Human papillomavirus: An update on cancer prevention and screening guidelines
Human papillomavirus (HPV) is the most common sexually transmitted infection. In total, more than 40 types of HPV can be transmitted through direct sexual contact, including those types classified as high risk for the development of cervical cancer.1 In 2016, cervical cancer was the seventh most common cancer among females and was the ninth leading cause of female cancer death in Hong Kong, accounting for 2.6% of all cancer deaths in females.2 In a recent interview, Dr. Wong, Tin-Yau Andrew, an infectious disease specialist in Hong Kong, shared his insights on preventing HPV-related cancer.
Burden of HPV-related diseases
Persistent infection with high risk HPV types can cause cellular changes that may progress to cancer or precancerous lesions in the cervix, vagina, vulva, anus, penis, head and neck.1 On the other hand, low risk types are associated with genital warts and recurrent respiratory papillomatosis, but rarely cause cancer.3 Approximately 90% of cervical cancers worldwide are caused by the high risk HPV types 16, 18, 31, 33, 45, 52, and 58. HPV6 and 11 are the low risk types of HPV that are responsible for 90% of genital warts and warts formation in the mouth and throat.4
HPV infection: How does it cause cervical cancer?
The majority of high risk HPV-positive women do not develop cancer as the innate immune system of the body will naturally clear the infection.5 However, a persistent infection or immunodeficiency can lead to increased likelihood of precancerous changes/cancer. A persistent infection with high risk types of HPV in the metaplastic epithelium of the cervical transformation zone can be associated with precancerous lesions. If not diagnosed and treated, the precancerous condition could result in cervical cancer.5 The peak period for acquiring HPV infection is observed in women under the age of 25, with a decline that plateaus around 30–35 years of age. In women who are negative for high risk HPV, the risk of cancer in the subsequent years remains nearly non-existent.5
The two most critical determinants of carcinogenic risk among HPV-infected women are persistence of infection and viral genotype. The available studies have shown the unique carcinogenicity of HPV16. Although most HPV infections resolve within months to years, prevalent infections such as HPV16 are associated with an increased risk of cancer.5
Cervical cancer screening is performed to find changes in the cells of the cervix that could be associated with development of cancer and includes cervical cytology. The cytology test was substituted with the primary HPV screening or by co-testing (HPV and cytology) in several countries.6 The minor cytologic and histologic abnormalities are correlated with the viral determinants during risk assessment. Therefore, the use of molecular and microscopic tests to determine the HPV type is important in measuring the risk of HPV-related cervical cancer.6
Cervical intraepithelial neoplasia-grade 3 (CIN3) or nowadays named as high grade squamous intraepithelial lesion (HSIL) is commonly used among clinical trials on cervical HPV infection as the disease endpoint.7 The exact time between the infection with high risk HPV and the development of CIN3 cannot be determined, because it depends on the intensity of surveillance and diagnostic limits of colposcopically directed biopsy.5 The natural history of HPV infection and the time from infection to progression to CIN3 is represented in Figure 1.5 The time from first development of a small CIN3/HSIL lesion to invasion could take
The best documented risk factors for invasive cancer among HPV-infected women are smoking, long-term use of hormonal contraceptives, multiparity, and human immunodeficiency virus (HIV) infection.8 Similarly, these risk factors are associated with increase in the risk of progression of persistent infection to CIN3/HSIL.9
HPV-related cervical cancer can be prevented by vaccination
The commercially available HPV prophylactic vaccines to date are Cervarix®, Gardasil® and Gardasil 9®. All three HPV vaccines are non-infectious subunit vaccines that contain virus-like particles specific to HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58.10 These vaccines are usually administered by the intramuscular route and the recommended regimen is for three doses to be given within a 6-month period. All vaccines demonstrated high efficacy rates in the prevention of persistent infections and precancerous lesions induced by the respective HPV types targeted by the vaccine.11,12
The recombinant DNA used in HPV vaccine is able to produce virus-like particles capable of mimicking the natural virus and eliciting high-titers of virus neutralizing antibodies.8 Furthermore, HPV infection is also associated with cell-mediated immune response.10 Although, the vaccines are not considered to have therapeutic effects on established HPV infections, it can protect the infected individuals from secondary infections of other HPV types.10
The accumulating evidence in favor of Cervarix® and Gardasil® in national immunization programs confirms their high effectiveness.13 Post hoc analyses of three clinical trials have provided further evidence of strong protection, induced in young women even after a single dose.14 In addition, surveillance studies also confirmed that a single dose can reduce infection and neoplastic disease incidence in national immunization programs.14
A successful HPV immunization program was initiated in Australia in 2007, targeting females aged 12-13 years old; the program was extended to males in 2013.15 The impact of HPV immunization was evaluated in 2015, reporting the longest surveillance follow-up to date and showing the decline of vaccine-targeted HPV types among young women.15 A substantial decrease in the number of HPV infections has also occurred in women aged 25–35 years, despite lower coverage. Strong herd protection and efficacy of vaccine doses despite non-adherent dosing schedules likely contributed to these reductions.15 However the current global trend recommendation is extended to “gender neutral” programs since vaccinating girls may provide partial protection for heterosexual men but only vaccinating boys will cover homosexual men.16
In Hong Kong, HPV vaccination among Primary Five female students was initiated in September 2019 as a government subsidiary program. The second dose will be administrated when they reach Primary Six.2 The HPV vaccination program in Hong Kong is introduced as a free, school-based scheme and is expected to be successful in boosting its coverage rate and raising awareness of its importance.
HPV-related anal cancer is increasing in the burden of disease
Globally, anal cancer accounts for approximately 20,000 new cancer cases each year. Among them, nearly 90% are caused by HPV.18,19 The incidence rate is higher among females compared to males.17 In HIV-positive men who have sex with men (MSM), the incidence rate is almost 100 times compared to the rate in the general population. Among HIV-positive MSM, the rates of other cancers except anal cancer have been reduced significantly in the era of highly active antiretroviral therapy (HAART). In contrast, there is a true possibility of cervical cancer being eliminated in the foreseeable future provided, there is good uptake of HPV vaccination among young women. Similar to other HPV-related cancers, the risk of anal cancer is increased by sexual exposure to HPV, HIV infection, immunosuppression, and more weakly, by tobacco smoking. Importantly, one should note that anal intercourse is not necessary for anal HPV infection to occur. In women, there was a study showing that front-to-back wiping was associated with significantly increased prevalence of high risk HPV infection and abnormal cytology and histology in the anus.20
Certain groups have been identified as high risk for anal cancer, such as MSM, transplant recipients, people with HIV/Acquired Immune Deficiency Syndrome (IDS), and women with a history of HPV-induced cervical, vaginal, or vulvar cancer.21 Among these high risk groups, women with a prior history of HPV-induced cancer have an increased incidence (3 to 22 times) of anal cancer, compared with the general population.21
Lin et al. have shown that data from routine HPV-based cervical screening program can be used to define the anal cancer risk profiles.22 The findings indicated that cervical and anal HPV infections were highly correlated and the HPV-based cervical cancer screening programs can help stratify the anal cancer risk, irrespective of HIV status.22
Anogenital HPV-induced cancers are largely preventable by prophylactic vaccination of HPV-naive individuals (primary prevention) or by screening for pre-cancers (secondary prevention). However, anal cancer screening has been recommended only for high risk groups, such as HIV-positive individuals, especially MSM and transplant patients.20,23 In addition, the findings of Lin and colleagues may imply that anal cancer screening could be recommended in women with cervical high risk HPV infection, especially if caused by HPV16 (irrespective of their HIV status).17,22 However, the benefits of such screening program in the general population have yet to be established.21
The data to date indicates that HPV16 is a priority target for the prevention of anal cancer, emphasizing the potential of HPV16-containing vaccines to prevent most anal cancers.21
Message to the physicians
The current educational approaches should be directed towards enhancing the awareness and knowledge regarding HPV and HPV-associated cancers among the general public by all healthcare professionals involved in the management of HPV-infected patients. The risk of HPV-related cancers should be assessed in all symptomatic patients during the follow-up visit. Patients with high risk HPV types should be screened as a matter of priority to identify HPV-related pre-cancers. HPV immunization should be encouraged in young females.
The high coverage of HPV vaccines could potentially eradicate HPV-related cervical and other anogenital cancers, if administered early (primary prevention). This applies mainly to our future generations. Once the disease is established, careful monitoring of groups known to be at higher risk of HPV related cancers; and providing treatment, which is still under investigation, may improve the prognosis by early detection of precancerous lesions (secondary prevention). Therefore, raising awareness among healthcare practitioners involved in the management and care of HPV is essential to maximize the public health benefits of HPV vaccination.