UAB Synopsis, Vol. 24, No. 6, February 21, 2005

GYN Oncologists Test HPV Vaccine

Three decades of research have defined the link between sexually transmitted HPV (human papilloma virus) and cervical cancer. As promising results from HPV clinical trials are published, it is likely that a HPV vaccine will be the first licensed immunization against a sexually transmitted infection. UAB researchers, aware of the enormous implications and global impact of such a vaccine, are attacking the issue full force.

"Early vaccination could prevent a large proportion of cervical cancer cases in the future," says Warner Huh, MD, assistant professor in UAB's Division of Gynecologic Oncology and associate scientist in the UAB Comprehensive Cancer Center. UAB researchers, including Dr. Huh, Ronald Alvarez, MD, Sharmila Makhija, MD, and J. Michael Straughn, MD, are now participating in four clinical trials addressing HPV vaccine efficacy and reliable testing methods. Collectively, more than 30,000 women will be enrolled internationally, involving as many as 50 academic medical centers. UAB will serve as a major enrollment site for two national clinical trials.

Efficacy/Safety/Reliability

Women have, on average, up to a 70% chance of acquiring 1 of HPV's more than 200 strains. Most infections clear spontaneously. However, some strains lead to genital warts or cervical dysplasia; if left untreated, dysplasia can progress to cervical cancer — of which HPV types 16 and 18 account for up to 75% of all cases. Because cervical cancer is most often asymptomatic until late stage and many women here and abroad are unable to obtain annual Pap smears, detection often comes too late. In the United States, 11,000 women are diagnosed with cervical cancer annually. But in underdeveloped countries and even in rural America, including portions of Alabama, cervical cancer is one of the most deadly female cancers.

Evidence supports the efficacy of some vaccines, including a study published in The Lancet (2004;364:1757-1765). Senior author Diane Harper of Dartmouth Medical School assessed the safety and efficacy of a HPV 16/18 virus-like particle vaccine in some 1,100 young women. GlaxoSmithKline manufactures the research vaccine. Investigators found it 91.6% effective against incident infection and 100% effective against persistent infection, according to study authors.

Now, the Cancer Center is recruiting patients for three clinical trials and following enrolled patients in a fourth. Specifically, the first three are looking at the effects of HPV research vaccines, including a phase 3 follow up of the vaccine developed by GlaxoSmithKline. The fourth trial, sponsored by Roche, examines the efficacy of polymerase chain reaction HPV testing. Nearly 19,000 women nationwide and 2,700 here will be enrolled in the fourth and largest trial. UAB is one of the major enrollment sites for Roche Molecular Systems' national clinical trial, designed to evaluate Roche's AMPLICOR HPV test for high-risk HPV infection in Pap smear-screening specimens. Women with both normal and abnormal Pap tests will be recruited for this study, whose ultimate goal is to determine clinical management when Pap tests yield an abnormal result and HPV is present.

"The AMPLICOR HPV test will determine if the patient is positive or negative for a high-risk HPV," Dr. Huh says. "By also performing Roche's linear array genotyping test (for investigational use only) in this trial, additional information will be generated that determines a woman's specific strain of HPV. Potentially, if a patient over age 30 has a normal Pap smear and a negative high-risk HPV test, she can be screened every 3 years instead of every year."

Dr. Huh adds the primary benefit is to explore alternative testing methods. Although the study lasts 7 years, it requires only one visit and no additional tests.

Not at risk

Dr. Huh stresses that patients who participate in the trials are not at risk for contracting HPV. "The vaccines we use don't have premalignant or malignant DNA. They contain only the outer viral shell, removing risk of infection," he explains.

Eligible participants must be HPV 16 positive and diagnosed with severe cervical dysplasia. "Half of all women with cervical cancer or dysplasia are HPV 16 positive," Dr. Huh says. Eligible patients will receive three vaccinations over an 8-week period and undergo a surgical biopsy at approximately 15 weeks to determine whether resolution has occurred. UAB is 1 of only 3 institutions in this study, along with the University of Texas Southwestern Medical Center and the University of Arizona in Tucson.

The Global Front

Cancer Center faculty also are fighting cervical cancer around the globe. In developing countries — where Pap smears are seldom routine — UAB has formed international partnerships to tackle daunting rates of cervical cancer. In India, it is the third leading cause of death among women (after auto accidents and cardiovascular disease), and Cancer Center Associate Scientist Makhija is leading efforts to establish cervical cancer clinical trials. Working with the national cooperative Gynecologic Oncology Group (GOG), she has established an official partnership — formally ratified in January — with the Indian government and Bombay's elite Tata Memorial Hospital. She hopes the alliance will not only bring the latest therapy but also educate physicians. She is working in collaboration with Vikrant Sahasrabuddhe, MPH, a postdoctoral fellow in the UAB School of Public Health (SOPH), and SOPH Professor of Epidemiology and Director of the Sparkman Center for Global Health Sten Vermund, MD, PhD, who also share the grant.

"In many ways, efforts in India are similar to those in rural Alabama," Dr. Makhija notes. "This is a poor population that often lacks access to care. Local taboos still insist cancer is a 'curse.' Even the wealthy seldom receive regular Pap tests. Above all, we must educate the physicians about the importance of regular screenings."

Dr. Makhija visited India twice in 2004 to establish partnerships and launch the initiative. Now that the protocol has been formally established, she will travel there yearly to supervise efforts and lead a campaign to educate Indian women about the importance of regular Pap tests. Working with Indian media and film personalities and Sahasrabuddhe, she also hopes to dispel the terrible myths surrounding cervical cancer. Upon completion of his fellowship, Sahasrabuddhe will move back to India to oversee such efforts and pursue his $250,000 grant from the National Institutes of Health to examine HIV and cervical cancer in Indian women.

"This work is critically important because we want to help women around the world," Dr. Makhija concludes. "Every life is precious."

Coming up: Read about HPV vaccine efforts in Africa