Hydroxyurea + d4T/ddI vs d4T/ddI
In Hamburg, OT Ruschmann, Bernard Hirschel and others from the Swiss HIV Cohort Study reported findings from a 24 week study comparing the triple regimen of hydroxyurea (HU) and d4T/ddI to the double nucleoside regimen of d4T+ddI. The purpose of the study, as defined by the investigators, was to determine the short term effects of the HU triple regimen.
144 participants were d4T naive, ddI naive or with <6 months prior experience. They were randomized to HU+d4T/ddI or d4T/ddI. The dosing regimens were: HU- 500 mg bid, ddI - 200 mg bid, d4T- 40 mg bid. After 12 weeks, those receiving ddI/d4T were given the option of adding HU.
72 individuals were randomized to each group. Prior to reaching 12 weeks 7 discontinued from the HU group (1 due to an adverse event); 3 discontinued from the d4T/ddI group (none due to adverse event). At week 12 there were 65 evaluable participants remaining in the HU arm and 69 in the placebo arm.
Results:
Adverse Events
d4T+ddI |
HU + d4T/ddI |
|
| Diarrhea | 9 |
15 |
| Nausea/vomiting | 7 |
11 |
| Pancreatitis | 1 |
0 |
| Fatigue | 2 |
10 |
| Neuropathy grade 1 | 6 |
9 |
| grade 2 | 4 |
6 |
| grade 3 | 0 |
3 |
| Neutropenia grade 1 | 3 |
11 |
| grade 2 | 0 |
2 |
| grade 3 | 0 |
1 |
| Elevated lipase | 3 |
5 |
| Elevated ALT/AST (LFTs) | 34 |
36 |
Investigators reported 27 participants withdrew at week 12 due to nausea (8), neuropathies (4), depression (3), lost to follow-up (8), and patient choice (4). Adverse events were more frequent in the HU arm (p<0.05).
The mean baseline CD4 and viral load were 367 cells and 4.53 log (about 33,900 copies/ml). The mean baseline CD8 was 1017, the total lymphocytes were 1774.
At the week 12 analysis there were 65 evaluable patients in the HU arm and 69 in the placebo arm.
Week 12 Changes from Baseline
| d4T/ddI | HU+ d4t/ddI | |
| CD4 | +107 | +28 |
| CD4% | +2.5 | +3.0 |
| CD8 | +5 | -124 |
| Total lymphocytes | +196 | -124 |
| HIV RNA (200 copy test) | -1.5 log | -1.9 log |
| HIV RNA (20 copy test) | -1.7 log | -2.3 log |
| %<200 copies/ml | 29% (20/69)* | 60% (39/65)* |
| %<20 copies/ml | 8% (6/72)* | 19% (14/72)* |
* These percentages are based on the number of evaluable participants. It is not an intent-to-treat analysis which would base the percentage on the 72 patients that started in each arm. However, the %<20 copies/ml is based upon the entire 72 patient groups that started the study. In the HU arm 26 had >200 copies/ml and in the placebo arm 49 had > 200 copies/ml. These individuals had viral loads ranging from 201 copies/ml on up.
After 24 weeks. At week 24, there were 19 evaluable patients still in the d4T/ddI arm, 24 in the group that added HU to d4T/ddI at week 12, and 34 who started and were continuing the triple regimen of HU+d4T/ddI.
Those who had a limited reduction in viral load from d4T/ddI, were characterized as poor responders, and who added HU at week 12 were able to produce a nice decrease in viral load approaching those observed in patients initialy randomized to the HU arm. 55% of these individuals who added HU had <200 copies/ml at week 24.
Generally, those initially randomized to the HU arm were able to sustain their viral load reductions at week 24. 84% who started the HU regimen and stayed with it remained <200 copies/ml at week 24.
Generally, the lower a person’s viral load was at baseline the more likely they were to reach undetectable. From a graph shown by the investigators it appeared as though most of those individuals with 1,000 to 10,000 copies/ml at baseline were able to reach <20 copies/ml. However, those with >100,000 copies/ml at baseline were less likely to reach <200 copies/ml (and more unlikely to reach the 20 copy test) than those with <100,000 copies/ml viral load at baseline. Commentary: This may be a factor to consider when deciding when to start antiretroviral therapy. If you accept the idea that lowering viral load to undetectable or to as low as possible should be the goal of therapy (when possible), beginning therapy when one’s viral load is no more than about 10,000 copies/ml may be a superior approach because it could be easier to reach <20 copies/ml and possibly easier to retain that reduction over the longer term.