Full text of DOI:10.2165/00003495-200060060-00007

Drugs 2000 Dec; 60 (6): 1329-1352
0012-6667/00/0012-1329/$25.00/0
DISEASE MANAGEMENT
© Adis International Limited. All rights reserved.
Current Recommendations for the
Treatment of Genital Herpes
Daniel T. Leung1 and Stephen L. Sacks2
1
2
Wake Forest University School of Medicine, Winston Salem, North Carolina, USA
Viridae Clinical Sciences Incorporated, Department of Pharmacology and Therapeutics, University
of British Columbia, Vancouver, British Columbia, Canada
Contents
Abstract
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1329
1. Existing Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1330
1.1 Drugs Used in Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1330
1.1.1 Aciclovir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1330
1.1.2 Valaciclovir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1331
1.1.3 Famciclovir and Penciclovir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1331
1.2 First-Episode Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1332
1.3 Episodic Treatment of Recurrent Episodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1333
1.4 Continuous Suppressive Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1334
1.4.1 Asymptomatic Shedding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1336
2. Recent Issues in the Treatment of Recurrent Genital Herpes . . . . . . . . . . . . . . . . . . . . . . 1337
2.1 Suppression of Viral Shedding in Pregnant Women . . . . . . . . . . . . . . . . . . . . . . . . 1337
2.2 Resistance and Alternative Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1338
3. Drugs for the Treatment of Aciclovir-Resistant Herpes Simplex Virus . . . . . . . . . . . . . . . . . . 1339
3.1 Foscarnet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1339
3.2 Cidofovir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1340
3.3 Trifluridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1341
3.4 Interferon-α, -β . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1341
4. New Drugs Under Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1342
4.1 Lobucavir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1342
4.2 Crofelemer (SP-303) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1342
4.3 Edoxudine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1343
4.4 Controlled-Release Aciclovir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1343
4.5 Resiquimod (VML-600) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1343
5. Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1343
5.1 Recombinant Glycoprotein-Subunit Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1343
5.2 DNA-Based Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1344
5.3 Replication Incompetent Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1345
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1345
The incidence of genital herpes continues to increase in epidemic-like fashion.
Abstract
Aciclovir (acyclovir) has been the original gold standard of therapy. The recent
addition of famciclovir and valaciclovir as antiherpes drugs has improved con-
venience as well as the efficacy of treatment. Although aciclovir remains a widely
prescribed and reliable drug, its administration schedule falls short of the ease of

1330
Leung & Sacks
usage that the newer nucleoside analogues offer, forboth episodic and suppressive
therapy. Suppression of symptomatic disease and asymptomatic shedding from
the genitalia have both become popular approaches, if not the primary targets of
antiviral therapy. Knowing that asymptomatic disease leads to most cases of trans-
mission strongly suggests that suppression with antiviral agents could reduce
transmission risk in discordant couples. Unfortunately, the role for antivirals in
reducing transmission remains to be proven in clinical trials. Neonatal herpes is
now successfully treated using aciclovir. Current randomised clinical trials are
examining aciclovir and valaciclovir administration, as well as safety and efficacy
for post-acute suppressive therapy. Prevention of recurrences in pregnancy is also
a topic under investigation, with a view to reducing the medical need for Cesarean
section, or alternatively (and far less likely to be accomplished) to protect the
neonate.
Although resistance is largely limited to the immunocompromised and a
change in resistance patterns is not expected, several drugs are available for the
treatment of aciclovir-resistant strains of herpes simplex. Foscarnet is the main
alternative with proven efficacy in this setting. Unfortunately, administration of
foscarnet requires intravenous therapy, although a single anecdote of topical fos-
carnet efficacy in this setting has been published. Alternatives include cidofovir
gel, which is not commercially available but can be formulated locally from the
intravenous preparation. Less effective alternatives include trifluridine and inter-
feron. Future possibilities for treatment of genital herpes include a microparticle-
based controlled-release formulation of aciclovir and resiquimod (VML-600;
R-848). The search for an effective therapeutic vaccine for genital herpes has not
been successful to date, although a live virus glycoprotein H-deficient (DISC)
vaccine is currently in clinical trials. Recent data suggest that seronegative
women are protected (albeit, not fully) by a glycoprotein D recombinant vaccine
with adjuvant.
Despite the established safety and convenience of current treatment options,
better suppressive options and topical treatment options are much needed. Studies
using existing agents as potential tools to avoid Cesarean section, or transmission
to neonate or partner are ongoing. Both vaccines and antivirals may eventually
play a role in prevention of infection.
Genital herpes is a sexually transmitted disease
of this high proportion of unrecognised cases, and
the frequency of asymptomatic (absence of symp-
toms) or subclinical (absence of lesions) shedding,
that genital herpes continues to spread worldwide.[6]
Antiviral therapy has played an important role in
the treatment and suppression of episodes of geni-
tal herpes.
with persistent latent infection leading to recurrent
genital lesions.[1] Most cases (95%)[2] are caused by
herpes simplex virus type 2 (HSV-2) infection,
though genital herpes due to infection with herpes
simplex virus type 1 (HSV-1) is on the rise.[3] Ac-
cording to the National Health and Nutrition Ex-
amination Surveys (NHANES) III from 1988 to
1994, the seroprevalance of HSV-2 in people 12
years or older in the US was 21.9%, a 30% increase
compared with data from NHANES II, which was
collected from 1976 to 1980.[4,5] In this survey,
fewer than 10% of seropositive individuals reported
a history of genital herpes infection. It is because
1. Existing Therapy
1.1 Drugs Used in Therapy
1.1.1 Aciclovir
Aciclovir (acyclovir), an acyclic guanosine ana-
logue, is a selective inhibitor of the replication of
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Drugs 2000 Dec; 60 (6)

Treatment of Genital Herpes
1331
HSV types 1 and 2 and varicella-zoster virus.[7] In
virally-infected cells, it is initially monophos-
phorylated by HSV-specific viral thymidine kinase
(TK),[8] then converted to its di- and triphosphate
forms by cellular enzymes. The active form is
aciclovir triphosphate, which lacks the 3′-hydroxyl
group required to elongate the DNAchain. Aciclovir
triphosphate competes with deoxyguanosine tri-
phosphate as a substrate for viral DNApolymerase,
thereby terminating viral DNA replication.[9] This
results in inactivation of viral DNApolymerase.[10]
Since its discovery 20 years ago,[7,11] aciclovir
has become one of the most widely prescribed anti-
viral drugs in the world. It has proven to be effec-
tive and well tolerated for the treatment of genital
herpes. As the first generation antiviral, it has had
an excellent record of safety and high potency; how-
Despite the higher drug exposure with valaciclovir,
its safety profile is similar to that of aciclovir.[20-22]
High doses of valaciclovir have been associated
with thrombotic microangiopathy in patients with
AIDS[23] and other immunocompromised states;
however, thrombotic microangiopathy was not
seen in a recent study of renal transplant patients
treated similarly high doses of valaciclovir.[24]
A
direct cause and effect relationship has not been
proven, and this high dosage (8 g/day) does not re-
flect the recommended dosages for genital herpes.
1.1.3 Famciclovir and Penciclovir
Like aciclovir, penciclovir is a nucleoside ana-
logue which inhibits herpesvirus DNA synthesis.[25]
Penciclovir also has an antiviral spectrum against
human herpesviruses similar to that of aciclovir.[26]
Famciclovir is the oral prodrug of penciclovir. Fol-
lowing oral administration of famciclovir, it is ab-
sorbed in the upper intestine and rapidly deacetylated
to its active compound penciclovir in intestinal wall
and liver.[27,28] Little or no unchanged famciclovir
is detected in plasma following absorption, mean-
ing that famciclovir undergoes extensive presyste-
mic metabolism. In addition, penciclovir is elimi-
nated unchanged in urine. Famciclovir has a high
bioavailability of 77%,[27] which gives it an advan-
tage over the poor bioavailability of oral aciclovir
or penciclovir.
The intracellular action of penciclovir is very
similar to that of aciclovir. Penciclovir is highly
selective against herpesviruses because it is phos-
phorylated in HSV infected cells, with its phos-
phorylation to the monophosphate highly depend-
ent on HSV TK.[25] Penciclovir monophosphate,
like aciclovir monophosphate, utilises cellular en-
zymes to be further converted to the triphosphate.[26]
Penciclovir triphosphate has a significantly longer
intracellular half-life than aciclovir triphosphate
(20 hours vs 1 hour) in HSV-2 infected cells.[29]
This allows famciclovir to be administered orally
less frequently during active infection. Although
penciclovir triphosphate also has a 30-fold higher
intracellular concentration than that of aciclovir
triphosphate under similar circumstances,[30] the
HSV DNA polymerases have a greater affinity for
ever, poor oral absorption (bioavailability ≈20%[12]
)
and compliance issues (5 times daily regimen)
have resulted in the developement of newer agents.
1.1.2 Valaciclovir
Valaciclovir, the l-valyl ester and prodrug of
aciclovir, is much better absorbed than aciclovir.
Valaciclovir is rapidly and almost completely con-
verted to aciclovir in the intestinal wall and liver
by valaciclovir hydrolase.[13-15] The absolute bio-
availability of aciclovir following oral administra-
tion of valaciclovir is 54%,[16] 3 to 4 times higher
than oral aciclovir itself. Valaciclovir is virtually
completely converted to aciclovir. In a study of four
healthy volunteers each receiving [14C]valaciclovir
1000mg, plasma valaciclovir concentrations were
undetectable only 3 hours after administration. By
168 hours, more than 99% of the radioactivity re-
covered in urine and faeces corresponded to acic-
lovir and its known metabolites. Oral administra-
tion of valaciclovir provides a much greater drug
exposure with time than a comparable dose of oral
aciclovir.[17]
The pharmacokinetics of aciclovir following
administration of valaciclovir are similar to those
of aciclovir in healthy volunteers, in patients with
renal disease, in the elderly, in patients with ad-
vanced HIV disease,[18] and in geriatric volunteers
with or without concomitant diuretic therapy.[19]
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1332
Leung & Sacks
aciclovir triphosphate compared with penciclovir
triphosphate. Thus, to a greater extent, differences
in mechanism are quantitative rather than qualita-
tive and tend to balance each other. Like aciclovir
triphosphate, penciclovir triphosphate inhibits the
viral DNA polymerase through competition with
deoxyguanosine triphosphate as a substrate for vi-
ral DNApolymerase, thereby terminating viral DNA
replication. Plaque reduction assays have shown
that the 50% inhibition values of clinical isolates
of HSV-2 for penciclovir (1.5 to 2.4 mg/L) are sim-
ilar to those obtained for aciclovir (0.6 to 1.3
mg/L).[31,26] Unlike aciclovir, penciclovir is not an
obligate chain terminator; however, chain termina-
tion is rapidly achieved with both drugs. Most
aciclovir-resistant clinical isolates of HSV are TK
deficient and cross-resistant to penciclovir. How-
ever, strains with altered TK or DNA polymerase
mutations may be selectively resistant to one or
another nucleoside.[32]
Famciclovir has a different effect on latency in
a mouse model, compared with valaciclovir. Early
therapy with oral famciclovir was superior to
valaciclovir in the reduction of reactivation of la-
tent virus in both immunocompetent and immuno-
suppressed mice.[33-35] Both compounds were ef-
fective in preventing disease progression when
therapy was commenced up to 5 days after virus
inoculation. However, after cessation of therapy,
when ganglia of mice from each treatment group
were explanted and incubated for 5 days to allow
reactivation to occur, there was a significant differ-
ence in viral reactivation between the 2 groups.[35]
Explanted ganglia from famciclovir-treated mice
had marked reductions in viral reactivation com-
pared with explanted ganglia from valaciclovir-
treated mice. Clinical trials in first episode disease
did not demonstrate a significant difference in
post-primary recurrence rates.
showed no significant pharmacokinetic interac-
tions between famciclovir and allopurinol, digoxin,
cimetidine, zidovudine or theophylline.[37] Fur-
thermore, the pharmacokinetics of penciclovir do
not appear to be different in the elderly,[38] nor does
the intake of food have any influence on the bio-
availability of penciclovir in healthy male volun-
teers.[39,40] In a study of male volunteers treated with
famciclovir for 4 months and 12 months, no detri-
mental effects on semenology parameters were
identified (unpublished observations).
1.2 First-Episode Treatment
Oral aciclovir 200mg 5 times daily for 10 days
(in the US; 5 days in Europe) effectively treats first
episodes of genital herpes, reducing the duration of
viral shedding, time to crusting and time to heal-
ing.[41,42] Aciclovir may also play a role in modify-
ing the course of neurological complications such
as aseptic meningitis and urinary retention.[41] In
severe cases with neurological complications, in-
travenous aciclovir administered 3 times daily
should be considered.[43,44] A study of high dose
oral aciclovir (4000 mg/day) compared with the
standard dose (1000 mg/day) for the treatment of
first-episode genital herpes infections did not show
any clinical benefit for the higher dosage.[45] There
were no significant differences in the duration of
symptoms or viral shedding, nor did the median
time to first recurrence differ between the 2 groups.
Adverse gastrointestinal effects developed in 8%
of patients receiving the higher dosage, compared
with none for the standard dose group. Unfortu-
nately, despite its efficacy, the requisite administra-
tion frequency of oral aciclovir can be both incon-
venient and embarrassing.
Valaciclovir has been approved for therapy of
first episode genital herpes at a dosage of 1000mg
twice daily for 10 days. In an international, multi-
centre comparative study of valaciclovir 1000mg
twice daily versus aciclovir 200mg 5 times daily
for the treatment of 643 otherwise healthy adults
with first-episode genital herpes, it was shown that
the two drugs are equally effective and well toler-
ated in accelerating the resolution of the episode.
Famciclovir has an excellent safety profile. In
an analysis of tolerability data from 13 completed
clinical studies, famciclovir was found to be well
tolerated by patients with genital herpes (n = 791),
with an adverse event profile similar to that of
placebo.[36] Studies in healthy male volunteers
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Treatment of Genital Herpes
1333
Aciclovir and valaciclovir did not differ signifi-
cantly in efficacy with respect to duration of viral
shedding, time to healing, duration of pain or time
to loss of all symptoms. Adverse events were sim-
ilar in the 2 groups.[46] The reduction in adminis-
tration frequency is often a clinical advantage, es-
pecially because of the embarrassment that often
accompanies first clinical episodes. Several coun-
tries have chosen to approve a first-episode dose
of 500mg twice daily based on pharmacokinetic
arguments.
Famciclovir has been studied in the treatment of
first-episode genital herpes at a dose of 250mg 3
times daily for 5 to 10 days, and has been shown
to be equal in efficacy with aciclovir for the treat-
ment of first-episode genital herpes. Acomparative
study of famciclovir 750mg 3 times daily for 5
days and oral aciclovir 200mg 5 times daily for 5
days showed no significant differences in the re-
duction of duration of viral shedding for the treat-
ment of first episodes of genital herpes.[47] In 2
other comparative studies of the treatment of first-
episode genital herpes, the effects of famciclovir
125, 250 or 500mg 3 times daily for 10 days were
not significantly different from aciclovir 200mg 5
times daily for 10 days.[48] Similarly, famciclovir
at 250mg, 500mg and 750mg 3 times daily for 5
days in the treatment of first-episode genital herpes
was found to be equal in efficacy to aciclovir
200mg 5 times daily for 5 days. No significant dif-
ferences in times to cessation of viral shedding,
complete healing or loss of all symptoms were ob-
served between the 2 groups in all 3 studies. Again,
reduced administration frequency is a practical ad-
vantage over aciclovir.
ised trial comparing aciclovir with valaciclovir,
both agents were shown to reduce pain.[52] Although
oral aciclovir therapy provided a statistically sig-
nificant benefit over placebo, the degree of clinical
improvement perceived by the patient is modest,
and 5 times daily administration is inconvenient.
The 1998 Genital Herpes Management Guidelines
from the Centers for Disease Control (CDC) and
Prevention[53] provides treatment options includ-
ing aciclovir at the standard dose or 400mg 3 times
daily or 800mg twice daily for 5 days. Neither al-
ternative dose has been properly studied in clinical
trials. Topical 5% aciclovir in polyethylene glycol
ointment has been studied in the treatment of re-
current genital herpes. In both patient-[54] and
clinic-initiated[55,56] studies, the treatment of recur-
rent episodes of genital herpes with topically ap-
plied aciclovir decreased the duration of viral shed-
ding but had no significant clinical benefits. Topical
aciclovir is neither approved nor recommended for
the treatment of recurrent genital herpes in the im-
munocompetent host.
Oral valaciclovir is approved, and is a recom-
mended CDC treatment choice, for the episodic
treatment of recurrent genital herpes at a dosage of
500mg twice daily for 5 days. In a placebo-controlled
trial of over 900 patients, valaciclovir was found
to be effective in the episodic treatment of recurrent
genital herpes.[20] Valaciclovir 500mg twice daily
or 1000mg twice daily for 5 days, administered
within 24 hours of onset of symptoms, accelerated
time to episode resolution and lesion healing and
time to cessation of viral shedding. Adverse events
were similar to placebo. In one study, an additional
10% (valaciclovir 31% vs 21% for placebo) of pa-
tients failed to progress to full vesiculo-ulcerative
lesions as a result of treatment with valaciclovir. A
subsequent study suggests that administration for
3 days may be sufficient in keeping with the natural
history of viral shedding.[57] In this randomised,
double-blind controlled trial of 800 patients, a 5-
day regimen of valaciclovir 500mg twice daily was
not significantly different from a 3-day regimen in
time to healing or duration of pain. In a compara-
tive trial of valaciclovir 500mg twice daily and
1.3 Episodic Treatment of
Recurrent Episodes
Oral aciclovir 200mg 5 times daily for 5 days
has been used in the episodic treatment of recurrent
episodes of genital herpes. Whereas the duration of
viral shedding, time to crusting and time to healing
are reduced, there were no improvements in the
duration of symptoms nor the length of time to recur-
rence.[49-51] In a large placebo-controlled random-
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Drugs 2000 Dec; 60 (6)

1334
Leung & Sacks
aciclovir 200mg 5 times daily in patient-initiated
episodic treatment of recurrent genital herpes, val-
aciclovir was found to have identical efficacy to
aciclovir.[58] Similarly, in a large-scale study of
1200 patients, valaciclovir 1000mg twice daily was
compared with aciclovir 200mg 5 times daily and
placebo for the treatment of recurrences of genital
herpes.[52] Both drugs were significantly more ef-
fective than placebo in reducing time to resolution
of herpetic episodes, lesion healing, duration of vi-
ral shedding and duration of pain. Twice daily ad-
ministration convenience, however, is a significant
clinical consideration.
a
100
Placebo
Famciclovir
125mg
80
60
40
20
0
250mg
500mg
b
100
80
60
Famciclovir is approved for the episodic treat-
ment of recurrent genital herpes at a dose of 125mg
twice daily for 5 days, and is recommended as such
by the CDC. In 2 multicentre studies of famciclovir
for the treatment of recurrent episodes of genital
herpes, famciclovir was significantly more effective
than placebo (fig. 1). Famciclovir given 125, 250
or 500mg twice daily, initiated within 6 hours of the
onset of symptoms, significantly reduced the time
to healing, the time to cessation of viral shedding,
and duration of lesion oedema in both patient-[59]
and clinic-initiated,[60] placebo-controlled studies.
Famciclovir treatment also significantly reduced
the symptoms of pain, burning, tenderness and tin-
gling. Famciclovir resulted in abortive episodes of
viral shedding (73% of patients treated with 125mg
twice daily vs 46% of patients in placebo group);
however, these studies were not powered to show
clinical changes in abortive episode frequencies
from early therapy.[61] In both trials, adverse events
of famciclovir were similar to those of placebo.
Famciclovir is effective for acute episodic treatment
of recurrent genital herpes and also provides the
convenience of twice daily administration.
40
20
0
c
100
80
60
40
20
0
0
1
2
3
4
5
6
7
8
9
10 11
Time (days)
Fig. 1. Kaplan-Meier survival curves for the intent-to-treat pop-
ulation comparing 5 days of oral famciclovir 125, 250 or 500mg
twice daily with placebo. The circles and triangles are not placed
at specific data points. (a) Time to cessation of viral shedding
(all lesions); (b) time to complete healing (all lesions); (c) time
to cessation of all uncomfortable lesion symptoms. Reproduced
from Sacks et al.,[59] with permission.
suppression can be maintained indefinitely with no
evidence of substantial adverse effects.[69] In the
past, it has been suggested that treatment be inter-
rupted every 12 months to reassess the need for
continued suppression.[70] This is now a conten-
tious issue. Interruption of therapy is not required
for all patients and should be tailored to lifestyle
and continuing physical and psychosocial needs
1.4 Continuous Suppressive Therapy
Aciclovir 400mg twice daily is effective for
continuous suppressive therapy for patients who
have frequent recurrences.[62-66] Daily administra-
tion reduces the frequency of recurrences by up to
80%, and 25 to 30% of patients had no further re-
currences while taking aciclovir.[67,68] Successful
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Treatment of Genital Herpes
1335
Acyclovir 400mg bid
for suppression. Reduction of the psychological
morbidity of patients is an important benefit of sup-
pressive therapy.[71] Additional benefits on asymp-
tomatic shedding (discussed in section 1.4.1) also
need to be considered when interrupting therapy.
Valaciclovir 500mg once daily (for patients with
10 or fewer recurrences/year) and 1000mg once
daily (for patients with more than 10 recurrences/
year) have recently been approved for the prophy-
laxis of recurrent genital herpes in the US. In a
study comparing valaciclovir 500mg once daily
with placebo, 69% of patients receiving valacic-
lovir 500mg once daily were recurrence free after
16 weeks, compared with only 9.5% of patients
receiving placebo.[22] Valaciclovir has been found
to be equal in efficacy to aciclovir for the suppres-
sion of genital herpes. In a large-scale study of
1479 patients who were immunocompetent, vary-
ing doses of once- and twice-daily regimens of
valaciclovir were compared with aciclovir 400mg
twice daily and placebo for the suppression of gen-
ital herpes recurrences.[72] A dose-response rela-
tionship for once daily valaciclovir regimens was
shown. The estimated proportions of patients re-
currence free at the end of one year were 50% for
valaciclovir 250mg twice daily, 49% for aciclovir
400mg twice daily, 48% for 1000mg valaciclovir
once daily, 40% for valaciclovir 500mg once daily,
22% for valaciclovir 250mg once daily, and 5% for
placebo (fig. 2). In patients with a history of <10
recurrences per year, the 500mg once daily regi-
men was not statistically different from the twice
daily regimens. However, valaciclovir 250mg twice
daily, 1000mg once daily, or aciclovir 400mg twice
daily were more efficacious than 500mg once daily
for patients with ≥10 recurrences per year. Accord-
ingly, for patients with relatively low or modest
recurrence rates, valaciclovir 500mg once daily is
a reasonable suppression option. However, once
daily antiviral suppression was studied as, and should
be utilised as, a once every 24 hours (q24h) regi-
men, since, even with the results presented here,
there are several hours per day when no antiviral
is detectable in the blood. This could explain the
increase in breakthroughs seen in patients with
Valaciclovir 250mg bid
Valaciclovir 1000mg od
Valaciclovir 500mg od
Valaciclovir 250mg od
Placebo
a
100
50
0
b
100
50
0
0
50 100
250
400
Days of 1st recurrence
Fig. 2. Proportions of patients recurrence free. (a) Results for all
patients in the study; (b) results for the subpopulation with 9 or
fewer annual recurrences prior to the study period. All doses
are displayed. Circles and squares are used to clarify the figure
and do not represent specific data points. P < 0.0001 for all
dosages comparing active treatment to placebo. Valaciclovir
1000mg once daily, 250mg twice daily; aciclovir 400mg twice
daily are not different for the total population. For the 9 or fewer
population, valaciclovir 500mg once daily is also not different
among these dosages. Reproduced from Reitano et al.,[72] with
permission. bid = twice daily; od = once daily.
higher-frequency recurrences who utilise once
daily therapy; however, this remains to be proven.
Famciclovir has also been shown to be effective
in the suppression of genital herpes recurrences,
and has been recently approved at a dose of 250mg
twice daily. In two studies of suppressive treatment
of recurrent genital herpes with famciclovir, oral
famciclovir administered continuously was signif-
icantly better than placebo in the prevention of
genital herpes recurrences, effectively prolonging
the time to the next episode of genital herpes. In a
multicentre dose-finding study of 375 women with
a history of ≥6 recurrent episodes of genital herpes,
multiple-dose (125mg once daily, 125mg twice
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Drugs 2000 Dec; 60 (6)

1336
Leung & Sacks
daily, 250mg once daily, 250mg twice daily, 500mg
once daily) famciclovir was given for a period of 4
months (fig. 3).[73] The median time to recurrence
of a symptomatic episode of genital herpes was sig-
nificantly (p < 0.001) longer for recipients of fam-
ciclovir 250mg twice daily (>120 days) than for
recipients of placebo (82 days). Furthermore, fam-
ciclovir 250mg twice daily, which was found to be
the optimal dose, suppressed recurrences in 90% of
its patient group, compared with 48% recurrence
suppression in the placebo group. In another study,
famciclovir suppressive therapy was given for 1
year at 125mg 3 times daily, 250mg twice daily or
250mg 3 times daily or placebo (fig. 4).[74] All 3
dosages of famciclovir significantly delayed the
appearance of clinically confirmed recurrences (me-
dian time to first recurrence was 336 days for the
250mg twice daily group) compared with placebo
(median time to first recurrence was 47 days), with
the twice daily as effective as the 3 times daily
regimens.
Famciclovir
Placebo
6 months
12 months
90
80
70
60
50
40
30
20
10
0
125mg 250mg 250mg Placebo 125mg 250mg 250mg Placebo
tid bid tid tid bid tid
Fig. 4. Proportion of patients who remained free of herpes sim-
plex virus recurrence. All comparisons are statistically signifi-
cant (p < 0.001). Reproduced from Diaz-Mitoma et al.,[74] with
permission. bid = twice daily; tid = 3 times daily.
favouring one drug over another. Suppression stud-
ies of the individual agents are notoriously difficult
to compare because of differences in antiviral ex-
perience and recurrence rate between entry patients
as well as differences in disease and efficacy defi-
nitions. Comparative studies between valaciclovir
and aciclovir show equivalence.[73] Famciclovir
and valaciclovir have been compared, but data
have not yet been presented. Factors such as yearly
costs, administration regimen and anticipated clin-
ical efficacy have to be considered before com-
mencing long term suppressive therapy.
Aciclovir, valaciclovir and famciclovir are all ef-
fective for long term suppression of recurrent gen-
ital herpes. Comparative studies involving all three
agents are needed to make any clinical decisions
125mg once daily (n = 60)
125mg twice daily (n = 65)
250mg once daily (n = 61)
250mg twice daily (n = 64)
500mg once daily (n = 61)
Placebo (n = 64)
0.8
0.6
0.4
0.2
0
1.4.1 Asymptomatic Shedding
Asymptomatic shedding of HSV is thought to
play a major role in transmission.[75] Antivirals have
been shown to significantly reduce asymptomatic
and subclinical (includes shedding on days of pro-
drome) viral shedding when used as continuous sup-
pressive therapy. In a crossover clinical trial of 34
women with a history of genital herpes for less than
2 years, aciclovir 400mg twice daily for 70 days
was found to suppress subclinical shedding (fig.
5).[76] Patients using aciclovir had significantly less
(p < 0.001) subclinical shedding, detected by viral
0
15
30
45
60
75
90
105 120
Time (days)
Fig. 3. Time to first clinically confirmed genital herpes episode
(in the intention-to-treat population) among patients treated with
oral famciclovir once or twice daily or with placebo for 120 days.
The time to first clinically confirmed genital herpes episode was
significantly prolonged by treatment with famciclovir 250mg
twice daily (p < 0.001) and 125mg twice daily (p = 0.03), but not
with 500mg once daily (p = 0.06), 250mg once daily (p = 0.07)
or 125mg once daily (p = 0.22) when compared with placebo
treatment. Reproduced from Mertz et al.,[73] with permission.
© Adis International Limited. All rights reserved.
Drugs 2000 Dec; 60 (6)

Treatment of Genital Herpes
1337
isolation (0.3% of days), than patients in the pla-
cebo group (6.9% of days).
4.6% of days for placebo to 0.1% of days for fam-
ciclovir.
Valaciclovir 500mg twice daily was compared
with aciclovir 400mg twice daily and placebo for
its effectiveness in the suppression of subclinical
viral shedding in both men and women in a cross-
over study which utilised both viral culture and
polymerase chain reaction (PCR) techniques to
identify viral shedding.[81] Measured by culture,
subclinical shedding occurred on 15.3% of days for
placebo, 0.7% of days for valaciclovir and 0.9% of
days for aciclovir. Measurement by PCR produced
subclinical shedding rates of 40.0, 7.5 and 8.4% of
days, respectively. Asymptomatic shedding has not
yet been assessed with once daily valaciclovir, al-
though studies are underway. Despite clear bene-
fits of all suppressive antivirals on asymptomatic
shedding, it remains to be proven that suppressive
therapy can result in a reduction of transmission
risk. Clearly, transmission can occur while a source
partner is taking suppressive therapy.[82] Studies of
discordant partners are ongoing to determine the
importance of suppressive treatment on transmis-
sion.
Famciclovir has also been shown to reduce
asymptomatic shedding of herpes virus, measured
by both virus isolation and polymerase chain reac-
tion.[77] In a study comparing famciclovir with pla-
cebo in the suppression of viral shedding in women,
famciclovir significantly reduced the percentage of
days of asymptomatic shedding.[78] The asympto-
matic shedding rates were 0.52, 0.41 and 3.1% of
days, for famciclovir 125mg 3 times daily, famcic-
lovir 250mg 3 times daily and placebo, respec-
tively. Another study found famciclovir 250mg
twice daily was significantly more effective than
placebo in the suppression of asymptomatic shed-
ding in men.[79] Famciclovir reduced asymptomatic
shedding rates to 0.08% of days, compared with
1.09% of days for placebo (p < 0.05). This confirms
that famciclovir is effective for the suppression of
asymptomatic shedding for both sexes. In a study
of patients with HIV infection, famciclovir 500mg
twice daily was found to be significantly better than
placebo in reducing both symptomatic and asymp-
tomatic shedding.[80] Asymptomatic shedding was
reduced from 5.1% of days for placebo to 1.2% of
days for patients who received famciclovir. Simi-
larly, symptomatic shedding was reduced from
2. Recent Issues in the Treatment of
Recurrent Genital Herpes
2.1 Suppression of Viral Shedding in
Pregnant Women
100
The main cause of neonatal herpes infection is
through contact with the herpes simplex virus at the
time of delivery from the mother’s birth canal.[83]
Infection could theoretically result from transpla-
cental infection, although this is very rare.[84] In the
neonate, presentations have been characterised as
disseminated, central nervous system, or skin and
mucous membrane disease, with treated mortality
rates of 50, 15 and 0% respectively. Significant mor-
bidity may result with long term neurological dam-
age for up to half of the survivors.[85,86] Because of
the large numbers of patients who have herpes but
no history,[87] the risk of asymptomatic shedding
during labour is high. Identifying those at risk is
difficult. Clinical tools, such as a detailed history
Acyclovir
80
60
40
20
Placebo
0
0
10
20
30
40
50
60
70
Subclinical days with cultures
Fig. 5. Time to first subclinical shedding of herpes simplex virus
among 34 women. Reproduced from Wald et al.,[76] with per-
mission.
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1338
Leung & Sacks
of genital symptoms, may also not be helpful.[88]
Neonatal transmission occurs in 20 to 50% of in-
fants born to mothers delivered vaginally with first
episode infections at term.[89,90] Transmission rates
are substantially lower (≈4%) for mothers with re-
current episodes.[85,91]
had recurrences, with 21 of them recurring in de-
livery, there were no recurrences in the treatment
group. No infants showed a clinically-evident ad-
verse reaction to aciclovir in any of the above studies.
Unfortunately, no studies in late pregnancy sup-
pression have been conclusive because of small
sample size and/or failure to stratify by serological
status, asymptomatic shedding or recurrence fre-
quency rates. Intuitively, it would be expected that
aciclovir suppression would reduce frequency rates
of both symptomatic and asymptomatic recurrences.
Nevertheless, more definitive details are needed.
Although there have been no reports of adverse
effects attributable to its use in this setting,[99]
aciclovir is not licensed for use for any indication
during pregnancy. In a study of oral aciclovir sup-
pressive therapy in neonates,[100] 12 of 26 infants
developed neutropaenia while receiving aciclovir,
with 10 of the 12 having spontaneous recovery
without interruption of treatment. Further studies
of the effects of aciclovir on the newborn are also
warranted. Routine use of aciclovir in late preg-
nancy has become the standard of care in some
communities. Although it appears to be both desir-
able and cost effective, this remains an unproven
approach, with adverse effects unlikely but safety
is not fully proven.
While there have not been any studies on fam-
ciclovir use in pregnancy, the pharmacokinetics of
oral valaciclovir in late pregnancy have been evalu-
ated.[101] Oral valaciclovir 500mg twice daily sup-
pressive therapy was compared with oral aciclovir
400mg 3 times daily in 20 women with a history of
recurrent genital herpes at 36 weeks’gestation. Val-
aciclovir therapy resulted in higher plasma aciclovir
concentrations than aciclovir therapy, and further
studies are underway to evaluate the efficacy and
safety of valaciclovir in pregnancy.
In a recent survey, among the infants born to 9
women who acquired genital HSV infection shortly
before labour, neonatal HSV infection occurred in
4 infants, one of whom died.[90] Neonatal risk from
mothers with established recurrent infection (pos-
itive HSV-2 Western blot in this study) is far lower.
However, because recurrences account for the vast
majority of active episodes, recurrent episodes still
account for some of the overall risk. To reduce
transmission rates to the neonate it has been recom-
mended that Caesarean sections be performed on
mothers with genital herpes lesions.[92,93] How-
ever, this imposes risks to the mother and fails to
properly address the differences in risk between
first and recurrent episodes. Caesarean sections for
suspected active recurrences are often unnecessary
in mothers with established recurrent disease, given
the low incidence of neonatal herpes infection in
this population.[94]
In order to reduce the rates of Caesarean section,
several groups have considered the use of suppres-
sive therapy late in pregnancy. A study of 5 women
undergoing suppressive aciclovir therapy did not
show any clinical benefit, and 1 out of the 5 neonates
was infected with HSV.[95] However, a study of 46
pregnant women with first episodes of genital her-
pes showed a significant reduction in clinical re-
currence and Caesarean section when given aciclo-
vir 400mg 3 times daily compared with placebo.[96]
No woman treated with aciclovir had a Caesarean
delivery as a result of herpes, compared with 9 of
the 25 placebo recipients. In a group of pregnant
women receiving aciclovir, there was evidence of
a predictable marked reduction in the number of
women experiencing symptomatic recurrences, af-
ter trial entry.[97] In addition, 150 women with a
history of genital herpes were given either aciclovir
200mg 3 times daily or placebo, beginning at 38
weeks.[98] While 33 patients in the placebo group
2.2 Resistance and Alternative Therapies
First reported in 1982,[102] aciclovir-resistant
strains of HSV have primarily been found in im-
munocompromised individuals, and have been as-
sociated with clinical disease progression.[103-107]
In that setting, studies have shown that the preva-
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Treatment of Genital Herpes
1339
lence of aciclovir-resistant isolates of HSV from
immunocompromised patients is approximately
5%.[107-109] Aciclovir resistance in a bone marrow
transplant population[110,111] has also been reported.
Although reports of emergence of resistance in im-
munocompetent patients[112-114] are rare (0.1 to 0.6%
prevalence in one study[108]), no correlation between
in vitro resistance and clinical progression has been
established. In the majority of cases, the mecha-
nism for viral resistance to aciclovir involves mu-
tant HSV strains unable to produce TK.[115-118] In
most cases, latent infection is not influenced by
treatment. Therefore, upon withdrawal of drug
pressure, reactivations most often revert to wild
type. However, reactivations of resistant virus
have been observed and may be explained by in
vivo complementation with viral heterogeneity[119]
or alterations in the quantity of TK production.
Such cases demonstrate that latent infection can be
affected by resistant mutations. However, these
can appear to revert to wild type eventually, if drug
therapy is withdrawn. Presumably, this reflects the
persistence of sensitive virus in latency as well as
the strong virulence advantage associated with ex-
pression of viral TK. Although much less common
than TK depletion, isolates have also been found
to have a mutation altering TK function[116] or the
DNA polymerase.[120,121] Such modifications would
leave virulence factors unaltered. These findings re-
veal the need for alternative mechanistic approaches
with antivirals against herpes.
Despite concerns over resistance, there is very
little cause for concern regarding a change in resis-
tance patterns overall. TK deficiency was observed
at the same levels prior to the introduction of acic-
lovir and the prevalence of resistant isolates has
been stable since the introduction of this drug. Vast
increases have been experienced in antiviral drug
use over the past 15 years with no alterations in
resistance patterns. Blower et al.[122] have suggested,
based on mathematical models, that any change in
resistance patterns, were they to occur, would take
decades to develop. This probably reflects the es-
tablished, largely unalterable pool of wild type la-
tent infection in the population, as well as the nat-
ural episodic nature of the infection.
3. Drugs for the Treatment of
Aciclovir-Resistant Herpes Simplex Virus
3.1 Foscarnet
Foscarnet is a pyrophosphate antagonist that ex-
hibits broad activity against DNA and RNA vi-
ruses.[123,124] It noncompetitively inhibits viral
DNA polymerase by binding to pyrophosphate
binding sites of viral DNA, thereby preventing py-
rophosphate exchange.[125] Since it does not re-
quire phosphorylation, it is active against aciclovir-
resistant TK-deficient HSV strains.[126] However,
foscarnet can be toxic in some situations. Potential
adverse effects of renal dysfunction, gastrointesti-
nal symptoms, metabolic abnormalities (such as
with magnesium and calcium), genital ulcers and
seizures have been reported.[127] Serious events
can usually be avoided through hydration, careful
monitoring and avoidance of concomitant use of
pentamidine.
Topical foscarnet had been studied, but has not
proven to be effective in the management of genital
herpes. In a study of 86 patients, therapy with 0.3%
foscarnet cream was patient initiated within 24
hours of a recurrent episode, then treatment con-
tinued with application every 2 hours for the first
day then 6 times daily for the next 4 days. Topical
foscarnet was found to be statistically significant
in reducing the time to healing of lesions.[128] How-
ever, a larger study of 230 patients demonstrated
no statistically significant efficacy.[129] Treatment
with 0.3% foscarnet cream for men and 1% fos-
carnet cream in women was clinically initiated
within 6 hours of a recurrence. There has been a
single case report of successfully utilised topical
foscarnet for herpes resistant to treatment with
both aciclovir and valaciclovir.[130] Studies of this
approach in immunocompromised patients are on-
going.
Use of intravenous foscarnet for aciclovir-
resistant herpes simplex infections was first de-
scribed by Sacks et al.[131] and its utility confirmed
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1340
Leung & Sacks
in subsequent studies.[106,132-135] In an uncontrolled
study, clinical response occurred in 81% of aciclovir-
resistant infections in patients with AIDS treated
with foscarnet.[136] In another study, intravenous
foscarnet was found to be more effective than
vidarabine in time to healing and time to cessation
of viral shedding in the treatment of aciclovir-
resistant mucocutaneous HSV infection in patients
with AIDS.[137]
Foscarnet has been approved for intravenous
use in aciclovir-resistant herpesvirus infections in
immunocompromised patients. Due to the nature
of intravenous administration, there are limitations
to this application. However, there are no oral for-
mulations of foscarnet because of its poor oral bio-
availability. Foscarnet-resistance strains of HSV
have been reported,[138,139] and strains resistant to
both foscarnet and aciclovir have also appeared.[140]
Resistance to foscarnet occurs as a result of muta-
tions in viral DNA polymerase.[141]
DNA polymerase reaction either as a competitive
inhibitor to terminate chain elongation or as an al-
ternative substrate to allow chain growth.[142,150]
Inhibition constants against HSV-1 and HSV-2 viral
DNA are 50- to 600-fold lower than the constants
for human DNA polymerase.[142,150,151] Cidofovir
was found to completely inhibit cytomegalovirus
(CMV) DNA synthesis at concentrations at least
100-fold lower than the concentrations required for
cellular DNA synthesis.[152] It is a broad spectrum
antiviral, with activity against HSV-1, TK-negative
HSV-1, HSV-2, varicella zoster virus, Epstein-Barr
virus, CMV, human herpesvirus type 6, human her-
pesvirus type 8, human adenoviruses, poxviruses,
hepadnaviruses and papovaviruses.[153] In animal
models of genital herpes infection, successful out-
comes have been observed in single-dose therapy
for guinea pigs that have been inoculated with
HSV-2.[146,154] In another genital herpes model, a
single topical application of 0.3, 1 or 3% cidofovir
topical gel 24 hours after HSV-2 inoculation sig-
nificantly prevented viral replication and lesion de-
velopment.[155]
3.2 Cidofovir
Cidofovir (HPMPC, GS-504), an acyclic nucle-
oside phosphonate analogue of deoxycytosine mono-
phosphate, is active against a broad spectrum of
viruses. Cidofovir is phosphorylated by cellular en-
zymes into its active diphosphate metabolite.[142,143]
Since cidofovir is a nucleotide, it bypasses the first
HSV-dependent phosphorylation step required for
nucleosides such as aciclovir. Therefore, cidofovir’s
conversion to its active metabolite is independent
of virally-encoded enzymes such as TK.[144] Since
cidofovir’s metabolism is not affected by HSV in-
fection,[142] it is active against both aciclovir-
sensitive and aciclovir-resistant HSV. This has
been demonstrated in vitro,[145] in animal models,[146]
and clinically.[147,148] Indeed, cidofovir showed en-
hanced in vitro potency against strains of HSV re-
sistant to aciclovir.[149] Cidofovir has also been
successful in the treatment of an aciclovir- and
foscarnet-resistant HSV-1 strain in a bone marrow
transplant patient.[140]
Cidofovir has a very long intracellular half-life.
After removal of cidofovir from the cell culture me-
dium, the intracellular concentrations of cidofovir
monophosphate and cidofovir diphosphate are 24
and 65 hours, respectively.[142,156] In the intrave-
nous treatment of CMV retinitis in patients with
AIDS, this long intracellular half-life permits sys-
temic administration at intervals of every 1 to 2
weeks. However, cidofovir has a poor oral bio-
availability of <5%, with a plasma half-life of 2.6
hours.[157,158]
There have been several studies using cidofovir
as a gel formulation for the topical treatment of
genital herpes. In a study of cidofovir gel compared
with placebo applied once daily for 5 days in the
treatment of aciclovir-unresponsive HSV infection
in 30 patients with AIDS, cidofovir was found to
have significant antiviral and clinical efficacy.[159]
Complete healing occurred in 27% of patients re-
ceiving 0.3% cidofovir, 33% for the 1% cidofovir
group, and 0% for patients treated with placebo.
Median lesion areas were decreased by 58% for
The antiviral effect of cidofovir is the result of
its interaction with viral DNA polymerase. The
diphosphate metabolite of cidofovir acts during the
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Treatment of Genital Herpes
1341
those treated with cidofovir versus 0% for placebo-
treated patients. However, the US Food and Drug
Administration (FDA) did not approve cidofovir
gel for this indication because studies were not
large enough to provide statistical power for proof
of efficacy. Given the low incidence of this prob-
lem, such FDA requirements could obviate the ap-
proval of any drug for this indication. Furthermore,
a multicentre dose-escalation study of single-dose
cidofovir gel compared with placebo in the treat-
ment of lesions of recurrent genital herpes in im-
munocompetent patients showed that cidofovir gel
had a significant antiviral effect.[160] Placebo or
cidofovir gel 1, 3 or 5% was given to patients within
12 hours of lesion appearance. Cidofovir gel at all
doses significantly decreased the median time to
negative virus culture compared with placebo. The
size of this pilot was not sufficient to show signif-
icant differences in the median time to complete
healing, in part because of local toxicities, which
prolonged healing times in some recipients. Local
toxicity was dose-dependent and seen in three of
the 23 patients treated with 5% cidofovir gel and
one of the 21 patients treated with 3% cidofovir
gel. While the efficacy of cidofovir in the treatment
of genital herpes has been demonstrated, the max-
imum strength that could be tolerated still has to
be determined by further studies.
feron (IFN)-α for isolates of aciclovir- or
aciclovir/foscarnet-resistant HSV.[164] Larger, con-
trolled studies would be required to establish the
clinical efficacy of trifluridine in the treatment of
genital herpes.
3.4 Interferon-α, -β
In the humoral immune system, INF production
is induced by viral infection. INF inhibits viral pro-
tein translation and creates an antiviral state in the
cell, causing resistance to infection, and playing an
important role in the host defence mechanism.
INF inhibits the proliferation of HSV types 1
and 2 in vitro.[165,166] Several studies have investi-
gated the efficacy of INF gel for the treatment of
genital herpes.[167-170] A clinic-initiated study
found that topical INFα-2a administered 6 times
daily in an aqueous solution to unroofed vesicles
after lesion onset was not effective in the treatment
of genital herpes lesions.[171] Another study failed
to show significant benefit with an INFα formu-
lated with nonoxinol-9, though a significant delay
in re-epithelialisation was observed with the appli-
cation of a high dose.[172] In a patient-initiated study
of 188 patients with recurrent genital herpes,[173]
high- or low-dose INFα, formulated in a methyl-
cellulose gel containing nonoxinol-9, or placebo
was topically applied 3 times daily for 5 days after
onset of lesions. Recipients of the high dose had
reductions in time to negative virus culture, dura-
tion of symptoms and times to healing. Similarly,
a placebo-controlled trial of 387 patients receiving
either INFα-2a gel or placebo 4 times daily for 4
days upon onset of lesions found that INF treat-
ment was effective in the treatment of recurrences
of genital herpes.[174] INF decreased the duration
of viral shedding for all patients, and there was a
significant reduction of pain, itching and time to
crusting for males. More recent studies have dem-
onstrated better efficacy in the use of INF. In a
study of 25 patients, INFβ was found to have ben-
eficial effects.[175] Topical INFs are not approved
for the treatment of recurrent genital herpes.
3.3 Trifluridine
Trifluridine is a pyrimidine nucleoside analogue
that, like cidofovir, acts independently of viral TK,
but toxicity prevents systemic administration;
however, an ophthalmic preparation has been suc-
cessfully employed in herpes keratitis.[161] Using
gauge pads, this ophthalmic product has been top-
ically applied in some cases of aciclovir-resistant
genital herpes. It has been reported to be beneficial
for the treatment of infection of aciclovir-resistant
HSV-2 in a patient with AIDS.[162] In patients with
HSV isolates that were either aciclovir- or aciclo-
vir/foscarnet-resistant, 3 episodes of recurrent an-
ogenital HSV lesions were improved with topical
trifluridine 3 times daily.[163] In another report,
trifluridine showed potential synergy with inter-
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1342
Leung & Sacks
sions than aciclovir cream at all concentrations
tested.
4. New Drugs Under Development
Several early safety and pharmacokinetic stud-
ies in humans have investigated the effects of
lobucavir on HIV- and CMV-seropositive individ-
uals. In a single-dose, placebo-controlled study in
40 patients, the absolute oral bioavailability was
found to be about 40%.[187] In a subsequent multi-
ple-dose study in 32 patients, twice daily adminis-
tration for 28 days produced linear increases in the
area under the plasma concentration/time curve
(AUC) at 20, 70 and 200mg, but not for the 400mg
dose.[188] In another placebo-controlled multiple-
dose (70mg or 200mg twice daily, 200mg or 400mg
4 times daily) study of lobucavir, there was a linear
relationship between exposure and dose up to
200mg.[189] Lobucavir was well tolerated in the
above trials, and the pharmacokinetics of lobucavir
is not influenced by the intake of food. Unfortu-
nately, the development of lobucavir for the treat-
ment of genital herpes has been discontinued.
4.1 Lobucavir
Lobucavir is a deoxyguanosine nucleoside ana-
logue. Like aciclovir, it is phosphorylated to the
monophosphate form by viral TK, then further
phosphorylated by cellular kinases into the active
triphosphate form.[176-178] It is a nonobligate DNA
chain terminator,[176,179-181] acting as an alternative
substrate for deoxyguanine triphosphate. Chain
termination results from the incorporation of lo-
bucavir triphosphate, a poor primer, into the DNA
by DNA polymerase. The intracellular half-life of
lobucavir triphosphate was found to be 10 hours.[182]
Lobucavir’s inhibition constants against HSV-1
and HSV-2 DNA polymerase (Ki = 0.017181 and
1.0183 μmol/L, respectively) were comparable
with that of aciclovir. Against HSV-1 and HSV-2
in vitro, the concentration effective against 50%
(EC50) was 0.04 to 0.007 and 0.04 to 0.01 mmol/L,
respectively, with lower values than aciclovir in
both cases.[182,183] However, the EC50 of lobucavir
against a TK deficient variant of HSV-1 was only
increased by about 30-fold (2 mmol/L), compared
with >700-fold for aciclovir.[183] This evidence
suggests that phosphorylation by viral TK is im-
portant, but not essential, for the antiviral activity
of lobucavir. Furthermore, a study of lobucavir in
human CMV-infected and mock-infected cells
show that phosphorylation of this drug can occur
in the absence of viral factors.[184] Phosphorylated
metabolite levels were only 2- to 3- times higher in
infected than mock-infected cells, with total lobu-
cavir metabolites being 2.3 and 0.8 pmol/106 cells,
respectively.
4.2 Crofelemer (SP-303)
Crofelemer (SP-303) is a natural bioflavonoid
plant extract, isolated from Croton lechleris, which
inhibits viral penetration into cells. It is a pro-
anthocyanidin oligomer and is active against both
HSV-1 and HSV-2. In one study, 15% crofelemer
ointment 3 times daily for between 14 and 42 days
was given to immunocompromised patients who
had undergone a period (median 1.5 months) of
ineffective aciclovir therapy.[190] There was no
complete healing in any patients, and adverse
events included local burning and pain. In a sub-
sequent trial, the drug was tested as a topical for-
mulation in a phase II study for safety and effec-
tiveness against recurrent genital herpes in patients
with AIDS.[191] Given 3 times daily for 3 weeks,
41% of the patients given crofelemer versus 14%
of the placebo group had complete healing. Unfor-
tunately, subsequent clinical trials of crofelemer
for the treatment of genital herpes have not shown
efficacy, and further investigations have been dis-
continued.
In mouse models, oral lobucavir was effective
in a variety of HSV-1, HSV-2 and murine CMV
infections, with a bioavailability of 80% based on
urinary excretion.[183,185] Topically applied lobucavir
has been evaluated for the treatment of herpes le-
sions in guinea pigs.[186] Starting at 3 hours after
inoculation, 5% lobucavir or 5% aciclovir cream
was applied twice daily to randomly assigned areas
for 5 days. Lobucavir was found to be significantly
better at reducing the duration and severity of le-
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Drugs 2000 Dec; 60 (6)

Treatment of Genital Herpes
1343
4.3 Edoxudine
4.5 Resiquimod (VML-600)
Resiquimod (VML-600, R-848, S-28463), is a
synthetic immune response modifier, a member of
the imidazoquinolines. An analogue of imiquimod,
resiquimod has been shown to induce the release
of a number of cytokines in vivo, including INFα,
tumour necrosis factor-α and several interleukins,
through modulation of monocyte/macrophage ac-
tivity.[198] Resiquimod was found to reduce the num-
ber of genital herpes recurrences in a guinea pig
model, even after discontinuation of the drug.[199]
It has also shown significant immunomodulating
effects when applied topically to humans in gel
form.[200] Arecent clinical trial showed that topical
resiquimod treatment delayed recurrences of gen-
ital herpes when applied to lesion ≤24 hours from
onset. In 52 immunocompetent adults with a his-
tory of ≥6 recurrences a year, median time to first
recurrence was 169 days for the resiquimod-
treated group and 57 days for those treated with
placebo.[201] This novel antiviral is currently in
phase III clinical trials.
Edoxudine (EDU) is a deoxythymidine ana-
logue that demonstrates significant in vitro and in
vivo antiherpesviral activity,[192-195] and has been
approved for the treatment of recurrent genital her-
pes in Germany and for recurrent genital herpes
episodes in women in Canada. Like other nucleo-
side analogues, edoxudine needs to be phosphory-
lated by viral TK into its active form, which inhib-
its DNA polymerase. Edoxudine is better absorbed
from its aqueous cream base than aciclovir from its
polyethylene glycol base; however, it is degraded
to its component base and sugar by pyrimidine nu-
cleoside phosphorylases virtually instantaneously.
The rate of absorption of edoxudine increases with
longer time allowed after application. In a multi-
centre study of topical 3% edoxudine cream for 5
days for the treatment of recurrent genital herpes
compared with placebo, edoxudine significantly re-
duced viral shedding in both sexes.[196] Viral shed-
ding was reduced from 3.4 for the placebo group
to 2.7 days for edoxudine-treated men. Similarly,
shedding wasreduced from 3.5 to 2.0 daysin women.
Edoxudine also reduced several signs of active, re-
current herpes in women, such as lesion and groin
tenderness and groin adenopathy.
5. Vaccines
Although vaccines for HSV have been studied
for decades, there have not been any effective ones
found for the prevention of infection.[202] The na-
ture of HSV infection, which includes regional in-
fection leading to latency, and which does not in-
clude systemic viremia, implies that even successful
induction of serum antibodies would still be inef-
fective against mucosal infection. Recent studies
of genital mucosal and sensory ganglia immunity
has established the importance of T cell protection,
even in the presence of HSV-specific antibod-
ies.[203,204] These findings indicate that future vac-
cine strategies must take into account the impor-
tance of the T cell response.
4.4 Controlled-Release Aciclovir
A microparticle-based controlled release for-
mulation of aciclovir has been developed.[197] It is
reported to result in prolongation of the short plas-
ma half-life (2.5 hours) of aciclovir and resulting
burdensome regimen. Treatment trials from Eur-
ope suggest equivalence with oral aciclovir. It is
possible that breakthrough recurrences often seen
on suppressive therapy regimens could be further
reduced through any approach which prolongs the
plasma half-life of an effective antiviral. Further
studies are required, however, to determine whether
the prolonged half-life of this formulation can be
translated into a therapeutic advantage.
5.1 Recombinant Glycoprotein-
Subunit Vaccine
Recent investigations have focused on recombi-
nant HSV-2 envelope glycoproteins D (gD) and B
(gB), 2 of the 8 glycoproteins embedded in the viral
© Adis International Limited. All rights reserved.
Drugs 2000 Dec; 60 (6)

1344
Leung & Sacks
envelope. Both of these subunits have a high de-
gree of homology (86% of DNA and amino acid
sequences are identical) between HSV-1 and HSV-
2, and they are highly conserved (99%) among dif-
ferent strains for the same viral type.[205] Both pro-
teins are highly immunogenic in humans, eliciting
strong antibody responses.[206] Mice that are im-
munised with the glycoproteins purified from virus-
infected cells are protected from viral challenge.[207]
Immunisation in guinea pigs with recombinant vi-
rus expressing HSV-2 gD reduced the severity of
genital herpes.[208]
In a clinical trial of an inactivated HSV-2 glyco-
protein vaccine administered to HSV-2 seronega-
tive sexual partners of individuals with genital her-
pes,[209] both humoral and cell-mediated immune
responses were elicited, but the vaccine was not
significantly better than placebo in preventing the
acquisition of infection. In a study of patients with
a history of recurrent genital herpes, a recombinant
gD vaccine increased HSV-2 and gD2-specific an-
tibody levels;[210] however, there was no signifi-
cant effect on the frequency of symptomatic out-
breaks. In a study of 137 HSV-2 seronegative
individuals, a recombinant subunit vaccine con-
taining gB2 and gD2 combined with a MF59 adju-
vant produced an increase in both humoral and cel-
lular responses to HSV-2.[211] However, 2 large,
multicentre, randomised trials of this vaccine
showed that the high titres of specific neutralising
antibodies do not confer increased protection
against HSV-2 infection.[212] In over 2000 HSV-2
seronegative patients, the HSV-2 acquisition rates
did not significantly differ between the placebo and
vaccine recipients.
2, 12 and 14 months.[214] The glycoprotein group
had significantly reduced time to healing in the first
genital herpes outbreak after the vaccination in
both men and women. Furthermore, glycoprotein-
specific and neutralising antibodies were boosted
by the vaccination. However, significant reduction
in the severity of the episode was only shown in
women, and the monthly rate of recurrences was
not significantly reduced in either group. There-
fore, this vaccine is not being currently pursued for
genital herpes.
A multicentre study compared the effects of a
killed vaccine with episodic treatment of aciclovir
in the suppression of recurrent HSV infection.[215]
Compared with the aciclovir group, the vaccinated
group had significant reductions of recurrences,
disease-free days, recurrence duration and active
disease days per year. However, several technical
aspects of this study are insufficient to support the
use of this vaccine as a preventative. Further stud-
ies are warranted. Arecent clinical trial of a recom-
binant gD2 vaccine with the adjuvant SBAS4
showed significant efficacy in preventing genital
herpes disease in HSV-1 and HSV-2 seronegative
females.[216] Vaccine efficacy was not observed in
either males or HSV-1-positive females. Although
full protection was not achieved, this finding
warants further studies into the immunopathogene-
sis of this disease.
5.2 DNA-Based Vaccine
DNA-based vaccines have also been under in-
vestigation for their possible role in immunisation,
first demonstrated in an experimental influenza virus
infection model in mice.[217] Subsequent studies
have examined this immunisation strategy in other
species,[218-221] and in other viral infections[222-225]
including the herpes virus,[226] and have shown ef-
fectiveness. In a study targeting the herpes virus, a
plasmid expressing the gene for HSV-2 gD2 and
under the control of the CMV immediate-early gene
promotor was used to immunise guinea pigs before
intravaginal infection with HSV-2, while control
animals were given gG2 and gD2 with Freund’s
adjuvant.[227] The DNA vaccine elicited humoral
A study of recombinant HSV-2 gB2 and gD2 in
an intramuscular subunit vaccine administered to
HSV-seronegative and HSV-1 seropositive women
showed that the vaccine elicited immunoglobulin
(Ig)G and IgAantibody levels comparable with those
of HSV-2 gB2 and gD2 responses to recurrent HSV-2
genital infection.[213] Furthermore, in a placebo-
controlled trial of recombinant gD2 and gB2 in
MF59, a novel adjuvant, either both glycoproteins
in MF59 or of MF59 alone were administered at 0,
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Drugs 2000 Dec; 60 (6)

Treatment of Genital Herpes
1345
immune responses similar to those seen after HSV-
2 infection, and protected the animals from pri-
mary genital HSV-2 infection. HSV-2 replication
in the genital tract was significantly reduced and
there were fewer recurrences after the primary in-
fection, with significantly reduced latent infection
in the sacral root ganglia. Phase I studies in human
are underway.
improvement over placebo in preventing classical
lesions. Such differences may have more to do with
study designs than inherent differences in the nu-
cleosides themselves. Direct comparisons have not
been presented. It is valid to try each drug in pa-
tients (not simultaneously) to determine which
they prefer. However, episodic therapy is not the
option of choice for many patients. Suppressive
therapy is becoming more universally recommen-
ded because of good safety and efficacy. Benefits
against asymptomatic shedding provide hope that
these agents may also be shown in the future to
modify transmission. However, this has yet to be
demonstrated. Aciclovir is conveniently adminis-
tered for suppression. It is just as effective as
valaciclovir, but has not been studied against fam-
ciclovir. For patients with low frequency disease,
there is a potential administration convenience ad-
vantage to once-daily valaciclovir. However, it is
generally thought that breakthroughs in immuno-
competent patients occur because of the short plasma
half-lives of each of these compounds, leading to
trough periods without antiviral activity. Accord-
ingly, it is our suggestion to reinforce with the pa-
tient that once daily dosing means every 24 hours,
twice daily means every 12 hours, 3 times daily
means every 8 hours, and so forth. We often com-
mence therapy with a twice daily approach, mov-
ing selected patients down to once daily valacic-
lovir. Other clinics may start patients with modest
frequency disease on a single daily dose and increase
frequency of administration in the case of treat-
ment failure.
5.3 Replication Incompetent Vaccines
A disabled infectious single cycle (DISC) vac-
cine, which has an altered gH, has shown immuno-
genicity in phase I clinical trials.[228] Several issues
could impede development of this vaccine. First,
there is no established serological assay that will
distinguish the gH-negative versus wild-type im-
mune response. Second, although this virus is re-
activation-impaired, the possibility that superin-
fection with wild type could provide an exogenous
source of gH sufficient to allow for reactivation
will be difficult to rule out. Assuming these issues
are possible to address, the potential for a live vac-
cine against genital herpes is very good.
6. Conclusion
Significant advances have been made in the
management of genital herpes over the past few
years. Two new agents, valaciclovir and famcic-
lovir, have been added to the treatment armamen-
tarium. At the same time, aciclovir has become
available through several generic sources, reduc-
ing its cost substantially. All three drugs appear to
be equipotent in the treatment of first episodes.
Since these are often complicated and prolonged,
all patients should be treated. Administration ad-
vantages with both famciclovir and valaciclovir of-
fer compelling reasons for use of either prodrug.
Five times daily administration of aciclovir is im-
practical and may be especially problematical dur-
ing this emotionally-intense phase of infection. All
three drugs are also effective in early treatment of
individual episodes. Again, the administration ad-
vantages of the prodrugs are valuable. Famciclovir
appears to have a broad effect against multiple
symptoms, while valaciclovir has shown a 10%
We continue to face an epidemic of genital her-
pes, which increases despite our best safer sex mes-
sages. While small strides have been made in pre-
vention with vaccination, much more work needs
to be done and significant advances in our under-
standing of immunopathogenesis are required.
Topical agents for recurrences and systemic agents
with prolonged plasma half-lives which might re-
duce the potential for breakthroughs during sup-
pressive therapy are lacking. Advances in prevent-
ing or reducing asymptomatic shedding provide
hope that transmission may be influenced through
© Adis International Limited. All rights reserved.
Drugs 2000 Dec; 60 (6)

1346
Leung & Sacks
15. de Miranda P, Burnette TC. Metabolism and pharmacokinetics
of the acyclovir prodrug BW 256U 87 in cynomolgus mon-
keys [abstract]. Antiviral Res 1992; 17 Suppl. 1: 53
16. Soul-Lawton J, Seaber E, On N, et al. Absolute bioavailability
and metabolic disposition of valaciclovir, the L-valyl ester of
acyclovir, following oral administration to humans. Anti-
microb Agents Chemother 1995; 39: 2759-64
17. Weller S, Blum MR, Doucette M, et al. Pharmacokinetics of the
acyclovir pro-drug valaciclovir after escalating single-dose
and multiple-dose administration to normal volunteers. Clin
Pharmacol Ther 1993; 54: 595-605
18. Weller S, Blum MR, Smiley ML. Phase I pharmacokinetics of
the acyclovir prodrug, valaciclovir. Antiviral Res 1993; 20
Suppl. 1: 144
19. Wang LH, Schults M, Weller S, et al. Pharmacokinetics and
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this approach; however, no transmission data are
yet available. It is worth considering the fact that,
if long term suppressive therapy may reduce the
risk of transmission, withdrawal of the same might
increase the risk. Accordingly, these issues should
be carefully followed in the design of future studies
and patients coming off suppressive therapy should
be so advised. Pending data from current trials,
suppressive therapy should be withdrawn care-
fully, and only where necessary and appropriate,
and with counselling and reinforcement of safer
sex practices.
20. Spruance SL, Tyring SK, DeGregorio B, et al. A large-scale,
placebo-controlled, dose-ranging trial of peroral valaciclovir
for episodic treatment of recurrent herpes genitalis. Arch Intern
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21. Beutner KR, Friedman DJ, Forszpaniak C, et al. Valaciclovir
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22. Patel R, Bodsworth NJ, Woolley P, et al. Valaciclovir for the
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Correspondence and offprints: Daniel T. Leung, Wake Forest
University Baptist Medical Center, Box 2774, Winston Salem,
NC 27157, USA.
E-mail: dleung@wfubmc.edu
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