Efficacy Study of Different Laboratory Management Strategies and Drug Regimens in HIV-infected Children in Africa
Condition: Human Immunodeficiency Virus
MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections
Intervention: Clinically Driven Monitoring (CDM); Laboratory plus Clinical Monitoring (LCM); Arm A: ABC+3TC+NNRTI; Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance; Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenance; Once-daily ABC+3TC; Twice-daily ABC+3TC; Continued cotrimoxazole prophylaxis; Stopped cotrimoxazole prophylaxis
Intervention description: Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.; Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.; Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.; Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.; Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.
Intervention MeSH terms: Lamivudine; Zidovudine; Efavirenz; Nevirapine; Abacavir; Dideoxynucleosides; Lamivudine, zidovudine drug combination; Trimethoprim; Sulfamethoxazole; Trimethoprim, Sulfamethoxazole Drug Combination
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Enrollment: 1206.0
Sex: All
Minimum age: 3 Months
Maximum age: 17 Years
Healthy volunteers: No
Keywords: HIV; Africa; children; antiretroviral therapy; laboratory monitoring; toxicity; CD4; induction maintenance; cotrimoxazole; prophylaxis; abacavir; lamivudine; once daily

Summary:

      The two original objectives were to determine in HIV-infected children initiating
      antiretroviral therapy (ART):

        1. Whether clinically driven monitoring (CDM) will have a similar outcome in terms of
           disease progression or death as routine laboratory and clinical monitoring (LCM) for
           toxicity (haematology/biochemistry) and efficacy (CD4)?

        2. Whether induction with four drugs from two ART classes followed by maintenance with
           three drugs after 36 weeks be more effective than a continuous non-nucleoside reverse
           transcriptase inhibitors (NNRTI)-based triple drug regimen in terms of CD4 and clinical
           outcome?

           Two secondary objectives were to determine

        3. Whether changing from twice daily lamivudine+abacavir to once daily lamivudine+abacavir
           after 48 weeks on ART will have a similar outcome in terms of virological suppression
           and will result in improvements in adherence to ART?

        4. Whether stopping daily cotrimoxazole prophylaxis in children over 3 years of age who
           have been on ART for at least 96 weeks has a similar outcome in terms of hospitalisation
           or death as continuing daily cotrimoxazole?
    

Eligibility criteria:

        For initial randomisation to CDM vs LCM, and to ART induction strategy:

        Inclusion Criteria:

          1. Children should have an adult carer in the household who is either:

               -  participating in the DART trial OR

               -  being treated with ART OR

               -  HIV positive but not yet needing treatment but with access to a treatment
                  programme when ART is required OR

               -  HIV negative. Children of DART participants should have first priority on any
                  available remaining slots to enter ARROW.

          2. Parents or guardians, and children where appropriate according to age and knowledge of
             HIV status, must be willing and able to give informed consent for randomisation to CDM
             or LCM and to first-line ART strategy.

          3. Participants must have a confirmed documented diagnosis of HIV-1 infection:

               1. For children aged under 18 months: two separate peripheral blood specimens from
                  different days, both results being positive with HIV-DNA polymerase chain
                  reaction (PCR).

               2. For children aged 18 months or over: antibody positive serology by ELISA test
                  (confirmed by licensed second ELISA or Western Blot) or WHO approved rapid test
                  (performed in series) both on the same sample. Any child previously tested at
                  another clinic should have a repeat test at an ARROW screening laboratory to
                  confirm their status.

          4. Age 3 months to 17 years (13-17 years to be capped at 10%)

          5. ART naïve (except for exposure to perinatal ART for the prevention of mother-to-child
             HIV transmission).

          6. Meeting criteria for requiring ART according to WHO stage and CD4 percent or count:

               -  WHO paediatric clinical stage IV disease: treat regardless of CD4 percent or
                  count

               -  WHO paediatric clinical stage III disease:

                    -  <12 months: treat all

                    -  >12 months: treat all children irrespective of the CD4 percent or count;
                       however, in children aged > 12 months with tuberculosis, lymphocytic
                       interstitial pneumonia (LIP), oral hairy leukoplakia (OHP) or
                       thrombocytopenia (low platelet count treat) be guided by CD4 cell assays
                       (see below).

               -  WHO paediatric clinical stage II or I disease: treat guided by CD4 percent or
                  count

                    -  CD4%<25% for infants <12 months;

                    -  CD4%<20% for children 1-<3 years;

                    -  CD4% <15% for children 3-<5years;

                    -  CD4% <15% for children > 5years (consideration should also be taken of the
                       CD4 count. A CD4 count <200 cells/mm3 can be used to guide starting ART and
                       CD4 should generally be <350 cells/mm3.)

        Exclusion Criteria:

          1. Cannot, or unlikely to attend regularly (e.g. usual residence too far from study
             centre)

          2. Likelihood of poor adherence

          3. Presence of acute infection (e.g. malaria, helminthiasis, acute hepatitis, acute
             pneumonia, septicaemia, meningitis). Children may be admitted after recovery of an
             acute infection. Children with chronic lung disease, including recurrent respiratory
             infections, are eligible. Children with tuberculosis (TB) will not be enrolled while
             on the intensive phase of anti-tuberculosis therapy, but should be re-evaluated after
             the intensive phase and a decision made then about starting ART (see 4 below)

          4. In receipt of medication contraindicated by ART

               -  children under three years of age receiving anti-tuberculosis therapy should not
                  be enrolled (as they will have to receive nevirapine).

               -  on chemotherapy for malignancy

          5. Laboratory abnormalities which are a contra-indication for the child to start ART
             (haemoglobin <8.5g/dL; neutrophils <0.50x109/L; aspartate transaminase (AST) or
             alanine transaminase (ALT) >5 x the upper limit of normal (ULN); grade 3 renal
             dysfunction - creatinine >1.9 x ULN).

             N.B. causes of anaemia, such as concurrent bacterial infection, malaria, helminthiasis
             and/or malnutrition should be investigated, and treatment for anaemia and its causes
             commenced prior to re-screening for eligibility.

          6. Being pregnant or breast-feeding an infant

          7. Perinatal exposure to nevirapine (either through prevention of mother-to-child
             transmission (pMTCT) or breastfeeding) for children aged 3 - 6 months only

        Eligibility criteria for the secondary randomisation to once vs twice daily
        lamivudine+abacavir Inclusion criteria

          1. Participating in ARROW

          2. On ART for at least 36 weeks

          3. Currently taking lamivudine+abacavir twice daily as part of their ART regimen and
             expected to stay on these two drugs for at least the next 12 weeks

          4. Parents or guardians, and children where appropriate according to age and knowledge of
             HIV status, must be willing and able to give informed consent for randomisation to
             once or twice daily lamivudine+abacavir

             Exclusion criteria

          5. Likely to switch to second-line therapy in the next 12 weeks

        Eligibility criteria for the secondary randomisation to stop or continue cotrimoxazole
        prophylaxis randomisation Inclusion criteria

          1. Participating in ARROW

          2. Aged at least 3 years

          3. Initiated ART at least 96 weeks previously, and received at least 96 weeks of ART
             allowing for any interruptions in ART

          4. Currently prescribed daily cotrimoxazole as primary prophylaxis

          5. Parents or guardians, and children where appropriate according to age and knowledge of
             HIV status, must be willing and able to give informed consent for randomisation to
             stop or continue daily cotrimoxazole prophylaxis

          6. If living in a malaria endemic area, has an insecticide treated bednet and prepared to
             use this for the child.

             Exclusion criteria

          7. Previous diagnosis of Pneumocystis jiroveci pneumonia (cotrimoxazole is secondary
             prophylaxis and should not be discontinued)