<title>1. INTRODUCTION</title> <p>Herpes simplex virus type 2 (HSV-2) is one of the most
prevalent sexually transmitted infections worldwide [##REF##12353183##1##]. HSV-2 is extremely
common in countries where HIV is endemic, and coinfects over 75% of
HIV-infected individuals living in or originating from these countries, but the
HSV-2 seroprevalence is also over 50% in HIV-infected individuals from the
developed world [##UREF##0##2##, ##UREF##1##3##]. Atypical or
unusual manifestations of genital herpes are not uncommon in HIV-coinfected
individuals, and persistent anogenital lesions due to HSV-2 were among the
first opportunistic infections described in those with the acquired
immunodeficiency syndrome (AIDS) [##REF##6272110##4##]. Opportunistic infections may transiently
worsen during the period of immune reconstitution following the initiation of
highly active antiretroviral therapy (HAART), a phenomenon known as immune
reconstitution inflammatory syndrome (IRIS), with HSV-2 reactivation accounting
for up to half of IRIS cases [##REF##16392092##5##]. However, the median time from initiating
HAART to developing IRIS is three months, and IRIS is rare once stable immune
reconstitution has been achieved [##REF##16392092##5##]. Antiviral-resistant
HSV is uncommon, although more frequently encountered among immunocompromised
individuals compared to immunocompetent persons [##REF##15494896##6##].</p> <p>Hypertrophic anogenital lesions are a rare complication of
HSV-2 in HIV-coinfected men and women [##REF##12890233##7##–##REF##12852374##10##], generally occurring in the
context of significant immune deficiency or during IRIS [##REF##11737324##11##], and these lesions
may be very difficult to diagnose and treat. We present the case of a 35
year-old, HIV-infected woman with a recalcitrant hypertrophic vulvar lesion due
to HSV-2. The development and prolonged persistence of this lesion after
near-complete immune reconstitution on HAART implies that there are significant
residual defects in host HSV-2 immune control, and that these may have
important clinical implications for patients and their care providers.</p>
<title>3. DISCUSSION</title> <p>We have presented a case of an African
female patient with recalcitrant hypertrophic genital HSV-2, which was
clinically resistant to standard antiviral therapy and to intravenous
foscarnet, but which responded promptly to topical 5% imiquimod. An initial
“typical” genital herpes outbreak occurred in the context of rapid immune
recovery, and was quite compatible with IRIS, as has been described in Ugandan
men starting therapy [##REF##11737324##11##]. However,
while this outbreak responded to standard herpes therapy, the hypertrophic
genital HSV-2 lesion developed and persisted despite near-complete immune
recovery for up to three years. The rapid clinical response that was seen to
topical imiquimod, an agonist of Toll-like receptor 7 (TLR7) that boosts both
host innate and adaptive antiviral immunity [##REF##12734440##12##], strongly implies that there
were clinically significant defects in host antiherpes immunity despite
HAART-induced immune recovery.</p> <p>Hypertrophic or squamoproliferative
anogenital lesions in HIV-positive individuals or those with AIDS are uncommon
and can pose a diagnostic dilemma. The
most likely cause of such lesions is either neoplasia or infection, although
the differential diagnosis can be wide [##REF##10701208##13##]. 
It may be difficult to determine the cause of a lesion based on
appearance alone, and the sensitivity of various diagnostic tests can be
affected by the reactive changes present in these lesions [##REF##12852374##10##]. Further, small biopsies may be inconclusive
or provide misleading information [##REF##11827427##8##]. 
It may be necessary to employ repeat biopsies and viral cultures in
cases suspicious for HSV. In our
patient, the first biopsy of the lesion in 2003 was positive for HSV-2, but a
second biopsy performed after the lesion had recurred in 2006 was negative for
HSV-1, HSV-2, cytomegalovirus (CMV), and spirochetes using immunohistochemical
special stains, showing only chronic granulation tissue present. This reinforces that it may be difficult to
demonstrate virus even in a generous biopsy specimen, especially in the
presence of chronic, extensive granulation tissue. Because this second biopsy was negative for
HSV, it is possible that
HSV reactivation occurred within this
proliferative mass, rather than causing it.
However, it is more likely that HSV was in fact the etiologic agent
responsible for the progression.</p> <p>The pathogenesis of proliferative
and hypertrophic HSV lesions in the immunocompromised patient population is
poorly understood. It is thought to be a
reflection of the increased duration of the disease course rather than any
inherent change in the pathogenicity of the HSV-2 itself [##REF##9366853##14##]. Early reports hypothesized that immune
dysfunction secondary to HIV, perhaps mediated by T-helper type 2 cytokines,
might result in the epidermal hyperplasia [##REF##8733396##15##]. 
Whatever the etiology of these lesions, their presence has been linked
to immune function. In HIV-infected
individuals, HSV-2 infection is associated with an increased number and size of
genital lesions relative to immunocompetent individuals [##REF##6328055##16##]. Vesicles and ulcers are typically more
necrotic, painful, and heal more slowly [##REF##3006227##17##]. 
Finally, as CD4 cell count drops and immune status worsens, recurrent
outbreaks increase in frequency and severity [##REF##1361745##18##].</p> <p>Underlying the increased severity of
HSV-2 disease in HIV-coinfected patients are defects in herpes-specific
immunity. In a recent report of herpes simplex vegetans in an HIV-infected
individual with severe CD4+ T cell depletion [##REF##17205432##19##], a specific defect was
demonstrated in the production of type I interferons by plasmacytoid dendritic
cells in response to HSV. Dendritic cells within the epithelium of the genital
tract itself are important in mediating protective immunity against HSV [##REF##12538655##20##],
but these cells are dramatically depleted in the genital mucosa of HIV-infected
individuals [##REF##17314521##21##]. Finally, HIV infection
may be associated with impaired HSV-2-specific CD8+ T cell responses, although
these defects improve progressively after starting HAART [##REF##17205480##22##]. In contrast, our patient had a normal CD4
count, an undetectable viral load, and had been on HAART for six months prior
to the development of her lesions. The pathogenesis of progressive hypertrophic
HSV-2 in this context, where such immune defects would be expected to
have improved substantially, is not clear, although a similar case has been
reported of a rapidly growing and recurrent genital mass in an HIV-infected
woman on HAART with a CD4 T cell count &gt;500/mm<sup>3</sup> [##REF##12890233##7##].</p> <p>Immunocompromised individuals are more
likely to be infected with HSV-2 that is resistant to antiviral medications 
[##REF##15494896##6##]. Resistance to acyclovir is usually associated with resistance to the other
nucleoside analog drugs, including famciclovir and valacyclovir [##REF##12428850##9##]. In such
cases, foscarnet or topical cidofovir may be useful, since they have different
mechanisms of action [##REF##16898926##23##]. Unfortunately, antiviral resistance testing was not
available for our patient, although the prompt response of her “classical”
ulcerative genital herpes outbreak to both acyclovir and valacyclovir, with
rapid recurrence when suppressive treatment was stopped, suggested drug
sensitivity. However, the hypertrophic lesion was clinically resistant to
multiple courses of famciclovir and valacyclovir, as well as to later courses
of intravenous foscarnet. Ultimately, there was a rapid and complete response
to topical 5% imiquimod cream. Others have reported varied success with the use
of imiquimod for HSV-2 therapy [##REF##17205432##19##, ##REF##12410731##24##], and this drug should be considered in
the armamentarium for resistant and recurrent genital HSV-2 in HIV-infected
individuals. Thalidomide has also been described as useful in HIV-positive
patients with hypertrophic lesions, although this drug was not used in our case 
[##REF##17479932##25##].</p> <p>While uncommon, hypertrophic or
squamoproliferative HSV disease in the HIV-positive population can be a very
challenging clinical condition. It is painful, disfiguring, and difficult to
diagnose and treat. As demonstrated by our patient, it can be seen in
individuals anywhere along the spectrum of immune dysfunction. If clinically
suspected, repeated attempts at diagnosis with viral cultures and biopsies are
warranted. These lesions are often resistant to first-line antiviral treatment,
and may require less commonly used therapies such as foscarnet, cidofovir,
imiquimod, or thalidomide. In our case, imiquimod eventually resulted in a good
clinical outcome.</p>
<p>Recommended by Susan Cu-Uvin</p> <p>Most HIV-infected individuals are coinfected by <italic>Herpes simplex virus</italic> type 2 (HSV-2). HSV-2 reactivates more frequently in HIV-coinfected individuals with advanced immunosuppression, and may have very unusual clinical presentations, including hypertrophic genital lesions. We report the case of a progressive, hypertrophic HSV-2 lesion in an HIV-coinfected woman, despite near-complete immune restoration on antiretroviral therapy for up to three years. In this case, there was prompt response to topical imiquimod. The immunopathogenesis and clinical presentation of HSV-2 disease in HIV-coinfected individuals are reviewed, with a focus on potential mechanisms for persistent disease despite apparent immune reconstitution. HIV-infected individuals and their care providers should be aware that HSV-2 may cause atypical disease even in the context of near-comlpete immune reconstitution on HAART.</p>
<title>2. CASE REPORT</title> <p>The patient was a 34-year old,
asymptomatic Zimbabwe-born woman with a positive HIV IgG ELISA on immigration
screening in 2002. There was no prior history of sexually transmitted
infections, genital or perianal ulceration, and syphilis serology was negative.
Her absolute CD4+ T cell count at diagnosis was 156/mm<sup>3</sup>, with an
HIV-1 RNA plasma viral load of more than 100 000 copies/mL. Antiretroviral
therapy was initiated one month later, in October 2002, with combivir one
tablet twice daily and nevirapine 200 mg twice daily, together with
trimethoprim/sulfamethoxazole as primary prophylaxis against <italic>P. jiroveci</italic> pneumonia. By January 2003,
her CD4+ T cell count had increased to almost 500/mm<sup>3</sup>, and her HIV
viral load remained persistently undetectable after March 2003, at which point
trimethoprim/sulfamethoxazole was discontinued. In April 2003, she noted
multiple painful papules on the left labia, with subsequent superficial
ulceration. She had no reported sexual contacts for over a year. Her family
physician prescribed empiric therapy with acyclovir 400 mg three times daily
and keflex 500 mg three times daily, followed by oral valacyclovir 500 mg twice
daily.</p> <p>In July 2003, nine months after starting
HAART, the shallow ulcerations had resolved but a pruritic 1 × 3 cm granulomatous
lesion developed on the left labia. This was associated with surrounding tissue
edema, and shotty left inguinal lymphadenopathy, and progressed over the
subsequent two months (##FIG##0##Figure 1(a)##). There was no response to azithromycin
1 gram weekly for 4 weeks, as empiric therapy for granuloma inguinale. Both a
superficial swab and a punch biopsy of the hypertrophic lesion demonstrated
HSV-2, with glassy nuclear chromatin, multinucleation and surrounding severe
acute and chronic inflammation (##FIG##0##Figure 1(b)##). Topical therapy was initiated with
trifluridine, together with oral valacyclovir 1 gram twice daily. There was no
clinical response, although valacyclovir discontinuation was followed by an
outbreak of painful, scattered shallow ulcerations that were culture positive
for HSV-2. From November 2003 and December 2005 she was treated with 4 one-month
courses of intravenous foscarnet; despite a near total clinical response to the
first course, the response waned progressively and the fourth course was
complicated by <italic>Staphylococcus aureus</italic> cellulitis
at the line site. Lesion cultures were repeatedly positive for HSV-2, and a
repeat labial biopsy in February 2006 showed only chronic granulation tissue.
There was no response to a trial of topical protopic (tacrolimus) in August
2006.</p> <p>In September 2006 there was a prompt
clinical response to topical imiquimod 5%, applied 3 times weekly, with
resolution of the lesion within eight weeks. She remains asymptomatic on
oral valacyclovir 1 gram twice daily combined with topical imiquimod 5% as
needed (approximately one topical application every two weeks) with minor
residual labial scarring.</p>
<title>ACKNOWLEDGMENTS</title> <p>This paper was supported by the Canadian Institutes of Health Research (RK, Grant
HOP-75350) and the Canadian Research Chair Programme (RK, salary support). The authors 
report no conflicts of interest.</p>
<fig id="fig1" position="float"><label>Figure 1</label><caption><p>Clinical and microscopic appearance of hypertrophic HSV-2
lesion.</p></caption></fig>
<graphic xlink:href="IDOG2008-592532.001"/>
[{"label": ["2"], "surname": ["Weiss"], "given-names": ["H"], "article-title": ["Epidemiology of Herpes simplex virus type 2 infection in the developing world"], "italic": ["Herpes"], "year": ["2004"], "volume": ["11"], "issue": ["supplement 1"], "fpage": ["24A"], "lpage": ["35A"]}, {"label": ["3"], "surname": ["Romanowski", "Myziuk", "Trottier"], "given-names": ["B", "L", "S"], "article-title": ["Seroprevalence of Herpes simplex virus in patients infected with HIV in Canada"], "conf-name": ["In: Proceedings of the 17th International Society for Sexually Transmitted Diseases Research"], "conf-date": ["July-August 2007"], "conf-loc": ["Seattle, Wash, USA"], "comment": ["abstract P243"]}]
Infect Dis Obstet Gynecol. 2008 Sep 4; 2008:592532