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Protease Inhibitors to Reduce Malaria Morbidity in HIV-Infected Pregnant Women (PROMOTE-PIs)

This study has been completed.
ClinicalTrials.gov Identifier:
First Posted: October 9, 2009
Last Update Posted: October 17, 2013
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Diana Havlir, University of California, San Francisco
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.

Condition Intervention Phase
Malaria HIV Infections Drug: Lopinavir/ritonavir Drug: Efavirenz Drug: Zidovudine Drug: Lamivudine Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Protease Inhibitors to Reduce Malaria Morbidity in HIV-Infected Pregnant Women

Resource links provided by NLM:

Further study details as provided by Diana Havlir, University of California, San Francisco:

Primary Outcome Measures:
  • Prevalence of malaria defined as positive placental blood smear or positive placental blood PCR [ Time Frame: Delivery ]

Secondary Outcome Measures:
  • Placental malaria defined as positive placental histopathology or positive rapid diagnostic test [ Time Frame: Delivery ]
  • Maternal malaria defined as the number of treatments for new episodes of malaria per time at risk [ Time Frame: Time from randomization until 24 months after delivery or cessation of breastfeeding ]
  • Prevalence of severe maternal anemia defined by hemoglobin < 8g/dl at any point during the trial in each treatment group [ Time Frame: Time from randomization until 24 months postpartum 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) [ Time Frame: Time from randomization until 24 months postpartum or cessation of breastfeeding ]
  • Incidence of pre-eclampsia defined by hypertension > 140/90 on two occasions measured > 6 hours apart with ≥1+ proteinuria on clean catch urine dipstick [ Time Frame: Time of randomization until 4 weeks postpartum ]
  • Maternal HIV RNA suppression of <400 copies/mL and of <50 copies/mL [ Time Frame: At delivery and 24 weeks after the start of the treatment regimen ]
  • Change in maternal CD4 cell counts and % CD4 [ Time Frame: From ART initiation to delivery and from delivery to the cessation of breastfeeding ]
  • Development of one or more new maternal HIV antiretroviral resistance mutations [ Time Frame: Measured at delivery and 24 weeks postpartum. ]
  • Incidence of maternal to child transmission of HIV, measured by infant HIV DNA PCR [ Time Frame: From delivery to 24 weeks of life or the cessation of breastfeeding if that occurs prior to 24 weeks of life ]
  • ART levels in plasma and hair samples [ Time Frame: Women at 30-34 weeks gestation and 12 weeks postpartum; Infants at delivery, 12 weeks and 24 weeks of life. ]
  • Prevalence of Grade 3 or 4 toxicity at any point during the trial in the two treatment groups in women and in infants [ Time Frame: Time from randomization until 24 months postpartum or cessation of breastfeeding ]

Enrollment: 391
Study Start Date: December 2009
Study Completion Date: July 2013
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group A
ZDV 300mg/3TC 150mg/LPV 200mg/r 50mg
Drug: Lopinavir/ritonavir
LPV 200mg/r 50mg
Other Names:
  • Kaletra
  • Aluvia
Drug: Zidovudine
Zidovudine 300 mg
Drug: Lamivudine
Lamivudine 150 mg
Active Comparator: Group B
ZDV 300mg/3TC 150mg/EFV 600mg
Drug: Efavirenz
Drug: Zidovudine
Zidovudine 300 mg
Drug: Lamivudine
Lamivudine 150 mg

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 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.


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   16 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

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.

  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00993031

Tororo District Hospital
Tororo, Uganda
Sponsors and Collaborators
University of California, San Francisco
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Principal Investigator: Diane Havlir, MD University of California, San Francisco
Study Chair: Deborah Cohan, MD, MPH University of California, San Francisco
Principal Investigator: Moses R Kamya, MBChB, MMed, PhD Makerere University
Study Chair: Pius Okong, MMed, PhD Ugandan Ministry of Health
Principal Investigator: Grant Dorsey, MD, PhD University of California, San Francisco
  More Information

Additional Information:
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 receiving combination antiretroviral therapy. PLoS One. 2012;7(8):e41934. doi: 10.1371/journal.pone.0041934. Epub 2012 Aug 7.
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.
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 dermatologic toxicity. J Acquir Immune Defic Syndr. 2013 Mar 1;62(3):e101-3. doi: 10.1097/QAI.0b013e31828011ca.
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.
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 Dec;59(6):441-6. doi: 10.1093/tropej/fmt044. Epub 2013 Jun 13.
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 Tororo, Uganda. J Clin Pharmacol. 2014 Feb;54(2):121-32. doi: 10.1002/jcph.167. Epub 2013 Sep 21.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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.
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 breastfeeding Ugandan women. AIDS. 2015 Apr 24;29(7):825-30. doi: 10.1097/QAD.0000000000000619. Erratum in: AIDS. 2015 Nov;29(17):2369.
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-infected pregnant Ugandan women. AIDS. 2015 Jan 14;29(2):183-91. doi: 10.1097/QAD.0000000000000531.
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 Supplements Among Pregnant HIV-Infected Ugandan Women Receiving Combination Antiretroviral Therapy. AIDS Behav. 2015 Aug;19(8):1535-47. doi: 10.1007/s10461-014-0947-0.
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- or efavirenz-based antiretroviral therapy. J Acquir Immune Defic Syndr. 2014 Oct 1;67(2):128-35. doi: 10.1097/QAI.0000000000000281.
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 malaria among HIV-infected pregnant women. J Infect Dis. 2014 Dec 15;210(12):1938-45. doi: 10.1093/infdis/jiu346. Epub 2014 Jun 23.
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 practices among HIV-infected Ugandan women receiving combination antiretroviral therapy. Matern Child Health J. 2014 Nov;18(9):2044-53. doi: 10.1007/s10995-014-1450-y.

Responsible Party: Diana Havlir, Professor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT00993031     History of Changes
Other Study ID Numbers: H5741-34342
P01HD059454 ( U.S. NIH Grant/Contract )
2009-141 ( Other Identifier: Makerere Univ Fac of Med Research and Ethics Committee )
HS-670 ( Other Identifier: Uganda National Council for Science and Tech )
592/ESR/NDA/DID-09/2009 ( Other Identifier: Uganda National Drug Authority )
H5741-34342 and 10-02958 ( Other Identifier: UCSF Committee on Human Research )
First Submitted: October 8, 2009
First Posted: October 9, 2009
Last Update Posted: October 17, 2013
Last Verified: October 2013

Keywords provided by Diana Havlir, University of California, San Francisco:
Placental Malaria
Protease inhibitors
Treatment experienced

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Protozoan Infections
Parasitic Diseases
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors

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