Simeprevir-induced severe withdrawal syndrome in an HIV/HCV coinfected patient on long-term maintenance methadone therapy

Abstract

Sir,The availability of second-generation direct-acting antivirals (DAAs) has further changed the treatment of chronic hepatitis C virus (HCV) infection [1]. The combination of simeprevir and sofosbuvir with or without ribavirin led to sustained virological response (SVR12 rates) close to 90 % in chronic HCV genotype 1 and 4 infected patients and was overall well tolerated [2,3]. Similar results have also been recently observed in HCV patients who are coinfected with human immunodeficiency virus (HIV) [4], which are, however, at higher risk of clinically relevant drug-to-drug interactions (DDI). Here, we report a case of an HIV/HCV patient on HAART and stable methadone maintenance therapy who developed symptoms of opioid withdrawal early after starting the combination of simeprevir and sofosbuvir with ribavirin.A 54-year-old white HIV/HCV infected man was admitted to our outpatient service with shakiness, diaphoresis, body aches, abdominal pain, anxiety, insomnia, and asthenia. He reported that the symptoms had started the previous day. Six days before, the patient had started taking simeprevir 150 mg/day, sofosbuvir 400 mg/day, and ribavirin 800 mg/day to treat chronic HCV genotype 4c/4d infection. The patient was on tenofovir/emtricitabine and raltegravir as antiretroviral therapy and was given methadone at 70 mg/day since 1990 for maintenance of former heroin addiction. No other comedications were reported.Liver function tests and haemoglobin were similar to those prior to the start of DAAs. The patient was diagnosed with methadone withdrawal syndrome. A blood sample drawn the same day retrieved a methadone plasma trough concentration of 300 ng/mL, which was in the usual narcotic stabilization range of 50-1000 ng/mL [5]. The patient was stabilized after administration of alprazolam and an increase in methadone dosage to 80 mg/day. Methadone plasma trough concentrations measured 4 days after the increase in the dose was 365 ng/mL. The dosage of methadone was further increased to 90 mg/day in the next weeks and the patient was fully stabilized.The metabolism of methadone, commonly used as opioid substitution in patients with a history of drug addiction, is not completely understood. However, evidence is available that it mainly undergoes oxidative metabolism to inactive metabolites by cytochrome P450 3A (CYP3A), by CYP2D6, and, to a lesser extent, by CYP2C8, CYP2B6, and CYP2C19 [6]. Sofosbuvir and GS-33100, its inactive nucleoside metabolite, neither inhibit nor induce the CYP enzyme system; therefore, these molecules are not expected to affect the concentrations of methadone [7]. Conversely, simeprevir is metabolized primarily by CYP3A, is a substrate for several drug transporters including the organic anion transporting polypeptides, and is a mild inhibitor of CYP1A2 and intestinal CYP3A [7]. It is, therefore, theoretically susceptible to DDIs with drugs that share the same pathways of absorption, transport, or metabolism,

Daclatasvir plus Sofosbuvir, with or without Ribavirin, in Real-World Patients with HIV–HCV Coinfection and Advanced Liver Disease

“…Although antiretroviral (ARV) drugs may be switched to allow compatibility with individual DAAs, changing stable cART is not risk-free for maintaining HIV virological control, particularly for patients with substantial prior ARV experience or known ARV drug resistance [15]. Potential DAA interactions resulting in loss of clinical maintenance among recovering PWID on oral opioid treatment are another source of concern [16] for which there are very few extrapolatable data from clinical trials.…”

DAA-Based Treatment for HIV–HCV-Coinfected Patients: Analysis of Factors of Sustained Virological Response in a Real-Life Study

“…However, few data from real-world studies are available on the efficacy and tolerability of DAA regimens in HIV-infected patients [23,26,27]. Moreover, the management of DAA treatment of HCV-HIVcoinfected patients may be complex, especially due to the presence of other co-pathologies and the drug-drug interactions with ART or other comedications, such as oral opioids in PWID [29]. However, switching ART regimens to avoid DAA-ARV interaction was associated with a loss of HIV control and with non-SVR [30].…”

Real-World Efficacy of Daclatasvir and Sofosbuvir, With and Without Ribavirin, in HIV/HCV Coinfected Patients With Advanced Liver Disease in a French Early Access Cohort

“…Treatment-limiting pharmacokinetic interactions with DAAs remain a significant issue with some types of combination antiretroviral (ARV) therapy (cART), 18,19 as does the risk of interaction between some DAAs and oral opioids in PWID on drug substitution treatment. 20 Switching cART regimens to avoid DAA–ARV interactions may be possible, but risks loss of HIV control, especially in those with previous ARV experience. 21 The complex medical needs and lifestyles of many HIV/HCV coinfected patients typically result in their exclusion from clinical efficacy studies, which, together with restrictions on permitted ARVs, has resulted in highly stratified recruitment estimated to exclude 60%–94% of the real-world coinfected population.…”