The REALITY trial: cotrimoxazole/isoniazid/pyridoxine tablets are bioequivalent to individual products and are acceptable to participants

A new agenda: lung health beyond 2015Polly Clayden, HIV i-Base

Cotrimoxazole/isoniazid/pyridoxine (CTX/INH/B6) scored fixed dose combination (FDC) tablets are bioequivalent to individual drugs and are acceptable, reduce pill burden and could improve adherence for adults and children, according to results from the REALITY trial presented at the 46th World Conference on Lung Health of the International Union Against Tuberculosis and Lung Disease (The Union).

FDCs are used widely for treatment of HIV and TB, which help both patients and health systems. HIV positive people, starting ART with low CD4 counts benefit from opportunistic infection (OI) and anti-TB prophylaxis.

But individual drug formulations of isoniazid and cotrimoxazole increase the pill burden of ART and could lead to adherence difficulties early in treatment when mortality risk is high.

Cipla have made a scored generic CTX/INH/B6 (960/300/25 mg) tablet. The new FDC was first used in the REALITY trial. Diana Gibb presented data on bioequivalence and from an acceptability and adherence questionnaire on behalf of the trial group.

The investigators evaluated the FDC tablets for bioequivalence compared with separate tablets of sulfamethoxazole 800 mg/trimethoprim160 mg and isoniazid 300 mg in an open-label, randomised, single-dose, two treatment, two period, 26 sample crossover pharmacokinetic (PK) study.

The evaluation was in 28 fasting healthy participants (18 male and 10 female and found LSGM ratios well within required 80-125% range (and close to 100%) for all parameters. For sulfamethoxazole, trimethoprim and isoniazid respectively these values were: Cmax 103.2% (90% CI: 99.5 to 107.0); 98.2% (90% CI: 93.4 to103.9); and 104.3% (90% CI: 95.1 to 114.4): AUC0-t 99.8% (90% CI: 96.2 to 114.4); 97.2 (90% CI: 93.7 to 100.9); and 103.8 (90% CI: 99.5 to 108.3).

The REALITY trial is looking at reducing early mortality in HIV positive adults and children starting ART. The trial has a 2x2x2 factorial, randomised trial design evaluating 12-week enhanced OI prophylaxis, 4-drug ART and enhanced nutrition in 1800 African adults/children from 5 years of age with CD4 less than 100 cells/mm3.

The trial is ongoing and being conducted in nine centres in four countries: Kenya, Malawi, Uganda and Zimbabwe. Each intervention is given in addition to and compared with local standard of care for 12 weeks. The trial started in June 2013 and will finish in April 2016. The primary endpoint is mortality at 48 weeks.

Dr Gibb presented acceptability and adherence findings from the enhanced prophylaxis part of the trial. In this factorial, participants are randomised to receive the CTX/INH/B6 FDC and fluconazole, plus five days azithromycin and single dose albendazole vs standard cotrimoxazole prophylaxis and isoniazid added from 12 weeks (except in Malawi, as this is not in guidelines).

An acceptability/adherence questionnaire was administered every 12 weeks. Within-individual data were collected weeks 12-24 on FDC vs cotrimoxazole alone (weeks 0-12) in 319 participants. Between-individual data were collected in weeks 0-12 among those receiving FDC plus fluconazole (n=543) vs cotrimoxazole (n=604).

The questionnaire revealed no within-individual differences in acceptability reported between FDC vs cotrimoxazole: 99.7% vs 99.4% reported none/not much interference with everyday life and 95.6% vs 96.6% reported that the drugs were very easy/easy to take.

The comparison between-individuals 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 approximately one dose within the last 12 weeks.

Overall the investigators concluded that the new FDCs are acceptable, reduce pill burden and could improve adherence as well as simplifying drug distribution for HIV programmes.


The REALITY trial will report in mid-2016 and will provide information on whether or not enhanced, immediate OI prophylaxis reduces mortality, TB and other OI morbidity, and/or increases toxicity in people starting ART with low CD4 counts (approximately 1 in 4 in African countries).

The CTX/INH/B6 FDC was submitted to WHO for prequalification in September 2014. A half-dose scored tablet is needed for less than five year-olds.


Gibb DM et al. Sulfamethoxazole/trimethoprim/isoniazid/pyridoxine scored tablets are bioequivalent to individual products and are acceptable to patients with advanced HIV infection in the REALITY trial. 46th World Conference on Lung Health of the International Union Against Tuberculosis and Lung Disease (The Union). HIV-TB LB.

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