Higher dose antiviral therapy for herpes infections is associated with a risk of serious adverse events in older adults with chronic kidney disease.

Antiviral use has been linked to encephalopathy and elevated serum creatinine concentrations in individuals with chronic kidney disease (CKD) in case reports. Using linked healthcare data in Ontario, we conducted a population-based cohort study on adults aged ≥66 years not receiving dialysis and newly prescribed oral acyclovir, valacyclovir, or famciclovir in the outpatient setting (2008-2022) at higher versus lower doses. The primary composite outcome, a hospital visit with encephalopathy or acute kidney injury (AKI) within 14 days of initiating antiviral treatment, was examined in a primary cohort. AKI was assessed in a secondary cohort of older adults with CKD with available linked hospital-based laboratory (lab) data. We used inverse probability of treatment weighting on the propensity score to balance comparison groups on baseline health. Weighted risk ratios (RR) and risk differences (RD) were obtained using modified Poisson and binomial regression. In the primary cohort, higher- versus lower-dose antiviral was not associated with an increased 14-day risk of hospital visit with encephalopathy or AKI. However, Higher- versus lower-dose antiviral was associated with a higher risk of a hospital visit with AKI when assessed using lab values (weighted number of events, 70 of 8407 [0.83%] versus 18 of 8230 [0.22%], respectively; weighted RR, 3.83 [95% CI, 1.87-7.87]; weighted RD, 0.62% [95% CI, 0.37%-0.86%]). In older adults with CKD, starting an antiviral at a higher versus lower dose was associated with a higher risk of AKI, although the absolute risk of this event was <1%.

Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients.

BACKGROUND: The risk of cytomegalovirus (CMV) infection in solid organ transplant recipients has resulted in the frequent use of prophylaxis to prevent the clinical syndrome associated with CMV infection. This is an update of a review first published in 2005 and updated in 2008 and 2013. OBJECTIVES: To determine the benefits and harms of antiviral medications to prevent CMV disease and all-cause death in solid organ transplant recipients. SEARCH METHODS: We contacted the information specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 5 February 2024 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing antiviral medications with placebo or no treatment, comparing different antiviral medications or different regimens of the same antiviral medications for CMV prophylaxis in recipients of any solid organ transplant. Studies examining pre-emptive therapy for CMV infection are studied in a separate review and were excluded from this review. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility, risk of bias and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: This 2024 update found four new studies, bringing the total number of included studies to 41 (5054 participants). The risk of bias was high or unclear across most studies, with a low risk of bias for sequence generation (12), allocation concealment (12), blinding (11) and selective outcome reporting (9) in fewer studies. There is high-certainty evidence that prophylaxis with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment is more effective in preventing CMV disease (19 studies: RR 0.42, 95% CI 0.34 to 0.52), all-cause death (17 studies: RR 0.63, 95% CI 0.43 to 0.92), and CMV infection (17 studies: RR 0.61, 95% CI 0.48 to 0.77). There is moderate-certainty evidence that prophylaxis probably reduces death from CMV disease (7 studies: RR 0.26, 95% CI 0.08 to 0.78). Prophylaxis reduces the risk of herpes simplex and herpes zoster disease, bacterial and protozoal infections but probably makes little to no difference to fungal infection, acute rejection or graft loss. No apparent differences in adverse events with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment were found. There is high certainty evidence that ganciclovir, when compared with aciclovir, is more effective in preventing CMV disease (7 studies: RR 0.37, 95% CI 0.23 to 0.60). There may be little to no difference in any outcome between valganciclovir and IV ganciclovir compared with oral ganciclovir (low certainty evidence). The efficacy and adverse effects of valganciclovir or ganciclovir were probably no different to valaciclovir in three studies (moderate certainty evidence). There is moderate certainty evidence that extended duration prophylaxis probably reduces the risk of CMV disease compared with three months of therapy (2 studies: RR 0.20, 95% CI 0.12 to 0.35), with probably little to no difference in rates of adverse events. Low certainty evidence suggests that 450 mg/day valganciclovir compared with 900 mg/day valganciclovir results in little to no difference in all-cause death, CMV infection, acute rejection, and graft loss (no information on adverse events). Maribavir may increase CMV infection compared with ganciclovir (1 study: RR 1.34, 95% CI: 1.10 to 1.65; moderate certainty evidence); however, little to no difference between the two treatments were found for CMV disease, all-cause death, acute rejection, and adverse events at six months (low certainty evidence). AUTHORS' CONCLUSIONS: Prophylaxis with antiviral medications reduces CMV disease and CMV-associated death, compared with placebo or no treatment, in solid organ transplant recipients. These data support the continued routine use of antiviral prophylaxis in CMV-positive recipients and CMV-negative recipients of CMV-positive organ transplants.

Signal mining study of severe cutaneous adverse events of valaciclovir or acyclovir based on the FAERS database.

OBJECTIVE: This study aimed to explore a comprehensive empirical investigation and assess SCARs related to valaciclovir or acyclovir based on FAERS database from FDA, thus providing a theoretical foundation for the rational application of drugs in clinic. METHODS: SCARs reports relevant to valaciclovir or acyclovir were searched in FAERS database from the 2004 Q1 to 2023 Q2. These data were further mined by a proportional analysis and Bayesian approach to detect signals of SCARs caused by two drugs. Meanwhile, the clinical characteristics, onset time, correlation, and stratification analysis of the two drugs in SCARs were analyzed. RESULTS: Both drugs exhibited positive signals for drug reaction with DRESS, AGEP, TEN, SJS-TEN overlap and SJS. The median onset time of SCARs caused by valaciclovir or acyclovir was 30 days vs 10 day for DRESS, 11 days vs 9 days for AGEP, 17 days vs 12 days (TEN) and 12 days vs 8 days (SJS). Excluding the effect of combinational drugs, there was an association between the two antiviral drugs and SCARs. CONCLUSION: By analyzing the FAERS database, the risk trends of SCARs caused by valaciclovir or acyclovir have been identified, providing valuable insights to recognize various types of SCARs in clinics.

Medicine-Induced Acute Kidney Injury Findings from Spontaneous Reporting Systems, Sequence Symmetry Analysis and a Case-Control Study with a Focus on Medicines Used in Primary Care.

INTRODUCTION: Primary care provides an opportunity to prevent community acquired, medicine or drug-induced acute kidney injury. One of the barriers to proactive prevention of medicine-induced kidney injury in primary care is the lack of a list of nephrotoxic medicines that are most problematic in primary care, particularly one that provides a comparison of risks across medicines. OBJECTIVE: The aim of this study was to consolidate evidence on the risks associated with medicines and acute kidney injury, with a focus on medicines used in primary care. METHOD: We searched the MEDLINE and EMBASE databases to identify published studies of all medicines associated with acute kidney injury identified from spontaneous report data. For each medicine positively associated with acute kidney injury, as identified from spontaneous reports, we implemented a sequence symmetry analysis (SSA) and a case-control design to determine the association between the medicine and hospital admission with a primary diagnosis of acute kidney injury (representing community-acquired acute kidney injury). Administrative claims data held by the Australian Government Department of Veterans' Affairs for the study period 2005-2019 were used. RESULTS: We identified 89 medicines suspected of causing acute kidney injury based on spontaneous report data and a reporting odds ratio above 2, from Japan, France and the US. Spironolactone had risk estimates of 3 or more based on spontaneous reports, SSA and case-control methods, while furosemide and trimethoprim with sulfamethoxazole had risk estimates of 1.5 or more. Positive association with SSA and spontaneous reports, but not case control, showed zoledronic acid had risk estimates above 2, while candesartan telmisartan, simvastatin, naproxen and ibuprofen all had risk estimates in SSA between 1.5 and 2. Positive associations with case-control and spontaneous reports, but not SSA, were found for amphotericin B, omeprazole, metformin, amlodipine, ramipril, olmesartan, ciprofloxacin, valaciclovir, mycophenolate and diclofenac. All with the exception of metformin and omeprazole had risk estimates above 2. CONCLUSION: This research highlights a number of medicines that may contribute to acute injury; however, we had an insufficient sample to confirm associations of some medicines. Spironolactone, furosemide, and trimethoprim with sulfamethoxazole are medicines that, in particular, need to be used carefully and monitored closely in patients in the community at risk of acute kidney injury.

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.

Acute kidney injury and acyclovir-associated encephalopathy after administration of valacyclovir in an elderly person with normal renal function: A case report and literature review.

INTRODUCTION: Acyclovir (ACV)-associated encephalopathy is related to an increase in plasma levels of 9-carboxymethoxymethylguanine, an ACV metabolite, and is often reported in patients with renal dysfunction. We report a case of ACV-associated encephalopathy with rapid progression of renal dysfunction after oral administration of valacyclovir (VACV) and review literature of previous ACV-associated encephalopathy cases. PATIENT CONCERNS: An 88-year-old man was diagnosed with herpes zoster. VACV (3000 mg/day) treatment was initiated. Serum creatinine (Cr) level was 0.80 mg/dL. However, irritability, memory impairment, and decreased responsiveness occurred after 3 days. The Cr level was 6.76 mg/dL on admission. DIAGNOSIS: He was diagnosed with ACV-associated encephalopathy with acute kidney injury. INTERVENTIONS: VACV was discontinued, hemodialysis was initiated on the day of admission, and then the signs and symptoms improved approximately 72 hours after the admission. CONCLUSION: Worsening of renal function and encephalopathy should be a focus when using VACV or ACV, regardless of age and original renal function. Acute kidney injury and ACV-associated encephalopathy may particularly occur in the elderly even when renal function is normal. Therefore, regular monitoring of renal function and consciousness is necessary during VACV treatment.

Different dosages of valaciclovir for the treatment of herpes zoster in adults: A randomized clinical study.

WHAT IS KNOWN AND OBJECTIVE: The dosages of valaciclovir used for herpes zoster treatment recommended by Chinese pharmaceutical companies can differ considerably from those reported in the literature. This randomized clinical study compares the efficacy and safety of different oral valaciclovir doses for the treatment of herpes zoster in adults. METHODS: A total of 214 patients with herpes zoster were enrolled and randomized into two groups according to age: 98 patients in the 18-44-year group (younger patients) and 116 patients in the 45-74-year group (middle-aged and elderly patients). Patients in the two age groups were then prescribed different doses of valaciclovir. The high-dose group was administered 900 mg of valaciclovir, three times daily for 10 days, whereas the low-dose group was administered 300 mg of valaciclovir, two times daily for 10 days. The efficacy and side effects of these regimens were recorded on days 6, 11 and 30. RESULTS: In total, 207 (of 214 enrolled) patients completed the study. Of the seven patients who discontinued the study, five discontinued because their follow-up time was not fixed and two withdrew after moving to other cities. At the 11th day after treatment, the clinical effect of high-dose valaciclovir groups were significantly better than that of the low-dose valaciclovir groups in middle-aged and elderly patients (p < 0.05). The difference in visual analog scale (VAS) pain scores between the two dose groups was statistically significant in middle-aged and elderly patients at the 6th day(p < 0.05), whereas there was no difference in younger patients (p > 0.05). The VAS scores were significantly lower in high-dose group than in low-dose group at day 11 in both groups of patients(p < 0.05).There was no statistically significant difference in the time to skin scab improvement between the two different dose groups in younger patients (p > 0.05). Among middle-aged and elderly patients, the incidence of postherpetic neuralgia (PHN) was significantly lower in the high-dose group than in the low-dose group (p < 0.05). The difference in the incidence of adverse reactions between the high-dose and low-dose groups was not statistically significant (p > 0.05). Overall, the main side effect was headache. WHAT IS NEW AND CONCLUSION: The present study indicates that early treatment with high-dose valaciclovir can significantly reduce pain in patients, especially in elderly patients, in whom it can also reduce the incidence of PHN. In terms of safety, no significant difference was noted in the incidence of adverse reactions between high- and low-dose groups.

Valaciclovir to prevent vertical transmission of cytomegalovirus after maternal primary infection during pregnancy: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Cytomegalovirus is a common congenital infection, with high morbidity after an early primary maternal infection. No effective means exist to prevent viral transmission to the fetus. We aimed to investigate whether valaciclovir can prevent vertical transmission of cytomegalovirus to the fetus in pregnant women with a primary infection acquired early in pregnancy. METHODS: This prospective, randomised, double-blind, placebo-controlled trial was done at the Infectious Feto-Maternal Clinic of Rabin Medical Center (Petach Tikvah, Israel). Pregnant women aged 18 years or older, with serological evidence of a primary cytomegalovirus infection acquired either periconceptionally or during the first trimester of pregnancy, were randomly assigned to oral valaciclovir (8 g per day, twice daily) or placebo from enrolment until amniocentesis at 21 or 22 gestational weeks. Randomisation was done separately for participants infected periconceptionally or during the first trimester and was done in blocks of four. Patients and researchers were masked to participant allocation throughout the entire study period. The primary endpoint was the rate of vertical transmission of cytomegalovirus. Statistical analyses were done according to per-protocol principles. The study was registered at ClinicalTrials.gov, NCT02351102. FINDINGS: Between Nov 15, 2015, and Oct 8, 2018, we enrolled and randomly assigned 100 patients to receive valaciclovir or placebo. Ten patients were excluded, five from each study group; therefore, the final analysis included 45 patients (all singletons) in the valaciclovir group and 45 patients (43 singletons and two sets of twins) in the placebo group. In the valaciclovir group, including both first trimester and periconceptional infections, five (11%) of 45 amniocenteses were positive for cytomegalovirus, compared with 14 (30%) of 47 amniocenteses in the placebo group (p=0·027; odds ratio 0·29, 95% CI 0·09-0·90 for vertical cytomegalovirus transmission). Among participants with a primary cytomegalovirus infection during the first trimester, a positive amniocentesis for cytomegalovirus was significantly less likely in the valaciclovir group (two [11%] of 19 amniocenteses) compared with the placebo group (11 [48%] of 23 amniocenteses; p=0·020. No clinically significant adverse events were reported. INTERPRETATION: Valaciclovir is effective in reducing the rate of fetal cytomegalovirus infection after maternal primary infection acquired early in pregnancy. Early treatment of pregnant women with primary infection might prevent termination of pregnancies or delivery of infants with congenital cytomegalovirus. FUNDING: None.

New evidence on prognostic features, prevention and treatment of congenital Cytomegalovirus infection.

PURPOSE OF REVIEW: Congenital Cytomegalovirus (CMV) infection remains a major cause of lifelong disability, with no systematic screening implemented in pregnancy or the postnatal period. In this review article, we outline the preventive strategies, antenatal prognostic features and experimental therapies as well as evidence of efficacy from recent trials. RECENT FINDINGS: A recent randomized, double blinded, placebo-controlled study investigated the efficacy of Valaciclovir in women contracting primary CMV in the periconception period or first trimester. They concluded that Valaciclovir at a dose of 8 g/day is effective in reducing the rate of foetal CMV infection following early maternal primary infection. Administration of CMV hyperimmune globulin (HIG) was investigated in a recent randomized double-masked controlled trial. This study concluded that CMV HIG was ineffective at reducing the risk of congenital CMV among women with primary CMV in early pregnancy. SUMMARY: Congenital CMV infection remains a significant cause of disability. There is currently no vaccine available, with the best preventive strategy being patient education on transmission as well as hygiene measures to reduce risk of exposure. Experimental therapies have been investigated in recent years and there is evidence supporting the use of Valaciclovir. Data for the efficacy of CMV HIG remains inconsistent and administration is currently limited to clinical trial settings.

PROSPECTIVE MONITORING OF DRUG USE: DRUG-INDUCED LIVER INJURY IN A PRIMARY HEALTHCARE CENTER.

BACKGROUND: Drug-induced liver injury is still misunderstood in Brazil due to diagnostic difficulties or lack of reporting incidents. OBJECTIVE: To assess the frequency of adverse events related to the use of medicines in a primary healthcare unit, in a city locate southwestern of the state of Bahia, Brazil. METHODS: Prospective study conducted at the Primary Center for Specialized Health (CEMEA), February at August of 2013 in Vitoria da Conquista, Bahia, Brazil. Interviews were conducted with patients over 18 years old, and their clinical and laboratorial data were collected. The CIOMS scale was used to validate the cases. RESULTS: A total of 149 patients, mainly Afro-Brazilian women, received follow-up. Among these patients, three cases of hepatotoxicity were identified, and the medicines associated to drug-induced liver injuries were: nimesulide, budesonide and valacyclovir. CONCLUSION: Drug-induced liver injury is rare in primary healthcare units. It also allowed estimating the incidence of hepatotoxicity induced by allopathic medicines which are standardized by public healthcare authorities.

Monitoramento prospectivo do uso de medicamentos: lesão hepática induzida por medicamentos em um centro municipal de saúde / Prospective monitoring of drug use: drug-induced liver injury in a primary healthcare center

ABSTRACT BACKGROUND: Drug-induced liver injury is still misunderstood in Brazil due to diagnostic difficulties or lack of reporting incidents. OBJECTIVE: To assess the frequency of adverse events related to the use of medicines in a primary healthcare unit, in a city locate southwestern of the state of Bahia, Brazil. METHODS: Prospective study conducted at the Primary Center for Specialized Health (CEMEA), February at August of 2013 in Vitoria da Conquista, Bahia, Brazil. Interviews were conducted with patients over 18 years old, and their clinical and laboratorial data were collected. The CIOMS scale was used to validate the cases. RESULTS: A total of 149 patients, mainly Afro-Brazilian women, received follow-up. Among these patients, three cases of hepatotoxicity were identified, and the medicines associated to drug-induced liver injuries were: nimesulide, budesonide and valacyclovir. CONCLUSION: Drug-induced liver injury is rare in primary healthcare units. It also allowed estimating the incidence of hepatotoxicity induced by allopathic medicines which are standardized by public healthcare authorities.

RESUMO CONTEXTO: As lesões hepáticas induzidas por drogas (DILI), ainda são mal compreendidas no Brasil devido a dificuldades diagnósticas ou à falta de relatos. OBJETIVO: Avaliar a frequência de eventos adversos relacionados ao uso de medicamentos em uma unidade básica de saúde, em uma cidade do sudoeste baiano. MÉTODOS: Estudo prospectivo realizado no período de fevereiro a agosto de 2013 em Vitória da Conquista, Bahia, Brasil. Entrevistas foram realizadas com pacientes maiores de 18 anos; os dados clínicos e laboratoriais foram coletados. A escala do CIOMS foi usada para avaliar causalidade dos casos. RESULTADOS: Um total de 149 pacientes, principalmente mulheres afro-brasileiras, receberam acompanhamento. Entre esses pacientes, três casos de hepatotoxicidade foram identificados e os medicamentos associados à DILI foram: nimesulida, budesonida e valaciclovir. CONCLUSÃO: DILI é raro em unidades básicas de saúde. Os três casos foram todos reversíveis, sem necessidade de internação hospitalar. Políticas de saúde que fomentam a prática da farmacovigilância são extremamente importantes para a prevenção e detecção de DILI.

Valacyclovir-induced Neurotoxicity in a Patient with a Preserved Renal Function.

Valacyclovir, a prodrug of acyclovir, is the first-line treatment for herpes zoster, but the renal function must be monitored, because acyclovir is metabolized by the kidneys. We herein report a case of valacyclovir-induced neurotoxicity with no preceding renal impairment. An 88-year-old man was admitted because of an impaired consciousness after the administration of valacyclovir at 3,000 mg daily for herpes zoster on the chest. His consciousness level gradually improved with hydration and valacyclovir withdrawal. It was later confirmed that the level of acyclovir on admission had been 35.45 µg/mL in the blood and 36.45 µg/mL in the cerebrospinal fluid.

Comparative Efficacy and Safety of Different Antiviral Agents for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation: A Systematic Review and Meta-Analysis.

Over the past 25 years, several randomized controlled trials have investigated the efficacy of different antiviral agents for cytomegalovirus (CMV) prophylaxis in allogeneic hematopoietic cell transplantation. We performed a systematic literature review, conventional meta-analysis, and network meta-analysis using a random-effects model and risk ratios (RRs) with corresponding 95% confidence intervals (CIs) as effect estimates. Fifteen randomized controlled trials were identified, including 7 different antiviral agents: acyclovir, ganciclovir, maribavir, brincidofovir, letermovir, valacyclovir, and vaccine. Twelve trials used placebo as comparator while 3 trials compared different antiviral agents. We found evidence for CMV disease and infection being significantly reduced by antiviral prophylaxis, with an RR of .66 (95% CI, .48 to .90) and .63 (95% CI, .50 to .79). Across the network, ganciclovir showed the best relative efficacy for CMV disease while letermovir provided first rank of being the best option for CMV infection. The risk for death was not significantly influenced by antiviral prophylaxis in the meta-analysis, with an RR of .92 (95% CI, .78 to 1.08), as well as in the network meta-analysis. In terms of safety, letermovir was at least similar in comparison with placebo and most agents while both letermovir and acyclovir showed significantly reduced risk for serious adverse events compared with ganciclovir, with RRs of .55 (95% CI, .30 to 1.00) for letermovir and .63 (95% CI, .42 to .93) for acyclovir. With a probability of 81%, letermovir appears to be the best option in terms of safety. Future randomized head-to-head comparisons are needed to evaluate the definite efficacy and safety of different prophylactic strategies.