Monday, May 14, 2007

Politics of the new HPV Vaccine

There is a new article in the NEJM this week about the implications of mandated HPV vaccination in the US. Texas and Virginia have mandated that girls at roughly 5th grade age be vaccinated. The Texas executive mandate has been widely talked about in the news, and this article in the New York Times illustrates some of the political battle that has occurred. Meanwhile, several states have rejected this kind of legislation, while a dozen others are currently exploring some sort of response to the new vaccine, Gardasil, recently released by Merck.

First, a little information on HPV. a great review article is "Vaccines for the Prevention of Human Papillomavirus and Associated Gynecologic Diseases: A Review" by Dr. Kevin Ault. How important is HPV in developing cervical cancer? There are several aspects to this group of viruses that can cause warts. There are over 100 of these viruses, not all of which can cause cancer. The wart that people get is a local manifestation of HPV; the skin that sheds off of that contains the virus.

HPV is a double stranded DNA virus with an icosahedral capsule around the DNA and a membrane, or envelope, around this. Some of its gene products affect the machinery of the cell, such as by inhibiting p53, a protein that regulates the cell to make sure it isn't defected when it replicates.

HPV 16 and 18 are the two most implicated in cervical cancer -- they appear to be involved in about 70% of these cancers. Interestingly, some strain of HPV is found in more than 99% of cervical cancers. It makes sense that vaccinating against something that is so closely linked epidemiologically could slow down or eliminate much of the disease.

Part of the controversy is that HPV is considered a sexually transmitted disease. Two of the other strains covered by the vaccine are HPV 6 and 11, which together cause roughly 90% of genital warts. These are unsightly, but tend to not be much of a health problem. Nonetheless, the political debate rages over whether treating this so-called std is in effect advocating for promiscuity and lax morals.

The vaccine works incredibly well, being practically 100% effective in creating antibodies against these 4 types of HPV. It brings us to the interesting ethical impasse that so many state legislatures also find themselves at: in one hand a quasi-miracle vaccine and in the other the weight of their constituency's moral demands.

One point is that HPV aims to protect the single vaccinated person, instead of the herd. This is different from other vaccines, which get spread from person to person and thereby can cause herd immunity with less effort. Also, HPV is an expensive vaccine, and the mandate is for girls between ages 11 and 12, rather young.

Some argue that introducing this at an early age suggests a mandate for sexual promiscuity. However, that has not happened with education about AIDS or pregnancy, which are more imminent dangers than cervical cancer. As the NEJM points out, it is almost as if recognizing that teenage sexual activity occurs is the same as endorsing such activity.

Compounding the concern is the fact that girls who begin sexual activity early may be those at highest risk for obtaining HPV, and of a lower socioeconomic status. As it is available today, the vaccine costs $119.75 per dose, in a series of three doses. Clearly, without a change in policy, these most at-risk populations would be among the last to benefit from the commercially available vaccine.

The issue remains controversial politically, but scientifically, it is clear that this vaccine can provide an almost instant public health benefit. The Centers for Disease Control (CDC) has voted unanimously that girls of 11-12 years receive the vaccine, and added Gardasil to the Vaccines for Children Program, which gives free vaccines to needy children.


mhatrw said...

To summarize this published medical journal article:

1. In the FUTURE I trial, GARDASIL demonstrated no clinical efficacy among the general subject population for overall reduction in the rates of grade 2 and grade 3 cervical intraepithelial neoplasia and adenocarcinoma -- the only recognized precursors to cervical cancer.

2. In the larger FUTURE II trial, GARDASIL demonstrated no clinical efficacy among the general subject population for overall reduction in the rates of grade 3 cervical intraepithelial neoplasia and adenocarcinoma -- the strongest (and many would argue only valid) precursors to cervical cancer.

3. Extrapolating from GARDASIL's very limited clinical "success" (in the FUTURE II study only) against grade 2 cervical dysplasias (40% of which regress spontaneously), 129 women would be have to be vaccinated (at a cost of about $60,000) to prevent a single grade 2 cervical dysplasia.

4. GARDASIL's protection against cancer associated HPV strains 16 and 18 appears to cause a disproportionate increase in of pre-cancerous dysplasias associated with other HPV strains associated with cervical cancer "raising the possibility that other oncogenic HPV types eventually filled the biologic niche left behind after the elimination of HPV types 16 and 18."

5. Even if look only at the FUTURE II results (in which for some reason GARDASIL performed better among the general female population), we are talking about just a 17% decrease in all high grade dysplasias -- many of which would spontaneously regress without treatment. So we would have vaccinate 129 women (at about $500 for the three shot regimen) to avoid a single, eminently treatable dysplasia. That's about $60,000 per dysplasia prevented.

This is all directly from the article linked above.

I myself would add that we currently have only 3 years of follow up to go on in terms of both GARDASIL's safety and efficacy among the 16 to 26 year female population, no data concerning its efficacy among 9 to 12 year old girls and only 18 months of follow up on less than 600 total preteen girls in terms of safety data about GARDASIL within its targeted population.

Also see : The Journal of the American Medical Association and The Wall Street Journal

It appears that the vaccinated cohort sees a 20%+ increase in high grade cervical dysplasias caused by cancer-associated HPV strains other than HPV 16 and 18. One possible explanation is that HPV 6 or HPV 11 infections are antagonistic to more dangerous HPV infections.

AMB said...
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AMB said...

**I am reposting this without some of the typos I made earlier; it was rather early the first time I wrote it**

I appreciate the time factor; we do only have a limited period of data from which to draw these conclusions, and as the WSJ and JAMA articles point out, caution may be a wise course of action. However, I will point out that this is not a medication, but rather a vaccine, and there is far less ambiguity about the mechanism and expected long-term effects than there would be with a new drug.

For your interpretations of the FUTURE trials, here is the text:

In the FUTURE I trial,5 rates of grades 1 to 3 cervical intraepithelial neoplasia or adenocarcinoma in situ per 100 person-years were 4.7 in vaccinated women and 5.9 in unvaccinated women, an efficacy of 20%. Analyses by lesion type indicate that this reduction was largely attributable to a lower rate of grade 1 cervical intraepithelial neoplasia in vaccinated women; no efficacy was demonstrable for higher-grade disease, but the trial may have lacked adequate power to detect a difference. Vaccinated women also had lower rates of external anogenital and vaginal lesions (1.3 vs. 2.1). In the larger FUTURE II trial,6 rates of grade 2 or 3 cervical intraepithelial neoplasia or adenocarcinoma in situ were 1.3 in vaccinated women and 1.5 in unvaccinated women, an efficacy of 17%. In analyses by lesion type, the efficacy appears to be significant only for grade 2 cervical intraepithelial neoplasia; no efficacy was demonstrable for grade 3 cervical intraepithelial neoplasia or adenocarcinoma in situ.

Both studies did show efficacy in the decrease of intraepithelial neoplasia and adenocarcinoma, the question though is whether that is significant. In the FUTURE I trial, the authors indicate that the failure to find significance for grade 2 and 3 neoplasias may be due to the lack of power in the study design. In statistics, this means there weren't enough people to have a significant result, and so the study should be expanded to increase the power. As the authors point out, regarding the FUTURE II results, "One factor is the apparent lack of efficacy among subjects with evidence of previous exposure to HPV types included in the vaccine." This is clearly an issue for the administration of the vaccine in the future, and something that should be researched to a greater extent.

However, the group that benefited the best were those previously unexposed, which would also be the target population of current legislation (11-12 year old girls).

The main problem remains the cost, which is $360 for the three shots. You point out that we would be spending a great deal of money for prevention of a rare outcome. However, much of what we vaccinate against is not a common outcome in the general population. Polio, for instance, only causes the paralysis that the disease is known for in roughly 1% of infections; 95% suffer a mild disease or are asymptomatic. That is similar to the 1 in 129 figure that is mentioned for Gardasil.

The interaction between HPV 6 and HPV 16 is also interesting. The paper cited is an epidemiological study using blood antigens to determine co-infections. They note that 6 may prevent 11 because they are antigenically similar, but that 16 has different surface proteins from 6 and so that mechanism of antagonism is less viable. They offer that the "antagonism between seropositivity to two papillomaviruses in cervical cancer might be at the level of the antibody response rather than on the infection itself." One might infer that the host immune response to disease is altered by a coinfection in the vaginal epithelium with another strain of HPV. Here is another area where more research into the mechanism of HPV immunity will be the most appropriate step.

There are over 30 types of HPV that are associated with cancer, and the vaccine attempts to go for the most prevalent, namely HPV 16 and 18. 31 and 45 have also been implicated, and it would make sense that these non-vaccinated strains would make up a larger proportion of disease once 16 and 18 are eliminated. That doesn't mean that these strains would be more carcinogenic than they are right now, but that carcinomas associated with vaccinated HPV strains would decrease.

Regardless, I point out that this is a vaccine, not a drug, and works against a relatively simple virus, therefore using our own immunity to mount a response; the efficacy of mounting an attack against new cases of these 4 HPV strains is excellent.

AMB said...

Also, to emphasize the importance of cervical cancer worldwide:

"It is the third most common cancer overall and the leading cause of death from cancer among women in developing countries." From the National Cervical Cancer Coalition

Clearly, an expensive vaccine is even more of a hurdle for developing countries, but the worldwide mortality is a clear incentive to expand any preventative measure.

Anonymous said...

I wrote a paper about this subject. It is interesting because the vaccine is marketed as a tool to prevent cervical cancer among women, when in reality it prevents HPV. Also, the vaccine is marketed only to women and girls, but men could recieve the vaccine as well, because men do also get HPV. Marketing the vaccine to men would increase its efficacy to prevent HPV in the general population.
In reality, the decision of certain states to make the vaccine mandatory is frivolous, and an example of incorrect priorities in public health. While HPV is the most prevalent STI, this is in part due to the large number of strains of the virus. The vaccine is highly expensive and states are finding difficulty in funding the cost of making the vaccine mandatory. This funding could be better spent on providing comprehensive sex education or in interventions to prevent cancers which are more prevalent in the population. This vaccine would be truly helpful in developing countries where HPV and cervical cancer are more serious problems, sadly however, the cost of the vaccine makes the marketing of this drug in the developing world nearly impossible.
Student, Yale EPH