Cervical Dysplasia/Cancer and Human Papilloma Virus (HPV)

Cervical changes - illustration

Cervical changes. Source: National Cancer Institute

Cervical dysplasia is the precursor to cervical cancer. It is characterized by transformation and abnormal growth of cervical keratinocytes.

Cervical dysplasia is classified by two systems [1]: by histopathology (biopsy) or by cytology (PAP smear). Based on histopathology, three CIN (cervical intraepithelial neoplasia) grades are defined: CIN1 (mild dysplasia), CIN2 (moderate dysplasia) and CIN3 (severe dysplasia) lesions. Based on cytology, two grades are defined: LSIL (low grade squamous intra-epithelial lesions) or HSIL (high-grade squamous intraepithelial lesions). Usually LSIL and CIN-1 overlap, and HSIL and CIN-2 and CIN-3 overlap. About 10% of LSIL/CIN-1 eventually progress to cervical cancer, while about 50% of HSIL/CIN-2/CIN-3 progress to cervical cancer. Effective treatment of cervical dysplasia therefore would prevent development of cervical cancer.

Human papilloma virus (HPV) is the most common sexually transmitted disease in the developed countries and much of the rest of the world. Genital HPV infection, in particular by “high-risk” strains of HPV is the underlying cause of most cases of cervical dysplasia and the consequent cervical cancer. Over 70% of cervical cancer is due to HPV 16 and 18 [2, 3]. Current recommendations for cervical cancer screening include detection of high-risk HPV. Prevention of HPV infection or treatment of HPV infection upon detection is therefore critical to avoid cervical cancer.

TEM of papillomavirus

TEM of papillomavirus. Source: Wikipedia

HPV Incidence Remains High in Spite of HPV Vaccine – Need for HPV Treatment Remains

HPV vaccines were introduced over a decade ago (Gardasil® was approved in 2006). While this has clearly resulted in a decrease in HPV incidence in certain age groups (ages 15-24), the impact on HSIL incidence overall remains modest [4].

Cervical Low- and High-Grade Squamous Intraepithelial Lesions — Prevalence per 1000 Person-Years Among Female Enrollees in Private Health Plans Aged 15–39 Years, by Age Group and Year, 2007–2014. Source: Centers for Disease Control and Prevention

This modest impact by HPV vaccines is due to its uptake. In the USA, the HPV vaccination rate in adolescent girls is ~50% country average, with many states below 50% and only 7 states >60% [5].

HPV Vaccination Rates among Adolescent Girls, by State. Source: https://wordpress.nejm.org/?p=19726

HPV Vaccination Rates among Adolescent Girls, by State. Source: NEJM

Advanced Cervical Dysplasia Current Treatments are Invasive with Side Effects

The most likely cervical dysplasia patient treatment path is shown in this figure [6, 7]:

Cervical Dysplasia: Patient Treatment Path. Source: National Cancer InstituteAssociation of Reproductive Health Professionals

Treatments for HSIL [8]

  • All treatments Invasive (LEEP is the most common procedure used)
  • All have risk of significant complications, including:
    • Bleeding
    • Cervical incompetence (which can result in miscarriage and preterm labor)
    • Cervical stenosis
    • Difficulty getting pregnant
  • Invasive treatment procedures (LEEP, etc.) are not always curative (HPV persists)

There is a high unmet need for a new, safe non-invasive treatment especially for HSIL, to resolve cervical dysplasia and become HPV free. Any treatment that would avoid the side effects associated with procedures like LEEP would be significant patient benefit and healthcare cost savings.