Brief Report: Anal Cancer in the HIV-Positive Population
Brief Report: Anal Cancer in the HIV-Positive Population
In this study, we found a remarkable increase in the incidence of anal cancer among HIV+ patients since the introduction of cART, predominantly among HIV+ MSM, followed by a slight decrease since 2006. CIs of the anal cancer incidence in MSM and heterosexual men and women did not overlap. This means that the incidence of anal cancer among MSM is significantly higher. Furthermore, a low nadir CD4 cell count, smoking, and alcohol abuse are associated with an increased risk of anal cancer.
In the past decade, several studies showed an increase in anal cancer incidence, predominantly among HIV+ MSM, despite the widespread use of cART. This seems conflicting with the finding that long-term use of cART is negatively associated with the risk of the anal cancer precursor AIN and the finding that a high current CD4 cell count decreases the risk of anal cancer. Possibly, the increased anal cancer risk caused by a longer lifespan in the cART era outweighs the presumed protective effect of immune restoration. Our study showed for MSM a peak incidence of 168 per 100,000 person-years in 2006. This is one of the highest incidence rates reported to date in this risk group. A review from 2012 reported incidences between 65 and 109 per 100,000 person-years in the cART era (evaluation periods ending in 2003–2007). So, widespread use of cART is not slowing the rising incidence.
Our findings regarding risk factors are in line with previous studies. A very low nadir CD4 cell count increases the risk of AIN 2/3. A study among HIV+ men showed a significant correlation between low nadir CD4 cell counts and anal cancer. Taking a nadir CD4 cell count <200 as reference, a nadir CD4 cell count between 200 and 350 cells per cubic millimeter showed a hazard ratio of 0.42 (P < 0.0001) for anal cancer and a nadir CD4 cell count of >350 a hazard ratio of 0.34. Another recent study showed a hazard ratio of 0.87 for anal cancer risk per log2 increase in nadir CD4 cell count. We found a hazard ratio for anal cancer of 2.42 in patients with a nadir CD4 cell count <110.
What is new in our study is that we found a decrease in anal cancer incidence after 2006. Although statistical significance could not be demonstrated (CIs overlap), it does show a steady trend. One previous study also suggested a plateau in the anal cancer incidence. The peak incidence in this study of 159 in 2000–2003 in HIV+ MSM was followed by a decrease to 131 in 2003–2007. Our study shows a continuing decreasing trend, to an incidence in HIV+ MSM of 100 in 2011/2012. The gradual small-scale introduction of AIN screening programs in the Netherlands cannot explain this. A more likely explanation might be that the long-term use of cART is negatively associated with the risk of the anal cancer precursor AIN, which in time might gradually affect anal cancer incidence, and furthermore, given the tendency to start cART with higher CD4 counts, the HIV+ MSM population less and less suffers from low nadir CD4 cell counts. For cervical cancer, no decrease in incidence has been observed yet in the cART era.
We found a hazard ratio of 1.60 for anal cancer in current or previous smokers. Smoking has previously been associated with an increased risk of anal cancer. Smoking is much more common in the HIV-positive population, and HIV-infected smokers lose more life-years to smoking than to HIV. To our knowledge, no previous studies showed a link between alcohol (ab)use and anal cancer. We found a hazard ratio of 2.23 for HIV+ MSM drinking more than 28 glasses of alcohol per week. Because alcohol use has a disinhibiting effect, it possibly leads to increased sexual risk behavior, which in turn is a risk factor for anal cancer.
Strong points of our study are the use of a nationwide database including all patients under HIV care in the Netherlands, confirmation of all histological diagnoses, and careful documentation of risk factors. We have possibly missed cases if the diagnosis anal cancer was not reported by the treating physician, but this means that the incidence of anal caner we found is likely an underestimation. A limitation of our study is that the low absolute number of anal cancers made it difficult to demonstrate statistical significance of the observed trends in time.
In conclusion, this study confirms the high incidence of anal cancer among HIV+ patients, predominantly among HIV+ MSM. Furthermore, our data suggest that continued use of cART, and starting cART at higher CD4 counts, might in time lead to a decrease in anal cancer incidence. In the meantime, although there is still uncertainty on the effectiveness of anal cancer screening programs, the very high anal cancer incidence justifies screening programs for AIN among HIV+ MSM.
Discussion
In this study, we found a remarkable increase in the incidence of anal cancer among HIV+ patients since the introduction of cART, predominantly among HIV+ MSM, followed by a slight decrease since 2006. CIs of the anal cancer incidence in MSM and heterosexual men and women did not overlap. This means that the incidence of anal cancer among MSM is significantly higher. Furthermore, a low nadir CD4 cell count, smoking, and alcohol abuse are associated with an increased risk of anal cancer.
In the past decade, several studies showed an increase in anal cancer incidence, predominantly among HIV+ MSM, despite the widespread use of cART. This seems conflicting with the finding that long-term use of cART is negatively associated with the risk of the anal cancer precursor AIN and the finding that a high current CD4 cell count decreases the risk of anal cancer. Possibly, the increased anal cancer risk caused by a longer lifespan in the cART era outweighs the presumed protective effect of immune restoration. Our study showed for MSM a peak incidence of 168 per 100,000 person-years in 2006. This is one of the highest incidence rates reported to date in this risk group. A review from 2012 reported incidences between 65 and 109 per 100,000 person-years in the cART era (evaluation periods ending in 2003–2007). So, widespread use of cART is not slowing the rising incidence.
Our findings regarding risk factors are in line with previous studies. A very low nadir CD4 cell count increases the risk of AIN 2/3. A study among HIV+ men showed a significant correlation between low nadir CD4 cell counts and anal cancer. Taking a nadir CD4 cell count <200 as reference, a nadir CD4 cell count between 200 and 350 cells per cubic millimeter showed a hazard ratio of 0.42 (P < 0.0001) for anal cancer and a nadir CD4 cell count of >350 a hazard ratio of 0.34. Another recent study showed a hazard ratio of 0.87 for anal cancer risk per log2 increase in nadir CD4 cell count. We found a hazard ratio for anal cancer of 2.42 in patients with a nadir CD4 cell count <110.
What is new in our study is that we found a decrease in anal cancer incidence after 2006. Although statistical significance could not be demonstrated (CIs overlap), it does show a steady trend. One previous study also suggested a plateau in the anal cancer incidence. The peak incidence in this study of 159 in 2000–2003 in HIV+ MSM was followed by a decrease to 131 in 2003–2007. Our study shows a continuing decreasing trend, to an incidence in HIV+ MSM of 100 in 2011/2012. The gradual small-scale introduction of AIN screening programs in the Netherlands cannot explain this. A more likely explanation might be that the long-term use of cART is negatively associated with the risk of the anal cancer precursor AIN, which in time might gradually affect anal cancer incidence, and furthermore, given the tendency to start cART with higher CD4 counts, the HIV+ MSM population less and less suffers from low nadir CD4 cell counts. For cervical cancer, no decrease in incidence has been observed yet in the cART era.
We found a hazard ratio of 1.60 for anal cancer in current or previous smokers. Smoking has previously been associated with an increased risk of anal cancer. Smoking is much more common in the HIV-positive population, and HIV-infected smokers lose more life-years to smoking than to HIV. To our knowledge, no previous studies showed a link between alcohol (ab)use and anal cancer. We found a hazard ratio of 2.23 for HIV+ MSM drinking more than 28 glasses of alcohol per week. Because alcohol use has a disinhibiting effect, it possibly leads to increased sexual risk behavior, which in turn is a risk factor for anal cancer.
Strong points of our study are the use of a nationwide database including all patients under HIV care in the Netherlands, confirmation of all histological diagnoses, and careful documentation of risk factors. We have possibly missed cases if the diagnosis anal cancer was not reported by the treating physician, but this means that the incidence of anal caner we found is likely an underestimation. A limitation of our study is that the low absolute number of anal cancers made it difficult to demonstrate statistical significance of the observed trends in time.
In conclusion, this study confirms the high incidence of anal cancer among HIV+ patients, predominantly among HIV+ MSM. Furthermore, our data suggest that continued use of cART, and starting cART at higher CD4 counts, might in time lead to a decrease in anal cancer incidence. In the meantime, although there is still uncertainty on the effectiveness of anal cancer screening programs, the very high anal cancer incidence justifies screening programs for AIN among HIV+ MSM.
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