Luisa M. Stamm

Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1

BACKGROUND Effective treatment for hepatitis C virus (HCV) in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains an unmet medical need. METHODS We conducted a multicenter, single-group, open-label study involving patients coinfected with HIV-1 and genotype 1 or 4 HCV receiving an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine, or raltegravir. All patients received ledipasvir, an NS5A inhibitor, and sofosbuvir, a nucleotide polymerase inhibitor, as a single fixed-dose combination for 12 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Of the 335 patients enrolled, 34% were black, 55% had been previously treated for HCV, and 20% had cirrhosis. Overall, 322 patients (96%) had a sustained virologic response at 12 weeks after the end of therapy (95% confidence interval [CI], 93 to 98), including rates of 96% (95% CI, 93 to 98) in patients with HCV genotype 1a, 96% (95% CI, 89 to 99) in those with HCV genotype 1b, and 100% (95% CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic response were similar regardless of previous treatment or the presence of cirrhosis. Of the 13 patients who did not have a sustained virologic response, 10 had a relapse after the end of treatment. No patient had confirmed HIV-1 virologic rebound. The most common adverse events were headache (25%), fatigue (21%), and diarrhea (11%). No patient discontinued treatment because of adverse events. CONCLUSIONS Ledipasvir and sofosbuvir for 12 weeks provided high rates of sustained virologic response in patients coinfected with HIV-1 and HCV genotype 1 or 4. (Funded by Gilead Sciences; ION-4 ClinicalTrials.gov number, NCT02073656.).

Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection

BACKGROUND Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct‐acting antiviral agents (DAAs) have limited retreatment options. METHODS We conducted two phase 3 trials involving patients who had been previously treated with a DAA‐containing regimen. In POLARIS‐1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir‐velpatasvir‐voxilaprevir group. In POLARIS‐4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir‐velpatasvir‐voxilaprevir (163 patients) or sofosbuvir‐velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir‐velpatasvir‐voxilaprevir group. RESULTS In the three active‐treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS‐1, the rate of sustained virologic response was 96% with sofosbuvir‐velpatasvir‐voxilaprevir, as compared with 0% with placebo. In POLARIS‐4, the rate of response was 98% with sofosbuvir‐velpatasvir‐voxilaprevir and 90% with sofosbuvir‐velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active‐treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower. CONCLUSIONS Sofosbuvir‐velpatasvir‐voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed. (Funded by Gilead Sciences; POLARIS‐1 and POLARIS‐4 ClinicalTrials.gov numbers, NCT02607735 and NCT02639247.)

Concordance of sustained virological response 4, 12, and 24 weeks post‐treatment with sofosbuvir‐containing regimens for hepatitis C virus

Historically, clinical trials of regimens to treat chronic infection with hepatitis C virus (HCV) have used, as their primary efficacy endpoint, a sustained virological response (SVR)—defined as HCV RNA levels below a designated threshold of quantification—24 weeks after the end of treatment (SVR24). More recently, regulatory authorities have begun to accept SVR at 12 weeks post‐treatment (SVR12) as a valid efficacy endpoint because of its high rate of concordance with SVR24. However, the concordance between SVR12 and SVR24 has not been systematically assessed with new regimens of recently approved direct‐acting antiviral agents. The aim of this study was to assess the concordance between SVR at various post‐treatment time points in phase III clinical trials of sofosbuvir (SOF)‐containing regimens. We conducted a retrospective analysis of five trials enrolling 863 patients infected with HCV genotypes 1‐6. The concordance between SVR at 4 weeks post‐treatment (SVR4) and SVR12, and between SVR12 and SVR24, were determined, as well as positive predictive values (PPVs) and negative predictive values (NPVs). Overall, 779 of 796 patients (98.0%) with an SVR4 also achieved an SVR12, making the PPV of SVR4 for SVR12 98% and the NPV 100%. Of the 779 patients with an SVR12, 777 (99.7%) also achieved an SVR24, making the PPV of SVR12 for SVR24 >99% and the NPV 100%. Of patients who relapsed post‐therapy, 77.6% did so within 4 weeks of completing therapy. Conclusion: Data from phase III studies demonstrate that with SOF‐based regimens, with or without interferon, SVR12 and SVR24 correlate closely. Thus, SVR12 can be used effectively to determine “cure” rates in trials and in clinical practice. (Hepatology 2015;61:41–45)

Efficacy of 8 Weeks of Sofosbuvir, Velpatasvir, and Voxilaprevir in Patients With Chronic HCV Infection: 2 Phase 3 Randomized Trials

BACKGROUND & AIMS Patients with chronic hepatitis C virus (HCV) infection have high rates of sustained virologic response (SVR) after 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor velpatasvir. We assessed the efficacy of 8 weeks of treatment with sofosbuvir and velpatasvir plus the pangenotypic NS3/4A protease inhibitor voxilaprevir (sofosbuvir-velpatasvir-voxilaprevir). METHODS In 2 phase 3, open-label trials, patients with HCV infection who had not been treated previously with a direct-acting antiviral agent were assigned randomly to groups given sofosbuvir-velpatasvir-voxilaprevir for 8 weeks or sofosbuvir-velpatasvir for 12 weeks. POLARIS-2, which enrolled patients infected with all HCV genotypes with or without cirrhosis, except patients with genotype 3 and cirrhosis, was designed to test the noninferiority of 8 weeks of sofosbuvir-velpatasvir-voxilaprevir to 12 weeks of sofosbuvir-velpatasvir using a noninferiority margin of 5%. POLARIS-3, which enrolled patients infected with HCV genotype 3 who had cirrhosis, compared rates of SVR in both groups with a performance goal of 83%. RESULTS In POLARIS-2, 95% (95% confidence interval [CI], 93%-97%) of patients had an SVR to 8 weeks of sofosbuvir-velpatasvir-voxilaprevir; this did not meet the criterion to establish noninferiority to 12 weeks of sofosbuvir-velpatasvir, which produced an SVR in 98% of patients (95% CI, 96%-99%; difference in the stratum-adjusted Mantel-Haenszel proportions of -3.2%; 95% CI, -6.0% to -0.4%). The difference in the efficacy was owing primarily to a lower rate of SVR (92%) among patients with HCV genotype 1a infection receiving 8 weeks of sofosbuvir-velpatasvir-voxilaprevir. In POLARIS-3, 96% of patients (95% CI, 91%-99%) achieved an SVR in both treatment groups, which was significantly superior to the performance goal. Overall, the most common adverse events were headache, fatigue, diarrhea, and nausea; diarrhea and nausea were reported more frequently by patients receiving voxilaprevir. In both trials, the proportion of patients who discontinued treatment because of adverse events was low (range, 0%-1%). CONCLUSIONS In phase 3 trials of patients with HCV infection, we did not establish that sofosbuvir-velpatasvir-voxilaprevir for 8 weeks was noninferior to sofosbuvir-velpatasvir for 12 weeks, but the 2 regimens had similar rates of SVR in patients with HCV genotype 3 and cirrhosis. Mild gastrointestinal adverse events were associated with treatment regimens that included voxilaprevir. ClinicalTrials.gov numbers: POLARIS-2, NCT02607800; and POLARIS-3, NCT02639338.

Sofosbuvir‐velpatasvir‐voxilaprevir with or without ribavirin in direct‐acting antiviral–experienced patients with genotype 1 hepatitis C virus

The optimal retreatment strategy for hepatitis C virus (HCV) genotype 1–infected patients who fail direct‐acting antiviral (DAA)‐based regimens remains unknown. In this phase 2, open‐label study conducted at a single center in the United States, patients with HCV genotype 1 infection who previously failed to achieve sustained virological response (SVR) on a DAA‐based regimen were randomized to receive treatment with a fixed‐dose combination tablet of sofosbuvir‐velpatasvir‐voxilaprevir with or without ribavirin (RBV) for 12 weeks. Patients were stratified by their cirrhosis and past nonstructural protein (NS) 5A inhibitor exposure. The primary efficacy endpoint was the proportion of patients with SVR at 12 weeks after treatment (SVR12). SVR12 was achieved by 24 of 24 patients (100%; 95% confidence interval [CI], 86‐100) receiving sofosbuvir‐velpatasvir‐voxilaprevir alone and 24 of 25 (96%; 95% CI, 80‐100) receiving the same treatment with RBV. None of the patients discontinued sofosbuvir‐velpatasvir‐voxilaprevir therapy because of an adverse event (AE). The most commonly reported AEs with sofosbuvir‐velpatasvir‐voxilaprevir alone were diarrhea and bronchitis; and with sofosbuvir‐velpatasvir‐voxilaprevir plus RBV were fatigue, anemia, gastroenteritis, and nausea. Conclusion: A fixed‐dose combination of sofosbuvir‐velpatasvir‐voxilaprevir was well tolerated and effective at achieving virological response in patients with HCV genotype 1 infection and past DAA treatment experience. (Hepatology 2017;65:1803‐1809).

LP03 : Safety and efficacy of short-duration treatment with GS-9857 combined with sofosbuvir/GS-5816 in treatment-naïve and DAA-experienced genotype 1 patients with and without cirrhosis

LP03 GS-9857 + SOF/GS-5816 in Treatment-Naïve and DAAExperienced Patients with GT 1 Infection ± Cirrhosis

Dysregulation of distal cholesterol biosynthesis in association with relapse and advanced disease in CHC genotype 2 and 3 treated with sofosbuvir and ribavirin

BACKGROUND & AIMS Hepatitis C virus (HCV) modulates host lipid metabolism for its replication and lifecycle. Our aims were to assess changes in the serum lipid and distal (post-squalene) cholesterol biosynthesis metabolite profile of HCV genotypes (GT) 2 and 3 patients treated with sofosbuvir+ribavirin. METHODS Serum samples [baseline, treatment week 12, 4weeks post-treatment] were analyzed for apolipoproteins B and E (apoB/E), total cholesterol, HDL, LDL, and 11 post-squalene sterol metabolites using a GC/MS platform. RESULTS We selected 127 patients (GT2 n=50, GT3 n=77), 50% cirrhotic patients, and 42% who experienced a virological relapse. At baseline, GT3 patients had lower level of serum lipids, apoB/E, 7-dehydrocholesterol, desmosterol, lathosterol, compared to GT2 (p<0.006). Baseline lathosterol was lower in relapsers with cirrhosis compared to cirrhotic patients with SVR (p=0.003). From baseline to treatment week 12, serum lipids, apoB/E, and key sterol pathway metabolites (7-dehydrocholesterol, desmosterol, lathosterol, lanosterol) increased in GT3. In contrast, in GT2 patients, apoB/E and dihydrolanosterol decreased with viral suppression (p<0.025). At follow-up week 4, cirrhotic SVR patients showed substantially greater increases in apoB and total sterols compared to cirrhotic relapsers regardless of HCV genotype. After adjustment for genotype and gender, baseline lathosterol was independently associated with virologic response (p=0.04). CONCLUSION HCV GT3 is associated with reduced circulation of lipids involved in the distal cholesterol biosynthesis pathway, resulting in relative hypocholesterolemia. HCV suppression during sofosbuvir+ribavirin restores distal sterol metabolites indicating viral interference with de novo lipogenesis or selective retention by hepatocytes.

Successful Re-treatment of Hepatitis C Virus in Patients Coinfected With HIV Who Relapsed After 12 Weeks of Ledipasvir/Sofosbuvir

UNLABELLED We assessed the efficacy and safety of ledipasvir/sofosbuvir plus ribavirin for 24 weeks in 9 human immunodeficiency virus/hepatitis C virus-coinfected patients who relapsed after receiving 12 weeks of treatment with ledipasvir/sofosbuvir. Eight of 9 (89%) achieved sustained virologic response 12 weeks after the end of treatment. One patient relapsed at posttreatment week 4. These results suggest an effective salvage therapy for patients for whom direct-acting antiviral treatment has failed. CLINICAL TRIALS REGISTRATION NCT02073656.

Ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic hepatitis C and bleeding disorders.

Chronic hepatitis C virus (HCV) infection is prevalent among patients with inherited bleeding disorders and is a leading cause of mortality in those with haemophilia.

The safety and efficacy of ledipasvir/sofosbuvir for the treatment of a nosocomial outbreak of HCV in patients with significant cardiovascular disease.

BACKGROUND There is an unmet need for interferon- and ribavirin-free treatment for chronic HCV infection in patients with comorbidities including cardiovascular disease (CVD). The aim of this study was to evaluate the rates of sustained virological response (SVR) and adverse events in a cohort of patients with nosocomially acquired HCV genotype-1b following 12 weeks of therapy with fixed-dose combination (FDC) ledipasvir/sofosbuvir (LDV/SOF). METHODS This is a prospective, single-centre, open-label study of five non-cirrhotic patients with HCV genotype-1b and significant comorbid CVD, conducted at the Massachusetts General Hospital. All patients were prescribed an FDC tablet (LDV 90 mg/SOF 400 mg) once daily for 12 weeks. Serial measurements of safety parameters, virology, host immune correlates and adherence were performed. The primary outcome was the proportion of patients with SVR (plasma HCV RNA level <25 IU/ml), 12 weeks after treatment completion (SVR12). RESULTS All five patients (100%) achieved SVR12, with no episodes of on- or post-treatment relapse. The most commonly reported adverse events were gastrointestinal illness and upper respiratory viral-type illness. There were no serious adverse events or discontinuations of medication attributable to the study drug. Deep sequencing analysis revealed no baseline NS3, NS5A or NS5B resistance-associated variants. CONCLUSIONS In this open-label, uncontrolled, pilot study enrolling patients with HCV genotype-1b and significant CVD, administration of a fixed-dose, oral combination of LDV and SOF for 12 weeks was associated with high rates of SVR and minimal adverse events. Larger prospective studies that also include patients with cirrhosis and prior treatment non-responders are necessary.