Clinical trial NCT01825031: Reduction of EArly mortaLITY in HIV-infected Adults and Children Starting Antiretroviral Therapy
Official title: Reduction of Early mortALITY in HIV-infected African Adults and Children Starting Antiretroviral Therapy: a Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Human Immunodeficiency Virus
Keywords: HIV
Lead sponsor: Medical Research Council
Sponsor class: OTHER_GOV
Collaborators: name: Department for International Development, United Kingdom
name: Wellcome Trust
name: Medical Research Council
name: PENTA Foundation
First posted: 2013-04-05
Enrollment: 1805
Sex: ALL
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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).

Primary outcomes:
measure: All-cause mortality over the first 24 weeks after starting ART
timeFrame: Week 24
Secondary outcomes:
measure: 48 week mortality (all-cause)
timeFrame: Week 48
measure: Safety
timeFrame: Week 0-48
measure: Hospital inpatient episodes and total days admitted
timeFrame: Week 0-48
measure: Adherence to ART and acceptability of each strategy
timeFrame: Week 0-48
measure: Endpoint relating to anti-infection intervention
timeFrame: 0-48 weeks
measure: Endpoint relating to anti-malnutrition intervention
timeFrame: 0-48 weeks
measure: Endpoint relating to anti-HIV intervention
timeFrame: 0-48 weeks
Other outcomes:
Locations:
city: Eldoret
country: Kenya
facility: Moi University Clinical Research Centre
city: Kilifi
country: Kenya
facility: KEMRI Wellcome Trust Research Programme
city: Blantyre
country: Malawi
facility: University of Malawi
city: Fort Portal
country: Uganda
facility: Joint Clinical Research Centre, Fort Portal
city: Gulu
country: Uganda
facility: Joint Clinical Research Centre, Gulu
city: Mbale
country: Uganda
facility: Joint Clinical Research Centre, Mbale
city: Mbarara
country: Uganda
facility: Joint Clinical Research Centre, Mbarara
city: Harare
country: Zimbabwe
facility: University of Zimbabwe Clinical Research Centre
Study officials:
affiliation: Medical Research Council
name: Diana M Gibb
role: STUDY_DIRECTOR
References:
citation: Kelly C, Tinago W, Alber D, Hunter P, Luckhurst N, Connolly J, Arrigoni F, Garcia Abner A, Kamn'gona R, Sheha I, Chammudzi M, Jambo K, Mallewa J, Rapala A, Mallon PWG, Mwandumba H, Klein N, Khoo S. Inflammatory pathways amongst people living with HIV in Malawi differ according to socioeconomic status. PLoS One. 2021 Aug 25;16(8):e0256576. doi: 10.1371/journal.pone.0256576. eCollection 2021.
citation: Kelly C, Tinago W, Alber D, Hunter P, Luckhurst N, Connolly J, Arrigoni F, Abner AG, Kamngona R, Sheha I, Chammudzi M, Jambo K, Mallewa J, Rapala A, Heyderman RS, Mallon PWG, Mwandumba H, Walker AS, Klein N, Khoo S. Inflammatory Phenotypes Predict Changes in Arterial Stiffness Following Antiretroviral Therapy Initiation. Clin Infect Dis. 2020 Dec 3;71(9):2389-2397. doi: 10.1093/cid/ciaa186.
citation: Kityo C, Szubert AJ, Siika A, Heyderman R, Bwakura-Dangarembizi M, Lugemwa A, Mwaringa S, Griffiths A, Nkanya I, Kabahenda S, Wachira S, Musoro G, Rajapakse C, Etyang T, Abach J, Spyer MJ, Wavamunno P, Nyondo-Mipando L, Chidziva E, Nathoo K, Klein N, Hakim J, Gibb DM, Walker AS, Pett SL; REALITY trial team. Raltegravir-intensified initial antiretroviral therapy in advanced HIV disease in Africa: A randomised controlled trial. PLoS Med. 2018 Dec 4;15(12):e1002706. doi: 10.1371/journal.pmed.1002706. eCollection 2018 Dec.
citation: Mallewa J, Szubert AJ, Mugyenyi P, Chidziva E, Thomason MJ, Chepkorir P, Abongomera G, Baleeta K, Etyang A, Warambwa C, Melly B, Mudzingwa S, Kelly C, Agutu C, Wilkes H, Nkomani S, Musiime V, Lugemwa A, Pett SL, Bwakura-Dangarembizi M, Prendergast AJ, Gibb DM, Walker AS, Berkley JA; REALITY trial team. Effect of ready-to-use supplementary food on mortality in severely immunocompromised HIV-infected individuals in Africa initiating antiretroviral therapy (REALITY): an open-label, parallel-group, randomised controlled trial. Lancet HIV. 2018 May;5(5):e231-e240. doi: 10.1016/S2352-3018(18)30038-9. Epub 2018 Apr 10.