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18 Months Therapy (Pegasys+Ribavirin): study found relapse rate reduced by 70%; viral response rate in genotype 1 increased by 50%
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"SUSTAINED VIROLOGICAL RESPONSE AFTER PROLONGED TREATMENT WITH PEGINTERFERON ALFA-2A (40KD) (PEGASYS®) AND RIBAVIRIN (COPEGUS®) IN TREATMENT-NAÏVE PATIENTS WITH CHRONIC HEPATITIS C AND DETECTABLE HCV RNA AFTER WEEK 4 OF THERAPY: TERAVIC-4 STUDY"
J.M. Sanchez-Tapias^{1}, M. Diago ^{2}, P. Escartin ^{3}, J. Enriquez ^{4}, R. Moreno ^{5}, M. Romero-Gomez ^{6}, R. Barcena ^{7}, J. Crespo ^{8}, R. Andrade ^{9}; The TeraViC-4 Study Group, Roche, Madrid, Spain;
^{1}H. Clinic I Provincial, Barcelona, Spain; ^{2}H. General, Valencia, Spain; ^{3}H. Puerta Hierro, Madrid, Spain; ^{4}H. Sant Pau, Barcelona, Spain; ^{5}H. La Princesa, Madrid, Spain; ^{6}H. U. Valme, Sevilla, Spain; ^{7}H. Ramón Y Cajal, Madrid, Spain; ^{8}H. Marqués Valdecilla, Santander, Spain; ^{9}H. Virgen Victoria, Málaga, Spain
Poster abstract presented at 39th Annual Meeting of the European Association for the Study of the Liver, April 14-18, 2004, Berlin, Germany)
BRIEF SUMMARY: Patients treated for 18 months had 45% SVR vs 32% for 12 months therapy (p=0.0144). The relapse rate was reduced by prolonged duration of therapy for 18 months therapy from 48% to 13% (p=0.005). For genotype 1 patients sustained viral response rate was 28% for 12 months vs 44% for 18 months of therapy. For patients with high baseline viral load (>800,000 IU/mL) sustained viral response rate was higher for 18 months compared to 12 months of therapy (37% vs 30%). For hard to treat patients (prior nonresponders, HIV+, cirrhosis, etc) 18 months therapy is worth considering. Obviously, unless one achieves undetectable viral load prolonging therapy is not useful.
TeraViC-4 targets patients with chronic hepatitis C who do not have very early virological responses after week 4 of therapy (no viral response at week 4 after initiating Pegasys/ribavirin therapy= detectable serum HCV RNA >50 IU/ml PCR). The study evaluates the risk:benefit ratio of extended duration of therapy, balancing increased response rates and adverse events.
Sustained response rates of pegylated interferon plus ribavirin, the standard of care for HCV, has produced overall sustained response rates of about 54% in phase III multinational clinical studies.
Analysis of data from these studies shows an absence of an early response, makes it highly unlikely (predictive value 97%) that patients will achieve a sustained virologic response. An early virologic response is defined as undetectable HCV RNA or >2 log decrease in HCV RNA (viral load) by week 12.
The authors also said that further analysis of the data suggests that the probability of achieving a sustained viral response is inversely proportional to the time taken to achieve undetectable HCV RNA levels. This leads to the hypothesis that extending the duration of treatment in patients who fail to clear HCV RNA rapidly will increase the sustained response rates. This strategy may be particularly important in patients with 'difficult-to-treat' characteristics, including those infected with genotype 1, high baseline viral load, previous nonresponders, and HIV-infected. The overall success of extended treatment is, of course, contingent on the assumption that extending treatment duration will have a positive effect on the risk:benefit ratio (i.e. response rates will increase but the incidence of adverse events will not). The TeraVIC-4 study was designed to test this hypothesis.
STUDY OBJECTIVE
The objective of this study is to compare sustained viral response rates in treatment-naïve patients randomized to 48 and 72 weeks of treatment with peginterferon alfa-2a (40KD) (Pegasys) and ribavirin (Copegus) after failing to achieve a rapid virological response at week 4 of combination therapy. Rapid virological response isdefined as undetectable serum HCV RNA by qualitative polymerase chain reaction (PCR) assay (COBAS AMPLICOR HCV Test v2.0; detection limit 50 IU/mL).
STUDY DESIGN
TeraVIC-4 is a phase III, randomized, parallel group, multicenter, Spanish study. All patients received Pegasys 180 ug/week and ribavirin 800 mg/day (400 mg bid, twice daily). The study was conducted at 28 centers in Spain. The first patient was enrolled in April 2001 and the last patient enrolled in September 2001.
BASELINE CHARACTERISTICS
Baseline characteristics of the randomized groups were similar.517 patients were randomized to 48 weeks (n=165) or 72weeks (n=162) of therapy. 69% men in 48 wk group, 63% men in 72week grp. Mean age: 43. Mean weight: 76 kg in 48 wk grp, 75 kg in 72 wk grp. Mean HCV RNA: 970 x 103 IU/mL in 48 wk group, 1093 103 IU/mL in the 72wk grp. MEDIAN HCV RNA: 638 vs 751 x 103 IU/mL in the 48 & 72 wk grps, respectively. Patients with high viral load: 39% in 48 wk grp, 46% in 72 wk grp. Genotype: 88% in 48 wk grp & 90% in 72wk grp.
RESULTS: EFFICACY ITT POPULATION
Afer 4 weeks of treatment, 327 of 511 (64%) patients had a positive qualitative PCR test and were randomized to treatment for a further 44 or 68 weeks. The remaining 184 patients with a rapid virologic response (negative PCR values by week 4) were entered into other parts of the protocol: 20 or 44 weeks therapy.
Sustained virologic response rates at the end of follow-up (6 months after stopping Pegasys/ribavirin treatment) were significantly higher in patients who were treated for a longer duration with combination therapy (45% vs 32%, p=0.0144).
In patients who were HCV RNAnegative at week 4, sustained viral responses were achieved in 79% of patients treated for a total of 24 weeks and 64% of patients treated for atotal of 48 weeks. The higher response rate of 79% reflects inclusion of patients with genotypes 2 and 3.
In patients who were HCV RNA positive at week 4, there was a significant difference in the maintenance of viral response rates during followup. In those treated for a total of 48 weeks, the viral response rate declined from 61% at completion of treatment to 32% at the end of followup. In contrast, the viral response rate declined from 52% at completion of treatment to 45% at the end of followup in those who received a total of 72 weeks of treatment.
Extended treatment was beneficial in patients with HCV genotype 1. Sustained viral response rates of 28% and44% were achieved in these patients after treatment for a total of48 and 72 weeks, respectively.
Sustained viral response rates were also consistently higher in patients treated for 72 weeks when the data are grouped by baseline viral load. For patients with high baseline viral load (>800,00 IU/mL) sustained viral response rates were 30% after 48 weeks vs 37% after 72 weeks of therapy.
For patients with low viral load (<800,000 IU/mL), sustained viral response rates were 34% after 48 weeks therapy vs 52% after 72 weeks therapy.
TOLERABILITY
The authors said the type and incidence of adverse events were generally similar for 48 and 72 weeks therapy. In particular, the incidence of neutropenia (reduced white blood cells-neutrophils) and thrombocytopenia (reduced platelets) was similar in the two groups.
ADVERSE EVENTS THAT OCCURRED DURING TREATMENT IN PATIENTS WHO WERE HCV RNA POSITIVE AT WEEK 4. Events reported by 10% of patients are included.
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48 wks
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72 wks
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Asthenia (fatigue)
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60%
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59%
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Headache
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30
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32
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Fever
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27
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28
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Flu-like symptoms
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24
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17
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Neuropenia
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24
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25
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Anorexia
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21
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15
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Pruritis (itching)
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21
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25
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Anemia
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18
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22
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Insomnia
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18
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25
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Irritability
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17
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22
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Myalgia
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14
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14
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Alopecia
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13
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17
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Thrombocytopenia
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13
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9
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Depression
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12
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20
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Coughing
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8
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10
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Injection site reaction
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7
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12
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Anxiety
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5
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12
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TREATMENT DISCONTINUATION. PATIENTS WHO WERE HCV RNA POSITIVE AT WEEK 4.
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48 wks
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72 wks
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Adverse events
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10.3%
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13%
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Lab abnormalities
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0
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1.2%
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Voluntary withdrawal
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4.2%
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17.3%
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Other
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2.4%
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4.3%
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The withdrawal rates were similar during the first 24 weeks of treatment for the 48 and 72 week treatment groups.A higher proportionof patients voluntarily withdrew from the 72 week group after week 24, which resulted in higher overall withdrawal rates.
BEFORE WEEK 24:
48 wk grp: 8.5%
72 wk grp: 6.2%
AFTER WEEK 24:
48 wk grp: 17%
72 wk grp: 36%
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