Early Hepatitis C viral (HCV) kinetics was previously shown to predict sustained virological response (SVR). The current consensus stopping rule is defined at 12 weeks of treatment with peginterferon-alfa and ribavirin. Earlier prediction is needed in order to improve the cost/effect ratio. However, the predictive value of earlier viral kinetics for the current standard of care has not yet been established.
 

The DITTO-HCV European funded project is for now the largest study of frequent early viral kinetics during therapy with peginterferon-alfa and ribavirin. The researchers aim to optimize viral kinetics prediction criteria in order to enable stopping or tailoring treatment as early as possible.

Primary objectives: 1) negative predictive value (NPV) as close as possible to 100% (thus minimalizing stopped patients with missed SVR), 2) high specificity (thus increasing the fraction of patients that can be safely stopped). 3) a high positive predictive value (PPV) using the same criteria.
 

134 chronically HCV infected naïve patients received peginterferon-alfa-2a (40KD) (Pegasys ®) (180 μg qw) plus ribavirin (Copegus ®) (1000-1200 mg qd) for 48 weeks. Of those, 67%, 28%, 4% and 1% had HCV genotype 1, 2-3, 4 or 5 respectively. Viral kinetics were measured according to centralized serum HCV RNA quantifications on days 0, 1, 4, 7, 8, 15, 22 and 29 (Cobas Amplicor^® HCV Monitor v2, Roche). SVR was defined as undetectable serum HCV RNA (<50 IU/ml) after 24 weeks of follow-up post treatment. The early viral response prediction criteria (EVR) and thresholds tested here (see Table 1 below) were prospectively defined.

Study Results

The overall SVR rate was 64%. The EVR studied, together with their NPV, PPV, specificity (SP), statistical significance and number of HCV-RNA quantifications needed (NSMP), are given in Table 1 below.

TABLE 1

The EVR-w12 criteria has good NPV (100%) but its specificity is low (21%), thus relatively few non-responders can be stopped. None of the simple 2nd-slope or Week-1 criteria shows NPV higher than 90%, thus not adequate for a stopping rule.

 

A new composite criteria (DITTO-2nd-slp) gives NPV=100% and specificity=34% already after 4 weeks of treatment. Furthermore, another new composite criteria (DITTO-1st-week) also gives NPV=100% with specificity=28% already after 1 week.

Although composite, these new criteria are simple to calculate and necessitate only 1 or 2 more viral quantifications compared to the current Week-12 criteria. Thus allowing to lower the mean cost by 2410 USD per patient. Note that SVR (56% for gen 1 and 87% for gen 2-3) is predicted independently of genotype.

 

Moreover, by selecting more strict thresholds for the DITTO-1st-week (e.g. 4.5 log at day 4 and 2 log decline at day 7) and DITTO-2nd-slope (e.g, 0.6 log/week) criteria one can obtain higher PPV up to 90%.

 

Conclusions:

Sustained viral response to treatment with peginterferon-alfa-2a (40KD) and ribavirin can be predicted, independent of genotype, as early as 1 or 4 weeks of treatment by new composite, but still simple and practical, criteria of viral kinetics. Similar NPV and PPV and better specificity was obtained here by the DITTO-1st-week or DITTO-2nd-slope prediction criteria, giving rise to significantly lower cost/effect as compared to the current stopping rule at 12 weeks. These results warrant future prospective testing in larger trials, since they can give rise to considerable saving in cost and quality of life related to over-treatment or alternatively allow early tailoring of treatment.

Discussion

Can the new predictive criteria move the current 12- week stopping rule to under a month?

The DITTO-HCV study retrospectively identified two new criteria to classify rapid viral responders and predict the likely treatment outcome. For the DITTO-1^st week criterion viral levels are measured at baseline and two times in the first week of treatment; while the DITTO-2^nd slope criterion uses three measurements of viral levels between the second and fourth week of treatment. 

“Both of these new criteria predicted who was and who was not likely to respond to treatment more accurately than the existing 12-week stopping rule. We had obtained 100 per cent negative predictive value (NPV) and 90 per cent positive predictive value (PPV) with these criteria” said Professor Avidan Neumann, from the Bar-Ilan University, Israel, and the DITTO-HCV study coordinator who presented the study results at an oral session at AASLD.

Using these criteria for stopping treatment in patients predicted early on not to respond will make treatment more cost-effective, even considering the added cost of the extra measurements of viral load.

“This is good news for patients and physicians.  Using these new criteria, we will be able to very early, identify more of those patients who will ultimately not achieve an SVR so we can advise them to stop taking their medication, thus improving their quality of life,” said Professor Neumann.

“We now know that tailoring treatment according to viral kinetics cannot improve SVR rates with the treatment choices we have at the moment.  However, by measuring viral levels earlier in treatment, a test physicians are already familiar with, we can likely move the stopping rule currently defined at week 12 down to week 4 or even week 1 and avoid having patients who will not achieve an SVR being treated unnecessarily. These novel prediction algorithms will hopefully be confirmed soon by other clinical trials and their feasibility in clinical practice will be assessed, thus allowing us to optimize the treatment of hepatitis C patients," concluded Prof. Neumann. 

10/27/03

Reference
AU Neumann and others. EARLY VIRAL KINETICS PREDICTION OF SUSTAINED VIROLOGICAL RESPONSE AFTER 1 OR 4 WEEKS OF PEG-INTERFERON-ALFA-2A AND RIBAVIRIN THERAPY

A Comparison of Standard Treatment Versus Dynamically Individualized Treatment in Patients with Chronic Hepatitis C
 

Combination therapy with peginterferon alfa and ribavirin for 48 weeks achieves sustained virologic response rates (SVR) of 54-61% in patients with chronic hepatitis C. However, the SVR rates are highly variable according to baseline (HCV genotype) and on-treatment parameters (initial viral decline). Thus, it must be anticipated that current standard therapy recommendations lead to under-treatment in some and over-treatment in other individual patients.
 

Comparison between a dynamically individualized treatment schedule according to the early virologic response versus the standard of care combination therapy with peginterferon alfa-2a (40KD) (Pegasys) (PEG-IFN) (180 μg qw) plus ribavirin (Copegus) (RBV) (1000-1200 mg qd) for 48 weeks.

The primary aim of the study was to increase SVR, while optimizing the available drugs, treatment duration, quality of life and the socio-economical burden of therapy. The secondary aim of the study was to enable a comprehensive analysis of viral/host/immune correlates of response to treatment (ongoing).
 

All patients (n=273) were initially treated with PEG-IFN/RBV for 6 weeks and initial viral kinetics were defined according to centralized serum HCV RNA quantifications (Cobas Amplicor HCV Monitor v2, Roche Molecular Systems) on baseline and days 0, 1, 4, 7, 8, 15, 22 and 29.

After classification into viral response categories at 6 weeks, patients were randomized (n=270) to individualized therapy (arms A1, A2, B1, B2, C, D) or continuation of standard therapy (STD arm). Treatment tailoring included: in rapid viral responders (RVR) - discontinuation of RBV (A1) or shortening of treatment duration to 24 weeks (A2); in slow partial responders (SPR) - addition of histamine (B1) or prolongation of treatment to 72 weeks (B2); in flat partial responders (FPR) - addition of histamine (C); in null responders (NUR) - retreatment with high-dose of PEG-IFN (360 μg qw) plus RBV (D). SVR was defined as undetectable serum HCV RNA (< 50 IU/ml) at the end of 24 weeks of untreated follow-up.
 

Study Results

Demographic and baseline virologic parameters were similar in the standard and the individualized treatment groups. According to the initial viral decline patients were categorized as RVR (51% for genotype 1 and 94% for genotype 2-3), SPR (35% and 5% accordingly), FPR (5% and 0% accordingly), NUR (10% and 1% accordingly) or unclassified (1%). The overall SVR rates for genotype 1 patients were 49% for the individualized and 56% for the standard treatment arm (NS), and for genotype 2-3 patients 90% and 87% respectively (NS). SVR rates (by ITT analysis) according to HCV genotype and within each initial viral response category and arm are given in Table 1 below.

Table 1

Conclusions

The overall sustained virologic response rates of 53% in genotype 1 and 88% in genotype 2-3 patients with chronic hepatitis C treated with Pegasys (peginterferon alfa-2a/40KD) in combination with ribavirin support previously presented data.

Individualized treatment according to initial viral kinetics appears to be clinically feasible, but did not improve the sustained virologic response rate with the drugs and dosages usable at the time of this study.

Nevertheless, the possibility that in rapid viral responders discontinuation of ribavirin does not decrease the sustained virologic response rate warrants future prospective trials.

Discussion

Rapid Viral Responders Have Most Promising Results

Rapid viral responders were prospectively defined as patients whose HCV RNA declined by at least 99 per cent during the first month of treatment. The study found that in this sub-group, even the most difficult-to-treat genotype 1 patients could achieve 83% SVR.

A relatively high SVR rate (71%) was obtained even for the rapid responding patients treated with ribavirin for only the first 6 weeks instead of the standard regimen of ribavirin during the whole peginterferon treatment of 48 weeks. These SVR rates are similar to that achieved by genotype 2/3 patients (88%), who traditionally have been easier to treat.

“It is therefore critical for these rapid responding patients to be identified” said Professor Zeuzem.  

Supported by the European Community (QLK2-2000-00836), Hoffmann La-Roche and Maxim Pharmaceuticals.

10/24/03

References

S Zeuzem and others (for the The DITTO-HCV study--Dynamically Individualized Treatment of Hepatitis C Infection and Correlates of Viral/Host Dynamics study).

INTERNATIONAL, MULTICENTER, RANDOMIZED, CONTROLLED STUDY COMPARING STANDARD VERSUS DYNAMICALLY INDIVIDUALIZED TREATMENT IN PATIENTS WITH CHRONIC HEPATITIS C (DITTO-HCV PROJECT). Abstract 317 (poster). 54^th AASLD. October 24-28, 2003. Boston, MA.

Ribavirin Dosage Significantly Affects Virological Response Rates in HCV Patients Treated with Interferon/Ribavirin
 

The influence of absolute dose and dose in mg per kg body weight of ribavirin on sustained virologic response (SVR) in interferon-based combination treatment of chronic hepatitis C as well as the influence of dose reduction is still controversial.
 

In this study, investigators address this problem by reanalyzing data of 343 previously untreated patients with chronic hepatitis C from a multicenter trial who were treated with Pegasys (interferon alfa-2a) plus ribavirin and amantadine or interferon alfa-2a plus ribavirin (Berg et al, Hepatology 2003, 37, 1359-1367) and completed therapy.

The researchers used a multivariate approach to account for correlations of the dose of ribavirin with body weight and body mass index (BMI) and known predictor variables from this data set which are low baseline HCV RNA, high platelet counts, high pretreatment ALT, and low γ glutamyl transpeptidase (GGT) as well as HCV genotype non-1.
 

Because per protocol, dosage of ribavirin was weight-adjusted (1000 mg for body weight below 75 kg and 1200 mg for body weight 75 kg or more) and body weight was positively correlated with GGT and negatively correlated with platelet counts, respectively, the investigators used a stratification with respect to genotype (GT 1 vs. non-1), GGT, and platelet counts in the analysis of ribavirin dose.

When comparing body weight, BMI, the absolute intention to treat (ITT) ribavirin dose as well as the ITT dose of ribavirin measured in mg per kg body weight and the respective ribavirin doses at the end of treatment (EOT), a significant association with SVR was found for the EOT ribavirin dosage (mg per kg body weight) and BMI (p=1.8% and p=3.0%, respectively).
 

For predicting SVR, a weight-based ribavirin dosage threshold of 13.75 mg/kg was calculated using receiver operating characteristics (ROC) curves. The SVR rate was 66% (112/169) in patients with a ribarivin dose of more than 13.75 mg/kg as compared with 46% (79/172) in patients receiving equal or less than 13.75 mg/kg ribavirin at EOT.
 

In conclusion, the analysis of ribavirin dosage motivates new considerations of weight-adjustments of the ribavirin dosage to further increase SVR in HCV-infected patients treated with combination therapy.

10/27/03

Reference
E Herrmann and others. IMPORTANCE OF RIBAVIRIN DOSAGE ON VIROLOGICAL RESPONSE RATES IN PATIENTS CHRONICALLY INFECTED WITH HEPATITIS C VIRUS AND TREATED WITH INTERFERON-BASED COMBINATION THERAPY. Abstract 296 (poster). 54^th AASLD. October 24-28, 2003. Boston, MA.

Preliminary Data Do Not Support Hypothesis That Higher SVR Rates in Genotype 1 HCV Patients Result from Extending Treatment from 48 to 72 Weeks

Treatment of patients infected with hepatitis C virus (HCV) genotype 1 (G1) remains a challenge necessitating innovative strategies to improve treatment outcome. Viral kinetic studies have shown that turnover of hepatocytes infected with HCV G1 is slower than in other genotypes. This implies that more aggressive antiviral treatments are required in patients infected with HCV G1.

Extending the treatment duration beyond 48 weeks is one strategy that may improve response rates in these difficult-to-treat patients.
The purpose of the current study was to compare the efficacy and safety of 48 weeks versus 72 weeks of treatment with peginterferon alfa-2a (40KD) (PEGASYS) in combination with ribavirin (COPEGUS) in treatment-naïve patients infected with HCV G1.
 

This multicenter, national, randomized, open-label parallel group study was conducted in accordance with local and international GCP guidelines. Treatment-naïve patients infected with HCV G1, aged ≥18 years with CHC infection, HCV RNA levels >1000 copies/mL, elevated ALT levels, liver biopsy findings consistent with a diagnosis of CHC, and compensated liver disease (Child-Pugh grade A) were eligible for the study.
 

After screening and signing of informed consent forms, patients were randomized to treatment with peginterferon alfa-2a (40KD) (PEGASY) 180 μg once weekly plus ribavirin (COPEGUS) 800 mg/day (400 mg BID) for either 48 weeks or 72 weeks. Patients were followed for an additional 24 weeks after the end of treatment. Virological response was defined as undetectable HCV RNA (<50 IU/mL by COBAS AMPLICOR HCV Test, v2.0, Roche Diagnostics) at the end of follow-up.
 

To date 459 patients have been enrolled in the trial and 305 have completed follow-up. The two treatment groups were comparable with regard to baseline characteristics. The results of the study, presented as intent-to-treat, missing data = failure (ITT; M=F), and on-treatment (OT) analysis (only patients with data included) are captured in the Table 1 below.
No major differences were observed in the frequency or intensity of SAEs and AEs.
 

Conclusions

The combination of peginterferon alfa-2a (40KD) (PEGASYS) and ribavirin (COPEGUS) was safe and effective in patients with HCV genotype 1. Despite the use of a dose of ribavirin (800 mg/day) that is lower than the recommended dose for patients infected with G1 (1000/1200 mg/day), approximately half of the patients in the study achieved an SVR.

Because the study could not be blinded, a bias might have influenced the outcome of the study as suggested by the unequal discontinuation rate. These preliminary data do not support the hypothesis that higher SVR rates can be achieved in patients with HCV G1 by extending treatment duration.

^{*ITT population, defined as all patients who took at least one dose of study medication and had at least one HCV RNA evaluation post-baseline.
**Safety population, defined as all patients who took at least one dose of the study medication.}

10/27/03

Reference
T Berg and others (German Pegasys + Copegus Genotype 1 HCV Study Group). COMPARISON OF 48 OR 72 WEEKS OF TREATMENT WITH PEGINTERFERON ALFA-2A (40KD) (PEGASYS^®) PLUS RIBAVIRIN (COPEGUS^®) IN TREATMENT-NAÏVE PATIENTS WITH CHRONIC HEPATITIS C INFECTED WITH HCV GENOTYPE 1. Abstract 328 (poster). 54^th AASLD. October 24-28, 2003. Boston, MA.

Patients with Increased Symptoms of Depression During Interferon/Ribavirin Therapy Are Less Likely to Clear HCV
 

Interferon (IFN)-alfa plus ribavirin is an effective treatment for chronic hepatitis C virus (HCV) infection, but is associated with a high rate of depression. Depressive symptoms have been linked to a worse outcome in a number of medical disorders.

To determine whether increased depressive symptoms during IFN alfa/ribavirin therapy were associated with reduced clearance of HCV, a prospective cohort design was used to evaluate HCV-infected patients at baseline and after 4, 8, 12 and 24 weeks of pegylated IFN-alfa-2b/ribavirin therapy.
 

The sample was derived from patients enrolled in a larger multi-center, randomized clinical trial of PEG-Intron (pegylated IFN-alfa-2b) plus fixed-dose versus weight-based ribavirin. 102 HCV-infected subjects who volunteered to participate and completed 24 weeks of IFN alfa/ribavirin treatment followed by viral load testing were included.

Severity of depressive symptoms was measured by the Zung Self-Rating Depression Scale (SDS). Viral clearance was defined as polymerase chain reaction (PCR) negative (less than 29 HCV IU/ml) at 24 weeks.
 

Study Results

Increased depressive symptoms during IFN-alfa/ribavirin therapy were associated with reduced viral clearance (P=0.006). Only 34% of subjects with a 20-point or greater increase in SDS Index (N=29) were HCV PCR negative at 24 weeks, compared to 63% of patients without a 20-point increase (N=73). These results remained significant after adjusting for ribavirin dose assignment, viral genotype, age, antidepressant usage, IFN-alfa/ribavirin dosage reduction and knowledge of viral load status during treatment.

Cumulative depressive symptoms over the 24 weeks of IFN-alfa/ribavirin therapy also predicted failure to clear virus (P=0.026).
 

Conclusions

HCV patients who experience significant increases in symptoms of depression during IFN-alfa/ribavirin therapy are less likely to clear virus, highlighting the potential importance of identifying and treating depressive symptoms in this patient population.

10/27/03

References
CL Raison and others. DEPRESSIVE SYMPTOMS DURING IFN-ALPHA/RIBAVIRIN THERAPY ARE ASSOCIATED WITH REDUCED VIRAL CLEARANCE IN PATIENTS WITH HEPATITIS C. Abstract 344 (poster). Program and Abstracts of the 54^th AASLD. October 24-28, 2003. Boston, MA.

Age and Adherence Are Significant Predictors of HCV Treatment Success
 

By Brian Boyle, MD

In clinical trials, the overall sustained virological response (SVR) rates to Pegasys (peginterferon alfa-2a) and Copegus (ribavirin) combination therapy for chronic hepatitis C virus (HCV) infection ranged from 56 to 61%.

The probability of achieving an SVR varies significantly depending upon the patient’s HCV genotype, viral load, histological status and other factors. In patients infected with HCV genotype (GT) 1, only pretreatment viral load had a greater influence than age on the probability of achieving an SVR.
 

In a study presented at the 54^th AASLD Conference, investigators evaluated the influence of age and adherence on the probability of achieving an SVR with Pegasys plus Copegus therapy in patient’s infected with HCV GT 1.

The study used data drawn from 2 international, randomized trials, in which 736 patients with chronic HCV GT 1 infection received Pegasys plus Copegus. For the purpose of the analysis, an adherent patient was defined as one who received the assigned dosages of Pegasys/Copegus for ≥80% of the planned duration of treatment.

Of the 736 patients, 336 (45.6%) achieved an SVR and 597 (81.1%) were considered adherent. When the model used in the analysis was programmed for a non-cirrhotic, Caucasian patient with a baseline ALT quotient of 3, HCV RNA level of 3.269 x 10⁶ copies/ml and a BMI of 25, the probability of a 20-year-old patient achieving an SVR was significantly higher than the probability for a 60-year-old doing so (74.4% vs. 44.2%, respectively).

When the model parameters include, in addition to those mentioned above, an assumption that the patient would be adherent, the probability of achieving an SVR increased to 85.4% and 52.9%, respectively.

Based on these data, the authors conclude, “In conclusion, patient age has a profound influence on the probability of achieving an SVR with peginterferon alfa-2a (40KD) and ribavirin therapy.

”Clinicians and their patients should consider the influence of patient age on the timing of the decision to start treatment. With our model, it is possible to predict the probability of achieving an SVR in an individual patient, and to demonstrate the impact of adherence on treatment outcome. This tool will be useful in motivating patients to adhere to treatment.”

10/29/03

Reference
TREATMENT OF CHRONIC HEPATITIS C WITH PEGINTERFERON ALFA-2A (40KD) (PEGASYS^®) AND RIBAVIRIN (COPEGUS^®): PATIENT AGE HAS A MARKED INFLUENCE ON THE INDIVIDUAL ESTIMATED PROBABILITY OF ACHIEVING A SUSTAINED VIROLOGICAL RESPONSE. Program and Abstracts of the 54^th Annual Meeting of the American Association for the Study of Liver Diseases.  October 24-28, 2003. Boston, MA.

Page Reviewed on Oct 27 03

RANTES Haplotypes Predictive of Sustained Virological Response to HCV Treatment

By Brian Boyle, MD

The chemokine RANTES (regulated upon activation, normally T cell expressed and secreted/CCL5) is a potent chemo-attractant for Th1 cells, and different RANTES gene variants affect HIV progression.

Recently the most frequent functional gene variants of RANTES (-403G/A and Intron1.1T/C) were shown to be in linkage disequilibrium in a study presented at the 54^th AASLD, the influence of three common RANTES haplotypes (R1: -403G/Int1.1T, R2: -403A/Int1.1T, R3: -403A/Int1.1C) on clinical, biochemical, and histological parameters of patients with chronic hepatitis C virus (HCV) infection was investigated.

In the study, RANTES variants -403G/A and Int1.1T/C were genotyped by RFLP-PCR analysis in 297 Caucasian patients with chronic hepatitis C and 152 control patients without viral infection. Of all patients with HCV infection, 268 underwent antiviral combination therapy with standard interferon-alpha and ribavirin and had at least one liver biopsy prior to treatment.

The allele frequencies of the -403G/A and Int1.1C/T polymorphisms did not differ between patients with HCV infection and controls. The combined analysis of both polymorphisms revealed three common haplotypes in chronic hepatitis C patients (R1 60.1%, R2 15.3%, R3 24.6%).

The RANTES haplotype R3 was detected significantly less frequently in patients with sustained virological response (SVR) to antiviral therapy (17.3%) compared to non-responders, whereas the other haplotypes were equally distributed between responders and non-responders.

Of note, the difference in RANTES haplotype distribution regarding outcome of antiviral therapy was also apparent in patients infected with HCV genotypes 1 and 4 (n = 209, SVR R3 13.2% vs. non-responders R3 30.0%; OR 2.7, P = 0.02).

Furthermore, in logistic regression analysis RANTES haplotype was associated with treatment outcome independently from HCV genotype and stage of fibrosis/cirrhosis.

Based upon these data, the authors conclude,

(1)     We detected a possible influence of interacting RANTES gene variants on outcome of antiviral therapy with interferon-alpha and ribavirin, which might have been missed in earlier studies investigating the promoter polymorphism -403G/A only.

(2)     Because the RANTES R3 haplotype has been demonstrated to result in down-regulation of RANTES transcriptional activity, these findings might serve to better define the host's polygenic immune response that predisposes to a positive or negative outcome of antiviral therapy in chronic hepatitis C.”

* Additional Sustained Virologic Response Stories from the 54th AASLD

10/31/03
 

Reference
H Wasmuth and others. INTERACTING RANTES/CCL5 GENE VARIANTS MODIFY THE RESPONSE TO COMBINATION THERAPY WITH INTERFERON-ALPHA AND RIBAVIRIN IN PATIENTS WITH CHRONIC HEPATITIS C. Abstract 188 (oral). 54^th Annual Meeting of the American Association for the Study of Liver Diseases. October 24-28, 2003. Boston, MA.

Results of Long-term Follow Up of Sustained Responders to Interferon Therapy in Chronic HCV Patients: A Meta-analysis
 

Sustained virological response (SVR) at six months after treatment is the key outcome for treatment efficacy in hepatitis C. However, reports about the incidence of clinical events during long term follow up of European patients with a sustained response to interferon treatment are scarce.

The objectives of the current study were to determine the virological relapse rate and to assess clinical endpoints during long-term follow-up in European sustained responders to interferon treatment.

In this study, researchers employed a meta-analysis of individual patient data of 8 European follow-up studies.

Study Results

286 sustained responders were followed up for 59 months (range 12-120). Fifteen sustained responders had cirrhosis before treatment. HCV-RNA was detected in 25 (8.7%) of 286 sustained responders; the late relapse rate at five years of follow up was 10.5%.

The only factor predictive of late virological relapse was the total dose of interferon, according to multivariate analysis. 216 MU was associated with the highest late relapse rate.

Two patients originally not classified as having cirrhosis, developed decompensation at 30 and 60 months of follow up (rate of decompensation at 5 year follow up: 1.0%, the latter died of this decompensated cirrhosis.

No HCCs were detected.

The outcome in cirrhotic patients did not differ from other patients with sustained response to interferon.

Conclusions

·         The late virological relapse rate at five years of follow up was 10.5% in sustained responders to interferon treatment;

·         Treatment with a high total dose of interferon reduces the risk of late virological relapse; 

·         The five-year occurrence of clinical events was 1.0 % among 286 sustained responders.

11/10/03

Reference
BJ Veldt and others (for the Eurohep study group). LONG TERM FOLLOW UP OF SUSTAINED RESPONDERS TO INTERFERON ALPHA IN CHRONIC HEPATITIS C: A META-ANALYSIS ASSESSING TRUE CLINICAL ENDPOINTS. Abstract 971 (poster). 54^th Annual Meeting of the American Association for the Study of Liver Diseases. October 24-28, 2003. Boston, MA.

A Dynamic Model to Predict Sustained Virological Response to Combination Treatment with Pegasys and Copegus in Patients with Chronic HCV
 

Overall, 56% of patients achieved sustained virological responses (SVR) after 48 weeks of treatment with the combination of peginterferon alfa-2a (40KD) (PEGASYS^®) 180 μg/week and ribavirin (COPEGUS^®) 1000 or 1200 mg/day in a large international, randomized, phase 3 trial. (Fried et al. N Engl J Med. 2002;347:975-982).

In this study, 97% of patients without an early virological response (EVR), defined as either a ≥2-log₁₀ drop in viral load or complete disappearance of HCV RNA in serum by 12 weeks of therapy, failed to achieve an SVR. This information is useful because it allows for the early termination of treatment in those unlikely to respond to a full course of treatment.
 
The purpose of the current study was to refine the ability to predict the likelihood of achieving a sustained virological response after treatment with peginterferon alfa-2a (40KD) and ribavirin, based on virological response data obtained at week 4 and week 12 of therapy.
 
The dynamic model is based on data from patients treated with peginterferon alfa-2a (40KD) 180 μg/week and ribavirin 1000 or 1200 mg/day for 48 weeks in a large, international, randomized trial (Fried et al. N Engl J Med. 2002;347:975-982).

For the purpose of this analysis, an early virological response (EVR) was defined as undetectable HCV RNA by qualitative polymerase chain reaction (PCR) assay (<50 IU/mL; COBAS AMPLICOR^® HCV Test, v2.0; Roche Diagnostics) or a decrease of ≥2 log₁₀ in HCV RNA levels as determined by quantitative PCR (COBAS AMPLICOR HCV MONITOR^® Test, v2.0; Roche Diagnostics) after 12 weeks of treatment.

For this analysis SVR was defined as a single undetectable HCV RNA level by qualitative PCR on or after week 60. Treatment was to be stopped in patients with detectable HCV RNA after 24 weeks.
 

Study Results
 

A total of 453 patients were randomized to treatment with peginterferon alfa-2a (40KD) and ribavirin and received study medication. The disposition of patients who were HCV RNA negative after 24 weeks of treatment is shown in the Table below and grouped according to their HCV RNA status at week 4, 12 and 24.

Patients with missing data at any of these time points were not included in the analysis. Patients with ≥2-log₁₀ drop in HCV RNA levels at a given time point, and who were negative at the previous and following time point, were grouped with patients assessed as HCV RNA negative at that time point (n = 8).

The probability of achieving an SVR increased in inverse proportion to the time taken to achieve undetectable HCV RNA levels. Thus, the highest SVR rate (89%) and, correspondingly, the lowest relapse rate during follow-up (8%), was obtained in patients who were consistently HCV RNA negative at weeks 4, 12 and 24.
 

Conclusions
 

• The outcome of combination therapy with peginterferon alfa-2a (40KD) (PEGASYS^®) and ribavirin (COPEGUS^®) is highly dependent on the rapidity of the virological response;
• Patients who become HCV RNA negative after 4 weeks have the best chance for achieving an SVR;
• It may be hypothesized that to decrease the frequency of relapse in the remaining patients, treatment longer than 48 weeks may be required. This approach should be tested in a prospective trial.

* End of treatment response (EOT) = HCV RNA negative at week 48.

11/19/03

Reference
P Ferenci and others. A DYNAMIC MODEL TO PREDICT SUSTAINED VIROLOGICAL RESPONSE TO COMBINATION PEGINTERFERON ALFA-2A (40KD) (PEGASYS^®) AND RIBAVIRIN (COPEGUS^®) THERAPY IN PATIENTS WITH CHRONIC HEPATITIS C. Abstract 995 (poster). Hepatology 38:4 (Suppl). October 2003. (54^th Annual Meeting of the American Association for the Study of Liver Diseases. October 24-28, 2003. Boston, MA.)