Update on the Management and Treatment of Hepatitis C Virus Infection: Recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office

ADDITIONAL GROUPS WITH SPECIAL CONSIDERATIONS FOR THERAPYThe following supplemental recommendations for each subgroup of patients have taken into account the natural history of disease, the likelihood of achieving an sustained virologic response (SVR), and the adverse effects and need for dose discontinuations with treatment.

 

I. TREATMENT FOR GENOTYPE 2- AND 3-INFECTED PATIENTS

The optimal treatment for HCV genotype 2 or 3 infection remains peginterferon alfa (PegIFN) and ribavirin (RBV) (1).  Data from a small single randomized trial suggest some efficacy of telaprevir against genotype 2 infection, and limited efficacy in genotype 3 infection (2).  Overall, HCV genotype 3 infection is less responsive to PegIFN and RBV than is genotype 2 (SVR 66-79% and 75-93%, respectively) (3, 4).  SVR was associated with low baseline HCV RNA (<600,000 IU/ml), minimal fibrosis, lower body weight, age <40, and higher ALT (5-7).  Several studies suggest that weight-based dosing of RBV in genotype 3 is superior to fixed dosing, particularly in short course therapy, with lower relapse rates (6, 8, 9).  These studies suggest that treatment duration, clinical factors associated with impaired response to PegIFN and RBV, and RBV dose should be considered carefully (3, 6, 10).

 

The most important predictor of SVR for genotype 2 or 3 infection remains achievement of rapid virologic response (RVR), with SVR rates of >80% with 24 weeks of therapy; if RVR is not achieved, SVR occurs in only 50-60% of patients (11).  In genotype 2-infected patients who achieve RVR, a treatment duration of 12-16 weeks might be sufficient but higher relapse rates (10-30%) have been reported (12-14).  In genotype 3-infected patients with low baseline viral load (HCV RNA <600,000 IU/ml) and RVR, SVR rates are similar with shortened treatment duration (12-16 weeks) versus standard therapy (24 weeks) (6, 12-15).  Based on unacceptably high relapse rates, a shortened treatment duration is not recommended in genotype 3-infected patients with high baseline HCV RNA (>600,000 IU/ml), METAVIR 3 or 4 fibrosis, obesity, metabolic risk factors or viral co-infections (6, 16).

 

Data of a retrospective pooled analysis of registration studies in non-RVR patients showed superior treatment outcome with weight based ribavirin and up to 48 weeks of therapy (17).  The role of treatment beyond 24 weeks has been evaluated only in a single prospective study (9). Treatment up to 36 weeks in genotype 3-infected patients without RVR resulted in a small but statistically insignificant, improvement in SVR as compared to treatment with 24 weeks (62% and 51%, respectively).

 

The decision to retreat a patient with genotype 2 or 3 infection should take into account prior treatment regimen, duration, and response.  Several trials have examined retreatment of genotype 2 and 3 infection, with SVR rates ranging from 53-63% with 48 weeks of therapy (18-21).  EPIC 3 enrolled 367 genotype 2- and 3-infected treatment-experienced patients and reported SVR rates of  59% (genotype 2) and 55% (genotype 3),  respectively.  Relapsers had an SVR rate of 61%, whereas nonresponders had an SVR rate of 46%.  Favorable predictors of retreatment response were: genotype (2 or 3 versus 1), low fibrosis score, previous treatment type, low viral load (<600,000 IU/ml), and previous response (relapser versus non-responder) (21).

Recommendations for treatment-naïve and –experienced patients with genotype 2 or 3 infection:

#36. Treatment-naïve patients should be treated with peginterferon-ribavirin for 24 weeks (Class I, Level A).

#37. For patients with low viral load (HCV RNA <600,000 IU/ml) and mild fibrosis who achieve a rapid virologic response, 12-18 weeks of treatment may be sufficient (Class I, Level A).

#38. For patients with genotype 3 infection and a high HCV RNA (>600,000 IU/ml), steatosis or advanced fibrosis, treatment beyond 24 weeks may improve response (Class I, Level B).

#39. Retreatment duration is 48 weeks (Class I, Level A).

 

II. PATIENTS WITH GENOTYPE 4-6 INFECTION

Patients with genotype 4 infection have higher SVR rates (69-79%) than patients with genotype 1 infection when treated with PegIFN and RBV for 48 weeks(22-24).  Insufficient clinical trial data are available in patients with HCV genotypes 5 and 6 to make treatment recommendations about optimal regimens at this time.

 

Recommendations in patients with genotype 4 infection:

#40. Appropriate candidates with HCV genotype 4 infection should be treated with peginterferon alfa-2a 180 mcg/week or peginterferon alfa-2b 1.5 mcg/kg/week plus ribavirin up to 1,400 mg/day for 48 weeks (Class I, Level A).

 

III. PATIENTS WITH Persistently Normal Serum ALT

Up to 20% of patients with persistently normal ALT have bridging fibrosis or cirrhosis (25).  Consequently, ALT elevation has not been an inclusion criterion in most recent clinical trials (26-29) and a normal ALT does not exclude patients from HCV treatment.

 

IV. PATIENTS WITH DECOMPENSATED CIRRHOSIS

Once clinical decompensation occurs,  as defined by variceal bleeding, formation of ascites, development of portosystemic encephalopathy, jaundice, or early-stage hepatocellular carcinoma, liver transplantation is the treatment of choice.  HCV therapy is contraindicated in patients with decompensated cirrhosis because of an increased risk of  life-threatening bacterial infections and further hepatic decompensation.  In 2003, an expert panel proposed that patients with HCV cirrhosis and a Child-Pugh score <7 and MELD ≤18 should be considered for antiviral therapy.  The panel further proposed that patients with Child-Pugh scores >11 or MELD >25 should not be treated.  Those with intermediate scores could be considered on a case-by-case basis (30). Several studies have examined the treatment of decompensated cirrhotics with standard interferon-ribavirin or peginterferon-ribavirin therapy (31-35).  SVR rates were consistently low in genotype 1- infected patients, ranging from 7% to 30%.  There are limited pharmacokinetic data on boceprevir in patients with hepatic decompensation, although telaprevir exposure is reduced by 46% in patients with Child-Pugh Class B.  Thus, telaprevir and boceprevir should not be administered to patients with hepatic decompensation (Child-Pugh Class B or C, score ≥7).  Treatment-naïve patients with low Child-Pugh and MELD scores who have favorable predictors of response such as genotype 2 or 3 infection may be considered for therapy with peginterferon and ribavirin, despite a history of clinical complications of liver disease.

 

Recommendations in patients with decompensated cirrhosis:

#41. Liver transplantation is the treatment of choice in patients with decompensated cirrhosis (Class I, Level B).

#42. Antiviral therapy is contraindicated in most patients with decompensated cirrhosis (Class II, Level B).

#43. Interferon-based therapy in combination with ribavirin may be considered in patients awaiting liver transplantation with a Child-Pugh score <7 and a MELD score ≤18 (Class I, Level A).

#44. If antiviral therapy is undertaken, reduced interferon doses should be used and growth factors can be given to counteract treatment-associated cytopenias (Class II, Level B).

 

V. PATIENTS WITH A HISTORY OF SOLID ORGAN TRANSPLANTATION

In general, interferon therapy is contraindicated in renal, cardiac, or pulmonary transplant recipients because of an increased risk of severe allograft rejection.  Treatment of HCV prior to transplant is advisable in patients who are otherwise good candidates for solid organ transplant.

 

After liver transplantation for HCV-related disease, graft reinfection is virtually universal.  The timing of treatment for hepatitis C has been evaluated in multiple small trials.  Pre-emptive therapy early after transplant is limited by significant adverse events, high patient dropout rates, and poor SVR rates.  Patients with at least stage 2 fibrosis on liver histology from recurrent HCV disease may be considered for antiviral therapy under the guidance of a transplant specialist.  Limited data suggest that treatment response in liver allograft recipients is lower than in immunocompetent individuals (36-39). Overall SVR was approximately 20-30% with 48 weeks of peginterferon alfa with or without ribavirin, but SVR may be somewhat higher with genotype 2 or 3 infection (37, 39).  Dose reductions for cytopenias are common and early growth factor support and/or transfusions are often necessary.  Based on small case series, the incidence of acute cellular rejection associated with peginterferon alfa appears higher than for standard interferon, so immunosuppression must be maintained and patients must be monitored closely (40).  HCV antiviral treatment with boceprevir or telaprevir combined with peginterferon-ribavirin is not routinely recommended because safety and efficacy data are not available in this population.  In addition, significant drug-drug interactions with boceprevir or telaprevir can occur with concomitant administration of certain immunosuppressants.  (Refer to Supplementary Table 2 on Drug-Drug Interactions).  The optimal treatment regimen in these patients remains to be defined.  If treatment is undertaken, therapy should be co-managed with a multidisciplinary team that includes experienced HCV providers and transplant specialists.

 

Recommendations in patients following solid organ transplantation:

#45. Interferon-based antiviral therapy is contraindicated following heart, lung or kidney transplantation (Class III, Level C).

#46. In patients with biopsy-proven chronic HCV disease following liver transplantation, peginterferon-ribavirin for 48 weeks may be considered (Class IIa, Level B).

#47. Toxicities of antiviral therapy should be managed with frequent monitoring, dose reductions and growth factor support (Class IIa, Level B).

#48. Post-liver transplant patients on antiviral therapy should be monitored closely for evidence of rejection and antiviral therapy should be stopped if rejection is documented (Class IIa, Level B).

#49. Pre-emptive antiviral therapy early post-transplantation in patients without histological recurrence should be avoided (Class IIa, Level B).

 

VI. PATIENTS WITH RENAL DISEASE INCLUDING HEMODIALYSIS

HCV infection is an independent predictor of morbidity and mortality due to increased progression to cirrhosis and hepatocellular carcinoma in patients with chronic kidney disease (CKD) (41, 42).  HCV-infected patients have a higher mortality rate post-renal transplant and reduced graft survival (43, 44).  Interferon remains contraindicated post-renal transplant; therefore, it is recommended to treat HCV infection in patients with concomitant kidney disease prior to kidney transplantation (45).

 

If treatment is undertaken, therapy should be co-managed with a multidisciplinary team that includes experienced HCV providers and renal specialists.  PegIFN needs to be renally adjusted for creatinine clearance below 50 ml/min (Refer to Table 3 in Main Document) (46-52). Based on pharmacokinetic studies, low doses of ribavirin (CopegusÒ) have been FDA-approved for use in CKD or hemodialysis patients (Refer to Table 3 in Main Document) (53, 54).  Increased side effects including severe hemolytic anemia requiring growth factors can occur.

 

A meta-analysis of 28 clinical trials reported an overall SVR of 39% and dropout rate of 19% in dialysis patients receiving standard interferon monotherapy (48).  Another meta-analysis of 16 clinical trials of PegINF monotherapy in dialysis patients showed comparable SVR rates, but found PegINF to be poorly tolerated (SVR 33%; dropout rate 23%) (49). Small studies of standard IFN or PegIFN plus ribavirin (200 mg/day or 200 mg thrice weekly), however, found SVR rates in over 50% of dialysis patients if hemoglobin levels were maintained by erythropoietin and iron therapy (55-58). As HCV treatment in post-renal transplant patients has achieved only low SVR rates and graft rejection is a serious problem (59, 60) anti-HCV therapy post renal transplant is not recommended, although there may be a role in rare cases of acute, fibrosing cholestatic hepatitis (61).

 

Efficacy data with protease inhibitor triple therapy in patients with CKD are lacking.  No dosage adjustment of telaprevir or boceprevir is required in patients with any degree of renal impairment.  The pharmacokinetics of telaprevir following a single dose of 750 mg has been evaluated in HCV-negative patients with Clcr <30 ml/min but telaprevir has not been evaluated in patients with ESRD or those on dialysis.  The pharmacokinetics of boceprevir following a single 800 mg dose was evaluated in HCV-negative patients on dialysis; the mean AUC of BOC was 10% lower and <1% of BOC was removed by hemodialysis. In HCV-infected patients, telaprevir has not been evaluated in those with Clcr ≤50 ml/min. Boceprevir has not been evaluated in HCV-infected patients with renal impairment (62, 63).

 

Recommendations in patients with renal disease:

#50. Patients should be considered for antiviral therapy with interferon (standard or pegylated) with ribavirin at modified doses (Table 3) (Class IIa, Level C).

#51. Antiviral therapy for HCV treatment is not recommended in patients post-renal transplant; however, it may be considered if patients develop fibrosing cholestatic hepatitis (Class III, Level C).

 

VII. Patients Age >65 and/or With Significant Comorbidities  

Before treatment is undertaken in patients >65 years old and/or in those with significant concomitant medical problems (e.g., coronary artery disease, diabetes, renal insufficiency, or chronic obstructive pulmonary disease), careful consideration to initiating therapy should be undertaken in light of reduced life expectancy and increased risk of adverse events.  However, age greater than 65 years per se is not a contraindication to treatment with peginterferon-ribavirin-protease inhibitor therapy.

 

Recommendations in patients with comorbid conditions:

#52. In patients with limited life expectancy from comorbid conditions, antiviral therapy is not recommended (Class I, Level C).

#53. In patients with significant comorbid conditions that will be exacerbated by peginterferon-ribavirin, treatment should be deferred (Class I, Level C).

 

VIII. PATIENTS ON METHADONE MAINTENANCE/OPIATE REPLACEMENT THERAPY

Patients receiving stable methadone doses and who have not used injection drugs for  six months may benefit from peginterferon-ribavirin treatment (64, 65). Patients receiving methadone maintenance have higher discontinuation rates, but theSVR rate among those who completed treatment was similar to the SVR among patients not on methadone.  Limited data are available about the use of peginterferon-ribavirin-protease inhibitor therapy in patients receiving methadone.  When co-administered with telaprevir, methadone levels in the blood are reduced but only clinical monitoring and possible methadone dose-adjustment are recommended (63).  Co-administration with boceprevir can potentially either raise or lower blood levels of methadone or buprenorphine; clinical monitoring is recommended (62).

 

Recommendations for patients on methadone:

#54. Antiviral therapy should be offered to patients enrolled in a methadone maintenance program who meet criteria for therapy (Class I, Level A).

#55. Treatment should be coordinated between HCV treatment providers and substance abuse specialists (Class I, Level B).

 

IX. PATIENTS WITH AT-RISKALCOHOL USE

To reduce the risk of liver disease progression, patients with HCV should limit or abstain from alcohol consumption.  Abstinence from alcohol for six months prior to HCV therapy is usually recommended despite limited data to indicate that treatment responses are improved.  Patients who drink alcohol have greater early treatment discontinuation rates with interferon-based therapy. However, among those who completed therapy, SVR rates were similar in drinkers and nondrinkers (66).

Recommendations in patients with ongoing alcohol use:

#56. Patients should be encouraged to decrease alcohol consumption or to abstain, and should be referred for behavioral intervention to reduce alcohol use (Class I, Level B).

#57. Antiviral therapy should be offered to patients who are otherwise appropriate candidates regardless of prior alcohol use (Class I, Level B).

#58. Alcohol consumption should be discouraged during antiviral treatment because alcohol reduces adherence and treatment response (Class I, Level B).

 

X. PATIENTS WITH BODY MASS INDEX >30 AND HEPATIC STEATOSIS

In multivariate analyses from two large registration trials of PegIFN and RBV, increased body weight was associated with decreased antiviral response (5, 67).  Lifestyle changes such as exercise and weight loss should be recommended as adjuncts to antiviral therapy. Metabolic disorders should be managed aggressively prior to interferon therapy.

 

Recommendations in obese patients and those with hepatic steatosis:

#59. Patients with a body mass index >30 should be considered for antiviral treatment (Class I, Level A).

#60. Comorbid conditions common in obese patients such as diabetes, hypertension and hyperlipidemia should be controlled prior to initiation of antiviral therapy (Class I, Level C).

 

XI. PATIENTS WITH HIV/HCV Coinfection

The combination of PegIFN and RBV remains the current standard of care for the treatment of HIV/HCV coinfection.  Three pivotal trials established that combination therapy with PegIFN (alfa-2a or alfa-2b) plus ribavirin was superior to combination therapy with standard interferon plus ribavirin (68-70).  Initial trials in HIV/HCV co-infected patients used lower RBV doses of 800 mg/day, which resulted in lower SVR rates among genotype 1 infected subjects.  The PRESCO trial employed RBV 1000-1200 mg daily in HIV/HCV coinfected patients, at times with extended duration of therapy; SVR rates were achieved in 35% of those with genotype 1 infection and 72% with genotype 2/3 infection (71).  Thus higher RBV doses may be preferable to lower doses, although additional studies are needed.  Cytopenias related to HCV antiviral treatment are more common, and may require erythropoietin and granulocyte colony stimulating factors in order to continue therapy.  Concomitant use of didanosine and ribavirin should be avoided. HIV/HCV coinfected patients with cirrhosis and a Child-Pugh score >6 should not receive HCV antiviral therapy.  For more information, see VA Recommendations for the Treatment and Management of Hepatitis C Virus Infection in Patients with HIV Infection (72).

 

Recommendations in patients with HIV-HCV coinfection:

#61. Patients with controlled HIV infection and evidence of liver disease on biopsy should be considered for HCV antiviral therapy (Class I, Level B).

#62. Patients should be treated with peginterferon-ribavirin at doses similar to those with HCV monoinfection (Class I, Level B).

#63. Patients should be treated with peginterferon-ribavirin for 48 weeks, regardless of genotype (Class I, Level A).

 

XII. HBV/HCV COINFECTION

Patients with HBV/HCV coinfection have an increased risk for cirrhosis, HCC and death. Pre-treatment detailed serological and virological evaluations are required for HBV/HCV coinfected patients before antiviral therapy.  PegIFN and RBV has been successfully used to treat HCV in HBV coinfected patients. No data are available on the use of HCV protease inhibitors in HBV/HCV coinfected patients although there is no reason why coinfection with HBV would deter use of a protease inhibitor.  After reaching SVR for HCV infection, HBV rebound may occur and thus, close monitoring for both viruses is recommended even for patients with initially suppressed HBV DNA. In some instances, treatment with PegIFN and RBV has successfully cleared hepatitis C and hepatitis B infection (73).

 

XIII. ACUTE HEPATITIS C

Studies of treatment for acute HCV infection have been heterogeneous and limited by small sample size, lack of randomization, differences in dose and schedule of administration, and duration of follow-up.  Because spontaneous viral clearance  usually occurs within the first three to six months of exposure, most studies have delayed treatment for 12 weeks after diagnosis (74, 75).  Studies with peginterferon alfa or interferon alfa monotherapy for 24 weeks have resulted in SVR of 80-100%.  The addition of ribavirin differs among experts.  Appropriate management of acute infection in active injection drug users is difficult. More than one third of such patients decline treatment, and of those who initiate therapy, fewer than half complete treatment, largely because of dose-limiting psychiatric side effects (76).

 

Recommendations in patients with acute HCV infection:

#64. Patients should be observed for a period of 8-20 weeks from time of initial exposure to monitor for spontaneous resolution of infection (Class I, Level C).

#65. For those who fail to resolve infection spontaneously, treatment should be initiated with peginterferon alfa with or without ribavirin for 24-48 weeks, based on genotype and HCV RNA response during therapy (Class I, Level B).

Contributors

Veterans Health Administration, Office of Public Health/Clinical Public Health, Washington, DC: Janet Durfee, RN, MSN, APRN (acting chief consultant); Technical Advisory Group: Matt B. Goetz, MD, Samuel B. Ho, MD; Core Working Group for the VA HCV Treatment Recommendations: Helen S. Yee, PharmD, Michael F. Chang, MD, Christine Pocha, MD, Joseph Lim, MD, David Ross, MD, PhD, Timothy R. Morgan, MD, and Alexander Monto, MD

 


Supplemental Table 1: Treatment Monitoring Guidelines for Patients on Peginterferon-Ribavirin ± Protease Inhibitor (Boceprevir or Telaprevir)

 

 

 

Week

Necessary

0

2

4

8

12

 

24

Every

4-weeks

Thereafter

End-of-

Treatment

 

24 weeks

Post-treatment

HCV RNA

 

Follow Algorithm for additional timepoints

CBC with differential

√*

Liver function tests

√*

Psychiatric/Substance Use Screening

√*

Renal panel

*

Glucose

*

TSH

*

Uric acid (if on telaprevir)

*

Pregnancy test

Recommended

 

 

 

 

 

 

Fundoscopic Exam**

 

 

 

 

 

Urine Toxicology Screen

 

 

 

 

 

*Intervals may need to be increased based on patient tolerance and response to treatment in patients with significant declines in blood counts, renal insufficiency, diabetes, cirrhosis or other indications.

**Recommended for all patients at baseline and periodically during antiviral treatment in patients with diabetes, hypertension or as needed for visual complaints.

 

 

 

Supplemental Table 2: Telaprevir and Boceprevir Drug-Drug Interactions

Contraindicated Drugs

(those that strongly inhibit or induce CYP3A4)

Class/Drug

DDI effect on the Class/Drug

DDI effect on Telaprevir

DDI effect on Boceprevir

Recommendations/

Comments

Alfuzosin ↑ alfuzosin levels leading to

↑ potential for arrhythmias and hypotension

↔ telaprevir ↔ boceprevir Do not co-administer with telaprevir or boceprevir.

 

 

Anticonvulsants

carbamazepine, phenytoin, phenobarbital

↔ phenytoin, carbamazepine, and phenobarbital levels Not contraindicated with telaprevir.  Refer to Established or Potentially Significant Drug-Drug Interactions ↓ boceprevir levels potentially leading to a loss of virologic response  to boceprevir Do not co-administer with boceprevir.

 

For use with telaprevir: Refer to Established or Potentially Significant Drug-Drug Interactions. Caution is warranted with telaprevir co-administration; clinical and lab monitoring recommended.

Benzodiazepines

triazolam and oral midazolam

↑ BZD levels leading to

↑ potential for prolonged sedation or respiratory depression

↔ telaprevir ↔ boceprevir Do not co-administer with telaprevir or boceprevir.

 

Refer to Established and Potentially Significant Drug-Drug Interactions with other benzodiazepines.

Cisapride ↑ cisapride levels leading to

↑ potential for arrhythmias

↔ telaprevir ↔ boceprevir Do not co-administer with telaprevir or boceprevir.
Drosperinone ↑ drosperinone levels leading to

↑ potential for hyperkalemia

Not contraindicated with telaprevir ↔ boceprevir Do not co-administer with boceprevir.

 

Refer to Established or Potentially Significant Drug-Drug Interactions with oral contraceptives and

boceprevir or telaprevir.

Ergot Derivatives

dihydroergotamine, ergonovine, ergotamine, methylergonovine

↑ levels of ergot derivatives potentially leading to ergot toxicity (characterized by peripheral vasospasm or ischemia)

 

↔ telaprevir ↔ boceprevir Do not co-administer with telaprevir or boceprevir.
HMG CoA Reductase Inhibitors

simvastatin, lovastatin, atorvastatin

 

↑ levels of HMG CoA Reductase Inhibitors potentially leading to myopathy, including rhabdomyolysis ↔ telaprevir ↔ boceprevir Do not co-administer with telaprevir.

 

For use with boceprevir:  Do not co-administer simvastatin or lovastatin with boceprevir.  Atorvastatin co-administration with boceprevir is not contraindicated.  If atorvastatin is co-administered with boceprevir, titrate atorvastatin carefully and do not exceed 20 mg/day.

PDE-5 inhibitors for Pulmonary Hypertension*

sildenafil (Revatio®),

tadalafil (Adcirca®)

 

↑ levels of PDE-5 inhibitors potentially leading to visual abnormalities, hypotension, prolonged erection, and syncope. ↔ telaprevir ↔ boceprevir Do not co-administer with telaprevir or boceprevir.

*If PDE-5 Inhibitors are used for erectile dysfunction, refer to Established or Potentially Significant Drug-Drug Interactions for recommendations.

Pimozide ↑ levels of pimozide potentially increasing the risk for arrhythmias ↔ telaprevir ↔ boceprevir Do not co-administer with telaprevir or boceprevir.
Rifampin ↔ rifampin ↓ telaprevir levels potentially leading to a loss of virologic response ↓ boceprevir levels potentially leading to a loss of virologic response Do not co-administer with telaprevir or boceprevir.
St. John’s Wort ↔  St. John’s Wort ↓ telaprevir levels potentially leading to a loss of virologic response ↓ boceprevir levels potentially leading to a loss of virologic response Do not co-administer with telaprevir or boceprevir.

Established (in trials) or Potentially Significant (predicted but not yet studied) Drug-Drug Interactions

Class

(drug)

DDI effect on the Class/Drug

DDI effect on Telaprevir

DDI effect on Boceprevir

Recommendations/

Comments

Antiarrhythmics

systemic lidocaine*, amiodarone, bepridil, flecainide, propafenone, quinidine

↑ antiarrhythmics

 

*Systemic lidocaine is not listed as DDI with boceprevir

↔ telaprevir

(Potentially Significant DDI)

↔ boceprevir

(Potentially Significant DDI except with systemic lidocaine)

For use with telaprevir or boceprevir:   Caution warranted and clinical monitoring recommended if co-administered with antiarrhythmics .

*Systemic lidocaine is not listed as DDI with boceprevir.

Antibacterial agents clarithromycin, erythromycin, telithromycin

 

↑  clarithromycin

↑  erythromycin (with telaprevir)

↑ telithromycin (with telaprevir)

↑ telaprevir

(Potentially Significant DDI)

↔ boceprevir

(Potentially Significant DDI)

For use with telaprevir:   Caution warranted and clinical monitoring recommended when co-administered.

For use with boceprevir:  Clarithromycin dose adjustment is not necessary with normal renal function.

Anticonvulsants carbamazepine, phenobarbital, phenytoin

 

↑carbamazepine

↑ or ↓phenytoin

↑ or ↓phenobarbital

↓ telaprevir

(Potentially Significant DDI)

 

↓ boceprevir  (Contraindicated with boceprevir ) For use with telaprevir:    Caution warranted and clinical monitoring recommended when co-administered with anticonvulsants.

For use with boceprevir: Refer to Contraindicated Drugs.

Antidepressants

desipramine, trazodone, escitalopram

 

↑ desipramine

↑ trazodone

↓ escitalopram

 

↔ telaprevir

(Established DDI with escitalopram; Potentially Significant DDI with desipramine, trazodone)

↔ boceprevir

(Potentially Significant DDI with desipramine and trazodone)

For use with telaprevir or boceprevir:   Caution warranted when co-administered with antidepressants. Consider lowering dose of desipramine or trazodone. Escitalopram dose may need to be adjusted when co-administered with telaprevir.
Antifungals

ketoconazole, itraconazole, posaconazole, voriconazole

↑ ketoconazole

↑ itraconazole

↑ posaconazole

↑ voriconazole (with boceprevir) and

↑ or ↓ voriconazole (with telaprevir)

↑ telaprevir

 

(Established DDI with ketoconazole.  Potentially  Significant DDI with other listed antifungals)

↑ boceprevir

 

(Established DDI with ketoconazole.  Potentially  Significant DDI with other listed antifungals)

Caution and clinical monitoring warranted when co-administered with antifungals.

For use with telaprevir: Do not exceed 200 mg/day of ketoconazole or itraconazole.   Avoid co-administration with voriconazole unless a benefit outweighs risk.

For use with boceprevir: Do not exceed 200 mg/day of ketoconazole or itraconazole.

Atorvastatin ↑ atorvastatin Contraindicated with telaprevir; refer to Contraindicated Drugs ↔ boceprevir

(Potentially Significant DDI)

For use with telaprevir:   Do not co-administer with HMG CoA Reductase Inhibitors: Refer to Contraindicated Drugs.

For use with boceprevir:    Titrate atorvastatin carefully and do not exceed 20mg/day.  Simvastatin and lovastatin coadministration are contraindicated; refer to Contraindicated Drugs.

Benzodiazepines

alprazolam, IV midazolam

↑ alprazolam

↑ IV midazolam

↔ telaprevir

(Established DDI)

 

↔ boceprevir

(Potentially Significant DDI)

Triazolam and oral midazolam are contraindicated with telaprevir or boceprevir; refer to Contraindicated Drugs.

For use with telaprevir:  Clinical monitoring warranted. Dose reduction of IV midazolam should be considered, especially if greater than a single dose is needed.

For use with boceprevir: Clinical monitoring warranted. Lower doses of midazolam IV or alprazolam should be considered.

Bosentan ↑ bosentan ↔ telaprevir

(Potentially Significant DDI)

↔ boceprevir

(Potentially Significant DDI)

For use with telaprevir or boceprevir:   Caution warranted and clinical monitoring recommended if co-administered.
Calcium channel blockers amlodipine, diltiazem, felodipine, nicardipine, nifedipine, and nisoldipine,  verapamil ↑ calcium channel blocker levels ↔ telaprevir

(Established DDI with amlodipine)

↔ boceprevir   (Established DDI with felodipine, nicardipine, nifedipine) For use with telaprevir or boceprevir:  Caution warranted if coadministered. Consider dose reduction and clinical monitoring recommended.

 

Colchicine ↑ colchicine ↔ telaprevir

(Potentially Significant DDI)

↔ boceprevir

(Potentially Significant DDI)

For use with telaprevir and boceprevir:  Avoid coadministration in renal or hepatic impairment (↑ risk of colchicine toxicity).

Colchicine dose reduction is necessary if co-administered with telaprevir or boceprevir in patients with normal renal and hepatic function:

Gout treatment:  0.6 mg for 1 dose, followed by 0.3 mg approx 1 hour later. Do not repeat dose before 3 days.

Gout prophylaxis: If original regimen was 0.6 mg twice a day, reduce dose to 0.3 mg daily.  If original regimen was 0.6 mg daily, reduce dose to 0.3 mg every other day.

Treatment of familial Mediterranean fever (FMF):  Maximum dose of 0.6 mg daily (or 0.3 mg twice a day).

Corticosteroids

systemic prednisone, systemic methylprednisolone, systemic dexamethasone, inhaled/nasal fluticasone and budesonide

↑ prednisone

↑ methylprednisolone

↑ fluticasone

↑budesonide

↔ dexamethasone

 

↓ telaprevir (with dexamethasone only)

 

(Established DDI)

 

↓boceprevir (with dexamethasone only)

 

(Established DDI listed for systemic dexamethasone, inhaled budesonide, and inhaled fluticasone).

For use with telaprevir: Avoid co-administration with systemic corticosteroids.  Avoid co-administration with inhaled/nasal steroids unless benefits outweigh risks of systemic steroids.

For use with boceprevir:  Avoid co-administration with systemic dexamethasone; use with caution if necessary. Avoid co-administration with inhaled steroids over an extended period of time (may decrease serum cortisol levels).

Digoxin ↑ digoxin levels ↔ telaprevir

(Established DDI)

↔ boceprevir

(Potentially Significant DDI)

For use with telaprevir:  Start with lowest dose of digoxin and carefully titrate dose based on serum digoxin levels.
HIV meds

atazanavir/ritonavir,  darunavir/ritonavir, fosamprenavir/ritonavir, lopinavir/ritonavir,

efavirenz,

tenofovir disoproxil fumarate

↑ atazanavir

↓ darunavir

↓ fosamprenavir

↔ lopinavir

↓ efavirenz

↑ tenofovir

 ↓ telaprevir with listed HIV meds except tenofovir

 

↔ telaprevir with tenofovir

 

(Established DDI)

↓ boceprevir with efavirenz, ritonavir

 

↔ boceprevir with tenofovir

 

(Established DDI with efavirenz, ritonavir, tenofovir.  Potentially Significant DDI with other listed HIV meds)

For use with telaprevir:  Avoid co-administration with ritonavir boosted with darunavir, fosamprenavir or lopinavir. Clinical and lab monitoring warranted with tenofovir co-administration; discontinue for tenofovir related toxicities.

 

For use with boceprevir: Avoid co-administration with efavirenz.  Effect of ritonavir-boosted HIV protease inhbitor on boceprevir is unknown.  Clinical and lab monitoring warranted with tenofovir co-administration.

Immunosuppressants cyclosporine, sirolimus

tacrolimus

↑cyclosporine

↑ sirolimus

↑tacrolimus

↔ telaprevir

(Established DDI with cyclosporine and tacrolimus. Potentially Significant DDI with sirolimus)

↔ boceprevir

(Potentially Significant DDI)

For use with telaprevir:  Significantly reduce dose and prolong dosing intervals of immunosuppressants; closely monitor blood levels and side effects.

 

Opioids

methadone, buprenorphine

↓ methadone with telaprevir

↑ or ↓ methadone with boceprevir

↑ or ↓ buprenorphine with boceprevir

↔ telaprevir

(Established DDI with methadone)

↔ boceprevir

(Potentially Significant DDI)

For use with telaprevir or boceprevir: Clinical monitoring is warranted.
Oral contraceptives drospirenone, ethinyl estradiol) ↓ethinyl estradiol

↑ drospirenone (only with boceprevir)

↔ telaprevir

(Established DDI only with ethinyl estradiol)

↔ boceprevir

(Drosperinone is contraindicated with boceprevir )

For use with telaprevir:  Use two effective non-hormonal methods of contraception during treatment and up to two weeks after telaprevir treatment.  After telaprevir has been discontinued for two weeks, oral contraceptives may be used as one of two forms of birth control during treatment and 6 months post-treatment.

For use with boceprevir:   Use two effective non-hormonal methods of contraception during treatment and 6 months post-treatment.

 

PDE-5 Inhibitors for Erectile Dysfunction

sildenafil, tadalafil, vardenafil

↑ sildenafil

↑ vardenfail

↑ tadalafil

↔ telaprevir

(Potentially Significant DDI)

↔ boceprevir

(Potentially Significant DDI)

For use with telaprevir or boceprevir: Do NOT exceed

sildenafil 25 mg in 48 hrs, vardenafil 2.5 mg in 72 hrs  or

tadalafil 10 mg in 72 hrs.

Co-administration is contraindicated if PDE-5 Inhibitors are used for pulmonary hypertension; refer to Contraindicated Drugs.

Rifabutin ↑ rifabutin ↔ telaprevir

(Potentially Significant DDI)

↓ boceprevir

(Potentially Significant DDI)

For use with telaprevir or boceprevir:  Co-administration not recommended.
Salmeterol ↑ salmeterol (potentially leading to increased risk of cardiovascular events) ↔ telaprevir

(Potentially Significant DDI)

↔ boceprevir

(Potentially Significant DDI)

For use with telaprevir or boceprevir:  Co-administration not recommended.
Warfarin ↑ or ↓  warfarin ↔ telaprevir

(Potentially Significant DDI)

↔ boceprevir

(Potentially Significant DDI)

For use with telaprevir or boceprevir: Monitor INR closely.
Zolpidem ↓ zolpidem levels ↔ telaprevir

(Established DDI)

Interaction not studied. For use with telaprevir:    Clinical monitoring and dose titration as needed.

The direction of the arrow (↑ = increase, ↓ = decrease, ↔ = no change) indicates the direction of the change.

 

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Posted on พฤษภาคม 18, 2013, in บทความ. Bookmark the permalink. ใส่ความเห็น.

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