Drug‐drug interactions in hepatitis C virus treatment: Do they really matter?

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Abbreviations

CYP3A4

cytochrome P450 3A4

DAA

direct‐acting antiviral

DDI

drug‐drug interaction

HCV

hepatitis C virus

PrOD

paritaprevir (inhibitor of OATP1B1/3) and dasabuvir

SVR

sustained virological response

The development of direct‐acting antiviral (DAA) agents has revolutionized the treatment of hepatitis C infection. Previously the only option for patients was combination therapy with interferon and ribavirin for up to 1 year, which at best resulted in a 50% sustained virological response (SVR) rate. DAA agents for hepatitis C virus (HCV) include NS3 protease inhibitors, NS5a inhibitors, and NS5b polymerase inhibitors, which are designed to inhibit viral replication by different mechanisms. Combinations of these agents have resulted in SVR rates of more than 95% across all genotypes with durations of therapies ranging from 8 to 24 weeks. This has also allowed clinicians to treat HCV populations who were previously either intolerant of or had contraindications to interferon and ribavirin.

Interferon and ribavirin were associated with minimal drug‐drug interactions (DDIs). DAAs have the potential for clinically important DDIs, which become more relevant given the significantly larger numbers of patients who have complex medical comorbidities who are now potential candidates for HCV treatment. As such, dose adjustment of medications and changes in dosing schedule may be required in such circumstances. A recent publication highlighted these issues when the authors determined that up to 44% of their cohort of 449 patients had potential DDIs that needed to be taken into consideration.1

All approved DAA agents have potential DDIs and depending on the interaction, the serum concentration can either increase to toxic levels or be reduced to ineffective levels. DAAs may also reduce or increase the serum concentrations of certain co‐administered medications resulting in subtherapeutic or toxic effects. However, with the broad range of choices for DAA‐based therapy, the number of patients taking medications where adjustments cannot be made to provide safe and effective therapy for hepatitis C is few.

The three classes of DAAs that are typically combined to treat hepatitis C are listed in Fig. 1. All DAAs may be used in HCV‐infected patients, including compensated cirrhosis (Child‐Turcotte‐Pugh class A), but the use of protease inhibitor class is contraindicated in Child‐Turcotte‐Pugh class B and C.

Figure 1.

Approved and future DAAs from multiple classes. *Expect approval in 2017.

The protease inhibitor class was the first DAA class investigated for hepatitis C, with telaprevir and boceprevir being approved in 2011 and used in combination with interferon and ribavirin.2 A significant number of DDIs were recognized with these first‐generation DAA‐based regimens. Telaprevir increased the concentration‐time curve (area under the curve) of tacrolimus by 70‐fold, raising the potential for adverse side effects and required dose adjustments.3 Despite these potentially harmful DDIs, clinicians were able to navigate HCV‐infected patients through antiviral therapy and achieve higher SVR rates. Fortunately, the newer generations of proteases inhibitors have a lower DDI risk profile, which has allowed the development of fixed‐dose oral combination therapies.

The first protease inhibitor used in an all‐oral regimen was simeprevir, in combination with sofosbuvir (Table 1). Simeprevir is metabolized by the cytochrome P450 3A4 (CYP3A4) pathway; therefore, strong inhibitors of CYP3A4 such as ritonavir can raise simeprevir levels, whereas strong inducers of CYP3A4 decrease simeprevir serum concentrations (Table 2).4 Other common inhibitors of the CYP pathway that require cautious administration or adjustments include antiarrhythmics, calcium channel blockers, and statins (Table 3). The DDIs of the ritonavir‐boosted fixed‐dose combination of paritaprevir (protease inhibitor) with ombitasvir (NS5A inhibitor) and dasabuvir (nonnucleoside polymerase inhibitor) are predominantly due to the presence of the CYP3A ritonavir, a potent CYP3A inhibitor. There are, however, minor contributions from paritaprevir (inhibitor of OATP1B1/3) and dasabuvir (PrOD). Ritonavir has a well‐characterized and extensive interaction profile that must be accounted for when using PrOD to treat hepatitis C.5 Grazoprevir is a near‐pan‐genotypic next‐generation protease inhibitor that is coformulated with elbasvir. Grazoprevir is a substrate of CYP3A4 and the transporter OATP1B1/3. Grazoprevir DDIs differ somewhat from the other proteases in that cyclosporine and other HIV protease inhibitors increase grazoprevir levels because of OATP1B1/3 inhibition.6

Table 1.

Protease Inhibitor Metabolism and Transporter Characteristics: Clinically Significant Effects

	Substrate	CYP Inhibition	UGT Inhibition	Transporter Inhibition
Simeprevir	CYP3A4, P‐gp, OATP1B1	Intestinal (but not hepatic) CYP3A4 and 1A2		P‐gp, OATP1B1/3
Paritaprevir	CYP3A4, P‐gp, OATP1B1/3, BCRP		Yes	P‐gp, OATP1B1/3
Grazoprevir	CYP3A4, P‐gp, OATP1B1			BCRP
Voxilaprevir	CYP3A4, 2C8, P‐gp, BCRP, OATPs			P‐gp, BCRP, OATP
Glecaprevira				P‐gp

^aPreliminary data.

Table 2.

NS5a Inhibitor Metabolism and Transporter Characteristics: Clinically Significant Effects

	Substrate	CYP Inhibition	UGT Inhibition	Transporter Inhibition
Ledipasvir	P‐gp
Ombitasvir	CYP3A4, P‐gp, BCRP		Yes
Daclatasvir				P‐gp
Elbasvir	CYP3A4, P‐gp, OATP			BCRP
Velpatasvir	CYP3A4, 2C8, 2B6; OATP1B1, OATP1B3, P‐gp, BCRP			BCRP
Pibrentasvira				P‐gp

^aPreliminary data.

Table 3.

Selected Drug‐Drug interactions of DAAs With Selected Medications

Concomitant Medications	DCV	LDV/SOF	SOF/VEL	SOF	SMV	PrOD	EBV/GRZ	SOF/VEL/VOX	GLE/PIB
Acid‐reducing agentsa		X	X			X		X
Alfuzosin/tamsulosin						X
Amiodarone	X	X	X	X	X	X
Anticonvulsantsa	X	X	X	X	X	X	X	X	X
Azole antifungalsa	X				X	X	X
Buprenorphine/naloxone						X
Calcineurin inhibitorsa					X	X	X		X
Calcium channel blockersa	X				X	X	X
Digoxin	X	X			X		X		X
Ethinyl estradiol‐containing products						X			X
Furosemide						X
Gemfibrozil						X
Glucocorticoidsa	X				X	X (inhaled, intranasal)	X
Herbals
St. John's wort	X	X		X	X	X	X	X	X
Milk thistle			X		X		X
3‐Hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase inhibitors (statins)a	X	X			X	X	X	X	X
Macrolide antimicrobialsa	X				X		X		X
Phosphodiesterase inhibitorsa					X	X	X
Rifamycin antimicrobialsa	X	X	X	X	X	X	X	X	X

^aAdapted from American Association for the Study of Liver Diseases/Infectious Diseases Society of America DDI interactions. http://www.hcvguidelines.org/evaluate/monitoring.

Abbreviations: DCV, daclatasvir; EBV, elbasvir; GLE, glecaprevir; GRZ, grazoprevir; LDV, ledipasvir; PIB, pibrentasvir; SMV, simeprevir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.

Two new pan‐genotypic protease inhibitors, glecaprevir and voxilaprevir, have been approved in 2017. Glecaprevir, which is coformulated with the NS5a inhibitor pibrentasvir, is minimally metabolized and excreted via bile.7 Preliminary data suggest that this protease inhibitor may have a more favorable DDI profile than previous generation protease inhibitors because initial reports have shown minimal interactions with calcium channel blockers and combination antiretroviral regimens in multiple‐dose studies, as well as no significant interactions with substrates of CYP3A, CYP2D6, CYP2C19, and CYP2C9.8, 9, 10 Glecaprevir appears to have a inhibition signal with digoxin when given with pibrentasvir.11 Voxilaprevir is a substrate of CYP3A4 and 2C8; a substrate and inhibitor of OATP1B1, OATP1B3, P‐gp, and BCRP; and will be coformulated with sofosbuvir and velpatasvir (NS5A inhibitor). In single‐ and multiple‐dose studies in healthy volunteers, it has been shown that voxilaprevir administration with CYP3A4 inhibitors or substrates is safe. Voxilaprevir appears to interact with potent hepatic OATP inhibitors, or potent or moderate inducers of CYPs and P‐gp.12, 13

The list of approved NS5a inhibitors (ledipasvir, ombitasvir, daclatasvir, elbasvir, and velpatasvir) should soon also include pibrentasvir, which has minimal DDIs. All of the approved NS5a inhibitors are substrates of p‐glycoprotein, and all approved NS5a inhibitors other than ledipasvir are substrates of CYP3A4. DDIs for this class in general are easily managed with limitations with the use of certain statins, antituberculosis medicines, and HIV regimens. Notably, both ledipasvir and velpatasvir require an acid milieu for optimal absorption. The use of proton pump inhibitors beyond 20 mg omeprazole is not recommended with ledipasvir, and the use proton pump inhibitors is not recommended with velpatasvir. Two large database studies have suggested that high‐dose proton pump inhibitors are associated with the slight reduction in SVR, with one study showing no reduction in SVR with conventional doses of proton pump inhibitors.14, 15

The nucleotide polymerase inhibitor sofosbuvir has been the backbone of therapy for many DAA regimens. Sofosbuvir is a p‐glycoprotein substrate, and strong p‐glycoprotein inducers should not be coadministered with sofosbuvir‐based therapy. The other important drug interaction is with the coadministration of amiodarone. There have been reports of severe symptomatic bradycardia and one death with sofosbuvir. Given the long half‐life of amiodarone, it should be held for at least 8 weeks before initiation of any sofosbuvir‐based regimen or an alternative DAA regimen should be used.

In summary, patients with hepatitis C who present for treatment should expect to be cured of their hepatitis C. With three classes of DAA agents to choose from with different antiviral mechanisms of action, high SVR rates can be achieved in virtually all patients including patients with medical comorbidities that would be contraindicated in the interferon era. Progress in DAA‐based regimens has led to pan‐genotypic combinations with high efficacy, minimal adverse effects, and manageable DDIs. Given the complexity of patients we are currently treating, the potential for DDIs will remain important in the pretreatment assessment and institution of DAA‐based regimens.