Hepatitis C Virus Therapy in the Direct Acting Antiviral Era

Current Opinion in Gastroenterology

Hepatitis C Virus Therapy in the Direct Acting Antiviral Era

Mitchell L. Shiffman
Curr Opin Gastroenterol. 2014;30(3):217-222.

Abstract and Introduction
Abstract
Purpose of review: The evolution of treatment for patients with chronic hepatitis C virus (HCV) is evolving at a rapid pace. Two new oral antiviral agents, simeprevir and sofosbuvir, have already been approved and are now available for treatment of patients with chronic HCV. Other antiviral agents will be available during 2014.

Recent findings: The protease inhibitor simeprevir was recently approved for use with peginterferon (PEGINF) and ribavirin (RBV) in patients with chronic genotype 1. About 80% of patients achieve a rapid virologic response and can be treated for 24 weeks. The sustained virologic response (SVR) in treatment-naive patients is about 80%. Sofosbuvir, the first polymerase inhibitor, is effective in all HCV genotypes. When utilized with peginterferon and RBV for 12 weeks in treatment-naive patients with genotypes 1, 4, 5 and 6, an SVR of 90% is observed. Sofosbuvir and RBV have also been studied without interferon and represent the first interferon-free therapy for chronic HCV.

Summary: It is now possible to cure chronic HCV in the vast majority of patients with chronic HCV and in many patients without interferon.
Introduction

The treatment of chronic hepatitis C virus (HCV) continues to evolve at an accelerating pace. In 2011, the first two protease inhibitors, telaprevir and boceprevir, were approved to be utilized with peginterferon (PEGINF) and ribavirin (RBV) to treat chronic HCV genotype 1.[1–5] The addition of a protease inhibitor to PEGINF and RBV represented a huge advance in HCV treatment and increased sustained virologic response (SVR) in the treatment-naive population with HCV genotype 1 from about 40% to 70–75%. The main limitation of these first-generation protease inhibitors was side-effects, particularly anemia, which were more severe than observed with PEGINF and RBV. These adverse events are even more severe and increase the risk of hepatic decompensation in patients with cirrhosis. In a study that included only patients with advanced fibrosis or cirrhosis, many of whom had previously failed PEGINF and RBV, nearly half of all patients treated with either telaprevir or boceprevir developed serious adverse events, 25% discontinued treatment, over half developed severe anemia and required a hematopoetic growth factor and 1–2% died as a result of hepatic decompensation.[6] The patients at greatest risk to develop hepatic decompensation included those with thrombocytopenia and a low serum albumin.[7] The SVR in this cohort was only 40%. In the subset of patients with cirrhosis who failed previous therapy, the SVR was under 20%.[6,7] Results like these caused many physicians who were treating HCV to pause and wait for a better alternative.

In late 2013, another protease inhibitor simeprevir and the first polymerase inhibitor, sofosbuvir, were approved for HCV treatment. These two antiviral agents offer significant advantages compared with telaprevir and boceprevir when treating patients with HCV genotype 1; the duration of therapy is shorter, the adverse effect profile is superior and the SVR is higher. In addition, sofosbuvir is effective against all genotypes and when utilized with RBV represents the first interferon-free treatment for chronic HCV.

During the past few years, several oral antiviral agents, which inhibit various HCV proteins, have been developed at a rapid pace. These include protease inhibitors, nucleotide and nonnucleotide polymerase inhibitors, NS5A inhibitors and cyclophilin inhibitors. Two or more oral antiviral agents from different classes have been combined and their evaluation in phase 3 clinical trials is well underway.[8–11] During 2015 multiple oral antiviral combinations are expected to be available to treat chronic HCV (Table 1). The rapid evolution of these treatments will make any recommendations for how to treat HCV in 2014 tentative at best. The treatments that will be available during 2014 are illustrated in Fig. 1. The rapid evolution of HCV treatment has also occurred at a pace that far exceeds the appearance of peer-reviewed publications. The vast majority of cited references are therefore abstracts, which have been presented at national and international meetings during 2013.



Simeprevir and Faldaprevir

Both simeprevir and faldaprevir are NS3–4A protease inhibitors.[12–16] Both act at the same binding site as telaprevir and boceprevir and are only effective in patients with HCV genotype 1. As a result, neither of these agents is likely to be effective in patients with resistance to telaprevir or boceprevir.

Simeprevir was approved for use in patients with HCV genotype 1 in late 2013 and faldaprevir is expected to be approved in early 2014. Both of these protease inhibitors will be utilized as triple therapy with PEGINF and RBV for 12 weeks followed by an additional 12–36 weeks of PEGINF and RBV. In patients who are treatment-naive or who have had prior relapse with PEGINF and RBV, the recommended total duration of therapy when utilizing simeprevir is 24 weeks, that is 12 weeks of simeprevir, PEGINF and RBV followed by an additional 12 weeks of PEGINF and RBV. Approximately, 80% of these patients will achieve a rapid virologic response (RVR) and be HCV RNA undetectable within 4 weeks of initiating treatment. The SVR in these patients is approximately 90%.[12,13] It is recommended that patients with HCV RNA more than 25 IU/ml at either weeks 4, 12 or 24 stop treatment. In patients with prior nonresponse to PEGINF and RBV, the total duration of therapy is 48 weeks, that is 12 weeks of simeprevir, PEGINF and RBV followed by an additional 36 weeks of PEGINF and RBV. The SVR rate in these patients is 53–65%.[14] It is recommended that patients with HCV RNA more than 25 IU/ml at either weeks 4, 12 or 24 also stop treatment. It is anticipated that the recommendations for faldaprevir will be quite similar.

Simeprevir and faldaprevir offer significant advantages over telaprevir and boceprevir. The most important of these is that neither of these agents cause additional anemia compared with PEGINF and RBV.[12–16] All of these agents are dosed as a single once daily tablet, no special diet is required during dosing and no significant drug-drug interactions have been observed. Simeprevir was not noted to have any adverse events with greater frequency than PEGINF and RBV.[12–14] Faldaprevir was noted to have a slightly higher incidence of rash.[15,16] However, the rash was graded as only mild or moderate in all cases and no grade 3 rashes were observed. Faldaprevir was also associated with a mild increase in total bilirubin without elevations in liver transaminases or alkaline phosphatase.

Controlled clinical trials comparing the various antiviral agents utilized for treatment of patients with HCV genotype 1 have not been conducted. As such, no direct comparison regarding the relative effectiveness of these agents can be made. Both simeprevir and faldaprevir triple therapies were evaluated against a placebo control with PEGINF and RBV. As a result, the improvement in SVR with the protease inhibitor over control could be compared for all of the available protease inhibitors.[1–5,12–16] Such a comparison suggests that RVR and SVR rates are somewhat higher in patients treated with simeprevir or faldaprevir compared with telaprevir and boceprevir. The high RVR rates observed with simeprevir and faldaprevir allow 80% of patients to be treated for only 24 weeks and lead to the higher SVR rates.

The success of treatment in patients treated with simeprevir or faldaprevir, like other protease inhibitors, is dependent upon an effective interferon response and this is modulated by interleukin-28B genotype. In treatment-naive patients, the SVR approaches 90% in patients with interleukin-28B genotype CC and declines in patients with the CT and TT genotypes.[12,13,15] In patients with prior nonresponse to PEGINF and RBV, the SVR rates during retreatment with simepreivr or faldaprevir triple therapy follow a similar trend of interferon responsiveness; higher rates of SVR with prior partial response and the lowest SVR rates in prior null responders.[14,16]

The primary limitation of simeprevir is that a mutation at the Q80K loci of HCV adversely impacts the antiviral efficacy of simeprevir and leads to a significant reduction in SVR.[12,13,17] This mutation is present in about 40% of patients with HCV genotype 1A. The Q80K mutation is only rarely seen in HCV genotype 1B. The Q80K mutation in HCV has the greatest impact and significantly lowers SVR in patients who are genetically less sensitive to interferon. In contrast, patients with interleukin-genotype CC, who are highly sensitive to interferon, have similar SVR rates even if the HCV Q80K mutation is present.[12,13] When treating patients with genotype 1A, it is therefore important that the patient is interleukin-28 genotype CC or that HCV does not contain the Q80K mutation. Testing the patient for their IL28B genotype and/or evaluating HCV for the presence of this mutation should be strongly considered if simeprevir is to be utilized. Patients with HCV genotype 1 and the Q80K mutation who are IL28B genotype CT or TT are best treated by an alternative antiviral agent.

Sofosbuvir

Sofosbuvir is the first polymerase inhibitor to be approved for the treatment of chronic HCV. It is a nucleotide analog, which inhibits the NS5B polymerase and is effective in all HCV genotypes. It is incorporated into the growing RNA sequence during replication and acts as a chain terminator. The appearance of resistance to sofosbuvir is extremely limited and when this does occur the viral species is unable to persist.

Sofosbuvir was studied as triple therapy with PEGINF and RBV for just 12 weeks in patients with genotypes 1, 4, 5 and 6[18**] This was a single arm study with no comparison with PEGINF and RBV because of the marked differences in the duration of treatment. Over 90% of patients treated with sofosbuvir triple therapy were HCV RNA undetectable within 2 weeks and virtually all patients achieved a RVR. The overall SVR rate was 90%: 89% in patients with genotype 1 and 96% in patients with genotype 4. In patients with cirrhosis, the SVR rate was 80%. All seven of the patients with HCV genotypes 5 and 6 achieved SVR. Sofosbuvir triple therapy has not been evaluated in patients who failed either PEGINF and RBV or triple therapy with a protease inhibitor.

The combination of sofosbuvir and RBV represents the first interferon-free regimen approved for use to treat patients with chronic HCV. This combination was initially studied and is approved for use in patients with HCV genotypes 2 and 3.[18**,19**] In patients with HCV genotype 2, sofosbuvir and RBV yielded superior SVR rates compared with PEGINF and RBV. In treatment-naive patients, 12 weeks of sofosbuvir and RBV achieved SVR rates of 91 and 98% in patients with and without cirrhosis respectively. In patients who had previously failed PEGINF and RBV SVR rates of 96 and 60% were observed with 12 weeks of treatment. Extending the duration of treatment from 12 to 16 weeks did increase the SVR in this subgroup of patients to 78%. The recommended duration of sofosbuvir and RBV for patients with HCV genotype 2 is 12 weeks.

In patients with genotype 3, treatment with sofosbuvir and RBV for 12 weeks yielded an SVR rate of only 61% in patients without cirrhosis and 34% in patients with cirrhosis.[18**,19**] These SVR rates are very similar to that observed with PEGINF and RBV. Extending the duration of sofosbuvir and RBV to 16 and 24 weeks increased the SVR rate in all patients with genotype 3 to about 62 and 84%, respectively.[19**,20,21] As a result, the recommended duration of sofosbuvir and RBV for patients with genotype 3 is 24 weeks.

Sofosbuvir and RBV were also studied in patients with genotypes 1, 2 and 3 who had co-infection with HIV.[22] The duration of treatment for patients with genotypes 1 and 3 was 24 and 12 weeks for patients with HCV genotype 2. SVR rates of 76, 92 and 88% were observed for patients with genotype 1, 2 and 3, respectively. This study led to the approval of sofosbuvir and RBV for the treatment of HCV in patients co-infected with HIV.

Sofosbuvir and RBV have also been studied without interferon in patients with HCV and liver cancer awaiting liver transplant and in patients with post-liver transplant recurrent HCV.[23,24] The duration of sofosbuvir and RBV in all of these studies was for 24 weeks. SVR rates of about 75% were achieved in each of these populations. These studies led to the recommendation that sofosbuvir and RBV be utilized in patients with HCV genotype 1 who were unable to receive PEGINF. The recommended duration of therapy in these patients was 24 weeks.

Sofosbuvir is a well tolerated antiviral agent with minimal side-effects. In a study in which sofosbuvir and RBV were compared with placebo in patients who could not take PEGINF and RBV, the only side-effects with increased frequency above placebo were anemia and pruritus, both of which were attributed to RBV.[19**]

Mixing and Matching Antiviral Agents

Both simeprevir and sofosbuvir are currently approved and available for treatment of chronic HCV. The combination of simeprevir and sofosbuvir with or without RBV for either 12 or 24 weeks was evaluated in about 160 patients with HCV genotype 1. Many of these patients had prior nonresponse to PEGINF and RBV and about half had advanced fibrosis or cirrhosis.[25] Over 93% of all patients achieved SVR. Treating for 24 weeks or using RBV was no more effective than 12 weeks of treatment with just simeprevir and sofosbuvir alone, without RBV. The SVR rate in patients with genotype 1B or genotype 1A without the Q80K mutation was 100%. Patients with genotype 1A and the Q80K mutation had an SVR rate of about 90%. Although the regulatory authorities did not specifically approve the combination of simeprevir and sofosbuvir for the treatment of patients with HCV, the approval by the US Food and Drug Administration states that simeprevir and sofosbuvir are 'indicated for the treatment of chronic HCV infection as part of a combination antiviral regimen'. This opens the door for the use of these agents along to treat patients with HCV genotype 1 and provides a cheaper, shorter and probably superior SVR than 24 weeks of sofosbuvir and RBV.

Identification of Patients With Hepatitis C Virus

An estimated 4 million persons in the United States and 300 million persons worldwide are infected with HCV.[1] In the United States, the vast majority were infected in the 1960–1980s through the transfusion of blood products and injection drug use. Many of these patients are asymptomatic and have evaded detection for many years. The need to identify these patients is why the Center for Disease Control and the US Preventive Services Task Force has recommended that all persons born between the years of 1945–1965 be screened for HCV.[26*,27*] If all persons in these birth cohort years were screened, it is estimated that 75% of all persons with HCV in the United States would be identified.

Conclusion

It is now possible to cure HCV in the vast majority of patients with chronic HCV. SVR rates of 80–90% can be routinely achieved in patients with all HCV genotypes in as little as 12–24 weeks. Of the antiviral agents currently available, sofosbuvir appears to be the easiest to manage, the most efficacious and the antiviral agent with the broadest of indications. Patients with HCV genotypes 1, 4, 5 and 6 can be treated with sofosbuvir, PEGINF and RBV for 12 weeks. SVR rates of 90% or better are achieved. Patients with genotype 1 who are unable to tolerate PEGINF and patients with HCV genotype 3 can be treated with sofosbuvir and RBV for 24 weeks. SVR rates in these patients range from 75 to 83%. Patients with genotype 2 can be treated with sofosbuvir and RBV for 12 weeks with an SVR exceeding 90%. Simeprevir offers an SVR of about 80%, but requires 24 weeks of PEGINF and RBV. Patients with HCV genotype 1A and the Q80K mutation have SVR rates that are significantly reduced. Perhaps the best use for simeprevir is with sofosbuvir for 12 weeks in patients with HCV genotype 1. Our ability to eradicate HCV is on the horizon. However, this cannot be achieved unless patients are recognized and this will require screening in those persons at greatest risk, which is now defined by the year of their birth.

Source - Medscape

References

1. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1195–1206.
2. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364:2405–2416.
3. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1207–1217.
4. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364:2417–2428; 8.
5. Sherman KE, Flamm SL, Afdhal NH, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 2011; 365:1014–1024.
6. Fontaine H, Hezode C, Dorival C, et al. SVR12 rates and safety of triple therapy including telaprevir or boceprevir in 221 cirrhotic non responders treated in the French early access program (anrs co20-CUPIC). J Hepatol 2013; 58 (Suppl 1):S27.
7. Bourlie` re M, Wendt A, Fontaine H, et al. How to optimize HCV therapy in genotype 1 patients with cirrhosis. Liver Int 2013; 33 (Suppl 1):46–55.
8. Kowdley KV, Lawitz E, Poordad F, et al. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333+/_ ribavirin in patients with chronic HCV GT1 infection: results from the AVIATOR study. J Hepatol 2013; 58 (Suppl; abstr 3).
9. Everson GT, Sims KD, Rodriguez-Torres M, et al. Interim analysis of an interferon (IFN)- and ribavirin (RBV)-free regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 in treatment-naive, hepatitis C virus genotype 1-infected patients. J Hepatol 2013; 58 (Suppl; abstr 1423).
10. Zeuzem S, Soriano V, Asselah T, et al. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl j Med 2013; 369:630–639.
11. Gane E, Hyland R, Ding X, et al. ELECTRON: 100% Suppression of Viral Load through 4 Weeks' Posttreatment for Sofosbuvir + Ledipasvir (GS-5885) + RBV for 12 Weeks in Treatment-naive and –experienced Hepatitis C Virus GT 1 Patients. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, GA, 2013. Abstract 41LB.
12. Manns M, Marcellin P, Poordad FPF, et al. Simeprevir (TMC435) with pegylated interferon/ribavirin for the treatment of chronic HCV genotype-1 infection in treatment-naive patients: results from QUEST-2, a phase 3 trial. J Hepatol 2013; 58 (Suppl; abstr 1413).
13. Jacobson I, Dore GJ, Foster GR, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatmentnaive patients: results from QUEST-1 a phase III trial. J Hepatol 2013; 58 (Suppl 1):S574.
14. Zeuzem S, Berg T, Gane E, et al. TMC435 in HCV genotype 1 patients who have failed previous pegylated interferon/ribavirin treatment: Final SVR24 results of the ASPIRE trial. J Hepatol 37:56. (suppl abstract 2).
15. Sulkowski MS, Asselah T, Lalezari J, et al. Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naive patients with chronic genotype 1 HCV: SILEN-C1 trial. Hepatology 2013; 57:2143–2154.
16. Sulkowski MS, Bourlie` re M, Bronowicki JP, et al. Faldaprevir combined with peginterferon alfa-2a and ribavirin in chronic hepatitis C virus genotype-1 patients with prior nonresponse: SILEN-C2 trial. Hepatology 2013; 57: 2155–2163.
17. Palanisamy N, Danielsson A, Kokkula C, et al. Implications of baseline polymorphisms for potential resistance to NS3 protease inhibitors in Hepatitis C virus genotypes 1a, 2b and 3a. Antiviral Res 2013; 99:12–17.
18. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368:1878–1887.
    
    **This is the first study to demonstrate the effectiveness of sofosbuvir for the treatment of patients with chronic HCV.
19. Jacobon IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotypes 2 or 3 in patients without treatment options. N Engl J Med 2013; 368:1867–1877.
    
    **This is the first manuscript to demonstrate that an all oral interferon-free regimen can lead to SVR for patients with chronic HCV.
20. Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. Hepatology 2013; 58 (Suppl Abstract 1085).
21. Lawitz E, Poordad F, Brainard DM, et al. Sofosbuvir in combination with PegIFN and ribavirin for 12 weeks provides high SVR rates in HCV-infected genotype 2 or 3 treatment experienced patients with and without compensated cirrhosis: results from the LONESTAR-2 Study. Hepatology 2013; 58 (Suppl Abstract LB4).
22. Sulkowski MS, Rodriguez-Torres M, Lalezari JP, et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected With HIV (PHOTON-1). Hepatology 2013; 58 (Suppl Abstract 212).
23. Curry MP, Forns X, Chung RT, et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Hepatology 2013; 58 (Suppl); Abstract 213.
24. Charlton MR, Gane EJ, Manns MP, et al. Sofosbuvir and ribavirin for the treatment of established recurrent hepatitis C infection after liver transplantation: preliminary results of a prospective, multicenter study. Hepatology 2013; 58 (Suppl Abstract LB2).
25. Jacobson IM, Ghalib RH, Rodriguez-Torres M, et al. SVR results of a once daily regimen of simeprevir plus sofosbuvir with or without ribavirin in cirrhotic and noncirrhotic HCV genotype treatment naive and prior null-responder patients. The COSMOS study. Hepatology 2013; 58 (Suppl AASLD abstract LB3).
26. Moyer VA, and the U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2013; 159:349–357.
    
    *This study demonstrates the importance of baby boomer cohort screening to detect persons infected with HCV.
27. Smith BD, Morgan RL, Beckett GA, et al. Hepatitis C virus testing of persons born during 1945-1965: recommendations from the Centers for Disease Control and Prevention. Ann Intern Med 2012; 157:817–822.
    
    * This study demonstrates the importance of baby boomer cohort screening to detect persons infected with HCV.

Watch Donald Jensen MD on Chicago Tonight on the high price of new hepatitis C treatments

Treating Hepatitis C Chicago Tonight 
April 28, 2014 10:30 am

An estimated 3.2 million Americans live with hepatitis C. Traditional treatments didn’t always cure the viral infection and often came with severe side effects. Late last year, the Food and Drug Administration approved two new drugs, Sovaldi and Olysio, for the treatment of hepatitis C. But the drugs come with a hefty price tag, starting at $66,000 for Olysio and $84,000 for Sovaldi. Brandis Friedman has more on the treatments and their costs.
Continue to article....

Hepatitis C - Off-label combinations of antiviral agents

Preparing for the uncertain yet inevitable: Off-label combinations of antiviral agents in hepatitis C virus 

Andrew Aronsohn,1,2 Nancy Reau,1 and Donald Jensen1

Article first published online: 1 MAR 2014

DOI: 10.1002/hep.26903

Hepatology

Early View (Online Version of Record published before inclusion in an issue)

The next generation of direct-acting antiviral agents (DAAs) will change the landscape of hepatitis C virus (HCV) therapy. Approval of complimentary oral agents will also introduce new opportunities for off-label treatment. Off-label therapy in HCV will include (1) combinations of approved drugs, used for the approved indication in an unapproved combination, such as combining two DAAs in an interferon (IFN)-sparing regimen, and (2) combinations of approved drugs used in an unapproved combination for an unapproved indication, such as using two available DAAs to treat patients post-LT (liver transplantation). Both providers and patients might find off-label combinations attractive; however, there may be limited data to support safety and efficacy. These treatment choices may also go against the recommendations published in therapeutic guidelines.

This article will address anticipated issues regarding off-label use of HCV medications, including the role of the U.S. Food and Drug Administration (FDA), consumer pressure, medical society guidelines, and third-party payers. Off-label issues specific to the United States will be described; however, many concepts, such as uncertainties of cost, label regulation, and reimbursement, can be applied to health care systems globally.

The FDA Regulation of Off-Label Use

The FDA regulates market entry for all new prescription drugs in the United States. Once approved, physicians are not bound to prescribe according to the label-in many cases, off-label prescriptions may be part of best practice or standard of care. Off-label prescribing is legal and has been shown to occur in over one fifth of office-based prescriptions.[1] Upcoming generations of DAAs represent robust therapeutic innovation, which will likely outpace the breadth and capacity of the FDA-approved label. Prescribing already approved agents in an off-label combination may be desired to improve efficacy. In addition, safety may also be improved using these combinations by potentially eliminating drugs with toxicity, such as IFN. FDA approval for these combinations would require a new and unique application for the combined regimen, which would be costly and would require partnership between separate manufacturers. As a result, although the FDA will not regulate a provider's ability to prescribe off-label HCV treatment as they see fit, appropriate applications of use may be ambiguous because they will ultimately be based on a combination of opinion and potentially limited available data.

Defining the Need for Off-Label Combinations

Over 185 million people are infected with HCV worldwide.[2] It has surpassed human immunodeficiency virus (HIV) as a cause for mortality and has been linked to higher all-cause mortality and diminished quality of life.[3, 4] Despite data showing that sustained viral response (SVR) reduces mortality, relatively few patients have undergone successful treatment.[5] Historically, suboptimal efficacy and toxicity of IFN-based therapy has limited therapeutic options for many; however, opportunity is on the horizon. Multiple agents are in the late stages of development. These drugs will target various aspects of the HCV life cycle, making combinations of these agents a natural strategy to more effectively treat HCV and eliminate intolerable side effects or adverse events. Data involving various combinations of DAAs, often from different manufacturers, is rapidly becoming available; however, many of these studies are performed as proof of concept and are unlikely to progress to FDA-approved combinations. Combining DAAs based on these data in an off-label manner may be an attractive option for patients unwilling to undergo IFN-based therapy in addition to patients with comorbidites that have previously disqualified candidacy for standard-of-care therapy. This strategy is not without risk. Insurers may be unwilling to pay for off-label therapy,[6] and these combinations may have inadequate supporting safety and efficacy data.

Recent Centers for Disease Control and Prevention and U.S. Preventive Services Task Force guidelines to screen all patients born between 1945 and 1965 will help identify many patients who have been infected for decades and are at risk for developing complications of chronic liver disease. Although most of these patients are candidates for standard-of-care therapy, with anticipated rates of SVR reaching 75%,[7, 8] many patients and providers have chosen to defer therapy in anticipation for IFN-free regimens. Deferring therapy comes with risk, which includes progression of disease, change in health status, which may make future treatment impossible, possibility of infecting others, and change in patient insurance status, making therapy unaffordable. Although FDA-approved IFN combinations will likely be available in upcoming years, patients and providers may begin to feel restless, deferring therapy, and opt for a readily available off-label IFN-free combination. This patient population will likely represent a short-term utilization of off-label DAA combinations, which will diminish as IFN-free regimens come to market.

Alternatively, there are many subsets of individuals with HCV that that are in need of DAA-based treatment, but will be excluded from upcoming FDA labels because of limitations in supporting data. These patients include those with decompensated cirrhosis, first-generation protease inhibitor failures, chronic kidney disease, pediatric populations, HIV coinfection, and post-LT. Because many of these populations represent relatively small numbers of patients with HCV, it may be difficult to accumulate requisite data and possibly cost prohibitive for manufacturers to apply for FDA approval. These patients may represent longer-term utilization of off-label treatment.

Is There Precedent for Off-Label Use of Therapy?

The Human Immunodeficiency Virus Paradigm
Acquired immune deficiency syndrome (AIDS) was identified in 1981; however, zidovudine was not available until 1987. Between 1987 and 2008, 25 anti-HIV (human immunodeficiency virus) compounds were licensed for use. Similar to HCV, these agents directly target various aspects of the HIV life cycle. As single agents were approved, there was pressure by clinicians and advocates to find off-label combinations that would prevent emergence of viral resistance. By 1996, combination regimens were widely accepted, although the first regimen, Combivir (zidovudine and lamivudine), was not FDA approved until September 26, 1997.[9] The turning point in therapeutics began in 1996, when data presented at the 11th International Conference on AIDS in Vancouver, British Columbia, Canada, represented HIV as a highly efficient virus, producing 10 billion virions per day. Several key publications followed, illustrating the substantial benefit of three agent-based highly active antiretroviral therapies.[10] Although multiagent therapy was quickly incorporated into clinical practice and eventually established as the standard of care, this principle was first supported by expert opinion and guidelines-not necessarily the package insert. In most instances, payers reimbursed these off-label combinations and the Ryan White Comprehensive AIDS Resources Emergency (CARE) Act provided support. A loud and vocal advocacy campaign provided the necessary impetus for this outcome.

Experience With Hepatitis B

Before the approval of entecavir and tenofovir for hepatitis B virus (HBV), the combination of adefovir and lamivudine was used to control HBV resistant to monotherapy, as well as to prevent the development of resistance in those considered at high risk. Tenofovir, commercially available as an approved drug for HIV, was used off label in the management of hepatitis B well before the FDA approved the drug for this indication. Truvada (tenofovir in combination with emtracitabine) continues to be used off label in the management of HBV. Clinical guidelines advocate for off-label combinations of these medications to manage resistant HBV.[11]

HCV Therapy May Be Different

Although there is precedent for off-label therapy in many diseases, HCV has unique considerations. First, unlike HIV, in patients without advanced fibrosis there is often no urgency to initiate therapy. Progression to clinically significant disease in HCV often takes decades, and patients and providers may be less willing to take on the risk of off-label treatment when an approved regimen is only months to years away. Second, for many patients, the current standard-of-care HCV treatment is safe and offers high rates of SVR. Alternatively, drug-resistant HBV, HIV, and many cancers may have limited, if any, FDA-approved treatments, making an off-label therapy the only option. Finally, there is not the same intensity of HCV advocacy as there had been for HIV, a pivotal factor in swaying third-party reimbursement.

Practical Considerations in Off-Label Use of DAAs

How Much Supporting Data Will Be Required?
Off-label use of upcoming DAAs will certainly occur; however, the degree of utilization will rely on availability of safety and efficacy data. One emerging source of data may come from prospective observational studies, such as HCV TARGET and CUPIC. These multicenter studies enroll large numbers of patients undergoing HCV therapy and have the potential to capture vast amounts of off-label therapeutic data. If a high level of evidence from observational studies or well-controlled clinical trials is available, it is possible that off-label combinations may be advocated by authoritative guidelines from well-respected academic associations. More likely, especially in understudied populations, robust data will not be available. In these cases, providers and patients will have to determine their minimal threshold of safety and efficacy data to initiate off-label therapy without the assistance of guidelines or a package insert. Treatment based on limited data will require extensive communication and understanding of therapeutic options between the patient and provider.

What Will Be the Role of Industry and How Will It Be Regulated?

Although prescribing practices are unregulated, industry promotion of off-label use is highly restricted. Pharmaceutical companies are required to submit final promotional materials to the FDA for review at the time of public dissemination. Off-label promotion in these materials is strictly prohibited and is subject to FDA regulatory action. In contrast, the FDA has taken a more lenient position on activities that fall under the safe harbor of scientific exchange of information. Recent guidelines allow for industry dissemination of scientific literature of non-FDA-approved drug use, provided it is in an unabridged form, published in a peer-reviewed journal, and accompanied by a clear statement that indicates the study involves off-label use of a given therapy.[12] Another potential outlet for marketing will be industry-sponsored continuing medical education activities, which may include nonpromotional discussion of off-label use of a therapy. Both of these practices are already highly utilized in the HCV therapy market and will likely increase in volume as new agents prepare to come to market and are approved. Providers who treat HCV will encounter vast amounts of data presented in these formats that are unregulated by the FDA and will be required to critically evaluate the quality and utility of these data before integrating it into clinical practice.

Reimbursement of Off-Label Therapy

Opportunities for off-label HCV treatment with newer DAAs will only be realized if payers reimburse drug costs. Because most health plans rarely publicize policy regarding off-label reimbursement, there tends to be heterogeneity among plans with regard to reimbursement procedures. In general, the likelihood of reimbursement can be thought of as a continuum in which FDA-approved use has the highest probability of reimbursement; mention of an off-label use in society guidelines, compendia, or peer-reviewed literature are less likely to be reimbursed, and expert opinions of off-label use, including data presented in non-peer-reviewed abstract form being least likely to be reimbursed. This continuum is affected by both cost of drug and availability of therapeutic alternatives. In 2009, 34 third-party payers representing approximately one quarter of Medicare and Medicaid beneficiaries nationwide were surveyed regarding practices in off-label reimbursement.[13] Approximately 25% of these payers refused payment for off-label therapy of any kind. Of those who did reimburse off-label therapy, data sources that were felt to be very important in determining eligibility for reimbursement included peer-reviewed literature (74%), clinical practice guidelines (53%), and cost-effectiveness data (21%). In instances where off-label reimbursement was allowed, restrictions of use were reported to be imposed 85% of the time. Examples of restrictions included requirement for previous authorization, step therapy (i.e., failing less costly treatment first), and quantity limits.

Off-label uses of therapies supported by high-quality evidence and seen as standard of care are more likely to be reimbursed by payers. The competitive development of HCV therapy is unique and may uncover exceptions to this rule. First, the rapid progress of the HCV therapeutic pipeline combined with the chronic nature of HCV and a highly effective standard-of-care therapy may deincentivize payers to reimburse off-label treatment when similar FDA-approved therapeutic regimens are projected to be only months away. For example, payers may be reluctant to allow for payment for both simeprevir and sofosbuvir based on the COSMOS trial when IFN-free regimens, offering similar safety and efficacy data, are under consideration for FDA approval in the near future.[14]In addition, as newer agents continue to minimize toxicity and optimize efficacy, payers will be less likely to reimburse potentially costly off-label regimens that offer only incremental benefits of efficacy, safety, or duration of therapy. Finally, because price will be independently negotiated on a per-drug basis, mixing different agents may skew cost/efficacy ratios and threaten to increase financial burden to payers.

Off-label HCV therapy will offer a unique opportunity for providers to use innovative combinations of drugs to treat patients in need; however, this treatment will come at a cost. To mitigate this cost, we can expect increasing payer requirements to justify off-label use. Ironically, third-party payers may become a de facto regulatory body by making decisions on which off-label regimens will be allowed.

Summary

The availability of new DAAs will provide unprecedented opportunities for off-label HCV therapies in many patients. These patients will include those who are unwilling to take, or intolerant of, IFN and those in need of HCV therapy with no other treatment options. For many, this will ultimately be tempered by FDA-approved all-oral options, but until that time, patients, prescribers, and payers will struggle in an environment where more questions exist than answers. There are no rules, and thus there will be little consistency. Historical precedent only serves as proof of concept. Hepatitis C therapy is not offered under the Ryan White CARE Act rules, and as a consequence, HCV treatment will certainly become polarized. No standard for the minimal amount of safety and efficacy data exists, and in many cases, providers will make treatment decisions without the support of the FDA or treatment guidelines. Patient communication, critical evaluation of available evidence, and meticulous management of off-label treatment recipients will be of paramount importance as we enter into the next era of on- and off-label DAA therapy.

Source

AASLD Launches new online guidance for the treatment of hepatitis C

 Culture Shock: Web-Based Hep C Tx Guidelines

Published: Jan 30, 2014

By Michael Smith, North American Correspondent, MedPage Today

The website was developed and will be run jointly by the American Association for the Study of Liver Diseases, the Infectious Diseases Society of America, and the International Antiviral Society-USA.

A panel of 26 experts will keep clinicians on top of HCV treatment options, spokesmen for the three societies told MedPage Today before the site went live.

He told MedPage Today that the site will contain information -- not only on approved uses, but also on specific off-label drug combinations that have not been through the FDA approval process.
That's because it's not realistic to get specific approval for all possible combinations in all possible patient types, Saag said. A major advantage of the new website, he said, is that the panel can look at all the evidence and "craft [regimens that] experts in the field would be using."

Indeed, the first iteration of the site suggests a combination of two new drugs -- simeprevir (Olysio) and sofosbuvir (Sovaldi) -- that is not specifically approved by the FDA, although both drugs are on the market, according to Donald Jensen, MD, of the University of Chicago Medical Center and a spokesman for the liver society.

Continue reading @ MedPage Today or access the complete report by clicking here. 

AASLD/IDSA Launches up-to-date guidance for the treatment of hepatitis C

Online Expert Advice for Clinicians Treating Hepatitis C Now Available at HCVguidelines.org

Today, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA), in collaboration with the International Antiviral Society- USA (IAS-USA), announced the launch of a new website, HCVguidelines.org, that will offer up- to-date guidance for the treatment of hepatitis C virus (HCV) infection.

It is estimated that between 3 and 4 million Americans are infected with HCV and have chronic liver disease as a result. The most recent generation of direct-acting antivirals has the potential to cure most patients with HCV. However, the rapid pace of drug development has left medical providers and insurance companies unsure what the optimal treatments are. The guidance provided through HCVguidelines.org will assist clinicians in using these and other treatments in the care of their patients. HCVguidelines.org is the result of an ongoing collaboration between the two medical professional societies and IAS-USA.

New sections will be added, and the recommendations will be updated on a regular basis as new information becomes available. An ongoing summary of "recent changes" will also be available for readers who want to be directed to updates and changes.

The Guidance was developed by a Panel of HCV experts in the fields of hepatology and infectious diseases, using an evidence-based review of information that is largely available to healthcare practitioners, access the complete report by clicking here. 

Full Report Menu
Full Report
INTRODUCTION
METHODS
HCV TESTING AND LINKAGE TO CARE
COMING SOON: In Whom and When to Initiate Treatment
INITIAL TREATMENT OF HCV INFECTION IN PATIENTS STARTING TREATMENT
RETREATMENT OF PERSONS IN WHOM PRIOR THERAPY HAS FAILED
COMING SOON: Monitoring Patients Who Are On or Have Completed Therapy
UNIQUE PATIENT POPULATIONS
COMING SOON: Management of Acute HCV Infection
REFERENCES
WEBSITE POLICIES

HCV Drug Olysio (simeprevir) - The New Kid On The Block

HCV Drug Olysio (simeprevir) - The New Kid On The Block

Hello everyone,
It sure is another cold weekend here in Michigan, hope it's warmer in your part of the world.

Today, as I sat cuddled in my warm chair, gazing out the window, I found myself watching the birds on our backyard feeder. One seed at a time, slowly they ate their afternoon meal. This arduous task ensures their survival, and will continue day in and day out, season after season.

The same can be said of hepatitis C patients, waiting day after day, year after year for new therapies to be approved. In some cases, the drugs are needed for patients to remain healthy, and yes, for others, they are needed for survival.

The HCV standard-of-care treatment in 2001 was the combination of pegylated interferon and ribavirin. Unfortunately this treatment only cured around 50% of individuals with genotype 1, which is the most prevalent HCV genotype in the US and Europe.  The HCV community waited ten years before a new drug was available, finally, in 2011 the first direct-acting antivirals (DAAs) boceprevir and telaprevir received FDA approval.

Two years later, and some 48 hours ago, the FDA approved Olysio (simeprevir), a new drug to treat HCV.

On this special occasion, and for the newly diagnosed, I thought a few links for reference purposes and a bit of information on simeprevir may be helpful.

Check back often, as new updates are available links and information will be provided below;

December 5-3 Updates
Simeprevir (Olysio): J & J Patient Access Programs

Video - Dr. Joseph Galati talks about HCV drug OLYSIO (simeprevir)

Olysio (simeprevir) - Resistant Variant (Q80K) 
Although, simeprevir appears to be slightly more effective than the standard of care, curing 80 percent of treatment-naïve patients, and easier to take, there are some drawbacks. Before starting simeprevir patients with HCV genotype 1a need to be screened for a genetic mutation called Q80K polymorphism.

November 26th updates: An article written by Marc Iskowitz on the cost of OLYSIO and an educational video from Janssen

OLYSIO (Simeprevir) Cost?
Janssen has priced Olysio at a wholesale acquisition price of $22,120 per bottle of 28 capsules (150 mg capsules), which is an approximately one-month supply. That's roughly $66,360 for a three-month course.
Read more here...

Video
Hepatitis C Drug OLYSIO™ (simeprevir)

The Basics

OLYSIO (Simeprevir) - The New Kid On The Block

Simeprevir is used to treat HCV genotype 1 infected subjects with compensated liver disease (including cirrhosis) in combination with peginterferon and ribavirin. Simeprevir has yet to be studied in patients who have previously failed therapy with a treatment regimen that includes other HCV protease inhibitors.

Before starting simeprevir patients with HCV genotype 1a should be screened for a genetic mutation called Q80K polymorphism. Alternative therapy should be considered for people with the mutation according to Prescribing Information.

Like Simeprevir, both boceprevir and telaprevir are protease inhibitors approved to treat HCV genotype 1 patients in combination with peginterferon and ribavirin.

Simeprevir and telaprevir are used for 12 weeks, boceprevir is used from 24 to 44 weeks.

Peginterferon and ribavirin are used with these drugs, from 24 to 48 weeks.

Simeprevir Duration of Treatment

The recommended duration of treatment with OLYSIO is 12 weeks in combination with peginterferon alfa and ribavirin. In all patients, treatment with OLYSIO should be initiated in combination with peginterferon alfa and ribavirin and should be administered for 12 weeks.

All treatment - naïve and prior relapser patients , including those with cirrhosis , should receive an additional 12 weeks of peginterferon alfa and ribavirin after completing 12 weeks of treatment with OLYSIO , peginterferon alfa and ribavirin (total treatment duration of 24 weeks)

All prior non - responder patients (including partial and null - responder s), including those with cirrhosis, should receive an additional 36 weeks of peginterferon alfa and ribavirin after completing 12 weeks of treatment with OLYSIO, peginterferon alfa and ribavirin (total treatment duration of 48 weeks)

The good news? Simeprevir is taken only once daily (capsule of 150 mg taken orally) with food.

*The type of food does not affect exposure to simeprevir. The capsule should be swallowed as a whole. 

Boceprevir and telaprevir are both taken three times a day with a meal or snack, telaprevir should be taken with a snack that contains protein (cheese, peanut butter, eggs). Although, in some patients telaprevir can be taken twice daily.

Lesson Learned

Telaprevir and boceprevir have significantly increased the ability to cure HCV, but both PIs have their own side effects, including those from interferon.

An important lesson we learned from these drugs may serve as a reminder for future DDAs, that is, once telaprevir and boceprevir were used in larger groups of patients, or in "real-life" settings - outside clinical trials, new response rates and adverse effects began to emerge.

For instance  Dr. Arpita Sheth presented a poster at the Interscience Conference which found 30% of veterans taking direct-acting antivirals boceprevir and telaprevir in "real-life" settings, discontinued treatment by week 24, despite high rates of early response. The study included a greater proportion of cirrhotic patients, then compared to clinical trials. Anemia was  increased by 15%  - over what has been reported elsewhere. The study appears in the 2013 August issue of Clinical Gastroenterology and Hepatology

Food For Thought

In an editorial, in which both simeprevir and sofosbuvir were the topic, researchers wrote; Time will tell if these first second wave DAA agents will prove to be safe and effective when used in large numbers of real life chronic HCV infected patients. The article was published in the November, December issue of Annals Of Hepatology.

Simeprevir Side Effects

Common side effects reported in clinical trials were rash, itching, and nausea, some patients experienced serious photosensitivity reactions which required a trip to the hospital.

The FDA’s advisory panel determined simeprevir was much easier to take than the first generation protease inhibitors (PIs) telaprevir and boceprevir. With SVR rates of 79%-80% in phase III studies and an impressive risk profile the drug was unanimously supported by the panel and approved by the FDA.

In the above mentioned editorial researchers agreed, both simeprevir and sofosbuvir, had a better safety profile and comparable, if not higher, efficacy then telaprevir and boceprevir. However,

In an article written by Elizabeth Mechcatie, the side effects reported in the simeprevir phase III trials included;

In phase III studies fatigue, headache, and influenza like illness, associated with PR, were the most common adverse events. The only deaths reported were in three patients treated with simeprevir after they stopped taking the drug, but were not considered related to the drug. During the first 12 weeks of treatment, dyspnea was also higher among those on simeprevir (12% vs. 8%), but so far, the cause has not been determined, according to the FDA reviewer. Hyperbilirubinemia was also higher among those on simeprevir (49% vs. 26%), mostly grade 1 and 2 abnormalities.

In the first 12 weeks in the phase III studies, rashes (including photosensitivity) were reported in 28% of those on simeprevir, vs. 20% of those on PR only. Pruritus was also more common among those on simeprevir (22% vs. 15%); 1% of patients discontinued treatment because of a rash.

Download the FDA review package for simeprevir and Johnson & Johnson document released Oct 23.

Drug-drug interactions

The complexity of managing drug–drug interactions is another similarity shared by the PIs. A study in the December 2013 issue of Alimentary Pharmacology & Therapeutics, investigating drug–drug interactions in patients using telaprevir and boceprevir reported;  Drug–drug interactions between a PI and drugs newly prescribed during anti-viral therapy were considerable in 42% of the patients.

Other medications used while treating with telaprevir and boceprevir can interfere with the way DDAs are metabolized. The drug–drug interactions can either increase drug concentrations which may cause toxicity and lead to side effects, or decrease drug concentrations leading to a loss of efficacy, and, if the PIs are affected, this may lead to treatment failure due to emergence of viral resistance and subsequently a virological breakthrough.

An excerpt from the study;

The next wave of DAAs including the protease inhibitors faldaprevir and simeprevir as well as the NS5B nucleotide inhibitor sofosbuvir may be available in early 2014 and more will follow in the upcoming years. 

Risk for DDIs differ between the various future DAA classes. The nucleotide NS5B inhibitor sofosbuvir does not seem to be involved in significant DDIs.[24, 25] In contrast, DDIs have to be considered for several nonnucleotide NS5B inhibitors.[15] DDIs may also play a role for some NS5A inhibitors. Daclatasvir is substrate and inhibitor of P-glycoprotein and substrate of CYP3A4. However, pharmacokinetic data suggest that risk for significant DDIs is far lower compared with using protease inhibitors.[15]  

Soon-available PIs faldaprevir and simeprevir are also both inhibitors and substrates of CYP3A4 and it has already been shown that drug levels are altered in the presence of other strong inhibitors or inducers of CYP3A4.[15] Taken together, it can be assumed that the challenge of DDIs will certainly accompany HCV therapy in upcoming years, in particular, as combination treatments with several DAAs will most likely be necessary to finally achieve an efficient interferon-free anti-viral treatment.[6, 26]

Continue to the full text @ Alimentary Pharmacology & Therapeutics

Simeprevir has a list of medications that can cause drug–drug interactions as well, those medications along with patient and prescribing information, can be found online at http://www.olysio.com/intro/.

Let this be an important reminder folks, to ensure a safe, successful treatment plan, provide a complete health history to your healthcare provider and include a list of all medications, vitamins, or herbs you are taking before and during HCV therapy. Going forward, treating with new agents, the importance of preparing for treatment can not be underestimated, communicating with your physician or treatment nurse is key to a promising outcome.

Simeprevir 

Sustained Virologic Response - SVR 

The results from three phase III studies used to determine the FDA approval of simeprevir were QUEST-1 and QUEST-2, made up of treatment-naïve patients. In PROMISE patients relapsed after prior interferon-based treatment – as well as data from the Phase 2b ASPIRE study in prior non-responder patients.

QUEST-1 and QUEST-2
In the two studies deemed QUEST-1 and QUEST-2, of 785 treatment-naive patients, 80 percent of those treated with simeprevir achieved sustained virologic response 12 weeks after the end of treatment, called SVR12, compared with 50 percent in the placebo groups.

PROMISE
In the third study called PROMISE of 393 prior-relapsers, 79 percent in the simeprevir group achieved SVR12 compared with 37 percent of patients in the placebo group.

ASPIRE
Results from ASPIRE led to sustained virologic response 24 weeks after the end of treatment (SVR24) in 65 percent of prior partial-responder patients and 53 percent of prior-null responder patients compared with 9 percent and 19 percent of prior partial- and null-responder patients in the placebo groups, respectively.

Links
OLYSIO Website
Simeprevir (Olysio): J & J Patient Access Programs
Prescribing Information
Patient Information
Important Safety Information

With great anticipation we patiently await for the approval of sofosbuvir, a nucleotide analog NS5B polymerase inhibitor. The FDA approval is expected to be announced in early December. Sofosbuvir will be used only with ribavirin, for treating adult HCV genotypes 2 and 3. However, in HCV genotype 1 and 4 treatment-naive patients, sofosbuvir will be used in combination with pegylated interferon and ribavirin. 

Off Label Use - Simeprevir and Sofosbuvir

Paul Sax, Editor-in-Chief at NEJM Journal Watch wrote an article this past summer; Both Simeprevir and Sofosbuvir Likely Approved by 2014 - Clinical/Ethical/Pharmacoeconomic Dilemmas Loom on the possibility of combining simeprevir and sofosbuvir with or without ribavirin, to create an off label interferon-free regimen;

The interim results of the COSMOS study, presented at CROI this year, showed a >90% cure rate in 80 prior null responders (no cirrhosis) who received simeprevir and sofosbuvir together for 12 or 24 weeks, with and without ribavirin. There was no interferon in this study. (The full slide set of the presentation is on NATAP.)

So if these two drugs are both approved as expected, one could easily make the case that the best treatment for HCV genotype 1 — in terms of efficacy, safety, tolerability, pretty much everything except drug-drug interactions and cost — will be the COSMOS regimen of simeprevir and sofosbuvir, with or without ribavirin. And emphatically without interferon.

And that, my dear friends, is off-label use.

Continue reading...

I hate to be redundant, but once again, in the editorial discussing simeprevir and sofosbuvir, I noticed the mention of off label use combining simeprevir and sofosbuvir;

THE FIRST ALL ORAL INTERFERON-FREE COMBINATION OUTSIDE CLINICAL TRIALS:OFF-LABEL USE OF SIMEPREVIR PLUS SOFOSBUVIR?

As soon as simeprevir and sofosbuvir become commercially available, it is possible that some people will entertain the possibility of combining both agents with our without RBV, to create an off label IFN free regimen. In this regard, it is important to review the results of the COSMOS study.23 This Phase 2 exploratory trial enrolled two cohorts of HCV genotype 1 null responders:one with fibrosis stage Metavir F0-F2 and the other with F3-F4. Both cohorts were randomized to receive simeprevir plus sofosbuvir with or without RBV for 12 vs. 24 weeks of fixed therapy duration.

Preliminary results are so far available only for the12 week arm of the first cohort, with less significant liver fibrosis. Among 27 patients that received simeprevir plus sofosbuvir with RBV, the rate of undetectable HCV RNA 8 weeks after the end of therapy (SVR-8) was 96%. Similarly, among 14patients treated with simeprevir plus sofosbuvir without RBV, SVR-8 was 93%. Overall, 24 patients already reached 12 weeks of follow-up after the end of therapy and all maintain undetectable HCV RNA(SVR-12). Eight patients reached week 24 follow up after the end of therapy and also remain HCV RNA undetectable (SVR-24). Only 2% of patients had to interrupt prematurely the trial for adverse events.These results are surely preliminary, however the message they send out is powerful: in some areas of the world we may start to see the first IFN free regimens already being used to treat chronic HCV patients in routine clinical practice as early as 2014. 

Continue reading...

Once sofosbuvir is FDA approved I assume we will be reading more on off label use, as is often the case, the patient is the last to know.

Other then simeprevir and sofosbuvir, there are many additional potent agents in the clinical pipeline. AbbVie reported this month an interferon-free combination of three drugs plus ribavirin achieved a sustained virologic response (SVR12) in 96 percent of previously untreated genotype 1 patients.

I am determined to remain optimistic that in the future, interferon-free regimens will provide safe and effective therapy in all different HCV infected patient populations.

Stay healthy and positive.