Reduction of Early mortaLITY in HIV-infected African adults and children starting antiretroviral therapy: REALITY trial

Lead Research Organisation: University College London

Abstract

The risk of dying AFTER starting treatment with antiretrovirals(ARVs) is about 7 times higher among HIV-infected adults and children in Africa than in developed countries, particularly if immunity is poor (low CD4 cell counts), because such people often harbour infections like tuberculosis and bacterial infections which show themselves when ARVs are started and immunity improves. The question about how to reduce high early death rates when people start ARVs has been identified by doctors and the African HIV community as being very important. In the REALITY trial, we will test 3 different ways to reduce high early death rates in 1200 adults and 600 children aged 5-12 years starting ARVs with CD4 cell counts less than 100 from 4 African countries (Uganda, Kenya, Zimbabwe, Malawi). Each approach will be compared with a standard approach (like doing 3 trials in one) and we will also be able to see if all approaches can provide additional benefits if used together in a package. The questions are whether any of the following reduce the risk of early death after starting ARVs:(1)using stronger ARVs(4 instead of 3 ARVs)for the first 3 months;(2)giving preventative treatment(prophylaxis)against life-threatening infections (e.g.tuberculosis, bacterial infections, cryptococcal meningitis) for 3 months after starting ARVs; (3) giving extra food to everyone (not just those with malnutrition) for 3 months; this might also help people take their ARVs as we know many get very hungry after starting ARVs. Adults and children over 5 years will be invited to join REALITY, and if they consent, at the time of starting ARVs, they will be given either the new approach or standard of care for each of the 3 questions. This will be done at random, like tossing a coin, but by a computer. All participants will be followed for at least one year to see how well they do, as well as to find out how acceptable these extra approaches are and whether there are any side effects. We will also measure whether these new approaches are cost effective to be rolled out in Africa. Adults and children are treated together in ARV clinics across Africa and have similar HIV progression and early death rates on ARVs: including adults and children aged over 5 years in the same integrated research study will provide the most relevant answers to improve the care of future patients.

Technical Summary

REALITY is an open-label randomised trial of 1800 adults, adolescents and children (600 aged 5-12 years) with low CD4 counts (!U100 cells/mm3) initiating antiretroviral therapy(ART), to be enrolled over 18 months and followed for 48 weeks in centres in 4 African countries (Uganda, Kenya, Zimbabwe, Malawi). The trial will simultaneously evaluate three potential interventions to reduce early mortality following ART initiation using a 2X2X2 factorial design: (i) increasing ART potency with 12-weeks induction using 4 antiretroviral drugs from 3 classes; (ii) augmented early prophylaxis against opportunistic and bacterial infections and helminths (5 days azithromycin, plus fluconazole, antihelminthic and isoniazid prophylaxis at ART initiation in addition to cotrimoxazole (for all); (iii) macronutrient intervention using ready-to-use food for 12 weeks to all (rather than only to those with malnutrition). Randomisation will be open for logistical reasons and because a key objective is to identify the acceptability of enhanced interventions around ART initiation which would not be possible using placebo pills. Use of an objective endpoint (mortality) will minimise potential bias. A major reason for including all three approaches in the same trial is efficiency: each targets a different mechanism and therefore running one large trial addressing all three questions rather than three large trials separately is more efficient. Furthermore, by using a factorial design in a large trial, interactions between interventions can be identified and the relative contribution of each explored; this has been allowed for in the sample size calculations. The design is pragmatic, aiming to recruit those as typical as possible of future late presenting patients, and treat them with practical interventions which could be implemented in ART rollout programs in Africa. Inclusion criteria are therefore broad, and prophylaxis and nutritional control groups are based on standard of care in national guidelines. We justify inclusion of children !Y5 years because the criteria for starting ART and risk factors for progression are the same as for young adults (in contrast to younger children) and early mortality following ART initiation and spectrum of causes of death overlap considerably (data from joint analysis of DART and ARROW trials); toxicity and tolerability can be addressed with inclusion of 600 children. The inclusion of children also adds to the efficiency and value for money of the trial as well as promoting family-based approaches to care and treatment. Key further areas will include economics and social science, as well as separately funded pharmacokinetic and diagnostic substudies.

Publications

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Description ICASA 2015 - Intenational Conference on AIDS and STIs in Africa. Oral presentation. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Oral presentation; abstract Title: Sulfamethoxazole/Trimethoprim/Isoniazid/Pyridoxine scored tablets are bioequivalent to individual products and are acceptable to patients with advanced HIV infection in the REALITY trial

Authors: Bwakura-Dangarembizi M2, Gibb DM1, Abhyankar D9, Agutu C3, Lugemwa A4, Abongomera G5, Miranda S6, Musiime V7, Mallewa J8, Siika A11, Baleeta K12, Mehta V9, Malhotra G9, Griffiths A1, Kityo C10, Maitland K3, Chidziva E2, Chepkorir P11, Szubert AJ1, Gogtay J9, Hakim J2 and the REALITY Trial Team

Background Patients initiating ART with low CD4 counts benefit from isoniazid and cotrimoxazole prophylaxis, but these increase pill burden; stockouts of single formulations are also common.
Methods: Sulfamethoxazole/Trimethoprim/Isoniazid/Pyridoxine (800/160/300/25mg) fixed-dose-combination (FDC) scored tablets (Cipla , India) were compared with Septrin®Forte (sulfamethoxazole-800mg/trimethoprim-160mg (GlaxoWellcome)) and Isoniazid-300mg (Sandoz) separate tablets in 28 healthy volunteers (18male; 10female) in an open-label, randomized, single-dose, two-treatment, two-period, 26-sample crossover pharmacokinetic bioequivalent study. Acceptability and adherence questionnaire data were collected in the ongoing, 2x2x2 factorial, REALITY randomised trial evaluating enhanced OI prophylaxis, 4-drug ART and enhanced nutrition for 12 weeks after ART initiation, in 1805 African adults/children(=5years) with CD4 <100cells/mm3. Within-individual data on FDC (weeks 12-24) vs cotrimoxazole alone (weeks 0-12) were compared in 319 patients; and in weeks 0-12 among those receiving FDC+fluconazole (for prophylaxis against cryptococcal disease) (n=543) vs cotrimoxazole (n=604).
Results: Geometric mean test-to-reference ratios for sulfamethoxazole (AUC: 99.8% (90% CI 96.2%-103.5%) and Cmax: 103.2%(99.5%-107.0%)), trimethoprim (97.2%(93.7-100.9)%; 98.2%(93.4-103.3)%) and isoniazid 103.8%(99.5-108.3); 104.3%(95.1-114.4)) were well within required 80-125% range. In REALITY, acceptability was similar between FDC (12-24 weeks) and cotrimoxazole (0-12 weeks): 99.7% vs 99.4% reported none/not much daily-life interference; 95.6% vs 96.6% reported drugs were very easy/easy to take. Comparing groups (0-12 weeks) gave similar results: 500/543(92.1%) vs 565/604(93.5%),(p=0.8) reported taking medication was very easy/easy; 4.0% vs 3.9% reported missing =1 dose.
Conclusions: Sulfamethoxazole/Trimethoprim/Isoniazid/Pyridoxine FDC tablets are bioequivalent to individual drugs (data submitted for WHO prequalification). They are acceptable, reduce pill burden and could improve adherence, in addition to simplifying drug distribution for programmes.
Year(s) Of Engagement Activity 2015
URL http://icasa2015zimbabwe.org/
 
Description The 46th Union World Conference on Lung Health, Cape Town, 2-6 December 2015. Oral Presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Abstract Title: Sulfamethoxazole/Trimethoprim/Isoniazid/Pyridoxine scored tablets are bioequivalent to individual products and are acceptable to patients with advanced HIV infection in the REALITY trial
Authors: Gibb DM1, Bwakura-Dangarembizi M2, Abhyankar D9, Szubert AJ1, Agutu C3, Lugemwa A4, Abach J5, Kemigisa M6, Mallewa J8, Siika A10, Mukuye A11, Mehta V9, Malhotra G9, Nambi E10, Thomason M1, Pett S1, Berkley J3, Meli B10, Kityo C7, Nathoo K2, Musiime V7, Walker AS1, Gogtay J9 and the REALITY Trial Team
Affiliations: 1MRC Clinical Trials Unit at UCL, London, UK; 2University of Zimbabwe, Harare, Zimbabwe; 3KEMRI Wellcome Trust Research Programme, Kilifi, Kenya; 4Joint Clinical Research Centre, Mbarara, Uganda; 5Joint Clinical Research Centre, Gulu, Uganda; 6Joint Clinical Research Centre, Fort Portal, Uganda; 7Joint Clinical Research Centre, Kampala, Uganda and Makerere University College of Health Sciences, Kampala, Uganda; 8University of Malawi, Blantyre, Malawi; 9Cipla Ltd., Mumbai, India; 10 Moi University Clinical Research Centre, Eldoret, Kenya, 11Joint Clinical Research Centre, Mbale, Uganda
Background: HIV-infected patients initiating antiretroviral therapy (ART) with low CD4 counts particularly benefit from OI and anti-tuberculosis prophylaxis. However, individual drug formulations of isoniazid and cotrimoxazole add to the pill burden of ART and adherence difficulties early in treatment when mortality is highest; stockouts are also frequent in low-resource settings.
Methods: Sulfamethoxazole/Trimethoprim/Isoniazid/Pyridoxine (800/160/300/25mg) fixed-dose-combination (FDC) scored tablets, made by Cipla, India, were evaluated for bioequivalence vs separate tablets of Septrin®Forte (sulfamethoxazole-800mg/trimethoprim-160mg (GlaxoWellcome)) and Isoniazid-300mg (Sandoz) in an open-label, randomized, single-dose, two-treatment, two-period, 26-sample crossover pharmacokinetic study. Acceptability and adherence questionnaire data were collected in the ongoing, 2x2x2 factorial, REALITY randomised trial evaluating 12-week enhanced OI prophylaxis, 4-drug ART and enhanced nutrition in 1805 African adults/children (=5years) with CD4 <100cells/mm3. Within-individual data on FDC (weeks 12-24) vs cotrimoxazole alone (weeks 0-12) were compared in 319 patients; and in weeks 0-12 among those receiving FDC+fluconazole (for prophylaxis against cryptococcal disease) (n=543) vs cotrimoxazole (n=604).
Results: Among 28 fasting healthy subjects (18 male; 10 female; Mean(range) age 31(18-45)years; BMI 25.1+2.9), geometric mean test-to-reference ratios for sulfamethoxazole (AUC: 99.8% (90% CI 96.2%-103.5%) and Cmax: 103.2%(99.5%-107.0%)), trimethoprim (97.2%(93.7-100.9)%; 98.2%(93.4-103.3)%) and isoniazid 103.8%(99.5-108.3); 104.3%(95.1-114.4)) were well within required 80-125% range. In REALITY, no within-individual differences in acceptability were reported between FDC (12-24 weeks) vs cotrimoxazole (0-12 weeks): 99.7% vs 99.4% reported none/not much interference with everyday life and 95.6% vs 96.6% reported drugs were very easy/easy to take. Comparing groups over 0-12 weeks gave similar results: 500/543(92.1%) vs 565/604(93.5%) (p=0.8) reported taking medication was very easy/easy; 4.0% vs 3.9% reported missing =1 dose.
Conclusions: Sulfamethoxazole/Trimethoprim/Isoniazid/Pyridoxine scored FDC tablets are bioequivalent to individual drugs; data have been submitted for WHO prequalification. They are acceptable, reduce pill burden and could improve adherence for adults/children =5 years, in addition to simplifying drug distribution for HIV programmes.
Year(s) Of Engagement Activity 2015
URL http://capetown.worldlunghealth.org/