164 Lesions are most contagious during the
ulcerative phase. The median duration of viral shedding as defined from onset to the
last positive culture is about 12 days.
142 The mean time from the onset of vesicles to
the appearance of the crust stage (~10.5 days) correlates well with the duration of
viral shedding. However, there is considerable overlap between the duration of viral
shedding and the duration of crusting. Women require a longer healing time than men,
19.5 and 16.5 days, respectively.
142 The mean duration of viral shedding from the
cervix is 11.4 days. Therefore, patients should be advised to refrain from sexual
activity until the lesions have completely healed; however, subclinical viral shedding
A genital herpes infection may be acquired from an individual who has never had
symptomatic genital lesions. States of asymptomatic or subclinical viral shedding
occur in the majority of women with recurrent genital herpes as a result of
reactivation of latent infection. These recurrent infections can have a primary disease
presentation, causing the patient to blame the most proximate sexual partner when in
actuality the exposure could have occurred in the distant past.
virologic typing can be used to determine whether this is a true primary infection.
Using sensitive detection techniques, such as PCR, women with recurrent HSV
asymptomatic spread can occur from multiple anatomic genital sites and in a bilateral
fashion, even with previous outbreaks of unilateral lesions.
Seropositive HSV patients also should be counseled to practice safer sex, using
male or female condoms, at all times, not just during symptomatic episodes.
CASE 72-14, QUESTION 4: Viral culture was negative for B.J., but HSV-2 point-of-care (POC) serology
The accuracy with which herpes genitalis can be diagnosed without the aid of
laboratory tests generally is difficult to achieve, especially if the infection is not
symptomatic. Thus, because of the potentially severe psychologic and physiologic
ramifications of such a diagnosis, either virologic and/or serologic confirmation of
the diagnosis may be obtained.
The laboratory diagnosis of HSV-1 or HSV-2 infection depends on isolation of
virus using viral culture, while HSV DNA detection by PCR is more expensive than
viral culture and not as widely available or HSV antigen detection using EIA or
DFA. Both PCR and EIA can differentiate HSV-1 from HSV-2. Currently, HSV DNA
PCR is the most sensitive method for detecting mucocutaneous herpes simplex
infection rather than simple viral culture in those with genital ulcers and is the
preferred method for CSF samples.
142 Tests that measure serologic response,
antibody production, are valuable in documenting primary infection, but they are not
very useful in recurrent infections or to determine when the initial infection occurred.
It is possible to differentiate between antibodies to HSV-1 and HSV-2 by means of
type-specific serologic assay. POC devices using HSV-2—specific antibody testing
kits offer ease, reduced time, differentiation between HSV-1 and HSV-2, and high
sensitivities and specificities.
Viral culture is more likely to yield false-negative results than other testing
12 A better antigen detection test could have been used, such as an EIA or
DFA. The lack of a positive viral culture does not rule out the diagnosis of a primary
infection in B.J., especially because the antibody test was positive. The fact that
B.J.’s partner’s antibody test was positive without a history of symptomatic disease
suggests a distant infection with asymptomatic shedding.
CASE 72-14, QUESTION 5: How should B.J.’s lesions be managed? Because the likelihood of recurrence
of genital herpes is high, what treatment and prevention measures are recommended currently?
A diagnosis of genital herpes is concerning because there is no cure for the
condition. Therapies ranging from antiviral agents and photoinactivation to
investigational vaccines have been tried. Currently, only acyclovir (ACV),
famciclovir (FCV), and valacyclovir (VCV) are useful in the treatment and
The ideal anti-HSV agent should (a) prevent infection, (b) shorten the clinical
course, (c) prevent the development of latency, (d) prevent recurrence in patients
with established latency, (e) decrease transmission of disease, and (f) eradicate
142 To date, no agent has been successful in achieving all
All three agents, ACV, FCV, and VCV, are effective for the short-term treatment of
some HSV infections. ACV, a nucleoside analog, is a substrate for HSV-specific
thymidine kinase. Through a series of phosphorylation steps, ACV is transformed to
ACV-triphosphate, a competitive inhibitor of viral DNA polymerase. ACV has
potent in vitro activity against both HSV-1 and HSV-2 and is far less active against
171 FCV, a prodrug of penciclovir, has increased oral
bioavailability compared with acyclovir. Once converted in the intestine and liver to
the active form, penciclovir, it is quickly phosphorylated in HSV in a similar manner
as ACV. VCV is the L-valyl ester prodrug of ACV. The oral bioavailability of VCV
is also significantly better than ACV, producing plasma levels of ACV comparable to
those attained with IV administered ACV, often eliminating the need for parenteral
172 All three antiviral drugs are equally effective for genital herpes infections.
Intravenous ACV (5 mg/kg/dose every 8 hours) significantly reduced the duration
of viral shedding in primary genital herpes, decreasing the duration of signs and
symptoms of disease by a mean of 5 days, and the time to healing of lesions by a
mean of 6 to 12 days compared with placebo-treated patients.
have been shown in the immunocompromised patient population.
or VCV also prevent HSV reactivation in seropositive immunocompromised patients
who are undergoing bone marrow transplantation.
175 For patients with HIV, ACV 400
mg PO 3 times daily, FCV 500 mg twice daily, or VCV 500 mg twice daily for 5 to
10 days have been used for recurrent episodes.
recommended only for patients with severe genital or disseminated infections who
Antiviral Chemotherapy of Genital HSV-2 Infections
Acyclovir Valacyclovir Famciclovir Duration Comments
1 g PO BID 250 mg PO TID 7–10 days May extend
250 mg PO BID Daily Reduces the
Not indicated Not indicated Variable Hospitalize and treat
c 500 mg PO BID 5–10 days Treat until clinical
Note: Regimen recommendations derived from 2002 CDC Recommendations.
aSafety and efficacy up to 6 years have been documented with the use of acyclovir.
syndrome or thrombotic thrombocytopenic purpura was observed.
Topical therapy with ACV ointment (5% in polyethylene glycol) has minimal
effect on the duration of viral shedding, symptoms, and lesion healing in first-episode
primary genital herpes, and it has no effect on the recurrence rate
recommended for primary genital herpes. Penciclovir 1% cream applied every 2
hours while awake is effective for treatment of herpes simplex labialis,
insufficient data exist to recommend its use for genital herpes infections.
Oral antivirals speed the healing and resolution of symptoms of first and recurrent
episodes of genital HSV-2 infections.
177 Treatment of primary infection after the first
week of infection does change the natural history of recurrent outbreaks; thus, patients
should be educated about risk of sexual transmission and prompt recognition of signs
and symptoms and the early use of antivirals.
178 The frequency of recurrence
decreases with time in most patients. Recurrent episodes of genital HSV-2 infection
can be treated with any of the three available oral antivirals (Table 72-8). Rather
than having to go into clinic, patients with recurrent infection should have a supply of
their antiviral drug with them to allow early initiation of therapy, which may abort or
reduce symptoms by 1 to 2 days.
Daily suppressive therapy with ACV, FCV, or VCV reduces the frequency of
recurrent episodes up to 70% to 80% among patients with frequent (five to eight
episodes per year) genital herpes.
181 Recurrent outbreaks diminish with time; thus,
after each year of continuous suppressive therapy, an effort should be made to
discuss discontinuing therapy with the patient. The use of suppressive therapy does
not completely eliminate viral transmission. However, a randomized, controlled
clinical trial of serodiscordant HSV-2—positive couples demonstrated a statistically
significant decrease in the rate of transmission to uninfected partners when infected
partners took 500 mg/day of VCV.
154 This 8-month study was restricted to
heterosexual partners with fewer than 10 recurrences per year. The CDC
recommends various dosing regimens for VCV, but the 500-mg once-daily dose
appears to be less effective than the 1-g once-daily dose in patients with frequent
recurrent episodes (i.e., >10 episodes per year).
showed a consistent prophylactic benefit if VCV was dosed at 250 mg twice daily or
Immunocompromised patients may require higher doses or
more frequent intervals for suppression.
183 Most cases of ACV-resistant HSV occurs
in the immunocompromised host; however, the resistance is less than 5%.
ACV-resistant strains are also resistant to VCV, and most are resistant to FCV as
well. Foscarnet 40 to 80 mg/kg IV every 8 hours or cidofovir 5 mg/kg once weekly
until clinical resolution may be used for severe ACV-resistant genital HSV
2 Cidofovir 1% gel (not commercially available in the United States but
has been compounded by pharmacists) applied once daily for 5 days may be an
alternative to IV foscarnet, but more studies are needed.
B.J. is not yet a candidate for daily suppressive ACV therapy. A summary of the
indications for ACV, FCV, and VCV is outlined in Table 72-8.
CASE 72-14, QUESTION 6: What adverse effects associated with ACV, FCV, or VCV should be
Overall, all forms of ACV, including VCV and FCV, are associated with relatively
few adverse reactions largely because of the drugs’ affinity for viral thymidine
Hematuria and an increase in blood urea nitrogen and serum creatinine may occur,
primarily in patients with underlying renal disease or those receiving concomitant
nephrotoxic agents. However, this complication is almost entirely associated with the
IV route. In addition, severe local reactions are possible with IV administration. In
patients with HIV/AIDS, VCV at a dosage of 8 g/day was associated with a
hemolytic uremic syndrome or thrombotic thrombocytopenic purpura-like syndrome.
However, this complication has not been observed with normal therapeutic doses. As
described previously, when given intravenously in high doses or with significant
dehydration, ACV crystallizes in the renal collecting tubules of animals, leading to
186 ACV should not be rapidly infused or administered at
concentrations greater than 10 mg/mL. Dose adjustment is necessary for all three
antiviral agents in patients with decreased renal function.
Although neurotoxicity is a rare side effect, case reports of coma and delirium
have been reported in patients with renal failure.
Intravenous ACV occasionally has been associated with cutaneous irritation and
phlebitis, reversible leukopenia,
189 and transient elevations of liver transaminases.
Oral ACV and VCV are relatively safe and do not produce any serious side effects at
normal doses. Patients receiving oral ACV, VCV, or FCV may complain of nausea,
dizziness, diarrhea, and headaches.
Patient Education and Counseling
Are other forms of local or symptomatic care useful?
Most genital herpes infections are benign, and lesions heal spontaneously unless
the patient is immunocompromised or the lesions have become infected secondarily.
The patient should be instructed to keep the involved areas clean and dry. To prevent
autoinoculation, the patient should be told not to touch the lesions and to wash his
hands immediately afterward if he comes in contact with the lesion. Local anesthetics
provide relief from the pain of genital lesions, but they should be avoided if possible
because they counteract efforts to keep the lesions dry. Local corticosteroid therapy
is contraindicated because it may predispose the patient to secondary infections.
Patient counseling should include the source contact and any future partner. Health
care practitioners should attempt to relieve patients’ feelings of guilt and anxiety;
discussion of long-term consequences should take place after the acute symptoms of
For individuals with frequent recurrences, efforts should be made to identify and
avoid stimulatory factors such as sunlight, trauma, or emotional stress. The
limitations of therapy and the decreased severity and frequency of recurrences with
time should be explained to the patient. The periods of infectivity and the need to
avoid sexual activity even when lesions are not present should be emphasized,
indicating the need for continuous barrier protection. Women with herpes genitalis
should be scheduled for routine Pap smears and should be instructed to discuss their
HSV with their physicians if they become pregnant.
Currently, there is no completely effective way to prevent the transmission of
HSV-2 infection. Barrier forms of contraception, in particular condoms, may reduce
the transmission of HSV, but this may be limited only to male-to-female transmission
owing to the large area that herpes lesions may occupy on the woman.
greater use of condoms by men can increase protection and is recommended to
160 Nonoxynol-9, a spermicide that has in vitro anti-HSV
activity, is ineffective in the prevention of established genital HSV infection and may
actually increase the risk of transmission of HSV by causing genital ulceration.
potential complications of herpes genitalis?
Previous research suggested that HSV-2 might be an oncogenic agent responsible
for carcinoma of the cervix. However, a large longitudinal nested case-control study
using nearly 20 years of seroepidemiologic and epidemiologic data combined with a
meta-analysis concluded that it is very unlikely that HSV-2 is associated with the
development of invasive cervical carcinoma.
191 Severe complications of herpes
genitalis include central nervous system disease, such as meningitis and encephalitis,
Herpes genitalis seropositivity in pregnant women occurs more frequently than in
nonpregnant women, with 20% to 30% of all pregnant women having serologic
192 When HSV is acquired by the mother near the time of
delivery, transmission to the neonate can be 30% to 50% but less than 1% in those
who acquired it early in pregnancy or had recurrent infection.
proportion of those infections occurring during pregnancy are limited to the cervix
and are totally asymptomatic, often eluding diagnosis.
Pregnant patients with a history of recurrent genital herpes should be examined
carefully when they present in labor for evidence of active disease. The safety of
systemic ACV and VCV in pregnant women has not been established in controlled
trials, but the CDC cites the lack of documented fetal harm to assert that ACV can be
used safely in all stages of pregnancy.
2 Thus, it is reasonable to recommend ACV to
treat HSV in this patient. Some small studies suggest ACV administered for several
weeks before delivery may decrease recurrent outbreaks and lessen the need for
herpes-related cesarean section,
193 whereas a larger randomized clinical trial did not
show a benefit in reducing the
need for a cesarean delivery with primary infection.
patients with symptomatic genital herpes benefit from cesarean section.
manufacturer of Zovirax (ACV) maintains an extensive database of fetal
complications related to ACV use. To date, no link between ACV and birth defects
196 The decision to treat HSV with ACV during pregnancy
should depend on the clinical severity of infection. Fetal exposure data to FCV or
VCV are limited. If the mother has an active herpes genitalis infection at the time of
delivery (either active genital lesions or HSV-2 cervicitis), the baby should be
delivered by cesarean section within 4 hours after the membranes have ruptured to
prevent exposure of the neonate to the virus.
142 However, if no genital lesions are
present at the time of labor, vaginal delivery may be recommended.
evidence that up to 70% of neonatal herpes cases occur in asymptomatic women, and
the use of ACV or VCV after 36 weeks gestation may decrease clinical disease and
Neonatal herpes is a devastating systemic infection of the newborn, associated
with high morbidity and mortality, especially when infected with HSV-2 versus
198 HSV is usually transmitted to the newborn during passage through an
infected birth canal, approximately 300 times greater than when HSV is not
195 The risk of transmission to the newborn is greatest in mothers who acquire
an initial infection late in the third trimester and lower in mothers with recurrent
infection or those who acquire herpes in the first trimester (25%–50% vs. <1% for
QUESTION 1: S.L., a 19-year-old woman, presents to the women’s health clinic for her annual pelvic
Human papiloma virus (HPV) is the cause of genital warts, or condylomata
acuminata. Types 6 and 11 account for more than 90% of genital warts.
of HPV, including 16 and 18, account for as much as 70% of cervical cancer
201 They are associated with Pap smear changes, including koilocytosis
and cervical dysplasia. In the United States, the seroprevalence of HPV 6, 11, 16,
and 18 is 32.5% for women and 12.2% among men aged 14 to 59 years.
Cervical intraepithelial neoplasia (CIN) is a common cervical cancer grading
system using histologic changes to classify specimens in three categories: CIN-1, -2,
and -3. The higher the number, the greater the chance of progressing to invasive
cervical cancer. Most new cases of HPV infection spontaneously regress but with
progressive histologic changes, the chance of spontaneously regressing diminishes
(CIN1, 60%; CIN2, 30%; CIN3, 10%).
203 Types of HPV are also classified as high
risk, or those likely to cause cancer, and low risk, those less likely to cause cancer.
HPV types 16, 18, 31, 33, 45, 52, and 58 are considered high risk and types 6 and 11
are low risk, the latter mostly resulting in genital warts. In women, visible warts
occur on the labia, introitus, and vagina. Subclinical lesions also commonly occur on
these sites and on the cervix, as in S.L.’s case. They are visible only by colposcopy
after applying acetic acid. Men can sexually transmit HPV infections to women as
well as exhibit genital warts, and anal and penile cancer associated with oncogenic
HPV types, especially type 16.
204 The goal of HPV therapy is the removal of
trichloroacetic acid 80%–90%, and cryotherapy), surgery (laser or scalpel), and
In a recent meta-analysis, locally applied interferon
showed a 44% lesion clearance compared with 27.4% for systemic interferon.
None of these treatments can eradicate HPV infection or alter the natural history of
HPV. It is important to individualize therapy, considering location and number of
warts, patient preference, cost, and convenience.
Podophyllin, compounded as a 10% to 25% solution in tincture of benzoin, is
applied by the health care provider to visible warts. After application, it is washed
off 3 to 4 hours later and then reapplied once or twice a week until the warts have
disappeared. Podofilox 0.5% solution or gel, the active component of podophyllin
resin, may be applied by the patient with a cotton swab, or podofilox gel with a
finger, to visible genital warts twice a day for 3 days, followed by 4 days of no
therapy. A total of four cycles, 0.5 mL/day, or application of an area larger than 10
cm2 should not be exceeded. Podofilox solution is not suitable for use with perianal
warts; the gel is more practical for this region. Podophyllin is potentially neurotoxic
if absorbed in large amounts. Podofilox has the advantage over podophyllin resin in
that it has a longer shelf life, does not need to be washed off, and has less systemic
206 Therefore, it should be applied in limited doses and should also be
avoided in pregnancy. The rate of wart recurrence after podophyllin therapy is
extremely high, probably 50%. With the high cost of clinic care and the high
recurrence rate, home treatment of HPV with podofilox solution may be more cost
effective and equally efficacious.
Imiquimod induces cytokines and activates the cell-mediated immune system. In
initial trials, complete clearance of warts took place in 37% to 50% of
immunocompetent patients, but up to 20% experienced recurrence.
is optimally applied by finger at bedtime 3 times per week and the 3.5% cream once
It is usually left on for 6 to 10 hours before it is
washed off with soap and water. Imiquimod may take as long as 8 weeks before
warts are cleared. Mild-to-moderate local irritation occurs in more than half of the
patients who use it, especially when used daily instead of 3 times weekly as directed.
The cream may weaken condoms and diaphragms.
Sinecatechins are green-tea extracts that contain active catechins with purported
immunostimulatory, antiprofliferative, and antitumor properties. In the United States,
a 15% topical ointment is available. There are limited data on this product, but
literature suggests it may be more effective than imiquimod or podofilox by clearing
up to 55% of external genital warts.
It is applied by finger directly to the wart 3
times a day up to 16 weeks with the most common side effects being local erythema,
Cryotherapy by application of liquid nitrogen can be more effective than
podophyllin, but it requires special equipment and highly trained personnel. Pain and
skin blistering after treatment is common. Cryotherapy is associated with minimal
systemic toxicity and is useful against oral, anal, urethral, and vaginal warts.
Trichloroacetic acid (80%–90%) is used topically in the treatment of some genital
warts, but its efficacy is uncertain. To date interferons are not recommended because
of expense and toxicity. Cases refractory to topical drug therapy should be
considered for surgical treatment.
In 2006, the first vaccine to prevent HPV types 6, 11, 16, and 18 was approved in the
United States. This quadrivalent vaccine was
tested in women from 15 to 26 years of age and demonstrated 98% to 100%
protection against HPV types contained in the vaccine.
quadrivalent vaccine efficacy was 62.1% to 89.4% against genital warts, depending
upon previous HPV exposure, leading to its approval for men and boys 9 to 26 years
214 Using bridging data, it is estimated that 99% to 100% of 9- to 15-year olds
will seroconvert. In 2014, a 9-valent HPV vaccine was approved to replace the
quadrivalent vaccine. The extra 5 types (31, 33, 45, 52, and 58) add 15% more
cervical cancer coverage protection to the 66% covered by types 16 and 18 in the
215 This three-dose series can be given as early as 9 years of age, but it
is CDC recommended at 11 to 12 years as part of a routine adolescent health care
visit and ideally before commencement of sexual activity. Because there are more
than 30 types of HPV associated with anogenital disease, a previous HPV infection is
not a contraindication to vaccination. It is also important to note that receipt of the
HPV vaccine does not change the recommendation for Pap smears. Lastly, it should
not be considered a therapeutic vaccine as it has no impact on active HPV infection.
Prevention and control of STDs have largely revolved around education and
antimicrobials. Immunization, however, holds the promise of protecting large
numbers of people before they are at risk for STDs as well as targeting those who
already have the infection. Hepatitis B is an example of an STD with a highly
effective vaccine that is now mandatory for school-aged children. The nine-valent
HPV vaccine is gaining momentum and a bivalent (HPV 16 and 18) is also approved
by the FDA, but the latter is not indicated for prevention of genital warts. Herpes
simplex vaccines have been extensively studied, but no candidate vaccine has been
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