Option B+: Study on Safety, Viral Suppression, and Survival on Second Line ART (S4)

Option B+: ART Safety and Durability During First and Subsequent Pregnancies

To characterize safety, durability, antiretroviral treatment (ART) resistance, and clinical outcomes for mothers and infants exposed to the efavirenz-based Option B+ regimen for Prevention of Mother to Child Transmission (PMTCT) and HIV treatment in Malawi.

Study Overview

Status

Completed

Detailed Description

Option B+ is an innovative strategy pioneered within Malawi that provides universal lifelong ART (tenofovir/lamivudine/efavirenz: TDF/3TC/EFV) for pregnant and breastfeeding women to promote maternal health and prevent HIV transmission to infants. The safety of a TDF/3TC/EFV based regimen used during pregnancy has not been systematically evaluated.

Objective 1: To characterize the long term safety, drug resistance patterns and clinical outcomes among women and their infants enrolled in the Malawi Option B+ program using TDF/3TC/EFV.

  • Hypothesis 1: Over 3+ years of anticipated treatment follow-up, TDF/3TC/EFV will be associated with a toxicity rate requiring ART discontinuation of <3% and >90% virologic suppression at 36 months.
  • Hypothesis 2: Women with baseline CD4 counts ≤ 350 cells/mm3 will experience greater rates of clinical events, treatment failure and ART toxicity compared to those with CD4 > 350 cells/mm3.

Objective 2: To critically evaluate women with subsequent pregnancies after initial engagement in the Option B+ Program.

Objective 2a: To determine the prevalence of treatment failure among pregnant women presenting to ANC on first-line therapy and evaluate the safety of ATZ/r based therapy among those women requiring second-line therapy.

  • Hypothesis 1: HIVRNA testing at first ANC visit among women with subsequent pregnancies will demonstrate that approximately 5% of women will be failing treatment and will identify key risk factors associated with treatment failure.
  • Hypothesis 2: ATZ/r based therapy during pregnancy is associated with toxicity rates requiring discontinuation in less than 5% of pregnant women.

Objective 2b: Among pregnant women defaulting from TDF/3TC/EFV, determine the treatment response to re-initiation of first-line therapy, need for second-line therapy, and characterize resistance.

- Hypothesis 1: Women re-engaging in care after program default will experience early ART treatment failure due to HIV drug resistance that developed after ART cessation during initial care.

Objective 3: To explore rates of adverse pregnancy and birth outcomes among women, presence of birth defects, and infant developmental delay among infants exposed to EFV-based ART after the first trimester (Objective 1), Efavirenz at conception (Objective 2a), and on second-line therapy with ATZ/r based ART (Objective 2a).

  • Hypothesis 1: Efavirenz exposure during the first trimester is associated with a higher rate of adverse pregnancy and birth outcomes than if exposed later in pregnancy.
  • Hypothesis 2: Infants exposed to EFV from first trimester will experience lower mean scores on Bayley neurodevelopment domains than those exposed later in pregnancy.

The investigators will collect data for maternal treatment outcomes, including vital status, per the national HIV program definitions: Alive, Dead, Default (>3 months since last visit), Stop, and Transfer Out. In addition to maternal treatment outcomes, the national HIV program collects data regarding the following outcomes, which the investigators will also collect: pregnancy and tuberculosis incidence after ART initiation, drug toxicity/ adverse event (Rash, Hepatitis, Lactic Acidosis, Anemia, Peripheral Neuropathy), adherence measurement (by pill count), WHO clinical stage at ART initiation, ART pharmacy refill information, and ART regimen.

Study Type

Observational

Enrollment (Actual)

12011

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Lilongwe, Malawi
        • UNC Project Malawi

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 50 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Sampling Method

Non-Probability Sample

Study Population

HIV+ pregnant women and their infants recruited from three clinic sites in Lilongwe, Malawi.

Description

Inclusion Criteria:

  • Female age ≥16 (includes adults and emancipated minors)
  • HIV positive by 2 rapid tests approved by the Malawi Ministry of Health
  • Willingness to provide informed consent

Exclusion Criteria:

  • Female <16 years
  • HIV negative
  • Incapable of providing informed consent

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Overall cohort: HIV+ women on Option B+ and their infants
Women (n=8000) visiting an antenatal clinic for care who will be followed prospectively for Malawi standard treatment outcomes and pregnancy outcomes as patients on Option B+
Sub-cohort A: first HIV diagnosis
Women (n=300) who present to the antenatal care clinic and are diagnosed for the first time with HIV. These women will be started on Option B+ as anti-retroviral treatment, per Malawi Ministry of Health standard of care.
Sub-cohort B: subsequent pregnancies failing 1st line ART
Women (n=150) who have failed first-line treatment (TDF/3TC/EFV) based on HIV RNA levels and CD4 count. These women will be switched to second-line treatment (AZT/3TC/ATZ/r) per Malawi Ministry of Health standard of care.
Sub-cohort C: subsequent pregnancies who default from 1st line
Women (n=150) who are HIV+ and have a subsequent pregnancy who have not been adherent to first-line (Option B+: TDF/3TC/EFV). These women will be re-initiated on first-line treatment for 3 months, then evaluated to assess whether continuation on first-line treatment is sufficient, or if they need to be switched to second-line treatment (AZT/3TC/ATZ/r) per Malawi Ministry of Health standard of care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of participants with failure on Option B+ first-line treatment
Time Frame: Up to 36 months
Proportion of women who fail first-line treatment as indicated by one or more of the following criteria: WHO Stage 3 or 4 events (as defined by Appendix 60 of the Adult AIDS Clinical Trials Group (AACTG)), or DAIDS grade 3 or 4 toxicity (lab serum markers), or proportion with treatment discontinuation (or death), or proportion with virologic failure (as measured by HIV RNA levels)
Up to 36 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pharmacokinetic: progesterone level in women using contraceptive implant
Time Frame: months 3, 6, 12, 24
Measure of serum progesterone and efavirenz levels among women with a contraceptive implant
months 3, 6, 12, 24
Micronutrient assessment
Time Frame: Baseline, months 6, 12, 24, 36
Baseline, months 6, 12, 24, 36
Maternal CD4 count
Time Frame: baseline, months 12, 24, 36 post-ART initiation
Standard of care
baseline, months 12, 24, 36 post-ART initiation
HIV RNA level measurement
Time Frame: baseline, months 3, 6, 12, 24, 36
Standard of Care, measured to assess resistance to first-line ART
baseline, months 3, 6, 12, 24, 36
PHQ-9 evaluation
Time Frame: baseline, months 6, 12, 18, 24, 30, 36
Assess maternal psychological well-being
baseline, months 6, 12, 18, 24, 30, 36
Laboratory serum markers
Time Frame: baseline, months 3, 6, 9, 12, 18, 24, 30, 36
Labs assessed include: renal function (creatinine and urinalysis), liver function, and hematology Measurements contribute to DAIDS grade 3 or 4 toxicity assessment.
baseline, months 3, 6, 9, 12, 18, 24, 30, 36
Pregnancy outcome assessment
Time Frame: At time of pregnancy completion (birth, termination)
Status of birth (live, stillborn, miscarriage), small for gestational age, congenital anomalies
At time of pregnancy completion (birth, termination)
HIV antibody testing- infant
Time Frame: age 1 year
age 1 year
Infant neuro-development assessment: Bayley score
Time Frame: Age 3 weeks, months 3, 6, 12, 18, 24, 30, 36
Age 3 weeks, months 3, 6, 12, 18, 24, 30, 36
Family planning use and proportion of women with subsequent pregnancy by 36 months
Time Frame: Up to 36 months
Assessing women's fertility preferences, usage of family planning methods, and pregnancy status post-ART initiation
Up to 36 months
ART Adherence: pill-count
Time Frame: months 3, 6, 9, 12, 18, 24, 30, 36
Assessment of adherence to anti-retroviral medications via direct pill count at each clinic visit
months 3, 6, 9, 12, 18, 24, 30, 36

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2015

Primary Completion (Actual)

September 1, 2020

Study Completion (Actual)

September 1, 2020

Study Registration Dates

First Submitted

September 11, 2014

First Submitted That Met QC Criteria

September 23, 2014

First Posted (Estimate)

September 26, 2014

Study Record Updates

Last Update Posted (Actual)

March 12, 2021

Last Update Submitted That Met QC Criteria

March 10, 2021

Last Verified

May 1, 2020

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • 14-1633
  • R01HD080485 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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