Chronic Hepatitis C Virus Management: 2000-2005 Update

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Chronic Hepatitis C Virus Management: 2000-2005 Update A. ; D. Shafran Ann Pharmacother.  2006;40(1):74-82.  ©2006 Harvey Whitney Books CompanyPosted 02/09/2006Abstract and IntroductionAbstractObjective: To review recent advances that have significantly changed the management of chronic hepatitis C virus (HCV) infection.Data Sources: A MEDLINE search (2000-July 2005) was conducted using key words such as hepatitis C, interferon, pegylated interferon, and therapy.Study Selection and Data Extraction: All articles pertaining to treatment of chronic HCV infection were identified. Studies evaluating HCV treatment in treatment-naive patients were considered for this review.Data Synthesis: Over the past several years, response to treatment for chronic HCV infection has significantly improved with the use of pegylated interferon and ribavirin therapy. Treatment response is influenced by HCV genotype and viral load, as well as patient-related factors, including adherence.Conclusions: Treatment of chronic HCV infection has improved, with overall response rates of approximately 55%. Identification and management of common adverse effects is important in maximizing adherence and response to therapy. Studies are needed to further delineate the optimum treatment of chronic HCV infection in specific patient populations.IntroductionHepatitis C virus (HCV) infection is the most common chronic blood-borne infection, with an estimated 170 million people infected worldwide.[1] Approximately 20% of patients with chronic HCV infection progress to cirrhosis after an average of 20 years, and 5% will develop hepatocellular carcinoma.[2-4] In the US, approximately 3 million people are chronically infected, and HCV infection is the leading cause of liver transplantation.[1,5] Mortality due to chronic HCV infection is expected to increase two- to threefold over the next 10-20 years. Thus, HCV infection is considered a major public health problem.The primary goal of therapy for chronic HCV infection is viral eradication. This is known as a sustained virologic response (SVR) and is defined as the absence of detectable HCV RNA in the serum using a sensitive qualitative HCV RNA assay 6 months following the completion of therapy.[6-8] Studies of combination therapy with interferon (IFN) alfa and ribavirin demonstrated SVRs of approximately 40%.[9-11] In recent years, there have been significant advances in the management of chronic HCV infection, including the introduction of pegylated IFN (PEG-IFN). Two forms of PEG-IFN, alfa-2a and alfa-2b, have been approved for HCV treatment. Although they differ in their pharmacologic properties, both possess an increased and sustained duration of activity due to longer serum half-lives than conventional IFN alfa.[12-14] PEG-IFN alfa-2b has a larger volume of distribution and faster clearance than PEG-IFN alfa-2a; plasma levels are dependent on body weight.[12,14] For this reason, PEG-IFN alfa-2b is administered at a dose of 1.5 µg/kg subcutaneously once weekly (when used in combination with ribavirin), whereas PEG-IFN alfa-2a is given at a fixed dose of 180 µg/wk subcutaneously. PEG-IFN alfa-2b is partially renally cleared; therefore, dosage adjustments are recommended by the manufacturer in patients with a creatinine clearance less than 50 mL/min.[15]Overall SVRs of 25-40% were achieved in PEG-IFN monotherapy studies.[16-19] Combination therapy with PEG-IFN and ribavirin yields higher response rates, with eradication of the virus in more than half of treated patients.[20-22] HCV genotype has been shown to be the single most important predictor of treatment response. There are 6 major HCV genotypes, with genotype 1 the most common in the US (70% of patients).[23] The prevalence of genotypes 2 and 3 is approximately 5% and 20%, respectively. Genotype 4 has a low prevalence in the US (<1%) and is mainly found in the Middle East and North Africa. Genotypes 5 and 6 are rarely seen outside isolated geographic areas in South Africa (genotype 5) and Southeast Asia (genotype 6).[24]In this article, we review recently published literature on the management of chronic HCV infection in treatment-naïve patients. A computerized search of MEDLINE was performed (2000-July 2005) using the following key words: hepatitis C, interferon, pegylated interferon, and therapy. All relevant articles that focused on antiviral treatment of chronic HCV infection in adults were included. We excluded data on treatment of acute HCV infection, HCV reinfection of transplanted livers, and coinfection with HIV or hepatitis B virus.Pegylated Interferon and Ribavirin Therapy in Treatment-Naïve PatientsEfficacy and Predictors of ResponseCombination therapy with PEG-IFN and ribavirin represents the standard of care for chronic HCV infection based on the results of 3 pivotal trials ( Table 1 ). The first 2 studies were designed to demonstrate the superiority of PEG-IFN over standard IFN when used in combination with ribavirin.[25,26] Manns et al.[25] also attempted to evaluate the effects of different ribavirin doses by randomizing patients to receive low-dose PEG-IFN/high-dose ribavirin and high-dose PEG-IFN/low-dose ribavirin treatment regimens. Both studies used the Food and Drug Administration-approved schedule of standard IFN alfa-2b and ribavirin (1000 mg/day for patients ≤75 kg, 1200 mg/day for patients >75 kg) as the comparator. Inclusion criteria were similar: biopsy-proven chronic hepatitis, HCV RNA-positive, and elevated serum alanine aminotransferase. Patients with decompensated cirrhosis, contraindications to therapy, and comorbid conditions were excluded.In the study by Manns et al.,[25] the highest overall SVR (intent-to-treat analysis) was seen in the higher-dose PEG-IFN arm. The response in the higher-dose PEG-IFN alfa-2b arm was comparable to the SVR with PEG-IFN alfa-2a plus ribavirin (54% and 56%, respectively). In both trials, SVR was dependent on genotype, with higher rates seen in genotype 2 or 3 compared with genotype 1.[25,26] The benefit of PEG-IFN over IFN alfa-2b was not seen in patients infected with HCV genotype 2 or 3 in the study by Manns et al.[25]; however, a higher SVR was noted in the standard IFN control arm in this study (79%) compared with the control arm in the study by Fried et al.[26] (61%). Aside from genotype, pretreatment variables associated with higher SVRs included lower baseline viral loads, younger age, lower body weight, and less liver fibrosis.[25,26]The attempt to evaluate the effects of different ribavirin doses by Manns et al.[25] was confounded by the use of different PEG-IFN doses. Secondary analyses of the data were performed and found higher SVRs in all groups when the dose of ribavirin was greater than 10.6 mg/kg body weight (ie, patients who weighed <75 kg). The observed response rate increased as ribavirin dose increased, up to about 13 mg/kg; between 13 and 15 mg/kg, the response rate was flat. Thus, based on these 2 studies,[25,26] it appears that the 2 forms of PEG-IFN have similar SVRs when combined with ribavirin; however, it is important to note that the dose of ribavirin used differed. In the absence of head-to-head trials, it is not possible to draw definitive conclusions regarding equivalence.Early Virologic Response. Manns et al.[25] noted that SVR was unlikely in patients with late viral clearance (>24 wk after the start of treatment). et al.[27] retrospectively analyzed the data from this study to determine a definition of early virologic response (EVR) that best excluded patients who would fail to achieve SVR. They determined that the "best" definition of EVR was at least a 2-log10 decrease in HCV RNA or polymerase chain reaction (PCR) negative by 12 weeks, irrespective of viral genotype. This definition had a negative predictive value of 100%; however, the positive predictive value was only 72%. This may be explained by the fact that SVR was lower in patients who had a 2-log10 decrease in the HCV RNA level, but remained PCR positive (15/72 [21%]), than in patients who had HCV RNA undetectable by PCR after 12 weeks (258/308 [84%]). Further analysis of the patients who achieved at least a 2-log10 decrease in HCV RNA at 12 weeks but remained PCR positive demonstrated that those who were PCR positive after 24 weeks had a low likelihood of achieving SVR.Based on these results, et al.[27] recommend an algorithm to test for EVR to identify patients unlikely to achieve SVR. For patients infected with genotype 1, EVR should be assessed at week 12 by quantitative HCV RNA. Testing for EVR in patients infected with HCV genotype 2 or 3 is not beneficial, as almost all such patients achieve EVR, and SVR occurs in most cases. A qualitative HCV RNA test at 24 weeks is necessary only in genotype 1 patients who achieve at least a 2-log10 decrease in HCV RNA at 12 weeks, but remain PCR positive. If the 24-week PCR remains positive, treatment can be discontinued, as the likelihood of achieving SVR is about 1%.Effect of Treatment Duration and Ribavirin Dose. The optimal length of combination therapy was not addressed in the studies performed by Manns et al.[25] and Fried et al.,[26] in which all patients were treated for 48 weeks. Previous studies of standard IFN alfa plus ribavirin demonstrated comparable SVRs with 24 and 48 weeks of treatment in patients infected with HCV genotypes 2 and 3.[9,10,28] An open-label trial of PEG-IFN alfa-2b 1.5 µg/kg once weekly and ribavirin for 24 weeks in genotype 2- and 3-infected patients[29] found an SVR comparable (81%) to that seen in the study by Manns et al.[25] Patients were treated with ribavirin 800-1400 mg/day based on body weight (<65 kg, 800 mg/day; 65-85 kg, 1000 mg/day; 86-105 kg, 1200 mg/day; >105 kg, 1400 mg/day).[29] This study also demonstrated that EVR predicts SVR. The SVR in patients infected with genotype 2 or 3 who had undetectable serum HCV RNA after 4 weeks of therapy was 94% and 85%, respectively.A randomized, double-blind trial was designed to assess differences in SVR in patients treated for 24 or 48 weeks with PEG-IFN alfa-2a in combination with either a low dose or standard weight-based dose of ribavirin.[30] Patients were stratified by HCV genotype (1 vs all non-1) and viral load (≤2 × 106 copies/mL vs >2 × 106 copies/mL). In genotype 1 patients, the highest SVR was seen in patients treated for a longer duration (48 wk) with the standard weight-based dose of ribavirin; this effect was independent of the pretreatment viral load. In patients with genotype 2 or 3, the SVRs were very high, regardless of the duration of therapy or ribavirin dosage.Given the high SVR achievable in patients with genotype 2 or 3, investigators have studied whether a treatment duration less than 24 weeks would be equally effective. In a noncontrolled, multicenter pilot study, 122 patients infected with HCV genotype 2 or 3 received PEG-IFN alfa-2b 1.5 µg/kg once weekly and ribavirin (800-1400 mg/day based on body weight).[31] Treatment was stopped at week 14 in patients with EVR (defined as undetectable HCV RNA at weeks 4 and 8). Patients who failed to achieve EVR were assigned to complete 24 weeks of treatment. A total of 95 (78%) patients achieved EVR and were treated for 14 weeks, while 27 (22%) were treated for 24 weeks. In the 14-week treatment group, 85 (90%) patients achieved SVR compared with 15 (56%) patients treated for 24 weeks. Overall, 100 (82%) patients achieved SVR. The absence of bridging fibrosis or cirrhosis was the only independent predictor of SVR; however, liver biopsy was unavailable in approximately one-quarter of patients.Mangia et al.[32] recently published a randomized study in patients with HCV genotype 2 or 3 that compared standard 24-week treatment consisting of PEG-IFN alfa-2b 1.0 µg/kg once weekly plus ribavirin (1000-1200 mg/day based on body weight) with a variable-duration regimen. Patients were assigned to a standard-duration group and a variable-duration group in a 1:3 ratio. For patients randomized to the variable-duration group, therapy was continued for 12 weeks in those with virologic response at 4 weeks (defined as undetectable HCV RNA) and for 24 weeks in those who did not achieve virologic response at 4 weeks. Forty-five (64%) patients in the standard-duration arm and 133 (62%) patients in the variable-duration arm had undetectable HCV RNA at week 4. There was no significant difference between the groups in terms of SVR (76% and 77% in the standard- and variable-duration arms, respectively). Not surprisingly, fewer patients in the variable-duration group who received the 12-week regimen withdrew from therapy due to adverse effects compared with the group treated for 24 weeks (p = 0.045). The above data suggest that patients with HCV genotype 2 or 3 and undetectable HCV RNA after 4 weeks of treatment achieve high response rates with 12 weeks of PEG-IFN and ribavirin therapy. Unfortunately, Mangia et al. used a lower dose of PEG-IFN alfa-2b and a higher dose of ribavirin than is recommended by current treatment guidelines[6-8] for this patient population. Nonetheless, these 2 studies suggest that an even shorter course of therapy (ie, <24 wk) for HCV genotype 2- or 3-infected patients who have an early response may be a strategy adopted in the near future.Effect of Adherence and Dose Maintenance. The importance of adherence to anti-HCV therapy and dose maintenance of IFN/PEG-IFN and ribavirin to maximize SVR rates has become more apparent.[33] A retrospective analysis of data from 3 randomized trials of IFN alfa-2b or PEG-IFN alfa-2b plus ribavirin[9,10,25] was undertaken to evaluate the effect of adherence on SVR.[34] The amount of each drug administered was determined by review of drug dispensing/return records and patient dosing diaries. Patients were separated into 2 groups for the analysis: (1) patients who received 80% or more of both the total IFN and ribavirin doses and who were treated for 80% or more of the expected duration of therapy and (2) patients who received reduced doses (<80% of one or both drugs for ≥80% of the expected duration of therapy). Patients who withdrew early from the study were excluded from the analysis.Higher SVRs were seen in patients who received 80% or more of both the total IFN and ribavirin doses compared with those who received less than 80% of the dose of one or both drugs. In the subset of patients who received PEG-IFN alfa-2b 1.5 µg/kg weekly plus weight-based ribavirin (>10.6 mg/kg/day), adherence of at least 80% increased the SVR to 72% compared with 57% in those with less than 80% adherence. The impact of adherence was most apparent in patients with genotype 1, with a significantly higher SVR in those with greater adherence (63% vs 34%). Although patients who received less than 80% of one or both drugs for less than 80% of the duration of treatment were excluded from further analysis, it was reported that these patients had very low SVRs (<25%). The main reason for poor adherence to therapy was reported to be adverse effects.[34]In a retrospective analysis of the study by Manns et al.,[25] dose maintenance was closely associated with the likelihood of achieving EVR.[27] Dose reductions of ribavirin or PEG-IFN to less than 80% of the prescribed dose during the first 12 weeks of therapy were common (~20% of patients). A decrease of either ribavirin alone or PEG-IFN alone reduced the chances of EVR compared with those who received full doses (60% and 70%, respectively, vs 80%), although the differences were not significant. Dose reduction or discontinuation of both drugs, however, significantly decreased EVR (33% vs 80%). The authors also found that dose reduction after EVR had been reached of one or both agents to less than 80% of the prescribed dose only reduced the chance of SVR from 72% to between 61% and 63%. However, early discontinuation or significant interruptions of treatment that resulted in less than 80% of the expected duration reduced the chance of SVR to 50%.Taken together, the above data suggest that treatment adherence and dose maintenance, particularly in the first 12 weeks, is important in achieving SVR. Dose reductions or discontinuation of both drugs substantially reduce the chances of achieving treatment success. Maximizing SVR in clinical practice requires close attention to the monitoring and management of adverse effects to improve adherence and achieve dose maintenance. Further data are needed from prospective trials to determine factors associated with adherence as well as strategies for improving adherence to enhance SVR.Special Patient PopulationsGenotype 4-Infected Patients. A small proportion (<3%) of patients enrolled in the major PEG-IFN/ribavirin trials were infected with genotype 4, 5, or 6.[25,26] More recently, there are some data on the management of HCV-genotype 4, however, no significant data exist for genotype 5 or 6. Combined analysis of HCV genotype 4-infected patients enrolled in 2 of the major trials[26,30] demonstrated that 19 (79%) of 24 patients treated with PEG-IFN alfa-2a and ribavirin 1000-1200 mg/day for 48 weeks achieved SVR.[35] Lower SVRs were achieved in patients (n = 8) who received ribavirin 800 mg for 48 weeks (SVR 63%) than in those receiving ribavirin 1000 or 1200 mg (n = 12) for 24 weeks (SVR 67%). None of the 5 patients treated with a lower dose of ribavirin (800 mg) for 24 weeks achieved SVR.An open-label, prospective study of PEG-IFN alfa-2b 1.5 µg/kg once weekly and ribavirin 1000-1200 mg/day for 48 weeks was performed in 66 treatment-naïve patients infected with HCV genotype 4.[36] The authors compared these patients with 20 consecutive patients infected with HCV genotype 1 who were treated with the same regimen of PEG-IFN and ribavirin over the same time period. Using intent-to-treat analysis, SVR was seen in 68% of genotype 4 patients compared with 45% of genotype 1 patients. The difference did not reach statistical significance; however, this may be due to the small number of genotype 1 patients enrolled. Significantly lower SVRs were seen in the genotype 4 patients who had cirrhosis or severe fibrosis.Khuroo et al.[37] conducted a meta-analysis of 6 randomized, controlled, open-label trials of treatment-naïve patients with chronic HCV genotype 4. Two of the studies were large trials (previously described in this review) performed in a Western population that included a small number of genotype 4-infected patients.[25,26] The remaining 4 trials enrolled patients from the Middle East.[38-41] A total of 424 patients were treated for one year. Three trials used PEG-IFN alfa-2a 180 µg per week,[26,39,40] while the other 3 trials used PEG-IFN alfa-2b.[25,38,41] In the PEG-IFN alfa-2b trials, 2 studies used a fixed dose of 100 µg per week,[38,41] and one study used the standard weight-based dose (1.5 µg/kg).[25] PEG-IFN alfa-2a was used in the control group in 2 trials[39,40] and PEG-IFN alfa-2b in 4 trials.[25,26,38,41] Fixed low-dose ribavirin (800 mg/day) was used in 4 trials,[25,38,39,41] while weight-based ribavirin (1000-1200 mg/day) was used in 2 trials.[26,40] Overall, the SVR in the PEG-IFN treatment groups was 54.8%.[37]The meta-analysis had several limitations. The SVR was calculated based on 4 trials that used fixed low-dose ribavirin, while a fixed dose of PEG-IFN alfa-2b was used in 2 trials. In addition, the meta-analysis included data from 2 large randomized trials in which there was a small percentage of HCV genotype 4 patients, and the study groups were not matched according to genotype. The majority of the remaining studies were available only as abstracts, and missing data prevented evaluation of other factors such as age, body weight, viral load, and presence or absence of cirrhosis.[37] To evaluate the treatment response and duration of therapy in patients with HCV genotype 4, a randomized, double-blind study of PEG-IFN alfa-2b and ribavirin was performed.[42] A total of 287 patients were randomly assigned to receive PEG-IFN alfa-2b 1.5 µg/kg once weekly plus daily ribavirin (1000-1200 mg) for 24, 36, or 48 weeks of treatment. The primary endpoint was viral clearance 48 weeks after treatment completion. Using intent-to-treat analysis, SVR was achieved in 29%, 66%, and 69% of patients treated for 24, 36, and 48 weeks, respectively. There was no significant difference in terms of SVR between 36 and 48 weeks of PEG-IFN alfa-2b and ribavirin treatment; however, the incidence of adverse events was higher in the group treated for 48 weeks. Factors predictive of SVR in multivariate analysis were viral load (≤2 million copies/mL), and age (≤40 y). Thus, the data available suggest that treatment response to genotype 4 lies somewhere between that for genotype 1 and genotypes 2 and 3. In addition, patients with HCV genotype 4 require more than 24 weeks of PEG-IFN and ribavirin treatment; however, 36 weeks of treatment may be as effective as 48 weeks.Black Patients. Several small studies have noted that black HCV-infected patients have lower response rates to IFN alfa than those of white patients.[43-45] One study found no difference in SVR between white and black patients infected with HCV genotype 1.[46] The author suggested that the difference seen in other studies was related to the higher incidence of genotype 1 in black patients. These studies were limited by their retrospective design and small numbers of black patients. The treatment response to PEG-IFN alfa-2b 1.5 µg/kg once weekly and ribavirin 1000 mg/day for the first 12 weeks followed by 800 mg/day for weeks 13-48 was evaluated in 100 black patients and 100 non-Hispanic white patients.[47] Ninety-eight percent of patients in each group were infected with genotype 1. The baseline characteristics of the groups were comparable except black patients had higher weights and higher incidences of diabetes mellitus and hypertension. The SVR was significantly higher among non-Hispanic whites than among blacks (52% vs 19%).[47] Adherence was similar, and race was the only predictor of response in the regression analyses. The reason for the difference in SVR is unclear; however, it may be related to differences in immune response among racial and ethnic groups. These data illustrate the importance of adequate enrollment of all racial and ethnic groups plus the need for further research to understand the poor response to IFN therapy in black patients infected with HCV.Adverse EffectsAdverse effects associated with IFN alfa and PEG-IFNs include fatigue, influenza-like symptoms, gastrointestinal disturbances, hematologic abnormalities, neuropsychiatric effects (particularly depression), thyroid dysfunction, and dermatologic effects, such as alopecia and pruritus.[33,48-50] The principal adverse effect of ribavirin is hemolytic anemia. The adverse effect profile appears to be similar between IFN alfa and PEG-IFN, although the frequency of certain adverse effects may vary. In the study by Fried et al.,[26] influenza-like symptoms, headache, alopecia, and depression occurred less frequently (by at least 5%) in the PEG-IFN alfa-2a arm compared with the IFN alfa arm. Manns et al.[25] found a higher incidence (≥5%) of influenza-like symptoms and some gastrointestinal effects (ie, nausea, diarrhea, weight loss) with PEG-IFN alfa-2b versus IFN alfa.Strategies for managing adverse effects include dose reduction or treatment discontinuation, although these are associated with reduced efficacy, as noted above. In the major PEG-IFN/ribavirin trials, hematologic abnormalities were the most common reasons for dose reductions; however, this rarely (≤3% of patients) resulted in discontinuation of therapy.[33] Gastrointestinal adverse effects, neuropsychiatric effects, and influenza-like symptoms are additional frequent causes for dose reductions or discontinuation.Because of the clear relationship between adherence and treatment response, strategies are needed to avoid dose reductions wherever possible. There is growing evidence that selective serotonin-reuptake inhibitors (SSRIs) are safe and effective in treating depression associated with IFN therapy.[51-56] An open-label, controlled, prospective study was recently published that evaluated whether preemptive treatment with citalopram can prevent major depression during treatment with PEG-IFN alfa-2b and ribavirin in HCV-infected patients with psychiatric disorders.[57] Patients with mild-to-moderate depressive symptoms but not receiving antidepressant therapy were initiated on citalopram 20 mg/day 2 weeks prior to starting PEG-IFN (group A; n = 14). These patients were compared with 2 control groups: group B was comprised of patients with psychiatric disorders but without a clinical need for present antidepressant therapy (n = 11), and group C was a nonpsychiatric control group (n = 11). The incidence of major depression during the first 6 months of antiviral treatment was significantly reduced in group A (14%) compared with that in groups B and C (64% and 55%, respectively; p = 0.032).[57] Larger prospective, randomized, controlled trials are needed to determine whether preemptive antidepressant therapy is also protective against IFN alfa-associated depression in patients without psychiatric risk factors.The mechanism of IFN alfa-induced depression is unknown; however, it is hypothesized to be related to decreased neurotransmission of serotonin, which would support the use of SSRIs.[56] In terms of safety, hepatotoxicity has rarely been seen with SSRI treatment in the general population.[58] In one case report, bupropion was used and found to be effective in treating PEG-IFN-associated depression in a female patient who was concerned about adverse effects associated with SSRIs (weight gain) and nefazodone (hepatotoxicity).[59] Further data are needed to elucidate the mechanism of IFN-induced depression as well as the best treatment.Anemia is also a common complication, with up to 23% of patients requiring dosage reductions of ribavirin.[25,26] Erythropoietin (epoetin alfa) has been used to improve anemia[60] and was evaluated in 2 randomized studies.[61,62] The first was an open-label study of 64 HCV-infected patients with hemoglobin levels of 12 g/dL or lower during the first 24 weeks of combination IFN alfa-2b/ribavirin therapy.[61] Patients were randomized to receive epoetin alfa 40 000 units subcutaneously once weekly for 16 weeks or standard of care (ie, ribavirin dose reduction or discontinuation).[61] Patients in the epoetin alfa arm had significantly higher mean hemoglobin levels at study completion and required significantly less reductions in ribavirin dosage (31 mg/day vs 179 mg/day with standard of care).[61] Based on these results, a randomized, double-blind, placebo-controlled trial was conducted to evaluate whether epoetin alfa could maintain ribavirin dosage in anemic HCV-infected patients receiving IFN or PEG-IFN plus ribavirin.[62] Patients who developed a hemoglobin of 12 g/dL or lower were randomized to receive epoetin alfa or placebo for an 8-week, double-blind period. Significantly more patients in the epoetin alfa arm had ribavirin dose success, which was defined as a ribavirin dose at week 8 that was greater than or equal to the dose at randomization. In addition, hemoglobin levels were higher in patients who received epoetin alfa.[62] Health-related quality of life was also shown to be significantly improved in epoetin alfa recipients, with the greatest improvements in patients with the largest hemoglobin increases.[63]Dose reductions of PEG-IFN or discontinuation of therapy are currently recommended for managing IFN-associated neutropenia.[50] Preliminary reports suggest that use of granulocyte colony-stimulating factor for neutropenia may be safe and effective in this patient population; however, further long-term studies are needed.[50,64] It remains to be determined whether the use of hematopoietic growth factors increases SVR by preventing dose reductions in anti-HCV treatments.Treatment RecommendationsBased on the significant advances in HCV treatment, the National Institutes of Health (NIH) convened a consensus conference in 2002 to update the 1997 NIH Consensus Statement. The 2002 NIH Consensus Statement[6] recommends that treatment-naïve patients be considered for treatment with combination PEG-IFN and ribavirin therapy. Patients eligible for treatment are those at increased risk of developing cirrhosis, including those with detectable HCV RNA levels greater than 50 U/mL, liver biopsy with portal or bridging fibrosis, and at least moderate inflammation and necrosis. For HCV genotype 2- or 3-infected patients, a ribavirin dose of 800 mg plus PEG-IFN for 24 weeks is recommended. Genotype 1-infected patients should be treated for 48 weeks with PEG-IFN and standard doses of ribavirin (1000-1200 mg/day). Of note, data used to establish treatment guidelines were not always replicated with both PEG-IFN alfa-2a and -2b; however, recommendations have been broadened to include both PEG-IFN preparations. The Consensus Statement defines EVR as a minimum 2-log10 decrease in viral load during the first 12 weeks of therapy.[6] Because the absence of EVR predicts future lack of SVR in more than 98% of patients with genotype 1, HCV RNA should be routinely monitored at week 12 in these patients. Therapy should be discontinued in genotype 1 patients who fail to achieve an EVR.The American Association for the Study of Liver Diseases Practice Guideline[8] and the Canadian Consensus guidelines[7] were updated in 2004 and recommend qualitative monitoring of HCV RNA at 24 weeks in genotype 1-infected patients who achieve a 2-log10 decrease at 12 weeks, but who do not clear HCV RNA from serum. In patients who fail to clear the virus at 24 weeks, it is recommended that therapy be withdrawn.[7,8]SummaryTreatment of chronic HCV infection has significantly improved over the past several years with combination PEG-IFN and ribavirin therapy. SVR is achievable in nearly half of patients with genotype 1 and about 80% of those with genotypes 2 and 3. Studies have shown that genotype 1-infected patients are best managed with higher doses of ribavirin (1000-1200 mg/day) in addition to PEG-IFN for 48 weeks. Patients infected with genotypes 2 and 3 have high response rates, even when treated with lower doses of ribavirin (800 mg/day) and a total treatment duration of 24 weeks. Based on limited data recently available on HCV genotype 4-infected patients, it appears these patients should be treated in a manner similar to that with HCV genotype 1; however, a shorter course of therapy (36 wk) may be considered. Data have shown that lack of EVR at 12 weeks in HCV genotype 1 is a strong predictor of not achieving SVR, enabling early treatment discontinuation in these patients.Treatment adherence and dose maintenance, most notably in the first 12 weeks, is important in achieving SVR. Decrease in the dose of both PEG-IFN and ribavirin, or discontinuation of therapy, substantially decreases treatment success. Adverse effects are the most common cause of poor adherence; therefore, monitoring for adverse effects and appropriate management are essential, in addition to patient education and support. SSRIs appear to be safe and effective in managing, and possibly preventing, IFN-related depression; however, larger controlled studies are needed. There is cumulating evidence that erythropoietin is effective in allowing dose maintenance of ribavirin in patients who develop anemia related to HCV therapy.While substantial advances have been made over the years, there is still a significant proportion of HCV genotype 1-infected patients who are unable to clear the virus. Further research is required on the optimal management of these patients, as well as for genotypes 5 and 6. In addition, efforts should continue in identifying therapies that can be used to successfully manage HCV treatment-related adverse effects.CLICK HERE for more information about this journal.Table 1. Randomized Controlled Trials of Pegylated Interferon and RibavirinReferenceRegimenPts. (n)Genotype 1 SVR (%)Genotype 2 or 3 SVR (%)Manns et al. (2001)[25]IFN alfa-2b 3 MU 3 times/wk and ribavirin (1000-1200 mg/day) for 48 wk5053379PEG-IFN alfa-2b 1.5 µg/kg weekly and ribavirin (800 mg/day) for 48 wk5114282PEG-IFN alfa-2b 1.5 µg/kg weekly × 4 wk, then 0.5 µg/kg weekly andribavirin (1000-1200 mg/day) for 48 wk5143480Fried et al. (2002)[26]IFN alfa-2b 3 MU 3 times/wk and ribavirin (1000-1200 mg/day) for 48 wk4443661PEG-IFN alfa-2a 180 µg weekly and placebo for 48 wk2242145PEG-IFN alfa-2a 180 µg weekly and ribavirin (1000-1200 mg/day) for 48wk4534676Hadziyannis et al. (2004)[30]PEG-IFN alfa-2a 180 µg weekly and ribavirin (800 mg/day) for 24 wk2142984PEG-IFN alfa-2a 180 µg weekly and ribavirin (800 mg/day) for 48 wk3654179PEG-IFN alfa-2a 180 µg weekly and ribavirin (1000-1200 mg/day) for 24wk2884281PEG-IFN alfa-2a 180 µg weekly and ribavirin (1000-1200 mg/day) for 48wk4445280ReferencesYen T, Keeffe EB, Ahmed A. The epidemiology of hepatitis C virus infection. J Clin Gastroenterol 2003;36: 47-53. DOI 10.1097/00004836-200301000-00015Herrine SK. Approach to the patient with chronic hepatitis C virus infection. Ann Intern Med 2002;136:747-57.Hoofnagle JH. Course and outcome of hepatitis C. Hepatology 2002; 36(5 suppl 1): S21-9. DOI 10.1053/jhep.2002.36227Seeff LB. Natural history of chronic hepatitis C. Hepatology 2002;36(5 suppl 1): S35-46. DOI 10.1053/jhep.2002.36806Kim WR. The burden of hepatitis C in the United States. Hepatology 2002;36(5 suppl 1): S30-4. 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Cleve Clin J Med 2004;71(suppl 3):S22Reprint AddressDr. , Faculty of Pharmacy and Pharmaceutical Sciences, 3126 Dentistry/Pharmacy Centre, University of Alberta, Edmonton T6G 2N8, AB, Canada, fax 780/492-1217, christine.hughes@...Christine A. , PharmD, Associate Professor, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta; Clinical Pharmacist, HIV, Capital Health Region, Edmonton, AB, Canada D. Shafran, MD FRCPC, Professor, Division of Infectious Diseases, Department of Medicine, University of AlbertaDisclosure: Dr. Shafran has received research grants and honoraria from Roche and Schering. sallyrobsallyrob@...