Clinical trial NCT02249962: Option B+: Study on Safety, Viral Suppression, and Survival on Second Line ART
Official title: Option B+: ART Safety and Durability During First and Subsequent Pregnancies
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: HIV
Infant Exposure to Efavirenz
Keywords: prospective
cohort
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: Ministry of Health and Population, Malawi
name: University of North Carolina
name: Lighthouse Trust
name: Baylor College of Medicine
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2014-09-26
Enrollment: 12011
Sex: FEMALE
Minimum age (years): 16
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
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.

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Proportion of participants with failure on Option B+ first-line treatment
timeFrame: Up to 36 months
Secondary outcomes:
measure: Pharmacokinetic: progesterone level in women using contraceptive implant
timeFrame: months 3, 6, 12, 24
measure: Micronutrient assessment
timeFrame: Baseline, months 6, 12, 24, 36
measure: Maternal CD4 count
timeFrame: baseline, months 12, 24, 36 post-ART initiation
measure: HIV RNA level measurement
timeFrame: baseline, months 3, 6, 12, 24, 36
measure: PHQ-9 evaluation
timeFrame: baseline, months 6, 12, 18, 24, 30, 36
measure: Laboratory serum markers
timeFrame: baseline, months 3, 6, 9, 12, 18, 24, 30, 36
measure: Pregnancy outcome assessment
timeFrame: At time of pregnancy completion (birth, termination)
measure: HIV antibody testing- infant
timeFrame: age 1 year
measure: Infant neuro-development assessment: Bayley score
timeFrame: Age 3 weeks, months 3, 6, 12, 18, 24, 30, 36
measure: Family planning use and proportion of women with subsequent pregnancy by 36 months
timeFrame: Up to 36 months
measure: ART Adherence: pill-count
timeFrame: months 3, 6, 9, 12, 18, 24, 30, 36
Other outcomes:
Locations:
city: Lilongwe
country: Malawi
facility: UNC Project Malawi
Study officials:
affiliation: UNC Project- Malawi
name: Mina C Hosseinipour, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References: