A randomized trial to estimate efficacy and safety of 2 doses of raltegravir and efavirenz for treatment

of HIV-TB co-infected patients :ANRS 12 180 REFLATE TB trial.

B. Grinsztejn1, N. De Castro2,3, V. Arnold4, V. Veloso1, M. Morgado5, JH. Pilotto6, C. Brites7, JV. Madruga8, N. Barcellos9, BR Santos10, C. Vorsatz1,

C. Grondin4, M. Santini-Oliveira1, O. Patey11, C. Delaugerre2,3, G. Chêne4, J-M. Molina2,3 and the ANRS 12 180 Reflate TB study group.

1 Laboratory of Clinical Research on STD/AIDS, IPEC, Fiocruz, Rio de Janeiro, Brazil, 2 University of Paris Diderot, Sorbonne Paris Cité, INSERM U941, 3 Hospital Saint-Louis, AP-HP, France, 4 INSERM U897 and University Bordeaux Segalen, 5 Laboratory of AIDS and Molecular Immunology, Fiocruz, Rio de Janeiro, Brazil, 6 Department of STD/AIDS, Nova Iguacu, Brazil, 7 Laboratory of Research in Infectious Diseases, Salvador de Bahia, Brazil, 8 Research Unit for Treatment of STD/AIDS, Sao Paulo, Brazil, 9 Department of Care and

Therapy, Porto Alegre, Brazil, 10 Department of Infectious Diseases, Porto Alegre, Brazil, 11 Department of Internal and Tropical Medicine, Villeneuve St George, France.

XIX International AIDS Conference July 26, 2012Abstract #:THLBB01

CMG-EC ISO 9001:2008 certified for its clinical research activities

Background• WHO guidelines: efavirenz (EFV)-based regimen 1st-line therapy for

HIV and Tuberculosis (TB) co-infected patients

• Potential limitations to EFV use– Adverse Events : cutaneous rash, central nervous system toxicity– Transmitted drug resistance to NNRTIs– Teratogenicity

• Potential interest of Raltegravir (RAL) in HIV-TB co-infection– Favorable safety profile– Not metabolized by CYP450– Induction by rifampin (RIF): ↓ Ctrough 61%, ↓AUC 40% in healthy

volunteers partially compensated by ↑ RAL 800 mg bid

• Objective of the ANRS 12180 REFLATE TB trial : estimate the antiviral efficacy of two doses of RAL +TDF+ 3TC, in HIV-1 naive patients co-infected with TB

ANRS 12 180

ANRS 12 180 Study design

Phase II open label randomized multicenter trial

W0 W 24 W48

1:1:1

+ RAL 800 mg bid

TDF245 mg qd + 3TC 300mg qd + EFV 600 mg qd

TDF245mg qd + 3TC 300mg qd + RAL 400 mg bid

+ RAL 400 mg bid

ANRS 12 180

Primary endpoint mITTHIV RNA<50copies/mL

TB drugs RHZE 2mo followed by RH 4mo

• HIV RNA>1000 cp/mL• ART naïve• Confirmed or probable

TB• RIF containing regimen

Sample size : 50 patients/arm, 80% power to show ≥70% success at W24

TDF245 mg qd + 3TC 300 mg qd

ANRS 12 180

4

Flow chart

Randomized n = 155

Not treated n = 1

RAL 400

n = 51

RAL 800

n = 52

Not treated n = 1

Not included n = 24 Lab abnormality n=9 HIV RNA < 1000cp/ml n=4 ARV treatment n=2 Death n=2 Other n=7

Screened n = 179

France n = 8

Brazil n = 171

EFV

n = 52

Disposition at W24

On study drug n = 43

Discontinued study drug n = 8

Adverse event n = 2

Virologic failure n = 4

Lost to follow up n = 0

Withdrawal n = 0

Death n = 2

ANRS 12 180

Not treated n = 0

mITT analysis n = 51 mITT analysis n = 51 mITT analysis n = 51

Disposition at W24

On study drug n = 50

Discontinued study drug n = 1

Adverse event n = 0

Virologic failure n = 0

Lost to follow up n = 0

Withdrawal n = 1

Death n = 0

Disposition at W24

On study drug n = 43

Discontinued study drug n = 8

Adverse event n = 3

Virologic failure n = 1

Lost to follow up n = 1

Withdrawal n = 1

Death n = 2

Baseline characteristicsEFV RAL 400 RAL 800

 N = 51  N = 51  N = 51Male, n (%) 39

(76)35

(69)38

(75)Age in years, median [IQR] 35

[29-45]37

[31-44]38

[33-43]Ethnicity, n (%)

Black 15 (29)

14 (27)

21 (41)

Mixed 21 (42)

21 (42)

7 (14)

White 15 (29)

16 (31)

23 (45)

BMI in kg/m2, median [IQR] 21 [19-23]

21 [19-23]

20 [17-23]

CD4+/mm3, median [IQR] 129 [45-308]

115 [50-213]

166 [80-367]

 CD4≤50 /mm3, n (%) 14 (27)

12 (24)

5 (10)

HIV RNA in log10 cp/ml, median [IQR] 5 [4.5-5.5]

4.9 [4.4-5.4]

4.9 [4.2-5.4]

HIV RNA>100,000 cp/ml, n (%) 26 (51)

20 (39)

24 (47)

TB location, n (%)Pulmonary only 20

(39)24

(47)25

(49)Pulmonary and Extrapulmonary 24

(47)19

(37)21

(41)Extrapulmonary only 7

(14)8

(16)5

(10)Bacteriologically confirmed TB, n (%) 23

(45)26

(51)25

(49)

Median time between anti-TB and ART, weeks [IQR] 5.7 [4.9-6.9]6.0

[4.9-7.1]5.9

[5-6.7]Hepatitis B or C co-infection, n (%) 2 (4) 8

(16)6

(12)

ANRS 12 180

Efficacy outcomes, W24Primary endpoint : HIV RNA<50 cp/mL at W20 and W24, mITT (M=F, D/C=F)

ANRS 12 180

Secondary endpoint : HIV RNA<400 cp/mL at W20 and W24, mITT (M=F, D/C=F)

EFV

N = 51

RAL 400

N = 51

RAL 800

N = 51

PRIMARY ENDPOINT n % [95% CI] n % [95% CI] n % [95% CI]

Success 32 63 [49-76] 39 76 [65-88] 40 78 [67-90]

Failure 19 37 [24-51] 12 24 [12-35] 11 22 [10-33] Virologic failure 15 12 4

AE leading to treatment discontinuation 2 0 3

Death 2 0 2

Withdrawal / Lost to Follow-up 0 0 2

EFV

N = 51

RAL 400

N = 51

RAL 800

N = 51

SECONDARY ENDPOINT n % [95% CI] n % [95% CI] n % [95% CI]

Success 39 76 [65-88] 41 80 [69-91] 42 82 [72-93]

Failure 12 24 [12-35] 10 20 [9-31] 9 18 [7-28]

Virologic failure 8 10 2

AE leading to treatment discontinuation 2 0 3

Death 2 0 2

Withdrawal / Lost to Follow-up 0 0 2

ANRS 12 180 % participants with HIV RNA<50 cp/mL at each visit (M=F, study treatment discontinuation=F)

Drug resistance by W24EFV

N = 51

RAL 400

N = 51

RAL 800

N = 51

VF with HIV RNA>50 cp/mL, n (%) 15 (29) 12 (24) 4 (8)

VF with HIV RNA>400 cp/mL, n (%) 8 (16) 10 (20) 2 (4)

Participants analyzed for resistance, n 6 5 2

Any INSTI-resistance , n 4 1

N155H 2

E92EQ 1

Y143R/C 1 1

Any NNRTI-resistance, n 4

K103N* 2

V106M 1

Y188L 1

Any NRTI resistance, n 5 4 1

M184V/I 5 4 1

K65R 3

Others (TAMs, K70E) 1 1

ANRS 12 180

* already present at baseline

Median CD4 cell count at each visit (available data)

ANRS 12 180

Adverse events (AE) through W24

EFV RAL 400 RAL 800

 n = 51  n = 51  n = 51

Any AE ≥ grade 2, n (%)39 (76) 37 (73) 37 (73)

Grade 3 or 4 clinical AE, n (%)13 (25) 11 (22)

12 (22)

AE leading to drug discontinuation, n 2 0 3

Hepatotoxicity* 0 0 2

Cutaneous rash 1 0 1

Gynecomastia 1 0 0

Grade 3 or 4 IRIS 1 1 3

AIDS-defining events, n (%) 2 (4)

3 (6) 0 (0)

Death**, n (%) 2 (4)

0 (0) 2 (4)

ANRS 12 180

* Both related to TB drugs: fulminant hepatitis with liver transplant in one patient**Causes of death: EFV arm: 1 TB meningitis W4, 1 sepsis related to TB W6 RAL 800 arm : 1 unknown W2, 1 TB meningitis W12

ANRS 12 180

EFV RAL 400 RAL 800

Laboratory AE of grade 3 or 4, n (%)  n = 51  n = 51  n = 51

At least one such AE 10 (19) 13 (25) 9 (17)

ALT > 5 ULN 3 (6) 1 (2) 1 (2)

AST > 5ULN 3 (6) 3 (6) 3 (6)

PAL > 5ULN 2 (4) 0 (0) 1 (2)

Bilirubin > 5ULN 2 (4) 0 (0) 0 (0)

Neutrophil count < 750/mm3 3 (6) 5 (10) 5 (10)

Platelets < 50 000/mm3 0 (0) 2 (4) 1 (2)

Haemoglobin < 7g/dl 1 (2) 2 (4) 1 (1)

Creatinine > 2.9 ULN 1 (2) 0 (0) 0 (0)

Glycemia > 16.5mmol/l 0 (0) 1 (2) 0 (0)

Laboratory AE (grades 3-4) through W24

Conclusion

• In this phase II study, high rates of success were achieved at week 24 with raltegravir 400 mg bid or 800 mg bid and EFV 600 mg qd in combination with TDF and 3TC, in patients receiving a rifampin-containing TB treatment

• In the context of HIV and TB co-infection, raltegravir (400 mg bid or 800 mg bid) had a good safety profile

• Raltegravir seems to be a suitable alternative to EFV for HIV-TB co-infected patients

• Optimal raltegravir dose yet to be defined based on PK sub-study and W48 follow-up data

ANRS 12 180

AknowledgementsANRS 12 180

The patients for their participation and their commitment during the study and the REFLATE TB Study Group:

INSERM-ANRSB. BazinS. Couffin-CadierguesA. DialloC. RekacewiczB. Larouzé (Chair, Brazil site)

BRAZILIAN AIDS PROGRAMC. Possas (co-Chair, Brazil site)

COORDINATING CTU INSERM U897/ISPEDG. Chêne (head)V. ArnoldA. BeuscartC. FagardC. GrondinN. StivalS. Tabuteau

INDEPENDANT DATA & SAFETYMONITORING COMMITTEEF. Raffi (chair)JP. AboulkerD. DescampsB. Durovni

MERCK SHARPE & DOHME-CHIBRET(donated raltegravir)F. DurandA. De Jacquelot

GILEAD(donated tenofovir)A. JacobP. PétourV. Tilliet

TRIAL STEERING COMMITTEEJM. Molina (Chair)X. AnglaretV. ArnoldB. BazinV. CalvezG. ChêneN. De CastroC. DelaugerreB. GrinsztejnM. MorgadoC. RekacewiczH. SauvageonAM. TaburetV. VelosoC. Vorsatz

CLINICAL CENTERSRio de Janeiro (B. Grinsztejn)Nova Iguaçu (JH.Pilotto)Salvador (C. Brites)Porto Alegre (N. Barcellos)Porto Alegre (B. Rigel Santos)Sao Paulo (J. Valdez Madruga)Saint-Louis, Paris (JM. Molina)Villeneuve Saint- Georges (O. Patey)

LABORATORY, PHARMACYRio de Janeiro (MC. Lourenço)Rio de Janeiro (E. Wreneck Barroso)Rio de Janeiro (T. Torres)Pitié-Salpêtrière, Paris (G. Carcelain)Saint-Louis, Paris (E. Cambau)Saint-Louis, Paris (I. Madelaine)

EVENTS VALIDATION COMMITTEEG. BretonB. DenisS. Wagner

BRAZIL CTULABORATORY OF CLINICALRESEARCH ON STD/AIDS - FIOCRUZB. Grinsztejn (head)R. MillanE. SampaioM. SantiniV. VelosoC. Vorsatz

CMG-EC ISO 9001:2008 certified for its clinical research activities