Protease Inhibitors to Reduce Malaria Morbidity in HIV-Infected Pregnant Women

Study Overview
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Brief Summary
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This study is an open-label, single site, randomized controlled trial comparing protease inhibitor (PI)-based antiretroviral therapy (ART) to non-PI based ART for HIV-infected pregnant and breastfeeding women of all CD4 cell counts at high risk of malaria. The study is designed to test the hypothesis that pregnant women receiving a PI-based ART regimen will have lower risk of placental malaria compared to pregnant women receiving a non-PI based ART regimen. The primary study endpoint of the study is placental malaria. This study also enrolls the infants of these women at the time of delivery.

Detailed Description
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The study site will be the Tororo district hospital campus situated in Eastern Uganda, an area of high malaria transmission. Using convenience sampling, we will enroll 500 HIV-infected pregnant women and their infants from the Tororo community. Eligible women between 12-28 weeks gestation will be randomized at enrollment to receive either a PI- based or an NNRTI-based ART regimen after stratification by gravidity (G1 versus G2+) and gestational age (<24 weeks versus ≥ 24 weeks at enrollment). Treatment group A will receive Zidovudine 300mg + Lamivudine 150mg + Lopinavir/ritonavir 200mg/50mg. Treatment group B will receive Zidovudine 300mg + Lamivudine 150mg + Efavirenz 600mg. At enrollment, all study participants will receive a long lasting ITN and, as available, a basic care package including a safe water vessel, multivitamins and condoms, as per current standard of care for HIV-infected pregnant women in Uganda, if they have not already received these interventions from the referral site. Two ITNs will be provided for each mother-infant pair. Participants will receive all routine and acute medical care at a designated study clinic open 7 days a week from 8 a.m. to 5 p.m. If medical care is needed after hours, participants will be instructed to come to Tororo District Hospital premises (where the study clinic is located) and request that the study physician on-call be contacted. They will be followed up from the time of enrollment during pregnancy and through the cessation of breastfeeding; seen monthly for routine assessments and laboratory evaluations. Following delivery, the infants of enrolled women will be followed until 6 weeks following the cessation of breastfeeding but not beyond 58 weeks of life. Study participants will be followed closely for adverse events potentially due to study drugs and for malaria and HIV treatment outcomes. During the follow-up period, all patients presenting to the clinic with a new episode of fever will undergo standard evaluation (history, physical examination and Giemsa-stained blood smear) for the diagnosis of malaria. Women will receive the study treatment from the time of study entry and randomization (12-28 weeks gestation) until 1 week following the cessation of breastfeeding (but no longer than 1 year + 1 week postpartum). If a subject experiences a toxicity endpoint, ART will be changed to provide antiviral activity prior to delivery. Exclusive breastfeeding will be encouraged until 24 weeks postpartum which is the standard of care in Uganda. As per updated WHO guidelines, women will be encouraged to introduce food at 6 months of life and continue breastfeeding until 1 year of life. Women will be counseled to wean over the course of 1 month and continue antiretrovirals for at least 1 week following weaning. Furthermore, if an infant is found to be HIV-infected, Uganda MOH and WHO guidelines recommend the continuation of breastfeeding until 2 years of life and daily TS. All women will receive daily oral trimethoprim/sulfamethoxazole (TS) per Ugandan MOH guidelines. Per Ugandan MOH guidelines, all newborns will receive nevirapine syrup (10mg/ml) starting within 12 hours after birth for 6 weeks, daily oral TS from 6 weeks of life until 6 weeks following the cessation of breastfeeding, and their mothers will be instructed on ITN use for their infants.

Official Title
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Protease Inhibitors to Reduce Malaria Morbidity in HIV-Infected Pregnant Women

Conditions
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Malaria, HIV Infections

Intervention / Treatment
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* Drug: Lopinavir/ritonavir
* Drug: Efavirenz
* Drug: Zidovudine
* Drug: Lamivudine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 16 years (if <18 years old, living independently from parents) Documentation of HIV status must come from two assays. Assays include DNA PCR, HIV RNA, Western blot, or rapid HIV antibody test Confirmed pregnancy by positive serum or urine pregnancy test or ultrasound Estimated gestational age between 12 and 28 weeks (based on first day of last menstrual period with physical exam confirmation and ultrasound confirmation) at time of enrollment Residency within 30 km of the study site Willing to provide informed consent Exclusion Criteria: Current or prior use of HAART Exposure to single-dose NVP (alone or with zidovudine or zidovudine/lamivudine or other abbreviated monotherapy or dual therapy for PMTCT) less than 24 months prior to enrollment Prior dose-limited toxicity to TS within 14 days of study enrollment Receipt of any contraindicated medications within 14 days of study enrollment (See Appendix III.) Active tuberculosis or other WHO Stage 4 diseases Screening laboratory values: Hemoglobin: <7.5 g/dL (Note: Women found to have a hemoglobin <7.5 at screening may receive iron and folic acid and/or a blood transfusion at the physician's discretion. If a repeat hemoglobin is ≥7.5 g/dL, the woman may be considered for study inclusion.) Absolute neutrophil count (ANC): <750/mm3 Platelet count: <50,000/mm3 ALT: >225 U/L (>5.0x ULN) AST: >225 U/L (>5.0x ULN) Bilirubin (total): > 2.5x ULN Creatinine: > 1.8x ULN Known cardiac conduction abnormalities or structural heart defect NOTE: A woman will be excluded from study participation during the current pregnancy if she goes into labor, experiences ruptured membranes or develops active tuberculosis or a WHO stage 4 condition following study enrollment but prior to study drug initiation.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>ZDV 300mg/3TC 150mg/LPV 200mg/r 50mg | Drug: Lopinavir/ritonavir<br>* LPV 200mg/r 50mg<br>* Other names: Aluvia;Drug: Zidovudine<br>* Zidovudine 300 mg<br>Drug: Lamivudine<br>* Lamivudine 150 mg<br>|
| Active Comparator: Group B<br>ZDV 300mg/3TC 150mg/EFV 600mg | Drug: Efavirenz<br>* 600mg<br>Drug: Zidovudine<br>* Zidovudine 300 mg<br>Drug: Lamivudine<br>* Lamivudine 150 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of Malaria Defined as Positive Placental Blood Smear | Number of participants with positive placental blood smear for malaria | Delivery | 
| Prevalence of Malaria Defined as Positive Placental Blood PCR | Number of participants with positive placental blood PCR for malaria | Delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Placental Malaria Defined as Positive Placental RDT | Number of participants with positive placental RDT for malaria. Malaria rapid diagnostic tests (RDTs) assist in the diagnosis of malaria by detecting evidence of malaria parasites (antigens) in human blood. RDTs permit a reliable detection of malaria infections particularly in remote areas with limited access to good quality microscopy services. | Delivery | 
| Maternal Malaria Defined as the Number of Treatments for New Episodes of Malaria Per Time at Risk During Pregnancy |  | Number of treatments given for clinical malaria based on postive blood smear from time from randomization until 24 months after delivery or cessation of breastfeeding | 
| Prevalence of Composite Clinical Outcome Defined by LBW, Stillbirth(Intrauterine Fetal Demise >20wks GA), Late Spontaneous Abortion(Miscarriage 12-20wks GA), Preterm Delivery(<37wks Gestation), Neonatal Death(Death of Liveborn Infant Within First 28days) | Percent of evaluated participants with composite clinical outcome defined by LBW, stillbirth (intrauterine fetal demise >20wks GA), late spontaneous abortion(miscarriage 12-20wks GA), preterm delivery(<37wks gestation), neonatal death(death of live-born infant within first 28 days) | Time from randomization until 24 months postpartum or cessation of breastfeeding | 
| Placental Malaria Defined Placental Histopathologic Analysis | Number of participants with positive placental histopathology slide for malaria | Delivery | 
| Maternal Malaria Defined as the Number of Treatments for New Episodes of Malaria Per Time at Risk After Pregnancy |  | Number of treatments given for clinical malaria based on postive blood smear from time from delivery until 24 months after delivery or cessation of breastfeeding | 
| Number of Participants With Severe Maternal Anemia Defined by Hemoglobin < 8g/dl at Any Point During the Trial in Each Treatment Group | Proportion of women with severe maternal Anemia (hemoglobin < 8g/dl by hemacue or CBC) at any point during the trial in Each Treatment Group | Time from randomization until one year follow up | 
| Incidence of Pre-eclampsia Defined by Hypertension > 140/90 on Two Occasions Measured > 6 Hours Apart With ≥1+ Proteinuria on Clean Catch Urine Dipstick | Pre-eclampsia Defined by Hypertension > 140/90 on Two Occasions Measured > 6 Hours Apart With ≥1+ Proteinuria on Clean Catch Urine Dipstick | Time from randomization until delivery | 
| Number of Participants With Maternal HIV RNA Suppression of <400 Copies/mL | Virologic suppression was defined as plasma HIV-1 RNA 400 copies/ml or less based on the lower limit of detection of the available test. | Time from randomization until delivery, an average of 20 weeks | 
| Change in Maternal CD4 Cell Counts | CD4 cell count recovery efavirenz at delivery | Time of randomization to delivery, an average of 20 weeks | 
| Number of Participants With Maternal to Child Transmission of HIV, Measured by Infant HIV DNA PCR | HIV tested by DNA PCR | Delivery to 48 weeks postpartum | 
| ART Levels in Hair Samples at Delivery | antiretroviral hair concentrations (per doubling) | delivery | 
| Number of Participants With Grade 3 or 4 Toxicity in the Two Treatment Groups in Women |  | Randomization to one month postpartum | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Placental Malaria, Pregnancy, Uganda, Protease inhibitors, Trimethoprim-sulfamethoxazole, Treatment experienced