Pattern of cancer risk in persons with AIDS in Italy in the HAART era

A record-linkage study was carried out between the Italian AIDS Registry and 24 Italian cancer registries to compare cancer excess among persons with HIV/AIDS (PWHA) before and after the introduction of highly active antiretroviral therapy (HAART) in 1996. Standardised incidence ratios (SIR) were computed in 21951 AIDS cases aged 16–69 years reported between 1986 and 2005. Of 101 669 person-years available, 45 026 were after 1996. SIR for Kaposi sarcoma (KS) and non-Hodgkin lymphoma greatly decreased in 1997–2004 compared with 1986–1996, but high SIRs for KS persisted in the increasingly large fraction of PWHA who had an interval of <1 year between first HIV-positive test and AIDS diagnosis. A significant excess of liver cancer (SIR=6.4) emerged in 1997–2004, whereas the SIRs for cancer of the cervix (41.5), anus (44.0), lung (4.1), brain (3.2), skin (non-melanoma, 1.8), Hodgkin lymphoma (20.7), myeloma (3.9), and non-AIDS-defining cancers (2.2) were similarly elevated in the two periods. The excess of some potentially preventable cancers in PWHA suggests that HAART use must be accompanied by cancer-prevention strategies, notably antismoking and cervical cancer screening programmes. Improvements in the timely identification of HIV-positive individuals are also a priority in Italy to avoid the adverse consequences of delayed HAART use.

consistently reported in persons with HIV/AIDS (PWHA), in particular Hodgkin lymphoma (HL), and cancers of the anus, lung, and liver (Grulich et al, 2007).
After the introduction of the highly active antiretroviral therapy (HAART) in 1996, huge declines in KS and NHL incidence have been consistently reported in high-resource countries (Grulich et al, 2002;Franceschi et al, 2003Franceschi et al, , 2008Engels et al, 2008;Polesel et al, 2008). The ultimate influence of the partial immune reconstitution and improved survival made possible by HAART on the risk of ICC and non-AIDS-defining cancers, notably HL, anal and liver cancer is, however, still unclear (Herida et al, 2003;Clifford et al, 2005;Dal Maso et al, 2005;Biggar et al, 2006;Engels et al, 2006;Hessol et al, 2007;Patel et al, 2008).
In Italy, a high-quality centralised AIDS Registry is active on a nationwide scale (Centro Operativo AIDS, 2008), whereas cancer registries (CRs) cover nearly one-third of the population (Curado et al, 2007). The aim of the present study was to provide updated information on cancer excess in Italian PWHA after the introduction of HAART, and compare it with corresponding findings prior to 1997. Attention will also be paid to the cancer pattern among the growing proportion of late presenters; that is, PWHA whose first HIV-positive test was concomitant with AIDS diagnosis (450% of new AIDS cases since 2002 in Italy, Centro Operativo AIDS, 2008).

MATERIALS AND METHODS
The general design of our record-linkage study has been described previously Dal Maso et al, 2003). In brief, reporting of AIDS cases to the Italian AIDS Registry started in 1982 on a voluntary basis and became mandatory in November 1986. At the end of 2005, a total of 57 531 AIDS cases had been reported nationwide (Centro Operativo AIDS, 2008). The AIDS Registry has been recording information on CD4 þ cell count, and HAART use at AIDS diagnosis, since 1990 and 1999, respectively, and that on first HIV-positive test since 1996.
A network of CRs has been active in Italy since the early 1980s (AIRT Working Group, 2006). In the late 1990s, 24 CRs had been established and included a population of 17.3 million (30% of the total Italian population, Table 1, Curado et al, 2007). Cancer registries vary both in size, covering populations of approximately 180 000 to nearly 2.1 million, and in duration of activity (Table 1). Routine indicators of data completeness and quality in Italian CRs are, however, satisfactory (Curado et al, 2007).
Record linkage between the AIDS Registry and CRs was performed using an updated version of an 'ad hoc' software application designed previously and validated (Dal Maso et al, 2001). Briefly, records were linked by last and first name, and by date of birth. The name -date algorithm required: (a) that the records be identical for at least one critical field and (b) that the other two critical fields, if not identical, differ only in prescribed ways. The procedures removed all personal identifiers and, hence, registry staff was blinded to which persons had been linked.
Persons with HIV/AIDS born outside Italy contributed 15% of person-years and 7.8% of cancer cases in 1997 -2004. They showed similar SIR for AIDS-defining illnesses and slightly lower SIR of non-AIDS-defining cancers (1.5; 95% CI: 0.7 -2.4) than PWHA born in Italy (data not shown).
Microscopic confirmation was available after 1996 for all ICC, anal cancer, and HL (16 mixed cellularity, 7 nodular sclerosis, and 14 HL of unspecified type), as well as 79% of lung cancer. Eleven out of 16 liver cancers were microscopically or instrumentally confirmed. Microscopic confirmation was available for only one (a glioma) out of eight brain tumours, and seven had a concomitant AIDS-defining illness in the brain (six toxoplasmosis and one leukoencephalopathy).

Epidemiology
For both AIDS-and non-AIDS-defining cancers the highest SIR emerged in the 3 months prior to or after AIDS diagnosis (Figure 1). Prior to AIDS diagnosis, a significant risk excess was only seen for HL (SIR ¼ 11.2; 95% CI: 4.5 -23.3), whereas elevated SIRs emerged for all examined cancers 4 -120 months after AIDS diagnosis.
SIR years for KS, NHL, and HL were lower among PWHA younger than 35 compared with older ones, whereas those for non-AIDS-defining cancers other than HL were higher (Table 3). Women showed higher SIR of KS, NHL, and cancer of the liver and lung than men, whereas the opposite was found for HL. With respect to HIV transmission category, SIRs were especially high for cancer of the liver and lung among IDUs, and for KS and HL among MSM. For all non-AIDS-defining cancers, the SIR was 3.6 (95% CI: 2.9 -4.3) among IDUs, 1.4 (95% CI: 1.1 -1.8) among heterosexuals, and 2.0 (95% CI: 1.5 -2.6) among MSM (Table 3).
Persons with HIV/AIDS who had less than 1-year interval between first HIV-positive test and AIDS diagnosis differed from other PWHA in many ways (Table 4). Among these late presenters, the contribution of person-years was much larger among heterosexuals, MSM, and PWHA born outside Italy, whereas HAART use was rarer and median CD4 þ cell count at AIDS diagnosis was lower than in other PWHA. The SIR for KS (1252) was also higher in late presenters than in other PWHA (Table 4). Conversely, SIR for non-AIDS-defining cancers increased from 1.3 (95% CI: 1.0 -1.7) in PWHA whose interval between first HIVpositive test and AIDS diagnosis was less than 1 year, to 2.8 (95% CI: 2.2 -3.5) and 3.9 (95% CI: 2.9 -5.0), respectively, in PWHA in whom the corresponding interval was 1 -9 years and 10 years or more (Table 4).

DISCUSSION
Our study showed substantial changes in the cancer pattern of Italian PWHA after the introduction of HAART in 1996. Non-Hodgkin lymphoma replaced KS as the most frequent cancer type and non-AIDS-defining cancers increased from 15 to 25% of all cancers. For the first time a significant excess of liver cancer emerged in the Italian AIDS linkage study (Dal Maso et al, 2003), in agreement with record-linkage studies from the United States Patel et al, 2008) and findings from HIV cohorts in Italy (Serraino et al, 2007) and Switzerland . As PWHA live longer, the appearance of an excess of liver cancer compared with the general population was predictable owing to the high prevalence of hepatitis B and, more notably, hepatitis C infection among PWHA. An association between liver cancer risk and low CD4 þ cell count in the year preceding liver cancer has recently been reported , suggesting that immunodeficiency may contribute to the liver cancer excess in PWHA (Weber et al, 2006).
The risk of HL, myeloma, and cancers of the cervix, anogenital tract, lung, brain, and skin (non-melanoma) continued to be significantly increased among PWHA after 1996. The greatest cancer excess was found in proximity to AIDS diagnosis, but persisted in the 10 years afterwards. Notably, elevated SIRs were seen overall and in each HIV transmission category for cancers of the cervix and the anogenital tract that are, in the vast majority, associated with HPV infection (IARC, 2007). Hence, it is not yet clear whether the partial immune reconstitution induced by HAART will ultimately also have a favourable effect on HPVassociated cancers (Frisch et al, 2000;Dorrucci et al, 2001;Ahdieh-Grant et al, 2004;Heard et al, 2004). Inadequate coverage by cervical cancer-screening programmes of women living with HIV, despite ubiquitous access to HAART and regular contact with medical services, has been suggested as the main reason for the greater excess risk of ICC in countries such as Italy  and Spain (Galceran et al, 2007) compared with the United States and Northern Europe (Franceschi and Jaffe, 2007). According to a survey of HIV clinics in Italy (Murri et al, 2006), HIV care providers in Italy are well aware of screening needs, but they fail to achieve good coverage among HIV-positive women mainly for organisational reasons.
With respect to HL, our findings confirm previous reports (Dal Maso et al, 2003;Biggar et al, 2006;Engels et al, 2006;Patel et al, 2008), but, contrary to what has been suggested in the United States , the SIR for HL did not increase compared with the pre-HAART period. It is noteworthy that MSM showed particularly elevated SIRs for HL though not for NHL in our study. The disappearance of excess risk for leukaemias in recent years suggests an improvement in the distinction between NHL and other lymphoid neoplasms (Dal Maso and Franceschi, 2003), but an elevated SIR for myeloma was confirmed in 1997-2004. An increased risk for lung cancer among Italian PWHA was also confirmed (Grulich et al, 2007), but it is likely to derive mainly from the high proportion of smokers, notably among IDUs . Conversely, we found no excess for head and neck cancers, which are also associated with smoking and, in a fraction of cases, HPV infection Kreimer et al, 2005). In respect to brain cancer, microscopic confirmation continues to be very rare and misclassification with other HIVrelated diseases located in the brain cannot be ruled out.
Skin cancer (non-melanoma) was increased by two-fold in PWHA as in previous reports Allardice et al, 2003;Dal Maso et al, 2003;Clifford et al, 2005). The excess risk observed in PWHA was confirmed, however, to be weaker than among transplant recipients (Grulich et al, 2007;Serraino et al, 2007).
Standardised incidence ratios for a broad range of cancer sites, including common neoplasms such as stomach, colon, breast, and prostate, were close to unity and hence compatible with no influence of immune status on the risk of several types of cancer.
Our present study has strengths and weaknesses. Strengths include the large number of AIDS cases and person-years available before and after HAART introduction. The completeness and quality of the AIDS Registry (Conti et al, 1997) and Italian CRs (Curado et al, 2007) have been shown to be satisfactory, and the linkage procedures are accurate (Dal Maso et al, 2001;Clifford et al, 2005). The limited population mobility, the strict rules for maintenance of 'legal residence' in Italy, and the possibility of verifing the vital status of PWHA with national mortality records provided reassurance on the accuracy of follow-up and allowed us to extend our observation period to 10 years after AIDS diagnosis. Censoring at 5 years after AIDS diagnosis would not, however, have modified our findings. Finally, microscopic or instrumental confirmation was available for most cancer sites for which we report risk increases. In particular, we were confident that no in situ carcinomas were misclassified as ICC or anal cancer.
Systematic reporting of HIV cases in Italy is limited to a few areas (Centro Operativo AIDS, 2008), and therefore a major weakness of our present study is reliance on AIDS case reporting only. The yearly number of AIDS cases has diminished three-fold in Italy between the peak in the mid-1990s and 2000 (Centro Operativo AIDS, 2008) and, most important, the meaning of AIDS onset has changed. Formerly an irreversible stage of HIV progression, AIDS often indicates, in the post-HAART era, poor adherence to treatment or development of resistance (Kaldor et al, 2009).
The availability (as from 1996) of information on the date of first HIV-positive test in the AIDS Registry allowed us, however, to focus on PWHA who had concomitant, or nearly concomitant, HIV infection and AIDS-defining illness. Such late presenters increased in Italy from 20.5% in 1996 to 55.5% of AIDS cases in 2007 (Centro Operativo AIDS, 2008). They were in the vast majority individuals who had acquired HIV through sexual intercourse and, unlike IDUs in the early phase of the HIV epidemic, did not perceive themselves as at high risk for the infection (Borghi et al, 2008). Persons with HIV/AIDS born outside Italy were also frequent. In addition, late presenters had never taken HAART and were severely immunocompromised more often than AIDS cases who had been HIVpositive for many years prior. With respect to cancer pattern, KS greatly predominated over all other tumours.
Our study showed that to prevent cancer in PWHA with increasing life expectancy, the use of HAART must be accompanied by more effective cancer-prevention strategies , notably antismoking, cervical cancer screening programmes, and, possibly, hepatitis C virus treatment. Improvements in the timely identification of HIV-positive individuals is also a priority in Italy to avoid the immunological deterioration associated with delayed HAART use, and also to provide a better tool to monitor the HIV epidemic (Borghi et al, 2008).

ACKNOWLEDGEMENTS
This study was supported by two Grants (No. 20G.3 and No. 20G.12) from the Istituto Superiore di Sanità, Rome and a Grant from OncoSuisse (ICP OCS 01355-03-2003). The authors thank Mrs Luigina Mei and Mrs Trudy Perdrix-Thoma for editorial assistance. Table 4 Distribution of selected characteristics at AIDS diagnosis, observed (Obs) cancers a , standardised incidence ratio (SIR), and corresponding 95% confidence interval (CI) by time elapsed since first HIV-positive test and AIDS. Italy, 1997Italy, -2004