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Background
Cervical cancer, a major health problem for women, is causally associated with 14 high-risk types of human papillomavirus (HPV) (Williamson et al, 2005). In the United States, HPV is the most common sexually transmitted infection; and sexually active adolescents are at particularly high-risk for HPV infection. More than 99 % of cervical cancers contain at least 1 high-risk HPV type, and approximately 70 % of cervical cancers contain HPV16 or HPV18 (Kahn, 2005).
Most cervical cancers are squamous cell carcinomas (Castellsague et al, 2006). Although the incidence of cervical squamous cell carcinomas has decreased, that of cervical adenocarcinoma has increased in recent years. The extent to which HPV infection and co-factors may explain this differential trend is unclear. Castellsague et al (2006) found that HPV16 and HPV18 were the 2 most commonly detected HPV types in patients with invasive cervical adenocarcinoma and control subjects. These 2 HPV types were present in 82 % of the patients. Co-factors that showed clear statistically significant positive associations with cervical adenocarcinoma overall and among HPV-positive women included never schooling, poor hygiene, sexual behavior-related variables, long-term use of hormonal contraception, high parity, as well as herpes simplex virus-2 seropositivity. Human papillomavirus appears to be the principal risk factor for cervical adenocarcinoma. Although cervical cancer screening has lowered the incidence of and mortality from invasive cervical cancer, it is not completely protective. Vaccination against main HPV types should reduce the incidence of cervical cancer.
In a randomized, double-blind, placebo-controlled, phase II clinical trial, Villa and associates (2005) evaluated the effectiveness of a prophylactic quadri-valent vaccine targeting the HPV types associated with 70 % of cervical cancers (types 16 and 18) and with 90 % of genital warts (types 6 and 11). A total of 277 young women (mean age of 20.2 years) were randomly assigned to quadri-valent HPV (20 ug type 6, 40 ug type 11, 40 ug type 16, and 20 ug type 18) L1 virus-like-particle (VLP) vaccine; and 275 young women (mean age of 20.0 years) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, subjects underwent regular gynecological examinations, cervico-vaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV type 6, 11, 16, or 18, or cervical or external genital disease (namely, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia [CIN], cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol. Combined incidence of persistent infection or disease with HPV type 6, 11, 16, or 18 fell by 90 % (95 % confidence interval [CI]: 71 to 97 %, p < 0.0001) in those assigned vaccine compared with those assigned placebo. These investigators concluded that a vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types. This is in agreement with the finding of Harper and colleagues (2004) who reported that the bi-valent HPV16/HPV18 L1 VLP vaccine was effective in preventing incident and persistent cervical infections with HPV16 and HPV18, and associated cytological abnormalities and lesions (n = 1,113), as well as that of Koutsky and co-workers (2002) who reported that administration of HPV16 vaccine reduced the incidence of both HPV16 infection and HPV16-related CIN (n = 2392).
Mao and colleagues (2006) noted that HPV VLP vaccines have demonstrated effectiveness in preventing persistent HPV infections. Whether protection lasts longer than 18 months and, thus, impacts rates of CIN 2-3, has not yet been established. In a randomized, double-blind, placebo-controlled study, these investigators presented results from an HPV16 L1 VLP vaccine trial through 48 months. A total of 2,391 women, aged 16 to 23 years, participated in this trial. Either 40 ug HPV16 L1 VLP vaccine or placebo was administered intra-muscularly at day 1, month 2, and month 6. Genital samples for HPV16 DNA and Pap tests were obtained at day 1, month 7, and then 6-monthly through month 48. Colposcopy and cervical biopsies were performed if clinically indicated and at study exit. Serum HPV16 antibody titer was measured by radioimmunoassay. Among 750 placebo recipients in the per protocol population, 12 women developed HPV16-related CIN 2-3 (6 CIN2 and 6 CIN3). Among 755 vaccinated subjects, there were no cases (vaccine efficacy 100 %, 95 % CI: 65 to 100 %). There were 111 cases of persistent HPV16 infection in placebo recipients and 7 cases in vaccinated subjects (vaccine efficacy 94 %, 95 % CI: 88 to 98 %). After immunization, HPV16 serum antibody geometric mean titers peaked at month 7 (1,519 milli-Merck units [mMU]/ml), declined through month 18 (202 mMU/ml), and remained relatively stable between month 30 and month 48 (128 to 150 mMU/ml). These researchers concluded that the vaccine HPV16 L1 VLP provides high-level protection against persistent HPV16 infection and HPV16-related CIN 2-3 for at least 3.5 years after immunization. Administration of L1 VLP vaccines targeting HPV16 is likely to reduce risk for cervical cancer.
A U.S. Food and Drug Administration (FDA) advisory panel recommended approval of Gardasil (Merck & Co., Inc., Whitehouse Station, NJ) the first vaccine developed to prevent cervical cancer. Gardasil, a quadri-valent HPV types 6, 11, 16, 18, recombinant vaccine, protects against the 2 strains of the HPV that are thought to cause about 70 % of all cervical cancer cases. The vaccine also protects against 2 other HPV strains that cause roughly 90 % of all genital warts. According to Merck, Gardasil could be administered to all females aged 9 to 26; but would be most effective if administered before females become sexually active. However, the advisory panel noted that vaccination should not reduce the importance of routine screening for cervical cancer, which has been attributed to reducing cervical cancer rates nationwide by 75 %, and that the vaccine would not protect against the many other HPV strains not included in the vaccine or be effective in individuals who are already infected with the four HPV strains in the vaccine. Regular cytology screening may still be necessary after vaccination since it is possible that reduction in the prevalence of the currently most common HPV types (16 and 18) may result in a rise in the incidence of infections with other cancer-associated types.
Gardasil was approved by the FDA for use in girls and young women aged 9 to 26 years. The FDA approved Gardasil for the prevention of cervical cancer, cervical precancers (cervical intraepithelial neooplasia (CIN) 2/3 and adenocarcinoma in situ (AIS)), vulvar precancers (vulvar intraepithelial neoplasia (VIN) 2/3), and vaginal precancers (vaginal intraepithelial neoplasia (VaIN) 2/3)) caused by HPV types 16 and 18. Gardasil is also approved for the prevention of genital warts and low-grade cervical lesions (CIN 1) caused by HPV types 6, 11, 16 and 18.
Gardasil is administered in 3 separate intramuscular injections in the upper arm or in the higher anterolateral area of the thigh over a 6-month period. It is recommended that the 2nd dose be administered 2 months after the 1st dose, and the 3rd dose 6 months after the 1st dose.
The FDA's approval of Gardasil was based on the results of 4 phase II and phase III randomized controlled clinical trials involving a total of 20,541 women aged 16 to 26 years. Study participants were followed up to 5 years after enrollment. In these studies, Gardasil prevented all of the HPV 16- and 18- related cervical precancers and non-invasive cervical cancers (CIN 2/3 and AIS). Gardasil prevented 95 % of low-grade cervical dysplasia and precancers (CIN 2/3 or AIS) caused by HPV 6, 11, 16 or 18. Gardasil was also found to prevent 99 % of genital warts caused by HPV 6 or 11. Gardasil also prevented 100 % of HPV 16- and 18-related vulvar and vaginal precancers (VIN2/3 or AaIN2/3) in women not previously exposed to the relevant HPV subtypes. These studies also showed that administration of Gardasil to women who are already infected with one or more vaccine related HPV types prior to vaccination protects them from clinical disease caused by the remaining vaccine types but may not alter the course of an infection that is already present.
The FDA approved Gardasil for use in adolescent girls aged 9 to 15 years based on a comparison of immune responses to Gardasil in adolescent girls to that for older women. Studies were performed to evaluate the immune responses for Gardasil in 10 to 15-year old girls compared to those in 16- to 23-year old adolescents and young adult women. The immune responses to Gardasil in 10- to 15-year-old girls were similar to those in 16- to 23-year-old women. Similar outcomes were observed in a comparison of immune responses among 9- to 15-year old girls to immune responses in 16- to 26-year old adolescents and women.
Gardasil is contraindicated in individuals who are hypersensitive to the active substances or to any of the excipients of the vaccine.
Hildesheim et al (2007) examined if vaccination against HPV types 16 and 18 increases the rate of viral clearance in women already infected with HPV. A total of 2,189 women aged 18 to 25 years were included in this study. Subjects were positive for HPV DNA at enrollment, had at least 6 months of follow-up, and had follow-up HPV DNA results. Participants were randomly assigned to receive 3 doses of a bivalent HPV-16/18 L1 protein viruslike particle AS04 candidate vaccine (n = 1,088) or a control hepatitis A vaccine (n = 1,101) over 6 months. Presence of HPV DNA was determined in cervical specimens by a molecular hybridization assay using chemiluminescence with HPV RNA probes and by polymerase chain reaction using SPF10 primers and a line probe assay detection system before vaccination and by polymerase chain reaction after vaccination. These researchers compared rates of type-specific viral clearance using generalized estimating equations methods at the 6-month visit (after 2 doses) and 12-month visit (after 3 doses) in the 2 study groups. There was no evidence of increased viral clearance at 6 or 12 months in the group who received HPV vaccine compared with the control group. Clearance rates for HPV-16/18 infections at 6 months were 33.4 % (82/248) in the HPV vaccine group and 31.6 % (95/298) in the control group (vaccine effectiveness for viral clearance, 2.5 %; 95 % CI: -9.8 % to 13.5 %). Human papillomavirus 16/18 clearance rates at 12 months were 48.8 % (86/177) in the HPV vaccine group and 49.8 % (110/220) in the control group (vaccine effectiveness for viral clearance, -2.0 %; 95 % CI: -24.3 % to 16.3 %). There was no evidence of a therapeutic effect for other oncogenic or non-oncogenic HPV categories, among women receiving all vaccine doses, among women with single infections, or among women stratified by the following entry variables: HPV-16/18 serology, cytologic results, HPV DNA viral load, time since sexual debut, Chlamydia trachomatis or Neisseria gonorrhoeae infection, hormonal contraceptive use, or smoking. The authors concluded that in women positive for HPV DNA, HPV-16/18 vaccination does not accelerate clearance of the virus and should not be used to treat prevalent infections. The findings of this study confirm that HPV vaccine has no therapeutic value for women with pre-existing infection, thereby reinforcing the importance of immunizing women before they initiate sexual activity and are possibly exposed to infection.
The Centers for Disease Control and Prevention/Advisory Committee on Immunization Practices (ACIP, 2007) stated that no evidence exists of protection against disease caused by HPV types with which females are infected at the time of vaccination. However, females infected with 1 or more vaccine HPV types before vaccination would be protected against disease caused by the other vaccine HPV types. The recommended vaccination schedule is a 3-dose series with the 2nd and 3rd doses administered 2 and 6 months after the first dose. The recommended age for vaccination of females is 11 to 12 years. Vaccine can be administered as young as age 9 years. Catch-up vaccination is recommended for females aged 13 to 26 years who have not been previously vaccinated. Vaccination is not a substitute for routine cervical cancer screening, and vaccinated females should have cervical cancer screening as recommended.
Vaginal and vulvar cancers among younger women are often related to infection with HPV. These cancers are preceded by high-grade vulval intra-epithelial neoplasia (VIN2-3) and vaginal intra-epithelial neoplasia (VaIN2-3). Joura et al (2007) performed a combined analysis of 3 randomized clinical trials to assess the effect of Gardasil on the incidence of these diseases. A total of 18,174 women (16 to 26 years) were enrolled and randomized to receive either Gardasil or placebo at day 1, and months 2 and 6. Individuals underwent detailed anogenital examination at day 1, 1 month after the 3rd dose, and at 6-12-month intervals for up to 48 months. Suspect genital lesions were biopsied and read by a panel of pathologists and vaccine HPV type-specific DNA testing was done. The primary end point was the combined incidence of VIN2-3 or VaIN2-3 associated with HPV16 or HPV18. Primary efficacy analyses were done in a per-protocol population. The mean follow-up time was 3 years. Among women naive to HPV16 or HPV18 through 1 month after the 3rd dose (per-protocol population; vaccine n = 7,811; placebo n = 7,785), the vaccine was 100 % effective (95 % CI: 72 to 100) against VIN2-3 or VaIN2-3 associated with HPV16 or HPV18. In the intention-to-treat population (which included 18,174 women who, at day 1, could have been infected with HPV16 or HPV18), vaccine efficacy against VIN2-3 or VaIN2-3 associated with HPV16 or HPV18 was 71 % (37 to 88). The vaccine was 49 % (18 to 69) effective against all VIN2-3 or VaIN2-3, irrespective of whether or not HPV DNA was detected in the lesion. The most common treatment-related adverse event was injection-site pain. Prophylactic administration of Gardasil was effective in preventing high-grade vaginal and vulval lesions associated with HPV16 or HPV18 infection in women who were naive to these types before vaccination.
In a phase III clinical trial, Garland and colleagues (2007) evaluated the effectiveness of Gardasil in preventing anogenital diseases associated with HPV types 6, 11, 16, and 18. This randomized, placebo-controlled, double-blind trial involved 5,455 women between the ages of 16 and 24 years; 2,723 received vaccine and 2,732 received placebo at day 1, month 2, and month 6. The co-primary composite end points were the incidence of genital warts, vulvar or vaginal intra-epithelial neoplasia, or cancer and the incidence of cervical intra-epithelial neoplasia, adenocarcinoma in situ, or cancer associated with HPV type 6, 11, 16, or 18. Data for the primary analysis were collected for a per-protocol susceptible population of women who had no virological evidence of HPV type 6, 11, 16, or 18 through 1 month after administration of the 3rd dose. Subjects were followed for an average of 3 years after administration of the 1st dose. In the per-protocol population, those followed for vulvar, vaginal, or peri-anal disease included 2,261 women (83 %) in the vaccine group and 2,279 (83 %) in the placebo group. Those followed for cervical disease included 2,241 women (82 %) in the vaccine group and 2,258 (83 %) in the placebo group. Vaccine effectiveness was 100 % for each of the co-primary end points. In an intention-to-treat analysis, including those with prevalent infection or disease caused by vaccine-type and non-vaccine-type HPV, vaccination reduced the rate of any vulvar or vaginal peri-anal lesions regardless of the causal HPV type by 34 % (95 % CI: 15 to 49), and the rate of cervical lesions regardless of the causal HPV type by 20 % (95 % CI: 8 to 31). The authors concluded that Gardasil significantly reduced the incidence of HPV-associated anogenital diseases in young women.
On September 12, 2008, the FDA approved expanded indications for Gardasil for the prevention of vaginal and vulvar cancer caused by HPV types 16 and 18 in girls and women aged 9 to 26 years. These 2 HPV types cause 70 % of cervical cancers, and are known to also cause some vaginal and vulvar cancers, but the percentages are not well-defined.
On October 16, 2009, the FDA approved the use of Gardasil for the prevention of genital warts due to HPV types 6 and 11 in boys and men aged 9 through 26 years. Gardasil's effectiveness was based on the results of a randomized trial of 4,055 males aged 16 through 26 years old. The results showed that in men who were not infected by HPV types 6 and 11 at the start of the study, Gardasil was nearly 90 % effective in preventing genital warts caused by infection with HPV types 6 and 11. Studies were conducted to measure the immune response to the vaccine in boys ages 9 through 15. The results showed that the immune response was as good as that found in the 16 through 26 years age group, indicating that the vaccine should have similar effectiveness.
On December 22, 2010, the FDA approved Gardasil for the prevention of anal cancer and associated pre-cancerous lesions due to HPV types 6, 11, 16, and 18 in people aged 9 through 26 years. The FDA approval was based on the results of a randomized, controlled trial of men who self-identified as having sex with men. This population was studied because it has the highest incidence of anal cancer. At the end of the study period, Gardasil was shown to be 78 % effective in the prevention of HPV 16 and 18 related anal intra-epithelial neoplasia. Because anal cancer is the same disease in both males and females, the effectiveness data was used to support the indication in females as well.
Gardasil will not prevent the development of anal pre-cancerous lesions associated with HPV infections already present at the time of vaccination. Gardasil's full potential for benefit is obtained by those who are vaccinated prior to becoming infected with the HPV strains contained in the vaccine.
Pawlita and Gissmann (2009) noted that recurrent respiratory papillomatosis (RRP) is a rare disease. It is characterized by proliferation of benign squamous cell papillomas within the respiratory-digestive tract, predominantly the larynx. This rare disease is caused by oral infection with HPV types 6 or 11. In aggressive disease, which within few months or even weeks requires multiple surgical interventions to remove papillomas, residual impairment of voice and breathing is almost inevitable. Nowadays immune stimulation with interferon alpha or topic application of cidofovir are recommended to lower the recurrence rate in aggressive disease but vaccination against mumps virus and photodynamic therapies has also been administered. The recently developed tetra-valent HPV vaccine Gardasil induces neutralizing antibodies against capsid antigens of the HPV types 16 and 18, which are associated with cervical cancer, as well as against types 6 and 11, which are associated with condylomata acuminata und respiratory papillomatosis. The vaccine has been shown to be safe and highly immunogenic. It can effectively prevent new genital infections by one of the 4 vaccine types as well as the epithelial lesions induced by them. However, the vaccine had no effect against pre-existing genital infections or lesions. These researchers proposed the hypothesis that HPV vaccination could have a therapeutic effect in RRP by preventing new papilloma formation at additional sites. First case reports on Gardasil vaccination in juvenile as well as adult onset RRP have become available. In view of the low risk of this adjuvant immunotherapy, a larger controlled multi-center trial was proposed to verify this hypothesis.
Chaudhary et al (2009) stated that head and neck malignancies are characterized by a multi-phasic and multi-factorial etiopathogenesis. Tobacco and alcohol consumption are the most common risk factors for head and neck malignancy. Other factors, including DNA viruses, especially HPV, may also play a role in the initiation or development of these lesions. The pathways of HPV transmission in the head and neck mucosal lesions include oral-genital contact, more than 1 sexual partner and peri-natal transmission of HPV to the neonatal child. The increase in prevalence of HPV infection in these lesions may be due to wider acceptance of oral sex among teenagers and adults as this is perceived to be a form of safe sex. The prevalence of HPV in benign lesions as well as malignancies has been assessed by many methods. Among these, the polymerase chain reaction is the most sensitive method. Review of literature reveals that HPV may be a risk factor for malignancies, but not in all cases. For confirmation of the role of HPV in head and neck squamous cell carcinoma, large population studies are needed in various clinical settings. Prophylactic vaccination against high-risk HPV types eventually may prevent a significant number of cervical carcinomas. Of the 2 vaccines currently available, Gardasil protects against HPV types 6, 11, 16 and 18, while the other vaccine, Cervarix protects against HPV types 16 and 18 only. However, to the best of the authors' knowledge, the HPV vaccine has not been tried in head and neck carcinoma.
Cervarix, a bi-valent HPV types 16 and 18, recombinant vaccine, was approved by the FDA on October 16, 2009 for use in girls and young women aged 10 through 25 years for the prevention of cervical cancer, CIN grade 2 or worse and adenocarcinoma in situ, and CIN grade 1, caused by oncogenic HPV types 16 and 18. The FDA’s approval of Cervarix was based on data from clinical trials of nearly 30,000 girls and young women receiving Cervarix. Cervarix was shown to be 93 % effective in the prevention of cervical pre-cancers associated with HPV 16 or 18 in women without evidence of current infection with, or prior exposure to, the same HPV type at the time of vaccination. The majority (approximately 75 %) of cervical cancers in North America are caused by HPV types 16 and 18.
Cervarix is administered as an intra-muscular injection in a 3 dose schedule that should be completed within 6 months of the initial dose (0, 1, and 6 months).
The FDA has approved both a bivalent and quadrivalent HPV vaccine; and the ACIP has recommended that HPV vaccination routinely be given to girls when they are 11 years or 12 years old. The vaccine can be given to individuals as young as 9 years; catch-up vaccination is recommended in females aged 13 years through 26 years. The American College of Obstetricians and Gynecologists (ACOG, 2010) endorsed these recommendations. Although obstetrician-gynecologists are not likely to care for many girls in the initial vaccination target group, they are critical to the catch-up vaccination period. Both HPV vaccines are most effective if given before any exposure to HPV infection (i.e., before sexual activity). However, sexually active girls and women can receive some benefit from the vaccination because exposure to all HPV types prevented by the vaccines is unlikely in females aged 13 years through 26 years. Vaccination with either HPV vaccine is not recommended for pregnant women. It can be provided to women who are breast-feeding. The need for booster vaccination has not been established but appears unnecessary. Health care providers are encouraged to discuss with their patients the benefits and limitations of the HPV vaccine and the need for routine cervical cytology screening for those aged 21 years and older.
On October 25, 2011, the ACIP recommended routine use of quadrivalent HPV vaccine (HPV4; Gardasil) in males aged 11 or 12 years. The ACIP also recommended vaccination with HPV4 for males aged 13 through 21 years who have not been vaccinated previously or who have not completed the 3-dose series; males aged 22 through 26 years may be vaccinated. These recommendations replaced the October 2009 ACIP guidance that HPV4 may be given to males aged 9 through 26 years. For these recommendations, the ACIP considered information on vaccine efficacy (including data available since October 2009, on prevention of grade 2 or 3 anal intra-epithelial neoplasia, a precursor of anal cancer), vaccine safety, estimates of disease and cancer resulting from HPV, cost-effectiveness, and programmatic considerations.
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