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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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HIV Infection

Intervention / Treatment
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* Drug: Highly active antiretroviral therapy (HAART)


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Continue HAART<br>Continue receiving HAART within 0-42 days after delivery or other pregnancy outcome. | Drug: Highly active antiretroviral therapy (HAART)<br>* 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.<br>|
| Active Comparator: Stop HAART<br>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)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 
| 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). | 
| 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). | 
| 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). | 
| 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). | 
| 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). | 
| 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) | 
| 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). | 
| 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). | 
| 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). | 
| 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. | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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). | 
| 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). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV Infection, HAART, Maternal Health