Nirmatrelvir for Vaccinated or Unvaccinated Adult Outpatients with Covid-19.

BACKGROUND: Nirmatrelvir in combination with ritonavir is an antiviral treatment for mild-to-moderate coronavirus disease 2019 (Covid-19). The efficacy of this treatment in patients who are at standard risk for severe Covid-19 or who are fully vaccinated and have at least one risk factor for severe Covid-19 has not been established. METHODS: In this phase 2-3 trial, we randomly assigned adults who had confirmed Covid-19 with symptom onset within the past 5 days in a 1:1 ratio to receive nirmatrelvir-ritonavir or placebo every 12 hours for 5 days. Patients who were fully vaccinated against Covid-19 and who had at least one risk factor for severe disease, as well as patients without such risk factors who had never been vaccinated against Covid-19 or had not been vaccinated within the previous year, were eligible for participation. Participants logged the presence and severity of prespecified Covid-19 signs and symptoms daily from day 1 through day 28. The primary end point was the time to sustained alleviation of all targeted Covid-19 signs and symptoms. Covid-19-related hospitalization and death from any cause were also assessed through day 28. RESULTS: Among the 1296 participants who underwent randomization and were included in the full analysis population, 1288 received at least one dose of nirmatrelvir-ritonavir (654 participants) or placebo (634 participants) and had at least one postbaseline visit. The median time to sustained alleviation of all targeted signs and symptoms of Covid-19 was 12 days in the nirmatrelvir-ritonavir group and 13 days in the placebo group (P = 0.60). Five participants (0.8%) in the nirmatrelvir-ritonavir group and 10 (1.6%) in the placebo group were hospitalized for Covid-19 or died from any cause (difference, -0.8 percentage points; 95% confidence interval, -2.0 to 0.4). The percentages of participants with adverse events were similar in the two groups (25.8% with nirmatrelvir-ritonavir and 24.1% with placebo). In the nirmatrelvir-ritonavir group, the most commonly reported treatment-related adverse events were dysgeusia (in 5.8% of the participants) and diarrhea (in 2.1%). CONCLUSIONS: The time to sustained alleviation of all signs and symptoms of Covid-19 did not differ significantly between participants who received nirmatrelvir-ritonavir and those who received placebo. (Supported by Pfizer; EPIC-SR ClinicalTrials.gov number, NCT05011513.).

Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19.

BACKGROUND: Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (Mpro) inhibitor with potent pan-human-coronavirus activity in vitro. METHODS: We conducted a phase 2-3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19-related hospitalization or death from any cause through day 28, viral load, and safety were evaluated. RESULTS: A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19-related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], -9.04 to -3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of -5.81 percentage points (95% CI, -7.78 to -3.84; P<0.001; relative risk reduction, 88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with nirmatrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of -0.868 log10 copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo. CONCLUSIONS: Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202.).

Successful Treatment of Prolonged, Severe Coronavirus Disease 2019 Lower Respiratory Tract Disease in a B cell Acute Lymphoblastic Leukemia Patient With an Extended Course of Remdesivir and Nirmatrelvir/Ritonavir.

A patient with B-cell acute lymphoblastic leukemia (ALL) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had persistent, progressive pneumonia with viremia after 5 months of infection despite monoclonal antibodies, intravenous (IV) remdesivir and prolonged oral steroids. Twenty days of nirmatrelvir/ritonavir and 10 days of IV remdesivir led to full recovery.

The interaction between diet and neurobehavior in very low birth weight infants.

BACKGROUND: Modulation of behavior and physiology by dietary perturbations early in life can provide clues to the pathogenesis of adult diseases. We tested the hypothesis that a period of early protein supplementation modulates sympathetic nervous system activity demonstrated indirectly by an increase in active sleep state distribution in very low birth weight (VLBW) infants. METHODS: VLBW infants (n = 71) were randomized to a total parenteral nutritional regimen providing 18% of the energy intake as amino acids (AA) or a conventional regimen providing 12.5% to achieve targeted AA intakes of 4 g/kg/day (0.004 kcal/kg/day) and 3 g/kg/day (0.003 kcal/kg/day), respectively. Both groups were weaned to enteral feeding and advanced to provide similar AA intake of 4 g/kg/day (0.004 kcal/kg/day). Six-hour daytime, behavioral sleep studies were performed when the infants reached full enteral intake (165 ml/kg/day). RESULTS: Infants in the high protein group spent more time in active sleep (77.2 ± 10.5% vs. 70.7 ± 11.8%), p < 0.01 and less time in quiet sleep (12.9 ± 3.4% vs. 17.7 ± 7.0%, p < 0.01) as compared to the conventional group. No group differences were observed for indeterminate sleep, awake, or crying states. CONCLUSIONS: These results suggest that dietary intake may indirectly influence sympathetic nervous system activity. IMPACT: Infants randomized to an early, high protein nutritional regimen spent an increased percentage of time in active sleep, supporting the hypothesis that nutrition and behavior are interactive. Furthermore, sleep states are an indirect measure of sympathetic nervous system activity, suggesting that dietary intake may influence sympathetic nervous system activity. This study highlights the importance of considering the impact of nutrition during critical periods of development in order to further understand and improve the long-term outcomes of very low birth weight infants.

Factors that impact on women's decision-making around prenatal genomic tests: An international discrete choice survey.

OBJECTIVE: We conducted a survey-based discrete-choice experiment (DCE) to understand the test features that drive women's preferences for prenatal genomic testing, and explore variation across countries. METHODS: Five test attributes were identified as being important for decision-making through a literature review, qualitative interviews and quantitative scoring exercise. Twelve scenarios were constructed in which respondents choose between two invasive tests or no test. Women from eight countries who delivered a baby in the previous 24 months completed a DCE presenting these scenarios. Choices were modeled using conditional logit regression analysis. RESULTS: Surveys from 1239 women (Australia: n = 178; China: n = 179; Denmark: n = 88; Netherlands: n = 177; Singapore: n = 90; Sweden: n = 178; UK: n = 174; USA: n = 175) were analyzed. The key attribute affecting preferences was a test with the highest diagnostic yield (p < 0.01). Women preferred tests with short turnaround times (p < 0.01), and tests reporting variants of uncertain significance (VUS; p < 0.01) and secondary findings (SFs; p < 0.01). Several country-specific differences were identified, including time to get a result, who explains the result, and the return of VUS and SFs. CONCLUSION: Most women want maximum information from prenatal genomic tests, but our findings highlight country-based differences. Global consensus on how to return uncertain results is not necessarily realistic or desirable.

"It's okay to not know " a qualitative exploration of faculty approaches to working with uncertainty.

BACKGROUND: Whilst it is recognised that a capacity to manage uncertainty is an essential aspect of working as a healthcare professional, there is little clear guidance on how to facilitate student learning in this domain. A lack of faculty development opportunities also suggests that health professions' educators may feel ill-equipped to assist students in developing effective approaches to uncertainty. The purpose of this study was to explore a faculty development intervention designed to help educators unpack students' experiences of uncertainty, and identify attributes which may help students to manage uncertain situations. METHODS: This qualitative study was informed by a constructivist methodological approach, where participants were encouraged to share meaning around the nature of uncertainty in health professions' education. Two 90-min faculty development sessions were held. These sessions invited participants to apply Han et al.'s taxonomy of uncertainty to role-played scenarios of student uncertainty within a focus group setting. Focus group data were collected, and examined using a two-stage, hybrid approach of deductive and inductive thematic analysis. RESULTS: Han et al.'s taxonomy helped participants to identify multiple sources and issues of uncertainty in the role played scenarios, thus unveiling the extent of uncertainties encountered by health professions' learners. Data analysis revealed four themes overall: "Sources of uncertainty", "Issues of uncertainty", "Uncertainty attributes", and "Learning environment." Participants also contributed to a list of attributes which they considered helpful to undergraduate health professions' students in managing uncertain situations. These included an awareness of the nature of uncertainty within healthcare practice, an ability to recognise uncertainty, and adopting attitudes of adaptability, positivity, and resilience. CONCLUSIONS: This study highlights the successful use of Han et al.'s taxonomy of uncertainty within a faculty development setting. Our findings suggest that the taxonomy is a practical and versatile tool that health professions' educators can use in shared reflections and conversations around uncertainty with students or colleagues.

How to deal with uncertainty in prenatal genomics: A systematic review of guidelines and policies.

Exome sequencing (ES) enhanced the diagnostic yield of genetic testing, but has also increased the possibility of uncertain findings. Prenatal ES is increasingly being offered after a fetal abnormality is detected through ultrasound. It is important to know how to handle uncertainty in this particularly stressful period. This systematic review aimed to provide a comprehensive overview of guidelines available for addressing uncertainty related to prenatal chromosomal microarray (CMA) and ES. Ten uncertainty types associated with prenatal ES and CMA were identified and defined by an international multidisciplinary team. Medline (all) and Embase were systematically searched. Laboratory scientists, clinical geneticists, psychologists, and a fetal medicine specialist screened the papers and performed the data extraction. Nineteen papers were included. Recommendations generally emphasized the importance of trio analysis, clinical information, data sharing, validation and re-analysis, protocols, multidisciplinary teams, genetic counselling, whether to limit the possible scope of results, and when to report particular findings. This systematic review helps provide a vocabulary for uncertainties, and a compass to navigate uncertainties. Prenatal CMA and ES guidelines provide a strong starting point for determining how to handle uncertainty. Gaps in guidelines and recommendations were identified and discussed to provide direction for future research and policy making.

Dealing with uncertain results from chromosomal microarray and exome sequencing in the prenatal setting: An international cross-sectional study with healthcare professionals.

OBJECTIVES: To conduct qualitative interviews with healthcare providers working in different countries to understand their experiences of dealing with uncertain results from prenatal chromosome microarray analysis (CMA) and exome sequencing (ES). METHODS: Semi-structured interviews with 31 healthcare providers who report or return prenatal CMA and/or ES results (clinicians, genetic counsellors and clinical scientists) in six countries with differing healthcare systems; Australia (4), Denmark (5), Netherlands (6), Singapore (4), Sweden (6) and United Kingdom (6). The topic guide explored the main sources of uncertainty and their management. RESULTS: There was variation in reporting practices both between and across countries for variants of uncertain significance, however, there was broad agreement on reporting practices for incidental findings. There was also variation in who decides what results are reported (clinical scientists or clinicians). Technical limitations and lack of knowledge (to classify variants and of prenatal phenotypes) were significant challenges, as were turnaround times and lack of guidelines. CONCLUSION: Health professionals around the globe are dealing with similar sources of uncertainty, but managing them in different ways, Continued dialogue with international colleagues on ways of managing uncertain results is important to compare and contrast the benefits and limitations of the different approaches.

The ubiquity of uncertainty: a scoping review on how undergraduate health professions' students engage with uncertainty.

Although the evidence base around uncertainty and education has expanded in recent years, a lack of clarity around conceptual terms and a heterogeneity of study designs means that this landscape remains indistinct. This scoping review explores how undergraduate health professions' students learn to engage with uncertainty related to their academic practice. To our knowledge, this is the first scoping review which examines teaching and learning related to uncertainty across multiple health professions. The scoping review is underpinned by the five-stage framework of (Arksey and O'Malley in Scoping studies: Towards a methodological framework International Journal of Social Research Methodology 8(1) 19-32, 2005). We searched MEDLINE, Embase, PsychINFO, ISI Web of Science, and CINAHL and hand-searched selected health professions' education journals. The search strategy yielded a total of 5,017 articles, of which 97 were included in the final review. Four major themes were identified: "Learners' interactions with uncertainty"; "Factors that influence learner experiences"; "Educational outcomes"; and, "Teaching and learning approaches". Our findings highlight that uncertainty is a ubiquitous concern in health professions' education, with students experiencing different forms of uncertainty at many stages of their training. These experiences are influenced by both individual and system-related factors. Formal teaching strategies that directly support learning around uncertainty were infrequent, and included arts-based teaching, and clinical case presentations. Students also met with uncertainty indirectly through problem-based learning, clinical teaching, humanities teaching, simulation, team-based learning, small group learning, tactical games, online discussion of anatomy topics, and virtual patients. Reflection and reflective practice are also mentioned as strategies within the literature.

Parental experiences of uncertainty following an abnormal fetal anomaly scan: Insights using Han's taxonomy of uncertainty.

For a number of prospective parents, uncertainty during pregnancy starts when an anomaly is found during a routine fetal anomaly scan. This may be followed by numerous tests to determine the etiology and nature of the anomaly. In this study, we aimed to understand how prospective parents perceive and manage uncertainty after being confronted with a structural anomaly during their routine ultrasound. Han's taxonomy of uncertainty was used as a framework to identify and understand the different types of uncertainty experienced. Interviews were held in the UK (n = 8 women and n = 1 male partner) and in the Netherlands (n = 7 women) with participants who had experienced uncertainty in their pregnancy after a fetal scan. Data were analyzed using thematic analysis, and the uncertainties experienced by parents were mapped against the dimensions of the Han taxonomy (sources, issues, and locus). Participants' experience of uncertainty was relevant to all dimensions and subcategories of the Han taxonomy, showing its applicability in the prenatal setting. Sources of uncertainty included receiving probabilistic or ambiguous information about the anomaly, or information that was complex and challenging to understand. Issues of uncertainty included were those that were scientific-such as a probable diagnosis with no further information, personal-such as the emotional impact of uncertainty, and practical-such as limited information about medical procedures and practical aspects of care. Additionally, participants described what helped them to manage uncertainty. This included active coping strategies such as searching for information on the Internet, external coping resources such as seeking social support, and internal coping resources such as using positivity and hope. Several recommendations for the healthcare professional to minimize uncertainty and help the patient deal with uncertainty have been proposed based on these findings.

Couples experiences of receiving uncertain results following prenatal microarray or exome sequencing: A mixed-methods systematic review.

BACKGROUND: Tests in pregnancy such as chromosomal microarray analysis and exome sequencing are increasing diagnostic yield for fetal structural anomalies, but have greater potential to result in uncertain findings. This systematic review investigated the experiences of prospective parents about receiving uncertain results from these tests. METHODS: A systematic search of three electronic databases was conducted. Data extraction was performed for studies that met the eligibility and quality criteria. Results were synthesised following the principles of thematic analysis. RESULTS: Fourteen studies (10 qualitative, 4 quantitative) were included. Findings were grouped into three overarching themes. Sources of uncertainty included the testing procedure, the diagnosis and prognosis, and health professionals' own uncertainty. The clinical impact of the uncertainty included parents struggling to make clinical decisions with the information available, the emotional impact included decisional-regret, shock, worry and feeling overwhelmed. To manage the uncertainty, parents sought support from healthcare professionals, friends, family, the internet and other parents as well as remaining hopeful. CONCLUSIONS: Prospective parents experience a myriad of uncertainties in the prenatal setting, which must be handled sensitively. Future research should explore optimal ways of managing uncertainty to minimise harm. Recommendations are made for discussing uncertainty during pre- and post-test counseling.

Summary of the safety and tolerability of two treatment regimens of ceftaroline fosamil: 600 mg every 8 h versus 600 mg every 12 h.

BACKGROUND: The recommended adult dose of ceftaroline fosamil is 600 mg q12h by 1 h intravenous (iv) infusion for 5-14 days in complicated skin and soft tissue infection (cSSTI) and 5-7 days in community-acquired pneumonia (CAP). A dosage of 600 mg q8h by 2 h iv infusion is approved in some regions for cSSTI patients with Staphylococcus aureus infection where the ceftaroline MIC is 2 or 4 mg/L. This analysis compares the safety profiles of the q8h and q12h regimens. METHODS: Safety data from six Phase III, randomized, double-blind clinical trials were collated into the q8h cSSTI pool (ceftaroline fosamil n = 506; NCT01499277) and the q12h pool {ceftaroline fosamil n = 1686; comprising five studies [two cSSTI (NCT00424190 and NCT00423657) and three CAP (NCT01371838, NCT00621504 and NCT00509106)]}. RESULTS: The pattern and incidence of adverse events were similar between the q8h and q12h ceftaroline fosamil pools. Most were gastrointestinal and of mild or moderate intensity. Overall, rash intensity was similar between the q8h pool and the q12h pool. For the q8h regimen, there was a higher frequency of rash in some Asian study sites, associated with longer duration of therapy (≥7 days); most cases were mild and resolved following treatment discontinuation. No dose-related vital sign or ECG abnormalities were detected with either regimen. CONCLUSIONS: The q8h regimen in cSSTI was generally well tolerated; the observed safety profile was consistent with the known safety profile of ceftaroline fosamil, reflective of the cephalosporin class and qualitatively consistent with the q12h regimen.

Scalp Lesions in a Pediatric Patient with Hyper IgM Syndrome: Clinical and Histologic Mimicry of Cryptococcus neoformans Infection.

We report a case of cutaneous cryptococcosis due to Cryptococcus neoformans in a pediatric patient with hyper IgM syndrome with scalp lesions that resembled tinea capitis on gross examination and mimicked juvenile xanthogranuloma on histologic examination. This case highlights the importance of considering cutaneous cryptococcosis in patients with hyper IgM syndrome.

Rabbit Neutering in Primary-Care Education: Insights from a Surgical Clinic.

Involvement in canine and feline surgical neutering clinics is generally considered to be a key element of primary-care veterinary education, yet opportunities for veterinary students to develop their surgical skills with rabbit patients are uncommon. This is despite the fact that rabbits are currently estimated to be the third most popular companion animal species and the fact that the British Small Animal Veterinary Association (BSAVA) recommends that all non-breeding rabbits be neutered soon after they attain sexual maturity. We describe a pilot rabbit-neutering clinic designed to provide high-quality care for rabbit patients while offering opportunities for undergraduate surgical and case-management skills development. We report on the clinical outcomes for patients. Rates of morbidity (n=18) and mortality (n=1) were low. Of complications reported, the majority (n=16) were considered minor. Challenges included ensuring that staff and students were trained in the specific features of rabbit anesthesia and recovery behavior. We conclude that rabbit surgical clinics offer excellent learning opportunities for undergraduate veterinary students. With prior training in handling and close individual supervision, it is possible to achieve good clinical outcomes and to have a positive impact on the welfare of companion animal populations.

Comparing Tolerance of Ambiguity in Veterinary and Medical Students.

Current guidelines suggest that educators in both medical and veterinary professions should do more to ensure that students can tolerate ambiguity. Designing curricula to achieve this requires the ability to measure and understand differences in ambiguity tolerance among and within professional groups. Although scales have been developed to measure tolerance of ambiguity in both medical and veterinary professions, no comparative studies have been reported. We compared the tolerance of ambiguity of medical and veterinary students, hypothesizing that veterinary students would have higher tolerance of ambiguity, given the greater patient diversity and less well-established evidence base underpinning practice. We conducted a secondary analysis of questionnaire data from first- to fourth-year medical and veterinary students. Tolerance of ambiguity scores were calculated and compared using the TAMSAD scale (29 items validated for the medical student population), the TAVS scale (27 items validated for the veterinary student population), and a scale comprising the 22 items common to both scales. Using the TAMSAD and TAVS scales, medical students had a significantly higher mean tolerance of ambiguity score than veterinary students (56.1 vs. 54.1, p<.001 and 60.4 vs. 58.5, p=.002, respectively) but no difference was seen when only the 22 shared items were compared (56.1 vs. 57.2, p=.513). The results do not support our hypothesis and highlight that different findings can result when different tools are used. Medical students may have slightly higher tolerance of ambiguity than veterinary students, although this depends on the scale used.

Development of a New Scale to Measure Ambiguity Tolerance in Veterinary Students.

The ability to cope with ambiguity and feelings of uncertainty is an essential part of professional practice. Research with physicians has identified that intolerance of ambiguity or uncertainty is linked to stress, and some authors have hypothesized that there could be an association between intolerance of ambiguity and burnout. We describe the adaptation of the TAMSAD (Tolerance of Ambiguity in Medical Students and Doctors) scale for use with veterinary students. Exploratory factor analysis supports a uni-dimensional structure for the Ambiguity tolerance construct. Although internal reliability of the 29-item TAMSAD scale is reasonable (α=.50), an alternative 27-item scale (drawn from the original 41 items used to develop TAMSAD) shows higher internal reliability for veterinary students (α=.67). We conclude that there is good evidence to support the validity of this latter TAVS (Tolerance of Ambiguity in Veterinary Students) scale to study ambiguity tolerance in veterinary students.

Neural correlates of self-injurious behavior in Prader-Willi syndrome.

Individuals with Prader-Willi syndrome (PWS), a genetic disorder caused by mutations to the q11-13 region on chromosome 15, commonly show severe skin-picking behaviors that can cause open wounds and sores on the body. To our knowledge, however, no studies have examined the potential neural mechanisms underlying these behaviors. Seventeen individuals with PWS, aged 6-25 years, who showed severe skin-picking behaviors, were recruited and scanned on a 3T scanner. We used functional magnetic resonance imaging (fMRI) while episodes of skin picking were recorded on an MRI-safe video camera. Three participants displayed skin picking continuously throughout the scan, three participants did not display skin picking, and the data for one participant evidenced significant B0 inhomogeneity that could not be corrected. The data for the remaining 10 participants (six male, four female) who displayed a sufficient number of picking and nonpicking episodes were subjected to fMRI analysis. Results showed that regions involved in interoceptive, motor, attention, and somatosensory processing were activated during episodes of skin-picking behavior compared with nonpicking episodes. Scores obtained on the Self-Injury Trauma scale were significantly negatively correlated with mean activation within the right insula and left precentral gyrus. These data indicate that itch and pain processes appear to underlie skin-picking behaviors in PWS, suggesting that interoceptive disturbance may contribute to the severity and maintenance of abnormal skin-picking behaviors in PWS. Implications for treatments are discussed.

A phase 2 study of filibuvir in combination with pegylated IFN alfa and ribavirin for chronic HCV.

OBJECTIVES: Filibuvir is a non-nucleoside inhibitor of hepatitis C virus (HCV) polymerase. This study evaluated the safety and efficacy of filibuvir plus pegylated interferon alfa-2a (pegIFN)/ribavirin. MATERIAL AND METHODS: Treatment-naïve, HCV genotype-1 patients were randomized to receive filibuvir 300 or 600 mg twice daily (BID) or placebo plus pegIFN (180 µg/wk) and ribavirin (1,000/1,200 mg BID) for 24 weeks. Filibuvir patients who achieved defined response through week 24 discontinued therapy at week 24. All other patients continued on open-label pegIFN/ribavirin through week 48. The primary endpoint was the proportion of patients who achieved sustained virologic response (SVR) defined as HCV RNA < 15 IU/mL at end of treatment (weeks 24 or 48) and week 72. RESULTS: Overall, 288 patients were randomized and treated. SVR was achieved by 41.7, 39.6, and 45.8% of patients in the filibuvir 300 mg, 600 mg, and placebo arms, respectively. While the addition of filibuvir to pegIFN/ribavirin improved on-treatment virologic response parameters, this did not translate into improved SVR rates due to a high rate of virologic relapse following completion of therapy (300 mg: 35.9%; 600 mg: 42.9%; placebo: 25.4%). The most commonly reported adverse events were nausea, fatigue, headache, and insomnia, and were reported at similar rates across arms. CONCLUSIONS: Filibuvir plus pegIFN/ribavirin did not improve the percentage of patients achieving SVR compared with administration of pegIFN/ribavirin alone. However, the agent was well tolerated and was associated with higher on-treatment virologic response parameters. Further evaluation of filibuvir in combination with other direct-acting antiviral agents may be considered.