Second International Congress Drug Therapy in HIV Infection 18-22 November 1994 Glasgow, UK

THE INFLUENCE OF COMBINATION THERAPY ON HIV-1 VIRAL LOAD AND DRUG RESISTANCE

BA Larder
Wellcome Research Labs., Beckenham, UK

Int Cong Drug Therapy HIV 1994 Nov 18-22;2:Abstract No. 5.1
AIDS 1994, Vol. 8 (Suppl. 4);S4

A wealth of data has now accumulated which demonstrates that monotherapy with selective antiretroviral drugs results in the emergence of drug-resistant strains of HIV. It is becoming apparent that this is due to incomplete suppression of viral replication during such treatment. These observations have reinforced the view that combinations of inhibitors, rather than monotherapy, will be required for the more successful treatment of HIV disease. Such strategies include regimens of inhibitors directed at different viral enzymes, in addition to the simultaneous co-administration of reverse transcriptase (RT) inhibitors. The latter approach offers potential advantages as deduced from in vitro virological studies, including: synergy between inhibitors and mutually exclusive resistance profiles (especially where resistance suppressing mutations have been observed). To determine whether combination therapy with two RT inhibitors delays the development of drug-resistance, we have completed a multicentre, double-blind, placebo-controlled trial where 183 individuals were randomised into treatment groups comparing AZT+ddl or AZT+ddC with AZT+placebo (the Wellcome 34,225-02 trial). These combinations did not significantly retard the emergence of AZT-resistance, as determined by, a number of criteria, including: PCR detection of the RT codon 215 mutation, DNA sequence analysis of the RT codon region and phenotypic testing of recombinant virus strains. However, very few mutations were seen by 48 weeks of treatment that confer ddl or ddC resistance, which might explain the significant effects of these combinations on viral load and CD4+ cell numbers. We have also determined changes in viral load (measured by quantitative RNA PCR) in serum samples from AZT-naïve individuals enrolled in a combination 'therapy trial comparing AZT+3TC with AZT+placebo (the Glaxo NUCB3001 trial). Analysis of sequential samples from 25 individuals In each group (weeks 0, 2, 4, 8, 12 and 24) revealed significant differences in viral load reduction. Since the patient populations were similar in terms of viral load at entry in both the 34,225-02 and NUCB3001 trials, we have been able to compare treatment effects with these two-drug combinations. Interestingly, the two AZT monotherapy groups in each trial showed an almost identical response to therapy (mean log reduction in RNA copies of 0.3 in serum RNA at week 12 and 0.11 -0.21 by week 24). The combinations could be ranked according to viral load reductions: AZT+3TC being the most pronounced (mean log reduction of 1.36 at week 12 and 1.25 at week 24) and AZT+ddl the least (mean log reduction of 0.67 at week 12 and 0.59 at week 24): Given the observed viral load changes, the results of larger clinical end-point trials assessing combinations will be of considerable interest.

1994-11-18
5.1

Originally published in AIDS Volume 8, Supplement 4 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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