- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02249962
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
Study Overview
Status
Conditions
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
Enrollment (Actual)
Contacts and Locations
Study Locations
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Lilongwe, Malawi
- UNC Project Malawi
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
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
How is the study designed?
Design Details
Cohorts and Interventions
Group / Cohort |
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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+
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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.
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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.
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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.
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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
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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)
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Up to 36 months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Pharmacokinetic: progesterone level in women using contraceptive implant
Time Frame: months 3, 6, 12, 24
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Measure of serum progesterone and efavirenz levels among women with a contraceptive implant
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months 3, 6, 12, 24
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Micronutrient assessment
Time Frame: Baseline, months 6, 12, 24, 36
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Baseline, months 6, 12, 24, 36
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Maternal CD4 count
Time Frame: baseline, months 12, 24, 36 post-ART initiation
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Standard of care
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baseline, months 12, 24, 36 post-ART initiation
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HIV RNA level measurement
Time Frame: baseline, months 3, 6, 12, 24, 36
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Standard of Care, measured to assess resistance to first-line ART
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baseline, months 3, 6, 12, 24, 36
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PHQ-9 evaluation
Time Frame: baseline, months 6, 12, 18, 24, 30, 36
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Assess maternal psychological well-being
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baseline, months 6, 12, 18, 24, 30, 36
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Laboratory serum markers
Time Frame: baseline, months 3, 6, 9, 12, 18, 24, 30, 36
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Labs assessed include: renal function (creatinine and urinalysis), liver function, and hematology Measurements contribute to DAIDS grade 3 or 4 toxicity assessment.
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baseline, months 3, 6, 9, 12, 18, 24, 30, 36
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Pregnancy outcome assessment
Time Frame: At time of pregnancy completion (birth, termination)
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Status of birth (live, stillborn, miscarriage), small for gestational age, congenital anomalies
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At time of pregnancy completion (birth, termination)
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HIV antibody testing- infant
Time Frame: age 1 year
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age 1 year
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Infant neuro-development assessment: Bayley score
Time Frame: Age 3 weeks, months 3, 6, 12, 18, 24, 30, 36
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Age 3 weeks, months 3, 6, 12, 18, 24, 30, 36
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Family planning use and proportion of women with subsequent pregnancy by 36 months
Time Frame: Up to 36 months
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Assessing women's fertility preferences, usage of family planning methods, and pregnancy status post-ART initiation
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Up to 36 months
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ART Adherence: pill-count
Time Frame: months 3, 6, 9, 12, 18, 24, 30, 36
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Assessment of adherence to anti-retroviral medications via direct pill count at each clinic visit
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months 3, 6, 9, 12, 18, 24, 30, 36
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Mina C Hosseinipour, MD, MPH, UNC Project- Malawi
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Other Study ID Numbers
- 14-1633
- R01HD080485 (U.S. NIH Grant/Contract)
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