1st International Workshop on HIV Drug Resistance & Treatment Strategies 25-28 June 1997, St. Petersburg, Florida, USA

PHENOTYPIC AND GENOTYPIC RESISTANCE TO INDINAVIR IN INDIVIDUALS WITH ADVANCED HIV-1 DISEASE

Antiviral Therapy 1997;2 (Suppl 5):24 (abstract no. 37)

L Ruiz¹, M Nijhuis³, CAB Boucher³, T Puig¹, S Marfil¹, A Bonjoch², D de Jong³, A Arnô¹ and B Clotet^1,2
1‘irsiCaixa’ Retrovirology Laboratory and ²HIV Clinical Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; ³Department of Virology, Eijkman-Winkler Institute, University Hospital Utrecht, Utrecht, The Netherlands

Our objective was to assess the efficacy of adding indinavir in advanced patients previously exposed to different reverse transcriptase (RT) nucleoside analogues. Twenty-seven patients with an initial median CD4+ cell count of 20 cells/mm³ (range 0-80) were treated with indinavir (dosage 800 mg q8 h). The median initial viral load (VL) was 5.4 log (range 3.6-6.7 log). Most of the patients had received for more than 6 months monotherapy or combination therapy with two of the following RT inhibitors: zidovudine, zalcitabine, didanosine and lamivudine. According to changes produced in plasma VL levels from baseline, we classified patients as follows:

• Responders (R): an initial decrease in VL ≥1.0 log and sustained response >0.5 log from baseline (n=14).
• Transient responders (TR): a decrease in VL ≥1.0 log at any time point of follow-up with a rebound above 0.5 log from baseline (n=6).
• Non-responders (NR): no decrease in VL >1.0 log at any time point of the follow-up period (n=6).

There were no statistically significant differences in baseline parameters in any of the three groups. Median increases from baseline in CD4+ cell counts were 149, 54 and 20 cells/mm³ for the R, TR and NR groups, respectively. At week 24, the mean decrease in VL in the R group was 1.56 log, while in TR and NR groups there was an increase of 0.02 and 0.34 log, respectively. Eighty percent of the R patients maintained viral RNA levels below the limit of detection of the assay (4000 copies/ml) at week 24.

No mutation related to indinavir resistance was observed in the R group at the end of the study (24 weeks). In contrast, we observed several mutations related to indinavir resistance in the TR and NR groups after the same interval.

Phenotypic resistance to indinavir was determined with the recombinant virus assay from plasma in a subset of eight patients (three R, two TR and three NR). In only two of three NR patients did we observe a four- and 8.5-fold increase in IC₅₀. This increase was associated with the presence of three resistance mutations in the protease gene.

In conclusion, we observed an initial response to indinavir in 76% of patients despite their advanced stage of the disease. This immunological and virological response was sustained in 54% of the patients at 24 weeks. A rebound in HIV-1 RNA levels was associated with a small increase in IC₅₀ and 2-3 mutations in the protease gene. Explanations for failure in the absence of phenotypic or genotypic resistance may be low drug levels due to incomplete compliance or pharmacokinetic interactions.

Download PDF of this abstract.

1997-06-25
37

Copyright © 1997 - International Medical Press Ltd. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the International Medical Press Ltd. 2-4 Idol Lane, London EC3R 5DD UK.