G. Everson, W. Towner, Mitchell N. Davis
Nov 10, 2015
Citations
2
Influential Citations
101
Citations
Quality indicators
Journal
Annals of Internal Medicine
Abstract
Context Pangenotypic treatments for hepatitis C virus (HCV) infection would be useful worldwide. Contribution In a small, phase 2, randomized, open-label clinical trial, combination therapy consisting of sofosbuvir plus 1 of 2 doses of velpatasvir was studied in treatment-naive noncirrhotic patients infected with HCV genotypes 1 to 6. Sustained virologic response rates at 12 weeks were high in all genotypes with 400 mg of sofosbuvir plus 100 mg of velpatasvir. No serious adverse events were noted. One death due to suicide occurred. Caution Few patients with genotype 4, 5, or 6 were included. Implication Velpatasvir may be a useful pangenotypic therapy for HCV infection and should be studied in larger clinical trials. Up to 150 million persons worldwide are chronically infected with hepatitis C virus (HCV) (1). Chronic HCV infection causes slowly progressive liver fibrosis, which can lead to cirrhosis, hepatic decompensation, and hepatocellular carcinoma (2, 3). Chronic HCV infection is curable, as measured by the end point of sustained virologic response (SVR), which is defined as undetectable HCV RNA 12 or 24 weeks after the end of treatment. For many years, however, HCV treatment regimens were based on recombinant interferon-, a poorly tolerated drug with moderate efficacy (4). The recent advent of drugs that directly target HCV viral replication has revolutionized treatment of HCV infection. The first such direct-acting antiviral agents (DAAs), the protease inhibitors telaprevir and boceprevir, were approved in combination with peginterferon and ribavirin in 2009, but these regimens are no longer recommended (5). With a second generation of DAAs, effective interferon-free treatment of HCV infection is now available. However, existing DAA combination regimens are not uniformly effective across the 6 HCV genotypes. The most effective regimens are for genotype 1 HCV, which accounts for approximately 46% of infections worldwide (6). Genotypes 2 and 3 HCV, the next most common genotypes, were historically grouped together in treatment guidelines, but recent studies have shown that infection with genotype 3, especially in patients with cirrhosis, is more difficult to treat (7, 8). Many interferon-free combinations are now available for these and the other 3 HCV genotypes (9, 10), but clinicians must take into account the genotype and even the subtype as well as patterns of antiviral resistance in the choice of a regimen. The development of a single, short-duration regimen that is safe and effective in all HCV genotypes would greatly simplify treatment and would reduce the need for pretreatment testing and on-treatment monitoring. Sofosbuvir is a pangenotypic HCV NS5B polymerase inhibitor approved in the United States and other regions for the treatment of HCV infection (11). Velpatasvir is a novel inhibitor of the HCV NS5A protein that has demonstrated pangenotypic antiviral activity in vitro (12) and in a 3-day monotherapy study in patients infected with genotypes 1, 2, 3, and 4 HCV (13). Drug interaction studies showed no clinically significant interactions between sofosbuvir and velpatasvir (14), and both can be administered once daily (15). The clinical potential of the combination of sofosbuvir and velpatasvir is suggested by their nonoverlapping viral targets, the proven success of sofosbuvir in combination with other NS5A inhibitors, and the in vitro potency of velpatasvir. We assessed the safety and efficacy of 8 or 12 weeks of velpatasvir coadministered with sofosbuvir. In addition, we examined the effect of adding ribavirin for patients receiving 8 weeks of treatment. Supplement. Original Version (PDF) Methods Study Overview Enrollment for this phase 2, multicenter, randomized, open-label study began on 22 August 2013, and data collection for the primary efficacy end point was completed on 12 August 2014 (Appendix Table). As originally designed, the study consisted of 6 groups of treatment-naive patients receiving 12 weeks of treatment: approximately 50 patients with genotype 1 HCV infection (groups 1 and 2); 50 with genotype 3 infection (groups 3 and 4); and 50 with genotype 2, 4, 5, or 6 infection (groups 5 and 6). Because interim analyses of results from these 6 groups (part A) indicated that patients with genotype 1 and 2 HCV infection achieved high rates of SVR at 12 weeks (SVR12), we amended the protocol to include part B, in which we evaluated 8 weeks of treatment with and without ribavirin in patients with genotype 1 infection (groups 7 to 10) and genotype 2 infection (groups 11 to 14). Appendix Table. Reasons for Screen Failure Setting and Participants The study was conducted at 48 sites in the United States. Patients were recruited partly through a posting of study details on ClinicalTrials.gov and partly through referral by their treating physicians. Treatment-naive noncirrhotic adults (aged 18 years) with HCV RNA levels greater than 10000 IU/mL were eligible. The HCV RNA genotype was determined by using the Siemens VERSANT HCV Genotype Assay, version 2 (LiPA 2.0), or, if results were inconclusive, the TRUGENE HCV 5'NC Genotyping Kit was used with the OpenGene DNA Sequencing System. Absence of cirrhosis was established by liver biopsy within 2 years of screening; a FibroTest score of 0.48 or less and an aspartate aminotransferaseplatelet ratio index of 1 or less during screening; or a Fibroscan score of 12.5 kPa or less within 6 months of baseline. Exclusion criteria were previous treatment for HCV infection, hepatic decompensation or co-infection with hepatitis B virus or HIV, aminotransferase levels greater than 10 times the upper limit of normal (ULN), direct bilirubin level greater than 1.5 times the ULN, platelet count less than 90109 cells/L, hemoglobin A1c level greater than 8.5%, creatinine clearance less than 60 mL/min (as calculated by the CockcroftGault equation), hemoglobin level less than 110 g/L for female patients or less than 120 g/L for male patients, albumin level less than 30 g/L, and prothrombin time (international normalized ratio) greater than 1.5 times the ULN. All patients provided written informed consent before screening. The protocol was approved by institutional ethics committees at all study sites. The study was conducted in accordance with good clinical practice and the Declaration of Helsinki and was registered with ClinicalTrials.gov (NCT01858766). Randomization and Interventions In part A, patients in each of the 3 HCV genotype categories were randomly assigned in a 1:1 ratio to receive 25 or 100 mg of velpatasvir once daily for 12 weeks. All patients received 400 mg of sofosbuvir once daily. Patients with genotype 1 HCV infection were stratified by HCV subtype (1a vs. 1b). Patients in groups 5 and 6 were stratified by HCV genotype. In part B, patients in each of the 2 HCV genotype categories were randomly assigned in a 1:1:1:1 ratio to receive 25 or 100 mg of velpatasvir once daily for 8 weeks or 25 or 100 mg of velpatasvir once daily plus ribavirin in a divided daily dose. All patients received 400 mg of sofosbuvir once daily for 8 weeks. Patients with genotype 1 HCV infection were stratified by HCV subtype (1a vs. 1b). Sofosbuvir was administered to all patients once daily in a 400-mg tablet. Velpatasvir was administered once daily in 25- or 100-mg tablets. Ribavirin was administered twice daily at a dose of 1000 mg/d (three 200-mg tablets in the morning and two 200-mg tablets in the evening) in patients with a total body weight less than 75 kg and 1200 mg/d (three 200-mg tablets twice daily) in those with a total body weight of 75 kg or greater (16). Patient randomization was managed by using an interactive Web response system (Bracket). A statistician employed by the sponsor (L.H.) generated the randomization code using a SAS program, which was validated by another statistician employed by the sponsor. Randomization was stratified by HCV genotype and used a block size of 4. Investigators, patients, and trial personnel were not blinded to treatment assignments at any point. Outcomes and Follow-up The primary efficacy outcome measure was SVR12, defined as a serum HCV RNA level below the lower limit of quantification (LLOQ) 12 weeks after completion of treatment. The HCV RNA concentration was measured using the Roche COBAS TaqMan HCV Test (v2.0) with the High Pure System, with an LLOQ of 25 IU/mL. On-treatment virologic failure was defined as an HCV RNA level of at least 25 IU/mL after 8 weeks of therapy. Relapse was defined as an HCV RNA level of at least the LLOQ during the posttreatment follow-up in patients who achieved a level below the LLOQ by the end of treatment. Levels of HCV RNA were measured at posttreatment weeks 4, 8, 12, and 24. Deep sequencing of the HCV NS5A and NS5B genes was performed from pretreatment plasma samples from all enrolled patients and from posttreatment samples from all patients with virologic failure. NS5A resistance-associated variants (RAVs) were defined as changes from a genotype-specific reference sequence at amino acid positions 28, 30, 31, 32, 58, 92, and 93. NS5B RAVs were defined as any change from the HCV reference sequence at positions 96, 142, 159, 282, 289, 320, and 321. Statistical Analysis The analysis set for efficacy and safety included randomly assigned patients who received at least 1 dose of the study drug. No inferential statistics or statistical comparisons were planned or conducted for efficacy or safety data. A 2-sided 95% CI for the proportion of patients with SVR12 within treatment groups was calculated by using the ClopperPearson method, which provides the exact CI based on the binomial distribution rather than an approximation to the binomial distribution (17). Patients with missing HCV RNA values for any reason at posttreatment week 12 and after were counted as treatment failures. No formal power or sample size calculations were used to determine group size. With a sample size of 25 patients in eac