June 15, 2014

-- Interferon- and Ribavirin-Free Therapy Effective against Genotype 1 HCV, Japan’s Most Prevalent Strain of the Disease --

-- Japanese Regulatory Submission for Ledipasvir/Sofosbuvir Anticipated by Year End --

FOSTER CITY, Calif.--(BUSINESS WIRE)--Jun. 15, 2014-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced topline results from a Phase 3 clinical trial (GS-US-337-0113) in Japan evaluating the investigational once-daily fixed-dose combination of the NS5A inhibitor ledipasvir (LDV) 90 mg and the nucleotide analog polymerase inhibitor sofosbuvir (SOF) 400 mg, with and without ribavirin (RBV), for the treatment of genotype 1 chronic hepatitis C virus (HCV) infection. Among patients receiving 12 weeks of LDV/SOF without RBV, 100 percent (n=83/83) of treatment-naïve and 100 percent (n=88/88) of treatment-experienced patients achieved a sustained virologic response 12 weeks after completing therapy (SVR12). Among patients receiving LDV/SOF plus RBV, 96 percent (n=80/83) of treatment-naïve and 100 percent of treatment-experienced patients (n=87/87) achieved SVR12. Across all arms of the study, patients with cirrhosis achieved a 99 percent (n=75/76) SVR12. The study met its primary endpoint of superiority compared to a predefined historical SVR12 rate. Patients who achieve SVR12 are considered cured of HCV infection.

Genotype 1 is the most common strain of HCV in Japan, accounting for approximately 70 percent of the more than one million people chronically infected with the disease. The majority of these infections are due to HCV genotype 1b. Current treatment options for genotype 1 HCV infection involve up to 48 weeks of therapy with pegylated interferon injections, RBV tablets and other oral medicines, which may not be suitable for certain patients.

“The cure rates observed with LDV/SOF in this study are impressive because they were achieved without the need for interferon or ribavirin, both of which involve more complex dosing requirements and may be associated with significant side effects,” said Norbert Bischofberger, PhD, Gilead’s Executive Vice President of Research and Development and Chief Scientific Officer. “These results suggest that a once-daily LDV/SOF tablet has the potential to be an efficacious and well-tolerated regimen for many HCV patients in Japan.”

In the study, 341 patients with genotype 1 HCV infection were randomized (1:1) to receive 12 weeks of all-oral therapy with LDV/SOF, with or without RBV. Of these, 166 patients were treatment-naïve, 175 were treatment-experienced and 76 had compensated cirrhosis. The intent-to-treat SVR12 rates in the study are summarized in the table below:

Capture

Overall, 338/341 patients (99 percent) in Study GS-US-337-0113 achieved SVR12. Of the three patients who failed to achieve SVR12, one patient relapsed after discontinuation of therapy, one patient discontinued therapy after one week of treatment due to rash and one patient died during the study.

Fewer adverse events were observed in the RBV-free arms compared to the RBV-containing arms in the study, most notably with regard to anemia, which was observed in 14 percent of patients taking LDV/SOF plus RBV compared to 2 percent of patients receiving LDV/SOF alone. Adverse events observed with LDV/SOF without RBV were generally mild and included nasopharyngitis (28 percent), headache (6 percent) and malaise (5 percent). Among those taking LDV/SOF plus RBV, in addition to anemia, the most common adverse events were nasopharyngitis (22 percent), pruritus (8 percent), rash (8 percent), headache (8 percent), stomatitis (6 percent), nausea (5 percent) and malaise (5 percent). No patients taking LDV/SOF and two patients taking LDV/SOF plus RBV discontinued treatment due to treatment-emergent adverse events. Full study results will be presented at a future scientific meeting.

Based on these data, Gilead plans to submit a New Drug Application for the LDV/SOF fixed-dose combination with the Japanese Pharmaceutical and Medical Devices Agency (PMDA) by the end of 2014. The product is currently under regulatory review in the United States and European Union.

On April 2, 2014, Gilead announced topline results from another Phase 3 study in Japan evaluating SOF as a single agent in combination with RBV for the treatment of genotype 2 HCV infection. The company plans to file for approval of SOF with the PMDA by mid-2014. SOF as a single agent has been approved by regulatory authorities in the United States, European Union and Canada under the tradename Sovaldi®.

LDV/SOF and SOF are investigational products in Japan and their safety and efficacy have not yet been established.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the possibility of unfavorable results from additional clinical trials involving SOF or the LDV/SOF fixed-dose combination in Japan and the possibility that the company may not file for regulatory approval of SOF as a single agent or the LDV/SOF fixed-dose combination in Japan in the currently anticipated timelines. Further, the PDMA and regulatory authorities in the United States and the European Union may not approve the LDV/SOF fixed-dose combination and the PMDA may not approve SOF as a standalone agent in Japan, and any marketing approvals, if granted, may have significant limitations on their use. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2014, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full prescribing information for Sovaldi is available at www.gilead.com.

Sovaldi is a registered trademark of Gilead Sciences, Inc.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Investors:
Patrick O’Brien, 650-522-1936
or
Media:
Cara Miller, 650-522-1616

Source

American Journal of Transplantation

'A Flood of Opportunity'

E. J. Gane, K. Agarwal

American Journal of Transplantation. 2014;14(5):994-1002.

Abstract and Introduction

Abstract

Chronic hepatitis C virus (HCV) is the leading cause of liver transplantation (LT) in adults. However, infection of the allograft is universal and associated with reduced graft and patient survival. Although successful eradication improves posttransplant outcome, current antiviral therapies have poor efficacy and tolerability. Direct acting antiviral agents (DAAs) provide new opportunities for treatment of HCV recurrence. The addition of a first-generation NS3/4A protease inhibitor (PI) has increased the efficacy of pegylated interferon and ribavirin in patients with chronic HCV genotype 1 infection. Preliminary efficacy results from open-labeled studies of PI-based triple therapy in LT recipients are encouraging. However, the tolerability of triple therapy is reduced following LT, because of increased anemia and drug–drug interactions. The use of PI-based triple therapy in LT recipients seems best suited to larger centers, experienced with management of PI toxicity. Fortunately, other classes of DAAs targeting different steps of HCV replication are in clinical trials, including nucleotide polymerase (NUC-NS5B) inhibitors, nonnucleotide polymerase (non-NUC-NS5B) inhibitors and NS5A inhibitors. Several dual and triple DAA regimens are in clinical development. Phase II studies conducted in patients before and after LT suggest that these regimens will dramatically reduce the impact of recurrent HCV.

Introduction

Chronic hepatitis C virus (HCV) infection is a global epidemic affecting almost 180 million people, with an estimated 3–4 million new infections every year.[1,2] Unfortunately, low treatment uptake combined with an aging HCV-infected cohort effect has resulted in increasing rates of complications. The proportion of the HCV-infected population with established cirrhosis is projected to double over the next decade[3,4] and numbers with hepatocellular carcinoma (HCC) and liver failure will treble by 2030.[5–7] HCV-related liver failure and HCC are already the leading indications for liver transplantation (LT).[8,9]

In a patient with active HCV infection at the time of LT, infection of the allograft is universal at the time of reperfusion. The natural history of HCV is accelerated following LT with 20–40% progressing to cirrhosis within 5 years.[10–12] As a result, graft and patient survival following transplantation for HCV cirrhosis is reduced compared with other elective indications.[13]

The increasing demand for transplantation for HCV-related end-stage liver disease, combined with the negative impact of recurrent HCV on patient and graft survival, has made recurrent hepatitis C the biggest unmet medical need facing LT units.

The primary goal in the management of recurrent HCV is prevention of graft loss through delay or prevention of fibrosis progression. Although several baseline viral, donor and recipient factors are associated with more rapid progression of HCV recurrence, few can be prospectively altered (Table 1). The only intervention that has been demonstrated to improve graft and patient outcomes is successful eradication of HCV infection with antiviral therapy either before or after LT.[14]

Table 1.  Baseline predictors of disease progression

(a.) Pretransplant

Viral Factors

  • High viral load
  • HIV co-infection

Host Factors

  • ↓CD4+, CD8+ responses
  • ↓innate NK/NKT responses
  • Cryoglobulinemia
  • IL-28B genotype

(b.) Posttransplant

Immunosuppression

  • Adjuvant therapy for rejection
  • Rapid weaning of steroids

Pattern of recurrence

  • Cholestatic hepatitis
  • Severe inflammation at 1 year
  • Persistently elevated ALT
  • Early high HCV RNA levels

(c.) Donor

  • Older age
  • Female donor
  • DCD donor
  • Steatosis
  • Diabetes
  • Ischemic time
  • IL-28B genotype

The effectiveness of antiviral therapy against chronic HCV mono-infection has improved dramatically over the past decade, with expected sustained virological response (SVR) rates of almost 75% in previously untreated patients, regardless of genotype. For patients infected with HCV genotype (GT)-2 or -3, the current standard of care is pegylated interferon plus ribavirin (PEG-IFN/RBV) for 24 weeks. For patients infected with HCV GT-1, the addition of one of the two recently approved first-generation protease inhibitors (PIs), telaprevir and boceprevir, to PEG-IFN/RBV for 48 weeks has increased the SVR rate from 45% to 75% and allowed shortened duration of therapy in most patients to 24–28 weeks.

However, these major advances in the treatment of HCV have not delivered a similar impact in the treatment of HCV recurrence. Post-LT patients represent a challenging population with multiple baseline negative predictors for viral response to IFN, including (i) host factors such as non-CC IL-28B genotype which is a negative predictor for response to retreatment with currently licensed; (ii) viral factors such as high prevalence of HCV GT-1 infection and high pretreatment viremia levels 1–2 logs higher than pretransplant, usually exceeding 106 units/mL;[12,15,16] (iii) direct effects of immunosuppression on IFN efficacy through blunting of HCV-specific T cell immune responses.[17,18] The most negative predictor for viral response is lack of tolerability from PEG-IFN/RBV—more than 80% of patients dose reduce and almost 30% cease therapy because of adverse effects. This reflects the co-morbidity spectrum associated with LT encompassing renal dysfunction, cytopenias and diabetes mellitus.

This review focuses on recent advances in antiviral therapy against HCV and their relevance to management of HCV infection before and after LT. We highlight the specific safety and tolerability issues associated with directly acting antiviral agents (DAAs) and summarize the efficacy of these DAA regimens in Phase II studies in these difficult-to-treat patient populations (Figure 1).

824568-fig1

Figure 1. Specific targets of the direct acting antiviral agents.

Current Therapies

SVR rates achieved with PEG-IFN/RBV in LT recipients with recurrent HCV GT-1 are significantly lower than those in non-LT patients. In the US multicenter PROTECT study, which is the largest open-label study to-date of PEG-IFN/RBV for recurrent HCV infection, only 36/125 (29%) patients achieved SVR following 48 weeks therapy.[19] Other studies report SVR rates from 18% to 43% (see Figure 2).[20–22]

824568-fig2

Figure 2. Treatment of recurrent hepatitis C virus infection with pegylated interferon plus ribavirin.

Studies have identified a number of baseline viral and host factors associated with SVR, of which viral genotype non-1 and host IL-28BCC genotype are the strongest predictors (see Table 2). IL-28B encodes for IFN-lambda and modulates host IFN-stimulated gene response to exogenous IFN, with the CC genotype associated with favorable response and SVR. In LT recipients with recurrent HCV, both donor and recipient IL-28B genotypes appear to be important in determining response to PEG-IFN/RBV. The highest rates were achieved when both donor and recipient were matched CC (86%) and lowest SVR rates when both were non-CC (16%).[23,24]

Table 2.  Predictors of response to PEG-IFN/RBV

1. Host factors

  • Younger donor age
  • Lack of severe fibrosis
  • Lack of insulin resistance
  • Donor IL-28B genotype CC
  • Recipient IL-28B genotype CC

2. Viral factors

  • Low pretransplant viremia level
  • Low posttransplant viremia level
  • HCV genotype 2/3
  • Lack of HIV co-infection

3. Treatment-related factors

  • Early on-treatment response
  • Adherence to PEG-IFN and RBV
  • Reduced time since transplant
  • Maintenance cyclosporine

Timing of commencement of antiviral therapy influences the likelihood of response. Several trials of early "preemptive" therapy prior to the onset of established graft fibrosis have reported very poor efficacy and tolerability due to the presence of renal impairment and cytopenias. In the largest randomized study of early preemptive therapy with PEG-IFN/RBV (the PHOENIX study), the rates of histological recurrence, graft loss and death were similar in the active and control groups.[25] Thus, antiviral therapy is best undertaken for established HCV recurrence rather than preemptive therapy. Given the limitations of current therapy, treatment should target those recipients with the greatest chance of response (including HCV GT-2/3 or GT-1/4 with D/R IL-28B CC genotype) and those at highest risk for rapid fibrosis progression, recurrent cirrhosis and graft loss. The most reliable predictor is the presence of moderate histological necroinflammation or fibrosis in the 1-year protocol allograft biopsy.[26–28] Measurement of hepatic venous pressure gradient may also be a valuable tool for predicting disease progression—in one study, the presence of hepatic venous pressure gradient of 6 mmHg or greater at 1 year posttransplant was strongly associated with subsequent hepatic decompensation.[29]

Finally, the choice of maintenance immunosuppression may impact on the outcome of HCV antiviral therapy. Several studies have reported higher SVR rates in patients receiving cyclosporine than in those receiving tacrolimus because of a lower risk of relapse.[30,31] The proposed mechanism is thought to be from a direct antiviral effect of cyclosporine through inhibition of NS5B binding to cyclophillin B.[32] This effect, however, is small, and currently, there is no firm evidence base to recommend switching patients to cyclosporine prior to commencing antiviral therapy.[33]

The development of robust models of HCV replication has driven the development of new classes of therapeutic agents termed DAAs, which are rapidly moving into the clinical arena. Importantly, rapid advances with new DAAs in the clinical trial environment utilizing combinations of different classes seem destined to deliver effective efficacy (approx. 90%) and allow shorter exposure, or indeed no exposure, to PEG-IFN. Since 2011, for patients with HCV GT-1infection, first-generation PIs, telaprevir and boceprevir, in combination with PEG-IFN/RBV is the standard of care in non-LT HCV, offering further improvements in SVR from 40% to 70–75% with shortened viral response guided duration.[34–37]

Initial large clinical trial data sets have now been supplemented by real-life experience in patients with advanced HCV cirrhosis and portal hypertension. The CUPIC (Compassionate Use of Protease Inhibitors in Viral C Cirrhosis) cohort demonstrated a higher rate of serious adverse events (49% telaprevir; 38% boceprevir) and a high rate of discontinuation due to severe adverse events (15% telaprevir; 7% boceprevir).[38] Grade 2 anemia (hemoglobin [Hb] <10.0 g/dL) occurred in approximately 20% of patients receiving telaprevir or boceprevir, while Grade 3/4 anemia (hemoglobin [Hb] <8.0 g/dL) occurred in 10% of patients, despite liberal use of growth factor support and blood transfusion; 71% of patients on telaprevir and 61% of patients on boceprevir had undetectable HCV RNA after 16 weeks of treatment.[39] However, the final SVR rates (40–41%) are sobering and reflect the complexity of PI-based, PEG containing triple therapy in this advanced population with the significant risks of sepsis, hepatic decompensation and death.

At present, the use of PI-based triple therapy cannot be recommended in patients' evidence of borderline decompensation due to a significant additive toxicity profile, with those having an albumin of <30 g/L and platelet count of <100 000/m3 demonstrating a 50% risk of decompensation with PI-based triple therapy.

PI-based triple therapy might play a limited role in patients listed for LT with HCC and compensated HCV cirrhosis. One study, reported in abstract form, treated 20 patients who were awaiting LT with predominately telaprevir, demonstrating 44% had undetectable HCV viral load at 4 weeks rising to 71% at 12 weeks.[40] Triple therapy was discontinued early in 25% of patients and 10% decompensated on treatment but 6/8 remained HCV negative at 12 weeks post-LT, inferring a lack of allograft infection.

Given the increasing impact of recurrent hepatitis C and lack of efficacy of PEG-IFN/RBV, it is not surprising that PI-based triple therapy has been attempted in this post-LT "population of need." Small case series and real life experience have preceded clinical trial data in this population, with SVR efficacy outcomes now reported in predominantly abstract form. Early pharmacokinetic data tempered expectations in the post-LT group. Data on the use of telaprevir in healthy volunteers resulted in a significant increase in cyclosporine (fivefold) and tacrolimus levels (70-fold) due to the inhibition of the cytochrome P450 3A metabolic pathway.[41] Drug–drug interactions remain a significant clinical issue and concern regarding toxicities and risk of rejection given the use of first-generation PIs with PEG-IFN/RBV mandated a cautious approach for clinicians. The required reduction in tacrolimus dosing (80–95%) is greater than that for cyclosporine (50–75%).[42–44]

An early report demonstrated significant drug–drug interactions between calcineurin inhibitors and boceprevir in five patients post-LT. Reduction in cyclosporine dose of 50% and up to 80% reduction in tacrolimus dose were required, steady levels being achieved by 4 days. Follow-up was limited to treatment week 12 but all patients achieved a virological response (≥2 log drop) during this time. Anemia was the more frequent side effect with all patients requiring erythropoietin. Although the numbers are small, this study demonstrated "proof of concept" that the newer DAAs can be used safely with encouraging on-treatment virological response rates.

Individual centers are now reporting their experience with the use of the new PIs in the posttransplant period.[42–48] Several generalizations emerge from the data:

  1. PI-based therapy has only been utilized in HCV patients with established recurrence. Parallel to the non-LT experience, outcomes and safety seem better in those without advanced HCV recurrence. Similarly, toxicity is similar to that reported in non-LT cohorts but with additive anemia, additive complexity in management, increased discontinuation rates and poor tolerability. Increased incidence of sepsis, requirement for dose adjustment and hospitalization is demonstrated. Two multicenter observational reports (US CRUSH-C Group and the European LT Group) both report SVR12 rates of approximately 50% in GT-1 HCV patients.[42,43] Discontinuation rates were observed in 23% of CRUSH-C and 40% European series (which comprised a higher proportion of recipients with more advanced HCV recurrence). Blood transfusion was required in 46% and 35% of patients, respectively. Additionally, mortality associated with sepsis and hepatic decompensation in advanced recurrent HCV post-LT was reported.

  2. Switching patients to cyclosporine appears to be common due to smaller variations in dosing, although tacrolimus-based immunosuppression levels appear to be manageable.[46,48] Meticulous management of immunosuppression with PI-based therapy avoids graft dysfunction and rejection.

  3. The use of a lead in phase with PEG-IFN/RBV informs patient and graft tolerability prior to the additive introduction of PI is widespread.

  4. The number of patients being treated is small. No data are currently available regarding the development of viral resistance and its impact in the post-LT period.

A Phase IIIb study of the use of telaprevir (REPLACE) in stable, noncirrhotic LT patients with GT-1 disease is currently ongoing and will report in early 2014.[49]

Overall, evidence is accruing that PI-based, PEG-IFN containing antiviral therapy is feasible and can deliver SVR, albeit at the price of significant toxicity and requiring intensive and meticulous on-treatment management. Although more effective and better tolerated IFN-free therapies are being developed, at this time, PI-based triple therapy should still be considered for those patients who are at greatest risk of graft loss and who have baseline predictors of response.

Combination DAA Therapy to Treat Established Recurrent Hepatitis C

The poor safety and efficacy of IFN-containing regimens in patients with end-stage liver disease and in LT recipients have hastened the development of IFN-free strategies for the prevention and treatment of recurrent HCV infection.

The HIV treatment paradigm suggests that combining DAAs, which target different steps of viral replication, should provide additive and possibly synergistic antiviral potency, prevent the emergence of DAA resistance and consequently remove the need for IFN. The first IFN-free DAA combinations against HCV consisted of a PI and a non-NUC-NS5B inhibitor—both DAA classes with low barriers to resistance.[50–52] Unfortunately, rapid emergence of dual resistance resulted in high rates of virological breakthrough and relapse, especially in patients infected with HCV subtype 1a and prior null responders to IFN-based therapy.

Fortunately, the addition of a third DAA, an NS5A inhibitor, to a PI and non-NUC NS5B inhibitor (ABT-267/ABT-333-r/ABT-450; daclatasvir/asunaprevir/BMS-791325) prevents the emergence of resistance and improves efficacy to over 90% across all HCV GT-1 patient populations, including those infected with subtype 1a and prior null responders.[53,54] These triple DAA regimens are now in Phase III registration studies for treatment of patients with chronic HCV infection GT-1. However, before they can be used to treat transplant recipients with recurrent HCV infection, extensive drug–drug interaction studies with the calcineurin inhibitors are required because both the PIs and the non-NUC NS5B inhibitors are substrates and inhibitors of CYP-3A4 and Pg-p metabolic pathways.

In contrast to the other DAA classes, the nucleotide polymerase inhibitors (NUCs) appear ideally suited for use following LT. Because these agents do not undergo hepatic metabolism, NUCs do not require dose adjustment in patients with allograft dysfunction and do not interact with calcineurin inhibitors. NUCs are chain terminators of HCV RNA synthesis. The target is the highly conserved catalytic site of the RNA-dependent RNA polymerase, thereby conferring pan-genotypic antiviral potency and a very high barrier to resistance. The uridine-based NUC sofosbuvir (SOF) was recently approved by the US Food and Drug Administration for the treatment of chronic HCV infection GT-1/2/3/5.[55] In Phase III studies in non-LT patients, 24 weeks of SOF plus RBV achieved SVR in 97% patients infected with HCV GT-2 and 85% infected with GT-3.[56–58] This same regimen achieves SVR12 in 55–84% patients with HCV GT-1 infection. No specific toxicities have been observed in more than 3000 patients treated to date.

The addition of an NS5A inhibitor (either daclatasvir or ledipasvir) to SOF increased the SVR rate to 100% across different patient populations including cirrhotic and prior nonresponders to both PEG-IFN/RBV and triple therapy with telaprevir or boceprevir.[59–62]

The efficacy and safety of IFN-free SOF-based regimens in LT recipients with recurrent HCV were confirmed in the published case report of successful rescue of an LT recipient with cholestatic HCV following 24 weeks treatment with SOF plus daclatasvir—an NS5A inhibitor.[63] At the time of treatment initiation, this patient had advanced allograft failure (jaundice, encephalopathy and refractory ascites with Model for End-Stage Liver Disease score of 24). Rapid viral suppression was accompanied by resolution of ascites and recovery of liver synthetic function, and at the time of writing, the patient remains well with normal allograft function and undetectable HCV RNA, more than 2 years posttreatment. Following this remarkable rescue of what had previously been a universally fatal condition, Gilead Sciences instituted a compassionate access program of SOF/RBV for LT recipients with allograft failure from severe recurrent hepatitis C.[64] In the first 44 patients (almost half with fibrosing cholestatic hepatitis C), on-treatment viral suppression was achieved in 78% and SVR in 69%. Virological response was associated with resolution of clinical signs of decompensation. Eight patients died during this study from complications of liver failure, reflecting the severity of liver disease at study entry.

In the first open-label Phase II study, 40 LT recipients with compensated recurrent hepatitis C (all HCV genotypes) were treated with SOF/RBV for 24 weeks.[65] All patients achieved RVR (undetectable HCV RNA at 4 weeks) and 77% achieved posttreatment SVR4.

It is expected that the addition of a second DAA will improve efficacy and shorten the duration of therapy to 12 weeks. Therefore, in the larger follow-on study, 300 patients with both compensated and decompensated recurrent hepatitis C will be randomized to either 12 or 24 weeks of the fixed dose combination of SOF plus the NS5A inhibitor ledipasvir plus RBV.[66] This study is actively recruiting and primary efficacy results are expected in late 2014.

In another open-label Phase II study, 30 LT recipients with compensated recurrent hepatitis C (HCV GT-1 only) are being treated with the AbbVie triple DAA regimen combined with RBV for 24 weeks.[67] Careful adjustment of the calcineurin inhibitor dose will be required because of the inhibition of CYP-3A4 by the ritonavir-boosted PI ABT-450. This study is fully recruited and primary efficacy results are expected in mid-2014.

In the latest open-label Phase II study, 40 patients with compensated recurrent hepatitis C (HCV subtype 1b only) will receive daclatasvir (NS5A inhibitor), combined with simeprevir (PI recently approved by the US Food and Drug Administration in combination with PEG-IFN/RBV) and RBV for 24 weeks.[68] This study has not yet commenced recruitment and primary efficacy results are expected in mid-2015.

Combination DAA Therapy to Prevent Recurrent Hepatitis C

Universal prophylaxis before or at the time of transplant to prevent HCV infection of the allograft is the ultimate goal. SOF-based regimens seem ideal for this purpose because of the excellent tolerability and lack of hepatic metabolism. In a recent landmark study, SOF plus RBV was administered to LT candidates listed with compensated HCV cirrhosis and HCC for 48 weeks or until the day of LT (whichever occurred earlier).[69] Of the 41 who have been transplanted, 65% have remained free from recurrence at least 6 months post-LT. The best predictor of freedom from HCV virological recurrence was the length of time that serum HCV RNA target was not detectable by sensitive PCR assays (target not detected [TND]) prior to transplant. HCV recurred in only 1/24 patients with TND for 30 days and in none if TND for 90 days.

It is hoped that successful HCV eradication in patients with decompensated HCV will rescue many patients from the need for transplantation, analogous to the impact of oral antiviral therapies in decompensated chronic hepatitis B.[70] The rapid viral suppression to undetectable and normalization of alanine aminotransferease observed in the Phase II and III programs of SOF/RBV would suggest that this treatment in patients with decompensated HCV cirrhosis will improve liver synthetic function and remove the need for LT. An ongoing study is now evaluating the safety and efficacy of SOF/RBV in patients with decompensated HCV cirrhosis.[71]

Like NUCs, the NS5A inhibitors have an excellent safety profile and do not undergo hepatic metabolism and both seem ideally suited for use in patients with end-stage liver disease. A study with the fixed dose combination of SOF plus ledipasvir is currently under way.[66] It seems possible that the increased antiviral potency of this combined DAA regimen will improve the likelihood of rescue from transplantation in patients with decompensated cirrhosis.

Although widespread uptake of effective combination DAA therapy should reduce the demand for transplantation for HCV-related liver failure, this may be offset by increasing demand for HCV-related HCC because: (i) there already exists a large population with established cirrhosis at risk for this complication; and (ii) DAA therapy will dramatically reduce end-stage liver disease deaths in this cirrhotic population, thereby increasing the number of patients with cirrhosis who remain at risk for HCC.[72] Longer follow-up of DAA studies in HCV cirrhosis will determine whether successful treatment will result in fibrosis regression and reduction in life-time risk of HCC, as has been observed with hepatitis B virus therapy.[73,74]

Conclusions

HCV cirrhosis remains the leading indication for LT and this demand is projected to double in the next decade. Unfortunately, HCV infection of the allograft is universal and associated with accelerated disease progression with reduced graft and patient survival compared to other transplant indications.

Current antiviral therapy, with a PEG-IFN/RBV component, has limited applicability peri- and post-LT because of poor tolerability and efficacy in these patient populations. The improved efficacy of first-generation PIs, boceprevir and telaprevir, in the treatment of recurrent hepatitis C is offset by increased toxicity in LT recipients, especially anemia, and significant drug–drug interactions, especially with tacrolimus.

In contrast, the NUC-NS5B inhibitors and the NS5A inhibitors lack toxicity and significant drug interactions with either cyclosporine or tacrolimus and seem ideally suited for post-LT treatment of recurrent HCV infection. Recent clinical studies of SOF plus RBV therapy confirm the safety and efficacy of IFN-free DAA therapy before and after LT. Subsequent studies of DAA combinations (SOF plus ledipasvir, or ABT-450/ABT-333/BT-267) are expected to achieve almost 100% response with shorter duration of therapy.

In summary, chronic hepatitis C is both the leading indication for LT and the leading cause of posttransplant graft loss. The poor tolerability of IFN-based therapy in decompensated liver disease has limited pretransplant treatment to well-compensated patients listed for HCC. The primary goal of IFN-based antiviral therapy was to improve posttransplant outcomes through delayed treatment of patients with established recurrence in the allograft. The superior efficacy and tolerability of direct antiviral agents should move the primary goal of antiviral therapy to universal pre-LT prophylaxis in all patients listed with HCV cirrhosis, thus abrogating the impact of HCV allograft infection and improving long-term graft and patient survival. Finally, combination DAA therapy may salvage patients presenting with decompensated HCV cirrhosis, thereby reducing both the demand for LT and the need for re-LT.

References

1. Shepard C, Finelli L, Alter M. Global epidemiology of hepatitis C infection. Lancet Infect Dis 2005; 5: 558–567.

2. World Health Organization. Available at: www.who.int. Accessed September 1, 2012.

3. Rein D, Wittenborn J, Weinbaum C, et al. Forecasting the morbidity and mortality associated with prevalent cases of precirrhotic chronic hepatitis C in the United States. Dig Liver Dis 2011; 43: 66–72.

4. Armstrong G, Wasley A, Simard E, et al. Prevalence of HCV infection in the United States. Ann Intern Med 2006; 144: 705–714.

5. Wise M, Bialek S, Bell B, et al. Changing trends in HCV-related mortality in USA. Hepatology 2008; 47: 1128–1135.

6. Davila J, Morgan R, Shaib Y, et al. HCV and increasing incidence of hepatocellular carcinoma: A population-based study. Gastroenterology 2004; 127: 1372–1380.

7. Davis G, Albright J, Cook S. Projecting future complications of chronic hepatitis C in United States. Liver Transpl 2003; 9: 331–338.

8. Williams R. Global challenges in liver disease. Hepatology 2006; 44: 521–526.

9. Lee MH, Yang H-I, Lu S-H, et al. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: A community-based long-term prospective study. J Infect Dis 2012; 206: 469–477.

10. Garcia-Retortillo M, Forns X, Feliu A, et al. Hepatitis C kinetics during and immediately after transplantation. Hepatology 2002; 35: 680–687.

11. Ballardini G, de Raffele E, Groff P, et al. Timing of reinfection and mechanisms of hepatocellular damage in transplanted HCV-infected liver. Liver Transplant 2002; 8: 10–20.

12. Gane E, Naoumov N, Qian K, et al. A longitudinal analysis of hepatitis C virus replication following liver transplantation. Gastroenterology 1996; 110: 167–177.

13. Forman L, Lewis J, Lewis J, et al. Association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 2002; 122: 889–896.

14. Carrion J, Navasa M, Garcia-Retortillo M, et al. Efficacy of antiviral therapy on HCV recurrence after liver transplantation: A randomised-controlled study. Gastroenterology 2007; 132: 1746–1756.

15. Chazouilleres O, Kim M, Coombs C, et al. Quantitation of HCV RNA in liver transplant recipients. Gastroenterology 1994; 106: 994–999.

16. Everhart J, Wei Y, Eng H, et al. Recurrent and new HCV infection after liver transplantation. Hepatology 1999; 29: 1220–1226.

17. Rosen H, Hinrichs D, Gretch D, et al. Association of multispecific CD4+ response to HCV and severity of recurrence after liver transplantation. Gastroenterology 1999; 117: 926–932.

18. Gruener N, Jung M, Ulsenheimer A, et al. Analysis of a successful HCV-specific CD8+ T cell response in patients with recurrent HCVinfection after orthotopic liver transplantation. Liver Transpl 2004; 10: 1487–1496.

19. Gordon FD, Kwo P, Ghalib R. Peginterferon-a-2b and ribavirin for hepatitis C recurrence postorthotopic liver transplantation. J Clin Gastroenterol 2012; 46: 700–708.

20. Berenguer M, Palau A, Aguilera V, et al. Clinical benefits of antiviral therapy in patients in recurrent HCV.AmJ Transplant 2008; 8: 679–687.

21. Calmus Y, Duvoux C, Pageaux G, et al. Treatment of recurrent HCV infection following liver transplantation: Results of a multicenter, randomized, versus placebo, trial of ribavirin alone as maintenance therapy after one year of PegIFN-2a plus ribavirin. J Hepatol 2012; 57: 564–571.

22. Cescon M, Grazi G, Cucchetti A, et al. Predictors of SVR after antiviral treatment for HCV recurrence following liver transplantation. Liver Transpl 2009; 15: 782–789.

23. Charlton M, Thompson A, Veldt B, et al. IL28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with HCV infection. Hepatology 2011; 53: 317–324.

24. Fukuhara T, Taketomi A, Motomura T, et al. Variants in IL28B in liver recipients and doors correlate with response to PEG/RBV therapy for recurrent hepatitis C. Gastroenterology 2010; 139: 1577–1585.

25. Bzowej N, Nelson D, Terrault D, et al. PHOENIX: A randomized controlled trial of peginterferon alfa-2a plus ribavirin as a prophylactic treatment after liver transplantation for hepatitis C virus. Liver Transpl 2011; 17: 528–538.

26. Gane E, Portmann B, Naoumov N, et al. Long-term outcome of hepatitis C infection after liver transplantation. N Engl J Med 1996; 334: 821–827.

27. Prieto M, Bereguer M, Rayon J, et al. High incidence of allograft cirrhosis in HCV genotype 1b following transplantation. Hepatology 1999; 29: 250–256.

28. Firpi R, Abdelmalek M, Soldevila-Pico C, et al. One-year protocol liver biopsy can stratify fibrosis progression in liver transplant recipients with recurrent hepatitis C infection. Liver Transpl 2004; 10: 1240–1247.

29. Blasco A, Forns X, Carrión JA, et al. Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C recurrence after liver transplantation. Hepatology 2006; 43: 492–499.

30. Firpi RJ, Soldevila-Pico C, Morelli GG, et al. The use of cyclosporine for recurrent hepatitis C after liver transplant: A randomized pilot study. Dig Dis Sci 2010; 55: 196–203.

31. ReViS-TC Study Group. Cyclosporine A-based immunosuppression reduces relapse rate after antiviral therapy in transplanted patients with hepatitis C virus infection: A large, multicenter cohort study. Transplantation 2011; 92: 334–340.

32. Firpi RJ, Zhu H, Morelli G, et al. Cyclosporine suppresses hepatitis C virus in vitro and increases the chance of a sustained virological response after liver transplantation. Liver Transpl 2006; 12: 51–57.

33. Rabie R, Mumtaz K, Renner E. Efficacy of antiviral therapy for hepatitis C after liver transplantation with cyclosporine and tacrolimus: A systematic review and meta-analysis. Liver Transpl 2013; 19: 36–48.

34. 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.

35. 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.

36. 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.

37. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364: 2417–2428.

38. Hezode C, Fontaine H, Dorival C, et al. Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC). J Hepatol 2013; 59: 434–441.

39. Hezode C, Fontaine H, Dufour F, et al. Efficacy and safety of telaprevir or boceprevir in combination with peginterferon alfa/ribavirin, in cirrhotics according to the age. Data from the CUPIC cohort (ANRS CO20). Hepatology 2013; 58 (Abstract #52): 218A.

40. Verna EC, Terry N, Lukose T, et al. High early response rates with protease inhibitor triple therapy in a multicenter cohort of HCV infected patients awaiting liver-transplantation. Hepatology 2012; 56. Abstract 52; 218A.

41. Garg V, van HR, Lee JE, Alves K, Nadkarni P, Luo X. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology 2011; 54: 20–27.

42. Verna EC, Burton JR, O'Leary JG, et al. A multicenter study of protease inhibitor-triple therapy in HCV-infected liver transplant recipients: Report from the CRUSH-C group. J Hepatol 2013; 58 (Suppl 1): S10–S11.

43. Rogers CC, Stevens DR, Kim M, et al. P239-III telaprevir can be used safely with concomitant tacrolimus in the post transplant setting. Am J Transplant 2012; 12: 431.

44. Burton JR, Everson GT. Initial experience with telaprevir for treating hepatitis C virus in liver recipients: Virologic response, safety and tolerability. Am J Transplant 2012; 12: 188 (LB-01).

45. de Oliveira Pereira AP, Shin HJ, Safdar A. Post liver transplant therapy with telaprevir for recurrent hepatitis C. Am J Transplant 2012; 12: 430.

46. Kwo P, Ghabril M, Lacerda M, et al. Use of telaprevir plus PEG interferon/ribavirin for null responders post OLT with advanced fibrosis/cholestatic hepatitis C. J Hepatol 2012; 56: S86.

47. Pungpapong S, Murphy J, Henry T, et al. P234-III initial experience utilising telaprevir with peginterferon and ribavirin for treatment of hepatitis C genotype 1 after liver transplantation. Am J Transplant 2012; 12: 430.

48. Coilly A, Roche B, Dumortier J, et al. Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: A multicenter experience. J Hepatol 2014; 60: 78–86.

49. An Efficacy and Safety Study of Telaprevir in Patients With Genotype 1 Hepatitis C Infection After Liver Transplantation (REPLACE). Available at: Clinicaltrials.gov: NCT01571583. Accessed November 20, 2012.

50. Zeuzem S, Soriano V, Asselah T, et al. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med 2013; 369: 630–639.

51. Di Bisceglie A, Nelson D, Gane E, et al. VX-22 with TVR alone or in combination with PEG-IFN and RBV in treatment naive patients with chronic HCV GT-1: ZENITH study interim results. J Hepatol 2011; 54: S540.

52. Poordad F, Lawitz E, Kowdley K, et al. 12 Week IFN-free regimen of ABT-450/r+ABT-333+RBV achieved SVR12 in more than 90% of treatment naïve HCV GT-1 infected subjects and in 47% of previous nonresponders. J Hepatol 2012; 56: S549.

53. Kowdley K, Lawitz E, Poordad F, et al. Safety and efficacy of IFN-free regimen of ABT-450/r, ABT-267 and ABT-333 +/− RBV in patients with chronic HCV GT-1 infection. J Hepatol 2013; 58: S2.

54. Everson G, Sims K, Rodriguez-Torres M, et al. Interim analysis of IFN-free and RBV-free regimen of daclatasvir, asunaprevir and BMS-791325 in treatment-naive HCV GT-1 infected patients. J Hepatol 2013; 58: S573.

55. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm377888.htm. Accessed December 6, 2013.

56. Jacobson I, Gordon S, Kowdley K, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013; 368: 1867–1877.

57. Lawitz E, Mangia A, Wiles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368: 1878–1887.

58. Zeuzem S, Dusheiko G, 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: 733A.

59. Sulkowski MS, Gardiner D, Rodriguez-Torres M, et al. Sustained virologic response with daclatasvir plus sofosbuvir±ribavirin (RBV) in chronic HCV genotype (GT) 1-infected patients who previously failed telaprevir (TVR) or boceprevir (BOC). J Hepatol 2013; 58: S570.

60. Gane E, Stedman C, Hyland R, et al. Nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B nonnucleoside inhibitor GS-9669 for hepatitis C genotype 1. Gastroenterology 2013; 146: 736–743.

61. Sulkowski M, Gardiner D, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014; 370: 211–221.

62. Gane E, Stedman C, Symonds W, et al. Once daily PSI-7977 plus RBV: Pegylated interferon-alfa not required for sustained virologic response in treatment-naïve patients with HCV GT2 or GT3. N Engl J Med 2013; 368: 34–44.

63. Fontana R, Hughes E, Bifano M, et al. Sofosbuvir and daclatasvir combination therapy in a liver transplant recipient with severe recurrent cholestatic hepatitis C. Am J Transplant 2013; 13: 1601–1605.

64. Forns X, Fontana R, Moonka D, et al. Initial evaluation of the sofosbuvir compassionate use program for patients with severe recurrent HCV following liver transplantation. Hepatology 2013; 58: 732A.

65. Charlton M, Gane E, Manns M, et al. Sofosbuvir and RBV for the treatment of established recurrent HCV infection after liver transplantation: Preliminary results of a prospective, multicenter study. Hepatology 2013; 58: LB2.

66. A Phase 2, multicenter, open-label study to investigate the safety and efficacy of sofosbuvir/ledipasvir fixed-dose combination+ribavirin administered in subjects infected with chronic HCV who have advanced liver disease or are post-liver transplant. Clinicaltrials. gov: NCT01938430. Accessed November 2013.

67. Open-label, single arm, Phase 2 study to evaluate the safety and efficacy of the combination of ABT-450/ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 coadministered with ribavirin (RBV) in adult liver transplant recipients with genotype 1 hepatitis C virus (HCV) infection. Available at: Clinicaltrials.gov: NCT01782495. Accessed November 20, 2012.

68. Phase 2, Open-label study to investigate the pharmacokinetics, efficacy, safety, and tolerability of the combination of simeprevir (TMC435), daclatasvir (BMS-790052) and ribavirin (RBV) in subjects with recurrent chronic hepatitis C genotype 1b infection after orthotopic liver transplantation. Available at: Clinicaltrials.gov: NCT01938625. Accessed December 15, 2012.

69. Curry M, Forns X, Chung R, et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Hepatology 2013; 58: 314A.

70. Liaw YF, Sheen IS, Lee CM, et al. Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology 2011; 53: 62–72.

71. A Phase 2, multicenter, open-label, randomized study to investigate the safety and efficacy of GS-7977 and ribavirin administered for 48 weeks in patients infected with chronic HCV with cirrhosis and portal hypertension with or without liver decompensation. Clinicaltrials.gov: NCT01687257. Accessed August 2013.

72. Kim WR, Kongley S, Roberts L, et al. Impact of highly effective antiviral therapy on burden of hepatocellular carcinoma in hepatitis C cirrhosis. J Hepatol 2013; 58: S653.

73. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 351: 1521–1531.

74. Kim WR, Berg T, Lomba R, et al. Long-term tenofovir therapy and the risk of hepatocellular carcinoma. J Hepatol 2013; 58: S19.

75. Mukherjee S, Rogge J, Weaver L, Schafer DF. Pilot study of pegylated interferon alfa-2b and ribavirin for recurrent hepatitis C after liver transplantation. Transplant Proc 2003; 35: 3042–3044.

76. Abdelmalek MF, Firpi RJ, Soldevila-Pico C, et al. Sustained viral response to interferon and ribavirin in liver transplant recipients with recurrent hepatitis C. Liver Transpl 2004; 10: 199–207.

77. Stravitz R, Shiffman M, Sanyal A, et al. Effects of interferon on liver histology and allograft rejection in patients with recurrent hepatitis C following liver transplantation. Liver Transpl 2004; 10: 850–888.

78. Rodriguez-Luna H, Khatib A, Sharma P, et al. Treatment of recurrent HCV infection after liver transplantation with combination Peg-IFN alpha 2b and ribavirin. Transplantation 2004; 77: 190–194.

79. Castells L, Vargas V, Allende H, et al. Combined treatment with pegylated interferon and ribavirin in the acute phase of HCV recurrence after liver transplantation. J Hepatol 2005; 43: 53–59.

80. Toniutto P, Fabris C, Fumo E, et al. Pegylated versus standard interferon-alfa in antiviral regimens for post-transplant recurrent hepatitis C: Comparison of tolerability and efficacy. J Gastroenterol Hepatol 2005 20: 577–582.

81. Babatin M, Schindel L, Burak K, et al. Peg-IFN alpha 2b and ribavirin for recurrent hepatitis C after liver transplantation. Can J Gastroenterol 2005; 19: 359–365.

82. Oton E, Barcena R, Moreno-Planas J, et al. Hepatitis C recurrence after liver transplantation: Viral and histologic response to full-dose PEG-interferon and ribavirin. Am J Transplant 2006; 6: 2345–2355.

83. Veldt B, Poterucha J, Watt K, et al. Impact of pegylated interferon and ribavirin treatment on graft survival in liver transplant patients with recurrent hepatitis C infection. Am J Transplant 2008; 8: 2426–2433.

84. Reiberger T, Rasoul-Rockenschaub S, Rieger A, et al. Efficacy of interferon in immunocompromised HCV patients after liver transplantation or with HIV co-infection. Eur J Clin Invest 2008; 38: 421–429.

85. Berenguer M, Aguilera V, Prieto M, et al. Worse recent efficacy of antiviral therapy in liver transplant recipients with recurrent hepatitis C. Liver Transpl 2009; 15: 738–746.

Source

A Home Run for Hepatitis C Treatment

Medscape Gastroenterology

Digestive Disease Week (DDW) 2014

William F. Balistreri, MD

June 05, 2014

HCV Antivirals: You Can't Tell the Players Without a Program

The rosters change almost daily, and new leaders emerge as the statistics accumulate rapidly. No, I am not referring to Major League Baseball; I am talking about antiviral agents used to treat hepatitis C virus (HCV) infection.

The past year has already seen the approval of new direct-acting agents and a change in recommendations.[1] And now, data from recent clinical trials have generated further excitement and promise -- that in the year of the 25th anniversary of its discovery, HCV can be cured.

At Digestive Disease Week (DDW) 2014, investigators updated attendees on the pace of progress in the discovery and validation of novel antivirals. The bottom line is that clinicians will soon have the option of using all-oral, interferon-free regimens that are highly effective against all HCV genotypes in all patients -- with "special population" designations no longer needed. There are clearly logistical details that will prove to be unique to each treatment regimen, and perhaps genotype-specific; however, these will be resolved with broader experience.

A Future Without Hepatitis C

But first, let's look at the not-so-distant past. An analysis presented at DDW indicates that overall treatment rates for patients with chronic HCV have been "dismally poor" and that treatment completion of both dual- and triple-therapy regimens -- pegylated interferon (pegIFN) and ribavirin (RBV) with or without a protease inhibitor, telaprevir or boceprevir -- is suboptimal in the real-world clinical setting.[2]

This comes at a high cost. Hasan and colleagues[3] reported that the cost of curing HCV genotype 1 with the triple-drug regimen was $125,000-$154,000. This estimate includes the associated costs of utilization of provider services, prescriptions, over-the-counter drug use, laboratory tests, and hospitalizations. These data indicate the need for simpler, safer, less expensive, and more effective options.

In the past month, a series of articles was published in the New England Journal of Medicine describing several new and different regimens. These strategies, based on an improved understanding of the HCV life cycle, have consistently produced rates of sustained viral response (SVR) of more than 90% after brief (8-24 weeks) periods of administration.

Accompanying editorials attest to the impact of these advances in treatment efficacy and safety, while highlighting the challenges presented by these "breakthrough medications." Chung and Baumert[4] state that "it may now be possible to imagine the global eradication of HCV infection"; however, they cite the need for early diagnosis and cost reduction, especially in low-income countries.

Jayasekera and colleagues[5] and Hoofnagle and colleagues[6] project that the use of these new agents will reduce the intensity of follow-up monitoring; the rate of hospitalizations for adverse effects; dependence on specialist care; and resource demands associated with disease progression, including those for liver transplantation and management of end-stage liver disease and liver cancer. However, with drug costs that may exceed $90,000 per course, it remains to be seen how these remarkable advances will extend to the estimated 150 million people with HCV infection living outside the targeted high-income markets for these agents.

Barriers to Care

Access to these medications is limited by case recognition. Recent recommendations for birth-cohort screening for HCV infection among US adults are predicated upon the belief that only a fraction of Americans with the infection has been diagnosed.

On the basis of data generated from a community-wide HCV screening project and a registry of known HCV patients, Kim and colleagues[7] calculated the proportion of more than 21,000 community residents with undiagnosed HCV infection. The overall prevalence was 2.2%; the age- and sex-specific HCV prevalence was highest (3.3%) in men aged 35-39 years and 45-49 years and lowest (1.0%) in women aged 30-34 years. Most had not been diagnosed.

These data support community-wide programs to institute birth-cohort-based screening as well as appropriate risk-based screening in individuals outside the birth cohort.

Antiviral Agents Soon to be Available

Although the results of multiple recent clinical trials have been reported, we will be unable to discuss all of the agents, studies, combinations, and screening and administration issues. I will therefore highlight a few strategies that have emerged.

Sofosbuvir-Based Regimens

Sofosbuvir (SOF) is a HCV NS5B nucleotide polymerase inhibitor. Several studies have demonstrated high SVR rates in patients with genotypes 1-6 infection treated with SOF combined with RBV with or without pegIFN for 12 or 24 weeks. High efficacy rates were demonstrated across many patient subtypes, including those considered difficult to treat (eg, HIV/HCV coinfection, treatment-experienced patients, and those with cirrhosis).

Many presentations at DDW 2014 described the efficacy and safety of SOF -- often used in combination with ledipasvir (LDV) -- without pegIFN. Subtle differences in response rates and ideal duration of therapy according to genotype were also reported, and these will ultimately be codified in guidelines.

Jacobson and colleagues[8] reported that the fixed-dose (single tablet) combination of SOF 400 mg/LDV 90 mg administered once daily for 12 weeks was highly effective and well tolerated in treatment-naive patients infected with HCV genotype 1, including those with cirrhosis. The addition of RBV did not enhance the SVR rate.

Kowdley and colleagues[9] reported that 8-week treatment with the fixed-dose combination regimen of SOF/LDV, with or without RBV, produced SVRs similar to those achieved with a 12-week regimen in noncirrhotic, previously untreated patients infected with HCV genotype 1.

Phase 3 studies[10] of SOF-based regimens have demonstrated high efficacy of this combination across genotypes, even in patients with multiple traditional negative predictors of diminished efficacy. SVR rates were somewhat lower in patients who had negative predictors; therefore, strategies focusing on addressing these hardest-to-cure populations may be required.

Patients who are considered more difficult to treat owing to advanced liver disease, genotype 3 infection, or previous treatment failure were studied by Gane and colleagues.[11] They reported that regimens involving SOF/LDV with or without RBV were efficacious in patients with more advanced liver disease and in those with previous treatment failure. In patients infected with the difficult-to-treat HCV genotype 3, the addition of RBV to SOF/LDV enhanced the SVR rate. The regimen was generally safe and well tolerated, with no additional safety issues in patients with decompensated liver disease.

Kwo and colleagues[12] reported that the SOF/LDV fixed-dose combination tablet can effectively be used to treat a population of treatment-experienced patients with HCV genotype 1 infection. The addition of RBV to the treatment, or extending the treatment from 12 weeks to 24 weeks, did not significantly increase the final SVR12 rates. Adverse events and laboratory abnormalities were more common in recipients of SOF/LDV with RBV and consistent with the safety profile of RBV.

Two additional studies documented successful retreatment.[13,14] In particular, the study reported by Nyberg and colleagues[14] included patients infected with HCV genotype 2 and genotype 3 in whom treatment had previously failed. Overall SVR rates were 100% for genotype 2-infected patients and 96% for genotype 3-infected patients after retreatment with SOF regimens for a longer duration.

Safety profile. In all of these clinical trials of SOF-containing regimens, adverse events and laboratory abnormalities were more common with pegIFN- or RBV-containing regimens, and SOF did not contribute to the frequency or severity of these expected events. Gordon and colleagues[15] also observed low rates of treatment discontinuation and no duration-related side effects.

Sofosbuvir was approved by the US Food and Drug Administration (FDA) in December 2013 for clinical use in the United States. Ledipasvir is not FDA-approved. On the basis of projections from Markov modeling and compared with current treatment regimens, sofosbuvir-based regimens should yield good future health outcomes and less liver disease complications and deaths across all genotypes, levels of treatment experience, severity stage, and coinfection status.[16]

ABT-Based Regimen

AbbVie's (North Chicago, Illinois) investigational HCV regimen consists of the following fixed-dose combination:

  • ABT-450 (an HCV NS3/4A protease inhibitor), 150 mg dosed with ritonavir 100 mg daily (ABT-450/r);

  • ABT-267 (a nonnucleoside NS5A inhibitor), 25 mg daily (ombitasvir); and

  • ABT-333 (a NS5B RNA polymerase inhibitor), 250 mg twice daily (dasabuvir).

This 3-drug (3D) regimen is administered with or without weight-based RBV. The multitargeted antiviral combination with 3 different mechanisms of action interrupts the HCV replication process, with the goal of optimizing SVR rates across different patient populations.

At DDW 2014, several investigators presented the results of clinical trials of this regimen. Kowdley and colleagues[17] conducted a double-blind, placebo-controlled study in noncirrhotic, treatment-naive patients with chronic HCV genotype 1 infection. Patients were randomly assigned to receive the coformulated 3D regimen or matching placebo for 12 weeks.

The intention-to-treat SVR12 rate for active drug recipients was 96%; on-treatment failure and post-treatment relapse occurred in 0.2% and 1.5% of patients, respectively. The most common treatment-emergent adverse events were fatigue and headache (approximately 30% each); discontinuation as a result of these events occurred in 0.6% of patients in each arm.

The interferon-free, 12-week 3D regimen was also effective in noncirrhotic, treatment-experienced, genotype 1-infected patients, a group typically associated with the lowest response rates.[18] The 3D plus RBV regimen led to an SVR12 of 96%.

Andreone and colleagues[19] also reported that a 12-week regimen of ABT 450/r/ABT-267 and ABT-333 with or without RBV achieved high rates of SVR12 (97% with 3D plus RBV, and 100% with 3D alone) in treatment-experienced patients. The regimen was generally well tolerated, as evidenced by the low rate of treatment discontinuation and serious adverse events.

In a phase 3 study of an all-oral, interferon-free regimen exclusively in HCV genotype 1-infected patients with compensated cirrhosis, treatment with 3D and RBV resulted in high rates (92%-96%) of SVR12 in both the 12- and 24-week treatment arms.[20]

This highly effective, well-tolerated, 3D HCV regimen is under FDA review.

Other Regimens

Another all-oral, ribavirin-free, interferon-free combination of 3 direct-acting agents -- daclatasvir (an NS5A inhibitor), asunaprevir (an NS3 inhibitor), and BMS-791325 (a nonnucleoside NS5B inhibitor) -- was shown to induce SVR12 in 92% of treatment-naive patients with chronic HCV genotype 1 infection.

Hassanein and colleagues[21] report that 12 weeks of the all-oral treatment combination achieved SVR12 in all noncirrhotic patients with genotype 4 infection, with no virologic failures. These results extend the potent antiviral activity of this regimen to patients with HCV genotype 4 infection, while maintaining the positive tolerability and safety profile documented previously in patients infected with genotype 1. The investigators state that the rapid attainment of SVR suggests that perhaps an even shorter duration of therapy or elimination of 1 of the agents in the combination may be as efficacious.

This regimen is not FDA approved.

Enhancing the Outcome

It was reported that statin use is associated with SVR in patients with HCV treated with pegIFN and RBV, independent of host metabolic factors.

Sanchez and colleagues[22] used the Veterans' Affairs Clinical Case Registry to conduct a retrospective cohort study of veterans infected with HCV genotypes 1, 2, and 3 who received treatment between 2002 and 2008. They found that continuous statin use was associated with increased SVR that persisted after adjustment for age, race, sex, body mass index, genotype, diabetes, hypertension, fibrosis, and high-density lipoprotein and low-density lipoprotein cholesterol levels. Although the mechanism responsible for this observation was not defined, it is known that statins have antiproliferative, antiangiogenic, and anti-inflammatory effects on hepatic cells.

Further studies are warranted to explore whether statin use will significantly reduce progression of liver fibrosis in patients with advanced chronic HCV infection treated with the new antiviral regimens.

A Final Note

Coffee drinking has been associated with a reduced risk for progression to cirrhosis and hepatocellular carcinoma. The mechanism is unclear, but caffeine has been proposed to have antifibrotic and antineoplastic effects.

Among HCV-infected veterans, overall coffee intake (but not decaffeinated coffee intake) was inversely associated with advanced fibrosis.[23] Coffee intake was higher in those with mild fibrosis compared with advanced fibrosis, although none of the comparisons were significant because of the sample sizes. In multivariate analysis adjusting for age, diabetes, alcohol use, obesity, and soda consumption, the inverse association between the number of daily cups of coffee and advanced fibrosis persisted.

So, have a cup of coffee -- it will help us to stay alert as we wade though the continually emerging and voluminous, yet exciting, data on the cure of HCV infection. We eagerly await the next inning.

References

1. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org/ Accessed May 25, 2014.

2. Vutien P, Kim Y, Brooks L, Livornese R, Nguyen MH. Low treatment rates and suboptimal treatment completion rates to hepatitis C virus (HCV) therapy: a real-world analysis of a large US cohort. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 648.

3. Hasan SS, Sears DM, Lorden AL. A real world analysis of the cost of current HCV treatment. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 377

4. Chung RT, Baumert TF. Curing chronic hepatitis C -- the arc of a medical triumph. N Engl J Med. 2014;370:1576-1578.

5. Jayasekera CR, Barry M, Roberts LR, Nguyen MH. Treating hepatitis C in lower-income countries. N Engl J Med. 2014;370:1869-1871.

6. Hoofnagle JH, Sherker AH. Therapy for hepatitis C -- the costs of success. N Engl J Med. 2014;370:1552-1553.

7. Kim WR, Wi CI, Larson JJ, Yawn BP, Yao JD, Therneau TM. The tip of an iceberg -- who is known to have hepatitis C? Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract Su1028.

8. Jacobson IM, Marcellin P, Mangia A, et al. All oral fixed-dose combination sofosbuvir/ledipasvir with or without ribavirin for 12 or 24 weeks in treatment-naive genotype 1 HCV-infected patients: the phase 3 ION-1 study. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract Tu2038.

9. Kowdley KV, Gordon SC, Reddy KR, et al. Sofosbuvir/ledipasvir with and without ribavirin for 8 weeks compared to sofosbuvir/ledipasvir for 12 weeks in treatment-naive non-cirrhotic genotype 1 HCV-infected patients: the phase 3 ION-3 study. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 764.

10. Jacobson IM, Christensen C, Conway B, et al. Sofosbuvir-based regimens are associated with high SVR rates across genotypes among patients with multiple negative predictive factors. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 647.

11. Gane E, Hyland RH, Pang P, Symonds WT, McHutchison JG, Stedman CA. Sofosbuvir/ledipasvir fixed dose combination is safe and effective in HCV infected populations including decompensated patients and patients with prior sofosbuvir treatment experience. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 238.

12. Kwo PY, Reddy KR, Pockros PJ, et al. All oral fixed-dose combination sofosbuvir/ledipasvir with or without ribavirin for 12 or 24 weeks in treatment-experienced genotype 1 HCV-infected patients: the phase 3 ION-2 study. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 236.

13. Jacobson IM, Sulkowski M, Hassanein T, et al. Successful retreatment of HCV genotype-1 infected patients who failed prior therapy with peginterferon + ribavirin plus 1 or 2 other direct-acting antiviral agents with sofosbuvir. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 237.

14. Nyberg LM, Lalezari J, Ni L, et al. Successful retreatment with sofosbuvir-containing regimens for HCV genotype 2 or 3 infected patients who failed prior sofosbuvir plus ribavirin therapy. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 239.

15. Gordon SC, Towner W, Aggarval A, et al. Integrated safety analysis of sofosbuvir-based HCV treatment regimens from phase 3 studies. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 650.

16. Saab S, Gordon SC, Park H, Ahmed A, Younossi ZM. A decision analytic Markov model to evaluate the health outcomes of sofosbuvir for previously untreated patients and those without treatment options with chronic hepatitis C virus. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 474.

17. Kowdley KV, Feld JJ, Coakley E, et al. SAPPHIRE I: phase 3 placebo-controlled study of interferon-free, 12-week regimen of ABT-450/r/ABT-267, ABT-333, and ribavirin in 631 treatment-naive adults with hepatitis C virus genotype 1. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 475.

18. acobson IM, Zeuzem S, Baykal T, et al. SAPPHIRE II: phase 3 placebo- controlled study of interferon-free, 12-week regimen of ABT-450/r/ABT-267, ABT-333, and ribavirin in 394 treatment-experienced adults with hepatitis C virus genotype 1. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 235.

19. Andreone P, Colombo M, Enejosa JV, et al. PEARL II: randomized phase 3 trial of interferon-free, 12-week regimen of ABT-450/r/ABT-267, ABT-333 with or without ribavirin in hepatitis C virus genotype 1b-infected, treatment-experienced patients. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 929e.

20. Kowdley K, Poordad F, Trinh R, et al. TURQUOISE-II: SVR12 rates of 92%-96% in 380 hepatitis C virus genotype 1-infected adults with compensated cirrhosis treated with ABT-450/r/ABT-267 and ABT-333 plus ribavirin (3D+RBV). Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract Tu2039.

21. Hassanein T, Everson GT, Sims K, et al. All-oral therapy with daclatasvir in combination with asunaprevir and Bms-791325 for treatment-naive patients with chronic HCV genotype 4 infection. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 763.

22. Sanchez MJ, Augustin S, Balakrishnan M, Lo Re V, Tate JP, Garcia-Tsao G. Statin use is associated with sustained virological response in patients with hepatitis C treated with pegylated interferon and ribavirin, independent of host metabolic factors. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract Su1050.

23. El-Serag H, Kuzniarek J, Ransey DJ, Tabasi ST, White DL, Kanwal F. Beverage intake and the risk of advanced fibrosis in HCV: coffee, tea, or soda? Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 775.

Source

Could Hepatitis B Vaccination Prevent Diabetes?

Medscape Medical News > Conference News

Lisa Nainggolan

June 15, 2014

SAN FRANCISCO — Provocative new data support an intriguing hypothesis: that vaccinating people against hepatitis B may prevent diabetes from developing, at least in some individuals.

Using participants from the NHANES study 2005–2010, researchers from California examined more than 7000 subjects without a prior history of diabetes; around 1400 of them had previously been vaccinated with hepatitis B, and these individuals had a 52% reduction in the risk for subsequent diabetes compared with individuals not vaccinated, even after adjustment for all potential confounders.

Horng-Yih Ou, MD, from City of Hope National Medical Center, Duarte, California, reported the findings during a guided poster session at the American Diabetes Association (ADA) 2014 Scientific Sessions yesterday.

"The study showed people vaccinated with hepatitis B have a much lower risk for diabetes," senior author Ken C. Chiu, MD, from the department of diabetes, endocrinology, and metabolism at the Beckman Research Institute, Duarte, California, told Medscape Medical News in an interview.

"If we can vaccinate patients effectively, there's a good chance for us to reduce the chance of diabetes by at least 50%," he added.

Dr. Chiu acknowledged that this is a controversial theory but said it's easily tested and that an intervention trial is now needed to further investigate this; his group is trying to get one off the ground.

"It would be so simple to do, we are thinking about it, and we are looking for a place that extensively vaccinates people against hepatitis B," he explained. The experiment would involve immunizing half of the participants for hepatitis B and not the remainder and following the individuals long term to compare diabetes rates, he noted.

Diabetes Differed Significantly Between Vaccinated and Nonvaccinated

Dr. Chiu explained that infection has been implicated in the pathogenesis of diabetes, and he notes than an association between the condition and hepatitis C is well recognized. Insulin resistance associated with hepatitis C infection has been inferred to play a role in the process. And the presence of the hepatitis C virus in pancreatic beta-cells has been linked with morphological cell changes and beta-cell dysfunction, he added.

"But no association with hepatitis B has been reported to date," Dr. Ou told delegates.

The group therefore decided to look for any similar association between hepatitis B and diabetes. They examined adult subjects from NHANES who had information available on both fasting blood glucose and hepatitis B status. Those with established diabetes were excluded.

Dr. Chiu noted that because they used fasting blood glucose only to determine diabetes status, they could not differentiate between types 1 and 2 diabetes, but due to the fact they were studying an adult population, the diabetes identified was likely predominantly type 2.

And to rule out people with hepatitis B, they specifically looked at those who were positive for hepatitis B surface antibody but negative for hepatitis B core antibody, "which means they are vaccinated, not infected," he explained.

Of 7142 subjects with no history of diabetes, 1412 were noted to be successfully vaccinated against hepatitis by the above assessment.

Diabetes was defined as fasting plasma glucose higher than 126 mg/dL, and the distribution of the disease "differed significantly between the subjects with and without vaccination," Dr. Ou said during in his poster presentation.

Diabetes occurred in 16 subjects (1.13%) with hepatitis B vaccination and 325 individuals (5.67%) without immunization.

This equated to a massive 81% reduction in diabetes risk, but Dr. Ou noted that those who received the hepatitis B vaccination were more likely to be female, younger, leaner by body mass index (BMI), with lower fasting plasma glucose, and were less likely to drink alcohol than those who were not immunized.

But even after multivariate adjustment for all potential variables, including age, gender, BMI, smoking status, physical activity, and race, the protective effect of hepatitis B vaccination was still large, with an odds ratio of 0.48 (95% confidence interval 0.28–0.82).

"To our knowledge this is the first report that hepatitis B vaccination could reduce the risk of diabetes in multiple racial/ethnic groups," Dr. Ou told attendees, adding that "a prevention trial is warranted."

The authors have reported no relevant financial relationships.

American Diabetes Association 2014 Scientific Sessions; June 14, 2014. Abstract 1488-P

Source

NCKU research team discovers new treatment for liver diseases

Taipei, Taiwan, June 3, 2014

part_123071_9918824_69957

A Tainan-based research team from National Cheng Kung University (NCKU) has discovered the pathogenesis of liver fibrosis and developed antibodies that reduce liver damage, inhibit hepatic fibrosis, and recover liver function.

Professor Ming-Shi Chang, PhD, Chair Professor of Biochemistry and Molecular Biology at NCKU, has led the team to make another breakthrough in their research on interleukin 20 (IL-20), the university revealed at a press conference on June 3.

Their research titled “IL-20 and IL-20R1 Antibodies Protect Against Liver Fibrosis” has been published in the May issue of Hepatology.

Currently, NCKU has been granted a patent in the United States of America, US 860347 B1, “Use of IL-20 Antagonists for Treating Liver Diseases”, which has attracted great interest from the biotechnology industry.
Hepatitis, fatty liver disease, and hepatotoxicity are some of the primary disorders that lead to the development of liver diseases, according to Professor Chang, who added that inflammation of the liver can evolve into liver fibrosis and cirrhosis, and that patients with liver cirrhosis at the final stage often develop liver cancer.

Inflammation is the source of many diseases, said Professor Chang. She also said that IL-20 is involved in several inflammatory diseases.

Professor Chang’s team discovered that IL-20 is an important cause of liver diseases, and they confirmed that the liver tissue of patients with liver fibrosis, liver cirrhosis, and liver cancer have significantly higher levels of IL-20. IL-20 causes liver inflammation and increases the amount of extracellular matrix, thus causing liver fibrosis and cirrhosis.

Therefore, Professor Chang went a step further by developing an antibody that inhibits IL-20, which has been tested and confirmed to effectively inhibit liver cirrhosis in mice and to attenuate the fatty liver disease resulting from the inflammation caused by the accumulation of visceral fat. The antibody also significantly recovers the liver function of mice, as attested by reduction of ALT and AST, which are the indicators of liver function.

IL-20 is a protein secreted by the human immune system, Professor Chang said. An excessive amount of IL-20 can damage body tissue and, therefore, lead to many diseases such as osteoporosis and a variety of liver diseases.

Most liver diseases result from liver damage caused by long-term chronic hepatitis. Patients with liver disease include people infected with the hepatitis B and C viruses, as well as alcoholic hepatitis and toxin-induced hepatitis.

Repeated or prolonged chronic hepatitis can seriously damage liver cells. This damage stimulates fibroblasts in the liver to produce collagen fibers, which are then deposited in the liver and fill up the empty spaces left by dead hepatocytes. Finally, this fibrosis causes liver cirrhosis.

Professor Chang and her research team observed that patients with liver fibrosis, liver cirrhosis, and liver cancer also had high levels of IL-20. After investigating this phenomenon, they discovered that IL-20 activates hepatic stellate cells and stimulates transforming growth factor (TGF)-beta1, tumor necrosis factor (TNF)-alpha, and Type I Collagen in these cells to increase the accumulation of extracellular matrix.

Because IL-20 is a protein secreted by the human body, Professor Chang and her research team developed anti-IL-20 monoclonal antibody, which inhibits the functions of IL-20 and stops IL-20-induced liver damage at the same time.

Professor Chang’s research has provided a solution to the therapeutic management of liver fibrosis and a new direction for treating liver diseases.

From the perspective of clinical medicine, anti-IL-20 monoclonal antibody could be an effective drug for treating liver fibrosis, fatty liver diseases, and liver cancer in the future.

Dr. Chang and her research team have also found that other than anti-IL-20 monoclonal antibody, monoclonal antibody that blocks the IL-20 receptor (IL-20 R1) can also protect the liver.

Liver disease is one of the most widely contracted types of diseases in Taiwan, and is widely known as one of the major types of diseases that cause a huge healthcare burden in developing countries all over the world.

At present, there is no marketed medication that can inhibit inflammation and stop liver fibrosis simultaneously.

The development of a new drug that can reverse liver fibrosis and prevent it from developing into liver cancer will benefit millions of patients with liver disease and create a huge business opportunity in the pharmaceutical sector of the world economy.

Source

Acquisition Expands Portfolio of Promising Investigational Therapies for Hepatitis C

Monday, June 9, 2014 7:30 am EDT

WHITEHOUSE STATION, N.J. & CAMBRIDGE, Mass.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, and Idenix Pharmaceuticals, Inc. (NASDAQ: IDIX), today announced that the companies have entered into a definitive agreement under which Merck will acquire Idenix for $24.50 per share in cash. The transaction, which values the purchase of Idenix at approximately $3.85 billion, has been approved by the boards of directors of both companies.

“Idenix has established a promising portfolio of hepatitis C candidates based on its expertise in nucleoside/nucleotide chemistry and prodrug technologies,” said Dr. Roger Perlmutter, president, Merck Research Laboratories. “Idenix’s investigational hepatitis C candidates complement our promising therapies in development and will help advance our work to develop a highly effective, once-daily, all oral, ribavirin-free, pan-genotypic regimen that has a duration of treatment as short as possible for millions of patients in need around the world.”

Idenix is a biopharmaceutical company engaged in the discovery and development of medicines for the treatment of human viral diseases, whose primary focus is on the development of next-generation oral antiviral therapeutics to treat hepatitis C virus (HCV) infection. The company currently has three HCV drug candidates in clinical development: two nucleotide prodrugs (IDX21437 and IDX21459) and a NS5A inhibitor (samatasvir). These novel candidates are being evaluated for their potential inclusion in the development of all oral, pan-genotypic fixed-dose combination regimens.

“Merck has established a strong legacy of leadership and innovation in treating hepatitis C,” said Ron Renaud, Idenix’s President and Chief Executive Officer. “This agreement creates shareholder value by positioning Idenix’s strong portfolio of candidates for future success with a leading healthcare company with the experience and commitment to develop fixed-dosed combinations with the potential to impact the global burden of hepatitis C.”

Merck’s research and development portfolio includes several HCV medicines in development, the leading of which is a combination of MK-5172, an investigational HCV NS3/4A protease inhibitor and MK-8742, an investigational HCV NS5A replication complex inhibitor. The combination of these two investigational candidates has received Breakthrough Therapy designation from the U.S. Food and Drug Administration for the treatment of HCV. In April 2014, Merck announced initiation of Phase 3 clinical trials for MK-5172/MK-8742 to evaluate the combination with and without ribavirin in various genotypes and across a broad range of patient populations with chronic HCV. Study information can be found at www.clinicaltrials.gov.

Under the terms of the agreement, Merck, through a subsidiary, will initiate a tender offer to acquire all outstanding shares of Idenix Pharmaceuticals, Inc. The closing of the tender offer will be subject to certain conditions, including the tender of shares representing at least a majority of the total number of Idenix’s outstanding shares (assuming the exercise of all options), the expiration of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act and other customary conditions. Upon the completion of the tender offer, Merck will acquire all remaining shares through a second-step merger. The companies expect the transaction to close in the third quarter of 2014.

Credit Suisse acted as financial advisor to Merck in this transaction and Hughes Hubbard & Reed LLP as its legal advisor. Centerview Partners acted as financial advisor to Idenix and Sullivan & Cromwell as its legal advisor.

Important Information about the Tender Offer

The tender offer for the outstanding shares of Idenix has not yet commenced. This press release is for informational purposes only and is neither an offer to purchase nor a solicitation of an offer to sell shares, nor is it a substitute for the tender offer materials that Merck and its subsidiary will file with the Securities and Exchange Commission (SEC). At the time the planned tender offer is commenced, a tender offer statement on Schedule TO will be filed by Merck with the SEC and Idenix will file a solicitation/recommendation statement on Schedule 14D-9, with respect to the tender offer. The tender offer materials (including an offer to purchase, a related letter of transmittal and other tender offer documents) and the solicitation/recommendation statement will contain important information that holders of Idenix common stock shares are urged to read carefully when they become available, as each may be amended or supplemented from time to time, and because they will contain important information that holders of shares of Idenix common stock should consider before making any decision regarding tendering their shares. The tender offer materials will be made available to Idenix’s stockholders at no expense to them. In addition, all of those materials (and other tender offer documents filed with the SEC) will be made available at no charge on the SEC’s website at www.sec.gov. Additional copies of the tender offer materials may be obtained at no charge by contacting Merck at One Merck Drive, Whitehouse Station, NJ, 08889 or by phoning (908) 423-1000. In addition, Merck and Idenix file annual, quarterly and current reports and other information with the SEC. You many read and copy any reports or other information filed by Merck or Idenix at the SEC public reference room at 100 F Street, N.E., Washington, D.C., 20549. For further information on the SEC public reference room, please call 1-800-SEC-0330. Merck’s and Idenix’s filings with the SEC are also available to the public from commercial document-retrieval services and at the SEC’s website at www.sec.gov.

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

About Idenix

Idenix Pharmaceuticals, Inc. is a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases. Idenix is headquartered in Cambridge, Massachusetts (USA). Its clinical development operations and drug discovery operations are conducted in Cambridge and in the Company's European laboratories in Montpellier, France. Idenix's current focus is on the treatment of patients with hepatitis C infection.

Merck Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Forward looking statements include statements regarding the timing and closing of the tender offer and the merger transactions, the ability of Merck to complete the transactions considering the various closing conditions, and any assumptions underlying any of the foregoing. These statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck’s patents and other protections for innovative products; the exposure to litigation, including patent litigation, and/or regulatory actions; timing of the tender offer and merger; uncertainties as to how many Idenix stockholders will tender shares in the tender offer; the possibility that competing offer may be made; the possibility that various closing conditions to transactions may not be satisfied or waived, including that a governmental entity may prohibit, delay or refuse to grant approval for the consummation of the transactions; or that a material adverse effect occurs with respect to Idenix.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2013 Annual Report on Form 10-K and the company’s other filings with the SEC available at the SEC’s Internet site (www.sec.gov).

Idenix Forward Looking Statement

This press release contains "forward-looking statements" for purposes of the safe harbor provisions of The Private Securities Litigation Reform Act of 1995, including but not limited to the statements regarding the Company's future business and financial performance. For this purpose, any statements contained herein that are not statements of historical fact may be deemed forward-looking statements. Without limiting the foregoing, the words "expect," "plans," "anticipates," "intends," "will," and similar expressions are also intended to identify forward-looking statements, as are expressed or implied statements with respect to the Company's potential pipeline candidates, including any expressed or implied statements regarding the efficacy and safety of samatasvir, IDX21437 or IDX21459 or any other drug candidate; the successful development of novel combinations of direct-acting antivirals for the treatment of HCV; the likelihood and success of any future clinical trials involving samatasvir, IDX21437 or IDX21459 or any other drug candidates; and expectations with respect to funding of operations and future cash balances. Actual results may differ materially from those indicated by such forward-looking statements as a result of risks and uncertainties, including but not limited to the following: there can be no guarantees that the Company will advance any clinical product candidate or other component of its potential pipeline to the clinic, to the regulatory process or to commercialization; management's expectations could be affected by unexpected regulatory actions or delays; uncertainties relating to, or unsuccessful results of, clinical trials, including additional data relating to the ongoing clinical trials evaluating its product candidates; the Company's ability to obtain additional funding required to conduct its research, development and commercialization activities; changes in the Company's business plan or objectives; the ability of the Company to attract and retain qualified personnel; competition in general; and the Company's ability to obtain, maintain and enforce patent and other intellectual property protection for its product candidates and its discoveries. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. These and other risks which may impact management's expectations are described in greater detail under the heading "Risk Factors" in the Company's annual report on Form 10-K for the year ended December 31, 2013 as filed with the SEC and in any subsequent periodic or current report that the Company files with the SEC.

All forward-looking statements reflect the Company's estimates only as of the date of this release (unless another date is indicated) and should not be relied upon as reflecting the Company's views, expectations or beliefs at any date subsequent to the date of this release. While Idenix may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so, even if the Company's estimates change.

Photos/Multimedia Gallery Available: http://www.businesswire.com/multimedia/home/20140609005610/en/

Contact:

Merck
Media:
Pamela Eisele, 267-305-3558
Steve Cragle, 908-423-3461
or
Investors:
Joe Romanelli, 908-423-5185
Justin Holko, 908-423-5088
or
Idenix
Media/Investors:
Teri Dahlman, 617-995-9807

Source