HPV Testing Method for Cervical Cancer

In low-resource settings, testing for human papillomavirus (HPV) might be the most effective method of cervical cancer screening. Compared with cytologic testing and visual inspection of the cervix with acetic acid (VIA), a single round of HPV testing significantly reduced the incidence of advanced cervical cancer and related mortality among women in rural India.

These are the conclusions of a study published in the April 2 issue of the New England Journal of Medicine.

The implications of the findings of this trial are immediate and global, according to Mark Schiffman, MD, MPH, and Sholom Wacholder, PhD, who are both from the National Cancer Institute.

"International experts in cervical cancer prevention should now adopt HPV testing for widespread implementation," they write in an accompanying editorial. "Low-resource countries do not need to establish large cytologic-testing (Papanicolaou) programs whose effectiveness requires repeated screening. VIA that is performed by health workers, the least expensive but least accurate option, may reduce mortality slightly."

International experts in cervical cancer prevention should now adopt HPV testing for widespread implementation.

There is a lack of effective screening programs for cervical cancer in developing countries, where 80% of cases occur every year. "A single HPV test that is performed 15 to 20 years after the median age of first sexual intercourse will detect many easily treatable, persistent infections and precancers, while limiting overtreatment," the editorialists note, but widespread implementation of HPV screening still faces a number of challenges.

To implement wide-scale HPV screening, they point out that regional, age-specific HPV prevalence patterns need to be defined; low-cost, simple, and accurate HPV tests need to be validated; and an infrastructure aimed at the treatment of HPV-positive women will have to be developed.

The introduction of prophylactic HPV vaccines does not diminish the importance of HPV screening, they emphasize. "Even when the vaccines become affordable and widely used, they will not substantially decrease rates of cervical cancer for decades because of the long latency between infection and cancer," they write.

In this study, researchers evaluated the effectiveness of a single round of HPV testing, cytologic testing, or VIA in reducing the incidence of cervical cancer and associated mortality rate in women residing in rural India.

All of the women with positive screening results, regardless of the modality used, were investigated, treated, and monitored in the same way, explained lead author Rengaswamy Sankaranarayanan, MD, who is head of the screening group at the International Agency for Research on Cancer, in Lyon, France.

"They had colposcopy, directed biopsy from colposcopically abnormal areas, and treatment of precancerous lesions with cryotherapy or excision," he told Medscape Oncology. "Invasive cervical cancer cases were referred for cancer-directed treatment."

Advanced Cancers and Death Rate Lowest in HPV-Testing Group

Screening took place between January 2000 and April 2003. A total of 131,746 healthy women between the ages of 30 and 59 years, from 52 clusters of villages, were randomly assigned to 1 of 4 groups: HPV testing (34,126 women), cytologic testing (32,058), VIA (34,074), or standard care (31,488, control group).

In the HPV-testing group, 2812 (10.3%) had positive results, as did 1787 (7.0%) in the cytologic-testing group, and 3733 (13.9%) in the VIA group.

The detection rate of cervical intraepithelial neoplasia (CIN) grade 1 was higher in the VIA cohort than in the other 2 groups, whereas detection rates of CIN grade 2 or 3 lesions and invasive cancer were similar in the 3 groups (P = .06 for CIN grade 2 and P = .16 for CIN grade 3 for all comparisons). The positive-predictive value for detecting CIN grade 2 or 3 lesions was 11.3% in the HPV-testing group, 19.3% in the cytologic-testing group, and 7.4% in the VIA group.

The proportion of stage I cancers was highest in the HPV testing and cytologic-testing groups (about 60%), 42% in the VIA group, and lowest in the control group (28%). The researchers noted that the incidence rate of stage II or higher cervical cancer and subsequent related death rates were significantly higher in the cytologic-testing group and the VIA group than in the HPV-testing group.

Clinical Stages of Cervical Cancer and Death Rate in All Women Assigned to Screening

Stage at Diagnosis	HPV Testing, n/total n (%)	Cytologic Testing, n/total n (%)	VIA, n/total n (%)
IA	47/127 (37)	60/152 (39.5)	35/157 (22.3)
IB	33/127 (26)	29/152 (19.1)	31/157 (19.7)
II or higher	39/127 (30.7)	58/152 (38.2)	86/157 (54.8)
Unknown	8/127 (26.8)	5/152 (3.3)	5/157 (3.2)
Death from cervical cancer	34/127 (26.8)	54/152 (35.5)	56/157 (35.7)

HPV Test More Sensitive

"We believe that HPV testing was more sensitive than VIA or cytologic testing in identifying women with real precancerous lesions with a potential to progress to frank cancer in our study," said Dr. Sankaranarayanan. "The early detection and treatment of such lesions resulted in a lower rate of advanced cancers, and a lower number of invasive cancers and cervical cancer deaths in the HPV-testing group."

He also pointed out that, compared with the other screening modalities, fewer of the HPV-test negative women developed cervical cancer during the 8-year follow-up period. "This reinforces the conclusion that HPV testing has a possibly high sensitivity to lead to the detection of biologically progressive precancerous lesions," he said. "The lower death rate in the HPV-testing group is due to lower advanced disease and higher prevented invasive cancers due to early detection and treatment of more 'real' precursor lesions."

HPV testing has a possibly high sensitivity to lead to the detection of biologically progressive precancerous lesions.

Compared with the control group, the hazard ratio for the detection of advanced cancer in the HPV-testing group was 0.47 (95% confidence interval [CI], 0.32 to 0.69) and the hazard ratio for death was 0.52 (95% CI, 0.33 to 0.83). There were no significant reductions in the numbers of advanced cancers or deaths observed in the cytologic-testing group or in the VIA group, compared with the control group.

HPV Test Most Objective and Reproducible

Overall, the researchers found HPV testing to be the most objective and reproducible of all cervical screening tests, as well as being less demanding in terms of training and quality assurance. A drawback is that it is more expensive and time-consuming than other types of screening tests, and it requires a sophisticated laboratory infrastructure.

However, they note that a simple, affordable, and accurate HPV test (careHPV test, Qiagen) has been evaluated in China. It produces results within 3 hours, and its accuracy is similar to that of the Hybrid Capture II test used in the current study. The careHPV test is expected to enter the market in the near future for use in developing countries.

The study was funded by the Bill and Melinda Gates Foundation, through the Alliance for Cervical Cancer Prevention. Dr. Schiffman reports being a medical monitor of a trial of prophylactic HPV vaccination sponsored by the National Cancer Institute (NCI). Dr. Wacholder reports serving as the statistician for the same NCI-sponsored HPV vaccination trial.

N Engl J Med. 2009;360:1385-1394.