Leading Global Awareness Efforts for HPV

To help understand why we mounted this campaign, it might be helpful to review a few facts about HPV: HPV-related cancers include cervical, anal, oropharyngeal, vulvar, vaginal and penile cancers.  These cancers, particularly cervical cancer, are among those common cancers worldwide, and together represent 5% of the global burden of cancer.  HPV is the most common sexually transmitted virus, with more than 80% of the sexually active population acquiring an anogenital HPV infection at some point in time during their lives.  Most patients do not make the connection between HPV and anogenital cancer.  The motivation behind the campaign was to address this gap in public knowledge around HPV itself.   

There were already many campaigns focused on HPV vaccination and cervical cancer screening.  A campaign focused specifically on HPV required that we create a different sort of campaign, and allowed us to explore novel themes.  This included emphasizing how common the virus is; that “HPV affects everyone” because we all or know someone who has been infected with HPV; that this binds all of us together around the world, including both men and women, and individuals of all ages; that people can protect themselves or loved ones through vaccination or screening; and that taking these actions is an act of love. The tagline of the campaign was “Give Love, Not HPV” and our website is www.givelovenothpv.org

IPVS is the premiere professional society for scientists around the world who engage in papillomavirus research, and its members played a central role in designing the HPV vaccine and cervical cancer screening efforts.  As the society representing the most authoritative voice in HPV globally, I thought that IPVS would be the ideal entity to implement a global awareness campaign about HPV.  The campaign was a great success with educational events of different kinds held all over the world.  It was really inspiring to see the same materials in so many different languages used in so many different settings.  This was only our first year, and we plan to use the lessons learned to make next year’s campaign even better. 

One of the reasons that we undertook the campaign is because there was very little HPV education going on anywhere.  Instead, the conversation has tended to focus on prevention of HPV-related cancer.  At the earlier end of the age spectrum, the focus has been on HPV vaccination to prevent cancer.  For those beyond vaccination age, the focus has been on screening for- and treatment of cervical cancer precursors to prevent cervical cancer. There has been little effort to connect these cancer prevention efforts to the underlying cause, namely HPV.  Relatively few people in the general population understand the connection between HPV infection and HPV-related cancers such as cervical cancer or anal cancer, and few understand how common HPV is.

In part, the lack of discussion about HPV itself stems from concerns that this would require discussing difficult issues such as sexual transmission.  Some fear that this could undermine public health campaigns to convince more parents to vaccinate their children.  Others are concerned about stigma.  We in IPVS feel   the public deserves to have the information, handled as sensitively as possible.  We understood that cultural sensitivities around a sexually transmitted virus would vary considerably around the world.  Since this was a global campaign, we provided the materials to our partners in different countries in a way that allowed them to select amongst the offerings most suitable for that setting. 

The most challenging misconception is that the vaccine is unsafe.  To date, all of the data continue to show that the HPV vaccines are safe, with most of the side effects being temporary local site injection reactions.  Some of these misconceptions relate to the HPV vaccines specifically, and some are linked to a broader distrust of vaccination in general.  There are elements of the population who are opposed to vaccination regardless of the data supporting the safety of the vaccine.

The internet has also played a role in propagating misconceptions.  In some countries, concerns about a link between the HPV vaccine and unanticipated side effects go viral quickly before the link can be investigated.  This has led to interruption of vaccination programs in some countries with substantial reduction in vaccine uptake even after the misinformation has been refuted. 

A second misconception is that giving the vaccine to adolescents will make them more sexually active since they might feel that they no longer need to fear the consequences of HPV infection.  This too has been clearly refuted.  A third misconception is that HPV is a “women’s problem,” and it doesn't make sense to vaccinate males.  HPV affects both males and females, and the number of countries where both sexes are vaccinated is growing. That includes the US where HPV vaccines are on the routine vaccination schedule for both girls and boys. A fourth misconception is that females who have been vaccinated no longer need to undergo cervical Pap smear testing.  While the frequency of cervical screening may not need to be as often among vaccinated women, for now at least, ongoing screening is still recommended. 

The barriers differ quite widely depending on the health care setting.  In developed countries such as ours, vaccine availability is not the issue. Instead, there are cultural barriers with some continuing to believe that the vaccine is unsafe or unnecessary, or may cause young people to become more sexually active. 

The countries with the highest vaccine uptake are those that deliver the vaccine in a school-based setting.  Australia is one of the countries with the highest vaccine uptake in the world, reflecting public funding of vaccination for both girls and boys in a school-based setting. That is not done uniformly in the US, and in many locations around the US, vaccination depends on the primary care provider, often a family physician or pediatrician.  In this situation, vaccination rates vary with the degree to which the clinician is supportive of the program.

In many developing countries, the cost of the vaccine is the major barrier, but there are often cultural issues as well.  Another barrier, regardless of the setting, is that three injections are required for full protection if vaccination begins at age 15 years or older.  The good news is that there is now evidence that two injections at least six months apart are enough when vaccination begins before age 15. Hopefully, this will increase vaccine uptake and reduce cost.

The HPV vaccine is meant to be a preventive vaccine, i.e., it works by preventing initial infection with the HPV types in the vaccine.  If infection with those HPV types can be prevented, then cancers related to HPV should not occur. The vaccine will not help people who have already been infected with a given HPV type before they are vaccinated, and those individuals can still develop a lesion due to those types. 

The good news is that the vaccine protects against nine different HPV types, and people will still be protected against the types to which they have not been exposed prior to vaccination. So, even if they have been exposed to one or two of the types in the vaccine, they will still be protected against the other seven types. The vaccine protects against infection with the types that cause most cases of genital warts, as well as more than 90% of cervical and anal cancer.  So if a girl or boy completes the vaccination series, ideally before initiation of sexual activity, they should be at very low risk of warts or anogenital cancer.

Another area of uncertainty regards the duration of protection.  Originally, it was thought that the protection afforded by the vaccine might wane in 5-10 years and that vaccinated individuals would require at least one booster to maintain protection.  The vaccine has performed beyond expectation with no evidence of waning protection, with more than 10 years of follow-up among vaccinated women.   

Cervical cancer is one of the most common causes of cancer-related death in women worldwide, and kills about 250,000 women per year.  The incidence of HPV-associated oropharyngeal cancers and anal cancers is increasing in the general population, and anal cancer is now one of the most common cancers developing in HIV-infected individuals, particularly men who have sex with men.  The HPV vaccine prevents infection with the seven most common types that cause cervical cancer, and globally these types cause about 90% of cervical cancer.  The impact of the vaccine on cancer is not expected to be seen for at least another decade because of the time that it takes for an initial HPV infection to progress to cervical cancer.  So the effects of the vaccine to date have been seen on more proximal predictors of cervical cancer risk, namely the earlier stages of the natural history of this disease: HPV infection itself and the cancer precursor, known as high-grade squamous intraepithelial lesions (HSIL).

Since HPV vaccination was introduced in 2006, we have seen a substantially reduced prevalence of vaccine types in the cervix of vaccinated birth cohorts, large reductions in genital wart incidence  and most importantly, large reductions in the incidence of cervical HSIL.  Other cancers caused by the same HPV types that cause cervical cancer include vulvar cancer, penile cancer, vaginal cancer, anal cancer and a subset of oropharyngeal cancers.  The vaccine is approved for prevention of vulvar, vaginal and anal cancer, but it likely will prevent the other cancers on this list as well.  As with cervical cancer, more time will be needed to actually demonstrate reduction in the incidence of these cancers.  

The HPV vaccine has been one of the great public health advances for cancer prevention of the last 20 years.  Of course, another highly effective vaccine is the vaccine against hepatitis B virus for prevention of hepatocellular carcinoma.  The level of protection provided by the HPV vaccine exceeded all expectations. 

While this provides hope for other cancer vaccines, where cancers are caused by infectious agents- Kaposi’s sarcoma caused by human herpes virus 8 (HHV-8), for example, or lymphomas and nasopharyngeal cancers caused by Epstein Barr virus-, there are some unique features of HPV biology that contributed to the success of the HPV vaccine that are not necessarily translatable to the other vaccines.  One is that HPV infects only one type of cell, the epithelial cell, limiting the variety of targets that need to be interfered with.  A second is the highly immunogenic nature of the virus-like particle that is used to mimic the native HPV capsid in the vaccine.  Consisting of pentameric repeat arrays of protein, the pattern presented by these virus-like particles to the immune system is ideal for producing high titers of high-quality antibodies.  Some scientists are using this information to improve the immunogenicity of other vaccines.

Progress has been made in the development of an EBV vaccine, although it is still early, and there are discussions about developing a vaccine against HHV-8. Another emerging area of interest is therapeutic vaccines against these viruses, including HPV.  Instead of preventing initial infection, these are designed to treat people with lesions due to those viruses by stimulating a host immune response that will clear the virus-infected cells. Some progress has been made with HPV therapeutic vaccines but these are not yet ready for clinical use. 

One of the great mysteries in the HPV field is why some people who acquire HPV infection develop cancer whereas most do not.  Only a tiny proportion of the 80% of sexually active adults who acquire a genital HPV infection develop HSIL and even fewer will develop cancer.  Most people control the virus and are never aware that they had it. Some of the answer undoubtedly lies in the host immune response to HPV, and recent developments in cancer genetics are providing insight into genetic predisposition to these cancers.  Another development has been in sequencing the genomes of HPV-related cancers.  This work is still at an early stage but will likely identify molecular pathways that are important in cancer pathogenesis and hopefully identify prognostic markers and new therapeutic targets.

There is hope that the molecular signatures of these cancers will lead to better treatment that is targeted to the specific pathways operative in an individual’s tumor, an example of personalized medicine. Some of the same technologies are being used to better characterize the HPV genomes in the cancers.  Deep sequencing is being used to identify molecular variants of the HPV in the lesions, and several approaches are being used to characterize post-translational modifications of the HPV genome such as methylation.

Anal cancer is very similar biologically to cervical cancer and is preceded by anal HSIL, the anal cancer precursor. The incidence of anal cancer is unacceptably high among men who have sex with men, HIV-infected men and women, individuals who are immunocompromised for reasons other than HIV,  and women with a history of cervical or vulvar cancer. However it is not yet known if treatment of anal HSIL reduces the risk of anal cancer, similar to the way treatment of cervical HSIL is known to reduce the risk of cervical cancer. 

The ANal Cancer/HSIL Outcomes Research (ANCHOR) study is a national study led by myself and my team at UCSF and funded by NCI and the Office of AIDS Research.  The main goal of the study is to determine if treatment of anal HSIL reduces the incidence of anal cancer.  We also have the opportunity to study the molecular pathogenesis of progression from HSIL to invasive cancer, a unique opportunity since it is standard of care to treat HSIL at other anatomic sites.

The study will screen approximately 17,000 HIV-infected men and women aged 35 years or older, at more than 15 sites around the U.S., and enroll 5,058 with biopsy-proven anal HSIL. Participants will be randomized to treatment or active monitoring (1:1) and followed every 3-6 months until five years after enrollment of the last participant.  Cases of cancer will be compared between the arms. A biobank of swab, tissue and serum specimens is being established that will allow us to understand the pathways through which HSIL progresses to cancer, discover biomarkers of progression to cancer, and potentially new therapeutic targets for prevention and treatment of cancer. 

Given the extensive similarities between anal cancer and other HPV-related cancers, including cervical cancer, we believe that these results may be generalizable to these other cancers as well. The ANCHOR study is still in its early stages, having completed a little more than a third of the recruitment at this point.  We are pleased that we have excellent representation of women and medically under-served minorities in the study, no study-related serious adverse events to date, and a very high retention rate.  We have seen the development of some cancers, but it is too early to conclude anything at this point. 

One of the especially interesting characteristics of HPV research is its cross-disciplinary nature.   HPV replication and its ability to transform target cells are really interesting from a basic research point of view. HPV is a sexually transmitted agent, and brings up all of the usual issues of sexual behavior and transmission.  HPV causes cancer, and raises all of the usual oncology issues.  Now we have an effective vaccine, and there has been great improvement in cervical screening algorithms with increasing incorporation of HPV testing. 

All of these considerations make global research on HPV particularly interesting.  We are united by our common susceptibility to HPV infection.  Yet there is enormous variability around the world in some of the cultural factors that may play a role in HPV transmission including age of onset of sexual initiation and number of sexual partners.  Talking with patients and providers about anal cancer, for example, and how individuals may acquire anal HPV infection is very challenging in some locations. 

HIV infection increases the risk of developing cancers in conjunction with HPV infection, and in some places, being both HIV-infected and a man who has sex with men leads to high levels of stigma and discrimination. The same is true for many HIV-infected women. Genetic factors that determine host response and HPV molecular variants vary considerably by region.  Other factors such as the HIV prevalence in the population, smoking and nutrition status play an important role and these vary considerably around the world. 

The public health response to HPV in terms of education, vaccination and screening to prevent cervical cancer vary enormously around the world as well and tend to track the overall level of a country’s development. Many of the same considerations apply to other cancers in a global research context, but relatively few cross as many boundaries as those associated with HPV.

The combination of the HPV vaccine and improved screening are expected to lead to a substantial reduction in HPV-related cancer over the next few decades.  The World Health Organization is now calling for elimination of HPV-related cancer, and hopefully International HPV Awareness Day will contribute to that. We will see increasing efforts to improve vaccine coverage globally, and implement more cost-effective screening for cervical cancer that increasingly involves HPV testing. Immunotherapies will likely play a more prominent role in treatment of HPV-related cancers and treatment of HSIL to reduce the risk of cancers.  The same checkpoint inhibitors shown to have efficacy against a variety of cancers by potentiating anti-tumor immune response may also have activity against HPV-related cancers, and are the focus of active clinical testing. 

HPV therapeutic vaccines will continue to be developed and improved, and may be used in conjunction with checkpoint inhibitors to improve their efficacy. Should the ANCHOR Study show that treating anal HSIL reduces the risk of anal cancer, we expect that screening for and treating these lesions will become standard of care for at-risk populations. There is also a great deal of interest in developing blood and/or saliva tests that identify individuals at risk of HPV-related oropharyngeal cancer since we don’t have an oral screening test equivalent to the cervical Pap smear.  

Overall, it’s a very exciting time in the HPV research field, made all the more amazing by the fact that the role of HPV in anogenital cancer was only described for the first time in the 1980’s.  There has been an enormous amount of progress since then, greatly facilitated by strong international, interdisciplinary scientific collaborations, supported by government and private research funding, and by professional organizations including the International Papillomavirus Society.