Management of direct-acting antiviral agent failures

doi:10.1016/j.jhep.2015.08.010

Journal of Hepatology

Volume 63, Issue 6, December 2015, Pages 1511-1522

https://doi.org/10.1016/j.jhep.2015.08.010 Get rights and content

Summary

Failure to respond to the approved combinations of multiple direct-acting antiviral agents is relatively low in hepatitis C virus treatment registration studies, with rates of 1% to 7%, depending on the patients’ baseline characteristics. In real life, failure is slightly higher, likely because of lower compliance. Treatment failures are usually related to relapse and less often to on-treatment viral breakthrough. Hepatitis C drug-resistant variants are detected in most patients who do not achieve viral eradication. The risk of developing these variants depends on host- and virus-related factors, the properties of the drugs used, and the treatment strategies applied. Patients who carry resistance-associated variants may not obtain benefits from treatment and are at risk of disease progression and transmission of the variants. Whether hepatitis C resistance-associated variants persist depends on their type: NS3-4A variants often disappear gradually after therapy is stopped, whereas NS5A variants tend to persist for more than 2 years.

The best way to prevent emergence of resistant variants is to eliminate the virus at the first treatment using highly potent antivirals with genetic barriers to resistance. In patients failing first-generation protease inhibitors, combination therapies with sofosbuvir and NS5 inhibitors have proven effective. Some salvage regimens can be shortened to 12 weeks by addition of ribavirin. The optimal treatment for patients who fail an NS5A inhibitor and those with multidrug-resistant variants remains to be defined, and research efforts should continue to focus on treatment for these patients.

Introduction

It is estimated that 170 million people worldwide live with chronic hepatitis C virus (HCV) infection [1], [2]. Most of these individuals are asymptomatic, but some experience disease progression with liver fibrosis, which can lead to cirrhosis and hepatocellular carcinoma. In 2010, more than 0.5 million deaths worldwide were attributed to infection by HCV [3].

The extraordinary recent developments in HCV treatment have completely changed the scenario of therapy for this condition. A series of new direct-acting antivirals (DAAs) against the HCV non-structural proteins have been developed, enabling incorporation of interferon-free regimens into clinical practice. These include drugs that can inhibit the NS3-4A protease, including telaprevir (TPV), boceprevir (BOC), simeprevir (SMV), and paritaprevir, agents that inhibit the NS5B polymerase, such as the nucleoside analogue, sofosbuvir (SOF), and the non-nucleoside analogue, dasabuvir (DSV), and drugs that act upon the NS5A replication complexes, such as ledipasvir (LDV), daclatasvir (DCV), and ombitasvir (OBV). Combinations of two or more of these drugs in interferon-free regimens have shown high effectiveness for viral clearance with only mild side effects. The following DAA combination regimens are currently used in clinical practice for patients infected with genotype (GT) 1 or 4 (Fig. 1): 1) SMV plus SOF ± ribavirin (RBV); 2) SOF plus an NS5A inhibitor such as DCV or LDV (the latter in a fixed-dose combination); 3) an NS3-4A protease inhibitor (PI), paritaprevir, boosted with ritonavir (PTV/r) plus an NS5A inhibitor, OBV, in a fixed-dose combination with a non-nucleoside polymerase inhibitor, DSV. This last DAA combination is also known as 3D regimen. Whichever of these regimens is used, sustained virologic response (SVR) rates in the registration studies involving GT1 or GT4 patients are higher than 90%.

The preliminary results on these DAA regimens in various real-world cohorts also show high SVR rates (80–90%), although they are slightly lower than those in the registration studies [4], [5], [6], [7], [8], [9], [10], [11], [12]. For patients with GT2 or GT3 infection, the first approved interferon-free regimen was SOF plus RBV for 12 to 24 weeks, which yielded SVR rates of 68% to 90% [13], [14], [15], [16]. In addition, two DAA combinations are available for GT3: SOF plus DCV and SOF/LDV. The extensive introduction of these regimens foresees that a fair number of patients will fail these newer antiviral treatments in the near future.

This review focusses on the management of DAA failures. We discuss the types of failures, the characteristics of patients who fail, the role of HCV drug resistance testing in this situation, and the available rescue strategies.

Section snippets

Triple therapy with first-generation NS3-4A protease inhibitors (PIs)

The NS3-4A PIs, TPV and BOC, in combination with pegylated interferon (P) and RBV were the first wave of DAAs approved for treating chronic HCV GT1, the most common HCV genotype worldwide. The efficacy of first-generation PIs depends on the viral sensitivity to interferon. Therapy failures have been reported in 20% of naïve patients and 80% of previous P/RBV null responders, particularly those with liver cirrhosis [17], [18], [19], [20], [21], [22], [23], [24]. Patients who fail to respond to

Variability of hepatitis C virus

HCV has a high turnover rate and an estimated half-life of only 2 to 5 h: 10¹⁰ to 10¹² virions are produced and cleared per day in an infected patient [66], [67], [68]. Because of the lack of proof-reading activity of the HCV-RNA-dependent RNA-polymerase (NS5B) and the high replication activity of HCV, a large number of viral variants are continuously produced during infection (error rate, approximately 10⁻³ to 10⁻⁴ mutations per nucleotide per genomic replication) [69]. Most of these variants

Methods for detecting resistance-associated variants

The genetic diversity of viral populations and RAV has been traditionally assessed by population sequencing (i.e., direct sequencing of a PCR product) or by clonal sequencing (i.e., cloning of a PCR product into plasmid vectors, followed by direct sequencing). The lower limit of detection of direct sequencing ranges from 15% to 25% [73]. Clonal sequencing is more sensitive, but also more expensive and time-consuming. These limitations are overcome by a technique known as deep sequencing, which

Management of antiviral failure

Failures to DAA combinations in pivotal trials are usually related to relapse and occur most often in treatment-experienced patients with cirrhosis infected by GT1a or GT3. In non-cirrhotic patients, failure is unusual and occurs only in those receiving short therapies (<12 weeks). Virologic breakthrough during treatment is uncommon and mainly related to noncompliance. Antiviral failure is associated with emergence of drug-resistant strains.

In patients who fail to respond to multiple DAA

Conclusions

In summary, HCV drug resistance is an upcoming clinical issue. Patients who fail first-generation PIs can be salvaged with a combination of SOF plus an NS5A inhibitor, with excellent SVR rates. However, the most appropriate therapy for patients who fail multiple DAA regimens remains to be determined. In the interim, prudence is the best advice. Patients with mild disease should wait for the results of drugs with greater activity against NS5A resistance. Patients with cirrhosis who urgently need

Conflict of interest

Maria Buti and Mar Riveiro-Barciela have received research grants from Gilead Sciences Europe. Maria Buti and Rafael Esteban have served as advisors for Gilead, Bristol Myers Squibb and Novartis.

Authors’ contributions

Maria Buti (MB) acts as guarantor of this article. Mar Riveiro-Barciela (MRB) performed the data acquisition. MB, MRB and Rafael Esteban (RE) drafted the manuscript. All authors approved the final version of the article.

Acknowledgement

English writing support was provided by Celine Cavallo.

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ReviewManagement of direct-acting antiviral agent failures

Summary

Introduction

Section snippets

Triple therapy with first-generation NS3-4A protease inhibitors (PIs)

Variability of hepatitis C virus

Methods for detecting resistance-associated variants

Management of antiviral failure

Conclusions

Conflict of interest

Authors’ contributions

Acknowledgement

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Review
Management of direct-acting antiviral agent failures