IMPAACT 1077HS: Examining Benefits of HAART Continuation in Postpartum Women

Study Description

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Brief Summary:

This study was a randomized strategy trial conducted among women who received highly active antiretroviral therapy (HAART) during pregnancy for purposes of prevention of mother-to-child transmission (PMTCT) of HIV but did not otherwise meet criteria to initiate HAART for their own health. The study was designed to determine whether continuation of HAART after delivery or other pregnancy outcome reduced morbidity and mortality compared to discontinuation and re-initiation of HAART when protocol specified criteria were met.

Condition or disease	Intervention/treatment	Phase
HIV Infection	Drug: Highly active antiretroviral therapy (HAART)	Phase 4

Detailed Description:

This randomized strategy trial addressed therapeutic questions for women from regions where antepartum HAART for PMTCT (for all CD4+ cell counts) and postpartum formula feeding is standard of care, and who also had both a pre-HAART CD4+ cell count >400 cells/mm^3 and a screening (on-HAART) CD4+ cell count > 400 cells/mm^3. For these women, the objectives related to the relative efficacy and safety of continuing HAART (when it is no longer used for PMTCT) versus discontinuing HAART.

Potential participants were identified/recruited and consented during pregnancy or after delivery or other pregnancy outcome. Study-specific screening was initiated in the third trimester or after pregnancy outcome. Women who were screened for the study were counseled to continue their HAART until they were randomized.

Randomization would occur within 0-42 days after pregnancy outcome. Women who did not carry their pregnancy to the third trimester but otherwise meet study eligibility criteria could be enrolled.

Participants were randomized to one of the two study arms:

Arm A: Continuation of HAART Arm B: Discontinuation of HAART and resume HAART when protocol-specified criteria were met

Participants were to be followed until 84 weeks after the last participant was randomized.

Key evaluations were conducted at Screening, Entry, post entry visits were scheduled to take place 4 weeks after entry, 12 weeks after entry, and every 12 weeks thereafter. Key evaluations included physical examinations, clinical assessments, and blood collection.

On 7 July 2015, the study sites received formal communications regarding the results of the Strategic Timing of Antiretroviral Treatment (START) study and associated changes were implemented to the 1077HS study in response to these results. All sites were instructed that all women in the 1077HS study were to be informed of the START study results and that antiretroviral therapy (ART) was recommended for all women based on the START study results.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	1653 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	IMPAACT 1077HS: HAART Standard Version of the Promoting Maternal and Infant Survival Everywhere (PROMISE) Study
Actual Study Start Date :	January 2010
Actual Primary Completion Date :	August 2016
Actual Study Completion Date :	August 2016

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Continue HAART; Continue receiving HAART within 0-42 days after delivery or other pregnancy outcome.	Drug: Highly active antiretroviral therapy (HAART); A combination of three or more HIV medications belonging to two or more drug classes. The preferred study-supplied HAART regimen was lopinavir/ritonavir (LPV/RTV) plus fixed dose combination tenofovir/emtricitabine (TDF/FTC). Additional ARVs provided for use in this study included fixed dose combination lamivudine/zidovudine (3TC/ZDV), lamivudine (3TC), zidovudine (ZDV), tenofovir (TDF), fixed dose combination tenofovir/emtricitabine/rilpivirine (TDF/FTC/RPV), didanosine (ddI), atazanavir (ATV), raltegravir (RAL), and ritonavir (RTV). While LPV/RTV plus TDF/FTC was the preferred study-supplied regimen, the study clinicians in conjunction with participants would determine the optimal drug combination for each participant.
Active Comparator: Stop HAART; Stop receiving HAART within 0-42 days after delivery or other pregnancy outcome and resume HAART when protocol specified criteria were met.	Drug: Highly active antiretroviral therapy (HAART); A combination of three or more HIV medications belonging to two or more drug classes. The preferred study-supplied HAART regimen was lopinavir/ritonavir (LPV/RTV) plus fixed dose combination tenofovir/emtricitabine (TDF/FTC). Additional ARVs provided for use in this study included fixed dose combination lamivudine/zidovudine (3TC/ZDV), lamivudine (3TC), zidovudine (ZDV), tenofovir (TDF), fixed dose combination tenofovir/emtricitabine/rilpivirine (TDF/FTC/RPV), didanosine (ddI), atazanavir (ATV), raltegravir (RAL), and ritonavir (RTV). While LPV/RTV plus TDF/FTC was the preferred study-supplied regimen, the study clinicians in conjunction with participants would determine the optimal drug combination for each participant.

Outcome Measures

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Primary Outcome Measures :

1. Incidence Rates of AIDS - Defining Illness, Serious Non-AIDS Defining, Cardiovascular, Renal, Hepatic Event, or Death [ Time Frame: From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up). ]
   AIDS defining illness, serious non-AIDS defining cardiovascular, renal, or hepatic event, or death refers to illness/diagnoses listed in Appendix II of the protocol. These events were reviewed and confirmed by an Endpoint review group. The incidence rate was obtained by using the Kaplan-Meier method.

Secondary Outcome Measures :

1. Incidence Rate of AIDS - Defining Illness [ Time Frame: From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up). ]
   AIDS defining illness, refers to illness/diagnoses listed in Appendix II of the protocol. These events were reviewed and confirmed by an Endpoint review group. The incidence rate was obtained by using the Kaplan-Meier method.
2. Incidence Rates of Serious Non- AIDS Defining Cardiovascular, Renal or Hepatic Event [ Time Frame: From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up). ]
   Serious non - AIDS defining cardiovascular, renal, or hepatic event, or death refers to illness/diagnoses listed in Appendix II of the protocol. These events were reviewed and confirmed by an Endpoint review group. The incidence rate was obtained by using the Kaplan-Meier method.
3. Incidence Rate of Deaths [ Time Frame: From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up). ]
   The incidence rate was obtained by using the Kaplan-Meier method.
4. Incidence Rate of HIV/AIDS Related Events [ Time Frame: From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up). ]
   HIV/AIDS related events refers to illness/diagnoses listed in Appendix II of the protocol. These events were reviewed and confirmed by an Endpoint review group. The incidence rate was obtained by using the Kaplan-Meier method.
5. Incidence Rate of HIV/AIDS Related Events or Death [ Time Frame: From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up). ]
   HIV/AIDS related events or death refers to illness/diagnoses listed in Appendix II of the protocol. These events were reviewed and confirmed by an Endpoint review group. The incidence rate was obtained by using the Kaplan-Meier method.
6. Incidence Rate of HIV/AIDS Related Events or WHO Clinical Stage 2 or 3 Events [ Time Frame: From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up). ]
   HIV/AIDS related events or WHO Clinical Stage 2 or 3 events refers to illness/diagnoses listed in Appendix II of the protocol. These events were reviewed and confirmed by an Endpoint review group. The incidence rate was obtained by using the Kaplan-Meier method.
7. Incidence Rate of Grade 2 and Above Toxicity [ Time Frame: All laboratory measures were done at entry,4 and 12 weeks after, and then every 3 months until study end. Signs and Symtoms were recorded from study entry to study end. All were followed until July 7, 2015 (an average of 125 weeks of follow-up) ]
   The toxicity events included all grade 2 and higher hematology or chemistry events and grade 3 or 4 sign or symptoms. These events were graded using the Division of AIDS (DAIDS AE Grading Table), Version 1.0, December 2004, Clarification August 2009, which is available on the RSC website (http://rsc.tech-res.com). The incidence rate was obtained by using the Kaplan-Meier method.
8. Incidence Rate of Cardiovascular or Other Metabolic Events [ Time Frame: From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up). ]
   This outcome was intended as an exploratory analyses and was not included in the primary analyses conditional on primary results and funding. Given the results of the primary analyses it was decided that this outcome was no longer scientifically important. No resources and funding was allocated.
9. Incidence Rate of Other Targeted Medical Conditions [ Time Frame: From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up). ]
   This outcome was intended as an exploratory analyses and was not included in the primary analyses conditional on primary results and funding. Given the results of the primary analyses it was decided that this outcome was no longer scientifically important. No resources and funding was allocated.
10. Incidence Rate of Any Condition Outlined in Appendix II of Protocol or Death [ Time Frame: From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up). ]
    This outcome was intended as an exploratory analyses and was not included in the primary analyses conditional on primary results and funding. Given the results of the primary analyses it was decided that this outcome was no longer scientifically important. No resources and funding was allocated.
11. Number of Virologic Failure (VF) Participants With HIV Resistance in the Continue HAART Arm [ Time Frame: At time of confirmation of VF. HIV-1 RNA testing to identify VF was done at week 4, 12, 24, and every 12 weeks thereafter until study end at an average of 125 weeks. If HIV-1 RNA was above 1000 copies/ml, confirmatory testing was done within 4 weeks. ]
    VF was defined as two successive measurements of HIV-1 RNA above 1000 copies/ml at or after 24 weeks of HAART. HIV drug resistance was defined using the Stanford database (Version 6.2)
12. Medication Adherence [ Time Frame: Measured at baseline, after 4 - 12 and 24 weeks, and then every 6 months until study termination. All participants were followed until July 7, 2015 (an average of 125 weeks of follow-up). ]
    This secondary outcome was not included in the primary analyses and will be defined in more detail in a separate analysis plan. The analyses are planned to be completed by May 2018, after which results will be reported to ct.gov.
13. Quality of Life [ Time Frame: Measured at baseline, after 4 - 12 and 24 weeks, and then every 6 months until study termination. All participants were followed until July 7, 2015 (an average of 125 weeks of follow-up). ]
    This secondary outcome was not included in the primary analyses and will be defined in more detail in a separate analysis plan. The analyses are planned to be completed by May 2019, after which results will be reported to ct.gov.
14. Changes in Plasma Concentrations of Inflammatory and Thrombogenic Markers [ Time Frame: Measured at baseline, after 4 and 12 weeks, and then every 6 months until study termination. All participants were followed until July 7, 2015 (an average of 125 weeks of follow-up). ]
    This outcome was intended as an exploratory analyses and was not included in the primary analyses conditional on primary results and funding. This outcome required additional funding for laboratory testing which was not available and so this outcome is not reported.
15. Cost Effectiveness and Feasibility of Treatment Models [ Time Frame: Measured at baseline, after 4 - 12 and 24 weeks, and then every 6 months until study termination. All participants were followed until July 7, 2015 (an average of 125 weeks of follow-up). ]
    This outcome was intended as an exploratory analyses and was not included in the primary analyses. Given the results of the primary analyses and changes in WHO guidelines to recommend lifelong antiretroviral therapy, the protocol team decided that this outcome was no longer scientifically important. No resources and funding was allocated.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Women age ≥ 18 years or who had attained the minimum age of independent consent, as defined by the local Institutional Review Board (IRB), and were willing and able to provide written informed consent Additionally, at sites with IRB approval to enroll younger participants, women age 16-17 years who were willing and able to provide written assent and whose parent or legal guardian was willing and able to provide written informed consent
• Confirmed HIV infection, documented by positive results from two samples collected at different time points prior to study entry, using protocol-specified tests (see protocol for more details)
• Documentation of hepatitis B surface antibody (HBsAb) status and hepatitis B surface antigen (HBsAg) status (if antibody was negative) within 12 months prior to study entry
• Within 0-42 days after pregnancy outcome
• Antiretroviral treatment naïve, defined as < 14 days of one or more antiretroviral agents, prior to therapy initiated during current pregnancy
• Receipt of at least four weeks of HAART prior to study entry, at least two weeks of which must have been prior to pregnancy outcome (up to seven consecutive days of missed therapy is permitted)
• CD4+ cell count ≥ 400 cells/mm^3 on a specimen obtained within 120 days prior to initiation of HAART for current pregnancy
• CD4+ cell count ≥ 400 cells/mm^3 on a specimen obtained on HAART and within 45 days prior to study entry

• The following laboratory values on a specimen obtained within 45 days prior to study entry:

  • Absolute neutrophil count ≥ 750/mm^3
  • Hemoglobin ≥ 7.0 g/dL
  • Platelet count ≥ 50,000/mm^3
  • AST (SGOT), ALT (SGPT), and alkaline phosphatase ≤ 2.5 x ULN
• Estimated creatinine clearance of ≥ 60mL/min within 45 days prior to entry using the Cockcroft-Gault formula
• Intent to remain in current geographical area of residence for the duration of the study
• Willingness to attend study visits as required by the study

Exclusion Criteria:

• Previous participation in PROMISE (P1077BF - NCT01061151)
• Clinical indication for HAART including any World Health Organization (WHO) Clinical Stage 3 or 4 condition, prior or current tuberculosis disease (a positive (Purified protein Derivative) PPD test alone was not considered exclusionary), and/or any other clinical indication per country-specific treatment guidelines
• Clinically significant illness or condition requiring systemic treatment and/or hospitalization within 30 days prior to study entry
• Social or other circumstances which, in the opinion of the site investigator, would hinder long-term follow up
• Use of any prohibited medications within 14 days prior to study entry (refer to the study MOP for a list of prohibited medications)
• Current compulsory detention (involuntary incarceration) in a correctional facility, prison, or jail for legal reasons or compulsory detention in a medical facility for treatment of either a psychiatric or physical (e.g., infectious disease) illness
• Currently breastfeeding or planning to breastfeed
• Current documented conduction heart defect (specialized assessments to rule out this condition were not required; a heart murmur alone and/or type 1 second-degree atrioventricular block (also known as Mobitz I or Wenckebach) was not considered exclusionary)
• Known evidence of HBV DNA levels >2000 IU/mL (approximately 10,000 copies/mL) in the presence of elevated (grade 1 and higher) ALT (HBV DNA testing was not required for study screening or enrollment but was considered to determine whether treatment for HBV was indicated)

Contacts and Locations

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  Show 50 Study Locations

Sponsors and Collaborators

International Maternal Pediatric Adolescent AIDS Clinical Trials Group

National Institute of Allergy and Infectious Diseases (NIAID)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

Study Chair:	Judith S. Currier, MD, MS	University of California, Los Angeles

More Information

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Additional Information:

Related Info 

WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological Classification of HIV-related Disease in Adults and Children (World Health Organization 2007). 

Publications:

U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 with Clarification dated August 2009, which can be found on the DAIDS RSC Web site: http://rsc.tech-res.com

Manual for Expedited Reporting of Adverse Events to DAIDS, Version 2.0, January 2010.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Currier JS, Britto P, Hoffman RM, Brummel S, Masheto G, Joao E, Santos B, Aurpibul L, Losso M, Pierre MF, Weinberg A, Gnanashanmugam D, Chakhtoura N, Klingman K, Browning R, Coletti A, Mofenson L, Shapiro D, Pilotto J; 1077HS PROMISE Team. Randomized trial of stopping or continuing ART among postpartum women with pre-ART CD4 ≥ 400 cells/mm3. PLoS One. 2017 May 10;12(5):e0176009. doi: 10.1371/journal.pone.0176009. eCollection 2017.

Responsible Party:	International Maternal Pediatric Adolescent AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:	NCT00955968 History of Changes
Other Study ID Numbers:	IMPAACT 1077HS; U01AI068632 ( U.S. NIH Grant/Contract )
First Posted:	August 10, 2009
Results First Posted:	February 16, 2018
Last Update Posted:	March 20, 2018
Last Verified:	February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by International Maternal Pediatric Adolescent AIDS Clinical Trials Group:

HIV Infection; HAART; Maternal Health

Additional relevant MeSH terms:

HIV Infections; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases	Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases