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by John C. Martin |
Article
Date: 06-02-04 |
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Treatment Designed for Previous
Nonresponders
Infergen (interferon alfacon-1), made by InterMune Pharmaceuticals, is
known as consensus interferon. When combined with
ribavirin, the interferon therapy is
targeted as treatment for patients with chronic
hepatitis C who have failed to respond to
pegylated interferon.
According to InterMune, about half of all patients treated with pegylated interferon/ribavirin combination treatment do not respond. In all, there are approximately 150,000 HCV patients in the U.S. who don't respond to this type of treatment, and InterMune says the number is expanding by some 50,000 patients per day, adding that retreatment options for this group of patients are "limited".
New SVR Data
Infergen has proven its value in other trials, such as a pilot study whose
initial findings were unveiled last year.3 But one of the two
latest studies demonstrated a
sustained viral response (SVR) by
Infergen and ribavirin in previous non-responders for the first time. SVR
is defined as evidence of undetectable levels of hepatitis C virus for at
least 6 months following the end of therapy.4
In that trial, whose findings were released at Digestive Disease Week 2004, an annual gastroenterology conference, investigators at the University of Tuebingen in Germany recruited 60 patients with chronic hepatitis C who had previously failed to respond to pegylated interferon therapy.
In the study, the patients were assigned at random to receive two treatment regimens of Infergen each day. Patients in one group received 9 mcg (micrograms) of Infergen daily for 4 weeks, followed by a combination of 9 mcg of daily Infergen plus ribavirin for up to 68 weeks additionally.
In the second group, patients received 27 mcg of daily Infergen alone for 4 weeks, followed by 18 mcg of Infergen plus ribavirin for 12 weeks, then a combination of 9 mcg of Infergen plus ribavirin for the remaining 56 weeks.
In both groups, patients received at least 48 weeks of therapy after their viral levels became undetectable, the investigators reported.
'Promising Response Rates'
At the end of the trial, 27 percent of the patients in the first group who
reached the 6-month point following the end of treatment achieved an SVR,
compared to 23 percent of those in group 2.
"This is the first SVR data to emerge regarding the use of daily Infergen in treating PEG-nonresponders," said Stephan Kaiser, M.D., director of the Liver Outpatient Department, Lecturer in Hepatology at the University of Tuebingen, and the study's chief investigator, in a statement. "This study demonstrates promising response rates that offer hope to patients who fail to respond to pegylated interferons plus ribavirin."
The investigators say the therapy was generally well-tolerated, but the most common side effect was flu-like symptoms. Trial drop-out rates, as well as incidence of side effects, were similar to what is found among patients taking pegylated interferon, the study authors reported.
"This data provides a strong rationale for additional study of daily Infergen plus ribavirin in this patient population," Kaiser said.
Similar Outcomes Elsewhere
In the second trial,2 doctors at the New Jersey Medical
Liver Center and Sammy Davis Jr. National Liver Center in Newark, New
Jersey conducted a retrospective analysis of Infergen in 137 patients who
had previously failed to respond to 12 weeks of pegylated interferon/ribavirin
combination treatment.
In the retrospective trial, conducted in conjunction with scientists from InterMune, patients were initially given 15 mcg of Infergen combined with 1000 to 1200 milligrams of ribavirin (based on weight) each day for 12 weeks. For any patients who achieved nondetectable levels of HCV in that timeframe, the dosage schedule was reduced to 15 mcg of Infergen three times per week plus 1000 to 1200 mg of ribavirin each day for an additional 36 weeks, for a total of 48 weeks.
Those patients who still had detectable viral loads after the initial 12-week medication schedule continued to receive 15 mcg of Infergen daily along with the same dose of ribavirin for the additional 36-week period, the investigators reported.
End-of-Treatment Response
The researchers discovered that Infergen/ribavirin combination treatment
reduced viral loads by 43%, on average, among the patients at the end of
the 48-week treatment schedule.
As in the first trial, side effects included flu-like symptoms, but the research team said no patients dropped out. SVR was not measured, initially, in this trial, but the investigators report that all patients will be monitored for an additional 24 weeks.
"In these difficult-to-treat nonresponder patients, treatment with Infergen plus ribavirin resulted in a clinically significant end-of-treatment response," said Carroll Leevy, M.D., director of Clinical Affairs at the New Jersey Medical Liver Center and Sammy Davis Jr. National Liver Center, who led the research. "These findings suggest that this regimen was well tolerated, and may benefit nonresponder patients."
Leevy said he and his colleagues plan to present findings related to sustained virologic response in these patients sometime in the future.
1. Kaiser S et al. Successful retreatment of pegylated
interferon alpha 2 nonresponder patients with chronic hepatitis C with
high dose consensus interferon (Interferon alfacon-1). Digestive Disease
Week (DDW) 2004. 2004 May 15-20. New Orleans, LA.
2. Leevy CB et al. End of treatment response for pegylated interferon
alpha 2 + weight-based ribavirin nonresponders retreated with interferon
alfacon-1 + weight-based ribavirin. Digestive Disease Week (DDW) 2004.
2004 May 15-20. New Orleans, LA.
3. Delivery of Consensus Interferon (Infergen) by continuous infusion for
the treatment of chronic hepatitis C: A pilot viral kinetic study. 54th
Annual Meeting of the American Association for the Study of Liver
Diseases. 2003 Oct 24-28. Boston, MA.
4. National Center for HIV, STD and TB Prevention. Centers for Disease
Control and Prevention (CDC).
John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.
http://www.hepatitisneighborhood.com/content/in_the_news/archive_1857.aspx
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| by John C. Martin |
Article
Date: 06-02-04 |
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Now, a new study says there may be a therapeutic approach to reperfusion injury.2
A New Way to Treat Reperfusion
Injury
Doctors at the University of North Carolina report that nitric oxide may
dramatically improve the viability of transplanted livers. In the study,
published in the June issue of the journal, Hepatology, the
investigators showed that the use of nitric oxide during reperfusion
protected rat liver cells in a laboratory specimen from cell death that
typically occurs from reperfusion stress.
"Reperfusion stress precipitates the death of the tissue," said chief study investigator John Lemasters, M.D., Ph.D., a professor of Cell and Developmental Biology at UNC. "But our results suggest that the way we reperfuse the liver can reduce injury to it."
Essential for Transplant Success
The UNC researchers stressed that approaches to ease this type of injury
in
liver transplant procedures is
essential to success of the operation.
According to the investigators, reperfusion-related cell death in the liver results from damage to the liver cell's mitochondria (mye-toe-KON-dree-uh), the site in a cell primarily responsible for its energy supply. This damage essentially blocks the mitochondria from generating necessary energy for the cell, resulting in the cell's death.
By contrast, nitric oxide protects the cell by blocking the injury process. Nitric oxide is a gas produced by the body that relaxes and widens blood vessels, and regulates the binding and release of oxygen into hemoglobin, the oxygen component of red blood cells, and thus controls the supply of oxygen to the mitochondria. Because of this, it has been used as a therapeutic approach in pulmonary hypertension, a disease in which the blood vessels in the lungs become abnormally constricted.3
"Our cell culture model mimics severe ischemia [oxygen deprivation], and nitric oxide was still effective in blocking cell death," said Jae-Sung Kim, Ph.D., an assistant professor of Cell and Developmental Biology, and the study's primary author.
A 'Meaningful' Intervention
The research team explains that using nitric oxide after cold storage of
a liver meant for transplant may help to maintain normal liver function
after the operation has ended. "Nitric oxide protects the liver during
the reperfusion phase, after ischemia has occurred, and this means we
can intervene in a meaningful way," Lemasters explained. "We can treat
after disease onset."
Because it reacts rapidly with oxygen, nitric oxide can cause damage to the transplanted liver when higher levels are used. Thus, an optimal concentration of the gas is necessary to ensure it still protects the organ, Lemasters and his colleagues stressed.
Generating Protective Molecules
In addition to its liver-protecting abilities, Lemasters and his fellow
researchers also discovered that nitric oxide can stimulate
liver cells to produce special
protective molecules in the body, essential for other biological
functions.
One example is the protective effect that these molecules exert against reperfusion stress that occurs after a heart attack. In fact, one of the theories that Lemasters and his team hope to research next is whether these protective molecules involved in protecting the heart also play a key role in protecting the liver from injury after transplantation.
The study was supported by a grant from the National Institutes of Health.
1. Yu YY, Ji J, Zhou GW et al. Liver biopsy in
evaluation of complications following liver transplantation. World J
Gastroenterol 2004 Jun 1;10(11):1678-81.
2. Kim J-S, Ohshima S, Peiaditakis P, Lmasters JJ et al. Nitric oxide
protects rat hepatocytes against reperfusion injury mediated by the
mitochondrial permeability transition. Hepatology 2004 Jun;
39(6):1533-43.
3. University of Chicago Medical Center.
John Martin is a long-time health journalist and an
editor for Priority Healthcare. His credits include coverage of health
news for the website of Fox Television's The Health Network, and
articles for the New York Post and other consumer and trade
publications.
http://www.hepatitisneighborhood.com/content/in_the_news/archive_1856.aspx
Treatment helps 26% of black Americans with chronic hepatitis C |
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Stem Cells Can Convert To Liver Tissue, Help Restore Damaged Organ
Bone marrow stem cells, when exposed to damaged liver tissue, can quickly convert into healthy liver cells and help repair the damaged organ, according to new research from the Johns Hopkins Kimmel Cancer Center.
In mouse-tissue cultures, scientists found that stem cells, in the presence of cells from damaged liver tissue, developed into liver cells in as little as seven hours. They also observed that stem cells transplanted into mice with liver injuries helped restore liver function within two to seven days. The work was published in the June 1 issue of the journal Nature Cell Biology.
Bone marrow stem cells, also known as hematopoietic stem cells, have the ability to differentiate and develop into all other blood and marrow cells. There has been debate among the scientific community over whether these cells also can differentiate into other tissue types such as the liver, says Saul J. Sharkis, Ph.D., senior author of the study and a professor of oncology at the Johns Hopkins Kimmel Cancer Center. Some studies suggest that the bone marrow cells fuse with other types of cells, taking on those cells' properties. But in this study, the researchers found, through highly thorough analysis with a microscope and other tests, that the cells did not fuse, suggesting that "microenvironmental" cues from existing liver cells caused them to convert.
"The hematopoietic stem cells were capable of taking on many characteristics of liver cell types, including specific gene and/or protein expression as well as typical function," Sharkis says. "These events occurred rapidly after injury exposure and restored liver abnormalities, indicating that the cells converted."
This type of stem cell technique could eventually be used to treat chronic diseases such as diabetes, cirrhosis of the liver, heart disease and cancer, he says. He cautions that many more studies must be completed before the stem cell therapy can be tested in humans.
For the study, Sharkis and colleagues cultured bone marrow stem cells together with either normal or damaged liver tissue in tissue culture dishes. Liver tissue was taken from mice that had been exposed to liver-damaging drugs. The two cell types were separated by a thin, permeable wall. Researchers performed several tests looking for expression of liver proteins.
In as little as seven or eight hours after culture with the injured liver tissue, some of the stem cells expressed the typical proteins present in liver cells cytokeratin 18 or albumin. Two days after culture, nearly 3 percent of all stem cells expressed these proteins. The researchers also observed the expression of many other proteins and products normally manufactured by liver cells in their earliest stages -- all detected within eight to 48 hours of culture.
The team then used a sensitive microscope test to examine the sex chromosomes of the cells, as the stem cells were taken from male mice and the liver tissue was taken from female mice. They identified some stem cells of male donor origin with four sex chromosomes typical of liver cells but not stem cells, indicating that the stem cells themselves physically had started to change and did not fuse with the liver cells.
Finally, the team transplanted the stem cells into injured livers in female mice and studied the amount of conversion at two and seven days following the transplant. More converted cells were observed at seven days versus two days, suggesting that the cells remained viable and continued dividing or converting. The liver functions of mice receiving the stem cells recovered as early as two days after transplant.
Sharkis' continuing studies will try to identify the environmental cues responsible for cells' conversion, and examine the ability of stem cells to repair other organs.
The study was funded by the National Heart, Lung and Blood Institute, the Ludwig Foundation and Hopkins' Institute for Cellular Engineering. Co-authors were Yoon-Young Jang M.D., Ph.D.; Michael I. Collector; Stephen B. Baylin, M.D.; and Anna Mae Diehl, M.D.
###
Jang, Yoon-Young et al, "Hematopoietic Stem Cells Convert Into Liver Cells Within Days Without Fusion," Nature Cell Biology, June 1, 2004.
Links:
Johns Hopkins Kimmel Cancer Center http://www.hopkinskimmelcancercenter.org/
Nature Cell Biology http://www.nature.com/ncb/
| Pegasys- or Peg-Intron-based combination therapy? Which is better? | |||||||||||||||||||||||||||||||||||||
People with genotype 1 and high viral loads face the following pressing questions about treatment:
The question about proper dosing of Peg-Intron should be answered by IDEAL. But a closer look at the data from a study comparing lower and higher doses of Peg-Intron monotherapy may give people with high viral loads cause for concern:
The SVR rates for both Peg-Intron doses were similar. But the end-of-treatment response rates (the percentage of people with undetectable viral loads at the time of stopping therapy) are substantially better in people taking higher dose Peg-Intron (35% vs. 20%) for people with high viral loads. This raises questions about how people with high viral loads will fare in the low-dose Peg-Intron arm. Ribavirin dosing raises other important concerns. Growing evidence suggests that maintaining an adequate dose of ribavirin increases the likelihood of achieving an SVR. But ribavirin can also cause hemolytic anemia (a drop in hemoglobin levels, reflecting the destruction of red blood cells). Hemolytic anemia can result in fatigue and other side effects. As a result, many people starting HCV treatment have to reduce their ribavirin doses, potentially lowering their chances of achieving an SVR. To counteract this toxicity, physicians are increasing prescribing red cell growth factors (erythropoietin or EPO, marketed as Procrit and Aranesp) to reverse anemia and maintain people on adequate ribavirin doses. Many leading clinicians are even using EPO proactively, to prevent the need for ribavirin dose reduction before hemoglobin levels drop too far. Final research data supporting this strategy is not yet available, but the goal is to increase SVR rates by maintaining original ribavirin doses. Based on data from large HCV treatment studies, Schering-Plough has estimated that between 14% and 22% of people in IDEAL will require ribavirin dose reductions due to drops in hemoglobin levels. The IDEAL study protocol dictates a reduction in ribavirin dose when hemoglobin levels fall below 10 g/dL. After dose reduction, EPO can be used to restore hemoglobin levels and allow a return to original ribavirin dosing, at the discretion of the treating physician. The catch is that the protocol mandates different reductions in ribavirin dosage, depending on whether the study participant is in the Pegasys arm or a Peg-Intron arm. People in the Pegasys arm will have their ribavirin dose reduced to 600 mg. But people in a Peg-Intron arm will have a two-step dose reduction, first lowering the ribavirin dose 600-1,000 mg, depending on original dose, and then down another 200 mg if necessary. This apparent double standard led some IDEAL study investigators to raise concerns that the different dose reduction protocols would bias the results of the Pegasys/Peg-Intron comparison in favor of Peg-Intron. Schering-Plough explains that the FDA required different dose reduction protocols based on available data. The two-step dose reduction for the Peg-Intron arms has been studied in the WIN-R trial, but never researched in Pegasys studies. The Pegasys dose reduction scheme is based on the protocol used in the original trials leading to FDA approval of Pegasys. In response to these concerns, Schering-Plough has countered that overall, people in the Pegasys arm will actually receive marginally higher average doses of ribavirin than people in the Peg-Intron arms. This projection presumably rests on the assumption that a substantial number of people receiving 1,400 mg of ribavirin with Peg-Intron will require ribavirin dose reductions. A final question is how the different ranges of initial weight-based ribavirin doses (800-1,400 mg for Peg-Intron arms, vs. 1,000-1,200 for the Pegasys arm) will affect treatment responses. Schering-Plough estimates that about 14% of study participants will fall into the lowest weight category, receiving 800 mg of ribavirin with Peg-Intron or 1,000 mg of ribavirin with Pegasys. In theory, the 800 mg dose (with Peg-Intron) may be more tolerable and easier to maintain in this group, while the 1,000 mg dose (with Pegasys) may require more reductions to 600 mg (thus possibly compromising treatment efficacy). Schering-Plough also estimates that about 11% of study participants will fall into the highest weight category, receiving 1,400 mg of ribavirin with Peg-Intron or 1,200 mg of ribavirin with Pegasys. In theory, the higher 1,400 mg ribavirin dose may be more effective for this sub-group.
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HCV Treatment for Nonresponders
Liz Highleyman
With recent improvements in therapy for hepatitis C,
there is a growing interest in the management of patients who have not
responded to previous treatment. Nonresponders are patients who do not
achieve a sustained virological response (SVR) six months after the end of
therapy. They fall into three groups: those who experience little or no
decrease in HCV viral load (complete nonresponders); those who achieve a
significant reduction in viral load at least 1-2 logs but do not clear the
virus completely (partial responders); and those who achieve an early
virological response (EVR) or end-of-treatment response (ETR) followed by a
viral load rebound (relapsers). About half of patients with HCV genotype 1
receiving the current best treatment do not achieve an SVR.
Three basic retreatment strategies are being studied for nonresponders. The
first involves administering the current standard of care, pegylated
interferon plus ribavirin, to patients who previously received suboptimal
therapy with standard interferon alone (monotherapy), standard interferon
plus ribavirin, or pegylated interferon monotherapy. The second strategy is
to administer pegylated interferon plus ribavirin at higher doses or for
longer periods. The third involves treatment with new drugs instead of, or
in addition to, pegylated interferon and ribavirin.
Current Standard of Care
Research indicates that about 20% of patients who did not respond to the
older standard interferon can achieve an SVR with pegylated interferon plus
ribavirin. For example, in the April 2004 issue of Gastroenterology,
Mitchell Shiffman and colleagues reported the first results from the
Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial.
The study evaluated 604 patients who did not respond to previous treatment
with standard interferon, with or without ribavirin. Subjects were retreated
with pegylated interferon (Pegasys) 180 µg per week plus ribavirin. Those
who achieved an EVR (undetectable HCV viral load at 20 weeks) continued
treatment for 48 weeks. At the end of treatment, 32% of patients had an
undetectable viral load; at the end of follow-up (72 weeks), 18% achieved an
SVR. Among those who achieved an EVR at 12 weeks, 34% went on to achieve an
SVR, but only three patients (1%) who did not achieve an EVR later achieved
an SVR. SVR rates were 14% for patients with HCV genotype 1, 65% for
genotype 2, and 54% for genotype 3. African Americans and patients over age
60 had lower SVR rates. The researchers concluded that "[s]elected
nonresponders to previous interferon-based therapy can achieve SVR following
retreatment with [Pegasys] and ribavirin."
The likelihood of successful retreatment is highest when patients who
originally received standard interferon monotherapy are retreated with
pegylated interferon plus ribavirin. It is uncommon for patients to respond
to retreatment with the same suboptimal regimen. In both HALT-C and ACTG
5071 (a study of patients coinfected with HCV and HIV), patients who started
at lower doses of ribavirin in an effort to reduce toxicity were less likely
to achieve an SVR, confirming that ribavirin helps prevent relapse.
It is also possible that individuals who did not respond well to Peg-Intron,
the first approved pegylated interferon, may do better with Pegasys. At the
May 2004 Digestive Disease Week (DDW) conference, N. Zeng and colleagues
from Johns Hopkins reported on the use of Pegasys plus ribavirin in 15
genotype 1 patients who failed to respond to Peg-Intron plus ribavirin. At
24 weeks, 40% (six subjects) had undetectable HCV viral load. One-third of
the continued nonresponders (3 out of 9) and just one of the responders were
African American. SVR rates are not yet available, and patients will
continue to be followed. A currently enrolling study called REPEAT will also
look at retreatment with Pegasys plus ribavirin in Peg-Intron nonresponders.
(For details and study sites, see
www.clinicaltrials.gov/ct/gui
/show/NCT00039871.)
Longer or Higher-Dose
Therapy
The usual course of therapy for HCV is 48 weeks for patients with genotype 1
HCV and 24 weeks for those with genotypes 2 or 3. While most genotype 2 or 3
patients do well with a 24-week course, some studies suggest that 72 weeks
may work better for those with genotype 1. This may be especially true for
HCV/HIV coinfected patients, who appear to respond more slowly to HCV
therapy. The benefits of higher doses are less clear, however. C. Bapin
reported at the April 2004 European Association for the Study of the Liver (EASL)
conference that 24% of previous standard interferon monotherapy or standard
interferon plus ribavirin nonresponders achieved a SVR after 48 weeks of
retreatment with Peg-Intron plus ribavirin. However, subjects who started
with an initial Peg-Intron dose of 2 µg/kg per week for the first 12 weeks
did not respond better than those who received the usual 1.5 µg/kg per week
dose for the entire 48 weeks.
Other Drugs
One therapy under study for treating nonresponders is consensus
interferon-alpha (Infergen), a recombinant product that combines the
features of several natural alpha interferons. At the recent DDW meeting,
Steve Kaiser reported on a study of high-dose Infergen in previous
nonresponders. In this study, 50 subjects (about half with genotype 1) who
did not respond to pegylated interferon plus ribavirin were retreated with
either 9 µg Infergen daily for 16 weeks or high-dose (27 µg) daily Infergen
induction therapy for 4 weeks followed by 18 µg daily for 12 weeks. All
patients then received continued therapy with 9 µg daily Infergen plus
ribavirin for an additional 34-56 weeks. Twenty-four weeks into the
combination therapy phase, 46% of subjects who started with 9 µg Infergen
and 52% of those who started with 27 µg achieved an undetectable HCV viral
load. ETR rates were 42% and 48%, respectively, and SVR rates were 23% and
27%. "[Consensus interferon] daily dosing/induction therapy together with
subsequent [ribavirin] combination therapy thus shows sustained viral
response rates in about one quarter of previous peginterferon combination
therapy nonresponders," the researchers concluded.
Another drug being studied in nonresponders is interferon-gamma-1b (Actimmune), now in Phase II trials. In a pilot study presented at the DDW conference, Carroll Leevy reported that after 24 weeks, 47% of previous Peg-Intron plus ribavirin nonresponders achieved an undetectable HCV viral load when retreated with a combination of Infergen 15 µg daily plus Actimmune 50 µg twice weekly plus ribavirin. SVR results are not yet available, and the study is continuing. Although both Kaiser and Leevy reported that treatment was generally well-tolerated in their studies, some physicians are skeptical about using high daily doses of Infergen and/or Actimmune due to potential toxicity. Further research is needed to determine whether less frequent or lower doses would produce similar results.
Future Prospects
Failure to achieve a sustained virological response can be discouraging. But
research indicates that patients may experience a histological response,
improved liver tissue health, or a reduced rate of fibrosis progression even
if they do not completely clear HCV. This is most likely in partial
responders who experience some decrease in viral load. Even in the absence
of SVR, treatment may help prevent progression to decompensated cirrhosis
and lower the risk of hepatocellular carcinoma (liver cancer). For this
reason, some experts believe nonresponders may benefit from interferon
maintenance therapy. Due to its toxicity, long-term therapy with full-dose
interferon is an unattractive prospect. But even low-dose maintenance
therapy may be useful. This is now being evaluated in a few large trials
including HALT-C.
Given the side effects, inconvenience, and cost of HCV therapy, the decision
whether to retreat can be difficult. The current National Institutes of
Health (NIH) consensus guidelines recommend that retreatment should be
considered especially for patients with advanced liver fibrosis or
cirrhosis, who stand to benefit the most from therapy. Improvements in HCV
therapy are rapidly emerging, and it is probable that future therapeutic
advances including drugs from entirely new classes such as protease
inhibitors will offer improved prospects for successful retreatment of
patients who have not previously responded to therapy.
| Complementary and Alternative Therapies for Chronic Hepatitis C: Randomized Trial Data Review | |
| Posting Date: June 4, 2004 |
http://www.clinicaloptions.com/hep//jopt/articles/article.asp?a=Coon-JHep-2004-03&page=capsule |
|
No Evidence of Sexual
Transmission of Hepatitis C among Monogamous Couples: Results of a
10-Year Prospective Study The risk of sexual transmission of hepatitis C virus (HCV) infection was evaluated among 895 monogamous heterosexual partners of HCV chronically infected individuals in a long-term prospective study, which provided a follow-up period of 8,060 person-years. Seven hundred and seventy-six (86.7%) spouses were followed for 10 yr, corresponding to 7,760 person-years of observation. One hundred and nineteen (13.3%) spouses (69 whose infected partners cleared the virus following treatment and 50 who ended their relationship or were lost at follow-up) contributed an additional 300 person-years. All couples denied practicing anal intercourse or sex during menstruation, as well as condom use. The average weekly rate of sexual intercourse was 1.8. Three HCV infections were observed during follow-up corresponding to an incidence rate of 0.37 per 1,000 person-years. However, the infecting HCV genotype in one spouse (2a) was different from that of the partner (1b), clearly excluding sexual transmission. The remaining two couples had concordant genotypes, but sequence analysis of the NS5b region of the HCV genome, coupled with phylogenetic analysis showed that the corresponding partners carried different viral isolates, again excluding the possibility of intra-spousal transmission of HCV. The authors conclude, “Our data indicate that the risk of sexual transmission of HCV within heterosexual monogamous couples is extremely low or even null. No general recommendations for condom use seem required for individuals in monogamous partnerships with HCV-infected partners.” 06/21/04
Reference
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Amantadine at a Dose of 300 mg Daily Is Safe, and Lowers ALT Blood Levels Significantly More Than 200 mg Daily in Patients with Chronic Hepatitis C
Amantadine reduces liver transaminase levels in some patients with chronic hepatitis C at doses of 200 mg daily and may improve the sustained virological response (SVR) when given with interferon and ribavirin. The primary purpose of the present investigation was to study the safety and toxicity of higher doses of amantadine in subjects who previously failed or were intolerant to interferon.
The secondary aim was to test the efficacy of higher dose of amantadine against hepatitis C.
An open-labeled prospective study was conducted starting with amantadine 200 mg daily and increasing to 500 mg daily while monitoring for safety, toxicity, and efficacy. An amantadine blood level exceeding 1,600 ng/ml was considered toxic requiring dose reduction.
The patient's symptoms, laboratory tests, and quality of life were monitored.
Results
One hundred patients enrolled in the study.
Normalization of alanine aminotransferase (ALT) for each dose was as follows: 200 mg (35%), 300 mg (49%), 400 mg (53%), and 500 mg (56%). The incidence of toxic amantadine plasma levels increased with dose, i.e., 200 mg (0%), 300 mg (6%), 400 mg (27%), and 500 mg (49%).
The frequency and severity of arthralgias and fatigue improved at all dosages administered. No changes in the occurrence or severity of headache, insomnia, or depression were reported.
Serious adverse events included myocardial infarction and suicide attempt. Other side effects included impotence, confusion, alopecia, and hoarseness.
Conclusions
Amantadine given at a dose of 300 mg daily is safe, and significantly lowers ALT blood levels more than 200 mg daily. The enzyme response rate does not significantly improve above 300 mg, but toxicity increases.
Department of Medicine, Department of Health Evaluation Sciences, Pennsylvania State University College of Medicine, The M.S. Hershey Medical Center, Hershey, Pennsylvania.
06/21/04
Reference
J P Smith and others. Amantadine therapy for chronic hepatitis C: a dose
escalation study.
American Journal of
Gastroenterology
99(6): 1099-1104. June 2004.
Articles on Amantadine Therapy in Chronic Hepatitis
C
http://www.hivandhepatitis.com/hep_c/news/2004/062104_b.html
The Case for Hepatitis C-related Arthritis
The objective of the current study was to present the data available
supporting the existence of an arthropathy (joint inflammation) associated
with hepatitis C infection.
The MEDLINE database was searched for "arthritis" intersecting with "hepatitis C" in addition to the authors' investigations and experience on this subject.
Results
Arthritis, not otherwise explained, has been noted in 2% to 20% of hepatitis C virus (HCV) patients. This arthritis is rheumatoid-like in two thirds of the cases and a waxing/waning oligoarthritis in the rest.
Cryoglobulinemia alone does not explain the arthritis, and there is difficulty in differentiating it from rheumatoid arthritis. The arthropathy is nonerosive/nondeforming.
Whereas non-steroidal anti-inflammatory drugs, low-dose corticosteroids, and hydroxychloroquine may be helpful, conventional treatment of arthritis may be problematic in the context of viral hepatitic arthropathy.
Antiviral therapy is most effective, even without viral clearance, but rheumatic complications may occur.
The authors conclude, “HCV arthropathy should be considered in the differential diagnosis of new-onset arthritis.”
06/16/04
Reference
I Rosner and
others. The case for hepatitis C arthritis.
Seminars in Arthritis
and Rheumatism
33(6): 375-387. June 2004.