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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 “Milk Thistle: Effects on Liver Disease and Cirrhosis and Clinical Adverse Effects,” 2005
This evidence report details a systematic review summarizing clinical studies of milk thistle in humans.
Overview
The scientific name for milk thistle is Silybum marianum. It is a member of the aster or daisy family and has been used by ancient physicians and herbalists to treat a range of liver and gallbladder diseases and to protect the liver against a variety of poisons.
Two areas are addressed in the report:
· Effects of milk thistle on liver disease of alcohol, viral, toxin, cholestatic, and primary malignancy etiologies.
· Clinical adverse effects associated with milk thistle ingestion or contact.
The report was requested by the National Center for Complementary and Alternative Medicine, a component of the National Institutes of Health, and sponsored by the Agency for Healthcare Research and Quality.
Reporting the Evidence
Specifically, the report addresses 10 questions regarding whether milk thistle supplements (when compared with no supplement, placebo, other oral supplements, or drugs):
· Alter the physiologic markers of liver function.
· Reduce mortality or morbidity, or improve the quality of life in adults with alcohol-related, toxin-induced, or drug-induced liver disease, viral hepatitis, cholestasis, or primary hepatic malignancy (hepatocellularcarcinoma).
One question addresses the constituents of commonly available milk thistle preparations, and three questions address the common and uncommon symptomatic adverse effects of milk thistle.
Methodology
Search Strategy
Eleven electronic databases, including AMED, CISCOM, the Cochrane Library(including DARE and the Cochrane Controlled Trials Registry), EMBASE, MEDLINE, and NAPRALERT, were searched through July 1999 using the following terms:
· Carduus marianus.
· Legalon.
· Mariendistel.
· Milk thistle.
· Silybin.
· Silybum marianum.
· Silybum.
· Silychristin.
· Silydianin.
· Silymarin.
An update search limited to PubMed was conducted in December 1999. English and non-English citations were identified from these electronic databases, references in pertinent articles and reviews, drug manufacturers, and technical experts.
Selection Criteria
Preliminary selection criteria regarding efficacy were reports on liver disease and clinical and physiologic outcomes from randomized controlled trials (RCTs) in humans comparing milk thistle with placebo, no milk thistle, or another active agent. Several of these randomized trials had dissimilar numbers of subjects in study arms, raising the question that these were not actually RCTs but cohort studies. In addition, among studies using non placebo controls, the type of control varied widely. Therefore, qualitative and quantitative syntheses of data on effectiveness were limited to placebo-controlled studies. For adverse effects, all types of studies in humans were used to assess adverse clinical effects.
Data Collection and Analysis
Abstractors (physicians, methodologists, pharmacists, and a nurse) independently abstracted data from trials; a nurse and physician abstracted data about adverse effects. Data were synthesized descriptively, emphasizing methodologic characteristics of the studies, such as populations enrolled, definitions of selection and outcome criteria, sample sizes, adequacy of randomization process, interventions and comparisons, cointerventions, biases in outcome assessment, and study designs.
Evidence tables and graphic summaries, such as funnel plots, Galbraith plots, and forest plots, were used to examine relationships between clinical outcomes, participant characteristics, and methodologic characteristics. Trial outcomes were examined quantitatively in exploratory meta-analyses that used standardized mean differences between mean change scores as the effect size measure.
Findings
Mechanisms of Action
Evidence exists that milk thistle may be hepato protective through a number of mechanisms: antioxidant activity, toxin blockade at the membrane level, enhanced protein synthesis, antifibriotic activity, and possible anti-inflammatory or immunomodulating effects.
Preparations of Milk Thistle
The largest producer of milk thistle is Madaus (Germany), which makes an extract of concentrated silymarin. However, numerous other extracts exist, and more information is needed on comparability of formulations, standardization, and bioavailability for studies of mechanisms of action and clinical trials.
Benefit of Milk Thistle for Liver Disease
· Sixteen prospective trials were identified. Fourteen were randomized, blinded, placebo-controlled studies of milk thistle's effectiveness in a variety of liver diseases. In one additional placebo-controlled trial, blinding or randomization was not clear, and one placebo-controlled study was a cohort study with a placebo comparison group.
· Seventeen additional trials used non placebo controls; two other trials studied milk thistle as prophylaxis in patients with no known liver disease who were starting potentially hepatotoxic drugs. The identified studies addressed alcohol-related liver disease, toxin-induced liver disease, and viral liver disease. No studies were found that evaluated milk thistle for cholestatic liver disease or primary hepatic malignancy (hepatocellular carcinoma, cholangiocarcinoma).
· There were problems in assessing the evidence because of incomplete information about multiple methodologic issues, including etiology and severity of liver disease, study design, subject characteristics, and potential confounders. It is difficult to say if the lack of information reflects poor scientific quality of study methods or poor reporting quality or both.
· Detailed data evaluation and syntheses were limited to the 16 placebo-controlled studies. Distribution of durations of therapy across trials was wide (7 days to 2 years), inconsistent, and sometimes not given. Eleven studies used Legalon®, and eight of those used the same dose. Outcome measures varied among studies, as did duration of therapy and the followup for which outcome measures were reported.
· Among six studies of milk thistle and chronic alcoholic liver disease, four reported significant improvement in at least one measurement of liver function (i.e., aminotransferases, albumin, and/or malondialdehyde) or histologic findings with milk thistle compared with placebo, but also reported no difference between groups for other outcome measures.
This evidence report details a systematic review summarizing clinical studies of milk thistle in humans.
Overview
The scientific name for milk thistle is Silybum marianum. It is a member of the aster or daisy family and has been used by ancient physicians and herbalists to treat a range of liver and gallbladder diseases and to protect the liver against a variety of poisons.
Two areas are addressed in the report:
· Effects of milk thistle on liver disease of alcohol, viral, toxin, cholestatic, and primary malignancy etiologies.
· Clinical adverse effects associated with milk thistle ingestion or contact.
The report was requested by the National Center for Complementary and Alternative Medicine, a component of the National Institutes of Health, and sponsored by the Agency for Healthcare Research and Quality.
Reporting the Evidence
Specifically, the report addresses 10 questions regarding whether milk thistle supplements (when compared with no supplement, placebo, other oral supplements, or drugs):
· Alter the physiologic markers of liver function.
· Reduce mortality or morbidity, or improve the quality of life in adults with alcohol-related, toxin-induced, or drug-induced liver disease, viral hepatitis, cholestasis, or primary hepatic malignancy (hepatocellularcarcinoma).
One question addresses the constituents of commonly available milk thistle preparations, and three questions address the common and uncommon symptomatic adverse effects of milk thistle.
Methodology
Search Strategy
Eleven electronic databases, including AMED, CISCOM, the Cochrane Library(including DARE and the Cochrane Controlled Trials Registry), EMBASE, MEDLINE, and NAPRALERT, were searched through July 1999 using the following terms:
· Carduus marianus.
· Legalon.
· Mariendistel.
· Milk thistle.
· Silybin.
· Silybum marianum.
· Silybum.
· Silychristin.
· Silydianin.
· Silymarin.
An update search limited to PubMed was conducted in December 1999. English and non-English citations were identified from these electronic databases, references in pertinent articles and reviews, drug manufacturers, and technical experts.
Selection Criteria
Preliminary selection criteria regarding efficacy were reports on liver disease and clinical and physiologic outcomes from randomized controlled trials (RCTs) in humans comparing milk thistle with placebo, no milk thistle, or another active agent. Several of these randomized trials had dissimilar numbers of subjects in study arms, raising the question that these were not actually RCTs but cohort studies. In addition, among studies using non placebo controls, the type of control varied widely. Therefore, qualitative and quantitative syntheses of data on effectiveness were limited to placebo-controlled studies. For adverse effects, all types of studies in humans were used to assess adverse clinical effects.
Data Collection and Analysis
Abstractors (physicians, methodologists, pharmacists, and a nurse) independently abstracted data from trials; a nurse and physician abstracted data about adverse effects. Data were synthesized descriptively, emphasizing methodologic characteristics of the studies, such as populations enrolled, definitions of selection and outcome criteria, sample sizes, adequacy of randomization process, interventions and comparisons, cointerventions, biases in outcome assessment, and study designs.
Evidence tables and graphic summaries, such as funnel plots, Galbraith plots, and forest plots, were used to examine relationships between clinical outcomes, participant characteristics, and methodologic characteristics. Trial outcomes were examined quantitatively in exploratory meta-analyses that used standardized mean differences between mean change scores as the effect size measure.
Findings
Mechanisms of Action
Evidence exists that milk thistle may be hepato protective through a number of mechanisms: antioxidant activity, toxin blockade at the membrane level, enhanced protein synthesis, antifibriotic activity, and possible anti-inflammatory or immunomodulating effects.
Preparations of Milk Thistle
The largest producer of milk thistle is Madaus (Germany), which makes an extract of concentrated silymarin. However, numerous other extracts exist, and more information is needed on comparability of formulations, standardization, and bioavailability for studies of mechanisms of action and clinical trials.
Benefit of Milk Thistle for Liver Disease
· Sixteen prospective trials were identified. Fourteen were randomized, blinded, placebo-controlled studies of milk thistle's effectiveness in a variety of liver diseases. In one additional placebo-controlled trial, blinding or randomization was not clear, and one placebo-controlled study was a cohort study with a placebo comparison group.
· Seventeen additional trials used non placebo controls; two other trials studied milk thistle as prophylaxis in patients with no known liver disease who were starting potentially hepatotoxic drugs. The identified studies addressed alcohol-related liver disease, toxin-induced liver disease, and viral liver disease. No studies were found that evaluated milk thistle for cholestatic liver disease or primary hepatic malignancy (hepatocellular carcinoma, cholangiocarcinoma).
· There were problems in assessing the evidence because of incomplete information about multiple methodologic issues, including etiology and severity of liver disease, study design, subject characteristics, and potential confounders. It is difficult to say if the lack of information reflects poor scientific quality of study methods or poor reporting quality or both.
· Detailed data evaluation and syntheses were limited to the 16 placebo-controlled studies. Distribution of durations of therapy across trials was wide (7 days to 2 years), inconsistent, and sometimes not given. Eleven studies used Legalon®, and eight of those used the same dose. Outcome measures varied among studies, as did duration of therapy and the followup for which outcome measures were reported.
· Among six studies of milk thistle and chronic alcoholic liver disease, four reported significant improvement in at least one measurement of liver function (i.e., aminotransferases, albumin, and/or malondialdehyde) or histologic findings with milk thistle compared with placebo, but also reported no difference between groups for other outcome measures.
Notes on “Good news for Hep B patients,” New Zealand Herald, 27.07.05
Scientists have created a powerful new treatment for hepatitis using a revolutionary technique that switches off harmful genes, providing hope for the two billion infected worldwide with the B strain of the virus.
The scientists have found that a few regular injections of the new drug can result in a 90 per cent reduction in the amount of virus circulating in the bloodstream of infected animals.
The replication of the hepatitis B virus is blocked by the phenomenon of RNA interference, which switches off the genes it needs for survival.
Results of a study have shown that RNA interference can work so effectively against invading viruses such as hepatitis that scientists believe the technique can be developed to produce an entirely new class of antiviral drugs.
RNA interference has been described as one of the most exciting developments in medical science and the latest study has shown it is able to stop the spread of hepatitis B virus in infected laboratory mice.
The results of the study, published in the journal Nature Biotechnology, are so encouraging that the scientists are planning to begin the first human trials of RNA interference on hepatitis B patients at the end of next year.
Some two billion people have been infected with the hepatitis B virus and more than 350 million have chronic or lifelong infections that often kill by causing liver cirrhosis and cancer.
Although there are vaccines to protect against infection, the drugs to treat hepatitis B are relatively ineffective as well as being prohibitively expensive for most of the people in the developing world who are chronically infected.
The latest study by David Morrissey and colleagues at the biotechnology company Sirna Therapeutics in Boulder, Colorado, used a form of RNA interference that switches off key genes of the hepatitis virus that it needs to replicate.
Dr Morrissey wrapped short molecules of RNA that were specifically targeted against the hepatitis B virus in a fatty globule that was able to carry or "deliver" the drug into infected cells of the liver.
A few daily injections were followed by a single injection given once a week, which reduced the amount of hepatitis B virus in the bloodstream by 90 per cent, with the effect lasting six weeks.
RNA interference was first described in 1998 and since then it has caused a stir inside the medical community because of its potential to deal with a range of illness, from cancer and viruses to inherited disorders such as Huntington's disease.
Sirna Therapeutics has already begun a trial of RNA interference on patients suffering from age-related macular degeneration, which causes visual impairment in many thousands of people over 50.
About a quarter of people over the age of 65 are affected by the disorder.
Sirna has developed a form of RNA interference designed to switch off or silence a key gene that is thought to stimulate the growth of blood vessels at the back of the eye which leads to macular degeneration.
Scientists have created a powerful new treatment for hepatitis using a revolutionary technique that switches off harmful genes, providing hope for the two billion infected worldwide with the B strain of the virus.
The scientists have found that a few regular injections of the new drug can result in a 90 per cent reduction in the amount of virus circulating in the bloodstream of infected animals.
The replication of the hepatitis B virus is blocked by the phenomenon of RNA interference, which switches off the genes it needs for survival.
Results of a study have shown that RNA interference can work so effectively against invading viruses such as hepatitis that scientists believe the technique can be developed to produce an entirely new class of antiviral drugs.
RNA interference has been described as one of the most exciting developments in medical science and the latest study has shown it is able to stop the spread of hepatitis B virus in infected laboratory mice.
The results of the study, published in the journal Nature Biotechnology, are so encouraging that the scientists are planning to begin the first human trials of RNA interference on hepatitis B patients at the end of next year.
Some two billion people have been infected with the hepatitis B virus and more than 350 million have chronic or lifelong infections that often kill by causing liver cirrhosis and cancer.
Although there are vaccines to protect against infection, the drugs to treat hepatitis B are relatively ineffective as well as being prohibitively expensive for most of the people in the developing world who are chronically infected.
The latest study by David Morrissey and colleagues at the biotechnology company Sirna Therapeutics in Boulder, Colorado, used a form of RNA interference that switches off key genes of the hepatitis virus that it needs to replicate.
Dr Morrissey wrapped short molecules of RNA that were specifically targeted against the hepatitis B virus in a fatty globule that was able to carry or "deliver" the drug into infected cells of the liver.
A few daily injections were followed by a single injection given once a week, which reduced the amount of hepatitis B virus in the bloodstream by 90 per cent, with the effect lasting six weeks.
RNA interference was first described in 1998 and since then it has caused a stir inside the medical community because of its potential to deal with a range of illness, from cancer and viruses to inherited disorders such as Huntington's disease.
Sirna Therapeutics has already begun a trial of RNA interference on patients suffering from age-related macular degeneration, which causes visual impairment in many thousands of people over 50.
About a quarter of people over the age of 65 are affected by the disorder.
Sirna has developed a form of RNA interference designed to switch off or silence a key gene that is thought to stimulate the growth of blood vessels at the back of the eye which leads to macular degeneration.
currently coinfected with HBV and HCV. Researchers evaluated their response to conventional or pegylated interferon combined with the antiviral ribavirin (the recommended treatment for hepatitis C) on patients, whose average age was 47. Fourteen patients were given standard interferon either alone or in combination with ribavirin, and 12 were given pegylated interferon and ribavirin. None tested positive for HBV DNA but all had HCV RNA and elevated ALT levels. Only two patients (one from each group) cleared the HCV following treatment. Researchers concluded that neither pegylated nor conventional interferon were highly effective for HBV-HCV coinfection, in which the dominant virus was HCV.
because of the risk of relapse is so great. Researchers Consider Using Antivirals During Third Trimester of Pregnancy to Prevent HBV Transmission While antivirals are used in pregnant HIV-infected women to lower viral load and prevent transmission to newborns, this preventive antiviral treatment is rare in pregnant, HBV-infected women. However, even with immediate administration of the hepatitis B vaccine and HBIG (hepatitis B antibodies) in newborns, between 5-10% of newborns still contract HBV infection from their mothers, due to the mother’s high viral load. Researchers also believe some HBV strains or genotypes are also more effective at infecting newborns. In China, there has been some experimentation with administering lamivudine in pregnant HBV-infected women during the third trimester of pregnancy to prevent HBV transmission. During the Clinical Care Options conference, Dr. Jacobson suggested that tenofovir and telbivudine may also be used in pregnant women with HBV. They are both category B drugs, considered safe during pregnancy, and tenofovir has reportedly been used to prevent HIV transmission in pregnant women. However, to date the FDA has not approved any antiviral for use during pregnancy to prevent HBV transmission. Longer Treatment with Conventional Interferon Improved Success Rate While most doctors use pegylated interferon today to treat hepatitis B, Chinese researchers tried using conventional interferon, the first interferon developed to treat hepatitis B, for just six months in a control group of 127 HBeAgpositive patients and for an average 10 months or longer in 247 HBeAg-positive patients to see if the extended treatment would benefit patients. The interferon treatment in the second, study group continued for as long as viral load was decreasing and ranged from 6 to 24 months. According to researchers’ report in the June 2008 issue of the Journal of Viral Hepatitis, when treatment ended 39% in the study had achieved normal ALT levels and low viral load, compared to 24% in the six-month treatment control group. After a three-year follow-up period, 40.5% of the study group maintained healthy ALT levels and low viral load, compared to 33% in the 3 control group. Inter-feron-alpha treatment tailored in length demonstrated significantly increased effectiveness, researchers noted. Severe Fibrosis More Common if Patients are Male, Older, and Have High ALT Levels Chinese researchers evaluated when Asian patients with HBV began developing liver fibrosis (inflammation) and cirrhosis (scarring) by performing “transient elastography,” a procedure involving sounds waves that can assess the condition of liver tissue. According to their report in the June 2008 issue of the American Journal of Gastroenterology, severe fibrosis was documented more frequently in older patients, reaching 20% in patients 65 years and older. Higher prevalence of severe fibrosis was seen in HBeAgpositive patients who were age 45 or older, compared to HBeAgnegative patients (58% vs. 43% respectively), and in patients with higher viral loads and ALT levels. Patients who had received antiviral treatment had lower ALT levels and prevalence of cirrhosis. Researchers concluded that the prevalence of severe fibrosis was 34% in the study group, with higher rates of fibrosis associated with older patients, males, and those with elevated ALT levels. Occult Hepatitis B Can Transmit Infection Through Blood Donations Historically, HBV is not considered a threat when blood donors have hepatitis B surface antibodies present, but several months after a blood transfusion, two patients developed acute hepatitis B, according to an article by Slovenian researchers published in the June 2008 Journal of Hepatology. A sample from the donated blood contained core and surface antibodies, but it also contained HBV DNA. Increasingly, researchers are recognizing that “occult” hepatitis – with no HBsAg or even surface antibodies – can still contain HBV DNA and transmit infection. Tenofovir and Lamivudine Combination Effective in Patients with Cirrhosis Who Don’t Respond to Adefovir Six patients with cirrhosis who did not respond to, or developed viral resistance to adefovir were treated with a combination of tenofovir and lamivudine for six months minimum. South Korean researchers monitored their response to see how effective the combination therapy was against adefovirresistant hepatitis B. Reporting in the journal Liver International, the researcher wrote that HBV DNA became undetectable in four patients after six months, and in all six patients after 12 months of treatment. ALT levels became normal in four patients after 12 months of treatment. “This study suggests that this combination may be a promising rescue therapy for these patients, particularly those with liver cirrhosis or pre-existing lamivudine resistance,” the researchers noted. Silymarin Cures Liver Inflammation Quickly in Laboratory Rats Researchers are beginning to analyze and test the benefits of silymarin, a traditional liver herbal treatment found in milk thistle, in improving liver health when viral infection occurs. Taiwanese researchers studied the impact high doses of silymarin had on the liver of rats, whose livers had inflammation and fibrosis. They reported in a recent issue of the Journal of Viral Hepatitis that liver fibrosis significantly decreased in rates treated with silymarin. HBV Genotype Has Little Impact on Antiviral Success, But Plays a Prominent Role in Interferon’s Success German researchers reviewed 20 studies that linked treatment success, such as HBeAg seroconversion and decline in viral load, to patients’ HBV genotype to explore whether hepatitis B treatment should ever be guided by a patient’s 4 genotype. Writing in the journal Antiviral Therapy, they concluded that response to antiviral treatment was not “significantly influenced by HBV genotype in HBeAg-positive or HBeAg-negative individuals.” “In contrast,” they noted, “HBV genotypes are informative concerning responses to interferon treatment in all patients with genotype A versus D and in HBeAg-positive patients with genotype B versus C. “Interferon may be considered as first-line therapy in all genotype A patients and in individuals with genotype B who are HBeAgpositive,” they concluded. Past HBV Infection Worsens Hepatitis C Prognosis, Weakens Interferon’s Effectiveness Two studies found that infection with HBV, common in many patients infected with the hepatitis C virus (HCV), worsens patients’ disease progression and limits the success of interferon treatment. In a recent article in Liver International, Brazilian researchers evaluated 31 HCV carriers who had previously been exposed to HBV, but were not currently infected. Compared to HCV patients without a past HBV infection, these patients had more liver damage and inflammation. They concluded that after 20 years of HCV infection, advanced liver fibrosis could be expected in 13% of those who acquired HCV before the age of 30 but had no prior HBV infection, and in 57% of those infected with HCV after age 30 who had a prior HBV infection. In another study, Turkish researchers, writing in the May 2008 Netherlands Journal of Medicine, examined the impact of interferon on patients
Notes on “When a Patient Should Be Treated, and What the First Hepatitis B Treatment Drug Should Be,” Christine Kukka, WWW.HBVADVOCATE.ORG HBV JOURNAL REVIEW Hepatitis B, Volume 5, Issue 7 July 01, 2008.
Leading experts on hepatitis B virus (HBV) infection addressed a variety of important treatment issues at a recent Clinical Care Options workshop. When Should You Treat Hepatitis B? Anna S. F. Lok, MD, director of clinical hepatology at the University of Michigan at Ann Arbor, discussed when to treat hepatitis B. She explained that physicians should answer three key questions before beginning treatment: . How active or advanced is the HBV-related liver disease now? . What is the risk that a patient will progress to cirrhosis or severe liver damage or cancer in the next 10-20 years? . And, what is the chance that once viral load (HBV DNA) is lowered from a limited course of treatment, it can be maintained for up to 3-5 years? Example1: Lok the case of a 27-year-old woman who had a high viral load but normal alanine aminotransferase (ALT) levels, which indicates no liver damage was occurring. This is called the immune tolerant stage, which is common in younger patients. Doctors are uncertain whether to treat this group of patients. While liver damage is still possible when a patient has high viral loads and normal ALTs, it occurs most frequently in patients age 40 and older, she noted. Given the risks of viral resistance from long-term antiviral treatment and the lack of success of interferon in patients with normal ALT levels, she did not recommend treatment in immune-tolerant patients who were younger than 35 years of age. Example 2: Lok explored whether to treat a 30-year-old woman with high viral load and normal ALTs, and who also had a family history of liver cancer in HBV-infected relatives. It is unclear whether the family “clusters” of HBV-related liver cancer is related to genetic or environmental factors or a more virulent strain of HBV, Lok HBV Journal Review A publication of the Hepatitis C Support Project Executive Director Editor-in-Chief, HCSP Publications Alan Franciscus Contributor Christine Kukka Managing Editor, Webmaster C.D. Mazoff, PhD Contact Information: The Hepatitis C Support Project PO Box 427037 San Francisco, CA 94142 www.hbvadvocate.org . 2008 Hepatitis C Support Project 1 noted. While some experts advocate treating all patients with a strong family history of liver cancer, even if they are in the immune tolerant stage, “it must be emphasized that there are no data to support the hypothesis that antiviral therapy can completely prevent liver cancer and there is no model to predict the risk of cancer in this patient. The potential benefits of antiviral therapy must be balanced against the risks of years of antiviral therapy that may indeed be lifelong, and those potential risks must be weighed particularly carefully for a young woman who might be planning to start a family in the near future,” she explained. Lok stressed that treatment is recommended if there is a high risk of liver damage and death in the next 5 to 10 years, and if there is a good chance of achieving or maintaining low HBV DNA throughout treatment. Treatment is not recommended if the risk of liver damage over the next 20 years is low, or if there is the possibility of achieving low viral load after a defined course of treatment is low, she added. Should you use interferon or an antiviral first? Ira M. Jacobson, MD, medical director of the Center for the Study of Hepatitis C at Weill Medical College of Cornell University, tackled what treatment to use first in patients who qualified for treatment. Pegylated interferon, which boosts the immune system, requires a weekly injection for up to one year, and may cause side effects such as depression and fatigue--while oral antivirals cause few side effects. But starting a patient on antivirals, “for most clinicians … is tantamount to the decision to continue (antiviral) therapy indefinitely,” Jacobson explained. As a result, interferon is favored for first-line therapy in patients who test negative for the hepatitis B “e” antigen (HBeAgnegative), but it is also a recommended option for HBeAg-positive patients. In HBeAg-positive patients, interferon causes HBeAg seroconversion (loss of “e” antigen and development of the “e” antibody) in 30% of patients after one year of treatment, compared to a 12% to 23% seroconversion rate after one year of antiviral treatment. However, researchers are discovering that longer-term antiviral treatment also causes seroconversion, with a 30% seroconversion rate after two years of treatment, and a 40% rate after three years. Interferon, however, has the advantage of inducing permanent clearance of the hepatitis B surface antigen (HBsAg), which indicates a patient has nearly cleared the infection. Interferon causes 3% to 8% of HBeAg–positive patients to lose HBsAg. Antivirals such as adefovir (Hepsera), lamivudine (Epivir-HBV) and telbivudine (Tyzeka) cause a HBsAg loss of less than 1% after one year of treatment and entecavir causes a 2% loss of HBsAg after one year. However, HBeAg-positive patients lost HBsAg at a rate of 5% and 3% after two years of treatment with entecavir (Baraclude) or lamivudine, respectively. In a recent trial of tenofovir (Viread-an antiviral that is expected to be approved soon by the U.S. Food and Drug Administration), 3% of HBeAg-positive patients lost HBsAg after one year. In HBeAg-negative patients, one year of interferon produces a sustained undetectable HBV DNA level, which continues in about 20% of patients four years after treatment ended. Which antiviral to use first? Doctors should select an antiviral that will cause the least viral resistance, experts say. All experts agree that the antiviral lamivudine should never be used as a patient’s first antiviral treatment unless it’s used to prevent reactivation in inactive HBsAg carriers who receive chemotherapy, which weakens the immune system. HBV quickly develop “resistance” to lamivudine at a rate of 23% after one year, and up to 71% after four or five years of treatment. The two antivirals recommended as first-line choices are entecavir and adefovir. Tenofovir has been commonly used “offlabel” by doctors and has been used for years 2 in HIV-infected patients, confers a much higher level of viral suppression than adefovir and should replace adefovir as the preferred antiviral for first-line therapy along with entecavir once the FDA approves it, according to Jacobson. When should you use an antiviral combination? There are no clear guidelines, but some clinicians routinely use two antivirals to prevent any potential viral cross-resistance in the following patients: . Those who already have developed resistance to one drug or more drugs, such as lamivudine and adefovir . Those who have cirrhosis, in whom it is critical to avoid a hepatitis “flare” or sudden resurgence of viral load and liver damage. . And, those with HIV-HBV coinfection, in whom it is important to prevent the development of antiviral resistance by either virus. When can you stop using an antiviral? Patients who seroconvert while on antivirals face a 10% to 25% risk of reverting back to HBeAgpositive status. But despite that risk, doctors recommend that patients make an attempt to discontinue treatment, although treatment should be continued for at least 6-12 months after seroconversion to reduce the risk of seroreversion. For HBeAg-negative patients, there is a paradox – it is easier for them to achieve undetectable viral load on antivirals, yet more than 95% will relapse if therapy is discontinued after one year. As a result, antiviral use should be continued indefinitely
Leading experts on hepatitis B virus (HBV) infection addressed a variety of important treatment issues at a recent Clinical Care Options workshop. When Should You Treat Hepatitis B? Anna S. F. Lok, MD, director of clinical hepatology at the University of Michigan at Ann Arbor, discussed when to treat hepatitis B. She explained that physicians should answer three key questions before beginning treatment: . How active or advanced is the HBV-related liver disease now? . What is the risk that a patient will progress to cirrhosis or severe liver damage or cancer in the next 10-20 years? . And, what is the chance that once viral load (HBV DNA) is lowered from a limited course of treatment, it can be maintained for up to 3-5 years? Example1: Lok the case of a 27-year-old woman who had a high viral load but normal alanine aminotransferase (ALT) levels, which indicates no liver damage was occurring. This is called the immune tolerant stage, which is common in younger patients. Doctors are uncertain whether to treat this group of patients. While liver damage is still possible when a patient has high viral loads and normal ALTs, it occurs most frequently in patients age 40 and older, she noted. Given the risks of viral resistance from long-term antiviral treatment and the lack of success of interferon in patients with normal ALT levels, she did not recommend treatment in immune-tolerant patients who were younger than 35 years of age. Example 2: Lok explored whether to treat a 30-year-old woman with high viral load and normal ALTs, and who also had a family history of liver cancer in HBV-infected relatives. It is unclear whether the family “clusters” of HBV-related liver cancer is related to genetic or environmental factors or a more virulent strain of HBV, Lok HBV Journal Review A publication of the Hepatitis C Support Project Executive Director Editor-in-Chief, HCSP Publications Alan Franciscus Contributor Christine Kukka Managing Editor, Webmaster C.D. Mazoff, PhD Contact Information: The Hepatitis C Support Project PO Box 427037 San Francisco, CA 94142 www.hbvadvocate.org . 2008 Hepatitis C Support Project 1 noted. While some experts advocate treating all patients with a strong family history of liver cancer, even if they are in the immune tolerant stage, “it must be emphasized that there are no data to support the hypothesis that antiviral therapy can completely prevent liver cancer and there is no model to predict the risk of cancer in this patient. The potential benefits of antiviral therapy must be balanced against the risks of years of antiviral therapy that may indeed be lifelong, and those potential risks must be weighed particularly carefully for a young woman who might be planning to start a family in the near future,” she explained. Lok stressed that treatment is recommended if there is a high risk of liver damage and death in the next 5 to 10 years, and if there is a good chance of achieving or maintaining low HBV DNA throughout treatment. Treatment is not recommended if the risk of liver damage over the next 20 years is low, or if there is the possibility of achieving low viral load after a defined course of treatment is low, she added. Should you use interferon or an antiviral first? Ira M. Jacobson, MD, medical director of the Center for the Study of Hepatitis C at Weill Medical College of Cornell University, tackled what treatment to use first in patients who qualified for treatment. Pegylated interferon, which boosts the immune system, requires a weekly injection for up to one year, and may cause side effects such as depression and fatigue--while oral antivirals cause few side effects. But starting a patient on antivirals, “for most clinicians … is tantamount to the decision to continue (antiviral) therapy indefinitely,” Jacobson explained. As a result, interferon is favored for first-line therapy in patients who test negative for the hepatitis B “e” antigen (HBeAgnegative), but it is also a recommended option for HBeAg-positive patients. In HBeAg-positive patients, interferon causes HBeAg seroconversion (loss of “e” antigen and development of the “e” antibody) in 30% of patients after one year of treatment, compared to a 12% to 23% seroconversion rate after one year of antiviral treatment. However, researchers are discovering that longer-term antiviral treatment also causes seroconversion, with a 30% seroconversion rate after two years of treatment, and a 40% rate after three years. Interferon, however, has the advantage of inducing permanent clearance of the hepatitis B surface antigen (HBsAg), which indicates a patient has nearly cleared the infection. Interferon causes 3% to 8% of HBeAg–positive patients to lose HBsAg. Antivirals such as adefovir (Hepsera), lamivudine (Epivir-HBV) and telbivudine (Tyzeka) cause a HBsAg loss of less than 1% after one year of treatment and entecavir causes a 2% loss of HBsAg after one year. However, HBeAg-positive patients lost HBsAg at a rate of 5% and 3% after two years of treatment with entecavir (Baraclude) or lamivudine, respectively. In a recent trial of tenofovir (Viread-an antiviral that is expected to be approved soon by the U.S. Food and Drug Administration), 3% of HBeAg-positive patients lost HBsAg after one year. In HBeAg-negative patients, one year of interferon produces a sustained undetectable HBV DNA level, which continues in about 20% of patients four years after treatment ended. Which antiviral to use first? Doctors should select an antiviral that will cause the least viral resistance, experts say. All experts agree that the antiviral lamivudine should never be used as a patient’s first antiviral treatment unless it’s used to prevent reactivation in inactive HBsAg carriers who receive chemotherapy, which weakens the immune system. HBV quickly develop “resistance” to lamivudine at a rate of 23% after one year, and up to 71% after four or five years of treatment. The two antivirals recommended as first-line choices are entecavir and adefovir. Tenofovir has been commonly used “offlabel” by doctors and has been used for years 2 in HIV-infected patients, confers a much higher level of viral suppression than adefovir and should replace adefovir as the preferred antiviral for first-line therapy along with entecavir once the FDA approves it, according to Jacobson. When should you use an antiviral combination? There are no clear guidelines, but some clinicians routinely use two antivirals to prevent any potential viral cross-resistance in the following patients: . Those who already have developed resistance to one drug or more drugs, such as lamivudine and adefovir . Those who have cirrhosis, in whom it is critical to avoid a hepatitis “flare” or sudden resurgence of viral load and liver damage. . And, those with HIV-HBV coinfection, in whom it is important to prevent the development of antiviral resistance by either virus. When can you stop using an antiviral? Patients who seroconvert while on antivirals face a 10% to 25% risk of reverting back to HBeAgpositive status. But despite that risk, doctors recommend that patients make an attempt to discontinue treatment, although treatment should be continued for at least 6-12 months after seroconversion to reduce the risk of seroreversion. For HBeAg-negative patients, there is a paradox – it is easier for them to achieve undetectable viral load on antivirals, yet more than 95% will relapse if therapy is discontinued after one year. As a result, antiviral use should be continued indefinitely
Notes on “Resistance to antiviral drugs is climbing,” Zosia Kmietowicz, BMJ 2005;331:308 (6 August).
Public health experts have warned of a worrying increase in resistance to antiviral drugs that is making infections such as HIV and hepatitis B more difficult to manage.
Evidence from research that followed 4500 British patients infected with HIV indicates that after two years of standard treatment with a combination of three different classes of antiretroviral drugs 10% of people become resistant to at least one drug. Six years after starting treatment 27% of patients are resistant to at least one of their drugs.
Speaking at the launch of the annual report of the Health Protection Agency for England and Wales, Peter Borriello, interim director of the agency's Centre of Infections, said the most worrying development is the emergence of strains of HIV that are resistant to all three classes of antiretroviral drugs currently available. Such triple resistance now affects one in 25 people with HIV, and although some antiviral drugs may dampen down the viral load in these patients their prognosis is much worse than in someone who shows no drug resistance.
"Up to one in five people who are being diagnosed with HIV are resistant to at least one drug, which suggests they have acquired the infection from someone who is already receiving treatment," said Professor Borriello. "This tells us we have to now reinforce behaviour messages."
There is also evidence that 20% of strains of hepatitis B viruses are now resistant to standard treatment, and work with the World Health Organization indicates that resistance to drugs for influenza was emerging, although less than 1% of people were showing resistance.
William Stewart, chairman of the agency, said: "The worrying trend is that viruses that are resistant to antiviral drugs are beginning to emerge. To a micro-biologist this may be unsurprising, but it is worryingly reminiscent of the development of antibiotic resistant bacteria over 50 years ago. The fight against microbial diversity is endless."
Although the development of resistance to antiviral drugs was inevitable, cooperation from public health departments in other countries would help in monitoring the situation and in devising protocols to limit the spread of resistance, experts agree. Development of new classes of drugs by pharmaceutical companies would also provide doctors with the means to treat infections with a reduced risk of resistance developing, said Professor Borriello.
Public health experts have warned of a worrying increase in resistance to antiviral drugs that is making infections such as HIV and hepatitis B more difficult to manage.
Evidence from research that followed 4500 British patients infected with HIV indicates that after two years of standard treatment with a combination of three different classes of antiretroviral drugs 10% of people become resistant to at least one drug. Six years after starting treatment 27% of patients are resistant to at least one of their drugs.
Speaking at the launch of the annual report of the Health Protection Agency for England and Wales, Peter Borriello, interim director of the agency's Centre of Infections, said the most worrying development is the emergence of strains of HIV that are resistant to all three classes of antiretroviral drugs currently available. Such triple resistance now affects one in 25 people with HIV, and although some antiviral drugs may dampen down the viral load in these patients their prognosis is much worse than in someone who shows no drug resistance.
"Up to one in five people who are being diagnosed with HIV are resistant to at least one drug, which suggests they have acquired the infection from someone who is already receiving treatment," said Professor Borriello. "This tells us we have to now reinforce behaviour messages."
There is also evidence that 20% of strains of hepatitis B viruses are now resistant to standard treatment, and work with the World Health Organization indicates that resistance to drugs for influenza was emerging, although less than 1% of people were showing resistance.
William Stewart, chairman of the agency, said: "The worrying trend is that viruses that are resistant to antiviral drugs are beginning to emerge. To a micro-biologist this may be unsurprising, but it is worryingly reminiscent of the development of antibiotic resistant bacteria over 50 years ago. The fight against microbial diversity is endless."
Although the development of resistance to antiviral drugs was inevitable, cooperation from public health departments in other countries would help in monitoring the situation and in devising protocols to limit the spread of resistance, experts agree. Development of new classes of drugs by pharmaceutical companies would also provide doctors with the means to treat infections with a reduced risk of resistance developing, said Professor Borriello.
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