Efficacy of Sofosbuvir and Velpatasvir, With and Without Ribavirin, in Patients With Hepatitis C Virus Genotype 3 Infection and Cirrhosis.

BACKGROUND & AIMS: In phase 3 trials and real-world settings, smaller proportions of patients with genotype 3 hepatitis C virus (HCV) infection and cirrhosis have a sustained virologic response 12 weeks after treatment (SVR12) with the combination of sofosbuvir and velpatasvir than in patients without cirrhosis. It is unclear whether adding ribavirin to this treatment regimen increases SVRs in patients with genotype 3 HCV infection and cirrhosis. METHODS: We performed a phase 2 trial of 204 patients with genotype 3 HCV infection and compensated cirrhosis (mean age 51 ± 7.4 years) at 29 sites in Spain from August 19, 2016 through April 18, 2017. Patients were assigned to groups given sofosbuvir and velpatasvir for 12 weeks (n = 101) or sofosbuvir and velpatasvir plus ribavirin for 12 weeks (n = 103). The primary efficacy end point was SVR12. RESULTS: The overall rates of SVR12 were 91% (92 of 101; 95% CI 84-96) for the sofosbuvir-velpatasvir group and 96% (99 of 103; 95% CI 90-99) for the sofosbuvir-velpatasvir plus ribavirin group. In the sofosbuvir-velpatasvir group, a smaller proportion of patients with baseline resistance-associated substitutions (RASs) in nonstructural protein 5A (NS5A) achieved an SVR12 (84%) than did patients without (96%). In the sofosbuvir-velpatasvir plus ribavirin group, baseline RASs had less effect on the proportion of patients with an SVR12 (96% for patients with baseline RASs; 99% for patients without). The most common adverse events (which occurred in ≥10% of patients) were asthenia (12%) in the sofosbuvir-velpatasvir group and asthenia (27%), headache (24%), and insomnia (12%) in the sofosbuvir-velpatasvir plus ribavirin group. CONCLUSIONS: Consistent with findings from previous studies, a high rate of patients (91% and 96%) with genotype 3 HCV infection and compensated cirrhosis achieved an SVR12 with sofosbuvir and velpatasvir, with or without ribavirin. Of patients treated with sofosbuvir and velpatasvir without ribavirin, fewer patients with baseline NS5A RASs achieved an SVR12 compared with patients without baseline NS5A. ClinicalTrials.govNCT02781558.

Sofosbuvir/velpatasvir for 12 weeks in genotype 1-4 HCV-infected liver transplant recipients.

BACKGROUND & AIMS: Sofosbuvir, an NS5B inhibitor, combined with velpatasvir, an NS5A inhibitor (SOF/VEL), produces high sustained virologic response rates 12 weeks after treatment (SVR12) in patients with genotype 1-6 HCV infection, and has no anticipated clinically relevant drug-drug interactions with immunosuppressants. This study evaluated the safety and efficacy of SOF/VEL in adults with recurrent chronic genotype 1-4 HCV infection after liver transplant. METHODS: Patients received SOF/VEL 400/100 mg daily for 12 weeks. Patients could be treatment experienced or treatment naïve with no cirrhosis or with compensated cirrhosis. The primary endpoints were SVR12 and discontinuations due to adverse events. RESULTS: A total of 79 patients were enrolled and treated in this study (37 [47%] had genotype 1, 3 [4%] genotype 2, 35 [44%] genotype 3, and 4 [5%] genotype 4 HCV). Of these, 81% were male, 82% were white, 18% had compensated cirrhosis, and 59% were treatment experienced. The most commonly used immunosuppressants were tacrolimus (71%), mycophenolic acid (24%), cyclosporine (14%), and azathioprine (11%). Median (range) time from liver transplantation was 7.5 (0.3, 23.9) years. The SVR12 rate was 96%. By genotype, SVR12 rates were 95% (genotype 1), 100% (genotype 2), 97% (genotype 3), and 100% (genotype 4). Two patients experienced virologic relapse: one with genotype 1a infection was non-cirrhotic and treatment naïve, and one with genotype 3 infection was non-cirrhotic and treatment experienced. One patient discontinued SOF/VEL due to hyperglycemia. No serious or severe adverse events were deemed SOF/VEL-related by the investigator, and no liver transplant rejection episodes or deaths occurred during the study period. CONCLUSIONS: Treatment with SOF/VEL for 12 weeks was highly effective and well tolerated in genotype 1-4 HCV-infected liver transplant recipients with and without cirrhosis. LAY SUMMARY: Sofosbuvir/velpatasvir is a combination of two drugs in one tablet that is approved for the treatment of patients with chronic hepatitis C virus (HCV) infection. When patients with chronic HCV infection receive a liver transplant, the HCV infection usually recurs, and damages the transplanted liver. This study tested the effects of 12 weeks of sofosbuvir/velpatasvir treatment in patients who had HCV recurrence after a liver transplant. Three months following the end of treatment, 96% of patients were cured of HCV infection. Clinical trial number: NCT02781571.

Comparison of BMD Changes and Bone Formation Marker Levels 3 Years After Bisphosphonate Discontinuation: FLEX and HORIZON-PFT Extension I Trials.

An ASBMR Task Force recommends a drug holiday for certain women treated for ≥5 years with oral alendronate or ≥3 years with intravenous zoledronic acid, with reassessment 2 to 3 years later. It is not known whether changes in bone mineral density (BMD) or bone turnover markers differ after oral or intravenous therapy. Our goal was to compare changes in BMD and procollagen type I N propeptide (PINP) after oral or intravenous bisphosphonate use. In the Fracture Intervention Trial Long-term Extension (FLEX), women who received a mean 5 years of alendronate were randomized to placebo or continued treatment. In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial Extension I (HORIZON-PFT E1), women who received 3 years of zoledronic acid were randomized to placebo or continued treatment. We examined the proportion of participants with BMD loss or PINP gain ≥ least significant change (LSC) and those whose values exceeded a threshold (T-score ≤-2.5 or PINP ≥36.0 ng/mL, a premenopausal median value). After 3 years of placebo, the FLEX group had greater mean total hip BMD decreases (-2.3% versus -1.2% in the HORIZON-PFT E1 group, p < 0.01) and greater rises in PINP (+11.6 ng/mL versus +6.7 ng/mL, p < 0.01). There was a greater proportion of individuals in FLEX with total hip BMD loss and PINP increases that exceeded LSC, and PINP values ≥36.0 ng/mL. In contrast, there were small changes in the proportion of women with femoral neck T-scores ≤-2.5 in both groups. In conclusion, 3 years after bisphosphonate discontinuation, a considerable proportion of former alendronate and zoledronic acid users had meaningful declines in total hip BMD and elevations in PINP. Despite a longer treatment course, alendronate may have a more rapid offset of drug effect than zoledronic acid. © 2018 American Society for Bone and Mineral Research.

Sofosbuvir-velpatasvir plus ribavirin in Japanese patients with genotype 1 or 2 hepatitis C who failed direct-acting antivirals.

BACKGROUND/PURPOSE: In Japan, there is a growing population of patients with chronic hepatitis C virus (HCV) infection who failed a direct-acting antiviral (DAA)-based regimen. In this Phase 3 study, we evaluated sofosbuvir-velpatasvir plus ribavirin in Japanese patients with genotype 1 or 2 HCV infection who previously received DAAs. METHODS: Patients were randomized 1:1 to receive sofosbuvir-velpatasvir plus ribavirin for 12 or 24 weeks. Randomization was stratified by HCV genotype and presence of cirrhosis. The primary endpoint was sustained virologic response 12-week post-treatment (SVR12). RESULTS: Of 117 participants, 81% had HCV genotype 1 infection, 33% had cirrhosis, and 95% had NS5A resistance-associated substitutions (RAS) at baseline. Overall, SVR12 rates were 97% (58/60; 95% CI 88-100%) with 24 weeks of treatment and 82% (47/57; 95% CI 70-91%) with 12 weeks. For HCV genotype 1 and 2 infected patients, the SVR12 rates with 24 weeks of treatment were 98% and 92%, respectively. In both treatment groups, SVR12 rates in HCV genotype 1 patients were statistically superior to a historical control rate of 50% (p < 0.001). For patients with NS5A RASs at baseline, 85% (46/54) in the 12-week group and 96% (54/56) in the 24-week group achieved SVR12. The most common adverse events were upper respiratory tract viral infection, anemia, and headache. Three (2.6%) patients discontinued treatment because of adverse events. CONCLUSION: Sofosbuvir-velpatasvir plus ribavirin was highly effective and well tolerated in Japanese patients who previously failed a DAA-based regimen. Baseline NS5A RASs did not affect treatment outcomes.

Ledipasvir/sofosbuvir for treatment-naive and treatment-experienced Chinese patients with genotype 1 HCV: an open-label, phase 3b study.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is a significant medical burden in China, affecting more than 10 million persons. In clinical trials and real-world settings, treatment with ledipasvir/sofosbuvir in patients with genotype 1 HCV infection resulted in high sustained virologic response rates. Ledipasvir/sofosbuvir may provide a highly effective, short-duration, single-tablet regimen for Chinese patients with HCV infection. METHODS: Chinese patients with genotype 1 HCV infection who were HCV treatment naive or treatment experienced, without cirrhosis or with compensated cirrhosis, were treated with open-label ledipasvir/sofosbuvir for 12 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after completing treatment (SVR12). For treatment-naive patients, SVR12 was compared to a historical rate of 57%. The primary safety endpoint was adverse events leading to permanent discontinuation of study drug; serious adverse events were also evaluated. The presence of resistance-associated substitutions (RASs) was evaluated by viral sequencing. RESULTS: All 206 enrolled patients achieved SVR12 (100%; 95% CI 98-100%), including 106 treatment-naive patients (100%; 95% CI 97-100%), which was superior to a historical SVR rate of 57% (p < 0.001). All patients with baseline NS5A and NS5B RASs (14 and 1% of patients, respectively) achieved SVR12. The most common adverse events were viral upper respiratory tract infection (17%), upper respiratory tract infection (14%), and cough (6%). There were no discontinuations due to adverse events; and no treatment-related serious adverse events were reported. CONCLUSION: Ledipasvir/sofosbuvir is a well tolerated and highly effective treatment for Chinese patients with genotype 1 HCV, regardless of prior treatment experience, cirrhosis status, or the presence of pretreatment RASs.

A model of BMD changes after alendronate discontinuation to guide postalendronate BMD monitoring.

CONTEXT: Women stopping alendronate are commonly monitored with serial bone mineral density (BMD) measurements, yet no information exists on how frequently or for whom these measurements should be performed. OBJECTIVE: The objective of the study was to develop a tool to guide post-alendronate BMD monitoring. DESIGN: A predictive model was constructed to estimate the time until a given percentage of women's BMD T-scores drop below a given threshold that indicates a management change (such as retreatment) would be considered. This model was then used to estimate the time it would take for groups of women defined by their baseline BMDs to drop below the given threshold. SETTING: Data were derived from the Fracture Intervention Trial Long Term Extension (FLEX), the largest multicenter clinical trial of its type to date. PARTICIPANTS: Four hundred four women who had received an average of 5.1 years of alendronate during the Fracture Intervention Trial and were subsequently observed for 5 treatment-free years (on placebo) during the FLEX trial were used to estimate the change in BMD over time. RESULTS: If a management change such as alendronate reinitiation would be considered when BMD T-score drops below -2.5, the model shows that women with total hip BMD greater than -1.9 T-scores at the time of alendronate discontinuation have less than a 20% probability that at follow-up, monitoring BMD will be below the threshold within 5 years. The model performed similarly, and results are provided over a range of management change thresholds from -1.75 to -3 T-scores. CONCLUSIONS: Using the tool developed in this analysis, it is possible to estimate when BMD repeat measurement after alendronate discontinuation could potentially be useful. Measuring BMD within 5 years after alendronate discontinuation is unlikely to change management for women with total hip BMD 0.6 T-scores above a prespecified retreatment threshold within the range of -1.75 to -3 T-scores.

Acute liver failure with thyrotoxicosis treated with liver transplantation.

OBJECTIVE: We describe a young woman with previously undiagnosed thyrotoxicosis who presented with acute liver failure (ALF). METHODS: We present a case report and review the relevant literature. RESULTS: An extensive evaluation excluded possible causes of ALF other than thyrotoxicosis. The management of thyrotoxicosis posed several unique challenges in the setting of ALF, particularly because we did not want to use potentially hepatotoxic thionamides. The patient was treated with prednisone and propranolol and was started on potassium iodide when she was listed for liver transplantation. She underwent an uncomplicated liver transplant and subsequent thyroidectomy and is doing well. CONCLUSION: This well-characterized case describes thyrotoxicosis as a possible cause of ALF after thoroughly excluding other possible causes and illustrates the challenges of simultaneously managing both disorders. To our knowledge, this is the first report of ALF possibly resulting from untreated thyrotoxicosis that was successfully treated with liver transplantation.

BMD changes and predictors of increased bone loss in postmenopausal women after a 5-year course of alendronate.

Management of women discontinuing bisphosphonates after 3 to 5 years of treatment is controversial. Little is known about how much bone mineral density (BMD) is lost after discontinuation or whether there are risk factors for greater rates of bone loss post-discontinuation. We report patterns of change in BMD and prediction models for the changes in BMD in postmenopausal women during a 5-year treatment-free period after alendronate (ALN) therapy. We studied 406 women enrolled in the Fracture Intervention Trial (FIT) who had taken ALN for a mean of 5 years and were then enrolled in the placebo arm of the FIT Long-Term Extension (FLEX) trial for an additional 5 years, describing 5-year percent changes in total hip, femoral neck, and lumbar spine BMD over the treatment-free period. Prediction models of 5-year percent changes in BMD considered all linear combinations of candidate risk factors for bone loss such as BMD at the start of the treatment-free period, the change in BMD on ALN, age, and fracture history. Serum for three markers of bone turnover was available in 76 women, and these bone turnover markers were included as candidate predictors for these 76 women. Mean 5-year BMD changes were -3.6% at the total hip, -1.7% at the femoral neck, and 1.3% at the lumbar spine. Five-year BMD losses of >5% were experienced by 29% of subjects at the total hip, 11% of subjects at the femoral neck, and 1% of subjects at the lumbar spine. Several risk factors such as age and BMI were associated with greater bone loss, but no models based on these risk factors predicted bone loss rates. Although about one-third of women who discontinued ALN after 5 years experienced >5% bone loss at the total hip, predicting which women will lose at a higher rate was not possible.

Probiotics for the prevention of nosocomial pneumonia: current evidence and opinions.

PURPOSE OF REVIEW: Nosocomial infections are common and are associated with considerable morbidity and mortality. The continuing evolution of multidrug resistant pathogens and ineffective therapy for the infections they cause has stimulated interest in the potential of probiotic products to prevent nosocomial infections. Probiotics are viable microorganisms that colonize the host and exert antibacterial and immunomodulatory effects. This article will review the current evidence for probiotics in preventing nosocomial infections, particularly pneumonia in a diverse population of critically ill patients. RECENT FINDINGS: Currently, there are insufficient data to conclusively determine whether probiotics are beneficial in the prevention of nosocomial infections, particularly nosocomial pneumonia. Most of the current literature is limited by poor trial design, inadequate blinding, small study samples, and poorly defined endpoints. SUMMARY: Probiotic products reduce pathogenic colonization of the host. Despite the theoretical plausibility, there is currently insufficient evidence that probiotic products reduce the incidence of nosocomial pneumonia. Large, multicenter, randomized clinical trials utilizing a rigorous, invasive diagnostic approach to nosocomial pneumonia need to be performed to prospectively evaluate the utility of probiotic products. In addition, bench research needs to be performed to select the most appropriate probiotic formulation for different clinical applications.