Ronald D. Alvarez, MD
Professor, Obstetrics and Gynecology
Chairman's Office, Department of Obstetrics and Gynecology

Warner K. Huh, MD
Assistant Professor, Obstetrics and Gynecology
Chairman's Office, Department of Obstetrics and Gynecology

Sharmila K. Makhija, MD
Associate Professor, Obstetrics and Gynecology
Chairman's Office, Department of Obstetrics and Gynecology

Edward E. Partridge, MD
Professor, Obstetrics and Gynecology
Chairman's Office, Department of Obstetrics and Gynecology

The University of Alabama at Birmingham
Birmingham, Alabama

In accordance with the Accreditation Council for Continuing Medical Education Standards for Commercial Support, the faculty report the following affiliations:

Ronald D. Alvarez, MD - grants/research support and honoraria from GlaxoSmithKline, Inc (GSK)

Warner K. Huh, MD - grants/research support from Merck, GSK, Cytyc and Roche Molecular Systems; consultant/honorarium from GSK, Merck, Cytyc, Roche Molecular Systems, MGI Pharma Biologics

Sharmila K. Makhija, MD - grants/research support from GSK, Genentech, Merck; consultant for GSK, Angstrom, Tibotec

Edward E. Partridge, MD has no conflicts of interest to disclose.

The University of Alabama School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The University of Alabama School of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The boards of nursing in many states, including Alabama, recognize Category 1 continuing medical education courses as acceptable activities for the renewal of license to practice nursing.

In June 2006, the US Food and Drug Administration approved Merck’s Gardasil (Quadrivalent Human Papillomavirus [HPV] Types 6, 11, 16, 18 Recombinant Vaccine), to prevent cervical cancer and lesions caused by HPV types 6, 11, 16, and 18. HPV type 16 causes an estimated 50% of cervical cancers worldwide, and type 18 contributes another 20% (Science. 2005;308:618-621). International studies confirmed the vaccine was virtually 100% effective for a 5-year period in preventing HPV-16 and HPV-18 infection.

“This is the first recombinant vaccine to prevent most cases of cervical cancer,” says UAB Comprehensive Cancer Center Interim Director Edward E. Partridge, MD. He and coprincipal investigator Sharmila K. Makhija, MD, compared Gardasil to placebo in UAB’s arm of the International Females United to Unilaterally Reduce Endo-ectocervical Disease II study of the vaccine’s safety, efficacy, and immunogenicity.

UAB Comprehensive Cancer Center Associate Scientist Warner K. Huh, MD, is principal investigator for a large pivotal phase 3 study of a GlaxoSmithKline HPV vaccine that has shown comparable efficacy to the recently approved Merck product.

“We have a real opportunity to dramatically decrease cervical cancer and its precursors with the HPV vaccine, particularly worldwide,” he says. “Without question, this vaccine is the most significant advance and achievement in cervical cancer screening and prevention since the Pap smear. It is our hope that all adolescents and appropriate women between 19 and 26 years of age will have access to this vaccine.”

Common Culprit

HPV is one of the most common sexually transmitted diseases (STDs) in the world, often traveling between partners asymptomatically. Twenty million Americans are currently infected, and 5.5 million new cases are reported annually. “The 4 strains selected for the vaccine represent the most common culprits in HPV infection,” Huh explains.

“Persistent infection with HPV-16 and HPV-18 is associated with increased risk of developing cervical dysplasia that can lead to cervical cancer,” he says. “HPV 16 is associated with squamous cell cervical cancers, and type 18 with glandular cell forms. Together, HPV-6 and HPV-11 cause more than 90% of genital warts.”

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) recommends the approved vaccine be given routinely to girls beginning at age 11 to 12 years, with a “catch-up” vaccine for women aged 13 to 26 years, and allowances for girls as young as 9 years, at the discretion of health care providers. In July 2006, the American Academy of Pediatrics issued guidelines mirroring ACIP recommendations. Pap and HPV screening prior to vaccination are not necessary.

The vaccine requires 3 intramuscular injections within 6 months. The vaccine works by using genes that code for a specific protein from each of the 4 HPV viral types.

Approximately 21,000 women aged 16 to 26 years participated in 3 international and 1 US trial of the recently approved vaccine. Two additional studies measured immune response in females aged 9 to 15 years; their immune response was similar to that found in the those aged 16 to 26 years, indicating similar efficacy.

In women not infected with HPV, the vaccine was nearly 100% effective in preventing precancerous cervical lesions, precancerous vaginal and vulvar lesions, and genital warts caused by infection with HPV-16 and HPV-18. Because there are more than 100 different types of HPV, including 30 strains typically transmitted through sexual contact, the vaccine is estimated to prevent only 70% of cervical cancers. The drug does not protect against less common HPV types and is no substitute for routine gynecological care, including Pap smears.

“Women should still continue regular screening methods to detect precancerous cervical changes or HPV-related symptoms as part of their routine physical exams,” Makhija says. “Although relatively few women who have HPV infection go on to develop cervical cancer, all cases of cervical cancer result from high-risk HPV infection.”

As liaison for the National Cancer Institute’s Gynecologic Oncology Group collaboration between UAB’s Division of Gynecologic Oncology and Tata Memorial Hospital in Mumbai, India, Makhija is investigating the potential benefit of yet another Merck HPV vaccine in women aged 25 to 45 years, which Merck is working to provide to Indian women at reduced cost.

The HPV vaccine is recommended but not required as part of a routine immunization program. Some conservative parental groups have indicated concerns that a preventive HPV vaccine administered prior to onset of sexual activity could suggest permission or approval for promiscuity, or “sabotage” abstinence messages. However, an ACIP member who is a former medical advisor for the evangelical nonprofit agency Focus on the Family voted to approve the vaccine. Health officials suggest parents take the opportunity to discuss the vaccine and risky sexual behavior with their children. Early intercourse and multiple partners dramatically increase chances of acquiring an STD and its potential long-term complications.

Youth Risk Behavior Surveillance System data show that about 4% of girls and 10% of boys have had sex before age 13 years. More than 32% of youths have had sex by ninth grade, and nearly 62% have had sex by their senior year (MMWR. 2006;55[SS-5]1-108). The incidence of HPV among American teens is highest in those aged 14 to 17 years.

The HPV vaccine is preventative, not curative; immunizing is most effective in preteen years, when the vaccine produces safe and effective titers and children are less likely to engage in sexual activity.

The American Cancer Society estimates more than 3500 women in the United States die each year from cervical cancer, despite advances in screening methods that have cut death rates from the disease by nearly 75% since 1955. However, cervical cancer is the second most commonly diagnosed cancer in women in the developing world, where Pap tests are not easily afforded or effectively administered.

A full series of HPV vaccine costs $360, more than a woman’s annual salary in undeveloped areas of the world, and an extravagant sum for many in the United States. The HPV vaccine’s price tag places it among the most expensive vaccines on the market today. In Alabama, cervical cancer rates are higher than national averages, and prevalence is particularly high among the state’s African American women. As the HPV vaccine becomes more widely available, pharmaceutical companies and government programs will face increased pressure to provide such valuable preventive strategies to those who need them most.

“This vaccine represents the first opportunity to help in parts of the world where access to cervical cancer screening is limited. Screening has dramatically reduced cervical cancer rates in the US, but the vaccine will further reduce risk for American women, and may have a dramatic impact on cervical cancer rates worldwide,” Huh says.

A safety and efficacy trial of the approved vaccine in adolescent boys is currently underway. Because men do not present with precancerous lesions following exposure to HPV, and penile cancer is rare, measuring the vaccine’s impact on men will be difficult. Men are involved in HPV transmission, however, so the vaccine could eventually become routine for both sexes, though Huh cautions it is too early to advise administering the vaccine outside ACIP guidelines.

Some experts suggest a vaccine similar to the current quadrivalent formulation could protect against anogenital neoplasias in both sexes, paving the way for a new generation of preventive medicines or effective therapies for cancers that begin with exposure to STDs.

“UAB has extensive experience investigating HPV vaccines as preventive strategies, and we are now conducting therapeutic vaccine trials in women who have already been exposed to HPV and have developed preinvasive disease. Unlike the recently approved vaccine, which induces an antibody response, these experimental therapeutic formulations focus on stimulating cell-mediated immunity,” Huh concludes.

For more information:

Dr. Warner Huh
Dr. Edward Partridge
Dr. Sharmila Makhija
1-800-UAB-MIST
mist@uabmc.edu

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