The known unknowns of HPV natural history

Abstract

The discovery that certain high-risk strains of human papillomavirus (HR-HPV) cause nearly 100% of invasive cervical cancer has spurred a revolution in cervical cancer prevention by promoting the development of viral vaccines. Although the efficacy of these vaccines has already been demonstrated, a complete understanding of viral latency and natural immunity is lacking, and solving these mysteries could help guide policies of cervical cancer screening and vaccine use. Here, we examine the epidemiological and biological understanding of the natural history of HPV infection, with an eye toward using these studies to guide the implementation of cervical cancer prevention strategies. IntroductionThe discovery that certain high-risk strains of human papillomavirus (HR-HPV) cause nearly 100% of invasive cervical cancer (1) has spurred a revolution in cervical cancer prevention. Randomized controlled trials (RCTs) have evaluated the efficacy of two prophylactic vaccines: Gardasil (also known as HPV4 or quadrivalent vaccine) targets two of the most carcinogenic HPV genotypes (HPV16 and HPV18), as well as two types responsible for more than 90% of anogenital warts (HPV6 and HPV11), and Cervarix (also known as HPV2 or bivalent vaccine) targets HPV16 and HPV18 alone. The results of the vaccine trials have been summarized in detail elsewhere (2-10), demonstrating nearly complete protection against cervical disease caused by the targeted genotypes in previously uninfected women for up to 8 years (11). In secondary prevention, primary screening using HPV DNA testing alone has been found to have performance comparable or superior to Pap smear-based screening in several large RCTs in Canada and Europe (12-16). The high predictive value of a negative HPV DNA test allows for safe extension of screening intervals to at least once every 3-5 years (17-19), which if broadly adopted would increase the efficiency of cervical cancer screening with minimal impact on cancer risk.The RCTs have demonstrated clear efficacy of HPV-based screening and vaccination, but questions about best practices for implementation remain (20,21). Many of the policy debates stem from specific uncertainties in our understanding of the natural history of HPV infection across the lifespan, and particularly in older women. The current model of HPV and cervical cancer natural history that anchors the decision models used in policy development is outlined in Figure 1 (reviewed in refs. 22, 23). Briefly, women acquire HPV through sexual intercourse with an infected partner, and thus HPV prevalence is high around the age of sexual debut, when exposure is high in the absence of immunity. Infections "clear" within 2 years in more than 90% of individuals (24)(25)(26). Approximately 60% of these infections will induce type-specific seroconversion, and if cervical samples are collected during productive viral infection, they may be associated with mild cervical abnormalities (i.e., low-grade squamous intraepithelial lesions [LSILs] or cervical intraepithelial neoplasia ...

HPV Seroconversion Following Anal and Penile HPV Infection in HIV-Negative and HIV-Infected MSM

“…Second, the number of penile HPV infections was relatively low compared with the number of anal infections, so we were not able to use the same detailed characterization of infection patterns. Third, in case of new HPV detection, it was impossible to distinguish between HPV acquisition and reactivation of latent infection (30). Our study population was not HPV-na€ ve, and as a result a proportion of "incident" infections might actually have been reactivations of long-standing infections, diluting our results.…”

High-Risk Human Papillomavirus Infection and P16 Expression in Men With Anogenital Lesions Attending a Dermatology Clinic

“…Sampling and methodological strategies used in prevalence studies may also have resulted in diagnostic losses due to the characteristics of HPV infection sites in men and the lack of routine preventive screening to detect anal lesions in at-risk men, whereas such screening is implemented for women (Palefsky et al 2011). The difficulty of measuring latent HPV infection reactivation must also be considered (Gravitt 2011).…”

Prevalence of cervical squamous intraepithelial lesion high grade according to age from Antônio Pedro University Hospital

“…When evaluating the natural history of the disease, we noticed that from the viral infection up to the appearance of an invasive carcinoma, approximately 10 years passed. When the changes in the sexual behavior of the population are taken into consideration, mainly after the popularization of the medication against male impotence and female hormone therapy, and the decrease in the immunity or reactivation of the latent infection, mainly in elderly and immunosuppressed women (16) , it is extremely important that we reflect on the existence of a new peak of incidence of later infection (therefore, a later appearance of these lesions) and discuss the necessity of amplifying the age group the screening covers, which has become more necessary in more advanced ages (12) . In this study, a significant number of patients over the age of 55 can be noted, revealing that a possible tendency in this direction will be exacerbated in the upcoming years.…”