HIV infection is associated with an increased risk of a range of cancers, including Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer, which are considered virus-related and AIDS-defining diseases.1,2 The advent of highly active antiretroviral therapy (HAART) has significantly changed the natural history of HIV by greatly reducing the incidence of AIDS-defining events (including AIDS-defining malignancies) and substantially improving the patients' life expectancy.3,4
Recent cohort studies have consistently reported an increased risk of non–AIDS-defining cancers (NADCs), whose incidence does not seem to be influenced by HAART.4–8 A recent meta-analysis by Shiels et al9 has shown that twice as many NADCs occur in HIV-positive subjects than in the general population, with excess risks in the case of infection-related [liver cancer and Hodgkin lymphoma (HL)] and smoking-related cancers (lung, laryngeal, and kidney tumors). Moreover, despite the immunoreconstitution induced by HAART, excess NADC mortality has been reported among HIV-1–infected patients.10
The potential mechanism underlying the increased risk of developing NADCs in the HIV-infected population probably involves complex interactions of multiple known and unknown factors. In addition to aging,11 an effect due to increased life expectancy, other contributing factors are (1) a high prevalence of coinfection with potentially oncogenic viruses [ie, human papillomavirus (HPV), hepatitis B and C viruses], which may be less efficiently controlled by the compromised immune system of HIV-infected patients12–14; (2) a high prevalence of high-risk behaviors such as tobacco smoking15; and (3) the effects of HIV infection, including direct viral effects,16 and the consequences of immunosuppression, with long-lasting immunosurveillance impairment possibly due to the disruption of various immune repertoires.17 It has also been speculated that the mutagenic effects of some antiretrovirals may have an adverse effect on the risk of NADCs, but the evidence is so far inconsistent.18
Most studies of the incidence and spectrum of NADCs give results for both genders combined (with a predominance of men), and only a few have provided specific information concerning the frequency and characteristics of NADCs in women.9 As there may be gender-related differences in the occurrence of specific NADCs, more data may help to define prevention and management strategies.
We examined the incidence rates and characteristics of NADCs in a cohort of 5924 HIV-positive men and 1542 HIV-positive women attending a single HIV Clinical Center in Milan, Italy.
Since 1985, the clinical data of all HIV-infected patients receiving continuous care at the L. Sacco Department of Clinical Science of the University of Milan have been prospectively entered in a database. Their demographic data and medical history, the mode of transmission, the date of the first positive HIV test, CD4 cell counts, and HIV RNA load (as from 1997) are prospectively updated every 3 months, and any new medical diagnoses, hospitalizations, pharmaceutical prescriptions, and laboratory and radiographic findings are recorded.
A retrospective analysis was made of the data relating to all of the patients with HIV with a follow-up of at least 6 months consecutively enrolled between January 1, 1985, and December 31, 2011. All of the incident cases of pathologically confirmed malignancies not classified as AIDS-defining diseases were identified and were considered for the analysis, which included only the first incident NADC. The Mann–Whitney nonparametric test and Pearson χ2 test (or Fisher exact test, when necessary) were respectively used to compare the continuous and categorical variables in the male and female populations. Person-years at risk for each HIV-positive subject were calculated from the date of HIV diagnosis to death, the last follow-up visit, or NADC diagnosis (whichever occurred first). NADC incidence rates were calculated as the number of cases per 1000 person-years, and Poisson regression was used to compare the rate in the period 1985–1996 (the pre-HAART era) with that observed in the period 1997–2011 (the HAART era).
The incidence of NADC per 1000 person-years of follow-up was also analyzed by stratifying the patients by the current CD4 cell count and HAART use. The incidence rates were calculated by accruing follow-up periods within the current CD4 cell count strata of <200, 200–500, and >500 per microliter. Person-years of follow-up were counted from the time of each CD4 determination to the next and censored when the most recent CD4 cell count was >6 months old.
Univariate and multivariate hazard ratios were calculated by means of Cox proportional hazard regression models to evaluate the effects of gender, age, risk factor (as fixed covariates), and AIDS diagnosis, nadir CD4 cell counts, and the use of HAART (as time-dependent covariates). HAART was defined as the use of at least 3 antiretroviral agents in accordance with the published guidelines.19
To compare the rates of specific cancers with those observed in the general population, the standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) (Byar's approximation of the Poisson method) were calculated using the number of expected cases based on the general population gender- and age-specific rates for Milan provided by the Milan Cancer Registry (MCR).20 The area covered by the MCR is the metropolitan area of Milan, which has about 1.3 million inhabitants and includes 29 hospitals coordinated by Milan's local health authority. The MCR has been operative since 1999, and the data are updated until 2006. We are aware that the period covered by the MCR is shorter than the period of our study, but the MCR is the only source of information regarding the incidence of specific cancers in Milan's general population. It is also important to note that the majority (60%) of the NADC events observed in our cohort were reported during the period covered by the MCR.
The cohort consisted of 5924 patients with more than 6 months of follow-up enrolled between January 1, 1985, and December 31, 2011, who contributed to a total of 50,990 person-years of follow-up; the 1542 women (26.0%) contributed 14,540 person-years. In the pre-HAART period (1985–1996), 4453 patients contributed 24,536 person-years; in the HAART period (1997–2011), 3603 patients contributed 26,454 person-years; and 59.2% (2132 of 3603 patients) contributed to both the periods.
A total of 144 NADCs were diagnosed during the study period: 113 in men (22 in the pre-HAART and 91 in the HAART period) and 31 in women (3 in the pre-HAART and 28 in the HAART period). HL and lung cancer were the most frequent NADCs in both periods. There was a significant expansion in the spectrum of NADCs in the HAART period, including previously unseen cancers, such as anus and liver cancer (hepatocellular carcinoma in almost all cases) in men and breast, anus, and vulva cancer in women (Fig. 1).
Table 1 shows the demographic and clinical characteristics of the patients at the time of NADC diagnosis. There were no significant gender differences in baseline characteristics, with the exception of a longer duration of HIV infection (16.0 vs 8.0 years; P = 0.007) and higher percentage of intravenous drug users among women.
The overall incidence of NADCs was higher during the HAART period in both men (from 1.2 cases/1000 person-years [95% CI: 0.7 to 1.8] in the pre-HAART period to 4.9 cases/1000 person-years [95% CI: 3.9 to 5.9] in the HAART period) and women (from 0.4 cases/1000 person-years [95% CI: 0 to 0.9] to 3.6 cases/1000 person-years [95% CI: 2.3 to 5.0]).
There was a decrease in the incidence of NADC with the increase in current CD4 counts both in patients on and off HAART that was not statistically significant. When the patients were on HAART, the incidence was 6.3 cases per 1000 person-years (95% CI: 3.1 to 9.5) in the patients with <200 cells per microliter, 3.8 cases per 1000 person-years (95% CI: 2.3 to 5.4) in the patients with 200–500 cells per microliter, and 3.5 cases/1000 person-years (95% CI: 3.1 to 5.0) in those with >500 cells per microliter; the corresponding figures in the patients off HAART were 4.5 cases per 1000 person-years (95% CI: 2.0 to 6.9), 2.4 cases/1000 person-years (95% CI: 1.2 to 3.7), and 2.0 cases/1000 person-years (95% CI: 0.7 to 3.2).
Univariate analysis showed that the patients who subsequently developed NADCs were older at the time of enrollment (34.6 vs 31.0 years; P < 0.001) and more frequently men (78.5% vs 73.9%, P = 0.047). Homosexual men were significantly more represented among the subjects who developed NADCs than among those who did not (22.9% vs 19.2%, P = 0.028). A higher proportion of patients who developed NADCs had a previous AIDS diagnosis (43.8% vs 42.5%; P < 0.001), a nadir CD4 cell count of <200 cells per microliter (65.3% vs 59.7%; P < 0.001), and a history of HAART (72.9% vs 46.2%; P = 0.001). Multivariate analysis showed that age, an AIDS diagnosis, and a nadir CD4 count of <200 cells per microliter were independently associated with the risk of developing NADC (Table 2).
Table 3 shows the expected cases and corresponding SIRs for all of the NADCs observed during the study period. The SIR for all of the NADCs combined was 1.9 (95% CI: 1.5 to 2.2) in men and 1.5 (95% CI: 1 to 2.2) in women. The observed incidences were higher than expected in the case of anus cancer (SIR = 91.5, 95% CI: 52.3 to 148.6 in men; SIR = 41.2, 95% CI: 4.6 to 148.8 in women), vulva cancer (SIR = 69.2, 95% CI: 22.3 to 161.4), tonsil cancer (SIR = 10.9, 95% CI: 1.2 to 39.4 in men), HL (SIR = 13.0, 95% CI: 8.5 to 19.1 in men; SIR = 7.5, 95% CI: 2.0 to 19.3 in women), liver (SIR = 7.1, 95% CI: 4.2 to 11.2 in men), and lung cancer (SIR = 2.1, 95% CI: 1.3 to 3.4 in men; SIR = 4.8, 95% CI: 1.3 to 12.2 in women).
After stratifying the SIRs of possibly HPV-related cancers in the male population by their reported risk factor, the SIR of anal cancer was 160.0 (95% CI: 68.9 to 315.0) among homosexuals and 83.3 (95% CI: 26.9 to 194.5) among the patients who reported being infected as a result of intravenous drug use.
We assessed the 26-year trends of the frequency and spectrum of NADCs in one of the main reference centers for HIV infection in Italy. Cohort enrollment started at the beginning of the AIDS epidemic and reflects epidemiological trends in Southern Europe, which are characterized by a marked prevalence of intravenous drug users and the significant involvement of women.
The increased incidence and broader spectrum of NADCs in the HAART period is in line with the findings of other studies.4–8 However, in addition to confirming this trend in men, our study allowed us to find a similar trend in women, who were underrepresented or whose risk was not separated from that of men in many previous studies.
There is conflicting evidence as to whether HAART itself has some effect on the risk of developing NADCs.21 Among patients with NADC diagnosis, 105 (72.9%) had a previous history of antiretroviral treatment, but the use of HAART was not associated with a higher risk of developing NADCs at multivariate analysis, which identified age, a nadir CD4 count of <200 cells per microliter, and a previous AIDS diagnosis as predictors of NADCs. Aging is a known risk factor for a number of cancers and has been confirmed to be independently associated with NADCs by other studies.6,8
It has also been widely reported that, unlike AIDS-related malignancies, NADCs are not strictly associated with a high degree of immunodepression at the time of diagnosis,22,23 and in our study, only 36.1% of the patients had CD4 counts of <200 cells per microliter at that time. Furthermore, the hypothesis that a low CD4 cell nadir and current CD4 cell counts have an effect on the risk of NADC is supported by the findings of some recent studies24,25 but not confirmed by others.26,27
In our study, the incidence of NADCs decreased with the increase in current CD4 counts regardless of whether the patients were on HAART or not, but this trend was not statistically significant. However, we cannot exclude the possibility that the retrospective nature of our study, the relatively small number of events, and the difference in the frequency of CD4 cell counts between the pre- and post-HAART periods might have limited our analysis. Conversely, a nadir CD4 cell count of <200 cells per microliter was independently associated with a higher risk of developing NADCs. These findings support the hypothesis that immunologic recovery in patients with previously severe immunodeficiency may not decrease the risk of NADCs, possibly because the recovery is incomplete. Larger prospective studies are needed to clarify the effects of the time-dependent severity and duration of immunosuppression on the risk of developing NADCs.
Cancers with a known or suspected infectious cause and smoking-related cancers accounted for 75% of the NADCs observed in our cohort. HL was the most frequent, and the excess risk for this cancer was similar to that reported in other studies for both genders.28 HL is almost always associated with Epstein–Barr virus in HIV-infected subjects and is more frequent in patients with moderate immune suppression29; this has raised a number of still unanswered questions concerning the relationship between the degree of immunodeficiency, persistent viral infection, and cancer, and it has also been suggested that the immune reconstitution induced by HAART may increase the risk of HL by increasing B-cell stimulation and the number of Epstein–Barr virus–infected lymphocytes.30
The patients in our cohort showed a significantly higher incidence of anal carcinoma in comparison with the general population. The risk of anal cancer was especially high in homosexual men, as described in many other studies,9 but was also high in men reporting intravenous drug use and women. The women also had a significantly increased risk of vulva carcinoma. There is considerable evidence indicating an association between anogenital cancers and HPV infections, and HIV-infected subjects are disproportionately infected with HPV, particularly high-risk HPV strains.12,13 Moreover, the interactions between HIV and HPV allows for persistence of HPV infection possibly leading to dysplasia and cancer.31 There is also evidence that HAART does not clear HPV infection, reduce the incidence of precursor anogenital cancer lesions, or induce the regression of existing high-grade lesions.32,33
It is worth noting that the HIV-positive men had an excess of tonsil cancer in comparison with the general population, a finding very similar to that reported by Frisch et al.34 Both tonsil cancers we observed were histopathologically identified as squamous cell tumors. This is interesting because recent data have shown that, together with smoking and alcohol, HPV may play a role in the development of squamous cell carcinomas arising from the lingual and palatine tonsils.35 A recent study found high-risk HPV genotypes closely associated with cancer in the oral region of 4.5% of HIV-seronegative and 13.7% of HIV-seropositive subjects, and a univariate analysis showed that tonsillar HPV infection closely correlated with HIV infection, immunosuppression, and sexual behavior.36
We found an increasing number of liver cancers (hepatocellular carcinoma in 17 of 18 cases) and an excess risk among men but no cases among women. This gender-related disparity in the incidence of liver cancer is similar to that observed in the general population. Liver injury caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the major risk factors for hepatocellular carcinoma with the vast majority of cases developing in the presence of underlying cirrhosis.37,38 Of the 18 patients with a diagnosis of liver cancer, 13 were chronically infected with HCV, 2 were chronically infected with HBV, 1 was chronically infected with both, and only 2 (1 with bile duct cancer) had no history of hepatitis virus infection.
Since 1992 (when we started systematically recording information about hepatitis virus serostatus), there has been a high prevalence of HCV (36.4%) and HBV coinfections (9.6%): the prevalence rates were, respectively, 37.5% and 10.9% in men and 10.9% and 6.1% in women. Although the information concerning HBV and HCV serostatus is incomplete for the years preceding 1992, the higher prevalence of HBV and HCV coinfection in men may partially explain the different incidence of liver cancer in both the genders. It is also possible that hormonal factors (ie, the stimulatory effect of androgen and the protective effect of estrogen) may somehow influence the difference in the risk of liver cancer in HIV-positive men and women, a hypothesis that is supported by the findings of epidemiological and experimental studies.39
Lung cancer was significantly more frequent than in the general population among both men and women. It has been reported that cigarette smoking is far more common in HIV-infected subjects than in the general population and that this contributes to increasing the rates of lung cancer in both men and women.40,41 Since 1998, when we started systematically recording information about cigarette smoking, 55% of the subjects (54.8% of men and 58.2% of women) have reported smoking addiction. Although the lack of previous records precluded the inclusion of smoking as a possible correlate of NADC risk in our regression model, these data confirm the high risk of smoking for both men and women, as found in other cohorts.15
Finally, we observed a relatively modest number of cases of melanoma and did not find any increased risk in comparison with the general population. This is in line with the findings of some other studies,42,43 including a linkage analysis of a large Italian population,44 but conflicts with others indicating an increased risk, particularly in men.6,7,45 The differences in melanoma SIRs between studies may be due to differences in latitude and dissimilarities in the study populations (ie, HIV risk factors, age, ethnicity/genetics, life style, etc.).
This study has some limitations that have been mentioned above, such as the fact that information concerning viral coinfections and smoking habits was not available for the earlier years of the study period. Moreover, as this was a single-centered study, the relatively few incident cases of cancer do not allow an analysis of the time trends of site-specific tumors.
Nevertheless, our findings confirm the increasing incidence and broadening spectrum of NADCs, and highlight the need to monitor HIV-infected men and women carefully for their occurrence. In particular, HIV-infected women show an excess risk of virus-related cancers (with the exception of liver cancer) and lung cancer that is similar to that observed in HIV-positive men.
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