Cigarette use and HIV infection are established, independent risk factors for myocardial infarction (MI). The prevalence of cigarette use among people with HIV (PWH) is approximately two to three times that of the general population, and smoking doubles cardiovascular risk in this group. Variation in the rate of nicotine metabolism may contribute to higher tobacco exposure and dependence; faster metabolism is linked to greater cigarette use, lower cessation rates, and higher exposure to tobacco-related toxins.
Nicotine is primarily metabolized by CYP2A6 to cotinine and then to 3-hydroxycotinine (3-HC). The nicotine metabolite ratio (NMR)—the ratio of cotinine to 3-HC measured in plasma—reflects enzymatic activity of CYP2A6 and captures genetic and environmental influences on nicotine clearance. Because faster nicotine clearance can lead to higher intake of tobacco smoke constituents, the NMR is hypothesized as a potential biomarker for cardiovascular risk among PWH who smoke. The objective of this study was to determine whether NMR is associated with incident MI in PWH who report regular cigarette use.
The investigators conducted a matched nested case-control study within the CFAR Network of Integrated Clinical Systems (CNICS), a prospective clinical cohort initiated in 1995 that includes more than 49,000 PWH across multiple US CFAR sites. Seven CNICS sites contributed to these analyses: Case Western Reserve, Johns Hopkins, University of Alabama at Birmingham, UC San Diego, UC San Francisco, University of North Carolina at Chapel Hill, and University of Washington.
Participants were eligible if they self-reported regular cigarette use, defined as smoking at least two consecutive time points at least one year apart and consistent reporting at intervening assessments, and if an aviremic plasma sample was available for NMR testing. Cases included all PWH who met the smoking criteria and had an adjudicated incident MI with an available plasma sample at the time of smoking report. Controls were selected by incidence density sampling and matched to cases on site, age, race, birth sex, viral load status at the time of MI (aviremic vs not), and calendar time (within the same 365-day period). Individuals with unconfirmed MI or unvalidated cardiovascular-equivalent diagnoses were excluded.
Myocardial infarction ascertainment in CNICS was adjudicated according to the cohort’s established procedures. Plasma cotinine and 3-hydroxycotinine concentrations were measured using standard liquid chromatography–tandem mass spectrometry (LC-MS). A cotinine value > 10 ng/mL served to confirm recent cigarette use. The NMR was calculated from these measurements and, because of non-normal distribution, analyzed on the log scale for statistical modeling.
The primary analysis used conditional logistic regression to estimate odds ratios (ORs) for the association between NMR and incident MI, accounting for the matched design. The NMR was examined as a continuous variable (log-transformed) and analyses adjusted for clinical covariates where specified. The authors additionally adjusted models for statin use, hypertension, and diabetes to assess whether these cardiovascular risk factors influenced the association between NMR and MI.
The analytic sample comprised 135 MI cases and 252 matched smoking controls. Median (interquartile range) NMR was higher among MI cases [0.51 (0.36, 0.73)] than among controls [0.47 (0.30, 0.70)]. Other participant characteristics examined included demographic factors, CD4 count, and clinical comorbidities such as hypertension, diabetes, and statin medication use; the full tabulated characteristics were reported in the study’s tables.
In conditional logistic regression, a higher NMR was associated with greater odds of MI: the estimated OR comparing higher versus lower NMR was 1.4 (95% CI 0.97–1.9). This association did not reach conventional statistical significance. Additional adjustment for statin use, hypertension, and diabetes produced a similar point estimate (OR 1.4) with a 95% CI of 0.92–2.0, indicating no substantive change after accounting for these cardiovascular risk factors.
The study observed a small-magnitude positive association between faster nicotine metabolism (higher NMR) and adjudicated MI among PWH who smoke; however, this association was not statistically significant in the available sample. The findings are consistent with the biological plausibility that faster nicotine clearance leads to higher tobacco intake and greater exposure to cardiovascular toxins, which could elevate MI risk. Because NMR captures both genetic and environmental determinants of CYP2A6 activity and is reliably measured in plasma, it remains a candidate biomarker for cardiovascular risk stratification in PWH.
The authors underscore that the point estimates suggest a possible effect but that further investigation with larger samples or pooled data will be needed to estimate the precise magnitude and statistical significance of the association. If confirmed, NMR could inform targeted smoking cessation interventions or risk-reduction strategies among PWH.
Within this CNICS nested case-control study of PWH who smoke, higher NMR values were more common among those with MI, but the association did not reach statistical significance after matching and adjustment. The NMR remains a potential biomarker of MI risk in PWH, and the authors recommend additional research to refine effect estimates and to determine whether NMR-guided strategies could reduce cardiovascular events in this population.