceptable among PWH, with excellent adherence to preloading, and benefits observed relative to ST following TQD in patch adherence, self-efficacy, cigarettes smoked per day, and carbon monoxide levels. The lack of effect of preloading on smoking abstinence suggests further study is needed.
Implications
Preloading with nicotine patch among PWH who smoke prior to the TQD may be an effective means of improving adherence to smoking cessation medications both pre- and post-quit. By increasing self-efficacy for quitting and lowering cigarette dependence, preloading may improve cessation rates and help reduce the burden of tobacco-related disease among PWH. Further research is needed.
Introduction
Smoking prevalence among people with HIV (PWH) (47%)1 is much higher than in the general population, and the incidence rate of smoking-related cancers among people with HIV who smoke (PWH-S) is over five times greater than in general population of people who smoke.2 It has been estimated that PWH now lose more years due to smoking than to HIV infection itself.3 Despite the recognized health risks, PWH-S face challenges in quitting, and prior smoking cessation trials have shown that PWH have low quit rates.4 Low cessation self-efficacy and poor adherence to therapy in PWH contribute to a lack of sustained abstinence.5 It has been suggested that interventions for PWH-S should focus on improving adherence to pharmacotherapy and enhancing self-efficacy for quitting.6
Nicotine replacement therapy (NRT) preloading, or using nicotine patch, lozenge, or gum before a quit date, aims to reduce the reinforcing effects of nicotine from cigarettes by providing people who smoke with a trial period of use prior to quit day. Preloading has been shown to increase cessation self-efficacy, reduce enjoyment, increase aversion, reduce urges to smoke, and improve NRT adherence post-quit.7 Studies have shown that NRT preloading increases the odds of abstinence by 28% at 4 and 12 weeks.8 Recently, the FDA encouraged further exploration of preloading to improve cessation rates in priority populations.9
This study aimed to explore the feasibility and acceptability of nicotine patch preloading (NRT-P) for 3 weeks prior to a target quit date (TQD) in PWH-S. The study also aimed to compare the initial efficacy of NRT-P against a standard treatment with no preloading (ST) by comparing 7-day point-prevalence abstinence (PPA) at 16 weeks. We also examined the effects of preloading on underlying mechanisms associated with smoking abstinence: cessation self-efficacy, cigarette dependence, and urge to smoke.
Materials and Methods
This randomized clinical trial assessed outcomes at 8, 12, and 16 weeks following baseline. The study was approved by the Brown University and Lifespan Institutional Review Boards and registered with Clinicaltrials.gov (NCT04994444).
Participants were recruited from the Miriam Hospital Immunology Center and the Providence vicinity. Eligible participants were PWH, aged 18 or older, smoking at least five cigarettes per day (CPD), with an exhaled carbon monoxide (CO) level greater than 5 ppm at baseline (using a Smokerlyzer ED50 CO meter [Bedfont Scientific, Haddonfield, NJ]), willing to use NRT, and ready to quit within 30 days (score of 7 or greater on the Contemplation Ladder).10 Exclusion criteria included current use of smoking cessation pharmacotherapy, unstable medical or psychiatric conditions, past-month suicidal ideation or past-year suicide attempt, or pregnancy. Of 134 individuals screened, 91 were eligible (see Figure 1). Baseline assessment was completed by 51 participants; 2 were ineligible and 49 were randomized into one of two groups (ie, NRT-P or ST) in a 1:1 ratio using urn randomization11 to balance on sex at birth and Fagerström Test for Cigarette Dependence (FTCD) score (0–5 vs. 6–10).12
Figure 1.
Consort diagram.
Procedures
Participants were enrolled from September 2022 through December 2023. After phone screening, participants completed a baseline in-person visit where they provided informed consent and completed baseline assessments via Qualtrics.
At their initial counseling appointment, 1 week after the baseline appointment, participants were informed of their study condition. Participants in the NRT-P group were provided information about preloading, and nicotine patch was applied during this counseling session. NRT-P participants were encouraged to smoke ad libitum during the 3-week preloading period. Both groups received five counseling sessions (two sessions pre-TQD, one session on the TQD, and two sessions post-TQD) delivered by the study nurse, based on standard smoking cessation guidelines,13 including instructions for using NRT (patch, lozenge, and gum). The initial counseling session about (~30 minutes) was held in-person, with the remaining sessions conducted by phone. Follow-up assessments were completed in-person at 8, 12, and 16 weeks by staff who were blinded to study assignment. Breath samples for CO were obtained at each study visit. Compensation up to US $210 was provided for completed sessions and was not contingent upon smoking status. Participants in both study conditions received 8 weeks of combination NRT (patch/lozenge or patch/gum) starting on the TQD (week 4), with dosing based on standard prescribing guidelines. Participants were encouraged to use lozenge or gum every 1–2 hours, with a goal of using at least five daily.
Measures
Demographic characteristics were collected via self-report at baseline. A Tobacco Use Questionnaire assessed all forms of tobacco use, use of electronic cigarettes, and cannabis. The CES-D, a 20-item scale that assesses depressive symptoms during the past week with a range of 0–60, was administered.14 Vital signs were obtained; participants with elevated blood pressure (>160/100) were excluded and referred for evaluation. Adults of childbearing potential completed a urine pregnancy test. Most recent CD4 T-cell value and HIV viral load were obtained from the medical record.
Feasibility and acceptability of preloading were assessed using timeline followback (TLFB)15 by calculating the number of days during the 21-day preloading period in which NRT-P participants used the nicotine patch. Adherence to nicotine patch post-TQD was also assessed using the TLFB method. We examined session attendance (continuous variable; range 1–5) and retention (dichotomous variable; completers/non-completers, based on completion of the 16-week follow-up). Treatment satisfaction was assessed with the Client Satisfaction Questionnaire (CSQ-8),16 an 8-item scale rated with 4-point response scales where 1 reflects quite dissatisfied and 4 reflects very satisfied (Cronbach’s alpha = .75). Efficacy was assessed by biochemically verified 7-day PPA at 16 weeks (CO <5 ppm = abstinent).17 CPD was assessed using the TLFB procedure at each follow-up session. Self-efficacy was measured using the Smoking Situations Questionnaire Confidence Inventory, a 13-item scale with response options 1 (not at all confident) to 5 (extremely confident; total score range 13–65).18 The FTCD12 was used to evaluate cigarette dependence, and urge to smoke was measured using the Questionnaire of Smoking Urges (QSU).19
Data Analysis Plan
Analyses examined baseline characteristics by condition, distribution properties of dependent and other variables, patterns of missing data by condition and correlations among outcome measures. Chi-square analysis was used to examine retention. t tests were conducted to compare the number of days adherent to NRT post-TQD, study visits attended, treatment satisfaction, CPD, and CO by study condition. We tested the effect of treatment condition on 7-day PPA at 16-weeks using a Chi-square test. Effectiveness analyses followed an intention-to-treat principle, assuming missing data corresponded with smoking. Changes in self-efficacy, cigarette dependence, and urge to smoke were examined within each condition using paired samples t tests, while differences between conditions were examined using independent samples t tests at each timepoint; these analyses used available data with no imputation.
Results
Baseline Characteristics
These characteristics are shown in Table 1. No significant or clinically meaningful differences were observed between the NRT-P and ST groups at baseline.
Table 1.
Participant characteristics and smoking history
| Overall (N = 49) a | Preload (N = 23) a | Standard care (N = 26) a | |
|---|---|---|---|
| Age | 52.4 (12.6) | 53.0 (14.1) | 52.0 (11.5) |
| Sex at birth | |||
| Male | 32 (65.3) | 14 (60.9) | 18 (69.2) |
| Gender identity | |||
| Woman | 28 (57.1) | 12 (52.2) | 16 (61.5) |
| Man | 19 (38.8) | 10 (43.5) | 9 (34.6) |
| Non-binary | 1 (2.0) | 1 (4.3) | 0 (0.0) |
| Trans woman | 1 (2.0) | 0 (0.0) | 1 (3.8) |
| Race | |||
| White | 31 (66.0) | 15 (65.2) | 16 (66.7) |
| Black or African American | 10 (21.3) | 5 (21.7) | 5 (20.8) |
| Ethnicity | |||
| Hispanic | 12 (24.5) | 6 (26.1) | 6 (30.0) |
| Years of education | 12.6 (2.5) | 13.0 (2.6) | 12.2 (2.5) |
| Employment | |||
| Disabled | 19 (38.8) | 6 (26.1) | 13 (50.0) |
| Unemployed | 14 (28.6) | 8 (34.8) | 6 (23.1) |
| Retired | 7 (14.3) | 4 (17.4) | 2 (7.7) |
| Employed | 9 (18.4) | 4 (17.4) | 5 (19.2) |
| Income | |||
| Less than US $12 000 | 28 (57.1) | 13 (56.5) | 15 (57.7) |
| US $12 000–US $24 999 | 11 (22.4) | 5 (21.7) | 6 (23.1) |
| US $25 000–US $49 999 | 3 (6.1) | 1 (4.3) | 2 (7.7) |
| US $50 000–US $149 999 | 6 (12.2) | 4 (17.4) | 2 (7.7) |
| Marital status | |||
| Single | 32 (66.7) | 14 (60.9) | 18 (72.0) |
| Married | 11 (22.9) | 5 (21.7) | 6 (24.0) |
| Divorced | 2 (4.2) | 1 (4.3) | 1 (4.0) |
| Widowed | 2 (4.2) | 2 (8.7) | 0 (0.0) |
| Not reported | 1 (2.1) | 1 (4.3) | 0 (0.0) |
| Years living with HIV | 21.8 (10.7) | 21.2 (12.0) | 22.2 (9.6) |
| Depressive symptom severity (CES-D) | 16.6 (11.6) | 16.6 (11.3) | 16.6 (12.0) |
| Cigarettes per day | 14.9 (9.2) | 14.1 (8.6) | 15.5 (9.8) |
| Years smoking cigarettes | 31.0 (15.5) | 32.2 (16.5) | 30.0 (14.7) |
| Urge to smoke (QSU) | 33.4 (18.8) | 30.0 (15.0) | 36.4 (21.4) |
| Carbon monoxide (CO) | 15.2 (9.0) | 15.0 (9.0) | 15.3 (9.2) |
| Lifetime quit attempts | 4.5 (5.2) | 4.7 (5.3) | 4.3 (5.2) |
| Quit attempts in the last 12 months | 1.9 (2.3) | 2.3 (2.8) | 1.2 (1.2) |
| Cigarette dependence (FTCD) | 4.8 (2.3) | 4.7 (2.0) | 4.9 (2.6) |
Mean (SD) or N (%).
CES-D = Center for Epidemiologic Studies Depression; QSU = Questionnaire of Smoking Urges; FTCD = Fagerström Test for Cigarette Dependence.
Feasibility and Acceptability
The mean number of study assessment sessions completed (feasibility) was 4.23 (SD 1.27) in ST (of 5 possible) and 4.26 (SD 1.48) in NRT-P, t(47) = −.076, p > .94. Study retention (acceptability) was high with 39 (80%) participants completing the study; retention did not differ by study condition. Treatment satisfaction at week 16 did not differ by condition: NRT-P (M 30.2 [SD 2.4]) and ST (M 29.9 [SD 2.0], t(37) = −.432, p = .67; scale range: 8–32). Mean days of preloading patch use (out of 21 days) was 19.7 (SD 2.7; median 21.0); 70% reported 21 days of patch use. Days of patch use post-TQD (out of 56 days) were greater 47.4 (SD = 13.2) among NRT-P participants compared to ST participants (32.7 [SD = 21.8], t(32.8) = −2.48, p = .01). No study related adverse events related to NRT were noted during the preloading or combination NRT treatment (treatment) period.
Efficacy of NRT Preloading on Smoking Abstinence
At week 16, eight (15.4%) participants had CO-verified 7-day PPA (four in each group). While no significant differences were observed in abstinence rates between groups, at weeks 4, 8, 12, and 16, NRT-P participants reported significantly fewer CPD in the past week compared to the ST group (see Figure S1). Participants in NRT-P also had significantly lower CO levels at week 16 (NRT-P: 5.22 [SD 3.6]; ST: 10.89 [SD 11.3], t(22) = 2.08, p = .04, d = .68).
Mechanisms Underlying Smoking Abstinence
Self-efficacy for quitting significantly increased from baseline (M 39.8, SD 8.3) to week 16 (M 52.5, SD 9.9) in the NRT-P group (t(18) = 4.72, p < .001), but not in the ST group (M 43.6, SD 2.5 to M 44.5, SD 2.1; p = .75). When comparing self-efficacy by condition, self-efficacy was significantly higher at weeks 8, 12, and 16 among the NRT-P group compared to ST (Figure S2A). Urge to smoke decreased significantly in both the NRT-P and ST groups between baseline and week 16. However, comparing urge to smoke by condition over time, it differed significantly at week 4 (t(43) = 2.23, p = .03), week 8 (t(21.5) = 2.16, p = .04), week 12 (t(25.6) = 2.37, p = .02), and week 16 (t(37) = −2.03, p = .02) with the NRT-P group reporting significantly lower urges (Figure S2B). The NRT-P group reported significantly lower cigarette dependence at weeks 4 and 8 compared to ST, but no significant differences were noted at weeks 12 and 16 (Figure S2C).
Discussion
This pilot trial provides important insights into the feasibility, acceptability, and preliminary efficacy of NRT preloading for PWH-S. Adherence was excellent in the preloading period, and participants in NRT-P demonstrated better adherence to NRT post-TQD than ST participants, who did not have the 3-week pre-quit NRT experience. This result is promising as adherence to medication in PWH-S has been a significant barrier to smoking cessation in previously reported trials. Retention and satisfaction were high in both groups, with 80% of participants completing the study, which is notable as previous studies have reported high dropout rates in cessation trials among PWH-S.5
Biochemically verified abstinence did not differ between groups and the relatively low cessation rate (15%) was consistent with rates found in other studies focused on PWH-S,5 further demonstrating the significant challenge this population faces when attempting to quit smoking. However, participants in NRT-P had significantly lower CPD and smoke exposure (CO levels) post-quit than those in ST. Recent publications support that smoking reduction may be a meaningful endpoint, and evidence suggests such reductions increase the likelihood of eventual cessation9,20; thus, the observed effects on CPD and CO may prove clinically meaningful in the long term. Furthermore, compared to ST, NRT-P was associated with significantly reduced urge to smoke and increased self-efficacy, both of which are key mechanisms associated with successful cessation. Given this study was not powered to detect differences on an abstinence outcome, the fact that preloading was acceptable to PWH-S and influenced a number of key cessation process outcomes (eg, CPD, craving, cessation self-efficacy) suggests further research is warranted to test efficacy with adequate power.
This study had several strengths, including its novelty in testing NRT preloading for PWH-S, and its indication that preloading improves adherence, increases cessation self-efficacy, and reduces smoking. However, the small sample size and single-site recruitment limit the generalizability of these findings. Future research should include larger samples and explore the optimal duration of preloading.
In conclusion, NRT preloading appears to be an acceptable and promising approach for improving self-efficacy for quitting and reducing CPD and urges to smoke in PWH-S. Further research is needed to confirm these findings in larger, adequately powered studies and to explore the optimal duration and/or dosing of preloading to maximize its effectiveness for this population. A recent perspective by the U.S. Food and Drug Administration suggests that innovative smoking cessation therapies, utilizing existing smoking cessation medications such as NRT in novel ways such as preloading, deserve further consideration and testing.9 Our study is an initial step in this direction.
Supplementary Material
Acknowledgments
The study investigators would like to acknowledge Suzanne Sales, Jennifer Schmidlin, and Timothy Souza for their significant support with data management and analyses.
Contributor Information
Patricia A Cioe, Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University School of Public Health, Providence, RI.
Garrett S Stang, Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University School of Public Health, Providence, RI.
Danish Azam, Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University School of Public Health, Providence, RI.
Megan E Piper, Center for Tobacco Research and Intervention, Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI.
Christopher W Kahler, Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University School of Public Health, Providence, RI; Center for Tobacco Research and Intervention, Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI.
Author Contributions
Patricia A. Cioe (Conceptualization [lead], Data curation [lead], Formal analysis [lead], Funding acquisition [lead], Investigation [lead], Methodology [lead], Project administration [lead], Resources [lead], Writing—original draft [lead]), Garrett S. Stang (Data curation [supporting], Formal analysis [supporting], Writing—review & editing [supporting]), Danish Azam (Writing—review & editing [equal]), Megan E. Piper (Conceptualization [supporting], Methodology [supporting], Writing—review & editing [supporting]), and Christopher W. Kahler (Conceptualization [supporting], Funding acquisition [supporting], Methodology [supporting], Writing—review & editing [supporting])
Funding
The research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R21CA261233 (Cioe). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was facilitated by the Providence/Boston Center for AIDS Research (P30AI042853).
Declaration of Interests
The authors have no conflicts of interest to declare.
Data Availability
Data will be made available by written request to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data will be made available by written request to the corresponding author.