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

HIV Infections Clinical Trial

— PROMOTE-PIs  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00993031
• Other study ID #: H5741-34342
• Secondary ID: P01HD0594542009-
• Status: Completed
• Phase: Phase 3
• Start date: December 15, 2009
• Est. completion date: July 2013

Study information

• Verified date: April 2019
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 389
• Est. completion date: July 2013
• Est. primary completion date: July 2013
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 16 Years and older

Eligibility

Inclusion Criteria:

1. Age > 16 years (if <18 years old, living independently from parents)

2. Documentation of HIV status must come from two assays. Assays include DNA PCR, HIV RNA, Western blot, or rapid HIV antibody test

3. Confirmed pregnancy by positive serum or urine pregnancy test or 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. Current or prior use of HAART

2. 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

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

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

5. Active tuberculosis or other WHO Stage 4 diseases

6. Screening laboratory values:

1. 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.)

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

7. 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.

Related Conditions & MeSH terms

• HIV Infections
• Malaria

Intervention

Drug:
• Lopinavir/ritonavir
LPV 200mg/r 50mg
• Efavirenz
600mg
• Zidovudine
Zidovudine 300 mg
• Lamivudine
Lamivudine 150 mg

Locations

Country	Name	City	State
Uganda	Tororo District Hospital	Tororo

Sponsors (2)

Lead Sponsor	Collaborator
University of California, San Francisco	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Country where clinical trial is conducted

Uganda, 

References & Publications (18)

Ades V, Mwesigwa J, Natureeba P, Clark TD, Plenty A, Charlebois E, Achan J, Kamya MR, Havlir DV, Cohan D, Ruel TD. Neonatal mortality in HIV-exposed infants born to women receiving combination antiretroviral therapy in Rural Uganda. J Trop Pediatr. 2013 D — View Citation

Bartelink IH, Savic RM, Mwesigwa J, Achan J, Clark T, Plenty A, Charlebois E, Kamya M, Young SL, Gandhi M, Havlir D, Cohan D, Aweeka F. Pharmacokinetics of lopinavir/ritonavir and efavirenz in food insecure HIV-infected pregnant and breastfeeding women in — View Citation

Cohan D, Mwesigwa J, Natureeba P, Aliba Luwedde F, Ades V, Plenty A, Kakuru A, Achan J, Clark T, Osterbauer B, Kamya M, Havlir D. WHO option B+: early experience of antiretroviral therapy sequencing after cessation of breastfeeding and risk of dermatologi — View Citation

Cohan D, Natureeba P, Koss CA, Plenty A, Luwedde F, Mwesigwa J, Ades V, Charlebois ED, Gandhi M, Clark TD, Nzarubara B, Achan J, Ruel T, Kamya MR, Havlir DV. Efficacy and safety of lopinavir/ritonavir versus efavirenz-based antiretroviral therapy in HIV-i — View Citation

Gandhi M, Mwesigwa J, Aweeka F, Plenty A, Charlebois E, Ruel TD, Huang Y, Clark T, Ades V, Natureeba P, Luwedde FA, Achan J, Kamya MR, Havlir DV, Cohan D; Prevention of Malaria and HIV disease in Tororo (PROMOTE) study. Hair and plasma data show that lopi — View Citation

Kakuru A, Natureeba P, Muhindo MK, Clark TD, Havlir DV, Cohan D, Dorsey G, Kamya MR, Ruel T. Malaria burden in a birth cohort of HIV-exposed uninfected Ugandan infants living in a high malaria transmission setting. Malar J. 2016 Oct 18;15(1):500. — View Citation

Koss CA, Natureeba P, Kwarisiima D, Ogena M, Clark TD, Olwoch P, Cohan D, Okiring J, Charlebois ED, Kamya MR, Havlir DV. Viral Suppression and Retention in Care up to 5 Years After Initiation of Lifelong ART During Pregnancy (Option B+) in Rural Uganda. J — View Citation

Koss CA, Natureeba P, Mwesigwa J, Cohan D, Nzarubara B, Bacchetti P, Horng H, Clark TD, Plenty A, Ruel TD, Achan J, Charlebois ED, Kamya MR, Havlir DV, Gandhi M. Hair concentrations of antiretrovirals predict viral suppression in HIV-infected pregnant and — View Citation

Koss CA, Natureeba P, Nyafwono D, Plenty A, Mwesigwa J, Nzarubara B, Clark TD, Ruel TD, Achan J, Charlebois ED, Cohan D, Kamya MR, Havlir DV, Young SL. Brief Report: Food Insufficiency Is Associated With Lack of Sustained Viral Suppression Among HIV-Infec — View Citation

Koss CA, Natureeba P, Plenty A, Luwedde F, Mwesigwa J, Ades V, Charlebois ED, Clark TD, Achan J, Ruel T, Nzarubara B, Kamya MR, Havlir DV, Cohan D. Risk factors for preterm birth among HIV-infected pregnant Ugandan women randomized to lopinavir/ritonavir- — View Citation

Marquez C, Chamie G, Achan J, Luetkemeyer AF, Kyohere M, Okiring J, Dorsey G, Kamya MR, Charlebois ED, Havlir DV. Tuberculosis Infection in Early Childhood and the Association with HIV-exposure in HIV-uninfected Children in Rural Uganda. Pediatr Infect Di — View Citation

Natureeba P, Ades V, Luwedde F, Mwesigwa J, Plenty A, Okong P, Charlebois ED, Clark TD, Nzarubara B, Havlir DV, Achan J, Kamya MR, Cohan D, Dorsey G. Lopinavir/ritonavir-based antiretroviral treatment (ART) versus efavirenz-based ART for the prevention of — View Citation

Nsanzabana C, Rosenthal PJ. In vitro activity of antiretroviral drugs against Plasmodium falciparum. Antimicrob Agents Chemother. 2011 Nov;55(11):5073-7. doi: 10.1128/AAC.05130-11. Epub 2011 Aug 29. — View Citation

Ochong E, Tumwebaze PK, Byaruhanga O, Greenhouse B, Rosenthal PJ. Fitness Consequences of Plasmodium falciparum pfmdr1 Polymorphisms Inferred from Ex Vivo Culture of Ugandan Parasites. Antimicrob Agents Chemother. 2013 Sep;57(9):4245-4251. doi: 10.1128/AAC.00161-13. Epub 2013 Jun 24. — View Citation

Parikh S, Kajubi R, Huang L, Ssebuliba J, Kiconco S, Gao Q, Li F, Were M, Kakuru A, Achan J, Mwebaza N, Aweeka FT. Antiretroviral Choice for HIV Impacts Antimalarial Exposure and Treatment Outcomes in Ugandan Children. Clin Infect Dis. 2016 Aug 1;63(3):41 — View Citation

Young S, Murray K, Mwesigwa J, Natureeba P, Osterbauer B, Achan J, Arinaitwe E, Clark T, Ades V, Plenty A, Charlebois E, Ruel T, Kamya M, Havlir D, Cohan D. Maternal nutritional status predicts adverse birth outcomes among HIV-infected rural Ugandan women — View Citation

Young S, Natamba B, Luwedde F, Nyafwono D, Okia B, Osterbauer B, Natureeba P, Johnson L, Michel C, Zheng A, Robine M, Achan J, Charlebois E, Cohan D, Havlir D. "I Have Remained Strong Because of That Food": Acceptability and Use of Lipid-Based Nutrient Su — View Citation

Young SL, Plenty AH, Luwedde FA, Natamba BK, Natureeba P, Achan J, Mwesigwa J, Ruel TD, Ades V, Osterbauer B, Clark TD, Dorsey G, Charlebois ED, Kamya M, Havlir DV, Cohan DL. Household food insecurity, maternal nutritional status, and infant feeding pract — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Prevalence of Malaria Defined as Positive Placental Blood Smear	Number of participants with positive placental blood smear for malaria	Delivery
Primary	Prevalence of Malaria Defined as Positive Placental Blood PCR	Number of participants with positive placental blood PCR for malaria	Delivery
Secondary	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
Secondary	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
Secondary	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
Secondary	Placental Malaria Defined Placental Histopathologic Analysis	Number of participants with positive placental histopathology slide for malaria	Delivery
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in Maternal CD4 Cell Counts	CD4 cell count recovery efavirenz at delivery	Time of randomization to delivery, an average of 20 weeks
Secondary	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
Secondary	ART Levels in Hair Samples at Delivery	antiretroviral hair concentrations (per doubling)	delivery
Secondary	Number of Participants With Grade 3 or 4 Toxicity in the Two Treatment Groups in Women		Randomization to one month postpartum