Global elimination of hepatitis C virus infection: Progresses and the remaining challenges

Table 1 Profile of direct-acting antiviral agents[4,37,40,42,44,48-78]

Direct-acting antiviral agent	Generic name (abbreviation)	Code name	Trade name	Active against HCV genotype (based on clinical trial outcomes)	Combination therapy
NS3/4A protease inhibitors (-previr)	Telaprevir (TVR)	VX-950	Incivek/Incivo	1	TVR + IFN ± RBV
	Boceprevir (BOC)	SCH-503034 EBP-520	Victrelis	1	BOC + IFN ± RBV
	Faldaprevir (FDV)	BI-201335	-	1	FDV + Peg-IFN + RBV
	Simeprevir (SIM)	TMC-435	Olysio	1 and 4	SIM + SOF ± RBV
	Vaniprevir (VNV)	MK-7009	Vanihep	1	VNV + IFN ± RBV
	Asunaprevir (ASV)	BMS-650032	Sunvepra	1 and 4	ASV + DCV
	Paritaprevir (PTV)	ABT-450	Veruprevir	1 and 4	PTV+R+OBV+DAV ± RBV
	Voxilaprevir (VOX)	GS-9857	-	Pan-genotypic antiviral activity	VOX + SOF + VPR
	Sovaprevir	ACH-1625	-	1	Sovaprevir + ODV + RBV
	Grazoprevir (GZP)	MK-5172	-	1a, 1b, 4 and 6	Zepatier (GZP + EBV)
	Danoprevir (DNV)	RG-7227	-	1 and 4	DNV + PEG-IFN + RBV
		ITMN-191			DNV + R + PEG-IFN + RBV
		ASC08
	Deldeprevir (DDV)	ACH-2684 ACH-0142684	-	1	DDV + ODV
	Neceprevir
	Narlaprevir (NVR)	SCH-900518	Arlansa	1	NVR + R + PEG-IFN ± RBV
	Vedroprevir (VDV)	GS-9451	-	1	VDV + LDV + SOF
					VDV + LDV + TGV + RBV
	Glecaprevir (GLE)	ABT-493	-	Pan-genotypic antiviral activity	GLE + PIB ± RBV
	-	GS-9256	-	1	GS-9256 + PEG-IFN + RBV
					GS-9256 + TGV + Peg-IFN ± RBV
NS5A replication complex inhibitors (-Asvir)	Daclatasvir (DCV)	BMS-790052	Daklinza	1, 2 and 3	Sovodak (DCV + SOF) ± RBV
					DCV + VX-135
	Ledipasvir (LDV)	GS-5885	-	1, 3, 4, 5 and 6	Harvoni (LDV + SOF) ± RBV
					LDV + SOF ± (VDV or Radalbuvir)
	Ombitasvir (OBV)	ABT-267	-	1 and 4	Viekira Pak (OBV + PTV + R + DSV) ± RBV
					Technivie (OBV + PTV + R)
	Elbasvir (EBV)	MK-8742	-	1a, 1b, 4 and 6	Zepatier (EBV + GZP) ± RBV
	Velpatasvir (VPR)	GS-5816	-	Pan-genotypic antiviral activity	Epclusa (VPR + SOF) ± RBV
	Odalasvir (ODV)	ACH-3102	-	1	ODV + Sovaprevir + RBV
	Ravidasvir (RVD)	PPI-668	-	4	RVD + SOF ± RBV
		ASC16
	-	PPI-461	-	1	-
	-	JNJ-56914845	-	1	GSK2336805 + PEG-IFN + RBV
		GSK2336805			GSK2336805 + VX-135 + SIM
	Samatasvir	IDX-18719 IDX-719	-	1, 2, 3 and 4	Samatasvir + SIM + RBV
		MK-1894
	-	BMS-824393	-	1	BMS-824393 + PEG-IFN + RBV
	Pibrentasvir (PIB)	ABT-530	-	Pan-genotypic antiviral activity	PIB + GLE ± RBV
	Ruzasvir (RZR)	MK-8408	-	Pan-genotypic antiviral activity	RZR + UPR + GZP
Nucleoside NS5B polymerase inhibitors	Sofosbuvir (SOF)	PSI-7977;	Sovaldi; Soforal	Pan-genotypic antiviral activity	SOF + IFN ± RBV
(-Buvir)		GS-7977			Sovodak (DCV + SOF) ± RBV
	Mericitabine (MCB)	RG-7128	-	1 and 4	MCB + PEG-IFN + RBV
		RO5024048			MCB + DNV
					MCB + R + DNV ± RBV
	-	VX-135	-	1	VX-135 + GSK2336805 + SIM
		ALS-2200			VX-135 + TVR + RBV
					VX-135 + DCV
					VX-135 + RBV
					VX-135 + SIM
	Valopicitabine	NM283	-	1	Valopicitabine + Peg-IFN
Non-nucleoside NS5B polymerase inhibitors (-Buvir)	Beclabuvir (BCV)	BMS-791325	-	1	BCV+ ASV+ DCV
	Dasabuvir (DAV)	ABT-333	Exviera	1	DAV + OBV+ PTV + R ± RBV
	Lomibuvir	VX-222	-	1	VX-222 + TVR + RBV
		VCH-222			VX-222 + Filibuvir
	Filibuvir	PF-00868554,	-	1	Filibuvir + Peg-IFN + RBV
		PF-868554			Filibuvir + VX-222
	Setrobuvir (STV)	ANA-598	-	1	STV + IFN + RBV
		RO-5466731			STV + R + DNV + RBV ± MCB
		RG-7790
	Nesbuvir (NBV)	HCV-796	-	1	NBV +Peg-IFN + RBV
		VB-19796
	Tegobuvir (TGV)	GS-9190	-	1	TGV + GS-9256 +Peg-IFN ± RBV
					TGV + LDV + VDV + RBV
	Deleobuvir (DBV)	BI-207127	-	1	DBV + PEG-IFN + RBV
					DBV + FDV
					DBV + FDV + RBV
	Uprifosbuvir (UPR)	MK-3682	-	Pan-genotypic antiviral activity	UPR + RZR
					UPR + RZR + GZP
	Radalbuvir	GS-9669	-	1	Radalbuvir + LDV + SOF
	AL-335	ALS-335	-	1	AL-335 + ODV + SIM

IFN: Interferon; RBV: Ribavirin; R: Ritonavir; PEG-IFN: Pegylated interferon.

Table 2 Vaccine candidates against hepatitis C virus in preclinical and clinical trials

Type of vaccine	Vaccine structure/adjuvant	Stage of development	Outcome	Application	Developer	Year	Current status	Ref.
Recombinant protein vaccine	Recombinant E1 or E2/MF59	7 chimpanzees	Induce strong humoral immune response; complete protection in 5 chimpanzees	Prophylactic vaccine	Chiron/ Novartis	1994	Completed	[101]
	Recombinant E1 or E2/Alum	4 Chimpanzees	Induce antigen-specific T-helper cytokines in either E1 or	Therapeutic vaccine	BPRC	2011	Published	[102]
	Recombinant E1/Alum	Phase I 20 healthy volunteers	E2-vaccinated animals; clear HCV infection in only E1-vaccinated animals (neutralizing antibodies) Induce strong cellular and humoral anti-E1 responses	Therapeutic vaccine	Fujirebio Europe	2004	Published	[103]
	Recombinant E1 and E2/MF59	Phase I 60 healthy volunteers	Induce humoral and cellular immune responses	Prophylactic vaccine	Novartis	2010	Completed	[104]
	Recombinant E1/Alum	Phase I/II 20 healthy volunteers and 35 patients with chronic HCV infection/122 HCV-infected patients	Induce HCV specific humoral and cellular immune responses (Th1 type); no change in HCV viral load	Therapeutic vaccine	Innogenetics/ GenImmune	2003/2008	Published	[103,105,106]
	HCV core protein/ISCOMATRIX	Phase I/IIa 30 healthy volunteers	Induce strong humoral immune responses in all except one patients; induce CD8+ T cell responses in 2 of 8 patients receiving the highest dose	Prophylactic vaccine	CSL Ltd	2009	Published	[107]
	GI5005: Inactivated recombinant Saccharomyces cerevisiae expressing NS3-core fusion protein/ GI-5005 plus SOC	Phase I/II 66 patients with chronic HCV infection/	Improve SVR	Therapeutic vaccine	GlobeImmune	2009/2010	Completed	[108,109]
Peptide-based vaccine	Peptide from core protein (C35-C44)/ISA51	Phase I 26 patients with chronic HCV infection	Induce peptide-specific cellular and humoral immune responses in 15 of 25 patients; decline HCV viral load in 2 of 25 patients	Therapeutic vaccine	Karume University	2009	Published	[110]
	Four peptides from E1, E2, NS3 and NS5A/Freund’s adjuvant	Phase I 12 nonresponder patients with chronic HCV infection	Induce peptide-specific cellular and humoral immune responses; decline HCV viral load in 3 patients	Therapeutic vaccine	Karume University	2007	Published	[111]
	Autologous dendritic cell delivered six CD8+ T cell epitope peptides from core, NS3 and NS4B	Phase I 6 nonresponder patients with chronic HCV infection	Induce transient T-cell response	Therapeutic vaccine	Burnet Institute + others	2010	Completed	[112]
	IC41: Five peptides from core, NS3, and NS4/Poly-L-arginine	Phase I/II 128 volunteers/60 non-responders with chronic HCV infection	Induce HCV-specific T-cell responses	Therapeutic vaccine	Intercell AG	2006/2008	Published	[113,114]
	IC41/Poly-L-arginine + imiquimod	Phase I 54 healthy volunteers	Induce significant T cell responses; low immunogenicity of topical imiquimod	Therapeutic vaccine	Intercell AG	2010	Published	[115]
	IC41 + imiquimod	Phase II 50 HCV-infected patients	Decline viral load; induce T cell responses	Therapeutic vaccine	Intercell AG	2012	Completed	[116]
Virus-like particles	Recombinant HCV-like particles (HCV-LPs) containing core, E1, and E2/AS01B	4 chimpanzees	Induce HCV-specific cellular immune responses; viral clearance	Prophylactic vaccine	NIH	2007	Published	[117]
	Recombinant baculovirus containing core, E1 and E2	Mice	Induce high titers of anti-E2 antibodies and strong HCV-specific cellular immune responses (CD8+ T and Th1 cells)	Prophylactic vaccine	NIH	2001	Published	[118]
Bacterial-vectored vaccine	Attenuated Salmonella typhimurium containing NS3 gene	Mice	Induce long-lasting T-cell responses	Therapeutic vaccine	NIH	2001	Published	[119]
Viral-vectored vaccine	Recombinant adenoviral vectors and plasmid DNA expressing NS3-NS5B	5 chimpanzees	Induce memory HCV-specific T cells; control of viremia	Prophylactic vaccine	NIH/Okairos	2012	Completed	[120]
	Multiple adenoviral vectors (Ad5, Ad6, Ad24, ChAd32 and ChAd33) expressing NS3-NS5B proteins	Mice and rhesus macaque	Induce strong cellular immune responses; long-term maintenance of memory cells	Prophylactic vaccine	Okairos	2006	Published	[121]
	Recombinant vaccinia viruses (rVV) expressing core, E1, E2, P7, NS2 and NS3	4 chimpanzees	Induce cellular immune responses; reduce viral load; resolve HCV infection	Prophylactic vaccine	NYC Blood Center	2008	Published	[122]
	Recombinant adenoviral vectors (Ad6 and ChAd3) expressing NS3-NS5B proteins	Phase I 40 healthy volunteers	Induce sustained HCV-specific T cell responses	Prophylactic vaccine	Okairos	2012	Completed	[123]
	Adenovirus vector (Ad6 and ChAd3) expressing NS3-NS5B proteins	Phase I 36 healthy volunteers	Highly immunogenic; induce HCV specific T cell responses	Prophylactic vaccine	Okairos and Oxford University	2009	Published	[124]
	TG4040: MVA vector expressing NS3, NS4 and NS5B proteins	Phase I 15 patients with chronic HCV infection	Decline HCV viral load in 7 of 15 patients associated with T-cell response	Therapeutic vaccine	Transgene	2009	Withdrawn	[125]
	MVA and ChAd3 vectors expressing NS3, NS4, NS5A and NS5B proteins	Phase I/II Healthy at risk population (68/472 IDU)	July 28, 2018: Final data collection date	Prophylactic vaccine	NIAID	2017	Ongoing	[126]
	TG4040 + SOC	Phase II 153 patients with chronic HCV infection	Induce HCV- and MVA-specific T-cell responses; develop anti-MVA antibodies; increase rate of early virologic response	Therapeutic vaccine	-	2014	Published	[127]
DNA vaccine	Recombinant DNA plasmid encoding E2	2 chimpanzees	Induce humoral and cellular immune responses; resolve the infection; prevent progression to chronicity	Prophylactic vaccine	NIAID/NIH	2000	Published	[128]
	Recombinant DNA plasmid and adenovirus vector expressing core, E1, E2 and NS3-5	8 chimpanzees	Induce HCV-specific T-cell and long-lasting E2-specific antibody responses; reduce viral load	Prophylactic vaccine	NIH	2005	Published	[129]
	Recombinant DNA plasmids and MVA vector expressing core, E1, E2 and NS3	6 chimpanzees	Induce HCV-specific immune responses; reduce viral load; early control of acute HCV infection; fail to impact on chronicity	Prophylactic vaccine	Transgene	2007	Published	[130]
	CIGB-230: Plasmid expressing core/E1/E2 plus recombinant core protein	Phase I 15 non-responder patients with chronic HCV infection	Induce humoral and cellular immune responses; no viral clearance	Therapeutic vaccine	University of Montreal + others	2009	Published	[131]
	ChronVac-C: Plasmid expressing NS3 and NS4A delivered by in vivo electroporation	Phase I/IIa 12 HCV-infected patients	Decline HCV viral load in 4 of 6 patients receiving the highest dose with corresponding HCV-specific T-cell response in 3 patients	Therapeutic vaccine	Tripep AB	2009	Recruiting	[132]

HCV: Hepatitis C virus; SOC: Standard-of-care (PEGylated-IFNalpha and ribavirin); Imiquimod: An activator of the toll-like receptor (TLR) 7; Ad: Human Adenovirus; ChAd: Chimpanzee Adenovirus; MVA: Modified vaccinia Ankara virus; IDU: Injecting drug user.