Separate HPV16, HPV18 Testing May Identify High-Risk Women

Laurie Barclay, MD

August 30, 2011

August 30, 2011 — Compared with cytology testing, separate testing for human papillomavirus (HPV)16 and HPV18 may offer improved detection of women at high risk for cervical cancer, according to the results of a study reported online August 23 and will appear in the September print issue of Lancet Oncology.

"The ATHENA study was designed to assess the performance of carcinogenic ...HPV testing and HPV16 or HPV18 genotyping compared with liquid-based cytology for cervical cancer screening in a large US population aged 21 years and older," write Philip E. Castle, MD, from the American Society for Clinical Pathology Institute in Washington, DC, and colleagues. "We did a subanalysis of this population to compare the screening performance of the cobas HPV test versus liquid-based cytology in women aged 25 years and older, and assess management strategies for HPV-positive women."

In 23 US states, women 25 years or older undergoing routine cervical screening were enrolled from 61 clinical centers. Liquid-based cytology and HPV DNA testing with 2 first-generation assays (Amplicor HPV test and Linear Array HPV genotyping test; Roche Molecular Systems, Pleasanton, California) and individual HPV16 and HPV18 detection by use of the second-generation cobas HPV test were performed on all cervical specimens.

Women with atypical squamous cells of undetermined significance (ASC-US) or worse cytologic features, those who tested positive with either first-generation HPV test, and a random sample of women who tested negative for HPV and cytology findings underwent colposcopy and diagnostic biopsies. Women not undergoing colposcopy were given their results and left the study. Until the colposcopy visit was completed, participants and colposcopists were blinded to the results of cytology and HPV testing. Histologically confirmed cervical intraepithelial neoplasia grade 3 (CIN3) or worse was the main study outcome for this analysis. Follow-up of this study is scheduled to be completed in December 2012.

Of 47,208 women enrolled from May 27, 2008, to August 27, 2009, a total of 41,955 met eligibility criteria, and 40,901 (97%) had valid cobas HPV and liquid-based cytology test results. Of the 40,901 women, cytology results were abnormal in 2617 (6%), 4275 (10%) tested cobas HPV positive, and 431 women were diagnosed with CIN2 or worse and 274 with CIN3 or worse.

For detection of CIN3 or worse among women who underwent colposcopy, the cobas HPV test was more sensitive than liquid-based cytology testing (92.0% vs 53.3%; difference, 38.7%; 95% confidence interval [CI], 31.9 - 45.5; P < .0001). Compared with HPV testing alone, adding liquid-based cytology testing increased sensitivity for CIN3 or worse to 96.7% (95% CI, 93.9 - 98.3), but at the cost of increasing the number of screen positives by 35.2%.

When used as a triage test to detect CIN3 or worse in HPV-positive women, identification of HPV16, HPV18, or both alone was comparable to identification of ASC-US or worse alone in sensitivity (59.5% vs 52.8%; P =·.11) and positive predictive value (PPV; 15.5% vs 14.1%; P = .20).

Compared with ASC-US or worse cytology results alone, detection of HPV16, HPV18, or both or low-grade squamous intraepithelial lesion or worse cytology findings had a better sensitivity among HPV-positive women (72.2%; P < .0001) and similar PPV (13.9%; P = .70) for detection of CIN3 or worse.

In addition, detection of HPV16, HPV18, or both or high-grade squamous intraepithelial lesion or worse cytology findings had a higher sensitivity (65.5%; P = .0011) and PPV (16.3%; P = .031) for detection of CIN3 or worse than ASC-US or worse cytology findings alone.

"HPV testing with separate HPV16 and HPV18 detection could provide an alternative, more sensitive, and efficient strategy for cervical cancer screening than do methods based solely on cytology," the study authors write.

Limitations of this study include cross-sectional design, possible lack of generalizability to other countries, and imperfect sensitivity of any triage strategies.

"[C]o-testing of HPV and cytology will probably be replaced by stand-alone HPV testing as primary screening test in high-income countries, because addition of cytology seems to provide little gain according to Castle and colleagues' findings," Guglielmo Ronco, from the Centre of Cancer Prevention in Turin, Italy, and colleagues, write in an accompanying Comment. "The study by Castle and colleagues, although designed for high-income countries, can also provide useful information about triage strategies for countries where high-quality cytology has been difficult to implement and combinations of HPV tests might eventually offer a more sustainable option."

Roche Molecular Systems funded this study, employs 3 of the study authors, and has financial relationships with 3 other study authors. Some of the study authors also have disclosed various financial relationships with BD Diagnostics, Qiagen, Gen-Probe, Ventana, Merck, and/or mtm laboratories. The editorialists have disclosed no relevant financial relationships.

Lancet Oncol. 2011;12:831-832, 880-890.


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