3rd International Workshop on HIV Drug Resistance & Treatment Strategies 23-26 June 1999, San Diego, California, USA

ANALYSIS OF VIROLOGICAL RESPONSE TO ABT-378/RITONAVIR THERAPY IN PROTEASE INHIBITOR-EXPERIENCED PATIENTS WITH RESPECT TO BASELINE VIRAL PHENOTYPE AND GENOTYPE

Antiviral Therapy 1999;4 (Suppl 1):6 (abstract no. 8)

D Kempf¹, H Mo¹, S Brun¹, A Molla¹, B Bernstein¹, K Hertogs², B Larder³, K Orth¹, C Fields¹, M King¹, Y Xu¹, A Japour¹, E Sun¹ and the M97-765 Study Team
¹Abbott Laboratories, Abbott Park, Illinois, USA; ²Virco, Mechelen, Belgium; and ³Virco, Cambridge, UK

BACKGROUND: ABT-378 is a potent protease inhibitor (PI) that, when co-dosed with small amounts of ritonavir, maintains plasma levels 25- to 100-fold above its EC₅₀ for wild-type HIV. ABT-378/ritonavir plus stavudine/lamivudine therapy produces a decline in HIV RNA to <400 copies/ml in 93-95% of antiretroviral-naïve patients at 24 weeks. Study M97-765 is an ongoing clinical trial of ABT-378/ritonavir in patients who have failed PI triple therapy with viral loads (VL) of 10³-10⁵ copies/ml.

OBJECTIVES: To analyse the response to ABT378/ritonavir therapy in PI-experienced patients with respect to baseline genotype and phenotype.

METHODS: Baseline phenotype was measured by the Virco Antivirogram method and compared to the phenotype of HXB2. Baseline genotype was determined by population sequencing. Data was obtained from 57/70 subjects at study baseline.

RESULTS: The EC₅₀ of ABT-378 against baseline viruses ranged from 0.005 to 0.18 µM (0.7- to 26-fold relative to wild-type, mean 2.8-fold). Quantifiable (>fourfold) change in EC₅₀ to PIs was as follows: nelfinavir, 57%; indinavir, 44%; ritonavir, 42%; ABT-378, 19%; and saquinavir, 10%. Declining or undetectable VL was observed in all treated patients during the first 2 week period, during which the only treatment change was replacement of the previous PI with ABT378/ritonavir. Neither initial decline from baseline nor VL at week 24 correlated with baseline genotype or baseline susceptibility to ABT-378. VL increase from the nadir to >1000 copies/ml, without reported treatment interruption during the increase, was observed in 4/13 (31%) patients whose baseline virus demonstrated >fourfold change in EC₅₀ to ≥2 drugs in their regimen, in contrast with 4/44 (9%) of patients whose baseline virus was susceptible (<fourfold change in EC₅₀) to at least three drugs.

CONCLUSIONS: Because of high and sustained plasma levels, ABT-378/ritonavir regimens suppress VL in many PI-experienced patients for ≥24 weeks despite significant resistance to PIs and RTIs. However, virological response in this population is lower than in naïve patients. The use of accompanying agents expected to have activity, in addition to ABT378/ritonavir, is likely to be necessary for a durable antiretroviral response.

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