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Pegylated Interferon plus Ribavirin: Pegasys/RBV in Co-infection (APRICOT Study, 72-week results)
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--and Comparative analysis with PegIntron and Second Pegasys/RBV Study
Reported by Jules Levin
Doug Dieterich reported at the Retrovirus Conference (SF, 2/10/04) the eagerly awaited final 72 weeks (48 weeks therapy plus 24 weeks follow-up) study results from APRICOT, "AIDS Pegasys Ribavirin International Co-infection Trial". At the same oral session at this conference the French ANRS group reported the final 72-week data on PegIntron plus ribavirin in co-infected patients and the AIDS Clinical Trials Group (ACTG) reported on a smaller Pegasys plus ribavirin study (ACTG 5071) in 133 coinfected patients. This report describes the results from APRICOT that Dieterich presented and a comparative analysis of APRICOT, the French ANRS Study and ACTG 5071. Forthcoming NATAP articles will report the precise details of the ANRS and ACTG studies. This was the first report on APRICOT, and further analysis of these study results will be reported in the future at upcoming conferences.
Brief Summary: overall sustained viral response (SVR) for patients receiving Pegasys/RBV was 40% vs 12% for patients receiving IFN/RBV. Patients with genotype 1: 29% with Pegasys/RBV vs 7% for IFN/RBV. For patients with genotype 2/3: 62% taking Pegasys/RBV vs 20% taking IFN/RBV. The discontinuation rate in this study was low-15%. The adverse event profile was similar for Pegasys/RBV and IFN/RBV. HCV therapy did not appear to negatively impact control of HIV.
In the Q&A from the audience Dieterich said there was about a 20% rate of drug dose reductions. It appears as though the analysis of early stop response at 12 weeks supported a similar rule in coinfection as we see in monoinfection, and this was also seen in the ANRS PegIntron Study but I think we need further analysis in coinfection. It may be premature to uniformly accept the early stop rulr--stopping at 12 weeks-- for coinfected patients until further study.
THE STUDY
868 patients at 95 centers in 19 countries participated in APRICOT: the countries contributing the most patients were the USA 278, Spain 158, Italy 85, Brazil 46, Austria 40, France 39, Germany 37, UK 30, Canada 33.
APRICOT Study Design
Patients were randomized to 1 of 3 treatment arms:
1. IFN alfa-2a (3 MIU, tiw) plus RBV (800 mg daily) n=285
2. PEG-IFN alfa-2a (40 kDa) (Pegasys) 180 ug, qw (once weekly) plus placebo n=286
3. PEG-IFN alfa-2a (40 kDa) (Pegasys) 180 ug, once weekly plus RBV 800 mg daily n=289
Dieterich reported that PEG-IFN alfa-2a combination therapy was blinded (RBV vs placebo. Patients were stratified by:
--genotype 1 vs non-1
--CD4 100 to <200 vs ≥ 200
--ART vs no ART (antiretroviral therapy, HAART)
--cirrhotic vs non-ciirhotic
--geographic region
This was a first cut of the data; more information is being culled from the stsudy data and will be reported at upcoming conferences.
Key inclusion criteria: naïve to IFN & RBV; HCV antibody positive; quantifiable HCV RNA; elevated serum ALT; liver biopsy (≤15 months before starting study) consistent with HCV infection; non-cirrhotic or cirrhotic (if cirrhotic, Child-Pugh Grade A). HIV criteria: quantifiable HIV RNA or HIV antibody; CD4 count 200 or 100 to 200 with <5000 copies/ml HIV RNA; stable HIV disease with or without ART.
Patients were excluded for: decompensated liver disease; other chronic liver disease; active HIV-related opportunistic infections; significant medical conditions: psychiatric/neurological, pulmonary, cardiac, thyroid/immunologically-mediated disease, retinopathy; pregnancy/male partners of pregnant women.
PRIMARY STUDY ENDPOINT: sustained virologic response (SVR), which means undetectable serum HCV RNA (Amplicor HCV test v2.0, sensitivity <50 IU/mL) at the end of 24-week treatment-free follow-up (week 72).
BASELINE CHARACTERISTICS
Male gender- 80%
Race- 78-80% Caucasian
Age- 40 yrs
Body Mass Index (kg/m2)- 24-25
Qualifying ALT (IU/L)- 85-87
Cirrhotic- 15-16%
Mode of Infection IVDU- 62-71%
Baseline HCV RNA (IU/mL x 106): 5.2 in IFN/RBV, 6.3 in Pegasys/placebo, 5.6 Pegasys/RBV. This is equivalent approximately to 15 million copies/ml using the older version of viral load measure. So HCV viral loads was on average high in this study.
HCV Genotype: 60% genotype 1. In ACTG 5071 Pegasys study 80% of patients had genotype 1 and 60% in ANRS PegIntron study 60% had genotype 1. The higher genotype 1 percent in ACTG study I think partly explains lower response in ACTG study, but I'll discuss results below.
Genotype 2: 4-6%
Genotype 3: 26-28%
Genotype 4: 6-8%
Patients with genotype 4 had viral responses in this study between those with genotype 1 and 2/3.
ART: 84% of patients were on ART
HIV RNA: 2.3 log10 copies/ml; 60% had <50 copies/ml
CD4 Counts: 520-542; 5-7% had <200 CD4s
RESULTS
SUSTAINED VIRAL RESPONSE
Pegasys/RBV: 40%
Pegasys/RBV placebo: 20%
IFN/RBV: 12%
The differences between each of the study arms was highly statistically significant: Pegasys/RBV vs Pegasys monotherapy p<0.0001; Pegasys/RBV vs IFN/RBV p<0.0001; Pegasys monotherapy vs IFN/RBV p=0.0084.
See comparative analysis below for these study results and those from PegIntron/RBV study and ACTG 5071 Pegasys/RBV.
RESPONSE BY GENOTYPE
Pegasys/RBV Genotype 1 SVR: 29%
Pegasys/RBV placebo Genotype 1 SVR: 14%
IFN/RBV genotype 1 SVR: 7%
Pegasys/RBV Genotype 2/3 SVR: 62%
Pegasys/RBV placebo genotype 2/3 SVR: 36%
IFN/RBV genotype 2/3 SVR: 20%
The relapse rate was lower than expected. The relapse rates were about the same observed for HCV monoinfected patients. 38% of patients with genotype 1 who received Pegasys/RBV had an end of treatment response and 29% had SVR. Similarly, the relapse rate was low for all others. For Pegasys monotherapy, 21% had ETR and 14% had SVR. For IFN/RBV ETR was 8% and SVR was 7%. For genotype 2/3 ETR was 64% for Pegasys/RBV and SVR was 62%. For Pegasys monotherapy ETR was 57% and SVR was 36%. For IFN/RBV ETR was 27% and SVR was 20%.
WITHDRAWAL FROM TREATMENT: rates were low
Pegasys/RBV: 25% overall, 15% for adverse events & lab abnormalities: 10% of patients discontinued for non-safety reasons; 12% for adverse events; 3% for lab abnormalities. 8% for serious adverse events.
Growth factors were permitted in this study for reduced hemoglobin (EPO) and neutropenia (reduced white blood cell counts.
Pegasys/RBV placebo: 31% overall, 16% for lababnormalities & adverse events: 15% withdrew for non-safety reasons; 12% for adverse events; 5% for lab abnormalities. 10% for serious adverse events.
IFN/RBV: 39% overall, 15% for adverse events & lab abnormalities: 24% withdrew for non-safety; 14% for adverse events; 0% for lab abnormalities.
Deaths (overall/treatment related): 3/1 for IFN/RBV; 5/0 for Pegasys monotherapy; 4/1 for Pegasys/RBV.
Patients with Serious Adverse Events
Pegasys/RBV: 8%, therapy-related; 17% all SAEs.
Pegasys/RBV placebo: 10%, therapy-related; 21% all SAEs.
IFN/RBV: 5%, therapy related; 15$ for all SAEs.
ADVERSE EVENTS
Neutropenia (<0.5 x 109/L): 11% for Pegasys/RBV; 13% for Pegasys monotherapy; <1% for IFN/RBV.
These were as expected and there were no great differences between the study arms. These are the percent of patients in the Pegasys/RBV arm who experienced these adverse events. These are adverse events reported by >20% of study patients.
Fatigue 40%
Pyrexia 41%
Headache 35%
Myalgia 32%
Nausea 22%
Insomnia 19%
Asthenia 26%
Depression 20%
CHANGE FROM BASELINE IN CD4 COUNTS and HIV VIRAL LOAD
Median CD4 counts did go down on average about 140 for patients on Pegasys/RBV during the 48 weeks of therapy but returned to their baseline numbers after stopping therapy. But the median CD4 % did not go down while on Pegasys/RBV. For all patients in the study, there was no change in mean HIV RNA. HIV viral load decreased 0.9 log for patients with detectable HIV viral load who were taking Pegasys while in study on Pegasys, and remained the same for patients taking IFN/RBV.
COMPARATIVE ANALYSIS by Jules Levin: In the RIBAVIC ANRS Study in which 416 coinfected patients were randomized to receive either PegIntron 1.5 ug/kg/week plus 800 mg RBV or IFN alfa-2a 3 MIU x 3/week for 48 weeks, the SVR (viral response rates) were 27% for patients receiving PegIntron/RBV and 19% for patients receiving IFN/RBV. The SVR with PegIntron (27%) was lower than the SVR for Pegasys/RBV (40%). The statistical significance for the difference between the two study arms was p=0.03. It is a no-no to compare between studies, as patient populations in studies are different. In the PegIntron study it appeared as though patients had more advanced liver disease as 40% had more advanced liver disease: (22-25%) F3 (bridging cirrhosis) and 14-18% had F4, cirrhosis. 60% had genotype 1, same as in APRICOT. HCV RNA was reported as 5.9 copies/ml, which appears to be a lower HCV RNA than in APRICOT. HIV status: (CD4 500; viral load: 65% <400 copies/ml, 3.6 log10 viral load for patients who were >400 c/ml). The discontinuation rate was higher in the PegIntron study than the APRICOT study: 38% did not complete treatment; so, this affects the percent of patients who achieve SVR.
In ACTG 5071, 133 coinfected patients were randomized to receive Pegasys/RBV or IFN/RBV. This study is much smaller than APRICOT so results aren't as significant. After 72 weeks, the SVR was 27% for patients receiving Pegasys/RBV and 12% for patients receiving IFN/RBV (p=0.03). SVR for genotype 1 was 14% (7/51) and a nice 73% (11/15) for non-1 genotype. The discontinuation rate in this study was low, 12%. However, patients were dose escalated from 600 mg RBV daily up to 100mg RBV daily, because when this study was designed they were concerned about RBV side effects in coinfected patients and tried to ameliorate the side effects. This may have effect of reducing SVR because we learned from HALT-C study that reduced RBV dose in the first few months after starting therapy can reduce response rates. There were 33% African-Americans in this study and 12-15% Hispanics, and this could have affected outcomes, as African-Americans and perhaps Hispanics don't respond as well to therapy. 80% of patients in this study had genotype 1 compared to 60% in APRICOT, so this may have also had negative affect in reducing SVR. 9-11% had cirrhosis (fibrosis 5-6) so this was a low rate of advanced liver disease. Median fibrosis score was 2.0 (out of 6 points). HCV RNA was 6.2 IU/mL, similar to APRICOT. 36% of non-responders were reported to have experienced histologic response. 62% receiving IFN/RBV and 52% receiving Pegasys/RBV had improved HAI (Hepatitis Activity Index), defined as decrease by 2 or more points. 100% of patients who did not have early viral response (>2 log HCV RNA drop) by 12 weeks on therapy did not achieve SVR.
More details on RIBAVIC and ACTG 5071 will be reported in forthcoming NATAP report.
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