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Medicine » Infectious Diseases » "Practical Management of Chronic Viral Hepatitis", book edited by Gaetano Serviddio, ISBN 978-953-51-1109-2, Published: May 29, 2013 under CC BY 3.0 license. © The Author(s).

Chapter 7

Treatment of Chronic HCV Infection in the Era of Protease Inhibitors

By R. Villani, F. Bellanti and G. Serviddio
DOI: 10.5772/56139

Article top

Overview

Genomic organization of hepatitis C polyprotein. The HCV genome (about 9000 nucleotides) is translated in a single polypeptide of 3000 aminoacids. Then the polypeptide is cleved to produce ten proteins whose role is explained below. During an alternative splicing within the core, a new protein (F protein) can be produced (this one not represented) (From :Poordad F, Dieterich D. Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents. J Viral Hepat 2012 Jul;19(7):449-464)..
Figure 1. Genomic organization of hepatitis C polyprotein. The HCV genome (about 9000 nucleotides) is translated in a single polypeptide of 3000 aminoacids. Then the polypeptide is cleved to produce ten proteins whose role is explained below. During an alternative splicing within the core, a new protein (F protein) can be produced (this one not represented) (From :Poordad F, Dieterich D. Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents. J Viral Hepat 2012 Jul;19(7):449-464)..
The nucleocapsid of the HCV genome is surrounded by an envelope that facilitates attachment and penetration into host cells. Upon entry into the host cell by endocytosis, the virus undergoes undergoes a fusion and uncoating step. Its RNA is translated into a polyprotein of approximately 3,000 aminoacids that is processed by cellular and viral proteases (including NS3) to yield structural and non structural proteins. Boceprevir and telaprevir block the polyprotein processing by stopping activity of NS3/NS4A complex, which has protease activity on the polypeptide (From Lindenbach BD, Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature 2005;436:933-938; Manns MP, Foster GR, Rockstroh JK, Zeuzem S, Zoulim F, Houghton M. The way forward in HCV treatment--finding the right path. Nat Rev Drug Discov 2007 Dec;6(12):991-1000).
Figure 2. The nucleocapsid of the HCV genome is surrounded by an envelope that facilitates attachment and penetration into host cells. Upon entry into the host cell by endocytosis, the virus undergoes undergoes a fusion and uncoating step. Its RNA is translated into a polyprotein of approximately 3,000 aminoacids that is processed by cellular and viral proteases (including NS3) to yield structural and non structural proteins. Boceprevir and telaprevir block the polyprotein processing by stopping activity of NS3/NS4A complex, which has protease activity on the polypeptide (From Lindenbach BD, Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature 2005;436:933-938; Manns MP, Foster GR, Rockstroh JK, Zeuzem S, Zoulim F, Houghton M. The way forward in HCV treatment--finding the right path. Nat Rev Drug Discov 2007 Dec;6(12):991-1000).
Telaprevir schedule. In naïve and prior relapser patients telaprevir should be administered for the first 12 weeks and peg-interferon plus ribavirin for 12 or 36 weeks additional. In case of eRVR (HCV RNA not detected at week 4 and 12 the treatment may be stopped after 24 weeks. If HCV RNA is still detected at week 12, peg-interferon and ribavirin should be continued for additional 36 weeks. In any case if HCV RNA is detectable at week 24 or results > 1000 UI/ml between 4 and 12 weeks, the treatment should be stopped. RBV, ribavirin; eRVR, extended rapid virologic response (From: Barritt AS, Fried MW. Maximizing opportunities and avoiding mistakes in triple therapy for hepatitis C virus. Gastroenterology 2012 May;142(6):1314-1323.)
Figure 3. Telaprevir schedule. In naïve and prior relapser patients telaprevir should be administered for the first 12 weeks and peg-interferon plus ribavirin for 12 or 36 weeks additional. In case of eRVR (HCV RNA not detected at week 4 and 12 the treatment may be stopped after 24 weeks. If HCV RNA is still detected at week 12, peg-interferon and ribavirin should be continued for additional 36 weeks. In any case if HCV RNA is detectable at week 24 or results > 1000 UI/ml between 4 and 12 weeks, the treatment should be stopped. RBV, ribavirin; eRVR, extended rapid virologic response (From: Barritt AS, Fried MW. Maximizing opportunities and avoiding mistakes in triple therapy for hepatitis C virus. Gastroenterology 2012 May;142(6):1314-1323.)
Boceprevir schedule. A “lead in” phase (4 weeks of peg-interferon and ribavirin before the beginning of the triple therapy) is considered for all patients. In naïve patients boceprevir should be administered for a minimum of 24 weeks. If HCV RNA is negative at week 8 and 24 all drugs must be stopped at week 28. If HCV RNA is detectable at week 8 o 24, boceprevir should be administrated for 32 weeks and peg-interferon plus ribavirin for additional 12 weeks.
Figure 4. Boceprevir schedule. A “lead in” phase (4 weeks of peg-interferon and ribavirin before the beginning of the triple therapy) is considered for all patients. In naïve patients boceprevir should be administered for a minimum of 24 weeks. If HCV RNA is negative at week 8 and 24 all drugs must be stopped at week 28. If HCV RNA is detectable at week 8 o 24, boceprevir should be administrated for 32 weeks and peg-interferon plus ribavirin for additional 12 weeks.
Estimating body surface area (BSA: body surface area) (From: Hezode C. Boceprevir and telaprevir for the treatment of chronic hepatitis C: safety management in clinical practice. Liver Int 2012 Feb;32 Suppl 1:32-38)
Figure 5. Estimating body surface area (BSA: body surface area) (From: Hezode C. Boceprevir and telaprevir for the treatment of chronic hepatitis C: safety management in clinical practice. Liver Int 2012 Feb;32 Suppl 1:32-38)

Treatment of Chronic HCV Infection in the Era of Protease Inhibitors

R. Villani1, F. Bellanti1 and G. Serviddio1

1. Introduction

Hepatitis C virus infection represents the most common cause of chronic hepatitis with potential evolution into cirrhosis and hepatocellular carcinoma [1]. The infected population appears heterogeneous for age, modalities of infection, and disease duration [2]. To date the standard of care of treatment (SOC) has been pegylated interferon alpha 2a or alpha 2b associated with ribavirin. The main goal of the therapy is the achievement of a sustained virological response (SVR) defined as undetectable HCV RNA 24 weeks after stopping treatment.

Several factors influence therapeutic schedules. First of all, HCV genotype 1 (G1) and 4 require longer treatment as compared to G2 and G3.

Early virologic negativization after starting therapy, together with virus genotype, are the most important predictors of sustained virological response.

The absence of a virologic response by week 12 has the highest negative predictive value for all genotypes suggesting that HCV RNA disappearance should be achieved as soon as possible [3].

Many other factors such as age, gender, degree of fibrosis and viral load influence SVR; more recently, the single nucleotide polymorphism (SNPs) of the IL28B gene has been demonstrated to be a good predictor of response [4].

The analysis of large cohorts demonstrates that, even in patients treated for 48 weeks, almost half of G1 infected patients does not reach a SVR, as compared to 20% of G2/3 [5].

Treatment failure is defined on the basis of the virological response to treatment, as follows:

  1. null responders, if the reduction of HCV RNA is less than 1 log10 at week 12 of therapy;

  2. virological nonresponse is considered when the serum HCV RNA level remains above the limit of detection throughout treatment and is defined as less than 2 log10 decline in HCV RNA between baseline and week 12;

  3. partial responders if the reduction of HCV RNA is at least 2 log10 at 12 weeks but it is still detectable at week 24;

  4. relapsers if HCV RNA decreases and remains below the limit of detection (<50 IU/mL) during treatment but becomes detectable after cessation of treatment [6].

HCV infection is often characterized by extrahepatic associated diseases. HCV is considered a stimulus for B-cell clonal expansion underlying benign and malignant B-cell dyscrasias including a subgroup of B-cells non Hodgkin’s lymphomas. In this context, we must consider that HCV infection is also characterized by several extrahepatic manifestations. The most common and well characterized is mixed cryoglobulinemia. This condition, as well as some B-cell non Hodgkin’s lymphomas, is the result of B-cell clonal expansion due to viral persistence [7].

Accordingly, the treatment of HCV chronic infection should be addressed not only to the treatment of chronic liver disease, but also to the prevention of HCV-associated diseases.

It is estimated that 25% of HCC worldwide is related to HCV [8].

If the rate of response to antiviral therapy increases to 80%, over the next ten years, the treatment of half of HCV-infected persons would reduce cirrhosis by 15%, hepatocellular carcinoma by 30% and death for liver disease by 34%. [9].

The application of the most effective therapy should be a common strategy to block permanently viral replication and avoid the progression to cirrhosis and the development of hepatocellular carcinoma.

Boceprevir and telaprevir are HCV protease inhibitors, recently approved for antiviral therapy in HCV infected patients, are effective to control the viral replication.

2. Target of protease inhibitors

HCV genome is a single strand RNA of 9000-9100 nucleotide encoding for three stuctural (C, E1, E2), seven non structural (xlink, NS3, NS4A, NS4B, NS5A, NS5B, p7) and F proteins whose role is unknown [10] (Fig 1).

HCV replicative cycle involves the translation of the HCV RNA into a single polyprotein that is subsequently cleaved to obtain every single structural and non structural proteins.

NS3 is a serine protease while NS4 serves as cofactor. NS3 and NS4A must be assembled in order to become active in catalyzing the cleavage of the other NS proteins from the HCV polyprotein at the NS3/NS4A, NS4A/NS4B, NS4B/NS5A and NS5A/NS5B junctions, a condition required for viral replication.

HCV virions turn over rapidly (with a half-life of about 3 h), and up to 1012 viruses are produced per day in an infected person [11].

media/image1.png

Figure 1.

Genomic organization of hepatitis C polyprotein. The HCV genome (about 9000 nucleotides) is translated in a single polypeptide of 3000 aminoacids. Then the polypeptide is cleved to produce ten proteins whose role is explained below. During an alternative splicing within the core, a new protein (F protein) can be produced (this one not represented) (From :Poordad F, Dieterich D. Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents. J Viral Hepat 2012 Jul;19(7):449-464)..

media/image2.png

Figure 2.

The nucleocapsid of the HCV genome is surrounded by an envelope that facilitates attachment and penetration into host cells. Upon entry into the host cell by endocytosis, the virus undergoes undergoes a fusion and uncoating step. Its RNA is translated into a polyprotein of approximately 3,000 aminoacids that is processed by cellular and viral proteases (including NS3) to yield structural and non structural proteins. Boceprevir and telaprevir block the polyprotein processing by stopping activity of NS3/NS4A complex, which has protease activity on the polypeptide (From Lindenbach BD, Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature 2005;436:933-938; Manns MP, Foster GR, Rockstroh JK, Zeuzem S, Zoulim F, Houghton M. The way forward in HCV treatment--finding the right path. Nat Rev Drug Discov 2007 Dec;6(12):991-1000).

Boceprevir and Telaprevir link to NS3/NS4A enzymatic complex in a covalent and reversible manner to disrupt the processing of the HCV polyprotein.

Even if the protease inhibitors are potent antiviral agent, their administration without interferon and ribavirin is characterized by rapid selection of resistant variants of the virus [12]. Accordingly boceprevir and telaprevir need to be administered in a regimen with pegylated-interferon and ribavirin, commonly named “triple therapy”.

During the initial 2 weeks of triple therapy the viral load decline is rapid and unaffected by ribavirin. However, beyond 2 weeks, viral breakthrough occurs if ribavirin is not administered. After 12 weeks, breakthrough occurs in 24% of patients treated with peg-interferon and telaprevir.

Ribavirin also affects the rate of viral relapse. In regimens without ribavirin, relapse occurs in 48% of patients as compared to 14-30% of patients treated with ribavirin [13].

3. Management of antiviral therapy in naive patients

Three trials (SPRINT-2, ADVANCE, ILLUMINATE) examined the efficacy of boceprevir and telaprevir in naïve patients.

Telaprevir obtained a SVR rate of 75% as compared to 44% of the SOC with peg-interferon plus ribavirin.

The schedule includes triple therapy (telaprevir + peg-interferon + ribavirin) for the first 12 weeks and peg-interferon+ribavirin for additional 36 weeks (fig 3). Telaprevir is administered at the dose of 750 mg thrice daily.

The tablets should be taken with high fat (>20 g) meal or snack for optimal adsorption (table 2).

Patients with undetectable HCV RNA at week 4 (rapid virological response, RVR) and 12 (extended rapid virological response, eRVR) can stop therapy after 24 weeks of treatment (response-guided therapy, RGT) [14].

In the contrast, telaprevir should be stopped when:

  1. HCV RNA is more than 1000 UI/ml at week 4 or 12 or

  2. HCV RNA is detectable at week 24

Boceprevir was differently studied in black and non-black populations.

The SVR rate was 53% and 68% in black and not-black population, respectively.

Boceprevir requires a “lead-in” phase with peg-interferon and ribavirin for 4 weeks and triple therapy (boceprevir + peg-interferon + ribavirin) for 24 or 32 weeks and again a dual therapy with peg-interferon and ribavirin for the last 4 weeks (fig 4).

The lead-in in phase is useful in naïve patients to assess the responsiveness to peg-interferon and ribavirin.

In fact, lower SVR rates and development of boceprevir-resistant mutants are more common in patients with HCV RNA reduction less than 1 log10 at week 4 independently from the treatment scheme [15].

The recommended dose of boceprevir is 800 mg thrice daily. Meal seems not influence the absorption as much as observed in telaprevir regimens.

In patients with RVR after the “lead-in” phase, SOC is still recommended since SVR is observed in 88% after 48 weeks of therapy [16].

Accordingly to the response-guided therapy, RGT, patients treated with boceprevir with undetectable HCV RNA at weeks 8 and 24 can stop therapy after 36 weeks of treatment.

If HCV RNA is detectable at week 8, the treatment should continue to 48 weeks.

Boceprevir should be stopped when:

  1. HCV RNA is more than 100 UI/ml at week 12 or

  2. HCV RNA is detectable at week 24.

4. Management of antiviral therapy in null responders

Retreatment of null responders with peg-interferon and ribavirin is effective in less than 5% of patients [17].

Telaprevir increases SVR to 31%.

The schedule requires 48 weeks of treatment, with the first 12 weeks of triple and the remaining 36 weeks with peg-interferon and ribavirin.

The stopping rules are the same of naïve patients.

Boceprevir trials did not include null responders and, to date, it is not recommended in such patients.

5. Management of antiviral therapy in partial responders

Retreatment of partial responders with SOC is effective in 7-15% of patients [17, 18].

Triple therapy with boceprevir or telaprevir may increase the rate of SVR to 52% and 57%, respectively.

Response-guided therapy is not recommended since 48 weeks are commonly requested.

6. Management of antiviral therapy in relapsers

Retreatment of relapsers with SOC induces a SVR in less than 1/3 of patients [17, 18].

Telaprevir is administered for the first 12 weeks and SOC for the further 36 weeks with a SVR rate of 86%.

Boceprevir requires the “lead-in” phase of SOC and triple therapy for the additional 44 weeks with a SVR of 75%.

If HCV RNA is not detected at weeks 8 and 24, the therapy may be stopped at week 32.

STUDY Drug Population Treatment arms Intervention SVR SOC
SVR
Main findings
SPRINT-2BoceprevirNaiveBlack-RGT
Black- 48 week
Non Black RGT
Non Black- 48 week
42%
53%
67%
68%
23%

40%
RGT therapy as effective as 48 weeks of therapy for non black patients. About 50% of patients elegible for RGT
ADVANCETelaprevirNaiveT8 (pooled 24- and 48-week total therapy)
T12 (pooled 24- and 48-week total therapy)
69%
75%
44%12-week telaprevir regiment preferable to 8-week regimen
ILLUMINATETelaprevirNaiveT12 overall
eRVR+24-week therapy
eRVR+48-week therapy
75%
92%
88%
N/A24-week total therapy for eRVR patients non inferior to 48 weeks of therapy. About 75% of patients eligible for shorter duration of therapy
RESPOND-2BoceprevirTreatment experiencedRGT- prior relapser
RGT-Prior non responder
48 weeks-relapsers
48week-non responders
69%
40%
75%
52%
29%
7%
Null responders excluded. Relapsers had similar outcomes as naive population
REALIZETelaprevirTreatment experiencedT12 (48-week total therapy)
Prior relapsers
Prior partial responders
Prior null responders
86%
57%
31%
24%
15%
5%
Relapers had similar outcomes as naive population

Table 1.

Summary of phase 3 clinical trials for boceprevir and telaprevir.eRVR, extended rapid virologic response; RGT, response guided therapy; SOC, standard of care; SVR, sustained virologic response; T8, 8-week telaprevir arm; T12, 12-week telaprevir arm (From: Barritt AS, Fried MW. Maximizing opportunities and avoiding mistakes in triple therapy for hepatitis C virus. Gastroenterology 2012 May;142(6):1314-1323).

Examples of food containing at least 20 g of fat
Bagel with cream cheese
½ cup of nuts
3 tablespoons of peanut butter
1 cup of ice cream
60 g of American or cheddar cheese
60 g of potato chips
½ cup of trail mix
33 g of granola
3 slices of homemade French toast
2 cups 3.3% whole milk
60 g of chocolate candy bar with almonds or peanuts
Two 60 g plain doughnuts
1 slice pecan pie
1 medium avocado
100 g of lean hamburger in bun
100 g of salami
4 slices of bologna
100 g of broiled pork chop
Three 100 g sausage patties
2 cup chow mein noodles
200 g of fried chicken breast
2 small roasted chicken legs

Table 2.

Food containing at least 20 g of fat (From: Kiser JJ, Burton JR, Anderson PL, Everson GT. Review and management of drug interactions with boceprevir and telaprevir. Hepatology 2012 May;55(5):1620-1628.)

media/image3.png

Figure 3.

Telaprevir schedule. In naïve and prior relapser patients telaprevir should be administered for the first 12 weeks and peg-interferon plus ribavirin for 12 or 36 weeks additional. In case of eRVR (HCV RNA not detected at week 4 and 12 the treatment may be stopped after 24 weeks. If HCV RNA is still detected at week 12, peg-interferon and ribavirin should be continued for additional 36 weeks. In any case if HCV RNA is detectable at week 24 or results > 1000 UI/ml between 4 and 12 weeks, the treatment should be stopped. RBV, ribavirin; eRVR, extended rapid virologic response (From: Barritt AS, Fried MW. Maximizing opportunities and avoiding mistakes in triple therapy for hepatitis C virus. Gastroenterology 2012 May;142(6):1314-1323.)

media/image4.png

Figure 4.

Boceprevir schedule. A “lead in” phase (4 weeks of peg-interferon and ribavirin before the beginning of the triple therapy) is considered for all patients. In naïve patients boceprevir should be administered for a minimum of 24 weeks. If HCV RNA is negative at week 8 and 24 all drugs must be stopped at week 28. If HCV RNA is detectable at week 8 o 24, boceprevir should be administrated for 32 weeks and peg-interferon plus ribavirin for additional 12 weeks.

In prior relapsers and partial responders boceprevir should be administered for 32 weeks and peg-interferon plus ribavirin for additional 12 weeks.

In any case, if HCV RNA is detectable at week 24 or HCV RNA is >100 UI/ml at week 12, the treatment should be stopped (From: Barritt AS, Fried MW. Maximizing opportunities and avoiding mistakes in triple therapy for hepatitis C virus. Gastroenterology 2012 May;142(6):1314-1323.).

7. Management of side effect of antiviral therapy

Even if only 2% are severe, almost all patients treated with boceprevir or telaprevir report side effects. Among all, anaemia is the most common, occurring in 50% of patients treated with protease inhibitor as compared to 20% of peg-interferon and ribavirin.

Blood count should be monitored during the first 4 weeks to identify those who will need support.

In patients treated with boceprevir, SVR has been observed more frequently in those who develop anaemia [19].

Administration of subcutaneous alpha-erythropoietin 40.000 UI once a week is effective in controlling anaemia induced by peg-interferon and ribavirin as well as protease inhibitors trying to maintain the blood level around 100 g/L.

If ineffective, ribavirin may be reduced and blood transfusion considered.

It has been reported that, in triple therapy regimen, ribavirin may be safely reduced without affecting the SVR rate.

When this strategy is insufficient and anaemia becomes more severe, blood transfusion is required.

Neutropenia occurs in 70-80% of patients treated with triple therapy and this is more commonly observed in those developing anaemia [20].

Filgrastim 30 MU subcutaneous one to three times a week usually maintains the count of neutrophils > 1000/µL.

Boceprevir Telaprevir
Complete blood count Baseline
week 2 and 4
weekly for the first month of triple therapy
(from week 4 to 8)
then monthly or
as necessary
Baseline
weekly for the first month of triple therapy
Every three weeks until the end of triple
then monthly during the left dual therapy or
as necessary
Liver function tests Baseline
week 4-6 and 8
then monthly
Baseline
Week 2-4 and 8
Then monthly
Serum electrolytes
Creatinine
Uric acid
Baseline
week 2
then monthly
Baseline
week 2
then monthly
TSH Baseline
week 12 and 24
then as necessary
Baseline
week 12 and 24
then as necessary
Cholesterol
Tryglicerides
Baseline
week 12 and 24
then as necessary
Baseline
week 12 and 24
then as necessary

Table 3.

Proposal for blood monitoring during triple therapy

HEMATOLOGICAL SIDE EFFECT CHANGE DURING THERAPY
Anemia < 100 g/LErythropoietin 40.000 UI once a week
< 90 g/LRibavirin dose reduction + Erythropoietin
< 80 g/LBlood transfusion
Thrombocytopenia ≥ 100.000/µLNo change
≥ 50.000/µLWeekly control then monthly
< 50.000/µLPeg-interferon dose reduction
< 25.000/µLStop therapy
Neutropenia < 1000/µLFilgrastim 30 MU once/ twice/ thrice a week
< 750/µLPeg-interferon dose reduction

Table 4.

Management of haematological side effects during triple therapy.

The adverse effects described during peg-interferon and ribavirin therapy such as rush, flu like and gastrointestinal symptoms are more commonly observed during triple therapy.

Fatigue, nausea, dysgeusia, chills, insomnia, alopecia, diarrhoea, decreased appetite, irritability, vomiting, arthralgia, dizziness, dry skin rash, asthenia, dyspnoea on exertion are more common during boceprevir [21]. In particular, dysgeusia affects almost 50% of patients. Telaprevir induces hyperuricemia, fatigue, pruritus, diarrhoea, vomiting, haemorrhoids, anorectal discomfort, dysgeusia and anal pruritus relative to patients on standard of care. Cutaneous rash is the less tolerated side effect of telaprevir. Fortunately, more than 90% of such events is mild or moderate and does not progress. Discontinuation occurs only in 6% of cases [22]. Oral antihistamines or a topical steroid is effective in controlling symptoms. Moderate rash may associate with pruritus or mucosal involvement. When more than 50% of the body surface is involved or vesicles, bullae or ulceration develop, rash is considered severe and telaprevir should be stopped; peg-interferon and ribavirin can be continued for additional 6-7 days. If the rash does not improve, all drugs should be stopped and hospitalization and appropriate therapy is required [23].

Haemorrhoids, anal pruritus, anorectal discomfort and anal burning observed during telaprevir may be managed with topic steroid or local lidocaine.

Life threatening or systemic reaction (Steven-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms – DRESS, erythema multiforme-EM) are rarely observed (refer to the specific chapter for details).

media/image5.png

Figure 5.

Estimating body surface area (BSA: body surface area) (From: Hezode C. Boceprevir and telaprevir for the treatment of chronic hepatitis C: safety management in clinical practice. Liver Int 2012 Feb;32 Suppl 1:32-38)

8. Drug interactions

Boceprevir and telaprevir are metabolized via the cytochrome P4503A pathway. They are potent inhibitors of CYP3A4 and also substrates and inhibitors of the drug transporter P-glycoprotein (P-gp).

Boceprevir and telaprevir availability depends on Child-Pugh but not on renal function.

Concentration of boceprevir in serum increases of 30% and 45-60% in patients with Child Pugh B and C, respectively.

Telaprevir is reduced of about 10-15% and 50% in Child Pugh B and C, respectively. Protease inhibitors greatly impact the metabolism of HMG-CoA reductase inhibitors.

Simvastatin and lovastatin are not recommended in patients treated with boceprevir or telaprevir. Atorvastatin should be avoided when telaprevir is administered and a lowest dose should be selected in boceprevir treated patients. Pravastatin is metabolized by other pathway and the risk of interaction is not completely defined. Rosuvastatin may be safely administered, even if it has not been specifically addressed in the trials.

STATINS Use during Boceprevir Use during Telaprevir
SimvastatinNONO
AtorvastatinPOSSIBLE (USE THE LOWEST DOSE)NO
LovastatinNONO
PravastatinYESNO DATA
RosuvastatinPOSSIBLEPOSSIBLE

Table 5.

Potential association between protease inhibitors and statins.

Both boceprevir and telaprevir may reduce contraceptive efficacy of ethinyl estradiol. Moreover, boceprevir can increase plasmatic level of drosperidone while telaprevir reduces norethindrone.

Benzodiazepines (triazolam, alprazolam, flurazepam) may be greatly affected by protease inhibitors and should be avoided until new data are available.

Both boceprevir and telaprevir increase metabolism of escitalopram and its effect may be reduced.

Zolpidem concentration is reduced by of 42% in patients treated with telaprevir as well as trazodone.

Boceprevir and telaprevir reduce the clearance of cyclosporine and tacrolimus. The exposure to cyclosporine increases 4-fold with telaprevir and 3-fold with boceprevir, while tacrolimus plasmatic concentration increases 70-fold after telaprevir administration and 17-fold after boceprevir. On the other hands, immunosuppressive drugs seen not change boceprevir and telaprevir metabolism.

DRUGS TO BE AVOIDED INCREASED CONCENTRATION OF CONCOMITANT MED OR HCV PI REDUCED CONCENTRATION OF CONCOMITANT MED OR HCV PI
Alpha-1 adrenoreceptor antagonistAlfuzosinDoxazosin
Terazosin
Tamsulosin
Silodosin
AnticonvulsantCarbamazepime
Phenobarbital
Phenytoin
AntifungalsKetoconazole
Itraconazole
Posaconazole
Voriconazole
AntimicrobialsClarithromycine
Erythromycin
AntimycobacterialsRifampin
Rifapentine
Rifabutin
Antiretroviral drugsLopinavir (TPV)
Darunavir (TPV)
Fosamprenavir (TPV) Efavirenz (BOC)
Efavirenz (TPV)*
Benzodiazepines and sleep aidsFlurazepam
Quazepam
Triazolam
Oral midazolam
Alprazolam
Trazodone
CardiovascularAmiodarone
Bosentan
Dofetilide
Flecainide
Lidocaine
Propafenone
Quinidine
sildenafil and tadalafil for pulmonary arterial hypertension
Calcium-channel blockers Digoxin
Carvedilol
Nabivolol
Irbesartan
Losartan
Ergot derivativesDihydroergotamine
Ergonovine
Ergotamine
Methylergonovine
Herbal productsSt. John’s wort
HMG-CoA reductase inhibitorsLovastatin
Simvastatin
Atorvastatin (TPV)
Atorvastatin (BOC)
Pravastatin
Rosuvastatin
ImmunosuppressantTacrolimus
Sirolimus
Cyclosporine
Oral contraceptivesDrosperinone (BOC)Ethynil estradiol
RespiratoryFluticasone
salmeterol
Second-generation antipsycoticQuetiapineIloperidone
aripiprazole

Table 6.

Summary of drugs to avoid and drugs to use with caution in combination with boceprevir (BOC) and telaprevir (TPV).

[i] - Interaction unique to one of the HCV protease inhibitors are indicated in parentheses (e.g. TPV or BOC).

[ii] - Abbreviation: Med, medication; PI, protease inhibitor; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A.

[iii] - *A higher dose of TPV [1,120 mg every 8 hours) has been studied with efavirenz with promising preliminary rates of SVR.

[iv] - ( From: Kiser JJ, Burton JR, Anderson PL, Everson GT. Review and management of drug interactions with boceprevir and telaprevir. Hepatology 2012 May;55[5]:1620-1628]

9. Triple therapy in cirrhotic and liver transplant patients

Cirrhosis increases morbidity and mortality and reduces SVR [24].

Clinical efficacy in cirrhosis has been investigated in phase 3 trials (ADVANCE, ILLUMINATE, REALIZE, RESPOND-2, SPRINT-2).

SVR is reached in 33% - 46% after 48 weeks of peg-interferon and ribavirin. [25, 26]

The addiction of a protease inhibitor improves the SVR to 50% [26]. In these cases, 48 weeks of treatment are commonly required.

In relapsers, the addition of a protease inhibitor increases SVR to 87%.

In partial responders SVR rate is lower (34% with triple therapy and 20% in peg-interferon and ribavirin schedule)

There are no benefits in cirrhotic null responders with by using telaprevir (14% vs 10%) [27].

The relapse rate remains high and side effects are too frequently observed in cirrhotic patients [24].

Until now, protease inhibitors are not approved for patients with liver transplantation for the interactions with immunosuppressive drugs [12].

10. Genetics and triple therapy

Interleukin 28B (IL28B) polymorfisms impacts the response to peg-interferon and ribavirin.

TRIPLE THERAPY rs 12979860
Boceprevir
SVR
C/C C/T T/T
80-82%65-71%55-59%
Telaprevir
SVR
C/C C/T T/T
90%71%73%

Table 7.

Response rate according to IL28B genotype in treatment-naive G1 HCV patients receiving triple therapy

[i] - (From: Thompson AJ. Genetic factors and hepatitis C virus infection. Gastroenterology 2012 May;142(6):1335-1339)

Peg-interferon plus ribavirin Polymorphism
CAUCASIAN (n=1171)rs 12979860
SVRC/CC/TT/T
69%33%27%
AFROAMERICANS (n=300)rs 12979860
SVRC/CC/TT/T
48%15%13%

Table 8.

Response rate according to IL28B genotype (rs12979860) in treatment-naive North American G1 HCV patients receiving 48 week peg-interferon alpha plus ribavirin. Genotype C/C achieves SVR in 69% (good response).

[i] - T/T genotype is associated with poor response.

[ii] - The response is lower in Afro-Americans.

[iii] - SVR, sustained virological response.

[iv] - (From: Thompson AJ. Genetic factors and hepatitis C virus infection. Gastroenterology 2012 May;142(6):1335-1339)

The rs12979860 polymorphism has three possible genotypes (C/C, C/T, T/T), with C/C showing 2.5 or grater rate of SVR during therapy with peg-interferon and ribavirin.

The rs 8099917 polymorphisms has G/G, G/T, T/T genotypes. T/T genotype associates with higher SVR.

In G1 infected naive-patients eligible for antiviral therapy, the response after the “lead-in” phase and IL28B genotype are the most powerful predictors of response. In selective cases, when the benefit versus risk ratio is difficult to define IL28 may support the final decision.

References

1 - L. B Seeff, F. B Hollinger, H. J Alter, E. C Wright, C. M Cain, Z. J Buskell, et alLong-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: A National Heart, Lung, and Blood Institute collaborative study. Hepatology 2001Feb;332455463
2 - A Wasley, M. J Alter, Epidemiology of hepatitis C: geographic differences and temporal trends. Semin Liver Dis 2000201116
3 - P Marcellin, H Cheinquer, M Curescu, G. M Dusheiko, P Ferenci, A Horban, et alHigh sustained virologic response rates in rapid virologic response patients in the large real-world PROPHESYS cohort confirm results from randomized clinical trials. Hepatology 2012Jun 18.
4 - F Bellanti, G Vendemiale, E Altomare, G Serviddio, The Impact of Interferon lambda 3 gene polymorfism on natural course and treatment of hepatitis C, Clinical and developmental Immunology. Clin Develop Immunol 2012
5 - S. J Hadziyannis, H Sette, Jr., Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004Mar 2;1405346355
6 - Food and drug administrationChronic hepatitic C infection: developing direct acting antiviral agents for treatment. Guidance for Industry 2010
7 - F Dammacco, D Sansonno, C Piccoli, V Racanelli, F. P D’Amore, G Lauletta, The lymphoid system in hepatitis C virus infection: autoimmunity, mixed cryoglobulinemia, and Overt B-cell malignancy. Semin Liver Dis 2000202143157
8 - P Michielsen, E Ho, S Francque, Does antiviral therapy reduce the risk of hepatocellular carcinoma in patients with chronic hepatitis C? Minerva Gastroenterol Dietol 2012Mar;5816579
9 - H. R Rosen, Clinical practice. Chronic hepatitis C infection. N Engl J Med 2011Jun 23;3642524292438
10 - S. L Tan, HCV genome and Life cycle. In: Horizon Bioscience, ed. Hepatitis C Viruses: Genomes and Molecular Biology. 2006
11 - D Brett, et alUnravelling hepatitis C virus replication from genome to function. Nature 2005436933938
12 - A. S Barritt, M. W Fried, Maximizing opportunities and avoiding mistakes in triple therapy for hepatitis C virus. Gastroenterology 2012May;142613141323
13 - C Hezode, N Forestier, G Dusheiko, P Ferenci, S Pol, T Goeser, et alTelaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009Apr 30;3601818391850
14 - I. M Jacobson, J. G Mchutchison, G Dusheiko, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011Jun 23;3642524052416
15 - M. P Manns, A. A Markova, S. B Calle, M Cornberg, Phase III results of Boceprevir in treatment naive patients with chronic hepatitis C genotype 1. Liver Int 2012Feb;32 Suppl 12731
16 - P Marcellin, N Reau, P Ferenci, S Hadziyannis, D Messinger, F Tatsch, et alRefined prediction of week 12 response and SVR based on week 4 response in HCV genotype 1 patients treated with peginterferon alfa-2a (40KD) and ribavirin. J Hepatol 2012Jun;56612761282
17 - S Zeuzem, P Andreone, S Pol, E Lawitz, M Diago, S Roberts, et alTelaprevir for retreatment of HCV infection. N Engl J Med 2011Jun 23;3642524172428
18 - B. R Bacon, S. C Gordon, E Lawitz, P Marcellin, J. M Vierling, S Zeuzem, et alBoceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011Mar 31;3641312071217
19 - C Hezode, Boceprevir and telaprevir for the treatment of chronic hepatitis C: safety management in clinical practice. Liver Int 2012Feb;32 Suppl 13238
20 - A. S Barritt, M. W Fried, Maximizing opportunities and avoiding mistakes in triple therapy for hepatitis C virus. Gastroenterology 2012May;142613141323
21 - J. J Kiser, J. R Burton, P. L Anderson, G. T Everson, Review and management of drug interactions with boceprevir and telaprevir. Hepatology 2012May;55516201628
22 - P Cacoub, M Bourliere, J Lubbe, N Dupin, P Buggisch, G Dusheiko, et alDermatological side effects of hepatitis C and its treatment: patient management in the era of direct-acting antivirals. J Hepatol 2012Feb;562455463
23 - Incivek package2012
24 - M Bourliere, A Khaloun, C Wartelle-bladou, V Oules, I Portal, S Benali, et alFuture treatment of patients with HCV cirrhosis. Liver Int 2012Feb;32 Suppl 1113119
25 - F Poordad, J Mccone, Jr., Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011Mar 31;3641311951206
26 - I. M Jacobson, J. G Mchutchison, G Dusheiko, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011Jun 23;3642524052416
27 - J Ahn, FS. Boceprevir versus telaprevir: a new era of directly acting antiviral therapy. Curr Hepatitis Rep 2012112333