Bacheler L, George H, Hollis G, Abremski K; Conference on Retroviruses and Opportunistic Infections.

Program Abstr 5th Conf Retrovir Oppor Infect Conf Retrovir Oppor Infect 5th 1998 Chic Ill. 1998 Feb 1-5; 5th: 210 (abstract no. 703).

DuPont Merck Pharmaceutical Company, Experimental Station, Wilmington, DE.

Efavirenz (SUSTIVA, DMP 266) is a potent inhibitor of the reverse transcriptase of HIV-1. In order to assess the potential for the development of resistance to efavirenz in vivo, we studied the circulating plasma virus in patients participating in clinical trials of efavirenz at doses of 200, 400, or 600 mg qd in combination with indinavir, an inhibitor of the HIV-1 protease, or ZDV/3TC, nucleoside inhibitors of the reverse transcriptase of HIV-1. We sequenced plasma virus from patients who, despite an initial decrease in viral load on efavirenz containing combination therapy, subsequently experienced a significant rebound in viral load. For each plasma sample studied, we cloned and sequenced multiple independently amplified HIV-I protease/RT gene segments. The most common mutation seen in either drug combination was a K103N mutation in the reverse transcriptase gene. Other mutations observed less frequently included Y188L and G19OS substitutions. Viral genomes with multiple RT gene mutations including K103N/V108I, L1001/K103N, or K103N/G19OS, were frequently identified but have not been observed to become the predominant plasma virus genotype in individual patients. In vitro drug susceptibility tests of recombinant virus constructs demonstrated that the K103N mutation was associated with approximately 19-fold resistance to efavirenz, while Y188L and G19OS constructs were associated with greater (100 to 200-fold) resistance to efavirenz. Despite the greater phenotypic resistance of virus constructs containing Yl88L or G190S mutations, plasma virus populations in vivo were only rarely dominated by these genotypes, suggesting that the more frequently observed Kl03N genotype offered some relative advantage. All of the mutations we have observed in patients experiencing rebounds in viral load on efavirenz containing therapy have been previously described as associated with resistance to one or more non-nucleoside reverse transcriptase inhibitor. To date, we have no evidence for additional novel mutations in the RT gene associated with resistance to efavirenz. In addition, we see no evidence of major changes in the spectrum of mutations associated with efavirenz treatment failure in the presence or absence of ZDV/3TC.

Publication Types:

• Meeting Abstracts

Keywords:

• Genotype
• HIV Protease
• HIV-1
• Humans
• In Vitro
• Lamivudine
• Mutation
• Oxazines
• RNA-Directed DNA Polymerase
• Reverse Transcriptase Inhibitors
• Treatment Failure
• Zidovudine
• efavirenz
• genetics
• reverse transcriptase, Human immunodeficiency virus 1

Other ID:

• 98929628

UI: 102236281

From Meeting Abstracts