Sunday, May 6, 2012

Hepatitis C Therapy Update-Where Are We Now?

From Current Opinion in Gastroenterology

Hepatitis C Therapy Update

Lisa C. Casey; William M. Lee

Posted: 05/04/2012; Curr Opin Gastroenterol. 2012;28(3):188-192.
© 2012 Lippincott Williams & Wilkins

Source-Medscape

Abstract and Introduction
Abstract

Purpose of review We review here the recent literature regarding hepatitis C treatment through January 2012. We discuss newly approved therapies and their clinical trial data and discuss what can be expected in this rapidly changing field.

Recent findings Two new directly acting antiviral agents were approved in 2011 for use in hepatitis C treatment, bringing shortened treatment durations, and increased treatment success to some patients with genotype 1 hepatitis C. Additional drugs using different viral targets are in development to further improve response rates, tolerance, and increase access to therapy.

Summary Telaprevir and boceprevir were approved in 2011 for use against genotype 1 hepatitis C, in combination with pegylated interferon and ribavirin. In most populations of genotype 1 patients, response rates are much improved but increased treatment related anemia has been seen. Additional options for therapy, including interferon-free regimens, are still needed and are under development.

Introduction
An estimated 130–170 million people are infected with hepatitis C virus (HCV) worldwide leading to significant morbidity, mortality, and financial burden on healthcare.[1] Most of the patients in the United States, an estimated 3.2–3.5 million people, were born between 1945 and 1964 and likely contracted the virus in the 1970s and 1980s when transmission rates were highest.[2] With the contribution of blood product screening, disposable medical equipment and public health education efforts, the US incidence of infection has been decreasing but in many parts of the world the virus remains unchecked due to unsafe medical practices, lack of public health education, and lack of funding for research and treatment. Currently, hepatitis C is the leading cause for liver transplantation worldwide. Out of 100 people that contract the infection, 75–85 people will develop chronic infection, 60–70 people will develop chronic liver disease, five to 20 people will develop cirrhosis over the course of their chronic infection and one to five people will die of complications including hepatocellular carcinoma (HCC).[3] Perz et al.[4] looked at 11 WHO-based regions in 2006 and estimated that globally 27% of cirrhosis was attributable to HCV and 25% of HCC was attributable to HCV. In addition to new infections, as the currently infected population ages, we are more likely to see increased consequences of the chronic infection. Studies confirming this have shown increases in HCV-related mortality and increasing prevalence of hepatitis C-related HCC and cirrhosis since the mid-1990s.[5,6] A sustained viral response (SVR) to hepatitis C therapy reduces liver-related, as well as all-cause mortality for patients with hepatitis C. Failure to respond to treatment correlates with poor liverrelated outcomes including death and liver transplantation.[7,8]

For the past 10 years, standard therapy has been some form of pegylated interferon and ribavirin for 24–48 weeks, based on genotype. The limitations of these medications are well known. For genotype 1, the most common genotype in the United States nd Europe, this has produced an SVR (equated with cure) rate of only about 40%. Pregnant patients or those with advanced renal disease are prohibited from using ribavirin. Likewise, interferon therapy excludes patients with autoimmune diseases, uncontrolled depression and mental illness, decompensated liver disease (Child-Turcotte-Pugh score more than 6), or decompensated cardiac or pulmonary disease. In addition to contraindications, side effects and low response rates have led to an aggressive search for treatment alternatives. Beginning in mid-2011, two new agents, known as direct-acting antivirals (DAA) were approved for use in conjunction with pegylated interferon and ribavirin.

Viral Structure
What we first knew as non-A, non-B hepatitis was designated hepatitis C in 1989 by Michael Houghton and scientists at Chiron Corporation while searching for the blood-borne cause of hepatitis in transfusion recipients.[9] Hepatitis C is a single stranded RNA flavivirus of the hepacivirus genus. It lacks proofreading ability leading to considerable genetic diversity and at least six different genotypes. Of the six genotypes, genotype 1 is the most prominent in the United States. When the virus enters a liver cell, it releases its RNA and is translated into a polyprotein containing structural and nonstructural regions. The polyprotein is processed by cellular and noncellular proteases into numerous polypeptides with functional roles in the virus life cycle. The virus replicates with the help of a polymerase and then is assembled, transported, and released from the cell. The nonstructural region codes for the polypeptides NS2, NS3, NS4A, NS4B, and NS5A and NS5B and these have become the focus of much recent interest, given that each of these polypeptides is a potential target for drug therapy. The NS3 region encodes a serine protease, RNA helicase and NTPase. The NS4A region produces cofactors for the serine protease. The NS4B product is the membranous web – a sort of scaffolding for the replication complex. The NS5B region encodes an RNA-dependent polymerase and the NS5A other products felt to be involved in replication, assembly, and release of HCV.[10,11] Initial cleavage of the polyprotein is performed by the NS3/4A protease, which seemsto be highly conserved across most strains and without which the HCV life cycle evolution cannot proceed. This region is the target of the newest drugs: telaprevir and boceprevir.

Direct-acting Antivirals
Until mid-2011, therapy of hepatitis C was limited to a pegylated interferon, which activates the immune system and inhibits viral replication, and ribavirin, a nonspecific antiviral that likely inhibits viral replication but also plays a role in viral clearance from the liver once replication declines. Given suboptimal success with nonspecific agents, many different drugs directly targeting aspects of the virus itself are being tested. These will reduce treatment duration and side effects, and improve efficacy and cost. Telaprevir, and boceprevir are both NS3–4A inhibitors, targeting the protease that cleaves the HCV polyprotein, inhibiting the replication process. Of note, these newer agents are specifically focused on the treatment of genotype 1 disease.

Telaprevir: The History
The data leading to the approval of telaprevir have been published over several studies: PROVE-1, PROVE-2, ADVANCE, and REALIZE. PROVE-1 and PROVE-2 were the phase II studies published in 2009. PROVE-1 included genotype 1 treatment naive patients and evaluated SVR data comparing standard therapy to differing treatment lengths of triple therapy with telaprevir, pegylated interferon, and ribavirin. PROVE-2 was similar except that it included an arm with telaprevir and pegylated interferon alone without ribavirin. An SVR rate of 61% in PROVE-1 and 69% in PROVE-2 was shown with 12 weeks telaprevir combined with 24 weeks of pegylated interferon and ribavirin (as compared with 46–48% SVR for standard of care). The important lessons from these trials come from the relapse rates (defined as detectable RNA during 24-week follow-up) and subgroup analyses.[12] In the PROVE-2 patients without ribavirin, there was 24% viral breakthrough by 12 weeks and a 48% relapse rate for patients that were virus negative at the end of treatment, suggesting the critical importance of ribavirin to prevent both viral breakthrough during treatment and relapse after treatment. In addition, low rates of relapse for 24-week triple therapy of only 14% after completion of therapy suggested that this shortened duration was acceptable for patients meeting certain criteria.[13]
In PROVE-1 a small subgroup of black patients was studied for their individual responses. With standard therapy, the black cohort only had an 11% response rate whereas their SVR rates were demonstrated collectively to be 44% in all of those in a telaprevir arm. These studies excluded patients with cirrhosis.

Phase III trials of telaprevir were published in June 2011 including ADVANCE and REALIZE. The ADVANCE trial enrolled 1088 treatment naive patients, evaluating response guided therapy, the length of therapy being determined by the time of first detectable viral clearance, the initial response. In addition, the study compared 12 versus 8 weeks of telaprevir combined with a total of 24 or 48 weeks of pegylated interferon and ribavirin. This study introduced the concept of eRVR (extended rapid viral response) as defined by undetectable RNA at weeks 4 and 12. Using this parameter, more than half (58%) of the patients in the telaprevir groups had eRVR, qualifying them for 24 weeks of therapy. Among the patients with eRVR assigned to receive a total of 24 weeks of therapy, 89% in the telaprevir 12-week group, and 83% in the telaprevir 8-week group achieved SVR.[14•] Of note, at week 12 in the telaprevir arms, there was a higher level of viral resistance in the patients that had received 8 weeks of telaprevir versus 12 weeks (10 versus 5%). Virologic failure was also more common in HCV genotype 1a infections than in genotype 1b infections suggesting that the genotype variation itself may have a relationship to the development of resistance patterns. Subgroup analyses compared the telaprevir groups with standard therapy in black patients, patients with baseline viral load more than 800 000 and in patients with bridging fibrosis or cirrhosis – in all of these groups, the telaprevir arms showed significantly higher SVR rates. Comparing the 12 week telaprevir dose regimens to standard therapy the response rates virtually doubled suggesting that the addition of DAA in these patients may overcome some of the previous barriers to therapeutic success. Another significant lesson in this trial was that of side effects – predominantly anemia and gastrointestinal side effects which were more apparent than observed with standard therapy. The REALIZE trial included 662 previously experienced patients (relapse, partial response, or null response) assigning them to 48 weeks of standard therapy, 12 weeks of telaprevir, and a total of 48 weeks of pegylated interferon and ribavirin, or a 4-week lead-in with pegylated interferon and ribavirin followed by 12 weeks of triple therapy ending with pegylated interferon and ribavirin alone for a total of 48 weeks.Of the study population 26% had cirrhosis. In prior null responders and partial responders, the presence of advanced fibrosis heralded a poorer response to triple therapy. Overall, adding 12 weeks of telaprevir to a 48-week course of pegylated interferon and ribavirin increased SVR rates from 24 to as high as 88% in relapsers, from 15 to 59% in partial responders and from 5 to 33% in null responders. Adding a lead-in phase did not significantly change response rates. In both trials, nausea, diarrhea, itching, rash, and anemia were at least 10% higher in either telaprevir group than in the standard therapy group and there were treatment discontinuations related to rash and anemia.[15•]

Boceprevir: The History
Boceprevir is the alternative NS3 protease inhibitor recently approved by the Food and Drug Administration. Although employing a similar mechanism to telaprevir, the approved treatment protocols are slightly different. Initially phase II trials were published beginning in 2009 with SPRINT-1. In SPRINT-1, the safety and efficacy of triple therapy with pegylated interferon, ribavirin, and boceprevir was assessed. Five hundred and twenty treatment naive patients were randomized from the United States, Canada, and Europe. Part 1 evaluated differing treatment durations and dosing with or without lead-in compared with 48 weeks of standard therapy. The patients were stratified by race and presence or absence of cirrhosis and then divided into five groups: standard therapy of pegylated interferon and ribavirin for 48 weeks, pegylated interferon, ribavirin, and bocepravir (triple therapy) for 28 or 48 weeks or therapy including a 4-week lead-in of pegylated interferon and ribavirin followed by an additional 24 or 44 weeks of triple therapy. SVR rates were significantly better than standard therapy in all four treatment groups containing boceprevir regardless of lead-in or duration of therapy. The SVR for 48 weeks of standard therapy in this study was 38%. In the combined (or triple) therapy groups with a 4-week lead-in interval, total therapy of 28 and 48 weeks had SVR¼56 and 75%, respectively. In the groups representing combined therapy without lead-in, 28 weeks of triple therapy had SVR¼54% and 48 weeks had SVR¼67%. The most common adverse events included anemia and dysgeusia. In response to anemia in this study, ribavirin dose reduction was encouraged and the use of concomitant epoietin and boceprevir dose reductions were allowed. Given that anemia is a common side effect of HCV therapy, part 2 of this study was developed to assess the result of reduced ribavirin dosing and its effect on outcomes. Treatment naive patients were randomized without stratification to triple therapy for 48 weeks with standard or reduced dose ribavirin based on weight. Triple therapy SVR was 50% and low-dose ribavirin triple therapy SVR was only 36%. There were significantly lower relapse rates in the 48-week triple therapy groups than in the standard therapy group and in the 28-week groups who were virus negative at week 4 (RVR). Overall, RVR while on triple therapy (undetectable virus at week 4) was associated with higher SVR – 74–94% across all boceprevir containing groups in part 1. In part 2, low-dose ribavirin was associated with higher relapse rates, again suggesting the important role of ribavirin in preventing viral breakthrough. Conceptually, lead-in was introduced to bring the baseline viral load down prior to starting boceprevir and, in turn, decrease the emergence of drug-resistant mutations. The lead-in groups showed a modestly lower rate of viral breakthrough than without lead-in (4 versus 9%) and there was no viral breakthrough in the control groups not exposed to boceprevir. SVR was similar in the 28 and 48-week groups that achieved at least a 1.5 log drop in viral load after the 4-week lead-in therapy phase. In 28-week patients, those patients not demonstrating at least a 1.5 log drop showed poor SVR of 30% or less at 28 weeks which was much higher in patients completing 48 weeks of therapy. These data support the conclusion that responseguided therapy based on 4-week labs would help predict best duration of treatment. The study discussion does suggest increased rates of SVR in patients receiving epoietin treatment for their anemia. The implication is that these patients could be supported through side effects and complete treatment though further studies are needed.[16•]

Phase III trial data was reported in SPRINT 2, a superiority study to determine best regimen. Nine hundred and thirty eight patients were enrolled and separated into black and nonblack cohorts given the marked differences in SVR in these populations. After a 4-week pegylated interferon/ribavirin leadin, patients were assigned to one of three groups: standard therapy with placebo for 44 weeks, triple therapy for 44 weeks, or triple for 24 weeks with the caveat that those patients with detectable virus between weeks 8 and 24 would receive an additional 20 weeks of pegylated interferon and ribavirin with a placebo pill (response guided therapy) with SVR rates comparable to previous data. Results supported the use of response-guided therapy in treatment naive patients and the data regarding the black versus nonblack patients was compelling in terms of improved response for black patients with addition of boceprevir (almost double that of standard therapy) but with persistently lower SVR rates than nonblacks, suggesting interferon resistance continued to play a role. The decision to include a lead-in with the final protocol was again supported by the goal to reduce viral resistance but also reinforced by the opportunity this provides to assess interferon responsiveness. Patients with a poor response to interferon in this setting might be best served by waiting for better upcoming therapies.[17•]

Where Are We Now?
Over the last year, we have seen great strides made in the treatment of hepatitis C genotype 1, but we are still a long way from the goal of being able to treat and cure all of our patients with hepatitis C. DAAs provide a tremendous improvement in SVR for many patients but there are still treatment failures, side effects, and many patients excluded. Ongoing research supports their successful use in the naive population as well as in previous nonresponders. The newer drugs provide an opportunity to treat these patients, most with mid to later-stage disease who cannot wait for additional options. We have seen greater anemia issues with the addition of these medications as well as new gastrointestinal side effects and rashes, which may be an important consideration in patient tolerance and selection of DAA.[18]

There is cross-resistance among the NS3/4A drugs, and therefore treatment failure/resistance to one drug in this category will likely be seen in all of them.[19•] New promise is anticipated with the polymerase inhibitors and other agents targeting cyclophilin or other intracellular proteins. Current DAA medications do show some efficacy against alternate genotypes and this expanded efficacy will likely be true for the newer generations.[20•,21] We anticipate that the longer-term picture will include a cocktail of several different DAA medications targeting different sites. Data from two recent trials suggest this is coming sooner than expected. Pharmasset, Inc., a wholly owned subsidiary of Gilead Sciences, Inc., Foster City, California, presented data at last years European Association for the Study of the Liver and American Association for the Study of Liver Diseases meetings regarding the success of their new drug PSI-7977, a uridine nucleotide analog, that has shown promise with a phase IIb trial in genotype 1 patients with pegylated interferon and ribavirin in early data and in genotypes 2 and 3 without interferon.[22•,23•] Bristol-Meyers Squibb also recently published data in a small open label phase IIb study combining daclatasvir (an NS5A replication complex inhibitor) and asunaprevir (a NS3 protease inhibitor) in previous genotype 1 nonresponders without or with pegylated interferon and ribavirin.[24••] While the study was small and resistance mutations were found with both study drugs, reasonable SVR rates were achieved in the interferon free regimen.

Conclusion
We are entering a dynamic and exciting time in the therapy of HCV. An important point in the treatment of HCV is that, as opposed to HIV or HBV, a cure is possible. Directly acting antivirals provide the opportunity to reduce treatment times in many patients and may increase cure rates to up to 70%. We are seeing new side effects and new resistance patterns as we employ DAA, but almost daily the literature reports improved tolerability of later generation drugs, new targets of action, innovative ways to approach resistance, efficacy with alternate genotypes, and the success of interferon free regimens. We anticipate well tolerated cocktails of oral medications in the not too distant future, providing the opportunity to change the face of hepatitis C therapy once again.

References
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  2. Armstrong G, Wasley A, Simard E, et al. The prevalence of hepatitis C virus infection in the United States, 1999-2002. Ann Inten Med 2006; 144:705–714.
  3. Alter H, Aragon T, AuBuchon J, et al. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Morb Mortal Wkly Rep 1998; 47 (RR19):1–39.
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  5. Wise M, Bialek S, Finelli L, et al. Changing trends in hepatitis C – related mortality in the United States, 1995•2004. Hepatology 2008; 47:1128–1135.
  6. Kanwal F, Hoang T, Kramer JR, et al. Increasing prevalence of HCC and cirrhosis in patients with chronic hepatitis C virus infection. Gastroenterology 2011; 140:1182–1188.
  7. Backus L, Boothroyd D, Phillips B, et al. A sustained virologic response reduces risk of all cause mortality in patients with hepatitis C. Clin Gastroenterol Hepatol 2011; 9:509–516.
  8. Dienstag J, Ghany M, Morgan T, et al. A prospective study of the rate of progression in compensated, histologically advanced chronic hepatitis C. Hepatology 2011; 54:396–405.
  9. Houghton M. The long and winding road leading to the identification of the hepatitis C virus. J Hepatol 2009; 51:939–948.
  10. Rosen H. Chronic hepatitis C infection. N Engl J Med 2011; 364:2429–2438.
  11. Davis G. Hepatitis C. Diseases of the, Liver, 10th ed. In: Schiff E, Sorrell M, Maddrey W, editors. Philadelphia: Lippincott Williams and Wilkins; 2007. pp. 807–835.
  12. McHutchison J, Everson G, Gordon C, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360:1827–1838.
  13. Hezode 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.
  14. Jacobson I, McHutchison J, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364: 2405–2416.
    •ADVANCE trial, phase III treatment naive response guided therapy trial, subgroups showed much improved response in blacks, fibrosis and high viral load with telaprevir.
  15. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364:2417–2428.
    •REALIZE – treatment experienced patients including cirrhotics, all groups improved SVR.
  16. Kwo P, Lawitz E, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatmentnaive patients with genotype 1 hepatitis C infection (SPRINT-1): an open label, randomized, multicentre phase 2 trial. Lancet 2010; 376:705–716.
    •The study tested various durations of treatment and lead-in concept.
  17. Poordad F, McCone J, Bacon B, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1195–1206.
    •SPRINT 2 – phase III, established lead-in use of response guided therapy.
  18. Schlutter J. Therapeutics: new drugs with the target. Nature 2011; 474:s5–s7.
  19. Halfon P, Locarnini S. Hepatitis C virus resistance to protease inhibitors. J Hepatol 2011; 55:192–206.
    •A detailed review of the viral structure, medications in development, and the development of resistance.
  20. Foster G, Hezode C, Bronowicki J, et al. Telaprevir alone or with peginterferon and ribavirin reduces HCV RNA in patients with chronic genotype 2 but not genotype 3 infections. Gastroenterology 2011; 141:881–889.
    •This study demonstrates some activity of DAA against alternate genotypes.
  21. Gottwein J, Scheel T, Jensen T, et al. Differential efficacy of protease inhibitors against HCV genotypes 2a, 3a, 5a and 6a NS3/4A protease recombinant viruses. Gastroenterology 2011; 141:1067–1079.
  22. Gane E, Stedman C, Hyland R, et al. Once daily PSI-7977 plus RBV; pegylated interferon-alfa not required for complete response in treatmentnaive patients with HCV GT2 or GT3. (AASLD Abstract) Hepatology 2011; 54:377A.
    •Demonstrates effectiveness of PSI-7977 against other genotypes as monotherapy and the high barrier to resistance of this drug, a uridine nucleotide analog.
  23. Lawitz E, Lalezari J, Hassanein T, et al. Once-daily PSI-7977 plus PEG/RBV in treatment-naive patients with HCV GT1: robust end of treatment response rates are sustained post treatment. Hepatology 2011; 54:472A.
    Phase II data dose finding for unique target new drug, very high RVR and eRVR in combined therapy
  24. Lok A, Gardiner D, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012; 366:216–224.
    ••A small study of previous nonresponders with interferon-free regimen of NS3 protease inhibitor and NS5A replication complex inhibitor, demonstrates proof of concept that SVR can be achieved without interferon.

    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 (pp. 287–288).
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