As the population of effectively treated HIV-infected persons grows, the burden of non-AIDS-defining cancers has increased . The availability of combination antiretroviral therapy (ART) since 1996 has led to a decrease in AIDS incidence and has improved survival after HIV diagnosis [2–7]. With the aging of the HIV-infected population, cancer has emerged as an increasingly important contributor to morbidity and mortality [1,5,7]. An increased risk of cancer among those with HIV is due in part to a high prevalence of cancer risk factors, including tobacco use. In a meta-analysis of 113 studies across developed countries, largely in North America and Western Europe, a large proportion (54%) of HIV-infected people were current smokers . A representative population-based survey of HIV-infected people in care in the United States during 2009 found that 42% were current smokers and another 20% were former smokers . As this population-based prevalence estimate of current smokers among adults with HIV was twice that for the US general population during the same time [9,10], there is a need to examine health risks from smoking among people living with HIV.
Smoking contributes to the cause of a range of cancers, including but not limited to cancers of the lung, larynx, liver, colon and rectum, kidney/renal pelvis, and oral cavity, as well as leukemia . Smoking can also contribute to additional cancers for which the etiologic role is less well established . Approximately 29% of all cancer deaths in the overall US population during 2010 were attributable to smoking . Less well defined is the contribution of smoking to the burden of cancer among individuals living with HIV infection and the combined effects of HIV infection and ART with smoking in relation to cancer incidence. In a study of HIV-infected individuals in Denmark, the fraction of cancer diagnoses attributable to smoking was estimated to be 27% for all cancers combined and 91% for smoking-related cancers . A comparable level of cancer mortality was attributed to smoking in an international study of HIV-infected people that included US participants . This current study describes the burden of cancer attributable to cigarette smoking in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), which captures data pertaining to a large HIV-infected population in North America , most of whom were followed after initiating ART. Estimates of population-attributable fractions (PAF) were based on the prevalence of ever smoking in the cohort and the hazard ratio for cancer incidence associated with this exposure during follow-up.
The NA-ACCORD is a consortium of 22 cohort studies of HIV-infected adults in care (≥18 years of age) . Sixteen cohorts (12 clinical and four interval) contributed validated cancer diagnoses and smoking data for the present analysis. The human patient research activities of NA-ACCORD and each participating cohort study were reviewed and approved by their respective local institutional review boards and by the Johns Hopkins School of Medicine. Individual cohorts validated cancer diagnoses through medical records, including pathology reports, or through linkage with cancer registries .
The 16 cohorts initially included 72 854 patients. For analysis, 34 people less than 18 years of age were excluded. There were 3080 people diagnosed with cancer within 6 months after their study entry date. These people were excluded, as were the 7724 people with follow-up time of less than 6 months. Another 9575 people with missing smoking status, whose history of smoking could not be imputed because of the absence of the complete set of demographic and clinical variables were also excluded.
Based on these criteria, there were 52 441 HIV-infected patients in the analytic cohort, all of whom were cancer free at study entry. They contributed 270 136 person-years of follow-up. The 50 135 people who remained cancer-free contributed 259 483 person-years. The 2306 people who were diagnosed with cancer during the study period contributed 10 653 person-years prior to their first cancer diagnoses, at which time follow-up was censored.
Study entry was taken to be the later of 6-months after the baseline date when a participant was initially enrolled in the study and the cancer observation start-date, with an administrative censoring date of 1 January 2000. Study exit was defined as the earliest date of first cancer diagnosis, death date, 1 year after last CD4+ cell count or viral load measurement, cancer observation stop-date, cohort close date, and 31 December 2015.
Categories of cancer included in analyses were all cancers combined, smoking-related cancers, and nonsmoking-related cancers. Cancers of the following anatomic sites, listed in descending order of occurrence in the study population, were considered smoking-related [11,18]: lung (N = 214), liver (N = 85), colon and rectum (N = 77), oral cavity (N = 74), kidney/renal pelvis (N = 47), cervix (N = 43), bladder (N = 29), larynx (N = 25), leukemia (N = 23), pancreas (N = 21), esophagus (N = 17), and stomach (N = 11). In addition to lung cancer, smoking-related cancers other than lung cancer were grouped for analysis. Nonsmoking-related cancers included melanoma and nonmelanoma skin cancer (N = 399), non-Hodgkin lymphoma (N = 307), cancer of the anus (N = 211), Kaposi sarcoma (N = 289) , prostate (N = 154), Hodgkin lymphoma (N = 87), breast (N = 78), brain and other nervous system (N = 26), myeloma (N = 21), thyroid (N = 18), testis (N = 15), soft tissue (N = 11), vulva (N = 10), penis (8), and ovary (N = 6). In a sensitivity analysis, anal and vulvar cancer were classified as smoking related.
Information on demographic characteristics, baseline HIV disease markers (CD4+ cell count and HIV RNA viral load), ART exposure, and medical comorbidities [hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and stage 4 chronic kidney disease] was obtained from participating cohorts. Cigarette smoking status (time fixed, ever versus never) was available as either observed or imputed data for all 52 441 participants. Observed data on ever versus never smoking status were available for 39 309 patients (75%) and data on ever versus never smoking status were imputed for 13 132 patients in the analytic cohort (25%). Data were assembled on the contribution of smoking to the incidence of first cancers for each cohort from electronic medical records, chart reviews, and patient reports. Although survey questionnaires administered to participants in some NA-ACCORD cohort studies included current versus past cigarette smoking history and intensity and duration of smoking, the reduced sample size of patient-reported smoking intensity and duration data precluded their use in the present analysis.
Two-sided chi-square tests were performed to measure associations between demographic, behavioral, and clinical characteristics of individuals and risk of cancer diagnosis (PROC FREQ, SAS version 9.3; SAS Institute, Cary, North Carolina, USA). Imputation of ever versus never smoking status was only performed for those people with missing smoking data and complete information for all other demographic and clinical variables in Table 1. Imputation was performed using logistic regression (PROC MI, SAS version 9.3; SAS Institute). Five sets of imputed values provided nearly identical PAF results (data not shown). Results from the first model are presented.
Cox proportional hazard models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) (lower or upper bound) associated with ever versus never smoking for specified cancer outcomes (PROC PHREG, version 9.3; SAS Institute). A threshold of P less than 0.05 was used for defining statistical significance. Unadjusted hazard ratios are presented along with hazard ratios adjusted for age, sex, race (nonwhite, white, and unknown), HIV risk group (IDU, non-IDU, and other/unknown), AIDS diagnosis at study entry, baseline CD4+ cell count (cells/μl: <200, ≥200, and missing), viral load (copies/ml: ≤400, >400, and missing), ART versus no ART prior to the baseline date for this study, HBV or HCV infection, and the presence of stage 4 chronic kidney disease. End-stage renal disease may only be on the causal pathway between smoking and some cancers. In sensitivity analyses, hazard ratios were recalculated after removing this variable. PAFs were calculated with a SAS macro (SAS version 9.3; SAS Institute) provided by Laaksonen et al.. As follow-up ended at the time of first cancer diagnosis, all PAF estimates describe the proportional contribution of smoking to the incidence of first cancers. The greater than 200 diagnoses of Kaposi sarcoma, non-Hodgkin lymphoma, and anal cancer provided sufficient numbers to fit adjusted models and present hazard ratios and PAF for these cancers. Although there were 399 melanoma and nonmelanoma skin cancer cases in the data set, PAFs were not estimated for this heterogeneous and unevenly reported subset of malignancies.
The analytic data set included 52 441 HIV-infected people, of whom 2306 (4%) were diagnosed with cancer. Median participant follow-up was 3.8 years, interquartile range: 1.5–8.1 years. The incidence rate of all cancer combined during 270 136 person-years was 8.53/1000. Table 1 presents demographic attributes by cancer outcome. A higher proportion of people with cancer than people without cancer diagnoses had ever smoked cigarettes (79 versus 73%, P < 0.001). Among people without incident cancer, 73% were classified as ever smokers using observed data and 72% based on imputed data. Among people with incident cancer, 79% with observed and 79% for imputed data were classified as ever smokers.
Compared with individuals without cancer diagnoses, individuals diagnosed with cancer were older (P < 0.001) at study entry and more frequently men (81 versus 78%, P < 0.003). More individuals with a cancer diagnosis than individuals without cancer diagnoses had an AIDS diagnosis at entry (25 versus 18%, P < 0.001), and more had started ART before enrollment into NA-ACCORD (56 versus 49%, P < 0.001). Excluding 2955 people with missing values (6%), 30% of individuals with a cancer diagnosis during follow-up had a CD4+ cell count of fewer than 200 cells/μl at entry compared with 24% of patients without a cancer diagnosis (P < 0.001). HBV infection was more common among individuals with incident cancer than those without a cancer diagnosis (11 versus 7%, P < 0.001), as was the proportion with HCV infection in those with cancer versus those without cancer (23 versus 18%, P = 0.001).
In adjusted analyses, as shown in Table 2, ever smoking cigarettes was associated with an elevated risk for all cancers combined [aHR = 1.33 (95% CI: 1.18–1.49)], including smoking-related cancers [aHR = 2.31 (1.80–2.98)] but not cancers not classified as smoking related [aHR = 1.12 (0.98–1.28)]. Among the smoking-related cancers, the association was strongest for lung cancer [aHR = 17.80 (5.60–56.63)] but remained statistically significant for all other smoking-related cancers, excluding lung cancer [aHR = 1.59, (1.22–2.06)]. The associations with smoking for three other cancers with at least 200 incident cancer events were as follows: Kaposi sarcoma [aHR = 1.03, (CI = 0.77–1.38)], non-Hodgkin lymphoma [aHR = 1.35, (0.98–1.86)], and anal cancer [aHR = 1.57, (1.08–2.28)]. In sensitivity analyses that removed end-stage renal disease from adjusted models, hazard ratios in Table 2 did not change appreciably (data not shown).
Table 2 also presents PAFs for having ever smoked. Unadjusted and adjusted models produced similar PAF estimates. Based on adjusted PAF models, we estimated that 19% (95% CI: 13–25%) of all cancers were attributable to ever smoking cigarettes, including 50% (39–59%) of smoking-related cancers and 9% (1–16%) of other cancers that we did not classify as being related to smoking. Almost all lung cancer in this study of HIV-infected individuals, 94% (82–98%) were attributable to cigarette smoking. The adjusted PAF of having ever smoked for Kaposi's sarcoma, non-Hodgkin lymphoma, and anal cancer were 3% (−19 to 20%), 22% (2–38%), and 32% (9–49%), respectively. Compared with the estimate in Table 2, in a sensitivity analysis that classified anal and vulvar cancers as smoking related, the adjusted PAF decreased from 50% (39–59%) to 45% (35–53%).
In our study of HIV-infected individuals treated with ART in North America, almost three-quarters were ever cigarette smokers, consistent with results from prior studies [8,9]. Compared with never smokers, the risk of a smoking-related cancer diagnosis was more than twice as high among those who ever smoked, and the risk of a lung cancer was nearly 18 times as high. Approximately one-fifth of cancer diagnoses in this population were potentially attributed to smoking, including 50% of smoking-related cancers and 94% of lung cancer diagnoses. Our findings indicated that a substantial fraction of cancer diagnoses among HIV-infected individuals potentially would not have occurred if they had never smoked.
We estimated that 19% of all cancers were attributed to ever smoking, consistent with the findings in an HIV cohort in Denmark.  That study used a more exclusive definition of smoking-related cancers [11,18]. The narrower definition yielded a higher smoking-related cancer PAF compared with our estimate (a 91% PAF for lung, head and neck, esophageal, and bladder cancers versus a 50% PAF based on our broader definition of smoking-related cancers). PAF estimates for smoking and cancer in the general population primarily focus on mortality and are not comparable with our incidence data [14,18]. Our estimate of PAF for smoking and incident lung cancer is, however, consistent with a recent PAF estimate for cigarette smoking and lung cancer in the general population . One explanation for why the PAF in our HIV population is not substantially higher than in the general population  is that Kaposi sarcoma constitutes a nonnegligible fraction of all cancers among HIV-infected people, and this type of cancer is not associated with smoking. As the PAF is a proportional measure, the elevated incidence rate of Kaposi's sarcoma (and to a lesser extent non-Hodgkin lymphoma) attenuates the relative contribution of smoking to the overall cancer burden .
Lung cancer is one of the most common cancers in HIV-infected people  and as we also found, almost all diagnoses in HIV-infected individuals occur among smokers . HIV infection can have a synergistic effect with tobacco in increasing the risk of this malignancy . Within the lung, smoking suppresses the protective function of pulmonary immunologic defenses, adding to the suppressive effects of HIV on CD4+ cell function. Smoking also increases peripheral immune activation, compounding the state of chronic inflammation produced by HIV infection and the risk of lung cancer.
If no one in our HIV-infected study population had ever smoked, we estimate that 9% of nonsmoking-related cancers would have been averted. This could be a consequence of smoking in the cause of some cancers that we did not classify as smoking-related or unmeasured relationships between smoking and other cancer risk factors. Anal cancer was diagnosed at similar frequency to lung cancer and was associated with smoking [aHR = 1.57, (1.08–2.28)]. References used in this report did not classify anal cancer as a smoking-related cancer [11,18]. Other data link smoking to the pathogenesis of invasive anal cancer [26,27], with current smokers at highest risk .
In accordance with the 2014 Surgeon General's Report , we classified seven leading cancers (N > 75) as nonsmoking-related cancers: melanoma and nonmelanoma skin cancer, non-Hodgkin lymphoma, anal cancer, Kaposi sarcoma, prostate cancer, Hodgkin lymphoma, and breast cancer. We are unaware of studies that show smoking is causal for these cancers among people living with HIV. As smoking could increase the risk of anogenital malignancies among HIV-infected individuals [28–31], a sensitivity analysis was performed in which anal and vulvar cancers were classified as smoking related. Compared with smoking-related cancers presented in Table 2, the adjusted PAF for this model was slightly attenuated. A protective effect of smoking on Kaposi sarcoma in a study preceding the ART era  was not replicated in this report [i.e. aHR = 1.03, (0.77–1.38)], possibly due to confounding with Kaposi sarcoma-related risk factors.
In the United States, the prevalence of smoking among HIV-infected people is substantially higher than in the general population, and most HIV-infected individuals either currently smoke or have previously smoked [9,14,15]. As ART has increasingly made HIV a chronic disease with decreasing AIDS-related mortality [2–7], there is a rising burden of noncommunicable diseases [1–7], including smoking-related cancers .
In the SMART trial, with 5472 HIV-infected people in 33 countries, 24% of all deaths in HIV-infected individuals were attributed to smoking, as were 25% of cardiovascular disease (CVD) events, 25% of bacterial pneumonia episodes, and 31% of non-AIDS-related cancers . Smoking among HIV-infected people increases the risk of death due to other causes through a combination of mechanisms, including as a driver of metabolic abnormalities among both ART-naive patients  and patients receiving ART [33,34]. Tobacco use in the presence of HIV infection also increases CVD risk  and reduces life expectancy . Thus, smoking-associated CVD is a prevalent and preventable cause of morbidity and mortality among people living with HIV infection, adding to our findings with respect to smoking and cancer. Although this study does not directly address the benefits of smoking cessation, as individuals who quit smoking remain in the ‘ever smoked’ group, the high prevalence of smoking in this and other studies of people living with HIV [9,14,15] clearly indicate a need for efforts to encourage smoking cessation in this patient population [36,37].
The substantial fraction of preventable cancers and elevated prevalence of smoking among HIV-infected individuals [8–10] warrants prioritized behavioral and pharmacologic smoking prevention and cessation interventions for this population [38,39]. Although duration of smoking was not considered in the present report on individuals infected with HIV, quitting smoking reduces the risk of cancer, including lung cancer, in the general population . As many HIV-infected smokers are motivated to quit, healthcare providers can assist HIV-infected people with smoking cessation at repeated clinical encounters by offering behavioral and pharmacologic interventions. High-quality resources exist specifically to assist HIV care providers in helping their patients to quit smoking [40,41]. In addition to behavioral modalities, which can have variable results depending on the frequency of therapy and patient literacy, pharmacologic interventions (e.g. bupropion, varenicline, nicotine substitution) are widely available and effective and have few reported interactions with ART.
Strengths of our study include the large representative cohort of HIV-infected people in North America with validated cancer diagnoses and smoking information. NA-ACCORD [16,17] is well suited for studies of HIV-related comorbidities because of the high uptake of ART compared with other studies [2–7]. Lack of details on smoking is the major limitation. Imputed smoking prevalence was unlikely to affect results as imputed and observed data were similar for people with and those without cancer. No substantial confounding of the association between smoking and cancer was observed in models adjusted for the factors that we considered, but potential confounding by unmeasured factors, such as second-hand smoke,  and human papillomavirus infection status [25–29], cannot be dismissed. Our study did not adjust for alcohol use and marijuana and crack-cocaine smoking, which increase the risk of certain cancers, or incorporate updated values of HIV disease markers. It is unclear whether the listed factors are major confounders, but to the extent they are, our estimates would be biased.
In conclusion, the prevalence of ever cigarette smoking in this HIV cohort study was estimated at 73%, and 19% of all incident cancers were attributed to smoking, including 50% of cancers previously defined as smoking related, and 94% of lung cancer diagnoses. These findings provide insight into the considerable cancer burden attributable to cigarette smoking among HIV-infected people and indicate a need for effective smoking cession programs for HIV-infected individuals [21,36,37].
Authors contributions were as follows: S.F.A.: concept, data analysis, critical review, article writing, submission. M.S.S.: concept, critical review, article writing. S.P.M.: concept, database administration, analysis, article writing. S.R.L.: concept, article writing. K.A.C.: data collection, article writing. M.A.K.: data collection, article writing. J.E.T.: critical review, article writing. W.C.M.: data collection, critical review, article writing. D.M.F.-S.: data collection, article writing. A.M.M.: data collection, article writing. J.M.G.: data collection, critical review, article writing. M.A.H.: data collection, critical review, article writing. J.T.B.: critical review, literature review, article writing. R.D.M.: study administration, critical review, article writing. M.J.S.: concept, data collection, critical review, analysis, article writing. K.N.A.: concept, study administration, critical review, analysis, article writing. E.A.E.: concept, detailed critical review, analysis, article writing.
The authors thank Aimee Freeman, Rosemary McKaig, Stephen Van Rompaey, and Yuezhou Jing for assistance with resource development, project planning, and data analysis and Charles Rabkin, James Libbey, and Dana Chomenko for editorial assistance.
The current work was supported by National Institutes of Health grants U01AI069918, F31DA037788, G12MD007583, K01AI093197, K23EY013707, K24AI065298, K24AI118591, K24DA000432, KL2TR000421, M01RR000052, N01CP01004, N02CP055504, N02CP91027, P30AI027757, P30AI027763, P30AI027767, P30AI036219, P30AI050410, P30AI094189, P30AI110527, P30MH62246, R01AA016893, R01CA165937, R01DA011602, R01DA012568, R01 AG053100, R24AI067039, U01AA013566, U01AA020790, U01AI031834, U01AI034989, U01AI034993, U01AI034994, U01AI035004, U01AI035039, U01AI035040, U01AI035041, U01AI035042, U01AI037613, U01AI037984, U01AI038855, U01AI038858, U01AI042590, U01AI068634, U01AI068636, U01AI069432, U01AI069434, U01AI103390, U01AI103397, U01AI103401, U01AI103408, U01DA03629, U01DA036935, U01HD032632, U10EY008057, U10EY008052, U10EY008067, U24AA020794,U54MD007587, UL1RR024131, UL1TR000004, UL1TR000083, UL1TR000454, UM1AI035043, Z01CP010214, Z01CP010176, and NIH grant supplement to U01AI069918, with American Recovery and Reinvestment Act of 2009 funds. Additional support was provided by the National Cancer Institute, National Institute for Mental Health, and National Institute on Drug Abuse. M.S.S. and E.A.E. were supported by the Intramural Research Program, National Cancer Institute. S.F.A. and S.R.L. were supported by the Division of Cancer Control and Population Sciences, National Cancer Institute.
Contracts CDC-200-2006-18797 and CDC-200-2015-63931 from the Centers for Disease Control and Prevention, USA; contract 90047713 from the Agency for Healthcare Research and Quality, USA; contract 90051652 from the Health Resources and Services Administration, USA; grants CBR-86906, CBR-94036, HCP-97105, and TGF-96118 from the Canadian Institutes of Health Research, Canada; Ontario Ministry of Health and Long Term Care; and the Government of Alberta, Canada.
NA-ACCORD Collaborating Cohorts and Representatives:
AIDS Clinical Trials Group Longitudinal Linked Randomized Trials: Constance A. Benson and Ronald J. Bosch
AIDS Link to the IntraVenous Experience: Gregory D. Kirk
Fenway Health HIV Cohort: Stephen Boswell, Kenneth H. Mayer and Chris Grasso
HAART Observational Medical Evaluation and Research: Robert S. Hogg, P. Richard Harrigan, Julio SG Montaner, Benita Yip, Julia Zhu, Kate Salters, and Karyn Gabler
HIV Outpatient Study: Kate Buchacz and John T. Brooks
HIV Research Network: Kelly A. Gebo and Richard D. Moore
Johns Hopkins HIV Clinical Cohort: Richard D. Moore
John T. Carey Special Immunology Unit Patient Care and Research Database, Case Western Reserve University: Benigno Rodriguez
Kaiser Permanente Mid-Atlantic States: Michael A. Horberg
Kaiser Permanente Northern California: Michael J. Silverberg
Longitudinal Study of Ocular Complications of AIDS: Jennifer E. Thorne
Multicenter Hemophilia Cohort Study-II: Charles Rabkin
Multicenter AIDS Cohort Study: Joseph B. Margolick, Lisa P. Jacobson, and Gypsyamber D'Souza
Montreal Chest Institute Immunodeficiency Service Cohort: Marina B. Klein
Ontario HIV Treatment Network Cohort Study: Sean B. Rourke, Anita R. Rachlis, and Patrick Cupido
Retrovirus Research Center, Bayamon Puerto Rico: Robert F. Hunter-Mellado and Angel M. Mayor
Southern Alberta Clinic Cohort: M. John Gill
Study of the Consequences of the Protease Inhibitor Era: Steven G. Deeks and Jeffrey N. Martin
Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy: Pragna Patel and John T. Brooks
University of Alabama at Birmingham 1917 Clinic Cohort: Michael S. Saag, Michael J. Mugavero, and James Willig
University of California at San Diego: William C. Mathews
University of North Carolina at Chapel Hill HIV Clinic Cohort: Joseph J. Eron and Sonia Napravnik
University of Washington HIV Cohort: Mari M. Kitahata, Heidi M. Crane, and Daniel R. Drozd
Vanderbilt Comprehensive Care Clinic HIV Cohort: Timothy R. Sterling, David Haas, Peter Rebeiro, Megan Turner, Sally Bebawy, and Ben Rogers
Veterans Aging Cohort Study: Amy C. Justice, Robert Dubrow, and David Fiellin
Women's Interagency HIV Study: Stephen J. Gange and Kathryn Anastos
NA-ACCORD Study Administration:
Executive Committee: Richard D. Moore, Michael S. Saag, Stephen J. Gange, Mari M. Kitahata, Keri N. Althoff, Michael A. Horberg, Marina B. Klein, Rosemary G. McKaig, and Aimee M. Freeman
Administrative Core: Richard D. Moore, Aimee M. Freeman, and Carol Lent
Data Management Core: Mari M. Kitahata, Stephen E. Van Rompaey, Heidi M. Crane, Daniel R. Drozd, Liz Morton, Justin McReynolds, and William B. Lober
Epidemiology and Biostatistics Core: Stephen J. Gange, Keri N. Althoff, Bin You, Brenna Hogan, Jinbing Zhang, Jerry Jing, Bin Liu, and Fidel Desir
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Grant support was received from the National Institutes of Health, U.S. Centers for Disease Control and Prevention, Agency for Healthcare Research and Quality, Health Resources and Services Administration, USA; Canadian Institutes of Health Research, Ontario Ministry of Health and Long Term Care; and the Government of Alberta, Canada.
Conflicts of interest
J.E.T. has received consultant fees from Gilead. M.J.S. has received research grants in the past from Pfizer and Merck. K.N.A. has served on medical and scientific advisory boards for Gilead Sciences, Inc., and TrioHealth. R.D.M. has received honoraria as a consultant to Medscape. J.M.G. has received honoraria from attendance as an ad-hoc member of the Canadian HIV Advisory Board of Merck, ViiVHealth, and Gilead. For the remaining authors, no conflicts of interest or sources of funding were declared.
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