March 9, 2012

Use of Protease Inhibitors in Liver Transplant Recipients

Gastroenterology & Hepatology Volume 8, Issue 3 March 2012

Gary L. Davis, MD, and Jacqueline G. O’Leary, MD
Liver Consultants of Texas
Baylor University Medical Center and
Simmons Transplant Institute
Dallas, Texas

G&H What is the currently approved therapy for treatment of hepatitis C virus infection in liver transplant recipients? How effective is such therapy?

GLD/JGO Hepatitis C virus (HCV) infection persists in all viremic HCV-infected persons who undergo liver transplantation, and reinfection is a major problem. Although recurrence can occasionally be severe, as in cases of fibrosing cholestatic hepatitis, recurrence typically results in less severe but varying degrees of inflammation of the graft. However, fibrosis progresses much faster in patients who have undergone liver transplantation than in nonimmunosuppressed individuals. Indeed, 20–40% of liver transplant recipients progress to cirrhosis within 5 years of transplantation, and graft failure ensues within 12 months in approximately 40% of these cases. Thus, curative antiviral treatment could have a major positive impact in patients with progressive liver injury. Unfortunately, pegylated interferon and ribavirin are poorly tolerated in this group, cytopenia is problematic, and sustained virologic response (SVR) occurs in fewer than 30% of patients who attempt therapy.

G&H How are liver transplant recipients different from HCV-infected patients who have not undergone transplantation?

GLD/JGO Although patients who have undergone liver transplantation are often highly motivated, treatment of this group is difficult and labor-intensive for several reasons. Liver transplant recipients tend to have higher viral loads, more pronounced cytopenia, and some degree of renal insufficiency. All of these factors contribute to more frequent dose reductions, greater need for use of growth factors such as erythropoietin and filgrastim (Neupogen, Amgen), and lower response rates. In addition, many of these patients have already failed antiviral therapy before they undergo transplantation.

G&H Do these factors alter clinicians’ therapeutic goals for HCV treatment in liver transplant recipients?

GLD/JGO No, the goal of therapy for a liver transplant recipient is the same as for any HCV-infected individual: namely, viral eradication. Viral suppression in the absence of complete viral eradication does not provide a documented benefit in liver transplant recipients. The only possible exception is in patients with fibrosing cholestatic hepatitis; viral suppression in these patients may improve liver function and be life-saving, even if SVR is not achieved.

G&H Why might protease inhibitors be considered to treat HCV infection in liver transplant recipients?

GLD/JGO Direct-acting antiviral agents—including the recently approved HCV protease inhibitors boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex)—can dramatically increase the chance of achieving SVR. This  increase is most apparent in patients who have the lowest response rates when treated with interferon and ribavirin alone, such as patients with high viral loads or previous nonresponders. For example, the addition of a protease inhibitor to standard therapy leads to a doubling of SVR rates in white patients, but it triples SVR rates in black patients (who have lower response rates when treated with interferon and ribavirin alone). Therefore, patients who are at the greatest disadvantage have the most to gain from the addition of a direct-acting antiviral agent.

G&H What are the risks associated with such therapy?

GLD/JGO First, it is important to mention that HCV protease inhibitors have not been studied in liver transplant recipients; as a result, the US Food and Drug Administration has not approved the use of protease inhibitors in such patients. Furthermore, in addition to the aforementioned obstacles associated with interferon and ribavirin therapy, there are a number of specific obstacles to using protease inhibitors in the liver transplant patient population. Most importantly, protease inhibitors are potent CYP3A4 and p-glycoprotein inhibitors, and they dramatically increase exposure to drugs that are metabolized by these pathways. For example, exposure to calcineurin and mammalian target of rapamycin (mTOR) inhibitors, the foundation of immunosuppression in transplant recipients, is dramatically increased when recipients receive protease inhibitors, making drug toxicity a real possibility.

G&H Are there any ways to reduce these risks?

GLD/JGO Clearly, if clinicians choose to treat liver transplant recipients, the levels of patients’ calcineurin and mTOR inhibitors must be followed extremely closely, and the doses of these immunosuppressant drugs would need to be adjusted downward accordingly. In addition, the patient’s medication list would need to be closely reviewed to ensure that no other drug-drug interactions occurred.

G&H Have there been any published cases of liver transplant recipients who received protease inhibitor therapy? What were the outcomes in these cases?

GLD/JGO A small case series by Mantry and colleagues was recently presented at the HEPDART 2011 meeting in Koloa, Hawaii. This series documented early experiences in post–liver transplantation patients who were treated with triple drug therapy. Of 7 patients, 4 patients experienced  rapid virologic response (RVR), 2 patients did not achieve RVR but remained on treatment, and 1 patient experienced early virologic failure and stopped therapy. One patient died of sepsis with a negative viral load.

G&H What is the current consensus regarding the use of protease inhibitors in liver transplant recipients?

GLD/JGO Clearly, given the increased risk of progressive liver disease in liver transplant recipients, there is a great need for effective therapy, which may well include protease inhibitors. However, such treatment will be clinically challenging, with real dilemmas (dosing and drug-drug interactions) and risks of adverse events. Given clinicians’ limited experience with protease inhibitor therapy in this population to date, it would be premature to make any specific recommendations regarding therapy.

G&H Would other new HCV drugs be subject to the same risks associated with protease inhibitors, or might future drugs be more suitable for use in liver transplant recipients?

GLD/JGO Certainly, side effects and drug-drug interactions will differ among the new compounds. Ideally, we would like medications with minimal side effects, more convenient dosing regimens, and fewer drug-drug interactions. However, such drugs are not available at this time.

G&H What further studies are needed regarding treatment of HCV infection in liver transplant recipients?

GLD/JGO Any new agents that are approved for treatment of HCV infection will need to be studied in liver transplant recipients. In the future, more potent drugs may allow eradication of virus in a very short period of time; such therapy might pave the way to clearing virus before or at the time of transplantation and avoid the problem of recurrence altogether.

Suggested Reading

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

Charlton M. Telaprevir, boceprevir, cytochrome P450 and immunosuppressive agents—a potentially lethal cocktail. Hepatology. 2011;54:3-5.

Roche B, Samuel D. Hepatitis C virus treatment pre- and post-liver transplantation. Liver Int. 2012;32(suppl 1):120-128.

Limaye AR, Firpi RJ. Management of recurrent hepatitis C infection after liver transplantation. Clin Liver Dis. 2011;15:845-858.


CROI 2012: Pipeline Asset Update for Daclatasvir (DCV; BMS-790052)


Pipeline Asset:
Discovered by Bristol-Myers Squibb through a genomics approach, daclatasvir, also known as BMS-790052 or DCV, is the first NS5A replication complex inhibitor to be investigated in hepatitis C clinical trials.

Current Phase of Development:
Phase III

Meeting or Publication:
Conference on Retroviruses and Opportunistic Infections (CROI)

Study Title:
Assessment Of HIV Antiretroviral Drug Interactions with the HCV NS5A Replication Complex Inhibitor BMS-790052 Demonstrates a Pharmacokinetic Profile Which Supports Coadministration with Tenofovir, Efavirenz and Atazanavir/Ritonavir

Presentation Number:
Poster Number 618

Date/Time of Presentation:
Thursday, March 8, 2012 from 2:00 – 4:00 PST

Study Objective:
To evaluate the potential for drug-drug interactions (DDI) between daclatasvir (DCV) and HIV antiretrovirals (ARVs) in healthy subjects prior to beginning clinical trials in HIV-HCV co-infected patients, establishing dosing modifications, if needed.

Study Conclusion:

Daclatasvir (DCV) plus tenofovir (TDF) had no clinically relevant drug-drug interactions.

A dose adjustment for daclatasvir is necessary when administered with atazanavir boosted with ritonavir (ATV/r) and when administered with efavirenz (EFV). A daclatasvir dose adjustment of 30 mg QD with atazanavir plus ritonavir (300/100 mg QD) and 90 mg QD with efavirenz (600 mg QD) is expected to generate daclatasvir exposure similar to that for 60 mg of daclatasvir administered alone.

Safety profiles were unremarkable in all three ARVs. No unexpected safety signals were observed. See full safety analysis in adverse events section below.

Table 1: Daclatasvir and tenofovir gave similar Cmax and AUCtau for each drug relative to administration alone (See Table 1)


Table 2: Daclatasvir and atazanavir/ritonavir

  • Dose-normalized increases in daclatasvir maximum plasma concentrations (Cmax) and area under the concentration-time curve in one dosing interval (AUCtau) were observed when dosed with ATV/r (See Table 2):
    • Geometric mean ratios (GMR) for Cmax and AUCtau of daclatasavir 20 mg when coadministered with atazanavir/ritonavir vs. daclatasvir 60 mg alone were below the predicted estimations. Non-normalized GMR for Cmax and AUCtau for the adjusted doses were less than 1.0 with atazanavir/ritonavir
    • Dose normalized (60 mg DCV) Cmax and AUCtau were 35% and 110% higher, respectively, when daclatasvir was co-administered with atazanavir/ritonavir
    • Based on linear pharmacokinetics, extrapolated doses of daclatasvir 30 mg once daily with atazanavir/ritonavir are estimated to give AUCtau similar to the daclastasvir 60 mg dose administered alone
    • Exposure of atazanavir was similar to historical data


Table 3: Daclatasvir and efavirenz

  • Dose-normalized decreases in daclatasvir maximum plasma concentrations (Cmax) and area under the concentration-time curve in one dosing interval (AUCtau) were observed when dosed with efavirenz (See Table 3):
    • Geometric mean ratios (GMR) for Cmax and AUCtau of daclatasavir 120 mg when coadministered with efavirenz vs. daclatasvir 60 mg alone were above the predicted estimations. Non-normalized GMR for Cmax and AUCtau for the adjusted doses were significantly greater than 1.0 with efavirenz
    • Dose normalized (60 mg DCV) Cmax and AUCtau were 17% and 32%, lower, respectively, when daclatasavir was co-administered with efavirenz.
    • Based on linear pharmacokinetics extrapolated doses of daclatasvir 90 mg once daily with efavirenz are estimated to give AUCtau similar to the daclastasvir 60 mg dose administered alone
    • Exposure of efavirenz was similar to historical data


Adverse Events:

Most Common Adverse Events (>25% in Any Study) by System Organ Class and Treatment:


aCombined data from studies AI444032, AI444033 and AI444034 (exposure 4–7 days); bAll subjects initially received EFV with DCV 60 mg (9 days) then 120 mg (5 days); cInter-study incidence range 33% to 45%; dInter-study incidence range 25% to 40%


  • No serious adverse events occurred in any study
  • 2/17 subjects enrolled to AI444034 discontinued for adverse events (treatment-unrelated myalgia, day 15; treatment-related dizziness, nausea and panic attack, day 7) and were not included in the evaluable population for DDI assessment
  • 1/21 subjects enrolled to AI444033 discontinued for adverse events (vomiting and syncope on daclatasvir alone considered treatment related) and was not included in the evaluable population for DDI assessment
  • Events in the most common classes on daclatasvir alone (GI and nervous system) occurred at similar rates in subjects receiving tenofovir alone

Daclatasvir (DCV) Background:

Daclatasvir (DCV) or BMS-790052 is an investigational, potentially first-in-class, highly selective hepatitis C virus replication complex inhibitor with broad genotypic coverage and picomolar potency in vitro.

Daclatasvir is one of several molecules Bristol-Myers Squibb is studying for the potential treatment of hepatitis C. The portfolio of investigational compounds, which also includes an NS3 inhibitor, an NS5B nucleotide polymerase inhibitor, and PEGInterferon Lambda, fits into the company’s overall R&D focus on diseases where there is unmet medical need.

Future studies are warranted to evaluate daclatasvir in HCV/HIV coinfected patients. Further DDI studies for daclatasvir plus boosted darunavir and daclatasvir plus lopinavir are planned.

Study Background:

These three open-label studies in healthy subjects evaluated steady-state pharmacokinetic interactions between daclatasvir and representative antiretroviral agents: nucleoside/tide reverse transcriptase inhibitors (or NRTI; tenofovir disoproxil fumarate), non-nucleoside reverse transcriptase inhibitors (or NNRTIs; efavirenz), and boosted protease inhibitors (or boosted PIs; atazanavir/ritonavir).

Three open-label studies in healthy subjects were evaluated for this assessment:

  • DCV + ATV/r: 14 healthy subjects received daclatasvir 60 mg, once daily on days 1 – 4; and then received daclatasvir 20 mg, once daily plus atazanavir/ritonavir 300 mg/100 mg, once daily, on days 5 – 14
  • DCV + EFV: 15 healthy subjects received daclatasvir 60 mg, once daily on days 1 – 4; then received daclatasvir 60 mg, once daily plus efavirenz 600 mg once daily on days 5 – 13; then received daclatasvir 120 mg plus efavirenz 600 mg once daily on days 14 - 18
  • DCF + TDF: 20 healthy subjects received daclatasvir 60 mg, once daily, or tenofovir 300 mg once daily or both for seven (7) days in a 3x3 crossover design


Key Inclusion Criteria:

  • Men and women, 18 to 49 years of age, inclusive
  • Healthy subjects as determined by no clinically significant deviation from normal in medical history, physical examination, vital signs, ECGs, and clinical laboratory determinations
  • Body Mass Index (BMI) of 18.0 to 32.0 kg/m2, inclusive

Key Exclusion Criteria:
  • Any significant acute or chronic medical illness
  • Current or recent (within 3 months of study drug administration) gastrointestinal disease indicated as clinically relevant by the Medical Investigator
  • Smoking more than 5 cigarettes per day
  • Recent (within 6 months of study drug administration) drug or alcohol abuse as defined in DSM IV, Diagnostic Criteria for Drug and Alcohol Abuse
  • History of cardiac conduction abnormalities
  • Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG or clinical laboratory determinations beyond what is consistent with the target population
  • Positive blood screen for hepatitis C antibody, hepatitis B surface antigen, HIV viral load, or HIV-1, -2 antibody
  • Pregnancy or lactation

Request for More Information and Media Interviews:
Investors: John Elicker, 609-252-4611,
Media: Cristi Barnett, 609-252-6028,

Supporting information:
The abstract and the presentation can be viewed on the CROI website.


Hepatitis C drug is 'a step change'

A new drug to combat hepatitis C, hailed as the biggest step forward in the fight against the disease for a decade, is likely to be approved for use on the NHS.

By Stephen Adams, Medical Correspondent

6:45AM GMT 09 Mar 2012

Boceprevir, which can clear the most common form of the hepatitis C virus from up to 70 per cent of patients, has been recommended for prescription by the National Institute for Health and Clinical Excellence (Nice).

Tens of thousands of patients could benefit if Nice confirms the final draft guidance that it has issued today, as is expected.

Around 200,000 people in Britain are thought to carry the hepatitis C virus, of which up to half have the most common subtype, called Genotype 1. However, only about half know they are hep C positive.

At the moment those diagnosed are offered two drugs together, peginterferon alfa and ribavirin.

Dr Stephen Ryder, a Nottingham-based consultant hepatologist, said these managed to cure about 40 per cent of new patients. Adding boceprevir to the drug treatment boosted that to about 70 per cent, he said.

"This is a big deal," he said. "It's the biggest step since standard treatment was introduced, about a decade ago."

He hoped it would prompt those at high risk of being carriers to come forward to be tested.

He said many did not because the chances of being cured were relatively low.

"It's a big psychological thing to say, 'This is more likely to work than not," he added.

Adding boceprevir, marketed as Victrelis by developer MSD, to the drug regime increases treatment cost from about £10,000 to £25,000, he said. However, Nice has decided this "represents a cost-effective use of NHS resources".

Charles Gore, chief executive of the Hepatitis C Trust, described the drug as "a step change" in treatment.

"It's the first step into a new era. While peginterferon alfa and ribavirin boost the immune system, this targets the virus itself and stops it replicating."

Hepatitis C, which causes liver damage including cirrhosis and can trigger cancer, is normally contracted from a contaminated blood transfusion or intravenous drug use.

Some people go decades without developing symptoms, while others show them quickly. Many are plagued by poor health without knowing the underlying cause, leading it to be dubbed the "silent epidemic".