A Pilot Study of the Short-Term Effects of Antiretroviral Management Based on Plasma Genotypic Antiretroviral Resistance Testing (GART) Compared With Antiretroviral Management Without Plasma GART

Overview

To determine the short-term virologic and immunologic effects of using plasma genotypic antiretroviral resistance testing (GART) results (interpreted by study virologists AS PER AMENDMENT 9/17/97) in the management of therapy for antiretroviral-experienced patients failing on one of the following regimens: 1. zidovudine (ZDV) + (lamivudine) 3TC + (indinavir) IDV 2. ZDV + 3TC + saquinavir (SQV) 3. ZDV + 3TC + ritonavir (RTV) 4. stavudine (d4T) + 3TC + IDV. \[AS PER AMENDMENT 11/26/97: To determine the short-term effects of using plasma GART in the management of antiretroviral-experienced patients failing on a triple drug regimen that includes a single protease inhibitor (indinavir \[IDV\], saquinavir \[SQV\], ritonavir \[RTV\], or nelfinavir \[NFV\]) and two licensed nucleoside reverse transcriptase inhibitors (NRTIs).\] A growing body of evidence suggests that antiretroviral resistance is associated with an increased risk of disease progression and death. All commercially available antiretrovirals and many of those in development have been associated with resistance. Fortunately, techniques are available to define HIV genotypic resistance in "real time" as compared to techniques that measure phenotypic resistance that is not practical in a clinical setting. Using genotypic antiretroviral resistance testing (GART) results, along with other currently available markers, may lead to improved treatment decisions compared with using currently available markers alone.

A growing body of evidence suggests that antiretroviral resistance is associated with an increased risk of disease progression and death. All commercially available antiretrovirals and many of those in development have been associated with resistance. Fortunately, techniques are available to define HIV genotypic resistance in "real time" as compared to techniques that measure phenotypic resistance that is not practical in a clinical setting. Using genotypic antiretroviral resistance testing (GART) results, along with other currently available markers, may lead to improved treatment decisions compared with using currently available markers alone. 128 patients are randomized to GART or no GART within each of four strata defined by current antiretroviral regimen: 1. ZDV plus 3TC plus IDV 2. ZDV plus 3TC plus SQV 3. ZDV plus 3TC plus RTV 4. d4T plus 3TC plus IDV. Each of the four strata contains 22 patients with CD4+ counts of 50 - 199/mm3 and 11 patients with CD4+ counts of 200 - 500/mm3. Upon randomization, clinicians determine a treatment strategy with supplied baseline GART results (GART arm) or without them (no-GART arm). All patients remain on the triple antiretroviral regimen initiated at the randomization visit until at least the 8-week visit. At this time, changes in treatment will be allowed based on an inadequate response to therapy. \[AS PER AMENDMENT 9/17/97: 128 patients are randomized to therapy based on GART results or therapy not based on these results. Patients are stratified into 8 groups defined by current antiretroviral regimen (ZDV/3TC/IDV vs. ZDV/3TC/SQV vs. ZDV/3TC/RTV vs. d4T/3TC/IDV) and screening CD4+ count (50-199 vs. 200-500). Management of patients assigned to the GART group is based on recommendations of study virologists after independent review of patient plasma GART results in addition to current clinical practice. Up to four different treatment regimens using only licensed drugs may be recommended, ranked but considered approximately therapeutically equivalent. The management of patients assigned to the no-GART group is based on current clinical practice and includes only licensed antiretrovirals.\] \[AS PER AMENDMENT 11/26/97: 160 patients are randomized to GART or no GART within each of 8 strata defined by current antiretroviral regimen (NRTI-1 plus NRTI-2 plus IDV vs. NRTI-1 plus NRTI-2 plus SQV vs. NRTI-1 plus NRTI-2 plus RTV vs. NRTI-1 plus NRTI-2 plus NFV) and screening CD4+ cell count.\]