An HPV vaccine - what it might really mean

As far as the mainstream media is concerned there is now a “100% effective” vaccine against the two strains of the human papilloma virus (HPV) that cause most cases of cervical cancer. It is not quite that simple.

Even though the trial results for the vaccine are very impressive, there are some hard and unanswered questions about how these results – obtained in strict clinical trial settings – will translate to the real world.

What’s more, the development of an HPV vaccine has become part of what is often called the United States' “culture war.” To be effective, the vaccine will need to be given universally to children before they become sexually active, and that’s not something which advocates of abstinence-only sexual health education are too happy about.

There are also wider ethical issues. Most cases of cervical cancer occur in the world’s poor countries. Will the vaccine be made available to these countries at a realistic cost?

These issues could prefigure and predict the moral and political debates which will almost certainly develop if vaccines for other sexually transmitted infections (STIs) are developed, not least HIV.

About HPV-related diseases

Over 30 different strains of HPV can be sexually transmitted and affect the genitals of both men and women. Cauliflower-like warts are the most commonly experienced consequence of infection with HPV. In most cases, the immune system clears the infection naturally, but in a small number of cases, and usually over many years, HPV can cause changes in the cells of the cervix, anus and rectum which can lead to cancer.

The two strains of HPV – types 16 and 18 - are considered particularly high-risk for the development of cancer and are present in 75% of all cases of cervical cancer. Before cancer develops, precancerous cell changes called cervical intraepithelial neoplasia (usually CIN for short)occur. The equivalent disease process for anal cancer begins with high-risk HPV infection and progresses through the three grades of precancerous lesions, known as anal intraepithelial neoplasia (AIN 1-3).

Cell changes in both the cervix and anus can be diagnosed using Pap smears.

Could a vaccine really be 100% effective at preventing cervical cancer?

Although there are currently over 50 different vaccines directed at HPV in laboratory or human trials, only two different vaccines, from Merck and GlaxoSmithKline (GSK), are likely to be approved next year at least in the United States, with Merck's Gardasil as the front-runner.

On October 7^th, the drug company Merck presented interim results from their still ongoing study into their HPV vaccine. The study involves over 12,000 women aged 16 – 23 who were equally randomised to receive the vaccine or a dummy placebo.

On the face of it, the results look very impressive. The news headlines screamed "100% effective", and apparently with some good reason. After 17 months of follow-up - but only seven months after receiving all three doses of the vaccine - no cases of high-grade pre-cancer cervical intraepithelial neoplasia (CIN 2/3) or the non-invasive cancer, adenocarcinoma in situ (AIS), were observed in women in the vaccine group who were not infected with HPV strains 16/18 at the start of the study. This compared to 21 cases in the placebo group, a difference which was statistically highly significant (p < 0.001).

However, Merck also performed a more rigorously modified intent-to-treat analysis in the women who received one dose or more and who were negative for HPV 16/18 before they received their first vaccine dose. This analysis looked at a situation more likely to be encountered in a “real-world” clinical setting. In particular, it included women who did not receive all three doses of the vaccine.

After an average of two years' follow-up, one woman in the vaccinated group developed CIN 2/CIN 3 or AIS, compared with 36 women out of 5766 in the placebo group. This meant that Merck's vaccine reduced the risk of precancerous cervical changes or non-invasive cancer by 97%, which is an impressive result, but not 100% protection.

Vaccinating children

Although Merck's results are promising - and GSK's Cervarix, which is about six months behind in terms of development, looks equally promising - so far we only know short-term data, and the trials reported upon so far have been in sexually active girls and women.

However, for a vaccine to substantially reduce the risk of the majority of sexually-acquired cervical cancers, it would need to be given to children or adolescents before their first sexual experiences, and the protective effects of the vaccine will need to last for a lifetime.

Within the first few years of sexual activity, women (and men) are likely to be infected with at least one HPV strain, and the risk continues to increase with increasing age and partner change.

And research from the United Kingdom shows that a significant minority of boys and girls are sexually active before the age of 16, many before the age of 13 (Wellings, 1994 and 2001).

In order to be most effective, both on an individual and population level, an HPV vaccine would need to be given to children rather than teenagers.

Vaccination early in life also appears to make good biological sense. Merck found that antibody response to their vaccine is stronger in 10 to 15 year-old males and females compared with 16 to 23 year-old females. Vaccinating the pre-teen ages of eleven or twelve might therefore be ideal.

The moral and political backlash

One might imagine that a vaccine that could prevent illness and death would be greeted with universal acclaim. However, a moral and political battle is now taking place in the United States because this kind of illness and death is via a sexually transmitted infection.

Some morally conservative parents together with Christian and right-wing pressure groups are voicing strong concerns, suggesting than an HPV vaccine would promote teenage sexual promiscuity. It’s an argument which wins no favour with Dr Jack Sobel, a professor of medicine and chief of infectious diseases at Wayne State University School of Medicine in Detroit. He recently told Medscape: “It is beyond belief that there has been public opposition to, and protesting against, a vaccine that will save lives. The concern of increased promiscuity is incomprehensible.”

Nevertheless, this week's Fortune magazine features a major article highlighting the debate. They quote members of powerful Christian and right-wing lobbying organisations including Tony Perkins, president of the Family Research Council, who said: "It sends the wrong message. Our concern is that this vaccine will be marketed to a segment of the population that should be getting a message about abstinence."

His views are echoed by Hal Wallis, a Dallas gynaecologist who is head of the conservative Physicians Consortium tells the magazine: "This isn't as much about morality as it is about good medicine. If you don't want to suffer these diseases, you need to abstain, and when you find a partner, stick with that partner." Leslie Unruh, of the National Abstinence Clearinghouse adds: "I personally object to vaccinating children against a disease that is 100% preventable with proper sexual behaviour."

Would they have the same objections if an to an effective preventative vaccine were developed for gonorrhoea, chlamydia, or even for HIV?

Is screening a better option?

But will the new vaccine really make any difference?

Each year, there are around 2500 new cases of cervical cancer in the UK. However, it is thought that cervical cancer screening prevents up to 3,900 cases of cervical cancer per year in the UK.

Since both Merck's and GSK's vaccines can only protect against the two high-risk strains associated with 75% of cervical cancers, at least 25% of cervical cancers would still occur if not caught via screening programmes, even if the vaccine was 100% effective for a lifetime.

Writing in November's issue of AIDS Treatment Update, two HIV/HPV specialists from London's Chelsea and Westminster Hospital suggest that the media hype over Merck's vaccine is somewhat premature.

"Current screening methods appear effective at preventing cervical cancer," write Dr Mark Bower and Dr Justin Stebbing, "and most of the 10,000 cases of cervical cancer that occur yearly in the US are usually in individuals who have 'dropped out' of the screening programme. Thus, the usefulness of this vaccine is questionable."

Screening for cervical cancer began in the UK in 1964. Screening involves a cervical (Pap) smear which women are recommended to have every three years (HIV-positive women are recommended to have annual smears). About 4.5 million women are screened annually in the UK and there has been a decline in the incidence of cervical cancer of around 40% over the last 20 years. Deaths from cervical cancer have also decreased dramatically, falling from 11.2 deaths per 100,000 women in 1950 to 3.3 in 1999.

However, not everyone accesses screening; screening cannot catch all cervical cancers, and it can also miss cancer that begins in cells that line the inside of organs cervix – adenocarcinoma – which is highly aggressive.

Will a vaccine help people already infected?

Given that HPV is the most common sexually transmitted infection in the UK, many people already infected with HPV will be asking if it the vaccine will be of any use to them.

The short answer is “no”. Current HPV vaccines are preventative, not therapeutic, therefore it is highly unlikely that the excitement over these vaccines will have much impact on the health of currently-infected individuals with HPV. Still, therapeutic HPV vaccines are also being developed to treat established HPV infections and HPV-associated cancers. If these therapeutic HPV vaccines prove as successful in patients as they have in early animal tests, HPV vaccines may one day have a role in the control of HPV infection and HPV-associated disease.

"Although the introduction of prophylactic HPV vaccines is an exciting advance in medicine," Doctors Bower and Stebbing write in November's ATU, "they are likely to be of limited application in our patient group and we await eagerly the development of an effective treatment vaccine."

However, for HIV-negative individuals, since it is now thought that infection with HPV at least doubles the risk of acquiring HIV, a preventative HPV vaccine may have some benefits for HIV prevention.

What about anal cancer?

Since HPV 16/18 are also associated with anal cancer, both Merck's and GSK's vaccines have the potential to protect men and women from developing anal cancer. Although everyone who is sexually active can be infected with anal HPV, HIV-positive gay men appear to be at the highest risk of anal HPV infection. A recent study of HIV-positive gay men in San Francisco found that 95% of them had anal HPV infection, and more than 50% had signs of precancerous lesions. The study also supported other studies that found that antiretroviral therapy is not protective against anal cancer.

In addition, sexually active HIV-positive heterosexual men and women are very likely to have anal HPV infection regardless of sexual behaviour. A French study from 2003 found that 46% of heterosexual male injection drug users who said they had never had anal sex had anal HPV infection and a US study found that about three quarters of HIV-positive women had anal HPV infection, and that anal HPV infection was more frequent than cervical HPV infection (Palefsky 2001). But although individuals with HIV, and HIV-negative gay men are more likely to have anal HPV infection, and are more likely to be diagnosed with anal cancer than the general population, none of the data from studies into HPV vaccines so far have included gay men or HIV-positive men, women or children. That will soon change. Merck is studying their vaccine in 4000 young men, including those who engage in sex between men, and the United States' National Institutes of Health is evaluating the response to Merck's vaccine in preteen HIV-positive boys and girls. GSK, however, claims it would not be cost-effective to vaccinate men, and have no plans for studies in men, or on anal cancer.

Dr Anne Szarewski, a clinical consultant at Cancer Research UK, recently told gay.com that more research is "desperately needed" into the issue of HPV and its links to anal cancer in gay men, especially those with HIV. "The whole HIV thing is interesting, because no one knows the impact the vaccine would have on HIV."

Who will get the vaccine?

In order for a vaccine to eradicate disease, it needs the widest coverage. At the moment, it appears that only young women, and possibly girls in their early adolescence, will be the first to access an HPV vaccine once it is approved in the United States.

Writing in GMHC Treatment Issues, David Gilden says: "The population most in need of the vaccine includes young people before sexual debut and those with high HIV risk. Gay and questioning teenagers are at the intersection of these criteria. Adolescents may not have the knowledge or means to obtain the vaccines on their own."However, these groups don’t seem to be the current target. Gilden adds, "company pre-approval presentations, meanwhile, already are replete with pictures of virginal, middle class young women. College students will certainly benefit from immunisation, but the public health benefits will be greatly circumscribed if availability is limited to affluent adult women. Without help in obtaining access, the younger, less empowered teens could prove the weak link in eliminating HPV and its associated malignancies."

More than 80% of deaths from cervical cancer occur in resource-limited countries, where there are no national screening programmes; India alone accounts for 30% of the world's cervical cancer mortalities. A recently-released report, Vaccine development: current status and future needs by the American Academy of Microbiology, suggests that the two vaccines are likely to be "prohibitively expensive for use in the developing world, where it is needed most."

The National Cancer Institute's, John Schiller, whose lab helped to develop both the Merck and GSK vaccines told Science magazine last April: "It's completely unacceptable if the vaccine works and the people who need it the most don't get it." He also warns that scientists in India and China may side-step patents and make generic versions of the vaccines if the Merck and GSK vaccines prove to be too expensive.

"It's naive to think that people in those countries can't do everything we can," Schiller says. "And it's more likely to get to women faster if they make it in their own country."

^{The November issue of AIDS Treatment Update will feature in-depth coverage of HPV-related disease prevention and treatment, including cervical and anal cancer, as it relates to HIV-positive individuals in the UK.}