54th Annual Meeting of
The American Association for
the Study of Liver Diseases
October 24, 28- 2003
Boston, Massachusetts
Page Five
Nonresponders and Relapsers
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http://www.hivandhepatitis.com/2003icr/03_assld/main.html
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 INTERNATIONAL, MULTICENTER, RANDOMIZED, CONTROLLED STUDY COMPARING STANDARD VERSUS DYNAMICALLY INDIVIDUALIZED TREATMENT IN PATIENTS WITH CHRONIC HEPATITIS C (DITTO-HCV PROJECT). Abstract 317 (poster). 54th AASLD. October 24-28, 2003. Boston, MA.
Treatment with PEG-Intron Plus Ribavirin Is
Effective in 50% of Relapsers to Standard Combination Therapy The aim of this randomized, multicenter study in France was to evaluate the efficacy and tolerability of induction dose pegylated-interferon and ribavirin vs pegylated- interferon and ribavirin as treatment strategies in relapsers to standard interferon + ribavirin in chronic hepatitis C patients. 110 patients, virological relapsers after a first treatment with standard interferon and ribavirin for at least 6 months, were randomized to receive either PEG-Intron (pegylated-interferon alfa-2b) 2 µg/kg Qw plus ribavirin 800-1000mg Qd during 8 weeks then Peg-Interferon alfa-2b 1 µg/kg Qw plus ribavirin 800-1000mg Qd during 40 weeks (n= 52 pts) or Peg-Interferon alfa-2b 1.5 µg/kg Qw plus ribavirin 800 -1000mg Qd during 48 weeks (n= 58 pts). Efficacy assessments consisted of serum HCV RNA level by PCR and serum ALT at the end of treatment and after 24 weeks of follow up (week 72) and liver fibrosis with METAVIR score before treatment and at week 72. Safety evaluations included adverse events and laboratory tests. Study Results Patients were not different for baseline characteristics in induction and non induction groups including sex (male 58 % and 71% ), mean age (50.1 and 49.4 years), weight ( 71.1 and 73.4 kg), mean duration since infection (19.6 and 20.8 years), route of transmission (IVDU : 25 and 24 %, transfusion: 42 and 52%), genotype (1: 49 and 75 %, 2-3: 41 and 25% ) and severe fibrosis (29 and 34 % p= 0.57 ). End of treatment response (ETR) was 77% HCV RNA negative in induction group and 75 % in non induction group (NS). End of follow up (SVR) response was not different in both treatment group (61 vs 47 % of HCV RNA negative, 56 % vs 37 % in genotype 1, 67 % vs 70 % in genotype 2-3).
Liver fibrosis METAVIR
score decreased in 41% of patients in non-induced group and in 19% of
patients in induced group (p=0,16) whatever the response (34% in sustained
responders and 25% in non responders or relapsers). Conclusions 1) Combination therapy with pegylated- interferon is efficient in half of relapsers to standard combination therapy. 2) The response is similar to the response observed in naive patients. 3) 8 weeks induction dose does not increase the virological response . 4) The investigators observed a regression of liver fibrosis in 30% of patients whatever the treatment regimen and virological response. 10/27/03
Reference
Treatment with PEG-Intron and Ribavirin
Produces Significant Sustained Virologic Response Rates in Patients Who
Failed Prior Therapy Eradicating HCV in the majority of infected patients remains an elusive goal, particularly in previously treated patients who failed or relapsed following prior therapy. The investigators hypothesize that response rates in these patients who are re-treated with pegylated Interferon and ribavirin will be improved compared to standard interferon preparations with or without ribavirin. The present
prospective study is designed to determine the efficacy and safety of
treatment with PEG-Intron (pegylated interferon alfa-2b) and ribavirin in a
group of patients who failed prior therapy with interferon with or without
ribavirin.
Adverse Events
Dose reduction was
required in 22% of pts most commonly due to leukopenia and anemia. Permanent
discontinuation of therapy was required in 8% most often due to depression
or anxiety
Serious adverse events:
(1.8% of pts) Included one patient each with neutropenia/MRSA sepsis, optic
neuritis with monocular blindness, perirectal abscess, cellulitis and
multi-organ failure, cutaneous and pulmonary sarcoidosis, pneumonia,
homicidal ideation, and suicide.
Conclusions
10/27/03
Reference
Weight-based Dosing of PEG-Intron or Double the Dose
Plus Ribavirin for Naïve Patients and Double Dose PEG-Intron Plus Ribavirin
for Nonresponders and Relapsers Pegylated interferon (Peg) plus ribavirin (RBV) is the mainstay of chronic hepatitis C treatment. However, an upper limit in terms of safety and efficacy for dosing with Peg has not been evaluated. In the current study, researchers studied a group of naïve patients using either conventional weight-based dosing of PEG-Intron (Peg); (1.5 μg/kg) or double the dose (3.0 μg/kg) plus RBV 13+ 2mg/kg/day for 48 weeks. Genotype 1 patients were randomized 1:1 and to receive medication accordingly in unblinded fashion, with intent to enroll a total of 1,100 naïve patients N, an additional 300 previous NR or R to any type of interferon + RBV in a non randomized arm, using only the 3.0 μg/kg Peg dose. Values for HCV RNA at week 12 were compared to those obtained at baseline. Study Results To date, 573 patients 306 N, 193 NR, 74 R have enrolled in the study. 175 patients 106 N, 48 NR, 21 R have reached week 12. HCV RNA results at week 12 are shown in the table below. Treatment was well tolerated in most patients. Dose reductions were required in 20% of N 1.5μg/kg Peg and 29% of N 3.0μg/kg Peg patients. Side effects were equivalent between the two groups as shown in the table below. Serious adverse events (SAE’s) were less than 5% and equally observed in both arms of the N patients. None were directly attributed to study drug. There were 25 patients in the wk 12 analysis that discontinued therapy. The reasons these patients were discontinued after reaching wk 12 were side effects (36%), + HCV RNA (32%). It is interesting to note that 40% of the patients that were discontinued had > 2 log drop or negative HCV-RNA at week 12 and a positive HCV RNA was not a reason for their discontinuation. Conclusions 3.0μg/kg Peg dosing does not appear to improve 12 wk viral response, but we await 24 wk results and sustained viral response rates. Of interest, increased side effects as a result of doubling the interferon dose were not observed. More data are needed to verify the long-term efficacy and safety of this dosing regimen for patients with chronic hepatitis C. Table 1
10/27/03
Reference
Efficacy of Pegasys vs Pegasys Plus Ribavirin in HIV-HCV
Coinfected Patients Who Are Nonresponders to Prior Interferon Therapy HCV co-infection is common among patients with HIV disease. It has been documented that HIV co-infection accelerates the course of liver disease in patients with HCV, and that liver failure is higher in co-infected patients.
At this
moment, there is no effective treatment for HCV non-responders to interferon
therapy. Interferon monotherapy and interferon-ribavirin combination is only
effective in 2-3% and 5-10% interferon-resistant patients respectively.
Treatment strategies to slow the progression to cirrhosis and to prevent
liver failure in this population are needed.
This report
examines the efficacy of Peg IFN alfa 2-a (Pegasys) vs Pegasys/RBV 800mg in
co-infected HCV/HIV patients that have not responded to a previous 6-12
months course IFN-alfa. The study also examines the histological benefit of
treatment in this population. All similar responders (group 2) continue treatment for a total of 48 weeks. Baseline demographics were similar between both groups. More than 70% of patients were nonresponders to IFN monotherapy. Most patients in both groups (80%) were genotype 1. The mean HIV baseline log was 2.92 (SD .64) group 1, vs 2.85 (SD .57) group 2 and most patients had baseline CD4 levels >400 cells, and were in stable antiretroviral therapy. The majority of patients (81%) are non cirrhotic, with mean grading group 1 6.63 (SD 3.24), group 2 7 (SD 3.64), and mean staging, group 1 3.51 (SD 2.2), and group 2 3.48 (SD 1.70).
Results ConclusionsSustained virological response (SVR) (Intention to treat), will be of the order of 5-20%. (11 group 2 results are pending). In this study, 10 patients were discontinued because of adverse events and 10 were lost to follow up, before week 24. SVR in patients that completed at least 24 weeks of therapy will be of the order of 7-26%. A significant number of end of treatment responders have relapsed at week 72. Histology analysis shows improvement in both groups of the mean grading and staging after treatment. In responders and relapsers the FPR becomes static or regressive. These results show that Pegasys /RBV therapy is effective in this population. The study also suggests that longer duration of therapy and higher doses of RBV should be studied in coinfected nonresponders 10/27/03
Reference
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Host Factors Responsible for a Viral Response May Be
Different in Responders Compared with Nonresponders and Independent of Serum
PEG-Intron Concentrations Approximately one half of hepatitis C virus (HCV) infected patients will fail to respond to current treatment regimens, pegylated interferon alfa and ribavirin. Modeling of HCV RNA decay in response to antiviral therapy can provide insight into viral and host determinants of viral response. Pharmacokinetic, pharmacodynamic, and immunologic outcomes were evaluated on 24 co-infected patients in order to: 1) evaluate the relationship between HCV RNA decay and PEG-IFN alfa2b serum concentrations in HIV/HCV co-infected patients and 2) Evaluate association between HCV-specific immune responses and virologic outcome. 24 co-infected, therapy-naïve patients were treated with PEG-IFN alfa2b 1.5μg/kg/wk and RBV 13 ± 2 mg/kg/day. Serum was obtained for HCV RNA, HIV-1 RNA and serum PEG-IFN alfa2b levels at baseline, after the first dose (6, 12, 24 hours) and on days 2, 3, 5, 6; after the second dose (6, 12, 24 hours) and on days 8, 9; and after the third dose on days 14, 15, and 16. Peripheral blood mononuclear cells were obtained at baseline, weekly for the first month, and monthly thereafter. HCV and HIV-1 RNA levels were determined by reverse-transcriptase polymerase chain reaction and PEG-IFN alfa2b levels were measured by ELISA. CD4+ cell proliferative responses to HCV antigens (core, NS3, NS4, NS5) and HIV-1 gag were performed at baseline, day 7 and 14, and weeks 4, 8, 12, and 24. Among 24 co-infected patients, 21 are males, the mean age was 46 ± 5.8 years, 8 are Caucasian, 12 are African-American and 4 are Hispanic. 20/24 patients were infected with genotype 1, 3/24 patients with genotype 2, and 1/24 with genotype 3a. Study Results Pharmacokinetics: To date, 21 patients have been evaluated. 10/21 patients were end of treatment responders, but 2 of these were “late responders” (i.e. HCV RNA declines after week 8 and is undetectable by week 24). Data fitting during the first seven days revealed a free virion clearance rate c of 13.3 (day-1) and an infected cell clearance rate δ of 0.21 (day-1). The half-lives were 2.7 hours and 4.0 days, respectively. Pharmacodynamics: Viron production was blocked after the first dose of PEG-IFN alfa with an average maximum effectiveness (εmax ) of 89%. We estimated that the fifty percent effective concentration (EC50) of PEG-IFN alfa2b, the theoretical in vivo drug concentration at which the drug efficacy is 50%, was five-fold lower in responders compared with non-responders while the maximum (Cmax) and minimum (Cmin) concentrations did not differ significantly (Table I). The calculated minimum (εmin) and maximum (εmax) efficacy were also significantly increased in responders. Immunologic: The mean number of CD4+, CD8+ and CD56+ cells did not differ significantly at baseline or during treatment between responders and nonresponders. Peripheral blood CD4+ HCV-specific proliferative responses did not differ significantly between responders and nonresponders except that the response to core antigen was increased in non-responders compared with responders at weeks 4 and 12. HIV gag CD4+ proliferative responses were stronger than HCV-specific responses at all time points evaluated.
Conclusions The serum PEG-IFN alfa2b concentration necessary for an end of treatment response is five-fold lower in responders compared with non-responders while there are no significant differences in the maximum and minimum PEG-IFN alfa-2b concentrations in responders and nonresponders. These data suggest that host factors responsible for a viral response may be different in responders compared with nonresponders, independent of serum PEG-IFN alfa2b concentrations.
Supported by the NIH and conducted at Weill Medical College of Cornell, NY, Los Alamos National Laboratory and New York Blood Center. 10/27/03
Reference Delivery of Consensus Interferon (Infergen) by Continuous Pump Shows Substantial Reduction of HCV RNA Levels Among Nonresponder HCV Patients Pegylation of interferon-alfa results in an improved pharmacokinetic profile by maintaining constant blood levels, resulting in higher sustained response rates (SVR). However, modification of interferon-alfa by pegylation also reduces biologic potency.
Delivery of
a bio-optimized alpha interferon in an unmodified form (consensus
interferon, Infergen®) by continuous infusion can be expected to provide
sustained and constant levels of a fully potent protein. Researcher s
hypothesize that such an approach may potentially result in greater
antiviral activity and improved tolerability by avoiding wide swings in
interferon levels. We conducted a phase 2 pilot study to assess the safety, tolerability and viral kinetics of Infergen (12 microgram/day) by continuous infusion using a subcutaneous infusion device (Medtronic MiniMed® pump) in combination with ribavirin (1000 mg or 1200 mg daily).
The MiniMed
model 508 micro infusion pump is cleared for use in the treatment of
diabetes. HCV RNA viral levels were measured at days 1, 3, 7, 10, 14, 21, 28
and then at weeks 6 and 12. Study ResultsAmong 10 nonresponders treated to date with Infergen by continuous infusion with available early viral kinetics data, 7 showed a substantial reduction in HCV viral levels (at least 1 log10 reduction in 4, and 2 log10 reduction in 3). All 7 of these patients were genotype 1 and 6 had less than 1.0 log10 decrease with prior treatment while 1 had a 1.5 log10 decrease at similar time-points with other combination therapy [either pegylated interferon/RBV (4 pts) or interferon-alfa/RBV (3 pts)].
No serious adverse events were reported and 3
patients discontinued (2 due to moderate interferon-related side effects and
1 due to inability to acclimate to the pump). Other patients continuing on
study experienced mild adverse events that have been tolerable. Conclusions Consensus interferon administered by continuous delivery via the Medtronic MiniMed pump shows early substantial reduction of HCV RNA levels among nonresponder patients and shows a good safety and tolerability profile. Updated data on a total of 22 patients (including 10 naïve genotype 1 patients) were presented. 11/07/03
Reference
61% of Prior Nonresponders Experience Early Virological
Response after 12 Weeks of Triple Therapy with Zadaxin (thymalfasin) +
Pegasys + Ribavirin: Interim Results of a Pilot Study Response rates for retreatment of HCV nonresponders with peginterferon alfa plus ribavirin have been disappointing. Zadaxin (thymalfasin) in association with Pegasys (peginterferon alfa-2a/PEG-IFN-2a) has been suggested to increase early virological response rates in HCV nonresponders. The objective of the current study is to investigate the effects of thymalfasin in combination with Pegasys and ribavirin in patients who did not respond to a previous course of IFN plus ribavirin. HCV patients who were nonresponders to previous combination therapy were treated with thymalfasin 1.6 mg twice a week plus Pegasys 180microgram/week plus ribavirin 1,000 mg/day. All patients had HCV RNA positive by PCR, elevated ALT and no evidence of decompensated cirrhosis. In addition, patients had to have a documented positive HCV RNA at the end of a previous course of therapy to qualify as true nonresponders. The early effect of therapy was assessed by the reduction in serum HCV RNA after 12 weeks: an early virological response (EVR, proportion of patients with > 2 Log drop in HCV RNA by PCR). The primary endpoint of the study is negative HCV RNA by PCR test (Roche Amplicor) measured at weeks 48 and 72. The secondary endpoints are normalization of ALT (a liver enzyme) measured at weeks 48 and 72. During the course of this study, patients will receive 12 months of triple therapy and will be observed for 6 months after completing therapy to measure sustained response. Interim Study Results This multicenter study is being conducted by a team led by Dr. Jorge L. Poo, Chief Scientific Officer of CIF-Biotech at the Medica Sur hospital in Mexico City. To date, the investigators have enrolled 24 patients (7 male, 17 female) with a median age of 49.3 yrs (range 27 to 64), 12 with baseline viral loads greater than 850,000 IU/mL. All patients were nonresponders to a previous course of IFN plus ribavirin. Of the 23 patients who had completed 12 weeks of therapy, 61% (14/23) reported an EVR (a 2 log or greater reduction in the level of HCV RNA) and 48% (11/23) tested negative for HCV RNA by PCR test (Roche Amplicor). Of the 20 patients infected with the difficult to treat HCV genotype 1, 60% (12/20) reported an EVR and 50% (10/20) tested negative for HCV RNA. Thymalfasin was well tolerated with no obvious side effects, but Pegasys or ribavirin adverse events were seen in 33% of patients, the most common being neutropenia or thrombocytopenia. Conclusions The authors conclude, “These data suggest that thymalfasin adds to the efficacy of PEG-IFN2a plus ribavirin in inducing EVR in patients with HCV who are non-responders to previous combination therapy.” Dr. Poo concluded, “These data suggest that ZADAXIN adds to the efficacy of pegylated interferon alfa plus ribavirin to induce an early virologic response in patients with hepatitis C who are nonresponders to previous combination therapy. ZADAXIN was well tolerated with no obvious side effects.” Commentary by Ronald Baker, PhD The fact that a high percentage of nonresponders receiving the triple combination of thymalfasin/peginterferon/ribavirin have experienced EVR is very encouraging. However, although a patient’s EVR is considered necessary to achieve a sustained virological response (SVR), a patient who demonstrates an EVR may or may not achieve a SVR, and therefore EVR may not be predictive of a successful outcome, especially for a nonresponder. SVR is the absence of hepatitis C virus measured six months after ending therapy. 48 and 72-week data from this pilot study are anxiously awaited as are data from the ongoing phase III trials of thymalfasin in combination with peginterferon. SciClone’s two phase 3 HCV clinical trials are designed to provide statistically significant results, and together represent one of the largest HCV clinical studies of patients being currently conducted in the US to date. The two trials are multi-center, randomized and double-blinded studies. The first trial includes patients with no cirrhosis and the second trial includes patients with mild cirrhosis. SciClone completed full enrollment of its first 500 patient phase 3 hepatitis C clinical trial in September and targets full enrollment of its second 500 patient trial during the first quarter of 2004. SciClone expects all 1,000 patients to have completed the trial by the second half of 2005. In each of the clinical trials, patients are assigned to a 12-month course of ZADAXIN plus pegylated interferon alfa or placebo plus pegylated interferon alfa. After completing treatment, the patients will be followed for a six-month observation period. Primary endpoints are a sustained virological response (clearance of the hepatitis C virus) and an improvement in the liver histological activity index measured at the end of the six-month observation period. 11/10/03
Reference
In Nonresponders at Week 48, High Dose PEG-Intron (3.0
mcg/kg/wk) Plus Ribavirin Produces Similar Viral Clearance Rate as Standard
Dose (1.5 mcg/kg/wk): The Renew Trial Ten percent of interferon/ribavirin nonresponders treated with conventional doses of peginterferon + ribavirin have a sustained virological response. The current trial was designed to see if better results could be achieved by retreating with higher doses of PEG-Intron (peginterferon alfa-2b /PEG2b) + weight-based ribavirin. The objectives were to compare the efficacy, safety and tolerability of three different doses of PEG2b + weight-based ribavirin among interferon/ribavirin nonresponders. Patients were randomized to 1 yr of treatment with PEG2b 0.5, 1.5 or 3.0 mcg/kg/wk, plus ribavirin 12-15 mg/kg/day. Treatment assignment was stratified for sex, race, HCV genotype and histologic fibrosis. Treatment was stopped at 24 wk if PCR(+). Doses were reduced by 33% for toxicity; growth factors were not allowed. Study ResultsPatients: Enrollment took place between February 2001 and November 2002, with 963 patients recruited from 100 centers; data forms have been received on 794 thus far. Enrollment was stopped in the low-dose group after FDA approval of higher doses of PEG2b. The study population is 31% female, 16% African-American, 93% genotype 1, and 63% F2/3/4. Efficacy: On-treatment virological response rates were dose-related at 24 wk but less so at 48 wk (see Table below). This was partly due to a higher rate of discontinuation after a satisfactory response at 24 wk on the higher dose. On-treatment response rates were lower among African-Americans and patients with more advanced fibrosis. Tolerability: The rate of dose reduction was 33% on PEG2b 1.5 mcg/kg/wk, vs. 45% on 3.0. Rates of discontinuation were the same for PEG2b 1.5 and 3.0 mcg/kg/wk: 25% vs. 24% overall, and 13% vs. 14% for adverse events. The frequencies of subjective adverse events were similar between the two groups. Some degree of neutropenia was observed in 27% on 1.5 mcg/kg/wk, vs. 32% on 3.0; however, only 14 patients in the study discontinued treatment for neutropenia overall. Conclusions
11/17/03
Reference
HCV-specific Immune Responses at Baseline Do Not Predict a
Favorable Retreatment Outcome in Patients with Advanced Disease The HALT-C study is a randomized, controlled clinical trial of patients with chronic hepatitis C and advanced liver fibrosis who previously failed interferon therapy. Subjects in the lead-in phase of the study were treated with Pegasys (peg-interferon alfa 2a) and ribavirin for 20 weeks; those with undetectable HCV RNA at that time point were considered to be week 20 (W20) on-treatment responders and completed 48 weeks of therapy and an additional 24 weeks of follow-up.
The
researchers hypothesized that vigorous immune responses at baseline would
favor virologic response to therapy and higher rates of sustained virologic
response (SVR). HCV-specific lympho-proliferative (LP) responses, neutralizing antibody (NA) responses, HCV quasi-species (QS) genetic diversity and complexity, intrahepatic cytolytic T cell (CTL) function, as well as quantification of intrahepatic viral genomes and replicative RNA were analyzed in specimens obtained prior to initiation of treatment (baseline). CD4+ and CD8+ T cell responses to HCV antigens were tested using LP and CTL assays, respectively. Presence of NA were measured using VSV pseudotyped viruses expressing HCV chimeric envelope glycoproteins E1 or E2.
HCV QS were
evaluated using clonal frequency analysis of the HCV E2 HVR1 gene. Serum HCV
RNA and intrahepatic viral genomes were quantified using the Roche Amplicor
Monitor assay v. 2.0, while negative strand HCV RNA was quantified by in
situ hybridization. Study Results The W20 response rate was 37% and the SVR rate was 18% in this cohort. The rates of HCV-specific LP, NA and CTL responses were 23%, 20% and 22%. Surprisingly, LP and NA responses were found less commonly at baseline in those who developed SVR. Specifically, positive LP responses to any HCV antigen (SI>3.0) were infrequently found in subjects who became SVRs (10.3%) compared to those classified as nonresponders or relapsers at Week 60 (W60) (28.6%, p=0.046). Similarly, subjects with baseline serum NA responses to either E1 and/or E2 (at 1:50 or 1:20) were less likely to achieve W20 virologic response (p=0.057) or SVR (p=0.023). Moreover, subjects with SVR displayed lower levels of HCV complexity (4.0) and diversity at baseline, implying decreased immune pressure on viral evolution, compared to those who were non-responder. No differences in baseline intrahepatic CTL activity, HCV RNA level, or replication were noted between those who developed W20 response or SVR compared to non-responders.
Factors more
strongly associated with response were non-genotype 1, non-African American
race, absence of previous ribavirin use, and absence of cirrhosis. Conclusions Patients with chronic HCV infection and advanced liver fibrosis who are refractory to treatment infrequently exhibit HCV-specific immune responses. However, subjects with immune responses detected prior to retreatment with peg-interferon-alfa 2a and ribavirin are less likely to achieve on-treatment virologic response or sustained eradication of HCV infection. Thus, the presence of HCV-specific responses per se does not necessarily portend a favorable re-treatment outcome in subjects with advanced disease. 11/21/03
Reference
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