Human Papillomavirus
        Vaccine to prevent HPV infection
Cigarette Smoking
Reproductive Behavior
Dietary Factors

Human Papillomavirus

Epidemiologic studies to evaluate risk factors for the development of squamous intraepithelial lesions (SIL) and cervical malignancy demonstrate conclusively a sexual mode of transmission of a carcinogen.[1] It is now widely accepted that human papillomavirus (HPV) is the primary etiologic infectious agent.[2-4] Other sexually transmitted factors, including herpes simplex virus 2, may play a cocausative role.[1] The finding of HPV viral DNA integrated in most cellular genomes of invasive cervical carcinomas supports epidemiologic data linking this agent to cervical cancer;[5] however, direct causation has not been demonstrated. More than 80 distinct types of HPV have been identified, approximately 30 of which infect the human genital tract. HPV types 16 and 18 are most often associated with invasive disease. Characterization of carcinogenic risk associated with HPV types is an important step in the process of developing a combination HPV vaccine for the prevention of cervical neoplasia. In a population-based study of HPV infection and cervical neoplasia in Costa Rica, 80% of high-grade squamous intraepithelial lesions (HSIL) and invasive lesions were associated with HPV infection by one or more of 13 cancer-associated types.[6] In this study, the risk of about half of HSIL and invasive cervical cancer was attributable to HPV-16. HPV-18 was associated with 15% of invasive disease but only 5% of HSIL, suggesting that HPV-18 may have a role in more aggressive cases of cervical malignancy.

Barrier methods of contraception are associated with a reduced incidence of SIL presumptively secondary to protection from sexually transmitted disease.[7,8] The effectiveness of condom use for the prevention of HPV infections has been evaluated in a prospective study of women aged 18 to 22 years who were virgins.[9] The number of vulvovaginal HPV infections was reduced with consistent condom use, and HPV infection rate was 37.8 infections per 100 patient-years among women whose partners used condoms 100% of the time in the 8 months before testing, compared with 89.3 infections per 100 patient-years among women whose partners used condoms less than 5% of the time (P trend = .005). No cervical SIL were detected among women reporting 100% condom use by their partner.[9]

Given the etiologic role of HPV in the pathogenesis of cervical neoplasia, vaccines to immunize against HPV infection would offer a primary prevention strategy for cervical cancer. A quadrivalent (HPV 6, 11, 16, and 18) vaccine using a late protein L1 construct to induce antibody-mediated immunity was approved for use by the U.S. Food and Drug Administration in 2006; a second bivalent (HPV 16, 18) vaccine is awaiting final review.

Persistent infection with oncogenic types of HPV such as HPV-16 and HPV-18 is associated with the development of cervical cancer.[10] A vaccine to prevent HPV infection with oncogenic-type viruses has the potential to reduce the incidence of cervical cancer. A vaccine against HPV-16 using empty-viral capsids called virus-like particles was developed and tested for efficacy in preventing persistent infection with HPV-16.

A multicenter, double-blind, placebo-controlled trial enrolled 2,391 women aged 16 to 23 years and randomly assigned them to receive either 40 µg of HPV-16 L1 virus-like particle (VLP) vaccine or placebo on day 1, at 2 months, and at 6 months. Papanicolaou (Pap) tests and genital samples for HPV-16 DNA were obtained on day 1, at 7 months, and every 6 months for 48 months. Colposcopy and cervical biopsies were obtained when clinically indicated at study exit. Serum HPV-16 antibody titers were obtained at study entry, at 7 months, and then every 6 months. A total of 1,505 women (755 receiving vaccine and 750 receiving placebo) completed all three vaccinations and had follow-up after month 7. After immunization, HPV titers peaked at month 7, declined through month 18, and then stabilized in months 30 through 48. There were no cases of cervical intraepithelial neoplasia (CIN) in the vaccine-treated women, but there were 12 cases in the placebo group (six CIN 2 and six CIN 3). HPV-16 infection that persisted for at least 4 months was seen in seven vaccine-treated women versus 111 placebo-treated women.[11]

An international, double-blind, placebo-controlled trial of a bivalent HPV-16/HPV-18 VLP vaccine was performed in 1,113 women aged 15 to 25 years.[12] Women received either vaccine or placebo at 0, 1, and 6 months and were assessed by cervical cytology and self-obtained cervicovaginal samples for up to 27 months. Follow-up analysis of 776 women showed that vaccinated women had stable serum antibody titers at 4.5 years and continued protection against HPV-16/HPV-18 infection. Incident infections decreased from 28 of 277 control women to 1 of 310 vaccinated women, a decline of 96.9% (confidence interval [CI], 81.3%–99.9%). Persistent infections according to 12-month definition decreased from 10 of 340 control women to 0 of 357 vaccinated women, a decline of 100% (CI, 57.0%–100%). CIN 1+ and CIN 2+ associated with HPV-16/HPV-18 were reduced from 13 of 470 control women to 0 of 481 vaccinated women. Incident infections with HPV-45 and HPV-31 were reduced by 94% and 54%, respectively. Adverse events, serious adverse events, and new-onset chronic disease were similar in vaccinated and placebo-treated women.

A quadrivalent vaccine (HPV types 6, 11, 16, and 18) was evaluated in two multinational, double-blind, randomized controlled trials of 5,455 women aged 16 to 24 years and in 12,167 women aged 15 to 26 years (FUTURE I and FUTURE II, respectively).[13,14] Women received either the HPV vaccine or placebo at 0, 2, and 6 months; participants were assessed by clinical exam, Pap test, and HPV DNA testing for up to 4 years. The composite endpoint for cervical disease included the incidence of HPV-16/18-related CIN 1 (FUTURE I only), CIN 2, CIN 3, adenocarcinoma in situ, or invasive carcinoma. Outcomes were reported as follows:

It is important to recognize that composite endpoints were utilized as the primary endpoint in both of these trials, a substantial proportion of the cases were CIN 1 and 2 lesions, which are known to have a high likelihood of spontaneous resolution without medical intervention. This could have potentially inflated the observed vaccine efficacy. No cases of invasive cervical cancer were identified during either trial.

As largely expected based upon their mechanism of action, L1/2 HPV vaccines do not appear to impact pre-existing infections. The FUTURE trials demonstrated markedly lower vaccine efficacy rates in the total randomized study populations, which included individuals positive for HPV at baseline, versus the “per-protocol” populations (44%–55% vs. 98%–100%, see table above).[13,14] Additionally, an intermediate analysis of a randomized controlled trial primarily evaluating the efficacy of the HPV-16/18 vaccine in preventing infection found no effect on viral clearance rates in women aged 18 to 25 years who were positive at the time of study enrollment.[15]

The type-specific vaccines, if successful in preventing invasive cancer, will offer protection for only a subset of cases, the proportion of which will vary worldwide.[16] Using data from a multicenter case-control study conducted in 25 countries, it was estimated that a vaccine containing the seven most common HPV types could prevent 87% of cervical cancers worldwide. A vaccine with HPV-16 and HPV-18 types, the two most common strains, would prevent 71% of cervical cancers worldwide.[16]

Cigarette smoking by women is associated with an increased risk for squamous cell carcinoma.[1,17,18] This risk increases with longer duration and intensity of smoking and may be present with exposure to environmental tobacco smoke, being as high as four times that of women who are nonsmokers and are not exposed to environmental smoking.[1] Case-control studies of women infected with HPV have examined the effect of various types and levels of tobacco exposure and found similar results.[18,19]

High parity has long been recognized as a risk factor for cervical cancer, but the relation of parity to HPV infection was uncertain. A meta-analysis of 25 epidemiologic studies including 16,563 women with cervical cancer and 33,542 women without, showed that the number of full-term pregnancies was associated with increased risk, regardless of age at first pregnancy. This finding was also true if analyses were limited to patients with high-risk HPV infections (relative risk = 4.99 [3.49–7.13] for seven or more pregnancies versus no pregnancies; linear trend test x² = 30.69; P < .001).[20]

Long-term use of oral contraceptives has also been known to be associated with cervical cancer, but its relation to HPV infection was also uncertain. A pooled analysis of HPV-positive women from the studies described above was undertaken. Compared with women who have never used oral contraceptives, those who have used them for fewer than 5 years did not have an increased risk of cervical cancer (odds ratio [OR] = 0.73; 95% CI, 0.52–1.03). The OR for women who used oral contraceptives for 5 to 9 years was 2.82 (1.46–5.42) and for 10 or more years the OR was 4.03 (2.09–8.02).[21] A meta-analysis of 24 epidemiological studies confirmed the increased risk associated with oral contraceptives, which is proportionate to the duration of use. Risk decreases after cessation and returns to normal risk levels in 10 years.[22]

Multiple case-control studies show an association between intake of some micronutrients and lower risk of cervical cancer, but results are conflicting and difficult to control for other risk factors. Two randomized trials of oral folate as a chemopreventive agent have shown no protective effect.

References

1. Brinton LA: Epidemiology of cervical cancer--overview. IARC Sci Publ (119): 3-23, 1992.  [PUBMED Abstract]
   
   
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 85 (12): 958-64, 1993.  [PUBMED Abstract]
   
   
3. Ley C, Bauer HM, Reingold A, et al.: Determinants of genital human papillomavirus infection in young women. J Natl Cancer Inst 83 (14): 997-1003, 1991.  [PUBMED Abstract]
   
   
4. Muñoz N, Bosch FX, de Sanjosé S, et al.: The causal link between human papillomavirus and invasive cervical cancer: a population-based case-control study in Colombia and Spain. Int J Cancer 52 (5): 743-9, 1992.  [PUBMED Abstract]
   
   
5. Reeves WC, Rawls WE, Brinton LA: Epidemiology of genital papillomaviruses and cervical cancer. Rev Infect Dis 11 (3): 426-39, 1989 May-Jun.  [PUBMED Abstract]
   
   
6. Herrero R, Hildesheim A, Bratti C, et al.: Population-based study of human papillomavirus infection and cervical neoplasia in rural Costa Rica. J Natl Cancer Inst 92 (6): 464-74, 2000.  [PUBMED Abstract]
   
   
7. Parazzini F, Negri E, La Vecchia C, et al.: Barrier methods of contraception and the risk of cervical neoplasia. Contraception 40 (5): 519-30, 1989.  [PUBMED Abstract]
   
   
8. Hildesheim A, Brinton LA, Mallin K, et al.: Barrier and spermicidal contraceptive methods and risk of invasive cervical cancer. Epidemiology 1 (4): 266-72, 1990.  [PUBMED Abstract]
   
   
9. Winer RL, Hughes JP, Feng Q, et al.: Condom use and the risk of genital human papillomavirus infection in young women. N Engl J Med 354 (25): 2645-54, 2006.  [PUBMED Abstract]
   
   
10. Wallin KL, Wiklund F, Angström T, et al.: Type-specific persistence of human papillomavirus DNA before the development of invasive cervical cancer. N Engl J Med 341 (22): 1633-8, 1999.  [PUBMED Abstract]
    
    
11. 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 107 (1): 18-27, 2006.  [PUBMED Abstract]
    
    
12. 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 367 (9518): 1247-55, 2006.  [PUBMED Abstract]
    
    
13. Garland SM, Hernandez-Avila M, Wheeler CM, et al.: Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 356 (19): 1928-43, 2007.  [PUBMED Abstract]
    
    
14. FUTURE II Study Group.: Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 356 (19): 1915-27, 2007.  [PUBMED Abstract]
    
    
15. Hildesheim A, Herrero R, Wacholder S, et al.: Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. JAMA 298 (7): 743-53, 2007.  [PUBMED Abstract]
    
    
16. Muñoz N, Bosch FX, Castellsagué X, et al.: Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer 111 (2): 278-85, 2004.  [PUBMED Abstract]
    
    
17. Hellberg D, Nilsson S, Haley NJ, et al.: Smoking and cervical intraepithelial neoplasia: nicotine and cotinine in serum and cervical mucus in smokers and nonsmokers. Am J Obstet Gynecol 158 (4): 910-3, 1988.  [PUBMED Abstract]
    
    
18. Brock KE, MacLennan R, Brinton LA, et al.: Smoking and infectious agents and risk of in situ cervical cancer in Sydney, Australia. Cancer Res 49 (17): 4925-8, 1989.  [PUBMED Abstract]
    
    
19. Ho GY, Kadish AS, Burk RD, et al.: HPV 16 and cigarette smoking as risk factors for high-grade cervical intra-epithelial neoplasia. Int J Cancer 78 (3): 281-5, 1998.  [PUBMED Abstract]
    
    
20. International Collaboration of Epidemiological Studies of Cervical Cancer.: Cervical carcinoma and reproductive factors: collaborative reanalysis of individual data on 16,563 women with cervical carcinoma and 33,542 women without cervical carcinoma from 25 epidemiological studies. Int J Cancer 119 (5): 1108-24, 2006.  [PUBMED Abstract]
    
    
21. Moreno V, Bosch FX, Muñoz N, et al.: Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study. Lancet 359 (9312): 1085-92, 2002.  [PUBMED Abstract]
    
    
22. Appleby P, Beral V, Berrington de González A, et al.: Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet 370 (9599): 1609-21, 2007.  [PUBMED Abstract]
    
    

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