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
Study type: Interventional
Phase: Phase 4

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?
    

Detailed description: 
      The ARROW (AntiRetroviral Research fOr Watoto) protocol describes an open-label randomised
      trial primarily evaluating two strategic approaches for management of antiretroviral therapy
      (ART) in 1200 symptomatic HIV-infected infants and children initiating ART following WHO
      guidelines in Uganda and Zimbabwe. The first strategy compares clinically driven monitoring
      (CDM) with laboratory plus clinical monitoring (LCM). In both groups, tests for toxicity
      (standard haematology and biochemistry panels) and efficacy (lymphocyte subsets including CD4
      count) will be done every 12 weeks. In LCM, all results will be returned for patient
      management. In CDM, physicians may request results from routine haematology/biochemistry
      panels if needed for clinical management, but results will not be returned routinely, and
      lymphocyte subsets will never be returned. Extra laboratory tests may be requested outside of
      the scheduled visits at any time in either group (except for lymphocyte subsets in CDM). The
      second strategy compares a continuous WHO-recommended first-line ART three-drug two-class
      regimen, comprising two Nucleoside Reverse Transcriptase Inhibitors (NRTIs) plus one
      Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), with induction with four drugs (two
      classes) for 36 weeks followed by maintenance with three drugs. After at least 36 and 96
      weeks on ART respectively, two further randomisations will assess simplification strategies
      which could improve long-term ART adherence (i) once versus twice daily lamivudine+abacavir
      NRTI drugs (ii) stopping versus continuing daily cotrimoxazole prophylaxis.
    

Intervention name(s): 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 type(s): Other; Other; Drug; Drug; Drug; Drug; Drug; Drug; Other
Intervention description(s): 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.
Other intervention name(s): ABC: abacavir: Ziagen; 3TC: lamivudine: Epivir; ABC+3TC co-formulated: Kivexa; NVP: nevirapine, Viramune; EFV: efavirenz, Sustiva; ZDV: zidovudine, azidothymidine, Retrovir; ABC: abacavir: Ziagen; 3TC: lamivudine: Epivir; ZDV+3TC co-formulated: Combivir; ABC+3TC co-formulated: Kivexa; ZDV+ABC+3TC co-formulated: Trizivir; NVP: nevirapine, Viramune; EFV: efavirenz, Sustiva; ZDV: zidovudine, azidothymidine, Retrovir; ABC: abacavir: Ziagen; 3TC: lamivudine: Epivir; ZDV+3TC co-formulated: Combivir; ABC+3TC co-formulated: Kivexa; ZDV+ABC+3TC co-formulated: Trizivir; NVP: nevirapine, Viramune; EFV: efavirenz, Sustiva; ABC: abacavir: Ziagen; 3TC: lamivudine: Epivir; ABC+3TC co-formulated: Kivexa; ABC: abacavir: Ziagen; 3TC: lamivudine: Epivir; ABC+3TC co-formulated: Kivexa; trimethoprim+sulfamethoxazole
Intervention MeSH terms: Lamivudine; Zidovudine; Efavirenz; Nevirapine; Abacavir; Dideoxynucleosides; Lamivudine, zidovudine drug combination; Trimethoprim; Sulfamethoxazole; Trimethoprim, Sulfamethoxazole Drug Combination
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: HIV; Africa; children; antiretroviral therapy; laboratory monitoring; toxicity; CD4; induction maintenance; cotrimoxazole; prophylaxis; abacavir; lamivudine; once daily