05 - Genital herpes

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Genital herpes
Raj Patel
Abstract
Human a-herpesvirus infections are characterized by initial primary infec-
from females to males.
� The impact of previous infection with the other viral type
on susceptibility in a partner has not been clearly estab-
lished. However, subsequent infections tend to be milder.
The risk of infection remains high, and the overall average
annual risk of acquisition of the disease is about 10% per
year of exposure, regardless of previous HSV infection.
� It is generally believed that there is little risk of re-infection
when the partner has already been infected with the same
viral type. Laboratory studies show that immunity to
subsequent re-infection is greatest at the site of initial
infection but can be overcome.
Raj Patel FRCP is a Consultant in the Department of Genitourinary
VIRAL INFECTIONS
Medicine at the Royal South Hants Hospital, Southampton, UK.
Competing interests: has been involved in speaker panels for GSK,
Novartis, Roche, Beckton Dickenson and advisory boards for GSK,
Novartis, and Astellas.
tions of variable severity followed by a period of neuronal latency that is
interrupted by reactivation. Both the acquisition illness and the recurrent
disease may become complicated. Although many individuals with genital
herpes are relatively problem free, herpes simplex virus (HSV) infections
can cause a wide range of problems. Troublesome symptoms can be
managed effectively with antiviral therapy. For those individuals with rela-
tively well-defined tolerable prodromes or occasional recurrences, and
who do not have complicated disease, episodic therapy offers a useful
alternative to continuous suppressive treatment. It was recently demon-
strated that short courses of therapy with valaciclovir, aciclovir or high-
dose famciclovir are as effective as longer courses of episodic therapy.
However, for many patients, suppressive therapy remains the most effec-
tive means of managing their problems. Not only will continuous therapy
control lesions and prodromal symptoms, it can also be highly effective at
managing psychosexual problems and transmission risk. The manage-
ment of HSV infection in pregnancy can be challenging. Third-trimester
new infections are extremely hazardous and clear guidelines on planned
caesarean section should be followed. The management of women with
recurrent disease is more controversial. Recurrences at term are associ-
ated with neonatal disease (up to 3% transmission) and can result in sub-
stantial anxiety. HSV infections remain an extremely active area of
research. New work shows the important role of genetic predisposition
in determining the occurrence of severe neurological dissemination and
the possibility of targeting new sites within the genome to effect better
treatment.
Keywords Antivirals; herpes simplex; HIV; HSV-1; HSV-2; transmission
Genital herpes simplex virus (HSV) is the most common cause of
genital ulceration, with local, systemic and psychosexual com-
plications. It is an important cause of neonatal morbidity and a
co-factor for HIV transmission, particularly in developing
countries.
The herpes viruses cause latent and recurrent infections in
humans and animals. They comprise three subfamilies (alpha,
beta and gamma). HSV is a human a-herpesvirus, with two
forms (HSV-1 and HSV-2) that are morphologically identical,
though their DNA is only 50% homologous. All a-herpes viruses
are able to establish latency and rely to some extent on inter-
mittent reactivation for survival and transmission. Following
initial infection, replication of HSV at the portal of entry results in
infection of sensory nerve endings. Viral nucleocapsids are then
transported by retrograde axonal flow to the neuronal cell nuclei
in sensory ganglia, where latency is established. In cells outside
MEDICINE 42:7 354
the sensory nervous system, a-herpesvirus infection does not
achieve latency, because viral replication leads eventually to cell
death through lysis.
Epidemiology and transmission
Sero-epidemiological studies suggest that the prevalence of HSV
infection worldwide is highly variable (Figure 1). Serial popula-
tion level studies in North America indicate that recent rises in
HSV-2 infection in the developed world may now have plateaued
in most of the heterosexual population. Levels of reported new
diagnoses in the UK have been relatively stable during 2010
e2012. Infection is widely distributed in the general population
and varies in severity. In many developing countries, HSV-1
infection is now the principal cause of first-episode genital
infection in most women and young men. Studies have shown
that less than 30% of those who are HSV-2 sero-positive are
aware of their genital herpes and 20% have no symptoms.
Although initial infections with HSV-1 and HSV-2 are indistin-
guishable, HSV-2 disease is more likely to be recurrent and
troublesome following genital infection (conversely, HSV-1
oropharyngeal infection is likely to recur most frequently).
Transmission occurs through genital-to-genital and orogenital
contact. It is most likely when there are visible lesions, but most
transmissions occur in the absence of local symptoms in the source
partner. Infectivity is also increased during the prodrome and
immediately after lesion healing. However, viral shedding from
genital surfaces has been shown to occur on an average of 2% of
days in the absence of symptoms or visible lesions. Such shedding
is considerably greater following initial infection, is related to
disease activity, is limited by an intact cell-mediated response to
HSV infection and is an important source of transmission.
Condoms give some protection,1 but do not cover the entire
genital area, and few couples are able to use them consistently.
Several factors affect transmission.
� Infection is more easily passed from males to females than
What’s new?
C HSV-1 is the principal cause of genital herpes although severe
frequent recurrent GH is still more commonly due to HSV-2
C Genital HSV infections increase the risk of HIV acquisition and
transmission e these effects cannot be modified by HSV-
suppressive therapy
C Episodic therapies for HSV are effective when given at high
doses for 1e3 days
� 2014 Published by Elsevier Ltd.
The populations studied included blood donors, partners of pregnant women in obstetric clinics and men in a fertility clinic
Seroprevalence of herpes simplex virus type 2
1980s
Blacks
50.2–
53.4%
1980s
Whites
25.3–
34.9%
USA
Iceland Sweden
1985
1979
Spain
France
Japan
DR Congo
Rwanda
Australia
Taiwan
General population1
Pregnant women
4.1% 23.4%
1983–1986
27.9%
1976–
1980
16.4%
1989–
1991
21.7%
1992
31%
1985–
1986
1985–
1986
9.7%7.4%
1984
15.9% 10.7%
1977–
1978
1985
17.3%
1988
6.7%
UK
1992
7.6%
1985
40.8%
1985
33.3%
1984–
1985
14.1%
1986–
1987
13.5%
Figure 1 Source: International Herpes Management Forum Slide Lecture Kit, PPS Europe Ltd
Herpes simplex virus type 2 and HIV seroprevalence in high-risk populations
Adult prevalence
 15–36%
 5–15%
 1–5%
 0.5–1%
 0.1–0.5%
 0–0.1%
 Not available
M 46%
F 64%
F 29.3%
39%
HIV 83%
75%
72%
M 14%
F 26%
32.3%
22.7%
55%
HIV MSM 23%
61%
42.9%
M 60%
75%
F 59%
F 76%
23%
M 35%
F 55%
25.7%
Figure 2
VIRAL INFECTIONS
MEDICINE 42:7 355 � 2014 Published by Elsevier Ltd.
Strong epidemiological data implicate HSV infection in either
partner as facilitating both transmission and acquisition of HIV.
Background prevalence of HIV worldwide varies proportionally
with HSV-2 prevalence (Figure2). It is estimated that HSV ac-
counts for 30% of cases of HIV and that the presence of genital
HSV doubles the risk of HIV acquisition (this risk is substantially
higher after first acquisition and appears to decline with time).2
Although these risks have been demonstrated consistently, in-
terventions using currently available antivirals to limit HSV
reactivation have not been shown to have an impact on either
HIV acquisition or transmission.3 These considerations, as well
as the partial impact of current antivirals on HSV transmission
itself, have stimulated renewed interest in the development of
newer antivirals. Currently, helicase primase inhibitors show the
most promise.
Clinical features
Primary genital infection
The incubation period is 2e14 days and the average untreated
episode lasts 22e28 days. The presence of pre-existing antibodies
to a different HSV type is associated with a milder initial infec-
tion. Primary genital herpes is usually severe. Initially,
erythematous papules form in which the characteristic herpetic
vesicles erupt (Figure 3). By the time of clinical presentation, the
primary HSV have symptoms suggesting meningeal irritation,
though few require hospitalization. The condition is usually
short-lived and self-limiting, and there is only a slight increase in
protein and lymphocytes in the CSF.
Autonomic nervous system dysfunction is a rare complication
that results in difficulties with urination, constipation, and
altered sensation in the perineal, sacral and lower back areas.
Transverse myelitis is another rare complication in which the
signs of autonomic involvement are coupled with absent deep
tendon reflexes and reduced strength in the legs.
HSV is one of the most common causes of erythema multi-
forme. Chronic, relapsing formsmay occur with recurrent attacks.
Recurrent episodes are usuallymilder and of shorter duration (up
to 8e12 days). Women are affected more severely than men. Le-
sions appear in localized sites and are usually unilateral; they
comprise only a few vesicles. Inguinal lymphadenopathy occurs in
only 25%of patients and is usually confined to the side affected by
the lesions. Dysuria is uncommon in recurrent episodes.
Many patients link the development of a recurrence to specific
triggers such as local trauma, menstruation or ultraviolet radiation.
About 50%ofpatients develop symptoms in theprodromal phase of
the illness. These vary from mild tingling sensations in the areas
affected by the eruption, to severe, shooting pains in the thigh,
buttocks or groin. In many patients, these symptoms of sacral
neuralgia are the most distressing features of the recurrence. Other
VIRAL INFECTIONS
Figure 3 Herpetic vesicles in a man with genital herpes.
vesicles have usually ruptured, and the resulting ulceration is the
dominant feature (Figure 4). The ulcers are typically superficial,
with an erythematous outline and a greyish base, and are
intensely painful. There is often severe dysuria. Lesions tend to
be bilateral, and painful, tender inguinal lymphadenopathy is
present. Symptoms tend to be more severe in women and ho-
mosexual men, in whom larger areas of epithelium are often
involved. The most common systemic symptoms are headache
and myalgia. Women are often tearful and miserable.
MEDICINE 42:7 356
Local complications, particularly fungal and bacterial super-
infection, are common. Even without neurological complications,
severe external dysuria can lead to urinary retention. Extensive
ulceration occasionally causes labial and vaginal adhesions. Un-
circumcised men may develop phimosis and paraphimosis.
Up to 10% of patients develop lesions in distant sites,
particularly the pharynx. Up to one-third of those with severe
Figure 4 Primary genital herpes in a woman.
� 2014 Published by Elsevier Ltd.
sorbent assay systems) have become widely available. These do
Management
Primary (first-episode) genital herpes
Nucleoside analogues (e.g. aciclovir, valaciclovir, famciclovir)
are effective in the treatment of primary genital herpes. Oral
antiviral treatment should be initiated on clinical suspicion.
Aciclovir, 200 mg five times daily, or 400 mg three times a day
for 5 days, is usually adequate. The dosing frequency can be
reduced if valaciclovir, 500 mg twice daily, or famciclovir, 250
mg three times daily, is used. The cost of these agents varies
considerably.5
Antiviral therapy is worthwhile when initiated up to 6 days
into an episode or when vesicles are still present. If new lesions
continue to develop, or if complications or severe systemic
symptoms are present, treatment should be continued beyond 5
days.
Symptomatic treatment with analgesics, saline bathing (one
teaspoon of salt per mug of water) and ice packs is usually
helpful. Patients should be warned that they will feel ill for a few
days, and advised to rest and take time off work. Complications
(particularly urinary retention associated with severe dysuria)
should be anticipated; patients can manage this symptom by
applying topical anaesthetic gels and by passing urine in the
bath. Counselling over an extended period of time may be
required. Patients must be aware of the likelihood of recurrence
and the possibility of disease transmission.
Recurrent genital herpes
VIRAL INFECTIONS
not require specialist transport media and give rapid results.
However, they are usually poorly sensitive and acceptable only
for assessing typical lesions.
Type-specific serology is now widely available, but its place in
clinical practice remains to be established. It can be used to identify
serologically discordant couples in high-risk situations (e.g. late
pregnancy) and would be a prerequisite for use of a prophylactic
vaccine. Serological determination may also be helpful in
excluding HSV when atypical genital symptoms are present.
Serology often detects isolatedHSV-1 antibodies (present in>50%
of the older population), in which case it is of little help in
excluding or establishing genital infection. IgM to HSV can be
detected but is often elevated in recurrences, so that testing for it is
rarely helpful in establishing the timeline of infection.5 Mixed in-
fections with other genital pathogens are common, and screening
for other STIs is essential in primary cases.
prodromal symptoms include malaise, fever, and hyperaesthesia at
the site where the lesions subsequently occur.
Many patients suffer ‘atypical’ recurrent episodes in which
vesicles and ulcers do not occur and various epithelial abnor-
malities may be seen, including fissuring, furuncles, excoriations
and non-specific erythema. Isolated neurological symptoms can
also occur.
The severity and frequency of recurrent episodes vary widely
between patients and may vary in an individual over time.
Genital recurrences are the most common in those infected with
HSV-2, particularly in the months immediately after the initial
infection.4 On average, patients experience fewer than four re-
currences per year, but many suffer 12 or more episodes per year.
Fear of transmitting the disease and the severity of the
recurrent illness can cause psychosexual morbidity. Cystitis is an
occasional sequel.
Diagnosis
Diagnosis of genital herpes is mainly clinical, but should be
confirmed by a laboratory method. Real-time polymerase chain
reaction (PCR) testing is now widely available and has become
the diagnostic method of choice.5 PCR has been shown to be
more sensitive than culture for all stages of HSV infection, for
early and late presentations, and provides a rapid turnaround of
specimens often within hours. PCR also allows viral typing and
in specialist hands can be used quantitativelyto assess levels of
viral shedding. Commercial platforms using a variety of nucleic
acid amplification methods have now been licensed.
Viral culture is occasionally still required. It is particularly
valuable when looking at persistent or atypical lesions in the
immunocompromised patient when viral types resistant to some
antivirals may be present. HSV grows in various cell systems,
and tissue culture is a relatively simple technique. The best re-
sults are obtained with vesicle fluid, but about 25% of swabs
taken from healing scabbed lesions are culture-positive. Cyto-
pathic effects in the culture media usually appear within 2e5
days, but occasionally results are not available for 2e3 weeks.
Viral culture followed by immunohistochemical staining allows
HSV-typing of isolates.
Several antigen detection systems using monoclonal anti-
bodies (with immunofluorescence and enzyme-linked immuno-
MEDICINE 42:7 357
Figure 5
Management of patients with recurrent episodes of 
genital herpes
Higher-frequency 
recurrences (4–6 episodes 
per year) or psychosexual 
disturbance
• Consider for psychosexual 
 support
• Consider suppressive 
 aciclovir therapy (aciclovir, 
 400 mg twice daily or 
 200 mg four times daily)
• Fix a review date
Stop treatment and 
review annually
Offer symptomatic treatment
• Saline baths
• Analgesics
• Patient-initiated episodic 
 antiviral therapy (e.g.
 aciclovir, 200 mg five times 
 daily for 5/7, or 800 mg 
 three times daily for 2 days, 
 famciclovir 1 g twice daily 
 for 1 day or valaciclovir, 
 500 mg twice daily for 
 3 days, with each episode)
Review annually
Low frequency or 
mild disease
Counselling and assessment
Mild or infrequent attacks require only symptomatic therapy.
Severe, complicated or frequent recurrences (often defined as six
or more per year) may be managed with antiviral treatment
(Figure 5).
� 2014 Published by Elsevier Ltd.
Short courses of antiviral treatment initiated early in an
episode (episodic therapy) reduce the duration and severity of
the recurrence. The patient should be given a small supply of the
drug to initiate treatment at the first sign of recurrence, if possible
during the prodrome. Recent studies have shown that the bene-
fits of episodic therapy are present mainly when treatment is
taken within the first 24e48 hours of the evolution of an episode,
and that there is little benefit in extending therapy beyond 3
days.6 High-dose therapy with specific antivirals over 1e3 days
has been shown to be as effective as standard 5-day courses of
treatment.
Daily aciclovir is effective in controlling recurrent disease, but
many patients experience occasional breakthrough episodes
while taking treatment. If suppression is initiated special moni-
toring is not required, except in those with advanced renal dis-
ease.5 However, the patient’s need for continued therapy should
be reassessed regularly. Suppressive therapy can be used to
manage many of the complications of genital infection, including
psychosexual problems, transmission anxiety, and medical
problems such as recurrent meningitis and erythema multiforme.
HSV
recurrence.10 Decisions around delivery should be made with the
mother. Several novel HSV vaccines are under development.
Therapeutic and prophylactic HSV glycoprotein subunit vaccines
have been shown to affect recurrence and the severity of disease,
but are not yet commercially available. A
REFERENCES
1 Martin ET, Krantz E, Gottlieb SL, et al. A pooled analysis of the effect
of condoms in preventing HSV-2 acquisition. Arch Intern Med 2009;
169: 1233e40.
2 Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ.
Herpes simplex virus 2 infection increases HIV acquisition in men and
women: systematic review and meta-analysis of longitudinal studies.
AIDS 2006; 20: 73e83.
3 Celum C, Wald A, Hughes J, et al; HPTN 039 Protocol Team. Effect of
aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive
women and men who have sex with men: a randomised, doubleblind,
placebo-controlled trial. Lancet 2008; 371: 2109e19.
4 Benedetti J, Corey L, Ashley R. Recurrence rates in genital herpes
after symptomatic first-episode infection. Ann Intern Med 1994; 121:
VIRAL INFECTIONS
livery e even in the presence of a suspected genital
Reducing transmission
Transmission of infection remains a major source of anxiety in
many patients with HSV infection.7 There is strong evidence to
show that condoms used consistently protect both men and
women from infection,1 and that continuous suppressive therapy
with some antivirals reduces the risk of transmission by 50%.8
The risk may be further reduced by educating patients to
recognize the disease (and thereby avoid sex) and encouraging
them to disclose their diagnosis (allowing both partners to
maintain vigilance).9 Mother-to-baby transmissions are rare but,
because of the serious consequences of neonatal disease, expert
advice should be sought in relation to all third-trimester acqui-
sitions to reduce transmission risk at delivery (which in these
cases may need to be by caesarean section).10 The risk of
recurrent infections at term is small and many guidelines now
emphasize the relative safety of a conservative approach to de-
MEDICINE 42:7 358
847e54.
5 British Association for Sexual Health and HIV. UK management
guidelines for genital herpes infections. Sex Transm Infect 1999;
75(suppl 1). Updated in 2014 at: http://www.bashh.org/.
6 Patel R. Making the most of episodic antiviral therapy for genital
herpes. Sex Health 2008; 5: 213e4.
7 Patel R, Cowan F, Barton SE. Advising patients with genital herpes.
BMJ 1997; 314: 85e6.
8 Corey L, Wald A, Patel R, et al. Valacyclovir HSV Transmission Study
Group. Once-daily valacyclovir to reduce the risk of transmission of
genital herpes. N Engl J Med 2004; 350: 11e20.
9 Patel R. Educational interventions and the prevention of herpes
simplex virus transmission. Herpes 2004; 11(suppl 3): 155Ae60.
10 Royal College of Obstetricians and Gynaecologists. Management of
genital herpes in pregnancy e green-top guideline no. 30. Available
at: www.blackwellpublishing.com/guidelines/ACYCLOVIR-RCOG_
Green_Top30-genital_herpes.pdf (accessed 24 Feb 2010).
� 2014 Published by Elsevier Ltd.
	Genital herpes
	Epidemiology and transmission
	Clinical features
	Primary genital infection
	Diagnosis
	Management
	Primary (first-episode) genital herpes
	Recurrent genital herpes
	Reducing transmission
	References