Cervical cancer

The Policy Committee of the International Papillomavirus Society describes how lessons learnt from the COVID-19 pandemic could propel a new approach to the elimination of cervical cancer that is more likely to be successful.

Global strategy to eliminate cervical cancer as a public health problem: are we on track?

Estimating the incidence and mortality rate of cervical cancer became necessary to establish prevention measures and healthy policies. The aim of this study was to estimate the updated incidence and mortality rate of cervical cancer in 2013 in China. According to the evaluation criteria developed by the National Central Cancer Registry of China, the data submitted from 255 cancer registries met the required standards in 2013. Cervical cancer cases were retrieved from the national database and combined with the 2013 national population data. The age-standardized incidence and mortality rates were based on the demographic structure of the national census 2000 and Segi's world population. In 2013, the estimated number of new cases and deaths from cervical cancer were 100,700 and 26,400, respectively. The crude incidence of cervical cancer was 15.17/100,000. The age-standardized incidence rates based on the Chinese standard population (ASIRC) and the world standard population (ASIRW) were 11.30/100,000 and 10.30/100,000, respectively. The incidence of cervical cancer in urban areas was 15.62/100,000 and the ASIRC was 11.12/100,000. The incidence of cervical cancer in rural areas was 14.65/100,000 and the ASIRC was 11.47/100,000. The mortality rate of cervical cancer was 3.98/100,000. The age-standardized mortality rates based on the Chinese (ASMRC) and world standard populations (ASMRW) were 2.76/100,000 and 2.62/100,000, respectively. The mortality rate of cervical cancer in urban areas was 3.85/100,000 and in rural areas was 4.14/100,000. Cervical cancer incidence and mortality increased with age. Urban areas had a higher incidence of cervical cancer and lower mortality rates when compared with rural areas. Dynamic monitoring of cervical cancer incidence and mortality is the fundamental work of cervical cancer prevention and control. Cervical cancer is a serious issue in women's health, and prevention strategies need to be enhanced, such as human papilloma virus (HPV) vaccination and screening programs.

HPV vaccination in south Asia: new progress, old challenges.

Impact of the human papillomavirus vaccine in low-resource settings

Cancer of the cervix - The view from Australia's nearest neighbour.

Maximizing the Potential Public Health Impact of HPV Vaccines: A Focus on Parents

The proposed Footprinting framework enables approximation of missing cervical cancer epidemiological data and derivation of context-specific impact projection of cervical cancer prevention measures, assisting public health decisions on cervical cancer prevention in India and other countries.

The proposed Footprinting framework enables approximation of missing cervical cancer epidemiological data and derivation of context-specific impact projection of cervical cancer prevention measures, assisting public health decisions on cervical cancer prevention in India and other countries.

Contrary to other developed countries, in Japan, recent years have seen increases in cervical cancer incidence and mortality among young people. However, the human papillomavirus (HPV) vaccine program, a key measure for avoiding cervical cancer, has been virtually suspended. Temporal changes in cervical cancer profiles in this unique situation have not been fully investigated epidemiologically. Our study aimed to determine the current status and future trends of the incidence and mortality of cervical cancer and precancerous lesions in Japan. Mortality rates of cervical cancer during 1975 to 2016 and incidence rates of cervical cancer and cervical intraepithelial neoplasia (CIN) 3 during 1975 to 2013 were examined using vital statistics and population-based cancer registry data in Japan. Bayesian age-period-cohort analyses were performed to analyze temporal changes of the three cervical cancer-related outcomes. We also calculated projections to 2028 for the three outcomes, assuming that HPV vaccination coverage and screening rates in Japan would be maintained at the current level after the resumption of the national vaccination program. The risk of occurrence of the three outcomes showed similar changes by birth cohort, peaking in the mid-1890s to 1900s birth cohorts, declining sharply in the 1940s birth cohort, and persistently increasing in the 1950s and later birth cohorts. Projections to 2028 show increases in cervical cancer incidence and mortality in the 30 to 69 age group, with a particular increase in CIN3 incidence in the 25 to 49 age group, if HPV vaccine programs and screening are not effectively implemented. These findings revealed an increasing cervical disease burden among reproductive age females in Japan.

Michaela had a Papanicolaou (Pap) test at age 17, less than 3 months from her first intercourse. The test was interpreted as atypical squamous cells of undetermined significance (ASC-US) and the laboratory automatically “reflexed” this to human papillomavirus (HPV) testing. Michaela tested positive for high-risk (carcinogenic) HPV, had colposcopy and biopsy and cryotherapy for cervical intraepithelial neoplasia, grade 1 (CIN 1). The result from her 4-month postcryo Pap test was ASC-US HPV positive.So what is the problem with Michaela's story? Everything! According to national guidelines, (1) she should not have had her first Pap test until 3 years after her first intercourse or age 211–4; (2) she should not have had HPV testing after the ASC-US interpretation of her Pap test unless she was at least 21 years old34; and (3) as an adolescent, she should not have had colposcopy for a minor Pap test abnormality or cryotherapy to treat cervical intraepithelial neoplasia 1 (CIN 1).34Why is it so important to adhere to national guidelines? Don't we (clinicians) know what is best for our patients? Well, clinically we know our patient best, and guidelines cannot foresee every variation in real clinical practice. However, guidelines created through rigorous evaluation of evidence-based data and a consensus process provide a framework for providing care that is optimum for most women at each phase in the timeline of their life. Guidelines cannot, and should not, trump clinical decisions for a unique patient situation.34 But variations from recommended guidelines should be the exception rather than the rule in clinical practice.Perhaps we need to go back to the beginning, to the dialogue between the King and the white rabbit in Lewis Carroll's wonderful Alice in Wonderland: “Where shall I begin, please, your majesties?” Like the King we will say, “Begin at the beginning and go until you come to the end. Then stop!” So, to understand how we can best protect our patients from cervical cancer, let's begin at the beginning …Cervical cancer is the first cancer identified as having a single obligatory cause, cervical infection by human papillomavirus (HPV).5 However, HPV is common; cervical cancer is not. Almost all who are sexually active have had 1 or more HPV infections in their life.5 Some HPV types are associated with cervical precancer and cancer and are therefore called “high risk” (also carcinogenic or oncogenic) HPV types. Other types that do not cause cancer are called “low-risk” HPV types. Most HPV infections, including those caused by high-risk HPV types, are benign, transient, and resolve spontaneously within a year or 2. Less commonly, high-risk HPV infections persist. The longer high-risk HPV infections persist, the more likely they are to cause a precancerous lesion, which, if not detected and treated in a timely fashion, can become cancerous.5 Fortunately, cancer is an uncommon outcome for an infection virtually everyone gets. The entire process of cervical carcinogenesis, from causal infection to invasive cancer, is usually slow, taking many years or decades. The success of cervical cytology, despite its limitations in sensitivity,67 has been the result of repeated screening, detection, and therapeutic intervention during the long sojourn from causal infection to invasion.8Testing for the virus that causes cervical cancer certainly makes sense because cervical cancer rarely, if ever, occurs without HPV. However, the natural history of HPV-induced carcinogenesis and the ubiquitous nature of HPV must temper and guide how we use HPV testing. Most young women are infected with HPV within a few years of becoming sexually active, but exceedingly few have precancer and far fewer still have cancer. Meanwhile older women have fewer HPV infections and are at greater risk for having precancer and cancer if they test positive for HPV. Misuse of HPV testing in young women identifies too many women with HPV who are not at risk for cervical cancer.For Michaela the harm was a Pap test when she had no risk of cervical cancer, while the likelihood of obtaining an abnormal cervical cytology result was very, very high; a HPV test at an age when HPV is ubiquitous and carries little prognostic value; the anxiety and discomfort of triage to colposcopy and cervical biopsy for HPV lesions of little risk; and the mental and physical trauma of cervical treatment for often transient CIN 1, a diagnosis that is synonymous with HPV infection. Although cryotherapy has not been shown to cause adverse reproductive outcomes, too many young women with minor abnormalities are being treated by cervical excision procedures (eg, loop electrosurgical excision or laser cone) that may increase the risk 2 to 4 fold of premature delivery and low-birth-weight infants.9–11Such a risk is acceptable if necessary to prevent progression to cervical cancer. But since there is so little cancer risk at Michaela's young age, our primary consideration is to avoid harm when there is little benefit. (The US rates of cervical cancer in women under the age of 25 are 2 in 100 000, only slightly higher than the rates of vaginal cancer, for which there is no screening recommended.) This is such an important tenet that if HPV testing is inadvertently performed in an adolescent, the results should be ignored and not be used to influence patient management.4As summarized by the HPV DNA Test Utilization Statement,12—based on the consensus guidelines developed by the American Society for Colposcopy and Cervical Pathology4 and endorsed by the American Cancer Society, American Society for Clinical Pathology, American Society for Colposcopy and Cervical Pathology, American Society of Cytopathology, American Society for Cytotechnology, College of American Pathologists, International Academy of Cytology, and Papanicolaou Society of Cytopathology— there is clear, documented benefit for HPV testing in the circumstances listed in the document.Human papillomavirus testing must be for high-risk HPV (HR-HPV) types only and should use an FDA-approved or equivalent test that has undergone peer review of a rigorous, masked evaluation involving an adequate sample size.13 Testing for low-risk HPV types that do not cause cervical cancer has no clinical benefit and therefore cannot be justified or condoned.13 Other than the indications listed in the HPV DNA Test Utilization Statement, HR-HPV testing generally should not be done because it potentially creates more harm than benefit. Importantly, cotesting with the Pap and HPV tests in women age 30 and older should not be done more frequently than every 3 years if both tests are negative. This combination of tests provides safety for at least 3 years, with recent studies1415 suggesting safety may extend for at least 6 years. Hence, testing more often of women who are at virtually no risk of having precancer adds cost without benefit. Excessive screening all too often identifies transient HPV infections and minor cytologic abnormalities that would resolve on their own if given wider screening intervals,16 adding unnecessary evaluations and procedures that create patient harm.Human papillomavirus testing should be avoided as a reflex test to any abnormal Pap test other than in cases of ASC-US, except in postmenopausal women with low-grade squamous intraepithelial lesion (LSIL). Less than 50% of postmenopausal women have LSIL due to HPV, and those with HPV-negative LSIL are at low risk for cancer and do not need colposcopy.Neither should HPV testing be done during the initial management of women with atypical glandular cells (AGC). Women with AGC may not have HPV-induced lesions—ie, tubal metaplasia of the endocervix, reactive endocervical cell changes, atypical endometrial hyperplasia, endometrial carcinoma, glandular lesions in the fallopian tubes, and ovary and glandular cancers from a variety of sources metastatic to the pelvis. However, once possible sources of a non-HPV induced lesion have been eliminated and colposcopy has not detected CIN or adenocarcinoma in situ (AIS), HPV testing can provide important information regarding the best follow-up option for women with AGC “not otherwise specified” (AGC NOS). Women with AGC NOS who are positive for high-risk HPV are at greater risk for subsequent detection of CIN 2/3 or AIS and are best followed up with a repeated Pap test and HPV test in 6 months, with referral back to colposcopy if either is abnormal. This is 1 of only 2 exceptions to the general rule that a positive HPV test result should not be repeated in less than a year. The other exception is in the 6-month surveillance period of women treated for CIN 2/3.There are a number of other areas for which HPV testing should not be done but are not mentioned in the HPV DNA Test Utilization Statement. Human papillomavirus testing should never be used as a screening test for sexually transmitted diseases (STDs) because HPV is so common and, unlike most STDs, has no treatment that would follow detection. Human papillomavirus testing should not be done as a screen prior to administering the HPV vaccine. The FDA-approved HPV test identifies a pool of high-risk HPV types and is not restricted to the 4 HPV types in the vaccine (HPV 6, 11, 16, and 18). Additionally, there is no commercially available serologic test that would identify past exposure to these 4 HPV types. The cost of prevaccination screening of all sexually active women would escalate the cost of vaccine administration. Human papillomavirus vaccination programs should target populations that will glean the greatest benefit for the cost: girls in early adolescence who are mostly naïve to HPV infections.17The HPV DNA Test Utilization Statement represents a convergence of many professional societies for the best practice of HPV testing in the screening and management of women for prevention of cervical cancer. The underpinnings for these recommendations, based on the ASCCP guidelines,4 are the natural history and epidemiology of HPV and cervical cancer. The underlying principle for using any screening or diagnostic test is to differentiate effectively those at risk of disease from those who are not.1819However, there must be an acknowledgment that no test, diagnostic procedure, or treatment is error-free. No measures can be taken to provide absolute reassurance against cervical cancer. As tests for high-risk HPV have become available, there is the misconception that its exhaustive use might eliminate all cervical cancer. Yet, excessive screening may result in excessive management and harmful treatment for benign conditions, while minimally reducing cancer incidence; most cases of cervical cancer (60%) occur in pockets of underscreened populations (http://www.cdc.gov/cancer/cervical/). For women of Michaela's age group, it is unproven whether additional or more sensitive screening can eliminate any of the rare cancers in women younger than 25 years.For those clinicians, laboratories, and pathologists conducting (or promoting) more HPV testing for financial gain,20 it is important to understand the risks being taken. The Pap test has been the most successful cancer screening test in the history of modern medicine. As a result, we have seen a drop in incidence of cervical cancer and its precursors. Consequently, a “positive” Pap test result is more likely to be a false-positive than a true-positive. The reason that HPV testing is such a powerful adjunct to cervical cytology is that it clarifies risk: women (aged 21 or older) with HPV-negative ASC-US are at exceedingly low risk of precancerous lesions21 and can return to routine screening without further clinical intervention, while women with HPV-positive ASC-US have a risk comparable to that associated with an LSIL cytologic profile. Prior to the advent of HPV testing, the patients with equivocal Pap results would most often have repeated Pap tests, multiple colposcopic evaluations with possibly multiple biopsies, all of which could lead to patient morbidity. With HPV testing, we can weigh the risk of having significant cervical disease against the costs of unnecessary intervention and harm.For HPV testing to fulfill its promise, clinicians must understand under which circumstances it should be used and under which it should not. Laboratories must question their client clinicians when HPV testing is ordered in a situation that is more likely to cause harm than benefit. Clinicians must not threaten to move their business to another laboratory as has been done when the laboratory refuses to do HPV testing that is not clinically indicated by the guidelines. Clinicians must also question the motives of laboratorians that urge HPV testing that is not in accordance with guidelines. We all share in the responsibility of making our patients as safe from harm as reasonably possible and making medicine as protective and cost-effective as possible. “Where shall I begin, please, your majesties?” Begin with understanding how common HPV is, yet how it can cause cervical cancer. Use your understanding of the natural history of HPV to make sage decisions that lead you to the best choices for your patients, choices that emphasize benefit and minimize harm. When we all reach that goal, we can feel confident that we have fulfilled that promise that we made when we took the Hippocratic oath, “First do no harm.”

Human papillomavirus (HPV) is a widespread viral infection affecting the reproductive tract and is associated with multiple types of cancer. It is a significant global health concern, with cervical cancer being one of the most common cancers affecting women worldwide. HPV infection has been found in both married and unmarried women.The burden of cervical cancer is particularly high in middle- and low-income countries, where HPV vaccination and screening programs are often limited. India faces a substantial challenge with cervical cancer and HPV infection. Cervical cancer ranks as one of the leading cancers among women in India. Studies over recent decades have indicated varying levels of HPV prevalence in the general female population in India. Recognizing the importance of addressing this issue, the Government of India has prioritized cervical cancer elimination as a national public health goal. A strategic plan has been launched to increase cervical cancer screening coverage in adult women and HPV vaccination coverage in girls. This review examines literature published from 2000 to 2023 on the epidemiology of cervical cancer and HPV in India. It also explores the development of prevention strategies, focusing on cervical screening and HPV vaccination programs. Government policy documents were analyzed to understand the national strategic vision and targets. The review concludes by discussing ongoing challenges and future directions for cervical cancer elimination efforts in India.

INTRODUCTION Cervical cancer (CC) is the fourth most common malignancy in women, with a global estimate of 570,000 new cases and 311,000 deaths in 2018.[1] Approximately 27,000 anal, 27,000 vulvar, 13,000 vaginal and 22,000 penile cancer cases are diagnosed worldwide annually.[2] Human papillomavirus (HPV) infection is the leading cause of CC and has been identified as a human carcinogen for vulvar, vaginal, penile and head and neck cancers, thus accounting for a significant proportion of the global cancer burden.[2-4] Most HPV-related diseases occur in underdeveloped or developing countries, with the incidence rates being higher in Central and South America, Sub-Saharan Africa and South Asia.[5,6] In Malaysia, CC is the third most common female cancer, with around 1,682 new cases and 944 deaths occurring annually.[1] The age-standardised incidence of HPV-related female CC in Malaysia is 10.5 per 100,000 women per year versus 17.2 per 100,000 women per year in Southeast Asia and 13.1 per 100,000 women per year worldwide.[1,3] Crude incidence rates for female anal, vulvar and vaginal cancers in Malaysia range from 0.2 to 0.7 per 100,000 women per year,[3] and rates of male anal and penile cancers are 0.0–0.3 and 0.1–0.7 per 100,000 men per year, respectively.[3] More than 200 HPV types have been identified; of these, 85 have been characterised.[7] HPV types 16/18/31/33/45/52/58 are high risk and oncogenic,[7] whereas HPV types 6/11 have been associated with genital warts. In Malaysia, high-risk HPV types account for 93% of all HPV infections in women aged 18–60 years[8] and oncogenic HPV types 16/18/52/58 account for 52.8%/35.9%/10.7%/8.9% of CC cases, 41.1%/8.2%/20.5%/8.2% of high-grade cervical lesions and 26.1%/4.3%/17.4%/(no data available for HPV 58) of low-grade cervical lesions.[3] In addition, HPV types 52 and 58 are the second and third most prevalent types detected from the cervicovaginal swabs of healthy adults in Malaysia, with detection rates of 12.8% and 8.1%, respectively.[8] These Malaysian estimates are higher than the global percentages of HPV 52/58-attributable CC, high-grade cervical lesions and low-grade cervical lesions (7.4%, 19.1% and 15.6%, respectively).[2] Globally, HPV types 16/18 account for approximately 70% of all CCs;[9] they are also the most common HPV types detected in patients with HPV-related anal (84.3%), vaginal (63.7%), penile (70.2%) and head and neck (85.2%) cancers.[9] Furthermore, HPV 16/18/31/33/45/52/58 together account for most of the HPV-related cervical (89.3%), anal (95.3%), vaginal (85.3%), penile (84.4%) and head and neck (90.0%) cancers.[9] Low-risk HPV types 6/11 have been linked to most genital wart cases worldwide, with an estimated global annual incidence of 1.60–2.89 cases per 1,000 people.[10] In Singapore, an analysis of data from the National Skin Centre estimated the annual genital warts incidence to be 0.28 cases per 1,000 people in 2008.[11] Although there is a dearth of data on local genital wart incidence, an earlier study conducted in Malaysia estimated that only 30% of genital wart cases (approximately 2,304 treated cases per year) in women received treatment annually.[12] The relative HPV disease burden attributed to various HPV types can be seen in Table S1 [see Supplemental Digital Appendix 2 https://links.lww.com/SGMJ/A50].[3,5,13-15] Currently, three HPV vaccines are available: a bivalent vaccine (2vHPV) targeting HPV 16/18, a quadrivalent vaccine (4vHPV) targeting HPV 6/11/16/18 and a nonavalent vaccine (9vHPV) targeting HPV 6/11/16/18/31/33/45/52/58.[16] As of 15 July 2020, 106 countries have introduced HPV immunisation programmes, including 15 out of 27 (56%) countries in the Western Pacific and 6 out of 11 (55%) countries in the Southeast Asian region (including Malaysia).[17] In countries where an HPV vaccination programme has been implemented, reduction in vaccine-type HPV infections, genital warts and cervical precancers has already been observed.[18] Currently, the CC cytology screening programme in Malaysia recommends women aged 20–65 years to be screened every 3 years; however, screening uptake is low at 22% and there is no active invitation to the programme.[3] In 2010, in an effort to prevent HPV-related diseases, Malaysia introduced routine HPV vaccination with either the 2vHPV or 4vHPV vaccine available in a three-dose schedule through schools and community health centres as part of its free national immunisation programme (NIP) for 13-year-old girls, which achieved 94% coverage in the target group by 2013.[19,20] the NIP converted the HPV vaccination to a two-dose schedule in 2014.[3] The Malaysian government also implemented catch-up vaccination for girls aged 18 years, which achieved an 87% coverage rate.[20] Neither the 2vHPV nor the 4vHPV vaccine protects against HPV 52/58-related infections, which are among the most prevalent types detected in women with invasive CC in Malaysia.[3] Because the 9vHPV vaccine provides broader coverage, including prevention against HPV 52/58-related infections, it is necessary to assess the potential impact of introducing 9vHPV as part of the Malaysian NIP. A large randomised clinical trial showed that the 9vHPV vaccine prevented HPV 31/33/45/52/58-related infections and diseases in a susceptible population and generated an antibody response to HPV 6/11/16/18 that was non-inferior to that generated by the 4vHPV vaccine.[21] In a subanalysis of an international phase 2b/3 study, the 9vHPV vaccine prevented HPV 31/33/45/52/58-related persistent (≥6 months) infections in Asian participants aged 16–26 years at sites in Hong Kong, Taiwan, Japan, South Korea and Thailand, with an efficacy of 95.8% (95% confidence interval [CI] 87.8–98.9).[22] Furthermore, the per-protocol efficacy population of this study demonstrated that 9vHPV reduced the incidence of HPV 52- and 58-related persistent infection by 91.3% (95% CI 74.5–97.7) and 100.0% (95% CI 86.3–100.0), respectively.[22] The objective of this study was to compare the public health and economic impact of implementing a routine vaccination programme with two-dose 9vHPV vaccination compared to two-dose 2vHPV or 4vHPV vaccination in 13-year-old girls in Malaysia. Results from this model will assist the Malaysian healthcare policymakers in identifying a cost-effective programme to avert HPV-related diseases. METHODS Model design A previously validated HPV-type transmission dynamic model simulating the natural history of HPV infections and estimating the cost associated with HPV-related diseases[23] was adapted to the Malaysia setting to evaluate the public health and economic impact of vaccinating 13-year-old girls with the 9vHPV versus the 2vHPV or 4vHPV vaccines. HPV infection and disease state transitions, lifetime duration of infection-derived immunity and unvaccinated compartments of the current model have been previously described in detail.[23] The population impact was estimated for the entire Malaysian population. Model compartments The age-structured mathematical population model incorporates epidemiology of HPV infection, disease and economics into a single dynamic model to capture both the direct and indirect herd immunity benefits and costs of HPV vaccination for the population over time in a transparent and reproducible manner. The model structure and assumptions have been previously described in detail [see Supplemental Digital Appendix 1 https://links.lww.com/SGMJ/A49].[23] The model comprises three connected modules: (1) a demographic variables model describing how individuals enter, age and exit the model (modelling of birth, ageing and death, and a behavioural model describing sexual activity);(2) an epidemiological model simulating the transmission of HPV 6/11/16/18/31/33/45/52/58, occurrence of genital warts, precancers such as cervical intraepithelial neoplasia (CIN) 1/2/3 and vaccine type-related CC; and (3) a disease variables model describing the rates of screening, HPV infection and HPV-related disease transmission.[23] Epidemiological model parameters Epidemiological model inputs comprising demographic details, sexual behaviour, disease and treatment patterns, and CC screening were taken from publicly available sources and unpublished data (provided by Prof Woo YL; available upon request) and are described in detail in Supplemental Digitial Appendix 1 https://links.lww.com/SGMJ/A49 and Table S2 [see Supplemental Digital Appendix 2 https://links.lww.com/SGMJ/A50].[3,10-13,16,18,24,25] Local Malaysia-specific data were utilised whenever available. The prophylactic efficacy of all three vaccines was assumed to be equivalent against HPV 6/11 (4vHPV and 9vHPV) and against HPV 16/18 (2vHPV, 4vHPV and 9vHPV) based on clinical trial data, as shown in Table S3 [see Supplemental Digital Appendix 2 https://links.lww.com/SGMJ/A50].[21,26-30] The model assumed lifelong duration of protection against HPV types 6/11/16/18/31/33/45/52/58 and herd immunity. Economic model parameters The economic model allowed us to estimate total costs, survival (life-years gained), quality-adjusted survival (quality-adjusted life-years [QALYs]) and incremental cost-effectiveness ratio (ICER). Inputs for the economic model included vaccine strategy and cost parameters. All costs were from a healthcare provider perspective and were reported in 2018 Malaysian ringgit (RM). A discount rate of 3% for costs and QALYs was applied to the model.[31] The base cases analyses were conducted according to two different scenarios: two-dose vaccination strategy of 9vHPV versus 4vHPV in 13-year-old girls and two-dose vaccination strategy of 9vHPV versus 2vHPV in 13-year-old girls. Both scenarios were assessed at a vaccine coverage rate (VCR) of 90%. Cost parameters used in the model included cost per episode of care, cost of vaccination and cost of screening tests, as shown in Table S4 [see Supplemental Digital Appendix 2 https://links.lww.com/SGMJ/A50]. Outcome parameters The following health outcome parameters were estimated using the model: the cumulative incidence and number of prevented cases of CIN (1/2/3), CC and genital warts, and the cumulative reduction of premature CC deaths. The model also estimated the following economic outcome parameters: cumulative HPV-related disease healthcare costs, QALYs of the model population, and the ICER, which was estimated as the ratio of incremental vaccination costs and incremental QALYs. Cost-effectiveness was assumed at a ceiling threshold of RM 43,378, or USD 10,252, which corresponded to 1 gross domestic product (GDP) per capita in Malaysia in 2020 and reflected the maximum willingness of decision-makers to pay for an additional QALY.[31,32] Health outcomes and costs were assessed over a 100-year time horizon because a long period of time is required before the benefit of HPV vaccination on clinical outcomes and costs become apparent.[33-35] All model equations and inputs were programmed in Mathematica (Wolfram Research, Champaign, IL, USA) version 5.2, and the NDSolve subroutine in Mathematica was used to generate numerical solutions for the differential equations making up the model. Model calibration Calibration of the current model is described in Supplemental Digital Appendix 1 https://links.lww.com/SGMJ/A49 and Tables S1 & S2 [see Supplemental Digital Appendix 2 https://links.lww.com/SGMJ/A50]. Sensitivity analyses Deterministic one-way sensitivity analyses were conducted to assess the sensitivity of ICER values to variables that may have an impact on cost-effectiveness. These included VCR for both males and females, which was assessed at different levels (VCR 80% and 95%), and discount rate of costs and QALYs (0% and 5%). RESULTS HPV-related disease incidence Over a 100-year period, greater overall reduction in estimated cumulative HPV-related disease incidence was observed for the 9vHPV vaccine versus the 2vHPV or 4vHPV vaccine [Table 1]. The predicted cumulative reduction in CC incidence over 100 years with the 9vHPV vaccine versus the 2vHPV or 4vHPV vaccine was 41,079 CC cases avoided (35.8% reduction), as shown in Table 1 and Figure S1A [see Supplemental Digital Appendix 3 https://links.lww.com/SGMJ/A51], whereas the predicted cumulative reductions in HPV 16/18-related CIN 1 and CIN 2/3 incidence with the 9vHPV versus the 2vHPV or 4vHPV vaccine were 143,455 (51.0% reduction) and 294,142 (48.9%) cases, respectively, as shown in Table 1 and Figures S1B & S1C [see Supplemental Digital Appendix 3 https://links.lww.com/SGMJ/A51]. The model also predicted cumulative reduction of 10,873 CC deaths (30.5%) when vaccinating with the 9vHPV vaccine versus the 2vHPV or 4vHPV vaccine, as shown in Table 1 and Figure S1D [see Supplemental Digital Appendix 3 https://links.lww.com/SGMJ/A51]. The 9vHPV vaccine also resulted in reduction of approximately 1.32 million and 1.15 million cases of genital warts (78.9% and 65.8% reduction, respectively) among females and males, respectively, versus 2vHPV [Table 1]. Reduction in the incidence of genital warts and HPV 6/11-related CIN 1 was projected to be observed as early as during the first 5 years after implementation of routine immunisation in females with the 9vHPV vaccine versus the 2vHPV vaccine, as shown in Table 1 and Figures S1E–S1G [see Supplemental Digital Appendix 3 https://links.lww.com/SGMJ/A51].Table 1: Cumulative reductions in incidence of HPV-related diseasea and deaths upon vaccination with the 9vHPV vs. 2vHPV & 4vHPV vaccines over a 100-year period.Cost-effectiveness analyses Cumulative disease-related costs were estimated to decrease by RM 1,262,728,192 and RM 94,913,034, with the 9vHPV vaccine versus the 2vHPV and 4vHPV vaccines, respectively [Table 2]. Cost reduction with the 9vHPV vaccine versus the 2vHPV vaccine was predicted to be attributable mainly to savings in HPV 6/11-related treatment, as shown in Figure S2A [see Supplemental Digital Appendix 3 https://links.lww.com/SGMJ/A51], together with cost savings related to HPV 31/33/45/52/58-related outcomes, whereas cost savings versus the 4vHPV vaccine were predicted to be attributable to savings in HPV 31/33/45/52/58-related treatment, as shown in Figure S2B [see Supplemental Digital Appendix 3 https://links.lww.com/SGMJ/A51]. When avoided HPV 6/11/16/18/31/33/45/52/58-related disease costs were applied to vaccination costs, net vaccination costs were RM 1,604,230,042 and RM 2,271,267,004 for 9vHPV versus 2vHPV and 4vHPV, respectively. Implementing a routine vaccination programme in females with the 9vHPV vaccine versus the 2vHPV and 4vHPV vaccines led to increases of 0.00402 and 0.00286 QALYs per person, respectively. As a result, the overall ICERs of implementing a routine vaccination programme in females with the 9vHPV vaccine versus the 2vHPV and 4vHPV vaccines were RM 12,593/QALY and RM 25,011/QALY, respectively [Table 3].Table 2: Estimated reductions in cumulative HPV-related disease costs with the 9vHPV vs. 2vHPV & 4vHPV vaccines over a 100-year period.Table 3: Cost–effectiveness analysis of HPV vaccination strategies.Sensitivity analyses When a sensitivity analysis was conducted for which VCR was adjusted, reducing the VCR to 80% was found to decrease ICERs of implementing a routine vaccination programme in females with the 9vHPV vaccine versus the 2vHPV and 4vHPV vaccines to RM 11,756/QALY and RM 23,321/QALY, respectively , as shown in Figure S3 [see Supplemental Digital Appendix 3 https://links.lww.com/SGMJ/A51]. In contrast, increasing the VCR to 95% was found to increase ICERs for the 9vHPV versus the 2vHPV and 4vHPV vaccines to RM 13,009/QALY and RM 25,865/QALY, respectively. Adjustment of discount rate of costs and QALYs had the largest impact on cost-effectiveness, as shown in Figure S3 [see Supplemental Digital Appendix 3 https://links.lww.com/SGMJ/A51]. When costs and QALYs were not discounted (0% discount rate), ICERs for the 9vHPV versus the 2vHPV and 4vHPV vaccines were found to be decreased to RM 3,791/QALY and RM 9,823/QALY, respectively. In contrast, increasing the discount rate of costs and QALYs to 5% was found to increase ICERs to RM 25,976/QALY and RM 50,535/QALY, respectively. DISCUSSION This analysis predicted the impact of replacing the 2vHPV and 4vHPV vaccines used in the current HPV NIP in Malaysia with the 9vHPV vaccine on HPV-related disease incidence and HPV-related healthcare costs. The model estimated that switching to the 9vHPV vaccine would lead to substantial reduction in CC and cervical lesions over the course of 100 years. As both the 4vHPV and 9vHPV vaccines protect against infection from HPV 6/11, estimated reductions in genital warts were deemed equivalent; similarly, as both the 2vHPV and 4vHPv vaccines protect against HPV 16/18, the 9vHPV vaccine demonstrated equivalent reduction in HPV 16/18-related CCs when compared to both of them. Previously, implementation of a school-based 2vHPV vaccination programme for 12-year-old girls in Singapore was shown to be cost-effective versus screening only and dominant over 4vHPV vaccination.[36] However, the study used a static lifetime Markov model, which is not the preferred model for HPV infection given that the force of infection can change over time following vaccination.[37] Furthermore, health disutility and the economic impact of genital warts were not considered in the base case analysis. Subsequently, a similar transmission dynamic model demonstrated that school-based 9vHPV vaccination of 11- to 12-year-old girls in Singapore would provide incremental benefit with the additional coverage of HPV 31/33/45/52/58-related precancerous lesions and CC, thus making 9vHPV vaccination a cost-effective strategy relative to either 2vHPV or 4vHPV.[38] It should be noted that the distribution of oncogenic HPV genotypes contributing to CC differs between Southeast Asia (i.e. Malaysia and Singapore) and Western countries (i.e. the USA and the United Kingdom), with HPV 52/58 being more prevalent in Southeast Asia.[39-42] Therefore, the benefit of 9vHPV vaccination in Malaysia would be similar to that in Singapore. Previous analyses showed that implementing national HPV vaccination programmes had overall positive clinical and economic impact. In Australia, implementation of the programme with the 4vHPV vaccine led to reduced incidence of genital warts in males and females,[43,44] and an analysis of surveillance data through June 2014 demonstrated that genital warts have become rare among young Australian women and heterosexual men.[45] In a systematic review of 10 years of experience in the real-world setting, prophylactic 4vHPV vaccination resulted in maximal reductions in low- and high-grade cervical abnormalities of 45% and 85%, respectively.[46] For example, within 5 years of implementing Australia's 4vHPV vaccination programme in females aged 12–26 years in Victoria, the overall reductions in low- and high-grade cervical cytological abnormalities were found to be 34% and 47%, respectively.[46,47] Similarly, other countries (Denmark and Colombia) have also reported the long-term effectiveness of the 4vHPV vaccine in terms of reduction in cervical cytological abnormalities after 6 years of follow-up.[48,49] Taken together, ensuring broad coverage against HPV infections may provide additional public health benefits and lessen the HPV-related burden on the national health system. A large community-based survey of healthy women in Malaysia reported that three of the top five most prevalent HPV types were the high-risk types 16/52/58 targeted by the 9vHPV vaccine.[8] Given the high prevalence of CC and the current low cervical screening uptake (uptake rate of 22%[3]) in Malaysia, expanding HPV vaccine coverage to include protection against five additional high-risk types with the 9vHPV vaccine is likely to be beneficial in the long term to overall CC and HPV-related cancer rates. When assessing disease costs, the estimated reduction in healthcare costs over 100 years after applying a 3% discount rate for the 9vHPV vaccine was 43.0% versus the 2vHPV vaccine and 5.4% versus the 4vHPV vaccine. The large reduction in costs when switching to the 9vHPV vaccine versus the 2vHPV vaccine is largely due to reduction in treating genital warts and HPV 31/33/45/52/58-associated cervical lesions and cancers. The 2vHPV and 4vHPV vaccines do not provide protection against HPV types 52/58, which are highly prevalent in Malaysia.[8] We did not assume any cross protection for 2vHPV. Previous studies evaluating the 2vHPV vaccine have demonstrated cross-protective efficacy against infection from HPV 31/33/45; however, cross protection was not consistent across studies and may have been confounded by differences in study design and co-infections with HPV 16/18.[50-53] In addition, there was little to no evidence of cross protection against HPV 52/58.[16] The cost-per-QALY gained of vaccination with the 9vHPV vaccine in 13-year-old girls in Malaysia was RM 12,593 versus the 2vHPV vaccine and RM 25,011 versus the 4vHPV vaccine, assuming equal vaccine efficacy, lifelong protection and no cross protection, which are well below the established threshold of RM 43,378 (1 GDP per capita in Malaysia in 2020).[31,32] Furthermore, sensitivity analyses demonstrated that vaccination with the 9vHPV vaccine remained cost-effective at VCRs of 80% and 95%. Although vaccination with the 9vHPV vaccine also remained cost-effective at a cost and QALYs discount rate of 0% (less than RM 10,000/QALY), cost-effectiveness at a 5% discount rate increased substantially for the 9vHPV versus the 2vHPV vaccines (RM 25,976/QALY) and exceeded the established threshold of RM 43,378 for the 9vHPV versus the 4vHPV vaccines (RM 50,535/QALY). This can be explained by the fact that the benefits of vaccinating girls aged 11–12 years in the prevention of CC and other HPV-related cancers are only realised at a late stage of the time horizon. Therefore, applying a high discount rate to future health outcomes will be less valuable, resulting in less-favourable outcomes from the economical evaluation. A limitation of this study is that our model is based on lifelong protection; however, the duration of protection for all HPV vaccines is not known. Another limitation of the study was that protection from the additional five HPV types targeted by the 9vHPv vaccine (31/33/45/52/58) was assumed only for CC; the impact of protection against HPV 31/33/45/52/58 on the incidence of vulvar, vaginal, anal, penile, and head and neck cancers was not estimated. This assumption provides a conservative estimate of the public health benefit associated with the 9vHPV vaccine. A further limitation is that cost-effectiveness was determined at a ceiling threshold of RM 43,378 or USD 10,252, which reflected the maximum willingness of decision-makers to pay for an additional QALY.[31,32] In addition, the model does not take into account improvements in cervical screening methods over the course of the 100 years, which could further reduce HPV-related healthcare costs. In conclusion, this analysis demonstrated that use of the 9vHPV vaccine in the national vaccination programme in Malaysia is projected to lead to greater reduction in HPV-related disease and to be highly cost-effective in comparison to either the 2vHPV or 4vHPV vaccine. Acknowledgement We thank Woo Yin Ling, MD, PhD, for her contributions to the development of this manuscript. Financial support and sponsorship This study was sponsored by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Medical writing assistance was provided by Max Chang, BSc (Hons), and Lei Bai, PhD, of ApotheCom (New York, NY, USA), and was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Conflicts of interest Hsu T-Y was an employee of MSD, Singapore, Pte Ltd when the study was conducted. Saxena K, Walia A and Prabhu VS are employees of and own stock in Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Pavelyev A is a paid consultant for Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and is working under contract with HCL America, Inc., Sunnyvale, CA, USA.

Histopathological evaluation of colposcopic biopsies, LLETZ and cold knife cone biopsies of the uterine cervix in post-menopausal women: considerations in the setting of the new Australian cervical HPV DNA screening program

The Indian government is quite correct not to prioritize HPV vaccination as a public health priority