Topical Treatment of Acyclovir-Resistant Herpes Simplex Virus Stomatitis after Allogeneic Hematopoietic Cell Transplantation.

INTRODUCTION: We report on patients who developed severe acyclovir-resistant (ACVr) herpes simplex virus 1 (HSV-1) stomatitis after allogeneic hematopoietic cell transplantation (HCT). PATIENTS: HCT patients suffering from HSV-1 stomatitis without response after 1 week of high-dose acyclovir (ACV) were tested for ACV resistance. Patients with proven ACV resistance were treated either topically with cidofovir solution and gel or with topical foscavir cream or with intravenous foscavir. RESULTS: Among 214 consecutive HCT patients, 6 developed severe ACVr HSV-1 stomatitis (WHO grade III n = 1, WHO grade IV n = 5). All 6 patients suffered from relapse of acute myeloid leukemia (AML) after HCT. ACVr stomatitis was treated topically with first-line (n = 4) or second-line (n = 2) cidofovir. Topical foscavir cream was applied as first-line (n = 1) or second-line (n = 1) therapy. Intravenous foscavir was used in 3 patients (first-line therapy, n = 1; second-line therapy, n = 2). Complete remission was reached by topical cidofovir (n = 3), topical foscavir (n = 1), and intravenous foscavir (n = 1), respectively. Five of the 6 patients died due to progression of leukemia. Only 1 patient survived. CONCLUSIONS: ACVr HSV-1 stomatitis is a severe complication in AML patients relapsing after HCT. It reflects the seriously impaired general condition of these patients. This analysis shows that topical treatment with cidofovir or foscavir might be a sufficient first-line therapy approach in ACVr HSV-1 stomatitis. It might serve as a less toxic alternative to intravenous foscavir.

Cost analysis of ganciclovir and foscarnet in recipients of allogeneic hematopoietic cell transplant with cytomegalovirus viremia.

BACKGROUND: Ganciclovir (GCV) and foscarnet (FOS) are the most commonly used antivirals for preemptive treatment of cytomegalovirus (CMV) viremia in recipients of allogeneic hematopoietic cell transplantation (alloHCT). The current literature indicates similar efficacy between these agents. Thus, the primary consideration for choice of initial anti-CMV treatment is the safety profile, time period after alloHCT, and concern of myelosuppression or renal dysfunction. METHODS: Herein, we retrospectively reviewed medical records of 124 alloHCT recipients who received GCV or FOS between April 27, 2014, and December 31, 2015, during the first year post-transplant. Healthcare resource use included drug, hospitalization, home health, dialysis, and growth factor costs. RESULTS: Total duration of therapy was longer in the GCV group (37 days vs 28 days, P = .21) but hospitalization days were similar (9 days) in both groups. The total treatment cost was significantly lower in the GCV group ($38 100 vs $59 400, P < .05). CONCLUSION: Preemptive anti-CMV therapy is associated with major healthcare resource costs, which were greater in patients who required FOS than those who were treated with GCV.

Recommended foscarnet dose is not associated with improved outcomes in cytomegalovirus salvage therapy.

BACKGROUND: Cytomegalovirus (CMV) infection causes significant morbidity and mortality in transplant recipients. Ganciclovir and valganciclovir have proven efficacy but are limited by resistance and toxicity, whereas foscarnet typically retains activity when CMV has become resistant to other antivirals. Foscarnet dosing used in practice may be discordant with what is recommended in product labeling, as the result of an unconventional dosing nomogram or prescriber preference; however, it is unknown how discordant foscarnet dosing affects outcomes. OBJECTIVE: Our purpose was to characterize the relationship between initial foscarnet dosing intensity (relative to product labeling) and key effectiveness and safety endpoints. STUDY DESIGN: This single-center, retrospective study included immunosuppressed adults with CMV viremia who received foscarnet between January 2012-July 2017. Subjects were divided into low dose (LD) and non-low dose (NLD) groups, according to foscarnet dose intensity. The primary endpoint was time-to-CMV eradication. Secondary endpoints included time-to-CMV clearance, acute kidney injury, hematologic toxicity, and mortality. RESULTS: Of 87 subjects, 38 met inclusion. Primary immunosuppression reasons were solid organ (63%) or hematopoietic cell transplant (29%). Seventeen and 21 subjects were in the LD and NLD groups, respectively. Median time-to-CMV eradication was 17 days (LD group) versus 13 days (NLD group), p = 0.823. Median time-to-CMV clearance was also non-significant (p = 0.505). There was no association between initial foscarnet dosing intensity and acute kidney injury, hematologic toxicity, or mortality (24% in both groups). CONCLUSIONS: These findings suggest outcomes may be sensitive to other factors and underscore the need for further studies to improve understanding of foscarnet dosing in immunosuppressed patients.

Acute retinal necrosis in a patient with remote severe herpes simplex encephalitis.

A 60-year-old man with a history of severe herpes simplex virus type 1 (HSV-1) encephalitis 2 years prior presented with acute onset of visual loss in the left eye. Dilated funduscopic examination showed retinitis and occlusive vasculitis with retinal necrosis. PCR of the vitreous fluid was positive for HSV-1, and he was diagnosed with acute retinal necrosis (ARN) due to HSV-1. The patient was treated with intravenous acyclovir and intravitreous foscarnet for 2 weeks, followed by high dose oral valacyclovir for 2 weeks. He was subsequently placed on planned life-long suppressive valacyclovir. His case demonstrates that acute visual loss concomitant with or subsequent to HSV-1 encephalitis warrants suspicion of ARN. Prompt therapy with effective antiviral medication is necessary to reduce the risk of sight-threatening complications. Chronic suppression with oral antiviral therapy after ARN is recommended to prevent involvement of the contralateral eye, though there is no consensus on the duration and dosage of antivirals.

Acyclovir Unresponsive Herpes Simplex Encephalitis in a child successfully treated with the addition of Foscarnet: Case report. / Encefalitis por herpes simple resistente al aciclovir en un niño tratado satisfactoriamente con el agregado de foscarnet: A propósito de un caso.

Herpes simplex encephalitis (HSE) is the most common cause of sporadic focal encephalitis worldwide. Acyclovir is the treatment of choice of HSE since the 1980s. After the widespread use of acyclovir, HSE related mortality rate had reduced but resistant strains emerged. Acyclovir resistant HSV incidence was reported as about 0.5 % and 3.5 %-10 % in immunocompetent and immunocompromised patients, respectively. Herein, a 12-year-old immunocompetent patient with HSV-1 encephalitis who was successfully treated with combined acyclovir and foscarnet therapy is described. In the case of deteriorating clinical condition under acyclovir treatment even if the absence of demonstration of increased CSF HSV viral load, the possibility of acyclovir resistant HSE and the addition of foscarnet to the acyclovir treatment might be considered.

La encefalitis por herpes simple (EHS) es la causa más frecuente de encefalitis focal esporádica en todo el mundo. El aciclovir es el tratamiento preferido para la EHS desde la década de 1980. Después del uso generalizado del aciclovir, se redujo la tasa de mortalidad relacionada con la EHS pero surgieron cepas resistentes. Se ha informado que la incidencia de virus del herpes simple (VHS) resistente al aciclovir es del 0,5 % y del 3,5 %-10 % aproximadamente en los pacientes inmunocompetentes e inmunocomprometidos, respectivamente. En este artículo, describimos el caso de un paciente inmunocompetente de 12 años de edad con encefalitis por VHS-1 tratado satisfactoriamente con aciclovir y foscarnet. En el caso de una condición clínica que desmejora con el tratamiento con aciclovir, incluso si no se demuestra un aumento de la carga viral del VHS en el líquido cefalorraquídeo, se podría considerar la posibilidad de EHS resistente al aciclovir y el agregado de foscarnet al tratamiento con aciclovir.

Improvement of refractory acyclovir-resistant herpes simplex virus type 1 infection by continuous acyclovir administration.

Resistant herpes simplex virus type 1 (HSV-1) infection is sometimes fatal for immunocompromised patients. Here, we report 10-year-old girl receiving hematopoietic stem cell transplantation developed refractory HSV-1 infection, which was persisted to intermittent acyclovir (ACV) or foscarnet (FOS) administrations but was improved by continuous ACV administration. The isolates from the lesion were identified with low susceptibilities to ACV and FOS by plaque reduction assay due to DNA pol gene mutation. Continuous ACV administration overcomes the efficacy of intermittent administration and could be the best option to treat severe HSV-1 infectious patients.

Resistant Cytomegalovirus Infection in Solid-organ Transplantation: Single-center Experience, Literature Review of Risk Factors, and Proposed Preventive Strategies.

BACKGROUND: Cytomegalovirus (CMV) infection causes morbidity and mortality in solid-organ transplant recipients. Drug-resistant CMV is an emerging problem with poor survival outcomes and limited therapeutic options. In this study we comprehensively address the issue of drug resistance in CMV when compared with standard therapies, such as ganciclovir (GCV) and foscarnet. METHODS: We conducted a retrospective review of adult patients diagnosed with CMV after solid-organ transplant at our center between 2013 and 2017, and identified 7 resistant CMV cases. To study risk factors in the published literature, we performed an extensive database search. RESULTS: All patients had documented UL97 mutations, and 3 patients harbored both UL97 and UL54 mutations. For cases with increasing viral load or failure to achieve clinical improvement despite optimal therapy, genetic resistance testing was carried out. Patients received GCV and foscarnet combination therapy. As an adjunct, CMV immunoglobulin, cidofovir, and leflunomide were added. Risk factors, including donor+/recipient- serostatus, persistent high viral replication, prolonged therapeutic GCV exposure (>2.5 months), and allograft rejection, were assessed. CONCLUSION: Patients at risk, especially those with D+/R- serostatus, should be judiciously monitored for resistance. Prolonged intravenous GCV exposure increases the risk for development of drug resistance. Therefore, precise guidelines are required for prevention of long-term GCV/VGCV exposure. Investigation regarding interferon-gamma release assay and adoptive transfer of T cells in diagnosed CMV patients is warranted to improve future prophylactic and management strategies against CMV, with a potential to reduce the requirement for available toxic antiviral drugs.

[Clinical study of low cytomegalovirus viral load thresholds for preemptive antiviral therapy in hematopoietic cell transplant recipients].

Objective: To investigate the threshold of cytomegalovirus (CMV) DNAemia for preemptive antiviral therapy in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Viral load between 1×10(3) copies/ml and 5×10(3) copies/ml was defined as low viral load by real time Q-PCR. Clinical data and outcome were collected. Results: A total of 95 allo-HSCT recipients with low viral load from September 2014 to February 2015 were recruited in this study. The control group included 37 patients who received preemptive initial antiviral therapy. The other 58 patients didn't received antiviral treatment after positive viremia was confirmed. During monitoring, CMV viremia was cleared spontaneously in 17 patients of study group. Among 41 patients with continuous positive viremia in study group, 26 patients received antiviral therapy after second positivity including 18 with viral load >5×10(3) copies/ml, 2 with fever but still low viral load, 2 with hemorrhagic cystitis and low viral load, 4 with continuous low viral load. Eleven patients received antiviral therapy after the third positivity including 5 with viral load >5×10(3) copies/ml, 1 low viral load patient with fever and diarrhea, 5 with continuous low viral load. Only 4 patients received antiviral therapy after the fourth positivity of >5×10(3) copies/ml. In the study group, 35 cases received ganciclovir and 6 cases received foscarnet. The incidence of neutropenia did not differ significantly between study and control groups [minimum of neutrophil count: (1.63±0.41)×10(9)/L vs. (1.58±0.36)×10(9)/L]. The proportion of viral load greater than 5×10(3) copies/ml in the first week was comparable in two groups. Successful viral clearance rate was not statistically different (P=0.87). Of all 95 patients, no CMV diseases developed, neither did patient die of CMV infection. Conclusions: Spontaneous clearance of viremia occurs in some patients receiving allo-HSCT with low CMV viral load. Delayed antiviral treatment of continuous positive viremia does not prolong the whole treatment duration, neither contributes to the progression of CMV diseases.

High-dose Valganciclovir Treatment for Resistant Cytomegalovirus Colitis due to UL97 and UL54 Mutations.

We report the first case of a ganciclovir-resistant cytomegalovirus (CMV) involving the gastrointestinal tract that was successfully treated with high-dose valganciclovir. A kidney transplant recipient developed drug-resistant CMV colitis which was initially treated with valganciclovir, but his CMV was found to have major resistance to ganciclovir and cidofovir due to UL97 and UL54 mutations. The patient was switched to intravenous foscarnet 40 mg/kg given every twelve hours. However, foscarnet had to be discontinued after 4 days of treatment due to acute kidney injury. Patient was restarted on valganciclovir at a higher target dose of 1800 mg twice a day based on the creatinine clearance. CMV became undetectable 2 weeks after valganciclovir treatment was completed. High-dose valganciclovir along with immune suppression reduction may be a treatment option for CMV colitis with ganciclovir resistance due to dual UL97 and UL54 gene mutations.

Ganciclovir Dosing Strategies and Development of Cytomegalovirus Resistance in a Kidney Transplant Recipient: A Case Report.

In renal transplant recipients, delayed graft function and accompanying renal impairment may lead to therapeutic underexposure of valganciclovir. We describe a case of a cytomegalovirus (CMV)-seronegative kidney transplant recipient from a CMV-seropositive donor, whose course was complicated during valganciclovir prophylaxis by CMV disease, ultimately progressing to ganciclovir, foscarnet, and cidofovir resistance. Assessments and adjustments for renal dysfunction, according to both Cockgroft-Gault and Modification of Diet in Renal Disease study equations, are described. Therapy was complicated by outpatient parenteral therapy with pump-administered antiviral therapy, which may have led to drug underexposure and the fostering of antiviral resistance. Suppression was ultimately achieved in conjunction with reduction in immunosuppressive therapy, CMV immunoglobulin, and initiation of leflunomide. At-risk recipients may benefit from 24 hour creatinine clearance assessments, direct creatinine clearance measurement, or therapeutic drug monitoring. Optimal dosing strategies in recipients with impaired kidney function remain undefined, with limited pharmacokinetic data to date.

Foscarnet calcium microcrystals as the intravitreal drug depot.

Foscarnet sodium is an antiviral drug for the treatment of CMV retinitis, currently in the form of twice-weekly intravitreal injection. Here we developed foscarnet calcium microcrystals as the drug depot, and using the rabbit model we demonstrated that the injected microcrystals maintained a therapeutically relevant drug concentration in the vitreous for more than 3 months.

Acyclovir resistant acute herpes simplex encephalitis associated with acute retinal necrosis: A case report and review of the literature.

A 55-year-old man was admitted to our hospital for investigation of high fever, decreased consciousness and bilateral visual impairment. His cerebrospinal fluid analysis revealed pleocytosis of mononuclear cells and an increased protein concentration. FLAIR images revealed multiple high-intensity lesions in the frontal lobe, part of which was enhanced with gadolinium. Despite initiating treatment with acyclovir and corticosteroids, his consciousness and visual acuity deteriorated. Immunopathological examination of brain biopsies showed numerous herpes simplex virus type 2-positive neurons and macrophages, leading to a diagnosis of herpes simplex encephalitis (HSE). Fundoscopic examination revealed multiple foci of retinitis with vasculopathies, and inflammation in the anterior chamber and vitreous, indicating acute retinal necrosis (ARN). Foscarnet treatment was initiated in place of acyclovir and his consciousness improved, with a slight improvement in visual acuity. ARN is typically caused by a herpes virus infection limited to the eyeball, and rarely in combination with HSE. In such cases, there is a latency of approximately 2-4 weeks between ARN and the onset of encephalitis. Our case is unique in that HSE and ARN developed simultaneously, and it highlights that there may not always be a latency between the onsets of the two disorders. Finally, foscarnet should be considered in cases of HSE and ARN with acyclovir resistance.

Recurrent Herpes Labialis in Adults: New Tricks for an Old Dog.

Herpes labialis remains a common worldwide affliction. Recent advances in understanding the basic pathogenesis have led to new therapeutic intervention, both on-label and off-label. Aside from reducing the duration and symptomatology of acute outbreaks, another goal of treatment is to decrease the frequency of future episodes. Oral and topical acyclovir and its analogues are the mainstay of both chronic suppressive and episodic therapy. A new muco-adhesive formulation of acyclovir provides a decrease in outbreaks, probably due to a diminution of herpesvirus load in all reservoir sites. Acyclovir-resistant strains are rare in immunocompetent hosts; parenteral foscarnet and cidofovir are administered in this situation. Parenteral acyclovir is the drug of choice for eczema herpeticum, which may begin as herpes labialis in an atopic dermatitis patient. Thermotherapy may be beneficial, and a certified device to deliver heat is available outside the United States.

J Drugs Dermatol. 2017;16(3 Suppl):s49-53.

Foscarnet-related Hypercalcemia During CMV Treatment in an Infant With SCID: A Case Report and Review of Literature.

Foscarnet is a main treatment for disseminated cytomegalovirus infection in immunocompromised patients. One of its documented side effects is hypocalcemia. Hypercalcemia, in contrast, was described anecdotally before, almost exclusively in adults with human immunodeficiency virus infection or posttransplantation. We describe a case of severe hypercalcemia during foscarnet treatment in an infant with IL-7 Rα deficient severe combined immunodeficiency, resolved after treatment cessation. We speculate that this unusual side effect is caused by foscarnet binding to the inorganic matrix of bone.

Cytomegalovirus sinusitis complicated by orbital apex syndrome in an immunocompromised host.

Sinusitis in immunocompromised patients can be caused by a wide variety of pathogens, primarily bacterial and fungal in nature. Tissue invasion can extend into the orbital apex and result in ophthalmoplegia and blindness. We report the first histologically proven case, to our knowledge, caused by cytomegalovirus infection.

Brincidofovir clearance of acyclovir-resistant herpes simplex virus-1 and adenovirus infection after stem cell transplantation.

Infections with adenovirus (AdV) and herpesviruses can result in considerable morbidity and mortality in pediatric hematopoietic stem cell transplant (SCT) recipients. Herpes simplex virus (HSV) reactivations are usually prevented by acyclovir (ACV) prophylaxis, whereas cidofovir (CDV) has been used off indication to manage AdV infections. We report a child with myelodysplastic syndrome undergoing multiple SCT, who experienced HSV-1 disease including severe mucositis and herpetic whitlow, as well as high viral load AdV DNAemia. Both ACV and CDV were ineffective; however, viral loads were decreased with brincidofovir, resulting in viral clearance. A subsequent Epstein-Barr virus disease with relevant meningoencephalitis responded to rituximab.

Brincidofovir treatment of acyclovir-resistant disseminated varicella zoster virus infection in an immunocompromised host.

Brincidofovir (BCV) is a broad-spectrum antiviral agent active in vitro against double-stranded DNA viruses including herpesviruses, adenoviruses, polyomaviruses, and poxviruses. We report successful BCV use in management of disseminated acyclovir- and cidofovir-resistant varicella zoster virus in an immunocompromised hematopoietic stem cell transplant patient with chronic graft-versus-host disease who was intolerant to foscarnet.