With the availability of vaccines against Human papillomavirus (HPV), there has been a surge of information about this infection in both the scientific and lay press. Medical-care providers desire more detailed information about HPV in order to answer the questions frequently posed by their patients and their parents or guardians. It’s important to have a thorough and accurate understanding of the incidence/prevalence; risk factors for infection; pathophysiology; disease consequences of infection; updated screening guidelines for disease detection; and the latest information about HPV immunization, including the Advisory Committee on Immunization Practices guidelines; efficacy in both viral-naïve and non-naïve populations; persistence of cross-neutralizing antibody levels; delayed anamnestic response to viral challenge; and potential adverse events from vaccine.
HPV infection is the most prevalent sexually transmitted infection (STI) in the United States. It is currently estimated that there are about 6.2 million new cases annually; about 20 million persons are currently infected. Data indicate an estimated 74 percent of all new HPV infections occur among individuals 15-24 years of age, resulting in about 9.2 million currently infected adolescents and young adults.1 The Centers for Disease Control (CDC) estimates that by 50 years of age, at least 50 percent of women will have or have had genital HPV infection.2
Diagnosis of infection in women is done using DNA-hybridization on Papanicolaou (Pap) tests that reveal atypical cells or squamous intraepithelial lesions or by doing type-specific HPV testing ; or by observing genital warts on examination. Since Pap tests are not routinely done in the male population, estimates of infection for them are not as accurate as those in the female population. In research settings, the diagnosis may also be made by doing PCR testing or identifying neutralizing antibodies from blood. When an individual tests positively for HPV, there must be a viral load significant enough to detect. If a person tests negatively, it may mean there is just not enough virus present to detect with current technology.
The genus of the family Human papilloma virus that may be oncogenic in the genital tract is Alpha papillomavirus. More than 100 species of HPV have been identified. Some are non-genital. About 40 occur primarily in the ano-genital tract. Munoz et al. found HPV-16 and 18 cause 70 percent of all cervical cancer, adenocarcinoma-in-situ of the cervix and cervical intraepithelial neoplasia-III (severe dysplasia), as well as vulvar and vaginal intraepithelial neoplasia-II and III (moderate and severe dysplasia). About 50 percent of all moderate cervical dysplasia is caused by these two species.3
HPV-6 and HPV-11 are the prototypes for species that primarily cause benign disease such as genital warts. Although these types may cause atypical cells and cervical intraepithelial neoplasia-I (mild dysplasia), there is seldom progression to higher-grade lesions.
Risk Factors for HPV Infection
The risk factors for infection with the sexually transmitted HPV are similar to those of any STI. Early sexual debut is a significant risk factor for the acquisition of any STI, since most persons who initiate intercourse at an early age will likely have multiple partners. Having a partner who has had multiple partners is also a significant risk factor for acquiring infection. About 45 percent of female college students will acquire HPV during their college careers. Using oral contraceptives has been mentioned as a risk factor, but that may be because women who use oral contraceptives are more sexually active than non-users. The association of sex with drugs, alcohol and cigarette smoking have also been reported as risk factors for HPV infection.4
Persistence of Infection
HPV infections are easily transmitted, presumably through microscopic tears in the surface epithelium that may occur with sexually intimate behavior. Any contact resulting in microabrasions may allow for transmission of the virus. Genital warts may be obvious and uncomfortable, but even with these lesions, most individuals are completely asymptomatic when infected. They do not know they have an infection and are transmitting the virus. Once the virus has been transmitted to the damaged surface epithelium, it penetrates to the basement membrane level and there may proliferate or remain quiescent.
Until three decades ago, HPV infection was regarded as benign and self-limited, resulting in cutaneous genital warts. The pioneering work of zur Hausen and colleagues in the 1970s (see related article in this issue) showed cancer of the cervix was most likely attributable to infection with a subset of genital HPVs rather than to other sexually transmitted pathogens.5
Most infections occur soon after the onset of intimate contact with an infected partner. Once infected, the majority of persons will clear their infection within 24 months via their host-immune defense mechanisms with type-specific immunity. It has been estimated that this occurs in about 90 percent of all women infected. Those who have persistent infection may have progression over time to cervical dysplasia (pre-cancer) or invasive cancer. Most early infections, aside from warts, are detected by the reading of atypical cells on a Pap test of the cervix. If there is progression to low-grade SIL, about 65 percent of these will spontaneously resolve. Thus the majority of infections and low-grade changes of the cervix will resolve to a level where HPV DNA cannot be detected by current methods. Of those whose infection persists, the HPV DNA is incorporated into the host cell genome and begins to control cellular proliferation and the ability to repair damaged cells, resulting in a dysplastic process. Even some higher-grade lesions may resolve with only biopsy as therapy.6
It is currently estimated that it takes about 12 to 24 months of persistence for atypia to develop. From this degree of cellular change, it may then take three to five years for CIN-I to develop; five to eight years for CIN-II/III to develop; and up to 20 years for invasive cancer to occur. In some situations, rapid progression from infection to high-grade dysplasia can occur.6
Although infection with types other than high-risk types 16 and 18 are most common, when infection occurs with type 16 in particular but with the other oncogenic types as well, there is a greater probability that there will be progression to cervical dysplasia and/or cancer. Most cervical cancers are caused by a single type of HPV; type 16 is the most prevalent. Low- and high-grade dysplasia are more frequently caused by multiple types. HPV-16 is involved as a causative agent in 58.7 percent of all cervical cancers, but in 54.6 percent of all cases it is a sole isolate. Together, types 16 and 18 are involved in 70.9 percent of all cervical cancers.3
Persistence of infection at the transformation zone (TMZ) of the cervix is key to the development of disease. The cervical transformation zone is the area of immature metaplasia between the squamous cells that line the vagina and lower cervix and the columnar cells that line the endocervix and the endometrium of the uterus. This zone or squamo-columnar junction is further out on the cervix in younger girls. This puts the individual at greater risk for acquisition of HPV when abraded or irritated areas of the cervix are exposed to the virus. Age, childbirth and invasive procedures all tend to cause the TMZ to move further up the endocervical canal. An adolescent with a vulnerable squamo-columnar junction may be exposed to HPV, be infected and, if the virus persists and is not eradicated by the host, may over months to years progress to dysplasia and eventually to cancer if HPV is not detected and treated. HPV has also been determined to be the etiologic agent for 40 percent of vulvar and vaginal cancers in women and about 35 percent of cancers of the oro-pharynx in men and women. It is the leading cause of squamous cell cancer of the penis in males.
Screening for Cervical Disease in Females
Since the Pap smear was introduced in the late 1940s, there have been dramatic reductions in the rates of invasive cervical cancer in the countries where this tool is used routinely. Unfortunately, because many developing nations do not have such screening readily available, there are an estimated 580,000 cases of cervical cancer worldwide with about 230,000 deaths annually. 7
In the United States, approximately 50 million Pap tests are done annually to screen for cervical disease. There are no reliable screening tests for men. The American Cancer Society recommends beginning cervical screening with a Pap test approximately three years after a woman begins having vaginal intercourse, but no later than 21 years of age. Screening should be done every year with regular Pap tests or every two years using liquid-based tests. At or after age 30, women who have had three consecutive normal test results may be screened every three yearswith reflex cytology or every five years with HPV screening alone. . Although there are occasional women who will have rapid progression of an abnormality to high-grade dysplasia, it is best not to initiate screening until after the adolescent or young woman is sexually active since this rapid progression is unusual. Aggressive management of cervical abnormalities in adolescents and teens is discouraged.
Decreasing the Risk for HPV Infection
Abstinence is obviously the best way to prevent the acquisition of any sexually transmitted infection, including HPV. Encouraging young people to delay their sexual debut is beneficial not only in decreasing the risk of STIs but also of non-marital pregnancy and the emotional sequelae of adolescent sexual involvement.
If an adolescent or teen is sexually active, it is important for him or her to understand his or her boundaries so he or she will not be manipulated into having intercourse before he or she is ready. The use of appropriate contraceptive methods should be discussed at home, in church or synagogue youth groups and in school health classes. Birth-control pills do not offer any protection from HPV infection. Although it would seem intuitively that condoms might offer protection from transmission of infection, the National Institutes of Health Condom Effectiveness Panel determined that there were not sufficient data to indicate that condoms are protective against HPV.8 Since the conclusions of this panel were published, others have indicated that there is some reduction in the risk of acquisition of HPV by using condoms.9 Unfortunately, continued, consistent use of condoms does not frequently occur over time even with appropriate condom-use counseling.10
It was very important to attempt to develop a vaccine that would serve as a primary prevention method for this infection. Research over the past two decades has focused on immunization with both a bivalent and a quadrivalent vaccine. If successful, over time this would help minimize the need for secondary prevention methods such as condoms and tertiary prevention methods that include biopsy of lesions, various types of conization or excision procedures of the cervix and even hysterectomy in more advanced cases of cervical disease.
HPV Immunization as A Primary Prevention Method
One might think cervical cancer should be the primary end point to evaluate such a vaccine. This is impractical for two reasons. In a placebo-controlled trial, it is not ethical to assign young women to the placebo arm and wait to see if they develop cervical cancer. Since it may take up to 20 years after initial infection to develop cancer, it is also not practical. Using infection itself as a primary end point is also not ideal since 90 percent of all infections resolve spontaneously without therapeutic intervention. Thus, the primary end points for efficacy to allow licensure, as developed by the Vaccines and Related Biological Products Advisory Committee of the Center for Biologics Evaluation and Research, were high-grade dysplasia of the cervix (CIN II/III) or adenocarcinoma-in-situ (AIS) of the cervix or endocervix, which are immediate and necessary precursors to cervical cancer; high-grade dysplasia of the vulva or vagina (VIN II/III, VaIN II/III); and genital warts.11 A secondary end point was low-grade dysplasia of the cervix (CIN I). As previously mentioned, 60 percent to 70 percent of CIN I will resolve spontaneously. The Advisory Committee also recommended that trials of such vaccines should enroll participants irrespective of baseline HPV status or Pap test results so trial results would indicate the efficacy and safety of the vaccine in a general population that includes women who have already been infected with the virus.13
Since infection with HPV can occur as soon as sexual activity begins, it was important to evaluate adolescents. Rather than enroll girls and young adolescents into these trials, the FDA allowed bridging to be used to demonstrate safety and immunogenicity. A population of girls and boys, 9-15 years of age, were given the vaccine to evaluate their ability to achieve an immune response and to ensure that the vaccine was as safe in them as in an older group of females. The results of these trials indicate younger adolescents achieve a more robust immune response than older subjects and have no increase in adverse events.12
HPV immunization with Gardasil is now approved and recommended for females ages 9-26 and males ages 9-19 with emphasis at ages 11-12. It is important to immunize before exposure to the virus. Parents may object to immunizing their children at younger ages; however, even if the child remains abstinent, he or she may be exposed to a partner who has previously been infected with HPV and acquire the infection also. Caution about oral-genital contact should be given in light of the rapid increase in soft-tissue cancers of the head and neck caused by HPV. Most HPV-related cancers are preventable with immunization.
By W. David Hager, M.D., Editor, KentuckyDoc
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