Hepatitis C Treatment

The paradigm of hepatitis C virus (HCV) treatment has changed drastically in the past 20 years. In the early 1990s, treatment included interferon monotherapy for 48 weeks, resulting in an approximate 10% sustained virologic response (SVR) rates for genotype 1.¹

In 1998, ribavirin was added to interferon to reduce the duration of treatment and to increase SVR rates to about 30%. Many toxicities were associated with this regimen, however, which made many patients ineligible for treatment and completing treatment challenging. By the early 2000s, pegylated interferon formulations had been developed to reduce toxicities and increase SVR rates to about 50%. The first protease inhibitors were approved in 2011 for treatment, leading to SVR rates of about 60% to 80% but also decreasing treatment duration to 24 to 28 weeks. In 2013, the FDA approved the first direct-acting antivirals (DAAs), simeprevir (SIM) and sofosbuvir (SOF). The advent of these agents allowed for interferon-free regimens, reduced the duration of treatment to as little as 12 weeks, and led to SVR rates of about 90%.

There are now 8 FDA-approved medications for HCV treatment, all of which bypass the use of interferon. The use of each medication varies based on HCV genotype, prior treatment exposure, presence of cirrhosis, HCV polymorphism, patient comorbidities, and drug—drug interactions (DDIs). Here is an overview of each FDA-approved HCV medication and its use as recommended by the American Association for the Study of Liver Diseases (AASLD).²

ELBASVIR/GRAZOPREVIR

Elbasvir/grazoprevir (EBR/GZR [Zepatier])3 is FDA-approved for the treatment of HCV genotypes 1 and 4. Baseline nonstructural protein 5A polymorphism testing is required in patients who are being treated for genotype 1a to determine the need for ribavirin and the duration of treatment. EBR/GZR are CYP3A (cytochrome P450, family 3, subfamily A) and P-glycoprotein substrates, though GZR weakly inhibits CYP3A. The effects of EBR/ GZR on other transporters are listed in TABLE 1^3-12. Recommendations for other DDIs can be found in (TABLE 2)^2-12,17 and (TABLE 3)^2-12. EBR/GZR can be taken with or without food, and no dosage adjustments are needed in patients with renal impairment or undergoing hemodialysis. EBR/GZR is contraindicated in patients with Child-Pugh scores B and C because of the lack of data and increases in GZR concentrations, respectively. The overall duration of therapy for EBR/GZR ranges from 12 to 16 weeks.

LEDIPASVIR/SOF

Ledipasvir (LDV)/SOF (Harvoni)4 is FDA approved for the treatment of HCV genotypes 1 and 4 through 6. Ribavirin may be required in combination with LDV/SOF for patients with decompensated cirrhosis or for patients who have received a liver transplant. LDV/SOF medications are not substrates, inhibitors, or inducers of the CYP enzymes. The effects on other transporters are listed in TABLE 1^3-12. Food intake minimally affects LDV/SOF concentrations; however, acid-suppression medications have been shown to decrease LDV concentrations. Therefore, antacids should be taken 4 hours apart from the LDV/SOF dose.

H₂-antagonists should be given simultaneously or 12 hours apart from LDV/SOF, and doses should not exceed famotidine 40 mg twice daily or its equivalent. Proton pump inhibitors (PPIs) can be given simultaneously if a patient is fasting and the dose does not exceed omeprazole 20 mg/day or its equivalent. Other serious DDIs include amiodarone, which has resulted in symptomatic bradycardia; concomitant therapy is not recommended. LDV/SOF should not be used in patients with an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m2 or those undergoing hemodialysis because of the lack of published studies.

LDV/SOF can be used in patients with any degree of hepatic impairment. The duration of therapy is always 12 weeks unless the patient has HCV genotype 1, is treatment naïve, is not cirrhotic, is not co-infected with HIV, and has a pretreatment HCV RNA less than 6 million IU/mL; 8 weeks of therapy is sufficient in these populations.

OMBITASVIR/PARITAPREVIR/RITONAVIR AND DASABUVIR

Ombitasvir/paritaprevir/ritonavir and dasabuvir (OMB/PTV/ RTV and DBV [Viekira Pak and Viekira XR])^5-7 are FDA approved for HCV genotype 1; OMB/PTV/RTV (Technivie)is approved for genotype 4 because DBV is not active against genotype 4. Ribavirin is routinely recommended for use with all 3 combination products unless Viekira Pak or Viekira XR is being used for the treatment of genotype 1b. Although it is not required that Technivie, Viekira XR, and Viekira Pak be taken with food, if prescribed with ribavirin, this is the recommendation because concentrations of ribavirin increase 70% when taken with a high-fat meal.⁸

PTV and RTV are substrates of CYP3A4. RTV is a strong inhibitor of CYP3A4 and leads to numerous DDIs (TABLE 2^2-12,17 and TABLE 3^2-12). For example, RTV can induce the metabolism of PPIs such as omeprazole. Study results have shown a 54% decrease in the area under the concentration time curve (AUC) of omeprazole, requiring higher doses of the drug.^6,7 There are no dosage requirements for patients with renal impairment or those undergoing hemodialysis; however, the use of these drugs is contraindicated in patients with Child-Pugh scores B and C. Treatment duration is typically 12 weeks unless the patient is treated with Viekira Pak or Viekira XR for genotype 1a with compensated cirrhosis; in these cases, treatment is 24 weeks.

TABLE 2. DRUG—DRUG INTERACTIONS WITH ANTIRETROVIRALS

Antiretroviral

SIM

LDV/SOF

DCV

EBR/GZR

OMB/PTV/RTV ± DBV

VLP/SOF

TDF

↑ TDF^a

Monitor

TAF

RPV

↑ RPV;

contraindicated

EFV

↓ SIM; contraindicated

↓ LDV;

not significant

↓ DCV;

DCV 90 mg/day

↓ EBR and GZR;

contraindicated

ND;

contraindicated

↓ VLP;

contraindicated

ETR

↓ SIM; contraindicated

↓ DCV;

DCV 90 mg/day

↓ EBR and GZR;

contraindicated

↓ OMB/PTV/RTV ± DBV;

contraindicated

ND;

contraindicated

ATV

↑ SIM; contraindicated

↑ GZR;

contraindicated

ATV 300 mg/day^b

ATV/r

↑ SIM; contraindicated

↑ ATV and LDV^a

↑ DCV;

DCV 30 mg/day

↑ EBR, GZR, and ATV;

contraindicated

ATV 300 mg/day^b

ATV/c

↑ SIM; contraindicated

↑ DCV;

DCV 30 mg/day

↑ GZR;

contraindicated

DRV/r

↑ SIM; contraindicated

↑ EBR and GZR;

contraindicated

DRV 800 mg/day or 600 mg twice a day^b

DRV/c

↑ SIM; contraindicated

↑ GZR;

contraindicated

ND;

contraindicated

LPV/r

↑ SIM; contraindicated

↑ EBR and GZR;

contraindicated

↑ PTV;

contraindicated

DTG

↑ DTG; ↓ PTV

EVG/c

↑ SIM; contraindicated

↑ DCV;

DCV 30 mg/day

↑ EBR and GZR;

contraindicated

ND;

contraindicated

↑ VLP and COBI

RAL

↑RAL

Green = no interactions thus no adjustments necessary; yellow = dose modifications necessary for at least 1 of the concomitent medications; and red = combination is contraindicated, thus should not be used.ATV = atazanavir; c/COBI = cobicistat; DBV = dasabuvir; DCV = daclatasvir; DRV = darunavir; DTG = dolutegravir; EBR = elbasvir; EFV = efavirenz; ETR = etravirine; EVG = elvitegravir; GZR = grazoprevir; LDV = ledipasvir; LPV = lopinavir; ND = no data; OMB = ombitasvir; PTV = paritaprevir; R = ritonavir; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SIM = simeprevir; SOF = sofosbuvir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; and VLP = velpatasvir.^aLDV/SOF given with TDF and a boosted HIV protease inhibitor, EFV, or RPV can result in increased TDF. Monitor for toxicity.^bRitonavir or cobicistat should not be used with HIV protease inhibitor because Viekira Pak and Technivie already include RTV.Adapted from references 2-12, 17.

SIM

SIM (Olysio)⁹ is FDA-approved for the treatment of HCV genotypes 1 and 4. However, it is recommended by the AASLD for genotype 1 only when given with SOF.² Ribavirin may be administered with SIM and SOF if the patient has compensated cirrhosis. SIM AUC increases less than 60% after a meal, so food intake is recommended with this medication. SIM also is a CYP3A4 substrate and inhibitor, which leads to multiple DDIs (TABLE 2^2—12,17 and TABLE 3^2—12).

TABLE 3. DRUG—DRUG INTERACTIONS WITH HMG-CoA REDUCTASE INHIBITORS

Drug Name

SIM

LDV/SOF

DCV

EBR/GZR

OMB/PTV/RTV ± DBV

VLP/SOF

Atorvastatin

Start low;

maximum dose 40 mg

↑ Statin

↑ Statin;

maximum dose 20 mg

↑ Statin;

contraindicated

Start low and titrate

Fluvastatin

↑ Statin

Start low and titrate

Lovastatin

Start low and titrate

↑ Statin

Start low and titrate

↑ Statin;

contraindicated

Pitavastatin

Start low and titrate

↑ Statin

Pravastatin

Start low and titrate

↑ Statin

↑ Statin;

maximum dose 40 mg

Rosuvastatin

Start at 5 mg;

maximum dose 10 mg

↑ Statin;

contraindicated

↑ Statin

↑ Statin;

maximum dose 10 mg

↑ Statin;

maximum dose 10 mg

↑ Statin;

maximum dose 10 mg

Simvastatin

Start low and titrate

↑ Statin

Start low and titrate

↑ Statin;

contraindicated

Green= no interactions thus no adjustments necessary; yellow= dose modifications necessary for at least 1 of the concomitant medications; and red= combination is contraindicated, thus should not be used.

DBV = dasabuvir; DCV = daclatasvir; EBR = elbasvir; GZR = grazoprevir; HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A; LDV = ledipasvir; OMB = ombitasvir; PTV = paritaprevir; RTV = ritonavir; SIM = simeprevir; SOF = sofosbuvir; VLP, velpatasvir; and ND = no data.

Adapted from references 2-12.

No dosage adjustments are required for patients with renal impairment, and removal by dialysis is unlikely because SIM is highly protein bound. Because high concentrations of SIM have been seen in patients with Child-Pugh scores B and C, its use is contraindicated in these populations. The duration of treatment with SIM is 12 weeks, but it can be 24 weeks in patients with compensated cirrhosis.

SOF

SOF (Sovaldi)¹⁰ is FDA-approved for HCV genotypes 1 through 4; however, it is coformulated with LDV and velpatasvir (VLP), which also are indicated for HCV genotypes 5 and 6. SOF should never be used as monotherapy for HCV. SOF can be taken with or without food, and because it does not affect the CYP enzymes, it has minimal DDIs. A 20-fold increase in SOF metabolite concentration can be seen in patients with an eGFR <30 mL/min/1.73 m2; therefore, use in this population is not recommended. No dosage adjustments are necessary for patients with hepatic impairment, and treatment duration depends on the other medications administered with SOF.

DACLATASVIR

Daclatasvir (DCV [Daklinza])11 is FDA-approved for HCV genotypes 1 and 3 and is recommended by the AASLD for HCV genotype 2.2 DCV must always be given with SOF and can be taken with or without food. Because it is a substrate of CYP3A4, the dosage should be reduced to 30 mg/day or increased to 90 mg/day if administered with an inhibitor or inducer, respectively. Dosage adjustments are not required in patients with renal or hepatic impairment. The duration of treatment with DCV is typically 12 weeks; however, 24 weeks may be necessary in patients with compensated cirrhosis.

VLP/SOF

VLP/SOF (Epclusa)¹² is the only product on the market that is indicated for the treatment of all HCV genotypes; it can be taken with or without food. VLP is a CYP3A4 substrate along with other enzymes (TABLE 1^3—12). Common DDIs are listed in TABLE 2^2—12,17 and TABLE 3^2—12 Antacids should be taken 4 hours apart from VLP/SOF. H₂-antagonists should be given simultaneously or 12 hours apart, with doses that do not exceed famotidine 40 mg twice daily or its equivalent. PPIs are not recommended for use because of the lack of data; however, if the benefits outweigh the risks, then VLP/SOF can be given 4 hours before omeprazole 20 mg or its equivalent with food. Treatment with VLP/SOF does not require any dosage adjustments in people with hepatic impairment; it has not been studied in patients with an eGFR <30 mL/min/1.73 m2, however. The duration of treatment with VLP/SOF is 12 weeks.

PIPELINE MEDICATIONS¹³

Glecaprevir/pibrentasvir is being studied by AbbVie for the treatment of HCV genotypes 1 and 3 through 6 in patients with kidney disease stages 4 and 5. In a study of 104 patients with HCV, SVR12 rates of 98% were observed.¹⁴ The duration of treatment was 12 weeks, but other study results regarding HCV genotype 1 in noncirrhotic patients have demonstrated treatment durations as low as 8 weeks.¹³ A new drug application (NDA) was submitted to the FDA in December 2016.

A combination of SOF/VLP/voxilaprevir is being studied by Gilead Sciences for salvage therapy in patients who previously failed DAAs, including LDV, DCV, and OMB. Genotypes 1 through 6 were studied, and SVR12 rates of 96% were seen after 12 weeks of treatment.¹⁵ In treatment-naïve patients, the duration of therapy can be 8 weeks. An NDA was submitted to the FDA in December 2016.

Merck & Co. is studying GZR, ruzasvir, and uprifosbuvir for the treatment of genotypes 1 through 3, resulting in SVR12 rates of 86% to 100%. Recent study results have demonstrated the benefit of this regimen in patients who previously failed DAAs.¹⁶ Odalasvir, AL-335, sovaprevir, and ACH-3422 also are being studied in various combinations with SIM by Janssen Pharmaceutical and Achillion Pharmaceuticals to identify lower pill burden and treatment duration regimens. These drugs are in phase 1 and 2 clinical trials.¹⁷

CONCLUSION

The availability of effective and well-tolerated regimens has revolutionized the treatment of patients with HCV. Because of the high numbers of patients awaiting treatment and the increasing number of therapies available, health care practitioners have a high likelihood of treating patients who are using one of these agents.

Dr. Binkley is a clinical pharmacy specialist in infectious diseases at Penn Presbyterian Medical Center in Philadelphia.Dr. Pandit is an associate professor and vice chair for research and scholarship in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy in Baltimore.

References

• Manns MP, Foster GR, Rockstroh JK, Zeuzem S, Zoulim F, Houghton M. The way forward in HIV treatment—finding the right path. Nat Rev Drug Discov. 2007;6(12):991-1000.
• American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. AASLD/IDSA website. hcvguidelines.org. Accessed April 6, 2017.
• Zepatier [package insert]. Whitehouse Station, NJ: Merck & Co; 2017.
• Harvoni [package insert]. Foster City, CA: Gilead Sciences, Inc; 2017.
• Technivie [package insert]. North Chicago, IL: Abbvie Inc; 2017.
• Viekira Pak [package insert]. North Chicago, IL: Abbvie Inc; 2017.
• Viekira XR [package insert]. North Chicago, IL: Abbvie Inc; 2017.
• Rebetol [package insert]. Whitehouse Station, NJ: Merck & Co; 2016.
• Olysio [package insert]. Titusville, NJ: Janssen Products; 2017.
• Sovaldi [package insert]. Foster City, CA: Gilead Sciences, Inc; 2017.
• Daklinza [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2017.
• Epclusa [package insert]. Foster City, CA: Gilead Sciences, Inc; 2017.
• Horsley-Silva JL, Vargas HE. New therapies for hepatitis C virus infection. Gastroenterol Hepatol (NY). 2017;13(1):22-31.
• Pugatch D, Lei Y, Kosloski MP, Gane E, et al. EXPEDITION-IV: safety and efficacy of GLE/PIB in adults with renal impairment and chronic hepatitis C virus genotype 1-6 infection. Paper presented at: The Liver Meeting; November 11-15, 2016; Boston. Abstract LB-11.
• American Association for the Study of Liver Diseases. AASLD 2016: 8-week triple combo cures most patients with genotype 1-6 hepatitis C. HIVandHepatitis website. hivandhepatitis.com/hcv-treatment/experimental-hcv-drugs/5926-aasld-2016-8-week-triple-combo-cures-most-patients-with-genotype-1-6-hepatitis-c. Published November 17, 2016. Accessed April 6, 2017.
• American Association for the Study of Liver Diseases. AASLD 2016: grazoprevir triple regimen demonstrates high cure rates, even for hard-to-treat patients. HIVandHepatitis website. hivandhepatitis.com/hcv-treatment/experimental-hcv-drugs/5933-aasld-2016-grazoprevir-triple-regimen-demonstrates-high-cure-rates-even-for-hard-to-treat-patients. Published November 17, 20 Accessed April 6, 2017.
• Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. AIDSinfo website. aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed April 13, 20