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.

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

* 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

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.