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Clinical data on the new extended release formulation of d4T
By Julio Montaner
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Julio Montaner, from the University of British Columbia in Vancouver, presented the first public human clinical data on the new extended release formulation of d4T used once per day. This presentation was given at a Late Breaker oral session at the Athens 8th European HIV Conference. He talked about how poor adherence is a contributing factor to viral failure. He said complex dosing schedules contribute to this and simplifying a patient's regimen to once a day may improve adherence and ultimate treatment outcome. I think regimen simplification may increase willingness to begin therapy for some patients. Montaner said d4T XR (extended release) has no food effect, implying you can take it with or without food.
Montaner presented results from a 48-week randomized, double-blinded study comparing d4T XR to d4T IR (standard d4T formulation) in combination with 3TC twice daily and efavirenz once daily. Patients were treatment-naïve (<7 days prior NRTI, NNRTI, or PI; no ART during 14 days prior to randomization). 14 days prior to starting regimen patients were required to have serum creatinine < 1.5 x ULN (upper limit of normal), total serum lipase < 1.4 x ULN, AST/ALT <3 x ULN.
Patients were stratified by viral load: below or above 30,000 copies/ml. Patients „60 kg of body weight received d4T 40 mg and patients with <60 kg of body weight received d4T 30 mg (I think a kg equals about 2.2 lbs.). All study patients received d4T XR plus d4T IR placebo or d4T IR plus d4T XR placebo. In cases of efavirenz intolerance nelfinavir substitution was permitted.
Average age was 34. Interestingly, a higher percentage of women (24-27% were females) were enrolled than we usually see in studies. 19% were Black and 7-13% were Hispanic. 26-32% were from South America and 68-74% were from North America. Montaner reported no differences between treatment groups observed regarding these demographics.
Viral load was 49,000 in the d4T XR arm and 42,600 in the d4T IR arm, no real difference. CD4s were 354 in the d4T XR arm vs 261 in the d4T IR arm. 75 patients were randomized and 74 treated in the XR arm, while 80 were randomized but 76 treated in the IR arm.
RESULTS
Premature Discontinuation Prior to 48-weeks
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d4T
XR |
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d4T
IR |
| Total |
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7(9%) |
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14(18%) |
| Adverse Event |
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1(1%) |
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5(6%) |
| Nonadherence |
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1(1%) |
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4(5%) |
| Lost to Followup |
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1(1%) |
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2(3%) |
| Diease prog |
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2(3%) |
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2(3%) |
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Total treated patients completing 48 weeks was 67 (91%) in XR arm and 62 (82%) in the IR arm.
Viral Load at Week 48
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d4T
XR |
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d4T
IR |
| ITT (NC=F) <400 |
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78% |
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67% |
| On Treatment <400 |
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88% |
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82% |
| ITT <50 |
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50% |
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49% |
| On Treatment<50 |
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56% |
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60% |
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CD4 increases were 232 in the XR arm and 195 in the IR arm.
Selected Clinical Adverse Events (related to study drug > grade 2)
The interesting observation is that neuropathy occurred more often in the regualr IR d4T formulation arm. |
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d4T
XR |
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d4T
IR |
| Neuropathy |
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1(1%) |
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8(11)% |
| Headache |
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5(7%) |
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1(1%) |
| Fatigue |
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4(5%) |
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2(3%) |
| Nausea |
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3(4%) |
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3(4%) |
| Diarrhea |
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3(4%) |
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1(1%) |
| Vomiting |
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2(3%) |
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2(3%) |
| GI Disorder |
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3(4%) |
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0 |
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Selected Lab Abnormalities (>grade 3/4)
AST/ALT: 3-4% in each arm
Alkaline phosphatase 0-1% in each arm
Hemoglobin 1% in each arm. Montaner reported fasting triglycerides, total cholesterol, HDL cholesterol, and other lab parameters were similar between treatment groups.
LACTATE
According to a chart Montaner presented average lactate levels were about the same in the XR and IR arms at each poit of measure: baseline, weeks 12, 24, and 48. There did appear to be an increase from baseline to week 48 for both the
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