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2013/2014 HCV DRUG PIPELINE UPDATE

July 2014

By Tracy Swan

Thanks to Jules Levin

This update includes presentations from the American Association for the Study of Liver Diseases (AASLD) Meeting, the Conference on Retroviruses and Opportunistic Infections (CROI), the European Association for the Study of the Liver (EASL) International Liver Congress, Digestive Disease Week (DDW), and publications from peer-reviewed scientific journals.


Time for a Cure

Worldwide, an estimated 500,000 people die from complications of hepatitis C virus (HCV) infection each year.1 In Spain and the United States, more people are now dying from HCV complications than from AIDS.2,3 In 2010, more than 16,000 people in the U.S.—most of them between 45 and 64 years of age—died from hepatitis C.3 Chronic hepatitis C infection increases the risk for, and rate of, all-cause mortality, and can shorten lifespan.4 People with chronic hepatitis C are dying twenty years earlier than their peers from non–liver related illnesses (heart attacks, type 2 diabetes, hypertension, and respiratory failure).5

Being cured of HCV (also referred to as sustained virologic response, or SVR) lowers the risk of liver-related and all-cause morbidity and mortality, regardless of HIV status or presence of advanced liver disease.6,7,8,9 SVR also is known to improve overall health-related quality of life, cognition, and fatigue.10,11,12



Moving into the Era of Direct-Acting Antivirals (DAAs)

In 2013 and 2014, research into the safety, efficacy, and tolerability of HCV treatment with oral, direct-acting antivirals (DAAs) have generated a wealth of data. Soaring cure rates have been reported in people with different HCV genotypes, HIV/HCV coinfection, and liver transplant candidates and recipients, regardless of treatment experience or extent of liver damage.

Second-Wave HCV Protease Inhibitors: Faldaprevir and Simeprevir

In November 2013, the U.S. Food and Drug Administration (FDA) approved simeprevir, the first once-daily HCV protease inhibitor, and the European Medicines Agency (EMA) followed suit in May 2014. Faldaprevir, another once-daily HCV protease inhibitor, did not make it to the finish line. Simeprevir and faldaprevir were developed with peginterferon and ribavirin (PEG-IFN/RBV) in HCV genotype 1.

Simeprevir offers more convenient dosing and fewer side effects than the first generation of protease inhibitors. Simeprevir does not rely on response-guided therapy; the treatment algorithm has been simplified (24 weeks for treatment-naive and relapsers; 48 weeks for partial and null responders). But as the peginterferon-free era gets under way, it is likely that simeprevir will not be used in the way it was developed.


Faldaprevir and Simeprevir Phase III

More treatment-naive participants and relapsers were eligible for shorter, response-guided treatment with faldaprevir or simeprevir-based regimens (>80%) than telaprevir- or boceprevir-based regimens (~60%).13,14,15,16,17 Cure rates ranged from 70 percent to over 80 percent in treatment-naive study participants, and from 75 to 85 percent in relapsers; most were treated for 24 weeks.13,16,17,18

In contrast, partial and null responders were treated for 48 weeks; cure rates ranged from 53 to 76 percent in partial responders, and from 33 to 51 percent in null responders.19,20

Simeprevir and faldaprevir share certain limitations. Each can cause rash and photosensitivity (hats, protective garments, and sunscreen are required during use), and both drugs are less effective against HCV genotype 1a than 1b. Neither drug may be appropriate for people with advanced liver damage (cirrhosis; Child–Pugh stage B and C), although both have been studied in people with early-stage cirrhosis (Child–Pugh stage A). In fact, simeprevir was approved without a dosing recommendation for people with Child–Pugh stage B or C.

With simeprevir, loss of efficacy is linked with the Q80K mutation (found almost exclusively in genotype 1a). The Q80K mutation significantly decreases simeprevir’s efficacy when it is used with PEG-IFN/RBV (data on the impact of Q80K in simeprevir-based, peginterferon-free regimens are limited).13 The FDA therefore recommends baseline resistance testing in genotype 1a, and that other treatment options be considered for people with the Q80K mutation.

In June 2014, Boehringer Ingelheim halted further development of faldaprevir. Deleobuvir (a non-nucleoside polymerase inhibitor paired with faldaprevir), had already been discontinued. 


The DAA Era

In step with the evolution of HCV treatment, simeprevir is being studied in peginterferon-free regimens. Simeprevir is in trials with VX-135, a nucleotide polymerase inhibitor, and is being studied with or without TMC647055/r (a ritonavir-boosted non-nucleoside polymerase inhibitor), ribavirin, and the NS5A inhibitor samatasvir (formerly IDX719) plus ribavirin. A trial of simeprevir and daclatasvir (NS5A inhibitor), with or without ribavirin, reported disappointing results in genotype 1a, possibly due to a suboptimal daclatasvir dose.21

COSMOS

All-oral regimens are urgently needed for people with hepatitis C genotype 1 and advanced liver damage, since peginterferon may be too dangerous, too toxic, or ineffective. In the COSMOS trial, simeprevir and sofosbuvir (with or without ribavirin) cured over 90 percent of trial participants with various poor prognostic factors (prior null response or cirrhosis) (see tables 1 and 2). COSMOS was a clinical collaboration between Janssen and Pharmasset. Gilead—which purchased Pharmasset—has refused to continue the collaboration.

Instead, Janssen is supporting OPTIMIST 1 and 2, phase III trials of simeprevir and sofosbuvir. On May 7, 2014, the company submitted a supplemental new drug application to the FDA, seeking formal approval for the simeprevir/sofosbuvir combination. These drugs can still be coprescribed in the absence of formal approval (known as off-label use); in fact, the regimen is included in HCV treatment recommendations from the AASLD and the Infectious Diseases Society of America (IDSA), the Department of Veterans Affairs, and EASL.

Even after approval, the high cost of this combination ($150,000 in the United States) may limit its accessibility.

Table 1. COSMOS Cohort 1: Null Responders, Mild Fibrosis (Metavir Score: F0 to F2); N = 39

Treatment Arms

SVR-12* Overall

Genosubtype and Q80K Mutation

1a +Q80K

1a -Q80K

1b

12 weeks, 2 drugs

93% (13/14)

83% (5/6)

100% (4/4)

100% (4/4)

12 weeks, 3 drugs

96% (26/27)

89% (8/9)

100% (12/12)

100% (6/6)

24 weeks, 2 drugs

93% (14/15)

100% (3/3)

100% (7/7)

100% (3/3)

24 weeks, 3 drugs

79% (19/24)

89% (8/9)

100% (7/7)

100% (4/4)

*5 nonvirologic failures were not included; there were 3 relapses.
Source: Sulkowski MS, Jacobson IM, Ghalib R, et al. Once-daily simeprevir (TMC-435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype-1 prior null responders with METAVIR F0-2: COSMOS study subgroup analysis (Abstract 7). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.


 

Table 2. COSMOS, Cohort 2: Treatment-Naive or Null Responders, Precirrhosis or Cirrhosis (Metavir Score: F3 or F4); N = 87

Treatment Arms

SVR-12* Overall

Genosubtype and Q80K Mutation

Cirrhosis Stage

1a +Q80K

1a -Q80K

1b

F3

F4

12 weeks, 2 drugs

93% (13/14)

100% (3/3)

88% (7/8)

100% (3/3)

100% (7/7)

86% (6/7)

12 weeks, 3 drugs

93% (25/27)

88% (7/8)

93% (13/14)

100% (5/5)

94% (15/16)

91% (10/11)

24 weeks, 2 drugs

100% (16/16)

100% (4/4)

100% (7/7)

100% (4/4)

100% (6/6)

100% (9/9)

24 weeks, 3 drugs

93% (28/30)

100% (11/11)

100% (11/11)

100% (6/6)

100% (16/16)

100% (12/12)

*2 nonvirologic failures were not included; there were 3 relapses.
Source: Lawitz E, Ghalib R, Rodriguez-Torres, et al. Simeprevir plus sofosbuvir with/without ribavirin in HCV genotype-1 prior null-responder/treatment-naive patients (COSMOS study): primary endpoint (SVR-12) results in patients with METAVIR F3-4 (cohort 2) (Abstract 0165). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.

 

Genotype 1

There are several short and highly effective DAA regimens in development for HCV genotype 1. Duration of treatment is generally 12 weeks, although it has been shortened to 6 or 8 weeks in treatment-naive people, and extended to 24 weeks in people with cirrhosis.

In clinical trials, SVR rates among both treatment-naive and treatment-experienced people range from 50 percent to 100 percent; most regimens cured over 90 percent of study participants (see tables 3 and 4). Cure rates  were either not reported—or did not differ significantly—by IL28B genotype.

Table 3. Interferon-Free Regimens for HCV Genotype 1, Treatment-Naive

Trial (regimen, N, population, and phase)

Treatment Arms

SVR-12 (unless otherwise noted)

Genosubtype 1a vs. 1b

Cirrhosis

Treatment Discontinuations and Common Adverse Events (AEs)

Sponsor: AbbVie

PEARL-I
ABT-450/r QD + ABT-267 QD (ombitasvir)
N = 42

G1b only

Noncirrhotic

Phase II

12 weeks, 2 drugs

95.2% (40/42)

N/A

N/A

No AE-related discontinuations;

AEs ≥10%:

headache, nausea, dry skin, fatigue, pruritus, diarrhea

PEARL-III
3-D regimen: ABT-450/r QD
+ ABT-267 QD (ombitasvir)
+ ABT-333 BID (dasabuvir)
± RBV

N = 419

G1b only

Noncirrhotic

Phase III

12 weeks, 3 drugs

99% (207/209)

 

N/A

N/A

No AE-related discontinuations;

AEs ≥5%: headache, fatigue, pruritus, nausea, insomnia, diarrhea

12 weeks, 4 drugs

99.5% (209/210)

PEARL-IV

3-D regimen ± RBV

N = 305

G1a only

Noncirrhotic

Phase III

12 weeks, 3 drugs

90% (185/205)

N/A

N/A

2 AE-related discontinuations;

AEs ≥5%: headache, fatigue, pruritus, nausea, insomnia, diarrhea

12 weeks, 4 drugs

97% (97/100)

SAPPHIRE-I

3-D regimen + RBV

N = 631

Placebo (N = 158)

Noncirrhotic

Phase III

12 weeks, 4 drugs

96.2% (455/473)

Higher in 1b

Lower in F3 than F0–F2

3 AE-related discontinuations;

AEs ≥10% (in active drug arm): fatigue, headache, nausea, pruritus, insomnia, diarrhea, asthenia, rash

TURQUOISE-II

3-D regimen + RBV

N = 160

Compensated cirrhosis

Phase III

12 weeks, 4 drugs

94% (81/86)

Higher in 1b

N/A

8 AE-related discontinuations (entire study,
N = 380);
AEs ≥10%: fatigue, headache, nausea, pruritus, insomnia, diarrhea, asthenia, rash, irritability, anemia, dyspnea

24 weeks, 4 drugs

95% (70/74)

Sponsor: BMS

A1443-014
asunaprevir BID
+ BMS-791325 BID (75 mg or 150 mg)
+ daclatasvir QD

N = 166

Cirrhosis: 9% (N = 15)

Phase II

12 weeks, 3 drugs

(75 mg of
BMS-791325)

92.2% (71/77)

Higher in 1b

Sample too small to determine

1 AE-related discontinuations;

AEs ≥10%:

headache, asthenia, diarrhea, nausea, abdominal pain

 

12 weeks, 3 drugs (150 mg of
BMS- 791325)

91.7% (77/84)

HALLMARK DUAL
asunaprevir BID
+ daclatasvir QD

N = 307
Placebo (N = 102)

G1b only

Cirrhosis: 11% (N = 33)

Phase III

24 weeks, 2 drugs

90% (182/203)

N/A

No significant difference

No AE-related discontinuations (active drug arm);

AEs ≥10%: headache, diarrhea, fatigue, nausea

Sponsor: Gilead

GS-5816 QD
(25 mg or 100 mg)
+ sofosbuvir QD

N = 55

Noncirrhotic

Subset of multigenotypic study

Phase II

12 weeks, 2 drugs
(25 mg of
GS-5816)

96% (26/27)

N/A

No significant difference

No AE-related discontinuations;

AEs ≥5%: fatigue, headache, nausea, constipation, diarrhea, anxiety, nasopharyngitis, vomiting, oropharyngeal pain, dyspepsia, rash, back pain, upper abdominal pain, dysmenorrhea, irritability

12 weeks, 2 drugs
(100 mg of GS-5816)

100% (28/28)

ION-1
FDC QD: sofosbuvir/
ledipasvir ± RBV

N = 865

Cirrhosis: 16% (N = 136)

Phase III

 

12 weeks, 2 drugs

99% (211/214)

Not reported

No significant difference

6 AE-related discontinuations (24- week arms);

AEs ≥10%: fatigue, headache, insomnia, nausea, asthenia, diarrhea, rash, irritability, cough, pruritus, arthralgia, anemia

12 weeks, 3 drugs

97% (211/217)

24 weeks, 2 drugs

98% (212/217)

24 weeks, 3 drugs

99% (215/217)

ION-3
FDC ± RBV

N = 647

Noncirrhotic

Phase III

 

8 weeks, 2 drugs

94% (202/215)

Slightly higher in 1b (8-week arms)

N/A

4 AE-related discontinuations;

AEs ≥5%: fatigue, headache, nausea, insomnia, irritability, diarrhea, arthralgia, constipation, dizziness, rash, pruritus, cough, anemia, muscle spasms, dyspnea

8 weeks, 3 drugs

93% (201/216)

12 weeks, 2 drugs

95% (206/216)

LONESTAR
FDC ± RBV

N = 60

Noncirrhotic

Phase II

8 weeks, 2 drugs

SVR-24:
95% (19/20)

No significant difference

N/A

No AE-related discontinuations;

AEs ≥5%: nausea, anemia, upper respiratory tract infection, headache, abdominal pain, bronchitis, back pain, decreased appetite, dermatitis, muscle spasms

8 weeks, 3 drugs

SVR-24:
100% (21/21)

12 weeks, 2 drugs

SVR-24:
95% (18/19)

Sponsor: Merck

C-SPIRIT
MK-5172 QD + RBV

N = 23

Noncirrhotic,

IL28B CC only

Phase II

12 weeks, 2 drugs (early responders)

62.5% (5/8)

45% (5/11) vs. 83% (10/12)

N/A

No AE-related discontinuations;

AEs ≥10%: headache, asthenia, insomnia, dyspepsia, anemia, nausea

 

24 weeks, 2 drugs
(did not meet criteria for shortened Tx)

50% (2/4)

24 weeks, 2 drugs

SVR-4:
72.7% (8/11)

C-WORTHY
MK-5172 QD
+ MK-8742 QD
(20 or 50 mg)
± RBV

N = 159

Noncirrhotic

Phase II

Genotype 1a only

8 weeks, 3 drugs

SVR-4:
83% (25/30)

N/A

N/A

4 discontinuations
(reasons not reported);

AEs ≥10%: fatigue, headache, nausea, diarrhea, insomnia

12 weeks, 3 drugs,

(20 mg or 50 mg MK-8742)

SVR-8:
94% (80/85)

12 weeks, 2 drugs (50 mg MK-8742)

SVR-8:
98% (43/44)

C-WORTHY
MK-5172 QD + MK-8742 QD (50 mg) ± RBV

N = 123

Cirrhotic

Phase II

12 weeks, 2 drugs

SVR-8:
97% (28/29)

Slightly higher in 1b

N/A

3 AE-related discontinuations

(includes 130 additional null responder participants);

AEs ≥10%: fatigue, headache, asthenia

12 weeks, 3 drugs

SVR-8:
90% (28/31)

18 weeks, 2 drugs

SVR-4:

97% (29/30)

18 weeks, 3 drugs

SVR-4:
97% (30/31)

Sponsor: National Institute of Allergy and Infectious Diseases

SYNERGY
FDC sofosbuvir/
ledipasvir
± GS-9669 or
± GS-9451

N = 60

Cirrhosis: (N = 3) in 12-week arm

Phase II

12 weeks, 2 drugs

100% (20/20)

No Significant difference (small sample size)

No AE-related discontinuations;

AEs ≥10%: headache, diarrhea, common cold, rash, night sweats, constipation, vomiting, nausea, shoulder pain

6 weeks, 3 drugs (+ GS-9669)SVR-2: 95% (19/20)
6 weeks, 3 drugs (+ GS-9451)SVR-4: 100% (20/20)

Sources:
Afdhal N, Zeuzem S, Kwo P, et al.; the ION-1 Investigators. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014 May 15;370(20):1889–98. doi: 10.1056/NEJMoa1402454.
Everson GT, Thuluvath PI, Lawitz E, et al. All-oral combination of daclatasvir, asunaprevir and BMS-791325 for HCV genotype 1 infection (Abstract 52). Paper presented at: 21st Conference on Retroviruses and Opportunistic Infections; 2014 March 3–6; Boston, MA.
Everson GT, Tran TT, Towner WJ, et al. Safety and efficacy of treatment with interferon-free, ribavirin-free combination of sofosbuvir + GS-5816 in treatment-naive patients with genotypes 1-6 HCV infection (Abstract 111). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014 Apr 24;370(17):1594–603. doi: 10.1056/NEJMoa1315722.
Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014 May 22;370(21):1983–92. doi: 10.1056/NEJMoa1402338.
Gane EJ, Ben Ari Z, Mollison L, et al. Efficacy and safety of MK-5172 + ribavirin in treatment-naive patients with hepatitis C virus genotype1 infection: final results of the C-SPIRIT study (Abstract 1233). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Kohli A, Sims Z, Marti M, et al. Combination oral, hepatitis C antiviral therapy for 6 or 12 weeks: results of the SYNERGY trial (Abstract 27 LB). Paper presented at: 21st Conference on Retroviruses and Opportunistic Infections; 2014 March 3–6; Boston, MA.
Kowdley KV, Gordon SC, Reddy KR, et al.; ION-3 Investigators. N Engl J Med. 2014 May 15;370(20):1879–88. doi: 10.1056/NEJMoa1402355.
Lawitz E, Vierling J, Murillo A, et al. High efficacy and safety of the all-oral combination regimen, MK-5172/MK-8742 ± RBV for 12 weeks in HCV genotype 1 infected patients: the C-WORTHY study (Abstract 76). Paper presented at: 64th Annual Meeting of the American Association for the Study of Liver Diseases; 2013 November 1–14; Washington, D.C.
Lawitz E, Hezode C, Varunok P, et al. Interferon- and ribavirin- free regimen of ABT-450/r + ABT-267 in HCV genotype 1b-infected treatment-naive patients and prior null responders (Abstract 74). Paper presented at: 64th Annual Meeting of the American Association for the Study of Liver Diseases; 2013 November 1–14; Washington, D.C.
Lawitz E, Poordad FF, Pang PS, et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet. 2014 Feb 8;383(9916):515–23. doi: 10.1016/S0140-6736(13)62121-2.
Lawitz E, Hezode C, Gane E, et al. Efficacy and safety of MK-5172 and MK-8742 ± ribavirin in hepatitis C genotype 1 infected patients with cirrhosis or previous null response: the C-WORTHY Study (Abstract 61). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Manns MP, Pol S, Jacobson IM, et al. All-oral dual therapy with daclatasvir and asunaprevir in patients with HCV genotype 1b infection: phase 3 HALLMARK-DUAL study results (Abstract 166). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014 May 22;370(21):1973–82. doi: 10.1056/NEJMoa1402869.

 

Table 4. Interferon-Free Regimens* for HCV Genotype 1, Treatment-Experienced

Trial (regimen, N, population, and phase)

Treatment Arms

SVR-12 (unless otherwise noted)

Genosubtype 1a vs. 1b

Cirrhosis

Treatment Discontinuations and Common Adverse Events (AEs)

Sponsor: AbbVie

PEARL-II
3-D regimen:
ABT-450/r QD
+ ABT-267 QD (ombitasvir)
+ ABT-333 BID (dasabuvir)
± RBV

N = 179

G1b only

Noncirrhotic

Phase III

12 weeks, 3 drugs

100% (91/91)

N/A

N/A

2 AE-related discontinuations;

AEs >10%: headache, fatigue

12 weeks, 4 drugs

97% (85/88)

SAPPHIRE-II
3-D regimen + RBV

N = 394

Noncirrhotic

Placebo (N = 97)

Phase III

12 weeks, 4 drugs

96.3% (286/297)

No significant difference

N/A

3 AE-related discontinuations;

AEs ≥10% (in active drug arm): fatigue, headache, pruritus

TURQUOISE-II
3-D regimen + RBV

N = 220

Compensated cirrhosis

Phase III

12 weeks, 4 drugs

94% (81/86)

Higher in 1a null responders 24-week arm

N/A

8 AE-related discontinuations (entire study, N = 380);

AEs ≥10%: fatigue, headache, nausea, pruritus, insomnia, diarrhea, asthenia, rash, irritability, anemia, dyspnea

24 weeks, 4 drugs

95% (70/74)

Sponsor: BMS

HALLMARK DUAL
asunaprevir BID
+ daclatasvir QD

N = 440

G1b only; Phase III

Treatment-experienced (N = 205)

Cirrhosis: 31% (63/205)

24 weeks, 2 drugs

82% (166/203); Null:
82% (98/119);

Partial:
81% (68/84)

N/A

No significant difference

No AE-related discontinuations (active drug arm);

AEs ≥10%: headache, diarrhea, fatigue, nausea, asthenia

Interferon-ineligible/
intolerant (N = 235)

Cirrhosis: 47% (111/235)

83% (192/235)

Sponsor: Gilead

ELECTRON
FDC sofosbuvir/
ledipasvir ± RBV

N = 19

Cirrhosis

Phase II

12 weeks, 2 drugs

70% (7/10)

No significant difference

N/A

No AE-related discontinuations;

AEs ≥15%: fatigue, headache, nausea, insomnia, upper respiratory tract infection, lethargy, diarrhea, exertional dyspnea

12 weeks, 3 drugs

100% (9/9)

ELECTRON-2
FDC sofosbuvir/
ledipasvir + RBV

N = 19

Prior sofosbuvir treatment, noncirrhotic

Phase II

12 weeks, 3 drugs

100% (19/19)

No significant difference

N/A

No AE-related discontinuations;

AEs ≥15%: fatigue, headache, nausea, insomnia, upper respiratory tract infection, cough, hemolytic anemia, rash

ION-2
FDC ± RBV

N = 440

Prior protease treatment: 52% (N = 231)

Cirrhosis: 31% (N = 136)

Phase III

 

12 weeks, 2 drugs

94% (102/109)

Not reported

 

No AE-related discontinuations;

AEs ≥10%: fatigue, headache, insomnia, nausea, diarrhea, rash, irritability, cough, dizziness, dyspnea, upper respiratory tract infection, muscle spasms, anemia, dry skin, arthralgia

12 weeks, 3 drugs

96% (107/111)

24 weeks, 2 drugs

99% (108/109)

24 weeks, 3 drugs

99% (110/111)

LONESTAR
FDC ± RBV

N = 40

Prior protease treatment: 50% (N = 20)

Cirrhosis: 20% (N = 8)

Phase II

12 weeks, 2 drugs

SVR-24: 95% (18/19)

Not reported

No significant difference

No AE-related discontinuations;

AEs ≥5% (in 100 participants, not broken out by treatment experience): nausea, anemia, upper respiratory tract infection, headache

12 weeks, 3 drugs

SVR-24: 100% (21/21)

Re-treatment Study
sofosbuvir
+ PEG-IFN/RBV

N = 80

Noncirrhotic

Prior treatment with DAAs

90% had ≥1 resistance associated variant [RAV])

Interim results: 67/80

Phase II

12 weeks, 3 drugs

74% (37/50)

 

RAVs–NS3:
50% (6/12)

NS3 + NS5A:
75% (18/24)

NS3 + NS5A + NS5B:
93% (13/14)

 

Not reported

N/A

No AE-related discontinuations; AEs ≥10%: fatigue, headache, nausea, neutropenia, rash, myalgia, dizziness, pruritus, anemia, insomnia, cough

Sponsor: Merck

C-WORTHY
MK-5172 QD
+ MK-8742 QD
± RBV

N = 130

Null responders;

Cirrhosis: 39% (N = 51)

Phase II

12 weeks, 2 drugs

SVR-8:
91% (30/33)

Slightly higher in 1b

Not reported

3 AE-related discontinuations

(includes 123 additional treatment-naive participants);

AEs ≥10%: fatigue, headache, asthenia

12 weeks, 3 drugs

SVR-8:
94% (30/32):

18 weeks, 2 drugs

SVR-4:
97% (29/30)

18 weeks, 3 drugs

SVR-4:

100% (32/32)

*Except for re-treatment trial.

Sources:
AbbVie (Press Release). AbbVie completes largest phase III program of an all-oral, interferon-free therapy for the treatment of hepatitis C genotype 1. 2014 January 31. Available from: http://abbvie.mediaroom.com/2014-01-31-AbbVie-Completes-Largest-Phase-III-Program-of-an-All-Oral-Interferon-Free-Therapy-for-the-Treatment-of-Hepatitis-C-Genotype-1. (Accessed on 2014 April 29)
Afdhal N, Reddy KR, Nelson DR, et al.; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014 Apr 17;370(16):1483–93. doi: 10.1056/NEJMoa1316366.
Andreone P, Colombo MG, Enejosa JV, et al.; on behalf of the PEARL-II investigators. PEARL-II: randomized phase 3 trial of interferon-free, 12-week regimen of ABT-450/r/ABT-267, ABT-333 with or without ribavirin in hepatitis C virus, genotype 1b-infected, treatment-experienced patients (Abstract SU 1061). Paper presented at Digestive Disease Week 2014; 2014 May 3–6; Chicago, IL.
Gane EJ, Stedman CA, Hyland RH, et al. Once-daily sofosbuvir/ledipasvir fixed-dose combination with or without ribavirin: data from the ELECTRON trials (Abstract 73). Paper presented at: 64th Annual Meeting of the American Association for the Study of Liver Diseases; 2013 November 1–14; Washington, D.C.
Gane EJ, Hyland RH, An D, et al. Ledipasvir/sofosbuvir fixed-dose combination is safe and effective in difficult-to-treat populations including GT3 patients, decompensated GT1 patients and GT1 patients with prior sofosbuvir experience (Abstract 6). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Lawitz E, Hezode C, Varunok P, et al. Interferon- and ribavirin- free regimen of ABT-450/r + ABT-267 in HCV genotype 1b-infected treatment-naive patients and prior null responders (Abstract 74). Paper presented at: 64th Annual Meeting of the American Association for the Study of Liver Diseases; 2013 November 1–14; Washington, D.C.
Lawitz E, Poordad FF, Pang PS, et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet. 2014 Feb 8;383(9916):515–23. doi: 10.1016/S0140-6736(13)62121-2.
Lawitz E, Hezode C, Gane E, et al. Efficacy and safety of MK-5172 and MK-8742 ± ribavirin in hepatitis C genotype 1 infected patients with cirrhosis or previous null response: the C-WORTHY Study (Abstract 61) Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Manns MP, Pol S, Jacobson IM, et al. All-oral dual therapy with daclatasvir and asunaprevir in patients with HCV genotype 1b infection: phase 3 HALLMARK-DUAL study results (Abstract 166). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Pol S, Sulkowski MS, Hassanein T, et al. Successful retreatment of HCV genotype-1 infected patients who failed prior therapy with peg-interferon and ribavirin plus one or two other direct-acting agents with sofosbuvir (Abstract 55). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014 May 22;370(21):1973–82. doi: 10.1056/NEJMoa1402869.
Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014 Apr 24;370(17):1604–14. doi: 10.1056/NEJMoa1401561.

 

Genotype 3

Given the global distribution of HCV genotype 3, there is urgent need for DAA regimens that are effective against it. Sofosbuvir is the backbone of HCV treatment in genotype 3; several sofosbuvir-based regimens have been studied in genotype 3. Combining sofosbuvir with an NS5A inhibitor (daclatasvir or GS-5816) has shown great promise; ongoing trials are exploring these combinations.

Triple therapy with sofosbuvir plus PEG-IFN and RBV is highly effective, regardless of treatment experience. In small trials, this combination cured 100 percent of treatment-naive, noncirrhotic participants and 83 percent to 91 percent of treatment-experienced, noncirrhotic participants.22,23,24,25

Without peginterferon, SVR rates are lower. Extending duration of treatment increases efficacy of sofosbuvir plus RBV. In treatment-naive, noncirrhotic study participants, SVR rates ranged from 56 percent after 12 weeks of treatment to 93 percent after 24 weeks of treatment in the FISSION and VALENCE trials.26,27

In FUSION, only 19 percent of treatment-experienced, cirrhotic participants were cured; adding 4 additional weeks of treatment increased SVR to 61 percent; in VALENCE, 24 weeks of sofosbuvir and RBV cured 60 percent of treatment-experienced cirrhotics.22,25 Adding peginterferon boosts cure rates: 83 percent to 88 percent of treatment-experienced cirrhotics were cured after 12 weeks of treatment with sofosbuvir plus PEG-IFN and RBV.22,25


Table 5. Regimens for HCV Genotype 3, Treatment-Naive and Treatment-Experienced

Trial (regimen, N, population, and phase)

Treatment Arms

SVR-12

SVR-12, Cirrhosis

Treatment Discontinuations and Common Adverse Events (AEs)

ELECTRON
sofosbuvir + RBV + PEG-IFN

N = 18

Treatment-naive, noncirrhotic

Phase II

12 weeks SOF + RBV,
4 weeks of PEG-IFN

100% (6/6)

N/A

No AE-related discontinuations;

AEs ≥10%: headache, fatigue, insomnia, nausea, rash, anemia, dizziness, myalgia, diarrhea, irritability, pruritus, decreased appetite, upper respiratory tract infection, arthralgia, back pain, pyrexia

12 weeks SOF + RBV,
8 weeks of PEG-IFN

100% (6/6)

12 weeks SOF + RBV,
12 weeks of PEG-IFN

100% (6/6)

ELECTRON-2
FDC: sofosbuvir/
ledipasvir ± RBV

N = 51

Treatment-naive;

Cirrhosis: 16% (N = 8)

Phase II

12 weeks, 2 drugs

64% (16/25)

Not reported

1 AE-related discontinuation (not likely to be treatment-related);

AEs ≥15%: headache, upper respiratory tract infection, nausea, fatigue, insomnia, cough, hemolytic anemia, rash

12 weeks, 3 drugs

100% (26/26)

 

FISSION
sofosbuvir + RBV vs.
PEG-IFN/RBV

N = 359

Treatment-naive;

Cirrhosis: 20% (N = 75)

Phase III

12 weeks SOF + RBV

56% (102 /183)

34% (13/38)

3 AE-related discontinuations in SOF arm,
26 in PEG-IFN/RBV arm;

AEs ≥15% (SOF arm only): fatigue, headache, nausea

 

24 weeks PEG-IFN/RBV

63% (110/176)

30% (11/37)

FUSION
sofosbuvir + RBV

N = 127

Treatment-experienced;

Cirrhosis: 40% (N = 49)

Phase III

12 weeks, 2 drugs

30% (19/64)

19% (5/26)

1 AE-related discontinuation;
AEs in ≥10%: anemia, nausea, diarrhea, fatigue, irritability, upper respiratory tract infection, arthralgia, dizziness, insomnia, cough pruritus, rash

16 weeks, 2 drugs

62% (39/63)

61% (14/23)

GS-5816 + sofosbuvir

N = 54

Treatment-naive,

noncirrhotic

Phase II

12 weeks, 2 drugs
(25 mg GS-5816)

93% (25/27)

N/A

No AE-related discontinuations;
AEs ≥5% (entire study population): fatigue, headache, nausea, constipation, diarrhea, anxiety, nasopharyngitis, vomiting, oropharyngeal pain, dyspepsia, rash, back pain, upper abdominal pain, dysmenorrhea, irritability

12 weeks, 2 drugs
(100 mg GS-5816)

93% (25/27)

 

LONESTAR-2

sofosbuvir + PEG-IFN/RBV

N = 24

Treatment-experienced;

Cirrhosis: 50% (N = 12)

Phase II

12 weeks, 3 drugs

83% (20/24)

83% (10/12)

1 AE-related discontinuation;

AEs in ≥15% (entire study population): flu-like symptoms, fatigue, anemia, neutropenia, nausea, headache, rash, thrombocytopenia

OPEN LABEL: RE-TREATMENT

(FISSION, FUSION, and POSITRON participants)

sofosbuvir + PEG-IFN/RBV or sofosbuvir + RBV

N = 96

Treatment-experienced;

Cirrhosis: 73% (N = 70)

Interim results from 60 participants

12 weeks, 3 drugs

91% (20/22)

88% (7/8)

No AE-related discontinuations;

AEs ≥10% (in SOF/RBV arm only): fatigue, headache, insomnia, irritability, depression, arthralgia, dry skin, pruritus

 

24 weeks, 2 drugs

63% (24/38)

47% (7/15)

PHOTON-1

sofosbuvir + RBV

N = 42

Treatment-naive, HIV-positive;

Cirrhosis: 14% (N = 6)

Phase II

12 weeks, 2 drugs

67% (28/42)

Not reported

2 AE-related discontinuations;

AEs in ≥10%: fatigue, insomnia, headache, nausea, diarrhea, irritability, upper respiratory tract infection

POSITRON

sofosbuvir + RBV

N = 98

IFN-unwilling/
ineligible/intolerant;

Cirrhosis: 13% (N = 14)

Phase III

12 weeks, 2 drugs

61% (57/84)

21% (3/14)

4 AE-related discontinuations (in sofosbuvir arm);

AEs in ≥10%: anemia, nausea, fatigue, headache, insomnia, pruritus

PROTON

sofosbuvir + PEG-IFN/RBV

N = 10

Treatment-naive, noncirrhotic

Phase II

12 weeks, 3 drugs

100% (10/10)

N/A

No AE-related discontinuations;

AEs (of at least moderate intensity) in ≥5%: hypertension, paresthesia

VALENCE

sofosbuvir + RBV

N = 250

Cirrhosis: 23% (N = 58)

Phase III

24 weeks, 2 drugs

All: 85% (212/250)

68% (39/58)

2 AE-related discontinuations;
AEs in ≥15%: headache, fatigue, pruritus, asthenia, nausea, insomnia

 

Treatment-naive: 42% (N = 105)

93% (98/105)

92% (12/13)

 

Treatment-experienced: 58% (N = 145)

79% (114/145)

60% (27/45)

 

Sources:
Esteban R, Nyberg L, Lalezari J, et al. Successful retreatment with sofosbuvir-containing regimens for HCV genotype 2 or 3 infected patients who failed prior sofosbuvir plus ribavirin therapy (Abstract 8). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Everson GT, Tran TT, Towner WJ, et al. Safety and efficacy of treatment with interferon-free, ribavirin-free combination of sofosbuvir + GS-5816 in treatment-naive patients with genotypes 1-6 HCV infection (Abstract 111). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus RBV for hepatitis C. N Engl J Med. 2013 Jan 3;368(1):34–44. doi: 10.1056/NEJMoa1208953.
Gane EJ, Hyland RH, An D, et al. Sofosbuvir/Ledipasvir fixed dose combination is safe and effective in difficult-to-treat populations including genotype-3 patients, decompensated genotype- 1 patients, and genotype-1 patients with prior sofosbuvir treatment (Abstract 6). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 patients without treatment options. N Engl J Med. 2013 May 16;368(20):1867–77. doi: 10.1056/NEJMoa1214854.
Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013 May 16;368(20):1878–87. doi: 10.1056/NEJMoa1214853.
Lawitz E, Poordad F, Brainard DM, et al. Sofosbuvir in combination with PegIFN and ribavirin for 12 weeks provides high SVR rates in HCV-infected genotype 2 or 3 treatment-experienced patients with and without compensated cirrhosis: results from the LONESTAR-2 Study (Abstract LB-4). Paper presented at: 64th Annual Meeting of the American Association for the Study of Liver Diseases; 2013 November 1–14; Washington, D.C.
Lalezari J, Lawitz E, Rodriguez-Torres M, et al. PROTON study: PSI-7977 QD with PEG/RBV: 12- week safety, RVR, cEVR, and SVR 12 in treatment-naive patients with HCV GT2 or 3 (Abstract 61). Paper presented at: 46th Annual Meeting of the European Association for the Study of the Liver; 2011 March 31–April 3; Berlin, Germany.
Ruane PJ, Ain D, Riad J, et al. Sofosbuvir plus ribavirin in the treatment of chronic HCV genotype 4 infection in patients of Egyptian ancestry (Abstract 1090). 64th Annual Meeting of the American Association for the Study of Liver Diseases; 2013 November 1–4; Washington, D.C.
Sulkowski MS, Rodriguez-Torres M, Lalezari J, et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2 and 3 infection in patients co-infected with HIV (PHOTON-1) (Abstract 212). 64th Annual Meeting of the American Association for the Study of Liver Diseases; 2013 November 1–4; Washington, D.C.
Zeuzem S, Dusheiko GM, Salupere R, et al.; the VALENCE Investigators. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med. 2014 May 22;370(21):1993–2001. doi: 10.1056/NEJMoa1316145.

 

Genotype 4

Although many DAAs are active against genotype 4, few have actually been studied—and only in small phase II trials. An ongoing phase II study in HCV genotype 4 combining simeprevir, samatasvir (an NS5A inhibitor) and ribavirin for 12 weeks reported SVR-4 of 100% in seven of nine treatment-naive participants (the remaining two participants were still on treatment).29

Table 6. Interferon-Free Regimens in Genotype 4, Treatment-Naive and Treatment-Experienced

Trial (regimen, N, population, and phase)

Treatment Arms

SVR-12 (unless otherwise noted)

Treatment Discontinuations and Common Adverse Events (AEs)

Sponsor: AbbVie

PEARL-I

FDC: ABT-450/r + ABT-267 (ombitasvir) ± RBV

Treatment-naive (N = 86)

Treatment-experienced (N = 49)

Noncirrhotic

Phase II

12 weeks, 2 drugs
Tx-naive

90.9% (40/44)

No AE-related discontinuations;

AEs in ≥15%: headache, asthenia, fatigue, nausea

12 weeks, 3 drugs
Tx-naive

100% (42/42)

12 weeks, 3 drugs
Tx-experienced

SVR-4: 100% (49/49)

Sponsor: BMS

A1443-014

asunaprevir BID + BMS-791325 BID + daclatasvir QD

N = 21; Treatment-naive; Cirrhosis: 10% (N = 2)

Phase II

12 weeks, 3 drugs
(75 mg BMS-791325)

100% (11/11)

No AE-related discontinuations;

AEs in ≥10%: headache, insomnia, nausea, pain

12 weeks, 3 drugs (150 mg BMS-791325)

100% (10/10)

Sponsor: Gilead

Sofosbuvir + RBV

N = 60

Cirrhosis: 24% (N = 14)

Phase II

12 weeks, 2 drugs
Tx-naive

79% (11/14)

1 AE-related discontinuation;

AEs in ≥20%: headache, insomnia, fatigue, cough, irritability, dizziness, pruritus, oropharyngeal pain, dyspnea, abdominal distention, pain, rash, myalgia, nausea, palpitations

12 weeks, 2 drugs
Tx-experienced

59% (10/17)

24 weeks, 2 drugs
Tx-naive

100% (14/14)

24 weeks, 2 drugs
Tx-experienced

SVR-4: 87% (13/15)

Sofosbuvir + GS-5816

N = 14

Treatment-naive, noncirrhotic

Phase II

12 weeks, 2 drugs (25 mg GS-5816)

100% (7/7)

No AE-related discontinuations;

AEs in ≥5% (of 154 participants): fatigue, headache, nausea, constipation, diarrhea, anxiety, nasopharyngitis, vomiting, oropharyngeal pain, dyspepsia, rash, back pain, upper abdominal pain, dysmenorrhea, irritability

12 weeks, 2 drugs (100 mg GS-5816)

86% (6/7)

Sources:
Everson GT, Tran TT, Towner WJ, et al. Safety and efficacy of treatment with interferon-free, ribavirin-free combination of sofosbuvir + GS-5816 in treatment-naive patients with genotypes 1-6 HCV infection (Abstract 111). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Hassanein T, Everson G, Simms KD, et al. All-oral therapy with daclatasvir in combination with asunaprevir and BMS-791325 for treatment-naive patients with chronic HCV genotype 4 infection (Abstract 763) Paper presented at: Digestive Disease Week 2014; 2014 May 3–6. Chicago, IL.
Hezode C, Marcellin P, Pol S, et al. Results from the phase II PEARL-I study: interferon-free regimens of ABT-450/r + ABT-267 with or without ribavirin in patients with HCV genotype 4 infection (Abstract 58). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Lawitz E, Rodriguez-Torres M, Nguyen T, et al. A phase II study of samatasvir (IDX 719) in combination with simeprevir and ribavirin in treatment-naive HCV-infected subjects with genotypes 1b and 4 (HELIX-1 study) (Abstract 1222). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Ruane PJ, Ain, D, Meshrekey R, et al. Sofosbuvir plus ribavirin, an interferon-free regimen, in the treatment of treatment-naive and treatment-experienced patients with chronic genotype 4 HCV infection (Abstract P1243). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.

 

Genotypes 5 and 6

These genotypes have not been adequately studied. A total of two people with genotype 5 have participated in trials of sofosbuvir-based regimens; both were cured. In a trial of sofosbuvir and GS-5816, 100 percent of the nine people with HCV genotype 6 were cured after 12 weeks of treatment.30

HIV Coinfection

More studies of DAA-based treatment—with and without peginterferon—have confirmed that HIV is no longer a poor prognostic factor for response to HCV treatment. In fact, SVR rates from some of the trials in HIV/HCV coinfected people have been higher than those in their HCV monoinfected counterparts, possibly because HIV-positive people have more experience with, and support for, adherence to antiviral treatment.

Drug-drug interactions (DDIs) between DAAs and HIV antiretrovirals (ARVs) may complicate HCV treatment by limiting ARV options (especially for people who are unwilling or unable to switch their HIV regimen, or lack access to certain ARVs).

Table 7. SVR in HIV/HCV Coinfection

Trial (regimen, N, population, and phase)

Treatment Arms

SVR-12 (unless otherwise noted)

ARVs Allowed

All

Treatment History

Genosubtype & IL28B

Cirrhosis

Sponsor: Boehringer Ingelheim

STARTVerso 4

faldaprevir (120 mg or 240 mg) + PEG-IFN/RBV

Genotype 1

Treatment-naive: 78% (240/308)

Relapsers: 22% (68/308)

Cirrhosis: 15% (45/308)

Phase III

24 weeks, 3 drugs (low-dose FDV)

SVR-4:
72% (89/123)

SVR-4:

Tx-naive: 71% (169/239)

Relapsers: 87% (60/69)

 

SVR-4:

G1a: 74% (178/242)

G1b: 77% (51/66)

 

IL28B:

CC: 89% (89/100)

CT: 67% (101/151)

TT: 67% (34/51)

SVR-4:
Noncirrhotic: 74% (194/261)

Cirrhosis: 76% (34/45)

abacavir, emtricitabine, enfuvirtide, lamivudine, maraviroc, raltegravir, rilpivirine, tenofovir

12 weeks, 3 drugs (high-dose FDV) + 12 or 36 weeks of PEG-IFN/ RBV

SVR-4:
79% (66/84)

 

24 weeks, 3 drugs (high-dose FDV) + 12 or 36 weeks of PEG-IFN/ RBV

SVR-4:
84% (72/86)

Sponsor: Gilead

PS7977-1910

sofosbuvir + PEG-IFN/RBV

N = 23

Treatment-naive, noncirrhotic, Genotypes 1, 2, 3, and 4

Phase II

12 weeks, 3 drugs

91%

N/A

N/A

N/A

atazanavir/r, darunavir/r, efavirenz, emtricitabine, raltegravir, rilpivirine, tenofovir

 

PHOTON-1

sofosbuvir + RBV

N = 182

Treatment-naive;

Cirrhosis: 6% (12/182)

Phase II

24 weeks, 2 drugs Genotype 1

76% (87/114)

Less effective in IL28B non-CC genotypes, black participants, people with cirrhosis, males, and genosubtype 1b

 

 

atazanavir/r, efavirenz, emtricitabine, darunavir/r, raltegravir, rilpivirine, tenofovir

12 weeks, 2 drugs Genotype 2

SVR-12: 88% (23/26)

12 weeks, 2 drugs Genotype 3

SVR-12: 67% (28/42)

Sponsor: Janssen

C212

simeprevir + PEG-IFN/RBV

N = 106

Genotype 1

Phase III

 

12 weeks, 3 drugs + 12 or 36 weeks of PEG-IFN/RBV

Tx-naive: 50% (53/106);

Relapsers: 14% (15/106)

74% (78/106)

Tx-naive: 70% (42/53)

1a + Q80K: 67% (20/30)

1a no Q80K: 72% (42/58)

1b: 89% (16/18)

Tx-naive:
F0-F2: 89% (24/27)

F3-F4: 57% (4/7)

abacavir, emtricitabine, enfuvirtide, lamivudine, maraviroc, raltegravir, rilpivirine, tenofovir

Relapsers: 87% (13/15)

Relapsers:
F0-F2: 78% (7/9)

F3-F4: 100% (2/2)

12 weeks, 3 drugs

+ 36 weeks of PEG-IFN/RBV

Partial responders: 10% (10/106);

Null responders: 26% (28/106)

Partial responders: 70% (7/10)

Partial responders:
F0-F2: 50% (1/2)

F3-F4: 67% (2/3)

Null responders: 57% (16/28)

Null responders:
F0-F2: 57% (4/7)

F3-F4: 60% (6/10)

Sponsor: Merck

C-WORTHY

MK-5172 + MK-8742 ± RBV

N = 59

Genotype 1, treatment-naive, noncirrhotic

Phase II

12 weeks, 2 drugs

90% (26/29)

N/A

1a: 2 virologic breakthrough

N/A

abacavir, emtricitabine, raltegravir, tenofovir

12 weeks, 3 drugs

97% (28/29)

1a: 1 relapse

Sponsor: NIAID

ERADICATE

FDC: sofosbuvir/
ledipasvir

N = 50

Genotype 1, HCV treatment-naive, noncirrhotic

Phase II

interim data

12 weeks, 2 drugs

ARV-treated, on current regimen for ≥8 weeks, CD4 >100/mm3, HIV RNA <40 copies/mL

SVR-4: 100% (22/22)

Not reported

efavirenz, emtricitabine, raltegravir, rilpivirine, tenofovir

12 weeks, 2 drugs

 No ARVs, stable CD4 with HIV RNA <500 copies/mL or CD4 >500/mm3

SVR-4: 100% (10/10)

Sources:
Dieterich D, Rockstroh J, Orkin C, et al. Simeprevir (TMC-435) plus peginterferon/ribavirin in patients co-infected with HCV genotype-1 and HIV-1: primary analysis of the C212 study (Abstract LBPS9/5). Paper presented at: 14th European AIDS Conference; 2013 October 16–19; Brussels, Belgium.
Osinusi A, Townsend K, Nelson A, et al. Use of sofosbuvir/eldipasvir fixed dose combination for treatment of HCV genotype-1 in patients coinfected with HIV (Abstract 14). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Rodriguez-Torres M, Rodriguez-Orengo J, Gaggar A, et al. Sofosbuvir and peginterferon alfa-2a/ribavirin for treatment-naive genotype 1-4 HCV-infected patients who are coinfected with HIV (Abstract 714). Paper presented at: IDWeek 2013 October 2–6; San Francisco, CA.
Rockstroh JK, Nelson M, Soriano V, et al.; on behalf of the STARTVerso 4 Study Team. STARTVerso 4 phase III trial of faldaprevir plus pegylated interferon α-2a and ribavirin in patients with HIV and HCV genotype-1 co-infection (Abstract 1066). Paper presented at: 64th Annual Meeting of the American Association for the Study of Liver Diseases; 2013 November 1–14; Washington, D.C.
Sulkowski MS, Rodriguez-Torres M, Lalezari J, et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2 and 3 infection in patients co-infected with HIV (PHOTON-1) (Abstract 212). Paper presented at: 64th Annual Meeting of the American Association for the Study of Liver Diseases; 2013 November 1-4; Washington, D.C.
Sulkowski MS, Mallolas J, Bourliere M, et al. Efficacy and safety of the all-oral regimen, MK-5172/MK-8742 +/- RBV for 12 weeks in G1 HIV/HCV coinfected patients: the C-WORTHY Study (Abstract 63). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.

 

The Last Frontier: Pre- and Posttransplant

People with advanced liver disease and their families, friends, advocates and physicians have been fighting for access to experimental HCV drugs, hoping that treatment will be lifesaving. There are encouraging data from small trials and compassionate use programs in people with decompensated cirrhosis, portal hypertension and hepatocellular carcinoma (HCC). In posttransplant, treatment may be effective for people with severe, recurrent HCV and decompensated cirrhosis, but earlier initiation is preferable.31     

Table 8. The Miracle Workers

Trial (regimen, N, population, and phase)

Treatment Arms

Outcomes

Treatment Discontinuations, Adverse Events (AEs)

Sponsor: AbbVie

M12-999

3-D FDC: ABT-450/r QD + ABT-267 QD (ombitasvir) + ABT-333 BID (dasabuvir)
+ RBV (600 or 800 mg/day)

N = 34

Genotype 1, ≥12 months posttransplant, noncirrhotic

TAC or CYA immunosuppressant use; prednisone ≤5mg/day

Phase II

24 weeks, 4 drugs

SVR-12: 96.2% (25/26) Interim data

1 AE-related discontinuation;

AEs ≥15%: headache, fatigue, insomnia, nausea, rash, asthenia, diarrhea, anemia, dizziness, muscle spasms, pyrexia

Sponsor: Gilead

COMPASSIONATE USE

sofosbuvir + RBV ± PEG-IFN (at investigator’s discretion)

N = 104

Transplant recipients with severe, recurrent HCV, compensated and decompensated cirrhosis; likely to have life expectancy of <1 year

Genotype 1, 2, 3, and 4

72 completed treatment

24 to 48 weeks

(not broken out by duration or regimen)

SVR-12: 62% (53/85)

60 people improved, 22 remained stable, and 22 worsened

 

 

14 AE-related discontinuations (AEs not reported)

13 deaths; 8 during treatment and 5 posttreatment

ELECTRON-2

FDC: sofosbuvir/
ledipasvir

N = 20

Genotype 1, treatment-naive, decompensated cirrhosis (CPT B)

Phase II

12 weeks, 2 drugs

SVR-12: 65% (13/20)

No AE-related discontinuations

AEs in ≥15%: headache, upper respiratory tract infection, nausea, fatigue, insomnia

Sofosbuvir + RBV

N = 52

Portal hypertension ± hepatic decompensation (CPT class A N = 20; CPT class B N = 29)

Genotype 1, 2, 3, 4; Treatment-naive and treatment-experienced

48 weeks (immediate vs. delayed treatment)

Phase II

24 weeks, 2 drugs

On-treatment response; undetectable HCV RNA at week 24: 95% (21/22)

CPT class A: 100% (7/7)

CPT class B: 93% (14/16)

Improvement in albumin and ALT among treated participants

1 AE-related discontinuation; AEs in ≥10% (active treatment arm only): nausea, asthenia, pruritus, rash, dizziness, insomnia, fatigue

2 discontinuations in observation arm for worsening liver disease

24 weeks, no drugs

 

Sofosbuvir + RBV

N = 40

Genotype 1, 2, 3, and 4

Liver transplant ≥6 months and <150 months; compensated cirrhosis (CPT score ≤7); treatment-naive and treatment-experienced

Phase II

24 weeks, 2 drugs

SVR-24: 70% (28/40)

2 AE-related discontinuations;

AEs in ≥15%: fatigue, diarrhea, headache, arthralgia, nausea, anemia, cough

AEs in ≥10%: fatigue, anemia, headache, nausea, rash, dyspnea, insomnia; 5 deaths occurred (cause not reported)

Sofosbuvir + RBV

N = 61

G 1, 2, 3, and 4

HCC, pretransplant; meeting MILAN criteria; CPT score ≤7;

Treatment-naive and treatment-experienced

Phase II

2 drugs, up to 48 weeks or transplantation

64% (25/39) had posttransplant response at week 12 (undetectable HCV RNA)

Having detectable HCV RNA for >30 days prior to transplantation associated with recurrent HCV

2 AE-related discontinuations

Multicenter Study

Compassionate Use

sofosbuvir + daclatasvir ± RBV

N = 12

Transplant recipients with severe, recurrent HCV (including hepatic decompensation and cholestatic hepatitis)

Genotypes 1 (N = 11) and 4 (N = 1)

Up to 24 weeks of treatment

At week 24, 100% (9/9) had undetectable HCV RNA; during treatment, 50% had improved MELD and Child–Pugh scores; 50% worsened

4 SAEs (not related to treatment): 2 primary biliary cirrhosis, 1 GI bleed, 1 pneumonia

Other AEs not reported

3 deaths during treatment: liver failure (week 2); upper GI bleeding (week 9); sepsis (week 9)

Sources:
Afdhal N, Everson G, Calleja JL, et al. Sofosbuvir and ribavirin for the treatment of chronic HCV with cirrhosis and portal hypertension with and without decompensation: early virologic response and safety (Abstract 68). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Curry M, Forns X, Chung R, et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation (Abstract 213). Paper presented at: 64th Annual Meeting of the American Association for the Study of Liver Diseases; 2013 November 1–14; Washington, D.C.
Didier S, Charlton M, Gane E, et al. Sofosbuvir and ribavirin for the treatment of recurrent hepatitis C after liver transplantation: results of a prospective, multicenter study (Abstract P1232). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Forns X, Prieto M, Charlton M, et al. Multigenotypes: sofosbuvir compassionate use program for patients with severe recurrent hepatitis C including fibrosing cholestatic hepatitis following liver transplantation (Abstract 62). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Gane EJ, Hyland RH, An D, et al. Ledipasvir/sofosbuvir fixed-dose combination is safe and effective in difficult-to-treat populations including GT3 patients, decompensated GT1 patients and GT1 patients with prior sofosbuvir experience (Abstract 6). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Kwo P, Mantry P, Coakley E, et al. Results of the phase II study M12-999: interferon-free regimen of ABT-450/r/ABT-267 +ABT-333 + RBV in liver transplant recipients with recurrent HCV genotype 1 infection (Abstract 144). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
Pellicelli A, Montalbano M, Lionetti R, et al. Sofosbuvir and daclatasvir combination for recurrent hepatitis C after liver transplantation: potent antiviral activity but lack of clinical benefit if treatment is given too late (Abstract P1235). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.

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ENDNOTES

  1. Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012 Dec 15;380(9859):2224–60. doi: 10.1016/S0140-6736(12)61766-8.
  2. García-Fulgueiras A, García-Pina R, Morant C, García-Ortuzar V, Génova R, Alvarez E. Hepatitis C and hepatitis B-related mortality in Spain. Eur J Gastroenterol Hepatol. 2009 Aug;21(8):895–901. doi: 0.1097/MEG.0b013e328313139d.
  3. Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med. 2012 Feb 21;156(4):271–8. doi: 10.7326/0003-4819-156-4-201202210-00004.
  4. Moorman AC, Gordon SC, Rupp LB, et al.; Chronic Hepatitis Cohort Study Investigators. Baseline characteristics and mortality among people in care for chronic viral hepatitis: the chronic hepatitis cohort study. Clin Infect Dis. 2013 Jan;56(1):40–50. doi: 10.1093/cid/cis815.
  5. Ly KN, Xing J, Klevens RM, Jiles RB, Holmberg SD. Causes of death and characteristics of decedents with viral hepatitis, United States, 2010. Clin Infect Dis. 2014 Jan;58(1):40–9. doi: 10.1093/cid/cit642.
  6. Mira JA, Rivero-Juárez A, López-Cortés LF, et al. Benefits from sustained virologic response to pegylated interferon plus ribavirin in HIV/hepatitis C virus-coinfected patients with compensated cirrhosis. Clin Infect Dis. 2013 Jun;56(11):1646–53. doi: 10.1093/cid/cit103.
  7. Morgan TR, Ghany MG, Kim HY, et al.; HALT-C Trial Group. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology. 2010 Sep;52(3):833–44. doi: 10.1002/hep.23744.
  8. van der Meer AJ1, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012 Dec 26;308(24):2584–93. doi: 10.1001/jama.2012.144878.
  9. Veldt BJ, Saracco G, Boyer N, et al. Long term clinical outcome of chronic hepatitis C patients with sustained virological response to interferon monotherapy. Gut. 2004 Oct;53(10):1504–8.
  10. Byrnes V, Miller A, Lowry D, et al. Effects of anti-viral therapy and HCV clearance on cerebral metabolism and cognition. J Hepatol. 2012 Mar;56(3):549–56. doi: 10.1016/j.jhep.2011.09.015.
  11. Daltro-Oliveira R, Morais-de-Jesus M, Pettersen KM, Paraná R, Quarantini LC. Impact of sustained virologic response on quality of life in chronic HVC carriers. Ann Hepatol. 2013 May–Jun;12(3):399–407. Review.
  12. Sarkar S, Jiang Z, Evon DM, Wahed AS, Hoofnagle JH. Fatigue before, during and after antiviral therapy of chronic hepatitis C: results from the Virahep-C study. J Hepatol. 2012 Nov;57(5):946–52. doi: 10.1016/j.jhep.2012.06.030.
  13. Jacobson I, Dore GJ, Foster GR, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naïve patients: results from QUEST-1 a phase III trial (Abstract 1425). Paper presented at 48th Annual Meeting of the European Association for the Study of the Liver; 2013 April 24–28; Amsterdam, the Netherlands.
  14. Jacobson IM, McHutchison JG, Dusheiko G, et al.; ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011 Jun 23;364(25):2405–16. doi: 10.1056/NEJMoa1012912.
  15. Poordad F, McCone J Jr, Bacon BR, et al.; SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011 Mar 31;364(13):1195–206. doi: 10.1056/NEJMoa1010494.
  16. Jensen D, Asselah T, Dieterich D, et al. A pooled analysis of two randomized, double-blind, placebo-controlled phase III trials (STARTVerso 1 and 2) of faldaprevir plus pegylated interferon α-2a and ribavirin in treatment-naïve patients with chronic hepatitis C genotype-1 infection (Abstract 1088). Paper presented at: 64th Annual Meeting of the American Association for the Study of Liver Diseases; 2013 November 1–14; Washington, D.C.
  17. Manns M, Marcellin P, Poordad F, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naive patients: results from QUEST-2 a phase III trial (Abstract 1413). Paper presented at: 48th Annual Meeting of the European Association for the Study of the Liver; 2013 April 24–28; Amsterdam, the Netherlands.  
  18. Lawitz E, Forns X, Zeuzem S, et al. Simeprevir (TMC435) with peginterferon/ ribavirin for treatment of chronic HCV genotype 1 infection in patients who relapsed after previous interferon-based therapy: results from Promise, a phase III trial. (Abstract 869). Paper presented at Digestive Disease Week 2013; 2013 May 18–21; Orlando, FL.
  19. Jacobson, I. Asselah T, Ferenci P, et al. STARTVerso3: A randomized, double-blind, placebo-controlled phase III trial of faldaprevir in combination with pegylated interferon alfa-2a and ribavirin in treatment-experienced patients with chronic hepatitis C genotype-1 infection (Abstract 1100). Paper presented at: 64th Annual Meeting of the American Association for the Study of Liver Diseases; 2013 November 1–14; Washington, D.C.
  20. Jacobson IM, Fried M, Ferenci P, et al. Simeprevir (TMC 435) in combination with peginterferon and ribavirin for treatment of HCV genotype 1 infection in treatment-naïve and –experienced patients (PILLAR and ASPIRE trials) (Abstract 1287). Paper presented at IDWeek 2012; 2012 October 17–21; San Diego, CA.
  21. Zeuzem S, Hezode C, Bronowicki JP, et al.; on behalf of the LEAGUE-1 study team. Daclatasvir in combination with simeprevir with or without ribavirin for hepatitis C virus genotype 1 (Abstract 28LB). Paper presented at: 21st Conference on Retroviruses and Opportunistic Infections; 2014 March 3–6. Boston; MA.
  22. Esteban R, Nyberg L, Lalezari J, et al. Successful retreatment with sofosbuvir-containing regimens for HCV genotype 2 or 3 infected patients who failed prior sofosbuvir plus ribavirin therapy (Abstract 8). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
  23. Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus RBV for hepatitis C. N Engl J Med. 2013 Jan 3;368(1):34–44. doi: 10.1056/NEJMoa1208953.
  24. Lalezari J, Lawitz E, Rodriguez-Torres M, et al. PROTON study: PSI-7977 QD with PEG/RBV: 12- week safety, RVR, cEVR, and SVR 12 in treatment-naive patients with HCV GT2 or 3 (Abstract 61). Paper presented at: 46th Annual Meeting of the European Association for the Study of the Liver; 2011 March 31–April 3; Berlin, Germany.
  25. Lawitz E, Poordad F, Brainard DM, et al. Sofosbuvir in combination with PegIFN and ribavirin for 12 weeks provides high SVR rates in HCV-infected genotype 2 or 3 treatment-experienced patients with and without compensated cirrhosis: results from the LONESTAR-2 Study (Abstract LB-4). Paper presented at: 64th Annual Meeting of the American Association for the Study of Liver Diseases; 2013 November 1–14; Washington, D.C.
  26. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013 May 16;368(20):1878–87. doi: 10.1056/NEJMoa1214853.
  27. Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial (Abstract 1085). Paper presented at: 64th Annual Meeting of the American Association for the Study of Liver Diseases; 2013 November 1–14; Washington, D.C.
  28. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 patients without treatment options. N Engl J Med. May 16;368(20):1867–77. doi: 10.1056/NEJMoa1214854.
  29. Lawitz E, Rodriguez-Torres M, Nguyen T, et al. A phase II study of samatasvir (IDX 719) in combination with simeprevir and ribavirin in treatment-naive HCV-infected subjects with genotypes 1b and 4 (HELIX-1 study) (Abstract 1222). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
  30. Everson GT, Tran TT, Towner WJ, et al. Safety and efficacy of treatment with interferon-free, ribavirin-free combination of sofosbuvir + GS-5816 in treatment-naive patients with genotypes 1-6 HCV infection (Abstract 111). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.
  31. Pellicelli A, Montalbano M, Lionetti R, et al. Sofosbuvir and daclatasvir combination for recurrent hepatitis C after liver transplantation: potent antiviral activity but lack of clinical benefit if treatment is given too late (Abstract P1235). Paper presented at: 49th Annual Meeting of the European Association for the Study of Liver Diseases Meeting; 2014 April 9–13; London, United Kingdom.