Salud Pública de México ISSN: Instituto Nacional de Salud Pública México

Transcription

1 Salud Pública de México ISSN: Instituto Nacional de Salud Pública México Giuliano, Anna R.; Viscidi, Raphael Mechanisms of HPV Transmission in the Era of HPV Prevention Vaccines Salud Pública de México, vol. 49, 2007, pp Instituto Nacional de Salud Pública Cuernavaca, México Available in: How to cite Complete issue More information about this article Journal's homepage in redalyc.org Scientific Information System Network of Scientific Journals from Latin America, the Caribbean, Spain and Portugal Non-profit academic project, developed under the open access initiative

2 Nuevos paradigmas en la prevención de cáncer cervicouterino: de la investigación a la acción Mesa redonda I Mechanisms of HPV Transmission in the Era of HPV Prevention Vaccines Anna R. Giuliano,(1) Raphael Viscidi(2) The rate of HPV transmission between men and women is central to the current discussion of whether there is a public health benefit to vaccinating both males and females or only females against HPV infection to reduce the burden of cervical cancer and pre-cancerous lesions. This review examines the existent literature with respect to HPV and cancer, the association between natural immunity and HPV acquisition in females, HPV prevalence in males and its association to disease in women, and estimates of HPV concordance and transmissibility between heterosexual partners. Throughout this review the research needed to fill in the information gaps with respect to quantifying the rate of HPV transmission between partners will be highlighted. Introduction Anogenital cancers and their precursor lesions have been strongly linked to infection with the sexually transmitted Human Papillomavirus (HPV) among men and women. 1-3 One of the most commonly occurring cancers caused by HPV is invasive cervical cancer, which is estimated to account for 12% of all cancers worldwide. 4 HPV infection has also been strongly associated with anal cancer in men and women, where approximately 85% of the 44,000 cases that occur annually worldwide are attributable to HPV infection. 5 In the US, anal cancer affects approximately 3400 men and women annually and has increased over 35% among women in the past 15 years. 6-8 Approximately 50% of cancers of the vulva, vagina, and penis may be attributable to HPV infection, as well as 20% of oropharyngeal cancers, and 10% of cancers of the larynx, respiratory and digestive tracts. 1, 9 Invasive cervical and anal cancers are preventable diseases, as the technology exists to screen, diagnose, and treat pre-neoplastic lesions. However, due to lack of infrastructure in some countries, and/or incomplete participation in existing screening programs, cytologic screening has not eliminated these cancers. To decrease health care costs and patient burden, strategies that can prevent HPV related lesions are needed. One approach is the development and dissemination of an HPV vaccine. Published data to date indicate that HPV prevention vaccines are safe and efficacious in reducing HPV persistence among women and CIN 2/3 lesions of the cervix. 11, 13 Phase III testing of a vaccine directed against HPV types 6, 11, 16, and 18 among men is currently underway internationally with one pharmaceutical company. Based on the success of the female Phase II and data from the female Phase III studies Merck received FDA licensure of their quadrivalent HPV vaccine GAR- DASIL (HPV 6, 11, 16, 18) for females ages 9-26 years in the Spring of The Advisory Committee on Immunization Practices (ACIP) at the CDC recommended that this vaccine be broadly disseminated to females ages 9-26 yr in the US. A large part of the current considerations at the ACIP is whether the vaccine should be recommended for dissemination to males and females (1) University of South Florida (2) Johns Hopkins University School of Medicine E35

3 Mesa redonda I Nuevos paradigmas en la prevención de cáncer cervicouterino: de la investigación a la acción or to females only. The discussion focuses on whether there is an added public health benefit to vaccinating both sexes compared with only females and what the cost-effectiveness of a broad dissemination approach is compared to a targeted one. Several groups internationally are actively developing models to provide information to assist with this decision. However, all are limited in their modeling by the lack of information regarding the transmissibility of HPV between sexual partners, a factor that significantly influences cost-effectiveness estimates of including males in vaccination programs. Only a large prospectively designed male:female transmission study can generate the needed information to inform future decisions to expand this recommendation. Association Between Natural Humoral Immunity and HPV Acquisition in Women Following an HPV infection of the cervix, approximately 50% of women develop a systemic humoral immune response directed at the major viral capsid protein, which is detectable by VLP-based ELISA assays. 15 Determining whether the response confers protection against re-infection with the same or related HPV types is important for understanding the natural history of HPV infection and has implications for HPV transmission and for vaccine efficacy. A large population-based prospective study of HPV in Guanacaste Province, Costa Rica, failed to demonstrate that serum antibodies to HPV types 16, 18 or 31 elicited by natural infection are associated with immune protection against re-infection with the homologous HPV type or heterologous types. 16 However a study of college age women in the US showed that sustained high levels of antibody to HPV 16 were associated with a reduced risk for subsequent infection with HPV 16 and genetically related types. 17 Direct comparison between the studies is difficult because demographic characteristics of the populations, definition of immune status, duration of followup, and methods of analysis differed. In a study of seropositivity to VLPs of HPV types 16, 18, 31, 35 and 45 and subsequent cervical HPV infection among HIV positive and negative women, no significant difference in the risk of new infection with the homologous type was found between HPV seropositive and -seronegative women. 18 Likewise, there was no evidence for significant group-specific protection conferred by HPV seropositivity. These results from natural history studies conflict with the reported 100% efficacy of VLP-based vaccines administered to human volunteers. 12 One explanation is that the level of antibody elicited by natural infection is too low to confer protection. Three studies that compared vaccinated women to HPV-exposed, unvaccinated women found that the levels of antibody induced by HPV 16 infection were fold lower than post HPV 16 VLP vaccination levels. 12, 19, 20 A second potential explanation is that some of the newly detected infections in the above studies may have been reactivation of previous infection rather than an exogenously reacquired (transmitted) or true incident infection. In fact, in the study of Viscidi and colleagues, among HIV-infected women, who would be expected to be susceptible to reactivation due to immunosuppression, there was a generally elevated risk of new HPV infection associated with HPV seropositivity. 18 Finally, the studies may have misclassified the immune status of subjects as serology may not identify all immune persons. Approximately 50% of HPV-infected women do not seroconvert but may nevertheless be protected against subsequent infection by HPV specific cell mediated immunity or as a result of being primed for a rapid anamnestic antibody response. To understand how humoral immunity following natural HPV infection may influence transmission, serial measures are needed to distinguish transient from persistent seropositivity and IgG, IgM and IgA class antibody responses should be measured at the time of detection of new infections to distinguish re-infection or reactivation from incident infection in a previously unexposed person. Finally, studies of one or a few HPV types have limited power to address the question of protection because of the low incidence of infection with any single HPV type; measurement of antibodies to all currently detected mucosal genital types is needed to develop a full understanding of how immunity influences HPV transmission. The Male Factor in Cervical Carcinogenesis E36

4 Nuevos paradigmas en la prevención de cáncer cervicouterino: de la investigación a la acción Mesa redonda I The question of whether or not males should be vaccinated against HPV arises from the recognition that male HPV infection significantly contributes to infection and subsequent cervical disease in women Case-control studies of women with cervical cancer and their husbands have demonstrated that men s sexual behavior affects women s risk of cervical neoplasia, even when controlling for female sexual activity In areas with a high incidence of cervical cancer, the male partner s sexual behavior is in itself a risk factor for cervical neoplasia. 25 Among men with a history of multiple sexual partners, male circumcision was associated with a reduced risk of penile HPV infection and a reduced risk of cervical cancer in their current female partners. 26 The information to date regarding penile HPV infection is derived from primarily three sources: (1) studies where husbands of female cervical cancer cases were examined; 25, (2) cross-sectional studies of select populations, such as STI patients and military recruits; 32, 33 and (3) small prospective studies. 34, 35 Our published study of a population attending an STI clinic is one of the few studies of penile HPV infection conducted in the US. 36 Reported rates of HPV infection in men vary widely, in part due to use of different analytical methods and populations studied. In our recently completed review of the literature we found consistent detection of HPV when samples from the glans, corona, prepuce, and shaft were obtained. 37 Although fewer studies sampled the scrotum, this anatomic site also appears to contribute significantly to the detection of HPV in men. 38, 39 In addition to insufficient sites sampled, many published studies report difficulties with sample quality as reflected in poor b-globin positivity. Altogether these data suggest that published HPV prevalence estimates in men under-represent the true prevalence. Few published studies carefully assessed factors associated with HPV detection in men. 29, 36, 40, 41 In these studies sexual behavior was consistently associated with HPV prevalence, while circumcision status and condom use were variably associated with HPV detection in men. Among studies that measured HPV seroprevalence a higher prevalence of HPV 6, 11, 16, and 18 antibodies was observed in women compared to men. In addition, HPV antibody titer levels appear to be lower in men than women. The significance of a lower antibody prevalence and titer level in men with respect to HPV persistence, re-acquisition of infection, and transmission to women is unknown. HPV infections may be less likely to persist in men than in women. In a Dutch study, persistent infection (defined as detection of HPV DNA of a specific type at 2 consecutive visits over a period of 365 days) was observed more frequently in women (OR=3.88) than in men. Twenty percent of HPVpositive women and 6% of men manifested intermittently persistent infection, while short-lasting infection with proven regression of HPV was demonstrated in 49% of infected men and 31% of infected women. 34 In a recently published study by Dr. Lazcano and colleagues approximately 45% of men were HPV positive at baseline and 29.4% had a persistent infection after one year of followup. 42 Reduced risk of persistent infection was observed among circumcised men. As male sexual behavior clearly impacts rates of HPV infection, cervical dysplasia, and invasive cervical cancer in female partners, a greater understanding of HPV infection in men and transmission to women is an essential component of cervical cancer prevention programs. HPV Studies of Heterosexual Partners Several small HPV partner studies among heterosexual couples have been published. 37 All of these studies are cross-sectional and most included a relatively small sample size and used relatively insensitive methods for HPV detection. As such none contribute to our understanding of the transmissibility of HPV between heterosexual couples. However, they do provide an indication of the extent of concordance of infection. In a small study comparing HPV status in the cervix and semen of heterosexual sex partners, Kyo et al demonstrated that 75% of women whose male partners were HPV positive had HPV DNA in their cervix, while only 39% of the men whose partners were HPV positive carried HPV DNA in their semen. 43 Similarly Nicolau and colleagues reported that 76% of male partners of women with HPV were HPV DNA positive. 44 Campion et al, examining HPV disease in women whose sexual partners had penile condyloma, found that 76% of the women had genital E37

5 Mesa redonda I Nuevos paradigmas en la prevención de cáncer cervicouterino: de la investigación a la acción HPV infections, including 36% with abnormal cervical cytology and 27.7% with cervical HPV DNA detected by hybridization. 45 Among 45 couples attending a sexually transmitted disease clinic, Baken and colleagues found 20 couples with both partners HPV DNA positive by PCR and 13 couples were concordant for HPV type. 46 In a recent study by Bleeker and colleagues found that 57.8% of couples had the same HPV type detected. 47 This concordance is considerably higher than reported by Hippelainen and colleagues who report 22.7% HPV type concordance. 48 In 2006 Burchell and colleagues attempted to approximate the probability of heterosexual HPV transmission using computer simulation of data from a female HPV natural history study. Using this approach they estimated the transmission probability to be between 5-100% with a median probability of 40% clearly illustrating the need for research that can precisely estimate the heterosexual transmission rate of HPV. 49 Altogether these limited reports indicate that HPV type concordance among couples is highly variable with a highly variable rate of transmission. This variability may be due to differences in rates of HPV acquisition between men and women as well as differences in duration of infection and limited study design to address the question. Summary Investigation at two pharmaceutical companies is rapidly progressing such that a licensed HPV vaccine is now available. There are compelling data to suggest that male HPV infection and subsequent transmission of HPV to female sexual partners strongly influences HPV infection and cancer in women. Initial dissemination of prevention HPV vaccines will only involve females as there is insufficient data to provide an estimate of the public health impact of vaccinating both males and females and the cost-utility of vaccinating both males and females. The information needed to fill in this gap is an estimate of the per contact infectivity of HPV among sexual partners and vaccine efficacy in males. References 1. Daling JR, Sherman KJ. Relationship between human papillomavirus infection and tumours of anogenital sites other than the cervix. IARC Sci Publ. 1992(119): Munoz N. Human papillomavirus and cancer: the epidemiological evidence. J Clin Virol. Oct 2000;19(1-2): Schiffman MH, Bauer HM, Hoover RN, et al. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst. Jun ;85(12): Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, CA Cancer J Clin. Mar-Apr 2005;55(2): The Current Status of Development of Prophylactic Vaccines against Human Papillomavirus Infection: Report of a Technical Meeting. Geneva: International Agency for Research on Cancer; February 16-18, Cancer Facts and Figures docroot/stt/stt_0_2001.asp?sitearea=stt&level=1. 7. Johnson LG, Madeleine MM, Newcomer LM, Schwartz SM, Daling JR. Anal cancer incidence and survival: the surveillance, epidemiology, and end results experience, Cancer. Jul ;101(2): Palefsky JM. Human papillomavirus infection and anogenital neoplasia in human immunodeficiency virus-positive men and women. J Natl Cancer Inst Monogr. 1998(23): Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev. Feb 2005;14(2): Harper DM, Franco EL, Wheeler C, et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet. Nov ;364(9447): Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet. Apr ;367(9518): Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. Nov ;347(21): Mao C, Koutsky LA, Ault KA, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol. Jan 2006;107(1): Villa LL, Costa RL, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebocontrolled multicentre phase II efficacy trial. Lancet Oncol. May 2005;6(5): Viscidi RP, Roden RB. Papillomavirus-like Particles and Their Applications in MolecularVirology, Human Serology and Vaccines E38

6 Nuevos paradigmas en la prevención de cáncer cervicouterino: de la investigación a la acción Mesa redonda I In: Campo MS, ed. Papillomavirus Research: From Natural History to Vaccines and Beyond: Caister Academic Press; 2006: Viscidi RP, Schiffman M, Hildesheim A, et al. Seroreactivity to human papillomavirus (HPV) types 16, 18, or 31 and risk of subsequent HPV infection: results from a population-based study in Costa Rica. Cancer Epidemiol Biomarkers Prev. Feb 2004;13(2): Ho GY, Studentsov Y, Hall CB, et al. Risk factors for subsequent cervicovaginal human papillomavirus (HPV) infection and the protective role of antibodies to HPV-16 virus-like particles. J Infect Dis. Sep ;186(6): Viscidi RP, Snyder B, Cu-Uvin S, et al. Human papillomavirus capsid antibody response to natural infection and risk of subsequent HPV infection in HIV-positive and HIV-negative women. Cancer Epidemiol Biomarkers Prev. Jan 2005;14(1): Harro CD, Pang YY, Roden RB, et al. Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst. Feb ;93(4): Villa LL, Ault KA, Giuliano AR, et al. Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18. Vaccine. Jul ;24(27-28): Agarwal SS, Sehgal A, Sardana S, Kumar A, Luthra UK. Role of male behavior in cervical carcinogenesis among women with one lifetime sexual partner. Cancer. Sep ;72(5): Buckley JD, Harris RW, Doll R, Vessey MP, Williams PT. Casecontrol study of the husbands of women with dysplasia or carcinoma of the cervix uteri. Lancet. 1981;2(8254): Thomas DB, Ray RM, Pardthaisong T, et al. Prostitution, condom use, and invasive squamous cell cervical cancer in Thailand. Am J Epidemiol. Apr ;143(8): Zunzunegui MV, King MC, Coria CF, Charlet J. Male influences on cervical cancer risk. Am J Epidemiol. 1986;123(2): Bosch FX, Castellsague X, Munoz N, et al. Male sexual behavior and human papillomavirus DNA: key risk factors for cervical cancer in Spain. J Natl Cancer Inst. 1996;88(15): Castellsague X, Bosch FX, Munoz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med. Apr ;346(15): Shah KV. Human papillomaviruses and anogenital cancers. N Engl J Med. Nov ;337(19): Castellsague X, Ghaffari A, Daniel RW, Bosch FX, Munoz N, Shah KV. Prevalence of penile human papillomavirus DNA in husbands of women with and without cervical neoplasia: a study in Spain and Colombia. J Infect Dis. Aug 1997;176(2): Franceschi S, Castellsague X, Dal Maso L, et al. Prevalence and determinants of human papillomavirus genital infection in men. Br J Cancer. Mar ;86(5): Munoz N, Castellsague X, Bosch FX, et al. Difficulty in elucidating the male role in cervical cancer in Colombia, a highrisk area for the disease. J Natl Cancer Inst. 1996;88(15): Thomas DB, Ray RM, Kuypers J, et al. Human papillomaviruses and cervical cancer in Bangkok. III. The role of husbands and commercial sex workers. Am J Epidemiol. Apr ;153(8): Hippelainen M, Syrjanen S, Koskela H, Pulkkinen J, Saarikoski S, Syrjanen K. Prevalence and risk factors of genital human papillomavirus (HPV) infections in healthy males: a study on Finnish conscripts. Sex Transm Dis. Nov-Dec 1993;20(6): Strand A, Rylander E, Evander M, Wadell G. Genital human papillomavirus infection among patients attending an STD clinic. Genitourin Med. Dec 1993;69(6): Van Doornum GJ, Prins M, Juffermans LH, et al. Regional distribution and incidence of human papillomavirus infections among heterosexual men and women with multiple sexual partners: a prospective study. Genitourin Med. Aug 1994;70(4): Wikstrom A, Popescu C, Forslund O. Asymptomatic penile HPV infection: a prospective study. Int J STD AIDS. Feb 2000;11(2): Baldwin S, Wallace D, Papenfuss M, Abrahamsen M, Hallum J, Giuliano AR. Human papillomavirus infection in men attending a sexually transmitted disease clinic. J Infect Dis. April ;187(7). 37. Dunne EF, Nielson CM, Stone KM, Markowitz LE, Giuliano AR. Prevalence of HPV infection among men: A systematic review of the literature. J Infect Dis. Oct ;194(8): Nielson CM, Abrahamsen M, Dunne EF, et al. Genital HPV detection in asymptomatic men: design and preliminary analysis of optimal sampling site or specimens. Paper presented at: 22 nd International Papillomavirus Conference and Clinical Workshop; April 30th-May 2nd, 2005; Vancouver, BC, Canada. 39. Weaver BA, Feng Q, Holmes KK, et al. Evaluation of genital sites and sampling techniques for detection of human papillomavirus DNA in men. J Infect Dis. Feb ;189(4): Baldwin SB, Wallace DR, Papenfuss MR, Abrahamsen M, Vaught LC, Giuliano AR. Condom use and other factors affecting penile human papillomavirus detection in men attending a sexually transmitted disease clinic. Sex Transm Dis. Oct 2004;31(10): Lazcano-Ponce E, Herrero R, Munoz N, et al. High prevalence of human papillomavirus infection in Mexican males: comparative study of penile-urethral swabs and urine samples. Sex Transm Dis. May 2001;28(5): Lajous M, Mueller N, Cruz-Valdez A, et al. Determinants of prevalence, acquisition, and persistence of human papillomavirus in healthy Mexican military men. Cancer Epidemiol Biomarkers Prev. Jul 2005;14(7): Kyo S, Inoue M, Koyama M, Fujita M, Tanizawa O, Hakura A. Detection of high-risk human papillomavirus in the cervix and semen of sex partners. J Infect Dis. Sep 1994;170(3): Nicolau SM, Camargo CG, Stavale JN, et al. Human papillomavirus DNA detection in male sexual partners of women with genital human papillomavirus infection. Urology. Feb 2005;65(2): Campion MJ, Singer A, Clarkson PK, McCance DJ. Increased risk of cervical neoplasia in consorts of men with penile condylomata acuminata. Lancet. Apr ;1(8435): Baken LA, Koutsky LA, Kuypers J, et al. Genital human papillomavirus infection among male and female sex partners: prevalence and type-specific concordance. J Infect Dis. Feb 1995;171(2): E39

7 Mesa redonda I Nuevos paradigmas en la prevención de cáncer cervicouterino: de la investigación a la acción 47. Bleeker MC, Hogewoning CJ, Berkhof J, et al. Concordance of specific human papillomavirus types in sex partners is more prevalent than would be expected by chance and is associated with increased viral loads. Clin Infect Dis. Sep ;41(5): Hippelainen MI, Yliskoski M, Syrjanen S, et al. Low concordance of genital human papillomavirus (HPV) lesions and viral types in HPV-infected women and their male sexual partners. Sex Transm Dis. Mar-Apr 1994;21(2): Burchell AN, Richardson H, Mahmud SM, et al. Modeling the sexual transmissibility of human papillomavirus infection using stochastic computer simulation and empirical data from a cohort study of young women in Montreal, Canada. Am J Epidemiol. Mar ;163(6): E40