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Effect of Treatment With Efavirenz on Neuropsychiatric Adverse Events of Interferon in HIV/HCV-Coinfected Patients
[Brief Report: Clinical Science]
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JAIDS Journal of Acquired Immune Deficiency Syndromes:Volume 49(1)1 September 2008pp 61-63
Quereda, Carmen MD*; Corral, Inigo MD, PhD; Moreno, Ana MD, PhD*; Perez-Elias, Maria J MD, PhD*; Casado, Jose L MD*; Dronda, Fernando MD, PhD*; Rodriguez-Sagrado, Miguel A PhD; Hernandez, Beatriz PhD*; Moreno, Santiago MD, PhD*
From the Service of *Infectious Diseases; Neurology; and Pharmacy, Hospital Ramon y Cajal, Madrid, Spain.
Abstract
Background: Mood disorders and other neuropsychiatric disorders are common adverse events limiting tolerability of _-interferon (IFN) therapy for hepatitis C virus (HCV). Because efavirenz (EFV) frequently produces neuropsychiatric side effects, we studied the effect of EFV in the incidence of these side effects in HIV/HCV patients receiving IFN.
Methods: Prospective cohort of HIV/HCV patients receiving IFN and ribavirin. Adverse events and concomitant medications were systematically recorded once monthly.
Results: Among 266 HIV/HCV patients starting a course of IFN (91% pegylated IFN) plus ribavirin, 53 (20%) received concomitant EFV and 213 (80%) did not. Most EFV patients (92%) were already on EFV before starting IFN (mean 26 months). Neuropsychiatric side effects were frequent, without significant differences between both groups (79% vs 65%, P = 0.051), and only 10 patients discontinued IFN. Mood disorders were reported more frequently in EFV patients (36% vs 23%, P = 0.046), but antidepressant therapy use was similar in both groups. The incidence of anxiety, insomnia, irritability, headache or prescription of anxiolytics or hypnotics was similar.
Conclusions: Neuropsychiatric adverse events are common in HIV/HCV patients receiving IFN, usually mild or moderate. EFV may favor symptoms of mood disorders, although it was not related to an increased risk of significant depression requiring specific treatment.
INTRODUCTION
The association of pegylated interferon-_ plus ribavirin (peg-IFN-RBV) is the gold standard therapy for chronic hepatitis C virus (HCV) infection, including patients with human immunodeficiency virus (HIV) infection.1-3 The tolerability of this treatment may be limited by depressive symptoms or other significant neuropsychiatric side effects, such as headache and insomnia.4 On the other hand, efavirenz (EFV), a first-line antiretroviral drug for HIV infection, may also cause neuropsychiatric side effects, mainly mood and sleep disorders, both on the short- and long-term follow-up.5,6 The safety of interferon (IFN) among HIV-infected patients receiving EFV has not been studied so far. The aim of the present study was to compare the incidence of neuropsychiatric side effects after the initiation of IFN-RBV therapy for HCV in a population of HIV-infected patients, considering the concomitant use (or not) of EFV.
DISCUSSION
HCV infection may condition antiretroviral treatment for HIV infection, due to an increased risk of drug-related hepatotoxicity in patients with HIV/HCV coinfection.8 In addition, there has been some concern about the use of EFV in patients with HIV/HCV-coinfection candidates for IFN-RBV, for the reported high incidence of neuropsychiatric side effects associated to both drugs, particularly mood disorders,4-6 might be further increased in case of coadministration. In our experience, there was a trend for an increased rate of neuropsychiatric side effects when EFV was used in combination with IFN-based therapies, but this did not reach statistical significance.
In a high proportion of our patients coinfected with HIV/HCV, neuropsychiatric symptoms were reported for the first time while on treatment with IFN-RBV, as has been previously reported in other studies.1-3,9 Therefore, this study accurately reflects the incidence of clinically significant neuropsychiatric symptoms in coinfected patients during IFN-RBV therapy in daily clinical practice. Data were collected prospectively, but physicians were unaware of specific future retrospective analysis. The fact that the attending physician was aware of the use of EFV, when recording side effects, could have biased our results toward a higher incidence of neuropsychiatric side effects in patients receiving this drug. Taking this into account, the differences found between patients with and without EFV were not statistically significant. However, one limitation of our study is the fact that neuropsychiatric symptoms were not assessed in a systematic manner, by means of specific validated scales, which may potentially reduce the strength of our results. Neuropsychiatric symptoms associated with IFN-RBV therapy were usually of mild to moderate intensity, as demonstrated by the low proportion of patients requiring treatment withdrawal.
Although symptoms related to mood disorders (ie, sadness) were more frequent in the EFV group, the proportion of patients with significant depression, as assessed by the prescription of antidepressant drugs, was similar in both groups. Other neuropsychiatric symptoms previously reported in patients with EFV treatment such as insomnia, memory disturbances, concentration difficulties, irritability, or headache appeared with the same frequency in the EFV group than in the non-EFV group.
Of note is the lower rate of neuropsychiatric AEs among cirrhotic patients in our series, with lower rates of insomnia and need of hypnotic drugs. This is in contrast with previous reports that have shown nonnucleoside reverse transcriptase inhibitors (NNRTI) plasma levels above the toxic threshold in patients with severe fibrosis, which might be correlated to a higher incidence of EFV-associated neurologic symptoms.10 Most patients in our study-including those with cirrhosis-were already under chronic treatment with EFV when IFN was initiated, and neuropsychiatric effects of EFV have been reported to be more frequent within the first weeks of treatment.10 Thus, the safety of initiating EFV immediately before, simultaneously, or after IFN cannot be ascertained in this study.
In conclusion, neuropsychiatric AEs are common among HIV/HCV-coinfected patients on IFN, but usually of mild or moderate intensity. Although concomitant EFV use may favor symptoms of mood disorders, it was not related to an increased risk of significant depression requiring specific treatment.
PATIENTS AND METHODS
From September 1999 (first availability of IFN-based combined therapy with ribavirin), all patients attended at the HIV-Outpatient Clinic of the Infectious Diseases Service at the Ramon y Cajal Hospital, a tertiary center in Madrid, Spain, starting treatment for HCV, have been included in a prospective ongoing cohort. Informed consent to record data was provided in all cases, and the study was approved by our local ethics and institutional review board.
For the purpose of this study, we considered the period of time encompassed from September 1999 to September 2006. Extensive chart review including clinical events, antiretroviral therapies, and laboratory data related to HIV and HCV infections has been performed for all patients. Prospective follow-up of the patients consisted in monthly visits including laboratory tests and clinical evaluation. At each visit, patients were systematically inquired for treatment-related adverse events (AEs), and the use of concomitant medications for any of them was carefully recorded. Decisions regarding psychopharmacological treatment were taken by the attendant physician or after specific psychiatric consultation if needed. All available data were included in an ongoing database.
Statistical analyses were performed with the SPSS (Statistical Package of Services Solutions, SPSS Inc, Chicago, IL) software, version 11.0. The frequency of neuropsychiatric symptoms presenting after the initiation of IFN-based therapy and the prescription for the first time of specific psychiatric treatment during treatment were compared between patients receiving and not receiving concomitant EFV as a part of their antiretroviral therapy. Comparisons were performed by means of the _2 test or Fisher exact test. P values <0.05 were considered significant.
RESULTS
During the study period (7 years), 266 HIV/HCV-coinfected patients started a course of IFN-RBV treatment at our Unit. Pegylated IFN was the most frequent formulation of IFN used (91%). Fifty-three subjects (20%) also received EFV during the treatment period (EFV group) and 213 (80%) did not (non-EFV group).
Most patients in the EFV group (n = 49, 92%) were already on EFV before the initiation of IFN, for a mean of 26 months (range 1-78); only 4 patients started EFV after the initiation of HCV therapy.
Table 1 shows the characteristics of patients in both groups, which were homogeneous regarding age, sex, history of drug addiction and alcohol consumption over 50 g per day, history of psychiatric diseases, percentage of patients under antidepressive treatment at initiation of IFN, percentage of patients with CD4 counts below 200/mL or with diagnosis of liver cirrhosis, and sustained virological response to HCV therapy. Simultaneous treatment with methadone was more frequent in the non-EFV group (P = 0.019) because it has been a common practice to avoid EFV therapy in patients under methadone due to relevant pharmacokinetic interactions between both drugs.7
Overall, the group of patients on EFV reported a trend to a higher proportion of neuropsychiatric symptoms during IFN treatment as compared with patients without EFV (79% vs 65%, P = 0.051). The frequency of neuropsychiatric symptoms reported for the first time while on IFN is shown in Table 2. Symptoms of mood disorders, such as sadness or apathy, were significantly more frequent among EFV patients (36% vs 23%, P = 0.046), but depression requiring antidepressant treatment was equally common in both groups (23% vs 16%, P = 0.25). There were no differences in the frequency of anxiety, insomnia, irritability, and headache and prescription of anxiolytics or hypnotics. Only 10 patients (0.3%) discontinued IFN because of neuropsychiatric AEs but without differences between groups.
Among patients on EFV, patients with cirrhosis had nonsignificantly lower neuropsychiatric AEs associated with IFN therapy than patients without cirrhosis (70% vs 85%, P = 0.2). The frequency of specific symptoms or use of psychiatric treatments was similar in both groups, with the exception of a lower frequency of insomnia in patients with cirrhosis (15% vs 55%, P = 0.008) and a trend for a less frequent use of hypnotics in them (15% vs 42%, P = 0.067).
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