Clinical Review of Risk of Nephrotoxicity with Acyclovir Use for Treatment of Herpes Simplex Virus Infections in Neonates and Children

In 1977, acyclovir (ACV), ((9-[(2-hydroxyethoxy) methyl] guanine), Zovirax), was identified as a selective and a specific inhibitor of the replication of herpes simplex virus (HSV), in vitro.¹  Since then, extensive work has been conducted to establish its in vivo efficacy and effectiveness against the herpes group of viruses and to assess its potential toxicity.²  ACV became the drug of choice to treat neonates and children with suspected or proven HSV infections.^3,4  Most ACV is cleared intact through the kidney.^5,6  Therefore, one of the major concerns with ACV administration is the impairment of renal function.^5,6  The mechanism of ACV nephrotoxicity is mostly attributed to the deposition of crystals in the lower nephron, causing obstructive nephropathy.^5–7  Acyclovir crystallization is most pronounced when the drug concentration in the kidney exceeds its solubility threshold. This can be prevented by slow intravenous infusion of the drug, adequate fluid hydration, and dosage reduction in patients with renal insufficiency.⁶  However, there have been several documented cases of ACV-induced nephrotoxicity in the absence of crystalluria.^8,9  Renal biopsies in these patients showed flattened, vacuolated, bulging epithelial cells or tubulointerstitial nephritis with intratubular casts and no evidence of crystals.^8,9  Thus, other proposed etiologies for ACV nephrotoxicity include microangiopathy, interstitial nephritis, and direct injury to renal tubular cells.^6,10 

Neonatal HSV type 1 and 2 infections occur in the United States at an estimated incidence of 8.4 to 60 cases per 100,000 births and are associated with substantial morbidity and mortality even with appropriate treatment.¹¹⁻¹⁵  Likewise, HSV type 1 and 2 infections in children are associated with long-term adverse neurologic outcomes despite proper antiviral therapy.¹⁶  The potentially devastating outcomes of these diseases are lessened with earlier initiation of ACV.^3,17  Thus, ACV is administered presumptively to both neonates and children with suspected HSV infections.^3,17  As a result, there is a need to balance the potential risk of these diseases with the possible side effects of ACV exposure, such as nephrotoxicity. We conducted an extensive search of the literature to assess the rates of kidney injury and identify risk factors for nephrotoxicity in neonates (ages <3 months) and children (ages ≥3 months to <12 years) receiving intravenous (IV) ACV for the management of invasive HSV type 1 and 2 infections (any neonatal infection or HSV encephalitis [HSE] in children). Our goals were first to clarify the risk of nephrotoxicity with IV use of ACV for the aforementioned indications and then identify gaps in current knowledge on ACV-associated nephrotoxicity in this patient population that could be further investigated.

Literature Search. Comprehensive literature searches were conducted (January 1, 1975–November 1, 2021) in PubMed, Embase, Web of Science, Cochrane Library, and CINAHL databases. We used the following search strategy (“acute kidney failure” OR “nephrotoxicity” OR “acute kidney injury” OR “kidney injury” OR “renal failure” OR “renal injury” OR “AKI”) AND (“acyclovir” OR “acyclovir” OR “Zovirax”). We then supplemented our search using references from included articles and relevant reviews.

Articles were included if they were written in English and evaluated ACV-associated nephrotoxicity in our patient population. They were excluded if they focused on the oral use of ACV, only evaluated its use for indications other than neonatal or pediatric invasive HSV type 1 and 2 infections, or examined the dosing of IV ACV in patients receiving continuous renal replacement therapy or extracorporeal membrane oxygenation therapy; they were also excluded if the study mainly described ACV pharmacokinetic properties or summarized the adverse events drug reports of various nephrotoxic drugs (Figure 1).

Earlier studies on ACV use included study cohorts that ranged from the neonatal age group through adult life. Thus, the summary of our search was divided into a list of studies that only assessed IV ACV use in neonates and another list that evaluated its use in children including some neonates.

Definition of Acute Kidney Injury. Acute kidney injury (AKI) is described as an acute decline in kidney function leading to disturbances in fluid balance, electrolytes, and wastes.¹⁸  Multiple studies have described an increased risk of chronic kidney disease in children^19,20  or neonates^21,22  who survived 1 episode of AKI. Unfortunately, studies that evaluated the risk of nephrotoxicity with IV ACV use adapted various definitions of AKI. The serum creatinine (SCr) concentration, a metabolic byproduct of muscle metabolism, is the most common biomarker used to diagnose AKI.²³  On the first day of life, SCr values reflect maternal levels. Subsequently, these values decrease over days to weeks such that neonatal concentrations average 0.1 to 0.3 mg/dL,²⁴  then progressively increase through childhood such that levels in older children average 0.4 to 0.8 mg/dL.²⁴  Serum creatinine can be used to calculate estimated glomerular filtration rate (eGFR), the combined total filtration rate of the functioning nephron units, using equations such as the modified Schwartz.^25–28  Acute kidney injury represents an abrupt decline in kidney function (eGFR), reflected as an increase in SCr from baseline. Multiple classifications of AKI have been published to stage the severity of AKI in adults, and these classifications have been further modified to account for the developmental changes in renal physiology between infants, children, and adults.^18,29–31  Although a detailed discussion of the differences between the various designations of AKI is beyond the scope of this manuscript, a summary of the definitions used in this review is listed in Table 1.

ACV-Associated Nephrotoxicity in Neonates. Neonatal HSV type 1 and 2 infections manifest as 1) skin, eye, and/or mouth (SEM) disease; 2) encephalitis with or without skin involvement (central nervous system [CNS]) disease; or 3) disseminated infections.³²  SEM is treated with a shorter course of ACV and has less morbidity than CNS or disseminated disease. Historically, the mortality of infants with disseminated HSV exceeded 50%, and more than 70% of surviving infants with neonatal HSV CNS disease had developmental impairment.³²  With the use of high dose (HD) ACV (60 mg/kg/day divided in 3 doses for 21 days), 1-year mortality has been reduced to approximately 30% in patients with disseminated disease.⁴  With the additional use of oral suppressive ACV therapy for 6 months, 69% of infants with neonatal HSV CNS disease had normal Bayley Mental Development Scales at 12 months.³³  Recently, the overall US national mortality rate of infants receiving a diagnosis of any category of HSV infection between 2003 and 2014 was estimated at 7.9%.¹⁴ 

Vidarabine was the first antiviral agent used to treat HSV infections.³⁴  In 1991, Whitley et al³⁵  conducted a randomized controlled trial (RCT) comparing 10 days’ therapy of vidarabine (30 mg/kg continuous IV infusion during 12 hours) vs ACV (30 mg/kg/day given parenterally every 8 hours) for the management of neonatal herpes (Table 2). The authors did not detect differences in mortality or morbidity between the 2 groups. There were no significant renal adverse effects reported with either drug. Because of its ease of administration, ACV supplanted vidarabine as the drug of choice for treatment of HSV and became licensed by the US Food and Drug Administration (FDA) for this indication in 1998.³⁶  Because the mortality and morbidity with neonatal HSV disease remained significantly elevated on standard dosage (SD; 30 mg/kg/day) of ACV, additional studies focused on the effect of higher dosing and longer duration of this drug. In 2001, Kimberlin et al⁴  evaluated the outcomes of 88 neonates primarily with CNS or disseminated HSV disease who received intermediate dosage (ID; 45 mg/kg/day) or HD (60 mg/dose/day) of ACV for 21 days and compared their outcomes to a historical cohort of infants who received SD³⁵  and duration (10 days)³⁵  of ACV. The authors determined that the mortality rates were significantly lower in patients who received HD vs SD of ACV.⁴  After controlling for confounding variables, the HD ACV group was also noted to have had a borderline improvement in their development outcomes at 12 months, compared with the SD ACV group.⁴  Approximately 17% and 6% of patients receiving ID and HD ACV, respectively, developed elevated SCr during ACV therapy, although the authors could not confirm the cause of renal insufficiency. In 2012, Vanderpluym et al³⁷  evaluated the renal adverse effects among 118 neonates who received IV ACV for empiric management of HSV. Only 3 infants had ACV-associated nephrotoxicity. The authors attributed this low rate to the diminished renal concentrating ability in neonates that can protect them from intratubular crystallization.

Although the American Academy of Pediatrics (AAP) recommended HD ACV for the treatment of neonatal HSV disease in 2015, the FDA did not approve HD ACV for this indication at that time.³⁸  Thus, in 2017, Ericson et al³⁹  evaluated the adverse effects of ACV therapy among 89 neonates ages ≤120 days who received ≥14 days of therapy or died while receiving ACV. Prolonged ACV therapy (≥14 days) was used as a proxy measure for clinical or confirmed diagnosis of HSV disease. A total of 89% of the study cohort received HD ACV. Nonetheless, elevated SCr (>1.7 mg/dL) was only detected in 2% of infants. Based on their results, the authors recommended that all neonates with HSV disease should receive HD ACV. In 2019, the FDA finally approved HD ACV for the treatment of neonatal HSV. A year later, Downes et al⁴⁰  published a retrospective cohort study that used the modified neonatal Kidney Diseases Improving Global Outcomes (KDIGO) criteria (Table 1)^18,29  to examine the risk of AKI among 1017 infants who were treated with ≥1 dose of IV ACV. Only 31 of 1017 patients had confirmed HSV disease. A total of 6% of the overall study population developed AKI during therapy or within 48 hours of ACV completion. Interestingly, nearly one-quarter of infants with confirmed disease who received ACV for ≥14 days developed AKI. Multivariate analysis identified confirmed HSV disease, receipt of mechanical ventilation, admission to intensive care unit, and receipt of ≥2 concomitant nephrotoxic medications on preceding day of AKI diagnosis as risk factors for AKI. The authors recommended close monitoring of kidney function during ACV therapy in neonates.

ACV-Associated Nephrotoxicity for Treatment of HSE in Children. Between 2000 through 2010, the US rates of HSE hospitalizations in nonfederal acute care hospitals were estimated at 5.76 ± 0.76, 0.34 ± 0.05, and 0.21 ± 0.02 per 100,000 for children ages <1, 1 to 4, and 5 to 19 years, respectively.⁴¹  Among childhood encephalitis, HSE still accounts for the highest rate of long-term sequelae (64%).¹⁶  Acyclovir is the current treatment of choice for HSE,³  although the risk of associated nephrotoxicity remains one of the main concern with its use.

In 1979, Selby et al⁷  were the first authors to report a transient impairment in renal function among 2 adult patients who received ACV for disseminated zoster. In 1982, Brigden et al⁵  reported reversible renal dysfunction among 58 of 354 pediatric and adult patients who received IV ACV for various indications (Table 3). That same year, Keeney et al⁴²  described a transient increase in SCr among 12% of 85 children who received “bolus” injections of ACV, whereas no adverse renal effects were observed among 42 children who received a 1-hour infusion of ACV. In 1984, Sköldenberg et al³  published the results of the first RCT that compared the efficacy of ACV vs vidarabine for the treatment of confirmed HSE among 53 patients, including 5 children ages <3 years. The authors reported significantly lower mortality and morbidity among ACV vs vidarabine recipients and described a transient increase in SCr in <1% of the study cohort. In a follow-up RCT in 1986, Whitley et al⁴³  compared the therapeutic use of ACV vs vidarabine among 208 patients (including 15 children) with suspected HSE. Consistent with previous findings, the authors reported lower mortality and morbidity among ACV vs vidarabine recipients. However, they described a higher risk of elevated SCr among ACV (6%) vs vidarabine (1%) groups. That same year, Potter and Krill⁴⁴  noted “massive crystalluria” with identification of needlelike crystals in the urine of 2 patients receiving ACV for HSV infection. They advocated for appropriate IV hydration and slow infusion of ACV to avoid the possibility of obstructive nephropathy. In 1991, Bianchetti et al⁴⁵  administered equal doses (per surface area) of ACV to 19 patients, including 12 and 7 immunocompromised and immunocompetent children with HSV infections and HSE, respectively. Hydration was restricted in patients with HSE as part of therapy for cerebral edema. Three children with presumed HSE developed an increase in SCr, whereas none of the immunocompromised children who received standard hydration showed renal laboratory disturbances. The authors observed that the renal disturbances resolved with appropriate hydration and were aggravated with the rapid infusion of the drug and the concomitant use of nephrotoxic drugs. A similar pattern of a reversible nonoliguric acute AKI was described in a 9-year-old who was fluid restricted and received IV ACV and ceftriaxone (another nephrotoxic drug) for presumed encephalitis.⁴⁶  The additive nephrotoxic effect of the concomitant use of ACV and ceftriaxone was highlighted in a case series of 17 children who received both medications for presumed HSE.⁹  Twelve patients experienced a transient increase in SCr. One child even underwent renal biopsy with findings suggestive of tubulotoxic injury. In 2008, Schreiber et al⁴⁷  conducted a retrospective chart review of 126 children, including 14 neonates and 30 immunocompetent children, who received ACV for various indications, and they noted a significant overall increase in SCr and decrease in GFR within 1 week of therapy. On multivariable analysis, underlying renal dysfunction (impaired baseline eGFR) and concomitant use of nephrotoxic drug were the 2 main factors that predicted ACV nephrotoxicity and accounted for 11% of the change in eGFR.

In 2005, following the evaluation of pharmacokinetics of HD ACV among 16 pediatric patients, the FDA approved the use of HD ACV (20 mg/kg/dose or 500 mg/m²/dose every 8 hours) for the treatment of HSE for children ages ≥3 months to 12 years.⁴⁷  The AAP Committee on Infectious Diseases endorsed these recommendations in 2006. However, in 2008, anecdotal reports of neurotoxicity and nephrotoxicity in older children receiving the HD ACV led the AAP to amend its recommendations on ACV dosing for HSE. Although the 2012 Red Book acknowledged that the FDA approved HD ACV for the treatment of HSE in children ages 3 months to 12 years, it recommended to use a dosage of 30 to 45 mg/kg/day in 3 divided doses.⁴⁸  In 2014, Kendrick et al⁴⁹  noted that the recommendation for HD ACV has not been consistently implemented at their institution secondary for concern for toxicity. Therefore, they designed a study to evaluate the occurrence of renal toxicity in patients ages 1 month through 18 years who received SD vs HD regimen in their institution. Interestingly, only 1 child in each group had confirmed diagnosis of HSE. The authors used either the pediatric Risk, Injury, Failure, Loss of Kidney Function, and End-Stage Kidney Disease (pRIFLE)^30,31  criteria or doubling or tripling of SCr to define renal insufficiency (Table 1) but did not detect a significant difference in median change in SCr from baseline between HD and SD groups.

The concern about the use of HD ACV was reassessed in 2015 in a case control study by Rao and colleagues.⁵⁰  Their study cohort included 371 children ages <1 week to 19 years (including 148 with suspected or proven HSE) who received ACV for various indications. For each case, all possible controls without renal dysfunction who had received at least the same number of ACV doses were identified. The authors used the pRIFLE classification system to assess the degree of AKI. Renal risk, injury, and failure were detected among 22%, 9.7%, and 3.8% of 373 (1 patient had 2 hospitalizations) hospitalizations, respectively. Although SCr returned to the normal range following ACV dose reduction or completion, eGFR did not return to patient baseline in most of the study population. The authors advocated for IV ACV dosing at ≤15 mg/kg/dose or ≤500 mg/m²/dose beyond the neonatal period to minimize the risk of nephrotoxicity and highlighted that beyond a weight of 20 kg, the ACV dose using 20 mg/kg/dose would exceed 500 mg/m²/dose. A year later, Stefanski et al⁵¹  described in a published abstract that 11% of all patients ages ≤21 years with suspected HSV infection who had received >1 dose of ACV in their institution, during a 5-year time line, met the pRIFLE criteria for AKI. However, their renal toxicity was transient. In 2020, Sandery et al⁵²  assessed ACV adverse effects among 150 children (including 58 with malignancies) who received ACV for various indications, including HSE and sepsis. The primary outcome was degree of renal insufficiency based on the KDIGO criteria (Table 1).³⁰  A total of 18% of children developed AKI, with 44% remaining in stage 1 on last measured SCr. The risk of AKI was significantly higher in oncology patients compared with the rest of the study group. Multivariate analysis showed that higher baseline eGFR was the only factor that significantly increased the risk of AKI. The authors speculated that elevated eGFR could be a manifestation of kidneys with little reserve or an indication of increased filtrate delivery hastening kidney injury. In 2021, Yalçinkaya et al⁵³  also evaluated the risk factors for ACV-associated AKI among 472 children (including 201 with presumed HSE) ages >1 to <18 years. The study cohort only included patients who did not have malignancies or baseline renal dysfunction and received ACV therapy at a calculated dosage of 1500 mg/m²/day. Almost 7% of the study population developed AKI per the pediatric KDIGO criteria.¹⁸  Multivariate analysis identified age >100.5 months, use of 1500 mg/m²/day ACV, and use of concomitant nephrotoxic drugs as the variables that independently increased the risk of nephrotoxicity. The authors also highlighted that older children were typically receiving more ACV per surface area compared with the younger children and advocated for an investigation of the lowest possible therapeutic doses of ACV in this age group.

Multiple studies have shown an association between nephrotoxicity and IV ACV use for the treatment of HSV infections. Acyclovir-associated nephrotoxicity has been mostly attributed to the low urine solubility leading to its crystallization in the kidney tubules and secondary obstructive nephropathy. The risk of ACV-associated nephrotoxicity seems to be lower in the neonatal population compared with the pediatric population. This is likely due to diminished renal concentrating ability in neonates. Acyclovir-associated nephrotoxicity can be minimized in both populations by ensuring adequate hydration, maintaining a high urine flow, and administering ACV at a slow infusion rate rather than bolus injection. In addition, renal function should be closely monitored and ACV dosing should be adjusted in patients with underlying kidney disease.

Our review of ACV-associated nephrotoxicity in neonates showed that recent literature mostly evaluated risk among all infants exposed to ACV, including those who have received empiric therapy and limited doses of ACV therapy, rather than only patients with confirmed HSV disease who required a longer duration of treatment. Thus, these findings might not be generalizable to infants who received a longer duration of therapy for confirmed HSV infection. On the other hand, the risk of ACV-associated toxicity appeared higher in the pediatric population. Although the abandoned practice of fluid restriction for possible cerebral edema may have contributed to these findings in earlier studies, more recent reports showed that older age (>8 years), concomitant use of nephrotoxic drugs, and ACV dose >1500 mg/m² were associated with a higher risk of renal adverse effects in the pediatric population. However, these studies 1) included patients with a wide age range who had different thresholds of ACV-associated renal toxicity, 2) assessed different units of dosing (per weight or surface area) of ACV, 3) adapted a wide variety of AKI classifications, and 4) evaluated potential renal adverse effects among patients with limited ACV exposure in patients with suspected rather than proven ACV infections. Thus, the risk of ACV-associated nephrotoxicity in the pediatric population might be higher in children who received prolonged ACV therapy for confirmed HSE.

Through the years, the AAP recommendations for IV ACV dose have also changed to reflect evidence on its efficacy and effectiveness for treatment of neonatal HSV and potential drug toxicity in the pediatric patients. Although the efficacy and safety of SD vs ID and HD of IV ACV have been evaluated in a cohort of neonates with confirmed HSV infections,^4,17  based on our review, no such study has been conducted for the management of HSE in the pediatric population.

During the last 3 decades, although the survival of neonates with disseminated HSV infections and the risk of long-term sequela of those with neonatal CNS disease have both improved,⁴  30% of patients with disseminated disease do not survive and 31% of patients with CNS disease have abnormal neurologic assessment at 12 months. In addition, the risk of long-term sequela of pediatric HSE remains substantial.¹⁶  The goal is to identify the optimal ACV dose where efficacy is maximized and toxicities are minimized. Although the intent of using lower ACV doses is to minimize ACV toxicity, this practice may be associated with increased risks of adverse sequelae. Future studies on risk of ACV-associated nephrotoxicity should adopt the current standard definition of AKI in neonates and children and include a larger proportion of patients with confirmed rather than suspected HSV infections in order to evaluate the efficacy and toxicity of the current ACV dosing. Studies should also follow these patients for at least 1 year after therapy to better understand the long-term sequelae of ACV dosing.

AAP

American Academy of Pediatrics;

ACV

acyclovir;

AKI

acute kidney injury;

CNS

central nervous system;

eGFR

estimated glomerular filtration rate;

FDA

US Food and Drug Administration;

HD

high dose

HSE

herpes simplex encephalitis;

HSV

herpes simplex virus

ID

intermediate dosage;

IV

intravenous;

KDIGO

Kidney Diseases: Improving Global Outcomes;

LD

low dose;

pRIFLE

Pediatric Risk, ­Injury, Failure, Loss of Kidney Function, and End-Stage Kidney Disease;

RCT

randomized controlled trial;

SCr

serum creatinine;

SD

standard dosage;

SEM

skin, eye, and/or mouth

We thank Lindsey Blake and Lauren Tong for their tremendous help in the literature review.