Safety and Antiviral Activity of Hydroxyurea (HU) with ddI - National AIDS Treatment Advocacy Project - NATAP

Safety and Antiviral Activity of Hydroxyurea (HU) with ddI

Eighty individuals without prior ddI, ddC and 3TC experience were enrolled in this multi-center, randomized, open-label study in which participants were randomized to receive ddI or ddI+HU for the first 12 weeks. Individuals randomized to ddI alone were permitted to add HU after week 12 . Participants were stratified by baseline CD4 (50-300, 301-600) to detect differences in CD4 responses to HU therapy. Prior HU studies have shown that despite viral load reductions, CD4 increases may not be proportionate and are sometimes slight.

The HU dose was 500 mg bid (twice daily). The ddI dose was adjusted for body weight: greater than or equal to 60 kg, 2 100 mg tablets bid; less than 60 kg 125 mg bid (a 100 mg tablet and a 25 mg tablet). Plasma HIV RNA was evaluated by Chiron’s bDNA assay. Exclusion criteria included: absolute neutrophil count <1500 cells/mm x mm x mm, SGOT, SGPT, alkaline phosphatase, or total billirubin <2.5 times upper limit of normal, evidence of pancreatitis (assessed by serum amaylase, pancreatitis amylase isoenzyme, and/or serum lipase) and evidence of peripheral neuropathy of grade 2 (moderate) or higher.

Safety
Dropout rate (n=80):

Discontinued prior to week 12 : Two out of 38 in the immediate HU group and 8/42 in the delayed HU group (the dropouts in the delayed group were primarily due to suboptimal plasma HIV RNA suppression and persisting gastrointestinal adverse events.)

Discontinuations weeks 13-24: 14 individuals in the immediate group dropped out primarly due to physician/participant decision. Six discontinued during weeks 13-24 in the delayed group also primarily due to physician/participant decision.

A total of 12 serious adverse events were reported but only 3 were determined as possibly study drug related:

Grand Mal Seizure - person was randomized to immediate Hu arm and experienced event 2 weeks after starting HU+ddI. At hospital patient was hypoglycemic (low blood glucose) and treated with insulin. HU and ddI were resumed after discharge from hospital. There have been no other reports of grand mal seizures associated with HU. Such seizures occurred in <1% of patients receiving high or recommended doses of ddI in ACTG 116B/117 and 116A.
Syncope, Hypotension, Dehydration, Pancytopenia - person was randomized to delayed HU and experienced event at week 18 (4 weeks after adding HU to ddI). Upon admission to the hospital, HU discontinued and patient’s hemotologic values were: hemoglobin 10.9 g/dl, WBC 2300/uL, platelets 72,000. HU resumed after discharged from hospital. Leukopenia, thrombocytopenia and anemia have been reported previously associated with HU.
Uterine Bleeding - person randomized to delayed HU and experienced event at week 24 (12 weeks after adding HU to ddI). At hospital admission patient’s hemotologic values were: hemoglobin 8.2, hematocrit 23.7%, WBC 1600; platelets 65,000. While hospitalized, the patient received 2 units of blood. The patient continued study meds during the event.

Thrombocytopenia was reported in 1% of patients receiving ddI in phase I studies. Thrombocytopenia (<50,000/uL) was reported in 1-4% of patients receiving the recommended or high dose ddI in ACTG 116B/117 and 116A. Thrombocytopenia has been reported as associated with HU and is usually preceded by leukopenia.

Week 12 HIV RNA and CD4 changes from Baseline by CD4 Strata

	Immediate HU		Delayed HU
CD4 strata	50-300	301-600	50-300	301-600
N=68	18	12	18	17
median base VL	68,545	44,665	153,400	34,890
median wk 12 VL	4,861	1,054	31,735	2,394
mean wk 12 log decrease	-1.1 log	-1.2 log	-0.6 log	-1.1 log
wk 12 <500 copies/ml	6 (27%)	7 (58%)	2 (11%)	8 (53%)
CD4 (n=68)	18	13	20	15
median base CD4	244	385	158	424
mediam wk 12 CD4	232	409	191	485
median wk 12 CD4 change	+7	+61	+27	+42

Interestingly, the CD4 group of 301-600 receiving ddI monotherapy had an equal reduction in viral load to the HU+ddI group at week 12. However, a key question is--will adding HU to ddI delay or prevent ddI failure due to the development of ddI resistance? See the report posted to the web site called Hydroxyurea as a Novel Approach to HIV Therapy, #2.

Week 24. After week 12 HU was added to ddI monotherapy and resulted in a mean 0.4 log reduction in HIV RNA beyond that seen with ddI alone (n=33). At week 24, the HIV RNA reduction for the delayed HU group was similar to that seen at week 24 for the immediate HU group (n=30).

At week 24 there was a trend suggesting that CD4 increases gained during the first 12 weeks for the ddI monotherapy group (delayed) was lost after adding HU. As well, median CD4 gains by the immediate HU group appear to be lost by week 24.