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| SUMMER 2009 EDITION |
Contents Article Section Clinical Impact of HPV 16 and 18 | Thomas C. Wright, Jr., MD Frequently Asked Questions #1: Has vaccination against HPV using the quadrivalent vaccine caused the death of some vaccine recipients? #2: My patients frequently tell me they have read on the web that they could have gotten infected with HPV by causal contact with an infected individual. Is this possible? #3: Does the web provide a good source of accurate HPV information for my patients? Clinical Impact of HPV 16 and 18 Thomas C. Wright, Jr., MD Now that we have both a vaccine capable of preventing infection with HPV 16 and 18 as well as an FDA-approved genotyping assay for both HPV 16 and 18, clinicians are frequently asking whether HPV 16 and 18 are truly more pathogenic than the other 13 high-oncogenic-risk HPV types. Based on the literature, the answer is clearly yes. A recent meta-analysis that evaluated all the studies investigating associations between specific types of HPV and high-grade cervical neoplasia found that irrespective of geographic area, HPV 16 is by far the most common type of HPV associated with either invasive cervical cancer or CIN 2, 3.1 In North American studies, HPV 16 was associated with 54% of invasive cervical cancers and 45% of all CIN 2, 3 lesions. Although HPV 18 is the second most common high-oncogenic-risk HPV type found in cervical cancers both worldwide and in North America (found in 16% and 22%, respectively), it is not particularly common in high-grade precursor lesions. HPV 18 was found in only 6% of CIN 2, 3 lesions in Europe and 10% of those from North America. Not only do cross-sectional studies of the association of HPV 16 and 18 with high-grade cervical neoplasia indicate that these are the most common types of HPV found in these lesions, but prospective follow-up studies clearly show that women infected with HPV 16 or 18 have the greatest risk of subsequently developing CIN 3 lesions. In the National Cancer Institutes Kaiser, Portland, OR follow-up study, the 10-year cumulative incidence rate of ≥ CIN 3 was 17.2% among women who were found to be positive for HPV 16 at enrollment into the study.2 The cumulative incidence rate of > CIN 3 lesions was 13.6% for women infected with HPV 18, but the > CIN 3 lesions took longer to develop in the HPV 18 infected women compared to women infected with HPV 16. For comparison, it was only 3% in women infected with other (non 16, 18) high-oncogenic-risk HPV types after 10 years of follow-up. Other prospective follow-up studies have found similar results. In a study of college students in Seattle, Winer et al. found that the 36- month cumulative incidence of CIN 2,3 lesions was 27% in women with incident HPV 16 or 18 infections.3 In contrast, it was only 11% in women with any incident HPV infection. In fact, many researchers have now concluded that HPV 16 is remarkably carcinogenic. The absolute risk that an HPV 16-infected woman will develop CIN 2, 3 or cancer reaches 40% after she has been persistently infected with HPV 16 for 3-5 years.4 What does this all mean for the practicing clinician? The most important implication of the finding that infection with HPV 16 and 18 confers a particularly elevated risk for developing high-grade cervical neoplasia is that clinicians need to make every effort to assure that all females between 11 - 26 years of age are vaccinated against HPV 16 and 18. Both the quadrivalent and the bivalent HPV vaccines (not yet approved for use in the U.S.) have been shown to be remarkably effective in preventing infection by HPV 16 and 18 and vaccination of women prior to being infected with HPV 16 and 18 essentially eliminates the risk that they will develop an HPV 16 or 18 associated cervical or vulvar neoplasia. Another important implication is that when women > 30 yrs are found to be high-oncogenic-risk HPV positive during routine cervical cancer screening, determining whether or not the patient is infected with HPV 16 or 18 will be useful in determining her risk for having CIN 2,3. 1. Smith JS, Lindsay L, Hoots B, et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer 2007;121(3):621-32.< 2. Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst 2005;97(14):1072-9. 3. Winer RL, Kiviat NB, Hughes JP, et al. Development and duration of human papillomavirus lesions, after initial infection. J Infect Dis 2005;191(5):731-8. 4. Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet 2007;370(9590):890-907.  Question #1: Has vaccination against HPV using the quadrivalent vaccine caused the death of some vaccine recipients? The Vaccine Adverse Events Reporting System (VAERS) is a national vaccine safety surveillance program co-sponsored by the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA). VAERS was established in 1990 and is specifically designed to capture adverse events following vaccination. By monitoring adverse events, VAERS helps to identify any important safety concerns associated with vaccination to ensure that the benefit of vaccination greatly outweighs any potential risks. The majority of reports to VAERS come from the vaccine manufacturers (42%) and health care providers (30%). The remaining reports are from state immunization programs (12%) or vaccine recipients and/or parents (7%) and other sources (9%). Because of concerns raised in the media about the safety of the quadrivalent vaccine, the CDC recently completed a full review of all the quadrivalent vaccine adverse events reported to VAERS. The CDC report can be found at http://www.cdc.gov/vaccinesafety/vaers/gardasil.htm. As of December 31, 2008, more than 23 million doses of the quadrivalent vaccine had been distributed within the U.S. and 11,916 VAERS reports of adverse events had been made. Of these, 94% were considered to be non-serious and 6% were considered to be serious. The most common non-serious events were fainting, pain and swelling at site of injection, headache, nausea and fever. After having carefully analyzed the serious adverse events, no common medical pattern was found to the reports that would suggest that they were caused by the vaccine.
2. Blood clots: Rarely, blood clots have been reported after the use of quadrivalent vaccine. Most of the individuals developing blood clots had a risk factor, such as taking oral contraceptives. 3. Deaths: As of December 31, 2008, there were 32 reports in the U.S. of death among vaccine recipients. However, there is no common pattern to the deaths that would suggest that they are related to vaccination. Deaths have been associated with viral illness, cardiac disease, diabetic ketoacidosis, drug overdose, and idiopathic seizure disorders. However, a number of the deaths are either of unknown cause or incompletely evaluated. Question #2: My patients frequently tell me they have read on the web that they could have gotten infected with HPV by causal contact with an infected individual. Is this possible? Anogenital HPV infections are highly infectious and are readily transmitted between individuals. However, there is very good data to indicate that anogenital HPV infections are almost always transmitted by close sexual contact that involves direct mucosa-to-mucosa or skin-to-skin contact. Support for the necessity of close sexual contact comes from prospective follow-up studies of college students and virginal women. In one prospective study of 444 HPV DNA negative Seattle college students, the cumulative 24-month incidence of HPV infection during follow-up was 39% in those who were sexually active.1 In contrast, the cumulative 24-month incidence among women who remained virgins throughout the course of the study was only 2.4%. Although nonpenetrative sexual contact was not associated with an increased risk of infection in sexually active women, nonpenetrative sexual contact (finger-vulvar, penile-vulvar, or oral-penile) was associated with an increased risk of genital HPV infection in virgins. Among virgins who reported some form of nonpenetrative sexual contact, 7 of 72 (9.7%) tested HPV positive, whereas only 1 of 76 women (1.3%) who reported no sexual contact tested HPV positive. Among 82 virginal women who reported their first sexual intercourse either during the study or within two weeks of enrolling in the study, the incidence of anogenital HPV infection was 89.3 per 100 person years among women who only rarely used condoms during sexual intercourse and 37.8 per 100 person years among those who used condoms during all acts of intercourse.2 Therefore, the use of condoms significantly reduces, but does not eliminate, the risk of anogenital HPV infection. 1. Winer RL, Kiviat NB, Hughes JP, et al. Development and duration of human papillomavirus lesions, after initial infection. J Infect Dis 2005;191(5):731-8. 2. Winer RL, Hughes JP, Feng Q, et al. Condom use and the risk of genital human papillomavirus infection in young women. N Engl J Med 2006;354(25):2645-54. Question #3: Does the web provide a good source of accurate HPV information for my patients? A recent Google search of "HPV" revealed 6,650,000 records, so clearly the web can be either an excellent source of information about HPV or a very bad one. The following two websites provide your patients with excellent information that is both accurate and not commercially-biased.
The CDC has produced a series of excellent, up-to-date brochures for patients that list just about everything they need to know about HPV infections. These can be downloaded as PDFs at: http://www.cdc.gov/STD/HPV/common/default.htm. The American Social Health Association The ASHA website has a considerable amount of information about HPV infections and vaccination against HPV. The information on the ASHA website is very patient friendly and is particularly good for college students and young women. The ASHA HPV website can be reached at: http://www.ashastd.org/hpv/hpv_overview.cfm.    |
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