Table 1:

Key outstanding issues related to HCV treatment

	Comment
HCV resistance type
HCV resistance
NS5B polymerase resistance to nucleotides	This class of RASs appears to have little impact on treatment outcomes with current nucleoside-based regimens (ie, sofosbuvir) and should not influence DAA regimen selection.
NS5A resistance	Key RASs may be clinically relevant for genotype 1a and 3 treatment outcomes, but not for genotype 1b or 2 outcomes.
NS3/4A protease resistance	NS3/4A RASs should have little impact on treatment selection because they typically do not influence treatment outcome with current first-line regimens.
Triple-class DAA combination regimens	The presence of RASs, including multiclass combinations in DAA treatment-experienced patients, can be overcome by triple-class combination regimens.
Ribavirin	Ribavirin continues to play a role in managing some scenarios involving RASs. The addition of ribavirin to elbasvir–grazoprevir maximizes SVR outcomes in treatment-naïve, genotype 1a infected patients with key NS5A RASs. The impact of ribavirin on SVR is more pronounced in patients receiving salvage treatment and in those with decompensated liver disease.
RAS management	All treatment-experienced patients, especially those with advanced fibrosis, may benefit from baseline resistance testing because the risk of virologic failure with a suboptimal regimen clearly has negative consequences for subsequent retreatment efforts. In these populations, baseline resistance testing provides an additional tool for selection of the most optimal DAA regimen and for informing the decision for or against ribavirin inclusion.
Decompensated cirrhosis
General statements	Decompensated patients should be evaluated for treatment in an expert setting. If a regimen with a predicted high likelihood of safety and virologic success is available, then treatment should be pursued. Protease inhibitors are contraindicated.
Treatment naive	Although lower than in those with compensated cirrhosis, SVR rates are high, ranging from 80% to 90%.
Failed previous DAA therapy	Data are lacking to inform clear recommendations.
HCC risk after HCV cure
All patients with cirrhosis	Screening in patients with cirrhosis is mandatory but often omitted.
De novo HCC	Little evidence supports concerns regarding increased HCC risk in DAA recipients without a previous HCC history.
Recurrent HCC	The risk for recurrent HCC remains unclear in the context of DAA exposure.

DAA = Direct-acting antiviral; HCC = Hepatocellular carcinoma; HCV = Hepatitis C virus; NS = nonstructural protein; RAS = Resistance-associated substitutions; SVR = sustained virologic response.