Herpes Simplex Virus: A Practical Guide to Diagnosis, Management, and Patient Counseling for the Primary Care Clinician.

Genital herpes is a chronic, lifelong sexually transmitted viral infection, which can cause recurrent, self-limited genital ulcers. It is caused by herpes simplex virus (HSV) type 1 and type 2 viruses. Genital HSV infection is a very prevalent STI, which causes self-limited, recurrent genital ulcers. Treatment decreases duration of symptoms and signs and can be provided as episodic or suppressive therapy. Genital herpes can have a substantial impact during pregnancy and on sexual health in general. Counseling on natural history, transmission, treatment, and management of sexual partners is an integral part of management of genital herpes.

Korean sexually transmitted infection guidelines 2023 revision, guideline update of viral infections: Genital herpes and anogenital warts.

The Korean Association of Urogenital Tract Infection and Inflammation and the Korea Disease Control and Prevention Agency regularly update, revise, and develop new content for the Korean sexually transmitted infection (STI) guidelines. These professional bodies respond to changing epidemiological trends and evolving scientific evidence, and consider advances in laboratory diagnostics and research. The principal recommendations of the 2023 Korean STI guidelines in terms of viral infection follow: 1) If genital herpes recurs more than 4-6 times annually, suppressive therapy with acyclovir 400 mg orally 2 times/day or famciclovir 250 mg orally 2 times/day or valacyclovir 500 mg orally once a day (for patients with <10 episodes/year) or valacyclovir 1 g orally once daily (for patients with ≥10 episodes/year) is recommended to prevent recurrence; 2) molecular human papillomavirus (HPV) testing is not recommended as a routine test for STI status, nor for determination of HPV vaccination status; and 3) patients should inform their current sexual partners about anogenital warts because the types of HPV that cause such warts can be passed to partners. These guidelines will be updated every 5 years and will be revised when new knowledge on STIs becomes available and there is a reasonable need to improve the guidelines. Physicians and other healthcare providers can use the guidelines to assist in the prevention and treatment of STIs.

The Evaluation and Treatment of an Infant Exposed to Nongenital HSV-2: A Case Report.

BACKGROUND: Pregnant persons with a primary genital herpes simplex virus (HSV) infection can transfer HSV to the fetus or infant through the placenta or birth canal, which can cause significant infant morbidity or mortality. Primary nongenital infections with HSV-1 or HSV-2 in pregnant persons and the risk of infant infection are not well documented, leaving the clinician to make non-evidence-based decisions on evaluation and treatment in such presentations. CLINICAL FINDINGS: A term newborn was delivered vaginally by a pregnant person with a nongenital HSV-2 infection. The pregnant person's rash first appeared around 32 weeks' gestation, started on their lower back, and terminated on the outer left hip. The rash improved but was still present at time of delivery, and this rash was their first known HSV outbreak. PRIMARY DIAGNOSIS: Prenatal exposure to HSV-2. INTERVENTIONS: Diagnostics included the pregnant person's rash surface culture, immunoglobulin G and immunoglobulin M for HSV-1 and -2; infant surface, cerebral spinal fluid (CSF), and serum HSV-1 and HSV-2 polymerase chain reactions (PCRs), infant CSF studies, blood culture, liver function tests, and treatment with intravenous acyclovir. OUTCOMES: This infant remained clinically well during hospitalization and was discharged home at 5 days of life when CSF, surface, and serum PCRs resulted negative. PRACTICE RECOMMENDATIONS: Risk for infant HSV infection versus parent/infant separation and exposure to invasive procedures and medications should be considered when pregnant persons present with primary versus recurrent nongenital HSV infections. Research is needed for the evaluation and treatment of infants born to pregnant persons with primary nongenital HSV infections in pregnancy.

Oral Self-Nanoemulsifying System Containing Ionic Liquid of BX795 Is Effective against Genital HSV-2 Infection in Mice.

BX795 is an emerging drug candidate that has shown a lot of promise as a next-generation non-nucleoside antiviral agent for the topical treatment of herpes simplex virus type-1 (HSV-1) and herpes simplex virus type-2 (HSV-2) infections. Our studies indicated that BX795 has limited oral bioavailability, which could be attributed to its low and pH-dependent solubility. Lipid-based formulations such as self-nanoemulsifying systems (SNESs) can improve the solubility and oral bioavailability of BX795, but the poor lipid solubility of BX795 further limits the development of SNES. To improve the loading of BX795 into SNES, we evaluated the ability of various bulky and biocompatible anions to transform BX795 into an ionic liquid (IL) with higher lipid solubility. Our studies showed that sodium lauryl sulfate and docusate sodium were able to transform BX795 into IL. Compared to pure BX795, the developed BX795 ILs showed differential in vitro cytocompatibility to HeLa cells but exhibited similar in vitro antiviral activity against HSV-2. Interestingly, BX795 docusate (BX795-Doc), an IL of BX795 with ∼135-fold higher lipid solubility than pure BX795, could be successfully incorporated into an SNES, and the developed BX795-Doc-SNES could readily form nanoemulsions of size ≤200 nm irrespective of the pH of the buffer used for dilution. Our in vitro studies showed that BX795-Doc-SNES retained the inherent antiviral activity against HSV-2 and showed similar in vitro cytocompatibility, indicating the availability of BX795 from the SNES in vitro. Finally, orally delivered SNES containing BX795-Doc showed a significant reduction in HSV-2 infection in mice compared to the untreated control. Thus, the transformation of BX795 into IL and the subsequent incorporation of the BX795 IL into the SNES are an effective strategy to improve oral therapy of genital herpes infection.

Recalcitrant ulcerative genital herpes in an immunocompetent individual treated successfully with imiquimod.

BACKGROUND: This case report describes the successful use of imiquimod to treat genital herpes in an immunocompetent individual with acyclovir-resistant HSV. CASE REPORT: A 32 year old male patient, presented with asymptomatic non-healing ulcers over the genital region for 2 years. The ulcers initially responded to acyclovir but became persistent after a few months. He also received multiple courses of antibiotics. On examination, the patient had bilateral inguinal lymphadenopathy and multiple painless ulcers over the coronal sulcus. Routine investigations were normal. The patient was treated with oral and intravenous acyclovir but showed no response. He was then started on topical imiquimod cream applied on alternate days. After one week, the patient presented with pain, redness, burning sensation, and fresh ulcer over the glans which were suspected to be imiquimod-induced irritant reaction or ulcer. Imiquimod was withheld for one week and then restarted at a twice-weekly schedule. After 1 month and 7 days of treatment with imiquimod at a twice-weekly schedule, there was healing of the ulcers. CONCLUSION: This case report illustrates the efficacy of imiquimod cream as a topical treatment for genital herpes simplex in an immunocompetent patient who had previously been unresponsive to treatment with acyclovir.

Understanding the Medical Dictionary for Regulatory Activities (MedDRA) reporting of herpes simplex virus (HSV) adverse events in atopic dermatitis clinical trials.

Drug efficacy is best evaluated by randomized, controlled, double-blind clinical trials; however, safety is harder to assess. The Medical Dictionary for Regulatory Activities (MedDRA) is used to track and categorize adverse events (AE) during clinical trials. Recent atopic dermatitis (AD) clinical trials were reviewed to illustrate how an understanding of MedDRA may be helpful when evaluating the rates and nature of adverse events related to herpes simplex virus (HSV) infection. All completed AD clinical trials (excluding phase I studies) with results on clinicaltrials.gov (01/01/2018-01/31/2023) were queried in January 2023. MedDRA version, preferred term (PT) for AEs captured as "HSV", PTs for other AEs possibly related to HSV, frequency thresholds for reporting non-serious AEs, and route of treatment were recorded. Of the 46 clinical trials, 17 had PTs for AEs captured as "HSV". Among all studies, 11 different versions of MedDRA were utilized, from versions 10 to 24.1. In all studies, PTs for AEs captured as "HSV" were listed in the Infections and Infestations system organ class (SOC) classification of MedDRA. PTs varied from "herpes simplex", "herpes virus infection", "herpes ophthalmic", "ophthalmic herpes simplex", "nasal herpes", "oral herpes", "herpes dermatitis", "eczema herpeticum", "genital herpes simplex", and "genital herpes." While one clinical trial of dupilumab (NCT03359356) simply reported the PT "oral herpes" as an AE, a clinical trial of DS107 (NCT03817190) reported the PTs "oral herpes", "herpes simplex", and "herpes virus infection" separately. In the DS107 clinical trial, it is unclear if the same adverse event was reported under multiple PTs or if multiple HSV-related AEs occurred. Although the definition of HSV is unchanged from 2018 to 2023 and there are few changes between MedDRA versions, coding for HSV is complex. HSV events can be reported in different ways, which may impact the interpretation of a drug's safety profile.

The Interplay of Genital Herpes with Cellular Processes: A Pathogenesis and Therapeutic Perspective.

Genital herpes, primarily caused by herpes simplex virus-2 (HSV-2), remains a pressing global health concern. Its remarkable ability to intertwine with cellular processes, from harnessing host machinery for replication to subverting antiviral defenses like autophagy and programmed cell death, exemplifies the intricate interplay at the heart of its pathogenesis. While the biomedical community has extensively researched antiviral interventions, the efficiency of these strategies in managing HSV-2 remains suboptimal. Recognizing this, attention has shifted toward leveraging host cellular components to regulate HSV-2 replication and influence the cell cycle. Furthermore, innovative interventional strategies-including drug repurposing, microbivacs, connecting the host microbiome, and exploiting natural secondary metabolites-are emerging as potential game changers. This review summarizes the key steps in HSV-2 pathogenesis and newly discovered cellular interactions, presenting the latest developments in the field, highlighting existing challenges, and offering a fresh perspective on HSV-2's pathogenesis and the potential avenues for its treatment by targeting cellular proteins and pathways.

Epigallocatechin Gallate-Modified Silver Nanoparticles Show Antiviral Activity against Herpes Simplex Type 1 and 2.

(1) Background: Epigallocatechin gallate (EGCG) has been recognized as a flavonoid showing antiviral activity against various types of DNA and RNA viruses. In this work, we tested if EGCG-modified silver nanoparticles (EGCG-AgNPs) can become novel microbicides with additional adjuvant properties to treat herpes infections. (2) Methods: The anti-HSV and cytotoxic activities of EGCG-AgNPs were tested in human HaCaT and VK-2-E6/E7 keratinocytes. HSV-1/2 titers and immune responses after treatment with EGCG-AgNPs were tested in murine models of intranasal HSV-1 infection and genital HSV-2 infection. (3) Results: EGCG-AgNPs inhibited attachment and entry of HSV-1 and HSV-2 in human HaCaT and VK-2-E6/E7 keratinocytes much better than EGCG at the same concentration. Infected mice treated intranasally (HSV-1) or intravaginally (HSV-2) with EGCG-AgNPs showed lower virus titers in comparison to treatment with EGCG alone. After EGCG-AgNPs treatment, mucosal tissues showed a significant infiltration in dendritic cells and monocytes in comparison to NaCl-treated group, followed by significantly better infiltration of CD8+ T cells, NK cells and increased expression of IFN-α, IFN-γ, CXCL9 and CXCL10. (4) Conclusions: Our findings show that EGCG-AgNPs can become an effective novel antiviral microbicide with adjuvant properties to be applied upon the mucosal tissues.

Tolerability, pharmacokinetics, and anti-herpetic activity of orally administered BX795.

Herpes simplex viruses type-1 (HSV-1) and type-2 (HSV-2) are ubiquitous human pathogens causing serious pathologies in the ocular, orofacial and anogenital regions. While current treatments such as nucleoside analogs are effective in most cases, the emergence of drug resistance necessitates the development of newer antivirals with different mechanisms of action. In this regard, BX795, a small molecule inhibitor has shown significant benefit in the treatment of herpesvirus infections previously when dosed topically. However, the efficacy of BX795's systemic dosage remains to be tested. In this study, we evaluated acute and short-term toxicity of orally administered BX795 at a concentration of 400 and 100 mg/kg respectively in mice. This was followed by an evaluation of pharmacokinetics and tissue distribution of BX795 on intravenous and oral administration. Based on these studies, we performed an in vivo antiviral study using murine models of ocular HSV-1 and genital HSV-2 infection. Our results indicate that orally administered BX795 is very well tolerated, had oral bioavailability of 56%, and reached ocular and genital tissues within the first 15 min of dosing. Our studies indicate that BX795 administered orally can significantly reduce herpesvirus replication in the ocular and genital tissue.

Inhibition Effects and Mechanisms of Marine Polysaccharide PSSD against Herpes Simplex Virus Type 2.

Genital herpes is a common sexually transmitted disease mainly caused by herpes simplex virus type 2 (HSV-2), which can increase the risk of HIV transmission and is a major health problem in the world. Thus, it is of great significance to develop new anti-HSV-2 drugs with high efficiency and low toxicity. In this study, the anti-HSV-2 activities of PSSD, a marine sulfated polysaccharide, was deeply explored both in vitro and in vivo. The results showed that PSSD had marked anti-HSV-2 activities in vitro with low cytotoxicity. PSSD can directly interact with virus particles to inhibit the adsorption of virus to the cell surface. PSSD may also interact with virus surface glycoproteins to block virus-induced membrane fusion. Importantly, PSSD can significantly attenuate the symptoms of genital herpes and weight loss in mice after gel smear treatment, as well as reducing the titer of virus shedding in the reproductive tract of mice, superior to the effect of acyclovir. In summary, the marine polysaccharide PSSD possesses anti-HSV-2 effects both in vitro and in vivo, and has potential to be developed into a novel anti-genital herpes agent in the future.

Genital Herpes Infection: Progress and Problems.

Genital herpes (GH) is a sexually transmitted infection causing recurrent, self-limited genital, buttock, and thigh ulcerations. Symptoms range from unrecognized or mild to severe with frequent recurrences. Herpes simplex viruses (HSV) type-1 or type-2 cause GH. HSV establishes latency in sacral ganglia and causes lifelong infection. Viral reactivation leads to genital ulceration or asymptomatic shedding which may lead to transmission. HSV infection during pregnancy can cause fulminant hepatitis and neonatal transmission. Severe and atypical manifestations are seen in immunocompromised people. Guanosine analogs treat symptoms and prevent recurrences, shedding, and transmission. Novel preventive and therapeutic strategies are in development.

Serologic Screening for Genital Herpes Infection: US Preventive Services Task Force Reaffirmation Recommendation Statement.

Importance: Genital herpes is a common sexually transmitted infection caused by 2 related viruses, herpes simplex type 1 (HSV-1) and herpes simplex type 2 (HSV-2). Infection is lifelong; currently, there is no cure for HSV infection. Antiviral medications may provide clinical benefits to symptomatic persons. Transmission of HSV from a pregnant person to their infant can occur, most commonly during delivery; when genital lesions or prodromal symptoms are present, cesarean delivery can reduce the risk of transmission. Neonatal herpes infection is uncommon yet can result in substantial morbidity and mortality. Objective: To reaffirm its 2016 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a reaffirmation evidence update on targeted key questions to systematically evaluate the evidence on accuracy, benefits, and harms of routine serologic screening for HSV-2 infection in asymptomatic adolescents, adults, and pregnant persons. Population: Adolescents and adults, including pregnant persons, without known history, signs, or symptoms of genital HSV infection. Evidence Assessment: The USPSTF concludes with moderate certainty that the harms outweigh the benefits for population-based screening for genital HSV infection in asymptomatic adolescents and adults, including pregnant persons. Recommendation: The USPSTF recommends against routine serologic screening for genital HSV infection in asymptomatic adolescents and adults, including pregnant persons. (D recommendation).

Superior antiviral activity of IFNß in genital HSV-1 infection.

Type I interferons (IFNs) present the first line of defense against viral infections, providing antiviral, immunomodulatory and antiproliferative effects. The type I IFN family contains 12 IFNα subtypes and IFNß, and although they share the same receptor, they are classified as non-redundant, capable to induce a variety of different IFN-stimulated genes. However, the biological impact of individual subtypes remains controversial. Recent data propose a subtype-specificity of type I IFNs revealing unique effector functions for different viruses and thus expanding the implications for IFNα-based antiviral immunotherapies. Despite extensive research, drug-resistant infections with herpes simplex virus type 1 (HSV-1), which is the common agent of recurrent orogenital lesions, are still lacking a protective or curing therapeutic. However, due to the risk of generalized infections in immunocompromised hosts as well as the increasing incidence of resistance to conventional antiherpetic agents, HSV infections raise major health concerns. Based on their pleiotropic effector functions, the application of type I IFNs represents a promising approach to inhibit HSV-1 replication, to improve host immunity and to further elucidate their qualitative differences. Here, selective IFNα subtypes and IFNß were evaluated for their therapeutic potential in genital HSV-1 infections. Respective in vivo studies in mice revealed subtype-specific differences in the reduction of local viral loads. IFNß had the strongest antiviral efficacy against genital HSV-1 infection in mice, whereas IFNα1, IFNα4, and IFNα11 had no impact on viral loads. Based on flow cytometric analyses of underlying immune responses at local and peripheral sites, these differences could be further assigned to specific modulations of the antiviral immunity early during HSV-1 infection. IFNß led to enhanced systemic cytokine secretion and elevated cytotoxic responses, which negatively correlated with viral loads in the vaginal tract. These data provide further insights into the diversity of type I IFN effector functions and their impact on the immunological control of HSV-1 infections.

Layer-by-layer vaginal films for acyclovir controlled release to prevent genital herpes.

Genital herpes is one of the most common sexually transmitted infections worldwide. It mainly affects women, as the rate of sexual transmission from male-to-female is higher than from female-to-male. The application of vaginal antivirals drugs could reduce the prevalence of genital herpes and prevent future infections. Layer-by-layer vaginal films were prepared by the solvent evaporation method using iota-carrageenan, hydroxypropyl methylcellulose and the polymethacrylates Eudragit® RS PO and Eudragit® S100, for the controlled release of acyclovir. The films were characterized by texture analysis and Raman spectroscopy. Swelling, mucoadhesion, and drug release studies were conducted in simulated vaginal fluid. The results show that Layer-by-Layer films exhibited adequate mechanical properties. The structuring of the layer-by-layer films allowed the controlled release of acyclovir and produced a prolonged mucoadhesion residence time of up to 192 h. The films formed in layer 2 by the combination of Eudragit® RS PO and S100 showed a controlled release of acyclovir for eight days, and adequate mechanical properties. These promising formulations for the prevention of genital herpes deserve further evaluation.