# 92 - 203 Human Papillomavirus Infections

### 203 Human Papillomavirus Infections

HUMAN BOCAPARVOVIRUSES
■
■DEFINITION
Human bocavirus 1 (HBoV1) of the genus Bocaparvovirus, discovered 
in 2005, causes both upper and lower respiratory tract infections in 
young children and affects almost all children before the age of 5 years. 
Three related bocaviruses, HBoV2, HBoV3, and HBoV4, are mainly 
found in fecal samples and are thus considered enteric, with disputed 
roles in gastroenteritis.
■
■EPIDEMIOLOGY
HBoVs are very common worldwide; the seroprevalences in Europe, 
already at 6 years of age, are 80% for HBoV1, 50% for HBoV2, 10% for 
HBoV3, and 0–1% for HBoV4, the latter being slightly more prevalent 
in China.
■
■CLINICAL MANIFESTATIONS AND DIAGNOSIS
HBoVs cause systemic infections with short viremia and induction 
of antibodies, which can be cross-reacting between the four HBoVs. 
HBoV1 causes mild to severe, rarely even life-threatening, respiratory 
tract infections (RTIs) in 0.5- to 5-year-old children (mean 2 years); it 
is the second to fourth most common finding (2–20%) in nasopharyn­
geal secretions of pediatric RTI patients. HBoV1 DNA, in decreasing 
levels, often remains detectable by sensitive PCRs in the airways for 
weeks or months after acute RTI, which is problematic, since RTI is 
commonly diagnosed by qualitative PCRs in respiratory secretions. 
This may lead to clinically incorrect interpretations of etiology, codetections with other respiratory pathogens, and doubts of the role 
of HBoV1 in pathogenesis. However, clinical disease due to HBoV1 
is associated with evidence of acute primary infection based on other 
diagnostic methods: sole infection, serology (IgG seroconversion or 
fourfold or greater increase in titer, IgM positivity, and/or low IgG 
avidity), viremia, and presence in respiratory secretions of spliced 
viral mRNA, high-load HBoV1 DNA (>104 genome copies/mL), or 
antigens. A combination of these methods should be applied in cases 
of severe or uncommon disease manifestations or for epidemiologic 
studies. HBoV1 causes both upper and lower RTIs, such as common 
cold, bronchiolitis, pneumonia, and exacerbations of asthma, with 
symptoms similar to those of other viral RTIs, with fever, cough, and 
wheezing commonly reported. In addition, diarrhea and acute otitis 
media often complicate HBoV1 infection. The role of the enteric 
HBoVs in childhood gastroenteritis remains to be established, but they 
have, like HBoV1, also been shown to cause encephalitis. There are no 
specific treatments or vaccines for HBoV infections.
OTHER HUMAN PARVOVIRUSES
■
■BUFA- AND CUTAVIRUSES
Bufavirus and cutavirus of the genus Protoparvovirus were recently 
discovered in diarrheal stools by metagenomics. The global serop­
revalence of bufavirus varies extensively from 3 to 85%, whereas that 
of cutavirus remains <6%. Although bufavirus DNA is found in 0.2–4% 
of diarrhea stools, the viral loads are low, and its pathogenic role is 
disputed. Interestingly, skin-persistent cutavirus has been shown to be 
associated with cutaneous T-cell lymphoma and its precursor, para­
psoriasis en plaques, the latter with up to 67% genoprevalence in skin 
biopsies. Whether this association is causal or consequential remains 
to be confirmed.
■
■PARVOVIRUS 4
Parvovirus 4 (parv4), in the genus Tetraparvovirus, was initially discov­
ered in a patient with an acute viral syndrome and has since been found 
in pooled plasma donations and blood or tissues of injection drug users 
and hemophiliacs, suggesting parenteral spread. Even though parv4 in 
general is considered apathogenic, occasional studies have detected its 
DNA in patients with rash and respiratory, gastrointestinal, or central 
nervous system infections.
■
■ADENO-ASSOCIATED VIRUSES
Adeno-associated viruses (AAV, with many serotypes), of the genus 
Dependoparvovirus, depend on helper functions from other viruses 

for their replication. Because of their ability to remain latent and their 
apathogenic nature, they have been developed as successful vectors in 
gene therapy. Nevertheless, in 2022, AAV2 was surprisingly associated 
with acute childhood hepatitis, but a causative role was not confirmed.

Acknowledgment
I thank the previous author, Kevin E. Brown, who wrote the prior 
edition’s chapter. Some material from that chapter has been retained here.
■
■FURTHER READING
Christensen A et al: Human bocaviruses and paediatric infections. 
Lancet Child Adolesc Health 3:418, 2019.
Crabol Y et al: Intravenous immunoglobulin therapy for pure red 
cell aplasia related to human parvovirus B19 infection: A retrospec­
tive study of 10 patients and review of the literature. Clin Infect Dis 
56:968, 2013.
Maple PA et al: Identification of past and recent parvovirus B19 
infection in immunocompetent individuals by quantitative PCR and 
enzyme immunoassays: A dual-laboratory study. J Clin Microbiol 
52:947, 2014.
Matthews PC et al: Human parvovirus 4 ‘PARV4’ remains elusive 
despite a decade of study F1000 Res 6:82, 2017.
Phan T et al: Cutavirus: A newly discovered parvovirus on the rise. 
Infect Gen Evol 80:104175, 2020.
Qiu J et al: Human parvoviruses. Clin Microbiol Rev 30:43, 2017.
Söderlund-Venermo M: Emerging human parvoviruses: The rocky 
road to fame. Ann Rev Virol 6:71, 2019.
Xiuong Y et al: The risk of maternal parvovirus B19 infection during 
CHAPTER 203
pregnancy on fetal loss and fetal hydrops: A systematic review and 
meta-analysis. J Clin Virol 114:12, 2019.
Human Papillomavirus Infections 
Darron R. Brown, Aaron C. Ermel

Human Papillomavirus 

Infections
Interest in human papillomavirus (HPV) infection began in earnest 
in the 1980s after Harold zur Hausen postulated that infection with 
these viruses was associated with cervical cancer. It is now recognized 
that HPV infection of the human genital tract is extremely common 
and causes clinical conditions ranging from asymptomatic infection 
to genital warts (condylomata acuminata); dysplastic lesions and 
invasive cancers of the anus, penis, vulva, vagina, and cervix; and a 
subset of oropharyngeal cancers. This chapter describes the epidemi­
ology of HPV as a virus and a pathogen, the natural history of HPV 
infections and associated cancers, strategies to prevent infection and 
HPV-associated disease, and treatment modalities for some conditions 
caused by HPV.
■
■PATHOGENESIS
Overview 
 HPV is an icosahedral, nonenveloped, 8000-basepair, double-stranded DNA virus with a diameter of 55 nm. Like 
the genomes of other papillomaviruses, HPV’s genome consists of 
an early (E) gene region, a late (L) gene region, and a noncoding region, 
which contains regulatory elements. The E1, E2, E5, E6, and E7 pro­
teins are expressed early in the growth cycle and are necessary for viral 
replication and cellular transformation. The E6 and E7 proteins are 
responsible for malignant transformation, targeting the human cellcycle regulatory molecules p53 and Rb (retinoblastoma protein) for 
degradation, respectively. Translation of the L1 and L2 transcripts and 
splicing of an E1^E4 transcript occur later. The L1 gene encodes the

54-kDa major capsid protein that makes up the majority of the virus 
shell; the 77-kDa L2 minor protein contributes a smaller percentage of 
the capsid mass.

More than 200 HPV types have been identified and are numerically 
designated on the basis of a unique L1 gene sequence. Approximately 
40 HPV types are regularly identified in the anogenital tract; these 
types are subdivided into high-risk and low-risk categories depending 
on the associated risk of cervical cancer. For example, HPV types 6 and 
11 cause genital warts and ~10% of low-grade cervical lesions and are 
thus designated low risk. HPV types 16 and 18 cause dysplastic lesions 
and a high percentage of invasive cancers of the cervix and are there­
fore considered high risk.
HPV is a tissue-tropic virus and targets basal keratinocytes of 
specific anatomic tissues after microtrauma allows exposure of these 
cells to the virus. HPV 1, for example, causes plantar warts but does 
not infect genital epithelium. The HPV replication cycle is completed 
as keratinocytes undergo differentiation. Virions are assembled in the 
nuclei of differentiated keratinocytes and can be visualized by electron 
microscopy. Infection is transmitted by contact with virus contained in 
these desquamated keratinocytes (or with free virus) from an infected 
individual.
The Immune Response to HPV Infection 
Unlike many viral 
infections, HPV infection has no viremic phase. This lack of viremia 
may account for the incomplete antibody response to HPV infec­
tion. Natural HPV infection of the genital tract gives rise to a detect­
able serum antibody response in 60–70% of individuals. Significant, 
although incomplete, protection against type-specific reinfection is 
associated with the presence of neutralizing antibodies. Serum anti­
bodies likely reach the cervical epithelium and secretions by transuda­
tion and exudation. Therefore, protection against infection relates to 
the amount of neutralizing antibody at the site of infection and lasts as 
long as sufficient levels of neutralizing antibodies are present.
PART 5
Infectious Diseases
A cell-mediated immune response plays an important role in 
controlling progression of HPV infection. Histologic examination 
of lesions in individuals who experience regression of genital warts 
demonstrates infiltration by T cells and macrophages. CD4+ T cell 
regulation is particularly important in controlling HPV infections, as 
evidenced by the higher rates of infection and disease in immunosup­
pressed individuals, particularly those who are infected with HIV. Spe­
cific T cell responses may be measured against HPV proteins, the most 
important of which appear to be the E2 and E6 proteins. In women 
with HPV16 cervical infection, a strong T cell response to HPV16–
derived E2 protein is associated with a lack of progression of cervical 
disease. However, measurable changes occur in the innate and adaptive 
immune systems of patients with HPV-associated cancers. There is 
suppression of the antigen-presentation process as well as suppression 
of antitumor activity. The end result is a reduction of HPV-specific 
antitumor immune responses and an increase in immunosuppressive 
cellular responses.
■
■THE NATURAL HISTORY OF HPV-ASSOCIATED 
MALIGNANCY
HPV is transmitted by vaginal or anal intercourse, by oral sex, and 
probably by touching a partner’s genitalia. In cross-sectional and 
longitudinal studies, ~50% of young women demonstrate evidence of 
HPV infection, with peaks during the teens and early twenties, within a 
few months after first coital experience. The number of lifetime sexual 
partners correlates with the likelihood of HPV infection and the subse­
quent risk of HPV-associated malignancy. HPV infection may occur in 
a monogamous person if that person’s partner is infected.
Most HPV infections become undetectable after 6 to 9 months, a 
phenomenon known as “clearance.” However, with prolonged followup and frequent sampling, the same HPV types may again be detected 
months or even years later. It is still debated whether such episodic 
detection indicates viral latency followed by reactivation or represents 
reinfection with an identical HPV type. Most evidence indicates that 
reactivation of latent virus is the cause of episodic detection of a spe­
cific HPV type.

While HPV is the causative agent of several cancers, most attention 
has focused on cervical cancer, which is the second most common 
cancer in women worldwide. More than 600,000 women are diagnosed 
and 300,000 die from invasive cervical cancer annually. More than 85% 
of all cervical cancer cases, as well as deaths, occur in women living in 
low-income countries, especially countries in sub-Saharan Africa, Asia, 
and South and Central America.
Evidence collected over 25 years shows that HPV causes nearly 100% 
of cervical cancers. Persistent HPV infection is the most significant risk 
factor for cervical cancer; relative risks range from 10 to 20 and exceed 
100 in case–control studies and prospective studies, respectively. The 
time from HPV infection to cervical cancer may exceed 20 years. Cer­
vical cancer peaks in the fifth and sixth decades of life for women living 
in developed countries and a decade or more earlier for women living 
in resource-poor countries. Persistent carriers of oncogenic HPV types 
are at greatest risk for high-grade cervical dysplasia and cancer.
Why HPV infections in some women but not others eventually 
lead to malignancy is not clear. Although oncogenic HPV infection 
is necessary for the development of cervical malignancy, only ~3–5% 
of infected women will ever develop this cancer, even in the absence 
of cytologic screening. Biomarkers that can predict which women 
will develop cervical cancer are not available, or incompletely char­
acterized. Immunosuppression in general plays a significant role in 
redetection/reactivation of HPV infections, while other factors, such 
as smoking, hormonal changes, chlamydial infection, and nutritional 
deficits, have an impact on viral persistence and cancer.
The International Agency for Research on Cancer (IARC) has con­
cluded that HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 
59 are carcinogenic in the uterine cervix. HPV type 16 is particularly 
virulent and causes at least 50% of cervical cancers. Worldwide, HPV 
types 16 and 18 cause at least 70% of cervical squamous cell carcinomas 
and 85% of cervical adenocarcinomas. Oncogenic types other than 16 
or 18 cause the remaining 30% of cervical cancers. HPV types 16 and 
18 also cause nearly 90% of anal cancers worldwide.
In addition to cervical and anal cancer, other HPV-associated can­
cers include vulvar and vaginal cancer (caused by HPV in 50–70% of 
cases), penile cancer (caused by HPV in 50% of cases), and at least 
65% of oropharyngeal squamous cell carcinomas (OPSCCs). Over the 
past two decades, an epidemic of OPSCC related to oncogenic HPV 
infection, primarily HPV type 16, has developed. Rates of OPSCC in 
the United States have been increasing in men from a low of 0.27 case 
per 100,000 in 1973 to 0.57 case per 100,000 per year in 2004; rates in 
women have remained relatively stable at ~0.17 per 100,000 per year. 
The greatest increase in the incidence of OPSCC is among white men 
40–50 years of age. Nearly 14,000 new cases were diagnosed in the 
United States in 2013. OPSCCs of the base of the tongue and tonsil 
cancer have increased annually by rates of 1.3 and 0.6%, respectively. 
Few data are available from developing countries about OPSCC.
■
■THE EFFECTS OF HIV ON HPV-ASSOCIATED 
DISEASE
HIV infection accelerates the natural history of HPV infections. HIVinfected individuals are more likely than other individuals to develop 
genital warts, and their lesions are more recalcitrant to treatment. HIV 
infection has been consistently associated with precancerous cervi­
cal lesions, including low-grade cervical intraepithelial lesions (CIN) 
and CIN 3, the immediate precursor to cervical cancer. Women with 
HIV/AIDS have significantly higher rates of cervical cancer as well as 
subsets of some vulvar, vaginal, and oropharyngeal tumors (Chap. 75) 
than women in the general population. Studies indicate a direct rela­
tionship between low CD4+ T lymphocyte count and the risk of cervi­
cal cancer. Some studies show a reduced likelihood of HPV infection 
and precancerous lesions of the cervix in HIV-infected women given 
antiretroviral therapy (ART). However, the incidence of cervical cancer 
in HIV-infected women has not changed significantly since ART was 
introduced, possibly because of preexisting oncogenic HPV infections 
that occurred before ART was initiated.
The burden of HPV-associated cancers is expected to increase in 
HIV-infected patients, given the prolonged life expectancies provided

with ART. For women living in developing countries where cervical 
cancer screening is not widely available, this trend will have significant 
consequences. Thus, elucidating the interactions of HIV infection and 
cervical cancer with cofactors such as diet, other sexually transmit­
ted infections, and environmental exposures is an important focus 
of research that impacts women living in low- and middle-income 
countries.
Similar to that of cervical cancer, the incidence of anal cancer is 
strongly influenced by HIV infection. HIV-infected men who have 
sex with men (MSM) and HIV-infected women have much higher 
rates of anal cancer than HIV-uninfected populations. Specifically, the 
incidence among HIV-infected MSM has been found to be as high as 
130 cases per 100,000 as opposed to 5 cases per 100,000 among HIVnegative MSM. The advent of ART has not impacted the incidence of 
anal cancer and high-grade anal intraepithelial neoplasia in the HIVinfected patient population.
More information regarding screening, prevention, and treatment 
in the HIV-infected population can be found at the Department of 
Health and Human Services website (https://clinicalinfo.hiv.gov/en/
guidelines).
■
■CLINICAL MANIFESTATIONS OF HPV INFECTION
HPV infects the male urethra, penis, and scrotum and the female vulva, 
vagina, and cervix. Perianal, anal, and oropharyngeal infections occur in 
both genders. Genital warts are caused primarily by HPV type 6 or 11 
and appear as soft sessile growths with a surface that is either smooth 
or rough with multiple finger-like projections. Penile genital warts are 
usually 2–5 mm in diameter and often occur in groups. A second type 
of penile lesion, the keratotic plaque, is slightly raised above normal epi­
thelium and has a rough, often pigmented surface. Figs. 203-1 to 203-3 
show vulvar and vaginal, penile, and perianal warts, respectively.
Vulvar warts are soft, whitish papules that are either sessile or have 
multiple fine, finger-like projections. These lesions are most often 
located in the introitus and labia. In nonmucosal areas, vulvar lesions 
are similar in appearance to those in men: dry and keratotic. Vulvar 
lesions can appear as smooth, sometimes pigmented papules that may 
coalesce. Vaginal lesions appear as multiple areas of elongated papillae. 
Biopsy of vulvar or vaginal lesions may reveal malignancy; differentia­
tion based on clinical exam is not always reliable.
Subclinical cervical HPV infections are common, and the cervix 
may appear normal on examination. Cervical lesions often appear 
FIGURE 203-1  Warts of the vulva and vagina caused by human papillomavirus. 
(Reproduced with permission from K Wolff et al: Fitzpatrick’s Color Atlas and 
Synopsis of Clinical Dermatology, 8th ed. New York: McGraw-Hill, 2013.)

FIGURE 203-2  Penile genital warts caused by human papillomavirus. (Reproduced 
with permission from K Wolff et al: Fitzpatrick’s Color Atlas and Synopsis of Clinical 
Dermatology, 8th ed. New York: McGraw-Hill, 2013.)
as papillary proliferations near the transformation zone. Irregular 
vascular loops are present beneath the surface epithelium. Patients 
who develop cervical cancer from HPV infection may present with a 
variety of symptoms. Early carcinomas appear eroded and bleed eas­
ily. More advanced carcinomas present as ulcerated lesions or as an 
exophytic cervical mass. Some cervical carcinomas are in the cervical 
canal and may be difficult to see. Bleeding, symptoms of a mass lesion 
in late stages, and metastatic disease that may manifest as bowel or 
bladder obstruction due to direct extension of the tumor also have 
been described.
CHAPTER 203
Patients with squamous cell cancer of the anus (Chap. 86) have 
more variable presentations. The most common presentations include 
rectal bleeding and pain or a mass sensation. Twenty percent of patients 
who are diagnosed with anal cancer may not present with any specific 
symptoms at the time of diagnosis, and the lesion is found fortuitously.
Human Papillomavirus Infections 
■
■PREVENTION OF HPV INFECTION AND DISEASE
Behaviors That Can Reduce Exposure to HPV 
HPV infec­
tions are transmitted through direct contact with infected genital skin 
FIGURE 203-3  Perianal warts caused by human papillomavirus. (Reproduced with 
permission from K Wolff et al: Fitzpatrick’s Color Atlas and Synopsis of Clinical 
Dermatology, 8th ed. New York: McGraw-Hill, 2013.)

or mucosal surfaces and secretions. Abstinence may possibly reduce 
HPV infections: for both men and women, numerous studies indicate 
that HPV infection and HPV-associated diseases correlate with the 
number of lifetime sexual partners, and people with no history of 
sexual intercourse have a lower detection rate of HPV. Fewer studies 
look at nonpenetrative sex on the risk of HPV infection and disease, 
but several studies indicate that HPV can be spread by any sexual 
intimacy, including touching, oral sex, or use of sex toys. It is therefore 
possible that individuals who have not partaken in sexual intercourse 
can become infected.

Use of latex condoms reduces the risk of HPV infection and HPVassociated disease, such as genital warts and cervical precancers. 
Correct and consistent condom use has also been associated with 
regression of CIN in women and regression of HPV-associated penile 
lesions in men. As a preventive measure, condom use should be con­
sidered partially effective at best and not a substitute for cervical cancer 
screening or vaccination against HPV.
HPV Vaccines 
The development of HPV vaccines effective in 
preventing infection and HPV-associated disease represents a major 
development in the past decade. The vaccines use virus-like particles 
(VLPs) that consist of the HPV L1 major capsid protein. The L1 protein 
self-assembles into VLPs when expressed in eukaryotic cells (i.e., yeast 
or insect cells). These VLPs contain the same epitopes as actual HPV 
virions. However, they do not contain genetic material and therefore 
cannot transmit infection. The immunogenicity of the HPV vaccines 
relies on development of conformational neutralizing antibodies 
directed toward epitopes displayed on viral capsids.
Several large vaccine trials have been completed and demonstrate 
the high degree of safety and efficacy of HPV vaccines. There have 
been three HPV vaccines developed, tested, and U.S. Food and Drug 
Administration (FDA) approved, as described below.
PART 5
Infectious Diseases
BIVALENT VACCINE (CERVARIX)  The bivalent HPV vaccine con­
tains L1 VLPs of HPV types 16 and 18 and is marketed under the 
name of Cervarix (GlaxoSmithKline). This vaccine was tested in 
18,644 women 15−25 years of age residing in the United States, South 
America, Europe, and Asia. It is administered by intramuscular injec­
tion three times (months 0, 1, and 6). The primary endpoints of the 
study included vaccine efficacy against persistent infections with HPV 
types 16 and 18. Investigators also assessed vaccine efficacy against 
CIN grade 2 or higher due to HPV 16 and 18 in women who had 
no evidence of HPV 16 or 18 infection at baseline. Vaccine efficacy 
related to HPV 16 or HPV 18 was 94.9% (95% confidence interval 
[CI], 87.7–98.4%) against CIN 2 or worse; 91.7% (95% CI, 66.6–99.1%) 
against CIN 3 or worse; and 100% (95% CI, –8.6–100%) against adeno­
carcinoma in situ (AIS). Adverse events associated with the bivalent 
vaccine were evaluated in phase 3 trials in a subset of 3077 women who 
received vaccine and 3080 women who received hepatitis A vaccine. 
Injection-site adverse events (pain, redness, and swelling) and systemic 
adverse events (fatigue, headache, and myalgia) were reported more 
frequently in the HPV vaccine group than in the control group. Seri­
ous adverse events, new-onset chronic disease, or medically significant 
conditions occurred in the same proportion (3.5%) of HPV vaccine 
recipients and control vaccine recipients. The bivalent HPV vaccine is 
approved in the United States for prevention of cervical cancer, CIN2 
or worse, AIS, and CIN 1 caused by HPV types 16 and 18. This vaccine 
is approved for females 9−25 years of age. Cervarix is not currently 
marketed in the United States.
QUADRIVALENT VACCINE (GARDASIL)  The quadrivalent L1 VLP 
vaccine (HPV types 6, 11, 16, and 18) is marketed under the name 
Gardasil (Merck). It is administered intramuscularly three times 
(months 0, 2, and 6). A combined efficacy analysis based on data 
from four randomized double-blind clinical studies including >20,000 
participants was performed; results demonstrated that vaccine effi­
cacy against external genital warts was 98.9% (95% CI, 93.7−100%). 
Vaccine efficacy was 95.2% (95% CI, 87.2−98.7%) against CIN; 100% 
(95% CI, 92.9−100%) against type 16- or 18-related CIN 2/3 or AIS; 
and 100% (95% CI, 55.5−100.0%) against type 16- or 18-related vulvar 

intraepithelial neoplasia grades 2 and 3 (VIN 2/3) and against vaginal 
intraepithelial neoplasia grades 2 and 3 (VaIN 2/3).
Safety data on the quadrivalent HPV vaccine are available from at 
least seven clinical trials, including nearly 12,000 women 9–26 years 
of age who received the vaccine and ~10,000 women who received 
aluminum-containing or saline placebo. A larger proportion of young 
women reported injection-site adverse events in the vaccine groups 
than in the placebo groups. Systemic adverse events were reported 
by similar proportions of vaccine and placebo recipients and were 
described as mild or moderate for most participants. The types of 
serious adverse events reported were similar for the two groups. Ten 
persons who received the quadrivalent vaccine and seven persons who 
received placebo died during the course of the trials; no deaths were 
considered to be vaccine related.
During the course of studies on the quadrivalent HPV vaccine, 
surveillance data for development of new medical conditions were 
collected for up to 4 years after vaccination. No statistically significant 
differences in the incidence of any medical conditions between vaccine 
and placebo recipients were demonstrated; this result indicated a very 
high safety profile for the vaccine. A recent safety review by the FDA 
and the Centers for Disease Control and Prevention (CDC) exam­
ined events related to Gardasil that had been reported to the Vaccine 
Adverse Events Reporting System (VAERS). The adverse events were 
consistent with what was seen in previous safety studies of the vaccine. 
Of note, rates of syncope and venous thrombotic events were higher 
with Gardasil than those usually observed with other vaccines.
The quadrivalent HPV vaccine is approved for (1) vaccination of 
females ages 9−26 years of age to prevent genital warts and cervical 
cancer caused by HPV types 6, 11, 16, and 18; (2) vaccination of the 
same population to prevent precancerous or dysplastic lesions, including 
cervical AIS, CIN 2/3, VIN 2/3, VaIN 2/3, and CIN 1; (3) vaccination of 
males 9−26 years of age to prevent genital warts caused by HPV types 6 
and 11; and (4) vaccination of patients ages 9−26 years to prevent anal 
cancer and associated precancerous lesions due to HPV types 6, 11, 16, 
and 18. While the duration of protection has not been established, no 
evidence of waning protection has been found after a three-dose series 
of the quadrivalent HPV vaccine, even after 10 years of follow-up from 
clinical trials. The quadrivalent HPV vaccine is no longer available in 
the United States but is still available in many other countries, although 
production is not likely to continue in the future.
NINE-VALENT VACCINE (GARDASIL-9)  In 2014, the FDA approved a 
new nine-valent L1 VLP vaccine. The nine-valent vaccine is marketed 
under the name Gardasil-9 (Merck). It is administered intramuscularly 
two times (months 0 and 6) for males and females from age 9 to the 
fifteenth birthday, then three times (months 0, 2, and 6) for males and 
females from age 15 through age 45. Three doses of HPV vaccine are 
recommended for persons starting the vaccination series on or after the 
fifteenth birthday and for persons with certain immunocompromising 
conditions, including HIV/AIDS.
The nine-valent vaccine targets HPV types 6, 11, 16, and 18 (the 
types also targeted by the quadrivalent HPV vaccine) as well as five 
additional oncogenic HPV types (31, 33, 45, 52, and 58). HPV types 
16 and 18 together cause up to 80% of all cervical cancers worldwide, 
and worldwide data show that HPV types 31, 33, 35, 45, 52, and 58 are 
the next most frequently detected types in invasive cervical cancers. 
Mathematical models estimate that the level of protection conferred by 
the nine-valent HPV vaccine against all HPV-associated squamous cell 
cancers worldwide could be raised to at least 90%.
In clinical studies of females 16−26 years of age, the nine-valent 
HPV vaccine generated a noninferior antibody response to HPV 
types 6, 11, 16, and 18 compared with the quadrivalent HPV vaccine. 
Bridging immunologic studies in male and female vaccine recipients 
9−15 years of age and in males 16−26 years of age indicated that the 
lower bound of the 95% CIs of the geometric mean titer ratio and 
seroconversion rates met criteria for noninferiority for all HPV types 
represented in the vaccine. In female recipients 16−26 years of age, 
vaccine efficacy against the combined endpoint of high-grade cervi­
cal, vulvar, or vaginal disease caused by any of the five additional

oncogenic HPV types was 96.7% (95% CI, 80.9–99.8%). Like the 
other available HPV vaccines, the nine-valent HPV vaccine is safe and 
extremely well tolerated. The nine-valent HPV vaccine is approved 
for 9- to 45-year-old males and females and has an FDA indication 
for prevention of cervical, vaginal, vulvar, and anal cancer and genital 
warts due to vaccine types.
CROSS-PROTECTION OF HPV VACCINES  Women who receive any of 
the available HPV vaccines produce neutralizing antibodies to virus 
types that are closely related to type 16 or 18. Analyses of data from 
clinical trials suggest that the HPV vaccines may offer limited crossprotection against nonvaccine virus types. Over short periods, the 
bivalent vaccine appears more efficacious against HPV types 31, 33, 
and 45 than the quadrivalent vaccine, but differences in study design 
make direct comparisons difficult if not impossible. In addition, in the 
bivalent vaccine trials, vaccine efficacy against persistent infections 
with HPV types 31 and 45 waned over time, whereas efficacy against 
persistent infection with HPV type 16 or 18 remained stable. These 
results suggest that cross-protection is likely to be shorter lived than 
efficacy against infection and disease caused by vaccine types.
SINGLE-DOSE VACCINATION  As a cost saving measure, the World 
Health Organization has recommended that 9- to 15-year-olds may be 
vaccinated with a single dose of an HPV vaccine. This strategy appears 
to yield similar antibody titers to a two-dose regimen, but the level 
and duration of protection against infection and disease are not fully 
understood. A single-dose strategy has not been recommended by the 
FDA or other regulatory agencies in the United States.
RECOMMENDATIONS FOR HPV VACCINATION  The most recent guide­
lines for HPV vaccination from the Advisory Committee on Immuni­
zation Practices (ACIP) are summarized below and provided in detail 
at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/hpv.html.
No prevaccination testing of any kind is recommended to establish 
whether the HPV vaccine should be administered to an individual. 
The HPV vaccine should be administered, if possible, before exposure 
to HPV through sexual activity because the vaccines are preventa­
tive against specific HPV types and have no effect on preexisting, 
type-specific HPV infections. Either the bivalent (where available) 
or nine-valent HPV vaccines may be used. An individual can begin 
a vaccine series with one HPV vaccine and then complete the series 
with another. For those who have completed a vaccination series with 
the bivalent or quadrivalent vaccine, an additional full series (two 
or three doses, depending on age as indicated above) of vaccination 
with the nine-valent vaccine may be given, but there are no data to 
determine the effectiveness of this approach.
For children, adolescents, and adults (male and female) 9−26 years 
of age, the ACIP recommends HPV vaccination at age 11 or 12 years, 
although vaccination can be initiated at 9 years of age per FDA approval 
as above. “Catch-up” HPV vaccination is recommended for men and 
women through 26 years of age who are not adequately vaccinated.
For adults (male and female) 27−45 years of age, catch-up HPV 
vaccination is not routinely recommended. Instead, the ACIP now 
recommends “shared clinical decision-making” (see below) regarding 
HPV vaccination for adults in this age range who are not adequately 
vaccinated. HPV vaccines are not licensed for use in adults older than 
45 years of age. For women, cervical cancer screening should continue 
according to age-specific guidelines regardless of having received an 
HPV vaccine (see cervical cancer screening section below).
SHARED CLINICAL DECISION-MAKING FOR ADULTS (MALES AND 
FEMALES) 27−45 YEARS OF AGE  A discussion with adults 27−45 years 
of age should occur prior to routine recommendation of the HPV 
vaccine. HPV infection occurs soon after first sexual activity in most 
people, and vaccine effectiveness is therefore lower in older individuals 
due to prior infections. HPV exposure usually decreases among older 
age groups. Although HPV vaccination is safe for adults 27−45 years 
of age, the benefit to the population is likely to be minimal. However, 
some men and women who are not vaccinated may be at risk for 
acquisition of new HPV infections and could therefore benefit from 
HPV vaccination.

In considering HPV vaccination of adults 27−45 years of age, some 
key points emphasized by the ACIP that should be discussed include 
the following:

•	 HPV is a common sexually transmitted infection, and most HPV 
infections are asymptomatic and do not lead to clinical disease.
•	 Most sexually active adults have been exposed to HPV, although not 
necessarily all of the HPV types targeted by vaccines.
•	 Some adults are at risk for acquiring new HPV infections through 
sexual activity. For example, having a new sex partner is a risk factor 
for acquiring a new HPV infection.
•	 Persons in a long-term, mutually monogamous sexual partnership 
are unlikely to acquire a new HPV infection.
•	 Antibody testing cannot determine whether a person is immune or 
susceptible to a specific HPV type.
•	 HPV vaccines are very effective in persons who have not been 
exposed to vaccine-type HPV before vaccination.
•	 Vaccine effectiveness is likely to be lower among persons with mul­
tiple lifetime sex partners because these individuals have probably 
had previous infections with vaccine-type HPV.
•	 HPV vaccines are prophylactic (i.e., they prevent new HPV infec­
tions). They have no utility in preventing established HPV infection 
from progressing to clinical disease, and they do not have a role in 
treatment of HPV-associated disease.
RECOMMENDATIONS FOR HPV VACCINATION IN PEOPLE LIVING WITH 
HIV (PLWH)  Guidelines for HPV vaccination of PLWH are summarized 
below and can be found in detail at https://hivinfo.nih.gov.
HPV vaccines are safe in PLWH. Administration of HPV vaccines 
generates high levels of antibody against HPV types represented in 
vaccine, although antibody levels are generally lower than in those 
who are HIV-uninfected. In addition, immune responses appear stron­
ger among PLWH who have the highest CD4 counts and the lowest 
HIV viral loads. Studies also indicate that HPV vaccination induces 
an anamnestic response in PLWH. Regarding efficacy in protect­
ing against HPV-associated disease, one randomized, double-blind, 
clinical trial evaluated the efficacy of the quadrivalent HPV vaccine in 
adults with HIV infection older than 27 years in prevention of new anal 
HPV infections or improvement in high-grade dysplastic anal lesions. 
The trial did not show efficacy, but many study participants had HPV 
infection detected at baseline, prior to vaccination.
CHAPTER 203
Human Papillomavirus Infections 
HPV vaccination is recommended (three doses) for girls and boys 
with HIV infection 11−26 years of age. Because some individuals with 
HIV infection (similar to HIV-uninfected individuals) have had many 
sex partners prior to vaccination, HPV vaccination may be less benefi­
cial in these patients than in those with few or no lifetime sex partners. 
Current data do not strongly support vaccination for those PLWH 
older than 26 years. The public health benefit for HPV vaccination 
of PLWH in this age range is likely to be minimal. However, although 
many PLWH ages 27–45 years will not fully benefit from the vaccine, 
there may be situations that suggest the possibility of vaccine ben­
efit, and the same shared clinical decision-making (described above) 
between the provider and patient is recommended.
■
■SCREENING FOR HPV-ASSOCIATED CANCER
Once HPV infection occurs, prevention of HPV-associated disease 
relies on screening. At present, screening for cervical cancer is widely 
accepted as cost-effective in preventing cervical cancer. Anal screen­
ing is accepted for screening in high-risk groups, though no national 
guidelines exist for screening intervals or ages for initiation and ces­
sation of screening. In resource-rich countries, the primary method 
of cervical cancer screening is cytology via Pap smear. The American 
Society of Colposcopy and Cervical Pathology (ASCCP) guidelines 
recommend initiation of cervical cancer screening at age 21, no mat­
ter the age of sexual debut. Women 21−29 years old should have a 
Pap smear every 3 years if their initial and subsequent Pap smears are 
normal. Although adolescent and young women often test HPV DNA 
positive, they are at very low risk of cervical cancer. Because the pres­
ence of HPV DNA does not correlate with the presence of high-grade

squamous intraepithelial neoplasia, co-testing (testing for HPV DNA 
at the time of Pap smear) is not recommended for women in this age 
group.

As a method of determining the need for colposcopy, HPV DNA 
co-testing is recommended for women 25−29 years of age in whom 
cytology detects abnormal squamous cells of undetermined signifi­
cance (ASCUS). Women 30−65 should have a Pap smear every 3 years 
if testing for HPV DNA is not performed. The screening interval for 
women in this age group can be extended to every 5 years if HPV DNA 
co-testing is performed and results are negative. HPV testing is not 
recommended for partners of women with HPV or for screening of 
conditions other than cervical cancer.
The role of HPV DNA testing as a primary screen for cervical cancer 
is changing. In the United States, there are three commercially avail­
able assays (cobas HPV Test [Roche Diagnostics], the BD Onclarity 
HPV Assay [Becton, Dickinson and Company], and Alinity m HR 
HPV Assay (Abbott Molecular Diagnostics)) that are FDA approved 
for primary screening using HPV DNA testing. However, more assays 
may gain approval for usage as the feasibility and evidence for their use 
in various populations globally come to light. These tests can be used 
to detect HPV DNA in specimens obtained from the cervix without 
cervical cytology for women ≥25 years of age. A positive result for HPV 
type 16 or 18 has a high enough positive predictive value in the general 
population that these women should have colposcopy performed. If 
high-risk HPV types other than HPV 16 or HPV 18 are detected, then 
cytology can be obtained. The complete set of algorithms for appropri­
ate age-specific screening guidelines, HPV DNA testing, and the man­
agement of abnormal Pap smears are available through the ASCCP at 
http://asccp.org/guidelines.
PART 5
Infectious Diseases
For women ≤30 years of age who are infected with HIV, cervical 
cytology is the preferred method of cervical cancer screening and HPV 
DNA co-testing is not recommended. Cervical cancer screening should 
begin within 1 year of diagnosis of HIV infection, regardless of the mode 
of HIV transmission. If the first Pap smear is normal, then subsequent 
Pap smears should be performed annually until three negative tests are 
obtained. Cytology can then be obtained every 3 years. For women 
≥30 years old, Pap testing is performed in the same manner as for 
younger women. However, HPV DNA co-testing can be used in women 
of this age group. If cytology and HPV DNA co-testing are negative, 
the next exam can be performed in 3 years. Positive HPV DNA co-test 
results are treated in the same manner as in HIV-uninfected women.
Women residing in developing countries with a lack of access to 
cervical screening programs have a higher rate of cervical cancer and 
a poorer cancer-specific survival. Approximately 75% of women liv­
ing in developed countries have been screened in the past 5 years, as 
opposed to ~5% of women living in developing countries. Economic 
and logistic obstacles likely impede routine cervical cancer screening 
for these populations. Many poor countries rely on an alternative 
method—visual inspection with acetic acid (VIA)—for cervical can­
cer screening. While some studies show a reduction in cervical cancer 
mortality in communities where VIA is widely utilized, other stud­
ies do not. In addition, the low specificity of VIA is problematic. As 
newer methods that use detection of oncogenic HPV DNA become 
available, even resource-limited countries may be able to replace VIA 
with such methods and achieve a reduction in cervical cancers as a 
result.
There are no anal cancer screening guidelines endorsed by organiza­
tions such as the United States Preventative Services Task Force. The 
International Anal Neoplasia Society has published consensus guide­
lines regarding screening for anal cancer in patients at higher risk such 
as those with HIV. Current HIV treatment guidelines suggest that there 
may be a benefit to screening, but an effect on the associated morbidity 
and mortality of anal squamous cell cancer has not been consistently 
demonstrated. Although the most effective method of screening for 
anal cancer has not been determined, data published from a random­
ized controlled treatment trial noted a significant reduction in progres­
sion of high-grade precancerous lesions of the anus to anal cancer in 
those who received treatment. Further studies on optimal screening 
strategies for anal cancer are ongoing.

The incidence of HPV-associated head and neck cancers in the 
United States has overtaken the incidence of cervical cancer as of 2020, 
but there are no established guidelines for screening for HPV-associated 
head and neck cancers. However, HPV vaccination is likely to be effec­
tive for both anal and head and neck cancers associated with HPV.
TREATMENT
HPV-Associated Disease
A variety of treatment modalities are available for various HPV 
infections, but none has been proven to eliminate HPV from 
tissue adjacent to the destroyed and infected tissue. Treatment 
efficacies are limited by frequent recurrences, presumably due to 
reinfection from an infected partner, reactivation of latent virus, or 
autoinoculation from nearby infected cells. The goals of treatment 
include prevention of viral transmission, eradication of premalig­
nant lesions, and reduction of symptoms.
Therapies are generally successful in eliminating visible lesions 
and grossly diseased tissue. Different therapies are indicated for geni­
tal warts, vaginal and cervical disease, and perianal and anal disease.
THERAPEUTIC OPTIONS
Imiquimod  Imiquimod (5 or 3.75% cream) is a patient-applied 
topical immunomodulatory agent thought to activate immune 
cells by binding to a Toll-like receptor that leads to an inflamma­
tory response. Imiquimod 5% cream is applied to genital warts at 
bedtime three times per week for up to 16 weeks. Warts are cleared 
in ~56% of patients, more often in women than in men; recurrence 
rates approach 13%. Local inflammatory side effects are com­
mon. Rates of clearance of genital warts are not as high with the 
3.75% formulation as with the 5% preparation, but the duration 
of treatment is shorter (daily application required for a maximum 
of 8 weeks) and fewer local and systemic adverse reactions occur. 
Imiquimod should not be used to treat vaginal, cervical, or anal 
lesions. The safety of imiquimod during pregnancy has not been 
established.
Interferon  Recombinant interferon α is used for intralesional 
treatment of genital warts, including perianal lesions. The recom­
mended dosage is 1.0 × 106 IU of interferon into each lesion three 
times weekly for 3 weeks. Interferon therapy causes clearance of 
infected cells by immune-boosting effects. Adverse events include 
headache, nausea, vomiting, fatigue, and myalgia. Interferon ther­
apy is costly and should be reserved for severe cases that do not 
respond to less expensive treatments. Interferon should not be used 
to treat vaginal, cervical, or anal lesions.
Cryotherapy  Cryotherapy (liquid nitrogen treatment) for HPVassociated lesions causes cellular death. Genital warts usually disap­
pear after two or three weekly sessions but often recur. Cryotherapy, 
which is nontoxic and is not associated with significant adverse 
reactions, can also be used for diseased cervical tissue. Local pain 
occurs frequently.
Surgical Methods  Exophytic lesions can be surgically removed 
after intradermal injection of 1% lidocaine. This treatment is well 
tolerated but can cause scarring and requires hemostasis. Genital 
warts can also be destroyed by electrocautery, in which no addi­
tional hemostasis is required.
Laser Therapy  Laser treatment affords destruction of exophytic 
lesions and other HPV-infected tissue while preserving normal 
tissue. Local anesthetics are generally adequate. Efficacy for genital 
lesions is at least equal to that of other therapies (60–90%), with low 
recurrence rates (5–10%). Complications include local pain, vagi­
nal discharge, periurethral swelling, and penile or vulvar swelling. 
Laser therapy has also been used successfully for cervical dysplasia 
and anal disease caused by HPV.
Therapeutic Vaccines  The innate and adaptive immune systems 
are altered in patients with HPV-associated cancers. Antitumor