HIV, Pregnancy Malaria, Sexually Transmitted Infection
Conditions
Keywords
STI Prevention, Cameroon, sub-Saharan Africa, HIV pregnancy, Malaria in pregnancy
Brief summary
More than 3 billion people worldwide are at risk of acquiring malaria and pregnant women living with HIV in Africa are at particular risk. An effective prophylaxis regimen capable of preventing malaria and other common perinatal infections would have great potential to improve adverse birth outcomes. The purpose of this randomized controlled trial is to evaluate a new combination prophylaxis regimen in pregnant women with HIV in Cameroon to determine its efficacy and safety.
Detailed description
The World Health Organization (WHO) recommends malaria prophylaxis for all pregnant women living in endemic areas in order to reduce maternal anemia, low birth weight and perinatal mortality by 25-45%. The most commonly used regimen is intermittently dosed sulfadoxine-pyrimethamine (SP).Unfortunately, SP prophylaxis is contraindicated for HIV-infected pregnant women since co-administration with TMPS (trimethoprim-sulfamethoxazole) causes serious adverse events. TMPS (Bactrim or Cotrimoxazole) is an effective, well-tolerated, low-cost antibiotic that is used as prophylaxis in HIV-patients with low CD4 counts. It has anti-malarial activity with prophylactic efficacy that is comparable to SP (30-90%). Daily TMPS is recommended as malaria prophylaxis in pregnant women with HIV in many African countries (including Cameroon) but malaria infection rates are high even when medication compliance is excellent; thus, new and improved options are urgently needed. Azithromycin (AZ) is a macrolide antibiotic with activity against malaria, a good safety profile in pregnancy and proven utility as a part of combination malaria prevention regimens (such as SP-AZ). It also has activity against sexually transmitted infections (STI) and perinatal pathogens, including chlamydia (CT), gonorrhea (GC), syphilis and GBS (Streptococcus agalactiae or Group B Streptococcus), a potential but understudied contributor to high rates of newborn sepsis and death in Africa. SP-AZ prophylaxis in HIV-uninfected pregnant women has been reported to reduce prevalence of low birth weight (RR 0.74, 95% confidence interval (CI) 0.6-0.9) and preterm delivery (RR 0.66, 95% CI 0.48-0.91) compared to SP alone. Thus, the central hypothesis is that a TMPS-AZ combination will be more effective than standard TMPS malaria prophylaxis in pregnant women with HIV, and that it will also decrease STI coinfection. Investigators plan a test-of-concept of the central hypothesis by conducting a double blinded, Phase II randomized controlled trial (RCT).
Interventions
DRUGAzithromycin/TMPS
2 tabs po daily x 3 days at enrollment and at each monthly follow up visit
DRUGPlacebo/TMPS
2 tabs po daily x 3 days at enrollment and at each monthly follow up visit
Sponsors
University of Alabama at Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
16 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Confirmed HIV-infection (documented in medical record) * Age ≥16 years * Confirmed pregnancy, \<28 weeks estimated gestational age (by best obstetric estimate which may include ultrasound or fundal height and LMP) * Live singleton pregnancy * Receiving prenatal care at Mboppi Hospital or Mutengene Hospital * Plan to receive follow up prenatal care and deliver at study facility * Capable of providing written informed consent * Able and agree to come to facility for febrile episodes or acute illness during pregnancy (with reimbursement of transportation costs). * Agree to avoid antimalarial medications outside of study protocol.
Exclusion criteria
* Severe anemia (last hemoglobin \<6) * History of severe adverse reaction to co-trimoxazole or azithromycin * Active medical problem requiring inpatient evaluation at the time of screening * Intention of moving far away from the facility during pregnancy or not likely to return for follow up care or delivery * Signs or symptoms of early or active labor * History of severe cardiac disease (including congestive heart failure, severe valvular disease or arrhythmias).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasmodium Falciparum Peripheral Parasitemia | At end of pregnancy (>35 weeks) or at delivery | P. falciparum detected by microscopy or polymerase chain reaction (PCR) |
| Proportion With Composite STI Outcome | will be measured in both groups (>35 weeks) or at delivery | Including chlamydia (NAAT (nucleic acid amplification test) positive) , gonorrhea (NAAT positive), syphilis (non-treponemal and treponemal test positive) infections. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maternal Adherence to the Prophylactic Regimen | Adherence of study medication taken at home will be documented from the date of randomization until the time of delivery, assessed up to 42 weeks. | Directly observed therapy (DOT) in clinic for the 1st dose of study medication. Self-report and pill count will be used to assess adherence and maternal tolerability for study medications taken at home from the time of enrollment until delivery. At each follow up visit and at delivery, participants will complete a medication adherence survey. They will self-report adherence to the 3 day study regimen (AZ or placebo). |
| Proportion of Participants With Symptomatic Malaria | From the date of randomization until the time of delivery, assessed up to 42 weeks. | Fever and positive malaria test (rapid diagnostic test) at routine visits or sick call visits or maternal report of malaria diagnosis. |
| Proportion With Placental Malaria | At delivery | Placentas will be collected on a subset of women and impression smear will be used to assess for malaria infection |
| Low Birthweight (<2500 Grams) | at birth | Neonatal weight measured with digital scale |
| Composite STI Measure (Including All STI Tests) | After 35 weeks GA or at delivery | Proportion of women with GC/CT (by NAAT), syphilis (by serology), Mycoplasma genitalium (NAAT). |
| GBS Colonization | at or near term or at delivery | anogenital GBS colonization detected by NAAT (PCR) |
| Proportion With Maternal Anemia and Severe Maternal Anemia | At the end of pregnancy (>35 weeks) or at delivery | anemia defined as hemoglobin \<11 g/dL, severe anemia defined as hemoglobin \<7 g/dL. |
| Proportion With Adverse Birth Outcomes | Birth outcomes will be measured at birth for all outcomes except early neonatal mortality defined as within 7 days of birth. Early neonatal mortality will be assessed at a six week follow up phone call. | Composite measure: low infant birthweight (\<2500 grams), miscarriage (\<28 weeks), preterm delivery (\<37 weeks), small for gestational age (SGA), congenital anomaly detected on surface examination, early neonatal mortality (within 7 days of birth) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Azithromycin/TMPS Azithromycin 1 gm po daily x 3 days at enrollment and at each 4 week follow up visit.
TMPS double strength 1 tablet po daily.
Azithromycin/TMPS: 2 tabs po daily x 3 days at enrollment and at each monthly follow up visit | 155 |
| Placebo/TMPS Azithromycin placebo 1 gm po daily x 3 days at enrollment and at each 4 week follow up visit.
TMPS double strength 1 tablet po daily.
Placebo/TMPS: 2 tabs po daily x 3 days at enrollment and at each monthly follow up visit | 153 |
| Total | 308 |
Baseline characteristics
| Characteristic | Placebo/TMPS | Total | Azithromycin/TMPS |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 153 Participants | 308 Participants | 155 Participants |
| Age, Continuous | 32 years | 32 years | 32 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 153 Participants | 308 Participants | 155 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Cameroon | 153 participants | 308 participants | 155 participants |
| Sex: Female, Male Female | 153 Participants | 308 Participants | 155 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 155 | 0 / 153 |
| other Total, other adverse events | 0 / 155 | 0 / 153 |
| serious Total, serious adverse events | 0 / 155 | 0 / 153 |
Outcome results
Primary
Plasmodium Falciparum Peripheral Parasitemia
P. falciparum detected by microscopy or polymerase chain reaction (PCR)
Time frame: At end of pregnancy (>35 weeks) or at delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin/TMPS | Plasmodium Falciparum Peripheral Parasitemia | 8 Participants |
| Placebo/TMPS | Plasmodium Falciparum Peripheral Parasitemia | 7 Participants |
Primary
Proportion With Composite STI Outcome
Including chlamydia (NAAT (nucleic acid amplification test) positive) , gonorrhea (NAAT positive), syphilis (non-treponemal and treponemal test positive) infections.
Time frame: will be measured in both groups (>35 weeks) or at delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin/TMPS | Proportion With Composite STI Outcome | 2 Participants |
| Placebo/TMPS | Proportion With Composite STI Outcome | 2 Participants |
Secondary
Composite STI Measure (Including All STI Tests)
Proportion of women with GC/CT (by NAAT), syphilis (by serology), Mycoplasma genitalium (NAAT).
Time frame: After 35 weeks GA or at delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin/TMPS | Composite STI Measure (Including All STI Tests) | 5 Participants |
| Placebo/TMPS | Composite STI Measure (Including All STI Tests) | 5 Participants |
Secondary
GBS Colonization
anogenital GBS colonization detected by NAAT (PCR)
Time frame: at or near term or at delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin/TMPS | GBS Colonization | 8 Participants |
| Placebo/TMPS | GBS Colonization | 7 Participants |
Secondary
Low Birthweight (<2500 Grams)
Neonatal weight measured with digital scale
Time frame: at birth
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin/TMPS | Low Birthweight (<2500 Grams) | 4 Participants |
| Placebo/TMPS | Low Birthweight (<2500 Grams) | 7 Participants |
Secondary
Maternal Adherence to the Prophylactic Regimen
Directly observed therapy (DOT) in clinic for the 1st dose of study medication. Self-report and pill count will be used to assess adherence and maternal tolerability for study medications taken at home from the time of enrollment until delivery. At each follow up visit and at delivery, participants will complete a medication adherence survey. They will self-report adherence to the 3 day study regimen (AZ or placebo).
Time frame: Adherence of study medication taken at home will be documented from the date of randomization until the time of delivery, assessed up to 42 weeks.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin/TMPS | Maternal Adherence to the Prophylactic Regimen | 148 Participants |
| Placebo/TMPS | Maternal Adherence to the Prophylactic Regimen | 148 Participants |
Secondary
Proportion of Participants With Symptomatic Malaria
Fever and positive malaria test (rapid diagnostic test) at routine visits or sick call visits or maternal report of malaria diagnosis.
Time frame: From the date of randomization until the time of delivery, assessed up to 42 weeks.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin/TMPS | Proportion of Participants With Symptomatic Malaria | 13 Participants |
| Placebo/TMPS | Proportion of Participants With Symptomatic Malaria | 13 Participants |
Secondary
Proportion With Adverse Birth Outcomes
Composite measure: low infant birthweight (\<2500 grams), miscarriage (\<28 weeks), preterm delivery (\<37 weeks), small for gestational age (SGA), congenital anomaly detected on surface examination, early neonatal mortality (within 7 days of birth)
Time frame: Birth outcomes will be measured at birth for all outcomes except early neonatal mortality defined as within 7 days of birth. Early neonatal mortality will be assessed at a six week follow up phone call.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin/TMPS | Proportion With Adverse Birth Outcomes | 13 Participants |
| Placebo/TMPS | Proportion With Adverse Birth Outcomes | 20 Participants |
Secondary
Proportion With Maternal Anemia and Severe Maternal Anemia
anemia defined as hemoglobin \<11 g/dL, severe anemia defined as hemoglobin \<7 g/dL.
Time frame: At the end of pregnancy (>35 weeks) or at delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin/TMPS | Proportion With Maternal Anemia and Severe Maternal Anemia | 2 Participants |
| Placebo/TMPS | Proportion With Maternal Anemia and Severe Maternal Anemia | 2 Participants |
Secondary
Proportion With Placental Malaria
Placentas will be collected on a subset of women and impression smear will be used to assess for malaria infection
Time frame: At delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin/TMPS | Proportion With Placental Malaria | 7 Participants |
| Placebo/TMPS | Proportion With Placental Malaria | 5 Participants |