Abstract: Smoking exacts a huge toll on the health of everyone who becomes addicted to nicotine. That toll is greater in people with HIV, and not only because as a group they smoke more than the general population. Research shows that smoking subtracts more years from the life of a middle-aged person with HIV than HIV itself. Nicotine addiction raises the risk of allcause mortality more in HIV-positive smokers than in HIV-negative smokers. A nationwide study in Denmark found that HIV-positive smokers run a 6 times higher risk of myocardial infarction than HIV-positive never-smokers, but current smoking only doubled the MI risk in HIV-negative people. Research in HIV-positive and negative men and women in the United States found that HIV-positive smokers who had prior AIDS pneumonia had a 3.5-fold higher risk of lung cancer than HIV-negative smokers. Metaanalysis of 18 studies involving more than 625,000 people with HIV found significantly higher rates of smoking-related cancer and infection-related cancer in HIV-positive people than in the general population. People who quit smoking enjoy rapid declines in their risk of smoking-related disease. In the US general population, people who quit by age 40 cut their risk of smoking-related death by 90%. Analysis of almost 5500 SMART trial participants determined that current HIV-positive smokers had a higher risk of five outcomes than former smokers with HIV: all-cause mortality, AIDS-related disease, major cardiovascular disease, non-AIDS cancer, and bacterial pneumonia. In a large DAD study analysis, cardiovascular disease incidence fell steadily as time since quitting rose. A CDC study of a nationally representative HIV population identified numerous factors independently linked to higher smoking prevalence: younger age, white or black race versus Hispanic ethnicity, less education, incarceration, poverty, noninjection drug use, binge alcohol drinking, major depression, and a viral load above 200 copies/mL.

Smoking leads all preventable causes of death across the world.1 And it's more deadly in people with HIV than in HIV-negative people.2 That's not a surprise, because smoking causes deadly diseases -- like myocardial infarction3 and lung cancer4 -- more in people with than without HIV. In North Americans and Europeans with HIV, smoking subtracts more years of life than HIV itself.5

Health professionals need no convincing that smoking imperils health by ravaging one organ after another, from top (stroke) to bottom (peripheral vascular disease). But it's easy to forget the prodigious scope of this assault. In the general population, smoking chops off at least 10 years of life, the CDC estimates,6 and smokers who quit by age 40 limit their risk of a smoking-related death by 90%. In the United States smoking causes more deaths every year than HIV infection, illegal drugs, alcohol, guns, and automobile accidents combined.7 Smoking has killed more than 10 times as many US citizens as all the wars in the history of this country.7

The news gets worse for people with HIV infection. A 2000-veteran study found that smoking raised the allcause death risk more in HIV-positive veterans than in HIV-negative veterans, and lighter smokers ran a death risk just as high as heavier smokers.2 This Veterans Aging Cohort Study (VACS) analysis involved 1034 HIV-positive veterans matched by age, sex, and study site to 739 veterans without HIV. Through a median followup of 5.3 years, 200 veterans with HIV (19.3%) and 72 without HIV (9.7%) died.

Compared with HIV-positive veterans who never smoked, HIV-positive current smokers had more than a doubled risk of all-cause death (adjusted incidence rate ratio [aIRR] 2.31, 95% confidence interval [CI] 1.53 to 3.49).2 In contrast, HIV-negative current smokers did not have an independently higher death risk than HIV-negative never-smokers (aIRR 1.32, 95% CI 0.67 to 2.61). And HIV-positive former smokers did not run a higher death risk than never-smokers (aIRR 1.29, 95% CI 0.81 to 2.04). All-cause death risk was more than 80% higher in HIV-positive smokers than in HIV-positive never-smokers whether they smoked under 20 pack-years (aIRR 1.82, 95% CI 1.20 to 2.76) or more pack-years (aIRR 1.87, 95% CI 1.21 to 2.89). (Pack-years equal the number of cigarettes smoked daily times the number of years a person has smoked. Twenty pack-years means smoking 1 pack a day for 20 years or a half-pack a day for 40 years. (See smokingpackyears.com.)

Analysis of almost 18,000 HIV-positive people in Europe and the United States figured that smoking shortens life expectancy more than HIV itself in the years after people start antiretroviral therapy.5 In a study population that excluded injection drug users, 60% smoked. Through 4 years of follow-up, smokers had a twice higher death rate than nonsmokers (mortality rate ratio [MRR] 1.94, 95% CI 1.56 to 2.41) and (in a separate analysis) a 70% higher death rate than neversmokers (MRR 1.70, 95% CI 1.23 to 2.34) (Figure 1). But mortality among former smokers proved similar to mortality in never-smokers (MRR 0.92, 95% CI 0.64 to 1.34). Compared with nonsmokers, current smokers had 6 times higher mortality from cardiovascular disease (MRR 6.28, 95% CI 2.19 to 18.0) and almost 3 times higher mortality from non-AIDS cancers (MRR 2.67, 95% CI 1.60 to 4.46).

Death Rate Over 4 Years in HIV-Positive Smokers vs. Nonsmokers
Death Rate Over 4 Years in HIV-Positive Smokers vs. Nonsmokers Figure 1. A 17,995-person analysis of HIV-positive people in Europe and the United States determined that smokers had almost a twice higher death rate than nonsmokers through 4 years of follow-up.5 In a separate analysis of current smokers, former smokers, and never smokers, current smokers had a nearly twice higher death rate than never smokers. But the death rate was similar in former smokers and people who never smoked.

The researchers calculated that 35-year-old men with HIV would lose 7.9 life-years if they smoked (95% CI 7.1 to 8.7). In comparison, HIV infection would subtract 5.9 years from a 35-year-old man's life (95% CI 4.9 to 6.9).5

HIV-positive current smokers ran a 6 times higher risk of myocardial infarction (MI) than HIV-positive neversmokers in a nationwide Danish analysis (aIRR 6.06, 95% CI 2.99 to 12.25).3 In contrast, current smoking only doubled the MI risk among HIV-negative people compared with HIV-positive never-smokers (aIRR 2.22, 95% CI 1.44 to 3.44). MI risk in HIV-positive former smokers also proved much lower than in HIV-positive current smokers compared with HIV-positive neversmokers (aIRR 2.64, 95% CI 1.16 to 6.01).

The Danish investigators calculated that 72% of MIs in people with HIV could be attributed to smoking, compared with only 24% of MIs in the HIV-negative comparison group (Figure 2).3 That means 3 of 4 heart attacks in people with HIV could be prevented if these people never smoked. Among current HIV-positive smokers, smoking accounted for 42% of MIs. In other words, 42% of MIs could be prevented if all current HIV-positive smokers quit. If all current smokers in the general population quit, it would prevent only 21% of MIs.

MIs Prevented by Never Smoking or Quitting Smoking
MIs Prevented by Never Smoking or Quitting Smoking Figure 2. If no HIV-positive people ever smoked, 72% of myocardial infarctions would be prevented in people with HIV, according to results of a nationwide Danish study.3 If all current HIV-positive smokers quit, 42% of MIs would be prevented. Proportions of preventable MIs would be much lower in a comparison group of HIV-negative people.

As with heart attacks, so with lung cancer: Your chances of getting it run higher if you smoke and have HIV than if you smoke and don't have HIV.4 That finding comes from a comparison of 2546 HIV-positive and negative women smokers in the Women's Interagency HIV Study (WIHS) and 4274 HIV-positive and negative men smokers in the Multicenter AIDS Cohort Study (MACS). Compared with HIV-negative smokers, HIV-positive smokers who had AIDS pneumonia in the past had more than a 3.5-fold higher risk of lung cancer (aIRR 3.56, 95% CI 1.67 to 7.61). Heavier smoking boosted lung cancer risk in women and men with and without HIV. Compared with people who smoked fewer than 10 pack-years, those who smoked 10 to 30 pack-years had almost a 5-fold higher risk of lung cancer (aIRR 4.75, 95% CI 1.62 to 13.96), and those who smoked more than 30 pack-years had an 11-fold higher risk (aIRR 11.09, 95% CI 3.72 to 33.11).

Rigorous research from around the world shows how thoroughly smoking assails the already-vulnerable health of people with HIV -- in lung, larynx, bone, bladder, and beyond.

Lung Disease

  • Current smoking more than doubled the risk of bacterial pneumonia in a 5-year study of 4942 people starting antiretroviral therapy in Italy at a median age of 36 (adjusted hazard ratio [aHR] 2.623, 95% CI 2.060 to 3.3339, P < 0.0001).8
  • Current smoking almost doubled the risk of bacterial pneumonia over 16 months in 5472 SMART trial participants in 33 countries (aHR 1.82, 95% CI 1.09 to 3.04, P = 0.02).9 Smoking in the past did not independently boost pneumonia risk (aHR 1.64, 95% CI 0.94 to 2.86, P = 0.08). This study group had a median age of 43, and all entered the trial with a CD4 count above 350 cells/mm3.
  • Meta-analysis of 14 cohort or case-control studies in HIV-positive adults determined that current smokers had more than a 70% higher risk of bacterial pneumonia than current nonsmokers (HR 1.73, 95% CI 1.44 to 2.06) and almost a 40% higher risk than former smokers (HR 1.37, 95% CI 1.06 to 1.78).10 Former smokers did not run a higher pneumonia risk than never-smokers (HR 1.24, 95% CI 0.96 to 1.60).
  • In a 176-person comparison of people with and without HIV in Italy, current smoking was the only independent predictor of chronic obstructive pulmonary disease (COPD).11 HIV-positive participants had a significantly higher COPD prevalence than HIV-negative controls matched for age, sex, and smoking status.
  • In the young (median age 36), antiretroviral-naive, international START trial population -- all with a CD4 count above 500 -- every 10 pack-years of smoking independently raised the risk of COPD.12
  • A cross-sectional study of 1446 HIV patients in Italy who had thoracic computed tomography found that 48% had emphysema, bronchiolitis, or both.13 Smoking more than tripled the odds of either diagnosis (adjusted odds ratio [aOR] 3.48, 95% CI 2.58 to 4.71) and proved a stronger predictor than age, injection drug use, body mass index, leukocyte count, or gender.

Invasive Pneumococcal Disease

  • A nationwide 1995-2012 study in Denmark determined that smoking independently boosted the risk of invasive pneumococcal disease by one third in people with HIV (adjusted relative risk [aRR] 1.34, 95% CI 1.26 to 1.42).14

Cancer

  • Comparing rates of non-AIDS cancers in people with HIV and the general population, metaanalysis of 18 studies involving 625,716 people with HIV found higher rates of smoking-related cancers (lung standardized incidence ratio [SIR] 2.6, 95% CI 2.1 to 3.1; kidney SIR 1.7, 95% CI 1.3 to 2.2; laryngeal SIR 1.5, 95% CI 1.1 to 2.0) and infectionrelated cancer (anal SIR 28, 95% CI 21 to 35; liver SIR 5.6, 95% CI 4.0 to 7.7; Hodgkin lymphoma SIR 11, 95% CI 8.8 to 15) in people with HIV.15
  • Smoking doubled the risk of non-AIDS cancers (anal, basal cell carcinoma, Hodgkin lymphoma, lung cancer) in a 3.8-year analysis of 3158 HIV-positive people starting antiretroviral therapy in AIDS Clinical Trials Group (ACTG) studies at a median age of 37 years (aRR 2.12, 95% CI 1.1 to 4.08).16
  • Compared with never smoking, current smoking and former smoking more than doubled the risk of death from non-AIDS cancer in a 33,308-person 3-year DAD cohort analysis (aRR 2.20, 95% CI 1.48 to 3.26 for current smoking; aRR 2.52, 95% CI 1.73 to 3.67 for former smoking).17
  • Comparison of 3503 HIV-positive people in Denmark and 12,979 people in the general population found almost a tripled risk of smoking-related cancers in the HIV group (aIRR 2.8, 95% CI 1.6 to 4.9) and an 11.5 time higher risk of virus-related cancers (aIRR 11.5, 95% CI 6.5 to 20.5).18 HIV-positive nonsmokers did not run a higher risk of nonvirus-related cancers than general population controls (aIRR 1.2, 95% CI 0.7 to 2.1).
  • Compared with HIV-positive people who never smoked, current smokers had nearly a doubled risk of non-AIDS cancer in a 5472-person 33-month SMART trial analysis (aHR 1.8, 95% CI 1.2 to 2.8, P = 0.008).19 Compared with former smoking, current smoking more than doubled the risk of non-AIDS cancer (aHR 2.3, 95% CI 1.5 to 3.6, P < 0.001).
  • In 2010 lung cancer displaced non-Hodgkin lymphoma as the leading cancer cause of death among people with HIV in a nationwide French study.20 Among 728 deaths, lung cancer accounted for 61 (8.4%), non-Hodgkin lymphoma for 53 (7.3%), and hepatitis-related cancer for 31 (4.3%).
  • Current smoking upped the odds of lung cancer in a Swiss HIV Cohort Study comparison of 68 HIV-positive people with lung cancer and 337 matched controls without lung cancer (aOR for current versus never-smokers 14.4, 95% CI 3.36 to 62.1).21 Neither CD4 count nor antiretroviral therapy predicted lung cancer in this analysis.
  • In a 6820-person comparison of HIV-positive and negative men and women in MACS and WIHS, HIV-positive smokers with AIDS pneumonia in the past had more than a 3 times higher risk of lung cancer than HIV-negative smokers (aIRR 3.56, 95% CI 1.67 to 7.61).4
  • Mortality after lung cancer proved more than twice higher in HIV patients than in matched HIV-negative controls in a nationwide Danish study (MRR 2.33, 95% CI 1.51 to 3.61).22 All 29 HIV-positive people diagnosed with lung cancer were current or former smokers.
  • In a matched comparison of HIV-positive and negative adults in California's Kaiser Permanente healthcare system, 5-year cancer-free survival was significantly lower with lung cancer in the HIV group than in the HIV-negative group (10% versus 19%, P = 0.002) but not in comparisons of HIV-positive and negative people with four other non-AIDS cancers -- anal, prostate, colorectal, or Hodgkin lymphoma.23

HPV Infection and Related Cancers

  • A study of 1797 US women with HIV linked smoking to higher prevalence and incidence of human papillomavirus (HPV) infection, including more than a 2-fold higher prevalence of cancer-causing HPV-18 (OR 2.45, 95% CI 1.86 to 3.22).24
  • Smoking correlated with cumulative HPV detection in an 11-year Women's Interagency HIV Study of 2543 women with HIV and 895 without HIV.25
  • In a 30-month comparison of 328 US women with HIV and 325 without HIV, current cigarette smoking doubled the risk of squamous intraepithelial lesions -- an invasive cervical cancer precursor -- in HIV-positive women (aRR 2.1, 95% CI 1.0 to 4.4, P = 0.06).26
  • A study of 2835 US men with and at risk for HIV infection found that smoking independently raised chances of HPV-related external genital warts (aRR 1.2, 95% CI 1.0 to 1.4).27
  • A case-control study of Swiss HIV Cohort Study members (85% men) with or without anal cancer found that current smoking more than doubled the odds of anal cancer (aOR 2.59, 95% CI 1.25 to 5.34).28
  • A cross-sectional study of 500 Australian men who have sex with men (half with HIV) determined that current smoking doubled the odds of oral HPV (aOR 2.2, 95% CI 1.2 to 3.9), a cause of oropharyngeal squamous cell carcinoma.29 Men with HIV had a significantly higher prevalence of any oral HPV type (19% versus 7%, P < 0.001).
  • A 2-year study of US women and men with and at risk for HIV infection found that HIV infection independently raised the risk of incident oral HPV infection, while current smoking increased the risk of oral HPV persistence.30

Cardiovascular Disease

  • Follow-up of 33,308 HIV-positive DAD cohort members for 3 years linked smoking to a doubled risk of cardiovascular death in current smokers (aRR 1.90, 95% CI 1.29 to 2.80) and former smokers (aRR 1.98, 95% CI 1.36 to 2.88).17
  • A 5472-person 33-month SMART trial analysis determined that current smoking doubled the risk of major cardiovascular disease compared with never smoking in people with HIV (aHR 2.0, 95% CI 1.3 to 3.1, P = 0.002).19 Compared with former smoking, current smoking raised the risk of major cardiovascular disease 60% (aHR 1.6, 95% CI 1.1 to 2.4, P = 0.02).
  • A comparison of 3251 HIV-positive people in Denmark and 13,004 general-population controls matched for age and gender found that current HIV-positive smokers had almost a tripled risk of myocardial infarction compared with current general-population smokers (aIRR 2.83, 95% CI 1.71 to 4.70).3 Previous HIV-positive smokers had almost a doubled risk compared with previous general-population smokers, but that association lacked statistical significance (aIRR 1.78, 95% CI 0.75 to 4.24). MI risk was equivalent in HIV-positive and general-population never-smokers (aIRR 1.01).
  • Smoking and family history of cardiovascular disease -- but not diabetes or hypertension -- independently boosted the odds of acute coronary syndrome in a case-control study of people with HIV infection.31 In people with HIV, more than half of acute coronary syndrome diagnoses could be attributed to smoking (54.35%), while lower proportions could be attributed to diabetes (30.58%) or hypertension (6.57%).
  • Among 27,136 HIV-positive current smokers in the DAD cohort study, cardiovascular disease risk dropped from an adjusted incidence rate ratio of 2.32 compared with never-smokers in the first year after stopping to 1.46 after more than 3 years since quitting.32
  • A 2000-2004 Women's Interagency HIV Study of 1725 women with HIV and 668 women at risk for HIV identified smoking as an independent predictor of metabolic syndrome in the HIV group (aOR 1.31, 95% CI 1.06 to 1.61) and the HIV-negative group (aOR 2.19, 95% CI 1.46 to 3.26).33

Osteoporosis and Fracture

  • Meta-analysis of 13 studies of incident fracture in HIV-positive people identified five studies in which smoking independently predicted any fracture or fragility fractures.34
  • Meta-analysis of 15 studies involving bone mineral density or fracture in people with HIV or HIV/HCV found that smoking predicted osteoporosis in univariate analysis in four studies, and smoking predicted fracture in univariate analysis in three studies.35

Chronic and Advanced Kidney Disease

  • A case-control study of 75 HIV-positive people admitted to the hospital for chronic kidney disease (CKD) and 461 HIV-positive people admitted without CKD determined that smoking independently tripled the odds of hospital admission for CKD (aOR 3.0, 95% CI 1.4 to 5.6, P = 0.005).36 There was a dose-response relationship between packs smoked per day and CKD risk.
  • A 35,192-person DAD study analysis determined that current smoking nearly doubled the risk of advanced CKD or end-stage renal disease compared with never smoking (aIRR 1.79, 95% CI 1.08 to 2.97).37

Oral Disease

  • Smoking quadrupled the risk of oropharyngeal candidiasis in a cross-sectional US study of 215 people with HIV (OR 4.07, 95% CI 1.18 to 14.08, P = 0.027).38
  • A 1995-2000 US study of 631 adults with HIV linked smoking to higher odds of prevalent oral candidiasis (OR 2.5, 95% CI 1.3 to 4.8) and incident oral candidiasis (OR 1.9, 95% CI 1.1 to 3.8).39
  • A cross-sectional US study 152 people with HIV identified more smoking pack-years as a risk factor for periodontitis.40
  • A US study of 415 people with HIV correlated smoking with higher prevalence of oral lesions (including oral candidiasis, salivary gland enlargement, and oral hairy leukoplakia), independently of CD4 count.41

Birth Outcomes

  • The impact of smoking on pregnant women and their neonates is well appreciated. In a 1998-2007 study of 1.6 million women with and without HIV across Florida, HIV infection and smoking independently predicted low birth weight, preterm birth, and infants small for gestational age.42

Quitting Turns the Tables Clinically

Compared with SMART trial participants who never smoked, current smokers in this six-continent study had higher risks of all-cause mortality, major cardiovascular disease, non-AIDS cancer, and bacterial pneumonia.19 This 5472-person analysis also found that current smokers ran a higher risk of five clinical outcomes than former smokers -- all-cause mortality (aHR 1.5, 95% CI 1.0 to 2.1, P = 0.04), AIDS-related disease (aHR 1.6, 95% CI 1.0 to 2.3, P = 0.03), major cardiovascular disease (aHR 1.6, 95% CI 1.1 to 2.4, P = 0.02), non-AIDS cancer (aHR 2.3, 95% CI 1.5 to 3.6, P < 0.001), and bacterial pneumonia (aHR 1.5, 95% CI 1.1 to 2.1, P = 0.01). These findings indicate that quitting confers a decided morbidity and mortality advantage.

Aquitaine cohort investigators set out to gauge the impact of quitting smoking on bacterial pneumonia risk.43 The analysis involved 3336 HIV-positive people who made at least two study visits from 2000 through 2007 and did not have bacterial pneumonia at their first visit. Compared with current smokers, people who never smoked had a 50% lower risk of bacterial pneumonia in an analysis adjusted for CD4 count, age, gender, HIV transmission category, antiretroviral therapy, cotrimoxazole prophylaxis, statin treatment, viral load, and previous AIDS diagnosis (aHR 0.50, 95% CI 0.29 to 0.86, P = 0.01). When the Aquitaine team compared people who had quit smoking for at least 1 year with current smokers, the decrease in bacterial pneumonia risk was almost exactly the same (aHR 0.48, 0.26 to 0.90, P = 0.02). A 14-study meta-analysis determined that current HIV-positive smokers had a 37% higher risk of bacterial pneumonia than HIV-positive people who kicked the habit (aHR 1.37, 95% CI 1.06 to 1.78, P = 0.02).10

DAD study investigators conducted a detailed analysis to assess the impact of quitting smoking on cardiovascular disease.32 They considered three cardiovascular outcomes, myocardial infarction (MI), coronary heart disease (CHD, including MIs, invasive coronary procedures, or death from other CHD), and cardiovascular disease (CVD, including CHD plus carotid artery endarterectomy or stroke). Poisson regression analysis to figure incidence rate ratios adjusted for age, sex, cohort, calendar year, family history of CVD, diabetes, lipids, blood pressure, and antiretroviral treatment.

Compared with people who never smoked, incidence rate ratios for MI fell from 3.73 per 100 person-years within the first year of quitting to 2.07 more than 3 years after quitting (Figure 3).32 Respective drops in incidence rate ratio were 2.93 to 1.83 for CHD and 2.32 to 1.49 for CVD (Figure 3). Compared with current smokers, people who had quit for more than 3 years had a 39% lower MI risk (IRR 0.61, 95% CI 0.36 to 1.04, P = 0.068), a 26% lower CHD risk (IRR 0.74, 95% CI 0.48 to 1.15, P = 0.176), and a 32% lower CVD risk (IRR 0.68, 95% CI 0.46 to 1.01, P = 0.058). The declines in risk for MI and CVD approached statistical significance.

Rates of MI, CHD and CVD After Smoking Stops
Rates of MI, CHD and CVD After Smoking Stops Figure 3. In the 3 or more years after DAD study members stopped smoking, rates of myocardial infarction (MI), coronary heart disease (CHD), and cardiovascular disease (CVD) (defined in text) declined steadily when compared with study members who never smoked.32 (Incidence rate ratios calculated per 100 person-years.)

Smoking, Adherence and Viral Load

Smoking imperils adherence to antiretroviral therapy and -- probably largely in consequence -- can threaten viral control and CD4 response. A SMART study analysis including 5295 people, 38% of them smokers, determined that current smoking independently raised the odds of suboptimal adherence (missing any pills by self-report) more than 50% (aOR 1.54, 95% CI 1.41 to 1.68, P < 0.0001).44 Current smoking also independently lowered MEMS-measured adherence in a 24-week study of 64 people taking lopinavir/ritonavir.45 Nonsmokers took 84.8% of prescribed doses, while current smokers took 63.5% (P < 0.001). Former smokers did not differ from never-smokers in adherence.

A study of 333 HIV-positive people in Boston found lower medication adherence and appointment keeping in smokers than in nonsmokers, and higher odds of a detectable viral load (OR 2.85, 95% CI 1.53 to 5.30) and recent hospital admission (OR 1.89, 95% CI 0.99 to 3.57).46 In New York City a comparison of smoking and nonsmoking HIV-positive gay men 50 and older found that current smokers were 68% less likely to have an undetectable viral load than never-smokers in an analysis adjusted for age, income, and illicit drug use (aOR 0.32, 95% CI 0.13 to 0.81).47 Current smokers proved 75% less likely to have an undetectable load than former smokers (aOR 0.25, 95% CI 0.10 to 0.62). But former smokers did not differ significantly from never-smokers in chances of having an undetectable viral load.

Women's Interagency HIV Study investigators assessed virologic and immunologic responses and risk of AIDS or death in 924 HIV-positive women starting antiretroviral between July 1995 and September 2003.48 More than half of the women, 57%, smoked. The WIHS team defined virologic response as the first viral load below 80 copies/mL after treatment began and immunologic response as the first CD4-cell gain of 100 cells/mm3. Virologic failure meant a rebound from below 80 copies/mL to above 1000 copies/mL, and immunologic failure meant a CD4 count below the pretreatment nadir. An analysis adjusted for age, race, HCV status, illicit drug use, and other variables determined that, compared with nonsmokers, smokers had:

  • A lower chance of a virologic response: aHR 0.79, 95% CI 0.67 to 0.93, P = 0.006
  • A lower chance of an immunologic response: aHR 0.85, 95% CI 0.73 to 0.99, P = 0.041
  • A higher chance of virologic failure: aHR 1.39, 1.06 to 1.69, P = 0.013
  • A higher chance of immunologic failure: aHR 1.52, 95% CI 1.18 to 1.96, P = 0.001

Why So Many HIV-Positive People Smoke

Smoking prevalence runs higher in people with HIV than in uninfected people. In high-income countries between 40% to 60% of HIV-positive people smoke.49 And people with HIV often supplement their cigarette smoking with other tobacco products, usually cigars or snuff. In a US smoking-cessation trial that enrolled 474 people with HIV, 22% of them used at least one tobacco product besides cigarettes, a rate far higher than the 1% to 6% recorded in recent general-population studies.50

The most comprehensive recent US analysis of smoking prevalence in people with HIV comes from a 2009 Medical Monitoring Project study by the Centers for Disease Control and Prevention (CDC).51 According to these nationally representative cross-sectional surveys, 42% of HIV-positive adults in care smoke, twice the 21% rate in the adult US population. Figuring the quit rate as the ratio of former smokers to the sum of former and current smokers, the CDC found a steeply lower ratio in adults with HIV than in the general population -- 32% versus 52%. Still, a one-third quit ratio in the US HIV population should encourage providers to continue pressing people with HIV to abandon tobacco.

Why do so many people with HIV smoke? An equally valid and perhaps more enlightening question is why so many smokers get HIV infection. A 2007 systematic review identified six studies probing the role of tobacco in HIV risk.52 Five of those six studies pinpointed smoking as in independent predictor of HIV acquisition, with adjusted odds ratios ranging from 1.6 to 3.5. But the authors of this review caution that residual confounding may explain that finding. In other words, smokers may have demographic and lifestyle traits that predispose them to HIV infection but did not get factored into the statistical analyses of these studies. Sifting some of the same data, a 2009 review "found little evidence that cigarette smoking increases the risk for acquiring HIV."53

No matter how one interprets the risk data, demographic and behavioral factors that incline one toward smoking clearly may also boost chances of picking up sexually transmitted infections like HIV. In a 2013 analysis of smoking and non-AIDS morbidity in people with HIV, workers from New York's Weill Cornell Medical Center observed that reasons for high smoking prevalence in HIV populations reflect links between smoking and factors routinely observed in HIV groups, such as "low socioeconomic and education levels, psychiatric comorbidity, concurrent illicit drug and alcohol use, and mental stress."49 To be sure, the CDC smoking prevalence study identified all or those factors -- and a few more -- as independent predictors of greater smoking prevalence in people with HIV: "older age, non-Hispanic white or non-Hispanic black race, lower educational level, poverty, homelessness, incarceration, substance use, binge alcohol use, depression, and not achieving a suppressed HIV viral load" (Figures 4 and 5).51

Factors Tied to Higher Smoking Rate in People With HIV
Factors Tied to Higher Smoking Rate in People With HIV Figure 4. In a nationally representative sample of people in care for HIV infection, factors independently associated with higher adjusted smoking prevalence included age 40 to 49 or age 50+ (versus 18 to 29), non-Hispanic white or black race (versus Hispanic), and less than a high school education or a high school education (versus more than high school).51 Figure 5 charts seven other independent predictors.
Factors Tied to Higher Smoking Rate in People With HIV
Factors Tied to Higher Smoking Rate in People With HIV Figure 5. A CDC study of a nationally representative sample of HIV-positive people in care identified several factors independently associated with higher adjusted smoking prevalence, including viral load (VL) not at or below 200 copies/mL and the other variables shown here and in Figure 4.51

How Smoking Does More Damage in People With HIV

Why does smoking undermine the health of people with HIV more than the health of HIV-negative people? At first the consistently higher prevalence of smoking in HIV-positive people than in the general population appeared to explain the difference in smoking's impact on morbidity and mortality, suggest Weill-Cornell researchers.49 But now, they observe, a growing trove of evidence hints that, in people with ongoing HIVinduced inflammation, "smoking may elicit additional inflammatory responses beyond what would be expected in a smoker without HIV infection."

The Weill-Cornell team notes that research unearthed two principal mechanisms of COPD-related lung inflammation or tissue destruction in all smokers: (1) tobacco smoked-induced inflammation, and (2) increased risk of bacterial colonization in remodeled lung.49 But in HIV-positive smokers, studies now suggest seven additional mechanisms may be at play: (1) independent influx of CD8 lymphocytes, (2) increased number of activated macrophages, (3) oxidantantioxidant imbalance, (4) HIV protein induction of apoptosis in lung endothelial cells, (5) antiretroviral effects, (6) increased susceptibility to bacterial pulmonary infection, and (7) increased susceptibility to Pneumocystis colonization after Pneumocystis infection.

On top of all that, HIV infection appears to ramp up nicotine metabolism and so heighten the effects of this highly addictive toxin in people with HIV.54 Two of four nicotine metabolites assessed reached plasma concentrations up to 3-fold higher in HIV-positive smokers than in smokers without HIV. Moreover, concentrations of nicotine itself proved 5-fold lower in people with HIV, a finding indicating its faster metabolism in HIV-positive smokers. Enhanced nicotine metabolism, these researcher observe, increases reactive oxygen species and reactive metabolites, which could promote both carcinogenesis and HIV replication.

Notably, nicotine, protease inhibitors, and nonnucleosides all get metabolized via cytochrome P450 enzymes. The resulting interactions can trim antiretroviral concentrations to subtherapeutic levels and contribute to worse viral control in smokers (reviewed under "Smoking, adherence, and viral load" above).55-57

Nicotine is bad news. Everyone who smokes should know just how bad: In animal studies, nicotine killed as readily as strychnine and tripled the lethal impact of arsenic.58

References

  1. World Health Organization. WHO report on the global tobacco epidemic, 2013: enforcing bans on tobacco advertising, promotion and sponsorship. Geneva, Switzerland. 2013.
  2. Crothers K, Goulet JL, Rodriguez-Barradas MC, et al. Impact of cigarette smoking on mortality in HIV-positive and HIV-negative veterans. AIDS Educ Prev. 2009;21(3 suppl):40-53.
  3. Rasmussen LD, Helleberg M, May MT, et al. Myocardial infarction among Danish HIV-infected individuals: population-attributable fractions associated with smoking. Clin Infect Dis. 2015;60:1415-1423.
  4. Hessol NA, Martinez-Maza O, Levine AM, et al. Lung cancer incidence and survival among HIV-infected and uninfected women and men. AIDS. 2015;29:1183-1193.
  5. Helleberg M, May MT, Ingle SM, et al. Smoking and life expectancy among HIV-infected individuals on antiretroviral therapy in Europe and North America. AIDS. 2015;29:221-229.
  6. Centers for Disease Control and Prevention. Smoking and tobacco use. Tobacco-related mortality. 2014.
  7. Centers for Disease Control and Prevention. Smoking and tobacco use. Health effects of cigarette smoking. 2014.
  8. Mussini C, Galli L, Lepri AC, et al. Incidence, timing, and determinants of bacterial pneumonia among HIV-infected patients: data from the ICONA Foundation Cohort. J Acquir Immune Defic Syndr. 2013;63:339-345.
  9. Gordin FM, Roediger MP, Girard PM, et al. Pneumonia in HIV-infected persons increased risk with cigarette smoking and treatment interruption. Am J Respir Crit Care Med. 2008;178:630-636.
  10. De P, Farley A, Lindson N, Aveyard P. Systematic review and meta-analysis: influence of smoking cessation on incidence of pneumonia in HIV. BMC Med. 2013;11:15.
  11. Madeddu G, Fois AG, Calia GM, et al. Chronic obstructive pulmonary disease: an emerging comorbidity in HIV-infected patients in the HAART era. Infection. 2013;41:347-353.
  12. Kunisaki KM, Niewoehner DE, Collins G, et al. Pulmonary function in an international sample of HIV-positive, treatment-naïve adults with CD4 counts > 500 cells/μL: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. HIV Med. 2015;16(suppl 1):119-128.
  13. Guaraldi G, Besutti G, Scaglioni R, et al. The burden of image based emphysema and bronchiolitis in HIV-infected individuals on antiretroviral therapy. PLoS One. 2014;9:e109027.
  14. Harboe ZB, Larsen MV, Ladelund S, et al. Incidence and risk factors for invasive pneumococcal disease in HIV-infected and non-HIV-infected individuals before and after the introduction of combination antiretroviral therapy: persistent high risk among HIV-infected injecting drug users. Clin Infect Dis. 2014;59:1168-1176.
  15. Shiels MS, Cole SR, Kirk GD, Poole C. A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr. 2009;52:611-622.
  16. Krishnan S, Schouten JT, Jacobson DL, et al. Incidence of non-AIDS-defining cancer in antiretroviral treatment-naive subjects after antiretroviral treatment initiation: an ACTG longitudinal linked randomized trials analysis. Oncology. 2011;80:42-49.
  17. The Data Collection on Adverse Events in Anti-HIV Drugs (D:A:D) Study Group. Factors associated with specific causes of death amongst HIV-positive individuals in the D:A:D study. AIDS. 2010;24:1537-1548.
  18. Helleberg M, Gerstoft J, Afzal S, et al. Risk of cancer among HIV-infected individuals compared to the background population: impact of smoking and HIV. AIDS. 2014;28:1499-1508.
  19. Lifson AR, Neuhaus J, Arribas JR, et al. Smoking-related health risks among persons with HIV in the Strategies for Management of Antiretroviral Therapy Clinical Trial. Am J Public Health. 2010;100:1896-1903.
  20. Vandenhende MA, Roussillon C, Henard S, et al. Cancer-related causes of death among HIV-infected patients in France in 2010: evolution since 2000. PLoS One. 2000;10:e0129550.
  21. Clifford GM, Lise M, Franceschi S, et al. Lung cancer in the Swiss HIV Cohort Study: role of smoking, immunodeficiency and pulmonary infection. Br J Cancer. 2012;106:447-452.
  22. Engsig FN, Kronborg G, Larsen CS, et al. Lung cancer in HIV patients and their parents: a Danish cohort study. BMC Cancer. 2011;11:272.
  23. Marcus JL, Chao C, Leyden WA, et al. Survival among HIV-infected and HIV-uninfected individuals with common non-AIDSdefining cancers. Cancer Epidemiol Biomarkers Prev. 2015;24:1167-1673.
  24. Minkoff H, Feldman JG, Strickler HD, et al. Relationship between smoking and human papillomavirus infections in HIV-infected and -uninfected women. J Infect Dis. 2004;189:1821-1828.
  25. Massad LS, Xie X, Burk R, et al. Long-term cumulative detection of human papillomavirus among HIV seropositive women. AIDS. 2014;28:2601-2608.
  26. Ellerbrock TV, Chiasson MA, Bush TJ, et al. Incidence of cervical squamous intraepithelial lesions in HIV-infected women. JAMA. 2000;283:1031-1037.
  27. Wiley DJ, Elashoff D, Masongsong EV, et al. Smoking enhances risk for new external genital warts in men. Int J Environ Res Public Health. 2009;6:1215-1234.
  28. Bertisch B, Franceschi S, Lise M, et al. Risk factors for anal cancer in persons infected with HIV: a nested case-control study in the Swiss HIV Cohort Study. Am J Epidemiol. 2013;178:877-884.
  29. Read TRH, Hocking JS, Vodstrcil LA, et al. Oral human papillomavirus in men having sex with men: risk-factors and sampling. PLoS One. 2012;7:e49324.
  30. Beachler DC, Sugar EA, Margolick JB, et al. Risk factors for acquisition and clearance of oral human papillomavirus infection among HIV-infected and HIV-uninfected adults. Am J Epidemiol. 2015;181:40-53.
  31. Calvo-Sánchez M, Perelló R, Pérez I, et al. Differences between HIV-infected and uninfected adults in the contributions of smoking, diabetes and hypertension to acute coronary syndrome: two parallel case-control studies. HIV Med. 2013;14:40-48.
  32. Petoumenos K, Worm S, Reiss P, et al. Rates of cardiovascular disease following smoking cessation in patients with HIV infection: results from the D:A:D study. HIV Med. 2011;12:412-421.
  33. Sobieszczyk ME, Hoover DR, Anastos K, et al. Prevalence and predictors of metabolic syndrome among HIV-infected and HIV-uninfected women in the Women's Interagency HIV Study. J Acquir Immune Defic Syndr. 2008;48:272-280.
  34. Shiau S, Broun EC, Arpadi SM, Yin MT. Incident fractures in HIV-infected individuals: a systematic review and meta-analysis. AIDS. 2013;27:1949-1957.
  35. Dong HV, Cortes YI, Shiau S, Yin MT. Osteoporosis and fractures in HIV/hepatitis C virus coinfection: a systematic review and meta-analysis. AIDS. 2014;28:2119-2131.
  36. Míguez-Burbano MJ, Wyatt C, Lewis JE, Rodríguez A, Duncan R. Ignoring the obvious missing piece of chronic kidney disease in HIV: cigarette smoking. J Assoc Nurses AIDS Care. 2010;21:16-24.
  37. Ryom L, Mocroft A, Kirk O, et al. Predictors of advanced chronic kidney disease and end-stage renal disease in HIV-positive persons. AIDS. 2014;28:187-199.
  38. Patel PK, Erlandsen JE, Kirkpatrick WR, et al. The changing epidemiology of oropharyngeal candidiasis in patients with HIV/AIDS in the era of antiretroviral therapy. AIDS Res Treat. 2012;2012:262471.
  39. Chattopadhyay A, Patton LL. Smoking as a risk factor for oral candidiasis in HIV-infected adults. J Oral Pathol Med. 2013; 42:302-308.
  40. Alpagot T, Duzgunes N, Wolff LF, Lee A. Risk factors for periodontitis in HIV patients. J Periodontal Res. 2004;39:149-157.
  41. Sroussi HY, Villines D, Epstein J, Alves MC, Alves ME. Oral lesions in HIV-positive dental patients -- one more argument for tobacco smoking cessation. Oral Dis. 2007;13:324-328.
  42. Aliyu MH, Weldeselasse H, August EM, Keith LG, Salihu HM. Cigarette smoking and fetal morbidity outcomes in a large cohort of HIV-infected mothers. Nicotine Tob Res. 2013;15:177-184.
  43. Bénard A, Mercié P, Alioum A, et al. Bacterial pneumonia among HIV-infected patients: decreased risk after tobacco smoking cessation. ANRS CO3 Aquitaine Cohort, 2000-2007. PLoS One. 2010;5:e8896.
  44. O'Connor JL, Gardner EM, Mannheimer SB, et al. Factors associated with adherence amongst 5295 people receiving antiretroviral therapy as part of an international trial. J Infect Dis. 2013;208:40-49.
  45. Shuter J, Bernstein SL. Cigarette smoking is an independent predictor of nonadherence in HIV-infected individuals receiving highly active antiretroviral therapy. Nicotine Tob Res. 2008;10:731-736.
  46. O'Cleirigh C, Valentine SE, Pinkston M, et al. The unique challenges facing HIV-positive patients who smoke cigarettes: HIV viremia, ART adherence, engagement in HIV care, and concurrent substance use. AIDS Behav. 2015;19:178-185.
  47. Ompad DC, Kingdon M, Kupprat S, Halkitis SN, Storholm ED, Halkitis PN. Smoking and HIV-related health issues among older HIV-positive gay, bisexual, and other men who have sex with men. Behav Med. 2014;40:99-107.
  48. Feldman JG, Minkoff H, Schneider MF, et al. Association of cigarette smoking with HIV prognosis among women in the HAART era: a report from the Women's Interagency HIV Study. Am J Public Health. 2006;96:1060-1065.
  49. Shirley DK, Kaner RJ, Glesby MJ. Effects of smoking on non-AIDS-related morbidity in HIV-infected patients. Clin Infect Dis. 2013;57:275-282.
  50. Tamí-Maury I, Vidrine DJ, Fletcher FE, Danysh H, Arduino R, Gritz ER. Poly-tobacco use among HIV-positive smokers: implications for smoking cessation efforts. Nicotine Tob Res. 2013;15:2100-2106.
  51. Mdodo R, Frazier EL, Dube SR, et al. Cigarette smoking prevalence among adults with HIV compared with the general adult population in the United States. Ann Intern Med. 2015;162:335-344.
  52. Furber AS, Maheswaran R, Newell JN, Carroll C. Is smoking tobacco an independent risk factor for HIV infection and progression to AIDS? A systemic review. Sex Transm Infect. 2007;83:41-46.
  53. Marshall MM, McCormack MC, Kirk GD. Effect of cigarette smoking on HIV acquisition, progression, and mortality. AIDS Educ Prev. 2009;21(3 suppl):28-39.
  54. Earla R, Ande A, McArthur C, Kumar A, Kumar S. Enhanced nicotine metabolism in HIV-1-positive smokers compared with HIV-negative smokers: simultaneous determination of nicotine and its four metabolites in their plasma using a simple and sensitive electrospray ionization liquid chromatography-tandem mass spectrometry technique. Drug Metab Dispos. 2014;42:282-293. Erratum in Drug Metab Dispos. 2014;42:1596-1598.
  55. Calvo M, Laguno M, Martínez M, Martínez E. Effects of tobacco smoking on HIV-infected individuals. AIDS Rev. 2015;17:47-55.
  56. Pal D, Kwatra D, Minocha M, Paturi DK, Budda B, Mitra AK. Efflux transporters- and cytochrome P-450-mediated interactions between drugs of abuse and antiretrovirals. Life Sci. 2011;88:959-971.
  57. Ande A, McArthur C, Kumar A, Kumar S. Tobacco smoking effect on HIV-1 pathogenesis: role of cytochrome P450 isozymes. Expert Opin Drug Metab Toxicol. 2013;9:1453-1464.
  58. Polito JR. Nicotine addiction 101. WhyQuit.com.