Provided by GastroEndo News
Issue: August 2013 Issue 64:8
by David Wild
Keeping up with the many exciting advances in the management of liver diseases is a difficult task. Gastroenterology & Endoscopy News asked three expert hepatologists to share their opinions of the top liver abstracts from The International Liver Congress 2013/ European Association for the Study of the Liver (EASL) and the 2013 Digestive Disease Week (DDW) meeting. Following are their selections and insights.
Sofosbuvir + Peginterferon + Ribavirin for 12 Weeks Achieves 90% SVR12 in Genotype 1, 4, 5, or 6 HCV Infected Patients: The NEUTRINO Study (Lawitz E et al. EASL Abstract 1411)
This Phase III open-label study included 292 treatment-naive patients with chronic hepatitis C virus (HCV) genotype (GT) 1 infection, 28 patients with HCV GT4 infection and seven patients with HCV GT5/6 infection. All patients received sofosbuvir, a pangenomic NS5B HCV polymerase inhibitor, 400 mg daily, along with ribavirin (RBV) 1,000 to 1,200 mg daily and pegylated interferon (PEG-IFN) 180 mcg weekly, for 12 weeks. Seventeen percent of patients had compensated cirrhosis and 29% had interleukin 28 B (IL28B) genotype CC. At baseline, patients had greater than 90,000 platelets per mcL, none had neutropenia and the mean HCV RNA viral load was 6.4 log10 IU/mL.
The researchers reported an overall sustained virologic response (SVR) rate of 90% at 12 weeks after treatment completion, a difference statistically higher than the 60% reported in historical controls, they said. All of the patients who did not achieve SVR at week 12 relapsed following an initial response to treatment. None of these patients were found to have NS5B S282T resistance after relapse.
Subgroup-specific SVR rates at week 12 were 80% in patients with cirrhosis, 89% in cirrhotic and non-cirrhotic patients with HCV GT1, 96% in HCV GT4 patients and 100% in HCV GT5/6 patients.
Common adverse events (AEs) of treatment included fatigue (59%), headache (36%), nausea (34%) and insomnia (25%); 2% of patients discontinued treatment. Serious AEs occurred in 1% of patients.
Dr. Basu: This study looked at the efficacy of a single dose of the pangenomic HCV NS5B polymerase nucleotide inhibitor, sofosbuvir, along with PEG-IFN and RBV, in patients with a range of HCV genotypes. These included patients with difficult-to-treat HCV GT1 and HCV GT4, as well as individuals with compensated cirrhosis. The SVR rates were impressive. Notably, 80% of all patients with cirrhosis achieved SVR at week 12.
All Oral Therapy With Sofosbuvir + Ribavirin for 12 or 16 Weeks in Treatment Experienced GT2/3 HCV-Infected Patients: Results of the Phase 3 FUSION Trial (Nelson DR et al. EASL Abstract 6)
This randomized, placebo-controlled, double-blind Phase III study of dual therapy with sofosbuvir 400 mg daily and RBV 1,000 to 1,200 mg daily, included 201 treatment-experienced patients with HCV GT2/3. Most of the patients were white men, with a mean age of 54 years. Thirty percent of patients had the IL28B genotype CC, 34% had compensated cirrhosis, 63% had HCV GT3, 75% had relapsed following prior treatment and 25% were prior null responders. Patients were randomized to receive either 12 weeks of treatment with sofosbuvir and RBV followed by four weeks of placebo, or 16 weeks of treatment with sofosbuvir and RBV.
In the 16-week treatment group, 78% of HCV GT2 patients with cirrhosis and 100% of HCV GT2 patients without cirrhosis achieved SVR compared with 60% and 96%, respectively, of patients in the 12-week treatment group. SVR rates in HCV GT3 patients in the 16-week treatment group were 61% and 63% for patients with or without cirrhosis, respectively, compared with 19% and 37%, respectively, of patients in the 12-week treatment group.
Serious AEs occurred in 3% and 5% of patients in the 16- and 12-week treatment groups, respectively, but no patients discontinued treatment because of drug-related AEs. Of patients in the 16- and 12-week groups, 10% and 5%, respectively, experienced a drop in hemoglobin greater than 10 g/dL, and 2% of patients in the 12-week treatment group had hemoglobin less than 8.5 g/dL. Common AEs in both treatment groups included fatigue, headache, insomnia, nausea, irritability, cough and diarrhea.
Dr. Basu: This trial looked at an interferon (IFN)-free regimen, including another pangenomic drug with no associated resistance to RBV. The study population again included very difficult-to-treat patients, including prior relapsers and null responders, a large population of patients with HCV GT3 and a significant number of patients with cirrhosis. The results indicate that this treatment regimen should be used in patients with HCV GT3, and extended to 16 weeks.
Telaprevir With Adjusted Dose of Ribavirin in Naive CHC-G1: Efficacy and Treatment in CHC in Hemodialysis Population. Target C Trial—A Placebo Randomized Control Clinical Trial (Basu P et al. DDW Abstract 517)
This randomized, placebo-controlled trial included 36 treatment-naive patients with chronic HCV GT1 undergoing hemodialysis.
Twelve patients were assigned to receive telaprevir 750 mg (three tablets twice daily on the day of dialysis, and two tablets three times daily post-dialysis) along with PEG-IFN 135 mcg once weekly and RBV 200 mg three times weekly and for 12 weeks, followed by an additional 12 weeks of treatment with PEG-IFN and RBV. Another 12 patients received the same dose of telaprevir along with PEG-IFN plus a placebo for 12 weeks, followed by treatment with PEG-IFN and RBV for an additional 24 weeks. A third group of 12 patients underwent treatment with PEG-IFN and RBV plus a placebo for 24 weeks, followed by a 12-week treatment pause and resumption of the same regimen between weeks 36 and 48. Forty-three percent of patients had HCV GT1a, 64% were black, 29% had IL28B genotype CC, 26% had IL28B genotype TT and 46% had IL28B genotype CT.
Rapid virologic response (RVR) occurred in 50% of patients in the telaprevir 24-week total treatment group, in 42% of patients in the telaprevir 36-week total treatment group and in 25% of placebo recipients. SVR rates at week 24 were 63%, 50% and 25% in the three groups, respectively.
One patient each in the 24-week telaprevir treatment group and the placebo group experienced viral breakthrough. Both patients were black, had HCV GT1a and IL28B genotype TT.
Thrombocytopenia, neutropenia, anemia, anorectal dysfunction, dysgeusia, depression and constipation were more common among patients who took telaprevir.
Dr. Basu: The patients included in this study were at high risk for transplantation, given that they had accelerated fibrosis (14%, F2; 72%, F3; 14%, F4) and that patients on hemodialysis have historically low SVR rates. Moreover, post-transplantation resumption of accelerated fibrosis is common, and 1.56% of hemodialysis patients with HCV experience graft failure after transplantation.
We hypothesized that if we could optimize the dosing regimen of telaprevir—a drug that does not undergo renal metabolism and is therefore safe for patients on hemodialysis—we might be able to increase SVR rates. After reviewing the literature, we found an interesting telaprevir dosing regimen: On the day of dialysis, patients are administered three tablets twice daily, and on the day after hemodialysis, they are given two tablets three times daily.
With our adjusted dosing schedule, we achieved higher SVR rates compared with the traditional standard of care in hemodialysis patients with HCV GT1. The extended 48-week treatment regimen showed no added benefit. We are now conducting a large, prospective trial to validate the findings.
Dr. Basu has received financial support from Bristol-Myers Squibb, Genentech, Gilead Sciences, Ironwood Pharmaceuticals, Merck & Co., Otsuka Pharmaceutical Co., Ltd., Salix Pharmaceuticals, Takeda Pharmaceuticals, Three Rivers Pharmaceuticals and Vertex Pharmaceuticals.
All-Oral Sofosbuvir-Based 12-Week Regimens for the Treatment of Chronic HCV Infection: The ELECTRON Study (Gane EJ et al. EASL Abstract 14)
Investigators set out to determine whether combining sofosbuvir, a uridine nucleotide analog HCV polymerase inhibitor, and a second direct-acting antiviral agent with a different mechanism of action, could improve SVR rates when administered with RBV in patients with HCV GT1. To this end, they evaluated sofosbuvir 400 mg once daily plus RBV 1,000 to 1,200 mg in 25 treatment-naive patients and 10 prior null responders with HCV GT1; two other groups of similar numbers of patients received the same treatment regimen plus either ledipasvir (GS-5885), an HCV NS5A inhibitor, 90 mg daily, or GS-9669, a non-nucleotide NS5B inhibitor, 500 mg daily. Treatment duration in all groups was 12 weeks. Mean baseline HCV RNA levels ranged from 5.9 log10 to 6.9 log10. None of the patients had cirrhosis, and most had HCV GT1a.
In the control group, 84% and 10% of treatment-naive and null responders, respectively, achieved SVR at week 12. In the ledipasvir treatment group, 100% of patients achieved SVR at week 12. In the GS-9669 group, 92% of treatment-naive patients achieved SVR at week 12, and among three prior null responders with data available at week 12 post-treatment, all achieved SVR.
Serious AEs occurred in one treatment-naive patient in the control group and in two treatment-naive patients who received ledipasvir.
Dr. Feld: Recognizing the caveats that this was a small trial in very healthy patients without cirrhosis, these data look very impressive and both combinations of treatments look extremely promising. The addition of ledipasvir seemed to overcome the issue of relapse seen in patients treated with sofosbuvir and ribavirin alone, particularly in prior null responders. For patients treated with 12 weeks of sofosbuvir and ribavirin, only 1 of 10 prior null responders achieved SVR. With the addition of ledipasvir, all prior null responders achieved SVR at week 12.
Sofosbuvir and ledipasvir have been combined into one pill, which taken once daily seems to be well tolerated and could improve compliance with medication. In future studies, it will be important to explore whether therapy can be shortened, and whether ribavirin can be eliminated, reducing the pill burden for patients and avoiding anemia. Eliminating ribavirin also would open the possibility of treating patients with renal failure or chronic anemia who cannot take ribavirin.
Clearly, these combinations of treatments will have to be studied in larger, Phase III trials including more difficult-to-cure patients, particularly those with cirrhosis and other HCV genotypes, against which both ledipasvir and GS-9669 have demonstrated activity. If these results hold up, this all-oral HCV antiviral regimen will compare favorably to other IFN-free options for patients with HCV GT1.
SVR12 Rates and Safety of Triple Therapy Including Telaprevir or Boceprevir in 221 Cirrhotic Non Responders Treated in the French Early Access Program (ANRS CO20-CUPIC) (Fontaine H et al. EASL Abstract 60)
As part of the French Early Access Program, 485 treatment-experienced HCV GT1a/b patients with cirrhosis were offered treatment with a first-generation HCV protease inhibitor (PI) in combination with PEG-IFN and RBV in an open-label fashion. The treating physicians decided whether to prescribe boceprevir- or telaprevir-based triple therapy: 190 individuals received the standard boceprevir-based regimen, and 295 patients underwent standard telaprevir-based treatment. The majority of patients were prior relapsers. All patients had cirrhosis, nearly all were Child-Pugh class A, and patients had a mean Model for End-stage Liver Disease score of 8.1.
Findings of the intent-to-treat analysis showed that 79% of telaprevir recipients had a virologic response at week 8, and 40% continued with SVR at week 12: This included 53% of prior relapsers, 32% of partial responders and 29% of null responders. Among those who discontinued treatment early, approximately 19% did so because of detectable HCV RNA, 27% relapsed, 41% experienced viral breakthrough and 14% experienced AEs.
In the boceprevir treatment group, 51% had a virologic response at week 8, and 41% continued with SVR at week 12, including 51% of prior relapsers, 40% of partial responders and 11% of null responders. Premature discontinuation of treatment in this group was due to detectable HCV RNA in approximately 36% of patients, relapse in 27%, viral breakthrough in 26% and AEs in 11%.
Serious AEs occurred in 54% and 51% of telaprevir and boceprevir recipients, respectively, and included a 2.4% and 1.6% mortality rate, respectively. Grade 3/4 infections occurred in 9.1% and 4.2% of telaprevir and boceprevir recipients, respectively, grade 3/4 hepatic decompensation occurred in 5.1% and 4.7%, respectively, grade 3 rash occurred in 5.4% and 1%, respectively, and grade 3/4 anemia in 12.9% and 10%, respectively.
Dr. Feld: The CUPIC (Compassionate Use of Protease Inhibitors in Cirrhotics) trial is a critical, real-world evaluation of two first-generation HCV PIs. The findings highlight the importance of conducting real-world studies to evaluate the true effectiveness and safety of approved regimens when their use expands beyond the highly selected trial populations.
Previous reports have shown a high rate of AEs in this cohort of prior relapsers and nonresponders with cirrhosis. The final safety data are somewhat reassuring because the rate and severity of AEs was similar at full follow-up to rates reported at week 16, suggesting that most problems occurred early in the course of therapy. However, the cumulative rate of AEs with both agents was high. Anemia was a major problem, with 18% and 13.7% of telaprevir and boceprevir recipients, respectively, requiring blood transfusions. Notably, RBV dose reduction was underutilized because the efficacy of this strategy was not recognized when the CUPIC trial began.
Efficacy data in this study also were disappointing. In the Phase III trials of both agents, relapsers with cirrhosis had very high rates of SVR; however, in this real-world experience, despite high on-treatment viral suppression, overall SVR rates were low.
Overall, the CUPIC data clearly demonstrate that triple therapy with an HCV PI is associated with a high risk for potentially severe toxicity and has somewhat limited efficacy in patients with cirrhosis. Given the extremely promising data with other IFN-free and IFN-containing regimens that will soon be available, the CUPIC data should give us pause for thought before rushing to treat all patients with HCV PIs.
Dr. Feld has served as a consultant or advisory board member for AbbVie, Achillion, Boehringer Ingelheim, Gilead Sciences, Janssen Pharmaceuticals, Merck & Co., Roche and Vertex Pharmaceuticals. He has received grant support from Boehringer Ingelheim, Gilead Sciences, Roche and Vertex Pharmaceuticals.
Safety and Efficacy of Interferon-Free Regimens of ABT-450/R, ABT-267, ABT-333 ± Ribavirin in Patients With Chronic HCV GT1 Infection: Results From The AVIATOR Study (Kowdley KV et al. EASL Abstract 3)
This subanalysis of the AVIATOR study included 247 non-cirrhotic patients with HCV GT1 who received a four-drug treatment regimen for 12 or 24 weeks in a randomized open-label fashion. Treatment included 100 or 150 mg once daily of ABT-450, a potent HCV NS3/4A PI, administered orally with 100 mg of ritonavir, as well as 25 mg once daily of ABT-267, an HCV NS5A inhibitor, 400 mg twice daily of ABT-333, a non-nucleoside HCV polymerase inhibitor, and 1,000 to 1,200 mg daily of RBV, administered in two doses. The 12-week treatment group included 79 treatment-naive patients and 45 prior null responders; the 24-week group had 80 treatment-naive patients and 43 prior null responders.
Findings showed that 99% of treatment-naive patients and 93% of null responders in the 12-week treatment arm achieved SVR at week 12, and 96% and 93% of the two groups, respectively, achieved SVR at week 24. In the 24-week treatment group, SVR at week 12 occurred in 93% and 98% of treatment-naive patients and null responders, respectively, whereas 90% and 95%, respectively, had SVR at week 24.
One treatment-naive patient in the 12-week treatment group and two in the 24-week group experienced relapse. Additionally, three prior null responders in the 12-week group and one in the 24-week group experienced viral breakthrough. Six patients discontinued treatment due to AEs, but researchers considered only four of these related to treatment. Four serious AEs were reported, but only one—a case of arthralgia—was believed to be treatment-related.
Dr. O’Leary: This exciting 12-week all-oral HCV treatment regimen promises excellent SVR rates for patients without cirrhosis, even if they were prior null responders to PEG-IFN and RBV. Notably, characteristics previously identified as predictors of poor response—including HCV GT1a, high pre-treatment HCV viral load, IL28B genetic polymorphism and fibrosis stage 2 to 3—did not change overall SVR rates, which were consistently 93% or higher for treatment-naive patients and prior null responders.
The safety profile of this regimen was excellent. There were very few serious AEs or treatment discontinuations secondary to serious AEs. Elevations in bilirubin and alanine transaminase were both rare (2.8% and 0.6%, respectively).
Questions that remain are how this brief, well-tolerated, IFN-free drug combination will perform in patients with compensated and decompensated cirrhosis, patients with HIV co-infection, and liver transplant recipients, especially given the drug–drug interactions that will need to be managed in some of these patients.
Despite these questions, the regimen is safe and effective, and given the risk for progressive fibrosis, hepatocellular carcinoma, insulin resistance and other non-hepatic consequences of HCV infection, it should no longer be possible for the U.S. Preventive Services Task Force to do anything other than follow the Centers for Disease Control and Prevention in recommending HCV screening for all baby boomers, followed by treatment of all persons identified with HCV infection.
Sustained Virologic Response With Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) in Chronic HCV Genotype (GT) 1–Infected Patients Who Previously Failed Telaprevir (TVR) or Boceprevir (BOC) (Sulkowski MS et al. EASL Abstract 1417)
Researchers randomized 41 HCV GT1 patients without cirrhosis who had failed prior treatment with telaprevir or boceprevir in combination with PEG-IFN and RBV to one of two treatment regimens: 21 patients received 60 mg daily of daclatasvir, an HCV NS5A replication complex inhibitor, along with sofosbuvir 400 mg daily, and 20 patients received the same regimen plus RBV, both for 24 weeks. Most patients had received telaprevir previously, most were white and approximately 60% were men. Most patients had HCV GT1a and IL28B genotype CT or TT. More than 80% of patients had METAVIR scores of F2 or higher. Mean HCV RNA for both groups was 6.3 log10 IU/mL. None of the participants had discontinued prior treatment with telaprevir or boceprevir because of an AE.
Findings showed that 91% and 80% of the RBV-free and RBV-containing treatment groups, respectively, experienced virologic response two weeks after treatment initiation, and 100% had a virologic response by the end of treatment. All participants also experienced SVR at weeks 4 and 12.
Common mild or moderate AEs in both groups included fatigue, headache, alopecia and arthralgia. Constipation and diarrhea each occurred in 5% of non-RBV recipients and in 20% of RBV recipients. No severe AEs occurred in the RBV-free group.
Dr. O’Leary: This pivotal abstract delivered a once-daily, all-oral HCV treatment regimen, with minimal side effects or drug–drug interactions. At week 12, 100% of patients who had failed first-generation HCV PI treatment achieved SVR.
We all have seen multiple exciting combinations with and without IFN that exceed currently available HCV treatment regimens and produce higher SVR rates, shorter courses of therapy and dramatically fewer side effects. Although a small study, this trial is the first to promise not just an IFN- and RBV-free regimen, but a cure for true telaprevir- or boceprevir-related treatment failures. Sulkowski et al have raised the bar on what is required for a successful HCV regimen to an all-time high!
Natural History of Inflammatory Bowel Disease After Liver Transplantation for Primary Sclerosing Cholangitis (Singh S et al. DDW Abstract 40)
Researchers from Mayo Clinic examined data from 101 patients with primary sclerosing cholangitis (PSC) who underwent liver transplantation for non-cholangiocarcinoma indications between 1998 and 2008 and who were followed for a median of 8.4 years post-transplantation. Eighty of these patients had inflammatory bowel disease (IBD) before liver transplantation. The researchers limited their analysis to 55 patients with IBD who had an intact colon at the time of transplantation. Pre-transplantation, 58% of patients (32 of 55) were not receiving medications for IBD, 38% (21 of 55) were undergoing treatment with 5-aminosalicylic acid (5-ASA), one patient was on immunomodulators or corticosteroids, and one patient was taking a tumor necrosis factor (TNF) inhibitor.
After transplantation, 51% of patients had stable disease, 47% required treatment initiation or intensification and one patient experienced improvement. Of the 32 patients who had not required medication before transplantation, after transplantation and despite transplant-related immunosuppression, six patients initiated use of 5-ASAs, nine started immunomodulators and/or corticosteroids and one patient began treatment with an anti-TNF or required surgery; 16 patients did not require post-transplantation medication. Among the 21 patients who had been treated with 5-ASAs pretransplantation, after transplantation 11 patients remained on 5-ASAs, six patients required immunomodulators and/or corticosteroids and three patients required an anti-TNF or surgery. Thirteen patients required a colectomy during the follow-up period.
Risk for disease progression after transplantation was 11% at one year, 36% at five years and 45% at 10 years, with use of tacrolimus increasing the risk (hazard ratio [HR], 5.6; 95% confidence interval, 1.1-103.4). Recurrence of PSC was associated with a decreased risk for disease progression (HR, 0.2; 95% CI, 0.1-0.6).
Finally, among the 21 patients who did not have IBD before liver transplantation, 11 developed the disease during follow-up. The risk for developing de novo IBD at one, five and 10 years after transplantation was 4.8%, 38.1% and 47.6%, respectively. The researchers did not identify any risk factors for de novo post-transplantation development of IBD.
Dr. O’Leary: These findings are surprising: A disease that is believed to be immune-mediated has a high risk for progression and de novo development in liver transplant recipients, despite their use of post-transplantation immunosuppressive therapy. Most of the 80 patients who had IBD before transplantation had mild disease, and despite post-transplantation immunosuppression, nearly half of the patients required initiation or escalation of therapy for IBD after transplantation. Furthermore, 47.6% of patients without IBD before transplantation developed de novo IBD after transplantation. Additionally, there was a 21.3% 10-year risk for colectomy after transplantation. Hopefully, this information will lead to greater insight into the mechanisms of IBD disease development and progression.
Dr. O’Leary has received fees for research, consulting or speaking from Genentech, Gilead Sciences and Vertex Pharmaceuticals.
