Trial Information

A Randomized Trial of the Efficacy and Safety of a Strategy of Starting With Nelfinavir Versus Ritonavir Added to Background Antiretroviral (AR) Nucleoside Therapy in HIV-Infected Individuals With CD4+ Cell Counts Less Than or Equal to 200/mm3

AR therapy is rapidly becoming the standard of care for the treatment of HIV infection. AR
therapy provides the best opportunity for maximizing viral suppression, reducing toxicity
and delaying the emergence of resistant strains. The newest class of AR agents, the HIV
protease inhibitors, exhibits the most potent anti-HIV effects described to date. This study
will compare 2 protease inhibitors, NFV and RTV for efficacy and safety in a population with
advanced HIV disease, who are taking various background nucleoside therapies.

Eligible patients will be randomized either to NFV plus background AR nucleoside therapy or
to RTV plus background AR nucleoside therapy. Background AR therapy may also be no
background therapy, although use of protease inhibitors as monotherapy is not recommended
unless there is no alternative. Patients will be allowed to cross over to the alternate
protease inhibitor if they reach a primary study endpoint. Data will be collected every 4
months.

[AS PER AMENDMENT 10/2/97: Patients assigned to the NFV arm who develop a significant
intolerance may switch to RTV or IDV; those assigned to the RTV arm who develop a
significant intolerance are encouraged to switch to IDV (NFV allowed if IDV
contraindicated). Switchover for intolerance is strongly discouraged during the first 4
weeks of follow-up. Patients initially assigned to NFV therapy who experience disease
progression may switch to RTV; if RTV is not tolerated, patients may switch to IDV. Because
of the cross-resistance between RTV and IDV, patients who progress on RTV should switch to
NFV.] [AS PER AMENDMENT 12/15/98: Patients originally assigned to NFV who experience poor
virologic control or disease progression should change to RTV or IDV or enroll in the PIP
protocol (CPCRA 057). Conversely, patients originally assigned to RTV should change to NFV
or enroll in the PIP protocol (such patients continue to be followed on this study).
Because of cross-resistance between RTV and IDV, change from RTV to IDV is discouraged.
Determination of poor virologic control or disease progression is at the discretion of the
patient's clinician. Change in background antiretroviral therapy should occur at the same
time that the protease inhibitor is changed for poor virologic control or progression; the
choice of new background antiretroviral agents is at the discretion of the clinician.]
Randomization is stratified by clinical site.] [AS PER AMENDMENT 3/11/98: SUBSTUDY CPCRA
045: At least 600 patients (>= 400 from CPCRA sites and >= 200 from CTN sites) will be
enrolled in the substudy. These patients will have a plasma sample collected for HIV RNA and
genotypic resistance within 30 days prior to randomization, at the 1-month visit, and at the
q-4-month study visits thereafter until the end of the study. CD4+ cell counts will be done
at the 1-month visit and at the q-4-month study visits until the end of the study. A subset
of patients will also have immunophenotyping of CD4+ and CD8+ cell TCR V-beta clones carried
out before and during treatment. Another subset of patients at selected sites will have
viral cultures performed for phenotypic drug sensitivity testing.

Initially, specimens for 50 randomly chosen patients in the group originally assigned RTV
will be identified for resistance testing. Of this group, specimens for those who have
received RTV/IDV for more than 1 month will be analyzed for genotypic resistance to obtain
an estimate of the rate of resistance development and to estimate the risk of disease
progression associated with resistance to RTV/ZDV. Based on these estimates, determination
will be made of the total number of patients and specimens in both treatment groups in order
to address the primary objective of comparing genotypic resistance in the two groups.]