S TAT E O F T H E A RT R E V I E W

Antiviral treatment of hepatitis C Eoin R Feeney,1 Raymond T Chung2 1

Division of Infectious Diseases, Massachusetts General Hospital, Boston, USA 2 Division of Gastroenterology, Massachusetts General Hospital, Boston MA 02114, USA Correspondence to: R T Chung [email protected] Cite this as: BMJ 2014;349:g3308 doi: 10.1136/bmj.g3308

A B S T RAC T

Hepatitis C virus (HCV) infection is a substantial health problem worldwide. Most patients infected with HCV remain chronically infected, with an increased risk of cirrhosis and hepatocellular carcinoma. Although they are associated with toxicities and low sustained viral response rates, interferon alfa and ribavirin have been the mainstay of treatment until recently. New direct acting antivirals, specifically designed to inhibit three viral proteins (the NS3/4A protease, the NS5A protein, and the NS5B RNA dependent RNA polymerase) are now becoming available. The NS3/4A inhibitor simeprevir and NS5B inhibitor sofosbuvir have recently been licensed and can reduce the length of antiviral treatment, improve response rates, and allow for interferon-free regimens for some HCV genotypes. Several other newer direct acting antivirals have shown promise in clinical studies and are likely to be licensed soon. These agents seem to facilitate the use of shortened courses of combination interferon-free therapy, which are associated with high (>95%) sustained response rates and relatively few toxicities. These regimens have also been successful in patients who were previously difficult to treat, including those with cirrhosis, HIV coinfection, and those who have undergone liver transplantation. The high cost of these agents may be the biggest challenge to their implementation worldwide. Introduction With the emergence of new direct acting antivirals, the treatment paradigm for hepatitis C virus (HCV) infection is currently undergoing its greatest change since the discovery of the virus 25 years ago. New data are routinely released for different combinations of these new agents, each reporting exceptionally high sustained response rates for an infection that was once notoriously difficult to treat. It is therefore difficult (even for those practising in the field) to keep abreast of present treatment options, or what is likely to be available in the next 12-18 months. Because newer antivirals have recently been licensed in the United States and Europe, and the results of several promising large phase III studies have been recently published, now is an opportune time to review the current treatment landscape for HCV, and to anticipate how that landscape might look in the coming years. In this article we will briefly review the natural course and life cycle of HCV infection. We will review the mechanism of action of direct acting antivirals, compare the data from major clinical studies of their use, and make recommendations from the currently available treatment options. We will also discuss current limitations of these new agents, and highlight areas where more research is needed. Most of the data presented here have been obtained from randomized controlled trials, and, where possible, we have based our recommendations on larger, phase III studies. Because of the rapidly evolving nature of this area, some data we consider in this review have been presented but not yet published.

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Incidence and prevalence HCV is a single stranded, positive sense RNA virus first described in 1989,1 which infects more than 180 million people worldwide.2 This equates to about 3% of the global population, with high prevalence (>3.5%) in central and eastern Asia, North Africa, and the Middle East, and moderate prevalence in South and South East Asia, subSaharan Africa, Central and South America, Australasia, and Europe.3 Many of those infected are unaware of their status—for example, in the US it is estimated that only half of those infected with HCV have been tested and diagnosed.4 Because most HCV infections are asymptomatic, it is difficult to estimate its incidence. SOURCES AND SELECTION CRITERIA We used the terms “hepatitis C”, “direct acting antivirals”, “protease inhibitors”, “NS5A”, and “NS5B” to search PubMed and Google Scholar from the year 2004 onwards. Bibliographies of articles were also searched for relevant studies. We also looked at abstracts from the recent 64th Annual Meeting of the American Association for the Study of Liver Diseases (Washington DC, November 2013), the 48th and 49th annual meetings of the European Association for the Study of the Liver (Amsterdam, April 2013 and London, April 2014), and the 21st Conference on Retroviruses and Opportunistic Infections (Boston, March 2014). We selected larger randomized controlled trials where possible.

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S TAT E O F T H E A RT R E V I E W HCV life cycle and natural course HCV infection occurs through exposure to blood products (including injected drug use), sexual contact, and vertically (from mother to child). Infection is followed by symptomatic acute hepatitis in only 20% of cases, with about 85% of those infected developing chronic infection (defined as detectable virus present six months after infection).5 Chronic infection with HCV is associated with ongoing liver inflammation and an increased risk of liver fibrosis or cirrhosis, as well as development of hepatocellular carcinoma (HCC).6 Coinfection with HIV, excess alcohol intake, and the presence of hepatic steatosis are associated with greater inflammation and more rapid progression to cirrhosis or HCC. HCV specifically infects hepatocytes, entering the cells through endocytosis (fig 1).7 After entry, the 9.6 kb viral genome undergoes cytoplasmic translation into a single polypeptide, which is subsequently cleaved into 10 viral proteins—three structural and seven non-structural (fig 2).8 Many of these non-structural viral proteins are the target of newer “direct acting antivirals” (fig 2). RNA replication occurs at sites on the endoplasmic reticulum; positive stranded RNA is used to synthesize a negative stranded RNA intermediate, which subsequently acts as a template for strands of positive RNA for new viral particles (as well as further polyproteins). Viral particles mature within the Golgi, and may be exported from hepatocytes by the same machinery that excretes very low density lipoproteins. Viral factors in treatment response: genotypes HCV exists as seven genotypes (GT; formerly called clades); GT1-4 are the most commonly encountered clinically and GT7 is exceedingly rare.9 These genotypes have been subdivided into 67 subtypes; the main clinically relevant subdivision is between subtype GT1a and GT1b. The geographic

distribution of HCV genotypes varies—GT1a predominates in the United States; GT1b in Europe; GT3 in India, Pakistan, and parts of the Middle East; and GT4 in Egypt and other Arabic countries. The natural course of infection seems to vary with the genotype—some are associated with a higher chance of acute infection being cleared (GT3 is more likely to clear than GT110), and GT3 is more commonly associated with hepatic steatosis.11 The main clinical use of genotyping is in planning the type and duration of treatment. GT2 and GT3 viruses have a higher rate of sustained viral response to standard treatment with peginterferon-ribavirin than do GT1 and GT4 (80% v 45%).12 In addition, certain genotypes and subtypes of HCV seem to harbor higher frequencies of polymorphism associated with resistance to several classes of direct acting antivirals. For example, baseline resistance to several protease inhibitors, NS5A inhibitors, and non-nucleotide polymerase inhibitors seem to differ between GT1a and GT1b viruses.13  14

Host factors in treatment response: IFNL3 and IFNL4 In addition to HCV genotype, other factors can predict therapeutic success. Asian or white ethnicity, lower concentration of HCV RNA, and absence of cirrhosis are associated with a higher chance of achieving a sustained virologic response. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with the gene encoding interferon λ3 (IFNL3, formerly IL28B), a type III interferon that is upregulated by viral infection and interferon α.15  16 These polymorphisms are associated with a significantly higher likelihood of achieving a sustained virologic response with pegylated interferon and ribavirin therapy for GT1 infection. Recently, a novel dinucleotide polymorphism (ss469415590, ΔG) was discovered adjacent to IFNL3,

Fig 1 | Life cycle of hepatitis C virus (HCV). HCV interacts with co-receptors on hepatocytes, which results in its endocytosis, then fusion of the virus with the endosome and uncoating of its RNA. This RNA is translated by host ribosomes into a polyprotein, which is cleaved by host and virally encoded proteases into 10 structural and non-structural proteins. The non-structural proteins form a replication complex on a “membranous web” derived from the endoplasmic reticulum that replicates HCV RNA. This in turn assembles with viral structural proteins in the Golgi into infectious viral particles, which are exocytosed from the cell

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S TAT E O F T H E A RT R E V I E W Fig 2 |  Hepatitis C virus (HCV) genome, protein products, and inhibitors. The HCV genome encodes three structural and seven nonstructural proteins. Protein functions are listed in red. Direct acting antivirals can inhibit three major nonstructural proteins—the NS3/4A protease, the NS5A protein, and the NS5B RNA dependent RNA polymerase. Direct acting antivirals in clinical use or development are listed in black. Those approved by the FDA are highlighted in bold

which is predicted to encode a form of interferon λ known as interferon λ4. Production of interferon λ4 seems to be associated with reduced spontaneous clearance of HCV and a reduced response to combination interferon-ribavirin therapy,17 raising the possibility that this protein may explain the observed clinical phenotypes. In the era of direct acting antivirals will these host factors still be relevant? The data on the effect of IFNL3 polymorphism with protease inhibitor therapy are mixed. One Japanese study found that favorable IFNL3 polymorphisms are associated with higher rates of sustained virologic response to combined telaprevir, pegylated interferon, and ribavirin therapy.18 However, in another study that looked exclusively at patients in whom pegylated interferon and ribavirin therapy had failed, these polymorphisms were not associated with a difference in response to telaprevir.19 Nonetheless, these polymorphisms will probably still play an important role in predicting success in direct acting antiviral regimens that contain interferon. By contrast, these polymorphisms may have much less of a predictive role to play in interferon-free regimens. For example, in the LONESTAR study of sofosbuvir and ledipasvir, with or without ribavirin, 85% of patients had less favorable IFNL3 genotypes, but only two of the 100 patients did not have a sustained virologic response.20

Antiviral classes and treatment of HCV The most important prognostic indicator while on HCV therapy is change in hepatitis C RNA or viral load. Several definitions are used when monitoring patients (box 1). The goal of treatment is to achieve a sustained virologic response, classically defined as undetectable HCV RNA 24 weeks after completion of treatment. This is associated with a very low risk of reactivation of HCV and a reduced risk of the progression of cirrhosis and the development of HCC, although the risk of HCC remains raised (albeit at a lower level) in those with cirrhosis.21  22 Undetectable HCV RNA at 12 weeks after completion of treatment seems to be highly predictive of a sustained virologic response at 24 weeks and is now accepted as a primary study endpoint by most regulatory bodies.23 For personal use only

Indirect acting antivirals—interferon alfa and ribavirin Until recently, all treatment regimens for HCV infection were based on combination therapy with interferon and ribavirin, and many still contain one or both of these agents. Despite the wealth of experience with their use, exactly how each agent exerts its antiviral effect is incompletely understood. Interferons are host proteins produced in response to infection and have broad actions, including antiviral, antiproliferative, and immunomodulatory effects.24 Interferons are divided on the basis of their receptor into three main types: type I (interferons α and β), type II (interferon γ), and type III (interferon λ). Binding of interferons (particularly type I interferons) to their respective receptor induces the expression of a multitude of interferon stimulated genes within cells, which trigger a wide variety of cellular antiviral functions.25 Ribavirin is an oral guanosine analog with broad antiviral activity against several RNA and DNA viruses. Its exact mechanism of action against HCV remains unclear, although modest inhibition of viral replication, depletion of cellular GTP, immunomodulatory effects, and possible induction of viral mutagenesis have all been proposed.26 Box 1 | Treatment responses in hepatitis C virus (HCV) infection Rapid viral response: undetectable HCV RNA at four weeks Early viral response: ≥2 log reduction in HCV RNA at 12 weeks End of treatment response: undetectable HCV RNA at the end of treatment Sustained virologic response (at 12 or 24 weeks): undetectable HCV RNA 12 or 24 weeks after completion of treatment Null response: early viral response not achieved Partial response: early viral response achieved, but virus not completely suppressed by week 24 Virologic breakthrough: HCV RNA undetectable during treatment, but virus re-emerges while still on treatment Relapse: reappearance of HCV RNA after cessation of treatment

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S TAT E O F T H E A RT R E V I E W

Table 1 | Newer hepatitis C agents in clinical use, or phase II-III studies Agent

Dosing

Phase

Telaprevir Boceprevir Simeprevir Faldaprevir Asunaprevir Danoprevir Vaniprevir ABT450‡ MK-5172 GS-9451

750 mg 3 times daily or 1125 mg twice daily* 800 mg 3 times daily† 150 mg once daily 240 mg once daily 100 mg twice daily 600 mg twice daily or 100 mg‡ twice daily 300 mg twice daily 150 mg once daily 100 mg once daily 200 mg once daily

Licensed Licensed Licensed III III III III III II-III II

NS5A inhibitors Daclatasvir Ledipasvir Ombitasvir (ABT-267) GS-5816 PPI-668 MK-8742

60 mg once daily 90 mg once daily 25 mg once daily 5-150 mg once daily 200 mg once daily 20-50 mg once daily

III III III II II II-III

400 mg once daily 1000 mg twice daily 200 mg once daily

Licensed III II

75-150 mg twice daily 250 mg twice daily 500 mg twice daily

III III II-III

NS3/4A protease inhibitors

NS5B inhibitors

Nucleos(t)ides:  Sofosbuvir  Mericitabine  VX-135 Non-nucleosides:  BMS-791325   Dasabuvir (ABT-333)  GS-9669 *Take with 20 g of fat per dose. †Take with food. ‡Boosted with ritonavir.

Interferon alfa (given subcutaneously in its pegylated form (peginterferon alfa, permitting once weekly dosing) combined with ribavirin had long been the standard of care for the treatment of HCV infection until the introduction of direct acting antivirals. Response is genotype dependent, with 66-80% of patients infected with GT2 or GT3 achieving a sustained virologic response (treated for 24 weeks) compared with about 45% of patients with GT1 or GT4 (treated for 48 weeks).27  28 This regimen is difficult to tolerate and is associated with many toxicities; 22-65% of patients will experience serious side effects, principally flu-like symptoms, anemia, neutropenia, thrombocytopenia, fatigue, depression, autoimmunity, and thyroid dysfunction.27  29 Even in well controlled clinical trial settings 9-15% of patients discontinue therapy owing to toxicity. It has therefore been clear for some time that more effective and tolerable treatment regimens for HCV are needed.

Direct acting antivirals Over the past 10-15 years the availability of robust in vitro systems to culture HCV has allowed the development of direct acting antivirals,30 which—unlike interferon and ribavirin—are specifically designed to target HCV proteins, particularly the non-structural proteins (fig 2; table 1). NS3/4A protease inhibitors The NS3/4A inhibitors target the serine protease NS3/4A, which cleaves the HCV polyprotein at four sites. The first direct acting antivirals to be licensed were the first generation protease inhibitors, telaprevir and boceprevir. The protease For personal use only

inhibitor simeprevir has recently been licensed, and others, such as faldaprevir, asunaprevir, vaniprevir, and ritonavir boosted ABT-450, are currently in phase II or phase III studies. Compared with first generation protease inhibitors, newer ones have easier dosing regimens and seem to have a lower propensity for toxicity and drug-drug interactions. They were initially designed for use against GT1 viruses, but newer agents have activity against other genotypes, particularly GT2, GT4, GT5, and GT6. For GT1 infection, protease inhibitors can increase the sustained virologic response from 45% with standard peginterferon alfa and ribavirin based treatment to as high as 80-90%, with lower responses typically seen in those with advanced cirrhosis or other markers of poor outcome (table 2). Because they are CYP3A4 substrates and inhibitors, telaprevir and boceprevir can interact with some antiretrovirals, immunosuppressants (including ciclosporin and tacrolimus), and other drugs. This may have important implications for their use in patients with solid organ transplants or HIVHCV coinfection. Because alternative treatment options are available for HCV, it may be best to avoid the use of these protease inhibitors in patients on these specific drugs. Resistance to protease inhibitors occurs mainly through newly acquired resistance mutations in the gene encoding the NS3 protease, at codons 36, 54, 155, 156, 168, and 170.31 In addition, some viruses may contain pre-existing polymorphisms associated with reduced response—for example, in the US up to 50% of GT1a viruses contain the Q80K polymorphism, although worldwide prevalence seems to be lower, at around 25%.13 This polymorphism is associated with about a threefold reduction in response to simeprevir, and a significant reduction in treatment response.32 Protease inhibitors are currently licensed for use in conjunction with peginterferon alfa and ribavirin, although interferon-free regimens (such as combined simeprevir and sofosbuvir, and asunaprevir or ABT-450 based treatment) are under investigation.

NS5A inhibitors The NS5A protein is essential for both viral assembly and replication. Inhibitors of NS5A are potent antivirals that act at picomolar concentrations, although the response differs between GT1a and GT1b viruses.33 Daclatasvir, ledipasvir, ABT-267, GS-5816, and MK-4782 are NS5A inhibitors being tested in phase II-III studies, with some likely to be licensed in the next year. These agents seem to have minimal adverse reactions, and no serious drug-drug interactions are yet known. Resistance mutations in the NS5A protein encountered in clinical trials to date include M28T, L31M/V, and Y93C/N. NS5B inhibitors The NS5B RNA dependent RNA polymerase is responsible for replication of HCV RNA. As with inhibitors of the HIV reverse transcriptase enzyme, there are two main classes of NS5B inhibitors. These are the nucleos(t)ide inhibitors (nucleoside or nucleotide inhibitors), which bind to the active site of the enzyme and cause premature chain termination, and the non-nucleoside inhibitors, which bind outside the active site, but cause a conformational change that inhibits RNA polymerase activity. 4 of 13

S TAT E O F T H E A RT R E V I E W Table 2 | Results of major studies of direct acting antivirals combined with peginterferon and ribavirin Agent (study)

N

Population

Comparator

Duration (weeks)

SVR

Comments Phase III. Telaprevir for first 12 weeks only; rash and anemia more common in telaprevir arm Phase III. Telaprevir for first 12 weeks only; rash and anemia more common in telaprevir arm Phase III. Boceprevir after 4 week lead-in; anemia and dysgeusia more common in boceprevir arm Phase III. Boceprevir after 4 week lead-in; non-responders not included Phase III. Simeprevir for 12 weeks; GT1a + Q80K; SVR only 58%

NS3/4A protease inhibitors

Telaprevir (ADVANCE)35

1088

TN, GT1

pegIFN/RBV

24-48

69-75%

Telaprevir (REALIZE)36

663

TE, GT1

pegIFN/RBV

48

Boceprevir (SPRINT 2)37

1097

TN, GT1

pegIFN/RBV

48

Boceprevir (RESPOND2)38 Simeprevir (QUEST I and II)39 Simeprevir (ASPIRE)40

403

TE, GT1

pegIFN/RBV

48

785

TN, GT1

pegIFN/RBV

24-48

64-66%; 83-88% in relapsers, 29-33% in non-responders 67-68% in non-black patients; 42-53% in black patients 69-75% in relapsers; 40-52% in partial responders 80%

462

TE, GT1

pegIFN/RBV

48

pegIFN/RBV

1309

Relapsers, GT1 TN, GT1

677

Phase III. Simeprevir for 12-48 weeks. SVR rates lowest in nonresponders with cirrhosis (31%)

24-48

77-89% in relapsers; 48-86% in partial responders; 38-59% in non-responders 79%

pegIFN/RBV

24-48

72-73%

TE, GT1

pegIFN/RBV

24-48

70% in relapsers; 47-58% in partial responders; 33% in non-responders

Phase III. Faldaprevir for 12 weeks; most patients eligible for 24 weeks’ treatment Phase III

395

TN, GT1

pegIFN/RBV

24-48

58-87%

Phase II. Rates lower in GT1a (58-60%) than in GT1b (78-87%)

151

TN, GT2/3

pegIFN/RBV

12-24

83-88% in GT2; 69-70% in GT3

Phase II. Most patients qualified for 12 or 16 weeks’ therapy; high relapse rates in weeks 0-12 in GT3

125 332

TN, GT1 TN, GT1/4/5/6 TN, GT1/4/5/6 TE, GT2/3

pegIFN/RBV None

24-48 12-24

91% 87-89%

Phase II. Mostly GT1 (also treated 25 patients with GT2/3) Phase II. Mostly GT1; no difference between groups at 12-24 weeks

None

12

90%

Phase III. Mostly GT1; SVR 80% in 54 patients with cirrhosis

None

12

83-96%

83% in GT3 patients with cirrhosis

Simeprevir (PROMISE)41 393 Faldaprevir (StartVerso1 and 2)42 Faldaprevir (StartVerso3)43

Phase III. Simeprevir for 12 weeks

NS5A inhibitors

Daclatasvir (COMMAND-1)47 Daclatasvir (COMMAND-2/3)48 NS5B inhibitors

Sofosbuvir (PROTON)49 Sofosbuvir (ATOMIC)50

Sofosbuvir (NEUTRINO51 327 Sofosbuvir (LONESTAR-2)52

47

GT=genotype; pegIFN=peginterferon alfa; Q80K= NS3 protease polymorphism; RBV=ribavirin; SVR=sustained viral response; TE=treatment experienced; TN=treatment naive

Several agents are currently in advanced stages of development, and the nucleos(t)ide inhibitor sofosbuvir recently became the first NS5B inhibitor to be licensed for treatment of HCV infection. Reassuringly, these nucleos(t)ide analogs have not yet shown any of the mitochondrial toxicity seen with early HIV nucleoside reverse transcriptase inhibitors. These agents seem to have pan-genotypic activity and minimal toxicity or drug interactions. In vitro resistance to sofosbuvir seems to occur with the development of an S282T mutation in the NS5B gene, although this has yet to be seen in large numbers of patients. This is in contrast to protease inhibitor based therapy, where resistance mutations are commonly seen when treatment fails.34

Clinical use of direct acting antivirals Interferon containing and interferon-free regimens are discussed in turn, focusing on the drugs from each class. Interferon containing regimens (table 2) NS3/4A protease inhibitors The first generation protease inhibitors, telaprevir and boceprevir, have been licensed since 2011 for the treatment of HCV GT1 infection in conjunction with peginterferon-ribavirin, on the basis of the findings of the ADVANCE, REALIZE, SPRINT2, and RESPOND2 studies (table 2). Both agents were initially given three times a day, but telaprevir was recently approved for twice daily use. For personal use only

Side effects with both agents are more common and more severe than with peginterferon-ribavirin alone. Adverse effects include anemia, rash, and perianal itching with telaprevir, and anemia and dysgeusia with boceprevir.35‑38 Simeprevir is a once daily, second wave protease inhibitor that has just been licensed by the Food and Drug Administration for use together with peginterferon-ribavirin in GT1 and GT4 HCV infection. Table 2 outlines the studies that relate to the approval of simeprevir. In the QUEST I and QUEST II studies, 785 treatment naive patients with GT1 HCV infection were randomized to placebo or simeprevir together with peginterferon-ribavirin for 12 weeks, followed by peginterferon-ribavirin for a further 12 or 36 weeks based on treatment arm and response guided therapy. In a pooled analysis, 80% of patients treated with simeprevir achieved sustained virologic response at 12 weeks compared with 50% in the placebo arm.39 The ASPIRE study randomized 462 treatment experienced patients with GT1 HCV infection to placebo or simeprevir at 100 mg or 150 mg daily for 12, 24, or 48 weeks along with peginterferon-ribavirin for 48 weeks. Those treated with simeprevir achieved sustained virologic response rates of 77-89%, 48-86%, and 38-59% in people who had previously relapsed, partial responders, and null-responders, respectively. Only 31% of patients with cirrhosis and a previous null response achieved sustained virologic response.40 5 of 13

S TAT E O F T H E A RT R E V I E W Finally, the PROMISE study randomized 393 people who had previously relapsed to simeprevir 150 mg or placebo for 12 weeks with peginterferon-ribavirin or ribavirin for a further 12-36 weeks on a response guided therapy basis. In this study, 79% of simeprevir treated patients achieved a sustained virologic response at 12 weeks compared with 37% of patients in the placebo arm, with highest sustained virologic response rates in those treated for 48 weeks.41 The NS3 Q80K polymorphism is commonly found in GT1a viruses and is associated with resistance in vitro and impaired response to simeprevir. For example, patients in QUEST infected with GT1a virus and with a baseline Q80K polymorphism had a sustained virologic response rate at 12 weeks of 58%, similar to that seen with placebo.39 It is therefore recommended that patients infected with GT1a HCV be screened for the presence of Q80K, and the use of another agent considered if present. Simeprevir is associated with a drug rash and unconjugated hyperbilirubinemia in 10-20% and 5-10% of patients, respectively.41 Several other protease inhibitors are in development (table 2). Faldaprevir is another once daily protease inhibitor that has shown efficacy in both treatment naive (sustained virologic response rates of 72-73%) and treatment experienced patients (sustained virologic response rates of 33-70%; table 2).42  43 Compared with peginterferon-ribavirin alone, the use of faldaprevir has been associated with more anemia (6% v 1%) and gastrointestinal side effects (20% v 6%). The twice daily protease inhibitor danoprevir, when compared with placebo for 12 weeks combined with peginterferon-ribavirin, followed by peginterferon-ribavirin for a further 12-36 weeks, in 237 treatment naive patients with GT1 HCV infection, achieved sustained virologic response rates of 68-85% (95% confidence interval 57-78% to 75-91%). However, reversible grade 4 elevations in alanine aminotransferase were seen in four patients who were treated with higher doses of danoprevir.44 Asunaprevir is a twice daily protease inhibitor that was assessed in a phase IIa study of 47 treatment naive patients with GT1 HCV at three doses with peginterferon-ribavirin for 48 weeks; those treated with asunaprevir achieved sustained virologic response rates at 24 weeks of 83-92%.45 Vaniprevir, another twice daily protease inhibitor, when given with peginterferon-ribavirin in a short four week lead in, followed by 44 weeks of peginterferon-ribavirin alone, achieved sustained virologic response rates at 24 weeks of 61-84% in 94 treatment naive patients with GT1 HCV. However, more gastrointestinal, side effects such as nausea, vomiting, and diarrhea, were seen in the vaniprevir treated group.46

NS5A inhibitors Of the two NS5A inhibitors currently in clinical studies (daclatasvir and ledipasvir) only daclatasvir has been evaluated with peginterferon-ribavirin for treatment of HCV. In the COMMAND-1 and COMMAND GT2/3 studies, daclatasvir showed efficacy in GT1, GT2, and GT3 HCV infection, although success rates in GT1a and GT3 infection were lower (table 2).47  48 Although the current COMMAND-3 trial is comparing daclatasvir with telaprevir with peginterferonribavirin in GT1b infection, it seems that NS5A inhibitors will mostly be used as components of interferon-free regimens (see below). For personal use only

NS5B inhibitors The NS5B sofosbuvir has recently been licensed for the treatment of GT1 and GT4 infection on the basis of the results of the PROTON, ATOMIC, and NEUTRINO studies (table 2). In the phase II PROTON study, 125 untreated patients with GT1 infection were treated with sofosbuvir or placebo with peginterferon-ribavirin for 12 weeks, followed by either 12 or 36 weeks of peginterferon-ribavirin alone. Sustained virologic response rates at 12 weeks were 91% (80% to 98%) for the sofosbuvir group versus 58% (37% to 77%) for the placebo group.49 The phase II ATOMIC study examined whether the further course of peginterferon-ribavirin alone was needed. In this study, 332 patients were treated with sofosbuvir plus peginterferon-ribavirin for 12 or 24 weeks, or sofosbuvir plus peginterferon-ribavirin for 12 weeks, followed by sofosbuvir or ribavirin alone for another 12 weeks. In all treatment groups the sustained virologic response at 12 weeks was greater than 90% (79% to 97%, 86% to 97%, and 85% to 95%) and 87-89% at week 24.50 Therefore, in the phase III NEUTRINO study, 327 treatment naive patients with GT1, GT4, GT5, or GT6 infection were treated with sofosbuvir or placebo combined with peginterferon-ribavirin for 12 weeks. Overall, 90% (87% to 93%) of those treated with sofosbuvir achieved a sustained virologic response at 12 weeks, including an 80% rate in 54 patients with cirrhosis.51 There is a relative paucity of data for sofosbuvir with peginterferon-ribavirin in treatment experienced patients with GT1 infection and cirrhosis, so this regimen should be used with caution in this group. The LONESTAR-2 study investigated treatment with sofosbuvir and peginterferon-ribavirin in 47 patients with GT2 and GT3 infection, and 89% achieved a sustained virologic response after 12 weeks of treatment.52 Notably, 83% of the patients with GT3 infection and cirrhosis (a group with relatively poor responses to drug regimens containing direct acting antivirals) achieved a sustained virologic response at 12 weeks. Although not licensed in this population, this may be a useful treatment option for patients with GT3 infection and compensated cirrhosis. Although these response rates are a great improvement on previous results, given the data from the phase III ION-1 study and others (see below), interferon-free regimens are likely to be licensed for GT1 and GT4 infection in the near future. This may be preferable to current interferon based sofosbuvir regimens, especially for patients ineligible for or intolerant of interferon. In summary, both protease inhibitor and sofosbuvir based regimens that also contain peginterferon-ribavirin are currently available for GT1 and GT4 infections, and sofosbuvir with peginterferon-ribavirin has shown efficacy in GT2 and GT3 infections, particularly cirrhotic GT3 infection. These regimens produce sustained virologic response rates of 70-90%, depending on the agent used and the patient population. Further protease inhibitor should be licensed in the next year to extend the available interferon based treatment options for GT1 infection. Interferon-free regimens (table 3) One of the most promising benefits of newer direct acting antivirals is the ability to construct effective interferonfree regimens, avoiding the need for subcutaneous injec6 of 13

S TAT E O F T H E A RT R E V I E W

Table 3 | Results of major studies of direct acting antivirals without interferon Agents Sofosbuvir + RBV (FISSION)51

N 499

Population GT2/3; TN

Sofosbuvir + RBV (POSITRON)53

278

Sofosbuvir + RBV (FUSION)53

201

Duration (weeks) SVR 12 67% in both arms; sofosbuvir + RBV: 97% in GT2, 56% in GT3 12 78% for sofosbuvir + RBV; 93% in GT2, 61% in GT3

Comments Phase III. Compared with pegIFN/RBV: SVR 78% in GT2 and 63% in GT3 Phase III. SVR 0% in placebo and RBV arm

12-16

Phase III. SVR 86-94% in GT2; SVR 30-62% in GT3

Sofosbuvir + RBV (VALENCE)

419

GT2/3; unsuitable for interferon GT2/3; nonresponders GT2/3

Sofosbuvir + RBV (SPARE)55

60

GT1; TN

24

68%

Sofosbuvir + simeprevir ± RBV (COSMOS)56

186

GT1; TN and TE

12-24

90%

Daclatasvir + sofosbuvir ± RBV57

211

24

98% in GT1; 93% in GT2/3

Sofosbuvir-ledipasvir ± RBV (LONESTAR-1)19 Sofosbuvir-ledipasvir ± RBV (ION-1)58

100

GT1/2/3; TN and TE (GT1); TN (GT2/3) GT1; TN, TE

8-12

95-100%

Phase II

865

GT1, TN

12-24 weeks

Phase III. 16% with cirrhosis

Sofosbuvir-ledipasvir ± RBV (ION-2)59

440

GT1, TE

12-24 weeks

ABT-450-ritonavir-ombitasvir + dasabuvir + RBV (SAPPHIRE-I)60 ABT-450-ritonavir-ombitasvir + dasabuvir +RBV (SAPPHIRE-II)61 ABT-450-ritonavir-ombitasvir + dasabuvir ± RBV (PEARL-IV)62 ABT-450- ritonavir-ombitasvir + dasabuvir ± RBV (PEARL-III)62 ABT-450-ritonavir-ombitasvir + dasabuvir + RBV (TURQUOISE-II)63 MK-5172 + MK-8742 ± RBV (C-WORTHY)64

636

GT1; TN

12

12 weeks + RBV 99%; 12 weeks no RBV 97%; 24 weeks + RBV 98%; 24 weeks no RBV 99% 12 weeks + RBV 96%; 12 weeks no RBV 94%; 24 weeks with and without RBV 99% 96%

394

GT1; TE

12

96%

305

GT1a, TN

12

With RBV 97%; without RBV 90%

419

GT1b, TN

12

With RBV 99.5%; without RBV 99%

380

GT1; TN, TE

12-24

12 weeks 92%; 24 weeks 96%

Phase III. No cirrhosis, SVR 95% in previous nonresponders Phase III. No cirrhosis; without RBV did not meet non-inferiority versus with RBV Phase III. No cirrhosis; without RBV non-inferior to with RBV Phase III. All had Child Pugh class A cirrhosis

65

GT1; TN

12

89-100%

Interim results similar ± RBV in GT1b

54

50% at 12 weeks; 73% at 16 weeks

GT2: 12; GT3: 24 93% in GT2, 85% in GT3

Phase III. 85 patients received placebo; SVR in GT3 TE patients with cirrhosis only 60% Phase II. Patients with predictors of poor response who were ineligible for interferon Phase II. Non-responders with low fibrosis indices (F0-F2) SVR at 12 weeks 79-96%; TN nonresponders with advanced fibrosis (F3-F4) SVR at 24 weeks 96-100% No apparent benefit to RBV or extending to 24 weeks

Phase III. 20% with cirrhosis; not powered to detect differences with or without RBV Phase III. No cirrhosis

GT=genotype; pegIFN=peginterferon alfa; RBV=ribavirin; SVR=sustained viral response; TE=treatment experienced; TN=treatment naive

tions and the multitude of toxicities associated with the use of interferon.

Sofosbuvir with or without ribavirin The NS5B nucleos(t)ide inhibitor sofosbuvir has recently been approved for use with ribavirin in interferon-free regimens for the treatment of GT2 infection (12 weeks) or GT3 infection (24 weeks). In the FISSION study, 499 treatment naive patients with GT2 or GT3 infection were treated with sofosbuvir and ribavirin for 12 weeks or peginterferonribavirin for 24 weeks. In both arms the sustained virologic response rate was similar, at 67%. In the sofosbuvir and ribavirin arm, 97% of patients with GT2 infection achieved a sustained virologic response compared with 78% in the peginterferon-ribavirin arm. In those with GT3 infection, these response rates were 56% and 63%, respectively.51 The POSITRON study treated 278 patients with GT2 or GT3 infection who were not suitable for treatment with interferon for 12 weeks with sofosbuvir or placebo and ribavirin. The sustained virologic response rate was 78% (72% to 83%; 93% in patients with GT2 infection, 61% in those with GT3) in the sofosbuvir arm compared with 0% in the placebo arm.53 The FUSION study treated 201 patients with GT2 or GT3 infection who had previously not responded to interferon containing regimens with 12-16 weeks of sofosbuvir and ribavirin and achieved sustained virologic response rates of 50% (40% to 60%) (12 weeks) and 73% (63% to 81%) For personal use only

(16 weeks).53 Sustained virologic response rates in people with cirrhosis were lower—31% with 12 weeks’ treatment and 66% with 16 weeks’ treatment, compared with 61% and 76%, respectively, in those without cirrhosis. Again, GT3 infected patients had significantly lower sustained virologic response rates than GT2 infected ones (30-62% v 86-94%). Finally, in the phase III VALENCE study, patients with GT2 or GT3 HCV infection were randomized to sofosbuvir and ribavirin or placebo; although it was initially planned to treat all patients for 12 weeks, a decision was made to treat patients infected with GT3 for 24 weeks. In the sofosbuvirRBV arms, 93% (85% to 98%) of patients with GT2 infection treated for 12 weeks and 85% (80% 89%) of patients with GT3 infection treated for 24 weeks achieved a sustained virologic response at 12 weeks after treatment.54 In the GT3 group the sustained virologic response rate at 12 weeks was 95%, 92%, 87%, and 62% in treatment naive patients without cirrhosis, treatment naive patients with cirrhosis, treatment experienced patients without cirrhosis, and treatment experienced patients with cirrhosis, respectively. The lower sustained virologic response rates seen in patients with GT3 infection and cirrhosis mirrors earlier studies—in those with cirrhosis in the POSITRON study, only 21% of GT3 infected patients achieved a sustained virologic response after 12 weeks, compared with 94% of GT2 infected patients. Similarly, in the FUSION study only 19% of GT3 infected patients with cirrhosis achieved a 7 of 13

S TAT E O F T H E A RT R E V I E W sustained virologic response after 12 weeks, compared with 60% of GT2 infected patients with cirrhosis. Taken together, these data suggest that GT3 infected patients with cirrhosis are currently the most challenging group of patients to treat. Treatment with sofosbuvir and ribavirin (without interferon) for 24 weeks can be used in GT1 infected patients who are intolerant or unable to take interferon. In a phase II study of 60 treatment naive patients with GT1 infection (SPARE), with varying predictors of poor response to treatment (unfavorable IFNL3 status, black race, high HCV viral load), 24 weeks of sofosbuvir-ribavirin led to an sustained virologic response rate of 68% (46% to 85%) in 25 patients treated with weight based ribavirin.55

Sofosbuvir with or without a protease inhibitor The combination of sofosbuvir with the NS3A/4A inhibitor simeprevir, both of which have recently been licensed, is a potential option for GT1 infection. In the COSMOS study of 186 patients, treatment naive patients and previous nonresponders with advanced fibrosis (F3-F4) or low fibrosis indices (F0-F2), were treated with simeprevir and sofosbuvir, with or without ribavirin, for 12-24 weeks. At 12 weeks sustained virologic response rates of 79-96% were achieved in non-responders with F0-F2 scores, whereas rates of 96-100% were reported in patients with advanced fibrosis at 24 weeks. An interim analysis suggested that 12 weeks of treatment was as effective as 24 weeks, and that the addition of ribavirin may not be needed to achieve high sustained virologic response rates.56 Although both agents are licensed for the treatment of HCV, their use in combination is off label. Sofosbuvir with or without other direct acting antivirals Sofosbuvir showed promise in combination with NS5A inhibitors in a study of 167 GT1 infected patients (126 treatment naive and 41 previously treated with telaprevir or boceprevir without a sustained virologic response) and 44 treatment naive GT2 or GT3 infected patients (211 in total). Patients were treated with daclatasvir and sofosbuvir with or without ribavirin for 24 weeks (31 patients initially received sofosbuvir monotherapy for one week). In this study, 164 of 167 patients (98%) with GT1 achieved a sustained virologic response at 12 weeks including 40 of 41 previously treated patients. In the 44 GT2 and GT3 infected patients, 41 (93%) achieved a sustained virologic response at 24 weeks.57 Despite this, further development of this combination in HCV monoinfection has been halted because the manufacturer of sofosbuvir, Gilead, has developed a fixed dose combination of sofosbuvir with the NS5A inhibitor ledipasvir. In the phase II LONESTAR-1 study, 60 treatment naive GT1 infected patients without cirrhosis were randomized to receive sofosbuvir and ledipasvir for eight weeks, with or without ribavirin, or sofosbuvir and ledipasvir for 12 weeks. Sustained virologic response rates at 12 weeks were 95-100% across all arms.20 In a second cohort, 40 patients infected with GT1 HCV who had not responded to a protease inhibitor based regimen (22 with cirrhosis) were randomized to receive sofosbuvir-ledipasvir for 12 weeks, with or without ribavirin. Sustained virologic response rates at 12 weeks were 95% in the sofosbuvir-ledipasvir arm and 100% in the sofosbuvirledipasvir-ribavirin arms.20 For personal use only

In the phase III ION-1 study, 865 patients with untreated GT1 HCV were treated with sofosbuvir-ledipasvir, with or without ribavirin for 12-24 weeks.58 Sustained virologic response rates were high: 99% (96% to 100%; 12 weeks, with ribavirin), 97% (94% to 99%; 12 weeks, without ribavirin), 98% (95% to 99%; 24 weeks, with ribavirin), and 99% (97% to 100%; 24 weeks, without ribavirin) depending on the treatment arm. In the phase III ION-2 study, 440 patients with previously treated GT1 infection were also treated with sofosbuvir-ledipasvir, with or without ribavirin, and had similarly high sustained virologic response rates across all four arms; 96% (91% to 99%; 12 weeks, with ribavirin), 94% (87% to 97%; 12 weeks, without ribavirin), 99% (95% to 100%; 24 weeks, with ribavirin), and 99% (95% to 100%; 24 weeks, without ribavirin).59 In another small study of sofosbuvir-ledipasvir-ribavirin in treatment naive patients with HCV GT1 infection, a sustained virologic response was seen after 12 weeks in all 25 patients, but in only 17 of 25 (68%) after a six week course.65 In the same study, a sustained virologic response was seen in 23 of 25 (92%) treatment naive patients treated with 12 weeks of sofosbuvir, the NS5B non-nucleoside inhibitor GS-9669, and ribavirin. In a cohort of previous non-responders with cirrhosis reported by the same study, a sustained virologic response was seen in all nine patients treated with sofosbuvir-ledipasvir-ribavirin for 12 weeks, but in only seven of 10 patients treated with sofosbuvir-ledipasvir without ribavirin. Finally, the SYNERGY study examined the use of sofosbuvir-ledipasvir, sofosbuvir-ledipasvir-GS-9669, and sofosbuvir-ledipasvir and the protease inhibitor GS-9451 in 60 treatment naive patients with characteristics associated with poor treatment outcomes. Patients were treated for six to 12 weeks (although those with cirrhosis were all treated for 12 weeks); rates of sustained virologic response at 12 weeks were 95-100% across the three arms.66 These results need to be confirmed in larger studies, but a six or 12 week interferon-free oral treatment regimen for HCV GT1 infection is likely to be available in the near future, even for those who previously did not respond to protease inhibitor based treatment and those with cirrhosis.

Protease inhibitors and other direct acting antivirals The combination of the NS3/4A protease inhibitor asunaprevir with the NS5A inhibitor daclatasvir (with or without peginterferon-ribavirin) has been studied in 101 patients with GT1 HCV who previously did not respond to treatment. Of 38 GT1b infected patients treated with daclatasvir and asunaprevir alone for 24 weeks, 27 (71%) achieved a sustained virologic response. By contrast, only one of 18 GT1a infected patients treated with daclatasvir-asunaprevir and ribavirin for 24 weeks achieved such a response.67 This combination is now being studied as triple therapy, with the addition of the NS5B non-nucleoside inhibitor BMS-791325 in HCV GT1a and GT1b infection, with more than 90% of 66 treatment naive GT1 infected patients achieving a sustained virologic response after 12 weeks of triple therapy.68 A similar combination of the NS3/4A protease inhibitor ABT-450, coformulated with a low dose (100 mg) of the HIV protease inhibitor (and strong cytochrome P450 inhibitor) ritonavir and the NS5A inhibitor ombitasvir (ABT-267), has recently shown promise when combined with the non8 of 13

S TAT E O F T H E A RT R E V I E W nucleoside inhibitor NS5B inhibitor dasabuvir (ABT-333). In the SAPPHIRE-I study, 636 patients with untreated GT1 HCV infection and no cirrhosis were treated with 12 weeks of this three drug combination and ribavirin; 96% (95% to 98%) of patients achieved a sustained viral response.60 In SAPPHIREII, 394 previously treated patients with GT1 HCV infection (and no cirrhosis) achieved sustained virologic response rates of 96% (94% to 98%) with the same 12 week regimen, with a response rate of 95% in previous non-responders.61 The PEARL studies examined the need for ribavirin. In the PEARL-III (GT1b, 419 patients) and PEARL-IV (GT1a, 305 patients) studies, untreated patients without cirrhosis were treated with ABT-450-ritonavir-ombitasvir and dasabuvir for 12 weeks, with or without ribavirin.62 All groups achieved high sustained response rates; however, in GT1a infection (PEARL-IV), those treated without ribavirin did not meet the criterion for non-inferiority when compared with those treated with ribavirin (90% (86% to 94%) without ribavirin v 97% (94 to 100%) with ribavirin). By contrast, in GT1b infection (PEARL-III), those treated without ribavirin were noninferior to those treated with ribavirin (sustained response rates 99% (98% to 100%) without ribavirin v 99.5% (99% to 100%) with ribavirin). Finally, the TURQUOISE-II study examined this three drug combination with ribavirin in patients with GT1 infection and cirrhosis; 380 patients were randomised to treatment for 12 or 24 weeks. Sustained viral response rates were 92% (97.5% confidence interval 88% to 96%) at 12 weeks compared with 96% (93% to 99%) at 24 weeks.63 Sustained response rates did not differ significantly between people treated for 12 weeks and those treated for 24 weeks, but those with GT1a infection who previously did not respond seemed to benefit from 24 weeks of treatment. In summary, 12 weeks of ABT450-ritonavir-ombitasvir with dasabuvir seems to produce high sustained viral response rates in GT1 infection, but ribavirin should be used in those with GT1a or cirrhosis. Patients with cirrhosis and GT1a infection who previously did not respond may benefit from 24 weeks of treatment. Another similar option in earlier stages of development is the combination of the protease inhibitor MK-5172 with the NS5A inhibitor MK-8742. In the phase II C-WORTHY study, 65 treatment naive patients infected with GT1 were treated for 12 weeks with MK-5172 and MK-8742, with or without ribavirin. Interim results showed sustained virologic response rates of 89-100% at 12 weeks, and that (in GT1b infection at least) ribavirin may not be needed.64 Sofosbuvir based interferon-free regimens are currently licensed for infection with GT2 and GT3 HCV, and sofosbuvir-simeprevir is an off-label option for GT1 infection. An increasing number of such regimens (and combinations to treat GT1 infection) should become available with approval of the NS5A inhibitors, newer protease inhibitors, and some NS5B inhibitors. These newer combinations have produced high (>95%) cure rates in many population groups, even with shorter courses (6-12 weeks) of treatment. Their efficacy in patients with cirrhosis and GT3 HCV infection, although promising, needs to be further studied.

Current recommendations Box 2 lists the currently available treatment regimens by genotype. For GT1 or GT4 infected patients, treatment with For personal use only

sofosbuvir and peginterferon-ribavirin for 12 weeks (based on the PROTON, ATOMIC, and NEUTRINO studies), or simeprevir and peginterferon-ribavirin for 24-48 weeks (based on the QUEST, ASPIRE, and PROMISE studies, depending on treatment history), are potential options. Because of the shorter treatment regimens and higher rates of sustained virologic response, sofosbuvir, rather than simeprevir, based treatment seems to be the better option if possible. For those who are intolerant to or not eligible for treatment with interferon, a 24 week course of sofosbuvirribavirin or a 12 week course of sofosbuvir-simeprevir (based on the data from the COSMOS study) can be considered. This last combination is off label, would be more expensive than either agent alone with peginterferon-ribavirin or ribavirin, and its approval may be challenged by payers. Nonetheless, it is an attractive option, with high rates of sustained virologic response in interferon intolerant or ineligible patients. On the basis of data from the FISSION, POSITRON, FUSION, and VALENCE studies, our current recommendation for treatment of HCV GT2 or GT3 infection is sofosbuvir with ribavirin for 12 weeks (GT2) or 24 weeks (GT3); however, given the data from LONESTAR-2, 12 weeks of sofosbuvir and peginterferon-ribavirin may be better a better option for GT3 infected patients with cirrhosis. The optimum treatment for patients with GT5 or GT6 infection is unclear. None of the direct acting antivirals is licensed for use in these patients, although small numbers of patients were treated with sofosbuvir with peginterferon-ribavirin in the NEUTRINO study. Currently, peginterferon-ribavirin based treatment, with or without sofosbuvir, seems to be most likely to achieve a clinical cure. In treatment settings where access to newer direct acting antivirals is limited, the addition of telaprevir or boceprevir is better than peginterferon-ribavirin alone for GT1 infection. Similarly, for GT2 and GT3 infection, peginterferon-ribavirin can be considered if direct acting antivirals are unavailable and prompt treatment is indicated. First generation protease inhibitors have been shown to be cost effective for the treatment of HCV.69 These newer direct acting antivirals are much more expensive (sofosbuvir is estimated to cost $1000 (£593; €732)/day70), but with higher sustained virologic response rates, shorter courses of treatment, and the potential to use interferon-free regimens they should ultimately be cost effective. A formal analysis will need to be performed, and the data will be especially important for national and state funded healthcare systems to guide decisions about which treatments to approve. As more treatment regimens with high cure rates become available, there may be some competition between companies on pricing, but this remains to be seen.

Special situations Patients who have not responded to previous treatment For those who do not respond to standard peginterferon-ribavirin therapy, sofosbuvir or simeprevir based regimens have a relatively high likelihood of cure and are worth considering. For those who do not respond to treatment with a first generation protease inhibitor and peginterferon-ribavirin, the data are less clear, but many newer interferon-free regimens containing two or more direct acting antivirals are the most promising, with excellent sustained virologic response rates even in this population. 9 of 13

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Box 2 | Current treatment options for treatment of treatment naive and previously treated patients with hepatitis C virus Genotype 1 Favored: Sofosbuvir + peginterferon + ribavirin for 12 weeks Alternatives: Simeprevir + peginterferon + ribavirin for 12 weeks, followed by peginterferon + ribavirin for 12-36* weeks (if GT1a, rule out Q80K polymorphism first) Sofosbuvir + simeprevir for 12 weeks Sofosbuvir + ribavirin for 24 weeks (if interferon intolerant; response rates are usually lower) Less favored: Telaprevir for 12 weeks + peginterferon + ribavirin for 24-48 weeks Boceprevir for 24-44 weeks + peginterferon + ribavirin for 28-48 weeks (with 4 week peginterferon + ribavirin lead-in) Not favored: Peginterferon + ribavirin for 48 weeks Genotype 2 Favored: Sofosbuvir + ribavirin for 12 weeks Less favored: Peginterferon + ribavirin for 24 weeks Genotype 3 Favored: Sofosbuvir + ribavirin for 24 weeks Alternatives: Sofosbuvir + peginterferon + ribavirin for 12 weeks Less favored: Peginterferon + ribavirin for 24 weeks Genotype 4 Favored: Sofosbuvir + peginterferon + ribavirin for 12 weeks Alternatives: Simeprevir + peginterferon + ribavirin for 12 weeks, followed by peginterferon + ribavirin for 12-36 weeks* Sofosbuvir + ribavirin for 24 weeks (if interferon intolerant; response rates are usually lower) Less favored: Peginterferon + ribavirin for 48 weeks *Treat treatment naive patients and those with previous relapse for 12 weeks. Treat partial and non-responders for 36 weeks.

Acute hepatitis C infection Sustained virologic response rates are higher after treatment of acute HCV infection (in those who do not spontaneously clear HCV within 12 weeks) with peginterferon alone than after established chronic infection, so treatment of acute HCV is usually recommended.71 The addition of ribavirin is thought to improve sustained virologic response rates in patients infected with HIV but not in HIV negative ones.72 In HIV infected men, telaprevir-peginterferon-ribavirin improved sustained virologic response rates and led to a shorter treatment duration of 12 weeks when compared with a non-randomized cohort of HIV infected patients treated with peginterferon-ribavirin alone for 24-72 weeks (most (77%) treated for 24 weeks).73 These data suggest that direct acting antivirals are likely to have an important role in treating acute HCV infection; however, further data on optimum regimens (particularly in HIV negative patients) are needed. For personal use only

Liver cirrhosis The treatment for patients with advanced liver fibrosis or compensated cirrhosis should broadly follow the guidelines above; these patients should be treated as soon as feasible to prevent hepatic decompensation. On the basis of the results of the COSMOS study, simeprevir and sofosbuvir could be considered in some patients with advanced fibrosis or compensated cirrhosis with GT1 infection. In those with GT3 infection, treatment with sofosbuvir and peginterferonribavirin could be considered owing to the lower chance of a sustained virologic response in this group with sofosbuvirribavirin alone. For patients with decompensated cirrhosis, interferon based therapy is contraindicated. There have been no studies on the use of sofosbuvir or other direct acting antiviral based interferon-free regimens in patients with decompensated cirrhosis, although in a group of 44 patients with severe recurrent HCV after liver transplantation, sofosbuvir seemed to be well tolerated.74 Liver transplantation HCV related cirrhosis is the most common cause of liver transplantation in the US,75 and recurrence of HCV in transplanted livers is almost universal if a sustained virologic response is not achieved before transplantation.76 Treatment of HCV recurrence in transplanted livers with peginterferonribavirin is associated with sustained virologic response rates at 24 weeks of only 20-25%.77 Both telaprevir and boceprevir have been shown in small studies to improve this rate to as high as 45-67%, but alterations in the immunosuppressive regimen are needed and side effects can be severe.78 In a study of recurrent post-transplant HCV in 40 patients, sofosbuvir with ribavirin for 24 weeks was well tolerated, with minimal interactions with immunosuppressant drugs. The sustained virologic response rate at four weeks was 77% in 35 patients; further complete data on sustained viral response at 12 weeks are awaited.79 In a study of the use of sofosbuvir and ribavirin before transplantation in 61 patients, this drug combination prevented HCV recurrence in 25 of the 39 patients who had undetectable HCV RNA at the time of transplantation.80 Of note, a longer duration of undetectable HCV RNA before transplantation (especially >30 days) was predictive of successful prevention of recurrence. Finally, preliminary data on a 24 week regimen of ABT-450-ritonavir-ombitasvir plus dasabuvir and ribavirin for recurrent HCV GT1 infection after liver transplantation showed a sustained viral response rate of 96% in 26 patients (results on a further eight patients are awaited).81 This regimen was well tolerated, but required dose adjustment of the calcineurin inhibitors used for immunosuppression. It is therefore hoped that direct acting antiviral based regimens will not only ultimately reduce the number of liver transplants needed for HCV, but that interferon-free regimens will improve sustained virologic response rates in this difficult to treat population. However, further research is needed to define the optimal treatment strategy. HIV coinfection The treatment of hepatitis C infection in HIV coinfected patients is more difficult than in hepatitis C monoinfection. In HIV infected patients, response rates to peginterferonribavirin are lower, treatment courses may be longer, and 10 of 13

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FUTURE RESEARCH QUESTIONS Are newer direct acting antivirals cost effective for the treatment of hepatitis C virus (HCV) infection? Is there a role for direct acting antivirals in the treatment of acute HCV infection? What is the optimum treatment for HCV genotype 3, and how long should it be given for? What is the optimum treatment for those who do not respond to protease inhibitor based peginterferon regimens? Do polymorphisms of the IFNL3 gene still have a predictive role with interferon-free regimens? What are the best treatment regimens for HCV in HCV-HIV coinfection? What is the best treatment for recurrent HCV in liver transplant recipients?

drug toxicities are more severe. In addition, drug-drug interactions between antiretrovirals and many direct acting antivirals (especially some protease inhibitors used to treat HCV or HIV and non-nucleoside reverse transcriptase inhibitors) may limit the treatment options available. Nonetheless, newer HCV agents clearly improve sustained virologic response rates in HIV infected patients and will play an important role in treatment. Both telaprevir and boceprevir are licensed for use in HIV-HCV GT1 coinfection and significantly improve sustained virologic response rates compared with peginterferon-ribavirin alone, although drug-drug interactions (predominantly anemia, fevers, and gastrointestinal symptoms) and twice or three times a day dosing schedules make their use problematic.82  83 The second generation protease inhibitors simeprevir and faldaprevir are more tolerable, easier to dose, and are efficacious in treating HCV GT1 infection in HIV infected patients, achieving sustained virologic response rates at 12 weeks of 57-88% when used with peginterferon-ribavirin, although drug-drug interactions may be a problem (more commonly with simeprevir).84  85 The combination of sofosbuvir and peginterferon-ribavirin for 12 weeks has been studied in 23 HIV infected patients with treatment naive HCV (19 infected with GT1 HCV); 21 of 23 achieved a sustained virologic response at 12 weeks.86 Interferon-free regimens are now being studied as well. In the PHOTON-1 study, HIV-HCV coinfected patients who had not previously been treated for HCV were treated with sofosbuvir and ribavirin for 24 weeks (GT1) or 12 weeks (GT2 or GT3). Sustained virologic response rates at week 12 were 76%, 88%, and 67% for GT1, GT2, and GT3, respectively.87 In addition to boosting sustained virologic response rates to levels similar to HIV negative patients with HCV, a major attraction of certain direct acting antivirals, such as sofosbuvir, is that they do not seem to interact with antiretroviral therapy.

Low resource settings Large numbers of HCV infected people worldwide live in low resource countries. Despite the lack of resources, the success rates of treatment with standard interferon or peginterferonribavirin based therapy in these settings are similar to those in higher income countries.88 The high cost of newer direct acting antiviral based regimens is likely to be a barrier to their use in poorer countries. However experience in the treatment of HIV shows that well structured treatment programs, simplified guidelines for testing and treatment, the use of fixed dose drug regimens, and both financial and political commitment can deliver a model of care that can greatly increase the number of patients accessing treatment.89 Shorter durations of treatment for HCV, and the potential for local agreements For personal use only

with drug manufacturers, could greatly reduce the cost of drugs in these settings.90

Emerging treatments The next generation of direct acting antivirals and the first interferon-free regimen for the treatment of HCV have recently been approved. Over the next one or two years, several new agents (protease inhibitors and NS5B inhibitors) and classes (NS5A inhibitors) of direct acting antivirals are likely to be licensed. Newer protease inhibitors will broaden the range of peginterferon-ribavirin containing regimens available, but most importantly the options available for interferon-free regimens will grow. The combinations of sofosbuvir-ledipasvir (which will be coformulated), sofosbuvir-GS-9669, and the regimens of ABT-450-ritonavir-ombitasvir-dasabuvir, and daclatasvir-asunaprevir-BMS-791325 are expected to be approved in the near future. These interferon-free regimens could enable many patients with HCV (even those with cirrhosis and those who have not responded to previous protease inhibitor based treatment) to be cured with an oral course of antivirals without the use of interferon and its associated side effects. Despite this optimism, challenges remain, particularly in the treatment of patients with HCV GT3, cirrhosis, hepatic decompensation, and liver transplantation. Guidelines HCV treatment guidelines are available from both the American Association for the Study of Liver Disease (AASLD; www. aasld.org) and the European Association for the Study of Liver Diseases (www.easl.eu). At the time of writing, while recommendations on use of the direct acting antivirals telaprevir and boceprevir are provided, neither of these guidelines includes the recently licensed agents simeprevir and sofosbuvir. Owing to the rapidly changing treatment landscape, AASLD and the Infectious Diseases Society of America (www.idsociety.org) have produced a website with newer guidelines for treatment of HCV (www.hcvguidelines.org). It is anticipated that this will be updated regularly as new agents become available. Conclusions The recent availability of new direct acting antivirals for the treatment of HCV infection has already completely changed recommendations for treatment, and allows for a shortened and easier to tolerate treatment course for most patients infected with the virus. The optimal treatment regimens remain to be determined. Over the next year or two we expect that even more effective interferon-free regimens, with high cure rates in almost every patient, will become available. These agents are expensive; however the potential for shortened courses of treatment with high cure rates should make them cost effective, and the availability of many newer agents may lead to some price competition. Contribution and guarantor statement: ERF and RTC both performed the literature searches and planned and wrote the manuscript. Both authors are guarantors. Competing interests: ERF: grant support—Harvard University Center for AIDS Research (NIH/NIAID fund 5P30AI060354-09). RTC has received consultancy fees from Abbvie and payment for clinical trials from Gilead Sciences, Mass Biologics, and Vertex; grant support: NIH DK098079, DA033541, and AI082630. Provenance and peer review: Commissioned; externally peer reviewed. 11 of 13

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72 Piroth L, Larsen C, Binquet C, Alric L, Auperin I, Chaix ML, et al. Treatment of acute hepatitis C in human immunodeficiency virus-infected patients: the HEPAIG study. Hepatology 2010;52:1915-21. 73 Fierer DS, Dietrich DT, Mullen MP, Branch AD, Uriel AJ, Carriero DC, et al. Telaprevir in the treatment of acute hepatitis C virus infection in HIV-infected men. Clin Infect Dis 2014;58:873-9. 74 Forns X, Fontana RJ, Moonka D, McHutchinson JG, Symonds WT, Denning JM. Initial evaluation of the sofosbuvir compassionate use program for patients with severe recurrent HCV following liver transplantation. Abstract 1084. 64th Annual Meeting of the American Association for the Study of Liver Diseases, 1-5 November 2013, Washington, DC. 75 United Network for Organ Sharing. www.unos.org. 76 Wright TL, Donegan E, Hsu HH, Ferrell L, Lake JR, Kim M, et al. Recurrent and acquired hepatitis C viral infection in liver transplant recipients. Gastroenterology 1992;103:317-22. 77 Wang CS, Ko HH, Yoshida EM, Marra CA, Richardson K. Interferon-based combination anti-viral therapy for hepatitis C virus after liver transplantation: a review and quantitative analysis. Am J Transplant 2006;6:1586-99. 78 Pungpapong S, Aqel BA, Koning L, Murphy JL, Henry TM, Ryland KL, et al. Multicenter experience using telaprevir or boceprevir with peginterferon and ribavirin to treat hepatitis C genotype 1 after liver transplantation. Liver Transplant 2013;19:690-700. 79 Charlton MR, Gane E, Manns MP, Brown RS, Curry MP, Kwo PY, et al. Sofosbuvir and ribavirin for the treatment of established recurrent hepatitis C infection after liver transplantation: preliminary results of a prospective, multicenter study. Abstract LB-2. 64th Annual Meeting of the American Association for the Study of Liver Diseases, 1-5 November 2013, Washington, DC. 80 Curry MP, Afdhal NH, Forns X, Chung RT, Terrault NA. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Abstract 213. 64th Annual Meeting of the American Association for the Study of Liver Diseases, 1-5 November 2013, Washington, DC. 81 Kwo P, Mantry P, Coakley E, Te H, Vargas H, Brown R, et al. Results of the phase 2 study M12-999: interferon-free regimen of ABT-450/r/ABT-267 + ABT333 + ribavirin in liver transplant recipients with recurrent HCV genotype 1 infection. Abstract O114. 49th Annual Meeting of the European Association for the Study of the Liver, 9-13 April 2014, London, UK. 82 Sulkowski M, Pol S, Mallolas J, Fainboim H, Cooper C, Slim J, et al. Boceprevir versus placebo with pegylated interferon alfa-2b and ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a randomised, doubleblind, controlled phase 2 trial. Lancet Infect Dis 2013;13:597-605. 83 Sulkowski MS, Sherman KE, Dieterich DT, Bsharat M, Mahnke L, Rockstroh JK, et al. Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIV: a randomized trial. Ann Intern Med 2013;159:86-96. 84 Dietrich D, Rockstroh J, Orkin C, Gutierrez F, Klein MB, Reynes J, et al. Simeprevir (TMC435) plus peginterferon/ribavirin in patients co-infected with HCV genotype-1 and HIV-1: primary analysis of the C212 study. Abstract PS9/5. 14th European AIDS Conference (EACS 2013), 2013, Brussels. 85 Rockstroh J, Nelson M, Soriano V, Arasteh K, Gua J. STARTVerso 4 phase III trial of faldaprevir plus peg interferon alfa-2a and ribavirin (PR) in patients with HIV and HCV genotype 1 coinfection: end of treatment response. Abstract 1099. 64th Annual Meeting of the American Association for the Study of Liver Diseases, 1-5 November 2013, Washington, DC. 86 Rodriguez-Torres M, Rodriguez-Orengo J, Gaggar A, Symonds W, McHutchison J, Gonzalez M. Sofosbuvir and peginterferon alfa-2a/ribavirin for treatment-naïve genotype 1-4 HCV-infected patients who are coinfected with HIV. Abstract 714. ID Week, San Francisco, 2-6 October 2013. 87 Sulkowski MS, Rodriguez-Torres M, Lalezari JP. 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. The 64th Annual Meeting of the American Association for the Study of Liver Diseases, 1-5 November 2013, Washington, DC. 88 Ford N, Kirby C, Singh K, Mills EJ, Cooke G, Kamarulzaman A, et al. Chronic hepatitis C treatment outcomes in low- and middle-income countries: a systematic review and meta-analysis. Bull World Health Organ 2012;90:540-50. 89 Ford N, Singh K, Cooke GS, Mills EJ, von Schoen-Angerer T, Kamarulzaman A, et al. Expanding access to treatment for hepatitis C in resource-limited settings: lessons from HIV/AIDS. Clin Infect Dis 2012;54:1465-72. 90 Datta PJ. Gilead, local generic players in talks to bring hepatitis C drug into India. The Hindu 2014. www.thehindubusinessline.com/companies/ gilead-local-generic-players-in-talks-to-bring-hepatitis-c-drug-into-india/ article5649841.ece.

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