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© 2003 American Society for Clinical Oncology Incidence of Non–AIDS-Defining Cancers Before and During the Highly Active Antiretroviral Therapy Era in a Cohort of Human Immunodeficiency Virus–Infected Patients
From the Institut National de la Santé et de la Recherche Médicale Equipe Mixte 0214 and Hôpital Tenon, Paris; Hôpital Archet 1, Nice; Hôpital Sainte-Marguerite and Hôpital de la Conception, Marseille; Hôpitaux de Brabois, Vandoeuvre; CISIH d’Alsace, Alsace; and Hôpital Antoine Béclère, Clamart, France. Address reprint requests to Murielle Mary-Krause, PhD, Institut National de la Santé et de la Recherche Médicale Equipe Mixte 0214, 56 Boulevard Vincent Auriol, BP 335, 75625 Paris Cedex 13, France; e-mail: murielle.mary-krause{at}ccde.chups.jussieu.fr.
Purpose: To determine incidence of non–AIDS-defining cancers (NADC) in HIV–infected patients before (P1) and during (P2) the use of highly active antiretroviral therapy (HAART) relative to that observed in the French general population (FGP) of the same age and sex. Patients and Methods: Sex- and age-adjusted NADC standardized incidence ratios (SIR), with FGP as reference, were estimated in 1992 to 1995 (P1) and in 1996 to 1999 (P2) in a French Hospital Database on HIV prospective hospital cohort study. Results: NADCs were diagnosed in 260 patients during P1 and 391 patients during P2 among the 77,025 patients included in the database between January 1, 1992, and December 31, 1999. Estimated incidence of all cancers was higher in HIV-infected men than in FGP during both periods (P1 SIR = 2.36 and P2 SIR = 1.91). No excess of cancers was observed among HIV-infected women in either period. Incidence of all cancers did not change from P1 to P2 in either sex (SIR = 0.96 for men and 1.00 for women). In contrast, incidence of Hodgkin’s disease (HD) was higher than in FGP in both sexes and both periods and increased in P2 as compared with P1; incidence of lung cancer was higher in both sexes during P2. Conclusion: Relative to FGP, the overall incidence of NADCs was increased in HIV-infected men but not in women and did not differ between P1 and P2. Only HD was much more common in HIV infection, and the potential role of HAART on HD cannot be excluded.
PEOPLE INFECTED with HIV are at an increased risk of developing Kaposi’s sarcoma (KS), non-Hodgkin’s lymphoma (NHL; particularly primary brain lymphoma), and invasive cervical cancer. All three cancers are AIDS-defining.1 The possible relationship of HIV infection and the resulting immune depression with other cancers has been addressed in several cohort and record linkage studies,2–11 but many questions remain. Indeed, with the exception of Hodgkin’s disease (HD), the types of cancer and the observed relative risks (RRs) vary widely among different studies. Moreover, the RRs are generally small, and confounding factors cannot always be ruled out.12 The increased risk of cancer associated with immune suppression has been known since the 1970s, with the increasing use of immunosuppressive drugs in the transplantation setting.13,14 HIV infection creates a similar situation through chronic B-cell stimulation secondary to HIV replication and through altered antitumoral immunity. These effects are magnified by coinfection with oncogenic viruses.15 HIV itself may induce malignancies by interacting either directly or indirectly with cell cycling and growth16 or by altering oncogene regulation after genomic integration.17 The effects of HIV on the expression of certain cytokines may promote tumor growth.18,19 The widespread use of highly active antiretroviral therapy (HAART) has improved the survival of HIV-infected patients20 and led to a decline in the incidence of KS and certain types of NHL.21,22 The incidence of non–AIDS-defining cancers (NADCs) during the HAART era has not yet been studied in a large patient cohort. Because of the low risk of malignancies in patients of the same age as most HIV-infected persons, large studies are needed to identify a possible difference between the general population and HIV-infected patients. The French Hospital Database on HIV (FHDH), which includes more than 75,000 patients and contains substantial follow-up data, offers the opportunity for such an analysis. We therefore compared the incidence of NADCs during the pre-HAART period (1992 to 1995) and the HAART era (1996 to 1999) with the estimated incidence in the French general population of the same age and sex. We also analyzed changes in incidence rates between the two periods.
Study Population The methodology of the FHDH has been described in detail elsewhere.23 Briefly, FHDH is a clinical epidemiologic network launched in 1992 in 61 French University Hospitals belonging to 29 HIV treatment and information centers. The only FHDH inclusion criteria are HIV-1 or HIV-2 infection and written informed consent. Trained research assistants prospectively collect information using DMI2 software (property of the French Ministry of Health). The standardized data collection forms include the transmission group, values of usual biologic markers such as CD4+ cell counts and HIV-RNA levels, clinical manifestations, treatments, participation in clinical trials, and death and causes of death, as reported in the medical records. A follow-up form is completed at least every 6 months or at each visit or hospital admission during which a new clinical manifestation is diagnosed, a new treatment is prescribed, or a change in biologic markers is noted. By the end of 1999, data on 77,025 HIV-infected persons had been entered in the database, with a median follow-up of 32 months. The pre-HAART period (P1) lasted from January 1, 1992, to December 31, 1995. As protease inhibitors became widely available in France during the first semester of 1996, the HAART period (P2) lasted from January 1, 1996, to December 31, 1999. Patients ranging in age from 15 to 69 years, with at least one follow-up visit after enrollment, were included in this analysis. Patients who died before the second visit or before the second hospital admission were also included. Exclusion criteria were past or ongoing cancer at enrollment.
Definition of Cancer
Calculation of Standardized Incidence Ratios Expected incident cases were calculated by multiplying these age- and sex-specific cancer incidence rates in the French general population in 1995 by the corresponding number of person-years in the FHDH for each study period, assuming that these incidence rates were constant during 1992 to 1999. SIRs were calculated for specific cancers with an expected number of cases of at least five in at least one of the two study periods, and also for HD, which is known to be more frequent in HIV-infected patients. Ninety-five percent confidence intervals (CIs) were based on the Poisson distribution.27 SIR values were also calculated according to the HIV transmission group in the male population; this was not possible for women, because of the small number of cases. To compare NADC incidence rates between P1 and P2, the expected number of incident cases in P2 was calculated by multiplying estimated age- and sex-specific cancer incidence rates in P1 by the corresponding numbers of age- and sex-matched person-years in P2. All analyses were performed with SAS statistical software version 8.2 (SAS Institute, Cary, NC).
Global Incidence of NADCs Of the 678 NADCs diagnosed between January 1, 1992, and December 31, 1999, 27 (4.0%) were excluded from the study because they occurred at the same date as one of the three AIDS-defining cancers listed above.
Among the 57,428 men (164,275 person-years), 226 and 332 NADCs were observed during P1 and P2, respectively. Among the 19,597 women (60,050 person-years), 34 and 59 NADCs were diagnosed during P1 and P2, respectively. Median CD4 cell counts and median follow-up were significantly different between the two periods, among both men and women. Men diagnosed with cancer during P2 were older than those diagnosed during P1 (Table 1
The overall incidence of NADC was higher in HIV-infected men than in the French general population during both periods: P1 SIR = 2.36 (95% CI, 2.09 to 2.69) and P2 SIR = 1.91 (95% CI, 1.71 to 2.13). No such increase was observed in HIV-infected women in either period: P1 SIR = 1.19 (95% CI, 0.83 to 1.67) and P2 SIR = 1.06 (95% CI, 0.81 to 1.37).
Specific NADCs in Men
SIR values were also calculated for the male population according to the HIV transmission group (homosexual intercourse, intravenous drug use, and heterosexual intercourse; Table 3  ). Global NADC and HD incidence rates were higher in all the transmission groups during both periods, whereas the risk of colon, rectal, and anal cancers was higher only in homosexual men during both periods. The lung cancer incidence rate was higher among intravenous drug users during both periods and among homosexual and heterosexual men during P2.
Specific NADCs in Women Only the incidence of HD was higher in women during both periods: P1 SIR = 9.70 (95% CI, 3.10 to 22.44) and P2 SIR = 14.29 (95% CI, 6.84 to 26.27; Table 4 ). As in men, the incidence of lung cancer was higher during P2: SIR = 6.59 (95% CI, 3.40 to 11.52). In contrast, the incidence of breast cancer was significantly lower in HIV-infected women than in the French general population during both periods: P1 SIR = 0.25 (95% CI, 0.07 to 0.65) and P2 SIR = 0.43 (95% CI, 0.24 to 0.73).
Comparison of the Pre-HAART and HAART Periods No significant difference was found in the overall incidence of NADC between the two periods in men or in women: SIR = 0.96 (95% CI, 0.86 to 1.06) for men and SIR = 1.00 (95% CI, 0.76 to 1.29) for women. The risk of lung cancer among men increased almost two-fold between P1 and P2: SIR = 2.05 (95% CI, 1.62 to 2.56). The incidence of HD increased slightly among men in P2 relative to P1: SIR = 1.38 (95% CI, 1.12 to 1.67). Even if the increase did not reach significance for women, the same tendency was observed (SIR = 1.50 [95% CI, 0.72 to 2.76]). We performed an overall analysis, therefore, to test an increase in HD incidence between P1 and P2 and found it significant (overall SIR P2/P1 HD = 1.39 [95% CI, 1.14 to 1.67]). In men, the median CD4 cell count at HD diagnosis was significantly higher during P2 than in P1 (234/mL v 134/mL; P = .02). Among men with HD, the proportion of patients with AIDS was significantly lower in P2 than in P1 (48% v 62%; P = .05).
In this prospective hospital cohort study, we estimated the incidence of NADCs in HIV-infected patients during two 4-year periods, before and during the HAART era, in comparison with the risk in the French general population. During both periods, the overall incidence of NADC was significantly higher in HIV-infected men by approximately two-fold. This is consistent with previous reports, in which the overall risk of NADC ranged from 1.6- to three-fold.7,9–11 No increase in the overall incidence of NADC was found in women, possibly because of underreporting of certain malignancies such as breast or uterus cancers, which are usually diagnosed in France by specialized teams and centers (such as anticancer centers) that are not directly involved in the database and do not systematically report cancer diagnosis to the HIV treatment center. The underreporting hypothesis seems plausible to explain that the overall NADC risk in HIV women is not increased. Regarding breast cancer, the only female malignancy with more than five expected cases in this cohort, we recorded only four and 14 cases during P1 and P2, respectively, compared with expected numbers of 15.75 and 32.24. To test this hypothesis, we estimated the global SIR for NADCs, replacing observed breast cancer cases by the expected number of breast cancer cases in each study period. The resulting SIR values were 1.58 (95% CI, 1.15 to 2.11) in P1 and 1.38 (95% CI, 1.09 to 1.73) in P2, values significantly higher than 1.00 and closer to those estimated in men. The apparent deficit in breast cancer, which was also observed in a recently published study,28 was explained either by underreporting or by competing mortality, according to the authors. Of the 19 groups of malignancies studied, only HD seemed to be strongly associated with HIV infection in both men and women, in both study periods. The incidence of HD was higher in men regardless of the HIV transmission group. An excess of HD has been reported in HIV-infected patients in numerous studies2,4,5,7–11,2,9–34 with SIRs, which vary widely from 5.0 to 50.9. The overall HD SIR was estimated to 20.5 (95% CI, 15.8 to 26.3) in P1 and 28.5 (95% CI, 23.5 to 34.4) in P2, in the range of the literature values. The increased HD incidence observed in our study as compared with the French general population was greater in men than in women. In the literature, few authors studied the impact of sex on the risk of HD. Some authors4,9 found a lower risk among women than among men, whereas others6,10 found similar risks for both sexes. We do not find any obvious explanation for this phenomenon because in the general population, the incidence of HD is higher in men.26 Most previous studies5,10,11,35 have suggested that the risk of HD increases as immunodeficiency advances. In contrast, we found that the incidence of HD was increased in the HAART era (P2) relative to the pre-HAART era (P1). The median CD4 cell count was significantly higher in P2 as compared with P1, and the proportion of patients with AIDS was lower. This suggests that HD, like certain types of NHL, is not only induced by advanced immunodeficiency. Cofactors such as latent Epstein-Barr virus infection could be involved in the pathogenesis of HIV-associated HD.36 We did not find a change in overall NADC incidence between P1 and P2. The proportion of PI therapy varied from 0% to P1 to 60% at the end of P2. This result argues against an oncogenic effect of HAART, at least in the first 4 years. However, the potential role of HAART cannot be excluded, as the incidence of HD increased between the period before and during the HAART era, even if two small studies22,37 showed no significant excess of HD since the advent of HAART. In our study, the incidence of lung cancer increased in P2 relative to P1 in both sexes. Some other authors7,9,10 have reported a higher incidence of lung cancer in HIV-infected patients. Our results could be partly explained by the improved survival of HIV-infected patients on HAART and decrease in competitive mortality risks. It is also well known that HIV patients are more often smokers than their counterparts in the general population,38 and because smoking is the strongest risk factor for lung cancer, the most plausible explanation for the increased risk in HIV patients is likely to be smoking rather than a direct effect of HIV infection, as was also suggested in the literature.39,40 The relative risk of lung cancer was higher in women than in men (P2 SIR = 6.28; 95% CI, 3.40 to 11.56). Between 1985 and 1995, the incidence of lung cancer increased by 56% among French women younger than 65 years.26 If the same tendency was observed between 1995 and 1999, then using the general population incidence in 1995 as reference results in underestimating the expected number of cases during P2 and, consequently, in overestimating the risk of lung cancer among HIV-seropositive women in the HAART period. The incidence of colon, rectal, and anal cancers was only increased in the first study period, and the risk was lower than that previously reported for anal cancer in HIV-infected patients.10,30,41 We pooled colon, rectal, and anal cancer because separate incidence rates were not available for the French general population. Colon cancer is one of the most common malignancies in France,26 and its incidence does not seem to be increased in HIV-infected patients.9,10 It is therefore likely that the increase in the risk of anal cancer associated with HIV infection was diluted in our study. Epidemiologic studies have shown a strong link between human papillomavirus (HPV) and anal intraepithelial lesions (the precursor lesions of anal cancer) in HIV-seropositive homosexual men.42 When we analyzed male colon, rectal, and anal cancer incidence rates according to the HIV transmission group, an increased risk was only found among homosexual men, during both study periods. However, the impact of HIV on the incidence of anal cancer is controversial, because of conflicting data.5,9,10,35 CNS tumors were significantly more frequent during the first study period only, confirming the results of contemporary studies,5,9,10 but possible misclassification with NHL of the brain undermines the value of this finding. The incidence of stomach cancer was also significantly increased in the first study period only. Other authors have found an excess risk of stomach cancer in women4,10 but on the basis of few cases. The risk of kidney cancer was higher in HIV-infected men in the second study period. An excess has already been found in a small population in the pre-HAART era.43 Because no histologic data were available in our database, it is difficult to speculate on the mechanism by which HIV infection could increase the risk of kidney cancer. Mutagenic effects have been described both in vitro and in animals with some antiretroviral drugs, and prolonged use of these agents may also promote malignancies in humans.44,45 However, no increase in the overall incidence of cancer was observed between P1 and P2, arguing against a general oncogenic effect of HAART, at least in the medium term, whereas the same is not true for the effect of HAART on HD. This study has several limitations. First, we excluded from the analysis those cancers recorded on the same date as the three AIDS-defining malignancies during the follow-up. When we included in the analysis these 27 cancers excluded for that reason, the overall SIRs for NADC in women were unaffected, whereas the overall SIRs for NADC in men were slightly increased: P1 SIR = 2.55 (95% CI, 2.24 to 2.89) and P2 SIR = 1.92 (95% CI, 1.72 to 2.14). More importantly, non–AIDS-defining clinical events are probably undernotified in the database on which our analysis was based, as we discussed previously. Thus the association between HIV and the risk of some cancers was probably underestimated. In contrast, the higher incidence of some cancers in this study is more likely to reflect a true increased risk. Data on risk factors such as smoking and some viral infections were not available, so their impact on cancer incidence rates could not be studied. We were also unable to study certain cancers (of the testes and penis, for example) because the corresponding incidence rates in the French general population were not available. Finally, the short HAART-era study period (4 years) may have been insufficient to detect an increased incidence of some tumors.46 Indeed, with the improvement of survival and the declining incidence of opportunistic infections during the HAART period, HIV-infected patients can survive long enough to develop diseases with long induction periods. This was not the situation during the pre-HAART period, during which time survival was shorter and so there were less competitive risks, and during which time patients died from opportunistic infections and did not have time to develop cancer. This study shows that the overall incidence of NADCs is significantly higher in HIV-infected men relative to the general population in France. As previously reported in smaller populations,22,47 the advent of HAART has had no measurable impact on the overall incidence of such cancers, suggesting that the latter are not triggered by immune suppression alone. Nevertheless, a slight increase in the incidence of HD was observed between the pre-HAART and during the HAART period, while at the same time the patients are less immunosuppressed. Therefore, we cannot exclude an oncogenic effect of HAART on HD. HD was the only NADC with a significantly increased incidence relative to the general population, regardless of sex, the study period (pre- or post-HAART), and the transmission group (among men). Lung cancer was more frequent in both sexes during P2, and colon, rectal, and anal cancers were more frequent in homosexual men, a finding probably linked more to lifestyle factors and exposure to carcinogens than to HIV infection. Clinicians should be aware that HIV patients who smoke, like smokers in the general population, are at an increased risk of lung cancer and should be given advice on prevention.
Clinical Epidemiology Group of the FHDH Scientific committee: Dr E. Billaud, Pr F. Boué, D. Costagliola, Dr X. Duval, Dr C. Duvivier, Dr P. Enel, Dr S. Fournier, Dr J. Gasnault, Dr C. Gaud, Dr J. Gilquin, Dr S. Grabar, Dr M.A. Khuong, Pr J.M. Lang, M Mary-Krause, Pr S. Matheron, Pr M.C. Meyohas, Pr G. Pialoux, Dr I. Poizot-Martin, Dr C. Pradier, Pr E. Rouveix, Pr D. Salmon-Ceron, Pr A. Sobel, Dr P. Tattevin, Dr H. Tissot-Dupont, and Dr Y. Yasdanpanah. DMI2 coordinating center: French Ministry of Health (Dr E. Aronica, Dr B. Haury, Dr V. Tirard-Fleury, and I. Tortay). Statistical analysis center: INSERM EMI 0214 (D. Costagliola, Dr S. Grabar, E. Lanoy, L. Lièvre, M. Mary-Krause, V. Potard). Centre d’ Information et de Soins de l’Immunodéficience Humaine (CISIH) Paris area: CISIH de Bichat-Claude Bernard (Hôpital Bichat-Claude Bernard: Pr S. Matheron, Pr J.P. Coulaud, Pr J.L. Vildé, Pr C. Leport, Pr P. Yeni, C. Mandet, Pr E. Bouvet, C. Gaudebout, Pr B. Crickx, Dr C. Picard-Dahan), CISIH de Paris-Centre Quest (Hôpital Européen Georges Pompidou: Pr L. Weiss, D. Tisne-Dessus; G.H. Tarnier-Cochin: Pr D. Sicard, Pr D. Salmon; Hôpital Saint-Joseph: Dr J. Gilquin, Dr I. Auperin; Hôpital Necker adultes: Dr J.P. Viard, Dr L. Roudière; CISIH de Paris-Sud (Hôpital Antoine Béclère: Pr F. Boué, Dr R. Fior; Hôpital de Bicêtre: Pr J.F. Delfraissy, Dr C. Goujard; Hôpital Henri Mondor: Dr Ph. Lesprit, C. Jung; Hôpital Paul Brousse), CISIH de Paris-Est (Hôpital Saint-Antoine: Pr M.C. Meyohas, Dr J.L. Meynard, Dr O. Picard, N. Desplanque; Hôpital Tenon: Pr J. Cadranel, Pr C. Mayaud, Dr G. Pialoux, Pr W. Rozenbaum), CISIH de Pitié-Salpétrière (Groupe Hospitalier Pitié-Salpétrière: Pr F. Bricaire, Pr C. Katlama, Pr S. Herson, Dr A. Simon), CISIH de Saint-Louis (Hôpital Saint-Louis: Pr J.M. Decazes, Pr J.M. Molina, Pr J.P. Clauvel, Dr L. Gerard; GH Lariboisière-Fernand Widal: Dr J.M. Salord, Dr Diermer), CISIH 92 (Hôpital Ambroise Paré: Dr C. Dupont, H. Berthé, Pr P. Saïag; Hôpital Louis Mourier : Dr E. Mortier, C. Chandemerle; Hôpital Raymond Poincaré: Dr P. de Truchis), CISIH 93 (Hôpital Avicenne: Dr M. Bentata, P. Berlureau; Hôpital Jean Verdier: J. Franchi, Dr V. Jeantils; Hôpital Delafontaine: Dr Mechali, B. Taverne). Outside Paris area: CISIH Auvergne-Loire (Centre Hospitalier Universitaire [CHU] de Clermont-Ferrand: Dr H. Laurichesse, Dr F. Gourdon; Centre Hospitalier Régional Universitaire [CHRU] de Saint-Etienne: Pr F. Lucht, Dr A. Fresard); CISIH de Bourgogne-Franche Comté (CHRU de Besançon; CHRU de Dijon; CH de Belfort: Dr J.P. Faller, P. Eglinger; CHRU de Reims); CISIH de Caen (CHRU de Caen: Pr C. Bazin, Dr R. Verdon), CISIH de Grenoble (CHU de Grenoble), CISIH de Lyon (Hôpital de la Croix-Rousse: Pr D. Peyramond, Dr A. Boibieux; Hôpital Edouard Herriot: Pr J.L. Touraine, Dr J.M. Livrozet; Hôtel-Dieu: Pr C. Trepo, Dr L. Cotte; CISIH de Marseille (Hôpital de la Conception: Dr I. Ravaux, Dr H. Tissot-Dupont; Hôpital Houphouët-Boigny: Pr J.P Delmont, Dr J. Moreau; Institut Paoli Calmettes: Pr J.A. Gastaut; Hôpital Sainte-Marguerite: Dr I. Poizot-Martin, Pr J. Soubeyrand, Dr F. Retornaz; Centre Hospitalier Général [CHG] d’Aix-En-Provence: Dr P.A. Blanc, Dr T. Allegre; Centre pénitentiaire des Baumettes: Dr A. Galinier, Dr J.M. Ruiz; CH d’Arles; CH d’Avignon: Dr G. Lepeu; CH de Digne Les Bains: Dr P. Granet-Brunello; CH de Gap: Dr L. Pelissier, Dr J.P. Esterni; CH de Martigues: Dr M. Nezri, Dr R. Cohen-Valensi; Centre Hospitalier Intercommunal de Toulon: Dr A. Laffeuillade, Dr S. Chadapaud), CISIH de Montpellier (CHU de Montpellier: Pr J. Reynes; CHG de Nîmes), CISIH de Nancy (Hôpital de Brabois: Pr T. May, Dr C. Rabaud), CISIH de Nantes (CHRU de Nantes: Pr F. Raffi, Dr E. Billaud), CISIH de Nice (Hôpital Archet 1: Dr C. Pradier, Dr P. Pugliese; CHG Antibes Juan les Pins), CISIH de Rennes (CHU de Rennes: Pr C. Michelet, Dr C. Arvieux), CISIH de Rouen (CHRU de Rouen: Pr F. Caron, Dr F. Borsa-Lebas), CISIH de Strasbourg (CHRU de Strasbourg: Pr J.M. Lang, Dr D. Rey, Dr P. Fraisse; CH de Mulhouse), CISIH de Toulouse (CHU Purpan: Pr P. Massip, Dr L. Cuzin, Pr E. Arlet-Suau, Dr M.F. Thiercelin Legrand; Hôpital la Grave; CHU Rangueil), CISIH de Tourcoing-Lille (CH Gustave Dron; CH de Tourcoing: Dr S. Alfandari, Dr Y. Yasdanpanah), CISIH de Tours (CHRU de Tours; CHU Trousseau). Overseas: CISIH de Guadeloupe (CHRU de Pointe-à-Pitre), CISIH de Guyane (CHG de Cayenne: Dr M. Sobesky, Dr R. Pradinaud), CISIH de Martinique (CHRU de Fort-de-France), CISIH de La Réunion (CHD Félix Guyon: Dr C. Gaud, Dr M. Contant).
The authors indicated no potential conflicts of interest.
We thank all the cohort participants and especially the local research assistants, without whom this work would not have been possible.
Supported by the Institut National de la Santé et de la Recherche Médicale, the Agence Nationale de Recherches sur le SIDA, and the Fondation pour la Recherche Médicale, Paris, France.
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