Report 10 -  4th International Workshop on HIV Drug Resistance and Treatment Strategies
Written by Jules Levin
Sitges, Spain, June 12-16 2000

DAPD REPORT: resistance in 15 day monotherapy study in treatment naÔve & experienced

BRIEF SUMMARY OF THIS REPORT

From preliminary studies in humans, it appears that DAPD should be effective for individuals with extensive NRTI experience and resistance. Viral load results were reported from two preliminary studies of DAPD at this Workshop. The results of a small study in 30+ individuals with NRTI experience was reported. After receiving 15 days of DAPD monotherapy in several doses, the individuals receiving the highest dose of 500 mg twice a day achieved a viral load reduction of -1.1 log. In a study of treatment naÔve individuals receiving various doses, the individuals receiving the highest dose of 500 mg twice a day achieved a viral load reduction of -1.6 log. More details are below. In addition, laboratory resistance experiments were conducted and reported at this meeting. The researchers found in these experiments that DAPD can be effective against viruses with AZT or AZT/3TC resistance. However, DAPD was effective against some viruses with "multi-nucleoside" resistance mutations, and was not effective against virus with different "multi-nucleoside" mutations. Larger studies are needed to confirm this information and to explore how to use DAPD.

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DAPD REPORT: resistance in 15 day monotherapy study in treatment naÔve & experienced

DAPD is an NRTI drug in development for the treatment of HIV and hepatitis B. Phillip Furman from Triangle Pharmaceuticals described the activity of the drug against different drug-resistant HIV isolates. From in vitro experiments, Furman reported that DAPD may be active against some HBV with 3TC resistance but not to all. DAPD is converted in the body to its active form DXG. Furman reported that DXG is active against HIV with multiple selected mutations causing resistance to AZT, 3TC or dual AZT/3TC resistance. He reported that recombinant viruses and clinical isolates of HIV-1 with mutations at codons 41L, 67N, 69D, 70R, 103N, 184V, 190A, 215Y, 219Q, and G333E, alone or in combination, from patients who failed NRTI and/or NNRTI combination therapies remain sensitive to DXG (DAPD).

Passaging experiments in the presence of increasing concentrations of DXG were performed to identify those mutations which might potentially occur clinically. The results identify two mutations--the L74V and the K65R. The l74V mutation caused a 4.2 fold increase in EC50 from wild-type. The K65R mutation caused a 7-fold increase in EC50 from wild-type.

The following resistance experiments were conducted in association with Virco. A virus with mutation associated with multi-NRTI resistance due to SS or SG insertions between codons 68/69 was sensitive to DXG.

The Q151M multi-nucleoside mutation in a background of AZT resistance mutations as well as the Q151M in combination with the 116Y showed moderate resistance (EC50 fold increase) to DXG. But when the K65R mutation was added to Q151M and T215Y the virus showed a 40-50 fold (increase in EC50) resistance to DXG. A virus with multiple AZT and 3TC mutations including the 333 was sensitive to DXG.

Steve Deeks presented, in a poster, the results of a 15 day phase I/II monotherapy study of DAPD. Among the 34 treatment-naÔve patients the following twice daily doses were administered: 25, 100, 200, 300 or 500 mg. The median baseline HIV RNA viral load was 31,600 copies/ml (range 9100-53,700), with a CD4 count of 400 (range 307 to 551).. The highest reduction in viral load of -1.6 log was achieved by the highest dose of PAPD. The viral load decrease in the five dose arms were -0.5, -1.0, -1.1, -1.5 and -1.6 log, respectively.  The 20 treatment-experienced patients twice-daily doses of 200, 300 or 500 mg. The median baseline viral load was 79,400 copies/ml,  and a CD4 count of 245.

The viral load decrease was -0.5, -0.5 and -1.1 log, respectively. Again the largest reduction in viral load of 1.1 log was achieved by the highest dose of DAPD (500 mg).

The most common adverse events were headache, other pain, nausea and diarrhea. Adverse laboratory events that were moderate or worse (at least "grade 2") were decreased white cells (neutrophils), increased glucose, increased creatine kinase (muscle enzyme), increased triglycerides , increased amylase (pancreas gland enzyme), increased ALT (liver enzyme), increased bilirubin. No patient discontinued due to toxicity.

DAPD is in phase I/II clinical trials for HIV but has not yet entered clinical trials for HBV.