ARTISTIC: A randomised trial of human papillomavirus (HPV) testing in primary cervical screening

The official published version of the article can be found at the link below.Objectives: Primary cervical screening uses cytology to detect cancer precursor lesions [cervical intraepithelial neoplasia stage 3 or beyond (CIN3+)]. Human papillomavirus (HPV) testing could add sensitivity as an adjunct to cytology or as a first test, reserving cytology for HPV-positive women. This study addresses the questions: Does the combination of cytology and HPV testing achieve a reduction in incident CIN3+?; Is HPV testing cost-effective in primary cervical screening?; Is its use associated with adverse psychosocial or psychosexual effects?; and How would it perform as an initial screening test followed by cytology for HPV positivity? Design: ARTISTIC was a randomised trial of cervical cytology versus cervical cytology plus HPV testing, evaluated over two screening rounds, 3 years apart. Round 1 would detect prevalent disease and round 2 a combination of incident and undetected disease from round 1. Setting: Women undergoing routine cervical screening in the NHS programme in Greater Manchester. Participants: In total 24,510 women aged 20–64 years were enrolled between July 2001 and September 2003. Interventions: HPV testing was performed on the liquid-based cytology (LBC) sample obtained at screening. Women were randomised in a ratio of 3:1 to have the HPV test result revealed and acted upon if persistently positive in cytology-negative cases or concealed. A detailed health economic evaluation and a psychosocial and psychosexual assessment were also performed. Main outcome measures: The primary outcome was CIN3+ in round 2. Secondary outcomes included an economic assessment and psychosocial effects. A large HPV genotyping study was also conducted. Results: In round 1 there were 313 CIN3+ lesions, representing a prevalence in the revealed and concealed arms of 1.27% and 1.31% respectively (p = 0.81). Round 2 (30–48 months) involved 14,230 (58.1%) of the women screened in round 1 and only 31 CIN3+ were detected; the CIN3 rate was not significantly different between the revealed and concealed arms. A less restrictive definition of round 2 (26–54 months) increased CIN3+ to 45 and CIN3+ incidence in the arms was significantly different (p = 0.05). There was no difference in CIN3+ between the arms when rounds 1 and 2 were combined. Prevalence of highrisk HPV types was age-dependent. Overall prevalence of HPV16/18 increased with severity of yskaryosis. Mean costs per woman in round 1 were £72 and £56 for the revealed and concealed arms (p < 0.001); an age-adjustment reduced these mean costs to £65 and £52. Incremental cost-effectiveness ratio for detecting additional CIN3+ by adding HPV testing to LBC screening in round 1 was £38,771. Age-adjusted mean cost for LBC primary screening with HPV triage was £39 compared with £48 for HPV primary screening with LBC triage. HPV testing did not appear to cause significant psychosocial distress. Conclusions: Routine HPV testing did not add significantly to the effectiveness of LBC in this study. No significant adverse psychosocial effects were detected. It would not be cost-effective to screen with cytology and HPV combined but HPV testing, as either triage or initial test triaged by cytology, would be cheaper than cytology without HPV testing. LBC would not benefit from combination with HPV; it is highly effective as primary screening but HPV testing has twin advantages of high negative predictive value and automated platforms enabling high throughput. HPV primary screening would require major contraction and reconfiguration of laboratory services. Follow-up continues in ARTISTIC while maintaining concealment for a further 3-year round of screening, which will help in screening protocol development for the post-vaccination era

HPV testing as a triage for borderline or mild dyskaryosis on cervical cytology: results from the Sentinel Sites study

BACKGROUND: Earlier pilot studies of human papillomavirus (HPV) triage concluded that HPV triage was feasible and cost-effective. The aim of the present study was to study the impact of wider rollout of HPV triage for women with low-grade cytology on colposcopy referral and outcomes. METHODS: Human papillomavirus testing of liquid-based cytology (LBC) samples showing low-grade abnormalities was used to select women for colposcopy referral at six sites in England. Samples from 10 051 women aged 25-64 years with routine call or recall cytology reported as borderline or mild dyskaryosis were included. RESULTS: Human papillomavirus-positive rates were 53.7% in women with borderline cytology and 83.9% in those with mild dyskaryosis. The range between sites was 34.8-73.3% for borderline cytology, and 73.4-91.6% for mild dyskaryosis. In the single site using both LBC technologies there was no difference in rates between the two technologies. The positive predictive value of an HPV test was 16.3% for CIN2 or worse and 6.1% for CIN3 or worse, although there was considerable variation between sites. CONCLUSION: Triaging women with borderline cytological abnormalities and mild dyskaryosis with HPV testing would allow approximately a third of these women to be returned immediately to routine recall, and for a substantial proportion to be referred for colposcopy without repeat cytology. Variation in HPV-positive rates results in differing colposcopy workload. British Journal of Cancer (2011) 105, 983-988. doi:10.1038/bjc.2011.326 www.bjcancer.com Published online 6 September 2011 (C) 2011 Cancer Research U

Improved Survival from Ovarian Cancer in Patients Treated in Phase III Trial Active Cancer Centres in the UK

Aims: Ovarian cancer is the principal cause of gynaecological cancer death in developed countries, yet overall survival in the UK has been reported as being inferior to that in some Western countries. As there is a range of survival across the UK we hypothesised that in major regional centres, outcomes are equivalent to the best internationally. Materials and methods: Data from patients treated in multicentre international and UK-based trials were obtained from three regional cancer centres in the UK; Manchester, University College London and Leeds (MUL). The median progression-free survival (PFS) and overall survival were calculated for each trial and compared with the published trial data. Normalised median survival values and the respective 95% confidence intervals (ratio of pooled MUL data to trial median survival) were calculated to allow inter-trial survival comparisons. This strategy then allowed a comparison of median survival across the UK, in three regional UK centres and in international centres. Results: The analysis showed that the trial-reported PFS was the same in the UK, in the MUL centres and in international centres for each of the trials included in the study. Overall survival was, however, 45% better in major regional centre-treated patients (95% confidence interval 9–73%) than the median overall survival reported in UK trials, whereas the median overall survival in MUL centres equated with that achieved in international centres. Conclusion: The data suggest that international survival statistics are achieved in UK regional cancer centres

Prevalence of type-specific HPV infection by age and grade of cervical cytology: data from the ARTISTIC trial

Human papillomavirus (HPV) infection causes cervical cancer and premalignant dysplasia. Type-specific HPV prevalence data provide a basis for assessing the impact of HPV vaccination programmes on cervical cytology. We report high-risk HPV (HR-HPV) type-specific prevalence data in relation to cervical cytology for 24 510 women (age range: 20–64; mean age 40.2 years) recruited into the ARTISTIC trial, which is being conducted within the routine NHS Cervical Screening Programme in Greater Manchester. The most common HR-HPV types were HPV16, 18, 31, 51 and 52, which accounted for 60% of all HR-HPV types detected. There was a marked decline in the prevalence of HR-HPV infection with age, but the proportion due to each HPV type did not vary greatly with age. Multiple infections were common below the age of 30 years but less so between age 30 and 64 years. Catch-up vaccination of this sexually active cohort would be expected to reduce the number of women with moderate or worse cytology by 45%, but the number with borderline or mild cytology would fall by only 7%, giving an overall reduction of 12% in the number of women with abnormal cytology and 27% in the number with any HR-HPV infection. In the absence of broader cross-protection, the large majority of low-grade and many high-grade abnormalities may still occur in sexually active vaccinated women

Benefits and harms of cervical screening from age 20 years compared with screening from age 25 years

This work is supported by Cancer Research UK (C8162/10406 and C8162/12537). The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication

Impact of cervical screening on cervical cancer mortality: estimation using stage-specific results from a nested case-control study

Cancer Research UK (A16892 to P.S.)

A Single-Arm, Proof-Of-Concept Trial of Lopimune (Lopinavir/Ritonavir) as a Treatment for HPV-Related Pre-Invasive Cervical Disease

BACKGROUND: Cervical cancer is the most common female malignancy in the developing nations and the third most common cancer in women globally. An effective, inexpensive and self-applied topical treatment would be an ideal solution for treatment of screen-detected, pre-invasive cervical disease in low resource settings. METHODS: Between 01/03/2013 and 01/08/2013, women attending Kenyatta National Hospital's Family Planning and Gynaecology Outpatients clinics were tested for HIV, HPV (Cervista®) and liquid based cervical cytology (LBC -ThinPrep®). HIV negative women diagnosed as high-risk HPV positive with high grade squamous intraepithelial lesions (HSIL) were examined by colposcopy and given a 2 week course of 1 capsule of Lopimune (CIPLA) twice daily, to be self-applied as a vaginal pessary. Colposcopy, HPV testing and LBC were repeated at 4 and 12 weeks post-start of treatment with a final punch biopsy at 3 months for histology. Primary outcome measures were acceptability of treatment with efficacy as a secondary consideration. RESULTS: A total of 23 women with HSIL were treated with Lopimune during which time no adverse reactions were reported. A maximum concentration of 10 ng/ml of lopinavir was detected in patient plasma 1 week after starting treatment. HPV was no longer detected in 12/23 (52.2%, 95%CI: 30.6-73.2%). Post-treatment cytology at 12 weeks on women with HSIL, showed 14/22 (63.6%, 95%CI: 40.6-82.8%) had no dysplasia and 4/22 (18.2%, 95%CI: 9.9-65.1%) were now low grade demonstrating a combined positive response in 81.8% of women of which 77.8% was confirmed by histology. These data are supported by colposcopic images, which show regression of cervical lesions. CONCLUSIONS: These results demonstrate the potential of Lopimune as a self-applied therapy for HPV infection and related cervical lesions. Since there were no serious adverse events or detectable post-treatment morbidity, this study indicates that further trials are clearly justified to define optimal regimes and the overall benefit of this therapy. TRIAL REGISTRATION: ISRCTN Registry 48776874