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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02249962
Recruitment Status : Completed
First Posted : September 26, 2014
Last Update Posted : March 12, 2021
Ministry of Health and Population, Malawi
University of North Carolina
Lighthouse Trust
Baylor College of Medicine
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

Brief Summary:
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.

Condition or disease
HIV Infant Exposure to Efavirenz

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.

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Study Type : Observational
Actual Enrollment : 12011 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Option B+: ART Safety and Durability During First and Subsequent Pregnancies
Actual Study Start Date : May 2015
Actual Primary Completion Date : September 2020
Actual Study Completion Date : September 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

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.

Primary Outcome Measures :
  1. 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)

Secondary Outcome Measures :
  1. 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

  2. Micronutrient assessment [ Time Frame: Baseline, months 6, 12, 24, 36 ]
  3. Maternal CD4 count [ Time Frame: baseline, months 12, 24, 36 post-ART initiation ]
    Standard of care

  4. HIV RNA level measurement [ Time Frame: baseline, months 3, 6, 12, 24, 36 ]
    Standard of Care, measured to assess resistance to first-line ART

  5. PHQ-9 evaluation [ Time Frame: baseline, months 6, 12, 18, 24, 30, 36 ]
    Assess maternal psychological well-being

  6. 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.

  7. Pregnancy outcome assessment [ Time Frame: At time of pregnancy completion (birth, termination) ]
    Status of birth (live, stillborn, miscarriage), small for gestational age, congenital anomalies

  8. HIV antibody testing- infant [ Time Frame: age 1 year ]
  9. Infant neuro-development assessment: Bayley score [ Time Frame: Age 3 weeks, months 3, 6, 12, 18, 24, 30, 36 ]
  10. 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

  11. 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

Biospecimen Retention:   Samples With DNA

Blood serum samples for:

  • HIV genotyping
  • micronutrient status
  • pharmacokinetics: efavirenz and progesterone levels for women using the contraceptive implant only

Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years to 50 Years   (Child, Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
HIV+ pregnant women and their infants recruited from three clinic sites in Lilongwe, Malawi.

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02249962

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UNC Project Malawi
Lilongwe, Malawi
Sponsors and Collaborators
University of North Carolina, Chapel Hill
Ministry of Health and Population, Malawi
University of North Carolina
Lighthouse Trust
Baylor College of Medicine
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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Principal Investigator: Mina C Hosseinipour, MD, MPH UNC Project- Malawi
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Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT02249962    
Other Study ID Numbers: 14-1633
R01HD080485 ( U.S. NIH Grant/Contract )
First Posted: September 26, 2014    Key Record Dates
Last Update Posted: March 12, 2021
Last Verified: May 2020
Keywords provided by University of North Carolina, Chapel Hill: