Nine Month Course of Anti-HIV Medications for People Recently Infected With HIV
11 september 2018 uppdaterad av: AIDS Clinical Trials Group
The SETPOINT Study - A Randomized Study of the Effect of Immediate Treatment With Potent Antiretroviral Therapy Versus Observation With Treatment as Indicated in Newly Infected HIV-1 Infected Subjects: Does Early Therapy After the Virologic Setpoint?
Although some doctors favor starting anti-HIV treatment as soon as possible after patients learn they are infected, it is not known if treatment for recently infected patients results in long-term benefits or harm.
The purpose of this study is to learn whether or not people should take anti-HIV drugs when they are first infected.
Studieöversikt
Status
Avslutad
Betingelser
Intervention / Behandling
Detaljerad beskrivning
Combination antiretroviral therapy has resulted in significantly decreased morbidity and mortality, incidence of opportunistic infections, and hospitalizations in HIV infected people. However, because of long-term toxicities associated with long-term use of antiretrovirals and the persistence of virus in latent reservoirs, it is unclear when it is best to initiate therapy in recently infected individuals. This study compared the virologic outcomes of adults recently infected with HIV who received emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), coformulated as Truvada, and lopinavir/ritonavir (LPV/RTV), coformulated as Kaletra [immediate treatment (IT arm)], with those who received no treatment [deferred treatment (DT arm)].
The original study lasted 96 weeks. Participants were randomly assigned to one of two groups (IT arm vs. DT arm). For the first 36 weeks of the study, IT arm participants received FTC/TDF once daily and LPV/RTV twice daily. Some IT arm participants received a different ART regimen as determined by the participant and study staff, if appropriate. DT arm participants received no treatment for the duration of the study. At Week 37, participants from both arms were offered treatment continuation or initiation until Week 96 if they had a high viral load, low CD4 count, or experienced HIV-related symptoms (Step 2). Study visits occurred at screening, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 37, 38, 40, and every 4 weeks thereafter. Clinical assessment and blood collection occurred at all visits. Urine tests occurred at selected visits. Participants were asked to complete an adherence questionnaire at Weeks 12, 24, and 36.
Per the recommendations the DSMB review in June 2009, this protocol was terminated as originally written with the exception of those participants in the IT arm in the middle of the first 36 weeks of treatment. Those participants were to continue on treatment until the end of the 36 weeks. At that point treatment decisions were made on best practice guidelines. In addition, the study duration was extended to include a 5 year follow up of participants who did not initiate long-term antiretroviral therapy (Step 3).
The study was reviewed by an SMC on December 8, 2010. The SMC recommended the study close to long term follow-up because only very few participants enrolled in this portion of the study.
All the results except for the CD4 analysis and time to treatment initiation and deaths were based on the database frozen on July 2, 2009. The results for the CD4 analysis and time to treatment initiation and deaths were based on the database frozen on January 30, 2012.
Studietyp
Interventionell
Inskrivning (Faktisk)
130
Fas
- Fas 2
Kontakter och platser
Det här avsnittet innehåller kontaktuppgifter för dem som genomför studien och information om var denna studie genomförs.
Studieorter
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California
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San Diego, California, Förenta staterna, 92103
- Ucsd, Avrc Crs (701)
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San Francisco, California, Förenta staterna, 94110
- Ucsf Aids Crs (801)
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Torrance, California, Förenta staterna, 90502
- Harbor-UCLA Med. Ctr. CRS (603)
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Colorado
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Aurora, Colorado, Förenta staterna, 80045
- University of Colorado Hospital CRS (6101)
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Florida
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Miami, Florida, Förenta staterna, 33139
- University of Miami AIDS CRS (901)
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Georgia
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Atlanta, Georgia, Förenta staterna, 30308
- The Ponce de Leon Center CRS
-
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Illinois
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Chicago, Illinois, Förenta staterna, 60611
- Northwestern University CRS (2701)
-
Chicago, Illinois, Förenta staterna, 60612
- Rush Univ. Med. Ctr. ACTG CRS (2702)
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Indiana
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Indianapolis, Indiana, Förenta staterna, 46202-5250
- Indiana University Hospital (2601)
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Maryland
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Baltimore, Maryland, Förenta staterna, 21201
- IHV Baltimore Treatment CRS (4651)
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Massachusetts
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Boston, Massachusetts, Förenta staterna, 02114
- Massachusetts General Hospital ACTG CRS (101)
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Boston, Massachusetts, Förenta staterna, 02115
- Brigham and Women's Hosp. ACTG CRS (107)
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Missouri
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Saint Louis, Missouri, Förenta staterna, 63110
- Washington University CRS (2101)
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New York
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New York, New York, Förenta staterna, 10003
- Beth Israel Medical Center
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New York, New York, Förenta staterna, 10032
- HIV Prevention & Treatment CRS (30329)
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Rochester, New York, Förenta staterna, 14642
- AIDS Care CRS (1108)
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Rochester, New York, Förenta staterna, 14642
- University of Rochester ACTG CRS (1101)
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North Carolina
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Chapel Hill, North Carolina, Förenta staterna, 27516
- Unc Aids Crs (3201)
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Greensboro, North Carolina, Förenta staterna, 27401
- Moses H. Cone Memorial Hospital CRS (3203)
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Greensboro, North Carolina, Förenta staterna, 27401
- Regional Center for Infectious Disease, Wendover Medical Center CRS (3203)
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Ohio
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Columbus, Ohio, Förenta staterna, 43210
- The Ohio State Univ. AIDS CRS (2301)
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Pennsylvania
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Philadelphia, Pennsylvania, Förenta staterna, 19104
- Hosp. of the Univ. of Pennsylvania CRS (6201)
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Rhode Island
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Providence, Rhode Island, Förenta staterna, 02906
- The Miriam Hosp. ACTG CRS (2951)
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Washington
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Seattle, Washington, Förenta staterna, 98104
- University of Washington AIDS CRS (1401)
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Seattle, Washington, Förenta staterna, 98104
- UW Primary Infection Clinic CRS (1404)
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Lima, Peru, 18 PE
- Asociacion Civil Impacta Salud y Educacion - Miraf CRS (11301)
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Lima
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San Miguel, Lima, Peru
- San Miguel CRS
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Deltagandekriterier
Forskare letar efter personer som passar en viss beskrivning, så kallade behörighetskriterier. Några exempel på dessa kriterier är en persons allmänna hälsotillstånd eller tidigare behandlingar.
Urvalskriterier
Åldrar som är berättigade till studier
18 år och äldre (Vuxen, Äldre vuxen)
Tar emot friska volontärer
Nej
Kön som är behöriga för studier
Allt
Beskrivning
Inclusion Criteria for Step 1:
- Recently infected with HIV
- No prior antiretroviral therapy (ART)
- CD4 count of 350 cells/mm3 or more AND a CD4% of 14% or more within 21 days prior to study entry
- HIV viral load of 500 copies/ml or more within 21 days prior to study entry
- Required laboratory values obtained within 21 days prior to study entry
- 18 years or older
- Ability and willingness to provide written informed consent
- Willing to use acceptable forms of contraception
Exclusion Criteria for Step 1:
- HIV progression to CDC category B or C disease
- Pregnancy or breastfeeding
- History of pancreatitis or coronary artery disease
- Prior ART. Participants who took antiretrovirals for postexposure prophylaxis more than one year prior to study entry are not excluded.
- Certain medications within 21 days prior to study entry. Participants who agree to receive an alternative ART regimen approved by the investigator will not be excluded.
- Previously received an investigational anti-HIV vaccine
- Current therapy with systemic corticosteroids. Patients who are taking a short course (less than 21 days) of corticosteroids are not excluded.
- Current therapy with systemic chemotherapeutic agents; nephrotoxic systemic agents; immunomodulatory treatments, including interleukin-2; or investigational agents
- Known allergy or sensitivity to study drugs or their formulations
- Current alcohol or drug use that, in the opinion of the investigator, would interfere with the study
- Serious medical or psychiatric illness that, in the opinion of the investigator, would interfere with the study
- Hepatitis B surface antigen positive within 21 days prior to study entry
- Known resistance to one or more components of the study drug regimen
Inclusion Criteria for Step 2:
subjects in DT arm who meet one of the following five criteria will be advised to enter step 2 and initiate ART:
- CD4 cell counts below 350 cells/mm3 on 2 consecutive determinations at least 4 weeks apart at or after the step 1, week 12 study visit
- HIV-1 RNA above 750,000 copies/mL confirmed on 2 consecutive determinations at least 1 week apart at or after the step 1, week 4 study visit
- HIV-1 RNA above 200,000 copies/mL on 2 consecutive determinations at least 1 week apart at or after the step 1, week 12 study visit
- Clinical progression to CDC category B or C disease
- CD4 count below 200 cells/mm3 or CD4 percent less than 14% at any time on study
subjects in IT arm who meet one of the following five criteria after discontinuing study medications will be advised to enter step 2 and re-initiate ART:
- CD4 cell counts below 350 cells/mm3 on 2 consecutive determinations at least 4 weeks apart at or after the step 1, week 12 post-treatment- discontinuation study visit
- HIV-1 RNA above 750,000 copies/mL confirmed on 2 consecutive determinations at least 1 week apart at or after the step 1, week 4 post-treatment- discontinuation study visit
- HIV-1 RNA above 200,000 copies/mL on 2 consecutive determinations at least 1 week apart at or after the step 1, week 12 post-treatment- discontinuation study visit
- Clinical progression to CDC category B or C disease
CD4 count below 200 cells/mm3 or CD4 percent less than 14% at any time on study
Exclusion Criteria for Step 2:
- Pregnancy or breastfeeding
Inclusion Criteria for Step 3:
- Study participants who were on Step 1, IT arm and had completed or ended prematurely the 36 week course of early ART and did not on ART either because they did not meet eligibility criteria for Step 2 or because they did not start ART even after meeting the Step 2 eligibility criteria.
- Study participants on Step 1, DT arm who were not on ART either because they did not meet eligibility criteria for Step 2 or because they did not start ART even after meeting the Step 2 eligibility criteria.
- Previous A5217 participants who had either completed the study or ended prematurely their participation in the study, AND were not on ART either because they never met eligibility criteria for Step 2 or because they had not started ART even after meeting the Step 2 eligibility criteria.
- All A5217 participants who were on Step 1 and in the midst of their 36 weeks of randomized ART and who completed a portion or all of the 36 weeks of originally recommended therapy, AND chose then to interrupt their ART.
Exclusion Criteria for Step 3:
- Participants who were on Step 1, IT arm of the study receiving ART.
- Participants in Step 2 or who had otherwise initiated long-term ART, regardless of whether they were on treatment.
Studieplan
Det här avsnittet ger detaljer om studieplanen, inklusive hur studien är utformad och vad studien mäter.
Hur är studien utformad?
Designdetaljer
- Primärt syfte: Behandling
- Tilldelning: Randomiserad
- Interventionsmodell: Parallellt uppdrag
- Maskning: Ingen (Open Label)
Vapen och interventioner
Deltagargrupp / Arm |
Intervention / Behandling |
|---|---|
|
Aktiv komparator: IT arm
IT (immediate treatment) arm participants received emtricitabine/tenofovir disoproxil fumarate once daily and lopinavir/ritonavir twice daily
|
once daily
twice daily
|
|
Inget ingripande: DT arm
DT (deferred treatment) arm participants received no treatment
|
Vad mäter studien?
Primära resultatmått
Resultatmått |
Åtgärdsbeskrivning |
Tidsram |
|---|---|---|
|
Ranked Log10 HIV-1 RNA Viral Load (log10 Copies/mL) Averaged at 72 and 76 Weeks for the IT Arm and DT Arm
Tidsram: At Weeks 72 and 76
|
The primary endpoint is (i) the average of log10 viral loads (VL) at wks 72 and 76 for participants who continued to wk 72 off ARV for the DT arm, (ii) average wk 72 and 76 VL for those who continued to wk 36 off ARV for the IT arm and (iii) an assigned VL rank for the "failures" who needed ARVs or met criteria for entry into Step 2 prior to these study visits.
The assigned rank for the failures was either the last observed rank carried forward or the worst rank relative to the other possible outcomes.
This approach was designed to, if anything, bias against finding a treatment effect.
To illustrate, consider five participants who enter the study (A, B, C, D, and E), 4 of whom (A, B, C, D) make it to 72 wks off therapy with RNA levels that increase from A to D. Participant E enters Step 2 at wk 12, at which time his RNA is in the 50th percentile.
This rank would be carried forward, so the rank order of the log10 HIV-1 RNA endpoints would be A B E C D.
|
At Weeks 72 and 76
|
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Ranked log10 HIV-1 RNA Viral Load (log10 Copies/mL) Averaged at Weeks 72 and 76 for the IT Arm and Ranked log10 HIV-1 RNA Viral Load (log10 Copies/mL) Averaged at Weeks 36 and 40 for the DT Arm
Tidsram: IT arm (weeks 72 and 76) and DT arm ( weeks 36 and 40)
|
The primary endpoint is (i) average wk 36 and 40 VL for those who continued to wk 36 off ARV for the DT arm, (ii) average wk 72 and 76 VL for those who continued to wk 36 off ARV for the IT arm and (iii) an assigned VL rank for the "failures" who needed ARVs or met criteria for entry into Step 2 prior to these study visits.
The assigned rank for the failures was either the last observed rank carried forward or the worst rank relative to the other possible outcomes.
This approach was designed to, if anything, bias against finding a treatment effect.
To illustrate, consider five participants who enter the study (A, B, C, D, and E), 4 of whom (A, B, C, D) make it to 72 wks off therapy with RNA levels that increase from A to D. Participant E enters Step 2 at wk 12, at which time his RNA is in the 50th percentile.
This rank would be carried forward, so the rank order of the log10 HIV-1 RNA endpoints would be A B E C D.
|
IT arm (weeks 72 and 76) and DT arm ( weeks 36 and 40)
|
|
Number of Participants Experiencing Either a CDC Category B or C Diagnosis, CD4<200 Cells/mm^3 or CD4 Percent <14%.
Tidsram: 96 weeks since randomization
|
96 weeks since randomization
|
Sekundära resultatmått
Resultatmått |
Åtgärdsbeskrivning |
Tidsram |
|---|---|---|
|
Change in CD4 Counts Cells/mm^3 From Week 36 for IT Arm and From Week 0 for DT Arm
Tidsram: IT arm (weeks 36, 60, 72, 84 and 96) and DT arm (weeks 0, 24, 36, 48 and 60)
|
IT arm (weeks 36, 60, 72, 84 and 96) and DT arm (weeks 0, 24, 36, 48 and 60)
|
|
|
Number of Participants Meeting Clinical, Virologic, or Immunologic Criteria for Treatment Initiation or Re-initiation
Tidsram: 96 weeks since randomization
|
The clinical, virologic, or immunologic criteria for treatment initiation or re-initiation include CD4 count below 350 cells/mm^3 on two consecutive determinations at least 4 weeks apart, at least 12 weeks into the study or 12 weeks post-treatment discontinuation, (2) confirmed CD4 count below 200 cells/mm^3 or CD4 percent below 14% at any time on study, (3) confirmed HIV-1 RNA level above 750,000 copies/mL 4 weeks into the study or above 200,000 copies/mL 12 weeks or more into the study, or (4) CDC Category B or C diagnosis.
|
96 weeks since randomization
|
|
Number of Participants in IT Arm Off Treatment Before 36 Weeks
Tidsram: At Week 36
|
The study provided fixed-dose combination emtricitabine/tenofovir DF 200/300 mg orally once daily and lopinavir/ritonavir 200/50 mg administered either as two tablets twice daily or four tablets once daily, for the first 36 weeks for individuals in the IT arm.
|
At Week 36
|
|
Time to Meeting the Clinical, Virologic, or Immunologic Criteria for Treatment Initiation or Re-initiation
Tidsram: 96 weeks since randomization
|
5th, 10th, 25th, 50th, 75th and 90th percentiles in weeks from randomization to meeting the criteria for treatment initiation or re-initiation which include CD4 count below 350 cells/mm^3 on two consecutive measurements at least 4 weeks apart, at least 12 weeks into the study or 12 weeks post-treatment discontinuation, confirmed CD4 count below 200 cells/mm^3 or CD4 percent below 14% at any time on study, confirmed HIV-1 RNA level above 750,000 copies/mL 4 weeks into the study or above 200,000 copies/mL 12 weeks or more into the study, or CDC Category B or C diagnosis.
|
96 weeks since randomization
|
|
Time From Study Entry in DT Arm Participants or From Week 36 in IT Arm Participants to Meeting the Clinical, Virologic, or Immunologic Criteria for Treatment Initiation or Re-initiation
Tidsram: 96 weeks since randomization
|
5th, 10th, 25th, 50th, 75th and 90th percentiles in weeks from randomization for DT arm or from week 36 for IT arm to meeting the criteria for treatment initiation or re-initiation which include two consecutive CD4 count below 350 cells/mm^3 at least 4 weeks apart, at least 12 weeks into the study or 12 weeks post-treatment discontinuation, confirmed CD4 count below 200 cells/mm^3 or CD4 percent below 14% at any time on study, confirmed HIV-1 RNA level above 750,000 copies/mL 4 weeks into the study or above 200,000 copies/mL 12 weeks or more into the study, or CDC Category B or C diagnosis.
|
96 weeks since randomization
|
|
Time to Treatment Initiation or Death
Tidsram: 5 years since randomization
|
5th, 10th, 25th, 50th and 75th percentiles in weeks from randomization to treatment initiation or death
|
5 years since randomization
|
Samarbetspartners och utredare
Det är här du hittar personer och organisationer som är involverade i denna studie.
Sponsor
Samarbetspartners
Utredare
- Studiestol: Christine Hogan, MD, Division of Infectious Diseases, Columbia University College of Physicians and Surgeons
Publikationer och användbara länkar
Den som ansvarar för att lägga in information om studien tillhandahåller frivilligt dessa publikationer. Dessa kan handla om allt som har med studien att göra.
Allmänna publikationer
- Fidler S, Oxenius A, Brady M, Clarke J, Cropley I, Babiker A, Zhang HT, Price D, Phillips R, Weber J. Virological and immunological effects of short-course antiretroviral therapy in primary HIV infection. AIDS. 2002 Oct 18;16(15):2049-54. doi: 10.1097/00002030-200210180-00010.
- Kassutto S, Rosenberg ES. Primary HIV type 1 infection. Clin Infect Dis. 2004 May 15;38(10):1447-53. doi: 10.1086/420745. Epub 2004 Apr 30.
- Little SJ, Holte S, Routy JP, Daar ES, Markowitz M, Collier AC, Koup RA, Mellors JW, Connick E, Conway B, Kilby M, Wang L, Whitcomb JM, Hellmann NS, Richman DD. Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med. 2002 Aug 8;347(6):385-94. doi: 10.1056/NEJMoa013552.
- Pilcher CD, Eron JJ Jr, Galvin S, Gay C, Cohen MS. Acute HIV revisited: new opportunities for treatment and prevention. J Clin Invest. 2004 Apr;113(7):937-45. doi: 10.1172/JCI21540. Erratum In: J Clin Invest. 2006 Dec;116(12):3292.
- Messer K, Vaida F, Hogan C. Robust analysis of biomarker data with informative missingness using a two-stage hypothesis test in an HIV treatment interruption trial: AIEDRP AIN503/ACTG A5217. Contemp Clin Trials. 2006 Dec;27(6):506-17. doi: 10.1016/j.cct.2006.07.003. Epub 2006 Jul 25.
- Hogan CM, Degruttola V, Sun X, Fiscus SA, Del Rio C, Hare CB, Markowitz M, Connick E, Macatangay B, Tashima KT, Kallungal B, Camp R, Morton T, Daar ES, Little S; A5217 Study Team. The setpoint study (ACTG A5217): effect of immediate versus deferred antiretroviral therapy on virologic set point in recently HIV-1-infected individuals. J Infect Dis. 2012 Jan 1;205(1):87-96. doi: 10.1093/infdis/jir699. Epub 2011 Dec 15.
Användbara länkar
Studieavstämningsdatum
Dessa datum spårar framstegen för inlämningar av studieposter och sammanfattande resultat till ClinicalTrials.gov. Studieposter och rapporterade resultat granskas av National Library of Medicine (NLM) för att säkerställa att de uppfyller specifika kvalitetskontrollstandarder innan de publiceras på den offentliga webbplatsen.
Studera stora datum
Studiestart
1 januari 2005
Primärt slutförande (Faktisk)
1 juli 2009
Avslutad studie (Faktisk)
1 maj 2011
Studieregistreringsdatum
Först inskickad
3 september 2004
Först inskickad som uppfyllde QC-kriterierna
3 september 2004
Första postat (Uppskatta)
6 september 2004
Uppdateringar av studier
Senaste uppdatering publicerad (Faktisk)
11 oktober 2018
Senaste inskickade uppdateringen som uppfyllde QC-kriterierna
11 september 2018
Senast verifierad
1 september 2018
Mer information
Termer relaterade till denna studie
Nyckelord
Ytterligare relevanta MeSH-villkor
- RNA-virusinfektioner
- Virussjukdomar
- Infektioner
- Blodburna infektioner
- Smittsamma sjukdomar
- Sexuellt överförbara sjukdomar, virala
- Sexuellt överförbara sjukdomar
- Lentivirusinfektioner
- Retroviridae-infektioner
- Immunologiska bristsyndrom
- Immunsystemets sjukdomar
- HIV-infektioner
- Molekylära mekanismer för farmakologisk verkan
- Anti-infektionsmedel
- Antivirala medel
- Omvända transkriptashämmare
- Nukleinsyrasynteshämmare
- Enzyminhibitorer
- Anti-HIV-medel
- Antiretrovirala medel
- Proteashämmare
- Cytokrom P-450 CYP3A-hämmare
- Cytokrom P-450 enzymhämmare
- HIV-proteashämmare
- Virala proteashämmare
- Tenofovir
- Emtricitabin
- Ritonavir
- Lopinavir
- Emtricitabin, Tenofovir Disoproxil Fumarate Läkemedelskombination
Andra studie-ID-nummer
- ACTG A5217
- 1U01AI068636 (U.S.S. NIH-anslag/kontrakt)
- AIEDRP AIN503
Läkemedels- och apparatinformation, studiedokument
Studerar en amerikansk FDA-reglerad läkemedelsprodukt
Nej
Studerar en amerikansk FDA-reglerad produktprodukt
Nej
produkt tillverkad i och exporterad från U.S.A.
Nej
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