[10] ANTIVIRAL ACTIVITY OF THE HIV-1 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI) CAPRAVIRINE AGAINST HIV-1 VARIANTS FROM NNRTI-EXPERIENCED PATIENTS

5th International Workshop on HIV Drug Resistance & Treatment Strategies

4-8 June 2001, Scottsdale, Arizona

[TITLE:] ANTIVIRAL ACTIVITY OF THE HIV-1 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI) CAPRAVIRINE AGAINST HIV-1 VARIANTS FROM NNRTI-EXPERIENCED PATIENTS

[AUTHOR(S):] TN Alexander¹, MC Leavitt¹, JJ Rudy¹, JS Isaacson¹, K Hertogs², BA Larder³ and AK Patick¹
¹ Agouron Pharmaceuticals, A Pfizer Company, La Jolla, Calif., USA; ² Virco, Mechelen, Belgium; and ³ Virco, Cambridge, UK
Antivir Ther. 2001;6 Suppl 1:8

Despite the success of combination antiretroviral regimens, many patients experience a loss of viral suppression with subsequent emergence of resistant HIV. Such cases present the need for new antiretroviral agents for use in the treatment of patients resistant to currently available antiretroviral drugs. Capravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 with potent in vitro antiviral activity against both wild-type HIV-1 clinical isolates as well as HIV-1 clinical isolates broadly cross-resistant to other NNRTIs. We have extended these studies and have evaluated the baseline phenotypic and genotypic resistance for patients entering a Phase II, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of capravirine in patients failing an NNRTI-containing regimen. Of 71 patients enrolled in the trial, 62, 32 and 1% reported prior use of nevirapine, efavirenz and emivirine, respectively; no prior NNRTI was reported for 5% of the patients. Antivirogram phenotype analyses demonstrated that capravirine exhibited potent antiviral activity with EC₅₀ values <70 nM for 45 of 52 (86%) isolates tested. No significant reduction in susceptibility (<4-fold) was observed for 26 of 52 (50%) isolates tested. In contrast, only 13% (7/53), 17% (9/53) and 38% (20/53) of the isolates were susceptible (<8-, <6- and <10-fold as defined by Virco for each drug) to nevirapine, efavirenz and delavirdine, respectively. Genotype analyses identified K103N as the predominant amino acid substitution, occurring alone or with up to four additional NNRTI mutations in 29 of 55 (53%) isolates examined. Full susceptibility to capravirine was observed for 18 of 28 (64%) K103Ncontaining isolates tested, including those with K103N alone or in combination with V108I or P225H. In contrast, only five of the 28 (18%) K103N isolates remained susceptible to nevirapine, delavirdine or efavirenz. These results indicate that capravirine merits further study in NNRTI-experienced patients.

PRESENTING AUTHOR: TN Alexander

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