Treating Patients with Decompensated
Cirrhosis: 20% sustained response rate
By Jules Levin
Greg Everson (University of Colorado at Denver, Section of Hepatology)
reported at the AASLD liver conference in November 2002 on treating patients
with chronic hepatitis C and decompensated liver cirrhosis with what he
calls LADR: low accelerating dose regimen.
Everson said there are two main reasons to treat patients with
decompensated liver cirrhosis:
The aims of this study are to determine the effectiveness of interferon
alfa-2b plus ribavirin in patients with advanced liver disease—(1) to see
the percent of patients with HCV-RNA negative viral load, (2) to define
factors predictive of clearance of HCV-RNA, (3) to determine the rate of
recurrence of HCV in liver transplant recipients.
Here is the summary by Everson and the data results from the study are
below. Clerance of HCV RNA occurred in 40% by the end of treatment and 20%
had a sustained viral response. SVR was more common in genotype 1 and for
patients able to achieve a full dose for >6 months. Response in the
short-term did not affect rate of transplantation, HCC (cancer), and death.
But the most important finding in this study was that no patient with HCV
RNA clearance who underwent transplant experienced post-transplant relapse
(recurrence of HCV RNA). There were 28% dropouts by patients; 8% experienced
complications; GCSF was required in 28% and EPO in 4% of patients. Everson
concluded treatment of early to moderately decompensated cirrhotics with
non-1 genotype is effective. Response in genotype 1 patients is linked to
ability to achieve adequate dose and duration of treatment. Additional
strategies are needed for genotype 1. Liver transplant recipients may
achieve greatest benefit due to reduction in risk of post-transplant
recurrence. LADR may be particularly suited for LDLT where determination of
time of transplantation is possible. Everson went on to say that he thought
effectiveness, particularly for genotype 1 patients, could be improved by
use of pegylated interferon, althoigh cytopenias may be a problem. The
long-term effect of clearance of HCV RNA will be to reduce disease
progression; and improve hepatic function which might avoid liver
transplant, For those who have liver transplant he thinks this approach of
LADR can prolong survival after transplantation.
102 patients were enrolled--
age: 37 to 71 yrs
EtOH: 50%
Genotype 1: 77%
Biopsy proven or clinical cirrhosis: 87%
Bridging fibrosis (stage 3): 13%
Platelet count <50K: baseline 5%, on treatment 36%
COMPLICATIONS
Variceal hemorrhage: 22%
Ascites: 45%
SBP: 6%
Encepholopathy: 37%
Patients with 1 or more complications: 66%
66% of patients with EGD (38/59) had varices
CHILDS-TURCOTTE-PUGH CLASS
The mean CTP score was 7.1±2.0. About 50% were Class A, Class B 30%, Class C
20%.
LADR PROTOCOL
--initially: IFN-a-2b 1.5 MU 3x/week plus ribavirin 600 mg/day
--2 weeks: increase IFN-2b to 3 MU 3x/week
--4 weeks: increase ribavirin by 200 mg/day, weekly
--CBC and Biochemistry q 2 weeks
--HCV RNA q 3 months
GOAL: 3 MU IFN with 1.0 to 1.2 g/day RBV
RESULTS
--6 patients dropped out of study very early
--40 patients had negative viral load at the end-of-treatment
--56 were non-responders
--of the 40 pts who were HCV-RNA negative 21 had an SVR (sustained viral
response) and 19 had a relapse
--of the 56 non-responders 38 were virologic non-responders, 16 were
discontinued from treatment due to adverse events, and 2 had a liver
transplant early on in the treatment.
Definition of SVR: classic definition--HCV-RNA negative with 6 months or
more post-treatment follow-up, but this includes 3 patients who were on
treatment at the time of liver transplant; one of these 3 patients was an
individual who stopped treatment early in the course, was RNA negative,
relapsed and was put back on treatment, and then was transplanted.
Rate of Clearance of RNA
--End of Treatment Response: 40/102 (39%) or 40/96 (42%)
--Sustained Response: 21/102 (21%) or 21/96 (22%)
Characteristics of Responders
which includes end-of treatment responders, ie SVRs and relapsers
Decompensation did not appear to be a factor as 64% of responders were
decompensated vs 56% of non-responders. Similarly, the Childs-Pugh
distribution was similar between sustained responders, non-responders and
relapsers. Suggesting that patients having more advanced liver disease could
respond as well.
Everson reported the two key factors he found to be important were
genotype and the ability to achieve a full dose by 6 months on treatment.
Genotype 1 patients were less likely to respond: 52% of responders were
genotype 1 vs 88% of the non-responders were genotype 1. The ability to
achieve full dose was important, particularly in genotype 1 patients.
Patients who were able to achieve a full dose for >month 6 were more likely
to respond and perhaps also for those who could achieve this for 3-6 months:
48% of responders got to full dose while only 30% of non-responders were
able to achieve a full dose. 28% of responders had an inadequate dose while
52% of non-responders had an inadequate dose.
VIRAL RESPONSE BY GENOTYPE
End-of Treatment Sustained
Genotype 1: 28% 11%
Genotype non-1: 79% 50%
COMPLICATIONS and USE of GROWTH FACTOR
--4 patients experienced encepholopathy. 3 of these patients
experienced encepholopathy in the setting of infection: staph skin abscess
with septicemia, E coli sepsis, multilobar pneumonia requiring mechanical
ventilation.
--3 patients suffered gastrointestinal bleeding: 2 for varisces and 1 for
Mallory-Weiss.
--no patient died while on treatment. 1 death occurred about 3 weeks after
discontinuing treatment for side effects.
Growth factors: GCSF used in 28% and erythropoetin (EPO, Procrit) in 4%.
RESULTS OF FOLLOW-UP (Short Term), relative to treatment response
In the short term this intervention did not affect rates of transplant,
liver cancer (HCC), or death as reflected in this table.
Treatment response Transplant HCC Death
Non-responders 28% 13% 13%
Relapsers 39% 6% 11%
Responders 48% 14% 10%
RESULTS WITH LIVER TRANSPLANTATION
The important benefits of this intervention is to those who ultimately
undergo liver transplantation. Of the 32 patients that had liver
tranplantation. All 22 patients who were HCV RNA positive before liver
transplantation remained HCV RNA positive after the transplant, about 70%
had post-transplant HCV recurrence after transplant.
10 patients who were HCV RNA negative before transplant and remained HCV
RNA negative post transplant. 9 of these 10 patients have been followed for
for greater than 6 months and all remain RNA negative. The one patient who
did not achieve the 6 month follow-up being negative died early
post-transplant from complications of the transplant.
May 20, 2002
Treatment of Chronic Hepatitis C in Decompensated Cirrhotics
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May 20, 2002 Treatment of Chronic Hepatitis C in
Decompensated Cirrhotics Gregory T. Everson, M.D. University of Colorado
School of Medicine, Denver, CO
There are two main reasons to treat patients with decompensated
cirrhosis. First, effective treatment could clear the virus prior to
transplantation and avoid post-transplant recurrence of hepatitis C.
Second, viral eradication may halt disease progression and possibly
avoid the need for transplantation. Currently, hepatitis C is the
leading indication for liver transplantation in the United States and
the proportion of patients with end stage liver disease due to hepatitis
C is increasing. Many studies have demonstrated that patients who are
HCV RNA positive prior to transplant will experience post-transplant
recurrence of infection and many of these may require retransplantation
due to progressive hepatitis and cirrhosis. Post-transplant treatment of
recurrent hepatitis C is problematic due to effects of immunosuppression
and intolerance to side effects of interferon-based treatment. For these
reasons, pre-transplant treatment and viral eradication is potentially
the most effective strategy in limiting the impact of post-transplant
recurrence of hepatitis C. Combination therapy with standard interferons
plus ribavirin in clinically stable populations without advanced liver
disease clears hepatitis C RNA in 50% to 60% on treatment, and clearance
is sustained in approximately 40%. Results with peginterferon plus
ribavirin are even more encouraging with on-treatment clearance rates of
70 to 80% and sustained viral clearance of approximately 55%. Most
studies, but not all, have indicated that rates of viral clearance are
lower in cirrhotic patients, due, in part, to dose reductions and side
effects of treatment. Nonetheless, many cirrhotic patients experience
both on-treatment and sustained response. Those that clear virus may
experience reduction or abolition of liver inflammation, arrest of
disease progression, and even resolution of fibrosis. The published
experience has mainly focused on compensated cirrhotics as
interferon-based treatment has generally been considered to be
contraindicated in those with clinical evidence of advanced liver
disease. Colorado Experience The expanding numbers of patients with
hepatitis C on the waiting list coupled with the problems of post
transplant recurrence of disease, stimulated us to consider treatment of
decompensated cirrhotics. Our treatment protocol was dubbed LADR
(low-accelerating dose regimen) to indicated initiation of therapy at
half doses of IFN and ribavirin followed by dose increases based upon
patient tolerance. G-CSF and erythropoietin analogue, were used to treat
cytopenias. Efficacy was defined by clearance of HCV RNA and tolerance
was assessed by occurrence of side effects, adjustments in dose of
interferon and ribavirin, frequency of dropouts from treatment, and use
of G-CSF or erythropoeitin to correct cytopenias. Our initial group of
86 candidates for treatment was male-predominant with 50% reporting
significant past alcohol use or abuse. The population was enriched in
hepatitis C genotype 1 and 86% had either biopsy-proven or obvious
clinical signs of cirrhosis. The remaining 14% had bridging fibrosis on
biopsy or other features suggesting advanced disease (spider
telangiectasia (a vascular lesion formed by dilatation of a group of
small blood vessels), thrombocytopenia). Sixty three percent had
experienced clinical decompensation with either variceal hemorrhage,
ascites, spontaneous bacterial peritonitis, or encephalopathy.
Two-thirds of patients who had upper endoscopy, had esophageal varices.
Treatment was difficult in this patient population. There were 21
dropouts, mainly for side effects of fatigue, neuropsychiatric symptoms,
or cytopenias. The rate of serious inter-current illness was what one
might expect in this population. 28% required G-CSF and only 1 required
erythropoeitin. Eleven of the 86 patients elected not to enroll in the
trial. Of the remaining 75, 21 dropped from treatment due to side
effects, 29 were nonresponders. 25 cleared RNA on treatment. Of the 25
on-treatment responders, 12 relapsed. RNA was positive by 3 months in
all who relapsed. The other 13 remain RNA negative but 4 were still on
treatment and 3 others were followed for less than 6 months
post-treatment. Overall, the on-treatment rate of clearance of RNA was
29% for all eligible patients, 33% for enrolled patients, and 46% for
those who enrolled and did not drop from treatment. Responders and
nonresponders were similar in terms of age, gender distribution, % with
obvious cirrhosis, or frequency of clinical decompensation. In this
initial experience, two factors seemed to be most important in
determining response. Nonresponders were enriched in genotype 1 and a
lower percentage of responders were able to achieve full doses of
treatment for at least 3 months. The effect of dose on response was
observed primarily in genotype 1. Of the 57 patients with genotype 1, 23
never achieved full dose for at least 3 months. Only 2 of these 23
patients cleared RNA on treatment and neither sustained this response.
The only sustained responses in patients with genotype 1 occurred in
those who were able to take at least 6 months of full dose treatment. In
contrast to patients with genotype 1, those with other genotypes cleared
RNA more frequently and there was less dependency upon dose. In fact, 2
sustained responders, who were treated for 12 months, never received
full dose therapy for over 3 months. Outcome in LADR Patients who were
Transplanted. Twenty six patients treated by LADR underwent
transplantation. Six were sustained responders prior to transplantation
and none have experienced post-transplant recurrence. Seven had
on-treatment response but relapsed prior to transplant. One was
retreated, became HCV RNA negative, was transplanted, and remains HCV
RNA negative for one year post-transplant. The other 6 relapsers were
not retreated, underwent transplant, and all recurred. All thirteen non
responders have post-transplant recurrence of hepatitis C. Implications
for Living Donor Liver Transplantation. Twenty eight patients infected
with HCV have received LDLT (living donor liver transplantation) at our
center between 8/97 - 4/2001. Fourteen received no treatment and
remained HCV positive pre- and post-transplant. Two of the remaining
twelve were non responders to interferon monotherapy and recurred
post-transplant. The 12 remaining patients received either standard
combination therapy or LADR. Four of the 12 were complete responders
on-treatment (33%) and remain free of HCV 6 months or more
post-transplant. Summary HCV RNA can be cleared in at least 33% of
cirrhotics with advanced liver disease using the LADR protocol. Best
response is achieved in non-1 genotypes and in genotype 1 patients able
to take full dose treatment for at least 3 months. Relapse, after
discontinuation of treatment, is more frequent in this group of patients
but retreatment of relapse prior to transplantation may clear virus and
prevent post-transplant recurrence. Those who experience sustained
response will not relapse post-transplant. LADR treatment may be
well-suited for application in the setting of LDL T where the timing of
transplantation in relation to treatment can be fixed. Treatment is
difficult in this population, dropouts are common, serious complications
can occur, and G-CSF or erythropoeitin may be needed. Conclusions LADR
may be warranted in decompensated cirrhotics, but genotype 1 patients
who become RNA negative should be maintained on treatment until time of
transplantation. In addition, if treatment is withdrawn in a responder,
HCV RNA should be monitored for relapse and consideration of
reinstitution of therapy. We also speculate that clearance or
suppression of hepatitis C RNA will slow disease progression, improves
hepatic function, and possibly reduces the need for transplantation |
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Conclusions LADR may be warranted in
decompensated cirrhotics, but genotype 1 patients who become RNA
negative should be maintained on treatment until time of
transplantation. In addition, if treatment is withdrawn in a responder,
HCV RNA should be monitored for relapse and consideration of
reinstitution of therapy. We also speculate that clearance or
suppression of hepatitis C RNA will slow disease progression, improves
hepatic function, and possibly reduces the need for transplantation |
