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

VIRAL RESPONSE DRIVEN ANTIRETROVIRAL THERAPY

Thomas C. Merioan
Stanford University, School of Medicine, Stanford, CA

Int Cong Drug Therapy HIV 1994 Nov 18-22;2:Abstract No. 2.1
AIDS 1994, Vol. 8 (Suppl. 4);S1

In advanced disease, AZT was able to prolong life and prevent infectious and neoplastic complications whereas on surrogate markers effects have been critical for licensing the other drugs. ddl, ddC and D₄T are most clearty indicated for use when AZT is toxic or failing. It is also clear that all these effects are trensient. Furthermore, the first course of a drug a patient receives is likely to be accompanied with the most striking effects. In trials in large numbers of patients, it has been demonstrated that there is beneficial effect from switching to a never previously utilized drug. This additional beneficial effect is also transient and exactly when to shift drugs as well as at what CD41evei to initiate therapy has not been precisely determined. In an effon to clarify this situation, my group has been working on the molecular mechanisms at play during the development of drug resistance and the biologic phenotypes which are associated with accelerated disease in patients treated with various regimens. We have developed viral load markers such as quantitative PCR for proviral DNA within CD4 cells and virion RNA present in plasma or serum. These techniques when applied to patients during AIDS Clinical Trials Group supported trials are revealing new findings in regard to the degree of suppression of virus actually achieved with various antiviral strategies including both combination and monotherapy with dideoxy drugs.

In addition, we are studying the patterns of induced mutations in viral reverse transcriptase on the various drug regimens and their impact on viral phenotypic dideoxy drug susceptibility as well as the development of more pathogenic viral variants during therapy. From these studies we have gained a number of specific insights. For example, the cell free virion shows these mutations sooner than the slower turning over proviral form in CD4 + T cells. Patients with high CD4 levels show a pattern of CD4 fall which relates closely to development of mutations with both mono and combination dideoxy drug therapies. Patients at low CD4 levels show a linkage between the development of drug resistance, high viral load and biological variant phenotypes. In addition, combination therapy produces different patterns of reverse transcriptase mutations than monotherapy. When one can identify cenain key mutations such as the codon 215 reverse transcriptase changes with respect to AZT or codon 74 changes with respect to ddl, then new kinds of clinical trial strategy can be developed. As these changes are initially only present in a small portion of the virus in the blood, and they are detectable before elevation of virus load, they could first signal the time to change therapy. A protocol based on changing drugs at the time of the 215 mutation at high CD4 + T cell levels has been started within the ACTG and could begin to answer the question as to whether or not by individualizing therapy, one can get more sustained drug action in this disease.

Presenting author: Thomas C. Merioan

1994-11-18
2.1

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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