New Hep C meds may override watchful waiting for patients with no symptoms

3.11.12 | Michael Kirsch, MD

I seemany patients with hepatitis C (HCV). None of them are under treatment and they all feel quite well. Why don’t I treat them? After all, potential consequences of HCV include:

• Cirrhosis
• Hepatocellular carcinoma. or liver cancer
• End stage liver disease with all the trimmings
• Liver transplantation
• Death

One would think that a portentous list like this would justify any treatment, even hazardous therapies. But, I’ve never seen it this way, and my hepatitis C patients are all doing well under periodic observation.

Yes, I know that the disease can be serious. I recall one patient with advanced disease whom I referred for consideration of a liver transplant many years ago. There may have been one or two others along the way who received treatment for the disease also.

The vast majority of hepatitis C patients I see in my community practice feel entirely well and the diagnosis was discovered by accident. In other words, these patients did not exhibit symptoms or abnormal findings on the physical examination that led a physician to suspect a liver condition, which then led to testing for hepatitis C. Some of them were picked up by the blood bank when their gift of life was declined. Sometimes, a life insurance company makes the diagnosis during their health assessment as they try to cull out from their enrollees those destined to ascend skyward prematurely. In most cases, patients are diagnosed with hepatitis C when physicians like me order diagnostic HCV blood test to evaluate abnormal liver blood tests. Nearly all of these patients have no symptoms of liver disease and the abnormal liver blood tests may not be a HCV manifestation.

What should we advise patients with HCV who feel perfectly well? Of course, patients should make the call after they have been informed of the risks and benefits of treatment. In my experience, after this discussion, none of these patients wants to proceed. Hopefully, I am meeting my obligation to present the issues to them fairly. I am certainly aware of my bias, and do my best to compartmentalize it.

I think that there has been a rush to treatment with these patients. Academic centers tend to be more enthusiastic about racing for the HCV cure with toxic medicines, although in fairness, their HCV population is very different from mine. Their patients are much more ill, so the risk/benefit analysis of treatmentmay calculate out differently. Nevertheless, academicians in writing and on the speaking circuit tend to extol the virtue of treatment, which they regard as the default response. Watchful waiting just doesn’t have the red meat appeal for liver gurus. They argue that eradicating the virus will prevent the dire consequences I listed at the top of this post. However, when there was only treatment available 20 years ago -injectable interferon - academics were gaga over this it, which had a full page of side effects and was effective in less than 20% of patients treated. I’m amazed that interferon slid by the FDA. Now,HCV can be cured in a majority of patients, according to data from two drugs approved in 2011 to treat the disease, although there remains substantial toxicity from the medications.

Even experts acknowledge that only a minority of HCV patients will develop serious complications. I’m not persuaded that we have a reliable method to determine who will progress and who won’t. And if we did, how firm is the evidence that treating a patient who is destined for cirrhosis will avert this outcome? Those who believe in HCV treatment will find data to support their view and practice. And those of who are skeptics will do the same. That’s the beauty of medicine. There’s always conflicting studies to choose from to support any view.

What would Newton say?

Many of my HCV patientscan date with some precision whenthey contracted the virus. The event may have been a blood transfusion decades ago or from intravenous drug use during a youthful period of hard times and bad judgement.Many of these patients, therefore, have had the virus for decades and are not suffering any illeffects. While I cannot guarantee a sanguine outcome, I view this in Newtonian terms.

An HCV virus that is asleep tends to remain asleep.

Other physicians don’t share my approach and may be dismissive of my nihilism. I wonder how many of them would accept a treatment with enormous toxicity and cost for themselves as readily as they prescribe it to others? This question applies to all physicians, including me, who prescibe medicine and advise patients. Remember, we physicians discuss the risks of all treatments with patients in advance. But, we don’t suffer the complications.

HCV patients, get informed. Make sure the treatment won’t be worse than the disease.

Source

‘Women constitute 75% Auto Immune Hepatitis patients’

Smriti Sharma Vasudeva : Chandigarh , Sun Mar 11 2012, 04:45 hrs

THE INDIAN EXPRESS

While Hepatitis B and C have acquired almost an epidemic status in our country, Auto Immune Hepatitis is largely overlooked in the list of liver diseases. Known to mostly affect women, AIH incidentally does not have any specific symptoms, making it a potential threat for Indian population.

World renowned couple Dr Giorgina Mieli-Vergani, emeritus professor of paediatric hepatology, King’s College Hospital, London and her husband Dr Diego Vergani, emeritus professor of liver immunopathology, King’s College Hospital London, said, “AIH is a progressive inflammatory liver disorder affecting mainly females, characterised by the presence of auto antibodies. As a result, our body’s infection fighting mechanism cells start behaving just the opposite. By the time, it is diagnosed, much of the damage to the liver is already done.”

If left untreated, AIH generally progresses rapidly to cirrhosis and liver failure. The peak incidence of the disease is before puberty and 75 per cent of the patients are girls.

“In fact researches have established that patients of Hepatitis C are at greater risk of developing AIH and since India has a significant number of patients of Hepatitis C virus, therefore it assumes larger significance”, said Dr Giorgina.

Top identify AIH patients in this part of the country, already a team of experts at the department of Immunopathology, PGIMER is on board a project with the doctor couple. “The only hindrance is about transportation of samples. We are working out on a modalities for the smooth continuation of the research to find out the pathogenesis of Indian patients with this condition,” said Dr Diego.

Already, the two are working on a research to find a possible cure for AIH wherein regulatory cells from the body of the patient suffering from AIH are taken out and developed in a controlled environment to outnumber the count of antibodies responsible for AIH.

The duo has even received funding of one million pounds from the British government agency to carry out the research.” It may take a few years and already a PhD student working with us on the research is undergoing a year’s training at Boston for the purpose,” added the duo.

Source

The effect of pegylated interferon-alpha2b and ribavirin combination therapy for chronic hepatitis C infection in elderly patients

Published on: 2012-03-10

The clearance of hepatitis C virus infection by interferon therapy significantly reduces the incidence of hepatocellular carcinoma and death in elderly chronic hepatitis patients. However, there are few reports concerning the efficacy and safety of pegylated interferon-alpha2b plus ribavirin combination therapy in elderly patients.

The aims of the present study were to examine the effect and safety of pegylated interferon-alpha2b plus ribavirin combination therapy in 427 patients with chronic hepatitis C infection. We compared the rates of sustained virological response--defined as the absence of detectable hepatitis C virus in serum 24 weeks after the treatment ended--and the treatment discontinuation rate between 319 younger patients aged <65 years and 108 elderly patients aged [greater than or equal to]65 years.

We also examined the factors contributing to a sustained virological response.

Results: There was no significant difference in the sustained virological response rate between younger patients and elderly patients according to their hepatitis C virus genotype (41.5% (100/241) and 40.7% (35/86) for genotype 1; P = 0.899, 89.7% (70/78) and 86.4% (19/22) for genotype 2; P = 0.703, respectively). There was also no significant difference in the treatment discontinuation rate between the two age groups (10.3% (33/319) and 13.9% (15/108), respectively; P = 0.378).

There were no serious adverse events requiring hospitalization. The factors contributing significantly to a sustained virological response in elderly patients were gender, hepatitis C virus genotype, platelet count, and the presence of a rapid or early virological response (undetectable hepatitis C virus in serum at weeks 4 or 12 of treatment, respectively).

However, upon multivariate analysis, the presence of an early virological response was the only significant factor (odds ratio: 0.115, 95% confidence interval: 0.040-0.330, P <0.001).

Conclusions: The efficacy and safety of pegylated interferon-alpha2b plus ribavirin combination therapy in elderly patients are not always inferior to those in younger patients. Obtaining an early virological response may be essential to achieve a sustained virological response in elderly patients with chronic hepatitis C infection.

Author: Hiroki NishikawaEriko IguchiYorimitsu KoshikawaSoichiro AkoTadashi InuzukaHaruhiko TakedaJun NakajimaFumihiro MatsudaAzusa SakamotoSinichiro HenmiKeiichi HatamaruTetsuro IshikawaSumio SaitoRyuichi KitaToru KimuraYukio Osaki

Credits/Source: BMC

Source

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.

Source

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 C_max and AUC_tau for each drug relative to administration alone (See Table 1)

Table 2: Daclatasvir and atazanavir/ritonavir

• Dose-normalized increases in daclatasvir maximum plasma concentrations (C_max) and area under the concentration-time curve in one dosing interval (AUC_tau) 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) C_max and AUC_tau 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 AUC_tau 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 (C_max) and area under the concentration-time curve in one dosing interval (AUC_tau) were observed when dosed with efavirenz (See Table 3):
  • Geometric mean ratios (GMR) for Cmax and AUC_tau of daclatasavir 120 mg when coadministered with efavirenz vs. daclatasvir 60 mg alone were above the predicted estimations. Non-normalized GMR for C_max and AUC_tau 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 AUC_tau 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%

Overall:

• 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, john.elicker@bms.com
Media: Cristi Barnett, 609-252-6028, cristi.barnett@bms.com

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

Source

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".

Source

CROI 2012: NATAP Updates and Slides

19th Conference on Retroviruses and
Opportunistic Infections
Seattle, WA March 5 - 8, 2011

Provided by NATAP

1. CROI: GS-7977 + Ribavirin in HCV Genotype 1 Null Responders: Results from the ELECTRON Trial - (03/7/11)
   
   
2. CROI: PHARMACOKINETIC INTERACTION BETWEEN THE HCV PROTEASE INHIBITOR BOCEPREVIR AND RITONAVIR-BOOSTED HIV-1 PROTEASE INHIBITORS ATAZANAVIR, LOPINAVIR, AND DARUNAVIR - (03/7/11)
   
   
3. CROI: The Pharmacokinetic Interactions of HCV Protease Inhibitor TMC435 with Rilpivirine, Tenofovir, Efavirenz or Raltegravir in Healthy Volunteers - (03/7/11)
   
   
4. CROI: Evaluation of NS3 Amino Acid Variants in a Phase 1b Study of GT 1 Infection with the HCV Protease Inhibitor, MK-5172 - (03/7/11)
   
   
5. CROI: Influence of the HCV Protease Inhibitor Boceprevir on the Pharmacokinetics of the HIV Integrase Inhibitor Raltegravir - (03/7/11)
   
   
6. CROI: Telaprevir in Combination with Peginterferon Alfa-2a/Ribavirin in HCV/HIV Co-infected Patients: SVR12 Interim Analysis - (03/7/11)
   
   
7. CROI: Boceprevir Plus Peginterferon/Ribavirin for the Treatment of HCV/HIV Co-Infected Patients - (03/7/11)
   
   
8. CROI: HCV PI Boceprevir Lowers Levels of Three Key HIV PIs - written by Mark Mascolini - (03/7/11)

Merck's hepatitis C drug wins UK cost endorsement

LONDON, March 9 | Thu Mar 8, 2012 7:01pm EST

LONDON, March 9 (Reuters) - U.S. drugmaker Merck & Co's new hepatitis C drug Victrelis was recommended for use within Britain's state health service on Friday, despite its hefty price tag.

The National Institute for Health and Clinical Excellence, which often spurns expensive new medicines on cost grounds, said significant improvements seen with Victrelis made it a cost-effective option.

The drug, also known as boceprevir, is designed for use in combination with peginterferon alfa and ribavirin for patients with liver disease due to genotype 1 chronic hepatitis C, the most common form.

It costs 30,800 pounds ($48,400) for a 44-week course, with the other two drugs increasing the bill by around 11,000 pounds.

The draft guidance from NICE is now open for consultation before the agency finally issues it.

Source

The long-term horizon: Patients who will remain untreated in the era of triple therapy

Clinical Liver Disease

Volume 1, Issue 1, pages 20–23, February 2012

Andrew Aronsohn M.D., Donald Jensen M.D.^‡,*

Article first published online: 6 MAR 2012

DOI: 10.1002/cld.5

Copyright © 2012 the American Association for the Study of Liver Diseases

Abstract

Watch the interview with the authors

Watch the video presentation of this article

Answer questions and earn CME

The direct-acting antivirals (DAAs) telaprevir and boceprevir have revolutionized hepatitis C virus (HCV) therapy by improving therapeutic outcomes for many patients. Although DAA-based therapy is a great leap forward, it is not a panacea, and many patients will not be appropriate candidates for this treatment. This review defines the patients who will remain untreated and explores emerging challenges in the era of triple therapy.

Patients with Contraindications to Pegylated Interferon (PEG) and Ribavirin (RBV)

PEG and RBV remain part of the current DAA-based therapy; therefore, patients with contraindications to the previous standard-of-care treatment are unlikely to be candidates for triple therapy (Table 1). This includes patients with previous adverse reactions to PEG or RBV and patients with uncontrolled autoimmune disease.1 In addition, interferon-induced bone marrow suppression, in combination with the hemolytic effects of RBV, can result in significant anemia and pancytopenia, and this makes patients with preexisting cytopenias, severe peripheral vascular disease, pulmonary disease, or coronary artery disease potentially unsuitable candidates for treatment.1 Finally, depression has been reported to occur in 23.2% of patients undergoing interferon therapy.2 Although patients tend to respond well to antidepressants during HCV therapy, severe uncontrolled depression remains a contraindication to treatment.1

DAA, direct-acting antivirals; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PEG, pegylated interferon; RBV, ribavirin; SVR, sustained virological response.

Patients with Contraindications or Limited Responses to DAA Therapy

Boceprevir and telaprevir have significant interactions with both cytochrome P450 3A and p-glycoprotein, and these result in significant drug-drug interactions (Table 2).3, 4 A thorough medication history should be taken before treatment, and it is possible in many cases to substitute or hold a contraindicated drug during HCV therapy. However, in rare instances, patients who are taking a contraindicated medication that cannot be modified may not be candidates for current DAA-based therapy.

Although triple therapy is highly effective in most patients, response rates among patients with cirrhosis (especially previous null responders) remain relatively low. In the Sprint (Serine Protease Inhibitor Therapy) 2 study, cirrhosis was a significantly negative predictor of sustained virological response (SVR) in patients treated with boceprevir [odds ratio = 2.5 (1.4–4.6), P = 0.003].5 Furthermore, in the REALIZE study, investigators performed a subgroup analysis of patients with cirrhosis who were treated with telaprevir-based therapy and were previous null responders, and they found an SVR rate of only 29%.6 Clearly, many patients with HCV-related cirrhosis (especially previous nonresponders) will have limited success with the current therapy and will require treatment beyond what is currently available.

Understudied Populations

HCV affects many patients who have unique characteristics that are beyond the scope of currently published phase 3 registration trials of DAAs. These patients may benefit from DAA therapy but will pose a significant challenge to clinicians because there are limited data (if any) for guiding their care (Table 3).

Patients Coinfected With Human Immunodeficiency Virus (HIV)

At least 17% of patients with HIV are coinfected with HCV.7 Progression to cirrhosis is more rapid in coinfected patients, and hepatic failure is an increasingly common cause of death in this patient population.8 The treatment of HCV in the setting of HIV is a longstanding clinical challenge because previous standard-of-care therapy with PEG/RBV has resulted in suboptimal SVR rates. In 2004, the AIDS Pegasys Ribavirin International Co-Infection Trial study group performed a multicenter, international study of HCV therapy in 868 patients coinfected with HIV. In genotype 1 patients, the SVR rate was 29%, which is lower than the published rates for PEG/RBV-based therapy in the non–HIV-infected population.9, 10 Currently, there are no available data describing DAA-based therapy in the HIV/HCV-coinfected population, and although improved treatment outcomes are anticipated, safety concerns (primarily involving drug-drug interactions) must first be addressed.

Liver Transplant Recipients

Patients with chronic HCV who undergo liver transplantation universally experience HCV recurrence in the transplanted liver. This leads to inferior posttransplant patient and graft survival in comparison with many other indications for liver transplantation.11 HCV therapy with PEG/RBV after liver transplantation has been largely unsuccessful because of poor SVR rates and significant adverse events, which include acute rejection.12, 13 Theoretically, direct-acting agents should be ideal in an immunocompromised host because there is less reliance on the host immune system for antiviral activity. Telaprevir and boceprevir are strong inhibitors of the enzyme cytochrome P450, which also plays a key role in the metabolism of the immunosuppressants commonly used in liver transplantation: cyclosporine and tacrolimus. Pharmacokinetic studies investigating the interaction between telaprevir and cyclosporine yielded extremely high drug concentrations of immunosuppressants when they were tested in healthy controls (a 70-fold increase in the tacrolimus concentration and a 4.6-fold increase in the cyclosporine concentration).14 Further prospective studies will be needed to determine safe and efficacious dosing strategies when these medications are used together.

Patients With Decompensated Cirrhosis

Successful HCV treatment in patients with cirrhosis has been shown to increase survival and decrease the development of ascites, esophageal varices, and hepatic encepaholpathy.15 Unfortunately, few decompensated patients with genotype 1 or 4 who undergo HCV treatment with PEG/RBV will achieve SVR (7%); therapy is often poorly tolerated, and frequent dose reductions and discontinuations are required.16 Current guidelines from the American Association for the Study of Liver Diseases recommend that for patients with decompensated cirrhosis, attempts at treatment should be “administered by experienced clinicians with vigilant monitoring for adverse events preferably in patients who have already been accepted as candidates for liver transplantation.”1 The risk of further decompensation along with the low SVR rates means that the previous standard-of-care treatment with PEG/RBV is rarely a viable option. With the use of more potent antiviral agents, SVR rates may increase; however, DAA metabolism appears to be different in patients with advanced cirrhosis versus patients with earlier stages of disease, and the tolerability and safety in this population remain largely unknown. Decisions to treat these patients with triple therapy rely solely on anecdotal accounts, and they should be made with extreme caution and should be based on physician experience and unique patient characteristics.

Pediatric and Elderly Populations

Recent National Health and Nutrition Examination Survey data suggest that approximately 0.2% to 0.4% of children up to 14 years old are infected with HCV.17 The majority of pediatric HCV infections occur as a result of maternal-fetal transmission. Because of the shorter period of chronic infection, pediatric patients usually have earlier stage disease at the time of diagnosis in comparison with adults; however, progression to cirrhosis and hepatocellular carcinoma has been reported.18, 19 In a pilot study of 62 patients between the ages of 2 and 17 years who were treated with PEG and RBV, 48% of the patients with genotype 1 achieved SVR.20 Although the results are based on limited data, the treatment outcomes appear to be similar to those of the adult population, and so are the adverse events during therapy, with the exception of spastic diplegia, which is a severe form of neurotoxicity seen in infants treated with interferon-α.17 The pediatric population would very likely tolerate and benefit from more potent agents; however, to date, there are no data on the use of telaprevir, boceprevir, or other new HCV therapies in this population. The current Food and Drug Administration treatment for patients who are 18 or less years old remains interferon plus RBV three times a week (3–18 years old) or PEG plus RBV once a week (5–18 years old).

In upcoming years, the highest prevalence of HCV infection will be seen in patients who are 65 years old or older.21 Older patients with HCV have a faster rate of progression to cirrhosis and have a higher incidence of hepatocellular carcinoma; this indicates a significant therapeutic need in this understudied population.22, 23 Patients more than 65 years old are more likely to be cirrhotic and have comorbidities that make treatment with PEG/RBV less effective. This was shown by Huang et al.24 in a study of 70 HCV patients older than 65 years who were treated with PEG/RBV. In comparison with younger cohorts, older patients had significantly inferior SVR rates and higher rates of dose reduction and therapy discontinuation. DAAs may improve response rates; however, there are significant concerns about the tolerability of triple therapy in this population and especially in patients who have been unable to tolerate PEG/RBV in the past. The consideration of alternate dosing schedules and treatment algorithms may be key to the use of DAA-based therapy in this population.

Patients With Previous DAA Exposure

Unlike dual-therapy treatment with PEG/RBV, treatment failure with DAAs is complicated by the emergence of resistant variants. Pawlotsky25 defined three major factors that influence the clinical ramifications of resistance: the genetic barrier to resistance, the fitness of the resistant variant, and the attainable drug exposure. First-generation protease inhibitors such as telaprevir and boceprevir have a low genetic barrier to resistance; however, after the discontinuation of therapy, the wild-type virus typically regains dominance, possibly to the point of the complete eradication of the resistant variants over time. Patients who develop resistant variants while they are being treated with one protease inhibitor will not likely be candidates for treatment with the other available protease inhibitor because boceprevir and telaprevir have been shown to share cross resistance in vitro. In addition, the emergence of resistance is also related to interferon insensitivity, which would hinder successful therapy with any DAA that requires interferon as part of the therapeutic regimen. As more DAAs become available, the treatment of patients who develop resistant variants may become similar to HIV treatment, in which combinations of agents are selected on the basis of viral resistance profiles.

Overcoming Current Challenges with DAA Therapy

This review describes many groups of patients who are underserved by currently available DAA therapy (Fig. 1). Fortunately, there are robust basic, translational, and clinical investigations aimed specifically at addressing these shortcomings. For those with limited responses or contraindications to telaprevir- or boceprevir-based treatment, ongoing clinical trials are evaluating the safety and efficacy of the next generation of protease inhibitors, polymerase inhibitors, and other novel agents such as cyclophilin inhibitors and short interfering RNA. In addition, many new agents are being investigated in interferon-free combinations that are targeted at patients who have deferred interferon-based treatment because of their own preference or medical contraindications. Finally, active research is taking place through both sponsored trials and investigator-initiated studies evaluating current DAA-based therapy in many of the understudied populations mentioned in this review.

Figure 1. Treatment algorithm for difficult-to-treat patients.

Chronic HCV progresses slowly, and most patients do not develop advanced liver disease until at least 2 to 3 decades after the time of infection. Within understudied and difficult-to-treat populations, patients with early-stage disease will have the luxury of waiting for safer or more effective therapies; however, patients who already have advanced disease will have limited options and will remain a challenge, even in the era of DAA therapy.

References

Source

The new standard of HCV therapy: Treatment in therapy-naive patients

Clinical Liver Disease

Volume 1, Issue 1, pages 12–15, February 2012

Saurabh Agrawal M.D.^1,*, Paul Y. Kwo M.D.²

Article first published online: 6 MAR 2012

DOI: 10.1002/cld.7

Copyright © 2012 the American Association for the Study of Liver Diseases

^† Potential conflict of interest: Nothing to report

Abstract

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The paradigm for hepatitis C virus (HCV) treatment relies on pegylated interferon and ribavirin (PR) as agents that enhance endogenous mechanisms for viral clearance and are dependent on host factors.1, 2 In May 2011, the US Food and Drug Administration (FDA) approved two new nonstructural 3 protease inhibitors, telaprevir (TVR) and response-guided therapy; SVR, sustained virological response; TID, three times a day; TVR, telaprevir

For genotype 1–infected individuals, the addition of TVR or BOC to PR markedly improves sustained virological response (SVR) rates. However, the newly approved protease inhibitors are associated with increases in the frequency and severity of side effects, which will require additional management strategies to allow patients the maximum opportunity for achieving SVR. The treatment of genotype 1–infected, therapy-naive patients with TVR is based on a recent international phase 3 trial (ADVANCE) that randomized subjects into three groups.3 Group 1 received PR and a placebo for 48 weeks. Groups 2 and 3 received TVR for either 8 or 12 weeks in addition to PR with response-guided therapy (RGT). Patients in whom HCV RNA was undetectable at weeks 4 and 12 [i.e., an extended rapid virological response (eRVR)] stopped taking PR in week 24, whereas those patients in whom HCV RNA was detectable at week 4 but undetectable at week 12 continued to complete 48 weeks of PR. Significantly higher SVR rates were seen in the patients on the 12-week regimens with TVR (75%) versus the control patients receiving 48 weeks of PR (44%), and this 12-week duration of TVR has been licensed in the United States in combination with PR as an RGT paradigm (Fig. 1). More than half of the individuals who received this treatment in trials were able to truncate their therapy at 24 weeks, and this was confirmed in a supplementary trial called ILLUMINATE (Illustrating the Effects of Combination Therapy With Telaprevir) in which 12 weeks of TVR in addition to 24 or 48 weeks of PR was shown to be equivalent if patients achieved an eRVR.4 Subsequent approval by the FDA recommended that patients with cirrhosis be considered for a full 48-week course of PR in addition to TVR for 12 weeks, regardless of the initial response to treatment.

Figure 1. Treatment paradigm with futility rules for TVR and PR in treatment-naive individuals infected with HCV genotype 1. *The assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL. This figure is based on a TVR package insert (May 2011).

The approval of BOC was based on the Serine Protease Inhibitor Therapy 2 study, also called SPRINT 2, in which patients were randomized to 48 weeks of PR or to BOC plus PR in either an RGT arm or a fixed-duration arm. In all groups, a 4-week PR lead-in was used, and this was followed by the addition of BOC.5 In the RGT arm, patients in whom HCV RNA was undetectable during weeks 8 to 24 completed triple therapy at week 28, whereas patients in whom HCV RNA was detectable at week 8 but undetectable by week 24 discontinued BOC at week 28 and continued to complete another 20 weeks of PR for a total of 48 weeks of therapy. Patients in the fixed-duration arm received the lead-in treatment and then 44 weeks of BOC plus PR. The addition of BOC led to overall sustained response rates of 63% to 66% versus 38% in the PR-alone group.5 In this study, two cohorts were predefined as nonblack and black. The SVR rates in the nonblack cohort were 67% for the RGT arm and 68% for the 44-week (fixed-duration) BOC arm, and these rates were significantly higher than the rate for the PR control arm, for which an SVR rate of 40% was observed. In the black cohort, the SVR rate was 42% for the RGT arm, 53% for the 44-week BOC arm, and 23% for the PR control arm. The FDA subsequently approved an RGT paradigm for treatment with BOC. Specifically, if HCV RNA levels are undetected at weeks 8 and 24, individuals may be treated for 28 weeks. If HCV RNA is detected at week 8 and is undetected at week 24 (approximately half of treated patients), then patients should receive PR with BOC for 36 weeks and then a 12-week PR tail for a total of 48 weeks of therapy. Patients who have cirrhosis or respond poorly to PR (<1-log reduction after the PR lead-in treatment) should receive PR for 4 weeks and then 44 weeks of PR and BOC (Fig. 2). On the basis of these data, the American Association for the Study of Liver Diseases has revised its guidelines for the management of treatment-naive, HCV genotype 1–infected persons as follows6:

1. The optimal therapy for chronic HCV genotype 1 infections is the use of BOC or TVR in combination with peginterferon-alfa and ribavirin (class 1, level A).
2. BOC and TVR should not be used without peginterferon-alfa and weight-based ribavirin (class 1, level A).
3. The recommended dose of BOC is 800 mg, and it should be administered with food three times a day (TID; every 7–9 hours) together with peginterferon-alfa and weight-based ribavirin for 24 to 44 weeks. This should be preceded by 4 weeks of a lead-in treatment with peginterferon-alfa and ribavirin alone (class 1, level A).
4. Patients without cirrhosis who are treated with BOC and PR (preceded by 4 weeks of a lead-in treatment with PR) and in whom HCV RNA is undetectable at weeks 8 and 24 may be considered for a shortened treatment duration of 28 weeks in all (4 weeks of a lead-in treatment with PR followed by 24 weeks of triple therapy; class 2a, level B).
5. Treatment with all three drugs (BOC, peginterferon-alfa, and ribavirin) should be stopped if the HCV RNA level is >100 IU/mL at treatment week 12 or HCV RNA is detectable at treatment week 24 (class 2a, level B).
6. The recommended dose of TVR is 750 mg, and it should be administered with food (not low-fat food) TID (every 7–9 hours) together with peginterferon-alfa and weight-based ribavirin for 12 weeks followed by an additional 12 to 36 weeks of peginterferon-alfa and ribavirin (class 1, level A).
7. Patients without cirrhosis who are treated with TVR and PR and in whom HCV RNA is undetectable at weeks 4 and 12 should be considered for a shortened therapy duration of 24 weeks (class 2a, level A).
8. Patients with cirrhosis who are treated with either BOC or TVR in combination with PR should receive therapy for a duration of 48 weeks (class 2b, level B).
9. Treatment with all three drugs (TVR, peginterferon-alfa, and ribavirin) should be stopped if the HCV RNA level is >1000 IU/mL at treatment week 4 or 12 and/or HCV RNA is detectable at treatment week 24 (class 2a, level B).

Figure 2. Treatment paradigm with futility rules for BOC and PR in treatment-naive individuals infected with HCV genotype 1. *The assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL and a limit of HCV RNA detection of approximately 10 to 15 IU/mL. TW, treatment week.

Triple antiviral therapy presents the provider and patient with new issues to address. Additional side effects and potential drug-drug interactions are part of the price that we pay for enhanced viral responses. With TVR, rashes, anemia, and gastrointestinal side effects are all more common than they are with PR alone. Rarely, Steven-Johnson syndrome or drug rash with eosinophilia and systemic symptoms has been reported, and this requires the immediate discontinuation of all drugs. However, the vast majority of patients are able to continue treatment despite rashes, and with careful management, a high SVR rate can still be achieved. With BOC, the primary additional side effect is anemia. Finally, drug-drug interactions will be important. There is a list of contraindicated medicines for both of these drugs that must be addressed before the initiation of therapy (Table 1). These will be discussed in more detail in the second issue of Clinical Liver Disease.

Click table to enlarge

In summary, the era of DAA agents has arrived. Approximately 70% of treatment-naive, genotype 1–infected individuals now may be treated successfully with PR plus DAA agents with RGT. High SVR rates have also been seen across difficult-to-treat groups, including patients with high viral levels, patients with advanced fibrosis, and black patients. Moreover, treatment may now be truncated at 6 months in approximately half of individuals. Finally, as we enter the era of DAA-based therapy for HCV, strict adherence to treatment futility rules should be maintained to prevent the emergence of resistance-associated variants that might hamper future therapy.

References

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The new standard of HCV therapy: Retreatment in experienced patients

Clinical Liver Disease

Volume 1, Issue 1, pages 16–19, February 2012

Naveen Gara M.D., Marc G. Ghany M.D., M.H.Sc.^§,*

Article first published online: 6 MAR 2012

DOI: 10.1002/cld.4

Copyright © 2012 the American Association for the Study of Liver Diseases

^† This research was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute (National Institutes of Health).

^‡ Potential conflict of interest: Nothing to report

Abstract

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Answer questions and earn CME

As the treatment for chronic hepatitis C virus (HCV) infection has improved over the last 2 decades, the number of patients for whom therapy fails has declined substantially. However, more than half of patients with HCV genotype 1 infections fail to achieve a sustained virological response (SVR) to pegylated interferon (PEG-IFN) and ribavirin (RBV).1–4 Subjects for whom combination therapy fails are a heterogeneous group and include individuals who experience virological breakthrough (detectable HCV RNA in serum during therapy after the achievement of an initial response) or virological relapse (the reappearance of HCV RNA in serum after the discontinuation of treatment and the achievement of an end of-treatment response) as well as individuals who fail to achieve an initial virological response [i.e., partial responders (≥2-log IU/mL decline in HCV RNA from the baseline to treatment week 12 but detectable HCV RNA at week 24) and null responders (≤2-log IU/mL reduction in HCV RNA from the baseline to treatment week 12; Fig. 1].

Figure 1. Virological responses during and after therapy for chronic HCV. Relapse refers to the reappearance of HCV RNA in serum after treatment is discontinued and an end-of-treatment response is documented. A nonresponse may be partial (>2-log decline in HCV RNA by week 12 but still positive results at week 24) or null (<2-log decline in HCV RNA by week 12).

DAA, direct-acting antiviral; FDA, Food and Drug Administration; HCV, hepatitis C virus; PEG-IFN, pegylated interferon; RBV, ribavirin; RGT, response-guided triple-drug therapy; SOC, standard of care; SVR, sustained virological response.

The reasons for treatment failure are not well understood. Resistance to interferon is believed to be an important cause. Specific polymorphisms of the interleukin-28b gene probably explain 50% or more of the resistance to PEG-IFN, but other host and viral factors are likely involved.5–7 Poor compliance with the prescribed regimen and adverse events requiring a dose reduction or discontinuation of therapy also contribute to treatment failure.8, 9 The latter two causes may be amenable to interventions, and successful retreatment with PEG-IFN and RBV may be permitted.

Until recently, retreatment options were limited for persons for whom a PEG-IFN/RBV regimen failed. Studies evaluating retreatment with PEG-IFN and RBV yielded SVR rates of only 6% to 9% in partial and null responders and 33% in prior relapsers with an HCV genotype 1 infection.10, 11 In comparison with standard therapy, a higher dose of PEG-IFN as induction therapy had no effect on either the end-of-treatment response rate or the SVR rate.10 However, extending therapy to 72 weeks resulted in a marginal increase in the SVR rate from 9% to 16%, primarily because of the prevention of virological relapse.10 Similarly, a different preparation of interferon, consensus interferon, was minimally effective.12 Three studies have evaluated the role of maintenance, low-dose PEG-IFN in prior nonresponders with advanced liver disease.3–5 All three studies showed no differences in clinical outcomes between treated and control subjects and suggested no benefit of maintenance, low-dose PEG-IFN in this group of patients. However, the Colchicine Versus PegIntron Long-Term study and the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis 3 study hinted at a lower rate of complications (particularly variceal bleeding) in patients with portal hypertension who were receiving colchicine or a placebo, respectively, instead of PEG-IFN.14, 15

In May 2011, two new direct-acting antiviral (DAA) agents belonging to a class of drugs known as protease inhibitors, boceprevir and telaprevir, were approved for use in combination with PEG-IFN and RBV for both previously untreated and treatment-experienced subjects.6–9 In comparison with PEG-IFN and RBV, these drugs led to 2- to 3-fold increases in SVR rates for patients with previous treatment failures17, 19 (Figs. 2 and 3). Consequently, boceprevir or telaprevir in combination with PEG-IFN and RBV now represent the new standard of care (SOC) for the retreatment of relapsers, prior partial responders, and null responders.17, 19

Figure 2. Boceprevir plus PEG-IFN/RBV: overall SVR rates and SVR rates according to prior responses in treatment-experienced subjects. Overall, the SVR rates were significantly higher for patients receiving a boceprevir-containing regimen versus patients receiving PEG-IFN and RBV (59% and 66% versus 21%). The response was dependent on the prior response, with prior relapsers responding better than prior partial responders. Adapted with permission from New England Journal of Medicine.17 RGT means response guided therapy. PR48 means pegylated interferon and ribavirin taken for 48 weeks.

Figure 3. Telaprevir plus PEG-IFN/RBV: overall SVR rates and SVR rates according to prior responses in treatment-experienced subjects. The SVR rates were significantly higher for patients receiving telaprevir with or without a lead-in phase. The SVR rates were not improved with a lead-in phase. There was a gradient in the response, with the highest SVR rates achieved by relapsers and partial responders and the lowest rates achieved by null responders. T12PR48: telaprevir × 12 weeks, pegylated interferon and ribavirin × 48 weeks; LI means ‘lead-in’ phase using pegylated interferon and ribavirin; SOC is ‘standard of care’ i.e., pegylated interferon and ribavirin.

The Retreatment With HCV Serine Protease Inhibitor Boceprevir and Peginterferon/Rebetol 2 study, also known as RESPOND-2, (a phase 3 boceprevir trial) enrolled relapsers and partial responders; previous null responders were excluded.17 The study design began with a 4-week lead-in phase of PEG-IFN and RBV for all subjects, after which the subjects were stratified to one of three study arms:

• Response-guided triple-drug therapy (RGT). The duration of PEG-IFN and RBV was tailored to the HCV RNA response after 4 and 8 weeks of triple therapy; all subjects in this arm received 32 weeks of boceprevir plus PEG-IFN and RBV and completed therapy at week 36 if HCV RNA was undetectable at weeks 8 and 12. Slow responders, that is, those for whom HCV RNA was detectable at week 8 but undetectable at week 12, received another 12 weeks of PEG-IFN and RBV alone after week 36 for a total duration of 48 weeks.
• Fixed-duration triple therapy for 44 weeks.
• SOC therapy. This comprised PEG-IFN and RBV plus a placebo for 48 weeks.

The study × demonstrated that SVR rates were significantly higher among subjects receiving a boceprevir-containing regimen versus patients receiving SOC therapy: 59% in the RGT arm and 66% in the fixed-duration arm versus 21% in the SOC arm (Fig. 2). Successful treatment was more common in prior relapsers (69%-75%) than prior partial responders (40%-52%); the response was lower in patients with cirrhosis, particularly in the RGT arm. Anemia, dry skin, dysgeusia, and rashes were reported more commonly by subjects who received boceprevir versus subjects who received SOC. On the basis of this phase 3 trial, the Food and Drug Administration (FDA) approved the regimen shown in Fig. 4. Because of low response rates in patients with cirrhosis receiving RGT,17 the FDA has recommended that this group of patients receive lead-in therapy and then triple therapy for a fixed duration of 44 weeks.20

Figure 4. Boceprevir plus PEG-IFN/RBV for previous partial responders and relapsers: the FDA-approved regimen. Subjects should start treatment with PEG-IFN and RBV for 4 weeks; after this, boceprevir (800 mg three times a day with food) is given. The duration of boceprevir use depends on the response to treatment at weeks 8 and 24. If HCV RNA is undetectable at weeks 8 and 24, patients should receive 32 weeks of triple therapy. If a patient is slow to respond and has detectable HCV RNA at week 8 but HCV RNA is undetectable at week 24, then triple therapy should be given for 32 weeks and should be followed by another 12 weeks of PEG-IFN and RBV. TW, treatment week.

The REALIZE study, a phase 3 trial of telaprevir with PEG-IFN and RBV in treatment-experienced patients, compared 12 weeks of triple therapy with or without a 4-week lead-in phase of PEG-IFN and RBV plus 36 or 32 weeks of PEG-IFN and RBV, respectively, for a total treatment period of 48 weeks to SOC therapy for 48 weeks. A response-guided approach was not investigated. The study included previous relapsers, partial responders, and null responders. SVR rates were significantly higher for patients receiving telaprevir with or without the lead-in phase (64% and 66%) versus patients receiving SOC therapy (17%). The SVR rates were similar for the arms with and without a lead-in strategy, and this demonstrated no advantage from a lead-in phase. There was a gradient in the response based on prior response, with the highest SVR rates found in relapsers (followed by partial responders) and the lowest rates noted in null responders. These results serve to emphasize the importance of knowing the previous response to treatment when retreatment is being considered. Among previous relapsers, SVR rates with telaprevir plus PEG-IFN and RBV were independent of the liver fibrosis stage. However, among partial and null responders, SVR rates declined with worsening fibrosis.19 Thus, the lowest response rate was observed for null responders with cirrhosis. Adverse events were more common in subjects receiving triple therapy containing telaprevir versus those receiving SOC, and they included fatigue, pruritus, rashes, nausea, anemia, anorectal symptoms, and diarrhea. On the basis of these results, the FDA approved the regimen shown in Fig. 5.20

Figure 5. Telaprevir for partial and null responders: the FDA-approved regimen. Partial and null responders should receive 12 weeks of triple therapy and then another 36 weeks of PEG-IFN and RBV. Relapsers should be treated in the same way as treatment-naive subjects and are eligible for response-guided therapy. This regimen resulted in SVR rates of 83%, 59%, and 29% for relapsers, partial responders, and null responders, respectively.

A majority of patients who fail to achieve an SVR in response to triple therapy (including boceprevir or telaprevir) develop antiviral resistance.17, 19 Some of these viral variants may persist over the long term, but the clinical significance of resistance mutations is unclear at this time.

Whether a subject should be retreated now or wait for potentially better therapy in the future depends on many factors, including the individual's desire to be retreated, the reasons underlying the failure (e.g., inadequate drug dosing or side-effect management), the severity of the underlying liver disease, the prior response to therapy, and the risk of disease progression over the next 3 to 5 years. More effective therapies that do not include interferon are likely to be available in the future. Indeed, a recent pilot trial compared a four-drug regimen (PEG-IFN, RBV, a protease inhibitor, and a nonstructural 5A inhibitor) to a combination of DAA agents without PEG-IFN or RBV in previous null responders. This pilot trial reported an impressive 100% response rate with the four-drug regimen, and 36% of nonresponders achieved an SVR after only 24 weeks of a combination of DAAs alone.21

There are currently no data on the management of individuals for whom a protease inhibitor–containing regimen has failed. Until such data become available, the implementation of futility rules and strict adherence to the drug regimen will be important to prevent the development of resistance and to optimize the chances for SVR while more effective and safer treatment is awaited.

In response to these registration studies, the guidelines committee of the American Association for the Study of Liver Diseases has approved the following guidelines for the use of antiviral therapy in treatment-experienced patients with HCV genotype 1:22

• Retreatment with boceprevir or telaprevir, together with PEG-IFNβ and weight-based RBV, can be recommended for patients who experienced virological relapse or were partial responders after a previous course of treatment with standard interferon-β or PEG-IFNβ and/or RBV (class 1, level A).
• Retreatment with telaprevir, together with PEG-IFNβ and weight-based RBV, may be considered for patients who were previously null responders to a course of standard interferon-β or PEG-IFNβ and/or weight-based RBV (class 2b, level B.)
• In the case of treatment-experienced patients, response-guided therapy with a boceprevir- or telaprevir-based regimen can be considered for relapsers (class 2a, level B for boceprevir; class 2b, level C for telaprevir), may be considered for partial responders (class 2b, level B for boceprevir; class 3, level C for telaprevir), but cannot be recommended for null responders (class 3, level C).
• Patients retreated with boceprevir plus PEG-IFNβ and RBV who continue to have detectable HCV RNA at levels > 100 IU at week 12 should be withdrawn from all therapy because of the high likelihood of developing antiviral resistance (class 1, level B).
• Patients retreated with telaprevir plus PEG-IFNβ and RBV who continue to have detectable HCV RNA at levels > 1000 IU at week 4 or 12 should be withdrawn from all therapy because of the high likelihood of developing antiviral resistance (class 1, level B).

References

Source

CROI 2012: UNC researchers make key HIV discovery

Published Thu, Mar 08, 2012 03:36 PM
Modified Thu, Mar 08, 2012 03:36 PM

By Jay Price - jprice@newsobserver.com

CHAPEL HILL -- Researchers at UNC-Chapel Hill have discovered what could be a vital step toward a cure for HIV.

By giving patients a drug normally used for treating some kinds of lymphoma, scientists have managed to make dormant, hidden HIV viruses reveal their presence.

That’s crucial if scientists want to find a way to target and completely eliminate the virus from the body, said Dr. David Margolis, a professor of medicine, microbiology and immunology, and epidemiology, who led the study.

Margolis spoke by telephone this afternoon from Seattle, just before presenting the findings at the 19th Conference on Retroviruses and Opportunistic Infections.

HIV is the virus that causes AIDS. In recent years, patients have been able to hold it at bay with elaborate cocktails of antiretroviral drugs.

Even though these regiments halt the progress of the disease, the virus remains, hiding in certain cells, and can turn active again if the drug regimen ends.

Researchers thought that a crucial step toward purging the body of HIV was finding a trigger to luring the virus from its hiding place. That’s what the UNC team did, for the first time.

The next steps in the research include a fuller exploration of the lymphoma drug’s effects on the virus, Margolis said.

The findings from that research will determine the next directions for research.

Source

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AIDS Cure Quest Advances as Merck Cancer Drug Attacks Hidden HIV

By Simeon Bennett - Mar 8, 2012 3:00 PM ET

The 30-year quest for an AIDS cure advanced as scientists succeeded for the first time in attacking HIV in its hardest-to-reach hideouts with a cancer drug made by Merck & Co.

In a trial among six men with HIV, researchers led by David Margolis at the University of North Carolina at Chapel Hill used a dose of Merck’s Zolinza to rouse the virus from inside certain immune-system cells, where it evades regular AIDS drugs. That’s a crucial step toward eliminating the virus from the body. The findings were presented at a conference in Seattle today.

While no patients were cured, the trial shows that Zolinza, or similar drugs, may have the potential to purge the virus, Margolis said. He said he expects to hear from the U.S. Food and Drug Administration within “a couple of weeks” on approval for an additional test using more doses of Zolinza.

“What people want to know is when can someone go to a doctor and be handed a pill and be cured,” Margolis said by phone. “That’s decades away. Think of it more in terms of curing cancer. I think in 10 years someone with HIV infection could go to a specialist and get a complicated treatment and have some likelihood of a prolonged remission of their HIV.”

Mysterious Virus

HIV was first observed in the U.S. as a mysterious, deadly illness among gay men in 1981. Since then it’s killed more than 30 million people globally, making it the world’s deadliest infectious disease.

The hunt for a cure has gathered pace because of improvements in the drugs used to control HIV, such as Gilead Sciences Inc. (GILD)’s once-daily pill Atripla, the world’s top-selling AIDS treatment.

While those drugs reduce HIV to undetectable levels in the body, they don’t completely clear it. The virus hides in certain cells, where it switches off the normal process of replication. That enables HIV to avoid detection by the medicines, which are designed to block steps in its reproduction.

Studies have shown that when patients who have the virus under control stop treatment, latent HIV reactivates and comes roaring back, forcing victims to resume daily pill therapy.

“It’s sort of like the virus is a rabbit at the bottom of a hole, but it needs a boost to get it out of the hole,”Margolis said. “It doesn’t fall in the hole very much, but when it does, it’s stuck there.”

Fine Line

Margolis and colleagues have been looking for ways to reactivate the virus without switching on the so-called resting CD4 T-cells in which it’s hiding. Arousing those cells may trigger a dangerous over-stimulation of the immune system that can cause lasting damage.

In the trial, the researchers recruited volunteers who were taking AIDS drugs to subdue the virus, then added Zolinza to see if they could reactivate latent HIV. It worked, with no serious side effects. The scientists saw an average 4.8-fold increase in HIV’s genetic fingerprints, showing the virus was awake and active inside the cells.

In theory, that means the drug has kick-started HIV’s normal process of replication. That could spur an immune-system attack that kills the host cells, or result in the virus exiting and killing the cells in search of new ones to infect. AIDS drugs patrolling the body would prevent it from doing so, and with nowhere left to go, the virus would die.

If that were to happen on a large enough scale, most latent HIV could be eradicated, enabling patients to stop their regular treatment without the virus rebounding -- a cure.

Next Trial

The study wasn’t designed to see whether Zolinza depleted the number of CD4 cells harboring HIV because the doses of the drug were too low, Margolis said. That’s the objective of the next trial now being considered by the FDA.

“We need to make some progress, we need some signal that we can potentially alter or disturb latently infected cells, and this study suggests that might be possible,” said Sharon Lewin, a professor at The Alfred Hospital in Melbourne. She’s also running a trial using multiple doses of Zolinza to target latent HIV and expects to have results from 10 patients later this year, she said.

Zolinza, also known as vorinostat and SAHA, was approved in 2006 for use against a rare type of blood cancer. The drug earned Merck $15 million in 2008, the last year the Whitehouse Station, New Jersey-based company disclosed sales of the medicine. Laboratory tests had shown it could purge HIV from cells in dishes, but the real challenge was to achieve the same result in humans.

“The study gives us hope because it provides an idea that’s worth exploring further,” said Daria Hazuda, Merck’s head of infectious diseases research, and one of the main developers of Isentress, an AIDS drug that generated $1.36 billion for Merck last year. “It’s a very important first step, but we’re still a long way away,” Hazuda said by telephone today.

Forcing Replication

The drug targets an enzyme called histone deacetylase, or HDAC, that helps HIV go to sleep in cells by interfering with its ability to replicate. By blocking HDAC, Zolinza would reactivate the virus, forcing replication.

This is Margolis’s second attempt at flushing out latent HIV. In 2005 he published a paper in The Lancet journal showing that Depakote, an approved treatment for bipolar disorder made by Abbott Laboratories, reduced the number of infected resting cells by as much as 84 percent when combined with Roche Holding AG’s AIDS drug Fuzeon, in a study involving four patients. Subsequent research by Margolis and others contradicted those findings.

Today’s results, the first to show that a mechanism known to keep HIV dormant could be successfully targeted in humans, were presented at the Conference on Retroviruses and Opportunistic Infections in Seattle.

To contact the reporter on this story: Simeon Bennett in Geneva at sbennett9@bloomberg.net

To contact the editor responsible for this story: Phil Serafino at pserafino@bloomberg.net

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