By Jules Levin
from jules: So what happened at AASLD, briefly. The major info is that boceprevir and telaprevir, the 2 new oral HCV protease inhibitors reported their phase 3 data, it looked good with 75% for telaprevir & 67% for non-black patients with boceprevir (both taken with peg/rbv) achieving a cure. For blacks response rates were very high with both drugs as with whites for patients who achieved very early viral responses, undetectable by weeks 4 and 12 for telaprevir and week 8 for boceprevir (see data below). It's expected the FDA will hold a public hearing & approve both drugs during the Summer of 2011.
What else happened? Probably the most anticipated story was the results from the BMS study looking at 2 oral drugs, their protease+ their NS5A inhibitor alone with peg/rbv in null responders. The response rate was about 50% after 12 weeks therapy but interestingly genotype 1a were the failures, genotype 1bs did not fail. Of note 9/10 patients, receiving peg/rbv plus the 2 orals had undetectable viral load after 12 weeks! Also of note patients who failed after taking only the 2 orals, most achieved undetectable by continuing with peg/rbv only, also very interesting. This information increases our knowledge about whether we can get rid of peg/rbv at least for some patients, but so far we don't have an answer, final results from this study will provide more information and they should be available in 2011. Other HCV protease inhibitors are in earlier development and some look more potent: Abbott's ABT-450, Tibotec's TMC435, Merck's 5172 and 7009; also Boerhinger Ingelheim has a protease moving along. BMSs NS5A inhibitor is potent, and Presido reported on their NS5A inhibitors in early pre-clinical development but going into patients study soon. The NS5a drugs look potent & the BMS drug is the furthest along. R7128 is a nuke, a polymerase inhibitor, and Roche reported very interesting & good results showing after 12 weeks of R7128+peg/rbv 88% of patients had undetectable viral load. As well, Pharmasset is developing 2 nucleotides 7977 & 938, which look very potent, both showing as much as 4.5 log reductions. These classes of drugs are important because they do not appear to show drug resistance develops easy as we see with protease inhibitors, so they provide a lot of interesting promise. Another very interesting development at AASLD was that Gilead has taken a very ambitious jump into HCV announcing they have 7 drugs in development and reporting results of an interesting study with 3 drugs, their protease+their polymerase inhibitor+ribavirin, As well, Boerhinger Ingelheim reported results of 2 orals, their Protease+their polymerase alone and in combination with ribavirin with 17/17 achieving undetectable with all 3 oral drugs. Of note BMS is developing peg lambda interferon, in case we can't get rid of interferon, the drug appears to be more tolerable, less side effects. The issue of drug resistance remains an open question. The question is: will drug resistance prevent a patient from reusing a protease inhibitor again as it does in HIV unless you have a 2nd generation protease that suppresses resistant virus, we don't know the answer to this question yet. Both drugs boceprevir & telaprevir had posters at the meeting showing drug resistance mutations can emerge (poster reports are on NATAP website), but we still don't know if they will persist and emerge again later if a protease is reused. Of particular note, Merck is developing a protease MK-5172, which shows it might suppress resistant virus but also looked very potent in the study reported at AASLD, so it might also be a firstline therapy because it looks so potent. Compliance (adherence) and the risk of developing drug resistance will be big concerns. Response Guided Therapy is important, this is as discussed below how we will be able to see if patients are responding well early on after weeks 4, 8 and 12, so if patients are not responding well they can stop the drugs and hope to prevent drug resistance. There will have to be major support programs devoted to the implementation of this & education for clinicians and patients.
Phase 3 data was reported for the new HCV protease inhibitors telaprevir from Vertex and boceprevir from Merck (Schering). Patients will take telaprevir for 12 weeks + peg/rbv, stop telaprevir after 12 weeks but continue taking peg/rbv for another 12 weeks. For telaprevir (plus peg/rbv) 75% of patients achieved SVR or cures. 68% of patients in studies had undetectable HCV viral load at 4 weeks and 58% at weeks 4 and 12, and 89% of these patients with undetectable viral load at weeks 4 and 12 achieved a cure or SVR after 24 weeks of total therapy. Relapse rates were low, 9%. On-treatment virologic failure rates were only 3%. Patients with no, mild or portal fibrosis did a little better with a 78% cure or SVR rate. Patients with cirrhosis or bridging fibrosis had a less response with a 62% cure rate. For African-Americans the cure rate was 62% and for Latinos 74%. In a separate press announcement Vertex reported that Blacks with undetectable HCV viral load at weeks 4 and 12, 88% achieved a cure, very good news. Vertex reported 56% of patients experienced a 'rash event', 6% a severe rash event, 7% discontinued telaprevir due to rash event, only 1.4% discontinued all study drugs (peg/rbv) due to rash events. 4% of patients discontinued telaprevir for anemia, on average hemoglobin went down from 12.3 g/dL approx to 11 by week 8. Previously Vertex reported prior treatment-experienced patients 65% achieved SVR: 86% for relapsers, 57% for partial responders, 31% for null responders. For boceprevir (plus peg/rbv) in the phase 3 data reported at AASLD in SPRINT2 Study, 67% of non-black patients achieved SVR after 24 weeks of therapy and 42% of Blacks with 24 weeks therapy but 53% with 48 weeks therapy. In this study patients received a 4-week lead in with peg/rbv before starting boceprevir, so the drug will likely be used this way in the clinic. For non-black patients with 1 log or more reduction in viral load after the lead-in period 82% achieved a cure, For non-black patients with undetectable HCV viral load at week 8 89% achieved undetectable viral load after 24 weeks and 91% after 48 weeks. For patients with undetectable viral load between weeks 8-24 97% achieved a cure after 24 weeks therapy and 96% after 48 weeks, and for patients with 'at least one detectable HCV viral load between weeks 8-24', 74% achieved a cure after 24 or 48 weeks total therapy. Blacks taking boceprevir, 87% (n=13/15) achieved SVR with 24 weeks therapy & 95% (n=18/19) with 48 weeks therapy if they had undetectable HCV viral load during weeks 8-24, the numbers of patients were small. For Blacks with detectable viral load at any visit from week 8-24 presumably however undetectable at weeks 8 & 24: 58% with 24 weeks achieved SVR (7/12) and 88% achieved SVR (7/8) with 48 weeks therapy. 57% of patients in the boceprevir 24 week arm had undetectable week 8 viral load: 60% non-black and 35% Black patients. Based on week 8 undetectable viral load: 89% of non-blacks & 78% of Blacks with 24 weeks therapy achieved SVR. But if week 8 was undetectable those receiving 48 weeks therapy had similar responses: 91% for non-blacks & 82% for blacks. But if week 8 viral load was detectable, 37% of non-blackd, 32% of blacks receiving 24 weeks therapy, and 43% of whites, 28% of blacks receiving 48 weeks therapy achieved SVR.
49% of patients experienced anemia, 1% discontinued due to anemia, 13% had dose reductions due to anemia, 24% used EPO for treatment of anemia. Anemia also occurred for patients taking telaprevirpeg/rbv but at a lower rate.
here are the slides for these studies presented at AASLD:
AASLD: Phase 3 - Response Guided Therapy (RGT) - Boceprevir Combined with peginterferon alfa-2b plus ribavirin for treatment-naïve patients with HCV genotype 1 (SPRINT-2 Final Results) - (11/03/1)
AASLD: Telaprevir in Combination with Peginterferon alfa-2a and Ribavirin in Genotype 1 HCV Treatment-Naïve patients: Final results of Phase 3 ADVANCE Study - (11/03/10)
---------------
AASLD: 5 New Potent HCV Protease inhibitors - (11/05/10)
AASLD: New HCV Drugs: R7128 nucleoside, PSI7977 nucleotide, PSI938 nucleotide, ANA598 nnrti (rash), danoprevir protease, IMO-2125, a TLR agonist - (11/05/10)
AASLD: HCV Late Breaker Posters this Morning at AASLD.....ABT450, BMS790052 NS5A+proteaseBMS650032, BI 201335+HCV polymerase inhibitor BI 207127+ribavirin - (11/02/10)
---------------------------------
ALL 60 REPORTs ARE HERE:
61th Annual Meeting of the American
Association for the Study of Liver Diseases
Boston, MA, Hynes Convention Center
October 30-November 3, 2010
------------------
AASLD: HCV New Drugs - (11/08/10)
Vertex's telaprevir and Merck's boceprevir: Compliance and resistance issues due ...
Nov 3, 2010 ... Both companies will present final Phase III study results at the upcoming American Association for the Study of Liver Diseases (AASLD) ... www.natap.org/2010/AASLD/AASLD_03.htm
**** AASLD: Merck's Investigational Medicine Boceprevir Achieved Significantly Higher SVR Rates In Treatment-Failure And Treatment-Naïve Adult Patients With Chronic Hepatitis C Genotype 1 Compared To Control - merck press release - (11/03/10)
**** AASLD: Telaprevir+pEg/RBV Based Combination Therapy in People with Hepatitis C, Regardless of Race or Stage of Liver Disease - 'up to 88% in African-Americans' - (11/01/10)
AASLD: Bristol-Myers, Gilead and other companies Seek AIDS Cocktail Success in Hepatitis C: '2 oral HCV drugs in combination' - (11/01/10)
AASLD: Black patients (& new HCV therapy) fare well on Vertex hepatitis C drug - (11/01/10)
AASLD: Sustained Virological Response of Antiviral Therapy and Clinical Outcomes in Elderly Patients with Compensated HCV - related Cirrhosis - (11/04/10)
AASLD: Coffee is associated with virologic response in chronic Hepatitis C: Findings from the Hepatitis C Long - Term Treatment against Cirrhosis Trial (HALT - C) . - (11/04/10)
AASLD: Clinical, Virological, Biochemical Outcomes After 20 Years of Sustained Virological Response (SVR) in Chronic Hepatitis C: The NIH Experience. - (11/04/10)
AASLD: Maintenance peginterferon (pegIFN) therapy to prevent hepatocellular carcinoma (HCC) in patients with advanced chronic hepatitis C: extended follow - up results from the HALT - C Trial - (11/04/10)
Source
November 10, 2010
Virological Tools to Diagnose and Monitor HCV Infection
Clinical Microbiology and Infection
DOI: 10.1111/j.1469-0691.2010.03418.x
Accepted Article (Accepted, unedited articles published online for future issues)
Copyright © 2010 European Society of Clinical Microbiology and Infectious
Author Information
French National Reference Center for Viral Hepatitis B, C and delta, Department of Virology & INSERM U955, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
*Correspondence: Correspondance: Dr Stephane CHEVALIEZ, PharmD, PhD Department of Virology Hôpital Henri Mondor 51 avenue du Maréchal de Lattre de Tassigny 94010 Créteil, France Tel : +33-1-4981-2828 Fax : +33-1-4981-2839 E-mail : stephane.chevaliez@hmn.aphp.fr
Publication History
Accepted manuscript online: 4 NOV 2010 12:03PM EST
Received Date: 18-Oct-2010Accepted Date: 22-Oct-2010
Abstract
Approximately 200 million people are chronically infected with hepatitis C virus. HCV infection is curable by therapy, with the current standard treatment based on the combination of pegylated interferon alpha and ribavirin. Viral eradication is however achieved in approximately half of treated-patients. In 2011 new antiviral treatment based on triple combination with a protease inhibitor will be available. Virological tools are essential to diagnose HCV infection, but they have found their principal application in guiding treatment decisions and assessing the virological responses to therapy. These include the anti-HCV antibody assay, measurements of HCV core antigen and HCV viral load and HCV genotyping. HCV RNA can be ideally assayed by a real-time assay with a limit of detection of 10-15 IU/mL. Monitoring of viral kinetics during the early phases of antiviral treatment is crucial in making treatment decisions such as early stopping rules and also in optimizing the treatment duration. The HCV genotype should be assessed before the start of treatment because it determines the treatment length and ribavirin dose and also offers prognostic information on treatment outcomes as certain genotypes respond more favorably to treatment.
Source
DOI: 10.1111/j.1469-0691.2010.03418.x
Accepted Article (Accepted, unedited articles published online for future issues)
Copyright © 2010 European Society of Clinical Microbiology and Infectious
Author Information
French National Reference Center for Viral Hepatitis B, C and delta, Department of Virology & INSERM U955, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
*Correspondence: Correspondance: Dr Stephane CHEVALIEZ, PharmD, PhD Department of Virology Hôpital Henri Mondor 51 avenue du Maréchal de Lattre de Tassigny 94010 Créteil, France Tel : +33-1-4981-2828 Fax : +33-1-4981-2839 E-mail : stephane.chevaliez@hmn.aphp.fr
Publication History
Accepted manuscript online: 4 NOV 2010 12:03PM EST
Received Date: 18-Oct-2010Accepted Date: 22-Oct-2010
Abstract
Approximately 200 million people are chronically infected with hepatitis C virus. HCV infection is curable by therapy, with the current standard treatment based on the combination of pegylated interferon alpha and ribavirin. Viral eradication is however achieved in approximately half of treated-patients. In 2011 new antiviral treatment based on triple combination with a protease inhibitor will be available. Virological tools are essential to diagnose HCV infection, but they have found their principal application in guiding treatment decisions and assessing the virological responses to therapy. These include the anti-HCV antibody assay, measurements of HCV core antigen and HCV viral load and HCV genotyping. HCV RNA can be ideally assayed by a real-time assay with a limit of detection of 10-15 IU/mL. Monitoring of viral kinetics during the early phases of antiviral treatment is crucial in making treatment decisions such as early stopping rules and also in optimizing the treatment duration. The HCV genotype should be assessed before the start of treatment because it determines the treatment length and ribavirin dose and also offers prognostic information on treatment outcomes as certain genotypes respond more favorably to treatment.
Source
AASLD: Carbohydrate Restriction Fastest Way to Reduce Triglycerides
Bob Roehr
November 9, 2010 (Boston, Massachusetts) — A 4.3% reduction in body weight and an approximate 42% reduction of triglyceride levels in subjects with nonalcoholic fatty liver disease (NAFLD) was achieved with 2 weeks of dietary intervention. Dietary restriction of carbohydrates was significantly more effective in reducing liver triglycerides than a low-calorie diet, due in part to enhanced lipid disposal by hepatic and whole-body β-oxidation.
Jeffrey D. Browning, MD, from the University of Texas Southwestern Medical Center, in Dallas, discussed his research with Medscape Medical News at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting, where he presented his group's findings. Dr. Browning said basic research has shown that lipogenesis — taking a carbohydrate, breaking it down, and building it up into a fat molecule — is hyperactive in patients who have fatty liver disease.
"Normally, that should happen after a meal in the presence of insulin. Lipogenesis should go up and, as your insulin falls off, lipogenesis should go down. But in patients with fatty liver disease, it is up and it stays up, regardless of whether they have eaten or not."
His hypothesis was that in limiting carbohydrates, not only would the synthesis of new fat in the liver be limited, it would also "open up a disposal pathway for the fat that may already be there by de-inhibiting mitochondrial oxidation."
The study randomized 18 patients with NAFLD to eat either a carbohydrate-restricted (<20 g/day) or a calorie-restricted diet (1200 to 1500 kcal/day) for 2 weeks. Weight loss was similar in the low-calorie and low-carbohydrate groups (–4.0 ± 1.5 vs –4.6 ± 1.5 kg; P = .363).
Dr. Browning said they designed the study to achieve equal weight loss "so that you couldn't argue that the reason why we were seeing more fat reduction in the liver was because they had more weight loss."
They also hypothesized that there would be an increase in ketone production and the respiratory quotient (the ratio of CO2 production to O2 use). "With a respiratory quotient of 1, you are primarily burning carbohydrate as your energy source. As you go lower, toward 0.7, you are primarily burning fat."
The respiratory quotients were much different in the 2 groups, suggesting that lipogenesis was limited because of the decrease in carbohydrate intake. Both groups had an increase in ketones from baseline, but the increase was much more dramatic in those on the carbohydrate-restricted diet.
"Others have shown that if you take this diet out 6 months, there is no difference in the amount of fat that is reduced in the liver. If you take this out 6 months to a year, it probably doesn't matter what diet you're eating, as long as you are losing weight," he said.
After 6 to 12 months of weight loss, "you have kind of leveled the playing field. A lot of these metabolic consequences of fatty liver disease are probably gone by 6 months, so there is no metabolic advantage to carbohydrate restriction."
Dr. Browning said the study "was more an exercise in knowing what the underlying physiology was. Can we manipulate it in the short term? This shows that we can." It may have implications in situations where a more rapid decline in triglycerides is desirable.
"I wouldn't tell a clinician that this [diet] is better than that [diet] based on this study, but I would say, whatever works for the patient is fine," he said.
The study was conducted under an National Institutes of Health grant. Dr. Browning has disclosed no relevant financial relationships.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract 630. Presented October 30, 2010.
Source
November 9, 2010 (Boston, Massachusetts) — A 4.3% reduction in body weight and an approximate 42% reduction of triglyceride levels in subjects with nonalcoholic fatty liver disease (NAFLD) was achieved with 2 weeks of dietary intervention. Dietary restriction of carbohydrates was significantly more effective in reducing liver triglycerides than a low-calorie diet, due in part to enhanced lipid disposal by hepatic and whole-body β-oxidation.
Jeffrey D. Browning, MD, from the University of Texas Southwestern Medical Center, in Dallas, discussed his research with Medscape Medical News at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting, where he presented his group's findings. Dr. Browning said basic research has shown that lipogenesis — taking a carbohydrate, breaking it down, and building it up into a fat molecule — is hyperactive in patients who have fatty liver disease.
"Normally, that should happen after a meal in the presence of insulin. Lipogenesis should go up and, as your insulin falls off, lipogenesis should go down. But in patients with fatty liver disease, it is up and it stays up, regardless of whether they have eaten or not."
His hypothesis was that in limiting carbohydrates, not only would the synthesis of new fat in the liver be limited, it would also "open up a disposal pathway for the fat that may already be there by de-inhibiting mitochondrial oxidation."
The study randomized 18 patients with NAFLD to eat either a carbohydrate-restricted (<20 g/day) or a calorie-restricted diet (1200 to 1500 kcal/day) for 2 weeks. Weight loss was similar in the low-calorie and low-carbohydrate groups (–4.0 ± 1.5 vs –4.6 ± 1.5 kg; P = .363).
Dr. Browning said they designed the study to achieve equal weight loss "so that you couldn't argue that the reason why we were seeing more fat reduction in the liver was because they had more weight loss."
They also hypothesized that there would be an increase in ketone production and the respiratory quotient (the ratio of CO2 production to O2 use). "With a respiratory quotient of 1, you are primarily burning carbohydrate as your energy source. As you go lower, toward 0.7, you are primarily burning fat."
The respiratory quotients were much different in the 2 groups, suggesting that lipogenesis was limited because of the decrease in carbohydrate intake. Both groups had an increase in ketones from baseline, but the increase was much more dramatic in those on the carbohydrate-restricted diet.
"Others have shown that if you take this diet out 6 months, there is no difference in the amount of fat that is reduced in the liver. If you take this out 6 months to a year, it probably doesn't matter what diet you're eating, as long as you are losing weight," he said.
After 6 to 12 months of weight loss, "you have kind of leveled the playing field. A lot of these metabolic consequences of fatty liver disease are probably gone by 6 months, so there is no metabolic advantage to carbohydrate restriction."
Dr. Browning said the study "was more an exercise in knowing what the underlying physiology was. Can we manipulate it in the short term? This shows that we can." It may have implications in situations where a more rapid decline in triglycerides is desirable.
"I wouldn't tell a clinician that this [diet] is better than that [diet] based on this study, but I would say, whatever works for the patient is fine," he said.
The study was conducted under an National Institutes of Health grant. Dr. Browning has disclosed no relevant financial relationships.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract 630. Presented October 30, 2010.
Source
AASLD: Cure Rates for HDV Depend on Genotype and Baseline Viral Load
Bob Roehr
November 10, 2010 (Boston, Massachusetts) — An estimated 20 million people worldwide are infected with hepatitis D virus (HDV), primarily in the Mediterranean region, sub-Saharan Africa, the Middle East, and the northern part of South America. Nearly a dozen studies on the topic were reported here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting, many of which show a virologic response rate of around 50% with interferon. Response to treatment depends on genotype and baseline viral load.
Sarah Hughes, MD, from the Institute of Liver Studies, King's College Hospital, London, United Kingdom, reported some of the better sustained viral response rates (SVR) with pegylated-interferon alfa-2a — 54% for patients with HDV and hepatitis B virus (HBV) coinfection.
Infection with HDV is often simultaneous with HBV infection, or happens subsequently through superinfection, Dr. Hughes told Medscape Medical News. HDV "hijacks the surface-antigen coat from [HBV], which is the only thing it requires from [HBV]. Without that, the delta capsule cannot be assembled and released. So it absolutely has to have the contemporary presence of [HBV] in order to propagate," she explained. HDV causes rapid liver decompensation with cirrhosis and an increase in mortality, she added.
Dr. Hughes said there were 4 published studies on treating HDV with pegylated-interferon alfa-2a prior to her team's investigation, "but they were all very small. I think the largest had 90 patients. The highest [SVR] rate was 43%, but the average was about 25%."
In her retrospective study (n = 17), 64% of the participants cleared HDV RNA by end of treatment with pegylated-interferon alfa-2a. After 24 weeks of follow-up, 54% achieved SVR.
Baseline HDV RNA level was a significant predictor of response to therapy in the study by Dr. Hughes and colleagues. Those who achieved a SVR had a baseline HDV RNA level of 1.3 × 104 copies/mL; nonresponders had a baseline HDV RNA level of 2.1 × 106 copies/mL (P = .003). HDV RNA levels higher than 1.96 × 105 copies/mL predicted treatment failure (P = .001; 100% positive predictive value and 100% sensitivity).
"All of our patients were treatment-naive, which may in part explain why our response rate was higher," she said.
Unlike the other studies in which patients predominately were HDV genotype 1 or unreported, "we have a spread of genotypes. What we found is that 100% of those who are genotypes 5/6 responded to interferon. That was despite the fact that 2 patients had truncated courses of treatment."
Viral load is associated with the ability to clear HDV on therapy, and the viral loads of genotypes 5/6 are much lower than those of genotype 1, which might in part explain their higher rate of viral clearance.
"Every genotype of [HDV] has a very specific geographic distribution. In London, where there is a very diverse immigrant population, . . . it is worth genotyping. If you live in Germany or Eastern Europe, then all of the patients will be genotype 1," she said.
"[Alanine aminotransferase levels] at baseline didn't make a difference in response, and the presence or absence of cirrhosis didn't seem to make any difference either," Dr. Hughes noted.
Dr. Hughes believes that the most likely use of this new information will be in attempting to see whether shorter courses of therapy — 24 rather than 48 weeks — are possible with the more easily cleared genotypes.
"If you don't look for [HDV], you are not going to find it. We routinely test all of our HBV antigen-positive patients for seroreactivity to [HDV]; we routinely do [HDV immunoglobulin G] on all of our patients." The patients often are coinfected with [hepatitis C virus] because of transmission through shared injection drug equipment, she said.
The HDV actually suppresses HBV replication to very low levels: "9 in 10 patients have no detectible [HBV] replication at all. I'm not saying you can ignore the B, but you have to treat the [HDV]. There are a subset of patients who are e-antigen positive, which is quite unusual, who do have slightly higher levels of HBV replication. In those patients, it probably is reasonable to treat B alongside D. It is absolutely not evidence-based, but theoretical," the British investigator said.
Sometimes with successful treatment of HDV, you "unmask some HBV replication, and at that stage, you probably treat those patients as if they were B-monoinfected," she added.
Support for the analysis came from the UK National Health Service and academic sources. Dr. Hughes has disclosed no relevant financial relationships.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract 455. Presented October 30, 2010.
Source
November 10, 2010 (Boston, Massachusetts) — An estimated 20 million people worldwide are infected with hepatitis D virus (HDV), primarily in the Mediterranean region, sub-Saharan Africa, the Middle East, and the northern part of South America. Nearly a dozen studies on the topic were reported here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting, many of which show a virologic response rate of around 50% with interferon. Response to treatment depends on genotype and baseline viral load.
Sarah Hughes, MD, from the Institute of Liver Studies, King's College Hospital, London, United Kingdom, reported some of the better sustained viral response rates (SVR) with pegylated-interferon alfa-2a — 54% for patients with HDV and hepatitis B virus (HBV) coinfection.
Infection with HDV is often simultaneous with HBV infection, or happens subsequently through superinfection, Dr. Hughes told Medscape Medical News. HDV "hijacks the surface-antigen coat from [HBV], which is the only thing it requires from [HBV]. Without that, the delta capsule cannot be assembled and released. So it absolutely has to have the contemporary presence of [HBV] in order to propagate," she explained. HDV causes rapid liver decompensation with cirrhosis and an increase in mortality, she added.
Dr. Hughes said there were 4 published studies on treating HDV with pegylated-interferon alfa-2a prior to her team's investigation, "but they were all very small. I think the largest had 90 patients. The highest [SVR] rate was 43%, but the average was about 25%."
In her retrospective study (n = 17), 64% of the participants cleared HDV RNA by end of treatment with pegylated-interferon alfa-2a. After 24 weeks of follow-up, 54% achieved SVR.
Baseline HDV RNA level was a significant predictor of response to therapy in the study by Dr. Hughes and colleagues. Those who achieved a SVR had a baseline HDV RNA level of 1.3 × 104 copies/mL; nonresponders had a baseline HDV RNA level of 2.1 × 106 copies/mL (P = .003). HDV RNA levels higher than 1.96 × 105 copies/mL predicted treatment failure (P = .001; 100% positive predictive value and 100% sensitivity).
"All of our patients were treatment-naive, which may in part explain why our response rate was higher," she said.
Unlike the other studies in which patients predominately were HDV genotype 1 or unreported, "we have a spread of genotypes. What we found is that 100% of those who are genotypes 5/6 responded to interferon. That was despite the fact that 2 patients had truncated courses of treatment."
Viral load is associated with the ability to clear HDV on therapy, and the viral loads of genotypes 5/6 are much lower than those of genotype 1, which might in part explain their higher rate of viral clearance.
"Every genotype of [HDV] has a very specific geographic distribution. In London, where there is a very diverse immigrant population, . . . it is worth genotyping. If you live in Germany or Eastern Europe, then all of the patients will be genotype 1," she said.
"[Alanine aminotransferase levels] at baseline didn't make a difference in response, and the presence or absence of cirrhosis didn't seem to make any difference either," Dr. Hughes noted.
Dr. Hughes believes that the most likely use of this new information will be in attempting to see whether shorter courses of therapy — 24 rather than 48 weeks — are possible with the more easily cleared genotypes.
"If you don't look for [HDV], you are not going to find it. We routinely test all of our HBV antigen-positive patients for seroreactivity to [HDV]; we routinely do [HDV immunoglobulin G] on all of our patients." The patients often are coinfected with [hepatitis C virus] because of transmission through shared injection drug equipment, she said.
The HDV actually suppresses HBV replication to very low levels: "9 in 10 patients have no detectible [HBV] replication at all. I'm not saying you can ignore the B, but you have to treat the [HDV]. There are a subset of patients who are e-antigen positive, which is quite unusual, who do have slightly higher levels of HBV replication. In those patients, it probably is reasonable to treat B alongside D. It is absolutely not evidence-based, but theoretical," the British investigator said.
Sometimes with successful treatment of HDV, you "unmask some HBV replication, and at that stage, you probably treat those patients as if they were B-monoinfected," she added.
Support for the analysis came from the UK National Health Service and academic sources. Dr. Hughes has disclosed no relevant financial relationships.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract 455. Presented October 30, 2010.
Source
Antiviral “Cocktail” Better than Single Drug for Children with Hepatitis C
Released: 11/10/2010 9:00 AM EST
Source: Johns Hopkins Medicine
Combo therapy better than single drug at wiping out the virus
Newswise — Children with hepatitis C fare decidedly better with a supercharged combination of two antiviral drugs than with the usual and standard single-drug regimen, according to research led by investigators at the Johns Hopkins Children Center.
“Our findings indicate that when it comes to getting rid of the hepatitis C virus, the combination therapy seriously outperforms the single-drug therapy and its effects appear to endure well after stopping the treatment,” says lead investigator Kathleen Schwarz, M.D., a gastroenterologist and director of the Pediatric Liver Center at Hopkins Children’s.
The results of the study, published online in the journal Gastroenterology, indicate that the combination is more than twice as effective in eliminating the liver-ravaging viral infection as the single-drug approach. Unlike its more stubborn cousin hepatitis B, the hepatitis C virus can be eradicated from the body with antiviral medications, stopping its harmful activity, a key factor in preventing liver damage.
The research, which involved 112 children, ages 5 to 17 years, treated at 11 U.S. hospitals, is believed to be the first large-scale, head-to-head comparison of the dual vs. single-drug approach in pediatric patients. The findings are particularly important, the scientists say, because treatment protocols in children with hepatitis C have not been studied well.
Of the 112 children, 57 received standard medication — weekly injections with long-acting pegylated interferon, or PEG interferon — plus a placebo, while 55 got a combination of PEG interferon injections and daily pills containing the antiviral drug ribavirin (RV). After the year-long treatment, patients treated with the PEG-ribavirin cocktail cleared the infection at a rate two and a half times greater than children receiving PEG interferon injections alone (53 vs. 21 percent). Viral clearance occurs when a child’s blood is free of viral traces at the end of the treatment, and sustained viral clearance, or full eradication, occurs when the blood remains clear for at least six months after stopping treatment. Full viral eradication is the hallmark of effective therapy and was where the greatest differences between the two approaches emerged. Children on the combination therapy were less likely to relapse after stopping treatment — 17 percent of them did — than children on the single-drug regimen (45 percent). In all, 41 of the 112 patients achieved complete viral eradication, and all of them continued to do well without medication at the one- and two-year check-ups. The researchers will continue to monitor these children for five years after stopping therapy.
Twenty-eight of the children receiving the PEG-placebo combination who didn’t respond to treatment after six months were offered treatment with the PEG-ribavirin combination. Nearly half of them (13) responded well and had undetectable viral loads at the end of a six-month treatment, and 11 of the 13 remained clear of infection six months after stopping the treatment. Children who responded well to standard PEG therapy continued on the same treatment.
The investigators note that because past research has shown ribavirin’s harmful effects on the fetus, it should be avoided or used cautiously during pregnancy.
The blood-borne hepatitis C virus is a leading cause of liver cancer, second only to hepatitis B, and a top reason for liver transplantation. An estimated 132,000 U.S. children are infected with the hepatitis C virus, and nearly 42,300 of them have a chronic infection, the researchers say.
Other Johns Hopkins investigators on the study: Alexandra Valsamakis, M.D.
Other institutions involved in the research include the University of Florida College of Medicine; Seattle Children’s Hospital; Indiana University School of Medicine; Children’s Hospital of Philadelphia; Children’s Hospital Boston; University of California San Francisco; Children’s National Medical Center, Washington, D.C., Cincinnati Children’s Hospital; University of Colorado; and Columbia University Medical Center.
The study was funded by the National Institutes of Health and the Food and Drug Administration. Manufacturer Hoffman-La Roche supplied the medications for the study and funded the lab costs and the data coordination for the study.
Conflict-of-interest disclosure: Schwarz receives research support from Roche, Bristol Myers, Squibb, Gilead and consulting fees from Novartis. Valsamakis receives research support from Roche. The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.
Related:
Johns Hopkins Children’s Center
http://www.hopkinschildrens.org/
Pediatric Liver Center
http://www.hopkinschildrens.org/pediatric-liver/
Kathleen Schwarz Profile
http://www.hopkinschildrens.org/Kathleen-Schwarz-MD.aspx
Gastroenterology journal
http://www.gastrojournal.org/
Managing Childhood Liver Disease
http://www.hopkinschildrens.org/managing-childhood-liver-disease.aspx
New Recommendations Issued for Children with Chronic Hepatitis B Infections
http://www.hopkinschildrens.org/New-Recommendations-Issued-for-Children-with-Chronic-Hepatitis-B.aspx
Source
Source: Johns Hopkins Medicine
Combo therapy better than single drug at wiping out the virus
Newswise — Children with hepatitis C fare decidedly better with a supercharged combination of two antiviral drugs than with the usual and standard single-drug regimen, according to research led by investigators at the Johns Hopkins Children Center.
“Our findings indicate that when it comes to getting rid of the hepatitis C virus, the combination therapy seriously outperforms the single-drug therapy and its effects appear to endure well after stopping the treatment,” says lead investigator Kathleen Schwarz, M.D., a gastroenterologist and director of the Pediatric Liver Center at Hopkins Children’s.
The results of the study, published online in the journal Gastroenterology, indicate that the combination is more than twice as effective in eliminating the liver-ravaging viral infection as the single-drug approach. Unlike its more stubborn cousin hepatitis B, the hepatitis C virus can be eradicated from the body with antiviral medications, stopping its harmful activity, a key factor in preventing liver damage.
The research, which involved 112 children, ages 5 to 17 years, treated at 11 U.S. hospitals, is believed to be the first large-scale, head-to-head comparison of the dual vs. single-drug approach in pediatric patients. The findings are particularly important, the scientists say, because treatment protocols in children with hepatitis C have not been studied well.
Of the 112 children, 57 received standard medication — weekly injections with long-acting pegylated interferon, or PEG interferon — plus a placebo, while 55 got a combination of PEG interferon injections and daily pills containing the antiviral drug ribavirin (RV). After the year-long treatment, patients treated with the PEG-ribavirin cocktail cleared the infection at a rate two and a half times greater than children receiving PEG interferon injections alone (53 vs. 21 percent). Viral clearance occurs when a child’s blood is free of viral traces at the end of the treatment, and sustained viral clearance, or full eradication, occurs when the blood remains clear for at least six months after stopping treatment. Full viral eradication is the hallmark of effective therapy and was where the greatest differences between the two approaches emerged. Children on the combination therapy were less likely to relapse after stopping treatment — 17 percent of them did — than children on the single-drug regimen (45 percent). In all, 41 of the 112 patients achieved complete viral eradication, and all of them continued to do well without medication at the one- and two-year check-ups. The researchers will continue to monitor these children for five years after stopping therapy.
Twenty-eight of the children receiving the PEG-placebo combination who didn’t respond to treatment after six months were offered treatment with the PEG-ribavirin combination. Nearly half of them (13) responded well and had undetectable viral loads at the end of a six-month treatment, and 11 of the 13 remained clear of infection six months after stopping the treatment. Children who responded well to standard PEG therapy continued on the same treatment.
The investigators note that because past research has shown ribavirin’s harmful effects on the fetus, it should be avoided or used cautiously during pregnancy.
The blood-borne hepatitis C virus is a leading cause of liver cancer, second only to hepatitis B, and a top reason for liver transplantation. An estimated 132,000 U.S. children are infected with the hepatitis C virus, and nearly 42,300 of them have a chronic infection, the researchers say.
Other Johns Hopkins investigators on the study: Alexandra Valsamakis, M.D.
Other institutions involved in the research include the University of Florida College of Medicine; Seattle Children’s Hospital; Indiana University School of Medicine; Children’s Hospital of Philadelphia; Children’s Hospital Boston; University of California San Francisco; Children’s National Medical Center, Washington, D.C., Cincinnati Children’s Hospital; University of Colorado; and Columbia University Medical Center.
The study was funded by the National Institutes of Health and the Food and Drug Administration. Manufacturer Hoffman-La Roche supplied the medications for the study and funded the lab costs and the data coordination for the study.
Conflict-of-interest disclosure: Schwarz receives research support from Roche, Bristol Myers, Squibb, Gilead and consulting fees from Novartis. Valsamakis receives research support from Roche. The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.
Related:
Johns Hopkins Children’s Center
http://www.hopkinschildrens.org/
Pediatric Liver Center
http://www.hopkinschildrens.org/pediatric-liver/
Kathleen Schwarz Profile
http://www.hopkinschildrens.org/Kathleen-Schwarz-MD.aspx
Gastroenterology journal
http://www.gastrojournal.org/
Managing Childhood Liver Disease
http://www.hopkinschildrens.org/managing-childhood-liver-disease.aspx
New Recommendations Issued for Children with Chronic Hepatitis B Infections
http://www.hopkinschildrens.org/New-Recommendations-Issued-for-Children-with-Chronic-Hepatitis-B.aspx
Source
Hepatitis C Substantially Impacts U.S. Work Productivity
Nov 10, 2010 09:15 ET
Kantar Health Research Wins Presidential Poster of Distinction Award at 2010 AASLD Meeting
NEW YORK, NY--(Marketwire - November 10, 2010) - Hepatitis C (HCV) places a burden on U.S. employers because of increased work productivity loss for those with the virus, according to the National Health and Wellness Survey, conducted by Kantar Health and presented recently in a poster at the 2010 American Association for the Study of Liver Diseases (AASLD) annual meeting. The study also suggests that HCV places a substantial burden on the U.S. healthcare system because of an increased number of emergency room and physician visits.
"HCV affects 2.7 million people in the United States, making it the most common blood-borne viral disease," says Marco DiBonaventura, Ph.D., Kantar Health's Director of Health Economics and Outcomes Research. "Although HCV can have dire long-term effects, such as increasing the risk of cirrhosis and hepatocellular cancer, the results of this study suggest that the virus can place a burden on patients even in earlier stages of infection."
For the study, HCV patients were compared with matched controls that were selected specifically because they were identical to patients in all respects except for the presence of HCV. When compared with these matched controls, HCV patients reported significantly higher work absenteeism, overall work impairment, impairment in daily activities, and worse physical quality of life. In addition, HCV patients reported significantly more physician visits and emergency room visits in the past six months compared to matched controls, highlighting the burden HCV can place on the healthcare system.
The poster, "The Impact of Hepatitis C on Health-Related Quality of Life, Work Productivity, and Healthcare Utilization," was selected as a Presidential Poster of Distinction at the 2010 AASLD meeting. It was developed in conjunction with a major pharmaceutical company and co-written by Dr. DiBonaventura.
About the National Health and Wellness Survey (NHWS)
The study's results were drawn from the 2009 U.S. National Health and Wellness Survey (NHWS), a nationally representative, self-administered survey conducted annually via the Internet and in-person surveys. Topics covered include the health status, attitudes, behaviors and outcomes among adults 18 or older.
Kantar Health conducts NHWS annually in the U.S., Europe and Asia. The survey is the largest self-reported database in the healthcare industry.
About Kantar Health (http://www.kantarhealth.com/)
Kantar Health is a leading healthcare-focused global consultancy, specializing in portfolio optimization, market access, safety and outcomes, and brand and customer insights. Formed by uniting Consumer Health Sciences, MattsonJack, TNS Healthcare and Ziment, it is the next-generation decision support partner to the pharmaceutical and biotech industries, delivering evidence-based guidance to support clients' global and local success.
With 40+ offices throughout the Americas, Europe, Asia-Pacific, the Middle East and Africa, Kantar Health provides the broadest global footprint, coupled with the strongest local knowledge to help drive clients' maximum performance in every geography. Market-leading solutions ensure optimal decisions and actions across the brand life cycle, from assessing opportunities and sizing markets... to developing products and building access strategies... to positioning brands and creating messaging... to managing stakeholder relationships and monitoring treatment outcomes.
Contact Information
For more information on Kantar Health, please contact
Paula Paradise
Vice President of Global Marketing
Email Contact
+1-484-442-1431
Source
Kantar Health Research Wins Presidential Poster of Distinction Award at 2010 AASLD Meeting
NEW YORK, NY--(Marketwire - November 10, 2010) - Hepatitis C (HCV) places a burden on U.S. employers because of increased work productivity loss for those with the virus, according to the National Health and Wellness Survey, conducted by Kantar Health and presented recently in a poster at the 2010 American Association for the Study of Liver Diseases (AASLD) annual meeting. The study also suggests that HCV places a substantial burden on the U.S. healthcare system because of an increased number of emergency room and physician visits.
"HCV affects 2.7 million people in the United States, making it the most common blood-borne viral disease," says Marco DiBonaventura, Ph.D., Kantar Health's Director of Health Economics and Outcomes Research. "Although HCV can have dire long-term effects, such as increasing the risk of cirrhosis and hepatocellular cancer, the results of this study suggest that the virus can place a burden on patients even in earlier stages of infection."
For the study, HCV patients were compared with matched controls that were selected specifically because they were identical to patients in all respects except for the presence of HCV. When compared with these matched controls, HCV patients reported significantly higher work absenteeism, overall work impairment, impairment in daily activities, and worse physical quality of life. In addition, HCV patients reported significantly more physician visits and emergency room visits in the past six months compared to matched controls, highlighting the burden HCV can place on the healthcare system.
The poster, "The Impact of Hepatitis C on Health-Related Quality of Life, Work Productivity, and Healthcare Utilization," was selected as a Presidential Poster of Distinction at the 2010 AASLD meeting. It was developed in conjunction with a major pharmaceutical company and co-written by Dr. DiBonaventura.
About the National Health and Wellness Survey (NHWS)
The study's results were drawn from the 2009 U.S. National Health and Wellness Survey (NHWS), a nationally representative, self-administered survey conducted annually via the Internet and in-person surveys. Topics covered include the health status, attitudes, behaviors and outcomes among adults 18 or older.
Kantar Health conducts NHWS annually in the U.S., Europe and Asia. The survey is the largest self-reported database in the healthcare industry.
About Kantar Health (http://www.kantarhealth.com/)
Kantar Health is a leading healthcare-focused global consultancy, specializing in portfolio optimization, market access, safety and outcomes, and brand and customer insights. Formed by uniting Consumer Health Sciences, MattsonJack, TNS Healthcare and Ziment, it is the next-generation decision support partner to the pharmaceutical and biotech industries, delivering evidence-based guidance to support clients' global and local success.
With 40+ offices throughout the Americas, Europe, Asia-Pacific, the Middle East and Africa, Kantar Health provides the broadest global footprint, coupled with the strongest local knowledge to help drive clients' maximum performance in every geography. Market-leading solutions ensure optimal decisions and actions across the brand life cycle, from assessing opportunities and sizing markets... to developing products and building access strategies... to positioning brands and creating messaging... to managing stakeholder relationships and monitoring treatment outcomes.
Contact Information
For more information on Kantar Health, please contact
Paula Paradise
Vice President of Global Marketing
Email Contact
+1-484-442-1431
Source
Predictors of early treatment discontinuation among patients with genotype 1 hepatitis C and implications for viral eradication
Clin Gastroenterol Hepatol. 2010 Nov;8(11):972-8. Epub 2010 Aug 6.
Beste LA, Ioannou GN, Larson MS, Chapko M, Dominitz JA.
Health Services Research and Development Center of Excellence, VA Puget Sound Healthcare System, Seattle, Washington, USA. Lauren.beste@va.gov
Abstract
BACKGROUND & AIMS: A significant proportion of patients with hepatitis C virus (HCV) infection discontinue antiviral treatment prematurely. Risk factors for discontinuation before 48 weeks among patients with genotype 1 HCV vary over the course of therapy. We investigated the rates and risk factors for treatment discontinuation within 12 weeks, 12-24 weeks, and 24-48 weeks.
METHODS: We retrospectively evaluated data from all Veterans Affairs (VA) patients with genotype 1 HCV who initiated pegylated interferon and ribavirin therapy from 2002-2007 (n = 11,019). We accounted for appropriate discontinuation because of viral nonresponse.
RESULTS: Overall, 53% of patients completed at least 38.4 weeks of therapy (80% of the projected 48 weeks), 16.5% discontinued early in the setting of viral nonresponse, and 30.9% discontinued despite viral response or in the absence of virologic data. Cirrhosis, diabetes, pretreatment substance use disorder, hemoglobin, and lack of hematopoietic growth factor use independently predicted discontinuation before 12 weeks (P < .05 for all). Among patients with documented early virologic responses, higher baseline levels of creatinine, depression, and lack of growth factor use predicted discontinuation from 12-24 weeks. No factors independently predicted discontinuation from 24-48 weeks among patients responding to treatment at 24 weeks.
CONCLUSIONS: Early discontinuation of antiviral therapy is common. Use of growth factors was the strongest independent predictor of treatment retention before 24 weeks and should be evaluated prospectively. Early interventions may also be warranted for other risk factors for early discontinuation, such as pre-existing substance use, depression, cirrhosis, or diabetes.
Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
Source
Beste LA, Ioannou GN, Larson MS, Chapko M, Dominitz JA.
Health Services Research and Development Center of Excellence, VA Puget Sound Healthcare System, Seattle, Washington, USA. Lauren.beste@va.gov
Abstract
BACKGROUND & AIMS: A significant proportion of patients with hepatitis C virus (HCV) infection discontinue antiviral treatment prematurely. Risk factors for discontinuation before 48 weeks among patients with genotype 1 HCV vary over the course of therapy. We investigated the rates and risk factors for treatment discontinuation within 12 weeks, 12-24 weeks, and 24-48 weeks.
METHODS: We retrospectively evaluated data from all Veterans Affairs (VA) patients with genotype 1 HCV who initiated pegylated interferon and ribavirin therapy from 2002-2007 (n = 11,019). We accounted for appropriate discontinuation because of viral nonresponse.
RESULTS: Overall, 53% of patients completed at least 38.4 weeks of therapy (80% of the projected 48 weeks), 16.5% discontinued early in the setting of viral nonresponse, and 30.9% discontinued despite viral response or in the absence of virologic data. Cirrhosis, diabetes, pretreatment substance use disorder, hemoglobin, and lack of hematopoietic growth factor use independently predicted discontinuation before 12 weeks (P < .05 for all). Among patients with documented early virologic responses, higher baseline levels of creatinine, depression, and lack of growth factor use predicted discontinuation from 12-24 weeks. No factors independently predicted discontinuation from 24-48 weeks among patients responding to treatment at 24 weeks.
CONCLUSIONS: Early discontinuation of antiviral therapy is common. Use of growth factors was the strongest independent predictor of treatment retention before 24 weeks and should be evaluated prospectively. Early interventions may also be warranted for other risk factors for early discontinuation, such as pre-existing substance use, depression, cirrhosis, or diabetes.
Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
Source
Transient elastography: A non-invasive tool for assessing liver fibrosis in HIV/HCV patients
ISSN 1007-9327 CN 14-1219/R
World J Gastroenterol 2010 November 7; 16(41): 5225-5232
BRIEF ARTICLE
Valentina Li Vecchi, Maurizio Soresi, Claudia Colomba, Giovanni Mazzola, Pietro Colletti, Maurizio Mineo, Paola Di Carlo, Emanuele La Spada, Giovanni Vizzini, Giuseppe Montalto
Valentina Li Vecchi, Maurizio Soresi, Giovanni Mazzola, Pietro Colletti, Maurizio Mineo, Emanuele La Spada, Giuseppe Montalto, Department of Clinical Medicine and Emerging Pathologies, University of Palermo, Via del Vespro 141, 90127 Palermo, Italy
Claudia Colomba, Paola Di Carlo, Infectious Diseases Section, Department of Health Promotion Sciences, University of Palermo, Via del Vespro 129, 90127 Palermo, Italy
Giovanni Vizzini, Department of Gastroenterology and Hepatology, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IsMeTT), University of Pittsburgh Medical Center, Via Tricomi 1, 90127 Palermo, Italy
Author contributions: Montalto G, Li Vecchi V and Mazzola G designed the research; Li Vecchi V, Mazzola G, La Spada E, Colletti P, Mineo M, Colomba C and Di Carlo P performed the research; Soresi M analyzed the data; Li Vecchi V and Montalto G wrote the paper; Montalto G, Soresi M and Vizzini G reviewed the paper.
Correspondence to: Giuseppe Montalto, Professor, Department of Clinical Medicine and Emerging Pathologies, University of Palermo, Via del Vespro 141, 90127 Palermo, Italy. gmontal@unipa.it
Telephone: +39-91-6552991 Fax: +39-91-6552977
Received: April 14, 2010 Revised: June 1, 2010
Accepted: June 8, 2010
Published online: November 7, 2010
Abstract
AIM: To assess the prevalence of advanced liver fibrosis (ALF) in human immunodeficiency virus (HIV), hepatitis C virus (HCV) and HIV/HCV patients using transient elastography, and to identify factors associated with ALF.
METHODS: Between September 2008 and October 2009, 71 HIV mono-infected, 57 HIV/HCV co-infected and 53 HCV mono-infected patients on regular follow-up at our Center were enrolled in this study. Alcohol intake, the main parameters of liver function, presence of HCV-RNA, HIV-RNA, duration of highly active anti-retroviral therapy (HAART) and CD4 cell count were recorded. ALF was defined as liver stiffness (LS) ≥ 9.5 kPa. To estimate liver fibrosis (LF) a further 2 reliable biochemical scores, aspartate aminotransferase platelet ratio index (APRI) and FIB-4, were also used.
RESULTS: LS values of co-infected patients were higher than in either HIV or HCV mono-infected patients (c2MH = 4, P < 0.04). In fact, LS ≥ 9.5 was significantly higher in co-infected than in HIV and HCV mono-infected patients (c2 = 5, P < 0.03). Also APRI and the FIB-4 index showed more LF in co-infected than in HIV mono-infected patients (P < 0.0001), but not in HCV mono-infected patients. In HIV⁄HCV co-infected patients, the extent of LS was significantly associated with alcohol intake (P < 0.04) and lower CD4+ cell count (P < 0.02). In HCV patients, LS was correlated with alcohol intake (P < 0.001) and cholesterol levels (P < 0.03). Body mass index, diabetes, HCV- and HIV-viremia were not significantly correlated with LS. In addition, 20% of co-infected patients had virologically unsuccessful HAART; in 50% compliance was low, CD4+ levels were < 400 cells/mm3 and LS was > 9.5 kPa. There was no significant correlation between extent of LF and HAART exposure or duration of HAART exposure, in particular with specific dideoxynucleoside analogues.
CONCLUSION: ALF was more frequent in co-infected than mono-infected patients. This result correlated with lower CD4 levels. Protective immunological effects of HAART on LF progression outweigh its hepatotoxic effects.
© 2010 Baishideng. All rights reserved.
Key words: Liver fibrosis; Transient elastography; Aspartate aminotransferase platelet ratio index; FIB-4 test; Fibrosis evaluation; Human immunodeficiency virus infection; Hepatitis C virus infection
Peer reviewer: Dr. Chao-Hung Hung, MD, Associate Professor, Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Niao Sung, Kaohsiung 833, Taiwan, China
Li Vecchi V, Soresi M, Colomba C, Mazzola G, Colletti P, Mineo M, Di Carlo P, La Spada E, Vizzini G, Montalto G. Transient elastography: A non-invasive tool for assessing liver fibrosis in HIV/HCV patients. World J Gastroenterol 2010; 16(41): 5225-5232 Available from: URL: http://www.wjgnet.com/1007-9327/full/v16/i41/5225.htm DOI: http://dx.doi.org/10.3748/wjg.v16.i41.5225
INTRODUCTION
In the last few years, liver disease associated with hepatitis C virus (HCV) has emerged as a significant problem in human immunodeficiency virus (HIV)-infected patients, thanks to improved survival in the highly active anti-retroviral therapy (HAART) era[1]. It has been reported that HIV and HCV co-infection leads to a more rapid progression of liver disease to cirrhosis[2,3]. Other factors such as severe immune suppression and alcohol consumption accelerate the progression of HCV-related fibrosis[4,5]. Virologically successful HAART slows the progression of liver fibrosis (LF) and reduces hepatic necroinflammatory activity in HIV/HCV co-infected patients[2,6]. In contrast, antiretroviral-related liver toxicity could contribute to liver damage in HIV- and HIV/HCV-infected patients[7]. Mitochondrial toxicity of nucleoside analogues[8], and glucose or lipid abnormalities, such as hyperglycemia and lipodystrophy, which are particularly common when using some protease inhibitors[9], may produce or enhance LF progression in HIV mono- and HIV/HCV co-infected patients. Currently, in this respect, a growing number of cases of cryptogenetic liver disease in symptomatic and asymptomatic HIV-infected patients has been reported[10,11].
Percutaneous liver biopsy is the gold standard for assessing LF. However, it may be associated with sampling variability[12], is an invasive technique with rates of morbidity of 3% and mortality of 0.03%[13,14], and as a consequence, is not suitable for repeated assessment, which is required when monitoring LF.
For these reasons, new non-invasive methods for the assessment of LF have been developed. Transient elastography (TE) (Fibro-Scan®; EchoSens, Paris, France) is a rapid, reliable and tolerable imaging technique for the assessment of LF by measuring liver stiffness (LS)[15,16].
On the other hand, many biochemical markers have been implemented to estimate LF, with the aim of reducing the number of liver biopsies[14].
The advent of TE and biochemical markers has been demonstrated to be very helpful in the non-invasive measurement of LF, particularly in asymptomatic HIV-infected patients in whom liver biopsy is not recommended[11]. TE has already been validated for the measurement of LF in HIV and HCV seropositive patients[17,18].
The aim of this study was to assess the prevalence of LF and cirrhosis in a group of HIV mono-infected, HCV mono-infected and HIV/HCV co-infected patients using TE and biochemical markers. In addition, we evaluated which of the factors studied correlated with advanced LF (ALF) and cirrhosis.
MATERIALS AND METHODS
Study population
Between September 2008 and October 2009 all consecutive HIV mono-infected and HIV/HCV co-infected patients on regular follow-up at the AIDS Center of the University of Palermo, as well as HCV mono-infected patients seen consecutively at the Outpatient Clinic of the Department of Clinical Medicine and Emerging Pathologies of the University of Palermo were enrolled in this study.
Information on age, gender, risk factors for HCV and HIV infections, cumulative exposure to non-nucleoside and nucleoside reverse-transcriptase inhibitors, protease inhibitors and specific antiretroviral drugs within each class were all recorded in a database designed for this study.
For all HIV-infected patients the absolute number of CD4+ T-cells and plasma HIV-RNA levels was assessed. In HCV-infected patients, HCV-genotype and plasma HCV-RNA levels were also recorded. In addition, at baseline, complete blood cell counts, alanine aminotransferase (ALT), aspartate aminotransferase (AST), g-glutamyl transferase (gGT), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides and glycemia were measured.
Alcohol intake > 20 g/d either at the time of the study or in the past was recorded through patient interviews. Diabetes or impaired fasting glucose (IFG) were defined according to the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus criteria[19].
Patients with acute liver decompensation, hepatocellular carcinoma or chronic hepatitis B were excluded.
The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Patients were enrolled after written informed consent was obtained.
Assessment of LF
LF was assessed by a single certified operator (trained by the manufacturer) using TE (FibroScan®; EchoSens, Paris, France). TE provides an assessment of LS expressed in kPa units. In brief, an ultrasound transducer probe is mounted on the axis of a vibrator. Vibrations of mild amplitude and low frequency are transmitted by the transducer, inducing an elastic shear wave that propagates through the underlying tissues. The speed of propagation of this vibration across the liver is directly related to tissue stiffness.
The tip of the probe transducer was placed in the intercostal spaces at the right lobe of the liver. Only patients with 10 valid elastometric measures, interquartile ranges > 30% and ≥ 60% success rate (the number of validated measurements divided by the total number of measurements) were considered to be reliable. ALF (severe fibrosis and cirrhosis) was defined as a median LS of 9.5 kPa. As previously published, this cut-off value is strongly correlated with a Metavir score of F3, both in HCV mono-infected and HCV⁄HIV co-infected patients[17,18].
LF was also assessed biologically using 2 different well-validated indices, the aspartate aminotransferase platelet ratio index (APRI) index and the FIB-4 index. The APRI was calculated as follows: AST⁄upper limit of normal × 100⁄platelet count (109⁄L)[20,21]. The FIB-4 index was calculated as follows: age × AST (IU⁄L)⁄{[platelet count (109⁄L)] × [ALT (IU⁄L)]1⁄2}[22]. The prevalence of ALF was estimated using as a reference a FIB-4 index > 3.25 and an APRI index > 1.5[20,22].
Statistical analysis
When data distribution was Gaussian, values were expressed as mean ± SD and their differences were calculated using the Student t-test; otherwise, data were expressed as the median and range and analyzed using the Mann-Whitney U test. Fisher’s exact and c2 tests, the c2 test of Mantel Haenszel, Spearman’s rank correlations (r) and Pearson’s correlation (r) were used where appropriate. Multiple linear regression analysis was used to study the association between increased values of LS and variables statistically significant at univariate analysis. All analyses were performed using the SPSS software package (version 13.0; Chicago, IL, USA).
RESULTS
Study population
A total of 201 patients on regular follow-up at both our Centers were enrolled in the study.
In 11 patients (4 HIV mono-infected, 6 HCV mono-infected and one co-infected) a valid elastometric assessment could not be obtained because of truncular obesity, therefore 190 patients were finally included in this study. There were 137 HIV-infected patients, including 71 HIV mono-infected and 66 HIV/HCV co-infected, and 53 HCV mono-infected patients. Patient characteristics at the time of LS measurement are summarized in Table 1.
HIV patients were significantly younger than HCV mono-infected individuals (P < 0.002). Body mass index (BMI) was significantly higher in HCV mono-infected patients than in HIV and HIV/HCV co-infected patients (P < 0.002). The most frequent risk factor of HCV contamination was intravenous drug use in co-infected vs mono-infected HCV patients (P < 0.0001), while it was transfusion of blood products in HCV mono-infected vs co-infected patients (P < 0.0001). Most HIV mono-infected (80.2%) and HIV/HCV co-infected patients (90.9%) were under HAART. However, only 62% of HIV mono-infected and 68% of HIV/HCV co-infected patients had an HIV-RNA load of < 47 copies/mL. In addition, 20% of co-infected patients had virologically unsuccessful HAART; in 50% compliance was low, and CD4+ levels were < 400 cells/mm3. HIV⁄HCV co-infected patients were more often infected by HCV genotype 3 compared with HCV mono-infected patients (P < 0.03).
Table 2 shows the main hematological and virological parameters in the 3 study groups. Serum ALT levels were significantly higher in HCV mono-infected patients than in HIV/HCV co-infected and HIV mono-infected patients (P < 0.02). Serum AST, ALT and gGT levels were significantly higher in HIV/HCV co-infected than in HIV mono-infected patients (P < 0.0001). Only gGT levels were more elevated in HIV/HCV co-infected patients than in HCV mono-infected patients (P < 0.01). TG levels were significantly higher in HIV mono-infected and HIV/HCV co-infected patients than in HCV mono-infected patients (P < 0.004).
Extent of LF
In the overall population LS measured by TE ranged from 3.2 to 48.8 kPa. In 9 HIV/HCV co-infected patients, HCV-RNA was undetectable and for this reason these patients were excluded from the analysis, which was thus carried out only in the remaining 57 co-infected patients. However, their LS was lower than in the remaining co-infected group (data not shown).
Table 3 shows the distribution of LS values measured in all 3 study groups. Co-infected patients had higher LS values than mono-infected patients (c2MH = 4, P < 0.04). The HIV⁄HCV-co-infected population had LS ≥ 9.5 kPa (50.9%) more often than HCV and HIV mono-infected patients (28.3%) (c2 = 5, P < 0.03). In this respect 60% of co-infected patients under virologically unsuccessful HAART showed LS ≥ F3. The individual values of LS increased from HIV to HCV and to HIV/HCV infected patients (r = 0.5, P < 0. 0001) (Figure 1).
Overall, by multiple linear regression analysis, the variables significantly associated with ALF were AST values (b = 0.47, P < 0.0001) and HIV/HCV co-infection (b = 0.25, P < 0.002). To better understand which variables were associated with LS in patients with HIV mono- and co-infection, we also performed multiple linear regression analysis of these 2 groups and found that ALF correlated positively with AST serum levels (b = 0.34, P < 0.0001) and presence of HIV/HCV co-infection (b = 0.4, P < 0.0001) and negatively with lower CD4+ cell counts (b = -0.21, P < 0.003).
Median values of APRI and FIB-4 were significantly higher in HCV mono- and co-infected patients than in HIV mono-infected patients. There were no significant differences in APRI and FIB-4 medians in HCV mono- and HIV/HCV co-infected patients (Table 4). Median values of LS were significantly lower in HIV mono-infected than in HCV mono- and HIV/HCV co-infected patients (P < 0.0001). Median values of HIV/HCV co-infected patients were also significantly higher than in HCV mono-infected patients (P < 0.05).
Overall, correlations between LS and APRI values and LS and FIB-4 values were statistically significant (r = 0.60, P < 0.0001 and r = 0.64, P < 0.0001, respectively). However, when correlations were made according to the 3 cut-off values of LS, we found a significant correlation only for values of LS ≥ 9.5 (r = 0.50, P < 0.0001 vs APRI and r =0.53, P < 0.0001 vs FIB-4) (Table 5).
Correlation between LS and risk factors studied
Table 6 shows the factors associated with LS in the 3 groups. No correlation between the studied parameters and LS was found in the HIV mono-infected group. In HCV mono-infected patients, LS positively correlated with alcohol intake > 20 g/d (P < 0.001) and AST serum level (P < 0.0001), while it negatively correlated with the number of platelets (P < 0.0001) and serum cholesterol levels (P < 0.03). APRI and FIB-4 values were significantly associated with LS both in HCV and HIV/HCV co-infected patients (P < 0.0001).
In HIV⁄HCV-co-infected patients the extent of LS was significantly correlated with alcohol intake (P < 0.04) AST level (P < 0.0001) and lower CD4+ cells count (P < 0.02) and was negatively correlated with platelets (P < 0.0001).
BMI, presence of diabetes or IFG, HCV- and HIV-viremia were not significantly correlated with LS in any of the 3 study groups. In addition, there was no significant correlation between the extent of LF under HAART exposure and duration of HAART exposure. There was no significant correlation either between extent of LF and cumulative exposure to each class of antiretroviral drugs (non-nucleoside/nucleoside reverse-transcriptase inhibitors, protease inhibitors) and of specific dideoxynucleoside analogues (didanosine, stavudine, zidovudine).
DISCUSSION
Our results, in agreement with other studies, confirmed that LF is more severe in HIV/HCV co-infected patients than in HCV or HIV mono-infected patients[5,23,24]. In addition, ALF was significantly associated with a lower CD4+cell count in co-infected patients. There is convincing evidence that co-infection with HIV worsens the prognosis of HCV-related liver disease. It has been reported that in patients co-infected with HIV and HCV the risk of progressing to cirrhosis and liver failure is higher than in those infected with only HCV[25,26], especially in individuals with CD4 < 200 cells/mL and alcohol consumption[2].
In our study, 20% of HIV/HCV co-infected patients were under virologically unsuccessful HAART and in 50% CD4+ levels were below 400 cells/mm3 suggesting, in agreement with former findings, that the less successful the response to HAART, the less marked is its clinical benefit. In fact, immune recovery under HAART has been associated with longer overall survival, slower progression of HCV-related liver damage in HIV co-infected patients and with lengthier survival times before death attributable to liver disease[27]. In the same way, Pineda et al[27] demonstrated that liver decompensation emerged earlier in patients who maintained an undetectable HIV viral load for a shorter period during follow-up. Nevertheless, the association between ALF and lower CD4 cell count suggests that the response to HAART, measured using CD4 cell gain and HIV viral load decline, determines the evolution of liver disease and that virologically and immunologically successful HAART may slow progression of LF in HIV/HCV co-infected patients.
On the other hand, antiretroviral-related liver toxicity could have further contributed to liver damage in our HIV population[7]. Mitochondrial toxicity of nucleoside analogues and glucose or lipid abnormalities, particularly common when using some protease inhibitors, may produce or enhance LF progression in HIV-seropositive patients. The correlation between use of antiretroviral drugs and LF in patients with HIV/HCV co-infection has been evaluated in different studies but with contradictory results[21,28-30].
Macías et al[21] reported that HAART regimens, including nevirapine, were associated with an increased degree of LF, while the use of protease inhibitor-based HAART was associated with less severe fibrosis and a slower progression of fibrosis in HIV/HCV co-infected patients. In contrast, Berenguer et al[28] found that exposure to NNRTI was associated with a reduction in LF progression. In addition, Halfon et al[29] showed that exposure to NNRTI was an independent factor in LF while Blanco et al[30] highlighted that exposure to dideoxynucleosides was an independent factor associated with ALF.
In our study, no correlation was found between HAART exposure, duration of HAART exposure or cumulative exposure to any class of antiretroviral drugs and LF. In addition, we analyzed the correlation between duration of exposure to dideoxynucleosides (in particular didanosine, stavudine, zidovudine) and LF but also in this case no correlation was observed, suggesting that these drugs could not play any role in the progression of LF.
ALF was significantly higher in HIV/HCV co-infected patients than in HCV mono-infected patients when the subset of co-infected patients with undetectable HCV-RNA were excluded from the analysis. Overall, HIV/HCV co-infected patients with undetectable HCV-RNA had either no or only mild fibrosis (F0-F1) compared to the remaining co-infected patients, suggesting that the presence of HCV is important in conditioning the progression of LF and that anti-HCV therapy is mandatory in HIV/HCV co-infected patients in order to eradicate the virus. In fact, other authors have reported that achieving HCV clearance may reduce liver-related complications and mortality[31,32] and probably permits at least a partial regression of LF[33]. However, in HIV-positive patients liver cirrhosis may also occur without chronic viral hepatitis, and possible causes of hepatic steatosis in patients with HIV may be due to HIV itself, pathological alcohol use, diabetes mellitus, obesity or antiretroviral medications[34].
Evaluation of LF using the 2 biochemical scores (APRI and FIB-4) was not in full agreement with LS measurement. In fact, these 2 biochemical tests were in agreement with TE values only for high-grade LF, but not in low and moderate LF, suggesting that at least in these cases liver biopsy could be necessary to assess the precise degree of LF. In this respect, we are aware that the lack of liver biopsy, as a reference tool of LF, is a limitation of our study.
More consideration, perhaps, should be given to transaminase levels. In fact, the HCV mono-infected group had the highest levels of transaminases, which may have influenced LS values by increasing them. This result could further support our observation that co-infected patients are at highest risk of LF because of their high AST levels and the immune suppression associated with a low CD4 cell count.
Finally, also in our area, HCV genotype 3 was confirmed to be more associated with HIV-positive patients, because of their habits as drug abusers[35].
In conclusion, in our population, HIV⁄HCV co-infected patients had more ALF than HCV and HIV mono-infected patients. This result was not correlated with long-term exposure to HAART but with a lower CD4 cell count, suggesting that immunologically successful HAART may protect from progression of liver damage in HIV/HCV co-infected patients. In addition, the detection of unsuspected ALF in HIV mono-infected patients confirms that FibroScan® is very useful in this population. HCV infection, with its different pattern of cytolysis, may condition LS values, but viral eradication is mandatory to reduce fibrosis progression. Finally, the use of these non-invasive parameters of LF should be considered with caution. In fact, from our data it emerges that both TE and the biochemical scores may be suitable only for high grades of LF. In contrast, for mild/moderate degrees of fibrosis, they could not replace liver biopsy in the correct evaluation of LF.
COMMENTS
Background
Liver disease associated with hepatitis C virus (HCV) has emerged as a significant problem in human immunodeficiency virus (HIV) patients, thanks to improved survival in the highly active anti-retroviral therapy (HAART) era. Co-infection with HIV is known to lead to a more rapid progression of HCV liver disease to cirrhosis. Other factors such as severe immune suppression and alcohol consumption accelerate the progression of HCV-related fibrosis. In addition, successful HAART slows the progression of liver fibrosis (LF), but antiretroviral-liver toxicity could contributes to hepatic damage in co-infected patients. The advent of transient elastography (TE) has demonstrated to be very helpful for the non-invasive measurement of LF.
Research frontiers
Percutaneous liver biopsy is the gold standard for assessing LF but it is an invasive technique with risk of morbidity and mortality. For these reasons new non-invasive methods for the assessment of LF have recently been developed. TE (FibroScan®) and biochemical markers have demonstrated to be very helpful in the non-invasive measurement of LF. In this study, using these non-invasive tools, i.e. TE plus 2 biochemical tests, aminotransferase platelet ratio index (APRI) and FIB-4, we showed that advanced LF was significantly higher in HIV/HCV co-infected patients than in mono-infected patients and that it was significantly associated with lower CD4+ cells count. The APRI and FIB-4 tests correlated only with the highest values of TE, i.e. ≥ 9.5, suggesting that they are useful tools in diagnosing high grade liver disease, but in the case of a low or moderate degrees of LF liver biopsy remains the best means for correctly diagnosing the degree of fibrosis. Furthermore, the results showed that, overall, a greater number of HIV/HCV co-infected patients with undetectable HCV-RNA had either no or mild fibrosis (F0-F1) compared to the remaining co-infected patients with detectable HCV-RNA.
Innovations and breakthroughs
Several studies have been carried out to identify factors related to an accelerated progression of LF in HIV/HCV co-infected patients. Conflicting results have been reported in the literature about the role of antiretroviral therapy on the progression of LF. In the study, information on alcohol intake, duration of HCV infection and cumulative exposure to non-nucleoside and nucleoside reverse-transcriptase inhibitors, protease inhibitors and specific dideoxynucleoside analogues (didanosine, stavudine, zidovudine) was evaluated. The results showed that on univariate analysis liver stiffness (LS) was significantly associated with alcohol intake > 20 g/d in both HCV mono-infected and co-infected patients, but we did not find any correlations between LF and duration of HCV infection, HAART exposure, duration of HAART exposure or cumulative exposure to any class of antiretroviral drugs.
Applications
A good adherence to antiretroviral therapy, when it is indicated, is important to reduce the risk of progression of LF in co-infected patients. In addition, HCV mono- and co-infected patients should modify negative habits and lifestyles, such as alcohol consumption, which could accelerate the progression of LF. Important fields for further study could include the use and evaluation of the applicability of FibroScan® for repeated assessment in the monitoring of LF.
Terminology
Transient elastometry (Fibro-Scan®; EchoSens, Paris, France) is a rapid, reliable and well-tolerated imaging technique for the assessment of LF by measuring LS.
Peer review
The authors aimed to assess the prevalence of advanced LF (ALF) in HIV, HCV and HIV/HCV patients using TE and to identify factors associated with ALF. They concluded that HIV/HCV co-infected patients had ALF more frequently at TE than HCV and HIV mono-infected patients. The title reflects accurately the contents of the article, and the abstract delineates concisely the research.
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S- Editor Tian L L- Editor Cant MR E- Editor Zheng XM
Source
World J Gastroenterol 2010 November 7; 16(41): 5225-5232
BRIEF ARTICLE
Valentina Li Vecchi, Maurizio Soresi, Claudia Colomba, Giovanni Mazzola, Pietro Colletti, Maurizio Mineo, Paola Di Carlo, Emanuele La Spada, Giovanni Vizzini, Giuseppe Montalto
Valentina Li Vecchi, Maurizio Soresi, Giovanni Mazzola, Pietro Colletti, Maurizio Mineo, Emanuele La Spada, Giuseppe Montalto, Department of Clinical Medicine and Emerging Pathologies, University of Palermo, Via del Vespro 141, 90127 Palermo, Italy
Claudia Colomba, Paola Di Carlo, Infectious Diseases Section, Department of Health Promotion Sciences, University of Palermo, Via del Vespro 129, 90127 Palermo, Italy
Giovanni Vizzini, Department of Gastroenterology and Hepatology, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IsMeTT), University of Pittsburgh Medical Center, Via Tricomi 1, 90127 Palermo, Italy
Author contributions: Montalto G, Li Vecchi V and Mazzola G designed the research; Li Vecchi V, Mazzola G, La Spada E, Colletti P, Mineo M, Colomba C and Di Carlo P performed the research; Soresi M analyzed the data; Li Vecchi V and Montalto G wrote the paper; Montalto G, Soresi M and Vizzini G reviewed the paper.
Correspondence to: Giuseppe Montalto, Professor, Department of Clinical Medicine and Emerging Pathologies, University of Palermo, Via del Vespro 141, 90127 Palermo, Italy. gmontal@unipa.it
Telephone: +39-91-6552991 Fax: +39-91-6552977
Received: April 14, 2010 Revised: June 1, 2010
Accepted: June 8, 2010
Published online: November 7, 2010
Abstract
AIM: To assess the prevalence of advanced liver fibrosis (ALF) in human immunodeficiency virus (HIV), hepatitis C virus (HCV) and HIV/HCV patients using transient elastography, and to identify factors associated with ALF.
METHODS: Between September 2008 and October 2009, 71 HIV mono-infected, 57 HIV/HCV co-infected and 53 HCV mono-infected patients on regular follow-up at our Center were enrolled in this study. Alcohol intake, the main parameters of liver function, presence of HCV-RNA, HIV-RNA, duration of highly active anti-retroviral therapy (HAART) and CD4 cell count were recorded. ALF was defined as liver stiffness (LS) ≥ 9.5 kPa. To estimate liver fibrosis (LF) a further 2 reliable biochemical scores, aspartate aminotransferase platelet ratio index (APRI) and FIB-4, were also used.
RESULTS: LS values of co-infected patients were higher than in either HIV or HCV mono-infected patients (c2MH = 4, P < 0.04). In fact, LS ≥ 9.5 was significantly higher in co-infected than in HIV and HCV mono-infected patients (c2 = 5, P < 0.03). Also APRI and the FIB-4 index showed more LF in co-infected than in HIV mono-infected patients (P < 0.0001), but not in HCV mono-infected patients. In HIV⁄HCV co-infected patients, the extent of LS was significantly associated with alcohol intake (P < 0.04) and lower CD4+ cell count (P < 0.02). In HCV patients, LS was correlated with alcohol intake (P < 0.001) and cholesterol levels (P < 0.03). Body mass index, diabetes, HCV- and HIV-viremia were not significantly correlated with LS. In addition, 20% of co-infected patients had virologically unsuccessful HAART; in 50% compliance was low, CD4+ levels were < 400 cells/mm3 and LS was > 9.5 kPa. There was no significant correlation between extent of LF and HAART exposure or duration of HAART exposure, in particular with specific dideoxynucleoside analogues.
CONCLUSION: ALF was more frequent in co-infected than mono-infected patients. This result correlated with lower CD4 levels. Protective immunological effects of HAART on LF progression outweigh its hepatotoxic effects.
© 2010 Baishideng. All rights reserved.
Key words: Liver fibrosis; Transient elastography; Aspartate aminotransferase platelet ratio index; FIB-4 test; Fibrosis evaluation; Human immunodeficiency virus infection; Hepatitis C virus infection
Peer reviewer: Dr. Chao-Hung Hung, MD, Associate Professor, Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Niao Sung, Kaohsiung 833, Taiwan, China
Li Vecchi V, Soresi M, Colomba C, Mazzola G, Colletti P, Mineo M, Di Carlo P, La Spada E, Vizzini G, Montalto G. Transient elastography: A non-invasive tool for assessing liver fibrosis in HIV/HCV patients. World J Gastroenterol 2010; 16(41): 5225-5232 Available from: URL: http://www.wjgnet.com/1007-9327/full/v16/i41/5225.htm DOI: http://dx.doi.org/10.3748/wjg.v16.i41.5225
INTRODUCTION
In the last few years, liver disease associated with hepatitis C virus (HCV) has emerged as a significant problem in human immunodeficiency virus (HIV)-infected patients, thanks to improved survival in the highly active anti-retroviral therapy (HAART) era[1]. It has been reported that HIV and HCV co-infection leads to a more rapid progression of liver disease to cirrhosis[2,3]. Other factors such as severe immune suppression and alcohol consumption accelerate the progression of HCV-related fibrosis[4,5]. Virologically successful HAART slows the progression of liver fibrosis (LF) and reduces hepatic necroinflammatory activity in HIV/HCV co-infected patients[2,6]. In contrast, antiretroviral-related liver toxicity could contribute to liver damage in HIV- and HIV/HCV-infected patients[7]. Mitochondrial toxicity of nucleoside analogues[8], and glucose or lipid abnormalities, such as hyperglycemia and lipodystrophy, which are particularly common when using some protease inhibitors[9], may produce or enhance LF progression in HIV mono- and HIV/HCV co-infected patients. Currently, in this respect, a growing number of cases of cryptogenetic liver disease in symptomatic and asymptomatic HIV-infected patients has been reported[10,11].
Percutaneous liver biopsy is the gold standard for assessing LF. However, it may be associated with sampling variability[12], is an invasive technique with rates of morbidity of 3% and mortality of 0.03%[13,14], and as a consequence, is not suitable for repeated assessment, which is required when monitoring LF.
For these reasons, new non-invasive methods for the assessment of LF have been developed. Transient elastography (TE) (Fibro-Scan®; EchoSens, Paris, France) is a rapid, reliable and tolerable imaging technique for the assessment of LF by measuring liver stiffness (LS)[15,16].
On the other hand, many biochemical markers have been implemented to estimate LF, with the aim of reducing the number of liver biopsies[14].
The advent of TE and biochemical markers has been demonstrated to be very helpful in the non-invasive measurement of LF, particularly in asymptomatic HIV-infected patients in whom liver biopsy is not recommended[11]. TE has already been validated for the measurement of LF in HIV and HCV seropositive patients[17,18].
The aim of this study was to assess the prevalence of LF and cirrhosis in a group of HIV mono-infected, HCV mono-infected and HIV/HCV co-infected patients using TE and biochemical markers. In addition, we evaluated which of the factors studied correlated with advanced LF (ALF) and cirrhosis.
MATERIALS AND METHODS
Study population
Between September 2008 and October 2009 all consecutive HIV mono-infected and HIV/HCV co-infected patients on regular follow-up at the AIDS Center of the University of Palermo, as well as HCV mono-infected patients seen consecutively at the Outpatient Clinic of the Department of Clinical Medicine and Emerging Pathologies of the University of Palermo were enrolled in this study.
Information on age, gender, risk factors for HCV and HIV infections, cumulative exposure to non-nucleoside and nucleoside reverse-transcriptase inhibitors, protease inhibitors and specific antiretroviral drugs within each class were all recorded in a database designed for this study.
For all HIV-infected patients the absolute number of CD4+ T-cells and plasma HIV-RNA levels was assessed. In HCV-infected patients, HCV-genotype and plasma HCV-RNA levels were also recorded. In addition, at baseline, complete blood cell counts, alanine aminotransferase (ALT), aspartate aminotransferase (AST), g-glutamyl transferase (gGT), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides and glycemia were measured.
Alcohol intake > 20 g/d either at the time of the study or in the past was recorded through patient interviews. Diabetes or impaired fasting glucose (IFG) were defined according to the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus criteria[19].
Patients with acute liver decompensation, hepatocellular carcinoma or chronic hepatitis B were excluded.
The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Patients were enrolled after written informed consent was obtained.
Assessment of LF
LF was assessed by a single certified operator (trained by the manufacturer) using TE (FibroScan®; EchoSens, Paris, France). TE provides an assessment of LS expressed in kPa units. In brief, an ultrasound transducer probe is mounted on the axis of a vibrator. Vibrations of mild amplitude and low frequency are transmitted by the transducer, inducing an elastic shear wave that propagates through the underlying tissues. The speed of propagation of this vibration across the liver is directly related to tissue stiffness.
The tip of the probe transducer was placed in the intercostal spaces at the right lobe of the liver. Only patients with 10 valid elastometric measures, interquartile ranges > 30% and ≥ 60% success rate (the number of validated measurements divided by the total number of measurements) were considered to be reliable. ALF (severe fibrosis and cirrhosis) was defined as a median LS of 9.5 kPa. As previously published, this cut-off value is strongly correlated with a Metavir score of F3, both in HCV mono-infected and HCV⁄HIV co-infected patients[17,18].
LF was also assessed biologically using 2 different well-validated indices, the aspartate aminotransferase platelet ratio index (APRI) index and the FIB-4 index. The APRI was calculated as follows: AST⁄upper limit of normal × 100⁄platelet count (109⁄L)[20,21]. The FIB-4 index was calculated as follows: age × AST (IU⁄L)⁄{[platelet count (109⁄L)] × [ALT (IU⁄L)]1⁄2}[22]. The prevalence of ALF was estimated using as a reference a FIB-4 index > 3.25 and an APRI index > 1.5[20,22].
Statistical analysis
When data distribution was Gaussian, values were expressed as mean ± SD and their differences were calculated using the Student t-test; otherwise, data were expressed as the median and range and analyzed using the Mann-Whitney U test. Fisher’s exact and c2 tests, the c2 test of Mantel Haenszel, Spearman’s rank correlations (r) and Pearson’s correlation (r) were used where appropriate. Multiple linear regression analysis was used to study the association between increased values of LS and variables statistically significant at univariate analysis. All analyses were performed using the SPSS software package (version 13.0; Chicago, IL, USA).
RESULTS
Study population
A total of 201 patients on regular follow-up at both our Centers were enrolled in the study.
In 11 patients (4 HIV mono-infected, 6 HCV mono-infected and one co-infected) a valid elastometric assessment could not be obtained because of truncular obesity, therefore 190 patients were finally included in this study. There were 137 HIV-infected patients, including 71 HIV mono-infected and 66 HIV/HCV co-infected, and 53 HCV mono-infected patients. Patient characteristics at the time of LS measurement are summarized in Table 1.
HIV patients were significantly younger than HCV mono-infected individuals (P < 0.002). Body mass index (BMI) was significantly higher in HCV mono-infected patients than in HIV and HIV/HCV co-infected patients (P < 0.002). The most frequent risk factor of HCV contamination was intravenous drug use in co-infected vs mono-infected HCV patients (P < 0.0001), while it was transfusion of blood products in HCV mono-infected vs co-infected patients (P < 0.0001). Most HIV mono-infected (80.2%) and HIV/HCV co-infected patients (90.9%) were under HAART. However, only 62% of HIV mono-infected and 68% of HIV/HCV co-infected patients had an HIV-RNA load of < 47 copies/mL. In addition, 20% of co-infected patients had virologically unsuccessful HAART; in 50% compliance was low, and CD4+ levels were < 400 cells/mm3. HIV⁄HCV co-infected patients were more often infected by HCV genotype 3 compared with HCV mono-infected patients (P < 0.03).
Table 2 shows the main hematological and virological parameters in the 3 study groups. Serum ALT levels were significantly higher in HCV mono-infected patients than in HIV/HCV co-infected and HIV mono-infected patients (P < 0.02). Serum AST, ALT and gGT levels were significantly higher in HIV/HCV co-infected than in HIV mono-infected patients (P < 0.0001). Only gGT levels were more elevated in HIV/HCV co-infected patients than in HCV mono-infected patients (P < 0.01). TG levels were significantly higher in HIV mono-infected and HIV/HCV co-infected patients than in HCV mono-infected patients (P < 0.004).
Extent of LF
In the overall population LS measured by TE ranged from 3.2 to 48.8 kPa. In 9 HIV/HCV co-infected patients, HCV-RNA was undetectable and for this reason these patients were excluded from the analysis, which was thus carried out only in the remaining 57 co-infected patients. However, their LS was lower than in the remaining co-infected group (data not shown).
Table 3 shows the distribution of LS values measured in all 3 study groups. Co-infected patients had higher LS values than mono-infected patients (c2MH = 4, P < 0.04). The HIV⁄HCV-co-infected population had LS ≥ 9.5 kPa (50.9%) more often than HCV and HIV mono-infected patients (28.3%) (c2 = 5, P < 0.03). In this respect 60% of co-infected patients under virologically unsuccessful HAART showed LS ≥ F3. The individual values of LS increased from HIV to HCV and to HIV/HCV infected patients (r = 0.5, P < 0. 0001) (Figure 1).
Overall, by multiple linear regression analysis, the variables significantly associated with ALF were AST values (b = 0.47, P < 0.0001) and HIV/HCV co-infection (b = 0.25, P < 0.002). To better understand which variables were associated with LS in patients with HIV mono- and co-infection, we also performed multiple linear regression analysis of these 2 groups and found that ALF correlated positively with AST serum levels (b = 0.34, P < 0.0001) and presence of HIV/HCV co-infection (b = 0.4, P < 0.0001) and negatively with lower CD4+ cell counts (b = -0.21, P < 0.003).
Median values of APRI and FIB-4 were significantly higher in HCV mono- and co-infected patients than in HIV mono-infected patients. There were no significant differences in APRI and FIB-4 medians in HCV mono- and HIV/HCV co-infected patients (Table 4). Median values of LS were significantly lower in HIV mono-infected than in HCV mono- and HIV/HCV co-infected patients (P < 0.0001). Median values of HIV/HCV co-infected patients were also significantly higher than in HCV mono-infected patients (P < 0.05).
Overall, correlations between LS and APRI values and LS and FIB-4 values were statistically significant (r = 0.60, P < 0.0001 and r = 0.64, P < 0.0001, respectively). However, when correlations were made according to the 3 cut-off values of LS, we found a significant correlation only for values of LS ≥ 9.5 (r = 0.50, P < 0.0001 vs APRI and r =0.53, P < 0.0001 vs FIB-4) (Table 5).
Correlation between LS and risk factors studied
Table 6 shows the factors associated with LS in the 3 groups. No correlation between the studied parameters and LS was found in the HIV mono-infected group. In HCV mono-infected patients, LS positively correlated with alcohol intake > 20 g/d (P < 0.001) and AST serum level (P < 0.0001), while it negatively correlated with the number of platelets (P < 0.0001) and serum cholesterol levels (P < 0.03). APRI and FIB-4 values were significantly associated with LS both in HCV and HIV/HCV co-infected patients (P < 0.0001).
In HIV⁄HCV-co-infected patients the extent of LS was significantly correlated with alcohol intake (P < 0.04) AST level (P < 0.0001) and lower CD4+ cells count (P < 0.02) and was negatively correlated with platelets (P < 0.0001).
BMI, presence of diabetes or IFG, HCV- and HIV-viremia were not significantly correlated with LS in any of the 3 study groups. In addition, there was no significant correlation between the extent of LF under HAART exposure and duration of HAART exposure. There was no significant correlation either between extent of LF and cumulative exposure to each class of antiretroviral drugs (non-nucleoside/nucleoside reverse-transcriptase inhibitors, protease inhibitors) and of specific dideoxynucleoside analogues (didanosine, stavudine, zidovudine).
DISCUSSION
Our results, in agreement with other studies, confirmed that LF is more severe in HIV/HCV co-infected patients than in HCV or HIV mono-infected patients[5,23,24]. In addition, ALF was significantly associated with a lower CD4+cell count in co-infected patients. There is convincing evidence that co-infection with HIV worsens the prognosis of HCV-related liver disease. It has been reported that in patients co-infected with HIV and HCV the risk of progressing to cirrhosis and liver failure is higher than in those infected with only HCV[25,26], especially in individuals with CD4 < 200 cells/mL and alcohol consumption[2].
In our study, 20% of HIV/HCV co-infected patients were under virologically unsuccessful HAART and in 50% CD4+ levels were below 400 cells/mm3 suggesting, in agreement with former findings, that the less successful the response to HAART, the less marked is its clinical benefit. In fact, immune recovery under HAART has been associated with longer overall survival, slower progression of HCV-related liver damage in HIV co-infected patients and with lengthier survival times before death attributable to liver disease[27]. In the same way, Pineda et al[27] demonstrated that liver decompensation emerged earlier in patients who maintained an undetectable HIV viral load for a shorter period during follow-up. Nevertheless, the association between ALF and lower CD4 cell count suggests that the response to HAART, measured using CD4 cell gain and HIV viral load decline, determines the evolution of liver disease and that virologically and immunologically successful HAART may slow progression of LF in HIV/HCV co-infected patients.
On the other hand, antiretroviral-related liver toxicity could have further contributed to liver damage in our HIV population[7]. Mitochondrial toxicity of nucleoside analogues and glucose or lipid abnormalities, particularly common when using some protease inhibitors, may produce or enhance LF progression in HIV-seropositive patients. The correlation between use of antiretroviral drugs and LF in patients with HIV/HCV co-infection has been evaluated in different studies but with contradictory results[21,28-30].
Macías et al[21] reported that HAART regimens, including nevirapine, were associated with an increased degree of LF, while the use of protease inhibitor-based HAART was associated with less severe fibrosis and a slower progression of fibrosis in HIV/HCV co-infected patients. In contrast, Berenguer et al[28] found that exposure to NNRTI was associated with a reduction in LF progression. In addition, Halfon et al[29] showed that exposure to NNRTI was an independent factor in LF while Blanco et al[30] highlighted that exposure to dideoxynucleosides was an independent factor associated with ALF.
In our study, no correlation was found between HAART exposure, duration of HAART exposure or cumulative exposure to any class of antiretroviral drugs and LF. In addition, we analyzed the correlation between duration of exposure to dideoxynucleosides (in particular didanosine, stavudine, zidovudine) and LF but also in this case no correlation was observed, suggesting that these drugs could not play any role in the progression of LF.
ALF was significantly higher in HIV/HCV co-infected patients than in HCV mono-infected patients when the subset of co-infected patients with undetectable HCV-RNA were excluded from the analysis. Overall, HIV/HCV co-infected patients with undetectable HCV-RNA had either no or only mild fibrosis (F0-F1) compared to the remaining co-infected patients, suggesting that the presence of HCV is important in conditioning the progression of LF and that anti-HCV therapy is mandatory in HIV/HCV co-infected patients in order to eradicate the virus. In fact, other authors have reported that achieving HCV clearance may reduce liver-related complications and mortality[31,32] and probably permits at least a partial regression of LF[33]. However, in HIV-positive patients liver cirrhosis may also occur without chronic viral hepatitis, and possible causes of hepatic steatosis in patients with HIV may be due to HIV itself, pathological alcohol use, diabetes mellitus, obesity or antiretroviral medications[34].
Evaluation of LF using the 2 biochemical scores (APRI and FIB-4) was not in full agreement with LS measurement. In fact, these 2 biochemical tests were in agreement with TE values only for high-grade LF, but not in low and moderate LF, suggesting that at least in these cases liver biopsy could be necessary to assess the precise degree of LF. In this respect, we are aware that the lack of liver biopsy, as a reference tool of LF, is a limitation of our study.
More consideration, perhaps, should be given to transaminase levels. In fact, the HCV mono-infected group had the highest levels of transaminases, which may have influenced LS values by increasing them. This result could further support our observation that co-infected patients are at highest risk of LF because of their high AST levels and the immune suppression associated with a low CD4 cell count.
Finally, also in our area, HCV genotype 3 was confirmed to be more associated with HIV-positive patients, because of their habits as drug abusers[35].
In conclusion, in our population, HIV⁄HCV co-infected patients had more ALF than HCV and HIV mono-infected patients. This result was not correlated with long-term exposure to HAART but with a lower CD4 cell count, suggesting that immunologically successful HAART may protect from progression of liver damage in HIV/HCV co-infected patients. In addition, the detection of unsuspected ALF in HIV mono-infected patients confirms that FibroScan® is very useful in this population. HCV infection, with its different pattern of cytolysis, may condition LS values, but viral eradication is mandatory to reduce fibrosis progression. Finally, the use of these non-invasive parameters of LF should be considered with caution. In fact, from our data it emerges that both TE and the biochemical scores may be suitable only for high grades of LF. In contrast, for mild/moderate degrees of fibrosis, they could not replace liver biopsy in the correct evaluation of LF.
COMMENTS
Background
Liver disease associated with hepatitis C virus (HCV) has emerged as a significant problem in human immunodeficiency virus (HIV) patients, thanks to improved survival in the highly active anti-retroviral therapy (HAART) era. Co-infection with HIV is known to lead to a more rapid progression of HCV liver disease to cirrhosis. Other factors such as severe immune suppression and alcohol consumption accelerate the progression of HCV-related fibrosis. In addition, successful HAART slows the progression of liver fibrosis (LF), but antiretroviral-liver toxicity could contributes to hepatic damage in co-infected patients. The advent of transient elastography (TE) has demonstrated to be very helpful for the non-invasive measurement of LF.
Research frontiers
Percutaneous liver biopsy is the gold standard for assessing LF but it is an invasive technique with risk of morbidity and mortality. For these reasons new non-invasive methods for the assessment of LF have recently been developed. TE (FibroScan®) and biochemical markers have demonstrated to be very helpful in the non-invasive measurement of LF. In this study, using these non-invasive tools, i.e. TE plus 2 biochemical tests, aminotransferase platelet ratio index (APRI) and FIB-4, we showed that advanced LF was significantly higher in HIV/HCV co-infected patients than in mono-infected patients and that it was significantly associated with lower CD4+ cells count. The APRI and FIB-4 tests correlated only with the highest values of TE, i.e. ≥ 9.5, suggesting that they are useful tools in diagnosing high grade liver disease, but in the case of a low or moderate degrees of LF liver biopsy remains the best means for correctly diagnosing the degree of fibrosis. Furthermore, the results showed that, overall, a greater number of HIV/HCV co-infected patients with undetectable HCV-RNA had either no or mild fibrosis (F0-F1) compared to the remaining co-infected patients with detectable HCV-RNA.
Innovations and breakthroughs
Several studies have been carried out to identify factors related to an accelerated progression of LF in HIV/HCV co-infected patients. Conflicting results have been reported in the literature about the role of antiretroviral therapy on the progression of LF. In the study, information on alcohol intake, duration of HCV infection and cumulative exposure to non-nucleoside and nucleoside reverse-transcriptase inhibitors, protease inhibitors and specific dideoxynucleoside analogues (didanosine, stavudine, zidovudine) was evaluated. The results showed that on univariate analysis liver stiffness (LS) was significantly associated with alcohol intake > 20 g/d in both HCV mono-infected and co-infected patients, but we did not find any correlations between LF and duration of HCV infection, HAART exposure, duration of HAART exposure or cumulative exposure to any class of antiretroviral drugs.
Applications
A good adherence to antiretroviral therapy, when it is indicated, is important to reduce the risk of progression of LF in co-infected patients. In addition, HCV mono- and co-infected patients should modify negative habits and lifestyles, such as alcohol consumption, which could accelerate the progression of LF. Important fields for further study could include the use and evaluation of the applicability of FibroScan® for repeated assessment in the monitoring of LF.
Terminology
Transient elastometry (Fibro-Scan®; EchoSens, Paris, France) is a rapid, reliable and well-tolerated imaging technique for the assessment of LF by measuring LS.
Peer review
The authors aimed to assess the prevalence of advanced LF (ALF) in HIV, HCV and HIV/HCV patients using TE and to identify factors associated with ALF. They concluded that HIV/HCV co-infected patients had ALF more frequently at TE than HCV and HIV mono-infected patients. The title reflects accurately the contents of the article, and the abstract delineates concisely the research.
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S- Editor Tian L L- Editor Cant MR E- Editor Zheng XM
Source
Transient elastography for the noninvasive assessment of liver fibrosis: A multicentre Canadian study
Original Article
The Canadian Journal of Gastroenterology
November 2010, Volume 24 Issue 11: 661-670
RP Myers, M Elkashab, M Ma, P Crotty, G Pomier-Layrargues
BACKGROUND: Liver stiffness measurement (LSM) using transient elastography (TE) is a promising tool for the noninvasive assessment of hepatic fibrosis.
OBJECTIVES: To determine the feasibility and performance of TE in a North American cohort of patients with chronic liver disease.
METHODS: LSMs were obtained using TE in 260 patients with chronic hepatitis B or C, or nonalcoholic fatty liver disease from four Canadian hepatology centres. The accuracy of TE compared with liver biopsy for the prediction of significant fibrosis (Metavir fibrosis score of F2 or greater), bridging fibrosis (Metavir fibrosis score of F3 or greater) and cirrhosis (Metavir fibrosis score of F4 ) was assessed using area under ROC curves (AUROCs), and compared with the aspartate aminotransferase-to-platelet ratio index. The influence of alanine aminotransferase (ALT) levels and other factors on liver stiffness was determined using linear regression analyses.
RESULTS: Failure of TE occurred in 2.7% of patients, while liver biopsies were inadequate for staging in 0.8%. Among the remaining 251 patients, the AUROCs of TE for Metavir fibrosis scores of F2 and F3 or greater, and F4 were 0.74 (95% CI 0.68 to 0.80), 0.89 (95% CI 0.84 to 0.94), and 0.94 (95% CI 0.90 to 0.97), respectively. LSM was more accurate than the aminotransferase-to-platelet ratio index for bridging fibrosis (AUROC 0.78) and cirrhosis (AUROC 0.88), but not significant fibrosis (AUROC 0.76). At a cut-off of 11.1 kPa, the sensitivity, specificity, and positive and negative predictive values for cirrhosis (prevalence 11%) were 96%, 81%, 39% and 99%, respectively. For significant fibrosis (prevalence 53%), a cut-off of 7.7 kPa was 68% sensitive and 69% specific, and had a positive predictive value of 70% and a negative predictive value of 65%. Liver stiffness was independently associated with ALT, body mass index and steatosis. The optimal LSM cut-offs for cirrhosis were 11.1 kPa and 11.5 kPa in patients with ALT levels lower than 100 U/L and 100 U/L or greater, respectively. For fibrosis scores of F2 or greater, these figures were 7.0 kPa and 8.6 kPa, respectively.
CONCLUSIONS: The major role of TE is the exclusion of bridging fibrosis and cirrhosis. However, TE cannot replace biopsy for the diagnosis of significant fibrosis. Because liver stiffness may be influenced by significant ALT elevation, body mass index and/or steatosis, tailored liver stiffness cut-offs may be necessary to account for these factors.
Source
The Canadian Journal of Gastroenterology
November 2010, Volume 24 Issue 11: 661-670
RP Myers, M Elkashab, M Ma, P Crotty, G Pomier-Layrargues
BACKGROUND: Liver stiffness measurement (LSM) using transient elastography (TE) is a promising tool for the noninvasive assessment of hepatic fibrosis.
OBJECTIVES: To determine the feasibility and performance of TE in a North American cohort of patients with chronic liver disease.
METHODS: LSMs were obtained using TE in 260 patients with chronic hepatitis B or C, or nonalcoholic fatty liver disease from four Canadian hepatology centres. The accuracy of TE compared with liver biopsy for the prediction of significant fibrosis (Metavir fibrosis score of F2 or greater), bridging fibrosis (Metavir fibrosis score of F3 or greater) and cirrhosis (Metavir fibrosis score of F4 ) was assessed using area under ROC curves (AUROCs), and compared with the aspartate aminotransferase-to-platelet ratio index. The influence of alanine aminotransferase (ALT) levels and other factors on liver stiffness was determined using linear regression analyses.
RESULTS: Failure of TE occurred in 2.7% of patients, while liver biopsies were inadequate for staging in 0.8%. Among the remaining 251 patients, the AUROCs of TE for Metavir fibrosis scores of F2 and F3 or greater, and F4 were 0.74 (95% CI 0.68 to 0.80), 0.89 (95% CI 0.84 to 0.94), and 0.94 (95% CI 0.90 to 0.97), respectively. LSM was more accurate than the aminotransferase-to-platelet ratio index for bridging fibrosis (AUROC 0.78) and cirrhosis (AUROC 0.88), but not significant fibrosis (AUROC 0.76). At a cut-off of 11.1 kPa, the sensitivity, specificity, and positive and negative predictive values for cirrhosis (prevalence 11%) were 96%, 81%, 39% and 99%, respectively. For significant fibrosis (prevalence 53%), a cut-off of 7.7 kPa was 68% sensitive and 69% specific, and had a positive predictive value of 70% and a negative predictive value of 65%. Liver stiffness was independently associated with ALT, body mass index and steatosis. The optimal LSM cut-offs for cirrhosis were 11.1 kPa and 11.5 kPa in patients with ALT levels lower than 100 U/L and 100 U/L or greater, respectively. For fibrosis scores of F2 or greater, these figures were 7.0 kPa and 8.6 kPa, respectively.
CONCLUSIONS: The major role of TE is the exclusion of bridging fibrosis and cirrhosis. However, TE cannot replace biopsy for the diagnosis of significant fibrosis. Because liver stiffness may be influenced by significant ALT elevation, body mass index and/or steatosis, tailored liver stiffness cut-offs may be necessary to account for these factors.
Source
Vertex Announces Plans to Enroll Additional Treatment Arm in Ongoing Phase 2 Combination Study of Telaprevir and VX-222 for the Treatment of People with Hepatitis C
Nov. 10, 2010, 8:00 a.m. EST
-New treatment arm to evaluate all oral, triple combination regimen of telaprevir, VX-222, and ribavirin-
CAMBRIDGE, Mass., Nov 10, 2010 (BUSINESS WIRE) -- Vertex Pharmaceuticals Incorporated /quotes/comstock/15*!vrtx/quotes/nls/vrtx (VRTX 34.55, +0.28, +0.82%) today announced plans to enroll an additional treatment arm as part of its ongoing Phase 2 clinical trial evaluating 12-week regimens of Vertex's lead investigational hepatitis C virus (HCV) protease inhibitor, telaprevir, in combination with its lead investigational HCV polymerase inhibitor, VX-222. The planned treatment arm is supported by emerging data from multiple ongoing clinical trials of direct-acting antiviral (DAA) therapies, including the trial of telaprevir/VX-222-based combination therapy, which suggest that adding ribavirin to a DAA treatment regimen may increase antiviral activity. In the additional arm, Vertex plans to evaluate a 12-week combination of three oral therapies -- VX-222, telaprevir and ribavirin -- dosed twice a day within a response-guided regimen.
"We are encouraged by the high viral cure rates and shorter treatment durations reported in Phase 3 studies of telaprevir-based combination therapy, and we remain focused on continuing to develop new potential treatments for hepatitis C," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. "Evaluating a 12-week combination of telaprevir, VX-222 and ribavirin will provide us with important information about the potential for this all-oral regimen that could be taken twice a day."
About the Ongoing Phase 2 Trial of Telaprevir and VX-222
Beginning in August 2010, patients enrolled in the randomized, parallel-group, dose-ranging Phase 2 trial started receiving treatment. The primary endpoint of this trial is to assess safety and tolerability of 12-week telaprevir/VX-222-based combination therapy in people with genotype 1 chronic hepatitis C. A secondary endpoint of this study is to assess on-treatment antiviral activity and the proportion of patients in each study arm who achieve a sustained viral response (SVR; defined as undetectable HCV RNA 24 weeks after the end of treatment). If patients meet response-guided criteria during treatment (undetectable HCV RNA at week 2 and week 8 of treatment), they may be eligible to stop all therapy at 12 weeks.
The study includes treatment arms that are evaluating 12-week, response-guided regimens of two- and four-drug telaprevir/VX-222 combination therapy, given twice daily, with and without Pegasys(R) (pegylated-interferon alfa-2a) and Copegus(R) (ribavirin). Trial sites for the two- and four-drug ongoing arms completed enrollment in October 2010. The additional three-drug treatment arm of telaprevir, VX-222 and ribavirin announced today is expected to begin patient enrollment in the first quarter of 2011, pending completion of institutional review board (IRB) approvals and consultation with regulatory agencies. Based on further results from the ongoing treatment arms, Vertex may add an additional arm in this study.
Additional Clinical Trial of VX-222 Combination Therapy
Vertex is also conducting a Phase 2 clinical trial evaluating the safety, tolerability and antiviral activity of VX-222 in combination with pegylated-interferon and ribavirin, which began in August 2010. Enrollment is ongoing and Vertex expects to enroll a total of 50 patients. Patients in this trial will receive one of two doses of VX-222 (400 mg or 750 mg twice daily) in combination with pegylated-interferon alfa-2a and ribavirin for 12 weeks, followed by pegylated-interferon alfa-2a and ribavirin alone for 36 weeks.
About Telaprevir and VX-222
Telaprevir is an investigational, oral inhibitor of HCV protease, an enzyme essential for viral replication, and is being developed by Vertex Pharmaceuticals in collaboration with Tibotec Pharmaceuticals and Mitsubishi Tanabe Pharma. Phase 3 studies of telaprevir in combination with pegylated interferon alfa-2a and ribavirin are complete and Vertex is on track to complete its rolling New Drug Application (NDA) submission to the U.S. Food and Drug Administration by the end of 2010.
VX-222 is an investigational, oral, non-nucleoside inhibitor of HCV NS5B polymerase. Vertex added VX-222 to its development pipeline as part of the acquisition of ViroChem Pharma Inc. in March 2009. Vertex retains worldwide commercial rights to VX-222.
About Hepatitis C
Hepatitis C is a liver disease caused by the hepatitis C virus, which is found in the liver and blood of people with the disease.(2) According to a 2010 report from the Institute of Medicine, up to 3.9 million people in the United States have chronic hepatitis C and 75% of those infected are unaware of their infection.(3)Approximately 60 percent of genotype 1 patients who undergo an initial 48-week regimen with pegylated-interferon and ribavirin, the currently approved treatment regimen, do not achieve SVR, (4,5,6)or viral cure.(1)
Hepatitis C is spread through direct contact with the blood of infected people.(2) Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.(2) Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.(2) If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.(7,8,9,10,11) In the United States, hepatitis C is the leading cause of liver transplantations and is reported to contribute to 4,600 to 12,000 deaths annually.(8) The majority of people with hepatitis C were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.(11) By 2029, total annual medical costs in the U.S. for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.(11)
Additional resources for media, including a hepatitis C backgrounder and glossary of common terms, are available at: http://investors.vrtx.com/press.cfm
About Vertex
Vertex Pharmaceuticals Incorporated is a global biotechnology company committed to the discovery and development of breakthrough small molecule drugs for serious diseases. The Company's strategy is to commercialize its products both independently and in collaboration with other pharmaceutical companies. Vertex's product pipeline is focused on viral diseases, cystic fibrosis, inflammation, autoimmune diseases, epilepsy, cancer and pain.
Vertex co-discovered the HIV protease inhibitor, Lexiva, with GlaxoSmithKline.
Lexiva is a registered trademark of the GlaxoSmithKline group of companies.
PEGASYS(R) and COPEGUS(R) are registered trademarks of Hoffman-La Roche.
References:
(1)Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40. (2) Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed May 25, 2010. (3) Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed May 25, 2010. (4)Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965. (5) Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982. (6)McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593. (7) Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115). (8)Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521. (9) Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755. (10) Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684. (11) Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. This report was commissioned by Vertex Pharmaceuticals, Inc. (12) Picchio G, et al. Discrepancies between definitions of null response to treatment with peginterferon alfa-2a and ribavirin: Implications for new HCV drug development. [poster 289]. In: Program and Abstracts of the 2010 International Liver Conference by the European Association for the Study of Liver Disease. . Athens, Greece: April 2010. (13)United States Food and Drug Administration. Chronic hepatitis C virus infection: developing direct-acting antiviral agents for treatment. http://www.federalregister.gov/articles/2010/09/14/2010-22806/draft-guidance-for-industry-on-chronic-hepatitis-c-virus-infection-developing-directacting-antiviral. Updated September 14, 2010. Accessed September 14, 2010.
Special Note Regarding Forward-looking Statements
This press release contains forward-looking statements including statements regarding (i) Vertex's plan to enroll an additional treatment arm as part of its ongoing Phase 2 clinical trial evaluating telaprevir in combination with VX-222; (ii) the support provided by emerging data suggesting that adding ribavirin to a direct-acting antiviral treatment regimen may increase antiviral activity; (iii) the plan to evaluate a 12-week combination of the three oral therapies -- VX-222, telaprevir and ribavirin -- dosed twice a day within a response-guided regimen; (iv) the expectation that evaluating a 12-week combination regimen of telaprevir, VX-222, and ribavirin will provide Vertex with important information about the potential for this all oral regimen that could be taken twice daily; (v) the expectation that the additional three-drug treatment arm will begin patient enrollment in the first quarter of 2011, pending completion of IRB approvals and consultation with regulatory agencies; (vi) the possibility that Vertex may add an additional treatment arm to this study; (vii) expectations regarding the additional clinical trial of VX-222 combination therapy; and (viii) Vertex being on track to complete its rolling NDA submission to the U.S. Food and Drug Administration by the end of 2010. While Vertex believes the forward-looking statements contained in this press release are accurate, these statements are subject to risks and uncertainties that could cause actual outcomes to vary materially from the outcomes referenced in the forward-looking statements. These risks and uncertainties include, among other things, the risks that efforts to develop telaprevir and VX-222 separately or in combination may not proceed due to technical, scientific, commercial, financial or other reasons, that clinical trials may not proceed as planned, that additional clinical trials of telaprevir and VX-222 will not reflect the results obtained to date, that an adverse event profile for telaprevir or VX-222 could be revealed in further nonclinical or clinical studies that could put further development of telaprevir or VX-222 in jeopardy or adversely impact their therapeutic value, and other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through the Company's website at www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.
(VRTX-GEN)
SOURCE: Vertex Pharmaceuticals Incorporated
Vertex Pharmaceuticals Incorporated
Media:
Amy Pasqua, 617-444-6992
or
Dawn Kalmar, 617-444-6992
or
Zachry Barber, 617-444-6992
or
Investors:
Michael Partridge, 617-444-6108
or
Lora Pike, 617-444-6755
or
Matthew Osborne, 617-444-6057
Source
-New treatment arm to evaluate all oral, triple combination regimen of telaprevir, VX-222, and ribavirin-
CAMBRIDGE, Mass., Nov 10, 2010 (BUSINESS WIRE) -- Vertex Pharmaceuticals Incorporated /quotes/comstock/15*!vrtx/quotes/nls/vrtx (VRTX 34.55, +0.28, +0.82%) today announced plans to enroll an additional treatment arm as part of its ongoing Phase 2 clinical trial evaluating 12-week regimens of Vertex's lead investigational hepatitis C virus (HCV) protease inhibitor, telaprevir, in combination with its lead investigational HCV polymerase inhibitor, VX-222. The planned treatment arm is supported by emerging data from multiple ongoing clinical trials of direct-acting antiviral (DAA) therapies, including the trial of telaprevir/VX-222-based combination therapy, which suggest that adding ribavirin to a DAA treatment regimen may increase antiviral activity. In the additional arm, Vertex plans to evaluate a 12-week combination of three oral therapies -- VX-222, telaprevir and ribavirin -- dosed twice a day within a response-guided regimen.
"We are encouraged by the high viral cure rates and shorter treatment durations reported in Phase 3 studies of telaprevir-based combination therapy, and we remain focused on continuing to develop new potential treatments for hepatitis C," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. "Evaluating a 12-week combination of telaprevir, VX-222 and ribavirin will provide us with important information about the potential for this all-oral regimen that could be taken twice a day."
About the Ongoing Phase 2 Trial of Telaprevir and VX-222
Beginning in August 2010, patients enrolled in the randomized, parallel-group, dose-ranging Phase 2 trial started receiving treatment. The primary endpoint of this trial is to assess safety and tolerability of 12-week telaprevir/VX-222-based combination therapy in people with genotype 1 chronic hepatitis C. A secondary endpoint of this study is to assess on-treatment antiviral activity and the proportion of patients in each study arm who achieve a sustained viral response (SVR; defined as undetectable HCV RNA 24 weeks after the end of treatment). If patients meet response-guided criteria during treatment (undetectable HCV RNA at week 2 and week 8 of treatment), they may be eligible to stop all therapy at 12 weeks.
The study includes treatment arms that are evaluating 12-week, response-guided regimens of two- and four-drug telaprevir/VX-222 combination therapy, given twice daily, with and without Pegasys(R) (pegylated-interferon alfa-2a) and Copegus(R) (ribavirin). Trial sites for the two- and four-drug ongoing arms completed enrollment in October 2010. The additional three-drug treatment arm of telaprevir, VX-222 and ribavirin announced today is expected to begin patient enrollment in the first quarter of 2011, pending completion of institutional review board (IRB) approvals and consultation with regulatory agencies. Based on further results from the ongoing treatment arms, Vertex may add an additional arm in this study.
Additional Clinical Trial of VX-222 Combination Therapy
Vertex is also conducting a Phase 2 clinical trial evaluating the safety, tolerability and antiviral activity of VX-222 in combination with pegylated-interferon and ribavirin, which began in August 2010. Enrollment is ongoing and Vertex expects to enroll a total of 50 patients. Patients in this trial will receive one of two doses of VX-222 (400 mg or 750 mg twice daily) in combination with pegylated-interferon alfa-2a and ribavirin for 12 weeks, followed by pegylated-interferon alfa-2a and ribavirin alone for 36 weeks.
About Telaprevir and VX-222
Telaprevir is an investigational, oral inhibitor of HCV protease, an enzyme essential for viral replication, and is being developed by Vertex Pharmaceuticals in collaboration with Tibotec Pharmaceuticals and Mitsubishi Tanabe Pharma. Phase 3 studies of telaprevir in combination with pegylated interferon alfa-2a and ribavirin are complete and Vertex is on track to complete its rolling New Drug Application (NDA) submission to the U.S. Food and Drug Administration by the end of 2010.
VX-222 is an investigational, oral, non-nucleoside inhibitor of HCV NS5B polymerase. Vertex added VX-222 to its development pipeline as part of the acquisition of ViroChem Pharma Inc. in March 2009. Vertex retains worldwide commercial rights to VX-222.
About Hepatitis C
Hepatitis C is a liver disease caused by the hepatitis C virus, which is found in the liver and blood of people with the disease.(2) According to a 2010 report from the Institute of Medicine, up to 3.9 million people in the United States have chronic hepatitis C and 75% of those infected are unaware of their infection.(3)Approximately 60 percent of genotype 1 patients who undergo an initial 48-week regimen with pegylated-interferon and ribavirin, the currently approved treatment regimen, do not achieve SVR, (4,5,6)or viral cure.(1)
Hepatitis C is spread through direct contact with the blood of infected people.(2) Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.(2) Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.(2) If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.(7,8,9,10,11) In the United States, hepatitis C is the leading cause of liver transplantations and is reported to contribute to 4,600 to 12,000 deaths annually.(8) The majority of people with hepatitis C were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.(11) By 2029, total annual medical costs in the U.S. for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.(11)
Additional resources for media, including a hepatitis C backgrounder and glossary of common terms, are available at: http://investors.vrtx.com/press.cfm
About Vertex
Vertex Pharmaceuticals Incorporated is a global biotechnology company committed to the discovery and development of breakthrough small molecule drugs for serious diseases. The Company's strategy is to commercialize its products both independently and in collaboration with other pharmaceutical companies. Vertex's product pipeline is focused on viral diseases, cystic fibrosis, inflammation, autoimmune diseases, epilepsy, cancer and pain.
Vertex co-discovered the HIV protease inhibitor, Lexiva, with GlaxoSmithKline.
Lexiva is a registered trademark of the GlaxoSmithKline group of companies.
PEGASYS(R) and COPEGUS(R) are registered trademarks of Hoffman-La Roche.
References:
(1)Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40. (2) Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed May 25, 2010. (3) Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed May 25, 2010. (4)Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965. (5) Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982. (6)McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593. (7) Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115). (8)Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521. (9) Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755. (10) Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684. (11) Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. This report was commissioned by Vertex Pharmaceuticals, Inc. (12) Picchio G, et al. Discrepancies between definitions of null response to treatment with peginterferon alfa-2a and ribavirin: Implications for new HCV drug development. [poster 289]. In: Program and Abstracts of the 2010 International Liver Conference by the European Association for the Study of Liver Disease. . Athens, Greece: April 2010. (13)United States Food and Drug Administration. Chronic hepatitis C virus infection: developing direct-acting antiviral agents for treatment. http://www.federalregister.gov/articles/2010/09/14/2010-22806/draft-guidance-for-industry-on-chronic-hepatitis-c-virus-infection-developing-directacting-antiviral. Updated September 14, 2010. Accessed September 14, 2010.
Special Note Regarding Forward-looking Statements
This press release contains forward-looking statements including statements regarding (i) Vertex's plan to enroll an additional treatment arm as part of its ongoing Phase 2 clinical trial evaluating telaprevir in combination with VX-222; (ii) the support provided by emerging data suggesting that adding ribavirin to a direct-acting antiviral treatment regimen may increase antiviral activity; (iii) the plan to evaluate a 12-week combination of the three oral therapies -- VX-222, telaprevir and ribavirin -- dosed twice a day within a response-guided regimen; (iv) the expectation that evaluating a 12-week combination regimen of telaprevir, VX-222, and ribavirin will provide Vertex with important information about the potential for this all oral regimen that could be taken twice daily; (v) the expectation that the additional three-drug treatment arm will begin patient enrollment in the first quarter of 2011, pending completion of IRB approvals and consultation with regulatory agencies; (vi) the possibility that Vertex may add an additional treatment arm to this study; (vii) expectations regarding the additional clinical trial of VX-222 combination therapy; and (viii) Vertex being on track to complete its rolling NDA submission to the U.S. Food and Drug Administration by the end of 2010. While Vertex believes the forward-looking statements contained in this press release are accurate, these statements are subject to risks and uncertainties that could cause actual outcomes to vary materially from the outcomes referenced in the forward-looking statements. These risks and uncertainties include, among other things, the risks that efforts to develop telaprevir and VX-222 separately or in combination may not proceed due to technical, scientific, commercial, financial or other reasons, that clinical trials may not proceed as planned, that additional clinical trials of telaprevir and VX-222 will not reflect the results obtained to date, that an adverse event profile for telaprevir or VX-222 could be revealed in further nonclinical or clinical studies that could put further development of telaprevir or VX-222 in jeopardy or adversely impact their therapeutic value, and other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through the Company's website at www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.
(VRTX-GEN)
SOURCE: Vertex Pharmaceuticals Incorporated
Vertex Pharmaceuticals Incorporated
Media:
Amy Pasqua, 617-444-6992
or
Dawn Kalmar, 617-444-6992
or
Zachry Barber, 617-444-6992
or
Investors:
Michael Partridge, 617-444-6108
or
Lora Pike, 617-444-6755
or
Matthew Osborne, 617-444-6057
Source
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