• Poster 751: Genotypic and Phenotypic Analysis of HIV-1 from Patients Receiving Combination Therapy Containing Two Nucleoside Reverse Transcriptase Inhibitors (NRTI), a Protease Inhibitor, and Emvirine (EMV, Coactinon) (Authored by K. Borroto-Esoda, J. Harris, C. Klish, J. Mewshaw, L Rimsky-Clarke, and B.J. McCreedy Triangle Pharm. Inc., Durham, NC)
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• Poster 752: Genotypic Characterization of Resistance in Patients Failing an EFV/ IDV/ NRTI Regimen (Study DMP266-020) (Authored by L. Wallace, E. Anton, J. Bunville, K. Krakowski, M. Aujay, K. Abremski, and L.T. Bacheler. DuPont Pharmaceuticals Co., Wilmington, DE)
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Poster 751: Genotypic and Phenotypic Analysis of HIV-1 from Patients Receiving Combination Therapy Containing Two Nucleoside Reverse Transcriptase Inhibitors (NRTI), a Protease Inhibitor, and Emvirine (EMV, Coactinon)

Emvirine (EMV, or Coactinon) is a non-nucleoside reverse transcriptase inhibitor (NNRTI), in the same category as delavirdine, nevirapine, and efavirenz. Patients in this randomized, double blind placebo-controlled trial were all naive to protease inhibitors and NNRTIs, but had at least 16 weeks prior treatment with AZT and 3TC. Viral loads were greater than 10,000 copies/ml. They were randomized to receive nelfinavir (Viracept) plus two new NRTIs and a placebo, or nelfinavir plus two new NRTIs and emvirine.

All patients who experienced virologic failure had DNA sequence analysis performed on the protease and reverse transcriptase genes, in order to determine if failure correlated with antiviral drug resistance.

Results

Following at least 24 weeks of therapy with emvirine, nelfinavir, and two NRTIs, NNRTI-associated mutations were seen in 56.8% of patients experiencing virologic failure. The most common mutation patterns were similar to those seen with other drugs of the NNRTI class, namely the K103N (10 of 25 patients), K103N + Y181C (4 of 25 patients), K103N + K101E (1 of 25 patients), Y181C (4 of 25 patients) and other patterns.

The data demonstrate that mutations at K101E, K103N, V108I, V179I, Y181C, Y188H/C, and G190A were observed in vivo following combination therapy with emvirine. HIV isolates that contain any combination of mutations, in which K103N is present, or K101E, are cross resistant to all currently approved NNRTIs. However, if these key mutations are lacking, susceptibility to at least one other NNRTI may be retained even in the presence of other mutations, such as Y181C, V108I, Y188H, or G190A. Interestingly, patients who had virologic failure of emvirine, nelfinavir, d4T, and ddI were more likely to develop the Y181C mutant (31.25%) than those on emvirine, nelfinavir, d4T and 3TC (3.7%). Viruses containing this mutation alone were resistant to emvirine, nevirapine, and delavirdine, but retained sensitivity to efavirenz.

Poster 752: Genotypic Characterization of Resistance in Patients Failing an EFV/ IDV/ NRTI Regimen (Study DMP266-020)

This abstract reports the resistance characteristics from patients enrolled in this early efavirenz study. All patients entered the study with viral loads of at least 10,000 copies/ml, CD4 count >50, on NRTIs for at least eight weeks, and naive to protease inhibitors and NNRTIs. Genotypic sequencing was performed to identify resistance mutations associated with virologic failure for patients on efavirenz-containing regimens.

Results

1. At baseline, no primary NNRTI or PI mutations were present. Secondary mutations in the protease region were common, but very uncommon in the NNRTI region.

2. 68% of patients had some baseline NRTI mutations, of which M184V (conferring resistance to 3TC) was most common. Types and prevalence of NRTI-resistance mutations at baseline were not substantially different between responders and virologic treatment failures.

3. K103N occurred in 65% (20/31) of virologic failures in the EFV/IND/NRTI arm. Interestingly, 32% of virologic failures had no detectable NNRTI resistance mutations in this study, which is somewhat higher than that seen in other studies.