Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia.

BACKGROUND: Coronavirus disease 2019 (Covid-19) is associated with immune dysregulation and hyperinflammation, including elevated interleukin-6 levels. The use of tocilizumab, a monoclonal antibody against the interleukin-6 receptor, has resulted in better outcomes in patients with severe Covid-19 pneumonia in case reports and retrospective observational cohort studies. Data are needed from randomized, placebo-controlled trials. METHODS: In this phase 3 trial, we randomly assigned patients who were hospitalized with severe Covid-19 pneumonia in a 2:1 ratio receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight) or placebo. Approximately one quarter of the participants received a second dose of tocilizumab or placebo 8 to 24 hours after the first dose. The primary outcome was clinical status at day 28 on an ordinal scale ranging from 1 (discharged or ready for discharge) to 7 (death) in the modified intention-to-treat population, which included all the patients who had received at least one dose of tocilizumab or placebo. RESULTS: Of the 452 patients who underwent randomization, 438 (294 in the tocilizumab group and 144 in the placebo group) were included in the primary and secondary analyses. The median value for clinical status on the ordinal scale at day 28 was 1.0 (95% confidence interval [CI], 1.0 to 1.0) in the tocilizumab group and 2.0 (non-ICU hospitalization without supplemental oxygen) (95% CI, 1.0 to 4.0) in the placebo group (between-group difference, -1.0; 95% CI, -2.5 to 0; P = 0.31 by the van Elteren test). In the safety population, serious adverse events occurred in 103 of 295 patients (34.9%) in the tocilizumab group and in 55 of 143 patients (38.5%) in the placebo group. Mortality at day 28 was 19.7% in the tocilizumab group and 19.4% in the placebo group (weighted difference, 0.3 percentage points; 95% CI, -7.6 to 8.2; nominal P = 0.94). CONCLUSIONS: In this randomized trial involving hospitalized patients with severe Covid-19 pneumonia, the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo at 28 days. (Funded by F. Hoffmann-La Roche and the Department of Health and Human Services; COVACTA ClinicalTrials.gov number, NCT04320615.).

Protease inhibitor-based direct-acting antivirals are associated with increased risk of aminotransferase elevations but not hepatic dysfunction or decompensation.

BACKGROUND & AIMS: Cases of acute liver injury (ALI) have been reported among chronic HCV-infected patients receiving protease inhibitor (PI)-based direct-acting antiviral (DAA) regimens, but no analyses have compared the risk of ALI in patients receiving PI- vs. non-PI-based DAAs. Thus, we compared the risk of 3 ALI outcomes between patients (by baseline Fibrosis-4 [FIB-4] group) receiving PI-based or non-PI-based DAAs. METHODS: We conducted a cohort study of 18,498 patients receiving PI-based DAA therapy (paritaprevir/ritonavir/ombitasvir±dasabuvir, elbasvir/grazoprevir, glecaprevir/pibrentasvir) matched 1:1 on propensity score to those receiving non-PI-based DAAs (sofosbuvir/ledipasvir, sofosbuvir/velpatasvir) in the 1945-1965 Veterans Birth Cohort (2014-2019). During exposure to DAA therapy, we determined development of: i) alanine aminotransferase (ALT) >200 U/L, ii) severe hepatic dysfunction (coagulopathy with hyperbilirubinemia), and iii) hepatic decompensation. We used Cox regression to determine hazard ratios (HRs) with 95% CIs for each ALI outcome within groups defined by baseline FIB-4 (≤3.25; >3.25). RESULTS: Among patients with baseline FIB-4 ≤3.25, those receiving PIs had a higher risk of ALT >200 U/L (HR 3.98; 95% CI 2.37-6.68), but not severe hepatic dysfunction (HR 0.67; 95% CI 0.19-2.39) or hepatic decompensation (HR 1.01; 95% CI 0.29-3.49), compared to those receiving non-PI-based regimens. For those with baseline FIB-4 >3.25, those receiving PIs had a higher risk of ALT >200 U/L (HR, 2.15; 95% CI 1.09-4.26), but not severe hepatic dysfunction (HR, 1.23 [0.64-2.38]) or hepatic decompensation (HR, 0.87; 95% CI 0.41-1.87), compared to those receiving non-PI-based regimens CONCLUSION: While risk of incident ALT elevations was increased in those receiving PI-based DAAs in both FIB-4 groups, the risk of severe hepatic dysfunction and hepatic decompensation did not differ between patients receiving PI- or non-PI-based DAAs in either FIB-4 group. LAY SUMMARY: Cases of liver injury have been reported among patients treated with protease inhibitor-based direct-acting antivirals for hepatitis C infection, but it is not clear if the risk of liver injury among people starting these drugs is increased compared to those starting non-protease inhibitor-based therapy. In this study, patients receiving protease inhibitor-based treatment had a higher risk of liver inflammation than those receiving a non-protease inhibitor-based treatment, regardless of the presence of pre-treatment advanced liver fibrosis/cirrhosis. However, the risk of severe liver dysfunction and decompensation were not higher for patients treated with protease inhibitor-based regimens.

Glecaprevir and Pibrentasvir in Patients with HCV and Severe Renal Impairment.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is more prevalent among patients who have chronic kidney disease than among those who do not have the disease. Patients with chronic kidney disease who also have HCV infection are at higher risk for progression to end-stage renal disease than those who have chronic kidney disease without HCV infection. Patients with both HCV infection and advanced chronic kidney disease have limited treatment options. METHODS: We conducted a multicenter, open-label, phase 3 trial to evaluate the efficacy and safety of treatment with the combination of the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir for 12 weeks in adults who had HCV genotype 1, 2, 3, 4, 5, or 6 infection and also had compensated liver disease (with or without cirrhosis) with severe renal impairment, dependence on dialysis, or both. Patients had stage 4 or 5 chronic kidney disease and either had received no previous treatment for HCV infection or had received previous treatment with interferon or pegylated interferon, ribavirin, sofosbuvir, or a combination of these medications. The primary end point was a sustained virologic response 12 weeks after the end of treatment. RESULTS: Among the 104 patients enrolled in the trial, 52% had genotype 1 infection, 16% had genotype 2 infection, 11% had genotype 3 infection, 19% had genotype 4 infection, and 2% had genotype 5 or 6 infection. The sustained virologic response rate was 98% (102 of 104 patients; 95% confidence interval, 95 to 100). No patients had virologic failure during treatment, and no patients had a virologic relapse after the end of treatment. Adverse events that were reported in at least 10% of the patients were pruritus, fatigue, and nausea. Serious adverse events were reported in 24% of the patients. Four patients discontinued the trial treatment prematurely because of adverse events; three of these patients had a sustained virologic response. CONCLUSIONS: Treatment with glecaprevir and pibrentasvir for 12 weeks resulted in a high rate of sustained virologic response in patients with stage 4 or 5 chronic kidney disease and HCV infection. (Funded by AbbVie; ClinicalTrials.gov number, NCT02651194 .).

Ombitasvir/paritaprevir/ritonavir and dasabuvir±ribavirin for chronic HCV infection in US veterans with psychiatric disorders.

Hepatitis C virus (HCV) infections are more common among US veterans receiving care through Veterans Affairs (VA) Medical Centers than among the general population. Historically, HCV therapies had lower efficacy rates in VA patients, possibly due to common comorbidities such as psychiatric disorders and substance abuse. The direct-acting antivirals ombitasvir/paritaprevir/ritonavir and dasabuvir (OBV/PTV/r+DSV)±ribavirin (RBV) are approved in the US for HCV genotype 1 (GT1)-infected adults with or without cirrhosis. This study prospectively evaluated the safety and efficacy of OBV/PTV/r+DSV±RBV in VA patients with HCV GT1 infection. TOPAZ-VA was a phase 3b, open-label trial. Adult US veterans with HCV GT1 infection, without cirrhosis or with compensated cirrhosis, were eligible for enrollment. Patients with GT1a infection received OBV/PTV/r +DSV+RBV for 12 weeks or 24 weeks (for those with cirrhosis); GT1b-infected patients without cirrhosis received OBV/PTV/r +DSV for 12 weeks; those with cirrhosis received OBV/PTV/r +DSV with RBV. The primary endpoint was sustained virologic response at posttreatment week 12 (SVR12); safety was also assessed. Ninety-nine patients were enrolled at 10 sites from May through November 2015. The majority were male (96%), white (60%), and with GT1a infection (68%); 49% reported ongoing psychiatric disorders. Overall, 94% (93/99) achieved SVR12; three patients had a virologic failure. The most common AEs were fatigue (28%), headache (20%), and nausea (15%); six patients discontinued treatment due to AEs. In US veterans with HCV GT1 infection, OBV/PTV/r +DSV±RBV yielded a 94% overall SVR12 rate and was well tolerated. The presence of psychiatric disorders and/or injection drug use did not impact efficacy.

Adherence to pan-genotypic glecaprevir/pibrentasvir and efficacy in HCV-infected patients: A pooled analysis of clinical trials.

BACKGROUND & AIMS: Adequate adherence to hepatitis C virus (HCV) treatment is believed to be a key component of treatment success because non-adherence can potentially result in treatment failure and the emergence of resistant viral variants. This analysis assessed factors associated with non-adherence to glecaprevir/pibrentasvir (G/P) therapy and the impact of non-adherence on sustained virological response at post-treatment week 12 (SVR12) rates in HCV genotype (GT) 1-6-infected patients. METHODS: Adherence was calculated by pill counts at study visits during treatment, and defined as having a lowest treatment adherence of ≥80% and ≤120% at each study visit. Exploratory logistic regression modelling assessed predictors of non-adherence to G/P therapy. SVR12 rates by treatment adherence were assessed in the intent-to-treat (ITT) population and modified ITT (mITT) population, which excludes non-virological failures. RESULTS: Overall, 97% (2024/2091) of patients were adherent to G/P therapy at all consecutive study visits. Alcohol use was the only baseline characteristic independently associated with non-adherence to G/P therapy (OR: 2.38; 95% CI: 1.13-5.01; P = .022). In the mITT population, overall SVR12 rates were high both in patients who were adherent to G/P therapy and those who were not (99% [1983/2008] and 95% [58/61] respectively; P = .047). Corresponding SVR12 rates in the ITT population were 98% (1983/2024) and 87% (58/67) respectively. CONCLUSIONS: Most patients adhered to G/P therapy. SVR12 rates were high both in patients who were adherent to G/P treatment and those who were not. Patient education on treatment adherence should remain an important part of HCV treatment. CLINICAL TRIALS REGISTRATION: NCT02604017, NCT02640482, NCT02640157, NCT02636595, NCT02642432, NCT02651194, NCT02243293, NCT02446717.

Hepatitis C in Patients With Minimal or No Hepatic Fibrosis: The Impact of Treatment and Sustained Virologic Response on Patient-Reported Outcomes.

Background: While the necessity of treatment of hepatitis C virus (HCV)-infected patients with advanced liver disease is widely accepted, the benefit of treating patients without significant liver disease is less well established. Our aim was to assess the effect of treating HCV in patients with no or minimal fibrosis (Metavir stage F0-F1) on patient-reported outcomes (PROs). Methods: HCV-infected patients with F0-F1 from 16 clinical trials were included. PROs were collected before, during, and after treatment. Results: A total of 1548 HCV-infected patients with F0-F1 were included (mean age 46 years, 43% male, 81% treatment-naive). Patients were treated with interferon (IFN) + sofosbuvir (SOF) + ribavirin (RBV) (n = 91) or SOF + RBV with or without ledipasvir (n = 479) or IFN- and RBV-free regimens with SOF + ledipasvir or SOF + velpatasvir or SOF + velpatasvir + voxilaprevir (n = 978). By the end of treatment, patients receiving IFN-containing regimens experienced significant decreases in most PRO domains (-4.5 to -28.7 on a 0-100 scale), while subjects treated with IFN-free RBV-containing regimens had a modest impairment (-2.3 to -8.9) (P ≤ .01). In contrast, treatment with regimens without IFN and RBV led to PRO improvements (+1.2 to +10.9). Regardless of the regimen, sustained virologic responses (SVRs) at 12 and 24 weeks were universally associated with PRO improvements (+2.1 to +14.7, P < .0001. Conclusions: HCV-infected subjects with no or minimal fibrosis treated with IFN- and RBV-free regimens experienced on-treatment and post-SVR PRO improvements.

Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection.

BACKGROUND: In phase 2 trials, treatment with the combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir resulted in high rates of sustained virologic response in patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3. METHODS: We conducted two randomized, phase 3, open-label studies involving patients who had received previous treatment for HCV genotype 2 or 3 and those who had not received such treatment, including patients with compensated cirrhosis. In one trial, patients with HCV genotype 2 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir, in a once-daily, fixed-dose combination tablet (134 patients), or sofosbuvir plus weight-based ribavirin (132 patients) for 12 weeks. In a second trial, patients with HCV genotype 3 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir for 12 weeks (277 patients) or sofosbuvir-ribavirin for 24 weeks (275 patients). The primary end point for the two trials was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Among patients with HCV genotype 2, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 99% (95% confidence interval [CI], 96 to 100), which was superior to the rate of 94% (95% CI, 88 to 97) in the sofosbuvir-ribavirin group (P=0.02). Among patients with HCV genotype 3, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 95% (95% CI, 92 to 98), which was superior to the rate of 80% (95% CI, 75 to 85) in the sofosbuvir-ribavirin group (P<0.001). The most common adverse events in the two studies were fatigue, headache, nausea, and insomnia. CONCLUSIONS: Among patients with HCV genotype 2 or 3 with or without previous treatment, including those with compensated cirrhosis, 12 weeks of treatment with sofosbuvir-velpatasvir resulted in rates of sustained virologic response that were superior to those with standard treatment with sofosbuvir-ribavirin. (Funded by Gilead Sciences; ASTRAL-2 ClinicalTrials.gov number, NCT02220998; and ASTRAL-3, NCT02201953.).

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.).

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.

Multimethod assessment of baseline depression and relationship to hepatitis C treatment discontinuation.

Objective The primary study objective is to determine which measures of depression are associated with early discontinuation of hepatitis C virus infection treatment and to determine which measure best characterizes the depression that develops during treatment. Methods Seventy-eight treatment-naïve subjects who initiated pegylated interferon/ribavirin treatment for hepatitis C virus infection were included. Baseline depression was assessed with the Structured Interview for the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), the Hamilton Depression Rating Scale, and the Beck Depression Inventory-II. The latter two measures were repeated at treatment weeks 12 and 24. Results Depression scores, as measured by the three instruments, lacked adequate consistency. Baseline depression as measured by the Beck Depression Inventory-II, but not by the other scales, was associated with early treatment discontinuation at weeks 12 and 24. Changes in depression during treatment were restricted to somatic symptoms. Of those who completed treatment, those who were not depressed at baseline tended to demonstrate significant depression increases during treatment. Conclusion The Beck Depression Inventory-II is recommended to assess depression prior to hepatitis C virus infection treatment. Somatic symptoms of depression should be monitored during treatment. Baseline depression as measured by the Beck Depression Inventory-II was associated with early treatment discontinuation. The Beck Depression Inventory-II, Structured Interview for DSM-IV, and Hamilton Depression Rating Scale yielded results that were not consistent with each other in this sample. Future research should focus on standardizing depression assessment in medically ill populations to identify measures that predict treatment discontinuation.

Sofosbuvir and Velpatasvir for the Treatment of Hepatitis C Virus in Patients Coinfected With Human Immunodeficiency Virus Type 1: An Open-Label, Phase 3 Study.

BACKGROUND: A safe, simple, effective, and pan-genotypic regimen to treat hepatitis C virus (HCV) infection in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains a medical need. We assessed the efficacy and safety of the NS5B polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir for HCV in patients coinfected with HIV-1. METHODS: This phase 3, open-label, single-arm study at 17 sites in the United States enrolled patients with HCV of any genotype and HIV-1 coinfection, including those with compensated cirrhosis. All patients received sofosbuvir-velpatasvir once daily for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). Efficacy and safety were assessed in all patients receiving at least 1 dose of treatment. RESULTS: Of 106 patients, 91 (86%) were men, 48 (45%) were black, and 19 (18%) had cirrhosis. SVR12 was achieved by 101 of 106 (95% [95% confidence interval {CI}, 89%-99%]) patients: 74 of 78 (95% [95% CI, 87%-99%]) with genotype 1; all 11 (100% [95% CI, 72%-100%]) with genotype 2; 11 of 12 (92% [95% CI, 62%-100%]) with genotype 3; and all 5 (100% [95% CI, 48%-100%]) with genotype 4. All 19 patients with cirrhosis had SVR12. Two patients relapsed, 2 were lost to follow-up, and 1 withdrew consent. Two discontinued treatment due to adverse events and 2 had serious adverse events. The most common adverse events were fatigue (25%), headache (13%), upper respiratory tract infection (8%), and arthralgia (8%). CONCLUSIONS: Sofosbuvir-velpatasvir for 12 weeks was safe and provided high rates of SVR12 in patients coinfected with HCV and HIV-1. CLINICAL TRIALS REGISTRATION: NCT02480712.

Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection.

BACKGROUND: In phase 2 studies, treatment with the all-oral combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir resulted in high rates of sustained virologic response among previously untreated patients with hepatitis C virus (HCV) genotype 1 infection. METHODS: We conducted a phase 3, open-label study involving previously untreated patients with chronic HCV genotype 1 infection. Patients were randomly assigned in a 1:1:1:1 ratio to receive ledipasvir and sofosbuvir in a fixed-dose combination tablet once daily for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis, 12% were black, and 67% had HCV genotype 1a infection. The rates of sustained virologic response were 99% (95% confidence interval [CI], 96 to 100) in the group that received 12 weeks of ledipasvir-sofosbuvir; 97% (95% CI, 94 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir plus ribavirin; 98% (95% CI, 95 to 99) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 97 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir plus ribavirin. No patient in either 12-week group discontinued ledipasvir-sofosbuvir owing to an adverse event. The most common adverse events were fatigue, headache, insomnia, and nausea. CONCLUSIONS: Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection. (Funded by Gilead Sciences; ION-1 ClinicalTrials.gov number NCT01701401.).

Greater decline in memory and global neurocognitive function in HIV/hepatitis C co-infected than in hepatitis C mono-infected patients treated with pegylated interferon and ribavirin.

The human immunodeficiency virus (HIV), hepatitis C virus (HCV), and the treatment of HCV with pegylated interferon and ribavirin (IFN/RBV) have been associated with neurocognitive and psychiatric abnormalities. The goal of this research was to prospectively evaluate neurocognitive functioning among a group of HCV mono-infected and HIV/HCV co-infected patients during the first 24 weeks of IFN/RBV treatment while accounting for practice effects, normal variations in change over time, and variations in IFN/RBV treatment exposure. Forty-four HCV mono-infected and 30 HIV/HCV co-infected patients were enrolled in a prospective study of patients beginning on IFN/RBV for chronic HCV infection. Patients were administered a depression inventory, a measure of fatigue, a structured psychiatric interview, and a neurocognitive battery at baseline and 24 weeks after initiation of treatment. Analyses were conducted to explore possible associations between neurocognitive functioning and the following: HIV/HCV co-infection vs. HCV mono-infection, IFN and RBV treatment exposure, psychiatric status, liver disease stage, and other medical characteristics. At baseline, there were no significant differences between the two groups' neuropsychiatric or neurocognitive function other than the mono-infected group had significantly higher reports of fatigue (p = 0.033). Over the course of 24 weeks of treatment after controlling for practice effects, the HIV/HCV co-infected patients experienced significantly greater declines in memory (t(56) = 2.14, p = 0.037) and global neurocognitive functioning (t(53) = 2.28, p = 0.027). In a well-characterized sample of mono-infected and co-infected patients, it appears that persons with HIV/HCV co-infection are potentially more vulnerable to neurocognitive sequalae during HCV treatment.

Ribavirin-Free Regimen With Sofosbuvir and Velpatasvir Is Associated With High Efficacy and Improvement of Patient-Reported Outcomes in Patients With Genotypes 2 and 3 Chronic Hepatitis C: Results From Astral-2 and -3 Clinical Trials.

BACKGROUND: Until recently, the approved treatment regimens for patients with hepatitis C virus (HCV) genotypes (GTs) 2 and 3 contain sofosbuvir (SOF) and ribavirin (RBV) for 12 or 24 weeks. The impact of RBV-free pan-genotypic regimen with SOF and velpatasvir (SOF/VEL) on patient-reported outcomes (PROs) of patients with genotype 2 and 3 has not been described. METHODS: PROs data were collected from participants of ASTRAL-2 and ASTRAL-3 studies before, during, and after treatment using 4 PRO instruments (Short Form-36, Chronic Liver Disease Questionnaire-HCV, Functional Assessment of Chronic Illness Therapy-Fatigue, and Work Productivity and Activity Index: Specific Health Problem), and compared between the SOF/VEL and SOF + RBV groups. RESULTS: A total of 818 HCV patients were included: 78% treatment naive, 25% cirrhosis. The rates of nearly all adverse events were lower in the RBV-free SOF/VEL group (all P < .03). The SOF/VEL group also experienced improvement of their PROs by treatment week 4 (+1.8% on average across all PROs), which continued throughout treatment (+4.1%) and post-treatment (+5.5%). In contrast, those in the SOF + RBV group had a modest decline in their PROs starting at treatment week 4 (up to -3.7%), which lasted until the end of treatment (up to -6.4%). In multiple regression analysis, the association of a treatment regimen with end-of-treatment PROs was significant for nearly all PROs; the average beta was +5.0% for the use of SOF/VEL (reference: SOF + RBV). CONCLUSIONS: Patients receiving ribavirin-free SOF/VEL reported significantly better PRO scores during treatment compared with those receiving the RBV-containing regimen. Furthermore, the interferon- and ribavirin-free SOF/VEL regimen resulted in a rapid improvement of PROs in HCV GTs 2 and 3 patients during treatment and after achieving sustained virologic response.

Improved Survival Among all Interferon-α-Treated Patients in HCV-002, a Veterans Affairs Hepatitis C Cohort of 2211 Patients, Despite Increased Cirrhosis Among Nonresponders.

BACKGROUND: As the era of interferon-alpha (IFN)-based therapy for hepatitis C ends, long-term treatment outcomes are now being evaluated. AIM: To more fully understand the natural history of hepatitis C infection by following a multisite cohort of patients. METHODS: Patients with chronic HCV were prospectively enrolled in 1999-2000 from 11 VA medical centers and followed through retrospective medical record review. RESULTS: A total of 2211 patients were followed for an average of 8.5 years after enrollment. Thirty-one percent of patients received HCV antiviral therapy, 15 % with standard IFN/ribavirin only, 16 % with pegylated IFN/ribavirin, and 26.7 % of treated patients achieved sustained virologic response (SVR). Cirrhosis developed in 25.8 % of patients. Treatment nonresponders had a greater than twofold increase in the hazard of cirrhosis and hepatocellular carcinoma, compared to untreated patients, whereas SVR patients were only marginally protected from cirrhosis. Nearly 6 % developed hepatocellular carcinoma, and 27.1 % died during the follow-up period. Treated patients, regardless of response, had a significant survival benefit compared to untreated patients (HR 0.58, CI 0.46-0.72). Improved survival was also associated with college education, younger age, lower levels of alcohol consumption, and longer duration of medical service follow-up-factors typically associated with treatment eligibility. CONCLUSIONS: As more hepatitis C patients are now being assessed for all-oral combination therapy, these results highlight that patient compliance and limiting harmful behaviors contribute a significant proportion of the survival benefit in treated patients and that the long-term clinical benefits of SVR may be less profound than previously reported.

Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study.

OBJECTIVE: To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin. DESIGN: In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNA

Integrated Care Increases Treatment and Improves Outcomes of Patients With Chronic Hepatitis C Virus Infection and Psychiatric Illness or Substance Abuse.

BACKGROUND & AIMS: Patients with hepatitis C virus (HCV) infection with psychiatric disorders and/or substance abuse face significant barriers to antiviral treatment. New strategies are needed to improve treatment rates and outcomes. We investigated whether an integrated care (IC) protocol, which includes multidisciplinary care coordination and patient case management, could increase the proportion of patients with chronic HCV infection who receive antiviral treatment (a combination of interferon-based and direct-acting antiviral agents) and achieve a sustained virologic response (SVR). METHODS: We performed a prospective randomized trial at 3 medical centers in the United States. Participants (n = 363 patients attending HCV clinics) had been screened and tested positive for depression, post-traumatic stress disorder, and/or substance use; they were assigned randomly to groups that received IC or usual care (controls) from March 2009 through February 2011. A midlevel mental health practitioner was placed at each HCV clinic to provide IC with brief mental health interventions and case management, according to formal protocol. The primary end point was SVR. RESULTS: Of the study participants, 63% were non-white, 51% were homeless in the past 5 years, 64% had psychiatric illness, 65% were substance abusers within 1 year before enrollment, 57% were at risk for post-traumatic stress disorder, 71% had active depression, 80% were infected with HCV genotype 1, and 23% had advanced fibrosis. Over a mean follow-up period of 28 months, a greater proportion of patients in the IC group began receiving antiviral therapy (31.9% vs 18.8% for controls; P = .005) and achieved a SVR (15.9% vs 7.7% of controls; odds ratio, 2.26; 95% confidence interval, 1.15-4.44; P = .018). There were no differences in serious adverse events between groups. CONCLUSIONS: Integrated care increases the proportion of patients with HCV infection and psychiatric illness and/or substance abuse who begin antiviral therapy and achieve SVRs, without serious adverse events. ClinicalTrials.gov # NCT00722423.

Fixed-dose combination therapy with daclatasvir, asunaprevir, and beclabuvir for noncirrhotic patients with HCV genotype 1 infection.

IMPORTANCE: The antiviral activity of all-oral, ribavirin-free, direct-acting antiviral regimens requires evaluation in patients with chronic hepatitis C virus (HCV) infection. OBJECTIVE: To determine the rates of sustained virologic response (SVR) in patients receiving the 3-drug combination of daclatasvir (a pan-genotypic NS5A inhibitor), asunaprevir (an NS3 protease inhibitor), and beclabuvir (a nonnucleoside NS5B inhibitor). DESIGN, SETTING, AND PARTICIPANTS: This was an open-label, single-group, uncontrolled international study (UNITY-1) conducted at 66 sites in the United States, Canada, France, and Australia between December 2013 and August 2014. Patients without cirrhosis who were either treatment-naive (n = 312) or treatment-experienced (n = 103) and had chronic HCV genotype 1 infection were included. INTERVENTIONS: Patients received a twice-daily fixed-dose combination of daclatasvir, 30 mg; asunaprevir, 200 mg; and beclabuvir, 75 mg. MAIN OUTCOMES AND MEASURES: The primary study outcome was SVR12 (HCV-RNA <25 IU/mL at posttreatment week 12) in patients naive to treatment. A key secondary outcome was SVR12 in the treatment-experienced cohort. RESULTS: Baseline characteristics were comparable between the treatment-naive and treatment-experienced cohorts. Patients were 58% male, 26% had IL28B (rs12979860) CC genotype, 73% were infected with genotype 1a, and 27% were infected with genotype 1b. Overall, SVR12 was observed in 379 of 415 patients (91.3%; 95% CI, 88.6%-94.0%): 287 of 312 treatment-naive patients (92.0%; 95% CI, 89.0%-95.0%) and 92 of 103 treatment-experienced patients (89.3%; 95% CI, 83.4%-95.3%). Virologic failure occurred in 34 patients (8%) overall. One patient died at posttreatment week 3; this was not considered related to study medication. There were 7 serious adverse events, all considered unrelated to study treatment, and 3 adverse events (<1%) leading to treatment discontinuation, including 2 grade 4 alanine aminotransferase elevations. The most common adverse events (in ≥10% of patients) were headache, fatigue, diarrhea, and nausea. CONCLUSIONS AND RELEVANCE: In this open-label, nonrandomized, uncontrolled study, a high rate of SVR12 was achieved in treatment-naive and treatment-experienced noncirrhotic patients with chronic HCV genotype 1 infection who received 12 weeks of treatment with the oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01979939.

Infections during peginterferon/ribavirin therapy are associated with the magnitude of decline in absolute lymphocyte count: results of the IDEAL study.

BACKGROUND: Myelosuppression due to pegylated interferon (peg-IFN) is common during treatment for hepatitis C virus. The relationship between infection risk and decreases in leukocyte lines, however, is not well established. The objective of this analysis was to determine the incidence of and risk factors for infections during peg-IFN/ribavirin (RBV) therapy. METHODS: A total of 3070 treatment-naive, chronic hepatitis C genotype 1-infected patients were treated for up to 48 weeks with peg-IFN alfa-2b 1.5 µg/kg/week or 1 µg/kg/week, or peg-IFN alfa-2a 180 µg/week plus RBV. On-treatment leukocyte counts were obtained every 2-6 weeks. Dose reduction was required for a neutrophil count <0.75 × 10(9) cells/L, and treatment discontinuation was required for a neutrophil count <0.5 × 10(9) cells/L. Granulocyte colony-stimulating factor was prohibited. Data on infections were captured at each study visit and categorized according to MedDRA version 13.0. RESULTS: A total of 581 (19%) patients experienced moderate, severe, or life-threatening infections as assessed by the investigator; 648 (21%) patients had at least 1 neutrophil count <0.75 × 10(9) cells/L, but only 242 (8%) sustained an infection and had a neutrophil count <0.75 × 10(9) cells/L at any time while on treatment. Twelve patients had severe or life-threatening infection and grade 3/4 neutropenia, but only 4 had temporally related infections. In a multivariate logistic regression model, nadir lymphocyte count, history of depression, and female sex, but not nadir neutrophil count, were associated with moderate, severe, or life-threatening infection. CONCLUSIONS: Nadir lymphocyte count, not nadir neutrophil count, was independently associated with moderate, severe, or life-threatening infections in the IDEAL study. Clinicians should be aware of their patients' absolute lymphocyte counts during peg-IFN/RBV therapy; peg-IFN dose reductions may be a consideration in patients with significant lymphocytopenia (<0.5 × 10(9) cells/L).

Severe Acute Liver Injury After Hepatotoxic Medication Initiation in Real-World Data.

Importance: Current approaches to classify the hepatotoxic potential of medications are based on cumulative case reports of acute liver injury (ALI), which do not consider the size of the exposed population. There is little evidence from real-world data (data relating to patient health status and/or the delivery of health care routinely collected from sources outside of a research setting) on incidence rates of severe ALI after initiation of medications, accounting for duration of exposure. Objective: To identify the most potentially hepatotoxic medications based on real-world incidence rates of severe ALI and to examine how these rates compare with categorization based on case reports. Design, Setting, and Participants: This series of cohort studies obtained data from the US Department of Veterans Affairs on persons without preexisting liver or biliary disease who initiated a suspected hepatotoxic medication in the outpatient setting between October 1, 2000, and September 30, 2021. Data were analyzed from June 2020 to November 2023. Exposures: Outpatient initiation of any one of 194 medications with 4 or more published reports of hepatotoxicity. Main Outcomes and Measures: Hospitalization for severe ALI, defined by either inpatient: (1) alanine aminotransferase level greater than 120 U/L plus total bilirubin level greater than 2.0 mg/dL or (2) international normalized ratio of 1.5 or higher plus total bilirubin level greater than 2.0 mg/dL recorded within the first 2 days of admission. Acute or chronic liver or biliary disease diagnosis recorded during follow-up or as a discharge diagnosis of a hospitalization for severe ALI resulted in censoring. This study calculated age- and sex-adjusted incidence rates of severe ALI and compared observed rates with hepatotoxicity categories based on cumulative published case reports. Results: The study included 7 899 888 patients across 194 medication cohorts (mean [SD] age, 64.4 [16.4] years, 7 305 558 males [92.5%], 4 354 136 individuals [55.1%] had polypharmacy). Incidence rates of severe ALI ranged from 0 events per 10 000 person-years (candesartan, minocycline) to 86.4 events per 10 000 person-years (stavudine). Seven medications (stavudine, erlotinib, lenalidomide or thalidomide, chlorpromazine, metronidazole, prochlorperazine, and isoniazid) exhibited rates of 10.0 or more events per 10 000 person-years, and 10 (moxifloxacin, azathioprine, levofloxacin, clarithromycin, ketoconazole, fluconazole, captopril, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and ciprofloxacin) had rates between 5.0 and 9.9 events per 10 000 person-years. Of these 17 medications with the highest observed rates of severe ALI, 11 (64%) were not included in the highest hepatotoxicity category when based on case reports. Conclusions and Relevance: In this study, incidence rates of severe ALI using real-world data identified the most potentially hepatotoxic medications and can serve as a tool to investigate hepatotoxicity safety signals obtained from case reports. Case report counts did not accurately reflect the observed rates of severe ALI after medication initiation.