Clinical trial NCT00993031: Protease Inhibitors to Reduce Malaria Morbidity in HIV-Infected Pregnant Women
Official title: Protease Inhibitors to Reduce Malaria Morbidity in HIV-Infected Pregnant Women
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malaria
HIV Infections
Keywords: HIV
Placental Malaria
Pregnancy
Uganda
Protease inhibitors
Trimethoprim-sulfamethoxazole
Treatment experienced
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2009-10-09
Enrollment: 389
Sex: FEMALE
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Prevalence of Malaria Defined as Positive Placental Blood Smear
timeFrame: Delivery
measure: Prevalence of Malaria Defined as Positive Placental Blood PCR
timeFrame: Delivery
Secondary outcomes:
measure: Placental Malaria Defined as Positive Placental RDT
timeFrame: Delivery
measure: Maternal Malaria Defined as the Number of Treatments for New Episodes of Malaria Per Time at Risk During Pregnancy
timeFrame: 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
measure: 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)
timeFrame: Time from randomization until 24 months postpartum or cessation of breastfeeding
measure: Placental Malaria Defined Placental Histopathologic Analysis
timeFrame: Delivery
measure: Maternal Malaria Defined as the Number of Treatments for New Episodes of Malaria Per Time at Risk After Pregnancy
timeFrame: 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
measure: Number of Participants With Severe Maternal Anemia Defined by Hemoglobin < 8g/dl at Any Point During the Trial in Each Treatment Group
timeFrame: Time from randomization until one year follow up
measure: Incidence of Pre-eclampsia Defined by Hypertension > 140/90 on Two Occasions Measured > 6 Hours Apart With ≥1+ Proteinuria on Clean Catch Urine Dipstick
timeFrame: Time from randomization until delivery
measure: Number of Participants With Maternal HIV RNA Suppression of <400 Copies/mL
timeFrame: Time from randomization until delivery, an average of 20 weeks
measure: Change in Maternal CD4 Cell Counts
timeFrame: Time of randomization to delivery, an average of 20 weeks
measure: Number of Participants With Maternal to Child Transmission of HIV, Measured by Infant HIV DNA PCR
timeFrame: Delivery to 48 weeks postpartum
measure: ART Levels in Hair Samples at Delivery
timeFrame: delivery
measure: Number of Participants With Grade 3 or 4 Toxicity in the Two Treatment Groups in Women
timeFrame: Randomization to one month postpartum
Other outcomes:
Locations:
city: Tororo
country: Uganda
facility: Tororo District Hospital
Study officials:
affiliation: University of California, San Francisco
name: Diane Havlir, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Deborah Cohan, MD, MPH
role: STUDY_CHAIR
affiliation: Makerere University
name: Moses R Kamya, MBChB, MMed, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ugandan Ministry of Health
name: Pius Okong, MMed, PhD
role: STUDY_CHAIR
affiliation: University of California, San Francisco
name: Grant Dorsey, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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 receiving combination antiretroviral therapy. PLoS One. 2012;7(8):e41934. doi: 10.1371/journal.pone.0041934. Epub 2012 Aug 7.
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 dermatologic toxicity. J Acquir Immune Defic Syndr. 2013 Mar 1;62(3):e101-3. doi: 10.1097/QAI.0b013e31828011ca. No abstract available.
citation: 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.
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 Tororo, Uganda. J Clin Pharmacol. 2014 Feb;54(2):121-32. doi: 10.1002/jcph.167. Epub 2013 Sep 21.
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 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.
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 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.
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 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.
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- or efavirenz-based antiretroviral therapy. J Acquir Immune Defic Syndr. 2014 Oct 1;67(2):128-35. doi: 10.1097/QAI.0000000000000281.
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-infected pregnant Ugandan women. AIDS. 2015 Jan 14;29(2):183-91. doi: 10.1097/QAD.0000000000000531.
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 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.
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 breastfeeding Ugandan women. AIDS. 2015 Apr 24;29(7):825-30. doi: 10.1097/QAD.0000000000000619.
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-Infected Pregnant and Breastfeeding Ugandan Women. J Acquir Immune Defic Syndr. 2016 Mar 1;71(3):310-5. doi: 10.1097/QAI.0000000000000860.
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 Dis J. 2016 May;35(5):524-9. doi: 10.1097/INF.0000000000001062.
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):414-22. doi: 10.1093/cid/ciw291. Epub 2016 May 3.
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 Acquir Immune Defic Syndr. 2017 Mar 1;74(3):279-284. doi: 10.1097/QAI.0000000000001228.
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. doi: 10.1186/s12936-016-1568-z.
citation: 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.
citation: 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.