Report 5

Highlights from Resistance Workshop June 23-26
Reported by Jules Levin

DAPD is a new nucleoside reverse transcriptase inhibitor in the early stages of development but appears promising for individuals with resistance to currently available NRTIs such AZT and 3TC. At the Resistance Workshop K. Borroto-Esoda, from Triangle pharmaceuticals, reported antiviral activity of DAPD against HIV resistant viruses from patients failing nucleoside therapy.

Initial studies in humans are just now starting. DAPD is a pro-drug for DXG. That means DAPD converts into DXG in your body. The overwhelming majority of DAPD is converted into DXG. DXG is highly active against HIV in cells and DAPD has very little HIV activity. So when you take DAPD for HIV it’s the DXG that is working. In a practical sense this information is not relevant to a person taking DAPD. You can apply all the resistance information that was reported and discussed below to a person taking DAPD. In other words if a person is taking DAPD they don’t have to consider or think about the DXG explanation above. I wrote it just to give a better explanation of how DAPD works.

But for Hepatitis B virus it’s different. For HBV both DXG and DAPD are active against HBV. So when you take DAPD both will be working against HBV. Human studies using DAPD in treating HBV may start by the end of 1999.

Reistance Data-

A single L74V mutation that demonstrated 4-fold resistance (4-fold increase in EC50) from in vitro selection of resistance mutations by passage (9 passages) of HIV in increasing concentrations of DAPD (DXG). Borroto-Esoda also reported that a K65R mutation has been seen after exposing HIV to DAPD (DXG), which results in an 8-fold increase in EC50. As you can see below a virus containing 74V with NNRTI mutations did not display DAPD resistance.

DAPD Active AZT/3TC Resistant Viruses. Recombinant viruses and clinical isolates (blood samples from patients exposed to NRTIs) with various mutations associated with resistance to NRTIs were exposed to DAPD. These viruses contained various mutations alone or in combination including 41L, 67N, 69D, 70R, 184V, 215Y, 219Q, DAPD had no resistance or less than 3-fold decreased susceptibility to recombinant viruses and clinical isolates with various AZT/3TC mutations.

Here is DAPD antiviral activity against a few AZT and 3TC recombinant viruses and clinical isolates. Against a recombinant virus with 184V, 215Y, and 219Q there was no resistance to DAPD but displayed >15 fold increase in resistance (increase in EC50) to AZT, and >20 fold resistance to 3TC. But only showed >3-fold resistance to abacavir. A recombinant virus with 41L, 67N, 69D, 184V, 210W, 215Y, and 219R/K had no resistance to DAPD but was resistant to AZT (>40-fold), and 3TC (>100-fold). A clinical isolate with AZT/3TC resistance with 67N, 70R, 184V, 215Y, and 219E had 2.3 increased EC50 against DAPD but 89-fold AZT decreased susceptibility and over 200-fold 3TC decreased susceptibility. A virus with 75M+184V* had >100 fold 3TC resistance but no resistance to AZT or DAPD

NRTI-MDR & 69 Gene Changes. DAPD displayed antiviral activity against NRTI multiply drug resistant (MDR) viruses. Several recombinant viruses containing the 69 insertion "mutations"were sensitive to DAPD (DXG)—62V, 69 (SS), 70R, 215Y (Virco data). A virus containing mutations in the RT gene associated with multi-NRTI resistance (S68Q, Q151M, T215Y) was said to remain sensitive to DAPD by the study authors, although there was a 5-fold increase in EC50 from wild-type.

Viruses with multiple mutations that included K65R, F116Y, and Q151M had 40 to 54-fold increase in EC50 for DAPD (high level resistance).

DAPD & Abacavir or PMEA (adefovir). So it appears that a K65R in combination with other mutations may spell danger. It certainly appears to when in combination with NRTI MDR mutations. Authors reported a virus with K65R had a 7-fold increase in EC50 when exposed to DAPD, a 10-fold in crease in EC50 when exposed to PMEA, a 7-fold increase when exposed to ddI, and an 8-fold increase when exposed to abacavir. In theory, failure from initial treatment with DAPD could lead to a K65R mutation leading to resistance to abacavir. Eight fold phenotypic resistance to abacavir spells an unlikelihood to respond to abacavir at all.

DAPD & NNRTI Mutations- Hypersensitivity. The authors reported 3 recombinant viruses with double mutations associated with NNRTI resistance were hypersensitive to DAPD—they had a decrease in EC50: K103N+V108I (0.1-fold change EC50); K103N+Y181C (0.15-fold change), V106A+G190A (0.25 fold change). Three recombinant viruses with multiple NRTI and NNRTI mutations had 2.5, 1.9 and 3.2 fold increases in EC50 for DAPD, displaying in effect no resistance to DAPD—

• 41L+74V+215Y+106A (2.5-fold EC50 increase for DAPD)
• 67N+69D+70R+74V+215F+219Q+103N+181C (1.9-fold EC50 increase for DAPD)*
• 41L+74V+184V+210W+215Y+181C+190A (3.2-fold EC50 increase for DAPD)*

However, this virus had a 7.8 increase in EC50 when exposed to DAPD:

41L+67N+74V+184V+210W+215Y+181C*

* Virco data

This in vitro data suggests that DAPD may be useful for individuals with NRTI drug resistant viruses. Humans studies are necessary to confirm this.