Cigarette smoking has been associated with numerous adverse health outcomes (1,2). Multiple pathogenetic mechanisms appear to be involved (1-3). Of particular concern for human immunodeficiency virus type 1 (HIV-1)-infected persons, smoking has been associated with a number of alterations in immune defenses (3-14) and an increased risk of certain infectious and neoplastic diseases (1,2,15-18). To examine the relationship between cigarette smoking and HIV-1 disease progression and survival, we analyzed the incidence of HIV-related clinical events by smoking status for persons enrolled in a large prospective cohort study sponsored by the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA).
PARTICIPANTS AND METHODS
The Terry Beirn CPCRA has enrolled persons with HIV-1 infection in observational and treatment protocols at 17 community-based clinical centers located in 13 U.S. cities. Characteristics of these study centers and CPCRA enrollment procedures have been previously described (19). Briefly, all CPCRA study centers provide primary health care to the population of patients enrolled in its protocols. Between September 1990 and November 1992, 5, 104 HIV-1-seropositive persons ≥13 years old were enrolled in the Observational Data Base protocol. A baseline CD4+ count was not required for enrollment. The current analysis is limited to persons enrolled in this protocol who had a baseline CD4+ cell count measured within 4 months of enrollment and a Karnofsky performance score of at least 70. These subjects were followed through July 1, 1994, when the protocol ended.
At enrollment, a medical history was obtained, current treatments were ascertained, and demographic data and HIV-1 risk behaviors were recorded on standardized data-collection forms (20). CD4+ lymphocyte measurements were performed by the clinical laboratories serving the CPCRA study centers. All subjects had scheduled visits no less frequently than every 6 months. New HIV-related diagnoses were recorded at each study visit, together with the date the clinical workup was initiated. The CPCRA list of diseases considered to qualify as evidence of HIV disease progression closely corresponds to the 1987 Centers for Disease Control (CDC) definition of AIDS-defining events except that mucocutaneous herpes simplex, non-visceral Kaposi's sarcoma, and coccidiomycosis are not included, and four disorders not on the 1987 CDC list, disseminated herpes zoster, lymphoma of any type, cervical cancer, and Salmonella septicemia, are included (21,22). The standard diagnostic criteria used by the CPCRA are also similar to the 1987 CDC surveillance criteria for AIDS (21,22). Disease ascertainment and criteria were verified on quarterly site-monitoring visits during which research records were audited.
Participants were classified as “never,” “former,” or “current” smokers on the basis of two questions asked at enrollment: (a) “Has the patient ever smoked cigarettes?” (b) “Does the patient now smoke cigarettes?” Current smokers were also asked how many cigarettes, on average, they smoked each day. Cigarette-smoking status was not recorded at subsequent visits. Use of injection drugs, alcohol, and “street” drugs, and other HIV-1 risk behaviors were assessed in a similar manner.
Informed, witnessed, signed consent was obtained from each subject. The study was approved by the Institutional Review Board of each participating institution.
For most analyses, patients were divided into three groups: never, former, and current cigarette smokers. Differences in baseline characteristics among smoking groups were summarized using stratified analysis of variance and Mantel-Haenszel chi-squared statistics (23). Rates of incident HIV-related clinical events and death were adjusted for CD4+ count and expressed per 100 person-years of follow-up (24). Proportional hazards regression analyses, stratified by CPCRA study center, were performed to compute adjusted relative hazard ratios (estimated relative risks) (25). These models included the following indicator variables: smoking status (with never smokers as the reference group), age, gender, race/ethnicity, HIV-1 risk behavior, prior disease progression, and baseline CD4+ cell count, Karnofsky score, use of antiretroviral therapy, use of Pneumocystis carinii pneumonia (PCP) prophylaxis, alcohol use, and “street” drug use (not including marijuana). Event times were measured from enrollment to the workup date of the event. For subjects who did not experience specific events, follow-up time was measured through death, the date that clinical status was last evaluated, or July 1, 1994, the end of the study. In general, subjects with a history of a particular clinical outcome at enrollment were excluded from the analysis for that outcome. They were not excluded, however, for clinical outcomes that commonly recur in HIV-infected persons, that is, herpes simplex, herpes zoster, anogenital warts, aphthous ulceration, bacterial pneumonia, and oral, vaginal, or esophageal candidiasis. PCP was examined three ways: all incident events, first episodes (that is, subjects with a prior history of PCP were excluded), and recurrent episodes.
Since cigarette smoking was highly correlated with HIV-1 risk group and with other forms of substance use, analyses were performed to assess whether associations were consistent among these subgroups. Proportional hazard models with interaction terms between risk group (homosexual/bisexual males; injection drug users; and “other,” predominantly women who reported having sex with an injection drug user) and smoking status, and substance use (injection drug use, alcohol use, and street drug use) and smoking status, were used (4 df chi-squared) for these investigations. To determine whether dose-response relationships were present among current smokers, proportional hazard regression analyses that included the variable number of cigarettes smoked per day were also performed.
Incubating or “subclinical” HIV-related disease processes present at baseline could have influenced an individual's smoking status at enrollment. To investigate this hypothesis, we also performed analyses that excluded events that occurred within 6 months of enrollment.
Characteristics of the Study Population
Of the 3,221 subjects included in this analysis, 57% were current cigarette smokers, 19% were former smokers, and 24% were never smokers. The proportion who were current smokers ranged from 38% to 93% across the 17 CPCRA study centers. Overall, current smokers reported smoking an average of 17 cigarettes per day. Only 16% of current smokers smoked more than one pack (20 cigarettes) per day and only 8% smoked two or more packs per day.
The three smoking groups differed with respect to a number of baseline characteristics (Table 1). After controlling for other characteristics, many of which were highly correlated, current smokers were more likely than former or never smokers to report injection drug use, alcohol use, and “street” drug use. Current smokers were also younger and more likely to be African-American than former smokers, and they had slightly lower baseline Karnofsky scores than never smokers.
Median follow-up was 36 months for current smokers, 37 months for former smokers, and 36 months for never smokers. At the close of the study on July 1, 1994, vital status was known for 85% of current smokers, 89% of former smokers, and 89% of never smokers, and 78% of all subjects were reevaluated for disease progression within 6 months of study closure or died prior to the end of the study. For each smoking group, subjects with unknown vital status or not seen within 6 months of study closure were more likely than others to have higher CD4+ cell counts (424 vs 310 × 106 cells/L for current smokers, 314 vs 227 × 106 cells/L for former smokers, and 345 vs 255 × 106 cells/L for never smokers).
Disease Progression and Survival
A total of 1,522 subjects died or developed a disease progression event. There was no difference between current smokers and never smokers in the overall risk (adjusted relative hazard) of HIV-1 disease progression [relative hazard (RH) = 1.05; 95% confidence interval (CI) 0.90-1.23; p = 0.52] or death (RH = 1.00; 95% CI 0.86-1.18; p = 0.97). However, differences were observed for several specific HIV-related diseases (Table 2). Current smokers were more likely than never smokers to develop bacterial pneumonia, oral candidiasis, and AIDS dementia complex but less likely to develop Kaposi's sarcoma, cytomegalovirus disease, extrapulmonary cryptococcosis, aphthous ulceration, and molluscum contagiosum. No differences were seen between former smokers and never smokers except that former smokers were marginally more likely to develop toxoplasmosis. The remainder of this report therefore focuses on differences observed between current and never smokers.
Because incubating or “subclinical” disease processes present at baseline could have influenced an individual's smoking status at enrollment, analyses were performed excluding events that occurred in the first 6 months of follow-up. No substantial changes were seen in any of the previously described associations (data not shown). There was also no evidence that the relationship between smoking status and any of the clinical outcomes examined in Table 2 varied by risk group (homosexual/bisexual male, injection drug user, other; p for interaction >0.20). However, for Kaposi's sarcoma (visceral and visceral or nonvisceral) and certain other outcomes, our ability to assess potential interactions was limited by the small number of events that occurred within some subgroups. Among current smokers, there was no detectable dose-response relationship for any of the clinical outcomes examined.
The association between baseline smoking status and bacterial pneumonia was further examined by PCP prophylaxis at enrollment, entry CD4+ cell count, and history of injection drug use. Although, as expected, CD4+-adjusted rates of bacterial pneumonia were lower among subjects taking trimethoprim-sulfamethoxazole and higher among those receiving no PCP prophylaxis, the relationship between smoking and bacterial pneumonia did not vary by type of PCP prophylaxis at enrollment (trimethoprim-sulfamethoxazole, pentamidine, dapsone, and none; p for interaction = 0.28). The relative hazard for current versus never smokers was also similar for subjects with entry CD4+ counts <200 and ≥200 × 106/L, but there were substantially fewer events among subjects with higher counts and the increased risk was not statistically significant for this subgroup (RH = 1.64; p = 0.02; and RH = 1.42; p = 0.17, respectively). Injection drug users and noninjection drug users also had similar relative hazards (RH = 1.97; p = 0.09; and RH = 1.53; p = 0.02, respectively).
In addition to cigarette smoking, an increased risk of AIDS dementia complex was associated with a lower entry CD4+ count (p < 0.001), prior disease progression (p = 0.01), and a lower baseline Karnofsky score (p = 0.02). There was no evidence for an interaction between smoking status and any of these three variables with regard to this outcome (p ≥ 0.20). Use of antiretroviral therapy was associated with a decreased risk of AIDS dementia complex (RH = 0.65; p = 0.04).
PCP was examined with regard to all incident events, first episodes, and recurrent episodes. As with all events (Table 2), there was no detectable association between smoking status and first episodes (RH = 0.78; p = 0.12) or recurrent episodes of PCP (RH = 1.32; p = 0.29).
Patients referred to a dermatologist for diagnosis and treatment of Kaposi's sarcoma may have been more likely than other subjects to receive other dermatologic diagnoses, including molluscum contagiosum. Because this could have led to a spurious association between current smoking and a reduced risk of molluscum contagiosum, we reevaluated this association for subjects who did not have a diagnosis of Kaposi's sarcoma at enrollment or at any time during follow-up. No evidence for this form of ascertainment bias was found. The relative hazard for molluscum contagiosum among current smokers who did not have a diagnosis of Kaposi's sarcoma was similar to the overall estimate (RH = 0.51; p = 0.006). In addition, cytomegalovirus disease has been associated with an increased risk of Kaposi's sarcoma (26). We therefore reexamined the association between smoking and these two outcomes after adding the other outcome as a time-dependent covariate in the respective proportional hazards model. Both associations were largely unchanged (RH = 0.59; p = 0.01, for Kaposi's sarcoma; and RH = 0.72; p = 0.04, for cytomegalovirus disease).
Because cigarette smoking was associated with injection drug use, alcohol use, and “street” drug use, and because adjustment for these variables in a proportional hazards model may not completely eliminate all confounding, we also examined the relationship between these three factors and each of the outcomes associated with cigarette smoking. Proportional hazards models that included the same covariates as the smoking analyses were used. Injection drug use was marginally associated with AIDS dementia complex (RH = 0.57; p = 0.05), alcohol use was marginally associated with any (visceral or nonvisceral) Kaposi's sarcoma (RH = 0.57; p = 0.04) and cryptococcosis (RH = 0.38; p = 0.07), and “street” drug use was marginally associated with bacterial pneumonia (RH = 1.35; p = 0.04) and AIDS dementia complex (RH = 0.57; p = 0.07). There were no significant interactions between smoking status and any of these other substance use variables with regard to these outcomes (p > 0.07).
Finally, relative hazards for bacterial pneumonia, oral candidiasis, and AIDS dementia complex were also computed for former smokers compared with current smokers. Former smokers were at decreased risk for bacterial pneumonia (RH = 0.72; p = 0.05) and oral candidiasis (RH = 0.81; p = 0.02). The relative hazard was similar for AIDS dementia complex, but there were fewer events and the difference was not statistically significant (RH = 0.74; p = 0.19).
This large cohort of HIV-seropositive individuals followed at 17 clinical centers throughout the United States provided substantial statistical power for assessing the potential influence of cigarette smoking on HIV-1 disease progression and survival. Although there was no association between cigarette smoking and the overall risk of disease progression or death, smoking was associated with an increased risk of certain HIV-related diseases and a decreased risk of others. These findings provide important confirmation for several previously described associations, including an increased risk of bacterial pneumonia (27) and oral candidiasis (28,29) and a decreased risk of Kaposi's sarcoma (30) and aphthous ulceration (29,31). The other associations described here have not, to our knowledge, been previously reported.
Cigarette smoking was highly prevalent in our cohort. The proportion of current smokers at enrollment was approximately twice that reported for a similarly aged, concurrent sample of the general population (32). This appeared to be closely related to the high proportion of persons in our study with a history of injection drug use, alcohol use, or “street” drug use, activities that were strongly associated with cigarette smoking.
The biologic basis for our finding of a higher mean CD4+ cell count among current smokers is uncertain, but it may simply reflect a loss of interest in smoking as HIV-1 disease progresses. Cigarette smoking has been associated with an increased CD4+ cell level in the general population and in HIV-seropositive cohorts (33-36). Among HIV-infected individuals, however, this elevation seems to disappear within 2-3 years of seroconversion (37-39). In our cohort, the lower mean CD4+ count seen among former smokers may have been largely due to an increased likelihood of smoking cessation among persons with more advanced disease.
The absence of an association between cigarette smoking and the overall risk of HIV-1 disease progression is consistent with the results of three other prospective studies (37,38,40). Like ours, each of these studies also found no association between smoking and the risk of PCP. One other study (41) reported that smoking was associated with a more rapid development of AIDS due to PCP, but several methodologic limitations make these data difficult to interpret (40).
The association of cigarette smoking with both increased and decreased risks for certain, different HIV-related diseases is not entirely surprising given the many and varied effects smoking can have on immune defenses, both in the respiratory tract and systemically (3-14). Some of these effects appear to be immunosuppressive while others result in immune activation. For example, cigarette smoking has been associated with an increase in certain alveolar macrophage functions such as lysosomal enzyme production and superoxide anion release (4,5,9), but a decrease in others, such as accessory cell function (7) and bactericidal and fungicidal activity (8,9). Other apparently immunosuppressive effects associated with smoking include a decline in serum immunoglobulin A (IgA) and IgG levels (10,11) and a reduced antibody response to influenza and hepatitis B vaccines (12-14).
Cigarette smoking has been associated with an increased risk of bacterial pneumonia and other respiratory tract infections in a number of HIV-seronegative populations (16-18), but most previous studies of HIV-infected individuals did not find a significant association (42-44), perhaps because of limited sample size, an extremely high prevalence of smoking in the study population, or an inability to control adequately for HIV disease stage. A more recent study has reported an increased risk of bacterial pneumonia among current smokers with entry CD4+ counts of <200 × 106/L (27). In our cohort, the overall increased risk of bacterial pneumonia among smokers was >50%. Although this increased risk was only significant statistically for subjects with entry CD4+ counts of <200 × 106/L, the relative hazard for persons with higher CD4+ counts was similar.
Oral candidiasis, the most frequent HIV-related event in our cohort, was also increased among current smokers. Previous studies have reported a similar association in HIV-1-seropositive and other immunocompromised populations (28,29,45). Coupled with the progressive immunosuppression of HIV-1 infection, both this association and the one observed with bacterial pneumonia could be due to one or more of the previously described suppressive effects of cigarette smoking on immune defenses.
Current smokers also had an almost twofold increased risk of AIDS dementia complex. One hypothesis for the pathogenesis of AIDS dementia complex is that infected peripheral blood monocytes act as a “Trojan horse” to transport HIV-1 into the central nervous system (CNS) (46,47). Progressive dementia is thought to result from interactions between activated macrophages and astrocytes (48,49). Cigarette smoking could potentially enhance this process in one or more ways. Smoking has been associated with increased levels of circulating monocytes (50) and increased adherence of monocytes to endothelial cells (51). Although we are unaware of any studies of the influence of cigarette smoking on CNS macrophages, smoking has been associated with increased plasma plateletactivating factor (PAF) activity (52) and PAF is a potent activator of monocytes and macrophages (5,53,54).
Biologically plausible mechanisms can also be postulated for the inverse associations observed in our cohort. Alternatively, as in any observational study, one or more of these associations could be due to an unmeasured or imprecisely measured confounding variable. Potential biologic mechanisms include smoking-induced alterations in cytokines or cytokine receptors (6,7,55,56), which may be particularly important with regard to Kaposi's sarcoma (30,57); smoking-induced macrophage activation (4,5,9), which could, at least in part, explain the decreased risk observed for extrapulmonary cryptococcosis, a condition in which the macrophage appears to have a pivotal defensive role (58); and smoking-related changes in specific endocrine levels that have been linked to altered immune responses. The latter include increased levels of dehydroepiandrosterone (DHEA) sulfate and other androgens (59-61). These hormones are believed to have a number of important physiologic effects through one or more mechanisms of action, including modulation of hormone-receptor interactions and regulation of gene expression (62). DHEA has been shown to inhibit transformation of human lymphocytes by Epstein-Barr virus (63) and to protect mice against acute lethal infection with herpes simplex virus type 2 and other viruses (64).
There was no detectable dose-response relationship among current smokers for any of the HIV-related diseases examined. This indicates that the associations found may be characterized by threshold levels, as has been suggested previously for the inverse association with Kaposi's sarcoma (30). Alternatively, our failure to detect a dose-response relationship could be due to the relatively small number of participants that reported heavy smoking (only 16% smoked >1 pack/day), since this reduces the statistical power for making this assessment.
As we have noted, cigarette smoking was highly associated with a history of injection drug use, alcohol use, and “street” drug use. Because adjustment for these variables may not completely eliminate all confounding, we examined them separately and tested for interactions. We found only marginal associations between these other forms of substance use and the outcomes associated with cigarette smoking. There were no significant interactions between smoking and these three variables with regard to these outcomes.
Several limitations of this study should be considered in interpreting our results. First, although participants in the CPCRA are broadly representative of persons with HIV in the United States (19), they are not a random sample of HIV-1-seropositive persons. Therefore, our results may not be generalizable to all HIV-infected populations. Second, smoking status was obtained only at enrollment, and biochemical tests such as plasma cotinine levels were not performed. It should be noted, however, that when compared with biochemical tests, self-reported smoking data have been shown to be remarkably accurate, particularly when they are obtained from adults enrolled in observational studies (65). Since advancing HIV-1 infection appears to be associated with a decline in the prevalence of smoking, our results are more likely to underestimate rather than overestimate associations with smoking. Third, CD4+ cell count, prior disease progression, and Karnofsky score are all admittedly imperfect measures of HIV-1 disease stage. If current smokers as a group were healtheir at enrollment than never smokers and inclusion of these measures in our analysis failed to adjust completely for this difference, the risks associated with smoking could be underestimated. This could result in overestimation of the reduced risk for inverse associations and underestimation of the increased risk for positive associations. Fourth, multiple comparisons were performed, increasing the likelihood of obtaining “statistically significant” results by chance alone. Thus, associations not hypothesized prior to the analysis and not reported previously (that is, the association with AIDS dementia complex and each of the inverse associations except for Kaposi's sarcoma and aphthous ulceration) should be interpreted with caution, especially when the strength of the association was more limited (p > 0.01).
If confirmed by other studies, these findings have a number of important clinical implications. First, HIV-infected persons who smoke cigarettes should be informed of the associations with bacterial pneumonia, oral candidiasis, and AIDS dementia complex, and smoking cessation should be encouraged. The relative hazard for each of these outcomes was lower for former smokers than current smokers, indicating that these risks may be reversible with smoking cessation. The Pulmonary Complications of HIV Infection Study Group has suggested that prophylactic antibiotics be considered for individuals at highest risk of bacterial pneumonia (43). Cigarette smoking should be considered in making these recommendations. To the extent that the incidence of oral candidiasis can be reduced by smoking cessation, patient symptoms, treatment costs, and individual and perhaps communitywide antifungal drug resistance might also be reduced. Even a small reduction in AIDS dementia complex and its devastating impact on the individual, aside from the large medical and nursing care costs often involved, could alone make a smoking cessation effort worth-while. The inverse associations of cigarette smoking with Kaposi's sarcoma, cytomegalovirus disease, extrapulmonary cryptococcosis, aphthous ulceration, and molluscum contagiosum should be studied further. If confirmed, elucidation of the mechanisms involved might suggest new prophylactic therapies for these conditions.
In summary, although there was no detectable association between cigarette smoking and the overall risk of HIV-1 disease progression or death, smoking was associated with an increased risk of bacterial pneumonia, oral candidiasis, and AIDS dementia complex, and a decreased risk of certain other HIV-related diseases. Further examination of these associations may provide new insights into the influence of cigarette smoking on immune function and the development of opportunistic diseases in HIV-infected individuals.
Acknowledgment: This article is dedicated to the memory of our coauthor, Michael Thurnherr, a tireless advocate for people with AIDS and HIV infection. This work has been sponsored by the National Institute of Allergy and Infectious Diseases.
The following centers and individuals constitute the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA): S. Johns, J. Ellison, M. J. Hickson, J. Lee (Addiction Research and Treatment Corporation); M. Thompson, T. Creagh, A. Morris (AIDS Research Consortium of Atlanta, Inc.); J. Ernst, C. Pollard, K. Anastos, M. Bar, E. Doramajian (Bronx-Lebanon Hospital Center); D. Blatt, D. Moore, R. Renzetti, R. Verheggen, R. Luskin-Hawk (Chicago Community Program for Clinical Research on AIDS); R. A. Torres (Clinical Directors Network of Region II, Inc.); D. Townley, K. Clanon, B. Morris, W. Owen, C. Brosgart (Community Consortium); L. R. Crane, J. Ebright, P. Schuman, W. Vallier, C. Fairclough (Detroit Medical Center HIV/AIDS Unit); W. J. Holloway, D. Winslow, S. Szabo, A. Bincsik, K. Swanson (Delaware Community Program for Clinical Research on AIDS); D. L. Cohn, R. R. Reves, M. J. Grodesky, C. A. Mesard, J. E. Gans (Denver Community Program for Clinical Research on AIDS); W. El-Sadr, L. Capps, C. Guity, M. Hardy, L. Fuentes (Harlem AIDS Treatment Group); L. Saravolatz, N. Markowitz, J. Kumi, D. Mastro-Polak (Henry Ford Hospital); R. Ryder, R. Vogel (Hill Health Corporation); J. Hutchinson, J. Walker, S. Pablovich, P. Simmons, N. Kimmel (Louisiana Community AIDS Research Program); J. Kocher, S. Weisholtz, A. Sheridan, V. M. Taylor, J. Braithwaite (North Jersey Community Research Initiative); J. H. Sampson, J. Godbey, M. Loveless, C. Salveson, N. Martinez (The Research and Education Group); T. M. Kerkering, C. Webster, E. Fisher, K. Link, L. Gernon (Richmond AIDS Consortium); A. Labriola, C. Gibert, J. Scott, E. Finley, K. Irvin (Washington Regional AIDS Program); T. A. Louis, T. Brelje, A. DuChene, G. Thompson, D. N. Wentworth (Statistical Center); and L. R. Deyton, J. Sanville, M. Foulkes (Division of AIDS).
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