New advances in the prevention of cervical cancer: HPV type 16 vaccine

February 2003

Each year more than 450,000 cases of cervical cancer are diagnosed worldwide, making it the third most common malignancy among women. Approximately 200,000 of these cases result in death with 80% of these deaths occurring in developing countries that lack appropriate funding for cervical cancer screening. Persistent human papillomavirus (HPV) infection of the genital tract is well known to be the precipitating factor for cervical cancer.

Papillomavirus (PV) was first discovered in 1933 after being isolated from rabbits. Two years later, researchers determined that PV infection was associated with the progression to malignant tumors. The first human squamous cells linked to PV infection were discovered in 1956. There are more than 100 types of HPV and approximately half reside in the genital tract. HPV types 16, 18, 31, 33 and 45 are the predominant subtypes accountable for cervical cancer. The World Health Organization International Agency has categorized HPV types 16 and 18 as carcinogenic for Research on Cancer. HPV type 16 is identified as the causative factor in 50% of cervical cancer cases.

HPV is considered a sexually transmitted disease (STD) affecting basal cells of the skin epithelium and also mucous membranes. Over the last 40 years, HPV infection has been on the rise. More than 5 million cases are identified each year. This increase has been attributed to more women using oral contraceptives than barrier methods of contraception. Risk factors for acquiring HPV are similar to those risks for cervical cancer (see table).

Asymptomatic vs. symptomatic

Women can experience different presentations of HPV infection. Latent infection is asymptomatic and is only identified by diagnostic procedures. Symptomatic infections present with the occurrence of genital warts. Typically, cervical HPV infections clear spontaneously. However, persistent, asymptomatic, latent infection can develop into cervical neoplasms. Despite routine screening procedures for cervical cancer [ie, Papanicolaou (Pap) smear], only one-half of the cervical neoplasm cases are identified in women who undergo regular screening. Secondary to the increased incidence of cervical cancer and the rise in cervical cancer deaths worldwide, preventative measures against HPV infections are necessary.

The development of a vaccine against HPV first began in 1991. Species-specific virus-like particles from the papillomavirus were isolated and injected into animals resulting in protection against wart formation. An experimental vaccine that targets HPV type 16 was eventually developed and found to be well tolerated among patients in small studies.

Laura A. Koutsky, PhD, and colleagues were the first to conduct a double-blind, multicenter, randomized trial to examine the use of a vaccine to prevent HPV infections in women.

This study evaluated young non-pregnant women aged 16 to 23 with a history of normal Pap smears, and five or fewer male sexual partners over their lifetimes. Eligible patients were randomly assigned to receive either three intramuscular injections of HPV type 16 vaccine (n=768) or placebo (n=765). Injections were given on day zero, month two and month six. For five days after each injection body temperatures were recorded. Adverse events were documented by patients for 14 days post-injection and also evaluated by study clinicians at months two, six, and seven.

Baseline gynecologic exams included Pap smears and collection of cervical samples for HPV type 16 DNA testing. Patients had follow-up visits one month after the last vaccination, six months after the last vaccination, and every six months after that until month 48. At each follow-up visit, a Pap smear was performed as well as HPV type 16 DNA testing and antibody measurement. Those patients with abnormal Pap smears underwent either colposcopy or received the standard of care dependent upon the type of abnormal cells present.

The primary efficacy hypothesis was that the HPV type 16 vaccine would decrease the incidence of persistent HPV type 16 infections compared with the placebo vaccine. The primary endpoint of the study was persistent infection with HPV type 16 determined by the presence of HPV type 16 DNA in cervical samples at two or more visits.

Patients were followed for a median of 17.8 months post-vaccination. There were 41 cases of persistent HPV type 16 infection in the placebo group (31 cases without cervical neoplasia; nine cases associated with cervical neoplasia grade 1 or 2; one patient with a positive test for HPV type 16 DNA diagnosed for the first time) compared with zero cases in the vaccination group. Therefore, the infection rate per 100 woman-years at risk was 0% in the vaccination group versus 3.8% in the placebo group (P<0.001). After month seven, 74 women (six in the vaccination group and 68 in the placebo group) tested positive for HPV type 16 DNA on at least one occasion (secondary analysis; not statistically evaluated). An additional efficacy analysis included patients with protocol violations (population included women who received all vaccinations, were seronegative for HPV type 16 on day zero, negative for HPV type 16 DNA on day zero and month seven, and all biopsy specimens were negative between day zero and month seven). This analysis also demonstrated 100% efficacy of the vaccine with an infection rate per 100 women-year at risk of 0% despite the inclusion of patients that were noncompliant with the protocol specifications. In addition, tolerability of the vaccine was the same as placebo.

HPV type 16 vaccine is not yet available. However, this study provides strong evidence for the prevention of persistent HPV type 16 infections with immunization. One important consideration, however, is the limitation of the HPV type 16 vaccine in prevention of persistent infection. This vaccine targets a specific HPV subtype and does not necessarily protect against other HPV subtypes associated with cervical neoplasia.

Controversy

Many questions and ethical dilemmas have emerged as a result of this study. The establishment of an HPV vaccination program has been widely debated. Concerning issues include the length of efficacy of the vaccination, the need for revaccination, the appropriate age to start vaccination, how to approach vaccination in women who do not complete treatment, and the question of HPV resistance developing to the vaccine. Few conclusions can be made based on this study regarding length of efficacy of the vaccine and there are no long-term data to support efficacy over time. Answering the many questions that have surfaced is necessary before proceeding with public vaccination. In addition, it is necessary to consider development of vaccines against other causative subtypes (18, 31, 33 and 45). It is speculated that vaccination against these subtypes, including HPV type 16, prior to a woman becoming sexually active would reduce the incidence of cervical cancer by at least 85%.

The need to educate young women regarding protection against HPV infections should not be overlooked. Young women need to be told about risk factors for cervical cancer (see table) and the use of barrier contraception to decrease the risk of HPV transmission. While the use of barrier contraception may not prevent the spread of HPV entirely, it does decrease the likelihood of transmission and most importantly prevents the spread of other STDs. It is also important that young women understand the importance of being screened for cervical cancer (Pap smears).

For more information:

• Crum CP. The beginning of the end for cervical cancer? N Engl J Med. 2002;347(21):1703-1705.
• Jastreboff AM, Cymet T. Role of the human papillomavirus in the development of cervical intraepithelial neoplasia and malignancy. Postgrad Med J. 2002;78(918):225-228.
• Bosch FX, Lorincz A, Munoz N, et al. The causal relation between human papillomavirus and cervical cancer. J Clin Path. 2002;55(4):244-265.
• Cothran MM, White JP. Adolescent behavior and sexually transmitted diseases: the dilemma of human papillomavirus. Health Care Women Int. 2002;23(3):306-319.
• Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002;347(21):1645-1651.
• Harro CD, Pang YY, Roden RB, et al. Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst. 2001;93(4):284-292.

• Megan B. Bestul, PharmD, is a Primary Care Specialty Resident, University of Colorado Health Sciences Center, School of Pharmacy, Denver.