The burden of human papillomavirus infections and the expected impact of the new vaccines

Human papillomavirus (HPV) infection is the sexually transmitted infection with the highest incidence in the USA. It is also the cause of almost 100% of cervical cancers. The second vaccine against a major human cancer, namely the HPV vaccine, may be an important breakthrough in the effort to reduce the burden of HPV infection and its consequences.

Approximately 100 HPVs have been identified, over 40 of which can infect the genital area. Globally, genital HPV infection is the most common sexually transmitted infection. In the USA, it is estimated that 6.2 million people are infected every year [1]. Almost half of the infections occur in those aged 15–25 years. At least half of all sexually active men and women will acquire a HPV infection at some point in their lifetime.

Genital HPV types are classified according to their association with cervical cancer into low- and high-risk types. Among low-risk types, HPV-6 and -11 cause the vast majority of clinical lesions. Recent studies have shown that HPV-6/11 cause approximately 100% of genital warts. Other lesions caused by HPV-6/11 include cervical intraepithelial neoplasia (CIN), Buschke–Lowenstein tumors, recurrent respiratory papillomatosis and, occasionally, anal, vulval and penile cancers (2.5–5% of these lesions) [2].

High-risk HPV types include types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59. Infection with a high-risk HPV type is a necessary factor for cervical cancer. However, this is not sufficient, since factors such as the number of full-term pregnancies, tobacco smoking and long-term use of hormonal contraceptives have been established as cofactors for the progression from cervical HPV infection to cancer [3]. HPV-16/18 accounts for approximately 70% of cervical cancer cases. These types are also responsible for 80–90% of anal cancers. Furthermore, variable percentages of vulvar, vaginal and penile cancers are positive for high-risk HPV types.

HPVs are DNA viruses with an 8-kb genome enclosed in a capsid shell composed of the major and minor capsid proteins L1 and L2. The genome encodes, apart from these two structural proteins, several early proteins (E1, E2, E4–E7) that enable viral transcription and replication. Viral proteins E6 and E7 have a critical role in the process of viral replication. Furthermore, they interact with cellular proteins and these interactions can induce immortalization and malignant transformation of infected cells.

The majority of HPV infections are benign, subclinical and self-limited. Approximately 90% of them regress spontaneously within 2 years of infection. Persistent cervical infection with a high-risk HPV type is the most important risk factor for high-grade dysplasia and invasive cancer.

The burden of HPV infection

Worldwide, cervical cancer is the second most common cause of female cancer mortality, with 510,000 newly diagnosed cases and 288,000 deaths annually [101]. Approximately 80% of the cases occur in developing countries, where cervical cancer accounts for 15% of female cancers. Since cervical cancer affects comparatively young women, it is an important cause of lost years of life. It has been estimated that cervical cancer was responsible for 2.7 million years of life lost globally in 2000 and it is the primary cause of years of life lost from cancer in the developing world [4]. Apart from cervical cancer, in 2002 there were approximately 68,300 HPV-associated noncervical cancers worldwide.

In most developed countries, cytology-based screening has reduced the incidence of cervical cancer over the last 50 years by up to 75%. Nevertheless, CIN-2/3 still cause significant morbidity in women. In the USA, approximately 750,000 women are diagnosed each year with CIN-2/3. The costs of routine cervical cancer screening, as well as the costs of evaluating women with abnormal cervical cytology and treating women with CIN-2/3, approach a yearly total of US$3.6 billion in the USA [5].

Conversely, genital warts do not usually result in major physical morbidity, but cause significant psychological morbidity and substantial healthcare costs. In the UK, approximately GB£31 million (US$54 million) are spent annually for the management of genital warts [6], while in the USA, the annual direct healthcare cost of genital warts is estimated to be approximately US$200 million [7].

The new vaccines

Two prophylactic HPV vaccines have been developed. Both are composed of HPV type-specific L1 proteins that self-assemble into noninfectious, recombinant virus-like particles (VLPs) that resemble the outer capsid of the virus. One of the vaccines is quadrivalent and protects against HPV-6, -11, -16 and -18 (Gardasil^®, Merck and Co., Inc.). This vaccine has been licensed in several countries, including the USA, Australia, Canada and some European countries. The other vaccine is a bivalent HPV-16/18 vaccine (Cervarix^®, GlaxoSmithKline Biologicals) that has not yet been approved.

Several studies have evaluated the efficacy of the quadrivalent vaccine in the prevention of HPV-related infection and disease. CIN-2/3 and adenocarcinoma in situ have been used as primary end points in these efficacy trials, since it would be ethically unacceptable to use invasive cancer as the end point. Results from the Future II Study, which were published recently [8], demonstrated 98% efficacy in preventing CIN-2/3 and adenocarcinoma in situ in 15–26 year old females who had no virologic evidence of infection with the HPV types that were included in the vaccine before vaccination. The Future I Study, also published recently [9], revealed 100% efficacy of the quadrivalent vaccine in preventing CIN-2/3, adenocarcinoma in situ, anogenital warts and all grades of vulvar and vaginal intraepithelial neoplasia in previously uninfected women.

What we already know about the quadrivalent vaccine is that it is highly effective in females of 15–26 years of age who are not infected with vaccine-type HPV before vaccination. In addition, the vaccine has no therapeutic action, since it does not appear to alter the course of HPV infection present before administration of the first vaccine dose. However, we do not know the duration of the vaccine’s protection on whether boosters are needed. The maximum reported follow-up period is 5 years [10]. Finally, we do not know whether the vaccine is effective in men. Adolescent males mount higher antibody responses to the vaccine than young adult females [11], but whether the vaccine can prevent genital infection and lesions in men remains to be proven.

Expected impact of the new vaccines

Currently, routine vaccination with the quadrivalent vaccine is recommended for females aged 11–12 years [12,13]. Ideally, vaccination should occur before sexual debut, since HPV infection is often acquired soon after the onset of sexual activity. Females aged 13–26 years could receive catch-up vaccination but, if they are already infected with some of the vaccine-specific HPV types, they would receive less benefit from the vaccine since they would only be protected against disease caused by the vaccine HPV types that they are not already infected with. Cervical cancer screening recommendations have not changed for females who receive the vaccine, since the HPV types that are included in the vaccine (HPV-16/18) are responsible for approximately 70% and not 100% of cervical cancers. The vaccine is not licensed yet for females older than 26 years or for males because there is a lack of data concerning its efficacy in these populations.

The development of vaccines against a major human cancer, namely the HPV vaccine, is a great advance in preventive medicine. Models that have been developed to evaluate the impact of HPV vaccine suggest that vaccination of an entire cohort of females aged 12 years could reduce the lifetime risk of cervical cancer by 20–66% [12]. However, since cervical cancer is quite uncommon in young women, the full benefit of vaccination on cancer rates might not be observed for 30–50 years. Models also indicate decreases in Pap test abnormalities and cervical cancer precursor lesions as a result of vaccination. However, in the context of existing cervical cytology screening, the clinical benefits of vaccination compared with screening alone will depend on the effectiveness of the screening program. In developed countries with well-organized screening programs, the cost–effectiveness of vaccination will depend on whether or not it will be acceptable to initiate screening at a later age, screen less frequently and adopt a conservative approach to managing equivocal and mildly abnormal screening test results.

Undoubtedly, the potential impact of a HPV vaccine will be greater in the developing world, where cervical cancer is the leading cause of cancer mortality in many countries and where most women have no access to screening or adequate treatment. However, several factors may limit the widespread distribution of the vaccines in developing countries. The vaccines are expensive to manufacture and distribute since they involve three intramuscular injections and a cold chain for storage. In addition, the target group is preadolescent girls, a group that will not be easily enrolled in a vaccination program. Third, factors such as those mentioned above need 30–50 years for a reduction in cervical cancer incidence due to vaccination; the incomplete high-risk type coverage of the vaccines, and their prophylactic, not therapeutic, potential may assign them a low priority in the real world of competing healthcare interventions.

HPV vaccination has the potential to make a huge impact on HPV-related morbidity and mortality. Nevertheless, several questions have to be answered, and multiple challenges have to be addressed, to make sure the vaccination is implemented in all populations in the most cost-efficient manner.

Financial disclosure

The authors have no relevant financial interests related to this manuscript, including employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.