Reduction of EArly mortaLITY in HIV-infected Adults and Children Starting Antiretroviral Therapy

Study Overview
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Brief Summary
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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
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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: 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); 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 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.

Official Title
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Reduction of Early mortALITY in HIV-infected African Adults and Children Starting Antiretroviral Therapy: a Randomised Controlled Trial

Conditions
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Human Immunodeficiency Virus

Intervention / Treatment
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* Drug: Raltegravir
* Drug: Fluconazole
* Drug: Azithromycin
* Drug: Albendazole
* Drug: Isoniazid
* Dietary Supplement: Ready to Use Supplementary Food


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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).

Ages Eligible for Study
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Minimum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Antiretroviral Therapy<br>Raltegravir twice daily for 12 weeks from antiretroviral therapy (ART) initiation in addition to 3 standard ARVs (2NRTIs/1NNRTI) compared with 3 standard ARVs | Drug: Raltegravir<br>* 400mg twice daily for the first 12 weeks only in addition to 3 standard ARVs<br>|
| Experimental: Opportunistic Infection (OI) Prophylaxis<br>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. | Drug: Fluconazole<br>* 100mg once daily for 12 weeks<br>Drug: Azithromycin<br>* 500mg once daily for 5 days<br>Drug: Albendazole<br>* a single dose 400mg<br>Drug: Isoniazid<br>* 300mg taken immediately in combination with cotrimoxazole<br>|
| Experimental: Nutritional Support<br>Supplementation with Ready to Use Supplementary Food (RUSF) for 12 weeks compared with supplementation for those with severe malnutrition as local practice. | Dietary Supplement: Ready to Use Supplementary Food<br>* 2x92g packets daily of high energy, low protein lipid-based paste for 12 weeks<br>* Other names: RUSF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality over the first 24 weeks after starting ART |  | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 48 week mortality (all-cause) |  | Week 48 | 
| Safety | serious adverse events grade 4 adverse events adverse events leading to modification of ART or other study drugs | Week 0-48 | 
| Hospital inpatient episodes and total days admitted |  | Week 0-48 | 
| Adherence to ART and acceptability of each strategy | 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. | Week 0-48 | 
| Endpoint relating to anti-infection intervention | Incidence of tuberculosis (TB), cryptococcal and candida disease, severe bacterial infections | 0-48 weeks | 
| Endpoint relating to anti-malnutrition intervention | BMI, weight and body fat assessed by bioimpedance analysis (BIA), height (in children) and grip strength | 0-48 weeks | 
| Endpoint relating to anti-HIV intervention | Changes in CD4 cell count | 0-48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV