HPV Test Alone IDs Cervical Precancer Earlier Than Pap

Veronica Hackethal, MD

July 03, 2018

Women who undergo cervical cancer screening with human papillomavirus (HPV) testing alone have a significantly lower incidence of cervical precancer at 48-month follow-up than do women who undergo a Papanicolaou (Pap) test alone, according to a study published online today in JAMA.

"These results have demonstrated that primary HPV testing detects cervical neoplasia

earlier and more accurately than cytology," write Gina Suzanne Ogilvie, MD, DrPH, professor and senior public health scientist at the Women's Hospital and Health Centre in Vancouver, British Columbia, Canada, and colleagues with the HPV FOCAL trial.

The findings have implications for whether HPV testing will eventually replace the Pap test for cervical cancer screening. The authors note, however, that further studies are needed regarding long-term outcomes and the cost-effectiveness of switching to screening with the HPV test alone.

Although screening and public health interventions have made progress, over 12,000 women developed cervical cancer and over 4200 women died of the disease in the United States in 2017, according to the authors. Those rates highlight the continued need to improve cervical cancer prevention.

About 99.7% of cervical cancers are caused by HPV. While an effective vaccine exists, current uptake is low and screening for cervical cancer remains important. 

For decades, the Pap test has been the mainstay of cervical cancer screening. Currently, the conventional Pap smear has largely been replaced with the liquid-based cytology (LBC) Pap test, in which cervical cells are collected with a brush and placed in a liquid solution for processing and analysis. But even the LBC Pap test has limitations. False-negative rates are suboptimal, and the test is subject to human error during processing.  

The leading candidate to replace the Pap test is the HPV test. A positive HPV test result may accurately identify HPV infection but give a false-positive result for cancer, which can lead to higher rates of unnecessary colposcopy.

Yet several randomized trials have suggested that initial HPV screening is more effective than the LBC Pap test for detecting cervical precancer. However, whether initial HPV testing alone works as well as the LBC Pap test alone is still being debated. Organizations such as the American Society of Clinical Oncology, US Preventive Services Task Force, and American Society for Colposcopy and Cervical Pathology have called for more research on the issue.

Therefore, Ogilvie and colleagues conducted a randomized clinical trial in collaboration with an organized cervical cancer screening program in Canada from January 2008 to May 2012, with follow-up through December 2016. Participants were enrolled through 224 clinicians in the Vancouver area and Greater Victoria.

The researchers randomly assigned 9552 women to HPV testing alone and 9457 to the LBC Pap test alone. Participants had a mean age of 45 years, and 76% were of European origin. The women had no history of cervical precancer in the past 5 years, either cervical intraepithelial neoplasia (CIN) 2+ or CIN3+. They also had no history of invasive cervical cancer or hysterectomy and no Pap test in the past 12 months. Pregnant women, HIV-positive women, and women receiving immunosuppressants were excluded.

Women with negative HPV test results returned for a follow-up at 48 months. Women with negative LBC Pap test results returned at 24 months and 48 months. At 48 months, both groups received combined HPV and LBC testing.

Results showed that the initial round of screening with HPV testing caught more cases of CIN3+ and CIN2+ than the LBC Pap test, which appeared to catch the missed lesions at a later stage 48 months later.

Specifically, at the first round of screening, significantly more women in the HPV testing group had CIN3+ (risk ratio [RR], 1.61 [95% confidence interval (CI), 1.09 - 2.37]; absolute difference in incidence rate [IR], 2.67/1000 [95% CI, 0.53 - 4.88]). Likewise, more women in the HPV screening group had CIN2+ than in the control group (RR, 1.61 [95% CI, 1.24 - 2.09]; absolute difference in IR, 5.84/1000 [95% CI, 2.70 - 9.07]).

By contrast, at 48 months, significantly fewer women in the HPV testing group had CIN3+ than did control: 2.3/1000 vs 5.5/1000 (absolute difference in IR, −3.22/1000 [95% CI, −5.12 to  −1.48]; RR, 0.42 [95% CI, 0.25 - 0.69]; P < .001). Rates for CIN2+ were also lower in the HPV testing group than in the control group, at 5.0/1000 vs 10.6/1000 (absolute difference in IR, −5.60/1000 [95% CI, −8.21 to −3.13]; RR, 0.47 [95% CI, 0.34 to 0.67]; P <.001).

In addition, more women with HPV testing were referred for colposcopy after the first round of testing than were women in the control group (referral rates: 57.0 vs 30.8; absolute difference, 26.2 [95% CI, 20.4 - 32.1]).

However, at 48 months, rates of colposcopy referral were lower with HPV testing vs the LBC Pap test (49.2 vs 70.5; absolute difference, −21.3 [95% CI, −28.3 to −14.8]).

In an accompanying editorial,  L. Stewart Massad, MD, professor of obstetrics and gynecology at the Washington University School of Medicine in St. Louis, Missouri, noted that the HPV FOCAL trial "adds important new information to that body of evidence" regarding the effectiveness of HPV testing vs Pap testing.

He notes that it is still unclear what will replace the Pap test, whether it will be a combined test or HPV testing alone and at what intervals. Currently, the US Preventive Services Task Force has draft recommendations but has yet to release a final version.

In the meantime, HPV vaccination promises to decrease the prevalence of HPV infection, which will likely lead to lower rates of cervical precancer. And, technological advances mean that HPV genotyping can now be done to identify women with the most carcinogenic strains of the virus who need immediate referral to colposcopy.  

But all this may not necessarily translate into improved screening and care for underserved women, Massad emphasized.

"[N]ew screening tools must be combined with redoubled efforts to engage inadequately

screened women in order to make further progress against cervical cancer," he concluded.

The study was funded by the Canadian Institutes of Health Research. Krajden and Coldman were principal investigators, and Ogilvie, van Niekerk, Franco, and Cook were coinvestigators on the industry-funded adjunct studies to the HPV FOCAL trial (Hologic Inc and Roche). In addition, one or more authors reports grants and/or personal fees from one or more of the following: Siemens, Roche Molecular Systems, Merck, Cook Myosite, Allergan, GlaxoSmithKline, and/or Roche. Massad reports consulting with malpractice attorneys in cases alleging missed cervical cancer. He also reports honoraria and travel expenses for educational activities and development of management guidelines. He was on the panel that recommended US Food and Drug Administration approval of the first HPV-based cervical cancer screening test and on the panel that developed interim guidance for its application. He was on the panel that developed American Cancer Society cervical cancer screening guidelines.

JAMA. 2018;320:43-52, 35-37. Published online July 3, 2018. Abstract, Editorial

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