High serum concentrations of the acyclovir main metabolite 9-carboxymethoxymethylguanine in renal failure patients with acyclovir-related neuropsychiatric side effects: an observational study.
BACKGROUND
Acyclovir (ACV) has been used for over two decades to treat herpes virus infections. Serious neurological adverse side effects have occurred during ACV treatment in patients with renal failure, but the cause of the symptoms remains unknown. We hypothesized that increased concentrations of the ACV main metabolite 9-carboxymethoxymethylguanine (CMMG) correlated to these symptoms.


METHODS
We conducted an observational study from 1991 to mid 1999 based on samples sent for analysis of ACV concentration from various hospital departments in Sweden. Patients with neuropsychiatric symptoms (NS+, n=49) were compared with patients without symptoms (NS-, n=44). ACV and CMMG concentrations were analysed by HPLC. Medical records were analysed for symptoms and compared with pertinent cases identified from Medline.


RESULTS
The serum CMMG levels were significantly higher in the NS+ group (mean=34.1 micro mol/l, 95% confidence interval 23.4-46.1) compared with the NS- group (mean=4.7 micro mol/l, 95% confidence interval 3.3-6.6; P<0.001). CMMG was the strongest predictor in a receiver-operating characteristics curve analysis (ROC), based on 77 patients, of ACV-related neuropsychiatric symptoms. The ROC curve for CMMG demonstrated that neuropsychiatric symptoms could be predicted with a sensitivity of 91% and a specificity of 93% with the use of a cut-off value of 10.8 micro mol/l of CMMG. Thirty-five of 49 patients in the NS+ group showed levels exceeding this concentration compared with only three of 44 of patients in the NS- group (P<0.001). ACV exposure, ACV concentration, creatinine clearance and creatinine concentration were weaker but statistically significant predictors. Haemodialysis reduced CMMG and ACV levels and relieved the symptoms.


CONCLUSIONS
The determination of CMMG levels in serum may be a useful tool in supporting the diagnosis of ACV-associated neuropsychiatric symptoms. Furthermore, the monitoring of CMMG levels may prevent the emergence of symptoms.
Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden. anders.hellden@hs.se
Anders
A
Helldén
Ingegerd
I
Odar-Cederlöf
Per
P
Diener
Lisbeth
L
Barkholt
Charlotte
C
Medin
Jan-Olof
JO
Svensson
Juliette
J
Säwe
Lars
L
Ståhle
D000212:Acyclovir / Q000009:adverse effects* / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use; D003404:Creatinine / Q000097:blood; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000097:blood*; D006562:Herpes Zoster / Q000150:complications / Q000188:drug therapy; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000150:complications; D008297:Male; D001523:Mental Disorders / Q000097:blood* / Q000209:etiology; D008875:Middle Aged; D020258:Neurotoxicity Syndromes / Q000097:blood* / Q000209:etiology; D012372:ROC Curve; D012680:Sensitivity and Specificity
D000998:Antiviral Agents; D006147:Guanine; D003404:Creatinine; C035400:9-carboxymethoxymethylguanine; D000212:Acyclovir