To the Editor:

We read a recent report¹ regarding development, immunologic parameters, and impact of the human papilloma vaccine on cervical cancer with pleasure. The most remarkable aspects of this report were the notes confirming the role of human papilloma virus (HPV) in the pathogenesis of cervical cancer, the effect of the viral-like particle HPV vaccines, and their good safety profiles in preventing genital warts, cervical neoplasia, and cancer. However, this report has raised several questions and challenges that have to be addressed to assess the health and economic benefit of HPV vaccines: first, existence of effective screening programs in less-developed regions, which will continue to serve as a critical component in prevention due to the limitations of the current vaccines (eg, duration or type restricted protection); second, the necessity to improved health care access to underserved areas; and third, the need to develop single-dose, heat-stable, needle-free, and affordable formulations of the HPV vaccine to overcome the socioeconomic barriers associated with this disease.

Cervical cancer became the second most common malignant neoplasm affecting women worldwide, accounting for nearly 10% of all cancers. It is estimated that 493,000 new cases of invasive cervical cancer were diagnosed in 2002, 83% of which in developing countries.² Recently, the burden of cervical cancer deaths in the whole of Europe was assessed by analyzing uterus cancer mortality in women younger than 45 years, and that this burden is particularly high across the whole of Eastern Europe. In 2004, approximately 31,000 women in the 25 members of the European Union developed cervical cancer and almost 14,000 died from this disease. A striking contrast was noted between the 15 old and 10 new European Union member states: world age-standardized incidence rates (per 10⁵ women-years) of 9.5 versus 16.7; standardized mortality rates of 4.9 versus 10.7; cumulative mortality rate of 0.27% versus 0.71%.³ Although cervical cancer detection methods (colposcopy, cytology) have existed for more than 50 years, the benefits of disease screening have been seen particularly in developed high-income countries. The worst situation still remains in some low-income countries in Africa, Latin America, and Asia, and surprisingly as mentioned earlier in some medium-income Central and Eastern European countries, including Slovakia (eg, where about 600 women get ill and 200 die yearly, which represents a level of morbidity of 19.6/100,000 and mortality of 7.1/100,000).⁴

Although, our health system allows one annual screening examination free of charge, including colposcopy and oncocytology examination, for all women older than 18 years, participation at national screening programs is still alarmingly low (15% to 20%). Limited financial sources in the health system, inefficiency of present cytology screening system (opportunistic, not organized) with the Papanicolaou technique (continued use of cotton swabs instead of cyto-brush by majority of gynaecologists resulting in poor sample collection, slide preparation, neglecting of endocervical pathology, high false-negative rate based on subjective interpretation in insufficiently equipped laboratories), and a low level of public health information caused, the current situation is not improved compared with 30 years ago, with moreover stable increased curves of incidence and mortality (Figs 1 and 2). In addition, we failed to reduce the proportion of advanced stages of disease, the precursors of adenocarcinoma in situ or adenocarcinoma, and general prevalence of early stages of squamous cell carcinoma to an appreciable extent. Nearly 50% of women visit their doctors in an advanced stage disease, when perspectives for effective treatment are very low. Thus, cervical cancer still remains a critical public health problem. While the problem of incidence and mortality of malignant tumors of the cervix in developed European countries (Fig 3) has been settled earlier (high rate of early stages treated), the progress in Slovakia (Figs 1, 2, and 3) and other Central and Eastern European countries is not satisfactory (Fig 4). Comparing accessible information from the period between 1971 and 2003, there has been a marked decrease in mortality in 16 of 21 European countries. The most significant decrease in mortality rate expressed by standardized death rate (SDR) was observed in Luxembourg, Finland, and Switzerland (100%, 87%, and 86.1%, respectively). Satisfying decrease was reached in the United Kingdom, Portugal, Sweden, and Holland (70% to 77%). On the contrary, increase in SDR was noted in five countries, including Slovakia (increase to 54.8%). Bulgaria and surprisingly Spain (240% and 98.7%, respecively; detailed view in Table 1) showed the most striking increase. Selective analysis including only Eastern European countries with data available over the past 15 years (after political changes to democracy in the majority of former socialistic countries in 1989) has revealed an alarmingly high SDR rate in Romania and Lithuania (12.06 and 9.67 per 100,000/women, age 0 to 64 years, respectively) and the increase in SDR in eight of 14 countries (Fig 4) with the highest rise in Bulgaria, Lithuania, and Belarus (53.9%, 40.1%, and 27.8%, respectively; Table 2). Apart from this increase in SDR, there is still a low number of tumors detected by preventive screenings in situ “early stage in Eastern European countries. The ratio between invasive, more or less advanced stages of the disease compared with in situ tumors is 2.5:1 to 3:1, while developed countries possess a higher prevalence of earlier stages.

Therefore, as national oncology programs are still not fully established or functional in every country, and cervical cancer has been shown to have a central causal agent (HPV infection),⁵ we strongly appreciated an introduction of a cervical vaccine on the market and recent randomized studies confirming the efficacy of prophylactic vaccination (first of all substantial reduction in the incidence of HPV16/18-related cervical precancer and cancer after administration of HPV vaccine to HPV-naive women, and women who are already sexually active, confirming the legitimacy of prophylactic vaccination), as well.^6-8

Since the beginning of 2007 the implementation of prophylactic HPV vaccination using quadrivalent type of HPV 6/11/16/18 (Merck Inc, Whitehouse Station, NJ) became reality in our clinical practice. In addition, a bivalent product HPV 16/18 (GlaxoSmithKline Biologicals SA, Rixensart, Belgium) is expected to be available by the end of 2007. Women who recognize the insufficient status of health system in the postsocialistic countries strongly inquire prophylactic vaccination, not only for themselves, but also for their children. Unfortunately, affordability remains low. Despite the unambiguous benefit of vaccination demonstrated in large studies^6-8 and cost-benefit to prevalent disease, this milestone in the prevention of cervical cancer did not become a part of a regular vaccination program for girls or for risk groups of the population (eg, in Slovakia the vaccine still remains on the list of drugs belonging to products requiring additional payment by patients). However, it is assumed that in the near future its benefit could be re-evaluated. Until then, health insurance companies in these countries will refund only a part of the total price of the vaccine. In Slovakia, it represents 10% (513 Slovak crowns = 21 US dollars). The difference (4,620 Slovak crowns = 233 US dollars) for the full price must be covered by the patient for each dose. Notifying the necessity of subsequent two applications (additional 466 US dollars) represents a total sum of $700 per one prophylactic vaccination cycle per woman. By the way, these costs are equal to the monthly salary for 70% of the population. Understanding the fact that high-risk HPV infection disease preferentially affects low-income inhabitants,⁹ and that the safety period and the seroconversion rates or antibody titers may be limited, is a medium income family (average monthly income $700 per adult member) is not likely to be protected by this vaccination. Even though we have the possibility to prevent cervical cancer, the affordability for this health care need, on current social and health system background not only in less-developed but also in medium-income European countries (eg, Slovakia, Poland, Hungary, Ukraine, and Bulgaria) is low, and vaccination remains a luxury for the majority. Screening programs have been developing for years, reform in the health care system are not effective, and economic status is increasing slowly. Thus, the argument of health insurance companies that not only prophylactic vaccination, but mainly organized screening may markedly contribute to decreased presence of cancer, is in this situation insufficient. Do we have time to wait another 10 to 15 years until effective screening and a functional health care system will be established? Is it not better to support the affordability of vaccines than to spend enormous resources on treatment for cancer in advanced stages? Under these queries health insurance companies and national and international cancer societies have to comprehend that the product of many years of research and subsequent validation that the world offers us,¹⁰ should be fully repaid and dedicated to everyone who can benefit from it, not only available for people of wealth. We believe the cost-benefit of such intervention will be evident.

Based on our experience and data showing worsening situation in cervical cancer mortality in Eastern European countries we strongly endorse a call for larger vaccine delivery in less-developed regions, the necessity to improve health care access to underserved areas, the need to develop an effective single-dose, heat-stable, needle-free HPV vaccine, and further investigation to determine the contribution of cellular immunity in eliminating persistent viral infections. Only this will make the implementation of the HPV vaccine a milestone in our effort toward preventing cervical cancer. Otherwise, those living in poverty cannot benefit from effective intervention such as HPV vaccines in fighting cervical cancer, and disparities could worsen dramatically.¹¹

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.