PH Professional Network: Drug-Drug Interactions: Treatment Considerations for Pulmonary Hypertension Patients With Human Immunodeficiency Virus and/or Hepatitis C
Managing pulmonary arterial hypertension (PAH) treatment is a complex balance of achieving the desired medication effect versus maintaining safe and tolerable side effects for the patient. The “balancing act” intensifies when PAH patients are faced with multiple disease states that require treatment medication. This article will focus on the drug-drug interactions that must be considered in PAH patients with concomitant human immunodeficiency virus (HIV) and/or hepatitis C virus (HCV) infection.
Both HIV and HCV are infections that are treated with medications that can cause significant and noteworthy drug-drug interactions with PAH medication therapies. The incidence of PAH, as a cardiovascular complication of HIV, is higher in the HIV population than the incidence of PAH for the normal population.1 The first recognized case of HIV-associated PAH was published in 1987,2 and the prevalence of this HIV complication was estimated in the early 1990s to be 0.5%.3 Over time, reported prevalence estimates have varied4; however, the development of highly active antiretroviral therapy (HAART) for the treatment of HIV has not changed the incidence of PAH for this patient population.5–8 PAH associated with HCV occurs as the result of an HCV treatment effect, rather than from the disease itself. A published case series by Renard et al9 suggests that sofosbuvir, an interferon-α medication and mainstay treatment for HCV, may be linked to the new or worsening development of PAH in sofosbuvir-treated HCV patients with other risk factors. Further studies are warranted for this patient population.
Currently approved medications to treat PAH include endothelin receptor antagonists (ERAs), phosphodiesterase-5 (PDE-5) inhibitors, prostacyclin analogs, a prostaglandin I2 receptor agonist, and a soluble guanylate cyclase (sGC) stimulator. Pathophysiologically, these medications undergo hepatic metabolism and thus drug-drug interactions in patients requiring medication for concomitant disease states must be carefully evaluated. PAH patients with HIV and/or HCV are particularly complex as many of the medications used to treat these diseases display drug-drug interactions as a result of how they are metabolized in the body. Table 1 identifies all systemic PAH, HIV, and HCV medications by class.
PATHOPHYSIOLOGY
Drug-drug interactions occur as a result of pharmacokinetic mechanisms that affect absorption, distribution, metabolism, and/or elimination of a medication. Understanding how these principles are affecting the incidence and intensity of a drug-drug interaction is vital to safely administering multiple medications to a single patient.
Many of the PAH-, HIV-, and HCV-specific medications are metabolized by various hepatic cytochrome P-450 (CYP-450) enzymes, P-glycoproteins (Pgp), and organic anion transporting polypeptides (OATPs), or may cause induction or inhibition of the CYP-450 enzyme.
To define what is being described in the context of this statement:
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Hepatic enzymes are the catalysts within the liver that bind to a substrate to activate a chemical reaction. Examples of hepatic enzymes would include CYP3A4 and CYP2C9, but there are many others.
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Substrates are the medications that are metabolized by a specific enzyme. For example, a medication metabolized by CYP3A4 would be called a CYP3A4 substrate.
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Induction occurs when a medication undergoes hepatic metabolism and it results in increased metabolic activity of the enzyme. The metabolizing enzyme is working overtime, which results in a decrease of the substrate level available to the body. For example, a medication that increases the CYP3A4 enzyme would be called a CYP3A4 inducer. If a patient is taking a CYP3A4 inducer concomitantly with a CYP3A4 substrate, the substrate medication level would be decreased compared to what is expected.
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Inhibition occurs when a medication undergoes hepatic metabolism and it results in decreased metabolic activity of the enzyme. The metabolizing enzyme's activity is hindered, which results in an increase of the substrate level available to the body. For example, a medication that decreases the CYP3A4 enzyme would be called a CYP3A4 inhibitor. If a patient is taking a CYP3A4 in hibitor concomitantly with a CYP3A4 substrate, the substrate medication level would be increased compared to what is expected.
The majority of PAH medications undergo metabolism via the CYP-450 enzyme system. Among the ERAs, bosentan is also a potent inducer of CYP2C9, CYP3A4, and to a certain extent CYP2C19, which potentiates the risk for significant drug-drug interactions with HIV protease inhibitors (PIs) and HCV direct-acting antivirals (DAAs). Ambrisentan and macitentan, on the other hand, do not induce CYP enzymes. However, they are metabolized by CYP3A4 and CYP2C19, thereby requiring close monitoring of therapy when coadministered with CYP-inhibitors. 12–14 The PDE-5 inhibitors are predominantly metabolized via CYP3A4, thereby leading to contraindications with coadministration of sildenafil and PIs.1516 Amongst the prostacyclin analogs, epoprostenol does not undergo hepatic metabolism while treprostinil is primarily metabolized by CYP2C8.1718 The IP receptor agonist selexipag is metabolized by CYP3A4 and CYP2C8, and therefore contraindicated with strong CYP2C8 inhibitors.19 And finally the sGC stimulator riociguat is metabolized by various CYP enzymes, including CYP3A4, as well as Pgp and the breast cancer resistance protein (BCRP).20 Agents that are metabolized via multiple pathways may carry a weaker potential for interactions due to the ability to bypass the primary CYP-mediated pathways.
Metabolic pathways for PAH medications may result in varying degrees of interaction with HIV antiretrovirals (ARVs) and HCV DAAs, particularly the non-nucleoside reverse transcriptase inhibitors (NNRTIs), which are potent CYP-enzyme inducers and the protease inhibitors (PIs), which are potent CYP-enzyme inhibitors. Tables 2–5 highlight the most notable drug-drug interactions between PAH medications and ARVs and HCV DAAs, and provide therapy adjustment recommendations, if needed.
CONCLUSION
In summary, treatment of PAH in patients with HIV and/or HCV requires the additional consideration of the potential for drug-drug interactions. Utilizing specialist pharmacists and resources such as the University of Liverpool's HIV and HCV drug interaction websites provide guidance for practitioners prescribing concomitant medications in these patient populations.2122 That being said, the key to managing these patients is a robust collaboration among the patient, treating PH physician, PH coordinator, pharmacists, and infectious diseases and/or hepatology medical specialists.