This systematic review synthesizes and compares results from all of the randomized trials with published results comparing cytology with HPV-based testing for cervical cancer screening. Although cervical cancer morbidity and mortality are the most relevant outcomes, cancer is rare in countries with established screening programs. Given that CIN2 reverts in up to 40% of cases,21
detection of CIN2 may result in overtreatment and morbidity in reproductive-aged women; therefore, CIN3 or greater is likely the most clinically relevant outcome in cervical cancer screening trials. One consistent finding from all the studies is that CIN3 or greater is an uncommon outcome, which necessitates a careful assessment of tradeoffs between sensitivity and specificity. The low rates of CIN3 or greater are of additional significance, given that the intervals between screening rounds in the studies (3-5 years) are greater than the screening interval of 1-2 years previously used in the United States until the recent introduction of new guidelines.5,6
The results presented here indicate that in randomized trials, HPV testing is significantly more sensitive for CIN3 or greater during the first round of screening for some, but not all, strategies. The fact that sensitivity of HPV testing is lower than that of cytology in the second round suggests that as more disease is detected and treated in the first round, there will be less disease to detect subsequently. After completion of both screening rounds, sensitivity for detection of CIN3 or greater was significantly increased only with strategies involving an active response to a positive HPV test (ie, immediate colposcopy).16,17
This approach, however, also increases false-positive results as indicated by the relative PPV for detection of CIN3 or greater of 0.50 for women aged 35-60 years in the NTCCS trial.16
The strategy that has been adopted in the United States is to add HPV testing to cytology for women over age 30 years, and to respond passively to HPV-positive results if the cytology is normal, rather than to perform immediate colposcopy.5,6
Four trials in our analysis used a similar passive response with cotesting.13,16,18,19
None of these trials demonstrated an overall significantly increased relative sensitivity for CIN3 or greater, and only 1 trial demonstrated a significantly increased relative sensitivity for CIN2 or greater.
Another important metric is the number of colposcopies needed to find a case of disease. In the ARTISTIC trial, significantly higher numbers of colposcopies were needed in the HPV cotesting arm for detection of CIN3 or greater in round 1, but this did not result in increased sensitivity. The calculated number of colposcopies likely underestimates the true number of colposcopies because it reflects the initial test positivity rate and does not include subsequent colposcopies resulting from increased surveillance in women who remain HPV positive over time. Thus, it will be important to monitor the impact of cotesting on overall colposcopy rates as the new screening guidelines are adopted.
There are many strengths of this review. All studies were high-quality randomized trials with large study populations and provide longitudinal data about disease detection over multiple rounds of screening. This review also provides a novel method to estimate and compare the impact of different screening strategies through the calculation of the number of colposcopies needed to detect a single case of CIN2 or greater or CIN3 or greater.
This review also has limitations. We chose to review randomized controlled trials based on the strength of their study methodology and, furthermore, assessed study quality using a validated tool. However, there were weaknesses in individual studies that fall outside the parameters measured in this tool. For example, 3 of the trials used HPV testing on women under the age of 30 years (), an age group in which HPV testing is less specific because of the higher prevalence of transient HPV infections. The rate of loss to follow-up was high in some of the studies (). As discussed in the Results
section, in 2 of the trials, the randomized screening strategy was not continued into the second round of screening.13,14,16
Additional limitations include the fact that results on relative specificity of HPV testing compared with cytology were not reported in most of the trials, limiting the ability to compare test performance. The varied strategies for incorporating HPV testing and the differing thresholds for colposcopy used by the studies presented significant challenges in comparing the performance of the screening strategies across studies. The studies were performed before the widespread uptake of HPV vaccination, and test performance is likely to change as the prevalence of HPV decreases. The number of screening rounds studied in these trials to date is insufficient to assess the impact of HPV testing over a woman’s lifetime. Further data will be forthcoming from additional rounds of screening from some of these trials. In addition, all of these studies were completed outside the United States and followed their respective country’s screening guidelines, all of which differed from US guidelines.
This review highlights the need for a longitudinal randomized trial performed in the United States over multiple screening rounds of 3-5 year intervals in which relative specificities and rates of colposcopy are reported. In addition, triage of women with HPV-positive results directly to colposcopy should be considered in any prospective US trial.
In summary, this systematic review indicates that after 2 rounds of screening, HPV-testing based screening strategies are more sensitive than cytology for the detection of CIN3 or greater only when referral to colposcopy follows a single positive HPV test. This strategy results in more colposcopies needed to detect a single case of CIN3 or greater or cancer, especially in women over 35 years of age. Because CIN3 and cervical cancer are rare in well-screened populations, the impact on increased disease detection needs to be balanced with the impact on cost, numbers of colposcopies, and morbidity associated with potential overtreatment.