ION-4  Design LDV/SOF Open-label ION-4 Study: LDV/SOF in HIV co-infection W12 ≥ 18 years Chronic HCV infection Genotype 1 or 4 HCV RNA ≥ 10,000 IU/ml.

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Presentation transcript:

ION-4  Design LDV/SOF Open-label ION-4 Study: LDV/SOF in HIV co-infection W12 ≥ 18 years Chronic HCV infection Genotype 1 or 4 HCV RNA ≥ 10,000 IU/ml Treatment-naïve or experienced Compensated cirrhosis allowed HIV infection on ART with HIV RNA 100/mm 3 Naggie S. NEJM 2015, July 21, ahead of print N = 335 SVR 12 –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 : SVR 12 (HCV RNA < 25 IU/ml), with 2-sided 95% CI

N = 335 Mean age, years52 Female18% Race : white / black61% / 34% Body mass index, mean27 Genotype 1a / 1b / 475% / 23% / 2% Cirrhosis20% IL28B CC genotype24% HCV RNA log 10 IU/ml, mean6.7 HCV treatment experienced55% CD4 /mm3, median628 ARV regimen : EFV / RAL / RPV48% / 44% / 9% Discontinuation, N Protocol violation Lack of efficacy Death Baseline characteristics and patient disposition ION-4 ION-4 Study: LDV/SOF in HIV co-infection Naggie S. NEJM 2015, July 21, ahead of print

SVR 12 (HCV RNA < 25 IU/ml), % (95% CI) * ( ) % 94 ( ) N ( Overall* 96 ( ) 96.1 ( ) 96.6 ( ) ( ) 185 Naïve ExpriencedNo cirrhosisCirrhosis 1a Genotype 1b ( ) * 2 on-treatment failures (noncompliance) ; 1 lost to follow-up ; 10 relapses ; 1 death (IVDU-related endocarditis/sepsis) ION-4 ION-4 Study: LDV/SOF in HIV co-infection Naggie S. NEJM 2015, July 21, ahead of print

SVR 12 (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 ( ) % 95.7 ( ) N ( ) Male 98.8 ( ) 97.8 ( ) 100 ( ) ( ) 217 BlackNon-black< 800,000≥ 800,000CC IL28B CTTT ( ) 94.9 ( ) 59 Baseline HCV RNA (IU/ml) RaceSex Female ION-4 ION-4 Study: LDV/SOF in HIV co-infection Naggie S. NEJM 2015, July 21, ahead of print

Multivariate analysis of factors associated with virologic relapse Odds ratio (95% CI)2-sided p value Black race17.73 (2.66-infinity) IL28B TT4.27 ( ) ARV : EFV3.26 ( )0.241  2 virologic breakthrough + 10 relapses  10 relapses –All black –7 had IL28B TT –8 were on EFV Virologic failure ION-4 ION-4 Study: LDV/SOF in HIV co-infection Naggie S. NEJM 2015, July 21, ahead of print

 Patients with genotype 1 : deep sequencing of NS5A at baseline : 59/325 (18%) patients with NS5A variants (RAVs) –55/59 (93%) achieved SVR 12 –258/266 (97%) with no baseline NS5A RAVs achieved SVR 12  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 ION-4 ION-4 Study: LDV/SOF in HIV co-infection Naggie S. NEJM 2015, July 21, ahead of print

 Stable CD4 through treatment and follow-up; No patient had confirmed HIV rebound Adverse events, N (%) ION-4 ION-4 Study: LDV/SOF in HIV co-infection Naggie S. NEJM 2015, July 21, ahead of print N = 335 Adverse events257 (77) Grade 3 ‒ 4 adverse event 14 (4) Serious adverse event8 (2) Treatment discontinuation due to adverse event0 Death 1 (<1) Staph. aureus sepsis in IV drug user Headache83 (25) Fatigue71 (21) Diarrhea36 (11) Nausea33 (10) Arthralgia22 (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 SVR 12 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 (SVR 12 : 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 Study: LDV/SOF in HIV co-infection Naggie S. NEJM 2015, July 21, ahead of print