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Sixty milligram daclatasvir is the right dose for hepatitis C virus treatment in combination with etravirine and darunavir/ritonavir

Smolders, Elise J.; Kanter, Clara T.M.M. de; Grintjes, Karin; D’Avolio, Antonio; Di Perri, Giovanni; van Crevel, Reinout; Drenth, Joost P.H.; Burger, David M.

doi: 10.1097/QAD.0000000000001089
Correspondence
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SDC

aDepartment of Pharmacy, Radboud University Medical Center, Nijmegen

bDepartment of Pharmacy, University Medical Center Utrecht, Utrecht

cDepartment of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

dUnit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy

eDepartment Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands.

Correspondence to Elise J. Smolders, MSc, Department of Pharmacy, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands. Tel: +31 24 3616405; fax: +31 24 3668755; e-mail: Elise.smolders@radboudumc.nl

Received 5 February, 2016

Revised 2 March, 2016

Accepted 7 March, 2016

The HIV and hepatitis C virus (HCV) share the same routes of transmission and HCV coinfection is therefore often prevalent in HIV-infected patients [1]. With the introduction of the direct-acting antivirals (DAAs), HCV treatment success became independent of coinfection with HIV [2]. Indeed, more than 90% of patients reached a sustained virologic response (SVR) after 12–24 weeks of treatment [2,3]. However, concomitant treatment of HIV and HCV increases the risk of drug–drug interactions.

The case report describes an HIV–HCV coinfected patient who received simultaneous treatment for HCV with sofosbuvir, daclatasvir, plus ribavirin while on etravirine and darunavir/ritonavir for his HIV infection.

In May 2015, a 54-year-old Ethiopian man with a 20-year history of HIV infection presented with progressive pulmonary hypertension and ascites. These symptoms were attributed to his liver cirrhosis [Child–Pugh score B (CP-B); alanine transaminase 37 UI/l; aspartate transaminase 27 UI/l; γ-glutamyl transpeptidase 54 UI/l]. Cirrhosis was caused by an HCV genotype 4 infection, for which he had been treated unsuccessfully with peg-interferon and ribavirin in 2006. Treatment with diuretics led to progressive kidney function loss, after which it was decided to initiate HCV therapy.

The proposed 12-week HCV treatment was a daily regimen containing 400 mg sofosbuvir, 800 mg ribavirin, and daclatasvir, in line with international [3] and Dutch guidelines [4]. For his HIV infection, he received 400 mg etravirine and 800/100 mg darunavir/ritonavir once daily, after experiencing mitochondrial and other toxicity on nucleoside reverse transcriptase inhibitor-based combinations. Thus, the HIV regimen could not be changed. His HIV viral load was undetectable.

We examined potential drug–drug interactions that could arise from both regimens. Etravirine and darunavir/ritonavir induce and inhibit cytochrome P450 (CYP) 3A4, respectively, and daclatasvir is a CYP3A4 substrate. Experimental studies have shown that daclatasvir pharmacokinetics is minimally affected by darunavir/ritonavir, obviating the need for dose adjustment. Coadministration of daclatasvir with etravirine may lead to decreased daclatasvir concentrations [5,6]. Although this has not been shown in humans, the Food and Drug Administration advises increasing the daclatasvir dose to 90 mg/day when coadministered with etravirine [6]. The normal daclatasvir dosage is 60 mg/day.

In view of the uncertain interaction between daclatasvir, etravirine, and darunavir/ritonavir, we started treatment with 60 mg daclatasvir, reasoning that CYP3A4 induction by etravirine would be compensated by inhibition of this enzyme by darunavir/ritonavir. However, no dose adjustment of daclatasvir is necessary; CYP3A4 is inhibited by darunavir/ritonavir. The area under the curve (AUC) and maximal plasma concentration (Cmax) of daclatasvir decreased by 41% and 23% when coadministered, respectively [5].

The pharmacokinetic curve of daclatasvir was recorded at steady state. Blood samples were taken at t = 0 (predose), 2, 6, 8, and t = 24 h (Ctrough) after daclatasvir intake. Plasma concentrations were determined with a validated liquid chromatography–mass spectrometry method and pharmacokinetic parameters were calculated using WinNonlin [7].

Figure 1 shows the pharmacokinetic curve and parameters of daclatasvir from our patient. Cmax and AUC0-tauwere 59% and 20% decreased, and Ctrough was 11% increased, compared with reference values obtained from literature [8]. The elimination half-life (t1/2) was 12.6 h, which is similar to the literature [8].

Fig. 1

Fig. 1

The patient completed a 12-week course of treatment and after follow-up SVR12 was achieved in January 2016.

AUC and Ctrough are the most important pharmacokinetic parameters to attain antiviral efficacy and both were similar with reference values [9–11]. Ctrough should be high enough to maintain viral inhibition throughout the complete dose interval, whereas a decreased Ctrough potentially leads to viral failure or induction of resistant strains.

Cmax was reduced in our patient, which is comparable with a trial describing decreased Cmax and AUC in CP-B patients. Additionally, the unbound daclatasvir fraction was equivalent between noncirrhotic HCV and CP-B patients, meaning that exposure to pharmacological active daclatasvir was unaffected [12]. Extrapolating this result to our patient, we believe that our patient is being treated with the right dose of daclatasvir.

Our pharmacokinetic data suggest that the inducing effect of etravirine can be mitigated by darunavir/ritonavir. This is analogous to the interaction between maraviroc (CYP3A4 substrate), efavirenz (CYP3A4 inducer), and protease inhibitors (CYP3A4 inhibitors). Boosted protease inhibitors mitigated the inducing effect of efavirenz on maraviroc, and hence the dose of maraviroc should be based on the presence of the boosted protease inhibitor [13].

Based on the pharmacokinetic parameters and the achievement of SVR12, we believe that the exposure to daclatasvir was adequate. This fuels our hypothesis that CYP3A4 induction by etravirine can be compensated through CYP3A4 inhibition by darunavir/ritonavir. Daclatasvir should be administered at a dose of 60 mg when combined with etravirine and darunavir/ritonavir.

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Acknowledgements

We thank the patient for participating and the laboratory personnel at the Clinical Pharmacology Laboratory of the Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin for analyzing the samples.

Author contributions: E.J.S.: study design and execution of the study, interpreting results, and drafting and editing of this article. C.T.K.: study design, interpreting results, and editing of this article. K.G.: treating nurse, study design, interpreting results, and editing of the paper. A.D.: analytical determination DAAs, and editing of this article. G.P.: analytical determination DAAs, and editing of this article. R.C.: treating physician, study design, interpreting results, and editing of this article. J.P.D.: interpreting results and editing of this article. D.M.B.: study design, interpreting results, and drafting and editing of this article.

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Conflicts of interest

E.J.S., C.T.K., K.G., R.C., G.P., and J.P.D. declare that they have no conflicts of interest that are directly relevant to the content of this review. A.D. received a payment from Novartis for manuscript preparation. D.M.B. joins advisory boards of Abbvie, BMS, Gilead, Janssen, and Merck and received sponsorship/research grants from BMS, Janssen, and Merck.

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