Prevention of Drug-drug Interactions in Hepatitis C

by Jane Kovalevich, PhD, and Gerald Morris, MD           

An estimated 80 million people worldwide live with chronic hepatitis C virus (HCV) infection, with the highest prevalence found in parts of Asia and Africa.^1,2 Approximately 700,000 people worldwide died from HCV in 2013.^2-4 If left untreated, HCV can cause cirrhosis of the liver, hepatocellular carcinoma, and death.^5,6

While successful development of an anti-HCV vaccine has remained elusive, considerable advances have been made in the treatment of HCV. In many individuals, HCV can be cleared from the body by non-interferon direct-acting antivirals (DAAs). These agents target specific nonstructural (NS) agents of the virus and interfere with viral replication and life cycle.⁷ The most advanced DAAs can be taken orally, are well-tolerated, offer short duration treatment regimens, and produce more than 90% cure rates in clinical trials.^8-11

Direct-acting Antivirals

At least 6 genotypes of HCV infection have been identified. Genotype 1 is the most common type and accounts for 46% of all infections worldwide.^1,12,13 Multiple highly effective combination DAA therapies are approved by the Food and Drug Administration (FDA) for the treatment of HCV genotype 1, including sofosbuvir/ledipasvir, sofosbuvir/simiprevir, sofosbuvir/daclatasvir, sofosbuvir/velpatasvir, paritaprevir/ritonavir/ombitasvir/dasabuvir (3D regimen; PrOD), and grazoprevir/elbasvir.^10,11,14-16

The 3D regimen includes: paritaprevir (administered with ritonavir, PTV/r; 150 mg/ 100 mg), ombitasvir (OBV; 25 mg), and dasabuvir (DSV; 250 mg twice daily), with or without weight-based ribavirin.^9,14,17,18 Paritaprevir is a nonstructural protein 3/4A protease inhibitor that is administered with the CYP3A inhibitor ritonavir (PTV/r) to increase plasma concentration and exposure of paritaprevir, allowing for once-daily administration.^9,19 Ombitasvir is an NS5A inhibitor with potent antiviral activity;²⁰ dasabuvir is a non-nucleoside NS5B polymerase inhibitor that interferes with viral replication.²¹

This 3D regimen of PTV/r, ombitasvir, and dasabuvir is highly effective in the treatment of HCV genotype 1 in individuals both new to treatment, and those who have received treatment previously, including those with compensated cirrhosis. All of the available DAA regimens, with the exception of simeprevir/sofosbuvir, are FDA-approved for patients with compensated cirrhosis.¹⁶ Drug interactions were observed with the 3D regimen and some commonly prescribed medications including gemfibrozil, carbamazepine, and contraceptives containing ethinyl estradiol. As liver cirrhosis is a common manifestation of chronic HCV infection, therapies that can be safely and effectively administered in patients with HCV and comorbid cirrhosis can increase treatment options for a greater population of HCV patients.

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 Comorbid Infections, and Drug/Supplement Interactions

Patients with HCV infection often experience both disease-related and nonrelated comorbidities. Additional medications are often indicated for these comorbidities, but the medications can potentially make patients ineligible to receive certain HCV therapeutics.²²

Advanced liver disease commonly results from HCV infection.²² Therefore, medications that depend heavily on metabolism by the liver (eg, boceprevir and telaprevir) should be avoided in HCV patients who have evidence of liver damage.²³ Acetaminophen is largely metabolized by the liver, and a small percentage of the drug is metabolized by cytochrome P450 enzymes into the hepatotoxic metabolite N-acetyl-p-benzoquinone imine (NAPQI).²⁴ Typically, NAPQI is rapidly detoxified by liver glutathione; however, in the cirrhotic state, liver glutathione levels are not sufficient to protect against oxidative damage from NAPQI,²⁴ and acetaminophen should be administered at a significant dose reduction in these patients. ²⁵

Although NSAIDs offer lower hepatotoxicity compared with acetaminophen in healthy individuals, they are also metabolized primarily by hepatic cytochrome P450 enzymes, and reports show use of ibuprofen in individuals with a compromised liver results in increases in hepatic transaminases, indicative of liver injury and potentially unsafe levels of drug in the bloodstream.²⁶ Therefore, dose-adjusted acetaminophen is often prescribed preferentially over NSAIDs in HCV patients with liver disease.²⁶

Patients with HCV infection may also look to complementary and alternative medicine (CAM) for the treatment of their condition.. Examples of CAM therapy often include herbal medicine, dietary supplements, and vitamins. However, use of these therapies among HCV patients may be contraindicated due to the increased risk of hepatotoxicity and the possibility of drug interactions with conventional DAA therapies.

Patients with HCV infection typically take multiple medications for related and nonrelated comorbid conditions such as cirrhosis, postliver transplant, HIV, hypertension, diabetes, anxiety, depression, epilepsy, and hyperlipidemia. Therefore, awareness of potential drug-drug interactions is critical. Unique patient populations with HCV genotype 1 infection who should receive special consideration for drug-drug interactions include persons with advanced (decompensated) cirrhosis, HIV, postliver transplant, obesity, hepatitis B coinfection, end-stage renal disease, as well as people of African descent, women who may be pregnant, and children. ²⁷

Drug interactions were observed with the 3D regimen and some commonly prescribed medications including gemfibrozil, carbamazepine, and ethinyl estradiol-containing contraceptives. Also, clinicians should be aware that proton pump inhibitors such as omeprazole can have significant drug interactions with ledipasvir and velpatasvir. Some natural products, such as over-the-counter St. John’s wort, can significantly reduce the efficacy of DAAs.²⁸. Additionally, ritonavir interacts with several classes of drugs including antipsychotics, sedatives/hypnotics, antiarrhythmics, and anti-gout medications.²⁹ Similarly, the coadministration of sofosbuvir with amiodarone can result in life-threatening bradycardia.³⁰

Co-infection with HIV and hepatitis B virus (HBV) may occur in HCV genotype 1 infection. As a result, HIV status should be obtained prior to starting any HCV treatment regimen. Furthermore, HBV testing should be performed due to the increased risk of HBV reactivation in individuals with HIV.³⁰

Ritonavir is a protease inhibitor that may be incorporated into the 3D treatment regimen for HCV and can also be used for the treatment of HIV in combination with additional HIV protease enzyme inhibitors, such as liponavir.³¹ However, if ritonavir is administered in the absence of liponavir or another suitable agent in HIV patients, patients can develop resistance to ritanovir and to subsequent HIV anti-viral treatments.³² Therefore, it is essential that HCV patients be tested for HIV prior to starting any ritonavir regimen.

Many patients are reluctant to undergo HIV testing, so it is important to educate physicians on the necessity of obtaining HIV status prior to starting therapy. Obtaining HIV status is paramount to properly treating HCV infection, particularly since 5% to 10% of HCV patients are also infected with HIV, and HIV co-infection is shown to increase the rate of HCV disease progression^.33 Additionally, the high percentage of HCV patients co-infected with HIV creates the potential for drug-drug interactions occurring between treatment regimens, requiring physicians to carefully balance treatment regimens to maximize therapeutic benefit while minimizing adverse reactions. (Continued on next page)

Measures and Physician Resources for Preventing Drug-drug Interactions

Obtaining and verifying a complete medication history, including prescription and over-the-counter medications, at every clinical visit of HCV-infected patients is a critical step physicians must take to inform dosing recommendations and avoid potentially serious drug-drug interactions. Patients should be encouraged to call their liver specialists with any and all medication changes. When asked about implications of drug-drug interactions in HCV patients and potential preventative measures that can be taken, Jordan Feld, MD, MPH, of Toronto General Hospital Research Institute, stated:

Drug interactions are a potentially serious issue with the new HCV medications. It is critical to get a complete and up-to-date medication history, including over-the-counter, herbal, and non-prescription supplements/medications. I tend to check all medications on all patients using the very useful University of Liverpool drug interaction website.³⁶ Our team pharmacist and our nurses also go over this in detail with the patients before starting; often doctors do not get the best medication history, and getting help from other team members is a good idea.

Resources for drug interactions with HCV medications include the pharmacy filling the prescription and the drug manufacturer. In addition to the University of Liverpool drug interaction website recommended by Dr Feld, which includes an interactive hepatitis drug interaction checker (http://www.hep-druginteractions.org/), several other resources exist to help determine the possibility for drug-drug interactions in the treatment of HCV. The New York and New Jersey AIDS Education and Training Center has released a quick guide for clinicians specifically for treatment of patients co-infected with HIV and HCV, which can be found here: http://www.nynjaetc.org/clinical_support.html. Additionally, the Toronto General Hospital University Health Network website contains drug interaction tables for each of the most common HCV therapeutics (http://www.hcvdruginfo.ca/tables.html). These tables contain additional information about interactions with food and potential treatment-related toxicities that could arise in cases of renal or hepatic impairment.

Conclusion

Although considerable scientific advances have been made in the treatment of chronic HCV infection, these therapies are not without toxicities and the potential for serious drug-drug interactions. Appropriate treatment depends on multiple factors, including HCV genotype and patient medical history, prior treatment regimens, comorbidities, and current medications. Physician obtainment of complete medical history, HIV status, and awareness of the numerous drug-drug interactions that can occur are critical to implementation of safe and effective HCV treatment strategies.

Jane Kovalevich, PhD, and Gerald Morris, MD, are medical writers at HE Institute, located in Ponte Vedra Beach, Florida.

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