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

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

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.

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.

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)