Variants of HPV16 Appear to Confer Differing Risks of Cervical Cancer Precursor Lesions

Naturally occurring variants in human papillomavirus type 16 (HPV16)may put infected women at differing levels of risk for high grade cervicalintraepithelial neoplasia (CIN 2-3), a precursor of invasive cervical cancer,according to a report in the June 4 Journal of the National Cancer Institute.

Long Fu Xi, PhD, University of Washington, Seattle, and colleagues explainthat HPV16, one of the HPV types most strongly associated with risk forhigh grade CIN and cervical cancer, is also the most commonly occurringHPV type in the normal (ie, cervical disease-free) population. It is known,say the authors, that only a minority of women infected with HPV16 developcervical cancer and, moreover, that not all women with CIN 2-3 will developthe cancer. Laboratory studies have shown that certain nucleotide alterationsin HPV 16 affect its cancer-promoting potential, they note, and the presenceof multiple variant forms of HPV16 has been demonstrated in all human populationsstudied. These findings, add Xi and co-workers, suggest that the naturalvariants of HPV16 in a given population may not have the same biologicbehavior.

This study was designed to assess the association between natural variantsof HPV16 and the risk of biopsy-confirmed CIN 2 or 3. Prospective studieswere conducted with two populations: female university students aged 18to 20 years and females aged 16 to 47 years who sought treatment at a sexuallytransmitted disease (STD) clinic. All study participants were interviewedto obtain information on demographic characteristics, sexual behaviors,and history of STDs. Vaginal and cervical cell samples for HPV detectionand typing were collected at enrollment and approximately every 4 monthsthereafter. HPV16 variants found in the samples taken from study participantswere characterized according to their similarity to a reference, or prototype,HPV 16 sample. Variants with relatively few nucleotide alterations differentfrom the prototype were called prototype-like, while those with a greaternumber of alterations unlike the prototype were designated nonprototype-like.

A total of 123 women who met the study criteria (not having CIN 2-3at study entry and having at least one HPV16-positive visit either at studyentry or during follow-up) were included in the analysis. Prototype-likevariants accounted for 79% of the HPV 16 detected in the university studentsand 86% of the virus detected in patients attending the STD clinic. CIN2-3 was confirmed by biopsy in nine of 57 HPV16-positive females attendingthe university and in 10 of 66 HPV16-positive females at the STD clinic.Among university students, those with HPV16 nonprototype-like variantswere 6.5 times more likely to develop CIN 2-3 than those with prototype-likevariants. A similar association was observed among females at the STD clinic.

These results, say the authors, suggest that the risk of developingCIN 2-3 is not the same with all variants of HPV 16 and that nonprototype-likevariants confer a greater risk compared with prototype-like variants. However,add Xi and colleagues, the important genetic differences in these HPV16variants that underlie this increased risk of CIN 2-3 remain to be determined.

In the editorial accompanying this report, Allan Hildesheim, PhD, ofthe National Cancer Institute, suggests that the findings by Xi et al,though based on a small sample, may have important implications both forour understanding of the natural history of HPV-related anal and genitaldiseases and for our efforts to develop HPV vaccines. Hildesheim notesthat, since HPV infection has been confirmed as the main causal agent incervical cancer, recent research has focused on identifying factors thatinfluence the progression of HPV infection, including external and lifestylefactors (eg, other infectious agents, oral contraceptives); the currentresults suggest that viral variants may impart different risks of disease.