Third International Congress Drug Therapy in HIV Infection 3-7 November 1996 Glasgow, UK

AN OVERVIEW OF DRUG RESISTANCE DURING SAQUINAVIR TREATMENT

E Race, SM Gilbert, JG Sheldon, AR Moffat, PW Tomlinson and JB Duncan


Int Cong Drug Therapy HIV 1996 Nov 3-7;3:Abstract No. OP2.5
AIDS 1996, Vol. 10 (Suppl. 2);S11

Of the three HIV proteinase inhibitors (PI) to have been approved for the treatment of HIV infection to date (saquinavir, indinavir and ritonavir) saquinavir (SQV, Invirase™, Ro-31-8959) is the best tolerated and is thus ideal for use in combination therapy. Concern has been aroused through a study with indinavir that the use of PI may be hindered by the rapid emergence of universally reduced sensitivity to such drugs.

Two mutations in the proteinase gene (48V and 90M) have been key to the development of reduced sensitivity to SQV, and this signature differs from other PI. In contrast to many of the mutations associated with resistance to indinavir (eg 10I, 63P, 71V, 82I/F), 48V and 90M have never been seen in samples from untreated patients. Mutations at ancillary sites which may increase erratically in a small percentage of patients during SQV therapy and others which remain at baseline levels, do not confer reduced sensitivity to SQV in the absence of mutations at 48 and 90. In phase I/II clinical trials of SQV, substitution at codons 48 or 90 were detected in around 40% of patients after 1 year of treatment. The double mutation was rare, occurring in only 6% of patients treated with SQV alone. More significantly the double mutation appeared in none of those patients who received SQV in combination with reverse transcriptase inhibitors. The incidence of reduced sensitivity to SQV parallelled these genetic changes.

NV 14256 is a randomised, double blind comparison of SQV and ddC over ddC alone, with respect to both time to AIDS defining events (reduced by 53%, p=0.0002) and survival alone (reduced by 71%, p=0.002). Virus isolates from patients recruited at 15 sub-study centres are currently being assessed for sensitivity to SQV at baseline and up to 72 weeks of treatment. Sequencing of the full viral proteinase gene is carried out on RNA from patients' plasma and on DNA from the in vitro passage of virus isolates. Reduced sensitivity to SQV has been defined as a ≥ 4 fold reduction in IC₅₀, based on an analysis of inter-assay variation, and the distribution of pre-treatment IC₅₀ values. To date a change in sensitivity to SQV above this threshold has been seen in 3/12 (25%) patients treated with SQV alone and in 2/9 (22%) patients on the combination treatment arm after 6 months of treatment. Amino acid substitutions in the proteinase gene have been in line with those seen in the phase I/II studies with mutations at codons 48 or 90 observed in the plasma RNA of approximately 40% of patients. Some patients have been seen to maintain a reduced viral load for 40 to 80 weeks after the appearance of virus with reduced saquinavir sensitivity and mutations at positions 48 and/or 90.

Virus and plasma samples from a further 20-30 patients, some of whom have now been treated with SQV for more than 72 weeks, are currently being changes assessed to provide an estimate of the incidence of genotypic and phenotypic changes after long term treatment, and the clinical significance of these changes.

The incidence of reduced sensitivity to SQV in the clinic is likely to be yet more significantly reduced by the use of other combinations which will substantially reduce viral replication and maintain viral load below the level of detection (eg SQV+ZDV+3TC or SQV+ritonavir).

Presenting author: JB Duncan

1996-11-03
OP2.5

Originally published in AIDS Volume 10, Supplement 2 and hosted with permission of the publisher Lippincott Williams & Wilkins, 250 Waterloo Road, London, SE1 8RD, UK. Tel: +44 (0)20 7981 0700 Fax: +44 (0) 7981 0701

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