**3. Routes of transmission**

new HPV isolate is recognized as a new genotype when the nucleotide sequence of the L1 gene differs by more than 10% from the genotype with which it has the greatest homology in DNA sequence. More than 100 HPV genotypes have been identified in humans from which over 40 genotypes infect mucosa of anogenital tract and other mucosal areas. As anogenital HPV infections is the interest of this chapter, focus is made on alpha-papillomavirus genus, which

270 Human Papillomavirus and Related Diseases – From Bench to Bedside A Diagnostic and Preventive Perspective

Mucosal HPVs are also classified according to their oncogenic potential: low-oncogenic risk genotypes (LR-HPVs) and high-oncogenic risk genotypes (HR-HPVs). LR-HPVs may cause benign lesions of the anogenital mucosa such as *condylomata acuminata* (genital warts) while HR-HPVs are linked to the development of pre- and malignant lesions. The latest classification published by the World Health Organization's International Agency for Research on Cancer referred genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59 as HR-HPVs[3, 4]. This classification also included many other genotypes as possibly carcinogenic, such as genotypes 26, 53, 66, 67, 68 70, 73 and 82 (Table 2). These genotypes are referred as possibly carcinogenic because the evidence about their carcinogenicity are more limited. Oncogenic potential classification of HPVs is updated frequently with the occurrence of new epidemiologic

Alpha-2 3, 10, 28,29, 78, 94

Alpha-7 18, 39, 45, 59, 68, 70, c85

Alpha-9 16, 31, 33, 35, 52, 58, 67 Alpha-10 6, 11, 13, 44, 55, 74

Alpha-4 2, 27, 57 Alpha-5 26, 51, 69, 82 Alpha-6 30, 53, 56, 66

Alpha-8 7, 40, 43, c91

Alpha-11 34, 73 Alpha-12 RhPV1 Alpha-13 54 Alpha-14 c90 Alpha-15 71

Alpha-3 61, 72, 81, 83, 84, c62 c86, c87, c89

include mucosal HPVs (Table 1) [2].

Classification of Human Alpha-Papillomavirus

\*Adapted from De Villiers et al., 2004 [1]

**Genus Species HPV Genotypes**

**Table 1.** Classification of species and genotypes of HPVs among the Alpha genus

Alpha-papillomavirus Alpha-1 32, 42

evidence[5].

#### **3.1. Primary route of transmission: Sexual contact with an infected partner**

Epidemiologic data supports that the primary route of HPVs transmission is via sexual contacts. The most important risk factors for prevalent infection as well as for acquisition or incidence in adults, are related to sexual behaviour variables: age at sexual debut and number of sexual partners, new, recent or lifetime for example [5-7]. Transmission may occur through peno-vaginal intercourse, but also via other sexual practices. Anal intercourse is also associated with HPV infection. History of receptive anal sex has been identified as an important risk factor for anal HPV infection among men [8-12]. Oral sex is also a possible route of HPV transmission as it has been associated with HPV oral infection [13-15]. Furthermore, digital-genital trans‐ mission is possible, as genital HPV genotypes have been found on fingers[16]. Insertive sex toys are also a possible of route of transmission[17]. Studies on genital HPV infection between women who have sex with women also suggest that HPV transmission is possible among lesbian partners[18].

#### **3.2. Non-sexual routes of transmission**

HPV genital infections can also origin from non-sexual route of transmission. For example, HPV DNA can be detected in genital or oral tract of newborns and children through perinatal/ vertical transmission [19-23]. Vertical transmission of HPV from mother to child (perinatal infection) was first reported in 1956 in a case of juvenile laryngeal papillomatosis[24]. Confir‐ mation of the perinatal transmission of HPV in different mucosa (genital, oral) was subse‐ quently supported by several studies although the route of transmission is not well understood[19-23, 25]. Direct maternal transmission during vaginal delivery or at caesarean section following early membrane rupture is possible as well as in utero through semen or ascending infection from mother's genital tract. Transplacental transmission seems possible since HPV DNA has been detected by PCR in amniotic fluid, placenta and cord blood [25, 26]. It is possible that transmission occurs through semen since it has been demonstrated that HPV DNA is found in sperm in a proportion of 8–64% of asymptomatic men[27]. Studies in vitro shown that HPVs may attach to sperm head, and that infected spermatozoids are able to penetrate oocyte and deliver HPV genome into it. Oocyte can actively transcribed HPV genes, for transmission to occur[28].

other important route of transmission have been suggested such as no penetrative sexual contact (for example, involving the fingers or mouth of partner), non-sexual contact, or HPV shedding from the vagina to the anus given the close proximity of these two areas[33, 34].

Epidemiology of Anogenital Human Papillomavirus Infections

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It has been suggested that vaginal and vulvar HPV infections are also very common in healthy women although much less data in available for these site specific areas. Some studies have detected HPVs in cervicovaginal samples compare to cervical samples and showed positivity for HPV in cervicovaginal swabs are higher compared to cervical specimens suggesting a higher prevalence HPV in the vagina or vulva than in the cervix only[35]. For example, a prevalence of 42.5% has been observed among females in United States using self-collected

High rates of incidence of HPV cervical infection are observed especially in young women. Cumulative incidence of more than 40% after 3 years of follow-up has been demonstrated among university students [5, 6, 37]. The highest incidence rates of cervical HPV infection are observed in young women corresponding to age of sexual intercourse debut. Thereafter, incidence in women tends to decline with age, although second peaks are sometimes observed in older women (such as for prevalence data)[5]. For example, in a cohort of women between 13 and 65 years of age in Bogota in Colombia[37], the cumulative incidence of any HPV after five years of follow-up among women aged 15-19, 20-24, 25-29, 30-44 and more than 45 years were 42.5%, 36.9%, 30.0%, 21.9%, and 12.4%,, respectively. The cumulative incidence after 5 years of follow-up in all age groups was 26.3% and infections rate with HR-HPVs were more frequent than infections with LR genotypes (5.0 cases and 2.0 cases/100 woman-years, respectively). Although some studies observed higher incidence of HR-HPV than LR-HPV, these comparisons depend on the assays used. More recent assays detect more types, many of

Cumulative incidence of anal HPV infection in a cohort of women of Hawaii (median age: 40 years old) has been evaluated at almost 70% in an average period of 1.3 years of follow-up. The rate of acquisition of anal HPV infection with any genotype was observed at 46.9 cases per 1000 woman-month. The incidence rate of anal HPV infections with HR-HPVs is also higher than with LR-HPV (such as for cervical infection) with estimates reported by Goodman et al (2008) at 19.5 and 8.2/1000 woman-months for an incident anal HR-HPV and LR-HPV, respectively[32]. Lower risk of acquisition of anal HR-HPV in women over 45 years of age have

To our knowledge, there are no estimates on the incidence of vagina and vulvar HPV infection

also been observed compared to women under 25 years of age.

**Vaginal and vulvar HPV infections**

cervicovaginal specimen[36].

**Cervical HPV infections**

which fall into the LR category.

**Vaginal and vulvar HPV infections**

**Anal HPV infections**

in healthy women.

*4.1.2. Incidence*

Other non-sexual skin contact transmission has been documented such as horizontal trans‐ mission via fingers, mouth and fomites[5, 17]. For example, it has been shown that HPV infected individuals may have HPVs in genital sample and in their hands showing that they can not only infect their sexual partners but also themselves somewhere else on their body (hands, conjunctive, etc.) as well as other individuals outside sexual contacts[16, 18].
