Study finds early shunting reduces recurrence of bleeding, improves survival
WEDNESDAY, June 23 (HealthDay News) -- Patients with cirrhosis of the liver who suffer acute variceal bleeding have improved chances for survival if a shunt is used earlier rather than later, a new study finds.
Variceal bleeding occurs when the pressure in the portal vein -- the large vein that feeds the liver -- becomes too high and causes bleeding in the surrounding vessels. It is a common complication of cirrhosis, where the liver is damaged. The standard treatment for most patients is to give them drugs to lower the blood pressure and put bands around the bleeding vessels to control the bleeding.
"The early use of transjugular intrahepatic portosystemic shunt (TIPS) with covered stents improves survival of those patients with cirrhosis in whom the use of the current recommended therapy of acute variceal bleeding has a high probability of failure," said lead researcher Dr. Juan Carlos Garcia-Pagan, from the Liver Unit at the Hospital Clinic of Barcelona in Spain.
Until now, TIPS has only been used when the initial treatment for acute variceal bleeding fails, he noted.
"In this situation, TIPS usually controls the bleeding episode, but at that time the patient has suffered a marked deterioration in the liver function, usually has become infected and, despite the control of bleeding, the patients often die of liver insufficiency," Garcia-Pagan added.
However, using TIPS right away in these patients seems to dramatically improve outcomes, according to the report in the June 24 issue of the New England Journal of Medicine.
For the study, Garcia-Pagan's group randomly assigned 63 cirrhosis patients with acute variceal bleeding to standard treatment or TIPS.
During 16 months of follow-up, only one of the TIPS patients had uncontrolled bleeding, compared with 14 on standard therapy, the researchers found.
Moreover, the odds of not having uncontrolled bleeding at one year were 50 percent among patients on standard therapy, but 97 percent among the TIPS patients.
Survival was also better among TIPS patients. The odds of surviving at one year were 61 percent among patients receiving standard treatment, compared with 86 percent among TIPS patients, the researchers found.
"In patients at high risk of treatment failure, the early use of TIPS using covered stents needs to be considered," Garcia-Pagan said. "Centers unable to perform emergent TIPS should refer these patients to centers able to do so."
Dr. Eugene Schiff, director of the Center for Liver Diseases at the University of Miami Miller School of Medicine, said that "TIPS reduces pressure in the portal vein."
In the procedure, a catheter threaded though the jugular vein places a stent in the portal vein in the liver, Schiff explained. The stent connects the portal vein with the hepatic vein, so that blood can be shunted from the portal vein to the hepatic vein. "When you do that, you decompress the pressure in the portal vein, and the pressure drops dramatically," he said.
However, one complication of the procedure is a side effect called hepatic encephalopathy, which causes cognitive changes, because restricted blood flow in the liver allows toxins to accumulate.
"It's a neuropsychiatric state where you have anywhere from confusion to staggering to coma," Schiff said.
Schiff had expected many of the patients with early TIPS to develop this problem, but the researchers found that this side effect occurred in fewer TIPS patients (28 percent) than in patients receiving standard care (40 percent).
This study will get people to rethink the early use of TIPS, Schiff said. "Maybe, TIPS should be put in early. Now, they wouldn't do that," he said. "I think you are going to see earlier use of TIPS."
SOURCES: Juan Carlos Garcia-Pagan, M.D., Ph.D., Liver Unit, Hospital Clinic of Barcelona, Spain; Eugene Schiff, M.D., professor, medicine, and director, Center for Liver Diseases, University of Miami Miller School of Medicine; June 24, 2010, New England Journal of Medicine
http://www.nlm.nih.gov/medlineplus/news/fullstory_100317.html
June 25, 2010
New Therapies in the Management of Hepatitis C Virus
Anthony J. Michaels; David R. Nelson
Posted: 04/30/2010; Curr Opin Gastroenterol. 2010;26(3):196-201.
© 2010 Lippincott Williams & Wilkins
Abstract and Introduction
Abstract
Purpose of review The present review discusses recent developments in drug discovery for hepatitis C. We are on the verge of a new era with the introduction of direct acting oral agents that will transform the treatment landscape. Both healthcare providers and patients need to stay abreast of these changes that will influence decisions to treat. This article will discuss the most promising up-to-date hepatitis C virus antiviral therapies in clinical investigation as well as the associated clinical trial results.
Recent findings First generation protease inhibitors will offer higher sustained viral response rates for both naive (70–80%) and treatment-experienced (40–50%) populations when added to standard pegylated interferon and ribavirin. However, these dramatic gains will be partially offset by new challenges with viral resistance and increased adverse events.
Summary There are currently a number of drugs under investigation that target the enzymes involved in hepatitis C virus replication. Year 2011 should bring the approval of the first generation of protease inhibitors that will offer higher cure rates for genotype 1 patients and open the door for the eventual testing of interferon-free regimens.
Introduction
Hepatitis C virus (HCV) infection is a global problem with an estimated prevalence of 1.6% in the United States.[1,2] The majority of patients acutely infected with HCV become chronically infected, which increases the risk of developing further complications associated with advanced liver disease. HCV-related end-stage liver disease is a leading cause of hepatocellular carcinoma and the most common indication for liver transplantation in the United States.[3] Current standard therapy for HCV includes pegylated interferon (PEG-IFN) in combination with ribavirin (RBV), and this combination is effective in approximately 40–50% of genotype 1-infected patients and 80% of genotype 2-infected and 3-infected patients.[4,5] Unfortunately, the majority of HCV patients in the United States are infected with genotype 1.[6] The relatively low response rate in treating genotype 1-infected patients, in combination with the long treatment durations and adverse side effect profile has led to a relatively small minority of patients opting for treatment. However, the introduction of specifically targeted antiviral therapy (STAT-C) is now on the horizon with anticipated higher cure rates and the potential for shorter treatment duration. Approval of the first STAT-C compounds is expected by mid-2011 and many patients are being 'warehoused' in anticipation.
Protease Inhibitors: Higher Sustained Viral Response, Shorter Duration, Resistance Emergence
Given the advancement of our understanding of the HCV life cycle over the past decade, there are a number of drugs under investigation that target the enzymes involved in HCV replication. The class of drugs furthest along in development is the inhibitors of the HCV serine protease NS3-NS4A.[7] Two protease inhibitors have now completed phase II testing and have yielded some consistent early lessons. For naive, genotype 1 patients, higher cure rates and shorter duration of therapy can be expected, but partially offset by new issues of resistance and increased adverse events. The recently published Protease Inhibition for Viral Evaluation (PROVE 1 and 2, evaluating telaprevir, TVR)[8••,9••] and Serine Protease Inhibitor Therapy (SPRINT-1, evaluating boceprevir, BOC)[10••] studies evaluated protease inhibitors in combination with PEG-IFN/RBV in genotype 1, naive patients. In PROVE 1, TVR was dosed at 750 mg every 8 h for 12 weeks in combination with PEG-IFN and RBV followed by an additional 12 weeks, or 36 weeks of standard of care (SOC). The sustained viral response (SVR) rate in SOC was 41%, compared with 61% (P = 0.02) in the 24 week treatment group and 67% (P = 0.002) in the 48 week treatment group. Relapse rates were highest in the control group (23%) compared with the 24 week (2%) and 48 week TVR treatment group (6%). However, more patients discontinued therapy in the TVR treatment groups secondary to adverse side effects, with rash being the most common reason for discontinuation.[8••] In the PROVE 2 trial, shorter duration treatment was explored with treatment groups receiving triple therapy (TVR + PEG-IFN/RBV) for only 12 weeks (with and without RBV) compared with an additional 12 weeks of SOC. SVR was 46% in the control group, compared with 36% in the non-RBV group (P = 0.20), 60% in the 12 week triple therapy TVR group (P = 0.12) and 69% in the 24 week triple therapy TVR group (P = 0.004). Relapse rates were highest in the non-RBV-treated group (48%) compared with the control group (22%), 12 week triple therapy group (30%) and 24 week triple therapy group (14%). Rash again occurred more commonly in the TVR treatment groups than in the control group[9••] (Fig. 1).
From PROVE 1 and 2, it appears that TVR has the ability to help overcome negative host and viral factors. A recent pooled analysis[11•] looked at a subgroup of patients with characteristics associated with low virologic response. The overall SVR for the pooled TVR treatment groups was 65 vs. 44% in the control group (P < 0.001). SVR rates were significantly higher with TVR-based vs. control treatment among patients with baseline HCV RNA at least 800 000 IU/ml (P < 0.05), patients with genotype 1a HCV infection (P < 0.05), patients with genotype 1b HCV infection (P < 0.05), men (P < 0.05), patients more than 50 years of age (P < 0.05) and those with bridging fibrosis (P < 0.05). The conclusion from this analysis is that TVR is effective across all subgroups of patients who have been traditionally considered to be difficult to treat. Another phase II trial with TVR was recently released that suggests SVR rates in naive patients may be higher than previously reported, especially when a response-guided duration is followed. In study C208,[12•] treatment-naive, genotype 1 patients (N = 161) were administered triple therapy for 12 weeks with the subsequent PEG-IFN/RBV treatment duration determined using a response-guided strategy. Patients who achieved rapid virologic response (RVR) received a total of 24 weeks of therapy and those who did not have an RVR continued PEG-IFN/RBV to week 48. The SVR rates in this study ranged from 81 to 85%, higher than those observed in the phase II PROVE trials. This study clearly suggests that response-guided therapy based on RVR at week 4 may optimize SVR and provides a useful guide for determining which patients should be treated for 24 vs. 48 weeks.
BOC is another oral NS3-NS4A protease inhibitor with potent antiviral activity. The final results from the HCV SPRINT-1 study have been reported in which HCV genotype 1 patients were randomly assigned to receive different combinations of PEG-IFN, RBV (400–1400 mg/day) and BOC (800 mg three times daily). The treatment regimens included a control group treated with 48 weeks of SOC compared to five BOC treatment regimens (4 weeks of PEG-IFN/RBV lead-in followed by triple therapy for 24 or 44 weeks; triple therapy for 28 or 48 weeks; triple therapy, but with low-dose RBV for 48 weeks). The following SVR rates were reported: control group, 38%; triple therapy 28 weeks, 55%; triple therapy 48 weeks, 67%; lead-in group 28 weeks, 56%; lead-in group 48 weeks, 75%; and low-dose RBV group, 36%. It should be noted that up to 50% of patients were treated with erythropoietin in this trial, highlighting the increased rates of anemia with BOC. Higher rates of discontinuation secondary to adverse side effects and viral breakthrough occurred in the BOC treatment groups compared with the control group. Of note, the highest reported viral breakthrough was seen in the low-dose RBV group.[10••]
Ribavirin is Required to Maximize Sustained Viral Response with Protease Inhibitors and Limit Resistance
As highlighted above, early phase II studies show strong evidence for the need of RBV in STAT-C drug regimens. Patients who did not receive RBV in the PROVE trials and those with low-dose RBV (400–1000 mg) in the SPRINT-1 trial had increased viral breakthrough, higher relapse and lower SVR. These data strongly indicate that standard-dose RBV is required to optimize response to these first generation protease inhibitors via a reduction in the development of resistance/breakthrough (Fig. 2).
It is also clear that the initial rapid drop in HCV viral levels on protease combination therapy is due to inhibition of wild-type virus that then leads to the 'uncovering' of preexisting resistant variants. The continued replication of these variants can then lead to a virologic breakthrough. Resistant variants are present in most patients at very low frequencies (<1%) and are usually detected after near complete suppression of the dominant, wild-type virus. Another important finding from the PROVE trials is the different rates of breakthrough detected between genotype 1a and 1b (much higher for 1a). The explanation for these observations is a difference in the genetic barrier to resistance between subtypes. For example, the V36M or R155K mutation that can confer drug resistance to TVR requires only one nucleotide change from genotype 1a sequence, whereas two substitutions are required in genotype 1b. Thus, it appears that HCV subtyping may play an important role in helping to select future treatment regimens and predict resistance development.
Protease Inhibitors: Hope for Nonresponders
An initial phase II trial with BOC-containing regimens in previous HCV genotype 1 nonresponders to SOC was not encouraging (SVR 14%), though in retrospect inadequate BOC dosing regimens were being used.[13] Since this early experience, a number of studies are starting to suggest reasonable response rates for the treatment-experienced population. In PROVE 3,[14••] treatment-experienced patients were randomized to one of four treatment arms (SOC for 48 weeks; TVR + PEG-IFN/RBV for 12 weeks, then SOC for an additional 12 weeks; TVR + PEG-IFN/RBV for 24 weeks, then SOC for an additional 24 weeks; or TVR + PEG-IFN for 24 weeks). SVR rates were 38–39% among previous nonresponders who received TVR-based triple therapy. Relapse rates were lowest among patients who received 24 weeks of triple therapy followed by 24 weeks of standard therapy (13 vs. 30–53% for other treatment arms). An important factor to consider in interpreting the results of the PROVE 3 trial is the stringent stopping rule established for TVR therapy. Because of concerns for high rates of resistance with incomplete viral suppression, patients in PROVE 3 discontinued TVR if HCV RNA remained detectable (>30 IU/ml) at week 4. It is now apparent that patients with declining but detectable HCV RNA at week 4 continue to experience HCV RNA reductions during treatment with TVR-containing regimens and have a high likelihood of achieving SVR with a total of 48 weeks of therapy. A hint of anticipated SVR with this response-guided approach to retreatment has now been reported from study 107 (patients in PROVE studies who did not achieve SVR in control group were retreated with triple therapy for 12 weeks followed by either 12 or 36 weeks of consolidation PEG-IFN/RBV). SVR rate for this well characterized population was 57% among prior nonresponders.[15]
Of interest, a similar SVR rate was seen in 'lead-in, null responders' from the SPRINT-1 trial. Kwo et al. conducted a retrospective analysis of SVR rates among patients who received 24 or 44 weeks of BOC and PEG-IFN/RBV following a 4-week lead-in period of PEG-IFN/RBV therapy. Among patients with a null response to the 4-week lead-in treatment period (< 1.0 log10 IU/ml HCV RNA reduction), the SVR rate was 25% for patients who continued 24 weeks of triple therapy and 55% for those who received 44 weeks of triple therapy. Thus, PROVE 3 suggests that prior nonresponders may be able to achieve at least a 39% SVR with retreatment with triple therapy-containing regimens, whereas these other emerging datasets suggest SVR rates of 55–57% with a response-guided approach may be obtainable (Fig. 3).
Polymerase Inhibitors: Unique Genetic Barrier to Resistance for Nucleosides
Multiple agents targeting the HCV RNA-dependent polymerase inhibitor, which is critical for viral replication, are also currently in trials. One of the most advanced of these polymerase inhibitors is RG7128, a nucleoside analogue. RG7128 showed potent antiviral activity as monotherapy in HCV genotype 1 patients who had failed prior standard therapy,[16] as well as in combination with PEG-IFN/RBV.[17,18] It also has been shown to have a similar safety profile as standard therapy with PEG-IFN/RBV and has demonstrated significant antiviral potency regardless of race, ethnicity or genotype.[17–19] Thus far, viral resistance has not been seen in any clinical trials with RG7128,[16,18] which suggests that the nucleoside class may offer a higher genetic barrier to viral resistance than the protease class of inhibitors.[20•]
Another nucleoside polymerase inhibitor, R1626, also showed potent HCV antiviral activity (virus negative at 48 weeks) when combined with PEG-IFN/RBV compared with the control group (84 vs. 65%, respectively). This trial also showed the importance of RBV in combination therapy as the end of treatment responses were less in the non-RBV groups compared with the control group. However, the development of this drug has been halted due to unacceptable rates of hematologic abnormalities, highlighted by lymphopenia.[21] Other second generation nucleotide polymerase inhibitors are in the early stages of development, such as PSI-7851 and IDX184, and have shown encouraging antiviral activity.[22,23] PSI-7851 has demonstrated dose-dependent HCV RNA reductions over 3 days of dosing, and patients receiving the 400-mg dose achieved a mean HCV RNA decrease of 1.95 log10 IU/ml. Population sequencing did not identify any evidence of treatment-emergent drug resistance and no patients discontinued treatment early.[22] Dose-dependent decreases in HCV RNA were also observed during the 3-day IDX184 dosing period with mean reductions ranging from 0.47 to 0.74 log10 IU/ml.[23]
In addition to the nucleoside RNA-polymerase inhibitors, nonnucleoside HCV RNA-polymerase inhibitors are also showing promise in early HCV trials. Nonnucleoside inhibitors such as GS-9190, filibuvir, BI207127, VCH-916, VCH-222, MK-3281 and ABT-333 have shown potent antiviral activity for patients with genotype 1 HCV infections and generally have been well tolerated in early clinical studies.[24–31] Even though the early results have shown promise, the genetic barrier to resistance for this class appears to be low, similar to the protease class.
Interferon-free Regimens
Given the continued need for PEG-IFN and full-dose RBV, there are many HCV-infected groups that may not benefit from the initial approval of STAT-C agents, including decompensated cirrhosis, renal failure, posttransplant and the IFN-intolerant group (which may consist of as many as 50–60% of all HCV-infected patients). Thus, what is desperately needed is the development of IFN-free regimens, that is, combination of small molecules similar to HIV therapy. A novel study called INFORM-1, the first dual combination clinical trial with oral antivirals in HCV patients, is ongoing and evaluates the safety and combined antiviral activity of RG7227, a protease inhibitor and RG7128, a polymerase inhibitor, in 14 days of combination therapy in treatment-naive patients infected with HCV genotype 1. The initial cohorts of this study were reported and appear to lay the foundation for more aggressive and prolonged non-IFN trial designs. Patients receiving this combination for 14 days experienced a median reduction in viral levels of 4.8–5.2 log IU in the higher doses tested and this combination was equally effective in both naive and previous nonresponder patients. No treatment-related serious adverse events, dose reductions, drug–drug interactions or discontinuations were reported.[32••] Given these encouraging data, many other trials are now beginning to explore combinations of STAT-C agents in the absence of PEG-IFN and/or RBV. Lastly, other strategies to improve the tolerability of IFN and RBV with new analogues of IFN and RBV are also being investigated.[33•,34•,35•,36]
Conclusion
In summary, potent viral suppression and shortened duration of therapy have been shown in clinical trials with the addition of protease inhibitors to standard therapy. Although there is optimism surrounding the new STAT-C agents in the treatment of HCV, there is also a concern on how resistance and new adverse events will impact future therapy. It also appears that the platform exists to begin to explore non-IFN-containing regimens, which would be an enormous step forward to accessing a large proportion of infected patients. The future looks encouraging for the clinician treating HCV, and more importantly, for the patients infected with HCV.
References
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McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360:1827–1838.
•• This is one of the key studies showing that the addition of TVR to current SOC with PEG-IFN and RBV in treatment-naive hepatitis C patients significantly improves SVR and may allow for shorter treatment durations.
Hézode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360:1839–1850.
•• This study is similar to the PROVE1 study, but shorter treatment durations were used. This important study shows that shorter treatment durations can be used with the addition of TVR to SOC in treating patients with chronic hepatitis C, and higher SVRs can be achieved compared with SOC.
Kwo P, Lawitz E, McCone J, et al. HCV SPRINT-1 final results: SVR 24 from a phase 2 study of boceprevir plus pegintron (peginterferon alfa-2b)/ribavirin in treatment-naïve subjects with genotype-1 chronic hepatitis C [abstract 4]. J Hepatol 2009; 50 (Suppl1):S4.
•• This study highlights the final results of the addition of BOC to SOC in treatmentnaive hepatitis C patients and shows that improved SVR rates are achieved with triple therapy compared with SOC.
Everson GT, Dusheiko GM, Ferenci P, et al. Telaprevir, peginterferon alfa-2a and ribavirin improved rates of sustained virologic response (SVR) in 'difficult-to-cure' patients with chronic hepatitis C (CHC): a pooled analysis from the PROVE1 and PROVE2 trials [abstract 1565]. Hepatology 2009; 50 (Suppl 4):1025A.
• This study shows that TVR in addition to SOC is effective across all subgroups of hepatitis C patients who have been traditionally difficult to treat.
Marcellin P, Forns X, Goeser T, et al. Virologic analysis of patients receiving telaprevir administered q8 h or q12 h with peginterferon-alfa-2a or -alfa-2b and ribavirin in treatment-naïve patients with genotype 1 hepatitis: study C208 [abstract 194]. Hepatology 2009; 50:395A.
• This study clearly suggests that response-guided therapy may optimize SVR and provides a useful guide for determining which patients should be treated for 24 vs. 48 weeks.
Schiff E, Poordad F, Jacobson I, et al. Boceprevir (B) combination therapy in null responders (NR): response dependent on interferon responsiveness [abstract 104]. J Hepatol 2008; 48:S46.
McHutchison JG, Manns MP, Muir A, et al. PROVE3 final results and 1-year durability of SVR with telaprevir-based regimen in hepatitis C genotype 1-infected patients with prior nonresponse, viral breakthrough or relapse to peginterferon-alfa-2a/b and ribavirin therapy [abstract 66]. Hepatology 2009; 50:334A–335A.
•• Unlike with PROVE 1 and PROVE 2, this study looks at previous nonresponders to SOC and continues to show improved SVR rates when TVR is added to SOC in this patient population.
Shiffman ML, Berg T, Poordad F, et al. A study of telaprevir combined with peginterferon-alfa-2a and ribavirin in subjects with well documented nonresponse or relapse after previous peginterferon-alfa-2a and ribavirin treatment: interim analysis [abstract 1852]. Hepatology 2008; 48:1135A–1136A.
Reddy R, Rodriguez-Torres M, Gane E, et al. Antiviral activity, pharmacokinetics, safety, and tolerability of R7128, a novel nucleoside HCV RNA polymerase inhibitor, following multiple, ascending, oral doses in patients with HCV genotype 1 infection who have failed prior interferon therapy [abstract LB9]. Hepatology 2007; 46:862A–863A.
Lalezari J, Gane E, Rodriguez-Torres M, et al. Potent antiviral activity of the HCV nucleoside polymerase inhibitor R7128 with PEG-IFN and ribavirin: interim results of R7128 500 mg bid for 28 days [abstract 66]. J Hepatol 2008; 48 (Suppl 2):S29.
Rodriguez-Torres M, Lalezari J, Gane EJ, et al. Potent antiviral response to the HCV nucleoside polymerase inhibitor R7128 for 28 days with PEG-IFN and ribavirin: subanalysis by race/ethnicity, weight and HCV genotype [abstract 1899]. Hepatology 2008; 48:1160A.
Gane EJ, Rodriguez-Torres M, Nelson DR, et al. Antiviral activity of the HCV nucleoside polymerase inhibitor R7128 in HCV genotype 2 and 3 prior nonresponders: interim results of R7128 1,500 mg bid with PEG-IFN and ribavirin for 28 days [abstract LB10]. Hepatology 2008; 48:1024A.
McCown MF, Rajyaguru S, Le Pogam S, et al. The hepatitis C virus replicon presents a higher barrier to resistance to nucleoside analogs than to nonnucleoside polymerase or protease inhibitors. Antimicrob Agents Chemother 2008; 52:1604–1612.
• This study highlights the concept that nucleoside polymerase inhibitors may present a higher barrier of viral resistance compared to nonnucleoside polymerase inhibitors or protease inhibitors.
Nelson D, Pockros PJ, Godofsky E, et al. High end-of-treatment response (84%) after 4 weeks of R1626, peginterferon alfa-2a (40kd) and ribavirin followed by a further 44 weeks of peginterferon alfa-2a and ribavirin [abstract 993]. J Hepatol 2008; 48:S371.
Rodriguez-Torres M, Lawitz E, Flach S, et al. Antiviral activity, pharmacokinetics, safety, and tolerability of PSI-7851, a novel nucleotide polymerase inhibitor for HCV, following single and 3 day multiple ascending oral doses in healthy volunteers and patients with chronic HCV infection [abstract LB17]. Hepatology 2009; 50:11A.
Lalezari J, Asmuth D, Casiro A, et al. Antiviral activity, safety and pharmacokinetics of IDX184, a liver-targeted nucleotide HCV polymerase inhibitor, in patients with chronic hepatitis C [abstract LB17]. Hepatology 2009; 50:11A–12A.
Bavisotto L, Wang CC, Jacobson IR, et al. Antiviral, pharmacokinetic and safety data for GS 9190, a nonnucleoside HCV NS5b polymerase inhibitor, in a phase-1 trial in HCV genotype 1 infected subjects [abstract 49]. Hepatology 2007; 46 (Suppl 1):255A.
Jacobson I, Pockros P, Lalezari J, et al. Antiviral activity of filibuvir in combination with pegylated interferon alfa-2a and ribavirin for 28 days in treatment naïve patients chronically infected with HCV genotype 1 [abstract 1052]. J Hepatol 2009; 50 (Suppl 1):S382.
Larrey D, Benhamou Y, Lohse AW, et al. Safety, pharmacokinetics and antiviral effect of BI 207127, a novel HCV RNA polymerase inhibitor, after 5 days oral treatment in patients with chronic hepatitis C [abstract 1054]. J Hepatol 2009; 50 (Suppl 1):S383.
Lawitz E, Cooper C, Rodriguez-Torres M, et al. Safety, tolerability and antiviral activity of VCH-916, a novel nonnucleoside HCV polymerase inhibitor in patients with chronic HCV genotype-1 infection [abstract 92]. J Hepatol 2009; 50 (Suppl 1):S37.
Bedard J, Nicolas O, Bilimoria D, et al. Identification and characterization of VCH-222, a novel potent and selective nonnucleoside HCV polymerase inhibitor [abstract 935]. J Hepatol 2009; 50 (Suppl 1):S340.
Cooper C, Larouche R, Bourgault B, et al. Safety, tolerability and pharmacokinetics of the HCV polymerase inhibitor VCH-222 following single dose administration in healthy volunteers and antiviral activity in HCV-infected individuals [abstract 935]. J Hepatol 2009; 50 (Suppl 1):S342.
Brainard D, Wright DH, Sneddon K, et al. Safety, tolerability, and pharmacokinetics after single and multiple doses of MK-3281 in healthy subjects [abstract 935]. J Hepatol 2009; 50 (Suppl 1):S341.
Rodriguez-Torres M, Lawitz E, Cohen D, et al. Treatment-naive, HCV genotype 1-infected subjects show significantly greater HCV RNA decreases when treated with 28 days of ABT-333 plus peginterferon and ribavirin compared to peginterferon and ribavirin alone [abstract 935]. Hepatology 2009; 50:5A.
Gane EJ, Roberts SK, Stedman C, et al. First-in-man demonstration of potent antiviral activity with a nucleoside polymerase (R7128) and protease (R7227/ITMN-191) inhibitor combination in HCV: safety, pharmacokinetics, and virologic results from INFORM-1 [abstract 935]. J Hepatol 2009; 50 (Suppl 1):S380.
•• This key study of the first dual combination clinical trial with oral antivirals in hepatitis C patients shows that interferon-free regimens may be a future possibility in treatment.
Zeuzem S, Sulkowski M, Lawitz E, et al. Efficacy and safety of albinterferon alfa-2B in combination with ribavirin in treatment-naive, chronic hepatitis C genotype 1 (CHC G1) patients [abstract 1041]. J Hepatol 2009; 50 (Suppl 1): S377.
• This study reports on a newer interferon agent that allows for less frequent dosing intervals compared with current therapy while still achieving comparable SVRs in the genotype 1 hepatitis C patient population.
Nelson D, Benhamou Y, Chuang WL, et al. Efficacy and safety results of albinterferon alfa-2B in combination with ribavirin in interferon-alfa treatment naive patients with genotype 2 or 3 chronic hepatitis C [abstract 1042]. J Hepatol 2009; 50 (Suppl 1):S378.
• This study reports on a newer interferon agent that allows for less frequent dosing intervals compared with current therapy while still achieving comparable SVRs in the genotype 2/3 hepatitis C patient population.
Lawitz E, Muir AJ, Poordad F, et al. Treatment week 24 results of weight-based taribavirin versus weight-based ribavirin, both with peginterferon alfa-2b, in naive chronic hepatitis C, genotype 1 patients [abstract 272]. Hepatology 2008; 48:433A.
• This study reports on an improved RBV agent with comparable SVR rates, but fewer cases of anemia compared with standard RBV.
Poordad F, Lawitz E, Hassanein T, et al. Sustained virologic response (SVR) results for weight-based-taribavirin versus weight-based-ribavirin, in naive chronic hepatitis C, genotype 1 patients [abstract 65]. Hepatology 2009; 50:334A.
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 290).
Curr Opin Gastroenterol. 2010;26(3):196-201. © 2010 Lippincott Williams & Wilkins
http://www.medscape.com/viewarticle/720695
Posted: 04/30/2010; Curr Opin Gastroenterol. 2010;26(3):196-201.
© 2010 Lippincott Williams & Wilkins
Abstract and Introduction
Abstract
Purpose of review The present review discusses recent developments in drug discovery for hepatitis C. We are on the verge of a new era with the introduction of direct acting oral agents that will transform the treatment landscape. Both healthcare providers and patients need to stay abreast of these changes that will influence decisions to treat. This article will discuss the most promising up-to-date hepatitis C virus antiviral therapies in clinical investigation as well as the associated clinical trial results.
Recent findings First generation protease inhibitors will offer higher sustained viral response rates for both naive (70–80%) and treatment-experienced (40–50%) populations when added to standard pegylated interferon and ribavirin. However, these dramatic gains will be partially offset by new challenges with viral resistance and increased adverse events.
Summary There are currently a number of drugs under investigation that target the enzymes involved in hepatitis C virus replication. Year 2011 should bring the approval of the first generation of protease inhibitors that will offer higher cure rates for genotype 1 patients and open the door for the eventual testing of interferon-free regimens.
Introduction
Hepatitis C virus (HCV) infection is a global problem with an estimated prevalence of 1.6% in the United States.[1,2] The majority of patients acutely infected with HCV become chronically infected, which increases the risk of developing further complications associated with advanced liver disease. HCV-related end-stage liver disease is a leading cause of hepatocellular carcinoma and the most common indication for liver transplantation in the United States.[3] Current standard therapy for HCV includes pegylated interferon (PEG-IFN) in combination with ribavirin (RBV), and this combination is effective in approximately 40–50% of genotype 1-infected patients and 80% of genotype 2-infected and 3-infected patients.[4,5] Unfortunately, the majority of HCV patients in the United States are infected with genotype 1.[6] The relatively low response rate in treating genotype 1-infected patients, in combination with the long treatment durations and adverse side effect profile has led to a relatively small minority of patients opting for treatment. However, the introduction of specifically targeted antiviral therapy (STAT-C) is now on the horizon with anticipated higher cure rates and the potential for shorter treatment duration. Approval of the first STAT-C compounds is expected by mid-2011 and many patients are being 'warehoused' in anticipation.
Protease Inhibitors: Higher Sustained Viral Response, Shorter Duration, Resistance Emergence
Given the advancement of our understanding of the HCV life cycle over the past decade, there are a number of drugs under investigation that target the enzymes involved in HCV replication. The class of drugs furthest along in development is the inhibitors of the HCV serine protease NS3-NS4A.[7] Two protease inhibitors have now completed phase II testing and have yielded some consistent early lessons. For naive, genotype 1 patients, higher cure rates and shorter duration of therapy can be expected, but partially offset by new issues of resistance and increased adverse events. The recently published Protease Inhibition for Viral Evaluation (PROVE 1 and 2, evaluating telaprevir, TVR)[8••,9••] and Serine Protease Inhibitor Therapy (SPRINT-1, evaluating boceprevir, BOC)[10••] studies evaluated protease inhibitors in combination with PEG-IFN/RBV in genotype 1, naive patients. In PROVE 1, TVR was dosed at 750 mg every 8 h for 12 weeks in combination with PEG-IFN and RBV followed by an additional 12 weeks, or 36 weeks of standard of care (SOC). The sustained viral response (SVR) rate in SOC was 41%, compared with 61% (P = 0.02) in the 24 week treatment group and 67% (P = 0.002) in the 48 week treatment group. Relapse rates were highest in the control group (23%) compared with the 24 week (2%) and 48 week TVR treatment group (6%). However, more patients discontinued therapy in the TVR treatment groups secondary to adverse side effects, with rash being the most common reason for discontinuation.[8••] In the PROVE 2 trial, shorter duration treatment was explored with treatment groups receiving triple therapy (TVR + PEG-IFN/RBV) for only 12 weeks (with and without RBV) compared with an additional 12 weeks of SOC. SVR was 46% in the control group, compared with 36% in the non-RBV group (P = 0.20), 60% in the 12 week triple therapy TVR group (P = 0.12) and 69% in the 24 week triple therapy TVR group (P = 0.004). Relapse rates were highest in the non-RBV-treated group (48%) compared with the control group (22%), 12 week triple therapy group (30%) and 24 week triple therapy group (14%). Rash again occurred more commonly in the TVR treatment groups than in the control group[9••] (Fig. 1).
Figure 1. Sustained viral response data in naive patients treated with telaprevir
PROVE, Protease Inhibition for Viral Evaluation; SVR, sustained viral response.
From PROVE 1 and 2, it appears that TVR has the ability to help overcome negative host and viral factors. A recent pooled analysis[11•] looked at a subgroup of patients with characteristics associated with low virologic response. The overall SVR for the pooled TVR treatment groups was 65 vs. 44% in the control group (P < 0.001). SVR rates were significantly higher with TVR-based vs. control treatment among patients with baseline HCV RNA at least 800 000 IU/ml (P < 0.05), patients with genotype 1a HCV infection (P < 0.05), patients with genotype 1b HCV infection (P < 0.05), men (P < 0.05), patients more than 50 years of age (P < 0.05) and those with bridging fibrosis (P < 0.05). The conclusion from this analysis is that TVR is effective across all subgroups of patients who have been traditionally considered to be difficult to treat. Another phase II trial with TVR was recently released that suggests SVR rates in naive patients may be higher than previously reported, especially when a response-guided duration is followed. In study C208,[12•] treatment-naive, genotype 1 patients (N = 161) were administered triple therapy for 12 weeks with the subsequent PEG-IFN/RBV treatment duration determined using a response-guided strategy. Patients who achieved rapid virologic response (RVR) received a total of 24 weeks of therapy and those who did not have an RVR continued PEG-IFN/RBV to week 48. The SVR rates in this study ranged from 81 to 85%, higher than those observed in the phase II PROVE trials. This study clearly suggests that response-guided therapy based on RVR at week 4 may optimize SVR and provides a useful guide for determining which patients should be treated for 24 vs. 48 weeks.
BOC is another oral NS3-NS4A protease inhibitor with potent antiviral activity. The final results from the HCV SPRINT-1 study have been reported in which HCV genotype 1 patients were randomly assigned to receive different combinations of PEG-IFN, RBV (400–1400 mg/day) and BOC (800 mg three times daily). The treatment regimens included a control group treated with 48 weeks of SOC compared to five BOC treatment regimens (4 weeks of PEG-IFN/RBV lead-in followed by triple therapy for 24 or 44 weeks; triple therapy for 28 or 48 weeks; triple therapy, but with low-dose RBV for 48 weeks). The following SVR rates were reported: control group, 38%; triple therapy 28 weeks, 55%; triple therapy 48 weeks, 67%; lead-in group 28 weeks, 56%; lead-in group 48 weeks, 75%; and low-dose RBV group, 36%. It should be noted that up to 50% of patients were treated with erythropoietin in this trial, highlighting the increased rates of anemia with BOC. Higher rates of discontinuation secondary to adverse side effects and viral breakthrough occurred in the BOC treatment groups compared with the control group. Of note, the highest reported viral breakthrough was seen in the low-dose RBV group.[10••]
Ribavirin is Required to Maximize Sustained Viral Response with Protease Inhibitors and Limit Resistance
As highlighted above, early phase II studies show strong evidence for the need of RBV in STAT-C drug regimens. Patients who did not receive RBV in the PROVE trials and those with low-dose RBV (400–1000 mg) in the SPRINT-1 trial had increased viral breakthrough, higher relapse and lower SVR. These data strongly indicate that standard-dose RBV is required to optimize response to these first generation protease inhibitors via a reduction in the development of resistance/breakthrough (Fig. 2).
Figure 2. Importance of ribavirin in combination with protease inhibitors
PROVE, Protease Inhibition for Viral Evaluation; SVR, sustained viral response.
It is also clear that the initial rapid drop in HCV viral levels on protease combination therapy is due to inhibition of wild-type virus that then leads to the 'uncovering' of preexisting resistant variants. The continued replication of these variants can then lead to a virologic breakthrough. Resistant variants are present in most patients at very low frequencies (<1%) and are usually detected after near complete suppression of the dominant, wild-type virus. Another important finding from the PROVE trials is the different rates of breakthrough detected between genotype 1a and 1b (much higher for 1a). The explanation for these observations is a difference in the genetic barrier to resistance between subtypes. For example, the V36M or R155K mutation that can confer drug resistance to TVR requires only one nucleotide change from genotype 1a sequence, whereas two substitutions are required in genotype 1b. Thus, it appears that HCV subtyping may play an important role in helping to select future treatment regimens and predict resistance development.
Protease Inhibitors: Hope for Nonresponders
An initial phase II trial with BOC-containing regimens in previous HCV genotype 1 nonresponders to SOC was not encouraging (SVR 14%), though in retrospect inadequate BOC dosing regimens were being used.[13] Since this early experience, a number of studies are starting to suggest reasonable response rates for the treatment-experienced population. In PROVE 3,[14••] treatment-experienced patients were randomized to one of four treatment arms (SOC for 48 weeks; TVR + PEG-IFN/RBV for 12 weeks, then SOC for an additional 12 weeks; TVR + PEG-IFN/RBV for 24 weeks, then SOC for an additional 24 weeks; or TVR + PEG-IFN for 24 weeks). SVR rates were 38–39% among previous nonresponders who received TVR-based triple therapy. Relapse rates were lowest among patients who received 24 weeks of triple therapy followed by 24 weeks of standard therapy (13 vs. 30–53% for other treatment arms). An important factor to consider in interpreting the results of the PROVE 3 trial is the stringent stopping rule established for TVR therapy. Because of concerns for high rates of resistance with incomplete viral suppression, patients in PROVE 3 discontinued TVR if HCV RNA remained detectable (>30 IU/ml) at week 4. It is now apparent that patients with declining but detectable HCV RNA at week 4 continue to experience HCV RNA reductions during treatment with TVR-containing regimens and have a high likelihood of achieving SVR with a total of 48 weeks of therapy. A hint of anticipated SVR with this response-guided approach to retreatment has now been reported from study 107 (patients in PROVE studies who did not achieve SVR in control group were retreated with triple therapy for 12 weeks followed by either 12 or 36 weeks of consolidation PEG-IFN/RBV). SVR rate for this well characterized population was 57% among prior nonresponders.[15]
Of interest, a similar SVR rate was seen in 'lead-in, null responders' from the SPRINT-1 trial. Kwo et al. conducted a retrospective analysis of SVR rates among patients who received 24 or 44 weeks of BOC and PEG-IFN/RBV following a 4-week lead-in period of PEG-IFN/RBV therapy. Among patients with a null response to the 4-week lead-in treatment period (< 1.0 log10 IU/ml HCV RNA reduction), the SVR rate was 25% for patients who continued 24 weeks of triple therapy and 55% for those who received 44 weeks of triple therapy. Thus, PROVE 3 suggests that prior nonresponders may be able to achieve at least a 39% SVR with retreatment with triple therapy-containing regimens, whereas these other emerging datasets suggest SVR rates of 55–57% with a response-guided approach may be obtainable (Fig. 3).
Figure 3. Lead-in viral decline and relationship to sustained viral response
HCV, hepatitis C virus.
Polymerase Inhibitors: Unique Genetic Barrier to Resistance for Nucleosides
Multiple agents targeting the HCV RNA-dependent polymerase inhibitor, which is critical for viral replication, are also currently in trials. One of the most advanced of these polymerase inhibitors is RG7128, a nucleoside analogue. RG7128 showed potent antiviral activity as monotherapy in HCV genotype 1 patients who had failed prior standard therapy,[16] as well as in combination with PEG-IFN/RBV.[17,18] It also has been shown to have a similar safety profile as standard therapy with PEG-IFN/RBV and has demonstrated significant antiviral potency regardless of race, ethnicity or genotype.[17–19] Thus far, viral resistance has not been seen in any clinical trials with RG7128,[16,18] which suggests that the nucleoside class may offer a higher genetic barrier to viral resistance than the protease class of inhibitors.[20•]
Another nucleoside polymerase inhibitor, R1626, also showed potent HCV antiviral activity (virus negative at 48 weeks) when combined with PEG-IFN/RBV compared with the control group (84 vs. 65%, respectively). This trial also showed the importance of RBV in combination therapy as the end of treatment responses were less in the non-RBV groups compared with the control group. However, the development of this drug has been halted due to unacceptable rates of hematologic abnormalities, highlighted by lymphopenia.[21] Other second generation nucleotide polymerase inhibitors are in the early stages of development, such as PSI-7851 and IDX184, and have shown encouraging antiviral activity.[22,23] PSI-7851 has demonstrated dose-dependent HCV RNA reductions over 3 days of dosing, and patients receiving the 400-mg dose achieved a mean HCV RNA decrease of 1.95 log10 IU/ml. Population sequencing did not identify any evidence of treatment-emergent drug resistance and no patients discontinued treatment early.[22] Dose-dependent decreases in HCV RNA were also observed during the 3-day IDX184 dosing period with mean reductions ranging from 0.47 to 0.74 log10 IU/ml.[23]
In addition to the nucleoside RNA-polymerase inhibitors, nonnucleoside HCV RNA-polymerase inhibitors are also showing promise in early HCV trials. Nonnucleoside inhibitors such as GS-9190, filibuvir, BI207127, VCH-916, VCH-222, MK-3281 and ABT-333 have shown potent antiviral activity for patients with genotype 1 HCV infections and generally have been well tolerated in early clinical studies.[24–31] Even though the early results have shown promise, the genetic barrier to resistance for this class appears to be low, similar to the protease class.
Interferon-free Regimens
Given the continued need for PEG-IFN and full-dose RBV, there are many HCV-infected groups that may not benefit from the initial approval of STAT-C agents, including decompensated cirrhosis, renal failure, posttransplant and the IFN-intolerant group (which may consist of as many as 50–60% of all HCV-infected patients). Thus, what is desperately needed is the development of IFN-free regimens, that is, combination of small molecules similar to HIV therapy. A novel study called INFORM-1, the first dual combination clinical trial with oral antivirals in HCV patients, is ongoing and evaluates the safety and combined antiviral activity of RG7227, a protease inhibitor and RG7128, a polymerase inhibitor, in 14 days of combination therapy in treatment-naive patients infected with HCV genotype 1. The initial cohorts of this study were reported and appear to lay the foundation for more aggressive and prolonged non-IFN trial designs. Patients receiving this combination for 14 days experienced a median reduction in viral levels of 4.8–5.2 log IU in the higher doses tested and this combination was equally effective in both naive and previous nonresponder patients. No treatment-related serious adverse events, dose reductions, drug–drug interactions or discontinuations were reported.[32••] Given these encouraging data, many other trials are now beginning to explore combinations of STAT-C agents in the absence of PEG-IFN and/or RBV. Lastly, other strategies to improve the tolerability of IFN and RBV with new analogues of IFN and RBV are also being investigated.[33•,34•,35•,36]
Conclusion
In summary, potent viral suppression and shortened duration of therapy have been shown in clinical trials with the addition of protease inhibitors to standard therapy. Although there is optimism surrounding the new STAT-C agents in the treatment of HCV, there is also a concern on how resistance and new adverse events will impact future therapy. It also appears that the platform exists to begin to explore non-IFN-containing regimens, which would be an enormous step forward to accessing a large proportion of infected patients. The future looks encouraging for the clinician treating HCV, and more importantly, for the patients infected with HCV.
References
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•• This is one of the key studies showing that the addition of TVR to current SOC with PEG-IFN and RBV in treatment-naive hepatitis C patients significantly improves SVR and may allow for shorter treatment durations.
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•• This study is similar to the PROVE1 study, but shorter treatment durations were used. This important study shows that shorter treatment durations can be used with the addition of TVR to SOC in treating patients with chronic hepatitis C, and higher SVRs can be achieved compared with SOC.
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•• This study highlights the final results of the addition of BOC to SOC in treatmentnaive hepatitis C patients and shows that improved SVR rates are achieved with triple therapy compared with SOC.
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• This study shows that TVR in addition to SOC is effective across all subgroups of hepatitis C patients who have been traditionally difficult to treat.
Marcellin P, Forns X, Goeser T, et al. Virologic analysis of patients receiving telaprevir administered q8 h or q12 h with peginterferon-alfa-2a or -alfa-2b and ribavirin in treatment-naïve patients with genotype 1 hepatitis: study C208 [abstract 194]. Hepatology 2009; 50:395A.
• This study clearly suggests that response-guided therapy may optimize SVR and provides a useful guide for determining which patients should be treated for 24 vs. 48 weeks.
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McHutchison JG, Manns MP, Muir A, et al. PROVE3 final results and 1-year durability of SVR with telaprevir-based regimen in hepatitis C genotype 1-infected patients with prior nonresponse, viral breakthrough or relapse to peginterferon-alfa-2a/b and ribavirin therapy [abstract 66]. Hepatology 2009; 50:334A–335A.
•• Unlike with PROVE 1 and PROVE 2, this study looks at previous nonresponders to SOC and continues to show improved SVR rates when TVR is added to SOC in this patient population.
Shiffman ML, Berg T, Poordad F, et al. A study of telaprevir combined with peginterferon-alfa-2a and ribavirin in subjects with well documented nonresponse or relapse after previous peginterferon-alfa-2a and ribavirin treatment: interim analysis [abstract 1852]. Hepatology 2008; 48:1135A–1136A.
Reddy R, Rodriguez-Torres M, Gane E, et al. Antiviral activity, pharmacokinetics, safety, and tolerability of R7128, a novel nucleoside HCV RNA polymerase inhibitor, following multiple, ascending, oral doses in patients with HCV genotype 1 infection who have failed prior interferon therapy [abstract LB9]. Hepatology 2007; 46:862A–863A.
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Rodriguez-Torres M, Lalezari J, Gane EJ, et al. Potent antiviral response to the HCV nucleoside polymerase inhibitor R7128 for 28 days with PEG-IFN and ribavirin: subanalysis by race/ethnicity, weight and HCV genotype [abstract 1899]. Hepatology 2008; 48:1160A.
Gane EJ, Rodriguez-Torres M, Nelson DR, et al. Antiviral activity of the HCV nucleoside polymerase inhibitor R7128 in HCV genotype 2 and 3 prior nonresponders: interim results of R7128 1,500 mg bid with PEG-IFN and ribavirin for 28 days [abstract LB10]. Hepatology 2008; 48:1024A.
McCown MF, Rajyaguru S, Le Pogam S, et al. The hepatitis C virus replicon presents a higher barrier to resistance to nucleoside analogs than to nonnucleoside polymerase or protease inhibitors. Antimicrob Agents Chemother 2008; 52:1604–1612.
• This study highlights the concept that nucleoside polymerase inhibitors may present a higher barrier of viral resistance compared to nonnucleoside polymerase inhibitors or protease inhibitors.
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Rodriguez-Torres M, Lawitz E, Flach S, et al. Antiviral activity, pharmacokinetics, safety, and tolerability of PSI-7851, a novel nucleotide polymerase inhibitor for HCV, following single and 3 day multiple ascending oral doses in healthy volunteers and patients with chronic HCV infection [abstract LB17]. Hepatology 2009; 50:11A.
Lalezari J, Asmuth D, Casiro A, et al. Antiviral activity, safety and pharmacokinetics of IDX184, a liver-targeted nucleotide HCV polymerase inhibitor, in patients with chronic hepatitis C [abstract LB17]. Hepatology 2009; 50:11A–12A.
Bavisotto L, Wang CC, Jacobson IR, et al. Antiviral, pharmacokinetic and safety data for GS 9190, a nonnucleoside HCV NS5b polymerase inhibitor, in a phase-1 trial in HCV genotype 1 infected subjects [abstract 49]. Hepatology 2007; 46 (Suppl 1):255A.
Jacobson I, Pockros P, Lalezari J, et al. Antiviral activity of filibuvir in combination with pegylated interferon alfa-2a and ribavirin for 28 days in treatment naïve patients chronically infected with HCV genotype 1 [abstract 1052]. J Hepatol 2009; 50 (Suppl 1):S382.
Larrey D, Benhamou Y, Lohse AW, et al. Safety, pharmacokinetics and antiviral effect of BI 207127, a novel HCV RNA polymerase inhibitor, after 5 days oral treatment in patients with chronic hepatitis C [abstract 1054]. J Hepatol 2009; 50 (Suppl 1):S383.
Lawitz E, Cooper C, Rodriguez-Torres M, et al. Safety, tolerability and antiviral activity of VCH-916, a novel nonnucleoside HCV polymerase inhibitor in patients with chronic HCV genotype-1 infection [abstract 92]. J Hepatol 2009; 50 (Suppl 1):S37.
Bedard J, Nicolas O, Bilimoria D, et al. Identification and characterization of VCH-222, a novel potent and selective nonnucleoside HCV polymerase inhibitor [abstract 935]. J Hepatol 2009; 50 (Suppl 1):S340.
Cooper C, Larouche R, Bourgault B, et al. Safety, tolerability and pharmacokinetics of the HCV polymerase inhibitor VCH-222 following single dose administration in healthy volunteers and antiviral activity in HCV-infected individuals [abstract 935]. J Hepatol 2009; 50 (Suppl 1):S342.
Brainard D, Wright DH, Sneddon K, et al. Safety, tolerability, and pharmacokinetics after single and multiple doses of MK-3281 in healthy subjects [abstract 935]. J Hepatol 2009; 50 (Suppl 1):S341.
Rodriguez-Torres M, Lawitz E, Cohen D, et al. Treatment-naive, HCV genotype 1-infected subjects show significantly greater HCV RNA decreases when treated with 28 days of ABT-333 plus peginterferon and ribavirin compared to peginterferon and ribavirin alone [abstract 935]. Hepatology 2009; 50:5A.
Gane EJ, Roberts SK, Stedman C, et al. First-in-man demonstration of potent antiviral activity with a nucleoside polymerase (R7128) and protease (R7227/ITMN-191) inhibitor combination in HCV: safety, pharmacokinetics, and virologic results from INFORM-1 [abstract 935]. J Hepatol 2009; 50 (Suppl 1):S380.
•• This key study of the first dual combination clinical trial with oral antivirals in hepatitis C patients shows that interferon-free regimens may be a future possibility in treatment.
Zeuzem S, Sulkowski M, Lawitz E, et al. Efficacy and safety of albinterferon alfa-2B in combination with ribavirin in treatment-naive, chronic hepatitis C genotype 1 (CHC G1) patients [abstract 1041]. J Hepatol 2009; 50 (Suppl 1): S377.
• This study reports on a newer interferon agent that allows for less frequent dosing intervals compared with current therapy while still achieving comparable SVRs in the genotype 1 hepatitis C patient population.
Nelson D, Benhamou Y, Chuang WL, et al. Efficacy and safety results of albinterferon alfa-2B in combination with ribavirin in interferon-alfa treatment naive patients with genotype 2 or 3 chronic hepatitis C [abstract 1042]. J Hepatol 2009; 50 (Suppl 1):S378.
• This study reports on a newer interferon agent that allows for less frequent dosing intervals compared with current therapy while still achieving comparable SVRs in the genotype 2/3 hepatitis C patient population.
Lawitz E, Muir AJ, Poordad F, et al. Treatment week 24 results of weight-based taribavirin versus weight-based ribavirin, both with peginterferon alfa-2b, in naive chronic hepatitis C, genotype 1 patients [abstract 272]. Hepatology 2008; 48:433A.
• This study reports on an improved RBV agent with comparable SVR rates, but fewer cases of anemia compared with standard RBV.
Poordad F, Lawitz E, Hassanein T, et al. Sustained virologic response (SVR) results for weight-based-taribavirin versus weight-based-ribavirin, in naive chronic hepatitis C, genotype 1 patients [abstract 65]. Hepatology 2009; 50:334A.
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 290).
Curr Opin Gastroenterol. 2010;26(3):196-201. © 2010 Lippincott Williams & Wilkins
http://www.medscape.com/viewarticle/720695
Ribavirin Causing Mitochondrial Toxicity in Patients With HIV/HCV Is a Good Sign: Study
From Reuters Health Information
By Will Boggs, MD
NEW YORK (Reuters Health) Jun 23 - In HIV patients being treated with ribavirin for hepatitis C, mitochondrial toxicity might actually be a good sign. It's associated with higher rates of sustained virologic response, say researchers from Austria.
"Mitochondrial toxicity is not necessarily a bad thing to happen during antiviral therapy for hepatitis C since it was not detrimental to our patients in any way," said senior author Dr. Markus Peck-Radosavljevic from Medical University of Vienna in e-mail to Reuters Health. Instead, he said, it could be a marker of adequate exposure to ribavirin.
In 48 patients infected with both viruses, Dr. Peck-Radosavljevic and colleagues studied the incidence of mitochondrial toxicity and hemolytic anemia during concomitant therapy with HAART and pegylated-interferon alpha (PEG-IFN) plus ribavirin. They also studied another 16 coinfected patients who were not receiving HAART.
During anti-HCV therapy with PEG-IFN plus ribavirin, patients with and without HAART had higher venous lactate levels (a marker of mitochondrial toxicity), although the increases were greater in patients with concomitant HAART, the authors report in a study published online May 20th in The Journal of Infectious Diseases.
By week 4, there was a significant correlation of higher doses of ribavirin and greater increases in venous lactate levels, but this association disappeared after week 24, when there was a dosage reduction of ribavirin for patients with HCV genotypes 1 and 4.
Fourteen patients developed asymptomatic hyperlactatemia. Lactate acidosis developed in only 1 patient who was treated with HAART and high-dose ribavirin. Nine patients who received high-dose ribavirin had severe weight loss.
Rates of hepatic steatosis tended to decrease among patients who received HAART and low-dose ribavirin (from 67% at baseline to 40% after treatment) and to increase in patients who received HAART and high-dose ribavirin (from 36% to 56%).
Patients who developed mitochondrial toxicity during treatment with PEG-IFN plus ribavirin had significantly higher ribavirin response rates at week 4 (51%) compared to patients without mitochondrial toxicity (21%; p = 0.015). Also, sustained virologic responses were more common in patients who had mitochondrial toxicity events than in those who didn't (73% vs 44%; p = 0.031).
"This has the potential to become an interesting tool for tailoring ribavirin dosages," the investigators say. Mitochondrial toxicity might eventually be used to titrate the dose of ribavirin prospectively.
"Adjusting the ribavirin-dose according to plasma levels has already been shown to be an effective means of getting optimal response, but this is technically demanding and not widely available," Dr. Peck-Radosavljevic said. "Instead, ribavirin dose could be titrated according to lactate levels, which are much easier to obtain."
As for treatment, he advises: "Do not be afraid of treating HIV-HCV coinfected patients under HAART with full-dose PEG-IFN/ribavirin just like you would treat any HCV-monoinfected patient."
The study was supported by Roche, which markets ribavirin. Dr. Peck-Radosavljevic and 2 of the other 8 authors reported having received research support, speaker fees, and/or travel grants from Roche.
J Infect Dis 2010;202:156-160.
http://www.medscape.com/viewarticle/724075
By Will Boggs, MD
NEW YORK (Reuters Health) Jun 23 - In HIV patients being treated with ribavirin for hepatitis C, mitochondrial toxicity might actually be a good sign. It's associated with higher rates of sustained virologic response, say researchers from Austria.
"Mitochondrial toxicity is not necessarily a bad thing to happen during antiviral therapy for hepatitis C since it was not detrimental to our patients in any way," said senior author Dr. Markus Peck-Radosavljevic from Medical University of Vienna in e-mail to Reuters Health. Instead, he said, it could be a marker of adequate exposure to ribavirin.
In 48 patients infected with both viruses, Dr. Peck-Radosavljevic and colleagues studied the incidence of mitochondrial toxicity and hemolytic anemia during concomitant therapy with HAART and pegylated-interferon alpha (PEG-IFN) plus ribavirin. They also studied another 16 coinfected patients who were not receiving HAART.
During anti-HCV therapy with PEG-IFN plus ribavirin, patients with and without HAART had higher venous lactate levels (a marker of mitochondrial toxicity), although the increases were greater in patients with concomitant HAART, the authors report in a study published online May 20th in The Journal of Infectious Diseases.
By week 4, there was a significant correlation of higher doses of ribavirin and greater increases in venous lactate levels, but this association disappeared after week 24, when there was a dosage reduction of ribavirin for patients with HCV genotypes 1 and 4.
Fourteen patients developed asymptomatic hyperlactatemia. Lactate acidosis developed in only 1 patient who was treated with HAART and high-dose ribavirin. Nine patients who received high-dose ribavirin had severe weight loss.
Rates of hepatic steatosis tended to decrease among patients who received HAART and low-dose ribavirin (from 67% at baseline to 40% after treatment) and to increase in patients who received HAART and high-dose ribavirin (from 36% to 56%).
Patients who developed mitochondrial toxicity during treatment with PEG-IFN plus ribavirin had significantly higher ribavirin response rates at week 4 (51%) compared to patients without mitochondrial toxicity (21%; p = 0.015). Also, sustained virologic responses were more common in patients who had mitochondrial toxicity events than in those who didn't (73% vs 44%; p = 0.031).
"This has the potential to become an interesting tool for tailoring ribavirin dosages," the investigators say. Mitochondrial toxicity might eventually be used to titrate the dose of ribavirin prospectively.
"Adjusting the ribavirin-dose according to plasma levels has already been shown to be an effective means of getting optimal response, but this is technically demanding and not widely available," Dr. Peck-Radosavljevic said. "Instead, ribavirin dose could be titrated according to lactate levels, which are much easier to obtain."
As for treatment, he advises: "Do not be afraid of treating HIV-HCV coinfected patients under HAART with full-dose PEG-IFN/ribavirin just like you would treat any HCV-monoinfected patient."
The study was supported by Roche, which markets ribavirin. Dr. Peck-Radosavljevic and 2 of the other 8 authors reported having received research support, speaker fees, and/or travel grants from Roche.
J Infect Dis 2010;202:156-160.
http://www.medscape.com/viewarticle/724075
FDA Approves Rapid Test for Antibodies to Hepatitis C Virus
FDA NEWS RELEASE
For Immediate Release: June 25, 2010
Media Inquiries: Erica Jefferson, 301-796-4988, erica.jefferson@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA
The U.S. Food and Drug Administration today announced approval of the first rapid blood test for antibodies to the hepatitis C virus (HCV) for individuals 15 years and older.
The OraQuick HCV Rapid Antibody Test is used to test individuals who are at risk for infection with HCV and people with signs or symptoms of hepatitis. HCV is transmitted through exposure to infected blood, which, for example, can occur during intravenous drug use. The virus can also be transferred from an infected mother to her child. Hepatitis C can lead to liver inflammation and dysfunction and, over time, to liver disease and liver cancer.
OraQuick is a test strip and does not require an instrument for diagnosis. It takes about 20 minutes to obtain results from the test.
“Approval of OraQuick means that more patients can be notified of their HCV infection faster so that they can consult with their physicians for appropriate health measures,” said Jeffrey Shuren, M.D., J.D., director of the FDA’s Center for Devices and Radiological Health. “Getting faster treatment is an important public health step to control this dangerous disease.”
OraQuick is not approved for HCV screening of the general population.
According to the U.S. Centers for Disease Control and Prevention, there are approximately 3.2 million people in the United States chronically infected with HCV and each year, about 17,000 people are newly infected. Chronic HCV infection is a leading reason for a liver transplants in the United States and HCV is associated with an estimated 12,000 deaths annually. Approximately 75 to 85 percent of people who become infected with the hepatitis C virus develop chronic infection.
OraQuick is manufactured by Bethlehem, Penn.-based OraSure Technologies Inc.
For more information:
FDA: Medical Devices
NIH: Hepatitis C
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm217318.htm
For Immediate Release: June 25, 2010
Media Inquiries: Erica Jefferson, 301-796-4988, erica.jefferson@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA
The U.S. Food and Drug Administration today announced approval of the first rapid blood test for antibodies to the hepatitis C virus (HCV) for individuals 15 years and older.
The OraQuick HCV Rapid Antibody Test is used to test individuals who are at risk for infection with HCV and people with signs or symptoms of hepatitis. HCV is transmitted through exposure to infected blood, which, for example, can occur during intravenous drug use. The virus can also be transferred from an infected mother to her child. Hepatitis C can lead to liver inflammation and dysfunction and, over time, to liver disease and liver cancer.
OraQuick is a test strip and does not require an instrument for diagnosis. It takes about 20 minutes to obtain results from the test.
“Approval of OraQuick means that more patients can be notified of their HCV infection faster so that they can consult with their physicians for appropriate health measures,” said Jeffrey Shuren, M.D., J.D., director of the FDA’s Center for Devices and Radiological Health. “Getting faster treatment is an important public health step to control this dangerous disease.”
OraQuick is not approved for HCV screening of the general population.
According to the U.S. Centers for Disease Control and Prevention, there are approximately 3.2 million people in the United States chronically infected with HCV and each year, about 17,000 people are newly infected. Chronic HCV infection is a leading reason for a liver transplants in the United States and HCV is associated with an estimated 12,000 deaths annually. Approximately 75 to 85 percent of people who become infected with the hepatitis C virus develop chronic infection.
OraQuick is manufactured by Bethlehem, Penn.-based OraSure Technologies Inc.
For more information:
FDA: Medical Devices
NIH: Hepatitis C
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm217318.htm
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