Hepatitis C virus: Here comes all-oral treatment

doi: 10.3949/ccjm.81a.13155 Cleveland Clinic Journal of Medicine March 2014 vol. 81 3 159-172

EDUCATIONAL OBJECTIVE: Readers will assimilate direct-acting antiviral drugs into the treatment of patients with chronic hepatitis C virus infection

MOHANNAD DUGUM, MD

ROBERT O’SHEA, MD⇑

+ Author Affiliations

ADDRESS: Robert O’Shea, MD, Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, 9500 Euclid Avenue/A30, Cleveland, OH 44195; e-mail: oshear@ccf.org

Abstract

Treatment for chronic hepatitis C virus (HCV) infection is evolving rapidly. The approval in 2013 of two new direct-acting antivirals—sofosbuvir (a polymerase inhibitor) and simeprevir (a second-generation protease inhibitor)—opens the door for an all-oral regimen, potentially avoiding interferon and its harsh side effects. Other direct-acting antivirals are under development.

Key points

In clinical trials of treatment for chronic HCV infection, regimens that included a direct-acting antiviral agent were more effective than ones that did not.

Sofosbuvir is approved in an oral dose of 400 mg once daily in combination with ribavirin for patients infected with HCV genotype 2 or 3, and in combination with ribavirin and interferon in patients infected with HCV genotype 1 or 4. It is also recommended in combination with ribavirin in HCV-infected patients with hepatocellular carcinoma who are awaiting liver transplantation.

Simeprevir is approved in an oral dose of 150 mg once daily in combination with ribavirin and interferon for patients with HCV genotype 1.

The new drugs are expensive, a potential barrier for many patients. As more direct-acting antiviral agents become available, their cost will likely decrease.

Combinations of direct-acting antiviral agents of different classes may prove even more effective and could eliminate the need for interferon entirely.

In late 2013, the US Food and Drug Administration (FDA) approved sofosbuvir and simeprevir, the newest direct-acting antiviral agents for treating chronic hepatitis C virus (HCV) infection. Multiple clinical trials have demonstrated dramatically improved treatment outcomes with these agents, opening the door to all-oral regimens or interferon-free regimens as the future standard of care for HCV.

See related editorial, page 173

In this article, we discuss the results of the trials that established the efficacy and safety of sofosbuvir and simeprevir and led to their FDA approval. We also summarize the importance of these agents and evaluate other direct-acting antivirals currently in the pipeline for HCV treatment.

HCV IS A RISING PROBLEM

Chronic HCV infection is a major clinical and public health problem, with the estimated number of people infected exceeding 170 million worldwide, including 3.2 million in the United States.¹ It is a leading cause of cirrhosis, and its complications include hepatocellular carcinoma and liver failure. Cirrhosis due to HCV remains the leading indication for liver transplantation in the United States, accounting for nearly 40% of liver transplants in adults.²

The clinical impact of HCV will only continue to escalate, and in parallel, so will the cost to society. Models suggest that HCV-related deaths will double between 2010 and 2019, and considering only direct medical costs, the projected financial burden of treating HCV-related disease during this interval is estimated at between $6.5 and $13.6 billion.³

Drugs mentioned in this paper

• boceprevir (Victrelis)
• interferon
• ribavirin (Rebetol, Copegus)
• simeprevir (Olysio)
• sofosbuvir (Sovaldi)
• telaprevir (Incivek)

RNA VIRUS WITH SIX GENOTYPES

HCV, first identified in 1989, is an enveloped, single-stranded RNA flavivirus of the Hepacivirus genus measuring 50 to 60 nm in diameter.⁴ There are six viral genotypes, with genotype 1 being the most common in the United States and traditionally the most difficult to treat.

Once inside the host cell, the virus releases its RNA strand, which is translated into a single polyprotein of about 3,000 amino acids. This large molecule is then cleaved by proteases into several domains: three structural proteins (C, E1, and E2), a small protein called p7, and six nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) (FIGURE 1).⁵ These nonstructural proteins enable the virus to replicate.

FIGURE 1

GOAL OF TREATING HCV: A SUSTAINED VIROLOGIC RESPONSE

The aim of HCV treatment is to achieve a sustained virologic response, defined as having no detectable viral RNA after completion of antiviral therapy. This is associated with substantially better clinical outcomes, lower rates of liver-related morbidity and all-cause mortality, and stabilization of or even improvement in liver histology.^6,7 This end point has traditionally been assessed at 6 months after the end of therapy, but recent data suggest the rates at 12 weeks are essentially equivalent.

Interferon plus ribavirin: The standard of care for many years

HCV treatment has evolved over the past 20 years. Before 2011, the standard of care was a combination of interferon alfa-polyethylene glycol (peg-interferon), given as a weekly injection, and oral ribavirin. Neither drug has specific antiviral activity, and when they are used together they result in a sustained virologic response in fewer than 50% of patients with HCV genotype 1 and, at best, in 70% to 80% of patients with other genotypes.⁸

Nearly all patients receiving interferon experience side effects, which can be serious. Fatigue and flu-like symptoms are common, and the drug can also cause psychiatric symptoms (including depression or psychosis), weight loss, seizures, peripheral neuropathy, and bone marrow suppression. Ribavirin causes hemolysis and skin complications and is teratogenic.⁹

An important bit of information to know when using interferon is the patient’s IL28B genotype. This refers to a single-nucleotide polymorphism (C or T) on chromosome 19q13 (rs12979860) upstream of the IL28B gene encoding for interferon lambda-3. It is strongly associated with responsiveness to interferon: patients with the IL28B CC genotype have a much better chance of a sustained virologic response with interferon than do patients with CT or TT.

Boceprevir and telaprevir: First-generation protease inhibitors

In May 2011, the FDA approved the NS3/4A protease inhibitors boceprevir and telaprevir for treating HCV genotype 1, marking the beginning of the era of direct-acting antiviral agents.¹⁰ When these drugs are used in combination with peg-interferon alfa and ribavirin, up to 75% of patients with HCV genotype 1 who have had no previous treatment achieve a sustained virologic response.

But despite greatly improving the response rate, these first-generation protease inhibitors have substantial limitations. Twenty-five percent of patients with HCV genotype 1 who have received no previous treatment and 71% of patients who did not respond to previous treatment will not achieve a sustained virologic response with these agents.¹¹ Further, they are effective only against HCV genotype 1, being highly specific for the amino acid target sequence of the NS3 region.

Also, they must be used in combination with interferon alfa and ribavirin because the virus needs to mutate only a little—a few amino-acid substitutions—to gain resistance to them.¹² Therefore, patients are still exposed to interferon and ribavirin, with their toxicity. In addition, dysgeusia is seen with boceprevir, rash with telaprevir, and anemia with both.^13,14

Finally, serious drug-drug interactions prompted the FDA to impose warnings for the use of these agents with other medications that interact with CYP3A4, the principal enzyme responsible for their metabolism. Thus, these significant adverse effects dampen the enthusiasm of patients contemplating a long course of treatment with these agents.

The need to improve the rate of sustained virologic response, shorten the duration of treatment, avoid serious side effects, improve efficacy in treating patients infected with genotypes other than 1, and, importantly, eliminate the need for interferon alfa and its serious adverse effects have driven the development of new direct-acting antiviral agents, including the two newly FDA-approved drugs, sofosbuvir and simeprevir.

SOFOSBUVIR: A POLYMERASE INHIBITOR

Sofosbuvir is a uridine nucleotide analogue that selectively inhibits the HCV NS5B RNA-dependent RNA polymerase (FIGURE 1). It targets the highly conserved nucleotide-binding pocket of this enzyme and functions as a chain terminator.¹⁵ While the protease inhibitors are genotype-dependent, inhibition of the highly conserved viral polymerase has an impact that spans genotypes.

Early clinical trials of sofosbuvir

Sofosbuvir has been tested in combination with interferon alfa and ribavirin, as well as in interferon-free regimens (TABLE 2).^16–20

Rodriguez-Torres et al,¹⁵ in an early double-blind clinical trial, randomized 64 previously untreated patients with HCV genotype 1 to receive one of three doses of oral sofosbuvir (100, 200, or 400 mg) plus interferon and ribavirin or placebo plus interferon and ribavirin for 4 weeks, followed by 44 weeks of interferon and ribavirin alone. The rates of sustained virologic response were:

• 56% with sofosbuvir 100 mg, peg-interferon, and ribavirin

• 83% with sofosbuvir 200 mg, peg-interferon, and ribavirin

• 80% with sofosbuvir 400 mg, peg-interferon, and ribavirin

• 43% with peg-interferon and ribavirin alone.

The ATOMIC trial¹⁶ tested the efficacy and safety of sofosbuvir in combination with peg-interferon and ribavirin in patients with HCV genotype 1, 4, or 6, without cirrhosis, who had not received any previous treatment. Patients with HCV genotype 1 were randomized to three treatments:

• Sofosbuvir 400 mg orally once daily plus peg-interferon and ribavirin for 12 weeks

• The same regimen, but for 24 weeks

• Sofosbuvir plus peg-interferon and ribavirin for 12 weeks, followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin.

The rates of sustained virologic response were very high and were not significantly different among the three groups: 89%, 89%, and 87%, respectively. Patients who were able to complete a full course of therapy achieved even higher rates of sustained virologic response, ranging from 96% to 98%. The likelihood of response was not adversely affected by the usual markers of a poorer prognosis, such as a high viral load (≥ 800,000 IU/mL) or a non-CC IL28B genotype. Although patients with cirrhosis (another predictor of no response) were excluded from this study, the presence of bridging fibrosis did not seem to affect the rate of sustained virologic response. The results in patients with genotypes other than 1 were very encouraging, but the small number of patients enrolled precluded drawing firm conclusions in this group.

Important implications of the ATOMIC trial include the following:

There is no benefit in prolonging treatment with sofosbuvir beyond 12 weeks, since adverse events increased without any improvement in the rate of sustained virologic response.

There is a very low likelihood of developing viral resistance or mutation when using sofosbuvir.

There is no role for response-guided therapy, a concept used with protease inhibitor-based regimens in which patients who have complete clearance of the virus within the first 4 weeks of treatment (a rapid virologic response) and remain clear through 12 weeks of treatment (an extended rapid viral response) can be treated for a shorter duration without decreasing the likelihood of a sustained virologic response.

Lawitz et al¹⁷ conducted a randomized double-blind phase 2 trial to evaluate the effect of sofosbuvir dosing on response in noncirrhotic, previously untreated patients with HCV genotype 1, 2, or 3. Patients with HCV genotype 1 were randomized to one of three treatment groups in a 2:2:1 ratio: sofosbuvir 200 mg orally once daily, sofosbuvir 400 mg orally once daily, or placebo, all for 12 weeks in combination with peg-interferon (180 μg weekly) and ribavirin in a dosage based on weight. Depending on the viral response, patients continued peg-interferon and ribavirin for an additional 12 weeks if they achieved an extended rapid viral response, or 36 weeks if they did not achieve an extended rapid virologic response, and in all patients who received placebo. Patients with HCV genotype 2 or 3 were given sofosbuvir 400 mg once daily in combination with interferon and ribavirin for 12 weeks.

As in the ATOMIC trial, all patients treated with sofosbuvir had a very rapid reduction in viral load: 98% of patients with genotype 1 developed a rapid virologic response, and therefore almost all were eligible for the shorter treatment course of 24 weeks.¹⁷ The latter finding again suggested that response-guided treatment is not relevant with sofosbuvir-based regimens.

Very high rates of sustained virologic response were seen: 90% in patients with genotype 1 treated with sofosbuvir 200 mg, 91% in those with genotype 1 treated with 400 mg, and 92% in those with genotype 2 or 3. Although 6% of patients in the 200-mg group had virologic breakthrough after completing sofosbuvir treatment, no virologic breakthrough was observed in the 400-mg group, suggesting that the 400-mg dose might suppress the virus more effectively.¹⁷

The ELECTRON trial¹⁸ was a phase 2 study designed to evaluate the efficacy and safety of sofosbuvir and ribavirin in interferon-sparing and interferon-free regimens in patients with HCV genotype 1, 2, or 3 infection. Sofosbuvir was tested with peg-interferon and ribavirin, with ribavirin alone, and as monotherapy in previously untreated patients with genotype 2 or 3. A small number of patients with genotype 1 who were previously untreated and who were previously nonresponders were also treated with sofosbuvir and ribavirin.

All patients had a rapid virologic response, and viral suppression was sustained through the end of treatment. All patients with genotype 2 or 3 treated with double therapy (sofosbuvir and ribavirin) or triple therapy (sofosbuvir, peg-interferon, and ribavirin) achieved a sustained virologic response, compared with only 60% of patients treated with sofosbuvir monotherapy. The monotherapy group had an equal number of relapsers among those with genotype 2 or 3. Of the genotype 1 patients treated with sofosbuvir and ribavirin, 84% of those previously untreated developed a sustained virologic response, whereas only 10% of the previous nonresponders did.

Phase 3 clinical trials of sofosbuvir

The NEUTRINO trial¹⁹ studied the efficacy and safety of sofosbuvir in previously untreated patients with HCV genotype 1, 4, 5, or 6. In this phase 3 open-label study, all patients received sofosbuvir plus peg-interferon and weight-based ribavirin therapy for 12 weeks. Of the patients enrolled, 89% had genotype 1, while 9% had genotype 4 and 2% had genotype 5 or 6. Overall, 17% of the patients had cirrhosis.

The viral load rapidly decreased in all patients treated with sofosbuvir irrespective of the HCV genotype, IL28B status, race, or the presence or absence of cirrhosis. Ninety-nine percent of patients with genotype 1, 4, 5, or 6 achieved a rapid virologic response, and 90% achieved a sustained virologic response at 12 weeks after completion of treatment with sofosbuvir and ribavirin. Patients with cirrhosis had a slightly lower rate of sustained virologic response (80%, compared with 92% in patients without cirrhosis). Also, patients with non-CC IL28B genotypes had a lower rate of sustained virologic response (87% in non-CC allele vs 98% in patients with the favorable CC allele).

The FISSION trial¹⁹ recruited previously untreated patients with genotype 2 or 3 and randomized them to therapy with either sofosbuvir plus ribavirin in a weight-based dose for 12 weeks, or 24 weeks of interferon and ribavirin. In this study, 20% of patients in each treatment group had cirrhosis.

As in the NEUTRINO trial, the viral load rapidly decreased in all patients treated with sofosbuvir irrespective of HCV genotype, IL28B status, race, or the presence or absence of cirrhosis. Here, 100% of patients with genotype 2 or 3 who were treated with sofosbuvir and ribavirin achieved a rapid virologic response. Differences in outcome emerged based on genotype: 97% of those with genotype 2 and 56% of those with genotype 3 achieved a sustained virologic response. The overall rate was 67%, which was not different from patients treated with peg-interferon and ribavirin. In the subgroup of patients with cirrhosis, 47% of those treated with sofosbuvir and ribavirin achieved a sustained virologic response, vs 38% of those who received peg-interferon plus ribavirin.

In both the NEUTRINO and FISSION trials, few patients discontinued treatment, with higher rates of most adverse events occurring in patients treated with peg-interferon and ribavirin.

POSITRON,²⁰ a phase 3 clinical trial, tested sofosbuvir in patients with HCV genotype 2 or 3 who were ineligible for peg-interferon, unwilling to take peg-interferon, or unable to tolerate peg-interferon (mainly because of clinically significant psychiatric disorders). Patients were randomized to two treatment groups for 12 weeks: sofosbuvir plus ribavirin, or placebo. About 50% of patients had HCV genotype 3, and 16% had cirrhosis.

The overall rate of sustained virologic response at 12 weeks after treatment was 78% in the sofosbuvir-and-ribavirin group (93% in genotype 2 patients and 61% in genotype 3 patients). Again, cirrhosis was associated with a lower rate of sustained virologic response (61% of patients with cirrhosis achieved a sustained virologic response vs 81% of patients without cirrhosis). None of the sofosbuvir-treated patients had virologic failure while on treatment.

FUSION,²⁰ another phase 3 trial, evaluated sofosbuvir in patients infected with HCV genotype 2 or 3 for whom interferon-based treatment had failed. They were randomized to either 12 weeks or 16 weeks of sofosbuvir and weight-based ribavirin treatment. About 60% of patients had HCV genotype 3, and 34% had cirrhosis.

The overall sustained virologic response rate was 50% in the patients treated for 12 weeks and 73% in those treated for 16 weeks: specifically, 86% of patients with genotype 2 achieved a sustained virologic response at 12 weeks and 94% at 16 weeks, whereas in those with genotype 3 the rates were 30% at 12 weeks and 62% at 16 weeks.

Cirrhosis was again a predictor of lack of response to sofosbuvir. In the group treated for 12 weeks, 31% of those with cirrhosis achieved a sustained virologic response compared with 61% in those without cirrhosis. In the group treated for 16 weeks, 61% of those with cirrhosis achieved a sustained virologic response compared with 76% in those without cirrhosis.

In both the POSITRON and FUSION trials, relapse accounted for all treatment failures, and no virologic resistance was detected in patients who did not have a sustained virologic response. The investigators concluded that 12 weeks of treatment with sofosbuvir and ribavirin can be effective for HCV genotype 2 infection, but extending the treatment to 16 weeks may be beneficial for genotype 3. This may be especially important in patients with cirrhosis or those who did not have a response to peg-interferon-based treatment.

VALENCE,²¹ an ongoing phase 3 trial in Europe, is assessing the safety and efficacy of sofosbuvir 400 mg once daily and weight-based ribavirin in patients with HCV genotype 2 or 3. Eighty-five percent of the trial participants have received previous treatment, and 21% have cirrhosis. Patients were originally randomized in a 4:1 ratio to receive sofosbuvir plus ribavirin for 12 weeks or matching placebo, but as a result of emerging data suggesting that patients with genotype 3 would benefit from more than 12 weeks of treatment, the study was subsequently amended to extend treatment to 24 weeks for patients with genotype 3.

Overall rates of sustained virologic response were 93% in patients with genotype 2 and 85% in patients with genotype 3. In previously treated patients with genotype 2 who were treated for 12 weeks, the rates of sustained virologic response were 91% in those without cirrhosis vs 88% in those with cirrhosis. In previously treated patients with genotype 3, the rates in those treated for 24 weeks were 87% in patients without cirrhosis vs 60% with cirrhosis. The safety profile was consistent with that of ribavirin.

Side effects of sofosbuvir

In clinical trials, side effects occurred most often when sofosbuvir was combined with interferon and ribavirin and were consistent with the known side effects of the latter two agents. The most frequently reported side effects included fatigue, insomnia, nausea, rash, anemia, headache, and arthralgia, with most of these adverse events rated by treating clinicians as being mild in severity.^15,20

In the ATOMIC trial, the most common events leading to drug discontinuation were anemia and neutropenia, both associated with interferon and ribavirin. Patients receiving sofosbuvir monotherapy after 12 weeks of triple therapy showed rapid improvement in hemoglobin levels and neutrophil counts, indicating that hematologic abnormalities attributed solely to sofosbuvir are minimal. In the FISSION trial, the incidence of adverse events was consistently lower in those receiving sofosbuvir-ribavirin than in patients receiving interferon-ribavirin without sofosbuvir.¹⁹

In the POSITRON trial, discontinuation of sofosbuvir because of adverse events was uncommon, and there were no differences in the incidence of adverse events and laboratory abnormalities between patients with and without cirrhosis when they received sofosbuvir and ribavirin.²⁰

Sofosbuvir dosage and indications

Sofosbuvir is approved in an oral dose of 400 mg once daily in combination with ribavirin for patients infected with HCV genotype 2 or 3 and in combination with ribavirin and interferon alfa in patients infected with HCV genotype 1 or 4 (TABLE 3). It could be considered for HCV genotype 1 in combination with ribavirin alone for 24 weeks in patients who are ineligible for interferon.

Sofosbuvir is also recommended in combination with ribavirin in HCV-infected patients with hepatocellular carcinoma who are awaiting liver transplantation, for up to 48 weeks or until they receive a transplant, to prevent posttransplant reinfection with HCV.

Sofosbuvir is expensive

A course of therapy is expected to cost about $84,000, which is significantly more than the cost of previous triple therapy (peg-interferon, ribavirin, and either boceprevir or telaprevir).²² This high cost will undoubtedly lead to less widespread use in developing countries, and potentially even in the United States. As newer direct-acting antiviral agents become available, the price will likely come down, enhancing access to these drugs.

SIMEPREVIR: A SECOND-GENERATION PROTEASE INHIBITOR

Telaprevir and boceprevir are NS3/A4 protease inhibitors that belong to the alfa-ketoamid derivative class. Simeprevir belongs to the macrocyclic class and has a different way of binding to the target enzyme.²³ Like sofosbuvir, simeprevir was recently approved by the FDA for the treatment of HCV genotype 1.

The therapeutic efficacy of simeprevir has been tested in several clinical trials (TABLE 4), including QUEST-1²⁴ and QUEST-2²⁵ (in previously untreated patients), PROMISE²⁶ (in prior relapsers), and ASPIRE²⁷ (in prior partial and null responders). Results from these trials showed high overall rates of sustained virologic response with triple therapy (ie, simeprevir combined with peg-interferon and ribavirin). It was generally well tolerated, and most adverse events reported during 12 weeks of treatment were of mild to moderate severity.

In QUEST-1 and QUEST-2, both double-blind phase 3 clinical trials, previously untreated patients infected with HCV genotype 1 were randomized in a 2:1 ratio to receive either simeprevir 150 mg daily or placebo for 12 weeks; both groups also received peg-interferon and ribavirin. Patients then received peg-interferon and ribavirin alone for 12 or 36 weeks in the simeprevir group (based on response) and for 36 weeks in the placebo group.

The overall rate of sustained virologic response at 12 weeks was 80% in the simeprevir group (75% in those with genotype 1a and 85% in those with genotype 1b) vs 50% in the placebo group (receiving peg-interferon and ribavirin alone).^24,25

PROMISE,²⁶ another double-blind randomized phase 3 clinical trial, evaluated simeprevir in patients with HCV genotype 1 who relapsed after previous interferon-based therapy. It had a similar design to QUEST-1 and QUEST-2, and 15% of all patients had cirrhosis.

The overall sustained virologic response rate at 12 weeks after treatment was 79% in the simeprevir group (70% in patients with genotype 1a and 86% in those with genotype 1b) vs 37% in the placebo group. Rates were similar in patients with absent to moderate fibrosis (82%), advanced fibrosis (73%), or cirrhosis (74%).

ASPIRE.²⁷ Simeprevir efficacy in patients with HCV genotype 1 for whom previous therapy with peg-interferon and ribavirin had failed was tested in ASPIRE, a double-blind randomized phase 2 clinical trial. Patients were randomized to receive simeprevir (either 100 mg or 150 mg daily) for 12, 24, or 48 weeks in combination with 48 weeks of peg-interferon and ribavirin, or placebo plus peg-interferon and ribavirin for 48 weeks.

The primary end point was the rate of sustained virologic response at 24 weeks. Overall, rates were 61% to 80% for the simeprevir treatment groups compared with 23% with placebo, regardless of prior response to peg-interferon and ribavirin. By subgroup, rates were:

• 77% to 89% with simeprevir vs 37% with placebo in prior relapsers

• 48% to 86% with simeprevir vs 9% with placebo in prior partial responders

• 38% to 59% with placebo vs 19% for prior nonresponders.

The best rates of sustained viral response at 24 weeks were in the groups that received simeprevir 150 mg daily: 85% in prior relapsers, 75% in prior partial responders, and 51% in prior nonresponders.

Simeprevir vs other direct-acting antiviral drugs

Advantages of simeprevir over the earlier protease inhibitors include once-daily dosing, a lower rate of adverse events (the most common being fatigue, headache, rash, photosensitivity, and pruritus), a lower likelihood of discontinuation because of adverse events, and fewer drug-drug interactions (since it is a weak inhibitor of the CYP3A4 enzyme).

Unlike sofosbuvir, simeprevir was FDA-approved only for HCV genotype 1 and in combination with interferon alfa and ribavirin. Compared with sofosbuvir, the treatment duration with simeprevir regimens is longer overall (interferon alfa and ribavirin are given for 12 weeks in sofosbuvir-based regimens vs 24 to 48 weeks with simeprevir). As with sofosbuvir, the estimated cost of simeprevir is high, about $66,000 for a 12-week course.

Simeprevir dosage and indications

Simeprevir was approved at an oral dose of 150 mg once daily in combination with ribavirin and interferon alfa in patients with HCV genotype 1 (TABLE 5).

The approved regimens for simeprevir are fixed in total duration based on the patient’s treatment history. Specifically, all patients receive the drug in combination with peg-interferon and ribavirin for 12 weeks. Then, previously untreated patients and prior relapsers continue to receive peg-interferon and ribavirin alone for another 12 weeks, and those with a partial or null response continue with these drugs for another 36 weeks.

Patients infected with HCV genotype 1a should be screened for the NS3 Q80K polymorphism at baseline, as it has been associated with substantially reduced response to simeprevir.

Sofosbuvir and simeprevir in combination

The COSMOS trial.²⁸ Given their differences in mechanism of action, sofosbuvir and simeprevir are being tested in combination. The COSMOS trial is an ongoing phase 2 randomized open-label study investigating the efficacy and safety of simeprevir and sofosbuvir in combination with and without ribavirin in patients with HCV genotype 1, including nonresponders and those with cirrhosis. Early results are promising, with very high rates of sustained virologic response with the sofosbuvir-simeprevir combination (93% to 100%) and indicate that the addition of ribavirin might not be needed to achieve sustained virologic response in this patient population.

THE FUTURE

The emergence of all-oral regimens for HCV treatment with increasingly sophisticated agents such as sofosbuvir and simeprevir will dramatically alter the management of HCV patients. In view of the improvement in sustained virologic response rates with these treatments, and since most HCV-infected persons have no symptoms, the US Centers for Disease Control and Prevention²⁹ recently recommended one-time testing of the cohort in which the prevalence of HCV infection is highest: all persons born between 1945 and 1965. This undoubtedly will increase the detection of this infection—and the number of new patients expecting treatment.

Future drugs promise further improvements (TABLE 6).^30–35 Advances in knowledge of the HCV molecular structure have led to the development of numerous direct-acting antiviral agents with very specific viral targets. A second wave of protease inhibitors and of nucleoside and nonnucleoside polymerase inhibitors will soon be available. Inhibitors of NS5A (a protein important in the assembly of the viral replication complex) such as daclatasvir and ledipasvir, are currently in phase 3 clinical trials. Other viral proteins involved in assembly of the virus, including the core protein and p7, are being explored as drug targets. In addition, inhibiting host targets such as cyclophilin A and miR122 has gained traction recently, with specific agents currently in phase 2 and 3 clinical trials.

Factors that previously were major determinants of response to treatment, such as IL28B genotype, viral load, race, age, extent of fibrosis, and genotype 1 subtypes, will become much less important with the introduction of highly potent direct-acting antiviral agents.

Many all-oral combinations are being evaluated in clinical trials. For example, the open-label, phase 2 LONESTAR trial tested the utility of combining sofosbuvir and ledipasvir (an NS5A inhibitor) with and without ribavirin for 8 or 12 weeks in previously untreated patients with HCV genotype 1, and for 12 weeks in patients with HCV genotype 1 who did not achieve a sustained virologic response after receiving a protease inhibitor-based regimen (half of whom had compensated cirrhosis).³⁶ Sustained virologic response rates were very high (95% to 100%) in both previously treated and previously untreated patients, including those with cirrhosis. Similar rates were achieved by the 8-week and 12-week groups in noncirrhotic patients who had not been previously treated for HCV. The typical hematologic abnormalities associated with interferon were not observed except for mild anemia in patients who received ribavirin. These results suggest that the combination of sofosbuvir and ledipasvir could offer a very effective, short, all-oral treatment for patients with HCV genotype 1, including those with cirrhosis, who up to now have been difficult to treat.

Challenges remaining

The success of sofosbuvir and simeprevir paves the way for interferon-free regimens.³⁷ For a long time, the treatment of HCV infection required close monitoring of patients while managing the side effects of interferon, but the current and emerging direct-acting antiviral agents will soon change this practice. Given the synergistic effects of combination therapy—targeting the virus at multiple locations, decreasing the likelihood of drug resistance, and improving efficacy—combination regimens seem to be the optimal solution to the HCV epidemic. Lower risk of side effects and shorter treatment duration will definitely improve the acceptance of any new regimen. New agents that act against conserved viral targets, thereby yielding activity across multiple genotypes, will be advantageous as well. TABLE 7 compares the rates of sustained virologic response of the different currently approved HCV treatment regimens.

Clinical challenges remain, including the management of special patient populations for whom data are still limited. These include patients with cirrhosis, chronic kidney disease, renal failure, and concurrent infection with human immunodeficiency virus, and patients who have undergone solid organ transplantation. Clinical trials are under way to evaluate the treatment options for these patients, who will likely need to wait for the emergence of additional agents before dramatic improvement in sustained virologic response rates may be expected.³⁸

As the treatment of HCV becomes simpler, safer, and more effective, primary care physicians will increasingly be expected to manage it. Difficult-to-treat patients, including the special populations above, will require specialist management and individualized treatment regimens, at least until better therapies are available. The high projected cost of the new agents may limit access, at least initially. However, the dramatic improvement in sustained virologic response rates and all that that implies in terms of decreased risk of advanced liver disease and its complications will undoubtedly make these therapies cost-effective.³⁹

• Copyright© 2014 The Cleveland Clinic Foundation

REFERENCES

Source

The Cost of Treatment Failure

Journal of Viral Hepatitis

Resource Use and Costs Incurred by Hepatitis C Virus Genotype 1-Infected Patients Who Do or Do Not Achieve Sustained Virological Response to Therapy

M. Backx, A. Lewszuk, J. R. White, J. Cole, A. Sreedharan, S. van Sanden, J. Diels, A. Lawson, K. R. Neal, M. J. Wiselka, T. Ito, W. L. Irving

J Viral Hepat. 2014;21(3):208-215

Abstract and Introduction

Abstract

Chronic hepatitis C virus (HCV) infection places a considerable economic burden on health services. Cost-effectiveness analyses of antiviral treatment for patients with chronic HCV infection are dependent on assumptions about cost reductions following sustained virological response (SVR) to therapy. This study quantified the medium-term difference in health resource usage and costs depending on treatment outcome. Retrospective chart review of patients with HCV genotype 1 infection who had received at least 2 months pegylated interferon and ribavirin therapy, with known treatment outcome was conducted. Disease status was categorized as chronic hepatitis, cirrhosis or decompensated liver disease. Health resource use was documented for each patient in each disease state. Unit costs were from the NHS 'Payment by Results' database and the British National Formulary. One hundred and ninety three patients (108 SVR, 85 non-SVR) with mean follow-up of 3.5 (SVR) and 4.9 (non-SVR) years were enrolled. No SVR patient progressed to a more severe liver disease state. Annual transition rates for non-SVR patients were 7.4% (chronic hepatitis to cirrhosis) and 4.9% (cirrhosis to decompensated liver disease). By extrapolation of modelled data over a 5-year post-treatment period, failure of patients with chronic hepatitis to achieve SVR was associated with a 13-fold increase (roughly £2300) in costs, whilst for patients who were retreated, the increase was 56-fold, equating to more than £10 000. Achievement of an SVR has significant effects on health service usage and costs. This work provides real-life data for future cost-effectiveness analyses related to the treatment for chronic HCV infection.

Introduction

An estimated 130–170 million people worldwide are chronically infected with hepatitis C virus (HCV), with around 216 000 living in the United Kingdom (UK).^[1] Chronic infection may result in progressive liver damage, leading to cirrhosis and its sequelae in at least 20–30% of individuals.^[2] Both hospital admissions and deaths related to chronic HCV infection are rising in the UK,^[1] and end-stage liver disease resulting from chronic HCV infection is now a leading indication for liver transplantation.^[3] It is estimated that by 2020, nearly 16 000 individuals will be living with HCV-related cirrhosis or hepatocellular carcinoma in England if left untreated.^[4] Estimates of direct medical expenses related to HCV infection in the USA predict a rise in total expenditure to over $10 billion in the next decade.^[5] The management of chronic HCV infection thus places a significant health and economic burden on national health services worldwide.

Until recently, the standard of care (SoC) for chronic HCV infection involved combination therapy with pegylated interferon and ribavirin. For genotype 1 disease, this resulted in a sustained viral response (SVR) in approximately 40–50% of patients,^[6] which in turn results in lower rates of liver-related morbidity and mortality.^[7] Recent advances in the understanding of HCV biology have led to the development of directly acting antiviral (DAA) agents. Two of these therapies, telaprevir and boceprevir, act on the viral NS3/4a protease and, in combination with pegylated interferon and ribavirin, have been shown to significantly improve SVR both in treatment-naïve and in treatment-experienced patients with genotype 1 disease. In the USA, triple therapy is now considered the new standard of care for patients with genotype 1 infection.^[8] In England and Wales, the National Institute for Health and Clinical Excellence (NICE) has recommended the use of telaprevir or boceprevir, each in combination with pegylated interferon and ribavirin, as treatment options for genotype 1 chronic HCV infection in adults with compensated liver disease for both treatment-naïve and treatment-experienced patients.^[9,10]

As treatment options for genotype 1 chronic HCV infection expand, it will be important to understand the cost reductions associated with achievement of an SVR, in addition to the obvious clinical benefits to an individual patient. Previous cost-effectiveness analyses of antiviral therapy have made assumptions that achieving an SVR reduces costs.^[11–13] Prior to this study, no previous paper has contrasted the resource use and costs of genotype 1 patients with and without SVR to assess the relative value of successful antiviral treatment in terms of offsetting morbidity costs.

This study aimed to compare disease progression, use of health services and costs to the UK National Health Service (NHS) between patients with genotype 1 infection who achieved an SVR following pegylated interferon and ribavirin therapy vs those who did not, using real-world data representative of routine NHS practice in the UK.

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Computed tomography findings in liver fibrosis and cirrhosis

19 February 2014, doi:10.4414/smw.2014.13923
Cite this as: Swiss Med Wkly. 2014;144:w13923

Huber Adrian^a, Ebner Lukas^a, Montani Matteo^b, Semmo Nasser^c, Roy Choudhury Kingshuk^d, Heverhagen Johannes^a, Christe Andreas^a

^a Institute of Radiology, University Hospital Inselspital, Bern, Switzerland
^b Institute of Pathology, University of Bern, Switzerland
^c Institute of Hepatology, University Hospital Inselspital, Bern, Switzerland
^d Statistics Department, University College Cork, Ireland

Summary

PRINCIPLES: Computed tomography (CT) is inferior to the fibroscan and laboratory testing in the noninvasive diagnosis of liver fibrosis. On the other hand, CT is a frequently used diagnostic tool in modern medicine. The auxiliary finding of clinically occult liver fibrosis in CT scans could result in an earlier diagnosis. The aim of this study was to analyse quantifiable direct signs of liver remodelling in CT scans to depict liver fibrosis in a precirrhotic stage.

METHODS: Retrospective review of 148 abdominal CT scans (80 liver cirrhosis, 35 precirrhotic fibrosis and 33 control patients). Fibrosis and cirrhosis were histologically proven. The diameters of the three main hepatic veins were measured 1–2 cm before their aperture into the inferior caval vein. The width of the caudate and the right hepatic lobe were divided, and measured horizontally at the level of the first bifurcation of the right portal vein in axial planes (caudate-right-lobe ratio). A combination of both (sum of liver vein diameters divided by the caudate-right lobe ratio) was defined as the ld/crl ratio. These metrics were analysed for the detection of liver fibrosis and cirrhosis.

RESULTS: An ld/crl-r <24 showed a sensitivity of 83% and a specificity of 76% for precirrhotic liver fibrosis. Liver cirrhosis could be detected with a sensitivity of 88% and a specificity of 82% if ld/crl-r <20.

CONCLUSION: An ld/crl-r <24 justifies laboratory testing and a fibroscan. This could bring forward the diagnosis and patients would profit from early treatment in a potentially reversible stage of disease.

Key words: liver fibrosis and cirrhosis; abdominal computed tomography; hepatic vein diameter; caudate right lobe ratio

Introduction

Liver cirrhosis is the final consequence of all chronic liver diseases [1]. Most common causes are alcoholic fatty liver disease (AFLD), nonalcoholic fatty liver disease (NAFLD) and viral hepatitis [2, 3]. Chronic inflammation leads to potentially reversible liver fibrosis and ends in irreversible cirrhosis with cross-linked collagen and regenerative nodules [4]. Early diagnosis improves the benefit of therapeutic strategies before the development of irreversible and potentially lethal complications such as loss of liver function, oesophageal variceal bleeding, hepatic encephalopathy and hepatocellular carcinoma [5, 6].

The noninvasive diagnosis of liver fibrosis and cirrhosis is built on laboratory testing and the well-established fibroscan [7]. Recently, new sensitive methods using magnetic resonance imaging (MRI) have been described, such as MR-elastography [8], double contrast-enhanced MRI [9] and diffusion weighted MRI [10]). Computed tomography (CT) is useful for imaging liver cirrhosis complications, such as portosystemic collaterals with bleeding or hepatocellular carcinoma (HCC). However, this is not an appropriate method for the primary diagnosis of liver fibrosis, because of the radiation dose and inferior accuracy compared to the fibroscan. On the other hand, clinically occult liver fibrosis as an auxiliary finding in routine abdominal CT scans is underdiagnosed. Even liver cirrhosis has a mediocre sensitivity (77.1%–84.3%) and specificity (52.9%–67.6%) in CT [11]. However, since CT is an important and frequently used diagnostic tool in modern medicine, an accurate method to detect liver fibrosis in CT scans could bring forward the diagnosis and enable treatment in an early stage of fibrosis before its clinical appearance.

We hypothesise that indirect findings of liver remodelling occur rather late when chronic portal hypertension has already been established (e.g. splenomegaly, gastrointestinal wall thickening, portosystemic collaterals, recanalisation of the umbilical vein and ascites [12–14]).

Qualitative direct signs of liver remodelling (atrophy of the right liver lobe with a notch between right and caudate lobe, heterogeneity of liver parenchyma, nodular surface, blunt liver edge and enlarged gall bladder fossa [12–14]) are limited parameters as a result of subjective reader impression and experience.

Thus, we propose the use of quantifiable direct signs of hepatic remodelling which are assessable in axial planes without the need for time-consuming image reconstructions.

There are two interesting metrics for direct liver remodelling: the caudate-right lobe ratio (crl-r) [18], which describes the width of the caudate lobe in proportion to the width of the right hepatic lobe, and measurement of the hepatic vein diameters [19]. We hypothesise that these metrics correlate with early liver fibrosis in a precirrhotic stage and can be used as quantifiable markers to depict liver fibrosis in abdominal CT scans. An analysis of these metrics alone and in combination for the detection of liver fibrosis was performed, as was a comparison with other qualitative and quantitative imaging findings.

Patients and methods

Patient population:

A total of 148 patients (108 male/40 female) were retrospectively included between January 2009 and March 2012 at our hospital, including 80 patients with histologically proven liver cirrhosis (fibrosis stage 4), 35 with histologically proven precirrhotic liver fibrosis stage 1–3 and a control group of 33 trauma patients without known liver pathology. The mean age of all selected patients was 57.3 years (range: 32–75 years). Informed consent was not required owing to the retrospective nature of this study.

The 80 patients (59 male/21 female) with liver cirrhosis (29 Child A, 31 Child B, 30 Child C) and the 35 patients with precirrhotic stage of liver fibrosis (6 fibrosis grade 1, 10 fibrosis grade 2 and 19 fibrosis grade 3) were included if they had undergone a CT scan with portal venous phase in the radiological information system (Centricity RISi 4.1, GE Healthcare) of our hospital. Liver fibrosis and cirrhosis was histologically proven by intercostal percutaneous biopsy from the right liver lobe with the “Menghini-technique” with pre- and post-procedural sonographic checks. Patients who had undergone an earlier partial liver resection or liver transplantation or those who had a transjugular portosystemic shunt (TIPS) were excluded.

Reasons for the abdominal CT scans were as follows (cirrhosis group/precirrhotic fibrosis group): HCC (40/18), tumour other than HCC (9/6), portal vein thrombosis (8/0), abscess (6/4), bleeding (7/0), acute abdomen (4/2), pancreatitis (3/3), trauma (2/1), abdominal hernia (1/0) and portal vein thrombosis (0/1).

The control group consisted of 33 consecutively selected trauma patients (23 male/10 female) with a mean age of 58.4 years (range: 51–70 years) who were examined with a portal venous phase abdominal CT scan. Patients with liver laceration, known liver fibrosis or cancer, and patients receiving potentially hepatotoxic medication were excluded. A summary of the patient population is shown in figure 1.

Figure 1 Patient population. Abdominal computed tomography scans of 148 patients were retrospectively analysed. Included were 80 patients with liver cirrhosis, 35 patients with earlier liver fibrosis and 33 control patients without known liver disease.

The clinical records of all patients in the fibrosis/cirrhosis group were surveyed. The aetiology of fibrosis was as follows: AFLD in 42 patients (37%), viral hepatitis in 45 patients (39%), NAFLD in 11 patients (10%), haemochromatosis in 5 patients (4%) and alpha-1–antitrypsin deficiency (A1AD) in 2 patients (2%). Aetiology of the fibrosis was unknown in 10 patients (9%).

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APASL 2014 CEVHAP Symposium summary

Friday March 14, 2014

Source CEVHAP

Hepatitis C Infection Tied to Higher Risk of Death From Non-liver Cancers

Reuters Health Information

By Bridgett Novak
February 26, 2014

NEW YORK (Reuters Health) - In addition to their increased risk of death from hepatocellular carcinoma, chronic hepatitis C virus (HCV)-infected patients also have a higher mortality rate from non-Hodgkin lymphoma and pancreatic, rectal, and oral and pharyngeal cancers, according to a new study.

The findings were presented February 20 at the annual meeting of the American College of Preventive Medicine in New Orleans, Louisiana.

Cancer-related mortality was analyzed for 12,126 chronic HCV-infected patients in the Centers for Disease Control and Prevention's (CDC) Chronic Hepatitis Cohort Study and compared to Multiple Cause-of-Death mortality data for 2006 to 2010 from the National Center for Health Statistics after age adjustment.

Twelve percent (1496) of the HCV patients died during the five-year period, 25% (372) of them from cancer. Compared to the general population, the HCV group was more likely to die from non-Hodgkin lymphoma (RR, 2.27) and rectal (RR, 2.60), pancreatic (RR, 1.63), and oral cavity or pharyngeal cancers (RR, 5.22).

As expected, the risk of dying from liver cancer was elevated among HCV-infected patients - nearly 30 times higher than among non-infected individuals.

Study author Dr. Robert D. Allison from Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, said it is important to point out that "chronic hepatitis C infection is a known risk factor for developing non-Hodgkin lymphoma (NHL). But to our knowledge, this is the first U.S. study to investigate and show that persons with chronic hepatitis C have a higher risk of death from NHL."

He said there are multiple possible explanations for the other cancers. "The HCV group had a higher rate of smoking and alcohol use than the general population. So, it's hard to say for sure if the increased risk of death from the three smoking-related cancers (oral, pancreatic, and rectal) was related to HCV infection. However, NHL is not associated with either smoking or alcohol use."

Dr. Allison told Reuters in an email, "We also analyzed the average age of death. We found that persons with chronic hepatitis C died an average of 12 years earlier than the general population from 12 different cancers - i.e., bladder, breast, colon, esophagus, leukemia, liver, lung, non-Hodgkin lymphoma, oral, pancreatic, prostate, and rectal cancers. This was an unexpected and concerning finding that may have HCV treatment and cancer screening implications."

Dr. T. Jake Liang, chief of liver diseases and deputy director for translational research at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, was not involved in the new research. He told Reuters Health, "These findings are significant in the sense that chronic HCV infection may predispose an infected person to cancer of organ systems other than the liver, where the virus infects."

Dr. Allison added, "Baby boomers make up 70% of the hepatitis C infected population in the U.S. (77% in our study). The CDC and the U.S. Preventive Services Task Force recommend that all these individuals - i.e., persons born between 1945 and 1965 - get tested."

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Image analysis of liver biopsy samples measures fibrosis and predicts clinical outcome

Journal of Hepatology

Article in Press

Yi Huang, W. Bastiaan de Boer, Leon A. Adams, Gerry MacQuillan, Max K. Bulsara, Gary P. Jeffrey 

Received 19 September 2013; received in revised form 20 January 2014; accepted 22 February 2014. published online 07 March 2014.
Accepted Manuscript

Abstract

Background & Aims

Histopathological scoring of liver fibrosis mainly measures architectural abnormalities and requires a minimum biopsy size (greater than or equal to 10mm). Liver collagen quantification may allow use of small size biopsies and improve the prediction of clinical outcomes. This study evaluated the ability of the collagen proportional area (CPA) measurement to predict clinical outcomes.

Methods

Clinical outcomes were determined using population based data-linkage for chronic hepatitis C (CHC) patients from 1992-2012. Quantitative digital image analysis of liver biopsies was used for CPA measurement.

Results

533 patients with a biopsy size greater than or equal to 5 mm were included. Median follow up was 10.5 years. 26 developed hepatocellular carcinoma (HCC), 39 developed liver decompensation and 33 had liver related death. 453 had Metavir F0-F2 and 80 had F3-F4. CPA ranged from 1.3%-44.6%. CPA and Metavir stage were independently associated with liver related death. Metavir stage, CPA stage and age were independently associated with HCC. CPA stage (C1: 0%-5%, C2: 5%-10%, C3: 10%-20%, C4: >20%) stratified risk and a significant difference in outcomes was present between all CPA stages for HCC and between C2-C3 and C3-C4 for decompensation and liver related death. The 15 year composite endpoint-free survival was 97% for C1, 89% for C2, 60% for C3, 7% for C4. C4 had significantly worse survival than ⩽C3 (p<0.001) in cirrhotic patients.

Conclusions

CPA stage gave additional information regarding risk stratification for adverse clinical outcomes independent of Metavir stage.

Abbreviations: CPA, collagen proportional area, CHC, chronic hepatitis C, HCC, hepatocellular carcinoma, HCV, hepatitis C virus, AUROC, area under receiver operating characteristic curves, HR, hazard ratio

Keywords: Collagen proportional area, Chronic hepatitis C, Histological stage, Liver complication, Liver related death

No full text is available. To read the body of this article, please view the PDF online.

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Prospective evaluation of Fibrotest®, Fibrometer® and Hepascore® for staging liver fibrosis in chronic hepatitis B: Comparison with hepatitis C

Journal of Hepatology

Article in Press

Vincent Leroy, Nathalie Sturm, Patrice Faure, Candice Trocme,  Alice Marl, Marie-Noëlle Hilleret, Françoise MorelJean-Pierre Zarski

Received 8 November 2013; received in revised form 24 January 2014; accepted 22 February 2014. published online 12 March 2014.
Accepted Manuscript

Abstract

Background & aims

Fibrosis blood tests have been validated in chronic hepatitis C. Their diagnostic accuracy is less documented in hepatitis B. The aim of this study was to describe the diagnostic performance of Fibrotest®, Fibrometer® and Hepascore® for liver fibrosis in hepatitis B compared to hepatitis C.

Methods

510 patients mono-infected with hepatitis B or C and matched on fibrosis stage were included. Blood tests were performed the day of the liver biopsy. Histological lesions were staged according to METAVIR.

Results

Fibrosis stages were distributed as followed: F0 n=76, F1 n=192, F2 n=132, F3 n=54, F4 n=56. Overall diagnostic performance of blood tests were similar between hepatitis B and C with AUROC ranging from 0.75 to 0.84 for significant fibrosis, 0.82 to 0.85 for extensive fibrosis and 0.84 to 0.87 for cirrhosis. Optimal cut-offs were consistently lower in hepatitis B compared to hepatitis C, especially for the diagnosis of extensive fibrosis and cirrhosis, with decreased sensitivity and negative predictive values. More hepatitis B than C patients with F greater than or equal to 3 were underestimated: Fibrotest®: 47% versus 26%, Fibrometer®: 24% versus 6%, Hepascore®: 41% versus 24%, p<0.01. Multivariate analysis showed that hepatitis B (0R 3.4, CI95% 1.2-19.2, p<0.02) and low γGT (OR 7.3, CI95% 2.0-27.0, p<0.003) were associated with fibrosis underestimation.

Conclusion

Overall the diagnostic performance of blood tests is similar in hepatitis B and C. The risk of underestimating significant fibrosis and cirrhosis is however greater in hepatitis B and cannot be entirely corrected by the use of more stringent cut-offs.

Abbreviations: CHC, chronic hepatitis C, CHB, chronic hepatitis B, TE, Transient elastography, FT, Fibrotest, AUROC, Area under the receiver operator characteristic, FM, Fibrometer, HS, Hepascore, HBV, Hepatitis B virus, HCV, Hepatitis C virus, PPV, Positive predictive value, NPV, Negative predictive value

Keywords: Blood tests, Fibrosis, Cirrhosis, Non-invasive diagnosis, Diagnostic performance

No full text is available. To read the body of this article, please view the PDF online.

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Hepatitis C treatments: Australia urged to subsidise 'revolutionary' new drugs

By Deborah Cornwall
Posted Sat 15 Mar 2014, 3:11pm AEDT

Professor Geoff McCaughan says the new hepatitis C treatments have limited side effects.
Giulio Saggin, file photo: ABC News

Public health experts say effective new drugs to treat hepatitis C should be subsidised in Australia to avert a looming strain on the national health system.

Australians who contracted hepatitis C decades ago are only now starting to develop terminal liver disease at an alarming rate.

More than half of Australia's 250,000 hepatitis C sufferers are baby boomers who contracted the virus back in the 1960s and 1970s, when experimental drug taking was rampant.

Most of these patients have, until now, remained in good health, but after 30 or more years living with the virus, the number getting liver cancer or waiting for liver transplants is now dramatically on the rise - leaping from 10 per cent to 40 per cent in the past five years.

It is a trend which could put pressure on healthcare resources.

Until recently, treatments have had such a low success rates and brutal side effects, even doctors have advised patients to wait for a better treatment to come along, hopefully before liver failure claims them first.

Audio: Listen to Deborah Cornwall's report (AM)

Public health researcher Jack Wallace is one of those with hepatitis C who has not treated the disease, hoping they are not among the one in three who will die of liver failure.

"I've been putting off treatment for the last 20 years because the current treatments, the side effects of them are too hard for me to contemplate actually doing treatment," he said.

However, one of Australia's leading hepatologists, Professor Geoff McCaughan, says a new "revolutionary" treatment is being rolled out in the United States and Europe.

"We are talking about 95 per cent cure rates with one or two tablets a day, essentially without any side effect," he said.

The drugs have arrived at a time when the first generation of hepatitis C sufferers in Australia - the baby boomers - are starting to succumb to liver failure.

"Liver cancer associated with hepatitis C is the most rapidly growing cancer in the Western world," Professor McCaughan said.

"So 40 to 50 per cent of liver cancer is hepatitis C; 40 to 50 per cent of adults requiring liver transplant, hepatitis C."

New hepatitis C treatment comes at a high price

Professor McCaughan and his colleagues are lobbying hard to have the new therapy subsidised in Australia, starting with the most vulnerable patients.

"If you walk in the door with chronic hepatitis C infection, academically and medically you should be able to get these medications at some stage within the next one to three to five years," he said.

"The problem at the moment is the cost of these drugs in Europe and the United States is extraordinarily high - you know, $90,000 to $100,000 or even more."

“The problem at the moment is the cost of these drugs in Europe and the United States is extraordinarily high - you know, $90,000 to $100,000 or even more.”

Professor Geoff McCaughan

Hepatitis C is also such a stigmatised disease there are no high-profile lobby groups and sufferers themselves tend to keep their condition a secret.

Mr Wallace says such is the lack of understanding of the disease, few Australians even realise most people with the virus are middle class citizens.

"Once you disclose you've got hepatitis C, you are publicly disclosing the fact that you've injected drugs, and injecting drugs in Australia is a shameful thing to admit," he said.

"It's really interesting - it's been 30 years since I last injected drugs, and most of the people that I interact with on a daily basis would have absolutely no idea of my history."

Professor McCaughham said hepatitis sufferers come from all walks of life.

"They're lawyers, some of them are doctors, some of them are bankers, musicians, tradesmen - you know, the late 60s and 70s was a pretty wild time," he said.

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Idenix files lawsuits in Europe, charging Gilead infringed on its patent by marketing hep C drug

Provided by The Boston Globe

By Robert Weisman | Globe Staff   March 14, 2014

Cambridge drug developer Idenix Pharmaceuticals Inc. has filed lawsuits in Europe charging that biotechnology giant Gilead Sciences Inc. infringed on an Idenix patent when it marketed a popular new hepatitis C treatment in England, France, and Germany.

The suits escalate a three-month-old legal battle between Gilead and Idenix over the drug, called Sovaldi. Idenix — in which a Boston hedge fund has taken a growing position — says it has exclusive rights to intellectual property for sofosbuvir, the compound on which Sovaldi is based. The company lodged similar complaints against Gilead in California in December.

Idenix has not specified how much it is seeking in damages. Its suits in Europe follow the granting of a patent by the European Union on Wednesday. The patents that are the subject of the US infringement cases were granted between 2005 and 2009.

“These are the first offensive moves Idenix has taken in this landscape of litigation against Gilead,” said Teri Dahlman, an Idenix spokeswoman. “We feel strongly about our intellectual property and we’re defending it.”

Amy Flood, a vice president at Gilead’s headquarters in Foster City, Calif., said her company rejects Idenix’s intellectual property assertion.

“Gilead will defend against any claim brought by Idenix and we will challenge the validity of Idenix’s European patent,” she said.

Shares of Idenix were unchanged at $6.94 on the Nasdaq exchange Friday. Gilead shares tumbled 3.8 percent to $75.05, a loss of $2.96 apiece.

Patients carrying the liver-ravaging hepatitis C virus have been gravitating to Sovaldi, approved by the Food and Drug Administration in December, because it is a pill that is easier to tolerate, can be taken for a shorter span than other treatments, and is considered more effective than previous drugs. The wholesale price of Gilead’s drug is $28,000 for a four-week treatment.

Analysts have projected Sovaldi could generate sales of at least $6 billion this year, which would make it one of the top-selling drugs of all time. Vertex Pharmaceuticals Inc., the Boston biotechnology company that markets rival hepatitis C drug Incivek, has lost business to Sovaldi and other new-generation treatments for the disease.

Idenix, founded in 1998, co-developed a hepatitis B treatment currently marketed exclusively by Novartis AG, the Swiss pharmaceutical company that has its worldwide research and development headquarters in Cambridge. Idenix has two hepatitis C drug candidates in clinical trials, and several others in preclinical development, drawing on intellectual property it has under patents awarded in the United States and Europe.

In a regulatory filing last month, Boston’s largest hedge fund, Seth Klarman’s Baupost Group, said it had accumulated a 35.4 percent stake in Idenix.

Robert Weisman can be reached at robert.weisman@globe.com. Follow him on Twitter @GlobeRobW.

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Video: Conversations from CROI 2014: Dr. Doug Dieterich

 

Uploaded on Mar 11, 2014

At the 2014 Conference on Retroviruses and Opportunistic Infections (CROI), Dr. Ron Valdiserri sat down for an in-depth conversation with Dr. Doug Deiterich of the Icahn School of Medicine at Mount Sinai Hospital in New York, who made several presentations and was involved in scientific posters shared during the conference on hepatitis C mono-infection and HIV/HCV co-infection. Dr. Valdiserri and Dr. Dieterich discussed important advances in the diagnosis and treatment of hepatitis C that received a lot of attention at the conference.

Their conversation includes messages for primary care providers and others in the healthcare field, as well as messages for individuals at risk for or living with hepatitis C virus (HCV) infection.

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Elastography tools displace liver biopsies

Provided by medicalphysicsweb

Mar 13, 2014

Millions of people throughout the world have diagnosed and undiagnosed chronic liver disease (CLD), including an estimated 40 million in the United States alone, according to the Chronic Liver Foundation. The most common types include chronic hepatitis B and C, alcoholic liver disease, hemochromatosis, nonalcoholic steatophepatits and nonalcoholic fatty liver disease. An aging global population, unhealthy diets and an obesity epidemic have contributed to its increase.

Ultrasound (US) elastography – and to a much lesser extent – magnetic resonance elastography (MRE) are increasingly being used to stage liver fibrosis and follow the impact of treatment by evaluating tissue elasticity in a non-invasive manner. The use of MR and US elastography was the topic of a scientific session at the European Congress of Radiology (ECR) in Vienna, Austria.

Untreated, CLD kills. The prognosis and management of the disease depends on the extent and progression of liver fibrosis. The gold standard for evaluating hepatic fibrosis is percutaneous biopsy followed by a histopathological examination of a liver sample. But this test is invasive, expensive, and because it is highly localized, targets only one small section of the liver.

Ultrasound elastography

A bigger picture is provided with US elastography, which was recommended in lieu of biopsy for liver fibrosis diagnosis in January 2013 by the Technology Assessment Centre (NTAC) of the UK's National Health Service. A concurrent economic modelling analysis based upon actual costs published by the York Health Economic Consortium estimated a gross saving of €616 per diagnosis.

Accessible options

The main techniques employed in US elastography are strain, shear wave, transient and acoustic radiation force imaging. Strain US elastography, also described as compression elastography, sonoelastography or real-time elastography, is the most commonly used method, explained Magdalena Wozniak of the Medical University of Lublin, Poland. To perform this exam, radiologists require dedicated software on a conventional higher-class ultrasound scanner, plus a transducer that's compatible with this software.

"The value of US elastography is the relatively low cost of the exam, that it is a proven diagnostic tool and the clinical availability and accessibility of ultrasound scanners," co-author Sabine Bensamoun, from the Université de Technologie de Compiègne in France, told medicalphysicsweb. "Like MRE, the probe sends vibrations inside the liver enabling a radiologist to analyse the displacement of the wave. It provides accurate information on tissue stiffness."

Biomechanics researcher Sabine Bensamoun

If the exam results merit further investigation, an MRE exam is appropriate. And if a patient is prescribed a hepatic MRI scan, it is easy to add the elastography portion, explained Bensamoun. This entails use of an active driver located outside the magnet room, which generates continuous low-frequency vibrations. The mechanical response to the pressure captures the type of manipulation that a doctor would perform when palpating an abdomen.

MRE is also performed on obese patients in lieu of an initial US elastography exam. The reason, explained Andrzej Pawel Wieczorek, director of the department of paediatric radiology at the Medical University of Lublin and chair of the ECR session, is that US elastography offers only a shallow wave depth. It has difficulty propagating itself with obese patients.

MR elastography

The benefits of MRE are that a comprehensive picture is produced and that all areas of fibrosis can be identified in the liver. "Seeing the total area of the liver through a series of slices enables a radiologist to more easily identify all the locations where the fibrosis is likely to exist. It is so much more comprehensive than biopsy. You can't biopsy 50 locations of suspected fibrosis, but the diagnostic images will show these clearly and also enable a radiologist to assess the surrounding tissue," said Bensamoun. Elastography can display the entire anatomical picture and also the functional properties of the tissue. MRE also is a very accurate way to follow up the patient and the effectiveness of treatment, she explained.

Broader scope

In addition to staging liver fibrosis, elastography is being used to help diagnose and follow treatment of many different types of diseases. Other presentations in the ECR session "Elastography as a new tool" session included the use of US elastography to help diagnose prostate cancer, and MR elastography of the brain to assess cerebral tissue structure. The technology is evolving rapidly, but its value is not as well understood as it should be, according to the presenters.

"Besides liver imaging, quite extensive applications in diagnosis of brain, testicles, breast and lymph nodes have been reported as well, some more extensively than others," Wiczorek told attendees. There are many other directions that are not well established, such as arterial wall/atheromatous plaque characterization, musculoskeletal applications, and diagnostics and evaluation of thrombosis or graft rejection of various transplanted organs.

Elastography is a new tool, and potentially a revolutionary technique that can make a great contribution to diagnostic imaging, the session presenters pointed out. It's time for radiologists to talk about it with their colleagues in medicine.

About the author

Cynthia E Keen is a freelance journalist specializing in medicine and healthcare-related innovations.

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Some Patients Receive Unnecessary Prioritization for Liver Transplantation, Penn Medicine Study Finds

February 5, 2014

Findings Could Influence Process for Allocation of Scarce Organ Resources

PHILADELPHIA — Patients waiting for liver transplants who develop hepatopulmonary syndrome (HPS), a lung disorder associated with end-stage liver disease, are eligible to move up on the wait list. In a new paper published in Gastroenterology, however, Penn Medicine researchers argue the so-called “exception points” given to these patients award some HPS patients unnecessary priority over others on the list, which includes about 17,000 patients

The current U.S. transplant allocation system prioritizes patients based on medical urgency using the Model for End Stage Liver Disease (MELD) score, which takes into account the expected three-month survival due to end-stage liver disease, but does not consider other, unrelated medical complications.  As a result, a system that allows wait-list candidates with certain conditions, HPS among them, to be eligible for exception points to increase their waitlist priority has been developed.

“To examine the impact of HPS MELD exception points on outcomes, we examined the relationship between patients’ blood oxygen levels and outcomes in a national cohort of patients who received HPS exception points, and compared survival in HPS vs. non-HPS patients,” says David Goldberg, MD, MSCE, instructor of Medicine at the Perelman School of Medicine of the University of Pennsylvania and lead author on the study.

HPS is found in approximately 20 percent of patients awaiting liver transplant and is associated with a worse health-related quality of life. The condition is known to double the risk of death among patients evaluated for liver transplantation. 

The Penn researchers looked at data from February 2002, the date the exception point program commenced, to December 2012.  During this time, 973 patients on the liver transplant list received HPS exception points. While post-transplant survival was similar in HPS vs. non-HPS patients, post-transplant survival in HPS patients varied based on the severity of pre-transplant oxygen saturation levels. 

The team found that patients with the poorest oxygen saturation levels (lower than 44 mm Hg) had a significantly lower three-year post-transplant patient survival rate. 

Comparatively, significantly more non-HPS waitlisted patients, who did not receive exception points, died on the waitlist or within 90 days of waitlist removal, while a great proportion of HPS waitlist candidates were transplanted (73 percent vs. 43 percent).  In addition, the study showed that only 49 percent of HPS transplant recipients had clear evidence of clinical indications for transplantation aside from HPS, as compared with 89 percent of non-HPS transplant recipients.

The findings refute recent reports and demonstrate an association between pre-transplant oxygen levels and post-transplant mortality, suggesting that the criteria for doling out exception points be adjusted based on patients’ oxygenation, and suggesting an over-prioritization of all HPS patients in the current system.

This study represents the largest analysis of liver transplant waitlist candidates with HPS to date.

“These data, we hope, can provide some guidance to UNOS, as the exception point policy comes under revision,” says Goldberg.  “As organs are a scarce resource, we want to make it easier for the patients in the most urgent need to be prioritized as such, according to evidence-based criteria.”

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Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2013 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2013, Penn Medicine provided $814 million to benefit our community.

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Hepatitis C patients with ITPA gene variants exhibit lower risk of relapse after treatment

News: Mar 11, 2014

Researchers at the Sahlgrenska Academy have identified a gene, which explains why certain patients with chronic hepatitis C do not experience relapse after treatment. The discovery may contribute to more effective treatment.

More than 100 million humans around the world are infected with hepatitis C virus. The infection gives rise to chronic liver inflammation, which may result in reduced liver function, liver cirrhosis and liver cancer. Even though anti-viral medications often efficiently eliminate the virus, the infection recurs in approximately one fifth of the patients.

Prevents incorporation in DNA

Martin Lagging and co-workers at the Sahlgrenska Academy have studied an enzyme called inosine trifosfatas (ITPase), which normally prevents the incorporation of defective building blocks into RNA and DNA.

Unexpectedly they found that the gene encoding for ITPase (ITPA) had significance for the treatment outcome in chronic hepatitis C virus infection.

Five times lower risk

Earlier studies had shown that approximately one third of all people carry variants of the ITPA gene that result in reduced ITPase activity. The research team at the Sahlgrenska Academy showed that patients with these gene variants exhibited a more than a five times lower risk of experiencing relapse after treatment.

Relapse a significant problem

The study encompassed over 300 patients and was carried out in cooperation with hepatitis researchers in several Nordic countries.

- Relapse after completed treatment is a significant problem in chronic hepatitis C, and the results may contribute to explaining why the infection recurs in many patients. Our hypothesis is that a low ITPase activity results in defective nucleotides being incorporated into the virus RNA, which makes the virus unstable, Martin Lagging said.

Important to other virus infections

According to Martin Lagging, the discovery may also have significance for other virus infections.

- A medication that interferes with the enzyme’s activity could have a broad antiviral effect, but this must be further investigated in future studies.

The article Variants of the inosine triphosphate pyrophosphatase gene are associated with reduced relapse risk following treatment for HCV genotype 2/3 was published online in the journal Hepatology on 13 January 2014.

Contact:
Martin Lagging, researcher at The Sahlgrenska Academy, University of Gothenburg
martin.lagging@medfak.gu.se

Source: University of Gothenburg

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Achillion Announces Oral Presentations Given at APASL 2014 Detailing Clinical Activity of ACH-3102, Second-Generation NS5A Inhibitor, Against Genotype 1b HCV

100% SVR Demonstrated in Combination With Sovaprevir, NS3/4A Protease Inhibitor, in Late Breaker Oral Presentation

NEW HAVEN, Conn., March 14, 2014 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced that two oral presentations were made at the 23^rd Asian Pacific Association for the Study of the Liver (APASL) Conference 2014 in Brisbane, Australia. Updated Phase 2 clinical trial results evaluating a 150 mg loading dose followed by 50 mg once daily of ACH-3102 in combination with either once daily 200 mg or 400 mg of sovaprevir and twice daily ribavirin showed that 100% of patients achieved SVR12 (n=8) including subjects who had Y93 mutations at baseline. A second oral presentation on ACH-3102 was made at APASL 2014 that discussed clinical virology and the lack of virologic breakthrough that was observed in the novel Phase 2 clinical trial evaluating ACH-3102 with ribavirin for patients with treatment-naïve genotype 1b HCV. Despite the presence of up to six linked mutations identified at baseline in the NS5A protein, ACH-3102, without the co-administration of interferon or a second direct-acting antiviral, was able to suppress viral replication with no virologic breakthrough observed during 12 weeks of treatment.

Dr. David Apelian, M.D., Ph.D., Chief Medical Officer of Achillion, commented, "The safety, tolerability, high barrier to resistance, and clinical activity observed in these two Phase 2 trials continue to support the differentiated profile of ACH-3102, our second-generation NS5A inhibitor. As a potential cornerstone compound in genotype 1b targeted regimens, we are evaluating ACH-3102 in combination with our macrocyclic NS3/4A protease inhibitor, ACH-2684, and look forward to initiating future clinical trials for broader HCV treatment evaluating ACH-3102 in combination with our NS5B nucleotide polymerase inhibitor, ACH-3422, which is poised to enter Phase 1 trials."

Oral Presentation Details
Session: Late Breaker Oral Presentation
Title: SVR4 results for the combination of ACH-3102 and sovaprevir, with ribavirin, in subjects with genotype 1 chronic hepatitis C infection.
Abstract: LB6
Presenter: David Apelian, M.D.
Date: Friday, March 14, 2014

Session: Concurrent Session
Title: ACH-3102 and ribavirin in genotype-1b hepatitis C patients: Confirmation of the high barrier to viral breakthrough in genotype-1b HCV.
Abstract: 437
Presenter: Mingjun Huang, Ph.D.
Date: Friday, March 14, 2014

e-Poster Presentation
Title: A single direct-acting anti-viral agent, ACH-3102, with ribavirin, is able to achieve a robust anti-viral response in subjects with genotype 1b chronic hepatitis C infection.
Authors: A. Muir, R. Brennan, et al.
Abstract: 625

Reprints of the oral presentation slides and poster will be accessible from the Achillion website at http://www.achillion.com.

About Achillion Pharmaceuticals

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's discovery, clinical development, and commercial teams have advanced multiple novel product candidates with proven mechanisms of action into studies and toward the market. Achillion is focused on solutions for the most challenging problems in infectious disease including HCV and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.

Cautionary Note Regarding Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors that could cause actual results to differ materially from those indicated by such forward-looking statements, including the following: the potential benefits of ACH-3102 as an agent to treat HCV-infected patients; and our plans to initiate additional clinical trials of ACH-3102 in combination with other compounds. Achillion may use words such as "expect," "anticipate," "project," "intend," "plan," "aim," "believe," "seek," " estimate," "can," and "may" and similar expressions to identify such forward-looking statements. Among the important factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to, among other things Achillion's ability to: demonstrate in any current and future clinical trials the requisite safety, efficacy and combinability of its drug candidates; advance the preclinical and clinical development of its drug candidates, including ACH-3422, ACH-3102 and ACH-2684, under the timelines it projects in current and future clinical trials; satisfactorily respond to the clinical hold placed on sovaprevir by the FDA; obtain and maintain necessary regulatory approvals; obtain and maintain patent protection for its drug candidates and the freedom to operate under third party intellectual property; establish commercial manufacturing arrangements; identify, enter into and maintain collaboration agreements with appropriate third-parties; compete successfully with other companies that are seeking to develop improved therapies for the treatment of HCV; manage expenses; manage litigation; raise the substantial additional capital needed to achieve its business objectives; and successfully execute on its business strategies. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Quarterly Report on Form 10-K for the year ended December 31, 2013, filed on March 7, 2014, and its subsequent SEC filings.

In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any duty to update any forward-looking statement, except as required by applicable law.

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