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Keywords:

  • cancer;
  • cohort;
  • HIV/AIDS;
  • incidence

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Objectives

The aim of the study was to investigate the incidence of AIDS-defining cancers (ADCs) and virus-related and non-virus-related non-AIDS-defining cancers (NADCs) in HIV-infected patients compared with the general population, and to assess the risk factors associated with these malignancies.

Methods

We performed a retrospective cohort study for the period from 1999 to 2009 of HIV-infected patients residing in the Local Health Authority of Brescia (northern Italy). Observed cancers in patients with HIV infection were compared with expected cancers in the population living in the same area using standardized incidence ratios (SIRs). Risk factors were assessed using Poisson regression analysis.

Results

A total of 5090 HIV-infected patients were included in the study, with 32 390 person-years of follow-up. We recorded 416 tumours in 390 HIV-infected patients. Two hundred of these (48.1%) were ADCs, 138 (33.2%) were non-virus-related NADCs and 78 (18.7%) were virus-related NADCs. An increased risk (SIR = 4.2) of cancers overall was found in HIV-infected patients. A large excess of ADCs (SIR = 31.0) and virus-related NADCs (SIR = 12.3) was observed in HIV-infected patients, while the excess risk for non-virus-related NADCs was small (SIR = 1.6). The highest SIRs were observed for Kaposi sarcoma among ADCs and for Hodgkin lymphoma among virus-related NADCs. Conversely, among non-virus-related NADCs, SIRs for a broad range of malignancies were close to unity. In multivariate analysis, increasing age and CD4 cell count < 50 cells/μL were the only factors independently associated with all cancers.

Conclusions

Among HIV-infected people there was an excess of ADCs and also of NADCs, particularly those related to viral infections. Ageing and severe immunodeficiency were the strongest predictors.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

The introduction of potent combination antiretroviral therapy (cART) has markedly reduced the incidence of opportunistic infections and, among AIDS-defining cancers (ADCs), of Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) [1, 2]. Conversely, cART has had little impact on the incidence of non-AIDS-defining cancers [1-4] (NADCs): Hodgkin lymphoma (HL), invasive anal carcinoma, lung cancer, hepatocellular carcinoma (HCC) and oropharyngeal malignancies have all been diagnosed at higher rates in HIV-infected patients than in the general population [5, 6], as well as melanoma, leukaemia, and vaginal, colon, rectal and kidney cancers according to some studies [5].

Both increased life expectancy [7] and the reduction of competing causes of death have contributed to the increased incidence of NADCs [8, 9], but the longer survival time as a result of cART only partially explains the increasing incidence of these malignancies. The pathogenesis of these tumours is highly variable: traditional cancer risk factors such as smoking [1, 10, 11] and alcohol consumption [10, 12] may contribute to the development of cancer. At the same time, HIV itself may play a role through a direct oncogenic effect (e.g. via the tat gene) [13] or as a consequence of immunosuppression.

In addition, several oncogenic viruses are thought to cause ADCs and NADCs: Epstein−Barr virus (HL, NHL, nasopharyngeal carcinoma and Burkitt's lymphoma) [14], human herpes virus 8 (KS and primary effusion lymphoma) [14], hepatitis C and hepatitis B viruses (HCC) [15] and human papilloma virus (HPV) (carcinoma of the cervix, vulva, vagina, penis, anus and oral cavity, oropharyngeal cancer and in particular tonsillar cancer) [16] have been recognized by the World Health International Agency for Research on Cancer (IARC) as potentially oncogenic viruses.

However, the incidence of cancers among HIV-infected persons and the risk factors associated with them have been less well studied, and some findings are contradictory. Moreover, many of the previous studies grouped all NADCs together and did not divide them according to their viral aetiology.

The main aims of this population-based research were to investigate the incidence of cancers in a single-centre cohort of HIV-infected patients and to investigate the risk factors associated with the development of ADCs, virus-related NADCs and non-virus-related NADCs in the cART era, as compared with the general population living in the same area.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

We conducted a retrospective cohort study for the period from January 1999 to December 2009 of HIV-infected patients residing in the Local Health Authority (LHA) of Brescia (northern Italy) and receiving care for HIV infection at the University Division of Infectious and Tropical Diseases of the University of Brescia or at the Infectious Diseases Department, Brescia Spedali Civili General Hospital. We started our study from January 1999 because data on cancer incidence in the Cancer Registry of Brescia were available from that year, when considering the cART era.

At their first contact with our centre, all patients provided written informed authorization to collect information for scientific purposes and research. Sociodemographic characteristics, laboratory test results, treatments for HIV/AIDS, and complications including opportunistic infections, cancer and death were recorded on a regular basis and stored in the electronic database utilized for routine clinical management. Cancer diagnoses were retrieved from this electronic database and completed with those recorded in the administrative database of the LHA of Brescia and that of the population-based Cancer Registry of the LHA: the details of this record linkage have been described elsewhere [17]. All cases of cancer were defined on the basis of histological or cytological examination.

Multiple primaries, i.e. cancers of different types occurring in the same subject, were included in the analysis and each cancer was analysed as a single case. We excluded malignancies already diagnosed before the start of observation or before the diagnosis of HIV infection.

Cancer type and site were coded according to the International Statistical Classification of Diseases and Related Health Problems, 10th revision (World Health Organization, 1992).

We categorized malignancies as ADCs [NHL, KS and invasive cervical carcinoma (ICC)] and NADCs. We further divided NADCs into two a priori categories: virus-related (HCC, HL, cancers of the vagina, vulva and penis, squamous cell anal cancer and certain squamous cell oral cavity/pharynx cancers, as defined by Chaturvedi et al. [18]) and non-virus-related (all the others).

For each person included in the study, the relevant time period for the calculation of person-years at risk began on 1 January 1999 or at the date of enrolment in the cohort, if later, and ended at cancer diagnosis, at the last follow-up visit, on 31 December 2009 or at death.

Expected numbers of cancers were computed on the basis of the incidence rates of the Cancer Registry of Brescia LHA for the periods 1999−2001 and 2004−2006, standardized by age. Observed cancers included incident cases in HIV-infected patients recorded during the study period. Observed numbers of cancers were compared with expected numbers by calculating standardized incidence ratios (SIRs), and their corresponding 95% confidence intervals (CIs), using the Poisson distribution.

Incidence rates (IRs) were calculated by dividing the number of observed cases by the corresponding person-years at risk and were standardized for age, using the direct method [19] with the European population as the standard.

Poisson regression analysis was used to evaluate the univariate and multivariate associations between covariates and cancers. A P-value of 0.05 was used for all the two-tailed statistical tests, although P-values close to the threshold are also shown. Age, race and sex 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 in univariate analysis were included in the multivariate model. A P-trend linear analysis was also performed when considering CD4 cell count.

All analyses were performed using stata 12 (StataCorp LP, College Station, TX).

This study involving human subjects was performed in accordance with the Helsinky Declaration of 1975 as revised in 2000 and it was approved by the local ethical committee of the Spedali Civili General Hospital of Brescia.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

A total of 5090 HIV-infected patients were included in the study, with 32 390 person-years of follow-up (median 6.44 person-years).

Table 1 reports the baseline characteristics of the patients. They were mainly Italian (81.9%) and male (71.9%), with a median age of 35 years (range 19–64 years). A large proportion (42.9%) acquired HIV through injecting drug use and 45.8% were coinfected with a hepatitis virus. Median CD4 cell count was 365 cells/μL (range 11−1190 cells/μL) and one-third of patients (33.6%) were on cART. Only 887 patients (17.43%) had an AIDS diagnosis (not including AIDS-defining malignancies) before baseline.

Table 1. Characteristics of HIV-infected patients at baseline and at first cancer diagnosis
CharacteristicBaselineAIDS-defining cancersVirus-related non-AIDS-defining cancersNon-virus-related non-AIDS-defining cancersP
(n = 5090)(n = 194)(n = 72)(n = 124)
  1. HBV, hepatitis B virus; HCV, hepatitis C virus.

Age (years) [median (range)]35 (19–64)41 (21–73)43.5 (25–63)49 (32–73)< 0.001
Male sex [n (%)]3660 (71.9)162 (83.5)55 (76.39)98 (79.03)0.356
Born in Italy [n (%)]4169 (81.9)163 (84)69 (95.8)115 (92.7)0.006
Reported HIV risk behaviour [n (%)]     
Injecting drug use2186 (42.9)53 (27.3)47 (65.3)36 (29)< 0.001
Heterosexual contact1784 (35.1)65 (33.5)18 (25)55 (44.4)0.018
Male homosexual/bisexual contact790 (15.5)56 (28.9)4 (5.5)27 (21.8)< 0.001
Other74 (1.5)4 (2.1)0 (0)2 (1.6)0.477
Unknown256 (5)16 (8.2)3 (4.2)4 (3.2)0.141
Hepatitis virus coinfection [n (%)]     
HCV1 944 (38.2)44 (22.7)40 (55.5)37 (29.8)< 0.001
HBV195 (3.8)8 (4.1)2 (2.8)9 (7.3)0.295
HCV and HBV192 (3.8)4 (2.1)10 (13.9)3 (2.4)< 0.001
HCV/HBV negative2329 (45.8)100 (51.5)19 (26.4)67 (54)< 0.001
Unknown430 (8.4)38 (19.6)1 (1.4)8 (6.5)< 0.001
Previous noncancer AIDS diagnosis [n (%)]887 (17.4)104 (53.6)44 (61.1)58 (46.8)0.146
CD4 count (cells/μL) [median (range)]365 (11–1190)173 (3–897)311 (14–2178)342 (16–1668)< 0.001
CD8 count (cells/μL) [median (range)]875 (157–2668)839 (95–2620)817 (88–3209)910 (213–3282)0.1239
Nadir CD4 count (cells/μL) [median (range)]241 (3–1063)109 (2–518)148 (5–902)171 (6–1668)0.0120
HIV RNA (copies/mL) [median (range)]163 (< 37–500 000)3634 (< 37–500 000)56 (< 37–1 000 000)410 (< 37–304 000)0.0017
Antiretroviral therapy [n (%)]1711 (33.6)79 (40.7)56 (77.8)81 (65.3)< 0.001

During the observation period, 416 tumours were observed in 390 patients; 22 patients had a second malignancy and two patients had three different cancers. 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.

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).

The mean incidence rate was 61.7/10 000 person-years for ADCs, which was higher than the mean incidence rates for non-virus-related NADCs (42.6/10 000 person-years) and virus-related NADCs (24.1/10 000 person-years).

Observed and expected numbers of cancers and corresponding SIRs are shown for cancer types or sites with at least two cases observed (Table 2). An increased risk (SIR = 4.2) in the HIV-infected population was found when all cancers were considered, and the risk in men was almost double that in women. An excess of ADCs (SIR = 31.0) and virus-related NADCs (SIR = 12.3) was observed.

Table 2. Observed and expected numbers of cancers in people living with HIV/AIDS in Brescia, 1999−2009, by gender, with standardized incidence ratios (SIRs) and corresponding 95% confidence intervals (CIs)
ICD-10; cancer type or siteMenWomenAll
ObservedExpectedSIR (95% CI)ObservedExpectedSIR (95% CI)ObservedExpectedSIR (95% CI)
nn nn nn 
  1. ICD, international classification of diseases. *There was one cancer in each of the following ICD-10 cancer type or site categories: C03−06; Gum, palate, mouth; C15; Oesophagus; C23−24; Gallbladder and biliary tract / C25; Pancreas / C40-41; Bone and articular cartilages / C47-49; Peripheral nerves, retroperitoneum and peritoneum, connective-soft tissues / C80; Without specification of site.

AIDS-defining cancers         
C46; Kaposi sarcoma900.7130.7 (106.3–160.7)60186 (83.6–414)960.7133.2 (109.1–162.7)
C82−8, C96; Non-Hodgkin lymphoma763.621.2 (16.9–26.5)190.920.6 (13.1–32.3)954.521.1 (17.2–25.7)
C53; Cervix uteri   91.27.3 (3.8–14.1)91.27.3 (3.8–14.1)
Total1664.338.8 (33.1–45.2)342.215.6 (10.8–21.8)2006.431 (26.8–35.6)
Virus-related non-AIDS-defining cancers         
C01-C02; Tongue10.42.6 (0.4–18.5)10.114.1 (2–100.1)20.44.4 (1.1–17.6)
C09-C10; Tonsil and oropharynx10.52 (0.3–14.2)0010.51.9 (0.3–13.8)
C21; Anus4075.2 (28.2–200.4)10.115.3 (2.1–108.4)50.142.1 (17.5–101.2)
C22; Liver293.38.7 (6.1–12.6)50.222.2 (9.3–53.4)343.59.6 (6.9–13.4)
C51-52, C57; Vulva and vagina   3062 (20–192.3)3062 (20–192.3)
C60; Penis2047 (11.7–187.8)   2047 (11.7–187.8)
C81; Hodgkin lymphoma231.121.4 (14.2–32.2)80.323.1 (11.6–46.3)311.421.8 (15.3–31)
Total605.510.9 (8.3–14)180.822.7 (13.4–35.8)786.312.3 (9.8–15.4)
Non-virus-related non-AIDS-defining cancers         
C16; Stomach632 (0.9–4.5)00.663.51.7 (0.8–3.8)
C18; Colon33.50.9 (0.3–2.7)0134.50.7 (0.2–2.1)
C19-C20; Rectum and rectosigmoid junction31.81.7 (0.5–5.2)20.44.7 (1.2–18.6)52.22.2 (0.9–5.4)
C32; Larynx31.71.8 (0.6–5.5)00.131.81.7 (0.5–5.2)
C33-34; Trachea/lung226.13.6 (2.4–5.4)10.61.6 (0.2–11.1)236.83.4 (2.3–5.1)
C43; Melanoma832.6 (1.3–5.3)01.184.11.9 (1–3.9)
C44; Skin non-melanoma3012.82.3 (1.6–3.3)114.12.6 (1.5–4.8)41172.4 (1.8–3.3)
C50; Breast10.18.6 (1.2–61.3)99.90.9 (0.5–1.7)10101 (0.5–1.8)
C61; Prostate76.31.1 (0.5–2.3)   76.31.1 (0.5–2.3)
C62; Testis72.23.1 (1.5–6.5)   72.23.1 (1.5–6.5)
C64-66; C68; Kidney43.51.1 (0.4–3)10.42.3 (0.3–16.5)53.91.3 (0.5–3)
C67; Bladder33.90.8 (0.2–2.4)00.234.10.7 (0.2–2.2)
C70-72; Brain and central nervous system21.51.3 (0.3–5.4)00.421.81.1 (0.3–4.3)
C73; Thyroid32.41.2 (0.4–3.9)12.60.4 (0–2.7)450.8 (0.3–2.1)
C90; Multiple myeloma/plasma cell neoplasm10.51.8 (0.2–12.8)10.26.3 (0.9–44.8)20.79.8 (0.7–11.2)
C92; Myeloid leukaemia20.73 (0.7–11.9)00.220.92.2 (0.5–8.7)
Other cancers*617
Total11159.71.9 (1.5–2.3)2725.11.1 (0.7–1.6)13884.91.6 (1.4–1.9)
All cancers33769.64.8 (4.3–5.4)7928.22.8 (2.2–3.5)41697.84.2 (3.9–4.7)

Among ADCs, the highest SIR was observed for KS, followed by NHL and ICC, and among virus-related NADCs, the SIR for HL was more than 20 (Table 2).

Interestingly, among non-virus-related NADCs, SIRs for a broad range of common malignancies, such as cancers of the breast, prostate, colon, thyroid and urinary tract, were close to unity or lower (Table 2).

We also examined cancer incidence trends over time. The age-standardized incidence rate of all cancers increased from 1999 to 2009 (Fig. 1a). Considering cancers divided into the three categories, there was a decrease in the age-standardized incidence rate of ADCs (Fig. 1b), but an increase in the rates of both virus-related and non-virus-related NADCs (Fig. 1c and d, respectively).

figure

Figure 1. Age-adjusted cancer incidence among HIV-infected patients by calendar year of diagnosis. Results are shown for all cancers (a) and separately for AIDS-defining cancers (b), virus-related non-AIDS-defining cancers (c) and non-virus-related non-AIDS-defining cancers (d). Incidence rates are per 10 000 person-years. The dashed lines correspond to results from the joinpoint regression. Vertical scales vary between the panels.

Download figure to PowerPoint

Table 3 shows the results of the univariate Poisson regression analysis. In the multivariate analysis (Table 4), increasing age and CD4 cell count < 50 cells/μL at cancer diagnosis were the only factors independently associated with all classes of cancer. In the multivariate analysis, homo/bisexuality remained a significant predictive factor for ADCs, as did injecting drug use for virus-related NADCs. Finally, having received cART for < 6 months at the time of cancer diagnosis was a significant independent predictor for both ADCs and non-virus-related NADCs.

Table 3. Univariate analysis of covariates associated with the three different categories of cancers
CharacteristicsAIDS-defining cancersVirus-related non-AIDS-defining cancersNon-virus-related non-AIDS-defining cancers
nIR/10,000 person-years (95% CI)Incidence rate (IRR) (95% CI)PnIR/10,000 person-years (95% CI)IRR (95% CI)PnIR/10,000 person-years (95% CI)IRR (95% CI)P
  1. ART, antiretroviral therapy; HBsAg, hepatitis B virus surface antigen; HCVAb, hepatitis C virus antibody; IR, incidence rate; IRR, incidence rate ratio.

Risk factor            
Heterosexual6865.1 (49.6–80.6)Reference1918.3 (10.1–26.5)Reference6157.9 (43.4–72.4)Reference
Male homosexual/bisexual contact57133.5 (98.8–168.1)2 (1.4–2.9)< 0.001614.3 (2.9–25.8)0.8 (0.3–2)0.6033376.3 (50.3–102.4)1.3 (0.9–2)0.201
Injecting drug use5434.3 (25.1–43.4)0.5 (0.4–0.7)< 0.0015031.4 (22.7–40.2)1.7 (1–2.9)0.0443723.5 (15.9–31)0.4 (0.3–0.6)< 0.001
Other4107.1 (2.1–212.1)1.6 (0.6–4.5)0.333000 (0–.)0.996254.7 (0–130.5)0.9 (0.2–3.9)0.937
Unknown17342.1 (179.5–504.7)  359.8 (0–127.5)  599.7 (12.3–187.1)  
Previous noncancer AIDS diagnosis            
NO6236.8 (27.6–45.9)Reference2615.4 (9.5–21.3)Reference6538.3 (29–47.6)Reference
Yes13895.3 (79.4–111.2)2.6 (1.9–3.5)< 0.0015236 (26.2–45.8)2.3 (1.5–3.7)< 0.0017350.3 (38.8–61.9)1.3 (0.9–1.8)0.109
CD4 count at cancer diagnosis (cells/μL)            
≥5001820.9 (11.2–30.6)Reference1820.8 (11.2–30.4)Reference3034.5 (22.1–46.8)Reference
201-4996444.5 (33.6–55.4)2.1 (1.3–3.6)0.0053322.9 (15.1–30.8)1.1 (0.6–2)0.7386142.1 (31.6–52.7)1.2 (0.8–1.9)0.369
≤ 20061120.3 (90.1–150.4)5.7 (3.4–9.7)< 0.0012039.7 (22.3–57.1)1.9 (1–3.6)0.0462243.9 (25.5–62.2)1.3 (0.7–2.2)0.391
≤ 5032438 (286.2–589.8)20.9 (11.8–37.3)< 0.001568.9 (8.5–129.3)3.3 (1.2–8.9)0.0189122 (42.3–201.7)3.5 (1.7–7.4)0.001
Missing2597.9 (59.5–136.2)  27.9 (0–18.8)  1662.7 (32–93.4)  
Nadir CD4 count (cells/μL)            
> 2004732.8 (23.4–42.2)Reference2618.1 (11.1–25.1)Reference5437.4 (27.4–47.3)Reference
≤ 20012888.5 (73.2–103.9)2.7 (1.9–3.8)< 0.0015034.6 (25–44.2)1.9 (1.2–3.1)0.0076847 (35.8–58.1)1.3 (0.9–1.8)0.209
Missing2597.9 (59.5–136.2)  27.9 (0–18.8)  1662.7 (32–93.4)  
HIV-RNA at cancer diagnosis            
Undetectable3627.4 (18.5–36.4)Reference3627.2 (18.3–36.1)Reference4937 (26.6–47.3)Reference
Detectable12580.2 (66.1–94.2)2.9 (2–4.2)< 0.0014025.8 (17.8–33.8)0.9 (0.6–1.5)0.8156944.2 (33.8–54.7)1.2 (0.8–1.7)0.335
Missing39148.2 (101.7–194.7)  27.7 (0–18.4)  2076 (42.7–109.3)  
ART before cancer diagnosis            
> 6 months16160.6 (51.3–70)Reference 7227.1 (20.8–33.4)Reference 11242 (34.2–49.8)Reference
< 6 months3981.3 (55.8–106.8)1.3 (0.9–1.9)0.100612.6 (2.5–22.6)0.5 (0.2–1.1)0.0712654.1 (33.3–74.9)1.3 (0.8–2)0.244
HBsAg            
Negative15154 (45.4–62.6)Reference 6322.5 (17–28.1)Reference 11641.3 (33.78–48.8)Reference 
Positive1353.2 (24.3–82.1)1 (0.6–1.7)0.9611352.6 (24–81.2)2.3 (1.3–4.2)0.0051456.7 (27–86.5)1.4 (0.8–2.4)0.260
Missing36388.9 (261.87–516)  222.3 (0–53.2)  888 (27–149)  
HCVAb            
Negative11580.9 (66.1–95.7)Reference2417.1 (10.2–23.9)Reference8861.3 (48.5–74.2)Reference
Positive5030.4 (22–38.8)0.4 (0.3–0.5)< 0.0015331.8 (23.3–40.4)1.9 (1.1–3)0.0114225.5 (17.8–33.2)0.4 (0.3–0.6)< 0.001
Missing35518.3 (346.6–690)  115.6 (0–46.3)  8123.2 (37.8–208.6)  
Table 4. Multivariate analysis of covariates associated with the three different categories of cancers
CharacteristicsAIDS-defining cancersVirus-related non-AIDS-defining cancersNon-virus-related non-AIDS-defining cancers
IRR (95% CI)PIRR (95% CI)PIRR (95% CI)P
  1. ART, antiretroviral therapy; CI, confidence interval; HCVAb, hepatitis C virus antibody; IRR, incidence rate ratio.

Age (per year)1.03 (1.02–1.05)< 0.0011.08 (1.05–1.11)< 0.0011.11 (1.09–1.12)< 0.001
Female gender0.7 (0.4–1.1)0.1591.1 (0.6–1.9)0.7390.8 (0.5–1.3)0.310
Risk factors      
Male homosexual/bisexual contact1.9 (1.2–3.1)0.0060.9 (0.4–2.4)0.8791.2 (0.7–2)0.414
Injecting drug use0.7 (0.4–1.3)0.2262.6 (1–6.5)0.0431.1 (0.5–2.4)0.741
CD4 count at cancer diagnosis (cells/μL)      
201-4993.5 (1.9–6.2)< 0.0010.9 (0.5–1.7)0.8031.4 (0.9–2.2)0.143
≤ 20015.9 (8.6–29.5)< 0.0011.6 (0.8–3)0.1951.5 (0.8–2.8)0.157
≤ 5051 (25.7–101)< 0.0012.8 (1–7.8)0.0413.5 (1.5–8.2)0.004
HIV detectable at cancer diagnosis2.7 (1.7–4.2)< 0.0011 (0.6–1.6)0.8731.3 (0.9–2)0.180
ART < 6 months7.5 (5.1–10.8)< 0.0011.7 (0.9–3.2)0.1262.4 (1.5–3.9)< 0.001
HCVAb positive0.6 (0.3–1.2)0.1401.4 (0.6–3.2)0.4500.9 (0.4–1.6)0.643

The P-trend linear analysis for CD4 cell count category gave significant results in univariate and multivariate analyses for ADCs (P < 0.001) as well as for NADCs, both virus-related (P < 0.05) and non-virus-related (P < 0.05) (data not shown).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

This was a population-based, registry-linkage study of individuals with HIV infection or AIDS, residing in the LHA of Brescia, who were followed between 1999 and 2009. It was based on a single-centre cohort, but we would like to point out that this LHA has a population of more than 1.1 million inhabitants [20] and has the highest incidence of AIDS among the provinces of northern Italy [21].

Cases of cancer were reported to our registry through passive and active surveillance systems [17]. The record linkage among three different sources allowed us to obtain records of cancer cases missing from our electronic clinic database (about 20% of all diagnoses [17]) and provided detailed clinical information.

Here, all patients infected with HIV, and not only those who developed AIDS, were considered, while other Italian epidemiological studies used a procedure of record linkage between the Italian AIDS Registry and Cancer Registries [22, 23]. Only one Italian cohort study [24] reported the incidence of malignancies in a cohort of HIV-infected patients; in that study, cancer cases were recorded during clinical visits and a comparison with the general population was not performed.

The old division between ADCs and NADCs has been widely used [1-6], and some recent studies divided malignancies into infection-related types and cancers unrelated to infectious diseases [25, 26]. In this study, a categorization in which cancers were divided into ADCs, virus-related NADCs and non-virus-related NADCs was used. Similarly to our study, Reekie et al. [27] divided NADCs into virus-related and non-virus-related types, but they included in the first group also cancers for which a viral aetiology is only suspected (e.g. cancer of the larynx) and they presumptively considered all oral cancers as HPV-related.

The SIRs in this study are particularly accurate and valid, as the incidence of cancers in our cohort was compared with the incidence rates from the Cancer Registry of Brescia, where our centre is located and which was the legal place of residency reported by all patients included in the study.

The risk of all cancers was 4-fold higher in HIV-infected patients than in the reference population. An excess of all malignancies in HIV-infected individuals in the cART era was also observed in Switzerland [28] and in the USA [6], but reported SIRs were lower than in our cohort [SIR = 3.0 (95% CI 2.6–3.6) and SIR = 1.9 (95% CI 1.8–2.1), respectively]. The Bonn cohort in Vogel et al. seems to be more similar to ours [25], with the risk in HIV-infected patients in the Vogel et al. study being four times higher in men [SIR = 4.4 (95% CI 3.6–5.3)] and about three times higher in women [SIR = 2.5 (95% CI 1.4–3.9)], relative to the general population.

Patterns of diseases among HIV-infected patients during the cART era are changing, with increased frequencies of non-AIDS-related conditions, such as tumours, end-stage liver diseases, cardiovascular diseases, severe infections and kidney diseases [29-31]. For malignancies, patterns of cancer incidence are also changing. Our results confirm previous reports that the incidence of ADCs has been reduced in the cART era [32], whereas a steady increase in the incidence of NADCs has been observed over the same period [33]. Actually, NADCs account for more than 50% of all cancers developing in HIV-infected persons [6] (51.9% in our cohort). Although other HIV-infected cohort studies have reported similar observations and suggest that the incidence of NADCs is on the rise in the potent cART era, the incidence of certain non-virus-related NADCs does not seem to show the same trend. In our cohort study, as in the few other studies that have used this classification, SIRs for common malignancies such as breast, prostate, colon, thyroid and urinary tract cancer were close to unity. These findings suggest that a more accurate classification must be used in epidemiological studies of malignancies in HIV-infected individuals.

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.

Finally, cART use for less than 6 months before cancer diagnosis was associated with an increased risk of ADCs and non-virus-related NADCs but not virus-related NADCs. Recently, data have been published suggesting a direct protective effect of cART on ADCs, independent of the cART effect on CD4 cell count [34]. The effect of cART use on the risk of NADCs seems to be more complicated, and conflicting data have been reported in the literature: some studies showed a protective effect of cART on the risk of NADCs [35, 36] and others reported no association [1, 22], while Powles et al. [37] found an adverse association between exposure to nonnucleoside reverse transcriptase inhibitors (NNRTIs) and risk of HL. The conflicting results may be attributable to the differences in the definition of cART use (e.g. in terms of the duration of use, cART type or the dose-response relationship with the duration of use) or differences in the classification or type of NADCs studied. Chao et al. [34] did not find a clear association between ART [any ART use, the cumulative duration of any ART use, or use of protease inhibitors (PIs) or NNRTIs] and the risk of infection-related or infection-unrelated NADCs, lung cancer or HL.

The current study has weaknesses and strengths. Data were lacking on important cancer cofactors such as smoking behaviour, alcohol use, family history of cancer and biomarkers to detect Epstein−Barr virus and HPV. In addition, we had no data on cancer screening practices and we could not therefore explore their influence on cancer incidence over time. Finally, all patients were observed exclusively in the cART era (1999 to 2009). Despite these limitations, our study has several strengths, which include the high-quality case ascertainment of cancer diagnoses, the duration and completeness of follow-up, and the good representation of women (almost 30%) and in different HIV-transmission categories.

Nevertheless, given the variability between cohorts in risk factors for HIV infection, oncogenic infections, and genetic and environmental factors, continuing evaluation of cancer risk in this population is needed.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
  • 1
    Clifford GM, Polesel J, Rickenbach M et al. Cancer risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy. J Natl Cancer Inst 2005; 97: 425432.
  • 2
    Engels EA, Pfeiffer RM, Goedert JJ et al. Trends in cancer risk among people with AIDS in the United States 1980-2002. AIDS 2006; 20: 16451654.
  • 3
    Herida M, Mary-Krause M, Kaphan R et al. Incidence of non-AIDS-defining cancers before and during the highly active antiretroviral therapy era in a cohort of human immunodeficiency virus-infected patients. J Clin Oncol 2003; 21: 34473453.
  • 4
    Spano JP, Costagliola D, Katlama C et al. AIDS-related malignancies: state of the art and therapeutic challenges. J Clin Oncol 2008; 26: 48344842.
  • 5
    Patel P, Hanson DL, Sullivan PS et al. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992-2003. Ann Intern Med 2008; 148: 728736.
  • 6
    Engels EA, Biggar RJ, Hall HI et al. Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer 2008; 123: 187194.
  • 7
    Lima VD, Hogg RS, Harrigan PR et al. Continued improvement in survival among HIV-infected individuals with newer forms of highly active antiretroviral therapy. AIDS 2007; 21: 685692.
  • 8
    Bonnet F, Burty C, Lewden C et al. Changes in cancer mortality among HIV-infected patients: the Mortalite 2005 Survey. Clin Infect Dis 2009; 48: 633639.
  • 9
    Marin B, Thiebaut R, Bucher HC et al. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy. AIDS 2009; 23: 17431753.
  • 10
    Hessol NA, Seaberg EC, Preston-Martin S et al. Cancer risk among participants in the Women's Interagency HIV Study. J Acquir Immune Defic Syndr 2004; 36: 978985.
  • 11
    Phelps RM, Smith DK, Heiling CM et al. Cancer incidence in women with or at risk for HIV. Int J Cancer 2001; 94: 753757.
  • 12
    Murillas J, Del Rio M, Riera M et al. Increased incidence of hepatocellular carcinoma (HCC) in HIV-1 infected patients. Eur J Intern Med 2005; 16: 113115.
  • 13
    De Falco G, Bellan C, Lazzi S et al. Interaction between HIV-1 Tat and pRb2/p130: a possible mechanism in the pathogenesis of AIDS-related neoplasms. Oncogene 2003; 22: 62146219.
  • 14
    International Agency for Research on Cancer (IARC) Working group on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs on the evaluation of carcinogenic risks to humans. 1997; volume 70: Epstein-Barr Virus and Kaposi's sarcoma Herpes virus/HumanHerpesvirus.
  • 15
    International Agency for Research on Cancer (IARC) Working group on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs on the evaluation of carcinogenic risks to humans. 1994; volume 59: Hepatitis viruses.
  • 16
    International Agency for Research on Cancer (IARC) Working group on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs on the evaluation of carcinogenic risks to humans. 2005; volume 90: HumanPapillomaviruses.
  • 17
    Calabresi A, Ferraresi A, Limina RM et al. A population-based database to study malignancies in HIV-infected patients in the Local Agency of Brescia between 1999 and 2009. Epidemiol Prev 2011 [Epub ahead of print].
  • 18
    Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinoma in the United States. J Clin Oncol 2008; 26: 612619.
  • 19
    Breslow NE, Day NE. Statistical methods in cancer research. The design and analysis of cohort studies. International Agency for Research of Cancer (IARC) scientific publication 1987; No 82, vol II.
  • 20
    Regione Lombardia/ASL Brescia. Documento di programmazione e coordinamento dei servizi sanitari e socio-sanitari dell'ASL di Brescia per l'anno 2012. Available at www.aslbrescia.it/media/pdf/2012%20Documento%20di%20programmazione.pdf (accessed 25 September 2012).
  • 21
    Centro Operativo AIDS. Aggiornamento delle nuove diagnosi di infezione da HIV al 31 dicembre 2009 e dei casi di AIDS in Italia al 31 dicembre 2010. Supplemento del notiziario dell'Istituto Superiore di Sanità 2011; 24: 132.
  • 22
    Polesel J, Franceschi S, Suligoi B et al. Cancer incidence in people with AIDS in Italy. Int J Cancer 2010; 127: 14371445.
  • 23
    Dal Maso L, Polesel J, Serraino D et al. Pattern of cancer risk in persons with AIDS in Italy in the HAART era. Br J Cancer 2009; 100: 840847.
  • 24
    Prosperi MC, Cozzi-Lepri A, Castagna A et al. Incidence of malignancies in HIV-infected patients and prognostic role of current CD4 cell count: evidence from a large Italian cohort study. Clin Infect Dis 2010; 50: 13161321.
  • 25
    Vogel M, Friedrich O, Lüchters G et al. Cancer risk in HIV-infected individuals on HAART is largely attributed to oncogenic infections and state of immunocompetence. Eur J Med Res 2011; 16: 101107.
  • 26
    Kesselring A, Gras L, Smit C et al. Immunodeficiency as a risk factor for non-AIDS-defining malignancies in HIV-1-infected patients receiving combination antiretroviral therapy. Clin Infect Dis 2011; 52: 14581465.
  • 27
    Reekie J, Kosa C, Engsig F et al. Relationship between current level of immunodeficiency and non-acquired immunodeficiency syndrome-defining malignancies. Cancer 2010; 116: 53065315.
  • 28
    Franceschi S, Lise M, Clifford GM et al. Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV Cohort Study. Br J Cancer 2010; 103: 416422.
  • 29
    Lewden C. Salmon D, Morlat P et al. Causes of death among human immunodeficiency virus (HIV)-infected adults in the era of potent antiretroviral therapy: emerging role of hepatitis and cancers, persistent role of AIDS. Int J Epidemiol 2005; 34: 121130.
  • 30
    Cohen MH, French AL, Benning L et al. Causes of death among women with human immunodeficiency virus infection in the era of combination antiretroviral therapy. Am J Med 2002; 113: 9198.
  • 31
    Louie JK, Hsu LC, Osmond DH, Katz MH, Schwarcz SK. Trends in causes of death among persons with acquired immunodeficiency syndrome in the era of highly active antiretroviral therapy, San Francisco, 1994-1998. J Infect Dis 2002; 186: 10231027.
  • 32
    Grulich AE. Cancer: the effects of HIV and antiretroviral therapy, and implications for early antiretroviral therapy initiation. Curr Opin HIV AIDS 2009; 4: 183187.
  • 33
    Cáceres W. Cruz-Amy M, Díaz-Meléndez V. AIDS-related malignancies: revisited. P R Health Sci J 2010; 29: 7075.
  • 34
    Chao C, Leyden WA, Xu L et al. Exposure to antiretroviral therapy and risk of cancer in HIV-infected persons. AIDS 2012; 26: 22232231.
  • 35
    Guiguet M, Boue F, Cadranel J et al. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study. Lancet Oncol 2009; 10: 11521159.
  • 36
    Crum-Cianflone N, Hullsiek KH, Marconi V et al. Trends in the incidence of cancers among HIV-infected persons and the impact of antiretroviral therapy: a 20-year cohort study. AIDS 2009; 23: 4150.
  • 37
    Powles T, Robinson D, Stebbing J et al. Highly active antiretroviral therapy and the incidence of non-AIDS-defining cancers in people with HIV infection. J Clin Oncol 2009; 27: 884890.