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Update of the Management and Treatment of Hepatitis C Viral Infection, 2012: Genotype 1

for Health Care Providers

Therapy against Hepatitis C in Patients with Genotype 1 Infection

IFN-based regimens will remain the "backbone" of HCV antiviral therapy for at least the next half decade. Either of the two pegylated IFNs, PegIFN alfa-2a (40 kD) or PegIFN alfa-2b (12 kD), administered subcutaneously once weekly in combination with oral RBV were the standard of care for treatment of HCV genotype 1 infection from 2001 to 2011, yielding overall SVR rates of 42-46% among treatment-naive patients (43, 44) . SVR rates were lower in specific patient populations, such as African Americans and cirrhotics (45) . Adverse events from either PegIFN alfa-2a or alfa-2b, and RBV are similar. The optimal RBV dose appears to be between 800 and 1,400 mg per day, based on weight in combination with either PegIFN product (Table 3) (46) . The standard treatment duration of PegIFN and RBV has been 48 weeks, except in patients who are slow responders (detectable HCV RNA at 12 weeks but undetectable HCV RNA by 24 weeks into treatment), in whom extending therapy to 72 weeks may be beneficial (47, 48) .

Two HCV protease inhibitors, TVR and BOC, were approved by the FDA in May 2011, for use in combination with PegIFN and RBV in treatment-naive and -experienced HCV genotype 1-infected patients with compensated liver disease. These oral agents selectively inhibit the HCV nonstructural 3/4A serine protease. Higher SVR rates are achieved in HCV genotype 1-infected patients, following the addition of TVR or BOC to PegIFN and RBV compared with PegIFN and RBV alone. The addition of an HCV PI to PegIFN and RBV represents a signficant advance in the treatment of patients with HCV genotype 1.

Therapy for previously untreated patients with genotype 1 infection: PegIFN alfa, RBV, and TVR or BOC

Phase 3 trials have shown signficantly higher SVR rates in previously untreated HCV genotype 1-infected patients following the addition of TVR or BOC to PegIFN and RBV compared with PegIFN and RBV alone; SVR 63-75% compared with 38-44%, respectively (Table 4). SVR was achieved in 87-97% of those who met RGT criteria for a shortened treatment duration (24-28 weeks). Approximately 44-65% of patients qualified for a shortened treatment duration if HCV RNA levels were undetectable (<10-15 IU/ml) at treatment weeks 4 and 12 with TVR-based regimens, or during treatment weeks 8-24 with BOC-based regimens. In traditionally difficult-to-treat populations, SVR was achieved in 42-62% of African Americans and 52-62% of cirrhotics with BOC- or TVR-based regimens, compared with 23-38% SVR in those receiving PegIFN and RBV alone (11, 12) .

The following pivotal and supplemental Phase 3 studies evaluated the safety and efficacy of BOC and TVR in combination with PegIFN and RBV (Table 4):

SPRINT-2 was designed to compare the efficacy of BOC/PegIFN/RBV after a 4-week PegIFN/RBV lead-in to PegIFN/RBV alone. Triple therapy for 44 weeks also was compared with a response-guided approach. PegIFN alfa-2b (1.5 mcg/kg per week) and RBV (600-1,400 mg orally daily), followed by the addition of BOC (800 mg orally every 8 h) or placebo, was studied in 1,099 treatment-naive HCV genotype 1-infected patients, including 158 African American patients (11) . The three treatment arms for randomization were: (i) PegIFN and RBV plus placebo for 48 weeks; (ii) 4 weeks of PegIFN and RBV, followed by the addition of BOC for 28 weeks of therapy in total, if HCV RNA was undetectable from treatment weeks 8 through 24; if virus was detectable at any of these timepoints, PegIFN and RBV were continued until week 48; (iii) a 4-week PegIFN and RBV lead-in, followed by the addition of BOC for 44 weeks. SVR was achieved in 38%, 63%, and 66%, respectively (11) , demonstrating clear superiority in SVR with the BOC-containing regimens. Patients with bridging fibrosis or cirrhosis who received BOC/PegIFN/RBV for 44 weeks achieved higher SVR rates than those treated with triple therapy for only 24 weeks (42 vs. 34%, respectively). Higher SVR rates were also achieved in African American patients in BOC-containing arms (42-53%) compared with control (23%). In late responders who were IFN responsive (≥ 1.0 log 10 decline in HCV RNA) following the 4-week lead-in with PegIFN and RBV, but had detectable HCV RNA at week 8, treatment with BOC/PegIFN/RBV for 44 weeks resulted in higher SVR than did treatment for only 24 weeks. In these patients, discontinuation of BOC at week 36, with continuation of PegIFN and RBV for another 12 weeks, was supported by modeling to limit adverse effects, and was recommended by the FDA, but this was not prospectively studied in SPRINT-2 (34) .

ADVANCE compared 8 and 12 weeks of TVR/PegIFN/RBV, with subsequent PegIFN/RBV duration of 12 to 40 weeks determined by a response-guided approach to PegIFN/RBV alone for 48 weeks. TVR (750 mg orally every 8 h) or placebo was combined with PegIFN alfa 2a (180 mcg once weekly) and RBV (1,000 or 1,200 mg orally daily) in 1,088 treatment-naive HCV genotype 1-infected patients (12) . The three arms for randomization were: (i) TVR for 8 weeks plus PegIFN and RBV for 24 weeks if HCV RNA was undetectable at weeks 4 and 12 (eRVR), 48 weeks if not; (ii) TVR for 12 weeks plus PegIFN and RBV for 24 weeks if eRVR was achieved, 48 weeks if not; (iii) PegIFN and RBV plus placebo for 48 weeks. SVR was achieved in 69%, 75%, and 44%, respectively, demonstrating the clear superiority of TVR-containing regimens. SVR was signficantly higher in the 12-week TVR-containing arm among cirrhotics (62%) and African American patients (62%) compared with PegIFN and RBV alone (25-33%), and lower relapse and resistance rates were seen compared with the 8-week TVR-treated arm. SVR was not signficantly reduced in the 8-week TVR-containing arm compared with the 12-week arm (69 and 75%, respectively) as such, TVR may be discontinued early if it is not well tolerated without compromising SVR.

The purpose of ILLUMINATE was to define the utility of RGT in patients who achieve eRVR (49) . All patients received 12 weeks of TVR/PegIFN alfa-2a/RBV (dosed as in ADVANCE), followed by 8 weeks of PegIFN and RBV. Those with eRVR were randomized at week 20 to either 4 or 28 additional weeks of PegIFN and RBV. The study included 540 treatment-naive genotype 1-infected patients. Patient characteristics when compared with ADVANCE were as follows: more North Americans (94 vs. 60%), slightly older (51 vs. 49 years), a higher proportion of African Americans (14 vs. 9%) and cirrhotics (11 vs. 6%). Despite these differences, results were similar to ADVANCE and confirmed the efficacy of shortened treatment duration if eRVR is achieved, with 92% SVR in patients with eRVR treated for 24 weeks, and 88% in those treated for 48 weeks. SVR occurred in 72% overall, and rates were relatively high in cirrhotics (63%) and African Americans (60%).

In the Phase 3 studies, only small proportions of patients were African American (9-15%), Hispanic or Latino (10-11% in TVR trials), Asian/other (4% in BOC trials), or had bridging fibrosis or cirrhosis (6-16%). Additional prospective studies with DAA/PegIFN/RBV are needed to evaluate their efficacy and tolerability in these subgroups of patients.

Table 3. Antiviral treatment for chronic hepatitis C in adults (32, 33, 34, 35, 57, 58)
Generic
(Trade name)
Recommended doseRecommended dose in renal or hepatic dysfunction
BOC, boceprevir; Clcr, creatinine clearance; HCV, hepatitis C virus; PegIFN, peginterferon; PI, protease inhibitor; PO, orally; RBV, ribavirin; SC, subcutaneous; TVR, telaprevir.
PegIFN alfa-2a (Pegasys®) 180 mcg SC once weekly Clcr <30 ml/min: 135 mcg SC once weekly
Hemodialysis: 135 mcg SC once weekly
PegIFN alfa-2b (PEG-Intron®) 1.5 mc/kg SC once weekly Clcr 30-50 ml/min: reduce dose by 25%
Clcr 10-29 ml/min: reduce dose by 50%
RBV (Copegus®, Rebetol®, Ribasphere®, RibaPak®)

Genotype 1:
1,000 mg (if ≤ 75 kg) or 1,200 mg (if >75 kg) PO daily in two divided doses,

Or

<65 kg: 800 mg PO daily in two divided doses
65-85 kg: 1,000 mg PO daily in two divided doses
>85-105 kg: 1,200 mg PO daily in two divided doses
>105 kg: 1,400 mg PO dailsy in two divided doses

Genotype 2 or 3:
800 PO daily in two divided doses

Clcr 30-50 ml/min: 200 mg PO daily, alternating with 400 mg PO daily
Clcr <30 ml/min: 200 mg PO daily
PIs for treatment of HCV genotype 1
BOC (Victrelis™) 800 mg (4 x 200 mg capsules) PO every 7-9 apart with food in combination with PegIFN-RBV following a 4-week lead-in with PegIFN-RBV Dose adjustments not necessary for renal or hepatic impairment (Child-Pugh <7)
TVR (Incivek™) 750 mg (2 x 375 mg tablets) PO every 7-9 h with food (20 grams fat) for 12 weeks, plus PegIFN-RBV for 24 or 48 weeks Dose adjustments not necessary for renal or hepatic impairment (Child-Pugh <7)

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Recommendations for therapy among treatment-naive patients with genotype 1 infection:

  1. PegIFN alfa and RBV, in combination with BOC (800 mg orally every 7-9 h with food) or TVR (750 mg orally every 7-9 h with 20 g of fat), is the standard of care for most treatment-naive genotype 1-infected patients (Class I, Level A).
  2. If a TVR-containing regimen is used in treatment-naive noncirrhotic patients who achieve eRVR, TVR should be discontinued at week 12 and PegIFN-RBV should be continued for an additional 12 weeks. If HCV RNA is detectable, but <1,000 IU/ml at treatment week 4, and remains <1,000 IU/ml or becomes undetectable by week 12, TVR should be discontinued at week 12, and PegIFN and RBV can be continued for another 36 weeks (refer to Figure 2; Class I, Level A).
  3. If a TVR-containing regimen is used in treatment-naive cirrhotics who achieve an HCV RNA that is undetectable or <1,000 IU/ml at treatment weeks 4 and 12, TVR should be discontinued at week 12, and PegIFN-RBV can be continued for another 36 weeks (refer to Figure 2; Class I, Level A).
  4. If a BOC-containing regimen is used in treatment-naive noncirrhotics, if HCV RNA declines by ≥ log 10 during the 4-week lead-in, and HCV RNA is undetectable at weeks 8-24, BOC-PegIFN-RBV for 24 weeks is sufficient. If HCV RNA is detectable at week 8, but <100 IU/ml at week 12 and negative at week 24, BOC-PegIFN-RBV should be continued until week 36, followed by PegIFN-RBV alone for 12 more weeks. If HCV RNA declines by <1 log 10 during the lead-in, BOC-PegIFN-RBV can be contined for 44 weeks (refer to Figure 3; Class I, Level A).
Table 4. SVR rates in genotype 1-infected patients treated with PegIFN/RBV ± BOC or TVR
Study cohort, NSVR to PI/PegIFN/RBV (arm 1 of trial)SVR to PI/PegIFN/RBV (arm 2 of trial)SVR with PegIFN/RBV
BOC, boceprevir; eRVR, extended rapid virologic response; HCV, hepatitis C virus; PegIFN, peginterferon alfa; PI, protease inhibitor; RBV, ribavirin; RGT, response-guided therapy; SVR, sustained virologic response; TVR, telaprevir.
Treatment-naive
BOC (SPRINT-2), SVR% 63 66 38
N = 1,099 (11) BOC/PegIFN/RBV RGT BOC/PegIFN/RBV 44 weeks PegIFN/RBV 48 weeks
TVR (ADVANCE), SVR% 69 75 44
N = 1,088 (12) TVR for 8 weeks/PegIFN/RBV RGT TVR for 12 weeks/PegIFN/RBV RGT PegIFN/RBV 48 weeks
TVR (ILLUMINATE), SVR% 71 73 NA
N = 540 (49) TVR for 12 weeks/PegIFN/RBV (24 total weeks) if eRVR TVR for 12 weeks/PegIFN/RBV(48 total weeks) if eRVR -
Treatment-experienced
TVR (REALIZE), SVR% overall - -
N = 662 (13) NA 64-66 17
TVR for 12 weeks/PegIFN/RBV (48 weeks total)
Prior relapsers (SVR%) - 83-88 24
Prior partial responders (SVR%) - 54-59 15
Prior null responders (SVR%) - 29-33 5
BOC (RESPOND-2), SVR% overall
N = 403 (14) 59 66 21
BOC/PegIFN/RBV (48 weeks total)
Prior relapsers (SVR%) 69 75 29
Prior partial responders (SVR%) 40 52 7

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Therapy for patients with HCV genotpye 1, who have failed to respond, or who have relapsed to IFN-based therapy with or without ribavirin

Nonresponders or relapsers to IFN-based therapy are a growing population, many of whom are infected with genotype 1 and have advanced liver disease. Before the availability of HCV PIs, there were limited retreatment options for these patients. Retreatment strategies included PegIFN/RBV at higher doses and for longer durations, or the combination of daily consensus IFN and RBV. However, only 7-16% of nonresponders to PegIFN/RBV achieved SVR using these retreatment approaches in randomized, controlled trials (50, 51) . PegIFN/RBV relapsers had improved response rates compared with nonresponders, with SVR occuring in approximately 50% of patients using these re-treatment strategies (50, 51, 52) .

Retreatment with PegIFN and RBV, plus BOC or TVR in patients with HCV genotype 1 has produced higher SVR rates than with PegIFN and RBV alone. As is the case with other retreatment regimens, BOC- or TVR-PegIFN/RBV therapy is more effective in relapsers than in nonresponders. With these triple therapies, SVR was achieved in 69-88% of relapsers and 29-33% of null responders, whereas SVR rates to PegIFN and RBV alone were 24-29 and 5%, respectively (13, 14, 34, 35) . The benefit of retreatment of prior null responders with a BOC- or TVR-containing regimen should be carefully considered. In REALIZE (discussed below), only approximately 30% of null responders achieved SVR, and viral resistance mutations developed in the majority of those who remained viremic (13) . Null responders were not included in the Phase 3 BOC trial RESPOND-2, and response rates for these patients were based on extrapolation. In RESPOND-2, HCV RNA decline after 4-week lead-in was a stronger predictor of SVR than was the historical treatment response.

The following pivotal Phase 3 and supplemental studies evaluated the safety and efficacy of retreatment of genotype 1 patients with BOC or TVR, in combination with PegIFN/RBV (Table 4):

REALIZE evaluated TVR (750 mg orally every 8 h) or placebo, in combination with PegIFN alfa-2a and RBV, in 663 patients who had previously failed PegIFN and RBV, including relapsers (53%), partial responders (19%), and null responders (27%) (13) . For all patients, the total treatment duration was 12 weeks with TVR or placebo, in combination with PegIFN and RBV for 48 weeks. One of the two TVR arms used a 4-week lead-in with PegIFN and RBV before the addition of TVR, and achieved a similar SVR rate as in the arm without the lead-in (SVR 66 and 64%, respectively). Both TVR-containing arms achieved higher SVR than PegIFN and RBV alone (17%, P<0.001). In TVR-containing arms, SVR was achieved in a greater proportion of PegIFN and RBV relapsers (83-88%) as compared with prior partial responders (54-59%) or prior null responders (29-33%), compared with control (24%, 15%, and 5%, respectively). Prior null responders with cirrhosis had similar SVR rates with a TVR-based regimen compared with PegIFN and RBV alone (14 and 10%, respectively). In contrast, SVR rates were higher in null responders with minimal or bridging fibrosis with a TVR-based regimen compared with PegIFN and RBV alone (39-41 and 0-6%, respectively).

In a subanalysis of null responders, IFN responsiveness during the 4-week lead-in before the addition of TVR was a predictor of SVR. In patients who had <0.5 log 10 decline and those with 0.5-1 log 10 decline in baseline HCV RNA during the PegIFN and RBV lead-in, SVR occurred in only 6 and 20%, respectively. In those with >1 log 10 decline during the PegIFN/RBV lead-in, SVR was achieved in 44-80% (53). The fact that the arm with a 4-week PegIFN and RBV lead-in before the addition of TVR allows IFN responsiveness to be determined raises the issue of whether this approach could be used with TVR in general.

RESPOND-2 evaluated BOC (800 mg orally every 8 h) or placebo, and PegIFN alfa-2b and RBV in 403 patients who had previously failed PegIFN and RBV, specifically prior partial responders and relapsers (14) . Previous null responders were not included in the trial. Patients were randomized 1:2:2 to treatment in 3 arms: (i) PegIFN and RBV plus placebo for 48 weeks; (ii) a 4-week PegIFN and RBV lead-in, followed by the addition of BOC, with 32 weeks of triple therapy if HCV RNA was undetectable at treatment weeks 8 and 12; if virus was detectable at week 8, but undetectable at week 12, triple therapy was continued to week 32, at which time BOC was discontinued, and PegIFN and RBV were continued until week 48 (RGT arm); (iii) a 4-week PegIFN and RBV lead-in, followed by 44 weeks of BOC/PegIFN/RBV. SVR rates were signficantly higher in the BOC-containing arms than in the arm receiving PegIFN and RBV (SVR 59% RGT, 66% BOC/ PegIFN/ RBV for 44 weeks, 21% control). PegIFN and RBV relapsers achieved higher SVR rates than prior partial responders in the BOC-treated arms (SVR 69-75 and 40-52%, respectively) and in the control arms (SVR 29% and 7%, respectively). The relapse rate was 12% in the BOC-containing arms vs. 32% for control. SVR was lower among patients with <1.0 log 10 decline in HCV RNA than in those with >1.0 log 10 decline in HCV RNA at treatment week 4 after a lead-in with PegIFN/RBV (SVR 33-34% BOC/ PegIFN/ RBV and 0% control vs. SVR 73-79% BOC/ PegIFN/ RBV and 25% control, respectively).

In an interim analysis of a single arm, multicenter rollover study (PROVIDE) of 48 patients who were null responders (<2 log decline in HCV RNA after 12 weeks of PegIFN and RBV without a HCV protease inhibitor) from SPRINT-2 and RESPOND-2, re-treatment using a 4-week lead-in with PegIFN-RBV followed by the addition of BOC for 44 weeks achieved SVR in 38% (54).

Recommendations for retreatment of nonresponders and relapsers with genotype 1 infection:

Recommendations for retreatment of nonresponders and relapsers with genotype 1 infection:

  1. For patients who previously failed PegIFN-RBV, retreatment with BOC or RBV and PegIFN-RBV may be considered, particularly in patients who were relapsers (Class I, Level A).
  2. If a BOC-containing regimen is used for re-treatment of noncirrhotic prior partial responders or relapsers, the recommended treatment duration is 36 weeks if HCV RNA is undetectable from weeks 8-24. If HCV RNA is detectable at week 12, but <100 IU/ml and is undetectable from weeks 24-36, BOC can be discontinued at week 36 and PegIFN-RBV can be continued for an additional 12 weeks (refer to Figure 3; Class I, Level B).
  3. If a BOC-containing regimen is used for re-treatment in cirrhotics, the treatment duration is 48 weeks if HCV RNA is detectable at week 12, but <100 IU/ml, and becomes undetectable from weeks 24-36 (refer to Figure 3; Class I, Level B).
  4. If a BOC-containing regimen is used for re-treatment of prior null responders, the treatment duration is 48 weeks if HCV RNA is detectable at week 12, but <100 IU/ml, and becomes undetectable from weeks 24-36 (refer to Figure 3; Class II, Level C).
  5. If a TVR-containing regimen is used for re-treatment of prior relapsers, and HCV RNA is undetectable from weeks 4 and 12, TVR should be discontinued at week 12 and PegIFN-RBV should be continued for an additional 12 weeks. If HCV RNA is detectable, but <1000 IU/ml at week 4 and/or 12, TVR can be discontinued at week 12, and PegIFN-RBV can be continued for an additional 36 weeks (refer to Figure 2; Class I, Level B).
  6. If a TVR-containing regimen is used for re-treatment of prior partial responders or null responders, and HCV RNA is <1000 IU/ml at weeks 4 and 12, TVR should be discontinued at week 12 and PegIFN alfa plus RBV should be continued for an additional 36 weeks (refer to Figure 2; Class I, Level B).

Issues related to triple therapy with BOC- or TVR-containing regimens

Regimen differences.

Both PegIFN alfa-2a and alfa-2b have been FDA-approved for use with BOC or TVR (14, 34, 35, 55, 56) . A 4-week lead-in period with PegIFN and RBV is required before the addition of BOC (Figure 3). Once BOC is combined with PegIFN-RBV, BOC remains part of triple therapy for the majority of the treatment duration based on RGT (Figure 3). TVR is administered with PegIFN and RBV for the first 12 weeks, followed by PegIFN and RBV alone, for a duration based on RGT (Figure 2). Additional studies are needed to confirm whether TVR given at 1,225 mg twice daily is as effective as 750 mg every 7-9 h (55) .

Drug-drug interactions.

BOC and TVR are strong CYP3A4 inhibitors and CYP3A substrates. Clinicians should be careful to avoid DDIs, and should make therapeutic substitutions before starting BOC- or TVR-containing regimens (e.g., replace simvastatin with pravastatin; refer to table on Drug-Drug Interactions in Supplementary Materials) (34, 35) . One important DDI with HCV PIs is with oral contraceptives, which may be rendered ineffective. Two non-hormonal methods of contraception (eg., spermicide, barrier methods, intra-uterine device) should be used in women during treatment with an HCV PI and RBV, and for at least 6 months after treatment has concluded (34, 35) .

Dose modifications.

BOC or TVR should not be dose-reduced or restarted if discontinued. On the basis of the pharmacokinetic and resistance potential of these medications, they should be either continued at full doses in combination with PegIFN and RBV, or permanently discontinued (± PegIFN and RBV) based on treatment response and tolerability. If RBV is stopped for 7 days or more in patients who are concomitantly receiving BOC or TVR, then BOC or TVR also should be permanently discontinued to avoid the potential development of HCV-resistant variants.

Pharmacological considerations.

Patients should be instructed not to take a missed dose if it is within 2 h or less of the next scheduled BOC dose, or within 4 h or less of the next scheduled TVR dose (34, 35) . TVR and BOC should be administered with food, three times daily, 7-9 h apart. TVR must be taken with food that contains approximately 20 g of fat (e.g., bagel with cream cheese, 1/2 cup nuts, 3 tablespoons peanut butter, 1 cup ice-cream, 2 oz American or cheddar cheese, 2 oz potato chips, or 1 1/2 cup trail mix). PegIFN should be refrigerated (36-46o F) during storage (57, 58) . BOC should be refrigerated (36-46o F) during storage, or stored at room temperature up to 77o F for up to 3 months (34) . TVR can be stored at room temperature between 59-86o F (35) .

Adverse effects

Almost all patients receiving hepatitis C antiviral therapy will experience some treatment-related adverse effects. Close monitoring is crucial throughout treatment. Poor tolerability can lead to early treatment discontinuation. Clinicians can promote adherence by counseling patients on the recognition and management of treatment-related adverse effects. Patients should be reassured that most treatment-related adverse effects can be minimized or managed.

The addition of DAA agents to PegIFN and RBV is associated with an increased incidence of adverse events, requiring discontinuation of the DAA agent in 10-21% of patients (11, 12, 13, 14, 59, 60) . Adverse events with increased frequency among subjects receiving a DAA agent include anemia, neutropenia (BOC), dysgeusia (altered taste), gastrointestinal upset, fatigue, rash (TVR), and perianal discomfort (TVR) (11, 12, 13, 14) . On the basis of the TVR adverse effect profile, BOC in combination with PegIFN-RBV may be more appropriate in patients with skin disorders (e.g., psoriasis) or gout.

Figure 2. Telaprevir (TVR)/Peginterferon (PegIFN)/ribavirin (RBV)* algorithm for both treatment-naive and treatment-experienced patients with HCV genotype 1

Figure 2

(See larger image)

* PegIFN alfa-2a 180 mcg per week or PegIFN alfa-2b 1.5 mcg/kg per week. RBV (in two divided doses) with food: <75 kg: 1,000 mg per day or ≥ 75 kg: 1,200 mg per day; alternative weight-based RBV dosing: <65 kg: 800 mg per day, 65-85 kg: 1,000 mg per day, >85-105 kg: 1,200 mg per day, >105 kg: 1,400 mg per day. TVR 750 mg (two 375 mg tablets) orally every 8 h with food (20 g fat).

† A sensitive real-time quantitative HCV RNA assay with a lower limit of detection of <10-15 IU/ml should be used for decision-making to determine treatment duration with response-guided therapy (RGT).

Figure 3. Boceprevir (BOC)/Peginterferon (PegIFN)/ribavirin (RBV)* algorithm for both treatment-naive and treatment-experienced patients with HCV genotype 1

figure 3

(See larger image)

* PegIFN alfa-2a 180 mcg per week or alfa-2b 1.5 mcg/kg per week. RBV (in two divided doses) with food: <75 kg: 1,000 mg per day or ≥ 75 kg: 1,200 mg per day; alternative weight-based RBV dosing: <65 kg: 800 mg per day, 65-85 kg: 1,000 mg per day, >85-105 kg: 1,200 mg per day, >105 kg: 1,400 mg per day. BOC 800 mg (four 200 mg capsules) orally every 8 h with food.

† A sensitive real-time quantitative HCV RNA assay with a lower limit of detection of <10-15 IU/ml should be used for decision-making to determine treatment duration with response-guided therapy (RGT).

** BOC was not studied in null responders; this population was excluded from the Phase 3 study of patients who had previously failed treatment. efficacy data and FDA labeling for this population is based solely on mathematical modeling.

*** Discontinuation of BOC at week 36 is supported by modeling, but was not directly studied in the clinical trials. Following a 4-week lead-in with PegIFN-RBV, the addition of BOC to Peg-RBV for 44 weeks achieved higher sustained virologic response (SVR) compared with 24 weeks in late responders (detectable HCV RNA at week 8) in the registration trials.

Table 5. General guidelines for PegIFN-RBV dose reduction or discontinuation (32, 33, 57, 58)
PegIFN dose recommendationa

ANC, absolute neutrophil count; BOC, boceprevir; GCSF, granulocyte colony-stimulating factor; Hb, hemoglobin; HCV, hepatitis C virus; PegIFN, peginterferon; RBV, ribavirin; TVR, telaprevir; WBC, white blood cell counts.

a Manufacturer package insert recommendations.

b If dose is maintained outside of manufacturer recommendations, monitor ANC more frequently, and counsel patient on neutropenic precautions. In post-liver transplantation or HIV/HCV-coinfected patients who remain neutropenic despite dose reduction, consider starting GCSF until resolution.

c If dose is maintained outside of manufacturer recommendations, monitor platelet counts, and signs or symptoms of unusual bleeding or bruising more frequently.

WBC
<1.5 x 109/l PegIFN alfa-2b: reduce dose to 1 mcg/kg per week,
then to 0.5 mcg/kg per week if needed
<1.0 x 109/l Discontinue PegIFN alfa-2b until resolution
ANCb
<0.75 x 109/lPegIFN alfa-2a: reduce dose to 135 mcg per week
PegIFN alfa-2b: reduce dose to 1 mcg/kg per week,
then to 0.5 mcg/kg per week if needed
<0.50 x 109/l Discontinue PegIFN until resolution
Plateletsc
<50 k/mm3PegIFN alfa-2a: reduce dose to 90 mcg per week
PegIFN alfa-2b: reduce dose to 1 mcg/kg per week,
then to 0.5 mcg/kg per week if needed
<25 k/mm3Discontinue PegIFN until resolution
RBV dose recommendation
Hb
<11.0, but >10 g/dl No change in RBV dose if patient has minimal symptoms
In a symptomatic patient, consider RBV dose reduction
<10.0, but >8.5 g/dl Decrease RBV, consider starting an erythropoietic growth factor
In patients with a cardiac history, reduce RBV dose and reduce PegIFN alfa-2b dose by 50%
<8.5 g/dl Discontinue RBV until resolution
If RBV is stopped for ≥ 7 days or discontinued in patients who are concomitantly receiving BOC or TVR, then BOC or TVR must be permanently discontinued
Anemia.

In clinical trials, signficant anemia (hemoglobin <10 g/dl) occurred nearly twice as frequently in BOC- or TVR-treated patients than in patients receiving PegIFN and RBV alone. This led to an additional decrease in hemoglobin levels of approximately 1-1.5 g/dl, which resulted in greater RBV dose interruptions and use of growth factors. In the Phase 3 TVR trials, initial dose reduction of RBV to 600 mg daily was mandated, and use of erythropoietin generally was prohibited. In contrast, RBV dose reductions occurred in 200 mg decrements, and erythropoietin use was allowed in the Phase 3 BOC trials. On the basis of retrospective subanalyses, RBV dose reduction alone did not appear to compromise SVR rates (61, 62, 63) . Initial management of HCV treatment-related anemia should consist of RBV dose reduction in a symptomatic patient with a hemoglobin level of <10 g/dl (Table 5). If an erythropoiesis stimulating agent is used, the dose should be reduced or held if the baseline hemoglobin increases by >1 g/dl in any 2-week period, and if hemoglobin levels exceed 11 g/dl (32, 33, 64, 65) based on the manufacturers ' warning of risks for cardiovascular and thrombotic events.

Neutropenia.

Initial management of HCV treatment-related neutropenia should consist of PegIFN dose reduction according to the manufacturer recommendations (Table 5) (57, 58) . Although the incidence of neutropenia (absolute neutrophil count (ANC) <750 per mm 3) was similar in patients treated with TVR/PegIFN/RBV and those treated with PegIFN and RBV alone (12 and 15%, respectively) (35) , BOC/PegIFN/RBV was associated with an increased incidence of neutropenia. BOC-treated patients (23%) experienced grade 3 (ANC 500 to <750 per mm 3) neutropenia and 7% experienced grade 4 (ANC <500 per mm 3) compared with 13 and 4%, respectively, in those receiving PegIFN-RBV alone. BOC-treated patients required more dose reductions of PegIFN and use of a granulocyte colony-stimulating factor (34) .

Rash and skin reactions.

Mild-to-moderate rash occurred in more than half of patients receiving TVR, with grade 3 (severe) rash occurring in up to 7% of patients and requiring discontinuation in approximately 6% (12, 13, 35, 59) . Rash often developed within 1 month of TVR initiation, and required 4-6 weeks after TVR discontinuation to resolve. Rashes were primarily eczematous, maculopapular, or papular-lichenoid and pruritic.

Mild-to-moderate rash can be treated with oral antihistamines and/or topical corticosteroids; systemic steroids are contraindicated in combination with TVR. If rash becomes severe (>50% of body surface area), TVR should be discontinued. All HCV therapy should be discontinued immediately for any rash associated with signficant systemic symptoms, including evidence of internal organ involvement (e.g., hepatitis, nephritis), facial edema, mucous membrane erosions or ulceration (e.g., conjunctivae, lips), target lesions, epidermal detachment, vesicles, or bullae. The patient should be promptly referred for urgent medical care and dermatological consultation (35) . Drug Rash with Eosinophilia and Systemic Symptoms and Stevens Johnson Syndrome occurred in <1% of TVR-treated patients (35) .

Anorectal signs and symptoms.

Anorectal symptoms, variously described as hemorrhoids, anorectal discomfort, anal pruritus, and rectal burning, were reported by approximately 25% of patients receiving TVR (12, 35) . The symptoms generally were were mild to moderate in severity and rarely required treatment discontinuation. Symptomatic treatment with topical steroids or local anesthetic can be considered.

Elevated uric acid levels.

Elevated uric acid levels occurred in up to 73% of patients receiving TVR, with onset during the first 2 weeks of therapy (12, 13, 35) . In patients receiving TVR, uric acid levels should be measured at baseline, at weeks 2, 4, 8, 12, and as clinically indicated (35) . Treatment with allopurinol can be considered if uric acid level is >10 mg/dl.

Elevated bilirubin levels.

Elevated bilirubin levels occurred more frequently in TVR-treated patients than in those treated with PegIFN-RBV alone (41 and 28%, respectively), but were not accompanied by liver dysfunction (35) . The steepest increase in bilirubin occurred during the first 1-2 weeks of TVR therapy. In patients receiving TVR, bilirubin levels should be measured at baseline, at weeks 2, 4, 8, 12, and as clinically indicated (35) .

Table 6. HCV PI (BOC or TVR): RGT criteria and futility rules (34, 35)
BOC-PegIFN/RBVTVR-PegIFN/RBV
HCV, hepatitis C virus; PegIFN, peginterferon; PI, protease inhibitor; RBV, ribavirin; RGT, response-guided therapy; TVR, telaprevir.
Candidates for RGT Noncirrhotics:
Treatment-naive: 28 weeks
Prior relapser/partial responder: 36 weeks
Noncirrhotics:
Treatment-naive: 24 weeks
Prior relapser: 24 weeks
Criteria for RGT HCV RNA undetectable (<10-15 IU/ml) weeks 8-24 HCV RNA undetectable (<10-15 IU/ml) weeks 4 and 12
Futility rules (stop all treatment if any of the following occur)

Week 12: HCV RNA ≥100 IU/ml

Or

Week 24: HCV RNA detectable

Or

HCV RNA rebounds at any timepoint (≥1 log10increase from the nadir HCV RNA)

Week 4 or 12: HCV RNA >1,000 IU/ml

Or

Week 24: HCV RNA detectable

Or

HCV RNA rebounds at any timepoint (≥1 log10 increase from the nadir HCV RNA)

Print table

Recommendations for dose modification:

  1. PegIFN alfa and RBV doses should be reduced in response to decreases in white blood cells, neutrophils, hemoglobin, or platelets, as outlined in Table 5 (Class I, Level A).
  2. If RBV is stopped for 7 days or more in patients who are concomitantly receiving BOC or TVR, then the PI also should be permanently discontinued (Class I, Level A).
  3. HCV PIs should be either continued at full dose or discontinued (Class I, Level A).
  4. Initial management of HCV treatment-related anemia should consist of RBV dose reduction in a symptomatic patient with a hemoglobin <10g/ dl, or as clinically indicated. Erythropoietin may be administered in patients with symptomatic anemia related to PegIFN-RBV therapy with or without BOC/TVR to limit anemia-related RBV dose reductions or dose discontinuations (Class II, Level C).
  5. Initial management of HCV treatment-related neutropenia should consist of PegIFN dose reduction for an ANC <750, or as clinically indicated. Granulocyte colony-stimulating factor should not be given as primary therapy to prevent PegIFN alfa dose reductions (Class I, Level C).

Monitoring therapy

Patients with a history of depression should be followed closely for recurrence of depression while receiving PegIFN therapy. Patients should also receive a clinical evaluation by a mental health professional if depression scores increase during treatment. Standardized depression screening instruments can be used to supplement the clinical exam.

Periodic laboratory monitoring of hemoglobin, hematocrit, white blood cell count with differential, platelet count, and serum alanine transaminase is necessary in all patients receiving hepatitis C antiviral therapy (refer to Monitoring Table in Supplementary Materials). Increasing the frequency of these tests is advised in patients with signficant reductions in hemoglobin, white blood cell count, or platelet count, or in those who experience significant clinical adverse events.

Quantitative and/or qualitative HCV RNA assays should be performed at weeks 4, 8 (with BOC-containing regimens), 12, and 24 of treatment, at the end-of-treatment, and 24 weeks after completion of therapy. Patients receiving BOC- or TVR-containing regimens may need additional HCV RNA determinations as clinically indicated.

HCV resistance.

Hepatitis C resistance is a new clinical entity with the introduction of PIs and other DAA agents. HCV resistance is defined as the selection of viral variants that have altered binding to the drug target and are less susceptible to the drug' s inhibitory activity (66) . HCV resistant viruses carrying amino acid changes in the nonstructural 3/4A position have been described in vitro and in vivo with BOC and TVR (67, 68, 69) . Resistant viruses can develop with all genotype 1 subtypes, but are more likely to occur in patients with genotype 1a than in those with genotype 1b, when treated with BOC or TVR (70) . More importantly, resistant viruses develop in most patients within 7 days of DAA use as monotherapy. Consequently, BOC and TVR should never be used without PegIFN-RBV.

Patients with poor IFN response (<1.0 log 10 decline in HCV RNA) to the PegIFN and RBV lead-in had lower SVR rates and higher resistance rates than IFN-sensitive patients. A good virologic response to the 4-week PegIFN and RBV lead-in, defined by a ≥1.0 log 10 decline in HCV RNA, was a strong predictor of SVR. Patients without such a response had lower SVR and higher resistance rates (11, 53) (. In patients with a <1.0 log 10 decline in HCV RNA during the lead-in and in prior null responders, consideration should be given as to whether the benefits of triple therapy outweigh the potential risk of developing resistance/cross-resistance to future therapies, along with determining whether the patient can wait for the availability of better treatment options.

Among patients who develop resistant viruses, the resistant variants are no longer detectable in the serum approximately 1-2 years after discontinuing BOC or TVR (66, 67, 68) . However, due to limitations of current tests for resistance, it is unclear whether small numbers of resistant viruses continue to be present for prolonged periods of time. Because of the similar resistant mutations to BOC and TVR, patients who develop resistance when treated with one PI (e.g., BOC) should not be treated with the other PI (e.g., TVR), because of the high likelihood of having or developing cross resistance to the second PI.

There are no commercial assays to test for the presence of resistant viruses before or during treatment (66) . The only way to suspect that a patient has developed a resistant virus is to monitor for HCV RNA rebound (>1 log 10 increase from the nadir HCV RNA) during treatment. Criteria for failure to respond adequately to BOC or TVR, necessitating stopping of the PI, as outlined in the package insert are given below (refer to section "Futility (stopping) rules") (34, 35) . Stopping rules because of failure to respond are the same for treatment-naive and for treatment-experienced patients.

Futility (stopping) rules.

Viral breakthrough with triple therapy was an infrequent event, particularly among patients who experienced eRVR with TVR-containing regimens or early response (HCV RNA <10-15 IU/ml by treatment week 8) with BOC-containing regimens (11, 12) . In patients with inadequate viral suppression on therapy, stopping treatment is important to limit the development of resistance mutations.

All treatment should be stopped if any of the following occur: (i) HCV RNA level >1,000 IU/ml at week 4 or 12 with a TVR-containing regimen, or HCV RNA level ≥ 100 IU/ml at week 12 with a BOC-containing regimen; or (ii) detectable HCV RNA levels at week 24 or at any timepoint thereafter; or (iii) HCV RNA rebounds at any timepoint (≥1 log 10 increase from the nadir HCV RNA) (34, 35) . In addition, BOC or TVR must be discontinued permanently if RBV is stopped for longer than 7 days; PegIFN monotherapy may be continued if appropriate (refer to Table 6).

PegIFN and RBV (without BOC or TVR) can be continued in patients with presumed resistant viruses, although the probability of achieving an SVR is low. The stopping rules for treatment with PegIFN and RBV (<2 log 10 decline in HCV RNA at Week 12 and/or detectable HCV RNA at Week 24) should be applied to patients in whom the DAA is discontinued early because of resistance or intolerability.

Recommendations for treatment monitoring:

  1. Patients should be monitored for treatment-related adverse effects at intervals of at least 2 weeks early in the course of therapy, and at intervals of 1-2 months during treatment as clinically indicated (Class I, Level C).
  2. Patient adherence to therapy should be assessed at every visit (Class I, Level C).
  3. Patients should be evaluated for depression, suicidal ideation, alcohol, and illicit drug use at each visit (Class I, Level C).
  4. Patients should be counseled about avoiding pregnancy by using two forms of contraception during treatment and for 6 months post-treatment, and pregnancy tests should be performed as indicated in (refer to Monitoring Table in Supplementary Materials).

    If a patient is receiving a BOC- or TVR-containing regimen, two alternative effective methods of contraception, such as intrauterine devices and barrier methods, should be used in at-risk patients and partners during and for at least 6 months after treatment (Class I, Level B).
  5. Serum markers of biochemical and virologic response should be measured, and treatment-related adverse effects monitored at intervals as outlined (refer to Monitoring Table in Supplementary Materials); Class I, Level C).
  6. In patients receiving TVR-PegIFN-RBV, all treatment should be stopped if any of the following occur: (i) HCV RNA level >1,000 IU/ml at week 4 or 12; or (ii) detectable HCV RNA levels at week 24 or at any timepoint thereafter; or (iii) HCV RNA rebounds at any timepoint (≥ 1 log10 increase from the nadir HCV RNA) (Class I, Level C).
  7. In patients receiving BOC-PegIFN-RBV, all treatment should be stopped if any of the following occur: (i) HCV RNA level ≥100 IU/ml at week 12 with a BOC-containing regimen; or (ii) detectable HCV RNA levels at week 24 or at any timepoint thereafter; or (iii) HCV RNA rebounds at any timepoint (≥1 log 10 increase from the nadir HCV RNA; Class I, Level C).
  8. If virologic failure occurs with a BOC- or TVR-containing regimen, the other PI must not be substituted (Class I, Level C).