The Current Knowledge About Genital HPV Infection Prevention

Abstract

HPV infection, the well-known cause of most types of cervical cancer, represents a condition that can be prevented by vaccination, early detection, and eventually treatment, before progressing into invasive cancer with an obscure prognosis. Developed countries have already implemented vaccination programs and populational screening for cervical cancer strategies and they aim to transform cervical cancer into a rare condition or even eradicated one. In Romania, unfortunately, the vaccination, as well as the screening program, are opportunistic, and the incidence of cervical dysplasia or even cervical cancer remains high. It is time to promote primary and secondary prevention, offer information to the patients, and assure the well-being of Romanian women.

Medical professionals have a unique chance in managing a difficult pathology, respectively cervical cancer. It is the chance of an early diagnosis of the clinical entities that present a high probability of developing cervical cancer. This change was unveiled almost a century ago by the research of an illustrious Romanian doctor - Aurel Babeș (1927) and was published and disseminated among specialists everywhere by Georgios Papanicolaou (1928), who practically laid the foundations of cytopathology. They described the neoplastic cells, scaly from the surface of the cervix, which can be collected from the vaginal level and stained on a slide, thus making the diagnosis before the clinical manifestation of the condition. Thus, the premises were created for screening programs, which, applied in many of the developed countries of the world, led to a spectacular decrease in the number of deaths from cervical cancer.

Herbert Zur Hausen hypothesized the involvement of human papillomavirus (HPV) in the etiopathogenesis of cervical cancer (1976), with his working group then confirming in the following decade that a high-risk HPV virus is required for oncogenesis, leading to being conferred the Nobel prize for medicine in 2008. Risk factors for the development of severe precancerous lesions have been identified: young age, multiple sexual partners, sexual practices, and smoking.

The next challenge for specialists was to create a vaccine that could prevent this condition. Ian Frazer's Australian team applied a new technology and created virus-like particles (VLPs), in cell cultures, based on the L1 and L2 capsid proteins of HPV (1991), which allowed the relatively rapid development of an HPV vaccine (the first vaccine against HPV 16, 18, 6 and 11 was approved in 2006).

And yet, with two solid elements of prevention in hand – primary prevention through vaccination and education, and secondary prevention through early diagnostic tests of severe precancerous lesions, worldwide, in Europe, and especially in Romania, people still die from cervical cancer.

One of the solutions is vaccination. Countries that have introduced mandatory vaccination for young girls older than 12 years old, such as Australia, Sweden, Great Britain, etc, and that have achieved vaccination coverage of over 80% in girls, already report spectacular results in prevention. The second solution is the simplification of screening, easy access, and acceptance by the population.

Thus, in the USA, a technologically advanced country, but with a rather opportunistic screening for cervical cancer, in 2021 there were 15,000 new cases of cervical cancer, and 4,300 women died from this disease. In the USA in 2020, the medium vaccination rate of adolescents aged between 13 and 17 is 58.6%, with different vaccination coverage, as the lowest vaccination rate is in Mississippi (31.9%) and the highest in Rhode Island (83.0%).

In Australia, in 2020, the official numbers are: 80.5% of females and 78% of males the age of 15, have benefitted from the HPV vaccination program, numbers which have increased compared to the year 2012 when the vaccination rate for females was 72%, and the year 2014 when the vaccination rate for males was 62%. The results of the HPV vaccination program are extremely promising as Australia has documented a 92% decrease in HPV types involved in 75% of cervical cancer, a 70% decrease in high-grade cervical dysplasia in young women under the age of 20, a 50% decrease in the group age 20-24 and a 19% decrease in the group age 25-29, rates that have been obtained by the year 2017. In 2020, cervical cancer become the 14th most frequent cancer in the female population, with just only 920 cases diagnosed in the whole continent.

Concerning Europe, every year there are 33 000 cervical cases diagnosed and 15 000 women die due to cervical cancer. In 2019, the vaccination rate of the target population varies between 14% in Luxembourg and 53% in the Netherlands. Europe’s Beating Cancer plan aims to assure a vaccination rate of at least 90% for girls and to increment the rate of vaccination for boys by 2030. The first attempt in Romania dates from 2008 when only 2% of the female candidates for the HPV vaccination program have been vaccinated. The current national vaccination program has been started in January 2020 and in 2022 we do not have yet official reports regarding the vaccination rate, but from unofficial sources, it is estimated around 10% of the target population. These last numbers raise questions and require solutions.

Screening has evolved from cytology to HPV testing and refinement of risk stratification (triage methods have emerged to help the specialist intervene to prevent the progression of a precancerous lesion to cancer). Both gynecologists and general physicians, as well as any physician who treats patients, need to understand the technological advancement that is leading to a change in screening for precancerous lesions of the cervix, namely HPV testing.

Although HPV infection is common, the persistence of an active infection is rare. That's why most tests will be negative. HPV genotyping is much more efficient for screening when the result is negative – the result can reassure both the patient and the clinician for a large range of years (negative predictive value is 85-90%). When the HPV test is negative, the patient can be scheduled for the next visit after three or five years, with no risk of developing a severe precancerous lesion during this period. The individual risk is assessed (factors that decrease the immune defense mechanisms, personal antecedents – precancerous conditions of the cervix monitored or treated, HPV vaccination status, etc.).

The discussion remains open on what to do, to be as effective as possible, when the HPV test result is positive, and how to assess and stratify the risk. A positive HPV test for strain 16 can hide a severe precancerous lesion (cervical intraepithelial lesion CIN3) in one out of ten cases, which is why a colposcopy is required. The risk for HPV 18 is the existence of adenocarcinoma in situ (AIS), and recent studies draw attention to the aggressive behavior of HPV 31.

However, most positive results will be HPV high-risk (HR) positive, non-16, or 18, and will need to be stratified. The proposed analysis, which comes closest to the biological truth (changes at the nuclear level) is double positive staining (immunohistology). This method identifies the co-expression of two nuclear markers that appear simultaneously only in dysplastic cells. Any positive immunohistological test confirms a precancerous lesion, which must be identified by the clinician directly, through a colposcopic examination (with an examination of the cervix, vagina, and vulva). In the case of an AIS, colposcopy is often inconclusive or negative, and an endocervical curettage or sometimes even conization is performed for diagnostic purposes.

The keyword is pre-cancer, the precancerous lesion, which in all situations must be detected, and, in certain situations, must be treated by excision to prevent the progression to cervical cancer.

Practitioners have noticed for a long time that some of the patients with persistent HPV HR infections have parallel co-infections with Chlamydia trachomatis or germs from the Mycoplasma/Ureaplasma family or frequently develop bacterial vaginosis. It is still questionable whether vaginal dysbiosis creates conditions for HPV persistence, as clinical studies have come up with controversial conclusions. Beyond a careful clinical examination, laboratory diagnosis through high-performance methods (molecular biology techniques) allows the establishment of appropriate treatment and restores the vaginal microbiome to physiological parameters.

In prevention, regardless of the condition, communication with patients is fundamental, to educate patients that HPV testing is an early screening test for a possible precancerous lesion of the cervix and that a positive test does not mean the patient has cervical cancer. If this test is positive, an analysis of the sampled fluid is sometimes required, which assesses whether the patient should also undergo a colposcopy. On the other hand, if the double staining is not positive, the patient must understand that for a good evolution, further monitoring will be needed. Self-testing methods, such as testing for sexually transmitted diseases, have been developed in technologically advanced countries to increase patient acceptance.

As members of the European Community and due to the major deficiencies in cervical cancer screening, it is high time to understand what the European Commission proposes about cervical cancer screening starting in 2022. Thus it has been established that HPV testing is aimed at women between 30-65 years, once every 5 years or more, also taking into account the HPV vaccination coverage in the respective country. This directive is quite close to the recommendation of the American Cancer Society (ACS, 2020), which specifies HPV testing as the only screening test for women over 25 years of age. The essential argument is the following: cervical cancers are very rare under the age of 25 and practically do not meet the criteria of a screening.

In conclusion, the tests will be realized for precancerous lesions, which can be diagnosed and treated promptly. The age of first HPV testing may be increased as the vaccination rate is increased (above 50% of the eligible population) and herd immunization is expected to be established. On the other hand, some specialists may advocate for co-testing (HPV and cytology in the liquid medium, emphasizing the value that cytology has in HPV-negative cancers). Studies show, however, that within a vaccinated population much positive cytology will be encountered, but it will not progress to CIN3, thus the role of cytology is limited. In addition, HPV HR is involved in Ear, Nose, and Throat (ENT) cancers, anal cancer, and penile cancer. There are no screening methods yet for these cancers. The association of an immunosuppressive condition such as HIV exposes patients to the major risk of developing HPV-induced cancer. Interdisciplinarity, and communication between specialists is essential in the correct management of the case and for the oncological safety of the patient.