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Back To Vidyya Studies Expand On Relationship Between Human Papillomavirus And Cervical Cancer

Research From The 21 February 2001 Issue Of The Journal Of The National Cancer Institute

Three articles in the Feb. 21 issue of the Journal of the National Cancer Institute focus on the causal relationship between human papillomavirus (HPV) and cervical cancer and its implications for prevention efforts.

The articles present results from a randomized, controlled study of a vaccine against HPV type 16 (HPV16), which is found in about half of cervical cancers; from a multicenter, randomized trial that examines the role of HPV testing in women with equivocal cytologic abnormalities; and from a case–control study of the cervical cancer risk associated with different variants of HPV16.

Clayton Harro, M.D., at The Johns Hopkins University, Douglas Lowy, M.D., of the National Cancer Institute, and colleagues have developed a vaccine against HPV16. They present the results the study, which was designed to show the safety and immunologic potency of this vaccine.

The vaccine, developed from a specific HPV16 protein and produced in insect cells, was first injected at low dose (10 µg) into some of the 72 volunteers (58 women and 14 men). When the 10-µg injection was determined to be safe, injections of 50 µg were given to the other volunteers. Volunteers received three injections and were evaluated throughout the study until 1 month after their third injection.

Results from the patients indicated that the vaccine was well tolerated and highly immunogenic. The authors noted that the vaccine induced an antibody response in most volunteers that was 40-fold higher than is usually seen after a natural infection. On the basis of these encouraging results, the authors have started a phase II trial with the 50-µg dose. They note that, as multiple types of HPV are known to cause cervical cancer, a "combined vaccine" will likely be needed to maximize protection.

The second paper, by Diane Solomon, M.D., of the National Cancer Institute, and colleagues concerns the management of women whose Pap tests reveal equivocal abnormal cervical cells, also known as atypical squamous cells of undetermined significance (ASCUS). More than 2 million women are diagnosed with ASCUS in the United States each year, and there is no agreement as to the appropriate methods to identify the minority of women who have clinically significant disease while avoiding excessive follow-up testing or management for others.

In this study, 3488 women with equivocal cervical abnormalities were enrolled through four clinical centers. The women were randomly assigned to either immediate colposcopy (magnified examination of the cervix and directed biopsy, considered to be the reference standard), colposcopy based on the result of testing for HPV types known to cause cervical cancer, or colposcopy based on the results of repeat Pap tests. The goal was to compare these three approaches for the timely detection of cervical precancerous lesions, specifically cervical intraepithelial neoplasia grade 3 (CIN3).

Sensitivity to detect CIN3 or worse by testing for cancer-associated HPV DNA was 96.3%, with 56.1% of women referred to colposcopy. Sensitivity of a single repeat cytology specimen with a triage threshold of high-grade lesions or worse was 44.1%, with 6.9% referred. Sensitivity of lower cytology triage threshold of atypical cells or worse was 85.3%, with 58.6% referred. Thus, the authors conclude that testing for cancer-associated HPV DNA is a viable option in the management of women with equivocal cervical abnormalities.

In the third paper, Allan Hildesheim, Ph.D., of the National Cancer Institute, and colleagues report on their study of the association of several variants of HPV16 with cervical cancer. Their study population involved 10,049 women randomly selected from one area of Costa Rica, plus nearly all women in that area who had been diagnosed with cervical cancer. This entire group was screened for type-specific HPV DNA by Hybrid Capture (Digene Corp., Gaithersburg, Md.). A subset of approximately 40% of cohort members, including all women with evidence of cervical lesions and those at high risk of HPV infection, was also tested for HPV DNA by a polymerase chain reaction (PCR)-based test. HPV16 DNA was detected by PCR in 190 subjects. Genetic sequencing of the long control region of HPV16, which contains the highest degree of variation in the viral genome, was performed in a blinded fashion on 176 of these subjects.

The authors report that HPV16 variants have different cancer-causing potentials. They previously found that HPV16 infection (all variants combined) in the study population is associated with a 710-fold increased risk of cervical cancer. Now they report that women infected with particular variants of HPV16—which they call NE for "non-European"—are 11 times more likely than those infected with the European prototype HPV16 virus to be diagnosed with cervical cancer. This finding suggests that the overall risk associated with infection with NE variants of HPV16 is indeed large.

Harald zur Hausen, M.D., Heidelburg, Germany, comments on these three articles in a related editorial. He notes that the paper by Harro et al. is the first published report of a phase I safety and immunogenicity trial of an HPV16 vaccine and that prospects for vaccination against HPV infections are remarkably promising. He says that past delays caused by epidemiologic considerations and the resulting reluctance of the pharmaceutical industry to consider vaccines against high-risk HPV infections may be costly, in light of the 400,000 cases of cervical cancer developed worldwide each year. Dr. zur Hausen says that the question of HPV identification as a screening tool in comparison to conventional cytology has resulted in controversial discussions for quite some time. The article by Solomon et al. reveals that HPV detection has a higher sensitivity to detect CIN3 or worse and a specificity comparable to that of a single additional cytologic test. He believes that test systems with higher specificity and sensitivity will become available to improve both the early diagnosis of HPV infections and, particularly, of progressing cervical lesions and that the work by Solomon et al. provides an excellent basis for future comparisons in randomized trials. Finally, Dr. zur Hausen says that Hildesheim et al. are to be commended for presenting convincing evidence for the role of strain variants in a prevalent case–control study of HPV16 and cervical cancer within a population-based cohort in Costa Rica.


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