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Anal cancer rate still high in HIV, even with combination ART
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Last Updated: 2012-10-23 18:40:28 -0400 (Reuters Health)
By Gabriel Miller
NEW YORK (Reuters Health) - Anal cancer rates in HIV patients are "still extremely high," with no apparent protection from antiretroviral therapy, French registry data show.
The anal cancer risk was high even for patients with high CD4 cell counts.
The results, researchers say, suggest that combination antiretroviral therapy (cART), despite strengthening the immune system, does not help control human papillomavirus (HPV) and may in fact be linked to development of HPV-related precancerous cells.
Dr. Michael Silverberg, an HIV researcher at Kaiser Permanente Northern California in Oakland who was not involved in the French study, told Reuters Health by email, "It is not surprising that ART did not have a significant protective effect. In fact, the risk seemed to be higher among ART users, similar to findings of others. This probably reflects the slow oncogenic effects of human papillomavirus."
HIV-positive patients are living longer, but their restored immune function may not be clearing HPV.
"Current thinking is that people with HIV infection have had more frequent HPV infections, and that they have reduced clearance of HPV infections," Dr. James Goedert, a senior investigator at the National Cancer Institute's Division of Cancer Epidemiology and Genetics, told Reuters Health in an email. "Longer survival with HIV, thanks to combination antiretroviral therapy, permits the emergence of these relatively long incubation period malignancies."
Dr. Goedert too was not involved with the French study, which was headed by Dr. Christophe Piketty of the Hopital Europeen Georges Pompidou in Paris.
Researchers analyzed data on 263 HIV-positive patients with invasive anal cancer drawn from a database of patient information from 69 French teaching hospitals between 1989 and 2008.
They compared these individuals to another 2,012 patients with invasive anal cancer drawn from general-population French cancer registries.
The investigators divided HIV-positive patients by time period of diagnosis: pre-cART (1992-1996) and early (1997-2000), intermediate (2001-2004), and recent (2005-2008) cART eras.
Among HIV-infected patients, the hazard ratio (HR) was 2.5 for developing anal cancer in the cART periods vs the pre-cART period.
Compared to people in the general population, HIV patients also had extremely high anal cancer rates, even in the most recent period studied from 2005-2008, when cART had been in use for the greatest amount of time.
For example, compared with the general population, HIV-infected men who have sex with men had a standard incidence ratio (SIR) of anal cancer of 109.8 for the period of 2005-2008.
Even patients with restored immune function had high rates of invasive anal cancer.
Among patients with a current CD4 cell count of at least 500/uL for at least two years before the diagnosis of anal cancer and whose lowest CD4 count was more than 200/uL, the SIR for anal cancer was 25.
In terms of reducing the risk of anal cancer, Dr. Goedert said HPV vaccination should be widely implemented, although that will only help "the next generation with HIV."
For the current population of HIV-positive patients, "The controversy is whether or not to screen for anal pre-cancer with anal cytology," Dr. Goedert said. "Clearly, monitoring HIV-infected patients for anal disease needs to be assiduous, with treatment appropriate to whatever anal disease is found."
Full results of the study were published online October 22 in the Journal of Clinical Oncology. Dr. Piketty did not respond to an email request for comment on the findings.
J Clin Oncol 2012.
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HIV Helps Explain Rise of Anal Cancer in US Males - (10/09/12) Shiels et al
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Incidence of HIV-Related Anal Cancer Remains Increased Despite Long-Term Combined Antiretroviral Treatment: Results From the French Hospital Database on HIV
Christophe Piketty, Hana Selinger-Leneman, Anne-Marie Bouvier, Aurelien Belot, Murielle Mary-Krause,
Claudine Duvivier, Manuela Bonmarchand, Laurent Abramowitz, Dominique Costagliola, and Sophie Grabar
Our findings are in agreement with those of previous studies indicating that cART-associated immune restoration is not associated with a reduction in the incidence of anal HPV infection or anal SILs, precursors of invasive anal cancer.4,6,7,9,35 cART, despite increasing the CD4 T-cell count and restoring immunity to several opportunistic pathogens,36-38 does not appear to enhance the control of HPV, measured in terms of anti-E6 and anti-E7 HPV-16 lymphoproliferative responses, and has been associated with progression of HPV-related anal SILs.7 Immunodepressionmayaccelerate progression from high-grade SILs to invasive anal cancer. Indeed, the CD4 cell nadir and AIDS onset, two markers of immunodeficiency, were independent risk factors for anal cancer in our study, and the risk grew as the CD4 cell nadir fell.
In conclusion, this study shows that the risk of HPV-associated invasive anal cancer is markedly increased in all groups of HIV-infected patients and especially in MSM and that this cancer occurs earlier in these patients groups than in the general population. The incidence of anal cancer remained increased in the recent cART period (2005-2008), indicating that long-term cART does not prevent this malignancy. These results emphasize the need to assess the clinical efficacy and cost-effectiveness of anal cancer screening and earlier treatment of HIV infection.
Purpose To study recent trends in the incidence of anal cancer in HIV-infected patients receiving long-term combined antiretroviral treatment (cART) compared with the general population.
Patients and Methods From the French Hospital Database on HIV, we identified 263 cases of invasive anal squamous cell carcinoma confirmed histologically between 1992 and 2008. We compared incidence rates of anal cancer across four calendar periods: 1992-1996 (pre-cART period), 1997-2000 (early cART period), and 2001-2004 and 2005-2008 (recent cART periods). Standardized incidence ratios (SIRs) were calculated by using general population incidence data from the French Network of Cancer Registries.
Results In HIV-infected patients, the hazard ratio (HR) in the cART periods versus the pre-cART period was 2.5 (95% CI, 1.28 to 4.98). No difference was observed across the cART calendar periods (HR, 0.9; 95% CI, 0.6 to 1.3). In 2005-2008, HIV-infected patients compared with the general population had an excess risk of anal cancer, with SIRs of 109.8 (95% CI, 84.6 to 140.3), 49.2 (95% CI, 33.2 to 70.3), and 13.1 (95% CI, 6.8 to 22.8) for men who have sex with men (MSM), other men, and women, respectively. Among patients with CD4 cell counts above 500/μL for at least 2 years, SIRs were 67.5 (95% CI, 41.2 to 104.3) when the CD4 nadir was less than 200/μL for more than 2 years and 24.5 (95% CI, 17.1 to 34.1) when the CD4 nadir was more than 200/μL.
Conclusion Relative to that in the general population, the risk of anal cancer in HIV-infected patients is still extremely high, even in patients with high current CD4 cell counts. cART appears to have no preventive effect on anal cancer, particularly in MSM.
Several studies showed an increased risk of anal cancer among HIV-infected patients before the advent of combination antiretroviral therapy (cART).1-4 The incidence of anal cancer was reported to be twice as high in HIV-infected men who have sex with men (MSM) as in their HIV-seronegative counterparts,1,2 and the relative risk of anal cancer among HIV-seropositive men and HIV-seropositive MSM was 37-fold and 59-fold higher, respectively, than in the general population.3 Some studies4-7 have shown no positive impact of cART-induced immune restoration on the prevalence or incidence of anal human papillomavirus (HPV) infection and anal squamous intraepithelial lesions (SILs) that are precursors of invasive anal cancer, although other data suggest a favorable effect of long-term cART on the incidence of anal SILs.8,9 Overall, the incidence of anal cancer appears to have risen with the widespread use of cART.4,10-17
Several studies14,15,18-22 have compared the risk of anal cancer, among other malignancies, in HIV-infected patients to that observed in the general population in North America and Europe and have shown an excess risk in the HIV-infected population. However, except for one recent study,23 these studies involved small numbers of anal malignancies (between 18 and 80) and could not account for HIV transmission groups or degree of immunodeficiency nor did they clearly conclude whether anal cancer occurs at an earlier age in HIV-infected patients.24
Here, we analyzed the incidence of anal cancer in a large French cohort of HIV-infected patients in both the pre-cART era and the cART era (until 2008), according to the HIV transmission group, current and past immunodepression, and age. The aim was to study temporal trends in anal cancer incidence rates in HIV-infected patients between 1992 and 2008 to determine the impact of long-term cART. Trends in this population were compared with those in the general French population.
DISCUSSION
Over an 18-year period (705,519 PY) during which cART was widely available for the last 12 of those years (575,288 PY), we found that the incidence of anal cancer increased markedly between the pre-cART and cART periods and then remained at that level but stable during the cART period. We confirmed the large excess risk of anal cancer reported in HIV-infected patients, particularly MSM, compared with that in the general population. We found that anal cancer occurred earlier in HIV-infected patients than in the general population and that even in HIV-infected patients whose CD4 cell counts remained above 500/L for more than 2 years before diagnosis, the risk was more than 20-fold higher.
Strengths and Limits
This study has three important strengths: (1) inclusion of a large population from a nationwide study in which patients belonging to various HIV transmission groups were prospectively recruited both before and after the advent of cART; (2) the large number of personyears of follow-up, especially during the cART era; and (3) to the best of our knowledge for the first time in France, a comparison with the general population. All 263 cases of anal cancer recorded in the FHDH were histologically validated, representing the largest series of anal cancer for which the risk could be studied individually according to sex. Previous studies pooled anal cancer with other non-AIDS-defining malignancies and/or included relatively few cases, and only one evaluated the risk in women.23 One limitation of our study is the potential under-reporting of anal cancer in the FHDH.27 This might have led to an underestimation of incidence rates, but there is no evidence that the rate of under-reporting differed according to the CD4 cell count or age. Our comparison with the general population did not allow us to adjust for individual characteristics other than age and sex, such as lifestyle and smoking.
Temporal Trends
As previously observed,4 we found that the incidence of invasive anal cancer increased in all HIV transmission groups after the introduction of cART in France. Moreover, during the 12-year period of widespread use of cART, the incidence remained high in all HIV transmission groups (especiallyMSM),with no trend toward a decline in the most recent period. The HR was 2.5 (95% CI, 1.28 to 4.98) for the cART versus pre-cART period and 0.9 (95% CI, 0.6 to 1.3) for the recent cART period (2001-2008) versus the early cART period (1997-2000). When cART was individually analyzed in the Cox regression model, the HR of cART was significantly increased (HR, 1.8; 95% CI, 1.1 to 2.7) and can probably be explained by the longer survival associated with cART rather than by a direct effect of cART.
Most, if not all, previous studies also showed a rise in the incidence of anal cancer between the pre-cART and cART periods. Although some studies suggested a stabilization,23,28 as observed here, two16,21 showed a continued increase during the cART period. It should be noted, however, that these two studies involved few cases of anal cancer (n1916) or a shorter period of trend estimation.
Our comparison with the general population highlights the higher risk of anal cancer in HIV-infected patients, regardless of sex, the HIV transmission group, and the calendar period. The SIRs increased between the pre-cART and cART periods in all the groups studied. During the cART era, the risk of anal cancer among MSM was nearly 100-fold higher than in the general male population. The risk was about 50-fold higher in other men and 13-fold higher in women relative to the general female population. Note that the relative risks are likely to be even higher, because SIRs tend to underestimate the relative risk when the prevalence of HIV/AIDS is high.29
Overall, our results are in keeping with those of previous studies, indicating that the risk of invasive anal cancer is increased in HIV-infected individuals, not only in the pre-cART era1-3 but also in the cART era4,10-13,15-17,23,30 and relative to the general population.14,15,18,20-23
One possible explanation for the excess risk of malignancies associated with HIV infection is provided by the premature aging hypothesis (ie, the occurrence of cancer at younger ages in HIV-infected patients). This hypothesis was recently tested by Shiels et al,14 who used an elegant method that takes into account the difference in the age distribution between the HIV-infected population and the general population. These authors found that age at cancer diagnosis did not differ between HIV-infected patients and the general population, with a few exceptions among which are anal cancer and lung cancer. Median age at diagnosis of anal cancer was significantly lower in HIV-infected patients than would have been expected in the general population (42 v 45 years; P .001).14 Likewise, we found that SIRs for anal cancer were markedly increased in HIV-infected men, particularly between the ages of 25 and 34 years (SIR, 419). These higher SIRs observed at younger ages are compatible with earlier acquisition of HPV infection among HIV-infected individuals as well an age accelerated carcinogenesis in HIV-infected patients.
Risk of Anal Cancer According to the CD4 Cell Count
at Diagnosis
Risk factors for invasive anal cancer in this study were older age, the HIV transmission group (MSM v others), prior AIDS, the cART calendar period, and a low CD4 cell nadir. An association between immunodepression and anal cancer has also been reported elsewhere.4,31-33 Here, the incidence of anal cancer was still high despite long-term cART, and even in patients who had been on effective cART for more than 2 years and had relatively high CD4 cell counts (500/L), the risk of anal cancer was still far higher than in the general population (SIR 20). The SIR rose to 67 when the nadir CD4 cell count had been below 200/L for more than 2 years, suggesting that not only the CD4 nadir but also the duration of low CD4 cell counts is associated with the risk of anal cancer.31 Therefore, to reduce this excess risk of anal cancer, ART should not only restore but also durably maintain near-normal immune function. Recent guidelines on the treatment of HIV-infected patients in industrialized countries recommend ART for asymptomatic patients with CD4 cell counts below 500/L.34 If these recommendations are broadly applied, the incidence of anal cancer is likely to fall in the future, because patients would be able to avoid low CD4 cell nadirs and AIDS-defining events.
Our findings are in agreement with those of previous studies indicating that cART-associated immune restoration is not associated with a reduction in the incidence of anal HPV infection or anal SILs, precursors of invasive anal cancer.4,6,7,9,35 cART, despite increasing the CD4 T-cell count and restoring immunity to several opportunistic pathogens,36-38 does not appear to enhance the control of HPV, measured in terms of anti-E6 and anti-E7 HPV-16 lymphoproliferative responses, and has been associated with progression of HPV-related anal SILs.7 Immunodepressionmayaccelerate progression from high-grade SILs to invasive anal cancer. Indeed, the CD4 cell nadir and AIDS onset, two markers of immunodeficiency, were independent risk factors for anal cancer in our study, and the risk grew as the CD4 cell nadir fell.
In conclusion, this study shows that the risk of HPV-associated invasive anal cancer is markedly increased in all groups of HIV-infected patients and especially in MSM and that this cancer occurs earlier in these patients groups than in the general population. The incidence of anal cancer remained increased in the recent cART period (2005-2008), indicating that long-term cART does not prevent this malignancy. These results emphasize the need to assess the clinical efficacy and cost-effectiveness of anal cancer screening and earlier treatment of HIV infection.
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