Relevance of persistent infection with high-risk HPV genotypes in cervical cancer progression

Forty years ago, cervical cancer was the leading cause of cancer death among women in the United States. Since then it has shown a decline, and now it does not appear in the list of the 10 most prevalent causes of cancer death. This does not mean, however, that cervical cancer has been controlled in the United States. In 2013, 12,340 new cases of invasive cervical cancer and 4,030 cervical cancer deaths have been estimated.¹ In addition, cervical cancer has remained the second most common cancer among women worldwide. The vast majority of deaths occur in women living in low- and middle-income countries.²

HPV and cervical cancer

There are two types of cervical cancer worldwide: squamous cell carcinoma and adenocarcinoma. It is now well understood that all cervical cancers are caused by human papilloma virus (HPV). HPVs are a group of more than 150 related DNA viruses, around 100 of which have been cloned and genotyped. More than 40 of these viruses are transmitted through direct skin-to-skin or skin-to-mucosa contact during vaginal, anal, and oral sex and are responsible for sexually transmitted infections.  Non-sexual routes account for a tiny proportion of HPV infections; they include perinatal transmission and, possibly, transmission by medical procedures and fomites.^{3, 4}

Approximately 79 million Americans are currently infected with HPV, and about 14 million become newly infected each year. HPV is so common that nearly all sexually active men and women will get at least one type of HPV at some point in their lives.⁵ Prevalence has been found to be highest among young persons within the first few years of sexual debut.^6-10

Classification of HPV types

Not all HPV types are cancer-causing. In 2005 the International Agency for Research on Cancer (IARC) working group classified HPV types into the following grades:¹¹

• Grade 1 (carcinogenic to humans): HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59
• Grade 2A (probably carcinogenic to humans) HPV 68
• Grade 2B (possibly carcinogenic to humans) 26, 53, 66, 67, 70, 73, 82, 30, 34, 69, 85, and 97
• Grade 3 (not carcinogenic) 6, 11

Currently, it is accepted that the following 14 HPV genotypes are the high-risk or oncogenic types and have caused invasive cervical cancer: 16, 18 ,31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68.

The following low risk genotypes do not cause cancer but can cause skin warts (condylomata acuminata) on or around the genitals or anus: 6, 11, 40, 42, 43, 44, 53, 54, 61, 72, 73, and 81. Ninety per cent of genital warts are caused by HPV 6 and 11.^12,13

Prevalence of a particular HPV genotype and its association with cervical cancer varies greatly with geography. On a global scale HPV 16 has been found to be the most prevalent type among both healthy women and cervical cancer cases.^14-19 HPV-16 has been detected in more than 50% of cases of cervical cancer globally. However, the distribution varies; HPV-16 has been detected in 77% of cases in Germany, 71% in South America, 59% in the United States, and 33% to 39% in Japan.^20-23 HPV 18, the second most common cervical cancer-causing genotype, with a global frequency of about 8%,^24,25 is ranked fifth in the United States, following 16, 52, 51, and 31.²⁶ HPV 52 has been found in 20% of cervical cancer cases in Japan but only in 2% of cases in the U.S.²⁷ The high-risk types that have been most commonly found worldwide are 16, 18, 31, 33, 35, 45, 52, and 58. In Asia, 52 and 58 are more prevalent; 33 is most prevalent in Europe; and so on.¹¹

Infection with multiple HPV genotypes

It is important to note that infection with one type of HPV does not prevent infection with another type concurrently or subsequently. Studies have shown that women with cervical abnormalities or cervical carcinoma frequently have infections from multiple HPV genotypes. It has been reported that in persons infected with mucosal HPV, 5% to 30% are infected with multiple types of the virus.²⁸ In a study conducted in the United States, as many as 14 HPV genotypes were detected in single specimens.²⁹ In a study conducted in Indonesia, HPV DNA of 12 different HPV types was detected in 96% of the specimens.³⁰

Table 1 illustrates the HPV genotypes in different countries in the order of decreasing prevalence from left to right.

Prognosis of HPV infection

The HPV virus infects the basal epithelium, and the infection is mostly asymptomatic. Approximately 90% of infections clear within two years.^{24, 42-47} It may take from 10 to 30 years for HPV infection to progress to cervical cancer.⁴⁴ Figure 1 shows the stepwise cellular transformation that takes place in the women’s cervix post-HPV infection that can lead to cervical cancer.⁴⁸

HPV’s natural history shows that only 5% of HPV infections progress to CIN 2 or 3 within three years.²⁴ Of those that progress, many CIN 3 lesions (80%) will regress, and approximately 20% progress to invasive carcinoma within five years. Of this 20%, only 40% progress to invasive carcinoma within 30 years.⁴³ Up to 90% of high-grade pre-cancerous lesions in young women regress without treatment in two years.^{24, 42- 47}

The cascade of events that the HPV virus undertakes at the molecular level is as follows:⁴⁹

Initial Infection → Viral DNA Replication → Viral Differentiation → Integration → Release to Re-infect

The genes involved are E1/E2 (viral DNA replication), E4/E5 (viral differentiation), and E6/E7 (integration).

Although integrated HPV genomes are the most prevalent form of the viral DNA in tumors, it is apparent that cancers can arise, in a significant number of cases, before genome integration. Thus the integration of the viral genome into the genome of the host cell is not a prerequisite for the development of malignancy. This variation also depends on the HPV genotype.¹¹ HPV types 16, 18, and 45 show genomic integration more frequently, whereas it is not so in the case of HPV genotypes 31 and 33;⁴⁸ yet they are just as significant in terms of propensity to cause cancer.

Persistent infection with high-risk HPV 

It is now unequivocally accepted that HPV infection can lead to cervical cancer only if the high-risk HPV type(s) persist for long enough to cause abnormalities in the cervix.^55-59 Type-specific persistence is defined as showing positive for the same HPV genotype in two or three (or more) consecutive samples during the follow-up.⁵³ 

The following factors have been found to increase a person’s risk of persistent infection and the progression of lesions to related cancers:^{57, 58} multiple partners; presence of HPV plus other sexually transmitted viruses; prostitution; sex without a condom/microbicides; high parity (> 3 children); low socioeconomic status (poor hygiene/sanitation/nutrition conducive to sexually transmitted diseases); immunosuppression; smoking; long-term oral contraceptive use; and age.

A small proportion of infected persons become persistently infected. Persistent infection is the most important risk factor for the development of cervical cancer precursor lesions. The most common clinically significant manifestation of persistent genital HPV infection is cervical intraepithelial neoplasia (CIN). Persistent HPV infection may progress directly to high-grade CIN 2 or CIN 3. If left undetected and untreated, years or decades later CIN 2 or CIN 3 can progress to cervical cancer.^{28, 53}

Changing scenario with HPV vaccination

Two vaccines are available at present: Gardasil (HPV Quadrivalent Recombinant Vaccine against HPV 6, 11, 16, and 18) and Cervarix (HPV Bivalent Recombinant Vaccine against 16 and 18). The vaccines are recommended for boys and girls of 11 to 12 years to protect them against infection from HPV types 16 and 18. The vaccines can be taken up to 26 years of age. Routine vaccination was introduced in the U.S. in late 2006. The Centers for Disease Control and Prevention (CDC) conducted a study in 2010 and analyzed HPV prevalence data from the vaccine era (2007–2010) and the pre-vaccine era (2003–2006) that were collected during National Health and Nutrition Examination Surveys. It was found that HPV 16 and 18 showed a decrease from 11.5% to 5.1% among 14-to-19 year olds even though vaccination coverage had been only 32%.⁶⁰ It can be predicted that vaccination will reduce incidence of cervical cancer from these two types; however, the possibility of cervical cancer from other HPV genotypes will still remain.^61,62 Hence routine screening (PAP and HPV DNA testing) should be continued to prevent development of cervical cancer.

Changing scenario with better genotyping techniques

In 2002, based on the technology available at that time, it was estimated that HPV 16 and 18 are responsible for 70% of worldwide cervical cancers.⁶³ However, knowledge about HPV genotypes is now evolving due to the availability of new genotyping techniques. As an example, in a recent study conducted at Methodist Hospital in Houston, Texas, a relatively high (4%) incidence of HPV Type 90 was observed in women with cervical abnormality.⁶³ The oncogenic risk from Type 90 is still unknown. With the advancement of molecular and specifically comprehensive HPV genotyping techniques, it is expected that more relevant information will emerge to enable earlier infection detection and tracking, which would help to eradicate cervical cancer.

Rajasri Chandra MS, MBA, serves as a Product Manager for molecular diagnostics provider AutoGenomics. She has more than 15 years experience in the field of clinical diagnostics and related areas.

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