# Presentation: 709341

## 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**
**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.**

## 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**

** **

**SQVhc**

** **

**SQVhc**

** **

**SQVhc**

** **

**SQVhc**

**Weeks   0                     8                           24**

**Weeks   0                     8                           24**

**Weeks   0                     8                           24**

**Weeks   0                     8                           24**

**SQVhc**

**SQVhc**

**SQVhc**

**SQVhc**

**  ****600mg tid**

**  ****600mg tid**

**  ****600mg tid**

**  ****600mg tid**

**SQVsgc**

**SQVsgc**

**SQVsgc**

**SQVsgc**

**  ****1200mg tid**

**  ****1200mg tid**

**  ****1200mg tid**

**  ****1200mg tid**

** ****IDV**

** ****IDV**

** ****IDV**

** ****IDV**

**   ****800mg q 8h**

**   ****800mg q 8h**

**   ****800mg q 8h**

**   ****800mg q 8h**

**IDV**

**IDV**

**IDV**

**IDV**

**test HIV-RNA,**
**if no response**
**cross to other PI**

** **

**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**

## 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 log****10****)**
**      ****25% <2500 and 25%>48,000**
**CD4 median****	****240**
**      ****25% < 144 and 25% > 320**

## Slide 5

## 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.**** **

## 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%)**

## Failures Rates by Baseline Covariates 

**   ****	**_**Parameter**_**	****  **_**Category**_**	****        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.of**** ****PI 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%)**

## Regression Model for Genotype Data

**Dropouts as Failures**

_**Model**_**  ****	****   **_**Parameter**_**	**** **_**p-value**_**	**_**Odds Ratio**_** ****	**_**95% 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**

## 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.**

## Slide 11