| |
Risk of AIDS-defining cancers among HIV1-infected patients in France between 1992 and 2009: Results from the FHDH-ANRS CO4 cohort
|
| |
| |
Download the PDF here
Clinical Infectious Diseases Advance Access published July 29, 2013
"Compared with the general population, patients on cART with CD4 cell counts ≥500/mm3 for at least 2 years and HIV RNA ≤500 copies/ml still had a significantly higher risk of KS (SIR=35.4 [18.3-61.9]), but there was no statistical difference for NHL (SIR=1.0 [0.4-1.8]) (Table 4). The SIR for cervical cancer could not be estimated because of the small number of observed and expected cases.
HIV-infected patients were diagnosed with ADC much earlier than the general population, with a median difference ranging from -13 years for cervical cancer to -17 years for KS and -31 years for NHL. After adjusting for the difference in age and sex structure between the two populations, the "real" difference was smaller but remained significant for KS (-2.2 years), cervical cancer (-3.2 years), and NHL (-11.3 years) (Table 5).
In conclusion, the increase of cART use and CD4 cell counts was associated with a further decline in the risk of AIDS-defining cancers, even for the cervical cancer, during the cART period. However, the risk remained higher than in the general population, even during the most recent period. Our results do not favor the hypothesis of premature aging in HIV patients for KS and cervical cancer. Among treated patients with immunological (i.e. CD4 count ≥500/mm3 during at least two years) and virological success, the risk was not increased for NHL but remained higher than in the general population for KS. This suggest that cART would be most beneficial to prevent the risk of cancer in HIV-infected patients, if it restores or maintains CD4 count above 500/mm3, thereby indicating the need for an earlier diagnosis of HIV infection and an earlier treatment initiation."
Abstract
Background. 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).
Methods. Age- and sex- standardized incidence rates were estimated in patients enrolled in the French hospital database on HIV, and in the general population in France during 4 calendar periods (1992-1996, 1997-2000, 2001-2004, and 2005-2009). Standardized incidence ratios (SIR) were calculated for all periods and separately for patients on cART, with CD4 cell counts ≥500/mm3 for at least 2 years and viral load ≤500 copies/ml.
Results. Although the incidence of ADC fell significantly across the calendar periods, the risk remained constantly higher in HIV-infected patients than in the general population. In patients with restored immunity, the relative risk remained significantly elevated for KS [SIR= 35.4 (95% CI; 18.3-61.9)], and was similar to that of the general population for NHL [SIR= 1.0 (95% CI; 0.4-1.8)]. ADC were diagnosed at a younger age in HIV-infected patients, with a particularly marked difference for NHL (-11.3 years, p<0.0001).
Conclusions. 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.
DISCUSSION
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 HIV infected and general populations (-2 and -3 years respectively), while the difference was more marked for NHL (-11 years).
The main strengths of this study are the large number of HIV-infected patients included and the large number of incident cancers recorded in each calendar period. This allowed us to estimate IRs and SIRs separately for each period and each cancer. As summarized by Chaturvedi et al. [27], in most instances, the SIR reasonably approximates the RR. But when HIV prevalence is high and/or cancer incidence in HIV-infected patients relative to non-infected persons is high, the SIR tends to underestimate the RR. This could have been the case for KS which is rare among individuals not infected with HIV. However, because there are no cancer registries in the French regions with the highest prevalence of HIV infection (Paris area and Provence-Alpes-Cote d'Azur), this phenomenon is minimized. Another possible limitation of our study is the incomplete ADC ascertainment. Indeed, we previously showed that the ADC ascertainment rate was 73% in 2006 [28], and verified that it was independent of the geographic origin and the CD4 cell count (not shown). Based on the results of regular audits comparing data in the FHDH database with those in the corresponding medical records, AIDS-defining events have been reported in consistent fashion since the launch of the database, and it is therefore unlikely that changes in the ascertainment rate over time would affect our results. Even if we underestimated the RRs with respect to the general population, this could not explain the excess risks observed here.
Between the pre- and early-cART periods [9-12, 14-17, 29] and also during the cART period [9-12, 14, 16, 17], most studies have shown a fall in the incidence of KS and NHL. This was also the case in our study, where the incidence of KS and NHL continued to decline until 2009. As previously showed [8], the elevated incidence of KS among HIV-infected women is likely due to the high proportion of women of sub-Saharan origin (26%), who are more at risk of KS. Indeed, in 2005-2009, the incidence of KS in HIV-infected women of sub-Saharan origin was 105.0 (63.6-146.5) per 100000 PY, while the incidence in other HIV-infected women was 36.0 (19.5-52.5) per 100000 PY. For cervical cancer, although most previous studies, which included limited numbers of cases (from 8 to 74), showed no change in the incidence [9, 11, 12, 15, 16], a study with 1276 cases [17] showed a decline among women with AIDS between 1991 and 2005. In the current study, which included all women infected with HIV and not only those with AIDS, and analyzed a large number of cases (n=180) with lengthy follow-up, the incidence of cervical cancer also declined over time.
The comparison of SIR values between different studies can be problematic as SIR estimation is not based on a common standard. Indeed, SIR values vary with the relative sizes of the different strata that compose the study population, such as sex, age and the transmission group [13, 30]. However, as in other studies [12, 13, 15, 16, 31], we observed a higher risk for all ADCs among HIV-infected patients compared to the general population during all the calendar periods. Furthermore, despite the decline in the RRs over time, the risk of the three ADC remained higher than in the general population during the late-cART period (300-fold for KS, 9-fold for NHL and 5-fold for cervical cancer). SIRs and excess IRs may lead to different interpretations of the risk according to the type of cancer and the baseline risk in the general population. For instance, in 2005-2009, the SIR was 150 for KS in HIV-infected men other than MSM, and 9 for NHL in all HIV-infected men, whereas the excess IRs were respectively 105 and 159 cases per 100000 PY. This illustrates the fact that, in addition to the RR, it is important to take the absolute risk into account. In the study population, the median CD4 cell count rose from 259/mm3 in the pre-cART era to 413/mm3 in the late-cART period, in line with the rise from 3.5% to 86% in the proportion of patients on cART. This is likely to account in large part for the decrease in the burden of the three ADC. However, the magnitude of the fall differed according to the cancer, gender and HIV transmission group. The reason for this heterogeneity is unclear, but it might involve differences in the relation between immunodeficiency and cancer risk, or differences in the proportion of persons co-infected with the relevant oncogenic virus.
In patients with restored immunity, the risk remained elevated for KS (SIR=35) and was not increased for NHL (SIR=1). The RR for cervical cancer could not be estimated due the relatively small number of PY of follow-up for women in this analysis. A previous study showed elevated RRs for KS and NHL (60 and 4 respectively) among HIV-infected individuals with current CD4 cell counts ≥500/mm3 compared to a group of HIV-uninfected individuals, after adjustment for several cancer risk factors [4]. Immune restoration was defined differently in the current analysis: instead of the current CD4 cell count, we used a continuous period of at least 2 years with high CD4 cell counts. The difference in the definition of the immune restoration could be an explanation for the different results observed in the two studies.
The younger age at ADC diagnosis among HIV-infected patients compared to the general population may be linked to 3 non-exclusive factors: (1) an earlier acquisition of oncogenic virus infection (HHV-8, EBV and HPV), (2) a closer medical surveillance of HIV-infected patients, leading to an earlier diagnosis, and/or (3) a specific effect of HIV infection. Due to the small difference in the age at diagnosis of KS (-2 years) and cervical cancer (-3 years), the third factor is not necessary to explain our results. In the case of NHL, the much larger difference (-11 years) cannot be explained only by the first 2 factors.
In conclusion, the increase of cART use and CD4 cell counts was associated with a further decline in the risk of AIDS-defining cancers, even for the cervical cancer, during the cART period. However, the risk remained higher than in the general population, even during the most recent period. Our results do not favor the hypothesis of premature aging in HIV patients for KS and cervical cancer. Among treated patients with immunological (i.e. CD4 count ≥500/mm3 during at least two years) and virological success, the risk was not increased for NHL but remained higher than in the general population for KS. This suggest that cART would be most beneficial to prevent the risk of cancer in HIV-infected patients, if it restores or maintains CD4 count above 500/mm3, thereby indicating the need for an earlier diagnosis of HIV infection and an earlier treatment initiation.
| |
| |
| |
|
|
|
