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Background: While recommending a human papillomavirus (HPV) single-dose vaccination schedule in 2022, the World Health Organization highlighted the need for long-term follow-up studies to monitor waning of protection. We report on vaccine efficacy against HPV infections in 1-, 2-, and 3-dose schedules and protection against cervical precancers at a median follow-up of 12 years postvaccination., Methods: This randomized multicenter study in India was originally designed to vaccinate unmarried girls aged 10-18 years with either 2 or 3 doses of quadrivalent HPV vaccine. A ministerial decree to halt vaccination in trials resulted in the creation of cohorts receiving different doses, including just a single dose. Cohorts were assessed for incident and persistent infections by genotyping cervical samples collected yearly for 4 consecutive years after participants were married. Cervical screening with an HPV test was initiated at age 25 years for married participants. Age- and site-matched unvaccinated married women were recruited to be compared with vaccinated cohorts. Vaccine efficacy was assessed using proportional incidence ratios., Results: The number of participants in the 1-, 2- (at 0 and 6 months), and 3-dose cohorts was 4949, 4980, and 4348, respectively. Of the recipients, 71%-82% in the different cohorts were eligible to provide samples for genotyping. Vaccine efficacy against persistent HPV 16 and 18 infection was 92.0% (95% confidence interval [CI] = 87.0% to 95.0%) in 3022 recipients of the single dose; and comparable with that observed in the 2-dose arm (94.8%, 95% CI = 90.0% to 97.3%) and the 3-dose arm (95.3%, 95% CI = 90.9% to 97.5%). No high-grade precancer associated with HPV 16 and 18 was detected among vaccinated participants compared with 8 precancers detected among the unvaccinated women., Conclusion: This observational cohort study has established that a single dose of HPV vaccine provides high protective efficacy against persistent HPV 16 and 18 infections and associated neoplasia 15 years postvaccination., (© The Author(s) 2024. Published by Oxford University Press.)

Long-term follow-up of a cohort of unmarried girls who received one, two, or three doses of quadrivalent HPV vaccine, between 10 and 18 years of age, in an Indian multi-centric study allowed us to compare antibody responses between the younger and older age cohorts at 10-years post-vaccination, and study the impact of initiation of sexual activity and cervical HPV infections on antibody levels. Among the younger (10-14 years) recipients of a single dose, 97.7% and 98.2% had detectable binding antibody titers against HPV 16 and HPV 18 respectively at ten years post-vaccination. The proportions among those receiving a single dose at age 15-18 years were 92.3% and 94.2% against HPV 16 and HPV 18 respectively. Mean HPV 16 binding antibody titers were 2.1 folds (95%CI 1.4 to 3.3) higher in those vaccinated at ages 10-14 years, and 1.9 folds (95%CI 1.2 to 3.0) higher in those vaccinated at 15-18 years compared to mean titers seen in the unvaccinated women. Compared to previous timepoints of 36 or 48 months, binding antibodies against HPV 16 and neutralizing antibodies against both HPV 16 and HPV 18 were significantly higher at 10 years. This rise was more pronounced in participants vaccinated at 15-18 years. No association of marital status or cervical HPV infections was observed with the rise in titer. Durability of antibody response in single dose recipients correlated well with the high efficacy of a single dose against persistent HPV 16/18 infections irrespective of age at vaccination, as we reported earlier.

Background: While cervical cancer deaths have declined steeply in high-income countries due to the widespread use of the Papanicolaou test (Pap test), the same trend has not emerged in low or middle-income countries (LMICs). Access to screening in LMICs like India is limited due to barriers such as limited healthcare infrastructures, lack of sexual health education, and stigma demarcating sexually transmitted infections (STIs). HPV self-sampling (HPV-SS), a woman-centered and at-home method for screening, can be utilized as a unique screening tool to overcome some of these barriers. Our study examined the effectiveness of HPV-SS, supported by family-centred arts-based sexual health literacy on the uptake of cervical cancer screening among hard-to-reach women in rural and remote areas in India., Methods: Our community-based mixed methods pilot study recruited 240 participants (120 women and 120 male partners or family members) through female Accredited Social Health Activists (ASHA) across 3 Indian villages of Shirgoan, Khodala, and Jamsar in Palghar district. Inclusion criteria included women ages 30-69 who were under or never screened (UNS) and their male partners/family members aged 18 or over. Knowledge and attitudes about cervical cancer and screening and their perceived stigma surrounding STI were assessed using validated scales prior to and after attending a 2-hour arts-based sexual health education (SHE). In addition, participants' uptake of cervical cancer screening was assessed after attendance in SHE., Findings: Results revealed significant improvement in knowledge and attitudes about cervical cancer and screening, and a reduction in the STI stigma after participation in SHE sessions (overall mean difference in Knowledge: z = 6.1 ± 2.4, P < 0.001; attitudes about Pap-test and VIA: z = 2.2 ± 8.4, P < 0.001 and z = 2.9 ± 8.2, P < 0.001; STI stigma: z = 2.8 ± 12.4, P < 0.001). 118 out of 120 female participants chose to be screened and 115 opted for HPV-SS., Conclusions: The implementation of HPV-SS coupled with family-centered arts-based and culturally appropriate SHE is highly promising in promoting cervical cancer screening among hard-to-reach women. Evidence from our study can be used to advance public health policies and inform the scale-up of similar initiatives in other villages and states across rural India and other LMICs., (© 2023. The Author(s).)

Background: The recent World Health Organization recommendation supporting single-dose of HPV vaccine will significantly reduce programmatic cost, mitigate the supply shortage, and simplify logistics, thus allowing more low- and middle-income countries to introduce the vaccine. From a programmatic perspective the durability of protection offered by a single-dose will be a key consideration. The primary objectives of the present study were to determine whether recipients of a single-dose of quadrivalent HPV vaccine had sustained immune response against targeted HPV types (HPV 6,11,16,18) at 10 years post-vaccination and whether this response was superior to the natural antibody titres observed in unvaccinated women., Methods: Participants received at age 10-18 years either one, two or three doses of the quadrivalent HPV vaccine. Serology samples were obtained at different timepoints up to 10 years after vaccination from a convenience sample of vaccinated participants and from age-matched unvaccinated women at one timepoint. The evolution of the binding and neutralizing antibody response was presented by dose received. 10-year durability of immune responses induced by a single-dose was compared to that after three doses of the vaccine and in unvaccinated married women., Results: The dynamics of antibody response among the single-dose recipients observed over 120 months show stabilized levels 18 months after vaccination for all four HPV types. Although the HPV type-specific (binding or neutralizing) antibody titres after a single-dose were significantly inferior to those after three doses of the vaccine (lower bounds of GMT ratios < 0.5), they were all significantly higher than those observed in unvaccinated women following natural infections (GMT ratios: 2.05 to 4.04-fold higher). The results correlate well with the high vaccine efficacy of single-dose against persistent HPV 16/18 infections reported by us earlier at 10-years post-vaccination., Conclusion: Our study demonstrates the high and durable immune response in single-dose recipients of HPV vaccine at 10-years post vaccination., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: A randomised trial designed to compare three and two doses of quadrivalent human papillomavirus (HPV) vaccine in adolescent girls in India was converted to a cohort study after suspension of HPV vaccination in trials by the Indian Government. In this Article, the revised aim of the cohort study was to compare vaccine efficacy of single dose to that of three and two doses in protecting against persistent HPV 16 and 18 infection at 10 years post vaccination., Methods: In the randomised trial, unmarried girls aged 10-18 years were recruited from nine centres across India and randomly assigned to either two doses or three doses of the quadrivalent HPV vaccine (Gardasil [Merck Sharp & Dohme, Whitehouse Station, NJ, USA]; 0·5 mL administered intramuscularly). After suspension of recruitment and vaccination, the study became a longitudinal, prospective cohort study by default, and participants were allocated to four cohorts on the basis of the number vaccine doses received per protocol: the two-dose cohort (received vaccine on days 1 and 180 or later), three-dose cohort (days 1, 60, and 180 or later), two-dose default cohort (days 1 and 60 or later), and the single-dose default cohort. Participants were followed up yearly. Cervical specimens were collected from participants 18 months after marriage or 6 months after first childbirth, whichever was earlier, to assess incident and persistent HPV infections. Married participants were screened for cervical cancer as they reached 25 years of age. Unvaccinated women age-matched to the married vaccinated participants were recruited to serve as controls. Vaccine efficacy against persistent HPV 16 and 18 infections (the primary endpoint) was analysed for single-dose recipients and compared with that in two-dose and three-dose recipients after adjusting for imbalance in the distribution of potential confounders between the unvaccinated and vaccinated cohorts. This trial is registered with ISRCTN, ISRCTN98283094, and ClinicalTrials.gov, NCT00923702., Findings: Vaccinated participants were recruited between Sept 1, 2009, and April 8, 2010 (date of vaccination suspension), and followed up over a median duration of 9·0 years (IQR 8·2-9·6). 4348 participants had three doses, 4980 had two doses (0 and 6 months), and 4949 had a single dose. Vaccine efficacy against persistent HPV 16 and 18 infection among participants evaluable for the endpoint was 95·4% (95% CI 85·0-99·9) in the single-dose default cohort (2135 women assessed), 93·1% (77·3-99·8) in the two-dose cohort (1452 women assessed), and 93·3% (77·5-99·7) in three-dose recipients (1460 women assessed)., Interpretation: A single dose of HPV vaccine provides similar protection against persistent infection from HPV 16 and 18, the genotypes responsible for nearly 70% of cervical cancers, to that provided by two or three doses., Funding: Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests PB has received research funding from GlaxoSmithKline through the Chittaranjan National Cancer Institute (Kolkata, India) during his previous position at the institute. NB has received research funding through her institute from GlaxoSmithKline and Merck. SJ has received funds from GlaxoSmithKline through the Jehangir Clinical Development Center (Pune, India) for a human papillomavirus vaccine study. All other authors declare no competing interests., (© 2021 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Among the screening tests for cervical cancer, advantages of screening with second generation molecular Hybrid Capture 2 (HC2) test is the high sensitivity and negative predictive value that makes it easy to implement as a cervical cancer screening policy necessitating less screening rounds. High income countries are now implementing HC2 test in their national cervical cancer screening program. Since the acceptance of any screening test depends on the sensitivity of the test, the current study was carried out to evaluate the sensitivity of HC2 test reported from Low- and Middle-income countries (LMIC) which share major burden of cervical cancer globally and to establish if HC2 test could be used as a primary screening test in India., Materials and Methods: The population based cross sectional studies from LMICs which evaluated HC2 test as a primary screening modality to diagnose Cervical intraepithelial neoplasm grade 2 and above (CIN2+) lesions were included., Results: A total of 18 studies from LMIC involving 1,13,086 women were reviewed for sensitivity of HC2 as a primary screening test. The overall average sensitivity and specificity to diagnose CIN2+ lesions were 79.84% (95% CI-71.01,86.73) and 85.63% (95% CI- 84.37,86.92) respectively. India demonstrated an average sensitivity and specificity of 65% (95% CI 57,77) and 93% (95% CI- 92,94) respectively., Conclusion: Results from LMIC demonstrate a comparably low sensitivity of HC2 test to diagnose CIN2+ lesions as compared to that reported from High income countries. Sensitivity of HC2 was substantially low for India. The current study discusses issues of HC2 assay and the role of untreated Reproductive tract infections as probable causes for low sensitivity of the test. This needs further research in an attempt to improve the sensitivity of the test in an era of self-sampling and low-cost HPV test on horizon to improve the coverage for cervical cancer., .

In context of the ongoing multi-centric HPV vaccine study in India, unvaccinated married women (N = 1484) aged 18-23 years were recruited in 2012-2015 as age-matched controls to the vaccinated women and followed up yearly. We assess type-specific prevalence, natural history and potential determinants of human papillomavirus (HPV) infection in these unvaccinated women. Cervical samples were collected yearly for at least four consecutive years. A Multiplex Type-Specific E7-Based polymerase chain reaction assay was used to detect 21 HPV types. HPV prevalence was 36.4% during 6 years. Most common HPV types were 16 (6.5%) and 31 (6.1%). Highest persistence were observed for HPV 35 (62.5%) and 52 (25%). New HPV acquisition rate was 5.6/1000 person-months of observation (PMO), highest for HPV 16 (1.1/1000 PMO). Type-specific clearance rates ranged between 2.9-5.5/100 PMO. HPV 16 and/or 18 infections were 41% (95% CI 4-63%) lower among women with 2-<3 years between marriage and first cervical sample collection compared to those with <2 years. HPV prevalence and acquisition rates in young Indian women were lower than their Western counterparts. HPV 16 infections being most common shows the importance and potential impact of HPV vaccination in India. Women with 2-3 years exposure had reduced risk possibly due to higher infections clearance., Competing Interests: The corresponding authors, on behalf of all authors, declares the following potential competing interests: Neerja Bhatla has received research funding through her institute from GlaxoSmithKline and Merck. Smita Joshi has received funds from GlaxoSmithKline through the Jehangir Clinical Development Center to do an HPV vaccine study. Partha Basu has received research funding from GlaxoSmithKline through Chittaranjan National Cancer Institute, India during his previous position at the institute. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors declare no competing interests.

Primary cervical cancer screening by HPV testing for high risk human papillomavirus (hrHPV) is expected to replace cytology-based programs in many parts of the world. Its high sensitivity and negative predictive value permit longer screening intervals up to beyond five years. However, low positive predictive value can lead to unnecessary referrals and overtreatment since most hrHPV infections are transient and will not develop disease. Therefore risk stratification is needed to effectively triage and identify women among the hrHPV positives, who are at an increased risk of cervical (pre)cancer who need further diagnostic evaluation to decide on further management. Several triage strategies like HPV16/18 genotyping, p16/Ki67 dual staining and DNA methylation markers (CADM1, MAL and miR-124-2) have been evaluated to determine suitable triage options. Triage with p16/Ki-67 dual-stain provided better long-term risk stratification than cytology with significant reduction in cumulative 5 years CIN3+ risk in p16/Ki-67 negative women. DNA methylation assays have shown higher specificity than cytology and higher sensitivity than HPV16/18 genotyping with added advantages of reproducibility and application on self-collected samples. Based on current evidence, Pap cytology with or without additional HPV16/18 genotyping remains the most recommended triage strategies for primary HPV screening. Other strategies will need more longitudinal studies to provide evidence of risk reduction in test negative results. WHO recommends Visual Inspection with Acetic Acid (VIA) for triaging HPV-positive women in LMIC settings. An optimal triage strategy that can be integrated with primary HPV screening should be able to segregate and reassure the large majority of women who are at very low risk of cervical cancer.

Disparities in the incidence and mortality due to cervical cancer between developed and developing countries continue to persist due to suboptimal health care systems in low- to middle-income countries (LMICs) that are unable to implement organized programs for screening which lack the technical, infrastructure and financial resources for adequate coverage and access to quality assured cervical cancer screening services that further reduce their effectiveness. The challenges in introducing quality cytology screening in LMICs led to the evaluation of alternative screening approaches such as visual inspection with acetic acid (VIA) and human papillomavirus (HPV) testing-based screening. Large-scale clinical trials have generated sufficient evidence of efficacy of HPV-based screening for the introduction as the primary technology in cervical cancer screening. Being more objective, automated with better sensitivity than cytology requiring fewer rounds of screening and opportunity for self-sampling, HPV testing is thus poised to be more cost-effective in providing opportunity for wider coverage, making it ideal for incorporating into primary screening programs of LMIC settings that could help reduce regional disparities. But its optimal implementation in public health programmatic settings in LMIC still faces barriers due to high operating cost and logistic challenges. This review summarizes and presents evidence for HPV primary screening leading to higher program efficiency in cervical cancer screening programs. Policy measures and strategies to overcome the resource limitations and weaknesses in health care service delivery in low resource settings need to be assessed and streamlined to leverage the initial high program costs with that of the long term potential benefits for HPV DNA testing to reach its full potential in reducing cervical cancer incidence and mortality.

Earlier publication from the ongoing multi-centric study of the International Agency for Research on Cancer to evaluate less than three doses of the quadrivalent Human Papillomavirus (HPV) vaccine in India amongst unmarried girls demonstrated non-inferior total antibody titres, neutralizing antibody titres and antibody avidity in 2-dose recipients compared to 3-dose recipients at 15-18 years of age (Bhatla et al., 2018) [7]. The number of participants recruited at 15-18 years of age was 1515 and 1795 in the 3-dose and the 2-dose groups respectively. At a median follow-up of 7 years, incident HPV 16/18 infections were detected in 1.6% women receiving two doses and 0.8% women receiving three doses at 15-18 years. Frequency of incident infection was 7.0% in the age- and site-matched unvaccinated women (N = 1484). No persistent infection from HPV 16 was observed in the 2- or 3-dose recipients and one (0.2%) persistent HPV 18 infection was documented, each in the 3-dose and 2-dose cohorts. Among the unvaccinated women, the frequency of HPV 16/18 persistent infection was 1.7%. The protection offered by two doses of quadrivalent HPV vaccine against incident and persistent infections in recipients at 15-18 years is comparable to that seen in 3-dose recipients at 15-18 years., (Copyright © 2019. Published by Elsevier B.V.)

Extending two-dose recommendations of HPV vaccine to girls between 15 and 18 years will reduce program cost and improve compliance. Immunogenicity and vaccine targeted HPV infection outcomes were compared between 1795 girls aged 15-18 years receiving two (1-180 days) and 1515 girls of same age receiving three (1-60-180 days) doses. Immunogenicity outcomes in 15-18 year old two-dose recipients were also compared with the 10-14 year old three-dose (N = 2833) and two-dose (N = 3184) recipients. The 15-18 year old two-dose recipients had non-inferior L1-binding antibody titres at seven months against vaccine-targeted HPV types compared to three-dose recipients at 15-18 years and three-dose recipients at 10-14 years of age. Neutralizing antibody titres at 18 months in 15-18 year old two-dose recipients were non-inferior to same age three-dose recipients for all except HPV 18. The titres were inferior to those in the 10-14 year old three-dose recipients for all targeted types. Frequency of incident infections from vaccine-targeted HPV types in the 15-18 year old two-dose recipients was similar to the three dose recipients. None of the girls receiving two or three doses had persistent infection from vaccine-targeted types. These findings support that two doses of HPV vaccine can be extended to girls aged 15-18 years., (Copyright © 2018. Published by Elsevier B.V.)

Purpose of Review: Cervical cancer still remains the fourth most common cancer, affecting women worldwide with large geographic variations in cervical cancer incidence and mortality rates. There exist vast disparities in cervix cancer control and prevention efforts globally. The present review addresses the current developments in cervical cancer prevention and control across both high-income countries and low-middle income countries and attempts to identify new strategies that might help address the gaps in cervical cancer care disparities globally., Recent Findings: Paradigms for cervix cancer screening are changing in high-resource settings from cytology-based screening to adoption of molecular screening and cotesting to achieve program effectiveness. Low-middle income countries with larger burden of cervical cancer continue to face financial and logistic limitations to make both cervix cancer screening and human papillomavirus vaccine available to their populations. Alternative low-cost screening technologies, operationally feasible implementation strategies, reduction of cost of procurement and delivery approaches for human papillomavirus vaccine need assessment to decrease cancer care disparities., Summary: Efforts directed toward cervix cancer prevention and early detection for improvements in cervical cancer outcomes of incidence and mortality have to be proportionately matched by access to acceptable standards of cancer care.

Cervical cancer is the fourth most common cancer among women globally and the second most common cancer among Indian women. India alone bears 23% of the global cervical cancer burden. In India, population-based cervical cancer screening is largely nonexistent in most regions due to competing healthcare priorities, insufficient financial resources and a limited number of trained providers. Hence, most of the cases present in advanced stages of the disease, thus leading to increased mortality and reduced survival. Various screening options like cytology, visual-based screening and testing for high-risk HPV are available. Several cross-sectional studies have looked at the comparative efficacy of different screening tests. Three important randomized controlled trials from India have shown the efficacy of screening once in a life time with HPV DNA, one-time screening with VIA by trained nurses and four-time screening with VIA by trained primary health workers, reducing mortality due to cervical cancers. Prevention of cervical cancers with two-dose HPV vaccination and early detection of precancerous cervical lesions of the eligible population through screening and their appropriate treatment with a single-visit 'screen-and-treat' approach appear to be promising for low-middle-income countries including India., (© 2016 S. Karger AG, Basel.)

Background: An increase in worldwide HPV vaccination could be facilitated if fewer than three doses of vaccine are as effective as three doses. We originally aimed to compare the immunogenicity and frequency of persistent infection and cervical precancerous lesions caused by vaccine-targeted HPV after vaccination with two doses of quadrivalent vaccine on days 1 and 180 or later, with three doses on days 1, 60, and 180 or later, in a cluster-randomised trial. Suspension of the recruitment and vaccination due to events unrelated to our study meant that some enrolled girls could not be vaccinated and some vaccinated girls received fewer than the planned number of vaccinations by default. As a result, we re-analysed our data as an observational cohort study., Methods: Our study was designed to be done in nine locations (188 clusters) in India. Participants were unmarried girls aged 10-18 years vaccinated in four cohorts: girls who received three doses of vaccine on days 1, 60, and 180 or later, two doses on days 1 and 180 or later, two doses on days 1 and 60 by default, and one dose by default. The primary outcomes were immunogenicity in terms of L1 genotype-specific binding antibody titres, neutralising antibody titres, and antibody avidity after vaccination for the vaccine-targeted HPV types 16, 18, 6, and 11 and incident and persistent infections with these HPVs. Analysis was per actual number of vaccine doses received. This study is registered with ISRCTN, number ISRCTN98283094; and with ClinicalTrials.gov, number NCT00923702., Findings: Vaccination of eligible girls was initiated on Sept 1, 2009, and continued until April 8, 2010. Of 21 258 eligible girls identified at 188 clusters, 17 729 girls were recruited from 178 clusters before suspension. 4348 (25%) girls received three doses, 4979 (28%) received two doses on days 1 and 180 or later, 3452 (19%) received two doses at days 1 and 60, and 4950 (28%) received one dose. Immune response in the two-dose HPV vaccine group was non-inferior to the three-dose group (median fluorescence intensity ratio for HPV 16 1·12 [95% CI 1·02-1·23] and for HPV 18 1·04 [0·92-1·19]) at 7 months, but was inferior in the two-dose default (0·33 [0·29-0·38] for HPV 16 and 0·51 [0·43-0·59] for HPV 18) and one-dose default (0·09 [0·08-0·11] for HPV 16 and 0·12 [0·10-0·14] for HPV 18) groups at 18 months. The geometric mean avidity indices after fewer than three doses by design or default were non-inferior to those after three doses of vaccine. Fewer than three doses by design and default induced detectable concentrations of neutralising antibodies to all four vaccine-targeted HPV types, but at much lower concentration after one dose. Cervical samples from 2649 participants were tested and the frequency of incident HPV 16, 18, 6, and 11 infections was similar irrespective of the number of vaccine doses received. The testing of at least two samples from 838 participants showed that there was no persistent HPV 16 or 18 infections in any study group at a median follow-up of 4·7 years (IQR 4·2-5·1)., Interpretation: Despite the limitations imposed by the suspension of the HPV vaccination, our findings lend support to the WHO recommendation of two doses, at least 6 months apart, for routine vaccination of young girls. The short-term protection afforded by one dose of HPV vaccine against persistent infection with HPV 16, 18, 6, and 11 is similar to that afforded by two or three doses of vaccine and merits further assessment., Funding: Bill & Melinda Gates Foundation., (© 2015 International Agency for Research on Cancer. Published by Elsevier Ltd/Inc/BV. All rights reserved.)