A significant proportion (40.5%) of HIV-infected participants in this large, multinational clinical trial reported current smoking at enrollment; more than one third also reported smoking at 1-, 3-, and 5-year follow-up visits. Our results show that smoking contributed to substantial morbidity and mortality in this population. Current smokers had significantly higher rates of non-AIDS cancers, CVD, bacterial pneumonia, and all-cause mortality than did nonsmokers. These findings remained robust: significantly higher risk persisted after adjustment for multiple potential confounders, CD4+ count, and HIV RNA level. The association between current smoking and adverse clinical outcomes also persisted after we controlled for SMART treatment arm and in analyses restricted to the continuous HAART group.
Smoking in HIV-infected persons is of great concern for many reasons. Smoking prevalence is higher among persons with HIV than among the general population.12–18
Many diseases that occur more often among smokers than among nonsmokers are more common in HIV-infected persons, and smoking may even further increase risk among this population. For example, HIV-infected persons are at increased risk for lung cancer, independent of smoking status32–34
; however, smoking even further raises lung cancer risk. An analysis that considered both HIV infection and smoking as lung cancer risk factors found a multivariate HR of 1.8 for each additional pack of cigarettes smoked per day.33
Smoking may negate many positive benefits of HIV treatment, including HAART. Recent HIV treatment guidelines recommend earlier HAART initiation in part because data (from SMART and other studies) show that untreated HIV infection may be associated with development of certain non–AIDS-defining diseases, such as CVD and malignancy.35,36
In the SMART data, episodic HAART was also associated with higher rates of bacterial pneumonia.37
If smoking promotes development of these serious non-AIDS events, it may counteract many of the benefits of earlier HAART.
Although the AHR in our analysis for current versus never smokers was not statistically significant for the combined category of AIDS-related events, smoking may still increase the risk of specific AIDS-defining clinical diseases among HIV-infected persons, again weakening HIV treatment benefits. Studies of HIV-infected patients have identified smoking as a risk factor for AIDS-defining pulmonary infections, including Pneumocystis jirovecii
pneumonia and tuberculosis.38,39
We also identified a significant association between current smoking and esophageal candidiasis, consistent with reports of an association between smoking and oral candidiasis.40–42
Among the possible pathogenic mechanisms for this association are mucosal injury and epithelial alterations from smoke that facilitate candida colonization, factors in cigarette smoke that directly promote candida growth, and suppression of local or systemic immunologic defenses against candida.42
Smokers’ use of inhaled or systemic steroids for smoking-related diseases may further promote candidiasis.
The association of smoking and many adverse effects, supported by our findings, strongly suggests that smoking may further increase morbidity and mortality associated with HIV infection. One study of US veterans reported mortality rates per 100 person-years of 1.76 for HIV-negative never smokers, 2.35 for HIV-negative current smokers, 2.45 for HIV-positive never smokers, and 5.48 for HIV-positive current smokers.17
Our analysis had several strengths. Participants in SMART were enrolled from 33 countries and represented a variety of demographic populations and HIV risk groups.29
Our findings are therefore applicable to a diverse population of HIV-infected persons. All clinical endpoints in SMART were reviewed according to standardized criteria by an independent endpoint review committee blinded to treatment status. SMART collected data on, and our analysis adjusted for, multiple risk factors and confounders, including CD4+ count, HIV RNA level, alcohol abuse and IDU, HBV and HCV infection, body mass index, diabetes, lipid levels, and hypertension treatment.
We analyzed and reported the relationship between smoking and adverse clinical events in several ways. HRs reflected the magnitude of association, expressing the hazard of developing death or disease among exposed versus unexposed groups. Attributable risk estimates reflected excess risk of disease among exposed compared with unexposed groups. PAR% expressed the proportion of disease among a population that was attributable to an exposure; this proportion helped to estimate the proportion of disease that would be reduced if the exposure were eliminated.30
Our findings that 24% of deaths and 23% to 31% of certain serious clinical events were attributable to current smoking highlight the serious health risk that smoking represents among this HIV-infected population.
Our findings strongly support recommendations that for HIV-infected persons who smoke, smoking cessation should be a central health promotion strategy and should be routinely integrated with other HIV health care services.18,43
Proven benefits of smoking cessation include reducing the risk of clinical diseases such as lung cancer, CVD, and stroke.44–47
Clinical practice guidelines for treating tobacco use and dependence recommend that providers systematically and regularly assess their patients for tobacco use and strongly urge tobacco users to quit.48
In practice, however, many HIV providers are unaware that their patients are currently smoking or do not assess the interest of their smoking patients in quitting.14,49
For patients who indicate that they are willing to make a quit attempt, multiple strategies are available and have been used in HIV-infected patients.18,43,50–52
Behavioral interventions include telephone quit lines, motivational interviewing, cognitive behavioral interventions, and other individual or group counseling approaches.18,43,48,50–53
Nicotine replacement therapy is available in multiple forms, including gum, lozenges, transdermal patches, inhalers, and sprays.18,43,48,51–54
Other pharmacological agents used for smoking cessation include bupropion and varenicline18,43,48,54
; because of the potential for drug–drug interactions, including with HAART medications,18,55,56
providers considering these drugs should first consult knowledgeable pharmacists and other current and authoritative sources of information.35
Because it is common for smokers to make multiple quit attempts before successful cessation, continued support is important.15,16,18,47
Approaches must be individualized; multiple strategies (such as behavior interventions and nicotine replacement therapy) have been employed simultaneously for some persons with HIV.18,51–53
Other underlying comorbidities, such as depression or substance abuse, may also need to be addressed.16,18
We had no specific information on date of smoking cessation for former smokers in our study. However, consistent with other studies,17,45,46
former smokers in our analysis had risks intermediate between current smokers and never smokers for both overall mortality and several specific clinical events. The risk difference between current and former smokers would be expected to increase with increasing duration of cessation.44–47
We also had no information on amount and duration of smoking (e.g., pack-years) for current or former smokers. Although heavy or prolonged smoking has greater adverse health consequences, even light smoking (1–4 cigarettes/day) has been associated with an increased risk (compared with that of nonsmokers) of dying from ischemic heart disease and of all-cause mortality.57
Current smoking at any level therefore represents a health risk among HIV-infected populations and highlights the importance of smoking cessation.
Many clinical outcomes in our analysis, including cancer and CVD, have multiple risk factors, and we cannot rule out additional potential confounders, such as other health-related behaviors (e.g., those related to diet or exercise) or other health conditions. However, our results concerning the relationship of smoking with all-cause mortality and development of serious adverse clinical events were robust in multiple analyses and were consistent with many other studies in varied populations.
Among HIV-infected participants in this clinical trial of 2 HAART treatment strategies, current smoking represented a significant risk factor for both all-cause mortality and several serious clinical disease outcomes, such as CVD, non-AIDS cancers, and bacterial pneumonia. Significant reductions in morbidity and mortality among HIV-infected patients achieved by advances in HIV therapy may be undercut by increases in adverse clinical outcomes attributable to smoking. The high prevalence of smoking among this population and other HIV-infected populations should cause encouraging smoking cessation to become a high priority for clinicians and other HIV service providers to promote health and reduce morbidity and mortality in their patients.