Bioscientia Medicina: Journal of Biomedicine & Translational Research eISSN (Online): 2598-0580 Genital Herpes in Human Immunodeficiency Virus Infected Patients Stella Sunur1*, Izazi Hari Purwoko 1, Yulia Farida Yahya 1, Raden Pamudji1 1 Department of Dermatology and Venereology, Faculty of Medicine, Universitas Sriwijaya/ Dr. Mohammad Hoesin Palembang, Indonesia A R T I C L E Keywords: genital herpes IN F O A B S T R A C T Genital herpes is a recurrent, lifelong sexual transmitted infection caused Human immunodeficiency virus HIV by HSV, especially type 2. Genital herpes is the most common infection in HIV patient. HSV-2 can increase the risk of HIV acquisition 2 to 3 times. HSV-2 Clinical manifestations of genital herpes can be different between HIV *Corresp ondi ng author: infected and non-HIV patients. HIV-infected patients have a high risk of developing chronic and severe genital ulcers with atypical manifestation, Stella Sunur prolonged healing, and resistant to treatment, depends on CD4 count. E-mail address: Genital herpes can be diagnosed based on history, clinical manifestation, stella.sunur@gmail.com All authors have approved the final manuscript. reviewed an d version of th e laboratory and histopathologic examination. Management of genital herpes includes education and counseling patients and sexual partners, systemic antiviral, and symptomatic treatment. https://doi.org/10.32539/bsm.v5i8.342 Introduction Virus (HIV).2 The incidence of genital herpes cannot be Genital herpes is a sexually transmitted infection reported with certainty, but an estimated 500,000 new caused by Herpes Simplex Virus (HSV), recurrent and cases occur each year. According to the World Health lifelong.1 There are 2 types of HSV, HSV-1 and HSV-2. Organization (WHO), an estimated 491 million people Generally, HSV-1 causes the majority of cases of aged 15-49 years (13%) worldwide were infected with orolabial herpes, while HSV-2 is associated with most HSV-2 in 2016 and it tends to increase. The highest cases of genital herpes. However, both can infect the prevalence occurred in Africa (44% women and 25% oral and genital areas.2,3 Herpes simplex virus type 2 men), followed by America (24% women and 12% men). (HSV-2) is the most common cause of genital ulcers. Prevalence also increases with age, with a peak of The clinical manifestations of genital herpes can be young adults and more women than men with an seen clearly, but most infections are asymptomatic and estimated 313 million women and 178 million men. 5,6 can be transmitted through sexual intercourse and vertical from mother to fetus. 2,4 Typical lesions of genital herpes are grouped vesicles with an erythematous base, pustules, and Genital herpes is a common sexually transmitted ulcers, accompanied by complaints of pain, itching, infection worldwide and a risk factor for the acquisition dysuria, vaginal / urethral discharge, and painful and transmission of the Human Immunodeficiency inguinal lymphadenopathy. There may be prodrome 758 symptoms such as fever, headache, malaise and transmission is highest when there are lesions or myalgia. The lesions heal within 2-3 weeks. Predilection prodrome in men in the glands of the penis and preputium, asymptomatic viral shedding. Fifty to 90% of sexual whereas in women on the vulva, perineum, buttocks, partners are unaware that they are infected with HSV. vagina, and cervix. The clinical manifestations of Asymptomatic viral shedding occurs most frequently in genital herpes can be divided into first episodes the first year after the primary episode. 9 (primary and non-primary) and recurrent episodes. 1,2 symptoms, it can also occur during HSV infection occurs when viral particles enter the Human Immunodeficiency Virus (HIV) is the cause skin or mucous membranes through abrasion or of Acquired Immune Deficiency Syndrome (AIDS), microtrauma. The entry of the virus is preceded by the which is a syndrome with symptoms of opportunistic attachment of the virus to the cell surface receptors infections or certain cancers due to a decreased (heparan sulfate). This fusion results in the viral capsid immune system due to HIV infection.7,8 HSV-2 being transported to the nuclear pore and releasing infection is the most common infection in HIV patients, viral DNA accounting for 60-90% of HIV-infected patients. HSV-2 transactivator of transcription, VP16, residing in the infection increases the risk of HIV acquisition 2 to 3 tegument, initiates transcription of a 3 gene cascade. times.5,6,8 The clinical manifestations of genital Viral α gene (immediate-early) starts replication and herpes patients with or without HIV can be different. activates β gene (delayed-early). Genes β produce Patients with HIV have a high risk of developing chronic enzymes needed for viral replication such as thymidine and severe genital ulcers with atypical features, kinase HSV and DNA polymerase. The last γ gene prolonged expressed healing, and are easily resistant to treatment. This depends on the CD4 codes cells, wherein the for structural prepackaged proteins. The nucleocapsid formation of the herpes virus begins in count. 4,9,10 the nucleus. The nucleocapsid together with the Pathogenesis Herpes into simplex virus-2 is a double-stranded envelope develops through the inner lamellae of the the plasma membrane. Envelope particles are transported α-herpesvirus, is to the cytoplasm through the plasma membrane by neurotropic, rapidly replicates, and infects various cell membrane-bound vesicles and the Golgi apparatus. types such as epithelial cells, fibroblasts, neurons, and The release of virion progeny takes place in the plasma leukocytes.3,9,11 Herpes virus consists of 4 parts, membrane. 9 Then the virus will spread to surrounding namely the electron-opaque nucleus, the icosahedral cells and damage epithelial cells to form vesicles capsid around the nucleus, the amorphous tegument containing cellular debris, inflammatory cells, and containing viral encoded proteins around the capsid, virion progeny. Next, the virus enters the sensory nerve and the outer envelope with glycoprotein spikes on its fibers and migrates to the sacral nerve ganglion. In the surface. The capsid is a protein structure surrounded ganglion of the sacral nerves, the virus causes latent by a tightly attached, tegumentary membrane. The infection where DNA transcription continues but at low capsid and tegument are surrounded by envelopes levels. These latent infections are lifelong which can containing and undergo periodic reactivation and replication. When polyamines. Glycoproteins function as an intermediary reactivation occurs, the virus descends from the nerve for the attachment of viruses to host cells and induce a ganglion deoxyribonucleic acid (dsDNA) Herpesviridae family subfamily glycoproteins virus (gB-gN), from lipids, host immune response against viruses. 3,9 The incubation period for HSV ranged from 2-12 days (mean 4 days).12 Transmission of HSV infection occurs through sexual contact with fluids from an HSV infected patient such as semen, saliva or direct contact with the vesicle fluid of herpes lesions.3 The risk of HSV to the skin or genital mucosa. This reactivation process generally causes genital ulcers, but it can also be asymptomatic. Herpes simplex virus can also spread via lymph vessels to regional lymph nodes.13,14 When an infection occurs, the body will activate cellular and humoral immunity to control the spread of infection and HSV replication. CD4 and CD8 759 lymphocyte T cells, natural killer cells (NK cells), results in undiagnosed genital herpes and the macrophages, and inflammatory cytokines such as continuous spread of HSV-2 and HIV.15 There are 3 interferons-γ are important protective cells against important mechanisms of HIV transmission in HSV-2 HSV. The cellular immune response is an important patients, namely: 12 factor in determining the severity and recurrence of 1. Symptomatic HSV-2 genital ulcers cause local HSV. The humoral immune response does not prevent inflammation and damage to the genital tract recurrences. mucosa thereby facilitating HIV-1 entry during 9 It has long been known that there is a synergistic relationship between HIV and HSV-2. HIV infection has clinical implications and can lead to HSV-2 reactivation. HSV-2 infection increases the risk of HIV infection acquisition and transmission (Figure 1).15,16 exposure to HIV-infected genital fluids. 2. HSV-2 genital ulcers selectively increase local recruitment of CD4 T cells that are targeted for mucosal adhesion of HIV-1. 3. Viral replication in HSV-2 lesions. The high rate of asymptomatic herpes virus shedding Figure 1. Inter-relationships between HSV-2 and HIV infections. 16 Some literature describes the mechanism of HSV-2 infection in enhancing HIV acquisition primarily HSV-2 also had a higher number of CD4expressing CD69 T-cells and DC-SIGN- through CD4 cell recruitment and increasing the expressing cervical dendritic cells higher in the expression of important HIV receptors at the port of cervicovaginal mucosa. There is also an influx of entry. dendritic cells and CD4 and CD8 T cells into - HSV-2 infection can increase the concentration recurrent HSV-2 ulcers. These cells, which have of cervical HIV target cells. HSV-2 infection is the CCR5, CXCR4, and DC-SIGN receptors, associated with a 10-fold increase in cervical persist for several months, despite resolution of CD4 T cells expressing CCR5, which is the main the lesion.16 Langerhans cells prevent HIV target of mucosal HIV infection. Women with transmission through the C-type lectin, langerin, 760 which can degrade the virus thereby reducing 8, and monocyte chemotactic protein-1 by transmission of HIV to T cells. Herpes simplex epithelial cells. 16 virus-2 can decrease the expression of langerin so that Langerhans cells are more susceptible to The clinical manifestations of HSV are varied and HIV infection. This makes it easier for HIV to can cause psychological and psychosocial problems. infect Langerhans cells and T cells. Several other The severity of clinical manifestations and recurrences studies have shown that keratinocytes infected is influenced by viral and host factors. The clinical with HSV-2 produce human β defensins and LL- manifestations of herpes can be divided into first 37 protein which can increase the expression of episodes and recurrent episodes. The first episode was HIV receptors in Langerhans cells. The two divided into primary, in patients without previous HSV- things previously mentioned prove that HSV-2 1 or HSV-2 antibodies, and non-primary, in patients not only inhibits Langerin function but also with previous HSV-1 or HSV-2 antibodies. Most HSV makes it easier for Langerhans cells to become infections are asymptomatic. 9 Predilection in men in infected with HIV. T cells, the main target of HIV the glands of the penis and prepuce, whereas in women infection, migrate to the genital skin and mucosa under the influence of the chemokine CXCL-9.17 The biopsy results containing the inflammatory infiltrate showed that local HIV replication was 3 to 5 times more than in areas without the inflammatory infiltrate.16 - Clinical manifestations HSV-2 infection decreases mucosal innate immunity and induces a mucosal inflammatory response. HSV-2 infection caused a significant reduction in secretory leukoprotease inhibitor (SLPI) gene expression by human cervical epithelial cells, which persisted despite acyclovir treatment. This suggests that the virus downregulates SLPI as a strategy to avoid the immune system. The SLPI gene can inhibit HIV infection. Decreased SLPI concentrations lead to increased transcription factor κB (NF-κB)- mediated proinflammatory pathways. Herpes simplex virus-2 can also directly activate NF-κB which induces HIV replication. During infection, HSV-2 induces innate and adaptive immune responses in the genital mucosa. Chemokine induction causes recruitment of CD4 T cells and dendritic cells, which are the target of HIV infection. The proinflammatory mediators produced by epithelial cells and immune cells facilitate HIV replication. Herpes simplex virus-2 induces HIV replication directly in HIV-1 long terminal repeat or indirectly through stimulation of the production of TNF-α, interleukin (IL) -6, IL- on the vulva, perineum, buttocks, vagina, and cervix. 1,2 Primary first episode genital herpes Primary genital herpes is characterized by local and systemic symptoms that last a long time. The most common local symptoms are pain, dysuria, urethral or vaginal discharge, genital and sacral paresthesias, accompanied by painful inguinal lymphadenopathy. Lesions occur 3-14 days after infection. Systemic symptoms occur early in the course of the disease, after a mean incubation period of 6-8 days, peak 4 days after disease onset and subside slowly in 3-4 days later. The most common systemic symptoms are headache, fever, myalgia, lethargy and photophobia. About 40% of men and 70% of women experience systemic symptoms during the primary episode. 1,9 Local symptoms of itching, erythema, and pain generally occur within 1-2 days of preceding the lesion. The first lesions appear as small, clustered, painful vesicles or pustules above the erythematous base, break easily and form ulcers within 2-4 days. Widespread lesions can coalesce to form large ulcers. Atypical features such as deep necrotic ulcers may occur. New cluster lesions may appear at week 2. At week 3, crusting begins and the process of reepithelialization begins. When the lesion is on the mucosa, usually no crusting or scarring occurs. On physical examination, there is an enlarged inguinal and femoral lymphadenopathy that is painful, hard, and does not fluctuate, which occurs at week 2 or 3 and persists even after the lesions have healed. 9 761 About 88% of women with a first-episode genital herpes can be misdiagnosed as recurrent vaginitis, herpes infection have cervicitis. Urethral discharge and urogenital tract infection, or candida infection in dysuria occur in one-third of men. The urethra was women and as folliculitis, condom allergy, or other clear and mucoid. HSV pharyngitis can occur with dermatoses in men. 9 orogenital sexual contact. The duration of time taken Genital herpes in HIV patients from lesion onset to resolution in women was longer The clinical manifestations of HSV infection in HIV (mean 20 days) than men (mean 16,5 days) and the vary depending on the patient's immune status.17 All duration of viral shedding (onset of lesions to viral clinical culture still positive in the lesion) was around 12 days. 9 immunocompetent patients can occur in HIV patients, Non-primary first episode of genital herpes especially during its early stages. However, as the manifestations of HSV infection in About 50% of first-episode HSV-2 genital ulcer immune status decreases, the clinical manifestations patients have HSV-1 antibodies. HSV neutralizing are often atypical, wider, longer lesion duration, antibodies inactivate extracellular viruses and interfere painful, easily resistant to treatment, and often with the spread of HSV infection. Non-primary first- recurrent, especially when the CD4 count is <250 cells episode patients had a lower frequency of systemic / mm3.9,18,19,20 HSV infection in HIV patients also has symptoms, shorter pain duration, fewer lesions, and a local and systemic symptoms that last longer and shorter duration of healing than primary infections. 9 spread the virus longer (more than 30 days), while the Recurrent genital herpes recurrence ranges from 0-20 episodes per year. The At least 90% of infected patients have recurrent recurrence frequency increases when the CD4 count is HSV-2 genital herpes and 88% of them have at least 1 <50 cells / mm3.17 Atypical features may include (1) recurrence within the first 12 months of the episode. hyperkeratotic Recurrence can be triggered by emotional stress, UV condyloma acuminata or carcinoma of the verosa in radiation, concomitant infections, and menstruation. advanced HIV patients (2) vegetative plaque, expanded, Most genital herpes patients can predict recurrence confluent with ulceration with yellow exudate (Figure through local prodromal symptoms, such as a mild 2) (3) chronic and persistent ulcers that are very painful tingling sensation that occurs about 48 hours before and large in size (Figure 3), and (4) generalized papular the lesion develops. The risk of viral shedding is high eruptions during prodrome symptoms, even when there are no papulovesicles, erosions, and crusts. Lesions may lesions. progressively become False prodromes (prodromal symptoms in / the verucous form of lesions discrete hemorrhagic mimicking papules and or necrotic. without genital lesions) may occur and are more Generally, it occurs in patients with CD4 counts less common in patients who have frequent recurrences. than 100 cells / mm3.9,21 Perianal herpes is common Recurrent genital herpes is the mildest form, with few in patients who have sex with men (MSM) with HIV / vesicles arising (about 3-5), in the glans penis or AIDS. This form is characterized by pain, the lesions prepuce of men and is usually unilateral. Systemic can last weeks to months, and tends to be a persistent symptoms experienced 5% of men and 12% of women. chronic ulcer. 19.20 The risk of asymptomatic HSV Women experience genital ulcer pain more often with a shedding was 4 times higher in HIV patients than longer duration than men. Peak viral shedding without HIV. There is an inverse correlation between occurred within 48 hours of lesion onset and lasted 4 CD4 days. The mean time from onset to crusting is about 5 correlation between plasma HIV ribonucleic acid (RNA) days. days. and shedding.9 In men, the lesion is on the glans penis Occasionally, only itching, erythema and edema are or shaft of the penis, while in women it is on the vulva, found ulcers perineum, buttocks, vagina, or cervix. Complaints are (asymptomatic). In patients with recurrent genital accompanied by pain, itching, dysuria, vaginal or herpes can also be found atypical features. Genital urethral Re-epithelialization without vesicles, occurs in crusting 6-10 or count and HSV-2 shedding and a discharge, and pain in direct inguinal 762 lymphadenopathy. Prodromal symptoms such as fever, headache, malaise and myalgia are common. 2 Figure 2. Vegetative ulcers of genital herpes in HIV patients. 9 Figure 3. Large and chronic ulcers in genital herpes patients with HIV. 9 especially in HIV patients.12 The laboratory tests used were direct HSV detection from the lesion and indirect serologics (Tables 1-3). For acute lesions, take a Diagnosis and work-up Although the classic clinical manifestations of HSV can be diagnosed with accuracy, they should still be confirmed by laboratory examination or biopsy, specimen from vesicle fluid. For longer lesions, the diagnostic yield is very low. In this case, the patient is advised to return if new vesicles develop.22 For tissue specimen collection, a biopsy is performed on the edge 763 of the ulcer.3 70-90% Laboratory examination decreasing in asymptomatic patients. Herpes 1. Direct diagnosis of HSV from clinical protein in can symptomatic also be patients detected by and ELISA examination using HSV-specific monoclonal or specimens polyclonal 1.1. Cytologic examination This examination uses a Tzanck, Papanicolaou, or Romanovsky smear. 22 The Tzanck smear is an easy, practical, and fast diagnostic test to detect HSV, but it is antibodies. Compared to viral culture, ELISA sensitivity was ≥ 95% with specificity ranging symptomatic patients. 22 from 62-100% in 1.3 Virus isolation and typing on cell culture nonspecific because it cannot distinguish HSV- The most widely used cells for HSV isolation 1, HSV-2, and varicella. This examination are primary human diploid fibroblasts and cell should be performed if the lesion forms lines, such as MRC-5 cells (human fibroblasts), vesicles. The swab is carried out from the base Vero cells (monkey of the vesicle. A positive result shows typical (laryngeal squamous cell carcinoma), hamster When mucocutaneous lesions develop, the viral antigen of the lesion can be detected by immunofluorescence (IF), immunoperoxidase (IP) staining, or enzymelinked immunosorbent assay (ELISA). Direct immunofluorescence (IF) is a rapid diagnostic test and can differentiate between types of HSV. HSV-1 and HSV-2 antigens can be detected by fluorescein-labeled type-specific monoclonal antibodies. The disadvantages of this examination are that the reagent is quite requires microscope), and is cells tube should be examined daily using a 1.2 Virus antigen detection expensive, Hep-2 kidneys, and rabbit kidney cells. The culture multinuclear giant cells. 19,10 direct kidney), tools less (fluorescent sensitive than stereoscopic microscope to check for the characteristics of the cytopathic effect of HSV, which generally occurs 24-72 hours after inoculation. Characteristics of the cytopathic effect of HSV are elongated and scattered cell changes to become large, round, refractile, ballooning, numerous, and granular. There may also be focal cell necrosis, syncytia and multinucleated giant cells. This examination has a low sensitivity for recurrent lesions (2550%) and dry ulcer or crusted lesions, whereas in primary and vesicle-shaped lesions, the sensitivity can up to 80-90% 19,22 molecular examinations, with a sensitivity of Table 1. Recommended specimen collection for the diagnosis of genital herpes. 22 Collection site Male skin or mucosal lesions (including the perianal area) Tools for sample collection o Sterile needles o Sterile cotton-tipped, Dacron, or nylon-flocked swab o Microscope slides Male urethra o Sterile cotton-wool, Dacron, or nylon-flocked swab Collection method o Unroof the vesicles with a sterile needle o Collect the contecnt of the vesicles with a sterile swab and: - Apply to a microscope slide (for immunofluorescence) or - Place on transport media for viral culture or NAAT o Clean the external urethral ostium (OUE) with a swab moistened in saline o Pull the prepuce backwards to avoid contaminating the specimen 764 Female skin or mucosal lesions (including the perianal area) Female urethra o Cotton swab and gauze o Microscope slides o Sterile gauze swab (to remove excess discharge) o Sterile cotton-wool, Dacron, or nylon-flocked swab Cervix o Vaginal speculum o Sterile gauze swab o Sterile cotton-wool, Dacron, or nylon-flocked swab 2. Virus detection and quantification using o Put a sterile swab into the OUE (to a depth of 0.5-2 cm) and collect urethral exudates o Similarly as for male skin or mucosal lesions o Clean the vaginal introitus using sterile gauze swab o Insert a sterile swab into the urethra (to a depth of 0.5 cm) to collect exudates o Insert a vaginal speculum moistened with warm saline solution, and clean the cervical canal opening with a sterile gauze swab o Insert a sterile cotton-wool swab or Dacron swab into the cervical canal (to a depth of 2 cm deep) and collect the material from lesions asymptomatic HSV shedding.22 This method of examination is often used and has replaced viral molecular techniques Nucleic Acid Amplification Test (NAAT) / Polymerase culture as the gold standard, because the procedure Chain Reaction (PCR) is the most sensitive test for and transport are easy and readily available, more detecting HSV, 11-71% superior to viral culture. The sensitive, and faster. However, the price of this Nucleic Acid Amplification Test can also detect inspection is still expensive. 19 Table 2. Direct laboratory methods for HSV diagnosis. 22 Method Principle Specimens Sensitivity Specificity Advantage Loss Cytological examination Tzanck smear, Papanicolaou (Pap), or Romanovsky stains Low Low Inexpensive o Fresh lesions o Suboptimal sensitivity and specificity Virus antigen detection Detection of infected cells by direct immunofluorescence o Skin or mucosal lesions o Biopsy o Conjunctival or corneal smears o Smears tissue section o Smear from base of vesicle Moderate (genital ulcers: 70-90%; asymptomatic: <40-50%) High (> 95%) o Inexpensive o Rapid (<4 hours) o Typing possible o Swab o Smears from lesions o Smear or vesicular fluid of exudate from base of vesicle Moderate (80%) High (90%) o Reagent cost o Rapid (<4 hours) o Does not require specimen integrity o Typing possible o Fresh vesicles o Suboptimal sensitivity o Timeconsuming o Labour intensive o Not standardized o Fresh vesicles o Suboptimal sensitivity Immunoperoxidase staining 765 ELISA Rapid test device Viral culture HSV cell isolation Molecular biology Detection of HSV DNA and / or quantity by NAAT, such as PCR o Swab o Vesicular fluid or exudate from base of vesicle o Swab o Vesicular fluid or exudate from base of vesicle o Swab o Skin lesions o Vesicular fluid or exudate from base of vesicle o Biopsy o Mucosa without lesions o Conjunctival / corneal smears o Neonates Hight (genital ulcers:> 95%) High (62100%) Unknown Unknown Point-of-care testing Not yet evaluated o Low to high depending on clinical manifestations o Vesicle fluid:> 90% o Swab: 70-80% o Mucosa without lesions: 30% o Ulcers: 95% High (~ 100%) o Swab o Skin lesions o Vesicular fluid or exudate from base of vesicle o Mucosa without lesions o Vitreous fluid o Corticospinal fluids o Blood Highest (98%) High (~ 100%) o Simplicity of sampling o Classically, “gold standart” method o Currently, “preferred” test o Virus typing o Resistance phenotype testing o High sensitivity o Currently, “preferred” test o Allows virus detection and typing in the same test o Rapid o Results in 24-48 hours, can be <3 hours o Resistance genotyping o Method of choice for CSF o Less sensitive than PCR o Sample storage and transport conditions influence sensitivity o Labour intensive o Expensive o Specialized laboratories o Results in 2-7 days o Specialized laboratories o Not standardized o Expensive Table 3. Virological and serologic approaches for the diagnosis of HSV-2 Direct HSV-2 HSV-1 specific IgG HSV-2 detection specific IgG Initial Positive Positive or negative Negative assessment of genital lesions Positive Positive or negative Positive o Fresh vesicles o No viral typing with or without lesions.22 Interpretation o Acute HSV-2 infection o HSV-2 specific serologic reset in 15-30 days o Recurrent HSV-2 infection with HSV-2 infection was acquired at least 6 weeks ago 766 No lesions Recurrent genital lesions Cannot be applied Negative Negative Cannot be applied Positive Negative Cannot be applied Positive Positive Positive Positive or negative Positive Negative Negative Positive 3. Serologic examination is indicative of HSV o Patients are at risk for infection with HSV-1 and / or orolabial or genital HSV-2 infection o Patients are at risk for infection with genital or orolabial HSV-2 o Old HSV-1 and HSV-2 infections o Recurrent HSV-2 infection o Possible recurrent HSV-2 infection o Other genital ulcer diseases need to be considered coalesce and form multinucleated giant cells. These changes initially appear in the basal layer, then involve diagnosis This examination is recommended in patients with the entire epidermis layer. There are 2 degenerative recurrent genital herpes, atypical features, resolved changes to form intraepidermal vesicles, namely lesions, and negative HSV cultures. Serologic testing of ballooning degeneration and reticular degeneration. In HSV-2 in HIV patients is part of the initial HIV ballooning degeneration, cells become swollen and loss evaluation and helps identify asymptomatic HSV of attachment to surrounding cells forms acantholysis. infection.15 HSV-2 infection can be diagnosed by This is characteristic of viral infection. Tzanck cells detecting a specific type of IgG against glycoprotein G appear homogeneous with eosinophilic cytoplasm. HSV-2 with a sensitivity and specificity of more than Occurs mainly at the base of the vesicle and vesicles 95% in HIV patients.23 IgG antibodies are generally are formed intraepidermally. In reticular degeneration, negative in primary genital herpes because IgG can epidermal cells become progressively swollen so that only be detected 2-12 weeks after symptom onset and the cells become large and clear, then rupture and form persists. The HSV IgM test can detect the initial vesicles. Reticular degeneration is not characteristic of infection of a patient whose IgG level is not detected. viral vesicles or bullae and can be seen in other IgM is positive during disease reactivation, but it is not diseases specific for virus type. Due to these limitations, this Eosinophilic intranuclear inclusion bodies appear in examination is swollen cells. There not recommended as a routine such as allergic is a contact dermatitis. large neutrophil and lymphocyte infiltrate. 9,19,24 examination.9 Old lesions show lichenoid infiltrates or histiocytes Biopsy and histopathologic Initial changes appear to be swollen epidermal with granulomatous inflammation. Verucous HSV nuclei and appear slate-gray with peripheral chromatin infection is characterized by widespread viral infection clumping, image of the epithelium involving the adnexes, including accompanied by nucleus ballooning and cytoplasmic necrosis of the sebaceous glands, hair follicles, and vacuolization (Figure 4 and 5). As the cells and plasma sweat glands. Generally, verucous HSV infection is membrane are not intact, the infected keratinocytes found in patients with CD4 counts <200 cells / mm3. 3 homogeneous ground glass 767 Figure 4. The histology of genital herpes shows ballooning degeneration, spongiosis and acanthosis.9 Figure 5. (a) HSV infection shows intraepidermal bullae (b) Appears of multinucleated giant cells with nuclear molding and thickened chromatin margins. 3 Management There is no drug that can eliminate HSV from the body. The goals of the management of HSV-2 infection asymptomatic viral shedding, and risk of sexual transmission. - Effectiveness of suppressive therapy in first-episode are to relieve symptoms, stimulate reepithelialization, genital reduce HSV-2 transmission, prevent lesions and symptomatic episodes. recurrence.9,15 Non-pharmacology Education Counseling patients and sexual partners is an important treatment. The goal of counseling is to assist patients in treatment and prevent sexual and perinatal transmission. Some topics that can be discussed when counseling patients with HSV infection are: 18 - Course of disease with possible recurrent episodes, herpes patients to prevent recurrent - Episodic therapy to reduce the duration of recurrent episodes. - Provide information to sexual partners about genital herpes and potential partners before having the first sexual intercourse. - Potential sexual transmission of HSV that can occur during the asymptomatic period (asymptomatic viral shedding is more common with HSV-2 infection than HSV-1 and generally occurs within the first 12 months after infection with HSV-2). 768 - Abstinence of sexual activity when prodromal the mainstay of therapy with a dose of 5-10 mg / kg body weight every 8 hours for 2-7 days or until the lesions or symptoms develop. - The effectiveness of using latex condoms on men consistently and appropriately can reduce (not lesions heal, followed by oral antiviral therapy for a minimum total of 10 days of total therapy. 10,18 eliminate) the risk of transmission of genital herpes. In HIV patients, anti-HSV-2 suppressive therapy - Asymptomatic HSV infection. can be considered. Several studies have shown that - Risk of neonatal HSV infection. acyclovir, valacyclovir, and famciclovir can lower - Increased risk of HIV acquisition in HSV-2 plasma and genital HIV RNA levels, but the mechanism seropositive patients who are exposed to HIV for this is unknown. 25 The standard suppressive dose (suppressive antiviral therapy does not reduce the of acyclovir is quite effective. The suppressive therapy risk of HIV transmission) recommended by the CDC 2015 (Table 5) is acyclovir 400-800 mg, orally, two to three times per day; or Pharmacology There is no therapy that can eliminate the virus valaciclovir 500 mg, orally, twice per day; or famciclovir guidelines 500 mg, orally, twice per day 18 for at least 6-12 developed an algorithm for the management of herpes months.19 The risk of resistance increases with severity in immunocompromised patients (Figure 6). Episodic of immunodeficiency. If the genital herpes lesions are or suppressive systemic antiviral therapy is effective in persistent or recurrent in the patient on adequate reducing the clinical manifestations of HSV in HIV antiviral therapy, HSV resistance can be considered patients. In patients with advanced HIV, it is necessary and virus isolation is required for sensitivity testing and to consider giving an antiviral dose 2 times the a biopsy can be performed. In HIV patients who are standard dose and if lesions persist on days 3-5, the resistant to acyclovir or its derivatives can be given dose may be increased. Based on the Centers for intravenous foscarnet (vidarabine) 40-80 mg / kg body Disease Control and Prevention (CDC) 2015 (Table 4), weight every 8 hours until reaching clinical resolution the antiviral doses given to HIV patients with episodic or intravenous cidofovir 5 mg / kg body weight once genital herpes infection, namely: acyclovir 400 mg, every week for 2 weeks. 2 from the body. The 2017 European orally, given three times per day for 5-10 days; or Topical can be given imiquimod or cidofovir 1% valaciclovir 1000 mg, orally, twice per day for 5-10 applied once a day for 5 days. 3,18 Topical antiviral days; or famciclovir 500 mg, orally, twice per day for 5- therapy in genital herpes is not recommended because 10 days.18 Treatment should be given for a minimum of 10 days or until the lesion is re-epithelialized. 10 In severe and complicated cases, intravenous acyclovir is it is less effective than systemic therapy. Potassium permanganate compresses can be applied to ulcer lesions to prevent secondary infection. 3 Table 4. Episodic genital herpes therapy in HIV according to the CDC 2015. 10 Drugs Acyclovir Valacyclovir Famciclovir Dosage and method of administration 3 x 400 mg orally 2 x 1000 mg orally 2 x 500 mg orally Duration 5-10 days or until the lesions heal 5-10 days or until the lesions heal 10 days or until the lesions heal Table 5. Suppressive therapy for genital herpes in HIV according to the CDC 2015. 10 Drugs Acyclovir Valacyclovir Famciclovir Dosage and method administration 2-3 x 400-800 mg orally 2 x 500 mg orally 2 x 500 mg orally of Duration Minimum 6-12 months Minimum 6-12 months Minimum 6-12 months 769 Immunocompromised patients with active HSV lesions suspect acyclovir resistance because of failed therapy with standard antiviral therapy or previous acyclovir resistance Confirm by PCR examination or viral culture If new lesions persist after 3-5 days, increase the dose of acyclovir to 800 mg orally five times per day, or valaciclovir 1 gram orally twice per day, or famciclovir 750 mg orally twice per day. Viral culture for resistance testing. This examination takes 5 days. Topical: Foscarnet cream 1% or Cidofovir gel 1% Systemic: Intravenous foscarnet 40 mg / kg body weight every 8 hours or Intravenous infusion of cidofovir 5 mg / kg with oral probenecid and adequate prehydration to reduce the risk of nephrotoxicity. Effective in acyclovir and foscarnet resistant patients. The initial dose is 5 mg / kg body weight per week, given by infusion within 1 hour, for 2 weeks. Systemic therapy can be continued until the Alternative: Topical trifluridine 8 hours until the lesion resolves alone or in combination with interferon-𝛼 or Imiquimod cream 3 times per week Figure 6. Algorithm for the management of herpes in immunocompromised patients. 10 Prevention either prophylactic or therapeutic, that has been Several efforts can be made to prevent HSV-2 approved. In experimental animals, vaccine- transmission, including: 9 - induced Abstinence. All patients should be advised to immunity fails to prevent viral replication in the genital tract and the presence avoid sexual contact at the time of prodrome, of latent infection in the sensory ganglion lesions, and for several days after recurrence. remains a challenge. 9 - Limit the number of sexual partners. - Avoid partners with a history of genital herpes. - Appropriate and consistent use of condoms is a Genital herpes is a sexually transmitted infection practical approach that is good enough to caused by HSV, especially type-2, is recurrent and minimize the risk of acquiring genital herpes. lifelong. HSV-2 infection is the most common infection However, this does not completely prevent the in HIV patients and can increase the risk of HIV transmission of genital herpes. acquisition 2 to 3 times. The main mechanism that Vaginal and rectal microbicides can inactivate occurs is the presence of CD4 cell recruitment and the virus at the port de entry, but this is still in increased expression of important HIV receptors at the the research stage. port de entry. Genital herpes patients with HIV have a - Antiviral therapy. high risk of developing chronic and severe genital - Vaccine. ulcers with atypical features, prolonged healing, and - Vaccines against HSV have been widely developed, but until now there is no vaccine, Summary are easily resistant to treatment. The diagnosis can be made based on history, clinical manifestations, 770 laboratory examination, and histopathologic biopsy. The antiviral therapy, and symptomatic therapy. management given was education, systemic Sexually Transmitted Infections. 2nd ed. New References 1. Corey L, Wald A. Genital herpes. In: Holmes KK, Sparling PF, Stamm WS, Piot P, Wasserheit JN, 10. 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