Treatment Of Herpes Simplex Virus Infections Research Articles

Management of oral herpes simplex virus infections: The problem of resistance. A narrative review.

Herpes Simplex Virus (HSV) type 1 (HSV-1) and type 2 (HSV-2) are among the most common human viral pathogens, affecting several billion people worldwide. Although in healthy patients clinical signs and symptoms of HSV infection are usually mild and self-limiting, HSV-infections in immunocompromised patients are frequently more aggressive, persistent, and even life-threatening. Acyclovir and its derivatives are the gold standard antiviral drugs for the prevention and treatment of HSV infections. Although the development of acyclovir resistance is a rather uncommon condition, it may be associated with serious complications, especially in immunocompromised patients. In this review, we aim to address the problem of drug resistant HSV infection and discuss the available alternative therapeutic interventions. All relative studies concerning alternative treatment modalities of acyclovir resistant HSV infection published in PubMed between 1989 to 2022 were reviewed. Long-term treatment and prophylaxis with antiviral agents predisposes to drug resistance, especially in immunocompromised patients. Cidofovir and foscarnet could serve as alternative treatments in these cases. Although rare, acyclovir resistance may be associated with severe complications. Hopefully, in the future, novel antiviral drugs and vaccines will be available in order to avoid the existing drug resistance.

Synthetic derivatives of the antifungal drug ciclopirox are active against herpes simplex virus 2

We previously showed that the anti-fungal drug ciclopirox olamine effectively inhibits replication of herpes simplex virus (HSV)-1 and HSV-2. Given the rise of HSV strains that are resistant to nucleos(t)ide analog treatment, as well as the incomplete efficacy of nucleos(t)ide analogs, new inhibitory compounds must be explored for potential use in the treatment of HSV infection. In the present study, we analyzed 44 compounds derived from the core structure of ciclopirox olamine for inhibitory activity against HSV. Thirteen of these derivative compounds inhibited HSV-2 replication by > 1000- to ∼100,000-fold at 1 μM and displayed EC50 values lower than that of acyclovir, as well as low cytotoxicity, indicating their strong therapeutic potential. Through structural comparison, we also provide evidence for the importance of various structural motifs to the efficacy of ciclopirox and its derivatives, namely hydrophobic groups at R4 and R6 of the ciclopirox core structure. Like ciclopirox, representative analogs exhibit some oral bioavailability but are rapidly cleared in vivo. Together, these results will guide further development of N-hydroxypyridones as HSV therapeutics.

Anti-Herpes Simplex Virus Efficacy of Silk Cocoon, Silkworm Pupa and Non-Sericin Extracts.

Herpes simplex virus (HSV) infections are prevalent worldwide and are the cause of life- threatening diseases. Standard treatment with antiviral drugs, such as acyclovir, could prevent serious complications; however, resistance has been reported specifically among immunocompromised patients. Therefore, the development of an alternative approach is needed. The silk cocoon derived from silkworm, Bombyx mori, has been recognized for its broad-spectrum biological activity, including antiviral activity; however, its effects against HSV infection are unknown. In this study, we investigated the inhibitory effects of silk extracts derived from the cocoon shell, silk cocoon, silkworm pupa and non-sericin extract, on blocking HSV-1 and HSV-2 binding to host cells, resulting in the inhibition of the virus infection in Vero cells. Non-sericin extract demonstrated the greatest effectiveness on inhibiting HSV-1 and HSV-2 binding activity. Moreover, the virucidal effect to inactivate HSV-1 and HSV-2 was determined and revealed that non-sericin extract also exerted the highest potential activity. Using the treatment of non-sericin extract in HSV-2-infected HeLa cells could significantly lower the HSV-induced cell death and prevent inflammation via lowering the inflammatory cytokine gene expression. The non-sericin extract was analyzed for its bioactive compounds in which gallic acid, flavonoid and xanthophyll were identified, and might have partially contributed to its antiviral activity. The finding in our study suggested the potential of silk extract as an alternative therapeutic treatment for HSV infection.

Developments in Vaccination for Herpes Simplex Virus.

Herpes simplex virus (HSV) is an alpha herpes virus, with two subtypes: HSV-1 and HSV-2. HSV is one of the most prevalent sexually transmitted infections. It is the cause of severe neonatal infections and a leading cause of infectious blindness in the Western world. As of 2016, 13.2% of the global population ages 15–49 were existing with HSV-2 infection and 66.6% with HSV-1. This high prevalence of disease and the fact that resistance to current therapies is on the rise makes it imperative to develop and discover new methods of HSV prevention and management. Among the arsenal of therapies/treatments for this virus has been the development of a prophylactic or therapeutic vaccine to prevent the complications of HSV reactivation. Our current understanding of the immune responses involved in latency and reactivation provides a unique challenge to the development of vaccines. There are no approved vaccines currently available for either prophylaxis or therapy. However, there are various promising candidates in the pre-clinical and clinical phases of study. Vaccines are being developed with two broad focuses: preventative and therapeutic, some with a dual use as both immunotherapeutic and prophylactic. Within this article, we will review the current guidelines for the treatment of herpes simplex infections, our understanding of the immunological pathways involved, and novel vaccine candidates in development.

Central Composite Design for Formulation and Optimization of Solid Lipid Nanoparticles to Enhance Oral Bioavailability of Acyclovir.

Treatment of herpes simplex infection requires high and frequent doses of oral acyclovir to attain its maximum therapeutic effect. The current therapeutic regimen of acyclovir is known to cause unwarranted dose-related adverse effects, including acute kidney injury. For this reason, a suitable delivery system for acyclovir was developed to improve the pharmacokinetic limitations and ultimately administer the drug at a lower dose and/or less frequently. In this study, solid lipid nanoparticles were designed to improve the oral bioavailability of acyclovir. The central composite design was applied to investigate the influence of the materials on the physicochemical properties of the solid lipid nanoparticles, and the optimized formulation was further characterized. Solid lipid nanoparticles formulated from Compritol 888 ATO resulted in a particle size of 108.67 ± 1.03 nm with an entrapment efficiency of 91.05 ± 0.75%. The analyses showed that the optimum combination of surfactant and solid lipid produced solid lipid nanoparticles of good quality with controlled release property and was stable at refrigerated and room temperature for at least 3 months. A five-fold increase in oral bioavailability of acyclovir-loaded solid lipid nanoparticles was observed in rats compared to commercial acyclovir suspension. This study has presented promising results that solid lipid nanoparticles could potentially be used as an oral drug delivery vehicle for acyclovir due to their excellent properties.

Pharmaceutically Acceptable Carboxylic Acid-Terminated Polymers Show Activity and Selectivity against HSV-1 and HSV-2 and Synergy with Antiviral Drugs

Polyanionic macromolecules including carboxylate-terminated polymers (polycarboxylates) are capable of inhibiting sexually transmitted viruses such as human immunodeficiency virus (HIV) and herpes simplex virus (HSV). Cellulose acetate phthalate (CAP), a pharmaceutically acceptable pH-sensitive polycarboxylate polymer, showed promising prophylactic activity against HIV and HSV, but the instability of CAP in an aqueous environment prevented its clinical development. Interestingly, several pharmaceutically acceptable polycarboxylates have features similar to CAP with an aqueous stability significantly higher than that of CAP. However, their activity against sexually transmitted viruses remains unexplored. Here, we evaluate the activity of various polycarboxylates such as polyvinyl acetate phthalate (PVAP), various grades of hydroxypropyl methylcellulose phthalate (HPMCP-50, HPMCP-55, and HPMCP-55S), and various grades of methacrylic acid copolymers (Eudragit L100-55, Eudragit L100, Eudragit S100, and Kollicoat MAE 100P) against HSV. We, for the first time, demonstrate that PVAP, HPMCP-55S, and Eudragit S100 have activity and selectivity against HSV-1 and HSV-2. Further, we report that polycarboxylates can be easily transformed into nanoparticles (NPs) and in the nanoparticulate form, they show similar or enhanced activity against HSV. Finally, using PVAP NPs, as a model, we demonstrate using in vitro HSV therapy studies that polycarboxylate NPs are capable of synergizing with antiviral drugs such as acyclovir (ACV), tenofovir, and tenofovir disoproxil fumarate. Thus, pharmaceutically acceptable carboxylic acid-terminated polymers and their NPs have the potential to be developed into topical formulations for the prevention and treatment of HSV infection.

Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections-a Nationwide, Population-Based Cohort Study in Taiwan.

This retrospective cohort study is to investigate the association between herpes simplex virus (HSV) infections and dementia, and the effects of anti-herpetic medications on the risk involved, using Taiwan's National Health Insurance Research Database (NHIRD). We enrolled a total of 33,448 subjects, and identified 8362 with newly diagnosed HSV infections and 25,086 randomly selected sex- and age-matched controls without HSV infections in a ratio of 1:3, selected from January 1, to December 31, 2000. A multivariable Cox proportional hazards regression model was used to evaluate the risk of developing dementia in the HSV cohort. This analysis revealed an adjusted hazard ratio of 2.564 (95% CI: 2.351-2.795, P < 0.001) for the development of dementia in the HSV-infected cohort relative to the non-HSV cohort. Thus, patients with HSV infections may have a 2.56-fold increased risk of developing dementia. A risk reduction of dementia development in patients affected by HSV infections was found upon treatment with anti-herpetic medications (adjusted HR = 0.092 [95% CI 0.079-0.108], P < 0.001). The usage of anti-herpetic medications in the treatment of HSV infections was associated with a decreased risk of dementia. These findings could be a signal to clinicians caring for patients with HSV infections. Further research is, therefore, necessary to explore the underlying mechanism(s) of these associations.

An Evidence Based Review on Oriental Medicine for the Treatment of Herpes Simplex Infections and Their Availability in Iran

Background: Herpes Simplex Virus (HSV) infections are very common in Iran and worldwide and the risk for resistance to anti-herpetic drugs has increased recently. Alternative antiherpetic agents seem necessary to control and reduce the emergence of -resistant strains. Oriental medicine suggests some herbal options for the treatment of herpes lesions. Aim: This study reviews some of the common herbal treatments in oriental medicine for herpes and their availability in Iran. Methods: In this narrative review, information on in vitro and in vivo studies and clinical trials was searched via international databases including PubMed and SCOPUS, using herpes, herb, Oriental medicine, Chinese medicine and the names of herbs as keywords, which resulted in 45 related articles; of these, 38 entered this review. The inclusion criteria were the in vitro and in vivo studies, randomized controlled trials and reviews with acceptable levels of evidence. Information regarding those herbs in traditional Iranian medicine, their availability in Iran, and the available pharmaceutical products in this country were investigated through Persian references. Results: Among herbs suggested by Oriental herbal medicine for the treatment of herpes lesions, Melia azedarach, Aloe barbadensis, Rheum palmatum, Salvia officinalis, Melissa officinalis, Melaleuca alternifolia, Hypericum perforatum, Crataegus pinnatifida, Punica granatum and Rheum palmatum, are backed by acceptable scientific evidence, and are available in Iran. Conclusion: Considering the evidence and availability of many of Oriental herbal medicines for herpes in Iran, they can be utilized for treatment and research purposes.

The future and prospects of lasers in dermatology

The field of pediatric dermatology has been rich in new developments. Part II of this continuing medical education article will focus on new therapeutic modalities for several entities encountered in pediatric dermatology. The treatment of atopic dermatitis, exciting advances in the use of propranolol and other beta-blockers for the use of infantile hemangiomas, the use of rapamycin for vascular anomalies, the use of biologics in children, the central nervous system risks of general anesthesia in young children, side effects in the use of isotretinoin, the treatment of tinea capitis, treatment of herpes simplex infections, and the use of technologies such as texting and social media in medicine will be discussed.

Herpes simplex virus and the alimentary tract

Herpes simplex virus (HSV) infection is well known as a sexually transmitted disease. However, relatively little has been published concerning the presentations and treatment of HSV infection within the gastrointestinal tract, where HSV most commonly affects the esophagus in both immunocompromised and immunocompetent patients. HSV proctitis is not uncommon and occurs primarily in males having sex with males. In patients with normal immune systems, gastrointestinal HSV infections are generally self-limited and rarely require antiviral therapy. Treatment of infection is suggested for immunocompromised patients, though no large randomized controlled trials have been performed. This article reviews the manifestations of HSV infection within the luminal gastrointestinal tract and options for diagnosis and treatment.

A sustained release dosage form of acyclovir for buccal application: An experimental study in dogs

Acyclovir is an antiviral agent and it has been particularly used for the treatment of herpes simplex infections. The treatment of infection in the oral cavity is often difficult, because of insufficient drug concentration in saliva when acyclovir is administered via the oral route in conventional tablet form for systemic uptake. Therefore, it was aimed to prepare a tablet for buccal administration and to investigate its effectiveness by performing in vitro and in vivo experiments.The solubility (1.559–4.584) and octanol/water partition coefficients ( − 2.176 to − 1.625) of the acyclovir were investigated at different pH conditions. A series of tablet formulations were prepared for buccal application and their dissolution properties were determined in artificial saliva medium. The effect of tablet ingredients on the release rate and mucoadhesion force was investigated. The dissolution properties of commercially available acyclovir tablets were also determined in the artificial gastric juice.Franz type diffusion cells were used to determine acyclovir penetration through buccal mucosa from prepared buccal tablets.Selected buccal tablets, commercial tablets and intravenous acyclovir solutions were administered to mongrel dogs and drug levels in the blood determined by HPLC.A pharmacokinetic model for buccal application was also developed and blood concentrations were calculated theoretically and compared with the experimental results. Prepared buccal tablets were found to be effective for the treatment of viral infections locally within the oral cavity and also for systemic treatment.

Induction of gene mutations by 5-(2-chloroethyl)-2′-deoxyuridine (CEDU), an antiviral pyrimidine nucleoside analogue

5-(2-Chloroethyl)-2′-deoxyuridine (CEDU) had been developed for the treatment of herpes simplex infections. In the Salmonella reverse mutation test, the compound was found to be mutagenic in strains TA1535 and TA102 at very high concentrations (≥2500 μg/plate), both with and without S9-mix. The mutagenic potential of CEDU was further investigated in vivo and in vitro. It did not induce DNA repair in rat hepatocyte primary cultures, and was negative in the micronucleus test in V79 cells and in the comet assay in human leukocytes. In vivo, CEDU was negative in the bone marrow micronucleus test in CD1 mice. The mouse spot test provided a clearly positive result. Treatment of mice on day 9 of pregnancy with 2000 mg/kg resulted in 5.9% of the F1 animals having genetically relevant spots, whereas the corresponding vehicle control group had a spot rate of 1.9%. Since these data clearly identified CEDU as an inducer of gene mutations in vivo, this potential was further investigated in lacZ transgenic Muta™Mouse. Six female animals were treated daily on five consecutive days with 2000 mg/kg/day and sacrificed, after a treatment-free sampling time, 14 days later. The data showed a clear increase in the mutant frequency in the bone marrow, the lung and in the spleen. CEDU is an exception in the group of nucleoside analogues, because it was found to be a strong gene mutagen and, in contrast to the other compounds of this group investigated so far, had no considerable clastogenic effects.

Diagnosis and Treatment of Herpes Simplex Infection During Pregnancy

When pregnant women acquire primary herpes simplex genital infections or experience recurrent infections around the time of delivery, the risk of transmitting the disease to their newborns is significant. This perinatal transmission can result in a serious neonatal illness. Issues surrounding screening, treatment, and mode of delivery to prevent perinatal transmission often are confusing and controversial. Nurses delivering care to childbearing women and their newborns must be aware of the current information to give accurate and helpful information and support. Nurses also need to understand the effect this disease has both physiologically and psychosocially on women with primary infections, recurrent infections, and women at risk of acquiring the infection during pregnancy.

Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy.

Acyclovir (aciclovir) is a nucleoside antiviral drug with antiviral activity in vitro against members of the herpes group of DNA viruses. As an established treatment of herpes simplex infection, intravenous, oral and to a lesser extent topical formulations of acyclovir provide significant therapeutic benefit in genital herpes simplex and recurrent orofacial herpes simplex. The effect of acyclovir therapy is maximised by early initiation of treatment, especially in non-primary infection which tends to have a less protracted course than the primary episode. Long term prophylactic oral acyclovir, in patients with frequent episodes of genital herpes simplex, totally suppresses recurrences in the majority of subjects; as with other infections responding to acyclovir, viral latency is not eradicated and pretreatment frequencies of recurrence return after discontinuation of treatment. Caution should accompany the prophylactic use of acyclovir in the general population, due to the theoretical risk of the emergence of viral strains resistant to acyclovir and other agents whose mechanism of action is dependent on viral thymidine kinase. Intravenous acyclovir is the treatment of choice in biopsy-proven herpes simplex encephalitis in adults, and has also been successful in the treatment of disseminated herpes simplex in pregnancy and herpes neonatorium. Intravenous and oral acyclovir protect against dissemination and progression of varicella zoster virus infection, but do not protect against post-herpetic neuralgia. In immunocompromised patients, intravenous, oral and topical acyclovir shorten the clinical course of herpes simplex infections while prophylaxis with oral or intravenous dosage forms suppresses reactivation of infection during the period of drug administration. Ophthalmic application of 3% acyclovir ointment rapidly heals herpetic dendritic corneal ulcers and superficial herpetic keratitis. Thus, despite an inability to eradicate latent virus, acyclovir administered in therapeutic or prophylactic fashion is now the standard antiviral therapy in several manifestations of herpes simplex virus infection, and indeed represents a major advance in this regard. With the exception of varicella zoster virus infections, early optimism concerning the use of the drug in diseases due to other herpes viruses has generally not been supported in clinical investigations.

Antiviral treatment of herpes simplex infection in neonates and pregnant women

Herpes simplex infections in neonates include (1) infections beginning in skin or mucous membranes, (2) infections of the central nervous system, and (3) disseminated herpes of the newborn. Early recognition of infections beginning in skin or mucous membranes is essential because 75% will disseminate internally if untreated. Skin lesions provide important diagnostic clues in herpes of the nervous system and disseminated herpes, but they often appear late and in only about 60% of infected neonates. Acyclovir and vidarabine are effective therapies but they must be administered early to prevent serious damage or death. Herpetic skin lesions in neonates may be confused with pyodermas. Direct immunofluorescence and cultures are reliable diagnostic tests. Congenital herpes may cause widespread skin involvement and multiple eye and nervous system diseases. The mother is the source of neonatal herpes in about two thirds of cases. Asymptomatic genital shedding of virus late in pregnancy does not accurately predict whether maternal cultures will be positive at the time of delivery. The risk of the infant acquiring neonatal herpes from a mother with recurrent herpes at birth is about 5%, but the risk is much higher if the mother has true primary genital infection.

Thymopentin treatment of herpes simplex infections

Twenty-seven patients suffering from long-standing, severe, recurrent herpes simplex (14 labial and 13 genital) who had not responded adequately to prior therapy were recruited for this open, monitored study. They were treated with thymopentin 50 mg subcutaneously three times weekly for a period of 6 weeks. Clinical controls were performed once a week and then again 6 weeks after cessation of therapy; laboratory investigations were done at time points 0, 3, and 6 weeks. Additionally, information was collected with regard to the clinical course during the following year. Thirteen of 14 patients with labial infection and 10 of the 13 with genital herpes improved markedly (p < 0.05) as shown by decrease in the relapse rate of at least 50%, shorter relapse episodes, and improvement of symptoms such as pain and itching. Fourteen of these 27 patients experienced no relapse for a period longer than 4 months after cessation of therapy. These favorable results were paralleled by a statistically significant increase in the T cell helper/suppressor ratio. This finding indicates that thymopentin acts as an immunodomulator; it is assumed that the activation of T helper cells induces — presumable via interleukin 2 — the proliferation of cytotoxic T lymphocytes and natural killer cells which play a major role in the natural immune defense. No serious side effects of thymopentin were recorded.

E-5-(2-bromovinyl)-2'-deoxyuridine vs. interferon in the systemic treatment of infection with herpes simplex virus of athymic nude mice.

The effects of systemic administration of E-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and interferon (IFN)--mouse IFN type I (MuIFN-alpha plus -beta), mouse IFN type II (MuIFN-gamma), and polyriboinosinic-polyribocytidylic acid (an IFN inducer)--on the development of herpetic skin lesions and associated mortality were studied in athymic nude (nu/nu) mice inoculated intracutaneously with herpes simplex virus (HSV) type 1 (strain KOS). BVDU was given intraperitoneally or orally at dosages of up to 5 mg per mouse per day; IFN and polyriboinosinic-polyribocytidylic acid were given intraperitoneally at dosages of up to 10(6) units per mouse per day and 100 microgram per mouse per day, respectively. Under conditions in which BVDU effectively suppressed the progression of the disease, IFN and polyriboinosinic-polyribocytidylic acid failed to suppress the disease. Thus, BVDU was superior to IFN in the treatment of HSV infection in immunologically compromised mice.

Inhibition of Herpes Simplex Virus Infection in Tissue Culture by Trisodium Phosphonoformate

SummaryThe present report describes the in vitro effect on herpes simplex virus (HSV) replication of trisodium phosphonoformate (PFA), a drug with low toxicity and which selectively inhibits the HSV induced DNA-polymerase and thus may have potential use in the treatment of HSV infection in man. The inhibitory effect of PFA on HSV replication was strictly dose-dependent and in the presence of 0.25 mM PFA the TCID50 titers of HSV-1 and HSV-2 reference strains in green monkey kidney cells were decreased by 2 log units. The amount of virus inoculated or produced in the culture and the time for PFA-HSV interaction were factors influencing the virus inhibitory effect of PFA. None of 41 HSV-1 and 39 HSV-2 wild strains were resistant to the drug. However, passage of plaque purified HSV in the presence of 0.25 mM PFA resulted in appearance of mutants gradually more PFA resistant.

Vidarabine ophthalmic ointment (vira-A)

Vidarabine (adenine arabinoside; ara-A) is an antiviral agent active against DNA viruses but with low toxicity for human cells. It is available for topical treatment of herpes simplex infections of the eye as an ointment with a soft paraffin base (Vira-A - Parke, Davis).

Effect of interferon on experimental herpes simplex virus infections (author's transl)

Herpes simplex virus (HSV) is reported to be relatively insensitive to the antiviral activity of interferon (IF), but no detailed information is available for it.To obtain basic data on the clinical application of IF to human beings, studies were made on the effect of IF against the newly isolated HSV, HSV-TM strain, both in the tissue culture system of mouse embryo cells and in the mouse system with animals suffering from skin eruption and encephalitis.1) Fifty per cent inhibition of the cytopathic effect, or virus yield, was observed when mouse embryo cells were treated with 10 units of IF and challenged with 50 TCID50 of HSV-TM strain. A complete inhibition was seen when mouse embryo cells were treated with 100 units of IF and challenged with 5, 000 TCID50 of HSV-TM.2) Hairless mice of the 88-k strain were treated intraperitoneally with IF 24 hours before viral inoculation and daily thereafter. Daily inoculation with concentrated mouse IF, the maximum titer of which was 1.7×105IU/0.3ml, did not inhibit the development of skin eruption in mice inoculated subcutaneously with 0.2ml of HSV-TM (105.5TCID50/ml or encephalitis in mice inoculated intracerebrally with 0.03ml of HSV-TM (30 TCID50).These results imply that the administration of larger doses of interferon may be required for prophylaxis or treatment of HSV infection in animals.