In this viral hepatitis case series, we highlight common patient case scenarios and the critical decision making that informs selection of optimal patient management strategies. This commentary features a woman with cirrhosis who is seeking retreatment after failure of first-line direct-acting antiviral (DAA) therapy. The impact of the recent approvals of sofosbuvir (SOF)/velpatasvir (VEL)/voxilaprevir (VOX) and glecaprevir (GLE)/pibrentasvir (PIB) on treatment for this class of patient is discussed.
Case Details A 59-year-old white woman with compensated cirrhosis (elastography 24 kPa) and genotype 1a HCV infection was previously treated with SOF/ledipasvir (LDV) for 12 weeks, but she experienced a relapse at posttreatment Week 6. She reports strict adherence to her previous regimen and is seeking advice on retreatment options.
Positioning Patients With Previous HCV Treatment Failure for Success With extremely high cure rates reported in clinical trials and replicated in real-world data, modern DAAs effectively cure the vast majority of patients infected with HCV. However, for a small minority of patients, treatment failure is a great concern. Before initiating HCV retreatment, it is important to evaluate why previous therapy failed. The key issues to consider include patient factors (eg, adherence, drug interactions that may have affected absorption) and virologic factors (eg, resistance). Careful examination of these characteristics will help to ensure that the same issues do not negatively influence retreatment. This is especially important because, for most patients, it will be difficult to treat a third time if 2 attempts are unsuccessful.
Two HCV treatment regimens - GLE/PIB and SOF/VEL/VOX - were recently approved by the FDA and have added significantly to our treatment armamentarium for DAA-experienced patients. The indications for these regimens are shown in Table 1.
Table 1. FDA Indications for SOF/VEL/VOX, GLE/PIB by Previous Treatment
If graphs do not show - see in links above or in https://www.clinicaloptions.com/Hepatitis/Treatment%20Updates/2017%20HEP%20Alerts/ClinicalThought/CT2.aspx
Note that the AASLD/IDSA recommendations do not weigh these regimens equally for some patients, including those for whom an NS5A inhibitor-containing regimen has failed (Table 2). For patients with NS5A inhibitor failure, such as the case patient, SOF/VEL/VOX is the recommended regimen, and GLE/PIB is considered an alternative regimen.
Table 2. AASLD/IDSA Recommended Regimens for DAA-Experienced Patients
If graphs do not show - see in links above or in https://www.clinicaloptions.com/Hepatitis/Treatment%20Updates/2017%20HEP%20Alerts/ClinicalThought/CT2.aspx
Let's look at some of the data supporting the use of these newly approved regimens for DAA-experienced patients.
SOF/VEL/VOX The once-daily, fixed-dose combination of SOF/VEL/VOX adds VOX, a pangenotypic NS3/4A PI, to previously approved SOF/VEL and was studied in 2 key retreatment trials, POLARIS-1 and POLARIS-4, with very impressive results.
The POLARIS-1 study included patients with genotype 1-6 HCV infection who had previous NS5A inhibitor experience. The overall SVR12 rate with 12 weeks of SOF/VEL/VOX was 96% in 263 patients. It is notable that all 6 relapses and the 1 virologic breakthrough occurred in patients with cirrhosis. These failures arose predominantly with genotypes 1a or 3 HCV infection. However, even in these "harder-to-treat" groups, the overall SVR12 rates ranged from 91% to 96%, emphasizing that the vast majority of patients will still likely respond.
The POLARIS-4 study compared SOF/VEL/VOX with SOF/VEL in treatment-experienced patients who had never been exposed to an NS5A inhibitor. One might have expected SOF/VEL to be equally effective in these NS5A-naive patients, but data clearly showed the superiority of 12 weeks of SOF/VEL/VOX, as overall SVR12 rates were 98% for SOF/VEL/VOX and 90% for SOF/VEL. Only 1 relapse was reported with SOF/VEL/VOX compared with 15 virologic failures in those receiving SOF/VEL. The cause for this heightened failure rate with SOF/VEL was not entirely obvious but suggests that some patients may be just more difficult to cure.
It is worth noting that the AASLD/IDSA guidelines slightly differ from the SOF/VEL/VOX product label for patients relapsing after a SOF-based, non-NS5A inhibitor-containing regimen, as the benefit of SOF/VEL/VOX was only clearly demonstrated for patients with genotypes 1a and 3 HCV infection. Those with other genotypes actually did very well with SOF/VEL alone. As such, the label recommends SOF/VEL/VOX for genotypes 1a and 3 only (Table 1), whereas the AASLD/IDSA guidelines expand this to genotypes 4, 5, and 6 (Table 2), likely with the rationale that the therapy is generally well tolerated and the small benefits of SOF/VEL/VOX over SOF/VEL may have been missed given the numbers of patients included. The guidelines also recommend SOF/VEL/VOX in genotypes 3-6 for patients previously failing PI-containing regimens. These are subtle, but important, differences.
In an integrated analysis, no obvious resistance profile identified patients who failed, and therefore, one could argue that pretreatment resistance testing is not necessary. In fact, current AASLD/IDSA recommendations do not require resistance testing for treatment-experienced patients prior to SOF/VEL/VOX retreatment. At this point, however, it may still be valuable to collect resistance data because the number of patients who failed in these trials was small, making the examination of clear predictors difficult. It may well be that some small subgroup of patients will need intensification of therapy - either a longer duration or the addition of RBV - although this would require additional study.
GLE/PIB GLE/PIB is a pangenotypic fixed-dose combination of an NS3/4A PI and NS5A inhibitor. Although this regimen is highly effective for treatment-naive patients, with activity against many common resistance associated substitutions, the SVR12 rates for retreatment have not been quite as impressive as those seen with SOF/VEL/VOX, particularly in patients with preexisting NS5A resistance.
MAGELLAN-1, Part 2, evaluated GLE/PIB in HCV-infected adults previously failing PI and/or NS5A inhibitor therapy. Overall SVR12 rates were 89% for 12 weeks of therapy and 91% for 16 weeks. This rate dropped to 83% in patients with baseline NS5A resistance receiving 12 weeks of GLE/PIB. Notably, only genotypes 1 and 4 were included in this study, and the study presentation did not break down SVR12 rates by subgenotype, even though patients with genotype 1a HCV infection would be expected to fare worse than others. These data suggest that GLE/PIB is potentially a suboptimal regimen for retreatment after an NS5A-based regimen.
The one area where GLE/PIB may be particularly useful, however, is in patients with renal failure, as this regimen is safe for patients with advanced kidney disease; SOF-based regimens are not currently advised for these patients. The patient subgroup that remains a challenge is those with decompensated cirrhosis, as both of the salvage regimens discussed here contain PIs and are not recommended in Child-Pugh B/C disease, with GLE/PIB contraindicated in patients with Child-Pugh C disease.
Bringing the Data Together When taken together, these data give us confidence that we can retreat the vast majority of patients for whom a first-line DAA regimen has failed, and for most patients, the retreatment strategy will be SOF/VEL/VOX. For the patient case discussed above, 12-week SOF/VEL/VOX is the choice recommended by the AASLD/IDSA guidance. The patient does not demonstrate any obvious barriers to this therapy, such as Child-Pugh B/C disease.
Dr. Feld's comments: about re-treatment, with Mavyret (glec/pib) versus Vosevi (sof/vel/vox) - similar to info found about re-treatment in the larger link (2017 Resource - Treatment Options ) and also covered in (2017 Resource - AASLD HCV Treatment Guidelines) - P. 38 of 247 - click on "re-treatment" link..
Clinical Care Options - Clinical Thought
The Impact of New Options for DAA-Experienced Patients With HCV - Jordan J. Feld, MD, MPH - 11/16/2017
https://www.clinicaloptions.com/Hepatitis/Treatment%20Updates/2017%20HEP%20Alerts/ClinicalThought/CT2.aspx
In this viral hepatitis case series, we highlight common patient case scenarios and the critical decision making that informs selection of optimal patient management strategies. This commentary features a woman with cirrhosis who is seeking retreatment after failure of first-line direct-acting antiviral (DAA) therapy. The impact of the recent approvals of sofosbuvir (SOF)/velpatasvir (VEL)/voxilaprevir (VOX) and glecaprevir (GLE)/pibrentasvir (PIB) on treatment for this class of patient is discussed.
Case Details
A 59-year-old white woman with compensated cirrhosis (elastography 24 kPa) and genotype 1a HCV infection was previously treated with SOF/ledipasvir (LDV) for 12 weeks, but she experienced a relapse at posttreatment Week 6. She reports strict adherence to her previous regimen and is seeking advice on retreatment options.
Positioning Patients With Previous HCV Treatment Failure for Success
With extremely high cure rates reported in clinical trials and replicated in real-world data, modern DAAs effectively cure the vast majority of patients infected with HCV. However, for a small minority of patients, treatment failure is a great concern. Before initiating HCV retreatment, it is important to evaluate why previous therapy failed. The key issues to consider include patient factors (eg, adherence, drug interactions that may have affected absorption) and virologic factors (eg, resistance). Careful examination of these characteristics will help to ensure that the same issues do not negatively influence retreatment. This is especially important because, for most patients, it will be difficult to treat a third time if 2 attempts are unsuccessful.
Two HCV treatment regimens - GLE/PIB and SOF/VEL/VOX - were recently approved by the FDA and have added significantly to our treatment armamentarium for DAA-experienced patients. The indications for these regimens are shown in Table 1.
Table 1. FDA Indications for SOF/VEL/VOX, GLE/PIB by Previous Treatment
If graphs do not show - see in links above or in https://www.clinicaloptions.com/Hepatitis/Treatment%20Updates/2017%20HEP%20Alerts/ClinicalThought/CT2.aspx
Note that the AASLD/IDSA recommendations do not weigh these regimens equally for some patients, including those for whom an NS5A inhibitor-containing regimen has failed (Table 2). For patients with NS5A inhibitor failure, such as the case patient, SOF/VEL/VOX is the recommended regimen, and GLE/PIB is considered an alternative regimen.
Table 2. AASLD/IDSA Recommended Regimens for DAA-Experienced Patients
If graphs do not show - see in links above or in https://www.clinicaloptions.com/Hepatitis/Treatment%20Updates/2017%20HEP%20Alerts/ClinicalThought/CT2.aspx
Let's look at some of the data supporting the use of these newly approved regimens for DAA-experienced patients.
SOF/VEL/VOX
The once-daily, fixed-dose combination of SOF/VEL/VOX adds VOX, a pangenotypic NS3/4A PI, to previously approved SOF/VEL and was studied in 2 key retreatment trials, POLARIS-1 and POLARIS-4, with very impressive results.
The POLARIS-1 study included patients with genotype 1-6 HCV infection who had previous NS5A inhibitor experience. The overall SVR12 rate with 12 weeks of SOF/VEL/VOX was 96% in 263 patients. It is notable that all 6 relapses and the 1 virologic breakthrough occurred in patients with cirrhosis. These failures arose predominantly with genotypes 1a or 3 HCV infection. However, even in these "harder-to-treat" groups, the overall SVR12 rates ranged from 91% to 96%, emphasizing that the vast majority of patients will still likely respond.
The POLARIS-4 study compared SOF/VEL/VOX with SOF/VEL in treatment-experienced patients who had never been exposed to an NS5A inhibitor. One might have expected SOF/VEL to be equally effective in these NS5A-naive patients, but data clearly showed the superiority of 12 weeks of SOF/VEL/VOX, as overall SVR12 rates were 98% for SOF/VEL/VOX and 90% for SOF/VEL. Only 1 relapse was reported with SOF/VEL/VOX compared with 15 virologic failures in those receiving SOF/VEL. The cause for this heightened failure rate with SOF/VEL was not entirely obvious but suggests that some patients may be just more difficult to cure.
It is worth noting that the AASLD/IDSA guidelines slightly differ from the SOF/VEL/VOX product label for patients relapsing after a SOF-based, non-NS5A inhibitor-containing regimen, as the benefit of SOF/VEL/VOX was only clearly demonstrated for patients with genotypes 1a and 3 HCV infection. Those with other genotypes actually did very well with SOF/VEL alone. As such, the label recommends SOF/VEL/VOX for genotypes 1a and 3 only (Table 1), whereas the AASLD/IDSA guidelines expand this to genotypes 4, 5, and 6 (Table 2), likely with the rationale that the therapy is generally well tolerated and the small benefits of SOF/VEL/VOX over SOF/VEL may have been missed given the numbers of patients included. The guidelines also recommend SOF/VEL/VOX in genotypes 3-6 for patients previously failing PI-containing regimens. These are subtle, but important, differences.
In an integrated analysis, no obvious resistance profile identified patients who failed, and therefore, one could argue that pretreatment resistance testing is not necessary. In fact, current AASLD/IDSA recommendations do not require resistance testing for treatment-experienced patients prior to SOF/VEL/VOX retreatment. At this point, however, it may still be valuable to collect resistance data because the number of patients who failed in these trials was small, making the examination of clear predictors difficult. It may well be that some small subgroup of patients will need intensification of therapy - either a longer duration or the addition of RBV - although this would require additional study.
GLE/PIB
GLE/PIB is a pangenotypic fixed-dose combination of an NS3/4A PI and NS5A inhibitor. Although this regimen is highly effective for treatment-naive patients, with activity against many common resistance associated substitutions, the SVR12 rates for retreatment have not been quite as impressive as those seen with SOF/VEL/VOX, particularly in patients with preexisting NS5A resistance.
MAGELLAN-1, Part 2, evaluated GLE/PIB in HCV-infected adults previously failing PI and/or NS5A inhibitor therapy. Overall SVR12 rates were 89% for 12 weeks of therapy and 91% for 16 weeks. This rate dropped to 83% in patients with baseline NS5A resistance receiving 12 weeks of GLE/PIB. Notably, only genotypes 1 and 4 were included in this study, and the study presentation did not break down SVR12 rates by subgenotype, even though patients with genotype 1a HCV infection would be expected to fare worse than others. These data suggest that GLE/PIB is potentially a suboptimal regimen for retreatment after an NS5A-based regimen.
The one area where GLE/PIB may be particularly useful, however, is in patients with renal failure, as this regimen is safe for patients with advanced kidney disease; SOF-based regimens are not currently advised for these patients. The patient subgroup that remains a challenge is those with decompensated cirrhosis, as both of the salvage regimens discussed here contain PIs and are not recommended in Child-Pugh B/C disease, with GLE/PIB contraindicated in patients with Child-Pugh C disease.
Bringing the Data Together
When taken together, these data give us confidence that we can retreat the vast majority of patients for whom a first-line DAA regimen has failed, and for most patients, the retreatment strategy will be SOF/VEL/VOX. For the patient case discussed above, 12-week SOF/VEL/VOX is the choice recommended by the AASLD/IDSA guidance. The patient does not demonstrate any obvious barriers to this therapy, such as Child-Pugh B/C disease.