Showing posts with label nonresponders. Show all posts
Showing posts with label nonresponders. Show all posts

Wednesday, July 5, 2017

Sofosbuvir, Velpatasvir and Voxilaprevir combination for the treatment of hepatitis C- Review Article

Expert Rev Gastroenterol Hepatol. 2017 Jul 4. doi: 10.1080/17474124.2017.1351295.
[Epub ahead of print]

Sofosbuvir, Velpatasvir and Voxilaprevir combination for the treatment of hepatitis C
Rebecca Voaklander & Ira M Jacobson

Received 19 Apr 2017, Accepted 03 Jul 2017, Accepted author version posted online: 04 Jul 2017

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The advent of direct-acting antiviral (DAA) treatments for chronic hepatitis C virus (HCV) infection has dramatically increased rates of cure. However, there remain difficult-to-treat populations, including patients with genotype 3 infection and cirrhosis, and limited salvage treatment options for those that have failed first-line DAA therapy.

Areas covered
This is a review of the preclinical and clinical development of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX), an interferon-free, oral, once daily, pangenotypic treatment for chronic HCV infection. All relevant literature from 2015 through June of 2017 is included.

Expert commentary
Voxilaprevir, a second-generation HCV protease inhibitor, in combination with the already approved combination of sofosbuvir and velpatasvir, was evaluated in the POLARIS trials and found to be a safe and effective regimen. Patients with prior DAA treatment failure, genotype 3, cirrhosis and/or unfavorable resistance profiles all achieved cure rates of 96% or greater. The most distinctive role for this potent regimen may prove to be as a salvage regimen for patients who have failed previous DAA therapy.

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Friday, June 30, 2017

Harvoni - Effectiveness and safety of ledipasvir/sofosbuvir ± ribavirin in the treatment of HCV infection: The real-world HARVEST study

Advances in Medical Sciences
Volume 62, Issue 2, September 2017, Pages 387–392

Original research article
Effectiveness and safety of ledipasvir/sofosbuvir ± ribavirin in the treatment of HCV infection: The real-world HARVEST study
Robert Flisiaka, , , Mariusz Łucejkoa, Włodzimierz Mazurb, Ewa Janczewskac, Hanna Berakd, Krzysztof Tomasiewicze, Iwona Mozer-Lisewskaf, Dorota Kozielewiczg, Andrzej Gietkah, Katarzyna Sikorskai, Marta Wawrzynowicz-Syczewskaj, Krzysztof Nowakk, Dorota Zarębska-Michalukl, Joanna Musialikm, Krzysztof Simonn, Aleksander Garlickio, Robert Pleśniakp, Barbara Baka-Ćwierzq, Iwona Olszokr, Krystyna Augustyniaks, Wojciech Stolarzt, Jolanta Białkowskau, Anna Badurekv, Anna Piekarskaw

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To evaluate the effectiveness and safety of ledipasvir/sofosbuvir (LDV/SOF) ± ribavirin (RBV) regimen in a real-world setting.

Patients received a fixed-dose combination tablet containing LDV and SOF with or without RBV, for 8, 12 or 24 weeks. Patients were assessed at baseline, end of treatment, and 12 weeks after the end of treatment. The primary effectiveness endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12).

Of the 86 patients, aged 20–80 years, 82.6% were HCV genotype 1b-infected and 50.0% were cirrhotic. More than half (52.3%) had previously followed pegylated interferon-containing (PEG-IFN) treatment regimens, and 38.5% were null-responders. SVR12 was achieved by 94.2% of patients. All non-responders were cirrhotic: two demonstrated virologic breakthrough and the remaining three relapsed. All patients treated with an 8-week regimen achieved SVR12 despite having high viral load at baseline (HCV RNA of >1 million IU/mL in 8/10 patients, including one with a viral load of >6 million IU/mL). Adverse events were generally mild and transient. Most frequently, fatigue (22.1%), headache (15.1%), and arthralgia (7.0%) were observed. Laboratory abnormalities included anemia and hyperbilirubinemia.

Treatment with LDV/SOF ± RBV is an effective and safe option for patients with HCV, including those with advanced liver disease or a history of non-response to PEG-IFN-based therapy.
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Tuesday, August 11, 2015

Tx Options for HCV GT 1 or 4 Non-responders

Tx Options for HCV GT 1 or 4 Non-responders
Posted on August 9, 2015

New study shows that genotype 1- or 4-infected non-responders, including patients with cirrhosis, achieve high SVR12 rates on the 24 week, quad treatment regimen of daclatasvir plus asunaprevir and peginterferon/ribavirin. The combination was well tolerated and no additional safety and tolerability concerns were observed compared with peginterferon/ribavirin regimens. A combination of Direct Acting Antivirals (DAAs) and peginterferon/ribavirin may provide a viable treatment option for those patients who experience virologic failure on all-oral, DAA regimens.

Some of the more difficult chronically-infected HCV patients to treat are those with a prior null or partial response to peginterferon/ribavirin therapy. Daclatasvir is a potent, pan-genotypic inhibitor of the HCV NS5A protein with activity against genotypes 1 to 6 in vitro.

Asunaprevir is an NS3 protease inhibitor with activity against genotypes 1 and 4. Positive results of HALLMARK-QUAD, a global, single-arm, open-label, phase 3 study evaluating the efficacy and safety of daclatasvir plus asunaprevir combined with peginterferon/ribavirin in patients (≥18 years) infected with HCV genotype 1 or 4 who were null or partial responders to peginterferon alfa-2a or -2b plus ribavirin (Study AI447029; number NCT01573351), were recently published in Journal of Hepatology (Jensen D, et al. J Hepatol. 2015 Jul;63(1):30-7).

  • Patients received daclatasvir 60 mg once-daily, asunaprevir 100 mg softgel capsule twice-daily and 180 μg peginterferon alfa-2a weekly and twice-daily ribavirin dosed according to bodyweight (<75 kg, 1000 mg daily; ≥75 kg, 1200 mg daily) for 24 weeks and were subsequently followed for 24 weeks post-treatment
  • Null response to peginterferon/ribavirin was defined as a <2 log10 decline in HCV RNA after ≥12 weeks of therapy, or a <1 log10 decline after ≥4 weeks of therapy
  • Partial responders had achieved a ≥2 log10 decline, but never achieved undetectable HCV-RNA after ≥12 weeks of peginterferon/ribavirin therapy, or became undetectable and subsequently had detectable HCV-RNA on-treatment
  • Patients with compensated cirrhosis were eligible but were capped at a maximum of 25% of the treated population
Of the 496 patients who were screened for the study, 354 with HCV genotype 1, and 44 with HCV genotype 4 treated between May 2012 and December 2013. The majority of patients (379/398; 95.2%) completed the 24- week treatment period.
  • The majority of patients were male (68.6%) and white (76.4%) with a median age of 52.7 years
  • Approximately two-thirds of the study population were null responders and as expected, a high proportion had a non- CC IL28B genotype
  • Overall, 23.4% of patients enrolled in the study had compensated cirrhosis; 45.5% of genotype 4-infected patients had compensated cirrhosis compared with 20.6% of genotype 1-infected patients
Daclatasvir plus asunaprevir and peginterferon/ribavirin demonstrated rapid early antiviral activity among genotype 1- and 4-infected patients. SVR12 rates of 92.9% (329/354) were achieved in genotype 1-infected patients. Among genotype 4-infected patients, the SVR12 rate was 97.7% (43/44).
  • One patient had a missing post-treatment week 12 HCV-RNA value, but subsequently achieved SVR24, yielding a 100% SVR rate in genotype 4-infected patients. Study authors noted that this supports the ongoing development of the all-oral triple DAA regimen of daclatasvir and asunaprevir plus beclabuvir (BMS-791325), which has achieved high SVR rates in both genotype 1 (89–94%) and genotype 4 (100%) patients (Everson GT, et al. Gastroenterology. 2014;146:420-429. Hassanein T, et al. J Hepatol. 2014;60(suppl1):S472). Other potential treatment options in development for this population include the combination of ABT-450/ritonavir plus ombitasvir, which achieved high SVR rates in a small cohort of 50 genotype 4-infected null and partial responders (Hezode C, et al. J Hepatol. 2014;60(suppl1):S24).
  • SVR12 rate 94.9% in genotype 1-infected patients who achieved RVR (82.5% [292/354]), compared with 83.1% among those who did not achieve RVR
  • A large number of cirrhotic null and partial responders were treated in this study (23%). Daclatasvir plus asunaprevir and peginterferon/ribavirin resulted in high SVR12 rates in both cirrhotic (90.4%; 66/73) and non-cirrhotic genotype 1 patients (93.6%; 263/281).
  • Baseline factors previously associated with a suboptimal response to peginterferon/ribavirin-based regimens, such as sex, age, body mass index, and baseline HCV-RNA did not appear to affect response, as SVR12 rates were high across all groups
  • SVR12 rates were slightly lower among the small number of black patients (87.9%; 29/33) compared with white patients (92.6%; 251/271)
  • SVR12 was higher among patients infected with subtype 1b (98.9%; 176/178) compared with subtype 1a (86.9%; 153/176)
Virological failure was observed infrequently among genotype 1-infected patients: 3.1% (11/354) experienced virological breakthrough, 0.6% (2/354) had detectable HCV-RNA at the end of treatment, and 2.4% (8/337) experienced relapse post-treatment.
  • Three patients with baseline asunaprevir resistance polymorphisms did experience virological breakthrough. Multiple linked resistance variants were present in two of these patients, which are unusual in protease inhibitor-naive patients, suggesting these patients may have been previously exposed to protease inhibitor-based therapy, but this could not be verified after further investigation.
  • No association between the presence of baseline daclatasvir resistance polymorphisms and virological failure was observed
  • No genotype 4-infected patients experienced virological failure
Daclatasvir plus asunaprevir and peginterferon/ribavirin was well tolerated in this patient population. The most frequent AEs and laboratory abnormalities observed during treatment were those typically associated with peginterferon/ribavirin therapy.
  • AEs occurring at a frequency >20% were fatigue, headache, pruritus, asthenia, influenza-like illness, insomnia, and rash
  • Serious AEs were reported in 5.5% (22/398) of patients during treatment, with nine events considered by the investigator to be related to study therapy: anemia, anemia/dehydration, encephalopathy, pneumonia, traumatic ulcer, lymphadenopathy, sepsis, hepatic enzymes increased, and dry skin in one patient each
  • No clinically relevant differences in hepatic laboratory abnormalities or AEs were noted between patients with or without cirrhosis
  • Grade 3/4 ALT and aspartate aminotransferase (AST) elevations occurred in 3.0% and 3.3% of patients, respectively.
Infrequent viral breakthrough and relapse, combined with a low rate of AE-related discontinuations, led to a high number of patients completing treatment in this study, compared with historical peginterferon/ribavirin-based studies.
  • Discontinuations due to AEs occurred in 4.5% (18/398) of patients; the most frequent events leading to discontinuation were rash, malaise, neutropenia, and vertigo, occurring in two patients each
Study authors noted that future therapeutic options for patients with a partial or null response to peginterferon/ribavirin are likely to focus on all-oral regimens such as daclatasvir in combination with other DAAs including asunaprevir and sofosbuvir, and simeprevir plus sofosbuvir, which are well tolerated and provide SVR rates comparable to those observed in this study. However, study authors also note that a combination of DAAs and peginterferon/ribavirin may provide a viable treatment option for those patients who experience virologic failure on all-oral regimens.

Source -

Saturday, October 19, 2013

Video: AVIATOR trial ABT-450/ABT-267/ABT-333/ribavirin/Interferon-free regimen effective 12-wk duration in hepatitis C patients

Interferon-free regimen effective for HCV at 12-week treatment duration

SAN DIEGO - Kris Kowdley, MD, director of the Liver Center of Excellence at the Digestive Disease Institute of Virginia Mason Medical Center in Seattle, discusses the results of the AVIATOR trial, which he presented at the American College of Gastroenterology Annual Scientific Meeting.

Wednesday, June 12, 2013

Noncompliance with guidelines 'stop rules' for the treatment of hepatitis C is frequent in daily practice.

Eur J Gastroenterol Hepatol. 2013 Jun 6. [Epub ahead of print]

Noncompliance with guidelines for the treatment of hepatitis C is frequent in daily practice.

Niederau C, Mauss S, Böker K, Lutz T, Heyne R, Moog G, John C, Witthöft T, Alshuth U, Hüppe D.


Department of Medicine, Katholische Kliniken Oberhausen, St Josef Hospital, Oberhausen bCenter for HIV and Hepatogastroenterology, Düsseldorf cCenter for Hepatology, Hannover dInfektiologikum Frankfurt, Frankfurt eLiver and Study Center Checkpoint fCenter of Gastroenterology, Berlin gMedical Office for Gastroenterology and Hepatology, Kassel hMedical Office for Gastroenterology and Hepatology, Stade iRoche Pharma AG, Virology, Grenzach-Wyhlen jCenter for Gastroenterology and Hepatology, Herne, Germany.



In trials of pegylated interferons (PEG-IFNs), the lack of an early virological response (EVR) was associated with sustained virological response (SVR) rates of only 0-3%. The rates were similarly low when hepatitis C virus (HCV)-RNA was positive at week 24. Treatment guidelines therefore recommend 'stop rules' on the basis of HCV-RNA levels at weeks 12 and 24 of treatment. We analyzed the use of these rules under 'real-life' conditions.


This was a prospective, community-based cohort study involving 467 physicians from institutions throughout Germany, including 4727 treatment-naive genotype-1 patients who received a full course of treatment with PEG-IFN α-2a plus ribavirin between 2003 and 2009.


The overall SVR rate was 43.1%. Failure to determine EVR decreased from 20% in 2003-2004 to 10% in 2006-2007. Unexpectedly, treatment was continued in 86.1% of patients without an EVR and in those who had an EVR but were HCV-RNA positive at week 24 (67.5%), resulting in SVR rates of 15.7 and 40.9%, respectively. Between 77.5 and 95.3% of physicians did not follow prescribed recommendations to reduce PEG-IFN or ribavirin in cases of hematological abnormalities.


Although recommendations to assess EVR and HCV-RNA at week 24 were increasingly observed in daily practice, the corresponding 'stop rules' in nonresponders were neglected. The subsequent SVR was 5-10 times higher than that reported in controlled trials. This may partly be because of the fact that reductions in PEG-IFN or ribavirin dose were not performed despite recommendations. The issue of stop rules will gain even more interest since the first HCV protease inhibitors have been approved. Prolongation of treatment beyond the new stop rules is associated with risks of resistant HCV variants. Thus, the new stop rules are to be observed more strictly when compared with previous therapy with interferons and ribavirin.

Wednesday, January 30, 2013

Interferon May Be Harmful in Retreatment of Hepatitis C

Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C

Some patients with chronic hepatitis C progress from a relatively benign condition to a life-threatening illness. Interferon has been used to try to prevent this but researchers have struggled to investigate its effects reliably. Ron Koretz from Granada Hills in the USA, tells us about the January 2013 update of the relevant Cochrane Review, outlining what the authors did to try to solve this and what they found.

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Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C Updated
Koretz RL, Pleguezuelo M, Arvaniti V, Barrera Baena P, Ciria R, Gurusamy KS, Davidson BR, Burroughs AK
Published Online:
January 31, 2013
Antiviral treatment for chronic hepatitis C infections is currently judged as being successful if, at least six months after therapy, blood tests for hepatitis C viral RNA are negative; this has been called a sustained viral response. In the past, other outcomes for treatment have included improvements in biochemical tests (especially liver enzyme tests such as the serum alanine aminotransferase) or evidence of reduced inflammation and/or fibrosis on subsequent liver biopsies. All of these outcomes are tests, and it has been assumed that if the test gets better the patient will as well. However, there is no direct evidence that has proven that these outcomes are valid because there have been no long-term trials that have shown that an improvement in these tests translates into reduced mortality or morbidity. Patients who fail to have sustained viral responses after an initial course of therapy do become potential candidates for retreatment; some of them may be intolerant to ribavirin, and possibly even the newer protease inhibitors, so retreatment would have to be with interferon alone. It has also been speculated that long-term treatment (namely treatment for several years) might be beneficial; such long-term therapy would be further complicated if multiple drugs were used because of the additional drug toxicities and costs, so interferon alone could be considered.....
Continue to updated material @  Cochrane Summaries


Chronic hepatitis C: Interferon may be harmful in re-treatment

People with hepatitis C and chronic liver disease who relapsed or failed to respond to initial treatment are unlikely to improve on interferon retreatment. In fact, they may face an increased risk of dying sooner, and are likely to experience a variety of adverse effects, according to an updated systematic review published in The Cochrane Library.

Hepatitis C affects around 170 million people worldwide. In some cases, infection leads to chronic liver disease, liver failure or liver cancer, eventually resulting in death. Treatment is based on antiviral drugs.

Interferon monotherapy, meaning using interferon alone, is not the first choice of therapy for most clinicians, but it is used in some patients when other drugs cannot be used. Despite costing thousands of dollars to treat one patient for a year, there is currently little evidence that it works. Treatment is considered to have been successful if the virus cannot be detected in a patient's blood six months after treatment. This outcome is known as sustained viral response (SVR). However, it has never been confirmed that SVR leads to an improvement in the patient's disease state or their chances of survival.

The authors of the review analysed data from seven trials involving a total of 1,976 patients with chronic hepatitis C liver disease who were being retreated with interferon monotherapy having previously been treated unsuccessfully. When they included all trials in their analysis, the risk of death was no higher for interferon than for placebo or no treatment. However, the researchers also performed a further analysis, leaving out studies that had a high risk of bias and gave less reliable estimates of effect. For example, one of these trials was not blinded, was stopped before the planned number of patients had been enrolled, and did not have all of those who had been enrolled counted in the final analysis. This left the two largest trials, together incorporating 1,676 patients. Focusing only on these trials, the risk of death was significantly higher at 9.4% for interferon retreatment compared to 6.7% for placebo or no treatment.

"It was troubling to see that in those trials providing the most reliable estimates of treatment effects, interferon seemed to increase the risk of death," said lead researcher Ronald Koretz of Granada Hills in California, US. "Based on these results, interferon monotherapy cannot be recommended for chronic hepatitis C patients who have already failed one course of treatment and are being retreated. Furthermore, patients who are receiving interferon as part of a combination therapy should be informed about this potential adverse effect."

Interferon treatment did seem to reduce levels of hepatitis C virus in the blood compared to controls, resulting in what would be considered successful treatment or SVR. However, since this response was not associated with an improvement in disease or risk of death, the review suggests that SVR may be inadequate as an indicator of a successful treatment outcome. "Sustained viral response did not suggest that a patient who was destined to develop symptoms or death from hepatitis C was cured, at least in this setting. This tells us that as a treatment outcome it is not universally reliable and needs to be validated before it can be viewed as the goal of any therapy in other clinical scenarios," said Koretz.

Patients in the treatment group were also more likely to suffer adverse effects. Although the drug did appear to reduce the incidence of nonfatal internal bleeding, the researchers conclude that it is so expensive that it may be hard to justify based on this one small benefit.

Interferon May Be Harmful in Retreatment of Hepatitis C


When patients with hepatitis C and chronic liver disease suffer relapses or fail to respond to initial treatment, monotherapy with interferon may not be a good idea, according to results from a recent meta-analysis. In fact, employing that approach may raise the risks for death and adverse effects.

The review is published in the January issue of the Cochrane Database of Systematic Reviews and was conducted by Ronald Koretz, MD, professor of medicine, digestive diseases and gastroenterology, David Geffen School of Medicine, University of California, Los Angeles, and colleagues.

"The widely-accepted treatment outcome for chronic hepatitis C is the sustained viral response (that is, no measurable viral RNA in blood six months after treatment). However, this surrogate outcome (as well as the previously employed biochemical and histologic ones) has never been validated," the authors write.

The lack of validation is not surprising, the authors say, because very few randomized clinical trials evaluating clinical outcomes (mortality or manifestations of cirrhosis) have been conducted, as patients usually do not die or develop cirrhosis until years after they have been infected.

Patients who undergo initial therapy but do not produce sustained viral responses become potential candidates for retreatment, the authors note, but for some patients in whom standard treatment with ribavirin or protease inhibitors cannot be tolerated, clinicians often consider retreatment with interferon to be a reasonable option.

All-Cause Mortality Worse
To find out more about the actual clinical effects of retreatment with interferon, the investigators reviewed data from 7 clinical trials in which monotherapy retreatment with interferon was compared with placebo or no treatment.

Two of the trials (the Hepatitis C Antiviral Long-term Treatment against Cirrhosis [HALT-C] and Evaluation of Peglntron in Control of Hepatitis C Cirrhosis [EPIC-3] trials) were considered to be at low risk for bias. Together, those trials included 1676 patients. Both assessed the clinical outcomes of patients with severe fibrosis who underwent long-term low-dose retreatment with pegylated interferon therapy.

The other 5 trials included a total of 300 patients and were considered to be at high risk for bias.
Dr. Koretz and colleagues report that when they included all trials with published outcomes in their review they saw no significant difference in all-cause mortality (78/843 [9.3%] vs 62/867 [7.2%]; risk ratio [RR], 1.30; 95% confidence interval [CI], 0.95 - 1.79; 3 trials). They also did not find a significant difference in hepatic-related mortality (41/532 [7.7%] vs 40/552 [7.2%]; RR, 1.07; 95% CI, 0.70 - 1.63; 2 trials).

However, when the reviewers included only the 2 trials considered at low risk for bias, they noted that all-cause mortality was significantly higher among patients who received interferon (78/828 [9.4%] vs 57/848 [6.7%]; RR, 1.41; 95% CI, 1.02 - 1.96).

They do note, however, that there was less variceal bleeding in patients who received interferon (4/843 [0.5%] vs 18/867 [2.1%]; RR, 0.24; 95% CI, 0.09 - 0.67; 3 trials). Still, the researchers comment that the prohibitive cost of interferon would not justify it for this indication alone.
Patients administered interferon were no more likely to develop ascites, encephalopathy, or hepatocellular carcinoma or to need liver transplants.

Only one of the trials included quality-of-life data, and in that trial pain scores were significantly worse in patients receiving interferon, the reviewers write. Patients receiving interferon were also more likely to suffer adverse effects, most commonly hematologic complications, infections, influenza-like symptoms, and rashes.

SVR a Surrogate Marker?
Interferon therapy did appear, however, to be associated with significantly better viral responses (20/557 [3.6%] vs 1/579 [0.2%]; RR, 15.38; 95% CI, 2.93 - 80.71; 4 trials). In addition, METAVIR activity scores, gauging degree of inflammation as well as the extent of fibrosis, also improved (36/55 [65%] vs 20/46 [43.5%]; RR, 1.49; 95% CI, 1.02 - 2.18; 2 trials). However, the reviewers say they saw no significant differences in histologic assessments of fibrosis.

The authors stress that the clinical data they reviewed were limited to patients with histologic evidence of severe fibrosis who were retreated with pegylated interferon.

"In this scenario, retreatment with interferon did not appear to provide significant clinical benefit and, when only the trials at low risk of bias were considered, retreatment for several years may even have increased all-cause mortality. Such treatment also produced adverse events," the authors note.

In conclusion, they write, "Two of the commonly employed surrogate markers, sustained viral response and markers of inflammation, failed to be validated since they improved even though the clinical outcomes did not (or may even have become worse). This failure to validate the sustained viral response in this group of patients with a low sustained viral response rate suggests that the presumed validity of the use of sustained viral responses in other groups of patients with chronic hepatitis C viral infections who receive treatment must be formally validated."

The authors have disclosed no relevant financial relationships.
Cochrane Database Syst Rev. 2013:1:CD003617.


Wednesday, August 10, 2011

Chronic hepatitis C infection and insulin resistance: two best friends

August 2011, Vol. 9, No. 8, Pages 555-558 , DOI 10.1586/eri.11.72

Chronic hepatitis C infection and insulin resistance: two best friends

Ludovico Abenavoli† & Piero L Almasio
† Author for correspondence

Approximately 170 million people worldwide are chronically infected by HCV, which can result in progressive hepatic injury and fibrosis, culminating in cirrhosis and end-stage liver disease. Among adults in the Western world, chronic hepatitis C (CHC) is the major cause of cirrhosis and the principal indication for liver transplantation [1]. The main treatment goal in patients with chronic HCV infection is sustained virological response (SVR) after treatment schedule. The ‘gold standard’ of therapeutic approach is the combination of pegylated IFN-α (PEG-IFN) with ribavirin (RBV) [2]. This association is highly successful in patients with genotype 2 and 3 infection, with SVR rate ranging between of 76 and 82% [3].

Nonalcoholic fatty liver disease (NAFLD) is among the most common causes of chronic liver disorder in the Western world. It is now recognized that patients with NAFLD have a multitude of severe comorbidities (e.g., diabetes, hypothyroidism and metabolic syndrome) [4]. NAFLD incidence in adults and children is rapidly rising because of the ongoing obesity epidemic and Type 2 diabetes. NAFLD is an umbrella term that includes steatosis, nonalcoholic steatohepatitis (NASH) and advanced fibrosis or cirrhosis related to this pathological entity.

Currently the biological mechanism of the underlying steatosis and the progression of liver disease is not entirely understood; it is probably due to the expression of a number of factors. Previously, a two-step hypothesis was proposed to explain this mechanism: initially the ‘first hit’ induces liver fat accumulation prior to the ‘second hit’, which prompts steatosis progression to NASH [5]. At present, obesity, insulin resistance (IR), oxidative stress and cytokine/adipokine are identified as the major factors involved in the NAFLD pathogenesis.

These factors can promote and boost inflammation, cell injury, apoptosis, fibrogenesis and carcinogenesis, leading to fat accumulation, a development and progression of the disease. Currently, the therapeutic approach to NAFLD involves a lifestyle intervention (e.g., weight reduction and regular physical activity) and the use of insulin-sensitizing drugs. Other treatment approaches have included the consumption of special diets and antioxidant and cytoprotective therapies [6].

Numerous observations suggest that liver steatosis is a common histological feature of CHC infection ranging from 40 to 86% [7]. The majority of patients have mild steatosis affecting less than 30% of hepatocytes. Thus, steatosis occurs more frequently in patients with CHC (55%) than in the general population (20–30%) of adults in the Western world [8]. Macrovesicular steatosis is found in the periportal region of the liver, different from the centrilobular distribution characteristic of NASH patients.


Moderate or severe steatosis is significantly less frequent in HCV genotype 4 than 3 and similar between genotype 4 and 1. In nondiabetic, overweight patients, moderate or severe steatosis is only present in 10–15% of genotype 4 or 1, compared with 40% of genotype 3 patients. In those with genotype 3 infection, the prevalence of steatosis is much higher, and is directly linked to HCV-mediated alterations in hepatic lipid metabolism. In contrast to genotype 1 infection, the presence of hepatic steatosis is a sign of underlying IR and features of the metabolic syndrome [9]. It is believed that steatosis enhances the progression of HCV infection to liver fibrosis and decreases the response to antiviral therapy. The pathogenic association between HCV infection and hepatic steatosis is multifactorial.

Pathogenesis & correlation

Insulin resistance is defined as an impaired ability to clear glucose from the circulation at a given level of circulating insulin. Both NAFLD and HCV are associated with increased gluconeogenic drive and IR as shown by the impaired suppression of hepatic glucose output by insulin [10]. Literature has reported that HCV core protein may block assembly of apolipoprotein A1-A2 with triglycerides. The result is a decreased export of triglycerides bound to apolipoprotein-β as very low density lipoproteins out of hepatocytes [11]. Okuda et al. have proposed that the core protein induces oxidative stress within the mitochondria that contributes to lipid accumulation [12], in particular in genotype 3 patients by the cytopathic effect of high titer of intracytoplasmic negative strand HCV-RNA [13].

It has been reported that IR plays a central role in the pathogenesis of NAFLD [5]. However, the mechanisms of the biological mechanism underlying liver steatosis in HCV patients, is not definitively understood. IR causes impaired metabolic clearance of glucose, compensatory hyperinsulinemia, and increased lipolysis. In fact, during exposure to insulin, subjects with NAFLD have impaired suppression of circulating free fatty acids and glycerol. These products of lipolysis mark the effects of insulin on peripheral lipolysis [8].

By contrast, subjects with HCV infection do not show any significant changes in peripheral levels of free fatty acids and glycerol.

Insulin resistance has also been associated with fibrosis progression in CHC patients [9,10]. This link is complex and genotype specific. In CHC due to genotype 1 and 4, IR is associated with hepatic steatosis and is either virus-mediated or due to host metabolic factors, such as visceral obesity [14,15]. Conversely, liver steatosis in HCV genotype 3 infection is predominantly a direct effect of the virus, occurring in the absence of other metabolic risk factors [16]. Genotype 3 is the only subtype that has been shown to be correlated to a higher grade of steatosis independent of other host-related factors, such as the presence of NAFLD. The severity of steatosis in these patients is directly related to the HCV-RNA viral load. Indeed, steatosis often resolves with the loss of viremia after antiviral treatment [17].

Liver steatosis & interferon nonresponse in HCV patients

Insulin resistance is associated with a poor response to antiviral treatment in patients with HCV genotype 1, 2 and 3 [18]. While the mechanisms underlying the failure of IFN therapy are not well understood, evidence indicates that several host factors are involved in addition to viral factors [15]. Among them, IR has been found to reduce the chances of achieving an SVR. Both impaired fasting glucose and Type 2 diabetes are associated with lower rates of SVR in patients treated with PEG-IFN and RBV. Multivariate analysis of the Virahep-C cohort showed that the homeostasis model assessment (HOMA) index, a measure of IR, was an independent predictor of SVR [19]. Although IR was more prevalent among African–American populations compared with Caucasian–American populations, this clinical feature, and nothing else, can explain the SVR differences between the two groups. A previous study of genotype 1-infected patients treated with PEG-IFN and RBV, demonstrated that the HOMA index is correlated with treatment response [20]. In this study, patients who had a normal HOMA (<2) presented an SVR of 60.5%, compared with 40% in patients with moderate IR (HOMA 2–4), and only 20% in patients with severe IR (HOMA >4). Literature supports a connection between HCV replication and IR. In fact, HOMA decreases when the virus is eradicated [21].

One mechanism by which IR and obesity may contribute to IFN nonresponse is through upregulation of suppressor of cytokine signaling 3 (SOCS3) [22]. SOCS3 blocks IFN signaling and may also exacerbate IR by promoting ubiquitin-mediated degradation of insulin receptor substrate 1 and 2 [23]. SOCS3 seems to be a key molecule for a cross-talk between IR and therapy nonresponse. In fact, hepatic expression of SOCS3 has a predictive value for the outcome of antiviral therapy in patients with HCV infection [24]. It is well known that IR increases hepatic lipid synthesis [25]. For HCV replication, lipid droplets play a central role. In fact, the accumulation of hepatic lipid droplets can increase HCV replication, and, as a consequence of this, poor responses to antiviral treatment are observed, even in patients with HCV genotypes 2 and 3 [25].

It has been demonstrated that the use of insulin-sensitizing agents, such as thiazolidinediones, in HCV treatment increases both SVR and rapid virological response rates. In particular, the use of pioglitazone (30 mg/day) concomitantly with the standard antiviral therapy in the treatment of naive, nondiabetic patients with genotype 4 HCV infection with IR (HOMA >2) increased SVR rates compared with standard of care (60.4 vs 38.7%, respectively; p = 0.04) [26].

Conclusion & future perspective

Steatosis development and CHC infection are clearly linked. It is well known that the accumulation of lipids in the infected hepatocyte could be a determinant for virus assembly. In fact, steatosis is an efficient mechanism for promotion of HCV replication. In addition, HCV induces IR by several pathogenetic mechanisms that are also implicated in treatment resistance and an increase of fibrosis progression. In this way, antiviral responsiveness remains a major clinical problem in the eradication of HCV, even with the use of new drugs. It is now clear that NAFLD is a frequent challenge in the clinical and histological management of patients with HCV, as well as for treatment efficacy. The use of pioglitazone as an adjuvant therapy appears to be promising in the treatment of CHC patients with IR. However, the optimal dose and treatment schedule is still debatable. In order to ameliorate the response to antiviral therapy, by a rational and targeted therapeutic approach, new research to define the underlying mechanisms of HCV-associated IR, is needed.

Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

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Friday, March 11, 2011

Early menopause is associated with lack of response to Hepatitis C therapy

Early menopause is associated with lack of response to antiviral therapy in women with chronic hepatitis, finds March's publication of Gastroenterology.

Chronic hepatitis C and liver fibrosis progress more rapidly in men and menopausal women than in women of reproductive age.

Professor Erica Villa and colleagues from Italy investigated the associations among menopause, sustained virologic response, and liver damage in patients with chronic hepatitis C.

The research team performed a prospective study of 1000 consecutive, treatment-naïve patients 18 years of age and older with compensated liver disease from chronic hepatitis C.

Liver biopsy samples were analyzed before patients received standard antiviral therapy.
Baseline levels of liver inflammation were higher among postmenopausal women

The research team collected data from 442 women on the presence, type, and timing of menopause, associated hormone and metabolic features, serum levels of interleukin-6, and hepatic tumor necrosis factor-α.

Postmenopausal women achieved sustained virological response less frequently than women of reproductive age, but as frequently as men.

By multivariate regression analysis, an independent significant predictor for women to not achieve a sustained virological response was early menopause.

In addition, levels of γ-glutamyl transpeptidase, infection with hepatitis C virus genotype 1 or 4, and cholesterol levels were independent significant predictor for women to not achieve a sustained virological response.

Early menopause was the only independent factor that predicted lack of a sustained virological response among women with genotype 1 hepatitis C virus infection.

The team observed that baseline levels of liver inflammation, fibrosis, steatosis, serum interleukin-6, and hepatic tumor necrosis factor-α were significantly higher among postmenopausal women than women of reproductive age.

Professor Villa and colleagues conclude, "Among women with chronic hepatitis C, early menopause was associated with a low likelihood of sustained virological response, probably because of inflammatory factors that change at menopause."

Gastroenterol 2011: 140(3): 818-82911 March 2011

Wednesday, January 19, 2011

IP-10: Chemokine antagonism may contribute to this inability to clear HCV infection.

Scientists at Inserm and Institut Pasteur have performed biomarker discovery on patients being treated for chronic hepatitis C infection. Their work, published in The Journal of Clinical Investigation, demonstrates that the plasma levels of the protein IP-10 predict, prior to treatment initiation, the efficacy of treatment with pegylated-interferon and ribavirin. Based on these results, the scientists have developed a prognostic test. Commercialization is anticipated in 2011, and will help inform physicians of the chances that patients will respond to standard treatment or if instead they will require new therapeutic cocktails (e.g., inclusion of protease inhibitors).

Importantly, hepatitis C is the leading cause of primary liver cancer (hepatocellular carcinoma) and it remains an important cause of liver failure due to fibrosis and cirrhosis. This infectious disease represents a major public health problem, with greater than 170 million cases worldwide. The World Health Organization estimates 3 to 4 million new cases per year and considers the virus a ” viral time bomb” due to the long term sequella of infection.

Currently, there is no approved vaccine available and approximately 80% of individuals infected by the virus develop chronic disease, a risk factor for cirrhosis, liver failure, liver cancer as well as other medical complications (e.g., diabetes).

For the past ten years, treatment has been based on the use of type I interferon given in combination with the anti-viral ribavirin. While effective, it results in a cure for only 50% of patients. Moreover, treatment is long (24 — 48 weeks), and it results in severe side effects (e.g., depression, anemia).

It is in this context that the Inserm and Institut Pasteur sponsored research lab of Dr. Matthew Albert, in close collaboration with the Liver Disease Unit headed by Prof. Stanislas Pol, evaluated plasma biomarkers to define predictors for patients’ response to treatment.

With the help of the Centre for Human Immunology at Institut Pasteur, the investigators involved have performed a prospective study. They identified the protein IP-10 as a prognostic biomarker — elevated in those patients for whom treatment was ineffective. This observation was paradoxical as IP-10 is considered a pro-inflammatory molecule, which should have facilitated migration of activated T cells to the liver, the exact cell types responsible for viral immunity. In fact, what was discovered is that the IP-10 had been catabolized and it was a truncated form present in the HCV patients. Strikingly, the short form of IP-10 is an antagonist and inhibits T cell recruitment. Thus, it is suggested that the antagonist form of IP-10 is responsible for the failure to respond to treatment in the 50% of patients who do not benefit from pegylated-interferon / ribavirin treatment.

The investigators worked in close collaboration with an American company, Rules Based Medicine, Inc., who will develop a diagnostic test to distinguish the different forms of IP-10 as a simple blood test. This test will be a significant step towards the improved management of patients with HCV as well as other chronic inflammatory diseases.

This scientific work was conducted under the direction of Matthew L. Albert, MD PhD, Mixed Institut Pasteur / Inserm Research Unit; and Stanislas Pol, MD PhD, Univerisity of Paris, Descartes and Institut Cochin. Financial support was provided by the ANRS and promotion of the study was taken by Inserm Medical.

Journal of Clinical Investigation.
and the related news article
Chemokine antagonism in chronic hepatitis C virus infection.Edgar D. Charles and Lynn B. Dustin
Journal of Clinical Investigation.
Published in Volume 121, Issue 1 (January 4, 2011) J Clin Invest. 2011;121(1):25–27. doi:10.1172/JCI45610. Copyright © 2011, American Society for Clinical Investigation

Chemokine antagonism in chronic hepatitis C virus infection
Edgar D. Charles and Lynn B. Dustin

Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, USA.

Address correspondence to: Lynn B. Dustin, Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, 1230 York Ave., Box 64, New York, New York 10065, USA. Phone: 212.327.7067; Fax: 212.327.7048; E-mail:

First published December 22, 2010

Immune responses to hepatitis C virus (HCV) fail to clear the virus in most individuals. Why patients who are less likely to clear HCV infection have high plasma levels of CXCL10 (also known as IP-10), a chemokine that directs T cells to sites of infection, has long been unclear. In this issue of the JCI, Casrouge and colleagues shed light on this paradox by showing that CXCL10 in the plasma of many HCV patients is enzymatically processed to produce a CXCL10 receptor antagonist. These findings introduce a role for chemokine antagonism during HCV infection and unveil new avenues for improved HCV diagnosis and therapy.

Over 120 million persons worldwide have chronic HCV infection (1), which is a major cause of liver failure and hepatocellular carcinoma (2). Up to one-quarter of persons who are acutely infected with HCV spontaneously clear their infection, and the current standard of care — pegylated IFN-α (peg–IFN-α) and ribavirin — eliminates virus in only about half of those treated (3). This means that a substantial number of patients remain chronically infected with HCV. In these chronically infected individuals, HCV-specific T cells are ineffective at eradicating virus, yet are potent mediators of hepatocellular injury. Evidence presented in this issue of the JCI by Casrouge et al. (4) suggests that chemokine antagonism may contribute to this inability to clear HCV infection. Their data (4) also provide an explanation as to why high levels of the chemokine CXCL10 in the plasma or serum of an HCV-infected patient portend a poor response to peg–IFN-α and ribavirin (5–8).

Salient features of chemokines
Chemokines have a central role in inflammation and host defense. These small (8–17 kDa) cytokine-like molecules act to guide leukocytes along a concentration gradient toward lymphoid organs and sites of inflammation. They also play roles in embryogenesis, angiogenesis, and lymphoid organ development. Chemokines involved in inflammation are displayed on proteoglycans near the site of their production. Chemokines bind to G protein–coupled, seven-transmembrane receptors, of which there are almost twenty. CXCR3, the CXCL10 receptor, is expressed on activated T cells, NK cells, and some B cells (9). In the hepatic sinusoid, leukocyte recognition of chemokines triggers conformational changes in the integrins that they express on their surface, which are then able to mediate binding to endothelial ligands. These steps permit leukocyte transmigration to target tissue (Figure 1) (reviewed in ref. 10).

Figure 1
Model of chemokine antagonism in the HCV-infected liver. CXCL10 produced in the infected liver recruits T cells from the blood to the infected hepatocyte via the liver sinusoid and the space of Disse (left). When processed by DPP4, CXCL10 becomes an antagonist of T cell recruitment (right). In this issue of the JCI, Casrouge and colleagues have shown that levels of this shortened antagonist form of CXCL10 are increased in many patients who fail to clear HCV (4), suggesting a role for chemokine antagonism in an ineffective anti-HCV response.

CXCL10 and liver disease
Among chemokines, CXCL10 plays a central role in liver inflammation, and it is expressed in the HCV-infected liver (11–13). Serum CXCL10 is also elevated during flares in HBV infection (14), in primary biliary cirrhosis, and in rheumatoid arthritis (15). In several independent studies, elevated serum/plasma levels of CXCL10 predict the failure of IFN-α–based HCV treatment (5–8).

Why a chemoattractant seemingly so potent as CXCL10 is elevated in patients who fail to clear HCV has been paradoxical. One possibility is that CXCL10 is overproduced in a futile attempt to draft pusillanimous T cells into the liver to combat infection. Indeed, chronic HCV infection is often associated with impaired function and reduced breadth of continuously activated, HCV-specific T cells (reviewed in ref. 16). However, in this issue of the JCI, data from Casrouge and colleagues suggest that CXCL10 may in fact be dissuading T cells from joining the fight (4).

Casrouge and colleagues performed a multianalyte profiling of patient plasma, confirming that CXCL10 levels are increased in patients that do not respond to anti-HCV therapy compared with those that do (4). They also observed that CXCL10 levels correlated with elevated numbers of circulating CXCR3+ cells. It had previously been proposed that the high levels of CXCL10 in patients who do not respond to anti-HCV therapy could act as an antagonist of T cell migration (5). Further, it has been reported that CXCL10 can be processed in vitro by dipeptidyl peptidase IV (DPP4; also known as CD26), which cleaves two amino acid residues from the amino terminus of CXCL10 and turns it into a CXCR3 antagonist (17), and that HCV patients have increased soluble DPP4 activity (18). However, distinguishing full-length from DPP4-processed CXCL10 in clinical samples has not been feasible until now.

After developing reagents to distinguish full-length from DPP4-processed CXCL10, Casrouge and colleagues found that, in many HCV-infected patients who do not respond to therapy, circulating CXCL10 is indeed processed into the shorter form (4). Importantly, patient blood had been collected in tubes containing a DPP4 inhibitor, as DPP4 remains active after blood collection. The authors demonstrated that before treatment, plasma DPP4 activity was higher in those individuals who went on to fail to respond to anti-HCV therapy than in patients who responded and healthy individuals. They also confirmed a previous report (17) showing that CXCL10 is cleaved by DPP4 in vitro. A DPP4 inhibitor, sitagliptin — which is used clinically in the treatment of type 2 diabetes — inhibited this cleavage. Using in vitro systems, Casrouge and colleagues showed that the full-length form of CXCL10, but not the short form, could direct the migration of CXCR3+ T cells (4). Short CXCL10 antagonized signaling by long CXCL10. Finally, they demonstrated that the short, antagonist form of CXCL10 predominates in the plasma of chronically infected patients who are destined to fail anti-HCV therapy; early virological responders were more likely than nonresponders to have undetectable amounts of short-form CXCL10. This latter finding will need to be confirmed in larger studies of patient cohorts carefully matched for liver function and inflammation. These results suggest that short-form CXCL10 in the plasma may antagonize T cell recruitment to the liver parenchyma (Figure 1).

Answers beget questions
The study by Casrouge et al. (4) raises new questions regarding HCV immunopathogenesis. Seemingly at odds with the study, plenty of T cells are present in the liver during HCV infection, even in those with elevated CXCL10 levels (19) and those with cirrhosis (13). It is unknown whether these T cells are all HCV-specific. One hypothesis to explain this discordance is that the short form of CXCL10 preferentially antagonizes T cells recognizing HCV peptides in an HLA-dependent context. Also, it is likely that chemotaxis of HCV-specific T cells to the liver depends upon the combinatorial effect of multiple chemokines with disparate roles and potencies. Of note, the importance of T cells in treatment-induced clearance of HCV remains controversial (16).

Importantly, the findings of Casrouge et al. (4) provide a rationale for the validation of short-form CXCL10 and DPP4 (which may be broad markers of inflammation) as clinically appropriate predictors of HCV clearance, potentially allowing for more individualized treatment decisions. It will also be useful to determine whether levels of DPP4 and short-form CXCL10 predict spontaneous resolution or chronic evolution of acute HCV infection. The successful validation of DPP4 and CXCL10 as predictors of spontaneous resolution could improve the early initiation of anti-HCV therapy in those who would most benefit, while sparing those who will clear HCV infection without treatment and those who will not respond to treatment from a therapy that has severe side effects and is therefore very poorly tolerated.

Hints about a link to diabetes?
Patients chronically infected with HCV are at increased risk of insulin resistance and frank type 2 diabetes (20, 21). Postprandial insulin secretion is controlled in part by the insulin secretagogue glucagon-like peptide–1 (GLP-1). The extremely short in vivo half-life of GLP-1 (1–2 minutes) is due to its inactivation by DPP4. The observation that DPP4 activity is increased in many HCV patients may provide clues about the pathogenesis of HCV-associated metabolic dysregulation. It is tempting to speculate that DPP4-mediated cleavage of GLP-1 may be partially responsible for HCV-related insulin resistance. Indeed, decreased levels of serum GLP-1 and increased levels of serum and liver DPP4 have been reported in HCV-infected patients relative to healthy volunteers (22). Intriguingly, levels of serum CXCL10 are also elevated in HCV patients with type 2 diabetes (23). Of course, much more work needs to be done to establish links between DPP4, CXCL10 levels, and type 2 diabetes. The next logical step is a comparison of levels of plasma DPP4 and GLP-1 in HCV-infected patients with and without impaired glucose tolerance or type 2 diabetes.

This work was supported in part by NIH grants R01AI60561 (to L.B. Dustin) and K08AI075301 (to E.D. Charles) and the Irma T. Hirschl/Monique Weill-Caullier Trust (to L.B. Dustin).


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Monday, December 6, 2010

Hepatitis C Treatment : Boceprevir In Non-responders

Research Fuels Hope for Hard-To-Treat Hepatitis C Patients
Released: 12/6/2010 12:00 PM EST
Source: Saint Louis University Medical Center

Newswise — The outlook for patients with hepatitis C continues to improve as results from a clinical trial led by a Saint Louis University researcher found that the drug boceprevir helped cure hard-to-treat patients. The findings were reported at the 61st annual meeting of the American Association for the Study of Liver Disease’s earlier in November.

Bruce R. Bacon, M.D., professor of internal medicine at Saint Louis University School of Medicine and co-principal investigator of the HCV RESPOND-2 study, studied the protease inhibitor, boceprevir, and found that it significantly increased the number of patients whose blood had undetectable levels of the virus.

“These findings are especially significant for patients who don’t respond to initial treatment,” said Bacon. “When the hepatitis C virus is not eliminated, debilitating fatigue and more serious problems can follow.”

Hepatitis C is caused by a virus that is transmitted by contact with blood. The infection may initially be asymptomatic, but for patients who develop chronic hepatitis C infection, inflammation of the liver may develop, leading to fibrosis and cirrhosis (scarring of the liver), as well as other complications including liver cancer and death.

The prognosis varies for patients with chronic hepatitis C. With the current standard therapy, about half fully recover after an initial course of peginterferon and ribavirin anti-viral therapy that may last from six months to a year.

The remaining patients, known as non-responders, may improve with initial treatment but the virus is not eliminated, or may not respond to treatment at all.

For this group, the only current option is to retreat patients with the same or similar drugs, which increases the likelihood of severe treatment side-effects. In addition, researchers have found that the success of treatment depends on the major strain, or genotype, of hepatitis C that a patient has.

The HCV RESPOND-2 study looked at 403 patients with chronic hepatitis C infections with genotype one, the most difficult strain of the virus to treat, who still had significant levels of the virus after being treated with peginterferon and ribavirin, the standard hepatitis C treatment.

"These results are very exciting," Bacon said. “In this study, boceprevir helped cure significantly more patients in 24 weeks of therapy than did treatment with peginterferon and ribavirin alone."

A second study, HCV SPRINT-2, examined patients with hepatitis C with genotype one who had not yet been treated with the standard treatment. They, too, responded well to the drug.

Bacon calls the progress made in treating hepatitis C remarkable.

“We’ve gone from the discovery of the virus in 1989 to where we are now, 22 years later, when we have the ability to cure a large majority of those with hepatitis C,” Bacon said. “It’s a true success story.”

“Drugs like boceprevir are going to revolutionize care of those with hepatitis C.”

The clinical trial was funded by Merck, which expects to begin seeking FDA approval this year.

Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.