HPV, the abbreviation of Human Papilloma Virus, is most well-known as the causative agent of cervical cancer. However, one must recognise that this destructive virus can lead to more devastating consequences than one could have ever contemplated. To be honest, when I started this post, I never intended for it to be completed a week later - Slightly preoccupied with personal affairs and struggles as well as insecurities, I start to feel more like the people I serve: those ridden with illnesses. Those seeking for reprieve from their maladies. Those seeking for redemption. HPV is one of those viruses that make you rethink life - one of those that are deadly enough to cause a wide range of cancers - not only cervical cancer, but also a series of head and neck cancers and anal cancer, as well as numerous less severe disorders, such as genital warts and laryngeal diseases. In July 2018, it had been announced that both boys and girls, aged 12 to 13, would be given HPV vaccination. [1] This reinforces the message that HPV is a gender-neutral illness, whereby individuals of both genders can be afflicted. Moreover, it instils the idea that 'herd immunity', where the entire populace can be benefited in virtue of the vaccination of a segment of society [2], can be augmented by the introduction of the programme to teenage boys, who are likely to commence sexual exploration at roughly the same period of time as girls (well...at least that's what I think the general teenage population do...). The programme covers not only teenage boys and girls, but also men who have sex with men aged up to and including 45 years, where there is a higher risk of HPV and HIV transmission [3]. The vaccine will be provided when such male patients present to sexual health and HIV clinics in England. Older boys (e.g. teenagers of other ages) will not receive free vaccination (HPV) due to the purported fact that they are expected to have received herd immunity from girls who have received free HPV vaccination, where the original programme has been up and running for the past 10 years. Before we explore the efficacy of vaccination and also the possible consequences vaccination can evade us from, let's talk about the basics.
What is the difference between HIV and HPV?
Diagram showing the 4 most prevalent subtypes of HPV: serotypes 6, 11, 16 and 18, where the latter two are carcinogenic (more prone to causing cancers). Owner of diagram is unidentified - if you own this diagram and wish to be identified as the owner, please feel free to contact me.
First of all, it's important to note the differences since abbreviations can sometimes be confusing. They start off as bits and bobs of convenience in our lives, but as time rolls by, their limited efficacy is overwhelmed by their glaring inconsistencies and flaws. The long version of HIV is Human Immunodeficiency Virus, whereby the virus cooperates with the body's immune system. T cells, part of the cell-mediated immunity, where they target cells harbouring microbes, are affected primarily. T Helper cells, the dutiful messengers, are brutally murdered in large numbers while the T regulatory cells, the traitors who suppress the immune system (well, they're essential to avoid hyper-activation of one's immunity in infections in general), are upregulated. Binding between a protein expressed by T regulatory cells (CD4) and a protein (glycoprotein to be exact, where there is a glucose stuck on top; name: gp120) on the surface of HIV, enhances the survival of T regulatory cells. Patients usually die of complications. HIV-positive patients also experience higher incidence of co-infections, mostly with rarer microbes such as Pneumocytis jirovecii (a type of fungus which leads to the emergence of bilateral lung infiltrates on the Chest X-Ray; nebulised, induced sputum required for diagnosis), HPV (hey ho) and tuberculosis (I use the word 'rare', presuming that we're talking about the Western world). [4-6]
HPV (Human Papilloma Virus) is different. It attacks through a different way. While HIV attacks through blood, so that it can come into contact with the various blood cells and launch its massive intrusion into one's immunity, HPV prefers to stick to epithelial cells. One good example is the skin cells located in the epidermis, which are deemed as a subclass of epithelial cells.* HPV causes genital warts on the skin. Let's have a look at the structure of the skin.
[7] Diagram showing the layers of the skin --> epidermis, dermis and hair follicles. However, the focus here is the epidermis, which is the 'epithelial tissue' of the skin (the outermost, protective layer).
[7] - Diagram showing the 5 different layers of the epidermis of the skin (from top to bottom: stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, stratum basalis).
As we see in the diagrams posted above, they show the structure of the epidermis. As explored in the previous post about teratomas (When a tumour (or cancer) has a face), we know that stem cells are the babies of the body. They are cells that can be differentiated into whatever cell type they like, subjected to limitations depending on what type of stem cell they are. Right in the bottom, we have the stratum basalis, which is the origin of skin cells. These skin cells progressively develop and grow as they ascend the ranks. Very sad to say, with the falcon-eyed amongst you can see, the middle purple circles of the cells start to disappear - at around the stratum lucidum. Yes, that's right. The cells die. They've devoted their lives to death, forming a keratin-filled layer for protection. The skin is so thick and strong that no living microbe can penetrate through it easily. An injury is often why, as an entry point is induced, they can come in and wreak havoc.
What about HPV? HPV is one of the exceptions to the rule. They love epithelial cells for some absurd reason. They have a proclivity for cells located in the stratum basalis (henceforth known as basal cells). They creep in through the injected genetic material and start to replicate, slowly but surely. However, copy numbers remain low and HPV does not want one misstep to ruin their big plan. With the stem cells located deep in the epidermis, it's best to be quiet since those nosy T-cell guards will be able to detect them. Wrapping themselves as episomes (i.e. genetic entities separate from the skin cell DNA), they wait until the basal cells proliferate. As the cells ascend the ladder, proliferation activity increases. HPV senses the first signs of its imminent success. Proteins E6 and E7 are believed to be crucial for increasing their proliferative capacity and oncogenic properties (the ability to cause cancer). The cells over the top don't die - instead, they proliferate to a rapid extent. HPV, unlike some other viruses, don't kill their host cells (maybe because they are grateful?). At this point, the cells at the top have vast copies of HPV, having succeeded in their mission. However, they still have a card up their sleeve. Skin cells undergo a process called 'desquamation' - meaning that they are sloughed off the surface in preparation of the arrival of a second generation. In such circumstances, HPV follows the detachment and spreads to its environment. That's why, during sexual intercourse, it's very easy for HPV to spread - owing to intimate sexual contact, the epithelial cells slough off and attach to the organ in contact (for instance, if a man has genital warts, then the HPV-infected cells in the warts get desquamated and transferred to the female reproductive tract during penetration). Alternatively, HPV can also infect mature cells at upper levels of the epidermis. As mentioned above, since the upper-layer cells don't die and sacrifice themselves for the clan but continue growing, the structure of the epithelium (or epidermis as an example) is distorted. This contributes to the typical wart-like appearance of HPV-infected lesions. [8-10]
Diagram showing genital skin tags (which are associated with HPV infection) (Skin tags are a related skin disorder which involves the distortion of the epithelium). Extracted from: https://www.healthline.com/health/skin-disorders/genital-skin-tags-or-warts.
Diagram showing genital warts (Image credit: DermNet NZ)
What are the cancers that HPV can cause?
As HPV is a virus (we've established this at the start), it naturally has the potential to cause cancer due to the disruption of the human genome (genetic materials in human cells). It has also been mentioned that some proteins produced by HPV, especially E6 and E7, are capable of promoting the risk of cancer by turning off what we call 'p53 proteins', plus other mechanisms. [10] p53 gene (thus transcribed and translated into a protein) is a tumour suppressor gene, serving as one of the bodily mechanisms preventing uncontrolled cellular proliferation, which is a road to cancer.
Unsurprisingly, as HPV involves the epithelial tissues, such cancers arise from this kind of tissue. HPV is thought to be involved in 90% of all cases of cervical and anal cancers, 70% of all vaginal and vulvar cancers, as well as 60% of penile cancers. [11] According to a study published on Lancet Global Health, reflecting data and trends in the year 2018, approximately 570,000 cases of cervical cancer and 311,000 deaths occurred worldwide. The estimated age-standardised incidence (meaning that the data will not be skewed by age) is 13.1 in 100,000 women globally, where the global average age of diagnosis is 53 years. Due to disparities in wealth and national vaccination programmes, 85% of global death figures are found in low to middle income countries. It is also found that the women with HIV co-infection are six times more likely than those with HPV-only infection to have cervical cancer. Given the higher rates of HIV in the developing world, [12, 14-15] However, it is wrong to assume that such serious mortality and morbidity figures are contrived by the 'equal contributions' of all HPV subtypes. The high-risk subtypes include 16 and 18, which account for roughly 70% of all cervical cancer and precancerous lesions (also known as cervical intraepithelial neoplasias**). The low-risk subtypes, i.e. those which cause benign skin problems including warts and skin tags, include 6 and 11. [13-14]
Substantial attention has been devoted to the understanding of HPV and its role in contributing to the mechanisms underlying genital cancers. However, one must not forget its role in the head and neck region. Many areas in the head and neck, including the oral cavity and oropharynx, are covered with a type of epithelial tissue called 'stratified squamous'. This is the same type of tissue found in the ectocervix (outside the squamo-columnar junction), vagina, vulva and anus (below the pectinate line). Indeed, it is found that HPV is detected in 25% of patients with newly diagnosed or recurrent head and neck cancers (arising from squamous cells). Oropharyngeal tumours are more likely to be HPV-positive, at 57%. If we zoom in, such oropharyngeal tumours usually arise from two types of tonsils (there are three in total): lingual tonsils (those located at the back of the tongue) and palatine tonsils (those over the posterior aspect of the soft palate). The vast majority of such HPV-induced cancers involve subtype 16. [16] Furthermore, HPV is also associated with laryngeal and hypopharyngeal cancers, the most aggressive form of head and neck cancer. Around 25% of all cases of laryngeal cancer harbour HPV DNA. In terms of laryngeal cancer, it can be due to the infection of a high-risk subtype, or the malignant transformation of laryngeal papillomatosis, a benign disease induced by a low-risk subtype at the first instance. [17-18]
Image of Laryngeal Papillomatosis from laryngoscopy (extracted from: http://i1.ytimg.com/vi/kRI9AVheKdQ/maxresdefault.jpg)
Vaccination Efficacy
Since HPV causes high burden of disease globally, leading to massive numbers of deaths and accounting for high percentages in a wide variety of cancers, it is a reasonable suggestion to extend the NHS vaccination programme to include teenage boys. However, just like the news regarding the three COVID-19 vaccines (Sorry, I've zoned out for a moment there - all the figures I read from the news kept popping up in my head...95%, 97%, 90%...), we can easily be blighted by the opportunities proffered before us. We rarely go sceptical and critically assess the information we are proffered. That is understandable given the persistent effects of lockdown and our ardent desire for everything to be normal again. At this point, one would sell one's soul just to get into the festivities of Christmas and have the chance to hold a normal Christmas party like last year. First, when we talk about HPV vaccines, we're usually referring to the quadrivalent type - the one offering protection for the four subtypes we've discussed in this article: types 6, 11, 16 and 18. This helps protect people from all types of HPV-induced diseases, not just malignant ones. However, once one is jabbed, does this protection stay forever? Or will the effects of the vaccine die in the course of time?
A Lancet paper again offers us tremendously fabulous news. It is a study performed on women (16-23 years of age) from Denmark, Iceland, Norway and Sweden who received 3 doses of quadrivalent vaccines. The study then followed these participants over the course of 14 years to assess whether any cervical lesions (both cancerous and precancerous) have unfortunately arisen. Antibody protection still stays strong after more than 12 years, with seropositivity rates higher than 90% (presence of antibodies in the cohort). No incidence of cervical precancerous and cancerous lesions caused by subtypes 16/18 can be identified through the 12 years succeeding the first vaccine dose. [19] However, the sceptic me is once again on the prowl. A recent article published by the Journal of the Royal Society of Medicine cast some doubt as to the purported efficacy of such HPV vaccines. It is cautious as to whether certain trials with shorter follow-up times reflect the true efficacy of the vaccine, since the antibodies take ages to develop. Moreover, the screening time is a significant issue. In general, 36 months are deemed to be the normal screening period. However, amidst such trials, cervical cell sampling and testing takes place every 6-12 months. More insignificant lesions (i.e. lesions that won't progress to cancer) are diagnosed. It is also not known whether these lesions will regress spontaneously or persist due to the short screening periods. More paramountly, studies can also have focused on the wrong outcomes. Instead of reporting the rates of occurrence of serious lesions (i.e. those which have high propensity of developing cancers), the focus might be cast on insignificant lesions. [20] Even so, such criticisms do not seem to apply to the Lancet study owing to the long follow-up period and the reported 100% vaccine efficacy against high-grade cancerous and precancerous cervical lesions. Nonetheless, a significant limitation of that study is the geographical coverage. Only women from 4 countries are included. These countries are also relatively racially homogenous. Hence, it remains a doubt as to whether such results can be replicated in HPV vaccination programmes in other countries.
In an Asian paper, the focus is not on a racial difference so significant that the efficacy of the vaccine is totally different from that reported. It is, instead, the high costs associated with the vaccine as well as poverty and the low school attendance which comes with it. Since many HPV vaccination programmes are implemented at school, where a country does not have policies mandating education for all children, community outreach programmes are necessary to ensure broader coverage. Cultural differences are also highlighted - the paper states that since HPV is primarily considered a sexually-transmitted infection (which, to be fair, coitus is a major transmission route), many parents are worried about the connotations of taking the vaccine. There are strong religious and cultural beliefs against vaccination, with unsubstantiated fears that the child will become more sexually promiscuous. This stresses on the need for education and promulgation, as well as debunking myths persuant to health misinformation. [21]
Gleaning from this, we also have to acknowledge that there are many more reasons behind the refusal of vaccination. It might not be because that the person is essentially an anti-vaxxer, but because the person does not know how important the vaccine is and what it actually does. Instead of accusing people refusing to get vaccinated as callous and inconsiderate, we are advised to not fall into this very trap. Be compassionate and listen to their stories. Convince rather than disparage.
HPV is a lethal virus causing myriads of life-threatening illnesses. NHS's decision to expand the net of vaccination is naturally welcomed.
*As clarification, epithelial tissues are all around us. There are four types of tissues in our body: epithelial, connective, muscular and nerve.. Epithelial cells form epithelial tissues. Other examples of epithelial cells are those along the uterine lining (including the cervical lining) and stomach lining (stomach mucosa).
**Cervical intraepithelial neoplasia does sound a mouthful - no worries, we can break it down. 'Cervical' is the adjective describing the location of the lesion. 'Intraepithelial' refers to the fact that the lesion is sandwiched within the epithelium, which is understandable since as mentioned, HPV proliferates in the cells when they are growing. Taking the epidermis as an example, the cells grow as they ascend the ranks. So does HPV. Neoplasia is a trickier word. In terms of carcinogenesis, there are many stages. At first, there might only be proliferation. Cells increase in number. However, when this is uncontrolled, these cells also show different morphological changes. This is due to the acquisition of numerous (progressively) genetic changes. Proliferation is followed by metaplasia, then dysplasia. Neoplasia is the next stage, a term including both benign and malignant tumours.
[1] HPV vaccine overview. NHS. (2020). Retrieved 27 November 2020, from https://www.nhs.uk/conditions/vaccinations/hpv-human-papillomavirus-vaccine/#:~:text=In%20July%202018%2C%20it%20was,UK%20health%20departments%20on%20immunisation.
[2] Chaturvedi AK, Graubard BI, Broutian T, et al. (2019). Prevalence of Oral HPV Infection in Unvaccinated Men and Women in the United States, 2009-2016. JAMA. 322(10):977–979. doi:10.1001/jama.2019.10508.
[3] Quinn R, Salvatierra J, Solari V, Calderon M, Ton TG, Zunt JR. (2012). Human papillomavirus infection in men who have sex with men in Lima, Peru. AIDS research and human retroviruses, 28(12), 1734–1738. https://doi.org/10.1089/AID.2011.0307.
[4] Naif HM. (2013). Pathogenesis of HIV Infection. Infectious disease reports, 5(Suppl 1), e6. https://doi.org/10.4081/idr.2013.s1.e6.
[5] Kleinman AJ, Sivanandham R, Pandrea I, Chougnet CA, Apetrei C. (2018). Regulatory T Cells As Potential Targets for HIV Cure Research. Frontiers in immunology, 9, 734. https://doi.org/10.3389/fimmu.2018.00734.
[6] Huang L, Cattamanchi A, Davis JL, et al. International HIV-associated Opportunistic Pneumonias (IHOP) Study, & Lung HIV Study (2011). HIV-associated Pneumocystis pneumonia. Proceedings of the American Thoracic Society, 8(3), 294–300. https://doi.org/10.1513/pats.201009-062WR.
[7] Biga L, Dawson S, Harwell A, et al. (2020). 5.1 Layers of the Skin. Open Oregon State University Education. Retrieved 27 November 2020, from https://open.oregonstate.education/aandp/chapter/5-1-layers-of-the-skin/.
[8] Longworth MS, Laimins LA. (2004). Pathogenesis of human papillomaviruses in differentiating epithelia. Microbiology and molecular biology reviews : MMBR, 68(2), 362–372. https://doi.org/10.1128/MMBR.68.2.362-372.2004.
[9] White E. (2019). Manipulation of Epithelial Differentiation by HPV Oncoproteins. Viruses, 11(4), 369. https://doi.org/10.3390/v11040369.
[10] Yim EK, Park JS. (2005). The role of HPV E6 and E7 oncoproteins in HPV-associated cervical carcinogenesis. Cancer research and treatment : official journal of Korean Cancer Association, 37(6), 319–324. https://doi.org/10.4143/crt.2005.37.6.319.
[11] HPV-Associated Cancer Statistics. CDC. (2020). Retrieved 28 November 2020, from https://www.cdc.gov/cancer/hpv/statistics/.
[12] Arbyn M, Weiderpass E, Bruni L, et al. (2020). Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. The Lancet Global Health, 8(2), e191-e203. https://doi.org/10.1016/s2214-109x(19)30482-6.
[13] Burd EM. (2003). Human papillomavirus and cervical cancer. Clinical microbiology reviews, 16(1), 1–17. https://doi.org/10.1128/cmr.16.1.1-17.2003.
[14] Human papillomavirus (HPV) and cervical cancer. WHO. (2020). Retrieved 28 November 2020, from https://www.who.int/news-room/fact-sheets/detail/human-papillomavirus-(hpv)-and-cervical-cancer#:~:text=Two%20HPV%20types%20(16%20and,570%2C000%20new%20cases%20in%202018.
[15] Frank T, Carter A, Jahagirdar D, et al. (2019). Global, regional, and national incidence, prevalence, and mortality of HIV, 1980–2017, and forecasts to 2030, for 195 countries and territories: a systematic analysis for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. The Lancet HIV, 6(12), e831-e859. https://doi.org/10.1016/s2352-3018(19)30196-1.
[16] Kobayashi K, Hisamatsu K, Suzui N, Hara A, Tomita H, Miyazaki T. (2018). A Review of HPV-Related Head and Neck Cancer. Journal of clinical medicine, 7(9), 241. https://doi.org/10.3390/jcm7090241.
[17] Ribeiro El-Achkar V, Duarte A, Pinto Saggioro F, et al. (2018). Squamous Cell Carcinoma Originating from Adult Laryngeal Papillomatosis: Case Report and Review of the Literature. Case Reports In Otolaryngology, 2018, 1-5. https://doi.org/10.1155/2018/4362162.
[18] Joo YH, Lee YS, Cho KJ, et al. (2013). Characteristics and prognostic implications of high-risk HPV-associated hypopharyngeal cancers. PloS one, 8(11), e78718. https://doi.org/10.1371/journal.pone.0078718.
[19] Kjaer S, Nygård M, Sundström K, et al. (2020). Final analysis of a 14-year long-term follow-up study of the effectiveness and immunogenicity of the quadrivalent human papillomavirus vaccine in women from four nordic countries. Eclinicalmedicine, 23, 100401. https://doi.org/10.1016/j.eclinm.2020.100401.
[20] Rees C, Brhlikova P, & Pollock A. (2020). Will HPV vaccination prevent cervical cancer?. Journal Of The Royal Society Of Medicine, 113(2), 64-78. https://doi.org/10.1177/0141076819899308.
[21] Toh ZQ, Licciardi PV, Russell FM, Garland SM, Batmunkh T & Mulholland EK. (2017). Cervical Cancer Prevention Through HPV Vaccination in Low- and Middle-Income Countries in Asia. Asian Pacific journal of cancer prevention : APJCP, 18(9), 2339–2343. https://doi.org/10.22034/APJCP.2017.18.9.2339.