HIV Protease Inhibitors for the Prevention of Malaria in Ugandan Children

Study Overview
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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.

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

Conditions
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Malaria, HIV Infections

Intervention / Treatment
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* Drug: Lopinavir/Ritonavir (LPV/r)
* Drug: Nevirapine (NVP)
* Drug: Efavirenz (EFV)
* Drug: 2 nucleoside reverse transcriptase inhibitor (NRTI)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Age 2 months to < 11 years 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 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 Agreement to come to the study clinic for any febrile episode or other illness Agreement to avoid medications administered outside study protocol Provision of informed consent by parent/guardian and agreement to have child's care at the clinical site Lives within 50 km of study site Exclusion criteria: ART-naïve children: children or their mothers that have received any dose of Nevirapine in the past 24 months Active medical problem requiring in-patient evaluation at the time of screening or enrollment History of cardiac conduction disorder or known significant cardiac structural defect Children receiving any disallowed medications (see section 4.3) 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) 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

Ages Eligible for Study
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Minimum Age: 2 Months
Maximum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lopinavir/ritonavir (LPV/r) +2 NRTI<br>Lopinavir/ritonavir (LPV/r) +2 nucleoside reverse transcriptase inhibitor (NRTI) | Drug: Lopinavir/Ritonavir (LPV/r)<br> <br> * Other names: Aluvia;Drug: 2 nucleoside reverse transcriptase inhibitor (NRTI)<br>* 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.<br>|
| Active Comparator: Nevirapine (NVP) or Efavirenz (EFV) +2 NRTI<br>Nevirapine (NVP) or Efavirenz (EFV) +2 nucleoside reverse transcriptase inhibitor (NRTI) | Drug: Nevirapine (NVP)<br>* NVP will be used for children < 3 years of age<br>Drug: Efavirenz (EFV)<br>* EFV for children ≥3 years of age<br>Drug: 2 nucleoside reverse transcriptase inhibitor (NRTI)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Pediatric HIV, Malaria, Uganda, Nevirapine, Zidovudine, Lamivudine, Lopinavir/ritonavir, Stavudine, Efavirenz