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First Major Study Showing 12 Week Viral Response to Pegasys/ribavirin in Coinfected Patients Predicts Outcome
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Reported by Jules Levin
Brief Summary: Researchers analyzed the large international 860-patient Apricot Study, in which coinfected patients received Pegasys plus ribavirin. If a patient in this study did not achieve an Early Viral Response (undetectable HCV viral load or >2 log reduction in viral load) by week 12 it was highly unlikely to achieve a sustained viral response (SVR). Only 2 of 85 patients (2%) who did not achieve an Early Viral Response was able to have an SVR. 56% (114/289) of patients who had an early viral response achieved an SVR. The study authors recommend if SVR is the only goal of therapy, treatment could be stopped in patients without an early viral response at week 12 in order to prevent adverse events and suffering of patients and to preserve health care resources. It must be noted that antiviral therapy for HCV may produce histological improvement (slowing of fibrosis & improved virus activity & liver inflammation) and retard disease progression in HCV/HIV coinfection, factors which must be considered when making treatment decisions. These study results show that coinfected patients with an early viral responsehave a good chance of achieving an SVR. These results are consistent with those obtained in HCV monoinfected patients, and suggest that 12 the week predictability algorithm may be extended to patients with HCV/HIV coinfection.
Note: also presented at EASL was study finding that for patients who failed to achieve a rapid viral response (undetectable) by week 4 after starting Pegasys/RBV 18 months therapy was much more effective than 12 months therapy.
http://www.natap.org/2004/EASL/easl_06.htm
The 12 Week Early Viral Response Rule has been accepted in treatment of HCV monotherapy. The Apricot Study is a large registration trial examining Pegasys plus ribavirin in coinfected patients. At EASL (April 14-18, 2004, Berlin) researchers presented a study analyzing Apricot, the aim of this study was to determine the predictive value of an early virologic response on the probability of achieving an SVR in HCV/HIV coinfected patients treated with Pegasys plus ribavirin (Copegus).
The 12 Week Stop Rule in HCV Treatment says if a 2 log reduction in viral load or undetectable HCV viral load has not been achieved by 12 weeks after starting pegylated interferon plus ribavirin you can consider stopping therapy, since the likelihood of achieving undetectable viral load is low. The rule is not hard and fast. For example, if viral load has been reduced significantly by 12 weeks continuing to 16 or 24 weeks may be advisable to give an opportunity for further reduction in viral load and achieving undetectable viral load. Also, if a patient has advanced HCV, cirrhosis or bridging cirrhosis, Maintenance Therapy may be advisable. Maintenance Therapy is continuing half dose of peginterferon and this is based on studies showing that interferon has antifibrotic effects, slowing of fibrosis.
The ability to identify patients most likely to achieve a sustained virologic response (SVR) allows those individuals to be targeted for a complete course of therapy and minimizes the likelihood of adverse events in those unlikely to achieve an SVR. In HCV monoinfection patients treated with pegylated interferon plus ribavirin, the absence of an early virologic response (defined as a minimum 2 log reduction in viral load by week 12 of therapy) has a high negative predictive value (NPV) (predicting no SVR) regarding the likelihood of achieving an SVR. The presence or absence of an early virological response may be used to guide treatment decisions about continuation or stopping of therapy in patients infected with genotype 1. The 12 Week Stop Rule has not been been confirmed although several small Spanish studies have had results supporting the 12 week Stop rule in HCV/HIV coinfected patients.
APRICOT
Patients in Apricot were randomized to 48 weeks of treatment with 1 of 3 regimens:
--Pegasys 180 ug/week plus ribavirin 800 mg/day
--Pegasys plus placebo
--interferon 3 MIU 3 times per week plus RBV 800 mg/day
SVR was defined as <50 IU/mL COBAS Amplicor HCV Test 2.0v at the end of 24 weeks of untreated followup. Early viral response was defined as undetectable HCV RNA or >2 log decline in HCV RNA by week 12 or 24. This analysis is based on data from patients treated with Pegasys plus RBV.
A total of 289 patients were treated with Pegasys/RBV. Baseline characteristics were: Patients had compensated liver disease and were coinfected with HCV & HIV. Average CD4 count was 520. HIV RNA was 2.3 log. 60% of patients had <50 copies/ml HIV RNA. HCV viral load was 5.6 x 106 IU/mL. 39 yrs old. 80% male. 24.2 kg/m2 BMI. Weight: 72.1 kg. 80% White, 11% Black. 61% genotype 1. 33% genotype 2/3.
A total of 116 of 289 (40%) treated with Pegasys/RBV in Apricot achieved an SVR. Among patients with HCV genotype 1 or 2/3, the SVR rates were 29% (51/176) and 62% (59/95). 20% of patients treated with Pegasys plus placebo achieved SVR. 12% of patients receiving IFN/RBV achieved SVR. 14% of genotype 1 patients receiving Pegasys alone achieved SVR and 7% of genotype 1 patients who received IFN/RBV achieved SVR. 20% of genotype 2/3 patients receiving IFN/RBV achieved SVR compared to nthe 62% of patients receiving Pegasys/RBV. For patients with genotype 2/3 the relapse rate was low: 64% had end of treatment response (undetectable after 48 weeks treatment) and 62% had SVR. Withdrawal rates for non-safety reasons, essentially viral non-response: 10% for Pegasys/RBV, 15% for Pegasys, 24% for IFN/RBV. Withdrawal for adverse events: 12% Pegasys/RBV; 12% Pegasys; 14% IFN/RBV; Withdrawal for lab abnormalities: 3% for Pegasys/RBV; 5% Pegasys; 0% IFN/RBV. Adverse events profile was similar for all treatment arms. Depression was 22% in IFN/RBV, 20% for Pegasys, and 26% for Pegasys/RBV. 40-44% of patients reported fatigue. Weight decreased in 14-20% of patients. Patients with serious adverse events possibly or probably related to therapy: 8% Pegasys/RBV; 10% Pegasys; 5% IFN/RBV.
WEEK 12 & 24 Early Viral Response: Patients with an early viral response (EVR) at week 12 were more likely to achieve an SVR than those without an EVR. At week 12, 204 of 289 (71%) patients had an EVR, of whom 114 (56%) achieved an SVR. Conversely, only 2 of 85 patients without an EVR at week 12 achieved SVRs. Negative Predictive Value was 98%. Positive Predictive Value was 56%. So, the NPV was similar to that seen with HCV monoinfection but the PPV was less than that seen with HCV monoinfection.
Similar results were obtained when early viral response data at week 24 was considered. At week 24, 75% of patients had EVR, of whom 53% achieved SVR. Only 1 of 73 patients without an EVR achieved an SVR. The Negative Predictive Value at week 24 was 99%. The Positive Predictive Value was 53%.
PREDICTION BY GENOTYPE. When the data are grouped by HCV genotype, the trends present in the overall results were retained. PPV was 63%, 110 of 176 patients achieved an EVR at week 12, of whom 50 patients (46%) achieved SVR. Only 1 of 66 patients without an EVR achieved an SVR.
For genotype 2/3 patients, 84 of 88 patients had an EVR (88%), of whom 59 patients achieved SVR (70%). 0 of 11 patients without an EVR achieved SVR.
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