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Cancer care in countries in the South Asian Association for Regional Cooperation (SAARC) is hindered by many challenges, including inadequate infrastructure, a shortage of skilled health-care professionals, and economic constraints. These factors contribute to disparities in timely diagnosis and treatment, leading to poorer health outcomes. Health-care systems within the region vary considerably, ranging from free public health care in Sri Lanka to predominantly out-of-pocket expenses in Bangladesh, highlighting inequities in financial access and service delivery for patients within this region. The absence of comprehensive national health insurance systems imposes substantial financial burdens on patients with cancer and their families, often resulting in catastrophic health-care costs. Paediatric oncology services reflect these disparities with greater clarity. Although Bangladesh has developed multiple treatment centres, issues such as delayed diagnoses and financial barriers persist. By contrast, countries such as Afghanistan and the Maldives have few specialised paediatric oncology services, necessitating costly referrals abroad that place large strains on families. Geriatric oncology remains underdeveloped across most SAARC nations, with few dedicated services and guidelines. Despite progress in India and Sri Lanka, gaps in specialised training and holistic care for older patients remain. Addressing these disparities requires coordinated efforts, including improving health-care infrastructure, expanding insurance coverage, and fostering regional collaborations. Implementing comprehensive national cancer control programmes across SAARC nations, leveraging intercountry networks, and ensuring political commitment are essential to achieving equitable cancer care and advancing Sustainable Development Goals in the region., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

South Asian Association for Regional Collaboration (SAARC) countries, home to 24% of the world's population, are facing the double burden of disease (ie, where a population experiences both an increasing incidence of cancers typically associated with affluence and a sustained or rising burden of cancers linked to infections and poverty) with non-communicable diseases (NCDs) attributing to 47% of the global burden of disease and to about 60% of all deaths. In 2022, cancer in this region accounted for approximately 9·3% of incidence worldwide and 12% of global mortality. Cancer is one of the major NCDs affecting South Asia, accounting for a large proportion of disability-adjusted life-years lost in this region. The most common cancers are lung, head and neck, and gastrointestinal cancers in both sexes, and cervix and breast cancers in females. The cancer burden is high in SAARC countries, although there are differences among countries and within urban and rural regions of each country, depending on the level of available resources, development, and epidemiological shift. Here we discuss various cancer care issues and challenges throughout the cancer care continuum in the SAARC region. We make an urgent call for regional collaboration to develop, modify, and implement a holistic cancer control plan and formulate a systematic approach directed to address the growing burden of cancer in this region. It is crucial to establish strong political will and commitment to take forward the recommended actions outlined in this Series to overcome and address the cancer crisis in the SAARC region, aligning with Sustainable Development Goal 2030 targets., Competing Interests: Declaration of interests WN received funding from the National Institutes of Health (R25CA288263 and R13CA257481). SA received funding from the National Institutes of Health (R13CA257481). MSH received funding from the Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA supporting the Global Health Catalyst. The content is solely the authors’ responsibility and does not necessarily represent the views of the National Institutes of Health or the Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The education and training of the oncological health-care workforce is vital for building effective health-care systems that deliver optimal care to patients with cancer. In the South Asian Association for Regional Cooperation (SAARC) nations, there is a notable shortage of both physician and non-physician oncology professionals, including oncologists, medical physicists, radiotherapy technologists, and oncology nurses. This shortage is primarily caused by inadequate education and training programmes. Oncology professionals across SAARC countries face several challenges, including a scarcity of trained personnel, poor health-care infrastructure (including resources and equipment), and insufficient educational opportunities. This Series paper examines the current state of oncology education and training programmes within the SAARC region, identifies the challenges faced by oncology professionals, and offers recommendations for improvement. Short-term strategies focus on developing a skilled, multidisciplinary oncology workforce and enhancing existing training programmes. In the long term, the goals are to establish self-sufficient cancer care systems, promote regional collaboration, and strengthen research infrastructure. Achieving these objectives will require comprehensive approaches, increased financial resources, advanced cancer care infrastructure, and innovative educational models. Regional and international collaborations are essential to raise awareness of cancer as a major public health concern, advance prevention and early detection efforts, and bolster research initiatives., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Cancer is a major global health threat, with 35 million new cases projected by 2050, predominantly in low-income and middle-income-countries. Within South Asian Association for Regional Cooperation (SAARC) countries, a notable gap in cancer research investment and output compared with high-income countries highlights the need to strengthen research capacity. The rising cancer incidence across SAARC countries is not being matched by local research, particularly in clinical trials in molecular biology, targeted therapy, immunotherapy, and cancer vaccines. This paucity of research is problematic as guidelines and therapies developed in high-income countries might not be directly applicable to low-income and middle-income countries due to distinct regional sociocultural, genetic, and environmental factors and are often impractical in these countries due to cost and implementation challenges. This Series paper examines the cancer research landscape within SAARC countries, focusing on Bangladesh, Nepal, Sri Lanka, India, Pakistan, Afghanistan, Bhutan, and Maldives. We analyse PubMed publication rates and examine available infrastructure, current research (including clinical trials), and limitations and disparities among SAARC countries in terms of cancer research. Key challenges include disparities in health-care access, cultural and economic barriers, and little funding and infrastructure. Strengthening cancer research in SAARC countries requires building collaborative networks, improving research facilities and training, focusing on local epidemiological studies, and developing affordable technologies and treatments. Effective policy and stakeholder engagement could greatly advance cancer care in the region., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

About 95% of cervical cancers worldwide are caused by human papillomavirus (HPV). Cervical cancer is preventable and curable if it is detected and treated early. We reviewed the latest national cervical cancer indicators, and barriers to HPV vaccination and cervical cancer screening in 21 Asian National Cancer Centers Alliance (ANCCA) member countries. Half (n = 11, 52%) of the countries have introduced HPV vaccination for girls as part of their national vaccination programme, three countries reported coverage of over 90%. Most ANCCA member countries have cervical cancer screening programmes, only five countries reported screening uptake of over 50%. The barriers to HPV vaccination coverage and cervical cancer screening participation have been identified. Ensuring health service accessibility and affordability for women, addressing sociocultural barriers, and strengthening the healthcare system and continuum of care are essential to increase HPV vaccination and cervical cancer screening coverage., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 Published by Elsevier Ltd.)

Background: "REACH-Bhutan" aimed to evaluate the feasibility and clinical performance of a community-based screening program for cervical cancer in rural Bhutan using self-collected samples for high-risk human papillomavirus (HR-HPV) testing., Methods: In April/May 2016, 2590 women aged 30-60 years were screened across rural Bhutan by providing a self-collected sample for careHPV testing. All careHPV-positive women, plus a random sample of careHPV-negative women, were recalled for colposcopy and biopsy. Self-samples also underwent GP5+/6+ polymerase chain reaction (PCR)-based HR-HPV DNA detection and genotyping. Cross-sectional screening indices were estimated against histological high-grade squamous intraepithelial lesions or worse (hHSIL+), including imputation of hHSIL+ in women without colposcopy., Results: HR-HPV positivity was 10.2% by careHPV and 14.8% by GP5+/6+ PCR. Twenty-two cases of hHSIL+ were histologically diagnosed, including one invasive cancer; an additional 7 hHSIL+ were imputed in women without colposcopy. HR-HPV testing by GP5+/6+ showed higher sensitivity for hHSIL+ (89.7%, 95% CI 72.6-97.8) than careHPV (75.9%, 95% CI 56.5-89.7). Negative predictive value was also slightly higher for GP5+/6+ (99.9%, 95% CI 99.6-100) than careHPV (99.7%, 95% CI 99.4-99.9). Specificity, however, was lower for GP5+/6+ (86.1%, 95% CI 84.6-87.4) than careHPV (90.6%, 95% CI 89.4-91.7), as was positive predictive value (6.9%, 95% CI 4.5-9.9 vs. 8.5%, 95% CI 5.4-12.6). Of 377 HR-HPV-positive women by GP5+/6+, 173 (45.9%) were careHPV-positive, including 54.7% HPV16-positive and 30.2% HPV18-positive women., Conclusions: The final REACH-Bhutan results show that screening for cervical cancer with self-collection of samples and HR-HPV testing, in addition to our previous report of achieving high participation, can also perform well to detect women with hHSIL+., (© 2023 International Agency for Research on Cancer; licensed by John Wiley & Sons Ltd. Cancer Medicine published by John Wiley & Sons Ltd.)

Competing Interests: Conflict of Interest None declared.

Background: Rare cancers (RCs) are challenging to manage and are "forgotten cancers" though they collectively constitute a significant proportion of all cancers (∼20%). As a first step towards streamlining care, there is an unmet need to map the epidemiology of RCs in South Asian Association for Regional Collaboration (SAARC) countries., Methods: The authors collected data from 30 Population-Based Cancer Registries (PBCR) of India and the published national registries of Nepal, Bhutan and Sri Lanka (SL) and compared them with the standard RARECAREnet RC list., Findings: With the standard definition of crude incidence rates (CR) ≤6/100,0000 per population, 67.5%, 68.3%, 62.3% and 37% of all incident cancers qualify as RCs in India, Bhutan, Nepal and SL, respectively. An arbitrary cut-off CR ≤3 appears more appropriate with 43%, 39.5%, 51.8% and 17.2% of cancers identified as RCs, respectively, due to the lower cancer incidence.There are similarities and notable differences between the RC lists of the SAARC region with that of the European RC list. Oral cavity cancers are rare in Europe, while pancreas, rectum, urinary bladder and melanomas are common. In addition, uterine, colon and prostatic cancers are rare in India, Nepal and Bhutan. In SL, thyroid cancer is common. There are gender-related and regional differences in RC trends in the SAARC countries., Interpretation: There is an unmet need in SAARC nations to capture epidemiological nuances in rare cancers. Understanding the unique issues in the developing world may guide policymakers to adopt appropriate measures to improve RC care and tailor public health interventions., Funding: None., Competing Interests: None of the authors have competing interests., (© 2023 The Authors.)

Purvish M. ParikhIn the year 2020, a total of 342 000 women were estimated to die of cervical cancer, of which 90%) were expected amongst low- and middle-income countries (LMIC). Globally incidence of cervical cancer has reduced as a result of improved personal hygiene, better living conditions and higher application of opportunistic screening programs. Yet GLOBOCAN shows that absolute number of cases are still increasing. We therefore conducted a 21 question multiple choice questionnaire online survey in Jan 2023 amongst 9 SAARC countries. A total of 367 replies were received and the representative answers for each country are being reported in this manuscript. A good possibility of achieving World Health Assembly target (Nov 17, 2020) was felt only by Bhutan and Nepal. For screening, most countries (Bhutan, India, Myanmar, Nepal, Pakistan and Sri Lanka) recommend for all asymptomatic eligible patients. Public health experts have suggested VIA / VILI as the best solution for LMICs. However, a dual screening strategy (HPV DNA plus) cytology was preferred by doctors in Afghanistan, Bhutan, India, Myanmar, Pakistan and Sri Lanka. Screening, triage and then treatment was the preferred by Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, Sri Lanka. HPV vaccination was recommended in all girls between ages 10 to 26 years in Bangladesh, India, Myanmar, Nepal, Pakistan and Sri Lanka. All the 9 countries would use HPV vaccination to all eligible patients if the cost of the vaccine was reasonably low. Our survey clearly outlines challenges faced in tackling cervical cancer in SAARC countries. We also provide consensus regarding several potential solutions that can be used in both public and private cervical cancer control programs., Competing Interests: Conflict of Interest None declared., (MedIntel Services Pvt Ltd. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Background: Colposcopy is a tool for triaging screen positive women regardless of method used for cervical cancer screening. The objective of this study was to evaluate the diagnostic performance of colposcopy in the diagnosis of histologic cervical intraepithelial neoplasia 2+ (CIN 2+) at Jigme Dorji Wangchuck National Referral Hospital (JDWNRH), Thimphu, Bhutan., Methods: This cross-sectional study was conducted from March 2021 to August 2021 among 299 women who availed colposcopy services at the colposcopy clinic of JDWNRH, Bhutan. Women included in this study were either screen positive (Pap smear) or were suspected to have invasive cancer; they underwent colposcopy and a cervical biopsy irrespective of colposcopy impression. This histopathologic assessment was considered as the gold standard test for the diagnosis of cervical intraepithelial neoplasia (CIN) or invasive cancer., Results: The mean age of the study participants was 43 years (ranges, 25-76 years). The sensitivity, specificity and accuracy of senior colposcopists to diagnose histologic CIN 2+ were 80.0% (95% CI 59.30, 93.17), 71.07% (95% CI 62.13, 78.95), and 72.60% (95% CI 64.61, 79.65), and for junior colposcopists were 59.46% (95% CI 42.10, 75.25), 76.72% (95% CI 67.97, 84.04), and 72.55% (95% CI 64.76, 79.45) respectively. The overall sensitivity, specificity, and accuracy of colposcopy to diagnose histologic CIN 2+ were 66.67% (95% CI 53.66, 78.05), 73.73% (95% CI 67.63, 79.23), and 72.24% (95% CI 66.79, 77.24) respectively., Conclusions: In this study, the senior and junior colposcopists had a comparable colposcopic accuracy to diagnose histologic CIN 2+, whereas senior had a higher sensitivity but a lower specificity than junior colposcopists., (© 2022. The Author(s).)

Stomach cancer is a common public health problem in South East Asia including Bhutan. Chronic infection with Helicobacter pylori is regarded as the principal cause of stomach cancer. Herein, we present the incidence of stomach cancer in Bhutan for eight years (from 2014 to 2021). We also discuss the steps taken for the prevention and early detection of stomach cancer., (© Association of Surgeons of India 2022.)

Cervical cancer is preventable and also curable when detected early and treated adequately, yet it remains a leading cause of morbidity and mortality among women. In Bhutan, cervical cancer is the most common cancer among women. Bhutan was the first country among the low- and middle-income economies to have instituted a national HPV vaccination program, in 2010, and has achieved >90% coverage. In 2019, Bhutan launched a cervical cancer elimination flagship program well ahead of WHO's launch of the global strategy for accelerated elimination of cervical cancer. Bhutan initiated vaccination of adolescent boys and adopted a gender-neutral vaccination program beginning September 2020 through its well-established network of primary healthcare centres. The flagship program aims to screen women aged 30-69 years with HPV testing using liquid-based cytology (LBC) as triaging for screen positive women. For women aged 25-29 years, LBC will be continued as per American Society of Colposcopy and Cervical Pathology guidelines. Colposcopy and treatment will be performed in camps to decrease loss of follow up of screen positive women. This program is also expected to improve early diagnosis of cervical cancer and provide timely and adequate cancer treatment and palliative care services. This article reviews the progress made and the challenges facing the 2030 cervical cancer elimination targets in Bhutan., (© 2021 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Rwanda and Bhutan, 2 low- and middle-income countries, implemented primarily school-based national human papillomavirus (HPV) vaccination in 2011 (Rwanda) and 2010 (Bhutan). We estimated vaccination effectiveness through urine-based HPV prevalence surveys in schools in 2013-2014 and 2017. In Rwanda, 912 participants from baseline surveys and 1,087 from repeat surveys were included, and in Bhutan, 973 participants from baseline surveys and 909 from repeat surveys were included. The overall effectiveness against vaccine-targeted HPV types (i.e., HPV-6/11/16/18) was 78% (95% CI 51%-90%) in Rwanda, and 88% (6%-99%) in Bhutan and against other α-9 types was 58% (21-78) in Rwanda and 63% (27-82) in Bhutan. No effect against other HPV types was detectable. Prevalence of vaccine-targeted HPV types decreased significantly, as well as that of other α-9 types, suggesting cross-protection. These findings provide direct evidence from low- and middle-income countries of the marked effectiveness of high-coverage school-based, national HPV vaccination programs.

Background: Bhutan implemented a national program for human papillomavirus (HPV) vaccination in 2010 involving girls aged 12 to 18 years and achieving nearly 90% coverage., Objective: To estimate HPV vaccine effectiveness in a city in Bhutan., Design: 2 cross-sectional surveys, 2011-2012 and 2018., Setting: 2 hospitals in Thimphu, capital of Bhutan., Participants: Sexually active women aged 17 to 29 years: 1445 participants from the baseline survey and 1595 from the repeated survey., Intervention: National HPV vaccination program., Measurements: HPV was assessed in cervical cell samples by using general primer GP5+/GP6+-mediated polymerase chain reaction. Human papillomavirus types were stratified as vaccine types (HPV6/11/16/18) and nonvaccine types. Age- and sexual behavior-adjusted overall, total, and indirect (herd immunity) vaccine effectiveness (VE) was computed as (1 - HPV prevalence ratio) for HPV among all women and among unvaccinated women., Results: Between the 2 surveys, the prevalence of HPV vaccine types decreased from 8.3% to 1.4%, whereas the prevalence of nonvaccine types increased from 25.8% to 31.4%. The overall and indirect adjusted VE against vaccine-targeted HPV types was 88% (95% CI, 80% to 92%) and 78% (CI, 61% to 88%), respectively. Among women younger than 27 years, who were targeted by the vaccination program, the overall and indirect adjusted VE was 93% (CI, 87% to 97%) and 88% (CI, 69% to 95%), respectively. No impact on nonvaccine HPV types was detectable., Limitation: Hospital-based recruitment; self-reported vaccination status., Conclusion: In Bhutan, the prevalence of vaccine-targeted HPV types has decreased sharply, providing the first evidence of the effectiveness of a high-coverage national HPV vaccination program in a lower-middle-income country., Primary Funding Source: Bill & Melinda Gates Foundation.

Context: Adnexal masses of ovarian origin are of growing concern due to high fatality associated with ovarian malignancy because they are diagnosed at advanced stage due to vague symptoms and absence of recommended screening tests., Aims: The aim was to study the prevalence of histopathologic types of adnexal masses in different age groups and to analyze the accuracy of preoperative evaluation in diagnosing ovarian malignancy., Settings and Design: This was a cross-sectional study carried out in the Department of Obstetrics and Gynecology of a tertiary care hospital in Bhutan with gynecologic-oncology services, from January to December 2017., Subjects and Methods: Women presenting with adnexal mass were evaluated and those meeting criteria were enrolled. They were evaluated preoperatively with complete history, examination, ultrasound, and tumor markers. Risk of malignancy index (RMI) was calculated for all patients. Following surgery, histopathology results were compared with preoperative evaluation., Statistical Analysis Used: Chi-square test, t -test, Cohen's Kappa, and receiver operating characteristic curve analysis were used for statistical analysis., Results: Of 165 patients evaluated, 127 fulfilling criteria were enrolled. Adnexal masses of ovarian origin were most common ( n = 102, 80.3%), of which 12.7% were malignant. Epithelial ovarian malignancy was the most common malignant ovarian tumor, serous cystadenocarcinoma being the most common. Malignancy was significantly more in older, postmenopausal women with high RMI. Seven out of 11 women with high RMI were diagnosed in Stage 3 or 4. RMI score at cutoff of 200 was 54.6% sensitive and 85.7% specific., Conclusions: Adnexal mass of ovarian origin was the most common. Malignancy was significantly more in older, postmenopausal women with high RMI. RMI showed moderate correlation in diagnosing epithelial ovarian malignancies., Competing Interests: There are no conflicts of interest.

To evaluate the performance of existing versus alternative cervical cancer screening protocols in Bhutan, cervical exfoliated cells were collected for cytology and high-risk human papillomavirus (HR-HPV) testing among 1,048 women aged 30-69 years. Conventional smears were prepared and read locally. HR-HPV was tested by GP5+/6+ polymerase chain reaction, followed by genotyping and human DNA methylation analysis among HR-HPV-positives, in Europe. Test positivity was 7.5% for ASCUS or worse (ASCUS+) cytology and 14.0% for HR-HPV. All women with ASCUS+ and/or HR-HPV positivity (n=192) were recalled for colposcopy, among whom a total of 29 cases of histologically confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+) were identified. An additional 7 CIN2+ cases were imputed among women without colposcopy. Corrected sensitivities for CIN2+ and CIN3+ were 61% and 74% for ASCUS+, 86% and 96% for HR-HPV, and 47% and 70% for ASCUS+ triage of HR-HPV. Specificity varied from 88% for HR-HPV up to 98% for ASCUS+ triage of HR-HPV, similarly for CIN2+ and CIN3+. Among HR-HPV-positive women with biopsies, methylation analysis offered similar discrimination of CIN2/3 and cervical cancer as ASCUS+, and better than HPV16/18 genotyping alone, but sample sizes were limited. In conclusion, the performance of cytology in Bhutan is in the mid-range of that reported in other screening settings. HR-HPV testing has the potential to improve detection of CIN2+, albeit with a higher referral rate for colposcopy. Cytological triage of HR-HPV-positives (performed in the absence of knowledge of HR-HPV status) reduced referral but missed more than one third of CIN2+., Competing Interests: CONFLICTS OF INTEREST P.J.F. Snijders has Honoraria from Speakers Bureau from Roche and is a consultant/advisory board member for Roche and Gen-Probe. P.J.F. Snijders and D.A.M. Heideman are minority shareholders of Self-Screen B.V., a spin-off company of VUmc which holds patents related to the work. The other authors disclose no potential conflicts of interest.

Objectives: The Bhutanese Screening Programme recommends a Pap smear every 3 years for women aged 25-65 years, and coverage ranges from 20% to 60%, being especially challenging in rural settings. The 'REACH-Bhutan' study was conducted to assess the feasibility and outcomes of a novel approach to cervical cancer screening in rural Bhutan., Design: Cross-sectional, population-based study of cervical cancer screening based on the care HPV test on self-collected samples., Setting: Women were recruited in rural primary healthcare centres, that is, Basic Health Units (BHU), across Bhutan., Participants: Overall, 3648 women aged 30-60 were invited from 15 BHUs differing in accessibility, size and ethnic composition of the population., Interventions: Participants provided a self-collected cervicovaginal sample and were interviewed. Samples were tested using care HPV in Thimphu (the Bhutanese capital) referral laboratory., Main Outcome Measures: Screening participation by geographic area, centre, age and travelling time. Previous screening history and care HPV positivity by selected characteristics of the participants., Results: In April/May 2016, 2590 women (median age: 41) were enrolled. Study participation was 71% and significantly heterogeneous by BHU (range: 31%-96%). Participation decreased with increase in age (81% in women aged 30-39 years; 59% in ≥50 years) and travelling time (90% in women living <30 min from the BHU vs 62% among those >6 hours away). 50% of participants reported no previous screening, with the proportion of never-screened women varying significantly by BHU (range: 2%-72%). 265 women (10%; 95% CI 9% to 11%) were care HPV positive, with a significant variation by BHU (range: 5%-19%) and number of sexual partners (prevalence ratio for ≥3 vs 0-1, 1.55; 95% CI 1.05 to 2.27)., Conclusions: Community-based cervical cancer screening by testing self-collected samples for human papillomavirus (HPV) can achieve high coverage in rural Bhutan. However, solutions to bring self-collection, HPV testing and precancer treatment closer to the remotest villages are needed., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Urine sampling may offer a less invasive solution than cervical sampling to test for human papillomavirus (HPV) for HPV vaccine impact monitoring., Methods: Paired samples of urine and exfoliated cervical cells were obtained for 89 women with history of high-risk (HR) HPV-positive normal cytology in Bhutan. Urine sampling protocol included self-collection of first-void urine immediately into a conservation medium and procedures to optimize DNA yield. Colposcopical abnormalities were biopsied. Two HPV assays were used: a multiplex type-specific PCR (E7-MPG) and a less analytically sensitive GP5+/6+ PCR followed by reverse line blot., Results: HPV positivity for 21 types common to both assays was similar in urine and cells by E7-MPG (62.9% and 57.3%, respectively, p = 0.32) but lower in urine by GP5+/6+ (30.3% and 40.4%, p = 0.05). HPV6/11/16/18 positivity did not significantly differ between urine and cells by either assay. Sensitivity of urine (using cells as gold standard) to detect 21 HPV types was 80% and 58% for E7-MPG and GP5+/6+, respectively, with specificity 61% and 89%. HPV type distribution in urine and cells was similar, regardless of assay. The 5 detected CIN3+ were HR-HPV positive in cells by both assays, compared to 4 and 3 by E7-MPG and GP5+/6+, respectively, in urine samples., Conclusion: For the monitoring of vaccine impact, we demonstrate validity of a urine sampling protocol to obtain HPV prevalence data that are broadly comparable to that from cervical cells. However, detection of HPV in urine varies according to assay sensitivity, presumably because low level infections are frequent.

GP5+/6+-based PCR followed by reverse line blot hybridization (GP5+/6+RLB) and multiplex type-specific PCR (E7-MPG) are two human papillomavirus (HPV) genotyping methodologies widely applied in epidemiological research. We investigated their relative analytical performance in 4,662 samples derived from five studies in Bhutan, Rwanda, and Mongolia coordinated by the International Agency for Research on Cancer (IARC). A total of 630 samples were positive by E7-MPG only (13.5%), 24 were positive by GP5+/6+RLB only (0.5%), and 1,014 were positive (21.8%) by both methods. Ratios of HPV type-specific positivity of the two tests (E7-MPG:GP5+/6+RLB ratio) were calculated among 1,668 samples that were HPV positive by one or both tests. E7-MPG:GP5+/6+RLB ratios were >1 for all types and highly reproducible across populations and sample types. E7-MPG:GP5+/6+RLB ratios were highest for HPV53 (7.5) and HPV68 (7.1). HPV16 (1.6) and HPV18 (1.7) had lower than average E7-MPG:GP5+/6+RLB ratios. Among E7-MPG positive infections, median mean fluorescence intensity (MFI; a semiquantitative measure of viral load) tended to be higher among samples positive for the same virus type by GP5+/6+RLB than for those negative for the same type by GP5+/6+RLB. Exceptions, however, included HPV53, -59, and -82, for which the chances of being undetected by GP5+/6+RLB appeared to be MFI independent. Furthermore, the probability of detecting an additional type by E7-MPG was higher when another type was already detected by GP5+/6+RLB, suggesting the existence of masking effects due to competition for GP5+/6+ PCR primers. In conclusion, this analysis is not an evaluation of clinical performance but may inform choices for HPV genotyping methods in epidemiological studies, when the relative merits and dangers of sensitivity versus specificity for individual types should be considered, as well as the potential to unmask nonvaccine types following HPV vaccination., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Bhutan (2010) and Rwanda (2011) were the first countries in Asia and Africa to introduce national, primarily school-based, human papillomavirus (HPV) vaccination programmes. These target 12 year-old girls and initially included catch-up campaigns (13-18 year-olds in Bhutan and ninth school grade in Rwanda). In 2013, to obtain the earliest indicators of vaccine effectiveness, we performed two school-based HPV urine surveys; 973 female students (median age: 19 years, 5th-95th percentile: 18-22) were recruited in Bhutan and 912 (19 years, 17-20) in Rwanda. Participants self-collected a first-void urine sample using a validated protocol. HPV prevalence was obtained using two PCR assays that differ in sensitivity and type spectrum, namely GP5+/GP6+ and E7-MPG. 92% students in Bhutan and 43% in Rwanda reported to have been vaccinated (median vaccination age = 16, 5th-95th: 14-18). HPV positivity in urine was significantly associated with sexual activity measures. In Rwanda, HPV6/11/16/18 prevalence was lower in vaccinated than in unvaccinated students (prevalence ratio, PR = 0.12, 95% confidence interval, CI: 0.03-0.51 by GP5+/GP6+, and 0.45, CI: 0.23-0.90 by E7-MPG). For E7-MPG, cross-protection against 10 high-risk types phylogenetically related to HPV16 or 18 was of borderline significance (PR = 0.68; 95% CI: 0.45-1.01). In Bhutan, HPV6/11/16/18 prevalence by GP5+/GP6+ was lower in vaccinated than in unvaccinated students but CIs were broad. In conclusion, our study supports the feasibility of urine surveys to monitor HPV vaccination and quantifies the effectiveness of the quadrivalent vaccine in women vaccinated after pre-adolescence. Future similar surveys should detect increases in vaccine effectiveness if vaccination of 12 year-olds continues., (© 2016 UICC.)

Background: Cervical cancer is the most common cancer in Bhutanese women. To help prevent the disease, the Ministry of Health (MoH) developed a national human papillomavirus (HPV) vaccine program., Methods: MoH considerations included disease incidence, the limited reach of cervical screening, poor outcomes associated with late diagnosis of the disease, and Bhutan's ability to conduct the program. For national introduction, it was decided to implement routine immunization for 12 year-old girls with the quadrivalent HPV6/11/16/18 (QHPV) vaccine and a one-time catch-up campaign for 13-18 year-old girls in the first year of the program (2010). Health workers would administer the vaccine in schools, with out-of-school girls to receive the vaccine at health facilities. From 2011, HPV vaccination would enter into the routine immunization schedule using health-center delivery., Results: During the initial campaign in 2010, over 130,000 doses of QHPV were administered and QHPV 3-dose vaccination coverage was estimated to be around 99% among 12 year-olds and 89% among 13-18 year-olds. QHPV vaccine was well tolerated and no severe adverse events were reported. In the three following years, QHPV vaccine was administered routinely to 12 year-olds primarily through health centers instead of schools, during which time the population-level 3-dose coverage decreased to 67-69%, an estimate which was confirmed by individual-level survey data in 2012 (73%). In 2014, when HPV delivery was switched back to schools, 3-dose coverage rose again above 90%., Discussion: The rapid implementation and high coverage of the national HPV vaccine program in Bhutan were largely attributable to the strength of political commitment, primary healthcare and support from the education system. School-based delivery appeared clearly superior to health centers in achieving high-coverage among 12 year-olds., Conclusions: Bhutan's lessons for other low/middle-income countries include the superiority of school-based vaccination and the feasibility of a broad catch-up campaign in the first year., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Bhutan has been engaged in good-quality cytology-based cervical screening since 2000 and has vaccinated >90% girls against human papillomavirus (HPV) since 2010. We explored the characteristics associated with lack of previous screening and screening coverage in women age ≥25 years., Methods: Women were invited at home or during their attendance at 2 outpatient clinics, in the capital, Thimphu, and nearby Lungthenphu. Age-adjusted odds ratios for lack of previous screening by selected characteristics were computed among 1,620 participating women. In Thimphu an invitation registry allowed to estimate screening history not only among participating women but also among additional 500 women who did not accept to join our study., Results: Among women who had a Pap smear, lack of previous screening was associated with age <35 or ≥45 years. It was also associated with some occupations; being single, or widowed/separated; and presence of HPV infection. Multiparity and use of contraceptive methods were associated with having been screened. In women invited at home in Thimphu screening history substantially differed by participation. Past screening attendance was 59% among women recruited in the 2 clinics, 53% in women who were invited from home and accepted the invitation, but only 25% in those who refused it. Based on all women recruited from home the estimate of population-based coverage in Thimphu is 34% (95% CI: 31-37)., Conclusions: Transition from an opportunistic screening to an all-reaching population-based screening is yet to be achieved in Bhutan, even in the capital. Better ways to target never-screened women are needed.

Background: Cervical cancer is the most common female cancer in Bhutan, the first low/middle-income country to implement a national human papillomavirus (HPV) vaccination programme., Methods: To provide a robust baseline for future evaluations of vaccine effectiveness, cervical cell specimens were obtained from 2,505 women aged 18-69 years from the general population, and biopsies from 211 cervical intraepithelial neoplasia grade 3 (CIN3) and 112 invasive cervical cancer (ICC) cases. Samples were tested for HPV using GP5+/6+ PCR., Results: Among the general population, HPV prevalence was 26%, being highest (33%) in women ≤24 years, but remaining above 15% in all age-groups. Determinants of HPV included age, marital status, and number of sexual partners. Among the eight percent with cytological abnormalities, 24 CIN3 and 4 ICC were histologically confirmed. Even after additional testing with a sensitive E7 PCR, no infections with vaccine-targeted HPV types were detected in the few vaccinated women (n = 34) compared to 6% prevalence in unvaccinated women of similar age (p = 0 · 215)., Conclusion: Based upon type-specific prevalence among biopsies, at least 70% of ICC in Bhutan are theoretically preventable by HPV16/18 vaccination, but screening programmes should be expanded among older women, who have an important underlying burden of CIN3 and ICC.