High rate of didanosine-related mitochondrial toxicity in HIV/HCV-coinfected patients receiving ribavirin.
BACKGROUND
Nucleoside analogues may induce mitochondrial toxicity, particularly didanosine. Ribavirin increases didanosine exposure, which might be clinically relevant when coadministered in HIV/HCV-coinfected patients.


OBJECTIVE
To evaluate, among 89 patients receiving highly active antiretroviral therapy (HAART) and therapy for chronic hepatitis C, clinically relevant mitochondrial toxicity in those treated with concomitant ribavirin and didanosine (n=35, 39%).


METHODS
From January 2000 to July 2002 longitudinal analysis of the incidence and clinical course of didanosine-related hyperamylasaemia, pancreatitis, hyperlactataemia/lactic acidosis or neuropathy. Risk factors were evaluated using univariate and multivariate Cox's proportional hazards model.


RESULTS
Among 35 patients who received concomitant didanosine (400 mg/day in 86%) and ribavirin (> or = 10 mg/kg/day in 91%), 20 (57%) developed one or more adverse events after a mean of 87 days. Most frequent laboratory abnormalities were hyperamylasaemia (18 patients, 51%) and hyperlactataemia (eight patients, 23%). Acute pancreatitis and symptomatic hyperlactataemia developed in 10 (28%) and six (17%) patients, respectively. Two patients (6%) with pancreatitis and severe lactic acidosis died; the other patients recovered uneventfully despite continuation of anti-HCV therapy in 83% after didanosine withdrawal in 40%. In the Cox's model higher baseline amylase levels (HR: 1.04, 95% CI: 1.02-1.06, P=0.001) and three nucleoside reverse transcriptase inhibitor-based HAART (HR: 5.3, 95% CI: 1.73-16.24, P=0.003) were significantly associated to toxicity.


CONCLUSIONS
The coadministration of didanosine and ribavirin should be avoided in HIV/HCV-coinfected patients, due to a high rate of clinically significant toxicity, particularly in triple nucleoside-based HAART. Amylase levels should be strictly monitored, especially if elevated at baseline.
Moreno
Ana
A
Infectious Diseases, Hospital Ramón y Cajal, Universidad de Alcalá de Henares, Madrid, Spain. amoreno.hrc@salud.madrid.org
Quereda
Carmen
C
Moreno
Leonor
L
Perez-Elías
María J
MJ
Muriel
Alfonso
A
Casado
Jose L
JL
Antela
Antonio
A
Dronda
Fernando
F
Navas
Enrique
E
Bárcena
Rafael
R
Moreno
Santiago
S
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use / Q000633:toxicity*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D000998:Antiviral Agents / Q000627:therapeutic use*; D016049:Didanosine / Q000627:therapeutic use / Q000633:toxicity*; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D006526:Hepatitis C / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology*; D028361:Mitochondrial Diseases / Q000453:epidemiology*; D016016:Proportional Hazards Models; D012254:Ribavirin / Q000627:therapeutic use*
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D012254:Ribavirin; D016049:Didanosine