1st National Conference Human Retroviruses and Related Infections Washington, DC - December 12-16, 1993

Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 8)

Eastman PS, Richman D, Urdea M, Kolberg J
Chiron Corporation, Emeryville, CA

Resistance to nucleoside analogs has been associated with specific mutations in the reverse transcriptase (RT) gene of HIV-1, most notably, the aa215 mutation associated with resistance to the nucleoside analog ZDV. We wished to determine the significance of a mutation at aa215 in patients undergoing combination therapy with ZDV and the non-nucleoside reverse transcriptase inhibitor, nevirapine. Five HIV-infected subjects with previous ZDV experience (range 13-157 weeks) were evaluated. Plasma from 2 patients on combination therapy and 3 patients on nevirapine monotherapy were analyzed. Viral load in these patients was determined by the Quantiplex™ HIV-RNA assay based on branched DNA technology. Both genotype and viral load were determined directly from the patient plasma as opposed to subcultured clinical samples to allow assessment of the relative amounts of viral populations. The presence of ZDV resistance in the plasma was semi-quantitated using the polymerase chain reaction (PCR) and differential hybridization for the determination of genotype at the aa 215 locus. In addition, the relative amounts of both genotypes were determined when viral mixtures were encountered. In all patients, significant amounts of aa 215 mutant sequences were observed at baseline. In 2 patients experiencing nevirapine monotherapy, plasma viral RNA levels declined or maintained with the addition of 12.5 mg/day nevirapine, only to rebound by 8 weeks indicating the development of resistance to nevirapine. An elevated dosage of nevirapine (400 mg/day) produced an additional decline in viral RNA levels. Similar results were observed with the 2 patients on combination therapy. In all patients, nevirapine therapy produced a dramatic decline in the aa 215 WT population. Preliminary data suggest that nevirapine preferentially affects the aa 215 WT population in the plasma.

Keywords: Acquired Immunodeficiency Syndrome, Anti-HIV Agents, Genotype, HIV, HIV Core Protein p24, HIV Infections, HIV Protease Inhibitors, HIV-1, HIV-1 Reverse Transcriptase, Humans, Nevirapine, RNA, Viral, Reverse Transcriptase Inhibitors, Viral Load, Zidovudine, genetics, immunology, methods, organization & administration

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1993-12-12
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