Costs and cost-effectiveness of cervical cancer screening strategies in women living with HIV in Burkina Faso: The HPV in Africa Research Partnership (HARP) study.

INTRODUCTION: This study estimated the costs and incremental cost per case detected of screening strategies for high-grade cervical intraepithelial neoplasia (CIN2+) in women living with HIV (WLHIV) attending HIV clinics in Burkina Faso. METHODS: The direct healthcare provider costs of screening tests (visual inspection with acetic acid (VIA), VIA combined visual inspection with Lugol's iodine (VIA/VILI), cytology and a rapid HPV DNA test (careHPV)) and confirmatory tests (colposcopy, directed biopsy and systematic four-quadrant (4Q) biopsy) were collected alongside the HPV in Africa Research Partnership (HARP) study. A model was developed for a hypothetical cohort of 1000 WLHIV using data on CIN2+ prevalence and the sensitivity of the screening tests. Costs are reported in USD (2019). RESULTS: The study enrolled 554 WLHIV with median age 36 years (inter-quartile range, 31-41) and CIN2+ prevalence of 5.8%. The average cost per screening test ranged from US$3.2 for VIA to US$24.8 for cytology. Compared to VIA alone, the incremental cost per CIN2+ case detected was US$48 for VIA/VILI and US$814 for careHPV. Despite higher costs, careHPV was more sensitive for CIN2+ cases detected compared to VIA/VILI (97% and 56%, respectively). The cost of colposcopy was US$6.6 per person while directed biopsy was US$33.0 and 4Q biopsy was US$48.0. CONCLUSION: Depending on the willingness to pay for the detection of a case of cervical cancer, decision makers in Burkina Faso can consider a variety of cervical cancer screening strategies for WLHIV. While careHPV is more costly, it has the potential to be cost-effective depending on the willingness to pay threshold. Future research should explore the lifetime costs and benefits of cervical cancer screening to enable comparisons with interventions for other diseases.

High-dose oral vitamin D supplementation and mortality in people aged 65-84 years: the VIDAL cluster feasibility RCT of open versus double-blind individual randomisation.

BACKGROUND: Randomised controlled trials demonstrating improved longevity are needed to justify high-dose vitamin D supplementation for older populations. OBJECTIVES: To demonstrate the feasibility of a large trial (n ≈ 20,000) of high-dose vitamin D in people aged 65-84 years through general practitioner (GP) practices, and to cluster randomise participating practices between open-label and double-blind randomisation to compare effects on recruitment, compliance and contamination. DESIGN: Twenty GP practices were randomised in matched pairs between open-label and double-blind allocation. Within each practice, patients were individually randomised to vitamin D or control (i.e. no treatment or placebo). Participants were invited to attend their GP practice to provide a blood sample and complete a lifestyle questionnaire at recruitment and again at 2 years. Randomisation by telephone followed receipt of a serum corrected calcium assay confirming eligibility (< 2.65 nmol/l). Treatment compliance was reported by quarterly follow-up forms sent and returned by e-mail or post (participant choice). GP visits and infections were abstracted from GP records. Hospital attendances, cancer diagnoses and deaths were ascertained by linkage to Hospital Episode Statistics and national registration through NHS Digital. SETTING: GP practices in England. PARTICIPANTS: Recruitment opened in October 2013 and closed in January 2015. A total of 1615 registered patients aged 65-84 years were randomised: 407 to vitamin D and 421 to no treatment in open practices; 395 to vitamin D and 392 to placebo in blind practices. INTERVENTIONS: There was a 24-month treatment period: 12 monthly doses (100,000 IU of vitamin D3 or placebo as 5 ml oily solution) were posted after randomisation and at 1 year (100,000 IU per month corresponds to 3300 IU per day). Reminders were sent monthly by e-mail, text message or post. MAIN OUTCOME MEASURES: Recruitment, compliance, contamination and change in circulating 25-hydroxyvitamin D [25(OH)D] from baseline to 2 years. RESULTS: Participation rates (randomised/invited) were 15.0% in open practices and 13.4% in double-blind practices (p = 0.7). The proportion still taking study medication at 2 years was 91.2% in open practices and 89.2% in double-blind practices (p = 0.4). The proportion of control participants taking > 400 IU vitamin D per day at 2 years was 5.0% in open practices and 4.8% in double-blind practices. Mean serum 25(OH)D concentration was 51.5 nmol/l [95% confidence interval (CI) 50.2 to 52.8 nmol/l] with 82.6% of participants < 75 nmol/l at baseline. At 2 years, this increased to 109.6 nmol/l (95% CI 107.1 to 112.1 nmol/l) with 12.0% < 75 nmol/l in those allocated to vitamin D and was unaltered at 51.8 nmol/l (95% CI 49.8 to 53.8 nmol/l) in those allocated to no vitamin D (no treatment or placebo). CONCLUSIONS: A trial could recruit 20,000 participants aged 65-84 years through 200 GP practices over 2 years. Approximately 80% would be expected to adhere to allocated treatment (vitamin D or placebo) for 5 years. The trial could be conducted entirely by e-mail in participants aged < 80 years, but some participants aged 80-84 years would require postal follow-up. Recruitment and treatment compliance would be similar and contamination (self-administration of vitamin D) would be minimal, whether control participants are randomised openly to no treatment with no contact during the trial or randomised double-blind to placebo with monthly reminders. TRIAL REGISTRATION: Current Controlled Trials ISRCTN46328341 and EudraCT database 2011-003699-34. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 10. See the NIHR Journals Library website for further project information.

High-dose vitamin D may reduce the risk of many diseases, but without large randomised controlled trials the evidence will remain inconclusive. We therefore proposed the Vitamin D and Longevity (VIDAL) trial, with 20,000 older people randomised to either no vitamin D medication or vitamin D medication for 5 years. The VIDAL feasibility study was conducted to establish the procedures required for the main trial, including assessment of recruitment, compliance (taking study treatment as directed) and contamination (how many control participants started taking vitamin D). This was done in two sets of general practitioner (GP) practices: (1) 'open' practices, in which participants knew their treatment allocation (2 years of 100,000 IU vitamin D monthly or no treatment), and (2) 'double-blind' practices, in which participants and their GPs did not know whether they were taking vitamin D or placebo oil. We invited 11,376 men and women aged 65­84 years from 20 GP practices in England and 1615 (14%) took part. Ninety per cent of participants allocated to monthly oil took it for 2 years and few participants used vitamin supplements outside the trial, with no marked differences between open-label and double-blind arms. The best way to conduct the main trial will therefore depend on other considerations. A double-blind trial provides reliable evidence on effects where reporting could be influenced by you or your doctor knowing your treatment, which is important for many illnesses and any side effects of treatment. However, any long-term effects are likely to be considerably greater if treatment continues instead of stopping after 5 years when the main trial ends. An open trial is easier to conduct and, when it ends, those taking vitamin D can be offered a continuing supply so that the effect of lifelong treatment can be studied for major diseases and life expectancy, which are unlikely to be affected by individuals knowing whether or not they are taking vitamin D.

HPV testing compared with routine cytology in cervical screening: long-term follow-up of ARTISTIC RCT.

BACKGROUND: The National Screening Committee (NSC) based its recommendation that human papillomavirus (HPV) testing should replace cytology in primary cervical screening largely on the 2009 follow-up results of the ARTISTIC trial (A Randomised Trial In Screening To Improve Cytology). The NSC must now decide on screening intervals and triage policy. Options include extending the screening interval up to 10 years for human papillomavirus-negative (HPV-) women, delaying recall for human papillomavirus-positive (HPV+) women with normal cytology (as their infections are usually transient), and basing triage on full HPV typing. METHODS: In ARTISTIC, 24,510 women were recruited who were attending routine cervical cytology in Greater Manchester in 2001-3. The women were randomly allocated between revealing and concealing their HPV test results and were recalled every 3 years. After 2009, the women returned to routine cytological screening with recall every 3 years for those aged < 50 years, and every 5 years for those aged 50-64 years. We have followed the cohort to 2015 through national cancer registration for CIN3 (cervical intraepithelial neoplasia grade 3) and cancer, and through linkage to the cervical screening call-recall system to obtain lifetime cytology records. RESULTS: The analysis comprised 24,496 women at round 1 and 13,591 women at round 2 (which was 30-48 months later). Follow-up via local histology laboratories and national cancer registration identified 505 cases of cervical intraepithelial neoplasia grade 3 or cervical cancer (CIN3+) (including 22 invasive cervical cancers). The cumulative CIN3+ risk 10 years after a negative HPV test [0.31%, 95% confidence interval (CI) 0.18% to 0.49%, in the revealed arm] was similar to that 3 years after negative cytology (0.30%, 95% CI 0.23% to 0.41%, in the concealed arm) and fell sharply with age, from 1.1% (95% CI 0.7% to 1.8%) in those women aged < 25 years to 0.08% (95% CI 0.03% to 0.20%) in those women aged > 50 years. The 10-year cumulative CIN3+ risk following a new HPV infection at round 2 was 3.4% (95% CI 2.1% to 5.4%). The highest risks were associated with type-specific persistent infections that, overall, resulted in a 10-year cumulative CIN3+ risk of 20.4% (95% CI 15.6% to 26.4%). CONCLUSIONS: We found a similar level of protection 10 years after a negative HPV test and 3 years after negative cytology. These data support a considerably longer screening interval after a negative HPV test than after a negative cytology test. About three-quarters of women with HPV infection and normal cytology clear their infections within about 3 years. Their risk of CIN3+ within this time frame is low (1.5%), suggesting that the current policy of annual repeat testing and referral after 2 years may be unnecessarily cautious. Approximately 40% of women who remained HPV+ had cleared their initial infection and acquired a new HPV type. The cumulative CIN3+ risks in women with type-specific persistent infections are about six times higher than in women with new infections. Triage strategies based on HPV persistence would, therefore, reduce unnecessary referral of women with new (and largely transient) infections. HPV assays that identify HPV types 31, 33, 45, 52 and 58 in addition to 16 and 18 could be useful in triage as well as in primary HPV testing. Similar results in recent routine HPV screening suggest that our results are generalisable despite changes in cytology and HPV assay methods. We are continuing to follow the ARTISTIC cohort into the new era of primary HPV screening. Future work will focus on the implications of more sensitive HPV testing for primary HPV screening policy and triage of HPV-positive women. Our results suggest that a more sensitive test is needed to detect occult CIN3 at high risk of progression to cancer, but this would substantially increase the overall HPV detection rate. Tests such as DNA (deoxyribonucleic acid) methylation for distinguishing HPV infection from neoplasia will be evaluated on stored samples and on further samples now being collected from women in the cohort who are still being screened. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 28. See the NIHR Journals Library website for further project information.

Human papillomavirus (HPV) causes cervical cancer. The latest scientific evidence shows that screening for HPV is better than screening for abnormal cytology with a 'smear' test, so HPV testing is being rolled out nationally. The main disadvantage is that more women will test positive and be referred for further tests. Most infections are harmless and clear without treatment, and balance must be achieved so that women who progress to CIN3 (pre-cancer) are identified but that unnecessary referral and anxiety for women is minimised. A Randomised Trial In Screening To Improve Cytology (ARTISTIC) recruited 24,510 women attending for cervical screening in Greater Manchester in 2001­3. Cervical samples taken at recruitment and again at screening 3 and 6 years later were tested for HPV. The women then returned to routine screening. We have followed them through national screening records and cancer registration until the end of 2015. By comparing the HPV results taken at entry with those collected 3 years later, we can categorise HPV infections into new and persistent. We have found that the CIN3 risk in women with persistent infections is about six times higher than in women with new infections, which in turn is about 30 times higher than in women with no infection. About three-quarters of women with HPV infection but no abnormal cells clear their infections within 3 years. Their risk of pre-cancer within 3 years is low (1.5%) and so intensive follow-up is unnecessary. Moreover, 40% of those who remain human papillomavirus positive (HPV+) have cleared their initial infection and acquired a new infection, meaning that they are also at much lower risk of disease than those with a persistent infection. The current practice in the national pilot study of annual repeat testing and referral of anyone who is still HPV+ after 2 years may, therefore, be too conservative. We have also shown that the CIN3 risk after 10 years in women testing negative for HPV is similar to the risk after about 3 years in women testing negative for cytology. This means that screening intervals could be extended for women testing negative for HPV.

The clinical effectiveness and cost-effectiveness of primary human papillomavirus cervical screening in England: extended follow-up of the ARTISTIC randomised trial cohort through three screening rounds.

BACKGROUND: The ARTISTIC (A Randomised Trial In Screening To Improve Cytology) trial originally reported after two rounds of primary cervical screening with human papillomavirus (HPV). Extended follow-up of the randomised trial cohort through a third round could provide valuable insight into the duration of protection of a negative HPV test, which could allow extended screening intervals. If HPV primary screening is to be considered in the national programme, then determining its cost-effectiveness is key, and a detailed economic analysis using ARTISTIC data is needed. AIMS/OBJECTIVES: (1) To determine the round 3 and cumulative rates of cervical intraepithelial neoplasia (CIN) grade 2 or worse (2+) and CIN grade 3 or worse (CIN3+) between the revealed and concealed arms of ARTISTIC after three screening rounds over 6 years. (2) To compare the cumulative incidence of CIN2+ over three screening rounds following negative screening cytology with that following negative baseline HPV. (3) To determine whether or not HPV screening could safely extend the screening interval from 3 to 6 years. (4) To study the potential clinical utility of an increased cut-off of 2 relative light unit/mean control (RLU/Co) for Hybrid Capture 2 (HC2) and HPV genotyping in primary cervical screening. (5) To determine the potential impact of HPV vaccination with Cervarix™ in terms of preventing abnormal cytology and CIN2+. (6) To determine the cost-effectiveness of HPV primary screening compared with current practice using cervical cytology in England. DESIGN: The ARTISTIC study cohort was recalled for a third round of screening 3 years after round 2 and 6 years following their enrolment to the study. Both arms of the original trial used a single protocol during round 3. SETTING: ARTISTIC study cohort undergoing cervical screening in primary care in Greater Manchester, UK. PARTICIPANTS: Between July 2007 and September 2009, 8873 women participated in round 3; 6337 had been screened in round 2 and 2536 had not been screened since round 1. INTERVENTIONS: All women underwent liquid-based cytology and HPV testing and genotyping. Colposcopy was offered to women with moderate dyskaryosis or worse and with HPV-positive mild dyskaryosis/borderline changes. Women with negative cytology or HPV-negative mild dyskaryosis/borderline changes were returned to routine recall. MAIN OUTCOME MEASURES: Principal outcomes were cumulative rates of CIN2+ over three screening rounds by cytology and HPV status at entry; HPV type specific rates of CIN2+; effect of age on outcomes correlated with cytology and HPV status; comparison of HC2 cut-off RLU/Co of both 1 and 2; and cost-effectiveness of HPV primary screening. RESULTS: The median duration of follow-up was 72.7 months in round 3. Over the three screening rounds, there was no significant difference in CIN2+ [odds ratio (OR): 1.06, 95% confidence interval (CI) 0.89 to 1.26, p = 0.5)] or CIN3+ (OR: 0.90, 95% CI 0.72 to 1.14, p = 0.4) rates between the trial arms (revealed vs. concealed). Overall, 16% of women were HC2 positive at entry, decreasing from 40% in women aged 20-24 years to around 7% in women aged over 50 years. Abnormal cytology rates at entry were 13% for borderline+ and 2% for moderate+ cytology. Following positive cytology at entry, the cumulative rate of CIN2+ was 20.5%, and was 20.1% following a HPV-positive result at baseline. The cumulative CIN2+ rate for women who were HPV negative at baseline was only 0.87% (95% CI 0.70% to 1.06%) after three rounds of screening, significantly lower than that for women with negative cytology, which was 1.41% (95% CI 1.19% to 1.65%). Women who were HPV negative at baseline had similar protection from CIN2+ after 6 years as women who were cytology negative at baseline after 3 years. Women who were HPV positive/cytology negative at baseline had a cumulative CIN2+ rate at 6 years of 7.7%, significantly higher than that for women who were cytology positive/HPV negative (3.2%). Women who were HPV type 16 positive at baseline had a cumulative CIN2+ rate over three rounds of 43.6% compared with 20.1% for any HPV-positive test. Using a HC2 cut-off of RLU/Co ≥ 2 would maintain acceptable sensitivity and result in 16% fewer HPV-positive results. Typing data suggested that around 55-60% of high-grade cytology and CIN2+, but less than 25% of low-grade cytology, would be prevented by HPV vaccine given current rates of coverage in the UK national programme. For the cost-effectiveness analysis, most of the primary HPV strategies examined where HPV was used as the sole primary test were cost saving in both unvaccinated and vaccinated cohorts under baseline cost assumptions, with a 7-18% reduction in annual screening-associated costs in unvaccinated cohorts and a 9-22% reduction for vaccinated cohorts. Utilising partial genotyping at the primary screening stage to identify women with HPV 16/18 and referring them to colposcopy was the most effective strategy (barring co-testing, which is significantly more costly than any other strategies considered), resulting in 83 additional life-years per 100,000 women for unvaccinated women when compared with current practice, and similar life-years saved compared with current practice for vaccinated women. In unvaccinated cohorts, however, this genotyping strategy is predicted to result in a 20% increase in the number of colposcopies performed in England, although in vaccinated cohorts the number of colposcopy referrals was predicted to be lower than in current practice. For all strategies in which HPV is used as the sole primary screening test, decreasing the follow-up interval for intermediate-risk women from 24 to 12 months increased the overall effectiveness of primary HPV screening. In exploratory analysis, strategies for which cytology screening was retained until either age 30 or 35 years, and for which HPV testing was used at older ages, were predicted to be of higher costs and intermediate effectiveness than those associated with full implementation of primary HPV screening from age 25 years. However, this finding should be interpreted with caution as it depends on assumptions made about screening behaviour and compliance with recommendations at the 'switch over' point. CONCLUSIONS: HPV testing as an initial screen was significantly more protective over three rounds (6 years) than the current practice of cytology and the use of primary HPV screening could allow a safe lengthening of the screening interval. A substantial decrease in high-grade cytology and CIN2+ can be expected as a consequence of the HPV vaccination programme. A HC2 cut-off of 2RLU/Co instead of the manufacturer's recommended cut-off of 1 would be clinically beneficial in terms of an optimal balance between sensitivity and specificity. Modelled analysis predicts that primary HPV screening would be both more effective and cost saving compared with current practice with cervical cytology for a number of potential strategies in both unvaccinated and vaccinated cohorts. Compliance with surveillance and optimal management of HPV-positive/cytology-negative women after primary HPV screening is of key importance. Limitations of the economic investigation included the need to make assumptions around compliance with screening attendance and follow-up for longer screening intervals in the future, assumptions regarding maintenance of current uptake vaccination in the future, and assumptions regarding the stability of cost of HPV and cytology tests in the future. Detailed sensitivity analysis across a range of possible assumptions was conducted to address these issues. This study and the economic evaluation lend support to convert from cytology to HPV-based screening. Future work should include researching (i) the attitudes of women who test HPV positive/cytology negative, (ii) the value of complementary biomarkers and (iii) activities relevant to primary HPV screening in unvaccinated and vaccinated populations from the point of view of QALY assessment. STUDY REGISTRATION: Current Controlled Trials ISRCTN25417821.

HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC): a randomised controlled trial.

BACKGROUND: Testing for human papillomavirus (HPV) DNA is reportedly more sensitive than cytology for the detection of high-grade cervical intraepithelial neoplasia (CIN). The effectiveness of HPV testing in primary cervical screening was assessed in the ARTISTIC trial, which was done over two screening rounds approximately 3 years apart (2001-03 and 2004-07) by comparing liquid-based cytology (LBC) combined with HPV testing against LBC alone. METHODS: Women aged 20-64 years who were undergoing routine screening as part of the English National Health Service Cervical Screening Programme in Greater Manchester were randomly assigned (between July, 2001, and September, 2003) in a ratio of 3:1 to either combined LBC and HPV testing in which the results were revealed and acted on, or to combined LBC and HPV testing where the HPV result was concealed from the patient and investigator. The primary outcome was the detection rate of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) in the second screening round, analysed by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number ISRCTN25417821. FINDINGS: There were 24 510 eligible women at entry (18 386 in the revealed group, 6124 in the concealed group). In the first round of screening 233 women (1.27%) in the revealed group had CIN3+, compared with 80 (1.31%) women in the concealed group (odds ratio [OR] 0.97, 95% CI 0.75-1.25; p>0.2). There was an unexpectedly large drop in the proportion of women with CIN3+ between the first and second rounds of screening in both groups, at 0.25% (29 of 11 676) in the revealed group and 0.47% (18 of 3866 women) in the concealed group (OR 0.53, 95% CI 0.30-0.96; p=0.042). For both rounds combined, the proportion of women with CIN3+ were 1.51% (revealed) and 1.77% (concealed) (OR 0.85, 95% CI 0.67-1.08; p>0.2). INTERPRETATION: LBC combined with HPV testing resulted in a significantly lower detection rate of CIN3+ in the second round of screening compared with LBC screening alone, but the effect was small. Over the two screening rounds combined, co-testing did not detect a higher rate of CIN3+ or CIN2+ than LBC alone. Potential changes in screening methodology should be assessed over at least two screening rounds. FUNDING: National Institute of Health Research Health Technology Assessment Programme.