Focus on Smoking Cessation During COVID-19: Review of Varenicline Pharmacogenomics

Background

The Centers for Disease Control and Prevention (CDC) states that patients with current or former smoking status may be at an increased risk of severe illness due to COVID-19. The CDC recommends that former smokers continue abstinence and encourages current smokers to quit, adding that counseling from a health care provider plus FDA-approved medications can double the chances of a successful quit attempt.¹

When recommending pharmacologic interventions for smoking cessation, varenicline, and combination nicotine replacement therapy (NRT) are first-line options. NRT offers the advantage of numerous dosage forms, several of which are available OTC, whereas varenicline offers the advantage of a flexible quit date.²

Literature exists regarding the pharmacogenetic (drug response in relation to variations across the genome) optimization of smoking cessation therapy.^3,4 Recall the nucleotides that make up DNA are adenosine (A), thymine (T), cytosine (C), and guanine (G). DNA molecules are made up of 2 strands held together by bonds between these nucleotides—adenosine can bond thymine and cytosine can bond guanine; DNA encodes genes, instructions for cells to make proteins.

There are several genes involved in tobacco use disorder, such as the cholinergic receptor nicotinic alpha 4 subunit (CHRNA4) and cholinergic receptor nicotinic alpha 5 subunit (CHRNA5), among others. Genetic variations—differences in the genetic code among individuals—can affect drug response.

The literature describes several variants related to tobacco use disorder, as well as single nucleotide polymorphisms (SNPs), genetic variants of 1 letter change in the DNA sequence. Versions of the same gene that have different DNA spelling changes are referred to as alleles, the effect of which on tobacco use disorder has been described.⁴

Overview of the Literature

In 2012, David et al. published a double-blind, placebo-controlled trial to compare smoking cessation efficacy in subjects randomized to bupropion and varenicline. The study examined whether genes important in the pharmacodynamics and pharmacokinetics of the drugs and nicotine could predict medication efficacy and adverse event profile.

Results revealed that for varenicline, continuous abstinence at weeks 9 to 12 was associated with multiple genes such CHRNB2, CHRNA5, and CHRNA4. The SNP most significantly associated with continuous abstinence from weeks 9 to 12 in the varenicline-treated group was rs7164594 on the LOC123688 (hydroxylysine kinase) gene (OR: 1.76, 95% CI: 1.23 — 2.52; p = 0.0019).⁵

In 2015, Rocha Santos et al. published a cohort study that included 483 smokers who received behavioral counseling and drug treatment with varenicline, bupropion, and/or NRT. The study aimed to determine whether the CHRNA4 (rs1044396 and rs2236196) or CHRNB2 (rs2072660 and rs2072661) polymorphisms were associated with smoking cessation response, defined as patients who completed 6 months of continuous abstinence. Results found that the CT or TT genotypes of the CHRNA4 rs1044396 variant were associated with higher success (OR = 1.67, 95% CI = 1.10—2.53; p = 0.02).⁶

In 2015, Tyndale et al. studied 654 smokers treated with placebo, nicotine patch, or varenicline to determine whether CHRNA5-A3-B4 variants were associated with smoking cessation outcomes. The primary endpoint was biochemically verified 7-day self-reported abstinence at the end of 11 weeks of treatment. Results revealed no statistically significant differences between CHRNA5-A3-B4 variants and smoking cessation.⁷

In 2017, Pintarelli et al. studied 337 smokers who received varenicline, bupropion, NRT, or NRT plus bupropion. Smoking habits and abstinence were assessed from the number of cigarettes smoked per day and the exhaled carbon monoxide at baseline and up to 12 months.

At baseline, both endpoints were associated with polymorphisms in CHRNA5 (rs503464, rs55853698, rs55781567 and rs16969968; P&thinsp;<&thinsp;0.01). Additionally, rs503464, was also associated with short-, mid- and long-term responses to therapy (P&thinsp;=&thinsp;0.011, P&thinsp;=&thinsp;0.0043, P&thinsp;=&thinsp;0.020, respectively).⁸

In 2018, Tomaz et al. studied a cohort who received NRT, bupropion, varenicline, or NRT plus bupropion. The study evaluated whether CHRNA2, CHRNA3, CHRNA5, and CHRNB3 polymorphisms were associated with severity of nicotine dependence. Smoking cessation success was defined as continuous abstinence for 6 months. Females with the GA or AA genotypes for CHRNA5 of rs16969968 and rs2036527 were associated with higher odds ratio for success (OR: 1.63, 95% CI: 1.04-2.54; P = 0.03 and OR: 1.59, 95% CI: 1.02 -2.48; P = 0.04; respectively).⁹

Summary

The variant rs7164594 on the LOC123688 gene is associated with continuous abstinence from weeks 9 to 12 in varenicline-treated smokers.⁵ Patients with the CT and TT genotype may be more likely to quit smoking by weeks 9 to 12 of treatment with varenicline compared with the CC genotype.⁴

The CT or TT genotypes of the CHRNA4 rs1044396 variant are associated with higher success compared with the CC genotype.⁶ Although Tyndale et al. revealed no statistically significant differences between CHRNA5-A3-B4 variants with smoking cessation, Pintarelli et al. concluded a polymorphism in CHRNA5 (rs503464) was associated with response to pharmacologic therapy for smoking cessation. Patients with the AA and AT genotypes may have increased response to smoking cessation therapies.^4,8

Lastly, females with the GA or AA genotypes for rs16969968 and rs2036527 on CHRNA5 were associated with higher odds of smoking cessation success compared to the GG phenotype.^4,9

Discussion

Although pharmacogenomics associated with smoking cessation and varenicline response have been described, guidelines state that therapy decisions should be governed by clinical judgment and influenced by patient preferences.² Additionally, a cost-effectiveness analysis of pharmacogenetic testing to tailor smoking cessation therapy suggested that an untailored approach when treating with varenicline is cost-effective.¹⁰

A 2012 meta-analysis on the effectiveness of testing for genetic susceptibility to smoking-related diseases on smoking cessation revealed positive short-term effects on risk perception, motivation to quit, and smoking cessation; however, these effects faded at longer follow-ups. The authors concluded there is not enough evidence to support the proposed beneficial effects on smoking cessation.¹¹

In the setting of the COVID-19 pandemic, the increased risk of severe illness in smokers, irrespective of a genomics, has been described and the risk also exists in former smokers.¹ Nevertheless, as the field of pharmacogenomics evolves, the considerations for varenicline efficacy could be applied to patients who have undergone genetic testing for these genes.⁴

References

• Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19). URL: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html#smoking (accessed 20 Sept. 2020).
• Barua RS, Rigotti NA, Benowitz NL, et al. 2018 ACC expert consensus decision pathway on tobacco cessation treatment. J Am Coll Cardiol, 2018; 72(25):3332-65.
• Chenoweth MJ, Tyndale RF. Pharmacogenetic optimization of smoking cessation treatment. Trends Pharmacol Sci, 2017; 38(1):55-66.
• PharmGKB. URL: https://www.pharmgkb.org/ (accessed 20 Sept. 2020).
• King DP, Paciga S, Pickering E, et al. Smoking cessation pharmacogenetics: analysis of varenicline and bupropion in placebo-controlled clinical trials. Neuropsychopharmacology, 2012; 37(3):641-650.
• Rocha Santos J, Tomaz PR, Issa JS, et al. CHRNA4 rs1044396 is associated with smoking cessation in varenicline therapy. Front Genet, 2015; 6:46.
• Tyndale RF, Zhu AZ, George TP, et al. Lack of Associations of CHRNA5-A3-B4 Genetic Variants with Smoking Cessation Treatment Outcomes in Caucasian Smokers despite Associations with Baseline Smoking. PLoS One, 2015; 10(5):e0128109.
• Pintarelli, G., Galvan, A., Pozzi, P. et al. Pharmacogenetic study of seven polymorphisms in three nicotinic acetylcholine receptor subunits in smoking-cessation therapies. Sci Rep, 2017; 7:16730.
• Tomaz PRX, Santos JR, Scholz J, et al. Cholinergic receptor nicotinic alpha 5 subunit polymorphisms are associated with smoking cessation success in women. BMC Med Genet, 2018; 19(1):55.
• Heitjan DF, Asch DA, Ray R, et al. Cost-effectiveness of pharmacogenetic testing to tailor smoking-cessation treatment. Pharmacogenomics J, 2008; 8(6):391-399.
• Smerecnik C, Grispen JEJ, Quaak M. Effectiveness of testing for genetic susceptibility to smoking-related diseases on smoking cessation outcomes: a systematic review and meta-analysis. Tobacco Control, 2012;21:347-354.