Introduction
Human papillomavirus and benign conditions
HPV vaccination
Future possibilities
References

Introduction

HPV is the cause of almost all cervical cancers, and vaccination against high-risk HPV cancer-inducing strains (HR-HPV) have been part of the routine vaccination programme for 12 and 13-year-old girls in the UK for 10 years. HPV infection is now recognised as an aetiology in anogenital cancers and oropharyngeal cancers.

HPV can also cause anogenital warts (condyloma acuminata) and other subtypes can cause verrucae and skin warts. HPV vaccination schedules have recently altered to include an older age group of susceptible individuals, i.e. men who have sex with men (MSM) and HIV positive men and women, at specialists’ discretion, and to include all young boys at 12-13 years old as well as girls, in routine vaccination.

Although it is too early to assess major outcomes, this seems an apt time to review current guidelines and knowledge in this developing area of global vaccination against cancers.

Human papillomavirus and benign conditions

HPV is a round double-stranded DNA virus that invades keratinocytes and inserts into the host genome. There are over 200 subtypes, and they can be simply partitioned into those which cause skin warts and verrucae, and those that infect mucosal surfaces, particularly at sites of transition zones, i.e. the junctions between two distinct types of epithelia. HPV can also be divided into low-risk (LR-HPV) and high-risk (HR-HPV) subtypes depending on their propensity to cause cancer. Once HPV has infected a cell nucleus it stimulates unlimited cell replication, if this is an oncogenic HR-HPV virus, particular oncogenes and proteins can be detected to suggest active virus.

Response and persistence of HPV infection has a genetic component, eg. an individual’s susceptibility to hand warts. More importantly, some women infected with HR-HPV do not develop cervical cancer. In HPV infection there is host activation of the “inflammasome” which triggers inflammatory cascade activation of the cell mediated immune defence system. At a molecular level this includes production of many cytokines and chemokines, e.g. activation of natural killer cell lymphocytes, proinflammatory interleukins, interferons and tumour necrosis factor. The person’s inflammasome and population polymorphisms partly determine HPV-host interaction and influences viral susceptibility, persistence or clearance and cancer progression; this is an area of active study.1 Individuals who are immunosuppressed may risk increased HPV persistence.

Hand warts are often due to LR-HPV 1, 2 and 4, and can spread across one’s own skin, through contact with someone else with a wart, and from the environment. Hand warts are frequently self-limiting in children and two-thirds of cases will clear up after 2 years, but they can persist for years, especially in adults.2 Warts can be destroyed by over-the-counter preparations, usually salicylic acid or cryotherapy. These warts can infect mucosa at times too. GPs require an index of suspicion as premalignant conditions or squamous cell skin cancers can look like warts, but harbour HR-HPV, especially in susceptible immunocompromised individuals.2

Genital warts are the most common sexually transmitted viral infections, but can unusually be transmitted to a baby at birth or occasionally from hand warts to the genital area. 90% of genital warts are due to LR-HPV 6 and 11, which is covered by the current 4-valent Gardasil vaccination programme for girls. This infection is benign, it may be asymptomatic, and it may be cleared by the patient. For some patients, though, warts may persist or be recurrent. They may occur anywhere round the vagina, perineum and rectal area, and are more common peri-anally and in the rectum in men who have sex with men (MSM). Condom use reduces infection rates. Occasionally, patients may have more than one HPV type and benign warts may be complicated by concomitant HR-HPV, causing dysplasia and risk of malignancy.3

Patients with one sexually-transmitted infection may have another and the usual GP practice is to refer to sexual health clinics for investigation and treatment. There has been a 90% reduction in first onset genital wart infections in 15-17 year-old girls between 2009- 2017, due to the national HPV vaccination programme.4

This success has added impetus to the recent decision to include boys to the HPV vaccination programme, and MSM under the age of 45 years old, via sexual health specialists. I will discuss this further below.

HPV related cancers

Cervical cancer

There were around 9 new cases of cervical cancer a day in the UK from 2013-2015 and cervical cancer accounted for 2% of all new female cancer cases in 2015.5 Just over half of cervical cancer deaths are under the age of 65 years. Since the early 1970s, cervical cancer mortality rates in the UK have reduced by 72%, and by 23% in the last decade. It is established that early diagnosis improves outcome and that cervical screening and treatment of precancerous stages CIN 2 and 3 prevents subsequent cancer. It is also established that HR-HPV is the main cause of cervical cancer in 99.7% of cases. Usually, though, women will not be infected with HR-HPV types and most women will clear the infection. Most women when tested have one subtype, but some may have multiple HPV types.

In a Brazilian study of HPV positive women with cervical lesions (to the nearest whole number) of women with single HPV types, 49% were HR-HPV 16 and 15% were HR-HPV 18 infections, with 14% having other HR-HPV types. For women with multiple HR-HPV types; HR-HPV 16 and 18 were together in 16% and with other types in another 4%, resulting in 20% of women with multiple HR-HPV infections. Less than 2% were LR-HPV types.6 In Europe, HR-HPV 16 accounts for 58% and HR-HPV 18 for 16% of cervical cancers.5 Risks of cervical cancer increase with early age of sex and increased numbers of partners, though a woman might be unlucky and contract a HR-HPV despite little sexual activity. A first degree relative with cervical cancer is a risk factor and a circumcised partner is a protective factor.5 Cervical cancer is usually a squamous cell cancer (70-80%) occurring at the transformation zone of ecto-squamous and columnar cervical endothelium on the visible cervix, but can be a cervical glandular neoplasia (10% cases), an adenocarcinoma originating from the endocervix, so harder to detect.

HPV infection is now recognised as an aetiology in anogenital cancers and oropharyngeal cancers

Cervical cytology screening

The history of the cervical smear programme follows our understanding of HR-HPV as an onco-virus. Cervical smears used to be taken using wooden spatulas and investigated for cellular abnormality, i.e. inflammation, borderline changes, mild, moderate and severe dyskaryosis of cells. At biopsy in colposcopy clinics, abnormal cells are determined as cervical intraepithelial neoplasia (CIN) 1, 2 and 3. At microscopy, actinomycosis and trichomonas vaginalis could also be reported, and smears could be performed in primary care to aid cancer-negative cervical diagnoses outside of cervical screening intervals.

This changed some years ago to liquid based cytology (LBC) using a cervical sampling brush, and subsequently reporting on the presence of HR-HPV infection. The use of LBC reduced inadequate rates, especially due to clumping of cells and other poor smear preparation significantly, from about 10% to less than 2% reporting inadequacy, resulting in quicker result turn around rates and less recalls for women due to inadequate smears. Other infections are no longer reported on and cervical cytology screening is not accepted outside of the usual screening ages and intervals. Any cervical abnormality, in symptoms or signs between or outside of the national programme, requires referral to colposcopy if suspicious of cervical malignancy or premalignancy or to gynaecology specialists if suspecting benign disease, at the discretion and time priority of the referring GP.

In 2013, England changed its cervical screening start age to 25 years and has had no increased incidence of cervical cancer in the younger age groups. This start age is now ubiquitous throughout the UK. Evidence suggests that treating cervical abnormalities in younger women is unnecessary as they will clear the HPV infection themselves in most cases, that infection with HPV is common and that treatment of the young cervix may cause more harm than benefit, especially with regard to possible premature labour7. Current screening ages and intervals for women with no cervical problems nor abnormal histories are: 25 -49 years old at 3 yearly intervals and 50-65 years old at 5 yearly intervals. As Scotland undertook cervical screening at an earlier age until 2016, researchers have demonstrated reductions in HPV virus due to vaccination at first screening from 28.9% in 2009 to 4.8% in 2015.8

GPs no longer urgently refer cervical screening abnormal tests to colposcopists; this is undertaken directly by the screening labs. In 2011 the cervical screening programme changed to detecting abnormal cells and then testing for HPV. A 2014 study9 concluded that primary detection of HPV is more sensitive for predicting cervical abnormalities (and therefore future cancer) than detection of abnormal cells in cervical screening. The UK National Screening Committee has recently recommended changing the cervical screening test to primary detection of HPV infection over the next couple of years throughout the UK. Those women requiring treatment for abnormalities will also have a test of cure for HR-HPV, and if negative can return to routine screening. Cervical vaccination should increase future negative screening outcome rates.

Other HPV cancers

HR-HPV is mainly 16 and 18 but is also 31, 39, 51, 52, 56, 58 and 59. HPV is a common infection with wide worldwide variation in prevalence rates. Finding HPV in a cancer does not necessarily mean that it is the aetiological agent, researchers look for various oncogenes and oncoproteins to prove that the HPV infection is part of carcinogenesis and not just an observer. There is therefore much controversy in this field. At present it is thought that lung cancer10 and oesophageal cancer are not caused by HPV infection. Laryngeal cancer is rarely associated with HPV according to the American Cancer Society,11 but UK Cancer Research suggests that 11% of laryngeal cancers may be associated with HPV.12

The WHO position paper 201713 states that HR-HPV 16 and 18 are associated with 85% of HPV-related head and neck cancers and 87% of anal cancers. HR-HPV 16 is the most common onco-virus type.

Table 1: HPV infection is implicated in:13

88% – Anus cancer

15-48% – Vulva cancer

78% – Vagina cancer

51% – Penis cancer

13-60% – Oropharyngeal cancer

Oropharyngeal cancer due to HR-HPV is increasing in incidence and occurs more commonly in men, more commonly in MSM and in a younger age group, who may not smoke or drink excessively. Like the other cancers, it is usually a squamous cell cancer. Tonsillar, back of the tongue and pharyngeal cancers can be difficult to detect if not visible to the GP and may present with recurrent or persistent sore throat, irritable cough or ear ache.

HPV vaccination

In 2008, England introduced a national vaccination programme using Cervarix, which vaccinates against HR-HPV 16 and 18 to prevent cervical cancer. Sex for men and women is illegal under 16 years old and sex under 13 years’ old is statutory rape. Girls aged 12-13 were targeted and had 3 IM injections of protein from the HPV virus (virus-like particle); there is no genetic material in the vaccine. Girls under 18 years old were also offered vaccination as a “catch up” group. The youngest girls are therefore now 22 years old, and not yet eligible for their first cervical screening test (25 years old).

In 2012, quadrivalent Gardasil replaced Cervarix and protects against HR-HPV 16, 18 and LR-HPV 6 and 11, which cause anogenital warts. Immunogenicity to both vaccines is so good that only two injections are now recommended.14 People over 15 years old are recommended to have the original three injection schedule (0, 1-2 and 6 months) as immune response reduces with age.

In July 2018, although boys and men benefit via herd immunity from female vaccination, the Joint Committee on Vaccination and Immunisation announced extending the HPV vaccination programme to year 8 schoolboys (12 and 13 years old) as well as girls.16 This is great news for boys, especially those who become MSM or bisexual and so are unprotected by female vaccination, and also improves protection for unvaccinated women.

In 2017, after a successful pilot scheme, Scotland and Wales extended the HPV vaccination programme to include MSM and this was approved in February 2018 for England too. MSM under 45 years old are vaccinated through sexual health, genitourinary medicine and HIV clinics. Other high-risk groups for HPV related diseases are also included, i.e. sex workers, HIV positive men and women.17

Future possibilities

In the future, it is possible that one injection of HPV vaccine may be determined as sufficient for long-term immunogenicity. Some countries use a 9-valent vaccine, Gardasil 9, which vaccinates against HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58. This helps protect against most of the outstanding 30% of HR-HPV types that are not due to HR-HPV 16 and 18. However, this effect may be diminished in public health terms because the current UK 4-valent Gardasil appears to offer some cross protection against HR-HPV subtypes 31, 33, and 45. HPV vaccination is now available in 82 countries and is effective at preventing anogenital warts (including amongst unvaccinated individuals due to herd immunity), and high grade CIN.

A study in Connecticut carried out between 2008 and 201518 found substantial reductions in high grade (CIN2+) in women aged 21-26 years old, consistent with increased HPV vaccination coverage. A Swedish study reported effectiveness of 75% in prevention of CIN2+ in women vaccinated before age 17 years old, with the vaccine more effective when given to women at a younger age.19 A recent Cochrane review of prophylactic HPV vaccination studies concluded that cervical vaccination provides a high likelihood of reducing precancer in women aged 15-25 years old, and also in older women who are HR-HPV 16 and 18 negative.20

It usually takes many years for persistent HR-HPV virus to cause cancer, and so outcome measures in cancer prevention are eagerly awaited. If successful it would be reasonable to lengthen cervical screening intervals in vaccinated individuals. It may become reasonable to extend vaccination to older women and to more immunocompromised groups.

Studies are also exploring outcomes in people who already have HR-HPV infections and CIN. In one study,21 women aged 20-45 years old were given HPV vaccination after excision treatment of their CIN2 or CIN3, and demonstrated that, compared to the control unvaccinated group who had had CIN2 or CIN3 treated, there was a significantly reduced risk of CIN recurrence. At present, there is no firm evidence for a role of HPV vaccination in the treatment of established intraepithelial neoplasia or cancer.

References

1. Crovella S, Pontillo A, Crovella S, et al.  Role of Inflammasome Genetics in Susceptibility to HPV Infection and Cervical Cancer Development Journal Of Medical Virology; 88 (9): p1646  -1651.

2. Sterling JC, Gibbs S, Haque Hussain SS, Mohd Mustapa MF, Handfield-Jones SE. British Association of Dermatologists’ guidelines for the management of cutaneous warts. 2014 at: http://www.bad.org.uk/library-media%5Cdocuments%5CWarts_2014.pdf

3. UK National Guidelines on the Management of Anogenital Warts 2015 Clinical Effectiveness Group British Association for Sexual Health and HIV  April 2015 at: https://www.bashhguidelines.org/media/1075/uk-national-guideline-on-warts-2015-final.pdf

4. Public Health England. Sexually transmitted infections and screening for chlamydia in England, 2017 Health Protection Report June 2018; 12 Number 20 (8) at: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/713944/hpr2018_AA-STIs_v5.pdf

5. Cancer Research UK. Cervical cancer statistics at: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/cervical-cancer

6. Tavares MCM, de Lima Júnior SF, Antonio VC, Coelho AVC et al. Tumor necrosis factor (TNF) alpha and interleukin (IL) 18 genes polymorphisms are correlated with susceptibility to HPV infection in patients with and without cervical intraepithelial lesion, Annals of Human Biology 2016; 43 (3): p 261- 268

7. National Services Division, National health Scotland. Cervical Screening Programme Change in Age Range and Frequency. 2016 at: https://www.nsd.scot.nhs.uk/services/screening/cervicalscreening/

8. Kavanagh K, Pollock KG, Cushieri K et al. Changes in the prevalence of human papillomavirus following a national bivalent human papillomavirus vaccination programme in Scotland: a 7 year cross-sectional study. Lancet Infect. Dis. Dec 2017; 17(12): p1293-1302

9. Kitchener H, Canfell K, Gilham C, Sargent A, Roberts C, Desai M, et al.The clinical effectiveness and cost-effectiveness of primary human papillomavirus cervical screening in England: extended follow-up of the ARTISTIC randomised trial cohort through three screening rounds. Health Technol Assess 2014;18(23)

10. Anantharaman DGheit TWaterboer T. et al. No causal association identified for human papillomavirus infections in lung cancer. Cancer Res.2014 Jul 1;74(13): p3525-34

11. American Cancer Society. Risk Factors for Laryngeal and Hypopharyngeal Cancers at: https://www.cancer.org/cancer/laryngeal-and-hypopharyngeal-cancer/causes-risks-prevention/risk-factors.html

12. Cancer Research UK. Laryngeal Cancer at: https://www.cancerresearchuk.org/about-cancer/laryngeal-cancer/risks-causes

13. World Health organization Human papillomavirus vaccines: WHO position paper, May 2017. Weekly epidemiological record. 12th May 2017; No 19: p241-269 at: http://www.who.int/immunization/policy/position_papers/hpv/en/

14. The Green Book. Human papillomavirus. Ch18a. at: https://www.gov.uk/government/publications/human-papillomavirus-hpv-the-green-book-chapter-18a

15. Complete routine immunisation schedule at: https://www.gov.uk/government/publications/the-complete-routine-immunisation-schedule

16. Joint Committee on Vaccination and Immunisation. Statement on HPV vaccination. July 2018 at: https://www.gov.uk/government/publications/jcvi-statement-extending-the-hpv-vaccination-programme-conclusions

17. Joint Committee on Vaccination and Immunisation. JCVI statement on HPV vaccination of men who have sex with men November 2015 at: https://www.gov.uk/government/publications/jcvi-statement-on-hpv-vaccination-of-men-who-have-sex-with-men

18. Niccolai LMMeek JIBrackney M et al. Declines in Human Papillomavirus (HPV)–Associated High-Grade Cervical Lesions After Introduction of HPV Vaccines in Connecticut, United States, 2008–2015 Clinical Infectious Diseases2017; 65(6): p. 884-889

19. Herweijer ESundström KPloner A et al. Quadrivalent HPV vaccine effectiveness against high-grade cervical lesions by age at vaccination: A population-based study.  International Journal of Cancer. 2016 June 15; 138 (12): p.1867-1874

20. Arbyn, M, Xu, L, Simoens, C and Martin-Hirsch, P.  Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. Cochrane Database of Systematic Reviews 2018, Issue 5

21. Woo Dae KangHo SunChoiSeok MoKim. Is vaccination with quadrivalent HPV vaccine after loop electrosurgical excision procedure effective in preventing recurrence in patients with high-grade cervical intraepithelial neoplasia (CIN2–3)? Gynecologic Oncology.2013 August; 130(2): p.264-268


Dr Jane Wilcock

Silverdale Medical Practice, Salford CCG, Assessment year lead, University of Liverpool school of medicine