Relevance and risks of cigarette smoking for HIV-infected patients Kristina Crothers, MD Assistant Professor Section of Pulmonary and Critical Care Medicine Yale University School of Medicine

Outline Magnitude of the problem Clinical relevance of smoking in HIV Symptoms and quality of life Morbidity and mortality Impact on effectiveness of HAART? Achieving smoking cessation in HIV Increasing awareness of smoking Limited data on effective methods Challenges in HIV populations

Smoking: Leading cause of morbidity and mortality CDC estimates for 1997-2001 in US 438,000 premature deaths 5.5 million years of potential life lost $92 billion in productivity losses Leading smoking attributable deaths 40% cancer (lung) 35% cardiovascular 26% respiratory MMWR 2005; 54(25): 625-28.

Smoking is highly prevalent in HIV+ populations Never smoker Prevalence 39 to 76% in other studies 65% current smokers in ICR in VA 22% in US general adult population 30% Current smoker 54% 16% Former smoker Rosen et al. AJRCCM 1995;152:738-45.

Smoking in HIV Predictor of respiratory symptoms Current or prior smoking: Significantly associated with all respiratory symptoms Diaz et al. Chest 2003;123:1977-1982.

Smoking is associated with decreased quality of life HIV+ current compared to non-smokers in pre-HAART era had lower* General health perception Physical functioning Bodily pain Energy Role functioning Cognitive functioning *All p<0.05 in multivariate models Turner et al. AIDS Pt Care STDS 2001;15(12):615-24.

Comorbid disease and relationship to smoking in HIV Susceptible to all complications of smoking as in HIV- HIV and smoking are risk factors for many of the same comorbid diseases: Infections COPD CAD Cancer Increased harm from smoking in HIV?

Smoking in HIV: Significantly increased infections Approximately 2-fold higher rates of Bacterial pneumonia1 Tuberculosis2 Pneumocystis pneumonia (PCP)3 Also associated with2 Acute bronchitis Viral infections (common cold, flu) Oral candidiasis 1. Kohli et al. CID 2006;43:90-8. 2. Arcavi et al. Arch Intern Med 2004;164(20):2206-16. 3. Miguez-Burbano et al. Addict Biol 2003;8(1):39-43.

Smoking, HIV and HAART: Significant increases in CAD Estimated risk of CHD (%) using Framingham risk equation Egger et al. AIDS 2001;15:S193-20.

Smoking and HIV: Independent risk factors for COPD HIV+ HIV- % with emphysema ≥12 pack years 37% (14/38) 0 (0/14) ≥ 25 pack years 46% (11/24) 0 (0/10) Only mild airflow obstruction associated with emphysema (FEV1/FVC 69%). Diaz et al. Annals of Int Med. 2000;132:369-372.

Smoking and HIV: Independent risk factors for COPD Veterans Aging Cohort 5 Site Study HIV+ veterans: 50-60% more COPD AOR* 1.47 (95% CI 1.01-2.13) by ICD-9 AOR* 1.58 (95% CI 1.14-2.18) by pt-report Supports independent risk from HIV * Adjusted for age, race/ethnicity, pack years, IDU, alcohol abuse Crothers et al. Chest, 2006; 130(5): 1326-33

Smoking: Risk factor for cancers encountered in HIV HIV Swiss Cohort – Incidence of cancer in HIV compared to cancer registries Smoking-attributable cancers greater in HIV including: Cervix (SIR 8.0, 95% CI 2.9-17.4) Lip, mouth, pharynx (SIR 4.1, 95% CI 2.1-7.4) Trachea, lung, bronchus (SIR 3.2, 95% CI 1.7- 5.4) J Natl Cancer Inst. 2005 Mar 16;97(6):425-32.

Smoking and HIV: Independent risk factors for lung cancer 2086 ALIVE cohort participants with 27 lung cancer deaths (96% were smokers) Increased lung cancer in HIV in adjusted analyses* HR 3.6; 95% CI 1.6–7.9 Mortality increased in the HAART era Mortality rate ratio 4.7; 95% CI 1.7–16 *Adjusted for age, sex, smoking status, and calendar period Kirk et al. CID 2007; 45:103-10.

Smoking and mortality in HIV Pre-HAART data Impact on mortality - contradictory results1-3 Likely due to competing mortality from AIDS-related causes Morbidity and mortality from smoking not investigated in HAART era 1. Burns et al. J AIDS Hum Retrovirol 1996;13(4):374-83. 2. Page-Shafer et al. Ann Epidemiol 1996;6(5):420-30. 3. Galai et al. J Acquir Immune Defic Syndr Hum Retrovirol 1997;14(5):451-8.

Impact of smoking on outcomes among HIV+ veterans in HAART era Prospective, observational study Veterans Aging Cohort 3 Site Study VACS 3 881 HIV+ veterans 3 VAMC - Cleveland, Houston, Manhattan Recruited from ID clinics 6/1999-7/2000 Crothers et al. JGIM 2005; 20:1142-45.

Results Smoking and respiratory illness Current Former ICD-9 dx OR (95% CI) OR (95% CI) COPD 5.3 (1.6-17.0) 5.3 (1.5-18.0) Bacterial PNA 2.8 (1.5-5.5) 1.9 (0.9-4.1) Crothers et al. JGIM 2005; 20:1142-45.

Results Smoking and outcomes Current Former HR (95% CI) HR (95% CI) Mortality* 2.0 (1.03-3.9) 1.6 (0.8-3.3) Beta (95% CI) Beta (95% CI) Quality of life* -3.3 (-5.3 to -1.4) -2.0 (-4.2 to 0.2) *Adjusted for age, race/ethnicity, CD4, HIV viral load, Hgb, illegal drug and alcohol use Crothers et al. JGIM 2005; 20:1142-45.

Impact of smoking on outcomes Are outcomes different than in HIV-? Are HIV+ more susceptible to negative outcomes associated with smoking than HIV-?

Smoking in HIV+ compared to HIV- veterans Compare impact of smoking on comorbid disease and outcome in HIV+ and HIV- patients1 Smoking status and pack years of exposure 1,031 HIV+ and 740 HIV- subjects in the Veterans Aging Cohort 5 Site Study (VACS 5)2 HIV- subjects block-matched to HIV+ by age, race/ethnicity, sex, and site of care 1. Crothers et al. AJRCCM 2007; 175:A249. 2. Justice et al. Med Care 2006;44(8 Suppl 2):S13-24

Results Characteristic HIV+ HIV- p-value Age, years 49 55 <0.001 Sex, male 99% 96% 0.003 Race/ethnicity <0.001 White/other 30% 42% Black 58% 47% Hispanic 12% 12%

Results Smoking HIV+ HIV- p-value Current 46% 35% <0.001 Former 19% 40% Never 25% 25% Median pack years 18 20 <0.001 Pack year strata 0 25% 26% 1-19 39% 33% 20-39 24% 23% ≥40 11% 17%

Prevalence of bacterial pneumonia according to smoking Smoking status Pack years of smoking

Prevalence of COPD according to smoking Smoking status Pack years of smoking

Prevalence of CAD according to smoking Smoking status Pack years of smoking

Unadjusted mortality rate per 100py according to smoking status HIV+ HIV- p-value Never 2.19 1.56 0.6 Former 3.89 1.35 0.002 Current 4.76 2.60 0.01 Attributable mortality for current smoking 2.57 1.04

Unadjusted mortality rate per 100py according to pack years HIV+ HIV- p-value 0 2.13 1.47 0.5 1-19 3.86 2.19 0.07 20-39 4.99 1.47 0.001 ≥40 5.43 2.19 0.03

Adjusted mortality per 100py according to pack years HIV+ (p-value) HIV- (p-value) 0 pkyrs 1.48 -- 1.43 -- 1-19 2.48 (0.07) 2.04 (0.4) 20-39 2.72 (0.045) 1.04 (0.6) ≥40 3.25 (0.02) 1.85 (0.6) Mortality also higher in HIV+ current smokers Interactions for HIV and smoking not significant

Enhanced susceptibility to smoking? Significantly increased comorbid disease and independently increased mortality for HIV+ patients Whether smoking has greater attributable mortality in HIV+ remains unclear Results may be due to less power in HIV- sample given fewer deaths during f/u

Mechanisms and diseases for increased mortality in smokers with HIV Focus of future studies Behaviors that co-vary with smoking Cause of death Known smoking-related diseases AIDS- vs non-AIDS related Effect on virologic response to HAART?

Association of cigarette smoking with HIV prognosis Women’s Interagency HIV Study 924 women Median of 5-yr f/u after initiation of HAART Determined impact of smoking (within last 6 months) on response to HAART Assessed by CD4 count, HIV viral load, death, and development of AIDS Feldman et al. AmJ Public Health 2006;96:1060-65.

CD4 cell counts after HAART according to smoking Non-smoker (n=400) Smoker (n=524) Mean CD4 count Feldman et al. AmJ Public Health 2006;96:1060-65.

HIV viral load after HAART according to smoking Smoker (n=524) Mean Log of Viral Load Non-smoker (n=400) Feldman et al. AmJ Public Health 2006;96:1060-65.

Worse immunologic and viral responses to HAART in smokers Adjusted* HR (95% CI) in smokers Viral response 0.79 (0.67-0.93) Immunologic response 0.85 (0.73-0.99) Virologic rebound 1.39 (1.06-1.69) Immunologic failure 1.52 (1.18-1.96) Death 1.53 (1.08-2.19) AIDS 1.36 (1.07-1.72) *Adjusted for age, race, hepatitis C infection, illicit drug use, previous ARV, and previous AIDS. Remained significant when adjusted for adherence, and when restricted to ≥ 95% adherence to HAART. Feldman et al. AmJ Public Health 2006;96:1060-65.

Summary Clinical relevance of smoking in HIV Risk for AIDS associated conditions PCP1, TB2, and candidiasis Risk for “non-AIDS” diseases Bacterial pneumonia (x1), acute bronchitis CAD, COPD Cancer (lung) Decreased response to HAART3 and more rapid progression to AIDS reported4 1. Miguez-Burbano et al. Addict Biol 2003;8(1):39-43. 2. Arcavi et al. Arch Intern Med 2004;164(20):2206-16. 3. Feldman et al. AmJ Public Health 2006;96:1060-65. 4. Nieman et al. AIDS 1993;7:705-10.

Outline Magnitude of the problem Clinical relevance of smoking in HIV Symptoms and quality of life Morbidity and mortality Impact on effectiveness of HAART? Achieving smoking cessation in HIV Increasing awareness of smoking Limited data on effective methods Challenges in HIV populations

Clinical relevance of smoking in HIV Implications Improvements in smoking cessation in HIV+ patients needed Interventions prior to 20 pack years may be particularly important, but may be able to benefit at any time as in HIV-1 1. Doll et al. BMJ 2004;328(7455):1519

Smoking cessation in HIV A lot of current smokers…. What works?

Characteristics of HIV+ smokers 123 current smokers in San Francisco1 63% thinking about quitting 72% had previous quit attempt 509 French HIV+, 51% regular smokers2 60% medium/strong nicotine dependence 40% motivated to quit smoking 14% appropriate for traditional programs Depression, co-dependence in others 1. Mamary et al. AIDS Pt Care STDS 2002;16:39-42. 2. Bernard et al. AIDS Pt Care STDS 2007; 21:458-68.

Limited studies on smoking cessation methods in HIV Nicotine patch and counseling1 50% cessation rate after 8 months Cellular telephones for counseling2 37% cessation rate in intervention group 10% in the usual care group at 3 months Similar success to HIV- patients utilizing telephone intervention3 Wewers ME et al. J Assoc Nurses AIDS Care 2000;11(6):37-44. Vidrine DJ et al. AIDS 2006;20(2):253-60. An LC et al. Arch Intern Med 2006;166(5):536-42.

Challenges to smoking cessation: Alcohol codependence Veterans Aging Cohort 3 Site study (VACS3) 881 HIV+ pts 67% current drinkers Justice et al. Med Care 2006;44: S52–S60.

Challenges to smoking cessation: Substance abuse Veterans Aging Cohort Study HIV+ HIV- Current illicit drug use 41% 27% Marijuana 28% 17% Cocaine 21% 14% Stimulants 4% 2% Opiates 9% 7% Justice et al. Med Care 2006;44: S13–S24

Challenges to smoking cessation: Comorbid conditions Conditions influencing relapse common Comorbid medical diseases1 Depression Other psychiatric conditions More contraindications2 to buproprion? Seizures Addiction to opiates, cocaine, stimulants Liver dysfunction, etc. J. Wagner et al. Addictive Behaviors 2006;31:1283–89. VA/DoD Clinical Practice Guidelines for Management of Tobacco Use, June 2004

Challenges to smoking cessation: Provider awareness Identified factors associated with failure to recognize current smoking among HIV and Gen Med VA providers Patient factors HIV status, demographics, respiratory symptoms, comorbidities, HIV vl, CD4 count Provider factors Specialty, training status, demographics Crothers et al. JGIM 2007;22:749-54.

Awareness of smoking among HIV care providers Provider confidence Degree of agreement to statement: “I can influence my patients to stop smoking.” Identification of current smoking Gold standard = patient report on survey Compared to provider report on survey of whether patient currently smoked Crothers et al. JGIM 2007;22:749-54.

Increased awareness of smoking among HIV care providers needed HIV care providers in VACS 5 Less aware of current smoking Less confident in counseling cessation Independent predictors of failure to recognize current smoking: HIV care provider Patient HIV status Crothers et al. JGIM 2007;22:749-54.

Increased awareness of smoking needed in high-risk groups Recognition of current smoking in HIV+ and HIV- not influenced by: Respiratory symptoms CAD COPD Bacterial pneumonia CD4>200 cells (HIV+ only) HIV viral load<500 copies (HIV+ only) Crothers et al. JGIM 2007;22:749-54.

Conclusions Smoking contributes substantially to morbidity and mortality in HIV+ patients Additional studies needed on cessation Integration into ID clinic Provider education is one component Unclear if brief interventions may be as successful or if more intensive methods needed in HIV+

Acknowledgements: VACS PI and Co-PI: AC Justice, DA Fiellin Participating VA Medical Centers: Atlanta (D. Rimland, C Jones-Taylor), Baltimore (KA Oursler, R Titanji), Bronx (S Brown, S Garrison), Houston (M Rodriguez-Barradas, N Masozera), Los Angeles (M Goetz, D Leaf), Manhattan-Brooklyn (M Simberkoff, D Blumenthal, J Leung), Pittsburgh (A Butt, E Hoffman), and Washington DC (C Gibert, R Peck) Core Faculty: S Braithwaite, C Brandt, K Bryant, R Cook, J Conigliaro, K Crothers, J Chang, S Crystal, N Day, J Erdos, M Freiberg, M Kozal, M Gaziano, M Gerschenson, B Good, A Gordon, J Goulet, M Hernan, K Kraemer, J Lim, S Maisto, K Mattocks, P Miller, L Mole, P O’Connor, R Papas, H Paek, J Robins, C Rinaldo, M Roberts, J Samet, B Tierney, J Whittle Staff: D Cohen, A Consorte, K Gordon, F Kidwai, F Levin, K McGinnis, M Rambo, J Rogers, M Skanderson, F Whitsett Major Collaborators: Immunology Case Registry, Pharmacy Benefits Management, Framingham Heart Study, Women’s Interagency HIV Study, Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Health Economics Research Center (HERC), Center for Health Equity Research and Promotion (CHERP) Funded by: National Institute on Alcohol Abuse and Alcoholism (2U10 AA 13566); National Institute on Aging (K23 G00826); Robert Wood Johnson Generalist Faculty Scholar Award; an Inter-Agency Agreement between National Institute on Aging, National Institute of Mental Health, and the Veterans Health Administration; the VHA Office of Research and Development; and, VHA Public Health Strategic Health Care Group.