About human papillomavirus
Human papillomavirus (HPV) is the most common sexually transmitted virus in the world and is responsible for 99.7% of cervical carcinomas. Over 100 HPV subtypes have been identified, which are divided into low- and high-risk categories, based on the risk that infection evolves to neoplasia and cancer.
HPV infection causes epithelial abnormalities
Infectious HPV particles introduced into the genital tract upon sexual intercourse can reach the basal cells of the squamous cell epithelium of the cervix uteri through micro-lesions (von Knebel Doeberitz, M. 1994).
Once infection is initiated in the basal cell layer, the viral DNA genome is maintained as a low copy circular episome. Basal cells are the only dividing cells in the epithelium, which generate other basal cells by lateral division and keratinocytes by upward division (K. Munger et al., 2004)
In some keratinocytes in the midzone, viral replication does not occur. In this situation, the viral episome persists as either an extra-chromosomal element or becomes integrated into the host cell chromosome at a random site .(C. Popescu and J.A. DiPaolo 1989). Viral integration into the host cell DNA is believed to be a necessary step in cellular transformation in mucosal HPV. The effect is deregulated cell cycle control and uncontrolled cellular proliferation, dependent on constitutive expression of the viral oncogenes E6 and E7 (von Knebel M. et al., 1994).
Through cell division, more and more cells in the are transformed and form high grade squamous epithelial lesions that histologically correspond to Grade 2 and Grade 3 cervical intraepithelial neoplasia (CIN 2 & CIN 3). When all cells are transformed, cervical cancer is diagnosed. This cancer becomes invasive when the tumour mass disrupts the basement membrane and spreads through the body.
A diagram representing HPV disease progression is given below.
HPV testing in cervical cancer screening was recently endorsed by IARC, USA in 2009 (Castle P., 2008) and is under preparation by the EC guidelines for quality assurance in cervical cancer screening (Arbyn A. 2012).
Its implementation is revealing a large population of women infected by HPV but who have not yet developed high-grade lesion. For these women, who are informed that they are infected with high risk oncogenic viruses, there are currently no therapeutic options available.
Because preventive vaccines are not curative and surgery is only recommended for high grade dysplasia, the only possibility is “watchful waiting”. This means regular HPV and cytology tests until these patients either develop high grade lesions or spontaneously clear the virus (and low grade lesions).
This is an uncomfortable and potentially hazardous situation for otherwise healthy individuals (Wright et al., 2007a, b). Genticel’s therapeutic vaccines are designed to fill this gap in therapeutic solutions for HPV infected women prior to the development of high grade lesions:
- Genticel’s lead product, ProCervix, currently in clinical evaluation, is a bivalent vaccine for individuals infected by HPV 16 or HPV 18.
- A second product is a multivalent vaccine that will provide worldwide coverage including the 7 HPV genotypes most frequently found in cervix carcinoma.
- Castle, P.E. (2008). The potential utility of HPV genotyping in screening and clinical management. J Natl Compr Canc Netw 6, 83-95. Marc Arbyn, oral presentation – Eurogin 2012, Prague, 8 – 11 July 2012
Cervical cancer is the second most common malignancy among women worldwide, with approximately 500,000 new cases diagnosed each year, and about 275,000 deaths per year.
Annually, 11,000 new cervical cancer cases and 4,000 deaths occur in the United States, and 52,000 new cases and 27,000 deaths occur each year in Europe (including new member states from Eastern Europe (Jemal 2009; Arbyn 2007).
Epidemiological data for each country and region are available on the WHO/ICO Information Centre on HPV and Cervical Cancer developed by the World Health Organisation and the Institut català d’Oncologia.
Of about 40 of the HPV subtypes known to be sexually transmitted, approximately 15 have been established as High Risk (HR) type in epidemiologic studies (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82) (Munoz et al., 2003);(De Villers et al., 2004) ;(Cogliano et al., 2005).
HPV 16 and HPV 18, the 2 genotypes targeted by ProCervix, are the most common. They are present as either single or multiple infections in at least 70% of SCC and 84% of ADC (Castellsague et al., 2006);(Smith et al., 2007). Additional genotypes that will be targeted by Genticel’s plurivalent product account for an additional 17% of invasive cervical cancers on a global base (Bosch et al., 2008).
Other risk factors (many related to increased risk of infection) include early age at first intercourse, multiple sexual partners, early first pregnancy, smoking, oral contraceptive use, chronic inflammation, immunosuppressive conditions, and most importantly the persistence of HR oncogenic HPV (Koshiol et al., 2008).
Indeed, it has been shown that women infected with HR HPV types, who cannot clear the viral infection and become persistent HPV carriers, are more exposed to the development of neoplastic lesions. Persistence of the infection is critical for cancer progression: the longer the infection lasts, the greater is the risk (Koshiol et al., 2008).
HPV testing has been introduced in cervical cancer screening based on the developing knowledge of the central role of HPV infection in cervical oncogenesis. It is used today for triage of ASC-US and post lesion treatment.
Further HPV genotyping is more often prescribed by gynecologists to distinguish HPV 16 and/or HPV 18 infections (Inno-Lipa of Innogenetics; Linear Array of Roche; PapilloCheck of Greiner Bio-One, etc.), mainly for women over the age of 16 and, in the context of vaccination programs, despite the fact that it is not yet recommended in current main practice.
In order to refine the granularity of the screening (higher predictive value for high grade lesions), tests detecting HPV E6 and E7 messenger RNA have now been developed (e.g. Pretect HPV Proofer by Norchip/Biomerieux, and HPV Haptima by Genprobe).
Numerous large clinical studies are evaluating the utility of using HPV genotyping in cervical cancer screening. Recently, the International Agency for Research on Cancer (IARC) has endorsed the use of oncogenic HPV testing alone as one option in primary cervical cancer screening (Castle, 2008).
Recently, Sankaranarayanan et al. (Sankaranarayanan et al., 2009) have published a study in New England Journal of Medicine demonstrating for the first time the direct benefit of performing HPV testing as a primary screening in India.
This has led to a new screening paradigm and since 2011 the American Congress of Obstetricians and Gynaecologists (ACOG), the American Society for Colposcopy and Cervical Pathology (ASCCP) and the American Cancer Society (ACS) recommend that HPV and Pap smear testing are conducted simultaneously at current intervals for women aged over 30 years old (Katki HA. et al., 2011)
In Europe, policies are evolving rapidly as well: a supplement to the EU Guidelines for quality assurance in cervical cancer screening is due for publication in early 2012, which will recommend only HPV testing in primary screening (Dr Marc Arbyn, oral presentation – Eurogin 2011, Lisbon, 8 – 11 May 2011).