WHO/HIV/2014.26 © World Health Organization 2014

WHO/HIV/2014.25 Global Hepatitis Programme © World Health Organization 2014

Guideline development for Hepatitis C virus Screening, Care and Treatment in low- and middle-income countries

WHO TECHNICAL REPORT ON MONITORING TIMEPOINTS IN ADULT PATIENTS TREATED FOR HCV WITH PEGYLATED INTERFERON ALPHA AND RIBAVIRIN

© World Health Organization 2014

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CONTENTS

CONTENTS ...... 3

1. BACKGROUND ...... 5 Table 1: Minimum number of monitoring timepoints recommended by EASL ...... 6 Table 2: Minimum number of monitoring timepoints recommended by AASLD ...... 7

2. TOXICITY MONITORING ...... 5

2.1 OBJECTIVES ...... 8

2.2 SEARCH METHODS ...... 8

2.3 DEFINITIONS ...... 8

2.4 MAIN RESULTS ...... 9

2.4.1 Incidence of side effects related to treatment with IFN/RBV ...... 9 Table 3: Incidence of side effects associated with treatment ...... 10 Table 4: WHO grading of side effects related to treatment ...... 12 Table 5: Serious events and events requiring dose modification or discontinuation ...... 13

2.4.2 Timing of adverse events ...... 13

2.4.3 Adverse events detected by laboratory monitoring ...... 14 Figure 1 Discontinuation of therapy over time ...... 14 Anaemia ...... 14 Figure 2 Cumulative incidence of severe anaemia during antiviral therapy ...... 15 Figure 3 Incidence of anaemia in patients treated with IFN/RBV and telaprevir ...... 16 Neutropenia ...... 17 Figure 4: Temporal evolution of neutrophil and lymphocyte counts...... 17 Thrombocytopenia ...... 18 Thyroid function ...... 18 Autoimmune disease...... 18 Pregnancy ...... 18

2.4.4 Adverse events detected on clinical review ...... 19 Depression...... 19 Figure 5: Mean depression scores in patients treated with consensus and pegylated IFN ...... 19 Rash ...... 20 Other side effects ...... 20

3. MONITORING FOR EFFICACY ...... 21

3.1 Dual therapy: Pegylated interferon alpha and ribavirin ...... 21

3

3.2 Predicting response to treatment in patients treated with dual therapy ...... 24

3.3 Triple therapy with boceprevir or telaprevir and pegylated interferon alpha and ribavirin ...... 25

4. SPECIAL CIRCUMSTANCES ...... 33

4.1 HIV/HCV coinfection ...... 33

4.2 Liver cirrhosis ...... 36

4.3 Acute hepatitis C infection ...... 37

4.4 Pregnancy ...... 37

4.5 Comorbidities ...... 37

5. CONCLUSIONS ...... 38

6. REFERENCES ...... 39

7. APPENDIX: CLINICAL TRIALS REVIEWED ...... 43

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1. BACKGROUND

Infection with hepatitis C virus (HCV) is a major health burden: between 130 and 150 million people are chronically infected with hepatitis C virus (1). Shared routes of transmission mean that co- infection with HIV is also common, affecting at least 4–5 million individuals (2). At the time of writing, treatment with pegylated interferon alpha (IFN) and ribavirin (RBV) is the treatment of choice in patients infected with HCV, given either alone (genotypes 2-6), or in combination with the NS3/4A protease inhibitors telaprevir or boceprevir (genotype 1) for a period of 24-48 weeks. Administration of these drugs is routinely carried out in specialised centres with frequent monitoring visits because of the severe toxicity profile associated with their use. Monitoring is also required to assess treatment efficacy and stopping rules are employed in cases where treatment is highly unlikely to be effective.

2. TOXICITY MONITORING

The side effect profile of interferon includes depression, fatigue, flu-like symptoms, neutropenia, thrombocytopenia, anaemia, thyroid imbalance (hyper or hypothyroidism), lowered CD4+ T cell count in HIV-positive patients, alopecia, arthralgia, anorexia, pneumonitis and may also have significant interactions with other medications in patients with comorbidity. Ribavirin can cause haemolytic anaemia and is teratogenic. Telaprevir may cause skin reactions which range from mild to severe as well as anal discomfort and itching. Boceprevir is associated with dysgeusia (an altered sense of taste). In addition, an increased incidence of neutropenia, anaemia and thrombocytopenia has been observed in patients receiving triple rather than dual therapy. Cirrhotic patients are at extremely high risk of serious adverse events (40% to 57%), particularly anaemia (3).

Monitoring during IFN and RBV treatment with or without PI therapy is currently recommended at multiple timepoints in both the American and European treatment guidelines (Tables 1 and 2). Additional timepoints are required for patients with evidence of side effects and in patients at highest risk (for example patients with cirrhosis and HIV).

We aimed to review the incidence of adverse events at varying timepoints in treatment trials of IFN, RBV with or without PI therapy in treatment naive patients.

Background 5

Table 1: Minimum number of monitoring timepoints recommended by the European Association for the Study of Liver Disease (EASL)

*EOT: end of treatment.

2. Toxicity monitoring 6

Table 2: Minimum number of monitoring timepoints recommended by the American Association for the Study of Liver Diseases (AASLD)

* Timepoint not explicitly recommended in AASLD guidelines (common practice in USA for patients on triple therapy)

**EOT: end of treatment.

2. Toxicity monitoring 7

2.1 Objectives

We aimed to review recommended monitoring timepoints for currently licensed HCV treatments and to summarise the risk of serious side effects at each timepoint.

2.2 Search methods

A search was carried out of all phase III hepatitis C treatment studies listed in PubMed using the search terms “hepatitis C”, “HCV”, “treatment”, “trial”, “phase III”. Selected articles were chosen from peer reviewed journals written in English.

2.3 Definitions

SVR/SVR24: A sustained virological response (SVR) is defined as a negative HCV viral load (VL) 24 weeks after the end of treatment.

SVR12: A sustained virological response at 12 weeks is defined as an SVR12 and is increasingly being used as an end-point for treatment success in clinical trials.

Partial response: A partial response is defined as a ≥2log10 drop in viral load during treatment but the absence of a negative VL during therapy.

Null response: A null response is defined as a <1 log10 HCV RNA decline at Week 4 or <2 log10 HCV RNA decline at Week 12 of treatment

Relapse: Relapse is defined as a negative VL during treatment but detectable VL within 6 months of follow-up after stopping treatment

Viral breakthrough: a negative VL during treatment but detectable viraemia while still on therapy at a later timepoint

Acute HCV: early hepatitis C infection (less than 6 months duration)

Chronic HCV: established hepatitis C infection (greater than 6 months duration)

EOT: end of treatment

2.1 Objectives 8

2.4 Main results

2.4.1 Incidence of side effects related to treatment with IFN/RBV

Adverse events occur universally in patients treated with IFN and RBV and the incidence of side effects from early phase III studies of IFN/RBV and IFN/RBV/PI is illustrated in Table 3. These range from mild to life threatening (Table 4) and include side effects that may be detected by laboratory monitoring and on clinical review. The addition of the PIs boceprevir or telaprevir for genotype 1 infection substantially increases the efficacy of treatment but also increases the likelihood of side effects. In patients treated with boceprevir, anaemia and dysgeusia are the most common adverse events, while patients treated with telaprevir develop rash, anaemia, pruritus, nausea and diarrhoea more commonly than with IFN/RBV therapy alone.

2.4 Main results 9

Table 3: Incidence of side effects associated with treatment in patients treated with pegylated IFN with or without PI therapy

Poordad Jacobson Fried Manns (SPRINT) (ADVANCE) 2011(4) 2011(5) 2001(6) 2001(7)

Treatment IFNα2a IFNα2b IFNα2a /IFNα2b cIFN*/IFNα2b RBV RBV RBV RBV Boceprevir Telaprevir

Arms Arm 1 PR T12PR IFNα2a/ RBV cIFNα2b/RBV Arm 2 PR/BOC RGT T8PR IFNα2b/ RBV HD** IFNα2b/RBV Arm 3 PR/BOC/48 PR IFNα2a/ placebo LD** IFNα2b/RBV Patient group Naive Naive Naive Naive Fatigue Arm 1 60% 57% 54% 60% Arm 2 53% 58% 55% 64% Arm 3 57% 57% 44% 62% Headache Arm 1 42% 41% 47% 58% Arm 2 46% 43% 52% 62% Arm 3 46% 39% 51% 58% Nausea Arm 1 42% 43% 29% 33% Arm 2 48% 40% 33% 43% Arm 3 43% 31% 26% 36% Anaemia Arm 1 29% 37% 22% 13% Arm 2 49% 39% 19% 9% Arm 3 49% 19% 4% 12% (requiring dose (requiring dose modification only) modification only) *** Pyrexia Arm 1 33% 26% 43% 33% Arm 2 33% 30% 56% 46% Arm 3 32% 24% 38% 44% Chills /rigors Arm 1 28% 13% 24% 41% Arm 2 36% 18% 35% 48% Arm 3 33% 15% 23% 45% Dysgeusia Arm 1 18% - - - Arm 2 37% Arm 3 43% Insomnia Arm 1 33% 32% 37% 41% Arm 2 32% 32% 39% 40% Arm 3 33% 31% 23% 40% Pruritus Arm 1 27% 50% 22% 28% Arm 2 24% 45% 20% 29% Arm 3 26% 36% 18% 26% Alopecia Arm 1 27% 23% 28% 32% Arm 2 20% 22% 34% 36% Arm 3 28% 20% 21% 29% Decreased appetite/ Arm 1 25% 15% 21% 27% anorexia Arm 2 26% 15% 22% 32% Arm 3 24% 11% 11% 29% Influenza-like illness Arm 1 26% 28% - - Arm 2 25% 29% Arm 3 23% 28% Myalgia Arm 1 26% 15% 42% 50% Arm 2 21% 21% 50% 56% Arm 3 25% 21% 42% 48% Rash Arm 1 23% 37% 21% 23% Arm 2 25% 35% 18% 24% Arm 3 24% 24% 13% 22% Neutropenia Arm 1 21% 14% 20% 8% Arm 2 25% 17% 5% 18% Arm 3 25% 19% 17% 10% Diarrhoea Arm 1 22% 28% - 17% Arm 2 22% 32% 22% Arm 3 27% 22% 16% 2.4 Main results 10

Irritability Arm 1 24% 22% 24% 34% Arm 2 22% 19% 28% 35% Arm 3 23% 18% 25% 34% Depression Arm 1 22% 18% 22% 34% Arm 2 23% 17% 30% 31% Arm 3 19% 22% 20% 29% Dry skin Arm 1 18% 17% - 23% Arm 2 18% 18% 24% Arm 3 23% 18% 18% Dyspnoea Arm 1 16% 13% - 24% Arm 2 18% 14% 26% Arm 3 23% 14% 23% Arthralgia Arm 1 18% 13% 27% 28% Arm 2 19% 15% 25% 34% Arm 3 20% 19% 29% 34% Dizziness Arm 1 17% 16% - 17% Arm 2 22% 14% 21% Arm 3 18% 14% 21% Cough Arm 1 21% 17% - 13% Arm 2 15% 21% 17% Arm 3 20% 24% 15% Vomiting Arm 1 16% 15% - 12% Arm 2 20% 15% 14% Arm 3 20% 11% 14% Asthenia Arm 1 19% 15% - 18% Arm 2 15% 17% 18% Arm 3 19% 16% 16% Injection site Arm 1 - 10% - 18% reaction Arm 2 13% 58% Arm 3 9% 59% Anorectal Arm 1 - 13% - - discomfort Arm 2 8% Arm 3 4% Anxiety Arm 1 - 10% - - Arm 2 9% Arm 3 12% Back pain Arm 1 - 8% - - Arm 2 7% Arm 3 12% Infections Arm 1 - 28% - - Arm 2 37% Arm 3 38% Eye disorders Arm 1 - 24% - - Arm 2 22% Arm 3 18% Weight decrease Arm 1 - - - 20% Arm 2 29% Arm 3 17% Musculoskeletal Arm 1 - - - 19% pain Arm 2 21% Arm 3 17% Impaired Arm 1 - - - 21% concentration Arm 2 17% Arm 3 16%

* cIFN Conventional interferon given as (3 MU subcutaneously three times per week) ** HD high dose IFNα2b (15ug/kg plus 800mg RBV) LD IFNα2b (1.5ug/kg plus 1000-1200mg RBV) *** Dose modification of RBV carried out at Hb<10g/dl

- Side effect not reported

2.4 Main results 11

Side effects including rash, anaemia and neutropenia may be categorised as grade 1-4 (mild to life- threatening) as outlined in Table 4. Some variability in the definition of these criteria is present in clinical trials – variation from WHO definitions are highlighted in the text.

Table 4: WHO grading of side effects related to treatment

The total incidence of serious adverse effects related to treatment in early phase III studies of previously treatment naive patients (IFN/RBV and IFN/RBV/PI) is summarised in Table 5. Adverse events requiring dose modification occurred in up to 42% of treated patients and discontinuation of therapy was required in 7-32% of patients in these studies. The exact timing of drug discontinuation or modification has not been extensively reported in detail but occurred most frequently within the first 12 weeks of therapy.

2.4 Main results 12

Table 5: Serious events and events requiring dose modification or discontinuation

Study Treatment Total AE Serious AE leading to dose Discontinued AE modification

Manns Arm 1 cIFNα2b/RBV - - 34% 13% Arm 2 pIFNα2b(HD)/RBV(LD*) 42% 14% Arm 3 pIFNα2b(LD**)/RBV(HD*) 36% 13%

Fried Arm 1 pIFNα2a/RBV - - IFN 11%/25% 22% RBV 21%/24%

Arm 2 cIFNα2b/RBV IFN 11%/ 8% 32% RBV 22%/19%

Arm 3 pIFNα2a/placebo IFN 6%/24% 32% Placebo 17%/ 4% Poordad Arm 1 (PR48) 98% 9% 26% 16% 2011 Arm 2 (BOC RGT) 99% 11% 40% 12% SPRINT Arm 3 (BOC/PR48) 99% 12% 35% 16%

Jacobson Arm 1 (pIFNα2a/RBV /TEL12) 99% 9% - 10% 2011 Arm 2 (pIFNα2a/RBV /TEL8) 99% 9% - 10% ADVANCE Arm 3 (pIFNα2a/RBV) 98% 7% - 7%

* Ribavirin was given as low dose (LD) – 800mg or high dose (HD) 1000-1200mg daily

** IFN was given as high dose (HD; 1.5ug/kg) or low dose (LD; 1.5ug/kg for 4 weeks then 0.5ug/kg) weekly

- Information not available

2.4.2 Timing of adverse events

The current EASL guidelines recommend monitoring at weeks 1, 2, 4 and 4-8 weekly intervals thereafter and the AASLD guidelines at monthly intervals during treatment. In order to assess the value of monitoring at each individual timepoint as recommended in the current HCV treatment guidelines, the incidence of side effects over time during treatment was reviewed. These were divided into those detected by laboratory monitoring (Hb, neutrophil and platelet counts, thyroid function) and those detected on clinical review. While the prevalence of side effects in patients treated with IFN/RBV is extensively described, studies reporting on the incidence of side effects at varying timepoints were limited in number (12 of 89 studies reviewed).

2.4 Main results 13

2.4.3 Adverse events detected by laboratory monitoring

Laboratory abnormalities are the most common reasons for dose reduction in patients treated with IFN and RBV (8). Anaemia, neutropenia and thrombocytopenia occurred most frequently in all trials reviewed within the first 8-12 weeks of therapy. However, late discontinuation due to adverse events also occurred in a significant number of individuals. In one early study comparing pegylated IFN/RBV with conventional IFN/RBV, discontinuation occurred within the first 24 weeks in 13.4% of individuals and in 5.5% within the final 24 weeks of therapy (Figure 1)(9).

Time (months)

Figure 1 Discontinuation of therapy over time (adapted from Bruno et al, 2004(9))

Cumulative rate of discontinuation of therapy in patients treated with pIFNα2b plus RBV (black) and in patients treated with cIFNα2b and RBV (red)(9).

Anaemia

Anaemia is a common adverse event (Table 3). It is more likely to occur in patients with cirrhosis, in older patients, in female patients, in those with low body weight, in HIV-positive individuals and in patients with haemoglobinopathies. The presence of variants within the inosine triphosphatase (ITPA) gene is associated with a lower likelihood of anaemia in some individuals of European ancestry (10). In early phase III treatment studies using pegylated IFN and RBV, anaemia occurred in up to 49% of treated individuals and necessitated dose reduction of ribavirin in around 15% of

2.4 Main results 14 treated individuals. Even in studies where extensive monitoring and early dose reduction were carried out, severe anaemia occurred in approximately 1% of the study population.

In one study, 466 chronic hepatitis C patients were treated with conventional IFNα2b or pegylated-

IFNα2b plus RBV (1000–1200 mg/day) for 24 weeks. The mean decrease of Hb was 3.9g/dl and 39% of patients developed a level of <10g/dl during therapy. Pre-treatment platelet counts <150mm6, age >50 years, female gender and low body weight (<65 kg) were independent factors associated with severe anaemia (Hb <10g/dl; Figure 2)(11).

Figure 2 Cumulative incidence of severe anaemia (<10g/dl) during antiviral therapy (adapted from Hung et al, 2006(11)) (A) age ≥50 years (dotted line) vs. <50 years (solid line),p<0.0001; (B) female (dotted line) vs. male (solid line), p<0.0001; (C) body weight <65 kg (dotted line) vs. ≥65 kg (solid line), p<0.0001; (D) platelet <15 × 104/mm3 (dotted line) vs. ≥15 × 104/mm3 (solid line),p<0.0001; (E) white cell count <4000/mm3 (dotted line) vs. ≥4000/mm3(solid line), p=0.0002.

2.4 Main results 15

Anaemia occurs more frequently in recipients of triple therapy (IFN/RBV/PI) versus dual therapy (IFN/RBV). Haemoglobin decreases below 10 g/dL (grade 2 toxicity) occurred in 49% of patients who received a boceprevir regimen compared to 29% of those who received dual therapy and 9% had a haemoglobin decline to <8.5 g/dL (grade 3 toxicity)(12). Among patients treated with telaprevir, PEG IFN and RBV (T12PR), haemoglobin levels of <10 g/dL were observed in 36% of patients compared with 14% of patients who received dual therapy and 9% had haemoglobin decreases to <8.5 g/dL. Haematopoietic growth factors were not permitted during the telaprevir trials and a 5%-6% higher rate of treatment discontinuation occurred among those who developed anaemia than those who did not.

Figure 3 Incidence of anaemia in patients treated with IFN/RBV and telaprevir (adapted from McHutchison et al 2010(13)) At each timepoint, data are shown for all patients whose Hb assessment was available. The duration of treatment with telaprevir is indicated by the grey bars.

2.4 Main results 16

Neutropenia Neutropenia (neutrophil count <1500/mm3) is associated with an increased risk of severe bacterial infections and is a common laboratory abnormality although there is currently little evidence to link neutropenia secondary to IFN therapy and an increase in infection. 18-20% of patients in the two large phase III clinical trials of dual therapy developed neutropenia (6, 7). In these trials, the dose was reduced by 50% for a neutrophil count of 750 mm3 and permanently discontinued at 500 mm3. Despite dose reduction strategies, severe neutropenia (<500 mm3; grade 3 toxicity) occurs in 3% to 5% of patients treated with IFN/RBV requiring discontinuation of therapy. Neutropenia is a common phenomenon in black patients (in one study 12% of black patients had a baseline neutrophil count of <1500/mm3) and for this reason, fewer black patients have been recruited into clinical trials. Decreases in neutrophil count occur during the first 4-8 weeks of treatment and plateau, rising to normal at the end of treatment (Figure 3)(14).

Figure 4: Temporal evolution of neutrophil and lymphocyte counts during interferon and ribavirin combination therapy (Soza et al 2002(14)). Neutrophil and lymphocyte counts are shown from 119 patients treated with IFN/RBV over time. Results from patients completing therapy at 24 weeks (or earlier) were censored at end of treatment.

2.4 Main results 17

Thrombocytopenia Thrombocytopenia is a less common side effect of treatment but commonly pre-exists in patients with HCV, particularly in those with underlying cirrhosis. Platelet counts < 50 × 109 cells/L occur in

3% to 5% of patients and can result in severe bleeding (15). Eltrombopag is a new, orally active thrombopoietin-receptor agonist that stimulates thrombopoiesis and this may allow treatment of patients with thrombocytopenia secondary to HCV-related cirrhosis(16).

Thyroid function Thyroid dysfunction is a well recognised side effect of IFN treatment. In one early study of 987 patients treated with IFN for 24 weeks, hypothyroidism occurred in 0.9% of patients and hyperthyroidism in 1.8%. These occurred at a median of 17.7 and 16.8 weeks into therapy respectively (range 12-24 weeks) and were more common in patients with pre-existing detectable antimicrosomal antibody titres (15).

Autoimmune disease The presence of autoimmune conditions prior to treatment is a relative contraindication to therapy (seropositive arthritis is a contraindication to treatment) and uncontrolled autoimmune disease such as seronegative arthritis and autoimmune hepatitis may be severely exacerbated by IFN therapy (8, 17). A significant challenge is that chronic HCV infection may be associated with the presence of a positive test for antinuclear antibodies. A prior history of autoimmune hepatitis, the presence of other autoimmune conditions and the identification of specific HLA characteristics may help and a liver biopsy may be indicated. An individualized approach with careful monitoring is recommended if treatment is initiated.

Pregnancy Pregnant patients must not be treated with RBV, thus all women of childbearing age should be tested for pregnancy prior to commencing treatment. All sexually active female and male patients should be advised of the risk of teratogenicity with RBV and the need for dual contraception during and for 6 months after treatment.

2.4 Main results 18

2.4.4 Adverse events detected on clinical review

Serious side effects related to IFN/RBV therapy detected commonly on clinical review include depression and rash. Unusual side effects include seizures (uncontrolled epilepsy is a contraindication for treatment), bacterial infections, autoimmune reactions, interstitial lung disease and neuroretinitis.

Depression Depression is one of the commonest side effects of IFN treatment, occurring in 17-31% of those treated, and suicide related to treatment has been reported (18). Severe depression may develop at any time during treatment and may be monitored using a number of scales. The BDI-II is one of the most widely used depression inventories, whereas the CES-D includes items that can differentiate somatic symptoms of depression from other symptoms of depression. In one study designed to assess the side effect profile of consensus versus pegylated IFN, the BD-II and CES-D scales were employed to assess the incidence of depression over time (Figure 4)(19).

Figure 5: Mean depression scores in patients treated with consensus and pegylated IFN (adapted from Sjorgen et al, 2007(19)) Mean average depression scores assessed by the Beck Depression Inventory-II (BDI-II) and the Centre for Epidemiological Studies Depression Scale (CES-D). CIFN, consensus interferon; PEG-IFN, pegylated interferon; RBV, ribavirin

2.4 Main results 19

Rash In the phase 3 telaprevir trials, a rash of any severity was noted in up to 56% of patients who received telaprevir compared with 32% of those who received dual therapy (12). The rash was typically eczematous and maculopapular and usually mild to moderate in severity but was severe (involving >50% of the body surface area) in 4% of cases. The development of rash resulted in discontinuation of telaprevir in 6% and of the entire regimen in 1% of patients. The Stevens Johnson Syndrome or Drug-Related Eruption with Systemic Symptoms (DRESS) occurred in <1%. The response of the rash to local or systemic treatment with corticosteroids and oral antihistamines is uncertain. Pruritus, commonly but not always associated with rash, was noted in around half of patients who received triple therapy.

Other side effects

Interstitial pneumonitis is a rare complication of IFN therapy and can occur with IFNα2a or IFNα2b at any time throughout treatment (the onset has been reported to occur in case series at varying timepoints between weeks 2 and 48 of treatment) and carries a mortality of around 7%(20).

2.4 Main results 20

3. MONITORING FOR EFFICACY

3.1 Dual therapy: Pegylated interferon alpha and ribavirin

The current standard of care for patients with non-genotype 1 chronic HCV infection is weekly subcutaneous pegylated interferon alpha (pegIFNα2a or pegIFNα2b) and daily oral RBV following the publication of two large phase III trials which revealed that weekly pegIFN had increased efficacy when compared with conventional three-times-weekly IFN and daily RBV, with overall sustained virological response rates (SVR) of 54-56% (6, 7). Genotype 1 patients however were found to respond less well to dual therapy (Table 6) and to benefit from 48 weeks rather than 24 weeks of therapy depending on initial response to treatment (21).

Monitoring for Efficacy 21

Table 6: SVR rates by genotype following dual therapy for treatment of chronic HCV in treatment naive patients

Treatment Overall Genotype 1 Genotype 2/3 Genotype 4/5/6 Reference

SVR SVR SVR SVR

Pegylated 54% 42% 82% 50% Manns et al,

IFNα2b (genotypes 4,5,6) 2001(7) and ribavirin

Pegylated 56% 46% 76% 77% Fried et al,

IFNα2a (genotype 4) 2002(6) and ribavirin

Genotype 1 infection and pegIFNα/RBV therapy

A number of studies have aimed to optimise dual therapy treatment for patients with genotype 1 infection. Prior to initiation of treatment, the likelihood of treatment response may be predicted by polymorphisms in the region upstream of the IL28B (IFNλ) gene (22). The duration of therapy may be shortened to 24 weeks or lengthened to 72 weeks in selected individuals on the basis of viral load measurements taken at the start of therapy and at 4 and 12 weeks into treatment(23). Increasing the dose of RBV (1000-1200 mg versus 800 mg) has also been found to be beneficial in genotype 1 infected patients. The use of pegylated IFNα2a and IFNα2b has been found to be broadly equivalent

(8).

The viral load at 4 weeks into infection may be used to identify patients who will benefit from a reduced duration of treatment (21). Patients who achieve an RVR have similar SVR rates after 24 and

48 weeks of therapy, regardless of RBV dose and are more likely to achieve SVR than those patients who do not achieve an RVR. Patients with a low baseline viral load (<600,000 IU/mL) are also

Monitoring for Efficacy 22 significantly more likely to attain RVR than those with a high baseline viral load (>600,000 IU/mL; p=0.0057). Shortened duration of therapy is therefore often appropriate in genotype 1 infected

patients with low baseline HCV loads who attain an RVR (Figure 6).

In contrast, patients infected with genotype 1 achieve higher SVR rates with a 72 week treatment

duration if they have a positive HCV RNA result at week 12; 29% versus 17% (IFNα2a and RBV; p=0.04)

31 and 39% versus 18% (IFNα2b and RBV ; p=0.03)(24) respectively. An extended treatment duration of 72 weeks has also been shown to benefit genotype 1 infected patients who have not achieved an

RVR (SVR rate 45% vs. 32%; p=0.014)(25).

Figure 6: PEG-IFN and RBV for genotype 1 HCV: Duration of therapy: Pegylated IFN and RBV used in combination to treat genotype 1 chronic HCV infection may be given for varying durations depending on the treatment response. An extended rapid virological response (eRVR) is associated with a high likelihood of SVR and therefore a reduced treatment duration of 24 weeks can be considered. Conversely, if patients have a slow virological response with a detectable VL at 12 weeks of treatment (and a ≥2 log10 drop), a prolonged 72 week course of therapy can be considered. If however the viral load drops less than 2 log10 at 12 weeks or is detectable at 24 weeks of therapy, treatment should be stopped.

Monitoring for Efficacy 23

Genotypes 2 and 3 and pegIFNα/RBV therapy

Patients with genotype 2 or 3 have improved SVR rates in comparison with genotype 1 and 4 infected patients and a shorter length of treatment (24 weeks) and lower dose of RBV (800 mg) are used. In one study, patients infected with genotype 2 HCV had an SVR rate of 94% following 16 weeks of treatment versus 95% with 24 weeks of therapy (26). In the ACCELERATE study, however,

SVR rates were significantly higher among genotype 2 infected patients treated for 24 weeks than among those treated for 16 weeks (91% versus 81%; p=0.001)(27). Shortening of therapy to 12-16 weeks can be considered in genotype 2 or 3 infected patients if they have achieved an RVR and have a low viral load (although a slightly higher relapse rate should be taken into consideration) and extended to 48 weeks if they have not achieved an RVR.

Genotypes 4, 5 and 6

Patients with genotype 4 infection have similar or slightly improved response rates to treatment when compared with genotype 1 infected individuals (Table 6). Small studies of genotype 5 and 6 infected patients have shown similar SVR rates to genotypes 2 and 3 (28, 29). Larger studies are required to confirm these results and to identify predictors of response or non-response to treatment.

3.2 Predicting response to treatment in patients treated with dual therapy

On-treatment viral load measurements

As discussed above, SVR in patients on treatment for hepatitis C can be predicted with a high degree of accuracy at 4 and 12 weeks of follow up. Patients failing to attain a 2-log reduction in HCV RNA by

12 weeks (early virological response; EVR) are unlikely to respond to further treatment and therapy can be stopped in these patients at this stage (30). One study revealed that treatment success can

Monitoring for Efficacy 24 be predicted after only one dose of IFN (31, 32). While week 4 results are useful for predicting the likelihood of successful treatment (positive predictive value) they are less useful for predicting lack of efficacy (negative predictive value)(33).

3.3 Triple therapy with boceprevir or telaprevir and pegylated interferon alpha and ribavirin

The first-generation linear protease inhibitors telaprevir and boceprevir are licensed for use in the

USA and Europe in combination with IFNα and RBV (triple therapy) for patients infected with genotype 1 HCV. These drugs act as reversible inhibitors of the HCV NS3/4A protease, a viral enzyme directly involved in HCV replication and also in subversion of the host innate immune response .

Inhibition of this target therefore reduces viral replication and the ability of the virus to evade the host immune response. The addition of this new class of drugs has already substantially improved treatment success rates both in untreated (naive) patients and in those who have previously failed therapy.

Treatment naive patients

The addition of a protease inhibitor to IFN/RBV dual therapy has significantly increased the likelihood of successful treatment in treatment-naive patients with genotype 1 HCV infection.

Response-guided treatment pathways have been developed for both boceprevir and telaprevir following large phase III clinical trials.

Response guided treatment for treatment-naive patients without cirrhosis

In the phase III ADVANCE study (5), patients were randomised to receive pegIFNα2a/RBV alone for 48 weeks or 8-12 weeks of telaprevir with 24-48 weeks of pegIFNα2a/RBV. The SVR rate in the 12 week telaprevir arm was superior to the 8 week telaprevir arm with an SVR rate of 75% (versus 44% in the pegIFNα2a/RBV arm) and this is now the recommended duration of telaprevir therapy. An SVR

Monitoring for Efficacy 25 occurred in 89% of patients that had an extended rapid virological response (eRVR; undetectable

HCV RNA at 4 and 12 weeks of treatment) versus a 54% SVR rate in those without an eRVR. In the pegIFN/RBV arm, patients that achieved an eRVR also had an excellent success rate of 97%, although far fewer patients in this treatment group had an eRVR (No Reference Selected). Black patients had a poorer response to treatment than white patients but the SVR rate was significantly higher in these patients when treated with triple versus dual therapy (Figure 7).

Figure 7 ADVANCE: SVR rates following treatment with telaprevir according to ethnicity(5)

SVR rates in black patients were found to be lower than non-black patients in the ADVANCE study following triple therapy with pegIFN, RBV and telaprevir (T12PR). They were however significantly higher than SVR rates in patients treated with dual therapy for 48 weeks (PR48)

In the phase III SPRINT 2 study (4), patients were treated with pegIFNα2b/RBV for 48 weeks or with a

4 week lead-in with pegIFNα2b/RBV followed by the addition of boceprevir for a further 24-44 weeks

(34). The SVR rate was higher in the boceprevir arms than in the pegIFNα2b/RBV arm. A significant disparity associated with ethnicity was also observed in this study (Figure 8). In nonblack patients, the SVR rate was 67-68% in the triple therapy arms versus 38% in the dual therapy arm. However, in black patients, the SVR rate was lower (42-53%), although significantly higher than in those treated with dual therapy (23%). SVR rates were higher in those who had a greater drop in HCV viral load

Monitoring for Efficacy 26 following the lead-in period. Again in this study, those who achieved an undetectable VL by 4 weeks of treatment had a 97% chance of SVR with dual therapy alone although there were only a minority of patients in this group. Patients with undetectable HCV RNA levels after the lead-in period may therefore not require addition of boceprevir. Nonblack patients that had a >1log drop in VL at 4 weeks had an 82% likelihood of SVR with triple therapy (52% with dual therapy) while black patients had a 61-67% likelihood of SVR versus 46% with dual therapy.

Figure 8 SPRINT-2: SVR and relapse rates following treatment with boceprevir and pegIFN/RBV according to ethnicity (4)

SVR rates in black patients were found to be lower than non-black patients in the SPRINT-2 study following triple therapy with pegIFN, RBV and boceprevir. PR48: pegIFN and RBV for 48 weeks BOC RGT: Response-guided treatment; 4 weeks pegIFN/RBV + 24-44 weeks boceprevir/pegIFN/RBV BOC/PR48: 48 weeks of pegIFN and RBV (4 week lead-in) with 44 weeks of boceprevir

The viral load at 8 and 24 weeks into treatment may be employed to determine length of treatment required in treatment naive patients treated with boceprevir (Figure 9). Treatment-naive patients commencing boceprevir start treatment with 4-weeks of lead-in pegIFN/RBV. Those who achieve an

Monitoring for Efficacy 27 extended rapid virological response to treatment, defined as an undetectable HCV RNA at Weeks 8 and 24, can complete treatment at Week 28. Those with a slower response who have detectable

HCV RNA at Week 8 but undetectable HCV RNA at Week 24 should continue boceprevir plus pegIFN/RBV to Week 36 and then pegIFN/RBV alone until Week 48. Patients who exhibit a poor

response to IFN and RBV alone during the 4 week lead-in period (< 1 log10 IU/mL drop), should receive triple therapy for 44 weeks. If the HCV RNA level exceeds 100 IU/ml at week 12, all therapy should be stopped.

Telaprevir is administered with pegIFN/RBV for the first 12 weeks of therapy, followed by pegIFN and RBV alone for 12-36 weeks depending on the HCV RNA response at Weeks 4 and 12. If the HCV

RNA is undetectable weeks 4 and 12 (eRVR), treatment can be completed at Week 24. Patients that have detectable HCV RNA ≤ 1000 IU/mL at Week 4 and/or Week 12 should be treated for a further

36 weeks until Week 48. Patients with cirrhosis should continue treatment for 48 weeks regardless of Week 4 and 12 response, to optimise the likelihood of SVR.

Monitoring for Efficacy 28

Figure 9: Response-guided protease inhibitor treatment of treatment-naive patients Response guided therapy checkpoints for patients receiving protease inhibitors are illustrated. Where undetectable viral loads are shown, the threshold of detection of HCV RNA is critical; this should be ≤25IU/ml for quantitation with a limit of detection of between 10 and 15 IU/ml. Patients with a detectable but unquantifiable VL have been found to have a significantly lower chance of SVR than those with an undetectable VL if given a shortened duration of treatment.

Response-guided treatment for treatment-experienced patients and those with cirrhosis

Patients previously treated with IFN/RBV have a varying likelihood of SVR with triple therapy

(including a protease inhibitor), based on their pattern of failure to previous treatment; relapse,

partial response or null response. Those with the best chance of SVR are previous relapsers, defined

as those who developed a negative HCV RNA on therapy but viral recrudescence within 6 months of

completing therapy. Such individuals have SVR rates very similar to that of treatment naive patients

Monitoring for Efficacy 29

(Figures 10 and 11). Partial responders are patients that achieve a ≥2 log10 drop in VL by 12 weeks of therapy but who do not ever become HCV RNA negative. Null responders have a ≤2log10 drop by 12 weeks of treatment. The pattern of failure following previous treatment for HCV is critical in determining the likelihood of response to triple therapy with pegIFN, RBV and telaprevir (Figure 10).

Figure 10: REALIZE: SVR to telaprevir in previous relapsers, partial responders, and null responders (35)

Dual therapy with pegIFN/RBV for 48 weeks (PR48) was compared with triple therapy with 12 weeks of telaprevir and 48 weeks of pegIFN/RBV (T12PR48) in the REALIZE study. Patients with previous relapse had a very high chance of SVR with triple therapy (83-88% depending on whether or not telaprevir was given with a lead-in [LI T12/PR48] or not).

The pattern of failure following previous treatment for HCV is also critical in determining the likelihood of response to triple therapy with pegIFN, RBV and boceprevir (Figure 11).

Monitoring for Efficacy 30

Figure 11: RESPOND-2: SVR to boceprevir in previous relapsers and nonresponders(36)

Dual therapy with pegIFN/RBV for 48 weeks (PR48) was compared with triple therapy with response- guided treatment (RGT) with boceprevir and 48 weeks of pegIFN/RBV and boceprevir in the RESPOND-2 study. Patients with previous relapse had a very high chance of SVR with triple therapy (69-75%).

Recommended treatment durations for treatment experienced patients as well as treatment naive patients with cirrhosis are illustrated in Figure 12.

Monitoring for Efficacy 31

Figure 12: Recommended treatment durations in treatment-experienced or cirrhotic patients: Treatment algorithms are shown for treatment experienced and cirrhotic patients treated with triple therapy. It is recommended that patients with cirrhosis or a previous null response are treated with a 48 week course of therapy as shown above. Patients who have had a previous relapse can be considered for response-guided therapy and if they achieve an eRVR can be offered shortened treatment duration. Patients treated with boceprevir who develop an eRVR with a previous partial response can also be offered a shortened course of treatment.

3.4 Predicting response to treatment with telaprevir and boceprevir in combination with pegIFN/RBV

As discussed above, factors predictive of a high likelihood of response to protease inhibitor–based triple therapy include white ethnicity, absence of advanced fibrosis/cirrhosis, attainment of rapid

Monitoring for Efficacy 32 virologic response (RVR; defined as HCV RNA clearance during the first 4 weeks of therapy) and previous relapse following dual therapy.

Host and virus genetic polymorphisms may both also influence outcome. The host rs12979860

IL28B CC genotype, a marker of interferon responsiveness, is predictive of outcome in patients treated with pegIFN/RBV and telaprevir and boceprevir as well as patients treated with pegIFN/RBV alone (37). In contrast, black ethnicity, advanced fibrosis or cirrhosis, genotype 1a HCV infection, lack

of RVR, previous null response to pegIFN/RBV, and the IL28B TT genotype are all associated with a lower likelihood of SVR.

4. Special circumstances

4.1 HIV/HCV coinfection

It is estimated that 4-5 million people are co-infected with HIV and HCV around the world due to shared routes of transmission (2). Liver disease has started to overtake AIDS-defining illnesses as a cause of death in many HIV-positive patient populations following the successful introduction of

HAART (38). However, the development of pegIFNα and RBV combination therapy has increased SVR rates considerably. In the RIBAVIC study 412 HIV/HCV-infected patients were randomized to receive standard IFNα and RBV versus pegIFNα and RBV (39). The overall SVR was higher in the pegIFNα arm

(27 vs. 20%) but nevertheless disappointing and thought to relate to a very high treatment discontinuation rate (42%).

The APRICOT study was the largest trial in this setting (40). This was an international study and enrolled 868 patients who were randomised to receive conventional IFNα three times weekly (3 MU) with RBV (800 mg/day), weekly pegIFNα monotherapy (180 μg) or a combination of weekly pegIFNα

(180 μg) and RBV (800 mg/day) for 48 weeks. The SVR rate was significantly higher in those who received combination therapy and reached 62% in genotype 2 or 3 infection but only 29% in

4. Special circumstances 33 genotype 1 infection. Treatment was associated with an average, reversible CD4+ T cell decline of

140 cells/mm3 and even in this highly selected group of patients, 25% of the patients in the combined arm of the study had to discontinue because of intolerable side effects or for other reasons. A serious concern was that liver failure occurred and was fatal in 6/14 patients. This was associated with cirrhosis with Child-Pugh scores of 5 or more at baseline and didanosine (DDI) - containing regimens (41). The nucleoside reverse transcriptase inhibitors DDI and stavudine (d4T) are contraindicated in patients receiving IFN/RBV therapy for this reason.

The pre-treatment viral load did not influence the response rate in those with genotypes 2 and 3 infection but in pegIFNα/RBV-treated genotype 1 patients the SVR rate was 61% in those with HCV

RNA levels of <800 000 IU/mL and 18% in those with higher levels.

When the APRICOT study was designed there were concerns that higher doses of RBV may not be tolerated by patients in whom anaemia is a common problem, particularly those treated with the nucleoside reverse transcriptase inhibitor zidovudine (AZT). Studies in HCV monoinfected patients revealed that higher doses of RBV in patients with genotype 1 infection were more effective and this appears to be the case in HIV/HCV-coinfected patients also (21). In the PRESCO study, higher weight- based dosing of RBV was used and extension of treatment duration from 48 to 72 weeks also improved the SVR rate in genotype 1 infected HIV-positive patients (53% versus 31%) (42).

Premature treatment discontinuations were common, however, and occurred in 45% in the prolonged treatment arm (2.6% due to severe anaemia). Extension of treatment duration from 24 to

48 weeks in genotype 2/3 also resulted in a higher SVR rate (82% versus 67%).

Viral kinetics have become increasingly important in this setting and it has been suggested that in genotype 2 or 3 infected patients, 24 weeks of therapy may be suitable, particularly for those with a low baseline HCV RNA level who demonstrate an RVR, can demonstrate good adherence and have no evidence of advanced hepatic fibrosis (43). An extended treatment course may also be

4. Special circumstances 34 considered when patients show a consistent but slow decline in the HCV RNA level. In future, it is likely that there will be more tailoring of treatment courses according to baseline host and virological parameters and to the initial virological response.

The APRICOT study also showed that even if patients did not achieve an SVR that in those who agreed to have a follow-up liver biopsy, there was nevertheless an improvement in liver histology

(44).

Depression rates as high as 40% have been recorded when treating patients with HIV and HCV with

IFN therapy. There are also reports of significant weight loss (45). As discussed above, severe anaemia, neutropenia and reductions in CD4+ T cell count are important dose-limiting factors when treating co-infected patients.

Triple therapy with boceprevir or telaprevir and pegIFN/RBV is currently being tested in HIV-positive patients in phase III clinical trials. A major potential problem is that of drug-drug interactions. Both boceprevir and telaprevir are inhibitors of CYP3A4, which mediates many drug metabolic pathways and therefore any potential interactions must be carefully evaluated prior to commencing treatment. A useful resource for searching for drug-drug interactions can be found at the following

website: http://www.hep-druginteractions.org.

Boceprevir is currently being evaluated in HIV-positive individuals either not on HAART therapy or who are being treated with a dual nucleoside reverse transcriptase inhibitor backbone plus one of the following agents: efavirenz, raltegravir, lopinavir/ritonavir, atazanavir/ritonavir or darunavir/ritonavir. Preliminary data from these studies has lead to the FDA recommendation that efavirenz and protease inhibitors should not be used with boceprevir. Telaprevir is currently in phase

III trials in patients receiving a dual nucleotide backbone plus one of efavirenz (telaprevir must be given in higher dose), raltegravir or atazanavir/ritonavir.

4. Special circumstances 35

Further studies exploring the potential for drug-drug interactions between HAART regimens and newer compounds under development for the treatment of HCV are eagerly awaited.

4.2 Liver cirrhosis

Patients with liver cirrhosis represent a difficult to treat population. Treating patients with evidence of hepatic decompensation is contraindicated and response rates in cirrhotic patients without evidence of decompensation are much lower. In the ADVANCE trial, 78% of patients with mild liver disease achieved SVR in the 12-week telaprevir triple therapy arm (5). Patients with advanced

(bridging) fibrosis or cirrhosis had SVR rates of 62% (13/21 with cirrhosis and 32/52 with bridging fibrosis). SVR rates were lower in cirrhotic patients treated with dual pegIFN/RBV therapy (33%) and so triple therapy increases the chance of success. Unfortunately patients with cirrhosis are at ongoing risk of complications such as hepatocellular carcinoma even if the infection is cured and such patients require lifelong surveillance.

Advanced liver disease also reduces the efficacy of boceprevir-based triple therapy. Among patients treated in the SPRINT-2 trial, 67% of patients with mild liver disease (F0-2) achieved SVR versus 41-

52% of patients with advanced liver disease (34). Fixed-duration boceprevir plus pegIFN/RBV for 48 weeks resulted in higher SVR rates than response-guided boceprevir-based therapy among patients with advanced liver disease. Boceprevir and telaprevir response-guided algorithms are therefore not recommended in patients with cirrhosis.

Patients who have received a liver transplant for HCV infection usually remain infected following transplant (46). Success rates with dual therapy have been limited and trials of newer treatment regimens are anticipated in this group. However interactions with immunosuppressive therapies will have to be carefully evaluated.

4. Special circumstances 36

4.3 Acute hepatitis C infection

Patients infected acutely with HCV are not usually identified clinically as early infection is usually asymptomatic. If patients are diagnosed acutely (within 6 months of infection), however, careful consideration should be given to treating early as success rates approach 100%. Patients who are immunocompetent and adherent have extremely high rates of viral clearance with a 6 month course of IFN monotherapy (47). Intravenous drug users may be more challenging to treat and lower SVR rates have been reported (approximately 69%)(48). HIV-infected individuals also do not achieve the same level of success and dual therapy is usually employed in these individuals (49, 50). Trials of triple therapy and of IFN-free regimens would be helpful in these populations to see if SVR rates can be increased further.

4.4 Pregnancy

It is critical that effective contraception is used during boceprevir- or telaprevir-based triple therapy primarily because of teratogenicity associated with RBV. Triple therapy involving RBV is contraindicated in pregnant women, men whose female partners are pregnant, women contemplating pregnancy during the course of treatment, and for 6 months after stopping RBV therapy. Effective contraception is considered to be 2 forms of contraception including a barrier

method as the efficacy of hormone-based methods may be reduced by protease inhibitor treatment.

4.5 Comorbidities

The advent of new treatment options including the possibility of IFN-free regimens is likely to make treatment available to groups of patients in whom IFN therapy is contraindicated for example patients with severe depression, autoimmune hepatitis, those with uncontrolled epilepsy and people with severe arthritis. Dose adjustments are likely to be required in individuals with renal failure and potential interactions with other medications must be evaluated carefully.

4. Special circumstances 37

5. Conclusions

Adverse events including severe or life-threatening adverse events are commonly associated with IFN/RBV therapy and for this reason, monitoring at multiple timepoints, especially during early treatment, is strongly recommended. The incidence of side effects is highest during the first 12 weeks of therapy, particularly those relating to abnormal laboratory values (anaemia, neutropenia and thrombocytopenia) and commonly necessitates dose adjustment of RBV or IFN (up to 42% of treated individuals) or discontinuation of therapy (7-32% of patients). Late-onset adverse events requiring discontinuation of treatment occurred in one study in 5.5% of individuals (between weeks 24 and 48 of therapy). Serious adverse events occur more commonly in patients with cirrhosis and comorbidity such as HIV and pre-treatment assessment is therefore paramount. The evidence of the need for both clinical and laboratory monitoring during treatment is strong. However, detailed reporting of the incidence of adverse events and treatment discontinuation as they occur over time during therapy is lacking.

Monitoring for efficacy allows early treatment cessation when SVR is extremely unlikely to occur with a resultant reduction in the risk of side effects and cost-saving.

Over the next 5-10 years, the spectrum of treatments available for HCV infection will expand (three new classes of antiviral drug have entered phase III clinical trials) and it is very likely that interferon- free regimens will become a reality within this time. These will result in a substantial improvement in treatment success rates, shortened duration of therapy and a substantially improved side effect profile. The key to success in low and middle income countries will be based on pricing decisions made by pharmaceutical companies and the availability of generic compounds.

5. Conclusions 38

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Soffredini R, et al. Randomized study of peginterferon-alpha2a plus ribavirin vs peginterferon-alpha2b plus ribavirin in chronic hepatitis C. Gastroenterology. 2010;138(1):108–15. 11 . Scotto G, Fazio V, Fornabaio C, Tartaglia A, Di Saracino A, et al. Peg-interferon alpha-2a versus Peg-interferon alpha-2b in nonresponders with HCV active chronic hepatitis: a pilot study. J Interferon Cytokine Res. 2008;28(10):623–9. 12 . Yenice N, Mehtap O, Gumrah M, Arican N. The effi pegylated interferon alpha 2a or 2b plus ribavirin in chronic hepatitis C patients. Turk J Gastroenterol. 2006;17(2):94–8. 13 . Fellay J, Thompson AJ, Ge D, Gumbs CE, Urban TJ, KV, et al. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature. 2010;464(7287):405–8. 14 . Ge D, Fellay J, Thompson AJ, Simon JS, Shianna K et al. Genetic variation in IL28B predicts hepatitis C treatmentinduced viral clearance. Nature. 2009;461(7262):399–401. 15 . Hung CH, Lee CM, Lu SN, Wang JH, Chen CH, Hu TH, Anemia associated with antiviral therapy in chronic hepatitis C: incidence, risk factors, and impact on treatment response. Liver Int. 2006;26(9):1079–86. 16 . Iwasaki Y, Ikeda H, Araki Y, Osawa T, Kita K, An Limitation of combination therapy of interferon and ribavirin for older patients with chronic hepatitis C. Hepatology. 2006;43(1): 54–63. 17 . Oze T, Hiramatsu N, Yakushijin T, Mochizuki K, O Hagiwara H, et al. Indications and limitations for aged patients with chronic hepatitis C in pegylated interferon alpha-2b plus ribavirin combination therapy. J Hepatol. 2011;54(4):604–11. 18 . McHutchison JG, Everson GT, Gordon SC, Jacobson M, Kauffman R, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360(18):1827–38. 19 . Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1195–206. 20 . Abergel A, Hezode C, Leroy V, Barange K, Bronowi A, et al. Peginterferon alpha-2b plus ribavirin for treatment of chronic hepatitis C with severe fibrosis: a multicentre randomized controlled trial comparing two doses of peginterferon alpha-2b. J Viral Hepat. 2006;13(12):811–20. 21 . Alfaleh FZ, Hadad Q, Khuroo MS, Aljumah A, Algam Alashgar H, et al. Peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C in Saudi patients commonly infected with genotype 4. Liver Int. 2004;24(6):568–74. J Gastroenterol

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123 22 . Andriulli A, Cursaro C, Cozzolongo R, Iacobellis MR, Mangia A, et al. Early discontinuation of ribavirin in HCV-2 and HCV-3 patients responding to Peg-interferon alpha-2a and ribavirin. J Viral Hepat. 2009;16(1):28–35. 23 . Angelico M, Koehler-Horst B, Piccolo P, Angelico Francioso S, et al. Peginterferon alpha-2a and ribavirin versus peginterferon alpha-2a monotherapy in early virological responders and peginterferon alpha-2a and ribavirin versus peginterferon alpha-2a, ribavirin and amantadine triple therapy in early virological nonresponders: the SMIEC II trial in naive patients with chronic hepatitis C. Eur J Gastroenterol Hepatol. 2008;20(7):680–7. 24 . Benhamou Y, Afdhal NH, Nelson DR, Shiffman ML, H DG, Heise J, et al. A phase III study of the safety and efficacy of viramidine versus ribavirin in treatment-naive patients with chronic hepatitis C: ViSER1 results. Hepatology. 2009;50(3): 717–26. 25 . Berg C, Goncales FL Jr, Bernstein DE, Sette H Jr Diago M, et al. Re-treatment of chronic hepatitis C patients after relapse: efficacy of peginterferon-alpha-2a (40 kDa) and ribavirin. J Viral Hepat. 2006;13(7):435–40. 26 . Berg T, von Wagner M, Nasser S, Sarrazin C, Hein T, et al. Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alpha-2a plus ribavirin. Gastroenterology. 2006;130(4):1086–97. 27 . Berg T, Weich V, Teuber G, Klinker H, Moller B, et al. Individualized treatment strategy according to early viral kinetics in hepatitis C virus type 1-infected patients. Hepatology. 2009;50(2):369–77. 28 . Bosques-Padilla F, Trejo-Estrada R, Campollo-Riv Hernandez C, Dehesa-Violante M, Maldonado-Garza H, et al. Peginterferon alpha-2a plus ribavirin for treating chronic hepatitis C virus infection: analysis of Mexican patients included in a multicenter international clinical trial. Ann Hepatol. 2003;2(3): 135–9. 29 . Brady DE, Torres DM, An JW, Ward JA, Lawitz E,Ha Induction pegylated interferon alpha-2b in combination with ribavirin in patients with genotypes 1 and 4 chronic hepatitis C: a prospective, randomized, multicenter, open-label study. Clin Gastroenterol Hepatol. 2010;8(1):66–71e1. 30 . Brandao C, Barone A, Carrilho F, Silva A, Patell et al. The results of a randomized trial looking at 24 weeks vs. 48 weeks of treatment with peginterferon alpha-2a (40 kDa) and ribavirin combination therapy in patients with chronic hepatitis C

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genotype 1. J Viral Hepat. 2006;13(8):552–9. 31 . Bressler B, Wang K, Grippo JF, Heathcote EJ. Pha and response of obese patients with chronic hepatitis C treated with different doses of PEG-IFN alpha-2a (40 kD) (PEGASYS). Br J Clin Pharmacol. 2009;67(3):280–7. 32 . Bronowicki JP, Ouzan D, Asselah T, Desmorat H, Z Foucher J, et al. Effect of ribavirin in genotype 1 patients with hepatitis C responding to pegylated interferon alpha-2a plus ribavirin. Gastroenterology. 2006;131(4):1040–8. 33 . Carr C, Hollinger FB, Yoffe B, Wakil A, Phillips et al. Efficacy of interferon alpha-2b induction therapy before retreatment for chronic hepatitis C. Liver Int. 2007;27(8): 1111–8. 34 . Ciancio A, Picciotto A, Giordanino C, Smedile A, Manca A, et al. A randomized trial of pegylated-interferonalpha2a plus ribavirin with or without amantadine in the retreatment of patients with chronic hepatitis C not responding to standard interferon and ribavirin. Aliment Pharmacol Ther. 2006;24(7):1079–86. 35 . Dalgard O, Bjoro K, Ring-Larsen H, Bjornsson E, M, Skovlund E, et al. Pegylated interferon alpha and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response. Hepatology. 2008;47(1):35–42. 36 . Diago M, Crespo J, Olveira A, Perez R, Barcena R Tapias JM, et al. Clinical trial: pharmacodynamics and pharmacokinetics of re-treatment with fixed-dose induction of peginterferon alpha-2a in hepatitis C virus genotype 1 true non-responder patients. Aliment Pharmacol Ther. 2007;26(8):1131–8. 37 . Ferenci P, Formann E, Laferl H, Gschwantler M, H Brunner H, et al. Randomized, double-blind, placebo-controlled study of peginterferon alpha-2a (40 kD) plus ribavirin with or without amantadine in treatment-naive patients with chronic hepatitis C genotype 1 infection. J Hepatol. 2006;44(2):275–82. 38 . Ferenci P, Brunner H, Laferl H, Scherzer TM, Mai Strasser M, et al. A randomized, prospective trial of ribavirin 400 mg/day versus 800 mg/day in combination with peginterferon alpha-2a in hepatitis C virus genotypes 2 and 3. Hepatology. 2008;47(6):1816–23. 39 . Ferenci P, Laferl H, Scherzer TM, Maieron A, Hof R, et al. Peginterferon alpha-2a/ribavirin for 48 or 72 weeks in hepatitis C genotypes 1 and 4 patients with slow virologic response. Gastroenterology. 2010;138(2):503–12e1. 40 . Fried MW, Jensen DM, Rodriguez-Torres M, Nyberg Bisceglie AM, Morgan TR, et al. Improved outcomes in patients with hepatitis C with difficult-to-treat characteristics: randomized

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study of higher doses of peginterferon alpha-2a and ribavirin. Hepatology. 2008;48(4):1033–43. 41 . Gish RG, Arora S, Rajender Reddy K, Nelson DR, O Y, et al. Virological response and safety outcomes in therapynaive patients treated for chronic hepatitis C with taribavirin or ribavirin in combination with pegylated interferon alpha-2a: a randomized, phase 2 study. J Hepatol. 2007;47(1):51–9. 42 . Glue P, Rouzier-Panis R, Raffanel C, Sabo R, Gup et al. A dose-ranging study of pegylated interferon alpha-2b and ribavirin in chronic hepatitis C. The Hepatitis C Intervention Therapy Group. Hepatology. 2000;32(3):647–53. 43 . Hasan F, Al-Khaldi J, Asker H, Al-Ajmi M, Owayed R, et al. Peginterferon alpha-2b plus ribavirin with or without amantadine [correction of amantidine] for the treatment of nonresponders to standard interferon and ribavirin. Antivir Ther. 2004;9(4):499–503. 44 . Helbling B, Jochum W, Stamenic I, Knopfli M, Cer Borovicka J, et al. HCV-related advanced fibrosis/cirrhosis: randomized controlled trial of pegylated interferon alpha-2a and ribavirin. J Viral Hepat. 2006;13(11):762–9. 45 . Herrine SK, Brown RS Jr, Bernstein DE, Ondovik M Te H. Peginterferon alpha-2a combination therapies in chronic hepatitis C patients who relapsed after or had a viral breakthrough on therapy with standard interferon alpha-2b plus ribavirin: a pilot study of efficacy and safety. Dig Dis Sci. 2005;50(4): 719–26. 46 . Hezode C, Forestier N, Dusheiko G, Ferenci P, Po et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360(18):1839–50. 47 . Ide T, Hino T, Ogata K, Miyajima I, Kuwahara R, et al. A randomized study of extended treatment with peginterferon alpha-2b plus ribavirin based on time to HCV RNA negative- status in patients with genotype 1b chronic hepatitis C. Am J Gastroenterol. 2009;104(1):70–5. 48 . Jacobson IM, Gonzalez SA, Ahmed F, Lebovics E, M Bodenheimer HC Jr, et al. A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis C. Am J Gastroenterol. 2005;100(11):2453–62. 49 . Jacobson IM, Brown RS Jr, Freilich B, Afdhal N, Santoro J, et al. Peginterferon alpha-2b and weight-based or flatdose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology. 2007;46(4):971–81. J Gastroenterol 123 50 . Jensen DM, Marcellin P, Freilich B, Andreone P,

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60 . Lodato F, Azzaroli F, Brillanti S, Colecchia A, Montagnani M, et al. Higher doses of peginterferon alpha-2b administered twice weekly improve sustained virological response in difficult-to-treat patients with chronic hepatitis C: results of a pilot randomized study. J Viral Hepat. 2005;12(5):536–42. 61 . Marcellin P, Horsmans Y, Nevens F, Grange JD, Br Vetter D, et al. Phase 2 study of the combination of merimepodib with peginterferon-alpha2b, and ribavirin in nonresponders to previous therapy for chronic hepatitis C. J Hepatol. 2007;47(4): 476–83. 62 . Marcellin P, Gish RG, Gitlin N, Heise J, Hallima et al. Safety and efficacy of viramidine versus ribavirin in ViSER2: randomized, double-blind study in therapy-naive hepatitis C patients. J Hepatol. 2010;52(1):32–8. 63 . McHutchison JG, Manns MP, Muir AJ, Terrault NA, IM, Afdhal NH, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010;362(14):1292–303. 64 . Mecenate F, Pellicelli AM, Barbaro G, Romano M, Mazzoni E, et al. Short versus standard treatment with pegylated interferon alpha-2A plus ribavirin in patients with hepatitis C virus genotype 2 or 3: the cleo trial. BMC Gastroenterol. 2010;10:21. 65 . Mendez-Navarro J, Chirino RA, Corey KE, Gorospe H, Moran S, et al. A randomized controlled trial of double versus triple therapy with amantadine for genotype 1 chronic hepatitis C in Latino patients. Dig Dis Sci. 2010;55(9):2629–35. 66 . Meyer-Wyss B, Rich P, Egger H, Helbling B, Mullh Rammert C, et al. Comparison of two PEG-interferon alpha-2b doses (1.0 or 1.5 lg/kg) combined with ribavirin in interferonnaive patients with chronic hepatitis C and up to moderate fibrosis. J Viral Hepat. 2006;13(7):457–65. 67 . Napoli N, Giannelli G, Antonaci A, Antonaci S. T peg-interferon alpha-2b regimens plus ribavirin in HCV- 1b-infected patients after rapid virological response does not affect the achievement of sustained virological response. J Viral Hepat. 2008;15(4):300–4. 68 . Pearlman BL, Ehleben C, Saifee S. Treatment exte 72 weeks of peginterferon and ribavirin in hepatitis c genotype 1-infected slow responders. Hepatology. 2007;46(6):1688–94. 69 . Roberts SK, Weltman MD, Crawford DH, McCaughan G Sievert W, Cheng WS, et al. Impact of high-dose peginterferon alpha-2A on virological response rates in patients with hepatitis C genotype 1: a randomized controlled trial. Hepatology. 2009;50(4):1045–55. 70 . Roffi L, Colloredo G, Pioltelli P, Bellati G, Po

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P, et al. Pegylated interferon-alpha2b plus ribavirin: an efficacious and well-tolerated treatment regimen for patients with hepatitis C virus related histologically proven cirrhosis. Antivir Ther. 2008;13(5):663–73. 71 . Rossignol JF, Elfert A, El-Gohary Y, Keeffe EB. virologic response in chronic hepatitis C genotype 4 treated with nitazoxanide, peginterferon, and ribavirin. Gastroenterology. 2009;136(3):856–62. 72 . Rustgi VK, Lee WM, Lawitz E, Gordon SC, Afdhal N F, et al. Merimepodib, pegylated interferon, and ribavirin in genotype 1 chronic hepatitis C pegylated interferon and ribavirin nonresponders. Hepatology. 2009;50(6):1719–26. 73 . Sanchez-Tapias JM, Diago M, Escartin P, Enriquez Gomez M, Barcena R, et al. Peginterferon-alpha2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology. 2006;131 (2):451–60. 74 . Shiffman ML, Salvatore J, Hubbard S, Price A, St Stravitz RT, et al. Treatment of chronic hepatitis C virus genotype 1 with peginterferon, ribavirin, and epoetin alpha. Hepatology. 2007;46(2):371–9. 75 . Shiffman ML, Suter F, Bacon BR, Nelson D, Harley et al. Peginterferon alpha-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med. 2007;357(2):124–34. 76 . Shiffman ML, Ghany MG, Morgan TR, Wright EC, Eve Lindsay KL, et al. Impact of reducing peginterferon alpha-2a and ribavirin dose during retreatment in patients with chronic hepatitis C. Gastroenterology. 2007;132(1):103–12. 77 . Sjogren MH, Sjogren R Jr, Lyons MF, Ryan M, Sant C, et al. Antiviral response of HCV genotype 1 to consensus interferon and ribavirin versus pegylated interferon and ribavirin. Dig Dis Sci. 2007;52(6):1540–7. 78 . Sood A, Midha V, Hissar S, Kumar M, Suneetha PV, et al. Comparison of low-dose pegylated interferon versus standard high-dose pegylated interferon in combination with ribavirin in patients with chronic hepatitis C with genotype 3: an Indian experience. J Gastroenterol Hepatol. 2008;23(2):203–7. J Gastroenterol

79 . Tang KH, Herrmann E, Pachiadakis I, Paulon E, Ta Zeuzem S, et al. Clinical trial: individualized treatment duration for hepatitis C virus genotype 1 with peginterferon-alpha 2a plus ribavirin. Aliment Pharmacol Ther. 2008;27(9):810–9. 80 . Toyoda H, Kumada T, Kiriyama S, Sone Y, Tanikawa Hisanaga Y, et al. Eight-week regimen of antiviral combination therapy with peginterferon and ribavirin for patients with chronic

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hepatitis C with hepatitis C virus genotype 2 and a rapid virological response. Liver Int. 2009;29(1):120–5. 81 . von Wagner M, Huber M, Berg T, Hinrichsen H, Ras Heintges T, et al. Peginterferon-alpha-2a (40 kD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology. 2005;129(2):522–7. 82 . von Wagner M, Hofmann WP, Teuber G, Berg T, Goes Spengler U, et al. Placebo-controlled trial of 400 mg amantadine combined with peginterferon alpha-2a and ribavirin for 48 weeks in chronic hepatitis C virus-1 infection. Hepatology. 2008;48(5): 1404–11. 83 . Yu ML, Dai CY, Lin ZY, Lee LP, Hou NJ, Hsieh MY, randomized trial of 24- vs. 48-week courses of PEG interferon alpha-2b plus ribavirin for genotype-1b-infected chronic hepatitis C patients: a pilot study in Taiwan. Liver Int. 2006;26(1):73–81. 84 . Yu ML, Dai CY, Huang JF, Hou NJ, Lee LP, Hsieh M randomised study of peginterferon and ribavirin for 16 versus 24 weeks in patients with genotype 2 chronic hepatitis C. Gut. 2007;56(4):553–9. 85 . Yu ML, Dai CY, Huang JF, Chiu CF, Yang YH, Hou N Rapid virological response and treatment duration for chronic hepatitis C genotype 1 patients: a randomized trial. Hepatology. 2008;47(6):1884–93. 86 . Zeuzem S, Diago M, Gane E, Reddy KR, Pockros P, et al. Peginterferon alpha-2a (40 kD) and ribavirin in patients with chronic hepatitis C and normal aminotransferase levels. Gastroenterology. 2004;127(6):1724–32. 87 . Zeuzem S, Pawlotsky JM, Lukasiewicz E, von Wagne I, Lurie Y, et al. International, multicenter, randomized, controlled study comparing dynamically individualized versus standard treatment in patients with chronic hepatitis C. J Hepatol. 2005;43(2):250–7. 88 . Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y et al. Efficacy of 24 weeks treatment with peginterferon alpha-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol. 2006;44(1): 97–103. 89 . Zeuzem S, Yoshida EM, Benhamou Y, Pianko S, Bain Shouval D, et al. Albinterferon alpha-2b dosed every two or four weeks in interferon-naive patients with genotype 1 chronic hepatitis C. Hepatology. 2008;48(2):407–17.

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