Evidence of Benefit
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. It is now widely accepted that human papillomavirus (HPV) is the primary etiologic infectious agent that causes virtually all cases of cervical cancer.[2,3] Other sexually transmitted factors, including herpes simplex virus 2 and Chlamydia trachomatis, may play a cocausative role. 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. 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.[6,7] 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. 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.
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 bivalent (HPV 16, 18) vaccine was approved in 2009.
Vaccine to prevent HPV infection
Persistent infection with oncogenic types of HPV such as HPV-16 and HPV-18 is associated with the development of cervical cancer. 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 (VLP) 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 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.
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 with normal cervical cytology who were seronegative for HPV-16, HPV-18, and 12 other oncogenic HPV types at enrollment. Women received either vaccine or placebo at 0, 1, and 6 months and were assessed by cervical cytology and self-obtained cervicovaginal samples for at least 18 months. A masked treatment allocation follow-up study was performed for an additional 3 years, for a combined analysis of up to 6.4 years of follow-up. The 12-month persistent infection rate of HPV-16 or HPV-18 in an “according-to-protocol” cohort (i.e., women who received all three doses of vaccine or placebo on the correct schedule) was 0 of 401 women in the vaccine arm versus 20 of 372 women in the placebo arm, with a vaccine efficacy of 100% (95% confidence interval [CI], 81.8–100). Diagnoses of CIN 2 or higher in a “total vaccinated” cohort (i.e., women who received at least one dose of vaccine or placebo) were 0 of 481 women in the vaccine arm versus 9 of 470 women in the placebo arm, with a vaccine efficacy of 100% (95% CI, 51.3–100). Adverse events were similar in vaccinated and placebo-treated women. It is important to note that neither analysis was intention-to-treat (ITT), making it difficult to know what the true vaccine efficacy for either virological or cytohistological endpoints would be in the routine clinical setting. Furthermore, cytohistological outcomes were reported only as composite endpoints (CIN 2+), making it impossible to distinguish the vaccine’s efficacy against invasive cervical cancer alone and potentially inflating the observed efficacy by including lesions with a relatively high probability (approximately 50% for CIN 2 ) of spontaneous regression.
A quadrivalent vaccine (HPV types 6, 11, 16, and 18) was evaluated in a multinational, double-blind, randomized controlled trial of 17,622 women aged 15 to 26 years (FUTURE I and II). 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 4 or more years. Two analyses were reported. One group was considered to be HPV naive: negative to 14 HPV types. The second group was an ITT analysis, which approximates a sexually active population. The composite endpoint for cervical disease included the incidence of HPV-16/18-related, CIN 2, CIN 3, adenocarcinoma in situ, or invasive carcinoma. Outcomes were reported as follows:
|Population||Point Estimate and 95% CI|
|CI = confidence interval; CIN = cervical intraepithelial neoplasia; HPV = human papillomavirus; ITT = intention-to-treat.|
|HPV naive population for HPV-CIN 3||100% (90.5%–100%) for lesions associated with HPV 6, 11,16, or 18|
|ITT CIN 3||45.3% (29.8%–57.6%) for lesions associated with HPV 6, 11, 16, or 18|
This study also demonstrated decreased rates of abnormal Pap tests and subsequential diagnostic procedures. No cases of invasive cervical cancer were identified during the trial.
As largely expected based upon their mechanism of action, L1/2 HPV vaccines do not appear to impact pre-existing infections. The FUTURE II trial demonstrated a markedly lower vaccine efficacy rate in the total randomized study population, which included individuals positive for HPV at baseline, versus the “per-protocol” population (44% for lesions associated with HPV 16 or 18 and 17% for lesions associated with any HPV type vs. 98%, see table above). 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.
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. 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.
Anal HPV infection
Anal cancer occurs rarely: the international age-adjusted annual incidence is about 1.5 cases per 100,000 women. However, rates have been increasing in Europe and the United States over the past few decades. As with cervical cancer, HPV-16 and HPV-18 are associated with a majority of anal cancer cases. To estimate the efficacy of the bivalent vaccine against anal HPV infections in women, investigators examined a subset of women participating in a randomized controlled trial principally designed to assess vaccine efficacy against persistent cervical HPV-16/18 infections and associated precancerous lesions. In the original trial, 6,352 women aged 18 to 25 years received three doses of the bivalent vaccine or a control hepatitis A vaccine and were followed for 4 years after the first administration. Women that attended the 4-year study visit, consented to provide anal specimens, and completed a survey regarding anal sexual behaviors (n = 4,210) were included in this secondary analysis. The efficacy of the vaccine against prevalent HPV-16/18 anal infections was 62% (95% CI, 47.1–73.1) for an ITT cohort. Limitations of this study include an inability to assess the baseline anal HPV infection rate in the population or to use HPV persistence as the endpoint of interest; given a high rate of spontaneous resolution of HPV infection, the endpoint of HPV prevalence will overestimate the efficacy of the vaccine. Additionally, there was a high attrition rate: the subgroup represented 56% of the original trial participants, of which 27% were lost due to noncompliance with anal sampling. The study provides no information about the efficacy of the vaccine against precancerous anal lesions or anal cancer.
Cigarette smoking by women is associated with an increased risk of squamous cell carcinoma.[1,18,19] In current smokers, this risk increases with the number of cigarettes smoked per day and younger age at initiation of smoking. Case-control studies of women infected with HPV have examined the effect of various levels of tobacco exposure and found similar results.
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 cervical cancer, 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).
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). 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.
Diethylstilbestrol (DES) Exposure
DES is a synthetic form of estrogen that was prescribed to pregnant women in the United States between 1940 and 1971 to prevent miscarriage and premature labor. DES is associated with a substantially increased risk of developing clear cell adenocarcinoma of the vagina and cervix among the daughters of women who used the drug during pregnancy (standardized incidence ratio, 24.23; 95% CI, 8.89–52.74); the risk persists as these women age into their 40s. Despite the greatly elevated risk relative to the general population, this type of cancer is still rare; about 1 in 1,000 daughters exposed to DES will develop a clear cell adenocarcinoma.
DES exposure in utero is also associated with an increased risk of developing cervical dysplasia. An evaluation of three cohorts, including the Diethylstilbestrol Adenosis study, the Dieckmann study, and the Women’s Health Study, with long-term follow-up of more than 4,500 women exposed in utero to DES, found that 6.9% of exposed women developed grade II or higher CIN versus 3.4% of nonexposed women (hazard ratio, 2.28; 95% CI, 1.59–3.27).
- Brinton LA: Epidemiology of cervical cancer--overview. IARC Sci Publ (119): 3-23, 1992. [PUBMED Abstract]
- Schiffman M, Castle PE, Jeronimo J, et al.: Human papillomavirus and cervical cancer. Lancet 370 (9590): 890-907, 2007. [PUBMED Abstract]
- Trottier H, Franco EL: The epidemiology of genital human papillomavirus infection. Vaccine 24 (Suppl 1): S1-15, 2006. [PUBMED Abstract]
- Ault KA: Epidemiology and natural history of human papillomavirus infections in the female genital tract. Infect Dis Obstet Gynecol 2006 (Suppl): 40470, 2006. [PUBMED Abstract]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- Castle PE, Schiffman M, Wheeler CM, et al.: Evidence for frequent regression of cervical intraepithelial neoplasia-grade 2. Obstet Gynecol 113 (1): 18-25, 2009. [PUBMED Abstract]
- Romanowski B, de Borba PC, Naud PS, et al.: Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years. Lancet 374 (9706): 1975-85, 2009. [PUBMED Abstract]
- 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]
- 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]
- 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]
- Stewart BW, Kleihues P, eds.: World Cancer Report 2003. Lyon, France: International Agency for Research on Cancer, 2003. Also available online. Last accessed January 30, 2015.
- Kreimer AR, González P, Katki HA, et al.: Efficacy of a bivalent HPV 16/18 vaccine against anal HPV 16/18 infection among young women: a nested analysis within the Costa Rica Vaccine Trial. Lancet Oncol 12 (9): 862-70, 2011. [PUBMED Abstract]
- Plummer M, Herrero R, Franceschi S, et al.: Smoking and cervical cancer: pooled analysis of the IARC multi-centric case--control study. Cancer Causes Control 14 (9): 805-14, 2003. [PUBMED Abstract]
- Appleby P, Beral V, Berrington de González A, et al.: Carcinoma of the cervix and tobacco smoking: collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological studies. Int J Cancer 118 (6): 1481-95, 2006. [PUBMED Abstract]
- 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]
- 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]
- 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]
- Verloop J, van Leeuwen FE, Helmerhorst TJ, et al.: Cancer risk in DES daughters. Cancer Causes Control 21 (7): 999-1007, 2010. [PUBMED Abstract]
- Hoover RN, Hyer M, Pfeiffer RM, et al.: Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med 365 (14): 1304-14, 2011. [PUBMED Abstract]