Multimedia;Videos and Podcasts-Updated
Transcript included, also from CCO the "Current Recommendations for Using Telaprevir and Boceprevir in Patients With Advanced Fibrosis or Cirrhosis."
Tuesday, January 31, 2012
Video-New FDA approved and experimental drugs to treat hepatitis C.
Transcript
Hi bear, here we are back at HCV new drugs to talk about new and experimental drugs to treat hepatitis C.
Hello bear, great to see you again. As you know in 2011 the two protease inhibitors Victrellis and Incivek were FDA approved . Studies show that Incivek cured 79% of patients and Victrellis cured 69%. The term used by the medical world is SVR or Sustained Virologic Response.The bottom line is a patient is considered cured or has achieved SVR statis when there is no detectable virus in the patients blood for six months after finishing treatment.
These two new FDA approved drugs still need to be used with standard therapy, right bear?
Yes,unfortunately patients still need to inject interferon and use ribavirin. But the SVR with these two drugs exceeded the old standard of care cure rates of 40 to 45 percent in genotype 1 patients.
What about patients who have cirrhosis? Or have failed prior standard therapy ? What are the stats on reaching SVR ?
Well, researchers found that Incivek, in hard-to-treat patients with hepatitis C and cirrhosis achieved a 47% sustained viral response. These patients had genotype 1 and had previously failed the standard two drug regimen of pegylated interferon plus ribavirin . Check out the link below for more information.
Telaprevir Effective in Hard-to-Treat Cirrhotic HCV
See additional information below from CCO.
Lets just use the term Peg, because pegylated interferon is difficult for you to pronounce. So Bear, tell me about two experimental new protease inhibitors that are in phase three trials, and fill me in on this cyclophillin inhibitor.
Okay, Lets talk about the HCV drugs in phase three clinical trials that are used in combination with standard therapy or peg and ribavirin. Currently in phase 3 trials is TMC 435, a protease inhibitor from Johnson and Johnson’s Tibotec unit.
Tell me about early interim results from the phase two trials. I remember them being released in February of 2011.
For HCV genotype 1 treatment-naïve patients using TMC 435 the SVR was 76 to 84 percent. The study was response-guided with 83% of patients being able to stop all therapy at 24 weeks.
What about the phase three trials.
Oh, you mean the QUEST studies, TMC 435 is currently being developed in three global phase III studies, QUEST-1 and QUEST-2 in treatment-naïve patients and PROMISE in patients who have relapsed after prior interferon-based treatment. In parallel with these trials, phase III studies for TMC 435 in Japan, in both treatment naive and treatment experienced hepatitis C genotype-1 infected patients, are ongoing. These phase III studies are fully recruited
You forgot to mention that TMC 435 is also being studied in combination with PSI-7977, we are talking about an interferon free combo . But more on that later.Right little bear?
Right . Hey bear, lets hope that these drugs currently in phase three trials will give patients better tolerability, increases cure rates, with a shorter duration of therapy.
That sure is the plan. Another drug in phase three trials is BI-201335 from Boehringer Ingelheim. The Phase three trial of the boehringer drug is in combination with peg and will include 3 treatment arms. They are BI-201335 in combination with peg plus ribavirin for 12 weeks or 24 weeks of treatment compared to 48 weeks of peg plus ribavirin without BI-201335. By the way, the FDA has granted Fast Track designations for BI-201335 plus standard-of care, and as part of the interferon-free combination with the polymerase inhibitor, BI-207127, in chronic genotype 1 Hepatitis C patients. The study is an interferon-free regimen deemed SOUND-C2 .
At the 2011 AASLD meeting we heard that in the SILEN-C1 trial of BI-201335 with standard therapy, HCV genotype 1 treatment- naïve patients achieved 82% to 84% SVR. In the trial deemed SILEN-C3, HCV genotype 1 treatment-naïve patients treated with BI-201335 plus standard therapy achieved an 80% SVR in the group that was treated for 12 weeks compared to 82% in the group that was treated for 24 weeks.You can find all this information and more by clicking on a link to HCV advocate and HCV new drug pipeline provided below.
HCV Advocate
Hepatitis C New Drug Pipeline
Another important drug in the mix is a cyclophilin inhibitor that disrupts a host function required for viral replication. This cyclophilin inhibitor formally known as DEB 025 is alisporivir from Novartis.
At the EASL in 2011 results from a Phase two study of 300 HCV genotype 1 treatment-naïve patients who were treated with alisporivir plus peg and ribavirin reported a 76% SVR rate in the group that was treated for 48 weeks compared to 55% in the group that received peg plus ribavirin without alisporivir.
Right, at the AASLD meeting in 2011 we heard of an interferon-free arm of alisporivir monotherapy and alisporivir plus ribavirin, It was reported that at week 6, 49% HCV genotype 2 and 3 treatment-naïve patients were HCV RNA undetectable. This was the highest rates seen in the alisporivir plus ribavirin arms.
The word is that these three experimental drugs,TMC 435, BI 201335 and alisporivir could be available in 2 years.
Speaking of interferon free, may we?
Yes, two drugs made headlines recently. They are Asunaprevir formally known as BMS-650032 and Daclatasvir formally known as BMS-790052 both drugs are made by Bristol-Myers Squibb.
A new term here is Quadruple Therapy. First off the four drugs used in combination were asunaprevir, daclatasvir, peg and ribavirin .The ten patients treated with all four drugs all had undetectable viral levels 12 weeks after treatment stopped, and nine still had undetectable levels after 24 and 48 weeks. This is where it gets exciting. Another 11 patients received only asunaprevir and daclatasvir, and four of them had a sustained virologic response at 12 and 24 weeks after treatment.
Daclatasvir is the first NS5A replication complex inhibitor to be investigated in HCV clinical trials and is currently in Phase III development. Asunaprevir is an investigational, oral, selective NS3 protease inhibitor. Please click on the link below to view the full results.
Hepatitis C Pills Clear Virus Without Injections
Another all oral combination in phase two trials is from Bristol-Myers Squibb and Pharmasset. The experimental combo of drugs are PSI-7977 and Daclatasvir (formally known as BMS-790052).
Thats right, the Phase two studies will evaluate the potential to achieve sustained virologic response 24 weeks post treatment or cure with an oral, once-daily treatment regimen in patients across HCV genotypes 1, 2 and 3. Specifically, the study will assess the safety, pharmacokinetics and pharmacodynamics of Daclatasvir-BMS-790052 in combination with PSI-7977, with and without ribavirin in 84 treatment-naïve patients chronically infected with HCV genotypes 1, 2, and 3.
Hey bear, in November of last year they added two new treatment arms with 120 HCV genotype 1 treatment-naïve patients. Both treatment arms will study the combination of PSI-7977 and BMS-790052 with and without ribavirin for a total treatment duration of 12 weeks.
This brings us to the phase two trial with PSI-7977 and TMC 435. According to the press release this past November from Medivir and Tibotec the interferon free combination will evaluate the two combination with and without ribavirin for 12 and 24 weeks in genotype 1 patients who had a prior null response to standard therapy.
We only covered a few drugs in this video today bear, I hope our listeners will click on the links below to view all the new drugs in development
HCV Advocate
Hepatitis C New Drug Pipeline
Advances will continue in the race for improved hepatitis C treatments. With more direct acting antiviral combination trials to come The dream is to cure all patients with hepatitis C, and to eliminate interferon and maybe even ribavirin from HCV therapy.
Until next time, say goodbye bear
Goodbye bear
Current Recommendations for Using Telaprevir and Boceprevir in Patients With Advanced Fibrosis or Cirrhosis
Paul J. Pockros, MD
Head, Division of Gastroenterology/Hepatology
Director, SC Liver Research Consortium
Clinical Director of Research, Scripps Translational Science Institute
The Scripps Clinic
La Jolla, California
Editor’s note: In this edition of Journal Options Hepatitis, we feature the 5 pivotal phase III studies that led to the approval in 2011 of boceprevir and telaprevir for the treatment of chronic hepatitis C. Each commentary in this series addresses a key issue or question of clinical relevance related to the use of these agents in clinical practice.
Patients with cirrhosis or advanced fibrosis due to hepatitis C virus (HCV) are a particularly challenging group to treat with combination therapy that includes 1 of the currently approved direct-acting antivirals (DAA), boceprevir or telaprevir. Patients with decompensated cirrhosis have the greatest need for curative therapy; however, these individuals were not studied in the pivotal trials of boceprevir and telaprevir and are not included in the prescribing information for either drug; therefore, there is significant risk associated with treating this group of patients in the absence of experience or guidelines.[1-3] Although patients with compensated cirrhosis were included in the phase III trials of both telaprevir and boceprevir, the number of these patients is too small on which to base treatment decisions with confidence. Furthermore, patients with cirrhosis who failed previous therapy—individuals comprising a significant proportion of our current patient population—do not respond as well as others to triple therapy and will often develop protease inhibitor–resistant variants at the time of treatment failure.[4]
So how should clinicians go about implementing telaprevir and boceprevir as treatment in patients with advanced fibrosis or cirrhosis? Here I describe what we know about telaprevir and boceprevir in patients with advanced liver disease based on data from the pivotal clinical trials, along with how my colleagues and I currently go about treating these individuals in clinical practice.
Compensated Cirrhosis
Implementing Telaprevir and Boceprevir
The combined data for patients with compensated cirrhosis in all 3 phase III trials of telaprevir revealed an overall sustained virologic response (SVR) rate of 62%, and combined data in fixed-duration and response-guided arms for boceprevir demonstrated an SVR rate of 48%, rates which are certainly high enough to warrant treating compensated cirrhosis.[5-9] Notably, the addition of IL28B testing does not provide sufficient specificity to aid in predicting which cases are likely to fail treatment, and thus we do not use this routinely in my practice for cirrhotic patients.[10,11]
Data from the REALIZE trial showed much lower SVR rates with telaprevir-based therapy among previous null responders to peginterferon/ribavirin with cirrhosis (14%) or bridging fibrosis (30%).[7] Similar data are not available for boceprevir because of the exclusion of null responders in the RESPOND-2 trial.[9] Subanalysis of the arm from REALIZE that received 4 weeks of lead-in treatment with peginterferon/ribavirin before addition of telaprevir indicated that a < 1 log10 IU/mL decrease in HCV RNA at Week 4 was associated with treatment failure in patients with compensated cirrhosis, whereas a ≥ 1 log10 IU/mL decrease in HCV RNA was associated with SVR in approximately 50%.[12] Although it is not recommended in the prescribing information for telaprevir, based on these findings, my colleagues and I routinely employ a 4-week peginterferon/ribavirin lead-in for all null responder patients with advanced liver fibrosis, and we do not initiate telaprevir until the HCV RNA value at Week 4 has been reviewed. For treatment-experienced patients lacking interferon sensitivity, we defer therapy for future clinical trials of quadruple therapy or interferon-free regimens (eg, daclatasvir, asunaprevir, and peginterferon/ribavirin; PSI-7977 plus ribavirin; others).[13]
Similarly, when planning to use boceprevir in patients with compensated cirrhosis, my colleagues and I implement the 4-week peginterferon/ribavirin lead-in phase, as indicated in the boceprevir prescribing information.[2] We wait to see the HCV RNA results at Week 4 before deciding whether to expose patients to boceprevir. If patients do not have at least a 1-log10 reduction in HCV RNA from baseline, we defer therapy or enroll patients in clinical trials. Other experts follow the recommendations in the prescribing information and continue therapy until the 12-week futility rule evaluation point and use response at this time point to determine whether treatment should be continued.
Duration of Therapy
Although we have no published data regarding the benefit of extending peginterferon/ribavirin therapy to 48 weeks in cirrhotic patients who achieve an extended rapid virologic response (ie, undetectable HCV RNA at Weeks 4 and 12) on telaprevir/peginterferon/ribavirin, the telaprevir prescribing information provides a small amount of data on this issue. Of 30 patients with cirrhosis who achieved an extended rapid virologic response, 67% (12 of 18) attained SVR when the duration of peginterferon/ribavirin was shortened to 24 weeks, and 92% (11 of 12) attained SVR when peginterferon/ribavirin was administered for the full 48 weeks.[1] These are very small numbers on which to base treatment decisions, and we need more robust studies in cirrhotics to evaluate the duration of peginterferon/ribavirin therapy when combined with telaprevir. Because these data are not yet available, I administer peginterferon/ribavirin for the full 48 weeks in cirrhotic patients if they can tolerate it; I shorten therapy to 24 weeks if they cannot.
With regard to boceprevir, the prescribing information clearly indicates that patients with compensated cirrhosis should receive 4 weeks of peginterferon/ribavirin followed by 44 weeks of boceprevir in combination with peginterferon/ribavirin.[2] This is based on data from clinical trials that clearly show a benefit of fixed-duration rather than response-guided therapy in this population.[2] Although the numbers are again small, among treatment-naive cirrhotic patients, SVR rates were 42% (10 of 24) with a fixed-duration 48-week regimen vs 31% (5 of 16) when response-guided therapy was employed. Among treatment-naive individuals, SVR rates were 77% (17 of 22) and 35% (6 of 17), respectively, with fixed vs response-guided therapy. Thus, when treating with boceprevir, I administer the recommended 48 weeks of peginterferon/ribavirin in cirrhotic patients if they can tolerate it. If the patient is unable to tolerate 48 weeks of peginterferon plus ribavirin, we push duration as long as possible to that point, but at least 24 weeks. It is expected that shortened durations of therapy would compromise efficacy.
Dosing
No dosage adjustment of boceprevir is recommended for patients with mild, moderate, or severe hepatic impairment.[2] Dose modification of telaprevir is not required when it is administered to patients with mild hepatic impairment (Child-Pugh A, score 5-6), although a 15% reduction in steady-state exposure was observed in HCV-negative subjects with mild hepatic impairment compared with healthy subjects.[1] When my colleagues and I treat patients with compensated cirrhosis with telaprevir, we do not adjust the telaprevir dosage. However, when treating patients with compensated cirrhosis with either protease inhibitor, we monitor weekly for expected reductions in white and red blood cell counts, and we implement higher thresholds for reducing the dosage of peginterferon or ribavirin when declines in absolute neutrophil count and hemoglobin occur. Specifically, we will normally dose-reduce ribavirin for hemoglobin levels < 10 g/dL and peginterferon for an absolute neutrophil count < 500.For more information on anemia management, see the accompanying commentary by Brian Pearlman.
Decompensated Cirrhosis
Telaprevir is not recommended for use in patients with moderate or severe hepatic impairment (Child-Pugh B or C, score ≥ 7).[1] My colleagues and I have selected a few patients with a prior history of a single decompensation event (eg, a remote history of variceal bleeding followed by stability and low Model of End-Stage Liver Disease scores for years) to undergo triple therapy with telaprevir/peginterferon/ribavirin. This was done only after patients completed a transplant evaluation and were approved and/or listed. Thus far, 3 of 6 patients have decompensated (1 from hepatic encephalopathy, 2 because of new-onset ascites with spontaneous bacterial peritonitis), likely due to the peginterferon component of the regimen. All 3 patients were hospitalized and treatment was stopped; all recovered.
The safety and efficacy of boceprevir have not been studied in patients with decompensated cirrhosis, and the poor safety and tolerability of peginterferon/ribavirin in patients with decompensated cirrhosis remains a contraindication to treatment in this population.[8,9] My colleagues and I have not yet treated patients with decompensated cirrhosis with boceprevir. However, the data in cirrhotics in the pivotal trials of boceprevir were equally as good as those with telaprevir, so we are currently beginning to start patients on this regimen.
To date, treatment with protease inhibitor–based therapy in decompensated cirrhotics cannot be recommended outside of centers highly experienced in the management of this patient population.
Please review the remaining 4 commentaries in this series on the use of boceprevir and telaprevir in clinical practice:
2. Victrelis [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
3. Ghany MG, Nelson DR, Strader DB, et al. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:1433-1444.
4. Pockros PJ. Drugs in development for viral hepatitis: care and caution. Drugs. 2011;71:263-271.
5. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416.
6. Sherman KE, Flamm SL, Afdhal NH, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011;365:1014-1024.
7. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417-2428.
8. Poordad F, McCone J, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.
9. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207-1217.
10. Pol S, Aerssens J, Zeuzem S, et al. Similar SVR rates in IL28B CC, CT or TT prior relapser, partial- or null-responder patients treated with telaprevir/peginterferon/ribavirin: retrospective analysis of the REALIZE study. J Hepatol. 2011;54(suppl 1):S6.
11. Poordad F, Bronowicki JP, Gordon SC, et al. IL28B polymorphism predicts virologic response in patients with hepatitis C genotype 1 treated with boceprevir (BOC) combination therapy. Program and abstracts of the 46th Annual Meeting of the European Association for the Study of the Liver; March 30 - April 3, 2011; Berlin, Germany. Abstract 12.
12. Zeuzem S, Foster GR, Andreone P, et al. Different likelihood of achieving SVR on a telaprevir-containing regimen among null responders, partial responders and relapsers irrespective of similar responses after a peginterferon/ribavirin 4-week lead-in phase: REALIZE study subanalysis. Hepatology. 2011;54(suppl):986A.
13. Lok A, Gardiner D, Lawitz E, et al. Quadruple therapy with BMS-790052, BMS-650032 and PEG-IFN/RBV for 24 weeks results in 100% SVR12 in HCV genotype 1 null responders. J Hepatol. 2011;54(suppl 1):S536.
Link to the original abstract
Paul J. Pockros, MD
Posting Date: December 19, 2011
Director, SC Liver Research Consortium
Clinical Director of Research, Scripps Translational Science Institute
The Scripps Clinic
La Jolla, California
Editor’s note: In this edition of Journal Options Hepatitis, we feature the 5 pivotal phase III studies that led to the approval in 2011 of boceprevir and telaprevir for the treatment of chronic hepatitis C. Each commentary in this series addresses a key issue or question of clinical relevance related to the use of these agents in clinical practice.
Patients with cirrhosis or advanced fibrosis due to hepatitis C virus (HCV) are a particularly challenging group to treat with combination therapy that includes 1 of the currently approved direct-acting antivirals (DAA), boceprevir or telaprevir. Patients with decompensated cirrhosis have the greatest need for curative therapy; however, these individuals were not studied in the pivotal trials of boceprevir and telaprevir and are not included in the prescribing information for either drug; therefore, there is significant risk associated with treating this group of patients in the absence of experience or guidelines.[1-3] Although patients with compensated cirrhosis were included in the phase III trials of both telaprevir and boceprevir, the number of these patients is too small on which to base treatment decisions with confidence. Furthermore, patients with cirrhosis who failed previous therapy—individuals comprising a significant proportion of our current patient population—do not respond as well as others to triple therapy and will often develop protease inhibitor–resistant variants at the time of treatment failure.[4]
So how should clinicians go about implementing telaprevir and boceprevir as treatment in patients with advanced fibrosis or cirrhosis? Here I describe what we know about telaprevir and boceprevir in patients with advanced liver disease based on data from the pivotal clinical trials, along with how my colleagues and I currently go about treating these individuals in clinical practice.
Compensated Cirrhosis
Implementing Telaprevir and Boceprevir
The combined data for patients with compensated cirrhosis in all 3 phase III trials of telaprevir revealed an overall sustained virologic response (SVR) rate of 62%, and combined data in fixed-duration and response-guided arms for boceprevir demonstrated an SVR rate of 48%, rates which are certainly high enough to warrant treating compensated cirrhosis.[5-9] Notably, the addition of IL28B testing does not provide sufficient specificity to aid in predicting which cases are likely to fail treatment, and thus we do not use this routinely in my practice for cirrhotic patients.[10,11]
Data from the REALIZE trial showed much lower SVR rates with telaprevir-based therapy among previous null responders to peginterferon/ribavirin with cirrhosis (14%) or bridging fibrosis (30%).[7] Similar data are not available for boceprevir because of the exclusion of null responders in the RESPOND-2 trial.[9] Subanalysis of the arm from REALIZE that received 4 weeks of lead-in treatment with peginterferon/ribavirin before addition of telaprevir indicated that a < 1 log10 IU/mL decrease in HCV RNA at Week 4 was associated with treatment failure in patients with compensated cirrhosis, whereas a ≥ 1 log10 IU/mL decrease in HCV RNA was associated with SVR in approximately 50%.[12] Although it is not recommended in the prescribing information for telaprevir, based on these findings, my colleagues and I routinely employ a 4-week peginterferon/ribavirin lead-in for all null responder patients with advanced liver fibrosis, and we do not initiate telaprevir until the HCV RNA value at Week 4 has been reviewed. For treatment-experienced patients lacking interferon sensitivity, we defer therapy for future clinical trials of quadruple therapy or interferon-free regimens (eg, daclatasvir, asunaprevir, and peginterferon/ribavirin; PSI-7977 plus ribavirin; others).[13]
Similarly, when planning to use boceprevir in patients with compensated cirrhosis, my colleagues and I implement the 4-week peginterferon/ribavirin lead-in phase, as indicated in the boceprevir prescribing information.[2] We wait to see the HCV RNA results at Week 4 before deciding whether to expose patients to boceprevir. If patients do not have at least a 1-log10 reduction in HCV RNA from baseline, we defer therapy or enroll patients in clinical trials. Other experts follow the recommendations in the prescribing information and continue therapy until the 12-week futility rule evaluation point and use response at this time point to determine whether treatment should be continued.
Duration of Therapy
Although we have no published data regarding the benefit of extending peginterferon/ribavirin therapy to 48 weeks in cirrhotic patients who achieve an extended rapid virologic response (ie, undetectable HCV RNA at Weeks 4 and 12) on telaprevir/peginterferon/ribavirin, the telaprevir prescribing information provides a small amount of data on this issue. Of 30 patients with cirrhosis who achieved an extended rapid virologic response, 67% (12 of 18) attained SVR when the duration of peginterferon/ribavirin was shortened to 24 weeks, and 92% (11 of 12) attained SVR when peginterferon/ribavirin was administered for the full 48 weeks.[1] These are very small numbers on which to base treatment decisions, and we need more robust studies in cirrhotics to evaluate the duration of peginterferon/ribavirin therapy when combined with telaprevir. Because these data are not yet available, I administer peginterferon/ribavirin for the full 48 weeks in cirrhotic patients if they can tolerate it; I shorten therapy to 24 weeks if they cannot.
With regard to boceprevir, the prescribing information clearly indicates that patients with compensated cirrhosis should receive 4 weeks of peginterferon/ribavirin followed by 44 weeks of boceprevir in combination with peginterferon/ribavirin.[2] This is based on data from clinical trials that clearly show a benefit of fixed-duration rather than response-guided therapy in this population.[2] Although the numbers are again small, among treatment-naive cirrhotic patients, SVR rates were 42% (10 of 24) with a fixed-duration 48-week regimen vs 31% (5 of 16) when response-guided therapy was employed. Among treatment-naive individuals, SVR rates were 77% (17 of 22) and 35% (6 of 17), respectively, with fixed vs response-guided therapy. Thus, when treating with boceprevir, I administer the recommended 48 weeks of peginterferon/ribavirin in cirrhotic patients if they can tolerate it. If the patient is unable to tolerate 48 weeks of peginterferon plus ribavirin, we push duration as long as possible to that point, but at least 24 weeks. It is expected that shortened durations of therapy would compromise efficacy.
Dosing
No dosage adjustment of boceprevir is recommended for patients with mild, moderate, or severe hepatic impairment.[2] Dose modification of telaprevir is not required when it is administered to patients with mild hepatic impairment (Child-Pugh A, score 5-6), although a 15% reduction in steady-state exposure was observed in HCV-negative subjects with mild hepatic impairment compared with healthy subjects.[1] When my colleagues and I treat patients with compensated cirrhosis with telaprevir, we do not adjust the telaprevir dosage. However, when treating patients with compensated cirrhosis with either protease inhibitor, we monitor weekly for expected reductions in white and red blood cell counts, and we implement higher thresholds for reducing the dosage of peginterferon or ribavirin when declines in absolute neutrophil count and hemoglobin occur. Specifically, we will normally dose-reduce ribavirin for hemoglobin levels < 10 g/dL and peginterferon for an absolute neutrophil count < 500.For more information on anemia management, see the accompanying commentary by Brian Pearlman.
Decompensated Cirrhosis
Telaprevir is not recommended for use in patients with moderate or severe hepatic impairment (Child-Pugh B or C, score ≥ 7).[1] My colleagues and I have selected a few patients with a prior history of a single decompensation event (eg, a remote history of variceal bleeding followed by stability and low Model of End-Stage Liver Disease scores for years) to undergo triple therapy with telaprevir/peginterferon/ribavirin. This was done only after patients completed a transplant evaluation and were approved and/or listed. Thus far, 3 of 6 patients have decompensated (1 from hepatic encephalopathy, 2 because of new-onset ascites with spontaneous bacterial peritonitis), likely due to the peginterferon component of the regimen. All 3 patients were hospitalized and treatment was stopped; all recovered.
The safety and efficacy of boceprevir have not been studied in patients with decompensated cirrhosis, and the poor safety and tolerability of peginterferon/ribavirin in patients with decompensated cirrhosis remains a contraindication to treatment in this population.[8,9] My colleagues and I have not yet treated patients with decompensated cirrhosis with boceprevir. However, the data in cirrhotics in the pivotal trials of boceprevir were equally as good as those with telaprevir, so we are currently beginning to start patients on this regimen.
To date, treatment with protease inhibitor–based therapy in decompensated cirrhotics cannot be recommended outside of centers highly experienced in the management of this patient population.
Please review the remaining 4 commentaries in this series on the use of boceprevir and telaprevir in clinical practice:
- To review strategies for management of telaprevir-associated rash and anorectal symptoms, click here.
- For a better understanding of futility rules and their importance with boceprevir and telaprevir, click here.
- To review the impact of the occurrence and management of anemia with boceprevir and telaprevir, click here.
- To review rules for following response-guided therapy guidelines with telaprevir and boceprevir, click here.
1. Incivek [package insert]. Cambridge, Mass: Vertex Pharmaceuticals Inc.; 2011.
2. Victrelis [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
3. Ghany MG, Nelson DR, Strader DB, et al. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:1433-1444.
4. Pockros PJ. Drugs in development for viral hepatitis: care and caution. Drugs. 2011;71:263-271.
5. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416.
6. Sherman KE, Flamm SL, Afdhal NH, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011;365:1014-1024.
7. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417-2428.
8. Poordad F, McCone J, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.
9. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207-1217.
10. Pol S, Aerssens J, Zeuzem S, et al. Similar SVR rates in IL28B CC, CT or TT prior relapser, partial- or null-responder patients treated with telaprevir/peginterferon/ribavirin: retrospective analysis of the REALIZE study. J Hepatol. 2011;54(suppl 1):S6.
11. Poordad F, Bronowicki JP, Gordon SC, et al. IL28B polymorphism predicts virologic response in patients with hepatitis C genotype 1 treated with boceprevir (BOC) combination therapy. Program and abstracts of the 46th Annual Meeting of the European Association for the Study of the Liver; March 30 - April 3, 2011; Berlin, Germany. Abstract 12.
12. Zeuzem S, Foster GR, Andreone P, et al. Different likelihood of achieving SVR on a telaprevir-containing regimen among null responders, partial responders and relapsers irrespective of similar responses after a peginterferon/ribavirin 4-week lead-in phase: REALIZE study subanalysis. Hepatology. 2011;54(suppl):986A.
13. Lok A, Gardiner D, Lawitz E, et al. Quadruple therapy with BMS-790052, BMS-650032 and PEG-IFN/RBV for 24 weeks results in 100% SVR12 in HCV genotype 1 null responders. J Hepatol. 2011;54(suppl 1):S536.
Link to the original abstract
Hepatitis C Drug Victrelis-Boceprevir released for public use in Australia.
A RECENTLY developed treatment for the most common form of hepatitis C has been approved for use in Australia by the Therapeutic Goods Administration (TGA).
Victrelis, also known as boceprevir, comes from a group of drugs known as a protease inhibitors.
Scientists say it is an effective way to fight hepatitis C, genotype 1.
The director of the AW Morrow Gastroenterology and Liver Centre in Sydney, Professor Geoff McCaughan, says people who suffer from this strand of hepatitis C now have their first new treatment option in a decade.
"In the last ten years there has been little development in the availability of treatments for hepatitis C and a significant proportion of patients fail to respond to current standard of care." Professor McCaughan said in a statement.
"Victrelis is an approved treatment that works directly on the hepatitis C virus and prevents it from replicating and therefore reproducing."
He said this was a big step forward in the battle against hepatitis C, genotype 1.
"Unfortunately, hepatitis C is a silent disease where there is very little awareness of the condition and patients often present late with severe complications.
"Hepatitis C is a huge burden for individuals and is still very heavily stigmatised, and having another new treatment option marks progress in the management of patients with the disease."
Hepatitis C affects more than 200,000 Australians, with 20,000 new cases reported each year.
A spokeswoman for the TGA said now that Victrelis had been approved it had been released for public use.
The Pharmaceutical Benefits Scheme Committee is to consider listing the drug at its March meeting.
Victrelis, also known as boceprevir, comes from a group of drugs known as a protease inhibitors.
Scientists say it is an effective way to fight hepatitis C, genotype 1.
The director of the AW Morrow Gastroenterology and Liver Centre in Sydney, Professor Geoff McCaughan, says people who suffer from this strand of hepatitis C now have their first new treatment option in a decade.
"In the last ten years there has been little development in the availability of treatments for hepatitis C and a significant proportion of patients fail to respond to current standard of care." Professor McCaughan said in a statement.
"Victrelis is an approved treatment that works directly on the hepatitis C virus and prevents it from replicating and therefore reproducing."
"Unfortunately, hepatitis C is a silent disease where there is very little awareness of the condition and patients often present late with severe complications.
"Hepatitis C is a huge burden for individuals and is still very heavily stigmatised, and having another new treatment option marks progress in the management of patients with the disease."
Hepatitis C affects more than 200,000 Australians, with 20,000 new cases reported each year.
A spokeswoman for the TGA said now that Victrelis had been approved it had been released for public use.
The Pharmaceutical Benefits Scheme Committee is to consider listing the drug at its March meeting.
Monday, January 30, 2012
Stem cells may shed light on hepatitis C, MIT researchers find
Stem cells may shed light on hepatitis, MIT researchers find
By Lori Valigra
Researchers at MIT and their colleagues said they have devised a way to produce liver-like cells from stem cells, a key step in studying why people respond differently to Hepatitis C.
An infectious disease that can cause inflammation and organ failure, Hepatitis C has different effects on different people, but no one is sure why, the researchers said in a press release from MIT. Some people are very susceptible to the infection, while others are resistant.
The researchers said that by studying liver cells from different people in the lab, they may determine how genetic differences produce these varying responses. However, liver cells are hard to get and very difficult to grow in a lab dish because they tend to lose their normal structure and function when removed from the body.
The researchers, from MIT, Rockefeller University and the Medical College of Wisconsin, have come up with a way to produce liver-like cells from induced pluripotent stem cells (iPSCs), which are made from body tissues rather than embryos. Those liver-like cells can then be infected with Hepatitis C and help scientists study the varying responses to the infection.
The scientists claim this is the first time an infection has been made in cells derived from iPSCs. Their new technique is described in the Jan. 30 issue of the Proceedings of the National Academy of Sciences. The development, they said, may also eventually enable personalized medicine, in which doctors could test the effect of different drugs on tissues derived from the patient being treated and then customize therapy for that patient.
The new study is a collaboration between Sangeeta Bhatia, professor of health sciences and technology and electrical engineering and computer science at MIT; Charles Rice, professor of virology at Rockefeller; and Stephen Duncan, professor of human and molecular genetics at the Medical College of Wisconsin.
The iPSCs are derived from normal body cells, often skin cells. By turning on certain genes in those cells, the scientists can revert them to an immature state that is identical to embryonic stem cells, which can turn into any cell type. Once the cells become pluripotent, they can be directed to become liver-like cells by turning on genes that control liver development.
The researchers’ goal is to take cells from patients who have unusual reactions to hepatitis C infection, transform them into liver cells and study their genetics to see why people respond as they do. “Hepatitis C virus causes an unusually robust infection in some people, while others are very good at clearing it. It’s not yet known why those differences exist,” Bhatia said in a statement.
By Lori Valigra
Researchers at MIT and their colleagues said they have devised a way to produce liver-like cells from stem cells, a key step in studying why people respond differently to Hepatitis C.
An infectious disease that can cause inflammation and organ failure, Hepatitis C has different effects on different people, but no one is sure why, the researchers said in a press release from MIT. Some people are very susceptible to the infection, while others are resistant.
The researchers said that by studying liver cells from different people in the lab, they may determine how genetic differences produce these varying responses. However, liver cells are hard to get and very difficult to grow in a lab dish because they tend to lose their normal structure and function when removed from the body.
The researchers, from MIT, Rockefeller University and the Medical College of Wisconsin, have come up with a way to produce liver-like cells from induced pluripotent stem cells (iPSCs), which are made from body tissues rather than embryos. Those liver-like cells can then be infected with Hepatitis C and help scientists study the varying responses to the infection.
The scientists claim this is the first time an infection has been made in cells derived from iPSCs. Their new technique is described in the Jan. 30 issue of the Proceedings of the National Academy of Sciences. The development, they said, may also eventually enable personalized medicine, in which doctors could test the effect of different drugs on tissues derived from the patient being treated and then customize therapy for that patient.
The new study is a collaboration between Sangeeta Bhatia, professor of health sciences and technology and electrical engineering and computer science at MIT; Charles Rice, professor of virology at Rockefeller; and Stephen Duncan, professor of human and molecular genetics at the Medical College of Wisconsin.
The iPSCs are derived from normal body cells, often skin cells. By turning on certain genes in those cells, the scientists can revert them to an immature state that is identical to embryonic stem cells, which can turn into any cell type. Once the cells become pluripotent, they can be directed to become liver-like cells by turning on genes that control liver development.
The researchers’ goal is to take cells from patients who have unusual reactions to hepatitis C infection, transform them into liver cells and study their genetics to see why people respond as they do. “Hepatitis C virus causes an unusually robust infection in some people, while others are very good at clearing it. It’s not yet known why those differences exist,” Bhatia said in a statement.
Hepatitis C News Ticker: The ELF test-Blood Test Instead of Liver Biopsy?
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In The News
Researchers at MIT and their colleagues said they have devised a way to produce liver-like cells from stem cells, a key step in studying why people respond differently to Hepatitis C.
An infectious disease that can cause inflammation and organ failure, Hepatitis C has different effects on different people, but no one is sure why, the researchers said in a press release from MIT. Some people are very susceptible to the infection, while others are resistant.
The researchers said that by studying liver cells from different people in the lab, they may determine how genetic differences produce these varying responses. However, liver cells are hard to get and very difficult to grow in a lab dish because they tend to lose their normal structure and function when removed from the body.
The researchers, from MIT, Rockefeller University and the Medical College of Wisconsin, have come up with a way to produce liver-like cells from induced pluripotent stem cells (iPSCs), which are made from body tissues rather than embryos. Those liver-like cells can then be infected with Hepatitis C and help scientists study the varying responses to the infection.
The scientists claim this is the first time an infection has been made in cells derived from iPSCs. Their new technique is described in the Jan. 30 issue of the Proceedings of the National Academy of Sciences. The development, they said, may also eventually enable personalized medicine, in which doctors could test the effect of different drugs on tissues derived from the patient being treated and then customize therapy for that patient.
The new study is a collaboration between Sangeeta Bhatia, professor of health sciences and technology and electrical engineering and computer science at MIT; Charles Rice, professor of virology at Rockefeller; and Stephen Duncan, professor of human and molecular genetics at the Medical College of Wisconsin.
The iPSCs are derived from normal body cells, often skin cells. By turning on certain genes in those cells, the scientists can revert them to an immature state that is identical to embryonic stem cells, which can turn into any cell type. Once the cells become pluripotent, they can be directed to become liver-like cells by turning on genes that control liver development.
The researchers’ goal is to take cells from patients who have unusual reactions to hepatitis C infection, transform them into liver cells and study their genetics to see why people respond as they do. “Hepatitis C virus causes an unusually robust infection in some people, while others are very good at clearing it. It’s not yet known why those differences exist,” Bhatia said in a statement.
Blood Test Instead of Biopsy Identifies Liver Damage
An infectious disease that can cause inflammation and organ failure, Hepatitis C has different effects on different people, but no one is sure why, the researchers said in a press release from MIT. Some people are very susceptible to the infection, while others are resistant.
The researchers said that by studying liver cells from different people in the lab, they may determine how genetic differences produce these varying responses. However, liver cells are hard to get and very difficult to grow in a lab dish because they tend to lose their normal structure and function when removed from the body.
The researchers, from MIT, Rockefeller University and the Medical College of Wisconsin, have come up with a way to produce liver-like cells from induced pluripotent stem cells (iPSCs), which are made from body tissues rather than embryos. Those liver-like cells can then be infected with Hepatitis C and help scientists study the varying responses to the infection.
The scientists claim this is the first time an infection has been made in cells derived from iPSCs. Their new technique is described in the Jan. 30 issue of the Proceedings of the National Academy of Sciences. The development, they said, may also eventually enable personalized medicine, in which doctors could test the effect of different drugs on tissues derived from the patient being treated and then customize therapy for that patient.
The new study is a collaboration between Sangeeta Bhatia, professor of health sciences and technology and electrical engineering and computer science at MIT; Charles Rice, professor of virology at Rockefeller; and Stephen Duncan, professor of human and molecular genetics at the Medical College of Wisconsin.
The iPSCs are derived from normal body cells, often skin cells. By turning on certain genes in those cells, the scientists can revert them to an immature state that is identical to embryonic stem cells, which can turn into any cell type. Once the cells become pluripotent, they can be directed to become liver-like cells by turning on genes that control liver development.
The researchers’ goal is to take cells from patients who have unusual reactions to hepatitis C infection, transform them into liver cells and study their genetics to see why people respond as they do. “Hepatitis C virus causes an unusually robust infection in some people, while others are very good at clearing it. It’s not yet known why those differences exist,” Bhatia said in a statement.
Blood Test Instead of Biopsy Identifies Liver Damage
Siemens is marketing the first rapid, automated biomarker test for diagnosing and assessing liver fibrosis. The ELF test (Enhanced Liver Fibrosis test) takes approximately one hour to complete and requires only a blood sample
The new test was developed by Siemens Healthcare in collaboration with University College London and can be used as a routine test on the Siemens ADVIA Centaur Immunoassay System.
Liver fibrosis is the result of chronic liver damage caused by vi-ral hepatitis, alcoholic cirrhosis, or fatty liver disease. It is characterized by scarring of the liver tissue, which can lead to cirrhosis or cancer of the liver over the long term — a frequent cause of death worldwide.
At present, the “gold standard” for assessing the severity of a liver fibrosis is a liver biopsy, which involves the removal of a small amount of liver tissue. This biopsy has drawbacks, however: It is painful; it entails some risk for the patient; and it tests only a small sample of the liver.
With the automated ADVIA Centaur ELF Test, a fast and mini-mally invasive technique is now available for determining both the severity of a liver fibrosis and the risk that it will worsen. The test examines three direct blood serum biomarkers: hyaluronic acid (HA), procollagen III N-terminal propeptide (PIIINP), and the tissue inhibitor of metalloproteinase 1 (TIMP-1). These direct biomarkers are molecules that are involved in the formation of fibrosis. In the test, special reagents react with the biomarkers and generate light in the process. The greater the intensity of this chemiluminescence, the greater the presence of the biomarker.
A special algorithm is used to convert the results of the three biomarkers into the ELF score, which indicates the degree of fibrosis. The combination of three biomarkers increases the accuracy of the test. As an international clinical trial has shown, the ELF test can precisely differentiate between slight, moderate, and serious cases of fibrosis. In the event of slight or moderate fibrosis, patients normally have no symptoms. Doctors can thus intervene before significant damage to the liver and monitor the progress of therapy.
To complement the ELF test, Siemens is also offering imaging and laboratory diagnostic technologies like hepatitis blood tests and ultrasound systems that help physicians identify liver fibrosis at an early stage and monitor its development.
Dr. Norbert Aschenbrenner | Source: Siemens Innovation News
Further information: www.siemens.com/innovationnews
A molecule in liver cell membranes that plays a role in cholesterol uptake also enables hepatitis C virus (HCV) to enter cells, according to research reported in the January 8, 2012, advance online edition of Nature Medicine.
Vertex Falls as Analyst Cuts Sales Estimates on Hepatitis C Pill
Vertex Pharmaceuticals Inc. (VRTX) fell the most in two months after an analyst with Leerink Swann & Co. cut sales predictions for the company’s hepatitis C pill that was approved by U.S. regulators last year.
Vertex’s Incivek, among the first new hepatitis C drugs to reach the market in nearly a decade, could be eclipsed by new pill-only treatments with fewer side effects and shorter courses of treatment. Incivek is given with interferon, an injected medicine. Merck & Co.’s similar pill, Victrelis, was also approved last year.
Shares of Cambridge, Massachusetts-based Vertex fell 4.2 percent to $34.48 at 10:18 a.m., after declining 5.2 percent in the biggest intraday drop since Nov. 14.
Howard Liang, an analyst with Leerink Swann in Boston, cut his sales forecast for Incivek by 35 percent from $2.3 billion this year to $1.5 billion. Liang also cut his target price for Vertex shares from $66 to $48.
“In light of recent development of interferon-free regimens and likely more aggressive development as a result of recent transactions in the space, we are further curtailing the Incivek tail,” Liang said in a note to clients today.
Vertex had $420 million in revenue from Incivek in the third quarter of 2011. Revenue from the drug accounts for 64 percent of the company’s sales.
To contact the reporter on this story: Drew Armstrong in Washington at darmstrong17@bloomberg.net;
Liver Cancer
Big Pharma
Vertex Falls as Analyst Cuts Sales Estimates on Hepatitis C Pill
Vertex Pharmaceuticals Inc. (VRTX) fell the most in two months after an analyst with Leerink Swann & Co. cut sales predictions for the company’s hepatitis C pill that was approved by U.S. regulators last year.
Vertex’s Incivek, among the first new hepatitis C drugs to reach the market in nearly a decade, could be eclipsed by new pill-only treatments with fewer side effects and shorter courses of treatment. Incivek is given with interferon, an injected medicine. Merck & Co.’s similar pill, Victrelis, was also approved last year.
Shares of Cambridge, Massachusetts-based Vertex fell 4.2 percent to $34.48 at 10:18 a.m., after declining 5.2 percent in the biggest intraday drop since Nov. 14.
Howard Liang, an analyst with Leerink Swann in Boston, cut his sales forecast for Incivek by 35 percent from $2.3 billion this year to $1.5 billion. Liang also cut his target price for Vertex shares from $66 to $48.
“In light of recent development of interferon-free regimens and likely more aggressive development as a result of recent transactions in the space, we are further curtailing the Incivek tail,” Liang said in a note to clients today.
Vertex had $420 million in revenue from Incivek in the third quarter of 2011. Revenue from the drug accounts for 64 percent of the company’s sales.
To contact the reporter on this story: Drew Armstrong in Washington at darmstrong17@bloomberg.net;
Liver Cancer
by George Ochoa
Two Mayo Clinic studies have clarified the importance of chronic hepatitis C virus (HCV) in the rising trend of liver cancer, or hepatocellular carcinoma (HCC).
One study (Yang et al. Mayo Clin Proc. 2012;87:9-16) analyzed longitudinal trends in the incidence, etiology, treatment of HCC and survival in community residents in Olmsted County, Minn. The researchers found that in earlier periods (1976-1990, 1991-2000), alcohol use was the most common risk factor, but, in 2001 to 2008, HCV filled that role. At the same time, HCC incidence rose dramatically, from 3.5 per 100,000 person-years for the 1976 to 1990 time period, to 3.8 for the period from 1991 to 2000, to 6.9 for the 2001 to 2008 period.
Study author W. Ray Kim, MD, associate professor of medicine, Mayo Clinic College of Medicine, Rochester, Minn., wrote in an email: “The biggest and unique risk factor of HCC is underlying liver disease. Our data showed that previously alcohol, more recently HCV has become the underlying cause.”
The second study (Shire et al. Mayo Clin Proc. 2012;87:17-24) investigated a sample of Somali immigrants seen at Mayo Clinic from July 1, 1996, to Oct. 31, 2009. Non-Somali Olmsted County residents served as controls. The frequencies of chronic hepatitis B virus (HBV) and HCV, and their associations with HCC, were studied. Both HBV and HCV occurred frequently in the sample of Somalis, but HCV was the major risk factor for HCC. There were significant differences in the HCV genotype distributions between Somalis and non-Somalis.
The high prevalence of HCV in the Somali sample came as a surprise to the researchers. “We didn’t expect it,” Abdirashid M. Shire, PhD, assistant professor of medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, said in an interview. The study, Dr. Shire added, “supports the value of early detection” of HCV. “It’s very important to screen for HCV.” Dr. Kim reported that his study also “indirectly” supports the value of early detection and treatment to improve outcomes.
Study author W. Ray Kim, MD, associate professor of medicine, Mayo Clinic College of Medicine, Rochester, Minn., wrote in an email: “The biggest and unique risk factor of HCC is underlying liver disease. Our data showed that previously alcohol, more recently HCV has become the underlying cause.”
The second study (Shire et al. Mayo Clin Proc. 2012;87:17-24) investigated a sample of Somali immigrants seen at Mayo Clinic from July 1, 1996, to Oct. 31, 2009. Non-Somali Olmsted County residents served as controls. The frequencies of chronic hepatitis B virus (HBV) and HCV, and their associations with HCC, were studied. Both HBV and HCV occurred frequently in the sample of Somalis, but HCV was the major risk factor for HCC. There were significant differences in the HCV genotype distributions between Somalis and non-Somalis.
The high prevalence of HCV in the Somali sample came as a surprise to the researchers. “We didn’t expect it,” Abdirashid M. Shire, PhD, assistant professor of medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, said in an interview. The study, Dr. Shire added, “supports the value of early detection” of HCV. “It’s very important to screen for HCV.” Dr. Kim reported that his study also “indirectly” supports the value of early detection and treatment to improve outcomes.
—Drs. Kim and Shire had no relevant financial disclosures
28 January 2012
Researchers at CIC Biogune, the Cooperative Centre for Research into Biosciences and led by Dr. Maria Luz Martinez Chantar, have found a strong relationship between high levels of Hu antigen R (HuR) protein and the...
By Denise Mann
HealthDay Reporter
HealthDay Reporter
THURSDAY, Jan. 26 (HealthDay News) -- Popular cholesterol-lowering statins may also lower risk for liver cancer among people with hepatitis B, a new study shows. Hepatitis B, an inflammation of the liver due to the hepatitis B virus, is one of the main causes of liver cancer.
This is not the first time that statins have shown promise in reducing risk for cancer. Other studies have hinted that these drugs may play a role in preventing certain types of cancer, including breast cancer.
In the new study of more than 33,000 individuals with hepatitis B followed from 1997 to 2008, those who took a statin were less likely to develop liver cancer, when compared to participants who were not prescribed statins. What's more, the longer a person took statins, the greater the liver-cancer risk reduction. Study participants were prescribed the statins to treat high cholesterol levels. Overall, 1,021 people developed liver cancer during the study period.
More research is needed to see how statins may lower liver cancer risk among people with hepatitis B, the researchers said.
"Statins have potential protective effects against cancers [and] carriers of hepatitis B virus infection have a substantial risk of [liver] carcinoma," said Dr. Pau-Chung Chen, a professor of environmental medicine and epidemiology at National Taiwan University, in Taipei. "Statin use is not only a benefit to preventing cardiovascular diseases, but also an additional, convenient and acceptable strategy for preventing hepatocellular carcinoma," or liver cancer, Chen said.
However, statins can cause a potentially dangerous rise in liver enzymes and liver damage. Regular liver function tests are required for all people who take statins.
The study appeared online Jan. 23 in the Journal of Clinical Oncology.
"This is exciting and unequivocally solid research," said Dr. Eugene Schiff, a professor of medicine and director of the Center for Liver Diseases at the University of Miami Miller School of Medicine.
"One of the issues is that statins are relatively contraindicated in people with liver disease," Schiff said. But "the take-home message for people with hepatitis B or anybody with liver disease is that statins are safe. This re-emphasizes the point that if someone has chronic hepatitis B and there is an indication for statins, they should get them and they may be beneficial far beyond lowering cholesterol: They may also reduce their risk for liver cancer."
Dr. David Bernstein, chief of hepatology at North Shore University Hospital and Long Island Jewish Medical Center in Manhasset, N.Y., is more cautious. "In almost all other liver conditions, cirrhosis must be present before [liver cancer] develops," he said. During cirrhosis, scar tissue replaces healthy liver tissue. "Statins must be used with caution in patients with cirrhosis, which can limit their use in patients with liver disease at risk of developing liver cancer," he said. "Further studies are needed in this patient population to confirm these findings."
More information
For information on hepatitis B, visit the U.S. National Digestive Diseases Information Clearinghouse.
Copyright © 2012 HealthDay. All rights reserved.
Transplant
27 January 2012
According to Johns Hopkins researchers, individuals who donate a portion of their liver for live transplantation usually recover safely from the procedure and can expect to live long, healthy lives...
A study in February's issue of Gastroenterology estimates early death, acute liver failure, and long-term mortality among live liver donors.
Dr Abimereki Muzaale and colleagues from Maryland, USA estimated the risk of perioperative mortality or acute liver failure for live liver donors in the United States, and avoid selection or ascertainment biases and sample size limitations.
The research team followed up 4111 live liver donors in the United States between 1994 and 2011 for a mean of 8 years.
Deaths were determined from the Social Security Death Master File. Survival data were compared with those from live kidney donors and healthy participants of the National Health and Nutrition Examination Survey (NHANES) III.
The team observed that 7 donors had early deaths.
Risk of early death among live liver donors is almost 2 per 1000 donors
Gastroenterology
The research team found that risk of death did not vary with age of the liver recipient or portion of liver donated.
There were 11 catastrophic events.
The team found that risk did not vary with recipient age, or portion of liver donated.
The researchers noted that long-term mortality of live liver donors was comparable to that of live kidney donors and NHANES participants.
Dr Muzaale's team concluded, "The risk of early death among live liver donors in the United States is almost 2 per 1000 donors."
"Mortality of live liver donors does not differ from that of healthy, matched individuals over a mean of 8 years."
30 January 2012
How common is transmission of hepatitis C through organ donation, and what types of preventive practices can be put into place to prevent this from happening?
Even after a liver transplant, patients can often experience a recurrence of hepatitis C. How should it be treated in this setting?
HCV Brain Function
Chronic HCV infection causes progressive liver disease and can also be associated with various CNS abnormalities. To date, however, few studies have investigated the mechanisms by which these abnormalities arise, that is, whether they are a result of impaired hepatic function or virus replication in the CNS. Thus, the researchers quantified HCV RNA levels in the brain and liver of 10 individuals infected with HCV. They also investigated the expression of HCV entry receptors in the brain, and conducted in vitro studies to ascertain whether two brain-derived endothelial cell lines could support HCV infection.
The issue of whether the hepatitis C virus (HCV) affects brain function continues to arouse interest, investigation, and debate. Symptoms such as fatigue, poor memory, and concentration ("brain fog") are commonplace and an effect of this infection on mental health related quality of life, which is independent of liver fibrosis, is well established this study provides a substantial link between HCV and cerebral dysfunction by demonstrating a reduction in spectroscopic markers of cerebral inflammation and an improvement in cognition, following HCV eradication
Research
This article takes an in-depth look at hepatitis C treatment options in a specialized community of people on methadone maintenance.
FDA
The FDA recently granted a waiver under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) to OraSure Technologies for its OraQuick HCV Rapid Antibody Test for use with fingerstick whole blood and venous whole blood specimens. With this waiver, the OraQuick HCV test now can be used by more than 180,000 sites in the United States to test individuals who are at risk for hepatitis C virus (HCV) infection.
The CLIA, passed by Congress in 1988, establishes quality standards for all laboratory testing to ensure the accuracy, reliability and timeliness of patient test results, regardless of where a test is performed. As defined by the CLIA, waived tests are categorized as “simple laboratory examinations and procedures that have an insignificant risk of an erroneous result.” The FDA determines the criteria for tests being simple with a low risk for error, and approves manufacturers’ applications for waivers.
The CLIA waiver granted for OraSure’s OraQuick HCV Rapid Antibody Test, extends the use of the assay to more than 180,000 facilities, such as outreach clinics, community-based organizations and physician offices, according to a press release from OraSure.
“A CLIA waiver for our OraQuick HCV test represents a critical milestone in our quest to make the test available to the widest possible range of at-risk individuals in the United States,” said Douglas A. Michels, president and CEO of OraSure Technologies. “The CLIA waiver will enable health care providers, those on the front lines of fighting this devastating disease, to use this simple and accurate test in physician offices and outreach settings so more individuals infected with hepatitis C can be diagnosed and treated.”
The OraQuick HCV Rapid Antibody Test is the first and only FDA-approved rapid test for the detection of antibodies to HCV. The test is approved for fingerstick whole blood specimens and venipuncture whole blood specimens in individuals aged 15 years or older, and provides results in 20 minutes. The assay has not been approved for use in patient populations without signs or symptoms of HCV, and its use has not been established for testing patients younger than 15 years of age or for pregnant women.
The CLIA waiver granted for OraSure’s OraQuick HCV Rapid Antibody Test, extends the use of the assay to more than 180,000 facilities, such as outreach clinics, community-based organizations and physician offices, according to a press release from OraSure.
“A CLIA waiver for our OraQuick HCV test represents a critical milestone in our quest to make the test available to the widest possible range of at-risk individuals in the United States,” said Douglas A. Michels, president and CEO of OraSure Technologies. “The CLIA waiver will enable health care providers, those on the front lines of fighting this devastating disease, to use this simple and accurate test in physician offices and outreach settings so more individuals infected with hepatitis C can be diagnosed and treated.”
The OraQuick HCV Rapid Antibody Test is the first and only FDA-approved rapid test for the detection of antibodies to HCV. The test is approved for fingerstick whole blood specimens and venipuncture whole blood specimens in individuals aged 15 years or older, and provides results in 20 minutes. The assay has not been approved for use in patient populations without signs or symptoms of HCV, and its use has not been established for testing patients younger than 15 years of age or for pregnant women.
—Based on a press release from OraSure Technologies
Healthy You
A study recently published in the Journal of Pain Research shows that practicing yoga boosts levels of the stress hormone cortisol and could help ease some symptoms of fibromyalgia such as pain, fatigue, muscle stiffness and depression.
Under stressful conditions yeast genomes become unstable, readily acquiring or losing whole chromosomes to enable rapid adaption. The musical spectrum was derived from the copy number data of the aneuploid yeast genomes selected under different stress conditions, where the gain and loss of chromosomes are represented as red and green bars, respectively.
Newswise — KANSAS CITY, MO— Cells trying to keep pace with constantly changing environmental conditions need to strike a fine balance between maintaining their genomic integrity and allowing enough genetic flexibility to adapt to inhospitable conditions. In their latest study, researchers at the Stowers Institute for Medical Research were able to show that under stressful conditions yeast genomes become unstable, readily acquiring or losing whole chromosomes to enable rapid adaption.
The research, published in the January 29, 2012, advance online issue of Nature, demonstrates that stress itself can increase the pace of evolution by increasing the rate of chromosomal instability or aneuploidy. The observation of stress-induced chromosome instability casts the molecular mechanisms driving cellular evolution into a new perspective and may help explain how cancer cells elude the body’s natural defense mechanisms or the toxic effects of chemotherapy drugs.
“Cells employ intricate control mechanisms to maintain genomic stability and prevent abnormal chromosome numbers,” says the study’s leader, Stowers investigator Rong Li, Ph.D. “We found that under stress cellular mechanisms ensuring chromosome transmission fidelity are relaxed to allow the emergence of progeny cells with diverse aneuploid chromosome numbers, producing a population with large genetic variation.”
Known as adaptive genetic change, the concept of stress-induced genetic variation first emerged in bacteria and departs from a long-held basic tenet of evolutionary theory, which holds that genetic diversity—evolution’s raw material from which natural selection picks the best choice under any given circumstance—arises independently of hostile environmental conditions.
“From an evolutionary standpoint it is a very interesting finding,” says graduate student and first author Guangbo Chen. “It shows how stress itself can help cells adapt to stress by inducing chromosomal instability.”
Aneuploidy is most often associated with cancer and developmental defects and has recently been shown to reduce cellular fitness. Yet, an abnormal number of chromosomes is not necessarily a bad thing. Many wild yeast strains and their commercial cousins used to make bread or brew beer have adapted to their living environs by rejiggering the number of chromosomes they carry. “Euploid cells are optimized to thrive under ‘normal’ conditions,” says Li. “In stressful environments aneuploid cells can quickly gain the upper hand when it comes to finding creative solutions to roadblocks they encounter in their environment.”
After Li and her team had shown in an earlier Nature study that aneuploidy can confer a growth advantage on cells when they are exposed to many different types of stress conditions, the Stowers researchers wondered whether stress itself could increase the chromosome segregation error rate.
To find out, Chen exposed yeast cells to different chemicals that induce various types of general stress and assessed the loss of an artificial chromosome. This initial screen revealed that many stress conditions, including oxidative stress, increased the rate of chromosome loss ten to 20-fold, a rate typically observed when cells are treated with benomyl, a microtubule inhibitor that directly affects chromosome segregation.
The real surprise was radicicol, a drug that induces proteotoxic stress by inhibiting a chaperone protein, recalls Chen. “Even at a concentration that barely slows down growth, radicicol induced extremely high levels of chromosome instability within a very short period of time,” he says.
Continued growth of yeast cells in the presence of radicicol led to the emergence of drug-resistant colonies that had acquired an additional copy of chromosome XV. Yeast cells pretreated briefly with radicicol to induce genomic instability also adapted more efficiently to the presence of other drugs including fluconazole, tunicamycin, or benomyl, when compared to euploid cells.
Interestingly, certain chromosome combinations dominated in colonies that were resistant to a specific drug. Fluconazole-resistant colonies typically gained an extra copy of chromosome VIII, tunicamycin-resistant colonies tended to lose chromosome XVI, while a majority of benomyl-resistant colonies got rid of chromosome XII. “This suggested to us that specific karyotypes are associated with resistance to certain drugs,” says Chen.
Digging deeper, Chen grew tunicamycin-resistant yeast cells, which had adapted to the presence of the antibiotic by losing one copy of chromosome XVI, under drug-free conditions. Before long, colonies of two distinct sizes emerged. He quickly discovered that the faster growing colonies had regained the missing chromosome. By returning to a normal chromosome XVI number, these newly arisen euploid cells had acquired a distinctive growth advantage over their aneuploid neighbors. But most importantly, the fast growing yeast cells were no longer resistant to tunicamycin and thus clearly linking tunicamycin resistance to the loss of chromosome XVI.
Researchers who also contributed to the work include William D. Bradford and Chris W. Seidel both at the Stowers Institute for Medical Research.
The study was funded in part by the National Institute of General Medical Sciences.
About the Stowers Institute for Medical Research
The Stowers Institute for Medical Research is a non-profit, basic biomedical research organization dedicated to improving human health by studying the fundamental processes of life. Jim Stowers, founder of American Century Investments, and his wife Virginia opened the Institute in 2000. Since then, the Institute has spent over 800 million dollars in pursuit of its mission.
Currently the Institute is home to over 500 researchers and support personnel; over 20 independent research programs; and more than a dozen technology development and core facilities. Learn more about the Institute at www.stowers.org.
New research finds milk drinkers scored better on memory and brain function tests
Pouring at least one glass of milk each day could not only boost your intake of much-needed key nutrients, but it could also positively impact your brain and mental performance, according to a recent study in the International Dairy Journal.1 Researchers found that adults with higher intakes of milk and milk products scored significantly higher on memory and other brain function tests than those who drank little to no milk. Milk drinkers were five times less likely to "fail" the test, compared to non milk drinkers.
Researchers at the University of Maine put more than 900 men and women ages 23 to 98 through a series of brain tests – including visual-spatial, verbal and working memory tests – and tracked the milk consumption habits of the participants. In the series of eight different measures of mental performance, regardless of age and through all tests, those who drank at least one glass of milk each day had an advantage. The highest scores for all eight outcomes were observed for those with the highest intakes of milk and milk products compared to those with low and infrequent milk intakes. The benefits persisted even after controlling for other factors that can affect brain health, including cardiovascular health and other lifestyle and diet factors. In fact, milk drinkers tended to have healthier diets overall, but there was something about milk intake specifically that offered the brain health advantage, according to the researchers.
In addition to the many established health benefits of milk from bone health to cardiovascular health, the potential to stave off mental decline may represent a novel benefit with great potential to impact the aging population. While more research is needed, the scientists suggest some of milk's nutrients may have a direct effect on brain function and that "easily implemented lifestyle changes that individuals can make present an opportunity to slow or prevent neuropsychological dysfunction."
New and emerging brain health benefits are just one more reason to start each day with lowfat or fat free milk. Whether in a latte, in a smoothie, on your favorite cereal, or straight from the glass, milk at breakfast can be a key part of a healthy breakfast that help sets you up for a successful day. The 2010 Dietary Guidelines for Americans recommend three glasses of lowfat or fat free milk daily for adults and each 8-ounce glass contains nine essential nutrients Americans need, including calcium and vitamin D.
About the National Milk Mustache "got milk?"® Campaign
The Milk Processor Education Program (MilkPEP), Washington, D.C., is funded by the nation's milk processors, who are committed to increasing fluid milk consumption. The National Fluid Milk Processor Promotion Board, through MilkPEP, runs the National Milk Mustache "got milk?"® Campaign, a multi-faceted campaign designed to educate consumers about the health benefits of milk. For more information, go to www.whymilk.com. Deutsch, A Lowe and Partners Company, is the creative agency for the National Milk Mustache "got milk?"® Campaign.
1Crichton GE, Elias MF, Dore GA, Robbins MA. Relation between dairy food intake and cognitive function: The Maine-Syracuse Longitudinal Study. International Dairy Journal. 2012; 22:15-23.
Chuck Garcia is launching the January 2012 collection of daily blog entries for the “31 Days of Wellness”, our annual celebration of the New Year, and the opportunity to start anew as we ring in the New Year. Enjoy, visit us daily, and send us your feedback.
Dr. Joe Galati
For Your Reading Pleasure
Chuck Garcia is launching the January 2012 collection of daily blog entries for the “31 Days of Wellness”, our annual celebration of the New Year, and the opportunity to start anew as we ring in the New Year. Enjoy, visit us daily, and send us your feedback.
Dr. Joe Galati
on 01/28/2012
OH My Aches And Pains
As I am getting ready to start Hepatitis C (HCV) treatment, I've been running across some pretty interesting pieces of information that I think will make my treatment experience more successful.
Behind The Headlines
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The idea that regularly eating fried foods causes heart attacks is a ‘myth’, The Daily Telegraph has today reported.
The newspaper has panned conventional wisdom based on a large Spanish study investigating how people’s fried food consumption was linked to their risk of events such as heart attacks and episodes of heart pain. To study the relationship researchers surveyed over 40,000 people on how much fried food they ate during the previous year, looking at any episodes related to coronary heart disease over an average period of 11 years.
In this particular setting the researchers found no link between consuming food fried in olive or sunflower oils and the risk of heart disease (the UK’s biggest killer) or death from any cause. However, while such a phenomenon could exist in the context of this specific group of people eating a specific type of diet, the research does not support the idea that fried food is generally harmless, or that it represents diets among the UK population. For example, most participants reported eating a relatively small amount of fried food each day, much less than might be typically found in a fry-up or a fast food meal. In short, it is not clear whether the same study conducted in the UK would have the same results.
Many news sources have reported the results in an accurate, measured way. However, The Daily Telegraph’s account has been somewhat overcooked, as the study did not look at the impact of factors such as frying with other types of fats, reusing oils several times (as is the case in most fast food outlets), or consuming fried snacks high in salt, sugar or calories.
Where did the story come from?
The study was carried out by a collaboration of researchers from Spanish universities and other health organisations based in Spain. It was funded by Spain’s FIS Fund for Health Research and published in the peer-reviewed British Medical Journal.
Media reports were generally balanced, with many making the point that the study was primarily concerned with a Mediterranean diet containing olive oil, which is typically very different from the dietary patterns in the UK. This limits how relevant this study is to the UK population. Many news sources also rightly warn against assuming that the study results suggested that consuming large amounts of fried foods is not harmful. The Telegraph included a picture of a full English breakfast, which is not a recognised part of a Mediterranean dietary pattern.
What kind of research was this?
This prospective cohort study investigated the association between people’s consumption of fried foods and their risk of experiencing coronary heart disease events such as heart attacks and heart pain (angina) which require surgery. It was conducted in a Spanish population.
Previous research has shown fried foods have been associated with high blood pressure, obesity and low levels of ‘good’ cholesterol (high-density lipoproteins or HDL cholesterol). However, existing studies into the association of fried food and coronary heart disease provided mixed results, the authors report.
When food is fried the nutritional content changes; water is lost and fat is absorbed, increasing the calorie content of the food. During frying, the oils also deteriorate and change into other forms, especially when reused, as is often the case in fried fast food outlets. This process leads to a loss of unsaturated fats and an increase in harmful trans fats.
A prospective cohort study is a good way of investigating whether fried foods are linked to heart disease because you can be sure the consumption of the food occurred before the development of the disease. However, the limitation is that you cannot be certain that fried foods caused a disease because its development may be influenced by numerous other factors, some measured in the research and some not.
The best type of study to definitively assess this link would be a large randomised controlled trial, providing it could be performed ethically. However, given the cost and complexity of such a task, this approach may ultimately be impractical.
What did the research involve?
The participants were Spaniards enrolled in a research project called the European Prospective Investigation into Cancer and Nutrition (the EPIC-Spain cohort). The analysed cohort consisted of 40,757 adults aged between 29 and 69 who were recruited between 1992 and 1996. They were followed up for an average of 11 years to see what diseases they developed and what they died of.
When enrolled, participants were asked by trained interviewers to complete a questionnaire about the food they consumed over a typical week during the previous 12 months. Only foods consumed at least twice a month were recorded.
The study’s authors report that this method had previously been shown to be accurate (validated) at assessing the diet of Spanish people. The type of oil used for frying (olive oil versus sunflower oil or other vegetable oils) was recorded and then checked again after two years. No further information on diet was collected at a later date.
At enrolment, the researchers also recorded non-dietary variables. These included demographic variables such as age and sex as well as educational level, body mass index (BMI), smoking and physical activity levels. Participants were also asked if they had coronary heart disease, diabetes, high blood pressure, cancer or angina or had experienced a heart attack or stroke in the past.
For the analysis, people were divided into four groups depending on their level of fried food consumption. The researchers specifically analysed how consuming fried food was linked to the chance of having a coronary heart disease event and dying from any cause (known as all-cause mortality) and how these varied for the four groups.
The analysis was adjusted for a large number of factors, including energy intake, educational level, smoking and physical activity. This statistical technique aims to minimise the effect these external factors have on the association of interest, in this case between fried food and heart disease.
What were the basic results?
An average of 138g of fried food was consumed daily, including 14g of oil used for frying. About 7% of the total amount of food consumed was fried. Of the total amount of fried food consumed, 24% (34g/day) was fish, 22% (31g/day) meat, 21% (30g/day) potatoes, and 11% (15g/day) eggs. Almost two thirds (62%) of participants used olive oil for frying, the rest used sunflower oil or other vegetable oils.
During the 11-year follow up, 606 definite cases of heart disease were recorded (466 heart attacks and 140 episodes of angina requiring surgery) and 1,135 deaths from all causes.
Fried food consumption was not associated with the risk of coronary heart disease after adjusting for possible confounders. There was also no association between fried fat consumption and death from all causes. These findings were no different in those who fried using olive oil compared to sunflower oil or other vegetable oils.
In the study, coronary heart disease events were defined as definite, probable and possible depending how they were assessed. The researchers first analysed their data using only the definite cases of coronary heart disease and found no association between fried food and these cases. The same result was found when they combined the definite coronary heart disease cases with those that were less certain (probable and possible groups).
How did the researchers interpret the results?
The researchers concluded that within the EPIC-Spanish cohort they found ‘no association between consumption of fried food and risk of coronary heart disease or all-cause mortality’.
They point out that their results are ‘directly applicable only to Mediterranean countries with frying methods similar to those in Spain’ and state that oil (mainly olive and sunflower) rather than solid fat is used for frying in Spain. They also point out that the majority of fried food eaten in Spain is not necessarily fast food.
They also make the important point that ‘frying with other types of fats, reusing oils several times, or consuming fried snacks high in salt may still be harmful’.
Conclusion
This study found no association between how often people ate fried food and their risk of coronary heart disease or death from any cause in a large Spanish cohort.
This study has strengths, including using a valid method of assessing diet, a large sample size and long follow-up time, but also has significant limitations. The following limitations should be considered when interpreting the findings of this study:
- The study looked at frying using olive oil or sunflower oil in the context of a Mediterranean diet. The authors make the important point that frying with other types of fats or reusing oils several times may still be harmful. Reusing oils is common in fast food preparation in the UK, and so this study does not show that consuming this type of food is not linked to heart disease.
- Diet was measured only when the participants were first enrolled. Any changes in diet after this will be missed and could lead to an association being masked because of error in the classification of fried food consumption.
- Fried food consumption was self-reported using a computerised questionnaire and so there may have been under-reporting given that many people perceive it to be unhealthy and may want to partially conceal the amount they eat. This could potentially hide an association.
- The study did not assess the extent to which the oils were reused, assuming that this was not common in foods consumed in the home. Hence, the effects of foods fried in reused oils are still unknown and may warrant further research as reusing oils is known to make them more harmful, the authors report.
- This study cannot separate the effect of the food from the cooking method. For example, the beneficial effect of omega 3 fatty acids from fish compared with the effect of frying this fish in oil that may be harmful. Therefore, the food itself blurs the link between the cooking method and disease. It is not clear whether the same results would be found if the study was conducted on the UK diet, which is generally considered less healthy than the Mediterranean diet.
- This study cannot say that consuming fried foods at a higher level than their highest consumption group (249.6g/day) does not increase risk of heart disease.
Bearing in mind the limitations, this study showed that there may not be a link between consuming foods fried in olive oil or vegetable oil and coronary heart disease in Spanish adults consuming a typical Mediterranean diet. The relevance of this to the UK is limited due to differences in diet and the type of fried foods consumed in the two countries.
It is important to note that frying foods with other types of fats, particularly saturated fats such as lard or butter, reusing oils several times, or consuming fried snacks high in salt may still be harmful.
Links to the headlines
Fried food 'fine for heart' if cooked with olive oil. BBC News, January 25 2012
Fried food heart risk 'a myth'. The Daily Telegraph, January 25 2012
You'll be oil right. The Sun, January 25 2012
Sunday, January 29, 2012
The Effect of Caffeine and Alcohol Consumption on Liver Fibrosis
From Liver International
The Effect of Caffeine and Alcohol Consumption on Liver Fibrosis
A Study of 1045 Asian Hepatitis B Patients Using Transient Elastography
Arlinking Ong; Vincent Wai-SunWong; Grace Lai-Hung Wong; Henry Lik-Yuen Chan
Posted: 01/25/2012; Liver International. 2011;31(7):1047-1053. © 2011 Blackwell Publishing
Role of caffeine consumption in chronic hepatitis B virus (HBV)-infected patients and the interaction with alcohol consumption is unclear.
Aim:
This study aimed to investigate the relationship between caffeine and alcohol consumption and liver stiffness in chronic HBV-infected patients.
Methods:
Chronic HBV-infected patients who underwent transient elastography examination in 2006–2008 were studied. Advanced fibrosis was defined as liver stiffness >9 kPa for patients with normal alanine aminotransferase (ALT) or >12 kPa for those with elevated ALT according to previous validation study. Caffeine and alcohol consumption was recorded using a standardized questionnaire. Excessive alcohol intake was defined as 30 g/day in men and 20 g/day in women.
Results:
The liver stiffness of 1045 patients who completed the questionnaire was 8.3 ± 6.2 kPa. Two hundred and sixteen (20.7%) patients had advanced fibrosis. Ninety-five (19.0%) patients who drank ≥1 cup of coffee had advanced fibrosis, compared with 121 (22.2%) patients who drank <1 cup (P=0.21). The amount of caffeine intake had positive correlation with the amount of alcohol intake (rs=0.167, P<0.001). Although 231 (22.1%) patients reported alcohol consumption, only 11 (1%) had excessive alcohol intake. The prevalence of advanced fibrosis among patients with mild to moderate alcohol intake (26, 18.8%) was comparable to that among non-drinkers (190, 21.0%) (P=0.57).
Conclusion: Caffeine intake does not affect liver stiffness in chronic HBV-infected patients. Patients who drink coffee regularly tend to drink alcohol. Most chronic HBV-infected patients do not have excessive alcohol consumption. The prevalence of advanced fibrosis among mild to moderate alcohol drinkers was low in this population.
Introduction
Chronic hepatitis B virus (HBV) infection is a global health problem affecting over 350 million people. Persistent hepatic inflammation because of chronic HBV infection will result in progressive liver fibrosis, which will eventually result in cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC).[1]
Alcoholism[2] is a primary chronic disease with genetic, psychosocial and environmental factors influencing its development and manifestations. Heavy alcohol consumption commonly causes alcoholic liver disease, cirrhosis and even HCC.[3] However, it is unclear whether consumption of a smaller amount of alcohol is safe in chronic hepatitis B patients.
On the other hand, consumption of coffee or caffeine may reduce liver injury. Greater coffee, and especially caffeine, intake was associated with a lower prevalence of abnormal alanine aminotransferase (ALT) activity in USA[4] and Japan.[5] Plasma glutathione was increased by 16% on coffee consumption in an Italian population.[6] In a prospective study among advanced Hepatitis C-related liver disease, regular coffee consumption was associated with lower rates of disease progression.[7] In human hepatoma cell lines, coffee and its major components (caffeine, cafestol and kahweol) alter expression and activity of enzymes involved in xenobiotic mechanisms.[8] Mice pretreated with cafestol and kahweol were protected from carbon tetrachloride toxicity by inhibiting cytochrome CYP 2E1,[9] an enzyme responsible for carbon tetrachloride bioactivation while caffeine specifically inhibited expression of connective tissue growth factor by interfering with transforming growth factor-β signaling through the SMAD pathway and upregulate peroxisome proliferator activated receptor γ levels. These in vitro and in vivo data suggested that caffeine has antifibrotic effects.[10]
A recent case control study among chronic hepatitis B carriers showed that coffee consumption reduced the risk of HCC by half with a significant dose-response effect.[11] It is uncertain if the beneficial effect is mediated through prevention of liver fibrosis and cirrhosis. In the past, large-scaled studies on risk factors of liver fibrosis and cirrhosis were difficult to conduct because the assessment required liver biopsy, which was invasive and not acceptable by all patients. In this study, we aimed to determine the effect of alcohol and caffeine consumption on the prevalence of advanced liver fibrosis among chronic HBV-infected patients using transient elastography.
Methods
Study Population We prospectively recruited chronic HBV-infected patients regardless of the disease activity for transient elastography. We received referrals from all primary care and hospital clinics in Hong Kong from July 2006 to February 2008.[12] Chronic HBV infection was diagnosed by positive serology tests for serum HBsAg for at least 6 months. We excluded patients with evidence of other chronic liver disease by screening with antibody against hepatitis C virus, antinuclear antibody, antismooth muscle antibody, antimitochondrial antibody, serum ceruloplasmin, transferrin saturation and ferritin.
From April to May 2008, patients from the original cohort were phone-interviewed with a verbal consent for this study. Questions concerning their alcohol and caffeine consumption (days per week of consumption and amount per day) in the previous year were asked from a standardized questionnaire. Patients who refused to give verbal consent for the phone-interview were not included in this study.
Clinical Evaluation
All patients received comprehensive clinical and laboratory assessment at the time of transient elastography. Serum HBV DNA levels were measured by the TaqMan real-time polymerase chain reaction assay with a range of detection from 100 to 109 copies/ml.[13] Anthropometric parameters including body weight, body height, hip circumference and waist circumference were measured. Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared. Overweight was defined as BMI≥23 kg/m2, and obesity as BMI≥25 kg/m2 according to the Asian and Chinese criteria.[14] We defined moderate and severe obesity as BMI≥28 kg/m2 M and ≥30 kg/m2 respectively. Excessive alcohol intake was defined as >30 g/day in men and >20 g/day in women.[15]
Liver Stiffness Measurement by Transient Elastography
Transient elastography (FibroScan®, Echosens, Paris, France) is one of the new noninvasive modality to evaluate liver fibrosis by measuring liver stiffness. It uses an ultrasound-based technique to measure the speed of propagation of the shear wave through the liver. It can assess approximately 1/500 of the liver's total mass thus reducing the sampling error. Transient elastography has been shown to accurately predict histological advanced fibrosis in different liver diseases.[16–21]
Liver stiffness measurement (LSM) was performed using transient elastography according to the instructions of the manufacturer. Details of the technical background and examination procedure was described previously.[22] Officially trained operators who had performed at least 50 measurements prior this study were responsible to perform the LSM for the patients who had kept fast for at least 8 h. The LSM was considered reliable only if 10 successful acquisitions were obtained, an interquartile range (IQR)/LSM of ≤30% and the success rate was ≥60%. Liver stiffness was expressed in kPa. We defined advanced fibrosis as liver stiffness >9 kPa for those with normal ALT or >12 kPa for those with elevated ALT (F3 fibrosis on histology).[23,24]
Hui's Index
Hui's index was a non-invasive model comprising of BMI, platelet count, serum albumin and total bilirubin [predictive probabilities=exp(3.148+0.167 × BMI+0.088 × bilirubin [μM]−0.151 × albumin [g/L]−0.019 × platelet [109/L])/(1+exp(3.148+0.167 × BMI+0.088 × bilirubin [μM]−0.151 × albumin [g/L]−0.019 × platelet [109/L]))] to predict significant fibrosis (F2 fibrosis on histology).[25] Among 235 chronic hepatitis B patients with liver biopsy, at a cutoff value of 0.15, the sensitivity, specificity, positive and negative predictive values for significant fibrosis were 93, 49, 41 and 95% respectively.
Phone-interview and Questionnaire
A structured questionnaire interview was conducted over the phone to collect data on alcohol and caffeine intake. Participants were specifically asked about the average quantity and frequency of beer, wine, or liquor consumption to estimate the amount of alcohol consumption. The average quantity and frequency of consumption of coffee (regular, instant, ground and decaffeinated), tea (any kind), cola-type soda (regular or decaffeinated) and chocolate (including chocolate milk) was also enquired to estimate the amount of caffeine consumption. Effect of alcohol and caffeine consumption was analyzed with respect to the severity of liver fibrosis as assessed by transient elastography, Hui's Index and other clinical and biochemical parameters
Statistical Analyses
Total caffeine consumption (mg/day) was estimated by summing caffeine from regular coffee (137 mg per cup), regular tea (47 mg per cup), regular and diet cola-type soda (46 mg per bottle or can) and chocolate (7 mg per serving).[26] As for the coffee cup equivalent, the total caffeine consumption per day was divided by 137 (Table 1).
Table 1. Caffeine content in beverages or food
Continuous variables were expressed in mean ± standard deviation or median (IQR) as appropriate. Qualitative and quantitative differences between subgroups were analyzed using χ2 or Fisher's exact test for categorical parameters as appropriate, and Student's t-test or Mann–Whitney test for continuous parameters as appropriate. Logistic regression analyses were performed to determine if caffeine and alcohol consumption was associated with liver fibrosis. The multivariate adjusted logistic regression model included covariates that were included in univariate analysis. Spearman's rank correlation was used to correlate caffeine and alcohol intake. All statistical tests were two-sided. Statistical significance was taken as P<0.05. Statistical analysis was performed by Statistical Package for Social Science (SPSS version 17.0, Chicago, IL, USA).
Results
Patient CharacteristicsOverall, 22.7% of 1532 patients in this study came from primary care clinics and 77.3% were from hospital clinics. Six patients were excluded because of anti-HCV positivity, 60 patients because of unreliable LSM results and 421 as we failed to contact for phone-interview because of various reasons (e.g. changed telephone numbers or no answer despite multiple attempts). For patients we able to contact via phone, none of them refused to give verbal consent for the phone interview. A total of 1045 chronic hepatitis B patients were thus included in this study. Majority of patients were males (652, 62.4%), of which 175 (26.8%) were overweight and 210 (32.2%) were obese. Two hundred forty seven (37.9%) male patients had elevated ALT with 71% having HBV DNA of more than 4 logs copies/ml. Four hundred and ninety-nine (47.8%) patients consumed one cup of coffee or more per day, while 231 (22.1%) patients drank alcohol. Only 26 (2.5%) patients reported no intake of both coffee and alcohol. The median (IQR) daily consumption of caffeine from food and beverages was 124 (51.6–275.6) mg/day or 1 (0.4–2.0) cup of coffee/day while alcohol consumption of >20 g/day was 1.9% (Table 2). Two hundred and sixteen (20.7%) patients had LSM suggestive of advanced fibrosis.
Table 2. Baseline characteristics of patients (n=1045)
ALT, alanine aminotransferase; BMI, body mass index; IQR, interquartile range; kPa, kilopascal; LSM, liver stiffness measurement; SD, standard deviation.
Caffeine Intake and Liver Fibrosis
Table 3 shows the median total caffeine consumption in mg/day and the coffee cup equivalent according to different patient characteristics where there was no significant difference in caffeine consumption among those with no fibrosis and advanced fibrosis.
Table 3. Daily caffeine consumption according to patient characteristics (n=1045)
All caffeine intakes were presented as median (interquartile range).
*P-values refer to the comparison of caffeine intake by Kruskal–Wallis's test between groups under the same characteristic (e.g. male vs. female).
There was no significant difference in LSM (Table 4). In addition, caffeine intake had no significant correlation with liver stiffness (rs=0.011, P=0.722) or the Hui's index (rs=−0.002, P=0.948).
Table 4. Characteristics of patients by category of caffeine consumption
*Categorical variables were compared by χ2-test, while continuous variables were compared by Kruskal–Wallis test.
HBV, hepatitis B virus; IQR, interquartile range; SD, standard deviation.
Based on LSM and the Hui's index, caffeine intake by univariate and multivariate analysis was not associated with the risk of advanced liver fibrosis (Table 5).
Table 5. Relationship of caffeine intake, advanced fibrosis and alcohol consumption
Alcohol Intake and Liver Fibrosis
Majority of patients (77.9%) did not consume alcohol while only 11 out of 231 patients with alcohol consumption had excessive alcohol drinking. The highest alcohol consumption per day was 88 g. Advanced fibrosis was only prevalent in 26 (18.8%) of those with mild to moderate alcohol consumption compared with 190 (21.0%) of those non-alcoholic drinkers (P=0.57).
Those who drink alcohol have significantly higher caffeine consumption than those who do not drink alcohol (Table 3). Caffeine intake had positive correlation with alcohol intake (rs=0.167, P<0.001).
DiscussionIn this large territory-wide observational study with prospective recruitment, we assessed the relationship between caffeine and alcohol consumption and the risk of advanced liver fibrosis in chronic hepatitis B patients with different disease severity. Caffeine intake was not associated with advanced fibrosis. Patients who drank coffee regularly were more likely to consume alcohol. On the other hand, few chronic hepatitis B patients in Hong Kong had excessive alcohol consumption. Mild to moderate alcohol consumption did not increase the risk of advanced fibrosis.
Coffee is a rich source of a number of phenol compounds with antioxidant effects in vitro, with main polyphenols are phenolic acids such as chlorogenic and caffeic acid.[27] Caffeine and its metabolites, 1-methylxanthine and 1-methyluric acid, have also been shown to have antioxidant properties.[28] Caffeine has also been reported to inhibit chemical carcinogenesis and ultraviolet B light induced carcinogenesis in mice.[29,30] Coffee is also found to decrease the progression of liver disease among those with advanced hepatic fibrosis[7] and even reduce the risk of HCC[31,32] One study[33] concluded that approximately 2 coffee cup equivalents/day was associated with less severe hepatic fibrosis, but the beneficial effect was only shown in patients with chronic hepatitis C rather than patients with other liver diseases. A case control study in Italy showed that the protective effect of coffee on HCC was mainly in people who are not chronically infected with HBV.[31] Overall, previous studies included mostly chronic hepatitis C patients and HBV patients were underrepresented. Based on our results, it appears that liver fibrosis in chronic hepatitis B patients is determined mainly by virological and genetic factors and less affected by caffeine intake.
In previous reports, men who have daily alcohol intake of 30–39 g and women who consumed 20–29 g of alcohol daily would have an increased risk of all cause mortality among the general population.[34] Seventy-eight percent of our cohort did not drink alcohol at all while only 1% of patient had history of excessive alcohol consumption. Nonetheless, we could not find any deleterious effect of mild to moderate alcohol consumption to liver fibrosis. As alcohol drinkers were mostly coffee drinkers as well, the concomitant caffeine intake might but one of the confounders leading to the absence of increased risk of advanced fibrosis in alcohol drinkers. Nonetheless only a minority (1% of the study population has excessive alcohol intake, we believe that the major reason of the absence of increased risk of advanced fibrosis in alcohol drinkers was the modest instead of excess amount of alcohol use. Because most of our patients had no advanced liver disease as compared with other studies (33, 35–38), our results could not be extrapolated to cirrhotic patients. Less than 20 g of alcohol intake tends not to increase risk of advanced fibrosis in our present study. Controlled prospective studies may be done in the future to verify this.
One of the limitations of our study was the lack of liver biopsy. As liver biopsy is an invasive procedure, studies using histological fibrosis as an endpoint might suffer from the problem of small sample size and selection bias towards patients with active or advanced liver disease.[39] On the other hand, a non-invasive test such as transient elastography could be applied to a large number of patients with different disease severity. In fact, transient elastography has been shown to be highly accurate in detecting histological advanced fibrosis and cirrhosis in chronic hepatitis B patients,[16,23] though the accuracy might be limited in settings of grossly elevated transaminase levels,[16] but not in the presence of steatosis.[18] Secondly, recall bias might occur during the questionnaire survey and affect the accuracy of the measurement of the caffeine intake measured. We have tried to minimize this bias by using a quantity-frequency questionnaire, which has been previously adapted in a study demonstrating the protective effect of coffee consumption from HCC.[11] There were 159 (15.2%) participants drinking >2–3 coffee-cup equivalents/day and 103 (9.9%) drinking >3 coffee-cup equivalents/day. Because the above numbers for these groups were low and previous finding showing 2 coffee-cup equivalents/day was associated to less severe liver fibrosis, we combined these groups for analysis. Because this is a cross sectional study, possible unmeasured as well as poorly measured confounding factors that may affect the interpretation of our data such as changes in the drinking habit of the patients, variability of caffeine intake over time, socioeconomic status, educational level were not considered in our analysis.
In conclusion, cross-sectional caffeine intake does not affect liver stiffness in chronic HBV-infected patients. The protective effect of caffeine on HCC demonstrated in previous studies is probably via the pathway other than reducing liver fibrosis. The prevalence of advanced liver fibrosis is low (20%) in chronic hepatitis B patients with daily alcohol consumption below 20 g.
The Effect of Caffeine and Alcohol Consumption on Liver Fibrosis
A Study of 1045 Asian Hepatitis B Patients Using Transient Elastography
Arlinking Ong; Vincent Wai-SunWong; Grace Lai-Hung Wong; Henry Lik-Yuen Chan
Posted: 01/25/2012; Liver International. 2011;31(7):1047-1053. © 2011 Blackwell Publishing
Abstract and Introduction
Background:Role of caffeine consumption in chronic hepatitis B virus (HBV)-infected patients and the interaction with alcohol consumption is unclear.
Aim:
This study aimed to investigate the relationship between caffeine and alcohol consumption and liver stiffness in chronic HBV-infected patients.
Methods:
Chronic HBV-infected patients who underwent transient elastography examination in 2006–2008 were studied. Advanced fibrosis was defined as liver stiffness >9 kPa for patients with normal alanine aminotransferase (ALT) or >12 kPa for those with elevated ALT according to previous validation study. Caffeine and alcohol consumption was recorded using a standardized questionnaire. Excessive alcohol intake was defined as 30 g/day in men and 20 g/day in women.
Results:
The liver stiffness of 1045 patients who completed the questionnaire was 8.3 ± 6.2 kPa. Two hundred and sixteen (20.7%) patients had advanced fibrosis. Ninety-five (19.0%) patients who drank ≥1 cup of coffee had advanced fibrosis, compared with 121 (22.2%) patients who drank <1 cup (P=0.21). The amount of caffeine intake had positive correlation with the amount of alcohol intake (rs=0.167, P<0.001). Although 231 (22.1%) patients reported alcohol consumption, only 11 (1%) had excessive alcohol intake. The prevalence of advanced fibrosis among patients with mild to moderate alcohol intake (26, 18.8%) was comparable to that among non-drinkers (190, 21.0%) (P=0.57).
Conclusion: Caffeine intake does not affect liver stiffness in chronic HBV-infected patients. Patients who drink coffee regularly tend to drink alcohol. Most chronic HBV-infected patients do not have excessive alcohol consumption. The prevalence of advanced fibrosis among mild to moderate alcohol drinkers was low in this population.
Introduction
Chronic hepatitis B virus (HBV) infection is a global health problem affecting over 350 million people. Persistent hepatic inflammation because of chronic HBV infection will result in progressive liver fibrosis, which will eventually result in cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC).[1]
Alcoholism[2] is a primary chronic disease with genetic, psychosocial and environmental factors influencing its development and manifestations. Heavy alcohol consumption commonly causes alcoholic liver disease, cirrhosis and even HCC.[3] However, it is unclear whether consumption of a smaller amount of alcohol is safe in chronic hepatitis B patients.
On the other hand, consumption of coffee or caffeine may reduce liver injury. Greater coffee, and especially caffeine, intake was associated with a lower prevalence of abnormal alanine aminotransferase (ALT) activity in USA[4] and Japan.[5] Plasma glutathione was increased by 16% on coffee consumption in an Italian population.[6] In a prospective study among advanced Hepatitis C-related liver disease, regular coffee consumption was associated with lower rates of disease progression.[7] In human hepatoma cell lines, coffee and its major components (caffeine, cafestol and kahweol) alter expression and activity of enzymes involved in xenobiotic mechanisms.[8] Mice pretreated with cafestol and kahweol were protected from carbon tetrachloride toxicity by inhibiting cytochrome CYP 2E1,[9] an enzyme responsible for carbon tetrachloride bioactivation while caffeine specifically inhibited expression of connective tissue growth factor by interfering with transforming growth factor-β signaling through the SMAD pathway and upregulate peroxisome proliferator activated receptor γ levels. These in vitro and in vivo data suggested that caffeine has antifibrotic effects.[10]
A recent case control study among chronic hepatitis B carriers showed that coffee consumption reduced the risk of HCC by half with a significant dose-response effect.[11] It is uncertain if the beneficial effect is mediated through prevention of liver fibrosis and cirrhosis. In the past, large-scaled studies on risk factors of liver fibrosis and cirrhosis were difficult to conduct because the assessment required liver biopsy, which was invasive and not acceptable by all patients. In this study, we aimed to determine the effect of alcohol and caffeine consumption on the prevalence of advanced liver fibrosis among chronic HBV-infected patients using transient elastography.
Methods
Study Population We prospectively recruited chronic HBV-infected patients regardless of the disease activity for transient elastography. We received referrals from all primary care and hospital clinics in Hong Kong from July 2006 to February 2008.[12] Chronic HBV infection was diagnosed by positive serology tests for serum HBsAg for at least 6 months. We excluded patients with evidence of other chronic liver disease by screening with antibody against hepatitis C virus, antinuclear antibody, antismooth muscle antibody, antimitochondrial antibody, serum ceruloplasmin, transferrin saturation and ferritin.
From April to May 2008, patients from the original cohort were phone-interviewed with a verbal consent for this study. Questions concerning their alcohol and caffeine consumption (days per week of consumption and amount per day) in the previous year were asked from a standardized questionnaire. Patients who refused to give verbal consent for the phone-interview were not included in this study.
Clinical Evaluation
All patients received comprehensive clinical and laboratory assessment at the time of transient elastography. Serum HBV DNA levels were measured by the TaqMan real-time polymerase chain reaction assay with a range of detection from 100 to 109 copies/ml.[13] Anthropometric parameters including body weight, body height, hip circumference and waist circumference were measured. Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared. Overweight was defined as BMI≥23 kg/m2, and obesity as BMI≥25 kg/m2 according to the Asian and Chinese criteria.[14] We defined moderate and severe obesity as BMI≥28 kg/m2 M and ≥30 kg/m2 respectively. Excessive alcohol intake was defined as >30 g/day in men and >20 g/day in women.[15]
Liver Stiffness Measurement by Transient Elastography
Transient elastography (FibroScan®, Echosens, Paris, France) is one of the new noninvasive modality to evaluate liver fibrosis by measuring liver stiffness. It uses an ultrasound-based technique to measure the speed of propagation of the shear wave through the liver. It can assess approximately 1/500 of the liver's total mass thus reducing the sampling error. Transient elastography has been shown to accurately predict histological advanced fibrosis in different liver diseases.[16–21]
Liver stiffness measurement (LSM) was performed using transient elastography according to the instructions of the manufacturer. Details of the technical background and examination procedure was described previously.[22] Officially trained operators who had performed at least 50 measurements prior this study were responsible to perform the LSM for the patients who had kept fast for at least 8 h. The LSM was considered reliable only if 10 successful acquisitions were obtained, an interquartile range (IQR)/LSM of ≤30% and the success rate was ≥60%. Liver stiffness was expressed in kPa. We defined advanced fibrosis as liver stiffness >9 kPa for those with normal ALT or >12 kPa for those with elevated ALT (F3 fibrosis on histology).[23,24]
Hui's Index
Hui's index was a non-invasive model comprising of BMI, platelet count, serum albumin and total bilirubin [predictive probabilities=exp(3.148+0.167 × BMI+0.088 × bilirubin [μM]−0.151 × albumin [g/L]−0.019 × platelet [109/L])/(1+exp(3.148+0.167 × BMI+0.088 × bilirubin [μM]−0.151 × albumin [g/L]−0.019 × platelet [109/L]))] to predict significant fibrosis (F2 fibrosis on histology).[25] Among 235 chronic hepatitis B patients with liver biopsy, at a cutoff value of 0.15, the sensitivity, specificity, positive and negative predictive values for significant fibrosis were 93, 49, 41 and 95% respectively.
Phone-interview and Questionnaire
A structured questionnaire interview was conducted over the phone to collect data on alcohol and caffeine intake. Participants were specifically asked about the average quantity and frequency of beer, wine, or liquor consumption to estimate the amount of alcohol consumption. The average quantity and frequency of consumption of coffee (regular, instant, ground and decaffeinated), tea (any kind), cola-type soda (regular or decaffeinated) and chocolate (including chocolate milk) was also enquired to estimate the amount of caffeine consumption. Effect of alcohol and caffeine consumption was analyzed with respect to the severity of liver fibrosis as assessed by transient elastography, Hui's Index and other clinical and biochemical parameters
Statistical Analyses
Total caffeine consumption (mg/day) was estimated by summing caffeine from regular coffee (137 mg per cup), regular tea (47 mg per cup), regular and diet cola-type soda (46 mg per bottle or can) and chocolate (7 mg per serving).[26] As for the coffee cup equivalent, the total caffeine consumption per day was divided by 137 (Table 1).
Table 1. Caffeine content in beverages or food
| Beverage or food | Caffeine content (mg per standard unit of consumption) | Units consumed per day (mean ± SD) | Proportion of caffeine consumed in the cohort (%) |
|---|---|---|---|
| Coffee (8 oz) | 137 | 0.30 ± 0.62 | 20.7 |
| Decaffeinated coffee (8 oz) | 3 | 0.01 ± 0.12 | 0 |
| Black tea (8 oz) | 47 | 3.21 ± 5.35 | 75 |
| Cola (12 oz) | 46 | 0.12 ± 0.24 | 2.8 |
| Caffeine free cola (12 oz) | 0 | 0.00 ± 0.06 | 0 |
| Chocolate bar (1 oz) | 7 | 0.38 ± 0.71 | 1.3 |
| Cocoa (8 oz) | 6 | 0.05 ± 0.16 | 0.2 |
Continuous variables were expressed in mean ± standard deviation or median (IQR) as appropriate. Qualitative and quantitative differences between subgroups were analyzed using χ2 or Fisher's exact test for categorical parameters as appropriate, and Student's t-test or Mann–Whitney test for continuous parameters as appropriate. Logistic regression analyses were performed to determine if caffeine and alcohol consumption was associated with liver fibrosis. The multivariate adjusted logistic regression model included covariates that were included in univariate analysis. Spearman's rank correlation was used to correlate caffeine and alcohol intake. All statistical tests were two-sided. Statistical significance was taken as P<0.05. Statistical analysis was performed by Statistical Package for Social Science (SPSS version 17.0, Chicago, IL, USA).
Results
Patient CharacteristicsOverall, 22.7% of 1532 patients in this study came from primary care clinics and 77.3% were from hospital clinics. Six patients were excluded because of anti-HCV positivity, 60 patients because of unreliable LSM results and 421 as we failed to contact for phone-interview because of various reasons (e.g. changed telephone numbers or no answer despite multiple attempts). For patients we able to contact via phone, none of them refused to give verbal consent for the phone interview. A total of 1045 chronic hepatitis B patients were thus included in this study. Majority of patients were males (652, 62.4%), of which 175 (26.8%) were overweight and 210 (32.2%) were obese. Two hundred forty seven (37.9%) male patients had elevated ALT with 71% having HBV DNA of more than 4 logs copies/ml. Four hundred and ninety-nine (47.8%) patients consumed one cup of coffee or more per day, while 231 (22.1%) patients drank alcohol. Only 26 (2.5%) patients reported no intake of both coffee and alcohol. The median (IQR) daily consumption of caffeine from food and beverages was 124 (51.6–275.6) mg/day or 1 (0.4–2.0) cup of coffee/day while alcohol consumption of >20 g/day was 1.9% (Table 2). Two hundred and sixteen (20.7%) patients had LSM suggestive of advanced fibrosis.
Table 2. Baseline characteristics of patients (n=1045)
| Characteristics | |
| Age (years, mean ± SD) | 46.5 ± 12.2 |
| BMI (kg/m2, mean ± SD) | 23.1 ± 3.3 |
| Waist circumference (cm, mean ± SD) | 84.5 ± 10 |
| Platelet [ × 109/L, median (IQR)] | 206 (167–250) |
| ALT [IU/L, median (IQR)] | 41 (26–68) |
| HBeAg positive (%) | 224 (21.4%) |
| HBV DNA (log copies/ml, mean ± SD) | 7.82 ± 8.51 |
| LSM [kPa, median (IQR)] | 6.4 (4.9–9.1) |
| Caffeine per day | |
| Overall [mg, median (IQR)] | 124.0 (51.6–275.6) |
| Coffee-cup equivalent [median (IQR)] | 1 (0.4–2.0) |
| Black-tea-cup equivalent [median (IQR)] | 3 (1.2–5.8) |
| Alcohol consumption per day [g, median (IQR)] | 0 (0–0) |
| 0 g (%) | 810 (77.5%) |
| >0–20 g (%) | 215 (20.6%) |
| >20 g(%) | 20 (1.9%) |
ALT, alanine aminotransferase; BMI, body mass index; IQR, interquartile range; kPa, kilopascal; LSM, liver stiffness measurement; SD, standard deviation.
Caffeine Intake and Liver Fibrosis
Table 3 shows the median total caffeine consumption in mg/day and the coffee cup equivalent according to different patient characteristics where there was no significant difference in caffeine consumption among those with no fibrosis and advanced fibrosis.
Table 3. Daily caffeine consumption according to patient characteristics (n=1045)
| Characteristics | N | Median caffeine intake (mg/day) | Coffee-cup equivalent (caffeine in mg divided by 137) | Black-tea-cup equivalent (caffeine in mg divided by 47) | P-value* |
|---|---|---|---|---|---|
| Sex | |||||
| Male | 652 | 131.5 (53.7–281.7) | 1.0 (0.4–2.1) | 2.9 (1.2–6.1) | 0.129 |
| Female | 393 | 111.9 (48.0–259.4) | 0.8 (0.4–1.9) | 2.3 (1.2–5.5) |  |
| Age | |||||
| ≤45 | 483 | 113.9 (47.0–263.1) | 0.8 (0.3–1.9) | 2.3 (0.9–5.5) | 0.163 |
| >45 | 562 | 128.9 (56.9–282.0) | 0.9 (0.4–2.1) | 2.6 (1.2–6.1) | |
| Body mass index | |||||
| Normal | 515 | 123.0 (48.9–247.7) | 0.9 (0.4–1.8) | 2.6 (1.2–5.2) | 0.315 |
| Overweight | 253 | 141.9 (53.6–284.4) | 1.0 (0.4–2.1) | 2.9 (1.2–6.1) | |
| Obese | 277 | 116.7 (53.1–282.0) | 0.9 (0.4–2.1) | 2.6 (1.2–6.1) | |
| Alanine aminotransferase | |||||
| ≤58 IU/L | 715 | 113.7 (47.4–262.1) | 0.8 (0.3–1.9) | 2.3 (0.9–5.5) | 0.074 |
| >58 IU/L | 330 | 144.1 (59.7–282.0) | 1.1 (0.4–2.1) | 3.2 (1.2–6.1) | |
| HBeAg status | |||||
| Positive | 224 | 137.3 (48.9–280.8) | 1.0 (0.4–2.0) | 2.9 (1.2–5.8) | 0.709 |
| Negative | 821 | 121.2 (53.1–274.7) | 0.9 (0.4–2.0) | 2.6 (1.2–5.8) | |
| Alcohol consumption | |||||
| No | 814 | 113.0 (46.7–243.8) | 0.8 (0.3–1.8) | 2.3 (0.9–5.2) | <0.001 |
| Yes | 231 | 180.1 (83.0–313.1) | 1.3 (0.6–2.3) | 3.8 (1.7–6.7) | |
| Liver stiffness measurement | |||||
| No fibrosis | 829 | 127.6 (48.1–282.0) | 0.9 (0.4–2.1) | 2.6 (1.2–6.1) | 0.355 |
| Advanced fibrosis and cirrhosis | 216 | 111.3 (54.1–239.0) | 0.8 (0.4–1.7) | 2.3 (1.2–4.9) | |
All caffeine intakes were presented as median (interquartile range).
*P-values refer to the comparison of caffeine intake by Kruskal–Wallis's test between groups under the same characteristic (e.g. male vs. female).
There was no significant difference in LSM (Table 4). In addition, caffeine intake had no significant correlation with liver stiffness (rs=0.011, P=0.722) or the Hui's index (rs=−0.002, P=0.948).
Table 4. Characteristics of patients by category of caffeine consumption
| | Coffee-cup equivalent of caffeine intake | P-value* | |||
|---|---|---|---|---|---|
| Non-drinker | >0–1/day | >1–2/day | >2/day | ||
| Number in cohort | 27 | 519 | 237 | 262 | |
| Age (years, mean ± SD) | 49 ± 13 | 46 ± 12 | 46 ± 13 | 47 ± 12 | 0.55 |
| Age (years) | |||||
| ≤45 | 11 (40.7%) | 246 (47.4%) | 110 (46.4%) | 116 (44.3%) | 0.80 |
| >45 | 16 (59.3%) | 273 (52.6%) | 127 (53.6%) | 146 (55.7%) | |
| Sex | |||||
| Female | 13 (3.3%) | 204 (51.9%) | 85 (21.6%) | 91 (23.2%) | 0.37 |
| Male | 14 (2.2%) | 315 (48.3%) | 152 (23.3%) | 171 (26.2%) | |
| Body mass index (kg/m2, mean ± SD) | 23.9 ± 3.3 | 23.1 ± 3.2 | 22.3 ± 8.7 | 24.6 ± 21.4 | 0.16 |
| Body mass index | |||||
| Normal | 12 (44.4%) | 262 (50.5%) | 124 (52.3%) | 117 (44.7%) | 0.36 |
| Overweight | 5 (18.5%) | 117 (22.5%) | 60 (25.3%) | 71 (27.1%) | |
| Obese | 10 (37.1%) | 140 (27.0%) | 53 (22.4%) | 74 (28.2%) | |
| Waist circumference (cm, mean ± SD) | 86.9 ± 11.1 | 84.5 ± 10.1 | 82.8 ± 15.2 | 84.9 ± 9.8 | 0.09 |
| Alanine aminotransferase (IU/L) | 38 (21–64) | 41 (26–64) | 42 (25–72.5) | 41 (27–72) | 0.37 |
| Alanine aminotransferase | |||||
| ≤58 IU/L | 19 (2.7%) | 371 (51.9%) | 154 (21.5%) | 171 (23.9%) | 0.19 |
| >58 IU/L | 8 (2.4%) | 148 (44.8%) | 83 (25.2%) | 91 (27.6%) | |
| Albumin (g/L, mean ± SD) | 44 ± 4 | 44 ± 4 | 44 ± 3 | 44 ± 3 | 0.68 |
| Total bilirubin [μmol/L, median (IQR)] | 13 (10–19) | 13 (9–17) | 13 (9–18) | 13 (9–18) | 0.58 |
| HBeAg status | |||||
| Positive | 4 (1.8%) | 108 (48.2%) | 55 (24.6%) | 57 (25.4%) | 0.73 |
| Negative | 23 (2.8%) | 411 (50.1%) | 182 (22.2%) | 205 (24.9%) | |
| HBV DNA (log copies/ml, mean ± SD) | 7.28 ± 7.98 | 7.91 ± 8.57 | 7.81 ± 8.51 | 7.62 ± 8.23 | 0.34 |
| Liver stiffness measurement (kPa, mean ± SD) | 8.0 ± 6.5 | 8.4 ± 6.6 | 8.4 ± 6.1 | 8.2 ± 5.5 | 0.95 |
| Liver stiffness measurement | |||||
| No fibrosis | 24 (88.9%) | 401 (77.3%) | 189 (79.7%) | 215 (82.1%) | 0.25 |
| Advanced fibrosis and cirrhosis | 3 (11.1%) | 118 (22.7%) | 48 (20.3%) | 47 (17.9%) | |
| Hui's index | |||||
| Unlikely to have fibrosis | 20 (74.1%) | 351 (67.6%) | 164 (69.2%) | 179 (68.3%) | 0.89 |
| With fibrosis | 7 (25.9%) | 168 (32.4%) | 73 (30.8%) | 83 (31.7%) | |
| Alcohol consumption | |||||
| No | 26 (96.3%) | 422 (81.3%) | 181 (76.4%) | 185 (70.6%) | 0.001 |
| Yes | 1 (3.7%) | 97 (18.7%) | 56 (23.6%) | 77 (29.4%) | |
| Daily alcohol intake [g, median (IQR)] | 0 (0–0) | 0 (0–0) | 0 (0–0) | 0 (0–1.1) | 0.001 |
HBV, hepatitis B virus; IQR, interquartile range; SD, standard deviation.
Based on LSM and the Hui's index, caffeine intake by univariate and multivariate analysis was not associated with the risk of advanced liver fibrosis (Table 5).
Table 5. Relationship of caffeine intake, advanced fibrosis and alcohol consumption
Click On Table 5 To Enlarge
Alcohol Intake and Liver Fibrosis
Majority of patients (77.9%) did not consume alcohol while only 11 out of 231 patients with alcohol consumption had excessive alcohol drinking. The highest alcohol consumption per day was 88 g. Advanced fibrosis was only prevalent in 26 (18.8%) of those with mild to moderate alcohol consumption compared with 190 (21.0%) of those non-alcoholic drinkers (P=0.57).
Those who drink alcohol have significantly higher caffeine consumption than those who do not drink alcohol (Table 3). Caffeine intake had positive correlation with alcohol intake (rs=0.167, P<0.001).
DiscussionIn this large territory-wide observational study with prospective recruitment, we assessed the relationship between caffeine and alcohol consumption and the risk of advanced liver fibrosis in chronic hepatitis B patients with different disease severity. Caffeine intake was not associated with advanced fibrosis. Patients who drank coffee regularly were more likely to consume alcohol. On the other hand, few chronic hepatitis B patients in Hong Kong had excessive alcohol consumption. Mild to moderate alcohol consumption did not increase the risk of advanced fibrosis.
Coffee is a rich source of a number of phenol compounds with antioxidant effects in vitro, with main polyphenols are phenolic acids such as chlorogenic and caffeic acid.[27] Caffeine and its metabolites, 1-methylxanthine and 1-methyluric acid, have also been shown to have antioxidant properties.[28] Caffeine has also been reported to inhibit chemical carcinogenesis and ultraviolet B light induced carcinogenesis in mice.[29,30] Coffee is also found to decrease the progression of liver disease among those with advanced hepatic fibrosis[7] and even reduce the risk of HCC[31,32] One study[33] concluded that approximately 2 coffee cup equivalents/day was associated with less severe hepatic fibrosis, but the beneficial effect was only shown in patients with chronic hepatitis C rather than patients with other liver diseases. A case control study in Italy showed that the protective effect of coffee on HCC was mainly in people who are not chronically infected with HBV.[31] Overall, previous studies included mostly chronic hepatitis C patients and HBV patients were underrepresented. Based on our results, it appears that liver fibrosis in chronic hepatitis B patients is determined mainly by virological and genetic factors and less affected by caffeine intake.
In previous reports, men who have daily alcohol intake of 30–39 g and women who consumed 20–29 g of alcohol daily would have an increased risk of all cause mortality among the general population.[34] Seventy-eight percent of our cohort did not drink alcohol at all while only 1% of patient had history of excessive alcohol consumption. Nonetheless, we could not find any deleterious effect of mild to moderate alcohol consumption to liver fibrosis. As alcohol drinkers were mostly coffee drinkers as well, the concomitant caffeine intake might but one of the confounders leading to the absence of increased risk of advanced fibrosis in alcohol drinkers. Nonetheless only a minority (1% of the study population has excessive alcohol intake, we believe that the major reason of the absence of increased risk of advanced fibrosis in alcohol drinkers was the modest instead of excess amount of alcohol use. Because most of our patients had no advanced liver disease as compared with other studies (33, 35–38), our results could not be extrapolated to cirrhotic patients. Less than 20 g of alcohol intake tends not to increase risk of advanced fibrosis in our present study. Controlled prospective studies may be done in the future to verify this.
One of the limitations of our study was the lack of liver biopsy. As liver biopsy is an invasive procedure, studies using histological fibrosis as an endpoint might suffer from the problem of small sample size and selection bias towards patients with active or advanced liver disease.[39] On the other hand, a non-invasive test such as transient elastography could be applied to a large number of patients with different disease severity. In fact, transient elastography has been shown to be highly accurate in detecting histological advanced fibrosis and cirrhosis in chronic hepatitis B patients,[16,23] though the accuracy might be limited in settings of grossly elevated transaminase levels,[16] but not in the presence of steatosis.[18] Secondly, recall bias might occur during the questionnaire survey and affect the accuracy of the measurement of the caffeine intake measured. We have tried to minimize this bias by using a quantity-frequency questionnaire, which has been previously adapted in a study demonstrating the protective effect of coffee consumption from HCC.[11] There were 159 (15.2%) participants drinking >2–3 coffee-cup equivalents/day and 103 (9.9%) drinking >3 coffee-cup equivalents/day. Because the above numbers for these groups were low and previous finding showing 2 coffee-cup equivalents/day was associated to less severe liver fibrosis, we combined these groups for analysis. Because this is a cross sectional study, possible unmeasured as well as poorly measured confounding factors that may affect the interpretation of our data such as changes in the drinking habit of the patients, variability of caffeine intake over time, socioeconomic status, educational level were not considered in our analysis.
In conclusion, cross-sectional caffeine intake does not affect liver stiffness in chronic HBV-infected patients. The protective effect of caffeine on HCC demonstrated in previous studies is probably via the pathway other than reducing liver fibrosis. The prevalence of advanced liver fibrosis is low (20%) in chronic hepatitis B patients with daily alcohol consumption below 20 g.
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