As more and more promising results of clinical trials on vaccination against human papillomaviruses are published, the more likely it becomes that an HPV vaccine will be the first licensed immunization against a sexually transmitted disease.
Because University of Alabama at Birmingham researchers are aware of the enormous implications and global impact such a vaccine would have, they are attacking the issue in full force.
“If we could vaccinate women early, we could hopefully prevent the development of a very large proportion of cervical cancer 20, 30 or 40 years down the road,” says Dr. Warner Huh, assistant professor in the UAB Division of Gynecologic Oncology and associate scientist in the UAB Comprehensive Cancer Center.
UAB researchers, including Huh and Drs. Ronald Alvarez, Sharmila Makhija and J. Michael Straughn, are participating in four clinical trials addressing HPV vaccine efficacy and reliable testing methods. Collectively, more than 30,000 women will be enrolled internationally and as many as 50 academic medical centers will be involved. UAB will serve as a major enrollment site for two of the national clinical trials.
The Link Between HPV and Cervical Cancer
Women’s health research over the last 30 years has definitively shown that cervical cancer is linked to the sexually transmitted HPV. Over the course of an adult woman’s lifetime, on average she has a 70 percent chance of acquiring HPV. There are more than 200 strains of HPV. Most are harmless and most infections clear spontaneously. However, some strains are more harmful and can lead to genital warts or the development of abnormal cervical cells, a condition known as cervical dysplasia. If left untreated, dysplasia can progress to cervical cancer — of which HPV types 16 and 18 account for 70 to 75 percent of all cases.
Although cervical cancer rates declined dramatically following the widespread implementation of the Pap test (Papanicolaou test or Pap smear — a screening tool used to detect early and abnormal cell changes), there are still many women who are unable to obtain annual Pap smears, as recommended by the American College of Obstetricians and Gynecologists and the American Cancer Society. Because cervical cancer is most often asymptomatic until its late stages, detection for these women often comes too late. In the United States, 11,000 women are diagnosed with cervical cancer annually. But in underdeveloped countries and even in some underserved, rural areas of the United States, including medically underserved portions of Alabama, cervical cancer is considered one of the most deadly cancers for women.
The Clinical Trials
The creation of a safe and effective vaccine against HPV could significantly reduce access to care issues and reduce the need for annual exams. Evidence already exists to support the efficacy of some vaccine strategies, including a study published in the November 13 issue of The Lancet. The study, whose senior author was Diane Harper of Dartmouth Medical School, assessed the efficacy and safety of a HPV 16/18 virus-like particle vaccine in just over 1,100 young women. The research vaccine is manufactured by GlaxoSmithKline. Researchers found the vaccine was 91.6 percent effective against incident infection and 100 percent effective against persistent infection, according to the study’s authors.
Currently, the UAB Comprehensive Cancer Center is recruiting patients for three clinical trials and following enrolled patients in a fourth clinical trial, all of which examine the role of HPV in cervical cancer. Specifically, three are looking at the effect the vaccines have on HPV, including the phase III follow-up trial of the vaccine developed by GlaxoSmithKline. The fourth trial examines the use and efficacy of Pap tests for HPV testing and is sponsored by Roche.
Huh stresses that patients who participate in the trials are not at risk of contracting HPV. “These vaccines don’t have the pre-malignant or malignant DNA. The vaccines only contain the outer shell of the virus, so there is no risk of getting an HPV infection from the vaccine,” he explains.
The trial studying the GlaxoSmithKline vaccine focuses on preventing persistent infection with a vaccine that specifically targets HPV 16 and 18 strains. Internationally, more than 28,000 women will be enrolled, including 200 at UAB, making UAB one of the larger enrollment sites for the study. The trial targets women between 19 and 25 from every populated continent except Australia.
During the study, women will receive three vaccinations within the first six months and then participate in 10 follow-up visits over a four-year period. Women randomized to the control group will receive a hepatitis A vaccine, but all women will be given the option to receive the HPV vaccine at the end of the clinical trial. Volunteers interested in enrolling can call (205) 975-7223.
A focused trial sponsored by Merck Research Laboratories is similar to the GSK trial, but instead targets patients between 24 and 45. In this trial, researchers will examine what is called a quadrivalent vaccine that targets HPV strains known to lead to genital warts and cancerous changes. The study will enroll 2,800 patients worldwide and 50 have been enrolled at UAB. Like the GSK trial, women will receive three vaccinations within the first six months, but will be followed through nine scheduled visits over a period of three years.
National Cancer Institute Trial
The third trial is offered through the National Cancer Institute’s (NCI) Gynecologic Oncology Group. The trial will study a heat-shock protein E7 protein vaccine. E7 is one of the two oncogenes expressed by HPV necessary to convert healthy cells into cancerous ones. Unlike other cancers, all cervical cancers express one of the two oncogenes — making the genes easy targets for a vaccine.
Eligible participants must be diagnosed with severe cervical dysplasia and be HPV 16-positive. “As much as half of all women with cervical cancer or dysplasia are HPV 16 positive,” Huh says. For those who meet the study criteria, they will receive three vaccinations over an eight-week period. They will then undergo a surgical biopsy procedure at the end of the trial (approximately 15 weeks) to determine whether resolution has occurred. UAB is one of only three institutions participating in this study, along with the University of Texas Southwestern Medical Center and the University of Arizona in Tucson.
On The Global Front
In addition to UAB researchers’ domestic work on HPV testing and prevention, some Cancer Center faculty are extending their efforts to fight cervical cancer around the globe. Because the disease is one of the leading causes of death for women in developing countries — where pap smears are not nearly as routine as in the United States — UAB has formed several international partnerships to tackle the daunting numbers of HPV infection.
Cancer Center Associate Scientist Sharmila Makhija, M.D., assistant professor of gynecologic oncology, is leading efforts to establish cervical cancer clinical trials in India, where cervical cancer is the third leading cause of death. Working with the Gynecologic Oncology Group (GOG), a national cooperative group, Makhija has established partnerships with the Indian government and with the elite Tata Memorial Hospital in Bombay. She hopes the alliance will not only bring cutting-edge therapy to a population with high rates of the disease, but also educate physicians about the importance of regular screening.
“In many ways, our efforts in India are similar to efforts in rural Alabama,” Makhija said. “This is a poor population that often doesn’t have access to care. Taboos still exist that cancer is a ‘curse.’ Even the wealthy do not regularly receive Pap tests. We must educate the physicians about the importance of screening.”
Makhija has visited India twice this year to establish partnerships necessary to launch the initiatives. Once the protocols have been established, she will visit yearly to supervise the efforts and lead a campaign to educate Indian women about the importance of regular Pap tests. Working with Indian media and film personalities, she hopes to dispel the myths that surround cervical cancer.
Makhija is joined by Vikrant Sahasrabuddhe, M.Ph., a post-doctoral fellow in the UAB School of Public Health. Upon completion of his fellowship, he will move back to India to oversee efforts. In addition, he has received a $250,000 grant from the National Institutes of Health to examine HIV and cervical cancer in Indian women.
Cancer Center Senior Scientist Groesbeck Parham, professor of gynecologic oncology, is spearheading similar efforts in Zambia, where one in four women have the virus that causes AIDS. Thanks to $15-million in U.S. federal funds, more African women are receiving antiviral drugs to delay the onset of AIDS. However, as these women live longer, more and more cases of cervical cancer will progress.
Prior to Dr. Parham’s work, there was no widespread program of cervical screening in Lusaka — in fact, there was only one gynecologist in the nation, and he was barely equipped to diagnose and treat the disease. As part of a grant through UAB’s Center for AIDS Research, Parham established a cervical cancer clinic through Lusaka’s University Hospital. He brought equipment and technology to diagnose the disease, and embarked on a mission to teach more physicians how to diagnose pre-invasive and invasive cervical cancer.
“We have been able to bring them technology, raise the skill level of physicians and educate others about the importance of screening for the disease,” Dr. Parham says. He is currently completing a study to determine the most accurate, cost-effective method of screening HIV positive women for cervical cancer in the city of Lusaka. Data is preliminary, but one fact is striking: out of 150 women who are HIV positive, half of them have evidence of invasive cervical cancer or high-grade squamous lesions, abnormal and potentially pre-cancerous cells.
To address this issue, Dr. Parham continues to spend time in Africa (about three months annually) to help women and train health professionals. In addition to teaching physicians how to screen, diagnose and treat the disease, he is working to secure grant money to establish innovative public health efforts to reach Zambia’s citizens. Ultimately, he would like to create a program similar to the Cancer Center’s Deep South Network, which empowers African-American community leaders in Alabama and Mississippi to teach their communities about the importance of early cancer detection and prevention. The program would be called ZHAN, the Zambian Health Advisor Network, and would also work to dispel myths that surround cervical cancer and other diseases.