HIV Protease Inhibitors for the Prevention of Malaria in Ugandan Children (PROMOTE-PEDS)

A Randomized Open Label Trial of HIV Protease Inhibitors for the Prevention of Malaria in HIV-Infected Children

HIV and malaria are major causes of morbidity and mortality in Sub-Saharan Africa and children bear the greatest brunt of both diseases. No single existing intervention is likely to control malaria in Africa. Rather, improvements in malaria prevention are likely to come from strategies that employ multiple proven interventions targeting different populations. HIV-infected children represent one of the most vulnerable subpopulations in these countries. It is possible that the use of protease inhibitor (PI) - based antiretroviral therapy (ART) in HIV-infected children living in areas of high malaria transmission could prevent malaria in this vulnerable population. An effective remedy that offers the possibility to further reduce malaria risk, such as PIs, is highly desirable. This study will determine whether a PI based ART regimen will reduce malaria among children living in a malaria endemic area of Uganda and receiving insecticide-treated bed nets (ITN) and TS. This study will compare two different ART regimens. Children enrolled in the study will start or continue to receive either standard Ugandan first line treatment ART regimen (NNRTI+2 NRTIs) or an ART regimen containing the HIV protease inhibitor (lopinavir/ritonavir +2 NRTIs) and followed for a period of 24 months.

Study Overview

• Status: Completed
• Conditions: HIV Infections; Malaria
• Intervention / Treatment: Drug: Lopinavir/Ritonavir (LPV/r); Drug: 2 nucleoside reverse transcriptase inhibitor (NRTI); Drug: Nevirapine (NVP); Drug: Efavirenz (EFV)

Detailed Description

This is an open label, single site, randomized clinical trial comparing PI-based ART to NNRTI-based ART for the prevention of malaria in HIV-infected children. The two ART drug regimens that will be used include: Treatment arm 1. LPV/r + 2 NRTIs and Treatment arm 2. NVP or EFV + 2 NRTIs. The study is designed to test the hypothesis that children receiving a PI-based ART regimen will have lower the incidence of malaria compared to children receiving an NNRTI- based ART regimen. The primary study endpoint of the study is malaria incidence.

The study site will be the Tororo District Hospital campus situated in Eastern Uganda, an area of high malaria transmission. Using convenience sampling, 300 HIV-infected children identified from the Tororo community aged 2 months to <11 years either eligible for ART-initiation or already receiving a first line ART regimen with HIV RNA<400 copies/ml will be evaluated for enrollment.

Eligible children will be randomized at enrollment to receive either a PI- based or an NNRTI-based ART regimen. At enrollment, all study participants will receive a long lasting ITN as part of a basic care package including a safe water vessel and multivitamins and given TS chemoprophylaxis, as per current standard of care for HIV-infected children in Uganda. On the day of ART initiation, patients will be counseled about the importance of adherence to ART and possible ART related toxicities. After 2 weeks, patients will be seen to assess adherence and toxicity to study medications by interview and clinical examination. Apart from this visit at week 2, patients will be seen at 4 week intervals timed from ART-initiation. Assessment of adherence will also be done for TS prophylaxis, ITN use and ART. Assessment of adherence to ART will be done by self report of missed doses and pill counts.

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. Parents/guardians will be asked to bring their child to the study clinic for all medical care. If 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 for at least 24 months and up to 3 years. They will be seen monthly for routine assessments with laboratory evaluations done at every 3 months. At these visits, the study protocol will be reinforced with discussion regarding the need to come to the study clinic promptly upon the onset of any illness and to avoid use of outside medications. Study participants will also 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.

• Study Type: Interventional
• Enrollment (Actual): 176
• Phase: Phase 3

Contacts and Locations

Study Locations

• Uganda
  • Tororo, Uganda
    • IDRC - Tororo Research Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 months to 10 years (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Age 2 months to < 11 years
2. Confirmed HIV diagnosis. i. Children > 18 months: Documentation of HIV status must come from two assays. Assays include DNA PCR, HIV RNA, Western blot, or rapid HIV antibody test ii. Children < 18 months: Documentation will be DNA PCR confirmation only along with documentation of testing from the referral entity
3. ART-naïve patients eligible for ART initiation per WHO/Uganda guidelines (see Table 1) or Patients receiving first line ART regimen with NNRTI +2 NRTI with at least one HIV RNA <400 copies/ml within the past 6 months
4. Agreement to come to the study clinic for any febrile episode or other illness
5. Agreement to avoid medications administered outside study protocol
6. Provision of informed consent by parent/guardian and agreement to have child's care at the clinical site
7. Lives within 50 km of study site

Exclusion criteria:

1. ART-naïve children: children or their mothers that have received any dose of Nevirapine in the past 24 months
2. Active medical problem requiring in-patient evaluation at the time of screening or enrollment
3. History of cardiac conduction disorder or known significant cardiac structural defect
4. Children receiving any disallowed medications (see section 4.3)

5. Moderate, Severe or Life-threatening (Grade 2, 3, or 4) AST or ALT found within 4 weeks prior to enrollment:

   • AST: >113U/L (>2.5xULN)
   • ALT: >113U/L (>2.5xULN)

6. Life-threatening (Grade 4) screening laboratory value found within 4 weeks prior to enrollment for the following:

   • Absolute neutrophil count: <500 mm3
   • Hemoglobin: <6.5 g/dL
   • Creatinine: >3.5xULN
   • Platelets: <25,000/mm3

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Lopinavir/ritonavir (LPV/r) +2 NRTI; Lopinavir/ritonavir (LPV/r) +2 nucleoside reverse transcriptase inhibitor (NRTI)	Drug: Lopinavir/Ritonavir (LPV/r); Other Names: Aluvia; Drug: 2 nucleoside reverse transcriptase inhibitor (NRTI); The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be Abacavir. Stavudine will be used in the event that a participant is unable to take Abacavir for safety or other reasons.
Active Comparator: Nevirapine (NVP) or Efavirenz (EFV) +2 NRTI; Nevirapine (NVP) or Efavirenz (EFV) +2 nucleoside reverse transcriptase inhibitor (NRTI)	Drug: 2 nucleoside reverse transcriptase inhibitor (NRTI); The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be Abacavir. Stavudine will be used in the event that a participant is unable to take Abacavir for safety or other reasons.; Drug: Nevirapine (NVP); NVP will be used for children < 3 years of age; Drug: Efavirenz (EFV); EFV for children ≥3 years of age

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence-density of Malaria Defined as the Number of Incident Episodes of Malaria Per Time at Risk.	Time from randomization to at least 24 months of follow up or until end of the study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Uncomplicated Malaria Episodes With Accompanying Adverse Events That Occurred in the 28 Days Following Antimalarial Therapy	The rates of adverse events, defined as severity grade 2 or higher that are possibly, probably or definitely related to study drugs over the course of the 28-day period after antimalarial therapy with artemether-lumefantrine (AL).	28 days after antimalarial therapy
Incidence-density of Malaria Defined as the Number of Incident Episodes of Complicated Malaria Per Time at Risk.		Time from randomization to at least 24 months of follow up or until end of the study
Estimates of the 6-month Risk of a First Episode of Malaria	To assess the effect of ART independently of potential interactions with antimalarial therapy after treatment for malaria, we compared the two groups with respect to the time to the first episode of malaria. Cumulative risk was estimated using the Kaplan-Meier product-limit formula.	Enrollment to 6 months follow up
28-day Risk of Recurrent Parasitemia	To assess the effect of potential interactions between ART and artemether-lumefantrine, the risks of recurrent parasitemia at 28 days were compared between the two groups.	28 days after antimalarial therapy
63-day Risk of Recurrent Malaria	To assess the effect of potential interactions between ART and artemether-lumefantrine, the risks of recurrent malaria at 63 days were compared between the two groups.	28 days after antimalarial therapy

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Grant Dorsey, MD, PhD, University of California, San Francisco; Study Director: Diane V Havlir, MD, University of California, San Francisco; Principal Investigator: Moses R Kamya MBChB, MMed, MPH, Makerere University; Principal Investigator: Ted Ruel, MD, University of California, San Francisco; Principal Investigator: Jane Achan, MBChB, MPed, Makerere University

Publications and helpful links

General Publications

• Achan J, Kakuru A, Ikilezi G, Ruel T, Clark TD, Nsanzabana C, Charlebois E, Aweeka F, Dorsey G, Rosenthal PJ, Havlir D, Kamya MR. Antiretroviral agents and prevention of malaria in HIV-infected Ugandan children. N Engl J Med. 2012 Nov 29;367(22):2110-8. doi: 10.1056/NEJMoa1200501.
• Ikilezi G, Achan J, Kakuru A, Ruel T, Charlebois E, Clark TD, Rosenthal PJ, Havlir D, Kamya MR, Dorsey G. Prevalence of asymptomatic parasitemia and gametocytemia among HIV-infected Ugandan children randomized to receive different antiretroviral therapies. Am J Trop Med Hyg. 2013 Apr;88(4):744-6. doi: 10.4269/ajtmh.12-0658. Epub 2013 Jan 28.
• 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.
• Ruel TD, Kakuru A, Ikilezi G, Mwangwa F, Dorsey G, Rosenthal PJ, Charlebois E, Havlir D, Kamya M, Achan J. Virologic and immunologic outcomes of HIV-infected Ugandan children randomized to lopinavir/ritonavir or nonnucleoside reverse transcriptase inhibitor therapy. J Acquir Immune Defic Syndr. 2014 Apr 15;65(5):535-41. doi: 10.1097/QAI.0000000000000071.
• Kakuru A, Achan J, Muhindo MK, Ikilezi G, Arinaitwe E, Mwangwa F, Ruel T, Clark TD, Charlebois E, Rosenthal PJ, Havlir D, Kamya MR, Tappero JW, Dorsey G. Artemisinin-based combination therapies are efficacious and safe for treatment of uncomplicated malaria in HIV-infected Ugandan children. Clin Infect Dis. 2014 Aug 1;59(3):446-53. doi: 10.1093/cid/ciu286. Epub 2014 Apr 23.
• Bartelink IH, Savic RM, Dorsey G, Ruel T, Gingrich D, Scherpbier HJ, Capparelli E, Jullien V, Young SL, Achan J, Plenty A, Charlebois E, Kamya M, Havlir D, Aweeka F. The effect of malnutrition on the pharmacokinetics and virologic outcomes of lopinavir, efavirenz and nevirapine in food insecure HIV-infected children in Tororo, Uganda. Pediatr Infect Dis J. 2015 Mar;34(3):e63-70. doi: 10.1097/INF.0000000000000603.
• Achan J, Kakuru A, Ikilezi G, Mwangwa F, Plenty A, Charlebois E, Young S, Havlir D, Kamya M, Ruel T. Growth Recovery Among HIV-infected Children Randomized to Lopinavir/Ritonavir or NNRTI-based Antiretroviral Therapy. Pediatr Infect Dis J. 2016 Dec;35(12):1329-1332. doi: 10.1097/INF.0000000000001318.
• Bangirana P, Ruel TD, Boivin MJ, Pillai SK, Giron LB, Sikorskii A, Banik A, Achan J. Absence of neurocognitive disadvantage associated with paediatric HIV subtype A infection in children on antiretroviral therapy. J Int AIDS Soc. 2017 Oct;20(2):e25015. doi: 10.1002/jia2.25015.

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): January 1, 2013
• Study Completion (Actual): January 1, 2013

Study Registration Dates

• First Submitted: September 14, 2009
• First Submitted That Met QC Criteria: September 15, 2009
• First Posted (Estimate): September 16, 2009

Study Record Updates

• Last Update Posted (Actual): December 28, 2018
• Last Update Submitted That Met QC Criteria: December 5, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: Nevirapine; HIV; Stavudine; Lamivudine; Malaria; Efavirenz; Zidovudine; Uganda; Lopinavir/ritonavir; Pediatric HIV
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Protease Inhibitors; Viral Protease Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Nevirapine; Ritonavir; Lopinavir; Reverse Transcriptase Inhibitors; Efavirenz
• Other Study ID Numbers: H5747-34097; NIH PO1 HD059454; 2009-114 (Other Identifier: Makerere Univ Fac of Med Research and Ethics Committee); HS-620 (Other Identifier: Uganda National Council for Science and Tech); 551/ESR/NDA/DID-08/09 (Other Identifier: Uganda National Drug Authority); H5741-34097 and 10-00991 (Other Identifier: UCSF Committee on Human Research)