Joshua A. Zeichner, md Department of Dermatology Mt Sinai Hospital 5 East 98th Street 5th Floor, Box 1048 New York, NY 10029 USA Tel: 212-659-9530 Fax: 212-348-7434 E-mail: firstname.lastname@example.org
Cervical cancer is a preventable health problem, yet is the second most common cancer of women worldwide. More than 80% of cases occur in developing countries, and this is expected to increase to 90% by the year 2020. The five-year survival rate of patients in developing countries is less than 50%, compared to 66% in developed nations. A worldwide HPV vaccine program would significantly reduce the spread of HPV 16 and 18 and lower the incidence of cervical cancer. Mathematical models have determined that vaccinating 66% of the population will decrease the incidence of cervical cancer by 80% over the next 40–60 years. For every five-year delay in a cervical cancer prevention/detection program, there will be an additional 1.5–2.0 million deaths. The introduction of a vaccination program will be a challenge due to high costs, unknown durability of the vaccine, and the potential for new oncogenic strains to emerge. A global effort will be required to eliminate cervical cancer from developing counties.
Cervical cancer is a preventable public health problem that ranks as the second most common cancer of women worldwide. Cervical cancer is most commonly diagnosed in women 35–50 years old. However, initial infection usually occurs decades earlier.1 There is an annual global incidence of nearly 500 000 new cases, with 274 000 deaths per year.2 More than 80% of these cases occur in developing countries, and this percentage is expected to increase to nearly 90% by the year 2020. The 5-year survival rate of patients in developing countries is less than 50% compared with 66% in developed nations.3 Morbidity and mortality from cervical cancer can have catastrophic social and economic effects, including decreased school attendance and poorer nutrition among surviving children (Fig. 1).4
Human papillomavirus (HPV) is one of several viruses with a known link to cancer.5 Dr. Harald zur Hausen was awarded the 2008 Nobel Prize for Physiology or Medicine for his contribution to demonstrating the link between HPV and cancer of the cervix.6 There are more than 100 different HPV strains, but the high risk HPV 16 and 18 are responsible for over 70% of cases worldwide.7 The introduction of the Papanicolaou test (Pap smear) into general screening programs in the United States has reduced the incidence of advanced forms of cervical cancer by 75% over the past few decades.8,9 However, underdeveloped nations lack funding to establish organized screening programs to detect cervical cancer at an early stage.
Efforts have been made to develop screening programs world-wide to detect and treat HPV-induced cervical cancer. The most cost-effective strategies for diagnosis and treatment would include the fewest number of screenings and laboratory tests possible, without sacrificing efficacy. While more frequent screening tests may be more effective, they are also more costly.10 Thus a balance must be reached. One-time screening reduces the lifetime risk of cervical cancer 25–36%; this risk declines by an additional 40% when two screenings are performed.11
The HPV vaccine
The quadrivalent HPV vaccine (Gardasil) is currently approved by the Food and Drug Administration for “girls and women nine through 26 years of age for the prevention of diseases caused by HPV types included in the vaccine.”12 These diseases include cervical, vulvar, vaginal and anorectal neoplasias, genital warts, cancer of the penis, bowenoid papulosis, Bowen’s disease, and oropharyngeal cancer (Fig. 2). Gardasil is a recombinant vaccine, composed of purified virus-like particles of the major capsid protein of four HPV types. Gardasil provides immunity to the high risk HPV 16 and 18, as well as HPV 6 and 11 strains, which are responsible for 90% of the cases of anogenital condylomata.12
Gardasil is targeted toward girls who have not previously been exposed to the HPV virus. The current recommendation is that patients should receive the vaccine prior to the onset of sexual activity, at approximately 12 years of age. Women as old as 26 should also be vaccinated as a catch-up strategy to treat as much of the general population as quickly as possible.13,14
Cost effectiveness of vaccination programs
An HPV vaccine program in underdeveloped nations would reduce the spread of HPV 16 and 18, and thereby significantly lower the incidence of the associated cervical cancer. It is estimated that for every 5-year delay in a cervical cancer prevention/detection program, there will be an additional 1.5–2.0 million deaths.15 Mathematical models have been constructed to predict the epidemiological and economic impact of vaccination.16 One example is a dynamic model of vaccinating a previously unscreened population in an underdeveloped nation. This model determined that vaccinating 66% of the population would decrease the incidence of cervical cancer by 80%. Furthermore, it would take 40–60 years of general population vaccination to see significant reductions in all HPV-related diseases, including extra-genital disease.1
The cost effectiveness of vaccination programs depends on several factors. First, the ages of the patients vaccinated and screened should be assessed. Kim and Goldie studied a model that was cost effective only when vaccinating 12-year-old girls, but not when adding a catch-up program for older girls and women.17 Second, the duration of immunity from the vaccine must be considered. Gardasil has been documented in clinical trials to have a durability of 5 years. Long-term protection after this time is unknown, and costly boosters may be necessary to maintain immunity.18,19 Moreover, it is unclear whether malnourished patients in developing countries will have an altered immune response to vaccination.4 Third, it is currently unclear how often screening tests need to be performed. The HPV vaccine protects against only two of the oncogenic HPV strains. Patients must be continually monitored despite vaccination as other oncogenic strains emerge. (Fig. 3).18
The cost of the vaccine will be the main determinant of whether vaccination programs may be launched in developing countries. Gardasil is the most expensive vaccine ever marketed in the United States. The direct material cost of the vaccine itself is approximately $120 per dose, and three doses are needed. Additional indirect costs include administering the vaccine, and screening, diagnosing, and treating the disease. Finally, costs related to accessibility must be evaluated, as patients must take leave from work and travel to the doctor’s office for treatment.4,17,18 This large financial burden would not be feasible in developing nations without massive financial subsidization. In developing countries with a gross domestic product of less than $1000 per capita, the cost for the three doses needed for complete vaccination would have to be lowered from $360, the retail cost, to $1 to $2 for the vaccination to be affordable.4
The Global Alliance for Vaccines and Immunization (GAVI) is a partnership that provides financial support and technical advice for countries with a gross national income of less than $1,000 per capita. Organizations that participate in GAVI include the World Health Organization, the World Bank Group, the Bill and Melinda Gates Foundation, pharmaceutical companies, public health institutions, and nongovernmental organizations (NGOs). Created in 2000, by 2006, GAVI’s financial support had prevented approximately 2.3 million premature deaths.15 GAVI’s efforts are critical in achieving the Millennium Development Goals set by the United Nations. These goals aim to significantly reduce childhood mortality. The question of whether GAVI will support an HPV vaccination program should be determined in the near future.20
The morbidity and mortality associated with untreated HPV infections in developing nations is significant. The high incidence of cervical cancer is closely associated with low levels of education, as well as a lack of financial resources, health care facilities, and outreach programs. Massive subsidization from governments, foundations, NGOs as well as dramatic reductions in the cost effectiveness of the vaccine will be necessary to mobilize such a program, which could potentially eradicate cervical cancer and other HPV-related diseases. The questions that need to be seriously addressed are whether there would be more value in investing scarce financial resources to support organized screening programs which have a proven efficacy and whether the introduction of a vaccination program where the hurdles of high cost, unknown durability of the vaccine, and the potential for other oncogenic viruses to emerge remains unresolved and/or unanswered is premature at this time.