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Progress in Meeting Today’s Demands in Genital Herpes:
An Overview of Current Management
Raj Patel
Department of Genito-Urinary Medicine, Royal South Hampshire
Hospital, Southampton, United Kingdom
Treatment of genital herpes requires accurate diagnosis, patient support, and effective treatment. Diagnosis is usually straightforward for classic presentations characterized by vesicular
lesions but can be challenging for atypical presentations, which are more common. Diagnosis
of asymptomatic infection requires access to molecular technology or type-specific serologic
assays. Misconceptions about herpes simplex infection are common and patient education is
essential. Patient concerns extend beyond disease frequency and severity—the psychological
impact should not be underestimated. Antiviral therapy is relevant at all stages of infection.
Acyclovir, valacyclovir, and famciclovir are effective and well tolerated for genital herpes
treatment. Continuous suppressive therapy controls all symptoms of recurrent disease and
helps to relieve disease complications. The prodrugs valacyclovir and famciclovir offer easier,
less-frequent dosing than required for acyclovir. Valacyclovir achieves effective suppression
when taken once a day. Interventions to prevent genital herpes transmission and to control
the global problem are urgently required.
The impact of genital herpes is broad ranging, but particularly affects the infected person, immediate families, and society
and poses a considerable economic burden on health care systems [1, 2]. The challenges of genital herpes and what effective
management should strive for are reviewed elsewhere [3]. Such
goals emanate from the perspectives of clinicians, the infected
patients, and public health bodies. While some of the ideals
have been achieved or are achievable in clinical practice today,
some are only partially met. Despite extensive research efforts
in recent years, vaccination for primary prevention of genital
herpes simplex virus (HSV) type 2 infection is still not possible
and reversal of HSV latency seems even farther away.
Here I review current management practice in genital herpes,
identify areas where improvements can be made in certain settings, and consider published findings that support the role and
future potential of valacyclovir in light of other alternatives.
My goal is to provide a practical evidence-based approach applicable predominantly to otherwise healthy immunocompetent
adults, although I have included a short section on managing
Presented in part: 4th Congress of the European Academy of Dermatology
and Venereology, Brussels, October 1995 (abstract P187); 2d European Congress of Chemotherapy and 7th Biennial Conference on Antiinfective Agents
and Chemotherapy, Hamburg, Germany, May 1998 (abstract M176).
Financial support: honoraria for consultancy and funding for clinical
research from GlaxoSmithKline under its present or former names (Wellcome Research Laboratories, UK; GlaxoWellcome R & D, UK and USA);
3M Pharmaceuticals (consultant).
Reprints or correspondence: Dr. Raj Patel, Dept. of Genito-Urinary Medicine, Royal South Hampshire Hospital, Brintons Terrace, Southampton,
Hampshire SO14 OYG, United Kingdom ([email protected]).
The Journal of Infectious Diseases 2002; 186(Suppl 1):S47–56
䉷 2002 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2002/18608S-0006$15.00
herpes in patients infected with human immunodeficiency virus
(HIV).
Effective management of genital herpes at the individual patient level relies on accurate and prompt diagnosis, the sharing
of relevant and factual information, a psychosocial assessment
of the impact of a diagnosis on the patient, and the appropriate
use of antiviral therapy. Clinicians and patients need to appreciate the implications of genital herpes, whether or not the
infection is symptomatic, and that the prevalence of HSV-2
infection is increasing in most regions of the world.
Genital Herpes Diagnosis
Although genital ulceration can be attributed to many causes,
recognition of classic primary herpes infection or typical recurrent disease is usually straightforward. The classic lesions
are papules that form shallow vesicular ulcers, which then scab
and reepithelialize. One challenge is that few patients present
with typical disease. Nonclassical (atypical) presentations are
more common, and genital HSV infection (type 1 or type 2)
should be considered routinely in the investigation of any patient with genital lesions or recurrent genital symptoms.
The ability to confirm one’s suspicions with an objective
diagnostic test is essential. Genital HSV-2 infection may be
associated with other sexually transmitted agents. At the time
of genital herpes diagnosis, it is appropriate to consider risks
and to instigate a range of investigations for other sexually
transmitted pathogens. Diagnostic testing in genital HSV infection should allow uncertainties to be dispelled and subsequently for counseling to be patient specific and focused rather
than hypothetical. In turn, this helps the patient make the necessary psychological and behavioral adjustments.
The most widely used diagnostic test for patients presenting
S48
with evidence of genital lesions is viral culture, which preferably
should be type specific. If virus typing for HSV-1 and -2 is
available, a degree of prognostication regarding recurrence frequency is possible [4]. The main disadvantage of viral culture
is that results are not available for a few days, thus prolonging
the period of anxiety for the patient facing a possible diagnosis
of herpes and the need for a return visit to the physician for
results. If the culture is positive, the physician should review
the initial effectiveness of prescribed therapy and encourage the
patient to participate in counseling programs. A rapid pointof-care antigen detection test would be a distinct advance in
the diagnosis of genital herpes. It would offer more immediate
diagnostic certainty, ensure prescription of the most relevant
therapy, and prompt an earlier start to patient support
initiatives.
Selection of the diagnostic test should be tailored to the patient’s situation. If genital lesions are apparent, direct detection
tests on swabs of genital lesions are most relevant. In addition
to viral culture, antigen tests such as EIA or the virus typespecific DNA polymerase chain reaction technique can be used.
Atypical presentation of genital HSV infection, often characterized by recurrent bouts of genital discomfort without physical signs that are not satisfactorily managed from the patient’s
perspective, requires a more creative approach. Type-specific
serologic testing may provide useful diagnostic insight. The
point-of-care type 2-specific POCkit-HSV-2 test (Diagnology)
is approved by the US Food and Drug Administration (FDA)
for use in adults and is available in a number of other countries.
Similarly an ELISA and immunoblot test (Focus Technologies)
have been approved by the FDA, even for use in pregnant
women.
The availability and performance of type-specific serology
tests for prior HSV infection has improved in recent years,
although care must be taken to interpret results in a meaningful
way in some situations (e.g., a positive result in a low-risk
patient). Caution should also be exercised when considering
serologic testing in suspected true primary genital HSV infection, since seroconversion can take up to 12 weeks and tests
vary in their ability to detect the relevant HSV antibodies [5–7].
False-positive and false-negative results occur. The proportion
of potentially misleading results is influenced by two factors:
the sensitivity and specificity of the test and the prevalence of
HSV infection in the patient’s population group. In general,
for any one test, the ability to correctly identify infection increases as the prevalence of infection increases; the higher the
sensitivity and specificity of the test, the more likely it is to give
an accurate result. These are the primary contributory factors
to the positive predictive value of diagnostic tests.
First-Episode Genital HSV Infection
The first episode of HSV infection is frequently a systemic
illness associated with vesicular ulcerative lesions and a pro-
Patel
JID 2002;186 (Suppl 1)
longed disease course that may last up to 21 days. True primary
genital herpes, defined as the first episode of genital herpes when
the patient has no preexisting antibodies against HSV-1 or -2,
is usually severe and prolonged [8, 9]. In the presence of antibodies against HSV-1, first episodes of genital HSV-2 infection
are usually milder and defined as nonprimary [8].
Although most patients with first-episode disease have an
uncomplicated course of infection, hospitalization may be required for urinary retention, meningism, or severe constitutional symptoms in association with adverse social circumstances. In the United Kingdom, if catheterization is required,
suprapubic catheterization is preferred, both on practical and
theoretical grounds (to prevent ascending infection). If a first
episode is untreated, the patient may develop general (systemic)
or local complications such as headache, photophobia, neck
stiffness, and difficulty urinating. Antiviral therapy is normally
highly effective and should be instigated in first-episode genital
herpes on clinical suspicion alone.
Supportive measures are important for keeping the patient
comfortable and for preventing some complications. Analgesics, antipyretics, and the encouragement of hydration are usually necessary. Saline bathing of the local area and care with
keeping lesions clean and dry should minimize the risk of superinfection and should help reduce the formation of adhesions.
Topical ointments (e.g., steroids and antibiotics) are usually not
recommended. Because of their limited effectiveness [10, 11],
topical antivirals cannot be recommended for treatment of firstepisode genital herpes. Occasionally, severe external dysuria
uncontrolled by analgesics will benefit from the judicious use
of topical anesthetics. As these agents frequently cause sensitization and are known to delay healing, routine use should be
avoided.
Antiviral therapy with oral acyclovir, its prodrug valacyclovir, or with famciclovir, is effective in treating first-episode genital herpes. A large, randomized, double-blind trial of valacyclovir (1000 mg twice/day) versus acyclovir (200 mg 5 times/
day) showed valacyclovir to be as effective as acyclovir on lesion
healing, loss of pain, and viral shedding [12]. Valacyclovir (500
mg twice/day) is considered sufficient for acute treatment of
first-episode genital herpes because the plasma acyclovir concentrations following 500 mg twice a day therapy are higher
than after oral acyclovir (200 mg 5 times/day) for 20 of 24 h
and provide about twice the daily acyclovir exposure (daily area
under the concentration-time curve, 99.5 and 49.3 mM.h for
valacyclovir and acyclovir, respectively) [13, 14]. The efficacy
of 500 mg twice a day therapy would, therefore, be expected
to be equivalent to that of the widely approved 1000 mg twice
a day regimen as recently confirmed in a study of valacyclovir
[15]. Preliminary communications on famciclovir in first-episode genital herpes suggest that 250 mg 3 times a day for 5
days provides acceptable efficacy [16, 17], although famciclovir
is not licensed for treatment of first-episode genital herpes in
the United States. Use of prodrugs such as valacyclovir and
JID 2002;186 (Suppl 1)
Management of Genital Herpes
famciclovir allows considerable simplification of the therapeutic
regimens compared with the 5 times a day oral acyclovir
regimen.
Although trials of antiviral therapy in first-episode genital
herpes have usually been conducted in patients presenting and
commencing treatment within a few days (3–5) of the onset of
clinical signs and symptoms, it is generally accepted that some
benefits of treatment will extend to all patients whose symptoms
have not completely resolved. The recommended duration of
treatment appears to be led by clinical convention (5–10 days).
If the shorter 5-day course of therapy is initially prescribed, it
is important to evaluate the patient towards the end of treatment and to continue therapy if new lesions continue to form,
if complications develop, or if systemic features have not settled.
The establishment of HSV latency is thought to occur early
in the course of primary infection [18, 19]. Treatment of a first
episode of genital herpes with either oral or intravenous acyclovir has not been shown to influence the subsequent development of recurrent herpes [20, 21]. The only indication for
the use of intravenous therapy is when the patient is unable to
swallow or tolerate oral medication.
There has been considerable recent interest as to whether
high dosages of valacyclovir and famciclovir, as prodrugs of
the nucleoside analogues acyclovir and penciclovir, administered early in the course of true primary genital HSV infection
can affect HSV-2 latency and reactivation dynamics and, thus,
limit the number and/or severity of subsequent recurrences. The
hypothesis was generated by results from studies in the mouse
ear pinna model of HSV infection, which showed some differential effects on HSV-1 and -2 titers within sensory ganglia
after administration of valacyclovir and famciclovir [22–24].
However, studies in another model, the mouse eye, showed no
differences between the agents [25]. A randomized controlled
clinical trial also found no evidence for any long-term effect
on recurrence frequency with high-dose prodrug therapy (valacyclovir, 1000 mg twice/day; famciclovir, 750 mg twice/day)
for true primary genital herpes [26].
There is currently no basis for recommending anything other
than standard doses of antivirals for the treatment of firstepisode genital HSV infection in immunocompetent persons.
The choice between acyclovir and a particular prodrug should
be based on local factors with considerations of price, patient
acceptability, and compliance being paramount.
Counseling of patients with first-episode genital herpes
should include a discussion of possible source(s) of infection,
provision of information on the natural history of HSV infection, including the risk of subclinical viral shedding, the risk
of transmission (sex , other), and treatment options for future
recurrences. The role and value of partner notification is unclear, although it would identify undiagnosed symptomatic
cases who could be taught to recognize herpes episodes [27,
28]. However, to what extent this identifies a significant level
of untreated illness or whether such a strategy would limit the
S49
spread of infection is disputed. When recurrences become evident, patients should be educated in early correct identification
and management. Some may benefit from participation in patient support groups.
There is considerable misinformation about the risks of HSV
transmission from an infected woman to a fetus during pregnancy, and women should be reassured and encouraged to inform obstetricians and midwives of a history of genital herpes.
They should be advised that HSV-associated risks exist
throughout pregnancy (e.g., miscarriage in early pregnancy,
prematurity, and vertical transmission of infection) [29]. Infected male partners should also be warned of the dangers of
genital HSV transmission to their uninfected female partners
since genital herpes acquired during the third trimester carries
a significant risk of transmission during delivery[30].
Recurrent Genital Herpes
In a patient with a prior diagnosis of genital herpes, the
appearance of new vesicular genital lesions is usually indicative
of HSV reactivation. In patients who lack a differential diagnosis at this stage, the opportunity to confirm the virus etiology
should be taken. The high proportions of asymptomatic and
unrecognized infections, plus the wide range of symptoms that
characterize the clinical presentation of genital herpes are key
contributors to underdiagnosis [31–33].
Most persons can be taught to recognize mild and some
atypical symptoms of genital HSV recurrences [27, 28]. They
should understand that asymptomatic or “nonlesional” shedding will occur in most cases of mild recurrent disease outbreaks. Patients with mild or asymptomatic infection may be
more highly motivated to participate in sessions to help them
detect the signs of a recurrent herpes episode if they understand
the importance of asymptomatic shedding in disease transmission and also the greater benefit of episodic antiviral therapy
if initiated early in the course of a recurrent outbreak.
Recognized symptomatic herpes recurrences are characterized by high levels of infectivity, but the importance of infectivity remaining between symptomatic outbreaks cannot be
overemphasized since most sexual HSV transmission occurs
during asymptomatic periods. Strategies for avoiding sexual
contact during lesional episodes or using barriers only occasionally are likely to be less effective in reducing the risk of
genital HSV infection than regular condom use [34, 35]. However, even regular condom use may not be a foolproof strategy
[36, 37].
When first-episode and recurrent genital herpes were compared, a series of differences were identified including symptom
severity, viral reactivation patterns, and psychological aspects.
This leads to somewhat different recommendations for treatment. The immediate psychological impact of a diagnosis of
first-episode genital herpes should not be assumed to be com-
S50
Patel
JID 2002;186 (Suppl 1)
Table 1. Comparative efficacy of valacyclovir and acyclovir as episodic therapy for recurrent
genital herpes.
Hazard ratio (95% confidence interval), P
Regimens compared
Valacyclovir
1000 mg 2⫻/day vs. placebo
500 mg 2⫻/day vs. placebo
500 mg 2⫻/day vs. acyclovir 200 mg 5⫻/day
Acyclovir 200 mg 5⫻/day vs. placebo
a
b
Episode duration
1.76
1.94
0.93
1.71
(1.55–2.01),
(1.64–2.31),
(0.79–1.08),
(1.41–2.06),
!.001
!.001
c
.34
!.001
Healing time
1.92
1.94
0.96
1.90
(1.67–2.21),
(1.59–2.36),
(0.80–1.14),
(1.55–2.34).
!.001
!.001
c
.62
!.001
NOTE. Data are from [14, 43, 44] and Barber J (personal communication).
a
Defined as total duration of all signs and symptoms (intent-to-treat analysis).
b
Time to complete healing of vesicular lesions (excludes patients with aborted lesions).
c
Not significant.
parable to that of symptomatic disease persisting over a number
of years [38, 39].
For most patients, genital herpes recurrences are self-limiting
and the symptoms they cause are generally considered minor
by clinicians. Classic recurrences usually appear short-lived and
are characterized by a few lesions that heal within 7 days. Decisions about how best to manage clinical recurrences ideally
should be made by the physician in partnership with the patient.
Treatment strategies include episodic and suppressive antiviral
therapy. After explaining the benefits of antiviral therapeutic
options, some patients with recurrent herpes may opt for a trial
period of supportive measures only (e.g., good hygiene, general
health care, and lifestyle) with analgesics as required. The most
appropriate strategy for an individual is expected to vary over
time and is influenced by recurrence frequency, symptom severity, and relationship status.
Most persons with genital herpes adjust psychologically to
the diagnosis and develop successful coping strategies, although
recurrences may slow down or prevent this process. Thus, at
each physician consultation attention should be paid to the
patient’s psychological well being. There should be appropriate
referral for support or counseling as necessary. Antiviral therapy itself has a significant role in supporting psychological adjustment to the symptoms of recurrent herpes [39, 40].
A major concern with genital herpes, the most common cause
of genital ulcer disease, is its role in facilitating the acquisition
and transmission of HIV infection. Considerable biologic and
epidemiologic evidence links genital herpes with HIV transmission. Epidemiologic studies have found a strong association
between HIV and HSV-2 seropositivity [41, 42]. Furthermore,
detection of HIV RNA in HSV-2 lesions suggests that HIV
transmission is enhanced in the presence of HSV-2 [43]. Although not proven, interventions to control HSV recurrences
may be expected to limit this risk. Clinical trials of suppressive
antiviral therapy are needed.
Episodic antiviral therapy for recurrent disease. Acyclovir,
valacyclovir, and famciclovir are approved in most countries
for the episodic treatment of genital herpes outbreaks. Compared with dosages of acyclovir 5 times a day, valacyclovir and
famciclovir offer the advantages of convenience and discretion
in twice-daily administration. Early trials of acyclovir (200 mg
5 times/day for 5 days) as episodic therapy for genital herpes
showed clearly measurable benefits. Median reductions of 30
h in lesion healing and 12–24 h in pain or discomfort were
demonstrated in large placebo-controlled studies in unselected
patients, persons who did not necessarily perceive the early
signs of an HSV outbreak (prodrome) before starting treatment.
Consequently, these studies may underestimate the likely impact of therapy in patients who can recognize early disease.
Clinical trials of acyclovir demonstrate the importance of
starting therapy early in the course of a recurrent herpes attack.
Significantly improved results (vs. placebo) were seen in duration of viral shedding and time to crusting and healing when
oral acyclovir was self-initiated by patients at the onset of prodrome or at the earliest symptoms compared with physicianinitiated treatment starting within 48 h of a recurrence [44, 45].
In order to ensure maximum benefit of episodic antiviral therapy, patients should be advised to carry their medication with
them and to start a treatment course as soon as a recurrence
is suspected.
The efficacy and safety of valacyclovir were originally evaluated in 3 randomized double-blind controlled trials in which
patients were required to self-initiate treatment within 24 h of
the first signs or symptoms of a recurrent herpes outbreak [14,
46, 47]. Valacyclovir (500 or 1000 mg twice/day) and acyclovir
(200 mg 5 times/day) administered for 5 days rapidly terminated
HSV shedding, significantly accelerated lesion healing, and reduced the total duration of symptoms and signs (episode duration) compared with placebo [46, 47]. Another study showed
no differences between valacyclovir (500 mg twice/day) and
acyclovir (200 mg 5 times/day) on these end points [14]. Table
1 summarizes the study results by meta-analysis of the clinical
end points.
A placebo-controlled study of famciclovir (125 mg twice/day
for 5 days) also demonstrated efficacy in lesion healing, symptom resolution, and viral shedding [48]. Patients were required
to initiate treatment within 6 h of the first symptoms of a genital
herpes recurrence. When acyclovir (200 mg 5 times/day for 5
days) was compared with famciclovir (125 mg twice/day) in a
protocol requiring treatment initiations within 12 h of first
JID 2002;186 (Suppl 1)
Management of Genital Herpes
symptoms of a recurrence, the 2 drugs had similar healing and
symptom resolution rates [49].
An additional benefit was recently described for valacyclovir.
The meta-analysis shown in table 1 utilized data on episode
duration (all patients, n p 2926 ) and lesion healing, applicable
to the subgroup whose herpes lesions progressed to the vesicle
stage before healing (n p 2219, 76%), thus identifying persons
whose clinical outcome was an aborted lesion. An aborted lesion is defined as one that did not progress beyond the papule
stage. Odds ratios (ORs) for the probability of herpes lesions
aborting for both valacyclovir regimens (500 or 1000 mg twice/
day) compared with placebo were statistically significant,
whereas the OR for acyclovir was not (table 2) [50]. The recommended valacyclovir regimen of 500 mg twice a day was
associated with a 44% increased likelihood of lesions aborting.
Another study of valacyclovir confirmed the logic of prompt
valacyclovir treatment being associated with better clinical outcome. Analysis of aborted lesion rates in relation to the time
of treatment initiation shows that the chance of genital herpes
lesions aborting increases almost two-fold when treatment commences within 6 h of symptom onset compared with after 6 h
(OR, 1.93; 95% confidence interval [CI], 1.28–2.90) [51]. This
benefit of valacyclovir was not seen by prospective analysis of
controlled studies of acyclovir nor has it been described for
famciclovir. It is an important benefit for patients too, since an
aborted lesion as a clinical outcome means prevention of the
development of painful vesicular lesions that must scab before
healing.
In controlled trials of antiviral treatment of recurrent genital
herpes, the median duration of viral shedding in placebo-treated
patients is 4 or 5 days [46–48]. With antiviral treatment, this
is reduced to 2 or 3 days [14, 46–48]. Two recent studies investigated the feasibility of episodic valacyclovir therapy for 3
days and compared it with the conventional 5-day regimen,
although neither study was placebo controlled [51, 52]. Overall,
the 3-day regimen was as effective as treatment for 5 days
(valacyclovir 500 mg twice/day) for the relief of clinical features
of disease: Lesion healing required 4.4–4.9 days and pain lasted
2.5–3.0 days (median values across both studies and regimens).
HSV shedding, monitored only in 1 study [51], persisted for a
median of 1.8 days for the 5-day treatment group and 1.7 days
for the 3-day group. Lesion abortion rates of about 25% were
observed in both studies [51, 52]. Although potentially attractive, 3-day therapy courses should at present be used with caution, especially in patients with severe symptoms or prolonged
recurrences where viral shedding and infectivity persist longer
and for whom 5-day regimens are better tested.
In all subjects prescribed episodic therapy, the therapeutic
strategy should be reevaluated after a few courses to ensure
that treatment is being used appropriately and that the patient
is benefiting from therapy. The psychological reminder of a
lifelong infection when genital herpes recurrences occur has a
deleterious effect on many patients, which should prompt the
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Table 2. Comparative efficacy of valacyclovir and acyclovir in preventing development of vesicular lesions (aborting genital herpes
lesions).
Treatment regimen
Valacyclovir
1000 mg 2⫻/day vs. placebo
500 mg 2⫻/day vs. placebo
500 mg 2⫻/day vs. acyclovir 200 mg 5⫻/day
Acyclovir 200 mg 5⫻/day vs. placebo
Probability of lesions
aborting: odds ratio
(95% confidence interval), P
1.31
1.44
1.02
1.24
(1.06–1.62),
(1.10–1.89),
(0.77–1.36),
(0.90–1.72),
.01
.01
a
.89
a
.18
NOTE. Data are from [50].
a
Not significant.
physician to consider treatment alternatives. Episodic therapy
is of limited benefit to patients with severe prodromal symptoms, such as those in whom HSV reactivation is associated
with severe lumbar or sciatic nerve pain, in patients unable to
recognize the early signs of a pending herpes outbreak, and in
those who have the established features of psychosexual problems. These patients are better managed with continuous suppressive therapy.
Continuous suppressive antiviral therapy. Suppressive therapy for recurrent genital herpes is highly effective for controlling all of the clinical features of the disease and can impact
on a number of troublesome complications of infection. Trials
of antiviral therapy have generally been conducted only in patients with ⭓6 recurrences per year, but this has largely been
for logistical and statistical reasons. Some patients with fewer
recurrences will benefit from continuous suppressive therapy.
When instigating suppressive therapy, it is important to review the patient’s expectations of treatment and explain how
therapy works, what it will achieve, and, of importance, what
it will not. Patients can be safely advised that well-timed regular
therapy should substantially reduce the frequency of recurrences. They should be told that suppressive therapy is not a
cure for latent HSV infection and that, although it does not
affect the natural history of recurrent disease, they may notice
fewer recurrences (compared with the number before therapy)
after suppression is discontinued. The patient should be encouraged to keep a record of any breakthrough episodes and
to bring this to the next review, since an adjustment in treatment
may be required. Women at risk of conception should be told
to avoid pregnancy during therapy.
Some controlled randomized trials for suppression have compared valacyclovir with acyclovir and placebo and acyclovir
and famciclovir with placebo [53–57]. Although there is no
direct head-to-head comparison of all 3 agents, the comparative
data suggest that, at the approved dosages, these agents have
comparable efficacy and prevent at least 70% of symptomatic
recurrences over 1 year (figure 1).
Recommended regimens of oral acyclovir for suppression of
recurrent genital herpes vary in different countries; 400 mg twice
a day is the most widely prescribed, but 200 mg 3 times a day
is also common. Although highly effective, regimens should
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JID 2002;186 (Suppl 1)
Figure 1. Relative efficacy of suppressive therapy for genital herpes: valacyclovir, acyclovir, and famciclovir vs. placebo. Dosages are once a
day (od) or twice a day (bd). Data from [53–57].
ideally meet the patient’s need for simple dosing [58]. Famciclovir is more effective if administered twice a day [56]; valacyclovir is efficacious in 500- or 1000-mg once daily regimens
[54, 55]. Genital herpes can be effectively controlled in most
patients with valacyclovir dosages of 500 mg once a day since
the average frequency of genital herpes outbreaks is about 5 a
year for males and 4 a year for females [59]. The minority who
has more frequent outbreaks may derive greater benefit from
either valacyclovir 1000 mg once/day or 250 mg twice/day; the
latter regimen is an approved alternative in some countries
outside the United States [55]. Once daily regimens of either
acyclovir or famciclovir are not considered sufficiently effective
and cannot be recommended for routine clinical use [56, 60].
Pharmacokinetic-pharmacodynamic analysis of the large
dose-ranging study in which patients with recurrent genital herpes were randomized to suppressive therapy with valacyclovir,
acyclovir, or placebo for 1 year identified a close relationship
between key plasma acyclovir pharmacokinetic parameters and
observed efficacy (figure 2) [61]. Valacyclovir regimens that
maintain plasma acyclovir concentrations above the acyclovir
in vitro IC50 value for HSV-2 for ⭓8.8 h a day (i.e., ⭓500 mg/
day as a single or divided dose) provide efficacy comparable
to that of the widely used acyclovir regimen of 400 mg twice
a day.
Some patients may have “breakthrough” herpes episodes
during suppressive therapy. Usually, these are infrequent and
short lived but, if troublesome, episodic antiviral treatment can
be instigated. If frequent breakthrough attacks continue despite
the patient being fully compliant with the suppressive regimen,
HSV should be cultured to confirm the nature of the breakthrough episodes. HSV resistance to antiherpes drugs remains
very rare in immunocompetent patients [62–65] and an alternative diagnosis or misinterpretation of symptoms by the patient is likely.
Considerable data have accumulated on the safety of long-
term continuous acyclovir therapy in patients with genital herpes and data for valacyclovir and famciclovir are increasing
with continuing use [66–68]. Valacyclovir, when used to manage
HSV infections, appears to inherit the safety profile of oral
acyclovir [67]. Patients have remained on acyclovir therapy for
up to 10 years with no evidence of clinically significant adverse
effects [66, 67, 69]. Stopping suppressive therapy does not appear to influence the natural history of genital HSV infection
in that recurrence frequency after cessation of suppressive therapy for 1 year remains comparable with that prior to commencing suppression [70]. Extensive natural history studies suggest a gradual waning of symptoms and a decrease in disease
frequency with time (i.e., 15 years) [71]. Patients who have
disease well controlled with suppressive antiviral therapy should
be advised to consider an occasional “drug holiday” to allow
for reassessment of the underlying disease. The decision to stop
therapy should be made with the patient and should take into
account the patient’s personal circumstances, lifestyle, and
needs.
Some patients request relatively short suppressive therapy
courses to cover specific situations or periods of concern (e.g.,
!1 month). Of note, for such an indication, therapy for ⭓5
days is required before a reliable suppressive effect is achieved
[72, 73].
Suppressive antiviral therapy is particularly valuable in managing some complications of recurrent genital herpes. Openlabel studies have shown an impact on the psychological disturbances associated with recurrent genital HSV disease [39,
74]. Such psychosexual disturbances are common in patients
with severe recurrent disease. A recent well-designed placebocontrolled study of valacyclovir in 1479 patients with an annual
recurrence rate of ⭓6 attacks a year showed a significant improvement in quality of life measures during the suppressive
therapy [40]. Suppression also favorably modified the features
of rarer complications such as recurrent erythema multiforme
JID 2002;186 (Suppl 1)
Management of Genital Herpes
S53
Figure 2. Systemic acyclovir exposure (time above IC50 value for HSV inhibition): Response relationship for valacyclovir and acyclovir
suppressive therapy regimens [61].
and aseptic meningitis associated with recurrent herpes outbreaks [75–77].
The cost of suppressive antiviral therapy for genital herpes
should not be seen as a barrier. Benefits already extend beyond
those of an immediate impact on clinical symptoms, and further
studies with valacyclovir are continuing to explore its potential
in limiting transmission risk. In the United States, analysis of
the costs of valacyclovir, acyclovir, and famciclovir prescribed
for a 1-year period clearly indicate the economic advantage of
the 500-mg valacyclovir once a day regimen [78]. By using the
lowest average US wholesale prices today [79], costs for 1 year
of suppressive therapy with valacyclovir (500 mg once/day),
famciclovir (250 mg twice/day), and (generic) acyclovir (400 mg
twice/day) would be $1235, $2683, and $1377, respectively. In
some situations, drug discounting may result in a lower price
to consumers for generic acyclovir than for the newer antivirals.
Genital Herpes in HIV-Infected Persons
HIV-infected patients are at high risk of disease attributable
to reactivation of latent HSV and often have severe or frequent
genital herpes recurrences. Before the introduction of highly
active antiretroviral therapy (HAART), suppressive antiviral
therapy rather than episodic treatment was commonly prescribed for genital herpes in patients with HIV/AIDS and was
preferred by the patients. With HAART more widely available,
the option of episodic therapy for recurrent HSV outbreaks
may be reconsidered, for example, on grounds of better control
of the declining immune system associated with fewer herpes
outbreaks, cost, or patient preference for a reduced “pill
burden.”
There has been no specific study with acyclovir for the acute
treatment of genital herpes in HIV-infected persons and few
published trials have quantified the efficacy of suppressive acyclovir on HSV-1 or HSV-2 reactivation in HIV-infected subjects.
Published studies of valacyclovir and famciclovir for herpes
management in persons with HIV infections were done before
the advent of HAART [80–82]. Valacyclovir (1000 mg twice/
day) had comparable efficacy to acyclovir (200 mg 5 times/day)
as episodic treatment for recurrent anogenital herpes and was
as effective as acyclovir on both episode duration and lesion
healing [80]. Famciclovir (500 mg twice/day) was as effective
as acyclovir (400 mg 5 times/day) in resolving the symptoms
of HSV-1 and -2 outbreaks at genital and orolabial sites [81].
The efficacy and safety of valacyclovir (500 mg twice/day or
1000 mg once/day) for prevention of recurrences of anogenital
HSV infection in HIV-infected persons was compared with acyclovir (400 mg twice/day) in a randomized trial. Patients were
required to have ⭓200 CD4 cells/mm3 before the 1-year treatment period. No statistically significant differences were seen
in the time to first recurrence or proportions of patients who
were recurrence free for the valacyclovir or acyclovir regimens.
However, valacyclovir (500 mg twice/day) appeared to provide
better protection than the once daily 1000-mg regimen in this
patient population (hazard ratio, 1.80; 95% CI, 1.26–2.57;
P p .001) [80]. Valacyclovir was well tolerated and there was
no evidence suggestive of thrombotic microangiopathy-like
syndrome.
Famciclovir has not been investigated long term as suppressive therapy for symptomatic herpes in HIV-infected persons
but it was evaluated in a small (n p 56) 8-week placebo-controlled trial in HIV-infected persons in which the primary focus
was symptomatic and asymptomatic HSV reactivation [82].
This study demonstrated clinically and statistically significant
S54
reductions with famciclovir (500 mg twice/day) in the genital
signs and symptoms associated with HSV reactivation and
symptomatic and asymptomatic shedding.
Disease Transmission Issues
Many patients express fear about transmission of herpes to
sex partners and may view continuous suppression as a means
of managing the risk. Suppressive antiviral therapy significantly
reduces the frequency of clinical and subclinical genital HSV
shedding but does not completely eliminate it [72, 73, 83, 84].
Patients must be reminded of the risk of herpes transmission
during asymptomatic periods [85, 86] and that some transmission risk probably remains throughout the course of suppressive
therapy. The results of an ongoing study designed to assess the
effect of suppressive valacyclovir on sexual transmission of genital HSV infection in immunocompetent couples are awaited
and should help clinicians in counseling patients about transmission risk.
Controversy remains about the role of counseling and condom use as means of substantially reducing transmission risk.
However, since neither intervention has an adverse outcome,
most clinicians advise their routine use. Recent data are supportive of the value of condoms to reduce risk of genital HSV
transmission [37]; hence the importance of their routine use
should be stressed to patients.
Pregnant women with genital HSV infection can transmit the
infection to the neonate during delivery. Caesarean section is
one strategy for management and antiviral therapy is another
option. Several small studies of suppressive acyclovir therapy
(200 mg 4 times/day) in late pregnancy indicate that antivirals
may reduce the clinical recurrence rate and the need for caesarean section [87–89]. Antiviral drugs are not licensed for use
in pregnancy, and there is insufficient evidence to draw definitive conclusions about the risks associated with antivirals during pregnancy. However, in over 1000 pregnancies followed by
the Acyclovir and Valacyclovir Pregnancy Registry, the rate of
birth defects was no greater than in the general population and
no pattern of defects was seen [90].
Transmission is of concern for patients with herpes, their sex
partners, and unborn children. Moreover, because the genital
HSV infection is pandemic worldwide, practical economic measures are urgently required to interrupt the spread of infection.
Our hopes for the future lie in vaccination to prevent primary
infection and immunotherapeutic agents to control the clinical
symptoms of genital herpes, ideally to reduce infectivity between persons.
Summary
Although HSV infection is at present incurable in absolute
terms, the clinician can do much to inform and empower patients so they share in the management of the disease. Accurate
Patel
JID 2002;186 (Suppl 1)
diagnosis of symptomatic infection is integral to the treatment
of genital herpes today. Antiviral therapy is the current standard
for managing symptoms and for alleviating some psychological
aspects of herpes. Information and support through clinicianpatient counseling and via patient networks are valuable resources and can do much to redress the misinformation surrounding many aspects of HSV infection.
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