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

Anna Griffiths, MRC

Status and phase: Completed; Phase 3

Conditions: Human Immunodeficiency Virus

Treatments: Drug: Isoniazid; Drug: Azithromycin; Drug: Albendazole; Drug: Fluconazole; Dietary Supplement: Ready to Use Supplementary Food; Drug: Raltegravir

Study type: Interventional

Funder types: Other; NETWORK

Identifiers

NCT01825031

ISRCTN43622374

Details and patient eligibility

About

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.

Full 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.

Enrollment: 1,805 patients

Sex: All

Ages: 5+ years old

Volunteers: No Healthy Volunteers

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).

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: None (Open label)

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1,805 participants in 3 patient groups

Antiretroviral Therapy

Experimental group

Description:

Raltegravir twice daily for 12 weeks from antiretroviral therapy (ART) initiation in addition to 3 standard ARVs (2NRTIs/1NNRTI) compared with 3 standard ARVs

Treatment:

Drug: Raltegravir

Opportunistic Infection (OI) Prophylaxis

Experimental group

Description:

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.

Treatment:

Drug: Albendazole

Drug: Isoniazid

Drug: Azithromycin

Drug: Fluconazole

Nutritional Support

Experimental group

Description:

Supplementation with Ready to Use Supplementary Food (RUSF) for 12 weeks compared with supplementation for those with severe malnutrition as local practice.

Treatment:

Dietary Supplement: Ready to Use Supplementary Food