Clinical Infectious Diseases

SUPPLEMENT ARTICLE

Diagnosis and Management of Genital Herpes: Key

Questions and Review of the Evidence for the 2021 Centers
for Disease Control and Prevention Sexually Transmitted
Infections Treatment Guidelines

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Christine Johnston1,2,3
1
Division of STD Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA; 2University of Washington, Seattle, Washington, USA; and 3Fred Hutchinson Cancer Research
Center, Seattle, Washington, USA

Genital herpes, caused by herpes simplex virus (HSV) type 1 or type 2, is a prevalent sexually transmitted infection (STI). Given
that HSV is an incurable infection, there are important concerns about appropriate use of diagnostic tools, management of infec-
tion, prevention of transmission to sexual partners, and appropriate counseling. In preparation for updating the Centers for Disease
Control and Prevention (CDC) STI treatment guidelines, key questions for management of genital herpes infection were developed
with a panel of experts. To answer these questions, a systematic literature review was performed, with tables of evidence including
articles that would change guidance assembled. These data were used to inform recommendations in the 2021 CDC STI treatment
guidelines.
Keywords.  genital herpes; herpes simplex virus; HSV-2; HSV-1; guidelines.

Genital herpes is a chronic sexually transmitted infection (STI)
characterized by recurrent, self-limited genital ulcers, caused
by herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2).
While HSV-1 is associated with both oral and genital infection,
HSV-2 nearly exclusively causes genital disease. HSV-1 and
HSV-2 are prevalent infections, with 47.8% and 12.1% of the
United States (US) population aged 14–49 years seropositive for
HSV-1 and HSV-2, respectively, in 2015–2016 [1]. HSV-1 sero-
prevalence reflects oral and genital infection, but HSV-1 is an
increasing cause of first-episode genital herpes, particularly in
well-resourced settings [2–4]. Genital herpes is unrecognized in
most people; in a National Health and Nutrition Examination
Survey study, only 13% of HSV-2–seropositive persons had
been diagnosed with genital herpes [5]. Accurate diagnosis of
genital herpes can be realized using type-specific molecular or
virologic tests when genital ulcers are present, and type-specific
serologic test to detect antibody when lesions are not present.
Genital herpes can be managed either by episodic antiviral
therapy, in which patients take short courses of antiviral therapy
at the time of a genital herpes recurrence, or suppressive anti-
viral therapy, in which patients take medications on a daily basis
to prevent recurrences and shedding. The virus may be present
Correspondence: C. Johnston, University of Washington, Box 359928, 325 Ninth Ave,
Seattle, WA 98104, USA (cjohnsto@uw.edu).
Clinical Infectious Diseases®  2022;74(S2):S134–43
Published by Oxford University Press for the Infectious Diseases Society of America 2022. This
work is written by (a) US Government employee(s) and is in the public domain in the US.
https://doi.org/10.1093/cid/ciab1056
in the genital tract without symptoms, leading to transmission
to sex partners or neonates, when present in the genital tract
during delivery. In addition, HSV-2 fuels the human immuno-
deficiency virus (HIV) epidemic, with a 3-fold increased risk of
HIV acquisition among persons with HSV-2 infection as com-
pared to those without HSV-2 infection [6]. Genital herpes is
associated with significant stigma, which can be combatted by
patient education of the natural history of infection. This ev-
idence review was performed to update approaches to the di-
agnosis, treatment, and prevention of transmission of genital
herpes infections to sex partners and neonates. Furthermore,
extragenital manifestations of genital herpes infections, such as
HSV-2 meningitis and HSV hepatitis, were reviewed. Finally,
treatment of HSV-2 infection in the setting of prevention and
treatment of HIV infection was also reviewed. Key questions
were generated with an expert panel, followed by a literature re-
view and summary of the published evidence. The findings were
presented at the Centers for Disease Control and Prevention
(CDC) STI treatment guidelines meeting in June 2019.
METHODS
Seven panel members with broad expertise in genital herpes in-
fection collaborated with CDC in generation and review of key
questions. The key questions were broken down into 6 specific
areas: diagnosis, treatment, prevention of sexual transmission/
management of sex partners, HSV-2/HIV interactions, preven-
tion of neonatal herpes, and counseling of adults with genital
herpes.

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Literature Review
Several search strategies of the literature were utilized to capture
articles published between 1 January 2013 and 5 February 2019.
This time encompassed the period since the prior literature
review for the 2015 CDC sexually transmitted diseases (STD)
treatment guidelines. The PubMed/Medline computerized da-
tabase of the US National Library of Medicine was searched,
and articles were filtered to include only human studies and
to exclude reviews. Medical Subject Heading (MeSH) search
terms included the following: HSV OR herpes simplex virus OR
herpes genitalis OR genital herpes AND therapeutics OR treat-
ment outcome OR antiviral agents. This search yielded 4760
manuscripts. An additional filter of “clinical trial” was added,
yielding 143 manuscripts. Additional searches to address key
questions included above herpes terms AND diagnostic, AND
serology, herpes simplex virus type 1 AND genital, AND ac-
quisition, AND transmission, AND meningitis AND treatment,
AND condoms, AND circumcision, AND tenofovir, AND HIV
AND treatment, AND prevention AND neonatal, AND hepa-
titis AND pregnancy, AND acyclovir resistant AND treatment,
AND counseling. Abstracts were reviewed and those that would
impact treatment recommendations were selected, reviewed,
and included in the Table of Evidence (Supplementary Table
1). The table included citation, study design, study population
type/setting, exposure/intervention, outcome measures, re-
ported findings, design analysis quality/biases, and subjective
quality rating in the context of the modified rating system used
by the US Preventive Services Task Force (USPSTF). The evi-
dence was then reviewed and incorporated into the 2021 CDC
STI treatment guidelines.
RESULTS
I. Diagnosis of Genital Herpes
Key Question 1: What are the optimal tests for HSV-1 or HSV-2
detection from a genital ulcer/lesion/suspected HSV outbreak?
As of 5 April 2019, 17 HSV nucleic acid amplification test
(NAAT)/polymerase chain reaction (PCR) diagnostic assays
were US Food and Drug Administration (FDA)–approved for
detection of HSV from clinical specimens [7]. Although these
tests vary in sensitivity and specificity, most available tests with
published data have >90% sensitivity and specificity [8–10]. In
addition, some laboratories use “in-house”–developed HSV
PCR assays, for which test performance characteristics may be
difficult to assess. Providers should be aware of the test char-
acteristics of HSV NAATs that are performed in their clinical
setting. Assays that differentiate between HSV-1 and HSV-2 in-
fection should be utilized, to provide patients with information
regarding expected natural history of genital herpes.
While HSV molecular assays are highly sensitive and specific,
there may be situations in which false-negative results occur.
For instance, the yield of HSV viral culture decreases as genital
Diagnosis and Management of Genital Herpes • CID 2022:74 (Suppl 2) • S135
ulcers heal [11]; it is likely that healing lesions may become neg-
ative for HSV DNA as well. HSV molecular assays should not
be obtained in the absence of a genital ulcer to diagnose gen-
ital herpes infection; due to the intermittent nature of genital
HSV shedding, swabs obtained in the absence of genital ulcers
would not be sensitive. In these situations, HSV serologic assays
should be performed.
HSV culture is less sensitive than NAAT/PCR [12]. When
available, NAAT/PCR assays are preferred. However, if HSV
culture is the only test available due to cost or laboratory avail-
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ability, it is reasonable to perform HSV culture to make the di-
agnosis of HSV genital ulcer disease. Given the lower sensitivity
of culture, if HSV is suspected and results are negative, further
investigation through the use of serology may be warranted,
particularly to rule out HSV-2 infection.
HSV direct immunofluorescence assay and Tzanck smear
lack sensitivity and are not recommended for diagnosis of HSV
genital ulcer disease [13].
Key Question 2: What is the optimal strategy for use of serologic
assays to diagnose HSV-1 and HSV-2 infection to avoid false-
positive or false-negative diagnoses?
Type-specific HSV serologic assays differentiate between
HSV-1 and HSV-2. FDA-approved, commercially available as-
says test sera for antibodies to HSV glycoprotein G-1 or HSV
glycoprotein G-2 using enzyme immunoassay (EIA) or chem-
iluminescent immunoassay (CLIA) [14]. The gold standard
for HSV serologic testing is Western blot/immunoblot assays,
which target antibodies to several HSV antigens in addition to
glycoprotein G [15]. Compared to the gold standard, there are
serious limitations to the EIA/CLIA for both HSV-1 and HSV-2
testing. HSV-1 assays lack sensitivity, which can result in false-
negative diagnoses. In one study, the sensitivity for detecting
HSV-1 antibodies was 70.2% [16].
Currently available HSV-2 serologic tests lack specificity.
The EIA results provide index values, which are quantitative
measures of the amount of antibody present. For the first ap-
proved EIA, the HerpeSelect, an index value <0.9 is negative,
0.9–1.1 is indeterminate, and >1.1 is considered positive per the
manufacturer’s label. However, compared to the Western blot,
HSV-2 specificity is very low, in one recent study only 57.4%
[16]. The test characteristics are highly dependent upon the
index value, with index values of 1.1–2.9 having only 39.8%
specificity, and index value of ≥3.0 having 78.6% specificity
[16]. Persons with HSV-1 infection are more likely to have a
false-positive HSV-2 test with a low index value compared to
those without HSV-1 infection [16]. Multiple studies have rep-
licated these results in a wide variety of settings, including STD
clinics [17].
The sensitivity of HSV-2 serologic testing is high, estimated at
92% [16]. False-negative tests may occur after acquisition of the
virus during the window period. The window period may be up
to 12 weeks [18]. Therefore, in someone who tests negative for
HSV-2 serology immediately after exposure, serologic testing
should not be repeated until 12 weeks after exposure to deter-
mine if HSV-2 was acquired.
HSV-2 is a chronic infection that impacts long-term
sexual health, and therefore accurate diagnosis is para-
mount. Serologic diagnosis of HSV-2 should ideally be per-
formed only if patients and providers are aware of the assay
limitations and low positive results (index value <3.0) can be
confirmed with a second assay using a different gG antigen.
Given the poor specificity of HerpeSelect assays, particularly
among those with HSV-1 infection, these results should ide-
ally be confirmed with a second method prior to giving results
to the patient. Prior studies have shown that using the Biokit
HSV-2 rapid assay as a confirmatory test improves the speci-
ficity of HerpeSelect from 93.2% to 98.7% when compared to
the gold-standard Western blot [19]. A strategy combining the
HerpeSelect with the Biokit assay improves the positive pre-
dictive value from 80.5% to 95.6%, and has the greatest impact
among low-prevalence populations [19]. If the Biokit is not
available, providers could consider using the Western blot as a
confirmatory test. However, access to both of these tests may be
limited in some settings. Given that specificity of these assays
improves substantially with higher index values, an index value
≥3.0 may be sufficient for diagnosis of HSV-2 infection without
further confirmatory testing. However, providers should be
aware that false positives have been described even at index
values >3.5 with HerpeSelect and other FDA-approved assays
[20]. Further research and tools are needed to optimize HSV
serologic testing.
Key Question 3: When should serologic diagnosis of HSV-2 be
obtained?
The USPSTF recommends against screening for HSV-2 infec-
tion among asymptomatic adolescents and adults [21]. Given
the current limitations of commercially available serologic tests
as noted above, this approach is reasonable for asymptomatic
people with low pretest probability of infection (few lifetime
sexual partners, no known HSV-2 seropositive partners, no
genital symptoms). In addition, screening of pregnant women
is not recommended [22].
Persons who have genital symptoms that could be consistent
with genital herpes infection should undergo HSV-2 serologic
testing to establish the diagnosis of HSV-2 infection. These
symptoms include classic or atypical genital symptoms. In ad-
dition, people who have been told that they have genital herpes
without a virologic diagnosis have a high pretest probability of
HSV-2 infection and should undergo HSV-2 serologic testing.
In addition, persons who are at increased risk of HSV-2 in-
fection based on epidemiologic risk could be considered for
HSV-2 serologic screening, with the goal of identifying undiag-
nosed symptomatic infection. Examples of increased epidemio-
logic risk include sexual activity with a partner with genital
HSV-2 infection.
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HSV-1 serologic testing does not distinguish between oral
and genital infection and should not be performed to diagnose
genital HSV-1 infection. Optimally, genital HSV-1 infection
should be diagnosed by recovering HSV-1 from genital surfaces
using PCR or culture. HSV-1 serologic screening to diagnose
genital HSV-1 infection is not recommended.
II. Treatment of Adults With Genital Herpes
Key Question 1: What are the most practical treatment regi-
mens for first clinical episode of genital herpes, episodic therapy,
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and suppressive therapy?
While several dosing strategies of anti-herpesvirus medications
(acyclovir, famciclovir, and valacyclovir) have been studied and
are FDA-approved for first clinical episode genital herpes, epi-
sodic therapy, and suppressive therapy, several regimens are less
practical for use than others due to frequency of dosing. Dosing
strategies that are most feasible for patient adherence should be
prioritized.
Although episodic and suppressive therapy for genital HSV-1
infection have not been studied as comprehensively as for gen-
ital HSV-2, the same medication dosages and frequencies are
recommended for genital HSV-1 infection.
Key Question 2: What are the preferred management ap-
proaches to the treatment of genital herpes?
There are 2 important goals for management of genital herpes:
(1) prevention of symptoms/recurrences and improvement in
quality of life and (2) prevention of transmission to sexual part-
ners. Given these goals, the recommended approaches to man-
agement of genital HSV infection differ based on the viral type
(HSV-1 vs HSV-2) and the presence and absence of symptoms.
HSV-2: Symptomatic Infection
Symptomatic HSV-2 infection may be managed by suppres-
sive therapy (daily medication to suppress recurrences and
prevent transmission to sexual partners) or episodic therapy
(short-term therapy to treat symptomatic recurrences). All pa-
tients should be aware of both treatment approaches to chronic
HSV-2 infection and should be offered suppressive therapy.
Although suppressive therapy to prevent HSV-2 transmission
was studied in heterosexual couples, the mechanism for preven-
tion is through suppression of viral shedding [23], and there is
no biologic rationale that shedding would not be prevented in
other populations. Therefore, suppressive therapy can be con-
sidered to prevent transmission in men who have sex with men
(MSM), women who have sex with women, and transgender
persons. However, suppressive therapy is not effective to de-
crease the risk of transmission among persons with HIV/HSV-2
coinfection [24].
HSV-2: Asymptomatic Infection
Approximately 20% of persons who are HSV-2 seropositive
do not note genital symptoms consistent with genital herpes,
even after receiving education about typical signs and symp-
toms of genital herpes [25]. Episodic and suppressive antiviral
therapy are used predominantly to treat recurrences, prevent
recurrences, and to prevent transmission to sexual partners.
For patients with serological evidence of HSV-2 infection
without symptomatic recurrences, neither episodic nor sup-
pressive therapy are indicated for prevention of recurrences.
The trial of suppressive therapy to prevent HSV-2 transmission
to heterosexual sexual partners was conducted in persons who
had symptomatic HSV-2 infection [23]. Among persons with
asymptomatic infection, the efficacy of suppressive therapy to
prevent HSV-2 transmission to sexual partners has not been
studied. Given the 50% reduced risk of shedding among those
with asymptomatic HSV-2 infection compared to symptomatic
infection [26], the benefit of suppressive therapy for prevention
of transmission is unknown in this population. Many persons
diagnosed with genital HSV-2 infection recognize symptoms
after education about the clinical manifestations of infection,
and therefore may realize that they are symptomatic [25].
Genital HSV-1 Infection
Recurrences are less frequent with genital HSV-1 infection
compared to genital HSV-2 infection [27, 28]. Given this, ep-
isodic therapy is preferred over suppressive therapy in persons
with genital HSV-1 infection. For patients with frequently re-
curring genital HSV-1, suppressive therapy may be considered.
For persons with either genital HSV-1 infection or those
with asymptomatic HSV-2 infection, suppressive therapy may
be considered for those who have substantial psychosocial dis-
tress due to genital herpes and/or anxiety about transmission to
sexual partners.
Table 1 summarizes the evidence base for episodic and sup-
pressive therapy among those with symptomatic HSV-1 and
HSV-2 infection or asymptomatic HSV-2 infection.
Key Question 3: Are there new therapies to treat recurrent gen-
ital herpes?
a. First clinical episode and episodic therapy
No new treatment regimens are FDA-approved for first clin-
ical episode HSV or episodic HSV therapy.
Table 1.  Evidence for Use of Suppressive Therapy Among Populations with HSV-1 and HSV-2 Infection, with USPSTF Grade framework [29]
Population Prevention of recurrences
People without HIV People with HIV
HSV-2, symptomatic A-high
HSV-2 seropositive, asymptomatic I-low
Genital HSV-1, symptomatic B-low, only among those with
frequent recurrences
HSV-1 seropositive N/A
Abbreviations: A, recommended, high certainty that benefit is substantial; B, recommended, high certainty of moderate benefit or moderate certainty that benefit is moderate to substantial;
C, recommend selectively–moderate certainty that there is small benefit; I, insufficient evidence to recommend; level of certainty, high, moderate, low.
a
Only studied in heterosexual population.
Diagnosis and Management of Genital Herpes • CID 2022:74 (Suppl 2) • S137
b. Suppression
No new treatment regimens are FDA-approved for suppres-
sive therapy of genital herpes recurrences.
Key Question 4: Are there new recommendations for treatment of
acyclovir-resistant genital herpes?
Case reports suggest that brincidofovir [30, 31], imiquimod
[32], and topical cidofovir [33] may be useful in the treatment
of acyclovir-resistant HSV infections. Clinical trials are ongoing
for helicase-primase inhibitors (see Key Question 7).
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Key Question 5: Of approved antiviral therapies, are there data
comparing the efficacy of antivirals for episodic or suppressive
therapy?
No new data comparing the efficacy of antivirals for episodic or
suppressive therapy are available.
Key Question 6: Are there any data on the effectiveness of
antivirals for genital HSV-1 vs genital HSV-2 infection?
No comparative data are available for treatment of genital
HSV-1 vs HSV-2 infection. Based on the known biology of the
infections and in vitro susceptibilities, it is not expected that
there would be a difference in efficacy for treatment between
the viral types.
Key Question 7: Are there new antivirals in development for
treatment of genital herpes that are approved or have entered
clinical trials?
Helicase-primase inhibitors have been studied in early-phase
clinical trials but have not been evaluated in phase 3 studies
and are not FDA-approved for treatment at this time [34–36].
There is currently an open-label study evaluating the helicase-
primase inhibitor pritelivir for use in immunocompromised
persons with acyclovir-resistant HSV infections (ClinicalTrials.
gov identifier NCT03073967), and an early-access program to
pritelivir has been initiated (https://www.aicuris.com/75n6/
Pritelivir-AIC316-.htm).
Tenofovir preparations (tenofovir [TFV] intravaginal gel and
oral tenofovir disoproxil fumarate [TDF]) have been studied in
a crossover study for prevention of genital shedding and recur-
rences among women with HSV-2 infection and without HIV
infection [37]. There was no difference in shedding or lesions
Prevention of transmission
People with
People without HIV HIV
~50% risk reduction in transmission Not effective
A-high B-moderatea, + C-high
I-low
I-low
I-low
with use of oral or vaginal tenofovir as compared to placebo
[37]. Tenofovir is not recommended for treatment of HSV-2
infection.
Key Question 8: What is the preferred treatment for HSV
meningitis?
HSV-2 meningitis is a rare complication of genital HSV-2 infec-
tion, which more commonly affects women [38]. HSV-2 menin-
gitis is characterized clinically by signs of meningitis (headache,
photophobia, fever, meningismus) and cerebrospinal fluid
(CSF) lymphocytic pleocytosis, accompanied by mildly elevated
protein and normal glucose [39]. HSV PCR from CSF should
be obtained in suspected cases [40, 41]. Optimal therapies for
HSV-2 meningitis have not been studied, and practice pat-
terns are highly variable [38]. For first episode HSV-2 menin-
gitis, acyclovir 10 mg/kg intravenously (IV) every 8 hours until
resolution of fever and headache, followed by valacyclovir 1 g
TID (3 times daily) to complete a 14-day course, is suggested.
Among persons with established recurrent HSV-2 meningitis,
oral therapy may be used for the entire course. It is essential
to distinguish cases of HSV encephalitis from HSV meningitis.
HSV encephalitis is a much more severe infection with high
neurologic morbidity and mortality, and should be treated with
14–21 days of IV acyclovir [42].
Recurrent HSV-2 meningitis is a rare complication of genital
HSV-2 infection. However, most cases of recurrent lymphocytic
meningitis are caused by HSV-2 (84% in 1 series [43], 78% in
another [44]).
A randomized clinical trial showed that suppressive therapy
(valacyclovir 500 mg twice daily [BID]) did not prevent recur-
rent HSV-2 meningitis episodes, but it is likely that the dose was
not sufficient for central nervous system penetration [45]. There
was a statistically significant increased risk of HSV-2 menin-
gitis the year after valacyclovir was discontinued, concerning
for rebound. Valacyclovir 500 mg BID is not recommended for
suppression of HSV-2 meningitis.
III. Prevention of Sexual Transmission of Genital Herpes/Management of
Sex Partners
Key Question 1: Are there new approaches for prevention
of HSV-1/2 transmission from persons with genital herpes
infection?
No new data were identified for prevention of HSV-1/2 trans-
mission to sexual partners. The pivotal study performed in
HSV-2–discordant, HIV-seronegative heterosexual couples
showed a 48% decreased risk of transmission for those HSV-2–
seropositive persons on valacyclovir 500 mg daily compared to
placebo [23].
a. What are the optimal strategies to prevent acquisition of gen-
ital herpes among persons who do not have HSV-2 or genital
HSV-1 infection?
There are no new strategies for prevention of HSV identified.
Consistent use of condoms and knowledge and disclosure
S138 • CID 2022:74 (Suppl 2) • Johnston
of HSV-2 serostatus have been shown to decrease the risk of
HSV-2 transmission previously [46, 47].
b. Are vaccines available to prevent HSV acquisition or
transmission?
Several therapeutic vaccines have been tested in early-phase
clinical trials, but none have reached phase 3 trials and none
are FDA-approved [48–50].
c. Are there new data on the effectiveness of condoms to prevent
genital herpes?
An observational study conducted among HIV/HSV-2
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serodiscordant heterosexual couples in several sites in Africa
showed that condoms reduced the per-act risk of transmission
from men to women by 96% (relative risk [RR], 0.04 [95%
confidence interval {CI}, .01–.16]), but were not significantly
effective in preventing transmission from women to men (RR,
0.35 [95% CI, .12–1.04]) [51]. These data are consistent with
prior studies of condoms for prevention of HSV-2 transmis-
sion, particularly showing the efficacy of male condoms for
prevention of transmission to women.
Key Question 2: Are there medications that can be taken as
preexposure prophylaxis (PrEP) to prevent acquisition of gen-
ital herpes?
d. There are no data to indicate that antiherpesvirus medication
(acyclovir, famciclovir, or valacyclovir) can be taken as PrEP
to prevent HSV-2 acquisition.
e. What is the impact of taking HIV PrEP (TDF or TDF/
emtricitabine [FTC]) on acquisition or reactivation of HSV-2
among HIV-seronegative persons?
Among HIV/HSV-2–seronegative men/women in HIV/
HSV-2–heterosexual discordant partnerships in Africa, daily
TDF was associated with 30% reduced risk of HSV-2 serocon-
version (95% CI, .49–.99) [52].
Among MSM and transgender women, daily TDF/FTC was
not associated with difference in HSV-2 acquisition, but there
was a lower risk of clinically graded moderate to severe ulcers
among those randomized to TDF/FTC [53].
Among MSM, on-demand PrEP (TDF/FTC) was not associ-
ated with decreased risk for HSV-2 acquisition [54].
Among women at high risk of acquiring HIV in South Africa,
pericoitally applied intravaginal 1% TFV gel was associated with
51% reduction in HSV-2 acquisition (95% CI, .30–.77) [55]. Daily
intravaginal 1% TFV gel with use confirmed by TFV detection in
plasma did not meaningfully reduce the risk of HSV-2 acquisition
among sexually active women in Africa (RR, 0.59; P = .60) [56].
Based on these data, oral TDF/FTC when used for HIV pre-
vention as daily PrEP may also decrease the risk of HSV-2 ac-
quisition among heterosexual populations. However, there is
insufficient evidence that TDF/FTC use among those who are
not at risk of HIV acquisition will prevent HSV-2 infection, and
it should not be used for this sole purpose.
TFV gel may also be associated with decreased risk of HSV-2
acquisition when used pericoitally or daily. However, TFV gel is
not FDA-approved at this time. In addition, there is insufficient
evidence that TFV gel should be used among those who are not
at risk of HIV acquisition to prevent HSV-2 infection.
Key Question 3: What is the impact of taking TDF/FTC on
acquisition or reactivation of HSV-2 among individuals living
with HIV?
Oral TDF does not prevent HSV-2 acquisition among persons
with HIV infection who are taking TDF as part of the antiretro-
viral regimen [57]. In a subgroup analysis, there was a reduced risk
of HSV-2 seroconversion among those with a CD4 count <200
cells/µL (reduced seroincidence by 56% [95% CI, 7%–80%]) [57].
In an observational study of persons with HSV-2 and HIV
coinfection on antiretroviral therapy (ART), there was no dif-
ference in HSV-2 shedding rate between those using TDF-
containing regimens vs non-TDF-containing regimens [58].
Key Question 4: What is the role of medical male circumcision
(MMC) for prevention of genital HSV-2 infection in men and
women?
Among men, there are inconsistent results regarding the effi-
cacy of MMC to prevent HSV-2 acquisition. In one randomized
controlled trial (RCT) of MMC in heterosexual adult men in
Rakai, Uganda, HSV-2 acquisition was significantly decreased
among men who underwent MMC (hazard ratio [HR], 0.72
[95% CI, .56–.92]) [59]. Additionally, a single-site study in
South Africa found a 30% reduction in HSV-2 acquisition (95%
CI, 1%–51%) [60]. However, another single-site study in Kenya
with high HSV-2 incidence in both arms found no significant
difference in HSV-2 acquisition with 72 months of follow-up
(HR, 0.89 [95% CI, .73–1.09]) [61].
A systematic review of trials of MMC showed high consist-
ency for decreased risk of HSV-2 acquisition among women with
a male partner who underwent MMC in studies in Africa [62].
From review of these data, we conclude that MMC may be
associated with decreased risk of HSV-2 acquisition in adult,
heterosexual men and may be associated with a decreased risk
of HSV-2 transmission from men to women.
IV. HSV-2/HIV Interactions
Key Question 1: What are the appropriate agents and regimens
for treatment of HSV in persons with HIV infection?
No new data are available to change prior recommendations for
treatment of HSV in persons with HIV infection.
Key Question 2: What is the effect of antiretroviral initiation on
genital HSV-2 infection?
Several studies have explored the impact of ART initiation on
genital ulcer disease (GUD), which is a common manifestation
of immune reconstitution inflammatory syndrome reported in
several studies [63, 64].
In an observational study comparing persons with HIV in-
fection who were ART treated vs ART naive, there was no dif-
ference in HSV-2 shedding rate. The shedding rate in this study
was low [65].
Diagnosis and Management of Genital Herpes • CID 2022:74 (Suppl 2) • S139
In an RCT of acyclovir 400 mg BID vs placebo among women
in Uganda who started ART when CD4 count decreased to
250 cells/μL, GUD increased during the first 3 months after
initiating ART and returned to baseline at 6 months [66]. The
risk of GUD was significantly reduced on acyclovir (prevalence
risk ratio, 0.42 [95% CI, .23–.74]) [51]. Another study showed
that GUD incidence increased after starting ART and shedding
increased; GUD incidence was lowest in persons on acyclovir
[67].
Based on these data, suppressive acyclovir should be con-
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sidered for the first 6 months after starting ART among people
who are HSV-2 seropositive to reduce the risk of GUD, partic-
ularly among those with CD4 count <200 cells/μL, who are at
highest risk of HSV-2 reactivation. Although valacyclovir and
famciclovir have not been studied in this setting, given that
these medications effectively suppress HSV-2 among people
living with HIV, it may be reasonable to use these as well.
Key Question 3: Should antiviral therapy for HSV be admin-
istered to reduce the risk of HIV or HSV-2 transmission to sex
partners in serodiscordant partnerships or to reduce mother-to-
child transmission (MTCT) of HIV?
Well-conducted, large RCTs have shown that suppressive acy-
clovir (400 BID) does not reduce the risk of HIV or HSV-2
transmission among ART-naive persons with HIV/HSV-2
coinfection in heterosexual discordant partnerships [68].
A systematic review showed that HSV-2 infection is associ-
ated with increased risk of MTCT of HIV (odds ratio, 1.57 [95%
CI, 1.17–2.11]) [69]. Studies of valacyclovir suppression to pre-
vent MTCT of HIV infection to infants were conducted in the
era before universal ART for all women who are pregnant with
HIV was recommended [70], but similar trials have not been
conducted in the universal ART era.
Based on these data, suppressive antiherpesvirus therapy
is not recommended to prevent HIV or HSV-2 transmission
among sexual partners of people with HIV/HSV-2 coinfection.
There are insufficient data to assess whether suppressive anti-
viral therapy for HSV is beneficial for prevention of MTCT of
HIV in the ART era.
Key Question 4: What is the role of anti–HSV-2 suppressive
therapy in people living with HSV-2 and HIV to prevent HIV
progression?
With HIV Infection, Not on ART
Suppressive valacyclovir (1 g BID) is associated with slight de-
crease in plasma HIV viral load compared to suppressive acy-
clovir (400 BID) [71]. These data are no longer relevant as ART
is now recommended for all persons.
With HIV Infection, Receiving ART
Suppressive antiherpesvirus therapy (valacyclovir 1 g daily) was
not associated with changes in CD4 cell counts or plasma HIV
viral load in a placebo-controlled study [72].
 In another study, valacyclovir 500 mg BID was not associated
with changes in inflammatory and immune activation markers
among persons with HIV infection on ART [73].
Based on these data, there is no evidence that suppressive
antiherpesvirus therapy is effective for delay of HIV disease
progression or associated with decrease in HIV-related inflam-
mation in persons on ART.
V. Prevention of Neonatal Herpes
Key Question 1: Is there evidence for or against routine screening
of pregnant women with HSV type-specific serologies?
The American College of Obstetrics and Gynecology recom-
mends against routine screening for HSV serostatus during
pregnancy based on a lack of evidence for cost-effectiveness
[22]. It is recommended to screen pregnant women for a his-
tory of genital herpes. There are no new data to inform routine
screening of pregnant women for serologic evidence of HSV
infection.
Key Question 2: Should women with HSV-2 infection receive
suppressive therapy during pregnancy to reduce the risk of ce-
sarean deliveries, HSV shedding, or HSV transmission to the
infant?
Prior randomized clinical trials have demonstrated that women
with a history of genital herpes have decreased risk of viral
shedding, recurrences, and cesarean deliveries when suppres-
sive acyclovir (400  mg TID) or valacyclovir 500  mg BID is
given starting at 36 weeks’ gestational age [74, 75]. A trial of 200
HSV-2–seropositive, HIV-seronegative women in Uganda ran-
domized to receive acyclovir 400 mg BID or placebo starting at
28 weeks’ gestation showed decreased risk of preterm birth and
a trend toward decreased risk of premature rupture of mem-
branes at 36 weeks among the acyclovir group [76]. However,
additional data are needed to replicate this finding among a
larger sample size.
Key Question 3: Are there any new data on the safety of HSV
antivirals during pregnancy?
A case-control study from the National Birth Defects Prevention
Study showed a 4.7-fold increased odds (95% CI, 1.7–13.3)
for gastroschisis among women who used antiherpes medi-
cations between the month prior to conception and the third
month of pregnancy [77]. There was also an increased risk
for gastroschisis among women who were not using antiviral
therapy but had a self-reported history of genital herpes. In ad-
dition, there were significant demographic differences between
cases and controls, and possible recall bias. Acyclovir remains
category B.
Key Question 4: Are there strategies to prevent neonatal herpes
among women who acquire genital herpes during pregnancies
and are at highest risk to transmit?
Treatment with suppressive-dose acyclovir (400 TID) at week
36 has been shown to prevent HSV recurrences requiring ce-
sarean delivery at term [74, 78]; whether this approach reduces
S140 • CID 2022:74 (Suppl 2) • Johnston
the risk of neonatal HSV is unknown. Infants with neonatal
herpes born to women who received suppressive therapy at the
end of pregnancy have been reported [79]. Providers should
be aware that acquisition of genital herpes during pregnancy is
associated with the highest risk of transmission [80]. Invasive
procedures at the time of delivery should be avoided if possible
[22]. All women who have active genital lesions or prodrome at
delivery should have a cesarean delivery [22].
Key Question 5: Are there strategies to prevent, diagnose, or
treat HSV hepatitis in pregnancy?
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Hepatitis is a rare manifestation of disseminated HSV, thought
to be acquired through the genital tract, in pregnant women,
characterized by severe hepatitis and fulminant liver failure
with associated high mortality (25%) [81]. Women most fre-
quently present in the second and third trimester with fever and
hepatitis, with markedly elevated aminotransferases [81]. They
may not have any genital or skin lesions. A high index of sus-
picion for HSV is necessary, and the diagnosis is made by HSV
PCR from blood [82]. HSV should be ruled out in pregnant
women with fever and unexplained severe hepatitis. In a small
case series, no deaths were seen in women who were treated
with empiric IV acyclovir [81]. For women who are diagnosed
with HSV hepatitis, IV acyclovir 10 mg/kg every 8 hours should
be given until resolution.
CURRENT GUIDELINES FOR NEONATAL HERPES
Recommendations regarding treatment of neonatal herpes are
beyond the scope of these guidelines. Guidance on manage-
ment of neonatal herpes is detailed in the Red Book 2021 [83].
Algorithms for management, evaluation, and treatment of neo-
natal herpes are provided in the Red Book [83].
Counseling of Adults With Genital Herpes
Key Question 1: Are there evidence-based strategies for coun-
seling persons with newly diagnosed genital herpes?
There are no evidence-based strategies for counseling patients
with newly diagnosed genital herpes.
Key Question 2: What information should be included when
counseling patients with newly diagnosed genital herpes?
Women have been shown to use various coping strategies after
learning of diagnosis of HSV-2 infection [84]. These coping
strategies decreased over time, suggesting that women adjust to
the diagnosis.
While there are no data available to guide best counseling
practices, information regarding the natural history (symp-
toms, asymptomatic shedding and transmission), management
(suppressive and episodic therapy), prevention (suppressive
therapy, no sex with prodrome/symptoms, disclosure, male con-
doms, suppressive therapy), and risk of genital herpes acquisi-
tion should be discussed. Information regarding asymptomatic
HSV-2 infection should also be included. A comprehensive
online genital herpes counseling tool has been developed by the
Government of Canada [85].
How Do Counseling Messages Differ for Those With Genital HSV-1 vs
HSV-2 Infection?
Genital HSV-1 infection is associated with less shedding and fewer
recurrences compared to HSV-2 [86]. Therefore, although trans-
mission to sexual partners is possible, it is less likely than HSV-2
because of decreased risk of shedding, particularly more than a
year after infection [87]. Episodic therapy is recommended for
recurrences. The risk-benefit ratio of suppressive therapy is un-
known because there are fewer recurrences in genital HSV-1 infec-
tion. Suppressive therapy for genital HSV-1 infection has not been
shown to reduce the risk of HSV-1 transmission to sexual partners.
CONCLUSIONS
Genital herpes remains an important STI given the high preva-
lence of HSV-2, the increasing proportion of cases due to HSV-1,
and morbidity associated with recurrences of GUD. HSV-2 has a
key role in fueling the HIV epidemic and, although rare, HSV-1
and HSV-2 are associated with devastating outcomes when ac-
quired during pregnancy, both among women and neonates.
Review of the literature for the 2021 CDC STI treatment guide-
lines has revealed few substantive advances for the management
of genital herpes infections. Greater availability of nucleic acid
amplification tests to diagnose HSV in the setting of genital ulcers
will improve diagnosis in the acute setting, but serologic assays
lack diagnostic accuracy and advances in the diagnostic algorithm
as well as new diagnostic tools are needed. While symptoms of
genital herpes can be managed and transmission to sexual part-
ners prevented with antiviral therapy, novel therapies with new
mechanisms of action will improve our ability to care for patients.
Given that genital herpes affects a substantial proportion of adults,
ongoing research to advance the field is urgently needed.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online.
Consisting of data provided by the authors to benefit the reader, the posted
materials are not copyedited and are the sole responsibility of the authors,
so questions or comments should be addressed to the corresponding author.
Notes
Acknowledgments. The following experts are thanked for their advice
and input:
Charles Ebel, Carolyn Gardella, Darrell Tan, Barbara Van Der Pol,
Nicholas Van Wagoner, Anna Wald.
Supplement sponsorship. This supplement is sponsored by The Centers
for Disease Control and Prevention.
Potential conflicts of interest. The author receives royalties from
UpToDate; has been a consultant for AbbVie and Gilead; has received funds
from MedPace for serving on a data and safety monitoring board; and
has received grants from the National Institutes of Health, the Centers for
Disease Control and Prevention, and the Bill & Melinda Gates Foundation.
The author has submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the con-
tent of the manuscript have been disclosed.
Diagnosis and Management of Genital Herpes • CID 2022:74 (Suppl 2) • S141
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