The use of HAART among HIV-infected individuals has led to a considerable decrease in the incidence of AIDS-defining cancers, most notably Kaposi sarcoma and non-Hodgkin lymphoma [1,2]. Compared to the pre-HAART era, HIV-infected adults in the HAART era have experienced an increased incidence and proportional mortality for certain non-AIDS-defining malignancies, including lung cancer [3–6]. This increase is partially due to longer life expectancy since the introduction of HAART, allowing HIV-infected individuals to reach older ages when the incidence rates of several common tumors, including lung cancer, begin to rise [7,8]. Additionally, HIV-infected adults are more likely to smoke tobacco than the general population [9–14], and almost all HIV-infected patients with lung cancer reported to date have had a history of cigarette smoking [12,13,15–17].
Although several studies have reported a higher incidence of lung cancer among people with HIV and AIDS as compared to population estimates [2,4,18], it is unclear whether this increase is due to HIV or to other risk factors for lung cancer such as cigarette smoking [12,19]. A study comparing HIV-infected with HIV-uninfected participants from the Women's Interagency HIV Study (WIHS) observed that the lung cancer incidence rates were similar in the two groups after adjusting for smoking history . A study comparing cancer incidence in the Multicenter AIDS Cohort Study (MACS) found that compared to HIV-uninfected MSM, HIV-infected men had elevated but not significantly different rates of lung cancer when controlling for history of cigarette smoking . Both these prior studies in the WIHS and the MACS were limited by a relatively small number of incident lung cancer cases (N = 14 in the WIHS and N = 15 in the MACS), and neither study considered risk factors such as prior lung disease or AIDS diagnosis in their analyses.
HIV-related immunosuppression can lead to chronic immune activation, inflammation, and immune system dysfunction, which can increase the risk of developing lung cancer [20,21]. Yet, the relationship between CD4+ lymphocyte count, duration of immunodeficiency, and lung cancer risk is uncertain, with some studies finding an association between CD4+ lymphocytes less than 200 [22–24], or duration of severe immunodeficiency  and incident lung cancer, whereas others have not [13,15,26,27].
Pre-existing lung disease, both infectious and noninfectious diseases, including asthma, has been associated with a trend toward increased lung cancer risk [15,28]. Consistent with these trends, a study investigating the role of AIDS-defining pulmonary infections on the subsequent risk of lung cancer reported that HIV-infected individuals with recurrent pneumonia were at a significantly higher lung cancer risk than those without this history, after adjusting for age, race, sex, HIV acquisition mode, CD4+ lymphocyte count, and AIDS diagnosis year . These studies suggest that factors other than HIV infection or immunodeficiency may increase the risk of lung cancer in HIV-infected individuals.
The aims of this investigation were to determine the incidence, risk factors, and survival time for lung cancer among the participants in two longitudinal studies of HIV infection in the US women and men. Both cohort studies include a comparison group of HIV-uninfected at-risk individuals. We hypothesized that the observed increased incidence of lung cancer among HIV-infected individuals would primarily be due to cigarette smoking and secondarily due to pre-existing pulmonary disease.
Data from participants in two US HIV/AIDS cohort studies – the WIHS and the MACS – were used for this investigation. In the WIHS cohort, recruitment of HIV-infected and HIV-uninfected women occurred in 1994–1995 and again in 2001–2002, for a total of 3766 women (2791 HIV-infected and 975 HIV-uninfected). Data for the WIHS were collected from the following six centers: Brooklyn, Bronx, Washington, District of Columbia, Chicago, the Los Angeles area, and the San Francisco Bay area. Women in the WIHS returned at 6-month intervals for a standardized interview-based questionnaire, physical examination, and collection of blood for laboratory testing and storage. Detailed information about the WIHS study methodology, quality assurance, and baseline characteristics of the enrollees has been published [30,31].
The MACS recruited a total of 6972 men (2943 HIV-infected and 4029 HIV-uninfected) during three recruitment periods: from April 1984 through March 1985, from April 1987 through September 1991, and from October 2001 through August 2003. Men who reported having had sex with men were enrolled at one of the four metropolitan areas in the United States (Baltimore, Maryland and Washington, District of Columbia; Chicago, Illinois; Pittsburgh, Pennsylvania; and Los Angeles, California). The details about the recruitment and characteristics of the MACS cohort have been reported elsewhere . Participants in the MACS returned at 6-month intervals for a detailed interview, physical examination, neuropsychological testing, and collection of blood for laboratory testing and storage.
All analyses were performed using data collected through 30 September 2012, but follow-up was censored on 30 September 2011, to allow cancer reporting delays (Federal and state law requires all new cancer diagnoses to be reported to the cancer registries within 180 days ). The individual institutional review boards of each institution involved approved these studies; all participants provided written informed consent.
Lung cancer diagnosis
Ascertainment of lung cancer cases was obtained via: searches of state-wide cancer registries, medical record confirmation of self-reported cancer diagnoses, and death certificates. Eight of the nine sites performed their state cancer registry matches between 2010 and 2012, with one site match in 2008. For this analysis, four participants who had lung cancer diagnosed more than 4 years after their last study visit were censored as being cancer-free at the time of their last study visit due to missing data preceding their cancer diagnosis.
Risk factors for cancer
The lung cancer risk factors included in this analysis were study cohort (WIHS women or MACS men), age, race/ethnicity (African American vs. all other), history of injection drug use (IDU) (ever vs. never), educational attainment (a high school degree or less vs. more than high school degree), BMI (kg/m2 per 10 unit increase), pack-years of smoking, history of asthma (excluded from MACS multiple regression analysis due to 32% missing data), calendar time, HAART use, and prior clinical AIDS diagnosis. Among the AIDS diagnoses, additional categorization was made for AIDS-related pneumonias – Pneumocystis jiroveci pneumonia (PCP) and recurrent bacterial pneumonia. Laboratory measures included HIV antibody status, nadir and peak CD4+ lymphocyte count (cells/μl), and quantitative plasma HIV-RNA levels. HIV medications were categorized as HAART or non-HAART using guidelines published by the Department of Health and Human Services at the time of the study visit .
All but one incident lung cancer occurred among participants who had reported a history of cigarette smoking at enrollment; therefore we restricted this study to the 6823 (2549 WIHS, 4274 MACS) participants who reported having smoked at least 100 cigarettes prior to their baseline study visit. Study participants were characterized at baseline using standard descriptive statistics. Lung cancer incidence rates were computed as the number of observed incident cancers divided by the number of person-years of follow-up, in which case follow-up time was measured from the baseline visit until the earliest of the lung cancer diagnosis, death, or the date of the last study visit on or prior to 30 September 2011. Lung cancer incidence rate comparisons were quantified using the incidence rate ratio (IRR) and were performed using exact Poisson regression whenever possible, and asymptotic results were obtained and reported when exact methods failed. To examine the effects of HIV-related factors such as HAART exposure, low CD4+ lymphocyte count, and prior AIDS diagnosis, we created separate indicator variables for HIV infection with and without the exposure of interest (e.g. HIV-infected and HAART-naïve vs. HIV-infected and HAART-exposed), and then compared the lung cancer incidence rates for each group to that of the HIV-uninfected reference group. We also assessed the association between lung cancer and a prior AIDS pneumonia diagnosis, and lagged the AIDS pneumonia diagnosis for up to 5 years to examine the possibility that those with a prior history of AIDS pneumonia might have had their lung cancer diagnosed earlier (diagnostic bias) than those without pneumonia due to an expanded pulmonary work-up of their AIDS pneumonia. All cofactors that varied over time were evaluated using time-varying covariates. We also added interaction terms to the final multiple regression models to determine whether the effect of any covariate differed significantly between WIHS and MACS.
Survival following lung cancer diagnosis was analyzed using Kaplan–Meier methods and Cox proportional-hazards models for the combined WIHS/MACS cohort. Except for age, which was calculated on the date of lung cancer diagnosis, participant characteristics were measured at the last study visit prior to diagnosis. For the multiple regression analysis, we forced cohort, age, and HIV status into the model and then examined the effects of geographic location, race, pack-years, more than a high school education, history of IDU, and lung cancer histology on survival. The final model included the factors forced into the model and also those that remained significant at the 0.05 level. The proportionality assumption was assessed by testing for an interaction between each covariate and the natural logarithm of time.
Two sensitivity analyses were performed to explore the possibility that higher AIDS-related morbidity and mortality during the pre-HAART era might have lowered the lung cancer incidence rates and altered the effects of certain risk factors on lung cancer incidence. We first repeated the multivariable analyses using only follow-up time accrued between 1995 and 2011, and then performed a competing risk analysis  of lung cancer incidence when death due to any cause was treated as a competing event. All analyses were performed using SAS 9.3 , STATA 12 , or StatXact 10.0 . Statistical significance was inferred from P values less than 0.05 using a two-sided test.
The baseline characteristics of the WIHS and MACS participants who reported a history of cigarette smoking are described in Table 1. Compared to men, notable differences for women at the time of enrollment included a higher proportion of African-Americans, less education, a lower cumulative number of smoking pack-years, and higher proportions with a history of asthma and IDU. In addition, the WIHS participants were significantly more likely to be infected with HIV and, among those with HIV, to have lower CD4+ lymphocyte counts.
Lung cancer histology
Of the 60 lung cancers, histology was known for 48 (80%). The most common histologic type was adenocarcinoma (n = 23), followed by nonsmall cell carcinoma (n = 9) and squamous cell carcinoma (n = 8). Histologic type did not differ significantly by HIV status (exact P value = 0.85) or between cohorts (exact P value = 0.39).
Lung cancer incidence
We observed 37 incident lung cancers (31 in HIV-infected participants and 6 in HIV-uninfected participants) among 2549 WIHS participants and 23 incident lung cancers (15 HIV-infected and 8 HIV-uninfected) among 4274 MACS participants (Table 2). The average age at diagnosis was 52.1 for the HIV-infected women, 51.3 for the HIV-uninfected women, 49.6 for the HIV-infected men, and 54.4 for the HIV-uninfected men. Overall, the lung cancer incidence rate was significantly higher among women than among men (P < 0.0001), and higher among HIV-infected participants than among uninfected participants (P = 0.001; Table 2).
In unadjusted analyses, lung cancer incidence rates were significantly higher in both cohorts among older participants and those who had accumulated more than 30 pack-years of smoking exposure. Lung cancer incidence rates were also elevated among African-Americans and those with a history of IDU among women and among less educated men (Table 3). Whereas women with a history of asthma also had a significantly higher lung cancer incidence rate, the data were not available to evaluate this risk factor among men.
HIV infection was not significantly associated with unadjusted lung cancer incidence rates in either cohort, but the IRRs suggested a two-fold higher incidence for HIV-infected men and women (Table 3). When we combined the two cohorts, HIV infection was significantly associated with lung cancer incidence [IRR 2.64, 95% confidence interval (CI) 1.43–5.21]. Among MACS participants infected with HIV, the unadjusted results indicate that higher lung cancer incidence was associated with lower CD4+ T-cell counts, higher peak HIV RNA levels, and a prior AIDS diagnosis (Table 3).
In multivariable analyses of the combined WIHS and MACS participants using all data (1984–2011), the factors that were found to be independently associated with a higher lung cancer incidence rate were older age, less education, 10 or more pack-years of smoking, and prior AIDS pneumonia diagnosis (Table 4). The association between lung cancer incidence and a prior AIDS pneumonia diagnosis remained significant even when the pneumonia diagnosis was lagged by up to 5 years (data not shown). By testing interaction terms, we determined that none of the effects of the risk factors included in the multiple regression analysis differed significantly between the WIHS and the MACS participants. Finally, in a subgroup analysis restricted to the women in the WIHS, lung cancer incidence was also independently associated with a history of asthma (IRR 2.44, 95% CI 1.17–5.06).
Of the 31 incident lung cancers among HIV-infected women in the WIHS, 20 reported a prior AIDS diagnosis, of which 14 consisted of pneumonia; all 14 were diagnosed with repeated bacterial pneumonia and 7 were also diagnosed with PCP. Of the 15 incident lung cancers among HIV-infected men in the MACS, six reported a prior AIDS diagnosis, of which three were pneumonia; all three were diagnosed with PCP and one was also diagnosed with repeated bacterial pneumonia.
Lung cancer survival
We examined survival following lung cancer diagnosis in 56 of the 60 cases, excluding four participants who had no follow-up time after lung cancer diagnosis. In cohort-stratified Kaplan–Meier survival time analyses of these 56 cases, there were 45 deaths, with an estimated median survival of 9.5 months for women in the WIHS and 6.2 months for men in the MACS (log-rank P value 0.71).
In unadjusted Cox proportional-hazard analyses among these 56 cases, the only factor associated with longer survival time was being diagnosed in 2001–2011 (vs. 1984–1994, hazard ratio 0.31, 95% CI 0.14–0.70; Table 5). In the final multivariable Cox model adjusted for cohort, age, and HIV infection, two variables remained significant: more recent calendar period (2001–2011) was associated with improved survival (hazard ratio 0.23, 95% CI 0.07–0.71) and history of IDU was associated with shorter survival time (hazard ratio 2.98, 95% CI 1.28–6.95; Table 5). When the final adjusted model was restricted to the 42 HIV-infected cases and evaluated for the effect of HAART use, prior AIDS diagnosis, prior AIDS-pneumonia, HIV viral load, and CD4+ lymphocyte count, the only HIV disease measure found to be independently associated with survival at the P 0.05 level was nadir CD4+ lymphocyte cell count less than 200 (hazard ratio 2.55, 95% CI 1.09–5.95).
Sensitivity analyses for both lung cancer incidence and survival were performed using a study sample that was restricted to HAART era observations (1995–2011), which included 37 lung cancer cases and 24 330 person-years of observation in the WIHS, and 14 lung cancer cases and 21 871 person-years of observation in the MACS. In this restricted cohort, the estimated IRRs were similar to those obtained using the entire cohort, although the CIs around the estimates were larger and education was not statistically significant (Table 4). Examination of interactions between cohort and each of the other covariates in the model revealed that the effect of nadir CD4+ lymphocyte cell count less than 200 differed significantly between the two cohorts (IRR 1.04, 95% CI 0.48–2.24 in WIHS vs. IRR 4.19, 95% CI 1.29–13.59 in MACS). We also found that the lung cancer incidence results obtained when death was treated as a competing risk were analogous to those reported in Table 4 (supplemental Table 1, https://links.lww.com/QAD/A693). Finally, the results of the survival analyses remained comparable to those obtained from the full study sample (data not shown).
Lung cancer incidence is significantly higher among HIV-infected individuals than the general population [2,4,18,39], yet the precise role of HIV and immune suppression remains somewhat elusive. By analyzing data from cohort studies of HIV-infected and HIV-uninfected at-risk participants, and then incorporating information on HIV status, CD4+ lymphocyte count, prior AIDS diagnosis, prior lung disease, age, education, and pack-years of smoking, we were better able to address the independent contribution of HIV infection to the increased rate of lung cancer among HIV-infected individuals. We found that approximately two-thirds of the effect of HIV infection was explained by a diagnosis of prior AIDS pneumonia. Our results are consistent with other studies that have reported an increased risk of lung cancer among HIV-infected adults with prior lung disease and/or AIDS pneumonia [15,28,29].
Reasons why the increased risk of lung cancer among HIV-infected persons may not be fully explained by the number of pack-years of smoking include lung damage from chronic or recurrent infections (which are more common in HIV-infected persons), an aberrant inflammatory response, or an HIV-mediated increase in susceptibility to tobacco carcinogens [15,40]. Inflammatory pulmonary disease and infections have been shown to play a role in the development of lung cancer in the general population , and this has also been observed among HIV-infected individuals, particularly in association with recurrent pneumonias . Chronic or recurrent infections (such as HIV and pneumonia, respectively), as well as chronic inflammation from smoking, can induce inflammatory and genetic changes that lead to the development of lung cancer in susceptible individuals.
Our observation that lung cancer survival has improved over time may be due to several recent trends, including increased pulmonary disease screening for people with HIV and thus the potential for earlier diagnosis of lung cancer; widespread use of HAART before, during, and after lung cancer treatment, thus preventing intercurrent infection and treatment delays, as well as progression to AIDS; and increased use and efficiency of cancer treatment in HIV-infected individuals over time. Other studies of HIV-infected adults have also reported longer lung cancer survival time for those diagnosed more recently [17,42–44].
Our study has a few limitations. First, the women in the WIHS differed from the men in the MACS on a number of measured and unmeasured potential risk factors for the development of lung cancer. Whereas we might be able to control for notable differences, such as race, we are unable to completely rule out differences that may be due to environmental factors, such as second-hand smoke, or health-related behaviors, such as diet and exercise. Second, all participants in this study had history of smoking and thus we did not asses the lung cancer risk among nonsmokers. However, there was only one case of lung cancer in a cigarette nonsmoker and that person reported a long history of smoking marijuana. Third, stage at cancer diagnosis and lung cancer treatment data were not available for 57 and 100% of the men, respectively, and 23 and 22% of the women, respectively, and thus we were unable to evaluate the effect of cancer stage or treatment on survival time. Finally, our results may not be applicable to all people living with, or at risk for HIV infection, especially those living in developing countries where tobacco use, environmental factors, and lung cancer diagnosis or treatment may differ from those in the United States.
Despite these limitations, our study is unique in many ways. A large number of study participants were included (over 6800 men and women), with many person-years of follow-up (69 738 person-years). A rich database was available, and included both HIV-infected participants as well as similar HIV-uninfected comparison groups. Our investigation spanned both pre-HAART and HAART time periods, thus allowing temporal comparisons. Additionally, the two cohorts were comprised of a racial/ethnic mix, which is quite diverse and fairly representative of men and women living with HIV nationally.
In summary, using data from two of the largest longitudinal studies of HIV infection among men and women in the United States, we found that HIV infection alone was not an independent risk factor for lung cancer, but that the amount of cigarette smoking over time and prior AIDS pneumonia among HIV-infected adults were major contributors for the development of lung cancer. Older age and pack-years of smoking were the strongest risk factors for lung cancer. Thus, encouraging and assisting younger HIV-infected smokers to quit and to sustain cessation of smoking is imperative to reduce the lung cancer burden in this population. Practitioners treating HIV-infected smokers have an ideal opportunity to teach their patients that serious and life-threatening health conditions may be exacerbated by smoking and can be ameliorated by quitting [45–48]. A better understanding of the role and consequence of HIV-related lung disease on lung cancer pathogenesis is needed.
N.A.H. contributed to the design and execution of the project, interpretation of results, and writing of the manuscript. O.M.-M. contributed to the execution of the project and writing of the manuscript. A.M.L. contributed to the design and execution of the project, interpretation of the results, and writing of the manuscript. A.M. contributed to the interpretation of the results and writing of the manuscript. J.B.M. contributed to the execution of the project, interpretation of results, and writing of the manuscript. M.H.C. contributed to the execution of the project and writing of the manuscript. L.P.J. contributed to the design and execution of the project and writing of the manuscript. E.C.S. was the statistician and analyst of this project and contributed to the design and execution of the project, interpretation of results, and writing of the manuscript.
Data in this manuscript were collected by the Women's Interagency HIV Study (WIHS) Collaborative Study Group with centers (Principal Investigators) at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, New York (Howard Minkoff); Washington, District of Columbia Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); Data Coordinating Center (Stephen Gange). The WIHS is funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (UO1-HD-32632). The study is co-funded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI Grant Number UL1 RR024131).
Data in this manuscript were also collected by the Multicenter AIDS Cohort Study (MACS) with centers (Principal Investigators) at The Johns Hopkins Bloomberg School of Public Health (Joseph B. Margolick, Lisa P. Jacobson), Howard Brown Health Center, Feinberg School of Medicine, Northwestern University, and Cook County Bureau of Health Services (John P. Phair, Steven M. Wolinsky), University of California, Los Angeles (Roger Detels), and University of Pittsburgh (Charles R. Rinaldo). The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute (UO1-AI-35042, UL1-RR025005 (GCRC), UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, UO1-AI-35041).
Human Participant Protection: Study protocols and consent materials were reviewed and approved by the institutional review boards at each of the collaborating institutions and informed consent was obtained from the participants.
Conflicts of interest
The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
Disclosure statement: The authors have no conflicts of interest to disclose.
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