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.

High-risk human papillomavirus (hrHPV) is readily transmitted through sexual contact^1,2 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.

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 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 CIN3.¹⁶ 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. 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 negative preceding screening results. Psychological harms, including adverse effects on anxiety, distress, and sexual satisfaction, were abstracted when reported.

Effectiveness of Screening

Key Question 1. What is the effectiveness of hrHPV testing, with or without cytology, as a primary screening strategy for reducing cervical cancer mortality and incidence compared with recommended 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 genotype 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.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.^24,37,43,44 Long-term evaluation of the US-based cohort found that risk of CIN3+ 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 = 0.52).

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, 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 than for women older than 35 years (range, 0.2%²³ to 0.5%^13,19,21,22). 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. 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 CIN3+ 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. 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 cohort^48,49 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 above^24,37,44 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. 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.

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 POBASCAM^27-29 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 = 0.24). A pooled estimate calculated with the NTCC trial biopsy rate included had unacceptably high statistical heterogeneity (I² = 99.1%; P < 0.001). 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. 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. 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

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.

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.

Source: This article was first published in JAMA on August 21, 2018 (JAMA. 2018;320(7):687-705).

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 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, and 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.

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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.⁴⁶

USPSTF indicates US Preventive Services Task Force.
^a One publication (Ronco 2010¹⁴) includes 2 trials (NTCC Phase I and NTCC Phase II), so it is counted as 2 publications instead of 1.
^b Reasons 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.

Abbreviations: ARTISTIC, A Randomized Trial in Screening to Improve Cytology; ASC-H, atypical squamous cells, cannot exclude HSIL; ASCUS, atypical squamous cells of undetermined significance; HPV FOCAL, Human Papillomavirus for Cervical Cancer Screening; hrHPV, high-risk human papillomavirus; HSIL, high-grade squamous intraepithelial lesion; KPNC, Kaiser Permanente Northern California; LBC, liquid-based cytology; LSIL, low-grade squamous intraepithelial lesion; NA, not applicable; NR, not reported; NTCC, New Technologies for Cervical Cancer Screening; POBASCAM, Population Based Screening Study Amsterdam; RCT, randomized clinical trial.
^a Assessed using criteria from the US Preventive Services Task Force.^46
b All time points are maximum follow-up, with the exception of the Swedescreen trial, which reported mean follow-up.
^c Some differences between trial sites.
^d HPV FOCAL had 2 randomized hrHPV groups: a safety group (screening every 2 years) and an intervention group (screening every 4 years). Only the latter is reported; results from the control group are reported at 4 years and include the 2-year screening round results.
^e Triage could be performed via LBC or dual-stained cytology.
^f Unblinding of human papillomavirus status 3 years after enrollment and 4 months after the completion of round 1.
^g Range, less than 0.1 to 7.7 years.

Abbreviations: ARTISTIC, A Randomized Trial in Screening to Improve Cytology; CIN, cervical intraepithelial neoplasia; CIN 3+, CIN 3 or worse; HPV FOCAL, Human Papillomavirus for Cervical Cancer Screening; hrHPV, high-risk human papillomavirus; LBC, liquid-based cytology; NR, not reported; NTCC, New Technologies for Cervical Cancer Screening; POBASCAM, Population Based Screening Study Amsterdam; RR, relative risk.
^a Assessed using criteria from the US Preventive Services Task Force.^46
b This table reports detection and relative risks for women of all ages included in the trial.
^c From author inquiry.
^d Calculated (unadjusted).
^e HPV FOCAL had 2 randomized hrHPV groups: a safety group (screening every 2 years) and an intervention group (screening every 4 years). Only the latter is reported; results from the control group are reported at 4 years and include the 2-year screening round results.
^f The 4-year results compare 1 round of human papillomavirus screening in the intervention group with 2 rounds of cytology screening in the control group.
^g Triage could be performed via LBC or dual-stained cytology.
^h Preliminary or incomplete results.

Abbreviations: ARTISTIC, A Randomized Trial in Screening to Improve Cytology; ASCUS, atypical squamous cells of undetermined significance; CC, conventional cytology; CIN, cervical intraepithelial neoplasia; HPV FOCAL, Human Papillomavirus for Cervical Cancer Screening; hrHPV, high-risk human papillomavirus; LBC, liquid-based cytology; NR, not reported; NTCC, New Technologies for Cervical Cancer Screening; POBASCAM, Population Based Screening Study Amsterdam.
^a Assessed using criteria from the US Preventive Services Task Force.^46
b With the exception of POBASCAM and ARTISTIC, only results from round 1 were reported.
^c Test positivity was defined based on trial protocol. Test findings that would lead to a clinical action based on the study protocol, such as colposcopy or more intensive follow-up, were considered test-positive. Thus, in some trials, the test positivity rate in the intervention group is simply the rate of hrHPV test positivity, whereas in others it is the rate of hrHPV+ with ASCUS+.
^d This table reports harms for women of all ages included in the trial.
^e HPV FOCAL had 2 randomized hrHPV groups: a safety group (screening every 2 years) and an intervention group (screening every 4 years). Only the latter is reported; results from the control group are reported at 4 years and include the 2-year screening round results.
^f Women with positive cotesting results on either hrHPV or cytology were referred for colposcopy.
^g Percentage of women; converted from rate per 1000 participants.
^h From author inquiry.
ⁱ Triage could be performed via LBC or dual-stained cytology.
^j  Estimated data from figure.
^k Preliminary or incomplete results.

Abbreviations: CIN, cervical intraepithelial neoplasia; CIN 3+, CIN 3 or worse; hrHPV, high-risk human papillomavirus; KQ, key question; NA, not applicable; RCT, randomized clinical trial.
^a Study quality assessed using criteria from the US Preventive Services Task Force.⁴⁶