Sofosbuvir/Velpatasvir/Voxilaprevir: A Highly Effective Option for Retreatment of Hepatitis C in Difficult-to-treat Patients

Abstract

Treatment for hepatitis C has escalated rapidly since the advent of direct-acting antivirals. Although there are highly efficacious, pangenotypic regimens available as standard of care, 5–10% of patients do not achieve virological cure. The recently approved fixed-dose combination of sofosbuvir, velpatasvir and voxilaprevir provides an option for retreatment in patients who have failed prior regimens and have characteristics which make them difficult to treat. This review provides a summary of the evidence for use of Vosevi®, a fixed-dose combination pill for treatment of hepatitis C in treatment-experienced patients.

Introduction

Hepatitis C infection (HCV) affects 71 million people worldwide and is a leading cause of death globally [1]. Since 2011, the implementation of direct-acting antivirals (DAAs) into HCV treatment regimens as standard of care has dramatically improved the treatment of HCV, with higher treatment efficacy, improved tolerability and ease of dosing with the majority of regimens available in once-daily oral dosing [2–5]. Since 2013, sofosbuvir, (SOF; trade name Solvadi^®, Gilead Sciences), a nucleotide NS5B polymerase inhibitor, has been integral in advancing the use of oral agents for HCV treatment due to its pangenotypic activity, high tolerability and high barrier to resistance [6,7]. In 2014, SOF was co-formulated with ledipasvir (LDV), an NS5A inhibitor, in a fixed-dose combination named Harvoni^® (Gilead Sciences). The approval of the combination was the advent for a new era of HCV treatment, however, it was not approved to treat genotype (GT) 2 or 3 infection [8]. Therefore, in 2016, the United States Food and Drug Administration (FDA) approved the fixed-dose combination of SOF and velpatasvir (VEL), a second-generation NS5A inhibitor, as a fixed-dose combination named Epclusa^® (Gilead Sciences), which became the first available pangenotypic oral regimen [9]. Then, in 2017, Gilead Sciences formulated SOF, VEL and a new NS3/4 protease inhibitor, voxilaprevir (VOX) as a fixed-dose combination named Vosevi^®, for use in patients who are treatment-experienced and failed prior treatment [10].

The goal of HCV treatment is to achieve a sustained virological response (SVR; or absence of plasma HCV RNA levels 12 weeks after completion of treatment) [5], and in order to do so, all quasispecies of the virus must be eliminated [11]. DAAs are associated with high rates of viral clearance, however, up to 5–10% of patients do not achieve SVR [12]. Many factors are associated with treatment failure, including infection with GT 1a or GT 3, presence of cirrhosis, previous exposure to interferon (IFN)-containing regimens [13,14] and the presence of viral resistance-associated substitutions (RASs) [13,15], which are nucleic acid substitutions in the HCV viral genome associated with reduced susceptibility to DAAs. The presence of RASs can pose a challenge in retreatment of patients with HCV by contributing to viral relapse [16] and limiting medication options [17–21]. Certain combinations of RASs have demonstrated greater than a 1,000-fold reduced susceptibility to certain DAAs such as LDV [22], however, the impact of baseline RASs in achieving SVR is conflicting. In a study by Lawitz et al. [23], 41 patients who had failed a previous treatment regimen of SOF/ LDV with or without ribavirin (RBV) for 8–12 weeks were retreated with SOF/LDV + RBV for 24 weeks. The presence or absence of RASs was shown to be the biggest predictor of SVR: 100% of the 11 patients without RASs achieved SVR₁₂, compared to only 60% of the 30 patients with baseline RASs. However, in a retreatment study by Wilson et al. [22], SVR₁₂ was achieved in 91% (31/34) of GT 1 patients who had failed a 4–6 week treatment of LDV/SOF (likely due to an insufficient initial treatment duration) and were re-treated with the same regimen for 12 weeks. The authors did not find that NS5A RASs affected SVR₁₂ (29 patients, or 89%, had NS5A RASs prior to retreatment). VEL may offer an advantage for therapeutic use as it has an improved susceptibility over LDV to key NS5A RASs, such as Q30, L31 and Y93 [24]. Though there are conflicting data on the clinical relevance of RASs in terms of achieving SVR (mainly due to the small sample size of retreatment studies), the majority of retreated patients appear to achieve SVR, so additional factors such as duration of retreatment and histological stage may also influence the probability of cure.

For patients who are DAA-experienced and require retreatment, genotyping assays can screen for pre-existing RASs to guide regimen choice, as real-life studies have shown successful retreatment of HCV when the regimen was resistance-guided [25–27]. Unfortunately, few therapeutic options are available for patients who have prior DAA exposure. Clinical trials have shown that the combination of SOF/VEL is effective in patients for retreatment in patients who have GT 1 or GT 3 infection and had prior treatment with a protease inhibitor, pegylated interferon-α (PEG-IFN-α), or RBV [9,28]. In a Phase II study by Pianko et al. [28], 321 treatment-experienced patients with HCV GT 1 or GT 3 received 12 weeks of SOF/VEL, with or without RBV. Of note, patients with GT 3 infection who were included in the trial had not had prior exposure to a DAA. The addition of RBV did not increase virological cure [28]; SVR₁₂ rates were 100% with use of SOF/ VEL alone.

Subsequently, the ASTRAL series of Phase III trials (ASTRAL 1–5) demonstrated the efficacy and safety of SOF/VEL among patients with HCV GT 1–6 infection, as well as varying levels of cirrhosis [9]. Patients were treatment-experienced with PEG-IFN-α/RBV and/or a protease inhibitor. In the ASTRAL-1 study [29], treatment-naive and treatment-experienced patients with GT 1, 2, 4, 5 or 6 infection received SOF/VEL daily for 12 weeks or placebo. The overall SVR₁₂ rate was 99% and there was no difference in adverse events between the intervention and placebo groups. In the ASTRAL-4 study [29], 267 treatment-naive and treatment-experienced patients with moderate decompensated cirrhosis (Child-Pugh-Turcotte Class B) were treated with SOF/ VEL. Patients who received SOF/VEL alone had an SVR₁₂ rate of 83%, while those who received SOF/VEL in addition to RBV for 12 weeks had an SVR₁₂ rate of 94%. Though both of these studies demonstrated the efficacy of SOF/VEL in patients who were treatment-experienced or had decompensated cirrhosis, an important limitation exists: in the ASTRAL-1 study [30], which included treatment-experienced GT 1 patients, and the ASTRAL-4 study [31], patients who had prior treatment experience with an NS5A or NS5B inhibitor were excluded.

Therefore, Gane et al. [32] evaluated the safety and efficacy of SOF/VEL with weight-based RBV for 24 weeks in patients with HCV infection of any GT who had not achieved SVR after prior treatment with NS5A-containing DAA regimens. Out of 65 patients, 59 (91%) were cured. Notably, of the GT-3-infected patients, 13 had NS5A mutations detected at the start of the study and this was thought to impact the rate of cure: among those with baseline RASs, 77% of patients achieved SVR₁₂, compared to 100% without [32]. The decreased SVR₁₂ rate among patients with GT 3 and RASs was also seen in the ASTRAL-3 study [33], which evaluated the efficacy of SOF/VEL in patients with GT 3 infection. The overall SVR₁₂ rate was 95%; however, among those with baseline NS5A RASs, the SVR₁₂ rate was 88% and 97% for those without RASs [33].

In order to overcome the challenges to retreatment caused by RASs and the varying efficacy of SOF/VEL in patients with RASs, Gilead Sciences formulated VOX, a pangenotypic NS3/4A protease inhibitor with improved coverage of GT 1 NS3 RASs associated with other HCV protease inhibitors [34], with SOF and VEL. This pangenotypic regimen, called Vosevi^®, is an option for patients who have been previously treated with a regimen containing an NS5A inhibitor, and is also indicated for retreatment in patients with GT 1a or 3 infection who have been previously treated with a SOF-containing regimen [10]. Vosevi^® received FDA approval in July 2017.

Clinical pharmacology

The pharmacology of SOF and VEL have been reviewed elsewhere extensively [6,9]. Briefly, SOF is an NS5B nucleotide polymerase inhibitor and has pangenotypic activity since the catalytic site of the NS5B RNA-dependent RNA polymerase (Figure 1) is highly conserved across HCV GT 1–6 [6,9]. VEL is a second-generation NS5A inhibitor (Figure 1) which also has pangenotypic activity [9]. SOF is metabolized by Cathepsin A, liver carboxylesterase 1 and human equilibrative nucleoside transporter (HENT1), so it has few interactions with the majority of medications metabolized through cytochrome (CY) P450 pathways [9]. VEL is metabolized by the CYP450 system (CYP2B6, CYP2C8 and CYP3A4) [9].

Figure 1

Mechanism of action: SOF/VEL/VOX (Vosevi)

VOX, previously known as GS-9857 in clinical trials, is a noncovalent, reversible inhibitor of the NS3/4A serine protease (Figure 1), necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A and NS5B proteins) and essential for viral replication [10]. It is metabolized by the CYP450 system (CYP1A2, CYP2C8 and primarily CYP3A4) [10], and therefore contraindicated in patients with decompensated cirrhosis.

Vosevi^® is a single, fixed-dose combination pill containing SOF 400 mg, VEL 100 mg and VOX 100 mg. It is indicated to treat patients with or without cirrhosis (compensated), any GT of infection, and previous treatment with an NS5A inhibitor or a SOF-containing regimen. No dosage recommendation can be made for anyone with an estimated glomerular filtration rate <30 ml/min/1.73 m², due to high exposures of the SOF metabolite.

Drug–drug interactions

Since SOF, VEL and VOX, are all substrates of the P-glycoprotein drug transporter, and VEL and VOX are substrates of the CYP450 system, it is important that patients undergo a thorough medication reconciliation before starting treatment. Drugs that are inducers of P-glycoprotein and/or inducers of CYP2B6, CYP2C8 or CYP3A4 may decrease the plasma concentration of any of the three drugs in Vosevi, and should not be used concomitantly [10]. Examples include St John's Wort and carbamazepine. Also, the use of OATP (organic-anion-transporting polypeptide) inhibitors (for example, cyclosporine), which may substantially increase exposure of VOX is not recommended.

Acid reducing agents must be used cautiously with Vosevi since these medications can reduce the concentration of VEL by increasing gastric pH [10]. The only proton pump inhibitor (PPI) that has been studied with Vosevi is omeprazole (20 mg); otherwise, concomitant use of PPIs should be avoided. If antacids are used, they should be separated by Vosevi administration by 4 h. H2-receptor antagonists, such as famotidine, should be used simultaneously or staggered from Vosevi, in doses that do not exceed the equivalent of famotidine 40 mg twice daily [10].

Amiodarone, anticonvulsants (carbamazepine, phenytoin, phenobarbital and oxcarbazepine), rifampin and cyclosporine are contraindicated with the use of Vosevi, and monitoring of digoxin levels and dabigatran is recommended when co-administered with Vosevi [10]. It is also recommended that the lowest approved dose of statin be used due to concern for myopathy and/or rhabdomyolysis, with the exception of rosuvastatin and pitavastatin, which are contraindicated [10].

There are several drug–drug interactions with Vosevi and antiretroviral therapy which must be considered. The protease inhibitors atazanavir, lopinavir, tipranavir and ritonavir are not recommended for use with Vosevi, as well as the non-nucleoside reverse transcriptase inhibitor, efavirenz. For patients who are on Vosevi and tenofovir-containing regimens concomitantly, renal function should be closely monitored.

Side effects

Based on data from Phase I and Phase II clinical trials (as discussed below), side effects of Vosevi are few. The most common, occurring in more than 10% of those receiving a 12-week course, are headache, fatigue, diarrhoea and nausea [10]. The rate of adverse events in clinical trials for Vosevi is similar to that of Epclusa, however, diarrhoea and nausea were not commonly reported with Epclusa [35].

Resistance

Resistance to SOF has been rarely reported and is likely not clinically relevant [6], and VEL appears to have a higher barrier to resistance than LDV [24]. In vitro, resistance to VOX was detected with NS3/4 protease-inhibitor RASs at positions 41, 156 and 168. Substitutions involving position 156 in particular confer a greater than 100-fold reduced susceptibility to VOX [10]. In a study by Lawitz et al. [34], the development of NS3 resistance with VOX monotherapy in patients with GT 1–4 disease was 12% (7/53; based on a 15% deep sequencing resistance assay cutoff). The lack of selection of NS3 RASs in the majority of patients demonstrates a moderate resistance barrier for VOX, which is amplified when used in combination with SOF and VEL.

Phase I and II clinical trials

Phase I studies established the safety, tolerability, antiviral activity and pharmacokinetics of GS-9857 (VOX) in patients with chronic HCV GT 1–4 infection [36–38]. Phase II studies demonstrated antiviral efficacy for GS-9857 with SOF/VEL and established efficacy in all GTs of HCV infection, treatment-experienced patients and patients with cirrhosis (Table 1).

Table 1

Summary of Phase II clinical trials

Study	Cohort	Patient population	n	Cirrhosis	Regimen	Duration	SVR₁₂, %
Lawitz et al. [39]	Cohort 1	GT 1, treatment- naive	33	Cirrhosis	SOF/VEL/VOX	8 weeks	94
			31		SOF/VEL/VOX + RBV	8 weeks	81
			34	No cirrhosis	SOF/VEL/VOX	6 weeks	71
			36		SOF/VEL/VOX	8 weeks	100
	Cohort 2	GT 1, DAA-experienced	32	Cirrhosis	SOF/VEL/VOX	12 weeks	100
			31	No cirrhosis	SOF/VEL/VOX	12 weeks	100
Gane et al. [40]	Cohort 1	GT 2–6, treatment-naive	33	No cirrhosis	SOF/VEL/VOX	6 weeks	88
		GT 2–6, treatment-naive	30	Cirrhosis	SOF/VEL/VOX	8 weeks	93
	Cohort 2	GT 2–6, treatment-experienced	36	No cirrhosis	SOF/VEL/VOX	12 weeks	100
		GT 2-6, treatment-experienced	29	Cirrhosis	SOF/VEL/VOX	12 weeks	97
LEPTON [41]		GT 1, treatment-experienced with PEG-IFN-α and RBV	17	Cirrhosis	SOF/VEL/VOX	8 weeks	100
		GT 1, treatment-experienced with protease inhibitor	28	+/- Cirrhosis	SOF/VEL/VOX	8 weeks	89
		GT 3, treatment-experienced with PEG-IFN-α and RBV	19	Cirrhosis	SOF/VEL/VOX	8 weeks	100
		GT 3, treatment-experienced with DAA	4	+/- Cirrhosis	SOF/VEL/VOX	8 weeks	100
TRILOGY-3 [44]		GT 1, treatment-experienced	24	+/- Cirrhosis	SOF/VEL/VOX	12 weeks	100
			25	+/- Cirrhosis	SOF/VEL/VOX + RBV	12 weeks	96

DAA, direct-acting antiviral; GT, genotype; PEG-IFN, pegylated interferon; RBV, ribavirin; SOF, sofosbuvir; SVR₁₂, absence of plasma HCV RNA levels 12 weeks after completion of treatment; VEL, velpatasvir; VOX, voxilaprevir.

Phase II clinical trials

Lawitz et al. [39] conducted a Phase II, open-label international trial with two cohorts of GT 1 patients. The first cohort included treatment-naive patients, with and without cirrhosis, who received either 6 or 8 weeks of SOF/VEL/VOX. In the second cohort, DAA-experienced patients with and without cirrhosis both received 12 weeks of SOF/VEL/VOX. In the first cohort, cure rates were lower in treatment-naive patients without cirrhosis who received 6 weeks of SOF/VEL/VOX versus 8 weeks (71% [24/34] versus 100% [36/36]). Among those with cirrhosis, RBV did not increase the SVR₁₂ rate when added to SOF/VEL/VOX (94% [31/33] without RBV versus 81% [25/31] with RBV). In the second cohort of treatment-experienced patients, all patients achieved SVR₁₂, regardless of whether they had cirrhosis. Pre-existing NS5A RASs did not appear to affect SVR₁₂ rates. This study concluded that 8 weeks of treatment was effective in GT 1 treatment-naive patients, and 12 weeks was effective in patients with GT 1 infection and prior DAA treatment experience. In addition, SOF/VEL/VOX was also shown to be safe in patients with compensated cirrhosis.

Gane et al. [40] conducted another Phase II study in patients with GT 2–6 infection. In this study, both treatment-naive and treatment-experienced patients with or without cirrhosis were enrolled. In cohort 1, treatment-naive patients without cirrhosis received 6 weeks of treatment with SOF/VEL/VOX and patients with cirrhosis received 8 weeks. Cohort 2 included patients who had experienced treatment with PEG-IFN-α or DAAs. Among treatment-naive patients, SVR₁₂ rates for patients without cirrhosis (6 weeks of treatment) and those with cirrhosis (8 weeks of treatment) were 88% (29/33) and 93% (28/30), respectively. Among treatment-experienced patients (who received 12 weeks of treatment), SVR₁₂ rates were 100% (36/36) for those without cirrhosis and 97% (28/29) for those with cirrhosis. Among patients with GT 3 and cirrhosis, those who were treatment-naive received 8 weeks of treatment and those who were treatment-experienced received 12 weeks of treatment. Both groups had an SVR₁₂ rate of 94% (17/18 and 16/17, respectively). Among treatment-experienced patients who had received prior DAA therapy, those without cirrhosis had an SVR₁₂ rate of 100% (36/36), compared to a 97% (28/29) rate in patients with cirrhosis. In 63 of 128 patients enrolled in the study, baseline NS3 or NS5A/5B RASs were detected by deep sequencing with a 1% cutoff. In treatment-naive patients with cirrhosis, SVR₁₂ rates for patients with and without baseline RASs were 92% and 94%, respectively. This study found that 8 weeks of treatment was effective in GT 2, 3, 4 or 6 treatment-naive patients (even those who had cirrhosis), and 12 weeks was effective in patients with prior DAA treatment experience. Similar to the study by Lawitz et al. [39], SOF/VEL/VOX was also shown to be safe in patients with compensated cirrhosis, even with the presence of RASs. In addition, the SVR₁₂ rate was high for patients with both GT 3 infection and cirrhosis (94%), who are often difficult to treat.

The LEPTON [41] study demonstrated the efficacy of only 8 weeks of SOF/VEL/VOX in difficult-to-treat patient populations, including patients who failed prior treatment, GT 3 patients, and those with cirrhosis. In this Phase II study, 161 were enrolled and treated: 120 GT 1 patients and 41 GT 3 patients. Among 17 patients with GT 1 infection and cirrhosis who had previously been treated with PEG-IFN-α and RBV, all (100%) achieved SVR₁₂ after 8 weeks of SOF/ VEL/VOX. 28 patients with GT 1 infection had been previously treated with a protease inhibitor-containing regimen, and 25 (89%) had SVR₁₂. In patients with GT 3 infection and cirrhosis, 8 weeks of SOF/VEL/VOX led to SVR₁₂ in 19/19 (100%) patients who had previously been treated with PEG-IFN-α and RBV and in 4/4 (100%) patients who had previous treatment with a DAA-based regimen. This study also included groups that received 4 or 6 weeks of treatment with SOF/VEL/VOX; the relapse rate was 73% (11/15) in patients who received only 4 weeks of treatment, 19% (15/78) in patients treated for 6 weeks and 4% (3/68) in patients treated for 8 weeks. Pre-existing RASs were present in 76/161 (47%) and 57/161 (35%) of patients when 1% and 15% cutoff were applied, respectively, but these RASs did not predict virological failure, even if patients had prior treatment experience. The SVR₁₂ rate in patients with RASs was 84% (63/75) and 86% (48/56) for the 1% and 15% threshold populations, respectively, and this rate was similar to the SVR₁₂ rate of 81% (68/84) for those who had no baseline RASs. The results from the LEPTON study demonstrated that an 8-week treatment course with SOF/VEL/VOX was the shortest duration that would lead to an acceptable virological response rate in difficult-to-treat populations, including GT 1 and GT 3 treatment-experienced patients with cirrhosis. In addition, similar to the aforementioned studies, the presence of baseline RASs did not predict virological failure. These studies con-firmed the role Vosevi has as a salvage DAA regimen and subsequently led to further development in Phase III clinical trials.

In the aforementioned studies, the most common adverse events were headache, nausea, fatigue and diarrhoea. It should be noted that in the study by Lawitz et al. [39], patients in the RBV group had more fatigue (32%) and anaemia (23%) than patients in the other groups. In the study by Gane et al. [40], 95 of 128 had at least one adverse event, and all but 3 were mild to moderate in severity. All adverse events in the LEPTON [41] study were mild to moderate except for three, found to be unrelated to study drug.

The rate of treatment-emergent RASs in all three studies was low. In the Lawitz et al. [39] study, treatment-emergent RASs by deep sequencing with a 1% cutoff rate were rare (3 of 18; 17%), and no treatment-emergent RASs among relapsers were detected with the 15% cutoff level. There were seven virological failures in the Gane et al. [40] study, and six of them were among treatment-naive patients. Among those six treatment-naive patients, there were the same or fewer to no RASs detected at time of relapse. The one DAA-experienced patient with GT 3a who experienced virological failure had the NS5A RAS Y93H at baseline and relapse and had a treatment-emergent NS3 RAS Q80R (41%), which does not confer in vitro resistance to VOX (it confers a 0.8-fold shift in 50% effective concentration in GT 3a replicon assays). Though the Q80R emerged as a result of VOX drug pressure, it is unclear if this RAS was solely responsible for virological failure. Last, 28 patients in the LEPTON [41] study had viral relapse, but only 2 had treatment-emergent RASs. One was a treatment-naive patient in the 6-week treatment group who had an NS3 V55A emerge at 2% of the viral population at the time of relapse. The second patient was PI-experienced, and after 8 weeks of treatment had an NS5A RAS Y93H emerge at 2% of the viral population (this patient also had a pre-existing NS3 RAS R155K). The low rate of treatment-emergent RASs in these three Phase II trials is consistent with the high barrier to resistance seen in vitro with this potent 3-drug combination [41].

Phase III clinical trials

The Phase III trials of SOF/VEL/VOX evaluated response in patients who had failed prior treatments and compared shorter duration regimens to the standard 12-week regimens (Table 2).

Table 2

Summary of Phase III clinical trials

Study	Patient population	n	Cirrhosis	Regimen	Duration	SVR₁₂, %
POLARIS-1 [42]	Any GT, treatment-experienced	263	+/- Cirrhosis	SOF/VEL/VOX	12 weeks	96
POLARIS-2 [43]	Any GT (except GT 3 with cirrhosis),	501	+/- Cirrhosis	SOF/VEL/VOX	8 weeks	95
	DAA-naive	440		SOF/VEL	12 weeks	98
POLARIS-3 [43]	Any GT, DAA-naive	110	Cirrhosis	SOF/VEL/VOX	8 weeks	96
		109		SOF/VEL	12 weeks	96
POLARIS-4 [42]	GT 1–4	182	+/- Cirrhosis	SOF/VEL/VOX	12 weeks	98
		151	+/- Cirrhosis	SOF/VEL	12 weeks	90

DAA, direct-acting antiviral; GT, genotype; SOF, sofosbuvir; SVR₁₂, absence of plasma HCV RNA levels 12 weeks after completion of treatment; VEL, velpatasvir; VOX, voxilaprevir.

Bourlière et al. [42] conducted the POLARIS-1 and POLARIS-4 trials, assessing the efficacy of SOF/VEL/ VOX in patients with HCV of any GT (including patients with cirrhosis) who had failed prior treatment with DAA-based regimens. In POLARIS-1, patients had prior treatment experience with an NS5A-based regimen, but in POLARIS-4, patients had been previously treated with any DAA regimen that did not include an NS5A inhibitor (with the exception that those who had received only a protease inhibitor with PEG-IFN-α and RBV were not included, since these patients have approved retreatment options). In POLARIS-1, 415 patients were treated, of whom 300 had GT 1 infection. GT 1 patients were randomized 1:1 to receive SOF/VEL/ VOX or placebo. The patients with non-GT 1 infection all received SOF/VEL/VOX. The overall SVR₁₂ rate was 96%. The SVR₁₂ rates for each GT were: GT 1a 96% (97/101), GT 1b 100% (45/45), GT 2 100% (5/5), GT 3 95% (74/78), GT 4 91% (20/22), GT 5 100% (1/1), GT 6 100% (6/6). The SVR₁₂ rate among those without cirrhosis was 99% and 93% among those with cirrhosis. In POLARIS-4, 333 patients were treated; 182 patients were randomly assigned to receive SOF/VEL/VOX, and 151 received SOF/VEL. No patients with GT 5 or 6 were enrolled in this arm of the study, and all patients with GT 4 (n=19) were enrolled in the SOF/VEL/VOX group. The overall SVR₁₂ rate was 98% among those who received SOF/VEL/VOX and was 90% among those who received SOF/VEL. Among patients without cirrhosis, the SVR₁₂ was 98% among those who received SOF/VEL/VOX and 94% among those receiving SOF/ VEL, compared to 98% and 86%, respectively, among patients with cirrhosis. With regard to pre-existing RASs, there were 248 patients in POLARIS-1 [42] who received SOF/VEL/VOX and for whom viral sequencing data was available; 205 patients (83%) had RASs to NS3 or NS5A inhibitors. Among these patients, 97% (99/205) achieved SVR₁₂, compared to 98% who had no pre-existing RASs. 6 of the 263 patients who received SOF/VEL/VOX in POLARIS-1 had viral relapse; 1 of these patients, with GT 4 infection, had development of the NS5A Y93H RAS. In POLARIS-4 [42], 49% of the patients had pre-existing RASs to NS3 or NS5A inhibitors. Among the patients who received SOF/VEL/ VOX, the SVR₁₂ rate for those with baseline RASs was 100% (83/83) and 99% (85/96) for those without RASs. Among those who received SOF/VEL, only 90% (63/70) and 89% (67/75) of those with and without RASs, respectively, achieved SVR₁₂.

Similar to that seen in Phase II trials, the most common adverse events were headache, fatigue, nausea and diarrhoea. In POLARIS-1, 78% of patients on SOF/ VEL/VOX had adverse events, compared to 70% on placebo. In POLARIS-4, the incidence of adverse events was 77% among patients who received SOF/VEL/VOX and 74% among those who received SOF/VEL. In addition, the rate of treatment-emergent RASs was low. In POLARIS-1 [42], six patients had viral relapse; only one patient with GT 4 had a treatment-emergent NS5A Y93H RAS. In POLARIS-4 [42], only one patient in the SOF/VEL/VOX group had viral relapse, and this patient had neither baseline nor treatment-emergent RASs.

The POLARIS-2 and POLARIS-3 studies by Jacob-son et al. [43] evaluated the efficacy of 8 weeks versus 12 weeks of SOF/VEL/VOX in DAA-naive patients. POLARIS-2 enrolled patients with or without cirrhosis and all GTs (except GT 3 patients with cirrhosis) and tested the noninferiority of 8 weeks of SOF/VEL/ VOX to 12 weeks of SOF/VEL (with a 5% noninferiority margin). POLARIS-3 was a separate study which enrolled patients with compensated cirrhosis who were excluded from POLARIS-2, including patients with GT 3 and cirrhosis. The POLARIS-3 study compared rates of SVR after 8 weeks of SOF/VEL/VOX and 12 weeks of SOF/VEL. In POLARIS-2 [43], 882 treatment-naive patients with GT 1–4 infection were randomized to receive SOF/VEL/VOX for 8 weeks or SOF/VEL for 12 weeks. There were 48 patients with GT 5 and 6 infection who were in the SOF/VEL/VOX group. The SVR₁₂ rate of patients in the 8-week group was 95% and did not meet the criterion for noninferiority to 12 weeks of SOF/VEL, which had an SVR₁₂ rate of 98%. The difference in efficacy was attributed to the number of patients with GT 1a infection who received 8 weeks of SOF/VEL/VOX (these patients likely needed 12 weeks for virological cure). In POLARIS-3 [43], 219 patients were randomized to receive SOF/VEL/VOX for 8 weeks and SOF/VEL for 12 weeks. In both treatment groups, 96% of patients achieved SVR₁₂. Viral resistance testing was performed for the patients receiving SOF/VEL/ VOX in POLARIS-2. Among those 498 patients, 250 had NS3 and/or NS5A RASs at baseline. Of those 250 patients, 94% achieved SVR₁₂, compared to an SVR₁₂ rate of 98% among those patients who did not have pre-existing RASs. For patients with GT 1a infection, the SVR₁₂ rate was 89% among those who had preexisting RASs and 95% among those who did not have RASs at baseline. In POLARIS-3, all 46 patients with baseline RASs achieved SVR₁₂.

The most common adverse events in POLARIS-2 and 3 are the same as POLARIS-1 and 4: headache, fatigue, nausea and diarrhoea. In POLARIS-2, 72% of patients who received SOF/VEL/VOX had adverse events, compared to 69% of those receiving SOF/VEL. In the POLARIS-3 trial, 75% of patients who received SOF/ VEL/VOX and 74% of patients who received SOF/VEL had adverse events. Similarly, in these studies, the emergence of RASs after treatment was rare. In POLARIS-2 [43], 21 patients who received SOF/VEL/VOX for 8 weeks had viral relapse compared to only 3 patients in the 12-week group. Of those 21 patients who relapsed, 1 had a treatment-emergent Q30R and L31M (NS5A RASs). In POLARIS-3 [43], two patients who received SOF/VEL/VOX had viral relapse compared to one patient in the SOF/VEL group. Neither of the patients who received SOF/VEL/VOX had treatment-emergent resistance, whereas both patients with virological failure in the SOF/VEL group had the Y93H variant (an NS5A RAS).

The POLARIS-1 and POLARIS-4 studies demonstrated success in retreatment of patients who had previous virological failure, however, they did not evaluate efficacy of SOF/VEL/VOX in patients who had discontinued previous treatment due to adverse events or who failed prior treatment due to medication non-adherence. The POLARIS-2 study did not demonstrate noninferiority of a short-duration, 8-week regimen of SOF/VEL/VOX compared to a 12-week regimen of SOF/VEL, however, POLARIS-3 demonstrated that the 8- and 12-week regimens had equal efficacy in cirrhotic patients with GT 3, providing an option for patients who may need a shorter duration of treatment.

These four international Phase III trials demonstrated that treatment with SOF/VEL/VOX for 12 weeks resulted in high rates of SVR₁₂ among treatment-naive and treatment-experienced patients with or without cirrhosis who had been previously treated with DAAs, including NS5A inhibitors. The presence of RASs did not significantly decrease the SVR₁₂ rates. Therefore, SOF/VEL/VOX is an effective option for retreatment among patients who have had virological failure, and especially among patients with cirrhosis, in whom hepatitis C treatment is a high priority.

Use of SOF/VEL/VOX with RBV

Since the addition of RBV has increased the rate of virological cure when added to DAA regimens, such as SOF/VEL in patients with decompensated cirrhosis [31], the TRILOGY-3 study [44] was a Phase II trial which evaluated whether there is an increased rate of virological cure when RBV is added to SOF/VEL/VOX. In this study, patients with GT 1 infection and prior treatment experience received either SOF/VEL/VOX alone or with weight-based RBV for 12 weeks. Patients with cirrhosis were included, but any patient with a history of decompensated cirrhosis was excluded. 49 patients received treatment in this study; 25 received an RBV-containing regimen, 25 patients had cirrhosis and 41% had failed a previous NS5A-containing therapy with or without another DAA. All 24 patients (100%) who received SOF/VEL/VOX alone achieved SVR₁₂, and 24 of 25 (96%) of those who received SOF/VEL/ VOX + RBV achieved SVR₁₂. In subgroup analyses, treatment efficacy was maintained despite presence of baseline RASs (13/13 [100%] without pre-existing RASs had SVR₁₂, compared to 34/35 [97%] with baseline NS5A, NS3 or multiple classes of RASs), cirrhosis or use of prior NS5A therapy. This study demonstrated that the addition of RBV does not improve outcomes when three potent DAAs are used in combination for retreatment of HCV. However, the American Association for the Study of Liver Diseases (AASLD) guidelines recommend that weight-based RBV be added to SOF/ VEL/VOX in treatment-experienced, GT 3 patients with cirrhosis to minimize the risk of relapse [45], since the four patients with GT 3 infection who failed SOF/ VEL/VOX in POLARIS-1 all had cirrhosis [42].

Options for those who fail SOF/VEL/VOX

For patients who fail therapy with SOF/VEL/VOX, options for retreatment are severely limited. Glecaprevir (an NS3/4A protease inhibitor) and pibrentasvir (an NS5A inhibitor) are newer DAAs available as a fixed-dose combination (trade name Mavyret^®, AbbVie) for retreatment of patients with GT 1 infection. The MAGELLAN-1 trial [46], evaluated the efficacy of glecaprevir and pibrentasvir for retreatment in patients with prior DAA exposure. Though 16/17 (94%) patients achieved SVR₁₂, it is unclear if these results are applicable to patients who have been exposed to both NS5A and protease inhibitors, as these patients were excluded from the trial. Thus, Mavyret carries no indication for retreatment of patients who have received VEL and VOX.

Cost effectiveness of SOF/VEL/VOX

Regimens containing SOF are more cost-effective than older regimens for HCV treatment, from the perspective of a third-party payer [47]. Per manufacturer review of a cost analysis model [48], SOF/VEL/VOX is a cost-effective treatment option in patients with chronic HCV with GT 1–6 who are NS5A-experienced as well as in GT 1–4 patients who are treatment (NS5A) naive. The National Institute for Health Care and Excellence (NICE), a United Kingdom based corporation, determined that SOF/VEL/VOX is a cost-effective treatment option for those with and without cirrhosis, particularly as a 12-week regimen for treatment-experienced patients with GT 1–6 infection, and as an 8-week regimen for treatment-naive patients with GT 3 infection (the latter differs from the AASLD guidelines) [49]. The cost of SOF/VEL/VOX is similar to that of SOF/VEL, however, by comparing the SVR rates in the POLARIS trials, it was determined that SOF/VEL/VOX offers higher quality-adjusted life-year gains and lower overall costs compared to SOF/VEL.

Conclusion

The potent SOF/VEL/VOX fixed-dose combination has been shown to be highly efficacious in both treatment-naive and treatment-experienced patients. Use of this regimen achieves high rates of virological cure, despite prior use of DAAs for HCV treatment (including NS5A inhibitors) or the presence of RASs. In addition, patients with GT 3 infection and cirrhosis, who are considered difficult to treat, have high rates of virological cure. The Vosevi regimen has been extensively studied for GT 1–6 infection, in patients that have failed prior treatment with multiple FDA-approved first-line therapies, in compensated cirrhosis, and is also being studied in patients coinfected with HIV as part of an ongoing clinical trial (NCT02745535).

As this effective combination continues to be used for HCV treatment, long-term outcomes will need to be followed. Since this regimen serves as a cost-effective HCV treatment for the aforementioned difficult-to-treat populations, future studies should evaluate the efficacy and safety of SOF/VEL/VOX in patients with mild renal impairment, decompensated cirrhosis and hepatitis B coinfection.

Footnotes

EW and SK have received research grants from Gilead Sciences Inc. paid to their institution. PM declares that she has no conflict of interest.

References

Polaris Observatory HCVC. Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study. Lancet Gastroenterol Hepatol 2017; 2: 161–176

Afdhal

, Zeuzem

, Kwo

Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014; 370: 1889–1898

Lawitz

, Poordad

F.F.

, Pang

P.S.

Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, Phase 2 trial. Lancet 2014; 383: 515–523

Sulkowski

M.S.

, Gardiner

D.F.

, Rodriguez-Torres

Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014; 370: 211–221

Kohli

, Shaffer

, Sherman

, Kottilil

Treatment of hepatitis C: a systematic review. JAMA 2014; 312: 631–640

Kattakuzhy

, Levy

, Kottilil

Sofosbuvir for treatment of chronic hepatitis C. Hepatol Int 2015; 9: 161–173

Dhingra

, Kapoor

, Alqahtani

S.A.

Recent advances in the treatment of hepatitis C. Discov Med 2014; 18: 203–208

Kish

, Aziz

, Sorio

Hepatitis C in a new era: a review of current therapies. P&T 2017; 42: 316–329

Lee

, Kottilil

, Wilson

Sofosbuvir/velpatasvir: a pangenotypic drug to simplify HCV therapy. Hepatol Int 2017; 11: 161–170

10.

Vosevi. Package insert 2017. Gilead Sciences, Inc., Foster City, CA, USA

11.

Bagaglio

, Uberti-Foppa

, Morsica

Resistance mechanisms in hepatitis C virus: implications for direct-acting antiviral use. Drugs 2017; 77: 1043–1055

12.

Chhatwal

, Chen

, Ayer

Hepatitis C virus re-treatment in the era of direct-acting antivirals: projections in the USA. Aliment Pharmacol Ther 2018; 47: 1023–1031

13.

Pérez

A.B.

, Chueca

, Garcia

Resistance testing for the treatment of chronic hepatitis C with direct acting antivirals: when and for how long?

Germs 2017; 7: 40–44

14.

Harrington

P.R.

, Komatsu

T.E.

, Deming

D.J.

, Donaldson

E.F.

, O'Rear

J.J.

, Naeger

L.K.

Impact of hepatitis C virus polymorphisms on direct-acting antiviral treatment efficacy: regulatory analyses and perspectives. Hepatology 2018; 67: 2430–2448

15.

Sorbo

M.C.

, Cento

, Di Maio

V.C.

Hepatitis C virus drug resistance associated substitutions and their clinical relevance: update 2018. Drug Resist Updat 2018; 37: 17–39

16.

Ahmed

, Felmlee

D.J.

Mechanisms of hepatitis C viral resistance to direct acting antivirals. Viruses 2015; 7: 6716–6729

17.

Lontok

, Harrington

, Howe

Hepatitis C virus drug resistance-associated substitutions: state of the art summary. Hepatology 2015; 62: 1623–1632

18.

Zuckerman

, Chastain

C.A.

, Naggie

Retreatment options following HCV direct acting antiviral failure. Curr Treat Options Infect Dis 2017; 9: 389–402

19.

Di Maio

V.C.

, Cento

, Lenci

Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies. Liver Int 2017; 37: 514–528

20.

Zeuzem

, Mizokami

, Pianko

NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: prevalence and effect on treatment outcome. J Hepatol 2017; 66: 910–918

21.

Zepatier. Package insert 2017. Merck & Co., Inc., Whitehouse Station, NJ, USA

22.

Wilson

E.M.

, Kattakuzhy

, Sidharthan

Successful retreatment of chronic HCV genotype-1 infection with ledipasvir and sofosbuvir after initial short course therapy with direct-acting antiviral regimens. Clin Infect Dis 2016; 62: 280–288

23.

Lawitz

E.F.S.

, Yang

J.C.

, Pang

P.S.

Retreatment of patients who failed 8 or 12 weeks of ledipasvir/sofosbuvir-based regimens with ledipasvir/sofosbuvir for 24 weeks. 50th Annual Meeting of the European Association for the Study of the Liver (EASL). 22–26 April 2015, Vienna, Austria. Abstract 0005

24.

Wilson

E.M.

, Rosenthal

E.S.

, Kattakuzhy

, Tang

, Kottilil

Clinical laboratory testing in the era of directly acting antiviral therapies for hepatitis C. Clin Microbiol Rev 2017; 30: 23–42

25.

Vermehren

, Susser

, Dietz

Retreatment of patients who failed DAA-combination therapies: realworld experience from a large hepatitis C resistance database. 51st Annual Meeting of the European Association for the Study of the Liver (EASL). 13–17 April 2016, Barcelona, Spain. Abstract PS103

26.

Cento

, Barbaliscia

, Bonora

Optimal efficacy of HCV resistance-based retreatments after PI failure. The Annual Conference on Retroviruses and Opportunistic Infections (CROI). 13–16 February 2017, Seattle, WA, USA. Abstract 565

27.

Pérez

A.B.

, Chueca

, García-Deltoro

Retreatment options after failing a first line of DAAs against hepatitis C virus. The Annual Conference on Retroviruses and Opportunistic Infections (CROI). 13–16 February 2017, Seattle, WA, USA. Abstract 566

28.

Pianko

, Flamm

S.L.

, Shiffman

M.L.

Sofosbuvir plus velpatasvir combination therapy for treatment-experienced patients with genotype 1 or 3 hepatitis C virus infection: a randomized trial. Ann Intern Med 2015; 163: 809–817

29.

Mismatched double-stranded RNA: PolyI: PolyC12U. Drugs R D 2004; 5: 297–304

30.

Feld

J.J.

, Jacobson

I.M.

, Hezode

Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 2015; 373: 2599–2607

31.

Curry

M.P.

, O'Leary

J.G.

, Bzowej

Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med 2015; 373: 2618–2628

32.

Gane

E.J.

, Shiffman

M.L.

, Etzkorn

Sofosbuvir-velpatasvir with ribavirin for 24 weeks in hepatitis C virus patients previously treated with a direct-acting antiviral regimen. Hepatology 2017; 66: 1083–1089

33.

Foster

G.R.

, Afdhal

, Roberts

S.K.

Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med 2015; 373: 2608–2617

34.

Lawitz

, Yang

J.C.

, Stamm

L.M.

Characterization of HCV resistance from a 3-day monotherapy study of voxilaprevir, a novel pangenotypic NS3/4A protease inhibitor. Antivir Ther 2018; 23: 325–334

35.

Epclusa. Package insert 2017. Gilead Sciences, Inc., Foster City, CA, USA

36.

Rodriguez-Torres

, Glass

, Hill

GS-9857 in patients with chronic hepatitis C virus genotype 1-4 infection: a randomized, double-blind, dose-ranging Phase 1 study. J Viral Hepat 2016; 23: 614–622

37.

Kirby

Evaluation of the pan-genotypic HCV NS3/4A protease inhibitor GS-9857 in healthy volunteers. The International Liver Congress 2015. 50th Annual Meeting of the European Association for the Study of the Liver. 22–26 April 2015, Vienna, Austria. Abstract P0861

38.

Taylor

Preclinical profile of the pan-genotypic HCV NS3/4A protease inhibitor GS-9857. The International Liver Congress 2015. 50th Annual Meeting of the European Association for the Study of the Liver. 22–26 April 2015, Vienna, Austria. Abstract P0899

39.

Lawitz

, Reau

, Hinestrosa

Efficacy of sofosbuvir, velpatasvir, and GS-9857 in patients with genotype 1 hepatitis C virus infection in an open-label, Phase 2 trial. Gastroenterology 2016; 151: 893–901

40.

Gane

E.J.

, Kowdley

K.V.

, Pound

Efficacy of sofosbuvir, velpatasvir, and GS-9857 in patients with hepatitis C virus genotype 2, 3, 4, or 6 infections in an open-label, Phase 2 trial. Gastroenterology 2016; 151: 902–909

41.

Gane

E.J.

, Schwabe

, Hyland

R.H.

Efficacy of the combination of sofosbuvir, velpatasvir, and the NS3/4A protease inhibitor GS-9857 in treatment-naive or previously treated patients with hepatitis C virus genotype 1 or 3 infections. Gastroenterology 2016; 151: 448–456

42.

Bourlière

, Gordon

S.C.

, Flamm

S.L.

Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med 2017; 376: 2134–2146

43.

Jacobson

I.M.

, Lawitz

, Gane

E.J.

Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 Phase 3 randomized trials. Gastroenterology 2017; 153: 113–122

44.

Lawitz

, Poordad

, Wells

Sofosbuvir-velpatasvir-voxilaprevir with or without ribavirin in direct-acting antiviral-experienced patients with genotype 1 hepatitis C virus. Hepatology 2017; 65: 1803–1809

45.

The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. 2017. (Accessed 20 August 2018.) Available from https://www.hcvguidelines.org

46.

Poordad

, Felizarta

, Asatryan

Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment. Hepatology 2017; 66: 389–397

47.

Chhatwal

, Kanwal

, Roberts

M.S.

, Dunn

M.A.

Cost-effectiveness and budget impact of hepatitis C virus treatment with sofosbuvir and ledipasvir in the United States. Ann Intern Med 2015; 162: 397–406

48.

Gilead Sciences. CADTH Common Drug Review: Pharmacoeconomic Review Report. 2018. (Accessed 20 August 2018.) Available from https://www.cadth.ca/sites/default/files/cdr/pharmacoeconomic/SR0529_Vosevi_PE_Report.pdf

49.

National Institute for Health and Care Excellence. Final appraisal determination: Sofosbuvir-velpatasvir-voxilaprevir for treating chronic hepatitis C. 2017. (Accessed 20 August 2018.) Available from https://www.nice.org.uk/guidance/ta507