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ACTG 333 The Antiviral Effect of Switching from Saquinavir to the New Formulation of Saquinavir vs. Switching to Indinavir After >1 year of Saquinavir Use DAP Analysis. ACTG 333 Study Objectives. Primary Objective

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Actg 333 study objectives

ACTG 333The Antiviral Effect of Switching from Saquinavir to the New Formulation of Saquinavir vs. Switching to Indinavir After >1 year of Saquinavir UseDAP Analysis


Actg 333 study objectives

ACTG 333 Study Objectives

Primary Objective

To determine if after >1 year SQVhc use, there was an fall in HIV-RNA upon switching to IDV or SQVsgc.

Secondary Objective for the DAP

To determine if amino acid substitutions at protease positions associated with in vitro SQV or IDV resistance at baseline predicted RNA responses.


Actg 333 study objectives

Protocol Design

Protocol Design

Protocol Design

Protocol Design

Patients with more than 48 weeks of prior SQVhc

Randomized, open label, 3 arm trial for 24 weeks

Weeks 0 8 24

Weeks 0 8 24

Weeks 0 8 24

Weeks 0 8 24

SQVhc

SQVhc

SQVhc

SQVhc

IDV

IDV

IDV

IDV

600mg tid

600mg tid

600mg tid

600mg tid

SQVsgc

SQVsgc

SQVsgc

SQVsgc

SQVhc

SQVhc

SQVhc

SQVhc

test HIV-RNA,

if no response

cross to other PI

1200mg tid

1200mg tid

1200mg tid

1200mg tid

IDV

IDV

IDV

IDV

800mg q 8h

800mg q 8h

800mg q 8h

800mg q 8h

Pre-entry-no antiretroviral change for 2 months

Pre-entry-no antiretroviral change for 2 months

Pre-entry-no antiretroviral change for 2 months

Pre-entry-no antiretroviral change for 2 months


Actg 333 study objectives

Baseline Characteristics (n=89)

Gender 89% male

Race 72% W, 12% Afr-AM

Age median 42 yr

Prior SQV use median 105 weeks

% on ≥ 2 NRTI at entry 85%

HIV-RNA median 12,451 (4.1 log10)

25% <2500 and 25%>48,000

CD4 median 240

25% < 144 and 25% > 320


Actg 333 study objectives

Determination of Protease Genotype

Population based sequencing

plasma RNA -> RT ->PCR -> sequence

Multiple PCR, independent clonal sequencing

plasma RNA -> RT -> multiple parallel PCR ->

insert into vectors -> sequence 1 clone each PCR

Amino acid positions of protease related to IDV and SQV resistance were selected for analysis. Mix = mutant.

Primary 32, 48, 82, 84, 90

Secondary 10, 20, 24, 33, 36, 46, 47, 54, 71, 73, 77, 88

(counted only if primary substitution present)

Differences in methods resolved.


Actg 333 study objectives

Number of PI Mutations

No. of Substitutions Subjects

None 28 (31%)

1 5 (6%)

2 5 (6%)

3 17 (19%)

4 11 (12%)

5 7 (8%)

6 7 (8%)

7 1 (1%

Missing 8 (9%)


Actg 333 study objectives

Failures Rates by Baseline Covariates

ParameterCategory Subjects with

RNA>500 (DAF)

Baseline RNA<3.5 3/15 (20%)

3.5 - 4.5 10/15 (67%)

4.5 - 5.5 15/16 (94%)

No.ofPI mutations zero 5/14 (36%)

one 2/4 (50%)

two 1/1 (100%)

three 9/12 (75%)

four 3/3 (100%)

five 4/4 (100%)

six 4/4 (100%)


Actg 333 study objectives

Regression Model for Genotype Data

Dropouts as Failures

ModelParameterp-valueOdds Ratio95% CI

A Baseline RNA 0.0001 7.67 2.91-26.98

1 log change

D Number of PI 0.0002 2.12 1.38 - 3.73

mutations

F No. PI mutations 0.0015 2.71 1.39 - 7.36

Baseline RNA 0.0002 12.99 2.87 - 140.3

1 log change


Actg 333 study objectives

Conclusions

1. HIV-RNA change was greater for IDV than SQVsgc and for SQVsgc than SQVhc.

2. There was trend between increasing number of protease mutations and greater use of SQV, higher baseline RNA, and lower CD4.

3. The number of protease mutations and viral load at baseline were predictive of HIV-1 RNA response. Patients with 0 or 1 select protease mutation had a greater RNA decrease. Subjects with ≥ 2 total protease mutations had a blunted RNA response.