Structured Treatment Interruptions Workshop Summary

From Project Inform

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: Advertisement 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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