HCV F1/F2 patients: treat now or continue to wait

Liver International

Special Issue: Proceedings of the 7th Paris Hepatitis Conference International Conference of the Management of Patients with Viral Hepatitis, 13–14 January 2014, Paris, France. Guest Editors: Patrick Marcellin and Tarik Asselah. The publication of this supplement was supported by an unrestricted educational grant from Gilead, Janssen Therapeutics, Janssen, Bristol-Myers Squibb, Roche, Boehringer Ingelheim, Merck, AbbVie, Novartis, Idenix and Alios.

Volume 34, Issue Supplement s1, pages 79–84, February 2014

Review Article

You have free access to this content

Mitchell L. Shiffman^1,2,*, Yves Benhamou^1,2

Article first published online: 23 DEC 2013

DOI: 10.1111/liv.12408

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Keywords: chronic hepatitis C virus;  faldaprevir;  sofosbuvir;  simeprevir

Abstract

The treatment of chronic HCV is evolving rapidly. In 2014, three new oral antiviral agents, simeprevir, faldeprevir and sofosbuvir will become available for patients with HCV genotype 1. These agents have far less side effects than the first generation protease inhibitors telaprevir and boceprevir. Treatment will therefore be easier for patients to tolerate but still require peginterferon and ribavirin (PEGINF/RBV). The first IFN free therapy, sofosbuvir (SOF) and ribavirin (RBV), will also become available in 2014. This treatment is highly effective for patients with HCV genotype 2. However, SVR rates with SOF/RBV appear to be similar to that achieved with PEGINF/RBV in patients with HCV genotype 3. The first IFN-free all oral antiviral therapy combination for patients with HCV genotype 1 may be available late in 2014 or early 2015. The factors which should be considered when deciding whether to treat a patient with HCV now or to delay treatment until IFN free therapies are available is discussed.

The treatment of chronic hepatitis C virus (HCV) continues to evolve at a rapid pace. Since the 2013 Paris Hepatitis Conference 1 year ago several new direct acting antiviral (DAA) agents have completed the clinical trials process and data supporting their efficacy and safety has or will soon be presented to the USA Food and Drug Administration, the European Medicines Agency and the health regulatory agencies in several other countries. By the time this manuscript appears at the 2014 Paris Hepatitis Conference we expect that simeprevir (SIM) and sofosbuvir (SOF) will have been approved and available for HCV treatment in the USA. We anticipate that faldaprevir (FAL) will be available during the first several months of 2014. All three of these agents should also be available in many European countries during 2014.

SIM and FAL are potent protease inhibitors (PIs) [1-4]. Both bind to the same site and inhibit the same NS3-4 protease as telaprevir (TVR) and boceprevir (BOC) and have a high rate of resistance if utilized as monotherapy. Clinical trials of both agents have been conducted in combination with peginterferon (PEG-IFN) and ribavirin (RBV) and both will likely be approved for use in patients with HCV genotype 1 who are either treatment naïve or who have failed previous treatment with PEGINF and RBV. Both of these PIs will be utilized according to the concepts of response guided therapy; similar to the way TPV has been utilized since that agent became available in mid-2011 [5]. SIM and FAL achieve high rates of rapid virological response (RVR) and this allows over 80% of patients to be treated for only 24 weeks. Sustained virological response (SVR) rates in the 75–85% range have been reported [1, 3]. SOF is a polymerase inhibitor and has antiviral activity against all HCV genotypes [6]. It is anticipated that this agent will be approved and utilized with PEG-IFN and RBV for treatment naive patients with HCV genotypes 1, 4, 5 and 6. RVR occurs in virtually all patients treated with SOF, PEG-IFN and RBV and SVR rates of 90% or better have been observed with just 12 weeks of treatment [6].

In 2014, the standard of care for the treatment of chronic HCV genotype 1 will continue to be the combination of a single DAA plus PEG-IFN and RBV [7]. The antiviral agent choices will include one of four protease inhibitors; TPV, BOC, SIM and FAL or the polymerase inhibitor SOF. The pharmacology, efficacy and side effect profile for each of these agents are detailed throughout this supplement to Liver International.

In 2014, an effective oral antiviral agent will for the first time be available for patients with HCV genotypes 2 and 3 [8]. The combination of SOF and RBV represents the first interferon free treatment for patients with chronic HCV. In patients with genotype 2 this treatment is highly effective. Virtually all patients achieve RVR and SVR rates with just 12 weeks of treatment are superior to that achieved with 24 weeks of PEG-IFN and RBV [6, 9]. In patients with HCV genotype 3, 12 weeks of SOF and RBV appears to have similar efficacy as 24 weeks of PEG-IFN and RBV. Extending the duration of SOF and RBV to 16 weeks appears to increase SVR especially in patients who have previously failed treatment with PEG-IFN and RBV and in patients with cirrhosis. We anticipate that the regulatory bodies will recommend that patients with HCV genotype 3 be treated for 16 weeks with SOF and RBV.

Several pharmaceutical manufacturers have independently developed either a PI, an NS5A replication complex inhibitor, a nucleoside polymerase inhibitor and/or a non-nucleoside polymerase inhibitor. When various combinations of these antiviral agents were evaluated in phase 2 clinical trials, with or without RBV, HCV RNA became undetectable very rapidly, and high rates of SVR were observed without resistance [10-13]. The results of these trials are reviewed throughout this supplement of Liver International. Phase 3 clinical trials of several interferon free oral antiviral therapies will be complete later in 2014. Table 1 summarizes those regimens we anticipate being approved and available for treatment of HCV genotype 1 during 2015.

Table 1. Interferon free all oral therapies for patients with HCV genotype 1 drugs that are expected to be available in 2015

At the 2013 Paris Hepatitis Conference the authors debated whether patients with chronic HCV should be treated in 2013 or wait for either a PI with less toxicity (which would be utilized with PEG-IFN and RBV) or an interferon free all oral antiviral regimen. These arguments were summarized in our contribution to the 2013 supplement to Liver International [14]. Frankly, the arguments to treat in 2014 or wait are not very different now than 1 year ago. The difference is that an interferon free therapy has arrived for patients with genotypes 2 and 3 and this is now only about 12–18 months away for patients with genotype 1. The current manuscript will re-evaluate the treatment landscape and provide arguments as to why some patients could be treated now and others could continue to defer therapy. These arguments should be considered by patients and physicians when deciding when to initiate HCV treatment.

Genotype 1

There was great enthusiasm in 2011 when the first protease inhibitors, TPV and BOC, were approved for the treatment of patients with chronic HCV. These two PIs when combined with PEG-IFN and RBV offered significant improvements in SVR and for the first time more patients were being cured instead of failing therapy [15-18]. An improvement in SVR compared with PEG-IFN and RBV was observed in nearly every patient population (treatment naïve or prior PEG-IFN and RBV failure) and subpopulation (race, degree of fibrosis, viral load or IL28B status). Unfortunately, these PIs substantially increased the toxicity of treatment compared with PEG-IFN and RBV. The biggest and most difficult to deal with side effect of TPV and BOC is anaemia. This occurs in approximately 40–50% of all persons treated with these PIs and is even more common when treating patients with cirrhosis [19]. Telaprevir also causes a rash in about 50% of patients [16, 18]. Although this is severe and progressive in only a limited number of patients several regulatory agencies insisted that physicians be informed of this potential toxicity and issued a ‘black box’ warning in 2012. Other side effects observed more frequently in patients treated with telaprevir include pruritus and gastrointestinal symptoms. TPV has to be taken with a high fat content meal or snack three times daily; although more recently data has demonstrated that this protease can be dosed twice daily without impacting efficacy [20]. BOC is associated with dysgeusia and is dosed three times daily. Both TPV and BOC have strong drug-drug interactions and several medications need to be either discontinued before the PI is started or the dosage and/or blood level of the alternate drug has to be closely monitored[21].

When first approved, the combination of TPV and BOC were disproportionately utilized in patients who had failed previous treatment with PEG-IFN and RBV and in patients with cirrhosis. In several centres treatment was even initiated in patients with cirrhosis and prior hepatic decompensation. In the largest cohort where this experience was described high rates of anaemia, significant morbidity and several mortalities were observed. The SVR observed in this cohort of patients with prior non-response and/or cirrhosis was only 41% [19, 22].

The two newer PIs, SIM and FAL and the PI SOF will also be utilized with PEG-IFN and RBV in patients with HCV genotype 1. However, these agents offer significant advantages over TPV and BOC. The most important of these is that none of these three agents cause additional anaemia compared with PEG-IFN and RBV [1-4, 6]. All of these agents are dosed as a single once daily tablet, no special diet is required during dosing and no significant drug-drug interactions have been observed. Neither SIM nor SOF were noted to have any adverse events with greater frequency than PEG-IFN and RBV [1, 2, 6]. FAL was noted to have a slightly higher incidence of rash [3, 4]. However, the rash was graded as only mild or moderate in all cases and no grade 3 rashes were observed. FAL was also associated with a mild increase in total bilirubin without elevations in liver transaminases or alkaline phosphatase.

Controlled clinical trials comparing the various antiviral agents utilized for treatment of patients with HCV genotype 1 have not been conducted. As such, no direct comparison regarding the relative effectiveness of these agents can be made. Both SIM and FAL triple therapies were evaluated against a placebo control with PEG-IFN and RBV. As a result, the improvement in SVR with the PI over control could be compared for TPV, BOC, SIM and FAL [1, 3, 15, 16]. Such a comparison suggests that the RVR and SVR rates might be slightly higher in patients treated with SIM and FAL compared with telaprevir and boceprevir. The high RVR rates observed with SIM and FAL allowed over 80% of patients to be treated for only 24 weeks according to response guided therapy guidelines.

The success of treatment in patients treated with SIM and FAL, like the other PIs, is dependent upon an effective interferon response and this is modulated by IL28B genotype. The SVR exceeds 90% in patients with IL28B genotype CC and declines in patients with the CT and TT haplotypes [1, 3]. SIM and FAL have also been studied in patients who failed to achieve SVR with PEG-IFN and RBV [2, 4]. In general the SVR rates observed during retreatment follow a similar trend as reported for TPV and BOC and decline according to interferon responsiveness as defined by the previous treatment response. Patients with prior relapse had the highest SVR rates regardless of which PI was utilized. Patients with prior null response had the lowest SVR rates.

SOF, PEG-IFN and RBV is administered for only 12 weeks and in the phase 3 trial no placebo control was utilized [6]. Virtually all patients treated with SOF triple therapy achieved a RVR and the overall SVR rate was 89%. In patients with cirrhosis the SVR rate was 80% [6]. SOF triple therapy has not been evaluated in patients who failed either PEG-IFN and RBV or triple therapy with a PI [23, 24].

There is no doubt that the newer antiviral agents SIM, FAL and SOF will be easier to tolerate and they appear to be more effective than TPV and BOC. The major impediment to their widespread use will be that these agents will still require PEG-IFN. Many patients, particularly those with less fibrosis may therefore choose to delay therapy and opt for a future all oral antiviral regimen which is anticipated to be available by late 2014 or in 2015. In contrast, patients with cirrhosis will be more likely to seek treatment, and physicians will be more likely to treat these patients now with an interferon containing regimen that appears safer and is perceived to be superior. We fully expect that SOF, SIM and/or FAL triple therapy will be widely utilized in patients with cirrhosis in much the same manner as TPV and BOC were soon after these agents became available several years ago. The CUPIC study and other studies in patients with advanced cirrhosis clearly demonstrated that treating such patients with an interferon containing regimen is associated with significant morbidity and yields an SVR rate far below that observed in phase 3 clinical trials [19, 22]. We would expect somewhat similar results when SOF, SIM and/or FAL triple therapy are utilized in this population as well.

Genotypes 4, 5 and 6

Genotype 4 is the most common genotype of HCV in Egypt and many other middle eastern countries [23, 24]. HCV genotype 5 is most prevalent in South Africa and HCV genotype 6 is most common in Vietnam and its neighbouring countries. In the USA and many European countries genotype 4 accounts for a small, but not insignificant percentage of patients with HCV whereas HCV genotypes 5 and 6 appear limited to those persons who emigrated from areas of the world where these genotypes of HCV are more common. SOF, PEG-IFN and RBV is highly effective in patients with HCV genotypes 4, 5 and 6. Although only 35 patients with genotypes 4–6 were included in the single arm phase 3 trial, 96% of patients with genotype 4, and all 7 patients with genotypes 5 and 6 achieved an SVR [6].

It is currently unknown if the interferon free oral antiviral regimens being developed for HCV genotype 1 would also be effective in patients with genotypes 4, 5 and 6. These genotypes were not included in the ongoing phase 3 clinical trials and it would therefore be very unlikely that these first generation interferon free regimens would be approved for use in patients with these other genotypes. For this reason it seems logical to proceed with treatment in all patients with genotypes 4, 5 and 6 now utilizing SOF triple therapy.

Genotype 2

SOF and RBV yield superior SVR rates compared with PEG-IFN and RBV in patients with HCV genotype 2. In treatment naïve patients 12 weeks of SOF and RBV achieved SVR rates of 91 and 98% in patients with and without cirrhosis respectively [6, 8]. In patients who had previously failed PEG-IFN and RBV SVR rates of 96 and 60% were observed with 12 weeks of treatment [8]. Why the SVR rate with 12 weeks of SOF and RBV was lower in patients with cirrhosis who previously failed PEG-IFN therapy compared with a treatment naïve population remains unclear. Extending the duration of SOF from 12 to 16 weeks did increase the SVR in this subgroup of patients with cirrhosis and prior PEG-IFN non-response to 78% [8]. Given these results in the absence of PEG-IFN there appears to be no good reason why treatment with SOF and RBV should not be initiated in any patient with HCV genotype 2. Although 12 weeks of treatment will be sufficient in the majority of patients, this should probably be prolonged to 16 weeks in patients with cirrhosis and prior PEG-IFN non-response. Whether the regulatory bodies make this recommendation remains to be seen.

Genotype 3

Genotype 3 is now the most difficult of all the HCV genotypes to cure. The reasons for this remain unclear, but could be related to the much higher percentage of hepatic steatosis associated with this type of HCV [25]. The same is true when these patients are treated with SOF and RBV. The SVR rate observed with 12 weeks of SOF and RBV were only 34 and 61% for patients with and without cirrhosis and very similar to that observed with PEG-IFN and RBV [6, 8]. Prolonging the duration of SOF and RBV to 16 weeks increased the SVR rate in all patients with this genotype to 63–61% [8]. We expect the regulatory authorities will recommend that patients with HCV genotype 3 be treated with SOF and RBV for 16 weeks. Given that the SVR rates with SOF and RBV are suboptimal and either similar to or only marginally higher than observed with PEG-IFN and RBV the main reason to select the all oral combination is to avoid the side effects associated with PEG-IFN and RBV.

Additional DAA agents, which could be utilized with SOF and RBV, are currently being evaluated for patients with HCV genotype 3. Until these agents are shown to be effective and approved it is very reasonable to defer treatment in patients with genotype 3 and mild fibrosis. In contrast, patients and their physicians will be more likely and willing to use SOF and RBV, despite a suboptimal SVR, in patients with cirrhosis. It is rationale to assume that adding PEG-IFN to SOF and RBV would elevate the SVR rate in patients with genotype 3. A small preliminary study suggests this may be correct; 20/24 (83%) patients including 10/12 (83%) with cirrhosis achieved SVR following 12 weeks of treatment with SOF, RBV and PEG-IFN [26]. Until larger studies confirm these findings it is unclear if regulatory bodies and insurance carriers would approve and fund this combination, SOF triple therapy in patients with HCV genotype 3.

Mixing and matching antiviral agents

In 2014, both SIM and SOF will have been approved and available for use in the USA and many European countries. Both agents are highly effective against HCV genotype 1. In a small pilot study of patients with HCV genotype 1 and prior non-response all patients treated with the combination of SIM and SOF for 12 weeks achieved SVR [27]. To our knowledge, no additional formal studies utilizing these two agents is planned by their respective manufacturers. It is therefore unlikely that regulatory authorities and payers will authorize payment for this combination. However, if such approval could be obtained the combination of SIM and SOF would appear to be an excellent and safe combination with which to treat all patients with HCV genotype 1, especially those with advanced cirrhosis.

A few thoughts about cost

It is relatively intuitive that patients would rather be treated and physicians would rather prescribe several non-toxic oral DAAs than deal with the side effects of a PEG-IFN containing regimen. This is especially true if the SVR rates for the two regimens are similar. There is no doubt that a therapy that cures more patients with HCV can be shown to be more cost effective than a treatment with a lower cure rate. However, the payer, whether a private insurance carrier or a government entity may not will be willing to pay a substantially higher cost for medication that yields a similar SVR even though the more economical choice is associated with a higher side effect profile. There are many patients with chronic HCV that already have favourable response profiles. This includes a low serum HCV RNA level, mild fibrosis, prior relapse and IL28B genotype CC. The later patients already enjoy an SVR rate of over 90% and both retrospective and prospective data strongly suggest that this high SVR rate can be preserved with just 12 weeks of TPV triple therapy [28, 29]. Waiting for an interferon free all oral regimen may yield an easier treatment, but it is unlikely that this would be associated with any higher chance of SVR in certain subpopulations. Health care dollars are becoming more limited and tailoring treatment to each patient's response characteristics may be a more rational approach than treating all HCV patients with a more costly albeit easier regimen.

Conclusions

Continued improvement in our ability to ‘cure’ HCV has been made within the past year when we last reviewed the reasons to treat or wait in patients with mild fibrosis. Two new PIs and a polymerase inhibitor are now or will soon be available. In patients with genotypes 2 and 3 an interferon free all oral treatment is already or will soon be available. In patients with genotype 1 these new agents will still be utilized with PEG-IFN; but an IFN-free all oral option appears to be only another 12–18 months away.

This manuscript has summarized our current treatment for HCV and provided reasons for treating now as well as reasons why patients with mild fibrosis should continue to defer treatment. These reasons are summarized in Table 2. The vast majority of patients can be cured of HCV with our current PEG-IFN containing therapies and the only reason to wait is to avoid the side effects of IFN. However, as the duration of therapy is reduced to as little as 3 months the concern for interferon side effects becomes less of an issue. No two patients are the same and in the end it all comes down to presenting the patient with their choices and proceeding with what the patient is most comfortable doing.

Table 2. Factors that affect the decision to treat now or delay therapy

	Treat now	Delay treatment
Genotype 1	IL28B genotype CC or CT Low viral load Compensated cirrhosis Previous relapse or partial response with PEG-IFN/RBV	IL28B genotype TT Mild fibrosis Decompensated cirrhosis Previous null response with PEGINF/RBV Failure to achieve SVR with a protease inhibitor PEG-IFN/RBV
Genotype 4, 5 and 6	All patients without cirrhosis and stable cirrhosis	Decompensated cirrhosis
Genotype 2	All patients
Genotype 3	All patients with bridging fibrosis and cirrhosis	Patients with mild fibrosis

Disclosure

MLS is an advisor for Abbvie, Achillion, Boehringer-Ingelheim, Bristol-Myers-Squibb, Gen-Probe, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis and Roche/Genentech; speaks on behalf of Bayer, Boehringer-Ingelheim, Gilead, Janssen, Merck, Roche/Genentech and Vertex and receives grant support from Abbvie, Achillion, Beckman-Colter, Bristol-Myers-Squibb, Boehringer-Ingelheim, Gilead, Idenix, Intercept, Merck, Novartis and Vertex. YB has no conflicts of interest to declare.

References

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Egyptians hold their breath as new Hepatitis C drugs promise cure

In Egypt, millions suffering from genotype 4 Hepatitis C count the days until the official approval of new breakthrough drugs, hoping for affordable prices

Ingy Deif, Tuesday 24 Dec 2013

Photo: Reuters

A development paving the road to the possible future eradication of Hepatitis C has emerged, causing the world to buzz with hope.

Recently, a number of Hepatitis C drugs had been introduced worldwide by five companies leading the research in that field. The aim was to produce a drug that, for the first time, was presented in the form of pills rather than injections – like the traditional Interferon – with minimal side effects, and with the ability to treat all 6 genotypes of Hepatitis C, with no drug interaction.

"Two drugs in particular were approved by the FDA a month ago," Dr Gamal Esmat, Professor of Hepatology and vice president of Cairo University, told Ahram Online. "Now the testing process is focusing on more than one drug in that regard, and those drugs under trial are either used by themselves or with other traditional Hepatitis C drugs depending on the programme, with a treatment duration varying from three to six months.”

Dr Wahid Doss, dean of the Liver Institute in Cairo and head of the National Committee for Control of Viral Hepatitis, told Ahram Online that although one of the new drugs – Sofosbuvir – was approved by the FDA, its introduction must probably be delayed until April. "The drug was tested on Egyptians abroad and proved effective, but we still have to make sure it complies with and suits the citizens living inside the country.”

Doss stressed that the new drug use cannot be officially initiated until those who undergo trial prove to be Hepatitis C free three months after the termination of drug administration.

Esmat spoke to Ahram Online about the strategy of introducing the new Hepatitis drugs in Egypt. “Five years ago the world witnessed a new approach of handling the disease which relies on tackling the enzymes that contribute to the reproduction and thriving of the virus," he said.

He added that in 2011 two new drugs – Tela Previr and Boceprevir – were introduced in Egypt, but they were not suitable with the genotype 4 Hepatitis C from which 90 percent of Egyptian patients suffer, and they caused side effects and drug interaction.

Of the six genotype strains of the virus, the fourth – previously treated with two combined drugs: Interferon, which targets the immune system, and Ribavirin – causes the majority of infections in Egypt.

Hepatitis C infection is notoriously the foremost step to the possibility of liver cirrhosis, liver failure, and ultimately liver cancer – the third leading cause of cancer-related deaths worldwide, which has spiked in Egypt from four percent in 1993 to 8.5 percent in 2005.

Although the primary tests hold very optimistic results and promise a breakthrough in eradicating the disease, the cost is unaffordable to the majority, with a price tag reaching $90,000.

"A classic case in that regard worldwide was the reduction of HIV medications provided to developing countries to put a halt to the ever increasing number of sufferers," Esmat said, adding that the government is currently negotiating ways to attain one of the new Hepatitis C drugs at an affordable price, exactly as was done with Interferon when it was provided in 23 government-related treatment centres in exchange for almost 10 percent of its original price, with the rest paid by medical insurance.

"Let’s hope that the same happens again with the new approved drug and an even better price reduction is offered to people. The upcoming months will hold the answer to that," he said.

In Egypt – which tops the list of countries suffering from this chronic disease – the soaring numbers of individuals carrying the Hepatitis C virus has been on the rise, causing much alarm.

The number had reached 8 million in 2008, according to the Health Ministry registry of that year, translating into nearly 10 percent of the population, while in some Upper Egypt and the Delta areas, the percentage is a staggering 20 percent.

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FDA's Fast Track

Provided by WLS-TV/DT

Thursday, December 26, 2013

December 26, 2013 (WLS) -- Speeding the development and availability of drugs that treat serious diseases are in everyone's interest, especially when the drugs are the first available treatment. The FDA developed a distinct approach to make sure these drugs are available as soon as possible, called Fast Track.

Researchers are on the fast track to develop a drug that could reverse fibrosis and cirrhosis in the kidneys, lungs, and liver of patients who have NASH-non-alcoholic steatohepatitis-more commonly known as fatty liver disease. Researchers say that currently there is not a FDA approved drug for fibrosis, so the potential is huge.

NASH affects between 9 to 15 million Americans. Over time, patients can develop fibrosis and about three million will develop cirrhosis. The phase 1 clinical trial will enroll patients at six clinical sites in the U.S.

Another potential breakthrough receiving fast track status is a treatment to improve overall survival in patients with metastatic non-small cell lung adenocarcinoma, who have progressed following one chemotherapy regimen.

The drug would be administered in combination with docetaxel. Lung cancer is the leading cause of cancer-related deaths in the world. Non-small cell adenocarcinoma accounts for 40 percent of all lung cancers. It is being evaluated in over 20 clinical trials.

By the way, in 2012 the FDA granted fast track status to 22 drugs. To learn more about the program, go to fda.gov.

BACKGROUND: Fast track is a new process that is created to speed the course of drug review. This was designed so patients with serious illness can receive their drugs at a quicker rate. This process will help patients who are in need of their medications to survive or to function. Heart failure, AIDS, cancer and Alzheimer's are all diseases that Fast Track will work with because it is imperative that these patients receive their medication and treatment. Other illnesses and conditions are considered for the process as well, like diabetes, epilepsy and depression. This process must be requested by the drug company and approved by the FDA before medication is administered, but this will cut the wait time for prescription drugs and keep patients more comfortable and satisfied. (Source: http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/speedingaccesstoimportantnewtherapies/ucm128291.htm)

NONALCOHOLIC STEATOHEPATITIS: Galectin Therapeutics was recently approved by the FDA to release GR-MD-02 to Fast Track. GR-MD-02 is a complex carbohydrate drug that focuses on the galectin-3 protein to reverse liver, kidney and lung cirrhosis. This drug is targeted towards patients who suffer from NASH, nonalcoholic steatohepatitis with advanced fibrosis. This "silent" liver disease affects two to five percent of Americans and is becoming more common due to the growth in obesity. Gelactin Therapeutics conducted a clinical trial on patients with NASH consisting of four weekly doses of GR-MD-02. Forty volunteers at six different clinical sites in the U.S. participated in the study to measure the tolerability and safety of the product. Below is a list of locations that hosted the study:

• The Mount Sinai Medical Center (Division of Liver Diseases)
• Emory University Hospital (Transplant Center Clinical Research)
• Indiana University School of Medicine
• Virginia Commonwealth University Medical Center
• Brooke Army Medical Center
• St. Louis University School of Medicine

(Source: http://digestive.niddk.nih.gov/ddiseases/pubs/nash/ and http://phx.corporate-ir.net/phoenix.zhtml?c=135403&p=irol-newsArticle&ID=1846800&highlight)

METASTATIC NON-SMALL CELL LUNG ADENOCARCINOMA: Lung cancer is the leading cause of cancer deaths in the U.S. in both men and women. However, it is one of the most preventable cancers if detected in early stages. Synta Pharmaceuticals released a drug to stop cancer cell processes. Synta held more than 20 clinical trials with over 700 patients for the product to evaluate the effects on patients. The clinical trial is still ongoing but is not recruiting volunteers. Here are the locations where the trial was studied:

U.S.
• Tucson, Arizona
• Boston, Massachusetts
• Santa Monica, California
• Winston-Salem, North Carolina
• Atlanta, Georgia
• Kettering, Ohio
• Chicago, Illinois
• Portland, Oregon

Other:
• Canada
• Russian Federation
• Croatia
• Serbia
• Czech Republic
• Spain
• Poland
• United Kingdom
• Romania
• Germany

(Source: mayoclinic.org/lung-cancer/ and syntapharma.com)

(Copyright ©2013 WLS-TV/DT. All Rights Reserved.)

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Patient heal thyself: Solution to treatment for chronic infections could lie in patient's blood

by PressRelease • December 26, 2013

This discovery gives hope for a more effective and cheaper treatment strategy to millions worldwide suffering from chronic infections

1. A recent discovery by scientists at A*STAR’s Singapore Institute for Clinical Sciences (SICS), in close collaboration with researchers at the Singapore Immunology Network (SIgN), provides hope for a new personalised treatment strategy that could use a patient’s own blood to treat the infection. This could help treat millions of people living with chronic infections such as HIV, Hepatitis B or Hepatitis C. These findings were published in the issue of The Journal of Clinical Investigation.

2. Patients suffering from chronic infections often have to undergo long periods of anti-viral drug therapy to control the virus. Anti-viral drugs are not fully effective against viruses such as Hepatitis B and Hepatitis C, which have chronically-infected about 400 million worldwide with more than 1,000,000 people dying from Hepatitis-related diseases every year.

3. Vaccines are a potentially effective means to treat chronic viral infections such as this because they can eliminate the virus naturally. However, vaccines for patients with chronic infections are often difficult to produce since these patients already have weak immune responses or the vaccine is not effective due to genetic diversity amongst viruses.

4. The team at SICS led by Prof Antonio Bertoletti has discovered that monocytes, a type of white blood cell that can activate an immune response, are able to capture the virus in chronically-infected patients and use the captured virus to boost the patient’s own immune response.

5. By using the viral antigen already present in the blood of the patient suffering from a chronic illness, this strategy redefines therapeutic vaccines by cutting down on time and resources as there is no need to specially isolate the viral proteins from patients, purify it, and then inactivate it to create a vaccine.

6. All the proteins present within the virus can be used to create a personalised vaccine for each individual. This also means that many of the complex issues associated with current vaccine therapy against chronic infections can be overcome, such as that of genetic diversity of viruses.

7. One of the greatest beneficiaries of this discovery would be chronically-infected patient populations in lower socio-economic strata. By tailoring vaccines to be more specific to each virus and each patient, vaccine production can be simplified and thus less costly. Vaccines produced via this discovery could improve the accessibility of such treatments.

8. Prof Bertoletti said, “Mobilizing the immune system to use the virus within the patient for a vaccine is a simple idea that could lead to a personalised, yet widely applicable, vaccine for chronic infections.”

9. Prof Judith Swain, Executive Director of SICS said, “This excellent collaborative discovery between SICS and SIgN is a milestone in vaccine therapy for chronic infections. I believe that these findings will go a long way in improving future therapeutic treatments for chronic infections.”

The research findings described in this media release can be found in the August 2013 online issue of The Journal of Clinical Investigation under the title, “Mobilizing monocytes to cross-present circulating viral antigen in chronic infection” by Adam J. Gehring1, Muzlifah Haniffa2,3, Patrick Kennedy4, Zi Zong Ho1, Carolina Boni5, Amanda Shin3, Nasirah Banu1, Adeline Chia1, Seng Gee Lim6, Carlo Ferrari5, Florent Ginhoux3, and Antonio Bertoletti1,7,8

1 Infection and Immunity Programme, Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore.
2 Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom.
3 Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Singapore.
4 Center for Digestive Disease, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, United Kingdom.
5 Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
6 Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
7 Program Emerging Viral Diseases, Duke-NUS Graduate Medical School, Singapore.
8 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

http://www.a-star.edu.sg

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HCV direct-acting antiviral agents: the best interferon-free combinations

Liver International

Special Issue: Proceedings of the 7th Paris Hepatitis Conference International Conference of the Management of Patients with Viral Hepatitis, 13–14 January 2014, Paris, France. Guest Editors: Patrick Marcellin and Tarik Asselah. The publication of this supplement was supported by an unrestricted educational grant from Gilead, Janssen Therapeutics, Janssen, Bristol-Myers Squibb, Roche, Boehringer Ingelheim, Merck, AbbVie, Novartis, Idenix and Alios.

Volume 34, Issue Supplement s1, pages 69–78, February 2014

Review Article

You have free access to this content

Raymond Schinazi^1,*,Philippe Halfon², Patrick Marcellin³, Tarik Asselah^3,*

Article first published online: 23 DEC 2013

DOI: 10.1111/liv.12423

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Keywords: asunaprevir; daclatasvir; faldaprevir; pegylated interferon; ribavirin; simeprevir; sofosbuvir

Abstract

For HCV infection, there have been major advancements during last several years with large numbers of ongoing trials with various direct-acting antivirals (DAA) showing high potency, favourable tolerability profile, higher barrier to resistance, shortened treatment duration, all oral regimen, pan-genotypic, fewer drug interactions and reduced pill burden. By 2014, several DAAs are anticipated to complete successful phase III trials and will be commercially available. Initially, a wave of IFN-based regimen (sofosbuvir, faldaprevir and simeprevir) will be available for treatment of HCV genotype 1. In the near future, combination of antiviral agents with additive potency that lack cross-resistance with good safety profile will likely be the new recommended regimens, making HCV, the first chronic viral infection to be eradicated worldwide with a finite duration of combination DAA therapy without IFN or ribavirin. The aim of this review was to summarize the results obtained from recent DAA combination studies without IFN.

Hepatitis C virus (HCV) is a major cause of chronic liver disease, with an estimated 170 million people infected worldwide [1]. HCV, identified in 1989, is an enveloped virus with a 9.6 kb single-stranded RNA genome [2], a member of the Flaviviridae family, genus Hepacivirus. The development of new molecules called direct-acting antivirals (DAA) is ongoing [3]. The aim of this review is to summarize recent results obtained with IFN-free regimens for HCV treatment.

Viral replication cycle and targets for drug development

The HCV replication cycle begins with virion attachment to its specific receptor. The HCV RNA genome serves as a template for viral replication and as a viral messenger RNA for viral production. It is translated into a polyprotein that is cleaved by proteases followed by viral assembly. Potentially, each step of the viral cycle is a target for drug development. The knowledge of the structures of HCV protease and HCV polymerase has allowed structure-based drug design to develop inhibitors targeting these enzymes [4, 5]. Several findings suggest that HCV modulation of IFN induction and signalling attenuates the expression of IFN stimulated genes, allowing HCV to escape the antiviral actions of the host response [6, 7].

All the major HCV-induced enzymes, namely, NS2-3 and NS3-4A proteases, NS3 helicase and NS5B RNA-dependent RNA polymerase (RdRp), are essential for HCV replication and are potential drug discovery targets (Fig. 1). Therefore, DAA with different viral targets, such as NS3 protease inhibitors, nucleoside/nucleotide analogue and non-nucleoside inhibitors of the RdRp, and NS5A inhibitors are under development. General characteristics of different classes of DAA are shown in Table 1.

Figure 1. Hepatitis C virus (HCV) genome and potential drug discovery targets. The HCV RNA genome serves as a template for viral replication and as a viral messenger RNA for viral production. It is translated into a polyprotein that is cleaved by proteases. All the HCV enzymes – NS2-3 and NS3-4A proteases, NS3 helicase and NS5B RdRp – are essential for HCV replication and are therefore potential drug discovery targets.

Protease inhibitors

The NS3 serine protease is located in the N-terminal region of NS3. The NS3 serine protease domain is associated with the NS4A cofactor to cleave four specific sites.

This enzyme has been extensively characterized at the biochemical level and its structure is known [4, 5]. The serine protease activity of NS3 is an attractive target for new drugs that could effectively block viral replication. The NS3/4A protease inhibitors can be divided into two chemical classes: macrocyclic inhibitors and linear tetra-peptide a-ketoamid derivatives. In 2003, a macrocyclic protease inhibitor (BILN 2061; ciluprevir) that blocks HCV replication in the replicon model was shown to be effective in humans [8-10]. Characteristics of protease inhibitors are presented in Table 2.

Although proteases inhibitors are potent, they have several potential limitations. Protease inhibitors are highly specific and as the amino acid sequence of the NS3 protease domain differs significantly between HCV genotypes, they exhibit varying activities across genotypes. For instance, telaprevir is less effective in treatment-naïve subjects infected with genotypes other than genotype 1. Furthermore, as HCV has a high mutation replication rate, with a lack of proofreading, resistance is an issue for this class of drugs.

The genetic barrier to resistance is defined as the number of amino acid substitutions required to confer full resistance to a drug. Usually, DAA with a low genetic barrier to resistance require only one or two amino acid substitutions for high resistance. DAA with a high barrier to resistance usually require three or more amino acid substitutions in the same region to confer loss of activity.

The genetic barrier to protease inhibitors is usually low and resistance differs significantly between HCV genotypes. Viral resistance to telaprevir occurred much more frequently in genotype 1a compared with genotype 1b. This is believed to be the result of nucleotide differences at position 155 in HCV subtype 1a (AGA, encodes R) vs. 1b (CGA, also encodes R). The mutation most frequently associated with resistance to telaprevir was R155K; changing R to K at position 155 requires only one nucleotide change in HCV subtype 1a and two nucleotide changes in subtype 1b isolates [11] making GT1a more susceptible to emergence of resistance. As illustrated with the R155K mutation, which reduces replication capacity in the replicon model [12], resistance mutations frequently impair viral fitness. However, under antiviral pressure, during continued therapy, second site mutations are selected that restore fitness, explaining why the R155K primary mutation is frequently found in association with V36M in genotype 1a viruses. Therefore, it is recommended to immediately discontinue treatment in subjects with viral breakthrough and good adherence to therapy.

The main weaknesses of the first-generation PIs are their low genetic barrier to resistance and the fact that their effectiveness is limited to GT-1 patients. Second-wave PIs have a higher barrier to resistance, better activity against multiple genotypes except GT-3, more convenient dosing schedules and improved safety and tolerance [13-18]. Second-generation PIs are compounds that are broadly active against all genotypes and against viral isolates that carry resistance mutations for first-generation PIs. In combination with PR, the new PIs appear to achieve greater SVR rates than the first-generation PIs. These new treatments allow for more convenient administration schedules (one or two administrations per day); this could result in improved pharmacokinetics and better patient compliance. Besides, the safety profile seems to be good. The pan-genotypic activity of these new treatments provides new therapeutic options for a greater number of patients, in particular for those infected with GT-4.

Table 2 provides an overview of the efficacy and tolerance of the second-wave PIs that are currently developed. Few data are available concerning second-wave PIs for cirrhotic patients. In a phase IIb study, 83 GT-1 treatment-experienced cirrhotic patients were treated with simeprevir 100 or 150 mg QD and PR for 12, 24 or 48 weeks followed by PR alone up to week 48. The SVR rates were 73% for previous relapsers, 82% for partial responders and 31% for null responders (for those treated with 150 mg QD); in all cases, the SVR rates were higher than in the PR arms.

In the pivotal Phase 3 trials, C208, C216 and HPC3007, simeprevir in combination with PR was demonstrated to be superior to placebo (in combination with PR) in achieving an SVR in both HCV treatment-naïve subjects and relapsers [13, 14]. In the subgroup of subjects with the Q80K baseline polymorphism, a substantial impact on the efficacy of simeprevir was observed.

Polymerase inhibitors

Polymerase inhibitors interfere with viral replication by binding to the NS5B RNA-dependent RNA polymerase. NS5B RNA polymerase inhibitors can be divided into two different types – nucleoside inhibitors (NI) and non-nucleoside inhibitors (NNI). NI mimic the natural substrates of the polymerase and are incorporated into the RNA chain causing direct chain termination [19, 20]. NI are compounds that require conversion to an active triphosphate form. As the active site of NS5B is highly conserved, NI are generally pan-genotypic (effective against all the different genotypes). However, single amino acid substitutions in every position of the active site may result in loss of function of the NI, but resistance to nucleoside analogue inhibitors is typically very low in humans as this virus has reduced fitness.

In contrast, NNI bind to several discrete sites outside of the HCV polymerase active centre, which results in conformational protein change before the elongation complex is formed [19, 20]. NS5B is structurally organized in a characteristic ‘right-hand motif’ containing finger, palm and thumb domains, and offers at least four NNI-binding sites, namely, benzimidazole (thumb 1)-binding, thiophene (thumb 2)-binding, benzothiadiazine (palm1)-binding and benzofuran-(palm 2)-binding sites.

Resistance is more frequent with NNI compared with NI. However, mutations at NNI-binding sites do not necessarily lead to impaired function of the enzyme. Characteristics of polymerase inhibitors are presented in Table 3.

NS5A inhibitors

The NS5A is a membrane-associated phosphoprotein present in basally phosphorylated (p56) and hyperphosphorylated (p58) forms [20-22]. It was previously reported that only p58-defective mutants could be complemented in trans, and NS5A is involved in HCV virion production, suggesting that different forms of NS5A exert multiple functions at various stages of the viral life cycle [21, 22]. The N terminus of NS5A (domain I) has been crystallized in alternative dimeric forms and contains both zinc- and RNA-binding domains, properties that have been demonstrated in vitro. NS5A has been shown to interact with a number of host proteins and plays a role in interferon resistancein vivo [20, 21]. Daclastavir is active at picomolar concentrations in vitro in HCV replicons expressing a broad range of HCV genotypes and acts in an additive to synergistic fashion with interferon and other DAAs [20-22]. The resistance profile of daclastavir reveals inhibitor sensitivity maps to the N terminus of domain 1 of NS5A [21]. It has been demonstrated that NS5A inhibitors could block hyperphosphorylation of NS5A, which is believed to play an essential role in the viral replication cycle.

Interferon-free combination trials

Several IFN-free combination trials are ongoing with different DAAs that target multiple viral sites: NS3/4a protease inhibitors, NS5B polymerase inhibitors (NI and NNI) and NS5A inhibitors. There have been major advancements in the last several years with large numbers of trials with various DAA showing increased SVR rates, favourable tolerability and shortened treatment duration with all oral regimens. The priorities for future combination are listed in Table 3. Fortunately, there will be opportunities to reduce cross-resistance[23]. Among unmet need, genotype 4-infected subjects need to be considered. Approximately 20% among the 170 millions of HCV-infected subjects worldwide are genotype 4 (approximately 34 millions). The standard treatment for HCV GT4 is PEG-IFN plus ribavirin for 48 weeks. Naive GT4 IL28B non-CC subjects have SVR rates lower than 50% with the standard PEG-IFN plus ribavirin for 48 weeks [24]. Furthermore, GT4 previous relapsers or non-responders have very low chance of being cured with the same regimen.

HCV drug development is shorter than, for example, HIV drug development because of short treatment duration, the option of open-label studies without the need of a control arm and also the primary end point for efficacy is SVR12 (12 weeks post-treatment follow-up), which is as relevant as 24 weeks to determine the SVR [25]. At present, several advanced studies of DAA combinations are ongoing, especially in more difficult-to-cure infected individuals.

IFN-free regimen for genotype 1-naïve and -experienced subjects

Results of IFN-free DAA regimens in treatment-naive GT1 individuals are presented in Figure 2 and for treatment-experienced GT1 in Figure 3.

Faldaprevir with or without RBV (Boehringer-Ingelheim)

SOUND-C2 is an open-label, randomized, Phase IIb study that enrolled 362 treatment-naïve HCV genotype-1 subjects into one of five treatment arms. The study evaluated the safety and efficacy of faldaprevir (protease inhibitor) and deleobuvir (polymerase inhibitor), with and without RBV [26, 27]. Final results from this study showed that up to 85% of HCV individuals infected with genotype-1b (GT-1b) achieved SVR. The optimal regimen was 28 weeks of faldaprevir (QD) and deleobuvir (BID). This study, which was the largest interferon-free trial of its kind to be conducted to date, included persons with cirrhosis. SVR was achieved in 70% overall subjects, compared with 85% seen in the prevalent GT-1b subject subgroup. Nine per cent of the total population had cirrhosis and this subgroup achieved SVR rates of up to 67% [26].

The most common adverse events (AEs) in SOUND-C2 were mild skin changes (itchy skin, rash or photosensitivity) or gastrointestinal disorders and transient indirect hyperbilirubinemia which sometimes presented as jaundice. Thirty six per cent of subjects experienced an AE, of which 12% were considered severe and 8% led to discontinuation of treatment. IFN-free phase III studies are ongoing.

Furthermore, faldaprevir plus deleobuvir plus PPI-668 (NS5A inhibitor) with or without ribavirin in persons with genotype 1a infection was studied [28]. Thirty-seven individuals with GT1a (without cirrhosis) were included. At week 4, HCV RNA was undetectable (<25 IU/ml) for 97% of subjects (35/36). SVR4 was available for 13 persons, and all had undetectable HCV RNA.

Aviator study: ABT-450/r, ABT-267, ABT-333 (Abbvie) with or without RBV

The Aviator phase 2b study assesses the safety and efficacy of ABT-450/r (dosed 100/100 mg to 200/100 mg QD), ABT-267 (25 mg QD), ABT-333 (400 mg BID) and RBV (weight based dosing) in non-cirrhotic treatment-naïve subjects and in prior PEG-IFN/RBV null responders for 8, 12 or 24 weeks [29]. ABT-450 is a ritonavir-boosted protease inhibitor [30]; ABT-267 is an NS5A inhibitor and ABT-333 is an NS5B polymerase NNI. Enrolment was open to GT1-infected individuals regardless of IL28B host genotype. SVR12 in treatment-naïve genotype 1 (GT1) subjects was 97.5% (77 of 79) and 93.3% (42 of 45) in GT1 null responder subjects. In GT1a subjects, SVR12 was achieved in 96% (52 of 54) of treatment-naïve subjects and 89% (25 of 28) of null responder subjects. In GT1b subjects, SVR12 was achieved in 100% of treatment-naïve (25 of 25) and null responder subjects (17 of 17). In addition, a separate Phase 2a, open-label study was conducted in treatment-naive and partial/null responders administered treatment for 12 weeks. A total of 19 subjects previously untreated subjects were enrolled in group 1, 14 previously untreated persons in group 2 and a total of 17 subjects with a null or partial response to previous therapy in group 3. Results from the 12-week triple-DAA regimen without RBV in treatment-naïve subjects showed that SVR12 was achieved in all individuals who completed treatment (95%) in group 1, 93% in group 2 and 47% in group 3.

The treatment was well tolerated. There was one treatment discontinuation in group 1 because of elevated levels of aspartate aminotransferase and alanine aminotransferase at week 2. No serious adverse event or death occurred in this study. The most common AEs were fatigue (47, 43 and 35%), nausea (21, 21 and 24%) and headache (26, 14 and 18%) for groups 1, 2, and 3 respectively.

Furthermore, ABT-450/r plus ABT-267 regimen was studied in genotype 1b-naive subjects (n = 42) and null responders (n = 40); all without cirrhosis [31] (PEARL I). SVR of 95.2% for treatment-naive subjects, and 90% for null responders was reported. The triple-DAA combination is currently being studied in Phase III clinical trials.

Sofosbuvir, GS-5885 and ribavirin (Gilead) (Electron study)

Interim data from the ongoing Phase 2 Electron study examining a 12-week course of therapy with the NS5B nucleotide inhibitor sofosbuvir, the NS5A inhibitor GS-5885 and ribavirin in subjects with genotype 1 chronic hepatitis C virus (HCV) infection were reported[32]. Among treatment-naïve individuals receiving this combination, 100% (n = 25/25) remained HCV RNA undetectable 4 weeks after completing therapy (SVR4). Among the nine genotype 1 previous null responders who were treated with sofosbuvir, GS-5885 and ribavirin for 12 weeks, three of the nine subjects have reached the 4-week post-treatment time point and all three remain HCV-negative. Both sofosbuvir in combination with RBV or GS-5885 plus RBV were well tolerated in this study. The most common AEs were headache, fatigue, upper respiratory tract infection and nausea. The most common clinically significant grade 3/4 laboratory abnormality was a haemoglobin reduction.

Phase 3 trial (ION-I) evaluating a fixed-dose combination of sofosbuvir and GS-5885 in treatment-naïve genotype 1 subjects are ongoing. This four-arm study is evaluating the fixed-dose combination with or without ribavirin for 12- and 24-week durations in 800 subjects, 20% of whom have evidence of cirrhosis.

Daclastavir (Bristol Myer Squibb) plus Sofosbuvir (Gilead) with or without RBV

This phase II trial was designed to test the combination of daclatasvir (NS5A inhibitor) and sofosbuvir in HCV GT1, 2 and 3, with or without RBV, for 12 or 24 weeks of therapy, and with or without a week-long run-in period with sofosbuvir [33].

A total of 44 subjects with the viral genotypes 2 and 3 were enrolled in three arms – one with a 7-day sofosbuvir run-in period followed by 23 weeks of the two together, one with the combination for 24 weeks and one with the combination plus ribavirin for 24 weeks. Eighty-eight per cent of subjects in the first group reached an SVR12, compared with 100% in the second group and 86% in the third group.

In genotype 1, the trial had 3 arms, with a total of 44 subjects with the same regimens as in the genotype 2/3 subjects. They also tested the combination with and without RBV for 12 weeks in a total of 82 subjects. All subjects receiving the first three regimens achieved an SVR12 and, all but one remained undetectable at SVR24. It was reported that out of the 82 subjects in the 12-week arms, 68 had reached 12 weeks post-treatment and all had SVR12.

Daclatasvir, asunaprevir and BMS-791325 (BMS)

Daclatasvir is the first NS5A replication complex inhibitor to be investigated in HCV clinical trials and is currently in Phase III development. Asunaprevir is an NS3 protease inhibitor in Phase III development with daclatasvir. BMS-791325 is a NS5B polymerase NNI, currently in Phase II development for HCV as a component of daclatasvir-based treatment regimens. A Phase II study evaluated the above three different classes of DAAs – daclastavir, asunaprevir and BMS-791325 administered for 12 or 24 weeks in treatment-naïve persons with genotype 1 chronic HCV infection [34]. In the 24-week group, 94% achieved SVR4 and in the 12-week treatment group, SVR12 was achieved in 94% of persons. One hundred sixty-six naive GT1 subjects were treated (GT1a 82%; cirrhosis n = 15). SVR12 was 91% for GT1a and 94% for GT1b. Phase III trials with three DAA fixed-dose combination (BID) are anticipated.

Daclatasvir and asunaprevir in genotype 1b prior null responders

Previous data on daclastavir (NS5A inhibitor) and asunaprevir (protease inhibitor) have reported exciting results in genotype 1b null responders [35]. A phase III trial of daclatasvir plus asunaprevir was undertaken that evaluated either IFN ineligible naive/intolerant (n = 135) and non-responders to prior IFN-based therapy (n = 87) in Japanese subjects with genotype 1b infection. The study reported SVR24 rate of 87% in IFN ineligible/intolerant individuals and 81% in non-responders [36].

MK-5172 (QD) plus MK-8742 (QD) (NS5A inhibitor) with or without ribavirin (C-WORTHY Study) (MSD)

This is a Phase 2 study (n = 65) evaluating the combination of once-daily MK-5172 (protease inhibitor) plus MK-8742 (NS5A inhibitor) with or without ribavirin, administered for 12 weeks in genotype 1a- and 1b-naive subjects [37]. Remarkably, the two arms achieved an SVR12 of 100%: MK-8742 dose of 20 mg/day with ribavirin (21/21) and MK-8742 dose of 50 mg/day without ribavirin (12/12), both in combination with 100 mg/day MK-5172.

Simeprevir plus sofosbuvir with or without ribavirin in GT1-naive subjects and prior null responders (COSMOS study)

COSMOS is a Phase 2a, randomized, open-label study that evaluated once-daily combination of protease inhibitor, simeprevir plus sofosbuvir with or without ribavirin for 12 or 24 weeks in GT1-naive subjects (cirrhotic and non-cirrhotic) and prior null responders [38]. Cohort 1 (n = 80) randomized prior null responders persons with METAVIR scores F0-F2 and Cohort 2 (n = 87) evaluated prior null responder and treatment-naïve GT1 individuals with METAVIR scores F3-F4.

In cohort 1, prior null responders with Metavir F0-F2, SVR8 was 93% (without ribavirin) and 96% (with ribavirin). Viral relapse was observed in three subjects, all in GT1a with Q80K polymorphism mutation. In cohort 2, SVR4 results from the 12-week groups was 96% (with RBV) and 100% (without RBV). SVR4 in cirrhotics was 94% (17/18).

IFN-free regimen for genotype non-1 subjects

Data from several phase III studies of sofosbuvir for genotype non-1 subjects are available [39-41].

The FISSION trial was a randomized, open-label, active-controlled, phase III study of sofosbuvir plus RBV in naïve subjects with GT2 or GT3 HCV infection; subjects with the two genotypes were enrolled in approximately 1:3 ratio [39]. Subjects were randomly assigned in a 1:1 ratio to receive either 12 weeks of sofosbuvir plus RBV or 24 weeks of PEG-IFN/RBV. The doses of sofosbuvir and RBV were the same as those administered in the Neutrino trial. The dose of RBV for subjects in the PEG-IFN/RBV group was 800 mg daily. Sofosbuvir–RBV was shown to be non-inferior to PEG-IFN/RBV. At 12 weeks, the rates of SVR for subjects receiving 12 weeks of sofosbuvir/RBV and those receiving 24 weeks of PEG-IFN/RBV were each 67%. A SVR occurred in 97% of subjects with GT2 and in 56% of those with GT3 in the group receiving sofosbuvir/RBV, as compared with response rates of 78 and 63%, respectively, in the group receiving PEG-IFN/RBV. Among subjects with cirrhosis at baseline, 47% of those receiving sofosbuvir/RBV had a SVR, as compared with 38% of those receiving PEG-IFN/RBV.

The POSITRON trial was a blinded, placebo−controlled phase III study that compared 12 weeks of treatment with sofosbuvir and RBV with matching placebo in GT2 and GT3 HCV-infected subjects who had previously discontinued IFN-therapy because of unacceptable adverse events, who had a concurrent medical condition precluding therapy with an IFN−containing regimen, or who had decided against treatment with an IFN−containing regimen [34]. The most common reasons that IFN treatment was not an option were clinically significant psychiatric disorders (in 57% of subjects) and autoimmune disorders (in 19%).

The rate of SVR at 12 weeks after treatment was 78% among subjects receiving sofosbuvir/RBV compared with 0% among those receiving placebo (P < 0.001). Among subjects who received sofosbuvir/RBV, 93% of subjects with GT2 HCV infection had an SVR compared with 61% with GT3 HCV infection. Likewise, 81% of subjects without cirrhosis (92% of subjects with GT2 HCV infection and 68% of those with GT3 HCV infection) had a SVR as compared with 61% of subjects with cirrhosis (94% of subjects with GT2 HCV infection and 21% of those with GT3 HCV infection).

The FUSION study was a blinded, active−controlled phase III study involving GT2 and GT3 HCV-infected subjects who had no response to prior treatment with an IFN−containing regimen [40]. Approximately 75% of the previously treated subjects enrolled had either virological breakthrough during the prior treatment or virological relapse afterwards; the remainder did not have a response. The rates of SVR achieved were superior to the historical control rate of 25%, with rates of 50% in the 12-week group and 73% in the 16-week group (P < 0.001 for each comparison). Rates of SVR between the groups showed that subjects receiving 16 weeks of treatment had a significantly higher rate of SVR than subjects receiving 12 weeks of treatment (P < 0.001). The rates of SVR among subjects with GT2 HCV infection who received 12 weeks of treatment and those who received 16 weeks of treatment were 86 and 94%, respectively, compared with 30 and 62% for 12 and 16 weeks of treatment, respectively, among subjects with GT3 HCV infection.

Cirrhosis was associated with a decreased rate of SVR, particularly among subjects with GT3 HCV infection who received 12 weeks of treatment. Among subjects with cirrhosis who received 12 weeks of treatment, the rate of SVR was 31% (60% with GT2 HCV infection and 19% with GT3 HCV infection) as compared with 61% among subjects without cirrhosis (96% with GT2 HCV infection and 37% with GT3 HCV infection). Among subjects with cirrhosis who received 16 weeks of treatment, the rate of SVR was 66% (78% with GT2 HCV infection and 61% with GT3 HCV infection) as compared with 76% among subjects without cirrhosis (100% with GT2 HCV infection and 63% with GT3 HCV infection). Results of these trials are summarized in Figure 4.

Figure 4. IFN-free trials for non-genotype 1 subjects

Conclusion

The standard of care for treatment of HCV GT1 improved with the introduction of telaprevir and boceprevir in 2011, which is used in combination with peg-IFN and RBV triple therapy. Triple therapy has improved SVR rates and treatment durations for many individuals with GT1 HCV infection. However, there has been a marked paradigm shift in the management of HCV infection as a result of the promising outcomes from recent studies with DAA combinations reporting increased SVR, low or no resistance and a good safety profile. There is a realistic hope for an all oral regimen against HCV in the near future, as several compounds with different mechanisms of action with synergistic interactions and pan-genotypic activity are in advanced drug development.

However, limitations to HCV treatment still exist particularly with comorbid conditions and in difficult-to-cure persons with advanced liver disease including those with decompensated cirrhosis. These individuals on newer therapy still have additional treatment-limiting adverse events and drug interactions. Furthermore, issues such as resistance and treatment failures, especially in the previously treated population, will need to be overcome with new drugs and combinations. Additional guidance may be obtained by genetic testing, but availability of alternative regimens for therapy is still needed for HCV. A pangenotypic once-daily or weekly regimens that will treat all populations with an SVR12 of greater than 95% is needed that can even be used safely in children and to prevent mother-to-child HCV transmission would be the ultimate goal. However, much progress has been made since HCV was first discovered in 1989. Based on the recent encouraging results from the widely studied IFN-free regimens in non-GT1 infection, it is possible that in the future, HCV may be the first chronic viral infection to be eradicated worldwide with one or more antiviral drug. The concept of treatment as prevention and a cure is gaining traction and will need to be applied globally to eradicate this virus from the face of the earth as we succeeded with smallpox in 1977.

Perspectives and therapeutic strategies

Simple strategies with complexes combination based or not based using back-bone of Nucleoside inhibitors are ongoing development regarding the availability of the new DAA:

In genotype 1 patients

• Using nucleoside analogues the combination with PR+sofosbuvir have to be in balance with the IFN-free based on NI+NS5A±RBV or NI+PI±RBV
• Without using nucleoside analogues: the combination with PR+PI have to be in balance with the IFN-free based on PI+NS5A±RBV or PI±NNI+RBV or PI±NNI+NS5A+RBV

In genotype 2 and 3 patients

• i. Genotype 2: the combination of sofosbuvir plus RBV for 12 weeks that leads to SVR higher than 90% might be the next standard of care
• ii. Genotype 3

Naïve: the combination of sofosbuvir plus RBV for 24 weeks that leads to SVR around 80%, or other DAAs in the near future, may be proposed

Treatment Experienced:

• iii. In non-cirrhotic patients, the combination of SOF+RBV for 24 weeks-treatment lead to a 85% SVR

In cirrhotic patients, the combination of PR+RBV+SOF for 12 weeks of treatment leading to a 83% SVR has to be in balance with the combination of SOF+RBV for 24 weeks of treatment, which leads to a 60% SVR. In genotype 4 patients, there will be several possibilities: PEG-IFN plus RBV, combination of SOF + RBV for 16–24 weeks, triple therapy with SOF plus PEG-IFN/RBV, or Simeprevir plus PEG-IFN/RBV for 12–24 weeks. Future IFN-free regimen might be available for HCV genotype 4-infected patients.

Acknowledgments

This work was supported in part by CFAR NIH grant 2P30AI-050409 (to RFS) and by the Department of Veterans Affairs (to RFS). We thank Judy Mathew and Steve Coats for proofing this manuscript. Dr. Schinazi is the founder and a major shareholder of RFS Pharma, LLC.

Conflicts of interest: Tarik Asselah is a speaker and investigator for BMS, Boehringer-Ingelheim, Tibotec, Janssen, Gilead, Roche and MSD. Patrick Marcellin is a speaker and investigator for BMS, Boehringer-Ingelheim, Tibotec, Janssen, Gilead, Roche and MSD. Raymond Schinazi is the founder and major shareholder of RFS Pharma, LLC. Philippe Halfon is a speaker for Roche, Merck, Janssen and shareholder of Alphabio and Genoscience.

References

Source

Is there still a role for PEG IFN+RBV therapy in patients with HCV genotype 1?

Liver International

Special Issue: Proceedings of the 7th Paris Hepatitis Conference International Conference of the Management of Patients with Viral Hepatitis, 13–14 January 2014, Paris, France. Guest Editors: Patrick Marcellin and Tarik Asselah. The publication of this supplement was supported by an unrestricted educational grant from Gilead, Janssen Therapeutics, Janssen, Bristol-Myers Squibb, Roche, Boehringer Ingelheim, Merck, AbbVie, Novartis, Idenix and Alios.

Volume 34, Issue Supplement s1, pages 11–12, February 2014

Review Article

You have free access to this content

Lawrence Serfaty^*

Article first published online: 23 DEC 2013

DOI: 10.1111/liv.12407

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Keywords: boceprevir; low viral load; Pegylated interferon; rapid virological response; ribavirin; telaprevir

Abstract

Boceprevir and telaprevir-based triple therapy is now the standard of care for the treatment of genotype 1 patients. However, dual therapy with pegylated interferon and ribavirin should be discussed in treatment-naïve patients with good predictors of response. A recent published trial has shown in non-cirrhotic patients with low viral load at baseline, similar efficacy of a 24-week course of dual therapy vs a 24-week course of boceprevir-based triple therapy in case of rapid virological response. Accordingly, addition of protease inhibitor should be discussed after 4 weeks of dual therapy in this easy-to-treat population.

Boceprevir (BOC) and telaprevir (TPV) are direct acting antiviral agents that target the protease of the hepatitis C virus (HCV). In combination with pegylated interferon (PEG) and ribavirin (RBV) they increase the effectiveness of antiviral therapy in naïve patients infected with genotype 1 resulting in an increase in sustained virological response (SVR) from around 40% to nearly 70% or more [1, 2]. The major disadvantages of protease inhibitors (PIs) are the possible development of viral resistance (which may be long lasting and reduce future treatment options) and a range of side effects. Furthermore, PIs are expensive and substantially increase the overall cost of therapy. Therefore, while triple therapy is now the standard of care for treatment of genotype 1 patients [3], we will discuss whether dual therapy with PEG-IFN/RBV has still a place and in which subgroup of patients.

Predictors of response to PEG-IFN/RBV

The factors favouring response to PEG/RBV have been well-identified. In treatment-naïve patients with genotype 1, they are mainly age (<40 years), viral load (<600 000 IU/ml), absence of severe fibrosis and absence of insulin resistance [4]. Nucleotide polymorphisms on chromosome 19 upstream of the interleukin 28B (IL28B) gene have been found to be strongly associated with SVR [5, 6]. The statistical weight of this parameter appears to be similar to that of viral genotype. In CC homozygotes (rs12979860) of Caucasian origin (around 30% of patients) without severe fibrosis, the percentage of SVR was estimated to be 86% vs 36% and 43% for genotypes TT and CT respectively [7]. Analysis of viral kinetics indicated that a rapid virological response (RVR) was obtained in 30% of CC patients vs 5% of CT or TT patients. Therefore, around 80% of patients that achieved a RVR were CC homozygotes. The chance of achieving a SVR in patients achieving a RVR was greater than 90%, regardless of IL28B genotype. In contrast, in CC homozygotes who do not achieve a RVR the probability of achieving a SVR was only 60% [7]. Thus, by considering IL28B genotype and virological response at week 4 it is possible to identify a subgroup of patients with mild fibrosis in whom PEG-IFN/RBV therapy results in a SVR in 90% and in whom triple therapy would probably not be more effective. It is interesting to note that in this group, triple therapy can be shortened from 48 weeks to 24 or 28 weeks.

PEG-IFN/RBV in patients with low viral load and rapid virological response

In patients with low baseline viral load (<400 000 IU/ml) who achieve RVR, a short course (24 weeks) of PEG-IFN/RBV therapy is sufficient to obtain a SVR [8]. In these patients, PEG-IFN/RBV is still clearly the best option. Accordingly, French guidelines have recommended that PEG-IFN/RBV therapy should be considered the first-line treatment in treatment-naive genotype 1 patients with predictive factors for a good response to treatment [9]. A recently published trial has confirmed these recommendations [10]. In 233 treatment-naïve patients with HCV genotype1 without cirrhosis and with a low baseline viral load (<600 000 IU/ml) who are treated with PEG-IFN/RBV lead-in therapy, 101 (48%) with a RVR were randomized to 20 weeks of additional therapy with PEG-IFN/RBV or to 24 weeks of PEG-IFN/RBV/BOC. The rate of SVR was similar in both groups (88% vs 90%), regardless of viral subtype, IL28B or ethnicity. Safety was also similar for side effects, rates of dose reduction (33% vs 33%) or discontinuation (8% vs 6%). These results indicate that adding PI does not change the duration of therapy or efficacy of treatment in treatment naïve patients without cirrhosis with a low baseline viral load who achieve RVR.

PEG-IFN/RBV in treatment-experienced patients ?

Triple therapy is clearly the standard of care in treatment-experienced patients [3, 9]. However, PEG-IFN/RBV can be a therapeutic option in some patients with a resistant variant in whom PI treatment has failed. We reported the case of a patient who relapsed after a 12 week course of TPV-based triple therapy and who was cured by a 48 week-course of dual therapy despite the presence of a resistant variant[11]. While waiting for new molecules retreatment with reinforced regimen of PEG-IFN/RBV could be a therapeutic option in genotype 1-naïve patients who relapse after PI-based triple therapy.

Conclusion

In the setting of first generation PI-based triple therapy, dual therapy with PEG-IFN/RBV is still a therapeutic option in treatment-naïve patients with HCV genotype 1 and good predictors of response (absence of cirrhosis, low baseline viral load ± IL28B CC). In this subgroup of patients, triple therapy should be discussed depending on the RVR at the end of a 4-week course of dual therapy. This discussion could theoretically be extended to the use of next generation PIs based on triple therapy such as simeprevir or faldaprevir, for a treatment duration of at least 24 weeks [12, 13]. Regarding sofosbuvir-based triple therapy, the 12 weeks fixed duration for all patients should be a strong argument against the use of dual therapy, [14]. In the near future, all-oral regimens with high SVR rates and good safety will probably mean the end of interferon-based therapy for the treatment of chronic hepatitis C [15].

References

Source