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Treating With Pegylated Interferon
If you are on treatment with Pegylated Interferon plus Ribavirin and have have not reached UD at 12 wks you may be wondering what's next?
Do you continue on to 24 wks and see if you clear the virus then. What if you are UD at 24wks and geno 1 / do you stay on treatment longer ?
Below we have complied some information that you may find beneficial.
Treatment Duration Based on Initial Response
Quick Response to Combination Therapy Signals Hope for HCV Patients
IDEAL Study Shows that Greater Hemoglobin Decline during Treatment with Pegylated Interferon plus Ribavirin Is Associated with Better Response
A response to combination therapy (interferon plus ribavirin) is defined as at least a 100-fold drop in viral load by week 12 of treatment
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Q: My husband is in the 9th month of combo treatment. His starting viral load was 6 million. By the 8th month, it was down to 80 thousand. His viral load is now up to 250,000. Is there any point in completing the last 3 months of this treatment? A: A response to combination therapy (interferon plus ribavirin) is defined as at least a 100-fold drop in viral load by week 12 of treatment. In your husband's case the would mean his viral load would have to drop from 6,000,000 down to 60,000. It sounds as if his viral load never dropped to that level. If the viral load has bounced back up, especially considering your husband has already completed 9 months of treatment, it is highly unlikely he will have a sustained clearance of the hepatitis C virus. I encourage you to talk with your husband's doctor; together you may decided that since therapy will not lead to viral clearance, it's time to stop.
Q: I've been taking pegylated interferon and ribavirin for 6 months. My viral count went from 1.5 million to 7,000 and my doctor told me that I'm a nonresponder. She advised me to stop the treatment. Is this right? A: Doctor use the drop in viral load at 12 weeks (3 months into therapy) to predict whether a person is likely to clear the hepatitis C virus on interferon-based treatment. You don't say by how much your viral load dropped within that first 12 weeks, so I can't directly respond to your question. Doctors look for at least a 100-fold drop at that 12 week time point. (In your case, that would be a drop from 1.5 million to 15,000.) If you're uncertain about why your doctor is recommending that you stop treatment at this point, ask her. She will explain her thinking and the reasons why she is making the recommendation to stop treatment. |
Not Reaching UD at 12wks should you continue on treatment or UD at 24 wks Geno 1 do you treat longer?
Below we have compiled some information from Donna
and Clinical Studies to answer those questions.
Donna J. C. Fanelli, MSN, NP-C, Medical Director of Primary Health and Wellness Center, LLC, in Milburn, NJ and Senior Clinical Research Coordinator of Gastroenterology Research Associates, LLC, in Cedar Knolls, NJ. She is certified as an Acute Care Nurse Practitioner, an Adult Nurse Practitioner.
Donna - My question is this. I had a 4 week PCR run. My viral load had gone from 1,050,000 to 139,000. My dr said I was a "slow responder" and that the 4 week viral load was the new standard. I had hoped that I had misunderstood - but since then I've done major reading. One study jumped out at me (most agreed with the 4 week being the new standard :o( ) that said for geno type 1's, at 4 weeks, if your viral load is over 100,000, you have less than a 3% chance of getting SVR. Do you have any more information on this? I'm going to stick it out for the 12 week viral load (so many encouraging words from this website), but if my chances really are less than 3%....I am contemplating waiting for the new meds or at least a clinical trial. Thanks! Dottie
Hi Dottie
The buzz word for the past 18 months or so has been RVR, Rapid Viral Response, meaning the viral count is undetectable at Week 4. I have routinely checked a PCR at Week 4 for awhile and now it's pretty much the standard. Each clinician uses the information differently. Some studies suggest treatment duration can be reduced, others predict an increased SVR. The bottom line, a 4 Week PCR is a guide. Yes it would be nice if you cleared at this point, but there is no data to suggest you won't achieve SVR. The study you're referring to looked at persons with more severe disease and I believe the treatment regimen was sub-optimal.
The 12 Week PCR provides a clearer picture, because there is more literature looking at the prognostic implications. I applaud you for sticking it out until then. If you are 'almost undetectable' at week 12, continue for another 6 weeks. Sometimes tweaking the regimen can yield better results. Assuming you clear at Week 18, you should stay on treatment for a minimum of an additional 36 weeks, preferably 42 weeks more. Again, this is in light of minimal side effects and the ability to remain on the maximum dose with minimal risk. It is imperative that you don't miss a dose of ribavirin, and don't delay taking your shot…even a couple of hours can make a big difference with weekly Peg- Intron or daily Infergen. Drink plenty of water, exercise and eat a diet high in complex carbohydrates and low in fat. Take Omega-3 fish oil capsules and you will do fine. Good luck to you.
Keep in touch and God Bless,
Donna Fanelli
Dear Donna,
My starting viral load was 1,050,000
4 weeks - 139,000
11 weeks - 9,000
24 weeks - UD
I'm definitely a slow responder - I would have to complete 72 weeks to have a chance for SVR and I'm very curious what the numbers are for the success rate of a 72 week tx when I didn't get UD until week 24 (I do believe I was UD a lot earlier than that - but for whatever reason couldn't get a viral load taken earlier than 24 weeks).
Would it be worth it to wait for the additional drugs for tx? My biopsy showed no fibrosis. Any thoughts you could give me on this would be very appreciated. I just completed shot 27 yesterday. Thanks for all that you do for this website! Dottie
Hi Dottie,
There is data to support a better chance of SVR with 72 weeks of treatment when undetectable at 24 weeks. The percentages vary depending the interferon used. Additionally, SVR at 72 weeks is dependant on the ability to maintain a full dose of ribavirin and PEG-IFN throughout treatment.
Needless to say, 72 weeks of these drugs will result in side effects and some long lasting. If your biopsy shows no fibrosis I’m not sure it’s worth the risk, because there are no guarantees. Without knowing anything about your history, it’s difficult for me to make a judgment.
I will share my decision making if you were my patient, at this point. I know it’s an accomplishment to achieve UD and if you were tolerating treatment without any side effects, continue as long as you feel relatively well. On the other hand, if you’re experiencing any of the following: changes in your blood counts, extreme fatigue, alterations in your mood and/or skin, eyes and a negative feeling of well-being, stop the treatment.
Better treatment options will be available soon and based on your biopsy, you can wait.
Good luck and God Bless you as you face a difficult decision
Stay Well,
Donna Fanelli
May 07 2009
Extended 72-week Treatment with Pegylated Interferon plus Ribavirin Did Not Improve Outcomes among Slow Responder Hepatitis C Patients
About half of chronic hepatitis C patients treated with pegylated interferon plus ribavirin do not achieve a cure, or sustained virological response (SVR). In an attempt to improve outcomes, researchers have explored longer treatment duration for selected patients at risk for suboptimal response. But extending therapy to 72 weeks did not increase the response rate for slow responders, according to a study presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) last month in Copenhagen.
The usual course of pegylated interferon (PegIntron or Pegasys) plus ribavirin is 48 weeks for people with hepatitis C virus (HCV) genotypes 1 or 4 and 24 weeks for those with easier-to-treat genotypes 2 or 3 (though many experts recommend 48 for HIV positive people regardless of genotype).
In the SUCCESS trial (Study to Assess Treatment With PegIntron And Rebetol in Naive Patients with Genotype 1 Chronic Hepatitis C and Slow Virological Response) -- sponsored by PegIntron manufacturer Schering-Plough -- an international research team evaluated the effect of extending treatment duration to 72 weeks for genotype 1 patients defined as slow responders.
More than 1400 participants enrolled in this prospective study were treated with 1.5 mcg/kg/week pegylated interferon alfa-2b (PegIntron) plus 800-1400 mg/day weight-adjusted ribavirin. More than half (61%) were men, the mean age was about 43 years, and more than 95% were white. At baseline, about 80% had HCV RNA > 800,000 IU/mL.
Slow
response was defined as achieving at least a 2 log drop but still
having detectable HCV RNA at week 12 of treatment, but undetectable
HCV RNA at week 24. At week 36, slow responders were randomly
assigned to continue treatment until they reached a total of either
48 weeks (n = 86) or 72 weeks (n = 73). Complete early virological
responders with undetectable HCV RNA at week 12 received treatment
for 48 weeks (n = 816). People with less than a 2 log drop in HCV
RNA at week 12 stopped therapy, since this is a strong predictor of
failure to achieve sustained response.
Results
816 patients (57%) achieved undetectable HCV RNA at week 12 of treatment.
43.0% for slow responders treated for 48 weeks;
"This, the largest prospective study among genotype 1 slow
responders, demonstrated no statistically significant difference
between 48 and 72 weeks of treatment," the investigators concluded.
However, they continued, "in these true slow responders, extending [pegylated
interferon alfa-2b plus weight-adjusted ribavirin] treatment is
associated with better SVR and a similar incidence of adverse
events."
"These results are in line with those observed in other
[weight-adjusted dose] ribavirin trials in slow responders" they
added.
The failure to increase response rates by extending the duration of
interferon-based therapy underscores the need for new therapies that
work by different mechanisms, such as the various directly targeted
"STAT-C" agents -- mostly HCV protease and polymerase inhibitors
-- now in development.
Vall d'Hebron Hospital General, Barcelona, Spain; Sourasky
Medical Center, Tel Aviv, Israel; Municipal Center of Prophylactic
AIDS and Other Infections, St. Petersburg Municipal Center, St.
Petersburg, Russia; Clinical Infection Hospital, Moscow, Russia;
Hospital of Infectious Diseases, Warsaw, Poland; Medizinische Klinik
I, Klinikum der J. W. Goethe Universität Frankfur, Frankfurt,
Germany; Vilnius University Hospital of Tuberculosis and Infection
Diseases, Vilnius, Lithuania; Schering-Plough Corporation,
Kenilworth, NJ.
5/08/09
Reference
M Buti, Y Lurie, NG Zakharova, and others.
Extended treatment duration in chronic hepatitis C genotype
1-infected slow responders: final results of the SUCCESS study.
44th Annual Meeting of the European Association for the Study of the
Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009.
Other Source
Schering-Plough. Schering-Plough Highlights Hepatitis C Clinical
Data Presentations at the European Association for the Study of the
Liver (EASL) Annual Meeting. Press release. April 27, 2009.
http://www.hivandhepatitis.com/2009icr/easl/docs/050809_b.html
Treatment Duration Based on Initial Response
In a study described in the January 2008 issue of Hepatology, Alessandra Mangia and colleagues explored whether a shorter duration of therapy might be sufficient for genotype 1 patients who experience rapid virological response (RVR), or undetectable viral load at Week 4. Nearly 700 participants were treated with standard doses of Pegasys or PegIntron plus 1000-1200 mg/day weight-based ribavirin. One group was randomly assigned to receive treatment for the standard 48-week duration, while the others were treated for 24, 48, or 72 weeks, depending on whether their viral load first became undetectable at Week 4, Week 8, or Week 72, respectively.
Similar proportions first achieved undetectable viral load at Week 4 (27%) and at Week 8 (28%), with a further 11% having cleared HCV at Week 12. Overall, 45% in the standard duration arm and 49% in the variable duration arm achieved SVR. Among patients who first achieved undetectable HCV RNA at Week 4, 87% in the standard duration arm and 77% in the variable duration (24-week) arm achieved SVR. However, the subset of patients in this group who had a high baseline viral load did better with 48-week than 24-week treatment (SVR 87% vs 73%). Among individuals who achieved undetectable HCV RNA at Week 8, SVR rates were similar in the standard and variable duration (48-week) arms (70% vs 72%). But among the slowest responders at Week 12, the SVR rates were 38% in the standard duration arm and 64% in the variable duration (72-week) arm, demonstrating a benefit from longer treatment.
Though less well studied, even earlier HCV clearance may predict ultimate treatment outcomes. In the ongoing GET-C study, looking at extended therapy for genotype 3 patients with a high baseline viral load, ultra-rapid virological response at Week 2 predicted SVR with 93% accuracy.
Response to hepatitis C treatment is described based on the amount of HCV RNA, or viral load, at different points in time:
-
Ultra-rapid virological response (URVR): undetectable HCV RNA at Week 2 of treatment.
-
Rapid virological response (RVR): undetectable HCV RNA at Week 4 of treatment.
-
Early virological response (EVR): traditionally, at least a 2-log drop in HCV RNA at Week 12 of treatment (though some researchers use undetectable viral load).
-
End-of-treatment response (EOT or ETR): undetectable HCV RNA at the completion of treatment (typically Week 24 for genotypes 2 or 3; Week 48 for genotype 1).
-
Sustained virological response (SVR): continued undetectable viral load 24 weeks after the completion of therapy (typically Week 48 for genotypes 2 or 3; Week 72 for genotype 1).
Longer Treatment for Genotype 1
As reported in the December 2007 issue of Hepatology, Brian
Pearlman and colleagues specifically assessed whether longer treatment would
produce a greater likelihood of SVR in previously untreated genotype 1
patients classified as “slow responders,” defined as having at least a 2-log
reduction but still detectable HCV RNA at Week 12, but undetectable viral
load at Week 24.
About 100 study participants were randomly assigned to receive PegIntron plus 800-1400 mg/day weight-based ribavirin for either the standard 48 weeks or an extended 72 weeks. End-of-treatment response rates were similar in the 48-week and 72-week arms, at 45% vs 48%, respectively. However, HCV relapse occurred less often with longer treatment, thus yielding a higher SVR rate (18% vs 38%). Despite longer therapy, the frequency of dose reductions and treatment discontinuation due to side effects were similar in both groups.
Longer treatment may also lead to sustained response in prior relapsers. As reported at the Digestive Disease Week 2007 conference, Jeffrey McMahon and colleagues assessed 72-week treatment with Pegasys plus ribavirin in four patients (three with genotype 1 and one with genotype 2) who relapsed after a previous 48-week course of combination therapy. During re-treatment, all experienced HCV clearance by Week 12 and achieved SVR.
Other HCV Genotypes
Tailored treatment durations may also benefit patients with other HCV
genotypes. Studies have suggested that treatment shorter than the standard
24 weeks can produce sustained response in many genotype 2 and 3 patients,
but the longer regimen appears to be superior overall.
In the July 12, 2007 New England Journal of Medicine, for example, Mitchell Shiffman and colleagues reported results from the ACCELERATE trial, in which 1,469 genotype 2 or 3 patients were randomly assigned to receive Pegasys plus 800 mg ribavirin for either 16 or 24 weeks. The overall SVR rates were 62% in the 16-week group and 70% in the 24-week group, and the relapse rate was significantly higher in the shorter treatment arm (31% vs 18%). However, among participants who achieved RVR at Week 4, the SVR rates were 79% and 85%, respectively. And among those with a low baseline viral load, SVR rates were similar in both treatment arms (82% vs 81%). The researchers concluded that “16 weeks may be adequate for a carefully selected subset of patients.”
Similarly, in the January 2008 issue of Hepatology, Olav Dalgard and colleagues reported that among 428 genotype 2 or 3 patients treated with PegIntron plus 800-1400 mg ribavirin who cleared HCV by Week 4, 81% achieved SVR with a 14-week course of treatment, compared with 91% of those treated for 24 weeks, which did not meet the non-inferiority criteria. “However,” they wrote, “the SVR rate after 14 weeks of treatment is high, and although longer treatment may give slightly better SVR, we believe economical savings and fewer side effects make it rational to treat patients with genotype 2 or 3 and RVR for only 14 weeks.”
Finally, as reported in the December 2007 issue of Hepatology, Sanaa Kamal and colleagues treated 358 Egyptian genotype 4 patients with PegIntron plus weight-based ribavirin for variable durations based on early response. Individuals with RVR at Week 4 were treated for 24 weeks, and 86% achieved SVR. This compared with 76% for patients with undetectable viral load at Week 12 treated for 36 weeks, and 56% for those with continued detectable HCV RNA at Week 12 treated for 48 weeks. In a control group, all participants were treated for 48 weeks regardless of early response, and 58% achieved SVR.
HIV/HCV Coinfection
Researchers have also explored variable treatment durations in HIV/HCV
coinfected individuals. HIV positive patients may clear HCV more slowly,
leading some experts to suggest that they might benefit from longer
treatment.
As reported in several recent conference abstracts and journal articles, the Spanish PRESCO trial included 389 coinfected participants, about half with genotype 1, treated with Pegasys plus 1000-1200 mg/day ribavirin. Those who achieved early virological response at Week 12 were randomly assigned to continue treatment for either 48 or 72 weeks (genotype 1 or 4) or for either 24 or 48 weeks (genotype 2 or 3). Overall, 36% of genotype 1 patients, 72% with genotype 2 or 3, and 33% with genotype 4 achieved SVR. Undetectable HCV RNA at Week 4 was the best predictor of sustained response. Extended treatment duration did not appear to reduce the risk of relapse.
Treat Long Enough – But Not Too Long
HCV viral load at Week 4 is “emerging as an important milestone” in the
management of chronic hepatitis C, according to Fred Poordad and colleagues.
Based on a recent review of past research, they concluded that shortening
treatment to 12-16 weeks is effective for genotype 2 or 3 patients who
attain RVR; for genotype 1 patients, RVR may be used as an indicator for
both shortened and extended treatment. RVR “represents a key opportunity to
individualize therapy according to treatment-related viral kinetics,” they
wrote in the January 1, 2008 issue of Clinical Infectious Diseases.
But clinicians should not be too quick to alter the duration of hepatitis C treatment. Even among patients who achieve RVR at Week 4, some may experience relapse with a shortened course of therapy. Conversely, in the October 2007 Journal of Hepatology, Patrick Marcellin, Jenny Heathcote, and Antonio Craxi advised against “indiscriminate extension of treatment,” since this can lead to prolonged side effects and higher cost for some patients who still will not achieve a cure. It remains a challenge, they wrote, to distinguishing at an early stage between “slow responders” and “null responders.”
In the future, the best hope for shortening hepatitis C treatment may come from targeted antiviral agents. For example, interim data from the PROVE 1 trial, looking at the HCV protease inhibitor telaprevir plus Pegasys with or without 1000-1200 mg/day ribavirin, showed that 61% of genotype 1 patients receiving the triple combination achieved SVR after 24 weeks of therapy—higher than the sustained response rate with pegylated interferon/ribavirin for 48 weeks in most studies.
References
-
Dalgard, O. et al. Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response. Hepatology 47(1): 35-42. January 008.
-
Kamal, S.M. et al. Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: The role of rapid and early virologic response. Hepatology 46(6):1732-40. December 2007.
-
Jacobson, I.M. et al. Interim analysis results from a Phase 2 study of telaprevir with peginterferon alfa-2A and ribavirin in treatment-naive subjects with hepatitis C. 58th AASLD. Boston. November 2-6, 2007. Abstract 177.
-
Mangia, A. et al. Individualized treatment duration for hepatitis C genotype 1 patients: A randomized controlled trial. Hepatology 47(1): 43-50. January 2008.
-
Marcellin, P. et al. Which patients with genotype 1 chronic hepatitis C can benefit from prolonged treatment with the ‘accordion’ regimen? Journal of Hepatology 47(4): 580-587. October 2007.
-
Martin-Carbonero, L. et al. Undetectable hepatitis C virus RNA at week 4 as predictor of sustained virological response in HIV patients with chronic hepatitis C. AIDS 22(1): 15-21, January 2, 2008.
-
McMahon, J. et al. Efficacy of a 72-week course of treatment for previous relapsers to PEG/ribavirin therapy. Digestive Disease Week 2007. Washington, DC. May 19-24, 2007. Abstract S1232.
-
Pearlman, B.L. et al. Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis C genotype 1-infected slow responders. Hepatology 46(6): 1688-1694. December 2007.
-
Pianko, S. et al. Ultra rapid virologic response predicts sustained virologic response in HCV infected patients with genotype 3 and high viral load: the Get-C Study. 58th AASLD. Boston. November 2-6, 2007. Abstract 349.
-
Poordad, F. et al. Rapid virologic response: a new milestone in the management of chronic hepatitis C. Clinical Infectious Diseases 46(1): 78-84. January 1, 2008.
-
Shiffman, M.L. et al Peginterferon Alfa-2a and Ribavirin for 16 or 24 Weeks in HCV Genotype 2 or 3. New England Journal of Medicine 357(2): 124-134. July 12, 2007.
http://www.hcvadvocate.org/news/newsLetter/2008/advocate0208.html
Differentiation of early virologic response (EVR) into RVR, complete EVR (cEVR) and partial EVR (pEVR) allows for a more precise prediction of SVR in HCV genotype 1 patients treated with peginterferon alfa-2a (40KD) (PEGASYS) and ribavirin (COPEGUS)
Reported by Jules Levin
AASLD, Nov 2-6, 2007, Boston, MA
P. Marcellin,1 D.M. Jensen,2 S.J. Hadziyannis,3 P. Ferenci4
1Universite Paris 7, Clichy, France; 2University of Chicago,
Chicago, IL, USA; 3Henry Dunant Hospital, Athens, Greece;
4Department of Internal Medicine IV, Medical University of
Vienna, Vienna, Austria
This research was funded by Roche, Basel, Switzerland.
CONCLUSIONS
This analysis demonstrates that the label
"difficult-to-cure" is a broad generalization that does not
apply to the majority of patients with HCV genotype 1
infection.
Indeed, more than half of genotype 1 patients clear HCV RNA
from serum by week 12 of treatment with peginterferon
alfa-2a (40KD) plus ribavirin and have an excellent chance
of achieving an SVR.
The on-treatment virologic response may be used to customize
the treatment duration as follows (Figure 3).
--Select patients achieving an RVR have high rates of SVR
and may benefit from an abbreviated 24-week treatment
regimen (among patients with low baseline HCV RNA levels who
achieve an RVR, the SVR rate is 93%[7]).[1]
--Patients with a complete EVR also have high rates of SVR,
but should be encouraged to remain on therapy for the
standard duration of therapy for HCV genotype 1 (48 weeks).
--Patients with a partial EVR have lower rates of SVR with
the standard 48-week regimen and may benefit from an
intensified 72-week treatment regimen.[8]
--Non-EVR patients have a low chance of achieving an SVR and
consideration should be given to changing the treatment
strategy.
Response-guided therapy has the potential to optimize
treatment outcomes in patients with HCV genotype 1
infection.
INTRODUCTION
In patients with chronic hepatitis C, the on-treatment
response at weeks 4 and 12 of pegylated interferon plus
ribavirin combination therapy may be used to predict the
probability of a sustained virologic response (SVR).
Patients achieving a rapid virologic response (RVR; HCV RNA
<50 IU/mL at week 4) have a high rate of SVR, irrespective
of HCV genotype.[1,2]
The standard definition of an early virologic response (EVR)
is undetectable HCV RNA (<50 IU/mL) by qualitative PCR or a
≥2 log drop in HCV RNA at week 12 by quantitative PCR.[3]
However, the positive predictive value of an EVR is not high
enough to be a useful clinical predictor of SVR.[4]
It may be possible to improve the prediction of SVR by
subdividing patients with an EVR (and no RVR) into those
with undetectable HCV RNA (referred to as a complete EVR),
those with a ≥2 log drop in HCV RNA but not cEVR (referred
to as a partial EVR) and those with <2 log drop in HCV RNA
at week 12 (non-EVR). This strategy may allow for tailoring
of the treatment duration to the individual response during
treatment.
OBJECTIVE
We performed a retrospective analysis of data from two
large, multinational phase III studies of patients treated
with peginterferon alfa-2a (40KD) plus ribavirin to
determine the probability of SVR in patients with an RVR,
complete EVR, partial EVR and non-EVR.[5,6]
METHODS
Patients
Treatment-naive adults eligible for these trials had chronic
hepatitis C, quantifiable HCV RNA, elevated alanine
aminotransferase levels in serum and compensated liver
disease.
Only patients infected with HCV genotype 1 were included in
this analysis.
Treatment
Patients included in this analysis were randomly assigned to
48 weeks of treatment with peginterferon alfa-2a (40KD) 180
_g/week plus a standard dose of ribavirin (1000 mg/day for
patients with a body weight ≦75 kg; 1200 mg/day for patients
with a body weight >75 kg).
Outcomes
Virologic response at weeks 4 and 12 was divided into four
mutually exclusive categories (Table 1).
RESULTS
A total of 569 patients with HCV genotype 1 infection were
included in the present analysis (intention-to-treat
population).
The proportion of patients with an RVR (16%), complete EVR
(42%), partial EVR (22%) and non-EVR (20%) are illustrated
in Figure 1.
Figure 1. Virologic responses at weeks 4 and 12 in
patients treated for 48 weeks with peginterferon alfa-2a 180
_g/week plus ribavirin 1000/1200 mg/day in two large
randomized international phase III studies.[5,6]
The rate of SVR was highest in patients with an RVR (87%)
and decreased progressively in patients with less rapid and complete virologic response: 68% among those with a complete EVR, 27% among those with a partial EVR and 5% among those without an EVR at week 12 (Figure 2).
REFERENCES
1. Jensen DM, Morgan TR, Marcellin P, et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006; 43(5): 954-960.
2. Shiffman ML, Suter F, Bacon BR, et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007; 357(2): 124-134.
3. Dienstag JL, McHutchison JG. American Gastroenterological Association medical position statement on the management of hepatitis C. Gastroenterology 2006; 130(1): 225-230.
4. Ferenci P, Fried MW, Shiffman ML, et al. Predicting sustained virologic responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin. J Hepatol 2005; 43(3): 425-433.
5. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347(13): 975-982.
6. Hadziyannis SJ, Sette H, Jr., Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140(5): 346-355.
7. Pegasys. Summary of Product Characteristics. Revised June 2007.
8. Sanchez-Tapias JM, Diago M, Escartin P, et al. Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology 2006; 131(2): 451-460.
http://www.natap.org/2007/AASLD/AASLD_56.htm
Assessment of HCV RNA at Week 4 and Week 12 Optimizes Prediction of Treatment Outcomes in HCV Patients Treated with Pegylated Interferon Alfa-2b (PegIntron) plus Ribavirin
HCV RNA level (viral load) prior to treatment is an important predictor of treatment outcomes in patients with chronic hepatitis C. Previously, Stefan Zeuzem and colleagues (AASLD 2006) proposed 400,000 IU/ml (assessed with the COBAS TaQMan HCV assay) as the optimal cut-off to best discriminate low and high viral load, based on the probability of achieving sustained virological response (SVR) in patients treated with pegylated interferon alfa-2b (PegIntron) plus ribavirin. In the current study, presented at the 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston, MA (November 2-6, 2007), researchers aimed to analyze the positive predictive value (PPV) of this cut-off value at baseline, the PPV of rapid virological response (RVR) at week 4, and the negative predictive value (NPV) of failure to achieve early virological response (EVR) at week 12 (non-EVR12), in patients treated with PegIntron plus ribavirin.A total of 408 consecutive patients (221 treatment-naive; 187 non-naive) received treatment with 1.5 mcg/kg/week pegylated interferon alfa-2b plus 800-1200 mg/day ribavirin according to weight. Patients with HCV genotypes 1, 4, or 5 and prior non-responders were treated for 48 weeks; treatment-naive patients with genotypes 2 or 3 were treated 24 weeks.
Serum HCV RNA was measured at baseline, week 4, week 12, end of treatment, and 6 months after the end of treatment using the quantitative Versant HCV 3.0 Assay (bDNA) (Siemens Medical Solution Diagnostics). Samples below the limit of quantification were tested with the Versant HCV RNA Qualitative Assay (TMA) (Siemens Medical Solution Diagnostic). SVR was defined as undetectable serum HCV RNA by TMA at end of 6 months post-treatment follow-up.
•
At treatment initiation PPV was defined with a cut-off set up at < 400,103 IU/mL.• At week 4, the PPV was defined as TMA undetectable or >2 log drop from baseline viral load.
• At week 12, the NPV was defined as TMA detectable or < 2 log drop from baseline viral load
•
The overall SVR rate was 46% (53% in treatment-naive patients and 38% in non-naive patients).|
PPV |
PPV |
PPV |
NPV |
NPV |
|
|
Baseline |
Week |
Week |
Week
|
Week |
|
|
Viral load |
<40,000 IU/ml |
TMA negative |
> 2 log drop |
TMA positive |
< 2 log drop |
|
All patients |
62% |
97% |
70% |
87% |
98% |
|
Naive |
63% |
96% |
78% |
83% |
100% |
|
Non-responder |
27% |
100% |
50% |
90% |
96% |
|
Relapser |
76% |
100% |
70% |
76% |
100% |
Conclusion
Based on these findings, the investigators concluded, "Undetectable HCV RNA at week 4 (RVR) when assessed with a sensitive assay (TMA) is more accurate (96%-100%) than baseline cut-off (<400,103 IU/mL) to predict SVR both in naive and in experienced patients."
The also noted, "The absence of EVR at week 12 (less than 2 log reduction of HCV RNA) is a strong predictor (96%-100%) of non response to therapy independently of the patient's pretreatment status."
Université paris VII, Hopital Beaujon, Clichy, France; 2Service d'Hépatologie, Hopital Beaujon, Clichy, France.
11/20/07
Reference
M Martinot-Peignoux, S Maylin, M P Ripault, and others.
Assessment of both Virological Response at Week 4 and at
Week 12 Optimizes Prediction of Treatment Outcome in
Patients with Chronic Hepatitis C Treated with Peginterferon
Alfa-2bg plus Ribavirin. 58th Annual Meeting of the American
Association for the Study of Liver Diseases. Boston, MA.
November 2-6, 2007. Abstract 304.
http://www.hivandhepatitis.com/2007icr/aasld/docs/112007_b.html
Use of Different Pegylated Interferon/Ribavirin Regimens after Rapid Virological Response Does Not Affect Sustained Response Rate
By Liz Highleyman
Several recent studies
have shown that rapid virological response (RVR) to
hepatitis C treatment with
pegylated interferon
plus ribavirin
- or undetectable HCV RNA after 4 weeks of therapy - is
a good predictor of sustained virological response (SVR)
6 months after completion of treatment.
In a study described in the current issue of the
Journal of Viral Hepatitis (April 2008), Italian
researchers investigated whether different dosages of
pegylated interferon plus ribavirin would influence the
likelihood of achieving SVR in patients who had already
achieved RVR.
The study included 45 previously untreated chronic
hepatitis C patients. All started treatment with
1.5 mcg/kg/week
pegylated interferon alfa-2b (PegIntron) plus 800-1200
mg/day weight-based ribavirin.
At week 4 of therapy, 31 patients (68.9%) attained RVR.
In addition, 4 individuals achieved early virological
responders (EVR), or undetectable HCV RNA at week 12.
The 31 rapid responders were then randomly assigned to
continue on either 1.5 mcg/kg/week (n=17) or 1.0
mcg/kg/week (n=14) PegIntron plus the same dose of
ribavirin for the remaining 44 weeks. The 2 groups were
well matched for age, sex, baseline alanine
aminotransferase (ALT) levels, HCV viral load, and
fibrosis scores.
Results•
After 6 months of post-treatment follow-up, 16 of 17 RVR
patients (94.1%) in the PegIntron 1.5 mcg/kg/week arm
had achieved SVR, compared with 13 of 14 (92.8%) in the
1.0 mcg/kg/week (a non-significant difference).
•
High
baseline HCV RNA (P = 0.01) and pre-existing bridging
fibrosis
or
cirrhosis
(P = 0.02) were associated with a lower likelihood of
achieving RVR.
• However, the ability of rapid responders to achieve
SVR did not correlate with these baseline
characteristics in either PegIntron dose group.
• The SVR rate among EVR patients who responded after
more than 4 but up to 12 weeks of treatment was
significantly lower than that observed for RVR patients
(25.0% vs 93.5%; P = 0.0058)
Conclusion
Based on these findings, the researchers concluded that
varying the dose of pegylated interferon did not affect
the likelihood of achieving sustained virological
response.
They attributed the difference in sustained response
rates to a higher prevalence of post-treatment relapse
among patients with early (12 week) but not rapid (4
week) virological response.
3/18/08
Reference
N Napoli, G Giannelli, A Antonaci, and others. The
use of different Peg-interferon alpha-2b regimens plus
ribavirin in HCV-1b-infected patients after rapid
virological response does not affect the achievement of
sustained virological response. Journal of Viral
Hepatitis 15(4): 300-304. April 2008.
April 19, 2007
Quick Response to Combination Therapy Signals Hope for HCV Patients
An analysis of several recent clinical trials shows how important early responses to treatment are for clearing the Hepatitis C virus. Now doctors can tell earlier than ever, the chances patients can be cured. Find out just how soon doctors can now determine the success of treatment and what this means for newly diagnosed patients.
Treatment Optimisation With PEGASYS Plus COPEGUS Offers Patients With Hepatitis C an Excellent Chance for a Cure
www.presseportal.de
High Response Rates Confirmed in 'Real-Life'
Study and Clinical
Trials
BASEL, Switzerland, April 13 /PRNewswire/
Patients with hepatitis C who respond quickly to
treatment have an
excellent chance of being cured of the disease,
according to data
presented today at the 42nd Annual Meeting of the
European
Association for the Study of the Liver (EASL).
Patients with genotype
1 hepatitis C (HCV) who clear the virus within a
month of starting
treatment with PEGASYS (peginterferon alfa-2a
(40KD)) plus COPEGUS
(ribavirin) have up to a 91% chance of achieving a
sustained
virological response (SVR), considered a cure by
researchers.
"Now we can tell earlier than ever - at just week
4 of treatment -
whether a patient has a good chance to be cured."
said Professor
Patrick Marcellin, Hôpital Beaujon, Clichy, France.
"Knowing their
virus levels in the first and third months of
treatment helps
patients take ownership of beating the disease and
helps motivate
them to stay on treatment. This information should
be made available
for everyone starting therapy."
Early Response to Treatment Means Patients Have
an Excellent
Chance for a Cure
An analysis of six different clinical trials
highlights the value
of checking how well patients with genotype 1 HCV
have responded to
treatment at weeks 4 and 12 of therapy(1). The
results of the
analysis showed that of those patients treated with
PEGASYS 180 mcg
weekly plus COPEGUS 1,000-1,200 mg daily:
- Up to one in five cleared the virus by week 4
of therapy
(called rapid viral response)
- 83-91% of patients with a rapid viral response
went on to be
cured of their hepatitis C
- About 40% of patients who did not achieve a
rapid viral response
managed to clear the virus by week 12 of therapy
(called complete
early virological response); 65-67% of these
patients were cured
Excellent Chance for a Cure for Rapid Viral
Responders Confirmed
in 'Real-Life' Study
A large real-life study involving 4,377 patients
conducted by the
Association of German Independent
Gastroenterologists confirms that
these results can be replicated in clinical
practice(2):
- One quarter of patients with
'difficult-to-cure' genotype 1
or 4 HCV who had their viral levels tested at week 4
of treatment
achieved a rapid viral response
- While the study is not yet complete, over 70%
of those who have
finished their 6-month post-treatment follow-up
period were cured
"These are really important results," said Dr
Elmar Zehnter,
Gastroenterologist and Hepatologist, Dortmund,
Germany, and
researcher in the study. "This study confirms that
the high cure
rates reported for rapid viral responders in
clinical trials
translate into clinical practice and are relevant to
the patients we
see every day. At the moment, testing viral levels
at 4 weeks of
treatment is not standard practice. Based on these
results, however,
testing viral levels at 4 weeks of therapy should
become a routine
test."
About Hepatitis C
Hepatitis C, the most common chronic blood-borne
infection, is
transmitted primarily through blood or blood
products. Hepatitis C
chronically infects 180 million people worldwide,
which makes it more
than four times more prevalent than HIV(3,4).
Alarmingly, many people
infected with hepatitis C don't even know they carry
the virus. For
example, it is estimated that 80-90% of people with
hepatitis C in
the UK are unaware that they are infected(5).
Hepatitis C is a
leading cause of cirrhosis, liver cancer and liver
failure, despite
the fact that many patients can be cured with
treatments that are
available today.
About PEGASYS
PEGASYS, the market leader worldwide in hepatitis
C therapy,
provides significant benefit over conventional
interferon therapy in
HCV patients of all genotypes. The benefits of
PEGASYS are derived
from its large 40 kilodalton (KD) branched-chain
polyethylene glycol
(PEG) construction, which allows for sustained drug
levels over the
course of a full week. PEGASYS also distributes more
readily to the
liver (the primary site of infection) than
conventional interferon.
PEGASYS is the only pegylated interferon available
as a
ready-to-administer solution. Each weekly
subcutaneous injection
contains 180 mcg of pegylated interferon alfa-2a
(40KD), which is the
approved dose for all patients, regardless of body
weight.
About Roche
Headquartered in Basel, Switzerland, Roche is one
of the world's
leading research-focused healthcare groups in the
fields of
pharmaceuticals and diagnostics. As the world's
biggest biotech
company and an innovator of products and services
for the early
detection, prevention, diagnosis and treatment of
diseases, the Group
contributes on a broad range of fronts to improving
people's health
and quality of life. Roche is the world leader in
in-vitro
diagnostics and drugs for cancer and
transplantation, a market leader
in virology and active in other major therapeutic
areas such as
autoimmune diseases, inflammation, metabolism and
central nervous
system. In 2006 sales by the Pharmaceuticals
Division totalled 33.3
billion Swiss francs, and the Diagnostics Division
posted sales of
8.7 billion Swiss francs. Roche employs roughly
75,000 worldwide and
has R&D agreements and strategic alliances with
numerous partners,
including majority ownership interests in Genentech
and Chugai.
Additional information about the Roche Group is
available on the
Internet at www.roche.com.
All trademarks used or mentioned in this release
are protected by
law.
Film footage is available for broadcast
journalists from The
NewsMarket at www.thenewsmarket.com. Video is
compressed in MPEG2 and
is available for download to your FTP server.
References
1. Marcellin P, Hadziyannis S, Berg T, et al.
Virological response
at 4 and 12 weeks predict high rates of sustained
virological
response in genotype 1 patients treated with
peginterferon alfa-2a
(40KD) plus ribavirin. In: 42nd Annual Meeting of
the European
Association for the Study of the Liver; 2007 April
11-15; Barcelona,
Spain; 2007.
2. Zehnter E, Mauss S, Boeker K, et al. Potential
relevance of
rapid viral response for SVR and optimisation of the
treatment of
hepatitis C (CHC) with peginterferon alfa-2a (PEG)
and ribavirin
(RBV). In: 42nd Annual Meeting of the European
Association for the
Study of the Liver; 2007 April 11-15; Barcelona,
Spain; 2007.
3. AIDS Epidemic Update. 2006. (Accessed February
27, 2007, at
http://www.who.int/hiv/mediacentre/2006_EpiUpdate_en.pdf.)
4. Initiative for Vaccine Research, Viral
Cancers, Hepatitis C.
World Health Organization, 2006. (Accessed July 24,
2006, at http://w
ww.who.int/vaccine_research/diseases/viral_cancers/en/index2.html.)
5. The hepatitis C scandal. London: All-Party
Parliamentary Group
on Hepatology; 2004.
ots Originaltext: Roche Pharmaceuticals
Im Internet recherchierbar: http://www.presseportal.de
Contact:
Contact: Janet Kettels, Roche, +1-862-596-9084;
Natalie Henson, Axon
Communications, +44(0)20-843-99-406
Posted by Editors at April 19, 2007 09:25 AM
http://www.hepatitis-central.com/mt/archives/2007/04/quick_response.html
Adherence to HCV therapy is one of the most
important predictors of successful HCV treatment. While there are well defined and established guidelines for other disease states such as HIV, hypertension and other diseases, it is less clear when it comes to adherence for HCV therapy. There is an established threshold of 80% for HIV, which means that if a patient does not take 80% of their medications, 80% of the time, the chance of a successful treatment outcome is greatly diminished. There have been retrospective (analyzing data from previous trials) studies on hepatitis C treatment adherence that have been able to establish the 80/80/80 rule. This means that someone taking hepatitis C medications is less likely to have a successful treatment outcome if they do not take 80% of interferon and 80% of ribavirin for 80% of the time. However, the 80/80/80 rule is controversial because it has not been studied in well designed prospective clinical trials. Another concern is that the 80/80/80 rule may be sending the wrong message about treatment adherence since it sets a lower threshold for taking medications rather than encouraging people to take 100% of the medications, 100% of the time or as close to 100% as possible – especially during the first twelve weeks of therapy.Currently, pegylated interferon and ribavirin do not become HCV resistant so the question of adherence is only important right now with respect to treatment outcomes. However, questions of adherence will become even more important in the future with the development of anti-viral therapies such as HCV protease and helicase inhibitors that will have the potential to mutate and become HCV resistant. We do know that it is important to take as much of the prescribed medications as possible, but this can be difficult considering the moderate to severe physical and psychological side effects of HCV therapy. There are a number of predictors of treatment response to HCV therapy that are well-recognized as important and this fact sheet will discuss the importance of adherence and well known strategies for helping people achieve a successful treatment outcome. It is also important to remember that not everyone will have a successful treatment outcome even with 100% adherence to HCV therapy.Continue reading.......... .http://www.hcvadvocate.org/hepatitis/factsheets_pdf/Adherence.pdf
IDEAL Study Shows that Greater Hemoglobin Decline during Treatment with Pegylated Interferon plus Ribavirin Is Associated with Better Response
By Liz
Highleyman
http://www.hivandhepatitis.com/2009icr/easl/docs/052209_a.html
Chronic hepatitis C patients who experience larger decreases in hemoglobin during treatment with pegylated interferon plus ribavirin are more likely to achieve sustained virological response (SVR), according to study findings presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) last month in Copenhagen.
Ribavirin may cause hemolytic anemia, a condition in which red blood cells are destroyed and levels of hemoglobin -- the protein that carries oxygen -- are reduced. This side effect leads to ribavirin dose reduction in approximately 30% of hepatitis C patients, and decreasing the ribavirin dose raises the risk of HCV relapse after completion of treatment. Erythropoietin (EPO), a hormone that stimulates red blood cell production, may be used to help patients stay on therapy.
In the IDEAL Study (sponsored by Schering-Plough), 3070 HCV genotype 1 patients were randomly assigned to receive 1.0 or 1.5 mcg/kg/week pegylated interferon alfa-2b (Schering-Plough's PegIntron) plus 800-1400 mg/day weight-adjusted ribavirin, or else 180 mcg/week pegylated interferon afa-2a (Roche's Pegasys) plus 1000-1200mg/day weight-adjusted ribavirin, all for 48 weeks.
As previously reported, patients who received Pegasys had a higher end-of-treatment (EOT) response rate, but those taking PegIntron had a lower relapse rate, so SVR rates ended up about the same.
In the analysis presented at this year's EASL meeting, investigators looked at the relationship between anemia and sustained response. Anemia was defined as a hemoglobin level < 10 g/dL; 3023 patients had hemoglobin measurements at baseline and at least once during therapy. EPO use was permitted for anemic patients after protocol-defined ribavirin reductions.
Results
Based on these findings, the investigators concluded, "Among HCV genotype 1-infected patients treated with [pegylated interferon/ribavirin], the magnitude of hemoglobin decline is strongly associated with the likelihood of SVR."
"The effect of EPO varied by time to anemia; no benefit was observed for patients who became anemic after treatment week 8," they continued. "These data suggest that hemoglobin decline may be a pharmacodynamic marker of treatment effectiveness and that the primary effect of EPO was to prevent treatment discontinuation in patients with early anemia."
Johns Hopkins University School of Medicine, Baltimore, MD; Virginia Commonwealth University Medical Centeru, Richmond, VA; Beth Israel Deaconess Liver Center, Boston, MA; University of Pennsylvania Health System, Philadelphia, PA; McCone Endoscopy Center, Alexandria, VA; Clinical Center for Liver Diseases, Dallas, TX; Thomas Jefferson University, Philadelphia, PA; Brooke Army Medical Center, Fort Sam Houston, TX; Schering-Plough Research Institute, Kenilworth, NJ; Duke Clinical Research Institute, Durham, NC.
5/22/09
Reference
M Sulkowski, M Shiffman, N Afdhal, and others.
Hemoglobin Decline Is Associated With SVR among HCV Genotype
1-Infected Persons Treated with Peginterferon (Peg)/Ribavirin (RBV):
Analysis from the IDEAL Study. 44th Annual Meeting of the
European Association for the Study of the Liver (EASL 2009).
Copenhagen, Denmark. April 22-26, 2009