**5. Natural history**

#### **5.1. Clearance and persistence of HPV infection**

#### *5.1.1. Clearance*

*4.1.3. Special population: HIV-positive women and sex workers*

women-years relatively to 26.81 per 100 women-years)[40].

**4.2. Anogenital HPV infections in men**

*4.2.1. Prevalence*

*4.2.2. Incidence*

HIV and HPV infection status has been under the projectors during the last years. In a systemat‐ ic reviewofHIV-positivewomenwithnocytologicalabnormalities,prevalenceofHPVhasbeen

More attention was also paid to sex workers in the last years. For example, in a study made in China, prevalence of any HPV genotype was estimated at 38.9% in this population[39]. A recent study in Spain also demonstrated a higher incidence and a higher risk of persistence of HR-HPV infection in sex workers compared to the general population (incidence of 3.98 per 100

Depending of the anatomic sites (coronal sulcus, glans, prepuce, shaft, urethra, scrotum, perianal area, anus, semen or urine) that is analysed, HPV prevalence (any genotypes) can vary from 1% to 84% among the general population of men and from 2% to 93% in high-risk men (such as STI clinic attendees, HIV-positive males, and male partners of women with HPV infection or abnormal cytology)[41]. For example, the site specific prevalences of HPV infection in male were estimated between 6.5%-50% in corona and/or glans, 5.6%-51.5% in penile shaft, 24%-50% in prepuce, 7.1%-46.2% in scrotum, and 8.7%-50% in urethra [27]. Contrarily to what is reported in women, HPV prevalence is relatively stable across age groups in men [41, 42]. Prevalence of anal HPV infection in men who have sex with women has been reported to range between 0% and 32.8% [27]. It is important to consider, however, that a high variability in the prevalence estimates may occurred in man due to the variability of sites tested or to the type of specimen used for which the detection method is not completly optimized (such as urine).

Few studies have reported HPV infections incidence in men. Cumulative incidence calculated with penile and scrotal sampling, in a cohort of USA men aged between 18-44 years old (mean age: 29.7 years) was 29.3% after a follow-up of 12 months[42]. Incidence rate in this cohort for any HPV genotype infection was 29.4 per 1000 men-months. Incidence rates of HPV-6, 11, 16,

HPV infection is strongly associated with the number of lifetime female sexual partners in men who have sex with women (MSW) and also with the number of male anal-sexual partners in men who have sex with men (MSM) [43]. For MSM, prevalence of any HPV genotype was estimated at 18.5% on the penis, 17.1% on the scrotum, 33.0% on the perineal/perianal region, 42.4% in the anal canal, and 48.0% at any site. The prevalence of HPV infection is high among young sexually active MSM, with the anal canal being the most common site of infection[44]. A study comparing the anal canal HPV prevalence in MSW (12.2%) to MSM (47.2%), confirmed

and 18 infections were 2.8, 0.5, 4.8, and 0.8 per 1000 men-months, resectively.

*4.2.3. Special population: Men who have Sex with Men (MSM) and HIV-positive men*

evaluated at 36.3% [38], higher than in worldwide estimated prevalence (11.7%)[29].

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

Although high prevalence of HPV is found in both males and females, most of the HPV infections will be cleared spontaneously. Literature has consistently shown that at least 80 to 90% of cervical HPV infections are transient and are no longer detectable within 1-2 years[49]. HR-HPV infections seem to persist longer than LR-HPV[5]. For example, in cervical swabs of female university students, LR-HPV and HR-HPV infections typically last (in average) 13.4 and 16.3 months, respectively[50]. In a review paper, the median duration (time for 50% of infections to be cleared) of cervical infection reported from published studies ranged from 4 to 20 months, with a tendency for HPV-16 infections to last a little longer[5].

Clearance has also been studied in men. For example, a study on the clearance of HPV infections in penile and scrotum sampling in a cohort of USA men has shown that the median time to clearance of any HPV infection was 5.9 months and that 75% of HPV infections cleared by 12 months[42]. Contrarily to women, LR-HPV and HR-HPV infections durations were almost the same with a median duration of 5.8 months and 6 months respectively. Recent data from a cohort study regrouping men from Brazil, Mexico and USA also supports that median duration of HPV infection is shorter in men than in women with 7.5 months for any HPVs[43].

#### *5.1.2. Persistence*

Persistence with an HR-HPV over long periods is an important risk factor for the development and progression of cervical malignant lesion[51]. Approximately between 10% and 20% of women fail to clear HPV infections, resulting in long-term cervical persistent infection[52]. It is not known, however, why some women will develop cervical cancer following persistent infection whereas others do not. Finally, persistence of HPV is recognised as an important step in the etiologic pathway of cervical cancer but it has not been studied in other anogenital cancers in women (vulva, vagina, anal cancer) and in men (penile and anal cancer).

which does not completely protect against future infections by the same HPV genotype, following new exposure via sexual activity later in life[58-60]. Recent studies have shown that reinfection with a same genotype is associated with new sexual partners suggesting that infection in adult women may results not only from reactivation of HPV infections acquired at a young age that never completely cleared, but also from new exposure via sexual activi‐ ty[37, 57]. There is no available study concerning the probability of reinfection with a same or

Epidemiology of Anogenital Human Papillomavirus Infections

http://dx.doi.org/10.5772/55825

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**6.1. Low-risk HPV genotypes are associated to non-cancerous anogenital lesions**

**6.2. High-risk HPV genotypes are associated to cancerous anogenital lesions**

**7. Economic and health care system burden of HPV infections**

The viruses cause approximately 15% of human cancers, and of this proportion, nearly half is attributable to HPVs with cervix, vulva, vagina, penis and anal cancers[64]. According to Centers for Disease Control and Prevention (CDC), it has now been accepted that HPV is a necessary cause of cervical cancer as virtually 100% of specimens presents HPV DNA. It is also now accepted that HPV is responsible for 50% of vulvar cancer, 65% of vaginal cancer 35% of

Clinical HPV infections are responsible for substantial morbidity and invoke high costs associated with the treatment of clinically relevant lesions[66]. Currently, two vaccines are available: a bivalent HPV 16/18 AS04-adjuvanted vaccine (GlaxoSmithKline Biologicals, Rixensart, Belgium) and a quadrivalent HPV 6/11/16/18 aluminum-adjuvanted vaccine (Merck and Co., West Point, PA, USA). Both vaccines are designed to protect against the two more prevalent HPV genotypes, HPV-16 and 18, that are responsible together for about 70% of all cervical cancer cases worldwide. The quadrivalent vaccine also offers a protection against

*Condylomata acuminata* or genital warts (GWs) in anogenital area are usually caused by lowrisk HPV genotypes. Recent studies have shown that about 100% of GWs are caused by either HPV-6 or 11 but that 20–50% of lesions also contain co-infections with HR-HPV genotypes. The majority of individuals who develop genital warts do so approximately 2–3 months after infection[61]. Approximately 30% of all warts will regress within the first four months of infection without any treatment, butrecurrence will be see in majority of case, even if adequate treatments have been done[62]. Long-term remission rates remain largely unknown. GWs cause also significant psychological morbidity and substantial healthcare costs. Occasional‐ ly, GWs persist for long periods of time and, rarely, such long-standing lesions may progress to malignancy. GWs are highly infectious and contribute significantly to spread of HPV

a different genotype in men.

infections[63].

**6. HPV related anogenital diseases**

penile cancers and 95% of anal cancers[65].

#### **5.2. Multiple HPV infections and reinfection with same or different HPV genotype**

### *5.2.1. Multiple HPV infections*

Individuals infected with multiple HPV genotypes are also a very common finding of many epidemiologic studies. For example, among the cohort of Brazilian women, between 1.9% to 3.2% were co-infected with multiples genotypes at a same visit (concurrently infected) whereas when considering cumulatively (period prevalence) during the first year and the first 4 years of follow-up, 12.3% and 22.3% were infected with multiple genotypes, respectively[53]. Coinfection in men have also been studied. In a healthy mexican military cohort, HPV prevalence was 44.6% at one of these sites (urethra, urethral meatus, scrotum, penile, shaft or coronal sulcus) and 51.1% of them had mutiple HPV genotypes[54]. MSM have been studied and are also at high risk of coinfection. For example, Dona et al (2012) in an Italian cohort demonstrated that 65.3% of the HPV-positive MSM had multiple HPV infections[8].

Consequences of multiple HPV infections are still debated, but multiple infections with HR-HPV as well as infection with other agents, such as HIV, may play a critical role in furthering the progression to cervical intraepithelial neoplasia and cervical cancer in women[55]. Coinfection with multiple HPV genotypes is common in women with premalignant lesion but the prevalence of co-infections decreases with the severity of the lesion. It is well recognized that cervical cancer specimen do not frequently harboured multiple HPV genotypes[56]. Although multiple genotypes infection may increase the risk of pre-malignant lesions[53], it is possible that co-infection with multiple HPV genotypes acts as a biomarker of immune failure to clear HPV (which allow HPV-16 to progress more easily) rather than etiologic factors that act synergistically to cause cancer.

### *5.2.2. Reinfection with same or different HPV genotype*

The risk of HPV reinfection with the same genotype is also well debated. What has been shown is that it is possible to see cervical reinfection with the same genotype[57]. However, the provenance of the virus is not well understood in re-infected women. Two hypotheses have been advanced to explain reinfection. The first is based on the assumption that infections acquired at a young age never completely clear but become latent; infections appearing later in life would mostly represent the reactivation of such latent infections acquired many years earlier. The second hypothesis is that infections do clear following an initial immune response, which does not completely protect against future infections by the same HPV genotype, following new exposure via sexual activity later in life[58-60]. Recent studies have shown that reinfection with a same genotype is associated with new sexual partners suggesting that infection in adult women may results not only from reactivation of HPV infections acquired at a young age that never completely cleared, but also from new exposure via sexual activi‐ ty[37, 57]. There is no available study concerning the probability of reinfection with a same or a different genotype in men.
