Abstract
We calculated the relative efficacy of treatment, defined as the rate of decline of virus levels in plasma during treatment relative to the rate of decline during highly potent combination therapy, in human immunodeficiency virus type 1 (HIV-1) patients treated for 56 days with different doses of the protease inhibitor nelfinavir. Relative efficacies based on the rate of decline of HIV-1 RNA levels in plasma over the first 14 to 21 days correlated with drug dose and viral load reduction by day 56. Calculation of relative treatment efficacies over the first 2 to 3 weeks of treatment can allow rapid assessment of new antiretroviral agents and dosing regimens, reducing the need to keep subjects in clinical trials on monotherapy for prolonged periods of time. Relative efficacy may also serve as a measure of treatment efficacy in patients in initiating established therapies.
Highlights
The development of active and potent inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and protease (Pr) has drastically changed the natural history of HIV-1 infection
We calculated the relative efficacy of treatment, defined as the rate of decline of virus levels in plasma during treatment relative to the rate of decline during highly potent combination therapy, in human immunodeficiency virus type 1 (HIV-1) patients treated for 56 days with different doses of the protease inhibitor nelfinavir
By retrospectively analyzing results from the phase I/II studies of nelfinavir mesylate, an inhibitor of HIV-1 Pr [37], we have shown that early measures of relative treatment efficacy can predict results of up to 2 months of monotherapy
Summary
The development of active and potent inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and protease (Pr) has drastically changed the natural history of HIV-1 infection. Given that treatment with monotherapy can select for the emergence of drug-resistant viruses and that combination therapy is the treatment standard, new approaches to the assessment of antiviral activity of a particular drug at a particular dose are urgently needed. We propose the use of a mathematically derived factor, “relative efficacy,” which we define as the rate of decline of HIV-1 RNA levels in plasma following treatment with the new antiviral drug divided by the rate of decline following highly potent combination therapies. By retrospectively analyzing results from the phase I/II studies of nelfinavir mesylate, an inhibitor of HIV-1 Pr [37], we have shown that early measures of relative treatment efficacy can predict results of up to 2 months of monotherapy We believe this represents a straightforward and practical method for assessing a new drug’s antiviral activity at a dose that can avoid prolonged periods of unacceptable exposure to monotherapy
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