Genotype 3: Treat now or wait for something better?

Watch a video presentation of this article

Watch the interview with the author

Abbreviations

AASLD/IDSA

American Association for the Study of Liver Diseases/Infectious Diseases Society of America

AE

adverse event

CYP3A4

cytochrome P450 enzyme 3A

DCV

daclatasvir

EC₅₀

half‐maximum effective concentration

GT

genotype 2

GT3

genotype 3

HCV

hepatitis C virus

NS5A

nonstructural protein 5A

PEG‐IFN

pegylated interferon

RBV

ribavirin

SOF

sofosbuvir

SVR12

sustained virologic response at 12 weeks

Hepatitis C virus (HCV) infection is a worldwide phenomenon that affects 130 to 150 million people globally, with 500,000 of these individuals expected to die of HCV‐related complications annually.1 Of the six major genotypes, genotype 3 (GT3) is the most aggressive, with increased progression to fibrosis and cirrhosis.2 Until now, the treatment regimens for GT3 included combinations based on a backbone of sofosbuvir (SOF) and ribavirin (RBV) and have had only limited success. The phase 3 FISSION trial showed noninferiority of 12‐week combination SOF + RBV to 24‐week pegylated interferon (PEG‐IFN) + RBV in previously untreated patients with genotype 2 (GT2) and GT3. Sustained virologic response at 12 weeks (SVR12) in this study was 56% in the GT3 group receiving SOF + RBV versus 63% in those receiving PEG‐IFN + RBV.3

Two subsequent phase 3 trials, POSITRON and FUSION, assessed the combination of SOF + RBV in PEG‐IFN–intolerant or –ineligible patients and PEG‐IFN nonresponders, respectively. In POSITRON, SVR12 for GT3 was 61%; 68% for those without cirrhosis and 21% for those with cirrhosis. The FUSION trial showed SVR12 of 30% (37% in patients without cirrhosis, 19% in patients with cirrhosis) and 62% (63% in patients without cirrhosis, 61% in patients with cirrhosis) at 12 and 16 weeks, respectively, for GT3.4 In both FISSION and FUSION trials, response rate was lower in patients with GT3 compared with GT2. The VALENCE trial extended treatment duration to 24 weeks. SVR12 was 85% overall, 91% in patients without cirrhosis and 68% in patients with cirrhosis.5 In all of these studies, SOF was given as a 400 mg daily dose, whereas RBV was weight based: 1000 mg for those less than 75 kg and 1200 mg for those ≥75 kg. The results of the VALENCE trial set the standard of GT3 for treatment in 2013 and 2014 with a very expensive regimen that was less than optimal for patients with cirrhosis.

Daclatasvir (DCV; BMS‐790052, DAKLINZA) is a newly approved pan‐genotypic nonstructural protein 5A (NS5A) inhibitor against GT 3 HCV. It was approved for use in Europe in August 2014 and in the United States in July 2015.6, 7 Clinical studies show the picomolar half‐maximum effective concentration (EC₅₀) is 146 ± 34 pM against HCV GT3 specifically with mean plasma elimination half‐life of 10 to 14 hours.8, 9 In vitro studies showed that DCV is a potent inhibitor of NS5A sequences with EC₅₀s of 120 to 870 pM for the three HCV GT3a strains.10 In vitro resistance was associated with variants at L31, Y93, M28, and A30. Only Y93 may have an associated worse clinical response.9, 10 The safety record of DCV has been demonstrated in more than 1900 patients in clinical studies and now in many more patients who have been treated in the last year in the European Union and Japan since the drug was approved in those countries.11 Hence it should offer a logical choice for treatment of our patients with GT3 in the United States who have been waiting for better options.

However, there are some important caveats to consider before treating with DCV. First, the approval in the United States was based primarily on the phase 3 ALLY‐3 study that evaluated only a 12‐week course of DCV plus SOF. Dosing for SOF was the standard 400 mg once daily, whereas for DCV, 60 mg was administered daily. The trial was RBV‐free, and the treatment duration was 12 weeks. The primary endpoint was SVR12 for both treatment‐naive (n = 101) and treatment‐experienced (n = 51) patients. SVR12 was 90% in treatment‐naive patients and 86% in treatment‐experienced patients. SVR12 was 96% versus 63% in those without and with cirrhosis, respectively.12 This is clearly not an acceptable treatment failure rate for patients with cirrhosis, and a longer regimen trial is currently under way for cirrhosis, evaluating a 12‐week versus 16‐week duration with RBV.13 With regard to adverse events (AEs), headache (20%), fatigue (19%), and nausea (12%) were the most common. However, generally, DCV is well tolerated, and in ALLY‐3 there were no AEs leading to drug discontinuation.12 DCV plus SOF with or without RBV was used in a phase 2 study that included 18 patients with GT3 who were treated for 24 weeks and achieved an SVR12 in 89%; however, no patients had cirrhosis.11

Second, DCV is a substrate and a very weak inducer of cytochrome P450 enzyme 3A (CYP3A4), and a substrate and inhibitor of P‐glycoprotein transporter (P‐gp). DCV also inhibits organic anion transporting polypeptide (OATP1B1), breast cancer resistance protein (BCRP), and organic cation transporter 1. Because DCV is metabolized primarily through the CYP3A, strong inducers of this are contraindicated in combination, particularly rifampin, phenytoin, carbamazepine, and St. John's wort. With moderate CYP3A inducers (efavirenz, etravirine, nafcillin, dexamethasone), a dosage increase to 90 mg daily should be applied. If administered with inhibitors of CYP3A (clarithromycin, some azoles, ritonavir), DCV dosage should be reduced to 30 mg daily.7 These drug–drug interactions make the use of DCV more complicated in patients who are coinfected with HIV‐HCV and those who must continue taking their medications.

Third, some critical information on the use of DCV in special populations is lacking. For those patients with any degree of renal impairment including chronic kidney disease classes 4 and 5, no dosage adjustment is necessary.7 However, no studies thus far have established safety or efficacy in decompensated patients with cirrhosis or in liver transplant recipients. Otherwise, DCV is safe to use without dosage adjustment in those with Child‐Pugh class A, B, or C hepatic impairment.7 Although there have been no large trials in transplant recipients, DCV does not require dosage adjustment with immunosuppressive agents and has been reported to be effective in a number of different regimens used by investigators in the posttransplant population.14, 15, 16, 17

For patients with baseline HCV polymorphisms, the ALLY‐3 trial provided a significant amount of baseline resistance information. Of the 148 patients assessed, 77 of 148 (52%) had a baseline NS5A polymorphism at a resistance‐associated position, with 9% being the Y93H polymorphism. In the Y93H polymorphism population, SVR12 was reduced as shown in Table 1. This was not seen with other NS5A resistance‐associated polymorphisms.12

Table 1.

SVR12 in HCV GT3 With and Without Y93H Polymorphism

Study Population	SVR12 With Y93H	SVR12 Without Y93H
All subjections	54% (7/13)	92% (124/135)
No cirrhosis	67% (6/9)	98% (105/107)
With cirrhosis	25% (1/4)	68% (19/28)

Reproduced from Daklinza (daclatasvir) package insert, Bristol‐Myers Squibb Company.7

The updated American Association for the Study of Liver Diseases/Infectious Diseases Society of America (AASLD/IDSA) guidance for use of DCV in GT3 infections recommends

“daily daclatasvir (60 mg*) and SOF (400 mg) for 12 weeks (no cirrhosis) or 24 weeks with or without weight‐based RBV (cirrhosis) for treatment‐naive patients with HCV GT3 infection. Rating: Class I, Level A (no cirrhosis); Class IIa, Level C (cirrhosis).”18 However, the certainty of the 24‐week duration recommendation in cirrhosis is far from clear. So what other options do we have for those patients? If they are willing and able to take PEG‐IFN, there is ample evidence showing that SOF in combination with PEG‐IFN and RBV has a reasonable efficacy.19, 20, 21 However, most patients now are unwilling or unable to tolerate this regimen.

That leaves the option of referring these patients for clinical trials that accept GT3 patients with cirrhosis. There are at least four regimens that I am aware of that are enrolling or have completed enrolling patients with GT3 cirrhosis; however, any efficacy and safety results have yet to be seen.13, 22, 23 Although a number of potentially safe and effective drugs are in development for GT3, we will have to wait for now until the data tell us more. In my own center at Scripps Clinic, we are ordering NS5A RAV testing in patients with GT3 with cirrhosis and deferring treatment with DCV/SOF if the Y93H mutation is present. Otherwise we are treating according to the updated AASLD/IDSA Guidance Document referenced in this article.14