Massive North American study strengthens case for HPV screening
February 8, 2012 - HPV (human papilloma virus) is a common sexually transmitted virus. Some strains
of HPV can cause ano-genital warts. Other strains of HPV can cause cells to develop abnormally and, in some cases,
transform into pre-cancer and cancer affecting the following parts of the body:
- cervix and vulva
- mouth, nose and throat
- possibly some cases of skin cancer
HIV infection weakens the immune system and makes people more susceptible to certain cancers. Although treatment
for HIV, commonly called ART or HAART, can improve quality of life, lengthen survival and greatly decrease the risk
for AIDS-related infections, a heightened risk for some cancers remains among HIV-positive people. In part, this
risk persists because despite ART the immune system is unable to completely repair itself. As many HIV-positive
people are likely to be co-infected with HPV, their risk for HPV-related cancer, particularly anal cancer,
Research teams across Canada (in Alberta, Ontario and Quebec) and in the U.S. have been collaborating by pooling
the health-related data they have collected on HIV-positive and -negative people. This pooled dataset is a powerful
tool that allows scientists to explore and understand many health issues that are important when caring for
HIV-positive people. This collaboration is called the NA-ACCORD.
The most recent analysis from the NA-ACCORD focused on 34,000 HIV-positive people, comparing their rates of anal
cancer with those of 114,000 HIV-negative people. Researchers confirmed the elevated risk for anal cancer
among a variety of HIV-positive people, including men who have sex with men (MSM), men who have sex with
women (MSW), and women. Rates of anal cancer were increasing over time but then stabilized about a
decade ago. Most importantly, the NA-ACCORD team notes that its findings underscore the need to
prevent and screen all HIV-positive people for anal cancer. In this CATIE News bulletin we
also present some findings from HPV vaccine research.
The NA-ACCORD analysed health-related information from the following populations:
- 34,189 HIV-positive people (55% MSM, 19% MSW and 26% women)
- 114,260 HIV-negative people (90% men, 10% women)
Participants enrolled in the study between 1996 and 2003 and were monitored until they developed anal cancer,
withdrew from the study or died, or until December 31, 2007-whichever occurred first. On average, participants
were monitored for four years.
The HIV-positive people ranged in age between 30 and 46 years and had about 300 CD4+ cells at the time they
entered the study.
Cases of anal cancer occurred during the study period among the following groups:
- HIV-positive MSM - 122 cases of anal cancer among 18,855 men
- HIV-positive MSW - 14 cases of anal cancer among 6,492 men
- HIV-positive women - 15 cases of anal cancer among 8,842 women
- HIV-negative men - 13 cases of anal cancer among 102,607 men
- HIV-negative women - 0 cases of anal cancer among 11,653 women
Among HIV-positive people, this difference between MSM and MSW or women was statistically significant.
In HIV-positive MSM, rates of anal cancer increased from 1996 to 2003. After 2003, the risk of anal cancer
remained elevated but stable for this group. A similar pattern was seen for HIV-positive MSW and HIV-positive
The importance of prevention
Based on the findings in the present analysis, the NA-ACCORD team called for "enhanced primary and secondary
prevention efforts [against anal cancer] among all HIV-infected persons."
Vaccines for HPV prevention
In high-income countries such as Canada, Australia and the U.S. and in Western Europe, there are two
vaccines-Cervarix and Gardasil-that can help prevent infection with strains of HPV (HPV-16, HPV-18).
These strains of HPV can cause cervical, vulvar and anal cancer. One of the vaccines, Gardasil,
also protects against strains of HPV (HPV-6, HPV-11) that can cause ano-genital warts.
However, it is important to note that both vaccines have mostly been tested in young HIV-negative people who
have had few or no sexual partners, and therefore little or no exposure to HPV, and who have not had ano-genital
warts or anal or cervical pre-cancer or cancer prior to vaccination.
Would these vaccines provide equal effectiveness among HIV-positive adults who have had considerable exposure
to HPV? Researchers are not certain about this and clinical trials are needed to conclusively answer this
question. Here is some information on preliminary studies with HPV vaccines among sexually active
adults, some of whom have HIV.
Among HIV-positive people
The American National Institutes of Health (NIH) funded an exploratory study of Gardasil among 100 HIV-positive
men who did not have a history of pre-cancerous anal lesions or anal cancer. The men in this study were in their
mid-40s; their CD4+ counts were around 500 cells and their HIV viral load was less than 10,000 copies.
The study team found that Gardasil was safe and did not significantly affect CD4+ counts or HIV viral
load. Skin reactions at places where the vaccine was injected were generally mild or moderate.
About 95% of the men developed antibodies against the strains of HPV covered by the vaccine. These antibodies
are necessary for attacking HPV. The concentrations of antibodies produced in these men were lower than reported
in some studies of HIV-negative people. For instance, their concentration of antibodies against HPV-16 was
about 50% less than seen in HIV-negative women between the ages of 34 and 45 years, and 40% less than
found in HIV-negative women between the ages of 16 and 26. However, the concentration of antibodies
was similar to that seen in HIV-negative MSM between the ages of 16 and 26 who had been vaccinated with Gardasil.
HIV-positive men who were taking ART in this study had greater concentrations of antibodies to HPV as a result
of the vaccine than men who were not using ART.
The U.S. researchers encourage further studies of HPV vaccines in HIV-positive men who are regularly screened
for abnormal anal growths and anal cancer.
In Canada, researchers are exploring the effect of HPV vaccination among HIV-positive girls and women in a trial
called CTN 236. For further information about this study, visit the Canadian HIV Trials Network site.
Among sexually active HIV-negative men
Doctors at New York City's Mt. Sinai School of Medicine conducted an observational study of 202 HIV-negative MSM, all of whom had
biopsy-proven pre-cancerous anal lesions caused by HPV infection. The men were between 20 and 79 years of age. After diagnosis and
treatment of anal lesions, all the men were offered vaccination with Gardasil, but only some chose to receive it. After about
two years of monitoring, researchers found that 14% of vaccinated men and 31% of unvaccinated men had a recurrence of
precancerous anal lesions.
Note that observational studies cannot by their nature produce definitive results. In this particular case, the study cannot prove
that vaccination with Gardasil reduced the risk of pre-cancerous growths recurring in some men. Such a conclusion may be reached from
a randomized, controlled clinical trial, which the Mt. Sinai researchers encourage.
Preventing anal cancer
Ideally, young people of both genders should receive HPV vaccination. Until well-designed clinical trials are conducted, it is not
clear how effective HPV vaccines will be at preventing abnormal anal growths, pre-cancer and anal cancer in HIV-positive people.
In the meantime, anal cancer screening programs 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. The results of the NA-ACCORD's recent analysis show that all HIV-positive
people, particularly MSM, need anal cancer screening.
A final note: Among sexually active men, correct and consistent use of condoms offers some protection from (re)infection with
HPV and many other sexually transmitted infections, including HIV.
We thank Marc Stebin MD for his expert review and helpful comments.
-Sean R. Hosein
Fairley CK, Read TR. Vaccination against sexually transmitted infections. Current Opinion in Infectious Diseases.
Park IU and Palefsky JM. Evaluation and management of anal intraepithelial neoplasia in HIV-negative and HIV-positive men who have sex with men. Current Infectious Disease Reports . 2010 Mar;12(2):126-33.
Palefsky JM, Giuliano AR, Goldstone S, et al. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. New England Journal of Medicine . 2011 Oct 27;365(17):1576-85.
Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. New England Journal of Medicine . 2011 Feb 3;364(5):401-11.
Silverberg MJ, Lau B, Justice AC, et al. Risk of anal cancer in HIV-infected and HIV-uninfected individuals in North America. Clinical Infectious Diseases . 2012; in press.
Downey JS, Attaf M, Moyle G, et al. T-cell signalling in antiretroviral-treated, aviraemic HIV-1-positive individuals is present in a raised state of basal activation that contributes to T-cell hyporesponsiveness. AIDS . 2011 Oct 23;25(16):1981-6.
Appay V, Almeida JR, Sauce D, et al. Accelerated immune senescence and HIV-1 infection. Experimental Gerontology . 2007 May;42(5):432-7.
Herbeuval JP, Nilsson J, Boasso A, et al. HAART reduces death ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infected macaques. AIDS . 2009 Jan 2;23(1):35-40.
Boasso A, Royle CM, Doumazos S, et al. Overactivation of plasmacytoid dendritic cells inhibits antiviral T-cell responses: a model for HIV immunopathogenesis. Blood . 2011 Nov 10;118(19):5152-62.
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;204(11):1711-22.
Gilbert M, Kwag M, Mei W, et al. Feasibility of incorporating self-collected rectal swabs into a community venue-based survey to measure the prevalence of HPV infection in men who have sex with men. Sexually Transmitted Diseases . 2011 Oct;38(10):964-9.
Lu B, Viscidi RP, Lee JH, et al. Human papillomavirus (HPV) 6, 11, 16, and 18 seroprevalence is associated with sexual practice and age: results from the multinational HPV Infection in Men Study (HIM Study). Cancer Epidemiology, Biomarkers & Prevention. 2011 May;20(5):990-1002.
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.
Kreimer AR, González P, Katki HA, et al. Efficacy of a bivalent HPV 16/18 vaccine against anal HPV 16/18 infection among young women: a nested analysis within the Costa Rica Vaccine Trial. Lancet Oncology . 2011 Sep;12(9):862-70.
Goldstone S, Palefsky JM, Giuliano AR, et al. Prevalence of and risk factors for human papillomavirus (HPV) infection among HIV-seronegative men who have sex with men. Journal of Infectious Diseases . 2011 Jan 1;203(1):66-74.
Wilkin T, Lee JY, Lensing SY, et al. Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in HIV-1-infected men. Journal of Infectious Diseases . 2010 Oct 15;202(8):1246-53.
Swedish KA, Factor SH, Goldstone SE. Prevention of recurrent high-grade anal neoplasia with quadrivalent human papillomavirus vaccination of men who have sex with men: a nonconcurrent cohort study. Clinical Infectious Diseases . 2012: in press .
Shepherd JP, Frampton GK, Harris P. Cochrane. Database of Systematic Reviews . 2011 Apr 13;(4):CD001035.
Nielson CM, Harris RB, Nyitray AG, et al. Consistent condom use is associated with lower prevalence of human papillomavirus infection in men. Journal of Infectious Diseases. 2010 Aug 15;202(3):445-51.
CATIE-News is written by Sean Hosein, with the collaboration of other members of the
Canadian AIDS Treatment Information Exchange, in Toronto.
From Canadian AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca
Source: CATIE: CANADIAN AIDS TREATMENT INFORMATION EXCHANGE