The effect of valacyclovir on secondary prevention of congenital cytomegalovirus infection, following primary maternal infection acquired periconceptionally or in the first trimester of pregnancy. An individual patient data meta-analysis.

OBJECTIVE: Recent studies have shown that a dosage of 8 g/d of oral valacyclovir reduces substantially the vertical transmission rate of cytomegalovirus in women with primary cytomegalovirus infection acquired periconceptionally or during the first trimester of pregnancy. This individual patient data meta-analysis aimed to assess the effectiveness and safety of valacyclovir treatment in the secondary prevention of congenital cytomegalovirus infection. DATA SOURCES: MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, the US registry of clinical trials (www. CLINICALTRIALS: gov), and gray literature sources were searched from inception to March 2023. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials and quasi-randomized studies administering 8 g/d of oral valacyclovir in pregnant women with primary cytomegalovirus infection acquired periconceptionally or during the first trimester of pregnancy were included. METHODS: All corresponding authors of the eligible studies were contacted. Cochrane's Risk of Bias 2 and Risk Of Bias In Non-randomised Studies - of Interventions tools were used for the risk of bias assessment. The result of amniocentesis was the primary outcome of interest. A 1-stage individual patient data meta-analysis was performed, using a generalized linear mixed model, clustered by the different trials. A subgroup analysis was performed, assessing separately the effect of valacyclovir in the periconceptional period and first trimester of pregnancy. RESULTS: Overall, 3 studies were included in the analysis (n=527 women). Valacyclovir reduced the vertical transmission rate of cytomegalovirus (adjusted odds ratio, 0.34; 95% confidence interval, 0.18-0.61). This reduction was apparent for both periconceptional period (adjusted odds ratio, 0.34; 95% confidence interval, 0.12-0.96) and first-trimester (adjusted odds ratio, 0.35; 95% confidence interval, 0.16-0.76) infections. Moreover, valacyclovir reduced the rate of neonatal infection (adjusted odds ratio, 0.30; 95% confidence interval, 0.19-0.47), in both periconceptional period (adjusted odds ratio, 0.30; 95% confidence interval, 0.14-0.61) and first-trimester (adjusted odds ratio, 0.30; 95% confidence interval, 0.17-0.54) infections. Furthermore, valacyclovir reduced the rate of termination of pregnancy because of cytomegalovirus-associated severe fetal findings (adjusted odds ratio, 0.23; 95% confidence interval, 0.22-0.24). The gestational age at the initiation of treatment has a positive correlation with all outcomes. The overall prevalence of severe side effects was 2.1%. CONCLUSION: A dosage of 8 g/d of oral valacyclovir reduced the vertical transmission rates of cytomegalovirus following primary maternal infection acquired periconceptionally or in the first trimester of pregnancy, with a low incidence of side effects.

New data on efficacy of valacyclovir in secondary prevention of maternal-fetal transmission of cytomegalovirus.

OBJECTIVE: Congenital cytomegalovirus (CMV) infection is the leading cause of non-genetic hearing and neurological deficits. The aim of our study was to evaluate the efficacy and safety of valacyclovir (VCV) treatment in preventing CMV transmission to the fetus after maternal primary infection. METHODS: This was a retrospective, multicenter study evaluating the rate of maternal-fetal CMV transmission in pregnancies with maternal primary CMV infection treated with VCV at a dosage of 8 g per day (VCV group) compared with a control group of untreated women. Each case underwent virological testing to confirm maternal primary infection and to provide accurate dating of onset of infection. The primary outcome was the presence of congenital CMV infection at birth diagnosed based on polymerase chain reaction analysis of saliva, urine and/or blood samples. The efficacy of VCV treatment was assessed using logistic regression analysis adjusted for a propensity score. RESULTS: In total, 143 patients were included in the final analysis, of whom 59 were in the VCV group and 84 were in the untreated control group. On propensity-score-adjusted analysis, VCV treatment was significantly associated with an overall reduction in the rate of maternal-fetal CMV transmission (odds ratio, 0.40 (95% CI, 0.18-0.90); P = 0.029). The rate of maternal-fetal CMV transmission, determined at birth, in the VCV vs control group was 7% (1/14) vs 10% (1/10) after periconceptional maternal primary infection (P = 1.00), 22% (8/36) vs 41% (19/46) after first-trimester maternal primary infection (P = 0.068) and 25% (2/8) vs 52% (14/27) after second-trimester maternal primary infection (P = 0.244). When analyzing the efficacy of VCV treatment according to maternal viremia at treatment initiation, there was a trend towards greater efficacy when patients were viremia-positive (21% vs 43%; P = 0.072) compared with when they were viremia-negative (22% vs 17%; P = 0.659). Maternal side effects associated with VCV were mild and non-specific in most cases. CONCLUSION: Our findings indicate that VCV treatment of pregnant women with primary CMV infection reduces the risk of maternal-fetal transmission of CMV and may be effective in cases with primary infection in the first and second trimesters. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Effectiveness and safety of prenatal valacyclovir for congenital cytomegalovirus infection: systematic review and meta-analysis.

OBJECTIVE: Universal screening for cytomegalovirus (CMV) infection in pregnancy is not recommended in most countries. One of the major deterrents is the lack of effective prenatal therapy. The role of valacyclovir therapy in reducing the risk of vertical transmission, symptomatic congenital CMV infection and adverse outcome is controversial. The main aim of this systematic review and meta-analysis was to investigate the safety and effectiveness of prenatal valacyclovir therapy in pregnancies with maternal CMV infection. METHODS: MEDLINE, EMBASE and Cochrane databases and ClinicalTrials.gov were searched. The inclusion criteria were pregnancy with confirmed maternal CMV infection, treated or untreated with valacyclovir. The primary outcome was the incidence of congenital CMV infection confirmed by a positive CMV polymerase chain reaction result of the amniotic fluid. The secondary outcomes were symptomatic and asymptomatic infection, perinatal death, termination of pregnancy, anomalies detected on follow-up ultrasound, on fetal magnetic resonance imaging or at birth, severe and mild-to-moderate symptoms due to congenital CMV infection, neurological, visual and hearing symptoms, and adverse events related to valacyclovir. Risk of bias was assessed using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2) or Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool, as appropriate. Head-to-head meta-analyses were used to compare the risk of each of the explored outcomes according to whether pregnancies with maternal CMV infection were treated with prenatal valacyclovir therapy. RESULTS: Eight studies (620 women) were included. Pregnancies treated with valacyclovir had a significantly lower risk of congenital CMV infection compared with those not receiving valacyclovir (three studies; 325 fetuses; pooled odds ratio (OR), 0.37 (95% CI, 0.21-0.64); I2 = 0%; P < 0.001). When stratifying the analysis according to gestational age at maternal infection, the risk of vertical transmission was significantly lower in pregnancies receiving valacyclovir following first-trimester maternal infection (three studies; 184 fetuses; pooled OR, 0.34 (95% CI, 0.15-0.74); I2 = 20.9%; P = 0.001), while there was no significant difference between the two groups in those acquiring CMV infection in the periconceptional period or in the third trimester of pregnancy. Only one study reported on the risk of vertical transmission in women infected in the second trimester, demonstrating a lower risk of congenital infection in women taking valacyclovir, although this was based on a small number of cases. Pregnancies treated with valacyclovir therapy had an increased likelihood of asymptomatic congenital CMV infection compared with those not receiving valacyclovir (two studies; 132 fetuses; pooled OR, 2.98 (95% CI, 1.18-7.55); I2 = 0%; P = 0.021), while there was no significant difference between the two groups in the risk of perinatal death (P = 0.923), termination of pregnancy (P = 0.089), anomalies detected at follow-up imaging assessment during pregnancy or at birth (P = 0.934) and symptoms due to CMV infection in the newborn (P = 0.092). The occurrence of all adverse events in pregnant individuals taking valacyclovir was 3.17% (95% CI, 1.24-5.93%) (six studies; 210 women), with 1.71% (95% CI, 0.41-3.39%) experiencing acute renal failure, which resolved after discontinuation of the drug. On GRADE assessment, the quality of evidence showing that valacyclovir reduced the risk of congenital CMV infection and adverse perinatal outcome was very low. CONCLUSIONS: Prenatal valacyclovir administration in pregnancies with maternal CMV infection reduces the risk of congenital CMV infection. Further evidence is needed to elucidate whether valacyclovir can affect the course of infection in the fetus and the risk of symptomatic fetal or neonatal infection. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Cost-effectiveness of screening and valacyclovir-based treatment strategies for first-trimester cytomegalovirus primary infection in pregnant women in France.

OBJECTIVE: To assess the effectiveness, cost and cost-effectiveness of four screening strategies for first-trimester (T1) cytomegalovirus (CMV) primary infection (PI) in pregnant women in France. METHODS: In a simulated pregnant population of 800 000 (approximate number of pregnancies each year in France), using costs based on the year 2022, we compared four CMV maternal screening strategies: Strategy S1, no systematic screening (current public health recommendations in France); Strategy S2, screening of 25-50% of the pregnant population (current screening practice in France); Strategy S3, universal screening (current medical recommendations in France); Strategy S4, universal screening (as in Strategy S3) in conjunction with valacyclovir in case of T1 PI. Outcomes were total cost, effectiveness (number of congenital infections, number of diagnosed infections) and incremental cost-effectiveness ratio (ICER). Two ICERs were calculated, comparing Strategies S1, S2 and S3 in terms of euros (€) per additional diagnosis, and comparing Strategies S1 and S4 in € per avoided congenital infection. RESULTS: Compared with Strategy S1, Strategy S3 enabled diagnosis of 536 more infected fetuses and Strategy S4 prevented 375 congenital infections. Strategy S1 was the least expensive strategy (€98.3m total lifetime cost), followed by Strategy S4 (€98.6m), Strategy S2 (€106.0m) and Strategy S3 (€118.9m). In the first analysis, Strategy S2 was dominated and Strategy S3 led to an additional €38 552 per additional in-utero diagnosis, compared with Strategy S1. In the second analysis, Strategy S4 led to an additional €893 per avoided congenital infection compared with Strategy S1, and was cost-saving compared with Strategy S2. CONCLUSIONS: In France, current screening practice for CMV PI during pregnancy is no longer acceptable in terms of cost-effectiveness because this strategy was dominated by universal screening. Moreover, universal screening in conjunction with valacyclovir treatment would be cost-effective compared with current recommendations and is cost-saving compared with current practice. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

High dose valacyclovir for cytomegalovirus prophylaxis following allogeneic hematopoietic cell transplantation.

INTRODUCTION: Cytomegalovirus (CMV) is one of the most common and clinically significant viral infections following allogeneic hematopoietic cell transplantation (HCT). Currently available options for CMV prophylaxis and treatment present challenges related to side effects and cost. METHODS: In this retrospective medical record review, the incidence of clinically significant CMV infection (CMV disease or reactivation requiring preemptive treatment) following allogeneic HCT was compared in patients receiving valacyclovir 1 g three times daily versus acyclovir 400 mg every 12 h for viral prophylaxis. RESULTS: Forty-five patients who received valacyclovir were matched based on propensity scoring to 35 patients who received acyclovir. All patients received reduced-intensity conditioning regimens containing anti-thymocyte globulin. Clinically significant CMV infection by day + 180 was lower in the valacyclovir group compared to the acyclovir group (18% vs. 57%, p = 0.0004). Patients receiving valacyclovir prophylaxis also had less severe infection evidenced by a reduction in CMV disease, lower peak CMV titers, delayed CMV reactivation, and less secondary neutropenia. CONCLUSION: Prospective evaluation of valacyclovir 1 g three times daily for viral prophylaxis following allogeneic HCT is warranted. Due to valacyclovir's favorable toxicity profile and affordable cost, it has the potential to benefit patients on a broad scale as an option for CMV prophylaxis.

Describing the Impact of Maternal Hyperimmune Globulin and Valacyclovir on the Outcomes of Cytomegalovirus Infection in Pregnancy: A Systematic Review.

Cytomegalovirus (CMV) is the leading infectious cause of congenital neurological disabilities. Valacyclovir and CMV hyperimmune globulin (HIG) may reduce vertical transmission and sequelae in neonates. A systematic review on valacyclovir and CMV HIG in preventing vertical transmission or reducing sequelae in neonates was conducted to 3 September 2021. Valacyclovir as a preventive strategy was supported by a well-conducted randomized controlled trial. Evidence supporting valacyclovir as a treatment strategy was limited to observational studies at moderate risk of bias. CMV HIG was not supported as a preventive strategy in 2 randomized controlled trials, which contrasted with observational studies. Evidence favoring CMV HIG as a treatment strategy was limited to observational studies at moderate risk of bias. The role of valacyclovir and CMV HIG in CMV infection in pregnancy is still being defined. Valacyclovir to prevent vertical transmission has the highest quality evidence in favor of use.

A comparative study of valaciclovir, valganciclovir, and artesunate efficacy in reactivated HHV-6 and HHV-7 infections associated with chronic fatigue syndrome/myalgic encephalomyelitis.

This study aimed to compare the efficacy of valaciclovir, valganciclovir, and artesunate in treating chronic reactivated human herpesvirus type 6 (HHV-6) and human herpesvirus type 7 (HHV-7) infection associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). From 255 patients (192 cases) with reactivated HHV-6 and HHV-7 infections (confirmed based on blood leukocyte PCR), valaciclovir, valganciclovir, or artesunate was administered at a dose of 3000, 900, and 100 mg/day, respectively, for 3 months (study group). The control group consisted of similar patients with ME/CFS (n = 63) not taking any antiviral drugs. The significance of differences was evaluated by Student's t-test and the nonparametric criterion-the number of Z-signs. Negative PCR results in patients with HHV-6 and HHV-7 treated with valaciclovir was achieved in 26% and 23% (first month), 34%, and 28% (second month), 37% and 34% of cases (third month), respectively (P < 0.05; Z < Z0.05 ). The same results with valganciclovir were obtained in 35% and 33% (first month), 44% and 39% (second month), 48% and 45% of cases (third month), but with artesunate in 44% and 41% (first month), 57% and 53% (second month), 68% and 63% of cases (third month), respectively (P < 0.05; Z < Z0.05 ). Artesunate is more effective than valganciclovir and valacyclovir in patients with ME/CFS with reactivated HHV-6 and HHV-7 infections.

Secondary prevention of congenital cytomegalovirus infection with valacyclovir following maternal primary infection in early pregnancy.

OBJECTIVE: Cytomegalovirus (CMV) maternal primary infection (MPI) in early pregnancy is the main risk factor for congenital CMV (cCMV) infection with long-term sequelae. Our aim was to evaluate, in a single center offering CMV serology screening at 11-14 gestational weeks, secondary prevention of cCMV by administration of high-dosage maternal oral valacyclovir (VACV) in the first trimester of pregnancy. METHODS: This was a case-control study in a longitudinal cohort of pregnancies with CMV-MPI diagnosed prior to 14 weeks of gestation by serology screening (immunoglobulin (Ig) M and IgG measurement and IgG avidity) between 2009 and 2020. From October 2019 onwards, all women presenting at our center with MPI before 14 weeks' gestation were offered treatment with high-dosage oral VACV (8 g/day, 4 g twice/day). We used propensity score matching to compare fetal infection rates in cases treated with maternal oral VACV (8 g/day) with those in untreated controls. Fetal infection was assessed following amniocentesis at 17-22 weeks of gestation, by polymerase chain reaction (PCR) analysis of amniotic fluid for viral DNA. RESULTS: Of 310 cases of CMV-MPI identified, 269 underwent amniocentesis for PCR. Of these, 66 were offered, and 65 accepted, treatment with VACV. From the remaining untreated cases, we selected 65 controls, matched for proportion of periconceptional infections and gestational age at amniocentesis. VACV was initiated at a median gestational age of 12.71 (interquartile range (IQR), 10.00-13.86) weeks and the median duration of treatment was 35 (IQR, 26-54) days. On multivariate logistic regression, fetal infection was lower in the treated group (odds ratio, 0.318 (95% CI, 0.120-0.841); P = 0.021). One treated patient developed acute renal failure 4 weeks after initiation of VACV therapy, but this resolved within 5 days after treatment was stopped. CONCLUSION: This study confirms the acceptability, tolerance and benefit of secondary prevention by VACV of cCMV infection in a clinical setting with a well-established routine maternal serum screening policy in the first trimester of pregnancy. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Neurotoxicity associated with acyclovir and valacyclovir: A systematic review of cases.

WHAT IS KNOWN AND OBJECTIVE: Acyclovir and valacyclovir are commonly used antivirals with good general tolerance. Despite their good safety profile, they can cause systemic adverse effects, such as neurotoxicity, which are less frequent and known. The objective of this review was to collect all the reported cases of neurotoxicity associated with acyclovir and valaciclovir published in the literature and characterize their clinical course and interventions. METHODS: A systematic review of cases was carried out following the guidelines established by "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA). The research was carried out using the PubMed-Medline and Embase databases, between July 1984 and March 2021. RESULTS AND DISCUSSION: A total of 119 cases with neurotoxicity mainly related to acyclovir (n = 88; 73.9%), followed by valaciclovir (n = 35; 29.4%) were analysed. 49.6% (n = 59) were men with a mean age of 59.5 years ± 21.1 (0.5-88). In 83.3% of the cases, renal impairment was documented and 57.1% (n = 68) with end-stage renal disease. The administered dose was higher than the renal adjustment recommendations in 59.7% of the cases. The global mean of onset of symptoms was 3.1 days ± 4.3 (0.2-28) after the start of antivirals. The mean recovery time was 9.8 days ± 21.7 (0.2-180). 74.4% of the patients had a recovery of ≤7 days, 15.9% between 8 and 15 days and 9.8% > 15 days. WHAT IS NEW AND CONCLUSION: The neurotoxicity induced by acyclovir and its derivative valacyclovir is a poorly known and rare adverse effect that can occur mainly in patients with advanced age and impaired renal function. The most characteristic symptoms are confusion, altered level of consciousness, hallucinations, agitation and dysarthria. The basis of treatment is the discontinuation of the antiviral, and in some cases, it may require additional clearance by dialysis.

Chemoproteomic Identification of Serine Hydrolase RBBP9 as a Valacyclovir-Activating Enzyme.

Prodrug discovery and development in the pharmaceutical industry have been hampered by a lack of knowledge of prodrug activation pathways. Such knowledge would minimize the risks of prodrug failure by enabling proper selection of preclinical animal models, prediction of pharmacogenomic variability, and identification of drug-drug interactions. Technologies for annotation of activating enzymes have not kept pace with the growing need. Activity-based protein profiling (ABPP) has matured considerably in recent decades, leading to widespread use in the pharmaceutical industry. Here, we report the extension of competitive ABPP (cABPP) to prodrug-activating enzyme identification in stable isotope-labeled cell lysates using a modified fluorophosphonate probe. Focusing on the antiviral ester prodrug valacyclovir (VACV), we identified serine hydrolase RBBP9 as an activating enzyme in Caco-2 cells via shotgun proteomics, validating the activity via the selective inhibitor emetine (EME). Kinetic characterization of RBBP9 revealed a catalytic efficiency (kcat·KM-1 = 104 mM-1·s-1) comparable to that of BPHL, the only known VACV-activating enzyme prior to this work. EME incubation in wild-type and Bphl-knockout jejunum and liver lysates demonstrated the near-exclusivity of VACV activation by RBBP9 in the intestine. Additionally, these studies showed that RBBP9 and BPHL are the two major and coequal VACV-activating enzymes in the liver. Single-pass intestinal perfusions of VACV ± EME in mice showed EME coperfusion significantly inhibited the intestinal activation of VACV, implying the in vivo relevance of RBBP9-mediated VACV activation. We envision that others might use the cABPP approach in the future for global, rapid, and efficient discovery of prodrug-activating enzymes.

[Herpes simplex virus infections during pregnancy: epidemiology, clinical presentation and management]. / Infections par les virus herpes simplex pendant la grossesse : épidémiologie, aspects cliniques et prise en charge.

The incidence of herpes simplex virus (HSV) neonatal infection is estimated to be 8.9 per 100,000 live births in Europe. Early treatment with intravenous acyclovir has transformed the prognosis but this infection remains severe since, despite the treatment, mortality is frequent in disseminated diseases and neurological sequelae are frequent when central nervous system is involved. The major risk factor for transmission is the type of maternal infection. In women shedding the virus in their genital tract during childbirth, neonatal infection rates are 44 %, 25 % and 1.3 % in primary, non-primary and recurrent infections, respectively. The goals for the management of this infection during pregnancy encompass 1) the prevention of any contact between the newborn and the maternal virus by suppressing viral replication in the genital tract in late pregnancy and recommending a cesarean section in cases of genital lesions at delivery, and 2) the development of strategies allowing rapid identification and treatment of infected newborns.

Periodontal herpesvirus morbidity and treatment.

Four billion individuals worldwide have a history of periodontitis, with the poorest people in society most affected. Periodontitis can lead to unsightly drifting of teeth and tooth loss that may interfere with the wellbeing of daily living and has also been linked to at least 57 medical diseases and disabilities. The etiology of severe periodontitis includes active herpesviruses, specific bacterial pathogens, and destructive immune responses, but herpesviruses seem to be the major pathogenic determinant. Periodontal herpesviruses that disseminate via the systemic circulation to nonoral sites may represent a major link between periodontitis and systemic diseases. Current treatment of periodontitis focuses almost exclusively on bacterial biofilm and will require revision. Periodontal therapy that targets both herpesviruses and bacterial pathogens can provide long-term clinical improvement and potentially reduces the risk of systemic diseases. Molecular diagnostic tests for periodontal pathogens may enable early microbial identification and preemptive therapy. This review details an efficient and reliable anti-infective treatment of severe periodontitis that can be carried out in minimal time with minimal cost.

Association between Concomitant Use of Acyclovir or Valacyclovir with NSAIDs and an Increased Risk of Acute Kidney Injury: Data Mining of FDA Adverse Event Reporting System.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are likely to be used concomitantly with acyclovir or valacyclovir in clinical practice, but the study on the safety of such combinations was seldom reported. The objective of the study was to investigate reports of acute kidney injury (AKI) events associated with the concomitant use of oral acyclovir or valacyclovir with an NSAID by using the United States Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database between January 2004 and June 2012. The frequency of AKI events in patients while simultaneously taking either acyclovir or valacyclovir and an NSAID was compared using the Chi-square test. The effect of concomitant use of acyclovir or valacyclovir and individual NSAIDs on AKI was analyzed by the reporting odds ratio (ROR). The results showed that AKI was reported as the adverse event in 8.6% of the 10923 patients taking valacyclovir compared with 8.7% of the 2556 patients taking acyclovir (p=NS). However, AKI was significantly more frequently reported in patients simultaneously taking valacyclovir and an NSAID (19.4%) than in patients simultaneously taking acyclovir and an NSAID (10.5%) (p<0.01). The results also suggested that increased risk of AKI was likely associated with the concomitant use of valacyclovir and some NSAIDs such as loxoprofen, diclofenac, etodolac, ketorolac, piroxicam or lornoxicam. The case series from the AERS indicated that compared with acyclovir, valacyclovir is more likely to be affected by NSAIDs, and the concomitant use of valacyclovir with some NSAIDs might be associated with increased risk of AKI. The drug interactions with this specific combination of medications are worth exploring further.

Antiviral Drugs Against Alphaherpesvirus.

The discovery of acyclovir and penciclovir has led to the development of a successful systemic therapy for treating herpes simplex virus infection and varicella-zoster virus infection, and the orally available prodrugs, valacyclovir and famciclovir, have improved antiviral treatment compliance. Acyclovir and penciclovir are phosphorylated by viral thymidine kinase and are incorporated into the DNA chain by viral DNA polymerase, resulting in chain termination. Helicase-primase plays an initial step in DNA synthesis to separate the double strand into two single strands (replication fork) and is a new target of antiviral therapy. The helicase-primase inhibitors (HPIs) pritelivir and amenamevir have novel mechanisms of action, drug resistance properties, pharmacokinetic characteristics, and clinical efficacy for treating genital herpes. The clinical study of amenamevir in herpes zoster has been completed, and amenamevir has been submitted for approval for treating herpes zoster in Japan. The clinical use of HPIs will be the beginning of a new era of anti-herpes therapy.

In Silico Absorption Analysis of Valacyclovir in Wildtype and Pept1 Knockout Mice Following Oral Dose Escalation.

PURPOSE: We developed simulation and modeling methods to predict the in vivo pharmacokinetic profiles of acyclovir, following escalating oral doses of valacyclovir, in wildtype and Pept1 knockout mice. We also quantitated the contribution of specific intestinal segments in the absorption of valacyclovir in these mice. METHODS: Simulations were conducted using a mechanistic advanced compartmental absorption and transit (ACAT) model implemented in GastroPlus™. Simulations were performed for 3 h post-dose in wildtype and Pept1 knockout mice following single oral doses of 10, 25, 50 and 100 nmol/g valacyclovir, and compared to experimentally observed plasma concentration-time profiles of acyclovir. RESULTS: Good fits were obtained in wildtype and Pept1 knockout mice. Valacyclovir was primarily absorbed from duodenum (42%) and jejunum (24%) of wildtype mice, with reduced uptake from ileum (3%) and caecum/colon (1%), for a total of 70% absorption. In contrast, the absorption of valacyclovir in Pept1 knockout mice was slow and sustained throughout the entire intestinal tract in which duodenum (4%), jejunum (14%), ileum (10%) and caecum/colon (12%) accounted for a total of 40% absorption. CONCLUSION: The ACAT model bridged the gap between in situ and in vivo experimental findings, and facilitated our understanding of the complicated intestinal absorption processes of valacyclovir.

Lipid Nanocarrier: an Efficient Approach Towards Ocular Delivery of Hydrophilic Drug (Valacyclovir).

This research focuses on the fabrication and evaluation of solid lipid nanoparticles (SLNs) for improved ocular delivery of valacyclovir (VAC). Stearic acid and tristearin were selected as the lipid carrier while Poloxamer 188 and sodium taurocholate were used as surfactant and co-surfactant, respectively. The physiochemical properties of the optimized batch (SLN-6) fulfil the prerequisites needed for an ideal ocular formulation like submicron size (202.5 ± 2.56 nm), narrow PDI (0.252 ± 0.06), high zeta potential (-34.4 ± 3.04 mV) and good entrapment efficiency (58.82 ± 2.45%). The in vitro release study of SLN-6 exhibited a sustained release profile (>60% in 12 h). The ex vivo studies performed on excised cornea exhibited enhanced drug permeation of SLNs (22.17 ± 1.41 µg/cm2 h) in comparison to the drug solution (3.78 ± 1.34 µg/cm2 h). Apart, the corneal hydration studies, histopathology and Hen's Egg Test Chorio Allantoic Membrane (HETCAM) assay, confirmed the non-irritancy of SLNs. The in vivo study confirmed improved ocular bioavailability of VAC from SLN-6 (AUC0-12: 856.47 ± 7.86 µg h/mL) in contrast to the drug solution (AUC0-12: 470.75 ± 8.91 µg h/mL). Hence, the overall studies suggested the potential of SLNs in efficient ocular delivery of a hydrophilic molecule like VAC.

Antiherpetic Drugs in Equine Medicine.

Since vaccination may not prevent disease, antiherpetic drugs have been investigated for the therapy of several equine herpesviruses. Drug efficacy has been assessed in horses with disease, but most evidence is in vitro, in other species, or empirical. Oral valacyclovir is most often administered in the therapy of equine herpesvirus type-1 (EHV-1) to protect adult horses from equine herpesvirus myeloencephalopathy, while oral acyclovir is frequently administered for EHV-5 infection in the therapy of equine multinodular pulmonary fibrosis. Other antiherpetic drugs are promising but require further investigation. Several topical drugs are also empirically used in the therapy of equine viral keratitis.

Herpes simplex virus keratitis: an update of the pathogenesis and current treatment with oral and topical antiviral agents.

Ophthalmic herpes simplex viral keratitis is responsible for a range of ocular manifestations from superficial epithelial disease to stromal keratitis and endotheliitis. The Herpetic Eye Disease Study has guided the management of herpetic eye disease for almost twenty years, but newer medications such as valacyclovir are now available and are considered to have better bioavailability than acyclovir. In this review, we examine the existing evidence on the pathogenesis of different ophthalmic herpes simplex viral keratitis disease modalities and the role of oral and topically administered antiviral drugs in the treatment of herpes simplex viral keratitis.

Herpes Simplex Encephalitis: Lack of Clinical Benefit of Long-term Valacyclovir Therapy.

BACKGROUND: Despite the proven efficacy of acyclovir (ACV) therapy, herpes simplex encephalitis (HSE) continues to cause substantial morbidity and mortality. Among patients with HSE treated with ACV, the mortality rate is approximately 14%-19%. Among survivors, 45%-60% have neuropsychological sequelae at 1 year. Thus, improving therapeutic approaches to HSE remains a high priority. METHODS: Following completion of a standard course of intravenous ACV, 87 adult patients with HSE (confirmed by positive polymerase chain reaction [PCR] for herpes simplex virus DNA in cerebrospinal fluid) were randomized to receive either valacyclovir (VACV) 2 g thrice daily (n = 40) or placebo tablets (n = 47) for 90 days (12 tablets of study medication daily). The primary endpoint was survival with no or mild neuropsychological impairment at 12 months, as measured by the Mattis Dementia Rating Scale (MDRS). Logistic regression was utilized to assess factors related to the primary endpoint. RESULTS: The demographic characteristics of the 2 randomization groups were statistically similar with no significant differences in age, sex, or race. At 12 months, there was no significant difference in the MDRS scoring for VACV-treated vs placebo recipients, with 85.7% and 90.2%, respectively, of patients demonstrating no or mild neuropsychological impairment (P = .72). No significant study-related adverse events were encountered in either treatment group. CONCLUSIONS: Following standard treatment with intravenous ACV for PCR-confirmed HSE, an additional 3-month course of oral VACV therapy did not provide added benefit as measured by neuropsychological testing 12 months later in a population of relatively high-functioning survivors. CLINICAL TRIALS REGISTRATION: NCT00031486.

Valganciclovir versus valacyclovir prophylaxis for prevention of cytomegalovirus: an economic perspective.

INTRODUCTION: Valganciclovir (vGCV) and valacyclovir (vACV) are used in cytomegalovirus (CMV) prophylaxis in renal transplant recipients. The aim of this study was to compare the economic impact of both regimens during 1-year follow-up. METHODS: A total of 117 renal transplant recipients at risk for CMV were randomized to 3-month prophylaxis either with vGCV (900 mg/day, n = 60) or vACV (8 g/day, n = 57) and their data used in a pharmacoeconomic analysis. The pharmacoeconomic evaluation involved all direct CMV-related expenses in the first year after transplantation. Sensitivity analysis was employed to examine the effects of various prices of antiviral drugs and diagnostic procedures on overall CMV-related costs. Simulation of the more expensive US healthcare perspective was performed, and a scenario involving costs of acute rejection (AR) was examined. RESULTS: Overall CMV-related costs were significantly lower in the vACV arm; median United States dollars (USD) 3473 (3108-3745) vs. USD 5810 (4409-6757; P < 0.001) per patient, respectively. Our data showed that the critical determinant of the major disparity between the prophylactic regimens was the prophylaxis price. Median cost of prophylaxis in the vACV group was USD 1729 (1527-2173) compared to USD 3968 (2683-4857) in the vGCV group (P < 0.001). In sensitivity analysis of the overall CMV-related costs, the least and the most expensive pharmacotherapy and diagnostic scenarios were used; nevertheless, the vACV arm remained markedly less expensive. Simulation considering the higher physician/nurse and hospitalization fees of the US healthcare system and the scenario including expenditure associated with AR episodes also favored vACV. CONCLUSION: VACV prophylaxis for CMV is associated with a significant 44% lower cost than vGCV at the first year after renal transplantation.