Reduction of EArly mortaLITY in HIV-infected Adults and Children Starting Antiretroviral Therapy
- Conditions
- Human Immunodeficiency Virus
- Interventions
- Dietary Supplement: Ready to Use Supplementary Food
- Registration Number
- NCT01825031
- Lead Sponsor
- Anna Griffiths, MRC
- Brief Summary
A randomised controlled trial to investigate three methods to reduce early mortality in adults, adolescents and children aged 5 years or older starting antiretroviral therapy (ART) with severe immuno-deficiency. The three methods are:
(i) increasing the potency of ART with a 12 week induction period using 4 antiretroviral drugs from 3 classes
(ii) augmented prophylaxis against opportunistic/bacterial infections and helminths for 12 weeks
(iii) macronutrient intervention using ready-to-use supplementary food for 12 weeks.
- Detailed Description
REALITY is a open-label randomised trial of 1800 adults, adolescents and children aged 5 years or more with low CD4 counts about to initiate ART.
The trial will have a factorial design with 3 randomisations, each to address one of the potential approaches to reduce early mortality in adults and children initiating ART with low CD4, namely:
1. Raltegravir for 12 weeks from ART initiation in addition to 3 standard ART (3-drug 2-class) versus standard of care first-line 3-drug 2-class ART (choice according to national guidelines for ART initiation);
2. Immediate enhanced opportunistic infections (OI) prophylaxis with isoniazid/pyridoxine and cotrimoxazole, plus 12 weeks fluconazole, 5 days azithromycin and a single dose of albendazole versus cotrimoxazole prophylaxis alone for the first 12 weeks followed by isoniazid and any prophylaxis and/or treatment prescribed at screening
3. supplementation with Ready to Use Supplementary Food (RUSF) for 12 weeks versus standard of care nutritional support to those with poor nutritional status according to local guidelines.
All participants will receive cotrimoxazole throughout the trial.
The primary objective of the trial is to identify effective, safe and acceptable interventions to reduce early mortality (all-cause) in HIV-infected adults, adolescents, and older children (5 years or more) initiating ART.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1805
- Aged 5 years or older
- Documented HIV infection by HIV ELISA or HIV rapid test
- Naive to ART
- CD4 T-cell count <100 cells/mm3 on blood test taken at screening for REALITY
- Results of screening haematology and biochemistry tests available and no contraindications to planned ART according to national guidelines
- Patient/carer provide informed consent (and children <18 years assent, as appropriate according to their age and knowledge of HIV status)
The lower age limit is because CD4 counts are less reliable predictors of immunodeficiency under 5 years: CD4 counts are recommended by guidelines in older children.
No patient with a CD4 count above 100 cells/mm3 should have ART delayed in order to subsequently meet eligibility criteria. Rather, patients eligible for REALITY will be those testing HIV positive for the first time with a low CD4 count (i.e. those delaying presentation to care), or those who have defaulted before initiating ART and only return to care at an advanced stage of immuno-deficiency.
- Contraindications to any proposed antiretroviral drugs (including integrase inhibitors), isoniazid, fluconazole, albendazole or azithromycin
- Pregnant or breastfeeding or intending to become pregnant during the first 12 weeks of the study
- Ever known to have previously received single-dose nevirapine for prevention of mother-to-child transmission (mother or child).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- FACTORIAL
- Arm && Interventions
Group Intervention Description Nutritional Support Ready to Use Supplementary Food Supplementation with Ready to Use Supplementary Food (RUSF) for 12 weeks compared with supplementation for those with severe malnutrition as local practice. Opportunistic Infection (OI) Prophylaxis Fluconazole Immediate isoniazid/pyridoxine and cotrimoxazole, plus 12 weeks fluconazole, 5 days azithromycin and a single dose of albendazole compared with immediate cotrimoxazole (if not already taking this) in all patients plus (not malawi)isoniazid/pyridoxine after 12 weeks. Opportunistic Infection (OI) Prophylaxis Albendazole Immediate isoniazid/pyridoxine and cotrimoxazole, plus 12 weeks fluconazole, 5 days azithromycin and a single dose of albendazole compared with immediate cotrimoxazole (if not already taking this) in all patients plus (not malawi)isoniazid/pyridoxine after 12 weeks. Opportunistic Infection (OI) Prophylaxis Azithromycin Immediate isoniazid/pyridoxine and cotrimoxazole, plus 12 weeks fluconazole, 5 days azithromycin and a single dose of albendazole compared with immediate cotrimoxazole (if not already taking this) in all patients plus (not malawi)isoniazid/pyridoxine after 12 weeks. Antiretroviral Therapy Raltegravir Raltegravir twice daily for 12 weeks from antiretroviral therapy (ART) initiation in addition to 3 standard ARVs (2NRTIs/1NNRTI) compared with 3 standard ARVs Opportunistic Infection (OI) Prophylaxis Isoniazid Immediate isoniazid/pyridoxine and cotrimoxazole, plus 12 weeks fluconazole, 5 days azithromycin and a single dose of albendazole compared with immediate cotrimoxazole (if not already taking this) in all patients plus (not malawi)isoniazid/pyridoxine after 12 weeks.
- Primary Outcome Measures
Name Time Method All-cause mortality over the first 24 weeks after starting ART Week 24
- Secondary Outcome Measures
Name Time Method Safety Week 0-48 * serious adverse events
* grade 4 adverse events
* adverse events leading to modification of ART or other study drugsHospital inpatient episodes and total days admitted Week 0-48 Adherence to ART and acceptability of each strategy Week 0-48 Adherence to ART, OI drugs and RUSF will be assessed in all participants at each visit by pill counts and short nurse-administered questions. Every 12 weeks, a more detailed adherence questionnaire will be adminstered.
Endpoint relating to anti-malnutrition intervention 0-48 weeks BMI, weight and body fat assessed by bioimpedance analysis (BIA), height (in children) and grip strength
Endpoint relating to anti-infection intervention 0-48 weeks Incidence of tuberculosis (TB), cryptococcal and candida disease, severe bacterial infections
Endpoint relating to anti-HIV intervention 0-48 weeks Changes in CD4 cell count
48 week mortality (all-cause) Week 48
Trial Locations
- Locations (8)
Joint Clinical Research Centre, Mbale
🇺🇬Mbale, Uganda
Moi University Clinical Research Centre
🇰🇪Eldoret, Kenya
KEMRI Wellcome Trust Research Programme
🇰🇪Kilifi, Kenya
University of Zimbabwe Clinical Research Centre
🇿🇼Harare, Zimbabwe
Joint Clinical Research Centre, Mbarara
🇺🇬Mbarara, Uganda
Joint Clinical Research Centre, Fort Portal
🇺🇬Fort Portal, Uganda
Joint Clinical Research Centre, Gulu
🇺🇬Gulu, Uganda
University of Malawi
🇲🇼Blantyre, Malawi