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Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy
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"......we treated 124 patients with advanced hepatitis C with clinical or biochemical decompensation using a LADR (low accelerating dose regimen) of interferon and ribavirin. Forty-six percent cleared HCV RNA from blood on treatment, and 24% had sustained clearance of HCV RNA. Virological response was highest in patients with non-1 genotypes, CTP class A, and who achieved a full course of therapy. Eighty percent of patients rendered HCV RNA-negative by LADR who underwent liver transplantation remained free of HCV after transplantation. Our experience suggests that antiviral therapy in patients with advanced HCV may stabilize disease and reduce the risk of posttransplantation recurrence...."
Hepatology
August 2005
Gregory T. Everson *, James Trotter, Lisa Forman, Marcelo Kugelmas, Arthur Halprin, Barbara Fey, Catherine Ray
Section of Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Denver, CO
Patients with advanced liver disease due to chronic hepatitis C virus (HCV) are at risk for death, need hepatic transplantation, and could benefit from effective antiviral therapy. Sustained virological response (SVR) in patients with Child-Turcotte-Pugh (CTP) class A cirrhosis has improved from 5% with interferon monotherapy[1][2] to a maximum of 50% with peginterferon plus ribavirin.[3-5] However, these results cannot be extrapolated to sicker patients, such as those on waiting lists for liver transplantation. In this study, we analyzed the effectiveness of a low accelerating dose regimen (LADR) of interferon plus ribavirin in patients with advanced chronic HCV. Seventy-three percent (n = 90) of these patients were listed before, during, or after LADR, and 38% (n = 47) underwent liver transplantation.
Patients with advanced hepatitis C virus (HCV) are at risk of death and are candidates for liver transplantation. After transplantation, HCV recurs and may rapidly progress to cirrhosis and graft loss.
Treatment is needed to prevent progression of disease and minimize recurrence after liver transplantation.
We evaluated the effectiveness, tolerability, and outcome of a low accelerating dose regimen (LADR) of antiviral therapy in the treatment of patients with advanced HCV.
Either interferon alfa-2b (Intron A 1.5 MU three times a week [n = 119]) or peginterferon alfa-2b (Pegintron 0.5 g/kg/wk [n = 5]) plus ribavirin (Rebetol 600 mg/d) was used initially. Peginterferon alfa-2b (Pegintron) or peginterferon alfa-2a (Pegasys initated at 90 g/wk) plus ribavirin (Rebetol or Copegus) was used in the retreatment of 15 patients. Adjustments were made incrementally every 2 weeks to reach maximally tolerated or target standard doses. Full course was defined by achievement of both target dose and duration (6 months for genotypes 2 and 3 or 12 months for other genotypes). Full duration defined a course with reduced dose or doses but for target duration (6 months for genotypes 2 and 3 or 12 months for genotypes 1, 4, and 6). Incomplete therapy defined a course with reduced doses and truncated duration of therapy.
One hundred twenty-four patients (male/female ratio 81:43; age range 37-71 years; 70% genotype 1) were treated with LADR. Sixty-three percent had clinical complications of cirrhosis (ascites, spontaneous bacterial peritonitis, varices, variceal hemorrhage, encephalopathy). The mean Child-Turcotte-Pugh (CTP) score was 7.4 ± 2.3, and the mean MELD score was 11.0 ± 3.7. Fifty-six patients were CTP class A, 45 were class B, and 23 were class C.
Forty-six percent were HCV RNA-negative at end of treatment, and 24% were HCV RNA-negative at last follow-up. Sustained virological response (SVR) was 13% in patients infected with genotype 1 HCV and 50% in patients infected with non-1 genotypes (P < .0001).
Non-1 genotype, CTP class A (genotype 1 only), and ability to tolerate full dose and duration of treatment (P < .0001) were predictors of SVR.
Twelve of 15 patients who were HCV RNA-negative before transplantation remained HCV RNA-negative 6 months or more after transplantation.
In conclusion, in a sizeable proportion of patients with advanced HCV, LADR may render blood free of HCV RNA, stabilize clinical course, and prevent posttransplantation recurrence.
MORE INFORMATION
HCV RNA was measured via quantitative (during therapy) or qualitative (for SVR) polymerase chain reaction using commercially available assays. Virological response was assessed at week 24 or by end of treatment (EOTR), and SVR was defined as HCV RNA-negative status 6 months after EOTR. EOTR in patients who were on treatment at the time of transplantation was the day of transplantation.
Granulocyte colony-stimulating factor at 150 to 300 g subcutaneously weekly or twice a week (Neupogen) was allowed for ANC <800/L. Erythropoeitin analog at 10,000 to 40,000 units of subcutaneously weekly (Epogen or Procrit) was allowed for hemoglobin <10 g/dL. Granulocyte colony-stimulating factor was administered to 33% of patients, but availablity limited erythropoeitin analog use to only 5% of patients, even though 56% had significant anemia during therapy. Anemia was managed primarily through dose reduction of ribavirin.
The outcome of 90 patients (73%) who were listed and 47 patients that underwent transplantation (38%) was examined.
Side effects of treatment sufficient to cause dose discontinuation and serious adverse events were evaluated. Serious adverse events included hepatic decompensation (encephalopathy, worsening ascites, spontaneous bacterial peritonitis, variceal hemorrhage), infection, other significant medical illness, or death. Causes of death and the possible relationship to antiviral treatment were evaluated.
Virological Response
Fifty-seven patients (46%) were HCV RNA-negative at EOTR, and 67 (54%) were nonresponders. Twenty-seven patients (22%) achieved SVR with the initial course of treatment. Thirty patients recurred, for a relapse rate of 53%. Eleven patients who relapsed were retreated, 3 with peginterferon/ribavirin and 8 with interferon/ribavirin, and became HCV RNA-negative. Three of these 11 underwent transplantation, and 2 have remained free of HCV after transplantation; the other 8 relapsed again. Twelve nonresponders were retreated with peginterferon/ribavirin; 1 (8%) of these 12 had SVR and is stable in long-term follow-up. Thus, a total of 30 (24%) of the 124 patients remained HCV RNA-negative in long-term follow-up after antiviral therapy.
Sixteen patients discontinued treatment for side effects, and 51 were virological nonresponders. Eleven of these 51 had less than 1 month of treatment either because of urgent transplantation (n = 8) or dropout from therapy (n = 3). All 8 with urgent transplantation had recurrent hepatitis C. The remaining 40 discontinued therapy because of a lack of virological response, but 25 of these 40 also experienced side effects.
Predictors of Virological Response
Genotype.
Eighty-six patients had genotype 1 infection (Fig. 2). EOTR was 30% (n = 26), SVR 13% (n = 11), and relapse rate 65% (n = 17). Thirty-eight patients were infected with non-1 genotypes. EOTR was 82% (n = 31), SVR 50% (n = 19), and relapse rate 42% (n = 13). EOTR (P < .0001) and SVR (P < .0001) were significantly higher in non-1 genotypes.
Severity of Liver Disease.
Laboratory characteristics according to CTP class are shown in Table 1. Mean MELD score of patients with most severe disease, CTP class C, was 16.8 ± 3.0. CTP class C had a higher proportion of patients infected with non-1 genotypes of HCV. EOTR was 46%, 42%, and 52%, and SVR was 25%, 22%, and 26% for CTP classes A, B, and C, respectively. For genotype 1, EOTR was 35%, 28%, and 21%, and SVR was 13%, 16%, and 7%. For non-1 genotypes, EOTR was 75%, 77%, and 100%, and SVR was 56%, 38%, and 56%. Differences in virological response between CTP classes did not reach statistical significance.
Dose and Duration of Therapy.
Thirty-six patients took a full course of therapy (Table 2). Of these, 30 (83%) had EOTR and 17 (47%) had SVR; 6 (17%) were nonresponders and 14 (47%) relapsed. Twenty-two patients took reduced doses but for full duration. Of these, 18 (82%) had EOTR and 9 (41%) had SVR; 4 (18%) were nonresponders and 10 (56%) relapsed. Sixty-six patients took neither a full course nor full duration of treatment. Of these, 9 (14%) had EOTR and 4 (6%) had SVR; 57 (86%) were nonresponders and 6 (67%) relapsed. EOTR (P < .0001) and SVR (P < .0001) were significantly lower with an incomplete course of therapy.
Dose and duration effects were most dramatic for patients infected with genotype 1 HCV. Nineteen patients with HCV genotype 1 took a full course of therapy. Of these, 14 (74%) had EOTR and 8 (42%) had SVR; 5 (26%) were nonresponders and 7 (50%) relapsed. Twelve patients took reduced doses but for full duration. Of these, 8 (75%) had EOTR and 3 (25%) had SVR; 4 (33%) were nonresponders and 10 (83%) relapsed. Fifty-five patients took neither a full course nor full duration of treatment. Of these, 4 (7%) had EOTR and 0 (0%) had SVR; 51 (93%) were nonresponders and all 4 (100%) with EOTR relapsed. EOTR (P < .0001) and SVR (P < .0001) were significantly lower with an incomplete course of therapy. One reason for the poor virological response in patients with genotype 1 HCV and CTP class C was intolerance to treatment. No patient with genotype 1 HCV and CTP class C could maintain a full course of therapy.
Seventeen patients infected with non-1 genotypes of HCV took a full course of therapy. Of these, 16 (94%) had EOTR and 9 (53%) had SVR; 1 (6%) was a nonresponder and 7 (44%) relapsed. Ten patients took reduced doses but for full duration. Of these, all 10 (100%) had EOTR and 6 (60%) had SVR; 0 (0%) failed to respond and 4 (40%) relapsed. Eleven pateints took neither full course nor full duration of treatment. Of these, 5 (45%) had EOTR and 4 (36%) had SVR; 6 (55%) were nonresponders and 3 (60%) relapsed. EOTR (P < .002) but not SVR (P value not significant) was significantly lower with an incomplete course of therapy.
Virological Response at Week 24.
EOTR was 84% and SVR 41% in patients who were HCV RNA-negative at week 24. EOTR was 4% and SVR 0% in those without a virological response at week 24.
Side Effects and Adverse Events
Cytopenia.
Mean values (±SD) for hemoglobin, absolute neutrophil count, and platelet count at baseline versus nadir were 15.2 ± 1.6 versus 12.1 ± 1.9 g/dL, 2.84 ± 1.16 versus 1.31 ± 0.71/[L ×1,000], and 107 ± 59 versus 81 ± 49/[L ×1,000], respectively. Five percent had hemoglobin 12 g/dL before treatment and 56% dropped below 12 g/dL during treatment. Three percent had absolute neutrophil count 1,000/L before treatment and 49% fell below 1,000/L during therapy. Nine percent had platelet counts 50,000/L before treatment and 33% drifted below 50,000/L during the course of treatment.
Morbidity During LADR.
There were 22 clinically significant adverse events that occurred in 15 patients. Adverse events included infection (n = 5), worsening ascites (n = 5), encephalopathy (n = 6), gastrointestinal bleeding (n = 2), diabetes mellitus (n = 1), severe thrombocytopenia (platelet count 2,000/L; n = 1), venous thrombosis with pulmonary embolus (n = 1), and culture-negative pneumonitis (n = 1). Seven patients suffered more than one adverse event. Treatment potentially contributed to two complications associated with patient mortality (venous thromboembolism and staphylococcal sepsis).
Recurrence of Hepatitis C After Liver Transplantation
Ninety patients were listed either before, during, or after LADR, and 47 underwent transplantation. Thirty-seven of the transplants were from deceased donors and 10 were from living donors. EOTR was 21% (7 of 34) in unlisted patients, 65% (28 of 43) in patients who were listed but had not undergone transplantation, and 47% (22 of 47) in patients who had undergone transplantation; SVR was 18% (6 of 34), 28% (12 of 43), and 26% (12 of 47), respectively. Fifteen patients were HCV RNA-negative before transplantation; 12 (80%) of these 15 remained HCV RNA-negative for at least 6 months after transplantation with repeated testing (Table 4). Eight of the 15 were on treatment up to time of transplantation; 2 of these relapsed after transplantation. Three of the 15 underwent transplantation within 3 months of stopping LADR; 1 of these relapsed. Four of the 15 underwent transplantation after SVR - 2 for advanced disease and 2 for hepatocellular carcinoma (HCC) - and none relapsed. One of the 3 relapsers had only 8 weeks of treatment before transplantation, another finished his course of therapy 4 weeks before transplantation, and another had a treatment course complicated by chemoembolization therapy for hepatoma just before transplantation. All 32 who were HCV RNA-positive before transplantation relapsed after transplantation.
Long-Term Outcome
Four patients were lost to follow-up, and 26 died - 9 transplant recipients and 17 others. Causes of death in transplant recipients included graft loss secondary to aggressive recurrence of HCV (n = 4), postoperative complications (n = 2), recurrent hepatoma (n = 1), cerebral hemorrhage (n = 1), and pancreatic cancer (n = 1). Causes of death in patients who did not undergo transplantation included hepatoma (n = 9), multiorgan failure (n = 3), progressive liver failure from HCV (n = 2), pulmonary embolus (n = 1), laryngeal cancer (n = 1), and unknown (n = 1). Mortality was higher in patients who were listed but did not undergo transplantation (26% vs. 18% for unlisted patients and 19% for transplant recipients).
HCC was diagnosed in 2 patients before LADR and in 18 others either during treatment with LADR or during follow-up. Ten patients with HCC underwent transplantation, and 1 died of recurrent HCC. Nine of the 10 without transplantation died from complications of HCC, and the remaining patient is alive with extensive HCC.
Thirty patients had SVR - 12 transplant recipients, 11 listed patients who did not undergo transplantation, and 7 unlisted patients. Two transplant recipients, 3 listed patients, and 1 unlisted patient died. The 10 surviving transplant recipients with SVR lack clinical, laboratory, or histological evidence for recurrent hepatitis. The 14 patients surviving without transplantation, including 8 who remain on the list, have experienced improvement in clinical status and laboratory profile. In contrast, only 17 (25%) of the 70 patients who remained HCV RNA-positive have remained stable both clinically and biochemically; the remaining 53 have shown either clinical or biochemical progression, and 30 (43%) have been retreated with interferon-based therapies. Four (13%) of these 30 - 1 nontransplantion and 3 posttransplantion - have cleared HCV RNA and stabilized.
AUTHOR DISCUSSION
By 2015, 3 million Americans will have more than 20 years of HCV infection, and 375,000 will have cirrhosis.[6-8] After cirrhosis develops, the risk of clinical deterioration is 3.6% to 6.0% per year, the risk of HCC is 1.4% to 3.3% per year, and the risk of death related to liver disease is 2.6% to 4.0% per year.[9-20] The number of patients with advanced liver disease and the proportion listed for liver transplantation is steadily increasing.
Although virological response is generally lower in patients with cirrhosis compared with those who do not have cirrhosis, results with interferon-based therapy are improving, with maximum rates for SVR of 40% to 50% for CTP class A.[3-5] We developed LADR for use in more advanced disease for three reasons.[21] First, patients with advanced disease may be intolerant of standard doses of interferon and ribavirin. Second, clearance of HCV may not only halt disease progression but may result in clinical remission and avoid the need for transplantation. Third, clearance or suppression of HCV before transplantation might avoid recurrence of HCV in the liver allograft, ultimately improving graft and patient survival.
The Consensus Development Conference on Liver Transplantation and Hepatitis C and the AASLD Practice Guidelines have suggested that patients with MELD scores of 18 or less could be considered for treatment,[22][23] with the caveat as long as treatment is administered by experienced clinicians, with vigilant monitoring for adverse events.[23] The severity of disease of patients that we treated with LADR was representative of that of patients with moderately advanced liver disease and similar to the majority of patients on the United States waiting list. Two thirds had a history of clinical decompensation; 90 (73%) were listed before, during, or after LADR; and 47 underwent transplantation.
Despite use primarily of nonpegylated interferon, and conservative application of growth factors, LADR achieved an EOTR of 46% and a SVR of 24% in patients with advanced disease. Virological response was compromised by genotype 1 infection, severity of liver disease (CTP class C), and failure to achieve target doses and duration of therapy. EOTR was 30% and SVR 13% in patients with genotype 1 infection, but was 82% and 50% in patients with non-1 genotypes. Side effects, complications of advanced liver disease, and cytopenias were commonly encountered, limited dose escalations, and contributed to dose reductions. Growth factors were used sparingly but allowed some patients to achieve full-dose therapy and SVR. Use of pegylated interferon, which has a greater antiviral effect, and maintenance of higher doses of antiviral drugs via more liberal use of growth factors may improve results with LADR.
Fifteen patients experienced 22 serious adverse events, 16 of which occurred during the course of treatment, and 2 that may have contributed to mortality. Most adverse events were complications common to patients with advanced liver disease (encephalopathy, gastrointestinal bleeding, worsening ascites). In contrast, certain complications, such as infection, diabetes, thrombocytopenia, and venous thromboembolism, may have been more directly related to interferon. This experience highlights the need to exercise caution in treatment and maintain very close supervision of these patients during the course of therapy.
Perhaps the most important finding of our study was the prevention of posttransplantation recurrence of HCV by pretransplantation antiviral therapy. Twelve (80%) of 15 patients who were HCV RNA-negative pretransplantation lacked posttransplantation recurrence. In contrast, all 32 patients who were HCV RNA-positive pretransplantation recurred after transplantation. Overall, 15 (32%) of 47 patients were rendered HCV RNA-negative at time of liver transplantation, and 12 (26%) of 47 were spared HCV recurrence. Six of the patients in our cohort were recipients of living donor liver transplantation, and none relapsed. The ability to schedule the date of living donor liver transplantation may be of particular advantage in the setting of pretransplantation antiviral therapy.
Two other groups have studied interferon therapy before transplantation.[24][25] Forns and colleagues[24] treated 30 patients who had cirrhosis - with an anticipated time to transplantation of less than 4 months - with interferon alfa-2b (5 MU/d) plus ribavirin 800 mg/d. Eighty-three percent had genotype 1b HCV, and the median duration of treatment was 9 weeks. Nearly all experienced significant side effects, and 63% required dose reductions in interferon or ribavirin. Nine patients (30%) were negative for HCV RNA at the time of transplantation; of these, 6 (20%) remained negative after transplantation. Thomas and colleagues[25] used daily injections of 5 MU interferon alfa-2b in 20 patients and reported that 12 (60%) were HCV RNA-negative at time of transplantation, but only 4 (20%) remained free of recurrence after transplantation. The 20% prevention of recurrence was similar to that observed in the Forns study (6 of 30, 20%) and in our experience with LADR (12 of 47, 26%).
Crippin and colleagues[26] treated 15 patients with more advanced disease (CTP score 11.9 ± 1.2). No patient experienced sustained response, 2 who underwent transplantation had recurrence of HCV, and the study was halted because of serious side effects. In contrast to Crippin, we reported an SVR of 26% in 23 patients with CTP class C treated with LADR, despite a CTP score of 11.1 + 1.1 and a MELD score of 16.8 ± 3.0. However, our patients with SVR were mainly infected with non-1 genotypes; only 1 of 14 patients with genotype 1 and CTP class C had SVR.
In conclusion, we treated 124 patients with advanced hepatitis C with clinical or biochemical decompensation using a LADR of interferon and ribavirin. Forty-six percent cleared HCV RNA from blood on treatment, and 24% had sustained clearance of HCV RNA. Virological response was highest in patients with non-1 genotypes, CTP class A, and who achieved a full course of therapy. Eighty percent of patients rendered HCV RNA-negative by LADR who underwent liver transplantation remained free of HCV after transplantation. Our experience suggests that antiviral therapy in patients with advanced HCV may stabilize disease and reduce the risk of posttransplantation recurrence.
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