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Stavudine (d4T) and Didanosine (ddI) Combination Therapy in HIV-Infected Subjects: Antiviral Effect and Safety in an On-going Pilot Randomized Double-Blinded Trial
Vancouver Abstract Th.B.293
Authors: R Pollard, D Peterson, D Hardy, L Pednault, V Rutkiewicz, I Pottage, R Murphy, J Gathe, G Beall, L Stovronsky, A Cross, L Dunkle
In January 1996 at the Human Retrovirus Conference, Dr. Richard Pollard presented data from a pilot randomized double-blinded study of antiretroviral naive individuals, which evaluates combination therapy of d4T and ddI for safety and antiviral effect.
Data was presented in Vancouver for additional study participants. Following is a discussion of this study.
Study Design:
Pollard said,
Eighty-five individuals started therapy with one of the following treatment regimens; 65 of the 85 study subjects had baseline RNA copies/ml of 1,000 or more:
ddI (mg/bid)* d4T (mg/bid)* Study Arm under 60 kg above 60 kg under 60 kg above 60 kg (60 kg=132 lbs) A 75 100 7.5 10 B 75 100 15 20 C 75 100 30 40 D 125 200 15 20 E 125 200 30 40 Baseline Characteristics: started therapy 1000 or more RNA copies/ml CD4 cell count/mm3 (n=82) (n=65) median 330 325 mean 343 337 Viral load (RNA log10) (n=73) (n=65) median 31,600 RNA copies/m 31,600 RNA copies/ml (4.5 log10) (4.5 log10) mean 15,800 RNA copies/ml 25,100 RNA copies/ml (4.2 log10) (4.4 log10)
Mean Change in Viral Load:
subjects with at least 1000 RNA copies/ml at baseline; combined data from all 5 dosing regimen groups; it is important to bear in mind that the number of subjects is small for each of the different dosing regimens, upon which this collective data is based, therefore results can vary when larger numbers of subjects are factored in--
baseline (n=65) 4 weeks (n=57) 1.20 log reduction from baseline 8 weeks (n=50) 1.20 16 weeks (n=46) 1.00 28 weeks (n=36) 1.30 52 weeks (n=18) 1.30
Comments--The sustained RNA reduction after 52 weeks may be at least partially due to the slow development of resistance to both drugs.
Mean Change in CD4:
for all subjects including those with RNA levels above and below 1000 RNA copies/ml at baseline, combined data from all 5 dosing regimen groups--
baseline (n=82) 4 weeks (n=72) 61 CD4 cell increase from baseline 8 weeks (n=76) 83 CD4 16 weeks (n=69) 81 CD4 28 weeks (n=66) 80 CD4 36 weeks (n=58) 88 CD4 52 weeks (n=35) 75 CD4 Antiviral Response (combined data of all 5 dosing groups) baseline RNA levels 1000 or more RNA copies/ml-- Weeks # of subjects 1 log fall 2 log fall n (%) n (%) 0 65 -- -- 4 57 37 (65) 10 (18) 8 50 28 (56) 9 (18) 16 46 18 (39) 9 (20) 28 36 23 (64) 11 (31) 52 18 10 (56) 6 (33)
Adverse Events Based on the set of data discussed above, Pollard reported the following information:
Prior to Vancouver, a set of data was available based on a fewer number of study participants, but the data was broken down by dosing regimen; again, it is important to remember the number of subjects for each dosing regimen group is small, and results can be less consistent with a smaller number of subjects. Therefore, these results may vary when larger numbers of study subjects are considered.
Mean Reduction in Viral Load:
for subjects with at least 1000 RNA copies/ml at baseline; in parenthesis is the n or number of study subjects in a particular study arm at the given time--
Group A B C D E baseline (n=11) (n=12) (n=11) (n=9) (n=11) 4 weeks -0.90 log -1.20 log -0.80 log -1.70 log -1.40 log (10) (10) (8) (8) (10) 8 -1.10 log -1.20 log -0.90 log-1.20 log -1.40 log (8) (10) (7) (6) (10) 16 -1.10 log -0.50 log -0.80 log -1.20 log -1.60 log (9) (8) (10) (6) (8) 28 -1.10 log -1.40 log -1.30 log -1.30 log -1.40 log (6) (7) (7) (4) (8) 52 -1.50 log -1.10 log -1.80 log -1.80 log -1.40 log (3) (4) (3) (2) (2) Mean increases in CD4 cell count: for all subjects, including those with and below 1,000 RNA copies at baseline-- Group A B C D E baseline (n=13) (n=16) (n=15) (n=13) (n=14) 4 weeks 70 68 62 44 47 (n=9-15/arm) 8 weeks 65 74 93 93 85 (n=11-16/arm) 16 weeks 57 86 89 52 90 (n=10-13/arm) 28 weeks 54 76 42 66 112 (n=8-12/arm) 52 weeks -22 64 72 85 141 (n=4-6/arm) Adverse Events: these events are based on the 2nd set of data for the smaller number of subjects (n=76), again, these results can also vary when larger numbers of subjects are factored in -- Number of Events A B C D E n=15 n=18 n=15 n=14 n=14 peripheral neuropathy - - 1 - - diarrhea - 1 1 1 - abdominal pain - - - 1 1 lipase elevation (grade 3 or 4 events) 1 2 - 1 - liver enzyme rise -SGOT 2 1 - 2 1 -SGPT 3 2 - 2 1 -bilirubin - 1 - - - neutropenia - - - - 1
The data has not been fully analyzed yet, but it appears as though there have been 2 discontinuations due to lipase elevations.
CSF Penetration:
Bristol-Myers says--
After a single d4T 40 mg dose in 12 healthy subjects, CSF and simultaneous plasma concentrations were determined. Mean CSF concentration was 40% of mean simultaneous plasma concentrations. Mean CSF concentration 4 to 5 hours post dose was 63.1 ng/ml (0.28 um). These results demonstrate that d4T does penetrate into the CSF and produces CSF concentration which exceed the ED50 of HIV clinical isolates."
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About the author: Jules Levin is the Executive Director of NATAP, based in New York City.
The National AIDS Treatment Advocacy Project (NATAP) is a New York State non-profit corporation dedicated to facilitating the effort for development of effective treatment for HIV.
Last modified 8/5/96 by Jules Levin
copyright © 1996 natap
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