1. 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

2. 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

3. Smoking: Leading cause of morbidity and mortality
CDC estimates for 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):

4. 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:

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

6. 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):

7. 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?

8. 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):
3. Miguez-Burbano et al. Addict Biol 2003;8(1):39-43.

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

10. 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:

11. 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 ) by ICD-9
AOR* 1.58 (95% CI ) 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):

12. 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 )
Lip, mouth, pharynx (SIR 4.1, 95% CI )
Trachea, lung, bronchus (SIR 3.2, 95% CI )
J Natl Cancer Inst Mar 16;97(6):

13. 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:

14. 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):
2. Page-Shafer et al. Ann Epidemiol 1996;6(5):
3. Galai et al. J Acquir Immune Defic Syndr Hum Retrovirol 1997;14(5):451-8.

15. 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:

16. Results Smoking and respiratory illness
Current Former
ICD-9 dx OR (95% CI) OR (95% CI)
COPD ( ) ( )
Bacterial PNA ( ) ( )
Crothers et al. JGIM 2005; 20:

17. Results Smoking and outcomes
Current Former
HR (95% CI) HR (95% CI)
Mortality* 2.0 ( ) ( )
Beta (95% CI) Beta (95% CI)
Quality of life* (-5.3 to -1.4) (-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:

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

19. 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

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

21. Results Smoking HIV+ HIV- p-value Current 46% 35% <0.001
Former 19% 40%
Never 25% 25%
Median pack years <0.001
Pack year strata
0 25% 26%
% 33%
% 23%
≥ % 17%

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

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

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

25. Unadjusted mortality rate per 100py according to smoking status
HIV+ HIV- p-value
Never
Former
Current
Attributable mortality for current smoking

26. Unadjusted mortality rate per 100py according to pack years
HIV+ HIV p-value ≥

27. Adjusted mortality per 100py according to pack years
HIV+ (p-value) HIV- (p-value)
0 pkyrs
(0.07) (0.4)
(0.045) 1.04 (0.6)
≥ (0.02) 1.85 (0.6)
Mortality also higher in HIV+ current smokers
Interactions for HIV and smoking not significant

28. 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

29. 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?

30. 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:

31. 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:

32. 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:

33. Worse immunologic and viral responses to HAART in smokers
Adjusted* HR (95% CI) in smokers
Viral response ( )
Immunologic response 0.85 ( )
Virologic rebound ( )
Immunologic failure ( )
Death ( )
AIDS ( )
*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:

34. 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):
3. Feldman et al. AmJ Public Health 2006;96:
4. Nieman et al. AIDS 1993;7:

35. 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

36. 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

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

38. 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:

39. 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):
An LC et al. Arch Intern Med 2006;166(5):

40. 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.

41. 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

42. 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

43. 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:

44. 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:

45. 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:

46. 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:

47. 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+

48. 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.