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Sofosbuvir and Velpatasvir for the Treatment of HCV in
Patients Coinfected with HIV-1: an Open-Label, Phase 3 Study
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CID - Clin Inf Dis March 2017 - David Wyles1, Norbert Brau2, Shyam Kottilil3, Eric S. Daar4, Peter Ruane5, Kimberly Workowski6, Anne Luetkemeyer7, Oluwatoyin Adeyemi8, Arthur Y. Kim9, Brian Doehle10, K.C. Huang10, Erik Mogalian10, Anu Osinusi10, John McNally10, Diana M. Brainard10, John G. McHutchison10, Susanna Naggie11, Mark Sulkowski12, for the ASTRAL-5 Investigators
Summary: At 17 sites in the United States, we evaluated the efficacy and tolerability of 12 weeks of sofosbuvir-velpatasvir in patients with hepatitis C virus infection who were coinfected with HIV-1. In total, 101/106 (95%) patients achieved sustained virologic response.
Presented in part at the 51st annual meeting of the European Association for the Study of the Liver. Barcelona, April 13-17, 2016 (oral).
Abstract
Background:
A safe, simple, effective, and pan-genotypic regimen to treat hepatitis C virus (HCV) infection in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains a medical need. We assessed the efficacy and safety of the NS5B polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir for HCV in patients coinfected with HIV-1.
Methods:
This phase 3, open-label, single-arm study at 17 sites in the United States enrolled patients with HCV of any genotype and HIV-1 coinfection, including those with compensated cirrhosis. All patients received sofosbuvir-velpatasvir once daily for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). Efficacy and safety were assessed in all patients receiving at least one dose of treatment.
Results:
Of 106 patients, 91 (86%) were men, 48 (45%) were black, and 19 (18%) had cirrhosis. SVR12 was achieved by 101 (95%; 95% CI 89 to 99) of 106 patients; 74 (95%, 87-99) of 78 with genotype 1, all 11 (100%, 72-100) with genotype 2, 11 (92%, 62-100) of 12 with genotype 3, and all 5 (100%, 48-100) with genotype 4. All 19 patients with cirrhosis had SVR12. Two patients relapsed, two were lost to follow-up, and one withdrew consent. Two discontinued treatment due to adverse events and two had serious adverse events. The most common adverse events were fatigue (25%), headache (13%), arthralgia (8%), and upper respiratory tract infection (8%).
Conclusions:
Sofosbuvir-velpatasvir for 12 weeks was safe and provided high rates of SVR12 in patients coinfected with HCV and HIV-1.
RESULTS
Of the 149 patients screened, 107 were enrolled and 106 received at least one dose of study treatment (Figure 1, Supplemental Table 3). Patient baseline demographics are presented in Table 1. Ninety-one of the 106 patients (86%) were male, 45% were black, 29% were HCV treatment-experienced, and 18% had compensated cirrhosis. Overall, 62% of patients had genotype 1a, 11% had genotype 1b, 10% had genotype 2, 11% had genotype 3, and 5% had genotype 4.
Patients were receiving a broad range of ARV regimens: protease inhibitor-based (47%), integrase inhibitor-based (34%), non-nucleotide reverse transcriptase inhibitor-based (12%), and other regimens (7%). Fifty-three percent of patients were receiving TDF as part of a ritonavir- or cobicistat-boosted regimen and 33% with TDF in a non-boosted regimen. Mean CD4+ cell count at baseline was 598 cells/μL (range 183 to 1513). Mean estimated glomerular filtration rate (by the Cockcroft-Gault Equation) was 98.4mL/min (range 57.4 to 198.4).
Efficacy
Of the 106 patients enrolled and treated, 101 (95%; 95% CI, 89 to 99) achieved SVR12 (Table 2). By genotype, SVR12 was achieved by 63 (95%; 87-99) of 66 patients with genotype 1a, by 11 (92%; 62-100) of 12 patients with genotype 1b, by 11 (100%; 72-100) of 11 with genotype 2, by 11 (92%; 62-100) of 12 with genotype 3, and by all 5 (100%; 48-100) with genotype 4.
SVR12 was achieved by all 19 (100%) patients with cirrhosis, by 45 (94%) of the 48 black patients enrolled, and by 29 (94%) of the 31 who had received previous treatment for HCV. SVR12 rates by treatment experience and cirrhosis status are provided in Supplemental Table 4.
Resistance was assessed in all 103 patients who had a virologic outcome. Overall, 13 patients (13%) had NS5A RASs at baseline using a 15% sensitivity threshold— including substitutions at positions 28, 30, 31, and 93. All patients with baseline NS5A RASs achieved SVR12, including the 3 patients with the velpatasvir-specific RASs Y93H (GT1a and GT3a) and Q30H/R+L31M (GT1a) (see Supplemental Tables 5-7 for further details on the resistance analysis).
Of the five patients who did not achieve SVR, two were lost to follow-up, one withdrew consent, and two experienced post-treatment HCV relapse after completing 12 weeks of treatment. The two patients with virologic failure (2% of the study population) were both black women with genotype 1a HCV infection, and no evidence of cirrhosis (Supplemental Table 7). One was a prior non-responder to pegylated-interferon plus ribavirin on ritonavir-boosted lopinavir plus emtricitabine/TDF. The other was treatment-naïve on ritonavir-boosted darunavir plus abacavir/lamivudine. Both patients achieved HCV RNA suppression on treatment (by 2 and 6 weeks) and HCV relapse was detected at post-treatment week 4. No evidence of RASs at baseline or time of relapse (1% and 15% thresholds) was found. On-treatment pill count and blood levels of the study drugs suggested adherence, and HCV re-infection was excluded by sequence analysis.
Pharmacokinetics
Pharmacokinetic parameters of sofosbuvir, GS-331007, velpatasvir and tenofovir were determined using established population pharmacokinetic models. Tenofovir exposure was assessed following results showing increased tenofovir exposure when coadministered with sofosbuvir-velpatasvir in Phase 1 studies in healthy patients.16-17
The exposure of sofosbuvir, GS-331007, and velpatasvir were generally similar following administration of sofosbuvir-velpatasvir with a variety of ARVs, including unboosted and boosted regimens (Supplemental Table 8). Exposures of SOF, GS-331007, and VEL were similar to those observed in HCV monoinfected patients in sofosbuvir-velpatasvir phase 2 and 3 studies. Tenofovir exposure was similar when TDF was administered as part of boosted or unboosted regimens with sofosbuvir-velpatasvir (Supplemental Table 9). These exposures were also within the range of exposure observed in HIV-monoinfected patients using boosted ARV regimens in the absence of sofosbuvir-velpatasvir.18
Safety
Overall, 76 patients (71%) experienced at least one adverse event, most of which were mild to moderate in severity (Table 3). The most common adverse events were fatigue (25%), headache (13%), arthralgia (8%), upper respiratory tract infection (8%), and diarrhea (8%). Two patients (2%) experienced serious adverse events. A 50-year-old white man had a serious event of acute radial nerve palsy on day 18 of treatment, but continued treatment and achieved SVR12. The other patient, a 61-year-old black male with cirrhosis, had three serious adverse events: 1) infection of the toe on day 27 of treatment, followed by 2) sepsis and urinary tract infection on day 46 of treatment and 3) persistent elevations in alanine and aspartate aminotransferase levels (attributed to sepsis and antibiotics). This individual discontinued study treatment on day 48 and achieved SVR12. The only other patient who discontinued study treatment due to adverse events was a non-cirrhotic 53-year-old white man with genotype 3a HCV who withdrew consent after experiencing a single episode of vomiting on day 4 of treatment. In both cases of treatment discontinuation, the adverse events were judged as unlikely to be related to study medications by the investigator. CD4+ counts remained stable and no patient experienced HIV virologic rebound.
Seven patients (7%) had grade 3 and one (1%) had grade 4 elevations of total bilirubin (unconjugated hyperbilirubinemia); all were receiving ritonavir-boosted atazanavir, and all had graded total bilirubin elevations at baseline/Day 1 and during treatment. The only other Grade 3 chemistry laboratory abnormalities reported for more than 1 patient were increased creatine kinase associated with exercise (2 patients), and increased serum glucose associated with a history of diabetes mellitus (2 patients).
Overall, few patients experienced renal laboratory abnormalities. Figure 2 shows creatinine clearance across study visits. Three patients, all receiving TDF-containing regimens, had a change from baseline of ≥0.4 mg/dL in serum creatinine while on treatment (Supplemental Table 10). One patient, a 54-year-old white man on ritonavir-boosted atazanavir plus emtricitabine/TDF with a history of chronic kidney disease (unclear etiology) and hypertension, developed worsening renal function at week 4 of treatment, with serum creatinine of 3.29 mg/dL (1.43 mg/dL at baseline), creatinine clearance of 26.5 mL/min (61.4 mL/min at baseline), 3+ proteinuria, and normoglycemic glycosuria. This event was predated by a bout of gastroenteritis with dehydration. At subsequent visits, serum creatinine ranged from 1.97-2.66 mg/dL. The patient completed study treatment without modification of his ARV regimen and achieved SVR12 . Two other patients experienced increases of ≥0.4 mg/dL in serum creatinine from baseline, but these increases were transient and asymptomatic. One was a 41-year-old white man on raltegravir plus emtricitabine/TDF who had a transient increase in serum creatinine to 1.44 mg/dL (from 0.98 mg/dL at baseline) at Week 10 while on trimethoprim/sulfamethoxazole for a ruptured ear drum and sinus infection. The other patient was a 57-year-old black man with a history of intravenous drug on ritonavir-boosted atazanavir plus emtricitabine/TDF who had an unconfirmed, transient increase in serum creatinine to 1.32 mg/dL (0.91 mg/dL at baseline) at Week 2 which was back to 1.01 mg/dL by the week 4 visit. Neither patient required changes to their ARV regimens. Two patients (2%) were identified as having a change from baseline in creatinine clearance to <50 mL/min while on treatment, including the 54-year-old patient described above. The second was a 69-year-old black man on elvitegravir/cobicistat/emtricitabine/TDF plus darunavir who had a creatinine clearance of 49 mL/min (64.2 mL/min at baseline) accompanied by an increase in serum creatinine to 1.59 mg/dL (1.21 mg/dL at baseline) at Week 2. This occurred in the setting of daily ingestion of protein powder and ibuprofen for knee pain.
Among all patients receiving TDF, serum creatinine remained stable from baseline through the end of treatment and at the posttreatment Week 12 follow-up visit (Figure 2). By posttreatment Week 12, creatinine values were close to baseline with an overall median change from baseline of +0.02 (IQR: 0.08, 0.10) mg/dL.
DISCUSSION
In this open-label, phase 3 study, 12 weeks of treatment with sofosbuvir-velpatasvir resulted in high rates of SVR12 in patients coinfected with HIV-1 and genotype 1-4 HCV. The study included patients with characteristics historically associated with lower response to interferon-based therapies: cirrhosis, prior treatment experience, HIV coinfection, and black race. None of these factors appeared to be associated with virologic failure, which occurred in only 2 patients. The 100% SVR12 rate in patients with cirrhosis, and 97% SVR12 rate in those with prior treatment failure are consistent with the findings of the larger ASTRAL 1-3 studies, which also demonstrated high SVR12 rates in HCV monoinfected individuals that included historically difficult-to-treat populations. Moreover, this high success rate was seen without the addition of ribavirin or the extension of therapy beyond 12 weeks.13-15 In the ION-4 study of ledipasvir-sofosbuvir in patients with HCV-HIV-1 coinfection, black race was unexpectedly found to be significantly associated with virologic relapse. Although in the current study the two patients with virologic relapse were black women, neither patient was on efavirenz (excluded in the trial) and an adverse interaction with ARVs was not assessed to be a likely contributor to viral relapse. Furthermore, the overall SVR rate was 94% in both black and white patients (45/48 and 51/54, respectively). While the rate of virologic failure was 4% (2 patients) in black patients and 0% in white patients, the study was not powered to detect a difference among racial groups. Taken together, the SVR12 rates observed in this population of patients with HIV/HCV coinfection are consistent with those observed in the ASTRAL 1-3 phase 3 registrational trials.13-15
The presence of RASs at baseline, particularly those associated with resistance to NS5A inhibitors, have emerged as a factor in decreased response to NS5A inhibitor-containing DAA therapies in certain populations.19-21 One of the potential advantages of this velpatasvir-containing regimen is that it appears to have improved efficacy in patients with baseline NS5A RASs without the addition of ribavirin or extension of treatment duration. Consistent with the experience in the larger ASTRAL 1-3 studies, no virologic failures were seen in our small sample size of patients (n=13) with NS5A class RASs at baseline.
The safety profile of sofosbuvir-velpatasvir for 12 weeks was also consistent with that observed for HCV monoinfected adults treated with sofosbuvir-velpatasvir. A major consideration in treating HCV in patients coinfected with HIV-1 is the potential for interactions with ARV drugs. Similar to ledipasvir-sofosbuvir, sofosbuvir-velpatasvir has been shown to increase plasma tenofovir exposure when co-administered with TDF in phase 1 studies.17,22 The current study enrolled patients receiving a wide variety of ARV regimens, including a relatively large number (n=56) of patients on ritonavir- or cobicistat-boosted regimens. We found that treatment with sofosbuvir-velpatasvir for 12 weeks was safe and well tolerated when used with a pharmacologically boosted agent and TDF. Interestingly in this study, tenofovir exposure was within the range of exposure observed in HIV monoinfected patients using boosted ARV regimens in the absence of sofosbuvir-velpatasvir. In addition, there were no discontinuations due to renal adverse events and no trends suggestive of renal toxicity were identified with intensive renal laboratory monitoring.
Three patients experienced increases in creatinine of >0.4 mg/dL during the study, including two patients on pharmacologically boosted ARV regimens that included TDF. All three patients had comorbid conditions (hypertension), epidemiologic factors (black race) or concomitant medications associated with an increased risk of renal dysfunction. This suggests that co-administration of sofosbuvir-velpatasvir with TDF in the setting of a pharmacologically boosted ARV regimen may be safe in select populations with GFR>60 mL/min but other risks for renal dysfunction. Although one patient had persistent changes in renal function, no renal safety signal attributable to sofosbuvir-velpatasvir was identified regardless of ARV regimen. These data support the current prescribing information for sofosbuvir-velpatasvir which allows for the co-administration of this regimen with most ARVs except those with moderate CYP induction potential such as efavirenz or etravirine.11
One of the major limitations of the present study is that despite its promising results, the numbers of patients in some difficult-to-treat subgroups (i.e., patients with cirrhosis, and NS5A RASs at baseline) are insufficient to definitively confirm the efficacy and safety of sofosbuvir-velpatasvir in these co-infected patients. However, when considered in the context of the companion ASTRAL 1-3 studies, and other trials suggesting that HIV-1 co-infection itself does not adversely impact response, the present study should reassure clinicians that co-infected patients can be effectively treated with the same regimen as monoinfected patients. Generalizability of these results to the coinfected population at large is limited by the small number of patients we enrolled with cirrhosis as well as HCV genotypes 1b, 2, 3 and 4, as well as the fact that no patients with HCV genotype 5 or 6 were enrolled.
In conclusion, sofosbuvir-velpatasvir for 12 weeks provides a simple, safe, and highly effective treatment for patients coinfected with HCV and HIV-1. Its effectiveness in a broad range of patients across a wide range of ARV regimens suggests that it could be used by the majority of patients with HIV/HCV coinfection including those with prior treatment experience, compensated cirrhosis and non-genotype 1 HCV infection.
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