Can Persons With Decompensated Cirrhosis Be Treated for HCV?

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Can Persons With Decompensated Cirrhosis Be Treated

for HCV?

Brief Summary:

Below are two studies reported at Dallas on this

important and

controversial question. The first study discussed

below looks at

treating individuals who appear more advanced in

disease stage as they

are on waiting lists for transplants. Less than half

of the patients

screened for the study met the criteria. The rate of

adverse events were

high: in 15 individuals, there were 23 complications

and 20 were severe

(thrombocytopenia & leucopenia were most common). One

patient died from

a fatal complication. But individuals were capable of

a virologic

response. The second study below looks at individuals

who appear not to

be as progressed in their liver disease and the

investigator also saw a

viral response, but the complications and side effects

were not as

severe. Investigators in this study used an increasing

dosing approach

to try for tolerability. Achieving RNA clearance

appeared to be related

to the ability to achieve full dosing for at least 3

months preferably

for 6 months. Of the 4 patients, for whom data is

available so far, able

to achieve SVR prior to transplant they remain RNA-

after transplant.

A Pilot Study of the tolerability and efficacy of

antiviral therapy in

patients awaiting liver transplantation for Hepatitis

C

Iverson, Univ of Colorado Health Science

Ctr, Denverr, CO;

Trouillot, Trottier, Skilbred,

UCSHC, Denver, CO;

Arthur Halprin, Carol McKinley, Univ of Colorado

Health Science Center,

Denver, CO; Barbara Fey, Ray, Epp, UCSHC,

Denver, CO

Patients were recruited from the waiting lists at 5

hospital centers:

Baylor University Med Ctr in Dallas; Mayo Clinic in

Rochester, Minn; Mt

Sinai Med Ctr in NYC; Univ of Cal, SF; Univ of

Nebraska, Omaha.

The purpose of the study was to determine whether

pretransplant

antiviral therapy is practical by studying the

tolerability and efficacy

of interferon a2b (IFN) with or without ribivarin

(RBV), in patients

with decompensated hepatitis C awaiting transplants.

So, this group of

patients is likely to be more advanced in their

disease stage than the

group in the next study.

Patients had to be on the active waiting list at one

of these centers

with a status 2b (Child-Pugh class C). They had to be

at or near the top

of the list so the transplant was imminent. They had

to have HCV-RNA

positive by PCR and no antiviral therapy within the

last 12 weeks prior

to enrollment in this study.

Patients were excluded for:

Severe renal insufficiency, serum creatinine >2.0

mg/dL

Platelet count <45,000

Hemoglobin <11 gm

Absolute neutrophil <1250

INR > 2.0

Patients were randomized to one of 3 arms:

A: IFN 2b, 1 million units subq. Daily

B: IFN 2b, 3 MU 3x/week

C: IFN 2b, 1 MU daily + RBV 400 mg twice daily

Laboratory values were checked at baseline, days 1, 3

and 7 and then

weekly. HCV-RNA was quantified using a coomercial bDNA

signal

amplification assay (HCV Quantiplex 2.0 Chiron). Lower

limit of

sensitivity of the assay was 0.2 x 106 vEq/ml.

Genotype was performed

by PCR.

IFN DOSE REDUCTION

IFN dose was reduced if neutrophil count was <750,

platelet count

<45,000 and RBV dose was capped at 400 mg per day if

hemoglobin was <10

gm.

DRUGS DISCONTINUED

IFN was stopped if

--neutrophil count was <500, or

--platelet count <20,000

RBV stopped if hemoglobin was <8.5 gm

Both drugs were stopped if serum creatinine >3.0 mg/dL

Less than half of the patients screened for this study

met entry

criteria, so they were a sick group in general. The

most common reasons

for exclusion were thrombocytopenia and leukopenia.

Fifteen patients were enrolled: 3 in arm A and 6 in

arms B & C. The

genotypes were:

1a- 7

1b- 1

1a/b- 3

2a/c- 1

3a- 1

untypeable- 2

BASELINE VIRAL LOAD

Undetectable- 3 patients

<5.0 (5 million) vEq/ml- 6 patients

5.0-10 vEq/ml- 1

>10 vEq/ml- 5

VIRAL RESPONSE

4/12 patients (33%) with detectable viral load at

baseline achieved

undetectable VL on treatment

A (1 MU IFN daily): 1 patient was in arm A with

genotype 1 and had

undetectable VL after 2 weeks

B ( 3 MU IFN 3x/wk): 2 patients in this arm achieved

undetectable VL: 1

person with genotype 3a after 3 days on therapy and 1

person with

genotype 2a/c after 2 weeks

C (IFN 1 MU daily+RBV 400 mg bid): only 1/6 achieved

undetectable

(genotype 1) and that occurred after 2 weeks on

therapy

6/12 patients (50%) had a decrease in VL of <1 log

Two patients at the time of closing the study went on

to

transplantation. One patient had undetectable VL by

bDNA assay at the

time of transplant but within 1 month the VL went up

to 42 million. The

second patient started with a VL of 4 million at

baseline which dropped

to 1.14 million while on therapy. One month after

transplant the VL was

8.41 million.

ADVERSE EVENTS

The author said the take home message from this study

was that there

were a large number of adverse events, and this was

the major concern.

In the 15 patients there were 23 adverse events, 20 of

which were

severe. Thrombocytopenia was the most common (n=8).

Leukopenia was

frequent (n=4). There was an equal distribution across

all treatment

arms. And they all resolved with dose

reduction/discontinuation.

Other adverse events occurring during the study:

hepatic encepholopathy (n=3) with out any other

obvious precipitating

causes

severe nausea/vomiting (n=2)

hyperbilirubinemia (n=1) from a baseline 3-4 to level

of 13

new onset of hypothyroidism (n=1)

acute pancreatitis (n=1) manifested by low level

elevations in serum

lipase/amylase which resolved with reduction of drugs

INFECTIOUS COMPLICATIONS

The author said the scary part of the study was the

infectious

complications occurring. He said most of these

patients run into

problems with infections. There were 2 patients with

such complications.

They were quite alarmed when one patient developed

septic (presence of

toxins in the blood or tissues) arthritis of a toe,

secondary to S.

aureus. This responded to antibiotic therapy. Another

patient developed

a culture negative empyema that progressed to

multi-system organ

failure, refractory hypotension and death despite

aggressive

(antibiotic) medical therapy.

AUTHOR'S SUMMARY:

Undetectable VLs are attainable

Adverse events are the rule and most patients don't

meet criteria (to

sick) for treatment

Dose reduction/discontinuation is common as only 4

patients were able to

complete 4 weeks therapy

1 fatal infectious complication

CONCLUSIONS:

In this group of patients who are already at high

risk, fatal

complications can occur

Undetectable VLs can occur and tolerability is low

But treatment of decompensated cirrhotics is possible.

The next study

discusses treatment in patients at an earlier stage

and that may be a

key

Treatment of Decompensated Cirrhotics with a

Low-Accelerating Dose

Regimen of Interferon alfa-2b and Ribivarin (LADR):

Safety & Efficacy

Crippin, Baylor University, Dallas, Tx;

Scheidner,

Mt Sinai Med Ctr, NY, NY; Norah Terrault, Univ of CAL,

SF, CA; Tim

McCashland, Univ of Nebraska Med Ctr, Omaha. NE; M

Charlton, Mayo

Clinic, Rochester, MN

Crippin reported on this pilot preliminary

study, and the author

suggested keeping that in mind if considering treating

patients in

similar circumstances. The author gave a little

background and the

reasons for his study. Patients with cirrhosis are

expandng the waiting

list for liver transplantation throughout the world.

Current medical

strategies are ineffective in preventing recurrence of

HCV or in

treating post transplant hepatitis C. Often, Hepatitis

C can recur

following transplantation. Everson said treatment

after transplant is

unlikely to clear HCV-RNA. The number of transplants

performed for

recurrent, progressive, allograft Hepatitis C is

increasing. Hepatitis C

is the number one indication for liver

transplantation. Therefore,

aggressive approaches designed to eradicate hepatitis

C in patients with

advanced liver disease awaiting transplant are needed.

However, the most effective antiviral therapy,

combination interferon

plus ribivarin, is relatively contraindicated due to

fear of

precipitation of decompensation of liver disease or

development of

dangerous cytopenias. This study's aim was to explore

the safety and

efficacy of treating advanced chronic hepatitis C with

decompensated

liver disease with combination IFN+RBV.

So, there are two main reasons to potentially treat

patients with

decompensated cirrhosis. If patients can clear HCV RNA

they may improve

or stabilize liver function and maybe they can come

off transplant list.

For other patients who may not yet be transplant

patients, stopping or

reversing disease progression may be possible.

The specific aims of the study were to determine if a

low accelerating

dosing approach (LADR) could clear HCV-RNA, if it's

tolerable (side

effects, dose adjustments, dropouts, use of G-CSF for

low WBC and

erythropoeitin), and if treatment reduces the risk of

post-transplant

recurrence of HCV.

Study patients (n=86) were eligible for in the

hepatology clinics of the

University of Colorado Health Sciences Center, and

were started on the

LADR protocol.

DEMOGRAPHICS

(half of patients are transplant candidates and 40%

are on waiting list)

Age: 24-66 years

Male- 52, female 34

Prior history of alcohol: 50%

Genotype 1: 77%

Biopsy proven cirrhosis: 62%

Clinical cirrhosis: 24%

Non-cirrhosis but had bridging fibrosis: 14%

63% had one or more of these complications:

Variceal hemorrage: 21%

Ascites; 44%

SBP: 7%

Encepholopathy: 34%

42 patients underwent endoscopy and 64% of them had

documented varisces

Lab studies indicated that 43% had albumin < 3.5 g/dl,

52% had INR >1.2,

33% had bilirubin >2 mg/dl, and 68% had platelet count

<130,000.

LADR Protocol:

Initial therapy: IFN-2b 1.5 MU tiw + Ribivarin 600

mg/day

After 2 weeks they tried to increase IFN dose to 3 MU

tiw (full dose),

if therapy was tolerable and WBC and platelet count

were stable

After 4 weeks they tried to increase RBV dose to 200

mg/day, on a weekly

basis in trying to reach goal of 1000 to 1200 mg/day

RBV (full dose),

based upon patient weight, tolerance, to medications,

and hemoglobin

level

Granulocyte-colony-stimulating factor (G-CSF) and

human recombinant

erythropoeitin were given as needed to maintain PMN

>800 and hemoglobin

>10 g/dl, respectively

CBC and Biochemistry done every 2 weeks and HCV PCR

done every 3 months

The goal was to achieve standard full dose therapy of

3 MU 3x/week IFN

plus 1000/1200 mg/day RBV.

TREATMENT OUTCOME

75 enrolled and began treatment. Some patients had

transplants and some

were non-adherent

21 patients dropped out

25 patients cleared RNA on treatment (<100 copies)

of the 25 that cleared RNA 12 relapsed and treatment

was discontinued

29 were viral non-responders

6 had sustained virologic response for >6 months

3 have virologic response but follow-up is <6 months

4 are in the last 3 months of treatment

DROPOUTS & COMPLICATIONS

There were 21 dropouts, 19 related to side effects and

2 due to

non-compliance. The most common were fatigue,

neuropsychiatric symptoms,

and cytopenias.

Serious intercurrent illnesses occurred in 6 patients:

encephalopathy

(n=3), responded to lactose; sepsis (n=2) (pathogens

or toxins in blood

or tissues) (one patient died related to sepsis; one

patient had staff

abscess at injection site); 1 GI bleeding.

G-CSF was used in 21 patients (28%) and erythropoeitin

in 1 patient, so

there was not much trouble with anemia in this

protocol.

RATE OF CLEARANCE of RNA

Everson reported clearance rates in several ways:

all patients (intent-to-treat) 25/86- 29%

enrolled patients 25/75- 33%

enrolled minus dropouts (as-treated)- 46%

CHARACTERISTICS of RESPONDERS

Everson stressed two points: The statistically

significant ability to

respond for genotype 1; and the response capacity

based upon reaching

full dose (see table below). He mentioned that being

able to take full

dose for at least 3 months was important to achieving

response.

Responders

Nonresponders p-value

Age (mean. Yr) 52.5 50.2

NS

M:F 15:10 34:16

NS

Cirrhosis 64% 56%

NS

Decompensation 64% 56%

NS

Genotype 1 52% 88%

<.001

DOSE EFFECT

Full dose >6 months 48% 30% .13

Full dose 3-6 months 24% 18%

Inadequate dose 28% 52%

The effect of dose on response was evident only in

Genotype 1 patient

<.05

RNA CLEARANCE in GENOTYPE 1

RELATIONSHIP TO DOSE

There were 57 patients with genotype 1. 23 never got

to full dose for 3

months or more and only 2 cleared HCV*.

N % SVR (n)

Full dose >6 months 8/23 35% 2

Full dose 3-6 months 3/11 27% 0

Reduced dose * 2/23 9% 0

RNA CLEARANCE in GENOTYPE 2, 3, 6

The relationship to dose was not as evident.

N % SVR (n)

Full dose >6 months 3/4 75% 1

Full dose 3-6 months 4/4 100% 1

Reduced doses 5/10 50% 2*

These 2 sustained responders received 12 months of

treatment.

RESULTS with LIVER TRANSPLANTATION

19 of the 86 patients were transplanted. All the

patients who were RNA+

before transplant (including relapsers &

nonresponders) were RNA+ after

transplant (so far 12 patients). Of the 4 SVRs for

whom data is

available so far remain RNA- after transplant. And

they have basically

normal ALT & liver function.

SUMMARY by Everson:

This is a preliminary pilot study, but they saw 33% of

patients (25/75),

particularly for genotype 2/3 patients. For genotype 1

patients, it's

important to achieve full dosing to clear RNA for at

least 3 months.

With pegylated IFN becoming available they may be able

to achieve

reasonable response rates of approaching 50%.

Sustained viral remission is rare (12%). Once you stop

treatment the

relapse rate is high. But if patients are able to

achieve SVR, they do

not appear to relapse post-transplant.

Dropouts are common (50%).

Serious complications occurred in 8%. I think Everson

said he would

expect this rate of complications in this population

anyway.

G-CSF required in 28% and Epo in 1%.

CONCLUSIONS:

LADR is warranted in decompensated cirrhotics

Genotype 1 patients who become RNA negative on

treatment should be

maintained on IFN+RBV until time of transplant

If treatment is withdrawn in a responder, monitor for

relapse and

consider reinstitution of therapy

Everson speculates that clearance of HCV-RNA will:

- Slow disease progression

- Improve hepatic function

- Reduce risk of post-transplant occurrence of

Hepatitis C

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