FDA and HPV: when did they know -- follow up

By Cynthia A. Janak

In my article dated December 12th, 2007, I referenced the first 27 pages of the "Reclassification Petition for Human Papillomavirus (HPV) DNA, Nested Polymerase Chain Reaction (PCR) Detection" published March 7, 2007. http://www.fda.gov/ohrms/dockets/dockets/07p0210/07p-0210-ccp0001-01-vol1.pdf

What I am going to do is what I promised which is give you the information that is contained in pages 28–68. Some of what I am going to quote will be a repetition of what I published on December 12th but it is important to this issue. The new information I am going to provide will show you that Gardasil is not necessary because of the test results given in this document.

What is interesting in this next segment is that they are finding that HPV types can be influenced by geographic area. That means that you can live in one area were HPV 16 and 18 are not prevalent. So why get a vaccine that will have no bearing on whether you get cervical cancer. NONE!

HPV genotype prevalence is subject to regional variations. The petitioner found that in the New Haven area the most prevalent is HPV-16, constituting 27.2% of the total isolates (see below). This percentage is similar to those reported by others who used nested PCR/DNA sequencing for their study, e.g. . 26% in Denmark [27] and 26.2 % in Germany [28]. Digene HC2 test fails to identify 18 of the 29 HPV-16 positive cases, a failure rate of 62% in this series. This discrepancy is probably in part due to the fact that there are numerous HPV-16 sequence variants [76] that may not be all targeted by the HC2 RNA cocktail probe, but share a highly conserved region of the L1 gene that the MY09/MY11 primers amplify effectively.

HPV-56 is the second most prevalent high-risk genotype detected (8 .5%), followed by HPV-31, -18, -54, -58 and -66, sharing about the same rate of prevalence (5 .6-6.5%).

The combined number of HPV-16 and -18 cases constitutes only 32 .8% of the single HPV isolates in this series. This raises the question if a type-specific vaccine targeting HPV-16 and HPV-18 can be as effective in prevention of HPV infection among the women living in the county of New Haven, Connecticut, as in other parts of the world. A similar question has been raised by a group of investigators in Quebec, after reviewing their DNA sequencing data which show that HPV-18 seems to play a relatively minor role among the high-risk HPV infections in Canada [77] .

In this next section I want you to note that Dr. Sin Hang Lee, M.D. has identified through testing that a person's genetic make-up may play an important factor in HPV persistent infections.

...Fifty percent (50%) of the HPV-54 isolates are identified by HC2 test as high-risk HPV although it is not a target of the cocktail probe. HPV-54 has been classified as a low-risk virus based on studies in other countries [86, 88], but is found to be associated with a 40-fold increase in risk among American Indian women with CIN 2/3. Only HPV-16 has shown a higher risk than HPV-54 among this subpopulation [89] . The latter finding supports the observation that genetic make-up of a patient may have to be considered in using HPV genotyping information for the follow-up of persistent infections [90] .

(3) Summary and Explanation

Human papillomavirus (HPV) testing was introduced to compensate for the poor sensitivity and specificity of the Pap smear cytology often used as a diagnostic tool for borderline precancerous lesions [15]. The Digene Hybrid Capture 2 (HC2) test is commonly used to determine if a cervicovaginal lavage contains "high-risk" oncogenic HPV [16]. The HC2 HPV test cannot provide specific genotyping for the HPV detected and it usually requires 100,000 copies of HPV DNA for a positive reading .

Recently, it has become more widely known that consistent detection of the same high-risk genotype of HPV in a patient on multiple occasions, which may be indicative of a persistent infection, is more clinically significant than finding different high-risk HPV genotypes over a period of time . Sequential, multiple infections, even caused by different high-risk HPV genotypes, are characteristically not associated with high risk of cervical cancer development. For the development and maintenance of high-grade SIL, the risk is greatest in women positive for the same genotype of HPV on repeated testing [8-10] . High-grade SIL is often associated with a viral DNA load lower than that observed in less severely affected cells [24] . High HPV viral loads and multiple HPV infections are more common in sexually active young women in whom the HPV infection is often transient with normal cervicovaginal cytology [4-7] . In 93% of initially infected women, the same viral type is not detected upon re-examination four menstrual cycles later [20] . The median duration of positivity detectable by PCR for a specific HPV type in these young women is 168 days [21].

Check out this next paragraph. The numbers tell the tale. Here you see it is proven that Gardasil is dangerous. I have not seen any data from Merck to suggest that they did any testing in this area. I actually have read that Merck omitted any potential test subject because of a positive test for HPV. Now, this document shows that Merck did do testing in this area but has not disclosed this information to the public. Was Merck trying to slant the results to hide the real possibilities that Gardasil is hazardous and has the real possibility of increasing the rate of cervical cancer? Only a Congressional hearing can determine that.

The one thing that I want you to note here is that HPV shows no symptoms and usually goes away in time. This was taken from my last article where I quote the "National Cancer Institute." "Most HPV infections occur without any symptoms and go away without any treatment over the course of a few years" Gardasil, according to Dr. Sin Hang Lee, M.D., may cause more harm than a placebo vaccination. This tells me that your chances of getting cervical cancer is far less without the vaccine than it is with the vaccine, interesting.

The recent introduction of type-specific HPV vaccines into the populace may require genotype monitoring of the HPV infection before and after immunization to develop prevention strategy for the individual patients when concurrent infection by a vaccine relevant HPV is suspected prior to vaccination. According to the VRBPAC Background Document on GardasilTM, the HPV Quadrivalent Vaccine, presented to the FDA by Merck & Co., Inc. at the May 18, 2006 VRBPAC Meeting [14], the vaccine may cause more harm than placebo when it is administered to subjects who have already contracted the infection by HPV-6,-11,-16 or -18 . In a subset of clinical trial data, among the 156 subjects who were seropositive and PCR-positive for these so-called vaccine relevant HPV types, 31 subjects developed grade 2/3 or worse CIN lesions after receiving the vaccine while only 19 of the 137 subjects in the same subgroup developed such precancerous lesions after receiving placebo . In other words, the vaccine may increase the risk of developing high-grade dysplasia by 44 .6% in a patient if she has concurrent infection by one of the four HPV types contained in the vaccine. In addition, diseases due to other HPV types also have the potential to counter the efficacy results of GardasilTM for the HPV types contained in the vaccine, according to this document.

Therefore, a sensitive, specific and reproducible method for HPV detection and to provide material suitable for genotyping to monitor HPV infection is needed to assist the health care providers in dealing with these new developments in clinical management .

The positive rate of HPV DNA Nest PCR Detection testTM" is between 11 % and 35% in cervicovaginal lavage specimens, subjected to geographic and demographic variations . No quantitative determination of viral load is implied. Most of the positive nested PCR products can be genotyped with direct automated DNA sequencing, using the GP6+ general PCR primer as the sequencing primer . Multiple HPV infections may be encountered in 4-15% of the HPV positive cases . Repeating the test may be indicated for the PCR-positive cases in which DNA sequencing fails to produce a definitive genotyping result through BLAST analysis or multiple HPV infections are detected . The natural history of multiple HPV infections is not known . High-risk persistent HPV infection is usually associated with one single HPV genotype infection .

XII. Conclusions and summary

In conclusion, the petitioner is requesting that HPV DNA PCR detection devices be reclassified from Class III to Class II by FDA . There have been significant advances in the understanding of the natural course of HPV infection and its relationship to the development of squamous intraepithelial lesions, precancerous lesions and cancer in the uterine cervix since 1988 when the FDA assigned the Digene's Virapap HPV assay a class III status. Since the 1990's, medical science has confirmed that most of the HPV infections, even caused by the so-called "high-risk" HPVs, are self-limiting. Only persistent infection caused and maintained by certain genotypes of HPV, often with low intracellular viral load, is truly of "high risk" to the host in causing precancerous lesions of the cervix. There is a close similarity between the infection of Helicobacter pylori (H. pylori) and that of HPV. Both agents can initiate chronic inflammation that may lead to cancer in the stomach and uterine cervix, respectively . The annual deaths due to gastric cancer which is related to the infection caused by H. pylori are about 3 times the number of deaths due to cervical cancer related to infections caused by HPV in the United States .

Therefore, it is reasonable to conclude that H. pylori infection is associated with a higher level of risk than HPV infection . Logically, an in vitro diagnostic device for preventing the development of gastric cancer is of more substantial importance in preventing impairment of human health than an in vitro diagnostic device for preventing the development of cervical cancer if the provision under 21 CFR §860 .3 (c)(3) is invoked as the criteria for risk-based classification of the subject device. Since the IVDs for the diagnosis of H. pylori infection are customarily classified as class II and class I devices by the FDA, the IVDs for the diagnosis of HPV infection should not be classified as higher than class II under 21 CFR §860 .3 (c)(3) .

I want you to take note here that Dr. Sin Hang Lee, M.D. says "precancerous lesions." This means that lesions are found before they turn into cancer. If a woman gets a yearly testing the persistent HPV infection would be found. Therefore, with monitoring these lesions would be found in their precancerous state and removed before they change into cancer. Here is another reason why education in prevention is the cure, not a vaccine.

Also, Dr. Sin Hang Lee, M.D. states that gastric cancer deaths are about three times that of cervical cancer. That means if there are 3,700 deaths from cervical cancer annually, gastric cancer claims 11,100 lives. Same thing goes for heart disease which kills 300,000 women and breast cancer that takes 40,460 women annually. My question here is how is cervical cancer an epidemic? I don't see it.

The molecular technology of PCR amplification of HPV DNA followed by nucleic acid-based genotyping for following the patients with persistent HPV infection was developed and introduced into the practice of laboratory medicine after 1988. It is self-evident that the PCR based detection systems represent a newer medical technology than the Digene's Virapap test approved in1988 by the FDA . The use of an old approval order of 1988 to block the introduction of a more sensitive and more specific, thus safer and more effective 2007 PCR-based technology for HPV DNA testing by imposing unnecessary PMA requirements to the sponsors is not consistent with the "least burdensome" principles in regulating the medical device industry set forth by the FDAMA of 1997 . Therefore, reclassification of the HPV DNA PRC detection devices into Class II devices by the FDA is long overdue.

The need for an FDA-approved PCR-based HPV DNA detection device with provision to prepare positive clinical samples for genotyping is more urgent now after the GardasilTM vaccine is made available to the populace. In a document submitted to the FDA by Merck & Co ., Inc ., it is recorded that injection of the HPV vaccine, GardasilTM, into women who are sero-positive and PCR-positive for the vaccine-relevant HPV genotypes increases the risk of developing highgrade intraepithelial lesions by 44 .6%. As of to-date, there are no FDA-approved PCR-based methods for HPV genotyping on the market in spite of the fact the PCR technology has been available for about 20 years. This petitioner urges the FDA to play a leadership role to guide the device manufacturers to introduce their most sensitive and most specific PCR-based IVDs to assist the sexually active women who are still considering immunization against HPV infections without inadvertently receiving a vaccine that is not only ineffective, but may augment the risk of developing a precancerous lesion in the cervix. The first step that the FDA should take is to down-classify the HPV DNA PCR detection devices to Class II as requested by this petitioner.

The FDA has known about HPV and the importance of DNA testing for 20 years. Why do women have to wait another 20 years before there is a device that is approved to assist in the diagnosing of this cancer? We should not be forced to wait another day. The FDA needs to rethink where it stands on this issue and do what is necessary for the public good not big business.

I want you to note one section highlighted above. Dr. Sin Hang Lee, M.D. stated that the vaccine is ineffective and may increase the risk of precancerous lesions. I am going to believe this doctor over pharmaceutical profit driven Merck.

To finish I want to quote the first two paragraphs and the last paragraph of the document Position Statement, HVP Vaccines, Cervical Cancer and Women's Health http://www.womenshealthclinic.org/resources/wih/WHC_HPV_policy_statement.pdf

At first glance, the recent approval of the HPV vaccine and the subsequent federal commitment of funding to support part of a vaccination program appears to be the long-awaited panacea to cervical cancer, but closer examination reveals more questions than answers. There is a lack of reliable and transparent information, a potential misplacement of scare public resources and the possibility of negative impacts on health and on existing reproductive health services.

The recent approval of the HPV vaccine and the federal commitment to funding a vaccination program is premature. We recommend that governments re-examine their plans regarding HPV vaccination and redirect these funds toward addressing existing gaps in care and further research.

Until we know more about long-term safety and duration of effectiveness of the Gardasil HPV vaccine, as well as about how effective it actually is in reducing cervical cancer rates, health care dollars may be better spent in enhancing Pap screening programs (including Pap registries), and reaching the most marginalized populations (poor women, new immigrants, Aboriginal, rural and remote women) with Pap screening.

By Women and Health Protection and the Canadian Women's Health Network, with assistance from Judy Norsigian, Robin Barnett, Alicia Priest. January 2007. www.cwhn.ca and www.whp-apsf.ca

I know that, for the most part, this is rather boring. But, for those affected by cervical cancer in some way this is a very intense and heartfelt subject. My heart goes out to all the parents that have to make the choice about vaccination. It has to be difficult when a friend or family member suffered greatly from the cancer. My prayers are with you and your family.

This is my suggestion.

What we need here is better education into the importance or regular physicals. The importance of getting that Pap smear with follow-up tests is proving to be paramount in the early detection of the HPV virus. Finding that you have a persistent HPV virus infection can then be monitored and taken care of quickly if cancerous lesions are then diagnosed. One of the reasons for cervical cancer death is that women neglect to get regular pap smears. This is the front line of defense against cervical cancer.

The other thing is that, in today's society, having multiple partners is acceptable. This just further spreads the virus to more women and men. What we need here is better education of our youth that abstinence is a good thing and waiting until you get married shows high moral character.

My mother used to say when I was a teenager that a girl should put a dime between her knees when faced with the question "To do or not to do." I thought that was crude at the time but now it makes sense.

Considering all that I have learned about the FDA, Merck and Gardasil, we need a Congressional hearing to commence immediately. I say this because I do not want to see the death rate to go up just like with Vioxx. The only winners here are the pharmaceutical companies and, in my opinion, the pockets of the FDA. The real losers are "We The People."

May your God bless you and your family.

© Cynthia A. Janak