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
     Gregory Iverson, Univ of Colorado Health Science Ctr, Denverr, CO; Thomas Trouillot, James Trottier, Justin Skilbred, UCSHC, Denver, CO; Arthur Halprin, Carol McKinley, Univ of Colorado Health Science Center, Denver, CO; Barbara Fey, Cathy Ray, James 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 commercial 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
     Jeffrey Crippin, Baylor University, Dallas, Tx; Patricia 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

Jeffrey 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 expanding 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.

DOSE EFFECT

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*.

RNA CLEARANCE in GENOTYPE 2, 3, 6

The relationship to dose was not as evident.

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