Hepatitis C

Educational Objectives

The goal of this program is to improve the management of hepatitis C. After hearing and assimilating this program, the clinician will be better able to:

1.   Recognize and modify, where applicable, factors that predict poor response to treatment of hepatitis C.

2.   Utilize recommended strategies for nonresponders to therapy.

3.   Distinguish the response patterns to treatment of hepatitis C and adjust therapy accordingly.

4.   Recognize that time to response is the most important variable in the treatment of hepatitis C.

5.   Discuss the 3 patterns seen in loss of response.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committe to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Davis has received research funding from Human Genome Sciences (HGS), Merck, Novartis, Roche, Schering-Plough, Tibotec, and Vertex. Dr. Shiffman is an investigator for Roche, Schering-Plough, Vertex, and Bio­lex, consults for Roche and Vertex, and is on the Speakers’ Bureau for Roche and Schering-Plough. The planning committee reported nothing to disclose.

Acknowledgements

Dr. Davis was recorded at the 33rd Annual Texas Program, held September 19-21, 2008, in Austin, TX, and spon­sored by the Texas Society for Gastroenterology and Endoscopy, the American College of Gastroenterology, and SGNA Texas Regional Societies. Dr. Shiffman was recorded at New Treatments in Chronic Liver Disease, held April 4-5, 2009, in San Diego, CA, and sponsored by the Scripps Clinic. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Treatment of Hepatitis C in Nonresponders

Gary L. Davis, MD, Director of Hepatology and Medical Director of Liver Transplantation, Baylor Health Care System and the Baylor Regional Transplant Institute, Dallas, TX

Strategies for nonresponders: optimize therapy during initial course to avoid treatment failure; develop rational in­dividualized strategy for retreatment of nonresponders; optimizing initial therapy  —  change factors that predict poor response; modify treatment for patients likely to have poor response; intensify treatment to achieve better re­sponse; factors that predict poor response  —  host factors include older age, advanced fibrosis, black ethnicity, poor compliance due to depression, substance abuse, difficult situations, obesity, and insulin resistance (IR; modifiable); viral factors (eg, genotype, viral load [VL])

Obesity: homeostasis model assessment (HOMA) score  —measure of IR; <2 normal; 61% of genotype 1 patients with normal IR respond to therapy; in mild to moderate IR, 40% response; in severe IR, only 20% respond to inter­feron (IFN) and ribavirin; reducing IR improves response to therapy; study showed that modest (10%) weight loss over 6-mo period reduced HOMA score significantly, with reductions seen in steatosis and fibrosis of liver; study  —   loss of 10% of body mass index (BMI) resulted in improved HOMA score (less IR) and improved sus­tained response rate (from 20%-60%); study  —increasing IFN dosage from 180 µg once weekly to 270 µg weekly increased response rate by 15% in patients with genotype 1, suggesting that obese patients have IFN resistance as well as IR; study  —  within each IFN dosage, higher doses of ribavirin resulted in higher response rates; 47% re­sponse rate seen in patients who received highest doses of IFN and ribavirin vs 28% rate with standard therapy

Slow responders: defined as patients with early virologic response (VR) and reduction in VL by 2-log₁₀ copies/mL (99%) but still virus-positive at 12 wk; by continuing standard-dose therapy for 48 wk, 15% to 30% response ob­tained, compared to those with virus-undetectable at 12 wk and 70% sustained VR (SVR); studies from Europe  —  standard dose of ribavirin 800 mg/day; no benefit from longer therapy if patients randomized at onset of treatment; if patients had rapid VR (RVR; virus undetectable at 4 wk) with treatment at that dose, therapy for 48 wk benefi­cial; if no RVR, continuation of therapy for 72 wk beneficial; only study in United States  —  standard dose of IFN (Schering) and standard weight-based dosing of ribavirin;  slow responders randomized to 48 or 72 wk; several pre­dictors of poor response in group (50% black; 80% with high VL; 25% with bridging fibrosis or cirrhosis; one-third obese; 20% with high fasting blood glucose); by extending therapy to 72 wk, SVR increased from 18% to 38%; achieved by decreasing relapse rate (almost 60% in patients treated for 48 wk); suggests that for slow responders, therapy should be extended to 72 wk

Optimizing initial therapy to avoid treatment failure: identify and correct factors (eg, depression, substance abuse) that hinder compliance; attempt weight loss in obese patient; optimize diabetes control; consider higher doses when appropriate; recognize slow responders and extend treatment to 72 wk

Strategies for nonresponders: retreatment with same regimen ineffective in true nonresponders, unless patient gen­otype 2 or 3; switching to different IFN ineffective; maintenance therapy also ineffective; effective strategies  —  optimizing dose and duration of therapy, particularly if underdosed during first treatment; avoiding unnecessary dose reduction; ensuring compliance (proactive treatment of side effects); utilizing higher doses of drugs; and try­ing new drugs; before retreatment, must know  —  type and dosage of previous treatment; genotype; VL; histology; whether dosing adequate; history of inappropriate dose responses and dose reductions; whether duration adequate; compliance with treatment; interfering habits (eg, alcohol); type of response

Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study: looked at maintenance therapy; in initial phase, retreated all nonresponders to verify status; found proportion of participants actually had SVR which correlated with initial type of treatment received; those treated initially with standard IFN alone had almost 30% response; with standard IFN and ribavirin, 20% response; if retreated with same regimen, 6% response; those who relapsed while on previous course of therapy had much better response to retreatment; effect of histology  —  patients (nonresponder and relapse group) with prefibrosis had much better response than patients with bridging fi­brosis or cirrhosis; effect of genotype  —  less response seen in patients with genotype 1; in patients with genotypes 2 and 3, even previous nonresponders to pegylated IFN (peg-IFN) and ribavirin, had 50% response to retreatment; suggests factors present in initial course of therapy possibly corrected with better compliance; patients with bridg­ing fibrosis and cirrhosis had lower response; patients virus-negative at end of treatment and relapse have greatest responses; those with no response at end of treatment, if virus-negative early in course of treatment, tended to have good response to retreatment; the later in course virus lost, the less the chance for response; if virus not reduced by 2 log₁₀ copies/mL in first course, chance of responding to retreatment low

Retreatment with PEgasys in pATients not responding to previous peg-IFN alfa-2b (12KDA)/ribavirin combi­nation therapy (REPEAT) study: 4 groups; first 2 groups had loading dose (induction therapy) with double dose of IFN for first 12 wk, then continued therapy for 48 wk or 72 wk with standard doses of IFN; all received weight-based ribavirin; group 3 received standard therapy, per labeling of IFN (control group); group 4 received longer therapy of 72 wk with standard-dose IFN and standard-dose ribavirin; end-of-treatment response same, regardless of whether induction therapy received; relapse rate and SVR also same (»15%); end-of-treatment response to stan­dard therapy same as that for longer therapy; higher relapse rate, with or without induction therapy; SVR decreased due to higher relapse rate; possible that when retreating nonresponders, longer therapy improves response, but re­sponse still low

New drugs: 2 major classes  —  protease inhibitors and polymerase inhibitors; viral protease  —  key enzyme; cleaves all nonstructural proteins necessary for replication; inhibits ability of infected cell to produce own IFN

Current Therapy for Hepatitus C

Mitchell Shiffman, MD, Chief, Hepatology Section, and Medical Director, Liver Transplant Program, Virginia Common­wealth University Medical Center, Richmond

Achieving SVR: 3 steps; 1) patient must achieve response (document); 2) once virus undetectable, response must be maintained; if patient breaks through and develops recurrent viremia at any time during therapy, response lost; check for virus periodically; 3) patient must not relapse; SVR function of VR minus breakthroughs, dropouts, and relapse; maximizing SVR requires maximizing response and limiting breakthroughs and dropouts

Response patterns: critical to recognize; RVR  —  hepatitus C virus (HCV) RNA or virus undetectable 4 wk after ini­tiation of therapy; highest SVR and lowest relapse rates; treated for shorter duration; complete early VR  —  virus-negative at wk 12; cure rate not as high as rapid responder; slow response  —  virus-undetectable by wk 24; 2-log₁₀ copies/mL drop by wk 12; must document that patient eventually virus-undetectable; important to differentiate slow responder from partial responder; partial response  —  2-log₁₀ copies/mL drop by wk 12, but virus plateaus and does not continue to fall; patient never becomes virus-undetectable; never had SVR and never virus-negative; do not treat >24 wk; important to recognize pattern to determine chances of achieving SVR

Genotype 1: RVR  —  seen in »15% of patients; expected SVR 90%; complete early VR  —  seen in one-third of geno­type 1 patients; SVR seen in two-thirds; slow responders  —  virus-negative at wk 24; 15% of genotype 1 patients; SVR 45%; chance of relapse higher than chance of achieving SVR; partial responders  —  15% of patients; no SVR; nonresponders  —  no 2-log₁₀ copies/mL drop, no early response; usually recognized by week 12; therapy should be discontinued

Genotypes 2 and 3: two-thirds have RVR, and SVR rate identical to what genotype 1 patients have when they achieve RVR (90%); slightly less than one-third have no RVR; virus undetectable by wk 12; if treated for only 24 wk, SVR only 49%; SVR of 49% identical to that obtained when genotype 1 patient who became virus-negative at wk 12 treated for only 24 wk; only 3% of patients with genotypes 2 or 3 never become virus-negative

Poor prognostic features: SVR rate decreased by black ethnicity, obesity, high VL, and cirrhosis; associated with slower responses; if patient with poor prognostic factor achieves RVR, cure rate as good as with RVR seen in all others

Retrospective data: »900 patients grouped by when HCV RNA became undetectable; first group (4 wk)  —  overall SVR rate »75% (dropouts removed); in obese patients (BMI >27), cure rate 77%; for whites, cure rate 76%, for blacks, 67%; with high VL, 71% SVR (78% with low VL); cirrhosis made no difference; all patients who achieved rapid response had similar SVR rates, regardless of baseline factors; second group (12 wk)  —  overall SVR 63% (obese, 59%; whites, 67%; blacks, 73%); third group (24 wk)  —  similar rates of SVR seen; conclusion  —  poor predictors shift response curve to right; reason for association with low SVRs is association with slower, partial, and non-responses

Time to response: most important; basis for modification of duration of therapy; slow responders  —  high relapse rate and poor SVR; therapy usually stopped at 6 mo; 5 published studies looking at extending therapy in slow re­sponders; study by Berg et al  —  all patients randomized to 48 wk or 72 wk of therapy at time of initiation of treat­ment; most patients receive no benefit from prolonged duration of treatment; inclusion of rapid responders and nonresponders in randomization washed out effect in group that does benefit from extended therapy; Sánchez-Tapias et al study  —  rapid responders excluded; showed improvement in SVR when therapy prolonged to 72 wk; Ferenci et al study  —  rapid responders and nonresponders excluded; randomized only those participants virus-negative between wk 12 and wk 24; studies show that extending therapy in slow responders improves SVR

A Study of Pegasys (peginterferon alfa-2a [40KD]) in Combination with Copegus (ribavirin) in interferon-naive patients with chronic hepatitis C infection (ACCELERATE) study: genotypes 2 and 3 patients virus-negative at wk 12 had SVR of 49%

Study by Hadziyannis et al:   genotypes 2 and 3 patients randomized to 24 wk or 48 wk, using different doses of rib­avirin; for non-RVR genotype 2 and 3 patients, highest SVR and lowest relapse rate (4%) seen in group treated for 48 wk with highest dose of ribavirin; group treated for 48 wk with lower dose of ribavirin had relapse rate of 13%; higher relapse rates (25%) seen in those treated for 24 wk; retrospective analysis suggests  —  extending therapy in genotypes 2 and 3 slow responders can reduce relapse rates, thus improving SVR

Reducing duration of therapy in rapid responders: genotypes 2 and 3 patients, most of whom were rapid respond­ers, treated for 24 wk; cure rate 90% (same as genotype 1 rapid responders); question of whether able to treat gen­otype 1 rapid responders for <48 wk; Hadziyannis data  —  rapid responders with genotype 1; with 24 wk of therapy, SVR 88% to 89%; with 48 wk, SVR 73%, but no relapse; all relapse rates low, suggesting that rapid responder re­quires only 24 wk of treatment; study by Ferenci  —  treated genotype 1 rapid responders for only 24 wk; overall, SVR rate 80% (72% with high VL); not much difference with fibrosis; European Union now recommends 24-wk therapy for genotype 1 rapid responders, except those with cirrhosis or high VL

Paradigm for treatment of hepatitis C  —  for complete early virologic responder (virus-negative at wk 12), optimal duration of therapy 48 wk; in most rapid responders, can compress therapy to 24 wk, with minimal risk for relapse; in slow responders virus-negative at 24 wk, duration of therapy extended to 72 wk to limit relapse

Individualized Dosing Efficacy vs flat dosing to Assess optimaL pegylated IFN therapy (IDEAL) study: com­pared peg-IFN alfa-2b (Peg-Intron) to peg-IFN alfa-2a (Pegasys); lower relapse rate with Peg-Intron response rates, SVR rates, and relapse rates identical to those seen in other studies; overall, SVRs identical; even lower doses of peg-IFN alfa-2b had excellent SVR rates; relapse rates higher in peg-IFN alfa-2a group; peg-IFN alfa-2a led to more virus-negative patients, but has higher relapse rate; time to response identical at wk 4; at wk 12, not statisti­cally different, but more late responses with peg-IFN alfa-2a; if late responder and duration of therapy not adjusted, relapse results

Null responders: no IFN responsiveness; able to determine in first 1 or 2 mo

Partial responders: sensitive to IFN; must intensify IFN dose; once patient virus-negative with intensified dose of IFN, therapy adjusted to achieve SVR

Patterns in loss of response: 3 patterns  —  relapse (viremia returns after treatment stopped); breakthrough (recurrent viremia while still in treatment); loss of response; in loss of response, patient initially responds, but some event causes patient to lose response; possible causes include unacceptable side effects, interruption of dosing, psychiat­ric issues, and severe anemia; measure VL frequently, so as not to miss patient who initially responds but loses re­sponse due to dose modification; if significant dose modification done, have patient return following month to recheck virus and ensure that response not lost; breakthroughs almost always due to missed doses (shown in study by Bronowicki)

HCV RNA assays: study showed that »1.5% of all assays contained errors; should be monitored frequently during treatment; allow recognition of VR sooner, encouraging patient to remain on treatment; also enable recognition of virologic nonresponse and loss of response sooner

Patients with cirrhosis: long-term follow-up of those who achieved SVR; those without SVR continued to have liver-related deaths over next 8 yr, while those who achieved SVR had significantly lower death rate; patients with SVR do not develop liver failure or complications of cirrhosis, although they still develop cancer; patients with SVR have identical risk of developing liver cancer 5 yr after being cured of hepatitis C, compared to patients who still have hepatitis C; screen for liver cancer twice yearly

Suggested Reading

Berg T et al: Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology 130:1086, 2006. Bronowicki JP et al: Effect of ribavirin in genotype 1 patient with hepati­tis C responding to pegylated interferon alfa-2a plus ribavirin. Gastroenterology 131:1040, 2006; Ferenci P et al: Austrian Hepa­titis Study Group. Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response. Gastroenterology 135:451, 2008; Hadziyannis SJ et al: Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 140:346, 2004. Herrine SK et al: Peginterferon alpha-2a combination therapies in chronic hepatitis C patients who relapsed after or had a viral break­through on therapy with standard interferon alpha-2b plus ribavirin: a pilot study of efficacy and safety. Dig Dis Sci 50:719, 2005; Hosogaya S et al: Analysis of prognostic factors in therapeutic responses to interferon in patients with chronic hepatitis C. Transl Res 148:79, 2006; Jensen DM et al: Re-treatment of patients with chronic hepatitis C who do not respond to peginterferon-alpha2b: a randomized trial. Ann Intern Med 21;150, 2009; Leevy CB: Consensus interferon and ribavirin in patients with chronic hepatitis C who were nonresponders to pegylated interferon alfa-2b and ribavirin. Dig Dis Sci 53:1961, 2008; Erratum in Dig Dis Sci 53:2009, 2008; Mathew A et al: Sustained viral response to pegylated interferon alpha-2b and ribavirin in chronic hepatitis C refractory to prior treatment. Dig Dis Sci 51:1956, 2006; Poynard T et al: Epic Study Group Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed interferon alfa/ribavirin therapy. Gastroenterology 136:1618, 2009; Sánchez-Tapias JM et al: Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology 131:451, 2006. Shiffman ML et al: ACCELERATE Investigators. Peginter­feron alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 12;357, 2007; Shiffman ML et al: Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C. Gastroenterology 132:103, 2007.