Stavudine (d4T) and Didanosine (ddI) Combination Therapy in HIV-Infected Subjects: Analysis of Antiviral Effect and Safety in a Randomized Double-Blind Study

R. Pollard, et al

Rationale for Study:

1. Stavudine(d4T) and didanosine(ddI) in cell culture show additive activity without additive cytotoxicity.
2. No pharmacokinetic interaction; both drugs given twice daily, so combination would be a convenient dosage schedule for the patient.
3. Development of resistance to ddI (modest) and to d4T (difficult to demonstrate) may be further reduced by this drug combination.

Major concern: Potential to develop peripheral neuropathy.

Objective of Study:

Safety
Activity over 52 week period
(virus load and CD₄ cell count)

Study Design:

Dose Groups	ddI (mg)	d4T (mg)
A	100	10
B	100	20
C	100	40
D	200	20
E	200	40

86 subjects received at least one day of therapy, 66 subjects had initial virus load (less than or equal to 1000 copies HIV RNA/ml) sufficient for inclusion in the virological assessment. There were no significant differences in base line characteristics between the groups. The median duration of therapy was 51 weeks.

Outcome: Safety

Only two patients had peripheral neuropathy requiring cessation of drug therapy. One of these, in group A having the lower dose of both drugs, occurred at about 6 weeks. The other patient, in group C, developed peripheral neuropathy at six months. After stopping drug therapy, the peripheral neuropathy resolved, and the patient was treated for a further 6 months at half dose without recurrence of the peripheral neuropathy.

The other adverse events did not appear to be dose related and none resulted in permanent impairment in any subject.

Outcome: Efficacy

Virus load decreased during the first month and this was sustained for the remainder of the year. About 60% of patients had a 10-fold (one-log) drop and 20% - 30% had a two-log drop in virus load. Comparing groups A & B (low dose) with C, D & E (all had full dose of at least one drug), there was a statistically (p Similarly, there was an early rise in CD₄ cell counts of about 60 to 80 cells which was maintained, or even increased, during the 52 week study period. As above, the higher dose group had the greater benefit (146 vs 45 cells/mm³ , p

Conclusion:

The data from this preliminary trial are encouraging. This combination will enter a phase III trial in April, to be tested as 2 drug therapy and with indinavir, a protease inhibitor.