HEPATITIS C VIRUS
| PREDICTING SUSTAINED VIROLOGIC RESPONSE —F. Fred Poordad, MD, Assistant Professor of Medicine,
and Chief, Hepatology and Liver Transplantation, David Geffen School of Medicine at the University of California,
Los Angeles
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| Background: Hadziyannis (2004)—set standard for use of 800 mg ribavirin for 6 mo as treatment of hepatitis C virus
(HCV) genotypes 2 and 3 (HCV-2; HCV-3); Zeuzem (2004)—used peginterferon alfa-2b (PEG-IFN alfa-2b)
1.5 µg/kg with weight-based dosing of ribavirin up to 1400 mg daily; 90% response rate with HCV-2, and 80% response
rate with HCV-3; patients with HCV-2 and high viral load (VL) or low VL responded well (90%); HCV-3
and low VL responded well; HCV-3 with high VL had poorer response (70%); higher doses of ribavirin provide
better response rates; HCV-3, particularly with high VL, does not respond as well (23% relapse rate); difficulty appears
related to high VL, not to steatosis associated with HCV-3
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| Rapid virologic response (RVR): 12-wk stopping rule for HCV genotype 1 (HCV-1); however, many patients with
HCV-2 or HCV-3 lose virus quickly and become HCV-negative by week 4 of treatment
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 | Dalgard et al (2004): looked at whether patients could be treated for shorter period to save money and reduce side
effects; patients who cleared HCV-2 and HCV-3 in 4 wk and 8 wk treated for 14 wk; control group treated with
PEG-IFN alfa-2b with weight-based ribavirin at 800 to 1400 mg for 24 wk; overall, 80% responded; patients
clearing virus at 4 wk or 8 wk had sustained virologic response (SVR) of 90%; patients with end-of-treatment response
but still viremic at 4 wk and 8 wk had 56% SVR; slow responders do not respond well, even at 24 wk; regardless
of VL, HCV-2 has 90% response rate; HCV-3 with high VL does not do as well as HCV-3 with low VL;
results statistically significant (P=0.019); standard for high VL depends on assay, ie, 600,000 IU/mL or 800,000
IU/mL
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| Mangia et al (2005): looked at truncating therapy to 12 wk for HCV-2 and HCV-3; group A (control)—70 patients;
received 1.0 µg/kg PEG-IFN alfa-2b (standard dose usually 1.5 µg/kg), with ribavirin at 1000 or 1200 mg daily for
24 wk; group B (experimental)—200 patients received PEG-IFN alfa-2b dose of 1.0 µg/kg with ribavirin at 1000
mg or 1200 mg daily; patients qualitatively polymerase chain reaction (PCR)-negative at 4 wk received 12 wk of
therapy; patients qualitatively PCR-positive at 4 wk received 24 wk of therapy; results—78% overall response
rate; patients with HCV-2 did better than those with HCV-3; comparable response rates for patients treated for 12
or 24 wk; 85% SVR with 12 wk of therapy if PCR qualitatively zero at 4 wk of therapy; if PCR qualitatively positive
at 4 wk, treatment for 12 or 24 wk produced overall SVR of 60%; relatively slow responders do not respond
nearly as well to 24 wk of therapy; limitations—novel dose of interferon; small study size; benefits—relapse rate
10%, even in 12-wk group; need to retreat only 1 of 10 patients big cost savings; two thirds of patients achieved
RVR; caveat—few cirrhotic patients, so results may not apply to patients with cirrhosis
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| Combined data sets: HCV-2 patients who cleared virus at 4 wk and were treated for 12 wk achieved 85% SVR; if
RNA-positive at 4 wk and treated for 24 wk, SVR 73%; HCV-3 patients RNA-negative at 4 wk and treated for
12 to 14 wk had 85% SVR; HCV-2 and HCV-3 behave identically if cleared quickly; HCV-3 patients RNA-positive
at 4 wk and treated for 24 wk have 50% overall response rate; will treating slow-responding HCV-3 patients for
>6 mo improve their SVR rates? data conflicting, large prospective study required; conclusion—rapid responders
clear virus regardless of genotype, even with truncated therapy
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| Treatment in clinical settings: treat conservatively; check 4-wk PCR; if virus cleared at 4 wk and therapy difficult for
patient, can stop or reduce dose at 12 to 14 wk
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| PEG-IFN alfa-2a (Pegasys) plus ribavirin (study): looked at outcome of 16 vs 24 wk of treatment in HCV-2 and
HCV-3 patients; used standard PEG-IFN alfa-2a dose plus 800 mg ribavirin; patients randomized to 16 or 24 wk of
therapy; results—intention-to-treat analysis showed 16-wk treatment resulted in 62% SVR; 24-wk treatment resulted
in 70% SVR; truncating therapy did not work, even in rapid responders; results not understood; speculation
that ribavirin 800 mg not as good as weight-based dosing; 16 wk not long enough to achieve steady state using
PEG-IFN alfa-2a; relapse rates—30% in 16-wk arm, 20% in 24-wk arm (compared to 10% at 12 wk in Mangia
study); conclusion—decline in SVR due to higher relapse rate
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| PEG-IFN alfa-2b plus ribavirin in HCV-1: is 24 wk of therapy in HCV-1 patients with low VL adequate? 5 previous
studies found that one third of 5000 patients with HCV-1 had low VL (<600,000 IU/mL); Zeuzem et al (2000)—
control patients treated with PEG-IFN alfa-2b with weight-based dosing of ribavirin, treated for 48 wk; experimental
group—received PEG-IFN alfa-2b 1.5 µg with 800 to 1400 mg ribavirin; all patients treatment-naive with HCV-1
and low VL; data do not apply to cirrhotic or HIV-coinfected patients; results—end-of-treatment response 80% at
24 wk, relapse rate 30%, and SVR 50%; however, patients with RVR (ie, those clearing virus at 4 wk), had 90%
SVR at 24 wk of therapy; so rapid clearance, even in HCV-1, means cure imminent and truncation of therapy possible;
relapse rate 8% in rapid responders; in patients not PCR-negative at 4 wk, relapse rate 75% with truncated therapy;
truncating therapy works only if PCR negative at 4 wk; occurred 50% of time in this study, so could
conceivably shorten treatment 50% of time in HCV-1 patients with low VL
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| Hadziyannis data set: retrospective study; 24 wk vs 48 wk, 800 mg (low dose) ribavirin vs 1200 mg (standard dose);
if HCV-1 patients cleared virus by 4 wk, 24 wk of therapy as good as 48 wk; patients with very low VL (<200,000
IU/mL) benefited most from shortened therapy; 20% of patients had RVR
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| Speaker’s suggestions: check qualitative PCR in all genotypes at 4 wk to determine positive predictability of clearing
virus; can then safely truncate therapy if necessary; HCV-3 with high VL possibly needs >24 wk of therapy; extending
therapy in slow-responding HCV-1 leads to better SVR and lower relapse rates
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| RULES FOR TREATMENT SUCCESS— Mitchell L. Shiffman, MD, Chief, Hepatology Section, and Medical Director,
Liver Transplant Program, Virginia Commonwealth University Medical Center, Richmond
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| Rules for success: patient who does not achieve virologic response certainly cannot achieve SVR; important to characterize
and monitor HCV RNA over time; adverse events of unanticipated severity may affect or necessitate dose
modification or early termination; however, this does not preclude treatment success during current or subsequent
treatment
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| RVR pattern: virus undetectable within 4 wk of initiating therapy; patients have 90% SVR, regardless of interferon
type or whether ribavirin utilized; must monitor HCV RNA for 4 wk to recognize; can modify therapy, even with
adverse events; occurs in 10% to 15% of patients with HCV-1
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| Response patterns: early virologic response (EVR)— drop in HCV RNA of ≥2 log units within first 12 wk of therapy;
capable of becoming virus-negative and attaining SVR; if EVR not achieved by wk 12, therapy may be discontinued;
2 types of nonresponders—1) null responders; no significant decline in HCV RNA; do not achieve EVR;
stop therapy once null response recognized (usually at wk 12); 2) partial responders; have initial EVR within 12
wk, then response diminishes; if not virus-negative by wk 24, they will not become virus-negative; stop therapy
at this point; insufficient to monitor patients on interferon-only therapy at wk 12 (cannot ascertain true response
pattern); breakthrough—patient becomes negative, but virus reappears while therapy continues; in speaker’s experience,
due to dose modifications or interruptions, especially with peginterferon
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| Treatment response by genotype: HCV-1—null response, 19%; partial response, 10% to 20%; EVR, 81%, two
thirds of whom become virus-negative; SVR, 40% to 45%; HCV-2 or HCV-3—null response, 3%; RVR, 66%;
EVR, 97%, and of these, 92% become virus-negative; SVR, 76%
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| Why patients fail therapy
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| Inherent resistance to interferon: results in null response; “interferon switch broken”; interferon binds to receptor,
but virus eradication does not occur; more common in blacks and accounts for their lower SVR; insufficient data
to determine whether higher doses of interferon more effective
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| Noncompliance: patient—does not take correct dose; frequently misses doses; consumes alcohol or uses illicit narcotics;
misses appointments
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| Adverse events result in stopping therapy: must balance treatment effects with ability to achieve SVR; side effects
include flu-like symptoms, myalgias, arthralgias, and anemia (due to ribavirin)
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| Adverse events result in markedly reducing dose: adherence effect (McHutchinson et al)—taking <80% of PEG-IFN
alfa-2b and/or <80% of ribavirin, for 80% of time (36 wk) resulted in SVR drop from 51% to 34%; if dose reduction
occurred early in treatment (within first 12 wk), marked reduction in SVR from 62% to 34%; dose reduction
occurring later resulted in less significant impact on SVR (62% to 51%); limitations of data—did not analyze impact
of reducing peginterferon separately from ribavirin; did not evaluate variable degrees of peginterferon and
ribavirin dose reduction; did not investigate possibility of period when dose of peginterferon and/or ribavirin
could be reduced without affecting SVR; did not evaluate impact of dose reduction on virologic response and relapse;
speaker calculates patient cannot achieve less than 80%/80%/80% by reducing dose, only by missing
doses; recent study by Ready et al (manuscript in preparation)—reducing dose of ribavirin does not affect end-of-
treatment virologic response (SVR), but SVR significantly reduced when patients miss several doses
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| Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial: 936 nonresponders with HCV-1;
during lead-in phase, patients treated with PEG-IFN alfa-2b plus ribavirin for 24 wk; in virus-negative patients
treatment continued to 48 wk; reducing interferon reduces virologic response; reducing ribavirin does not reduce
virologic response until treatment stopped; SVR not possible unless virologic response present; when interferon
reduced, SVR not achieved because of lack of initial virologic response; reducing ribavirin has no impact on
SVR; stopping medication results in no SVR, causing relapse; lumping data (as in McHutchinson analysis) can
lead to wrong conclusion
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| Monitoring response: if HCV RNA not monitored at regular intervals or for long enough time, cannot determine
whether patient is relapser or partial responder; monitoring schedule—for HCV-1, measure at baseline, at wk 4 to
check for EVR, then monthly until patient virus-negative; once negative, no need to document unless dose modified,
then look for breakthrough; repeat test at wk 48; document SVR or relapse at wk 72; stop measuring when
EVR achieved; for HCV-2, same schedule; want to know if patient rapid responder (two thirds are); document response
(or lack thereof), then measure for relapse; severe adverse events (eg, anemia)—when result in temporary
suspension of treatment early, do not restart treatment until adverse events addressed; relapse—later the patient becomes
virus-negative, lower the chance of achieving SVR and higher the chance of relapse; patients who become
virus-negative late in treatment may need longer treatment to prevent relapse; SVR combination of ability to respond
(driven by interferon) and ability to prevent relapse; reduce relapse rate by using higher (weight-based) dose
of ribavirin and by increasing duration of therapy; can therapy be reduced in HCV-2 patients? depending on study,
shortening therapy (from 24 to 16 wk), even in patients with RVR, can increase or double relapse rate
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| Summary: patients with RVR require less intense therapy and still achieve SVR; monitoring HCV RNA at regular intervals
until undetectable identifies patients capable and not capable of responding; reducing ribavirin dose does
not affect SVR, as long as patient remains on full dose of PEG-IFN alfa-2a and ribavirin not stopped (can reduce
dose after patient virus-negative but cannot stop); patients with late response have high relapse rate (overcome by
prolonging treatment); relapse can be reduced by using higher ribavirin dose; reduced duration of treatment in
HCV-2 or HCV-3 patients not likely to yield similar SVR as standard 24-wk duration
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Educational Objectives
| The purpose of this program is to provide the listener with information on management of hepatitis C. After hearing
and assimilating this program, the clinician will be better able to:
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| 1. Describe the differences between a rapid virologic response and a sustained virologic response.
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| 2. Summarize the treatment regimens for hepatitis C genotypes 1, 2, and 3 using peginterferon with ribavirin.
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| 3. Identify response patterns in patients being treated for hepatitis C.
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| 4. Discuss why patients fail therapy.
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| 5. Summarize mechanisms for maximizing sustained virologic response.
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Discussed on This Program
Ribavirin [Copegus, Rebetol, Ribaspheres, Ribatab, Virazole]
Peginterferon alfa-2a [Pegasys]
Peginterferon alfa-2a with ribavirin [Copegus]
Peginterferon alfa-2b [PEG-Intronl]
Suggested Reading
Aberle, JH et al: Prospective study of viral clearance and CD4(+) T-cell response in acute hepatitis C primary infection
and reinfection. J Clin Virol 36:24, 2006; Castillo I et al: Hepatitis C virus replicates in the liver of patients who
have a sustained response to antiviral treatment. Clin Infect Dis 43:1277, 2006; Dalgard O, Mangia A: Short-term
therapy for patients with hepatitis C virus genotype 2 or 3 infection. Drugs 66:1807, 2006; Ferenci P: Pegylated interferon
plus ribavirin for chronic hepatitis C: the role of combination therapy today, tomorrow and in the future. Minerva
Gastroenterol Dietol 52:157, 2006; Ferenci P et al: Randomized, double-blind, placebo-controlled study of
peginterferon alfa-2a (40KD) plus ribavirin with or without amantadine in treatment-naive patients with chronic hepatitis
C genotype 1 infection. J Hepatol 44:275, 2006; Helbling G et al: HCV-related advanced fibrosis/cirrhosis: randomized
controlled trial of pegylated interferon alpha-2a and ribavirin. J Viral Hepat 13:762, 2006; Homoncik, M et
al: Erythropoietin treatment is associated with more severe thrombocytopenia in patients with chronic hepatitis C undergoing
antiviral therapy. Am J Gastroenterol 101:2275, 2006; Hung, CH et al: Anemia associated with antiviral
therapy in chronic hepatitis C: incidence, risk factors, and impact on treatment response. Liver Int 26:1079, 2006;
Jensen, DM et al: Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40
kd)/ribavirin therapy Hepatology 43:1410, 2006; Lai AR et al: Antiretroviral Medication Considerations for Individuals
Coinfected with HIV and Hepatitis C Virus. AIDS Patient Care STDS 20:678, 2006; McHutchison JG et al: A randomized,
double-blind, placebo-controlled dose-escalation trial of merimepodib (VX-497) and interferon-alpha in
previously untreated patients with chronic hepatitis C. Antivir Ther 10:635, 2005; Morishima C et al: HCV RNA detection
by TMA during the hepatitis C antiviral long-term treatment against cirrhosis (Halt-C) trial. Hepatology
44:360, 2006; Narasimhan G et al: Treatment rates in patients with chronic hepatitis C after liver biopsy. J Viral
Hepa. 13:783, 2006; Oze T et al: Early decline of hemoglobin correlates with progression of ribavirin-induced
hemolytic anemia during interferon plus ribavirin combination therapy in patients with chronic hepatitis C. J Gastroenterol
41:862, 2006; Pockros PJ et al: The safety and tolerability of daily infergen plus ribavirin in the treatment of
naive chronic hepatitis C patients. J Viral Hepat 10:55, 2003; Schwarz, KB et al: Safety, efficacy and pharmacokinetics
of peginterferon alpha2a (40 kd) in children with chronic hepatitis C. J Pediatr Gastroenterol Nutr 43:499, 2006;
Sethi A, Shiffman ML: Approach to the management of patients with chronic hepatitis C who failed to achieve sustained
virologic response. Clin Liver Dis 9:453, 2005; Shiffman ML: Chronic hepatitis C: treatment of pegylated interferon/ribavirin
nonresponders. Curr Gastroenterol Rep 8:46, 2006; Shiffman ML, Rustgi VK: Use of ribavirin in
patients with chronic HCV genotype 1: when enough is really enough. Gastroenterology 131:1339, 2006; Trepo C et
al: Viral hepatitis. Curr Opin Infect Dis 12:481, 1999; Yee HS et al: Management and treatment of hepatitis C viral infection:
recommendations from the department of veterans affairs hepatitis C resource center program and the national
hepatitis C program office. Am J Gastroenterol 101:2360, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue, Dr.
Poordad has disclosed that he is a consultant for Schering-Plough, Roche, Bristol-Myers Squibb, Gilead, and Valeant
Pharmaceutical International. Dr. Shiffman has disclosed that he is a consultant for Schering-Plough, Roche, and Valeant
Pharmaceutical International.
Dr. Poordad addressed the 7th Annual Update in Gastroenterology, held September 15-17, 2006 in Napa, CA, and
sponsored by Cedars-Sinai Medical Center, Los Angeles. Dr. Shiffman addressed New Treatments in Chronic Liver
Disease, held April 1-2, 2006, in La Jolla, CA, and sponsored by the Scripps Clinic, San Diego. The Audio-Digest
Foundation thanks the speakers, Cedars-Sinai Medical Center, and the Scripps Clinic for their cooperation in the production
of this program.
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