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Viral load level at
week 8 may be as accurate as "12-week rule" for predicting failure to
achieve SVR in HCV patients |
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By Dorothy J. Schirf, MD
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September 23, 2005 ˇŞ
The currently accepted 12-week threshold for cessation of therapy in
chronic hepatitis C patients who fail to have an early virologic
response was firmly upheld by a recent retrospective, international
study. Investigators further determined that even earlier time points of
4 and 8 weeks can reliably be used to predict therapeutic response using
specific viral load levels. These findings by Terrault and colleagues
represent the combined effort of a multicenter cohort study based at the
University of California San Francisco, San Francisco, California.
Although interferon formulations in combination with ribavirin have been
very successful in treating chronic hepatitis C, they are associated
with significant and sometimes severe side effects. Predicting early
during therapy that a patient is unlikely to respond to treatment can
substantially reduce morbidity and cost. The "12-week rule"--stopping
therapy upon failure to exhibit at least a 2-log drop or undetectable
HCV RNA by 12 weeks of treatment--has been shown to accurately predict
the failure to achieve a sustained virologic response (SVR) 24 weeks
after the end of therapy. This "rule" has a negative predictive value (NPV)
of 98%, and accordingly has been adopted as a recommendation in the
National Institutes of Health Consensus Development Conference
Statement.
The current study was undertaken to investigate the use of precise
viral loads levels for predicting whether chronic HCV patients given
interferon plus ribavirin will achieve SVR. Alternate decision rules
were tested with the idea of accurately predicting nonresponse as early
as feasible for the widest scope of patients. Performance of various
stopping rules combining viral load and decline in viral load from
baseline was also evaluated.
Researchers collected archive data on 351 patients at 5 North
American centers as well as 1 center in France. Previously recorded
baseline demographic and medical data including age, ethnicity, gender,
stage of hepatic disease, nature and duration of prior HCV therapy, and
genotype specifics were used for analysis.
All patients were at least 18 years of age, had documented serologic
evidence of HCV infection, and had undergone recent liver biopsy
confirming either cirrhosis or a defined constellation of inflammatory
changes. Study subjects were gathered from clinical trials (n = 231) as
well as from private practice (n = 138) and were divided into a 24-week
group (minimum of 20 weeks of therapy) and a 48-week group (minimum of
44 weeks of therapy).
Most of the patients were white males, treatment-naive, and without
cirrhosis, and roughly half were in the 24-week treatment group. A total
of 165 patients achieved SVR, while the remaining 186 were defined as
nonresponders. Not surprisingly, they found SVR patients more likely to
be treatment naive with non-1 viral genotypes and recipients of a
48-week regimen.
Univariate logistic regression analysis of baseline data showed viral
genotype, viral load, treatment duration, and age were all significantly
predictive of SVR.
Viral load determinations not only validated the existing "12-week"
guideline but also established that 8-week decision thresholds were
comparable in performance to 12-week measures, an outcome yet to be
verified with other drug combinations. Moreover, predicted nonresponse
rates (%) for an expanded range of specific viral loads could enable
more confident clinical decisions when discontinuation of treatment is
being considered.
Specifically, the study revealed that the failure to achieve SVR for
patients with non-1 viral genotypes could be predicted with high
accuracy. A 4-week viral load ˇÝ 100,000 IU/mL or an 8- or 12-week viral
load ˇÝ 10,000 IU/mL were equally indicative of a 0% chance for SVR.
Similarly, these cut-off values provided valuable early time points for
considering stopping therapy for genotype 1 patients. At 4 weeks, an HCV
RNA level ˇÝ 100,000 IU/mL had an NPV of 96.5% for failure to achieve
SVR, and at 8 and 12 weeks, an HCV RNA level ˇÝ 100,00 IU/mL had an NPV
of 98.5% and 96.9%, respectively. These NPV values were comparable to a
2-log decline or undetectable HCV RNA at 12 weeks, which in this study
was 97.1% for genotype 1 patients.
Researchers noted that the thresholds for stopping therapy were
accurate for all patients studied, despite a variety of treatments and
settings. No exceptions were encountered in either treatment-naive or
treatment-experienced patients or in clinical trial participants vs
those from clinical practice. The investigators noted that these results
need to be verified in patients receiving peginterferon plus ribavirin,
the current standard of treatment, as this study was limited to patients
taking interferon plus ribavirin. Nevertheless, they wrote that "this
study confirms the central role of viral quantitation in the clinical
management of HCV-infected patients undergoing antiviral therapy."
References
Terrault N, Pawlotsky J-M, McHutchison J, et al. Clinical utility of
viral load measurements in individuals with chronic hepatitis C
infection on antiviral therapy. J Viral Hepatitis. 2005;12:465-472.
National Institutes of Health Consensus on Management of Hepatitis C:
2002. NIH Consens State Sci Statements. 2002;19:1-46.
http://clinicaloptions.com/hep/news/news_imed_398.asp
Viral Load Measurements
in Hep C with Antiviral Therapy
SourceURL:http://www.gastrohep.com
Measuring absolute viral loads or change in
viral load from baseline, are highly predictive of non-sustained
virological response at 8 and 12 weeks, finds the latest Journal
of Viral Hepatitis.
Absolute viral load was found clinically useful
in predicting sustained virological response and lack of sustained
virological response to treatment.
Log decline in viral load from baseline was
also found useful in predicting sustained virological response and
non-sustained virological response to treatment.
Dr Terrault and colleagues assessed the
clinical utility of Hepatitis C virus RNA quantitation and changes
in viral load.
The researchers included 351 Hepatitis
C-infected individuals treated with interferon plus ribavirin.
The team showed that viral load decision
thresholds provided negative predictive values of more than 95% at
week 4 using a 100 000 IU/mL cut-off.
The researchers found similar results at weeks
8 and 12 using 10 000 IU/mL cut-offs.
A 2-log decline from baseline provided 95%
negative predictive values at week 8 – Journal of Viral Hepatitis
The team noted that a 2-log decline from
baseline provided negative predictive values of more than 95% at
weeks 8 and 12.
Combinations of absolute viral loads and viral
load from baseline did not enhance the performance of the rules for
predicting non-sustained virological response.
The positive predictive values at weeks 8 and
12 were 59% and 67%, respectively.
The team noted that the results highlight the
importance of viral quantitation in gauging therapeutic response in
chronic Hepatitis C with antiviral therapy.
Dr Terrault's team concluded, "Early changes in
viral load, measured as absolute viral loads or change in viral load
from baseline, are highly predictive of non-sustained virological
response at 8 and 12 weeks."
"Positive predictive values are modest but
these data may provide encouragement to patients who are in the
early phases of treatment when side effects are frequent."
"Additionally, we demonstrated the need for
cautious interpretation of stopping rules when the values are at or
near the decision thresholds."
J Viral Hepat 2005: 12(5):465
http://www.hcvadvocate.org/news/newsRev/2005/NewsRev-115.html#3
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Is There a Correlation Between HCV Viral Load and
Severity of Liver Disease?
The significance of hepatitis C virus (HCV) serum titers (HCV
viral load) has been examined in several clinical
situations. There is much evidence that patients with a lower viral load
have better response rates to anti-viral therapy compared to those with
higher levels.
Moreover, a direct
association has been observed between serum titers of HCV and transmission
rates of the virus.
The aim of the present
study was to determine if there was any correlation between HCV viral load
and the severity of
liver disease.
Fifty patients with HCV
infection were included in the study. These comprised of 34 subjects with a
history of alcohol use and 16 non-alcoholics.
Quantitative serum HCV RNA assay
was carried out using the branched DNA (bDNA) technique. Linear regression
analysis was performed between serum viral titers and liver tests.
In addition, for the
purpose of comparison, the subjects were divided into two groups: those with
low viral titers (<=50 genome mEq/mL) and high titers (>50 mEq/mL).
Results
All subjects were men,
with a mean+/-SD age of 47+/-7.8 years. The mean HCV RNA level in the blood
was 76.3X10(5)+/-109.1 genome equivalents/mL.
There was no correlation
between
HCV RNA levels and age of
the patients (r = 0.181), and the history or amount (g/d) of
alcohol consumption (r = 0.07).
Furthermore, no
correlation was observed between serum HCV RNA levels and the severity of
liver disease as judged by the
values of serum albumin (r =
0.175), bilirubin (r = 0.217),
ALT (r = 0.06) and
AST (r = 0.004) levels.
Similarly, no significant
difference was observed between patients with low viral titers and high
titers with respect to any of the parameters.
Conclusion
The authors conclude, “Our
results indicate that the severity of liver disease is independent of serum
levels of hepatitis C virus. These findings are important since they have a
direct impact on the current debate regarding the role of direct cytopathic
effect of hepatitis C virus versus immune-mediated injury in the
pathogenesis of HCV-related liver damage.”
Digestive Diseases Section (111D), VA
Medical Center, 2002 Holcombe Blvd. Houston, Texas.
08/06/04
Reference
B S Anand and M
Velez. Assessment of correlation between serum titers of hepatitis c virus
and severity of liver disease.
World Journal of
Gastroenterology
10(16):2409-12411. August 15, 2004.
http://www.hivandhepatitis.com/hep_c/news/2004/080604_a.html
The Latest Viral Load Tests
By Alan Franciscus
On
July 9th, 2001 Roche Diagnostics Corporation announced FDA marketing
approval for two hepati-tis C tests. The tests approved for marketing are
the AMPLICOR HCV (r) Test, version 2.0, and the COBALT AMPLICOR (tm) HCV
Test, version 2.0. These tests are the first qualitative RNA tests (viral
load tests) to be approved for marketing by the FDA and are designed to
directly detect the hepatitis C virus in patients that are HCV antibody
positive.
The AMPLICOR HCV Tests detect the presence of HCV RNA in serum and plasma; a
positive result indicates current active infection. However, it is important
to note that it does not distinguish between acute and chronic states of
hepatitis C infection but is an improvement over antibody tests that only
measure the presence of an immune response to the virus, not the actual
virus itself. In fact when antibody tests are used alone in the clinical
setting they provide little information beyond evidence of exposure to the
virus and can induce anxiety for patients who do not have access to a follow
up viral load test.
There are currently three types of viral load tests utilized in hepatitis C
and until now they have been considered investigational only. There are two
different categories of viral load tests - qualitative measures the presence
of virus while quantitative measures the amount of virus. The most commonly
used viral load testing for HCV to date utilizes one of the following types
of technology:
1. Polymerase Chain Reaction ( PCR) - detects the presence of HCV RNA in the
serum which indicates current infection. These tests are very sensitive and
can measure viral load down to < 50 viral particles per milliliter. (This is
the type of viral load test that has now been approved for marketing by the
FDA). New applications of PCR technology beyond viral load testing may allow
prediction of disease predis-position and individualization of patient
therapy, which could result in earlier treatment and improved patient care.
2. Branched-Chain DNA Assay - a method that is easier (and cheaper) to apply
to a large number of samples, but only measures viral loads >200,000 viral
particles
3. Transcription Mediated Amplification (TMA) -this technology allows for
the amplification and detection of nucleic acids in serum or plasma. This
test appears easy to use, streamlines assay processing, produces consistent,
reliable and speedier results.
Prior to the recent FDA approval of the first viral load tests for HCV there
has been controversy because the results vary depending on the way that the
sample is handled and stored. Furthermore, results may vary from lab to lab.
It should also be added that the immediate value of the quantitative test is
questionable since the amount of virus de-tected does not correlate with
disease progression. This test however does have significant value when
measuring virus before, during and after treatment with interferon or
interferon plus ribavirin. In addition viral load measurement prior to
treatment is a predictor of response with a low viral load prior to
treatment being a predictor of better response.
There are many benefits to the FDA approv-ing HCV viral load testing. Most
importantly it will practically guarantee reimbursement by insurance
companies and government agencies. In addition, the recently FDA approved
Amplicor HCV tests are the first HCV RNA assays to be reported in
International Units (IU/ml), as defined by the World Health Organization
(WHO) International Standard for HCV RNA for Nucleic Acid Amplification
Technology (NAT) Assays. The FDA now requires all approved viral load tests
to be reported in International Units (IU/ml) which will result in
consistency in comparing results from one test to another or from one lab to
another. Additionally, it will make it easier to draw conclusions from one
clinical trial to another when viral load measurements are standardized.
Quest Diagnostics Announces Availability of HEPTIMAX
Ultra-Sensitive Quantitative Hepatitis C Virus Test
TETERBORO, N.J., July 23 /PRNewswire/ -- Quest Diagnostics Incorporated
(NYSE: DGX - news),
T he
nation's leading provider of gene-based medical testing, information and
services, announced the availability of a new ultra-sensitive viral load
test for hepatitis C virus (HCV) that is approximately 10 times more
sensitive than any other commercially available test. The test detects the
level of hepatitis C virus based on an innovative application of
transcription mediated amplification (TMA) technology to HCV testing. Quest
Diagnostics developed the test and is the first laboratory in the world to
offer it.
The new offering, called the HEPTIMAX(TM) viral load test, is capable of
detecting minute quantities of hepatitis C virus down to as few as 5
International Units (IUs) per milliliter (ml). The ability to detect minute
quantities of virus is useful to physicians in monitoring the effectiveness
of various treatments for hepatitis C in patients. The HEPTIMAX(TM) viral
load test not only delivers the maximum sensitivity but also offers the
maximum range (5 IUs/ml to 8.3 million IUs/ml).
This proprietary test is ordered by physicians to monitor and confirm
hepatitis C viral infection and to demonstrate post-treatment resolution of
the infection. Because the HEPTIMAX(TM) viral load test combines the new TMA
technology with traditional quantitative viral load testing using branched
DNA technology, it simplifies patient management by allowing physicians to
order just one test to cover the complete range of possible viral load
values from 5 IUs to 8.3 million IUs per ml.
``The improved sensitivity of the HEPTIMAX(TM) viral load test is
particularly relevant to physicians with the advent of new forms of
hepatitis C therapeutics,'' said Jorge Leon, Ph.D., Vice President for
Applied Genomics at Quest Diagnostics. ``New combination therapies utilizing
sustained-action forms of interferon have shown better treatment responses
in clinical trials that translate to lower levels of virus in patients.''
``Preliminary studies comparing the HEPTIMAX(TM) viral load test to other
technologies and laboratories confirm it has superior sensitivity,'' said
Dr. Peter Heseltine, Medical Director of Infectious Diseases for Quest
Diagnostics. ``We are planning additional studies with other outside
investigators to confirm and publish our findings.''
A study published in the October 2000 issue of the journal ``Hepatology''
utilizing a hepatitis C qualitative version of the TMA test, showed it to be
a better predictor of end-of-treatment resolution than the other methods.
The new test was developed by Quest Diagnostics at Nichols Institute and
is offered exclusively through Quest Diagnostics' national laboratory
network. The highly sensitive HEPTIMAX(TM) HCV assay utilizes reagents from
Bayer Diagnostics, based on proprietary TMA technology made available
through Bayer's exclusive agreement with Gen-Probe, San Diego, CA.
The HEPTIMAX(TM) viral load test is the latest addition to Quest
Diagnostics' comprehensive test menu for hepatitis C disease management.
Quest Diagnostics provides a complete selection of tests for initial
diagnosis, treatment monitoring and managing HCV infected patients. The menu
also features the DupliType(TM) HCV genotype test, which helps physicians
establish the appropriate duration of HCV therapy. Quest Diagnostics
introduced the HCV DupliType(TM) test to provide subtyping for a broader
range of hepatitis C viral isolates than was previously available using
other technologies.
An estimated 4 million people are infected with hepatitis C virus in the
United States, and approximately 130,000 patients currently receive
treatment. Physicians monitor viral loads in infected patients to test the
effectiveness of various types of combination therapies.
Quest Diagnostics' gene-based testing focuses on infectious disease,
oncology and heritable conditions, and helps physicians target individual
treatment regimes, monitor resistance to therapies and predict
predisposition to various genetic conditions. Quest Diagnostics is a leading
innovator in genomics testing, through its research and development center
and esoteric testing laboratory, the world-renowned Nichols Institute, as
well as through alliances with leading academic and commercial technology
developers.
About Quest Diagnostics
Quest Diagnostics is the nation's leading provider of diagnostic testing,
information and services with annual revenues of $3.4 billion in 2000. The
company's diagnostic testing yields information that enables health care
professionals and consumers to make better decisions to improve health.
Quest Diagnostics offers patients and physicians the broadest access to
diagnostic testing services through its national network of approximately 30
full-service laboratories, 150 rapid response laboratories and more than
1,300 patient service centers, where specimens are collected. Quest
Diagnostics is the leading provider of esoteric testing, including
gene-based testing, and is the leader in routine medical testing, drugs of
abuse testing, and non-hospital-based anatomic pathology testing. Through
partnerships with pharmaceutical, biotechnology and information technology
companies, Quest Diagnostics provides support to help speed the development
of health care insights and new therapeutics. Additional company information
can be found on the Internet at: http://www.questdiagnostics.com.
The statements in this press release which are not historical facts or
information may be forward-looking statements. These forward-looking
statements involve risks and uncertainties that could cause the outcome to
be materially different. Certain of these risks and uncertainties are
described in the Quest Diagnostics Incorporated 2000 Form 10-K and
subsequent filings.
The HEPTIMAX viral load test and DupliType HCV genotype test are
trademarks of Quest Diagnostics Incorporated.
SOURCE: Quest Diagnostics Incorporated
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Spontaneous Fluctuations in Viral
Load (Untreated)
Assessment of spontaneous
fluctuations of viral load in untreated patients with chronic hepatitis C by
two standardized quantitation methods: Branched DNA and Amplicor monitor
Abstract: Quantitation of hepatitis C virus (HCV) RNA in serum has been used
to predict and monitor the efficacy of interferon therapy in chronic HCV
infection. We prospectively studied the fluctuation of viremia by a
longitudinal follow-up of HCV RNA levels for 2 months in six untreated
patients. Spontaneous fluctuations of HCV RNA ranged from 2.8- to 5.7-fold
with branched DNA assay and from 2.9- to 5.6-fold with Monitor. These large
spontaneous fluctuations (up to 0.75 log), observed daily, weekly, and
monthly, raise doubt about the clinical value of a single assessment of
pretherapeutic viremia. AUTHOR: Halfon P, Bourliere M, Halimi G, Khiri H,
Bertezene P, Portal I, Bota-Fridlund D, Gauthier AP, Jullien M, Feryn JM,
Gerolami V, Cartouzou G SOURCE: JOURNAL OF CLINICAL MICROBIOLOGY 36: (7)
2073-2075 JUL 1998 |
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Viral Load not Dependent on
Genotype
Comparative analysis of
quantification of viral load in patients infected with hepatitis C virus:
quantiplex HCV RNA assay and amplicor monitor assay. Olaso V, Cordoba J,
Lopez B, Arguello L, Molina J, Lainez B, Ortiz V, Pastor M, Prieto M,
Berenguer J Servicio de Medicina Digestiva, Hospital "La Fe", Valencia,
46009, Espana.
OBJECTIVE: two standardized techniques, Quantiplex HCV RNA 2.0 (bDNA) and
Amplicor Monitor, were evaluated for the quantification of hepatitis C virus
(HCV) load. Our objectives were: 1) to determine the relationship between
viral load and genotype, and 2) to evaluate viral load in serial serum
samples and in patients with normal or slightly elevated liver enzyme values
in an area with a high prevalence of genotype 1.
RESULTS: the viral loads detected with the two methods correlated
significantly (r = 0.7, p ), but viral load was smaller with the Monitor
than with the Quantiplex assay, and was independent of genotype. The
Monitor/Quantiplex ratio was lower in patients with a non-1 genotype than in
patients with genotype 1b. Virological characteristics were similar in
patients with normal or slightly elevated enzyme levels and in patients with
elevated enzyme values. Neither method showed a relationship between viral
load and age, sex, duration of the infection, mode of transmission, or
histological activity index.
CONCLUSION: viral load was not dependent on genotype. Measurement of
viral load in a single serum sample adequately reflected the viral load
measured in several serum samples from patients with chronic HCV infection.
Patients with normal liver enzyme levels are not good candidates, in
virological terms, for treatment with interferon. |
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Viral Load may not be Linked to
Liver Damage
VIRAL LOAD MAY NOT BE LINKED TO LIVER DAMAGE
Increased intrahepatic
hepatitis C virus (HCV) load may not be associated with more severe liver
injury, according to a report from Australia. The pathogenesis of HCV
induced hepatic injury remains unidentified and could be attributable to
either direct cytopathic damage by HCV or immune-mediated hepatic injury
induced by HCV. It is also possible that both could act simultaneously. "One
way to identify whether liver damage is attributable to direct cytopathic
damage is to examine whether the degree of viral load correlates with the
degree of liver injury," researcher Peter H. McGuinness and colleagues wrote
("Intrahepatic HCV RNA Levels Do Not Correlate with Degree of Liver Injury
in Patients with Chronic Hepatitis C," Hepatology, April
1996;23(4):676-687). "Most studies addressing this question have measured
the amount of HCV in serum. Ideally, HCV RNA viral load should be estimated
directly from liver tissue itself, because serum levels of virus may be
contributed to and influenced by extrahepatic sources. Also, the presence of
serum immune complexes may introduce further variables. Doubt has also been
raised as to the validity of HCV RNA quantitation in serum compared with
plasma." HCV has been shown to consist of many distinct genotypes, and while
some investigations have found a link between genotype and the severity of
liver disease, others have not. "This may be because of the geographical
difference in genotype populations, " McGuinness and colleagues wrote. "Most
studies may be biased toward a subset of genotypes. This may obscure
relationships between genotypes and pathogenicity. "Many researchers have
compared HCV load with genotype in blood. Most have demonstrated that
genotype 1b tends to be associated with the highest HCV RNA levels. In
contrast, there has been no analysis of the effect of different genotypes on
intrahepatic HCV RNA levels. Therefore, an analysis of intrahepatic HCV RNA
levels must take into account the effect of these genotypes." In this study
McGuinness et al. attempted to determine whether there was a correlation
between liver HCV RNA load and the degree of liver injury and to examine the
effect of interferon alpha (INF-(alpha)) treatment on hepatic HCV RNA load.
Liver tissues (n = 56) were obtained from 47 patients with chronic HCV (nine
before and after IFN-(alpha) therapy). Total RNA was isolated and
quantitated for specific HCV RNA by dot-blot polymerase chain reaction (DB-PCR)
using a standard curve created from synthetic HCV RNA of known titer to
calculate actual RNA levels. A multivariate analysis was undertaken to
determine the relationship of intrahepatic HCV RNA levels with risk factors,
length of HCV exposure, and histological injury scores. The confounding
effect of HCV genotype was examined by direct sequencing of the NS5b region.
Liver HCV RNA ranged from 10(2) to 3.1x10(7) molecules per microgram total
liver RNA. "The multiple regression analysis showed no effect of length of
HCV exposure, risk factors, degree of bile duct damage, steatosis, or total
Scheuer or Knodell score on RNA levels," McGuinness et al. wrote. "No
significant confounding effect of HCV genotype on the degree of liver injury
was observed. However, genotype 1b had a significantly higher mean
intrahepatic HCV RNA load compared with the other genotypes detected." In
the nine patients who received IFN-(alpha) treatment, seven had no
detectable HCV after treatment. This was associated with a significant
decrease in intrahepatic HCV RNA levels (7.57 +/- 2.53x10(5) to 1. 82
+/-1.80x10(3) molecules per microgram total liver RNA +/- SEM, n = 9m P =
.0005). The authors conclude that intrahepatic viral load appears to be
significantly increased in patients with genotype 1b, but their results do
not support the hypothesis that increased intrahepatic HCV load is
associated with more severe liver injury. "These data suggest that the HCV
virus does not cause liver injury by simply expanding the viral load and
thus resulting in a cytopathic process," McGuinness et al. wrote. "The role
of intrahepatic anti- HCV-specific and nonspecific immune responses
therefore needs to be examined. It is clear that anti-HCV-specific and
nonspecific immune responses are detected in this disease. Their role and
the role of intrahepatic cytokine responses in the induction of chronic HCV
liver injury clearly require further investigation. Careful sequential
studies that simultaneously examine both the virus and the immune response
in liver tissue and serum are also clearly needed." The corresponding author
for this study is Geoffrey W. McCaughan, The A.W. Morrow Gastroenterology
and Liver Center, Royal Prince Alfred Hospital, Missenden Road, Camperdown
NSW 2050, Australia. |
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Viral Load in the First 24 Hours of
Treatment
Date: Mar 11, 2001 (Sun, 23:32:33) Subject: INFO:Kinetics of the
hepatitis C virus during interferon therapy
This study demonstrated that
the exponential decay slope of the viral load during the first 24 h was an
important predictor of the response to IFN therapy as well as the initial
viral load and HCV serotype. J Gastroenterol Hepatol 2001 Jan;16(1):29-33
Related Articles, Books, LinkOut Kinetics of the hepatitis C virus during
interferon therapy as a marker of therapeutic response. Nakamuta M, Fukutomi
T, Shimohashi N, Kinukawa N, Uchimura K, Tada S, Motomura K, Enjoji M, Kato
M, Iwamoto H, Tanabe Y, Imari Y, Sakamoto S, Sakai H, Nawata H Department of
Medicine and Bioregulatory Science, Graduate School of Medical Sciences,
Kyushu University, Fukuoka, Japan. nakamuta@intmed3.med.kyushu-u.ac.jp
[Medline record in process] BACKGROUND: The viral load and subtype of
hepatitis C virus (HCV) are predictors of the efficacy of interferon (IFN)
therapy. The kinetics of HCV during IFN therapy have been described
recently, suggesting that HCV infection is highly dynamic. These
observations have raised the issue as to whether early monitoring of the
viral load can help guide IFN therapy. METHODS: We measured HCV-RNA levels
at 0, 24 and 48 h after the start of IFN-alpha treatment (10 MU daily for 2
weeks and then three times weekly for 22 weeks) or IFN-beta treatment (6 MU
daily for 6 weeks). Then we analyzed the relationship between HCV kinetics
and therapeutic response using stepwise multivariate logistic regression
analysis. RESULTS: The exponential decay slope of the viral load during the
first 24 h, not the first 48 h or the next 24 h, was a predictor of viral
eradication at 6 months after completion of the treatment (sustained
response; P = 0.0023). This decay slope was not affected by the HCV serotype
or the type of IFN used. Initial viral load and HCV serotype were also
predictors, as reported previously (P
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Viral Load in 12 Weeks of Treatment
Clinical Utility of HCV RNA
Quantification Using the Test as an Early Predictor of Sustained Response
(AASLD abstract 802)
Mitchell L. Shiffman, Medical College of Virginia, Richmond, VA, et al.
This
analysis was designed to determine whether quantification of HCV RNA (COBAS
AMPLICOR HCV MONITOR) prior to and during the first 16 weeks of therapy,
with either PEG(40kDa) IFN -2a (PEGASYS ®) or unmodified IFN -2a, could be
used to predict sustained virological, biochemical, and histological
responses. Data were obtained from 122 patients involved in a randomized,
open label study who received PEG(40kDa) IFN -2a (45, 90, 180, or 270 µg) or
IFN -2a for 48 weeks. HCV RNA levels at weeks 8, 12, and 16 were highly
predictive of sustained virological response and sustained biochemical
response, and to a lesser extent, histological response. The lower the HCV
RNA level during the first 16 weeks of treatment, the greater the likelihood
that the patient ultimately achieved a sustained response after the
cessation of therapy. For example, patients who had HCV RNA levels of <10
5 , <10 4 , and <10 3 copies/mL at week 12 were, respectively,
29-, 39-, and 50-fold more likely to achieve a sustained virological
response than patients with HCV RNA levels above these values. Similar
results were obtained at the other timepoints and for predicting the
likelihood of achieving a sustained biochemical response. Baseline HCV RNA
levels were somewhat less predictive of response than were levels during the
first 16 weeks of therapy. These data suggest that quantification of HCV RNA
levels at 8, 12, and 16 weeks of therapy can be used to predict a sustained
response among patients receiving either PEG(40kDa) IFN -2a or unmodified
IFN -2a, and may be used to individualize therapeutic regimens. "These data
suggest that quantification of HCV RNA levels at 8, 12, and 16 weeks of
therapy can be used to predict a sustained response among patients receiving
either PEG(40kDa) IFN -2a or unmodified IFN -2a, and may be used to
individualize therapeutic regimens."
Prognostic Factors and Early Predictability of
Sustained Viral Response in Patients Treated with PEG(40kDa) IFN -2a (PEGASYS)
(AASLD abstract 803)
K. Rajender Reddy, University of Miami
School of Medicine, Miami, FL, et al.
This study was designed to determine
whether the dynamics of the viral response to therapy with PEG(40kDa) IFN
-2a (PEGASYS) are similar to those reported for IFN -2a monotherapy and IFN
-2a plus ribavirin combination therapy. Data from 3 large phase III trials
involving 814 patients treated with PEG(40kDa) IFN -2a were analyzed. A
stepwise logistic regression model was developed to identify baseline
factors associated with sustained virological response. Viral measurements
for all studies were analyzed using the COBAS AMPLICOR™ HCV test (lower
limit of detection = 50 IU/mL) for qualitative measure, and the COBAS
AMPLICOR HCV MONITOR™ for measurement of viral levels. The results indicate
that baseline prognostic factors associated with a sustained response (ie,
genotype, viral load, age, weight, and fibrosis stage) are similar to those
previously reported for other therapies. In addition, similar to what has
been reported in hepatitis B, the prognostic value of pretreatment
necroinflammatory markers was reported for the first time. A baseline
histology activity index (HAI) score >10, or an alanine aminotransferase
level more than 3 times the upper limit of normal, were predictive for
response.
"Patients on PEG(40kDa) IFN -2a who
did not achieve an undetectable virus or a viral decline of 2 log from
baseline had only a 2% probability of achieving a sustained virological
response (ie, 0.98 negative predictive value)." Based on an intent-to-treat
analysis among 564 patients who received PEG(40kDa) IFN -2a, the positive
predictive value for achieving a sustained virological response for either
an undetectable HCV RNA level (<100 copies/mL) or a 2-log drop in viral load
from baseline was 0.45. However, the negative predictive value of this
parameter was much higher. Patients on PEG(40kDa) IFN -2a who did not
achieve an undetectable virus or a viral decline of 2 log from baseline had
only a 2% probability of achieving a sustained virological response (ie,
0.98 negative predictive value).
The authors concluded that it is
possible to reliably predict patients who have a very low likelihood of
sustained viral response to PEG(40kDa) IFN -2a as early as week 12.
"Delayed Responders" Revisited: A Low Viral
Load at Week 12 Predicts Sustained Responders to IFN -2b/Ribavirin Therapy
(AASLD abstract 821)
Leland J. Yee, University of
Alabama Liver Center, Birmingham, AL, et al.
This study examined whether viral load
after 12 weeks of treatment with IFN -2b plus ribavirin combination therapy
is predictive of sustained virological response among patients who had a
delayed response (ie, decreased but detectable HCV RNA levels at week 12).
HCV RNA was measured at weeks 12 and 24 during therapy, and at 24 weeks
after the end of therapy among 47 patients with a delayed response. All were
treated for 48 weeks if they had undetectable HCV RNA at week 24. "RNA
levels at week 12 are useful in guiding treatment decisions among patients
receiving IFN -2b plus ribavirin." Among 34 patients who had a week 12 viral
load of <10,000 copies/mL, 14 (41%) achieved a sustained virological
response. In contrast, none of the 13 patients with a 12-week viral load
>10,000 copies/mL achieved a sustained virological response. The authors
concluded that HCV RNA levels at week 12 are useful in guiding treatment
decisions among patients receiving IFN -2b plus ribavirin. In particular,
week 12 viral levels should be useful in deciding if treatment that is
prescribed solely for elimination of HCV RNA should be continued.
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Viral Load per Liver Cell Before
Treatment as a New Marker
CHRONIC HEPATITIS C - THE VIRAL LOAD PER LIVER CELL BEFORE TREATMENT AS A
NEW MARKER TO PREDICT LONG-TERM RESPONSE TO IFN-ALPHA THERAPY
So far, there are no
reliable parameters that can predict the long-term sustained response to
treatment with interferon-alpha in patients with chronic hepatitis C, In
this study, we have developed a semi-quantitative method to determine the
viral load per liver cell and have correlated this factor with the outcome
of hepatitis C patients treated with interferon-alpha. Methods: Hepatitis C
virus RNA levels were measured in serum, peripheral blood mononuclear cells
and liver cells of randomly chosen hepatitis C patients before treatment
with interferon-cr (n=37), The number of cells present in the liver biopsies
was determined by a polymerase chain reaction-based quantitation of the
housekeeping gene beta-globin, The patients were divided into a responder
(''R'', n=15, 41%) and a non-responder (''NR'', n=22, 59%) group, as defined
by normal liver enzymes and negative hepatitis C virus-polymerase chain
reaction 6 months after treatment. Results: Long-term sustained responders
had a significantly lower viral load per liver cell (median: 5 vs, 650
copies/1000 liver cells, p-value: 0.0001), lower age (median: 32 vs, 54
years, p- value: 0.006) and lower percentage of geno- or serotype 1 (46% vs.
91%), Regarding viral load in serum and peripheral blood mononuclear cells,
alanine aminotransferase levels, gamma-globulin levels and histological
changes, no statistically significant differences were observed.
Conclusions: In chronic hepatitis C infection, a high viral load per liver
cell represents a new marker to predict long-term response to therapy with
IFN-alpha. AUTHOR: G GERKEN, UNIV MAINZ, DEPT MED 1, LANGENBECKSTR 1 D-55101
MAINZ,
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Increase in HCV Viral Load After
Interferon Treatment SERIAL QUANTITATION OF SERUM CORE PROTEIN
AND VIRAL RNA OF HEPATITIS C VIRUS AFTER INTERFERON THERAPY - INCREASE IN
VIRAL LOADS IN BIOCHEMICAL RESPONDERS Objectives:
Interferon (IFN) therapy is
often ineffective in eradicating hepatitis C virus (HCV). Some patients show
normal serum ALT levels for a long time after IFN therapy despite the
presence of HCV. These patients are considered not virological responders
but biochemical responders. We investigated the changes in the amount of HCV
after IFN therapy in biochemical responders. Methods: Nine biochemical
responders and 11 nonresponders were studied. Serum HCV amount was measured
by fluorescence enzyme immunoassay for HCV core (pg/ml) and Amplicor HCV
Monitor test for HCV RNA (logarithms of copy numbers per milliliter).
Results: In biochemical responders, core protein and HCV RNA were increased
significantly at 1 month after IFN therapy (291 +/- 191 pg/ml and 5.4 +/-
0.9, respectively; p |
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Reviewed Oct 10 2005
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