Human papilloma virus vaccine for low and middle income countries: A step too soon?

ABSTRACT

Cervical Cancer is the most common genital cancer in women in India. Human papilloma virus (HPV) causes precancerous lesions that often develop into cervical cancer suggesting that cervical cancer has an infective etiology and is potentially preventable by preventing HPV infection through the use of HPV vaccines. The incidence in developing nations is largely under-reported due to large population size, poor and incomplete database. HPV vaccine is being considered for inclusion in the immunization schedule of developing countries. An effective surveillance system for a vaccine requires that the baseline incidence, prevalence, and mortality rates of cervical cancer are established for a given population. The lessons learnt from the polio vaccine must be applied to every vaccine being introduced for its optimal utilization. HPV vaccines might be used as a cost-effective scientific intervention to prevent cervical cancer but need to be combined with good screening methods in developing countries for a paradigm shift in the management of cervical cancer

KEYWORDS:

• Cervical
• cancer
• HPV
• vaccine

Introduction

Cervical Cancer is the fourth most common cancer in women worldwide representing 7.5% of all female cancer deaths in 2012. In developed countries, early screening and treatment prevents up to 80% of cervical cancers, but in developing countries poor screening leads to a higher number of deaths, which can be reduced by effective screening and treatment program.¹ It is estimated that by year 2020 there will be almost 20 million new cases leading to the number of new cases from India rising by ∼70%. Although the cancer incidence rate in developing nations is less than that of Western countries, this disparity may be due to large population size as well as a poor and incomplete database.²

Sexually acquired infections with HPV types 16 and 18 lead to 70% of precancerous cervical lesions and cervical cancers but also lead to cause anal cancer, vaginal, vulvar, penile and head and neck cancers. A majority of HPV infections are asymptomatic and resolve spontaneously within 2 y. However if left untreated, these infections might lead to precancerous lesions which may progress to cervical cancer, a progression that usually takes many years. In low- and middle-income countries, 70% of cancerous lesions present at advanced stages due to lack of an organized cancer screening program.³ The lifetime risk of HPV infection for sexually active individual is >50%. In sexually active women of less than 25 y of age, the prevalence of HPV is ∼20%.⁴

Primary prevention involves vaccinating girls or boys aged 9–13 y before they become sexually active. By mid-2016, 65 countries had introduced the 2 available HPV vaccines.

HPV vaccine prevents HPV infection and is intended to prevent all of its consequences. These vaccines are directed against both HPV 16 and 18, which are considered to cause at least 70% of cervical cancers.1 Although HPV vaccination is preventive against the most common oncogenic HPV types, but regular cervical screening is still necessary. HPV vaccine is under consideration for inclusion in the national immunization schedule of developing countries like India.

Basis of vaccination

In India, the prevalence of high-risk HPV infection is similar to that in the high-risk areas in Latin America and varies between 7 and 13%.⁵ Although only 50% of women infected with HPV develop antibodies and seroconversion may take 18 months, it is not necessary that the antibodies remain protective against reinfection with the same HPV type. The other associated risk factors for progression to high-grade dysplasia and cancer include persistence of HPV infection, infection with highly oncogenic HPV types, age more than 30 years, infection with multiple HPV types, and immunosuppression.⁶

Purified recombinant L1 structural proteins self-assemble to form virus-like particles (VLPs), which are formulated into the vaccines. Immunization induces a protective immune response which is much stronger and long-lasting and induces partial cross-protection against non-vaccine-related serotypes as compared with natural infection.⁶ HPV vaccines are designed for prophylactic use only; they do not clear existing HPV infection or treat HPV-related disease.⁷ To ensure that the recipients receive maximum protection, the target population should be young adolescent girls or boys (9–13 y of age) who are not yet sexually active and who will mount a better immune response.

The magnitude of the antibody response is highest for HPV16 for both vaccines. The antigen levels in the vaccines are adjusted for assuring strong immune responses to each antigen. As a result, the protein content of Gardasil (9vHPV, types 6, 11, 16, 18, 31, 33, 45, 52 and 58) is 120 μg. Cervarix (2vHPV, types 16 + 18) induces an equally high and sustained antibody response to HPV 16/18. The vaccine is relatively safe but may cause local reactions such as pain and systemic adverse effects such as fever in 4% of vaccinees. No serious vaccine-related adverse events have been reported. HPV vaccine is not licensed for use in females or males younger than 9 y or older than 26 y or for use in pregnant women. Although it has not been causally associated with adverse outcomes of pregnancy, data are limited. Although lactating women and immunosuppressed female patients can receive the vaccine, the efficacy and degree of immune response could be weaker in the latter group.⁸

Indian context of HPV

Mattheij et al. in their review questioned the epidemiology data of cervical cancer in India. It has been highlighted that the cancer registries and surveillance systems in India provide an inadequate basis for information because they are not complete or comprehensive in their coverage of every region in India. Cancer incidence data has unequal representation of different parts of India, that is, underrepresentation of east, far north, and rural India, given that their data are mainly collected in the major cities, hospitals, and medical colleges. If the vaccine is to be implemented in a given country, every subpopulation should be represented equally.⁹

The World Health Organization (WHO) advises that the epidemiology of the disease should be known and be of sufficient importance to justify its prioritization and that surveillance systems should be capable of assessing the impact of a vaccine intervention following its introduction.¹⁰

An effective surveillance system for HPV vaccine requires that the baseline incidence, prevalence, and mortality rates of cervical cancer are established. There is no general account in the literature of cancer surveillance in India. The cancer registries show that incidence rates are significantly declining. This declining trend is also described in many studies.^11,12 The standardized cervical cancer rate per 100,000 population of India (27) is lower as compared with other developing countries, that is, Zimbabwe (50) and Brazil (Goiania,38).¹³ These data again raise the question of whether India needs a vaccination or a comprehensive screening program for cervical cancer as its first priority. Although both strategies can go simultaneously, this is not feasible in resource poor settings like India.

HPV vaccination programmes should proceed where there are both strong epidemiological evidence and adequate surveillance and monitoring systems. In the absence of comprehensive cancer surveillance, WHO criteria with respect to monitoring effectiveness of the vaccine and knowledge of disease trends cannot be fulfilled.

Efficacy of vaccine

The 4vHPV (and its successor vaccine 9vHPV based on immunological comparability) and 2vHPV vaccines have demonstrated efficacy of > 90% against persistent infection due to genotype 16 or 18 for women who received 3 doses of HPV vaccine.^14-17

The minimum antibody titer level that confers protective efficacy has not been determined yet. A recent mathematical model of the immunological data from 2vHPV vaccine predicts that antibody titres above baseline may be observed 20 y after vaccination.¹⁸

The actual effectiveness of HPV vaccination in the female or male population will also depend on the levels of vaccine uptake or coverage in the population and compliance in completing all vaccine doses.HPV vaccine and the cervical screening programmes need to be strengthened together to benefit from the effectiveness of the vaccine

Cost effectiveness

An individual-based stochastic model with vaccine coverage of 70% with the 3-dose regimen, a life-long protection against HPV 16 and 18 documented vaccination alone was preferable to screening alone. A combined approach of pre-adolescent vaccination and screening 3-times per lifetime (at the ages of 35, 40, and 45) using visual inspection (VIA) cost $290 per YLS (Years of Life Saved, a measure of cost effectiveness of the measure) and is also considered very cost-effective. The combined approach was found to be most effective but may not be applicable in all regions in India. With VIA and HPV DNA screening available or with only HPV DNA screening available, the ICER (Incremental Cost Effectiveness Ratio, a statistic used in cost effectiveness analysis to summarize the cost effectiveness of a health care intervention, and defined by the difference in cost between 2 possible interventions divided by difference in their effect) alone was cost-saving if cost per vaccinated female was assumed at $10. With only HPV DNA testing available, screening alone or a combined approach becomes more cost-effective as the price per vaccinated female exceeds $30 per vaccinated female (ICER of vaccination-alone being $390/YLS compared with $1780/LYS (life-year saved) with the combined strategy.¹⁹

Social acceptance

Level of awareness of HPV vaccine in developing countries is discouraging. For the acceptance of a vaccine, it is imperative that the population has a background knowledge about the importance of the vaccine and its safety profile. The lessons learned from polio vaccine must be applied to every vaccine to be introduced and should be optimally used. The community, especially parents accepting the vaccine, may consider that vaccination is construed as parental consent for their children to engage in sexual practice. In the realistic policy scenario, a perceived urgent necessity to introduce HPV vaccines is unlikely, given the low awareness of the viral etiology of cervical cancer and the possibility of preventing it by vaccination.

Impact of vaccination

A coverage rate >50% in developing nations has led to a significantly decreased infection rate. Furthermore, anogenital warts in girls 13–19 y of age, in boys younger than 20 y of age and in women 20–39 y of age decreased significantly as seen in developed nations. Sentinel surveillance to monitor the impact of HPV vaccination in the US indicated a 72% decline in CIN2 (or worse) lesions in women who vaccinated 4 or more years before the screening test that led to the diagnosis of CIN2+ disease.²⁰ With HPV vaccination in National Immunization schedules, one can consider the HPV test as a primary screen, with triage to cytology in women who test HPV positive,21 and then the screening can be reduced by lengthening the screening interval and perhaps delaying the initial screening to 25 y of age. The women who choose to be vaccinated still need to be screened, as life time protection cannot be confirmed.²¹

Conclusion

The introduction of HPV vaccination is the major step toward prevention of one of the most common cancers in the world. Cancer registration and surveillance systems should be extended across all population groups and should be established for the collection of mortality data. HPV vaccination will be a cost-effective medical intervention but needs to be combined with screening methods such as Papanicolaou (pap) smear, and HPV DNA tests in developing nations for a paradigm shift in the management of cervical cancer.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.