[Skip to Content]
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
Purchase Options:
[Skip to Content Landing]
Figure 1.
Analytic Framework: Screening for Cervical Cancer With High-Risk Human Papillomavirus Testing
Analytic Framework: Screening for Cervical Cancer With High-Risk Human Papillomavirus Testing

Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display the key questions that the review will address to allow the USPSTF to evaluate the effectiveness and safety of a preventive service. The questions are depicted by linkages that relate interventions and outcomes. Further details are available in the USPSTF procedure manual.10

Figure 2.
Literature Search Flow Diagram: Screening for Cervical Cancer With High-Risk Human Papillomavirus Testing
Literature Search Flow Diagram: Screening for Cervical Cancer With High-Risk Human Papillomavirus Testing

USPSTF indicates US Preventive Services Task Force.

aOne publication (Ronco 201014) includes 2 trials (NTCC Phase I and NTCC Phase II), so it is counted as 2 publications instead of 1.

bReasons for exclusion: Aim: Study aim was not relevant. Setting: Study was not conducted in a country relevant to US practice or not conducted in, recruited from, or feasible for primary care or a health system. Comparative effectiveness: Active comparator (eg, liquid-based cytology vs conventional cytology alone). Outcomes: Study did not have relevant outcomes or had incomplete outcomes. Population: Study was not conducted in an included population. Intervention: Intervention was out of scope. Design: Study did not use an included design. Language: Publication not in English. Quality: Study was poor quality. Unable to Locate: Review staff was unable to locate article.

Table 1.  
Study Characteristics of Randomized Clinical Trials and Cohort Studies of hrHPV Screening
Study Characteristics of Randomized Clinical Trials and Cohort Studies of hrHPV Screening
Table 2.  
Effectiveness of hrHPV Screening for CIN 3+ and Invasive Cervical Cancer Incidence, Based on Randomized Clinical Trials (Key Question 1)
Effectiveness of hrHPV Screening for CIN 3+ and Invasive Cervical Cancer Incidence, Based on Randomized Clinical Trials (Key Question 1)
Table 3.  
Colposcopy Referrals and False-Positive Rates as Harms of hrHPV Screening, Based on Randomized Clinical Trials (Key Question 2)
Colposcopy Referrals and False-Positive Rates as Harms of hrHPV Screening, Based on Randomized Clinical Trials (Key Question 2)
Table 4.  
Summary of Evidence by Key Question and hrHPV Screening Strategy
Summary of Evidence by Key Question and hrHPV Screening Strategy
1.
Schiffman  M, Castle  PE, Jeronimo  J, Rodriguez  AC, Wacholder  S.  Human papillomavirus and cervical cancer.  Lancet. 2007;370(9590):890-907. doi:10.1016/S0140-6736(07)61416-0PubMedGoogle ScholarCrossref
2.
Ziegert  C, Wentzensen  N, Vinokurova  S,  et al.  A comprehensive analysis of HPV integration loci in anogenital lesions combining transcript and genome-based amplification techniques.  Oncogene. 2003;22(25):3977-3984. doi:10.1038/sj.onc.1206629PubMedGoogle ScholarCrossref
3.
Bosch  FX, Lorincz  A, Muñoz  N, Meijer  CJ, Shah  KV.  The causal relation between human papillomavirus and cervical cancer.  J Clin Pathol. 2002;55(4):244-265. doi:10.1136/jcp.55.4.244PubMedGoogle ScholarCrossref
4.
American Cancer Society. Cancer Facts & Figures 2016. American Cancer Society website. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2016.html. Published 2016. Accessed June 27, 2017.
5.
Forman  D, de Martel  C, Lacey  CJ,  et al.  Global burden of human papillomavirus and related diseases.  Vaccine. 2012;30(suppl 5):F12-F23. doi:10.1016/j.vaccine.2012.07.055PubMedGoogle ScholarCrossref
6.
Dunne  EF, Unger  ER, Sternberg  M,  et al.  Prevalence of HPV infection among females in the United States.  JAMA. 2007;297(8):813-819. doi:10.1001/jama.297.8.813PubMedGoogle ScholarCrossref
7.
Partridge  EE, Abu-Rustum  N, Giuliano  A,  et al; National Comprehensive Cancer Network.  Cervical cancer screening.  J Natl Compr Canc Netw. 2014;12(3):333-341. doi:10.6004/jnccn.2014.0035PubMedGoogle ScholarCrossref
8.
Surveillance, Epidemiology, and End Results (SEER). Cancer Stat Facts: cervical cancer. SEER website. https://seer.cancer.gov/statfacts/html/cervix.html. Published 2017. Accessed July 3, 2018.
9.
Moyer  VA; U.S. Preventive Services Task Force.  Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement  [published correction appears in Ann Intern Med. 2013;158(11):852].  Ann Intern Med. 2012;156(12):880-891. doi:10.7326/0003-4819-156-12-201206190-00424PubMedGoogle ScholarCrossref
10.
Huynh  J, Howard  M, Lytwyn  A.  Self-collection for vaginal human papillomavirus testing: systematic review of studies asking women their perceptions.  J Low Genit Tract Dis. 2010;14(4):356-362. doi:10.1097/LGT.0b013e3181dc115bPubMedGoogle ScholarCrossref
11.
Vesco  KK, Whitlock  EP, Eder  M,  et al.  Screening for Cervical Cancer: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality; 2011. AHRQ publication 11-05156-EF-1.
12.
Canfell  K, Caruana  M, Gebski  V,  et al.  Cervical screening with primary HPV testing or cytology in a population of women in which those aged 33 years or younger had previously been offered HPV vaccination: results of the Compass pilot randomised trial.  PLoS Med. 2017;14(9):e1002388. doi:10.1371/journal.pmed.1002388PubMedGoogle ScholarCrossref
13.
Ogilvie  G, van Niekerk  D, Krajden  M,  et al.  Effect of screening with primary cervical HPV testing vs cytology testing on high-grade cervical intraepithelial neoplasia at 48 months: the HPV FOCAL randomized clinical trial.  JAMA. 2018;320(1):43-52. doi:10.1001/jama.2018.7464PubMedGoogle ScholarCrossref
14.
Ronco  G, Giorgi-Rossi  P, Carozzi  F,  et al; New Technologies for Cervical Cancer Screening (NTCC) Working Group.  Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial.  Lancet Oncol. 2010;11(3):249-257. doi:10.1016/S1470-2045(09)70360-2PubMedGoogle ScholarCrossref
15.
United Nation Development Programme.  Human Development Report. New York, NY: United Nations; 2016.
16.
McCredie  MR, Sharples  KJ, Paul  C,  et al.  Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study.  Lancet Oncol. 2008;9(5):425-434. doi:10.1016/S1470-2045(08)70103-7PubMedGoogle ScholarCrossref
17.
Harris  RP, Helfand  M, Woolf  SH,  et al; Methods Work Group, Third US Preventive Services Task Force.  Current methods of the US Preventive Services Task Force: a review of the process.  Am J Prev Med. 2001;20(3)(suppl):21-35. doi:10.1016/S0749-3797(01)00261-6PubMedGoogle ScholarCrossref
18.
Wells  GA, Shea  BJ, O’Connell  DPJ, Welch  V, Losos  M, Tugwell  P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analysis. Ottawa Hospital Research Institute website. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. 2014. Accessed June 27, 2017.
19.
Cook  DA, Mei  W, Smith  LW,  et al.  Comparison of the Roche cobas® 4800 and Digene Hybrid Capture® 2 HPV tests for primary cervical cancer screening in the HPV FOCAL trial.  BMC Cancer. 2015;15:968. doi:10.1186/s12885-015-1959-5PubMedGoogle ScholarCrossref
20.
Ronco  G, Giorgi-Rossi  P, Carozzi  F,  et al; New Technologies for Cervical Cancer Screening Working Group.  Results at recruitment from a randomized controlled trial comparing human papillomavirus testing alone with conventional cytology as the primary cervical cancer screening test.  J Natl Cancer Inst. 2008;100(7):492-501. doi:10.1093/jnci/djn065PubMedGoogle ScholarCrossref
21.
Ogilvie  GS, Krajden  M, van Niekerk  D,  et al.  HPV for cervical cancer screening (HPV FOCAL): complete round 1 results of a randomized trial comparing HPV-based primary screening to liquid-based cytology for cervical cancer.  Int J Cancer. 2017;140(2):440-448. doi:10.1002/ijc.30454PubMedGoogle ScholarCrossref
22.
Ogilvie  GS, van Niekerk  DJ, Krajden  M,  et al.  A randomized controlled trial of human papillomavirus (HPV) testing for cervical cancer screening: trial design and preliminary results (HPV FOCAL trial).  BMC Cancer. 2010;10:111. doi:10.1186/1471-2407-10-111PubMedGoogle ScholarCrossref
23.
Leinonen  MK, Nieminen  P, Lönnberg  S,  et al.  Detection rates of precancerous and cancerous cervical lesions within one screening round of primary human papillomavirus DNA testing: prospective randomised trial in Finland.  BMJ. 2012;345:e7789. doi:10.1136/bmj.e7789PubMedGoogle ScholarCrossref
24.
Zorzi  M, Frayle  H, Rizzi  M,  et al; Veneto HPV-Screening Working Group.  A 3-year interval is too short for re-screening women testing negative for human papillomavirus: a population-based cohort study.  BJOG. 2017;24(10):1585-1593. doi:10.1111/1471-0528.14575PubMedGoogle ScholarCrossref
25.
Ronco  G, Giorgi-Rossi  P, Carozzi  F,  et al; New Technologies for Cervical Cancer Screening Working Group.  Human papillomavirus testing and liquid-based cytology in primary screening of women younger than 35 years: results at recruitment for a randomised controlled trial.  Lancet Oncol. 2006;7(7):547-555. doi:10.1016/S1470-2045(06)70731-8PubMedGoogle ScholarCrossref
26.
Ronco  G, Segnan  N, Giorgi-Rossi  P,  et al; New Technologies for Cervical Cancer Working Group.  Human papillomavirus testing and liquid-based cytology: results at recruitment from the new technologies for cervical cancer randomized controlled trial.  J Natl Cancer Inst. 2006;98(11):765-774. doi:10.1093/jnci/djj209PubMedGoogle ScholarCrossref
27.
Bulkmans  NW, Rozendaal  L, Snijders  PJ,  et al.  POBASCAM, a population-based randomized controlled trial for implementation of high-risk HPV testing in cervical screening: design, methods and baseline data of 44,102 women.  Int J Cancer. 2004;110(1):94-101. doi:10.1002/ijc.20076PubMedGoogle ScholarCrossref
28.
Rijkaart  DC, Berkhof  J, Rozendaal  L,  et al.  Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial.  Lancet Oncol. 2012;13(1):78-88. doi:10.1016/S1470-2045(11)70296-0PubMedGoogle ScholarCrossref
29.
Dijkstra  MG, van Zummeren  M, Rozendaal  L,  et al.  Safety of extending screening intervals beyond five years in cervical screening programmes with testing for high risk human papillomavirus: 14 year follow-up of population based randomised cohort in the Netherlands.  BMJ. 2016;355:i4924. doi:10.1136/bmj.i4924PubMedGoogle ScholarCrossref
30.
Naucler  P, Ryd  W, Törnberg  S,  et al.  Human papillomavirus and Papanicolaou tests to screen for cervical cancer  [published correction appears in N Engl J Med. 2008;359(15):1637].  N Engl J Med. 2007;357(16):1589-1597. doi:10.1056/NEJMoa073204PubMedGoogle ScholarCrossref
31.
Elfström  KM, Smelov  V, Johansson  AL,  et al.  Long term duration of protective effect for HPV negative women: follow-up of primary HPV screening randomised controlled trial.  BMJ. 2014;348:g130. doi:10.1136/bmj.g130PubMedGoogle ScholarCrossref
32.
Kitchener  HC, Fletcher  I, Roberts  C, Wheeler  P, Almonte  M, Maguire  P.  The psychosocial impact of human papillomavirus testing in primary cervical screening—a study within a randomized trial.  Int J Gynecol Cancer. 2008;18(4):743-748. doi:10.1111/j.1525-1438.2007.01113.xPubMedGoogle ScholarCrossref
33.
Kitchener  HC, Almonte  M, Gilham  C,  et al; ARTISTIC Trial Study Group.  ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening.  Health Technol Assess. 2009;13(51):1-150. doi:10.3310/hta13510PubMedGoogle ScholarCrossref
34.
Kitchener  HC, Almonte  M, Thomson  C,  et al.  HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC): a randomised controlled trial.  Lancet Oncol. 2009;10(7):672-682. doi:10.1016/S1470-2045(09)70156-1PubMedGoogle ScholarCrossref
35.
Kitchener  HC, Canfell  K, Gilham  C,  et al.  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.  Health Technol Assess. 2014;18(23):1-196. doi:10.3310/hta18230PubMedGoogle ScholarCrossref
36.
Castle  PE, Fetterman  B, Poitras  N,  et al.  Variable risk of cervical precancer and cancer after a human papillomavirus-positive test.  Obstet Gynecol. 2011;117(3):650-656. doi:10.1097/AOG.0b013e318209da59PubMedGoogle ScholarCrossref
37.
Katki  HA, Kinney  WK, Fetterman  B,  et al.  Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice  [published correction appears in Lancet Oncol. 2011;12(8):722].  Lancet Oncol. 2011;12(7):663-672. doi:10.1016/S1470-2045(11)70145-0PubMedGoogle ScholarCrossref
38.
Katki  HA, Schiffman  M, Castle  PE,  et al.  Five-year risks of CIN 3+ and cervical cancer among women who test Pap-negative but are HPV-positive.  J Low Genit Tract Dis. 2013;17(5)(suppl 1):S56-S63. doi:10.1097/LGT.0b013e318285437bPubMedGoogle ScholarCrossref
39.
Katki  HA, Schiffman  M, Castle  PE,  et al.  Benchmarking CIN 3+ risk as the basis for incorporating HPV and Pap cotesting into cervical screening and management guidelines.  J Low Genit Tract Dis. 2013;17(5)(suppl 1):S28-S35. doi:10.1097/LGT.0b013e318285423cPubMedGoogle ScholarCrossref
40.
Gage  JC, Schiffman  M, Katki  HA,  et al.  Reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test.  J Natl Cancer Inst. 2014;106(8):dju153. doi:10.1093/jnci/dju153PubMedGoogle ScholarCrossref
41.
Gage  JC, Katki  HA, Schiffman  M,  et al.  Age-stratified 5-year risks of cervical precancer among women with enrollment and newly detected HPV infection.  Int J Cancer. 2015;136(7):1665-1671. doi:10.1002/ijc.29143PubMedGoogle ScholarCrossref
42.
Ibáñez  R, Autonell  J, Sardà  M,  et al.  Protecting the underscreened women in developed countries: the value of HPV test.  BMC Cancer. 2014;14:574. doi:10.1186/1471-2407-14-574PubMedGoogle ScholarCrossref
43.
Petry  KU, Luyten  A, Scherbring  S.  Accuracy of colposcopy management to detect CIN3 and invasive cancer in women with abnormal screening tests: results from a primary HPV screening project from 2006 to 2011 in Wolfsburg, Germany.  Gynecol Oncol. 2013;128(2):282-287. doi:10.1016/j.ygyno.2012.10.017PubMedGoogle ScholarCrossref
44.
Luyten  A, Buttmann-Schweiger  N, Luyten  K,  et al.  Early detection of CIN3 and cervical cancer during long-term follow-up using HPV/Pap smear co-testing and risk-adapted follow-up in a locally organised screening programme.  Int J Cancer. 2014;135(6):1408-1416. doi:10.1002/ijc.28783PubMedGoogle ScholarCrossref
45.
McCaffery  K, Waller  J, Forrest  S, Cadman  L, Szarewski  A, Wardle  J.  Testing positive for human papillomavirus in routine cervical screening: examination of psychosocial impact.  BJOG. 2004;111(12):1437-1443. doi:10.1111/j.1471-0528.2004.00279.xPubMedGoogle ScholarCrossref
46.
US Preventive Services Task Force.  US Preventive Services Task Force Procedure Manual. Rockville, MD: Agency for Healthcare Research and Quality; 2015.
47.
Ronco  G, Dillner  J, Elfström  KM,  et al; International HPV Screening Working Group.  Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials.  Lancet. 2014;383(9916):524-532. doi:10.1016/S0140-6736(13)62218-7PubMedGoogle ScholarCrossref
48.
Castle  PE, Kinney  WK, Xue  X,  et al.  Effect of several negative rounds of human papillomavirus and cytology co-testing on safety against cervical cancer: an observational cohort study.  Ann Intern Med. 2018;168(1):20-29. doi:10.7326/M17-1609PubMedGoogle ScholarCrossref
49.
Demarco  M, Lorey  TS, Fetterman  B,  et al.  Risks of CIN 2+, CIN 3+, and cancer by cytology and human papillomavirus status: the foundation of risk-based cervical screening guidelines.  J Low Genit Tract Dis. 2017;21(4):261-267. doi:10.1097/LGT.0000000000000343PubMedGoogle ScholarCrossref
50.
Gage  JC, Hunt  WC, Schiffman  M,  et al; New Mexico HPV Pap Registry Steering Committee.  Similar risk patterns after cervical screening in two large U.S. populations: implications for clinical guidelines.  Obstet Gynecol. 2016;128(6):1248-1257. doi:10.1097/AOG.0000000000001721PubMedGoogle ScholarCrossref
51.
Coldman  AJ, Gondara  L, Smith  LW,  et al.  Disease detection and resource use in the safety and control arms of the HPV FOCAL cervical cancer screening trial.  Br J Cancer. 2016;115(12):1487-1494. doi:10.1038/bjc.2016.368PubMedGoogle ScholarCrossref
52.
Martin-Hirsch  PP, Paraskevaidis  E, Bryant  A, Dickinson  HO, Keep  SL.  Surgery for cervical intraepithelial neoplasia.  Cochrane Database Syst Rev. 2010;(6):CD001318.PubMedGoogle Scholar
53.
Nuovo  J, Melnikow  J, Willan  AR, Chan  BK.  Treatment outcomes for squamous intraepithelial lesions.  Int J Gynaecol Obstet. 2000;68(1):25-33. doi:10.1016/S0020-7292(99)00162-9PubMedGoogle ScholarCrossref
54.
Kyrgiou  M, Mitra  A, Arbyn  M,  et al.  Fertility and early pregnancy outcomes after conservative treatment for cervical intraepithelial neoplasia.  Cochrane Database Syst Rev. 2015;(9):CD008478.PubMedGoogle Scholar
55.
Conner  SN, Frey  HA, Cahill  AG, Macones  GA, Colditz  GA, Tuuli  MG.  Loop electrosurgical excision procedure and risk of preterm birth: a systematic review and meta-analysis.  Obstet Gynecol. 2014;123(4):752-761. doi:10.1097/AOG.0000000000000174PubMedGoogle ScholarCrossref
56.
Vesco  KK, Whitlock  EP, Eder  M, Burda  BU, Senger  CA, Lutz  K.  Risk factors and other epidemiologic considerations for cervical cancer screening: a narrative review for the U.S. Preventive Services Task Force.  Ann Intern Med. 2011;155(10):698-705. doi:10.7326/0003-4819-155-10-201111150-00377PubMedGoogle ScholarCrossref
57.
Benard  VB, Thomas  CC, King  J, Massetti  GM, Doria-Rose  VP, Saraiya  M; Centers for Disease Control and Prevention (CDC).  Vital signs: cervical cancer incidence, mortality, and screening—United States, 2007-2012.  MMWR Morb Mortal Wkly Rep. 2014;63(44):1004-1009.PubMedGoogle Scholar
58.
Snijders  PJ, Verhoef  VM, Arbyn  M,  et al.  High-risk HPV testing on self-sampled versus clinician-collected specimens: a review on the clinical accuracy and impact on population attendance in cervical cancer screening.  Int J Cancer. 2013;132(10):2223-2236. doi:10.1002/ijc.27790PubMedGoogle ScholarCrossref
59.
Racey  CS, Withrow  DR, Gesink  D.  Self-collected HPV testing improves participation in cervical cancer screening: a systematic review and meta-analysis.  Can J Public Health. 2013;104(2):e159-e166.PubMedGoogle Scholar
60.
Singh  GK, Williams  SD, Siahpush  M, Mulhollen  A.  Socioeconomic, rural-urban, and racial inequalities in US cancer mortality: part I—all cancers and lung cancer and part II—colorectal, prostate, breast, and cervical cancers.  J Cancer Epidemiol. 2011;2011:107497. doi:10.1155/2011/107497PubMedGoogle ScholarCrossref
61.
Rositch  AF, Nowak  RG, Gravitt  PE.  Increased age and race-specific incidence of cervical cancer after correction for hysterectomy prevalence in the United States from 2000 to 2009.  Cancer. 2014;120(13):2032-2038. doi:10.1002/cncr.28548PubMedGoogle ScholarCrossref
US Preventive Services Task Force
Evidence Report
August 21, 2018

Screening for Cervical Cancer With High-Risk Human Papillomavirus Testing: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

Author Affiliations
  • 1University of California, Davis, Center for Healthcare Policy and Research, Sacramento
  • 2Kaiser Permanente Research Affiliates Evidence-based Practice Center, Center for Health Research, Kaiser Permanente, Portland, Oregon
JAMA. 2018;320(7):687-705. doi:10.1001/jama.2018.10400
Abstract

Importance  Cervical cancer can be prevented with detection and treatment of precancerous cell changes caused primarily by high-risk types of human papillomavirus (hrHPV), the causative agents in more than 90% of cervical cancers.

Objective  To systematically review benefits and harms of cervical cancer screening for hrHPV to inform the US Preventive Services Task Force.

Data Sources  MEDLINE, PubMed, PsycINFO, and the Cochrane Collaboration Registry of Controlled Trials from January 2011 through February 15, 2017; surveillance through May 25, 2018.

Study Selection  Randomized clinical trials (RCTs) and cohort studies comparing primary hrHPV screening alone or hrHPV cotesting (both hrHPV testing and cytology) with cytology (Papanicolaou [Pap] test) screening alone.

Data Extraction and Synthesis  Two investigators independently reviewed abstracts and full-text articles and quality rated included studies; data were qualitatively synthesized.

Main Outcomes and Measures  Invasive cervical cancer; cervical intraepithelial neoplasia (CIN); false-positive, colposcopy, and biopsy rates; psychological harms.

Results  Eight RCTs (n = 410 556), 5 cohort studies (n = 402 615), and 1 individual participant data (IPD) meta-analysis (n = 176 464) were included. Trials were heterogeneous for screening interval, number of rounds, and protocol. For primary hrHPV screening, evidence was consistent across 4 trials demonstrating increased detection of CIN 3 or worse (CIN 3+) in round 1 (relative risk [RR] range, 1.61 [95% CI, 1.09-2.37] to 7.46 [95% CI, 1.02-54.66]). Among 4 hrHPV cotesting trials, first-round CIN 3+ detection was not significantly different between screening groups; RRs for cumulative CIN 3+ detection over 2 screening rounds ranged from 0.91 to 1.13. In first-round screening, false-positive rates for primary hrHPV screening ranged from 6.6% to 7.4%, compared with 2.6% to 6.5% for cytology. For cotesting, false-positives ranged from 5.8% to 19.9% in the first round of screening, compared with 2.6% to 10.9% for cytology. First-round colposcopy rates were also higher, ranging 1.2% to 7.9% for primary hrHPV testing, compared with 1.1% to 3.1% for cytology alone; colposcopy rates for cotesting ranged from 6.8% to 10.9%, compared with 3.3% to 5.2% for cytology alone. The IPD meta-analysis of data from 4 cotesting trials and 1 primary hrHPV screening trial found lower risk of invasive cervical cancer with any hrHPV screening compared with cytology alone (pooled RR, 0.60 [95% CI, 0.40-0.89]).

Conclusions and Relevance  Primary hrHPV screening detected higher rates of CIN 3+ at first-round screening compared with cytology. Cotesting trials did not show initial increased CIN 3+ detection. Both hrHPV screening strategies had higher false-positive and colposcopy rates than cytology, which could lead to more treatments with potential harms.

Introduction

High-risk human papillomavirus (hrHPV) is readily transmitted through sexual contact1,2 and is recognized as a causative agent in more than 90% of cervical cancers.3 Persistent infection with hrHPV types 16 and 18 is responsible for most cases.4,5 Although a high proportion of sexually active women become infected with some human papillomavirus type by age 25 years, most infections resolve spontaneously.6 Effective screening and treatment for precancerous lesions are associated with low rates of cervical cancer mortality in the United States.7 Annual age-adjusted cervical cancer incidence in the United States was 7.4 cases per 100 000 women and mortality was 2.3 deaths per 100 000 women (2011-2015), with the highest incidence among black (8.4 per 100 000) and Hispanic (8.9 per 100 000) women. Black women also had the highest mortality rate (3.7 deaths per 100 000 women).8

In 2012, the US Preventive Services Task Force (USPSTF) recommended screening women aged 21 to 65 years for cervical cancer with cytology (Papanicolaou [Pap] smear) every 3 years, with an option for women 30 years and older for hrHPV cotesting (cytology and cervical swab for hrHPV) every 5 years (A recommendation).9 This systematic review, conducted to update evidence on cervical cancer screening, focused on the effectiveness of hrHPV screening strategies relative to cytology-based screening to support an updated USPSTF recommendation.

Methods
Scope of Review

Cytology is the foundation for long-standing cervical cancer screening recommendations, with well-established benefits and harms. The USPSTF commissioned this review to evaluate direct evidence from trials and large observational cohort studies on the comparative effectiveness of screening approaches that use hrHPV screening. Specifically, the 2 key questions (KQs) (Figure 1) aimed to identify the benefits (KQ1) and harms (KQ2) of cervical cancer screening using hrHPV screening alone as the initial test (primary screening) or paired with cytology (cotesting), compared with screening with cytology as the primary test. Additional methodological details regarding the review search strategies, including detailed study inclusion criteria, excluded studies, and description of data analyses, are available in the full evidence report at https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/cervical-cancer-screening2.

Data Sources and Searches

Comprehensive literature searches were performed for primary literature in MEDLINE, PubMed, PsycINFO, and the Cochrane Collaboration Registry of Controlled Trials from January 2011 through February 15, 2017, bridging from the dates of the previous USPSTF review.11 Database searches were supplemented with experts’ suggestions and by reviewing reference lists from other relevant systematic reviews. After February 2017, ongoing surveillance continued through article alerts and targeted searches of high-impact journals to identify major studies published in the interim that could affect the conclusions or understanding of the evidence and the related USPSTF recommendation. The last surveillance was conducted on May 25, 2018, and resulted in the addition of the initial results of the Compass trial.12 The final results of the HPV FOCAL trial, published in JAMA in July 2018, have also been incorporated in this review.13

Study Selection

Two reviewers independently reviewed 2972 unique citations and 164 full-text articles against specified inclusion criteria (Figure 2). Discrepancies were resolved through consensus and consultation with a third investigator when required.

Eligible studies were rated as fair or good quality, published in English, and conducted in highly developed countries.15 Quality assessment criteria are reported in eTable 1 in the Supplement. Studies had to be conducted in primary care or generalizable settings (eg, family planning clinics); studies based on laboratory results alone without an identified cohort were excluded. Randomized clinical trials (RCTs), individual participant data (IPD) meta-analyses, systematic reviews, and large ( ≥ 10 000 women) longitudinal cohort studies that examined the benefits or harms of primary hrHPV screening or cotesting among average-risk women 21 years and older were included. Studies in women without a cervix, at high risk for cervical cancer, or who were pregnant were excluded. Studies evaluating hrHPV as a triage test after cytology compared with cytology alone were excluded. Cohort studies including fewer than 10 000 women were excluded, unless they addressed a subpopulation of interest (eg, underscreened women).

Invasive cervical cancer generally develops over years, preceded by progressive precancerous changes of the cervix, defined as cervical intraepithelial neoplasia (CIN) categorized as CIN 1, CIN 2, and CIN 3.16 For KQ1, because invasive cervical cancer is a rare event in countries with organized screening programs such that even large trials did not have sufficient sample size or duration to detect changes in invasive cervical cancer incidence, CIN 3 or worse (CIN 3+) was chosen as the primary outcome. CIN 3+ was consistently reported because of broad consensus that detection and treatment of CIN 3 can prevent progression to invasive cervical cancer. For KQ2, studies were included if they reported false-positive CIN 2+ or false-negative invasive cervical cancer screening test results; biopsy rates, colposcopy rates, or both; or psychological harms (eg, labeling, stigma, distress, quality of life).

Data Extraction and Quality Assessment

Two investigators independently assessed the quality of included studies using USPSTF design-specific criteria for RCTs17 and the Newcastle-Ottawa Scale for observational studies.18 Each study was rated as good, fair, or poor (eTable 1 in the Supplement). Disagreements in quality ratings were resolved by consensus and by consultation with a third investigator if required. Poor-quality studies with major flaws (eg, attrition >40%, differential attrition >20%) or multiple important limitations that could invalidate the results were excluded. One investigator extracted study-level data (study design details, population and intervention characteristics, outcomes) into standardized evidence tables and a second investigator confirmed the accuracy of the data.

Data Synthesis and Analysis

Because of the heterogeneity of screening tests, screening protocols, follow-up protocols, and settings, results were qualitatively synthesized. Summary tables of study design, population characteristics, protocols, and intervention and follow-up details for each round of screening were created. Results were synthesized by KQ and screening strategy, either primary hrHPV screening or cotesting. When possible, results were also stratified by age (<30-35 years vs ≥30-35 years) because of lower prevalence of hrHPV in women 30 years and older. Results were based on a “number of women screened” denominator, rather than intention-to-treat calculations using all women randomized. Relative risks (RRs) and 2-sided 95% confidence intervals were calculated when not reported in the study. Stata version 15.1 (StataCorp) was used for all analyses.

To estimate potential harms or burden of screening, test positivity, colposcopy rates, and false-positive rates were reported or calculated from available data. The false-positive rate was reported to quantify the extent to which women in a cervical cancer screening program experienced positive screening test results necessitating further follow-up (ie, triage testing, repeat screening, colposcopy, and biopsy) and were not found to have precancerous lesions or cervical cancer (ie, CIN 2+). This was calculated as the number with a positive screening test result without diagnosis of CIN 2+ as a proportion of women screened who were not diagnosed with CIN 2+. This pragmatic definition relies on colposcopy as a reference standard, recognizing that there is variability in the accuracy of colposcopy and biopsy.19 False-negatives were defined as the proportion of invasive cervical cancer cases occurring among women with negative preceding screening results. Psychological harms, including adverse effects on anxiety, distress, and sexual satisfaction, were abstracted when reported.

Results
Effectiveness of Screening

Key Question 1. What is the effectiveness of human papillomavirus for hrHPV testing, with or without cytology, as a primary screening strategy for reducing cervical cancer mortality and incidence compared with currently recommended screening strategies for women in the United States?

Four fair- or good-quality cervical cancer screening RCTs were identified that compared primary hrHPV screening with cytology (n = 282 838),12-14,19-23 and 4 RCTs compared cotesting with cytology (n = 127 717) (Table 1).14,25-35 One IPD meta-analysis combined 176 464 women from 1 primary hrHPV screening trial and 4 hrHPV cotesting trials to examine invasive cervical cancer incidence.47 Four large cohort studies were included: 1 of primary hrHPV screening (n = 48 736),24 2 of cotesting (n = 351 613),36-42,48,49 and 1 reporting on cotesting outcomes in 1832 unscreened women.42 Trials varied in the number of reported screening rounds (1 or 2), the screening interval (3-5 years), consistency between screening rounds (eg, randomization maintained, cytology only or cotesting for both intervention and control groups in the second screening round), and the protocols for evaluation of abnormal screening results. For primary hrHPV screening, follow-up varied and included cytology triage from a specimen obtained at the time of initial screening and held, hrHPV genotyping with follow-up based on viral type, or immediate colposcopy (Table 1). Four RCTs offered consistent evidence that primary hrHPV screening will detect higher rates of CIN 3+ at an initial screening round compared with cytology, while trials of cotesting did not show initial increased CIN 3+ detection at round 1. Data on mortality from cervical cancer were not reported in any included studies.

Primary hrHPV Compared With Cytology Screening

Across 4 trials with variable protocols and hrHPV test types, conducted in women aged 25 to 65 years, evidence was consistent in demonstrating that primary hrHPV screening led to a statistically significant increased detection of CIN 3+ in the initial round of screening (RR range, 1.61 [95% CI, 1.09-2.37]) to 7.46 [95% CI, 1.02-54.66]) (Table 2).12,13,19,21,22 The New Technologies for Cervical Cancer (NTCC) Phase II trial of primary hrHPV screening (in which all women with a positive hrHPV test result were referred to colposcopy) had complete results from 2 rounds of screening, but the screening strategy was not maintained (at round 2 screening, all women received cytology testing).14,20 In that study, CIN 3+ detection in round 1 was 3 times higher in the hrHPV screening group, with cumulative detection 1.8 times higher after the second round of screening. In the recently published 48 -month screening results of the HPV FOCAL trial, all women received cotesting at the second round of screening.13 CIN 3+ detection in the hrHPV screening group was higher in round 1 (RR, 1.61 [95%CI, 1.09-2.37]) but significantly lower in round 2 (RR, 0.42 [95% CI, 0.25-0.69]). Results of a single-group cohort study of primary hrHPV screening at 3-year intervals were consistent with trial findings (eTable 2 in the Supplement).24

Cotesting Compared With Cytology Screening

Four cotesting trials followed up enrolled women aged 25 to 64 years through 2 rounds of screening, but only 1 trial (A Randomized Trial in Screening to Improve Cytology [ARTISTIC]) maintained the randomly assigned screening protocol in the second round (Table 1).32-35 None of the trials demonstrated significantly higher detection of CIN 3+ with cotesting in the first round of screening, with the RR ranging from 0.96 (95% CI, 0.74-1.23) to 1.31 (95% CI, 0.92-1.87) (Table 2). By the second round of screening 3 to 5 years later, CIN 3+ detection in 2 trials was significantly lower, with RRs ranging from 0.53 (95% CI, 0.29-0.98)30,31 to 0.73 (95% CI, 0.55-0.96).27-29 Cumulative detection of CIN 3+ over 2 rounds was similar in all trials, with no RR significantly different than 1.0. Long-term follow-up was reported for 2 cotesting trials: the Swedescreen trial reported up to 13 years by tracking study participants in the National Quality Registry for Cervical Cancer Prevention,31 and the Population-based Screening Study Amsterdam (POBASCAM) trial reported 14 years of follow-up tracked through the nationwide network and registry of histopathology and cytopathology.29 In both studies, no statistical difference in cumulative CIN 3+ rates was detected between the intervention and control groups.

Two large single-group cohort studies of cotesting showed higher detection of CIN 3+ in the first screening round relative to a follow-up round (eTable 2 in the Supplement).24,37,43,44 Long-term evaluation of the US-based cohort found that risk of CIN 3+ in women cotesting negative was very low 3 and 5 years after testing (0.06% and 0.1%, respectively).49

To examine the effect of hrHPV screening on invasive cervical cancer in cervical cancer screening trials, Ronco et al conducted an IPD meta-analysis of 5 trials: 4 trials of cotesting and a single trial of primary hrHPV screening (NTCC Phase II).47 Participant data were pooled, although these trials had distinctly different screening protocols, screening intervals, and hrHPV test types. The IPD meta-analysis included 176 464 women with 1 214 415 person-years of follow-up, with a total of 107 cases of invasive cervical cancer in a median follow-up period of 6.5 years. Cumulative detection of invasive cervical cancer was 46.7 per 100 000 in the hrHPV-screened women, compared with 93.6 per 100 000 women in the cytology groups. With a random-effects model, the overall pooled rate ratio for invasive cervical cancer in the hrHPV-screened women was 0.61 (95% CI, 0.41-0.91). The I2 test for statistical heterogeneity was not significant (0.0%, P = .52).

Key Question 1a. Does the effectiveness of hrHPV testing to reduce cervical cancer outcomes vary by subpopulation (eg, age, race/ethnicity, screening history, hrHPV immunization status, and socioeconomic status)?

No trials provided data on race/ethnicity, screening history, or socioeconomic status for primary hrHPV screening. Several studies reported on outcomes by age group (eTables 3 and 4 in the Supplement), and 1 study reported on outcomes by age corresponding to the introduction of a population-based hrHPV immunization program.12 One cohort study reported outcomes of a single round of cotesting in underscreened women.42

Primary hrHPV Compared With Cytology Screening Stratified by Age

In 4 trials of primary hrHPV screening, first-round CIN 3+ detection with hrHPV screening was consistently higher (range, 0.6%14,20 to 2.4%13,19,21,22) among women younger than 35 years (eTable 4 in the Supplement) than for women older than 35 years (range, 0.2%23 to 0.5%13,19,21,22) (eTable 3 in the Supplement). The RR for CIN 3+ detection between screening groups, however, was similar to the overall findings in both the younger (<30-35 years) and older (≥30-35 years) age groups. In the Compass trial,12 participants were recruited from a population having 70% hrHPV vaccination coverage among women 33 years and younger. Primary hrHPV screening detected higher rates of CIN 3+ compared with cytology for both the younger (25-33 years) and older (34-64 years) age groups. Absolute detection rates were higher for women younger than 30 to 35 years, regardless of the screening test, in all primary hrHPV screening trials.

Cotesting Compared With Cytology Screening Stratified by Age

Three trials of cotesting reported outcomes by age group (eTables 3 and 4 in the Supplement). CIN 3+ detection was higher in women younger than 30 to 35 years compared with older women, but no trial found a significantly higher RR for cotesting compared with cytology among women younger than 30 to 35 years. Among women 35 years and older, only NTCC Phase I had a significantly higher RR for cotesting compared with cytology at round 1 (RR, 1.57 [95% CI, 1.02-2.43]). The effect estimates for CIN 3+ detection between screening groups were generally similar across age groups, with the exception of NTCC Phase I, with an RR of 0.89 (95% CI, 0.51-1.57) for women younger than 35 years and 1.57 (95% CI, 1.02-2.43) among women 35 years and older.

Gage et al published an age-stratified analysis of 1 313 128 women in a large US-based cohort who were screened for cervical cancer with cotesting from 2003 to 2013.50 The 5-year risk of CIN 3+ was highest for women aged 25 to 29 years (1.23% [95% CI, 1.09%-1.39%]) and lowest for women aged 50 to 64 years (0.25% [95% CI, 0.22%-0.28%]).

In summary, while risks of hrHPV-positive results were consistently higher in women younger than 30 to 35 years, in most studies differences in CIN 3+ detection between screening methods were consistent across age groups.

Screening With hrHPV Cotesting in Underscreened Populations

A prospective single-cohort study from Spain described the outcomes of initial cotesting in a cohort of 1832 women older than 39 years with no documented cervical cancer screening in the previous 5 years.42 No comparison group was included, and women older than 65 years were excluded after receiving negative initial cotesting results. Of 1494 remaining women, 767 (51.3%) completed follow-up. Nine women were diagnosed with CIN 3+, and 2 women had invasive cervical cancer (eTable 2 in the Supplement). Two women with CIN 3 were detected only by the hrHPV test.

Key Question 1b. For each primary screening strategy, how does the rescreening interval relate to future cancer incidence or progression?

Data were not adequate to compare outcomes of different rescreening intervals. One trial (HPV Testing for Cervical Cancer Screening [HPV FOCAL])13,19,21,22 was designed to directly compare different rescreening intervals (2 years for cytology vs 4 years for primary hrHPV screening).51 CIN 3+ detection was higher at initial screening in the hrHPV group compared with the cytology group (0.7% vs 0.4%; RR, 1.61 [95% CI, 1.09-2.37]) and lower at the 4-year exit-round screen compared with the cytology group (0.2% vs 0.6%; RR, 0.42 [95% CI, 0.25-0.69]) (Table 2).13 The POBASCAM trial with 5-year screening intervals exhibited CIN 3+ detection and RRs for cotesting similar to those reported in cotesting trials with 3-year screening intervals.27-29 In 13- to 14-year follow-up of the Swedescreen and POBASCAM trials, CIN 3+ risk remained persistently low in women who tested hrHPV-negative on initial screening, suggesting that 5-year intervals for hrHPV screening are no less effective than 3-year intervals over longer time frames.29,31

Recently published analyses of the large US-based cotesting cohort48,49 evaluated the risk of CIN 3+ and invasive cervical cancer at 3 and 5 years after screening and found that after a negative hrHPV test result (regardless of the cytology result), risk of subsequent CIN 3+ was very low at 5 years (0.114% [95% CI, 0.106%-0.122%]) and only slightly lower at 3 years (0.085% [95% CI, 0.079%-0.092%]). Women with a negative cotesting result followed by a second negative hrHPV test result had risks of CIN 3+ of 0.04% (95% CI, 0.04%-0.05%) at 3 years and 0.06% (95% CI, 0.05%-0.07%) at 5 years. For each of 3 age groups (30-39, 40-49, and ≥50 years), each consecutive negative hrHPV test result was associated with progressively lower risk of CIN 3+. No cases of invasive cervical cancer were detected.48

Key Question 1c. Does the appropriate rescreening interval for each primary screening strategy vary by subpopulation (eg, age, race/ethnicity, screening history, hrHPV immunization status, socioeconomic status)?

No data were available to address rescreening intervals by subpopulation.

Harms of hrHPV Screening

Key Question 2. What are the potential adverse effects of hrHPV testing, with or without cytology, as a primary screening strategy compared with currently recommended screening strategies for women in the United States?

The same 8 RCTs,12-14,19-23,25-35 IPD meta-analysis,47 and 3 observational cohort studies described above24,37,44 were included for harms, along with an additional cross-sectional study that assessed psychological harms among 428 women.45 Studies reported screening test performance (ie, false-negative and false-positive results), procedures conducted to evaluate positive screening test results (ie, colposcopy and biopsy), and potential psychological harms (eg, quality of life, anxiety or distress, partner discord). Overall, screening with hrHPV primary or cotesting was associated with more false-positive results and higher colposcopy rates. Limited evidence suggested that positive hrHPV test results may be associated with greater psychological harm than abnormal cytology results. None of the included studies reported on harms occurring from the screening test, diagnostic testing, or treatments.

Primary hrHPV Screening

Trial differences in the protocol for follow-up of positive hrHPV screening test results affected colposcopy and false-positive rates. In the NTCC Phase II protocol, all hrHPV-positive results were referred directly to colposcopy.14,20 Accordingly, the false-positive rate for CIN 2+ was higher with hrHPV screening (7.4% vs 3.2%), as was the colposcopy rate (7.9% vs 2.8%), than with cytology screening in the trial (Table 3). Most women referred to colposcopy underwent the procedure (93.6% in the intervention group, 90.6% in the control group), and more women in the hrHPV screening group underwent biopsy (3.2% vs 1.3% in the control group). The HPV FOCAL trial used a liquid-based cytology triage strategy for hrHPV-positive results.13,19,21,22 In round 1 of screening, 5.7% of women in the hrHPV testing group were referred to colposcopy, compared with 3.1% in the cytology-only control group, and 94.1% of the trial participants referred to colposcopy attended.13 Colposcopy referral rates in round 1 of the Compass trial for hrHPV screening compared with cytology screening were 3.8% vs 2.7%.12 In the FINNISH trial,23 primary hrHPV screening false-positive rates (7.2%) and colposcopy referral rates (1.2%) were similar to cytology screening false-positive (6.5%), and colposcopy referral (1.1%) rates. In 3 trials reporting age-stratified results, colposcopy referrals in round 1 of screening for women younger than 30 to 35 years ranged from 2.3% to 13.1% with hrHPV testing, compared with a range from 1.9% to 4.7% for cytology screening (eTable 7 in the Supplement). Among women older than 30 to 35 years, colposcopy referrals ranged from 0.9% to 5.8% for hrHPV testing, compared with 1.0% to 2.5% for cytology screening (eTable 6 in the Supplement).

False-negative results for invasive cervical cancer (based on interval detection) were uncommon. The NTCC Phase II trials reported no CIN 3 or invasive cervical cancer cases among screen-negative women in either group in follow-up after the first round of screening (3.5 years maximum).14,20 The larger FINNISH trial reported invasive cervical cancer among screen-negative women in 0.01% (5/57 135) of the hrHPV testing intervention group participants and 0.003% (2/61 241) of the cytology control group participants after 1 round of screening with 5 years of follow-up.23 Data on invasive cervical cancer among screen-negative women were not available for the HPV FOCAL or Compass trials.

No studies reported on the psychological effects of primary hrHPV screening.

hrHPV Cotesting

Colposcopy rates were reported in only 2 trials of cotesting (ARTISTIC and NTCC Phase I) (Table 3).32-35 In the ARTISTIC trial, higher false-positive rates were observed with cotesting relative to the cytology screening control group at round 1 (19.9% vs 10.9%) and round 2 (11.2% vs 4.6%). Colposcopy rates in round 1 were 6.8% in the cotesting group and 5.2% in the cytology group.32-35 The proportion of women attending colposcopy and undergoing biopsy was not reported. Only the NTCC Phase I trial reported age-stratified colposcopy and false-positive rates. In that trial, hrHPV-positive women 35 years and older and those with results positive for atypical squamous cells of undetermined significance were referred directly to colposcopy; colposcopy rates were 3 times higher for cotesting compared with cytology (10.6% vs 3.0%).14,25,26 Of those referred, 94% in the intervention group and 91% in the control group received a colposcopy. For the Swedescreen trial,30,31 colposcopies were not reported and false-positive rates could not be calculated. The POBASCAM27-29 trial did not report colposcopy rates, but false-positive rates were twice as high with cotesting (5.8% vs 2.6%) at round 1 and similar at round 2, in which both the intervention group and the control group received cotesting (6.4% vs 6.5%).

The IPD meta-analysis obtained additional data from 5 trials (4 trials of cotesting and a single trial of primary hrHPV screening) and reported similar overall biopsy rates for women assigned to hrHPV cotesting or primary testing compared with cytology in analysis of the POBASCAM, Swedescreen, and ARTISTIC trials, which had a fixed-effects pooled rate ratio for biopsy of 1.02 (95% CI, 0.97-1.07; I2 = 30.7%; P = .24). A pooled estimate calculated with the NTCC trial biopsy rate included had unacceptably high statistical heterogeneity (I2 = 99.1%; P < .001). The rate ratio for biopsy from the NTCC trials was 2.24 (95% CI, 2.09-2.39) with hrHPV testing, likely because of the direct-to-colposcopy triage protocol.47

False-negative rates were difficult to estimate. No invasive cervical cancer cases were observed in screen-negative women in either screening group in 2 studies,14,25,26,32-35 and 1 did not report rates of invasive cervical cancer among screen-negative women.30,31 In the POBASCAM trial, 1 case of invasive cervical cancer was detected in a screen-negative woman in the control group and no cases in the intervention group, with 4 years follow-up on the first screening round.27-29 In 14 years of long-term follow-up, there were no statistically significant differences in incidence of invasive cervical cancer among women in the intervention group who screened hrHPV-negative and cytology-normal at baseline and among those in the control group with normal cytology findings at baseline.29 Findings of a large US-based cohort of women who received cotesting suggested that hrHPV testing has few false-negative cases of CIN 3+ detected by cytology: the 5-year risk of CIN 3+ was 0.12% (95% CI, 0.11%-0.12%) for women testing hrHPV-negative, compared with 0.10% (95% CI, 0.09%-0.10%) for women with negative cotesting results.49

Estimates of colposcopy rates from large observational cohort studies were similar to or lower than those observed in trials (eTable 5 in the Supplement). Just more than 6% of women were referred to colposcopy over 2 rounds of hrHPV primary screening in an Italian cohort study (n = 48 751).24 In a German study of hrHPV cotesting (n = 19 795), 3.9% of women were referred to colposcopy at the first round of screening and 1% at a second round.44

Two included studies reported psychological effects of hrHPV cotesting.32,45 In a substudy of the ARTISTIC trial,45 samples of women aged 20 to 64 years were surveyed approximately 2 weeks after receiving screening results (n = 2508). Women assigned to the study intervention screening group who received hrHPV results in addition to their cytology screening results reported lower sexual satisfaction but similar levels of distress and anxiety in the short term. A smaller cross-sectional study (n = 428) by McCaffery et al45 surveyed women 1 week after they received cervical cancer screening results and found that for women who underwent cotesting and had normal cytology findings, those with hrHPV-positive results were more distressed and anxious than women with hrHPV-negative results and had worse feelings about their current, past, and future sexual partners regardless of cytology results.

Key Question 2a. Do the adverse effects vary by subpopulation (eg, age, race/ethnicity, and hrHPV immunization status)?

Three primary hrHPV screening trials and 1 cotesting trial reported age-stratified colposcopy rates (eTables 6 and 7 in the Supplement). In all trials, women younger than 30 to 35 years screened with primary hrHPV testing or cotesting had higher referral rates for colposcopy (range, 2.3%-13.1%) than women screened with cytology (range, 1.9%-4.7%).14,20,22,23 In the Compass trial of primary hrHPV screening, colposcopy referrals were higher with hrHPV screening among women aged 25 to 33 years (8.5% in the intervention group vs 4.7% in the control group) and lower for women aged 34 to 64 years (2.6% in the intervention group vs 2.2% in the control group) in both screening groups, despite expected vaccination rates in younger women of approximately 70%.12

Key Question 2b. Do adverse effects vary by screening strategy, including by rescreening interval?

The influence of screening interval and strategy on potential harms of missed cancer cases or possible overdetection could not be directly ascertained from available evidence because of lack of within–trial interval comparisons and variability of protocols across studies. Screening intervals of included trials ranged from 2 to 5 years, with the longest intervals from FINNISH23 and POBASCAM.27-29 The trials with longer intervals reported some invasive cervical cancer cases among women who had tested hrHPV-negative, but these trials (FINNISH and POBASCAM) also had larger samples and there were very few invasive cervical cancer cases overall, limiting inferences that can be drawn from between-study comparisons. After 2 negative cotesting results, rates of invasive cervical cancer in the US-based cohort were very low (0.003% [95% CI, 0.002%-0.006%]) and equal at 3- and 5-year screening intervals.48

Discussion

A summary of the evidence for this review is shown in Table 4. Four RCTs of primary hrHPV screening and 4 of cotesting (both hrHPV testing and cytology) compared the use of hrHPV screening for cervical cancer screening with cytology alone for the detection of CIN 3+ and invasive cervical cancer. The evidence was consistent across trials that primary hrHPV screening increased detection of CIN 3+ in the initial round of screening by as much as 2 to 3 times when compared with cytology. Evidence was mixed in cotesting trials; CIN 3+ detection in round 1 was not significantly higher for cotesting. No trials compared hrHPV primary testing with cotesting. Evidence on subgroups was limited to age and a single-cohort study focused on previously underscreened women. Women younger than 35 years had consistently higher rates of hrHPV positivity and of CIN 3+, but the RR of CIN 3+ detection with primary hrHPV screening or cotesting compared with cytology was similar between younger and older women.

False-positive rates were higher in the intervention group for both primary hrHPV screening and cotesting in the first screening round. Colposcopy referrals were often reported but biopsy rates were not, limiting estimation of the downstream harms of screening. In 3 primary hrHPV screening trials and all cotesting trials, rates of colposcopy referral were higher in the intervention group, indicating a greater relative burden with hrHPV screening and potential differences in downstream consequences of treatment compared with screening cytology. Harms of treatment of the cervix to remove precancerous cells were not reported in any of the included studies but include pain and bleeding, which on rare occasion requires vaginal packing or transfusion.52,53 Harms related to subsequent pregnancy outcomes, particularly risk of second-trimester pregnancy loss and preterm birth, may occur after cold knife conization or loop electrosurgical excision procedure deeper than 10 mm.54,55 Limited evidence suggested that, compared with abnormal cytology results, hrHPV test positivity may be associated with greater short-term psychological harm.32-35

Cervical cancer incidence and mortality have substantially decreased since the introduction of screening programs more than half a century ago; the lowest rates are found in countries with organized screening programs. All of the RCTs included in this review were conducted in countries with robust, organized screening programs. Organized screening programs are well-suited for comparative trials of screening strategies; however, the generalizability of findings from this review to women in the United States is limited by the lack of organized screening programs for the majority of US-based women. Most cervical cancer screening in the United States is opportunistic, without population-based registries or regular invitations to screening. More than 50% of women diagnosed with cervical cancer in the United States have not been screened in the prior 3 to 5 years.56 The highest proportions of unscreened women are those without insurance (23.1%) or no regular clinician (25.5%).57

Cervical cancer predominantly affects underscreened women in the United States; thus, a substantial effect on cervical cancer incidence and mortality requires the identification of effective outreach strategies. Limited evidence from a single cohort study of poorly screened women in Spain suggests that the increased sensitivity of hrHPV screening may be particularly important for early detection among underscreened women.42 Several systematic reviews summarize evidence that hrHPV screening via self-collection of samples may be a sufficiently accurate and acceptable strategy for reaching underscreened and unscreened populations.10,58,59 Further research is needed to examine the effect of self-collection screening strategies on overall screening rates, adherence to follow-up, and health outcomes for women with limited access to health care or low rates of participation in screening programs.60,61

Limitations

This review was limited by the quality and heterogeneity of the included studies. First, the quality of many of the included studies was rated as fair because of problems with attrition, protocol changes, and lack of blinding of outcome assessment. Second, the overall body of evidence was limited by trials having no more than 2 and often only 1 randomized round of screening available for comparisons. Only 1 trial (ARTISTIC) maintained the same strategy over 2 rounds of screening.32-35 Third, outcome reporting on colposcopy and biopsy rates was inconsistent, and none of the trials reported on adverse events associated with the screening tests or with diagnostic and treatment procedures resulting from screening. Fourth, the trial evidence was supplemented with results of large cohort studies of primary hrHPV screening or cotesting over 2 screening rounds; however, none of the cohort studies had a comparison group screened with cytology only.

Conclusions

Primary hrHPV screening detected higher rates of CIN 3+ at first-round screening compared with cytology. Cotesting trials did not show initial increased CIN 3+ detection. Both hrHPV screening strategies had higher false-positive and colposcopy rates than cytology, which could lead to more treatments with potential harms.

Back to top
Article Information

Corresponding Author: Joy Melnikow, MD, MPH, Center for Healthcare Policy and Research, University of California, Davis, 4860 Y St, Ste 2300, Sacramento, CA 95817 (jamelnikow@ucdavis.edu).

Accepted for Publication: June 28, 2018.

Correction: This article was corrected online on October 11, 2018, to to correct study quality information reported for 1 study in Tables 1-4.

Author Contributions: Dr Melnikow and Dr Henderson had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Melnikow, Henderson, Burda, Senger.

Acquisition, analysis, or interpretation of data: Melnikow, Henderson, Burda, Durbin, Weyrich.

Drafting of the manuscript: Melnikow, Henderson, Burda, Weyrich.

Critical revision of the manuscript for important intellectual content: Melnikow, Henderson, Burda, Senger, Durbin.

Statistical analysis: Burda.

Obtained funding: Melnikow.

Administrative, technical, or material support: Melnikow, Burda, Senger, Durbin, Weyrich.

Supervision: Melnikow, Henderson.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This research was funded under contract HHSA-290-2012-00015-I, Task Order 6, from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, under a contract to support the USPSTF.

Role of the Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight, reviewed the report to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript findings. The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Human Services.

Additional Contributions: We gratefully acknowledge the following individuals for their contributions to this project: the AHRQ staff; the US Preventive Services Task Force; Evelyn P. Whitlock, MD, MPH (Patient-Centered Outcomes Research Institute; formerly at the Kaiser Permanente Center for Health Research), for mentoring and project oversight; and Smyth Lai, MLS, and Katherine Essick, BS (Kaiser Permanente Center for Health Research), for technical and editorial assistance. USPSTF members, peer reviewers, and federal partner reviewers did not receive financial compensation for their contributions.

Additional Information: A draft version of this evidence report underwent external peer review from 10 content experts (David Chelmo, MD, Virginia Commonwealth University; Sarah Feldman, MD, MPH, Harvard Medical School/Brigham and Women’s Hospital; Robert Goulart, MD, New England Pathology Associates; Herschel Lawson, MD, Emory University School of Medicine; L. Stewart Massad, MD, Washington University School of Medicine in St. Louis; Diana Petitti, MD, MPH, University of Arizona College of Medicine; Mona Saraiya, MD, MPH, Centers for Disease Control and Prevention; Debbie Saslow, PhD, American Cancer Society; Mark Schiffman, MD, MPH, National Cancer Institute; Alan Waxman, MD, MPH, University of New Mexico School of Medicine) and 3 federal partners (the Centers for Disease Control and Prevention, the National Institutes of Health, the Indian Health Service). Comments were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence review.

Editorial Disclaimer: This evidence report is presented as a document in support of the accompanying USPSTF Recommendation Statement. It did not undergo additional peer review after submission to JAMA.

References
1.
Schiffman  M, Castle  PE, Jeronimo  J, Rodriguez  AC, Wacholder  S.  Human papillomavirus and cervical cancer.  Lancet. 2007;370(9590):890-907. doi:10.1016/S0140-6736(07)61416-0PubMedGoogle ScholarCrossref
2.
Ziegert  C, Wentzensen  N, Vinokurova  S,  et al.  A comprehensive analysis of HPV integration loci in anogenital lesions combining transcript and genome-based amplification techniques.  Oncogene. 2003;22(25):3977-3984. doi:10.1038/sj.onc.1206629PubMedGoogle ScholarCrossref
3.
Bosch  FX, Lorincz  A, Muñoz  N, Meijer  CJ, Shah  KV.  The causal relation between human papillomavirus and cervical cancer.  J Clin Pathol. 2002;55(4):244-265. doi:10.1136/jcp.55.4.244PubMedGoogle ScholarCrossref
4.
American Cancer Society. Cancer Facts & Figures 2016. American Cancer Society website. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2016.html. Published 2016. Accessed June 27, 2017.
5.
Forman  D, de Martel  C, Lacey  CJ,  et al.  Global burden of human papillomavirus and related diseases.  Vaccine. 2012;30(suppl 5):F12-F23. doi:10.1016/j.vaccine.2012.07.055PubMedGoogle ScholarCrossref
6.
Dunne  EF, Unger  ER, Sternberg  M,  et al.  Prevalence of HPV infection among females in the United States.  JAMA. 2007;297(8):813-819. doi:10.1001/jama.297.8.813PubMedGoogle ScholarCrossref
7.
Partridge  EE, Abu-Rustum  N, Giuliano  A,  et al; National Comprehensive Cancer Network.  Cervical cancer screening.  J Natl Compr Canc Netw. 2014;12(3):333-341. doi:10.6004/jnccn.2014.0035PubMedGoogle ScholarCrossref
8.
Surveillance, Epidemiology, and End Results (SEER). Cancer Stat Facts: cervical cancer. SEER website. https://seer.cancer.gov/statfacts/html/cervix.html. Published 2017. Accessed July 3, 2018.
9.
Moyer  VA; U.S. Preventive Services Task Force.  Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement  [published correction appears in Ann Intern Med. 2013;158(11):852].  Ann Intern Med. 2012;156(12):880-891. doi:10.7326/0003-4819-156-12-201206190-00424PubMedGoogle ScholarCrossref
10.
Huynh  J, Howard  M, Lytwyn  A.  Self-collection for vaginal human papillomavirus testing: systematic review of studies asking women their perceptions.  J Low Genit Tract Dis. 2010;14(4):356-362. doi:10.1097/LGT.0b013e3181dc115bPubMedGoogle ScholarCrossref
11.
Vesco  KK, Whitlock  EP, Eder  M,  et al.  Screening for Cervical Cancer: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality; 2011. AHRQ publication 11-05156-EF-1.
12.
Canfell  K, Caruana  M, Gebski  V,  et al.  Cervical screening with primary HPV testing or cytology in a population of women in which those aged 33 years or younger had previously been offered HPV vaccination: results of the Compass pilot randomised trial.  PLoS Med. 2017;14(9):e1002388. doi:10.1371/journal.pmed.1002388PubMedGoogle ScholarCrossref
13.
Ogilvie  G, van Niekerk  D, Krajden  M,  et al.  Effect of screening with primary cervical HPV testing vs cytology testing on high-grade cervical intraepithelial neoplasia at 48 months: the HPV FOCAL randomized clinical trial.  JAMA. 2018;320(1):43-52. doi:10.1001/jama.2018.7464PubMedGoogle ScholarCrossref
14.
Ronco  G, Giorgi-Rossi  P, Carozzi  F,  et al; New Technologies for Cervical Cancer Screening (NTCC) Working Group.  Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial.  Lancet Oncol. 2010;11(3):249-257. doi:10.1016/S1470-2045(09)70360-2PubMedGoogle ScholarCrossref
15.
United Nation Development Programme.  Human Development Report. New York, NY: United Nations; 2016.
16.
McCredie  MR, Sharples  KJ, Paul  C,  et al.  Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study.  Lancet Oncol. 2008;9(5):425-434. doi:10.1016/S1470-2045(08)70103-7PubMedGoogle ScholarCrossref
17.
Harris  RP, Helfand  M, Woolf  SH,  et al; Methods Work Group, Third US Preventive Services Task Force.  Current methods of the US Preventive Services Task Force: a review of the process.  Am J Prev Med. 2001;20(3)(suppl):21-35. doi:10.1016/S0749-3797(01)00261-6PubMedGoogle ScholarCrossref
18.
Wells  GA, Shea  BJ, O’Connell  DPJ, Welch  V, Losos  M, Tugwell  P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analysis. Ottawa Hospital Research Institute website. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. 2014. Accessed June 27, 2017.
19.
Cook  DA, Mei  W, Smith  LW,  et al.  Comparison of the Roche cobas® 4800 and Digene Hybrid Capture® 2 HPV tests for primary cervical cancer screening in the HPV FOCAL trial.  BMC Cancer. 2015;15:968. doi:10.1186/s12885-015-1959-5PubMedGoogle ScholarCrossref
20.
Ronco  G, Giorgi-Rossi  P, Carozzi  F,  et al; New Technologies for Cervical Cancer Screening Working Group.  Results at recruitment from a randomized controlled trial comparing human papillomavirus testing alone with conventional cytology as the primary cervical cancer screening test.  J Natl Cancer Inst. 2008;100(7):492-501. doi:10.1093/jnci/djn065PubMedGoogle ScholarCrossref
21.
Ogilvie  GS, Krajden  M, van Niekerk  D,  et al.  HPV for cervical cancer screening (HPV FOCAL): complete round 1 results of a randomized trial comparing HPV-based primary screening to liquid-based cytology for cervical cancer.  Int J Cancer. 2017;140(2):440-448. doi:10.1002/ijc.30454PubMedGoogle ScholarCrossref
22.
Ogilvie  GS, van Niekerk  DJ, Krajden  M,  et al.  A randomized controlled trial of human papillomavirus (HPV) testing for cervical cancer screening: trial design and preliminary results (HPV FOCAL trial).  BMC Cancer. 2010;10:111. doi:10.1186/1471-2407-10-111PubMedGoogle ScholarCrossref
23.
Leinonen  MK, Nieminen  P, Lönnberg  S,  et al.  Detection rates of precancerous and cancerous cervical lesions within one screening round of primary human papillomavirus DNA testing: prospective randomised trial in Finland.  BMJ. 2012;345:e7789. doi:10.1136/bmj.e7789PubMedGoogle ScholarCrossref
24.
Zorzi  M, Frayle  H, Rizzi  M,  et al; Veneto HPV-Screening Working Group.  A 3-year interval is too short for re-screening women testing negative for human papillomavirus: a population-based cohort study.  BJOG. 2017;24(10):1585-1593. doi:10.1111/1471-0528.14575PubMedGoogle ScholarCrossref
25.
Ronco  G, Giorgi-Rossi  P, Carozzi  F,  et al; New Technologies for Cervical Cancer Screening Working Group.  Human papillomavirus testing and liquid-based cytology in primary screening of women younger than 35 years: results at recruitment for a randomised controlled trial.  Lancet Oncol. 2006;7(7):547-555. doi:10.1016/S1470-2045(06)70731-8PubMedGoogle ScholarCrossref
26.
Ronco  G, Segnan  N, Giorgi-Rossi  P,  et al; New Technologies for Cervical Cancer Working Group.  Human papillomavirus testing and liquid-based cytology: results at recruitment from the new technologies for cervical cancer randomized controlled trial.  J Natl Cancer Inst. 2006;98(11):765-774. doi:10.1093/jnci/djj209PubMedGoogle ScholarCrossref
27.
Bulkmans  NW, Rozendaal  L, Snijders  PJ,  et al.  POBASCAM, a population-based randomized controlled trial for implementation of high-risk HPV testing in cervical screening: design, methods and baseline data of 44,102 women.  Int J Cancer. 2004;110(1):94-101. doi:10.1002/ijc.20076PubMedGoogle ScholarCrossref
28.
Rijkaart  DC, Berkhof  J, Rozendaal  L,  et al.  Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial.  Lancet Oncol. 2012;13(1):78-88. doi:10.1016/S1470-2045(11)70296-0PubMedGoogle ScholarCrossref
29.
Dijkstra  MG, van Zummeren  M, Rozendaal  L,  et al.  Safety of extending screening intervals beyond five years in cervical screening programmes with testing for high risk human papillomavirus: 14 year follow-up of population based randomised cohort in the Netherlands.  BMJ. 2016;355:i4924. doi:10.1136/bmj.i4924PubMedGoogle ScholarCrossref
30.
Naucler  P, Ryd  W, Törnberg  S,  et al.  Human papillomavirus and Papanicolaou tests to screen for cervical cancer  [published correction appears in N Engl J Med. 2008;359(15):1637].  N Engl J Med. 2007;357(16):1589-1597. doi:10.1056/NEJMoa073204PubMedGoogle ScholarCrossref
31.
Elfström  KM, Smelov  V, Johansson  AL,  et al.  Long term duration of protective effect for HPV negative women: follow-up of primary HPV screening randomised controlled trial.  BMJ. 2014;348:g130. doi:10.1136/bmj.g130PubMedGoogle ScholarCrossref
32.
Kitchener  HC, Fletcher  I, Roberts  C, Wheeler  P, Almonte  M, Maguire  P.  The psychosocial impact of human papillomavirus testing in primary cervical screening—a study within a randomized trial.  Int J Gynecol Cancer. 2008;18(4):743-748. doi:10.1111/j.1525-1438.2007.01113.xPubMedGoogle ScholarCrossref
33.
Kitchener  HC, Almonte  M, Gilham  C,  et al; ARTISTIC Trial Study Group.  ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening.  Health Technol Assess. 2009;13(51):1-150. doi:10.3310/hta13510PubMedGoogle ScholarCrossref
34.
Kitchener  HC, Almonte  M, Thomson  C,  et al.  HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC): a randomised controlled trial.  Lancet Oncol. 2009;10(7):672-682. doi:10.1016/S1470-2045(09)70156-1PubMedGoogle ScholarCrossref
35.
Kitchener  HC, Canfell  K, Gilham  C,  et al.  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.  Health Technol Assess. 2014;18(23):1-196. doi:10.3310/hta18230PubMedGoogle ScholarCrossref
36.
Castle  PE, Fetterman  B, Poitras  N,  et al.  Variable risk of cervical precancer and cancer after a human papillomavirus-positive test.  Obstet Gynecol. 2011;117(3):650-656. doi:10.1097/AOG.0b013e318209da59PubMedGoogle ScholarCrossref
37.
Katki  HA, Kinney  WK, Fetterman  B,  et al.  Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice  [published correction appears in Lancet Oncol. 2011;12(8):722].  Lancet Oncol. 2011;12(7):663-672. doi:10.1016/S1470-2045(11)70145-0PubMedGoogle ScholarCrossref
38.
Katki  HA, Schiffman  M, Castle  PE,  et al.  Five-year risks of CIN 3+ and cervical cancer among women who test Pap-negative but are HPV-positive.  J Low Genit Tract Dis. 2013;17(5)(suppl 1):S56-S63. doi:10.1097/LGT.0b013e318285437bPubMedGoogle ScholarCrossref
39.
Katki  HA, Schiffman  M, Castle  PE,  et al.  Benchmarking CIN 3+ risk as the basis for incorporating HPV and Pap cotesting into cervical screening and management guidelines.  J Low Genit Tract Dis. 2013;17(5)(suppl 1):S28-S35. doi:10.1097/LGT.0b013e318285423cPubMedGoogle ScholarCrossref
40.
Gage  JC, Schiffman  M, Katki  HA,  et al.  Reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test.  J Natl Cancer Inst. 2014;106(8):dju153. doi:10.1093/jnci/dju153PubMedGoogle ScholarCrossref
41.
Gage  JC, Katki  HA, Schiffman  M,  et al.  Age-stratified 5-year risks of cervical precancer among women with enrollment and newly detected HPV infection.  Int J Cancer. 2015;136(7):1665-1671. doi:10.1002/ijc.29143PubMedGoogle ScholarCrossref
42.
Ibáñez  R, Autonell  J, Sardà  M,  et al.  Protecting the underscreened women in developed countries: the value of HPV test.  BMC Cancer. 2014;14:574. doi:10.1186/1471-2407-14-574PubMedGoogle ScholarCrossref
43.
Petry  KU, Luyten  A, Scherbring  S.  Accuracy of colposcopy management to detect CIN3 and invasive cancer in women with abnormal screening tests: results from a primary HPV screening project from 2006 to 2011 in Wolfsburg, Germany.  Gynecol Oncol. 2013;128(2):282-287. doi:10.1016/j.ygyno.2012.10.017PubMedGoogle ScholarCrossref
44.
Luyten  A, Buttmann-Schweiger  N, Luyten  K,  et al.  Early detection of CIN3 and cervical cancer during long-term follow-up using HPV/Pap smear co-testing and risk-adapted follow-up in a locally organised screening programme.  Int J Cancer. 2014;135(6):1408-1416. doi:10.1002/ijc.28783PubMedGoogle ScholarCrossref
45.
McCaffery  K, Waller  J, Forrest  S, Cadman  L, Szarewski  A, Wardle  J.  Testing positive for human papillomavirus in routine cervical screening: examination of psychosocial impact.  BJOG. 2004;111(12):1437-1443. doi:10.1111/j.1471-0528.2004.00279.xPubMedGoogle ScholarCrossref
46.
US Preventive Services Task Force.  US Preventive Services Task Force Procedure Manual. Rockville, MD: Agency for Healthcare Research and Quality; 2015.
47.
Ronco  G, Dillner  J, Elfström  KM,  et al; International HPV Screening Working Group.  Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials.  Lancet. 2014;383(9916):524-532. doi:10.1016/S0140-6736(13)62218-7PubMedGoogle ScholarCrossref
48.
Castle  PE, Kinney  WK, Xue  X,  et al.  Effect of several negative rounds of human papillomavirus and cytology co-testing on safety against cervical cancer: an observational cohort study.  Ann Intern Med. 2018;168(1):20-29. doi:10.7326/M17-1609PubMedGoogle ScholarCrossref
49.
Demarco  M, Lorey  TS, Fetterman  B,  et al.  Risks of CIN 2+, CIN 3+, and cancer by cytology and human papillomavirus status: the foundation of risk-based cervical screening guidelines.  J Low Genit Tract Dis. 2017;21(4):261-267. doi:10.1097/LGT.0000000000000343PubMedGoogle ScholarCrossref
50.
Gage  JC, Hunt  WC, Schiffman  M,  et al; New Mexico HPV Pap Registry Steering Committee.  Similar risk patterns after cervical screening in two large U.S. populations: implications for clinical guidelines.  Obstet Gynecol. 2016;128(6):1248-1257. doi:10.1097/AOG.0000000000001721PubMedGoogle ScholarCrossref
51.
Coldman  AJ, Gondara  L, Smith  LW,  et al.  Disease detection and resource use in the safety and control arms of the HPV FOCAL cervical cancer screening trial.  Br J Cancer. 2016;115(12):1487-1494. doi:10.1038/bjc.2016.368PubMedGoogle ScholarCrossref
52.
Martin-Hirsch  PP, Paraskevaidis  E, Bryant  A, Dickinson  HO, Keep  SL.  Surgery for cervical intraepithelial neoplasia.  Cochrane Database Syst Rev. 2010;(6):CD001318.PubMedGoogle Scholar
53.
Nuovo  J, Melnikow  J, Willan  AR, Chan  BK.  Treatment outcomes for squamous intraepithelial lesions.  Int J Gynaecol Obstet. 2000;68(1):25-33. doi:10.1016/S0020-7292(99)00162-9PubMedGoogle ScholarCrossref
54.
Kyrgiou  M, Mitra  A, Arbyn  M,  et al.  Fertility and early pregnancy outcomes after conservative treatment for cervical intraepithelial neoplasia.  Cochrane Database Syst Rev. 2015;(9):CD008478.PubMedGoogle Scholar
55.
Conner  SN, Frey  HA, Cahill  AG, Macones  GA, Colditz  GA, Tuuli  MG.  Loop electrosurgical excision procedure and risk of preterm birth: a systematic review and meta-analysis.  Obstet Gynecol. 2014;123(4):752-761. doi:10.1097/AOG.0000000000000174PubMedGoogle ScholarCrossref
56.
Vesco  KK, Whitlock  EP, Eder  M, Burda  BU, Senger  CA, Lutz  K.  Risk factors and other epidemiologic considerations for cervical cancer screening: a narrative review for the U.S. Preventive Services Task Force.  Ann Intern Med. 2011;155(10):698-705. doi:10.7326/0003-4819-155-10-201111150-00377PubMedGoogle ScholarCrossref
57.
Benard  VB, Thomas  CC, King  J, Massetti  GM, Doria-Rose  VP, Saraiya  M; Centers for Disease Control and Prevention (CDC).  Vital signs: cervical cancer incidence, mortality, and screening—United States, 2007-2012.  MMWR Morb Mortal Wkly Rep. 2014;63(44):1004-1009.PubMedGoogle Scholar
58.
Snijders  PJ, Verhoef  VM, Arbyn  M,  et al.  High-risk HPV testing on self-sampled versus clinician-collected specimens: a review on the clinical accuracy and impact on population attendance in cervical cancer screening.  Int J Cancer. 2013;132(10):2223-2236. doi:10.1002/ijc.27790PubMedGoogle ScholarCrossref
59.
Racey  CS, Withrow  DR, Gesink  D.  Self-collected HPV testing improves participation in cervical cancer screening: a systematic review and meta-analysis.  Can J Public Health. 2013;104(2):e159-e166.PubMedGoogle Scholar
60.
Singh  GK, Williams  SD, Siahpush  M, Mulhollen  A.  Socioeconomic, rural-urban, and racial inequalities in US cancer mortality: part I—all cancers and lung cancer and part II—colorectal, prostate, breast, and cervical cancers.  J Cancer Epidemiol. 2011;2011:107497. doi:10.1155/2011/107497PubMedGoogle ScholarCrossref
61.
Rositch  AF, Nowak  RG, Gravitt  PE.  Increased age and race-specific incidence of cervical cancer after correction for hysterectomy prevalence in the United States from 2000 to 2009.  Cancer. 2014;120(13):2032-2038. doi:10.1002/cncr.28548PubMedGoogle ScholarCrossref
×