July 10, 2001
This was a study to look at the feasibility of adding the polyethylene glycol-conjugated form of interferon alpha to failing HAART regimens. Previous studies have shown that interferon alpha has anti-HIV activity and may be synergistic with nucleoside analogues. Pegylation of interferon A allows much higher drug exposure and once-a-week dosing.
This study was a phase II, double-blind, placebo-controlled, multi-center, safety and efficacy trial. Patients were randomized 1:1:1:1:1 to receive placebo or one of four doses of interferon. A phase III pivotal study will follow this one.
Patients were HIV-infected with CD4 counts >200 cells/ml and at least five months of continuous exposure to HAART, consisting of a protease inhibitor and two NRTIs or an NNRTI and two NRTIs. They had to be failing their current HAART regimen, defined as HIV RNA of at least 2000 copies/ml and RNA >3 fold (0.5 log) increase in pVL or no longer undetectable. Exclusion criteria included: a history of severe depression, dementia or other psychiatric illness, any CNS abnormality requiring use of seizure medications, significant hematologic, hepatic or renal abnormalities, intercurrent illness, vaccinations or use of any immune modulators within two weeks of study entry and use of systemic corticosteroids, other immunosuppressants, ribavirin, or cytotoxic agents within two weeks of study entry.
PEG-Intron was dosed at 0.5, 1.0, 1.5 or 3.0 mcg/kg once weekly and placebo PEG was given once weekly.
The primary endpoint of the trial was the mean change in HIV RNA from baseline to week four. Secondary endpoints were AUC for HIV RNA from baseline to week four and the change in absolute CD4 cont and percent over this period. Responders were defined as subjects with a decrease in HIV RNA of at least 0.5 log 10, after four weeks of PEG-Intron and they were continued on a 24-week observational study with optimization of antiretroviral regimens after four weeks, using genotypes and phenotypes obtained at the start of the study. Non-responders were subjects with <0.5 log 10 decrease in plasma RNA.
A total of 259 patients were recruited. They were well matched for age and race.
|Selected Baseline Parameters|
|0.5 mcg/kg||1.0 mcg/kg||1.5 mcg/kg||3.0 mcg/kg||Placebo|
|RNA log 10||4.20||4.26||4.12||4.43||4.17|
|Yrs HIV dx||8.5||7.4||7.5||8.4||7.9|
Results were as follows:
|Virology Response: Reduction from baseline >0.5 log 10|
|End of Week 4||12||23%||20||39%||19||35%||28||57%||7||14%|
PEG-Intron showed a dose-dependent decrease in viral load in all arms and the three higher doses were all clearly superior to placebo.
Adverse events, however, were also dose-related.
|Adverse Events (AE) Through the End of Week Four|
|All AEs||18 (89%)||45 (88%)||51 (93%)||48 (96%)||40 (78%)|
|Grade 3 and 4||7 (13%)||7 (14%)||10 (18%)||17 (34%)||4 (8%)|
|D/c due to AEs||3 (6%)||5 (10%)||6 (11%)||11 (22%)||1 (2%)|
Twenty-two (14%) patients discontinued study drug because of drug toxicities:
The authors concluded that PEG-Intron at doses of 1.0, 1.5 and 3.0 mcg/kg weekly decreased plasma HIV RNA levels in these highly experienced patients. Adverse events were frequent in all subjects but more so in the highest dose group.
PEG-Intron may be a useful tool to use in patients failing all HIV therapies who have no other options. It is always possible that it could also add efficacy in patients who are not as experienced or who are not failing as badly. Further studies need to be done and a Phase III trial is in the process of being designed based on this study.
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