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

HIV Infection Clinical Trial

Official title:

IMPAACT 1077HS: HAART Standard Version of the Promoting Maternal and Infant Survival Everywhere (PROMISE) Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00955968
• Other study ID #: IMPAACT 1077HS
• Secondary ID: U01AI068632
• Status: Completed
• Phase: Phase 4
• Start date: January 1, 2010
• Est. completion date: August 31, 2016

Study information

• Verified date: August 2023
• Source: International Maternal Pediatric Adolescent AIDS Clinical Trials Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1653
• Est. completion date: August 31, 2016
• Est. primary completion date: August 31, 2016
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• HIV Infection
• HIV Infections

Intervention

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.

Locations

Country	Name	City	State
Argentina	Hospital General de Agudos (5082)	Buenos Aires
Botswana	Gaborone Prevention/Treatment Clinical Research Site (12701)	Gaborone
Botswana	Molepolole Prevention/Treatment Clinical Research Site (12702)	Gaborone
Brazil	School of Medicine, University of Minas Gerais - FUNDEP (5073)	Belo Horizonte
Brazil	University Caxias do Sul (5084)	Caxias do Sul
Brazil	Hospital Nossa Senhora da Conceicao (5117)	Porto Alegre
Brazil	Hospital Santa Casa (5098)	Porto Alegre
Brazil	Hospital dos Servidores do Estado (5072)	Rio de Janeiro
Brazil	Hospital Geral De Nova Igaucu (5097)	Rio de Janeiro
Brazil	Instituto de Puericultura E Pediatria Martagao Geseira - FUJB (5071)	Rio de Janeiro
Brazil	Ribeirao Preto Medical School, University of Sao Paulo (5074)	Sao Paulo
China	Guangxi Center for HIV/AIDS Prevention and Control (30274)	Nanning	Guangxi
Haiti	Les Centres GHESKIO (30022)	Port-au-Prince
Peru	IMPACTA Barranco Clinical Research Site (11301)	Lima
Peru	IMPACTA San Miguel Clinical Research Site (11302)	Lima
Puerto Rico	San Juan City Hospital (5031)	San Juan
Puerto Rico	University of Puerto Rico Pediatric HIV/AIDS Research Program (6601)	San Juan
Thailand	Bhumibol Adulyadej Hospital (5124)	Bangkok
Thailand	Siriraj Hospital Mahidol University CRS (5115)	Bangkok	Ratchathewi,
Thailand	Prapokklao Hospital (5123)	Chanthaburi
Thailand	Chiang Mai University (31784)	Chiang Mai
Thailand	Chiang Rai Regional Hospital (5116)	Chiang Rai
Thailand	Chonburi Hospital (5125)	Chon Buri
Thailand	Phayao Provincial Hospital (5122)	Phayao
United States	University of Southern California MCA Center (5048)	Alhambra	California
United States	University of Colorado (5052)	Aurora	Colorado
United States	Johns Hopkins University School of Medicine (5092)	Baltimore	Maryland
United States	Boston Medical Center (5011)	Boston	Massachusetts
United States	Bronx-Lebanon Hospital Center (5114)	Bronx	New York
United States	Jacobi Medical Center (5013)	Bronx	New York
United States	Ann & Robert H Lurie Children's Hospital of Chicago (4001)	Chicago	Illinois
United States	Wayne State University/Children's Hospital of Michigan (5041)	Detroit	Michigan
United States	Duke University Medical Center (4701)	Durham	North Carolina
United States	Children's Diagnostic and Treatment Center (5055)	Fort Lauderdale	Florida
United States	Baylor College of Medicine Texas Children's Hospital (3801)	Houston	Texas
United States	University of Florida at Jacksonville (5051)	Jacksonville	Florida
United States	David Geffen School of Medicine at UCLA (5112)	Los Angeles	California
United States	St Jude Children's Research Hospital (6501)	Memphis	Tennessee
United States	University of Miami Pediatric/Perinatal Clinical Research Site (4201)	Miami	Florida
United States	Tulane University (5095)	New Orleans	Louisiana
United States	Metropolitan Hospital (5003)	New York	New York
United States	Pitt CRS (1001)	Pittsburgh	Pennsylvania
United States	UCSD Mother-Child-Adolescent HIV Program (4601)	San Diego	California
United States	Seattle Children's Hospital (5017)	Seattle	Washington
United States	SUNY Stony Brook University Medical Center (5040)	Stony Brook	New York
United States	University of South Florida at Tampa (5018)	Tampa	Florida
United States	Harbor (UCLA) Medical Center (5045)	Torrance	California
United States	Georgetown University (1008)	Washington	District of Columbia
United States	Howard University (5044)	Washington	District of Columbia
United States	Washington Hospital Center (5023)	Washington	District of Columbia

Sponsors (3)

Lead Sponsor	Collaborator
International Maternal Pediatric Adolescent AIDS Clinical Trials Group	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Argentina,  Botswana,  Brazil,  China,  Haiti,  Peru,  Puerto Rico,  Thailand, 

References & Publications (2)

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

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence Rates of AIDS - Defining Illness, Serious Non-AIDS Defining, Cardiovascular, Renal, Hepatic Event, or Death	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.	From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up).
Secondary	Incidence Rate of AIDS - Defining Illness	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.	From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up).
Secondary	Incidence Rates of Serious Non- AIDS Defining Cardiovascular, Renal or Hepatic Event	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.	From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up).
Secondary	Incidence Rate of Deaths	The incidence rate was obtained by using the Kaplan-Meier method.	From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up).
Secondary	Incidence Rate of HIV/AIDS Related Events	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.	From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up).
Secondary	Incidence Rate of HIV/AIDS Related Events or Death	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.	From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up).
Secondary	Incidence Rate of HIV/AIDS Related Events or WHO Clinical Stage 2 or 3 Events	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.	From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up).
Secondary	Incidence Rate of Grade 2 and Above Toxicity	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.	All laboratory measures were done at entry,4 and 12 weeks after, and then every 3 months until study end. Signs and Symptoms were recorded from study entry to study end. All were followed until July 7, 2015 (an average of 125 weeks of follow-up)
Secondary	Incidence Rate of Cardiovascular or Other Metabolic Events	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 by NIH.	From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up).
Secondary	Incidence Rate of Other Targeted Medical Conditions	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 by NIH.	From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up).
Secondary	Incidence Rate of Any Condition Outlined in Appendix II of Protocol or Death	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 by NIH.	From study entry to study termination, all participants were followed until July 7, 2015 (an average of 125 weeks of follow-up).
Secondary	Number of Virologic Failure (VF) Participants With HIV Resistance in the Continue HAART Arm	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)	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.
Secondary	Medication Adherence - Last Time Missed Medications	Medication adherence was evaluated by a self reported questionnaire. The number of participants who indicated predefined choice is provided.	week 0, 48 and 96
Secondary	Medication Adherence - How Closely Followed Schedule	Medication adherence was evaluated by a self reported questionnaire. The number of participants who indicated predefined choice is provided.	week 0, 48 and 96
Secondary	Medication Adherence - How Often Follow Instructions	Medication adherence was evaluated by a self reported questionnaire. The number of participants who indicated predefined choice is provided.	week 0, 48 and 96
Secondary	Medication Adherence - Missed Dose Within Past 4 Days	Medication adherence was evaluated by a self reported questionnaire. The number of participants who indicated predefined choice is provided.	week 0, 48 and 96
Secondary	Quality of Life - General Health Outcome	Quality of Life was evaluated by a self reported questionnaire. The number of participants who indicated predefined choice is provided.	week 0, 48 and 96
Secondary	Quality of Life (QoL) - Health Rating Score	QoL - health rating score was evaluated by a self reported questionnaire. Health rating score of 0 was indicative of death or worst possible health and a score of 100 was being in perfect or best possible health and the mean of score is calculated. Higher scores indicate better Quality of Life (QoL). The range is 0-100 units on a scale	week 0, 48 and 96
Secondary	Changes in Plasma Concentrations of Inflammatory and Thrombogenic Markers	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.	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).
Secondary	Cost Effectiveness and Feasibility of Treatment Models	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 by NIH.	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).

External Links

•   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).