Wednesday, March 1, 2017

Hepatitis C - Real-life data on potential drug-drug interactions in patients undergoing interferon-free DAAs

Real-life data on potential drug-drug interactions in patients with chronic hepatitis C viral infection undergoing antiviral therapy with interferon-free DAAs in the PITER Cohort Study
Loreta A. Kondili , Giovanni Battista Gaeta, Donatella Ieluzzi, Anna Linda Zignego, Monica Monti, Andrea Gori, Alessandro Soria, Giovanni Raimondo, Roberto Filomia, Alfredo Di Leo, Andrea Iannone, Marco Massari, Romina Corsini,
Published: February 28, 2017

There are few real-life data on the potential drug-drug interactions (DDIs) between anti-HCV direct-acting antivirals (DAAs) and the comedications used.

To assess the potential DDIs of DAAs in HCV-infected outpatients, according to the severity of liver disease and comedication used in a prospective multicentric study.

Data from patients in 15 clinical centers who had started a DAA regimen and were receiving comedications during March 2015 to March 2016 were prospectively evaluated. The DDIs for each regimen and comedication were assigned according to HepC Drug Interactions (

Of the 449 patients evaluated, 86 had mild liver disease and 363 had moderate-to-severe disease. The use of a single comedication was more frequent among patients with mild liver disease (p = 0.03), whereas utilization of more than three drugs among those with moderate-to-severe disease (p = 0.05). Of the 142 comedications used in 86 patients with mild disease, 27 (20%) may require dose adjustment/closer monitoring, none was contraindicated. Of the 322 comedications used in 363 patients with moderate-to-severe liver disease, 82 (25%) were classified with potential DDIs that required only monitoring and dose adjustments; 10 (3%) were contraindicated in severe liver disease. In patients with mild liver disease 30% (26/86) used at least one drug with a potential DDI whereas of the 363 patients with moderate-to-severe liver disease, 161 (44%) were at risk for one or more DDI.

Based on these results, we can estimate that 30–44% of patients undergoing DAA and taking comedications are at risk of a clinically significant DDI. This data indicates the need for increased awareness of potential DDI during DAA therapy, especially in patients with moderate-to-severe liver disease. For several drugs, the recommendation related to the DDI changes from “dose adjustment/closer monitoring”, in mild to moderate liver disease, to “the use is contraindicated” in severe liver disease.

Discussion Only

Polypharmacy has become an important issue among patients with HCV mono-infection, and DDIs are one of the challenges in the DAA-based treatment of these patients [9,10]. The most frequently reported drug interactions modify drug metabolism by inducing or inhibiting the cytochrome P450, leading to abnormal drug exposure [10].

Many of the DDI studies have been performed in healthy volunteers, yet HCV-infected patients with cirrhosis may have impaired CYP450 capacity and higher plasma concentrations of CYP450 substrates compared to healthy individuals. This would mean that they are at even more risk for drug toxicity when a DDI occurs. In light of this, different profiles of potential drug-drug interactions have been hypothesized in patients with moderate-to-severe liver disease, however, few data are available for real-life patients [1113].

Our real-life data stress that potential DDIs are an important clinical issue for individuals treated with DAAs for chronic HCV infection. We found that a wide variety of drugs belonging to different classes were used, even wider than that reported by Siederdissen et al. [6], who conducted a single center survey and whose patients were around 10 years younger, presumably with fewer comorbidities than those in our cohort.

The profile of the patients in our study mirrored the epidemiology of HCV infection in Italy, whose prevalence is greatest among the elderly [14]. As a consequence, in our cohort, polypharmacy was relatively common in patients with mild liver disease as in those with moderate-to-severe liver disease. Of the patients with mild liver disease, 30% reported a potential Category 2 DDI, for which the most suitable approach is monitoring for the early detection of adverse events [6,15]. These data indicate that in patients with mild liver disease, through careful pre-treatment assessment of concomitant medications and monitoring or dose-modifications, significant DDIs can be avoided even in elderly patients who generally take multiple comedications for different comorbidities [10,1619]. However, the use of contraindicated comedications (Category 3 of DDI) should always be checked and, if present, an alternative comedication should be provided, regardless of the severity of liver impairment. Our data showed that none of the patients with mild liver disease were taking contraindicated comedications during DAA treatment, whereas 10% of the comedications were contraindicated in patients with moderate-to-severe liver disease. Patients with moderate-to-severe liver disease were a group of particular interest, due to the intersection between older age, comorbidities and severity of liver disease. In this study, 44% of patients with severe liver disease were affected by more than one DDI. Of these patients, 17% used comedications that are contraindicated in cases of severe liver damage, mainly because of the possible deterioration of liver disease. That these drugs were prescribed and the lack of important clinical outcomes during ongoing DAA therapy could be explained by the fact that all were classified with Child-Pugh A liver cirrhosis, which indicated that the liver impairment was not very severe. However, clinicians should be aware of the possible interactions reported for different comedications and DAAs, in particular in patients with severe liver impairment [20].

Our series showed that DAA regimens containing a protease inhibitor (3D combination with ritonavir or SOF/SIM) was associated with a higher risk for DDIs (38% and 32%, respectively), compared to other SOF-containing regimens (11–23%). Furthermore, these regimens were contraindicated in patients with advanced/decompensated liver cirrhosis. The mechanism of DDIs in patients receiving the 3D regimen can primarily be attributed to the ritonavir component of 3D, whose mechanism of action is to modify the metabolism of concomitant drugs, mainly increasing concomitant drug concentrations [16].

Warnings on the administration of comedications with the DAA regimens that include protease inhibitors (3D and Simeprevir regimens) were released in 2015, when our data were being collected, which, over time, may have increased the awareness of possible DDIs related to these regimens [15,21,22].

In general, regimens with the NS5B inhibitor sofosbuvir plus an HCV NS5A inhibitor (i.e., ledipasvir, daclatasvir), which do not affect CYP450, were relatively free of significant pharmacokinetic interactions, even in patients with moderate to severe liver impairment.
PPIs were the most frequently used comedication in our study (used in 19% and 34% of patients with mild and moderate-to-severe liver disease, respectively). The possible DDIs between PPIs and DAAs has been emphasized recently, given that gastric pH could affect DAA bioavailability due to increased or decreased pharmacokinetics, as reported for 3D and SOF/LDV and in other DAA regimens containing NS3/4A protease inhibitors, such as grazoprevir, and the NS5A inhibitor elbasvir [2326]. However, the finding of a post-hoc analysis provides reassurance that the co-administration of 3D and PPI does not negatively affect the chance of viral eradication [27].
In conclusion, hundreds of thousands of patients are currently being treated with DAAs, and, based on our real-life data, 30–44% of those taking comedications are at risk of a DDI. For several drugs, the recommendation related to a potential DDI depends on the severity of liver disease, and a careful evaluation of DDIs is required, particularly in patients with severe liver impairment. This stresses the need for increased awareness of this issue and for additional extensive research.

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