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

NCT00993031 | Completed Phase 3 Results DMC

• 6 other identifiers: H5741-34342P01HD0594542009-141HS-670592/ESR/NDA/DID-09/2009H5741-34342 and 10-02958
• Study Type: interventional
• Target: 389
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Malaria; HIV Infections

Keywords

HIV; Placental Malaria; Pregnancy; Uganda; Protease inhibitors; Trimethoprim-sulfamethoxazole; Treatment experienced

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (12)

• Placental Malaria Defined as Positive Placental RDT

  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)

  Time from randomization until 24 months postpartum or cessation of breastfeeding

• Placental Malaria Defined Placental Histopathologic Analysis

  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

Study Arms (2)

Group A

EXPERIMENTAL

ZDV 300mg/3TC 150mg/LPV 200mg/r 50mg

Drug: Lopinavir/ritonavir; Drug: Zidovudine; Drug: Lamivudine

Group B

ACTIVE COMPARATOR

ZDV 300mg/3TC 150mg/EFV 600mg

Drug: Efavirenz; Drug: Zidovudine; Drug: Lamivudine

Interventions

Lopinavir/ritonavir DRUG

LPV 200mg/r 50mg

Also known as: Kaletra, Aluvia

Group A

Efavirenz DRUG

600mg

Group B

Zidovudine DRUG

Zidovudine 300 mg

Group A; Group B

Lamivudine DRUG

Lamivudine 150 mg

Group A; Group B

Eligibility Criteria

• Age: 16 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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:
• 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.

Sponsors & Collaborators

• University of California, San Francisco: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

Tororo District Hospital

Tororo, Uganda

Location

Related Publications (20)

• 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.

  PMID: 21876053 BACKGROUND

• 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.

  PMID: 23796921 BACKGROUND

• 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.

  PMID: 22879899 RESULT

• 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. No abstract available.

  PMID: 23924639 RESULT

• 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.

  PMID: 23764539 RESULT

• 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.

  PMID: 24038035 RESULT

• 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 lopinavir, ritonavir, and efavirenz all transfer from mother to infant in utero, but only efavirenz transfers via breastfeeding. J Acquir Immune Defic Syndr. 2013 Aug 15;63(5):578-84. doi: 10.1097/QAI.0b013e31829c48ad.

  PMID: 24135775 RESULT

• 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.

  PMID: 24585398 RESULT

• 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.

  PMID: 24958908 RESULT

• 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.

  PMID: 25072616 RESULT

• 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.

  PMID: 25426808 RESULT

• 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.

  PMID: 25416075 RESULT

• 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.

  PMID: 25985404 RESULT

• 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-Infected Pregnant and Breastfeeding Ugandan Women. J Acquir Immune Defic Syndr. 2016 Mar 1;71(3):310-5. doi: 10.1097/QAI.0000000000000860.

  PMID: 26397935 RESULT

• 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 Dis J. 2016 May;35(5):524-9. doi: 10.1097/INF.0000000000001062.

  PMID: 26771662 RESULT

• 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):414-22. doi: 10.1093/cid/ciw291. Epub 2016 May 3.

  PMID: 27143666 RESULT

• 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 Acquir Immune Defic Syndr. 2017 Mar 1;74(3):279-284. doi: 10.1097/QAI.0000000000001228.

  PMID: 27828878 RESULT

• 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. doi: 10.1186/s12936-016-1568-z.

  PMID: 27756308 RESULT

• Finkelstein JL, Herman HS, Plenty A, Mehta S, Natureeba P, Clark TD, Kamya MR, Ruel T, Charlebois ED, Cohan D, Havlir D, Young SL. Anemia and Micronutrient Status during Pregnancy, and Their Associations with Obstetric and Infant Outcomes among HIV-Infected Ugandan Women Receiving Antiretroviral Therapy. Curr Dev Nutr. 2020 Apr 25;4(5):nzaa075. doi: 10.1093/cdn/nzaa075. eCollection 2020 May.

  PMID: 32440638 DERIVED

• McDonald CR, Conroy AL, Gamble JL, Papp E, Hawkes M, Olwoch P, Natureeba P, Kamya M, Silverman M, Cohan D, Koss CA, Dorsey G, Kain KC, Serghides L. Estradiol Levels Are Altered in Human Immunodeficiency Virus-Infected Pregnant Women Randomized to Efavirenz-Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy. Clin Infect Dis. 2018 Jan 18;66(3):428-436. doi: 10.1093/cid/cix772.

  PMID: 29136115 DERIVED

MeSH Terms

Conditions

Malaria; HIV Infections

Interventions

Lopinavir; lopinavir-ritonavir drug combination; efavirenz; Zidovudine; Lamivudine

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Thymidine; Pyrimidine Nucleosides; Dideoxynucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Zalcitabine; Deoxycytidine; Cytidine

Limitations and Caveats

A semi-immune population of adults at relatively low risk for malaria; a high rate of TMP-SMX prophylaxis ; A lower than expected incidence of malaria, resulting in the possibility that the study was underpowered

Results Point of Contact

• Title: Diane V Havlir, MD
• Organization: University of California, San Francisco

dhavlir@php.ucsf.edu

01-415-476-4082

Study Officials

• Diane Havlir, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• Deborah Cohan, MD, MPH

  University of California, San Francisco

  STUDY CHAIR

• Moses R Kamya, MBChB, MMed, PhD

  Makerere University

  PRINCIPAL INVESTIGATOR

• Pius Okong, MMed, PhD

  Ugandan Ministry of Health

  STUDY CHAIR

• Grant Dorsey, MD, PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: October 8, 2009
• First Posted: October 9, 2009
• Study Start: December 15, 2009
• Primary Completion: July 1, 2013
• Study Completion: July 1, 2013
• Last Updated: May 14, 2019
• Results First Posted: December 2, 2017

Record last verified: 2019-04

Locations

UG (1)