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HCV Advocate Newsletter

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May 2011 HCV Advocate

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In This Issue:

EASL 2011: Cure without Interferon/Ribavirin
Alan Franciscus, Editor-in-Chief


Hepatitis C and Bleeding Disorders
CD Mazoff, PhD

HCV Snapshots from EASL 2011
Lucinda K. Porter, RN and Alan Franciscus, Editor-in-Chief

HealthWise: Special Report of the 2011 EASL Meeting
Lucinda K. Porter, RN



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EASL 2011: Cure without Interferon/Ribavirin
—Alan Franciscus, Editor-in-Chief

The HCV Advocate’s coverage of this year’s European Association for the Study of the Liver (EASL) Conference will be three pronged—I will be writing about the first HCV treatment without interferon/ribavirin that produced a cure.  HCV SnapShots and HealthWise will also cover some of the most important and interesting studies released at this year’s EASL conference.  

Without a doubt the most important study that was released at EASL was a presentation by Dr. Anna Lok on the results the BMS combination study of BMS-790052 (NS5a inhibitor) and BMS-650032 (protease inhibitor) with and without pegylated interferon plus ribavirin (PegIFN/RBV).  All patients in the study were HCV genotype 1 prior null-responders to a previous course of treatment with pegylated interferon plus ribavirin (less than a 2 log10 drop in HCV RNA at 12 weeks)—the most difficult patients to re-treat.

There were two arms of the study:

  • Arm A:  BMS 79005 & 650032 (without PegIFN/RBV)—11 patients treated for 24 weeks with a 48-week follow-up period.
    • 4 out of 11 patients achieved an SVR12. Note: patients who had a viral breakthrough (presence of HCV RNA after initially becoming negative) were offered up to 48 weeks of therapy with PegIFN/RBV.

  • Arm B:  BMS-79005 & 650032 combined with PegIFN/RBV for 24 weeks with a 48-week follow-up period.
    • 10 out of 10 patients achieved an SVR12; one patient tested HCV RNA positive during the 24-week follow-up period—9 out of 10 patients achieved an SVR 24.

Side effects were mild to moderate—fatigue, diarrhea, headache, and nausea were the most common side effects reported.  There were no serious side effects or treatment discontinuations due to side effects.    

This is the first study to prove that HCV can be cured with an all DAA combination without the use of pegylated interferon and ribavirin.  It is also encouraging because the patients in the study are typically the most difficult to treat.  Although this is a small study it does prove that it can be done—a critical first step.  Larger studies are needed to replicate these results and also to find out more information about why some responded and others didn’t. 

Another important part of this study is about the patients who had viral breakthrough and were subsequently treated for 48 weeks with PegIFN/RBV.  If treatment using PegIFN/RBV prevented drug resistance this may tell us if it is safe to use the DAA combo as a first line of treatment and then, if a cure is not achieved, to use PegIFN/RBV as an additional therapy or at the very least as an interim step while waiting for more potent combinations with 3 or 4 DAAs.
This “response-guided” approach may bring us closer to a complete viral cure without the use of pegylated interferon and ribavirin.


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Hepatitis C and Bleeding Disorders
—CD Mazoff, PhD

Before effective screening of the blood supply and viral inactivation techniques were introduced in the mid 1980’s, the population most at risk for getting hepatitis C and other blood-borne viruses, such as HIV and hepatitis B, was largely made up of those with various types of bleeding disorders.  

This is because the standard treatment at the time was either to use whole blood transfusions, or infusions of cryoprecipitates derived from frozen blood plasma.  Cryoprecipitates are able to distill certain clotting factors in the blood into concentrated amounts: things like fibrin, which is a glue-like protein that helps platelets to stick together.

Now, only rarely are plasma derived products used to treat bleeding disorders in the U.S., Canada and other non-third world nations, and they are heat-treated.  The majority are now produced in labs and are called recombinant factors since they are composed of recombined genes and proteins.

“Bleeding disorders” is a general term for a wide range of medical problems that lead to poor blood clotting and continuous bleeding.  Medical terms referring to bleeding disorders include coagulopathy, abnormal bleeding and clotting disorders. There are many types of bleeding/clotting disorders that affect the blood’s ability to heal wounds and stop bleeding.  

A person with a bleeding disorder has a tendency to bleed longer. The disorders can result from defects in the blood vessels or from abnormalities in the blood itself. The abnormalities may be in blood clotting factors or in platelets. Unfortunately, the liver is intimately involved in the production of clotting factors and platelets; so having hepatitis C on top of a blood disorder is not a good thing.

Because bleeding disorders can cause excessive bleeding in joints (think of bruise that gets bigger and bigger and doesn’t go away), many people with bleeding disorders suffer from pain and some become permanently disabled, as the joints become destroyed.

Clotting Illustration

Source: National Hemophilia Foundation1

Blood clotting, or coagulation, is the process that controls bleeding. It changes blood from a liquid to a solid. It’s a complex process involving as many as 20 different plasma proteins, or blood clotting factors. Normally, a complex chemical process occurs using these clotting factors to form a substance called fibrin that stops bleeding. When certain coagulation factors are deficient or missing, the process doesn’t occur normally.

Causes of Blood Disorders
There are many causes of blood disorders:

  • von Willebrand’s disease, which is an inherited blood disorder, thought to affect between 1% and 2% of the population
  • Immune system-related diseases, such as allergic reactions to medications, or reactions to an infection
  • Cancer, such as leukemia, which is a blood cancer
  • Liver disease
  • Bone marrow problems
  • Disseminated intravascular coagulation, which is a condition often associated with child bearing, cancer, or infection, in which the body’s clotting system functions abnormally
  • Pregnancy-associated eclampsia, also known as severe toxicity of pregnancy
  • Antibodies, a type of immune system protein, that destroy blood clotting factors
  • Medicines, such as aspirin, heparin, warfarin, are drugs used to break up blood clots.1

Congenital bleeding disorders are very rare, and with the exception of hemophilia and von Willebrand’s disease, education about them has not been a priority of the medical community. Most have only been discovered and described in the past few decades.

Types of Bleeding Disorders
There are many different types of bleeding/clotting disorders.  Some are hereditary (genetic), and others idiopathic (unknown origin).  Some are the result of autoimmune triggers (for example overstimulation of the immune system by interferon when on treatment for HCV).  For an exhaustive list see “Patient Information Resource: Alphabetic List of Benign and Premalignant Hematologic (Blood) Disorders” from the Arizona Telemedicine Program.2

Bleeding Disorders and HCV Treatment
As we all know, advanced liver disease can cause bleeding disorders as the liver becomes too diseased to manufacture clotting factors and hormones to make platelets.  In this regard, a liver transplant (often required when HCC occurs, or the liver fails completely) may also cure some bleeding disorders as well, since the cause of some of these is a genetic defect in the liver itself.

Interferon is a known cause of thrombocytopenia, or a reduction in platelet production—which affects clotting, and ribavirin can cause hemolytic anemia, which affects red blood cell counts.

Two studies looked at the relationship between treatment for hepatitis C and bleeding disorders.

“Peginterferon alfa-2a and Ribavirin in Patients with Chronic Hepatitis C and Inherited Bleeding Disorders,” by Malekzadeh, et al. (Hepatitis Monthly Volume: 4 Issue: 7 Summer 2004 59- 64 and “Ribavirin and Use of Clotting Factors in Patients with Hemophilia and Chronic Hepatitis C,” by Honda, et al., Jama 2005;293(10):1190-1192. doi: 10.1001/jama.293.10.1190-c.

The first study, by Malekzadeh, investigated the use of biopsy as part of the treatment protocol for those with bleeding disorders.  Because liver biopsy carries a high risk of severe bleeding, the question becomes how do we assess the effect of treatment on liver damage if we cannot do a biopsy? 

Surprisingly, the doctors found that response rates (SVR) and side effect profiles for those with bleeding disorders were on a par with those of patients who did not have bleeding disorders—across all genotypes.  The researchers were surprised because they assumed that patients with bleeding disorders would have been exposed to multiple genotypes as a result of receiving many blood factors over time, and they further assumed  that this would affect treatment response, but it didn’t.

The second study looked at the need to increase the use of clotting factors in HCV-positive patients with hemophilia while they were being treated with ribavirin and IFN.  Patients with mild hemophilia rarely use clotting factors, so the focus was on those patients with moderate to severe disease.

Again, there was a big surprise: the reverse turned out to be true.  As it turned out patients who were treated with interferon and ribavirin actually were able to reduce the amount of clotting factors taken during the treatment period. The researchers concluded that the reduced use of clotting factors was associated with the addition of ribavirin.

FACTOR OTHER NAME INCIDENCE BLEEDING SEVERITY
Factor I fibrinogen 1 in 1,000,000 Usually mild, except with complete absence of fibrinogen
Factor II prothrombin 1 in 1,000,000 Usually mild
Factor V parahemophilia 1 in 1,000,000 Usually mild
Combined F V
and F VIII
  1 in 1,000,000 Usually mild
Factor VII Alexander's 1 in 1,000,000 Severe when Factor VII levels are low
Factor VIII Hemophilia 1 in 10,000 Severe when Factor VIII levels are below 1%
Factor IX Hemophilia B 1 in 50,000 Severe when Factor IX levels are below 1%
Factor X Stuart-Prower 1 in 500,000 Moderate to severe when Factor X levels are below 10%
Factor XI Hemophilia C 1 in 100,000 Mild to moderate when Factor XI levels are below 15%
Factor XIII   1 in 3,000,000 Severe
Source: Canadian Hemophilia Society3

Clotting disorders and HCV Treatment

Thrombophilia
Thrombophilia is the opposite of  hemophilia.  While people with hemophilia have an increased tendency to bleed, people with thrombophilia have an increased tendency to clot.  Just as hemophilia is caused by an abnormality of a blood-clotting factor, some forms of thrombophilia are also caused by an abnormality or deficiency of a blood-clotting factor.1  

Chronic hepatitis C and treatment with interferon have often been associated with a procoagulant state, and may cause a protein C and S deficiency (natural anticoagulants synthesised in the liver). This deficiency has been known to cause mesenteric vein thrombosis, and can be fatal.4 

Thrombotic Thrombocytopenic Purpura (TTP or Moschcowitz Syndrome)
TPP is a rare disorder of the blood-coagulation system, causing extensive microscopic thromboses to form in small blood vessels throughout the body.5 

This disorder is associated with both hepatitis C and treatment with interferon and ribavirin.  There are quite a few studies demonstrating that interferon treatment can trigger TTP, most probably as a result of heightened immune system response.

Conclusions:
Today, with the advent of recombinant factors and heat treatment, the chances of getting hepatitis C have all but disappeared for those suffering from blood disorders.  There are a few bleeding disorders that still require whole plasma infusion, and there is always the HCV window period to worry about, but the risk is considered to be less than 1 chance per 2 million units of transfused blood.  However, persons with bleeding disorders are still at risk from shared needles, unsafe tattoos, and medical procedures in which the protocols have not been followed, i.e., improper sterilization, re-use of single use items.

As for blood clotting disorders, hopefully with the advent of new direct-acting antiviral therapy and interferon-free combinations, the incidence of thrombophilia and TTP will be greatly reduced because these new treatments have a greater chance of curing HCV, thus getting rid of these associated conditions.

References:

1. http://www.hemophilia.org
2. http://www.nhlbi.nih.gov/health/public/blood
/index.htm

3. www.hemophilia.ca
4. (Gastroenterol Hepatol. 2007 May;30(5):271-3. “Mesenteric vein thrombosis and protein C and S deficiency in a patient with chronic hepatitis C on treatment with interferon and ribavirin”. Monterrubio Villar J, Córdoba López A.  http://www.ncbi.nlm.nih.gov/pubmed/
17493436

5. http://en.wikipedia.org/wiki/Thrombotic_
thrombocytopenic_purpura



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HCV Snapshots from EASL 2011
—Lucinda K. Porter, RN and Alan Franciscus, Editor-in-Chief

Abstract: The ESSENTIAL Study – Once Daily Alisporivir (DEB025) plus Peg-IFN-Alfa-2A/ Ribavirin Results in Superior Sustained Virologic Response (SVR24) in Chronic Hepatitis C Genotype 1 Treatment-Naïve Patients - R Flisiak, JM Pawlotsky, R Crabbe, et al.
Source: The European Association for the Study of the Liver (EASL) 46th Annual Meeting March 30 – April 3, 2011 Abstract 190

Alisporivir (DEB025) is a cyclophilin inhibitor, which interferes with HCV replication, and in this study it was taken orally twice daily. This randomized, placebo-controlled Phase II study of 288 treatment-naïve genotype 1 HCV subjects had four arms.

  • Placebo plus PegIFN/RBV for 48 weeks (73 subjects)
  • Alisporivir plus PegIFN/RBV for 48 weeks (72 subjects)
  • Alisporivir plus PegIFN/RBV for 24 weeks (72 subjects)
  • Response-guided therapy using alisporivir plus PegIFN/RBV for 24 or 48 weeks – those with an RVR stopped treatment at week 24 (71 subjects)

The Bottom Line: Of those receiving alisporivir, 76% achieved SVR compared to 55% of those receiving Placebo plus PegIFN/RBV. Those in the 24-week alisporivir plus PegIFN/RBV arm had results similar to those in the 48-week PegIFN/RBV arm (53% vs 55%). Those with the unfavorable gene pattern, IL28B, were twice as likely to respond to alisporivir plus PegIFN/RBV than to the standard of care. The response-guided arm using alisporivir plus PegIFN/RBV had 69%. In general, alisporivir was well-tolerated with a slight, reversible increase in elevated bilirubin, and drug resistance was low.

Editorial Comment: Although this study did not outshine the others I summarized, it is worth mentioning. First, this drug is not a protease or polymerase inhibitor, so it broadens the choices of weapons we have to fight HCV. Second, these are still good numbers. It will be interesting to see what happens as researchers tweak the possibilities of how to use this drug. (LKP)

A Guide to Abbreviations:

EVR = early virologic response; complete early virologic response (cEVR) refers to non detectable HCV viral load by week 12; partial EVR means at least a 2-log drop in virus by week 12

GT = genotype

HCV = hepatitis C virus

HCV RNA = HCV viral load

n = number of participants

PegIFN/RBV = peginterferon and ribavirin (also known as standard of care = SOC)

QD = once daily, as in taking medication

RVR = rapid virologic response; refers to non-detectable HCV viral load by week 4

eRVR = extended rapid virological response; non-detectable HCV viral load by week 4 that remains non-detectable at week 12

SVR = sustained virologic response; refers to non-detectable HCV viral load by week 48 and stays non-detectable for 6 months after treatment is discontinued.

For definitions of terms, see the Medical Glossary at www.hcvadvocate.org

Abstract:  SILEN-C1: early antiviral activity and safety of BI 201335 combined with peginterferon alfa-2a and ribavirin in treatment-naive patients with chronic genotype 1 HCV infection—MS Sulkowski, E Ceasur, T Asselah, et al.
Source: EASL 46th Annual Meeting, Abstract 60

The goal of the study was to evaluate the safety and effectiveness of BI 201335 (240 mg QD), an HCV protease inhibitor, in combination with PegIFN/RBV compared to placebo with PegIFN/RBV in HCV genotype 1 treatment-naïve non-cirrhotic patients.  This trial also included a 3-day lead-in with the PegIFN/RBV only  arms.  Treatment duration was 24 or 48 weeks based on eRVR.

The Bottom Line:  The SVR rates were up to 83% in the group that received 240 mg QD and results were similar between the 24- and 48-week arms.  Serious adverse events and treatment discontinuations were seen more frequently in the 240 mg QD groups compared to the lower dose and placebo group.  There was no benefit seen with the lead-in arms compared to the arms that started BI 201335 plus PegIFN/RBV from the beginning of treatment.

Editorial Comment:  Phase III studies have begun on BI 201335 plus PegIFN/RBV and when completed will give us a better understanding of the effectiveness and importantly of the side effect profile.  With improved effectiveness and shorter duration of treatment this is definitely one drug to watch. (AF)

 

Abstract:  First Report of SVR12 For A NS5a Replication Complex Inhibitor, BMS-790052 in Combination with Peg-IFNa-2a And RBV: Phase 2a Trial in Treatment-Naive HCV-Genotype 1 Subjects—S Pol, RH Ghalib, VK Rustig, et al.
Source:  EASL  46th Annual Meeting,  Abstract 2 (late breaker)

This was a Phase IIa study of 48 chronically-infected HCV genotype 1 treatment-naïve (non-cirrhotic) patients.  Patients were treated with PegIFN/RBV plus placebo or PegIFN/RBV with BMS-790052, an NS5a inhibitor, taken orally (3,10, 60 mg) QD. All groups were treated for 48 weeks with a 24-week follow-up period. 

The Bottom Line:  The findings included:

  • SVR12:  42% , 92% and 88% (3 mg, 10 mg and 60 mg respectively) compared to 25% in the placebo group
  • The side effect profile of BMS-790052 group was consistent with the side effects seen with PegIFN/RBV plus placebo
  • The combination of BMS-790052 plus PegIFN/RBV produced similar SVR12 rates regardless of IL28B genotype (CC,CT, or TT)
  • Similar SVR12 was noted in HCV genotypes 1a and 1b

Editorial Comment:  The 10 mg dose group had the highest SVR12 results (92%—11 out of 12 patients) and a better side effect profile.  More studies are needed to confirm these findings and (in my opinion) to investigate if response guided therapy can shorten treatment duration. (AF)

 

Abstract:  Activity of Danoprevir Plus Low-dose Ritonavir (DNV/R) in Combination with Peginterferon Alfa-2a (40KD) plus Ribavirin (PEGIFN a-2A/RBV) in Previous Null Responders—Rouzier R, Larrey D, Gane EJ, et al.
Source:  EASL  46th Annual Meeting, Abstract 62

Previous studies of higher dose danoprevir produced ALT elevations.  The goal of the current study was to assess the safety and effectiveness of a 12-week course of a lower dose of danoprevir (100 mg) boosted with low-dose ritonavir (100 mg) in combination with PegIFN/RBV followed by 36 weeks of PegIFN/RBV alone.  Twenty-four 24 HCV genotype 1a and 1b prior non-responders (< 2 log10 decrease in HCV RNA at week 12 of treatment) were enrolled. 

The Bottom Line:  The interim 12-week results showed that 88% of the HCV genotype 1b patients were HCV RNA negative with a low rate of viral breakthrough and a good side effect profile.  However, HCV genotype 1a did not fare well due to a high rate of viral breakthrough that necessitated discontinuation of enrollment of all HCV genotype 1a patients in the study.  The authors noted that adding another HCV antiviral will hopefully prevent viral breakthrough in HCV genotype 1a patients.  A study of DNV/R plus RG7128 (mericitabine) in combination with PegIFN/RBV (MATTERHORN) is planned for 2011. 

Editorial Comment:   The good news is that the addition of low dose ritonavir to a lower dose danoprevir (with PegIFN/RBV) increased the response rates in HCV genotype 1b prior null-responders, but this is tempered by the high rate of viral breakthrough seen in HCV genotype 1a patients.  Hopefully, the MATTERHORN study will find that the addition of another antiviral will prevent viral breakthrough.  (AF)

 

Abstract: JUMP-C Trial – First SVR Data with the Nucleoside Analogue Polymerase Inhibitor Mericitabine (RG7128) Combined With Peginterferon/Ribavirin in Treatment-Naive HCV G1/4 Patients: Interim Analysis – P Pockros, D Jensen, N Tsai, et al.
Source: EASL 46th Annual Meeting,  Abstract 1359

Mericitabine (RG7128) is a polymerase inhibitor and, in this Phase II study, was tested with PegIFN/RBV on 166 treatment-naïve HCV patients (mostly genotype 1 with 6 genotype 4 participants). Subjects were randomly assigned to either a) mericitabine (twice daily, orally) with PegIFN/RBV or b) standard PegIFN/RBV. Those in the mericitabine group with an eRVR only had 24 weeks of treatment. Those without eRVR and those in the standard PegIFN/RBV were treated for 48 weeks with PegIFN/RBV alone. This is a 36-week interim analysis. 

The Bottom Line:

  • By week 24, 91% of those who received mericitabine were HCV-negative, compared to 62% of those receiving PegIFN/RBV.
  • Of those in the mericitabine group, 60% had an eRVR and stopped treatment at week 24; 76% remained HCV RNA undetectable 12 weeks later (12 more weeks are left on this study), and 24% relapsed.
  • Mericitabine appears to have a similar safety and side effect profile as PegIFN/RBV with no reports of mericitabine-resistant variants. 

Editorial Comment: The high response rate, good safety profile, potential for shorter treatment and apparent lack of drug-resistant variants make this treatment very attractive. This is a small study, but definitely one to pay attention to. (LKP)

 

Abstract:  EMERGE Week 12 Interim Analysis: PegIFN Lambda Associated With Higher Virologic Response Rates in Patients With Genotype 1/4 HCV and Similar Rates in Patients With Genotype 2/3 HCV vs PegIFN alfa-2a, With Fewer Dose Reductions—Zeuzem S, Arora S, Bacon B, et al.
Source:  EASL 46th Annual Meeting, Abstract 1360

The objective of the study was to access the safety and effectiveness of PEG-Interferon lambda (120-240 µg/week) plus ribavirin compared to PegIFN alfa-2a/RBV in 526 HCV genotype 1, 2, 3, and 4 treatment- naïve patients. The patients were randomized into 4 arms:

  • PegIFN alfa-2a (Pegasys) 180 µg/week plus RBV
  • PegIFN lambda 120 µg/week plus RBV
  • PegIFN lambda 180 µg/week plus RBV
  • PegIFN lambda 240 µg/week plus RBV

Note:  Genotype 1 and 4 patients were treated for 48 weeks (RBV dose 1000-12000 mg/day)

Genotype 2 and 3 patients were treated for 24 weeks (RBV dose 800 mg/day)

The Bottom Line:  The cEVR in the genotype 1 and 4 patients was 55% to 56.3% in the PegIFN lambda groups compared to 37.9% in the Pegasys/RBV group.  The cEVR in the HCV genotype 2 and 3 patient groups was 83.3% to 96.6% compared to 86.2% in the Pegasys/RBV group.  It was reported that PegIFN lambda had less blood related (anemia, neutropenia, platelet) adverse events than PegIFN alfa 2a while elevated ALT/AST and bilibrubin (direct) occurred more frequently in the PegIFN lambda group.  Treatment-related discontinuations between the groups were similar

Editorial Comment:  This is early interim data, but the higher effectiveness and lower incidence of blood-related side effects from PegIFN lambda is encouraging.  The SVR results will give us a much better picture of the effectiveness and side effect profile.  Larger Phase III studies, however, are needed to understand the true potential of PegIFN lambda.  (AF)

 

Abstract: The PROTON Study – PSI-7977 QD Plus PEG/RBV In HCV GT1: 98% Rapid Virologic Response, Complete Early Virologic Response – D R Nelson, J Lalezari, E Lawitz, et al.
Source:  EASL 46th Annual Meeting, Abstract 1362

The goal of this study was to assess the safety, tolerability, and efficacy of PSI-7977 plus PegIFN/RBV for 12 weeks in 121 HCV genotype 1 treatment-naïve patients.  PSI-7977 is a polymerase inhibitor in Phase II studies. This abstract provides a 12-week interim analysis. Patients were assigned to:

  • PSI-7977 200 mg/PegIFN/RBV (n=48)
  • PSI-7977 400 mg/ PegIFN/RBV (n=47)
  • Placebo/ PegIFN/RBV (n=26)

The Bottom Line: All participants in the PSI-7977 arms had undetectable HCV RNA by week 12, with no viral breakthrough (an indication of resistance). Four subjects were discontinued prior to week 12, none due to PSI-7977-related adverse events. 90 out of 95 met the qualifications in order to have 24 weeks rather than 48 weeks of therapy.  

Editorial Comment: Interim analysis for a small study is not enough data from which to draw any conclusions, but it is certainly enough to capture my interest. (LKP)

 

Abstract: PROTON Study – PSI-7977 QD with PEG/RBV: 12-week Safety, RVR, cEVR, & SVR12 in Treatment-naïve Patients with HCV GT2 or GT3 – J Lalezari, E Lawitz, M Rodriguez-Torres, et al.
Source:  EASL 46th Annual Meeting, Abstract 325

Similar to the genotype 1 study just summarized, these results were from 25 treatment-naive patients with HCV genotypes 2 or 3 who received 400 mg PSI-7977 and PegIFN/RBV for 12 weeks. This was not an interim analysis as subjects were treated for 12 weeks.

The Bottom Line: One subject did not continue in the study (lost to follow-up), so if you count the 24 remaining subjects, the response rate was 100% (96% if you count the drop-out). As in the genotype 1 study, PSI-7977 was well-tolerated with no serious adverse events or discontinuations due to side effects.

Editorial Comment: Again, a small study, but with a near perfect 100% after only 12 weeks of treatment, this is a test drug to watch. (LKP)

 

Abstract: NUCLEAR Study – PSI-938 and PSI-7977 Purine and Pyrimidine Nucleotide Analogues Demonstrate Favorable Safety/Tolerability and Robust 14-Day Antiviral Activity Alone and in Combination against Genotype 1 HCV – E Lawitz, M Rodriguez-Torres, J Denning, et al.
Source: EASL 46th Annual Meeting, Abstract 1370

Known as the NUCLEAR Study, this is a 14-day proof-of-concept study investigating two nucleotides: PSI-938 and PSI-7977. Forty HCV- genotype 1 patients with no prior treatment were assigned to one of four groups (10 in each group – 8 received the test drug(s) and 2 received placebo). All patients were offered full-course PegIFN/RBV starting on Day 15.

  • Group 1: PSI-938 for Days 1-14
  • Group 2: PSI-938 for Days 1-7, PSI-938 + PSI-7977 for Days 8-14
  • Group 3: PSI-7977 for Days 1-7, PSI-938 + PSI-7977 for Days 8-14
  • Group 4: PSI-938 + PSI-7977 for Days 1-14

The Bottom Line: Significant reductions in HCV RNA were observed, with some participants reaching non-detectable HCV RNA levels in as little as 3 days. One arm reported 100% with non-detectable HCV RNA. Of the 47% who began with elevated ALTs, all normalized during the study. Over the 14 day test period, PSI-938 and PSI-7977 (alone or in combination) were generally safe and well-tolerated, without any serious adverse events or discontinuations. Side effects included mild headache, fatigue, dizziness, and non-cardiac related chest pain.

Editorial Comment: This is a small proof-of-concept study, but one to keep an eye on. (LKP)

 

Abstract: The ASPIRE Trial – TMC435 In Treatment-Experienced Patients with Genotype 1 HCV Infection Who Have Failed Previous PegIFN/RBV Treatment: Week 24 Interim Analysis – S Zeuzem, G R Foster, M W Fried, et al.
Source:  EASL 46th Annual Meeting, Abstract 1376

This Phase II study featured 463 chronically-infected genotype 1 HCV patients who previously failed peginterferon/ribavirin (PegIFN/RBV) treatment. Subjects received standard dosing of PegIFN/RBV with placebo or PegIFN/RBV with TMC435, a protease inhibitor taken orally, once daily. This study has seven treatment arms of varying treatment lengths and dosing. 

The Bottom Line: The 24-week data analysis revealed:

  • Among previous non-responders (null response), the highest response arm was for those taking higher dose PegIFN/RBV plus TMC435 for 24/48 weeks (87%) vs. 45% for  PegIFN/RBV plus placebo (48 weeks).
  • Among previous partial responders, the highest response arm was for those taking higher dose PegIFN/RBV plus TMC435 for 24/48 weeks (89%) vs. 20% for PegIFN/RBV plus placebo (48 weeks).
  • Among previous responder-relapsers, the response was high across the board–as much as 96% for those on 12 weeks of PegIFN/RBV plus TMC435 vs. 83% for 48 weeks of PegIFN/RBV plus placebo.

There was a slight increase of side effects reported for those taking TMC435, particularly flu-like symptoms and pruritus (itching). Discontinuation due to side effects was 5.6% for TMC435/ PegIFN/RBV vs. 1.5% for placebo/ PegIFN/RBV group. There were slight, reversible increases in bilirubin in the TMC435 group. Side effects did not significantly increase with higher doses of TMC435.

Editorial Comment: This is very encouraging data, but it is an interim analysis. It will be interesting to see the final data for this phase. TMC435 is currently in Phase III clinical trials and that data will tell us even more. The once daily feature of TMC435 makes it very attractive compared to the three times a day regimen of some of the other drugs in the pipeline. Stay tuned…(LKP)

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HEALTHWISE: Special Report of the 2011 EASL Meeting
—Lucinda K. Porter, RN

Emily Dickinson wrote, “Hope is the thing with feathers…” Less poetically, I say, “Hope is the data that was presented at the 2011 meeting of the European Association for the Study of the Liver (EASL).” There is so much promising data for chronic hepatitis C virus (HCV) infection that I am keeping my HealthWise column short and focusing on HCV Snapshots. Honestly, it was hard to choose which to write about. In fact, there were so many exciting presentations that Alan Franciscus is also writing some Snapshots.

I covered six studies, all using combinations of HCV direct-acting antiviral (DAAs) along with peginterferon and ribavirin. Alan writes about other test drugs, including an alternative to interferon-alfa. In a couple of instances, some of the results yielded 100% response rates. However, keep in mind that some of these studies are small and although encouraging, more research needs to be conducted.

This year, there were two presentations about HCV vaccines. It was not long ago that the very idea of an HCV vaccine seemed out of reach; now it seems possible.

 One vaccine was therapeutic, meaning that it is used after a person is infected with HCV. However, the other vaccine study was prophylactic. Both studies were small; both yielded encouraging results.

In addition to exciting research presentations, new clinical practice guidelines for managing HCV were announced at this year’s EASL meeting. These guidelines do not take into account the new therapies that are soon to be launched, but they are worth considering. Most noteworthy is the issue of liver biopsy—once considered a basic requirement prior to initiating HCV treatment, the necessity of it is now debated. The guidelines challenge the traditional practice of liver biopsies, suggesting that there are circumstances where it can be avoided.

Another interesting aspect of the HCV clinical practice guidelines is the inclusion of response-guided therapy. The guidelines recommend that genotype 1 patients with a rapid response can be treated for 24 weeks. The guidelines will be published in the Journal of Hepatology.

This year’s EASL meeting all boils down to better HCV management,  a more expansive cure for HCV in our future AND choices about how we get there. And if I dare to really hope, if an HCV vaccine is on the horizon, our future would radically change. Hope is more than just a thing with feathers—it is picturing a world without HCV.


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