II. DISEASE TRANSMISSION & AT-RISK POPULATIONS

HPV is a sexually transmitted disease.  HPV can be transmitted through sexual contacts including vaginal, anal, oral sex, or intimate skin-to-skin contact with someone who has the virus.  Newborn infants can be transmitted from infected mothers at birth.  About 90% of HPV infections are latent and eliminated by the body’s immune system in two years.  The incubation period of genital warts development is 2 weeks to 8 months, most commonly 2-3 month after HPV infection.  The latency period from the first HPV exposure to the development of cervical cancer is quite long and variable, and CDC offers no statistic data on this.  HPV is very infectious and the possibility of contracting HPV at a single sexual contact with an infected person is about 60%.  Because the immune system plays an important role to protect bodies from HPV infection, people with compromised or weak immune system have a higher risk of HPV infection progressing to cervical cancer.  At-risk people for HVP infections include smokers, HIV+ individuals, younger mothers, and mothers with many children. 

PREVALENCE

The prevalence of cancer-causing HPV infection in healthy women worldwide is reported to be 10%.  Rough statistics by continent indicate 22.9% in Africa, 20.5% in Central America/Mexico, 14.3% in South America, 13.8% in Northern America, 8.3% Asia, and 6.6% in Europe in 2007. Higher rates in Africa and Central America/Mexico most likely reflects the number of at-risk populations such as HIV+ individuals, mothers of many children, and young mothers.  Although HVP is not the single cause of the cervical cancer, the association between HVP infection and cervical cancer development is as high as 70%.  This prevalence interestingly corresponds with the mortality rates of cervical cancer in each region as shown GAVI's map below.

http://www.cdc.gov/globalhealth/immunization/sis/vacs_detail.htm

http://www.nature.com/nature/journal/v488/n7413_supp/full/488S2a.html

TRANSMISSION IN DETAILS (PATHOGENESIS)

Cancer-causing HPVs typically infect in the transformation zone of the cervix following a causative sexual contact.  HPVs gain an entry into the host cell  through a micro-abrasion or small tears sometimes occur in the lining of the cervical epithelium.  HPV viral particles opportunistically invade the cervical epithelium and infect down in the basal layer cells.  The HPV infection has a long clinically latency period, and papilloma virus replicate themselves with a faithful and robust mechanism in the dividing basal cells as episomal DNA. When dividing basal cells move up and begin to differentiate, viral genome activates amplification, which is followed by synthesis and assembly of the capsid proteins, and finally release of the virus in the upper layers of the epithelium. 

http://www.nature.com/nrc/journal/v7/n1/fig_tab/nrc2050_F1.html

In normally dividing cells, two proteins p53 and pRb (retinoblastoma) carefully regulate the cell replication process. P53 is responsible for DNA repair at cell cycle checkpoint and apoptosis.  pRb is responsible for preventing replication of damaged DNA in the cell.  Upon infection, HPVs express E6 and E7 genome and produce E6 and E7 proteins that interact with and block P53 and pRb respectively. These dis-regulated cells are instructed to divide and produce multiple copies of the HPV viral DNA. As a result of this unscheduled replication, abnormal cells are accumulated and the structural appearance of the epithelial tissue is disrupted. This results in the unscheduled cell replication. 

The extension of this disorganization of host cells throughout the upper layers and to the surface of the epithelium is clinically used to classify the degree of the lesion as follows:

▪️CIN1 (cervical intraepithelial neoplasia grade 1): Abnormal cell growth in the lower 1/3 of the basil epithelium (mild dysplasia)

▪️CIN2: Abnormal cell growth extends up to 2/3 of way from the basil epithelium (moderate to marked dysplasia)

▪️CIN3: Abnormal cell growth extends more than 2/3 from the basil epithelium.  This is the immediate precursor to cervical cancer (severe dysplasia to carcinoma in situ)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785934/

http://www.cdc.gov/vaccines/pubs/surv-manual/chpt05-hpv.html

http://www.nlm.nih.gov/medlineplus/ency/article/001491.htm

TREATMENT

At this moment, there is no cure for any types of HPV infection. In terms of warts-causing HPV, warts may go away without treatment as the immune system fights off the HPV infection.  The warts can be removed by freezing (cryotherapy) or by burning with an electric current (electrocautery) or by surgical removal.

High-risk cancer-causing HPV infection is most treatable when diagnosed early.  If Pap tests (==> see below "PREVENTION") show abnormal cells, treatments to remove these cells are available based on the woman's age, the abnormality of cells, and medical history. 

               

Laser therapy: use a narrow beam of intense light to destroy or remove abnormal cells

Cryotherapy: destroy by freezing abnormal tissue developed in a small area

LEEP (loop electrosurgical excision procedure): remove tissue by an electrical current that is passed through a thin wire loop 

         Conization: remove a cone-shaped piece of tissue using a knife, a laser, or the LEEP technique.

PREVENTION

As the rule of thumb for avoiding any STD infection, abstinence is the best way to prevent the HPV infection.  Also, other common safe practices apply for this virus infection, which include: using latex condoms, avoiding sexual contact with those having multiple sex partners.  There are vaccine called GARDASIL and CERVARIX available in the United States to prevent infections by two of the most common high-risk HPVs that cause genital cancer and two of the most common low-risk genital HPVs that cause genital warts.  For these vaccines to be effective, pre-teen girls/boys should receive three dozes of vaccine over a period of six months, before they initiate any sexual activities.   The vaccine works only for the type of HPVs included, but does not work to other types of HPVs.  Also, the vaccine does not treat already infected people.  Common side effects of HPV vaccines include pain, redness, or swelling in the arm at the shot was given, fever, headache, nausea, muscle or joint pain.  This vaccine is included as mandatory vaccines only in Virginia and Washington, DC, in the United States.  According to CDC, only 38% of girls aged 13-17 years had received the complete 3-dose vaccination in 2013, and the uptake rate among boys are much lower.

http://www.cdc.gov/std/stats13/other.htm

 Whether or not vaccinated in the past, women of ages 21-65 should take a Papnicolaou smear test (Pap-smear test) routinely to see if the cervix has abnormal or pre-cancerous cells.  The Pap-smear test procedure includes collecting the small amount of cells from the cervix, examining under microscope, and determining if cells are abnormal or cancerous.  In addition to the Pap-smear test, women aged 30-65 should take a separate HPV DNA test as the incident rate of cervical cancer is higher as the age goes up.  

            

http://www.cancer.gov/types/cervical/pap-hpv-testing-fact-sheet

MY COMMENTS

The HPV has years of latent period, and the infection does not immediately manifest any apparent signs or symptoms resulting devastating cancer developments, the pathological causal association is now clearly established.  Considering that cervical cancer is the second most prevalent cancer among women worldwide, affecting 11,000 women each year in the United States, and that 70% of cervical cancer is caused by the HPV infection, I think the cancer-causing HPV infection should be prevented as much as possible with any available means including vaccines and Pap tests for the better quality of life. Common side effects are reported, but no death is immediately associated with the vaccine shot.  However, from my personal point of view regarding mandatory vaccinations, HPVs should be prevented or treated at one’s discretions, rather than a part of the government-lead health care.  Because HPVs are different from other highly contagious diseases like chicken pox, measles, etc., in terms of clinical occurrence rates, and vaccinations cannot effectively establish herd immunity because HPVs infections are too prevalent.  Also, in the long years of clinical latency, people could die from other cause of death than HPV infections.  

At the same time, though, from epidemiologist’s point of view, I think the vaccine benefits outweigh the cost of getting cancer from the cost-benefit analysis, and could improve public health in general.  Especially, vaccines are effective for HPV-induced cancer in men, because it is hard to detect until signs become apparent.  In any way, the government should not stop encouraging people to receive HPV vaccines through financial supports and education so that all people are equally informed and have an access to the vaccines.

IV. REVIEW OF A POPULAR MEDIA PIECE

VACCINE! VACCINE! VACCINE!

YES, now we have HVP vaccines!

Currently, more than 11,000 women in the U.S. are diagnosed for cervical cancer each year, and cervical cancer become the second most cancer for women next to breast cancer.  Of 70% of cervical cancer is caused by HPV infection.  Vaccines against cancer-causing HPV were developed and approved by FDA, first to Merck’s “GARDASIL” in 2006, and second to GlaxoSmithKline’s “CERVARIX” in 2007.  These vaccines work to prevent from infection by two of each major warts-causing HPVs and cancer-causing HPVs.  For the best results, pre-teen girls/boys receive three dozes of vaccine over a period of six months, before they start any sexual activities.  HPV vaccination in the United States is not mandatory in all states but Virginia and Washington DC, and a half of states (29 states) leave it as optional to individuals.  According to CDC, only 38% of girls aged 13-17 years had received the complete 3-dose vaccination in 2013, and the uptake rate among boys are much lower. 

Don’t do it?!

Earlier this month (June 2015), several online-based published articles warning the safety of HPV vaccines, citing a clinical report presented by Dr. Fangjian Guo et al of University of Texas Medical Branch, at the annual meeting of the American Association for Cancer Research.  One of them was posted on The Healthier Life entitled “Cervarix & Gardasil: Thousands Of Teenage Girls Are Affected By HPV Vaccines.” Below is the copy of the part that the online article referring to Guo’s report:

The latest research from the University of Texas has finally proven that these vaccines won’t protect any girl from the human papillomavirus (HPV) that can cause cervical cancer.

In fact, the vaccine may be helping to cause cancer instead — including some of the deadliest and most aggressive kinds.

Fangjian Guo, a researcher at the University of Texas Medical Branch, dropped a bombshell at a recent meeting of the American Association for Cancer Research.

He found that women who got the original Gardasil shot were infected with high levels of dangerous strains of HPV — the same HPV that can cause cervical cancer… the same HPV that Gardasil and Cervarix is supposed to protect our daughters from.

Guo and his research team analyzed medical records for nearly 600 women in their 20s. And those who were vaccinated with the HPV vaccines were a whopping 40 per cent more likely to be infected with strains of HPV classified as “high risk.”

That means these HPV strains may be more likely to develop into cancer. …..

Don’t allow your daughter to be another victim of this snake oil. A simple Pap smear reveals cervical cancer in the earliest stage when it’s least dangerous and highly treatable… and if you really want to protect your daughter against cervical cancer, talk to her about practicing safe sex.

Our message is clear: Don’t do it. 35,000 reported adverse effects and 200 deaths certainly tell a completely different story to what we’re being told by Big Pharma, paediatricians and the media.

I have read many other new articles criticizing or being skeptical about the effect and safety of HPV vaccines but this one looked a little different because it was referring to a report by doctors at the University of Texas Medical Branch.  I was curious if Dr. Guo really “prove these vaccines won’t protect any girl from the HPV”, and he really found that “women who got the original Gardasil shot were infected with high levels of dangerous strains of HPV”?  So I looked for his article and found its abstract.  Basically, Dr. Guo’s study was about the HPV prevalence, comparing vaccinated vs. non-vaccinated young adult women.  His finding was that HPV vaccine was effective for all vaccine types (HPVs 6, 11, 16, 18) but vaccinated women are more likely to get infected with high-risk type HVPs other than HPVs 6, 11, 16, 18, than non-vaccinated women.  Nothing in his report “prove that these vaccine won’t protect any girl.”  Apparently, the author of the website article does not even know that there are over 100 types of HVPs and not all high-risk cancer-causing HPVs are covered by these vaccine from the beginning.  What I see here is that the author intentionally or unintentionally misrepresented the contents of the report, used this authority to seemingly justify his/her argument, and jumped into a conclusion “Don’t do it.”

What to trust?

Guo’s report is not a pseudo-science, but I thought I should exercise caution when reading any articles citing scientific reports, because they may present such reports in a way to support their opinion.  

Whether we should make HPV vaccines mandatory to pre-teen children is a big question.  Cervical cancer could be effectively prevented by uptaking routine Pap-smear tests.  If so, isn’t HPV vaccine most suitable option for only boys in this country and boys/girls in rather developing countries where an access to Pap-smear tests is limited?  Considering such a high prevalence and a high incidence of the HPV infection worldwide, the herd immunity may be unlikely to be established.  Also, in the course of years of HPV's clinical latency, one could die any way from other cause of death, whether or not the person is immune to HPV.  Unlike other highly infectious diseases such as polio, chicken pox, or measles, 90% of HVP infection could disappear by the body's natural immune system, and its clinical occurrence rate is very low.  Yes, vaccines can reduce the risk of getting cervical cancer, but if the means to prevent the disease are available, should we mandate all of them using our tax?  At some point, we must draw a line what disease be considered as a thread to public health, and be prevented by the government.    

Yet, CDC and the other government organizations back the campaign to uptake HPV vaccines for girls and boys, stating 18,000 women and 8,000 men suffer preventable cancers of the cervix, anus, penis and throat.  But who knows that these government officials may be lobbied by Merck, who are also paying $4500 per seminar to supporting doctors?  

Award winning artistic Merck's poster/advertisement

Cost vs. Benefit Analysis
Whether or not the pharmaceutical companies are conducting aggressive marketing in the medical field, the adequate decision may be lead by the cost-benefit analysis from the aspect of the improvement of public health.  After all, three-time shots in life time save a lot of money compared to routine pap-smear tests from age 21 to 65 (though the Pap test is recommended to those who received vaccine in the past).  What is more, the pap test does not prevent infection but only help detecting the onset of cervical cancer only.  The Pap test cannot detect other form of HPV induced cancer in anus and throat.  If abnormal cells are found in the Pap test, the follow-up treatments will cost more and patients will experience more pain than the prick of vaccine shots.  Also, if women forget to take routine Pap tests, they may end up losing their lives from cervical cancer.  Importantly, male populations can be protected from cancers in throat, anus, and penis by the vaccine.  These cancers are usually hard to detect in men until signs become apparent.  In terms of risks, CDC discloses common side effects of redness or swelling disease  nausea, and headache, and some reported deaths among people who received an HPV vaccine, but also explains that these death cases were further studied and concluded that "there is no diagnosis that would suggest the vaccine caused the death."  Of all or in part of those benefits and risk are considered, researchers calculated the cost per quality adjusted life year gained by vaccination to 12 years old girl be $3,906 - $14,723 in 2005 US dollar.  How much it would cost if not vaccinated and hospitalized etc. is unknown, so whether we consider this dollar amount is high or not will be a matter of politics.  I am more inclined to think that overall benefits outweigh risk and cost of receiving the HPV vaccine and support that the mandatory vaccinations to all pre-teen children from the public health point of view.

As to Guo’s research, the report was interesting because of the higher prevalence of high-risk HVP in vaccinated women, I would like to see further investigations using more simple tissue models, rather than clinical settings because it is often very hard to eliminate variable factors in the clinical settings.  And if his study is proven to be more plausible, the vaccine should include the extra HPV types as well.  

“Cervarix & Gardasil: Thousands Of Teenage Girls Are Affected By HPV Vaccines”

http://www.thehealthierlife.co.uk/natural-health-articles/cancer/cervarix-gardasil-hp-vaccine-side-effects16638/

Fangjian Guo, et al. “Comparison of HPV prevalence between HPV-vaccinated and non-vaccinated young adult women (20-26 years)” presented at the annual meeting of the American Association for Cancer Research.  Apr 19, 2015.

http://www.abstractsonline.com/plan/ViewAbstract.aspx?mID=3682&sKey=7f019f73-accb-484e-becc-5ecc405f8ec5&cKey=e2313b32-d6ac-4443-ab2d-49c368ea3b89&mKey=19573a54-ae8f-4e00-9c23-bd6d62268424#

http://www.cdc.gov/vaccinesafety/Vaccines/HPV/hpv_faqs.html#seven

"Drug Makers’ Push Leads to Cancer Vaccines’ Rise"

http://www.nytimes.com/2008/08/20/health/policy/20vaccine.html?pagewanted=all

"Cost-effectiveness of Human Papillomavirus Vaccination in the United States"
http://wwwnc.cdc.gov/eid/article/14/2/07-0499_article