for Health Care Providers
Groups with Special Considerations for Therapy
Given the complexities of current therapies, treatment is more clearly indicated in some patients than in others. The following recommendations have taken into account the natural history of disease, the likelihood of achieving SVR, and the adverse effects and need for dose discontinuations with treatment.
Patients with Compensated Cirrhosis
For patients with advanced fibrosis or cirrhosis, the annual risk of decompensation or HCC is 4-6%. Good response to antiviral treatment is achievable, although patients with bridging fibrosis (stage III) or cirrhosis (stage IV) appear to respond less well to therapy than those with minimal or no fibrosis (13, 14) .
Even in the absence of viral clearance, interferon-based therapy appears to slow fibrosis progression (28, 29) . In patients with advanced fibrosis who failed standard treatment, maintenance doses of peginterferon alfa-2a at 90 mcg/wk and peginterferon alfa-2b at 0.5 mcg/kg/wk are under evaluation. Interim data from the ongoing COPILOT study reported a reduced risk of variceal bleeding and no worsening in Child-Pugh score by 2 points with peginterferon alfa-2b maintenance therapy after a median of ≥2 yr (30) .
RECOMMENDATIONS IN PATIENTS WITH CIRRHOSIS
1. Patients with compensated cirrhosis and adequate neutrophil (ANC >1.5 k/mm3) and platelet (>70 k/mm3) counts to tolerate therapy should be treated with peginterferon alfa plus ribavirin at standard doses (II-2).
2. In patients who do not achieve viral suppression with combination therapy, long-term maintenance therapy with low-dose peginterferon alfa may be considered on an individual basis (III).
Patients Who Have Failed to Respond or Have Relapsed with Prior HCV Therapy
Nonresponders or relapsers to standard interferon with or without ribavirin may be retreated with peginterferon alfa in combination with ribavirin. Currently, no therapy is FDA approved for patients who do not achieve SVR with peginterferon alfa and ribavirin. The decision to retreat should include consideration of the following factors: (1) prior drug regimen, (2) previous response achieved, (3) stage of fibrosis, (4) previous adherence to treatment, (5) tolerability and side effects with prior therapy, (6) infecting genotype, (7) pretreatment viral load, and (8) patient motivation.
For interferon nonresponders, 28% achieved SVR when retreated with peginterferon alfa and ribavirin for 48 wk. However in nonresponders to both interferon and ribavirin, only 10-15% achieved SVR when retreated with peginterferon alfa and ribavirin (31, 32) . Response is better in retreatment of relapsers, with SVR occurring in 39-47% (31, 32) . Failure to achieve an EVR was a predictor of nonresponse with continued therapy in patients retreated with peginterferon alfa-2a or alfa-2b and ribavirin, and early treatment discontinuation should be considered (33) .
Peginterferon alfa and ribavirin nonresponders rarely benefit from retreatment with the same agents unless treatment doses or adherence can be improved. If retreatment is undertaken in patients previously intolerant of ribavirin or peginterferon alfa, adjunctive therapy with epoetin or granulocyte colony stimulating factor (GCSF) may be considered (section "Growth Factors"). In patients undergoing retreatment who demonstrate viral response, the duration should be at least 48 wk regardless of genotype. Current practice suggests variations in treatment for this group. Studies of consensus interferon and studies of high doses and different durations of peginterferon alfa and ribavirin are currently underway (34) . Patients with advanced fibrosis may be considered for maintenance therapy (section "Patients with Compensated Cirrhosis").
RECOMMENDATIONS IN NONRESPONDERS AND RELAPSERS
1. For nonresponders and relapsers to interferon with or without ribavirin, retreatment with peginterferon alfa and ribavirin should be considered on an individual basis (II-1).
2. For nonresponders and relapsers to peginterferon alfa plus ribavirin, retreatment with peginterferon alfa and ribavirin may be considered only if substantial improvements in treatment dose or adherence can be made (III).
3. If retreatment is undertaken, the duration is at least 48 wk in those who demonstrate viral response on therapy (III).
Patients with Minimal Histologic Evidence of Liver Disease
Patients with grade 1 inflammation and minimal fibrosis are at low risk for developing advanced liver disease. After a thorough discussion of prognosis and treatment options, the physician and patient may agree to observation without treatment. Liver biopsy may be repeated in 3-5 yr if results would change management. Treatment should be reconsidered if the liver disease has progressed. Treatment should also be provided to patients, despite minimal fibrosis, who desire treatment and/or who have significant symptoms. Patients with extrahepatic manifestations of HCV infection should be considered for HCV therapy, regardless of the severity of their liver disease. In patients with genotype 2 or 3 infection, the high SVR may shift the risk-benefit ratio in favor of treatment even for those with minimal histologic disease (35) .
RECOMMENDATIONS IN PATIENTS WITH MILD DISEASE
1. Treatment should be deferred in patients with minimal inflammation and/or minimal portal fibrosis on liver biopsy, unless the patient elects to undergo therapy with a goal of viral eradication (III).
2. If treatment is deferred, liver biopsy may be repeated in 3-5 yr if results would change management (III).
3. In patients with histological evidence of disease progression, treatment should be considered (III).
Patients with Persistently Normal Serum ALT
Approximately 30% of patients with chronic HCV have persistently normal serum ALT levels. However, up to 20% of patients with normal ALT levels have bridging fibrosis or cirrhosis (36) . Therefore, laboratory evaluation alone without liver biopsy cannot reliably differentiate between "mild disease" and those with more advanced fibrosis. Patients with proven minimal or no fibrosis on liver biopsy may be reassured about their favorable prognosis, and they may choose to defer therapy; those with more than stage I fibrosis should be advised to consider treatment. SVR with peginterferon alfa and ribavirin in patients with persistently normal ALT levels was similar to those with elevated serum ALT levels (37) .
For patients with genotype 2 or 3 infection, SVR with peginterferon alfa plus ribavirin therapy is high; these patients may elect to undergo therapy regardless of stage of disease and thus, obviate the need for liver biopsy.
RECOMMENDATIONS IN PATIENTS WITH NORMAL ALT
1. Liver biopsy to stage fibrosis should be performed prior to starting treatment regardless of ALT level, especially in patients with genotype 1 infection (III).
2. Treatment should be considered in patients with more than portal fibrosis on liver biopsy, regardless of ALT values (I).
Patients with Genotype 4-6 Infections
In patients with genotype 4 infection, higher SVR (79%) was achieved with peginterferon alfa-2a plus ribavirin 1,000 or 1,200 mg/day for 48 wk than with other regimens with shorter treatment durations (67%), lower ribavirin doses (63%), or peginterferon alfa-2a monotherapy (44%) (38, 39) . Similarly, high SVR was demonstrated with 36 or 48 wk of treatment with peginterferon alfa-2b and ribavirin in genotype 4-infected patients (SVR 66% and 69%, respectively) (40) . Insufficient clinical trial data are available in HCV genotype 5 and 6 infections to make recommendations about optimal regimens at this time.
RECOMMENDATION IN PATIENTS WITH HCV GENOTYPE 4 INFECTION
1. Appropriate candidates should be treated with peginterferon alfa-2a 180 mcg/wk or peginterferon alfa-2b 1.5 mcg/kg/wk plus ribavirin 1,000 or 1,200 mg/day for 48 wk (I).
Patients >65 Yr and/or with Significant Comorbidities
Age alone should not preclude antiviral therapy. Before treatment is undertaken in patients >65-yr-old and/or in those with significant concomitant medical conditions (Table 3), careful consideration to initiating therapy should be given in light of reduced life expectancy. If life expectancy is estimated to be shortened by these comorbidities, and particularly if there is the potential for adversely affecting these medical conditions with peginterferon plus ribavirin, treatment should be deferred.
RECOMMENDATIONS IN PATIENTS >65 YR AND/OR WITH COMORBID CONDITIONS
1. In patients with limited life expectancy from significant comorbid conditions, antiviral therapy should be deferred (III).
2. In patients with significant comorbid conditions that will be exacerbated by peginterferon alfa and ribavirin, treatment should be deferred (III).
3. In otherwise healthy patients, treatment should be considered regardless of age (III).
Patients on Methadone Maintenance
Prior or ongoing injection drug users comprise the largest group of individuals with chronic HCV in the United States. Peginterferon alfa and ribavirin treatment has been evaluated in chronic HCV patients on methadone maintenance (41, 42) . Although higher treatment discontinuation rates occurred in methadone patients, SVR was similar in methadone patients who completed a full course of therapy compared with those not on methadone. Side effects and antidepressant use were similar in methadone patients compared with control group.
RECOMMENDATIONS FOR PATIENTS ON METHODONE
1. Patients with ongoing injection drug use should be referred to a substance use specialist and reevaluated for HCV treatment at a later date (III).
2. Antiviral therapy should be offered to patients enrolled in a methadone maintenance program who meet criteria for therapy (II-1).
3. HCV treatment should be coordinated with substance abuse specialists (III).
Patients with Ongoing Alcohol Use
Alcohol is an important cofactor in the progression of HCV disease to cirrhosis and HCC (43) . Thus, patients with hepatitis C should limit or abstain from alcohol consumption. Limited data suggest that heavy alcohol consumption of >80 g/day (approximately eight drinks or more per day) reduces HCV treatment response. It is unknown whether consuming less alcohol compromises HCV treatment response (44) . In patients with recent alcohol consumption, there were higher treatment discontinuation rates; however, in those who completed HCV therapy, SVR was similar in drinkers and nondrinkers (45) . Thus, alcohol users should not be excluded from antiviral therapy but treatment adherence should be stressed (9) .
RECOMMENDATIONS IN PATIENTS WITH ONGOING ALCOHOL USE
1. Patients should be encouraged to decrease consumption or to abstain (III).
2. Patients should be referred for behavioral intervention to reduce alcohol use (III).
3. Antiviral therapy should be offered to patients regardless of prior alcohol use who otherwise meet criteria for therapy (II-2).
4. Alcohol consumption should be discouraged during antiviral treatment, because alcohol reduces adherence and treatment response (III).
African Americans have lower response rates to peginterferon alfa and ribavirin than Caucasians (17, 19) . In one study of genotype 1 patients treated with peginterferon alfa-2b plus ribavirin for 48 wk, SVR occurred in 19% of African Americans and 52% of Caucasians (17) . In another study of genotype 1 patients treated with peginterferon alfa-2a plus ribavirin for 48 wk, SVR occurred in 26% of African Americans and 39% of Caucasians. Side effects were similar except for a higher incidence of neutropenia in African Americans, but this was not associated with increased risk of infection (19) .
RECOMMENDATION IN AFRICAN AMERICANS
1. Antiviral therapy should be offered to patients regardless of race (III).
Patients with Body Mass Index >30 and Hepatic Steatosis
In RCTs of peginterferon alfa plus ribavirin, increased body weight was associated with decreased antiviral response (13, 14) . Reasons for reduced response in obese patients are likely multifactorial. Obesity results in steatosis of the liver, which is associated with increased risk of fibrosis and decreased antiviral efficacy (46, 47) .
Hepatic steatosis is often associated with metabolic syndromes (e.g., insulin resistance/diabetes mellitus, hypertriglyceridemia) and with HCV genotype 3 infection (26) . Metabolic disorders should be managed aggressively prior to interferon therapy, in part because interferon can aggravate these underlying medical conditions. Lifestyle changes (e.g., exercise and weight loss) should be recommended as adjuncts to antiviral therapy. Even modest weight loss (5.9 kg) has been shown to decrease hepatic steatosis (48) .
RECOMMENDATIONS IN OBESE PATIENTS AND THOSE WITH HEPATIC STEATOSIS
1. Patients with a BMI >30 should be considered for antiviral treatment (III).
2. Comorbid conditions common in obese patients such as diabetes, hypertension, and hyperlipidemia should be well controlled prior to initiation of antiviral therapy (III).
Patients with HIV/HCV Coinfection
All patients with HIV should be tested for and counseled about HCV. Conversely, those with HCV infection should also be offered HIV testing and counseling. Patients infected with both HIV and HCV may be at greater risk for liver disease progression than those with HCV infection alone, and thus the need for treatment of these individuals is high.
Three RCTs have demonstrated the superiority of peginterferon alfa plus ribavirin compared with interferon plus ribavirin for 48 wk in HIV/HCV coinfected patients (49, 50, 51) . SVR was lower in this population than those reported in HCV-monoinfected patients, particularly for those with genotype 1 infection.
Peginterferon alfa-2a (180 mcg/wk) plus ribavirin (800 mg/day) is FDA-approved for this indication (52) . However, HCV therapy is contraindicated in cirrhotic patients with a Child-Pugh score ≥6 (53) . For genotype 1 patients coinfected with HIV, ribavirin dosing of 1,000-1,200 mg/day should be attempted because inadequate ribavirin doses likely contributed to lower observed SVR (49, 50, 51) . Side effects including cytopenias are more common in HIV/HCV coinfected patients. For more information, see Management and Treatment of Hepatitis C Viral infection in HIV-infected Adults: Recommendations from the Veterans Affairs Hepatitis C Resource Program and National Hepatitis C Program Office (54) .
RECOMMENDATIONS IN PATIENTS WITH HIV/HCV COINFECTION
1. Patients with controlled HIV infection and evidence of liver disease on biopsy should be considered for HCV antiviral therapy (III).
2. Patients should be treated with peginterferon alfa and ribavirin at doses similar to those with HCV monoinfection (III).
3. Patients should be treated with peginterferon alfa and ribavirin for at least 48 wk, regardless of genotype (III).
4. Concomitant use of didanosine (ddI) and ribavirin should be avoided (II-3).
5. Cytopenias related to HCV treatment are more common, and may require erythropoietin and granulocyte colony stimulating growth factors in order to continue therapy (III).
6. HIV/HCV coinfected patients with cirrhosis and a Child-Pugh score ≥6 should not receive HCV antiviral therapy (II-3).
Patients with Renal Disease including Hemodialysis
The prevalence of HCV antibodies in patients on chronic hemodialysis is 8.6% (55) and HCV infection is an independent risk factor for death in this population (56) . Although interferon is contraindicated following kidney transplantation because of an increased risk of rejection, HCV therapy should be attempted in patients with end-stage renal disease who are being considered for transplantation.
Case series of interferon monotherapy in dialysis patients had an overall SVR of 33%, with SVR of 26% in genotype 1 patients (57) . The role of peginterferon alfa in dialysis patients is being defined. A single dose study of peginterferon alfa-2a in chronic hemodialysis revealed no added toxicity but clearance was reduced by 30% (58) . In hemodialysis patients, peginterferon alfa-2b at 0.5 mcg/kg and 1.0 mcg/kg has been safely used, with the higher dose showing improved EVR but with increased side effects (59) .
Both peginterferon alfa-2a and alfa-2b should be used cautiously when the creatinine clearance is <50 mL/min and doses should be renally adjusted (Table 5) (12, 60) . Ribavirin is contraindicated when the creatinine clearance is <50 mL/min (11, 61) . Virologic relapse and side effects are common with antiviral therapy in hemodialysis patients. Patients should be monitored closely for toxicity.
RECOMMENDATIONS IN PATIENTS WITH RENAL DISEASE
1. Patients should be considered for antiviral therapy with peginterferon alfa at doses modified for renal disease (Table 5) (II-2).
2. Ribavirin should be avoided with a creatinine clearance <50 mL/min (II-3).
Patients with Acute Hepatitis C
Acute HCV infection is rarely identified clinically because infection is asymptomatic in 85% of cases. Yet, treatment in the acutely infected patient is highly effective in preventing persistent infection (62) . Studies of treatment for acute HCV infection have been limited.
If spontaneous viral clearance occurs, it is usually within the first few weeks of exposure. Several studies that delayed treatment for 12 wk after diagnosis did not appear to adversely affect SVR. This approach unnecessarily avoids therapy in those who would resolve spontaneously (63, 64) . Studies with peginterferon alfa or interferon alfa monotherapy for 24 wk have resulted in SVR of 80-100%, suggesting that treatment duration may be shorter than for those with chronic HCV infection. Two small studies have suggested that ribavirin did not significantly augment treatment response in the acute setting (65, 66) .
RECOMMENDATIONS IN PATIENTS WITH ACUTE HCV INFECTION
1. Patients should be observed for a period of 8-12 wk from time of initial exposure in order to monitor for spontaneous resolution of infection (III).
2. For those who fail to resolve infection spontaneously, treatment should be initiated with peginterferon alfa alone for 24 wk, regardless of genotype (II-1).
Patients with Decompensated Cirrhosis
Once clinical complications of cirrhosis develop (e.g., gastroesophageal bleeding, ascites, encephalopathy, jaundice, HCC), liver transplantation is the treatment of choice. In general, HCV therapy is contraindicated in this population because of increased risk for life-threatening bacterial infection and further hepatic decompensation. One large case series from a single center reported using a low, accelerating dose regimen (LADR) of standard interferon and ribavirin in 102 patients (67) . SVR was achieved in 11% and 50% of those with genotype 1 and genotype 2/3 infections, respectively (67) .
In 2003, an expert panel proposed that patients with HCV cirrhosis and a Child-Pugh score ≤7 and MELD score ≤18 should be considered for antiviral therapy. However, in those with Child-Pugh scores >11 or MELD scores >25, treatment is contraindicated. Those with intermediate scores should be considered on a case-by-case basis (68) . Treatment-naïve patients with favorable predictors of response such as genotype 2 or 3 infection should be considered for therapy with low Child-Pugh and MELD scores, despite a history of clinical complications of liver disease. In those with genotype 1 infection, the risk-benefit ratio is lower, since the likelihood of viral clearance with therapy is less. Given the limited safety experience of antiviral therapy in patients with hepatic decompensation, treatment should only be undertaken in centers with specialized expertise. If peginterferon alfa is administered, it should be initiated at a reduced dose, with extremely close follow-up and with early use of growth factors to manage treatment-associated cytopenias. Ribavirin, if administered, should be initiated at reduced doses particularly if there is underlying renal insufficiency but is contraindicated if the clearance creatinine is <50 mL/min.
RECOMMENDATIONS IN PATIENTS WITH DECOMPENSATED CIRRHOSIS
1. Liver transplantation is the optimal treatment in patients with decompensated cirrhosis (II-3).
2. Antiviral therapy is contraindicated in most patients with decompensated cirrhosis (II-3).
3. Interferon-based therapy in combination with ribavirin may be considered in patients awaiting liver transplantation with a Child-Pugh score ≤7 and a MELD score ≤18 (II-1).
4. If antiviral therapy is undertaken, reduced interferon doses should be used and growth factors should be given to counteract treatment-associated cytopenias (III).
Patients with a History of Solid Organ Transplantation
In general, interferon therapy is contraindicated in renal, cardiac, or pulmonary transplant recipients because of an increased risk of severe allograft rejection. However, HCV infection is considered an absolute contraindication to transplantation for certain solid organs, such as heart and lung. Thus, eradication of HCV infection in patients who are otherwise good candidates for solid organ transplantation may enhance transplant candidacy.
After liver transplantation for HCV-related disease, graft reinfection is virtually universal. Patients with more than stage I fibrosis on liver histology from recurrent HCV disease may be considered for antiviral therapy under the guidance of a transplant specialist. Limited data suggest that treatment response in liver allograft recipients is lower than in immunocompetent individuals (69, 70, 71, 72) . Overall SVR was approximately 20-30% with peginterferon alfa with or without ribavirin for 48 wk; however, SVR may be somewhat higher with genotype 2 or 3 infection (70, 72) . Dose reductions for cytopenias are common and early growth factor support is often necessary. If antiviral therapy is initiated, reduced interferon and ribavirin doses should be used with incremental increases until a tolerable dose is reached (72) . Based on small case series, the incidence of acute cellular rejection associated with peginterferon alfa appears higher than for standard interferon, and patients must be closely monitored and immunosuppression maintained (73) . The optimal treatment regimen remains to be defined.
RECOMMENDATIONS IN PATIENTS FOLLOWING SOLID ORGAN TRANSPLANTATION
1. Interferon-based antiviral therapy is contraindicated following heart, lung, or kidney transplantation (II-3).
2. In patients with biopsy-proven chronic HCV disease following liver transplantation, antiviral therapy with peginterferon alfa and ribavirin for 48 wk may be considered (II-1).
3. If treatment is given following liver transplantation, peginterferon alfa and ribavirin should be initiated at reduced doses (II-3).
4. Toxicities of antiviral therapy in liver transplant recipients should be managed with frequent monitoring, dose reductions, and growth factor support (III).
5. Liver transplant recipients on antiviral therapy should be monitored closely for evidence of rejection and antiviral therapy should be stopped if rejection is documented (II-3).
6. Preemptive antiviral therapy early posttransplantation in patients without histological recurrence should be avoided (II-3).