ion-4 design ldv/sof open-label ion-4 study: ldv/sof in hiv co-infection w12 ≥ 18 years chronic...

ION-4

Design

LDV/SOF

Open-label

ION-4 Study: LDV/SOF in HIV co-infection

W12

≥ 18 yearsChronic HCV infection

Genotype 1 or 4HCV RNA ≥ 10,000 IU/ml

Treatment-naïve or experiencedCompensated cirrhosis allowed

HIV infection on ART with HIV RNA < 50 c/ml and CDA > 100/mm3

Naggie S. NEJM 2015, July 21, ahead of print

N = 335SVR12

– Co-formulated ledipasvir-sofosbuvir (LDV 90mg/SOF 400 mg) : 1 pill QD– ARV regimens : FTC and TDF + EFV or RAL or RPV

Objective– Primary endpoint : SVR12 (HCV RNA < 25 IU/ml), with 2-sided 95% CI

N = 335Mean age, years 52

Female 18%

Race : white / black 61% / 34%

Body mass index, mean 27

Genotype 1a / 1b / 4 75% / 23% / 2%

Cirrhosis 20%

IL28B CC genotype 24%

HCV RNA log10 IU/ml, mean 6.7

HCV treatment experienced 55%

CD4 /mm3, median 628

ARV regimen : EFV / RAL / RPV 48% / 44% / 9%

Discontinuation, NProtocol violationLack of efficacyDeath

9621

Baseline characteristics and patient disposition

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SVR12 (HCV RNA < 25 IU/ml), % (95% CI)

25

50

100

75

96.1*(93.5-97.9)

%94

(85.4-98.3)

N 335

95.3(90.6-98.1

Overall*

96(92.8-98.1)

96.1(89-99.2)

96.6(93.7-98.5)

250 77268 67158

96.8(93.1-98.8)

185

Naïve Exprienced No cirrhosis Cirrhosis 1a

Genotype

1b 4

8

100(63.1-100)

* 2 on-treatment failures (noncompliance) ; 1 lost to follow-up ; 10 relapses ;1 death (IVDU-related endocarditis/sepsis)

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SVR12 (HCV RNA < 25 IU/ml), % (95% CI)

Significantly lower response in black patients (p < 0.001) Response similar in patients who had undergone previous treatment and those who

had not, in patients receiving various concomitant HIV antiretroviral regimens

25

50

100

75

96.4(93.4-98.2)

% 95.7(92.7-97.7)

N 276

89.6(82.5-94.5)

Male

98.8(93.3-100)

97.8(94.6-99.4)

100(90.3-100)

81 18536 67115

99.5(97.5-100)

217

Black Non-black < 800,000 ≥ 800,000 CC

IL28B

CT TT

69

88.4(78.4-94.9)

94.9(85.9-98.9)

59

Baseline HCV RNA(IU/ml)

RaceSex

Female

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Multivariate analysis of factors associated with virologic relapse Odds ratio (95% CI) 2-sided p value

Black race 17.73 (2.66-infinity) 0.0012

IL28B TT 4.27 (0.89-27.5) 0.0751

ARV : EFV 3.26 (0.59-33.63) 0.241

2 virologic breakthrough + 10 relapses

10 relapses– All black– 7 had IL28B TT– 8 were on EFV

Virologic failure

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Patients with genotype 1 : deep sequencing of NS5A at baseline : 59/325 (18%) patients with NS5A variants (RAVs)

– 55/59 (93%) achieved SVR12

– 258/266 (97%) with no baseline NS5A RAVs achieved SVR12

2 patients with virologic breakthrough : no baseline NS5A RAVs but emergence of NS5A RAVs at failure

10 relapses: NS5A RAVs at baseline in 4, and in 8 at the time of relapse

No NS5B S282T in any patient at baseline or virologic failure

Virologic resistance testing

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Stable CD4 through treatment and follow-up; No patient had confirmed HIV rebound

Adverse events, N (%)

ION-4



N = 335Adverse events 257 (77)

Grade 3‒4 adverse event 14 (4)

Serious adverse event 8 (2)

Treatment discontinuation due to adverse event 0

Death1 (<1)

Staph. aureus sepsis in IV drug user

Headache 83 (25)

Fatigue 71 (21)

Diarrhea 36 (11)

Nausea 33 (10)

Arthralgia 22 (7)

Upper respiratory tract infection 18 (5)

Grade 3‒4 laboratory abnormality 36 (11)

Summary

– In this Phase III study of 335 HIV/HCV-coinfected patients, 96% achieved SVR12 after 12 weeks of a once-daily, single-tablet regimen of LDV/SOF

• Prior HCV treatment status or the presence or absence of cirrhosis did not impact outcome

• In contrast to larger studies among monoinfected patients, a lower response rate was observed among coinfected black patients treated with LDV/SOF (SVR12 : 90%)

– LDV/SOF was well tolerated, with no treatment discontinuations due to adverse events and no adverse impact on HIV disease or its treatment

ION-4



ion-4 design ldv/sof open-label ion-4 study: ldv/sof in hiv co-infection w12 ≥ 18 years chronic...

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