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Chronic Hepatitis C Therapy: Changing the Rules of Duration
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4:963–971
Chronic Hepatitis C Therapy: Changing the Rules of Duration BRIAN L. PEARLMAN Center for Hepatitis C, Atlanta Medical Center, Atlanta; and Medical College of Georgia, Emory University School of Medicine, Atlanta, Georgia
Traditional durations of therapy for patients with chronic hepatitis C can potentially be modified in hopes of cost savings, diminished exposure to medication side effects, and even improved rates of sustained virologic response. Clinical and viral kinetic studies suggest that shortened treatment durations for certain patients with genotype 2 and 3 infections might be equally effective as regimens of 24 weeks; for patients achieving undetectable viremia at 4 weeks of therapy, treatment durations of 12–16 weeks are sufficient. Nevertheless, abbreviated treatment courses might be inappropriate for those patients with advanced fibrosis or for genotype 3–infected patients with high viral loads. Similarly, if a rapid virologic response is obtained in those patients with genotype 1 infection and a low viral load, a truncated treatment course of merely 24 weeks is feasible. Conversely, slow virologic responders typically seen in genotype 1–infected individuals with high viral loads might benefit from an extended course of therapy; however, this approach needs to be validated prospectively. This review focuses on the evidence supporting such treatment individualization and discusses potential treatment algorithm modifications.
he hepatitis C virus (HCV) is the most common cause of death from liver disease in the USA.1 In population-based studies, HCV accounts for more than 40% of chronic liver disease and causes about 10,000 deaths per year.2 Treatment with pegylated interferon-alfa (PEG-IFN) plus ribavirin has become the therapy of choice for HCV infection with sustained virologic response (SVR) rates of approximately 55%. Genotype 2– and 3–infected patients have SVR rates of 76%– 84%, but patients with genotype 1 infection attain SVR rates of only 42%–52% and even lower in those with high viral loads.3–5 Because HCV medications are costly and have significant toxicities, there has been interest in abbreviating genotype 2– or 3–infected patients’ treatment regimens. Conversely, because genotype 1–infected patients have inferior treatment responses, prolonging therapy could potentially improve SVR rates. The aim of this review was to examine evidence regarding truncation and prolongation of therapy for chronic HCV.
T
Treatment Truncation Genotypes 2 and 3 The standard of care for the treatment of genotype 2– and 3–infected chronic HCV patients is PEG-IFN plus ribavirin therapy for 24 weeks6; more than 75% of patients with genotype 2 and 3 achieve SVR with this regimen.5 However, similar efficacy might be achievable with curtailed treatment duration. Three small studies from Japan have shown that patients with genotype 2 infection attained SVR with only 6 –16 weeks of standard IFN.7–9 Case reports of patients withdrawing from PEG-IFN– based therapy prematurely have also affirmed favorable rates of SVR.10 Furthermore, viral kinetics suggest that shorter treatment durations might be feasible. An initial decrement in the HCV RNA level, referred to as phase 1, occurs hours after IFN administration; it reflects blocking of virus production. A subsequent, slower decline in viremia, phase 2, occurs days after IFN is initiated and represents clearance of HCV-infected hepatocytes. The phase 2 response is the better predictor of ultimate HCV RNA clearance.11,12 This second phase decline is significantly faster in genotype 2– and 3–infected patients than in genotype 1–infected patients.13,14 Therefore, virus concentrations at various points can help predict treatment outcome. Failure to achieve an early virologic response (EVR), defined by a minimum 2-log decline from baseline in serum HCV RNA during the first 12 weeks of therapy, predicts treatment failure.15,16 Alternatively, the decline in HCV RNA at week 4 of therapy might be predictive.15 Patients who have undetectable viremia as early as 4 weeks of therapy have higher rates of SVR than those who clear virus after 12 weeks.17 This former group is said to have achieved a rapid virologic response (RVR). Patients can be treated Abbreviations used in this paper: CI, confidence interval; EVR, early virologic response; HCV, hepatitis C virus; IFN, interferon-alfa; PEG-IFN, pegylated interferon-alfa; RVR, rapid virologic response; SVR, sustained virologic response. © 2006 by the American Gastroenterological Association Institute 1542-3565/06/$32.00 doi:10.1016/j.cgh.2006.05.022
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Table 1. Summary of Treatment Trials With Truncated Courses of PEG-IFN Plus Ribavirin in Genotype 2– and 3–Infected Chronic Hepatitis C Patients Study
Year
Country
Study design
Number of patients
Dalgard et al18 2004 Norway
Pilot study uncontrolled
122
Mangia et al19
2005 Italy
Randomized
283
Von Wagner et al21
2005 Germany Randomized
153
Therapy used
RVR definition
Treatment durationa
SVR rates
PEG-IFN alfa-2b 1.5 g/ wk ⫹ ribavirin 800– 1400 mg/day PEG-IFN alfa-2b 1.0 g/ wk ⫹ ribavirin 1000– 1200 mg/day
4 wk: ⬍50 IU/mL
14 wk
14 wk, 90%; 24 wk,b 56%
4 wk: ⬍50 IU/mL
12 wk
PEG-IFN alfa-2a 180 g/ wk ⫹ ribavirin 800– 1200 mg/day
4 wk: ⬍600 IU/mL
16 wk
Standard group: 24 wk, 76%. Variable group: 12 wk, 85%; 24 wk,b 64% 16 wk, 82%; 24 wk, 80%; 24 wk,b 36%
aCompared bNone
to 24 weeks of therapy. of these patients achieved RVR; thus their response rates were inferior to those treated for 14 weeks.
with shorter than standard durations of therapy if RVR is achieved (Table 1). Dalgard et al18 studied a 14-week course of therapy in genotype 2– and 3–infected HCV patients. In this nonrandomized trial, 122 treatment-naïve patients were recruited from 20 hospitals in Norway. Patients were treated with PEG-IFN alfa-2b weekly with weight-based daily ribavirin dosing. Patients achieving undetectable viremia at weeks 4 and 8 were treated for 14 weeks; however, those with detectable HCV RNA at 8 weeks received 24 weeks of therapy. The overall SVR was 82% (95% confidence interval [CI], 75%– 89%). Those treated for 24 weeks (22% of patients) achieved an SVR rate of 56%, whereas those treated for 14 weeks had a 90% SVR rate. The response rate was inferior in those treated for 24 weeks, because none in this group had undetectable viremia at 4 weeks. Adverse events were less frequent in the shorter duration arm compared with the longer duration group. The authors concluded that 14 weeks of therapy are adequate for genotype 2– or 3–infected patients who have undetectable viremia at 1 month of treatment. The only independent predictor of SVR was absence of severe liver disease. The majority of relapsers in the shorter treatment duration group had bridging fibrosis or cirrhosis, which prompted the authors to caution against the use of 14 weeks of treatment for those with advanced disease. Critiques of this study include its nonrandomized design and its patient population. The median patient age was 37 years, and 77% of those for whom histologic data were available had minimal liver fibrosis. Furthermore, the median body mass index was 25, which is not representative of a cohort in the USA. A larger, randomized, multicenter trial of shortened treatment duration was performed in treatment-naïve
genotype 2– or 3–infected patients. Mangia et al19 randomized 283 patients to a 24-week regimen (70 patients) or to a variable duration regimen (213 patients). Patients were treated for 24 weeks if their HCV RNA was detected at week 4 of therapy, irrespective of group assignment. Patients randomized to the variable duration group, whose RNA was undetectable at 4 weeks, were only treated for 12 weeks. Overall, rates of SVR were 76% (95% CI, 66%– 86%) in the standard duration group versus 77% (95% CI, 71%– 83%) in the variable duration group. Sixty-four percent of patients in the standard duration group attained an RVR compared with 62% with a similar response in the variable duration group. For patients who achieved RVR, SVR rates were similar between those treated for 12 weeks compared with those treated for 24 weeks (85% vs 91%, respectively; 95% CI, ⫺16% to 4%). For those with detectable virus at 4 weeks, those in the standard duration group had an SVR of 48% (95% CI, 28%– 67%) versus 64% (95% CI, 53%–74%) in the variable duration group. The shorter treatment group experienced fewer side effects and treatment discontinuations than those treated for longer durations. The authors concluded that for those genotype 2– or 3–infected patients who have undetectable HCV RNA after 4 weeks, 12 weeks of therapy are adequate. The study by Mangia et al19 has been criticized because of the unusual doses of administered PEG-IFN alfa-2b (1.0 g · kg⫺1 · week⫺1) and ribavirin (1000 –1200 mg/day). The authors counter that in the aforementioned study from Norway,18 the dose of PEG-IFN alfa-2b was not statistically associated with 12-week or 4-week responses.20 Furthermore, in the product’s registration trial, genotype 2– or 3–infected patients had similar response rates, irrespective of PEG-IFN dosing.3 Other points of contention are that
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the demographics of cohorts in the USA are different from those in Italy.20 Moreover, even when confounding factors like ethnicity or genotype are eliminated, SVR rates are lower in centers in the USA than those in non-USA centers.4 Another multicenter, randomized, controlled study from Germany compared 16 weeks of treatment in patients with genotype 2 or 3 infection. Von Wagner et al21 treated 153 patients with PEG-IFN alfa-2a plus weight-based ribavirin. After 4 weeks of therapy, patients who had HCV RNA below 600 IU/mL (97% and 92% of patients with genotype 2 and 3 infections, respectively) were randomized to treatment duration of 16 weeks or 24 weeks. Those not achieving a viral load less than 600 IU/mL at 4 weeks were treated for 24 weeks. The overall SVR rate was 78%; those patients treated for 16 weeks attained an SVR rate of 82%, whereas those treated for the customary interval achieved an SVR of 80%. However, those patients who did not achieve adequate viral suppression by week 4 had a poorer rate of SVR (36%). In multivariate analysis, predictors of response included genotype 2 infection, low viral load, and low ␥-glutamyltransferase. Adverse events were similar in the 16-week treatment group compared with the 24-week groups. Thus, the authors concluded that 16 weeks of therapy with PEG-IFN alfa-2a plus weight-based ribavirin are adequate for those patients with genotype 2 and 3 infections. However, because of inferior response rates, genotype 3–infected patients with high viral loads might require longer treatment durations (see below). Study limitations include the lack of applicability to USA populations. Furthermore, the use of a 4-week threshold of less than 600 IU/mL of viral RNA, instead of more sensitive assays, might have skewed results. Nonstandard dosing of ribavirin was also used. Not all genotype 2– or 3–infected patients benefit from an abbreviated treatment course. A preliminary analysis from the aforementioned Norwegian and Italian studies has shown that those with advanced fibrosis had poorer RVR and SVR rates compared with those with milder disease.22 Patients with bridging fibrosis or cirrhosis attained an RVR only 56% of the time compared with 70% for those with lesser disease (P ⫽ .03). Similarly, patients with more advanced histology had a 67% SVR rate compared with 83% for patients with milder disease (P ⫽ .004). Furthermore, genotype 3–infected patients had inferior responses compared with those with genotype 2 infections; these patients might require longer durations of therapy. Interferon-based therapy might achieve better results in genotype 2–infected patients compared with genotype
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3–infected ones, particularly those with high viral loads; in fact, some authors have suggested that SVR rates be stratified by a single genotype and not by any combination of genotypes (eg, non– genotype 1).18,23,24 The mechanism for inferior responses might be related to genotype 3–infected patients’ high degree of steatosis on liver biopsy.25 In all aforementioned studies of shortened treatment durations, genotype 3 infection had a bearing on response rates. In the Norwegian study,18 patients treated for 14 weeks with genotype 3 infection and high viral load had significantly higher SVR rates compared with those with genotype 3 infection and low viral load treated for the same duration (98% vs 79%; P ⫽ .019). In the Italian study,19 100% of genotype 3–infected patients achieved SVR with 24 weeks of therapy, but only 77% of patients achieved SVR with 12 weeks. Finally, in the German study,21 SVR rates were superior in genotype 2–infected patients compared with genotype 3–infected individuals (92% vs 73%). Moreover, patients with genotype 3 infections and high baseline viral loads showed inferior response rates compared with those with low viral loads (59% vs 85%, P ⫽ .003). In all 3 studies of shortened treatment duration, those patients failing to achieve an RVR had relatively poor SVR rates compared with patients who had attained this milestone; SVR rates in patients who were RVR failures compared with those achieving RVR were 56% versus 90% (Dalgard et al18), 64% versus 85% (variable duration arm) (Mangia et al19), and 36% versus 80% (24week arm) (Von Wagner et al21). Thus, despite receiving standard treatment duration of 24 weeks, individuals with genotype 2 or 3 infections who did not achieve RVR had inferior response rates. Future studies are necessary to determine whether this patient group would benefit from even longer than standard therapy durations. It is likewise important to emphasize that all 3 studies of abbreviated treatment duration used weight-based ribavirin dosing for genotype 2 and 3 infections rather than the standard of care, 800 mg ribavirin daily. Preliminary evidence from the Accelerate Trial revealed that truncated treatment courses might be inferior when using flat ribavirin dosing.26 One thousand four hundred sixty-nine treatment-naïve, genotype 2– or 3–infected patients from 8 countries were randomized to receive PEG-IFN alfa-2a (180 g weekly) and ribavirin (800 mg daily) for either 16 or 24 weeks. Even if patients achieved an RVR (90% of patients), rates of SVR were statistically superior in the 24-week group (n ⫽ 679) versus those of the 16-week group (n ⫽ 630) (76% vs 65%, respec-
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Figure 1. Alternative treatment algorithm for chronic hepatitis C patients infected with genotype 2 or 3 viruses. Not recommended for patients with advanced fibrosis or for those with genotype 3 infection and high viral load. aAlternatively, use 1000 –1200 mg ribavirin daily; busing qualitative or sensitive quantitative RNA assay; cconsider extending treatment duration.
tively). Thus, prescribers are cautioned against truncated treatment courses when using standard PEG-IFN and ribavirin dosing for genotype 2– or 3–infected patients. Nevertheless, it might be reasonable to shorten treatment duration in those genotype 2– and 3–infected HCV patients achieving rapid viral clearance at 4 weeks of therapy (Figure 1) when using weight-based doses of ribavirin. Abbreviating therapy duration might help avoid potentially debilitating side effects of unnecessary treatment and could engender significant cost savings; 14 weeks of treatment in those achieving an RVR could save about 32% in therapy cost and drug exposure.18 However, exceptions might apply to certain subgroups. Avoiding therapy truncation might be prudent in heavier patients until further studies are performed. Likewise, it might be reasonable to offer the traditional 24-week treatment duration for those patients with high viral load and genotype 3 or in those with advanced fibrosis, barring further data. The GET-C study, a prospective, randomized trial initiated in Australia, will help to determine the optimum treatment duration for those genotype 3–infected patients with high viral loads.27 Genotype 1 In the more difficult to treat, genotype 1–infected HCV patients, treatment is typically given for 48 weeks.5,6 However, it is possible that for some of these patients, a full 48-week therapy course might be unnecessary. Irrespective of whether IFN is used as monotherapy28 or as dual therapy combined with ribavirin,29 baseline viral load affects treatment responsiveness. In treatment trials with standard IFN plus ribavirin, pa-
tients with low baseline viral loads and genotype 1 virus had reasonable SVR rates even when treated for 24 weeks.30,31 Until recently, it was unclear whether genotype 1– infected patients with low levels of HCV RNA could be similarly treated for 24 weeks with newer PEG-IFN regimens. In a randomized, phase III trial that examined therapy duration in treatment-naïve patients, 36% of more than 700 patients with genotype 1 infection achieved an SVR after 24 weeks of treatment with PEG-IFN alfa-2a plus ribavirin.5 An analysis of this trial sought to identify factors predictive of an RVR and SVR in those given this abbreviated therapy course.32 Among patients who achieved a 4-week RVR, there was no significant difference in rates of SVR in patients treated for 24 or 48 weeks. Conversely, the highest SVR in patients without an RVR was in those treated for 48 weeks. A regression analysis demonstrated that a low baseline HCV RNA level was the only independent factor predictive of an RVR in those patients treated for 24 weeks. Patients with baseline HCV RNA levels of ⬍200,000 IU/mL and between 200,000 – 600,000 IU/mL were more likely to achieve an RVR than those with baseline levels ⬎600,000 IU/mL (P ⬍ .0001 and P ⬍ .0057, respectively). The authors concluded that an RVR is the single best predictor of an SVR, and those likely to achieve it are those with low baseline viral loads. In an international, randomized, controlled study of treatment-naïve chronic HCV patients comparing treatment tailored by virologic response with standard-of-care therapy,33 genotype 1–infected patients who experienced
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a ⱖ2-log HCV RNA decrement at 4 weeks achieved an SVR rate of 65% when treated for 24 weeks; however, this was statistically inferior to the SVR rate in those patients achieving this same milestone who received 48 weeks of therapy (83%). Nonetheless, the difference was not statistically significant in those in whom the baseline viral load was low (HCV RNA ⬍800,000 IU/mL). Thus, it might be possible to treat for 24 weeks without losing efficacy in those patients attaining RVR with genotype 1 infection and low levels of baseline viremia. Similar conclusions come from another recently completed trial. Zeuzem et al34 completed a phase IV, single-arm, open-label, historical control trial conducted in 43 European centers. Two hundred thirty-seven genotype 1–infected HCV patients with baseline viremia ⬍600,000 IU/mL were treated with PEG-IFN alfa-2b plus weight-based ribavirin for 24 weeks. Subjects were compared to a historical control arm of 38 patients from the registration trial of PEG-IFN alfa-2b3; these “control” patients were selected if they had received PEGIFN alfa-2b plus ribavirin dosed at ⱖ10.6 mg/day for 48 weeks. Although SVR rates were inferior in the investigational arm (50% for 24 treatment weeks) compared with the control arm (71% for 48 treatment weeks), the subgroup of patients who were RNA negative at 4 weeks (47% of all subjects treated for 24 weeks) had similar rates of SVR to those in the control group (89% vs 85%, respectively). In multivariate analysis, only baseline HCV RNA levels (P ⬍ .0001) and therapy duration for 16 weeks or longer (P ⫽ .0135) were independent predictors of SVR. Treatment discontinuations or dose reductions for adverse events occurred at significantly lower rates than those in the historical control arm, supporting the notion that shorter treatment durations provoke fewer side effects. The authors concluded that most chronically infected HCV patients with genotype 1 infection should be treated for 48 weeks. However, those genotype 1–infected patients with low levels of baseline viremia achieving an RVR at 4 weeks can be treated successfully for 24 weeks. A criticism of this study is the historical control group taken from a previously released protocol from more than a half decade ago. Only 12% of the cohort was analyzed, because those selected had to satisfy a number of criteria. For example, the patients were selected if they had received ⱖ10.6 mg/day of ribavirin; this selected out relatively lean patients. Furthermore, only those patients who had viral loads tested frequently could be analyzed, which might have biased the control group toward optimal adherence.35 Another limitation was the low mean
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fibrosis score in the investigational arm (Knodell score, 1.2). Thus, it would be imprudent to draw any conclusions about using abbreviated treatment courses in genotype 1–infected patients with advanced fibrosis. Despite these criticisms, the European Commission has approved revised dosing instructions for PEG-IFN alfa-2b that includes a 24-week course of combination therapy with ribavirin for those patients with genotype 1 infection, low viral load, and undetectable viremia at 4 weeks of treatment.36 Preliminary results of an economic analysis have affirmed a minimum 27% cost savings if genotype 1– infected patients with low viral loads are treated for 24 weeks.37 Finally, preliminary results are available from another prospective, randomized, multicenter trial designed to determine whether response rates in genotype 1–infected patients could be improved by individualizing treatment on the basis of viral kinetics.38 All 366 patients were treatment-naïve and infected with either genotype 1 or genotype 4 virus. Patients were treated with PEG-IFN alfa-2a plus weight-based ribavirin. Results are available from the subgroup of patients who had undetectable (⬍50 IU/mL) HCV RNA at 4 weeks of therapy. These patients, whom the authors deem “super responders,” were treated for only 24 weeks (approximately 30% of patients). Of the genotype 1–infected super responders, 82% achieved an SVR. When results were stratified by viral load, those with low levels of viremia attained an SVR of 92%; yet even those with high viral load had an SVR of 74%. The authors concluded that treatment duration in patients with genotype 1 infection should be based on RNA levels at 4 weeks. The limitation of the study is the absence of a control arm that likewise achieved RVR, but that was given the standard 48-week therapy duration. A suggested treatment algorithm for genotype 1–infected chronic HCV patients and low viral loads is shown in Figure 2.
Therapy Extension Although it might be feasible to curtail therapy duration in certain patients, it might also be worthwhile to extend treatment duration in more difficult to treat patient subgroups. Patients with genotype 1 infection and high baseline viral load represent up to 50% of typical USA chronic HCV patients,39 and when treated for 48 weeks, they achieve lower rates of SVR than those with more favorable characteristics.3,4 Prolonging therapy beyond 48 weeks might improve response rates in these patients.
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Figure 2. Alternative treatment algorithm for chronic hepatitis C patients infected with genotype 1 virus and low viral load (⬍800,000 IU/ mL). Not recommended for patients with advanced fibrosis. aAlternatively, use 1000 –1200 mg ribavirin daily; busing qualitative or sensitive RNA assay; cif 12-week EVR achieved but RNA still detected, consider checking 24-week RNA; if positive, stop treatment.
In a retrospective analysis17 of data from more than 1000 adults with chronic HCV treated with either PEGIFN alfa-2a with or without ribavirin or standard IFN alfa-2b plus ribavirin,4 the probability of an SVR increased with the rapidity of viremia suppression. Conversely, those patients with the slowest rate of HCV RNA diminution had poorer response rates. In fact, those patients who had delayed or slow virologic response (ⱖ2-log drop in baseline viral load at 12 weeks but RNA still detectable) experienced high rates of relapse. Thus, prolongation of therapy in these “slow responders” could potentially improve rates of SVR. Several authors have attempted to improve response rates by extending therapy in those patients with genotype 1 infection who exhibit a slow or delayed response to therapy. A group of investigators sought to determine whether the state-of-the-art 48-week treatment duration for genotype 1–infected patients was adequate. Drusano and Preston40 hypothesized that the longer the duration of HCV viral load undetectability during therapy, the better the probability of an SVR. Data were examined from a large phase III, multicenter, randomized trial of PEGIFN alfa-2b plus ribavirin3 to develop a treatment model based on the duration of viremia suppression. The patients analyzed were those from whom a complete set of serial viral load findings were available, which included 771 of 1000 patients in a model-building group and 229 of 411 patients in a model-validation group. The impact of 11 different variables on the probability of therapy failure was examined by logistic regression; demographic
(eg, race), biochemical (eg, baseline ALT), and virologic (eg, genotype) variables were included. The authors built a prediction model on the basis of the above covariables. Of all the variables, the duration of viral clearance had the strongest effect on the probability of SVR. The model was highly statistically significant (P ⬍ .001). When the model was applied to the modelvalidation group, it predicted SVR well (positive predictive value, 96.9%; negative predictive value, 91.3%). In patients with genotype 1 infection, an undetectable HCV RNA was required for 32 continuous weeks to have an 80% chance of SVR. For a 90% chance, the required duration of undetectable viremia was 36 weeks. The average time to clear serum of genotype 1 virus was 30.4 weeks; thus, the authors concluded that the standard 48-week duration of therapy for genotype 1–infected patients is suboptimal. It was estimated that rates of SVR could be improved by approximately 14% if this model were used to customize therapy duration. Limitations of this study were its retrospective data analysis and the selecting out of adherent patients because of the serial viral load testing requirement. Even if this model were prospectively validated, it might not be cost-effective because monthly viral loads might be costprohibitive. Furthermore, patients received 800 mg of ribavirin, which limits the model’s applicability regarding genotype 1–infected patients who have improved SVR rates with weight-based ribavirin dosing.41 A group of investigators from Spain and Israel first showed that therapy extension of PEG-IFN plus ribavirin in
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slow virologic responders might be beneficial.42 Eight genotype 1–infected patients with high viral load were given 72 weeks of PEG-IFN-2b (1.0 m · kg⫺1 · week⫺1) plus ribavirin (900 mg/day). All were slow virologic responders as defined by a ⱖ2-log decrease in baseline viremia yet detectable HCV RNA at 12 weeks (EVR achieved). Seven of 8 patients treated for 72 weeks achieved SVR (88%); this result stands in contrast to an SVR of 21% in slow responders treated for 48 weeks in the registration trial for PEG-IFN alfa-2b plus ribavirin.16 Obviously the sample’s small size limits the study’s conclusions. Furthermore, the dosing of both the PEG-IFN and ribavirin used in this protocol was suboptimal. Further support for treatment extension in late responders comes from analysis of a retrospective review of a German multicenter trial.43 Late virologic response was defined by virus detectability at 12 weeks of treatment but undetectability at 24 weeks. Four hundred fifty-six genotype 1–infected treatment-naïve patients were randomized to 48 or 72 weeks of treatment with PEG-IFN alfa-2a plus ribavirin. No statistically significant differences were noted between the 2 treatment groups in baseline characteristics or in overall rate of SVR (53% in 48-week group and 54% in 72-week group; P ⫽ .8). When data were analyzed according to late virologic response, however (22% of all patients studied), late virologic responders in the 72-week group had a significantly lower rate of relapse than the relapse rate in late responders treated for 48 weeks (40% vs 64%, respectively; P ⫽ .021). At week 12 of treatment, only patients with low-level viremia (⬍6000 IU/mL HCV RNA) were found to have benefited from therapy prolongation (91% relapse for 48-week treatment vs 87.5% relapse for 72-week treatment, P ⫽ not available, but significant). The authors concluded that in patients with slow virologic response, relapse rates can be reduced by extending therapy to 72 weeks. The study’s drawbacks are the use of a suboptimal ribavirin dosing for genotype 1 infections (800 mg/day) and its retrospective and subgroup analysis.
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Finally, preliminary results from a large phase III trial might also support treatment extension beyond 48 weeks.44 The TeraViC-4 study is a randomized, multicenter clinical trial from Spain that evaluated the effects of therapy duration with PEG-IFN alfa-2a and ribavirin in treatment-naïve patients. Three hundred twenty-seven of the 517 enrolled patients who did not achieve an RVR were randomized to 48 or 72 weeks of therapy. The SVR rate was significantly higher in those treated for 72 weeks versus 48 weeks in all genotypes (45% vs 32%, P ⫽ .014). An even greater difference in SVR rates was seen in those with genotype 1 infection treated for 72 versus 48 weeks (44% vs 28%, P ⬍ .001). In addition, the frequency of adverse events was similar in the standard duration and extended duration groups. The authors conclude that prolonging treatment duration from 48 to 72 weeks in slow responders (those without an RVR) can significantly improve SVR without compromising safety. As in the previous study, the ribavirin dose was low. It is unclear whether using weight-based ribavirin dosing for genotype 1 infection (the current standard of care) would yield similar results.
Conclusion On the basis of available evidence, it might be possible to individualize therapy of certain treatmentnaïve chronic HCV patients by truncating or extending standard durations of therapy (Table 2). For genotype 2– or 3–infected patients treated with weight-based dosing of ribavirin who achieve an RVR, it might be reasonable to stop treatment as early as 12 weeks. However, difficult-to-treat subgroups such as those with advanced fibrosis and cirrhosis, HCV– human immunodeficiency virus coinfection, and genotype 3 infections with high viral loads likely need longer durations of treatment. Likewise, those with genotype 1 infection and low levels of baseline viremia achieving a 4-week RVR might have respectable rates of SVR with merely 24 weeks of therapy.
Table 2. Potential Modifications to Chronic Hepatitis C Treatment Algorithms by Using PEG-IFN Plus Ribavirin Genotype
Treatment modification
References
Two or threea Two or three
12–16 weeks of therapy for patients with 4-week RVRb Extended therapy beyond 24 weeks for patients without 4-week RVR 24 weeks of therapy for patients with low viral load 72 weeks of therapy for patients with slow virologic response
18, 19, 21 NA
Randomized, controlled, trial NA
31, 32, 35 31, 41–43
Open label trial with historical control Preliminary data from randomized trial
Onec One
NA, not available. those with advanced fibrosis or genotype 3–infected patients with high viral loads. bPatients treated with weight-based ribavirin. cExcluding those with advanced fibrosis. aExcluding
Best supportive evidence
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Albeit promising, data are less satisfactory for extension of therapy to 72 weeks in genotype 1–infected patients who are slow virologic responders. For these patients, prospective trials are warranted with weightbased ribavirin dosing. Furthermore, studies are needed to clarify the optimum treatment duration in patients failing to achieve an RVR and in difficult-to-treat individuals such as African Americans. A randomized trial from Australia, the GET-C study, will prospectively determine whether patients with genotype 3 infections and high viral load require longer treatment duration. Tremendous advantages can be realized with treatment individualization; therapy truncation might engender cost savings and diminished exposure to medication side effects, whereas therapy extension might improve rates of SVR. Clearly, the “one size fits all” algorithms for chronic HCV infection treatment no longer apply; the era of individualization for IFN-based therapy has arrived.
References 1. Kim WR. The burden of hepatitis C in the United States. Hepatology 2002;36:S30 –S34. 2. Alter MJ. Epidemiology of hepatitis C. Hepatology 1997;26:S62– S65. 3. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358:958 –965. 4. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–982. 5. Hadziyannis SJ, Sette H, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346 –355. 6. National Institutes of Health Consensus Development Conference Statement: management of hepatitis C 2002. Hepatology 2002;36:S3–S20. 7. Nomura H, Tsuchiya Y, Maruyama T, et al. The effects of a high dose, short course of interferon on hepatitis C. J Gastroenterol Hepatol 1999;14:85– 89. 8. Ide T, Kumashiro R, Hino T, et al. Short term and two-step interferon therapy for chronic hepatitis C patients with low HCV RNA levels. Hepatol Res 2002;22:145–151. 9. Tabaru A, Narita R, Hiura M, et al. Efficacy of short-term interferon therapy for patients infected with hepatitis C virus genotype 2a. Am J Gastroenterol 2005;100:862– 867. 10. Nousbaum J, Cadranel J, Savary O, et al. Sustained virologic response after a short course of treatment with interferon and ribavirin in two chronic hepatitis C patients. J Hepatol 2003;39: 655– 656. 11. Lam NP, Neumann AU, Gretch DR, et al. Dose-dependent acute clearance of hepatitis C genotype 1 virus with interferon alfa. Hepatology 1997;26:226 –231. 12. Neuman AU, Lam NP, Dahari H, et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 1998;282:103–107. 13. Neumann AU, Lam NP, Dahari H, et al. Differences in viral dynamics between genotypes 1 and 2 of hepatitis C virus. J Infect Dis 2000;182:28 –35.
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14. Zeuzem S, Herrmann E, Lee J, et al. Viral kinetics in patients with chronic hepatitis C treated with standard or peginterferon alpha2a. Gastroenterology 2001;120:1438 –1447. 15. Zeuzem S, Lee JH, Franke A, et al. Quantification of the initial decline of serrum hepatitis C virus RNA and response to interferon alfa. Hepatology 1998;27:1149 –1156. 16. Davis GL, Wong JB, McHutchison JG, et al. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003;38:645– 652. 17. Ferenci P, Fried MW, Shiffman ML, et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD)/ribavirin. J Hepatol 2005;43:425– 433. 18. Dalgard O, Bjoro K, Hellum KB, et al. Treatment with pegylated interferon and ribavirin in HCV infection with genotype 2 or 3 for 14 weeks: a pilot study. Hepatology 2004;40:1260 –1265. 19. Mangia A, Santoro R, Minerva N, et al. Peginterferon alfa-2b and ribavirin for 12 versus 24 weeks in HCV genotype 2 or 3. N Engl J Med 2005;352:2609 –2617. 20. Borg BB, Hoofnagle JH. Peginterferon alfa-2b and ribavirin for 12 weeks versus 24 weeks in HCV infection. N Engl J Med 2005; 353:1182–1183. 21. Von Wagner M, Huber M, Berg T, et al. Peginterferon-alfa-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 in chronic hepatitis C. Gastroenterology 2005;129:522– 527. 22. Andriulli A, Rotondo SG, Dalgard O, et al. Short-term treatment duration for HCV-2 and HCV-3 infected patients with chronic hepatitis (abstract). Hepatology 2005;42:528A–529A. 23. Zeuzem S, Hultcrantz R, Bourliere M, et al. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotype 2 or 3. J Hepatology 2004;40:993–999. 24. Alberti A. Optimizing PEG-interferon and ribavirin combination therapy for patients infected with HCV-2 or HCV-3: is the puzzle completed? J Hepatol 2004;40:1032–1035. 25. Poynard T, Ratziu V, McHutchison JG, et al. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with heaptitis C. Hepatology 2003;38:75– 85. 26. Shiffman ML, Pappas S, Nyberg L, et al. Peginterferon alfa-2a plus ribavirin for 16 or 24 weeks in patients with HCV genotype 2 or 3: final results of the Accelerate Trial (abstract 734). Proceedings of the 41st Annual Meeting of the European Association For The Study of Liver Diseases, April 26 –29, 2006, Vienna, Austria. 27. Effects of 48 weeks versus 24 weeks of therapy with peg-intron/ ribavirin in patients with chronic hepatitis C, genotype 3 (Study P04143). Available at: http://www.clinicaltrials.gov/ct/show/ NCT00255034. Accessed January 27, 2006. 28. Rumi M, Ninno ED, Parravicini ML, et al. A prospective, randomized trial comparing lymphoblastoid recombinant interferon alfa 2a as therapy for chronic hepatitis C. Hepatology 1996;24: 1366 –1370. 29. Berg T, Sarrazin C, Herrmann E, et al. Prediction of treatment outcome in patients with chronic hepatitis C: significance of baseline parameters and viral dynamics during therapy. Hepatology 2003;37:600 – 609. 30. Poynard T, Marcellin P, See SS, et al. Randomised trial of interferon alfa2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alfa2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998;352: 1426 –1432. 31. McHutchison JG, Gordon S, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339:1485–1492. 32. Jensen D, Morgan TR, Marcellin P, et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alfa-2a (40 kD)/ribavirin therapy. Hepatology 2006;43:954 – 960.
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33. Zeuzem S, Pawlotsky JM, Lukasiewicz E, et al. International, multicenter, randomized, controlled study comparing dynamically individualized versus standard treatment in patients with chronic hepatitis C. J Hepatol 2005;43:250 –257. 34. Zeuzem S, Buti M, Ferenci P, et al. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol 2006;44:97–103. 35. Craxi A, Camma C. Treating patients with HCV genotype 1 and low viraemia: more than meets the eye. J Hepatol 2006;44:4 –7. 36. Short course pegintron plus rebetol approved in Europe for HCV patients with genotype 1 and low viral load. Available at: http:// www.hivandhepatitis.com/hep_c/news/2005/ad/100705_a.html. Accessed January 29, 2006. 37. Wong JB, Zeuzem S, Manns MP, et al. Clinical and economic implications of a 4-week viral negative response to peginterferon alfa-2b plus ribavirin for chronic hepatitis C and genotype 1 with low viral load (abstract). Hepatology 2005;42:679A. 38. Ferenci P, Bergholz U, Laferl H, et al. Is shorter treatment with peginterferon alfa-2a (40KD) plus ribavirin possible in HCV genotype 1 “super-responders”? preliminary results of a prospective randomized clinical trial (abstract). Hepatology 2005;42:218A. 39. Blatt LM, Mutchnick MG, Tong MJ, et al. Assessment of hepatitis C virus RNA and genotype from 6807 patients with chronic hepatitis C in the United States. J Viral Hepat 2000;7:196 –202. 40. Drusano GL, Preston SL. A 48-week duration of therapy with pegylated interferon alfa-2b plus ribavirin may be too short to
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41.
42.
43.
44.
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maximize long-term response among patients infected with genotype-1 hepatitis C virus. J Infect Dis 2004;189:964 –970. Jacobson IM, Brown RS, Freilich B, et al. Weight-based ribavirin dosing increases sustained viral response in patients with chronic hepatitis C: final results of the WIN-R study, a US community-based trial (abstract). Hepatology 2005;42:749A. Buti M, Valdes A, Sanchez-Avila F, et al. Extending combination therapy with peginterferon alfa-2b plus ribavirin for genotype 1 chronic hepatitis C late responders: a report of 9 cases. Hepatology 2003;37:1226 –1227. Berg T, Von Wagner M, Nasser S, et al. Extended treatment duration for hepatitis C virus type 1: comparing 48 to 72 weeks of peginterferon alfa-2a plus ribavirin. Gastroenterology 2006; 130:1086 –1097. Sanchez-Tapias JM, Diago M, Escartin P, et al. Longer treatment duration with peginterferon alfa-2a (40KD) and ribavirin in naïve patients with chronic hepatitis C and detectable HCV RNA by week 4 of therapy: final results of the randomized, multicenter Teravic-4 study (abstract). Hepatology 2004:40;218A.
Address requests for reprints to: Brian Pearlman, MD, FACP, Center for Hepatitis C, 315 Boulevard NE, Suite 200, Atlanta, GA 30312. e-mail: [email protected]. Dr Pearlman is on the Speakers Bureau for Schering-Plough, the manufacturer of one of the interferon molecules mentioned in this article (PEG-Intron).
Chronic Hepatitis C Therapy: Changing the Rules of Duration BRIAN L. PEARLMAN Center for Hepatitis C, Atlanta Medical Center, Atlanta; and Medical College of Georgia, Emory University School of Medicine, Atlanta, Georgia
Traditional durations of therapy for patients with chronic hepatitis C can potentially be modified in hopes of cost savings, diminished exposure to medication side effects, and even improved rates of sustained virologic response. Clinical and viral kinetic studies suggest that shortened treatment durations for certain patients with genotype 2 and 3 infections might be equally effective as regimens of 24 weeks; for patients achieving undetectable viremia at 4 weeks of therapy, treatment durations of 12–16 weeks are sufficient. Nevertheless, abbreviated treatment courses might be inappropriate for those patients with advanced fibrosis or for genotype 3–infected patients with high viral loads. Similarly, if a rapid virologic response is obtained in those patients with genotype 1 infection and a low viral load, a truncated treatment course of merely 24 weeks is feasible. Conversely, slow virologic responders typically seen in genotype 1–infected individuals with high viral loads might benefit from an extended course of therapy; however, this approach needs to be validated prospectively. This review focuses on the evidence supporting such treatment individualization and discusses potential treatment algorithm modifications.
he hepatitis C virus (HCV) is the most common cause of death from liver disease in the USA.1 In population-based studies, HCV accounts for more than 40% of chronic liver disease and causes about 10,000 deaths per year.2 Treatment with pegylated interferon-alfa (PEG-IFN) plus ribavirin has become the therapy of choice for HCV infection with sustained virologic response (SVR) rates of approximately 55%. Genotype 2– and 3–infected patients have SVR rates of 76%– 84%, but patients with genotype 1 infection attain SVR rates of only 42%–52% and even lower in those with high viral loads.3–5 Because HCV medications are costly and have significant toxicities, there has been interest in abbreviating genotype 2– or 3–infected patients’ treatment regimens. Conversely, because genotype 1–infected patients have inferior treatment responses, prolonging therapy could potentially improve SVR rates. The aim of this review was to examine evidence regarding truncation and prolongation of therapy for chronic HCV.
T
Treatment Truncation Genotypes 2 and 3 The standard of care for the treatment of genotype 2– and 3–infected chronic HCV patients is PEG-IFN plus ribavirin therapy for 24 weeks6; more than 75% of patients with genotype 2 and 3 achieve SVR with this regimen.5 However, similar efficacy might be achievable with curtailed treatment duration. Three small studies from Japan have shown that patients with genotype 2 infection attained SVR with only 6 –16 weeks of standard IFN.7–9 Case reports of patients withdrawing from PEG-IFN– based therapy prematurely have also affirmed favorable rates of SVR.10 Furthermore, viral kinetics suggest that shorter treatment durations might be feasible. An initial decrement in the HCV RNA level, referred to as phase 1, occurs hours after IFN administration; it reflects blocking of virus production. A subsequent, slower decline in viremia, phase 2, occurs days after IFN is initiated and represents clearance of HCV-infected hepatocytes. The phase 2 response is the better predictor of ultimate HCV RNA clearance.11,12 This second phase decline is significantly faster in genotype 2– and 3–infected patients than in genotype 1–infected patients.13,14 Therefore, virus concentrations at various points can help predict treatment outcome. Failure to achieve an early virologic response (EVR), defined by a minimum 2-log decline from baseline in serum HCV RNA during the first 12 weeks of therapy, predicts treatment failure.15,16 Alternatively, the decline in HCV RNA at week 4 of therapy might be predictive.15 Patients who have undetectable viremia as early as 4 weeks of therapy have higher rates of SVR than those who clear virus after 12 weeks.17 This former group is said to have achieved a rapid virologic response (RVR). Patients can be treated Abbreviations used in this paper: CI, confidence interval; EVR, early virologic response; HCV, hepatitis C virus; IFN, interferon-alfa; PEG-IFN, pegylated interferon-alfa; RVR, rapid virologic response; SVR, sustained virologic response. © 2006 by the American Gastroenterological Association Institute 1542-3565/06/$32.00 doi:10.1016/j.cgh.2006.05.022
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Table 1. Summary of Treatment Trials With Truncated Courses of PEG-IFN Plus Ribavirin in Genotype 2– and 3–Infected Chronic Hepatitis C Patients Study
Year
Country
Study design
Number of patients
Dalgard et al18 2004 Norway
Pilot study uncontrolled
122
Mangia et al19
2005 Italy
Randomized
283
Von Wagner et al21
2005 Germany Randomized
153
Therapy used
RVR definition
Treatment durationa
SVR rates
PEG-IFN alfa-2b 1.5 g/ wk ⫹ ribavirin 800– 1400 mg/day PEG-IFN alfa-2b 1.0 g/ wk ⫹ ribavirin 1000– 1200 mg/day
4 wk: ⬍50 IU/mL
14 wk
14 wk, 90%; 24 wk,b 56%
4 wk: ⬍50 IU/mL
12 wk
PEG-IFN alfa-2a 180 g/ wk ⫹ ribavirin 800– 1200 mg/day
4 wk: ⬍600 IU/mL
16 wk
Standard group: 24 wk, 76%. Variable group: 12 wk, 85%; 24 wk,b 64% 16 wk, 82%; 24 wk, 80%; 24 wk,b 36%
aCompared bNone
to 24 weeks of therapy. of these patients achieved RVR; thus their response rates were inferior to those treated for 14 weeks.
with shorter than standard durations of therapy if RVR is achieved (Table 1). Dalgard et al18 studied a 14-week course of therapy in genotype 2– and 3–infected HCV patients. In this nonrandomized trial, 122 treatment-naïve patients were recruited from 20 hospitals in Norway. Patients were treated with PEG-IFN alfa-2b weekly with weight-based daily ribavirin dosing. Patients achieving undetectable viremia at weeks 4 and 8 were treated for 14 weeks; however, those with detectable HCV RNA at 8 weeks received 24 weeks of therapy. The overall SVR was 82% (95% confidence interval [CI], 75%– 89%). Those treated for 24 weeks (22% of patients) achieved an SVR rate of 56%, whereas those treated for 14 weeks had a 90% SVR rate. The response rate was inferior in those treated for 24 weeks, because none in this group had undetectable viremia at 4 weeks. Adverse events were less frequent in the shorter duration arm compared with the longer duration group. The authors concluded that 14 weeks of therapy are adequate for genotype 2– or 3–infected patients who have undetectable viremia at 1 month of treatment. The only independent predictor of SVR was absence of severe liver disease. The majority of relapsers in the shorter treatment duration group had bridging fibrosis or cirrhosis, which prompted the authors to caution against the use of 14 weeks of treatment for those with advanced disease. Critiques of this study include its nonrandomized design and its patient population. The median patient age was 37 years, and 77% of those for whom histologic data were available had minimal liver fibrosis. Furthermore, the median body mass index was 25, which is not representative of a cohort in the USA. A larger, randomized, multicenter trial of shortened treatment duration was performed in treatment-naïve
genotype 2– or 3–infected patients. Mangia et al19 randomized 283 patients to a 24-week regimen (70 patients) or to a variable duration regimen (213 patients). Patients were treated for 24 weeks if their HCV RNA was detected at week 4 of therapy, irrespective of group assignment. Patients randomized to the variable duration group, whose RNA was undetectable at 4 weeks, were only treated for 12 weeks. Overall, rates of SVR were 76% (95% CI, 66%– 86%) in the standard duration group versus 77% (95% CI, 71%– 83%) in the variable duration group. Sixty-four percent of patients in the standard duration group attained an RVR compared with 62% with a similar response in the variable duration group. For patients who achieved RVR, SVR rates were similar between those treated for 12 weeks compared with those treated for 24 weeks (85% vs 91%, respectively; 95% CI, ⫺16% to 4%). For those with detectable virus at 4 weeks, those in the standard duration group had an SVR of 48% (95% CI, 28%– 67%) versus 64% (95% CI, 53%–74%) in the variable duration group. The shorter treatment group experienced fewer side effects and treatment discontinuations than those treated for longer durations. The authors concluded that for those genotype 2– or 3–infected patients who have undetectable HCV RNA after 4 weeks, 12 weeks of therapy are adequate. The study by Mangia et al19 has been criticized because of the unusual doses of administered PEG-IFN alfa-2b (1.0 g · kg⫺1 · week⫺1) and ribavirin (1000 –1200 mg/day). The authors counter that in the aforementioned study from Norway,18 the dose of PEG-IFN alfa-2b was not statistically associated with 12-week or 4-week responses.20 Furthermore, in the product’s registration trial, genotype 2– or 3–infected patients had similar response rates, irrespective of PEG-IFN dosing.3 Other points of contention are that
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the demographics of cohorts in the USA are different from those in Italy.20 Moreover, even when confounding factors like ethnicity or genotype are eliminated, SVR rates are lower in centers in the USA than those in non-USA centers.4 Another multicenter, randomized, controlled study from Germany compared 16 weeks of treatment in patients with genotype 2 or 3 infection. Von Wagner et al21 treated 153 patients with PEG-IFN alfa-2a plus weight-based ribavirin. After 4 weeks of therapy, patients who had HCV RNA below 600 IU/mL (97% and 92% of patients with genotype 2 and 3 infections, respectively) were randomized to treatment duration of 16 weeks or 24 weeks. Those not achieving a viral load less than 600 IU/mL at 4 weeks were treated for 24 weeks. The overall SVR rate was 78%; those patients treated for 16 weeks attained an SVR rate of 82%, whereas those treated for the customary interval achieved an SVR of 80%. However, those patients who did not achieve adequate viral suppression by week 4 had a poorer rate of SVR (36%). In multivariate analysis, predictors of response included genotype 2 infection, low viral load, and low ␥-glutamyltransferase. Adverse events were similar in the 16-week treatment group compared with the 24-week groups. Thus, the authors concluded that 16 weeks of therapy with PEG-IFN alfa-2a plus weight-based ribavirin are adequate for those patients with genotype 2 and 3 infections. However, because of inferior response rates, genotype 3–infected patients with high viral loads might require longer treatment durations (see below). Study limitations include the lack of applicability to USA populations. Furthermore, the use of a 4-week threshold of less than 600 IU/mL of viral RNA, instead of more sensitive assays, might have skewed results. Nonstandard dosing of ribavirin was also used. Not all genotype 2– or 3–infected patients benefit from an abbreviated treatment course. A preliminary analysis from the aforementioned Norwegian and Italian studies has shown that those with advanced fibrosis had poorer RVR and SVR rates compared with those with milder disease.22 Patients with bridging fibrosis or cirrhosis attained an RVR only 56% of the time compared with 70% for those with lesser disease (P ⫽ .03). Similarly, patients with more advanced histology had a 67% SVR rate compared with 83% for patients with milder disease (P ⫽ .004). Furthermore, genotype 3–infected patients had inferior responses compared with those with genotype 2 infections; these patients might require longer durations of therapy. Interferon-based therapy might achieve better results in genotype 2–infected patients compared with genotype
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3–infected ones, particularly those with high viral loads; in fact, some authors have suggested that SVR rates be stratified by a single genotype and not by any combination of genotypes (eg, non– genotype 1).18,23,24 The mechanism for inferior responses might be related to genotype 3–infected patients’ high degree of steatosis on liver biopsy.25 In all aforementioned studies of shortened treatment durations, genotype 3 infection had a bearing on response rates. In the Norwegian study,18 patients treated for 14 weeks with genotype 3 infection and high viral load had significantly higher SVR rates compared with those with genotype 3 infection and low viral load treated for the same duration (98% vs 79%; P ⫽ .019). In the Italian study,19 100% of genotype 3–infected patients achieved SVR with 24 weeks of therapy, but only 77% of patients achieved SVR with 12 weeks. Finally, in the German study,21 SVR rates were superior in genotype 2–infected patients compared with genotype 3–infected individuals (92% vs 73%). Moreover, patients with genotype 3 infections and high baseline viral loads showed inferior response rates compared with those with low viral loads (59% vs 85%, P ⫽ .003). In all 3 studies of shortened treatment duration, those patients failing to achieve an RVR had relatively poor SVR rates compared with patients who had attained this milestone; SVR rates in patients who were RVR failures compared with those achieving RVR were 56% versus 90% (Dalgard et al18), 64% versus 85% (variable duration arm) (Mangia et al19), and 36% versus 80% (24week arm) (Von Wagner et al21). Thus, despite receiving standard treatment duration of 24 weeks, individuals with genotype 2 or 3 infections who did not achieve RVR had inferior response rates. Future studies are necessary to determine whether this patient group would benefit from even longer than standard therapy durations. It is likewise important to emphasize that all 3 studies of abbreviated treatment duration used weight-based ribavirin dosing for genotype 2 and 3 infections rather than the standard of care, 800 mg ribavirin daily. Preliminary evidence from the Accelerate Trial revealed that truncated treatment courses might be inferior when using flat ribavirin dosing.26 One thousand four hundred sixty-nine treatment-naïve, genotype 2– or 3–infected patients from 8 countries were randomized to receive PEG-IFN alfa-2a (180 g weekly) and ribavirin (800 mg daily) for either 16 or 24 weeks. Even if patients achieved an RVR (90% of patients), rates of SVR were statistically superior in the 24-week group (n ⫽ 679) versus those of the 16-week group (n ⫽ 630) (76% vs 65%, respec-
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Figure 1. Alternative treatment algorithm for chronic hepatitis C patients infected with genotype 2 or 3 viruses. Not recommended for patients with advanced fibrosis or for those with genotype 3 infection and high viral load. aAlternatively, use 1000 –1200 mg ribavirin daily; busing qualitative or sensitive quantitative RNA assay; cconsider extending treatment duration.
tively). Thus, prescribers are cautioned against truncated treatment courses when using standard PEG-IFN and ribavirin dosing for genotype 2– or 3–infected patients. Nevertheless, it might be reasonable to shorten treatment duration in those genotype 2– and 3–infected HCV patients achieving rapid viral clearance at 4 weeks of therapy (Figure 1) when using weight-based doses of ribavirin. Abbreviating therapy duration might help avoid potentially debilitating side effects of unnecessary treatment and could engender significant cost savings; 14 weeks of treatment in those achieving an RVR could save about 32% in therapy cost and drug exposure.18 However, exceptions might apply to certain subgroups. Avoiding therapy truncation might be prudent in heavier patients until further studies are performed. Likewise, it might be reasonable to offer the traditional 24-week treatment duration for those patients with high viral load and genotype 3 or in those with advanced fibrosis, barring further data. The GET-C study, a prospective, randomized trial initiated in Australia, will help to determine the optimum treatment duration for those genotype 3–infected patients with high viral loads.27 Genotype 1 In the more difficult to treat, genotype 1–infected HCV patients, treatment is typically given for 48 weeks.5,6 However, it is possible that for some of these patients, a full 48-week therapy course might be unnecessary. Irrespective of whether IFN is used as monotherapy28 or as dual therapy combined with ribavirin,29 baseline viral load affects treatment responsiveness. In treatment trials with standard IFN plus ribavirin, pa-
tients with low baseline viral loads and genotype 1 virus had reasonable SVR rates even when treated for 24 weeks.30,31 Until recently, it was unclear whether genotype 1– infected patients with low levels of HCV RNA could be similarly treated for 24 weeks with newer PEG-IFN regimens. In a randomized, phase III trial that examined therapy duration in treatment-naïve patients, 36% of more than 700 patients with genotype 1 infection achieved an SVR after 24 weeks of treatment with PEG-IFN alfa-2a plus ribavirin.5 An analysis of this trial sought to identify factors predictive of an RVR and SVR in those given this abbreviated therapy course.32 Among patients who achieved a 4-week RVR, there was no significant difference in rates of SVR in patients treated for 24 or 48 weeks. Conversely, the highest SVR in patients without an RVR was in those treated for 48 weeks. A regression analysis demonstrated that a low baseline HCV RNA level was the only independent factor predictive of an RVR in those patients treated for 24 weeks. Patients with baseline HCV RNA levels of ⬍200,000 IU/mL and between 200,000 – 600,000 IU/mL were more likely to achieve an RVR than those with baseline levels ⬎600,000 IU/mL (P ⬍ .0001 and P ⬍ .0057, respectively). The authors concluded that an RVR is the single best predictor of an SVR, and those likely to achieve it are those with low baseline viral loads. In an international, randomized, controlled study of treatment-naïve chronic HCV patients comparing treatment tailored by virologic response with standard-of-care therapy,33 genotype 1–infected patients who experienced
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a ⱖ2-log HCV RNA decrement at 4 weeks achieved an SVR rate of 65% when treated for 24 weeks; however, this was statistically inferior to the SVR rate in those patients achieving this same milestone who received 48 weeks of therapy (83%). Nonetheless, the difference was not statistically significant in those in whom the baseline viral load was low (HCV RNA ⬍800,000 IU/mL). Thus, it might be possible to treat for 24 weeks without losing efficacy in those patients attaining RVR with genotype 1 infection and low levels of baseline viremia. Similar conclusions come from another recently completed trial. Zeuzem et al34 completed a phase IV, single-arm, open-label, historical control trial conducted in 43 European centers. Two hundred thirty-seven genotype 1–infected HCV patients with baseline viremia ⬍600,000 IU/mL were treated with PEG-IFN alfa-2b plus weight-based ribavirin for 24 weeks. Subjects were compared to a historical control arm of 38 patients from the registration trial of PEG-IFN alfa-2b3; these “control” patients were selected if they had received PEGIFN alfa-2b plus ribavirin dosed at ⱖ10.6 mg/day for 48 weeks. Although SVR rates were inferior in the investigational arm (50% for 24 treatment weeks) compared with the control arm (71% for 48 treatment weeks), the subgroup of patients who were RNA negative at 4 weeks (47% of all subjects treated for 24 weeks) had similar rates of SVR to those in the control group (89% vs 85%, respectively). In multivariate analysis, only baseline HCV RNA levels (P ⬍ .0001) and therapy duration for 16 weeks or longer (P ⫽ .0135) were independent predictors of SVR. Treatment discontinuations or dose reductions for adverse events occurred at significantly lower rates than those in the historical control arm, supporting the notion that shorter treatment durations provoke fewer side effects. The authors concluded that most chronically infected HCV patients with genotype 1 infection should be treated for 48 weeks. However, those genotype 1–infected patients with low levels of baseline viremia achieving an RVR at 4 weeks can be treated successfully for 24 weeks. A criticism of this study is the historical control group taken from a previously released protocol from more than a half decade ago. Only 12% of the cohort was analyzed, because those selected had to satisfy a number of criteria. For example, the patients were selected if they had received ⱖ10.6 mg/day of ribavirin; this selected out relatively lean patients. Furthermore, only those patients who had viral loads tested frequently could be analyzed, which might have biased the control group toward optimal adherence.35 Another limitation was the low mean
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fibrosis score in the investigational arm (Knodell score, 1.2). Thus, it would be imprudent to draw any conclusions about using abbreviated treatment courses in genotype 1–infected patients with advanced fibrosis. Despite these criticisms, the European Commission has approved revised dosing instructions for PEG-IFN alfa-2b that includes a 24-week course of combination therapy with ribavirin for those patients with genotype 1 infection, low viral load, and undetectable viremia at 4 weeks of treatment.36 Preliminary results of an economic analysis have affirmed a minimum 27% cost savings if genotype 1– infected patients with low viral loads are treated for 24 weeks.37 Finally, preliminary results are available from another prospective, randomized, multicenter trial designed to determine whether response rates in genotype 1–infected patients could be improved by individualizing treatment on the basis of viral kinetics.38 All 366 patients were treatment-naïve and infected with either genotype 1 or genotype 4 virus. Patients were treated with PEG-IFN alfa-2a plus weight-based ribavirin. Results are available from the subgroup of patients who had undetectable (⬍50 IU/mL) HCV RNA at 4 weeks of therapy. These patients, whom the authors deem “super responders,” were treated for only 24 weeks (approximately 30% of patients). Of the genotype 1–infected super responders, 82% achieved an SVR. When results were stratified by viral load, those with low levels of viremia attained an SVR of 92%; yet even those with high viral load had an SVR of 74%. The authors concluded that treatment duration in patients with genotype 1 infection should be based on RNA levels at 4 weeks. The limitation of the study is the absence of a control arm that likewise achieved RVR, but that was given the standard 48-week therapy duration. A suggested treatment algorithm for genotype 1–infected chronic HCV patients and low viral loads is shown in Figure 2.
Therapy Extension Although it might be feasible to curtail therapy duration in certain patients, it might also be worthwhile to extend treatment duration in more difficult to treat patient subgroups. Patients with genotype 1 infection and high baseline viral load represent up to 50% of typical USA chronic HCV patients,39 and when treated for 48 weeks, they achieve lower rates of SVR than those with more favorable characteristics.3,4 Prolonging therapy beyond 48 weeks might improve response rates in these patients.
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Figure 2. Alternative treatment algorithm for chronic hepatitis C patients infected with genotype 1 virus and low viral load (⬍800,000 IU/ mL). Not recommended for patients with advanced fibrosis. aAlternatively, use 1000 –1200 mg ribavirin daily; busing qualitative or sensitive RNA assay; cif 12-week EVR achieved but RNA still detected, consider checking 24-week RNA; if positive, stop treatment.
In a retrospective analysis17 of data from more than 1000 adults with chronic HCV treated with either PEGIFN alfa-2a with or without ribavirin or standard IFN alfa-2b plus ribavirin,4 the probability of an SVR increased with the rapidity of viremia suppression. Conversely, those patients with the slowest rate of HCV RNA diminution had poorer response rates. In fact, those patients who had delayed or slow virologic response (ⱖ2-log drop in baseline viral load at 12 weeks but RNA still detectable) experienced high rates of relapse. Thus, prolongation of therapy in these “slow responders” could potentially improve rates of SVR. Several authors have attempted to improve response rates by extending therapy in those patients with genotype 1 infection who exhibit a slow or delayed response to therapy. A group of investigators sought to determine whether the state-of-the-art 48-week treatment duration for genotype 1–infected patients was adequate. Drusano and Preston40 hypothesized that the longer the duration of HCV viral load undetectability during therapy, the better the probability of an SVR. Data were examined from a large phase III, multicenter, randomized trial of PEGIFN alfa-2b plus ribavirin3 to develop a treatment model based on the duration of viremia suppression. The patients analyzed were those from whom a complete set of serial viral load findings were available, which included 771 of 1000 patients in a model-building group and 229 of 411 patients in a model-validation group. The impact of 11 different variables on the probability of therapy failure was examined by logistic regression; demographic
(eg, race), biochemical (eg, baseline ALT), and virologic (eg, genotype) variables were included. The authors built a prediction model on the basis of the above covariables. Of all the variables, the duration of viral clearance had the strongest effect on the probability of SVR. The model was highly statistically significant (P ⬍ .001). When the model was applied to the modelvalidation group, it predicted SVR well (positive predictive value, 96.9%; negative predictive value, 91.3%). In patients with genotype 1 infection, an undetectable HCV RNA was required for 32 continuous weeks to have an 80% chance of SVR. For a 90% chance, the required duration of undetectable viremia was 36 weeks. The average time to clear serum of genotype 1 virus was 30.4 weeks; thus, the authors concluded that the standard 48-week duration of therapy for genotype 1–infected patients is suboptimal. It was estimated that rates of SVR could be improved by approximately 14% if this model were used to customize therapy duration. Limitations of this study were its retrospective data analysis and the selecting out of adherent patients because of the serial viral load testing requirement. Even if this model were prospectively validated, it might not be cost-effective because monthly viral loads might be costprohibitive. Furthermore, patients received 800 mg of ribavirin, which limits the model’s applicability regarding genotype 1–infected patients who have improved SVR rates with weight-based ribavirin dosing.41 A group of investigators from Spain and Israel first showed that therapy extension of PEG-IFN plus ribavirin in
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slow virologic responders might be beneficial.42 Eight genotype 1–infected patients with high viral load were given 72 weeks of PEG-IFN-2b (1.0 m · kg⫺1 · week⫺1) plus ribavirin (900 mg/day). All were slow virologic responders as defined by a ⱖ2-log decrease in baseline viremia yet detectable HCV RNA at 12 weeks (EVR achieved). Seven of 8 patients treated for 72 weeks achieved SVR (88%); this result stands in contrast to an SVR of 21% in slow responders treated for 48 weeks in the registration trial for PEG-IFN alfa-2b plus ribavirin.16 Obviously the sample’s small size limits the study’s conclusions. Furthermore, the dosing of both the PEG-IFN and ribavirin used in this protocol was suboptimal. Further support for treatment extension in late responders comes from analysis of a retrospective review of a German multicenter trial.43 Late virologic response was defined by virus detectability at 12 weeks of treatment but undetectability at 24 weeks. Four hundred fifty-six genotype 1–infected treatment-naïve patients were randomized to 48 or 72 weeks of treatment with PEG-IFN alfa-2a plus ribavirin. No statistically significant differences were noted between the 2 treatment groups in baseline characteristics or in overall rate of SVR (53% in 48-week group and 54% in 72-week group; P ⫽ .8). When data were analyzed according to late virologic response, however (22% of all patients studied), late virologic responders in the 72-week group had a significantly lower rate of relapse than the relapse rate in late responders treated for 48 weeks (40% vs 64%, respectively; P ⫽ .021). At week 12 of treatment, only patients with low-level viremia (⬍6000 IU/mL HCV RNA) were found to have benefited from therapy prolongation (91% relapse for 48-week treatment vs 87.5% relapse for 72-week treatment, P ⫽ not available, but significant). The authors concluded that in patients with slow virologic response, relapse rates can be reduced by extending therapy to 72 weeks. The study’s drawbacks are the use of a suboptimal ribavirin dosing for genotype 1 infections (800 mg/day) and its retrospective and subgroup analysis.
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Finally, preliminary results from a large phase III trial might also support treatment extension beyond 48 weeks.44 The TeraViC-4 study is a randomized, multicenter clinical trial from Spain that evaluated the effects of therapy duration with PEG-IFN alfa-2a and ribavirin in treatment-naïve patients. Three hundred twenty-seven of the 517 enrolled patients who did not achieve an RVR were randomized to 48 or 72 weeks of therapy. The SVR rate was significantly higher in those treated for 72 weeks versus 48 weeks in all genotypes (45% vs 32%, P ⫽ .014). An even greater difference in SVR rates was seen in those with genotype 1 infection treated for 72 versus 48 weeks (44% vs 28%, P ⬍ .001). In addition, the frequency of adverse events was similar in the standard duration and extended duration groups. The authors conclude that prolonging treatment duration from 48 to 72 weeks in slow responders (those without an RVR) can significantly improve SVR without compromising safety. As in the previous study, the ribavirin dose was low. It is unclear whether using weight-based ribavirin dosing for genotype 1 infection (the current standard of care) would yield similar results.
Conclusion On the basis of available evidence, it might be possible to individualize therapy of certain treatmentnaïve chronic HCV patients by truncating or extending standard durations of therapy (Table 2). For genotype 2– or 3–infected patients treated with weight-based dosing of ribavirin who achieve an RVR, it might be reasonable to stop treatment as early as 12 weeks. However, difficult-to-treat subgroups such as those with advanced fibrosis and cirrhosis, HCV– human immunodeficiency virus coinfection, and genotype 3 infections with high viral loads likely need longer durations of treatment. Likewise, those with genotype 1 infection and low levels of baseline viremia achieving a 4-week RVR might have respectable rates of SVR with merely 24 weeks of therapy.
Table 2. Potential Modifications to Chronic Hepatitis C Treatment Algorithms by Using PEG-IFN Plus Ribavirin Genotype
Treatment modification
References
Two or threea Two or three
12–16 weeks of therapy for patients with 4-week RVRb Extended therapy beyond 24 weeks for patients without 4-week RVR 24 weeks of therapy for patients with low viral load 72 weeks of therapy for patients with slow virologic response
18, 19, 21 NA
Randomized, controlled, trial NA
31, 32, 35 31, 41–43
Open label trial with historical control Preliminary data from randomized trial
Onec One
NA, not available. those with advanced fibrosis or genotype 3–infected patients with high viral loads. bPatients treated with weight-based ribavirin. cExcluding those with advanced fibrosis. aExcluding
Best supportive evidence
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BRIAN L. PEARLMAN
Albeit promising, data are less satisfactory for extension of therapy to 72 weeks in genotype 1–infected patients who are slow virologic responders. For these patients, prospective trials are warranted with weightbased ribavirin dosing. Furthermore, studies are needed to clarify the optimum treatment duration in patients failing to achieve an RVR and in difficult-to-treat individuals such as African Americans. A randomized trial from Australia, the GET-C study, will prospectively determine whether patients with genotype 3 infections and high viral load require longer treatment duration. Tremendous advantages can be realized with treatment individualization; therapy truncation might engender cost savings and diminished exposure to medication side effects, whereas therapy extension might improve rates of SVR. Clearly, the “one size fits all” algorithms for chronic HCV infection treatment no longer apply; the era of individualization for IFN-based therapy has arrived.
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Address requests for reprints to: Brian Pearlman, MD, FACP, Center for Hepatitis C, 315 Boulevard NE, Suite 200, Atlanta, GA 30312. e-mail: [email protected]. Dr Pearlman is on the Speakers Bureau for Schering-Plough, the manufacturer of one of the interferon molecules mentioned in this article (PEG-Intron).