Smoking's Pernicious Impact Worse With HIV Infection

Spring 2016

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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

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This article was provided by The Center for AIDS Information & Advocacy. It is a part of the publication Research Initiative/Treatment Action!. Visit CFA's website to find out more about their activities and publications.

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