Option B+: Study on Safety, Viral Suppression, and Survival on Second Line ART
Condition: HIV; Infant Exposure to Efavirenz
Study type: Observational

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.
    

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.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        HIV+ pregnant women and their infants recruited from three clinic sites in Lilongwe,
        Malawi.
      
Biospecimen description: 
      Blood serum samples for:

        -  HIV genotyping

        -  micronutrient status

        -  pharmacokinetics: efavirenz and progesterone levels for women using the contraceptive
           implant only
    
Keywords: prospective; cohort