Stress Management Interventions Among U.S. High School Adolescents: A Meta-Analysis.

BACKGROUND: Adolescent ineffective stress management has been associated with negative health outcomes, such as anxiety and depression. Comprehensively evaluating the effects of stress management interventions is needed. AIMS: The aim of this study was to quantitatively evaluate the effects of stress management interventions on mental health outcomes (stress, anxiety, depression, and positive and negative affect) and perform moderation analysis to identify moderators of intervention effects on stress, anxiety, and depression among U.S. high school adolescents. METHODS: Four databases (CINAHL, ERIC, PubMed, and PsycINFO) were searched. After literature screening, 24 articles describing 25 studies were retained. Hedge's g was calculated using random-effects models. Exploratory moderation analyses were performed to identify moderators. RESULTS: The pooled effects on reducing stress were -0.36. The interventions had small effects on decreasing anxiety (g = -0.31) and depression (g = -0.23). Long-term follow-up effects were -0.77 on perceived stress, -0.08 on anxiety, and -0.19 on depression. Mind-body and cognitive-behavioral interventions had moderate effects on reducing anxiety (g = -0.51). Interventions with longer duration (>8 weeks) were more effective in reducing anxiety (-0.39 vs. -0.26) and depression (-0.36 vs. -0.17). CONCLUSIONS: These findings support the short-term effectiveness of stress management interventions in improving mental health among high school adolescents in the United States. Subsequent research efforts should focus on sustaining long-term effects.

Teaching Social Determinants of Health in Nursing Programs: An Integrative Review of Strategies and Effectiveness.

BACKGROUND: Incorporating social determinants of health (SDoH) into clinical decision-making can clarify disease causes, enhance care planning, and improve health outcomes. Nurse educators should know which strategies are most effective for teaching SDoH in bachelor of science in nursing (BSN) programs. OBJECTIVE: This integrative review synthesizes the literature on familiarizing BSN students with SDoH and identifies effective teaching interventions for SDoH in these programs. METHODS: The researchers searched CINAHL, PubMed, Web of Science, and ERIC databases, and 21 articles met the inclusion criteria. The PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analysis) guidelines were followed for reporting. RESULTS: The curriculum method, service learning, and international outreach experiences were frequently used teaching strategies. Qualitative evaluation was used to evaluate student outcomes. CONCLUSIONS: Nurse educators should be mindful of these strategies. Interdisciplinary teamwork can bolster students' understanding of disadvantaged populations while integrating SDoH in nursing curricula. Quantitative evaluations of learning outcomes are needed to determine teaching effectiveness.

Associations between hair cortisol and blood pressure: a systematic review and meta-analysis.

OBJECTIVE: Stress is widely considered to be a risk factor for high blood pressure (BP), but evidence on the associations between biomarkers of chronic stress and BP is inconsistent. This systematic review and meta-analysis assessed the current state of the science on relationships between measures of cortisol concentration reflecting chronic stress exposure [hair cortisol concentration (HCC), nail cortisol concentration)] and BP. METHODS: PubMed, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Cochrane Library, and Embase were searched. Random effects models were used to assess the pooled effect size. Exploratory moderation analysis was performed. RESULTS: Out of 34 014 identified, 16 articles met eligibility criteria and were included in the review, while 14 were included in the meta-analysis. No articles were reported on the association between nail cortisol concentration and BP. Small, positive associations were observed between HCC and SBP [ r  = 0.19 (95% confidence interval (CI): 0.08-0.29)] and HCC and DBP [ r  = 0.13 (95% CI: 0.04-0.22)]. Cortisol analysis method was identified as a significant moderator of the association between HCC and DBP. HCC was largely, positively associated with hypertension status [odds ratio = 3.23 (95% CI: 2.55-4.09), P  < 0.001]. CONCLUSIONS: Current evidence suggests that higher HCC may be associated with elevated BP and a potential risk factor for hypertension. However, results should be interpreted with caution because HCC can be affected by hair color, hair care products, and analytic methods. Given the limitations of studies included in this review, further research is needed.

Extraction vs nonextraction of premolars for orthodontic treatment: A scoping review examining the extent, range, and characteristics of the literature.

INTRODUCTION: The debate about whether malocclusion can or should be treated with or without extraction of premolars continues. This scoping review quantifies the literature, summarizes the outcomes researched and methods, and proposes a way to reduce uncertainty in this area. METHODS: Electronic and gray literature searches were undertaken without language restriction, but non-English language titles and abstracts were not translated. A minimum of 2 people independently screened the titles and abstracts. RESULTS: Searches identified 9010 articles, of which 3851 were duplicates; 5159 were screened, and 4617 were excluded (1092 laboratory or animal studies, 1219 case reports or series, 2306 with no information). By consensus, 399 articles contained information concerning differences between orthodontic patients treated with or without premolar extractions (143 were unclear). The majority (n = 372) reported outcomes in 8 areas. Fifty-seven were review articles (32 systematic reviews and 25 nonsystematic reviews or opinions). The most common research design in the remainder was a cohort (n = 280, 82% of 342 articles reporting primary data), of which a very large majority were considered retrospective (n = 249, 89% of articles reported for subjects over ≥2 time points). Only 28 (8% of articles reporting primary data) were judged to involve prospective data collection (4 randomized controlled trials [RCTs], 23 cohorts, 1 unclear design). Excluding reviews and unclear articles, 99% (332 out of 336) were considered observational research and only 1% were interventional. CONCLUSIONS: There was limited low-quality evidence that extracting premolars in orthodontic patients have a possible negative effect in 2 outcome areas and a positive effect in 1 outcome area. Most study reports were of low methodological quality, and further reviews are unlikely to provide new information. Investigators should concentrate on collecting primary data of outcomes important to patients. A protocol has been made available to help reduce methodological differences, assist future meta-analyses and increase the generalizability of findings: https://doi.org/10.17605/OSF.IO/CQ49Y.

Antibiotic stewardship to reduce inappropriate antibiotic prescribing in integrated academic health-system urgent care clinics.

OBJECTIVE: To develop and implement antibiotic stewardship activities in urgent care targeting non-antibiotic-appropriate acute respiratory tract infections (ARIs) that also reduces overall antibiotic prescribing and maintains patient satisfaction. PATIENTS AND SETTING: Patients and clinicians at the urgent care clinics of an integrated academic health system. INTERVENTION AND METHODS: The stewardship activities started in fiscal 2020 and included measure development, comparative feedback, and clinician and patient education. We measured antibiotic prescribing in fiscal years 2019, 2020, and 2021 for the stewardship targets, potential diagnosis-shifting visits, and overall. We also collected patient satisfaction data for ARI visits. RESULTS: From FY19 to FY21, 576,609 patients made 1,358,816 visits to 17 urgent care clinics, including 105,781 visits for which stewardship measures were applied and 149,691 visits for which diagnosis shifting measures were applied. The antibiotic prescribing rate decreased for stewardship-measure visits from 34% in FY19 to 12% in FY21 (absolute change, -22%; 95% confidence interval [CI], -23% to -22%). The antibiotic prescribing rate decreased for diagnosis-shifting visits from 63% to 35% (-28%; 95% CI, -28% to -27%), and the antibiotic prescribing rate decreased overall from 30% to 10% (-20%; 95% CI, -20% to -20%). The patient satisfaction rate increased from 83% in FY19 to 89% in FY20 and FY21. There was no significant association between antibiotic prescribing rates of individual clinicians and ARI visit patient satisfaction. CONCLUSIONS: Although it was affected by the COVID-19 pandemic, an ambulatory antimicrobial stewardship program that focused on improving non-antibiotic-appropriate ARI prescribing was associated with decreased prescribing for (1) the stewardship target, (2) a diagnosis shifting measure, and (3) overall antibiotic prescribing. Patient satisfaction at ARI visits increased over time and was not associated with clinicians' antibiotic prescribing rates.

Antiviral Drug Discovery for the Treatment of COVID-19 Infections.

The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recently emerged human coronavirus. COVID-19 vaccines have proven to be successful in protecting the vaccinated from infection, reducing the severity of disease, and deterring the transmission of infection. However, COVID-19 vaccination faces many challenges, such as the decline in vaccine-induced immunity over time, and the decrease in potency against some SARS-CoV-2 variants including the recently emerged Omicron variant, resulting in breakthrough infections. The challenges that COVID-19 vaccination is facing highlight the importance of the discovery of antivirals to serve as another means to tackle the pandemic. To date, neutralizing antibodies that block viral entry by targeting the viral spike protein make up the largest class of antivirals that has received US FDA emergency use authorization (EUA) for COVID-19 treatment. In addition to the spike protein, other key targets for the discovery of direct-acting antivirals include viral enzymes that are essential for SARS-CoV-2 replication, such as RNA-dependent RNA polymerase and proteases, as judged by US FDA approval for remdesivir, and EUA for Paxlovid (nirmatrelvir + ritonavir) for treating COVID-19 infections. This review presents an overview of the current status and future direction of antiviral drug discovery for treating SARS-CoV-2 infections, covering important antiviral targets such as the viral spike protein, non-structural protein (nsp) 3 papain-like protease, nsp5 main protease, and the nsp12/nsp7/nsp8 RNA-dependent RNA polymerase complex.

The Experiences and Support Needs of Women With Gestational Breast Cancer in Singapore: A Descriptive Qualitative Study.

BACKGROUND: Gestational breast cancer is diagnosed during pregnancy or within the first postpartum year. There is a lack of studies on the experiences of ethnically diverse Asian women with gestational breast cancer. OBJECTIVE: The aim of this study was to explore the experiences of Asian women with gestational breast cancer so necessary support can be rendered. METHODS: This qualitative descriptive study used purposive sampling to recruit 7 women with gestational breast cancer who were following up at the breast center of a tertiary women's hospital in Singapore. Semistructured, individual, face-to-face, audio-recorded interviews were used to explore the in-depth experiences of these women. Data were transcribed verbatim and analyzed using thematic analysis. RESULTS: Three main themes emerged from the thematic analysis: (1) being a sick woman, (2) juggling between being a mother and a patient, and (3) seeking normalcy. Women had to contend with disruptive changes from gestational breast cancer, both emotionally and physically. They were constantly distressed by their altered body images, and family support was vital to help these women cope with their treatments. Alternative support sources included healthcare professionals and the Internet. CONCLUSION: Gestational breast cancer experiences varied based on the women's encounter perceptions and existing support. Their experiences may be improved through further support to mediate their coping efforts. Future quantitative and qualitative research should explore and evaluate the various aspects of the long-term disease and psychosocial effects of gestational breast cancer. IMPLICATIONS FOR PRACTICE: Hospitals should include support strategies in antenatal classes and postnatal workshops to lessen disruptions of the motherhood experiences.

Biomarkers for the clinical development of antiviral therapies.

With the morbidity and mortality associated with the COVID-19 pandemic that we are witnessing this year, the risks posed by emerging viral diseases to global health are all too obvious. This pandemic highlights the importance of antiviral drug discovery, which targets emerging viral pathogens, as well as existing pathogenic viruses that undergo continuous evolution. Drug discovery and development is a long and resource intensive process; however, the use of biomarkers can accelerate clinical development of antivirals by providing information regarding diagnosis of specific viral infections, status of infection, potential safety parameters, and antiviral responses. In clinical practice, many of the biomarkers initially utilized to support clinical development are also used for patient care. While viral load is a standard and essential biomarker used to detect the desired viral suppression induced by an antiviral agent, it has become apparent that additional biomarkers, whether related to the virus, the host or as a consequence of the drug's mechanistic effects, are also important for monitoring clinical outcomes associated with an antiviral therapy. This review summarizes the biomarkers used in the clinical development (as well as in clinical practice, where appropriate) of antiviral therapies for hepatitis C virus, hepatitis B virus, human immunodeficiency virus, and severe acute respiratory syndrome coronavirus 2.

Chyloma: A Manifestation of Chyle Leak Six Months After Neck Dissection.

Chyle leaks after a neck dissection usually manifest within the immediate postoperative period. However, masked chyle leaks may present as a chyloma months later. A 54-year-old male patient with squamous cell carcinoma of the tongue underwent bilateral neck dissection, subtotal glossectomy, anterolateral thigh flap reconstruction and postoperative radiotherapy. Intraoperatively, chyle leak was encountered in level IV of the left neck. We managed it by ligation of the thoracic duct, application of Tisseel™ sealant (Baxter Inc., Illinois, USA) and one week of prophylactic fat-free feeds. Six months later, an asymptomatic chyloma of the left neck was identified on surveillance MRI. Five weeks after the diagnosis, streptococcal infection developed within the chyloma. However, initiation of fat-free diet, serial aspiration, pressure dressing and antibiotic therapy allowed the chyloma to resolve within two weeks. Further surveillance MRI over three years showed no recurrence of the chyloma. Low-volume chyle leaks may manifest as an occult chyloma. Prophylactic measures cannot replace meticulous ligation of chylous channels in left level IV neck dissection.

Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Adolescents With Chronic Hepatitis C Virus: Part 1 of the DORA Study.

The pangenotypic regimen of glecaprevir and pibrentasvir (G/P) is approved to treat adults with chronic hepatitis C virus (HCV) infection and has yielded high cure rates in adults in clinical trials. Approved treatment options for pediatrics may include ribavirin. A pangenotypic regimen for pediatric patients remains an unmet need. DORA is an ongoing phase 2/3, nonrandomized, open-label study evaluating the pharmacokinetics (PK), safety, and efficacy of G/P in pediatric patients with chronic HCV. This analysis includes Part 1 of the study, conducted in adolescent patients 12-17 years of age given the adult regimen of G/P (300 mg/120 mg) once daily for 8-16 weeks according to the indication durations used in adults. Patients were either treatment naïve or experienced with interferon-based regimens. The primary PK endpoint was steady-state exposures for glecaprevir and pibrentasvir; the primary efficacy endpoint was sustained virologic response 12 weeks after treatment (SVR12). The secondary efficacy endpoints were on-treatment virologic failure, relapse, and reinfection. Safety and tolerability were monitored. Part 1 enrolled 48 adolescent patients infected with genotypes 1, 2, 3, or 4, of whom 47 were administered G/P. All 47 patients (100%) achieved SVR12. No on-treatment virologic failures or relapses occurred. PK exposures of glecaprevir and pibrentasvir were comparable to exposures in adults. No adverse events (AEs) led to treatment discontinuation, and no serious AEs occurred. Conclusion: Adolescent patients with chronic HCV infection treated with G/P achieved a comparable exposure to adults, 100% SVR12 rate, and safety profile consistent with that in adults. This pangenotypic regimen demonstrated 100% efficacy within the adolescent population in as little as 8 weeks of treatment.

Glecaprevir/Pibrentasvir in patients with chronic HCV genotype 3 infection: An integrated phase 2/3 analysis.

Glecaprevir coformulated with pibrentasvir (G/P) is approved to treat hepatitis C virus (HCV) infection and was highly efficacious in phase 2 and 3 studies. Treating HCV genotype (GT) 3 infection remains a priority, as these patients are harder to cure and at a greater risk for liver steatosis, fibrosis progression and hepatocellular carcinoma. Data were pooled from five phase 2 or 3 trials that evaluated 8-, 12- and 16-week G/P in patients with chronic HCV GT3 infection. Patients without cirrhosis or with compensated cirrhosis were either treatment-naïve or experienced with interferon- or sofosbuvir-based regimens. Safety and sustained virologic response 12 weeks post-treatment (SVR12) were assessed. The analysis included 693 patients with GT3 infection. SVR12 was achieved by 95% of treatment-naïve patients without cirrhosis receiving 8-week (198/208) and 12-week (280/294) G/P. Treatment-naïve patients with cirrhosis had a 97% (67/69) SVR12 rate with 12-week G/P. Treatment-experienced, noncirrhotic patients had SVR12 rates of 90% (44/49) and 95% (21/22) with 12- and 16-week G/P, respectively; 94% (48/51) of treatment-experienced patients with cirrhosis treated for 16 weeks achieved SVR12. No serious adverse events (AEs) were attributed to G/P; AEs leading to study drug discontinuation were rare (<1%). G/P was well-tolerated and efficacious for patients with chronic HCV GT3 infection, regardless of cirrhosis status or prior treatment experience. Eight- and 12-week durations were efficacious for treatment-naïve patients without cirrhosis and with compensated cirrhosis, respectively; 16-week G/P was efficacious in patients with prior treatment experience irrespective of cirrhosis status.

Sequence Analysis of the Fusion Protein Gene of Human Respiratory Syncytial Virus Circulating in China from 2003 to 2014.

The human respiratory syncytial virus (HRSV) fusion (F) protein is important for HRSV infection, but few studies have examined the genetic diversity of the F gene from Chinese samples. In this study, a total of 330 HRSV F sequences collected from different regions of China between 2003 and 2014 were analyzed to understand their genetic characteristics. In addition, these sequences were compared with 1150 HRSV F sequences in Genbank from 18 other countries. In phylogenetic analysis, Chinese HRSV F sequences sorted into a number of clusters containing sequences from China as well as other countries. F sequences from different genotypes (as determined based on the G gene sequences) within a HRSV subgroup could be found in the same clusters in phylogenetic trees generated based on F gene sequences. Amino acid analysis showed that HRSV F sequences from China and other countries were highly conserved. Of interest, F protein sequences from all Chinese samples were completely conserved at the palivizumab binding site, thus predicting the susceptibility of these strains to this neutralizing antibody. In conclusion, HRSV F sequences from China between 2003 and 2014, similar to those from other countries, were highly conserved.

Hepatitis C virus genetic diversity by geographic region within genotype 1-6 subtypes among patients treated with glecaprevir and pibrentasvir.

Hepatitis C virus (HCV) is genetically diverse and includes 7 genotypes and 67 confirmed subtypes, and the global distribution of each HCV genotype (GT) varies by geographic region. In this report, we utilized a large dataset of NS3/4A and NS5A sequences isolated from 2348 HCV GT1-6-infected patients treated with the regimen containing glecaprevir/pibrentasvir (GLE/PIB) to assess genetic diversity within HCV subtypes by geographic region using phylogenetic analyses, and evaluated the prevalence of baseline amino acid polymorphisms in NS3 and NS5A by region/country and phylogenetic cluster. Among 2348 NS3/4A and NS5A sequences, phylogenetic analysis identified 6 genotypes and 44 subtypes, including 3 GT1, 8 GT2, 3 GT3, 13 GT4, 1 GT5, and 16 GT6 subtypes. Phylogenetic analysis of HCV subtype 1a confirmed the presence of two clades, which differed by geographic region distribution and NS3 Q80K prevalence. We detected phylogenetic clustering by country in HCV subtypes 1a, 1b, 2a, 2b, and 5a, suggesting that genetically distinct virus lineages are circulating in different countries. In addition, two clades were detected in HCV GT4a and GT6e, and NS5A amino acid polymorphisms were differentially distributed between the 2 clades in each subtype. The prevalence of NS3 and NS5A baseline polymorphisms varied substantially by genotype and subtype; therefore, we also determined the activity of GLE or PIB against replicons containing NS3/4A or NS5A from HCV GT1-6 clinical samples representing 6 genotypes and 21 subtypes overall. GLE and PIB retained activity against the majority of HCV replicons containing NS3/4A or NS5A from HCV GT1-6 clinical samples, with a median EC50 of 0.29 nM for GLE and 1.1 pM for PIB in a transient replicon assay. The data presented in this report expands the available data on HCV epidemiology, subtype diversity by geographic region, and NS3 and NS5A baseline polymorphism prevalence.

Pooled Resistance Analysis in Patients with Hepatitis C Virus Genotype 1 to 6 Infection Treated with Glecaprevir-Pibrentasvir in Phase 2 and 3 Clinical Trials.

Over 2,200 patients infected with hepatitis C virus (HCV) genotypes (GT) 1 to 6, with or without cirrhosis, who were treatment naive or experienced to interferon, ribavirin, and/or sofosbuvir were treated with glecaprevir/pibrentasvir for 8, 12, or 16 weeks in eight registrational phase 2 and 3 clinical studies. High rates of sustained virologic response at 12 weeks postdosing (SVR12) were achieved with a <1% virologic failure (VF) rate. The prevalence of baseline polymorphisms (BPs) in NS3 at amino acid position 155 or 168 was low (<3%) in patients infected with GT1, GT2, GT3, GT4, and GT6, while 41.9% of the GT5-infected patients had NS3-D168E; BPs were not detected at position 156 in NS3. The prevalence of NS5A-BPs was high across genotypes, driven by common polymorphisms at amino acid position 30 or 31 in GT2, 58 in GT4, and 28 in GT6. The prevalence of NS5A T/Y93 polymorphisms was 5.5% in GT1, 4.9% in GT3, and 12.5% in GT6. Consistent with the activity of glecaprevir and pibrentasvir against most amino acid polymorphisms in vitro, BPs in NS3 and/or NS5A did not have an impact on treatment outcome for patients infected with GT1 to GT6, with the exception of treatment-experienced GT3-infected patients treated for 12 weeks, for whom a 16-week regimen of glecaprevir/pibrentasvir was required to achieve SVR12 rates of ≥95%. Among the 22 patients experiencing VF, treatment-emergent substitutions were detected in NS3 in 50% of patients and in NS5A in 82% of patients, frequently as a combination of substitutions that conferred resistance to glecaprevir and/or pibrentasvir. The glecaprevir/pibrentasvir regimen, when the recommended durations are used, allows for a pan-genotypic treatment option without the need for baseline resistance testing.

Resistance Analysis of a 3-Day Monotherapy Study with Glecaprevir or Pibrentasvir in Patients with Chronic Hepatitis C Virus Genotype 1 Infection.

Glecaprevir (an NS3/4A protease inhibitor) and pibrentasvir (an NS5A inhibitor) are potent and pangenotypic hepatitis C virus (HCV) direct-acting antivirals. This report describes the baseline polymorphisms and treatment-emergent substitutions in NS3 or NS5A detected in samples from HCV genotype 1-infected patients receiving 3-day monotherapy of glecaprevir or pibrentasvir, respectively. None of the NS3 polymorphisms detected in the 47 baseline samples collected prior to glecaprevir monotherapy conferred reduced susceptibility to glecaprevir. The NS3 A156T substitution, which conferred resistance to glecaprevir but had low replication efficiency, emerged in one genotype 1a-infected patient among the 35 patients with available post-baseline sequence data. Baseline NS5A polymorphisms were detected in 12 of 40 patients prior to pibrentasvir monotherapy; most polymorphisms were single-position NS5A amino acid substitutions that did not confer resistance to pibrentasvir. Among the 19 patients with available post-baseline NS5A sequence data, 3 had treatment-emergent NS5A substitutions during pibrentasvir monotherapy. All treatment-emergent NS5A substitutions were linked multiple-position, almost exclusively double-position, substitutions that conferred resistance to pibrentasvir. Replicons engineered with these double-position substitutions had low replication efficiency. In conclusion, resistance-conferring substitutions emerged in a small number of genotype 1-infected patients during glecaprevir or pibrentasvir monotherapy; unlike other NS5A inhibitors, pibrentasvir did not select single-position NS5A substitutions during monotherapy.

Highlights of the Structure-Activity Relationships of Benzimidazole Linked Pyrrolidines Leading to the Discovery of the Hepatitis C Virus NS5A Inhibitor Pibrentasvir (ABT-530).

Curative interferon and ribavirin sparing treatments for hepatitis C virus (HCV)-infected patients require a combination of mechanistically orthogonal direct acting antivirals. A shared component of these treatments is usually an HCV NS5A inhibitor. First generation FDA approved treatments, including the component NS5A inhibitors, do not exhibit equivalent efficacy against HCV virus genotypes 1-6. In particular, these first generation NS5A inhibitors tend to select for viral drug resistance. Ombitasvir is a first generation HCV NS5A inhibitor included as a key component of Viekira Pak for the treatment of patients with HCV genotype 1 infection. Since the launch of next generation HCV treatments, functional cure for genotype 1-6 HCV infections has been achieved, as well as shortened treatment duration across a wider spectrum of genotypes. In this paper, we show how we have modified the anchor, linker, and end-cap architecture of our NS5A inhibitor design template to discover a next generation NS5A inhibitor pibrentasvir (ABT-530), which exhibits potent inhibition of the replication of wild-type genotype 1-6 HCV replicons, as well as improved activity against replicon variants demonstrating resistance against first generation NS5A inhibitors.

Efficacy and Safety of Glecaprevir/Pibrentasvir in Patients Coinfected With Hepatitis C Virus and Human Immunodeficiency Virus Type 1: The EXPEDITION-2 Study.

Background: Once-daily glecaprevir coformulated with pibrentasvir (glecaprevir/pibrentasvir) demonstrated high rates of sustained virologic response 12 weeks after treatment (SVR12) in patients with hepatitis C virus (HCV) genotype 1-6 infection. This phase 3 study evaluated the efficacy and safety of glecaprevir/pibrentasvir in patients with chronic HCV genotype 1-6 and human immunodeficiency virus type 1 (HIV-1) coinfection, including patients with compensated cirrhosis. Methods: EXPEDITION-2 was a phase 3, multicenter, open-label study evaluating glecaprevir/pibrentasvir (300 mg/120 mg) in HCV genotype 1-6/HIV-1-coinfected adults without and with compensated cirrhosis for 8 and 12 weeks, respectively. Patients were either HCV treatment-naive or experienced with sofosbuvir, ribavirin, or interferon, and antiretroviral therapy (ART) naive or on a stable ART regimen. Treatment-experienced genotype 3-infected patients were excluded. The primary endpoint was the SVR12 rate. Results: In total, 153 patients were enrolled, including 16 (10%) with cirrhosis. The SVR12 rate was 98% (n = 150/153; 95% confidence interval, 95.8-100), with no virologic failures in 137 patients treated for 8 weeks. One genotype 3-infected patient with cirrhosis had on-treatment virologic failure. Most adverse events were mild in severity; 4 patients (2.6%) had serious adverse events, all deemed unrelated to glecaprevir/pibrentasvir. Treatment discontinuation was rare (<1%). All patients treated with ART maintained HIV-1 suppression (<200 copies/mL) during treatment. Conclusions: Glecaprevir/pibrentasvir for 8 weeks in noncirrhotic and 12 weeks in cirrhotic patients is a highly efficacious and well-tolerated treatment for HCV/HIV-1 coinfection, regardless of baseline HCV load or prior treatment with interferon or sofosbuvir. Clinical trial registration: NCT02738138.

Glecaprevir-Pibrentasvir for 8 or 12 Weeks in HCV Genotype 1 or 3 Infection.

BACKGROUND: Glecaprevir and pibrentasvir are direct-acting antiviral agents with pangenotypic activity and a high barrier to resistance. We evaluated the efficacy and safety of 8-week and 12-week courses of treatment with 300 mg of glecaprevir plus 120 mg of pibrentasvir in patients without cirrhosis who had hepatitis C virus (HCV) genotype 1 or 3 infection. METHODS: We conducted two phase 3, randomized, open-label, multicenter trials. Patients with genotype 1 infection were randomly assigned in a 1:1 ratio to receive once-daily glecaprevir-pibrentasvir for either 8 or 12 weeks. Patients with genotype 3 infection were randomly assigned in a 2:1 ratio to receive 12 weeks of treatment with either glecaprevir-pibrentasvir or sofosbuvir-daclatasvir. Additional patients with genotype 3 infection were subsequently enrolled and nonrandomly assigned to receive 8 weeks of treatment with glecaprevir-pibrentasvir. The primary end point was the rate of sustained virologic response 12 weeks after the end of treatment. RESULTS: In total, 1208 patients were treated. The rate of sustained virologic response at 12 weeks among genotype 1-infected patients was 99.1% (95% confidence interval [CI], 98 to 100) in the 8-week group and 99.7% (95% CI, 99 to 100) in the 12-week group. Genotype 3-infected patients who were treated for 12 weeks had a rate of sustained virologic response at 12 weeks of 95% (95% CI, 93 to 98; 222 of 233 patients) with glecaprevir-pibrentasvir and 97% (95% CI, 93 to 99.9; 111 of 115) with sofosbuvir-daclatasvir; 8 weeks of treatment with glecaprevir-pibrentasvir yielded a rate of 95% (95% CI, 91 to 98; 149 of 157 patients). Adverse events led to discontinuation of treatment in no more than 1% of patients in any treatment group. CONCLUSIONS: Once-daily treatment with glecaprevir-pibrentasvir for either 8 weeks or 12 weeks achieved high rates of sustained virologic response among patients with HCV genotype 1 or 3 infection who did not have cirrhosis. (Funded by AbbVie; ENDURANCE-1 and ENDURANCE-3 ClinicalTrials.gov numbers, NCT02604017 and NCT02640157 .).

Efficacy of Glecaprevir/Pibrentasvir for 8 or 12 Weeks in Patients With Hepatitis C Virus Genotype 2, 4, 5, or 6 Infection Without Cirrhosis.

BACKGROUND & AIMS: Hepatitis C virus (HCV) has high genotypic diversity and global distribution. Agents that are effective against all major HCV genotypes, with shorter treatment duration, are needed to reduce disease burden. Glecaprevir (an NS3/4A protease inhibitor) and pibrentasvir (an NS5A inhibitor) have a high barrier to resistance and synergistic antiviral activity. We evaluated the safety and efficacy of 8 and 12 weeks' treatment with glecaprevir/pibrentasvir in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis in 3 separate phase 3 trials. METHODS: We performed 2 open label, single-arm studies (SURVEYOR-II, Part 4 and ENDURANCE-4) and a randomized, double-blind, placebo-controlled study (ENDURANCE-2). In the ENDURANCE-2 study, adult patients with untreated or previously treated HCV genotype 2 infection without cirrhosis were randomly assigned (2:1) to groups given once-daily oral glecaprevir/pibrentasvir (n = 202; 300 mg/120 mg) or placebo (n = 100) for 12 weeks. In the SURVEYOR-II, Part 4 and ENDURANCE-4 studies, adult patients with untreated or previously treated patients with HCV genotype 2, genotype 4, genotype 5, or genotype 6 infection, without cirrhosis, were given once-daily oral glecaprevir/pibrentasvir (n = 121 in ENDURANCE-4 and n = 145 in SURVEYOR-II) for 12 or 8 weeks, respectively. In all studies the primary endpoint was sustained virologic response at 12 weeks after treatment (SVR12) in the intention-to-treat population. RESULTS: Among patients receiving glecaprevir/pibrentasvir for 8 weeks, rates of SVR12 were 98% (95% CI, 94.1-99.3) in those infected with HCV genotype 2 and 93% (95% CI, 83.6-97.3) in those infected with HCV genotypes 4, 5, or 6. Among patients receiving glecaprevir/pibrentasvir for 12 weeks, rates of SVR12 were 99.5% (95% CI, 98.5-100) in those infected with HCV genotype 2 and 99% (95% CI, 97.6-100) in those infected with HCV genotype 4, 5, or 6. No virologic failures occurred in patients with HCV genotype 4, 5, or 6 infections. The frequency and severity of adverse events in patients receiving glecaprevir/pibrentasvir were similar to those of patients who received placebo. CONCLUSION: In 3 Phase 3 studies, 8 weeks' treatment with glecaprevir/pibrentasivr produced an SVR12 in at least 93% of patients with chronic HCV genotype 2, 4, 5, or 6 infection without cirrhosis, with virologic failure in less than 1%. The drug combination had a safety profile comparable to 12 week's treatment with glecaprevir/pibrentasvir. ClinicalTrials.gov numbers: NCT02640482 (ENDURANCE-2), NCT02636595 (ENDURANCE-4), and NCT02243293 (SURVEYOR-II).