Standard versus higher induction doses of peginterferon

Standard versus higher induction doses of peginterferon alfa-2a (40KD) and/or higher ribavirin (RBV) in HCV G1 patients with high viral load and body weight ≥85 kg: Final results of the PROGRESS study -- see attached full oral slide report

from Jules: this study did not find high dose induction Pegasys+ribavirin provided higher SVR rates except ir did in patients with steatosis (NAS score>/=3) and for patients over 95 kg in body weight. After the oral presentation Jay Hoofnagle went to the microphone and said these results put to bed any notion that high dose pegINF can improve SVR rates in difficult to treat patients. I totally disagree. This study does not settle the question. This study did not report adherence data, perhaps patients who completely adhered to regimen would have had better responses, since we know side effects can be worse at higher dose. The concept of high dose peginf is an important one for nonresponders and difficult to treat patients and deserves a better study. Several years ago early studies on this question suggested better responses using higher doses so this study should have been better designed to address the adherence question. My feeling is that with good adherence higher dose peg/RBV would provide better SVR rates. Some HCV studies are poorly conducted. The HALT-C Study investigators reported 2 years ago that maintenance Pegasys therapy did not provide benefit, then at this AASLD they reported patient with transient suppression on maintenance therapy DID in fact benefit, but they had already 2 years ago declared in absolute terms that maintenance therapy was useless, and this convinced many doctors and patients not to use based on their reported findings and declaration.

SVR Improves Survival, Risk for Liver Cancer, Decompensated Liver Disease and Liver Transplant/Death - Also, Transient Viral Suppression (breakthroughs/relapsers) Improves Clinical Outcomes Too - (11/09/09)


Reported by Jules Levin, AASLD Oct 30-Nov3 2009, Boston, MA

K. Rajender Reddy*, Mitchell L. Shiffman, Maribel Rodriguez-Torres, Djamal Abdurakhmanov, Igor Bakulin, Giovanni Faria Silva, Hugo Cheinquer, Michael Rabbia, Jean Depamphilis, Michael McKenna, Stephen A. Harrison

*Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, USA



Summary of efficacy

Genotype 1 patients weighing ≥85 kg with baseline viral load ≥400 000 IU/mL showed no RVR, cEVR or SVR advantage with more intensive dosing of peginterferon alfa-2a or RBV; SVR rates ranged from 38%–44%

Subset analyses suggest a trend towards some treatment advantage with intensive dosing over SOC

-- For patients ≥95 kg

-- For patients with steatohepatitis (NAS score ≥3)



Summary of safety

-- Small increases in some AEs were observed in patients receiving more intensive doses of either peginterferon alfa-2a or RBV

-- No differences in SAEs or premature treatment discontinuation due to safety reasons were seen across treatment arms

-- Rates of grade 4 neutropenia (ANC <0.5 x 109 /L) were similar across treatment arms

-- Grade 4 anemia (Hgb <8.5 g/dL) was more frequent in patients receiving higher RBV doses



Conclusions

- In this difficult-to-cure population, the standard dose of peginterferon alfa-2a provided a comparable rate of SVR to induction pegylated interferon alfa-2a and/or high dose RBV regimens

- Induction dosing with peginterferon alfa-2a and/or high dose RBV led to higher rates of SVR in patients ≥95 kg and those with a NAS score ≥3

- High doses of peginterferon alfa-2a and/or RBV were well tolerated

- Similar rates of SAEs and discontinuation rates across all arms