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Preliminary Results of Twice Daily Dosing (Q12 hr) Of Telaprevir (TVR) for Treatment Naïve and Previously Treated Patients with Genotype 1 HCV: Comparable RVR, eRVR and SVR12 to Standard Daily Dosing at Q8 hr
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Reported by Jules Levin
AASLD 2012 November Boston, USA
Paul Pockros1,2; Douglas Hunt1; Andrea Scherschel1 - 1Gastro/Hepatology, Scripps Clinic, La Jolla, CA, United States; 2Scripps Translational Science Institute, La Jolla, CA, United States.
AASLD: OPTIMIZE Trial: Noninferiority of Twice-daily Telaprevir Versus Administration Every 8 Hours inTreatment-naïve, Genotype 1 HCV-infected Patients - (11/13/12)
AASLD: Vertex Presents New Phase 3 Data that Showed People with Hepatitis C Treated with Twice-Daily Telaprevir Achieved Viral Cure (SVR12) Rates Similar to Those Treated Three Times Daily - (11/14/12)
CONCLUSIONS
1. This early data demonstrates that on-treatment response rates with Q12 hr dosing of TVR are equivalent to or better than those published to date with Q8 hr dosing in a difficult-to-treat population with mostly advanced fibrosis, G1a and unfavorable IL28B genotypes.
2. This is the first study of Q12hr dosing in non-responder patients and the results merit further studies in this population.
3. Q12 hour dosing regimen should be instituted in all treatment-naïve and relapse G1 patients if the phase 3 trial (OPTIMIZE) confirms earlier favorable results.
DISCUSSION
We have reported a challenging experience at Scripps Clinic among 103 patients treated with telaprevir between 31 May 2011 and 31 May 2012. Most of these patients had compensated cirrhosis and were genotype 1a with a non-favorable IL28B genotype allele. Despite this challenging population, our interim data analysis suggests that Q12 hour dosing of TVR results in similar rates of RVR, eRVR and SVR rates as one would expect with Q8 hour dosing in this group of patients. Our treatment-naïve results, when corrected for the percentage of cirrhotic patients is equivalent to that reported in the phase 3 trials. The results seen in out NR group is at least equivalent to what would be expected in a population with 87% advanced fibrosis based on the REALIZE trial results.1
Data from the real life experience with telaprevir and boceprevir were recently presented from the CUPIC (Compassionate Use of Protease Inhibitors in viral C Cirrhosis) study in France.7 The data included HCV genotype 1 patients with compensated cirrhosis (Child-Pugh A) who were non-responders (relapsers and partial responders; null responders were excluded). High rates of on-treatment virological response were observed; however, high rates of severe adverse events (SAE) [38.4% for boceprevir and 48.6% for telaprevir] and high rates of discontinuation due to adverse events (AE) [7.4%and 14.5%, respectively] were observed. Most of these SAEs were due to anaemia requiring ribavirin dose reduction, transfusion or growth factor use. These results in a real life experience of treatment of cirrhotic patients suggested that an easier dosing schedule would likely improve adherence and simplify a very difficult regimen for these patients and support our decision to dose patients with F3-F4 with a Q12 hour regimen.
The challenges of interferon-based treatments have remained in place during the first year of the DAA era. These include all of the previously reported contraindications of interferon therapy and of ribavirin therapy. We have now added the drug-drug interactions and medication interactions of telaprevir and boceprevir to our problem list.8,9 It is likely that we will continue using triple therapy for HCV patients with advanced liver disease until 2014 in the US and perhaps longer in other countries. And it is possible that barriers to response will continue to exist with all-oral therapies in certain patient populations such as cirrhotics10. As such, a Q12 hour regimen of telaprevir therapy would be a welcome respite for patients treated with this regimen and should be instituted in all patients if the phase 3 trial confirms earlier favorable results.
The results of the OPTIMIZE trial have been released in a late-breaker abstract at AASLD 201211. In their abstract, the authors indicated that 744 patients were randomized and 740 treated of which15% had bridging fibrosis and 14% had compensated cirrhosis. The efficacy results indicated that TVR BID vs q8h was non-inferior: difference 1.5% (95% CI: -4.9%, 12.0%).
The adverse event (AE) profile was generally similar between arms. The authors concluded that even with "a high proportion of patients with bridging fibrosis or compensated cirrhosis, the efficacy of 1125mg bid TVR was non-inferior to 750mg q8h offering the potential of simplified dosing to G1 HCV-infected patients [and] that safety and tolerability were generally similar between regimens". These mirror our conclusions from a smaller single-center trial.
ABSTRACT
Twice daily dosing of TVR in combination with PegIFN+RBV has not been extensively studied in G1 HCV patients. The obvious benefit of twice daily dosing is ease of administration (taken at the same time as RBV) and improved adherence, which could result in better viral clearance rates. The purpose of this study is to assess the effectiveness of TVR dosed at 1125 mg Q12hr in treatment naïve and previously treated patients with genotype 1 chronic HCV infection. We obtained informed consent and treated 118 consecutive patients with TVR 1125mg po Q12 hrs. 103 of these have completed therapy or reached week 12 of treatment with HCV RNA measurements at baseline and monthly thereafter. We collected data on IL28B, RBV dose reduction, use of EPO, AEs, early discontinuations, treatment failures and SVR12/24.
Results: Of the 103 evaluable patients 58/103 (56.3%) are treatment naïve (TN) or relapsers and 45/103 (43.6%) are treatment failures (NR). 33/103 (32%) have F0-2 fibrosis and 70/103 (68%) have F3/4. 70 (71.5%) and 28 (28.5%) patients have genotype 1a and 1b respectively.
IL28B genotyping was available in 39/103 patients and was CC in 20.5% and non-CC in 79.5%.
55 of the 58 (94.8%) TN patients were HCV RNA undetectable (UND) or <43 IU/ml at week 4 and UND at week 12 (eRVR=32/55). 30 of these have reached week 24 and all remain UND. 10 patients who completed therapy at week 24 have reached 12 weeks of F/U and all are SVR12.
23 of 45 (51.1%) NR were HCV RNA UND or <43 IU/ml and UND at week 12 and 19 of these have reached week 24; all remain UND. 6 NR patients who DC therapy early have achieved SVR12. 17 of the 22 (77%) patients who failed therapy in the NR group had F3/4.
Safety: 27/103 patients stopped therapy prior to week 12 due to hepatic decompensation (4), SAEs (7), viral breakthrough or lack of milestone (12) or other reasons (4). 24/27 early DCs had advanced fibrosis and 2/27 achieved SVR12. The remainder relapsed. 5/103 patients developed hepatic decompensation (ascites, SBP, bleeding or HE) and 4/5 were hospitalized. There were no deaths. RBV dose reductions for anemia (Hgb<10 g) were re¬quired in 49/103 (44.7%) patients and EPO was used in 45/49 of these patients. Platelet or neutrophil growth factors were used in 6 and 2 patients re¬spectively. 34/49 (73.5%) of patients requiring growth factor had cirrhosis.
Conclusions: This early data demonstrates that on-treatment response rates with Q12 hr dosing of TVR are equivalent to or better than those published to date with Q8 hr dosing in a difficult-to-treat population with mostly advanced fibrosis, G1a and unfavorable IL28B genotypes. This is the first study of Q12hr dosing in NR patients.
BACKGROUND
Current approved doing schedules for both telaprevir and boceprevir required the drugs be taken every 8 hours with food1,2. For patients taking telaprevir, this requirment includes at least 20 grams of fat with each pill ingestion1. This dosing schedule is rigorous, requiring patient be extremely diligent and have the opportunity to take medication with food during the workday. For many patients who are employed, this is a difficult task and is likely to result in missed dosing during the 12-week drug regimen. As well, many patients are not well adherent to the requirement for 20 gm of fat Q 8 hours because of nausea, inconvenience or non-compliance.
In prior phase Ib clinical trials, dose comparisons of TLV monotherapy showed that the largest reduction in HCV-RNA corresponded with the highest mean TLV trough levels (1054 ng/mL) in patients receiving TLV 750 mg every 8 hours3. Most patients receiving doses of 450 mg/8h or 1250 mg/12h experienced HCV rebounds or plateau responses, whereas patients receiving 750 mg/8h showed a continuous decline in HCV-RNA [See Figure 1]. It should be highlighted that with the latest dose, TLV exposure at C min was 14-fold above the IC504. These monotherapy viral kinetics were the basis for the q8hr dosing of TLV in phase II and III studies, however they were not validated in patients receiving PegIFN+RBV in combination with TLV. Therefore, we do not know that the q12hr dosing regimen would not be equivalent when used in combination.
In fact, a pilot study has previously shown that telaprevir 1,125 mg Q 12 hour dosing is an equivalent regimen to 750 mg Q8 hours in a small group of patients5. A large, phase 3b multi-center trial was initiated in 2011 (OPTIMIZE) to confirm equivalency of this dosing regimen and final data lock is due in late 20126. Because of the characteristics of the patient population initially started on anti-viral therapy at our center, we choose to start many of them on Q12 hour dosing after the approval of telaprevir in June, 2011. The common characteristics we selected were that patients who either worked regularly during day¬time hours, had a prior history of medication non-adherence or partial adherence, had F3-F4 fibrosis on liver biopsy, or were deemed unlikely to be adherent to a Q8 hour regimen by one of the providers caring for them.
METHODS
We obtained informed consent and treated 118 consecutive patients with TVR 1125mg po Q12 hrs. 103 of these have completed therapy or reached week 12 of treatment with HCV RNA measurements at baseline and monthly thereafter. Demographic information for all patients was collected at baseline including gender, age, fibrosis score on liver biopsy, baseline laboratory values, HCV RNA titer, HCV genotype, prior treatment results and HIV status [Table 1]. All HIV-positive patients were excluded from enrollment as were patients with prior history of severe psychiatric illness, active alcohol or substance abuse, other causes of liver disease or contra-indications to PEGIFN, RBV or telaprevir therapies.
We prospectively collected data on IL28B, RBV dose reduction, use of epoetin-alfa (EPO), adverse events, early discontinuations, treatment failures and SVR12/24. Data were reviewed at 2 different time points: the first in June, 2012 (in order to complete abstract submission to AASLD) and the second in late October, 2012 (in order to complete poster submission to AASLD). The final results shown herein are de¬rived from the latest data review. All patient information was entered onto a web-protected database that was updated weekly.
RESULTS
The baseline demographics of our 103 patients are shown on Table 1. 58/103 patients were treatment-naïve (TN) or prior relapsers (R) from PegIFN+RBV therapy and the majority were genotype 1a, had an unfavorable IL28B genotype, and roughly half had advanced fibrosis or cirrhosis. 45/103 patients were prior partial or null responders (NR), and the majority had genotype 1a, IL28B non-CC allele and advanced fibrosis or cirrhosis.
The virologic responses are shown on Table 2 and Figure 2. For the TN/R group, 67% of patients were HCV RNA undetectable at week 4, 64 % at weeks 4 and 12, and 70 % of patients who reached 4 weeks in follow-up (47/58 patients) attained an SVR4. All patients with SVR 4 who have reached weeks 12 and 24 of follow-up have remained HCV RNA undetectable (28 and 14 patients respectively). For the NR group, 33% of patients were HCV RNA undetectable at week 4, 33 % at weeks 4 and 12, and 43 % of patients who reached 4 weeks in follow-up (15/35 patients) attained an SVR4. All patients with SVR 4 who have reached weeks 12 and 24 of follow-up have remained HCV RNA undetectable (12 and 7 patients respectively).
A total of 36/103 patients discontinued therapy prematurely (Table 3). The major reasons for early discontinuation were severe SAEs (7 patients), hepatic decompensation (4 patients), viral breakthrough or failure to achieve virologic milestone (17 patients) and other reasons (7 patients). The early discontinuations occurred much more often in NRs than in the TN/R group and most were due to early virologic failure. The causes of the SAEs in the 7 patients who stopped therapy early are listed on Table 4.
There were 5/103 patients developed hepatic decompensation (ascites, SBP, bleeding or HE) and 4/5 were hospitalized. One patient was able to complete therapy without discontinuation and went on to have an SVR. There were no deaths. RBV dose reductions for anemia (Hgb<10 g) were required in 49/103 (44.7%) patients and EPO was used in 45/49 of these patients. Platelet or neutrophil growth factors were used in 6 and 2 patients respectively. 34/49 (73.5%) of patients requiring growth factor had cirrhosis (Table 5).
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