The 28th International Papillomavirus Conference and Clinical Workshop was held in December 2012 in San Juan, Puerto Rico. The IPV conference is designed to bring together the best HPV experts in the world to discuss research from three perspectives: basic, clinical, and epidemiological. This is the third consecutive year the HPV and Anal Cancer Foundation represented the anal cancer patient community at IPV. We have summarized the workshops and research presentations we attended. Note that the presentations cover policies and research underway worldwide. To find the studies referenced in this document, review the HPV 2012 abstracts documents. At the end of the blog, we have a list of acronyms used throughout the text.
What did we learn?
● Rates of HPV-associated cancer are rising, particularly anal and oral cancers, and particularly in men. Latest data: >30,000 HPV-associated cancer cases occur every year in the US.
● Treatment options for patients with HPV-associated cancers remain limited to antiquated conventional chemo/radiotherapies. The absence of novel therapies puts increased burden on vaccination/screening/prevention to reduce the burden of HPV-associated cancers.
● Clinicians/scientists continue to debate correct screening algorithms to detect anal pre-cancer for at-risk groups. There are three viable options: anal pap smears, digital anal rectal exams, and high-resolution anoscopy (HRA). The International Anal Neoplasia Society (www.ians.memberlodge.org), which started operations in 2012 following a seed grant from the HPV and Anal Cancer Foundation, is working to develop this consensus.
● Most US researchers highlighted the importance of screening screen high-risk groups from anal cancer until we get more data on High Grade Anal Intraepithelial Neoplasia (HGAIN) progression/regression rates. More data collection will be helpful in assessing the risk-benefit of preventative measures such as HRA due to high costs and high levels of discomfort associated with the procedure. Several Australian researchers at the conference cited concern that too many people will be referred to HRA in the absence of standardized guidelines and that possible discomfort from screening procedures should be considered. However, others stated that it is unacceptable to wait until precancerous lesions develop into cancer in order to take active steps to treat it.
● Female-only vaccination campaigns send the incorrect message that HPV is a single-sex issue. Men are infected with HPV at the same rates as women, although currently more women are diagnosed with HPV-related cancer than men. Female-only vaccination is particularly discriminatory against men-who-have-sex-with-men, who are not protected by “herd immunity” in countries with high female vaccination rates. Lowering dosing schedule for the vaccine (two or even one shot) may be effective in providing coverage against HPV-related morbidities in low-resource communities. Lower prices would improve the cost-effectiveness of vaccinating men in countries that have high vaccine uptake rates in females.
● Oral HPV incidence is highest in middle-aged men. In the UK, incidence of HPV-related head-and-neck cancer (HNC) increased significantly from 1995 to 2010 (at an annual increase of 7.2%), whereas non-HPV related cancer rates remained stable. The number of HPV-related HNCs is expected to increase by 270% and 370% in men and women, respectively, in the next 25 years.
● Basic science research presented at the conference focused largely on how to increase specificity of diagnostic tests for HPV precancer. One common theme was how to better understand the “natural history” of cancers, particularly cervical cancer. Natural history studies help to demonstrate which cervical precancers will progress to cervical cancer and which will regress and never become cancer. Researchers are conducting studies to discern which biomarkers will indicate cancer progression.
● HPV-based screening may be more effective than pap-smears in preventing invasive cervical cancer. A single test for HPV DNA has a high long-term negative predictive value. Implementation of testing for high-risk HPV types in primary screening may thus permit a safe extension of screening intervals. The current challenge with HPV testing is the rate of false positives.
● We cannot fully measure the incidence of anal cancer world-wide because many developing countries do not have the capacity to maintain cancer registries.
● While the highest number of research presentations were focused on cervical cancer, we found that anal cancer, head and neck cancer, and penile cancer garnered more attention in this papillomavirus conference than previous conferences we attended.
Update on HPV Vaccination Rates, and Cost-Effectiveness of Vaccinating Boys
Two Wrongs Don’t Make It Right
Healthcare is a scarce resource. Fiscal austerity has sharpened governmental medical bodies’ focus on cost-effectiveness of each new initiative/treatment introduced to the healthcare system, especially in national public healthcare systems in the UK and Australia. There is a standard protocol to evaluate whether a new treatment fits the cost-effectiveness “threshold” – measured by Quality-Adjusted Life Years, or QALYs. QALYs are designed to estimate how much extra “life” a patient should gain as a result of treatment. According to NICE, the UK National Health Service (NHS) approval body for new treatments, “if a treatment costs more than GBP20,000-30,000 per QALY, then it would not be considered cost effective.”
At IPV2012, researchers across the globe presented data on the cost-benefit of vaccinating boys with the HPV vaccine.
Australia is currently implementing a school-based vaccination program for both boys and girls. In Australia, 73% of girls aged 12-13 were given a three-dose schedule of the vaccine. In November 2012, the Australian Pharmaceutical Benefits Advisory Committee recommended boys (http://www.health.gov.au/internet/ministers/publishing.nsf/Content/mr-yr13-tp-tp008.htm) receive the vaccine. Starting February 2013, the program was incorporated into schools for 12-13 year old boys with catch up programs for 14-16 year olds. Australian researchers cited the increased burden of disease in both genders, particularly of anal and oral cancers, as reason to expand the school-based vaccination program to boys.
In the UK, the high rate of vaccination amongst girls has discouraged the authorities from extending the vaccine to boys. The thinking behind this decision is if all girls are vaccinated, and all boys have sexual contact with only the vaccinated girls, it is not necessary to vaccinate boys (they will be protected via “herd immunity”). The Foundation has long argued the discrimination inherent in this approach: 1) we have clear data showing that men shoulder a significant burden of the overall HPV cancer load, and HPV-associated cancer in men is growing at an alarming rate (which could possibly overtake current cancer rates in women in a decade); 2) men-who-have-sex-with-men will have no or limited protection from herd immunity; 3) any man who travels to a foreign country (with a lower vaccination rate) or has sexual contact with a foreign, unvaccinated person living in the UK will not be protected. Our conclusion is that the UK cost-effectiveness modeling is just too simple: it assumes a static, closed-system and today’s reality is much more dynamic. In the UK, the rubella immunization program was aimed largely at women. Resurgences of rubella in the mid 1990s were attributed to susceptibility among males. In 1998, the rubella vaccine was introduced in the UK for ALL children (boys and girls). Subsequently, rubella was reduced dramatically: in 2010 there were only 12 cases in England and Wales.
In other countries, like the US, female vaccination rates are low enough (53%) that the cost-effectiveness debate becomes irrelevant. In 2011, the Advisory Committee on Immunization Practices (ACIP) passed a regulation that all boys should be routinely vaccinated against HPV (the ACIP first recommended HPV vaccination for girls in 2006). In 2011, 8.3% of eligible boys were vaccinated with the quadrivalent vaccine in the United States.
At the conference, there was a general consensus that unless there are major changes in the US health system, low male vaccination rates will continue. Providers have a huge influence on the vaccination decisions made by families, and we need to look at the best ways to reach providers/patient families. Greg Zimet conducted an online survey of 750 parents of 7-11 year old boys in the United States. Parents cited the following reasons for non-vaccination: 40% practitioners did not recommend, 22% did not know the vaccine was available to males. We must be more active with the American Academy of Pediatrics, the American Academy of Family Physicians, and the Society for Adolescent Health and Medicine. All endorse the vaccine but none have commented on use in boys. More steps are needed, including educational materials in the hands of parents.
The current landscape for HPV-associated cancers has few standardized screening protocols (which the exception of cervical Pap tests to detect precancer), and there are very antiquated treatment choices for people who develop later-stage cancer. However, there is a vaccine available to us which not only prevents cancer, but also prevents genital warts. Oropharyngeal cancer incidence is threefold higher in men than women and has a higher incidence rate in men than cervical cancer in women. PeIN is also increasing. The incidence of genital warts is higher in men than in women.
The cost of the vaccine is clearly one of the biggest input factors to decide whether or not boys will be vaccinated in places that have a high female vaccination rate. In Canada, Jean-Francois Laprise studied the incremental cost-effectiveness of vaccinating boys. He modeled the vaccine impact in heterosexual females, males, and men-who-have-sex-with-men (MSM). In his study, he assumed a relative risk (RR) of anal cancer of 17.3 in MSM compared to heterosexual males and of 3.1 for all other HPV-related diseases. Adding boys would be cost-effective at $27 per dose, according to his analysis. “If HPV vaccination is cheaper it would be more cost-effective to vaccinate populations. In populations with no or very limited screening, it’s more cost-effective to vaccinate,” one researcher said.
Rolando Herrero presented a paper evaluating the prevalence and risk factors for mucosal HPV types detected in the oral region of women with cancer (half of which were vaccinated). They found a 93% reduction in HPV 16/18 prevalence after 4 years of vaccine protection in the vaccinated cohort. Vaccine efficacy was actually higher in the mouth than in the cervix, but this could have been due to more cervical infections at baseline (study did not measure positive cervical HPV at the start), therefore results do not directly indicate that the vaccine prevents oral cancer.
Data from Uganda suggested that girls who miss one dose of the three-dose bivalent HPV vaccine developed a strong immune response that should afford protection, even when compared to three-dose recipients. Programmatic efforts should always focus on delivery of all three doses; in resource-limited environments like Uganda, however, two doses might be easier and less costly to implement. If this regimen is sufficient to adequately protect vaccinated girls from future infections with vaccine-type HPV, low-resource settings may elect to adopt a two-dose schedule, as has been done in British Columbia, Canada, which also allows for a third dose five years after vaccination if required. This strategy is under consideration by Mexico and Quebec, Canada.
Further Reading: A 2007 study that explores some of the initial considerations surrounding male HPV and vaccination.
Screening
One of the Foundation’s central missions is to improve screening protocols for HPV-associated cancer. The HPV and Anal Cancer Foundation distributed an educational grant in 2012 to seed the International Anal Neoplasia Society (www.ians.memberlodge.org), a medical society which aims to generate a clinical / scientific consensus about who to treat, what to treat and how to treat in the pre-cancer setting. Determining screening protocols is critical for increasing detection of anal cancer and precancer. The National Cancer Institute (NCI) review on the 10-year trends in cancer incidence illustrates that cancers that have good screening protocols – cervical cancer, breast cancer, prostate cancer, are decreasing. Cancers like anal and oral cancer, which have virtually no screening protocols, continue to rise.
Recent data from the Netherlands shows that more than 50% of cervical cancers occur in women who did not attend the cervical cancer screening program. Multiple studies have indicated that offering a HPV-self test to non-attendees could increase the screening participation and therefore decrease the incidence and mortality of cervical cancer while lowering cost and increasing screening compliance. In a study based on 4 Large Randomized Screening Trials, Guglielmo Ronco showed that HPV-based screening is about 40% more effective than cytological screening in preventing invasive cervical cancer. He suggested that HPV-based screening could be recommendable at 30 years of age. 5-year intervals between HPV tests are deemed to be “safe.” Louise Thirstrup Thomsen presented a study that a single negative test for high-risk (HR) HPV DNA has a high long-term negative predictive value. Implementation of testing for HR HPV types in primary screening may thus permit a safe extension of screening intervals. Furthermore, the results corroborate that low-risk HPV types play no major role in cancer. (Studies do show that low-risk HPV has the potential to cause cancer, although it is much more infrequent. Laia Alemany Vilches’ research illustrated that 8% of HPV-related penile cancers were caused by HPV 6 and 11, which are generally considered to be low-risk types.)
During the conference, a symposium focused on anal cancer was held to discuss the benefits and drawbacks of screening and treatment for precancerous anal lesions, particularly in high-risk groups. There was overall agreement on the need for annual digital anal exams. Everyone present in the conference room also agreed that a very important step in establishing preventative protocols is discovering predictive biomarkers, which will help doctors to understand which precancerous lesions progress to cancer and which lesions are benign. Screening methods include a digital anal exam (also sometimes called a digital rectal exam), anal Pap smears or cytology (similar to cervical Pap smear), and high resolution anoscopy or HRA (similar to cervical colposcopy).
Several researchers at the anal cancer symposium at IPV2012 felt it was important to screen and treat high risk groups from anal cancer despite limited randomized clinical data studies of HGAIN progression/regression rates on the premise that we should screen and treat anal precancerous lesions until we have data that tells us we should not. Other researchers at the symposium thought more data should be collected before making that decision by assessing the risk-benefit of preventative measures such as HRA due to costs and discomfort associated with the procedure. The natural history of anal HPV should be better understood to prevent too many patients from being referred to HRA without standardized guidelines on interval screening, who should be treated and how. (Both sides agree we need more information – the discrepancy relates to how to treat populations in the meantime. In 2011, the HPV and Anal Cancer Foundation led a coalition of organizations in an advocacy effort to the NIH’s Clinical and Translational Research Operations Committee to fund the HOST-HGAIN Outcome Study, the first randomized controlled trial for anal precancer screening and treatment. The study is still pending funding.)
During the anal cancer discussion, researchers pointed to increasing AC rates and highlighted the reality that 30% of stage I AC patients die. Those who survive can have long term side effects, which is a compelling reason to screen and treat precancerous lesions. Anal cancer stems from the same disease as cervical cancer, therefore we should provide the same service of care to the anal cancer patient as we do for the cervical cancer patient.
Screening can also have its downsides, including side effects and over-diagnosis (see http://www.cancer.gov/cancertopics/factsheet/detection/PSA for a recent discussion on the debate about prostate cancer biomarkers). There can also be discomfort associated with screening. For example, as part of the Study for the Prevention of Anal Cancer (SPANC) in Australia, David Templeton investigated the side effects of the digital anal exam (DAE), anal swab cytology, and high resolution anoscopy (HRA) in men. At baseline, DAE, swab, and HRA were reported to be “fairly” or “very” uncomfortable by 9%, 35%, and 47% of men respectively. Less than half the men screened found anal Pap swab and HRA to be “acceptable” procedures. Some researchers, especially in locations with limited resources, have asked whether it is worth having the patient endure the discomfort of screening if the rate of regression of HGAIN is high, and instead to monitor and treat Stage I cancer as an alternative to aggressively treating precancerous lesions. However, taking the “let’s wait until it develops into cancer, and just treat the cancer” approach is clearly not acceptable for patients when their lives are on the line. There is no other HPV-associated pre-cancer lesion that we consciously elect not to treat.
Naomi Jay of UCSF, US showed that anal cytology (the anal Pap smear) is highly predictive in finding High-Grade Anal Intraepithelial Neoplasia (HGAIN), or the last stage of anal precancer before developing into cancer. High-risk patients who test positive for anal cytology should be referred for high resolution anoscopy (HRA) follow-up.
HPV Prevalence
Every year, new studies come out showing the ubiquity of HPV – the more we learn about the disease, the more we realize it is everywhere. The more we also realize that there will continue to be a large number of people diagnosed with HPV-associated disease for years to come.
Researcher Vitaly Smelov found that HPV infection is common in the anal canal of men-who-have-sex-with-women (MSW). His study cohort examined Russian men with an average age of 31.6 years. Overall anal HPV prevalence was 16.1% in HIV negative Russian MSW. Smelov also collected human DNA samples from 17 airport bathrooms across Eurasia and the Middle East. 94% of the collected samples contained human DNA, and 29% of those samples tested positive for HPV.
Gypsyamber D’Souza showed that oral HPV prevalence is higher among men than women and is positively associated with oral sex frequency. One possible explanation is that cervical fluids have a higher HPV load than the penile shaft, so men may be more persistently HPV+ in the mouth due to oral sex performed on women. Oral HPV infection persistence increases with age.
Karly Louie assessed the burden of HPV-related Head & Neck Cancer (HNC) in England from 1995 to 2010 and sought to project the burden of HNC rates through 2035. Incidence of HPV-related HNCs increased significantly from 1995 to 2010 at an annual percentage change of 7.2%, whereas non-HPV related HNCs remained stable. The incidence rate for HPV-related HNCs increased by three times during this period. This figure is expected to increase by 270% and 370% in men and women, respectively, in the next 25 years.
Stina Syrjanen examined the relationship between an HPV-infected mother and her children. In the Finnish Family HPV study, 329 pregnant women were enrolled and followed up for 6 years. 331 infants were delivered. Oral HPV-detection in children varied from 8.7% to 22.8% during the mean follow-up time of 51.9 months. At delivery, nearly 23% of newborns carry oral HPV but the detection rate declines with age. HPV antibody build-up might contribute to clearance of oral HPV infections in early childhood. The researchers followed up with the children at 11-13 years old, and the children with the highest percentage of HPV were those whose mothers had abnormalities caused by HPV.
Risk Factors
One of the central challenges with HPV-associated oral cancer is discovering risk-factors that might lead to early detection of difficult-to-spot oral pre-cancer. Aimee Kreimer conducted an evaluation of HPV antibodies and risk of subsequent head & neck cancer by taking international blood samples. They identified 638 HNC and 300 esophageal cancers, as well as 1599 comparable controls from 10 countries in Europe. HPV16 antibodies were present more than 10 years prior to diagnosis of oral-pharyngeal cancers, and because of its near-absence in controls, may potentially be useful as a biomarker for early detection of oral-pharyngeal cancer.
Data at IPV 2012 reiterated the ways in which smoking weakens the immune system. Matthew B. Schabath showed that incidence of HPV infections were statistically significantly higher among current smokers, followed by former smokers, and lowest among never-smokers. Current smokers exhibited an increased risk of 26% for any type of HPV infection compared to never smokers. Esther Roura demonstrated that smoking status, duration, intensity, and pack-years were positively associated with CIN2-3/carcinoma in-situ and cervical cancer. Time since quitting smoking gradually reduced the risk of CIN2-3/CIS and ICC (showing a two-fold decreased risk in women who stopped smoking for 20 or more years compared to current smokers). Passive smoking was not statistically associated increased risk with high-grade disease. Esther Roura also showed that women who use oral contraceptives for a long time (> 15 years) are at a higher risk of developing cervical cancer, and suggested that those women be carefully monitored in cervical cancer screening programs.
Marie-Claude Boily also showed that smoking, higher number of sexual partners, older age (55+), and male gender were associated with higher oral HPV prevalence. The modes of oral transmission may include oral sex and open-mouth kissing.
HIV individuals are at higher risk for the development of anal cancer. Howard Strickler examined data from 1996 to 2009 in six US HIV/AIDS and cancer registries and found that anal cancer incidence was significantly elevated in HIV+ women and men relative to the general population. Jennifer Cameron showed that anal HPV infection and anal dysplasia are common in HIV-infected women.
Paula Gonzalez sought to study HPV persistence among women that are not considered high-risk, and found that the rates of anal and cervical HPV persistence appear comparable in young healthy women in Costa Rica. Ana Patricia Ortiz found that anal HPV infection is more common than cervical infection, and strongly associated with cervical infection. The association persisted even after adjusting for age, education, number of sexual partners, anal sex and smoking status. Considering the lower rates of anal cancer compared to cervical cancer, more research is needed.
Boily also highlighted that anal intercourse is another risk factor for HPV infection and anal cancer, and investigated trends in anal intercourse among young adults. Anal intercourse is practiced in young heterosexual populations across the world and may have increased in the last decade for females in America and Europe, although trends are under-researched.
There is a continued search for effective biomarkers, or clues, which can indicate who is at increased risk for developing HPV-associated cancer. So far, we have do not have any clear winners. Erin Siegel demonstrated that oxidant load biomarkers are not associated with risk of CSIL up to 24 months prior to lesion detection. Smoking, inflammation, and decreased antioxidant nutrients contribute to persistent HPV infection. Excess iron stores are associated with decreased clearance of incidental HPV, and elevated iron is associated with longer HPV disease. Other studies have shown iron may be associated with viral increase.
Potential Therapeutic Agents
While there were relatively few sessions on potential therapeutic agents, Mario Castellanos gave a presentation on results from a curcumin-based vaginal cream called Vacurin to treat cervical lesions. Curcumin, a component of the culinary spice turmeric, has anticancer and antiviral properties, however “its use is limited by low plasma solubility, rapid clearance and overall poor oral bioavailability.” The study, which occurred in cultures and mouse models and has not yet been tested in humans, showed that curcumin selectively eliminates HeLa, Me180, SiHa, and SW756 cells. It suppresses HPV E6, dramatically inhibits the expression of EGFR and concomitantly induces p53. According to Castellanos, “there is a worldwide need for an effective treatment against HPV, especially in developing countries with limited resources. Our compound is promising as it is derived from a low cost nutraceutical. Our curcumin-based vaginal cream effectively and preferentially eradicated HPV (+) cancer cells. Our preclinical data demonstrates a safe and novel therapy for the treatment of cervical lesions associated with HPV.”
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Overall, we welcomed the increased amount of data presented at this year’s conference on anal cancer and non-cervical HPV cancers. Although even more data and presentations of therapeutic options for HPV-related cancers is needed to improve outcomes and quality of life for people with HPV-associated malignancies, there is hope that we will continue to see HPV data mining as demonstrated by the breadth of research at this year’s conference.
Acronyms and Terms
AC = anal cancer
CIN = cervical intraepithelial neoplasia
CSIL = cervical squamous intraepithelial neoplasia
Cytology = cervical pap smear test
HGAIN - high grade anal intraepithelial neoplasia
HNC = head and neck cancer
HPV = human papillomavirus
HRA = high resolution anoscopy
PeIN = penile cancer
