- Email: [email protected]
Efficacy of Sofosbuvir Plus Ribavirin in Veterans With Hepatitis C Virus Genotype 2 Infection, Compensated Cirrhosis, and Multiple Comorbidities
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Efficacy of Sofosbuvir Plus Ribavirin in Veterans With Hepatitis C Virus Genotype 2 Infection, Compensated Cirrhosis, and Multiple Comorbidities Samuel B. Ho,* Alexander Monto,‡ Adam Peyton,§ David E. Kaplan,jj Sean Byrne,¶ Scott Moon,¶ Amanda Copans,¶ Lorenzo Rossaro,¶ Anupma Roy,¶ Hadley Le,¶ Hadas Dvory-Sobol,¶ Yanni Zhu,¶ Diana M. Brainard,¶ William Guyer,¶ Obaid Shaikh,# Michael Fuchs,** and Timothy R. Morgan,‡‡ on behalf of the VALOR study team
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From the *Veterans Affairs San Diego Healthcare System, San Diego, California; ‡San Francisco Veterans Affairs Healthcare System, San Francisco, California; §Miami Veterans Affairs Healthcare System, Miami, Florida; jjCorporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania; ¶Gilead Sciences, Foster City, California; #Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania; **Richmond Veterans Affairs Medical Center, Richmond, Virginia; and ‡‡ Veterans Affairs Long Beach Healthcare System, Long Beach, California BACKGROUND & AIMS:
We conducted a phase 4, open-label study with limited exclusion criteria to evaluate the safety and efficacy of sofosbuvir and ribavirin in veterans with hepatitis C virus genotype 2 infection, and compensated cirrhosis. This population is often excluded from clinical studies.
METHODS:
We performed a prospective study of treatment-naive (n [ 47) and treatment-experienced (n [ 19) patients with chronic hepatitis C virus genotype 2 infection and compensated cirrhosis at 15 Department of Veterans Affairs sites. All subjects were given sofosbuvir (400 mg, once daily) plus ribavirin (1000–1200 mg/day) in divided doses for 12 weeks. Patients with major psychiatric diseases or alcohol or substance use disorders were not excluded. The primary endpoint was sustained virologic response 12 weeks after therapy.
RESULTS:
Fifty-two patients achieved a sustained virologic response 12 weeks after therapy (79%; 95% confidence interval, 67%–88%); 16 of these patients were treatment experienced (84%; 95% confidence interval, 60%–97%) and 36 were treatment naive (77%; 95% confidence interval, 62%–88%). All patients had at least 1 comorbidity. Thirty-five percent had depression, 24% had posttraumatic stress disorder, and 30% had anxiety disorder. In addition, 29% had current substance use. Of the 7 patients (11%) who discontinued the study treatment prematurely, 3 did so because of adverse events. The most common adverse events were fatigue, anemia, nausea, and headache. Serious adverse events occurred in 8 patients. Only 2 of the serious adverse events (anemia and nausea) were considered to be related to study treatment.
CONCLUSIONS:
In a phase 4 study, 12 weeks treatment with sofosbuvir and ribavirin led to a sustained virologic response 12 weeks after therapy in almost 80% of veterans with hepatitis C virus genotype 2 infection, compensated cirrhosis, and multiple comorbidities, regardless of their treatment history. ClinicalTrials.gov, Number: NCT02128542
Keywords: VA; DAA; NS5B Inhibitor; Substance Abuse; Clinical Trial.
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he Department of Veterans Affairs (VA) is the largest single provider of hepatitis C virus (HCV) care in the United States, with more than 174,000 HCVinfected patients receiving care annually.1 The overall prevalence of HCV infection among VA patients born between 1945 and 1965 is estimated to be 10.3%.2 Yet only a minority of VA patients has received antiviral treatment for HCV,1 in part because of high prevalence of psychiatric and substance use disorders, which precluded use of interferon-based therapy.3–6 Direct-acting
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antiviral (DAA) therapies for HCV have improved efficacy and reduced treatment-related side effects.7 However, VA patients have largely been underrepresented or Abbreviations used in this paper: CI, confidence interval; DAA, directacting antiviral; HCV, hepatitis C virus; SVR, sustained virologic response; ULN, upper limit of normal; VA, Veterans Affairs. © 2016 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2016.05.024
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excluded from clinical trials in part because of their high prevalence of medical or psychiatric comorbidities. As a result, efficacy and safety of DAA therapies among VA patients are not well established. Patients with HCV with cirrhosis have an increased risk of developing hepatocellular carcinoma8,9 and/or decompensated cirrhosis. Because of these risks, these patients are a high priority treatment group for the VA and other payers. Despite their priority, no prospective trial has been designed to specifically evaluate the genotype 2 cirrhotic population. Therefore, the purpose of this trial was to conduct a prospective, open-label study in HCV genotype 2–infected VA patients with compensated cirrhosis to evaluate the effectiveness, safety, and tolerability of 12 weeks of sofosbuvir and ribavirin.
Methods Study Participants Participants were 18 years with chronic (6 months) genotype 2 HCV monoinfection and plasma HCV RNA 103 IU/mL and either HCV treatment naive or treatment experienced. Cirrhosis was defined by liver biopsy showing cirrhosis (Metavir ¼ 4 or Ishak 5), Fibroscan >12.5 kPa, FibroTest 0.75, aspartate transaminase/platelet ratio index >2, or imaging evidence suggestive of cirrhosis or portal hypertension. Patients were excluded if they had evidence of or history consistent with decompensated cirrhosis, coinfection with human immunodeficiency virus or hepatitis B, creatinine clearance <50 mL/min, albumin <3 g/dL, international normalized ratio of prothrombin time >1.5 upper limit of normal (ULN) unless the patient was stable on an anticoagulant regimen, hemoglobin <11 g/dL for females and <12 g/dL for males, direct bilirubin >1.5 ULN, alanine transaminase or aspartate transaminase >10 ULN, or prior exposure to an NS5B polymerase inhibitor. All patients provided written informed consent.
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Molecular Systems, Inc, Branchburg, NJ), which has a lower limit of quantification of 15 IU/mL.
Viral Sequencing The full-length NS5B gene was amplified and deep sequenced using MiSeq (Illumina, Inc, San Diego, CA) by DDL Diagnostics Laboratory BV (Rijswijk, the Netherlands) for patients who relapsed. Presence of viral variants was evaluated with an assay cutoff of 1%.
Safety Assessments During treatment and at the Week 4 follow-up visit, safety evaluations included reported adverse events, laboratory tests, vital signs, concomitant medications, and physical examinations. Laboratory tests, vital signs, and physical examinations were evaluated at the Week 12 follow-up visit. Clinical adverse events were summarized using the Medical Dictionary for Regulatory Activities, version 18.0. Laboratory abnormalities were determined based on the GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities, version June 18, 2012.
Endpoints and Statistical Analyses Descriptive statistics were provided for key demographic and baseline characteristics. The point estimate and the associated 2-sided 95% exact confidence interval (CI; Clopper-Pearson method) were calculated for
Study Design VALOR-HCV was a phase 4, prospective, open-label study conducted at 15 US VA sites. Patients received 12 weeks of oral sofosbuvir, 400 mg once daily plus weight-based ribavirin, 1000–1200 mg/day in divided doses. Each institution received institutional review board approval, and all coauthors had access to the study data and reviewed and approved the final manuscript.
Efficacy Assessments Plasma samples for determining HCV RNA levels were drawn at screening; on Day 1 before dosing; at treatment Weeks 2, 4, 8, and 12; and at follow-up Weeks 4 and 12. Plasma HCV RNA was analyzed by using the Roche COBAS TaqMan HCV RNA CAP/CTM 2.0 (Roche
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Figure 1. Patient disposition throughout the study.
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Table 1. Patient Demographics and Baseline Characteristics Treatment naive (n ¼ 47) Median (range) age, y Male, n (%) Race, n (%) White Black or African American Hawaiian or Pacific Islander Other (not specified) Ethnicity, n (%) Hispanic or Latino Not Hispanic or Latino Median (range) BMI, kg/m2 Median (range) HCV RNA, log10 IU/mL HCV genotype, n (%) 2b 2a/2c 2 subtype unspecified Prior HCV treatment response, n (%) Relapse/breakthrough Nonresponse Interferon intolerant Interferon eligibility, n (%) Eligible Ineligible Intolerant IL-28B, n (%) CC CT TT Cirrhosis, n (%) Present Median (range) ALT, U/L Median (range) creatinine clearance,a mL/min Comorbidities, n (%) Hypertension Musculoskeletal and connective tissue Gastrointestinal Metabolic Diabetes mellitus Psychiatric Depression Posttraumatic stress disorder Anxiety Current substance use Alcohol Marijuana Methamphetamine and other Cardiac disorders Median (range) APRI Median (range) FIB-4 Median (range) MELD Concomitant medications, n (%) No. taking 1 medication Most common, n (%) Drugs for acid-related disorders Beta-blocking agents
Treatment experienced (n ¼ 19)
Total (n ¼ 66)
63 (49–85) 47 (100)
63 (54–71) 19 (100)
63 (49–85) 66 (100)
37 8 1 1
(79) (17) (2) (2)
17 (89) 2 (11) 0 0
54 10 1 1
(82) (15) (2) (2)
4 43 30 6.1
(9) (92) (18–41) (3.9–7.3)
2 17 30 6.7
6 60 30 6.3
(9) (91) (18–51) (3.9–7.3)
(11) (90) (21–51) (5.7–7.2)
37 (79) 8 (17) 2 (4)
17 (89) 0 2 (11)
54 (82) 8 (12) 4 (6)
— — —
9 (47) 1 (5) 9 (47)
9 (14) 1 (2) 9 (14)
34 (72) 13 (28) 0
10 (53) 0 9 (47)
44 (67) 13 (20) 9 (14)
25 (53) 19 (40) 3 (6)
8 (42) 10 (53) 1 (5)
33 (50) 29 (44) 4 (6)
47 (100) 59 (12–245) 101.7 (43.0–233.9)
19 (100) 53 (15–213) 112.6 (77.4–205.5)
— — — — — — — — — — — —
— — — — — — — — — — — —
— — —
— — —
— — — —
— — — —
66 (100) 57 (12–245) 105.5 (43.0–233.9) 42 43 41 41 13 39 23 16 20 19 10 8 5 17 2.5 3.4 7
(64) (65) (62) (62) (20) (59) (35) (24) (30) (29) (15) (12) (8) (26) (0.5–8.5) (0.9–12.7) (6–25)
65 (98) 31 (47) 25 (38)
ALT, alanine transaminase; APRI, aspartate transaminase/platelet ratio index; BMI, body mass index; FIB-4, fibrosis-4; MELD, Model for End-Stage Liver Disease. a Estimated using the Cockroft-Gault equation.
the primary endpoint, sustained virologic response 12 weeks after therapy (SVR12) rate, in all enrolled and treated patients by prior HCV treatment experience (treatment naive vs treatment experienced) and overall.
SVR12 was defined as achieving HCV RNA less than lower limit of quantification 12 weeks after treatment. A univariate exact logistic regression was performed ad hoc to explore the relationship between SVR12 and
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Table 2. Patients Who Discontinued Therapy 407 349 408 350 Days on study Reason for 409 351 Treatment Mental health Substance/ treatment SOF Virologic discontinuation of 410 352 a No. experience history or ongoing alcohol use (out of 84 days) adherence , % outcome study treatment 411 353 412 354 1 TN Major depression No 58 68 Failure Investigator’s discretion 2 TN None Unknown 42 36 Otherb Noncompliance 413 355 3 TN Anxiety, depression No 51 61 SVR12 Adverse eventc 414 356 d e 4 TN PTSD, depression, Yes 18 35 Failure Adverse event 415 357 personality disorder 416 358 5 TE Anxiety, depression Yes 61 36 Failure Noncompliance 417 359 Withdrew consent 6 TN Depression No 43 35 Otherb 7 TN None No 75 87 SVR12 Adverse eventf 418 360 419 361 420 362 Q8 PTSD, posttraumatic stress disorder; SOF; TE; TN. a 421 363 Adherence defined as total amount of study drug dispensed minus returned, relative to the amount of study drug required for a 12-week regimen. b Did not have a confirmed virologic outcome at follow-up Week 12. 422 364 c Abdominal pain, constipation, fatigue, hyperbilirubinemia, jaundice, nausea. 423 365 d This patient had 18 days on study treatment, but only returned 1 pill from a bottle of 30, indicating there was medication unaccounted for. The patient was 424 366 questioned and did not recall what happened to it. e Arthralgia, dyspnea, swollen tongue. 425 367 f Esophageal variceal hemorrhage. 426 368 427 369 key baseline demographic and clinical factors, including (5 of 7). Two had substance or alcohol use and 6 of 7 had 428 370 age (65 or <65 years old), race (black or nonblack), less than 80% adherence to sofosbuvir based on defined 429 371 2 body mass index (30 or <30 kg/m ), prior HCV adherence (Table 2). Two still achieved SVR12. 430 372 treatment experience (treatment experienced or treat431 373 ment naive), baseline HCV RNA viral load (800,000 or Sustained Virologic Response 432 374 <800,000 IU/mL), IL28B genotype (CC or non-CC), 433 375 baseline weight (<75 or 75 kg), platelets (<75,000 434 376 Overall, 79% (52 of 66; 95% CI, 67%–88%) achieved versus 75,000/mL), current substance use (defined as 435 377 SVR12 (Table 3). SVR rates among treatmentalcohol, methamphetamine, cocaine, heroin, marijuana, 436 378 experienced patients were higher than treatment-naive other; yes/no), psychiatric disorder (yes/no), and patients, although the difference was not statistically 437 379 adherence to sofosbuvir (80% or <80%; defined as the significant. No patients experienced on-treatment viro438 380 total amount of study drug administered [assumed to be logic failure. All patients had HCV RNA less than lower 439 381 the difference between the dispensed pill count and the limit of quantification at Week 12 of treatment. Subgroup 440 382 returned pill count] relative to the amount of study drug analyses suggested that similar SVR12 rates were 441 383 required for a 12-week regimen). The odds ratio esti442 384 Q6 observed among patients with various demographics and mate and its associated 90% CI were reported. 443 385 disease characteristics (Figure 2), although the study was 444 386 not powered to detect significant differences. Results Patients with history of psychiatric disorder had a 445 387 numerically higher rate of SVR12, 82% (32 of 39; 95% CI, 446 388 66%–92%), than those who did not, 74% (20 of 27; 95% CI, 447 389 Study Participants 54%–89%), although the difference was not statistically 448 390 449 391 Sixty-six patients with genotype 2 HCV infection and different. SVR12 rates were 78% (18 of 23; 95% CI, 450 392 compensated cirrhosis (47 treatment naive and 19 56%–93%) for those with depression and 94% (15 of 16; 451 393 treatment experienced) were enrolled and treated from 95% CI, 70% to >99%) for those with posttraumatic stress 452 394 July 2014 through January 2015 (Figure 1). Forty-three disorder. SVR12 was achieved in 89% of patients with 453 395 patients did not meet eligibility criteria at screening, current substance use (17 of 19; 95% CI, 67%–99%), and in 454 396 the most common reason being absence of cirrhosis 74% in those without (35 of 47; 95% CI, 60%–86%). In the entire study population, 83% (55 of 66) had 455 397 (n ¼ 23). All patients were male, median age was 456 398 63 years (range, 49–85 years), and 15% were black greater than 80% adherence to sofosbuvir. Among the 457 399 persons. All patients had at least 1 comorbidity (Table 1), patients with less than 80% adherence to sofosbuvir, 55% 458 400 including 59% with psychiatric disorders. A total of 35% (6 of 11; 95% CI, 23%–83%) achieved SVR12, whereas 459 401 of patients had depression or major depression, 24% had 84% (46 of 55; 95% CI, 71%–92%) of those who were 460 402 posttraumatic stress disorder, and 30% had anxiety or more than 80% adherent to sofosbuvir reached SVR12. 461 403 an anxiety disorder. During the study, 19 patients (29%) Of the 11 patients with less than 80% adherence to 462 404 reported current substance use. Of the 7 patients who sofosbuvir, 6 discontinued treatment early and are rep463 405 discontinued study treatment prematurely, most were resented in Table 2. Adherence to ribavirin did not seem 464 406 treatment naive (6 of 7) or had a mental health history to have a meaningful impact on treatment outcome.
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Table 3. Virologic Response Treatment Treatment naive experienced Total (n ¼ 47) (n ¼ 19) (n ¼ 66) HCV RNA <15 IU/mL, n/n (%) At Week 4 of treatment 43/46 (93) At end of treatmenta 46/47 (98) After treatment Week 4 37/47 (79) Week 12 (SVR) 36/47 (77) 95% CI 62%–88% Virologic failure, n/n (%) On treatment 0/47 Relapse 8/46 (17)
17/19 (89) 19/19 (100)
60/65 (92) 65/66 (98)
17/19 (89) 16/19 (84) 60%–97%
54/66 (82) 52/66 (79) 67%–88%
0/19 3/19 (16)
0/66 11/65 (17)
a
End of treatment could occur at any planned on-treatment visit.
Ribavirin dose reduction or discontinuation did not lead to lower response rates. Among the patients who completed treatment, the SVR12 rate was 95% (19 of 20; 95% CI, 75% to >99%) for those who had ribavirin dose reduced, interrupted, or discontinued, versus 82% (31 of 38; 95% CI, 66%–92%) for those who did not have ribavirin dose reduction or discontinuation. Based on the ad hoc univariate exact logistic regression analysis, the estimated odds of achieving SVR12 in patients with 80% adherence to sofosbuvir was 3.14 times higher than that in patients with adherence <80% (odds ratio, 4.14; 90% CI, 1.03–16.51; P ¼ .09). No other baseline factors explored were significant at a significance level of 0.10.
Viral Sequencing Among the 11 patients who experienced virologic relapse, successful sequencing for both baseline and
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posttreatment Week 12 was obtained in 9 patients. One patient did not qualify for sequencing (low viral load at relapse), and the other patient had assay failure. Of the 11 who relapsed, 10 had genotype 2b HCV infection, and 1 had mixed genotype 2a/2c. NS5B nucleotide inhibitors resistance-associated variants emerged in 3 patients at the time of relapse: L159F emerged in 2 patients and M289I in 1. Additionally, 2 patients with NS5B resistance-associated variants at baseline, 1 with L159F and another with M289I, were observed to have the same variants after treatment. NS5B S282T was not observed in any patients.
Safety The most common adverse events were fatigue, anemia, nausea, and headache (Table 4). Three patients discontinued prematurely because of adverse events (abdominal pain, arthralgia, constipation, dyspnea, fatigue, hyperbilirubinemia, jaundice, nausea, esophageal variceal hemorrhage, and swollen tongue). Of these patients, only 1 patient was assessed to have experienced treatment-related adverse events of abdominal pain, constipation, hyperbilirubinemia, fatigue, jaundice, and nausea (sofosbuvir or ribavirin unspecified). Eight patients experienced serious adverse events. Only 2 of these events (anemia and nausea) were considered related to study treatment by the investigator; both occurred in the same patient and required dose reduction of ribavirin. Eight patients developed hemoglobin <10 g/dL on treatment. One of these patients received a transfusion of packed red blood cells; erythropoietin was not required. No patients experienced postbaseline hemoglobin <8.5 g/dL. Five patients experienced total bilirubin elevations between 2.5 and 5.0 ULN. In all cases, this increase was mainly driven by an increase in
Figure 2. SVR12 rates by subgroup. ALT, alanine transaminase; BMI, body mass index; IL, interleukin; RBV; SOF.
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Table 4. Treatment-Emergent Adverse Events and 581 Laboratory Abnormalities 582 583 Total 584 (n ¼ 66) 585 Patients with any adverse event, n (%) 58 (88) 586 Patients with a serious adverse event, n (%) 8 (12) 587 Patients with an adverse event 3 (5) 588 leading to discontinuation, n (%) 589 Deaths, n 0 590 Adverse eventsa in 5% of patients, n (%) Fatigue 22 (33) 591 Anemia 16 (24) 592 Nausea 12 (18) 593 Headache 11 (17) 594 Dizziness 6 (9) 595 Dyspnea 5 (8) Rash 5 (8) 596 Depression 4 (6) 597 Diarrhea 4 (6) 598 Dyspepsia 4 (6) 599 Insomnia 4 (6) 600 Musculoskeletal pain 4 (6) Vomiting 4 (6) 601 a Serious adverse events, n (%) 602 Anemia 1 (2) 603 Bacteremia 1 (2) 604 Cardiac failure congestive 1 (2) 605 Chest pain 1 (2) Chronic obstructive pulmonary disease 1 (2) 606 Drug withdrawal convulsions 1 (2) 607 Endocarditis staphylococcal 1 (2) 608 Hyperhidrosis 1 (2) 609 Nausea 1 (2) 610 Esophageal varices hemorrhage 1 (2) Rhabdomyolysis 1 (2) 611 Sepsis 1 (2) 612 Laboratory abnormalities, n (%) 613 Hemoglobin, 7.0 to <9.0 g/dL 6 (9) 614 Total bilirubin, >2.5 to 5.0 ULN 5 (8) 615 Serum hyperglycemia, >250 to 500 mg/dL 3 (5) Urinalysis 616 Hematuria, >75 RBC/HPF 2 (3) 617 Glycosuria (dipstick), 4þ 1 (2) 618 AST, >10.00 ULN 1 (2) 619 Lymphocytes, <350/mm3 1 (2) 620 INR, >2.0 to 3.0 ULN 1 (2) 621 622 AST, aspartate transaminase; HPF; INR, international normalized ratio; RBC, 623 Q9 red blood cells. a 624 As reported by the investigator. 625 626 indirect bilirubin with corresponding decreases in he627 moglobin, consistent with ribavirin-associated hemolytic 628 anemia, and none was associated with aspartate trans629 aminase and alanine transaminase elevation. 630 631 Discussion 632 633 634 In this phase 4, prospective, open-label study, 12 weeks 635 of sofosbuvir and ribavirin resulted in an SVR rate of 79% 636 in VA patients with genotype 2 HCV infection and 637 compensated cirrhosis. The inclusion and exclusion criteria 638 in this trial are used in general clinical practice in the VA
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system, reflecting common patient types. Even though a high percentage of patients had comorbidities, including 59% with psychiatric disorders and 29% with current substance use, the SVR12 rates for 12 weeks of sofosbuvir and ribavirin in these patients was comparable with that of the sofosbuvir registration trials,10–12 in which the SVR12 rates ranged from 60% to 94% in smaller numbers of treatment-experienced and treatment-naive genotype 2 patients with cirrhosis. Similar SVR12 rates were observed in a large, retrospective VA cohort of HCV genotype 2 patients with cirrhosis treated with sofosbuvir and ribavirin for 12 weeks, which also included decompensated patients.13 Additionally, in HCV-TARGET, a real-world, multicenter, observational cohort, 80 patients with HCV genotype 2 and cirrhosis were treated with sofosbuvir and ribavirin for 12 weeks (n ¼ 58) or sofosbuvir plus ribavirin for 16 weeks (n ¼ 22), with a combined SVR12 rate of 75% (64 of 80).14 Taken together, these results suggest that with these regimens VA patients may expect to achieve results similar to patients in registration trials. Current VA guidelines and American Association for the Study of Liver Diseases guidelines recommend sofosbuvir and ribavirin for 16 weeks, whereas the Food and Drug Administration–approved label is for 12 weeks. The recommendations for 16 weeks are based on a total of 24 patients from the BOSON (87% [13 of 15] SVR12)15 and FUSION trials (78% [7 of 9] SVR12),11 although it seems that in real-world settings most patients with genotype 2 cirrhosis are receiving 12 weeks of sofosbuvir and ribavirin as per label.13,14 In our study, reduced adherence to sofosbuvir was the only factor associated with lower rates of SVR12. The presence of depression, posttraumatic stress disorder, or substance use did not impact the treatment outcome, indicating that patients with these coexisting conditions can expect to achieve SVR rates similar to those without them. In contrast to VA guidelines, which recommend evaluation on a case-bycase basis,16 several state Medicaid programs restrict access to DAA therapy based on active substance use.17 Adherence and side effect management continue to represent important aspects of treatment with sofosbuvir and ribavirin. Of the 7 patients that discontinued study treatment early, 3 were because of nonserious adverse events and 2 were because of noncompliance with study drug. This suggests that strategies for optimizing patient case management continue to be important for increasing patient engagement in care and adherence to treatment.18 For this genotype 2 cirrhotic population, additional therapies may become available that obviate ribavirin.19,20 However, sofosbuvir plus ribavirin will still be an important treatment option in populations and geographies where newer treatments are not available or reimbursed. Limitations of this study include the high proportion of patients who failed screening, although the most common reason for screening failure was absence of cirrhosis. In conclusion, this prospective clinical trial of VA patients demonstrated an overall SVR rate of 79%, and
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represents the largest group of HCV genotype 2 patients with cirrhosis studied in a prospective trial of sofosbuvir and ribavirin to date. These data suggest that VA patients may expect to achieve similar results to those in registration trials in the DAA era, despite high comorbidities and ongoing substance use. Adherence to treatment continues to be an important issue.
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3: Results of the HCV-TARGET Study. Hepatology 2015; 62(Suppl S1):727A. 15. Foster GR, Pianko S, Brown A, et al. Efficacy of sofosbuvir plus ribavirin with or without peginterferon-alfa in patients with hepatitis C virus genotype 3 infection and treatment-experienced patients with cirrhosis and hepatitis C virus genotype 2 infection. Gastroenterology 2015;149:1462–1470. 16. Department of Veterans Affairs. Chronic hepatitis C virus (HCV) infection: treatment considerations from the Department of Veterans Affairs National Hepatitis C Resource Center Program and the Office of Public Health. Available at: http://www.hepatitis.va.gov/pdf/treatmentconsiderations-2015-02.pdf. Accessed November 9, 2015. 17. Barua S, Greenwald R, Grebely J, et al. Restrictions for Medicaid reimbursement of sofosbuvir for the treatment of hepatitis C virus infection in the United States. Ann Intern Med 2015; 163:215–223. 18. Ho SB, Bräu N, Cheung R, et al. Integrated care increases treatment and improves outcomes of patients with chronic hepatitis C virus infection and psychiatric illness or substance abuse. Clin Gastroenterol Hepatol 2015;13:2005–2014.
4. Rowan PJ, Tabasi S, Abdul-Latif M, et al. Psychosocial factors are the most common contraindications for antiviral therapy at initial evaluation in veterans with chronic hepatitis C. J Clin Gastroenterol 2004;38:530–534.
19. Feld JJ, Jacobson IM, Hézode C, et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 2015;373:2599–2607.
5. Rifai MA, Moles JK, Short DD. Hepatitis C treatment eligibility and outcomes among patients with psychiatric illness. Psychiatr Serv 2006;57:570–572.
20. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med 2015; 373:2608–2617.
6. Gundlapalli AV, Nelson RE, Haroldsen C, et al. Correlates of initiation of treatment for chronic hepatitis C infection in United States veterans, 2004–2009. PLoS One 2015;10:e0132056. 7. Lam BP, Jeffers T, Younoszai Z, et al. The changing landscape of hepatitis C virus therapy: focus on interferon-free treatment. Therap Adv Gastroenterol 2015;8:298–312. 8. Morgan TR, Ghany MG, Kim H-Y, et al. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology 2010;52:833–844. 9. Morgan RL, Baack B, Smith BD, et al. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med 2013;158:329–337. 10. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368:1878–1887. 11. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013;368:1867–1877. 12. Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med 2014; 370:1993–2001. 13. Backus LI, Belperio PS, Shahoumian TA, et al. Effectiveness of sofosbuvir-based regimens in genotype 1 and 2 hepatitis C virus infection in 4026 U.S. Veterans. Aliment Pharmacol Ther 2015; 42:559–573. 14. Welzel TM, Nelson DR, Morelli G, et al. Safety and efficacy of sofosbuvir and ribavirin for the treatment of HCV genotype 2 and
Reprint requests Address requests for reprints to: Samuel B. Ho, MD, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, California 92161. e-mail: [email protected]; fax: 858-552-4327.
Q1
Acknowledgments Jennifer King (August Editorial) provided writing assistance. VALOR Study Investigators are as follows: Geri Brown (Dallas VA Medical Center), Ramsey Cheung (VA Palo Alto Health Care System), Michael Fuchs (McGuire Research Institute), Bruce Gilliam (VA Maryland Health Care System), Sam Ho (VA San Diego Healthcare System), Lennox Jeffers (Miami VA Medical Center), David Kaplan (Philadelphia Veterans Affairs Medical Center), Joseph Lim (Yale University School of Medicine), Alexander Monto (San Francisco VA Medical Center), Timothy Morgan (VA Long Beach Healthcare System), Susanna Naggie (Durham VA Medical Center), Prashant Pandya (Kansas City VA Medical Center), Adam Peyton (Miami VA Medical Center), David Rimland (Atlanta VA Medical Center), Obaid Shaikh (Veterans Affairs Pittsburgh Healthcare System), Rohit Talwani (VA Maryland Health Care System), Boris Yoffee (Baylor College of Medicine), and Emily Cartwright (Atlanta VA Medical Center)..
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Conflicts of interest These authors disclose the following: Samuel B. Ho has received research and grant support from Genetech, Inc, and Gilead Sciences; served on advisory boards for Gilead Sciences; and been on the speakers bureau for Prime Education, Inc, and Abbvie, Inc. Alexander Monto has served as a principal investigator for trials funded by Gilead Sciences and Abbvie, Inc. David E. Kaplan has received research and grant support from Bayer Pharmaceuticals and Inovio Pharmaceuticals, Inc. Timothy R. Morgan has received research and grant support from AbbVie, Genentech, BristolMyersSquibb, Gilead Sciences, and Merck. Sean Byrne, Scott Moon, Yanni Zhu, Amanda Copans, Lorenzo Rossaro, Anupma Roy, Hadley Le, Hadas Dvory-Sobol, Diana M. Brainard, and William Guyer are employees of Gilead Sciences and may hold stock interest in the company. The remaining authors disclose no conflicts.
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Funding Funding for this study was provided by Gilead Sciences, Inc.
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Efficacy of Sofosbuvir Plus Ribavirin in Veterans With Hepatitis C Virus Genotype 2 Infection, Compensated Cirrhosis, and Multiple Comorbidities Samuel B. Ho,* Alexander Monto,‡ Adam Peyton,§ David E. Kaplan,jj Sean Byrne,¶ Scott Moon,¶ Amanda Copans,¶ Lorenzo Rossaro,¶ Anupma Roy,¶ Hadley Le,¶ Hadas Dvory-Sobol,¶ Yanni Zhu,¶ Diana M. Brainard,¶ William Guyer,¶ Obaid Shaikh,# Michael Fuchs,** and Timothy R. Morgan,‡‡ on behalf of the VALOR study team
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From the *Veterans Affairs San Diego Healthcare System, San Diego, California; ‡San Francisco Veterans Affairs Healthcare System, San Francisco, California; §Miami Veterans Affairs Healthcare System, Miami, Florida; jjCorporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania; ¶Gilead Sciences, Foster City, California; #Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania; **Richmond Veterans Affairs Medical Center, Richmond, Virginia; and ‡‡ Veterans Affairs Long Beach Healthcare System, Long Beach, California BACKGROUND & AIMS:
We conducted a phase 4, open-label study with limited exclusion criteria to evaluate the safety and efficacy of sofosbuvir and ribavirin in veterans with hepatitis C virus genotype 2 infection, and compensated cirrhosis. This population is often excluded from clinical studies.
METHODS:
We performed a prospective study of treatment-naive (n [ 47) and treatment-experienced (n [ 19) patients with chronic hepatitis C virus genotype 2 infection and compensated cirrhosis at 15 Department of Veterans Affairs sites. All subjects were given sofosbuvir (400 mg, once daily) plus ribavirin (1000–1200 mg/day) in divided doses for 12 weeks. Patients with major psychiatric diseases or alcohol or substance use disorders were not excluded. The primary endpoint was sustained virologic response 12 weeks after therapy.
RESULTS:
Fifty-two patients achieved a sustained virologic response 12 weeks after therapy (79%; 95% confidence interval, 67%–88%); 16 of these patients were treatment experienced (84%; 95% confidence interval, 60%–97%) and 36 were treatment naive (77%; 95% confidence interval, 62%–88%). All patients had at least 1 comorbidity. Thirty-five percent had depression, 24% had posttraumatic stress disorder, and 30% had anxiety disorder. In addition, 29% had current substance use. Of the 7 patients (11%) who discontinued the study treatment prematurely, 3 did so because of adverse events. The most common adverse events were fatigue, anemia, nausea, and headache. Serious adverse events occurred in 8 patients. Only 2 of the serious adverse events (anemia and nausea) were considered to be related to study treatment.
CONCLUSIONS:
In a phase 4 study, 12 weeks treatment with sofosbuvir and ribavirin led to a sustained virologic response 12 weeks after therapy in almost 80% of veterans with hepatitis C virus genotype 2 infection, compensated cirrhosis, and multiple comorbidities, regardless of their treatment history. ClinicalTrials.gov, Number: NCT02128542
Keywords: VA; DAA; NS5B Inhibitor; Substance Abuse; Clinical Trial.
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he Department of Veterans Affairs (VA) is the largest single provider of hepatitis C virus (HCV) care in the United States, with more than 174,000 HCVinfected patients receiving care annually.1 The overall prevalence of HCV infection among VA patients born between 1945 and 1965 is estimated to be 10.3%.2 Yet only a minority of VA patients has received antiviral treatment for HCV,1 in part because of high prevalence of psychiatric and substance use disorders, which precluded use of interferon-based therapy.3–6 Direct-acting
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antiviral (DAA) therapies for HCV have improved efficacy and reduced treatment-related side effects.7 However, VA patients have largely been underrepresented or Abbreviations used in this paper: CI, confidence interval; DAA, directacting antiviral; HCV, hepatitis C virus; SVR, sustained virologic response; ULN, upper limit of normal; VA, Veterans Affairs. © 2016 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2016.05.024
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excluded from clinical trials in part because of their high prevalence of medical or psychiatric comorbidities. As a result, efficacy and safety of DAA therapies among VA patients are not well established. Patients with HCV with cirrhosis have an increased risk of developing hepatocellular carcinoma8,9 and/or decompensated cirrhosis. Because of these risks, these patients are a high priority treatment group for the VA and other payers. Despite their priority, no prospective trial has been designed to specifically evaluate the genotype 2 cirrhotic population. Therefore, the purpose of this trial was to conduct a prospective, open-label study in HCV genotype 2–infected VA patients with compensated cirrhosis to evaluate the effectiveness, safety, and tolerability of 12 weeks of sofosbuvir and ribavirin.
Methods Study Participants Participants were 18 years with chronic (6 months) genotype 2 HCV monoinfection and plasma HCV RNA 103 IU/mL and either HCV treatment naive or treatment experienced. Cirrhosis was defined by liver biopsy showing cirrhosis (Metavir ¼ 4 or Ishak 5), Fibroscan >12.5 kPa, FibroTest 0.75, aspartate transaminase/platelet ratio index >2, or imaging evidence suggestive of cirrhosis or portal hypertension. Patients were excluded if they had evidence of or history consistent with decompensated cirrhosis, coinfection with human immunodeficiency virus or hepatitis B, creatinine clearance <50 mL/min, albumin <3 g/dL, international normalized ratio of prothrombin time >1.5 upper limit of normal (ULN) unless the patient was stable on an anticoagulant regimen, hemoglobin <11 g/dL for females and <12 g/dL for males, direct bilirubin >1.5 ULN, alanine transaminase or aspartate transaminase >10 ULN, or prior exposure to an NS5B polymerase inhibitor. All patients provided written informed consent.
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Molecular Systems, Inc, Branchburg, NJ), which has a lower limit of quantification of 15 IU/mL.
Viral Sequencing The full-length NS5B gene was amplified and deep sequenced using MiSeq (Illumina, Inc, San Diego, CA) by DDL Diagnostics Laboratory BV (Rijswijk, the Netherlands) for patients who relapsed. Presence of viral variants was evaluated with an assay cutoff of 1%.
Safety Assessments During treatment and at the Week 4 follow-up visit, safety evaluations included reported adverse events, laboratory tests, vital signs, concomitant medications, and physical examinations. Laboratory tests, vital signs, and physical examinations were evaluated at the Week 12 follow-up visit. Clinical adverse events were summarized using the Medical Dictionary for Regulatory Activities, version 18.0. Laboratory abnormalities were determined based on the GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities, version June 18, 2012.
Endpoints and Statistical Analyses Descriptive statistics were provided for key demographic and baseline characteristics. The point estimate and the associated 2-sided 95% exact confidence interval (CI; Clopper-Pearson method) were calculated for
Study Design VALOR-HCV was a phase 4, prospective, open-label study conducted at 15 US VA sites. Patients received 12 weeks of oral sofosbuvir, 400 mg once daily plus weight-based ribavirin, 1000–1200 mg/day in divided doses. Each institution received institutional review board approval, and all coauthors had access to the study data and reviewed and approved the final manuscript.
Efficacy Assessments Plasma samples for determining HCV RNA levels were drawn at screening; on Day 1 before dosing; at treatment Weeks 2, 4, 8, and 12; and at follow-up Weeks 4 and 12. Plasma HCV RNA was analyzed by using the Roche COBAS TaqMan HCV RNA CAP/CTM 2.0 (Roche
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Figure 1. Patient disposition throughout the study.
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Table 1. Patient Demographics and Baseline Characteristics Treatment naive (n ¼ 47) Median (range) age, y Male, n (%) Race, n (%) White Black or African American Hawaiian or Pacific Islander Other (not specified) Ethnicity, n (%) Hispanic or Latino Not Hispanic or Latino Median (range) BMI, kg/m2 Median (range) HCV RNA, log10 IU/mL HCV genotype, n (%) 2b 2a/2c 2 subtype unspecified Prior HCV treatment response, n (%) Relapse/breakthrough Nonresponse Interferon intolerant Interferon eligibility, n (%) Eligible Ineligible Intolerant IL-28B, n (%) CC CT TT Cirrhosis, n (%) Present Median (range) ALT, U/L Median (range) creatinine clearance,a mL/min Comorbidities, n (%) Hypertension Musculoskeletal and connective tissue Gastrointestinal Metabolic Diabetes mellitus Psychiatric Depression Posttraumatic stress disorder Anxiety Current substance use Alcohol Marijuana Methamphetamine and other Cardiac disorders Median (range) APRI Median (range) FIB-4 Median (range) MELD Concomitant medications, n (%) No. taking 1 medication Most common, n (%) Drugs for acid-related disorders Beta-blocking agents
Treatment experienced (n ¼ 19)
Total (n ¼ 66)
63 (49–85) 47 (100)
63 (54–71) 19 (100)
63 (49–85) 66 (100)
37 8 1 1
(79) (17) (2) (2)
17 (89) 2 (11) 0 0
54 10 1 1
(82) (15) (2) (2)
4 43 30 6.1
(9) (92) (18–41) (3.9–7.3)
2 17 30 6.7
6 60 30 6.3
(9) (91) (18–51) (3.9–7.3)
(11) (90) (21–51) (5.7–7.2)
37 (79) 8 (17) 2 (4)
17 (89) 0 2 (11)
54 (82) 8 (12) 4 (6)
— — —
9 (47) 1 (5) 9 (47)
9 (14) 1 (2) 9 (14)
34 (72) 13 (28) 0
10 (53) 0 9 (47)
44 (67) 13 (20) 9 (14)
25 (53) 19 (40) 3 (6)
8 (42) 10 (53) 1 (5)
33 (50) 29 (44) 4 (6)
47 (100) 59 (12–245) 101.7 (43.0–233.9)
19 (100) 53 (15–213) 112.6 (77.4–205.5)
— — — — — — — — — — — —
— — — — — — — — — — — —
— — —
— — —
— — — —
— — — —
66 (100) 57 (12–245) 105.5 (43.0–233.9) 42 43 41 41 13 39 23 16 20 19 10 8 5 17 2.5 3.4 7
(64) (65) (62) (62) (20) (59) (35) (24) (30) (29) (15) (12) (8) (26) (0.5–8.5) (0.9–12.7) (6–25)
65 (98) 31 (47) 25 (38)
ALT, alanine transaminase; APRI, aspartate transaminase/platelet ratio index; BMI, body mass index; FIB-4, fibrosis-4; MELD, Model for End-Stage Liver Disease. a Estimated using the Cockroft-Gault equation.
the primary endpoint, sustained virologic response 12 weeks after therapy (SVR12) rate, in all enrolled and treated patients by prior HCV treatment experience (treatment naive vs treatment experienced) and overall.
SVR12 was defined as achieving HCV RNA less than lower limit of quantification 12 weeks after treatment. A univariate exact logistic regression was performed ad hoc to explore the relationship between SVR12 and
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Table 2. Patients Who Discontinued Therapy 407 349 408 350 Days on study Reason for 409 351 Treatment Mental health Substance/ treatment SOF Virologic discontinuation of 410 352 a No. experience history or ongoing alcohol use (out of 84 days) adherence , % outcome study treatment 411 353 412 354 1 TN Major depression No 58 68 Failure Investigator’s discretion 2 TN None Unknown 42 36 Otherb Noncompliance 413 355 3 TN Anxiety, depression No 51 61 SVR12 Adverse eventc 414 356 d e 4 TN PTSD, depression, Yes 18 35 Failure Adverse event 415 357 personality disorder 416 358 5 TE Anxiety, depression Yes 61 36 Failure Noncompliance 417 359 Withdrew consent 6 TN Depression No 43 35 Otherb 7 TN None No 75 87 SVR12 Adverse eventf 418 360 419 361 420 362 Q8 PTSD, posttraumatic stress disorder; SOF; TE; TN. a 421 363 Adherence defined as total amount of study drug dispensed minus returned, relative to the amount of study drug required for a 12-week regimen. b Did not have a confirmed virologic outcome at follow-up Week 12. 422 364 c Abdominal pain, constipation, fatigue, hyperbilirubinemia, jaundice, nausea. 423 365 d This patient had 18 days on study treatment, but only returned 1 pill from a bottle of 30, indicating there was medication unaccounted for. The patient was 424 366 questioned and did not recall what happened to it. e Arthralgia, dyspnea, swollen tongue. 425 367 f Esophageal variceal hemorrhage. 426 368 427 369 key baseline demographic and clinical factors, including (5 of 7). Two had substance or alcohol use and 6 of 7 had 428 370 age (65 or <65 years old), race (black or nonblack), less than 80% adherence to sofosbuvir based on defined 429 371 2 body mass index (30 or <30 kg/m ), prior HCV adherence (Table 2). Two still achieved SVR12. 430 372 treatment experience (treatment experienced or treat431 373 ment naive), baseline HCV RNA viral load (800,000 or Sustained Virologic Response 432 374 <800,000 IU/mL), IL28B genotype (CC or non-CC), 433 375 baseline weight (<75 or 75 kg), platelets (<75,000 434 376 Overall, 79% (52 of 66; 95% CI, 67%–88%) achieved versus 75,000/mL), current substance use (defined as 435 377 SVR12 (Table 3). SVR rates among treatmentalcohol, methamphetamine, cocaine, heroin, marijuana, 436 378 experienced patients were higher than treatment-naive other; yes/no), psychiatric disorder (yes/no), and patients, although the difference was not statistically 437 379 adherence to sofosbuvir (80% or <80%; defined as the significant. No patients experienced on-treatment viro438 380 total amount of study drug administered [assumed to be logic failure. All patients had HCV RNA less than lower 439 381 the difference between the dispensed pill count and the limit of quantification at Week 12 of treatment. Subgroup 440 382 returned pill count] relative to the amount of study drug analyses suggested that similar SVR12 rates were 441 383 required for a 12-week regimen). The odds ratio esti442 384 Q6 observed among patients with various demographics and mate and its associated 90% CI were reported. 443 385 disease characteristics (Figure 2), although the study was 444 386 not powered to detect significant differences. Results Patients with history of psychiatric disorder had a 445 387 numerically higher rate of SVR12, 82% (32 of 39; 95% CI, 446 388 66%–92%), than those who did not, 74% (20 of 27; 95% CI, 447 389 Study Participants 54%–89%), although the difference was not statistically 448 390 449 391 Sixty-six patients with genotype 2 HCV infection and different. SVR12 rates were 78% (18 of 23; 95% CI, 450 392 compensated cirrhosis (47 treatment naive and 19 56%–93%) for those with depression and 94% (15 of 16; 451 393 treatment experienced) were enrolled and treated from 95% CI, 70% to >99%) for those with posttraumatic stress 452 394 July 2014 through January 2015 (Figure 1). Forty-three disorder. SVR12 was achieved in 89% of patients with 453 395 patients did not meet eligibility criteria at screening, current substance use (17 of 19; 95% CI, 67%–99%), and in 454 396 the most common reason being absence of cirrhosis 74% in those without (35 of 47; 95% CI, 60%–86%). In the entire study population, 83% (55 of 66) had 455 397 (n ¼ 23). All patients were male, median age was 456 398 63 years (range, 49–85 years), and 15% were black greater than 80% adherence to sofosbuvir. Among the 457 399 persons. All patients had at least 1 comorbidity (Table 1), patients with less than 80% adherence to sofosbuvir, 55% 458 400 including 59% with psychiatric disorders. A total of 35% (6 of 11; 95% CI, 23%–83%) achieved SVR12, whereas 459 401 of patients had depression or major depression, 24% had 84% (46 of 55; 95% CI, 71%–92%) of those who were 460 402 posttraumatic stress disorder, and 30% had anxiety or more than 80% adherent to sofosbuvir reached SVR12. 461 403 an anxiety disorder. During the study, 19 patients (29%) Of the 11 patients with less than 80% adherence to 462 404 reported current substance use. Of the 7 patients who sofosbuvir, 6 discontinued treatment early and are rep463 405 discontinued study treatment prematurely, most were resented in Table 2. Adherence to ribavirin did not seem 464 406 treatment naive (6 of 7) or had a mental health history to have a meaningful impact on treatment outcome.
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Table 3. Virologic Response Treatment Treatment naive experienced Total (n ¼ 47) (n ¼ 19) (n ¼ 66) HCV RNA <15 IU/mL, n/n (%) At Week 4 of treatment 43/46 (93) At end of treatmenta 46/47 (98) After treatment Week 4 37/47 (79) Week 12 (SVR) 36/47 (77) 95% CI 62%–88% Virologic failure, n/n (%) On treatment 0/47 Relapse 8/46 (17)
17/19 (89) 19/19 (100)
60/65 (92) 65/66 (98)
17/19 (89) 16/19 (84) 60%–97%
54/66 (82) 52/66 (79) 67%–88%
0/19 3/19 (16)
0/66 11/65 (17)
a
End of treatment could occur at any planned on-treatment visit.
Ribavirin dose reduction or discontinuation did not lead to lower response rates. Among the patients who completed treatment, the SVR12 rate was 95% (19 of 20; 95% CI, 75% to >99%) for those who had ribavirin dose reduced, interrupted, or discontinued, versus 82% (31 of 38; 95% CI, 66%–92%) for those who did not have ribavirin dose reduction or discontinuation. Based on the ad hoc univariate exact logistic regression analysis, the estimated odds of achieving SVR12 in patients with 80% adherence to sofosbuvir was 3.14 times higher than that in patients with adherence <80% (odds ratio, 4.14; 90% CI, 1.03–16.51; P ¼ .09). No other baseline factors explored were significant at a significance level of 0.10.
Viral Sequencing Among the 11 patients who experienced virologic relapse, successful sequencing for both baseline and
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posttreatment Week 12 was obtained in 9 patients. One patient did not qualify for sequencing (low viral load at relapse), and the other patient had assay failure. Of the 11 who relapsed, 10 had genotype 2b HCV infection, and 1 had mixed genotype 2a/2c. NS5B nucleotide inhibitors resistance-associated variants emerged in 3 patients at the time of relapse: L159F emerged in 2 patients and M289I in 1. Additionally, 2 patients with NS5B resistance-associated variants at baseline, 1 with L159F and another with M289I, were observed to have the same variants after treatment. NS5B S282T was not observed in any patients.
Safety The most common adverse events were fatigue, anemia, nausea, and headache (Table 4). Three patients discontinued prematurely because of adverse events (abdominal pain, arthralgia, constipation, dyspnea, fatigue, hyperbilirubinemia, jaundice, nausea, esophageal variceal hemorrhage, and swollen tongue). Of these patients, only 1 patient was assessed to have experienced treatment-related adverse events of abdominal pain, constipation, hyperbilirubinemia, fatigue, jaundice, and nausea (sofosbuvir or ribavirin unspecified). Eight patients experienced serious adverse events. Only 2 of these events (anemia and nausea) were considered related to study treatment by the investigator; both occurred in the same patient and required dose reduction of ribavirin. Eight patients developed hemoglobin <10 g/dL on treatment. One of these patients received a transfusion of packed red blood cells; erythropoietin was not required. No patients experienced postbaseline hemoglobin <8.5 g/dL. Five patients experienced total bilirubin elevations between 2.5 and 5.0 ULN. In all cases, this increase was mainly driven by an increase in
Figure 2. SVR12 rates by subgroup. ALT, alanine transaminase; BMI, body mass index; IL, interleukin; RBV; SOF.
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Table 4. Treatment-Emergent Adverse Events and 581 Laboratory Abnormalities 582 583 Total 584 (n ¼ 66) 585 Patients with any adverse event, n (%) 58 (88) 586 Patients with a serious adverse event, n (%) 8 (12) 587 Patients with an adverse event 3 (5) 588 leading to discontinuation, n (%) 589 Deaths, n 0 590 Adverse eventsa in 5% of patients, n (%) Fatigue 22 (33) 591 Anemia 16 (24) 592 Nausea 12 (18) 593 Headache 11 (17) 594 Dizziness 6 (9) 595 Dyspnea 5 (8) Rash 5 (8) 596 Depression 4 (6) 597 Diarrhea 4 (6) 598 Dyspepsia 4 (6) 599 Insomnia 4 (6) 600 Musculoskeletal pain 4 (6) Vomiting 4 (6) 601 a Serious adverse events, n (%) 602 Anemia 1 (2) 603 Bacteremia 1 (2) 604 Cardiac failure congestive 1 (2) 605 Chest pain 1 (2) Chronic obstructive pulmonary disease 1 (2) 606 Drug withdrawal convulsions 1 (2) 607 Endocarditis staphylococcal 1 (2) 608 Hyperhidrosis 1 (2) 609 Nausea 1 (2) 610 Esophageal varices hemorrhage 1 (2) Rhabdomyolysis 1 (2) 611 Sepsis 1 (2) 612 Laboratory abnormalities, n (%) 613 Hemoglobin, 7.0 to <9.0 g/dL 6 (9) 614 Total bilirubin, >2.5 to 5.0 ULN 5 (8) 615 Serum hyperglycemia, >250 to 500 mg/dL 3 (5) Urinalysis 616 Hematuria, >75 RBC/HPF 2 (3) 617 Glycosuria (dipstick), 4þ 1 (2) 618 AST, >10.00 ULN 1 (2) 619 Lymphocytes, <350/mm3 1 (2) 620 INR, >2.0 to 3.0 ULN 1 (2) 621 622 AST, aspartate transaminase; HPF; INR, international normalized ratio; RBC, 623 Q9 red blood cells. a 624 As reported by the investigator. 625 626 indirect bilirubin with corresponding decreases in he627 moglobin, consistent with ribavirin-associated hemolytic 628 anemia, and none was associated with aspartate trans629 aminase and alanine transaminase elevation. 630 631 Discussion 632 633 634 In this phase 4, prospective, open-label study, 12 weeks 635 of sofosbuvir and ribavirin resulted in an SVR rate of 79% 636 in VA patients with genotype 2 HCV infection and 637 compensated cirrhosis. The inclusion and exclusion criteria 638 in this trial are used in general clinical practice in the VA
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system, reflecting common patient types. Even though a high percentage of patients had comorbidities, including 59% with psychiatric disorders and 29% with current substance use, the SVR12 rates for 12 weeks of sofosbuvir and ribavirin in these patients was comparable with that of the sofosbuvir registration trials,10–12 in which the SVR12 rates ranged from 60% to 94% in smaller numbers of treatment-experienced and treatment-naive genotype 2 patients with cirrhosis. Similar SVR12 rates were observed in a large, retrospective VA cohort of HCV genotype 2 patients with cirrhosis treated with sofosbuvir and ribavirin for 12 weeks, which also included decompensated patients.13 Additionally, in HCV-TARGET, a real-world, multicenter, observational cohort, 80 patients with HCV genotype 2 and cirrhosis were treated with sofosbuvir and ribavirin for 12 weeks (n ¼ 58) or sofosbuvir plus ribavirin for 16 weeks (n ¼ 22), with a combined SVR12 rate of 75% (64 of 80).14 Taken together, these results suggest that with these regimens VA patients may expect to achieve results similar to patients in registration trials. Current VA guidelines and American Association for the Study of Liver Diseases guidelines recommend sofosbuvir and ribavirin for 16 weeks, whereas the Food and Drug Administration–approved label is for 12 weeks. The recommendations for 16 weeks are based on a total of 24 patients from the BOSON (87% [13 of 15] SVR12)15 and FUSION trials (78% [7 of 9] SVR12),11 although it seems that in real-world settings most patients with genotype 2 cirrhosis are receiving 12 weeks of sofosbuvir and ribavirin as per label.13,14 In our study, reduced adherence to sofosbuvir was the only factor associated with lower rates of SVR12. The presence of depression, posttraumatic stress disorder, or substance use did not impact the treatment outcome, indicating that patients with these coexisting conditions can expect to achieve SVR rates similar to those without them. In contrast to VA guidelines, which recommend evaluation on a case-bycase basis,16 several state Medicaid programs restrict access to DAA therapy based on active substance use.17 Adherence and side effect management continue to represent important aspects of treatment with sofosbuvir and ribavirin. Of the 7 patients that discontinued study treatment early, 3 were because of nonserious adverse events and 2 were because of noncompliance with study drug. This suggests that strategies for optimizing patient case management continue to be important for increasing patient engagement in care and adherence to treatment.18 For this genotype 2 cirrhotic population, additional therapies may become available that obviate ribavirin.19,20 However, sofosbuvir plus ribavirin will still be an important treatment option in populations and geographies where newer treatments are not available or reimbursed. Limitations of this study include the high proportion of patients who failed screening, although the most common reason for screening failure was absence of cirrhosis. In conclusion, this prospective clinical trial of VA patients demonstrated an overall SVR rate of 79%, and
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Sofosbuvir for HCV Genotype 2 With Cirrhosis
represents the largest group of HCV genotype 2 patients with cirrhosis studied in a prospective trial of sofosbuvir and ribavirin to date. These data suggest that VA patients may expect to achieve similar results to those in registration trials in the DAA era, despite high comorbidities and ongoing substance use. Adherence to treatment continues to be an important issue.
References 1. Beste LA, Ioannou GN. Prevalence and treatment of chronic hepatitis C virus infection in the US Department of Veterans Affairs. Epidemiol Rev 2015;37:131–143. 2. Backus LI, Belperio PS, Loomis TP, et al. Hepatitis C virus screening and prevalence among US veterans in Department of Veterans Affairs care. JAMA Intern Med 2013;173:1549–1552. 3. Ho SB, Nguyen H, Tetrick LL, et al. Influence of psychiatric diagnoses on interferon-alpha treatment for chronic hepatitis C in a veteran population. Am J Gastroenterol 2001;96:157–164.
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3: Results of the HCV-TARGET Study. Hepatology 2015; 62(Suppl S1):727A. 15. Foster GR, Pianko S, Brown A, et al. Efficacy of sofosbuvir plus ribavirin with or without peginterferon-alfa in patients with hepatitis C virus genotype 3 infection and treatment-experienced patients with cirrhosis and hepatitis C virus genotype 2 infection. Gastroenterology 2015;149:1462–1470. 16. Department of Veterans Affairs. Chronic hepatitis C virus (HCV) infection: treatment considerations from the Department of Veterans Affairs National Hepatitis C Resource Center Program and the Office of Public Health. Available at: http://www.hepatitis.va.gov/pdf/treatmentconsiderations-2015-02.pdf. Accessed November 9, 2015. 17. Barua S, Greenwald R, Grebely J, et al. Restrictions for Medicaid reimbursement of sofosbuvir for the treatment of hepatitis C virus infection in the United States. Ann Intern Med 2015; 163:215–223. 18. Ho SB, Bräu N, Cheung R, et al. Integrated care increases treatment and improves outcomes of patients with chronic hepatitis C virus infection and psychiatric illness or substance abuse. Clin Gastroenterol Hepatol 2015;13:2005–2014.
4. Rowan PJ, Tabasi S, Abdul-Latif M, et al. Psychosocial factors are the most common contraindications for antiviral therapy at initial evaluation in veterans with chronic hepatitis C. J Clin Gastroenterol 2004;38:530–534.
19. Feld JJ, Jacobson IM, Hézode C, et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 2015;373:2599–2607.
5. Rifai MA, Moles JK, Short DD. Hepatitis C treatment eligibility and outcomes among patients with psychiatric illness. Psychiatr Serv 2006;57:570–572.
20. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med 2015; 373:2608–2617.
6. Gundlapalli AV, Nelson RE, Haroldsen C, et al. Correlates of initiation of treatment for chronic hepatitis C infection in United States veterans, 2004–2009. PLoS One 2015;10:e0132056. 7. Lam BP, Jeffers T, Younoszai Z, et al. The changing landscape of hepatitis C virus therapy: focus on interferon-free treatment. Therap Adv Gastroenterol 2015;8:298–312. 8. Morgan TR, Ghany MG, Kim H-Y, et al. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology 2010;52:833–844. 9. Morgan RL, Baack B, Smith BD, et al. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med 2013;158:329–337. 10. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368:1878–1887. 11. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013;368:1867–1877. 12. Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med 2014; 370:1993–2001. 13. Backus LI, Belperio PS, Shahoumian TA, et al. Effectiveness of sofosbuvir-based regimens in genotype 1 and 2 hepatitis C virus infection in 4026 U.S. Veterans. Aliment Pharmacol Ther 2015; 42:559–573. 14. Welzel TM, Nelson DR, Morelli G, et al. Safety and efficacy of sofosbuvir and ribavirin for the treatment of HCV genotype 2 and
Reprint requests Address requests for reprints to: Samuel B. Ho, MD, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, California 92161. e-mail: [email protected]; fax: 858-552-4327.
Q1
Acknowledgments Jennifer King (August Editorial) provided writing assistance. VALOR Study Investigators are as follows: Geri Brown (Dallas VA Medical Center), Ramsey Cheung (VA Palo Alto Health Care System), Michael Fuchs (McGuire Research Institute), Bruce Gilliam (VA Maryland Health Care System), Sam Ho (VA San Diego Healthcare System), Lennox Jeffers (Miami VA Medical Center), David Kaplan (Philadelphia Veterans Affairs Medical Center), Joseph Lim (Yale University School of Medicine), Alexander Monto (San Francisco VA Medical Center), Timothy Morgan (VA Long Beach Healthcare System), Susanna Naggie (Durham VA Medical Center), Prashant Pandya (Kansas City VA Medical Center), Adam Peyton (Miami VA Medical Center), David Rimland (Atlanta VA Medical Center), Obaid Shaikh (Veterans Affairs Pittsburgh Healthcare System), Rohit Talwani (VA Maryland Health Care System), Boris Yoffee (Baylor College of Medicine), and Emily Cartwright (Atlanta VA Medical Center)..
Q2
Conflicts of interest These authors disclose the following: Samuel B. Ho has received research and grant support from Genetech, Inc, and Gilead Sciences; served on advisory boards for Gilead Sciences; and been on the speakers bureau for Prime Education, Inc, and Abbvie, Inc. Alexander Monto has served as a principal investigator for trials funded by Gilead Sciences and Abbvie, Inc. David E. Kaplan has received research and grant support from Bayer Pharmaceuticals and Inovio Pharmaceuticals, Inc. Timothy R. Morgan has received research and grant support from AbbVie, Genentech, BristolMyersSquibb, Gilead Sciences, and Merck. Sean Byrne, Scott Moon, Yanni Zhu, Amanda Copans, Lorenzo Rossaro, Anupma Roy, Hadley Le, Hadas Dvory-Sobol, Diana M. Brainard, and William Guyer are employees of Gilead Sciences and may hold stock interest in the company. The remaining authors disclose no conflicts.
Q3
Funding Funding for this study was provided by Gilead Sciences, Inc.
Q4
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