On Again, Off Again … On Again? The Role of Resistance Testing in the Current Era of HCV Therapy

The hepatitis C virus is primed to develop resistance to direct acting antiviral drugs (DAAs). This stems from several aspects of HCV biology including an extraordinary rate of viral turnover in infected individuals and the error-prone nature of the viral RNA dependent RNA polymerase. Assumptions based on these characteristics led to modeling studies that predicted that every possible single and double mutant virus is created daily in chronically infected individuals. These assertions, combined with data from protease inhibitor monotherapy studies in humans, demonstrated the rapid emergence of viral resistant variants and led to early declarations that resistance to HCV DAAs had the potential to significantly impact clinical treatment responses, particularly in cases of re-treatment of patients who had previously failed DAA containing therapy.

These concerns were further supported by Phase 3 data of simeprevir, an NS3 protease inhibitor, plus pegylated interferon and ribavirin, which demonstrated a significant negative impact of baseline resistance (in the form of the Q80K variant) in genotype 1a patients treated with this combination. Based on this data, we saw the first FDA label indicating that alternative therapy should be selected in individuals with the Q80K, effectively ushering in the first era of HCV resistance testing. Resistance testing was “on,” sort of.

In practice, simeprevir was rarely used in combination with interferon and ribavirin. Sofosbuvir, a potent nucleotide polymerase inhibitor with an extremely high barrier to resistance, was approved at roughly the same time. Based on the COSMOS data, these two medications were used in combination as the first widely-available interferon-free HCV DAA regimen. While there were still questions regarding the impact of the Q80K variant on responses with this regimen, real-world cohort data suggested few clinicians ordered resistance testing before embarking on a treatment course with sofosbuvir plus simeprevir.

Before prospective data on the impact of resistance and the role resistance testing might play in optimizing patient management were available, Phase 3 data from the next set of DAA regimens quickly cast doubt on whether resistance would play a significant role in HCV management. The arrival of the data from the sofosbuvir/ledipasvir and paritaprevir/r/ ombitasvir plus dasabuvir Phase 3 programs, with SVR rates greater than 95% for nearly all genotype 1 groups and subpopulations swung the pendulum toward the opposite conclusion: resistance testing was “off again.” In the background of these extremely high overall SVR rates, it is difficult to define additional baseline factors after accounting for cirrhosis and treatment status, which negatively impact responses in a significant fashion (either statistically or clinically) when analyzed in a single clinical trial. Indeed most analyses have only found a significant impact in combined data sets with a specific regimen, and then only when multiple negative predictors accumulate in individual patients. Personally, I think HCV resistance (either baseline or selected) should be viewed in much the same fashion, as one of a number of potential negative factors that may only alter treatment responses sufficiently to warrant testing in select clinical scenarios.

So what has changed in the last year to bring HCV resistance “back” once again? Three observations, in my opinion, have combined to bring HCV resistance back to the forefront of the HCV consciousness. First, data presented on the retreatment of patients who had failed sofosbuvir/ledipasvir indicated that those with NS5A resistance going into retreatment with the same regimen for a longer period of time did significantly worse than those without resistance (60 percent SVR vs. 100 percent SVR, respectively).1 Second, it appears once NS5A resistance is selected those resistant variants persist in individuals for prolonged periods of time, in most cases more than two years.2

Importantly, these observations are all in an HCV treatment landscape where NS5A inhibitors are a component of the vast majority of DAAregimens and there is broad-cross resistance among currently available NS5A inhibitors. Finally, combined data sets looking at the impact of baseline NS5A resistant variants clearly show a negative impact of variants on treatment responses. In fact, in a combined analysis of genotype 1a patients treated with grazoprevir (a next generation NS3 protease inhibitor) in combination with elbasvir (NS5A inhibitor), only baseline HCV viral load and the presence of NS5A resistance were significant predictors of response in a multivariable analysis.3 Similarly, combined data sets with sofosobuvir/ledipasvir treated patients show consistently lower SVR rates in those with baseline NS5A resistance.

If resistance testing is back, when should it be done? Two scenarios make sense for HCV resistance testing currently: 1) after failure of an NS5A-containing DAA regimen and 2) at baseline to guide treatment approaches when using certain regimens in specific populations. Based on limited data, patients failing an NS5A-containing regimen who do not have NS5A resistance may be retreated with a regimen containing an NS5A inhibitor, provided other things are also changed, such as extension of treatment duration or the addition of ribavirin. In contrast, those with NS5A resistance seem most likely to benefit from the addition of DAAs with different mechanisms of action.

The case for baseline resistance testing is best exemplified by treatment with grazoprevir/ elbasvir in patients with genotype 1a HCV. In this case, baseline NS5A resistance testing is the best indicator for choosing the appropriate treatment regimen;12 weeks without ribavirin in those with no NS5A resistance and 16 weeks plus ribavirin in those with baseline resistance. Indeed, the product label for this regimen, recently approved by FDA, does recommend baseline NS5A resistance testing in genotype 1a patients.

Is resistance here to stay? It seems unlikely to me. The next wave of DAA regimens will not only be truly pangenotypic, but are composed of inhibitors with improved resistance profiles. Combine this with triple-class regimens, which are not far off, and it becomes difficult to envision a large role for HCV resistance testing, even in patients who have previously failed a DAA regimen. A small resistance niche may still exist, not for determining which regimen, but in determining how a given regimen will be used. For example, does treatment duration need to be extended or ribavirin added in select situation with resistance present? However, for the vast majority of patients resistance testing will (again) not be needed. Of course, we have underestimated HCV resistance before … and maybe I am again.

Dr. Wyles has worked on research supported by grants from AbbVie, BMS, Gilead, Merck and Tacere, and serves as a consultant to AbbVie, BMS, Gilead and Merck.

References

1. Lawitz, E. et al. O005.z, E. . BIBL {“custom”:[s who failed 8 or 12 weeks of ledipasvir/sofosbuvir-based regimens with ledipasvir/sofosbuvir for 24 weeks. J. Hepatol. 62, Supplement 2, S192 (2015).
2. Pedrosa MC, Farraye FA, Shergill AK et al. Minimizing occupational hazards in endoscopy: personal protective equipment, radiation safety, and ergonomics. Gastrointest Endosc 2010, 72:227-35
3. Ridtitid W, Cote, GA, Leung W et al. Prevalence and risk factors for musculoskeletal injuries related to endoscopy. Gastrointest Endosc 2015,81:294- 302

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