HIV AIDS News [International Conference on AIDS (12th: 1998: Geneva, Switzerland)]

[41213] Virologic Resistance to Efavirenz

12th World AIDS Congress
June 28 - July 3, 1998
Geneva, Switzerland
Lee Bacheler, O. Weislow, S. Snyder, G. Hanna
Dupont Merck Pharmaceutical Company, Wilmington, DE; SRA Technologies,
Rockville, MD; Massachusetts General Hospital, Boston, MA, USA
Objective: Efavirenz (SUSTIVA(tm), DMP 266) is a potent non-nucleoside reverse
transcriptase inhibitor (NNRTI) currently in Phase III clinical development for reduction
of HIV-1 RNA load when used in combination with other antiretroviral drugs. In order
to assess the potential for development of virological resistance to efavirenz, genotypic
and phenotypic characterization of plasma virus and virus isolates from patients
participating in clinical trials of efavirenz was undertaken. Methods: Nucleic acid
sequencing of multiple, independently amplified plasma virus genomes, isolation and
in vitro drug susceptibility testing of viruses from patient PBMCs, and population
based sequencing of these replicating virus isolates were used to characterize resistance
to efavirenz. Results: Nucleic acid sequencing of plasma virus from patients whose
viral load rebounded on efavirenz-containing combination therapy revealed the
emergence of K103N RT-mutant viruses around the time of viral load rebound, often
followed by the appearance of viruses with multiple mutations (K 103N/V 108I and K
103N/P225H combinations were the most common). In studies to date (NNRTI naive
patients), the spectrum of mutations observed in patients who failed efavirenzcontaining combination therapy was not influenced by the other antiretrovirals used,
nor by the dose of efavirenz (200 to 600 mg qd). Virus isolates from these patients
demonstrated phenotypic resistance to efavirenz as well as resistance to nevirapine and
delavirdine. K103N, Y188L and/or V108I mutations in the RT gene were found in
efavirenz-resistant virus isolates.
Conclusions: K103N was the predominant NNRTI-resistant viral genotype observed in
vivo among efavirenz treatment failures. In most cases, a single nucleotide substitution
generated this drug resistant mutant virus, which can emerge when virus suppression
is suboptimal. Post treatment failure virus isolates carrying K103N, V108I and/or
Y188L mutations showed a >=20 fold increase in the in vitro IC50 for efavirenz
compared to pre-therapy isolates.