1495CHAPTER 197 Parvovirus Infections

amenable to investigational treatment with TPOXX or brincidofovir.

As mentioned above, vaccinia immune globulin is licensed for the

treatment of vaccinia infections.

■ FURTHER READING

Beer EM, Rao VB: A systematic review of the epidemiology of human

monkeypox outbreaks and implications for outbreak strategy. PLoS

Negl Trop Dis 13:e0007791, 2019.

Meza-Romero R et al: Molluscum contagiosum: An update and

review of new perspectives in etiology, diagnosis, and treatment. Clin

Cosmet Investig Dermatol 12:373, 2019.

Parvoviruses, members of the family Parvoviridae, are small (diameter,

~22 nm), nonenveloped, icosahedral viruses with a linear single-strand

DNA genome of ~5000 nucleotides. These viruses are dependent

on either rapidly dividing host cells or helper viruses for replication. At least five groups of parvoviruses infect humans: parvovirus

B19 (B19V), dependoparvoviruses (adeno-associated viruses; AAVs),

human tetraparvoviruses (PARV4 and PARV5), human bocaparvoviruses (HBoVs), and human protoparvoviruses (bufavirus, tusavirus,

and cutavirus). Human dependoparvoviruses are nonpathogenic and

will not be considered further in this chapter.

197 Parvovirus Infections

Kevin E. Brown

15

13

11

9

7

5

3

1

14

4

1.0

0.2

0

100

50

10

0

2 6 10 20

Days

Inoculation or infection

Normals

B19 Virus B19 Antibodies

Hemoglobin

(g%)

Clinical

manifestations

IgM

IgG

Reticulocytes

(g%)

10

Fever,

chills,

headache,

myalgia

Rash,

arthralgia

A 15

13

11

9

7

5

3

1

14

4

10

8

0

100

50

10

0

2 6 10 20

Days

Infection

TAC

B19 Virus B19 Antibodies

Hemoglobin

(g%)

Clinical

manifestations

IgM

IgG

Reticulocytes

(g%)

10

Symptoms

of anemia

B 15

13

11

9

7

5

3

1

14

4

10

8

0

100

50

10

0

2 6 10 20

Days

Infection

PRCA

B19 Virus B19 Antibodies

Hemoglobin

(g%)

Clinical

manifestations

IgM and IgG Reticulocytes

(g%)

10

Symptoms

of anemia

C

FIGURE 197-1 Schematic of the time course of parvovirus B19 infection in (A) normals (erythema infectiosum), (B) transient aplastic crisis (TAC), and (C) chronic anemia/

pure red cell aplasia (PRCA). (From NS Young, KE Brown: Parvovirus B19. N Engl J Med 350:586, 2004. Copyright © 2004 Massachusetts Medical Society. Reprinted with

permission from Massachusetts Medical Society.)

PARVOVIRUS B19

■ DEFINITION

B19V is the type member of the genus Erythroparvovirus. On the basis

of viral sequence, B19V is divided into three genotypes (designated 1,

2, and 3), but only a single B19V antigenic type has been described.

Genotype 1 is predominant in most parts of the world; genotype 2 is

rarely associated with active infection; and genotype 3 appears to predominate in parts of western Africa.

■ EPIDEMIOLOGY

B19V exclusively infects humans, and infection is endemic in virtually

all parts of the world. Transmission occurs predominantly via the

respiratory route and is followed by the onset of rash and arthralgia. By

the age of 15 years, ~50% of children have detectable IgG antibody to

B19V; this figure rises to >90% among the elderly. In pregnant women,

the estimated annual seroconversion rate is ~1%. Within households,

secondary infection rates approach 50%.

Detection of high-titer B19V in blood is not unusual (see “Pathogenesis,” below). Transmission can occur as a result of transfusion,

most commonly of pooled components. To reduce the risk of transmission, plasma pools are screened by nucleic acid amplification technology, and high-titer pools are discarded. B19V is resistant to both heat

and solvent-detergent inactivation.

■ PATHOGENESIS

B19V replicates primarily in erythroid progenitors. This specificity

is due in part to the limited tissue distribution of the primary B19V

receptor, blood group P antigen (globoside). Infection leads to hightiter viremia, with >1012 virus particles (or IU)/mL detectable in the

blood at the apex (Fig. 197-1), and virus-induced cytotoxicity results

1496 PART 5 Infectious Diseases

in cessation of red cell production. In immunocompetent individuals, viremia and arrest of erythropoiesis are transient and resolve as

the IgM and IgG antibody response is mounted. In individuals with

normal erythropoiesis, there is only a minimal drop in hemoglobin

levels; however, in those with increased erythropoiesis (especially with

hemolytic anemia), this cessation of red cell production can induce a

transient crisis with severe anemia (Fig. 197-1). Similarly, if an individual (or, after maternal infection, a fetus) does not mount a neutralizing

antibody response and halt the lytic infection, erythroid production is

compromised and chronic anemia develops (Fig. 197-1).

The immune-mediated phase of illness, which begins 2–3 weeks

after infection as the IgM response peaks, manifests as the rash of fifth

disease together with arthralgia and/or frank arthritis. Low-level B19V

DNA can be detected by polymerase chain reaction (PCR) in blood and

tissues for months to years after acute infection. The B19V receptor is

found in a variety of other cells and tissues, including megakaryocytes,

endothelial cells, placenta, myocardium, and liver. Infection of these

tissues by B19V may be responsible for some of the more unusual

presentations of the infection. Rare individuals who lack P antigen are

naturally resistant to B19V infection.

■ CLINICAL MANIFESTATIONS

Erythema Infectiosum Most B19V infections are asymptomatic

or are associated with only a mild nonspecific illness. The main manifestation of symptomatic B19V infection is erythema infectiosum,

also known as fifth disease or slapped-cheek disease (Figs. 197-2 and

A1-1A). Infection begins with a minor febrile prodrome ~7–10 days

after exposure, and the classic facial rash develops several days later; after

2–3 days, the erythematous macular rash may spread to the extremities

in a lacy reticular pattern. However, its intensity and distribution vary,

and B19V-induced rash is difficult to distinguish from other viral exanthems. Adults typically do not exhibit the “slapped-cheek” phenomenon

but present with arthralgia, with or without the macular rash.

Polyarthropathy Syndrome Although uncommon among children, arthropathy occurs in ~50% of adults and is more common

among women than among men. The distribution of the affected

joints is often symmetrical, with arthralgia affecting the small joints

FIGURE 197-2 Young child with erythema infectiosum, or fifth disease, showing

typical “slapped-cheek” appearance.

of the hands and occasionally the ankles, knees, and wrists. Resolution usually occurs within a few weeks, but recurring symptoms can

continue for months. The illness may mimic rheumatoid arthritis, and

rheumatoid factor can often be detected in serum. B19V infection may

trigger rheumatoid disease in some patients and has been associated

with juvenile idiopathic arthritis.

Transient Aplastic Crisis Asymptomatic transient reticulocytopenia occurs in most individuals with B19V infection. However,

in patients who depend on continual rapid production of red cells,

infection can cause transient aplastic crisis (TAC). Affected individuals include those with hemolytic disorders, hemoglobinopathies, red

cell enzymopathies, and autoimmune hemolytic anemias. Patients

present with symptoms of severe anemia (sometimes life-threatening)

and a low reticulocyte count, and bone marrow examination reveals

an absence of erythroid precursors and characteristic giant pronormoblasts. As its name indicates, the illness is transient, and anemia

resolves with the cessation of cytopathic infection in the erythroid

progenitors.

Pure Red Cell Aplasia/Chronic Anemia Chronic B19V infection has been reported in a wide range of immunosuppressed patients,

including those with congenital immunodeficiency, AIDS (Chap. 202),

lymphoproliferative disorders (especially acute lymphocytic leukemia),

and transplantation (Chap. 143). Patients have persistent anemia with

reticulocytopenia, absent or low levels of B19V IgG, high titers of B19V

DNA in serum, and—in many cases—scattered giant pronormoblasts

in bone marrow. Rarely, nonerythroid hematologic lineages also are

affected. Transient neutropenia, lymphopenia, and thrombocytopenia

(including idiopathic thrombocytopenic purpura) have been observed.

B19V occasionally causes a hemophagocytic syndrome.

Studies in Papua New Guinea, Gabon, and Ghana, where malaria is

endemic, suggest that co-infection with Plasmodium and B19V plays

a major role in the development of severe anemia in young children.

Case reports from other countries are rare, but further studies are

required to determine whether B19V infection contributes to severe

anemia in other malarial regions.

Hydrops Fetalis B19V infection during pregnancy can lead to

hydrops fetalis and/or fetal loss. The risk of transplacental fetal infection is ~30%, and the risk of fetal loss (predominantly early in the

second trimester) is ~9%. The risk of congenital infection is <1%.

Although B19V does not appear to be teratogenic, anecdotal cases of

eye damage and central nervous system (CNS) abnormalities have been

reported. Cases of congenital anemia have also been described. B19V

probably causes 10–20% of all cases of nonimmune hydrops.

Unusual Manifestations B19V infection may rarely cause hepatitis, vasculitis, myocarditis, glomerulosclerosis, or meningitis. A variety

of other cardiac manifestations, CNS diseases, and autoimmune infections have also been reported. However, B19V DNA can be detected

by PCR for years in many tissues; this finding is of no known clinical

significance, but its interpretation may cause confusion regarding

B19V disease association.

■ DIAGNOSIS

Diagnosis of B19V infection in immunocompetent individuals is generally based on detection of B19V IgM antibodies (Table 197-1). IgM can

be detected at the time of rash in erythema infectiosum and by the third

day of TAC in patients with hematologic disorders; these antibodies

remain detectable for ~3 months. B19V IgG is detectable by the seventh

day of illness and persists throughout life. Quantitative detection of

B19V DNA should be used for the diagnosis of early TAC or chronic

anemia. Although B19V levels fall rapidly with the development of the

immune response, DNA can be detectable by PCR for months or even

years after infection, even in healthy individuals; therefore, quantitative

PCR should be used. In acute infection at the height of viremia, >1012

B19V DNA IU/mL of serum can be detected; however, titers fall rapidly

within 2 days. Patients with aplastic crisis or B19V-induced chronic

anemia generally have >105

 B19V DNA IU/mL.

1497CHAPTER 197 Parvovirus Infections

TABLE 197-1 Diseases Associated with Human Parvovirus B19 Infection and Methods of Diagnosis

DISEASE HOSTS IgM IgG PCR QUANTITATIVE PCR

Fifth disease Healthy children Positive Positive Positive >104

 IU/mL

Polyarthropathy syndrome Healthy adults (more often

women)

Positive within 3 months

of onset

Positive Positive >104

 IU/mL

Transient aplastic crisis Patients with increased

erythropoiesis

Negative/positive Negative/positive Positive Often >1012 IU/mL, but rapidly

decreases

Persistent anemia/pure

red cell aplasia

Immunodeficient or

immunocompetent patients

Negative/weakly positive Negative/weakly

positive

Positive Often >1012 IU/mL, but should be

>106

 in the absence of treatment

Hydrops fetalis/congenital

anemia

Fetuses (<20 weeks) Negative/positive Positive Positive amniotic

fluid or tissue

n/a

Abbreviations: IU, international units (1 IU equals ~1 genome); n/a, not applicable; PCR, polymerase chain reaction.

TREATMENT

Parvovirus B19 Infection

No antiviral drug effective against B19V is available, and treatment

of B19V infection often targets symptoms only. TAC precipitated by

B19V infection frequently necessitates symptom-based treatment

with blood transfusions. In patients receiving chemotherapy, temporary cessation of treatment may result in an immune response

and resolution. If this approach is unsuccessful or not applicable,

commercial immune globulin (IVIg; Gammagard, Sandoglobulin)

from healthy blood donors can cure or ameliorate persistent B19V

infection in immunosuppressed patients. Generally, the dose used

is 400 mg/kg daily for 5–10 days. Like patients with TAC, immunosuppressed patients with persistent B19V infection should be

considered infectious. Administration of IVIg is not beneficial for

erythema infectiosum or B19V-associated polyarthropathy. Intrauterine blood transfusion can prevent fetal loss in some cases of

fetal hydrops.

■ PREVENTION

No vaccine has been approved for the prevention of B19V infection,

although vaccines based on B19V virus-like particles expressed in

insect cells are known to be highly immunogenic. Phase 1 trials of a

putative vaccine were discontinued because of adverse side effects.

HUMAN TETRAPARVOVIRUSES (PARV4/5)

■ DEFINITION

The PARV4 viral sequence was initially detected in a patient with an

acute viral syndrome. Similar sequences, including the related PARV5

sequence, have been detected in pooled plasma collections. The DNA

sequence of PARV4/5 is distinctly different from that of all other parvoviruses, and this virus is now classified as a member of the newly

described genus Tetraparvovirus.

■ EPIDEMIOLOGY

PARV4 DNA is commonly found in plasma pools but at lower concentrations than the levels of B19V DNA found before in plasma pools

prior to screening. The higher levels of PARV4 DNA and IgG antibody

in tissues (bone marrow and lymphoid tissue) and sera from IV drug

users than in the corresponding specimens from control patients suggest that the virus is transmitted predominantly by parenteral means in

the United States and Europe. Evidence for nonparenteral transmission

in other parts of the world is limited.

■ CLINICAL MANIFESTATIONS

To date, PARV4/5 infection has been associated only with mild clinical

disease (rash and/or transient aminotransferase elevation).

HUMAN BOCAPARVOVIRUSES

■ DEFINITION

Animal bocaparvoviruses are associated with mild respiratory symptoms and enteritis in young animals. Human bocavirus 1 (HBoV1)

was originally identified in the respiratory tract of young children

with lower respiratory tract infections. More recently, HBoV1 and the

related viruses HBoV2, HBoV3, and HBoV4 have all been identified

in human fecal samples.

■ EPIDEMIOLOGY

Seroepidemiologic studies with HBoV virus-like particles suggest that

HBoV infection is common. Worldwide, most individuals are infected

before the age of 5 years.

■ CLINICAL MANIFESTATIONS

HBoV1 DNA is found in respiratory secretions from 2–20% of children with acute respiratory infection, often in the presence of other

pathogens; in these circumstances, the role of HBoV1 in disease

pathogenesis is unknown. Clinical disease due to HBoV1 is associated with evidence of primary infection (IgG seroconversion or the

presence of IgM), HBoV1 DNA in serum, or high-titer HBoV1 DNA

(>104

 genome copies/mL) in respiratory secretions. Symptoms are not

dissimilar from those of other viral respiratory infections, and cough

and wheezing are commonly reported. There is no specific treatment

for HBoV infection. The role of HBoVs in childhood gastroenteritis

remains to be established.

HUMAN PROTOPARVOVIRUSES

■ DEFINITION

Bufavirus, tusavirus, and cutavirus were all identified in clinical samples by a metagenomics approach used for identifying new pathogens.

These viruses are classified as members of the Protoparvovirus group

along with the original prototype member of the Parvoviridae, minute

virus of mice.

■ EPIDEMIOLOGY

Little is known about the epidemiology of these viruses. Antibodies

against bufavirus were very low in Finland and the United States (<4%)

but >50% in countries like Iraq, Iran, and Kenya. In contrast, antibodies against cutavirus were only found in <6% of all populations and

tusavirus antibodies in none. To date, tusavirus has been identified in

only a single patient with diarrhea in Tunisia, and it is not clear if it is

a human pathogen.

■ CLINICAL MANIFESTATIONS

Although bufavirus DNA is found in 0.2–4% of stools from children

and adults with diarrhea in many countries, often it is detected in

conjunction with other viruses. The role of bufavirus in childhood

gastroenteritis remains to be confirmed. Similarly, although cutavirus has been found in biopsies of individuals with cutaneous T-cell

lymphoma and melanoma, it has also been found in skin swabs from

healthy individuals.

■ FURTHER READING

Crabol Y et al: Intravenous immunoglobulin therapy for pure red

cell aplasia related to human parvovirus B19 infection: A retrospective study of 10 patients and review of the literature. Clin Infect Dis

56:968, 2013.

1498 PART 5 Infectious Diseases

Guido M et al: Human bocavirus: Current knowledge and future challenges. World J Gastroenterol 22:8684, 2016.

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.

Söderlund-Venermo M: Emerging human parvoviruses: The rocky

road to fame. Ann Rev Virol 6:71, 2019.

Söderlund-Venermo M et al: Human parvoviruses, in Clinical

Virology, 4th ed. DD Richman et al (eds). Washington, DC, ASM

Press, 2016, pp 679–700.

Su C-C et al: Effects of antibodies against human parvovirus B19 on

angiogenic signaling. Mol Med Rep 21:1320, 2020.

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 epidemiology of

HPV as a virus and a pathogen, the natural history of HPV infections

and associated cancers, strategies to prevent infection and HPVassociated disease, and treatment modalities for some conditions

caused by HPV.

■ PATHOGENESIS

Overview HPV is an icosahedral, nonenveloped, 8000-

base-pair, 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

proteins 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 125 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 therefore considered high risk.

HPV targets basal keratinocytes after microtrauma allows exposure

of these cells to the virus. The HPV replication cycle is completed as

keratinocytes undergo differentiation. Virions are assembled in the

198 Human Papillomavirus

Infections

Darron R. Brown, Aaron C. Ermel

nuclei of differentiated keratinocytes and can be detected 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 infection.

Natural HPV infection of the genital tract gives rise to a 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 antibodies likely reach

the cervical epithelium and secretions by transudation 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.

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 immunosuppressed individuals, particularly those who are infected with HIV.

Specific 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 HPV type 16 cervical infection, a strong T-cell response

to type 16–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, oral sex, and probably by touching a partner’s genitalia. In cross-sectional and longitudinal studies, ~40% of young women demonstrate evidence of HPV

infection, with peaks during the teens and early twenties, soon after

first coital experience. The number of lifetime sexual partners correlates with the likelihood of HPV infection and the subsequent 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 6–9 months, a phenomenon known as “clearance.” However, with prolonged follow-up

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.

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 500,000 women are diagnosed

and 275,000 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 prospective and case–control studies, respectively. The time

from HPV infection to cervical cancer may exceed 20 years. Cervical

cancer peaks in the fifth and sixth decades of life for women living in

developed countries and as much as a decade 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%

1499CHAPTER 198 Human Papillomavirus Infections

■ 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 epithelium and has a rough, often pigmented surface.

Figs. 198-1–198-3 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; differentiation 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 as

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. 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 has concluded

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 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 cancers 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 HPVASSOCIATED DISEASE

HIV infection accelerates the natural history of HPV infections.

HIV-infected 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 cervical 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. 70) than women in the general population. Studies indicate

a direct relationship between low CD4+ T lymphocyte count and the

risk of cervical 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 transmitted

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 (aidsinfo.nih.gov/guidelines).

FIGURE 198-1 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 198-2 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.)

1500 PART 5 Infectious Diseases

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 easily. More

advanced carcinomas present as ulcerated lesions or as an exophytic

cervical mass. Some cervical carcinomas are located 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 have also

been described.

Patients with squamous cell cancer of the anus (Chap. 81) 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.

■ PREVENTION OF HPV INFECTION AND DISEASE

Behaviors That Can Reduce Exposure to HPV HPV infections are transmitted through direct contact with infected genital skin

or mucosal surfaces and secretions. Does abstinence 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 and 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 penetrative sex can become

infected.

Use of latex condoms reduces the risk of HPV infection and

HPV-associated 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 considered 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.

BIVALENT VACCINE (CERVARIX) The bivalent HPV vaccine contains

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 injection 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 adenocarcinoma 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. Serious 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 efficacy 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

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) examined events related to Gardasil that had been reported to the Vaccine

Adverse Events Reporting System (VAERS). The adverse events were

FIGURE 198-3 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.)

1501CHAPTER 198 Human Papillomavirus Infections

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 people 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

three times (months 0, 2, and 6). 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 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 to 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 cervical, 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 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

cross-protection 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.

TWO-DOSE VERSUS THREE-DOSE SCHEDULE FOR HPV VACCINATION In an effort to simplify the dosing schedule and potentially

reduce costs and improve vaccine uptake, a two-dose schedule has been

considered. In several randomized vaccine trials among adolescent

girls, geometric mean concentrations (GMCs) of antibodies to HPV

type 16 were shown to be noninferior up to 24 months after a two-dose

schedule to GMCs after a three-dose schedule. Numerous countries

have adopted a two-dose HPV vaccination schedule. In the United

States, the CDC now recommends two doses of HPV vaccine (at 0

and 6−12 months) for persons starting the vaccination series before

the fifteenth birthday, as the immunologic response is rigorous in this

age group. Three doses of HPV vaccine (at 0, 1−2, and 6 months) are

recommended for persons starting the vaccination series on or after the

fifteenth birthday and for persons with certain immunocompromising

conditions, including HIV/AIDS.

RECOMMENDATIONS FOR HPV VACCINATION The most recent guidelines for HPV vaccination from the Advisory Committee on Immunization Practices (ACIP) are summarized below and provided in detail

at https://www.cdc.gov/mmwr/volumes/68/wr/mm6832a3.htm.

No prevaccination testing of any kind is recommended to establish

whether or not the HPV vaccine should be administered to an individual to determine if the vaccine will or will not be effective. The HPV

vaccine should be administered, if possible, before exposure to HPV

through sexual activity because the vaccines are preventative 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 (three doses) 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. “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 regarding HPV vaccination

for certain adults 27−45 years of age who are not adequately vaccinated

(see below). 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 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 multiple 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 infections). 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.

1502 PART 5 Infectious Diseases

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://aidsinfo.nih.gov/

guidelines/html/4/adult-and-adolescent-opportunistic-infection/343/

human-papillomavirus.

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 stronger 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 protecting

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 study participants had high levels

of HPV infection at baseline.

HPV vaccination is recommended 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 beneficial

in these patients than in those with few or no lifetime sex partners.

Current data do not 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 most PLWH

ages 27–45 years will not benefit from the vaccine, there may be situations that suggest the possibility of vaccine benefit, 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 screening

is accepted for screening in high-risk groups, though no national guidelines exist for screening intervals or ages for initiation and cessation 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 matter 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 presence 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 significance (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 two commercially available

assays (cobas HPV Test [Roche Diagnostics] and the BD Onclarity

HPV Assay [Becton, Dickinson and Company]) 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 are detected other than HPV 16 or HPV 18, then

cytology can be obtained. The complete set of algorithms for appropriate age-specific screening guidelines, HPV DNA testing, and the

management of abnormal Pap smears are available through the ASCCP

at http://asccp.org/guidelines.

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 living 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 cancer

screening. While some studies show a reduction in cervical cancer

mortality in communities where VIA is widely utilized, other studies

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.

Currently, there is no broad consensus regarding the screening for

anal cancer and its precursors, including high-grade anal intraepithelial lesions. The reason is a lack of understanding of optimal treatment

for low- or high-grade anal dysplasia found during cytologic screening.

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.

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

effective 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 premalignant lesions, and reduction of symptoms.

Therapies are generally successful in eliminating visible lesions

and grossly diseased tissue. Different therapies are indicated for

genital 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 inflammatory 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