Louise Kuhn1, Rakiya Saidu2, Rosalind Boa2, Ana Tergas3, Jennifer Moodley4, David Persing5, Scott Campbell5, Wei-Yann Tsai6, Thomas C Wright7, Lynette Denny2. 1. Gertrude H Sergievsky Center, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY, USA; Vagelos College of Physicians and Surgeons and Department of Epidemiology, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY, USA. Electronic address: lk24@cumc.columbia.edu. 2. Department of Obstetrics and Gynecology, University of Cape Town, Cape Town, South Africa. 3. Department of Obstetrics and Gynecology, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY, USA; Vagelos College of Physicians and Surgeons and Department of Epidemiology, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY, USA. 4. Women's Health Research Unit, School of Public Health and Family Medicine and South African Medical Research Council Gynaecologic Cancer Research Centre, University of Cape Town, South Africa. 5. Cepheid, Sunnyvale, CA, USA. 6. Department of Biostatistics, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY, USA. 7. Department of Pathology, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY, USA.
Abstract
BACKGROUND: HPV-based screen and treat is the recommended approach for cervical cancer screening in low-resource settings, but quite low specificity of human papillomavirus (HPV) testing, particularly in women living with HIV, leads to overtreatment. We evaluated whether HPV type restriction and more stringent cutoffs on Xpert HPV optimise performance characteristics of this assay for screen and treat. METHODS: We recruited HIV-negative and HIV-positive women aged 30-65 years from a primary care facility and a referral colposcopy clinic in Cape Town, South Africa. Women included had no history of any anogenital cancer or treatment for cervical dysplasia, had no hysterectomy, and were not pregnancy at the time of recruitment. All women had cervical samples collected for Xpert HPV (an assay that detects high-risk HPV types in five channels: HPV type 16; HPV types 18 or 45, or both; HPV types 31, 33, 35, 52, or 58, or more than one of these types; HPV types 51 or 59, or both; and HPV types 39, 56, 66, or 68, or more than one of these types) and underwent colposcopy and histological sampling with consensus pathology review. Logistic regression and receiver operating characteristic curves were used to evaluate improvements in specificity attained by modifying cycle threshold cutoffs to define screen-positive results. RESULTS: We recruited 1121 women aged 30-65 years, 586 of whom were HIV-negative and 535 HIV-positive. Sensitivity of detecting cervical intraepithelial neoplasia grade 2 or greater in HIV-negative women using manufacturer-defined cycle threshold cutoffs for all channels was 88·7% (95% CI 83·1-94·3), and specificity was 86·9% (83·4-90·4). Sensitivity was 93·6% (90·0-97·3) and specificity 59·9% (54·1-65·7) in HIV-positive women. Cycle threshold values from channels detecting HPV type 16, HPV types 18 or 45 (or both), and HPV types 31, 33, 35, 52, or 58 (or more than one of these types) were informative to predict cervical intraepithelial neoplasia grade 2 or greater. Shifting cycle threshold cutoffs on these three channels allowing sensitivity to decline to 75-85%, led to specificities of 91·3-95·3% in HIV-negative women and 77·0-85·8% in HIV-positive women. INTERPRETATION: More stringent cycle threshold cutoffs on selected channels in Xpert HPV improve specificity with only modest losses in sensitivity, making this assay an optimal choice for HPV-based screen and treat in settings with a high prevalence of HIV. These modifications can be made from standard output with no need for new engineering. Decision making about performance characteristics of HPV testing can be shifted to programme implementers and cutoffs selected according to resource availability and community preferences. FUNDING: Supported by the National Cancer Institute UH2/3 CA189908.
BACKGROUND: HPV-based screen and treat is the recommended approach for cervical cancer screening in low-resource settings, but quite low specificity of human papillomavirus (HPV) testing, particularly in women living with HIV, leads to overtreatment. We evaluated whether HPV type restriction and more stringent cutoffs on Xpert HPV optimise performance characteristics of this assay for screen and treat. METHODS: We recruited HIV-negative and HIV-positive women aged 30-65 years from a primary care facility and a referral colposcopy clinic in Cape Town, South Africa. Women included had no history of any anogenital cancer or treatment for cervical dysplasia, had no hysterectomy, and were not pregnancy at the time of recruitment. All women had cervical samples collected for Xpert HPV (an assay that detects high-risk HPV types in five channels: HPV type 16; HPV types 18 or 45, or both; HPV types 31, 33, 35, 52, or 58, or more than one of these types; HPV types 51 or 59, or both; and HPV types 39, 56, 66, or 68, or more than one of these types) and underwent colposcopy and histological sampling with consensus pathology review. Logistic regression and receiver operating characteristic curves were used to evaluate improvements in specificity attained by modifying cycle threshold cutoffs to define screen-positive results. RESULTS: We recruited 1121 women aged 30-65 years, 586 of whom were HIV-negative and 535 HIV-positive. Sensitivity of detecting cervical intraepithelial neoplasia grade 2 or greater in HIV-negative women using manufacturer-defined cycle threshold cutoffs for all channels was 88·7% (95% CI 83·1-94·3), and specificity was 86·9% (83·4-90·4). Sensitivity was 93·6% (90·0-97·3) and specificity 59·9% (54·1-65·7) in HIV-positive women. Cycle threshold values from channels detecting HPV type 16, HPV types 18 or 45 (or both), and HPV types 31, 33, 35, 52, or 58 (or more than one of these types) were informative to predict cervical intraepithelial neoplasia grade 2 or greater. Shifting cycle threshold cutoffs on these three channels allowing sensitivity to decline to 75-85%, led to specificities of 91·3-95·3% in HIV-negative women and 77·0-85·8% in HIV-positive women. INTERPRETATION: More stringent cycle threshold cutoffs on selected channels in Xpert HPV improve specificity with only modest losses in sensitivity, making this assay an optimal choice for HPV-based screen and treat in settings with a high prevalence of HIV. These modifications can be made from standard output with no need for new engineering. Decision making about performance characteristics of HPV testing can be shifted to programme implementers and cutoffs selected according to resource availability and community preferences. FUNDING: Supported by the National Cancer Institute UH2/3 CA189908.
Authors: Proma Paul; Jennifer L Winkler; Rosario M Bartolini; Mary E Penny; Trinh Thu Huong; Le Thi Nga; Edward Kumakech; Emmanuel Mugisha; Jose Jeronimo Journal: Oncologist Date: 2013
Authors: Jeremy D Goldhaber-Fiebert; Lynette E Denny; Michelle De Souza; Thomas C Wright; Louise Kuhn; Sue J Goldie Journal: Cost Eff Resour Alloc Date: 2005-11-15
Authors: Groesbeck P Parham; Mulindi H Mwanahamuntu; Sharon Kapambwe; Richard Muwonge; Allen C Bateman; Meridith Blevins; Carla J Chibwesha; Krista S Pfaendler; Victor Mudenda; Aaron L Shibemba; Samson Chisele; Gracilia Mkumba; Bellington Vwalika; Michael L Hicks; Sten H Vermund; Benjamin H Chi; Jeffrey S A Stringer; Rengaswamy Sankaranarayanan; Vikrant V Sahasrabuddhe Journal: PLoS One Date: 2015-04-17 Impact factor: 3.240
Authors: Lauren G Johnson; Rakiya Saidu; Cecilia Svanholm-Barrie; Rosalind Boa; Jennifer Moodley; Ana Tergas; David Persing; Scott A Campbell; Wei-Yann Tsai; Thomas C Wright; Lynette Denny; Louise Kuhn Journal: Cancer Epidemiol Biomarkers Prev Date: 2022-03-01 Impact factor: 4.090
Authors: Oscar Holmström; Nina Linder; Harrison Kaingu; Ngali Mbuuko; Jumaa Mbete; Felix Kinyua; Sara Törnquist; Martin Muinde; Leena Krogerus; Mikael Lundin; Vinod Diwan; Johan Lundin Journal: JAMA Netw Open Date: 2021-03-01
Authors: Grant B Ellsworth; Elizabeth A Stier; Elizabeth Y Chiao; Shelly Y Lensing; Teresa Darragh; Naomi Jay; J Michael Berry-Lawhorn; Mark Einstein; Luis F Barroso; Ross D Cranston; Rebecca Levine; Humberto M Guiot; Audrey L French; Stephen E Goldstone; Wolfgang Preiser; Mathilda Claassen; Joel M Palefsky; Timothy J Wilkin Journal: J Acquir Immune Defic Syndr Date: 2021-07-01 Impact factor: 3.771
Authors: Brady Hunt; José Humberto Tavares Guerreiro Fregnani; David Brenes; Richard A Schwarz; Mila P Salcedo; Júlio César Possati-Resende; Márcio Antoniazzi; Bruno de Oliveira Fonseca; Iara Viana Vidigal Santana; Graziela de Macêdo Matsushita; Philip E Castle; Kathleen M Schmeler; Rebecca Richards-Kortum Journal: Int J Cancer Date: 2021-04-03 Impact factor: 7.316
Authors: Helen A Kelly; Admire Chikandiwa; Bernard Sawadogo; Clare Gilham; Pamela Michelow; Olga Goumbri Lompo; Tanvier Omar; Souleymane Zan; Precious Magooa; Michel Segondy; Nicolas Nagot; Nicolas Meda; Sinead Delany-Moretlwe; Philippe Mayaud Journal: PLoS Med Date: 2021-03-04 Impact factor: 11.069
Authors: Adam Keane; Chiu Wan Ng; Kate T Simms; Diep Nguyen; Yin Ling Woo; Marion Saville; Karen Canfell Journal: Int J Cancer Date: 2021-08-25 Impact factor: 7.316
Authors: Rakiya Saidu; Louise Kuhn; Ana Tergas; Rosalind Boa; Jennifer Moodley; Cecilia Svanholm-Barrie; David Persing; Scott Campbell; Wei-Yann Tsai; Thomas C Wright; Lynette Denny Journal: J Low Genit Tract Dis Date: 2021-01-01 Impact factor: 3.842