Long-term study sorts out the risks for HPV infection and cervical lesions

More than half of sexually active young women will be infected with human papilloma virus (HPV) if they remain sexually active over three years, a UCSF study shows. That risk is boosted 10-fold with each new partner.

Contrary to some previous research, the study reported in the June 20 issue of the Journal of the American Medical Association showed that once a woman is infected with HPV, she is not certain to develop benign changes in the cells of the cervix called LSIL, or low-grade squamous intra-epithelial lesions. Approximately 30 percent of study subjects developed LSIL over a period of five years. The level of sexual activity or presence of other sexually transmitted diseases did not, as earlier studies seemed to show, increase a woman's risks of LSIL - HPV infection itself was the major identifiable cause, with an additional boost from daily cigarette smoking.

The report comes from the longest-running longitudinal study of women and human papilloma virus, a National Cancer Institute-sponsored project now in its 11th year. Anna-Barbara Moscicki, MD, UCSF professor of pediatrics, and her colleagues have followed a cohort of adolescents and young women since relatively early in their sexually active lives. Using frequent medical exams and laboratory tests, they are tracing the natural history of HPV and the benign and sometimes cancerous lesions that it causes.

Human papilloma virus is the most common sexually transmitted disease, infecting more than five million Americans each year, according to the American Social Health Association. HPV is considered to be the main cause of LSIL and other lesions in the cervix, including cancer. The American Cancer Society estimates that there will be about 12,900 new cases of invasive cervical cancer in the United States in 2001. While early detection and treatment saves many women's lives, about 4,400 will die this year from the disease.

"We know little about the progression of HPV to cervical cancer. This longitudinal study tells us something about the beginning of the story," Moscicki said. Her project continues to follow women with LSIL and with other cell changes including high-grade squamous intra-epithelial lesions (HSIL).

"Our data show that some biological and behavioral risks thought to be associated with LSIL are in fact risks for the acquisition of HPV," she said. "This report also supports earlier work from our group and others, showing that HPV is necessary but not sufficient by itself to cause these lesions. Other behavioral and biological factors must be involved, most likely persistence of the viral infection, and the woman's own immune reaction."

Most data on LSIL and other HPV-caused lesions comes from cross-sectional studies comparing women with lesions against women without lesions. These have not been able to sort out which risks boost a woman's chances of infection with the virus, and which are associated with a progression of HPV infection to cervical lesions, Moscicki said, because all women with LSIL have HPV and those without LSIL are less likely to be infected with the virus.

Since 1990, Moscicki's group has followed a cohort of more than 800 adolescents and young women who attended family planning clinics. So far, they have overturned a number of assumptions about HPV. Most strikingly, they have shown that for most young women, HPV is not necessarily a life-long infection. Most appear to clear the virus from their bodies.

JAMA STUDY RESULTS

The report in JAMA addresses one of the original aims of the longitudinal study: to sort out the factors that lead some women to develop LSIL, usually the earliest cell changes caused by HPV. Moscicki's group collected data from women who did not have LSIL at the time they enrolled in the study, including 105 who were not infected with HPV and 496 who were HPV positive. The women were followed for a median of five years. Every four months for HPV positive women and every six months for those who were HPV negative, Moscicki and her colleagues combined comprehensive gynecological exams with laboratory tests. They performed a colopscopy exam using a magnifying instrument to search for lesions on the cervix and nearby areas. This allowed them to identify early signs of LSIL and also to identify women who developed HSIL or carcinoma in situ. The scientists tested for HPV and other sexually transmitted diseases. They used DNA testing with PCR amplification to determine whether a woman was newly infected or remained infected, and to identify particular strains of HPV.

They found good and bad news about HPV infection and LSIL, Moscicki said:

- Over 36 months, 55 percent of sexually active young women who did not have HPV became infected.

- Women who took oral contraceptives cut their relative risk of HPV infection in half. This good news must be tempered by the fact that other research shows a long-term association between oral contraceptives and cervical lesions, the researchers warned.

- Each new sexual partner per month increased a woman's risk of HPV infection by 10 fold - four new partners meant a 40-fold increase.

- Infection with herpes simplex virus also increased the risk, as did a history of vulvar warts. These other sexually transmitted diseases may influence immune response or create lesions that make it easier for HPV to start new infections, the researchers said.

- Previous results from the same study showed that up to 90 percent of young women clear the HPV virus from their systems within 36 months. However, many become reinfected.

The study was the first to show the time lapse from HPV infection to signs of LSIL:

- A woman's chances of developing LSIL are greatest in the first year after HPV infection, and remain high in the second and third year. The relative hazard leveled off after the fourth year.

- When followed for 60 to 80 months, 70 percent of HPV-infected women did not develop LSIL. Most women who developed LSIL later cleared the lesions.

- Daily cigarette smoking increased the chances that HPV infection would lead to LSIL. Cigarettes' role in cancer is well documented. The association with LSIL may reflect an influence on the immune response to the virus, Moscicki said.

Moscicki is professor of pediatrics in the department of adolescent medicine at UCSF and a clinician in adolescent medicine with UCSF Children's Medical Center, part of the UCSF Medical Center. Her co-authors on the JAMA article include: Stephen Shiboski, PhD, UCSF associate professor of biostatistics; Nancy Hills, MA, biostatistician in the UCSF Department of Pediatrics, Joel Palefsky, MD, UCSF professor of medicine in the department of stomatology and an expert on human papilloma virus; Teresa Darragh, MD, UCSF associate professor of medicine in the department of anatomic pathology and an expert on cancer cytology; Kim Powell, NP, Naomi Jay, NP, Evelyn Hanson, NP, Jeanette Broering, NP - nurse practitioners who cared for patients and participated in patient examinations during the study; Susanna Miller, BA, the study coordinator who cared for many of the subjects, Lisa Clayton, UCSF data manager and Sepideh Farhat, MS, lead technician of the Moscicki laboratory.