INTRODUCTION — Human
papillomavirus is a sexually transmitted pathogen that causes
anogenital disease in males and females. Persistent viral infection with
high-risk human papillomavirus (HPV) genotypes causes virtually all
cancers of the cervix. The same HPV genotypes (or "types") that cause
cancer of the cervix also cause most cases of anal cancer [
1]
and significant proportion of oropharyngeal cancer in men and women, a
significant proportion of vulvar and vaginal cancer, and significant
proportion of penile cancer. Three vaccines have been developed against
HPV infection; one is a quadrivalent vaccine (Gardasil), one is 9-valent
(Gardasil 9), and the other is a bivalent vaccine (Cervarix).
This
topic will cover issues related to routine immunization
recommendations, vaccination in special patient populations, and vaccine
safety. The natural history, details on epidemiology, and immunology of
HPV infection, as well as clinical trial data on HPV vaccines are
discussed elsewhere. (See
"Epidemiology of human papillomavirus infections" and
"Clinical trials of human papillomavirus vaccines" and
"The life cycle, natural history, and immunology of human papillomaviruses".)
DISEASE ASSOCIATIONS
HPV-related disease in females
Cervical cancer and precursor lesions — Cervical
cancer is the third most common female cancer worldwide, with an
estimated incidence of 530,000 and 270,000 related deaths in 2012; the
attributable fraction due to HPV infection was estimated to be 100
percent [
2,3].
HPV types 16 and 18 cause approximately 70 percent of cervical cancers
and 50 percent of precancerous cervical lesions (ie, cervical
intraepithelial neoplasia grade 2 and grade 3
[CIN2/3]). HPV types 31, 33, 45, 52, and 58 are estimated to cause an additional 19 percent of invasive cervical cancers [
4].
The estimated annual incidence in the United States of CIN among
females who undergo cervical cancer screening is 0.4 percent for CIN 1
and 0.5 percent for CIN
2/3 [
5]. (See
"Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis" and
"Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and prevention", section on 'Incidence'.)
Vulvar and vaginal cancer and precursor lesions — Vulvar
and vaginal cancer are rare cancers globally, with an estimated
incidence of 27,000 vulvar cancers and 13,000 vaginal cancers in 2008;
the attributable fraction due to HPV infection has been estimated to be
43 percent for vulvar cancer and 70 percent for vaginal cancer [
2].
Other data have suggested that only 29 percent of vulvar cancers are
HPV positive whereas 87 percent of vulvar intraepithelial neoplasia
(VIN) are HPV positive [
6].
HPV 16 and HPV 18 cause approximately 60 percent of HPV-positive
vaginal cancers and precancerous vaginal lesions; HPV 16 and HPV 18
cause approximately 35 to 77 percent of HPV-positive vulvar cancers and
75 to 80 percent of precancerous vulvar lesions [
6,7]. (See
"Vaginal cancer" and
"Vulvar intraepithelial neoplasia".)
HPV-related disease in females and males
Anal cancer and precursor lesions — Anal cancer is a rare cancer globally, with an estimated incidence of 27,000 in 2008 [
2]. The attributable fraction of cases due to HPV is approximately 88 percent [
2,8].
HPV types 16 and 18 cause approximately 70 to 85 percent of anal
cancers and precancerous anal lesions (ie, anal intraepithelial
neoplasia grade 2 and grade 3
[AIN2/3]) [
1,8,9]. Although it remains an uncommon cancer, the incidence of anal cancer is increasing in the United States and other countries [
10-12].
In data from the Surveillance, Epidemiology and End Results program of
the National Cancer Institute, the annual incidence among males and
females between 1994 and 2000 was approximately 2 per 100,000 [
10].
The annual incidence of anal cancer among men who have sex with men
(MSM) was estimated to be as high as 37 per 100,000 prior to the HIV
epidemic [
13], and the incidence of anal cancer among HIV-positive MSM is estimated to be approximately twice that of HIV-negative MSM [
14,15]. (See
"Classification and epidemiology of anal cancer", section on 'Epidemiology and risk factors'.)
Genital warts — HPV
types 6 and 11 also cause 90 percent of genital warts. The incidence of
HPV infection was evaluated in 8800 females who were enrolled in the
placebo arms of two randomized trials of the HPV quadrivalent vaccine [
16].
Three percent of the placebo recipients developed genital warts over
approximately four years, the vast majority of which were associated
with HPV 6 or HPV 11 infection. (See
"Epidemiology of human papillomavirus infections", section on 'Genital warts'.)
Genital
warts are associated with physical and psychological morbidity and have
a high rate of treatment failure; furthermore, treatment of recurrent
episodes is costly [
17]. (See
"Condylomata acuminata (anogenital warts) in adults".)
Oropharyngeal cancer — HPV
infection may also play a role in the pathogenesis of squamous cell
carcinomas of the head and neck. HPV-associated oral cancers are
primarily found in the oropharynx and base of the tongue and tonsil [
18-20]. HPV has also been linked to cancer of the larynx [
21].
In the United States, the incidence of HPV-associated oropharyngeal
cancers has been rising and the incidence of non-HPV-associated cancers
has been declining, such that the incidence of the former now exceeds
that of the latter [
12,22]. (See
"Human papillomavirus associated head and neck cancer".)
HPV-related diseases in males
Penile cancer and precursor lesions — Penile
cancer is rare globally, with an estimated incidence of 22,000 cancers
in 2008; the attributable fraction due to HPV was 50 percent [
2]. HPV 16 and HPV 18 cause approximately 35 to 40 percent of penile cancers and 70-80 percent of HPV-positive penile cancers [
23].
AVAILABLE VACCINES — Three different vaccines, which vary in the number of HPV types they contain, are available in the United States:
●Gardasil, a quadrivalent HPV vaccine, targets HPV types 6, 11, 16, and 18 [
24].
●Gardasil
9, a 9-valent vaccine, targets the same HPV types as the quadrivalent
vaccine (6, 11, 16, and 18) as well as types 31, 33, 45, 52, and 58 [
25].
●Cervarix, a bivalent vaccine, targets HPV types 16 and 18 [
26].
Dosing and administration is discussed elsewhere. (See
'Vaccine dose and administration' below.)
These
are all prophylactic vaccines, designed to prevent 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 [
27].
EFFICACY AND IMMUNOGENICITY IN FEMALES
Immunogenicity — Excellent antibody responses have been reported following immunization with both quadrivalent and bivalent vaccines [
28-30].
Immunogenicity of the 9-valent vaccine among 9 to 26 year old females
is comparable to that of the quadrivalent vaccine for the shared HPV
types (6, 11, 16, and 18) [
31,32].
Because
efficacy studies were restricted to sexually active females, 15 years
of age and older, immunological "bridging" studies have been conducted
in females aged 9 to 15 years to demonstrate safety and immunogenicity.
Following vaccination with the quadrivalent vaccine, the vaccine
geometric mean titers (GMT) after 18 months in females aged 9 to 15
years were two- to threefold higher than in females aged 16 to 26 years
for all targeted types [
33].
Following vaccination with the 9-valent vaccine, the GMT in females
aged 9 to 15 years were approximately twofold higher than in females
aged 16 to 26 years for all targeted types [
34,35].
Following vaccination with the bivalent vaccine, the GMT after seven
months in females aged 10 to 14 years was noninferior to that observed
in females aged 15 to 25 years, and in some studies, measured up to
twofold higher [
36-38].
In
a head-to-head comparison of the immunogenicity of quadrivalent and
bivalent HPV vaccines, immunization with the bivalent vaccine induced
geometric mean titers 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 [
39].
Whether the induction of higher serum titers against HPV 16 and 18 has
any impact on the degree and duration of protection is unknown.
Furthermore, there is no defined minimum threshold titer for protection.
Seroconversion from prior exposure has been shown to reduce the risk of
incident HPV infection, suggesting 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 [
40,41].
Efficacy
Cervical, vaginal, and vulvar disease — Quadrivalent HPV vaccine [
33,42], 9-valent HPV vaccine [
31], and bivalent HPV vaccine [
43] have been demonstrated in large clinical trials to prevent cervical disease, including cervical intraepithelial neoplasia
(CIN2/3)
and adenocarcinoma in situ. In these studies, HPV status was determined
through serologic testing and DNA detection in cervical specimens, and
vaccine effectiveness was greatest in females who did not have prior HPV
infection. In addition, quadrivalent vaccine has also been demonstrated
to reduce the incidence of genital warts and vaginal and vulvar
intraepithelial neoplasia (VAIN and VIN 1-3).
●Quadrivalent HPV vaccine
— Two large, randomized, double-blind, placebo-controlled trials have
evaluated the efficacy of quadrivalent HPV vaccine in more than 17,000
adolescents and young females [
33,42].
•Among
HPV-naïve populations, the efficacy of quadrivalent HPV vaccine for
preventing CIN2 or more severe disease due to HPV types included in the
vaccine, was 97 to 100 percent.
•In
the overall population of study participants (with or without prior HPV
infection), the efficacy of quadrivalent HPV vaccine for preventing
CIN2, or more severe disease due to HPV types included in the vaccine
was significantly lower at approximately 44 percent after a mean
follow-up period of three years. This reduction in efficacy reflects the
fact that the vast majority of enrollees in this trial were already
sexually active and many had been previously infected with vaccine HPV
types. (See
'Timing of immunization' below.)
●9-valent vaccine
— An international trial reported the efficacy of the 9-valent vaccine
in approximately 14,000 females aged 16 to 26 years who were randomly
assigned to receive the quadrivalent or 9-valent vaccine [
31].
•Among
HPV-naïve populations, the efficacy of 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 was 97 percent.
•In
the overall population of study participants (with and without prior
HPV infection), 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 —
One large randomized clinical trial in more than 18,000 young females
aged 15 to 25 years demonstrated the efficacy of bivalent HPV vaccine [
43].
•Among
HPV-naïve patients, the efficacy of the bivalent vaccine for preventing
CIN2 or more severe disease due to HPV types included in the vaccine
was 93 percent, comparable with the efficacy of the HPV quadrivalent
vaccine.
•In
the overall population of study participants (with and without prior
HPV infection), vaccine efficacy for preventing CIN2 or more severe
disease due to HPV types included in the vaccine was significantly lower
at 53 percent after a mean follow-up period of approximately three
years. These data are consistent with those seen with HPV quadrivalent
vaccine and emphasize the need to vaccinate individuals before the onset
of sexual activity to gain the greatest benefit and maximize cost
effectiveness. (See
'Timing of immunization' below.)
HPV
vaccination appears to be safe and effective in preventing subsequent
infection in older women, but the overall benefit is less than that in
younger females [
44].
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 40
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 44 percent overall [
45].
Among those who did not have a prior history of HPV infection and
received all three doses of vaccine, vaccine efficacy was 81 percent.
Rates of vaccine-type associated CIN2 or more severe diagnoses were not
statistically different between HPV-naïve women who received vaccine or
placebo.
Anal disease — There
are no direct efficacy data regarding the prevention of anal
intraepithelial neoplasia (AIN) and anal cancer in females specifically;
however, since the majority of anal cancers in females are related to
HPV 16 and HPV 18, a beneficial impact of vaccination to prevent anal
intraepithelial neoplasia and anal cancer in females is anticipated.
Additionally, in a study of women who had participated in a trial of the
bivalent vaccine, vaccine efficacy against prevalently detected anal
HPV types 16 and 18 infection was 84 percent, similar to the efficacy
against cervical infection with these types [
46]. Prevention of AIN and anal cancer is an indication for vaccination in females with the quadrivalent vaccine. (See
'Recommendations for HPV immunization in females' below.)
Oral disease — Bivalent
HPV vaccination has also been associated with reduction in the
prevalence of oral infection with HPV types 16 and 18. In a trial
originally designed to evaluate the 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) [
47].
Vaccine efficacy for the prevention of oral HPV was estimated to be 93
percent. Whether HPV vaccination can prevent the development of
HPV-related oropharyngeal cancer has not yet been evaluated.
RECOMMENDATIONS FOR HPV IMMUNIZATION IN FEMALES
Indications and choice of vaccine — Various
guideline committees have made recommendations regarding the use of HPV
vaccine, which are discussed below. We are in general agreement with
the recommendations from the United States Advisory Committee on
Immunization Practices (ACIP). (See
'Advisory Committee on Immunization Practices' below.)
While
all guidelines target the same age group for routine vaccination, they
differ in the catch-up age range. This is primarily due to
cost-effectiveness analyses which show the benefit and cost
effectiveness is lower when vaccination is given at older ages. (See
'Cost effectiveness' below.)
Advisory Committee on Immunization Practices — The
United States Advisory Committee on Immunization Practices (ACIP)
recommends the bivalent, quadrivalent, or 9-valent HPV vaccine for
females aged 11 to 12 for the prevention of cervical, vaginal, and
vulvar cancer and the related precursor lesions caused by the HPV types
targeted by these vaccines [
48-50].
The ACIP also recommends the quadrivalent or 9-valent HPV vaccine for
the prevention of anal cancer and its precursor lesions, and genital
warts in females.
These vaccines can be administered to females as
young as age nine. Catch-up vaccination is also recommended for females
aged 13 to 26 years who have not been previously vaccinated or who have
not completed their vaccine series.
We recommend the 9-valent
vaccine given its greater HPV type coverage than the other HPV vaccines.
Re-vaccination with the 9-valent vaccine is likely not warranted for
individuals who have completed a series with a different HPV vaccine.
Pediatric, gynecologic, and family practice societies — Recommendations
from the American Academy of Pediatrics (AAP), the American Academy of
Family Practice (AAFP), and the American College of Obstetricians and
Gynecologists (ACOG) are all largely consistent with the ACIP guidelines
above.
American Cancer Society — Similar
to the ACIP, the American Cancer Society (ACS) guidelines recommend
that HPV vaccination should be routinely offered to females aged 11 to
12 years; immunization may begin at nine years of age [
51].
However, the ACS recommends catch-up vaccination for females aged 13 to
18 who have not been previously vaccinated or completed their vaccine
series. The ACS notes that there is insufficient evidence to recommend
for or against vaccination of females aged 19 to 26 years.
World Health Organization — The World Health Organization (WHO)
position paper suggests that girls within the age range of 9 through 13 years should be the primary target population for HPV immunization (
www.who.int/wer).
It notes 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 vaccinating the primary target population or
screening for cervical cancer.
Timing of immunization — 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").
Thus, the optimal time for HPV immunization is prior to an individual’s
sexual debut. Neither vaccine treats or accelerates the clearance of
pre-existing vaccine-type HPV infections or related disease.
Females
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 [
49].
However, immunization is less beneficial for females who have already
been infected with one of more of the HPV vaccine types.
EFFICACY AND IMMUNOGENICITY IN MALES — Interest
in HPV vaccine efficacy and safety in young males has not only included
prevention of HPV-related diseases (genital warts, anal cancer, and
penile cancer), but also possible decreased transmission of HPV
infection to female sex partners and potential for prevention of oral
cancers associated with HPV 16 and 18 [
20].
Immunogenicity — Studies
with quadrivalent HPV vaccine, 9-valent HPV vaccine, and bivalent HPV
vaccine have demonstrated that the proportions of vaccine recipients who
achieve seroconversion is comparable in males (eg, 99 to 100 percent)
and females (eg, 93 to 100 percent) [
34,52,53].
Eighteen months following vaccination with the quadrivalent vaccine,
the geometric mean titers (GMTs) against all four targeted types in
males aged 9 to 15 years were noninferior to those in females of the
same age [
53].
Following vaccination with the 9-valent vaccine, the GMTs against all
included HPV types in males aged 9 to 15 and aged 16 to 26 years were
similar to those in females aged 16 to 26 years [
34,35].
Following vaccination with bivalent vaccine, the GMTs against both
targeted types in males aged 10 to 18 years and 10 to 14 years were
higher than those historically reported for females aged 15 to 25 years
and 10 to 14 years, respectively [
52]. As in females, there is no defined minimum threshold titer for protection in males. (See
'Immunogenicity' above.)
Efficacy — In
a placebo-controlled international trial, the efficacy of quadrivalent
HPV vaccine was evaluated among 4065 males aged 16 to 26 [
54]. The following results were demonstrated:
●The
efficacy of immunization against the development of external genital
lesions and persistence of HPV infection (by HPV 6, 11, 16, or 18 types)
was 90 percent and 86 percent, respectively, among HPV-naïve males (no
evidence of infection with the relevant HPV vaccine types at enrollment)
who received all three doses of vaccine.
●In
contrast, vaccine efficacy was significantly lower among the overall
patient population with or without HPV infection at enrollment (66
percent for the prevention of external genital warts and 48 percent for
the prevention of persistent HPV infection).
●The
efficacy of HPV immunization in preventing anal intraepithelial
neoplasia secondary to the relevant HPV vaccine types was assessed in a
planned sub-study of 602 men who have sex with men (MSM). Similar to the
above results, vaccine efficacy was higher in the HPV-naïve compared
with the overall MSM population (78 versus 50 percent, respectively).
RECOMMENDATIONS FOR HPV IMMUNIZATION IN MALES
Indications and choice of vaccine — The
Advisory Committee on Immunization Practices (ACIP) recommends the
routine use of quadrivalent or 9-valent HPV vaccine in males aged 11 or
12 years [
48-50].
The vaccination series can be administered to individuals as young as
nine years. Vaccination is also recommended for males aged 13 to 21
years who have not been vaccinated previously or who have not completed
the three-dose series. For males who have sex with males (MSM) and for
males who are immunocompromised (including HIV infection), ACIP
recommends vaccination through age 26 for those not previously
vaccinated.
For other males, the ACIP supports "permissive use" of
HPV vaccination in males aged 22 through 26 years. 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 are less likely to be covered by a
patient’s health insurance company.
We recommend the 9-valent
vaccine over the quadrivalent vaccine for males given its greater HPV
type coverage. Although it is not clear that greater HPV type coverage
would substantially improve male cancer prevention, it would likely
further reduce the risk of cervical cancer in women indirectly through
herd immunity. Repeat vaccination with the 9-valent vaccine is likely
not warranted for individuals who have completed a series with a
different HPV vaccine.
The decision of the ACIP panel to recommend
HPV vaccination among males was based on: a) vaccine efficacy data on
genital warts and persistent HPV infection and prevention of anal
intraepithelial neoplasia in MSM [
54,55] and b) vaccine safety data [
56]. Cost-effectiveness analyses have suggested that male vaccination is less cost effective than female vaccination [
57,58].
However, the overall cost effectiveness of male vaccination depends on a
range of assumptions, such as vaccine efficacy, vaccine coverage of
females, the range of health outcomes included, and the effect of
HPV-associated diseases on quality of life [
49].
Male vaccination may be more cost effective with low vaccination
coverage among females, which is the current situation in the United
States [
59].
Timing of immunization — 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").
Thus, the optimal time for HPV immunization is prior to an individual’s
sexual debut. Neither vaccine treats or accelerates the clearance of
pre-existing vaccine-type HPV infections or related disease.
Males
who are sexually active may still be vaccinated consistent with
age-specific recommendations. A history of anal intraepithelial
neoplasia, genital warts, or HPV infection is NOT a contraindication to
HPV immunization [
49]. However, immunization is less beneficial for males who have already been infected with one or more of the HPV vaccine types.
Controversies — Opponents of HPV immunization in males argue that [
60]:
●The
burden of HPV-associated diseases such as anal, penile, and
oropharyngeal cancers in males is less than that of cervical cancer in
females [
61].
●Public
health initiatives should be most focused on attaining high rates of
immunization in young girls as it is the most cost effective.
Proponents of HPV immunization in males argue that:
●Immunization rates in young girls have been generally low, particularly when immunizations are not mandatory [
62]. It is under these conditions that both incremental benefit and cost effectiveness of vaccinating males have been shown [
63].
●High
coverage programs in females confer protection against HPV-related
infection and disease in heterosexual males, but not MSM.
●HPV infection is common in males and is readily transmitted, influencing disease infection rates in both males and females [
64,65].
One modeling study highlighted the incomplete protection of men from HPV-associated disease if only females are vaccinated [
63].
Using population data from the Netherlands, it estimated that the
burden of HPV-associated cancers in men would be reduced by 37 and 66
percent if vaccine uptake among girls and young women were 60 and 90
percent, respectively. Vaccine uptake among females is considerably less
than 60 percent in many locations. (See
'Strategies to improve vaccine coverage' below.)
IMMUNIZATION IN SPECIAL PATIENT POPULATIONS
Pregnant females — Although
none of the approved HPV vaccines contain live virus, use in pregnancy
is not recommended because of limited data on safety [
49].
Lactating females can receive the immunization series since subunit
vaccines do not affect the safety of infant breastfeeding. (See
"Immunizations during pregnancy".)
If
a woman receives the HPV vaccine before she knows that she is pregnant
she should be reassured that there is no evidence that this vaccine will
harm the pregnancy. This is discussed in detail elsewhere. (See
"Immunizations during pregnancy", section on 'Human papillomavirus'.)
Females
who have started the series, but become pregnant before completion of
all three shots, may resume the series when postpartum. (See
"Immunizations during pregnancy".)
Both vaccine manufacturers maintain pregnancy registries to monitor fetal outcomes of pregnant females exposed to HPV vaccine [
49].
In the United States, exposures to the quadrivalent vaccine can be
reported by calling 877-888-4231, and exposures to the bivalent vaccine
can be reported by calling 888-452-9622.
Immunization in females with pre-existing cervical abnormalities or genital warts — A
history of genital warts, abnormal cytology, or positive HPV DNA test
result is not evidence of prior infection with any or all of the vaccine
HPV types, and vaccination can still provide protection against
infection with HPV vaccine types not already acquired. Thus, the
Advisory Committee on Immunization Practices (ACIP) recommends
immunization for females (up to 26 years of age) with any such history [
48,49].
Additionally, the ACIP recommends against assessment with Pap testing
or screening for existing HPV infection as part of the determination for
HPV vaccine candidacy.
However, these patients should be advised
that vaccination will have no therapeutic effect on pre-existing HPV
infection or cervical intraepithelial neoplasia, and the potential
benefit of HPV vaccination is not as great as if they were vaccinated
before they started having sex.
Studies of the HPV quadrivalent vaccine in HIV-infected adult men [
66], HIV-infected women aged 16 to 23 years [
67,68], and HIV-infected boys and girls aged 7 to 12 years [
69]
suggest that it is both immunogenic and safe in these populations.
However, efficacy data are not yet available. Studies in other
immunocompromised populations are ongoing.
HPV vaccine is
recommended by the ACIP for persons who are immunocompromised as a
result of infection, disease, or medications through age 26 years if
they have not already received any or all vaccine doses [
48,49]. It is not a live vaccine. HPV vaccination in transplant recipients is discussed 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'.)
Cervical
cancer screening continues to play an important role in detection and
treatment of cervical intraepithelial neoplasia (CIN) 2, 3, and cervical
cancer in these high-risk females. Although there are no formal
guidelines regarding screening for precancerous anal lesions, some
specialists recommend anal cytologic screening for HIV-1-infected males
and females. (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'.)
Healthcare workers — The
Advisory Committee on Immunization Practices (ACIP) immunization
schedule of 2012 indicates that healthcare personnel are not at
increased risk of HPV infection due to occupational exposure; age-based
recommendations noted above still apply [
70].
PREVACCINATION ASSESSMENT — The ACIP does not recommend serologic or HPV DNA testing prior to immunization in females or males [
49].
VACCINE DOSE AND ADMINISTRATION
Immunization schedule — In the United States, the HPV vaccine series is three vaccine doses given over a minimum of 24 weeks [
49].
The minimum interval between the first two doses is four weeks and the
minimum interval between the second and third doses is 12 weeks. The
quadrivalent vaccine (Gardasil) and 9-valent vaccine (Gardasil 9) are
typically administered in three doses at time zero, and at two and six
months of follow-up. The bivalent vaccine (Cervarix) is typically
administered in three doses at time zero, and at one and six months of
follow-up. HPV vaccine can be safely administered at the same time as
other age-appropriate vaccines at a different anatomic site.
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 [
50].
In
some countries, two doses of HPV vaccine are recommended because of
evidence of generally comparable immunogenicity and, for some outcomes,
efficacy after two versus three doses. This evidence is discussed in
detail elsewhere (see
'Missed doses/alternative schedules'
below). As an example, the Strategic Advisory Group of Experts on
Immunizations (SAGE) of the World Health Organization recommends two
doses for females under the age of 15 and three doses for those who
initiate vaccination later [
71].
Practitioners outside the United States should consult local guidelines
for the recommended immunization schedule in their country.
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 [
72,73].
Missed doses/alternative schedules — Patients often do not follow up for their immunizations on schedule [
74].
The Advisory Committee on Immunization Practices (ACIP) recommends that
if the vaccination series is interrupted for any length of time, it can
be resumed without restarting the series.
Because of the
frequency of missed doses and the suboptimal adherence to a three dose
vaccine schedule, there has been interest in whether fewer doses or
greater time intervals between doses remain effective. Randomized trials
are planned to evaluate this issue. Some observational data suggest
that administration of two vaccine doses has comparable efficacy against
vaccine type HPV infection and, for the quadrivalent vaccine, the
incidence of genital warts, and is comparably immunogenic as three
doses, but there have been no studies evaluating the efficacy of fewer
than three doses on prevention of cervical neoplastic disease. In some
countries (not the United States), the recommended vaccine series for
certain individuals consists of two doses. A single vaccine dose is not a
recommended option. (See
'Immunization schedule'
above.) In an analysis of data from two trials of the bivalent HPV
vaccine in young women (aged 15 to 25 years) who had no HPV type 16 or
18 infection at baseline and who had at least 12 months of follow-up,
vaccine efficacy against six-month persistent infection with those HPV
types was no different in women who received the intended three doses
compared with those who received fewer doses (89, 90, and 97 percent
efficacy with three, two, and one vaccine doses, respectively) [
75].
For women who received only two doses, vaccine efficacy was generally
similar among those who received the second dose one or six months after
the first. However, cross-protective efficacy against non-vaccine types
with two doses given one month apart was inferior to both three doses
and two doses given six months apart.
Similarly, one observational
study suggested that two quadrivalent vaccine doses provided
substantial protection against genital warts, although completion of
three doses was slightly superior [
76].
In the study, over one million Swedish females aged 10 to 24 years who
did not have a history of genital warts or HPV vaccination at study
entry were followed for a mean of 3.8 years. Receipt of three doses of
vaccines was associated with the lowest subsequent incidence of genital
warts (128 versus 528 events per 100,000 person years without
vaccination), but receipt of two doses and one dose were also associated
with a substantially lower incidence (174 events and 384 per 100,000
person years, respectively). Among females who were aged 10 to 16 years
when first vaccinated, after adjusting for parental education and age,
three doses of the vaccine were associated with 59 fewer events per
100,000 person-years (95% CI 2-117) than two doses and 75 fewer events
per 100,000 person years (95% CI -7-157) than one dose. 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 [
77].
Other
studies have examined the effects of varied dosing schedules on
immunogenicity, as an indirect measure of potential efficacy. In an
analysis of a Costa Rican trial of bivalent HPV vaccination,
seropositivity against HPV types 16 and 18 four years after vaccination
was 100 percent among those who had only received one dose (n = 78), two
doses separated by one month (n = 140), or two doses separated by six
months (n = 52) [
78].
Antibody levels were comparable between those who received two doses
separated by six months and a random selection of women who received all
three doses as intended. A clinical trial in Vietnam, which evaluated
three alternative schedules with longer intervals between vaccine doses
compared with standard dosing among 809 girls (aged 11 to 13 years),
found equivalent HPV antibody titers one month after the final dose [
79]. A follow-up analysis suggested that antibody titers were comparable across dosing schedules after two and a half years [
80].
A randomized trial to evaluate the immune response to two doses (at
zero and six months) versus standard three doses (at zero, two and six
months) found that the antibody responses following two doses was
noninferior to three doses for all four HPV types at seven months but
inferior for HPV18 and HPV6 at 36 months [
81].
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.
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 42 months following vaccination among female trial
participants [
82]. Persistent antibody levels and protection against HPV infection have been reported up to 10 years following vaccination [
83-85].
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.
VACCINE SAFETY — All
vaccines use virus-like particles (VLPs), which mimic the viral capsid.
VLPs do not contain genetic material and are produced in biologic
systems, which have well-established safety records [
86].
All
vaccines appear to be safe in the context of clinical trials, although
more is known about the safety profile of the quadrivalent vaccine than
the 9-valent or bivalent vaccines due to availability of more
postlicensure data, which are summarized below [
87].
Quadrivalent vaccine (Gardasil) — Vaccine
safety data are now available from both registration trials and in
postlicensure safety surveillance systems. Different types of
information can be gleaned from these two processes. The advantage of
safety reviews within the context of a clinical trial is that medical
chart reviews of adverse events are usually more thorough and complete,
whereas surveillance systems are voluntary and passive. However,
postlicensure surveillance systems have the advantage of identifying a
potentially serious side effect that may have been too rare to detect
during prelicensure trials.
The postlicensure safety profile is
broadly consistent with safety data from prelicensure trials that
suggest the vaccine is safe and well tolerated apart from mild injection
site reactions, although syncopal events have emerged as a potential
serious adverse effect [
88].
The incidence of syncope among adolescents has increased overall with
the introduction of other routine immunizations as well, such as
meningococcal vaccine [
88,89].
The ACIP recommends a routine 15-minute waiting period following
vaccination so that the patient may continue in a sitting or supine
position as needed; this may decrease the risk of syncope with
subsequent injury.
In light of the growing data on the safety of
the HPV vaccine, the World Health Organization’s Global Advisory
Committee on Vaccine Safety stated that the benefit-risk profile remains
favorable [
90].
Additionally, it notes concern about claims of harm raised on the basis
of anecdotal reports in the absence of biological or epidemiological
substantiation.
Prelicensure trial data — The
safety profile of the quadrivalent vaccine was evaluated in diverse
populations of females from resource-rich and resource-limited settings [
33,42]. Mild injection site reactions were the most commonly observed adverse events [
91,92]. The safety profile of quadrivalent vaccine in males was reported to be similar to that of studies in females [
54].
Postlicensure data — In
the United States, adverse events following immunization are collected
and analyzed within the Vaccine Adverse Event Reporting System (VAERS) [
88,93,94].
Adverse events following HPV vaccine are compared with background rates
following other immunizations. Between June 2006 and March 2013,
approximately 57 million doses of quadrivalent HPV vaccines were
distributed in the United States. Reports of adverse events to VAERS
have been consistent with the pre-licensure data:
●From 2006 to 2013, VAERS received 21,194 reports of adverse events following HPV immunization among females [
94].
The vast majority (92 percent) were considered mild. The proportion of
events reported as serious peaked in 2008. Among serious events,
headache, nausea, vomiting, fatigue, dizziness, syncope, and generalized
weakness were the most frequently reported. There is no increased risk
of Guillain-Barré Syndrome compared with other vaccines in similar age
groups [
88].
●Through
2011, 72 post-vaccination deaths had been reported, of which 34 were
confirmed. There was no unusual pattern or clustering to the deaths that
would suggest that they were caused by the vaccine [
93].
Other studies have similarly observed that the quadrivalent vaccine is generally safe [
56,95,96].
There
does appear to be an increased risk of syncope with the quadrivalent
vaccine, but whether this is unique to this vaccine is unclear. A
disproportionate number of syncopal events following quadrivalent
vaccine administration had been reported to the VAERS [
88].
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 healthcare system who received at least one vaccine
dose, emergency department visits or hospitalizations were higher during
the post-vaccine period compared with a subsequent control period for
10 of 265 diagnostic categories evaluated, including viral, bacterial,
and skin infections and congenital anomalies [
95].
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.
Other adverse events that
appeared to be vaccine-related have not been substantiated by further
study. Although venous thromboembolism (VTE) rates reported to the VAERS
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) [
88].
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) [
56].
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 [
97].
Anaphylaxis had also been reported following administration of the quadrivalent vaccine [
88,98],
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 [
98].
However, some of those cases were subsequently thought not to have
represented anaphylaxis and other studies from Australia did not confirm
this high rate [
99,100].
In the VAERS surveillance system, only 10 cases met predefined criteria
for anaphylaxis; the overall risk ratio was 0.1 case per 100,000 doses
distributed [
88]. (See
"Allergic reactions to vaccines".)
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 [
101].
9-valent vaccine (Gardasil 9) — In
a trial in which over 7000 females received the 9-valent vaccine, the
main reported adverse effects were mild or moderate injection site
reactions (pain, erythema, and swelling). These occurred slightly more
frequently than with the quadrivalent vaccine [
34].
The frequency of systemic adverse effects (eg, headache, fever, nausea,
dizziness) was similar with the 9-valent and quadrivalent vaccines.
Bivalent vaccine (Cervarix) — In
a phase III, multinational prospective, double-blind,
placebo-controlled trial of more than 18,000 females aged 15 to 25
years, the vaccine was well tolerated and there were no differences in
serious adverse events between vaccine and placebo recipients. Because
of low uptake of Cervarix in the US as of September 2011, only sparse
postlicensure data are available. As of September 2011, there have been
52 VAERS reports of adverse events following administration of bivalent
vaccine and the majority of these adverse events (98 percent) were
considered nonserious.
Behavioral impact — Some
surveys of parents found a concern for sexual disinhibition in
adolescent girls following HPV vaccine receipt, particularly among older
and ethnic minority parents [
102,103]. Studies have not supported an increase in risky sexual behavior following vaccination [
104-106].
In a retrospective study of preteenage girls enrolled in a large
healthcare 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 [
104].
After adjustment for baseline healthcare 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 [
93]. 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.
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 [
107-109].
In the United States, uptake of HPV vaccination has been suboptimal. In
2012, based on results of a national survey among adolescents who had
provider-reported vaccination records, estimated vaccine coverage among
females aged 13 to 17 was 54 percent for at least one dose and only 33
percent for three doses [
94].
In the 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. This highlights a lack of
understanding about the rationale for HPV vaccination on the part of the
parent and the important role of the healthcare provider in
consistently and clearly educating parents about vaccination.
Lack
of opportunity did not appear to be a major reason for low vaccine
coverage. Of the unvaccinated females in the survey, 84 percent had at
least one medical visit at which they were given a different vaccine but
not the HPV vaccine [
94].
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 [
110]. 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 three-dose HPV vaccination coverage to 80 percent in
females, approximately 53,000 additional cases of cervical cancer could
be prevented in the US over the lifetimes of those currently aged
≤12 years [
58,94].
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 [
111].
IMPORTANCE OF CANCER SCREENING
Cervical screening — Cervical
cancer screening with cervical cytology (ie, Papanicolaou test) has
reduced the incidence and mortality of cervical cancer by more than 70
percent over the past six decades [
112]. Screening for cervical cancer by cervical cytology
and/or HPV testing is recommended for all females beginning at age 21 [
113]. A preventive healthcare visit is an opportune time to discuss and offer HPV vaccination
and/or cervical screening depending on the age of the woman [
51]. Detailed information regarding screening for cervical cancer is found elsewhere. (See
"Screening for cervical cancer".)
Cervical
cancer screening continues to be of great importance since immunization
with the bivalent or quadrivalent HPV vaccine will not prevent
approximately 25 to 30 percent of cervical cancers in HPV-naïve females
and does not protect females already infected with carcinogenic HPV
types against the development of 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, screening
should continue for all vaccinated females.
COST EFFECTIVENESS — Mathematical models have examined the cost effectiveness of HPV vaccination [
114-117].
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 [
114].
Vaccination
becomes increasingly less cost effective with increasing age. Assuming
that HPV vaccine provides lifelong immunity, the cost-effectiveness
ratio is $43,600 per quality-adjusted life-year (QALY) gained when
vaccinating 12-year-old girls [
118]. However, in one analysis the cost of extending immunizations up to the age of 26 years was $152,700 per QALY [
118].
As in all cost-effectiveness studies, interpretation of these findings
is limited by uncertainty and multiple assumptions made in the models.
In
various models, vaccinating both males and females is predicted to be
more beneficial in reducing HPV infection and disease than by
vaccinating only females, but at a higher cost than vaccinating females
alone [
118-120]. However, models of cost effectiveness are limited by uncertainty regarding major issues such as duration of protection [
121],
the effect of herd immunity, level of vaccine uptake among girls and
females, and the prevalence of vaccine-specific HPV types circulating in
age-specific populations [
122]. (See
"Epidemiology of human papillomavirus infections".)
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 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.)
SUMMARY AND RECOMMENDATIONS
●Persistent
viral infection with carcinogenic HPV types causes virtually all cancer
of the cervix and most cases of anal cancer. The carcinogenic types,
HPV 16 and HPV 18, which are targeted by the current HPV vaccines, cause
approximately 70 percent of all cervical cancers worldwide and 72
percent of anal cancers. HPV types 31, 33, 45, 52, and 58 are estimated
to cause an additional 19 percent of invasive cervical cancers. HPV 6
and HPV 11 cause approximately 90 percent of genital warts. (See
'Disease associations' above.)
●The
quadrivalent vaccine (Gardasil) includes HPV types 6, 11, 16, and 18.
The 9-valent vaccine (Gardasil 9) includes HPV types 6, 11, 16, 18, 31,
33, 45, 52, and 58. The bivalent vaccine (Cervarix) includes HPV types
16 and 18. (See
'Available vaccines' above.)
●HPV immunization is most effective among individuals who have not yet been infected with HPV (eg, before sexual debut). (See
'Timing of immunization' above.)
●Multicenter,
double-blind, placebo-controlled trials have demonstrated 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 vaccines also have demonstrated high efficacy against vaccine
type-associated vaginal and vulvar intraepithelial neoplasia. They also
protect against genital warts associated with HPV 6 and HPV 11. The
efficacy of any HPV vaccine for the prevention of anal intraepithelial
neoplasia has not been studied in females. (See
'Efficacy and immunogenicity in females' above.)
●We recommend HPV immunization of females, as advised by multiple expert panels (
Grade 1A). If cost and availability are not issues, we recommend the 9-valent vaccine for females in whom HPV vaccination is indicated (
Grade 1B).
Routine immunization should be offered to girls 11 to 12 years of age,
but can be administered as early as nine years. Catch-up vaccination
should be offered for females aged 13 to 26 years who have
not been previously vaccinated. (See
'Recommendations for HPV immunization in females' above.)
●Quadrivalent
HPV vaccine is effective in preventing genital warts in young males and
anal intraepithelial neoplasia among men who have sex with men (MSM).
Immunogenicity of the 9-valent vaccine in males is similar to that in
females. (See
'Efficacy and immunogenicity in males' above.)
●We recommend HPV vaccination in males, as advised by expert panels (
Grade 1B). If cost and availability are not issues, we recommend the 9-valent vaccine for males in whom HPV vaccination is indicated (
Grade 1B).
Routine immunization should be offered to boys aged 11 to 12, but can
be administered as early as nine years of age. Catch-up vaccination
should be offered for males between the ages of 13 to 21 who have not
been previously vaccinated. For MSM, catch-up vaccination should be
offered up to age 26. (See
'Indications and choice of vaccine' above.)
●Although neither HPV vaccine contains live virus, use in pregnancy is not recommended because of limited data on safety. (See
'Pregnant females' above.)
●The
quadrivalent vaccine and 9-valent are administered in three doses at
time zero, and at two and six months of follow-up. The bivalent vaccine
is administered in three doses at time zero, and at one and six months
of follow-up. (See
'Vaccine dose and administration' above.)
●In prelicensure clinical trials and postlicensure monitoring, vaccines have been demonstrated to be generally safe. (See
'Vaccine safety' above.)
Polio is an infectious disease caused by a virus that
lives in the throat and intestinal tract. It is most often spread
through person-to-person contact with the stool of an infected person
and may also be spread through oral/nasal secretions. Polio used to be
very common in the United States and caused severe illness in thousands
of people each year before polio vaccine was introduced in 1955. Most
people infected with the polio virus have no symptoms; however, for the
less than 1% who develop paralysis it may result in permanent disability
and even death.
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