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A pilot study of safety and efficacy of HCV retreatment with sofosbuvir/velpatasvir/voxilaprevir in patients with or without HIV (RESOLVE STUDY)
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Jnl of Hepatology Sept 2019 - Eleanor Wilson1, Emily Covert1,2, Jennifer Hoffmann1, Emily Comstock1, Benjamin Emmanuel1, Lydia Tang1, Jennifer Husson1, Joel Chua1, Angie Price1, Poonam Mathur1, Elana Rosenthal1, Sarah Kattakuzhy1, Henry Masur2, Shyam Kottilil1
1Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; 2Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
Treatment responses were similar in patients with HIV, poor adherence or non-completion of therapy.
In summary, our data supports the use of SOF/VEL/VOX in the retreatment of patients who have not previously achieved SVR12 in response to combination DAA treatments. This is the first study of this retreatment regimen in HIV/HCV coinfection, particularly in combination with dolutegravir-based antiretroviral therapy, and it shows that the regimen is a safe and effective option for these patients. Additionally, in patients with previous poor adherence, treatment interruption, or non-completion of therapy, this regimen was also safe, effective, and well-tolerated.
Efficacy
Overall, in an intention-to-treat analysis, 90.9% (n = 70) of patients retreated with 12 weeks of SOF/VEL/VOX achieved SVR12, as shown in Fig. 2. In a per protocol analysis of patients (n = 71) who completed 12 weeks of study medication and all study visits, 99% (70/71) achieved SVR12. One patient experienced virologic relapse with the same subgenotype as the original HCV infection, despite having an HCV RNA LLOD by week 4 on treatment and through the end of therapy (week 12); by post-treatment week 4, HCV RNA was 16,400 copies/ml and by post treatment week 12, HCV RNA was 2,600,000. This patient denies any re-exposure or high-risk behavior and reported 100% adherence to study medications, which was verified by pill counts at on treatment visits. Of the 6 patients who did not complete the treatment course, 3 discontinued early, 1 died, and 2 patients were lost to follow-up. One patient suffered a traumatic subdural hematoma on week 5 of treatment, and the medication was stopped during hospital admission and rehabilitation. Another patient stopped the medication after day 3 of treatment following a hypertensive stroke. A third patient developed colitis on day 5 of treatment and self-discontinued the medication. One patient died on treatment: the patient had a history of compensated cirrhosis at baseline with negative ultrasound surveillance for hepatocellular carcinoma (HCC) 6 months prior to enrollment but developed hepatic decompensation at week 9 on treatment, due to thrombosis of the hepatic vein related to a new diagnosis of HCC, and passed away 1 week after diagnosis. These events were all, after review of the medical records, deemed unrelated to the study medication by the primary investigator and independent medical monitor. The final 2 patients were lost to follow-up: 1 at week 4 and another at week 8. Both were subsequently re-engaged in care more than 8 months after discontinuation, with confirmation of virologic relapse and resistance testing.
Highlights
• This study included 77 patients with relapsed HCV genotype 1, who were treated with 12 weeks of SOF/VEL/VOX.
• >90% of patients achieved sustained virologic response 12 weeks after the end of treatment in an intention-to-treat analysis.
• Treatment responses were similar in patients with HIV, poor adherence or non-completion of therapy.
• SOF/VEL/VOX is a safe, effective, and well-tolerated option for the retreatment of relapsed HCV genotype 1.
Background & Aims
Cure rates in response to retreatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) are high, but this regimen has not been studied in patients with a history of poor adherence or treatment interruption, nor in patients with HIV/HCV coinfection. Herein, we aimed to assess the safety and efficacy of this combination in patients with genotype 1 HCV infection who had relapsed following combination direct-acting antiviral (DAA) therapy, regardless of HIV infection or previous treatment course.
Methods
The RESOLVE study was a multicenter, open-label, phase IIb study investigating the safety, tolerability and efficacy of SOF/VEL/VOX in 77 patients with virologic rebound following combination DAA therapy. Efficacy was defined as HCV RNA below the lower limit of detection 12 weeks after the end of treatment (SVR12), while safety endpoints included the incidence of grade 3 and 4 adverse events (AEs) following treatment, and the proportion of patients who stopped treatment prematurely due to AEs.
Results
In an intent-to-treat analysis, 70/77 (90.9%, 95% CI 82.1–95.8%) patients achieved SVR12, including 14/17 (82.4%) HIV coinfected participants and 18/22 (81.8%) of those with previous non-completion of DAA therapy. In an analysis of all patients who completed 12 weeks of study medication, 70/71 patients (99%) achieved SVR12. One patient experienced a grade 3 AE, and 4 experienced a grade 4 AE, all unrelated to study participation. Reported AEs were similar in HIV-coinfected patients, and patients receiving dolutegravir-based antiretroviral treatment experienced no clinically significant increases in aminotransferases.
Conclusion
Retreatment with 12 weeks of SOF/VEL/VOX was safe and effective in patients with relapsed HCV following initial combination DAA-based treatment. Treatment response was not affected by HIV coinfection or previous treatment course.
Lay summary
Twelve weeks of the combination of direct-acting antivirals (SOF/VEL/VOX) was safe and effective in patients with relapsed hepatitis C virus infection who had previously received combination therapy with direct-acting antivirals. Treatment response was not diminished by HIV coinfection, or non-completion of previous direct-acting antiviral-based therapy.
Of the patients with HIV coinfection (n = 17), 82% (14/17) achieved SVR12, with the remaining 3 patients experiencing virologic relapse (n = 1) and early discontinuation due to unrelated AEs (n = 2, colitis and hypertensive stroke as above). Among patients with HIV coinfection, we observed a median increase in CD4 count of 70 cells/µl (IQR −38 to 129) from pre-retreatment baseline to 12 weeks after the end of treatment, although this was not statistically significant.
Of those patients with HIV (n = 17), all were on antiretroviral therapy. Eight patients (47%) were on dolutegravir coformulated with abacavir/lamivudine. Other regimens included rilpivirine with emtricitabine/tenofovir disoproxil fumarate (n = 4, 24%), raltegravir with emtricitabine/tenofovir disoproxil fumarate (n = 2, 12%), darunavir boosted with ritonavir (n = 2, 12%) with either tenofovir disoproxil fumarate/emtricitabine (n = 1) or abacavir/lamivudine (n = 1), and atazanavir with abacavir/lamivudine (n = 1, 6%).
Introduction
Treatment of chronic HCV infection has changed dramatically in the past 5 years. Combinations of direct-acting antivirals (DAAs) can achieve high rates of sustained virologic response (SVR), synonymous with eradication or cure of HCV, of above 95% in clinical trials, regardless of stage of hepatic fibrosis, treatment history, or HCV genotype.1 Recently, real world efficacy studies have confirmed high cure rates, with SVR rates of 90–95% outside of clinical trials.2, 3, 4 The proportion of patients in these reports who do not achieve SVR is low, at less than 10%, when combining those who have virologic relapse, are lost to follow-up, or discontinue treatment due to adverse events (AEs). Nevertheless, given that there are an estimated 71 million people with chronic HCV worldwide,5 the number of patients who will require HCV retreatment is substantial and will increase as HCV treatment becomes more accessible.
The fixed-dose combination DAA regimen of sofosbuvir (SOF, a pangenotypic NS5B nucleotide polymerase inhibitor), velpatasvir (VEL, a pangenotypic NS5A inhibitor), and voxilaprevir (VOX, a pangenotypic NS3/4a protease inhibitor) has been shown to be highly effective in the treatment of DAA-experienced patients.6 The drug was the first Food and Drug Administration (FDA)-approved treatment for chronic HCV in patients who had previously been treated with sofosbuvir or NS5A inhibitors.7, 8 However, there is no data regarding treatment outcomes in patients who discontinued their initial combination DAA-based regimen due to non-completion of therapy, either due to early discontinuation or poor adherence,6 or in those with concurrent chronic viral infections with HIV and/or hepatitis B virus (HBV) coinfection.6, 8, 9
Indeed, it remains controversial whether HCV treatment is as successful in patients with HIV/HCV coinfection as those with HCV monoinfection. Recent cohort studies have differed regarding whether HIV coinfection predicts poor outcomes, with several studies showing that HIV worsens cure rates for HCV treatment2, 10, 11 while others suggest that treatment outcomes are comparable if drug interactions can be managed.3, 4, 12 If patients with HIV/HCV coinfection are less likely to respond to combination DAA-based treatments, as some suggest, retreatment regimens will require further study. Data regarding SOF/VEL/VOX safety and efficacy in HIV or HBV coinfected patients is urgently needed, and such data is the objective of the RESOLVE study.
Patient population
Across all 3 sites, 89 patients were screened and 77 enrolled (54 at the IHV, 14 at Parkside, and 9 at Walker Jones) between May 2016 and January 2018 (Fig. 1). The baseline characteristics of the enrolled patient population are described in Table 1. The participants were primarily Black (n = 66, 86%), non-Hispanic (n = 77, 100%) and male (n = 64, 83%) with GT-1a infection (n = 58, 75%). Seventeen patients (22%) were HIV positive and 3% (n = 2) were coinfected with HBV and HIV. A majority, 51% of participants (n = 39), reported previous intravenous drug use, while 32% of participants (n = 25) reported previous heavy alcohol use. Baseline staging showed 40% (n = 31) had compensated cirrhosis, while 36% (n = 28) had early stage hepatic fibrosis (≤Stage 2). Staging was done in accordance with the American Association for the Study of Liver Diseases (AASLD)/Infectious Disease Society of America (IDSA) guidelines, and was achieved primarily by vibration-controlled transient elastography (40%, n = 31) or FibroSure® (47%, n = 36), but also by liver biopsy (6%, n = 5) or imaging consistent with cirrhosis (i.e. “nodular” appearance to the liver, in which case the diagnosis of advanced fibrosis was confirmed with APRI [asparate aminotransferase to platelet ratio index] and Fibrosis-4 calculations, 6%, n = 5).
Safety
All participants experienced at least 1 AE. In general, AEs deemed related to study drug were mild. Those reported by ≥5% of participants include fatigue (27%, n = 21), headache (25%, n = 19), diarrhea (21%, n = 16), abdominal pain (9%, n = 7), nausea (9%, n = 7), and constipation (6%, n = 5). There was 1 grade 3, and 4 grade 4 AEs, all unrelated to study participation, including hospitalization for exacerbation of pulmonary hypertension, 2 new carcinoma diagnoses (HCC, squamous cell), hypertensive stroke, and traumatic subdural hematoma. There were 7 grade 3 and 4 laboratory abnormalities listed in Table 3, which were all deemed to be unrelated to study participation by the primary investigator and independent medical monitor.
Regarding safety in HIV-coinfected study participants, AEs were similar to those reported in the cohort as a whole. Of the 8 patients on dolutegravir-based antiretroviral therapy, none experienced clinically significant aspartate aminotransferase or alanine aminotransferase elevations. Monitoring of HIV viral load revealed that no patient experienced an HIV viral “blip” of greater than 100 copies/ml, and we observed no evidence of HBV reactivation or flare in the 2 HIV/HBV/HCV-coinfected patients.
Discussion
Our results show that retreatment with SOF/VEL/VOX is safe and effective, even in patients with HIV/HCV coinfection and those with prior non-completion of therapy, even when due to poor adherence. We found that overall the response rates were preserved in patients with HIV coinfection or a history of poor adherence. Retreatment was safe and extremely well-tolerated, consistent with previously published studies of SOF/VEL/VOX.8 No patient discontinued medication due to side effects deemed related to the study medication.
This is the first study of SOF/VEL/VOX in patients with and without HIV coinfection, and similar efficacy was observed in the 2 populations. Patients with HIV on regimens containing dolutegravir have been excluded from previous clinical trials, given the FDA warning regarding elevation in the liver function tests of patients with dolutegravir and viral hepatitis,14 but this antiretroviral regimen is widely used in patients with HIV and HCV coinfection given the lack of predicted significant drug-drug interactions.15 Approximately half of our HIV+ patients were on dolutegravir-based therapy, and they experienced similar efficacy and side effect rates as both those patients on other antiretroviral regimens and those without HIV coinfection. We did not find any clinically significant liver function test elevations in those patients who received dolutegravir and SOF/VEL/VOX, nor did we observe any HIV viral load blips >100 copies/ml in any HIV coinfected patient during HCV treatment. One patient was taking unboosted atazanavir and experienced no treatment related side effects attributable to this medication; the SOF/VEL/VOX package insert lists atazanavir as a medication with the potential for significant drug interactions, with increased voxilaprevir concentrations.
Patients with previous non-completion of combination DAA-based therapy also did well with SOF/VEL/VOX for retreatment. In a per protocol analysis, 95% (18/19) of patients achieved SVR12, showing that initial non-compliance, treatment interruption, or non-completion of therapy does not appear to diminish future treatment response. Indeed, the majority of those patients (12/14, 86%) with poor adherence to their initial regimen were able to complete treatment and achieve SVR. Thus, initial non-adherence to therapy does not justify withholding retreatment in these patients.
As DAAs continue to be more widely used, the relevance of RASs remains uncertain, particularly in the context of previous treatment experience. A recent analysis of registrational studies of SOF/VEL/VOX found no impact of pre-existing RASs nor did they find patterns of treatment-emergent RASs on SOF/VEL/VOX treatment.16 Of the patients who did not achieve SVR, those who presented for follow-up testing were noted to all have NS5A RASs: 75% (3/4) had Y93 substitutions (although this pre-existed retreatment in all 3 patients). Half (2/4) of those who did not achieve SVR12 had NS3 protease inhibitor Q80K NS3/4 substitutions (which have not been associated with reduced susceptibility to VOX17), but overall, of the 11 patients with previous protease inhibitor experience (including simeprevir, grazoprevir, boceprevir, asunaprevir, and GS-9451), 8/11 (73%, 95% CI 43–91%) achieved SVR12.
An unanticipated finding of this study was that 3 patients screened for retreatment after initial evidence of treatment failure were actually found to have undetectable HCV RNA when testing was repeated 12 weeks after the completion of initial combination DAA therapy. Our study shows that when virus is detected following DAA treatment, this should be verified before retreatment is initiated.
The strengths of this study include the inclusion of patients who had not previously been studied with this regimen, specifically patients with HIV coinfection, thus providing evidence supporting the safety and efficacy of SOF/VEL/VOX in patients receiving dolutegravir antiretroviral therapy. We also were able to include a majority of non-white patients, traditionally under-represented in clinical trials and disproportionately affected by hepatitis C. Historically, treatment and SVR rates in this population have been lower in both clinical practice and research settings. This study further demonstrates the efficacy of retreatment in a sample reflective of the real-world population, and underscores the need to consider disparities in HCV treatment in marginalized and hard to treat populations, especially for those who are DAA-experienced. Finally, we studied the breadth of patients with previous DAA-experience, including patients with prior non-completion of therapy due to poor adherence or treatment interruption, who have not previously been studied.
Our study has a few limitations, including its open-label and non-randomized design. Additionally, we were unable to exclude occult reinfection (that is, reinfection with the same subgenotype within the 3 months following initial combination DAA therapy), but in a real-world setting, this would be indistinguishable from virologic failure. Another limitation is our relatively small sample size, and it is important to note that our study was not powered to compare outcomes between patients with and without HIV coinfection. However, the strong evidence for efficacy of retreatment with SOF/VEL/VOX in this study supports its excellent efficacy in a challenging patient population.
In summary, our data supports the use of SOF/VEL/VOX in the retreatment of patients who have not previously achieved SVR12 in response to combination DAA treatments. This is the first study of this retreatment regimen in HIV/HCV coinfection, particularly in combination with dolutegravir-based antiretroviral therapy, and it shows that the regimen is a safe and effective option for these patients. Additionally, in patients with previous poor adherence, treatment interruption, or non-completion of therapy, this regimen was also safe, effective, and well-tolerated.
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