DAPD shows activity in vitro against multidrug-resistant HIV but initial results from monotherapy in treatment experienced subjects are disappointing

16 July 2000. Related: Conference reports, Antiretrovirals, Intl Drug Resistance Workshop 4 Sitges 2000.

DAPD is a dioxolane purine nucleoside analogue being developed by Triangle Pharmaceuticals.

It displays potent activity against both HIV and HBV in vitro. DAPD is deaminated to yield DXG, the triphosphate of which is the active compound. In vitro data was presented at this meeting suggesting that DAPD retains activity against a wide range of NA resistant clinical isolates and resistant recombinants as well as the results of a 15 day monotherapy study in both treatment naive and treatment experienced subjects.

Phillip Furman of Triangle Pharmaceuticals presented data on the in vitro activity of DAPD against both clinical isolates from patients showing reverse transcriptase inhibitor resistance as well as recombinant HIV containing mutations known to confer reduced susceptibility to nucleoside analogues [4]. The clinical isolates displayed fold changes in EC50 to DAPD between 0.17 and 2.3. Recombinant HIV containing mutations known to confer resistance to ZDV and 3TC all retained sensitivity to DAPD (< 3 – fold change in EC50). Most multi-drug resistant recombinant HIV also retained sensitivity (< 7 – fold change in EC50) including those recombinants containing the 151M or the 69 [SS] insertion. A recombinant containing mutations at 65R, 116Y and 151M did, however, display high level resistance to DAPD (>35 – fold).

L74V and K65R mutations have both been produced by serial passage of HIV in increasing concentrations of DXG. These mutations confer a 4 – fold and an 8 – fold increase in EC50 respectively. The K65R on a backbone of multinucleotide resistance clearly led to high level resistance to DAPD. The corresponding effect of the L74V was not tested.

In a separate poster Steve Deeks, UCSF, San Francisco, presented the antiretroviral activity during a 15 day monotherapy trial of DAPD at various dosages in both treatment naive and treatment experienced subjects [1]. 34 treatment naive and 20 treatment experienced (minimum of six months of treatment with evidence of failure on either ZDV/3TC or d4T/3TC) were included in this study. Concentrating on the 200, 300 and 500 mg BID dosages, the respective virological response (log copies HIV RNA/mL) at day 15 is shown below.

Table 1.

Pre and post treatment HIV genotypic analysis showed no RT gene alterations and their was good tolerability at the doses tested over the 15 days.

Although the numbers of subjects are small, there appears to be a clear reduction in virological response in the treatment experienced group. It should also be observed that the treatment experience in these subjects was not extensive. These preliminary data appear to contradict the in vitro data presented above suggesting retained activity in resistant HIV and may suggest another mechanism of resistance to DAPD in these subjects other than genotypic. Phenotypic analysis of clinical isolates from patients in this monotherapy study were not available. Additional studies appear warranted to determine the dose related activity plateau in experienced patients as the highest dose used (500mg BID) does not appear to be optimum.

Reference:

1. Deeks S, Kessler H, Eron J et al. Short-term monotherapy of DAPD in HIV-infected patients. 4th International Workshop on HIV Drug Resistance & Treatment Strategies. 12-16 June 2000, Sitges, Spain. Abstract 9.