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Keywords:

  • chronic hepatitis C genotype 1;
  • non responder;
  • therapeutic options;
  • treatment options

Abstract

  1. Top of page
  2. Abstract
  3. Treatment-naïve patients
  4. Relapsers and nonresponders
  5. Long-term maintenance therapy
  6. Conclusion
  7. Conflicts of interest
  8. References

Most infections with hepatitis C virus (HCV) fail to resolve spontaneously and progress to chronic hepatitis C. Genotype 1 HCV accounts for most hepatitis C infections in North America, Western Europe, and Japan. Patients infected with HCV genotype 1 are the most resistant to treatment, which results in poor treatment outcomes. Although sustained virologic response (SVR) rates have significantly improved with introduction of combination therapy with pegylated interferon alfa and ribavirin, the rates are still lower than those in genotype 2 or 3 infections. This review discusses how treatment outcomes in patients with HCV genotype 1 infection can be optimized by using the drugs currently licensed for treatment of hepatitis C: pegylated interferon alfa-2a/b and ribavirin. Dose modifications and variations of treatment duration are the two strategies that have been investigated best, so far. Treatment – naïve patients and non-responders and relapsers to prior antiviral therapy are discussed separately.

Abbreviations:
BMI,

body mass index;

cEVR,

complete early virological response;

EVR,

early virological response;

G1,

genotype 1;

HCC,

hepatocellular carcinoma;

HCV,

hepatitis C virus;

IFN,

interferon;

NIH,

The National Institutes of Health;

NPV,

negative predictive value;

PCR,

polymerase chain reaction;

PEG-IFN,

pegylated interferon;

pEVR,

partial early virolgical response;

PPV,

positive predictive value;

RBV,

ribavirin;

RNA,

ribonucleic acid;

RVR,

rapid virological response;

SVR,

sustained virologic response

Chronic hepatitis C is a major health concern. The most recent estimates indicate that more than 170 million people are infected worldwide, and approximately 280 000 deaths each year are attributable to chronic hepatitis C virus (HCV) infection (1, 2). Complications of HCV infection, such as cirrhosis and its sequelae, including liver failure and hepatocellular carcinoma, may result in liver transplantation and long-term care, which consequently imposes a significant burden on the healthcare system (3). Eradication of HCV by antiviral therapy improves liver histology and patient outcome (3–5). Therefore, sustained virologic response (SVR), defined as undetectable serum HCV RNA (<50 IU/ml) by a sensitive molecular assay 24 weeks after the end of treatment, is the main goal of antiviral therapy in chronic hepatitis C. However, by current standard therapy with pegylated interferon-alfa (IFN) in combination with ribavirin (RBV) given for 48 weeks, rates of SVR are still unsatisfying, especially for patients with a HCV genotype 1 infection. Whereas SVR can be achieved in 81 to 84% of patients with a HCV genotype 2 or 3 infection after 24 weeks of combination therapy, the rate of SVR is much lower in patients with a HCV genotype 1 infection. These patients show only a SVR rate of 34 to 52% after 48 weeks of combination therapy with pegylated IFN-α and RBV (6–8). Management of HCV genotype 1 infected patients with relapse or non-response to prior antiviral therapy is even more challenging than management of treatment-naïve patients.

Improvements in the management of patients with chronic HCV genotype 1 infection are urgently needed. The primary goal of all efforts must be an increase in the rates of SVR. Moreover, a reduction of the sometimes severe treatment related morbidity is warranted. This review discusses, how treatment outcomes in patients with HCV genotype 1 infection can be optimized by using the drugs currently licensed for treatment of hepatitis C: pegylated interferon alfa-2a/b and ribavirin. Dose modifications and variations of treatment duration are the two strategies that have been investigated best, so far. Treatment – naïve patients and non-responders and relapsers to prior antiviral therapy are discussed separately.

Treatment-naïve patients

  1. Top of page
  2. Abstract
  3. Treatment-naïve patients
  4. Relapsers and nonresponders
  5. Long-term maintenance therapy
  6. Conclusion
  7. Conflicts of interest
  8. References

Drug dosing and adherence

Weight-based versus fixed ribavirin dosing

Ribavirin dosing can influence treatment outcomes. Data from large clinical trials suggest that an adequate balance between efficacy and tolerability can be achieved when using a ribavirin dosage in the range of 11–15 mg/kg/d (9).

Two large trials confirmed superiority of weight-based ribavirin doses in HCV genotype 1 infected patients, compared with fixed doses of 800 mg/d ribavirin (7, 10). Weight-based dosing was particularly effective in the difficult-to-treat patient subgroups, namely those with HCV genotype 1 infection (34 vs 28.9%; P=0.005), HCV genotype 1 infection and high viral load (31.2 vs 26.7%; P=0.056), and African American patients with HCV genotype 1 infection (21 vs 10%; P=0. 0006) (10, 11).

A small, prospective study of 10 patients with HCV genotype 1 infection and high baseline viral load (>800 000 IU/ml) showed the feasibility of treatment with even higher doses of ribavirin without major treatment interruption (12). Ribavirin dose was calculated from a pharmacokinetic formula based on renal clearance to achieve a steady state ribavirin concentration of >15 μmol/ml. After dose adjustments, at week 24, the average ribavirin dosage administered was 2540 mg/d (range: 1600–3600 mg). Following this regimen, individualized ribavirin dosing with standard PEG-IFN alfa-2a therapy yielded SVRs in 9 of 10 patients. However, prophylactic and as-needed administration of erythropoietin and blood transfusions were required in single patients.

Adherence

As with other chronic viral infections, such as HIV, adherence to treatment enhances the likelihood of therapeutic response. Patients undergoing PEG-IFN alfa – based therapy are subjected to regular subcutaneous injections, twice-daily oral administration of ribavirin, regular monitoring, and drug-related side effects, which results in noncompliance or even discontinuation of therapy in some patients.

A retrospective analysis of data from three previous trials involving 1521 patients treated with IFN alfa-2b, PEG-IFN alfa-2b, or PEG-IFN alfa-2b plus ribavirin evaluated the impact of adherence to therapy on SVR (13). Among HCV G1 infected patients who were adequately compliant, defined as having received ≥80% of their total PEG-IFN alfa (1.5 μg/kg/week) and ribavirin (>10.6 mg/kg) dosages for ≥80% of the expected duration of therapy, SVR rates were significantly higher than in those patients who were less compliant (63 vs 34%; P=0.008). Adherence in the real-world, community setting may be lower than in the clinical trial setting, which makes efforts to monitor and enhance adherence more critical to improve patient outcomes.

Treatment duration

The standard duration of therapy with PEG-IFN alfa/ribavirin combinations is 48 weeks for patients with HCV G1 infection. However, several factors – positively or negatively – affect treatment outcome. Among these factors, viral load before treatment and HCV RNA decline during early therapy are most important for prediction of SVR (14).

Therefore, HCV RNA levels are monitored before initiation of treatment and during the first 12 weeks of therapy. Early virologic response (EVR) is defined as either a≥2 log10 reduction (partial EVR, pEVR) or undetectable serum HCV RNA at 12 weeks (complete EVR, cEVR), determined by a sensitive molecular test.

Fried et al. first recognized the prognostic value of EVR (6). Their pivotal observation acknowledged that not attaining EVR at week 12 was associated with failure to attain SVR in 97% of patients (negative predictive value [NPV]). Conversely, the positive predictive value (PPV) of the week 12 EVR (the proportion of patients with EVR who attain SVR) was 65% (6). Similarly, a retrospective analysis of data from the Manns et al. study revealed that the overall PPV of patients attaining EVR was 72%, whereas the overall NPV for patients attaining EVR was 100% (15). Based on these data, failure to reach EVR at week 12 is currently used for early identification of non-responders to therapy and for early treatment discontinuation in these patients (16–22).

Shortening treatment duration

More recently, virologic response at 4 weeks (RVR; defined as undetectable serum HCV RNA by sensitive molecular test at week 4) was evaluated as a method for identifying rapid responders in whom shorter duration of treatment may be appropriate (23–27).

Up to 47% of patients with HCV genotype 1 infection – and especially those with a low baseline viremia – achieve RVR during antiviral therapy with PEG-IFN alfa and ribavirin (12–47%) (23–30). Jensen et al. (24) reported in a post hoc analysis of the data of Hadziyannis et al. (7) that approximately one third of patients with HCV G1 can be successfully treated with a 24-week regimen. Overall, 89% of patients who attained RVR attained SVR. Among the variable treatment regimens investigated in this analysis, SVR rates ranged between 73% (in patients receiving PEG-IFN alfa 2a 180 μg/week plus ribavirin 800 mg/d for 48 weeks) and 91% (PEG-IFN alfa 2a 180 μg/week plus ribavirin 1000–1200 mg/d for 48 weeks) in patients who attained RVR. In contrast, SVR rates were in the range of 16% (PEG-IFN alfa 2a 180 μg/week plus ribavirin 800 mg/d for 24 weeks) to 44% (PEG-IFN alfa 2a 180 μg/week plus ribavirin 1000–1200 mg/d for 48 weeks) in patients who did not attain RVR. In this study, the principal difference between patients who attained RVR and those who did not was the incidence of relapse after completion of treatment. Though end-of-treatment response rates were similar to SVR rates in patients who attained RVR (73–97 vs 73–91%), in patients who did not attain RVR, there was a marked decrease in response rates from end of treatment to end of follow-up (56–70 vs 16–44%) (24). In accordance with these data, a recent prospective trial by Ferenci et al. reported a SVR rate of 80% in patients with an RVR and a HCV genotype 1 or HCV genotype 4 infection treated with PEG-IFN alfa 2a 180 μg/week plus ribavirin 1000/1200 mg/day for 24 weeks (23). In this trial, comparison of baseline characteristics revealed significant differences between patients with or without RVR. A younger age, lower body weight, genotype 4 and a low baseline HCV RNA were significantly associated with an RVR. Among patients with RVR no additional baseline predictors for SVR could be identified. A baseline viral load of more than 800 000 IU/ml appeared associated with treatment failure in patients with RVR, although this trend was not statistically significant (23).

Two further studies also suggest, that baseline viremia has an important impact on treatment outcome in patients with RVR and treatment duration for 24 weeks (25, 26). Mangia et al. reported lower rates for SVR in patients with RVR and a baseline viral load ≥400 000 IU/ml with 24 weeks compared with 48 weeks of PEG-IFN alfa 2a/b plus ribavirin (73% [57/78] versus 87% [33/38], P=0.14). In patients with RVR and a baseline viral load <400 000 IU/ml SVR rates were comparable between both treatment groups (84% [38/45] and 83% [20/24] for 24 and 48 weeks of treatment, respectively; P=0.83 (25). Yu et al. (26) also observed similar SVR rates between the 24-week and 48-week arms of therapy with PEG-IFN alfa 2a (180 μg/week) plus ribavirin (1000/1200 mg/d) in patients with RVR and a baseline HCV RNA <400 000 IU/ml (96 and 100%, respectively). When SVR rates of all patients with RVR irrespective of their baseline viral load were compared, the shorter treatment duration was inferior to the 48-week regimen mainly due to a higher relapse rate (89 versus 100%, P=0.056).

So far, no consensus has been established which cutoff for baseline HCV RNA might discriminate best between patients with RVR who are sufficiently treated with 24 weeks and these who will need 48 weeks of PEG-IFN alfa 2a/b and ribavirin to optimise treatment outcome. While the latter two trials report a cutoff at 400 000 IU/ml, another trial used a cutoff at 600 000 IU/ml (27) and the trial by Ferenci et al. (23) applied a cutoff at 800 000 IU/ml for baseline HCV RNA. This question needs to be addressed prospectively in future clinical trials.

Lengthening treatment duration

The possible benefits of extending treatment beyond 48 weeks to improve SVR rates in patients with HCV genotype 1 were investigated in several recent studies (25, 28, 30, 31). In a multicenter, prospective, randomized trial Berg et al. evaluated the relative efficacy of 48 versus 72 weeks of treatment with PEG-IFN alfa-2a (180 μg/week) plus ribavirin (800 mg/d) in 455 treatment-naïve patients with HCV G1 infection. The overall rate of SVR did not differ between 48 or 72 weeks of treatment (53 vs 54%, P=0.80). Patients who attained RVR or EVR attained excellent SVR rates, ranging from 76–84%, independent of treatment duration. Patients who had detectable HCV RNA at week 12 showed significantly higher SVR rates when treated for 72 weeks than when treated for 48 weeks (29 vs 17%, P=0.04). The benefit of extending treatment duration was most obvious in slow virologic responders (patients who had detectable HCV RNA at week 12 but undetectable HCV RNA at week 24), with relapse rates of 40% (72-week treatment) versus 64% (48-week treatment) (P=0.021). Overall, the authors concluded that extended treatment, though not generally recommended for patients with HCV genotype 1 infection, may be appropriate for the subset of patients who are slow virologic responders.

A recent study by Pearlman and colleagues reported similar observations in HCV genotype 1 infected “slow responder” patients (31). In this study, treatment-naïve patients with chronic hepatitis C were treated with 1.5 μg/kg/week PEG-IFN alfa-2b and weight-based ribavirin (800–1400 mg/day). Patients (n=101) considered slow virological responders, defined as patients who achieved at least a 2-log reduction in HCV RNA from baseline, yet, had detectable HCV RNA at 12 weeks (PCR, TaqMan, Roche, detection limit 10 IU/ml) were randomized 1:1 to continue treatment for a total of 48 or 72 weeks. Overall SVR rates were significantly higher in the 72-week treatment group than in the 48-week treatment group (38 vs 18%, respectively; P=0.026). The SVR rate observed in the 72-week treatment group is remarkable considering that, in addition to being infected with HCV G1, these patients had several other negative prognostic factors at baseline, including African American race (48%), high baseline viral load (78%), F3/4 fibrosis (26%) and high BMI (≥30 kg/m2; 34%).

Whereas the above described studies evaluated treatment extension in patients with pEVR but slow response at week 12, TeraViC-4 examined treatment extension for patients without RVR (HCV RNA >50 IU/ml) at week 4 (30). In this study, treatment-naïve patients without RVR were randomly assigned to continue receiving PEG-IFN alfa-2a (180 μg/week) plus RBV (800 mg/d) for a total of 48 (group A, n=165) or 72 weeks (group B, n=161). Patients with undetectable HCV RNA were allocated to standard treatment according to genotype and baseline viral load: G2/3 patients and G1 patients with baseline viral load ≤800 000 IU/ml continued treatment for an additional 20 weeks (group C, n=148) and patients with HCV genotypes 1/4 and baseline viral load >800 000 IU/ml continued for an additional 44 weeks (group D, n=36). Randomly assigned patients (groups A and B) were included in the efficacy analysis. End-of-treatment response was identical in groups A and B (61%); however, higher relapse significantly affected SVR rates in patients with the shorter treatment regimen. Relapse rates were significantly higher (48 vs 26%; P=0.003) and SVR rates consequently were significantly lower (32 vs 45%; P=0.014) in patients receiving treatment for 48 weeks than in those treated for 72 weeks. These differences remained significant when only G1 patients or only patients with low baseline viral load (≤800 000 IU/ml) were analyzed. When only patients with high baseline viral load were considered, there was a difference in SVR rates between the 48-week and 72-week regimens which did, however, not reach statistical significance.

Moreover, this study questioned the clinical validity of the week 12 stopping rule for patients who do not attain EVR (undetectable HCV RNA or a 2 log10 decrease) (30). As expected, not attaining EVR at week 12 was associated with a high NPV for patients randomly assigned to 48 weeks of treatment (92%). However, in patients treated for 72 weeks, the week 12 NPV decreased to 85%, suggesting that a small population of patients who do not attain EVR may still attain SVR if given an extended duration of therapy. In total, 4 (8%) of 51 patients receiving treatment for 48 weeks and 6 (15%) of 41 patients treated for 72 weeks did not attain EVR yet still reached SVR. A week 24 stopping rule (undetectable HCV RNA or a 2 log10 decrease) was more reliable in this study with NPVs of 94 and 95% for the 48- and 72-week regimens (30).

In a recently published trial (25), Mangia et al. investigated treatment extension to 72 weeks in a subgroup of HCV genotype 1 infected patients who first became HCV RNA negative at week 12 of treatment with PEG-IFN alfa 2a/b plus weight-based ribavirin. After 72 weeks of treatment 33/52 (63.5%) showed an SVR as compared with 8/21 (38.1%) after 48 weeks of therapy (P=0.068).

The above described data demonstrate that a significant number of patients may benefit from extended duration of therapy. However, so far there is no consensus for whom treatment extension should be applied – for patients without RVR or cEVR – and also how long treatment should be extended. This area clearly merits further research.

Individualized treatment duration

The DITTO-HCV study used a dynamically individualized approach to treatment of hepatitis C, basing decisions regarding choice of therapy and treatment duration on initial decline in HCV RNA (32). Among patients with RVR, end-of-treatment responses were 91% in patients receiving combination therapy for 24 weeks and 92% in those treated for the standard (control) 48 weeks. SVR rates were also similar between the 24-week and 48-week regimens (79 vs 85%). However, in G1 patients, SVR rates were lower for the 24-week regimen than for the 48-week regimen, though the difference between these groups was not statistically significant (65 vs 83%). When further stratifying this sample according to baseline HCV RNA, it becomes clear that, in G1 patients with high baseline viral load (>800 000 IU/ml), the 24-week regimen is significantly inferior to the 48-week regimen; however, in G1 patients with low baseline viral load (≤800 000 IU/ml), there was no significant difference in SVR rates between the two treatment durations. In G1 patients with slow partial response, SVR rates were similar in patients who received combination therapy for 72 weeks or 48 weeks (50 vs 43%), whereas, in flat, and null responders, the number of G1 patients in each group was too low (<10) for meaningful comparisons (32).

Berg et al. recently reported on the use of individualized treatment strategies in G1 patients (33). In this study, patients received PEG-IFN alfa-2b (1.5 μg/kg/week) plus weight-based ribavirin (800–1400 mg/d) for 48 weeks or according to an individualized treatment strategy based on time to HCV RNA <615 IU/ml. Patients attaining HCV RNA levels <615 IU/ml at weeks 3, 4, 5, 6, 7, or 8 were treated for 18, 24, 32, 36, 42, or 48 weeks, respectively. Overall, the individualized treatment strategy was less effective than the standard treatment approach, with SVR rates of 34% in patients randomly assigned to the individualized approach and of 48% in patients receiving 48-week standard therapy (P=0.004). The lower SVR rates in the individualized therapy group were attributed to the higher incidence of relapse (32 vs 14%). Among patients undergoing the individualized treatment approach, SVR rates were 63, 57, 41, 35, and 12% in patients treated for 18, 24, 30, 36–42, and 48 weeks, respectively.

In conclusion, to date no valid recommendations for complete individualization of treatment regimens can be given. Further investigations regarding optimal criteria for determination of treatment duration are needed.

Relapsers and nonresponders

  1. Top of page
  2. Abstract
  3. Treatment-naïve patients
  4. Relapsers and nonresponders
  5. Long-term maintenance therapy
  6. Conclusion
  7. Conflicts of interest
  8. References

Nonresponders are defined as patients who have detectable serum HCV RNA at the end of treatment. Relapsers are patients with undetectable HCV RNA at the end of treatment but with detectable HCV RNA at 24 weeks of follow-up (16–22).

In the recent past, physicians were often confronted to patients with non-response or relapse to previous antiviral therapies with IFN monotherapy, PEG-IFN monotherapy or IFN plus ribavirin. For these patients retreatment with the meanwhile established new standard combination therapy consisting of PEG-IFN alfa/ribavirin is a reasonable treatment option. SVR can be obtained in this patient population in 8 to 42% using PEG-IFN alfa/ribavirin combination therapy. Former non-responders respond less well than relapsers. Furthermore, HCV genotype 1, a high baseline viral load and non-Caucasian ethnicity negatively affect treatment outcome (34–36). As in treatment-naïve patients, dose reductions result in reduced SVR rates. Dose reduction of PEG-IFN to equal or less than 60% during the first 20 weeks reduced SVR rates from 17 to 5% (all HCV genotypes). Dose reduction of ribavirin did not impair SVR rates unless ribavirin was interrupted for more than 7 consecutive days or discontinued prematurely. Discontinuation of ribavirin, however, reduced SVR rates to 4% (all HCV genotypes) in the lead-in phase of the HALT-C trial (37).

Today, more and more patients present themselves with failure to PEG-IFN alfa/ribavirin combination therapy. Retreatment of patients with relapse to prior PEG-IFN alfa/ribavirin combination therapy with another course of PEG-IFN alfa/ribavirin leads to SVR rates of 32–34% (all HCV genotypes) (38). The EPIC3 study included also patients with F2 to F4 fibrosis (Metavir) who were nonresponsive to or relapsed after previous therapy with IFN (n=1203) or PEG-IFN alfa-2a/b (n=820) with or without ribavirin. Patients were re-treated with PEG-IFN alfa-2b (1.5 μg/kg/week) and ribavirin (800–1400 mg/d) for 48 weeks. Overall SVR rate was 22%. However, as expected, patients with a HCV genotype 1 infection had a less favorable treatment outcome with a SVR rate of 15% compared to SVR rates of 59 and 45% in patients with HCV genotype 2 or 3 infection. The degree of fibrosis and platelet count at baseline correlated also with treatment outcomes. Patients with a Metavir Score of 4 achieved SVR in 17% whereas patients with a score of 2 showed SVR in 30%. In thrombocytopenic patients with less than 100.000 platelets/mm3 at baseline the SVR rate was low with 8% as compared to a SVR rate of 27% in patients with more than 200.000 platelets/mm3 at baseline (39). Prior relapsers responded better than prior non-responders (38 vs 14%). SVR rates were especially low for non-responders to prior PEG-IFN alfa/ribavirin combination therapy with SVR rates of less than 10% (6–7%, all HCV genotypes). This low rate of SVR in the EPIC 3 trial for non-responders to prior therapy with PEG-IFN alfa plus ribavirin and retreatment with current standard therapy (PEG-IFN alfa/ribavirin combination in standard dose for 48 weeks) was recently confirmed by the REPEAT trial. Only 9% (all HCV genotypes) of patients with prior non-response to PEG-IFN alfa-2b plus ribavirin and retreatment with PEG-IFN alfa-2a and ribavirin combination in standard dose for 48 weeks achieved SVR (40). Therefore, more promising treatment options for these patients are urgently needed.

The available PEG-IFN alfas – PEG-IFN alfa-2a and PEG-IFN alfa-2b – have distinct pharmacokinetic and pharmacodynamic profiles that may result in different clinical efficacies. Therefore, retreatment with one PEG-IFN alfa in nonresponders to the other PEG-IFN alfa might be an option. However, as described above, this strategy led to only 9% SVR in the REPEAT trial, where in one of the four study arms patients with prior non-response to PEG-IFN alfa-2b plus ribavirin received retreatment with PEG-IFN alfa-2a and ribavirin combination in standard dose for 48 weeks (40). The ESPECIAL trial is an ongoing, multicenter trial designed to evaluate the efficacy and safety of weight-based PEG-IFN alfa-2b (1.5 μg/kg/week) plus ribavirin (800–1400 mg/d) in approximately 150 patients with chronic hepatitis C (HCV G1) who either did not respond to or who relapsed after treatment with PEG-IFN alfa-2a (180 μg/week) plus ribavirin (1000 or 1200 mg/d). Results are expected in 2009.

In the REPEAT trial two further strategies were evaluated for their effect on SVR rates, i.e. extension of treatment duration to 72 weeks and high-dose PEG-IFN alfa-2a induction therapy (40). HCV-infected patients who were previously nonresponsive to PEG-IFN alfa-2b plus ribavirin were randomized 2:1:1:2 to four treatment arms: Patients received either high-dose PEG-IFN alfa-2a induction therapy with 360 μg/week PEG-IFN alfa-2a for 12 weeks followed by standard dosing for a total duration of 72 weeks (Arm A, n=317) or 48 weeks (Arm B, n=156) plus ribavirin 1000–1200 mg/d or PEG-IFN alfa-2a standard dosing 180 μg/week for 72 weeks (Arm C, n=156) or 48 weeks (Arm D, n=313). SVR rates were higher in patients treated for 72 instead of 48 weeks, irrespective of induction, with 16% SVR in arm A and 14% in arm C as compared to 7 and 9% in arms B and D, respectively.

Long-term maintenance therapy

  1. Top of page
  2. Abstract
  3. Treatment-naïve patients
  4. Relapsers and nonresponders
  5. Long-term maintenance therapy
  6. Conclusion
  7. Conflicts of interest
  8. References

There are no universal guidelines on maintenance therapy for patients who were nonresponsive to IFN alfa–based therapies, so far. Final data are available of two large multicenter trials evaluating potential benefits of maintenance therapies – the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial, sponsored by the NIH, and the Colchicine vs PEG-IFN alfa-2b Long-Term (COPILOT) study.

The COPILOT study was a randomized, open-label, active control, parallel-group study designed to compare a low, weekly dosage of PEG-IFN alfa-2b (0.5 μg/kg/week) versus colchicine (0.6 mg twice daily) (41). The primary outcome of this study was to determine the effect of treatment on 4-year survival or hepatic transplantation; variceal or portal hypertensive bleeding; development of jaundice, ascites, encephalopathy or hepatocellular carcinoma; and deterioration of Child–Pugh–Turcotte score. 555 patients with prior failure to IFN-based antiviral therapy were randomized to PEG-IFN alfa-2b (n=286) or colchicine (n=269). Twenty percent of patients showed a clinical endpoint within the study period. Development of a hepatocellular carcinoma was more often observed in patients on PEG-IFN alfa-2b (n=26) than in patients on colchicine (n=12). Complications of portal hypertension, above all variceal hemorrhage, were more common in the colchicine (n=39) than in the PEG-IFN alfa-2b (n=26) group. Only in patients with portal hypertension at 2 and 4 years PEG-IFN alfa-2b was superior to colchicine with respect to event free survival. Premature discontinuation of medicine was common (49% of patients), mostly due to failure to comply (36%) and to a lesser extent due to side effects (13%).

The HALT-C trial was a prospective, randomized, controlled study of long-term maintenance therapy with PEG-IFN alfa-2a in patients with chronic hepatitis C and advanced fibrosis or cirrhosis (Ishak 3–6) who did not attain SVR after treatment with IFN alfa or IFN alfa plus ribavirin (36). The HALT-C trial consisted of two phases: a lead-in phase (see above) and a long-term maintenance phase. In the lead-in phase, patients received PEG-IFN alfa-2a (180 μg/week) plus ribavirin (1000 or 1200 mg/d). Patients with detectable HCV RNA after 20 weeks of combination therapy entered the maintenance phase and were randomly assigned to receive either 90 μg/week PEG-IFN alfa-2a or no treatment at all for an additional 3.5 years. 1050 patients who failed to achieve SVR with PEG-IFN 180 μg/week and RBV during the HALT-C lead-in phase were evaluated. 517 patients were randomized to maintenance PEG-IFN 90 μg/week and 533 received no additional treatment for 3.5 years (controls). By the end of the study period, after 3.5 years, there was no difference between the control group and treated group in the frequencies of study endpoints like death, hepatic decompensation or development of HCC (33.8 vs 34.1%, respectively) (42). The risks for development of HCC were further evaluated in a later analysis of the HALT-C study cohort (43). Whereas the cumulative five year incidence was not significantly different between treated and untreated patients (5.7 and 5.1%, respectively, P=0.91), the presence of cirrhosis significantly enhanced the rate of HCC development as compared to bridging fibrosis in the liver histology (7.2 vs 4.2%, P=0.03). Older age, lower BMI, lesser physical activity, low platelet count, higher alkaline phosphatase, and higher des-gamma-carboxy prothrombin also increased the risk for HCC development. Interestingly, a sub-analysis of the HALT-C cohort (379 patients with and 386 patients without maintenance therapy) demonstrated that a marked HCV RNA suppression of at least 4 log during the lead-in phase in 178 patients (23%) significantly reduced the risk for hepatic decompensation, death or HCC whether or not these patients received maintenance therapy (44). The rates of clinical end-points were 20% vs 7–10% for patients with versus without marked viral decline during the lead-in phase of the HALT-C trial (P<0.05).

Conclusion

  1. Top of page
  2. Abstract
  3. Treatment-naïve patients
  4. Relapsers and nonresponders
  5. Long-term maintenance therapy
  6. Conclusion
  7. Conflicts of interest
  8. References

SVR rates in patients with HCV G1 are approximately half the rates attained in patients with HCV G2 or G3. The standard of care for the treatment of HCV G1 patients is a combination of PEG-IFN alfa with ribavirin for 48 weeks. Clinical evidence suggests that the duration of therapy, however, can be adjusted according to baseline viral load and virologic response characteristics, with shorter durations for patients with low baseline viremia and RVR and longer durations for slow virologic responders. Additional changes such as PEG-IFN alfa and ribavirin dosing alterations may also improve outcomes in this subpopulation. Adherence to treatment and dose maintenance is also an important factor for attaining SVR. Failure rates after re-treatment of relapsers or nonresponders are high for HCV G1 patients, particularly those with poor predictive characteristics such as high baseline viremia or advanced fibrosis. Data are promising from recent and ongoing studies investigating combination therapies of PEG-IFN/ribavirin with new antiviral agents and provide hope for a better outcome in patients infected with G1 HCV.

Conflicts of interest

  1. Top of page
  2. Abstract
  3. Treatment-naïve patients
  4. Relapsers and nonresponders
  5. Long-term maintenance therapy
  6. Conclusion
  7. Conflicts of interest
  8. References

Prof. Zeuzem is a consultant and has served on the Speaker's Bureau for Roche Pharmaceuticals, Nutley, NJ, Schering-Plough, Kenilworth, NJ and HGS/Novartis, East Hanover, NJ. The remaining authors declare no conflicts of interests.

References

  1. Top of page
  2. Abstract
  3. Treatment-naïve patients
  4. Relapsers and nonresponders
  5. Long-term maintenance therapy
  6. Conclusion
  7. Conflicts of interest
  8. References
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