Challenges and opportunities to making Indian women cervical cancer free

Cervical cancer (CaCx) is the fourth most predominant cancer among women the world over with an estimated 604,127 new cases and about 341,831 deaths reported in 20201. Reportedly, one woman dies due to CaCx every 3 min globally. Despite CaCx is fully preventable and curable if detected early, in India, it is still a major public health problem and ranks second in women and the leading cause of deaths (77,348) annually23. The infection of human papillomavirus (HPV) is established to be the prime causative agent for CaCx, the prevalence of which has been found to be the highest in India23. Therefore, the role of regular screening, early detection and treatment are most essential in reducing morbidity, mortality and burden of cervical cancer.

In 2018, the World Health Organization (WHO) called for the global elimination of CaCx by 2030, by implementing three coordinated interventive actions; (i) 90 per cent HPV vaccination, (ii) 70 per cent high-performance cervical screening and (iii) 90 per cent early effective treatment for those already infected and have diseases1. However, eradication of CaCx in low- and middle -income countries (LMICs), particularly in India and southeast Asia, is highly challenging, hence inordinately delayed. The question arises whether LMICs, in particular India, will at all be able to achieve this goal even with the availability of an affordable new single-dose HPV vaccine, (CERVAVAC^®, Serum Institute of India Pvt. Ltd., Pune). India with a population of more than 1.4 billion along with a relatively low socioeconomic status, inadequate health infrastructure, lack of trained workforce, limited budget, absence of universal screening, lack of awareness, vaccine hesitancy, social/religious stigma and no effective curative care when compared to those available in developed countries.

Numerous epidemiological, experimental, molecular, pathological and clinical studies2 have established that infection of HPV, a DNA tumour virus, is the principal aetiologic human carcinogen that causes CaCx in women. For this discovery, a Nobel Prize was awarded in 2008 to Harald zurHausen from the German Cancer Research Center, Heidelberg, Germany (https://www.dkfz.de/en/zurhausen/). Of all cancers, it is the first cancer among women which has the effective vaccines to prevent it, early detection methods to screen pre-cancer lesions and access to early treatment as it takes 10-20 years to develop an invasive cancer. An estimated 341,831 deaths were recorded around the globe in 2020 while ~91 per cent (312,373) of CaCx-related deaths were recorded in LMICs compared to only 8.6 per cent in high-income countries (HICs)4. This is mainly due to inadequate control/prevention and treatment facilities5. There are neither many attempts till date to introduce the HPV vaccine in its National Immunization Programme (NIP) nor any initiative for a universal screening programme in India despite the high annual incidence of CaCx and high associated mortalities. It indicates that CaCx is primarily a disease of poor women from LMICs which have no affordable HPV immunization, organized national screening programmes and adequate treatment and follow up facilities are in place. In India, not only almost 100 per cent of CaCx but also 90 per cent of anal, 20-70 per cent head-and-neck and 9-35 per cent oesophageal cancers are also associated with high-risk (HR) oncogenic HPV infection, specifically type 166.

HPV vaccination is challenging and delayed in India

Although till date more than 100 countries have introduced the HPV vaccines in their NIP, India and all of South Asian countries which needed this vaccine, most have not been able to introduce it. In fact, in 2009, a ‘demonstration pilot project’ on HPV vaccine the immunogenicity testing was launched in India by the Programme for Appropriate Technology in Health (PATH) in the States of Gujarat and Andhra Pradesh, but the trial was suspended due to the death of a few adolescent school girls after HPV vaccination3. The deaths were, however, later proved to be unrelated to HPV vaccination. However, it is still not cleared of litigation, and the controversy still exists about the safety as well as the efficacy of HPV vaccines in the public mind leading to negligible coverage (~1%) of HPV vaccination in India.

Current HPV vaccines are all preventive and not therapeutic

At present, there are three major Food and Drug Administration (FDA)-approved HPV preventive vaccines: (i) Gardasil (a tetravalent against HPV types 6, 11, 16 and 18), (ii) Cervarix (a bivalent against HR-HPV types 16 and 18) and (iii) Gardasil-9 (a nonavalent against HPV types 6, 11, 16, 18, 31, 33, 45, 52 and 58) are available since 20087. Besides these, there are three more vaccines: Cecolin and Walvax are for girls aged 9-14 yr as a two-dose schedule while CERVAVAC^® is for both girls and boys aged 9-14 yr for a single-dose or two-dose schedule for six months apart. These vaccines reportedly provide ≥90 per cent protection against major oncogenic HPV types. Although these vaccines are based on recombinant DNA technology using VLPs (virus-like particles), which have been found to be highly immunogenic, 100 per cent safe, reportedly develop herd immunity and produce high antibody titre if given to adolescent girls aged between 9 -19 yr7. However, the benefit of eliminating the pre-existing infections is not possible as these vaccines have no therapeutic efficacy, so it is not effective if one has already been infected with HPV. Therefore, women vaccinated before their sexual debut or prior to HPV infection will receive the highest protection against the virus infection.

HPV vaccination strategies in developed countries: A path to eradicating cervical cancer

Since serious challenges to HPV immunization exist in India, the success stories of HPV vaccination from developed nations can serve as a roadmap for developing countries. Notably, European countries, the United States and Australia have achieved the highest immunization and screening rates, particularly for adolescent girls but also including boys28910. Developed nations exhibit a tangible impact, with 88 per cent of these introducing HPV immunization programmes, more than 30 per cent of adolescents receiving the vaccine and over 60 per cent of women undergoing cervical cancer screening11. Their success in reducing incidence and mortality of CaCx can be attributed to comprehensive HPV vaccination strategies, school-based initiatives, expanded age groups, technological advancements, public education and awareness with robust monitoring.

A remarkable example from the European nations is Belgium’s Flanders region, achieving a 91 per cent vaccination coverage. Their awareness programmes on available vaccines for healthcare professionals, parents and school-based vaccination programme with digital vaccine approaches were highly successful12. Recently survey in Sweden also suggested a 93 per cent coverage rate, showing positive attitude and importance of health information among healthcare workers13. Australia’s National HPV Immunization Programme stands out, with vaccine coverage rates exceeding 89 per cent for girls and 86 per cent for boys at the age of 15 yr for the single dose in 2017914. The high coverage of HPV vaccination in developed countries indicates that they may soon be able to achieve successful elimination of cervical cancer.

India develops a cost-effective single-dose HPV vaccine, CERVAVAC^®: Opportunity for elimination of cervical cancer

Recently, a new cheaper (₹ 200-400 equivalent to US$ 2.5-5) HPV vaccine, ‘CERVAVAC^®’, is approved by the Drug Controller General of India (DCGI) and is being introduced in India as a single dose for girls aged between 9 and 19 yr15. However, despite having this opportunity, it is still doubtful to achieve the goal of complete elimination of HPV and CaCx by 2030 or later in India as there are a huge number of issues including ethical, moral, societal, religious, vaccine acceptance, myths, misinformation, lack of awareness, lack of an organized screening programme, adequate trained manpower, and access to effective treatment. It will be successful only if an active initiative is taken by the Government of India to introduce this vaccine as a mandatory vaccine through NIP for adolescents taking cues of our success story of polio, smallpox and COVID-19 vaccination. Furthermore, the vaccine may also be made free for all girls and boys.

A working model for universal elimination of cervical cancer

• (i) Smart HPV-Immunization and Awareness Programme: ‘Smart HPV-immunization and screening programme’ for rapid scale-up of HPV vaccination in India using the COVID-19 vaccination model should be developed. There is need for a strong awareness programme for teachers, students, parents, adolescents, policymakers, social workers and political leaders including gynaecologist, paediatrician and public health professionals and the public at large. The use of print and electronic media, mobile health and artificial intelligence for success of such an immunization programme is recommended.

• (ii) School/college/university-based vaccination programmes: A compulsory school- and college-based HPV immunization programme for 9-19 yr adolescents is required to scale up HPV vaccination for both boys and girls. Help from parents and teachers for successfully implementing such a programme is recommended.

• (iii) Difficult-to-reach populations: Targeting adolescents at the worksite for difficult-to-reach teenagers not attending school or college will allow for a better coverage.

• (iv) Only one dose schedule: Since single-dose HPV vaccine is equally effective and gives long-term protection comparable to three doses, it will help in preventing and reducing CaCx burden. The low-cost single-dose Indian-made new HPV vaccine, CERVAVAC^®, is effective and a game changer for India as it is capable of increasing acceptability, feasibility and affordability.

• (v) Door-to-door or camp-based mass vaccination programme: Such a drive will lead to success of mass vaccination of HPV and be useful to catch-up hard-to-reach adolescents.

• (vi) Gender-neutral HPV vaccination: A step towards inclusive public health comprises inclusion of both adolescent girls and boys in India’s immunization programme, a promising strategy to combat CaCx and HPV-related diseases in a full-proof manner because males are the host of HPV.

HPV testing offers reliable cervical cancer screening

Since HPV cannot be cultured in vitro, HPV diagnostics rely mainly on nucleic acid technologies that detect HPV DNA/RNA in cervical samples. Several molecular techniques are available for the detection of HPV infection and are proven to be highly sensitive and specific than conventional Pap test (Papanicolaou) and VIA (visual inspection with acetic acid). Before the introduction of CERVAVAC^® or any available HPV vaccines in India, it is important to know the prevalence of HR-HPV types in different geographic regions (high in Chennai and low in Kashmir) and among communities such as significant high prevalence in tribal population16 whereas low prevalence in Muslim population56. Investigations are also needed to discover additional HPV types, subtypes/variants or new HPV types circulating in Indian population. It is intriguing that no new HPV genotype has been described yet despite global HPV prevalence being highest in India.

Alternative approaches for prevention or elimination of HPV infection

Currently, no therapeutic vaccine or drug is available for the treatment of HPV, but several alternative anti-HPV preventive/ therapeutic formulations/drugs are available, which have been clinically validated to show clearance of HPV infection or stop viral replication at early pre-cancer (CIN1-CIN2) stages when HPV is not integrated into the host cell genome. Several products, for example, Wartec17, cidofovir18, hexaminolevulinate19, curcumin2021, berberine22 and sulindac23, have strong anti-HPV effects and either clear (80-90%) or inhibit progression/viral replication or oncogene expression when used as topical intravaginal applications (4 wk ± menstrual days)24. The polyherbal creams, such as Praneem (Panacea biotec, New Delhi) and Basant (Bipha Bioscience, Kerala), can reportedly clear ≥90 per cent HPV infection in women with pre-cancerous lesions in phase II randomized controlled trials2526. These derivatives are commonly used for elimination of HPV infection at an early stage, but there is inadequate evidence to introduce these in general clinical practice.

Challenges in India

The WHO’s proposed triple interventional approaches appear to be feasible in HICs for global elimination of HPV, but it is challenging in LMICs including India. In LMICs and India, national HPV immunization and cytology-based screening programmes such as Pap test or even VIA have not yet been implemented at national level, in spite of the fact that ≥85 per cent of mortalities occur due to cervical and other HPV-related cancers in India3. There are several factors such as inadequate infrastructure, trained human resource, low budget; vaccine safety, supply and hesitancy, religious/social beliefs/culture, myths, poor vaccine acceptance, illiteracy and lack of knowledge and awareness are responsible for low coverage of HPV vaccination. Therefore, HPV vaccination and screening essential for reducing/eliminating CaCx are of enormous challenge. It requires coordinated efforts of all stakeholders, specifically the government, NGOs, the public healthcare system and the population at large including awareness through social, electronic and print media including mobile health and other available methods. In addition, training of gynaecologists, paediatricians, cytopathologists, public health and social workers in primary health centres, community health centre and Mohalla (community) clinics, ESIC (Employees’ State Insurance Corporation) hospitals and regional cancer centres with clear, realistic and focussed goals is crucial for successful elimination of HPV and CaCx in India and LMICs by 2047, if not by 2030.

Future perspectives

• (i) Gender-neutral HPV vaccination for both boys and girls is most essential for the drastic reduction or complete elimination of HPV infection/transmission of HPV-related diseases. Males are also affected by HPV for tongue/oropharyngeal, oesophageal and head-and-neck, penile, anal, mouth, larynx and tonsil cancers2728, and most importantly, males serve as reservoirs/hosts of HPV which is sexually transmitted to females. Almost ~91 per cent of men and 85 per cent of women who have had a sexual relationship will have HPV infection at any time in their lifetime and more than 50 per cent of men remain as carrier29. It has been also shown that men are more vulnerable to HPV infection as they have low immune response against HPV than women30. Therefore, the universal HPV vaccination programme can offer the greatest protection against the virus for both men and women contributing towards the effective elimination of HPV. Further, the risk of HPV transmission in gay and bisexual men is high and they are reportedly 17 times more likely to develop anogenital cancer than heterosexual males (https://www.cdc.gov/msmhealth/STD.htm).

• (ii) Non-invasive point-of-care method with self-sampling for quick test of HPV will improve easy screening and testing of HPV using urine or saliva samples which have been well correlated with gold standard biopsy313233.

• (iii) The development of oral vaccination and its inclusion in childhood immunization (within five years of age) would be desirable instead of the present intramuscular injectable vaccine. This will be an easy approach for effective vaccination which will be highly acceptable the world over.

• (iv) Development of DNA/mRNA universal HPV vaccine for all HR-HPV types to prevent their infection and associated cancer. This is now essential because, as reported, there is development of cervical lesions in already vaccinated women by non-vaccine HPV types9. It is a natural phenomenon that when some pathogenic viruses/bacteria are controlled, often the other related microbes/viruses get activated to cause similar diseases.

To sum up, cervical cancer continues to be a major public health problem affecting middle-aged women, particularly in India and other LMICs where the highest burden of all infection-associated cancers is often linked with low economic status and lack of knowledge and awareness among medical/public health professionals and the public at large. The recent landmark discovery of a cost-effective and single-dose indigenous HPV vaccine, CERVAVAC^®, should be accepted and implemented without further delay for an effective prevention and control of cervical cancer and other HPV-related diseases in India which need it the most.