The HPV2010 conference we just attended in Montreal, Canada, was a huge success. Every year researchers, clinicians, and government representatives gather from around the world to attend this HPV conference. Visitors share their latest findings, participate in workshops and meet others studying and working on the Papillomavirus. There was a good buzz regarding progress in research about anal cancer and AIN (anal intraepithelial neoplasia – abnormal growths) and as a young foundation in development to support the cause, we were very well received.
Anal cancer garnered the most amount of attention at this conference than any other HPV conference, according to the scientists. Dr Joel Palefsky moderated a 1.5 hour symposium on AIN (anal precancer) and Anal Cancer, which was just incredible. There was standing room only! Dr. Palefsky presented our foundation, newly named The Foundation for HPV and Anal Cancer, to the community in his opening speech and we stood up to show ourselves. We also put a poster up outside the plenary hall. Awesome visibility! We met with other community groups, members of the NIH, the President of the IPV Society, and many, many scientists. We learned about so much, including male vaccination and why it’s important, why the US lacks an effective campaign targeting the vaccination of women, prevention/screening strategies to identify potential anal cancer patients before they are sick, and some interesting findings on new approaches regarding the development of therapies for people fighting advanced, systemic cancer that could be better than chemotherapy. We have summarized below three days worth of sessions in the fields of basic science (HPV at the molecular level), clinical (the practice in the doctor’s office) and epidemiology (public health policy and statistics related to HPV.)
In the US, anal cancer is rising at a rate of 2% per year; deaths are also rising. There are 17,350 women and 7,568 men diagnosed in the United States with HPV-associated cancer every year (this is data from 1998-2003.) In Denmark, anal cancer is increasing slightly faster in women than in men. This suggests that the popular theory for why anal cancer rates are rising—better survival in the HIV+ MSM (men who have sex with men) population due to HAART (antiretroviral therapy)—needs further development because it is not telling the whole story. The increase in HPV-associated anal cancer is almost exclusively in the younger (sub-60) population. HPV causes at least 80%, although perhaps as much as 90% of anal cancer in the general population.
Anal cancer has four sub-populations with different risk profiles: HIV+ MSM, HIV- MSM, HIV+ Women, and HIV- Women. Incidence of anal cancer is highest in the HIV+ MSM population. Healthy MSW (men who have sex with women) were hardly discussed at all in context of anal cancer, even though they are in contact with healthy people currently undergoing treatment for advanced cancer. Each risk group may require a different screening protocol. For example, in HIV+ MSM, nadir CD4 count and presence of specific HPV types are important prognostic indicators of anal cancer from AIN. In fact, anal cancer has the highest CD4 correlation versus any other cancer in the HIV+ population. Given the high incidence of AIN and anal cancer in the HIV+ MSM population, the case for a massive screening roll out in this population is overwhelming. Yet there is resistance by some clinicians who cite that high rates of “spontaneous regression” (the resolution of the infection by the body without medical treatment) make prevention protocols “not cost effective.” Healthy women with a history of cervical or vaginal/vulvar disease (cancer or pre-cancer) are at greater risk for developing anal cancer.
There is a large debate on the optimal screening method to use in any population. Dr Palefsky showed that the anal pap smear in urban MSM was only 50% sensitive (in other words, missed 50% of “true positives”.) This is similar to the rates that we have seen for the cervical pap smear in predicting which women have the disease. The digital anal exam, not the digital rectal exam, is a technique used in a few clinics, although there is no data indicating how frequently the test should be used. HGAIN (high-grade anal intraepithelial neoplasia – i.e., precancerous growths) progresses to cancer on an average of 4 months. In theory then, a digital anal exam every four months might be done for some patients. Anal HPV testing is a good start, particularly to screen for High-Risk HPV types, though incidence of Anal HPV in both women and MSM is higher than cervical HPV in women. However, the lower rate of cancer in spite of this statistic suggests that the rate of spontaneous regression is much higher than in the cervix (the anus is more resilient to disease, perhaps.) Over 95% of HIV+ MSM are HPV+, so the anal HPV test in that population is basically useless. Yet in a lower risk population, like healthy women, the anal HPV test could be a better initial screen. The high resolution anoscopy is far harder to do than the colposcopy, and there are far more clinicians who need to know how to do it. However, that is the gold standard diagnosis tool available to the leading AIN clinicians at the moment.
In all of the studies presented, no one treated for HGAIN developed cancer. But what is the rate of cancer development in the untreated population? One researcher showed that 7.5% of those with HGAIN develop squamous cell carcinoma if left untreated; another showed that 9-18% of AIN2+ will progress to cancer over a 5-yr period. Once an HGAIN is identified, external lesions can be treated with chemicals or cryotherapy. Intra-anal lesions must be treated with ablation (electrocautery, laser), partial ablation (cryotherapy, topical agents), excision, or imiquimod. There may be a role for local 5-FU as well. With an infrared coagulator, the HIV- MSM population had 100% clearance after 3 treatments, but it did take almost a year to clear up.
One study showed a 22-factor increase for women who had cervical HPV to get anal HPV, whereas anal to cervical transmission is less likely (only 8.5x.) More HPV types in the cervix mean a higher likelihood of anal HPV infection. Only 35% of transmission events between the cervix and anus were observed in the population who have anal intercourse (they have not evaluated the data for fingering/sex toys/other contact), where 65% did not have anal sex. The researchers suggested site-to-site transmission of HPV between the cervix and anus is thus possible, in the absence of intercourse. Another presenter showed how women with CIN3 (high grade cervical lesions) are more likely to get anal cancer. Should we therefore be screening all women with cervical dysplasia for anal cancer, regardless of sexual behavior?
There was a very interesting symposium where epidemiologists and clinicians argued the case for male vaccination. In men, HPV prevalence is not associated with age (same at age 25 as age 55.) In heterosexual males, HPV prevalence in the anus is between 15% and 20%, and over 60% for the entire genital area. So how safe and effective is the vaccine in males? In a cohort, 598 HIV- young MSM were randomized to receive Gardasil. There was a 77.5% reduction in AIN compared with placebo. The safety profile is similar to what’s been shown in women studies. In terms of health economics, with low vaccination rates in females like there are in the US, it becomes more cost-effective to vaccinate males. Male vaccination will ensure the greatest protection for women, as it will decrease the chance that the infection is transmitted. Male vaccination for teenagers is also important as we may not know who will be MSM. Genital warts and cancer is costly, and a gender neutral approach is more equitable. We need to increase awareness and acceptability of the vaccine in the male population. An important step would be a cancer indication for males (right now, it is only approved for genital warts, even though we know it prevents HPV+ head & neck cancer.) In a US survey, only 25% of men knew that HPV can cause cancer. In heterosexual men, 63% had heard of the vaccine and only 2% thought it worked in men. In gay/bisexual men, 73% had heard of the vaccine and 29% thought it worked in men.
There are 217 HPV strains currently known. HPV infection can resolve itself or lay dormant in cells. The community needs biomarkers to distinguish different stages of cancer development and to understand whether a recurrent infection is a reactivation or reinfection. However, scientists do not have any good biomarkers available at the moment. We know that HPV16 produces the lowest anti-body response (in other words, it is better at evading the immune system than other HPVs). There is a strong case to move to HPV testing in the cervix. In the UK, 62% of women with fully invasive cancer had been screened within 5 years of diagnosis. Half of women who have the disease have a negative result on a pap smear, whereas being negative for high-risk HPV (16/18) gives you a period of protection about twice as long as a pap smear. This indicates that testing for HPV 16/18 can be a useful screening method in terms of identifying high-risk patients. The HPV test is also less expensive, although most providers do not use it effectively. Any women HPV16+ should be referred for colposcopy.
Herd immunity is immunity that occurs when the vaccination of a portion of the population provides protection to unvaccinated individuals. This means that the incidence of men with HPV infections should decrease with high vaccination rates in women. Herd immunity must be modeled into cost-benefit analysis because it increases effectiveness for the female population by about 25% once inoculation rates pass a certain threshold. There is evidence of herd immunity in Australia as early data shows declining prevalence of genital warts in males after just two years of vaccine implementation in women. There has been no change in the unvaccinated MSM population. There is good vaccine coverage in the USA for vaccines that are required for school-entry, although there is poor vaccine coverage when they are not required for school entry. The HPV vaccine is not currently required for school entry, except in DC & Virginia. Vaccine policy is essentially determined by states. The vaccine coverage is horrific in the U.S. compared to other OECD countries, with only 20% of young women receiving all three shots. The rates in other countries: UK: 88.6%; AU 64-82%; Cad: 55-85%; Mex: 60%; US: 37%. Interestingly, the vaccine is also effective in women who have already been treated for HPV disease. It reduced future disease by 53%. That means that, even if you’ve been exposed to the virus, you should still get vaccinated.
On therapeutic strategies, an area we are very interested, there was very little to talk about. This was the biggest disappointment of the conference. It seems like therapeutic vaccines (where they stimulate your immune system to recognize and attack cancer cells) is gaining traction due to the success of a prostate cancer drug, Provenge, that just hit the market. Median survival was 4 months longer on the drug, although patients were very ill/at a later stage when they received it so it’s possible that an earlier use would be more effective. Eventually, the tumor finds a way to escape this treatment, but nevertheless, it opens up the door for more involvement in HPV immunotherapy.
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