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. Author manuscript; available in PMC: 2021 Mar 1.
Published in final edited form as: Addict Behav. 2019 Oct 22;102:106151. doi: 10.1016/j.addbeh.2019.106151

Correlates of Varenicline Adherence among Smokers with HIV and its Association with Smoking Cessation

Mackenzie Hosie Quinn a, Anna-Marika Bauer a, Alex Flitter a, Su Fen Lubitz a, Rebecca L Ashare a, Morgan Thompson a, Frank Leone b, Robert Gross c,d, Robert Schnoll a,1
PMCID: PMC6934914  NIHMSID: NIHMS1545139  PMID: 31783245

Abstract

Introduction:

With medical advances, the life expectancy of people living with HIV/AIDS (PLWHA) has improved; however, tobacco use remains a prominent risk for mortality. Although studies have examined the efficacy of varenicline for treating smoking among PLWHA, the relationship between varenicline adherence and cessation and correlates of varenicline adherence remain under-studied.

Methods:

We conducted secondary analyses from a randomized placebo-controlled trial of varenicline for smoking among PLWHA, using data from participants who received varenicline (N=89). The relationship between varenicline adherence (based on pill count) and end-of-treatment smoking cessation was assessed, as were correlates of varenicline adherence.

Results:

Those who were abstinent took an average of 137.1 pills (SD=39.3), or 83% of pills prescribed, vs. 105.3 pills (SD=64.1), or 64%, for those who were smoking (OR=1.01, 95% CI: 1.001–1.021, p=0.03); 52/89 (58%) participants were adherent based on taking ≥ 80% of pills. The quit rate for adherent participants was 35% (18/52) vs. 19% (7/37) for non-adherent participants. Adherent participants were older, smoked fewer cigarettes each day, started smoking at an older age, and had lower baseline creatinine vs. non-adherent participants (p<0.05). There was a significant time-by-group interaction effect for anxiety (F[1,72]=6.24, p=0.02), depression (F[1,72]=4.2, p=0.04), and insomnia (F[1,72]=7.73, p=0.007), indicating that adherent participants had less depression, anxiety, and insomnia during the initial weeks of treatment, vs. non-adherent participants.

Conclusions:

Our findings underscore the importance of varenicline adherence for determining cessation and highlight the role of early changes in anxiety, depression, and insomnia determining varenicline adherence.

Keywords: Adherence, smoking cessation, varenicline, HIV, depression, anxiety

1. Introduction

The life expectancy for people living with HIV/AIDS (PLWHA) has greatly improved over the past decade with advances in the effectiveness of antiretroviral therapies (ART) [1]. At the same time, the importance of addressing modifiable risk factors for HIV mortality such as tobacco use, has also steadily grown [2,3]. Now, more life-years are lost among PLWHA to tobacco smoking than to the virus itself [4], and tobacco cessation among PLWHA represents one of the most significant ways to substantially improve life-expectancy in this population [5]. Regrettably, upwards of 40% of the population with HIV/AIDS are smokers [6], which greatly exceeds the prevalence of smoking in the general population [7,8].

Varenicline is an effective treatment for tobacco dependence [9] among smokers with and without medical and psychiatric comorbidities [10,11]. Two recent placebo-controlled trials – one in France [12] and one by our group [13] – found that varenicline is safe and effective for treating tobacco use among PLWHA, but yields quit rates that are substantially lower than those reported in the general population [14]. Varenicline adherence – defined as self-reported use of ≥80% of prescribed pills – rarely exceeds 64% in any sample [15] and non-adherence significantly reduces the likelihood of cessation [16]. Few studies, however, have examined predictors of adherence in any smoking populations to develop interventions to increase varenicline adherence [17]. The limited literature indicates that lower varenicline adherence is associated with female gender [18], younger age [15,19], less education [15], non-white race [15,19], higher nicotine dependence [20], and greater side-effects [21]. However, little is known about other variables such as depression, anxiety, nicotine craving or withdrawal, or common varenicline-related side effects as correlates of varenicline adherence. Thus, to help guide interventions to address varenicline adherence, this study examined the relationship between varenicline adherence and cessation among smokers with HIV and examined correlates of varenicline adherence, including demographic variables, factors associated with HIV, depression and anxiety, varenicline side effects, and smoking-related characteristics.

2. Methods

We used data from a completed clinical trial () that compared placebo to varenicline for tobacco use among PLWHA for the present analyses. The methods and results of this trial, which was approved by the University of Pennsylvania IRB and was conducted between October 2012 and June 2018, have been reported elsewhere [13].

2.1. Participants

We recruited participants through Penn medical clinics, media advertisements, and through a community-based HIV clinic. To be eligible, participants had to be ≥ age 18, had to have a confirmed HIV diagnosis and were receiving treatment with ART, and had to have HIV viral loads <1000 copies/ml. Participants were excluded for a lifetime history of psychosis or a suicide attempt, self-reported current or planned pregnancy, self-reported current use of smoking cessation medications, and indications of unstable or untreated alcohol/substance abuse. Of the 179 participants who were eligible and randomized to the trial, this secondary analysis included only participants in the varenicline arm (N = 89).

2.2. Procedures

Participants provided written informed consent. Varenicline was provided for 12 weeks based on U.S. Food and Drug Administration dosing guidelines: Day 1-Day 3 (0.5 mg once daily); Day 4–7 (0.5 mg twice daily); and Day 8-Day 84 (1.0 mg twice daily). All participants were offered six standardized, Public Health Service guideline-based smoking cessation counseling sessions at Weeks 0, 1, 3, 5, 7, and 9, in-person or by telephone [22–24], which included a target quit day at week 1.

2.3. Measures

Prior to treatment, we assessed demographic (e.g., age, race, education, income), HIV-related (e.g., mode of transmission, viral load, creatinine) and smoking-related (e.g., current smoking rate, level of nicotine dependence, including heaviness of smoking index and time-to-first-cigarette) characteristics. HIV information was ascertained from the medical record and included creatinine to assess functional status, and type of ART, since we found that efavarinz was associated with nicotine metabolism [13].

At baseline and week 3, the Hospital Anxiety and Depression Scale (HADS) [25] was used to assess current depression and anxiety, the brief Questionnaire of Smoking Urges (QSU-B) [26] measured an individual’s urge to smoke, the Shiffman-Jarvik Withdrawal Form (SJWF) [27] measured withdrawal symptoms, and an established checklist tracked varenicline-related side effects (e.g., nausea, sleep problems, depressive symptoms, hostility) [11,22], which were rated from 0 (none) to 3 (severe) and summed to create a side-effects index total score and averaged to provide a mean side effect severity measure. Nausea and insomnia, which are common to varenicline, were assessed individually as well.

Varenicline adherence was assessed at Weeks 0, 1, 3, 5, 7, 9, and 12 using the timeline follow-back method [28] and blister-pack collection as done previously [22,29]. We assessed the total number of pills taken out of the total pills prescribed and computed an overall proportion of medication adherence (adherence defined by taking ≥80% of prescribed medication) [17] If a discrepancy regarding the number of pills taken arose between blister-packs and what was reported during timeline follow-back, the amount in the blister-pack was recorded and used.

Smoking behavior was assessed using the timeline follow-back procedure as done previously [22,24] and cessation was determined using 7-day point-prevalence abstinence at Week 12 based on no self-reported tobacco use (not even a puff) during the 7 days preceding the assessment and exhaled carbon monoxide (CO) ≤8ppm [30,31].

2.4. Analyses

We assessed the relationship between adherence and week 12 abstinence using logistic regression. We used ANOVA (for continuous measures) and chi-square tests (for categorical measures) to evaluate differences in demographic, disease, and smoking-related factors between adherent and non-adherent participants, which identified covariates for subsequent analyses. We used mixed ANOVA, with time (week 0 to week 3) as the repeated measure variable and adherent vs. non-adherent as the between group measure, to evaluate changes between week 0 and week 3 in anxiety, depression, craving, withdrawal, and side effects as correlates of varenicline adherence, controlling for covariates. We chose this timeframe since it takes 2–3 weeks for steady state varenicline to be reached and this is when most relapse to smoking will occur if it does, making this the timeframe that is most likely to be sensitive to change and effects on adherence. Lastly, to examine the unique contributions to predicting adherence, variables associated with adherence were included in a logistic regression model predicting varenicline adherence. For missing data, the participant was not included in the specific analysis.

3. Results

3.1. Sample Characteristics

Table 1 shows the characteristics of the participants, overall and separately for those who were adherent (58%) vs. non-adherent (42%). Of note, 72% of the sample was male, 79% were Black, smoked 13.5 cigarettes per day, and 84% of the sample had undetectable viral loads. As shown in Table 1, adherent participants were significantly older, smoked fewer cigarettes each day, started smoking at an older age, and had lower baseline creatinine compared to non-adherent participants (p’s < 0.05). These variables were included as covariates in all subsequent analyses.

Table 1.

Baseline demographic, smoking-related, and disease-related characteristics for the sample by adherence

Non-Adherent (N=37) Adherent (N=52) Total (N=89)
Variable N (%) or M (SD) N (%) or M (SD) N (%) or M (SD)
Demographic variables
Race (% African American) 29 (80.6) 40 (78.4) 69 (79.3)
Sex (% Male) 26 (70.3) 38 (73.1) 64 (71.9)
Education (% High School Grad or less) 19 (51.4) 27 (51.9) 46 (51.7)
Annual Household Income (<20K) 19 (51.4) 36 (69.2) 55 (61.8)
Age (Range: 21–70 years) 45.4 (9.5) 51.0 (9.9) 48.7 (10.1)a
BMI (Range: 18.8–58.2) 28.3 (7.1) 27.0 (7.2) 27.5 (7.2)
# Alcohol Drinks in Past 7 Days (Range: 0–21) 1.2 (2.4) 3.1 (6.1) 2.3 (5.0)
 
Smoking-related variables
% High HSI 11 (29.7) 11 (21.2) 22 (24.7)
% TTFC within 5 minutes 15 (40.5) 22 (42.3) 37 (41.6)
Cigarettes/Day in Past 24 hours (Range: 1–40) 13.0 (7.9) 9.9 (5.2) 11.2 (6.6)a
Breath CO, ppm (Range: 1–60) 15.7 (10.3) 14.5 (10.5) 15.0 (10.4)
Number of Years Smoking (Range: 6–56) 30.7 (8.5) 32.5 (12.1) 31.8 (10.8)
# Times Quit Smoking for >24 Hours (Range: 0–500) 3.6 (3.8) 12.5 (69.1) 8.8 (52.9)
Age Started Smoking (Range: 9–40) 14.8 (3.3) 17.5 (6.1) 16.4 (5.3)a
 
Disease-related characteristics
% of ART Prescribed in Past 2 Weeks Taken (Range: 79–100) 99 (0.03) 99 (0.04) 99 (0.03)
% Undetectable Viral Load (<50 copies/ml) 29 (78.4) 46 (89.5) 75 (84.3)
CD4+ cells/mm3 (Range: 218–1932) 714.2 (262.2) 753.5 (371.7) 737.2 (329.5)
% Acquired HIV via Sex 30 (81.1) 43 (82.7) 73 (82)
% ART regimen containing efavirenz 6 (16.2) 8 (15.7) 14 (15.9)
Estimated creatinine clearance (mL/min) 107.7 (39.2) 103.5 (38.9) 105.6 (39.0)a
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Note. BMI=Body Mass Index; CO=Carbon Monoxide; HSI=Heaviness of Smoking Index; TTFC=Time to First Cigarette.

a

difference, p<.05

3.2. Association of Varenicline Adherence with Smoking Cessation

Participants were prescribed 165 pills and those who had quit smoking took an average of 137.1 pills (SD = 39.3), or 83% of pills prescribed, compared to 105.3 pills (SD = 64.1), or 64%, for those who had not quit smoking (OR = 1.01, 95% CI: 1.001–1.021, p = 0.03). At Week 12, 28.1% of participants had quit smoking. The quit rate for adherent participants was 35%, compared to 19% for non-adherent participants.

3.3. Correlates of Varenicline Adherence

Changes in craving, withdrawal, and total and mean side effects from week 0 to week 3 were not significantly different between adherent and non-adherent participants (all p’s > 0.05). In contrast, we found a significant time-by-group interaction effect for anxiety (F[1,72] = 6.24, p = 0.02) and depressive (F[1,72] = 4.2, p = 0.044) symptoms. Likewise, we found a significant time-by-group interaction effect for insomnia (F[1,72] = 7.73, p = 0.007). As shown in Figure 1, compared to non-adherent participants, adherent participants showed a decrease in symptoms of anxiety, depression, and insomnia from week 0 to week 3. Lastly, when covariates and anxiety and depression symptoms, and insomnia (all variables associated in univariate analysis with adherence) were entered into a logistic regression model, baseline creatinine (OR = 0.97, 95% CI: 0.96–0.99, p = 0.006), changes in anxiety symptoms (OR = 1.36, 95% CI: 1.09–1.69, p = 0.007), and changes in insomnia (OR = 3.28, 95% CI: 1.04–10.33, p = 0.042) remained significant. Analyses were re-run controlling for smoking status at week 3 and the results were unchanged. Also, analyses were rerun for the placebo arm, where adherence was 76%, but the rate of adherence in the placebo arm was not associated with smoking cessation or the correlates assessed here.

Figure 1.

Figure 1.

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Changes in Anxiety and Depression Symptoms and Insomnia between Adherent and Non-Adherent Participants

4. Discussion

The objective of this study was to describe the relationship between varenicline adherence and varenicline efficacy and, in turn, to examine correlates of varenicline adherence among PLWHA. Few studies have assessed the role of factors beyond demographic characteristics and side effects as correlates of varenicline adherence [9,10] and, thus, the literature on targets of adherence interventions is relatively under-developed. The results from the present analyses underscore the importance of varenicline adherence in determining cessation outcomes. While we cannot disentangle medication effects on mood and insomnia from mood and insomnia effects on adherence, the results also highlight that anxiety, depression, and insomnia may be potential targets of interventions to boost adherence among PLWHA trying to quit smoking with varenicline.

First, 42% of the sample reported suboptimal varenicline adherence, which converges with previous studies with smokers in the general population [32] and with smokers with HIV [19]. Further, the sizable impact of adherence on cessation is similar to past studies with the general population of smokers and with smokers with HIV [19,32]. Thus, suboptimal adherence is a major barrier to quitting smoking with varenicline, which necessitates the development of interventions to address.

Second, older age, smoking fewer cigarettes per day, becoming a regular smoker later in life, and lower baseline creatinine were associated with greater adherence. These findings are consistent with those of past studies that examined correlates of tobacco treatment adherence among PLWHA [19,33–35]. and can be useful in targeting interventions to increase adherence to sub-groups most in need of formal support. Non-consistent results may be from comparing a sample of smokers with HIV to past findings with non-HIV samples.

Lastly, we identified three factors that were prospectively associated with varenicline adherence in the sample: a reduction in depression, anxiety, and insomnia. These reactions may be a consequence of changes in smoking behavior or may be side effects of greater varenicline use. These results suggest that managing these reactions to cessation or the medication may serve as useful intervention targets to promote greater varenicline adherence in this population. Since depression occurs twice as frequently in smokers and three times as frequently in PLWHA [36,37], methods to address depression within an adherence intervention may be particularly important. Likewise, anxiety is a common, yet less studied, reaction to quitting smoking that can trigger a relapse to smoking and insomnia is a common side effect of varenicline [38,39]. Our results indicate that anxiety, depression, and insomnia may also be important for driving varenicline adherence and should be targeted by an adherence intervention.

4.1. Limitations

These results should be considered in the context of study limitations. First, the sub-sample of those in the varenicline treatment arm was relatively small and may have resulted in analyses that were under-powered. Yet, we still found a strong effect of adherence. Second, the inclusion and exclusion criteria used to control for potential confounding variables may limit the generalizability of the results. Indeed, the sample may not be representative of the population of PWLHA who are regular smokers and caution should be exercised when generalizing results to the overall population of smokers with HIV. It is important to recognize the limitation of using self-reported pill counts to measure adherence. Self-report data is not always accurate; however, the self-reported number of pills taken was checked against the blister packs. Another limitation is that we cannot determine causality from the results, meaning that it is plausible that these changes in anxiety, depression, and insomnia led to changes in adherence or were effects of changes in adherence. It is also unclear if changes in depression, anxiety, and insomnia are side effects of the medication or symptoms of withdrawal [13]. Prior research highlights how the measures used to assess withdrawal symptoms and side effects overlap, which hinders our ability to distinguish one from the other [13]. It is also possible that a third factor may be influencing adherence and these side effects, like smoking cessation success, rather than these side effects affecting adherence to varenicline. This is consistent with recent studies, which found improvement in psychological well-being following smoking cessation [40–43].

4.2. Conclusions

This is one of the first studies to prospectively evaluate early changes in common experiences following cessation using varenicline that may influence adherence to varenicline. The results can offer information useful for targeting adherence interventions to those at-risk and for developing the content of such interventions. Unfortunately, there have been very few studies that have designed and tested formal interventions to address tobacco use medication adherence among PLWHA. The results from this study can help move that field forward so that in the coming years we have a better understanding of effective methods to increase varenicline adherence so that we can capitalize on its effectiveness and improve the lives of PLWHA.

Highlights.

  • Quit rate for adherent participants was 35%

  • Adherent participants had less depression, anxiety, and insomnia

  • Adherent participants were older and had lower baseline creatinine

Acknowledgments

Role of Funding

This work was supported by National Institutes of Health grants K24 DA045244 and R01 DA033681 and support from the Penn Center for AIDS Research (P30 AI 045008) and the Penn Mental Health AIDS Research Center (P30 MH 097488).

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Conflicts of Interest

Dr. Schnoll receives medication and placebo free from Pfizer and has provided consultation to Pfizer. Dr. Schnoll has provided consultation to GlaxoSmithKline and CuraLeaf. Dr. Gross serves on a Data and Safety Monitoring Board for a Pfizer drug unrelated to HIV or smoking.

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