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  42nd ICAAC Meeting
San Diego, Sept 27-31, 2002
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T-20 and T-1249
Reported by Jules Levin
  At the Intl AIDS Conference in Barcelona the main study results were reported for the 2 T-20 studies, TORO 1 and TORO 2. Results after 24 weeks of therapy were reported. Here at ICAAC study researchers reported a subgroup analysis of TORO 1 to see why some individuals responded better than others. This information should be helpful in utilizing T-20 and in predicting response and in optimizing therapy. In sum, the information reported below shows that T-20 helps reduce virus even if the patient has very few good additional drug options, but it is better to use T-20 with several active drugs. As well, the researchers for this study found adherence was important in doing well. Patients in this study who had better adherence had better viral load reductions.
There are 500 patients in the study and they have advanced HIV. Their viral load was over 100,000 before starting the study. Cd4s were on average 80 and 84% had prior AIDS defining events. Patients received either T-20, which is administered twice daily by subcutaneous injection, plus other drugs or a regimen without T-20. Resistance testing was used to select the best regimen for patients. After 24 weeks the patients receiving T-20 plus the optimized regimen had a -1.70 log reduction in viral load compared to a -0.76 log reduction for the patients not receiving T-20.
Researchers here at ICAAC reported that patients receiving T-20 regimen had similar viral load reductions regardless if they were male or female, white or non-white, < 40 years or age or >40 years of age. The response to T-20 was similar for patients with above or below 100,000 copies viral load. Patients with CD4s >100 appeared to get a better viral load response than patients with <100 CD4s, but patients with <100 CD4s still had a rebust viral load reduction.
The addition of Fuzeon (T-20) also provided benefit regardless of how resistant the virus was to drugs in the patient's individualized background regimen. But, the magnitude of viral suppression in both treatment arms depended on the number of active drugs in the individualized background regimen. There was greater viral suppression in patients who had more agents in their background regimen to which the virus was sensitive. Thus, patients with no active drugs in their background regimen had 0.92 log10 copies/mL suppression on the Fuzeon containing arm compared to 0.12 log10 copies/mL on the individualized background alone. In patients with 1-2 active drugs (evaluated by genotypic testing) viral load reduction was -1.2 log for patients receiving T-20 and about -0.70 log for other patients. In patients who had three to four drugs in their regimen to which the virus was sensitive, suppression on the Fuzeon arm was 2.3 log10 copies/mL, compared to 1.5 log10 copies/mL on individualized background alone. In both cases, the addition of Fuzeon provided an additional benefit of approximately 0.8 log10 copies/mL. A key message here is to combine T-20 with at least 1 or 2 active drugs, and it's better to combine it with 3-4 active drugs. This is because resistance to T-20 can develop if there is little support from other drugs in the regimen. T-20 is no different than other HIV drugs, if you give a patient one drug resistance will develop. If you don't have adequate additional active drugs besides T-20 resistance can develop to T-20.
The researchers reported 98% of patients in TORO 1 and 2 experienced at least 1 local injection site reaction and 3% of study patients discontinued the study due to this. Roche will be providing doctor and patient education programs to teach how to reconstitute the T-20 powder and inject properly.
The final analysis of an early Phase I/II monotherapy study of T-1249, a second-generation fusion inhibitor was also presented in an oral session right after T-20 here at ICAAC. T-1249 was given open-label as monotherapy administered by subcutaneous injection for 14 days. Fusion inhibitor-naive, heavily treatment-experienced patients were examined in 10 patient groups who received daily doses of 6.25 mg to 200 mg. In the initial dosing groups patients received 6.25 mg of T-1249 once or twice daily; 12.5 mg once or twice daily, and 25 mg once or twice daily. Additional dosing groups were 50 mg once daily, 100 mg once daily, 150 mg once daily, and 200 mg once daily.
Of 115 patients entering the study, 113 completed the 14-day dosing period. Patients exhibited dose-dependent decreases in HIV viral load, including an average maximum change of -2.0 log10 copies/mL in patients receiving T-1249 at a once-daily dose of 200 mg/day. Patients receiving 150 mg once daily also had a 2 log reduction after 14 days. The other dose regimens achieved viral load reductions. 89% of the 115 patients were men. Baseline viral load was on average 5.31 log (well over 100,000 copies), and average CD4 count was 57. 114 patients had prior experience with an average of 10 prior anti-HIV drugs. 2 patients discontinued the study early. 1 patient for hypersensitivity/allergic reaction. 1 patient for missed study visits.
The most common adverse events were: 57% of patients experienced injection site reactions, headache 14%, fever 14%, diarrhea 9%. . Three serious adverse events possibly related to T-1249 occurred: grade 4 neutropenia (25 mg QD), hypersensitivity reaction (25 mg BID), and fever associated with injection site reaction (150 mg QD). Researchers reported there was no pattern of adverse events within or across the dosing cohorts, except injection site reactions. The researchers reported that the injection site reactions were more frequent in patients receiving the 50 mg/ml formulation of T-20. Dose response was observed for patients in 50-200 mg once daily groups. There were no study discontinuations reported due to injection site reactions.