LIDに報告された、Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1)。単一アーム、オープンラベル、多施設第3相試験。
The once-daily, ribavirin-free, pangenotypic, direct-acting antiviral regimen, glecaprevir coformulated with pibrentasvir, has shown high rates of sustained virological response in phase 2 and 3 studies. We aimed to assess the efficacy and safety of 12 weeks of coformulated glecaprevir and pibrentasvir in patients with hepatitis C virus (HCV) infection and compensated cirrhosis.
We did this single-arm, open-label, multicentre phase 3 study at 40 sites in Belgium, Canada, Germany, South Africa, Spain, and the USA. We enrolled patients aged 18 years or older with HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. Patients were either HCV treatment-naive or had not responded to treatment with interferon or pegylated interferon with or without ribavirin, or sofosbuvir plus ribavirin with or without pegylated interferon. Oral glecaprevir (300 mg) coformulated with pibrentasvir (120 mg) was administered once daily for 12 weeks. The primary efficacy endpoint was sustained virological response at post-treatment week 12 (HCV RNA <15 IU/mL). We assessed efficacy and safety in all patients who received at least one dose of study drug (intention-to-treat population). This study is registered with ClinicalTrials.gov, number NCT02642432.
Between Dec 7, 2015, and May 4, 2016, we enrolled 146 patients with compensated cirrhosis, of whom 48 (33%) had genotype 1a HCV infection, 39 (27%) had genotype 1b infection, 34 (23%) had genotype 2 infection, 16 (11%) had genotype 4 infection, two (1%) had genotype 5 infection, and seven (5%) had genotype 6 infection. 12 weeks after treatment, 145 patients (99%, 95% CI 98–100) achieved sustained virological response, with one (1%) relapse at post-treatment week 8. We recorded 101 (69%) adverse events, of which 65 (64%) were mild. The most common adverse events were fatigue (n=28 [19%]) and headache (n=20 [14%]). 11 (8%) patients had serious adverse events, none of which were deemed related to study drugs. No patients had elevations in alanine aminotransferase and no patients prematurely discontinued treatment because of adverse events.
Our results show that 99% of patients treated with once-daily glecaprevir plus pibrentasvir achieved a sustained virological response at 12 weeks. Furthermore, this drug regimen had a favourable safety profile in previously treated or untreated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. These findings could help simplify treatment algorithms and reduce treatment burden.
Oral glecaprevir (300 mg) coformulated with pibrentasvir (120 mg) was administered once daily for 12 weeks.
New anti-HCV drug combinations: who will benefit?
However, the limitation of access to these potentially life-saving medications cannot be solved by introduction of new treatments alone. The biggest question is how these new drugs will be used. Overall, their e cacy is minimally better than that of the already available drug combinations. In patients with genotype 1b infection, treatment with ombitasvir, paritaprevir, and dasabuvirisase ectiveastreatmentwithcoformulatedglecaprevir and pibrentasvir; in patients without cirrhosis, even 8 weeks of treatment with ombitasvir, paritaprevir, and dasabuvirissu cient. Thesameistrueforpatientswith genotype 4 infection.The only relevant advantage of coformulated glecaprevir and pibrentasvir compared with ombitasvir, paritaprevir, and dasabuvir is that patients have to take three tablets instead of four. Ribavirin is not needed with coformulated glecaprevir and pibrentasvir in patients with genotype 1a infection, thus preventing ribavirin-induced side efects.
The most commonly reimbursed treatment for chronic hepatitis C in Europe is ombitasvir, paritaprevir, and dasabuvir with or without ribavirin. Drug pricing is not transparent in Europe, but ombitasvir, paritaprevir, and dasabuvir seems to be the cheapest drug combination on the market. The price of a particular drug varies considerably among the EU member states. Usually hepatitis C drugs are most expensive in Germany and cheapest in Romania. As a hepatologist, it is not my job to recommend how to market a drug. The price will probably dictate which drug will be paid for by third-party payers. Drug prices are xed in bazaar-like negotiations; thus, neither glecaprevir coformulated with pibrentasvir nor sofosbuvir, velpatasvir, and voxilaprevir are likely to be rst-line drugs, at least outside the USA. From the prescriber side, the best solution would be that all drugs cost the same and the treater has the possibility to choose the best option for the patient. The hope is that Abbvie will not take ombitasvir, paritaprevir, and dasabuvir from the market to increase the sales of glecaprevir and pibrentasvir. The same argument can be made for the Gilead drugs.
Coformulated glecaprevir and pibrentasvir and sofosbuvir, velpatasvir, and voxilaprevir will most likely be used to treat non-response to or relapse after rst-line treatment. NS5A resistance-associated substitutions are mostly responsible for treatment failure with the currently available regimens. Pibrentasvir is e ective against the most common NS5A resistance-associated substitutions at positions 30, 31, and 93. None of the patients included in the EXPEDITION-1 trial had failure of a previous NS5A inhibitor-containing regimen, but 40% of those sequenced had NS5A mutations at baseline, including the one patient who relapsed at week 8 after treatment with glecaprevir and pibrentasvir.
Society should be happy to have safe drugs with high e cacy for treatment of HCV.
However, optimal use of these drugs will depend on them being accessible to infected patients worldwide, and receiving high priority on the political agenda.
Proton-pump inhibitors and glecaprevir plus pibrentasvir in HCV infection
Drug interactions between proton-pump inhibitors and direct-acting antiviral drugs are a great concern in patients with hepatitis C virus infection, because of the potential for suboptimal plasma concentrations of direct-acting antiviral drugs leading to compromised outcomes.1, 2 In the phase 3 trial reported by Xavier Forns and colleagues,3 31 (21%) patients with hepatitis C virus infection and compensated cirrhosis receiving glecaprevir plus pibrentasvir were concurrently treated with proton-pump inhibitors. On the basis of a post-hoc subgroup analysis, the authors concluded that the concomitant use of proton-pump inhibitors did not affect the efficacy of glecaprevir and pibrentasvir;3 however, no information on the type, dose, frequency, or duration of the concomitant proton-pump inhibitor was given.
The degree of the interactions between proton-pump inhibitors and glecaprevir plus pibrentasvir has been shown to be highly dependent on the type, dose, frequency, and duration of the proton-pump inhibitor.4, 5 In a dedicated drug–drug interaction study, no clinically meaningful change (<30%) in the plasma peak and systemic exposure of glecaprevir and pibrentasvir was observed when coadministered with 20 mg of omeprazole once per day, whereas a statistically significant reduction, by more than 50%, was observed for glecaprevir in response to 40 mg of omeprazole once per day.4On the basis of these findings, the European Medicines Agency (EMA) stated that glecaprevir plus pibrentasvir could be administered concurrently with no more than 20 mg of omeprazole once per day.4 Furthermore, the concomitant use of 40 mg of omeprazole once per day is contraindicated, and not recommended because of the risk of impaired efficacy.4, 5
The post-hoc subgroup analysis in the phase 3 trial by Forns and colleagues3 should be interpreted with caution. If the proton-pump inhibitors were grouped together, rather than stratified by type, dose, frequency, and duration in the post-hoc analysis, the extent of such drug-drug interaction would be mitigated. As such, the clinical relevance of the drug interactions between proton-pump inhibitors and glecaprevir plus pibrentasvir cannot be ruled not. Moreover, the precise effect of long-term use of a specific proton-pump inhibitor at a specific dosing regimen on glecaprevir plus pibrentasvir efficacy cannot be determined. Given the limited sample size of patients who used concurrent proton-pump inhibitors in the phase 3 trial, we believe that Forns and colleagues'3conclusion that “use of concomitant proton-pump inhibitors had no effect on efficacy” is premature. We now support, in line with the labelling recommendation,4 the avoidance of long-term use of glecaprevir plus pibrentasvir with 40 mg of omeprazole once per day.
We declare no competing interests.
Proton-pump inhibitors and glecaprevir plus pibrentasvir in HCV infection – Authors' reply
We appreciate Guo Yu and colleagues highlighting the limitations of post-hoc analyses; however, in our study,1 we concluded that the sustained virological response 12 weeks after completion of treatment (SVR12) of 97% (30/31) of patients receiving proton-pump inhibitors suggested an absence of effect on efficacy, rather than concluding that high doses of proton-pump inhibitors (equivalent to 40 mg per day of omeprazole) have no effect on efficacy. Conclusions cannot be reached given the small sample size of the subpopulation of patients receiving proton-pump inhibitors in only one study.
Different from studies of other direct-acting antiviral drug regimens2, 3 that concluded the exposure of NS5A inhibitors is significantly reduced by omeprazole use, phase 1 pharmacokinetic studies4showed that when given with 40 mg of omeprazole, pibrentasvir exposures were unaffected, whereas glecaprevir exposures were lower (area under the curve 51% lower). Exposure and response analyses indicate that decreases in the exposure of glecaprevir (as observed in patients using high doses of proton-pump inhibitors) had no effect on efficacy.4 Additionally, efficacy data showed patients enrolled in phase 2 dose-ranging studies, with approximately the same exposure of glecaprevir, compared with that from patients in phase 3 studies (who received 200 mg, instead of the marketed 300 mg, of glecaprevir and 120 mg of pibrentasvir) achieved SVR12 rates of 99% (117/118 patients; unpublished).
An integrated analysis from 2369 patients treated with glecaprevir and pibrentasvir in phase 2 and 3 clinical trials included 263 patients with concomitant proton-pump inhibitor use; in this analysis the efficacy of glecaprevir and pibrentasvir with either 20 mg or 40 mg of omeprazole per day, and other proton-pump inhibitors, was evaluated.5 25% (66/263 patients) received proton-pump inhibitors in doses equivalent to 40 mg of omeprazole, and 75% (197/263 patients) received 20 mg of omeprazole or equivalent. The intention-to-treat SVR12 rate was not affected by concomitant proton-pump inhibitor use (97% with or without concomitant proton-pump inhibitor use). The rate of virologic failure in patients receiving proton-pump inhibitors was 0·3% (1/263 patients; one GT1-infected patient was receiving proton-pump inhibitors at doses equivalent to 20 mg per day); no patients receiving doses equivalent to 40 mg per day experienced virologic failure.1 An article that will evaluate the effect of proton-pump inhibitor coadministration on efficacy of glecaprevir and pibrentasvir, and will include these results in patients enrolled in phase 2 and 3 studies, is in development by Flamm and colleagues.
XF receives grant support from AbbVie, and is an advisor to Gilead, AbbVie, and Janssen. FJM is an AbbVie employee and holds AbbVie stock or stock options. AbbVie participated in the data interpretation and in the writing, review, and approval of this letter. AbbVie funded the original article and the medical writing support for this letter. Both authors had full access to all relevant data. Medical writing support was provided by Zoë Hunter of AbbVie.