CONCISE ADVICE FOR CLINICIANS
Antiviral Drugs to Prevent Clinical Recurrence in
Patients with Genital Herpes
Megan Sands-Lincoln, PhD, MPH, David R. Goldmann, MD
Evidence-Based Medicine, Elsevier, Philadelphia, Pa.
Adults with recurrent genital herpes due to herpes simplex
virus type 1 (HSV-1) or herpes simplex virus type 2 (HSV-
2) are often prescribed long-term suppressive antiviral
therapy with acyclovir, famciclovir, valacyclovir. In
reviewing a systematic review, clinical trial, and practice
guideline on the efcacy of these treatments compared with
placebo, the evidence found to be efcacious and reason-
ably safe in preventing clinical recurrences of genital
herpes.
WHAT IS THE CLINICAL QUESTION?
What are the comparative effectiveness and safety of anti-
viral drugs to prevent clinical recurrence in patients with
genital herpes?
WHAT DOES THE EVIDENCE CONCLUDE?
Quality of Balance Between
Intervention Evidence* Benets and Harms
Antiviral medication Low Likely to be benecial
vs placebo
*Quality of evidence: Quality of evidence scale (GRADE): high,
moderate, low, and very low. For more information on the GRADE rating
system, see http://gdt.guidelinedevelopment.org/app/handbook/
handbook.html.
Balance between benets and harms: The Guideline Elements Model:
http://gem.med.yale.edu/default.htm.
What Are the Parameters of Our Evidence
Search?
Population: Adults with recurrent genital herpes due to
herpes simplex virus type 1 (HSV-1) or herpes simplex virus
type 2 (HSV-2), excluding HIV and hepatitis C patients
Funding: None.
Conict of Interest: Neither author has a conict of interest.
Authorship: Both authors had full access to the data and each partic-
ipated in the writing of this article.
Requests for reprints should be addressed to Maria Middleton,
Evidence-Based Medicine, Elsevier, 1600 John F. Kennedy Blvd, Phila-
delphia, PA 19103.
E-mail address: m.middleton@elsevier.com
0002-9343/$ -see front matter
http://dx.doi.org/10.1016/j.amjmed.2016.08.007
Setting: Outpatient
Intervention: Antiviral therapy with acyclovir, famci-
clovir, and valacyclovir; administered orally, any dose;
suppressive therapy consisting of daily treatment for
6
months
Comparator: Placebo, active comparators
Outcomes: Proportion of patients with at least one
recurrence over 12-month follow-up; any harms/adverse
events
WHAT IS THE BASIS FOR OUR CONCLUSION?
See Table.
WHAT DO CLINICAL GUIDELINES SAY?
US Centers for Disease Control and Prevention. Sexually
Transmitted Disease Guidelines, 2015.1 (AGREE II Score:
not available).
 Antiviral chemotherapy offers clinical benets to most
symptomatic patients and is the mainstay of management.
 Systemic antiviral drugs can partially control the signs
and symptoms of herpes episodes when used to treat rst
clinical and recurrent episodes or when used as daily
suppressive therapy.
 Of note, these drugs neither eradicate latent virus nor
affect the risk, frequency, or severity of recurrences
after the drug is discontinued.
 Randomized trials have indicated that 3 antiviral medi-
cations provide clinical benet for genital herpes:
acyclovir, valacyclovir, and famciclovir.
 Suppressive therapy reduces the frequency of genital
herpes recurrences by 70%-80% in patients who have
frequent recurrences.
 Safety and efcacy have been documented among pa-
tients receiving daily therapy with acyclovir for as long as
6 years and with valacyclovir or famciclovir for 1 year.
UK National Guideline for the Management of Ano-
genital Herpes, 2014.2 (AGREE II Score: 66%).
 Oral acyclovir, valacyclovir, and famciclovir reduce the
duration and severity of recurrent genital herpes.
2 The American Journal of Medicine, Vol -, No -, - 2016

 Head-to-head studies show no advantage of one therapy

events by authors because

of poor reporting quality
over the others.

No conclusion on adverse
 Patients should be given full information on the advan-
tages and disadvantages of suppressive therapy, balancing

Favors treatment

Favors treatment

Favors treatment

Favors treatment
the frequency of recurrence with the cost and inconve-

Estimate of the relative effect of 3 antivirals across supporting studies; cannot make conclusion with regard to signicance, because of poor reporting quality and lack of data synthesis.
nience of treatment.

Comments
AUTHOR COMMENTARY

Notes: Recurrent genital herpes simplex virus was dened as at least 4 occurrences per year. Parallel parallel-group design trial; crossover crossover-group design trial.
We searched PubMed, EMBASE, the Cochrane Database of
Systematic Reviews, and the National Guideline Clearing-
house and retrieved one high-quality systematic review,3

Condence in the
recent clinical trial,4 and 2 clinical practice guidelines.1,2

Effect Estimates
The overall quality of the evidence was low due to high
risk of bias in the individual studies and inconsistency. The

Very low
(GRADE)
methodological concerns were a function of the large

Low

Low

Low

Low
number of participant withdrawals and differential missing

CI condence interval; GRADE Grading of Recommendations Assessment, Development and Evaluation; RCT randomized controlled trial.
data from the intervention and placebo groups, which sug-
gested high risk of bias in the included trials.
Findings from the systematic review indicate that the

Number of Participants
proportion of patients with at least one recurrence per year
was signicantly reduced among those treated with long-

2049 (9 RCTs)3

1788 (4 RCTs)3
250 (5 RCTs)3

732 (2 RCTs)3

852 (4 RCTs)3
term suppressive antiviral therapy (acyclovir, famciclovir,
or valacyclovir) compared with placebo (low-quality evi-
dence) (Table). In comparing acyclovir and valacyclovir (Studies)
Risk of Clinical Recurrence of Genital Herpes in Patients Treated with Oral Antiviral Medications

treatments head to head, there is minimal evidence to

suggest that the risk of having at least one recurrence is
different across treatments reviewed.3,5 The systematic re-
view also included a network meta-analysis of all parallel
0.48 (0.39-0.58)

0.35 (0.29-0.42)

0.41 (0.24-0.69)

0.57 (0.50-0.64)
Relative Effect

arm trials that compared efcacy for both direct and indirect
comparisons across all 3 treatments, and results did not
(95% CI)

indicate superiority of any one treatment.3 There was no

0.67
signicant dose response across ranges of 400-1000 mg per
day for acyclovir, 250-1000 mg per day for valacyclovir,
and 125-750 mg per day for famciclovir.
Current clinical practice guidelines recommend
Corresponding Risk*

acyclovir, valacyclovir, or famciclovir for preventing clin-

ical recurrence, and with limited data from head-to-head
studies there is minimal evidence indicating that one treat-
valacyclovir (parallel)

famciclovir (parallel)
acyclovir (crossover)
583/1131

686/1497

265/654

331/561

ment is more effective than another as suppressive treat-

Antiviral
acyclovir (parallel)

80/250

ment. They suggest that these treatments are generally safe,

with supporting safety data from over 1-6 years (data not
shown).1,2
antiviral

The potential for resistant HSV strains with long-term

Assumed Risk*

use of antivirals is unknown, particularly among immuno-

Placebo vs

Placebo vs

Placebo vs

Placebo vs

Placebo vs

compromised patients. A long-term cohort study on he-

879/918

232/250

229/291

130/178

115/291
Placebo

matopoietic stem-cell transplant recipients suggested that

the probability of resistance is very low.6 However, research
*Illustrative comparative risks.

on alternative treatment (eg, with inosine pranobex) is un-

derway. One randomized trial recently suggested lower rates
of 3-month recurrence for treatment with inosine pranobex
(number of patients)

compared with acyclovir (26.6% vs 47.6%; P .015),4 but

Risk of recurrence

it was associated with development of hyperuricemia.

adverse events
Any reported

Although our chosen outcome measure did not distin-

(at least 1)
Outcomes

guish between greater and fewer recurrences over 12 months

Table

of follow-up, the overall body of evidence suggests that

treatment to prevent recurrent genital herpes with antivirals
Sands-Lincoln and Goldmann Genital Herpes
(acyclovir, famciclovir, and valacyclovir) is efcacious and
reasonably safe (Table).
References
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3
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