HIV Protease Inhibitors for the Prevention of Malaria in Ugandan Children
Condition: Malaria; HIV Infections
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 3

Summary: 
      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: 
      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.
    

Intervention name(s): Lopinavir/Ritonavir (LPV/r); Nevirapine (NVP); Efavirenz (EFV); 2 nucleoside reverse transcriptase inhibitor (NRTI)
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): NVP will be used for children < 3 years of age; EFV for children ≥3 years of age; 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.
Other intervention name(s): Aluvia
Intervention MeSH terms: Ritonavir; Lopinavir; Nevirapine; Efavirenz; Reverse Transcriptase Inhibitors
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Pediatric HIV; Malaria; Uganda; Nevirapine; Zidovudine; Lamivudine; Lopinavir/ritonavir; Stavudine; Efavirenz; HIV