Human Papillomavirus Vaccination

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Human papillomavirus vaccination

Authors: J Thomas Cox, MD, Joel M Palefsky, MD
Section Editor: Martin S Hirsch, MD
Deputy Editor: Allyson Bloom, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2019. | This topic last updated: Jun 21, 2019.
INTRODUCTION
Human papillomavirus (HPV) is a sexually transmitted pathogen that causes anogenital and
oropharyngeal disease in males and females. Persistent viral infection with high-risk HPV genotypes
causes virtually all cancers of the cervix. The high-risk HPV genotypes (or "types") 16 and 18 cause
approximately 70 percent of all cervical cancers worldwide, and types 31, 33, 45, 52, and 58 cause an
additional 20 percent. HPV types 16 and 18 also cause nearly 90 percent of anal cancers and a
significant proportion of oropharyngeal cancer, vulvar and vaginal cancer, and penile cancer. HPV
types 6 and 11 cause approximately 90 percent of anogenital warts.
Vaccines have been developed to protect against acquisition of HPV infection and development of
subsequent HPV-associated disease. This topic will cover issues related to routine immunization
recommendations, vaccination in special patient populations, and vaccine safety.
The natural history, epidemiology, and disease associations of HPV infection are discussed
elsewhere. (See "Human papillomavirus infections: Epidemiology and disease associations".)
AVAILABLE VACCINES
Three different vaccines, which vary in the number of HPV types they contain and target, have been
clinically developed, although not all are available in all locations:
● Quadrivalent HPV vaccine (Gardasil) targets HPV types 6, 11, 16, and 18.
● 9-valent vaccine (Gardasil 9) targets the same HPV types as the quadrivalent vaccine (6, 11, 16,
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and 18) as well as types 31, 33, 45, 52, and 58.
● Bivalent vaccine (Cervarix) targets HPV types 16 and 18.
In the United States, only the 9-valent vaccine is available. Practitioners in other locations should
confirm vaccine availability locally.
Dosing and administration is discussed elsewhere. (See 'Administration' below.)
These are all prophylactic vaccines, designed to prevent initial HPV infection and subsequent HPV-
associated lesions. Therapeutic vaccines, designed to induce regression of existing HPV-associated
lesions, are in development but are not clinically available [1].
RATIONALE
Females — Vaccination with 9-valent, quadrivalent, or bivalent HPV vaccine provides a direct benefit
to female recipients by safely protecting against cancers that can result from persistent HPV infection.
This preventive effect is most notable and best studied with cervical cancer, which is one of the most
common female cancers worldwide. HPV types 16 and 18, which are targeted by all three HPV
vaccines, cause approximately 70 percent of all cervical cancers worldwide, and HPV types 31, 33,
45, 52, and 58, which are additionally targeted by the 9-valent vaccine, cause an additional 20
percent. HPV types 16 and 18 also cause nearly 90 percent of anal cancers and a substantial
proportion of vaginal, vulvar, and oropharyngeal cancers. Vaccination with the quadrivalent or 9-valent
HPV vaccine also protects against anogenital warts (90 percent of which are caused by HPV types 6
and 11); although they are benign lesions, they are associated with physical and psychological
morbidity and have a high rate of treatment failure. The adverse effects of HPV vaccination are
generally limited to mild local reactions. Vaccine efficacy and safety are discussed below. (See
'Efficacy' below and 'Vaccine safety' below.)
Details on HPV-associated diseases and the burden of HPV infection among females are found
Various modeling studies have outlined the potential benefits of HPV vaccination, which appear to be
cost effective for the recommended age range [2-6]. One study suggested that vaccination of the
entire United States population of 12-year-old girls would annually prevent more than 200,000 HPV
infections, 100,000 abnormal cervical cytology examinations, and 3300 cases of cervical cancer if
cervical cancer screening continued as currently recommended [2]. In settings where there has been
high uptake of vaccine among females there is also evidence of herd immunity among males of
similar age, reflected by a reduction in genital warts [7].
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Males — HPV vaccination provides a direct benefit to male recipients by safely protecting against
cancers that can result from persistent HPV infection. HPV types 16 and 18 cause nearly 90 percent
of anal cancers and substantial proportion of oropharyngeal and penile cancers. Vaccination with
9-valent or quadrivalent vaccine also protects against anogenital warts (90 percent of which are
caused by HPV types 6 and 11). The overall burden of HPV-associated cancers and precancers
among males is less than the burden of cervical cancer in females. Nevertheless, despite a smaller
direct absolute benefit of HPV vaccination in males compared with females, the overall benefit of
vaccinating males outweighs its potential risks because of additional population benefits from herd
immunity and the documented safety of HPV vaccines. (See 'Vaccine safety' below and 'Efficacy'
below.).
Details on HPV-associated diseases and the burden of HPV infection among males are found
Various models have indicated that vaccinating both males and females is more beneficial in reducing
HPV infection and disease than by vaccinating only females, although male vaccination is less cost
effective than female vaccination [8-14]. However, cost-effectiveness analyses are limited by
uncertainty regarding different variables that affect the impact of male vaccination. These include
vaccine efficacy and duration of protection, vaccine coverage of females, the effect of herd immunity,
the range of health outcomes included, and the effect of HPV-associated diseases on quality of life
[15].
In particular, models have found that the cost-effectiveness of male vaccination is higher in the setting
of lower levels of female coverage. This is because there would be less herd protection from female
vaccination, and thus males would have more direct benefit from vaccination. In one study that used
population data from the Netherlands, the burden of HPV-associated cancers in men could be
reduced by an estimated 37 and 66 percent if vaccine uptake among girls and young women reached
60 and 90 percent, respectively, but vaccine uptake among females is considerably less than 60
percent in many locations [13]. Furthermore, even if vaccine uptake were sufficiently high among
females to confer protection against males, this would have minimal effect on men who have sex with
men, who have substantially higher rates of HPV-associated anal cancer and precursor lesions than
heterosexual males.
In resource-limited settings, expert groups recommend that public health efforts focus primarily on
vaccinating young females, the group in which the absolute benefit and cost-effectiveness of HPV
vaccination is the highest.
ADMINISTRATION
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Indications and age range — In accordance with the Advisory Committee on Immunization Practices
(ACIP) in the United States, we recommend routine HPV vaccination for all females and males
[16-19]. The ACIP recommended age ranges for vaccination are as follows:
● Females – HPV vaccine is recommended at 11 to 12 years. It can be administered starting at 9

years of age, and catch-up vaccination is recommended for females aged 13 to 26 years who
have not been previously vaccinated or who have not completed the vaccine series.
● Males – HPV vaccine is recommended at 11 to 12 years. It can be administered starting at 9

years of age, and catch-up vaccination is recommended for males aged 13 to 21 years who have
not been previously vaccinated or who have not completed the vaccine series.
Among males 22 to 26 years old, catch-up HPV vaccination is recommended if they are men who
have sex with men or immunocompromised (including HIV-infected males). Otherwise,
"permissive use" of HPV vaccination is recommended for this age range. Permissive use means
that the vaccine is recommended but not considered to be of sufficient priority to include on
routine vaccination schedules. Vaccines recommended on a permissive basis may not be
covered by a patient's health insurance provider.
The main reason that routine catch-up HPV vaccination is not recommended for individuals older than
26 years is the increased likelihood of prior exposure to HPV vaccine types with age, which reduces
the potential individual benefit and thus the cost-effectiveness of HPV vaccination. However, for some
individuals in this age group, such as those with no prior sexual experience or certain lifelong sexual
monogamy, the risk of prior HPV exposure may be very low. We offer HPV vaccination to such
individuals, as it may be beneficial if they are deemed to have a future risk of HPV exposure; studies
have suggested that HPV vaccination is immunogenic, efficacious, and safe in older women [20-23].
However, clinicians and patients should be aware that HPV vaccination of individuals older than 26
years may not be covered by insurance providers or other payers.
These recommendations are consistent with other expert groups in the United States, including the
American Academy of Pediatrics (AAP), the American Academy of Family Practice (AAFP), the
American College of Obstetricians and Gynecologists (ACOG), the American Cancer Society (ACS),
and the International Papillomavirus Society [24-28]. These are also largely consistent with
recommendations for resource-rich settings from the American Society of Clinical Oncology (ASCO)
guidelines on cervical cancer prevention [29].
Recommendations from other expert groups for resource-limited settings are somewhat different. The
World Health Organization (WHO) recommends that the primary target of HPV vaccination programs
be females aged 9 to 14 years and that local public health programs should recommend vaccination
of older females only if it is affordable and cost effective and does not divert resources from
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vaccinating the primary target population or screening for cervical cancer [30]. ASCO
recommendations for resource-limited settings are similar [29].
Optimal timing — Within the recommended age range, the optimal time for HPV immunization is
prior to an individual's sexual debut. Clinical trial data of vaccine efficacy in males and females
suggest that immunization with HPV vaccine is most effective among individuals who have not been
infected with HPV (eg, patients who are "HPV-naïve"). None of the available HPV vaccines treat or
accelerate the clearance of preexisting vaccine-type HPV infections or related disease. (See
'Indications and age range' above.)
Individuals who are sexually active should still be vaccinated consistent with age-specific
recommendations. A history of an abnormal Papanicolaou test, genital warts, or HPV infection is NOT
a contraindication to HPV immunization [17]. However, immunization is less beneficial for those who
have already been infected with one of more of the HPV vaccine types. (See 'Preexisting HPV-
associated disease' below.)
Choice of vaccine — Not all HPV vaccines are available in all locations. If cost and availability are
not an issue, we recommend the 9-valent vaccine. In the United States only the 9-valent vaccine is
available (since 2017). The greater HPV-type coverage provided by the 9-valent compared with the
quadrivalent and bivalent vaccines protects against additional cervical cancers. Although it is not clear
that greater HPV-type coverage by vaccinating males with the 9-valent rather than quadrivalent
vaccine would substantially improve male cancer prevention, it would likely further reduce the risk of
cervical cancer in women indirectly through herd immunity.
In general, the same formulation should be used to complete the series, if possible. However, if the
HPV vaccine formulation initially used is unknown or unavailable, or if the 9-valent vaccine is being
introduced into the formulary, a different HPV vaccine formulation can be used to complete the series
[18].
Immunization schedule — In the United States, the recommended dosing schedule depends on the
age of the patient at vaccine initiation [16,17,19]:
● Individuals initiating the vaccine series before 15 years of age – Two doses of HPV vaccine
should be given at 0 and at 6 to 12 months.
If the second dose was administered less than five months after the first, the dose should be
repeated a minimum of 12 weeks after the second dose and a minimum of five months after the
first.
● Individuals initiating the vaccine series at 15 years of age or older – Three doses of HPV
vaccine should be given at 0, 1 to 2 (typically 2), and 6 months.
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The minimum intervals between the first two doses is four weeks, between the second and third
doses is 12 weeks, and between the first and third dose is five months. If a dose was
administered at a shorter interval, it should be repeated once the minimum recommended interval
since the most recent dose has passed.
● Immunocompromised patients – Three doses of HPV vaccine should be given at 0, 1 to 2, and

6 months regardless of age. (See 'Immunocompromised patients' below.)
This ACIP recommended vaccination schedule is the same as that recommended by the Strategic
Advisory Group of Experts on Immunizations (SAGE) of the World Health Organization (WHO) [31].
The two-dose series is similarly recommended in many other countries. Practitioners outside the
United States should consult local guidelines for the recommended immunization schedule in their
country.
HPV vaccine can be safely administered at the same time as other age-appropriate vaccines at a
different anatomic site. Administering HPV vaccine at the same time as certain other vaccines (ie,
tetanus, acellular pertussis, and diphtheria vaccine and inactivated poliovirus vaccine) does not
appear to adversely affect the immune response to either the HPV vaccine or the concomitant vaccine
[32,33].
Although the initial clinical efficacy studies evaluated a three-dose schedule (see 'Efficacy' below),
subsequent studies found that two vaccine doses in young individuals have similar or greater
immunogenicity compared with three doses in older females (the group in whom vaccine efficacy was
established in clinical trials) [34-39]. For the quadrivalent vaccine, furthermore, two doses are
comparably effective as three doses for prevention of genital warts [40,41]. There have been no
studies directly evaluating the efficacy of fewer than three doses for prevention of cervical neoplastic
disease. Three doses of HPV vaccine are still recommended for individuals 15 and older because of
the lower immunologic response to HPV vaccination in this population.
As an example of supportive evidence for the two-dose schedule, a trial of 1518 participants randomly
assigned to receive the 9-valent vaccine at different dosing schedules demonstrated that antibody
titers for HPV vaccine types were consistently higher among females and males aged 9 to 14 years
who received two vaccine doses spaced 6 or 12 months apart compared with females aged 16 to 26
years who received three vaccine doses over six months [37]. One cohort of females aged 9 to 14
years in this trial was also assigned to receive three vaccine doses; among females in this age group,
antibody responses were generally comparable with two- versus three-vaccine doses, and many
vaccine-type titers trended higher with two doses.
While no efficacy studies have been conducted to directly evaluate a two-dose schedule, a post hoc
analysis of data from two trials of the bivalent HPV vaccine in young women (aged 15 to 25 years)
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who had no HPV type 16 or 18 infection at baseline suggests that two vaccine doses can effectively
protect against HPV infection [42]. Of those with at least 12 months of follow-up, vaccine efficacy
against six-month persistent infection with HPV types 16 and 18 was no different in women who
received the intended three doses compared with those who received only two (89 and 90 efficacy,
respectively).
Observational studies have examined effectiveness by number of doses, but are difficult to evaluate
primarily because of a number of unmeasured confounders. One observational study of over one
million Swedish females suggested that two quadrivalent vaccine doses provided substantial
protection against genital warts, although completion of three doses was slightly superior (128 versus
174 events per 100,000 person-years with two doses, compared with 528 events per 100,000 years
without vaccination) [40]. In a similar study from Denmark, three quadrivalent vaccine doses were also
associated with an overall lower risk of genital warts than two doses, but when the two vaccine doses
were administered at least six months apart, the reduction in risk for genital warts appeared
comparable to that with three doses [41].
Missed doses — Patients often do not follow up for their immunizations on schedule [43]. The ACIP
recommends that if the vaccination series is interrupted for any length of time, it can be resumed
without restarting the series.
Postvaccination instructions — Because of a potential for syncope with any vaccine, and
particularly with the HPV vaccine, a routine 15-minute waiting period in a sitting or supine position
following HPV vaccination is recommended [17]. This may decrease the risk of syncope with
subsequent injury. (See 'Vaccine safety' below.)
Unnecessary evaluation
Prevaccination assessment — HPV vaccination can be administered without special evaluation.

Serologic or HPV DNA testing is not warranted prior to immunization [17]. Pregnancy testing is also
not necessary.
Postvaccination serology — There is no evidence that the measurement of postvaccination

antibody titers to monitor immunity is useful for determining who is protected against infection by the
vaccine-targeted types.
Limited benefit of revaccination — HPV vaccines have demonstrated durable protection from HPV-
associated diseases, and there is no evidence that revaccination is necessary. (See 'Duration of
protection' below.)
For patients who have already completed HPV vaccine series with the bivalent or quadrivalent
vaccine, which target the most common high-risk HPV types, revaccination with the 9-valent vaccine
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is likely of marginal individual benefit, and we do not suggest it. (See 'Available vaccines' above and
'Efficacy' below.)
SPECIAL POPULATIONS
Pregnant or breastfeeding females — HPV vaccination during pregnancy is not recommended

because of limited information about safety; however, data from inadvertent use in this setting are
increasingly available and reassuring. Thus, if a woman is found to be pregnant after initiating the
vaccination series, she can be reassured that available evidence does not indicate any increase in
risk of adverse pregnancy outcome with vaccination. Nevertheless, the remainder of the series should
be delayed until the woman is no longer pregnant. This is discussed in detail elsewhere. (See
"Immunizations during pregnancy", section on 'Human papillomavirus'.)
Lactating females can receive the immunization series since subunit vaccines do not affect the safety
of infant breastfeeding.
In the United States, the 9-valent vaccine manufacturer maintains a registry to monitor fetal outcomes
of pregnant females exposed to HPV vaccine [17,18]; prenatal exposures to the 9-valent vaccine can
be reported by calling 800-986-8999.
Preexisting HPV-associated disease — A history of genital warts, a positive HPV test result, or
abnormal cervical, vaginal, vulvar, or anal cytology all indicate a prior HPV infection but not
necessarily with the HPV types included in the vaccines. Vaccination is still recommended in
individuals within the recommended age range who have evidence of prior HPV infection, as it can
still provide protection against infection with HPV vaccine types not already acquired [16,17].
However, these patients should be advised that vaccination will have no therapeutic effect on
preexisting HPV infection or HPV-associated disease, and the potential benefit of HPV vaccination is
not as great as if they were vaccinated before their sexual debut. (See 'Optimal timing' above.)
Immunocompromised patients — Immunocompromised patients, particularly transplant recipients

and HIV-infected patients with CD4 cell counts <200 cells/microL, are at especially high risk for HPV-
related disease [44]. HPV vaccination with a three-dose schedule (at 0, 1 to 2, and 6 months) is
recommended for all immunocompromised patients through 26 years of age if they have not already
been vaccinated. Immunocompromising conditions that warrant this three-dose schedule include
B-lymphocyte antibody deficiencies, complete or partial T-lymphocyte defects, HIV infection,
malignant neoplasm, transplantation, autoimmune disease, and immunosuppressive therapy.
Direct efficacy data on HPV vaccination in immunocompromised hosts are lacking. Efficacy data are
emerging in patients with HIV, but they are not conclusive. In a study of females older than nine years
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with HIV who received quadrivalent vaccination, the incidence of new persistent vaccine-type HPV
infection was 1.1 per 100 person-years; although low, this rate was higher than that reported in
cohorts of women without HIV [45]. No cases of cervical intraepithelial neoplasia or worse were
detected in women with normal baseline cytology. In a separate trial of adults older than 26 years with
HIV, quadrivalent vaccination did not prevent persistent anal HPV infection, but the lack of efficacy
was likely related to prevalent prior HPV infection [46]. (See 'Anal disease' below.)
Nevertheless, studies of the HPV quadrivalent vaccine in adult men with HIV [47], women aged 16 to
23 years with HIV [48,49], and boys and girls aged 7 to 12 years with HIV [50] suggest that it is both
immunogenic and safe in these populations. Some [51] but not all [52] studies suggest a less robust
and shorter-lived immune response in the setting of HIV infection. Studies in other
immunocompromised populations are ongoing.
HPV vaccination in transplant recipients is discussed in detail elsewhere. (See "Immunizations in solid
organ transplant candidates and recipients", section on 'Human papillomavirus' and "Immunizations in
hematopoietic cell transplant candidates and recipients", section on 'Human papillomavirus'.)
Cancer screening continues to play an important role in detection and treatment of HPV-associated
disease in these high-risk individuals. (See 'Importance of cancer screening' below.)
EFFICACY AND IMMUNOGENICITY
Immunogenicity — Excellent antibody responses have been reported following immunization with
the 9-valent, quadrivalent, and bivalent vaccines, with seroconversion rates of 93 to 100 percent in
females and 99 to 100 percent in males [53-57]. Elicited titers are generally higher in younger than in
older individuals. Although there is no defined minimum threshold titer for protection, seroconversion
from prior exposure has been shown to reduce the risk of incident HPV infection with the same HPV
type [58,59]. This suggests that the titers resulting from natural infection, which are an order of
magnitude lower than those elicited in vaccine studies, provide some level of protection against
reinfection with the same HPV type.
Because initial efficacy trials were restricted to sexually active females 15 years of age and older,
immunological "bridging" studies conducted in younger females and in males demonstrate safety and
immunogenicity and thus support vaccine use in these other populations. With each of the three
vaccines, the geometric mean titers (GMT) of postvaccination antibodies among females aged 9 to 15
years were generally twofold higher than those observed in females aged 16 to 26 for all targeted
HPV types [55,60-64]. Similarly, GMT of postvaccination antibodies among males ages 9 to 26 were
at least comparable to those in females aged 16 to 26 years [55-57,61].
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In a head-to-head comparison of the immunogenicity of quadrivalent and bivalent HPV vaccines in

females ages 18 to 45 years, immunization with the bivalent vaccine induced GMT of serum
neutralizing antibodies 2.3- to 4.8-fold higher for HPV 16 and 6.8- to 9.1-fold higher for HPV 18 across
all age strata compared with the quadrivalent vaccine [65]. However, whether the induction of higher
serum titers against HPV 16 and 18 has any impact on the degree and duration of protection is
unknown.
Efficacy
Cervical, vaginal, and vulvar disease — HPV vaccination is effective in preventing cervical
disease, including cervical intraepithelial neoplasia (CIN2 or 3) and adenocarcinoma in situ [66]. This
has been demonstrated in large randomized trials of quadrivalent, 9-valent, and bivalent vaccines
and, as discussed below, has been supported by population data from regions reporting declines in
incidence of cervical disease following widespread HPV vaccination. In addition, quadrivalent and
9-valent HPV vaccines have been demonstrated to reduce the incidence of vaginal and vulvar
intraepithelial neoplasia (VAIN and VIN 1-3). Vaccine efficacy is greatest in those who do not have
prior HPV infection.
In the large licensing trials for the HPV vaccines, baseline HPV infection status was determined
through serologic testing and DNA detection in cervical specimens. Efficacy in the overall trial
populations was consistently lower than among the HPV-naïve population (those without baseline
HPV infection), as presented below. This reflects the fact that many trial participants were already
sexually active and previously infected with vaccine HPV types and highlights the importance of
vaccination prior to the onset of sexual activity to maximize effectiveness. (See 'Optimal timing'
above.)
● Quadrivalent HPV vaccine – Two large, randomized, double-blind trials compared quadrivalent
HPV vaccine with placebo among more than 17,000 females aged 15 to 26 [60,67]. After three
years, the efficacy of quadrivalent HPV vaccine for preventing CIN2 or more severe disease due
to HPV vaccine types was:
• 97 to 100 percent among HPV-naïve populations

• 44 percent among the overall population
Efficacy for preventing VIN2 or 3 and VaIN2 or 3 was similarly 100 percent among HPV-naïve
populations and 62 percent among the overall population [60].
● 9-valent HPV vaccine – An international randomized trial compared the 9-valent vaccine with
quadrivalent vaccine in approximately 14,000 females aged 16 to 26 years [68]. The efficacy of
the 9-valent vaccine for preventing CIN2 or more severe disease, VIN2 or 3, and VaIN2 or 3
associated with HPV types 31, 33, 45, 52, and 58 (the types not contained in the quadrivalent
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vaccine) was:
• 97 percent among the HPV-naïve population
In the overall population of study participants, the rates of high-grade cervical, vaginal, and vulvar
disease were the same among women who received the 9-valent vaccine and those who
received the quadrivalent vaccine (14 cases/1000 person-years in both groups).
● Bivalent HPV vaccine – Two large randomized trials compared bivalent HPV vaccine with
placebo or a non-HPV comparator vaccine in females aged 15 to 25 years [69,70]. Vaccine
efficacy was high in HPV-naïve populations in both of these trials. As an example, in one of the
trials, which included nearly 16,000 females, efficacy in preventing CIN2 or more severe disease
due to HPV vaccine types was:
• 93 percent among the HPV-naïve population

• 53 percent among the overall population
HPV vaccination also appears to be safe and effective in preventing subsequent infection and cervical
disease in older women, but the overall benefit is less than in younger females [20,21,71]. In a trial of
5752 women older than 25 years who were randomly assigned to receive bivalent vaccine or placebo
and followed for a mean of 84 months, vaccine efficacy for the combined endpoint (preventing six-
month persistent cervical HPV type 16 or 18 infection or vaccine-type associated CIN grade 1 or more
severe diagnoses) was 22 percent overall [20,21]. Among those who did not have a prior history of
HPV infection and received three doses of vaccine, vaccine efficacy was 91 percent.
Data collected outside the clinical trial setting are also favorable [72-81]; some of these demonstrate
decreased prevalence of HPV-related cervical disease following introduction of HPV vaccines into
national immunization programs. As an example, the 2007 implementation of a national program to
administer the quadrivalent vaccine to women aged 12 to 26 years in Australia led to high rates of
vaccine coverage, particularly among females under 18 years of age. In one study of the cervical
cytology registry in Victoria, Australia, there was a progressive decrease in the incidence of high-
grade cervical squamous intraepithelial lesions among girls 18 years of age or younger in the two
years after the vaccination program compared with the four years preceding it [72]. Reductions in
cervical disease have also been observed where vaccine uptake has been suboptimal. As an
example, in a study from New Mexico in the United States, where vaccine uptake ranged from 17 to
40 percent, the incidence of CIN continually decreased among females aged 15 to 19 years between
2007 and 2014 (10 and 40 percent reduction annually for CIN2 and CIN3, respectively) [78]. Although
many of these studies did not formally link individual vaccination status or implicated HPV type with
disease occurrence, they suggest an association between widespread vaccination and population
decreases in HPV-related disease that is consistent with the efficacy observed in clinical trials of the
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HPV vaccines and that may reflect vaccine-associated herd immunity.
All licensing trials and most observational data on HPV vaccination describe results with an intended
three-dose series. Results with fewer than three doses are discussed elsewhere. (See 'Immunization
schedule' above.)
Anal disease — Data informing the impact of HPV vaccine on anal intraepithelial neoplasia (AIN)
and anal cancers are more limited than that for cervical disease but suggest efficacy in males and
expected efficacy in females. As with cervical infection and disease, prior HPV infection appears to
attenuate vaccinate efficacy for anal infection and disease.
In a planned sub-study of 602 men who have sex with men aged 16 to 26 who participated in a large
placebo-controlled trial of the quadrivalent vaccine, efficacy in preventing AIN secondary to the
relevant HPV vaccine types was 78 percent among HPV-naïve males and 50 percent in the overall
population [82].
Among females, there are no direct efficacy data regarding prevention of AIN, but bivalent HPV
vaccination has been demonstrated to reduce the incidence of anal infection with HPV types 16 and
18 [83]. Since the majority of anal cancers in both females and males are related to HPV 16 and HPV
18, a beneficial impact of vaccination on AIN and anal cancer risk in females is anticipated [83].
Although a randomized trial of quadrivalent vaccination in nearly 600 HIV-infected individuals older
than 26 years demonstrated poor vaccine efficacy (approximately 20 percent compared with placebo)
in preventing new persistent anal HPV infection, baseline HPV infection and seropositivity were high,
and one-third had existing anal high-grade squamous, intraepithelial (HSIL) lesions [46]. Thus, the
findings are consistent with the understanding that the impact of HPV vaccination is reduced among
those with prior HPV infection. (See 'Optimal timing' above.)
Oral disease — Data informing the impact of HPV vaccine on oral disease are limited to studies
demonstrating a reduction in oral HPV infection following vaccination [46,84,85]. As an example, in a
trial originally designed to evaluate bivalent HPV vaccine efficacy against cervical HPV disease
among 7466 females in Costa Rica, fewer participants who were randomly assigned to receive
bivalent HPV vaccination (1 of 2910) had detectable HPV types 16 or 18 on an oral specimen four
years after vaccination compared with those who received the control hepatitis A vaccination (15 of
2924) [84]. Vaccine efficacy for the prevention of oral HPV infection was estimated to be 93 percent.
Whether HPV vaccination can prevent the development of HPV-related oropharyngeal cancer has not
yet been evaluated.
Anogenital warts — Clinical trials in females and males have demonstrated the efficacy of
quadrivalent HPV vaccine for preventing anogenital warts (condylomata acuminata) which are most
often caused by HPV types 6 and 11. Because 9-valent vaccine also targets these HPV types, it is
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expected to have similar efficacy. The bivalent HPV vaccine does not target these HPV types and thus
does not prevent anogenital warts.
In a large randomized trial among females aged 16 to 24 years, quadrivalent HPV vaccine efficacy for
preventing vulvar and vaginal condylomata was 100 percent among HPV-naïve participants (without
evidence of HPV vaccine types at enrollment) and 70 to 78 percent among the overall population (with
or without HPV infection at enrollment) [60]. Similarly, in a placebo-controlled randomized trial among
over 4000 males aged 16 to 26, quadrivalent HPV vaccine efficacy for preventing external genital
warts was 90 percent among HPV-naïve participants and 66 percent among the overall populations
[82].
Observational studies have also suggested that quadrivalent HPV vaccination prevents anogenital
warts [86-91]. As an example, in a study of nearly 400,000 females born between 1989 and 1999 in
Denmark, quadrivalent HPV vaccination was associated with a substantially lower risk of developing
genital warts (229 cases among 248,403 vaccinated versus 2241 cases among 151,367 unvaccinated
individuals after an average of 3.5 years of follow-up) [89]. Declines in the incidence of anogenital
warts have also been temporally associated with vaccine availability in both young women and men in
various countries, including Australia [87,88] and the United States [90,92].
Other HPV-associated disease — Human papillomavirus (HPV) vaccination might impact the
burden of recurrent respiratory papillomatosis, a benign but morbid laryngeal tumor in children thought
to be caused by HPV (typically types 6 and 11) acquired during passage through the birth canal of an
infected mother. In a study from Australia, the incidence of recurrent respiratory papillomatosis
decreased from 0.16 to 0.02 cases per 100,000 children between five and nine years of age following
introduction of a national quadrivalent HPV vaccination program among females [93]. All cases
occurred in offspring of unvaccinated females.
Some small studies have also suggested that HPV vaccination is associated with a decreased need
for surgery in patients with existing respiratory papillomatosis, but data are overall sparse and of
relatively low quality [94].
Duration of protection — HPV vaccines have shown excellent duration of protection for the time
periods through which they have been studied. Continued protection against high-grade cervical,
vaginal, and vulvar neoplasia has been observed through at least 10 years following vaccination
among female trial participants [95-97]. Persistent antibody levels and protection against HPV
infection have also been reported up to 10 years following vaccination [98-102]. Of note, the precise
level of antibody needed for protection against infection is unknown. Further data will become
available in the future as female and male participants in vaccine studies are followed over time.
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VACCINE SAFETY
Overview — All HPV vaccines have documented safety in large clinical trials, and extensive post-
licensure data (following approval and clinical use) on the quadrivalent vaccine support this safety
profile (see 'Quadrivalent vaccine (Gardasil)' below). They all use virus-like particles (VLPs), which
mimic the viral capsid, do not contain genetic material, and are produced in biologic systems, which
have well-established safety records [103].
In light of the growing data on the safety of the HPV vaccine, the World Health Organization (WHO)
Global Advisory Committee on Vaccine Safety stated that the benefit-risk profile remains favorable
[104]. Additionally, it warned against claims of harm that are raised on the basis of anecdotal reports
in the absence of biological or epidemiological substantiation.
Quadrivalent vaccine (Gardasil) — Data from both registration trials and post-licensure safety
surveillance systems demonstrate that the vaccine is safe and well tolerated apart from mild injection
site reactions. Postvaccination syncopal events have emerged as a potential serious adverse effect,
although it does not appear unique to HPV vaccination, since syncope after vaccination occurs with
other vaccines administered to adolescents [105,106]. A waiting time after vaccination is
recommended to try to reduce the likelihood of injury from possible syncope. (See 'Postvaccination
instructions' above.)
In the large licensing trials, the safety profile of the quadrivalent vaccine was evaluated in diverse
populations of females from both resource-rich and resource-limited settings [60,67]. Mild injection
site reactions were the most commonly observed adverse events in these studies as well as in trials in
males [82].
Subsequently, surveillance systems and observational studies of vaccinated populations have

supported the safety of quadrivalent vaccination []. As an example, in the United States, reports of
adverse events to the Vaccine Adverse Event Reporting System (VAERS) have been consistent with
the pre-licensure data [105,107]. Between June 2006 and March 2013, approximately 57 million
doses of quadrivalent HPV vaccines were distributed in the United States. Over this time, VAERS
received 21,194 reports of adverse events following HPV immunization among females; the vast
majority (92 percent) were considered mild [107]. Among serious events, headache, nausea,
vomiting, fatigue, dizziness, syncope, and generalized weakness were the most frequently reported.
There was no increased risk of Guillain-Barré Syndrome compared with other vaccines in similar age
groups [105].
There does appear to be an increased risk of syncope with the quadrivalent vaccine, but whether this
is unique to this vaccine is unclear. In the United States, a disproportionate number of syncopal
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events following quadrivalent vaccine administration had been reported to the VAERS [105]. Among
the 1896 syncopal events reported, 15 percent resulted in a fall or injury. Similarly, in an industry-
sponsored study of almost 190,000 females in a large health care system who received at least one
vaccine dose, emergency department visits or hospitalizations were higher during the postvaccine
period compared with a subsequent control period for 10 of 265 diagnostic categories evaluated,
including viral, bacterial, and skin infections and congenital anomalies [108]. An independent safety
committee concluded that same-day syncopal events (OR 6.0, 95% CI 3.9-9.2) and local skin
infections within two weeks of vaccination (OR 1.8, 95% CI 1.3-2.4) were the only adverse events
likely associated with vaccine administration. The incidence of syncope among adolescents has
increased overall with the introduction of other routine immunizations as well, such as meningococcal
vaccine [105,106].
A number of other adverse events have been described or reported to the VAERS following
administration of HPV vaccine, although causality is difficult to establish based on isolated reports. In
many cases, an association between vaccination and the specific adverse event was not
substantiated by further study [105,109-111]. Examples include the following:
● Although venous thromboembolism (VTE) rates reported to the VAERS in the United States were
higher for quadrivalent vaccine than other vaccines, of the 31 patients with thromboembolism
reported through 2008, 28 (90 percent) had a known risk factor (ie, estrogen-containing birth
control pills or a family history of clotting disorder) [105]. In a study of adverse events following
over 600,000 quadrivalent vaccine doses administered to females in seven large managed care
organizations, there was a nonsignificant increase in the risk of VTE following vaccination among
females aged 9 to 17 years, but individual review of the eight potential VTE cases indicated that
only five met the standard case definition and all had other known risk factors for VTE (eg, oral
contraceptive use, coagulation disorders, smoking, obesity, or prolonged hospitalization) [109].
Additionally, in a study of 1.6 million Danish women, of whom 30 percent had received
quadrivalent HPV vaccine, there were over 4000 cases of incident VTE, but there was no
association between vaccine receipt and VTE [112].
● Anaphylaxis had also been reported following administration of the quadrivalent vaccine
[105,113], although this risk has not been confirmed in other studies. In a mass school-based
national vaccination program in Australia, the incidence of anaphylaxis was 2.6 per 100,000
doses [113]. However, some of those cases were subsequently thought not to have represented
anaphylaxis and other studies from Australia did not confirm this high rate [114,115]. In the United
States VAERS surveillance system, only 10 cases met predefined criteria for anaphylaxis; the
overall risk ratio was 0.1 case per 100,000 doses distributed [105]. (See "Allergic reactions to
vaccines".)
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● Although anecdotal and sporadic case reports had raised concerns about a potential causal
relationship between HPV vaccination and development of multiple sclerosis and other
demyelinating disorders, larger studies have refuted this. In a study of nearly four million Swedish
and Danish females aged 10 to 44 years, receipt of quadrivalent vaccination was not associated
with demyelinating diseases, including multiple sclerosis, optic neuritis, transverse myelitis, and
acute disseminated encephalomyelitis, as documented by billing codes [110].
9-valent vaccine (Gardasil 9) — Fewer post-licensure safety data are available for the 9-valent
vaccine than the quadrivalent vaccine. The overall safety profile appears similar, although the
frequency of mild local reactions might be higher with the 9-valent vaccine. (See 'Quadrivalent vaccine
(Gardasil)' above.)
In an analysis of seven trials in which over 15,000 individuals received at least one dose of the
9-valent vaccine, the most common adverse effects were mild or moderate injection site reactions
(pain, erythema, and swelling) [116]. These occurred slightly more often than with the quadrivalent
vaccine. The frequency of systemic adverse effects (eg, headache, fever, nausea, dizziness) was
similar with the 9-valent and quadrivalent vaccines. Serious adverse effects occurred in <0.1 percent.
Bivalent vaccine (Cervarix) — Data from large placebo-controlled randomized trials indicate that
bivalent HPV vaccine is safe. As an example, in one trial of more than 18,000 females aged 15 to 25
years, there were no differences in serious adverse events between vaccine and placebo recipients.
Post-licensure data are sparse from the United States, where almost all HPV vaccine used through
2015 was quadrivalent vaccine. In the United States, there were 52 reports to VAERS of adverse
events following administration of bivalent vaccine through September 2011, and 98 percent were
considered nonserious.
Behavioral impact — Some surveys of parents of adolescent girls identified a concern for sexual
disinhibition following HPV vaccine receipt, particularly among older and ethnic minority parents
[117,118]. Studies have not supported an association between vaccination and increased risky sexual
behavior [119-122]. In a retrospective study of preteenage girls enrolled in a large health care system,
the combined incidence of pregnancy testing, chlamydia testing, and contraception counseling was
determined among those girls who did (n = 493) and did not (n = 905) receive at least one HPV
vaccine dose [119]. After adjustment for baseline health care utilization, race, and socioeconomic
status, HPV vaccination was not associated with an increased rate of these sexual activity-related
outcomes.
Where to report adverse events — Additional data on the Vaccine Adverse Event Reporting System
are available on the web. Instructions for reporting adverse events to the Vaccine Adverse Event
Reporting System are available at www.vaers.hhs.gov or by calling 800-822-7967 in the United
States.
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STRATEGIES TO IMPROVE VACCINE COVERAGE
Some countries, such as Australia, the United Kingdom, and Denmark, have achieved relatively high
full-dose uptake of HPV vaccination (>60 percent) through inclusion of the vaccine in national
vaccination programs [123-125]. In the United States, uptake of HPV vaccination has been suboptimal
[126,127]. In 2015, based on results of a national survey among adolescents who had provider-
reported vaccination records, estimated vaccine coverage among females and males aged 13 to 17
was 63 and 50 percent for at least one dose and only 42 and 28 percent for at least three doses (at a
time when three doses was the recommended schedule for all recipients) [126]. In an earlier survey,
parents who did not intend to have their daughters vaccinated gave the following as their top five
reasons: the vaccine was not needed, the vaccine was not recommended, concern about vaccine
safety, lack of knowledge about the vaccine or disease, and lack of sexual activity by their daughter
[107]. This highlights a lack of understanding about the rationale for HPV vaccination on the part of
the parent and the important role of the health care provider in consistently and clearly educating
parents about vaccination. Other studies have also identified an association between direct provider
recommendation and vaccine receipt [128,129].
Lack of opportunity does not appear to be a major reason for low vaccine coverage. Of the
unvaccinated females in the survey described above, 84 percent had at least one medical visit at
which they were given a different vaccine but not the HPV vaccine [107]. Vaccination rates may be
particularly low among certain demographic subgroups. As an example, in a survey of 3253 females
aged 15 to 25 years, only 29 percent reported initiating HPV vaccination despite 84 percent being
aware of it [130]. Among self-described lesbians, only 9 percent of those aware of HPV vaccination
had received it.
The implications of these findings are significant. Some experts estimate that by increasing complete-
dose HPV vaccination coverage (with either bivalent or quadrivalent vaccine) to 80 percent in
females, approximately 53,000 additional cases of cervical cancer could be prevented in the United
States over the lifetimes of those currently aged ≤12 years [131]. More cervical cancers would
conceivably be prevented with similar coverage with the 9-valent vaccine.
Attempted community- or practice-based interventions to improve uptake of HPV vaccine include

patient reminders, physician-focused interventions (auditing and feedback or alerts to remind
physicians to offer vaccination), school-based vaccination programs, and social marketing strategies.
In a systematic review of studies evaluating the efficacy of such interventions, most suggested an
improvement in at least one HPV vaccination outcome (eg, initiation or completion of greater number
of doses) with these strategies [132].
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IMPORTANCE OF CANCER SCREENING
Cervical screening — Clinicians should be aware that HPV immunization is not effective in clearing
HPV infection, genital warts, or cervical intraepithelial neoplasia that is already present, and the
vaccine does not protect against 100 percent of types known to cause cervical cancer. Thus, HPV
vaccination status does not impact cervical cancer screening recommendations. In the United States,
cervical cancer screening is recommended for all females beginning at age 21 (table 1). A preventive
health care visit is an opportune time to discuss and offer HPV vaccination and/or cervical screening
depending on the age of the woman [133]. Detailed information regarding screening for cervical
cancer is found elsewhere. (See "Screening for cervical cancer".)
The optimal approach to cervical cancer screening in HPV-naïve females who have received the
9-valent vaccine and are thus protected against 90 percent of cervical cancer is unclear, but until
further data are available and new screening guidelines issued, screening should continue for all
vaccinated females.
Anal screening — Although there are no formal guidelines regarding screening for precancerous
anal lesions, some specialists recommend anal cytologic screening for HIV-infected males and
females and other populations known to be at increased risk of anal cancer. (See "Cervical
intraepithelial neoplasia: Terminology, incidence, pathogenesis, and prevention" and "HIV and
women" and "Immunizations in HIV-infected patients" and "Anal squamous intraepithelial lesions:
Diagnosis, screening, prevention, and treatment", section on 'Screening for anal SIL'.)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Immunizations in children and
adolescents" and "Society guideline links: Immunizations in adults" and "Society guideline links:
Cervical cancer screening and prevention".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The
Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and
they answer the four or five key questions a patient might have about a given condition. These articles
are best for patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These
18 de 36 04/07/2019 22:12
articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth
information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Human papillomavirus (HPV) vaccine (The Basics)" and
"Patient education: Anogenital warts (The Basics)" and "Patient education: Pap tests (The
Basics)" and "Patient education: Vaccines for children age 7 to 18 years (The Basics)")
● Beyond the Basics topics (see "Patient education: Human papillomavirus (HPV) vaccine (Beyond
the Basics)" and "Patient education: Genital warts in women (Beyond the Basics)" and "Patient
education: Cervical cancer screening (Beyond the Basics)" and "Patient education: Vaccines for
children age 7 to 18 years (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
● Three human papillomavirus (HPV) vaccines have been clinically developed, although not all are
available in all locations:
• Quadrivalent vaccine (Gardasil) targets HPV types 6, 11, 16, and 18.
• 9-valent vaccine (Gardasil 9) targets HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58.
• Bivalent vaccine (Cervarix) targets HPV types 16 and 18.
In the United States, only the 9-valent vaccine has been available since the end of 2016. (See
'Available vaccines' above.)
● Vaccination with 9-valent, quadrivalent, or bivalent HPV vaccine provides a direct benefit to
female and male recipients by safely protecting against cancers that can result from persistent
high-risk HPV infection. HPV types 16 and 18 cause approximately 70 percent of all cervical
cancers worldwide and nearly 90 percent of anal cancers, as well as a significant proportion of
oropharyngeal cancer, vulvar and vaginal cancer, and penile cancer. Quadrivalent and 9-valent
vaccine also protect against anogenital warts, 90 percent of which are caused by HPV types 6
and 11. Although the burden of HPV-associated disease is lower in males than females and thus
the direct absolute benefit to males is smaller, the indirect benefit to males from vaccinating
females only is incomplete and vaccinating males provides additional population benefits from
herd immunity. (See 'Rationale' above.)
● In accordance with the Advisory Committee on Immunization Practices (ACIP) in the United
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States, we recommend routine HPV vaccination for females (Grade 1A) and males (Grade 1B).
The recommended age ranges for administration are as follows:
• For females – Routine immunization should be offered at 11 to 12 years of age, but can be
administered starting at 9 years. Catch-up vaccination should be offered for females aged 13
to 26 years who have not been previously vaccinated.
• For males – Routine immunization should be offered at 11 to 12 years of age, but can be
administered starting at 9 years. Catch-up vaccination should be offered for males between
the ages of 13 to 21 who have not been previously vaccinated. For men who have sex with
men (MSM) and immunocompromised males, catch-up vaccination should be offered up to
age 26.
Within the recommended age range, the optimal time for HPV immunization is prior to an
individual's sexual debut. HPV vaccination is also reasonable for older individuals who have a low
risk of prior HPV exposure (eg, no prior sexual experience or certain lifelong sexual monogamy)
but are at risk for future exposure. (See 'Indications and age range' above and 'Optimal timing'
above.)
● If cost and availability are not issues, we recommend the 9-valent HPV vaccine rather than other
HPV vaccines (Grade 1B). For individuals starting any HPV vaccine series when they are
younger than 15 years old, we suggest administering a two- rather than a three-dose vaccine
series (Grade 2C). In such patients, the two doses are administered at least six months apart.
For individuals starting any HPV vaccine series at 15 years and older, the HPV vaccine is
administered in three doses at 0, at 1 to 2 months, and at 6 months. Immunocompromised
patients should also receive a three-dose series. (See 'Immunization schedule' above.)
● HPV vaccination during pregnancy is typically avoided because of limited information about
safety; however, data from inadvertent use in this setting are increasingly available and
reassuring. (See 'Pregnant or breastfeeding females' above.)
● Excellent antibody responses have been reported following immunization with the 9-valent,
quadrivalent, and bivalent vaccines, with seroconversion rates of 93 to 100 percent in females
and 99 to 100 percent in males. Elicited titers are generally higher in younger than in older
individuals. (See 'Immunogenicity' above.)
● Multicenter, double-blind, placebo-controlled trials have demonstrated the efficacy of

quadrivalent, 9-valent, and bivalent HPV vaccines against incident and persistent cervical HPV
infection due to vaccine types and the development of cervical intraepithelial neoplasia.
Quadrivalent and 9-valent HPV vaccines have also demonstrated high efficacy against vaccine
type-associated vaginal and vulvar intraepithelial neoplasia. They have demonstrated efficacy
20 de 36 04/07/2019 22:12
against genital warts associated with HPV 6 and HPV 11. Reduction in anal intraepithelial
neoplasia in MSM, anal HPV infection in females, and oral HPV infection in females has also
been demonstrated in trials. (See 'Efficacy' above.)
● Data from both registration trials and post-licensure safety surveillance systems demonstrate that
the vaccine is safe and well tolerated apart from mild injection site reactions. Postvaccination
syncopal events have emerged as a potential serious adverse effect, although it does not appear
unique to HPV vaccination. (See 'Vaccine safety' above.)
● Clinicians should be aware that HPV immunization is not effective in clearing HPV infection,
genital warts, or anogenital intraepithelial neoplasia that is already present. HPV vaccination
status does not impact cervical cancer screening recommendations. (See 'Importance of cancer
screening' above and "Screening for cervical cancer".)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Philip Castle,
PhD, MPH, who contributed to an earlier version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
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51. Brophy J, Bitnun A, Alimenti A, et al. Immunogenicity and Safety of the Quadrivalent Human
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Papillomavirus Vaccine in Girls Living With HIV. Pediatr Infect Dis J 2018; 37:595.
52. Levin MJ, Huang S, Moscicki AB, et al. Four-year persistence of type-specific immunity after
quadrivalent human papillomavirus vaccination in HIV-infected children: Effect of a fourth dose
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53. GlaxoSmithKline Vaccine HPV-007 Study Group, Romanowski B, de Borba PC, et al. Sustained
efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted
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374:1975.
54. Vesikari T, Brodszki N, van Damme P, et al. A Randomized, Double-Blind, Phase III Study of the
Immunogenicity and Safety of a 9-Valent Human Papillomavirus L1 Virus-Like Particle Vaccine
(V503) Versus Gardasil® in 9-15-Year-Old Girls. Pediatr Infect Dis J 2015; 34:992.
55. Gardasil 9 (Human papillomavirus 9-valent vaccine, recombinant. US FDA approved product inf
ormation; Whitehouse Station, NJ: Merck & Co, Inc. December 2014.
56. Petäjä T, Keränen H, Karppa T, et al. Immunogenicity and safety of human papillomavirus
(HPV)-16/18 AS04-adjuvanted vaccine in healthy boys aged 10-18 years. J Adolesc Health
2009; 44:33.
57. Reisinger KS, Block SL, Lazcano-Ponce E, et al. Safety and persistent immunogenicity of a
quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in
preadolescents and adolescents: a randomized controlled trial. Pediatr Infect Dis J 2007;
26:201.
58. Lin SW, Ghosh A, Porras C, et al. HPV16 seropositivity and subsequent HPV16 infection risk in
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59. Safaeian M, Porras C, Schiffman M, et al. Epidemiological study of anti-HPV16/18 seropositivity

and subsequent risk of HPV16 and -18 infections. J Natl Cancer Inst 2010; 102:1653.
60. Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human
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61. Van Damme P, Olsson SE, Block S, et al. Immunogenicity and Safety of a 9-Valent HPV
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64. Pedersen C, Petaja T, Strauss G, et al. Immunization of early adolescent females with human
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65. Einstein MH, Baron M, Levin MJ, et al. Comparison of the immunogenicity and safety of
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66. Arbyn M, Xu L, Simoens C, Martin-Hirsch PP. Prophylactic vaccination against human

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67. FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-
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68. Joura EA, Giuliano AR, Iversen OE, et al. A 9-valent HPV vaccine against infection and
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69. Paavonen J, Naud P, Salmerón J, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-
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374:301.
70. Hildesheim A, Wacholder S, Catteau G, et al. Efficacy of the HPV-16/18 vaccine: final according
to protocol results from the blinded phase of the randomized Costa Rica HPV-16/18 vaccine
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71. Castle PE, Schmeler KM. HPV vaccination: for women of all ages? Lancet 2014; 384:2178.
72. Brotherton JM, Fridman M, May CL, et al. Early effect of the HPV vaccination programme on
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73. Crowe E, Pandeya N, Brotherton JM, et al. Effectiveness of quadrivalent human papillomavirus
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vaccination on cervical neoplasia--nationwide follow-up of young Danish women. J Natl Cancer
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75. Smith LM, Strumpf EC, Kaufman JS, et al. The early benefits of human papillomavirus
vaccination on cervical dysplasia and anogenital warts. Pediatrics 2015; 135:e1131.
76. Hofstetter AM, Ompad DC, Stockwell MS, et al. Human Papillomavirus Vaccination and Cervical
Cytology Outcomes Among Urban Low-Income Minority Females. JAMA Pediatr 2016; 170:445.
77. Garland SM, Kjaer SK, Muñoz N, et al. Impact and Effectiveness of the Quadrivalent Human
Papillomavirus Vaccine: A Systematic Review of 10 Years of Real-world Experience. Clin Infect
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78. Benard VB, Castle PE, Jenison SA, et al. Population-Based Incidence Rates of Cervical
Intraepithelial Neoplasia in the Human Papillomavirus Vaccine Era. JAMA Oncol 2016.
79. Silverberg MJ, Leyden WA, Lam JO, et al. Effectiveness of catch-up human papillomavirus
vaccination on incident cervical neoplasia in a US health-care setting: a population-based case-
control study. Lancet Child Adolesc Health 2018; 2:707.
80. Palmer T, Wallace L, Pollock KG, et al. Prevalence of cervical disease at age 20 after
immunisation with bivalent HPV vaccine at age 12-13 in Scotland: retrospective population
study. BMJ 2019; 365:I1161.
81. McClung NM, Gargano JW, Park IU, et al. Estimated Number of Cases of High-Grade Cervical
Lesions Diagnosed Among Women - United States, 2008 and 2016. MMWR Morb Mortal Wkly
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82. Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV
Infection and disease in males. N Engl J Med 2011; 364:401.
83. Kreimer AR, González P, Katki HA, et al. Efficacy of a bivalent HPV 16/18 vaccine against anal
HPV 16/18 infection among young women: a nested analysis within the Costa Rica Vaccine
Trial. Lancet Oncol 2011; 12:862.
84. Herrero R, Quint W, Hildesheim A, et al. Reduced prevalence of oral human papillomavirus
(HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLoS
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One 2013; 8:e68329.
85. Chaturvedi AK, Graubard BI, Broutian T, et al. Effect of Prophylactic Human Papillomavirus
(HPV) Vaccination on Oral HPV Infections Among Young Adults in the United States. J Clin
Oncol 2018; 36:262.
86. Tabrizi SN, Brotherton JM, Kaldor JM, et al. Fall in human papillomavirus prevalence following a
national vaccination program. J Infect Dis 2012; 206:1645.
87. Donovan B, Franklin N, Guy R, et al. Quadrivalent human papillomavirus vaccination and trends
in genital warts in Australia: analysis of national sentinel surveillance data. Lancet Infect Dis
2011; 11:39.
88. Read TR, Hocking JS, Chen MY, et al. The near disappearance of genital warts in young women
4 years after commencing a national human papillomavirus (HPV) vaccination programme. Sex
Transm Infect 2011; 87:544.
89. Blomberg M, Dehlendorff C, Munk C, Kjaer SK. Strongly decreased risk of genital warts after
vaccination against human papillomavirus: nationwide follow-up of vaccinated and unvaccinated
girls in Denmark. Clin Infect Dis 2013; 57:929.
90. Bauer HM, Wright G, Chow J. Evidence of human papillomavirus vaccine effectiveness in
reducing genital warts: an analysis of California public family planning administrative claims
data, 2007-2010. Am J Public Health 2012; 102:833.
91. Yakely AE, Avni-Singer L, Oliveira CR, Niccolai LM. Human Papillomavirus Vaccination and
Anogenital Warts: A Systematic Review of Impact and Effectiveness in the United States. Sex
Transm Dis 2019; 46:213.
92. Flagg EW, Schwartz R, Weinstock H. Prevalence of anogenital warts among participants in
private health plans in the United States, 2003-2010: potential impact of human papillomavirus
vaccination. Am J Public Health 2013; 103:1428.
93. Novakovic D, Cheng ATL, Zurynski Y, et al. A Prospective Study of the Incidence of Juvenile-
Onset Recurrent Respiratory Papillomatosis After Implementation of a National HPV Vaccination
Program. J Infect Dis 2018; 217:208.
94. Rosenberg T, Philipsen BB, Mehlum CS, et al. Therapeutic Use of the Human Papillomavirus
Vaccine on Recurrent Respiratory Papillomatosis: A Systematic Review and Meta-Analysis. J
Infect Dis 2019; 219:1016.
95. Lehtinen M, Paavonen J, Wheeler CM, et al. Overall efficacy of HPV-16/18 AS04-adjuvanted
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vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study

analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol 2012; 13:89.
96. Huh WK, Joura EA, Giuliano AR, et al. Final efficacy, immunogenicity, and safety analyses of a
nine-valent human papillomavirus vaccine in women aged 16-26 years: a randomised, double-
blind trial. Lancet 2017; 390:2143.
97. Kjaer SK, Nygård M, Dillner J, et al. A 12-Year Follow-up on the Long-Term Effectiveness of the
Quadrivalent Human Papillomavirus Vaccine in 4 Nordic Countries. Clin Infect Dis 2018; 66:339.
98. Rowhani-Rahbar A, Mao C, Hughes JP, et al. Longer term efficacy of a prophylactic monovalent
human papillomavirus type 16 vaccine. Vaccine 2009; 27:5612.
99. Naud PS, Roteli-Martins CM, De Carvalho NS, et al. Sustained efficacy, immunogenicity, and
safety of the HPV-16/18 AS04-adjuvanted vaccine: final analysis of a long-term follow-up study
up to 9.4 years post-vaccination. Hum Vaccin Immunother 2014; 10:2147.
100. Ferris D, Samakoses R, Block SL, et al. Long-term study of a quadrivalent human
papillomavirus vaccine. Pediatrics 2014; 134:e657.
101. Toh ZQ, Russell FM, Reyburn R, et al. Sustained Antibody Responses 6 Years Following 1, 2, or
3 Doses of Quadrivalent Human Papillomavirus (HPV) Vaccine in Adolescent Fijian Girls, and
Subsequent Responses to a Single Dose of Bivalent HPV Vaccine: A Prospective Cohort Study.
Clin Infect Dis 2017; 64:852.
102. Donken R, King AJ, Bogaards JA, et al. High Effectiveness of the Bivalent Human
Papillomavirus (HPV) Vaccine Against Incident and Persistent HPV Infections up to 6 Years
After Vaccination in Young Dutch Women. J Infect Dis 2018; 217:1579.
103. Frazer IH, Cox JT, Mayeaux EJ Jr, et al. Advances in prevention of cervical cancer and other
human papillomavirus-related diseases. Pediatr Infect Dis J 2006; 25:S65.
104. World Health Organization. Global Advisory Committee on Vaccine Safety statement on the cont
inued safety of HPV vaccination. March 12, 2014. http://www.who.int/vaccine_safety/committee/t
opics/hpv/GACVS_Statement_HPV_12_Mar_2014.pdf (Accessed on September 04, 2014).
105. Slade BA, Leidel L, Vellozzi C, et al. Postlicensure safety surveillance for quadrivalent human
papillomavirus recombinant vaccine. JAMA 2009; 302:750.
106. Centers for Disease Control and Prevention (CDC). Syncope after vaccination--United States,
January 2005-July 2007. MMWR Morb Mortal Wkly Rep 2008; 57:457.
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107. Human Papillomavirus Vaccination Coverage Among Adolescent Girls, 2007–2012, and
Postlicensure Vaccine Safety Monitoring, 2006–2013 — United States. MMWR Recomm Rep
2013; 62:591.
108. Klein NP, Hansen J, Chao C, et al. Safety of quadrivalent human papillomavirus vaccine
administered routinely to females. Arch Pediatr Adolesc Med 2012; 166:1140.
109. Gee J, Naleway A, Shui I, et al. Monitoring the safety of quadrivalent human papillomavirus
vaccine: findings from the Vaccine Safety Datalink. Vaccine 2011; 29:8279.
110. Scheller NM, Svanström H, Pasternak B, et al. Quadrivalent HPV vaccination and risk of
multiple sclerosis and other demyelinating diseases of the central nervous system. JAMA 2015;
313:54.
111. Naleway AL, Mittendorf KF, Irving SA, et al. Primary Ovarian Insufficiency and Adolescent
Vaccination. Pediatrics 2018; 142.
112. Scheller NM, Pasternak B, Svanström H, Hviid A. Quadrivalent human papillomavirus vaccine
and the risk of venous thromboembolism. JAMA 2014; 312:187.
113. Brotherton JM, Gold MS, Kemp AS, et al. Anaphylaxis following quadrivalent human
papillomavirus vaccination. CMAJ 2008; 179:525.
114. Douglas RJ. Anaphylaxis following quadrivalent human papillomavirus vaccination - even safer
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disinhibition. Sex Transm Infect 2011; 87:349.
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vaccination within the free-of-charge childhood vaccination programme in Denmark. Vaccine
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Area Vaccination Coverage Among Adolescents Aged 13-17 Years - United States, 2016.
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J Pediatr 2019; 206:33.
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and younger in the United States. Sex Transm Dis 2014; 41:656.
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133. Saslow D, Castle PE, Cox JT, et al. American Cancer Society Guideline for human
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Clin 2007; 57:7.
Topic 8325 Version 74.0
33 de 36 04/07/2019 22:12
GRAPHICS
Cervical cancer screening recommendations from United States professional

organizations*
Recommended
screening test Post-
Age to Age to
and frequency hysterectomy HPV
Organization initiate discontinue
for benign vaccination
(years) (years) Age 21 to
Age ≥30 disease
29
(years)
(years)
ACS/ASCCP/ASCP 21 ¶ 65 Δ Pap test One of these Not indicated ◊ Same

(2012) every 3 years methods: recommendations
(preferred) Co-testing as unvaccinated
(Pap test women
and HPV
testing)
every 5
years
(preferred)
Pap test
every 3
years
ASCCP/SGO 21 N/A Can consider Can consider N/A N/A

(2015 interim primary HPV primary HPV
guidelines) testing testing every 3
every 3 years years
for women
age ≥25
USPSTF (2018) 21 65 § Pap test One of these Not indicated ¥ Same

every 3 years methods: recommendations
Pap test as unvaccinated
every 3 women
years
hrHPV
testing
alone
every 5
years
Co-testing
(Pap test
and HPV
testing)
every 5
years
ACOG (2016) 21 65 ‡ One of these One of these Not indicated † Same

methods: methods: recommendations
Pap test Co-testing as unvaccinated
every 3 (Pap test women
years and HPV
Can testing)
consider every 5
primary years
HPV (preferred)
testing Pap test
34 de 36 04/07/2019 22:12
every 3 every 3
years years
for Can
women consider
age ≥25 primary
HPV testing
every 3
years for
women age
≥25
ACP (2015) 21 65 § Pap test One of these Not indicated ¥ N/A

every 3 years methods:
Pap test
every 3
years
Alternative:
Co-testing
(Pap test
and HPV
testing)
every 5
years
HPV: human papillomavirus; ACS: American Cancer Society; ASCCP: American Society for Colposcopy and Cervical Pathology;
ASCP: American Society for Clinical Pathology; SGO: Society of Gynecologic Oncology; USPSTF: United States Preventive
Services Task Force; ACOG: American College of Obstetricians and Gynecologists; ACP: American College of Physicians;
hrHPV: high-risk human papillomavirus; DES: diethylstilbestrol; HIV: human immunodeficiency virus; CIN: cervical
intraepithelial neoplasia.
* These guidelines are intended for the general population and are not intended for women who have a history of cervical
cancer, high-grade cervical precancers, DES in utero exposure, or who are immunocompromised, as with HIV infection.
¶ Regardless of the age of sexual initiation or other risk factors.
Δ For women with evidence of adequate negative prior screening (3 consecutive negative cytology results or 2 consecutive
negative co-tests within the previous 10 years, with the most recent test within the previous 5 years) and no history of CIN 2
or greater within the last 20 years. Screening should not be resumed for any reason, even if a woman has a new sexual
partner.
◊ For women who have had a benign hysterectomy with removal of the cervix who do not have a history of CIN 2, CIN 3 in the
past 20 years, or a history of cervical cancer ever. Evidence of adequate negative prior screening not required.
§ For women with evidence of adequate negative prior screening, specified as 3 consecutive negative cytology results or 2
consecutive negative co-tests within the previous 10 years, with the most recent test within the previous 5 years.
¥ For women who have had a benign hysterectomy with removal of the cervix who do not have a history of CIN 2 or higher.
‡ For women with no history of CIN 2 or higher with evidence of prior adequate screening (3 or more negative cytology test
results in a row or 2 consecutive negative co-tests in the past 10 years, with the most recent within the past 5 years).
† For women who have had a benign hysterectomy with removal of the cervix who do not have a history of CIN 2, CIN 3, or
cervical cancer. Women in whom a negative history cannot be documented should continue to be screened.
Reference:
1. Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical
Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of
cervical cancer. CA Cancer J Clin 2012; 62:147.Curry SJ. Screening for cervical cancer: United States Preventive
Services Task Force recommendation statement. JAMA 2018; 320:674.
2. Cervical cytology screening. ACOG Practice Bulletin No. 157. American College of Obstetricians and Gynecologists.
Obstet Gynecol 2016; 127:e1
3. Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer
screening: Interim clinical guidance. Gynecol Oncol 2015; 136:178. http://dx.doi.org/10.1016/j.ygyno.2014.12.022.
4. Sawaya GF, Kulasingam S, Denberg TD, et al. Cervical Cancer Screening in Average-Risk Women: Best Practice Advice
From the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med 2015; 162:851.
Graphic 82951 Version 19.0
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Human papillomavirus vaccination - UpToDate https://bibvirtual.upch.edu.pe:2050/contents/human-papillomavirus-vacc...

Official reprint from UpToDate®

● Bivalent vaccine (Cervarix) targets HPV types 16 and 18.

Dosing and administration is discussed elsewhere. (See 'Administration' below.)

● Females – HPV vaccine is recommended at 11 to 12 years. It can be administered starting at 9

● Males – HPV vaccine is recommended at 11 to 12 years. It can be administered starting at 9

● Immunocompromised patients – Three doses of HPV vaccine should be given at 0, 1 to 2, and

Prevaccination assessment — HPV vaccination can be administered without special evaluation.

Postvaccination serology — There is no evidence that the measurement of postvaccination

Pregnant or breastfeeding females — HPV vaccination during pregnancy is not recommended

Immunocompromised patients — Immunocompromised patients, particularly transplant recipients

EFFICACY AND IMMUNOGENICITY

In a head-to-head comparison of the immunogenicity of quadrivalent and bivalent HPV vaccines in

• 97 to 100 percent among HPV-naïve populations

• 97 percent among the HPV-naïve population

• 93 percent among the HPV-naïve population

HPV vaccines and that may reflect vaccine-associated herd immunity.

Subsequently, surveillance systems and observational studies of vaccinated populations have

STRATEGIES TO IMPROVE VACCINE COVERAGE

Attempted community- or practice-based interventions to improve uptake of HPV vaccine include

IMPORTANCE OF CANCER SCREENING

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

● Multicenter, double-blind, placebo-controlled trials have demonstrated the efficacy of

Use of UpToDate is subject to the Subscription and License Agreement.

against HPV infection? Recommendation based on cost-effectiveness analyses. J Infect Dis

practices. MMWR Morb Mortal Wkly Rep 2015; 64:300.

22. Castellsagué X, Muñoz N, Pitisuttithum P, et al. End-of-study safety, immunogenicity, and

27. Saslow D, Andrews KS, Manassaram-Baptiste D, et al. Human papillomavirus vaccination

Clinical Oncology resource-stratified guideline. March 17, 2017. http://www.asco.org/practice-gui

32. Kosalaraksa P, Mehlsen J, Vesikari T, et al. An open-label, randomized study of a 9-valent

38. Ogilvie G, Sauvageau C, Dionne M, et al. Immunogenicity of 2 vs 3 Doses of the Quadrivalent

41. Blomberg M, Dehlendorff C, Sand C, Kjaer SK. Dose-Related Differences in Effectiveness of

59. Safaeian M, Porras C, Schiffman M, et al. Epidemiological study of anti-HPV16/18 seropositivity

66. Arbyn M, Xu L, Simoens C, Martin-Hirsch PP. Prophylactic vaccination against human

One 2013; 8:e68329.

vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study

125. Widgren K, Simonsen J, Valentiner-Branth P, Mølbak K. Uptake of the human papillomavirus-

Topic 8325 Version 74.0

Cervical cancer screening recommendations from United States professional

ACS/ASCCP/ASCP 21 ¶ 65 Δ Pap test One of these Not indicated ◊ Same

ASCCP/SGO 21 N/A Can consider Can consider N/A N/A

USPSTF (2018) 21 65 § Pap test One of these Not indicated ¥ Same

ACOG (2016) 21 65 ‡ One of these One of these Not indicated † Same

ACP (2015) 21 65 § Pap test One of these Not indicated ¥ N/A

Graphic 82951 Version 19.0

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