HIV Protease Inhibitors for the Prevention of Malaria in Ugandan Children

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

176 participants

Study Classification

INTERVENTIONAL

Study Start Date

2009-09-30

Study Completion Date

2013-01-31

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Malaria HIV Infections

Keywords

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Pediatric HIV Malaria Uganda Nevirapine Zidovudine Lamivudine Lopinavir/ritonavir Stavudine Efavirenz HIV

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

NONE

Study Groups

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Lopinavir/ritonavir (LPV/r) +2 NRTI

Lopinavir/ritonavir (LPV/r) +2 nucleoside reverse transcriptase inhibitor (NRTI)

Group Type ACTIVE_COMPARATOR

Lopinavir/Ritonavir (LPV/r)

Intervention Type DRUG

2 nucleoside reverse transcriptase inhibitor (NRTI)

Intervention Type DRUG

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.

Nevirapine (NVP) or Efavirenz (EFV) +2 NRTI

Nevirapine (NVP) or Efavirenz (EFV) +2 nucleoside reverse transcriptase inhibitor (NRTI)

Group Type ACTIVE_COMPARATOR

Nevirapine (NVP)

Intervention Type DRUG

NVP will be used for children \< 3 years of age

Efavirenz (EFV)

Intervention Type DRUG

EFV for children ≥3 years of age

2 nucleoside reverse transcriptase inhibitor (NRTI)

Intervention Type DRUG

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.

Interventions

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Lopinavir/Ritonavir (LPV/r)

Intervention Type DRUG

Nevirapine (NVP)

NVP will be used for children \< 3 years of age

Intervention Type DRUG

Efavirenz (EFV)

EFV for children ≥3 years of age

Intervention Type 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.

Intervention Type DRUG

Other Intervention Names

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Aluvia

Eligibility Criteria

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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

Minimum Eligible Age

2 Months

Maximum Eligible Age

10 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Diane V Havlir, MD

Role: STUDY_DIRECTOR

University of California, San Francisco

Moses R Kamya MBChB, MMed, MPH

Role: PRINCIPAL_INVESTIGATOR

Makerere University

Grant Dorsey, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Ted Ruel, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Jane Achan, MBChB, MPed

Role: PRINCIPAL_INVESTIGATOR

Makerere University

Locations

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IDRC - Tororo Research Clinic

Tororo, , Uganda

Site Status

Countries

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Uganda

References

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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.

Reference Type RESULT

PMID: 23190222 (View on PubMed)

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.

Reference Type RESULT

PMID: 23358639 (View on PubMed)

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.

Reference Type RESULT

PMID: 21876053 (View on PubMed)

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.

Reference Type RESULT

PMID: 24326597 (View on PubMed)

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.

Reference Type RESULT

PMID: 24759826 (View on PubMed)

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.

Reference Type RESULT

PMID: 25742090 (View on PubMed)

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.

Reference Type RESULT

PMID: 27580060 (View on PubMed)

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.

Reference Type DERIVED

PMID: 29052340 (View on PubMed)