Integrating daclatasvir into hepatitis c therapy

Watch a video presentation of this article

Watch the interview with the author

Abbreviations

AASLD

American Association for the Study of Liver Disease

DAC

daclatasvir

FDA

US Food and Drug Administration

HCV

hepatitis C virus

HIV

human immunodeficiency virus

IDSA

Infectious Disease Society of America

IFN

interferon

PEG

peginterferon

RBV

ribavirin

SOF

sofosbuvir

SVR

sustained virological response

Therapy for hepatitis C virus (HCV) infection has progressed dramatically with well‐tolerated and highly effective regimens. Daclatasvir, an NS5A replication complex inhibitor with in vitro activity against genotypes 1 to 6, is the latest antiviral to enter practice.1 Daclatasvir in combination with sofosbuvir was approved by the US Food and Drug Administration (FDA) in July 2015 for genotype 3. The daclatasvir and sofosbuvir regimen addresses limitations in HCV treatment, particularly among patients with genotype 3, but also for human immunodeficiency virus (HIV)‐HCV coinfection and those patients who are unable to tolerate ribavirin.

HCV Genotype 3

Before daclatasvir, sofosbuvir with ribavirin was the only interferon‐free option for genotype 3. The VALENCE trial established higher sustained virological response (SVR) rates for genotype 3 by extending sofosbuvir and ribavirin to 24 weeks. SVR12 rates in VALENCE was 93% among treatment‐naive patients and 77% among patients who did not respond positively to interferon.2 However, the long duration, need for ribavirin, and low rates with cirrhosis were limitations for sofosbuvir and ribavirin. Furthermore, the BOSON trial found that peginterferon, ribavirin, and sofosbuvir for 12 weeks led to higher SVR rates than 16 or 24 weeks of sofosbuvir and ribavirin.3 Accordingly, the American Association for the Study of Liver Disease (AASLD) and the Infectious Disease Society of America (IDSA) recommended peginterferon, ribavirin, and sofosbuvir for genotype 3 and relegated sofosbuvir and ribavirin to alternative regimen status (Table 1).4

Table 1.

American Association for the Study of Liver Disease/Infectious Disease Society of America 2015 Treatment Recommendations for Genotype 3

Genotype and Treatment History	Peginterferon + Sofosbuvir + Ribavirin	Sofosbuvir + Ribavirin	Daclatasvir + Sofosbuvir
Naive	Recommended 12 weeks	Alternative 24 weeks	Recommended, 12 weeks Cirrhosis: 24 weeks ± ribavirin
Peginterferon/Ribavirin failure	Recommended 12 weeks		Recommended if IFN ineligible, 12 weeks Cirrhosis: 24 weeks + ribavirin
Sofosbuvir failure	Recommended 12 weeks		Recommended if IFN ineligible, 24 weeks + ribavirin

Abbreviation: IFN, interferon.

In the ALLY‐3 trial, daclatasvir and sofosbuvir without ribavirin for 12 weeks achieved SVR12 in 90% of treatment‐naive and 86% of treatment‐experienced genotype 3 patients.5 The AASLD/IDSA recommends daclatasvir and sofosbuvir for 12 weeks for noncirrhotic genotype 3 patients, including treatment‐naive patients and patients with unsuccessful peginterferon therapy.4 In ALLY‐3, lower SVR occurred with cirrhosis (Fig. 1). The ALLY‐3+ study was reported at the 2015 Liver Meeting and treated patients with bridging fibrosis or cirrhosis with daclatasvir, sofosbuvir, and ribavirin for 12 or 16 weeks. All patients with bridging fibrosis were cured, and SVR12 rates for patients with cirrhosis were 83% for 12 weeks and 89% for 16 weeks.6 The AASLD/IDSA guidance panel has recommended 24 weeks' duration with sofosbuvir, daclatasvir, and ribavirin for cirrhotic genotype 3 patients.

Figure 1.

ALLY‐3 study results of daclatasvir and sofosbuvir for 12 weeks for genotype 3. Abbreviation: SVR, sustained virological response.

HCV Genotype 1

The daclatasvir plus sofosbuvir combination is pangenotypic, and the AASLD/IDSA recommends this regimen for genotype 1 patients. The duration is 12 weeks without ribavirin if no cirrhosis and 24 weeks with or without ribavirin in patients with cirrhosis (Table 2).4 Although no large phase 3 trial evaluated genotype 1–naive patients, these recommendations are supported from a phase 2 trial (Fig. 2), ALLY‐1 in advanced cirrhosis and post–liver transplantation, and ALLY‐2 in HIV/HCV coinfection (Fig. 3).7, 8, 9 The phase 2 study was an early demonstration of the potency of this regimen with SVR in 40 of 41 (98%) patients who did not respond successfully to a first‐generation protease inhibitor regimen.7 ALLY‐1 added ribavirin and demonstrated high SVR rates in all patient groups except Child‐Pugh class C.8 Daclatasvir and sofosbuvir is not FDA‐approved for genotype 1, and the likelihood of coverage by payers may determine whether clinicians can offer this regimen to patients.

Table 2.

American Association for the Study of Liver Disease/Infectious Disease Society of America 2015 Treatment Recommendations for Genotypes 1 and 2

Genotype and Treatment History	Daclatasvir + Sofosbuvir
Genotype 1, naive or PEG/PI failure
No cirrhosis	Recommended, 12 weeks
Cirrhosis	Recommended, 24 weeks ± RBV
Genotype 2
Naive	Recommended, 12 weeks
PEG/RBV failure	Limited data
Sofosbuvir failure	Recommended if interferon ineligible, 24 weeks ± RBV

Abbreviations: PEG, peginterferon; RBV, ribavirin; PI, protease inhibitor.

Figure 2.

Phase 2 results of daclatasvir (DAC) and sofosbuvir (SOF) for genotype 1. Abbreviations: RBV, ribavirin; SVR, sustained virological response.

Figure 3.

ALLY‐2 study 12‐week arm results of daclatasvir and sofosbuvir for human immunodeficiency virus/hepatitis C virus coinfection. Abbreviation: SVR, sustained virological response.

HCV Genotype 2

The first‐line treatment option for treatment‐native patients with genotype 2 is sofosbuvir and ribavirin for 12 weeks with 16 weeks if cirrhotic.4 No large phase 3 study was conducted for daclatasvir and sofosbuvir for genotype 2 patients, and the combination is not FDA‐approved for genotype 2. In the phase 2 study, genotype 2 treatment‐naive patients achieved SVR12 in 24 of 26 (92%) patients with 24 weeks of sofosbuvir and daclatasvir.7 In the HIV/HCV coinfection ALLY‐2 study, all 11 treatment‐naive patients and both treatment‐experienced genotype 2 patients achieved SVR12 with 12 weeks of daclatasvir and sofosbuvir.9 The AASLD/IDSA recommends 12 weeks of daclatasvir and sofosbuvir for treatment‐naive patients who cannot tolerate ribavirin (Table 2).4 No specific recommendation was made for peginterferon and ribavirin failures because of limited data. Patients with genotype 2 with unsuccessful sofosbuvir therapy are recommended to receive sofosbuvir in combination with peginterferon and ribavirin. If interferon‐ineligible, daclatasvir and sofosbuvir with or without ribavirin is recommended.

HIV/HCV Coinfection

The ALLY‐2 study evaluated daclatasvir and sofosbuvir in HIV/HCV coinfection. A key finding of the study was that 8 weeks' duration was ineffective. In the 12‐week arms, daclatasvir and sofosbuvir for 12 weeks achieved high SVR rates in HIV/HCV genotypes 1 to 4 regardless of previous HCV treatment or cirrhosis (Fig. 3).9 Treatment of HIV/HCV coinfected patients requires management of the drug–drug interactions between the HCV and HIV. Daclatasvir offers a potential advantage over other agents with limited drug–drug interactions (Table 3) and flexibility in dosing. Daclatasvir comes in the standard dose of 60 mg but also 30‐mg tablets. As an example, patients receiving moderate CYP3A inducers like efavirenz would require increased dosing of daclatasvir from 60 mg to 90 mg. Patients on strong CYP3A inhibitors like atazanavir/ritonavir would require reduced dosing of daclatasvir to 30 mg. This flexibility potentially would allow some patients to avoid alterations in their HIV antiretroviral regimens.

Table 3.

Drug–Drug Interactions Between Highly Active Antiretroviral Therapy and Daclatasvir10, 11

Nucleoside reverse‐transcriptase inhibitors
Abacavir	a, b
Didanosine	b
Emtricitabine	a, b
Lamivudine	b
Stavudine	b
Tenofovir	b
Zidovudine	b
Non‐nucleoside reverse‐transcriptase inhibitor
Efavirenz	Daclatasvir ↓c
Etravirine	Daclatasvir ↓c
Nevirapine	c
Rilpivirine	a, b
Protease inhibitors
Atazanavir/Ritonavir	Daclatasvir ↑c
Darunavir/Ritonavir	Daclatasvir ↑b
Fosamprenavir	c
Lopinavir/Ritonavir	Daclatasvir ↑b
Saquinavir	c
Integrase inhibitors
Dolutegravir	Dolutegravir ↑b
Elvitegravir/Cobicistat	a, c
Maraviroc	a, b
Raltegravir	a, b

^aNot studied/no data.

^bNo clinically significant interaction expected.

^cPotential interaction that may require a dosage adjustment, altered timing of administration, or additional monitoring.

Conclusion

Daclatasvir in combination with sofosbuvir offers major advantages for genotype 3 patients with a once‐daily, ribavirin‐free regimen for noncirrhotic patients and improved response rates for patients with cirrhosis through extended duration and the addition of ribavirin. Although the FDA approval for only genotype 3 may limit access, the pangenotypic nature of the regimen offers other options to patients who cannot tolerate ribavirin. The favorable drug–drug interaction profile and flexible dosing may be preferable to patients with HIV/HCV coinfection.