NS3 protease inhibitors for treatment of chronic hepatitis C: Efficacy and safety

Table 1 Direct-acting antivirals approved or at the computed tomography stage (phase II or III )

NS3/4A protease inhibitors	Polymerase inhibitors		Inhibitors
	Nucleotides/nucleosides	Non-nucleoside	NS5A	Cyclophilin
Generation I: Boceprevir (Merck)1 Telaprevir (Vertex)1	PSI-7977 (Pharmasset)1 PSI-938 (Pharmasset)1 Mericitabine (Roche/ Genentech)1 IDX-184 (Idenix)	Filibuvir (Pfizer)1 VX-222 (Vertex)1 Tegobuvir (Gilead)1 ANA-598 (Anadys)1 ABT-072 (Abbott)1 ABT-333 (Abbott)1	Daclatasvir (Bristol-Myers Squibb) GS-5885 (Gilead)1	Alisporivir (Novartis)1 SCY-635 (Scynexis)1
Generation II: Simeprevir (Tibotec) BI 201335 (Boehringer Ingelheim) Danoprevir (Roche/Genentech), studied with Ritonavir; Vaniprevir (Merck)2 BMS-650032 (Bristol-Myers Squibb)2 GS-9451 (Gilead)1 GS-9256 (Gilead)2 ACH-1625 (Achillion)1 ABT-450 (Abbott) MK-5172 (Merck)1

¹Approved by the United States Food and Drug Administration; phase II CT; phase III CT;

²Not studied. From Short Guide to Hepatitis C 2013, Mauss S, Berg T, Rockstroh J, Sarrazin C, Wedemeyer H.

Table 2 General protease inhibitor description with computed tomography results since 2011

PI	Genotype	PI treatment duration (wk)	Treatment duration (wk)	Treatment regimen	PEG-IFNα	Publication date
Telaprevir	1а/1b/1с/unknown	12/8	20/24/44/48	750 mg TID	(+)	2011
Boceprevir	1а/1b/unknown	24/32/44	28/36/48	800 mg TID	(+)	2011
Daclatasvir	1а/1b	24	24	60 mg/d	(+/-)	2012
Asunaprevir	1а/1b	24	24	600 mg BID	(+/-)	2012
АВТ-450	1а/1b	12	12	250/150 mg/d	(-)	2013

PI: Protease inhibitor; PEG-IFNα: PEGylated interferon-α.

Table 3 Telaprevir: clinical parameters

RCT	Dose frequency	Duration	SVR	Possible AE
Prove 1	Each 8 h, 6 t/d	24 wk: 12 wk of triple therapy, 12 wk of conventional treatment	61%	Rash, anemia, nausea, diarrhea
Advance	Every 8 h, 6 t/d	24-48 wk: 8-12 wk of viral response-based treatment followed by conventional treatment	69%-75%	Rash, anemia, nausea, diarrhea
Illuminate	Every 8 h, 6 t/d	24-48 wk: 12 wks of viral response-based treatment: 12 wk of triple therapy followed by conventional treatment	64%-92%	Rash, anemia, nausea, diarrhea
Optimize	Every 12 h, 6 t/d	24-48 wk: 12 wk of viral response-based treatment: 12 wk of triple therapy followed by conventional treatment for 12 to 36 wk	58%-81% (depending on fibrosis stage)	Rash, anemia, nausea

AE: Adverse event.

Table 4 Adverse events under telaprevir-based therapy

Agent RCT	Telaprevir
	Advance		Realize		Illuminate
	PR	T8/12PR	PR48	(lead-in) T12PR48	T12PR24/48
Serious AE	7%	9%	5%	12%	9%
Discontinued AVT due to AE	7%	10%	3%	15%-11%	18%
Anorectal symptoms	4%	8%-13%	7%	15%-12%	-
Taste disturbances	-	-	6%	12%	-
Anemia	19%	39%-37%	15%	30%-36%	39%
Severe neutropenia	19%	17%-14%	11%	14%-13%	-
Rash	24%	35%-37%	19%	37%-36%	37%
Fatigue	57%	58%-57%	40%	55%-50%	68%
Pruritus	36%	45%-50%	27%	52%-50%	51%
Nausea	31%	40%-43%	23%	35%-33%	47%
Diarrhea	22%	32%-28%	14%	25%-26%	30%

AE: Adverse event.; AVT: Antiviral treatment.

Table 5 Boceprevir: clinical parameters

RCT	Dose frequency	Duration	SVR	Possible AE
SPRINT 1	12 pills for 3 intakes	28-wk triple therapy vs 4-wk lead-in phase	54%-56%	Metal taste, anemia
		48-wk triple therapy vs 4-wk lead-in phase	67%-75%
SPRINT 2	12 pills for 3 intakes	28-48 wk: ''viral response-based treatment''; ''lead-in period''; if HCV RNA (-) by week 8 and 24, to stop at week 28; if HCV RNA (+), 20 wk of double therapy	67% And 44% were given abridged AVT	Taste disturbances, anemia, neutropenia

AE: Adverse event; AVT: Antiviral treatment; HCV: Hepatitis C virus.

Table 6 Adverse events under triple therapy

AgentRCT	Boceprevir
	SPRINT-2		RESPOND-2
	PR48	PR4/ PRB24/44	PR48	PR4/ PRB32/44
Serious AE	9%	11%-12%	5%	10%-14%
Discontinued AVT due to AE	16%	12%-16%	2%	8%-12%
Anorectal symptoms	-	-	-	-
Taste disturbances	18%	37%-43%	11%	43%-45%
Anemia	29%	49%	20%	43%-46%
Severe neutropenia	14%	24%-25%	9%	19%-20%
Rash	23%	25%-24%	5%	17%-14%
Fatigue	60%	53%-57%	50%	53.7%-57.1%
Pruritus	27%	24%-26%	17.50%	18.5%-19.3%
Nausea	42%	48%-43%	37.50%	43.8%-39.1%
Diarrhea	22%	22%-27%	15%	22.8%-23%

AE: Adverse event; AVT: Antiviral treatment.

Table 7 Effectiveness of combined therapy with asunaprevir n (%)

	Null response(n = 21)	Contraindications to IFN-basedtherapy (n = 22)
RVR4	20 (95.2)	15 (68.2)
RVR12	19 (90.5)	14 (63.6)
SVR24	19 (90.5)	14 (63.6)

Data of BMS CT, Suzuki et al[36], 2012. IFN: Interferon.

Table 8 Adverse event structure for asunaprevir

	Lok et al[35] AI447-011		Suzuki et al[36]
	ASV + DCV + conventional therapy(n = 10)	ASV + DCV(n = 11)	Null response (n = 21)	Contraindications to IFN-based therapy (n = 22)
Diarrhea	70.0%	72.7%	43%	9%
Fatigue	70.0%	54.5%	-1	-1
Headache	50.0%	45.5%	38%	27%
Nausea	50.0%	18.2%	-1	-1
Coughing	20.0%	27.3%	-1	-1
Subfebrile temperature	27.3%	10.0%	14%	23%

¹Adverse events are not shown because they were observed in fewer than 3 patients. AE: Adverse event; ASV: Asunaprevir; DCV: Daclatasvir; IFN: Interferon.

Table 9 AVIATOR, phase IIa study (combination of ABT-450 + ritonavir + ABT-333 + ribavirin)

Study arm	n	Genotype	Status	Combination	Duration	Treatment regimen	SVR
Total: group 1 + 2	33	1а/1b (28/5)	Naive	АВТ-450 + ritonavir + АВТ-333 + ribavirin	12 wk	АВТ-450, 250 mg/d or 150 mg/d + ritonavir, 100 mg/d; АВТ-333, 400 mg BID; ribavirin, body weight-based	93%-95%
3	17	1а/1b (16/1)	partial virologic response, null response	АВТ-450 + ritonavir + АВТ-333 + ribavirin	12 wk	АВТ-450, 150 mg/d; ritonavir, 100 mg/d; АВТ-333, 400 mg BID; ribavirin, body weight-based	47%

Table 10 SVR rate depending on IL28B polymorphism

Study arm	Status	CC-genotype	CT-genotype	TT-genotype	SVR
1	Naive	10/9	7/7	2/2	95%
2	Naive	5/4	7/7	2/2	93%
3	Partial virologic response, null response	0/0	12/6	5/2	47%

Table 11 Adverse event incidence of ABT-450 + ritonavir + ABT-333 + ribavirin combination

AEs with incidence above 20%	AE incidence
Headache	14%-26%
Fatigue	35%-47%
Insomnia	0-26%
Nausea	21%-24%
Rash	6%-21%

AE: Adverse event.

Table 12 SVR rate in genotype 1 hepatitis C virus patients n (%)

	GS-9256 + tegobuvir(n = 15)	GS-9256 + tegobuvir + ribavirin by weight (n = 13)	GS-9256 + tegobuvir + ribavirin by weight + PEG-IFNα(n = 14)
Week 4, RVR	1/15 (7)	6/13 (46)	10/14 (71)
Week 12, EVR	3/15 (20)	8/13 (62)	14/14 (100)
Week 24, SVR	10/15 (67)	13/13 (100)	13/14 (94)

PEG-IFNα: PEGylated interferon-α.

Table 13 Most common adverse event after 4 treatment weeks

	GS-9256 + tegobuvir	GS-9256 + tegobuvir + ribavirin by weight	GS-9256 + tegobuvir + ribavirin by weight + PEG-IFN1
AE incidence	50%	93%	81%-100%
Anemia	0	0	0-13%
Eye pain	0	0	0-13%
Diarrhea	19%	20%	6%-40%
Nausea	13%	20%	6%-40%
Flu-like syndrome	0	0	44%-80%
Fatigue	6%	33%	13%-33%
Headache	31%	47%	13%-40%
Insomnia	0	20%	6%-13%
Dry skin	0	13%	0%
Pruritus	6%	20%	0%-7%

¹Mean value of two CT phases. AE: Adverse event; PEG-IFN: PEGylated interferon.

Table 14 SVR dependence in null responders for various direct-acting antiviral combinations

Ref.	n	Combination	Duration	SVR
Zeuzem et al[39]	37	Telaprevir-based triple therapy	48 wk	33%
Bacon et al[25]	58	Boceprevir-based triple therapy	48 wk	52%
Lok et al[35]	11	DCV + ASV	24 wk	36%
Lok et al[35]	10	DCV + ASV + conventional therapy	24 wk	90%
Suzuki et al[36]	21
Poordad et al[37]	7	ABT-450 + ritonavir + АВТ-333 + ribavirin	12 wk	43%

DCV: Daclatasvir; ASV: Asunaprevir.