Treatment of Chronic Hepatitis C with Interferon:Historical perspectives and the data Todd M. Hulgan, MD Internal Medicine Resident Grand Rounds
Case presentation • HPI: 38yo WM; new pt. visit for BP check and DOT exam. Only c/o mild chronic intermittent low back pain, relieved with NSAIDs. • PMH: h/o “hepatitis C” dx 5-6 yrs ago. No f/u, no hospitalizations, no surgeries.
Case presentation • Meds: occasional OTC ibuprofen. • ALL: NKDA • SH: 30 pack-yr smoker; rare EtOH use socially; commercial truck driver; married; denies promiscuous hetero- or homosexual contacts; no IVDA; no transfusions. • FH: unremarkable.
Case presentation • ROS: essentially negative; denies fatigue, wt. loss, N/V, abd. pain, fever, jaundice. • Exam:T 988, HR 90, BP 140/92, wt 111kg. Obese, pleasant WM; not jaundiced. Exam unremarkable. No hepatomegaly. No other stigmata of acute or chronic liver disease.
Case presentation • Labs: Electrolytes wnl alk phos 144 (nl 39-117) AST 87 (nl 0-37) ALT 70 (nl 0-36) • Hepatitis C Ab positive by EIA.
Clinical Questions • Should all patients with hepatitis C and elevated LFTs be referred for treatment with interferon? • If not, who should be offered treatment and what factors determine this? • What benefits are expected with treatment?
Objectives • To examine and summarize the recent consensus statements and guidelines related to treatment of chronic hepatitis C. • To review the history of hepatitis C and its treatment. • To identify specific areas of controversy regarding treatment of HCV. • To look closely at key clinical trial data related to treatment of chronic hepatitis C. • To draw conclusions from this data.
NIH Consensus Development Conference Panel Statement, September 1997Hepatology; 26 (supplement): 2S-10S. • Prevalence in U.S. of 1.5% in non-hispanic whites, 3.2% in blacks, 2.1% in hispanics. • Approximately 4 million Americans infected. • Primarily parenteral transmission. • Chronic hepatitis develops in about 85%. • Progression to cirrhosis in about 20% of these patients within two decades. • Probably 1-5% HCC risk after two decades.
NIH Consensus Statement (cont’d) • “Based on [serum ALT and HCV RNA by PCR], randomized clinical trials have demonstrated that treatment with interferon alfa benefits some patients with chronic hepatitis C.” • Initial dose: 3 MU subcutaneously 3x/week for 12 months. • “…important factors associated with a favorable response to treatment include HCV genotype 2 or 3, low serum HCV RNA level (<1,000,000 copies/ml), and absence of cirrhosis.” • “It is appropriate that a percutaneous liver biopsy specimen be obtained before initiating therapy with interferon...” • “Current studies suggest that treatment of patients with persistently normal ALT is not beneficial…”
NIH Consensus Statement (cont’d) • “Treatment is recommended for the group of patients…who are at greatest risk for progression to cirrhosis. These patients are characterized by persistently elevated ALT, positive HCV RNA, and a liver biopsy with either portal or bridging fibrosis and at least moderate degrees of inflammation and necrosis.” • “It should be recognized that although interferon treatment may be associated with favorable effects on biochemical and virological markers, its effects on important clinical outcomes such as quality of life and disease progression remain undetermined.”
The Early Years... • 1975: Non A-non B hepatitis first described by Feinstone, et al.. • Few clinical trials for several years. • 1982: Response of the intrinsic interferon (IFN) system to viral hepatitis described. • 1985: Small prospective study of acyclovir by Hoofnagle, et al..
1986: Preliminary study of IFN for NANB hepatitisHoofnagle, et al. NEJM; 315: 1575-8 • 10 pts with chronic NANB hepatitis. • Variable dosing with IFN alfa-2b for variable length of therapy. • 8/10 pts had mean ALT decrease of 206 u/L, mean AST decrease of 76 u/L. • 3 patients had repeat biopsies showing histologic improvement. • No post-treatment follow up. • Concluded that IFN caused prompt improvement in aminotransferase levels and histology; RCTs needed. • Study supported by Schering Corporation.
The Late 1980s: The breakthrough... • Early 1989: NANB hepatitis organism isolated and cloned. • First assay for circulating antibody developed. • New name unveiled: Hepatitis C. • November, 1989: First large RCTs published simultaneously in New England Journal of Medicine.
November, 1989: The first RCTsDavis, et al., N Engl J Med; 321: 1501-6. • Prospective, multicenter RCT. Not placebo controlled. • 166 pts; post-transfusion, elevated ALT x 1 yr, + liver biopsy (86% of pts subsequently tested were HCV Ab positive). • 3 treatment arms: - 3 MU IFN alfa-2b TIW x 24 weeks (58 pts) - 1 MU IFN alfa-2b TIW x 24 weeks (57 pts) - No treatment (51 pts) • Follow up varied; 2 - 46 weeks after treatment. • Main outcomes were ALT levels, liver histology, and relapses after treatment.
November, 1989: The first RCTsDavis, et al., N Engl J Med; 321: 1501-6. • Results: Complete response (normal ALT at week 24): 3 MU group 22/58 (38%) 1 MU group 9/57 (16%); p=0.01 untreated group 2/51 (4%); p=0.001 - NNT with 3 MU IFN vs. no treatment to achieve complete response at week 24 = 3. - Histologic improvement in 52% of 3 MU group vs. 29% of 1 MU group, but histological and biochemical response did not correlate. - 48 % had biochemical relapse by mean f/u of 17 wks.
November, 1989: The first RCTsDavis, et al., N Engl J Med; 321: 1501-6.
November, 1989: The first RCTsDavis, et al., N Engl J Med; 321: 1501-6. Study validity: • Strengths - large size; good randomization with equal distribution of variables; intention to treat (ITT) analysis; biopsy comparisons blinded. - Lack of placebo probably did not affect outcomes measured. • Weaknesses - Almost 15% of pts HCV Ab negative (should be accounted for by adequate randomization). - ? significance of “near-complete” responders. - ? clinical importance of outcomes. - Supported by Schering-Plough (???).
November, 1989: The first RCTsDavis, et al., N Engl J Med; 321: 1501-6. • Conclusions: - A six-month course of IFN alfa at 3 MU TIW was well tolerated and induced significant biochemical and histological improvement in about half of patients treated. - Almost half of the responders relapsed rapidly after treatment was stopped. - “…the effects of interferon therapy on viral replication, infectivity, and the long-term natural history of chronic hepatitis C remain to be defined.”
November, 1989: The first RCTsDiBisceglie, et al., N Engl J Med; 321: 1506-10. • Prospective, dbl-blinded, placebo-controlled RCT. • 41 pts; h/o blood product exposure, ALT 2x nl for 2 years, + liver biopsy. (90% subsequently HCV AB +) • 22% hepatitis Bs or core Ab positive. • 2 groups: - 1 MU IFN alfa-2b QD x 1wk, then 2 MU TIW x 23 wks. - placebo injections by same schedule. • Follow up for at least 6 months after treatment. • Outcomes were ALT levels during and after treatment, histology, side effects, and pre-treatment predictors of response.
November, 1989: The first RCTsDiBisceglie, et al., N Engl J Med; 321: 1506-10. • Results: - 33% of treated patients had normal ALT levels at end of treatment. - Data presented as “average percent change”: 62% decrease in ALT in treated group vs. 22% in placebo (p=0.0002). - Numerical data on placebo pts with ALT normalization not given. - Only 2/21 treated pts (10%) had normal ALT levels at 6 months. - Significant improvement in “piecemeal necrosis” and “current hepatic injury” in treatment group over placebo group (p=0.01). - Side effects of IFN were “usually mild.” There were significant differences in fatigue, wt. loss, decreased WBC and platelets in IFN group vs. placebo. - Patients with higher pre-treatment ALTs were less likely to have complete response.
November, 1989: The first RCTsDiBisceglie, et al., N Engl J Med; 321: 1506-10.
November, 1989: The first RCTsDiBisceglie, et al., N Engl J Med; 321: 1506-10. Study Validity: • Strengths - Well designed; adequate blindedness; ITT analysis. • Weaknesses - Small size. - 10% HCV Ab negative. - >20% with prior HBV exposure. - Significantly lower pre-treatment ALTs in IFN group. - Placebo data not stated; unable to calculate NNT. - ? Clinical importance of endpoints. - Supported by Schering-Plough.
November, 1989: The first RCTsDiBisceglie, et al., N Engl J Med; 321: 1506-10. • Conclusions: - IFN alfa at 2 MU TIW for 6 months decreased ALT levels in 1/3 of pts treated. - Benefits in the majority of pts were transient. - Some histologic parameters were improved at the end of treatment. - Pts with higher pre-treatment ALTs were less likely to respond to IFN. - “Future studies should focus on higher doses...given for longer periods.”
The early 1990s:The door opens... • HCV Ab makes diagnosis possible. • First meta-analysis of RCTs published in early 1991. • Epidemiologic and natural history data begin to emerge. • February, 1991: FDA approves IFN alfa-2b for treatment of chronic HCV (3MU TIW for 6 months). • Placebo-controlled trials end.
Natural History • Seeff, et al., N Eng J Med 1992; 327: 1906-11 - Retrospective study of >1500 post-transfusion pts from 1970s. - 568 patients with NANB hepatitis and two control groups. - 18 yr follow up for all-cause and liver mortality. All-cause mortality: Liver mortality: hepatitis group 51% 3.3% control group 1 52% 1.1% control group 2 50% 2.0%
1992-1997:Questions (and answers ?) abound... • 1992: PCR for HCV RNA described as quantitative measure of viral activity. • 1993: Lau, et al. (Lancet;341:1501-4.) note correlation between lower RNA levels and treatment response. • RCTs proliferate; new questions and controversies arise...
1992-1997:Questions (and answers ?) abound... • What is the optimum dose and duration of interferon therapy? - Originallyapproved by the FDA at 3 MU SC TIW for 6 months. - March, 1997: Recommended length of treatment increased to 12 to 24 months. - Appears unlikely that higher doses give better response, but possibly longer duration?
1992-1997:Questions (and answers ?) abound... • What type of interferon is most effective? - At least seven types of IFN have been prospectively evaluated: alfa-2b; 2a; 2c; n1; n3; beta; and consensus IFN. - Only alfa-2b and 2a approved for use in the U.S. - Large controlled trials with consensus interferon near completion; next to be approved? - There appears to be no significant difference in efficacy between formulations.
1992-1997:Questions (and answers ?) abound... • Are there reliable pre-treatment predictors of response? - Higher pre-treatment ALT and RNA levels, HCV genotype 1, and presence of cirrhosis are all associated with poor response to treatment. - According to most recent guidelines, only advanced or decompensated cirrhosis is an absolute contraindication to treatment.
1992-1997:Questions (and answers ?) abound... • What is the best method for following treatment response? - ALT levels most accessible and least expensive. - Spontaneous fluctuations within course of the infection common. - Questionable correlation with HCV RNA levels and histological response. - Is it worth the cost of serial RNA measurements and/or the risk of multiple biopsies to have potentially more accurate measures of response?
1992-1997:Questions (and answers ?) abound... • Should patients with relapses or previous non-responders be re-treated? - RCTs have shown that patients who initially responded to IFN then relapsed are more likely to have a second response to re-treatment than non-responders. - No definite recommendations at this time.
1992-1997:Questions (and answers ?) abound... • Does treatment have any impact on long-term morbidity and/or mortality? - The most important question remains glaringly unanswered (perhaps unanswerable?). It certainly seems reasonable to assume that biochemical, virological, and histological endpoints would correlate with more important clinical outcomes, but where data is lacking, the individual clinician must decide at what cost these assumptions can be made.
1995: RCTs of dose and durationPoynard, et al., N Engl J Med; 332: 1457-62 • Prospective, blinded RCT. • 329 consecutive pts with NANB hepatitis; elevated ALT x 1yr; + liver biopsy (88% subsequently tested HCV Ab +). • All pts treated for 6 months with 3 MU TIW x 6 months; 303 then randomized to 3 treatment arms: - Group 1: 3 MU TIW for 12 more months (103 pts). - Group 2: 1 MU TIW for 12 more months (101 pts). - Group 3: No further treatment (complex protocol for pts in this group with elevated ALT for 3 consecutive months; most of these were re-treated with initial regimen). • Followed for a total of 2 yrs after treatment.
1995: RCTs of dose and durationPoynard, et al., N Engl J Med; 332: 1457-62 • Outcomes were ALT levels and repeat biopsies. • Results: nl ALT @ 18 mo@ 2 yrsimproved histology Group 145% 22% 70% Group 2 27% (p=.08) 10% (p=.02) 48% (p=.02) Group 3 30% (p=.04) 8% (p=.005) 39% (p<.001) (31 and 22 patients dropped out of groups 1 and 2, respectively) - NNT with 3MU for 18 months vs. 6 months to have one pt with a normal ALT at 18 months = 7. - NNT to have one pt with a normal ALT at 2 yrs = 7. - NNT to have one pt with improved histologic-activity index on repeat biopsy at 18 months = 3.
1995: RCTs of dose and durationPoynard, et al., N Engl J Med; 332: 1457-62
1995: RCTs of dose and durationPoynard, et al., N Engl J Med; 332: 1457-62 Study validity: • Strengths -Large, multicenter study; good randomization. - Reasons for drop-outs clearly stated and ITT analysis used. • Weaknesses - > 10 % HCV Ab negative. - Difficult to discern what happened to untreated group, but ITT analysis should keep these variables from affecting outcomes measured. - Again, ? clinical significance of outcomes. - Supported by Schering-Plough.
1995: RCTs of dose and durationPoynard, et al., N Engl J Med; 332: 1457-62 • Conclusions: - Pts treated with 3 MU for 18 months were more likely to have biochemical and histological improvement both at 18 months and 2 yrs after treatment over those treated with a lower dose or shorter duration. - “Serum ALT responses were significantly associated with histological improvement, but we do not believe this association was strong enough to justify its use in clinical practice….We believe a repeated liver biopsy is required to assess the efficacy of treatment with interferon.”
1995: RCTs of dose and durationLin, et al., J Hepatology; 23: 487-96. • Prospective, multicenter, open-label RCT. • 230 patients with elevated ALT (or AST in 29 pts) x 6 months; + liver biopsy; all pts HCV Ab +. • Randomized to 3 treatment arms: Group a: 3 MU IFN alfa-2b TIW x 6 months (72 pts). Group b: 5 MU TIW x 6 months (75 pts). Group c: 3 MU TIW x 2 years (80 pts; 40 completed trial). • Follow up for 6 months after treatment ended. • Outcomes were ALT/AST levels at end of treatment and 6 months, relapses, and histology.
1995: RCTs of dose and durationLin, et al., J Hepatology; 23: 487-96. • Results: short-term responselong-term response Group a 61% 20% Group b 64% 17% - NNT with 5 MU vs. 3 MU for 6 months to achieve one more short-term or long-term response = 33. - IFN dose had no significant effect on histological improvement. - There was no significant difference in adverse events/drop outs in 3 MU group vs. 5 MU group. • Conclusion: A 6 month course of therapy with 5 MU IFN did not improve short or longer-term biochemical or histological responses over treatment with 3 MU.
1995: RCTs of dose and durationLin, et al., J Hepatology; 23: 487-96.
1995: RCTs of dose and durationLin, et al., J Hepatology; 23: 487-96. Study validity: • Strengths - Large, multicenter, RCT. - Methodology clearly outlined; good randomization. - ITT analysis. • Weaknesses - Large number of drop-outs in 2 year treatment group led to analysis of variable lengths of treatment. Data difficult to interpret. Should not have affected comparisons between first two groups, however. - Supported by Schering-Plough.
1992-1997:Questions (and answers ?) abound... • Also in 1995, DiBisceglie, et al. published a RCT of 29 HCVAb + pts treated with either ribavirin or placebo for 12 months. - 35% of treated patients had short-term ALT improvement vs. none of the placebo group; no decreases in HCV RNA levels; only 7% had sustained response. - They concluded that ribavirin alone was unlikely to be of benefit; based on earlier preliminary trials and several abstracts, there was enthusiasm that combination therapy may increase response rates. • This era of HCV research culminated with the findings and recommendations of the consensus panel published in late 1997.
1998: The future begins…Ribavirin and interferon Reichard, et al., Lancet; 351: 83-87. • First large RCT of combination therapy. • 100 consecutive patients with HCV Ab; +HCV RNA; elevated ALT; +liver biopsy. • Randomized to 2 groups: 1. IFN 3 MU TIW x 6 months 2. IFN + ribavirin 1000-1200mg daily x 6 months • Follow up at 24 and 48 weeks after treatment. • Primary endpoint was sustained virological response (SR); i.e. undetectable RNA levels.
1998: The future begins…Ribavirin and interferon Reichard, et al., cont’d • Results: combination groupIFN alone virological SR 36% 18% ( p= 0.047) - NNT with combination therapy vs. IFN alone to achieve one virological SR = 5-6. - Biochemical SR was increased; p= 0.057, NNT= 5 - End of treatment responses were not different. - Pts with high RNA levels ( >3 x 10 6 Eq/ml) were more likely to have SR with combination therapy than with IFN alone; 41% vs. 4%, p= 0.009, NNT= 3.
1998: The future begins…Ribavirin and interferon Reichard, et al., cont’d • Conclusions: - More patients treated with IFN + ribavirin for 24 weeks had virological SR than those treated with IFN alone. - This benefit was greatest in the subset of patients with higher pre-treatment viral RNA levels. - ETRs were not different, suggesting ribavirin may affect rates of relapse after treatment is stopped. - Combination therapy was associated with more treatment drop-outs and adverse effects. - “The question of whether a SR predicts an improved long-term prognosis has not been answered.”
1998: The future begins…Ribavirin and interferon Reichard, et al., cont’d Study validity: • Strengths - Methodologically sound; good randomization; equal treatment of groups outside of intervention. - Adequate blindedness at all points. - ITT analysis makes larger number of drop-outs in treatment group unlikely to have affected outcomes/results. - ? RNA levels more clinically applicable endpoint. • Weaknesses - ? Supported by grant from Schering-Plough.
1998: The future begins…Ribavirin and interferon • November, 1998: The largest RCT of HCV treatment to date published in NEJM by McHutchinson, et al. and the Hepatitis Interventional Therapy Group. - Over 900 pts randomized to either IFN alone for 24 or 48 wks or IFN + ribavirin for 24 or 48 wks. - The results confirmed those of Reichard, et al. - Combination therapy resulted in significantly higher rates of virological SR than IFN alone at both lengths of therapy, with p < 0.001 for both comparisons. - NNT with IFN + ribavirin for 24 wks vs. IFN alone to achieve one virological SR = 5.
Conclusions, take home points, and what to tell my patient... • About 8 out of 10 pts with HCV infection will develop chronic hepatitis as defined by elevated LFTs and/or histologic changes. • Chronic HCV usually has a prolonged course. • About 20% with chronic HCV will progress to cirrhosis over a period of time probably not less than two decades. • It is not clear that overall mortality is increased. • Interferon has been studied extensively as a treatment for chronic HCV.
Conclusions, take home points, and what to tell my patient... • Treatment with IFN alfa-2b at 3 MU TIW for at least 12 months normalizes ALT levels in about half of patients. • Less than half of these will have a sustained response 6 months to 2 years after treatment. • IFN also improves liver histology, but less is known about sustained response. • Increasing the length of therapy, but probably not the dose, improves response rates.
Conclusions, take home points, and what to tell my patient... • Adding ribavirin to IFN increases sustained responses, especially in those pts with higher viral RNA levels. • A liver biopsy is recommended before initiating treatment. Advanced cirrhosis is the only absolute contraindication to treatment. • ALT levels are the most commonly used measure of treatment response, but viral RNA levels may be a more accurate (and more expensive) marker. • Genotype and RNA levels are predictors of response, but not contraindications to therapy.