COMMENTARY

Hepatitis C Therapies Perform Well in Challenging Patients

William F. Balistreri, MD

Disclosures

July 03, 2017

New Data on Pangenotypic Combination Treatments

At this year's Digestive Disease Week, several studies looked into the nuances of treating hepatitis C virus (HCV)infection. Of particular interest were new data regarding difficult-to-treat groups and the validation of shorter, simpler regimens.

Glecaprevir and Pibrentasvir

In several phase 2 and 3 clinical trials, patients who received the pangenotypic direct-acting antivirals (DAAs) glecaprevir (GLE) and pibrentasvir (PIB) achieved sustained virologic response (SVR) rates of 92%-100% across all six major HCV genotypes.

Puoti and colleagues[1] presented an integrated analysis of these studies to document the efficacy of 8 and 12 weeks of GLE/PIB treatment, without coadministered ribavirin, in noncirrhotic patients with chronic HCV genotype 1-6 infection. Patients were either treatment-naive or treatment-experienced, having received interferon- or sofosbuvir-based regimens. In total, 1981 patients without cirrhosis were enrolled, and 1975 received GLE/PIB.

In the intention-to-treat population, 98% of patients achieved SVR at post-treatment week 12 (SVR12), with similar rates of 97% and 98% in patients treated for 8 and 12 weeks, respectively. Across all genotypes, breakthroughs, relapses, or discontinuations occurred in < 1% of patients, and GLE/PIB was well-tolerated.

This analysis suggests that the GLE/PIB regimen, which yielded high SVR12 rates across all genotypes regardless of prior treatment experience or treatment duration, could provide an effective 8-week interferon- and ribavirin-free treatment option for patients with HCV genotype 1-6 infection without cirrhosis.

Patients with chronic HCV who have virologic failure after DAA therapy may have a decreased response or develop resistance to subsequent treatment. Poordad and colleagues[2] addressed a potential salvage strategy for such patients, evaluating the efficacy and safety of GLE/PIB in HCV-infected patients who had experienced prior virologic failure with at least one NS5A and/or NS3/4A protease inhibitor-containing therapy.

In a randomized, open-label study, 91 patients with chronic HCV infection were stratified by HCV genotype and prior DAA experience to receive either 12 or 16 weeks of coformulated GLE/PIB (300/120 mg). Of participants, 74% had HCV genotype 1a, 21% had genotype 1b, and 4% had genotype 4 infection, and 30% of patients had compensated cirrhosis. The primary endpoints were safety and efficacy (the percentage of patients achieving an SVR12, defined as HCV RNA level < 15 IU/mL at post-treatment week 12).

Overall, SVR12 was achieved by 89% and 91% of patients who received 12 and 16 weeks of GLE/PIB, respectively. The majority of adverse events were mild, and no patient discontinued the drug owing to an adverse event.

Retreatment with GLE/PIB of HCV genotype 1- or genotype 4-infected patients (with or without compensated cirrhosis) who had experienced prior DAA therapy failure resulted in high overall SVR12 rates.

Sofosbuvir/Velpatasvir/Voxilaprevir

A pangenotypic combination of sofosbuvir (SOF), velpatasvir (VEL), and voxilaprevir (VOX) was designed to inhibit three distinct HCV targets: the NS5B polymerase, the NS5A protein, and NS3/4A protease, respectively.

Flamm and colleagues[3] presented cumulative data from 1056 patients with and without compensated cirrhosis who were infected with HCV genotype 1-6 and treated with the once-daily fixed-dose combination tablet of SOF/VEL/VOX in phase 3 studies.

Of the DAA-experienced patients, 59% had received an NS5A inhibitor-containing regimen, whereas 20% of the DAA-naive patients had prior treatment failure with pegylated interferon plus ribavirin.

The studies enrolled a diverse patient population that included a significant number of patients with historically negative predictors of response, including cirrhosis and prior exposure to DAA-containing regimens.

SOF/VEL/VOX was administered to DAA-experienced patients with HCV genotype 1-6 infection for 12 weeks, and DAA-naive patients received treatment for 8 weeks. Cirrhosis was observed in 38% of patients, and 70% had an HCV RNA level ≥ 800,000 IU/mL.

The resultant SVR12 rate was 96% in NS5A inhibitor-experienced patients and 97% in DAA-experienced patients who had not previously received an NS5A inhibitor. Thus, this ribavirin-free regimen of SOF/VEL/VOX achieved high rates of SVR across subgroups.

Predicting Treatment Outcomes

Reddy and colleagues[4] evaluated the effect of baseline resistance-associated substitutions (RASs) on treatment outcome and sought the emergence of RASs in patients who experienced virologic failure.

NS3, NS5A, and NS5B deep sequencing was performed at baseline for all patients and at the time of virologic failure. The investigators found that 79% of NS5A inhibitor-experienced patients had baseline NS3 and/or NS5A RASs. Of these patients, 75% had NS5A RASs—the most common RAS—at baseline.

SVR12 rates were similar in patients with and those without NS3 and/or NS5A RASs, and in those with and those without VOX- or VEL-specific RAS. Specifically, RASs at NS5A position Y93 were present in 25% of patients, of whom 95% achieved SVR12. All patients with more than two NS5A RASs achieved SVR12. In addition, 95% of patients with NS5B nucleoside inhibitor RASs achieved SVR12; two patients had S282T present at baseline, and both achieved SVR12. The overall prevalence of baseline NS3 and/or NS5A RASs was 47%, and all achieved SVR12. No NS3, NS5A, or NS5B RASs emerged in any patient who had relapse after treatment with SOF/VEL/VOX for 12 weeks.

Therefore, the investigators documented that baseline RASs had no impact on the virologic response in DAA-experienced patients in this cohort after treatment with SOF/VEL/VOX for 12 weeks, and that virologic relapse was not associated with the emergence of viral resistance.

DAAs provide a virologic cure for most patients with chronic hepatitis C with compensated cirrhosis; however, patients with decompensated cirrhosis experience a variety of outcomes after achieving SVR. Vittal and coworkers[5] hypothesized that genetic risk factors for steatosis would predict clinical recovery in patients with decompensated cirrhosis after SVR.

They analyzed the rs738409 single-nucleotide polymorphism of the patatin-like phospholipase domain-containing 3 (PNPLA3) gene—an important genetic risk factor for both alcoholic liver disease and nonalcoholic fatty liver disease—in a prospective cohort study of 30 patients with Child-Pugh class B or C cirrhosis due to HCV infection who underwent interferon-free DAA therapy. The demographic and baseline clinical characteristics of the patients were similar, except that patients with the rs738409 CC genotype had a significantly higher mean body mass index.

Child-Pugh scores improved by at least 1 point in 81% of the patients with CC genotype, compared with only 56% of patients with the CG or GG genotype. None of the patients with CC genotype had worsening of their Child-Pugh scores. In contrast, Child-Pugh scores worsened by at least 1 point in 13% of those with the CG or GG genotype.

Model for End-Stage Liver Disease (MELD) scores improved by at least 1 point in 50% of patients with CC genotype and in 38% of patients with CG or GG genotypes. Conversely, MELD scores worsened by at least 1 point in 6% of patients with CC genotype and in 19% of patients with the CG or GG genotype. The CG/GG genotype was associated with a higher delta Child-Pugh score and a higher delta MELD score in multivariable linear regression adjusting for confounders.

In terms of Child-Pugh components, patients with CG/GG genotype had a slower recovery of encephalopathy, ascites, and bilirubin. Thus, the presence of the rs738409 CG/GG genotype earmarks a subgroup of patients with decompensated HCV cirrhosis who may have suboptimal clinical recovery, despite achieving SVR.

These results may help target patients for liver transplant evaluation on the basis of individual genetic risk factors, because the PNPLA3 genotype could inform the decision as to whether a patient with decompensated cirrhosis should be evaluated for liver transplant or effectively treated with DAAs—a step toward precision medicine.

Survival Among Liver Transplant Recipients

Recurrent HCV infection is universal among liver transplant recipients with HCV viremia at the time of transplantation. Compared with immunocompetent HCV patients, rapid progression, resulting in graft fibrosis and cirrhosis, has been observed in liver transplant recipients. This has led to graft failure and recipient death unless retransplantation is performed. With the judicious use of highly effective DAAs, the long-term survival rates among liver transplantation recipients with recurrent HCV infection should improve.

Latt and colleagues[6] evaluated patient and graft survival among 3575 liver transplant recipients with recurrent HCV infection treated during three eras: before 2006; 2006-2010; and after 2011 (the early DAA era). They compared outcomes in these patients with outcomes those among liver transplant recipients who were not HCV-infected.

Graft survival significantly improved across the three eras in both noninfected and HCV-infected patients (P = .001), whereas patient survival significantly improved only among the HCV-infected patients. Five-year graft survival rates among non–HCV-infected patients rose from 72% to 82% over the three eras, and patient and graft survival rates among HCV-infected patients also rose, from 67% to 82%. A significant improvement in both graft and patient survival rates was observed between 2006-2010 and after 2011 (the DAA era) among HCV-infected recipients, whereas only modest improvement between the before-2006 era and 2006-2010 was observed.

The investigators postulated that the observed improvement in noninfected recipients paralleled the reported trend of progressive improvement of liver transplantation outcomes nationwide, whereas the improvement of graft and patient survival in HCV recipients in recent years can be attributed to a positive impact of DAA therapy.

Of note, the early DAA protease inhibitors required coadministration of pegylated interferon and ribavirin, whereas interferon- and ribavirin-free DAA combinations emerged after 2014; therefore, it is possible that contemporary outcomes would be further improved.

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