Evicenter
P&T meetings

Hovilpri (pritelivir)

Refractory mucocutaneous herpes simplex virus infection in immunocompromised adults

Also known as AIC316
Last updated
239 sources

Product information and disease descriptionPlace of product in therapyApproaches to treatmentCurrent treatment options and standard of care

High-dose and continuous-infusion acyclovir

20 evidence topics · 12 sources

British Association for Sexual Health and HIV guideline: partially resistant strains

“Partially resistant strains may sometimes be successfully treated with high dose intravenous aciclovir and other nucleoside analogues but fully aciclovir-resistant strains are resistant to valaciclovir and ganciclovir, and the majority are resistant to famciclovir.” (opens the source at this quote in a new tab)

European guideline for genital herpes: partially resistant strains

“Partially resistant strains may sometimes be successfully treated with high‐dose intravenous aciclovir and other nucleoside analogues but fully aciclovir‐resistant strains are resistant to valaciclovir and ganciclovir, and the majority are resistant to famciclovir.” (opens the source at this quote in a new tab)

Cross-resistance of acyclovir-resistant strains in United States guidelines

“All acyclovir-resistant strains are also resistant to valacyclovir, and most are resistant to famciclovir.” (opens the source at this quote in a new tab)

“All acyclovir-resistant strains are also resistant to valacyclovir, and the majority are resistant to famciclovir.” (opens the source at this quote in a new tab)

High-dose intermittent acyclovir as a first step in a review algorithm

“An initial step in case of treatment failure with oral drugs is to switch to high doses of intravenous ACV (10 mg/kg of body weight every 8 h adjusted for renal function).” (opens the source at this quote in a new tab)

“Most successful treatment of refractory ACV-resistant HSV infections has been achieved with the use of FOS.” (opens the source at this quote in a new tab)

Labeled indication and dose of intravenous acyclovir for mucocutaneous HSV infection in immunocompromised patients

“ZOVIRAX for Injection is indicated for the treatment of initial and recurrent mucosal and cutaneous herpes simplex (HSV-1 and HSV-2) in immunocompromised patients.” (opens the source at this quote in a new tab)

“Adults and Adolescents (Aged 12 years and older): 5 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.” (opens the source at this quote in a new tab)

“A maximum dose equivalent to 20 mg/kg every 8 hours should not be exceeded for any patient.” (opens the source at this quote in a new tab)

Continuous-infusion regimen and regulatory status as tabulated in a review
FieldQuoted entry
Dose“30–50 mg/kg daily continuous infusion”
Clinically significant adverse reactions“Nephrotoxicity: interstitial nephritis or renal tubular necrosis”“Neurotoxicity: agitation, confusion, dysarthria, hallucination, and impaired consciousness”
Monitoring“Serum creatinine”
FDA approval or off-label use“Off-label use”
Continuous infusion in 6 allogeneic transplant recipients: population and prior treatment failure

“We present a series of patients with ACV-resistant HSV following HCT who were successfully treated with continuous infusion high-dose ACV after failing standard treatment regimens for ACV-resistant HSV.” (opens the source at this quote in a new tab)

“Six HCT recipients experienced severe HSV disease requiring i.v. antiviral therapy and did not respond or could not tolerate conventionally dosed, intermittent, therapy with either ACV or FOS” (opens the source at this quote in a new tab)

“Five of 6 had undergone myeloablative transplants, and 5 of 6 experienced GVHD, which required the administration of systemic immunosuppressive medication at the time of development of HSV disease.” (opens the source at this quote in a new tab)

“All had ACV resistance, the majority of which with very high levels of resistance to both ACV and FOS.” (opens the source at this quote in a new tab)

“Dose ranges: ACV 400 mg by mouth 5 times daily to 10 mg/kg i.v. every 8 hours; CID 5 mg/kg weekly; FOS 40-50 mg/kg; FAM 1-3 g by mouth daily (in divided doses).” (opens the source at this quote in a new tab)

Continuous infusion in 6 allogeneic transplant recipients: dose and outcome by case
CaseHSV type and locationFailed treatment regimensContinuous acyclovir dose (mg/kg/day)Outcome and time to response
Case 1“HSV-2; Genitalia Naris”“ACV PO FAM PO ACV IV FOS i.v. CID i.v.”“30”“Resolved 6 weeks”
Case 2“HSV-2; Genitalia, buttocks, thighs”“ACV i.v. FOS i.v.”“45”“Resolved 2 months”
Case 3“HSV-1; OP”“ACV i.v. FOS i.v.”“30”“Resolved 1 week”
Case 4“HSV-1; OP”“ACV i.v. FAM PO”“30-50”“Partially resolved”
Case 5“HSV-1; Naris”“ACV PO FAM PO”“30”“Resolved 1 week”
Case 6“HSV-1; OP”“ACV i.v.”“30”“Resolved 1 week”
Continuous infusion in 6 allogeneic transplant recipients: clinical response

“With the exception of the patient described in case 1, all the patients in this series were treated for their HSV disease with high-dose continuous infusion ACV alone with good clinical response.” (opens the source at this quote in a new tab)

“For most of the cases described here, clinical response was seen within 72 hours of continuous ACV administration” (opens the source at this quote in a new tab)

“Four of 6 patients failed to improve when receiving the same total daily dose given on an intermittent dosing schedule.” (opens the source at this quote in a new tab)

“Interestingly, 4 of the 6 isolates demonstrated in vitro resistance to foscarnet” (opens the source at this quote in a new tab)

“She died a week later from respiratory failure not thought to be related to her oral HSV infection.” (opens the source at this quote in a new tab)

Continuous infusion in 6 allogeneic transplant recipients: tolerability

“In each case, continuous ACV dosing was well tolerated, even in patients with renal insufficiency and concurrent administration of systemic immunosuppressive therapies such as cyclosporine and tacrolimus.” (opens the source at this quote in a new tab)

“No toxicity, including episodes of neutropenia, exacerbations of other cytopenias, or worsening in renal function, was observed during continuous ACV administration.” (opens the source at this quote in a new tab)

“No substantive changes in dosages of concomitant medications were required during continuous ACV therapy.” (opens the source at this quote in a new tab)

Continuous infusion in 6 allogeneic transplant recipients: limits of the evidence and conclusion

“It is not known whether serum ACV levels consistently correlate with clinical outcome.” (opens the source at this quote in a new tab)

“Without serum levels, it is difficult to determine the exact pharmacologic determinate of clinical success for these 6 patients.” (opens the source at this quote in a new tab)

“It is also possible that immunologic factors such as improvement in T cell function could also have played a role in resolution of HSV infection.” (opens the source at this quote in a new tab)

“Continuous infusion of high-dose ACV is a well-tolerated alternative treatment for patients with infection because of ACV-resistant or multidrug resistant HSV who are failing or intolerant of therapy with standard-dose intermittent infusion of ACV, FOS, CID, or ganciclovir.” (opens the source at this quote in a new tab)

Earlier reports of continuous infusion as summarized in the transplant series

“A search of the PubMed database revealed only 2 small case series and 1 case report showing the success of continuous infusion high-dose ACV for severe HSV infection” (opens the source at this quote in a new tab)

“In 1 report, 3 patients with mucocutaneous lesions because of HSV improved after receiving high-dose continuous infusion at 29 to 150 mg/kg ACV per day, with steady-state concentrations targeted between 20 to 80 μmol/liter for 8 to 46 days” (opens the source at this quote in a new tab)

“In a second report, 2 patients with acquired immunodeficiency syndrome with severe ulcerative proctitis because of ACV-resistant HSV were successfully treated with 6 weeks of high-dose, continuous acyclovir infusion (1.5-2.0 mg/kg/hour, 36 to 48 mg/kg/day).” (opens the source at this quote in a new tab)

“These patients achieved plasma ACV levels between 4.5 and 6.75 mg/L without adverse events” (opens the source at this quote in a new tab)

Continuous infusion for HSV-2 proctitis in 2 people with AIDS

“Two patients with acquired immunodeficiency syndrome who developed severe ulcerative proctitis caused by herpes simplex virus type 2 that was resistant to acyclovir were successfully treated with 6 weeks of high-dose, continuous-infusion acyclovir sodium (1.5 to 2.0 mg/kg per hour).” (opens the source at this quote in a new tab)

“Viruses cultured from the lesions were resistant to acyclovir in vitro after the patients had received prolonged therapy with oral and intravenous acyclovir in traditional divided doses.” (opens the source at this quote in a new tab)

“The first patient's isolate was deficient of all thymidine-kinase activity, while the second patient's isolate had a thymidine kinase with altered substrate specificity for acyclovir.” (opens the source at this quote in a new tab)

“The continuous infusion was safe, well tolerated, and done in an outpatient setting with weekly clinic visits and monitoring of creatinine and acyclovir levels.” (opens the source at this quote in a new tab)

Real-world cohort of 125 hematopoietic cell transplant recipients: high-dose intravenous acyclovir before second-line therapy

“Of 43 patients who received HD IV acyclovir, 33 patients (76.7%) eventually received foscarnet.” (opens the source at this quote in a new tab)

“Seventy-seven percent of patients who received HD acyclovir were switched to second-line therapies.” (opens the source at this quote in a new tab)

“One-third of patients received high-dose IV acyclovir before second-line therapies, despite limited data for efficacy of high-dose IV acyclovir for acyclovir-resistant HSV.” (opens the source at this quote in a new tab)

“Clinical responses with continuous infusion of high-dose IV acyclovir have also been described in a case series” (opens the source at this quote in a new tab)

Single-center cohort of 18 allogeneic transplant recipients: intravenous acyclovir before foscarnet or cidofovir

“All patients were initially treated with high-dose oral valacyclovir (1000 mg every 8 hours) or intravenous acyclovir (5–10 mg/kg every 8 hours) without a response and then were transitioned to foscarnet and/or cidofovir (topical or intravenous).” (opens the source at this quote in a new tab)

“IV acyclovir treatment dose used 5 to 10 mg /kg iv q 8 hours” (opens the source at this quote in a new tab)

“Moreover, in our cohort, few patients responded to either intravenous foscarnet or high-dose intravenous acyclovir despite having isolates that were phenotypically resistant to either antiviral therapy.” (opens the source at this quote in a new tab)

Continuous infusion as assessed in a review of transplant recipients

“Higher doses of ACV administered through continuous i.v. infusion were previously used to overcome ACV resistance in HCT recipients” (opens the source at this quote in a new tab)

“High-dose continuous i.v. ACV was administered at 30 mg/kg/day for four patients and up to 45 or 50 mg/kg/day for two patients.” (opens the source at this quote in a new tab)

“Positive clinical responses were reported in five patients within 72 hours of therapy.” (opens the source at this quote in a new tab)

“The role of continuous i.v. ACV as a proper therapeutic strategy for patients with R/R HSV infections is worth exploring.” (opens the source at this quote in a new tab)

Published evidence for systemic options as characterized in a multicenter cohort report

“Additionally, treatment outcomes for resistant HSV with these regimens remain understudied, with descriptions often limited to case reports or case series that are impacted by success bias.” (opens the source at this quote in a new tab)

Renal warnings and precautions in the intravenous acyclovir prescribing information

“Intravenous infusions must be given over a period of at least 1 hour to reduce the risk of renal tubular damage” (opens the source at this quote in a new tab)

“Renal failure, in some cases resulting in death, has been observed with acyclovir therapy” (opens the source at this quote in a new tab)

“Precipitation of acyclovir crystals in renal tubules can occur if the maximum solubility of free acyclovir (2.5 mg/mL at 37°C in water) is exceeded or if the drug is administered by bolus injection.” (opens the source at this quote in a new tab)

“Ensuing renal tubular damage can produce acute renal failure.” (opens the source at this quote in a new tab)

“Concomitant use of other nephrotoxic drugs, pre-existing renal disease, and dehydration make further renal impairment with acyclovir more likely.” (opens the source at this quote in a new tab)

“Administration of ZOVIRAX by intravenous infusion must be accompanied by adequate hydration.” (opens the source at this quote in a new tab)

Neurologic and other adverse reactions in the intravenous acyclovir prescribing information

“Approximately 1% of patients receiving intravenous acyclovir have manifested encephalopathic changes characterized by either lethargy, obtundation, tremors, confusion, hallucinations, agitation, seizures, or coma.” (opens the source at this quote in a new tab)

“Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), which has resulted in death, has occurred in immunocompromised patients receiving acyclovir therapy.” (opens the source at this quote in a new tab)

“The adverse reactions listed below have been observed in controlled and uncontrolled clinical trials in approximately 700 patients who received ZOVIRAX at ~5 mg/kg (250 mg/m2) 3 times daily, and approximately 300 patients who received ~10 mg/kg (500 mg/m2) 3 times daily.” (opens the source at this quote in a new tab)

“The most frequent adverse reactions reported during administration of ZOVIRAX were inflammation or phlebitis at the injection site in approximately 9% of the patients, and transient elevations of serum creatinine or BUN in 5% to 10%” (opens the source at this quote in a new tab)

“Nausea and/or vomiting occurred in approximately 7% of the patients” (opens the source at this quote in a new tab)

Dose adjustment of intravenous acyclovir for renal impairment
Creatinine clearance (mL/min/1.73 m2)Percent of recommended doseDosing interval (hours)
Greater than 50“100%”“8”
Greater than 25 to 50“100%”“12”
Greater than 10 to 25“100%”“24”
10 or less“50%”“24”