Ananthakrishnan Ramani

Effectiveness of Simeprevir Plus Sofosbuvir, with or Without Ribavirin, in Real-World Patients with HCV Genotype 1 Infection

BACKGROUND & AIMS The interferon-free regimen of simeprevir plus sofosbuvir was recommended by professional guidelines for certain patients with hepatitis C virus (HCV) genotype 1 infection based on the findings of a phase 2 trial. We aimed to evaluate the safety and efficacy of this regimen in clinical practice settings in North America. METHODS We collected demographic, clinical, and virologic data, as well as reports of adverse outcomes, from sequential participants in HCV-TARGET--a prospective observational cohort study of patients undergoing HCV treatment in routine clinical care settings. From January through October 2014, there were 836 patients with HCV genotype 1 infection who began 12 weeks of treatment with simeprevir plus sofosbuvir (treatment duration of up to 16 weeks); 169 of these patients received ribavirin. Most patients were male (61%), Caucasian (76%), or black (13%); 59% had cirrhosis. Most patients had failed prior treatment with peginterferon and ribavirin without (46%) or with telaprevir or boceprevir (12%). The primary outcome was sustained virologic response (SVR), defined as the level of HCV RNA below quantification at least 64 days after the end of treatment (beginning of week 12 after treatment--a 2-week window). Logistic regression models with inverse probability weights were constructed to adjust for baseline covariates and potential selection bias. RESULTS The overall SVR rate was 84% (675 of 802 patients, 95% confidence interval, 81%-87%). Model-adjusted estimates indicate patients with cirrhosis, prior decompensation, and previous protease inhibitor treatments were less likely to achieve an SVR. The addition of ribavirin had no detectable effects on SVR. The most common adverse events were fatigue, headache, nausea, rash, and insomnia. Serious adverse events and treatment discontinuation occurred in only 5% and 3% of participants, respectively. CONCLUSIONS In a large prospective observational cohort study, a 12-week regimen of simeprevir plus sofosbuvir was associated with high rates of SVR and infrequent treatment discontinuation. ClinicalTrials.gov: NCT01474811.

Safety profile of boceprevir and telaprevir in chronic hepatitis C: Real world experience from HCV-TARGET

BACKGROUND & AIMS The safety profiles of boceprevir and telaprevir in the treatment of chronic hepatitis C, administered in academic and community centres across the United States, were evaluated. METHODS In 90 medical centres, patients with chronic HCV received pegylated interferon, ribavirin, and either telaprevir or boceprevir per local standard of care. Demographic, adverse event, clinical, and virological data were collected during treatment and follow-up. RESULTS A total of 2084 patients (97% HCV genotype 1) received at least one dose of a protease inhibitor. At baseline, 38% of patients had cirrhosis, and 57% had received at least one prior treatment for hepatitis C. Serious adverse events occurred in 12% of patients receiving protease inhibitor therapy. Overall, 66% of patients experienced anaemia, leading to frequent ribavirin dose reductions (42%) and erythropoietin use (37%); 11% received blood transfusion. More than 90% of patients had adverse events that led to a prescription, treatment, or dosage change, and 39% of patients discontinued treatment early, most commonly because of adverse events (18%) or lack of efficacy (16%). Hepatic decompensation events occurred in 3% of all patients. Age, female gender, cirrhosis, HCV genotype 1 subtype, creatinine clearance, platelet levels, albumin levels and haemoglobin levels were independent predictors of anaemia. Five deaths occurred. Overall, 52% of all patients achieved a sustained virologic response. CONCLUSIONS In academic and community centres, where chronic hepatitis C patients commonly have advanced liver disease, triple therapy was associated with a high rate of adverse events and involved frequent treatment modifications and adverse event management.

Ceftaroline fosamil for treatment of diabetic foot infections: the CAPTURE study experience

To ascertain which demographic, clinical, and microbiological factors might affect clinical outcomes of patients with diabetic foot infections, excluding known osteomyelitis, by analysing Clinical Assessment Program and Teflaro® Utilization Registry study data of patients treated with ceftaroline fosamil.

Contemporary use of ceftaroline fosamil for the treatment of community-acquired bacterial pneumonia: CAPTURE study experience

Abstract The Clinical Assessment Program and Teflaro® Utilization Registry (CAPTURE) is a multicenter cohort study designed to collect information on the contemporary use of ceftaroline fosamil in the US. Data collected from 398 evaluable patients with community-acquired bacterial pneumonia (CABP) (mean age 64 years) during the first 18 months of the study are presented. Most patients had co-morbidities (76%; primarily structural lung disease), and ≧2 signs and symptoms of CABP (76%). Overall clinical success was 79% which varied little with ceftaroline fosamil usage (monotherapy vs concurrent therapy; first-line vs second-line therapy). Most patients were discharged home (60%) or to another healthcare facility (35%). These data suggest that ceftaroline, in contemporary clinical use, is an effective antibiotic for the treatment of patients with CABP, including those with significant co-morbidities or who required a change of their prior antibiotic therapy.

Ceftaroline fosamil for the treatment of community-acquired bacterial pneumonia in the intensive care unit.

The Clinical Assessment Program and Teflaro® Utilization Registry (CAPTURE) is a multicenter study evaluating the clinical use of ceftaroline fosamil in patients with community-acquired bacterial pneumonia (CABP) or acute bacterial skin and skin structure infection. Data were collected between August 2011 and February 2013, from 398 evaluable patients receiving treatment at 33 sites in the USA. This manuscript presents data collected from patients with CABP who received care in an intensive care unit (ICU) or in general medical wards (35% and 64% of evaluable patients, respectively). The majority of ICU and general medical ward patients had underlying comorbidities (78% and 74%, respectively), with structural lung disease being the most common (42% in the ICU and 40% in general medical wards). Patients admitted to the ICU had a longer duration of stay, a longer duration of symptoms before treatment, and a longer duration of ceftaroline fosamil therapy than did general medical ward patients. Most patients treated in the ICU and in general medical wards were given ceftaroline fosamil as second-line therapy (87% and 80%, respectively). The overall rate of clinical success for patients treated with ceftaroline fosamil was 68% in the ICU and 85% in the general medical wards. Clinical success for patients receiving ceftaroline fosamil as a second-line agent was 84% in the ICU and 86% in general medical wards. These findings indicate that ceftaroline fosamil is a viable treatment option for CABP, both in the ICU and in general medical wards.

Prevalence and impact of baseline resistance-associated substitutions on the efficacy of ledipasvir/sofosbuvir or simeprevir/sofosbuvir against GT1 HCV infection

Baseline resistance-associated substitutions (RASs) have variable impacts in clinical trials but their prevalence and impact in real-world patients remains unclear. We performed baseline resistance testing using a commercial assay (10% cutoff) for 486 patients treated with LDV/SOF or SMV/SOF, with or without ribavirin, in the multi-center, observational HCV-TARGET cohort. Linkage of RASs was evaluated in selected samples using a novel quantitative single variant sequencing assay. Our results showed that the prevalence of NS3, NS5A, NS5B RASs was 45%, 13%, and 8%, respectively, and 10% of patients harbored RASs in 2 or more drug classes. Baseline LDV RASs in GT1a, TE, and cirrhosis LDV/SOF subgroup was associated with 2–4% lower SVR12 rates. SMV RASs was associated with lower SVR12 rates in GT1a, treatment-experienced, cirrhotics SMV/SOF subgroup. Pooled analysis of all patients with baseline RASs revealed that SVR12 was 100% (19/19) in patients treated for longer than 98 days but was 87% (81/93) in patients treated for shorter than 98 days. These results demonstrate that RASs prevalence and their impact in real world practice are in general agreement with registration trials, and suggest that longer treatment duration may overcome the negative impact of baseline RASs on SVR12 rates in clinical practice.

679Ceftaroline Fosamil (CPT-F) for the Treatment of Acute Bacterial Skin and Skin Structure Infections (ABSSSIs) in Obese Patients

Background. Obesity rates are increasing in the US and the treatment of ABSSSI in these patients is often challenging. CPT-F is approved for the treatment of ABSSSI and community-acquired bacterial pneumonia in the US, and for similar indications in the EU. CAPTURE is a multicenter retrospective study evaluating patients (pts) treated with CPT-F in the US. Data on the treatment of obese pts with CPT-F for ABSSSI are presented. Methods. Data were collected at participating centers by randomly ordered chart review between September 2011 and February 2014 which included demographics, disease characteristics, antibiotic use, pathogens, location of care, and clinical response. Obesity was defined as a body mass index ≥ 30 kg/m. Pts with a clinical outcome determined were evaluable. Results. Of evaluable pts treated for ABSSSI, 883/1735 (51%) were obese. The mean age was 58.5 years (SD ± 15.8), 49% were male, 53% had diabetes and 39% were morbidly obese (BMI ≥ 40 kg/m). Infection types included deep/extensive cellulitis (67%), major abscesses (15%), and infected ulcers (13%). The most common infection sites were the leg/thigh (59%) and foot (24%). Most pts, 807 (91%), were treated in a general hospital ward. Pathogens were recovered in 47% of pts, most commonly MRSA (20%) and MSSA (11%). MRSA and MSSA were isolated mainly from the ABSSSI site (> 96%), also from blood (< 9%) or both ABSSSI and blood (< 7%). Other antibiotics were used prior to CPT-F therapy in 80% of pts, most commonly vancomycin (53%) and piperacillin-tazobactam (24%). Concurrent antibiotics were used in 33% of pts, most commonly clindamycin (19%) and vancomycin (13%). The mean duration of CPT-F therapy was 5.8 days (SD ± 4.2). Clinical success was 91% in obese pts overall, and 90% in the morbidly obese. In pts with diabetes, clinical success was 89%. Clinical success for CPT-F monotherapy was 92% and for concurrent therapy, was 89%. In patients with MRSA and MSSA, clinical success rates were 88% and 93%, respectively. Conclusion. In obese pts, clinical success with CPT-F therapy was high, including pts with diabetes. These data support the use of CPT-F as a treatment option for ABSSSI in pts with obesity, including those with diabetes. Disclosures. K. Kaye, Forest Laboratories, Inc.: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Grant recipient and Speaker honorariumD. Guervil, Forest Laboratories, Inc.: Investigator, Research support A. Ramani, Forest Laboratories, Inc.: Investigator and Speaker’s Bureau, Research support and Speaker honorariumA. Jandourek, Cerexa, Inc.: Employee, SalaryH. D. Friedland, Forest Laboratories, Inc.: Employee and Shareholder, Salary