1 INTRODUCTION

An estimated 1% of the US population, or approximately 3 million individuals, has chronic hepatitis C virus (HCV) infection.¹ The prevalence of HCV infection among US military veterans is reported to be more than twice as high as in the general population and is approximately fourfold greater among US veterans when limited to the 1945 to 1965 birth cohort.^{2, 3} Interferon (IFN)-based antiviral regimens demonstrated suboptimal efficacy and unfavorable safety profiles in US veterans who receive care within the Department of Veterans Affairs (VA).^4-6 In addition, psychiatric comorbidities and substance use disorders are prevalent in VA patients, and IFN-based HCV therapy is associated with psychiatric side effects, limiting its use in these patients.^{7, 8}

The introduction of IFN-free direct-acting antivirals (DAAs) has provided additional treatment options for these patients. Approximately 80% of VA patients with HCV infection have HCV genotype 1 (GT1),⁷ and real-world studies of the efficacy of DAAs in this population have demonstrated sustained virologic response (SVR) rates of 90% or greater in GT1-infected patients.^{6, 9, 10} The 3-DAA regimen of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) and dasabuvir (DSV)±ribavirin (RBV) demonstrated high SVR rates and a favorable safety profile in registrational trials in patients infected with HCV GT1^11-13; however, these results have not been confirmed in the VA population. The TOPAZ-VA study (NCT02442284) prospectively evaluated the efficacy and safety of OBV/PTV/r+DSV±RBV for 12 or 24 weeks in VA patients with GT1 infection, including those with ongoing psychiatric disorders and/or ongoing or a history of substance use.

2 METHODS

3 RESULTS

Of 115 patients screened, 99 were enrolled in the study and received study treatment. Demographics and baseline disease characteristics are shown in Table 1. The study population was 96% male and 40% non-white race. Baseline FibroTest scores ranged from 0.18 to 1.0 (median: 0.66); aspartate aminotransferase to platelet ratio ranged from 0.18 to 8.1 (median: 0.56); and FIB-4 score ranged from 0.60 to 12.24 (median: 1.90) (Table 1). Overall, 29% (29/99) of patients received the OBV/PTV/r+DSV for 12 weeks without RBV; the remaining patients received OBV/PTV/r+DSV+RBV for 12 weeks (55%; 54/99) or 24 weeks (16%; 16/99). Medications including prior HCV medication administered to patients before the treatment period and concomitant medications during the treatment period are listed in Table 2.

The SVR12 rate was 94% (93/99; 95% confidence interval [CI]: 87-97%) in the ITT population (Figure 1). Of the six patients who did not achieve SVR12, one had an on-treatment virologic failure at week 4 and two patients relapsed (one at posttreatment week 4 and one at posttreatment week 12). The remaining three patients failed due to premature discontinuation of study drug (one due to adverse events [AEs] and two due to withdrawal of consent). All of the patients who experienced virologic failure or relapse had a history of psychiatric disorder, including posttraumatic stress disorder, schizophrenia, bipolar disorder, and prior substance use. Of note, the patient who experienced a viral breakthrough on treatment was more than 80% compliant with the study drug. One patient who relapsed had baseline RASs in NS5A (Q30H and Y93H), but no baseline RASs in NS3 or NS5B. At the time of virologic failure, all three patients had RASs in NS3 and NS5A and one of three had RASs in NS5B (Table S1). One patient who achieved SVR12 had a late relapse between posttreatment weeks 12 and 24; details on this patient are included in Table S1. None of the three patients with virologic failure had cirrhosis or required an RBV dose modification. Among patients with ongoing psychiatric comorbidities, the SVR12 rate was 95.8% (46/48; 95% CI: 86.0-98.8); the SVR12 rate was 93% (55/59; 95% CI: 83.8-97.3) among patients with a history of injection drug use (Figure 1) Adherence to OBV/PTV/r was 99% (95/96), adherence to DSV was 98% (94/96), and adherence to RBV was 99% (67/68).

Treatment-emergent AEs occurred in 80% (79/99) of patients. Fatigue, headache, nausea, insomnia, and pruritus each occurred in more than 10% of patients (Table 3). Ten treatment-emergent serious AEs occurred in seven (7%) patients. One treatment-emergent serious AE (mental status change due to drug interaction between DAAs and quetiapine) was considered possibly related to treatment. Six patients (6%) discontinued study drug due to a range of mild to moderate AEs, with no pattern of intolerance related to psychiatric disorders. One of these patients failed to achieve SVR12; this subject completed only 24 days of treatment and discontinued due to numerous complaints, both somatic (eg, diarrhea, dry skin, and asthenia) and neuropsychiatric (eg, dysesthesia, anger, anxiety, and paranoia), that were largely attributed to RBV. The other five patients who discontinued due to AEs completed between 57 and 114 days of study drug treatment and all achieved SVR12. Among patients receiving RBV, 19% (13/70) required RBV dose modification due to an AE, of which 62% (8/13) were due to a decrease in hemoglobin. No grade 3 or higher ALT elevations occurred during the study; one patient had a single grade 3 total bilirubin elevation, which was not associated with an AE.

4 DISCUSSION

In the TOPAZ-VA study, HCV GT1-infected VA patients treated with OBV/PTV/r+DSV±RBV for 12 or 24 weeks had an ITT SVR12 rate of 94%, consistent with findings of large real-world observational studies of newer DAA regimens in US veterans. The treatment combination was well tolerated, and the safety profile was consistent with what has been previously reported in registrational trials.^{12, 13}

During the IFN era of HCV treatment, psychiatric disorders and ongoing substance abuse were among the most common contraindications for HCV treatment among US veterans.^{14, 15} Here, an ongoing psychiatric disorder or a history of injection drug use did not impact SVR12 rates. These results are consistent with a real-world analysis of 21 242 US veterans with HCV GT1 infection treated with DAAs, which found that a diagnosis of a mental health disorder or alcohol or substance abuse was not predictive of achieving virologic response.¹⁰ In another real-world cohort of 1068 US veterans with HCV infection, neither psychiatric disorders nor substance abuse was predictive of virologic response, including in sub-analyses of GT1 HCV-infected patients or African-American patients.¹⁶ Despite the high efficacy rates of IFN-free DAAs, alcohol and drug abuse were still associated with low rates of DAA treatment initiation in US veterans.¹⁷ The high proportion of African-American patients enrolled in this trial (38%) are a strength and allows the findings to be more readily generalized to the population of interest.

This study demonstrated high adherence (>98%) to all components of the OBV/PTV/r+DSV±RBV regimen, although assessment of adherence by pill count in clinical trials may be insensitive to dosing errors, for example, in the timing of administration. Two real-world studies of US veterans used pharmacy records to assess adherence to treatment through medication procession ratio^{5, 16}: individual adherence rates of 90% or greater were seen in 88% of patients treated with IFN-based therapy⁵ and 94% of patients treated with an IFN-free DAA regimen.¹⁶ In both studies, lower treatment compliance was associated with reduced SVR rates.^{5, 16}

This prospective, interventional trial demonstrates the efficacy and safety of OBV/PTV/r+DSV±RBV in US veterans, including those with psychiatric or substance use disorders. While this regimen is no longer in use in the United States, the findings of this study are relevant to the use of other DAAs in this unique patient population, particularly with regard to the issue of potential drug-drug interactions with psychiatric medications, which are likely to be of less concern with next-generation therapies.¹⁸ A recent integrated analysis by Back et al¹⁹ confirms that patients with neuropsychiatric disorders can be safely and effectively treated with regimens such as glecaprevir/pibrentasvir.

In addition to the specific DAA regimen used, the limitations of this study include the small number of patients enrolled and the single-arm, open-label design. Patients with current heavy alcohol use were excluded from this study; therefore the impact of heavy alcohol use on virological response could not be assessed. A substantial proportion of the patients enrolled in this study had minimal fibrosis, and the majority were treatment-naïve; thus, results may have differed if a greater proportion of patients had advanced fibrosis or were IFN-experienced. While the small number of patients enrolled makes it difficult to conclude whether treatment responses differed by these baseline patient characteristics, previous registrational trials utilizing this regimen did not demonstrate a difference in efficacy between treatment-experienced and treatment-naïve populations,^{13, 20} or between patients with or without cirrhosis when treated according to the current product label.¹²

In conclusion, OBV/PTV/r+DSV±RBV was well tolerated in US veterans and achieved high SVR rates. In this population with a high rate of comorbidities, no new safety signals were observed; psychiatric and substance abuse disorders did not impact efficacy. These data confirm real-world evidence supporting the use of IFN-free DAA therapy for the treatment of HCV infection in US veterans with these comorbidities.

CONFLICT OF INTERESTS

Michael Fuchs: research support to McGuire Research Institute: AbbVie, Gilead, Intercept, Conatus, Galectin, Genfit, BMS, Novartis; Royalties: Springer. Norbert Bräu: Research Support: AbbVie, Gilead, BMS; Speaker Bureau: AbbVie, Gilead, Merck; Advisory Boards: AbbVie, Gilead, BMS. Warren Schmidt: Investigator in AbbVie-sponsored clinical studies. Michael Kozal: Yale/VACT receives research support from: Pfizer, Gilead, AbbVie, ViiV, and Bristol Myers Squibb for studies that Dr Kozal serves(d) as the primary investigator. Dr Kozal is an employee of the federal government and does not receive any salary support from these grants. Susanna Naggie: Research support: AbbVie, Gilead, BMS, Tacere. Ramsey Cheung: Investigator for AbbVie and Gilead. Mariem Charafeddine, Gretja Schnell, Yao Yu, Kristine Richards, Victoria Mullally, Daniel Cohen: Employees of AbbVie and may own stock or options. Alexander Monto: Investigator in AbbVie-sponsored clinical studies. Doris Toro: Investigator in AbbVie-sponsored clinical studies.

AUTHOR CONTRIBUTIONS

MF, AM, NB, MC, WS, MK, SN, RC, GS, YY, KR, VM, DEC, and DT designed the study, performed the research, analyzed the data, provided feedback on manuscript preparation, and revised the manuscript for final submission.