1. Sulfamethoxazole/Trimethoprim/Isoniazid/Pyridoxine scored tablets are bioequivalent to individual products and are acceptable to patients with advanced HIV infection in the REALITY trial
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 E7, Thomason M1, Pett S1, Berkley J3, Meli B10, Kityo C7, Nathoo K2, Musiime V7, Walker AS1, Gogtay J9 and the REALITY Trial Team
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; 10Moi University Clinical Research Centre, Eldoret, Kenya; 11Joint Clinical Research Centre, Mbale, Uganda

2. Background What about FDCs for long-term OI prophylaxis?
Fixed dose combination (FDC) tablets of triple ART help health systems and patients:
Decrease risk of stock-outs of individual drugs
Improve adherence (once daily likely more important than number of drugs, but latter also important)
Make keeping drugs easier (stigma)
What about FDCs for long-term OI prophylaxis?

3. OI Prophylaxis HIV-infected adults & children
Cotrimoxazole (960mg OD):
60% reduction in morbidity/mortality at ART start CD4<350
Benefit continues after CD4 recovery
Isoniazid (300mg OD):
Reduced risk of TB by 30-40% and is additive to ART
Benefits are long term only if stay on INH
No evidence of induced resistance
B6 (25mg) prevents INH-induced neuropathy
CPT & INH prophylaxis recommended by WHO +/- on ART

4. OI Prophylaxis - adults & children
Cotrimoxazole (960mg OD):
60% reduction in morbidity/mortality at ART start CD4<350
Benefit continues after CD4 recovery
Isonazid (300mg OD):
Reduced risk of TB by 30-40% and is additive to ART
Benefits are longterm only if stay on INH
No evidence of induced resistance
B6 (25mg) prevents INH-induced neuropoathy
CPT and INH both recommended longterm by WHO
Whether or not on ART
Need to get the publication

5. INH-CTX-B6 Fixed-dose Combination
Made by CIPLA, India
On WHO EOI List
Submitted to WHO prequalification Sept 2014
First used in REALITY
Adults – one tablet once daily
Children 5-12y–1/2 tablet once daily =
Who EIO list?
Cotrimoxazole 960mg
Isoniazid 300mg
Vitamin B6 25mg

6. Objectives of the presentation
Results of PK BE study
Acceptability and adherence of FDC vs Cotrimoxazole alone in ongoing REALITY trial

7. (1) Bioequivalence PK study CTX+INH FDC
To evaluate relative bioavailability of sulfamethoxazole, trimethoprim and isoniazid after single dose
Open-label, randomized, 2-treatment, 2-period, 2-sequence, 26-sample crossover study (AB or BA)
Number of subjects: 28 healthy non-tobacco using adults (18 male and 10 female)
Fasting status: 10 hours prior to dosing and 4 hours post dosing (except water)
Parameter for bioequivalence: 90% confidence intervals on geometric mean test-to-reference ratios for AUC0-t and Cmax within %
A bioequivalent study was carried out to evaluate the relative Bioavailability of sulfamethoxazole, trimethoprim and isoniazid after a single dose of novel FDC under fasted conditions in healthy adult subjects.
CTX/INH/B^ made by CIPLA was compared with septrin (Glaxo Wellcome) ,INH 300mg from Sandoz.
A= test formulation, B=Reference formulation

8. Bioequivalence (BE) outcomes
Parameter
Treatment
LS geometric mean (GM)
LSGM ratio (%)
90% CI
(%)
BE outcome
Sulfamethoxazole concentrations
AUC 0-t
Test
777.6
99.8
Pass
Reference
779.3
C max
52.92
103.2
51.30
Trimethoprim concentrations
25504
97.2
26240
1616
98.2
1645
Isoniazid concentrations
20995
103.8
20230
5833
104.3
5593
No SAEs. AEs: 5 test, 6 reference: 9 mild, 2 moderate
Among 28 fasting healthy subjects (18 male; 10 female; Mean(range) age 31(18-45)years; BMI ), 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%( )%; 98.2%( )%) and isoniazid 103.8%( ); 104.3%( )) were well within required % range.

9. 2) REALITY (ISRCTN )
Reduction of EArly mortaLITY in HIV-infected adults and children starting antiretroviral therapy
Increasing the potency of ART with a 12 week induction period using 4 antiretroviral drugs from 3 classes (2NRTI, NNRTI, INI)
Augmented prophylaxis against opportunistic/bacterial infections and helminths for 12 weeks
Macronutrient intervention using ready-to-use supplementary food (RUSF) for 12 weeks
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 in 4 African countries

10. 2) REALITY (ISRCTN )
Reduction of EArly mortaLITY in HIV-infected adults and children starting antiretroviral therapy
Increasing the potency of ART with a 12 week induction period using 4 antiretroviral drugs from 3 classes (2NRTI, NNRTI, INI)
Augmented prophylaxis against opportunistic/bacterial infections and helminths for 12 weeks
Macronutrient intervention using ready-to-use supplementary food (RUSF) for 12 weeks

11. (B) OI prophylaxis drugs
Isoniazid:
Evidence suggests immediate prophylaxis to HIV+ individuals with low CD4, regardless of TST status, and having excluded active TB on symptom screen reduces the overall risk of TB
Fluconazole:
Cryptococcal disease and candida oeseophagitis among most common causes of IRIS
Azithromycin:
Broad spectrum once-daily antibiotic
Albendazole:
Helminth infections may affect HIV-1 progression

12. HIV-infected adult, adolescent or child aged 5 years or older; Naïve to ART & CD4 T-cell count <100
All patients enter the three randomisations A, B, C simultaneously
RANDOMISE (A)
ANTI-HIV
Standard 2 NRTI+NNRTI
plus integrase inhibitor for 12 weeks
Standard 2 NRTI+NNRTI
RANDOMISE (B)
ANTI-INFECTION
Enhanced prophylaxis with
FDC of cotrimoxazole, isoniazid, B6 fluconazole plus 5 days azithromycin and single dose albendazole
Standard cotrimoxazole prophylaxis plus isoniazid from 12 weeks (not Malawi as not in guidelines)
RANDOMISE (C)
ANTI-MALNUTRITION
/MALABSOPTION
12 weeks Ready-to-Use Supplementary Food (RUSF)*
Standard nutritional support*
* all patients meeting criteria for Ready to Use Therapeutic Food will receive this, regardless of randomisation

13. Methods Patient/carer reported
Acceptability
Interference with everyday life
Ease of taking medication
Adherence
Cotrimoxazole alone (weeks 0-12) vs FDC (weeks 12-24) (within-individual)
Weeks 0-12 cotrimoxazole vs FDC+fluconazole (between-individual)
An acceptability/adherence questionnaire was administered every 12 weeks
Within-individual data on FDC (weeks 12-24) vs cotrimoxazole alone (weeks 0-12) were compared in 319 patients
in weeks 0-12 among those receiving FDC+fluconazole (for prophylaxis against cryptococcal disease) (n=543) vs cotrimoxazole (n=604).

14. Characteristics at ART (n=1805)
Total (n=1805)
Age (years)
5-12
13-17
≥18
40 (2%)
32 (2%)
1733 (96%)
Male
961 (53%)
CD4 (cells/mm3)
37 (16, 63)
BMI (kg/m2) (n=1797)
19 (17, 21)
WHO stage (n=1804) 1 2 3 4
300 (17%)
558 (31%)
691 (38%)
255 (14%)
Country
Kenya
Malawi
Uganda
Zimbabwe
351 (19%)
630 (35%)
569 (32%)
Most were adults over 18yr,WHO stage 3/4

15. Interference with everyday life CTX (0-12 weeks) vs FDC (12-24 weeks)
No within-individual differences: 99.4% vs 99.7% reported none/not much interference with everyday life:
There were no within individual differences in interference with daily life between those who took CTX and those who took FDC
n=318

16. 96.6% vs 95.6% reported medication very easy/easy to take:
Ease of taking medication (within-individual) CTX (0-12 weeks) vs FDC (12-24 weeks)
96.6% vs 95.6% reported medication very easy/easy to take:
No difference in ease of taking medication
n=319

17. Ease of taking medication (between-individual) CTX vs FDC+fluconazole over 0-12 weeks
565/604 (93.5%) vs 500/543 (92.1%) (p=0.8) reported taking medication very easy/easy:

18. Week 12: 4.0% vs 3.9% missing ≥1 dose within last 12 weeks
Missing ≥1 dose (between individual) FDC+fluconazole vs CTX over 0-12 weeks
Week 12: 4.0% vs 3.9% missing ≥1 dose within last 12 weeks
FDC + fluconazole
Cotrimoxazole
N with data
570
508
643
545
610
504
598
490

19. Summary & Conclusions FDC scored Cotrimoxazole, Isoniazid & B6:
PK is bioequivalent to individual drugs
Compared with cotrimoxazole alone:
Reported Acceptability and adherence are similar
In adults and children >5 years
They are acceptable, reduce pill burden and could improve adherence,
and simplify drug distribution for programmes.
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.

20. Summary & Conclusions REALITY trial will report in 2016
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.

21. Acknowledgments
We thank all the patients and staff from all the centres participating in the REALITY trial.
Participating Centres: Joint Clinical Research Centre (JCRC), Kampala, Uganda (coordinating centre for Uganda): P Mugyenyi, C Kityo, V Musiime, P Wavamunno, E Nambi, P Ocitti, M Ndigendawani. JCRC, Fort Portal, Uganda: S Kabahenda, M Kemigisa, J Acen, D Olebo, G Mpamize, A Amone, D Okweny, A Mbonye, F Nambaziira, A Rweyora, M Kangah and V Kabaswahili . JCRC, Gulu, Uganda: J Abach, G Abongomera, J Omongin, I Aciro, A Philliam, B Arach, E Ocung, G Amone, P Miles, C Adong, C Tumsuiime, P Kidega, B Otto, F Apio. JCRC, Mbale, Uganda: K Baleeta, A Mukuye, M Abwola, F Ssennono, D Baliruno, S Tuhirwe, R Namisi, F Kigongo, D Kikyonkyo, F Mushahara, D Okweny, J Tusiime, A Musiime, A Nankya, D Atwongyeire, S Sirikye, S Mula, N Noowe. JCRC, Mbarara, Uganda: A Lugemwa, M Kasozi, S Mwebe, L Atwine, T Senkindu, T Natuhurira, C Katemba, E Ninsiima, M Acaku J Kyomuhangi, R Ankunda, D Tukwasibwe, L Ayesiga. University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe: J Hakim, K Nathoo, M Bwakura-Dangarembizi, A Reid, E Chidziva, T Mhute, GC Tinago, J Bhiri, S Mudzingwa, M Phiri, J Steamer, R Nhema, C Warambwa, G Musoro, S Mutsai, B Nemasango, C Moyo, S Chitongo, K Rashirai, S Vhembo, B Mlambo, S Nkomani, B Ndemera, M Willard, C Berejena, Y Musodza, P Matiza, B Mudenge, V Guti. KEMRI Wellcome Trust Research Programme, Kilifi, Kenya: A Etyang, C Agutu, J Berkley, K Maitland, P Njuguna, S Mwaringa, T Etyang, K Awuondo, S Wale, J Shangala, J Kithunga, S Mwarumba, S Said Maitha, R Mutai, M Lozi Lewa, G Mwambingu, A Mwanzu, C Kalama, H Latham, J Shikuku, A Fondo, A Njogu, C Khadenge, B Mwakisha. Moi University Clinical Research Centre, Eldoret, Kenya: A Siika, K Wools-Kaloustian, W Nyandiko, P Cheruiyot, A Sudoi, S Wachira, B Meli, M Karoney, A Nzioka, M Tanui, M Mokaya, W Ekiru, C Mboya, D Mwimali, C Mengich, J Choge, W Injera, K Njenga, S Cherutich, M Anyango Orido,G Omondi Lwande, P Rutto, A Mudogo, I Kutto, A Shali, L Jaika, H Jerotich, M Pierre. Department of Medicine and MLW Clinical Research Programme, College of Medicine, Blantyre, Malawi: J Mallewa, S Kaunda, J Van Oosterhout, B O'Hare, R Heydermann, C Gonzalez, N Dzabala, C Kelly, B Denis, G Selemani, L Nyondo Mipando, E Chirwa, P Banda, L Mvula, H Msuku, M Ziwoya, Y Manda, S Nicholas, C Masesa , T Mwalukomo, L Makhaza, I Sheha, J Bwanali, M Limbuni.
Sponsor: Medical Research Council, UK
Funders: REALITY is funded by Joint Global Health Trials Scheme of the UK Department for International Development (DFID), the Wellcome Trust and Medical Research Council (MRC). Additional funding support is provided by the PENTA foundation.
Cipla Ltd, Gilead Sciences, ViiV Healthcare/GlaxoSmithKline, Merck Sharp & Dohme donated drugs for REALITY and Valid International supplied Ready-to-Use-Supplementary-Food (RUSF).
Trial Coordination and Oversight: MRC Clinical Trials Unit at UCL, London, UK: D Gibb, M Thomason, AS Walker, S Pett, A Szubert, A Griffiths, H Wilkes, C Rajapakse, M Spyer, A Prendergast, N Klein, E Little. Trial Steering Committee: I Weller (Chair), E Malianga, C Mwansambo, F Miiro, P Elyanu, E Bukusi, E Katabira, O Mugurungi, D Gibb, J Hakim, A Etyang, P Mugyenyi, J Mallewa. Data Monitoring Committee: T Peto (Chair), P Musoke, J Matenga, S Phiri. Endpoint Review Committee (independent members): H Lyall (Co-Chair), V Johnston (Co-Chair), F Fitzgerald, F Post, F Ssali, A Prendergast. Social Science Group: F Cowan, J Seeley, R Kawuma, Z Mupambireyi. Independent REALITY Trial Monitors: F Kyomuhendo, S Nakalanzi, J Peshu, S Ndaa, J Chabuka, N Mkandawire, L Matandika, C Kapuya

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