**6. HPV related anogenital diseases**

*5.1.2. Persistence*

*5.2.1. Multiple HPV infections*

that act synergistically to cause cancer.

*5.2.2. Reinfection with same or different HPV genotype*

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).

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

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

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

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,

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

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

*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 infections[63].

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

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