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French study finds increased anal cancer risk despite ART
19 December 2012 - HIV attacks the immune system, causing it to become increasingly weak and dysfunctional.
Treatment with combinations of potent anti-HIV drugs (commonly called ART or HAART) greatly reduces production of HIV in the
body. As less HIV is produced, the immune system can begin repairs. These repairs are generally sufficient to keep
AIDS-related infections at bay. However, because defects in immunity persist, there is an elevated risk for
certain cancers in some ART users. The degree of this elevated cancer risk varies from one HIV-positive
person to another and arises from a complex intersection of factors, likely including some of the following:
- prolonged exposure to proteins produced by HIV-infected cells
- persistent inflammation incited by HIV infection (such inflammation is only partially reduced by ART)
- certain behaviours, such as smoking tobacco, excessive intake of alcohol and/or use of other substances
- insufficient exercise
- obesity
- co-infection with certain viruses
Viruses and cancer
Due to similar routes of transmission, some HIV-positive people are also infected with other viruses. Some of these viruses can
cause cells to develop abnormally. Such abnormal cells can transform into pre-cancers and, in some cases, even cancer. Some
viruses with this cancer-causing potential include the following:
- HBV (hepatitis B virus) and HCV (hepatitis C virus) - these infect and damage the liver and increase the risk for liver cancer
- EBV (Epstein-Barr virus) - a member of the herpes virus family, EBV has been linked to the development of a cancer of the immune system called lymphoma
- HHV-8 (human herpes virus-8) - another member of the herpes virus family, HHV-8 can cause Kaposi's sarcoma (KS) and is linked to a cancer-like condition called Castleman disease
- HPV (human papillomavirus) - some strains of HPV can cause ano-genital warts; other strains can cause cancer of the anus and penis in men and cancers of the anus, cervix and vulva in women. Emerging research suggests that some strains of HPV may be linked to cancers of the mouth, lips and throat.
Anal cancer and risk
Researchers have found that in the time before ART became available, cases of anal cancer were twice as high among HIV-positive men
who have sex with men (MSM) compared to HIV-negative MSM.
Furthermore, compared to the average HIV-negative man, the relative risk of anal cancer is many times greater for HIV-positive men
who are not MSM (37-fold) and even greater for HIV-positive MSM (60-fold).
Anal cancer risk and ART
Some studies have found no reduction in the risk of anal cancer among HIV-positive people in the current era in places where ART
is widely available. In contrast, two studies suggest a decreased risk of this cancer with prolonged use of ART. However, what all
studies of anal cancer in high-income countries in the current era have in common is that cases appear to be increasing compared
to the time before ART was available.
Most studies comparing anal cancer risk among HIV-positive people have involved a relatively small number of cases-between 18
and 80. Such studies did not generally account for factors such as the following:
- different sub-populations of HIV-positive people
- different degrees of immunodeficiency
Also, most of these studies could not clearly conclude whether anal cancer was occurring at a younger age in HIV-positive people
compared to HIV-negative people.
The French Hospital Database
To address this and other issues, researchers in France conducted an analysis of their database, which has collected health-related
information from nearly 110,000 HIV-positive people. The researchers also compared the data on HIV-positive people with that from
HIV-negative people with anal cancer.
Surprisingly, in their report, the French team found no significant difference in the relative risk for anal cancer in the
pre-HAART era (1992 to 1996) and the HAART-era (1997 to 2008). Furthermore, no differences in anal cancer risk were found
in the early HAART era (1997 to 2000) and the later HAART era (2005 to 2008). Additional findings from this important
study appear later in this CATIE-News bulletin, along with steps on how to reduce anal cancer risk.
Study details
The French Hospital Database has collected health-related information on 109,771 HIV-positive people from 69 clinics in hospitals across
France.
For purposes of comparison, the researchers obtained information on anal cancer cases in HIV-negative people from a database called
FRANCIM (France-cancer-incidence et mortalité). That database contained information collected from about 12 million people.
In the present study, the analysis on anal cancer focused on the period between January 1992 and December 2008.
Results-Distribution of anal cancer
Over the 16 years of the study, cases of anal cancer were distributed as follows:
HIV-positive people: 263 cases
- men - 91% of cases; average age at cancer diagnosis was 46 years
- women - 9% of cases; average age at cancer diagnosis was 42 years
HIV-negative people: 2,012 cases
- men - 29% of cases; average age at cancer diagnosis was 67 years
- women - 71% of cases; average age at cancer diagnosis was 72 years
Trends
Rates of new cases of anal cancer were highest among HIV-positive MSM, followed by what the researchers called "other"
HIV-positive men, and then HIV-positive women.
Risk factors linked to anal cancer among HIV-positive people
Anal cancer was more likely to occur among HIV-positive people with the following profile:
- older participants, "particularly MSM," noted the researchers
- participants who had been diagnosed with AIDS
- participants with a lower nadir (lowest-ever) CD4+ cell count
The risk of anal cancer nearly tripled in the current era compared to the pre-HAART era. This likely arose because of differences
in survival. For instance, in the pre-HAART era, participants were much more likely to die at a younger age from complications
stemming from an AIDS-related infection. In the HAART era, in high-income countries, such complications are no longer
common. This means that people live longer with both HIV and HPV infection, which allows more time for tumours to
develop. In the present era, thanks to HAART, HIV-positive people likely feel better, and so interest in sex
returns. This leads to resurgence in sex, which may also mean more exposure to strains of HPV that are associated with tumours.
Having a high CD4+ cell count did not seem to be protective from anal cancer because cases of anal cancer were documented even among
HIV-positive people whose CD4+ counts were greater than 500 cells. Furthermore, among participants whose CD4+ cell counts were greater
than 500 cells for two years before the diagnosis of anal cancer, their risk for this cancer was 20-fold greater than among
HIV-negative people.
More trends-Limitations to HAART
The researchers found that all sub-groups of HIV-positive people experienced an increase in diagnoses of anal cancer after ART
became available. Although the rate of anal cancer among HIV-positive people in France has stabilized in the current era,
according to French researchers it remains very high compared to that seen in HIV-negative people.
Montréal researcher François Coutlée, MD, has also been studying HPV and has reviewed studies comparing HPV-related
disease in the pre-HAART and HAART eras. In a recent article in the journal Sexual Health , Dr. Coutlée wrote: "If HAART was truly
protective against [HPV-related pre-cancers, new cases of anal cancer] would be decreasing, which is not what is being observed."
Specific risks per group
The French study uncovered a high risk of anal cancer among HIV-positive people, particularly in men and especially MSM. The risk of
anal cancer in the current era among HIV-positive people compared to HIV-negative people was as follows:
- HIV-positive MSM - 100-fold greater risk than the average HIV-negative male
- HIV-positive non-MSM - 50-fold greater risk than the average HIV-negative male
- HIV-positive women - 13-fold greater risk than the average HIV-negative woman
Possible explanations for elevated risk
Researchers in both France and the U.S. have sought explanations for the excessive risk of anal cancer seen in HIV-positive people.
One possibility is that MSM and others at high risk for HIV infection may become infected with cancer-causing strains of HPV at an
earlier age than HIV-negative people. This may allow HPV-infected cells more time to develop abnormally, thus a greater risk of
developing pre-cancer and cancer.
In general, the immune system becomes less effective as people age and there is a suggestion that viral infections, particularly
those caused by CMV (cytomegalovirus, a member of the herpes family of viruses), may prematurely age the immune system. Added to
this is the burden of HIV infection, which is associated with hints of acceleration in the aging of the immune system. Being
co-infected with different viruses may weaken the immune system's ability to contain and control the growth of pre-cancers and tumours.
Theories and evidence for accelerated aging of the immune system in the context of HIV infection are somewhat controversial and require
further research.
Earlier HIV therapy
In most high-income countries the threshold for starting ART is at least 350 cells. In cases where symptom-free HIV-positive people
have co-existing health issues-including conditions that affect major organs such as the brain, heart, liver and kidneys-treatment
may be recommended or encouraged at higher CD4+ count thresholds, even if a person has more than 500 cells. In such cases,
treatment helps to strengthen the immune system and reduce HIV-related inflammation and the risk of damage to
organ-systems caused by HIV and/or co-infections.
A key risk factor for anal cancer in the French study was having a low nadir CD4+ cell count. On average, 50% of HIV-positive participants
who developed anal cancer had a nadir CD4+ count less than 95 cells.
The French researchers stated that if more HIV-positive people initiated ART at relatively high CD4+ counts, then fewer people would
experience low nadir CD4+ cell counts and would therefore be at greatly reduced risk for the subsequent development of anal cancer.
Researchers in Québec have also found that a low nadir CD4+ count is associated with an increased risk for anal pre-cancer and
cancer among HIV-positive men.
Prevention
Here are some steps that might help reduce the future risk for HPV-related cancers, including anal cancer:
Early initiation of ART
Starting ART before the CD4+ count falls to low levels helps to reduce damage to the immune system. A stronger immune system should
be better able to fend off cancers.
HPV vaccination
There are two vaccines-Cervarix and Gardasil-that provide protection against two strains of HPV that are associated with cancer.
One of these vaccines (Gardasil) also provides protection against ano-genital warts. Although the effectiveness of these vaccines
was tested in HIV-negative people, researchers at the U.S. National Cancer Institute recently estimated that these vaccines
could provide "substantial" protection against HPV-related pre-cancer and cancer particularly in HIV-positive people.
Speak to your doctor about coverage for this vaccine in your region.
Tobacco and other substances
Reducing exposure to factors associated with cancer (such as tobacco smoke, excessive alcohol and injecting street drugs) is a good
step. Another important step is getting help for the mental and emotional health conditions that often underpin some people's
susceptibility to addictive behaviours and substance use.
Safer sex
This helps to protect people not only from HIV infection (and for HIV-positive people, new strains of the virus) but also from many
sexually transmitted infections. Correct and consistent use of condoms offers some protection from (re)infection with HPV.
Cancer screening
Anal cancer screening programs for HIV-positive people may be available in some larger cities. Often such programs are funded as part
of research studies and may not be the standard of care. Speak to your doctor about the availability of this screening in your region
Resource
Canadian Cancer Society - Anal cancer
overview
-Sean R. Hosein
REFERENCES:
- Piketty C, Selinger-Leneman H, Bouvier AM, et al. Incidence of HIV-related anal cancer remains increased despite long-term combined antiretroviral treatment: Results from the French Hospital Database on HIV. Journal of Clinical Oncology . 2012; in press .
- de Pokomandy A, Rouleau D, Ghattas G, et al. HAART and progression to high-grade anal intraepithelial neoplasia in men who have sex with men and are infected with HIV. Clinical Infectious Diseases. 2011 May;52(9):1174-81.
- Coutlée F, de Pokomandy A, Franco EL. Epidemiology, natural history and risk factors for anal intraepithelial neoplasia. Sexual Health . 2012;9:547-555.
- Appay V, Fastenackels S, Katlama C, et al. Old age and anti-cytomegalovirus immunity are associated with altered T-cell reconstitution in HIV-1-infected patients. AIDS . 2011 Sep 24;25(15):1813-22.
- Barrett L, Fowke KR, Grant MD. Cytomegalovirus, aging, and HIV: a perfect storm. AIDS Reviews. 2012 Jul;14(3):159-67.
- Deeks SG, Verdin E, McCune JM. Immunosenescence and HIV. Current Opinion in Immunology . 2012 Aug;24(4):501-6.
- Dock JN, Effros RB. Role of CD8 T cell replicative senescence in human aging and in HIV-mediated immunosenescence. Aging and Disease . 2011 Oct;2(5):382-397.
- Rasmussen LD, Kessel L, Molander LD, et al. Risk of cataract surgery in HIV-infected individuals: a Danish nationwide population-based cohort study. Clinical Infectious Diseases . 2011 Dec;53(11):1156-63.
- Sahasrabuddhe VV, Castle PE, Follansbee S, et al. HPV genotype attribution and estimation of preventable fraction of anal intraepithelial neoplasia among HIV-infected men who have sex with men. Journal of Infectious Diseases . 2012; in press .
- Nyitray AG, Carvalho da Silva RJ, et al. Six-month incidence, persistence, and factors associated with persistence of anal human papillomavirus in men: the HPV in men study. Journal of Infectious Diseases . 2011 Dec 1;204(11):1711-22.
- Van de Velde N, Boily MC, Drolet M, et al. Population-level impact of the bivalent, quadrivalent, and nonavalent human papillomavirus vaccines: a model-based analysis. Journal of the National Cancer Institute . 2012 Nov 21;104(22):1712-23.
- Phillips DH, Hewer A, Scholefield JH, et al. Smoking-related DNA adducts in anal epithelium. Mutation Research . 2004 Jun 13;560(2):167-72.
- Reepalu A, Blomé MA, Björk J, et al. The risk of cancer among persons with a history of injecting drug use in Sweden-a cohort study based on participants in a needle exchange program. Acta Oncologica . 2012 Jan;51(1):51-6.
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From CATIE: CANADIAN AIDS TREATMENT INFORMATION EXCHANGE. For more information visit CATIE's Information Network
at http://www.catie.ca
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