Question

A 65-year-old obese, black, Dominican man with a medical history of hypertension and hyperlipidemia is diagnosed with chronic hepatitis C, genotype 1a with an HCV-RNA = 4 million IU/mL. RAS testing for Y93H was positive. He is going to start therapy for his hepatitis for the first time. His medications at home include: enalapril 10 mg po QD and rosuvastatin 40 mg po QD. His physician insists on keeping all his current medications and asks you for recommendations:

1. Collect

2. Asses

3. Plan

4. Implement

5. Follow-up

Answer 1

1. Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease. Hepatitis C can make it harder for your liver to do its main job: break down and filter out substances from your bloodstream. As a result, medications, herbs, drugs, and alcohol may stay in your system longer, and have a more powerful effect. Some substances pose the risk of serious liver damage.
2. Assessment of liver disease severity is necessary prior to ther- apy. Identifying patients with cirrhosis (METAVIR score F4) or advanced (bridging) fibrosis (METAVIR score F3) is of particular importance, as the choice of treatment regimen and the post- treatment prognosis depend on the stage of fibrosis
3. Boceprevir and telaprevir are inhibitors and substrates of the cytochrome P450 3A4 family. With the use of these HCV protease inhibitors as part of standard therapy for chronic hepatitis C genotype 1 infection, drug–drug interactions with multiple medications being inductors, inhibitors, or substrates of cytochrome P450 3A4 can be expected
4. Statins are effective therapy for hypercholesterolemia and are commonly indicated in patients with HIV and hepatitis C virus infections.
5. Direct-acting antivirals (DAAs) used for the treatment of a chronic hepatitis C virus (HCV) infection are known for their drug-interacting potential. They are both substrates and inhibitors/inducers of drug-metabolizing enzymes and drug transporters, making them victims and perpetrators of drug–drug interactions (DDIs) [1–3].
6. Numerous papers have shown that HCV patients are polypharmacy patients, meaning that they use high numbers of drugs and a diverse combination of medications [4–7]. This includes the usual suspects that we would expect in HCV-infected patients, such as immunosuppressive agents (liver transplantation), antiretroviral agents (HIV co-infection), and psychoactive medications, because of the high incidence of mental illnesses. However, drugs used for cardiovascular risk management are also frequently used by HCV-infected patients, e.g., statins (HMG-CoA reductase inhibitors), anticoagulant agents, and antihypertensive drugs [4–7]. We can explain this by the fact that we are now treating aging HCV-infected patients, and polypharmacy has a positive correlation with age [6–8]. In addition, extrahepatic manifestations associated with HCV such as diabetes mellitus and renal and cardiovascular disease could be an explanation for the use of these kinds of drugs [9, 10].

To date, there are no published reviews in the literature concerning DDIs between cardiovascular drugs (CVDs) and DAAs, despite the fact that cardiovascular agents are one of the most frequently prescribed drugs [4]. For drug interactions with DAAs, the scientific community has focused on the most commonly prescribed drugs in HCV patients. However, in daily practice, clinical pharmacists are frequently asked many questions about combining DAAs with anticoagulation agents, ACE inhibitors, β-blockers, and statins. Some interactions are easy to manage (monitoring blood pressure), whereas others are highly complex due to the metabolic profile of the DAAs and the CVD (e.g., clopidogrel). This is, for instance, reported by de Lorenzo-Pinto et al. [11], who reported a significantly increased acenocoumarol dose because of the interaction with paritraprevir/ritonavir, ombitasvir, and dasabuvir (PrOD). Comparable interaction was seen with warfarin, resulting in a subtherapeutic international normalized ratio (INR) during concomitant treatment with PrOD [11]. Both of these cases showed that there were significant DDIs between anticoagulants and PrOD, making increased monitoring necessary. Other case reports describing severe bradycardia, which even caused death, were reported in patients using amiodarone in combination with sofosbuvir and NS5A inhibitors. This was an unexpected DDI, showing that not all DDIs can be predicted [12, 13].

This review aims to provide clinical guidance to cardiologists managing CVDs when patients are treated with DAAs, hepatologists/infectious disease specialists, and also to other physicians, such as general practitioners, who are now allowed to prescribe the DAAs. All of these physicians should have detailed knowledge of the pharmacotherapy of both disease areas and should be able to choose the appropriate DAA regimen with the least number of DDIs for these patients. The review begins by describing the drug metabolism of DAAs and CVDs and presenting the in vivo drug interactions found in the literature. Next, drug interactions between DAAs and CVDs are predicted based on drug metabolism and drug transport, which are accompanied with recommendations for clinical decision-making.