Chronic hepatitis C: future treatment

Figures & data

Table 1 Overview of clinical efficacy of second-wave PIs

Protease Inhibitor (PI)	Company	Current Clinical Phase	Number of patients	Dose Per Day	Duration of Therapy	Viral Response	Side Effects	Active against HCV Genotype
Simeprevir TMC-435^Citation15,Citation16,Citation96^–^Citation98	Tibotec	II	461	150 mg QD	PI + PR 12–24–48 w +PR 24–36	Null-R G1: SVR: 51% Relapsers G1: SVR: 85% Partial R G1: SVR: 75%	Anemia 20% Bilirubin increase	1,2,4,5,6
		III	394 48 cirrhotic		QUEST-1: PI + PR 12 w +PR 12–36W (RGT)	Naïve G1: SVR: 80% Cirrhosis naïve GT-1 SVR12: 58%
		III	391 32 cirrhotic		QUEST-2: PI + PR 12 w +PR 12–36W (RGT)	Naïve G1: SVR: 81% Cirrhosis naïve GT1: SVR12: 65%
Faldaprevir BI-201 135^Citation17,Citation18	Boehringer	III	656	120 mg vs 240	PI 12/24 w + 24/48 w PR	Naïve GT1: SVR: 80%	Rash; jaundice	1,2
	Ingelheim	II	288	240 mg QD	PI + PR 24 w ± 24 w PR	Null-R G1: SVR: 35% Partial R G1: SVR: 50%
Danoprevir ITMN-191, RG 7227^Citation19,Citation20	Roche	II	421	DAUPHINE: 200/r mg BID 100/r mg BID	PI/r + PR 24 w	Naïve G1: SVR24: 89% 79% 66%	Nausea, diarrhea, neutropenia ALT increase	1,2,4
			29	50/r mg BID		G4: SVR12: 100%
			49	100/r mg BID	PI/r + PR 24 w	Partial R: SVR 12: 56% G1b 91%, G1a 30%
Vaniprevira MK-7009^Citation21,Citation22	Merck	II/III	94	Naïve: 300 mg BID 600 mg BID 600 mg QD 800 mg QD	4w/44 PR	Naïve G1: SVR 61% SVR 80% SVR 78% SVR 84%	Nausea	1,2
			211	Treatment-experienced: 600 mg BID 24 w 600 mg BID 24 w + 24 w PR 600 mg BID 48 w 300 mg BID 48 w	PI + PR 24 w ± PR 24 PI + PR 48 w	Trt-experienced Null-R SVR: 71% SVR: 50% SVR: 85% SVR: 80% SVR: 67% SVR: 50% SVR: 78% SVR: 40%
ABT-450^Citation23	Abbott	II	35	100/r or 200/r mg QD	PI + PR 12 w + 12–36 w PR	Naïve G1: SVR12: 88%	AE profile similar to PR	1
Sovaprevir ACH-1625^Citation24	Achillion	II	64	200–800 mg QD	PI + PR 28 d + PR 44 w	Naïve G1: SVR12: 63–86%	AE profile similar to PR	1
			58		PI + PR 12 w + 36 PR w	Naïve G1: EOT: 69–100%
Asunaprevir BMS-650032^Citation25,Citation26	BMS	II	47	200–600 mg BID 600 mg BID + Daclatasvir 60 mg QD ± PR 24 w	PI + PR48 w PI + NS5A inhibitor 24 w PI + NS5A inhibitor + PR 24 w	Naïve G1: SVR: 83–92% Null-R G1: SVR: 36% SVR: 100%	AE profile similar to PR	1,4

Abbreviations: AE, adverse event; BID, twice daily; EOT, end of treatment response; HCV, hepatitis C virus; PI, protease inhibitor; PI/r, ritonavir-boosted protease inhibitor; PR, pegylated–interferon + ribavirin; QD, once daily; RBV, ribavirin; RGT, response-guided therapy; RVR, rapid virologic response (Week 4); SVR, sustained virologic response; SVR12, sustained virologic response at week 12; SVR24, sustained virological response at week 24; w, week; /r, ritonavir-boosted; vs, versus.

Table 2 Overview of clinical efficacy of NS5B NIs or NNIs polymerase inhibitors

Polymerase inhibitors	Company	Current clinical phase	Number of patients	Dose per day	Duration of therapy	Viral response	Side effects	Active against HCV genotype
Nucleoside or nucleotide inhibitors
RG-7128 Mericitabine^Citation32^–^Citation34	Roche	II	408	1000 mg BID	NIs + PR 12 w + PR 12/36 w RGT	Naïve: SVR24 G1/G4: 33%–51%	AE profile similar to PR	1,4
		II	166	1000 mg BID	NIs + PR 24 w ± PR 24 w RGT	Naïve SVR 24: 57%		1,4
		II	25	1500 mg BID	NIs + PR 4 w + PR 20/40 w RGT	Relapsers G2/3 SVR: 70% Null responders G2/3 SVR: 60%		2,3
GS-7977 Sofosbuvir^Citation35^–^Citation39, ^Citation99^–^Citation105	Gilead	II	25	400 mg QD	NIs + PR 12 w	Naïve SVR 12: 100%	AE profile similar to PR	2,3
		II	95	ELECTRON 400 mg QD	NIs + RBV 12 w + PR (4,8,12 w in total) INF-free: NIs + RBV 12 w	Naïve GT2,3 SVR 12: 100% Naïve GT1: SVR: 84% Null-R GT1: SVR4: 11%		2,3 1,2,3
			34		INF-free : NI+NS5A.I (LDV)+RBV 12w	Naïve GT1: SVR12: 100% Null-R GT1: SVR12: 100%
			35		INF-free : NI+NNI (GS 9669) +RBV 12w	Naïve GT1: SVR12: 92% Null-R GT1: SVR12: 100%
			71		NIs + PR 12 w + PR (12/36 w)	Naïve GT1: SVR 12: 88%–91%
		II	332	PROTON 200–400 mg QD	NIs + PR 12 w ±NI 12 w or NI + RBV 12 w	Naïve GT1: SVR24 : 87–89%		1
		II			NI + PR 24 w	Naïve GT4,6 SVR24: 82%, 100%
			34	ATOMIC	INF-free:NIs + LDV + RBV 12 w	Naïve GT1: SVR12: 100%		1,4,6
		II		400mg QD		Naïve GT1: SVR12: 100%
		III	327	NEUTRINO 400mg QD	NI+PR 12w	Naïve GT1,4,5,6: SVR12: 90%; cirrhosis 80%
Non nucleoside inhibitors
NNI-Site 1 inhibitors BI 207 127^Citation40			400 mg TID 600 mg TID 800 mg TID		NNIs + PR 28 days + PR 40 w	Naïve G1: RVR: 50% RVR: 57% RVR: 50%
		II	57			Trt-experienced G1	Nausea, vomiting, diarrhea, rash	1
	Bohringer Ingelheim			400 mg TID 600 mg TID 800 mg TID		RVR: 0% RVR: 22% RVR: 18%
NNI-Site 2 inhibitors Filibuvir^Citation41	Pfizer	II	35	200 mg BID300 mg BID 500 mg BID	NNIs + PR 28 day + PR 44 w	Naïve G1 RVR: 60% SVR12: 30% RVR: 75% SVR12: 50% RVR: 63% SVR12: 50%	Nausea asthenia	1
NNI-Site 2 inhibitorsVX-222^Citation42	Vertex	I	24	250 mg BID 500 mg BID 750 mg BID 1500 mg QD	NNIs 3 days	Mean HCV RNA reduction −3.2 log 10 IU/ml	Diarrhea (25%) Headache (20%) Nausea (12%)	1
NNI-Site 3 inhibitors Setrobuvir ANA598^Citation43	Anadys	II	60	200 mg BID 400 mg BID	NNIs + PR 12 w + PR 24/36 w	Naïve G1: RVR: 56% EVR: 73% RVR: 42% EVR: 75%	Rash	1
NNI-Site 3 inhibitors ABT-333^Citation44	Abbott	II	16	400 mg BID 800 mg BID	NNIs 2 days + PR 12 w + PR 36 w	Naïve G1 SVR24: 63% SVR24: 63%	AE profile similar to PR	1
NNI-Site 3 inhibitors ABT-072^Citation44	Abbott	II	23	100 mg QD 300 mg QD 600 mg QD	NNIs + PR 12 w + PR 36 w	Naïve G1: SVR24: 50% SVR24: 25% SVR24: 86%	AE profile similar to PR	1
NNI-Site 4 inhibitors Tegobuvir (GS9190)^Citation45	Gilead	II	252	40 mg BID	NNIs + PR 24 w or 48 w	Naïve SVR: 56%	Rash	1

Abbreviations: AE, adverse event; EVR, early virologic response (Week 12); BID, twice daily; HCV, hepatitis C virus; NI, nucleotide inhibitor; NNI, non-nucleoside inhibitor; PR, pegylated–interferon + ribavirin; RBV, ribavirin; RGT, response-guided therapy; QD, once daily; RVR, rapid virologic response (Week 4); SVR, sustained virologic response; SVR12, sustained virologic response at week 12; w, week.

Table 3 Overview of clinical efficacy of DAAs combination studies

Combination trials	Company	Current clinical phase	Number of patients	Dose per day	Duration of therapy	Viral response	Active against HCV genotype
PI and NS5B NIs
Danoprevir and mericitabine^Citation20,Citation61,Citation62	Roche			INFORM -1
		I	64	Danoprevir + Mericitabine 900 mg BID + 1000 mg BID	14 days then PR 48 W	Naïve: EOT: 100% < LLQ Null- Rito: EOT: 66% < LLQ	1
				INFORM SVR
		II	54	Danoprevir/rito+ Mericitabine + RBV	24 w	Naïve SVR: 41% (G1b:71%, G1a:26%)	1
				MATTERHORN
			31	Danoprevir/rito+ Mericitabine + RBV	24 w	Partial R SVR: G1b: 39% Null-R SVR: G1b: 55%
			124	Or Danoprevir/rito+ Mericitabine + RBV +PEG (100 mg BID/100 mg BID + 1000 mg BID)	24 w	Partial R: G1b: 96%/G1a:75% Null-R: G1b: 100%/G1a: 73%	1
TMC-435 + GS -7977 Simeprevir and Sofosbuvir^Citation95,Citation106	Tibotec Gilead	II	80	Simeprevir + Sofosbuvir ± RBV 150 mg QD + 400 mg QD	PI + NIs 12 w or 24 w PI + NIs + RBV 12 w or 24 w	Null –R G1 SVR12: 93%	1
PI and NS5B NNIs
BI 201335 (Faldaprevir) + BI	Bohringer			SOUND-C2
207127-(Deleobuvir)^Citation63^–^Citation65	Ingelheim	IIb	362	Faldaprevir + BI 207127 + RBV 120 mg QD + 400/600 mg TID	PI + NNIs + RBV 16 w 28 w or 48 w	Naïve: SVR12: G1b 55%–84%, G1a 38%–47%	1 1
Telaprevir + VX-222^Citation65,Citation66	Vertex	II		ZENITH
			5,6	Telaprevir + VX-222+ RBV 1125 mg BID + 100/400 mg BID or	PI + NNIs + RBV 12 w	Naïve: SVR: G1b: 70%, G1a: 73%	1
			13,14	Telparevir + VX 222 + PR 1125 mg BID + 100/400 mg BID	PI + NNIs + PR 12 w + PR 12 w	Naïve: SVR12: 83%–90%
GS 9256 + GS9190 (Tegobuvir)^Citation68	Gilead	II	42	GS 9256 + Tegobuvir 75 mg BID + 40 mg BID	PI + NNIs 4 w + PR 44 w PI + NNIs + RBV 4 w + PR 44 w PI + NNIs + PR 4 w + PR 44 w	Naïve G1: RVR: 7% RVR: 38% RVR: 100%	1
ABT-450/rito + ABT-333^Citation69,Citation70	Abbott	II	50	ABT-450/rito + ABT-333 + RBV Naïve GT1:250/100 mg or 150/100 mg BID + 400 mg BID Null-R GT1: 150/100 mg BID + 400 mg BID	PI/r + NNIs 12 w	Naïve G1 SVR12: 93%–95% Null-R G1 SVR12: 47%	1
			40	Naïve GT1: 150/100 mg BID + 400 mg BID		Naïve GT1 SVR12: 85,4%
ABT-450/rito + ABT-072^Citation71	Abbott	II	11	ABT-450/rito + ABT-072 +RBV	PI/r + NNIs +RBV 12 w	Naïve G1 ILB28CC SVR 24: 91%	1
PI and NS5A Inhibitor
BMS-650032 + BMS-790052 (Asunaprevir + Daclatasvir)^Citation26, ^Citation50,Citation72	BMS	II	21	Asunaprevir + Daclatasvir ± PR 200 mg BID + 60 mg QD	PI + NS5A ± PR 24 w	Null-R: SVR24: 91% Intolerants: SVR: 64%	1b
			38	Asunaprevir + Daclatasvir 24 w 200 QD or BID + 60 mg	PI+ NS5A 24 w	Null-R: SVR12: 65%–78%	1b
			41	Asunaprevir + Daclatasvir + PR24 w 200 QD or BID + 60 mg	PI + NS5A + PR 24w	Null-R: SVR 4: 90%–95% GT-1a: 88%	1
ABT-450/rito + ABT267^Citation70	Abbott	II	124	ABT-450/rito + ABT-267 + RBV	PI + NS5A + RBV 12 w	Naïve GT1 SVR12: 87.3% Null-R GT1 SVR12: 89%	1
GS-9451+ GS-5885(Ledipasvir)^Citation107^–^Citation109	Gilead	II	244	GS-9451 + GS-5885 + PR 200 mg QD + 30 mg QD + PR	6 w or 12 w	Naïve GT-1 IL28BCC : SVR 12 (6w) :79% SVR 12 (12w) : 98%
			348	Versus PR	12 or 24 w according to RVR	Naïve GT-1 : SVR 12 : 84%
			163		24 or 48 w according to RVR	TE GT-1 non cirrhotic : SVR 12 : 70%
NS5A Inhibitor + NS5B NIs
BMS-790052 + GS-7977 (Daclatasvir + Sofosbuvir)^Citation51,Citation73,Citation110,Citation111	BMS Pharmasset	II	88 (44 GT1, 44 GT2,3)	Daclatasvir + Sofosbuvir ± RBV 60 mg QD + 400 mg QD	24 w	Naïve G2,3: SVR24: 88–100% Naïve G1: SVR24: 93–100%	1, 2, 3
			41 TE GT-1 PI-failure		24 w	TE, PI-failure GT-1 non cirrhotic : SVR12 : 100%	1
PI + NS5A Inhibitor + NS5B NNIs
BMS-650032 (Asunaprevir) + BMS-791325+ BMS-790052 (Daclatasvir)^Citation74	BMS	II	32	Asunaprevir + BMS-791325 + Daclatasvir	12 w or 24 w	Naïve G1 SVR4: 94% (GT1a: 92–100%)	1
ABT-450/rito+ ABT-333 + ABT-267^Citation70	Abbott	II	80	ABT-450/R + ABT-333 + ABT-267 + RBV	8 w	Naïve GT1 SVR12: 87,5%	1
			124	ABT-450/R + ABT-333 + ABT-267 + RBV	12 w	Naïve GT1 SVR12: 99% Null-R GT1 SVR12: 93%
			70	ABT-450/R + ABT-333 + ABT-267	12 w	Naïve GT1 SVR12: 87%
GS-9451 + GS-5885 + Tegobuvir^Citation52,Citation53,Citation92^–^Citation94	Gilead	II	94	GS-9451 + GS-5885 ± tegobuvir ± RBV	12 w or 24 w	Naïve GT1 SVR4: 97% (GT1a 96%, GT1b 100%)	1

Abbreviations: AE, adverse events; DAA, direct antiviral agents; EVR, early virologic response (Week 12); PI, protease inhibitor; PR, pegylated–interferon + ribavirin; RBV, ribavirin; RGT, response-guided therapy; /r, ritonavir boosted; RVR, rapid virologic response (Week 4); SVR, sustained virologic response; SVR12, sustained virologic response at week 12; w, week.

Table 4 Overview of clinical efficacy of NS5A inhibitors

NS5A-Inhibitor	Company	Phase	Number of patients	Dose per day	Duration	Viral response	Side effects	Active against genotype
Daclatasvir (DCV) BMS-790052^Citation47^–^Citation49	BMS	II	395 (G1 365, G4 30) COMMAND-1	20–60 mg QD	NS5A.I + PR 12–24 w + PR 12–36 w (max 48 w)	Naïve GT1: SVR12: 64% (G1a: 58%, G1b: 78–87%) GT4: SVR12: 100%	Nausea and dry skin	1,4
			419 COMMAND-2	20–60 mg QD	NS5AI + PR 24 w	Null-R: cEVR: 30–34% Partial R: cEVR: 44–57%		1
			151 COMMAND-GT2/3	60 mg QD	NS5A.I + PR 12 w ± PR 12 w RGT NS5A.I + PR 16 w ± PR 12 w RGT versus PR 24 w	Naïve G2: cEVR: 83–92% vs 77% Naïve G3: cEVR: 81–89% vs 59%	Profile similar to PR	2–3
ABT 267^Citation52	Abbott	II	29	5–200 mg QD	NS5A.I + PR 12 w + PR 36 w	Naïve GT1: cEVR: 80–100%	Profile similar to PR	1

Abbreviations: cEVR, complete early virologic response (Week 12); PR, pegylated–interferon + ribavirin; QD, once daily; RBV, ribavirin; RGT, response-guided therapy; RVR, rapid virologic response (Week 4); SVR, sustaines virologic response; SVR12, sustained virological response at week 12; wk, week.

Table 5 Estimate of first approval for the new HCV treatments in the USA and Europe

Protease inhibitor	Company	Current clinical phase	FDA approval expected	EMEA approval expected
Simeprevir TMC-435^Citation14,Citation15	Tibotec	III	2013	2014
Faldaprevir BI-201 135^Citation16,Citation17	Boehringer Ingelheim	III	2014	2014
Danoprevir (ITMN-191, RG 7227)^Citation18,Citation19	Roche	II	2015?	2015 ?
Vaniprevir (MK-7009)^Citation20,Citation21	Merck	III	No 2014(Japon)	No
ABT-450^Citation22	Abbott	III	2014	2014
Sovaprevir ACH-1625^Citation23	Achillion	II	?	?
Asunaprevir BMS-650032^Citation24,Citation25	BMS	III	2014	2014
GS-9256^Citation67	Gilead	II	?	?
MK-5172	MSD	II	2015/2016	2015/2016
Polymerase inhibitors
RG-7128 Mericitabine ^Citation31^–^Citation33	Roche	II	?	?
GS- 7977 Sofosbuvir^Citation34^–^Citation38	Gilead	III	2013	2013
NNI-Site 1 inhibitors BI 207 127^Citation39	Bohringer Ingelheim	III	2014	2014
NNI-Site 1 inhibitors BMS 791325^Citation73	BMS	II	2014/2015	2014/2015
NNI-Site 2 inhibitors Filibuvir^Citation40	Pfizer	II	?	?
NNI-Site 2 inhibitors VX-222^Citation41	Vertex	II	?	?
NNI-Site 3 inhibitors Setrobuvir ANA598^Citation42	Anadys	I	?	?
NNI-Site 3 inhibitors ABT-333^Citation43	Abbott	III	2014	2014
NNI-Site 3 inhibitors ABT-072^Citation43	Abbott	II	?	?
NNI-Site 4 inhibitors Tegobuvir (GS9190)^Citation44	Gilead	II	?	?
NS5A-inhibitor
Daclatasvir (DCV) BMS-790052^Citation46^–^Citation48	BMS	III	2014	2014
ABT 267^Citation51	Abbott	III	2014	2014
Ledipasvir GS-5885 www.clinicaltrial.gov	Gilead	III	2014	2014

Abbreviations: EMEA, European Medicines Agency; FDA, US Food and Drug Administration; HCV, hepatitis C virus.

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