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Cancers in HIV+, recent published studies
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From jules: mixed bag results suggesting reduced risks in ART era but still increased risk for certain cancers, suggesting earlier HAART, higher CD4s and undetectable load can be protective
From the last study reported below: "Although it remains unclear whether HIV-infected individuals are truly exposed to a greater risk for non-virus-related NADCs, or if the confounding by unadjusted cancer risk factors may be responsible for the increased incidence, cancer may increase as a cause of morbidity and mortality in an aging HIV population. However, cART appears to be protective against the development of these malignancies, indicating that an earlier and more effective therapy may result in a reduced cancer incidence in the population level."........[The figure suggests that cancer incidence in increasing over time, but this may be due to increased screening at later time points or decreased deaths from other causes over the HAART era (i.e survivor bias). The other major issue is the low numbers of cancers overall.]
Incidence of AIDS-defining cancers and virus-related and non-virus-related non-AIDS-defining cancers among HIV-infected patients compared with the general population in a large health district of northern Italy, 1999-2009 - (08/12/13)
......In multivariate analysis, increasing age and CD4 cell count < 50 cells/μL were the only factors independently associated with all cancers.........At the time of first cancer diagnosis, patients with non-virus-related NADCs were older than those with ADCs and with virus-related NADCs (P < 0.001) and they had higher CD4 cell counts (P < 0.001) and higher CD4 nadirs (P < 0.05) (Table 1). Patients with ADCs had the highest HIV viral loads (P < 0.05), and cART was less frequently received in this group (P < 0.001) (Table 1)........Even if the incidence of the three ADC among HIV-infected patients in France fell between the pre-cART and cART periods and continued to decline during the cART period, the risks remained significantly higher than in the general population during all the calendar periods. Patients with restored immunity for at least 2 years and controlled viral load on cART still had a strongly elevated risk of KS (35-fold), while the risk of NHL was similar to that of the general population. Age at KS and cervical cancer diagnosis was only slightly different between HIVinfected and general populations (-2 and -3 years respectively), while the difference was more marked for NHL (-11 years)......."An increased risk (SIR = 4.2) of cancers overall was found in HIV-infected patients. .....The risk of all cancers was 4-fold higher in HIV-infected patients than in the reference population.....Two hundred of the cancers (48.1%) were ADCs, while 138 (33.2%) were non-virus-related NADCs and 78 (18.7%) were virus-related NADCs. The most frequent ADC was KS, accounting for 96 cases, followed by NHL (n = 95) and ICC (n = 9). Among non-virus-related NADCs, the most frequent were skin non-melanoma (n = 41) and trachea/lung cancers (n = 23), while among the virus-related NADCs, HCC accounted for 34 and HL for 31 cases.......KS data may be due to African patients in study
"The majority of cases (n= 3265, 55%) occurred in
the pre-cART, followed by 1015 cases (17%) in the early-cART, 807 cases (14%) in the intermediate-cART, and 803 cases (14%) in the late-cART period."
......At the time of first cancer diagnosis, patients with non-virus-related NADCs were older than those with ADCs and with virus-related NADCs (P < 0.001) and they had higher CD4 cell counts (P < 0.001) and higher CD4 nadirs (P < 0.05) (Table 1). Patients with ADCs had the highest HIV viral loads (P < 0.05), and cART was less frequently received in this group (P < 0.001) (Table 1)........Older age and severe immunodeficiency were associated with an increased risk for all classes of cancer in our study. Ageing of HIV-infected patients as a result of the increased life expectancy provided by effective cART has increased the risk of many diseases, including malignancies. The accelerated ageing process that occurs in the immune system, also known as "immunosenescence", during HIV infection could account for the higher risk of cancer in people living with HIV infection. The association of virus-related NADCs with low CD4 cell counts suggests that a defect in immunosurveillance on infection with oncogenic agents is permissive for malignant transformation. Several variables have been used to study the relationship between cancer and immunodeficiency, resulting in conflicting findings depending on the variable used (i.e. CD4 count nadir, baseline CD4 count, time-updated CD4 count or cumulative time with a given CD4 count), and there is not a unique, commonly accepted and clear "marker" of immunodeficiency that is associated with the cancer risk.
Risk factors for anal HPV infection and anal precancer in HIV-infected men who have sex with men - (08/12/13)......Journal of Infectious Diseases Advance Access published August 1, 2013
Use of Highly Active Antiretroviral Therapy Is Associated With Lower Prevalence of Anal Intraepithelial Neoplastic Lesions and Lower Prevalence of Human Papillomavirus in HIV-Infected Men Who Have Sex With Men - (08/12/13)......Sexually Transmitted Diseases: July 2012
IAS: Risk of cancer among HIV-positive women in British Columbia, Canada: Importance of screening and detection programs - (07/20/13)
The Incidence of AIDS-Defining Illnesses at a Current CD4 Count ≥200 Cells/μL in the Post-Combination Antiretroviral Therapy Era - (08/29/13).....Clinical Infectious Diseases Advance Access published August 6, 2013.......Opportunistic Infections Working Group on behalf of the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study in EuroCOORDa
A. Mocroft,1 H. J. Furrer,2 J. M. Miro,3 P. Reiss,4,5 C. Mussini,6 O. Kirk,7,8 S. Abgrall,9,10,11 S. Ayayi,12 B. Bartmeyer,13
D. Braun,14 A. Castagna,15 A. d'Arminio Monforte,16 B. Gazzard,17 F.
Gutierrez,18 I. Hurtado,19 K. Jansen,20 L. Meyer,21,22 P. Munoz,23 N. Obel,8 P. Soler-Palacin,24 A. Papadopoulos,25 F. Raffi,26 J. T. Ramos,27 J. K.
Rockstroh,28 D. Salmon,29
C. Torti,30,31 J. Warszawski,32 S. de Wit,33 R. Zangerle,34 C. Fabre-Colin,35,36 J. Kjaer,7 G. Chene,35,36 J. Grarup,7 and
J. D. Lundgren7,8;
Risk of AIDS-defining cancers among HIV1-infected patients in France between 1992 and 2009: Results from the FHDH-ANRS CO4 cohort - (08/16/13) .......Clinical Infectious Diseases Advance Access published July 29, 2013
We examined trends in the incidence of the 3 AIDS-defining cancers (ADC) (Kaposi's sarcoma (KS), non-Hodgkin's lymphoma (NHL) and cervical cancer) among HIV-infected patients relative to the general population between 1992 and 2009 in France, focusing on age at ADC diagnosis and on patients with controlled viral load and restored immunity on combined antiretroviral therapy (cART).......the incidence of all ADC continued to fall, including cervical cancer, in the cART period, but the risk remained higher than in the general population in 2005-2009. In patients with stably restored immunity, KS remained significantly more frequent than in the general population.
Burden of Non-AIDS-Defining and Non-Virus-Related Cancers Among HIV-Infected Patients in the Combined Antiretroviral Therapy Era (appears to come from same Italian group from Brescia as the first study at the very top of this report)
AIDS RESEARCH AND HUMAN RETROVIRUSES
2013
"Although it remains unclear whether HIV-infected individuals are truly exposed to a greater risk for non-virus-related NADCs, or if the confounding by unadjusted cancer risk factors may be responsible for the increased incidence, cancer may increase as a cause of morbidity and mortality in an aging HIV population. However, cART appears to be protective against the development of these malignancies, indicating that an earlier and more effective therapy may result in a reduced cancer incidence in the population level."........[The figure suggests that cancer incidence in increasing over time, but this may be due to increased screening at later time points or decreased deaths from other causes over the HAART era (i.e survivor bias). The other major issue is the low numbers of cancers overall.
"The only predictors of non-virus-related NADCs included older age [incidence rate ratio
(IRR) = 1.10; 95% CI, 1.08-1.12 per each additional year, p < 0.001] and a shorter or no exposition to combined
antiretroviral therapy (cART) (IRR= 2.31; 95% CI, 1.38-3.89, p = 0.002). A CD4+ count lower than 50/mm3 was
significantly associated with cancers only in the univariate model (IRR= 1.40; 95% CI, 0.99-1.98, p = 0.057). HIVinfected
men showed a 2-fold increased risk of non-virus-related NADCs compared to the general population.
However, the use of cART appeared to be beneficial in protecting against the development of these malignancies."
"During the study period, we recorded a trend toward a significant increase (p=0.070) in the incidence rate of combined non-virus-related NADCs (ß-coefficient of regression line: 1.53) (Fig. 1). The primary sites of cancer diagnoses are shown in Table 2, with skin nonmelanoma, lung, and breast malignancies reported in most of the patients. Overall, the incidence rate of all non-virus-related NADCs combined was higher among HIV-infected patients compared to the HIV-negative population living in the same area (SIR=1.63; 95% CI 1.38-1.94). However, stratifying for gender only the males showed SIR for all non-virus-related NADCs significantly greater compared to the general population (male SIR=1.86; 95% CI 1.55-2.26 versus female SIR=1.07; 95% CI 0.71-1.57). Concerning specific cancer sites, the HIV-infected man reported the greatest risk of lung carcinoma (SIR=3.59; 95% CI 2.36-5.45), followed by testis cancer (SIR=3.11; 95% CI 1.48-6.52). Interestingly, among our HIV-positive population prostate and breast cancers showed SIR null or below null (SIR=1.10; 95% CI 0.53-2.32 and SIR=0.91; 95% CI 0.47-1.74, respectively)."
"Since the advent of cART, HIV infection has progressively been transformed from a relative acute terminal condition into a chronic illness carrying various comorbidities as NADCs. Analyzing the HIV-positive population registered in the Local Health Authority of Brescia, we recorded a trend toward a significant increase in cancer burden attributable to non-virus-related NADCs over the study period (1999-2009). Interestingly, we found that HIV-infected men had a 2-fold increased risk of these cancers compared to the general population living in the same area. However, because of the high incidence ratio of smoking-related cancers, it is possible that the greater risk detected in HIV-positive males is due to their greater exposure to non-HIV risk factors, such as tobacco smoking and drinking."
"Through the multiple linear regression models, only older age and a shorter or no exposition to cART were independently associated with a higher risk of non-virus-related NADCs (IRR=1.10; 95% CI 1.08-1.12 per each additional year, p<0.001 and IRR=2.31; 95% CI 1.38-3.89, p=0.002, respectively) (Table 3). Afterward, we separately analyzed the 23 patients who reported a diagnosis of lung cancer. The median age at diagnosis was 53.8 (range, 21.2-71.4) years old, which was significantly lower than the ages of the HIV-negative population living in Northern Italy (over 75 years old).30 The majority of cases (n=21, 91.3%) were cigarette smokers and all patients had at least one risk factor associated with lung cancer, or predisposing comorbidities (e.g., a chronic obstructive pulmonary disease) or a previous pneumonia. All patients except two (n=21, 91.3%) had a diagnosis at stage IV of cancer with metastases and therefore were deceased, with a median survival of 5.95 (range, 0.03-29) months."
Laura Albini,1 Alessandra Calabresi,1 Daria Gotti,1 Alice Ferraresi,1 Andrea Festa,2 Francesco Donato,2 Michele Magoni,3 Francesco Castelli,1 and Eugenia Quiros-Roldan1
1Department of Infectious Diseases, University of Brescia, Brescia, Italy.
2Department of Experimental and Applied Medicine, Institute of Hygiene, Epidemiology, and Public Health, University of Brescia, Brescia, Italy.
3Local Health Authority (LHA) of Brescia Province, Brescia, Italy.
ABSTRACT
The risk of cancer is substantially increased in HIV-infected patients. However, little is known about non-AIDS-defining cancers (NADCs) without an infectious etiology. A total of 5,090 HIV-infected patients registered in the Local Health Authority (LHA) of Brescia and receiving primary care at our clinic were included in a retrospective (1999-2009) analysis. The cancer diagnoses were obtained through a record-linkage procedure between our database and the LHA general database and population-based Cancer Registry of LHA. We compared risks of these malignancies with those of the general population living in the same health area by using age-standardized incidence ratios (SIRs). Poisson regression analysis was used to assess factors associated with non-virus-related NADCs. We recorded an increase in the SIR of non-virus-related NADCs over time, with 138 cancers diagnosed in 131 patients. The mean incidence rate was 42.6/10,000 person years and the median age at the diagnosis was 49 (range, 28-78) years old. Stratifying for gender, only HIV-infected males had an increased risk of non-virus-related NADCs [SIR=1.86; 95% confidence interval (CI), 1.55-2.26]. Risk was higher for lung (SIR=3.59; 95% CI, 2.36-5.45) and testis cancer (SIR=3.11; 95% CI, 1.48-6.52). However,, cancers of the prostate and breast in HIV-positive men and women were null (SIR=1.10; 95% CI, 0.53-2.32 and SIR=0.91; 95% CI, 0.47-1.74, respectively). The only predictors of non-virus-related NADCs included older age [incidence rate ratio (IRR)=1.10; 95% CI, 1.08-1.12 per each additional year, p<0.001] and a shorter or no exposition to combined antiretroviral therapy (cART) (IRR=2.31; 95% CI, 1.38-3.89, p=0.002). A CD4+ count lower than 50/mm3 was significantly associated with cancers only in the univariate model (IRR=1.40; 95% CI, 0.99-1.98, p=0.057). HIV-infected men showed a 2-fold increased risk of non-virus-related NADCs compared to the general population. However, the use of cART appeared to be beneficial in protecting against the development of these malignancies.
Introduction
Combined antiretroviral therapy (cART) has dramatically improved the life expectancy of HIV-positive subjects, turning this infection into a complex chronic disease.1 Although there are currently fewer patients succumbing to infectious complications of AIDS, other HIV-related morbidities have become increasingly important.2,3 In particular, the spectrum of cancer diagnosis has shifted from AIDS-defining cancers (ADCs), primarily Kaposi's sarcoma and aggressive non-Hodgkin's lymphoma, to non-AIDS-defining cancers (NADCs).4,5 Although the increased life expectancy and the reduction of competing causes of death may be contributing to this increased incidence, patients with HIV infection still have a greater tendency compared to the general population to develop not only non-AIDS-defining cancers with a confirmed or suspected virus pathogenesis6-8 but also non-virus-related cancers.9,10
While the etiology of virus-related ADCs and NADCs has been deeply investigated, emerging as a complex interplay between immunodeficiency and concomitant oncogenic virus infections,11-13 the potential mechanism underlying the increased risk of developing non-virus-related cancers in the HIV-infected population still remains obscure. The high prevalence of high-risk behaviors such as tobacco smoking and alcohol consumption,14,15 the direct oncogenic effects of HIV itself, chronic inflammation besides immunodeficiency, and long-term exposure to cART have all been suggested to mediate the increased risk of non-virus-related NADCs among HIV-infected people.16,17 However, the few available data regarding these malignancies have been extracted mostly from studies that investigated the incidence rates of all NADCs without distinguishing between virus and non-virus-related cancers.
In a meta-analysis of the incidence of NADCs in HIV-infected individuals, Shiels et al. reported elevated summary standardized incidence ratios (SIRs) for malignancies associated with cigarette smoking, such as lung, laryngeal, and kidney tumors.8 Although the prevalence of cigarette smoking among HIV-infected patients is 2- to 3-fold higher than that of the general population,18 the risk of developing lung cancer remains two to four times greater even after adjusting for smoking intensity and duration.19,20
Moreover, the literature reports that non-virus-related NADCs occur in younger subjects and they are more aggressive and diagnosed at a more advanced stage compared to the HIV-negative population.21-23
As far as we know, for the first time the non-virus-related NADCs have been separately analyzed to estimate their incidence rates in a large single-center HIV cohort during the cART era compared to the general population living in the same area. Moreover, we investigated whether factors linked to HIV infection represent specific risk factors for the development of these malignancies.
Materials and Methods
Patients
We carried out a retrospective single-center cohort study from January 1999 to December 2009 involving HIV-infected patients registered in the Local Health Authority (LHA) of Brescia (Northern Italy) and receiving primary care for HIV infection at the Clinic of Infectious and Tropical Diseases of the University of Brescia.
Our study is considering cancer incidence only in the post-cART era; we chose 1999 as the year of study initiation because data from the Cancer Registry of Brescia LHA were available starting from that year. Both cART-naive and experienced HIV-infected patients who were >18 years of age have been included in the analysis.
The study was approved by the local institutional review board and the patients gave written informed consent for the collection of their data at the first visit of follow-up. The demographic data and medical history, mode of transmission, data from the first positive HIV test, CD4+ cell counts, and HIV-RNA load were prospectively updated every 3 months, and any new medical diagnoses, hospitalizations, pharmaceutical prescriptions, and laboratory and radiographic findings were recorded. These data were collected and registered in an electronic database employed for the routine management of patients.
All diagnoses of cancer were provided by this electronic database and integrated with those recorded on two other clinical sources: the administrative database of the LHA of Brescia and the population-based Cancer Registry of the LHA. The record-linkage procedure of our clinical database with the LHA general database and Cancer Registry has been described in detail previously.24 All cancer cases were defined on the basis of either histological, hematological, or cytological examination, or a clinical diagnosis through autopsy or through a death certificate based on postmortem report. Non-AIDS-defining non-virus-related cancers were defined as any type of malignancy not including AIDS-defining cancers (i.e., non-Hodgkin lymphoma, Kaposi sarcoma, and invasive cervical carcinoma) and cancers with a known infectious etiology (Hodgkin lymphoma, which is Epstein-Barr virus related; cervix, vagina, vulva, penis, anal squamous cells, and certain oral cavity/pharynx squamous cell cancers defined by Chaturvedi et al.,25 which are human papillomavirus related; liver cancer, which is hepatitis B and C related; and stomach cancer, which is Helicobacter pylori related).
All non-virus-related NADCs that occurred after entrance in the study were considered as endpoints. Multiple primaries (i.e., cancers of a different type occurring in the same subject) were included in the analysis and each malignancy was analyzed as a single case. Benign cancers and cancer diagnoses previous to the HIV diagnosis date or the patient entrance in the study were excluded. Cancer type or site has been classified using the International Statistical Classification of Diseases and Related Health Problems, 10th revision.26
For the purpose of this study, the AIDS diagnosis has been defined as an AIDS event and/or a CD4 T cell count lower than 200 cells/μl. The cART was defined as treatment with two or more nucleoside reverse transcriptase inhibitors in combination with at least one protease inhibitor or one nonnucleoside reverse transcriptase inhibitor, or an abacavir-containing or a tenofovir-containing regimen of three or more nucleoside reverse transcriptase inhibitors.
Statistical analyses
For each patient included in the study, person-years at risk have been calculated either starting from January 1, 1999 or from the date of enrollment in the cohort, whichever was later. The observation period ended either on December 31, 2009 or with a cancer diagnosis, on the last follow-up visit, or death, whichever occurred first.
Patient characteristics (age, sex, mode of HIV exposure, CD4+ cell count, HIV viral load, prior AIDS diagnosis, and cART) for the entire cohort were described at the entrance to the study and for the cases the same were described at the time of cancer diagnosis.
Two separate descriptive analyses of data were performed: (1) the temporal trend showed by the incidence rates of non-virus-related NADCs in our cohort of HIV-infected patients, during the period 1999-2009, and (2) the comparison between the HIV-positive population and the general population living in the same area. For the first point, the incidence rates (IRs) of each type of non-virus-related NADC and their 95% confidence intervals (95% CI) were calculated dividing observed cases by the corresponding person-years at risk per year and they were age standardized by using the direct method with the European population as the standard.27 For the analysis of the time trend, the beta coefficient of the regression line of age-standardized incidence cancer rates per year of follow-up was computed as a measure of the linear trend of cancer frequency over the period.
A comparison between the incidence of non-virus-related cancers in our HIV-positive population and the general population living in the Brescia area was performed using the indirect method of standardization, with the Brescia area population as the standard. For this, the expected number of malignancies was calculated by multiplying the person-years at risk by appropriate age- and gender-specific incidence rates, as derived from the incidence rates obtained from the Cancer Registry of Brescia LHA for the general population during the periods 1999-2001 and 2004-2006, when incidence data from the population-based Cancer Registry were available,28,29 standardized by age. SIRs and their corresponding 95% CIs (Poisson distribution) have been calculated as the ratio between the observed cancer incident cases recorded in the HIV-infected patients and the expected numbers of cancer diagnoses during the study period.
Poisson regression analysis was used to evaluate the univariate and multivariate associations between covariates and non-virus-related NADC diagnoses. A p-value of 0.05 was used for all the two-tailed statistical tests. Age, sex, reported HIV risk behavior, and prior AIDS diagnosis were included in the fitted models as possible confounders, regardless of statistical significance. For all other variables, only those with a p value<0.05 at univariate analysis were included in the multivariate model.
All analyses were performed using STATA 12 (StataCorp LP, College Station, TX).
Results
Five thousands and ninety HIV-infected patients were included in the study, with a median follow-up of 6.75 [interquartile range (IQR), 2.62-10.99] person-years. The baseline characteristics of the cohort are shown in Table 1. The patients were mainly male (71.91%), born in Italy (81.91%), and intravenous drug users (42.95%), with a median age of 35 (IQR, 31-40) at the entrance to the study. Of the HIV-positive patients 38.06% were on a cART regimen at the entrance to the study and 1,034 (20.31%) patients had a previous AIDS diagnosis.
Over a total of 32,482.23 person-years of follow-up since entrance to the study, 138 non-virus-related NADCs were diagnosed in 131 patients. The characteristics of these patients at the time of cancer diagnosis are given in Table 1.
During the study period, we recorded a trend toward a significant increase (p=0.070) in the incidence rate of combined non-virus-related NADCs (ß-coefficient of regression line: 1.53) (Fig. 1). The primary sites of cancer diagnoses are shown in Table 2, with skin nonmelanoma, lung, and breast malignancies reported in most of the patients. Overall, the incidence rate of all non-virus-related NADCs combined was higher among HIV-infected patients compared to the HIV-negative population living in the same area (SIR=1.63; 95% CI 1.38-1.94). However, stratifying for gender only the males showed SIR for all non-virus-related NADCs significantly greater compared to the general population (male SIR=1.86; 95% CI 1.55-2.26 versus female SIR=1.07; 95% CI 0.71-1.57). Concerning specific cancer sites, the HIV-infected man reported the greatest risk of lung carcinoma (SIR=3.59; 95% CI 2.36-5.45), followed by testis cancer (SIR=3.11; 95% CI 1.48-6.52). Interestingly, among our HIV-positive population prostate and breast cancers showed SIR null or below null (SIR=1.10; 95% CI 0.53-2.32 and SIR=0.91; 95% CI 0.47-1.74, respectively).
Through the multiple linear regression models, only older age and a shorter or no exposition to cART were independently associated with a higher risk of non-virus-related NADCs (IRR=1.10; 95% CI 1.08-1.12 per each additional year, p<0.001 and IRR=2.31; 95% CI 1.38-3.89, p=0.002, respectively) (Table 3). Afterward, we separately analyzed the 23 patients who reported a diagnosis of lung cancer. The median age at diagnosis was 53.8 (range, 21.2-71.4) years old, which was significantly lower than the ages of the HIV-negative population living in Northern Italy (over 75 years old).30 The majority of cases (n=21, 91.3%) were cigarette smokers and all patients had at least one risk factor associated with lung cancer, or predisposing comorbidities (e.g., a chronic obstructive pulmonary disease) or a previous pneumonia. All patients except two (n=21, 91.3%) had a diagnosis at stage IV of cancer with metastases and therefore were deceased, with a median survival of 5.95 (range, 0.03-29) months.
Discussion
Since the advent of cART, HIV infection has progressively been transformed from a relative acute terminal condition into a chronic illness carrying various comorbidities as NADCs. Analyzing the HIV-positive population registered in the Local Health Authority of Brescia, we recorded a trend toward a significant increase in cancer burden attributable to non-virus-related NADCs over the study period (1999-2009). Interestingly, we found that HIV-infected men had a 2-fold increased risk of these cancers compared to the general population living in the same area. However, because of the high incidence ratio of smoking-related cancers, it is possible that the greater risk detected in HIV-positive males is due to their greater exposure to non-HIV risk factors, such as tobacco smoking and drinking.
The SIR related to lung cancer found in our study has resulted in a much greater incidence than in the general population only in the HIV-positive male population, different from what was found by Franzetti et al.31 Moreover, unlike Dubrow et al. who reported relative risks null or below null for most non-viral-related epithelial cancers,32 skin nonmelanoma was the most frequent cancer diagnosed among our HIV-infected patients, with a SIR from 2-fold to 3-fold higher than the general population, as occurred in the study of Silverberg et al.33 However, this finding may be partially correlated with exposure to greater sunlight typical of the Mediterranean countries such as Italy. Moreover, our HIV outpatient care services provide a weekly dermatology consultation and that could be the cause of early and numerous diagnoses. In accordance with previous studies,7,34,35 we estimated a SIR for lung cancer equal to 3.4, whereas HIV infection does not seem to have an effect on breast cancer development.7
However, the routine breast cancer screening by mammography is significantly lower in HIV-infected women compared to the general population, as emerged from the Women's Interagency HIV Study.36 Interestingly, we also diagnosed breast cancer in one HIV-infected male. This malignancy is very uncommon both in HIV-infected and -uninfected men with only a few cases reported in the literature37,38 and with an annual European incidence that does not exceed 1/100,000. Lastly, in our analysis HIV-positive men did not show an increased risk of prostate cancer compared to their HIV-negative counterparts. However, it is interesting to note that cART might have a direct protective effect on prostate cancer independent of its effect in increasing the CD4+ cell count, as reported by Chao et al.39
Unsurprisingly, aging was significantly associated with all non-virus-related NADCs. As a result of effective cART, patients are now living longer, and are therefore at increased risk of many age-associated comorbidities including cancers. Indeed, in Swiss and Italian studies, the increased incidence of NADCs in the cART era was largely explained by the aging of HIV-positive patients.7,34 Today, a direct association with immunodeficiency has been established only for AIDS-defining and non-AIDS-defining cancers with a known infectious etiology, whereas the data concerning those non-virus-related cancers are inconsistent.40-42 From our analysis it emerged that neither the nadir of the CD4+ cell count nor the CD4+ cell count at the time of diagnosis represents an independent risk factor for non-virus-correlated NADCs, although a CD4+ cell count <50/mm3 resulted in a significant association in the univariate model.
Also the effect of cART on cancer development is controversial in the literature,39,43 although experimental data suggest that certain antiretroviral drugs, such as protease inhibitors, may have anticarcinogenic properties and therefore may exert a direct protective effect on cancer development.44,45 In the current study, a shorter exposition or no exposition to cART was associated with a higher risk of non-virus-related NADCs.
Interestingly, in comparison with the mean age of lung cancer occurrence reported in the literature for the general population, this malignancy has been diagnosed at a younger age in our HIV-positive patients, although 91.3% of them were cigarette smokers. Moreover, these patients showed a median survival of about 6 months, in accordance with the results of other studies, which indicate an overall survival rate in HIV subjects with lung cancer ranging from 3 to 9 months.46,47
Some potential limitations in our study should be considered when interpreting the results. First, although our non-virus-related NADC rates are similar to whose reported in other studies, we were limited by the low number of diagnoses so we were unable to assess the risk factors associated with each individual cancer type. Second, we were unable to adjust our analysis for traditional cancer risk factors since tobacco smoking, alcohol use, or family history of cancers were not systematically collected. Finally, we had no data on cancer screening practices and it was not possible to explore their influence on cancer incidence over time. Despite these limitations, our study has several important strengths. First, our Clinic of Infectious and Tropical Diseases is the only clinical center to provide care for HIV infection in the area of Brescia Province, encompassing a population of more than 1.1 million inhabitants. As opposed to the few Italian epidemiological studies previously published based on a record linkage between the Italian AIDS Registry and Cancer Registries,7,48 we considered all patients infected by HIV and not only those who developed AIDS. Moreover, through a record linkage with the LHA general database and Brescia's Cancer Registry, all cancer cases have been captured.24 Finally, the SIRs were accurately estimated, since we compared the incidence of cancers that occurred in our cohort with the incidence rates extracted from the Cancer Registry of Brescia, where our center is located and where all study patients reported a legal residence.
Although it remains unclear whether HIV-infected individuals are truly exposed to a greater risk for non-virus-related NADCs, or if the confounding by unadjusted cancer risk factors may be responsible for the increased incidence, cancer may increase as a cause of morbidity and mortality in an aging HIV population. However, cART appears to be protective against the development of these malignancies, indicating that an earlier and more effective therapy may result in a reduced cancer incidence in the population level.
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