HPV and Cervical Cancer: One Less or One More?

 HPV and Cervical Cancer: One Less or One More? 
There are at least 100 types of Human Papillomaviruses that have been discovered. Some types of HPV may cause genital warts while at least 30 types may go on to cause precancerous lesions, if the conditions are right. The Gardasil vaccine targets 4 types of HPV. Type 6 and 11 targets the prevention of genital warts, and type 16 and 18 targets the prevention of cervical cancer. 
 
Gardasil package insert-
http://www.fda.gov/cber/label/gardasilLB.pdf 
 
VAERS Reports-
http://www.medalerts.org/vaersdb/ (use code HPV4 under vaccine) 
 
Merck’s Licensing Trial-
http://www.fda.gov/cber/review/hpvmer060806r.pdf 
 
HPV vaccine efficiency against high grade lesions: Future II Study:  
 
http://content.nejm.org/cgi/content/full/356/19/1915 
 
We’ve heard repeatedly that Gardasil is a cancer vaccine. That it is an STI vaccine. Let’s take a look at what is known, what is not known, and what has been lost in the hype. 
 
It is known that babies and children under 7 can have HPV passed on in utero, at birth and after birth. 

 

 The current study shows that high-risk HPV DNA can be detected both in the oral and genital mucosa of infants during the first 3 years of life and that some HPV infections are persistent. HPV DNA has been mostly detected during the first year of infancy, reaching the peak (21%) in oral samples at 6 months of age. This increase might have resulted from both diminished maternal HPV antibodies in infants [21] and newly acquired HPV infections. In addition to vertical transmission, HPV infections might be transmitted horizontally from other family members (e.g., via caring hands or by autoinoculation) [22–24]. The present study showed a decreasing rate of carriage of high-risk HPV DNA during the first year of life, but HPV DNA was still detectable in 10% of mucosal samples obtained at the 3-year follow-up visit. This finding is in line with some earlier studies [25, 26], but the percentage of positive results is lower in the present study than in a study in which the rate of detection was 45%  
 
The results of the present study showed that 36%–42% of infants acquired high-risk HPV DNA in oral or genital mucosa, and 11%–14% of HPV DNA–positive infants cleared virus during the 3-year follow-up period. Both cumulative incidence and clearance rates ran in parallel for oral and genital mucosa. (1)  

 

 

 

 

 
Papillomaviruses are ubiquitous. They have been passed down for millions of years within the human population, mammals, and within all vertebrates. Therefore, it is not only a sexually transmitted infection. 

 “It’s a very tricky virus. To put it in some perspective, the virus family is 100 million years old. Papillomavirus is in, effectively, all the vertebrates: snakes, amphibians, birds, and almost all the mammals. This virus coevolved with the vertebrate kingdom, and it’s just part of what it is to be alive. It’s a virus that’s extraordinarily successful at persisting and passing itself down to the next generation not just in people, but in any animal you’ve ever seen. So it’s something we just have to deal with.” (2) 

 

 

 

 

 The FDA has known for the last four years that HPV is not the cause of cervical cancer, unless the infection is persistent, according to their own admission according to the March 7, 2007 Reclassification Petition: 

 “Based on new scientific information published in the past 15 years, it is now generally agreed that identifying and typing HPV infection does not bear a direct relationship to stratification of the risk for cervical cancer. Most acute infections caused by HPV are self-limiting [1, 4-7]. It is the persistent HPV infection that may act as a tumor promoter in cancer induction [8-11]. Identifying and typing HPV is an important tool for following patients with persistent HPV infection. Repeated sequential transient HPV infections, even when caused by “high-risk” HPVs, are characteristically not associated with high risk of developing squamous intraepithelial lesions, a precursor of cervical cancer.” (3) 

 

 

 

 

 So, it appears it is the persistent infection, not simply aquiring the virus, that determines the cancer risk. What else may increase the risk?  Third world countries, demographics, life style, nutrition, birth control pill use, and sexual activity also increase the incidences and push the percentages of cervical cancer rates upwards. The cervical cancer rate in the U.S. is 1%, while 80% occurs in third world countries. (4)  

“HPV is primarily a problem of poverty, of the underdeveloped portions of the world…but I want to emphasize that major parts of the world, for instance the Soviet Union, the Islamic world, have not even been surveyed, so in many cases we don’t know how severe it is…” (5)

 

 

 

 

 The American Cancer Society provides a detailed list of risk factors with explanations as to why each of these factors increases the risk. It can be viewed at:  

http://www.cancer.org/docroot/CRI/content/…al_cancer_8.asp .
 
Before a vaccine program for HPV is recommended for all young girls, or eventually boys, it is important to know all routes of transmission, the age of susceptibility, along with who is at higher risk for not clearing the infection naturally. 


  
Infection with high-risk human papillomaviruses (HPV) is the most significant risk factor for cervical cancer and it may be possible to prevent this malignancy by immunisation. Before immunisation programmes can be designed, however, it is necessary to know the age of acquisition and all routes of infection for these viruses. Sexual transmission is well documented and vertical transmission has also been demonstrated, although the frequency of transmission remains controversial. We previously showed that vertical transmission frequently results in persistent infection, and now present data on the prevalence of HPV-16 DNA (the most prevalent high-risk HPV type) in healthy children. Buccal samples from 267 healthy children aged 3-11 years were tested for HPV DNA by generic PCR (MY09/MY11), and a HPV-16 specific nested PCR. Reverse transcriptase (RT)-PCR was used to determine the prevalence of transcriptionally active HPV-16 infection in a subset of children. HPV-16 DNA was detected by nested PCR in 138 of 267 (51.7%) samples, whereas HPV DNA was detected in only 45 (16.8%) specimens by generic PCR, that has a lower analytical sensitivity. There were no significant differences in prevalence according to age or sex. Early region mRNA was detected by RT-PCR in six (11.3%) of 53 HPV-16 E5 DNA positive samples. HPV-16 E5 DNA sequences from 10 children confirmed the identity of the sequences detected and identified 13 HPV-16 variants. (6) 

 

  
Since HPV is not a threat to most young girls or women of any age and HPV infection can be detected with pap smear screening, along with the majority of women who will clear the virus naturally, then who does benefit from the vaccine? Logically, you would assume the high risk population. And you may be asking yourself, “Why vaccinate young girls?” Let’s take a look at the four safety and effectiveness quadrants: 
 
Quadrant I: Non-Sexually Active  
No Gardasil vaccine  
 
Quadrant II: Non-Sexually Active 
Receives Gardasil vaccine  
 
Quadrant III: Sexually Active 
No Gardasil vaccine  
 
Quadrant IV: Sexually Active 
Receives Gardasil vaccine 
 
 
Now let’s look at the Likely Outcomes of each quadrant: 
 
Quadrant I Outcome: No risk of cervical cancer 
Quadrant II Outcome: No medical benefit of the vaccine 
Quadrant III Outcome: HPV presence is self-limiting and will not lead to cervical cancer 
Quadrant IV Outcome: 44.6% increase risk of precancerous lesions. No reduction in cancer risk 

 
If you are thinking there must be a typo in Quadrant IV Outcomes, it isn’t. That does indeed say a 44.6% INCREASE risk of precancerous lesions and no reduction in cancer risk, for those who are sexually active and receives the Gardasil vaccine. Gardasil has the potential to increase the risk of precancerous cervical lesions by 44.6% in women who already carry HPV in a harmless state. According to an FDA VRBPAC document: 

 
“PCR-based HPV detection device with provision for accurate HPV genotyping is more urgently needed now because vaccination with Gardasil of the women who are already sero-positive and PCR-positive for vaccine-relevant genotypes of HPV has been found to increase the risk of developing high grade lesions by 44.6%. (7) 
 
 
“…Another thing that has not been totally talked about is this is a prophylactic vaccine. It is not a therapeutic vaccine. Anybody who has HPV today is not going to directly benefit from the vaccine. We still need to do the research to develop therapeutic vaccines and certainly in the meantime to improve screening tests for these and any other papillomaviruses. We need to develop a comprehensive network of clinics, especially in the third world. “(8) 
 
 
“…Finally, there is compelling evidence that the vaccine lacks therapeutic efficacy among women who have had prior exposure to HPV and have not cleared previous infection (PCR positive and seropositive), which represented approximately 6% of the overall study populations.” (9) 

 

 

 

 

 So, it is already known that vaccinating women with Gardasil will provide no protection if they have prior exposure to the virus, nor provide protection to those who have not cleared previous infections. However, if the vaccine is given to a woman who carries the HPV in a harmless state, it has the potential to active the virus from a harmless state into an active state, and thus cause precancerous lesions to develop. What happens if we start vaccinating American women when there is evidence that the vaccine may increase lesions by 44.6%? Cervical cancer rates will skyrocket!  
 
Therefore, the only group left that may benefit from the vaccine are young girls who have not had sex. But does Gardasil vaccine work? That remains to be seen. And there is a caveat to that however. Let’s take a look: 

“We do know that serologic titers declined steadily following the third shot, as you saw from Neal’s presentation. The response is extraordinarily robust to these particles, but we simply don’t have a timeline on what amount of serologic capability will be left after, say, 10 years or 15 years. We don’t know how long protective immunity will persist and whether it would be restimulated quickly through memory cells upon exposure to an actual infecting agent. But it may become necessary to have booster shots somewhere down the line, especially if 10- or 12-year-old children are being vaccinated, and maybe somewhere in their 20s or 30s and maybe there’s going to be a divorce and a second marriage where there’s a reexposure to other sources may require booster shots later in life. We simply don’t know.” (10)  
 
 
“At least 15 oncogenic HPV types have been identified, 4 so targeting only 2 types may not have had a great effect on overall rates of preinvasive lesions. Findings from the FUTURE II trial showed that the contribution of nonvaccine HPV types to overall grade 2 or 3 cervical intraepithelial neoplasia or adenocarcinoma in situ was sizable. In contrast to a plateau in the incidence of disease related to HPV 
types 16 and 18 among vaccinated women, the overall disease incidence regardless of HPV type continued to increase, raising the possibility that other oncogenic HPV types eventually filled the biologic niche left behind after the elimination of HPV types 16 and 18.” (11)  
 
“…a cautious approach may be warranted in light of important unanswered questions about overall vaccine effectiveness, duration of protection, and adverse effects that may emerge over time.” (12) 
 
And: 
 
“…that only either two or four of the types of 46 that can infect mucosa are even included. We don’t know, but I frankly do strongly suspect that when we do eradicate or minimize the HPV 16 and 18, that their very, very close relatives will fill in. Nature abhors the vacuum and these ecological niches are going to be vacant when HPV 16 and 18 and 6 and 11 are minimized, and I’m deeply concerned that there’ll be backfill of those ecologic niches by these very, very similar types. I think it’s imperative to expand the coverage in the vaccines.  
We don’t know, however, because the studies have never been done, whether a cocktail with 14 types would be equally effective against all 14 or whether they might actually conflict with each other. We simply don’t know. We don’t suspect that there’s much cross protection of one type to any other even similar type. So far the evidence doesn’t suggest that. We also do not know if these vaccines would be effective in the context of immunodeficient diseases. Certainly HIV/AIDS stands out, but other parasitic diseases, even malnutrition or chronic illness. In a study I did, people with end-stage renal failure were reactivating their latent HPV in middle-age years, so immune capacity and capability makes a big difference. (13) 

 

 

 

 

According to the New England Journal of Medicine sited above, you will find that Gardasil has a 13% effectiveness and that serotype replacement is a concern.  
The 13-17% effectiveness is seen only for the lower grade neoplasias (the ones most likely to regress on their own) and no statistically significant effectiveness at all against actual cervical cancer.  
 
The average age for a woman to develop cervical cancer, if the conditions are right, is approximately 48. The true effectiveness or the real dangers of this vaccine will not be known for at least a decade or more. With 19 high-risk types of HPV that can cause cancer and Gardasil only targets two, what happens with the rest of them? They may very well step-in and proliferate, as noted above. 
 
If you read through the package insert provided above, you will see that the claims for effectiveness in preventing cervical cancer are based on indirect efficacy measurements. When you look at the number of subjects, the age of the subjects, and the duration of the trials, you will see that there is no proof that even one case of cervical cancer has been prevented by this vaccine.  
 
Gardasil contains 225mcg of Aluminum (amorphous aluminum hydroxyphosphate sulfate adjuvant), which is a known neurotoxin. Neither Merck nor the FDA ever disclosed how much Aluminum was used in the placebo. In the clinical trials, it appears the aluminum and saline groups were lumped together instead of a saline group alone. If you look at Table 6, page 10, it has a chart with a saline placebo group and an aluminum placebo group. Adverse Experience and Systemic Reactions in the aluminum and saline groups were combined. That can skew results as Aluminum plays a major part in side effects, and a reactive placebo can artificially increase the appearance of safety in a clinical trial. Merck nor the FDA do not reveal in public documents how many 9 to 15 year old girls were in the clinical trials either, or how many received the Hep B vaccine along with Gardasil or the aluminum placebo.  
 
 
Cervical cancer is preventable, treatable, and curable. Women who receive regular Pap smears, DNA testing for HPV, are not in the high-risk categories, or have appropriate follow-up care, don’t develop cervical cancer. It is more of a concern for women who don’t have access to good healthcare, are not getting regular Pap smears, and women who are not receiving follow-up and treatment. While HPV affects us all to some degree, cervical cancer does not. With so many unknowns and knows to date, the HPV vaccine should be carefully weighed-Does the possible small benefit of 13% effectiveness outweigh the risk? Might it be better health wise, and more cost efficient, to educate young girls on the risks of unprotected sex, condom use, regular pap screening, and what HPV is, versus a vaccine that can damage them for life?  
 
  
REFERENCES: 
 
1. Clinical Infectious Diseases, 2005. High-Risk Types of Human Papillomavirus (HPV) DNA in Oral and Genital Mucosa of Infants during Their First 3 Years of Life: Experience from the Finnish HPV Family Study.

http://www.journals.uchicago.edu/doi/full/10.1086/498114 
 
 
2. Center For American Progress. “PREVENTING HPV, EASY AS 1, 2, 3 SHOTS? ENSURING ACCESS TO THE NEW ANTI-CANCER VACCINES” (pg 23)
http://www.americanprogress.org/kf/hpv_event_transcript.pdf 
 
 
3. Reclassification Petition, March 7, 2007. (pg 7) 
http://www.fda.gov/ohrms/dockets/dockets/0…001-01-vol1.pdf 
 
4. Preparing for the introduction of HPV vaccines: policy and programme guidance for countries. WHO 2006.  
http://www.who.int/reproductive-health/pub…ccines/text.pdf 
 
 
5. Center For American Progress. “PREVENTING HPV, EASY AS 1, 2, 3 SHOTS? ENSURING ACCESS TO THE NEW ANTI-CANCER VACCINES” (pg. 13)
http://www.americanprogress.org/kf/hpv_event_transcript.pdf  
 
 
6. J. Med. Virol. 61:70-75, 2000. © 2000 Wiley-Liss, Inc. High prevalence of human papillomavirus type 16 infection among children Philip S. Rice 1 2, Christine Mant 1 2, John Cason 1 2, Jon M. Bible 1 2, Peter Muir 1 2, Barbara Kell 1 2, Jennifer M. Best 1 2 * 1Richard Dimbleby Laboratory of Cancer Virology, Department of Infection, Guy’s, King’s College, London, United Kingdom 2St. Thomas’ School of Medicine, King’s College London, St. Thomas’ Hospital, London, United Kingdom.  
http://www3.interscience.wiley.com/cgi-bin…ETRY=1&SRETRY=0 
 
7.
Reclassification Petition – Human Papillomavirus (HPV) DNA Nested Polymerase Chain 
There are at least 100 types of Human Papillomaviruses that have been discovered. Some types of HPV may cause genital warts while at least 30 types may go on to cause precancerous lesions, if the conditions are right. The Gardasil vaccine targets 4 types of HPV. Type 6 and 11 targets the prevention of genital warts, and type 16 and 18 targets the prevention of cervical cancer. 
 
Gardasil package insert-
http://www.fda.gov/cber/label/gardasilLB.pdf 
 
VAERS Reports-
http://www.medalerts.org/vaersdb/ (use code HPV4 under vaccine) 
 
Merck’s Licensing Trial-
http://www.fda.gov/cber/review/hpvmer060806r.pdf 
 
HPV vaccine efficiency against high grade lesions: Future II Study:  
 
http://content.nejm.org/cgi/content/full/356/19/1915 
 

Reaction (PCR) Detection Device (K063649 ) http://www.fda.gov/ohrms/dockets/dockets/07p0210/07p-0210-ccp0001-01-vol1.pdf

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