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Structured Treatment Interruptions Workshop Summary

January 31, 2001

Protocol Proposals

Table 1 - Primary Infection
Study Title / Sponsor ANRS 1000 "PRIMSTOP"
Population Primary Infection (within 4 weeks of symptoms)
Study Type Pilot -- no controls
Regimen HAART + HU
Size 24 patients
Comparison None
Plan 3 STI of increasing length (2, 4 and 8 weeks) at 34, 48 and 72 weeks for patients with suppressed VL (<20 copies).
Duration 82 weeks
Follow-up Until 108 weeks
Primary Endpoint HIV RNA < 20 copies for at least 6 months from last TI.
Secondary Endpoints 1. Resistance; 2. Proviral DNA; 3. Cellular RNA; 4. HIV-1-specific T-lymphocyte response.
Enrollment started: 5/2000

Table 2 - Chronic Suppressed

Study Title / Sponsor TIBET AUTOVAC II
Population Chronic Suppressed <50 for 1 year; CD4 >500 for 6 months Chronic suppressed <50 for 2 years
Study Type Pilot, no controls Randomized
Regimen HAART HAART w/without IL-2
Size 10 patients 50 patients
Comparison None Continuous versus STI w/without IL-2
Plan of Interruptions Stop treatment until CD4+ count drops <350. Restart and continue until resuppressed. Cycle between 2 weeks off and 4 weeks on treatment w/without IL-2. After 6 cycles, stop treatment in all arms and observe until CD4 drops <350.
Duration - 9 months
Follow-up - -
Primary Endpoint Safety Time off treatment.
Secondary Endpoints Time off treatment, cost, QOL, immune monitoring. Immune monitoring.
Enrollment started: - -

Table 3 - Chronic Suppressed

Study Title / Sponsor Philadelphia Wistar Institute Gladstone Institute Garcia/Gatell
Population Chronic Suppressed Prior VL > 10,000; current VL < 50. Nadir CD4 count > 100 cells; current CD4 count > 400. Chronic Suppressed Chronic Suppressed
Study Type Individualized Protocol - Randomized. Pilot - no controls. Randomized
Regimen HAART HAART Multiple strategies
Size 52 patients 20 patients 175 patients
Comparison IT by group under continued ART versus group with previous periodic TI. None Multiple strategies: Continuing treatment vs. STI w/without HU; w/without Immune mod. w/without immunogen.
Plan of Interruptions Continuous ART for 40 weeks - (non-adherent patients will be excluded). Stop (comparison TI). Versus
1) Stop for 2 weeks (priming TI).
2) Restart and treat with ART until RNA <50 for 4 weeks.
3) Following suppression for 4 weeks, stop for 4 weeks (boost TI).
4) Restart and treat until RNA < 50 for four weeks.
5) Following suppression for 4 weeks, stop for 6 weeks (CD8 boost TI).
6) Restart and treat until RNA <50 for four weeks.
7) Following suppression for 4 weeks, open-ended TI (comparison TI).

After suppressed on HAART for 3 months:

1. Stop treatment for 2 months.

2. Restart and treat for 6 months. Repeat cycle 3 times.

1) Continue HAART for 1 year, then stop.

2) HAART/STI

3) HAART/STI + HU

4) HAART/STO + general immune modulator

5) HAART/STI + immunogen.

Duration 12 - 18 months ~ 3 years 18 months
Follow-up ~ 48 months ~ 3 years -
Primary Endpoint Time to RNA > 5000 during comparison TI. Demonstrated adherence by electronic monitors required. Viral load levels Proportion with VL set point < 10,000 after 6 months off treatment.
Secondary Endpoints 1. CD4+ proliferation.
2. CD8+ response.
3. Amplitude of successive VL rebounds.
4. T-cell phenotype; resistance; thymic function.
5. Quality of life
Intensive immuno-logic monitoring. Quality of life.

HIV-1 specific CTL response.

HIV-1 specific T-help response.

Enrollment started: Underway Underway Proposal

Table 4 - Chronic, Previously Untreated

Study Title / Sponsor ACTG A5102 SITACI
Population Patients on first ART regimen; HIV RNA < 200 copies; CD4+ > 500 cells. Chronic, previously untreated.
Study Type Randomized Randomized
Regimen HAART with or without IL-2 HAART
Size 80 patients 10 patients
Comparison IL-2 versus no IL-2 Continuous versus STI
Plan of Interruptions 1) Treat w/without IL-2 for 18 weeks.
2) If CD4 > 500 then stop until CD4 drops < 350 (2x).
3) Restart and treat with ART for 6 months
4) If RNA < 200 continue w/without IL-2 for 18 weeks.
5) If CD4 > 500, stop until CD4 drops < 350 (2x).
6) Restart and treat with ART for 6 months
7) If RNA < 200, continue w/without IL-2 for 18 weeks.
Cycle between 3 months on treatment and 1 month off. At 16 months, stop treatment in both arms and observe until CD4 drops <350.
Duration ~ 18 months to primary endpoint (end of step 2) 16 months +
Follow-up ~ 5 years -
Primary Endpoint CD4+ cell count at end of first 18 weeks w/without IL-2; rate of CD4 decline during TI. Safety
Secondary Endpoints 1. Duration of 1st & 2nd TI.
2. Rate of resuppression.
3. Replicative capacity, fitness, resistance
4. Others
Resistance, time off treatment, immune monitoring
Enrollment started: 12/2000 Proposed

Table 5 - Chronic, Unsuppressed or MDR

Study Title / Sponsor ANRS 097 "GigaHAART" OPTIMA Tri-national study ACTG A5086 CPCRA 064
Population

Chronic unsuppressed.

VL > 75,000;

CD4+ < 200.

Chronic unsuppressed. MDR, have failed 2 regimes including 3 classes. Chronic unsuppressed.
VL > 10,000; CD4 > 150.
At least one prior virologic failure; heavily pretreated.

Chronic unsuppressed.

MDR virus. VL > 10,000.

Study Type Randomized Randomized Randomized Randomized
Regimen 3-4 NRTI, an NNRTI, HU, RTV+APV or IDV, SQV, NFV

MegaHAART is > 5 drugs.

Retreatment based on baseline genotype.

Best available regimen based on baseline viral genotype, pheno-type and treatment history. Regimen selected based on genotyping / phenotyping at baseline.
Size 90 patients 1300 patients 220 patients 480 patients
Comparison Begin ""Giga-HAART"" immediately or wait 8 weeks to begin. Continue, stop or switch to Mega-HAART Begin new regimen immed-iately or wait 16 weeks to begin. Begin new regimen immediately or wait 16 weeks to begin.
Plan of Interruptions Deferred group has an 8-week washout before starting. 3 to 6 months drug-free period for interruption arm. Deferred arm waits 16 weeks to begin new regimen. Deferred arm waits 16 weeks to begin new regimen.
Duration - 2 years 64 weeks 24 months
Follow-up - 3 years - -
Primary Endpoint Virological response = > 1.0 log reduction in VL at weeks 12 and 24. Time to AIDS or death. Proportion with VL < 400 at 48 weeks. Progression to AIDS or death.
Secondary endpoints and monitoring Toxicity, genotype, PI plasma concentrations. Toxicity, illness, QOL, standard markers, economics. VL < 50 at 24, 48, 64 weeks.
Adherence; Stratify above and below VL= 100,000; CD4+ above and below 200.
Resistance and Immunology substudies proposed.
Genotype, VL, CD4+, drug levels, fitness assays. QOL adherence. Stored plasma and cells.
Enrollment started: Underway Proposed Proposed Underway


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