1. F.Xavier BLANC, MD, PhD, Nantes University, France
Decreasing mortality in HIV-infected adults with severe immune suppression: The STATIS (ANRS 12290) randomized trial
F.Xavier BLANC, MD, PhD, Nantes University, France
26/07/2013

2. STATIS – ANRS 12290
Systematic empirical vs. Test-guided Anti-tuberculosis Treatment Impact in Severely immunosuppressed HIV-infected adults initiating antiretroviral therapy with CD4 cell counts <100/mm3
26/07/2013

3. Independent Data Safety & Monitoring Board (DSMB)
Chair: Peter GODFREY- FAUSSETT
Coordinating Investigators
François-Xavier BLANC - Kouao Médard Serge DOMOUA
Trial Management Team
François-Xavier BLANC
Kouao Médard Serge DOMOUA
Didier LAUREILLARD, vice Coordinating Investigator
Stephen D. LAWN, vice Coordinating Investigator (†)
Xavier ANGLARET, Christine DANEL
Maryline BONNET
Scientific Advisory Board
Chair: Anthony D. HARRIES
Sponsor:
ANRS
N. Rouveau
A. Diallo
Methodology/Data Management Center: MEREVA (Abidjan, Bordeaux)
International Project Manager: Alle Baba DIENG then Anani BADJÉ
Statistics: Delphine GABILLARD; Modeling: Eric OUATTARA
Monitoring : Jérôme LE CARROU, Sylvain JUCHET
Data Managers: Larissa N’GESSAN-KOFFI, Cyril YAO YAPI, Sophie KARCHER
Cambodia (Phnom Penh)
S. SOVANNARITH - D. LAUREILLARD
L. BORAND
Côte d'Ivoire (Abidjan)
E. MESSOU - X.ANGLARET
A. BADJÉ
Uganda (Mbarara)
C. MUZOORA - M. BONNET
J. MWANGA
Vietnam (Ho Chi Minh City)
NGUYEN Huy D.- D. LAUREILLARD
D. RAPOUD then A. DOMERGUE

5. Tuberculosis: key facts in 2016
10.4 millions incident cases [ ], incl million MDR-TB [ ]
9-14% of TB cases occur in people living with HIV/AIDS
Geography:
Asia: 61%, Africa: 26%
Mortality:
HIV-neg.: million [ ]
HIV-pos.: million [ ]

6. HIV & TB: FRIGHTENING DATA
20-25% HIV+ patients still present for care with severe immunosuppression (CD4<100 cells/µl) in sub-Saharan Africa (JAIDS 2014; 65:e8-16)
High prevalence of TB at ART initiation  20-25%
High incidence of TB after ART initiation  10-20%
Majority of cases occur early after initiation of ART
TB is still a major cause of death in HIV+ patients! 6

7. - Prospective trial of 1,771 HIV-infected patients with CD4 <200 cells/µl or a prior AIDS-defining illness
TB incidence and mortality: maximal during the first 3-6 months following initiation of ART 7

8. Autopsy studies among PLHIV showing percentage of TB diagnosis
Among PLHIV receiving ART
References: Cox et al, PLoS One, 2012; Wong et al, PLoS One, 2012; Some et al, CROI 2013: Kilale et al, Tan J Hea Res, 2013 8
26/07/2013

9. Our responsability is to find a solution
In severely immunosuppressed HIV-infected patients, what is the best option to reduce mortality?
Use new diagnostic tools for TB?
Give systematic TB treatment? 9

10. STATIS ANRS NCT
In HIV-infected adults with severe immunosuppression, impending ART initiation and no overt evidence of active TB,
can systematic empirical first line 6-months TB treatment initiated 2 weeks before the introduction of ART reduce mortality and invasive bacterial infections, compared to an extensive TB diagnostic strategy of combined Xpert MTB/RIF, urine LAM, chest X-ray and continuous symptom evaluation to guide further use of point-of-care tests? 10

11. Urine LAM Determine® TB-LAM Ag: dipstick (like a pregnancy test).
Result available in minutes.
Lipoarabinomannan (LAM) : lipopolysaccharide of the cell wall of Mycobacterium tuberculosis 11

12. Urine LAM + Xpert MTB/RIF12
26/07/2013

13. Main objective of STATIS
To compare the benefits and risks of two experimental strategies in HIV-1 infected adults who start ART with a CD4 count <100/mm3:
extensive continuous active TB screening using point-of-care modern rapid diagnostic tools to initiate TB treatment in the sole patients diagnosed with active TB;
systematic empirical TB treatment for all patients. 13

14. STATIS primary endpoint
Composite endpoint:
24-week all-cause mortality, and
24-week occurrence of invasive bacterial infections. 14

15. STATIS secondary objectives
The benefits and risks of the 2 strategies will be assessed over a period of 24 and 48 weeks, comparing:
Mortality and occurrence of invasive bacterial infections
Occurrence of AIDS-defining morbidity
Occurrence of severe HIV-non-AIDS morbidity
Occurrence of TB
Occurrence of TB-associated IRIS & non TB-associated IRIS
Occurrence of grade 3 or 4 adverse events
Adherence to ART
Probability of being lost to follow-up
Immunological and virological efficacy of ART
Care consumption (hospital stays, visits, tests, investigations, drugs), costs and cost-effectiveness
Risk of resistance to TB drugs 15

16. STATIS inclusion criteria
Age ≥18 years;
HIV-1 infection as documented at any time prior to trial entry, as per national testing procedures;
CD4 <100 cells/mm3;
No history of antiretroviral drug use, except transient ART for PMTCT;
Able to correctly understand the study and to sign the informed consent. 16

17. STATIS non-inclusion criteria
HIV-2 co-infection
Contra-indication to efavirenz
AST or ALT >5 times the upper limit of normal
Creatinine clearance < 50 ml/mn
Overt evidence that TB treatment should be started immediately
Ongoing TB chemoprophylaxis (isoniazid preventive therapy)
History of TB treatment in the past 5 years
Any condition that would lead to differ ART initiation (e.g. acute condition requiring investigations and/or treatment prior to ART initiation)
Current pregnancy or breastfeeding 17

18. STATIS trial design Arm 1 (525 patients) Arm 2 (525 patients)
Screening at OI/ART site
CD4 <100/mm3
ART naïve
Age ≥18 yrs
HIV-1 positive
No TB treatment <5 years
No ongoing IPT
STATIS trial design
End of follow-up
Week 48
Primary endpoint
at Week 24:
All-cause mortality and invasive bacterial infections (composite)
Pre-inclusion
No overt evidence of TB
Able to start ART immediately
Arm 1 (525 patients)
Extensive TB screening
Xpert MTB/RIF
Urine LAM
Chest X-ray
No TB
ART
Search for active TB if symptomatic at anytime
TB treatment
Inclusion
CD4 <100/mm3 (confirmation)
Absence of non-inclusion criteria TB
ART
Arm 2 (525 patients)
Systematic TB treatment
Chest X-ray
TB treatment
ART
Day 0
Inclusion/randomization W2 W4 W8
W12
W16
W20
W24
W36
W48
7 days
3 days
INTERVENTION
Informed consent signature 18
26/07/2013

19. 300 patients 300 patients 150 patients 300 patients
Initial targets
300 patients
300 patients
150 patients
300 patients
Africa: patients
SE Asia: 450 patients 19

20. End of inclusions: 3rd May 2017
742 (71%) patients with CD4 ≤ 50 cells/µL
308 (29%) patients with CD4 > 50 cells/µL
Onset of inclusions
Total number of enrolled patients %
Ivory Coast
29th Sep 2014
304 29
Uganda
12th May 2014
281 27
Cambodia
22nd Jan 2015
199 19
Vietnam
7th Mar 2015
266 25
TOTAL
1 050
100

21. Gender of included patients
Male
Female
Ivory Coast
113 (37%)
191 (63%)
Uganda
177 (63%)
104 (37%)
Cambodia
109 (55%)
90 (45%)
Vietnam
213 (80%)
53 (20%)
TOTAL
612 (58%)
438 (42%)

22. Characteristics of included patients
Age: 36 ± 9 years [18-68]
CD4: 36 ± 27 cells/mm3 [0-99]
HIV viral load: 5.4 ± 0.6 log10 copies/mL [ ]
Hb: 11.6 ± 2.3 g/dL
BMI: 20.1 ± 3.5 kg/m2
Mean ± SD [min-max]

23. CONCLUSION
A lot of HIV+ patients still present for care with severe immunosuppression
Mortality remains high in this population, mainly due to tuberculosis
STATIS: part of the answer by the end of 2017
RCT designed for HIV+ patients with CD4 < 100/µL
Extensive TB diagnostic strategy vs. systematic empirical TB Rx
Primary endpoint: mortality + invasive bacterial infections at 24 wks
Inclusion of 1050 patients (56% in Africa, 44% in SE Asia) finished on May 3rd, 2017; 71% of enrolled patients had CD4 < 50/µL 23

24. Thanks for your attention