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HepB Forum : Unofficial Research Thread (URT) Tx info
I am reposting articles / summaries on the treatment management of chronic HepB. "cajim" located these articles which are quite informative. I thought about putting them on a seaprate Health Page but didn't think it was appropriate since we didn't write them.
Let's make this a sort of "Unofficial Research Thread" or "URT" for this type of information. Let's keep this URT free of comments. For comments, start a new thread indicating that it's in reference to URT.
We'll see how it goes.
Let's make this a sort of "Unofficial Research Thread" or "URT" for this type of information. Let's keep this URT free of comments. For comments, start a new thread indicating that it's in reference to URT.
We'll see how it goes.
Notes on “Basal core-promoter mutant of hepatitis B virus and progression of liver disease in hepatitis B e antigen-negative chronic hepatitis B,” Chih-Lin Lin et al., Liver International, Volume 25 Issue 3 Page 564 - June 2005.
Background/Aims: The long-term outcomes in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B are distinct from those in HBeAg-positive chronic hepatitis. However, the molecular virological factors that contribute to the progression of liver disease in this special clinical setting remain largely unknown. We thus investigated the association of hepatitis B virus (HBV) genotypes as well as precore/basal core-promoter mutations with the clinical and virological characteristics of patients with HBeAg-negative chronic hepatitis B in Taiwan.
Methods: HBV genotypes and sequences of precore and basal core-promoter regions of the HBV genome were determined in 174 HBeAg-negative chronic HBV infection patients including 62 inactive carriers and 112 with different stages of liver disease.
Results: HBV carriers with older age (>50 years) (odds ratio, 9.09; 95% confidence interval (CI), 3.2225, P<0.001) and basal core-promoter mutant of HBV (odds ratio, 4.12; 95% CI, 1.4112.03, P=0.01) were associated with the development of liver cirrhosis and hepatocellular carcinoma (HCC). The gender-related risk factors associated with the development of liver cirrhosis and HCC were further analyzed, and basal core-promoter mutant was only associated with the development of liver cirrhosis and HCC in male carriers (odds ratio, 4.35; 95% CI, 1.3014.52, P=0.02).
Conclusions: The risk of development of liver cirrhosis and HCC is significantly increased in patients with advanced age as well as with basal core-promoter mutant of HBV. In addition, basal core-promoter mutant might contribute to the gender difference of the progression of liver disease in HBeAg-negative chronic hepatitis B in Taiwan.
Background/Aims: The long-term outcomes in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B are distinct from those in HBeAg-positive chronic hepatitis. However, the molecular virological factors that contribute to the progression of liver disease in this special clinical setting remain largely unknown. We thus investigated the association of hepatitis B virus (HBV) genotypes as well as precore/basal core-promoter mutations with the clinical and virological characteristics of patients with HBeAg-negative chronic hepatitis B in Taiwan.
Methods: HBV genotypes and sequences of precore and basal core-promoter regions of the HBV genome were determined in 174 HBeAg-negative chronic HBV infection patients including 62 inactive carriers and 112 with different stages of liver disease.
Results: HBV carriers with older age (>50 years) (odds ratio, 9.09; 95% confidence interval (CI), 3.2225, P<0.001) and basal core-promoter mutant of HBV (odds ratio, 4.12; 95% CI, 1.4112.03, P=0.01) were associated with the development of liver cirrhosis and hepatocellular carcinoma (HCC). The gender-related risk factors associated with the development of liver cirrhosis and HCC were further analyzed, and basal core-promoter mutant was only associated with the development of liver cirrhosis and HCC in male carriers (odds ratio, 4.35; 95% CI, 1.3014.52, P=0.02).
Conclusions: The risk of development of liver cirrhosis and HCC is significantly increased in patients with advanced age as well as with basal core-promoter mutant of HBV. In addition, basal core-promoter mutant might contribute to the gender difference of the progression of liver disease in HBeAg-negative chronic hepatitis B in Taiwan.
Notes on “Entecavir Could Dominate First-Line Hepatitis-B Monotherapy,” Reports Pharmaprojects, 2005.
LONDON, May 19 /PRNewswire/ -- Bristol-Myers Squibb's recently-launched anti-hepatitis B (HBV) drug, entecavir (Baraclude), could dominate the hepatitis-B therapeutic market, according to information reported in Pharmaprojects, the leading pharmaceutical pipeline-tracking database. Results presented at the recent 18th International Conference on Antiviral Research held in Barcelona, Spain, last month appeared to support entecavir's superiority over the widely-used anti-hepatitis-B drug, lamivudine (Epivir). Hepatitis-B is seen as a growing threat across the world, with calls in the UK last week for vaccination to be offered to all infants, and not just at-risk populations.
Bristol Myers Squibb's entecavir, indicated for the first-line treatment of chronic HBV infection in previously-untreated adults and as second-line therapy in patients who have failed lamivudine therapy, was launched in early April 2005 in the US, and is awaiting EU registration. It acts by inhibiting viral replication and slowing the progression of chronic hepatitis-B. Its initial approval is based on 3 clinical trials conducted in hepatitis-B, where it was compared to lamivudine over 48 weeks. As Pharmaprojects' extensive clinical trial information reports, patients treated with entecavir showed significant improvement in liver histology, including reduced liver inflammation and liver scarring, and there was a greater reduction in HBV viral load compared to lamivudine. Furthermore, a higher proportion of patients treated with entecavir showed significant improvement compared to lamividine. It also demonstrated comparable safety to lamivudine and the adverse events were typical of those seen with HBV therapy.
There are currently 58 drugs in active development for the treatment or prevention of HBV, of which 10 are listed on Pharmaprojects as being launched. These include the antivirals lamivudine and adefovir, adefovir dipivoxil, and a number of unmodified pegylated interferons. Other interesting candidates which have not yet reached the market include Novartis' telbivudine, which is in a multicentre Phase III trial which is expected to be completed by late 2005. Further back along the pipeline are projects such as MIV-210, an antiviral prodrug inhibitor of HBV, underdevelopment by Medivir. Phase I trials for this promising candidate are complete, and a Phase II a trial is scheduled for 2005. However, now launched, entecavir could be set to be the primary therapeutic option for the foreseeable future.
Chronic hepatitis-B is a potentially life-threatening disease affecting approximately 1.25 million Americans, according to the US Centers for Disease Control and Prevention. Worldwide, it afflicts 400 million people, 75% of which live in the Asia-Pacific region. It is caused by the hepatitis-B virus which attacks the liver, and can lead to lifelong infection, cirrhosis of the liver, liver cancer, liver failure and even death. The HBV market in 2004 was estimated at US $551 million with 2-fold more sales accounted for by antivirals than immunomodulators. Some sources suggest that entecavir will exceed the US $300 million per year mark before its patent expires, and will dominate first-line HBV therapy.
LONDON, May 19 /PRNewswire/ -- Bristol-Myers Squibb's recently-launched anti-hepatitis B (HBV) drug, entecavir (Baraclude), could dominate the hepatitis-B therapeutic market, according to information reported in Pharmaprojects, the leading pharmaceutical pipeline-tracking database. Results presented at the recent 18th International Conference on Antiviral Research held in Barcelona, Spain, last month appeared to support entecavir's superiority over the widely-used anti-hepatitis-B drug, lamivudine (Epivir). Hepatitis-B is seen as a growing threat across the world, with calls in the UK last week for vaccination to be offered to all infants, and not just at-risk populations.
Bristol Myers Squibb's entecavir, indicated for the first-line treatment of chronic HBV infection in previously-untreated adults and as second-line therapy in patients who have failed lamivudine therapy, was launched in early April 2005 in the US, and is awaiting EU registration. It acts by inhibiting viral replication and slowing the progression of chronic hepatitis-B. Its initial approval is based on 3 clinical trials conducted in hepatitis-B, where it was compared to lamivudine over 48 weeks. As Pharmaprojects' extensive clinical trial information reports, patients treated with entecavir showed significant improvement in liver histology, including reduced liver inflammation and liver scarring, and there was a greater reduction in HBV viral load compared to lamivudine. Furthermore, a higher proportion of patients treated with entecavir showed significant improvement compared to lamividine. It also demonstrated comparable safety to lamivudine and the adverse events were typical of those seen with HBV therapy.
There are currently 58 drugs in active development for the treatment or prevention of HBV, of which 10 are listed on Pharmaprojects as being launched. These include the antivirals lamivudine and adefovir, adefovir dipivoxil, and a number of unmodified pegylated interferons. Other interesting candidates which have not yet reached the market include Novartis' telbivudine, which is in a multicentre Phase III trial which is expected to be completed by late 2005. Further back along the pipeline are projects such as MIV-210, an antiviral prodrug inhibitor of HBV, underdevelopment by Medivir. Phase I trials for this promising candidate are complete, and a Phase II a trial is scheduled for 2005. However, now launched, entecavir could be set to be the primary therapeutic option for the foreseeable future.
Chronic hepatitis-B is a potentially life-threatening disease affecting approximately 1.25 million Americans, according to the US Centers for Disease Control and Prevention. Worldwide, it afflicts 400 million people, 75% of which live in the Asia-Pacific region. It is caused by the hepatitis-B virus which attacks the liver, and can lead to lifelong infection, cirrhosis of the liver, liver cancer, liver failure and even death. The HBV market in 2004 was estimated at US $551 million with 2-fold more sales accounted for by antivirals than immunomodulators. Some sources suggest that entecavir will exceed the US $300 million per year mark before its patent expires, and will dominate first-line HBV therapy.
Notes on “Viral Load in Chronic Hepatitis B Emerges as Strong Predictor of
Hepatocellular Carcinoma Risk,” Bruce Sylvester.
CHICAGO, IL -- May 17, 2005 -- An elevated level of serum hepatitis B virus (HBV) DNA is a strong predictor of hepatocellular carcinoma (HCC) in chronically infected patients, regardless of their serum alanine aminotransaminase level (ALT), researchers report.
The findings were presented here in a "Poster of Distinction" on May 16th at the 2005 Digestive Diseases Week.
Treatment guidelines for HCC, which exclude chronic hepatitis B patients with normal serum ALT need to be reevaluated, said presenter and lead investigator Uchenna Iloeje, MD, director, Epidemiology and Outcome Research in Virology, Bristol-Myers Squibb, Wallingford, Connecticut, United States.
"Subjects who are currently on the guidelines and have normal serum ALT don't qualify for treatment," Dr. Iloeje said.
"We found that, in this subset of patients, you can use the hepatitis B DNA viral level to stratify patients for risk of progression to hepatocellular carcinoma, and identifying those who might become candidates for beneficial therapy who are now being overlooked," Dr. Iloeje said.
"For the practicing physician, this would mean that for the patient who has normal ALT who is now viewed as at no risk, a change of clinical attitude is needed, he explained.
Dr. Iloeje said that physicians should be aware of the viral load in HBV patients with normal ALT, and depending on the viral load, determine the need for progressive monitoring and whether treatment intervention will be needed.
The investigators enrolled 3851 subjects who had been diagnosed with chronic HBV from seven townships in Taiwan between 1991 and 1992. Cohort baseline serum samples were analyzed for hepatitis B surface antigen (HBsAg), hepatitis Be antigen (HBeAg), and serum ALT. HBV DNA was evaluated by polymerase chain reaction.
They determined diagnoses of HCC using data linkage with computerized profiles of the National Cancer Registry and Death Certification System in Taiwan.
Based on data from 43,993 person-years of follow-up over 11 years, 176 subjects were eventually diagnosed with HCC (4.6%).
Of the 3851 subjects, 84.9% were seronegative for HBeAg at entry and of these, 34.3% had elevated serum HBV DNA levels, and 32.2% had normal serum ALT levels.
The researchers noted that 15% of the total cohort were found to be HBeAg-positive, with 96% of them having elevated HBV DNA at study entry and 83% having normal serum ALT levels.
"In subjects with normal ALT, HBV DNA level strongly predicts future HCC events, the investigators concluded. "Serum HBV DNA may be a better and more reliable predictor of subjects at risk of a future HCC event than serum ALT level.
"Patients with normal serum ALT and high levels of circulating virus are at high risk of HCC and deserve consideration for therapy," they added.
Hepatocellular Carcinoma Risk,” Bruce Sylvester.
CHICAGO, IL -- May 17, 2005 -- An elevated level of serum hepatitis B virus (HBV) DNA is a strong predictor of hepatocellular carcinoma (HCC) in chronically infected patients, regardless of their serum alanine aminotransaminase level (ALT), researchers report.
The findings were presented here in a "Poster of Distinction" on May 16th at the 2005 Digestive Diseases Week.
Treatment guidelines for HCC, which exclude chronic hepatitis B patients with normal serum ALT need to be reevaluated, said presenter and lead investigator Uchenna Iloeje, MD, director, Epidemiology and Outcome Research in Virology, Bristol-Myers Squibb, Wallingford, Connecticut, United States.
"Subjects who are currently on the guidelines and have normal serum ALT don't qualify for treatment," Dr. Iloeje said.
"We found that, in this subset of patients, you can use the hepatitis B DNA viral level to stratify patients for risk of progression to hepatocellular carcinoma, and identifying those who might become candidates for beneficial therapy who are now being overlooked," Dr. Iloeje said.
"For the practicing physician, this would mean that for the patient who has normal ALT who is now viewed as at no risk, a change of clinical attitude is needed, he explained.
Dr. Iloeje said that physicians should be aware of the viral load in HBV patients with normal ALT, and depending on the viral load, determine the need for progressive monitoring and whether treatment intervention will be needed.
The investigators enrolled 3851 subjects who had been diagnosed with chronic HBV from seven townships in Taiwan between 1991 and 1992. Cohort baseline serum samples were analyzed for hepatitis B surface antigen (HBsAg), hepatitis Be antigen (HBeAg), and serum ALT. HBV DNA was evaluated by polymerase chain reaction.
They determined diagnoses of HCC using data linkage with computerized profiles of the National Cancer Registry and Death Certification System in Taiwan.
Based on data from 43,993 person-years of follow-up over 11 years, 176 subjects were eventually diagnosed with HCC (4.6%).
Of the 3851 subjects, 84.9% were seronegative for HBeAg at entry and of these, 34.3% had elevated serum HBV DNA levels, and 32.2% had normal serum ALT levels.
The researchers noted that 15% of the total cohort were found to be HBeAg-positive, with 96% of them having elevated HBV DNA at study entry and 83% having normal serum ALT levels.
"In subjects with normal ALT, HBV DNA level strongly predicts future HCC events, the investigators concluded. "Serum HBV DNA may be a better and more reliable predictor of subjects at risk of a future HCC event than serum ALT level.
"Patients with normal serum ALT and high levels of circulating virus are at high risk of HCC and deserve consideration for therapy," they added.
Notes on “Combination of Nucleoside Analogues in the Treatment of Chronic Hepatitis B,” 2005.
Long-term antiviral therapy is therefore required in most patients with chronic hepatitis B who do not mount a vigorous immune response, to avoid relapse of viral replication after treatment withdrawal.
However, the major drawback of prolonged therapy is the selection of drug-resistant mutants generated by the spontaneous error rate of the viral polymerase. Therefore, one of the major research areas is the evaluation of combination anti-HBV therapy to delay or prevent the occurrence of drug-resistant mutants.
Owing to the persistence of hepatitis B virus (HBV) and the selection of drug-resistant mutants, a new concept of antiviral therapy for chronic hepatitis B relies on the combination of nucleoside analogues. In experimental models of HBV infection, several key points concerning these combinations were addressed:
(i) Is it possible to achieve a synergic antiviral effect with polymerase inhibitors?
(ii) Is it possible to impact on intracellular viral covalently closed circular DNA?
(iii) What is the impact of the cross-resistance patterns of the different nucleoside analogues?
(iv) What is the effect of viral load suppression on the restoration of specific antiviral cellular responses?
The clinical impact of these key issues is discussed in the perspective of new clinical trials.
It is important to note that most of the nucleoside analogues administered in monotherapy may select for drug-resistant mutants, as this was shown with HIV. It was shown that lamivudine (Epivir-HBV) and emtricitabine share the same cross-resistance profile with the selection of the M204V or M204I polymerase mutants that are susceptible to adefovir (Hepsera).
To date, telbivudine is associated with the emergence of the M204I mutant, which is resistant to lamivudine and emtricitabine.
Adefovir selects for the A181V and N236T mutants, which are susceptible to lamivudine.
Entecavir is less active against lamivudine-resistant strains and selects for specific resistance mutations on a genetic background of lamivudine resistance mutations.
Clevudine is not active against the lamivudine-resistant strains and was shown to select for the same resistant mutants in woodchucks chronically infected with WHV. It also exhibits some antiviral activity against the adefovir-resistant strains in vitro.
Elvucitabine is not active against the lamivudine-resistant mutants but is active against the adefovir-resistant strains.
Tenofovir shows a good antiviral efficacy against the lamivudine-resistant strains and slightly decreased activity against the adefovir-resistant mutants. A tenofovir-resistant mutant was also recently described.
Given the cross-resistance profile of these drugs, the rationale is to combine the drugs that would inhibit the emergence of drug-resistant strains to one or the other drug. This may lead to an improved management of antiviral therapy of chronic HBV infection in the long term.
Perspectives for the Treatment of Chronic Hepatitis B
The current understanding of chronic HBV infection and its treatment suggest that the patients who are more likely to seroconvert anti-HBeAg antibodies should first receive a course of pegylated interferon alfa.
In this setting, pegylated interferon therapy may be the best option because of the possibility of short-term therapy and the absence of selection of resistant mutants. On the other hand, the majority of patients who are non-seroconverters or are infected with a pre-core mutant will require long-term maintenance therapy to control viral replication and liver disease. In this view, the development of clevudine and emtricitabine opens new avenues in the management of these patients.
Clevudine, with its unusual antiviral activity profile, may be the first nucleoside analogue to be used as a relative short-term treatment and to achieve sustained control of viral replication even after treatment withdrawal.
On the other hand, emtricitabine, as well as other drugs in development, offers a new option for combination of nucleoside analogues that do not share the same cross-resistance profile. For instance, it may be used in combination with adefovir or tenofovir.
The evaluation of these combination strategies will need to rely on accurate endpoints and timing for such analysis.
Long-term antiviral therapy is therefore required in most patients with chronic hepatitis B who do not mount a vigorous immune response, to avoid relapse of viral replication after treatment withdrawal.
However, the major drawback of prolonged therapy is the selection of drug-resistant mutants generated by the spontaneous error rate of the viral polymerase. Therefore, one of the major research areas is the evaluation of combination anti-HBV therapy to delay or prevent the occurrence of drug-resistant mutants.
Owing to the persistence of hepatitis B virus (HBV) and the selection of drug-resistant mutants, a new concept of antiviral therapy for chronic hepatitis B relies on the combination of nucleoside analogues. In experimental models of HBV infection, several key points concerning these combinations were addressed:
(i) Is it possible to achieve a synergic antiviral effect with polymerase inhibitors?
(ii) Is it possible to impact on intracellular viral covalently closed circular DNA?
(iii) What is the impact of the cross-resistance patterns of the different nucleoside analogues?
(iv) What is the effect of viral load suppression on the restoration of specific antiviral cellular responses?
The clinical impact of these key issues is discussed in the perspective of new clinical trials.
It is important to note that most of the nucleoside analogues administered in monotherapy may select for drug-resistant mutants, as this was shown with HIV. It was shown that lamivudine (Epivir-HBV) and emtricitabine share the same cross-resistance profile with the selection of the M204V or M204I polymerase mutants that are susceptible to adefovir (Hepsera).
To date, telbivudine is associated with the emergence of the M204I mutant, which is resistant to lamivudine and emtricitabine.
Adefovir selects for the A181V and N236T mutants, which are susceptible to lamivudine.
Entecavir is less active against lamivudine-resistant strains and selects for specific resistance mutations on a genetic background of lamivudine resistance mutations.
Clevudine is not active against the lamivudine-resistant strains and was shown to select for the same resistant mutants in woodchucks chronically infected with WHV. It also exhibits some antiviral activity against the adefovir-resistant strains in vitro.
Elvucitabine is not active against the lamivudine-resistant mutants but is active against the adefovir-resistant strains.
Tenofovir shows a good antiviral efficacy against the lamivudine-resistant strains and slightly decreased activity against the adefovir-resistant mutants. A tenofovir-resistant mutant was also recently described.
Given the cross-resistance profile of these drugs, the rationale is to combine the drugs that would inhibit the emergence of drug-resistant strains to one or the other drug. This may lead to an improved management of antiviral therapy of chronic HBV infection in the long term.
Perspectives for the Treatment of Chronic Hepatitis B
The current understanding of chronic HBV infection and its treatment suggest that the patients who are more likely to seroconvert anti-HBeAg antibodies should first receive a course of pegylated interferon alfa.
In this setting, pegylated interferon therapy may be the best option because of the possibility of short-term therapy and the absence of selection of resistant mutants. On the other hand, the majority of patients who are non-seroconverters or are infected with a pre-core mutant will require long-term maintenance therapy to control viral replication and liver disease. In this view, the development of clevudine and emtricitabine opens new avenues in the management of these patients.
Clevudine, with its unusual antiviral activity profile, may be the first nucleoside analogue to be used as a relative short-term treatment and to achieve sustained control of viral replication even after treatment withdrawal.
On the other hand, emtricitabine, as well as other drugs in development, offers a new option for combination of nucleoside analogues that do not share the same cross-resistance profile. For instance, it may be used in combination with adefovir or tenofovir.
The evaluation of these combination strategies will need to rely on accurate endpoints and timing for such analysis.
· Adequate blinding.
· Detailed data about Systematic standardized surveillance for adverse effects.
· Attention to specific study populations (e.g., patients with hepatitis B virus [HBV], or hepatitis C virus [HCV], or mixed infection or coinfection with human immunodeficiency virus [HIV]), comorbidities, alcohol consumption, and potential confounders.
There also should be detailed attention to preparation, standardization, and bioavailability of different formulations of milk thistle (e.g., standardized silymarin extract and silybin-phosphatidylcholine complex).
Precise mechanisms of action specific to different etiologies and stages of liver disease need explication. Further mechanistic investigations are needed and should be considered before, or in concert with, studies of clinical effectiveness. More information is needed about effectiveness of milk thistle for severe acute ingestion of hepatotoxins, such as occupational exposures, acetaminophen overdose, and amanita poisoning.
· Detailed data about Systematic standardized surveillance for adverse effects.
· Attention to specific study populations (e.g., patients with hepatitis B virus [HBV], or hepatitis C virus [HCV], or mixed infection or coinfection with human immunodeficiency virus [HIV]), comorbidities, alcohol consumption, and potential confounders.
There also should be detailed attention to preparation, standardization, and bioavailability of different formulations of milk thistle (e.g., standardized silymarin extract and silybin-phosphatidylcholine complex).
Precise mechanisms of action specific to different etiologies and stages of liver disease need explication. Further mechanistic investigations are needed and should be considered before, or in concert with, studies of clinical effectiveness. More information is needed about effectiveness of milk thistle for severe acute ingestion of hepatotoxins, such as occupational exposures, acetaminophen overdose, and amanita poisoning.
· Available data were insufficient to sort six studies into specific etiologic categories; these were grouped as chronic liver disease of mixed etiologies. In three of the six studies that reported multiple outcome measures, at least one outcome measure improved significantly with milk thistle compared with placebo, but there were no differences between milk thistle and placebo for one or more of the other outcome measures in each study. Two studies indicated a possible survival benefit.
· Three placebo-controlled studies evaluated milk thistle for viral hepatitis. The one acute viral hepatitis study reported latest outcome measures at 28 days and showed significant improvement in aspartate aminotransferase and bilirubin. The two studies of chronic viral hepatitis differed markedly in duration of therapy (7 days and 1 year). The shorter study showed improvement in aminotransferases for milk thistle compared with placebo but not other laboratory measures. In the longer study, milk thistle was associated with a nonsignificant trend toward histologic improvement, the only outcome measure reported.
· Two trials included patients with alcoholic or nonalcoholic cirrhosis. The milk thistle arms showed a trend toward improved survival in one trial and significantly improved survival for subgroups with alcoholic cirrhosis or Child's Group A severity. The second study reported no significant improvement in laboratory measures and survival for other clinical subgroups, but no data were given.
· Two trials specifically studied patients with alcoholic cirrhosis. Duration of therapy was unclear in the first, which reported no improvement in laboratory measures of liver function, hepatomegaly, jaundice, ascites, or survival. However, there were nonsignificant trends favoring milk thistle in incidence of encephalopathy and gastrointestinal bleeding and in survival for subjects with concomitant hepatitis C. The second study, after treatment for 30 days, reported significant improvements in aminotransferases but not bilirubin for milk thistle compared with placebo.
· Three trials evaluated milk thistle in the setting of hepatotoxic drugs: one for therapeutic use and two for prophylaxis with milk thistle. Results were mixed among the three trials.
· Exploratory meta-analyses generally showed positive but small and nonsignificant effect sizes and a sprinkling of significant positive effects.
· No studies were identified regarding milk thistle and cholestatic liver disease or primary hepatic malignancy.
· Available evidence does not establish whether effectiveness of milk thistle varies across preparations. One Phase II trial suggested that effectiveness may vary with dose of milk thistle.
Adverse Effects
Adverse effects associated with oral ingestion of milk thistle include:
· Gastrointestinal problems (e.g., nausea, diarrhea, dyspepsia, flatulence, abdominal bloating, abdominal fullness or pain, anorexia, and changes in bowel habits).
· Headache.
· Skin reactions (pruritus, rash, urticaria, and eczema).
· Neuropsychological events (e.g., asthenia, malaise, and insomnia).
· Arthralgia.
· Rhinoconjunctivitis.
· Impotence.
· Anaphylaxis.
However, causality is rarely addressed in available reports. For randomized trials reporting adverse effects, incidence was approximately equal in milk thistle and control groups.
Conclusions
Clinical efficacy of milk thistle is not clearly established. Interpretation of the evidence is hampered by poor study methods and/or poor quality of reporting in publications. Problems in study design include heterogeneity in etiology and extent of liver disease, small sample sizes, and variation in formulation, dosing, and duration of milk thistle therapy.
Possible benefit has been shown most frequently, but not consistently, for improvement in aminotransferases and liver function tests are overwhelmingly the most common outcome measure studied.
Survival and other clinical outcome measures have been studied least often, with both positive and negative findings. Available evidence is not sufficient to suggest whether milk thistle may be more effective for some liver diseases than others or if effectiveness might be related to duration of therapy or chronicity and severity of liver disease.
Regarding adverse effects, little evidence is available regarding causality, but available evidence does suggest that milk thistle is associated with few, and generally minor, adverse effects.
Despite substantial in vitro and animal research, the mechanism of action of milk thistle is not fully defined and may be multifactorial. A systematic review of this evidence to clarify what is known and identify gaps in knowledge would be important to guide design of future studies of the mechanisms of milk thistle and clinical trials.
Future Research
The type, frequency, and severity of adverse effects related to milk thistle preparations should be quantified. Whether adverse effects are specific to dose, particular preparations, or additional herbal ingredients needs elucidation, especially in light of equivalent frequencies of adverse effects in available randomized trials. When adverse effects are reported, concomitant use of other medications and product content analysis should also be reported so that other drugs, excipients, or contaminants may be scrutinized as potential causal factors.
Characteristics of future studies in humans should include:
· Longer and larger randomized trials.
· Clinical as well as physiologic outcome measures.
· Histologic outcomes.
· Three placebo-controlled studies evaluated milk thistle for viral hepatitis. The one acute viral hepatitis study reported latest outcome measures at 28 days and showed significant improvement in aspartate aminotransferase and bilirubin. The two studies of chronic viral hepatitis differed markedly in duration of therapy (7 days and 1 year). The shorter study showed improvement in aminotransferases for milk thistle compared with placebo but not other laboratory measures. In the longer study, milk thistle was associated with a nonsignificant trend toward histologic improvement, the only outcome measure reported.
· Two trials included patients with alcoholic or nonalcoholic cirrhosis. The milk thistle arms showed a trend toward improved survival in one trial and significantly improved survival for subgroups with alcoholic cirrhosis or Child's Group A severity. The second study reported no significant improvement in laboratory measures and survival for other clinical subgroups, but no data were given.
· Two trials specifically studied patients with alcoholic cirrhosis. Duration of therapy was unclear in the first, which reported no improvement in laboratory measures of liver function, hepatomegaly, jaundice, ascites, or survival. However, there were nonsignificant trends favoring milk thistle in incidence of encephalopathy and gastrointestinal bleeding and in survival for subjects with concomitant hepatitis C. The second study, after treatment for 30 days, reported significant improvements in aminotransferases but not bilirubin for milk thistle compared with placebo.
· Three trials evaluated milk thistle in the setting of hepatotoxic drugs: one for therapeutic use and two for prophylaxis with milk thistle. Results were mixed among the three trials.
· Exploratory meta-analyses generally showed positive but small and nonsignificant effect sizes and a sprinkling of significant positive effects.
· No studies were identified regarding milk thistle and cholestatic liver disease or primary hepatic malignancy.
· Available evidence does not establish whether effectiveness of milk thistle varies across preparations. One Phase II trial suggested that effectiveness may vary with dose of milk thistle.
Adverse Effects
Adverse effects associated with oral ingestion of milk thistle include:
· Gastrointestinal problems (e.g., nausea, diarrhea, dyspepsia, flatulence, abdominal bloating, abdominal fullness or pain, anorexia, and changes in bowel habits).
· Headache.
· Skin reactions (pruritus, rash, urticaria, and eczema).
· Neuropsychological events (e.g., asthenia, malaise, and insomnia).
· Arthralgia.
· Rhinoconjunctivitis.
· Impotence.
· Anaphylaxis.
However, causality is rarely addressed in available reports. For randomized trials reporting adverse effects, incidence was approximately equal in milk thistle and control groups.
Conclusions
Clinical efficacy of milk thistle is not clearly established. Interpretation of the evidence is hampered by poor study methods and/or poor quality of reporting in publications. Problems in study design include heterogeneity in etiology and extent of liver disease, small sample sizes, and variation in formulation, dosing, and duration of milk thistle therapy.
Possible benefit has been shown most frequently, but not consistently, for improvement in aminotransferases and liver function tests are overwhelmingly the most common outcome measure studied.
Survival and other clinical outcome measures have been studied least often, with both positive and negative findings. Available evidence is not sufficient to suggest whether milk thistle may be more effective for some liver diseases than others or if effectiveness might be related to duration of therapy or chronicity and severity of liver disease.
Regarding adverse effects, little evidence is available regarding causality, but available evidence does suggest that milk thistle is associated with few, and generally minor, adverse effects.
Despite substantial in vitro and animal research, the mechanism of action of milk thistle is not fully defined and may be multifactorial. A systematic review of this evidence to clarify what is known and identify gaps in knowledge would be important to guide design of future studies of the mechanisms of milk thistle and clinical trials.
Future Research
The type, frequency, and severity of adverse effects related to milk thistle preparations should be quantified. Whether adverse effects are specific to dose, particular preparations, or additional herbal ingredients needs elucidation, especially in light of equivalent frequencies of adverse effects in available randomized trials. When adverse effects are reported, concomitant use of other medications and product content analysis should also be reported so that other drugs, excipients, or contaminants may be scrutinized as potential causal factors.
Characteristics of future studies in humans should include:
· Longer and larger randomized trials.
· Clinical as well as physiologic outcome measures.
· Histologic outcomes.
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