What are human papilloma viruses, and are all HPV types dangerous?

Immunology & Infectiology, by Dr. Annabelle Eckert

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Human papillomaviruses play an important role in the development of genital warts and the far more dangerous cervical carcinoma. They are the most common sexually transmitted viruses in the world. There are over 140 different HPV types, of which around 40 can infect the anogenital region. The genital HPV types are divided into 2 groups: Low Risk and High-Risk HPV Group (Source 1).

Love, desire, and lifestyle

Fortunately, most infections occur only with the low-risk HPV types, as the infection rate of the population is high at 80%. Mostly the lesions caused by HPV heal symptomlessly. In 10% of cases, however, HPV infection can persist. In 1-3% of patients, cervical carcinoma can develop after many years of HPV infection. In the unvaccinated 20-25 age group, 38.1% HPV was positive, around 20% even for high-risk HPV type 16 (Sources 2, 3). The lifestyle of young adults is one of the main reasons for the high prevalence of this age group (Source 4). I, therefore, think that HPV vaccination makes sense for girls and boys. HPV infection is also an important risk factor for penile cancer (Sources 5, 6). The following lists (List 1) from the S3 guideline show the most important risk factors (Sources 7).

List 1: Risk factors for the development of cervical cancer (Source 7).

Non-genetic risk factors / co-factors
- Smoking (> 15 cigarettes per day)
- Immunocompromised patients (HIV, medication)
- Early onset of sexual activity (< 14 years of age)
- Frequently changing sexual partners (> 4 in 10 years)
- other infections (e.g. genital herpes, chlamydia, gonococcus)
- Low socioeconomic status
- Poor sexual hygiene
- Long-term use of oral contraceptives > 5 years
- number of births

Genetic risk factors/cofactors
- Additional factors such as genetic variations (somatic) can affect the development of tumors. To what extent this clinical relevance is shown still unclear. They have a nearly 2-fold increased odds ratio. In comparison, the OR for HPV high-risk positivity is 150, for HPV 16 Positivity even at > 400. Nicotine abuse with an OR of 2.17 is also a higher risk. Exemplary without claim to
the following SNPs are currently the focus of research:
- HPV persistence: IRF 3, OAS3, SULF1, DUT, GTF2H4
- Progression to invasive cervical carcinoma: FANCA, IFNG, EVER1/EVER2
- cervical carcinoma specific: TP 53, CCND1
- General tumor disposition genes: ATM, NBN, CHEK 2

Do condoms actually protect against HPV?

Infection with human papillomaviruses occurs through the direct skin and mucous membrane contact during unprotected sexual intercourse. But even wearing condoms only protects in 50% of cases. The infected epithelial cells react with uncontrolled growth. Usually, benign lesions, so-called genital warts, develop in this way. After an HPV infection has been overcome, however, reinfection is possible.

Cervarix® and Gardasil®, hopeful items in the fight against cervical carcinoma

The first HPV vaccine delivered a global breakthrough in cervical cancer prevention in 2006. If all girls were vaccinated in time, 1.506 deaths could be prevented in Germany (according to data from the Robert Koch Institute 2014). Timely means in this case the age range of 9-14 years or before the start of sexual practices. As an example, so far only 40% of young girls in Germany have been vaccinated (Source 8).

Which HPV types does vaccination with the new vaccine Gardasil® protect against?

Nonavalent HPV vaccine protects against high-risk HPV types 16, 18, 31, 33, 45, 52, 58 and low-risk HPV types 6 and 11; Gardasil® provides 100% protection against grade 3 cervical intraepithelial neoplasias (Sources 9,10).

Cervical carcinoma screening - What's new?

The cancer screening guidelines for cervical cancer adopted by the German Federal Joint Committee have been modified and are to be implemented by 2018. "The aim of this reorganization is to further reduce the incidence and mortality of cervical cancer in Germany," writes the German Federal Ministry of Health, since "Germany would only occupy a mid-range position in terms of cervical cancer rates in Europe" (Source 12).

The health insurance companies inform about the innovations in cervical cancer screening by means of invitation letters and information brochures. The final version of this invitation letter dated 29 September 2017 of the Institute for Quality and Efficiency in Health Care (In German: IQWiG) can be found on IQWiG's website.

What remains, of course, is an annual clinical examination for women between 20-80 years. For the 20-35 age group, only the cytological examination is performed. A smear of the cervix will not be taken in this age group in future. A combination of a cervical smear and HPV test is intended every 3 years for women aged 35-60. The HPV test can reduce the incidence of cervical carcinoma. Patients with a CIN3 lesion of the cervix can be fished out earlier by a subsequent colposcopy. However, the new screening algorithm still does not distinguish between HPV vaccinated and unvaccinated women. Young German women also seem to still suffer from vaccination fatigue, as the vaccination rate of 30-40% is far too low (Source 13).

If you are one of the 30-40% of women vaccinated against HPV, you should still visit your gynecologist regularly, as other diseases such as vulvar carcinoma should be excluded.

HPV positivity: Does vaccination make sense?

A negative HPV test and a subsequent HPV vaccination rule out the occurrence of cervical carcinoma with 100% certainty. However, with HPV positivity and inconspicuous cytology, opinions diverge.

Despite a surgically corrective removal of the infected cells in CIN-3 lesions, recurrences may occur in 5-25% of cases (Source 13). In such cases, HPV vaccination appears to make sense because there is still a risk of reinfection with the same or a different HPV subtype after cervical conization. What do you think? What would be the right decision here? In such a case, can an HPV vaccination save the patient from the worst or has the train left for this long ago?

1. Friebe K. et al. (2017). The Value of Partial HPV Genotyping After Conization of Cervical Dysplasias. Geburtshilfe Frauenheilkd. 2017 Aug; 77(8): 887–893. 
2. Deleré Y. et al. (2014). Human Papillomavirus prevalence and probable first effects of vaccination in 20 to 25-year-old women in Germany: a population-based cross-sectional study via home-based self-sampling. BMC Infect Dis. 2014 Feb 19;14:87.
3. Meites E. et al. (2016). Use of a 2-Dose Schedule for Human Papillomavirus Vaccination — Updated Recommendations of the Advisory Committee on Immunization Practices. Am J Transplant. 2017 Mar;17(3):834-837.
4. Grandahl M. et al. (2017). Catch-up HPV vaccination status of adolescents in relation to socioeconomic factors, individual beliefs and Catch-up sexual behaviour. PLoS One. 2017 Nov 3;12(11):e0187193.
5. FitzGerald S. et al. (2017). Men's perspectives on cancer prevention behaviors associated with HPV. Psychooncology. 2017 Jul 28.
6. Stratton KL. et al. (2016). A Contemporary Review of HPV and Penile Cancer. Oncology (Williston Park).  2016 Mar;30(3):245-9.
7. http://www.awmf.org/uploads/tx_szleitlinien/032-033OLl_S3_Zervixkarzinom_2014-10.pdf
8. Poethko-Müller C. et al. (2014). Impfstatus und Determinanten der Impfung gegen humane Papillomviren (HPV) bei Mädchen in Deutschland. Ergebnisse der KiGGS-Studie – Erste Folgebefragung (KiGGS Welle 1). Bundesg
9. Huh WK. et al. (2017). Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16-26 years: a randomised, double-blind trial. Lancet. 2017; 390(10108):2143-59
10. Lehtinen M. et al. (2012).Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol. 2012 Jan; 13(1):89-99.
11. Zielinski GD. et al. (2004). HPV testing and monitoring of women after treatment of CIN 3: review of the literature and meta-analysis. Obstet Gynecol Surv. 2004;59:543–553.
12. https://www.bundesgesundheitsministerium.de/themen/praevention/nationaler-krebsplan/was-haben-wir-bisher-erreicht/ziel-2a.html
13. https://www.iqwig.de/de/projekteergebnisse/projekte/gesundheitsinformation/p15-02-einladungsschreiben-und-entscheidungshilfe-zum-zervixkarzinom-screening.6621.html

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