Protease Inhibitors to Reduce Malaria Morbidity in HIV-Infected Women

Condition(s) targeted: Malaria; HIV Infections

Intervention: Lopinavir/ritonavir (Drug); Efavirenz (Drug); Zidovudine (Drug); Lamivudine (Drug)

Phase: Phase 3

Status: Not yet recruiting

Sponsored by: University of California, San Francisco

Official(s) and/or principal investigator(s):
Diane Havlir, MD, Principal Investigator, Affiliation: University of California, San Francisco
Deborah Cohan, MD, MPH, Study Chair, Affiliation: University of California, San Francisco
Moses R Kamya, MBChB, MMed, PhD, Principal Investigator, Affiliation: Makerere University
Pius Okong, MMed, PhD, Study Chair, Affiliation: Ugandan Ministry of Health
Grant Dorsey, MD, PhD, Principal Investigator, Affiliation: University of California, San Francisco

Overall contact:
Diane V Havlir, MD, Phone: 01-415-476-4082, Ext: 400, Email: dhavlir@php.ucsf.edu

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.

Official title: Protease Inhibitors to Reduce Malaria Morbidity in HIV-Infected Women

Study design: Prevention, Randomized, Open Label, Parallel Assignment, Safety/Efficacy Study

Primary outcome: Prevalence of malaria defined as positive placental blood smear or positive placental blood PCR

Secondary outcome:

Placental malaria defined as positive placental histopathology or positive rapid diagnostic test

Maternal malaria defined as the number of treatments for new episodes of malaria per time at risk

Prevalence of severe maternal anemia defined by hemoglobin < 8g/dl at any point during the trial in each treatment group

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)

Incidence of pre-eclampsia defined by hypertension > 140/90 on two occasions measured > 6 hours apart with ≥1+ proteinuria on clean catch urine dipstick

Maternal HIV RNA suppression of <400 copies/mL and of <50 copies/mL

Change in maternal CD4 cell counts and % CD4

Development of one or more new maternal HIV antiretroviral resistance mutations

Incidence of maternal to child transmission of HIV, measured by infant HIV DNA PCR

ART levels in plasma and hair samples

Prevalence of Grade 3 or 4 toxicity at any point during the trial in the two treatment groups in women and in infants

Detailed description: 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 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 + Efavirenz 600mg. Treatment group B will receive Zidovudine 300mg + Lamivudine 150mg + Lopinavir/ritonavir 200mg/50mg.

At enrollment, all study participants will receive a long lasting ITN as part of 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, they will be instructed to bring them 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 24 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 24 weeks postpartum or until the cessation of breastfeeding if that occurs prior to 24 weeks postpartum. If a subject experiences a toxicity endpoint, ART will be changed to provide antiviral activity prior to delivery. All women will receive daily oral trimethoprim/sulfamethoxazole (TS) per Ugandan MOH guidelines.

Per Ugandan MOH guidelines, all newborns will receive zidovudine syrup 4mg/kg PO BID starting within 12 hours after birth for 7 days, 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. Breastfeeding will be encouraged until 24 weeks postpartum which is the standard of care in Uganda. Furthermore, if an infant is found to be HIV-infected, Uganda MOH guidelines recommend the continuation of breastfeeding and daily TS beyond these 24 weeks.

Minimum age: 16 Years. Maximum age: N/A. Gender(s): Female.

Criteria:

Inclusion Criteria:

1. Age > 16 years

2. Confirmed diagnosis of HIV infection (positive rapid HIV test plus confirmatory Western Blot or HIV RNA)

3. Confirmed pregnancy by positive serum or urine pregnancy test and confirmed by ultrasound

4. 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

5. Residency within 30 km of the study site

6. Willing to provide informed consent

Exclusion Criteria:

1. Signs of cervical incompetence (documented cervical change or 2 centimeter dilation without uterine cramping or contractions) or preterm labor (documented cervical change or 2 centimeter dilation with uterine cramping or contractions) at time of enrollment

2. Current or prior use of HAART

3. 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

4. Prior dose-limited toxicity to TS within 14 days of study enrollment

5. Receipt of any contraindicated medications within 14 days of study enrollment (See Appendix III.)

6. Active tuberculosis or other WHO Stage 4 diseases

7. Screening laboratory values:

1. Hemoglobin: <7. 5 g/dL

2. Absolute neutrophil count (ANC): <750/mm3

3. Platelet count: <50,000/mm3

4. ALT: >225 U/L (>5. 0x ULN)

5. AST: >225 U/L (>5. 0x ULN)

6. Bilirubin (total): > 2. 5x ULN

7. Creatinine: > 1. 8x ULN

8. Known cardiac conduction abnormalities or structural heart defect

Diane V Havlir, MD, Phone: 01-415-476-4082, Ext: 400, Email: dhavlir@php.ucsf.edu

Tororo District Hospital, Tororo, Uganda

Starting date: October 2009
Ending date: July 2014
Last updated: October 8, 2009