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Epidemiology and Social

Risk of smoking-related cancers among women and men living with and without HIV

Hessol, Nancy A.a,b; Barrett, Benjamin W.c; Margolick, Joseph B.d; Plankey, Michaele; Hussain, Shehnaz K.f; Seaberg, Eric C.c; Massad, L. Stewartg

Author Information
doi: 10.1097/QAD.0000000000002717

Abstract

Introduction

As people living with HIV (PLWH) are aging, largely because of effective ART, cancer – particularly non-AIDS defining cancer – has become a more common cause of morbidity and mortality [1]. The high prevalence of cancer risk factors among PLWH, especially tobacco use, contributes to the increased risk of cancer. In the United States, the estimated percentage of adult PLWH who smoke was twice that of the United States general population and the smoking prevalence varied by HIV risk behavior groups [2–4]. A better understanding of the contribution of smoking to the development of cancer in PLWH can help promote smoking cessation among smokers living with HIV.

In 2010, approximately 29% of all cancer deaths in the United States were attributable to cigarette smoking [5]. The contribution of smoking to the cancer burden among PLWH is less well defined. In a study of PLWH in Denmark, the estimated percentage of smoking-related cancer diagnoses attributable to smoking was 91% [6].

A limitation of prior studies investigating cancer risk in PLWH has been the lack of an appropriate comparison group, which has traditionally been the general population. PLWH are very different from the general population, and thus comparisons are confounded by other cancer risk factors like cigarette smoking, human papilloma virus (HPV) and hepatitis C virus (HCV) infection, and substance use. For example, women in the Women's Interagency HIV Study (WIHS) had a high prevalence of smoking (more than twice the national average) independent of HIV status [7]. Similarly, the prevalence of smoking in the men with and without HIV in the Multicenter AIDS Cohort Study (MACS) is almost twice as high as the national average [8].

The present study has the unique advantage of a highly similar HIV-uninfected comparison group, as well as the ability to precisely adjust for potential confounders and examine sex-related differences. This investigation had three aims. First, to determine whether the effect of smoking on the incidence of smoking-related cancers differs by HIV-infection status among participants in the MACS and WIHS. We hypothesized that for a given smoking history, the incidence of smoking-related cancers would be higher among PLWH vs. those without HIV [6]. Second, to determine whether sex modifies the impact of cancer risk factors among WIHS and MACS participants. We hypothesized that the adjusted risk of smoking-related cancers would be higher among women (both with and without HIV) than among men [9]. Third, to estimate the sex-specific attributable risk of smoking on smoking-related cancers among women in the WIHS and men in the MACS. We hypothesized that approximately 50% of smoking-related cancers would be prevented if PLWH refrained from smoking [10].

Methods

Study population

Data collected through 30 September 2019, from participants in two US HIV/AIDS cohort studies, the WIHS and the MACS, were used for this investigation. The WIHS is a multisite prospective cohort study of 4982 women with or at risk for HIV established in 1994. Women were enrolled at one of 11 centers across the United States and returned at 6-month intervals for a standardized interview-based questionnaire, physical examination including pelvic exam, Pap test with referral for colposcopy for any abnormality, and collection of blood for laboratory testing and storage. Detailed information about the WIHS study methodology and baseline characteristics of enrollees has been published [11,12].

The MACS is a multisite prospective cohort study of 7358 men who reported having had sex with men. Men were enrolled, starting in 1984, at four metropolitan areas in the United States. Details about the recruitment and characteristics of the MACS cohort have been reported elsewhere [13]. Participants returned at 6-month intervals for a detailed interview, physical examination, and collection of blood for laboratory testing and storage.

Participants who had at least one follow-up visit, reported their history of tobacco use, and entered the study without a prior or prevalent (diagnosed within 6 months of study enrollment) smoking-related cancer were included in these analyses (6789 men and 4423 women). All analyses were performed using data collected through 30 September 2019, but follow-up was censored on 31 December 2018 to allow for cancer reporting delays (federal and state law requires all new cancer diagnoses to be reported to the cancer registries within 180 days) [14]. The institutional review boards of each institution approved these studies; all participants provided written informed consent.

Cancer diagnosis

Cancer diagnoses were ascertained using medical records, cancer registry matches, and death certificates. Each confirmed cancer was classified according to the SEER site recoding scheme, which is based on the International Classification of Diseases for Oncology 3rd edition[15], and all cancers with an initial diagnosis date that was at least 6 months after enrollment into the cohort study (to account for a lag time in diagnosis) were further classified as ‘incident’ cancers. We then identified smoking-related incident cancers: lung/bronchus, larynx, liver, colon, rectum, small intestine, kidneys, oral cavity, nose and middle ear, acute myeloid leukemia, cervix, vagina, vulva, penis, anus, pancreas, esophagus, bladder, and stomach [16–18]. We created a single combined endpoint where the first occurrence of any of these cancers was treated as an event. Those who developed a nonsmoking-related cancer continued in follow-up.

Risk factors for cancer

The independent variables included several known cancer risks, such as tobacco use, alcohol consumption, illicit substance use, BMI, and coinfection with HPV and HCV. Other variables included sociodemographic characteristics, behavioral factors, characteristics of HIV infection, geographic region, and calendar period. For further details regarding independent variables, see Appendix, https://links.lww.com/QAD/B867.

Statistical analysis

Study participants were characterized at baseline using standard descriptive statistics. Smoking-related cancer incidence rates were computed as the number of observed incident cancers divided by person-years of follow-up, where follow-up time was measured from 6 months after the baseline visit until the earliest of the first smoking-related cancer diagnosis, death, or date of the last study visit. Incidence rates of smoking-related cancers were adjusted for age and compared by cumulative pack-years smoked lagged by 10 years (as smoking-related cancers take at least 10 years to manifest) [19], years since smoking cessation, HIV status, and sex (MACS vs. WIHS). HIV serostatus was considered as a time-varying variable to allow for the possibility of HIV seroconversion during follow-up (see Appendix, https://links.lww.com/QAD/B867).

Smoking-related cancer incidence rate comparisons were quantified using the incidence rate ratio (IRR) and performed using exact Poisson regression wherever possible. For the IRR analyses, the dependent (outcome) variable for this investigation was smoking-related cancer, yes or no. The effects of HIV-related variables were examined in two ways. First, unadjusted models were stratified by HIV serostatus. Second, pooled univariate models included indicator variables for HIV infection with and without the exposure of interest, compared with the HIV-uninfected reference group. All variables collected at each study visit (see Appendix, https://links.lww.com/QAD/B867) were evaluated using time-varying covariates. Interaction terms were added to the final multiple regression models to determine whether a covariate effect differed significantly by sex.

To explore the possibility that higher AIDS-related morbidity and mortality during the pre-ART and early ART era lowered the smoking-related cancer incidence rates and altered the effects of certain risk factors on cancer incidence, we repeated the multivariable analyses using only follow-up time accrued between 2001 and 2018 (the modern ART treatment era). As several of the smoking-related cancers may also have viral causes, we repeated the age-adjusted incident rates and adjusted IRR analyses and excluded anal, cervix, gum and mouth, larynx, liver, penis, pharyngeal, salivary gland, stomach, tongue, tonsil, and vagina/vulva cancers from the definition of smoking-related cancers to see how this impacted the association between smoking history and the development of smoking-related malignancies. Last, as anal cancers were three times more common in men than women, we repeated the adjusted population attributable fraction (PAF) analyses excluding anal cancers from the definition of smoking-related cancers to assess sex differences for the remaining smoking-related malignancies.

Pooled as well as stratified (MACS and WIHS) relative risks and adjusted PAFs were calculated for all incident smoking-related cancers; cancers strongly associated with smoking (lung/bronchus and larynx; average PAF range in men and women combined 78–97%); cancers moderately associated with smoking (esophagus, gum and mouth, lip, nose and middle ear, pharyngeal, and lower urinary tract; PAF range 31–60%); and cancers weakly associated with smoking (acute myeloid leukemia, anal, cervix, colon/rectum, liver, pancreas, penis, salivary gland, small intestine, stomach, tongue, tonsil, and vagina/vulva; PAF range 8–25%) [20]. For additional details regarding the PAF models and SAS macro [21], see Appendix, https://links.lww.com/QAD/B867. All analyses were performed using SAS 9.4 [22].

Results

Of the potentially eligible participants enrolled in the MACS (7358) and the WIHS (4982), 569 men and 559 women were excluded because of either no accrual of follow-up time (473 men and 376 women), lack of information about pack-years of smoking (89 men and 148 women) or because they had a smoking-related cancer prior to or within 6 months of their baseline visit (7 men and 35 women).

The remaining 4423 WIHS and 6789 MACS participants exhibited many significant differences at baseline (Table 1). Most notably, men were enrolled in earlier years and at younger ages; were more likely to be non-Latinx white and HIV-uninfected; had more education, higher household incomes, lower BMIs, and more lifetime sex partners; and consumed more alcohol (all P < 0.01). Women were more likely to smoke and had a higher prevalence of HCV, HIV, lower CD4+ cell counts, higher HIV viral loads, and a greater prevalence of clinical AIDS (all P-values <0.01).

Table 1 - Baseline characteristics of participants in the Multicenter AIDS Cohort Study and Women's Interagency HIV Study.
MACS WIHS
N (%) P value
Geographic region of recruitment site <0.01
 West coast 1964 (28.93) 1266 (28.62)
 East coast 3264 (48.08) 2641 (59.71)
 Midwest 1561 (22.99) 516 (11.67)
Enrollment cohort <0.01
 1984–1987 5302 (78.10) 0 (0.00)
 1994–1995 0 (0.00) 2301 (52.02)
 2001–2002 1149 (16.92) 957 (21.64)
 2010+ 338 (4.98) 1165 (26.34)
Race/ethnicity <0.01
 Non-Latinx white 4929 (72.62) 591 (13.36)
 Non-Latinx black 1129 (16.63) 2763 (62.47)
 Other 729 (10.74) 1069 (24.17)
Baseline educational attainment <0.01
 High school or less 1234 (18.30) 2924 (66.23)
 Some college 1991 (29.52) 1159 (26.25)
 College graduate 1505 (22.31) 233 (5.28)
 At least some postgraduate education 2015 (29.87) 99 (2.24)
Annual household income <0.01
 <$29 999 1072 (71.99) 3711 (86.50)
 ≥$30 000 417 (28.01) 579 (13.50)
Smoking status <0.01
 Never 2690 (39.62) 1532 (34.64)
 Former 1335 (19.66) 559 (12.64)
 Current 2764 (40.71) 2332 (52.72)
Alcohol use <0.01
 Abstainer 574 (8.61) 1957 (44.88)
 >0–7 drinks/week 3767 (56.49) 1788 (41.00)
 >7–12 drinks/week 715 (10.72) 183 (4.20)
 >12 drinks/week 1612 (24.18) 433 (9.93)
Smoked an illicit drug <0.01
 No 2617 (38.55) 2951 (66.72)
 Yes 4172 (61.45) 1472 (33.28)
Injected an illicit drug <0.01
 No 6255 (92.13) 4145 (93.71)
 Yes 534 (7.87) 278 (6.29)
Took an illicit drug other than through smoking/injection <0.01
 No 3119 (45.94) 4306 (97.35)
 Yes 3670 (54.06) 117 (2.65)
Any HPVa
 No 1534 (50.43)
 Yes 1508 (49.57)
Oncogenic HPVa
 No 2294 (75.41)
 Yes 748 (24.59)
Hepatitis C virus <0.01
 No 6375 (94.65) 3414 (80.96)
 Yes 360 (5.35) 803 (19.04)
HIV infection <0.01
 No 3805 (56.05) 1150 (26.00)
 Yes 2984 (43.95) 3273 (74.00)
CD4+ cell count/μl (PLWH only) <0.01
 <200 185 (6.34) 595 (18.61)
 200–500 1073 (36.78) 1368 (42.78)
 >500 1659 (56.87) 1235 (38.62)
HIV viral load detectable (PLWH only) <0.01
 No 481 (45.16) 1063 (33.42)
 Yes 584 (54.84) 2118 (66.58)
HIV viral load ≥4000 copies/ml (PLWH only) <0.01
 No 592 (55.59) 1526 (47.91)
 Yes 473 (44.41) 1659 (52.09)
Exposure to ART (PLWH only) <0.01
 No 2473 (82.88) 2327 (71.10)
 Yes 511 (17.12) 946 (28.90)
History of clinical AIDS (PLWH only) <0.01
 No 2969 (99.50) 2636 (80.54)
 Yes 15 (0.50) 637 (19.46)
Pre-ART nadir CD4+ cell/μl count (PLWH only) <0.01
 <200 1497 (50.37) 1004 (43.22)
 ≥200 1475 (49.63) 1319 (56.78)
Post-ART nadir CD4+ cell/μl count (PLWH only) <0.01
 <200 389 (28.21) 1098 (40.13)
 ≥200 990 (71.79) 1638 (59.87)
Peak HIV viral load (PLWH only) <0.01
 ≤10 000 copies/ml 563 (20.01) 1041 (31.81)
 >10 000 copies/ml 2251 (79.99) 2232 (68.19)
Median (IQR)
Cumulative pack-years smoked (never smokers excluded) 14.70 (4.58–28.84) 7.75 (3.00–15.50) <0.01
Years since smoking cessation 5.00 (1.00–8.25) 1.27 (0.30–5.78) <0.01
Age (years) 33.37 (28.28–39.42) 36.77 (30.63–43.52) <0.01
BMI (kg/m2) 23.30 (21.70–25.50) 27.20 (23.40–33.10) <0.01
Lifetime number of sexual partners 102.00 (34.00–400.00) 11.00 (5.00–35.00) <0.01
Total number of participants 6789 4423
Bold indicates statistical significance. Due to missing values, participant frequencies within variable categories may not sum to total participant counts. HPV, human papilloma virus; MACS, Multicenter AIDS Cohort Study; PLWH, people living with HIV; WIHS, Women's Interagency HIV Study.
aMACS participants not tested for HPV at baseline visit.

Smoking-related cancer incidence

We observed 214 smoking-related incident cancers among the MACS participants and 192 among the WIHS (see Table, Supplemental Digital Content 1, https://links.lww.com/QAD/B858). The majority of smoking-related cancers were lung/bronchus and were diagnosed in the modern ART era. Seven men and eight women had more than one primary smoking-related malignancy.

The age-adjusted incident rates for smoking-related cancers was higher among PLWH than participants without HIV (P < 0.01) and higher among women than men (P < 0.01; Table 2). Among those who smoked, incidence ratios among PLWH were higher than among those without HIV when stratifying by cumulative pack-years of smoking (all P values <0.01). When the smoking-related cancer incident rates among all women were compared with all men, the IRR was 2.0 (95% CI: 1.6–2.4). For women with HIV vs. men with HIV the IRR was 1.6 (95% CI: 1.2–2.0) and for women without HIV vs. men without HIV the IRR was 2.0 (95% CI: 1.3–3.0). Ten or more years as cessation of smoking resulted in a reduced incident rates of smoking-related cancers (P < 0.01).

Table 2 - Smoking-related cancer incidence among participants in the Multicenter AIDS Cohort Study and Women's Interagency HIV Study.
Baseline Smoking-related cancer incidence
N % N P-yrs IR per 100 000a [95% CI] P value
HIV infection
 Seronegative [ref] 4955 44 118 63 642 162.2 [133.6–196.9]
 Seropositive 6257 56 271 75 883 347.6 [303.1–398.5] <0.01
Cohort
 MACS [ref] 6789 61 206 92 047 197.5 [169.4–230.3]
 WIHS 4423 39 183 47477 391.6 [333.7–459.6] <0.01
Cumulative pack-yearsb
 Never smokers [ref] 6271 56 86 64 947 141.7 [114.1–175.9]
 1–10 2391 21 81 32 684 266.0 [212.4–333.1] <0.01
 11–20 1205 11 65 16 740 373.2 [290.1–480.0] <0.01
 21–30 647 6 47 10 634 379.5 [282.0–510.7] <0.01
 >30 698 6 110 14 521 480.3 [388.3–594.1] <0.01
Years since smoking cessationc
 <10 [ref] 1632 89 59 23 216 260.3 [192.8–351.6]
 10–19 144 8 15 10 909 100.1 [57.9–172.9] <0.01
 ≥20 62 3 24 7994 132.0 [81.0–215.1] <0.01
Cohort by HIV serostatus
 MACS seronegative [ref] 3805 34 85 50 542 138.3 [110.3–173.4]
 MACS seropositive 2984 27 121 41 505 279.0 [230.8–337.4] <0.01
 WIHS seronegative [ref] 1150 10 33 13 100 276.3 [195.5–390.5]
 WIHS seropositive 3273 29 150 34 377 434.1 [364.4–517.2] 0.02
Cumulative pack-years by HIV serostatusb
 Never smokers seronegative [ref] 2871 26 37 31 805 116.6 [84.1–161.6]
 Never smokers seropositive 3400 30 49 33 142 170.6 [128.5–226.5] 0.08
 1–10 seronegative [ref] 881 8 14 12 591 122.4 [72.3–207.1]
 1–10 seropositive 1510 13 67 20 091 358.8 [280.3–459.2] <0.01
 11–20 seronegative [ref] 505 5 13 6683 190.1 [110.1–328.5]
 11–20 seropositive 700 6 52 10057 497.6 [375.9–658.7] <0.01
 21–30 seronegative [ref] 310 3 11 4645 201.2 [110.9–365.2]
 21–30 seropositive 337 3 36 5989 527.8 [376.9–739.2] <0.01
 >30 seronegative [ref] 388 3 43 7918 329.8 [240.1–453.0]
 >30 seropositive 310 3 67 6602 668.1 [515.6–865.7] <0.01
Years since smoking cessation by HIV serostatusc
 <10 seronegative [ref] 789 43 15 10 131 152.8 [90.2–259.1]
 <10 seropositive 843 46 44 13 085 348.0 [248.3–487.8] <0.01
 10–19 seronegative [ref] 49 3 7 5354 93.2 [43.2–201.5]
 10–19 seropositive 95 5 8 5555 106.7 [51.8–220.0] 0.79
 ≥20 seronegative [ref] 24 1 5 4171 48.3 [19.1–121.8]
 ≥20 seropositive 38 2 19 3823 228.6 [135.2–386.4] <0.01
 Total 11 212 100 389 139 524 278.8 [252.4–307.9]
Bold indicates statistical significance. CI, confidence interval; IR, incidence rate; MACS, Multicenter AIDS Cohort Study; P-years, person-years; WIHS, Women's Interagency HIV Study.
aAll estimates adjusted for age.
bLagged by 10 years.
cStudy population limited to former smoking participants.

In unadjusted analysis and for participants without HIV, IRRs for smoking-related cancers were higher for older ages, non-Latinx blacks compared to non-Latinx whites, increasing cumulative pack-years of smoking compared with never smokers, those with a history of injecting drugs, and those with HCV at baseline (Table 3). People without HIV with more years of education also had lower unadjusted IRRs for smoking-related cancers. Similar results were seen for PLWH, with higher unadjusted IRRs for smoking-related cancers associated with older age, non-Latinx blacks, higher cumulative pack-years of smoking, history of injecting drugs, and HCV infection at baseline. Lower IRRs were associated with more years of education, as well as greater household income. In PLWH, higher IRRs were associated with having a prior AIDS diagnosis and exposure to ART, and lower IRRs associated with having CD4+ cell counts at least 200.

Table 3 - Unadjusted smoking-related cancer incidence rates among participants in the Multicenter AIDS Cohort Study and Women's Interagency HIV Study, stratified by HIV serostatus.
HIV seronegative HIV seropositive
Number of cancers P-yrs IR per 100 000 IRR [95% CI] P value No. cancers P-yrs IR per 100 000 IRR [95% CI] P value
Geographic region of recruitment site
 West coast [ref] 32 18 801 170.2 91 24 545 370.7
 East coast 76 34 552 220.0 1.3 [0.8–2.0] 0.26 140 36 518 383.4 1.0 [0.8–1.4] 0.86
 Midwest 10 10 288 97.2 0.6 [0.3–1.2] 0.15 40 14 819 269.9 0.7 [0.5–1.1] 0.11
Calendar period
 Before 1996 [ref] 22 24 454 90.0 21 16 983 123.7
 1996–1999 4 4046 98.9 1.1 [0.3–3.2] 1.00 27 9632 280.3 2.3 [1.2–4.2] <0.01
 2000–2003 8 7921 101.0 1.1 [0.4–2.6] 0.92 29 9288 312.2 2.5 [1.4–4.7] <0.01
 2004–2007 15 8180 183.4 2.0 [1.0–4.1] 0.06 47 11 664 402.9 3.3 [1.9–5.7] <0.01
 2008–2011 30 7279 412.1 4.6 [2.6–8.3] <0.01 60 10 275 583.9 4.7 [2.8–8.2] <0.01
 2012–2015 23 6762 340.1 3.8 [2.0–7.1] <0.01 47 10 017 469.2 3.8 [2.2–6.7] <0.01
 2016–2018 16 5001 319.9 3.6 [1.7–7.1] <0.01 40 8024 498.5 4.0 [2.3–7.2] <0.01
Age (years)
 <40 [ref] 8 20 781 38.5 22 24 679 89.1
 40–49 18 19 444 92.6 2.4 [1.0–6.4] 0.05 74 26 996 274.1 3.1 [1.9–5.2] <0.01
 50–59 44 14 239 309.0 8.0 [3.7–19.7] <0.01 117 17 876 654.5 7.3 [4.6–12.2] <0.01
 ≥60 48 9178 523.0 13.6 [6.4–33.3] <0.01 58 6332 916.0 10.3 [6.2–17.6] <0.01
Race/ethnicity
 Non-Latinx white [ref] 67 43 512 154.0 107 34 094 313.8
 Non-Latinx black 39 12 910 302.1 2.0 [1.3–3.0] <0.01 122 27 476 444.0 1.4 [1.1–1.9] 0.01
 Other 12 7207 166.5 1.1 [0.5–2.0] 0.90 42 14 312 293.5 0.9 [0.6–1.3] 0.79
Baseline educational attainment
 High school or less [ref] 46 14 332 321.0 146 30 342 481.2
 Some college 26 16 147 161.0 0.5 [0.3–0.8] <0.01 74 22 555 328.1 0.7 [0.5–0.9] <0.01
 College graduate 15 13 132 114.2 0.4 [0.2–0.6] <0.01 22 10 979 200.4 0.4 [0.3–0.7] <0.01
 At least some postgraduate education 31 19 770 156.8 0.5 [0.3–0.8] <0.01 29 11 879 244.1 0.5 [0.3–0.8] <0.01
Annual household income
 <$29 999 [ref] 35 19 640 178.2 147 39 335 373.7
 ≥$30 000 33 25 318 130.3 0.7 [0.4–1.2] 0.24 42 20 961 200.4 0.5 [0.4–0.8] <0.01
BMI (kg/m2)
 Under or normal weight (<25) [ref] 24 20 864 115.0 76 26 627 285.4
 Overweight (25–29) 18 19 427 92.7 0.8 [0.4–1.5] 0.59 51 20 883 244.2 0.9 [0.6–1.2] 0.44
 Obese (≥30) 17 13 877 122.5 1.1 [0.5–2.1] 0.96 29 16 224 178.7 0.6 [0.4–1.0] 0.04
Smoking status
 Never [ref] 16 20 340 78.7 20 22 155 90.3
 Former 27 21 242 127.1 1.6 [0.8–3.2] 0.17 57 22 372 254.8 2.8 [1.7–5.0] <0.01
 Current 24 18 163 132.1 1.7 [0.9–3.4] 0.14 92 26 447 347.9 3.9 [2.4–6.6] <0.01
Cumulative pack-yearsa
 Never smokers [ref] 37 31 805 116.3 49 33 141 147.9
 1–10 14 12 592 111.2 1.0 [0.5–1.8] 1.00 67 20 092 333.5 2.3 [1.5–3.3] <0.01
 11–20 13 6682 194.6 1.7 [0.8–3.2] 0.16 52 10 057 517.1 3.5 [2.3–5.3] <0.01
 21–30 11 4644 236.9 2.0 [0.9–4.1] 0.07 36 5989 601.1 4.1 [2.6–6.4] <0.01
 > 30 43 7918 543.1 4.7 [2.9–7.5] <0.01 67 6603 1014.7 6.9 [4.7–10.1] <0.01
Years since smoking cessationb
 <10 [ref] 15 10 131 148.1 44 13 085 336.3
 10–19 7 5354 130.7 0.9 [0.3–2.3] 0.98 8 5555 144.0 0.4 [0.2–0.9] 0.03
 ≥20 5 4171 119.9 0.8 [0.2–2.3] 0.90 19 3823 497.0 1.5 [0.8–2.6] 0.20
Alcohol use
 Abstainer [ref] 14 12 615 111.0 89 25881 343.9
 >0 to 7 drinks/week 31 32 542 95.3 0.9 [0.4–1.7] 0.74 54 33 666 160.4 0.5 [0.3–0.7] <0.01
 >7 to 12 drinks/week 10 6883 145.3 1.3 [0.5–3.2] 0.65 9 4644 193.8 0.6 [0.2–1.1] 0.12
 >12 drinks/week 10 7467 133.9 1.2 [0.5–2.9] 0.80 16 6018 265.9 0.8 [0.4–1.3] 0.41
Smoked an illicit drug
 No [ref] 108 44 170 244.5 210 51 565 407.3
 Yes 10 19 471 51.4 0.2 [0.1–0.4] <0.01 61 24 317 250.9 0.6 [0.5–0.8] <0.01
Injected an illicit drug
 No [ref] 118 63 013 187.3 265 74 212 357.1
 Yes 0 629 110.5 0.6 [–∞–2.6] 0.62 6 1670 359.3 1.0 [0.4–2.2] 1.00
Took illicit drugs other than through smoking/injection
 No [ref] 112 50 417 222.1 257 62 667 410.1
 Yes 6 13 225 45.4 0.2 [0.1–0.5] <0.01 14 13 215 105.9 0.3 [0.1–0.4] <0.01
History of injection drug use
 No [ref] 100 59 434 168.3 204 65 911 309.5
 Yes 18 4207 427.9 2.5 [1.4–4.2] <0.01 67 9964 672.4 2.2 [1.6–2.9] <0.01
Any HPV
 No [ref] 0 457 151.7 0 836 82.9
 Yes 3 1240 215.1 1.4 [0.2–∞] 0.78 4 2388 153.4 1.9 [0.3–∞] 0.60
Oncogenic HPV
 No [ref] 1 1117 89.5 1 1864 53.6
 Yes 2 581 344.2 3.8 [0.2–226.8] 0.54 3 1360 220.6 4.1 [0.3–215.9] 0.41
Lifetime number of sexual partners
 <30 [ref] 33 10 845 304.3 86 21 916 392.4
 30–59 12 10 328 116.2 0.4 [0.2–0.8] <0.01 45 11 518 390.7 1.0 [0.7–1.4] 1.00
 60–89 9 6458 139.4 0.5 [0.2–1.0] 0.04 26 5452 476.9 1.2 [0.8–1.9] 0.44
 ≥90 64 36 010 177.7 0.6 [0.4–0.9] 0.02 114 36 996 308.1 0.8 [0.6–1.1] 0.11
Hepatitis C virus at baseline
 No [ref] 99 60 196 164.5 188 64 552 291.2
 Yes 19 3060 620.9 3.8 [2.2–6.2] <0.01 75 10 185 736.4 2.5 [1.9–3.3] <0.01
CD4+ cell/μl count (HIV seropositive only)
 <200 [ref] 37 9455 391.3
 200–500 72 25 197 285.7 0.7 [0.5–1.1] 0.15
 >500 59 31 825 185.4 0.5 [0.3–0.7] <0.01
HIV viral load detectable (HIV seropositive only)
 No [ref] 104 33 789 307.8
 Yes 55 24 050 228.7 0.7 [0.5–1.0] 0.09
HIV viral load ≥4000 copies/ml (HIV seropositive only)
 No [ref] 119 39 778 299.2
 Yes 40 18 074 221.3 0.7 [0.5–1.1] 0.11
Exposure to ART (HIV seropositive only)
 No [ref] 85 29 323 289.9
 Yes 186 46 559 399.5 1.4 [1.1–1.8] 0.02
History of clinical AIDS (HIV seropositive only)
 No [ref] 132 55 726 236.9
 Yes 139 20 156 689.6 2.9 [2.3–3.7] <0.01
Pre-ART nadir CD4+ cell/μl count (HIV seropositive only)
 <200 [ref] 120 28 689 418.3
 ≥200 139 40 954 339.4 0.8 [0.6–1.0] 0.11
Post-ART nadir CD4+ cell/μl count (HIV seropositive only)
 <200 [ref] 124 23 331 531.5
 ≥200 82 37 673 217.7 0.4 [0.3–0.5] <0.01
Peak HIV viral load (copies/ml–HIV seropositive only)
 ≤10 000 [ref] 55 14 776 372.2
 >10 000 207 59 889 345.6 0.9 [0.7–1.3] 0.67
 Total 118 63 642 185.4 271 75 882 357.1
Bold indicates statistical significance. CI, confidence interval; IR, incidence rate; IRR, incidence rate ratio; MACS, Multicenter AIDS Cohort Study; P-years, person-years; WIHS, Women's Interagency HIV Study
aLagged by 10 years.
bStudy population limited to former smoking participants.

In adjusted analyses, combining participants with and without HIV, the variables that remained significantly associated with an increased IRR for smoking-related cancer were ages 40 and above, 11 or more cumulative pack-years of smoking, and having HIV with or without a prior AIDS diagnosis (Table 4, column 2). Factors associated with a decreased IRR for smoking-related cancers were annual household income at least $30 000 and for PLWH, having CD4+ cell counts greater than 200. Significant cohort interactions (Table 4, column 3) were observed for age 40–49 years (effect stronger in the WIHS), other race (effect stronger in the MACS), smoking 1–20 cumulative pack-years (effect stronger in the WIHS), and among PLWH for CD4+ cell counts of 200–500 cells (effect stronger in the MACS). In analyses that were restricted to only those alive in the modern ART era (year ≥2001), exposures significantly associated with an increased or decreased risk of smoking-related cancers (Table 4, columns 4 and 5) were highly similar to those for all years (Table 4, columns 2 and 3). Additionally, PLWH in the modern ART era who had a detectable HIV viral load had a lower risk for these cancers (Table 4, column 4).

Table 4 - Adjusted smoking-related cancer incidence rate ratios among participants in the Multicenter AIDS Cohort Study and Women's Interagency HIV Study.
All years (1984–2018) Modern ART years (2001–2018)
IRR [95% CI] P value for cohort interactiona IRR [95% CI] P value for cohort interactiona
Age (years)
 <40 [ref]
 40–49 2.0 [1.1–3.6] 0.05 1.9 [0.8–4.2] 0.24
 50–59 4.9 [2.8–8.7] 0.11 3.9 [1.8–8.4] 0.37
 ≥60 6.6 [3.6–12.1] 0.18 5.7 [2.6–12.7] 0.56
Race/ethnicity
 Non-Latinx white [ref]
 Non-Latinx black 1.2 [0.8–1.8] 0.74 1.2 [0.8–1.9] 0.89
 Other 0.6 [0.3–1.2] 0.04 0.6 [0.3–1.3] 0.04
Annual household income
 <$29 999 [ref]
 ≥$30 000 0.6 [0.4–0.8] 0.58 0.6 [0.4–0.9] 0.44
Cumulative pack-yearsb
 Never smokers [ref]
 1–10 1.3 [0.8–2.1] 0.02 1.3 [0.8–2.2] 0.02
 11–20 2.0 [1.2–3.2] 0.04 1.7 [0.9–2.9] 0.03
 21–30 2.7 [1.7–4.4] 0.20 2.4 [1.4–4.1] 0.28
 > 30 3.4 [2.1–5.3] 0.06 3.3 [2.0–5.3] 0.08
Alcohol use
 Abstainer [ref]
 >0–7 drinks/week 0.7 [0.5–1.1] 0.17 0.8 [0.6–1.2] 0.22
 >7–12 drinks/week 0.9 [0.4–1.7] 0.53 0.6 [0.3–1.5] 0.63
 >12 drinks/week 1.2 [0.8–2.0] 0.68 1.4 [0.8–2.3] 0.73
History of injection drug use
 No [ref]
 Yes 1.2 [0.8–1.7] 0.38 1.2 [0.8–1.8] 0.75
Hepatitis C virus at baseline
 No [ref]
 Yes 1.1 [0.7–1.7] 0.21 1.2 [0.8–1.9] 0.26
HIV status
 Seronegative [ref]
 Seropositive and no history of clinical AIDS 1.5 [1.1–2.2] 0.67 1.5 [1.0–2.2] 0.75
 Seropositive and history of clinical AIDS 3.0 [2.0–4.4] 0.92 2.7 [1.7–4.2] 0.62
CD4+ cell count/μl (PLWH only)
 <200 [ref]
 200–500 0.5 [0.3–0.9] 0.03 0.5 [0.3–0.9] 0.16
 >500 0.3 [0.2–0.6] 0.20 0.3 [0.2–0.6] 0.65
HIV viral load detectable (PLWH only)
 No [ref]
 Yes 0.8 [0.5–1.2] 0.43 0.4 [0.2–0.9] 0.05
Exposure to ART (PLWH only)
 No [ref]
 Yes 1.1 [0.7–1.9] 0.67 0.8 [0.4–1.6] 0.61
Bold indicates statistical significance. CI, confidence interval; IRR, incidence rate ratio; MACS, Multicenter AIDS Cohort Study; PLWH, people living with HIV; WIHS, Women's Interagency HIV Study.
aTests whether the effect of the given covariate differs between MACS and WIHS.
bLagged by 10 years.

Excluding virus-associated cancers from the definition of smoking-related cancers did not affect the association between smoking and smoking-related cancer risk but did affect the observed differences between PLWH and people without HIV (data not shown). This suggests that PLWH are more likely to develop virus-associated cancers than people without HIV, and that those cancers may have contributed to the higher incidence of smoking-related cancers in PLWH. Excluding just anal cancer from the definition of smoking-related cancers strengthened the association between smoking and smoking-related cancer incidence among both the men and the women equally (data not shown).

On the basis of adjusted PAF models with cumulative pack-years groups of 0–5 pack-years (reference), 6–20 pack-years, and more than 20 pack-years, an estimated 34% (95% CI: 21–46%) of all smoking-related cancers were attributable to smoking cigarettes among all participants, 31% (95% CI: 15–45%) among PLWH, and 41% (95% CI: 13–60%) among participants without HIV (Fig. 1). The adjusted PAFs were nonsignificantly higher in the women than in men: 39 vs. 28% for all participants (P = 0.35), 34 vs. 25% among PLWH (P = 0.58), and 67 vs. 27% among those without HIV (P = 0.11). When virus-associated cancers were removed from these analyses, the point estimates were higher in all groups but still well within the 95% CI of the full sample results (data not shown).

F1
Fig. 1:
Adjusted population attributable fractions of smoking on smoking-related cancer incidence in the Multicenter AIDS Cohort Study and Women's Interagency HIV Study.

When cancer types were stratified by the strength of their association with smoking, the adjusted PAF estimates were 85% (95% CI: 60–94%), 19% (95% CI: −24–47%), and 14% (95% CI: −6–30%) for cancers strongly, moderately, and weakly associated with smoking, respectively (Fig. 1). In these stratified analyses, the adjusted PAFs were not significantly different for women compared with men. The removal of virus-associated malignancies increased the point estimate for cancers strongly associated with smoking whereas the point estimates for cancers moderately and weakly associated with smoking fluctuated but all were still within the 95% CI of the total sample (data not shown).

Discussion

With over 139 500 person-years of follow-up, this is one of the largest cohort studies to examine the contribution of smoking on the cancer burden among PLWH relative to highly similar people without HIV. Among those with a history of smoking, the observed incidence of smoking-related cancers was significantly higher among PLWH than participants without HIV, as hypothesized in our aim 1. This reaffirms that HIV infection is associated with a higher risk of smoking-related cancers beyond what would be expected from cigarette smoking alone, a finding reported in previous studies [6,23–25]. However, these prior studies did not have a highly similar comparison group of participants without HIV or detailed smoking and other behavioral histories, as in the present study.

In both minimally and fully adjusted analyses, we observed that women have a higher risk of smoking-related cancers than men. The reasons for this are unclear and the exact mechanism may be confounded by unmeasured factors that might differentially and adversely affect women – such as the environment (air pollution and second-hand smoke), genetics, physiology, and hormones. The majority of the women in this study were African American and had fewer pack-years of smoking than the men. Studies indicate that African American smokers have a higher risk for lung cancer compared with whites [26], and this racial difference is most pronounced at lower levels of daily cigarette consumption [27]. In addition, women appear to have a higher incidence of lung cancer than men [28–30]. This may be because of an increased susceptibility to tobacco carcinogens among women, smaller lung size in women, or the effect of hormones in carcinogenesis, such as the role of estrogens as promoters of lung cancer [29,31,32].

In our PAF models that pooled men and women, an estimated 31% (95% CI: 15–45%) of all smoking-related cancers were attributed to smoking more than 5 pack-years in a lifetime among PLWH. This is within the range reported by other studies of PLWH [10,33,34], although we found higher estimates for women than for men. Our investigation has the added advantage of a more precise adjustment for smoking, as well as adjustment for other important confounders such as CD4+ cell count, HIV viral load detectability, and exposure to ART. Varying degrees of association between smoking and smoking-related cancers likely influenced our PAF estimates. When smoking-related cancers were stratified by strength of association, the estimated PAF for cancers strongly associated with smoking (lung, bronchus, and larynx) was 74% among men and 87% among women. When we removed laryngeal cancers from this group (a virus-associated cancer) [35], the PAF was 86% for men and 93% for women suggesting that inclusion of virus-related cancers may dilute the effect of smoking on these cancers. Our estimates for lung and bronchial cancers are higher than estimates reported in other studies of the general population (men 75–84% and women 70–79%) [16]. Our estimates were similar to another study of PLWH (82–98% for lung cancer) [10], which supports the interpretation that HIV is a risk factor for cancers that are strongly associated with smoking.

There is a substantial burden of smoking-related cancers among PLWH and unless the high prevalence of cigarette smoking is reduced, this will likely increase over time because of increasing longevity among PLWH on ART. One study reported that among PLWH who adhere to ART, smoking is projected to be a much greater health threat than HIV [36]. Another study assessed the impact of smoking cessation on cancer risk among PLWH and observed that the lung cancer IR was reduced by more than half but was still elevated 5 years after cessation (from an adjusted IRR of 19.08–8.69), although the incidence of other smoking-related cancers was found to decline to that of nonsmokers after 1–2 years of cessation (from an adjusted IRR of 2.06–1.32) [37].

In addition to smoking-related cancers, preventing the initiation of smoking and smoking cessation lessens the burden for all smoking-related diseases. For PLWH, this is especially important, given the elevated risk for several other diseases that can be exacerbated by smoking, including CVD, pulmonary infections, COPD, and pneumonia [33,38–40].

This investigation was not without limitations. First, certain smoking-related cancers, such as gum and mouth, had very few events – perhaps because of competing causes of death among PLWH. Our risk estimates for smoking-related cancers may, therefore, be biased towards the null. Despite this limitation, we were able to demonstrate significantly elevated risk of these cancers among PLWH compared with highly similar people without HIV. Second, these two cohorts of men and women differed in other ways in addition to sex and we were unable to adjust for unmeasured risk factors, such as the living environment (second hand smoke, air pollution, etc.), which may have contributed to their cancer burden. Nevertheless, we were able to adjust our analyses for many other potential risk factors – far more than most other studies that have investigated the cancer burden in PLWH. Last, as per WIHS protocol, the women received screening for cervical, vaginal, and vulvar cancers. Screening may have led to treatment of precancers and reduced the cancer burden for these malignancies. Earlier cancer detection from screening may have also resulted in those cancers occurring at lower cumulative pack-years of smoking, and therefore, attenuated the effect estimates between smoking and smoking-related cancer incidence.

The strengths of this longitudinal study include a large and diverse sample with many person-years of follow-up, a highly similar comparison group of people without HIV infection, detailed baseline and follow-up social and clinical histories, and a study period that spans the pre-ART, early ART, and current ART era. Notably, the adjusted IRR point estimates for smoking-related cancer risk factors among participants in the modern ART era were virtually identical to the estimates among participants across all years, indicating that these have not dramatically changed since the introduction of potent therapy. Because of these strengths, we were able to do what few, if any, have been able to do before us: compare men to women and those with and without HIV, as well as to fully adjust our models for a multitude of potential cancer-causing risk factors.

Our results, along with those from prior well designed observational studies, provide strong evidence of the excess risk of smoking-related cancers among PLWH who smoke compared with smokers without HIV. What is novel in our study are the sex differences, with women LWH having a greater risk of smoking-related cancers than men LWH. These data lend strong support for integrating smoking cessation interventions into ongoing HIV programs and educating PLWH, especially women, about the harm of smoking and the benefits of quitting to reduce their risk of smoking-related cancers. There is indisputable evidence of the harm caused by smoking in PLWH and an equally clear opportunity for healthcare providers to intervene as part of comprehensive care of PLWH.

Acknowledgements

Data in this manuscript were collected by the MACS/WIHS Combined Cohort Study (MWCCS). The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH). MWCCS (Principal Investigators): Atlanta CRS (Ighovwerha Ofotokun, Anandi Sheth, and Gina Wingood), U01-HL146241; Baltimore CRS (Todd Brown and Joseph Margolick), U01-HL146201; Bronx CRS (Kathryn Anastos and Anjali Sharma), U01-HL146204; Brooklyn CRS (Deborah Gustafson and Tracey Wilson), U01-HL146202; Data Analysis and Coordination Center (Gypsyamber D'Souza, Stephen Gange and Elizabeth Golub), U01-HL146193; Chicago-Cook County CRS (Mardge Cohen and Audrey French), U01-HL146245; Chicago-Northwestern CRS (Steven Wolinsky), U01-HL146240; Connie Wofsy Women's HIV Study, Northern California CRS (Bradley Aouizerat and Phyllis Tien), U01-HL146242; Los Angeles CRS (Roger Detels), U01-HL146333; Metropolitan Washington CRS (Seble Kassaye and Daniel Merenstein), U01-HL146205; Miami CRS (Maria Alcaide, Margaret Fischl, and Deborah Jones), U01-HL146203; Pittsburgh CRS (Jeremy Martinson and Charles Rinaldo), U01-HL146208; UAB-MS CRS (Mirjam-Colette Kempf and Deborah Konkle-Parker), U01-HL146192; UNC CRS (Adaora Adimora), U01-HL146194. The MWCCS is funded primarily by the National Heart, Lung, and Blood Institute (NHLBI), with additional co-funding from the Eunice Kennedy Shriver National Institute Of Child Health & Human Development (NICHD), National Human Genome Research Institute (NHGRI), National Institute On Aging (NIA), National Institute Of Dental & Craniofacial Research (NIDCR), National Institute Of Allergy And Infectious Diseases (NIAID), National Institute Of Neurological Disorders And Stroke (NINDS), National Institute Of Mental Health (NIMH), National Institute On Drug Abuse (NIDA), National Institute Of Nursing Research (NINR), National Cancer Institute (NCI), National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute on Deafness and Other Communication Disorders (NIDCD), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). MWCCS data collection is also supported by UL1-TR000004 (UCSF CTSA), UL1-TR003098 (Johns Hopkins Institute for Clinical and Translational Research, P30-AI-050409 (Atlanta CFAR), P30-AI-050410 (UNC CFAR), and P30-AI-027767 (UAB CFAR).

We would like to acknowledge the National Program of Cancer Registries of the Centers for Disease Control and Prevention (CDC) for the funds that helped support the collection and availability of the cancer registry data and thank the following state cancer registries for their help: AL, CA, FL, GA, IL, MD, MS, NY, NC, OH, PA, and VA. The authors assume full responsibility for analyses and interpretations of these data.

Sources of funding: National Institutes of Health.

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

There are no conflicts of interest.

References

1. Shiels MS, Pfeiffer RM, Gail MH, Hall HI, Li J, Chaturvedi AK, et al. Cancer burden in the HIV-infected population in the United States. J Natl Cancer Inst 2011; 103:753–762.
2. Mdodo R, Frazier EL, Dube SR, Mattson CL, Sutton MY, Brooks JT, Skarbinski J. Cigarette smoking prevalence among adults with HIV compared with the general adult population in the United States: cross-sectional surveys. Ann Intern Med 2015; 162:335–344.
3. Jamal A, King BA, Neff LJ, Whitmill J, Babb SD, Graffunder CM. Current cigarette smoking among adults - United States, 2005-2015. MMWR Morb Mortal Wkly Rep 2016; 65:1205–1211.
4. Lifson AR, Lando HA. Smoking and HIV: prevalence, health risks, and cessation strategies. Curr HIV/AIDS Rep 2012; 9:223–230.
5. Jacobs EJ, Newton CC, Carter BD, Feskanich D, Freedman ND, Prentice RL, Flanders WD. What proportion of cancer deaths in the contemporary United States is attributable to cigarette smoking?. Ann Epidemiol 2015; 25:179.el–182.e1.
6. Helleberg M, Gerstoft J, Afzal S, Kronborg G, Larsen CS, Pedersen C, et al. Risk of cancer among HIV-infected individuals compared to the background population: impact of smoking and HIV. AIDS 2014; 28:1499–1508.
7. Hessol NA, Weber KM, D'Souza G, Burton D, Young M, Milam J, et al. Smoking cessation and recidivism in the Women's Interagency Human Immunodeficiency Virus Study. Am J Prev Med 2014; 47:53–69.
8. Akhtar-Khaleel WZ, Cook RL, Shoptaw S, Surkan P, Stall R, Beyth RJ, et al. Trends and predictors of cigarette smoking among HIV seropositive and seronegative men: the Multicenter Aids Cohort Study. AIDS Behav 2016; 20:622–632.
9. Hessol NA, Martinez-Maza O, Levine AM, Morris A, Margolick JB, Cohen MH, et al. Lung cancer incidence and survival among HIV-infected and uninfected women and men. AIDS 2015; 29:1183–1193.
10. Altekruse SF, Shiels MS, Modur SP, Land SR, Crothers KA, Kitahata MM, et al. Cancer burden attributable to cigarette smoking among HIV-infected people in North America. AIDS 2018; 32:513–521.
11. Bacon MC, von Wyl V, Alden C, Sharp G, Robison E, Hessol N, et al. The Women's Interagency HIV Study: an observational cohort brings clinical sciences to the bench. Clin Diagn Lab Immunol 2005; 12:1013–1019.
12. Barkan SE, Melnick SL, Preston-Martin S, Weber K, Kalish LA, Miotti P, et al. The Women's Interagency HIV Study. WIHS Collaborative Study Group. Epidemiology 1998; 9:117–125.
13. Kaslow R, Ostrow D, Detels R, Phair J, Polk BF, Rinaldo CR. The Multicenter AIDS Cohort Study: rationale, organization, and selected characteristics of the participants. Am J Epidemiol 1987; 126:310–318.
14. Hofferkamp J. Standards for cancer registries volume iii: standards for completeness, quality, analysis, management, security and confidentiality of data. Springfield, Illinois: North American Association of Central Cancer Registries; 2008.
15. Surveillance Epidemiology and End Results (SEER) Program. Surveillance Research Program, Cancer Statistics Branch. In. SEER 9 Regs Public-Use (1973-2001) ed: National Cancer Institute, Division of Cancer Control and Population Science; 2004.
16. Islami F, Goding Sauer A, Miller KD, Siegel RL, Fedewa SA, Jacobs EJ, et al. Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States. CA Cancer J Clin 2018; 68:31–54.
17. U.S. Department of Health and Human Services. The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014.
18. Moore TO, Moore AY, Carrasco D, Vander Straten M, Arany I, Au W, et al. Human papillomavirus, smoking, and cancer. J Cutan Med Surg 2001; 5:323–328.
19. Peto J. That the effects of smoking should be measured in pack-years: misconceptions 4. Br J Cancer 2012; 107:406–407.
20. Freedman ND, Abnet CC, Caporaso NE, Fraumeni JF Jr, Murphy G, Hartge P, et al. Impact of changing US cigarette smoking patterns on incident cancer: risks of 20 smoking-related cancers among the women and men of the NIH-AARP cohort. Int J Epidemiol 2016; 45:846–856.
21. Laaksonen MA, Virtala E, Knekt P, Oja H, Harkanen T. SAS Macros for calculation of population attributable fraction in a cohort study design. J Stat Softw 2011; 43:1–25.
22. SAS Institute Inc. SAS/STAT User's Guide, Version 9. 4. Cary, North Carolina: SAS Institute Inc; 2014.
23. Kirk GD, Merlo C, O’ Driscoll P, Mehta SH, Galai N, Vlahov D, et al. HIV infection is associated with an increased risk for lung cancer, independent of smoking. Clin Infect Dis 2007; 45:103–110.
24. Shiels MS, Cole SR, Mehta SH, Kirk GD. Lung cancer incidence and mortality among HIV-infected and HIV-uninfected injection drug users. J Acquir Immune Defic Syndr 2010; 55:510–515.
25. Sigel K, Wisnivesky J, Gordon K, Dubrow R, Justice A, Brown ST, et al. HIV as an independent risk factor for incident lung cancer. AIDS 2012; 26:1017–1025.
26. Ward E, Jemal A, Cokkinides V, Singh GK, Cardinez C, Ghafoor A, Thun M. Cancer disparities by race/ethnicity and socioeconomic status. CA Cancer J Clin 2004; 54:78–93.
27. Haiman CA, Stram DO, Wilkens LR, Pike MC, Kolonel LN, Henderson BE, Le Marchand L. Ethnic and racial differences in the smoking-related risk of lung cancer. N Engl J Med 2006; 354:333–342.
28. Thomas L, Doyle LA, Edelman MJ. Lung cancer in women: emerging differences in epidemiology, biology, and therapy. Chest 2005; 128:370–381.
29. Henschke CI, Yip R, Miettinen OS. International Early Lung Cancer Action Program Investigators. Women's susceptibility to tobacco carcinogens and survival after diagnosis of lung cancer. JAMA 2006; 296:180–184.
30. Pakkala S, Chen Z, Rimland D, Owonikoko TK, Gunthel C, Brandes JR, et al. Human immunodeficiency virus-associated lung cancer in the era of highly active antiretroviral therapy. Cancer 2011; 118:164–172.
31. Marquez-Garban DC, Pietras RJ. Estrogen-signaling pathways in lung cancer. Adv Exp Med Biol 2008; 617:281–289.
32. Zang EA, Wynder EL. Differences in lung cancer risk between men and women: examination of the evidence. J Natl Cancer Inst 1996; 88:183–192.
33. Althoff KN, Gebo KA, Moore RD, Boyd CM, Justice AC, Wong C, et al. North American AIDS Cohort Collaboration on Research and Design. Contributions of traditional and HIV-related risk factors on non-AIDS-defining cancer, myocardial infarction, and end-stage liver and renal diseases in adults with HIV in the USA and Canada: a collaboration of cohort studies. Lancet HIV 2019; 6:e93–e104.
34. Lifson AR, Neuhaus J, Arribas JR, van den Berg-Wolf M, Labriola AM, Read TR. INSIGHT SMART Study Group. 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.
35. Li X, Gao L, Li H, Gao J, Yang Y, Zhou F, et al. Human papillomavirus infection and laryngeal cancer risk: a systematic review and meta-analysis. J Infect Dis 2013; 207:479–488.
36. Reddy KP, Kong CY, Hyle EP, Baggett TP, Huang M, Parker RA, et al. Lung cancer mortality associated with smoking and smoking cessation among people living with HIV in the United States. JAMA Intern Med 2017; 177:1613–1621.
37. Shepherd L, Ryom L, Law M, Petoumenos K, Hatleberg CI, d’Arminio Monforte A, et al. Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study Group. Cessation of cigarette smoking and the impact on cancer incidence in human immunodeficiency virus-infected persons: the data collection on adverse events of Anti-HIV Drugs Study. Clin Infect Dis 2019; 68:650–657.
38. Bigna JJ, Kenne AM, Asangbeh SL, Sibetcheu AT. Prevalence of chronic obstructive pulmonary disease in the global population with HIV: a systematic review and meta-analysis. Lancet Glob Health 2018; 6:e193–e202.
39. Benard A, Mercie P, Alioum A, Bonnet F, Lazaro E, Dupon M, et al. Groupe d’Epidémiologie Clinique du Sida en Aquitaine. Bacterial pneumonia among HIV-infected patients: decreased risk after tobacco smoking cessation. ANRS CO3 Aquitaine Cohort, 2000-2007. PLoS One 2010; 5:e8896.
40. Fitzpatrick ME, Kunisaki KM, Morris A. Pulmonary disease in HIV-infected adults in the era of antiretroviral therapy. AIDS 2018; 32:277–292.
Keywords:

cancer; HIV infection; incidence; risk factors; sex differences; smoking

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