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Twice Weekly Injections of PegIntron
Reported by Jules Levin
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Forman and Ferenci reported at AASLD (abstract 502) on a study exploring the drug concentrations and viral load response kinetics over 28 days of administering PegIntron either once or twice weekly. This study was supported by an unrestricted grant from Roche but nonetheless I think this is an interesting study.
20 interferon naive patients with chronic hepatitis C due to infection with genotype 1a or 1b were enrolled. All patients were antibody positive, virus was detected by HCV PCR in all patients, and all patients had elevated ALT for at least 6 months.
It is of note that patients received PegIntron dose of 1 ug/kg, while 1.5 ug/kg dose is approved for use in the US. In the large Manns phase III study of PegIntron the 1.5 ug/kg dose had a significantly better viral response than the 1.0 ug/kg dose in patients with genotype 1 (42% vs 34% SVR), but not in genotype 2/3 (82% vs 80% SVR). It is also important to note that this is a 28-day study looking at early viral load responses, so we don't know if the differences seen early responses in this study between once and twice weekly PegIntron injections will predict differences in sustained viral responses.
Patients in the Ferenci study were randomized to receive PegIntron 1 ug/kg either once (n=10) or twice weekly (n=10) for 4 weeks. After completion of the study all patients received Pegasys 180 ug once weekly in combination with ribavirin (COPEGUS, the Roche brand of ribavirin) 1000/1200 mg/day for 48 weeks. Both quantitative and qualitative HCV RNA testing was performed: qualitative by Cobas Amplicor Monitor Test v2.0, with a lower limit of detection of <600 IU/ml (Roche); quantitaive HCV RNA tested by Cobas Amplicor HCV Test v2.0 with a lower limit of detection of <50 IU/ml.
PATIENT CHARACTERISTICS. Study investigators reported there was no significant difference between the two patient groups in baseline ALT, baseline viral load, age, gender, weight, body mass index, and histologic grade or stage. All patients completed the study phase according to study protocol. There were 9 men in the once weekly group and 6 men in the twice weekly group; average age was 32 in once weekly group and 45 in twicw weekly group; average weight was 83 kg in once weekly and 80 in twice weekly group; fibrosis (F1/2/3/4, n) was 1/5/-/3 in once weekly and -/7/-/3 in twice weekly group; average ALT was 66 in once weekly group and 41 in twicw weekly group. Average viral load was low: 455,000 IU/ml (range 60,000 to 687,000) in once weekly group and 439,000 IU/ml (range 64,000 to 850,000) in the twice weekly group.
RESULTS
PegIntron Concentrations in the Blood
PegIntron was administered on day 0 and day 3 in the twice weekly group. And on day 7 and day 10 in the second week and likewise for the next 2 weeks of the study. The maximum blood concentrations of PegIntron was observed 24 hours after the first dose on day 0 (about 700 pg/mL). During subsequent days, there was a linear decline in blood concentrations in the once weekly group, this decline continued throughout the week: the average was about 450 pg/mL on day 2; about 350 pg/mL on day 3; about 200 pg/mL on day 4. On day 6 levels of PegIntron were below the limit of detection in 2 of 10 patients. On day 7 (immediately before the administration of the drug) 9 of 10 patients had levels of PegIntron below the levels of detection. The same pattern was reported to be observed during the next 3 weeks of therapy in this study.
In the patients receiving PegIntron twice weekly, levels of PegIntron were detectable at any time point. On days 4, 7, 9, 10, 11, 14 and 21, the difference in levels was significantly higher in the group of patients receiving twice weekly injections.
In the patients receiving twice weekly injections PegIntron levels peaked on the day after the first injection during weeks 1 and 2. Two days after the first injection on day 3 PegIntron levels declined to a low before the next injection several days later. Apparently this pattern repeated itself.
During the first week of the study: on day 4 in the patients receiving twice weekly injections, after receiving the second weekly injection on day 3 the average PegIntron levels reached a peak of about 900 pg/mL; on day 7 in these patients levels dropped to low of about 350 pg/mL. After the next injection on day 7 levels increased on average to about 700 on day 8 and 900 pg/mL on day 9, but declined to about 550 pg/mL on day 10. On day 11 after the second weekly injection levels increased again to 800 pg/mL and declined to about 425 pg/mL on day 14 before receiving injection. The study investigators reported these fluctutations in levels continued throughout the 4 week study in the patients receiving twice weekly injections.
HCV RNA Viral Load Levels
A similar pattern appeared regarding HCV viral load suggesting a relationship between drug levels and viral load response for these genotype 1 patients in this short term study. This study is small and not a controlled study. A similar study of Pegasys in genotype 1 patients would also be helpful.
All 20 patients in this study responded to the first dose of PegIntron by a marked drop in viral load from an average of 400,000-500,000 at baseline to 30,000-100,000 after the first injection on day 1. The study investigators said that in 8 patients in each dosing group, the 24-hour drop was >0/8 log indicating they were not primary interferon resistant subjects. However, on day 3 viral load values increased again. In the once weekly group of patients, virus levels increased further until day 7. A similar pattern was observed in the second week.
In the twice weekly patient group, viral load decreased on day 4 (24 hours after the second injection of PegIntron). Viral load was significantly different between the two dosing groups of patients at each time point until the end of the kinetic study period of 28 days. At day 28, 4 patients (3 of them were HCV RNA negative) in the once weekly group versus 9 patients (5 of them were HCV RNA) negative) in the twice weekly group had a viral load drop of
>1 log (p=0.057). Several studies show that viral response during the first few days of therapy and the first few weeks of therapy correlates with achieving a sustained response. Incidentally, the 12 week early response data appears to be more reliably predictive of sustained response than using response after several days or weeks. In general genotype 1 patients do not respond as well to therapy as patients with genotype 2/3. A few experimental studies explored ways to increase response. One study found that using daily interferon on day 1 in conjunction with initiating pegylated interferon plus ribavirin may increase response rates. This study was reported at the Viral Hepatitis Workshop in Boston just prior to AASLD and a report of the study can be found on the NATAP website Conference Reports section. Another study called RENEW reported early preliminary study results in previous non-responders showing using double the dose of PegIntron (3.0 ug/kg) improved viral response rates and discontinuation rates appeared higher in the higher dose group. But increasing dose may be a way to improve response rates for hard to treat patients including genotype 1 and non-responders.
Platelet and Neurophil Counts
As expected, both platelet and neutrophil counts decreased on treatment. There was no significant difference between the two groups at any given time point. However, like viral load, both parameters decreased continuously during the first two weeks in patients receiving PegIntron twice weekly but increased from day 3 (and day 10) on in the once weekly group.
As stated above, it is noteworthy that patients received PegIntron dose of 1 ug/kg in this study, while 1.5 ug/kg dose is approved for use in the US. In the large Manns phase III study of PegIntron the 1.5 ug/kg dose had a significantly better viral response than the 1.0 ug/kg dose in patients with genotype 1 (42% vs 34% SVR), but not in genotype 2/3 (82% vs 80% SVR). This Ferenci study did not report on adverse events, so we do not know the the difference in adverse events between once or twice weekly adverse events.
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