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REVIEW ARTICLE
Year : 2020  |  Volume : 38  |  Issue : 1  |  Page : 6-10

Valacyclovir toxicity in peritoneal dialysis


Department of Nephrology, Sri Manakula Vinayagar Medical College and Hospital, Madagadipet, Puducherry, India

Date of Submission24-Apr-2020
Date of Decision24-Apr-2020
Date of Acceptance14-May-2020
Date of Web Publication31-Dec-2020

Correspondence Address:
Dr. P Ravi Kumar
Department of Nephrology, Sri Manakula Vinayagar Medical College and Hospital, Madagadipet, Puducherry
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IOPD.IOPD_4_20

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  Abstract 


Valacyclovir (Prodrug) an antiviral agent is not well cleared by peritoneal dialysis and can cause neuropsychiatric manifestations in patient with renal failure on peritoneal dialysis and having Herpes Zoster infection being treated with this drug. Methodology followed for the collection of data and literature review was by using a medline search using the terms Acyclovir, nervous system effects, Valacyclovir, neurotoxicity and peritoneal dialysis. The representative case discussed is about an elderly gentleman with chronic renal failure on CCPD presenting with hallucinations, altered sensorium and restlessness following treatment with Valacyclovir 1000 mg three times per oral daily who was admitted and evaluated. It is of vital importance to consider the differential diagnosis of Herpes zoster encephalitis in the differential diagnosis of these patients as it is difficult to rule it out. The mechanism of this drug induced neurotoxicity is thought to be probably, the accumulation of serum carboxymethoxymethyl guanidine (CMMG), a toxic metabolite of valacyclovir.As peritoneal dialysis is not very effective in removal of this drug, it is thought to be beneficial to change to Hemodialysis for short duration so as to clear the drug from the system as shown in the case and in the discussion. Safe doses in peritoneal dialysis are not clearly delineated. Extreme precaution must be exercised while prescribing these group of anti-viral drugs in patients with CKD and especially those on peritoneal dialysis. If such a patient does manifest neuropsychiatric symptoms it is necessary to immediately stop the drug concerned. Methods to increase the excretion of the drug must be employed immediately or to remove it by intensification of PD or ideally to aggressively remove it by means of hemodialysis. Moreover there is a paucity of similar reports in the literature.

Keywords: ACYCLOVIR, carboxymethoxymethyl guanidine, continuous ambulatory peritoneal dialysis, neuropsychiatric toxicity


How to cite this article:
Kumar P R. Valacyclovir toxicity in peritoneal dialysis. Indian J Perit Dial 2020;38:6-10

How to cite this URL:
Kumar P R. Valacyclovir toxicity in peritoneal dialysis. Indian J Perit Dial [serial online] 2020 [cited 2021 Jun 14];38:6-10. Available from: https://www.ijpd.org.in/text.asp?2020/38/1/6/305753




  Introduction/Background Top


Acyclovir is commonly used for the treatment of Herpes Infections caused by Herpes Simplex Virus (HSV) or Varicella Zoster infections (VZV).It has significantly improved the mortality and morbidity of patients with suspected HSV Encephalitis when given empirically to a patient until a diagnosis is confirmed. Valacyclovir (VCV) is a pro-drug that is quickly metabolized in the liver to its active form acyclovir. Valacyclovir has the advantage of increased oral bio-availability of 55% compared to acyclovir (10-20%) and quickly reaches 3-5 times higher plasma concentrations than oral Acyclovir.[1]

Drug side effects including headache, nausea and gastro-intestinal discomfort have been reported.[2] However there is increasing knowledge that acyclovir may cause more serious side effects such as neurological toxicities[3],[4] and Thrombotic Microangiopathy especially in those patients with decreased renal function.


  Methods/Methodology Top


A Medline search for acyclovir and central nervous system side effects revealed at least 100 case reports. However only 8 such reports involving valacyclovir and onlythree other single case reports mentioning neurotoxicity in peritoneal dialysis patients were found.[3],[4],[5],[6],[8],[9] Each of the major articles were further looked at in detail and data was gleaned, extracted, analysed and arranged in logical sequence pertaining to the various sections being described in this article.

The data linking high acyclovir concentrations with neurotoxicity have not been conclusive, however several reports have suspected this.[2],[3] There are only a very few studies evaluating the safety of Valacyclovir use in CAPD patients. The recommended dosage of valacyclovir for patients with renal clearance less than15ml/min is 1000mg per day for treatment of Herpes Zoster.[7] Even after the administration of Valacyclovir 500mg per day to 12 APD patients, subtherapeutic acyclovir serum levels were found.[6] The safe dosages in APD are not well known [Appendage 1].




  Pathophysiology Top


The reason for the neurotoxicity is not clear. The drug toxicities are known to regress once the offending drug is stopped or removed by increased hydration or by using aggressive Peritoneal dialysis or switching to hemodialysis. This goes in favor of the causative aetiology being a direct drug toxicity causing the neuropsychiatric symptomswhich is wholly reversible within a fortnight .But amongst the mechanisms proposed is a direct self –limiting metabolic Gliopathy.[3]

Detailed case discussions on valacyclovir toxicity are rare so we decided to present this topic review with a representative case discussion.


  Representative INDEX CASE Top


We report a 68 year old man with ESRD on PD was admitted to hospital with a one day history of hallucinations, restlessness and incoherent speech. His presentation was similar to that of an acute delirium. Upon questioning his wife, it was found that his family practitioner had started him on valacyclovir (Valtrex) 1000mg po three times daily the day before for a suspected Herpes Zoster rash on the right side of his neck (C2-C3) dermatomes. His past medical history included significant coronary artery disease; he had suffered a non-ST elevation myocardial infarction in May 2006, undergone a Femoral-Popliteal bypass a few years ago, history of diabetes mellitus, presence of concentric left ventricular hypertrophy, evidence of atrial fibrillation, elevated serum cholesterol levels and past history of gout.

His current medications at the time included Tablet Allopurinol 100mg po once daily, Atorvastatinpo 20mg at bedtime, Calcium carbonate 1250mg po twice daily, Cinacalcet 90mg po once a day, Metoprolol 25mg po once a day, Renal multivitamin 1capsule po once a day, Repaglinide 1mg po twice daily, Sevelamer hydrochloride 1600mg po twice daily, and warfare 5mg po once daily. Upon examination, patient was found to be conscious though drowsy at times. There was no peripheral edema, Blood Pressure was 140/90 mmHg., heart rate was 100 beats a minute, Oxygen saturation was 100% on room air, lungs were clear, heart sounds were normal , His per abdomen exam was soft and there was no localizing neurological deficits. Biochemical investigations were normal except for the following: Serum Calcium of 1.99 mol/l, Serum Phosphate of 1.48mmol/l, Blood sugar 15mmol/l, Serum Lactate of 4.7mmol/l and an INR of 1.64.His warfarin was on hold due to the possibility of requiring a lumbar puncture to aid in the diagnosis. He was continued on his CCPD prescription of 10 liters over 10 hours, using alternatively two liter volumes of 1.5% and 2.5%. His last exchange was Icodextrin 2 litres. After careful history taking and review of his medications, a presumptive diagnosis of Valacyclovir toxicity was made. However other metabolic causes or an encephalitis could not be ruled out at the time. The neurology service was consulted and they also concurred with the diagnosis of Valacyclovir toxicity in the form of the neuropsychiatric impairment. They recommended a Lumbar puncture, EEG and an MRI brain. However due to his restless condition and the possibility that he may have to be sedated in order to do the procedure, the lumbar puncture was withheld. No obvious localizing signs were seen on the CT/MRI Scans. His neurological signs persisted for two more days with increasing restlessness and hallucination. At times he was very confused and was even seen wandering in the hallways of the hospital. On day four of his admission, the team discovered that his current CCPD prescription was not removing Valacyclovir from his system and hence hemodialysis was initiated to remove the drug. He underwent 2 hemodalysis sessions of 4 hours duration each on two consecutive days through his left AV Graft which was luckily still intact and was working. His serum Lactate decreased from 4.7 to 1.4.After his dialysis sessions his general condition improved and he was restarted on his previous CCPD prescription.


  Pharmokinetics Top


Valacyclovir

After oral administration of Valacyclovir (a Prodrug), in humans, it is rapidly and completely converted into Acyclovir to provide a high level of acyclovir bio-availability in comparison with that following oral administration of acyclovir. The plasma acyclovir levels following oral administration of Valacyclovir in such cases is similar to those achieved with intravenous doses of acyclovir. Acyclovir excretion via CAPD is expected to be low due to the drug's extensive volume of distribution.[5],[6] Thus the removal of Acyclovir via the peritoneal dialysis is considered “non-dialyzable.” One report found that less than 10% of acyclovir is removed by CAPD.[1] The estimated half-life of valacyclovir in CAPD is 13-18hours.[1] However the plasma elimination is less than 30 minutes due to its rapid enzymatic hydrolysis to acyclovir.[1]


  Discussion Top


Majority of the cases of valacyclovir/acyclovir toxicities are associated with the altered levels of renal impairment and in those on renal replacement therapies, because of the higher drug levels in these patients.

One potential mechanism of neurotoxicity is the accumulation of a toxic metabolite of acyclovir. Acyclovir can also be metabolized by alcohol-dehydrogenase to 9-CMMG (carboxymethoxymethyl guanidine) and to a smaller extent to 8-hydroxy -9 (2-hydoxyethoxymethyl guanidine).Currently there are no recommendations or diagnostic tools to distinguish between acyclovir associated side effects or Herpes Simplex Encephalitis. The ability to measure serum carboxymethoxymethyl guanidine would be especially useful in aiding with the diagnosis in patients on CAPD.

Patients with suspected valcyclovir toxicity due to carboxymethoxymethyl guanidine (CMMG) accumulation and severe symptoms such as unconsciousness or coma are likely to improve with hemodialysis treatment.[10] A single hemodialysis session decreases the CMMGand acyclovir levels by 50% which often results in dramatic clinical improvement.[2] It is important to take these urgent clinical measures to prevent permanent damage. For patients who present with less severe symptoms of valacyclovir/acyclovir toxicity, discontinuation of the drug in combination with methods to increase the secretion of CMMG renal excretion through hydration and forced diuresis are usually successful. Hence the dictum to be followed in any case of neurotoxicity in a CKD patient on dialysis is to choose hemodialysis as the modality of treatment of choice in these patients.

A High CSF or serum level of the main acyclovir metabolite, 9- carboxymethoxymethylguanine (CMMG), is highly indicative of acyclovir neurotoxicity.[11]

Krasny et al. recommended a 50% reduction of the usual daily Intravenous dose of Valacyclovir in dialysis patients and a supplemental dose after each dialysis session.[12]

Actually CAPD has been reported to remove less than 10% of the administered dose of Acyclovir/Valacyclovir.[13]

Since late 1980s the neurotoxic manifestations of acyclovir have been mentioned in many articles.[14] The clinical manifestations include headache, insomnia, altered sensorium, giddiness, vertigo, hallucinations dysarthrias, paresthesias, coma, myoclonus and seizures .[14],[15],[16],[17],[18],[19],[20],[21] If a CKD patient develop neuropsychiatric symptoms during anti-viral treatment, it is very important to discontinue the suspicious drug involved and to rule out drug toxicity.

Even though Peritoneal dialysis can remove some amount of the drug, hemodialysis has definitely better drug clearance rates.[14],[15] There have also been occasional reports that intensification of the PD protocol (increased exchanges) have helped in improvement of the neurological symptoms.[22],[23]

There is even a report of a patient on valacyclovir having a relapse of neurotoxicity while on hemodialysis necessitating another hemodialysis run.[24] This emphasizes the point that acyclovir and its analogues need to be prescribed with extreme caution in patients with CKD.

Valacyclovir neurotoxicity has also been indirectly ascribed to its tendency to worsen the renal function by means of precipitation of its crystals in the tubules and to cause further interstitial and tubular dysfunction.[25] Yet another mechanism proposed is due to altered mitochondrial dysfunction by inhibition of the DNA polymerase enzyme subsequent cellular damage and neurotoxicity.[26]

The other diagnostic conundrum is as regards eliminating the diagnosis of Herpes zoster encephalitis as in an immune-compromised individual. If left untreated, it can lead to disastrous consequences and if in a case of valcyclovir neurotoxicity, by giving more of valacyclovir, itwillactually worsen the drug toxicity. But the dilemma is further compounded by the fact that there is no single test which will lead to a correct diagnosis. Hence in an ideal setup, drawing the blood, urine and CSF levels of acyclovir may help in distinguishing drug toxicities. Also if the patient does not improve symptomatically, inspite of repeated hemodialysis sessions then a diagnosis of HZVE ( Herpes ZosterViral Encephalitis/HSV/VZV ) may still be entertained.[26] The other differentials in terms of diagnosis, lower down in the list are metabolic encephalopathy, meningitis, sub-arachnoid hemorrhage, other cerebro-vascular and mental disorders which again have to be exclude by means of radiological evaluations (MRI, CT, PET and SPECT scans), Lumbar puncture, EEG and neurology and psychiatric consultations.

Valcyclovir, the L-valine ester of acyclovir is well known to cause more neurotoxicity in the elderly and actually these groups of patients are more vulnerable to the drug toxicities . Hence it is prudent to exercise more caution while prescribing it in this aged subgroup of patients with due diligence, ensuring adequate hydration, and ensuring close monitoring.[27]

And even status epilepticus has been described in cases of acyclovir/valcyclovir toxicity and occurring also during the treating dialysis sessions.[28]

In one study, the mean recovery time for the HD group was significantly shorter than that of patients treated only through termination of acyclovir therapy.[29]

Haemodialysis can also be a diagnostic tool for acyclovir toxicity, as there will be no clinical response in case of viral encephalitis.[3],[35]

It is believed that CRRT has a good effect on clearing drugs with middle and large molecular weights orwith high protein binding rate. Though valacyclovir is soluble and has a low protein binding rate, but we do not have any evidence or literature on the role of CRRT in clearing valacyclovir from the circulation.[30]


  Conclusion Top


If a conscious patient deteriorates while on treatment with acyclovir for a viral infection and has a normal brain CT scan and LP investigations, then neurotoxicity due to the drug must be considered.[31] The use of valcyclovir in patients on peritoneal dialysis has not been well studied. However the potential for serious side effects, especially neurological toxicities must always be considered and cannot be underestimated. Careful and close monitoring of patients on peritoneal dialysis who are prescribed valcyclovir is of paramount importance.Even when dose adjusted acyclovir is prescribed, neurotoxicity has been reported in CKD patients.[32],[33] Hemodialysisis considered as the most effective and specific treatment for valacyclovir neurotoxicty.[36] Though acyclovir toxicity can be difficult to distinguish from Herpes zoster encephalitis , it is not wise to only rely on theplasma drug levels as studies do suggest that plasma concentrations of the drug need not correlatewith the neurotoxic effects.[37],[38]

Even at proper renally adjusted doses of valacyclovir, elevated serum acyclovir doses were found[2] and thus increased awareness is required.

Hence all patients need to be closely monitored during the duration of treatment with Valacyclovir/acyclovir.

Ethics and Consent

Patient consent was taken for this paper after duly anonymyzing all the clinical and laboratory data gathered.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Acknowledgement

I wish to express my deep sense of gratitude to my mentor Late Dr.D.G.Oreopoulosfor his constant encouragement and invaluable guidance in drafting this manuscript. I also wish to express my humble thanks to Ms.EmilyKo , Renal Pharmacist for going through this manuscript and for her valuable suggestions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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