Clinical Significance of Drug-Drug Interactions in HCV
The 115 patients who were selected to receive a PI had a mean age of 54 years and the majority had advanced liver fibrosis or cirrhosis. Overall, only 101 patients were treated with a PI due to a weak response or a poor tolerability to Peg-IFN/RBV therapy in the lead-in phase. A total of 69 patients were treated with TVR and 34 with BOC, including two patients who were switched from TVR to BOC during therapy due to TVR-related adverse events. The median observed PI treatment duration was 12 weeks (range: 4 days–48 weeks) (Table 1).
Regular out-patient medication of the 115 patients included 116 different drugs. Almost one of four patients (23%) took more than four different drugs at baseline, while only 29 patients (25%) did not have any regular out-patient medication before HCV treatment was initiated (Figure 2a). Overall, the mean number of regular drugs was 2.7 with a maximum of eleven co-medications. Most commonly used drugs were selective beta-blocking agents, proton pump inhibitors and levothyroxine (Table 2). The risk for DDIs with a PI was considered to be negligible (Category 1) for the majority of baseline drugs (62%), whereas for 29%, some DDIs were suspected, but dose modifications or careful monitoring may have been considered as sufficient for management (Category 2). Only 4% of the drugs were contraindicated for co-administration with a PI (Category 3). However, 10% of the patients took one of these contraindicated drugs. In the remaining 5% of the drugs, significant DDIs could not be excluded due to a lack of information (Category 0) (Figure 2b). This majorly affected herbal products and so-called alternative medicine. Overall, 49% of the patients were suspected to be at risk of experiencing significant DDIs, including the 7% of patients taking at least one drug belonging to risk category 0 (Figure 2c). Drug classes most often suspected to be involved in significant DDIs with a PI were thyroid hormones, dihydropyridine derivatives and herbal drugs/alternative medicine (Table 3).
(Enlarge Image)
Figure 2.
Risk for drug–drug interactions between a protease inhibitor and the regular out-patient medication of the 115 patients prior to the initiation of anti-viral treatment: Number of different drugs in the regular out-patient medication (a). Percentage of the different drugs in the regular out-patient medication containing to risk category 1, 2, 3 and 0 for drug–drug interactions with an HCV protease inhibitor (b). Portion of patients with a high risk (taking at least one category 3 drug), an uncertain risk (no category 3, but one or more category 0 drug), significant, but no severe risk (one or more category 2, but no category 0 and 3 drugs) and those without any risk for drug–drug interactions with an HCV protease inhibitor (no or only category 1 drugs in the regular out-patient medication) (c).
The included patients received 254 new drugs during PI treatment, mostly due to side effects of triple therapy. Most frequently, these new drugs were specific skin lotions, analgesics or antihistamines. Medications were usually prescribed by the HCV-treating physician, but also frequently by the patient's general practitioners or other physicians. In 8%, the name of the newly prescribed drug could not be evaluated retrospectively affecting 9% of the patients. In only 3% of the patients were new co-medications not suitable for co-administration with a PI. More than half of the patients (59%) either did not take any new drugs during treatment or only those considered to be safe in terms of significant DDIs with a PI (Figure S1a–c).
In 16% of the patients, at least one drug of the regular out-patient medication was stopped before PI treatment commenced due to suspected DDIs. In an additional 5% of cases, dose adjustments of the respective co-medication were applied before PI treatment was initiated. During PI treatment, discontinuation and dose adjustments of co-medication became necessary each in five cases (5%). Overall, suspected DDIs were managed by dose adjustments and discontinuation of co-medication before or during PI therapy in 7% and 21% of the patients respectively. In six patients (6%), a supposed treatment with certain drugs was either delayed until the end of PI therapy or an alternative medication was chosen due to DDI considerations.
Results
Patient Characteristics and Anti-viral Treatment
The 115 patients who were selected to receive a PI had a mean age of 54 years and the majority had advanced liver fibrosis or cirrhosis. Overall, only 101 patients were treated with a PI due to a weak response or a poor tolerability to Peg-IFN/RBV therapy in the lead-in phase. A total of 69 patients were treated with TVR and 34 with BOC, including two patients who were switched from TVR to BOC during therapy due to TVR-related adverse events. The median observed PI treatment duration was 12 weeks (range: 4 days–48 weeks) (Table 1).
Drug-Drug Interactions With the Regular Out-patient Medication Assessed at Baseline
Regular out-patient medication of the 115 patients included 116 different drugs. Almost one of four patients (23%) took more than four different drugs at baseline, while only 29 patients (25%) did not have any regular out-patient medication before HCV treatment was initiated (Figure 2a). Overall, the mean number of regular drugs was 2.7 with a maximum of eleven co-medications. Most commonly used drugs were selective beta-blocking agents, proton pump inhibitors and levothyroxine (Table 2). The risk for DDIs with a PI was considered to be negligible (Category 1) for the majority of baseline drugs (62%), whereas for 29%, some DDIs were suspected, but dose modifications or careful monitoring may have been considered as sufficient for management (Category 2). Only 4% of the drugs were contraindicated for co-administration with a PI (Category 3). However, 10% of the patients took one of these contraindicated drugs. In the remaining 5% of the drugs, significant DDIs could not be excluded due to a lack of information (Category 0) (Figure 2b). This majorly affected herbal products and so-called alternative medicine. Overall, 49% of the patients were suspected to be at risk of experiencing significant DDIs, including the 7% of patients taking at least one drug belonging to risk category 0 (Figure 2c). Drug classes most often suspected to be involved in significant DDIs with a PI were thyroid hormones, dihydropyridine derivatives and herbal drugs/alternative medicine (Table 3).
(Enlarge Image)
Figure 2.
Risk for drug–drug interactions between a protease inhibitor and the regular out-patient medication of the 115 patients prior to the initiation of anti-viral treatment: Number of different drugs in the regular out-patient medication (a). Percentage of the different drugs in the regular out-patient medication containing to risk category 1, 2, 3 and 0 for drug–drug interactions with an HCV protease inhibitor (b). Portion of patients with a high risk (taking at least one category 3 drug), an uncertain risk (no category 3, but one or more category 0 drug), significant, but no severe risk (one or more category 2, but no category 0 and 3 drugs) and those without any risk for drug–drug interactions with an HCV protease inhibitor (no or only category 1 drugs in the regular out-patient medication) (c).
Drug-Drug Interactions With Medication Started During Anti-viral Treatment
The included patients received 254 new drugs during PI treatment, mostly due to side effects of triple therapy. Most frequently, these new drugs were specific skin lotions, analgesics or antihistamines. Medications were usually prescribed by the HCV-treating physician, but also frequently by the patient's general practitioners or other physicians. In 8%, the name of the newly prescribed drug could not be evaluated retrospectively affecting 9% of the patients. In only 3% of the patients were new co-medications not suitable for co-administration with a PI. More than half of the patients (59%) either did not take any new drugs during treatment or only those considered to be safe in terms of significant DDIs with a PI (Figure S1a–c).
Impact of DDI Considerations Before and During PI Therapy
In 16% of the patients, at least one drug of the regular out-patient medication was stopped before PI treatment commenced due to suspected DDIs. In an additional 5% of cases, dose adjustments of the respective co-medication were applied before PI treatment was initiated. During PI treatment, discontinuation and dose adjustments of co-medication became necessary each in five cases (5%). Overall, suspected DDIs were managed by dose adjustments and discontinuation of co-medication before or during PI therapy in 7% and 21% of the patients respectively. In six patients (6%), a supposed treatment with certain drugs was either delayed until the end of PI therapy or an alternative medication was chosen due to DDI considerations.
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