Secondary Logo

Journal Logo

A new era of therapy for hepatitis C virus infection

Nyalakonda, Harita; Utay, Netanya S.

Current Opinion in Infectious Diseases: October 2015 - Volume 28 - Issue 5 - p 471–478
doi: 10.1097/QCO.0000000000000190
GASTROINTESTINAL INFECTIONS: Edited by A. Clinton White Jr and Gagandeep Kang
Free

Purpose of review Previous treatments with pegylated interferon (PEG-IFN) and ribavirin for hepatitis C virus (HCV) infection resulted in significant adverse events and low cure rates, even with the addition of first-generation protease inhibitors. The standard of care for chronic HCV infection changed dramatically in 2013 with the approval of second-generation direct-acting antivirals, which led the way for IFN-free combination regimens.

Recent findings All-oral combinations of direct-acting antivirals, with or without ribavirin, have shown high efficacy and are well tolerated in patients with the predominant genotypes, advanced fibrosis stages, and HIV co-infection. New fixed-dose co-formulations of direct-acting antivirals have allowed simpler regimens with shorter treatment durations and low rates of discontinuation, but are associated with substantial costs.

Summary Since 2013, all-oral, IFN-free regimens with direct-acting antivirals have quickly become the mainstay of treatment for HCV infection as they provide high rates of sustained virologic response with a relatively short duration of treatment and low side-effect profile.

University of Texas Medical Branch, Galveston, Texas, USA

Correspondence to Netanya S. Utay, MD, University of Texas Medical Branch, 301 University Boulevard, Marvin Graves Building 4.210, Galveston, TX 77555, USA. Tel: +1 409 747 0240; e-mail: neutay@utmb.edu

Back to Top | Article Outline

INTRODUCTION

Hepatitis C virus (HCV) infects more than 170 million persons worldwide [1]. This small, spherical, enveloped, positive-strand RNA virus [2] is transmitted parenterally more than sexually or vertically. Acute HCV infection is usually asymptomatic, but progresses to chronic infection in 75–85% of patients. Eventually, 5–20% of patients with chronic infection will develop cirrhosis and have an increased risk of hepatocellular carcinoma [1].

Treatment course and response vary based on HCV genotype. Genotypes 1a and 1b comprise 60–70% of isolates in the United States [3]. Genotype 3 is prevalent in Asia, genotype 4 in Africa and the Middle East, and genotypes 5 and 6 in South Africa and Southeast Asia [2,4].

The primary goal of HCV treatment is cure [5], defined as sustained virologic response (SVR), that is, undetectable circulating HCV-RNA, 12 weeks after treatment completion [6]. SVR rates with pegylated interferon (PEG-IFN) and ribavirin are approximately 45–55%, with complications including severe depression, influenza-like symptoms, and anemia [7,8]. Adding a first-generation protease inhibitor – telaprevir or boceprevir – improved SVR rates to 65–70% with shorter treatment duration but additional adverse events [9–12]. Since the US Food and Drug Administration (FDA) began approving agents that do not require concomitant PEG-IFN in November 2013, the standard of care for chronic HCV treatment has become all-oral, IFN-free combinations of direct-acting antivirals, with or without ribavirin. We will focus this review on select studies of all-oral regimens for HCV treatment (Table 1).

Table 1

Table 1

Box 1

Box 1

Back to Top | Article Outline

INTERFERON-FREE TREATMENT REGIMENS

Direct-acting antivirals target specific steps of the HCV lifecycle. RNA replication is inhibited by sofosbuvir – a nucleotide NS5B polymerase inhibitor that competitively binds to the catalytic site of RNA polymerase. Dasabuvir and beclabuvir are non-nucleoside NS5B polymerase inhibitors that work through allosteric inhibition [48]. Polyprotein processing is targeted by NS3/NS4 serine protease inhibitors, including boceprevir, telaprevir, simeprevir, paritaprevir, asunaprevir, and grazoprevir. Inhibitors of NS5A, which likely modulates viral RNA replication, include ledipasvir, ombitasvir, daclatasvir, and elbasvir [1]. Ribavirin's mechanism of action remains unclear [49]. Like HIV, HCV replication is highly error-prone, and optimal treatment requires targeting multiple steps of the lifecycle. Thus, the new all-oral regimens contain at least two agents (direct-acting antivirals and/or ribavirin) with different targets.

Back to Top | Article Outline

Genotype 1

The combination of sofosbuvir and simeprevir (both US FDA-approved in 2013), with or without ribavirin, was among the first all-oral regimens to be studied. Lawitz et al.[13▪▪] demonstrated that 92–96% of 80 previously treated null-responders with Metavir score F0–F2 and 87 previously untreated or treated null-responders with Metavir score F3–F4 responded without an apparent benefit from ribavirin or extended treatment duration (the COSMOS trial). Twenty-four weeks of treatment yielded SVR in 96–100% of cirrhotic patients [13▪▪].

Ledipasvir/sofosbuvir fixed-dose combination was US FDA-approved in October 2014. Afdhal et al.[15▪▪] described 865 treatment-naïve patients who received ledipasvir/sofosbuvir with or without ribavirin for 12 or 24 weeks (the ION-1 trial). SVR was achieved in 97–99% in all groups [15▪▪]. Adding ribavirin or treating for 24 weeks conferred no additional benefit [50]. Response rates among cirrhotic and noncirrhotic patients were similar [15▪▪]. Further data showed that 12 weeks of ledipasvir/sofosbuvir is well tolerated and effective for treatment-naïve patients with genotype 1 and compensated cirrhosis [51]. Kowdley et al.[17] evaluated 647 treatment-naïve patients without cirrhosis (the ION-3 trial). Of patients with baseline HCV-RNA level less than 6 million IU/ml, 97% achieved SVR with 8 weeks of ledipasvir/sofosbuvir. Adding ribavirin or treating for 12 weeks did not improve outcomes. However, 10% of patients with baseline HCV-RNA level greater than 6 million IU/ml relapsed after 8 weeks of treatment compared to 1% after 12 weeks [17].

Afdhal et al. evaluated ledipasvir/sofosbuvir in treatment-experienced patients (the ION-2 trial). SVR rates of 94–99% were achieved with ledipasvir/sofosbuvir with or without ribavirin for 12 or 24 weeks. Rates were similar regardless of previous protease inhibitor use or whether patients were null-responders or relapsers [50]. In cirrhotic patients, SVR rates of 82–86% were achieved with 12 weeks of ledipasvir/sofosbuvir with or without ribavirin, compared to 95–100% among noncirrhotic patients and 99–100% among cirrhotic patients receiving 24-week regimens [16]. In a post-hoc analysis, 90% of cirrhotic treatment-experienced patients achieved SVR after 12 weeks of ledipasvir/sofosbuvir compared to 96–100% with adding ribavirin [51]. Bourliere et al.[18] demonstrated that treatment-experienced patients with compensated cirrhosis had similarly high SVR rates of 96–97%, whether treated with ledipasvir/sofosbuvir + ribavirin for 12 weeks, or ledipasvir/sofosbuvir for 24 weeks (the SIRIUS trial). Thus, treatment duration of ledipasvir/sofosbuvir will vary from 8 to 24 weeks, depending on HCV viral load, treatment experience, and cirrhosis.

The US FDA approved the co-formulation of ritonavir-boosted paritaprevir with ombitasvir and dasabuvir (ombitasvir/r-paritaprevir and dasabuvir) in December 2014. Feld et al.[25▪▪] showed that 96.2% of 631 treatment-naive noncirrhotic patients who received 12 weeks of this regimen achieved SVR (the SAPPHIRE-1 trial). Ferenci et al.[24] examined the need for ribavirin with ombitasvir/r-paritaprevir and dasabuvir in treatment-naïve genotype 1 patients without cirrhosis (the PEARL trials). Patients with genotype 1b infection had SVR rates exceeding 99% with or without ribavirin [23,24]. Patients with genotype 1a infection had SVR rates of 97% with ribavirin and 90.2% without ribavirin, indicating the need for ribavirin in genotype 1a [24].

Zeuzem et al.[26] demonstrated that 96.3% of 394 noncirrhotic treatment-experienced patients achieved SVR after 12 weeks of ombitasvir/r-paritaprevir and dasabuvir with ribavirin (the SAPPHIRE-2 trial). Similarly high SVR rates were seen in noncirrhotic treatment-experienced patients with genotype 1b infection treated with 12 weeks of ombitasvir/r-paritaprevir and dasabuvir with or without ribavirin [26]. Poordad et al.[28] studied ombitasvir/r-paritaprevir and dasabuvir with ribavirin in treatment-experienced and naive patients with cirrhosis (the TURQUOISE-2 trial). Twelve weeks of ombitasvir/r-paritaprevir and dasabuvir with ribavirin rendered SVR of 91.8%, comparable to the SVR achieved after 24 weeks. A multivariate logistic regression analysis showed SVR in 86.7% of prior null-responders with 12 weeks of treatment compared to 95.2% with 24 weeks of treatment. These rates were lower (80 vs. 92.9%, respectively) in patients with genotype 1a infection with 12 versus 24 weeks of treatment. Patients with genotype 1b infection and prior null response had the same 100% SVR with either treatment duration. Thus, treatment with ombitasvir/r-paritaprevir and dasabuvir will last 12–24 weeks and include ribavirin, dependent on genotype 1a or 1b, treatment experience, and cirrhosis [28].

Daclatasvir (approved in Europe and Japan) and sofosbuvir, with or without ribavirin, for 12 or 24 weeks, resulted in SVR rates of 98% in 126 treatment-naive and 41 treatment-experienced patients. SVR rates were similar in subgroups including those who received ribavirin and subtypes 1a and 1b [29]. Recent data suggest that cirrhotic patients who receive sofosbuvir and daclatasvir for 24 weeks or for 12 weeks may have better responses than cirrhotic patients who receive sofosbuvir and daclatasvir for 12 weeks [30]. Poordad et al.[31] showed that 12 weeks of sofosbuvir, daclatasvir, and ribavirin in cirrhotic patients had an overall SVR of 82% (the ALLY-1 trial).

Manns et al.[33] studied daclatasvir and asunaprevir for genotype 1b (the HALLMARK-DUAL trial). Twelve weeks of treatment yielded SVR in 90% of treatment-naive and 82% of prior nonresponders or IFN-intolerant/ineligible participants, with similar SVR rates among cirrhotic and noncirrhotic patients [33]. Initially, daclatasvir with asunaprevir yielded low SVR rates for genotype 1a [34], but Poordad et al.[35] found that 90% of genotype 1a and 98% of genotype 1b achieved SVR with 12 weeks of daclatasvir/asunaprevir/beclabuvir fixed-dose combination (the UNITY-1 trial). Muir et al.[36▪] found that rates were 98% in treatment-naive and 93% in treatment-experienced cirrhotic patients with ribavirin, but 93 and 87%, respectively, without ribavirin (the UNITY-2 trial).

Sulkowski et al.[37] showed that grazoprevir and elbasvir for 12 weeks yielded SVR rates of 92–95% regardless of ribavirin inclusion or genotype 1a or 1b infection (the C-WORTHY trial). SVR rates exceeding 90% were attained in treatment-experienced and/or cirrhotic patients regardless of ribavirin inclusion (the C-WORTHY and C-EDGE trials) [38▪,39,40]. Poordad et al.[42] found that 6 weeks of grazoprevir, elbasvir, and sofosbuvir resulted in SVR rates of 87% in 30 noncirrhotic patients and 80% in 20 cirrhotic patients, and lengthening to 8 weeks yielded SVR of 94% in 18 cirrhotic patients (the C-SWIFT trial).

In sum, many IFN-free all-oral agents are now available for patients with HCV genotype 1, with durations ranging from 6 to 24 weeks, depending on treatment experience and the presence of cirrhosis.

Back to Top | Article Outline

Genotype 2

Fewer direct-acting antivirals are available that target HCV genotype 2. Lawitz et al.[43] found SVR rates of 97% in noncirrhotic patients receiving 12 weeks of daily sofosbuvir and ribavirin (the FISSION trial). Jacobson et al.[44] studied 12 weeks of sofosbuvir and ribavirin in 207 IFN-ineligible patients, with overall SVR rates of 93%, 92% in noncirrhotic patients, and 94% in cirrhotic patients (the POSITRON trial). Jacobson et al. also demonstrated that 94% of previously treated null-responders receiving 16 weeks of sofosbuvir and ribavirin achieved SVR compared to 86% of previously treated null-responders receiving only 12 weeks of sofosbuvir and ribavirin. Secondary analysis revealed that 60% of cirrhotic patients treated for 12 weeks achieved SVR compared to 96% of noncirrhotic patients. Treatment for 16 weeks rendered SVR in 100% of noncirrhotic patients, but only 78% of cirrhotic patients (the FUSION trial) [44]. Similarly, Zeuzem et al.[45▪▪] found that 12 weeks of sofosbuvir and ribavirin yielded SVR rates exceeding 93% among treatment-naive noncirrhotic or cirrhotic patients, or treatment-experienced noncirrhotic patients, but only 78% of nine treatment-experienced noncirrhotic patients (the VALENCE trial). Extending treatment to 24 weeks did not improve SVR rates in any group.

Brown et al.[41] demonstrated that grazoprevir with ribavirin yielded SVR of 67% among noncirrhotic patients and 80% with the addition of elbasvir (the C-SCAPE trial). However, a ribavirin-free option may soon be available: 92% of 26 patients with HCV genotype 2 who received 24 weeks of daclatasvir and sofosbuvir with or without ribavirin achieved SVR, with no benefit conferred by ribavirin [29].

Back to Top | Article Outline

Genotype 3

Genotype 3 initially proved difficult to treat with direct-acting antivirals. Only 61% of patients achieved SVR after 12 weeks of sofosbuvir and ribavirin and 21% of cirrhotic patients (the POSITRON trial) [44]. Jacobson et al.[44] found that treatment-experienced patients achieved SVRs of 30 and 62% with sofosbuvir and ribavirin for 12 and 16 weeks, respectively, and 19% for cirrhotic patients treated for 12 weeks (the FUSION trial). Extension of treatment to 16 weeks for cirrhotic patients rendered a 61% SVR [44]. Zeuzem et al.[45▪▪] demonstrated that 85% of 250 patients achieved SVR after 24 weeks of sofosbuvir and ribavirin (the VALENCE trial). Among treatment-naïve patients, 92% of cirrhotic and 95% of noncirrhotic patients reached SVR. Rates of SVR were lower among treatment-experienced patients: 62% for cirrhotic patients and 87% for noncirrhotic patients [45▪▪]. Increased efficacy with 24 weeks of therapy was seen across all fibrosis stages.

Gane et al.[21] studied 12 weeks of ledipasvir/sofosbuvir with or without ribavirin in 51 treatment-naïve patients, including cirrhotic patients (the ELECTRON-2 trial). In the ribavirin-treated group, 100% achieved SVR compared with only 64% in the ribavirin-free group, suggesting that sofosbuvir and ribavirin could be shortened to 12 weeks with the addition of ledipasvir [21].

Daclatasvir and sofosbuvir with or without ribavirin have also been evaluated for genotype 3. Of 18 patients, 89% achieved SVR after 24 weeks of treatment [29]. Nelson et al.[32] showed that 90% of 101 treatment-naïve and 86% of 51 treatment-experienced patients reached SVR after 12 weeks of daclatasvir and sofosbuvir (the ALLY-3 trial). Although 96% of noncirrhotic patients achieved SVR, only 63% of cirrhotic patients reached SVR [32].

Recently, Poordad et al.[42] found that grazoprevir, elbasvir, and sofosbuvir for 8 or 12 weeks in 29 noncirrhotic patients and 12 weeks for 11 cirrhotic patients yielded SVR rates of 93, 100, and 91%, respectively (the C-SWIFT trial). Thus, shorter and ribavirin-free regimens may soon be available for patients with genotype 3 infection.

Back to Top | Article Outline

Genotype 4

Although recommended by numerous advisory groups, data on sofosbuvir and simeprevir for genotype 4 were only recently presented. Twelve weeks of this combination resulted in an 89% SVR after 12 weeks or 100% with the addition of ribavirin or extension to 24 weeks [14]. Kapoor et al.[19] studied ledipasvir/sofosbuvir fixed-dose combination for 12 weeks (the SYNERGY trial). On the basis of interim data, 95% of 20 patients, including those with treatment experience and advanced fibrosis, achieved SVR [19]. Sofosbuvir with ribavirin yielded SVR in 93% of treatment-experienced and naive patients treated for 24 weeks and 68% in patients treated for 12 weeks [47].

Hezode et al.[22] studied ombitasvir/r-paritaprevir with or without ribavirin for 12 weeks in noncirrhotic patients with genotype 4 infection (the PEARL-1 trial). SVR was achieved in 100% of treatment-naïve patients with the ribavirin-containing regimen, and 90.9% with the ribavirin-free regimen. SVR was achieved by 100% of treatment-experienced patients in the ribavirin-containing group [22].

Zeuzem et al.[40] found that 100% of 18 treatment-naive patients treated with grazoprevir/elbasvir for 12 weeks achieved SVR (the C-EDGE trial). Among treatment-experienced patients, three of five patients who received 12 weeks of grazoprevir/elbasvir achieved SVR, but 93% of 15 and 100% of eight patients who also received ribavirin, for 12 and 16 weeks, respectively, achieved SVR [39]. Thus, many agents effective for genotype 1 have also been shown to be efficacious for genotype 4.

Back to Top | Article Outline

Genotypes 5 and 6

Several IFN-free regimens have been studied for genotypes 5 and 6. Grazoprevir/elbasvir with ribavirin for 12 weeks achieved SVR in all four noncirrhotic patients with genotype 5 infection, but only one of the four treated without ribavirin achieved SVR [41]. Among genotype 6 patients, eight of 10 treatment-naïve patients who received grazoprevir/elbasvir (no ribavirin) achieved SVR [40].

Ledipasvir/sofosbuvir for 12 weeks may be another option for patients with genotype 6 infection. SVR rate of 96% was achieved among 25 treatment-naïve and treatment-experienced patients, including two with cirrhosis [21].

More studies are needed to expand on the results of these small studies, but preliminary data indicate that patients with genotypes 5 and 6 may soon have several all-oral options.

Back to Top | Article Outline

HIV CO-INFECTION

Liver-related mortality is the second highest cause of death in HIV-infected individuals, much of which is attributed to HCV infection [52]. HIV infection accelerates the progression of HCV to cirrhosis, liver decompensation, and hepatocellular carcinoma [53]. PEG-IFN with ribavirin was considered the treatment of choice for co-infected patients [52], but its use was limited due to the high prevalence of psychiatric and other comorbidities and adverse reactions [54].

Interferon-free regimens have been tested in patients with HIV/HCV co-infection with similar treatment outcomes to those with HCV mono-infection. Twelve weeks of ledipasvir/sofosbuvir rendered SVR in 98% of 50 noncirrhotic, treatment-naïve patients with HCV genotype 1 and HIV co-infection [20]. Molina et al.[46] studied 275 patients with HCV genotypes 1, 3, and 4 and stable HIV co-infection, including cirrhotic patients, who received sofosbuvir and ribavirin for 24 weeks and 12 weeks for genotype 2 (the PHOTON-2 trial). SVR rates were 84–89% for all genotypes [46]. Sulkowski et al.[27] studied ombitasvir/r-paritaprevir and dasabuvir with ribavirin for 12 or 24 weeks in HIV co-infected patients with genotype 1 infection (the TURQUOISE-1 trial). More than 90% of these treatment-experienced and cirrhotic patients on antiretroviral treatment with CD4+ cell counts exceeding 200/μl reached SVR [27].

Modifying antiretroviral treatment should be done in co-infected patients to avoid possible interactions with direct-acting antivirals and improve tolerability and adherence. Indeed, HIV-resistance profiles and antiretroviral treatment options may play a major role in choosing direct-acting antiviral-based regimens [55,56]. Our preference is to switch rather than stop antiretroviral treatment during HCV treatment, given the risk of rebound inflammation, morbidity, and mortality, and to ensure the tolerability of the new antiretroviral treatment regimen prior to starting the direct-acting antivirals. The ability to cure HIV co-infected patients will have a substantial impact on the future morbidity and mortality in this population.

Back to Top | Article Outline

REINFECTION

Continued injection drug use puts many patients at risk for reinfection after achieving SVR, rendering treatment of injection drug users controversial. In a review of six studies, reinfection rates ranged from 0.8 to 4.7 per 100 person-years. Focusing on people with ongoing risk behavior, the reinfection rates ranged from 2.50 to 28.57 per 100 person-years. The overall rate of HCV reinfection is low even among persons who continue injection drug use during and after treatment, suggesting that HCV treatment should not be withheld due to concerns about reinfection alone [57].

Incidence of HCV reinfection in the HIV population, especially among HIV-infected men who have sex with men, is a concern due to risk factors for transmission such as genital ulcers, unprotected anal intercourse, and injection drug use. A retrospective analysis of 191 HIV-infected men who have sex with men with sexually acquired HCV, who spontaneously cleared or underwent successful treatment, were found to have a reinfection rate of 7.8 per 100 person-years [58]. Among 48 HIV-infected men who have sex with men with HCV reinfection, 43 patients had SVR and five patients had spontaneous clearance after their first episode. A genotype switch was observed in 60% of patients during their second episode [59]. Increased efforts at modification of behavioral risk factors could lead to lower rates of reinfection in HIV-infected men who have sex with men.

Back to Top | Article Outline

COST-EFFECTIVENESS

Birth-cohort testing for HCV infection has been recommended by the US Centers for Disease Control and Prevention and the US Preventive Services Task Force for Americans born during 1945–1965. Financing the treatment for these undiagnosed individuals will be challenging, as direct-acting antivirals are highly effective, but also considerably expensive. Medicare spent more than $4.5 billion on HCV treatment in 2014 [60].

To minimize the financial burden of these new regimens, some payers are prioritizing treating patients with advanced fibrosis, who will have increased morbidity and healthcare costs [61]. One model generalized costs of a direct-acting antiviral regimen to $100 000 with 90% treatment effectiveness, and found that treatment at fibrosis level F2 compared to F3 costs $37 300 per quality-adjusted life-year gained, whereas treatment at F0 or F1 costs $242 900 or $174 100 per quality-adjusted life-year gained compared to F2. Thus, treating patients with moderate and advanced fibrosis may be more cost-effective than treating patients with minimal fibrosis [62]. Another model estimated the cost of treating treatment-naive genotype 1 patients, regardless of fibrosis stage, with ombitasvir/r-paritaprevir and dasabuvir with or without ribavirin, compared to no treatment as $19 193 per quality-adjusted life-year, decreasing to $11 792 for treating F3–F4 only [63]. Other studies have shown progressively lower incremental cost-effectiveness ratios with initiating direct-acting antivirals at more advanced fibrosis, although the cost per quality-adjusted life-year varies widely based on the regimen [64]. While treating patients with more advanced fibrosis may be cost-effective, the potential for widespread treatment to limit HCV spread should also be considered.

Back to Top | Article Outline

CONCLUSION

Since 2013, all-oral, IFN-free regimens with direct-acting antivirals have quickly become the mainstay of treatment for HCV infection. The regimens provide high SVR rates with a short duration of treatment and low side-effect profile. Patients who were once unable to receive therapy with IFN-based regimens can be treated successfully. Patients who were once difficult to treat, such as people with cirrhosis or HIV co-infection, can now be cured. The cumulative cost associated with these oral direct-acting antiviral regimens will continue to increase as more patients are identified by birth-cohort screening, but as the number of treatment options and therefore competition increases, the cost of these direct-acting antiviral-based regimens is anticipated to decrease.

Back to Top | Article Outline

Acknowledgements

None.

Back to Top | Article Outline

Financial support and sponsorship

None.

Back to Top | Article Outline

Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
Back to Top | Article Outline

REFERENCES

1. Kohli A, Shaffer A, Sherman A, Kottilil S. Treatment of hepatitis C: a systematic review. J Am Med Assoc 2014; 312:631–640.
2. Ansaldi F, Orsi A, Sticchi L, et al. Hepatitis C virus in the new era: perspectives in epidemiology, prevention, diagnostics and predictors of response to therapy. World J Gastroenterol 2014; 20:9633–9652.
3. Chak E, Talal AH, Sherman KE, et al. Hepatitis C virus infection in USA: an estimate of true prevalence. Liver Int 2011; 31:1090–1101.
4. Mohd HK, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology 2013; 57:1333–1342.
5. van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among subjects with chronic hepatitis C and advanced hepatic fibrosis. J Am Med Assoc 2012; 308:2584–2593.
6. Webster DP, Klenerman P, Dusheiko GM. Hepatitis C. Lancet 2015; 385:1124–1135.
7. Manns MP, Mchutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358:958–965.
8. Fried M, Shiffman M, Reddy R, et al. Pedinterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347:975–982.
9. Jacobson I, Mchutchison J, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364:2405–2416.
10. Poordad F, McCone J, Bacon B, et al. Boceprevir for untreated chronic HCV genotype 1 infections. N Engl J Med 2011; 364:1195–1206.
11. Bacon B, Gordon S, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1207–1217.
12. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364:2417–2428.
13▪▪. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in nonresponders to pegylated interferon and ribavirin and treatment-naïve subjects: the COSMOS randomized study. Lancet 2014; 384:1756–1765.

This study discusses the first all-oral US FDA-approved regimen of simeprevir and sofosbuvir for HCV genotype 1.

14. Fontaine H, Hezode C, Zoulim F, et al.. Efficacy of the oral sofosbuvir-based combinations in HCV genotype 4-mono-infected patients from the French observational cohort ANRS C022 Hepathe. [Abstract LP28]. 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, Austria; 22–26 April 2015.
15▪▪. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014; 370:1889–1898.

This study discusses the efficacy of the first US FDA-approved fixed-dose combination oral regimen of ledipasvir and sofosbuvir for HCV genotype 1.

16. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated genotype 1 infection. N Engl J Med 2014; 370:1483–1493.
17. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370:1879–1888.
18. Bourliere M, Bronowicki JP, de Ledinghen V, et al. Ledipasvir-sofosbuvir with or without ribavirin to treat subjects with HCV genotype 1 infection and cirrhosis nonresponsive to previous protease-inhibitor therapy: a randomized, double-blind, phase 2 trial (SIRIUS). Lancet Infect Dis 2015; 15:397–404.
19. Kapoor R, Kohli A, Sidharthan S, et al.. All oral treatment for genotype 4 chronic hepatitis C infection with sofosbuvir and ledipasvir: interim results from the NIAD SYNERGY trial [Abstract 240]. 65th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). Boston, MA; 7–11 November 2014.
20. Osinusi A, Townsend K, Kohli A, et al. Virologic response following combined ledipasvir and sofosbuvir administration in subjects with HCV genotype 1 and HIV co-infection. J Am Med Assoc 2015; 313:1232–1239.
21. Gane EJ, Hyland RH, An D, et al.. High efficacy of LDV/SOF regimens for 12 weeks for subjects with HCV genotype 3 or 6 infection [Abstract LB11]. 65th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). Boston, MA; 7–11 November 2014.
22. Hezode C, Asselah T, Reddy K R, et al. Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naïve and treatment-experienced subjects with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomized, open-label trial. Lancet 2015; 385:2502–2509.
23. Andreone P, Colombo MG, Enejosa JV, et al. ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced subjects with HCV genotype 1b infection. Gastroenterology 2014; 147:359–365.
24. 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; 370:1983–1992.
25▪▪. 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; 370:1594–1603.

This study discusses the efficacy of the US FDA-approved regimen of ombitasvir/r-paritaprevir and dasabuvir.

26. 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; 370:1604–1614.
27. Sulkowski MS, Ron JJ, Wyles D, et al. Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in subjects co-infected with HIV-1: a randomized trial. J Am Med Assoc 2015; 313:1223–1231.
28. 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; 370:1973–1982.
29. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014; 370:211–221.
30. Pol S, Bourliere M, Lucier S, et al.. Safety and efficacy of the combination daclatasvir-sofosbuvir in the HCV genotype 1-mono-infected patients from the French observational cohort ANRS Co22 Hepather [Abstract L03]. 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, Austria; 22–26 April 2015.
31. Poordad E, Schiff ER, Vierling JM, et al.. Daclatasvir, sofosbuvir, and ribavirin combination for HCV patients with advanced cirrhosis or posttransplant recurrence: phase 3 ALLY-1 study [Abstract L08]. 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, Austria; 22–26 April 2015.
32. Nelson DR, Cooper JN, Lalezari JP, et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in subjects with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology 2015; 61:1127–1135.
33. Manns M, Pol S, Jacobson IM, et al. All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet 2014; 384:1597–1605.
34. Lok AS, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012; 366:216–224.
35. Poordad F, Sievert W, Mollison L, et al.. All-oral, fixed-dose combination therapy with daclatasvir/asunaprevir/beclabuvir for noncirrhotic patients with chronic HCV genotype 1 infection: UNITY-1 phase 3 SVR12 results [Abstract LB7]. 65th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). Boston, MA; 7–11 November 2014.
36▪. Muir AJ, Poordad F, Lalezari JP, et al. All-oral fixed-dose combination therapy with daclatasvir/asunaprevir/beclabuvir, +/− ribavirin, for patients with chronic HCV genotype 1 infection and compensated cirrhosis: UNITY-2 phase 3 SVR12 results [Abstract LB2]. 65th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). Boston, MA; 7–11 November 2014.

This study reveals new all-oral regimens that may prove useful in cirrhotic patients with HCV genotype 1 infection.

37. Sulkowski M, Hezode C, Gerstoft J, et al. Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomized, open-label phase 2 trial. Lancet 2015; 385:1087–1097.
38▪. Lawitz E, Gane E, Pearlman B, et al. Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomized, open-label phase 2 trial. Lancet 2015; 385:1075–1086.

This study reveals new all-oral regimens that seem to be effective for HCV genotype 1 infection.

39. Kwo P, Gane E, Peng C-Y, et al.. Efficacy and safety of grazoprevir/elbasvir +/− RBV for 12 weeks in patients with HCV G1 or G4 infection who previously failed peginterferon/RBV: C-EDGE treatment-experienced trial [Abstract P0886]. 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, Austria; 22–26 April 2015.
40. Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevir-elbasvir combination therapy for treatment-naïve cirrhotic and noncirrhotic patients with chronic HCV genotype 1, 4, or 6 infection: a randomized trial. Ann Intern Med 2015; 163:1–13.
41. Brown A, Hezode C, Zuckerman E, et al.. C-SCAPE: efficacy and safety of 12 weeks of grazoprevir and elbasvir with or without ribavirin in patients with HCV GT2, 4, 5 or 6 infection [Abstract P0771]. 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, Austria; 22–26 April 2015.
42. Poordad E, Lawitz E, Gutierrez JA, et al.. C-SWIFT: Grazoprevir/elbasvir + sofosbuvir in cirrhotic and noncirrhotic, treatment-naïve patients with hepatitis C virus genotype 1 infection, for durations of 4, 6, or 8 weeks and genotype 3 infection for durations of 8 or 12 weeks [Abstract O006]. 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, Austria; 22–26 April 2015.
43. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368:1878–1887.
44. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in subjects without treatment options. N Engl J Med 2013; 368:1867–1877.
45▪▪. Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med 2014; 370:1993–2001.

This study discusses the US FDA-approved regimen of sofosbuvir and ribavirin which has shown efficacy against HCV genotypes 2 and 3.

46. Molina JM, Orkin C, Iser DM, et al. Sofosbuvir plus ribavirin for treatment of hepatitis C virus in subjects co-infected with HIV (PHOTON-2): a multicenter, open-label, nonrandomised, phase 3 study. Lancet 2015; 385:1098–1106.
47. Ruane PJ, Ain D, Stryker R, et al. Sofosbuvir plus ribavirin for the treatment of chronic genotype 4 hepatitis C virus infection in subjects of Egyptian ancestry. J Hepatol 2015; 62:1040–1046.
48. Yau AH, Yoshida EM. Hepatitis C drugs: the end of the pegylated interferon era and the emergence of all-oral interferon-free antiviral regimens: a concise review. Can J Gastroenterol Hepatol 2014; 28:445–451.
49. Koh C, Liang TJ. What is the future of ribavirin therapy for hepatitis C? Antiviral Res 2014; 104:34–39.
50. Keating GM. Ledipasvir/sofosbuvir: a review of its use in chronic hepatitis C. Drugs 2015; 75:675–685.
51. Reddy KJ, Bourliere M, Sulkowski M, et al. Ledipasvir and sofosbuvir in subjects with genotype 1 HCV and compensated cirrhosis: an integrated safety and efficacy analysis. Hepatology 2015; 62:79–86.
52. Sulkowski MS. Management of acute and chronic HCV infection in persons with HIV coinfection. J Hepatol 2014; 61 (1 Suppl):S108–S119.
53. Rockstroh JK. Optimal therapy of HIV/HCV co-infected subjects with direct acting antivirals. Liver Int 2015; 35 (Suppl 1):51–55.
54. Coppola N, Martini S, Pisaturo M, et al. Treatment of chronic hepatitis C in subjects with HIV/HCV coinfection. World J Virol 2015; 4:1–12.
55. Burgess S, Partovi N, Yoshida EM, et al. A review of drug interactions with direct-acting antivirals for hepatitis C: implications for HIV and transplant subjects. Ann Pharmacother 2015; 49:674–687.
56. Kaur K, Gandhi MA, Slish J, et al. Drug-drug interactions among hepatitis C virus (HCV) and human immunodeficiency virus (HIV) medications. Infect Dis Ther 2015; 4:159–172.
57. Grady BP, Schinkel J, Thomas XV, Dalgard O. Hepatitis C virus reinfection following treatment among people who use drugs. Clin Infect Dis 2013; 57 (2 Suppl):S105–S110.
58. Martin TC, Martin NK, Hickman M, et al. Hepatitis C virus reinfection incidence and treatment outcome among HIV-positive MSM. AIDS 2013; 27:2551–2557.
59. Ingiliz P, Krznaric I, Stellbrink HJ, et al. Multiple hepatitis C virus (HCV) reinfections in HIV-positive men who have sex with men: no influence of HCV genotype switch or interleukin-28B genotype on spontaneous clearance. HIV Med 2014; 15:355–361.
60. Ornstein C. New hepatitis C drugs are costing Medicare billions. The Washington Post [Internet]. March 29, 2015 [Cited May 4, 2015]; Health & Science. http://www.washingtonpost.com/national/health-science/medicare-spent-45-billion-on-new-hepatitis-c-drugs-last-year-data-shows/2015/03/29/66952dde-d32a-11e4-a62f-ee745911a4ff_story.html.
61. Cure S, Guerra I, Dusheiko G. Cost-effectiveness of sofosbuvir for the treatment of chronic hepatitis C-infected subjects. J Viral Hepat 2015; [Epub ahead of print].
62. Leidner AJ, Chesson HW, Ward JW, et al. Cost-effectiveness of hepatitis C treatment for subjects in early stages of liver disease. Hepatology 2015; 61:1860–1869.
63. Johnson SJ, Misurski DA, Juday TR, et al.. Cost-effectiveness of treating different stages of genotype 1 hepatitis C virus (HCV) with AbbVie 3D (ABT-450/ritonavir/ombitasvir and dasabuvir) with or without ribavirin compared to no treatment in the United States [Abstract P0815]. 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, Austria; 22–26 April 2015.
64. Najafzadeh M, Andersson K, Shrank WH, et al. Cost-effectiveness of novel regimens for the treatment of hepatitis C virus. Ann Intern Med 2015; 162:407–419.
Keywords:

antiviral therapy; direct-acting antivirals; hepatitis C virus; interferon-free

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.