Week 240 Efficacy and Safety of Fostemsavir Plus Optimized Background Therapy in Heavily Treatment-Experienced Adults with HIV-1.

INTRODUCTION: Efficacy and safety of the attachment inhibitor fostemsavir + optimized background therapy (OBT) were evaluated through 48 and 96 weeks in the phase 3 BRIGHTE trial in heavily treatment-experienced (HTE) adults failing their current antiretroviral regimen. Here, we report 240-week efficacy and safety of fostemsavir + OBT in adults with multidrug-resistant human immunodeficiency virus (HIV)-1 in BRIGHTE. METHODS: Heavily treatment-experienced adults failing their current regimen entered the randomized cohort (RC; 1-2 fully active antiretrovirals available) or non-randomized cohort (NRC; no fully active antiretrovirals available) and received open-label fostemsavir + OBT (starting Day 8 in RC and Day 1 in NRC). Endpoints included proportion with virologic response (HIV-1 RNA < 40 copies/mL, Snapshot), immunologic efficacy, and safety. RESULTS: At Week 240, 45% and 22% of the RC and NRC, respectively, had virologic response (Snapshot); 7% of the RC and 5% of the NRC had missing data due to coronavirus disease 2019 (COVID-19)-impacted visits. In the observed analysis, 82% of the RC and 66% of the NRC had virologic response. At Week 240, mean change from baseline in CD4+ T-cell count was 296 cells/mm3 (RC) and 240 cells/mm3 (NRC); mean CD4+/CD8+ ratio increased between Weeks 96 and 240 (RC 0.44 to 0.60; NRC 0.23 to 0.32). Between Weeks 96 and 240, four participants discontinued for adverse events, one additional participant experienced a drug-related serious adverse event, and six deaths occurred (median last available CD4+ T-cell count, 3 cells/mm3). COVID-19-related events occurred in 25 out of 371 participants; all resolved without incident. CONCLUSION: Through ~5 years, fostemsavir + OBT demonstrated durable virologic and immunologic responses with no new safety concerns between Weeks 96 and 240, supporting this regimen as a key therapeutic option for HTE people with multidrug-resistant HIV-1. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02362503.

Evaluating caretaker satisfaction with same-day discharge after gastrostomy tube placement.

BACKGROUND: Same-day discharge (SDD) after laparoscopic gastrostomy tube (G-tube) placement, using written and video-based preoperative education, has been our standard institutional practice since 2017. We aim to evaluate caretaker satisfaction with this protocol. METHODS: All patients planned for SDD after G-tube placement from February 2021-February 2022 were identified. Chart review was performed to identify demographic information, successful same-day discharge or reason for postoperative admission, time to first postoperative feed, length of stay (LOS), and complications requiring emergency department evaluation, readmission, or reoperation. Telephone follow-up at two weeks postoperatively was conducted to evaluate satisfaction with the SDD protocol. RESULTS: Forty-nine patients were eligible for SDD with a median age of 1.1 years [0.7, 4.4]. Forty-two (86%) patients were successfully discharged the same day with a median LOS of 7.5 h [6.7, 8.1], and 7 (14%) were admitted postoperatively for further education or emesis with a median LOS of 30.4 h [26.9, 31.2]. Median time to initiation of feeds was 2.3 h [1.7, 2.9]. 8 (16%) patients were evaluated in the emergency department within 30 days postoperatively, resulting in two re-admissions: one for peri­stomal erythema and fever requiring oral antibiotics at 21 days and one for G-tube dislodgement requiring reoperation and replacement at 28 days. On two-week telephone follow-up, 42 caretakers (100%) felt that their education was adequate for same-day discharge and felt comfortable with the same-day discharge protocol. Six (14%) caretakers stated their child's pain was not well controlled at some point between discharge and survey follow-up, and three caretakers (7%) called a provider within the first 24 h for issues with pain. Forty-one caretakers (98%) expressed satisfaction going home the day of surgery. CONCLUSION: Caretaker satisfaction and comfort with same-day discharge following laparoscopic G-tube placement are high, ascribed to comprehensive preoperative education and anticipatory guidance. TYPE OF STUDY: Prognostic. LEVEL OF EVIDENCE: Level 1.

Influence of Light Phase Exposure to LED Lighting on Circadian Levels of Neuroendocrine Hormones in Sprague-Dawley Rats.

Light and lighting protocols of animal research facilities are critically important to the outcomes of biomedical research that uses animals. Previous studies from our laboratory showed that the wavelength (color) of light in animal housing areas affects the nocturnal melatonin signal that temporally coordinates circadian rhythms in rodents. Here, we tested the hypothesis that exposure to LED light enriched in the blue-appearing portion (460-480 nm) of the visible spectrum during the light phase (bLAD) influences circadian concentrations of select neuroendocrine hormones in adolescent Sprague-Dawley rats. Male and female rats (4 to 5 wk old) were housed on a novel IVC system under a 12L:12D in either cool-white fluorescent (control, n = 72) or bLAD (experimental, n = 72) lighting. Every third day, body weight and food and water consumption were measured. On Day 30, rats were anesthetized with ketamine/xylazine and terminal collection of arterial blood was performed to quantify serum concentrations of melatonin, corticosterone, insulin, and glucose at 6 circadian time points (0400, 0800, 1200, 1600, 2000, 2400). As compared with male and female rats housed under cool white fluorescent (CWF) lighting, rats in bLAD lighting showed a 6-fold higher peak in dark phase serum melatonin (P < 0.05). Effects on serum corticosterone were sex dependent, as CWF and bLAD females had significantly higher corticosterone levels than did CWF and bLAD males, respectively. CWF and bLAD females had significantly higher serum glucose overall as compared with males. However, serum insulin was not affected by sex (M or F) or lighting conditions (CWF or bLAD). These data show that housing Sprague-Dawley rats under bLAD lighting conditions increases circadian peaks of melatonin without increasing serum levels of corticosterone, glucose or insulin, indicating less variation of circadian cycling of key neuroendocrine hormones in bLAD-exposed rats.

Week 96 Genotypic and Phenotypic Results of the Fostemsavir Phase 3 BRIGHTE Study in Heavily Treatment-Experienced Adults Living with Multidrug-Resistant HIV-1.

In the phase 3 BRIGHTE study in heavily treatment-experienced adults with multidrug-resistant HIV-1, fostemsavir plus optimized background therapy (OBT) resulted in sustained rates of virologic suppression through 96 weeks. HIV-1 RNA <40 copies/mL was achieved in 163/272 (60%) Randomized Cohort (RC) participants (with 1 or 2 remaining approved fully active antiretrovirals) and 37/99 (37%) Non-randomized Cohort (NRC) participants (with 0 fully active antiretrovirals). Here we report genotypic and phenotypic analyses of HIV-1 samples from 63/272 (23%) RC participants and 49/99 (49%) NRC participants who met protocol-defined virologic failure (PDVF) criteria through Week 96. The incidence of PDVF was as expected in this difficult-to-treat patient population and, among RC participants, was comparable regardless of the presence of predefined gp120 amino acid substitutions that potentially influence phenotypic susceptibility to temsavir (S375H/I/M/N/T, M426L, M434I, M475I) or baseline temsavir 50% inhibitory concentration fold change (IC50 FC). The incidence of PDVF was lower among participants with higher overall susceptibility score to newly used antiretrovirals (OSS-new), indicating that OSS-new may be a preferred predictor of virologic outcome in heavily treatment-experienced individuals. Predefined gp120 substitutions, most commonly M426L or S375N, were emergent on treatment in 24/50 (48%) RC and 33/44 (75%) NRC participants with PDVF, with related increases in temsavir IC50 FC. In BRIGHTE, PDVF was not consistently associated with treatment-emergent genotypic or phenotypic changes in susceptibility to temsavir or to antiretrovirals in the initial OBT. Further research will be needed to identify which factors are most likely to contribute to virologic failure in this heavily treatment-experienced population (ClinicalTrials.gov, NCT02362503).

Changes in self-image after pectus carinatum brace treatment.

BACKGROUND/PURPOSE: Pectus carinatum (PC) is a chest wall deformity resulting in anterior protrusion of the chest. PC does not typically result in significant physical or cardiopulmonary symptoms, but patients with this condition can experience a disturbed body image, lower self-esteem and reduced quality of life.  The purpose of this study was to investigate the relationship between self-image and non-surgical correction of PC using a brace. METHODS: This study was a descriptive, pre-post survey design. The sample included children ages 11 to <18 years undergoing PC treatment with the dynamic compressor system. Subjects completed the modified Pectus Excavatum Evaluation Questionnaire (mPEEQ) at the onset of bracing and again once PC correction was completed. RESULTS: Ninety-seven subjects were enrolled at the time of bracing, and 41 achieved correction and took the second survey. The mean age was 14 years and 80% were male. There was a statistically significant (p<0.001) improvement in body self-image between the first and second surveys. CONCLUSIONS: Non-surgical correction of PC with the dynamic compressor system resulted in an improvement in the self-image of children. PROGNOSIS STUDY: Level of Evidence II.

Phase III/IV, Randomized, Fifty-Two-Week Study of the Efficacy and Safety of Belimumab in Patients of Black African Ancestry With Systemic Lupus Erythematosus.

OBJECTIVE: Enrollment of patients of Black African ancestry with systemic lupus erythematosus (SLE) in phase II and phase III of the belimumab trials was not reflective of the racial distribution observed in the lupus population. This study was undertaken to assess the efficacy and safety of intravenous (IV) belimumab plus standard therapy in patients of self-identified Black race. METHODS: EMBRACE (GSK Study BEL115471; ClinicalTrials.gov identifier: NCT01632241) was a 52-week multicenter, double-blind, placebo-controlled trial in adults of self-identified Black race with active SLE who received monthly belimumab 10 mg/kg IV, or placebo, plus standard therapy. The optional 26-week open-label extension phase included patients who completed the double-blind phase. The primary end point of the study was SLE Responder Index (SRI) response rate at week 52 with modified proteinuria scoring adapted from the SLE Disease Activity Index 2000 (SLEDAI-2K) (SRI-SLEDAI-2K). Key secondary end points included SRI response rate at week 52, time to first severe SLE flare, and reductions in prednisone dose. RESULTS: The modified intent-to-treat population comprised 448 patients, of whom 96.9% were women and the mean ± SD age was 38.8 ± 11.42 years. The primary end point (improvement in the SRI-SLEDAI-2K response rate at week 52) was not achieved (belimumab 48.7%, placebo 41.6%; odds ratio 1.40 [95% confidence interval 0.93, 2.11], P = 0.1068); however, numerical improvements favoring belimumab were observed, in which the SRI-SLEDAI-2K response rates were higher in those who received belimumab compared with those who received placebo, especially in patients with SLE who had high disease activity or renal manifestations at baseline. The safety profile of belimumab was generally consistent with that observed in previous SLE trials. Adverse events were the primary reasons for double-blind phase withdrawals (belimumab 5.4%, placebo 6.7%). CONCLUSION: The primary end point of this study was not achieved, but improvement with belimumab versus placebo was observed, suggesting that belimumab remains a suitable treatment option for SLE management in patients of Black African ancestry.

Patient-Reported Outcomes in the Phase III BRIGHTE Trial of the HIV-1 Attachment Inhibitor Prodrug Fostemsavir in Heavily Treatment-Experienced Individuals.

INTRODUCTION: Heavily treatment-experienced (HTE) people living with HIV-1 (PLWH) have limited viable antiretroviral regimens available because of multidrug resistance and safety concerns. The first-in-class HIV-1 attachment inhibitor fostemsavir demonstrated efficacy and safety in HTE participants in the ongoing phase III BRIGHTE trial. OBJECTIVES: We describe patient-reported outcomes (PROs) through week 48. METHODS: Eligible participants for whom their current regimen was failing were assigned to the randomized cohort (RC; one to two fully active agents remaining) or the nonrandomized cohort (NRC; no fully active agents remaining). PRO assessments included the EQ-5D-3L, EQ-VAS, and Functional Assessment of HIV Infection (FAHI) instruments. RESULTS: Both cohorts achieved increases in EQ-5D-3L US- and UK-referenced utility score from baseline at week 24. Mean visual analog scale (VAS) scores in the RC and NRC increased from baseline by 8.7 (95% CI 6.2-11.2) and 5.6 points (95% CI 1.5-9.7) at week 24 and increased from baseline by 9.8 (95% CI 7.0-12.6) and 4.9 points (95% CI 0.6-9.2) at week 48, respectively. Mean increases in FAHI total score from baseline to weeks 24 and 48 in the RC were 6.9 (95% CI 4.2-9.7) and 5.8 (95% CI 2.7-9.0), respectively, whereas mean increases in physical and emotional well-being subscale scores were 2.7 (95% CI 1.9-3.6) and 2.4 (95% CI 1.3-3.4) and 3.2 (95% CI 2.2-4.2) and 2.6 (95% CI 1.6-3.7), respectively, with little to no change in other subscales. CONCLUSIONS: Improvements in major domains of the EQ-VAS and FAHI through week 48, combined with efficacy and safety results, support the use of fostemsavir for HTE PLWH. TRIAL REGISTRATION NUMBER AND DATE: NCT02362503; February 13, 2015.

Long-term efficacy and safety of fostemsavir among subgroups of heavily treatment-experienced adults with HIV-1.

OBJECTIVES: The aim of this study was to understand how demographic and treatment-related factors impact responses to fostemsavir-based regimens. DESIGN: BRIGHTE is an ongoing phase 3 study evaluating twice-daily fostemsavir 600 mg and optimized background therapy (OBT) in heavily treatment-experienced individuals failing antiretroviral therapy with limited treatment options (Randomized Cohort 1-2 and Nonrandomized Cohort 0 fully active antiretroviral classes). METHODS: Virologic response rates (HIV-1 RNA <40 copies/ml, Snapshot analysis) and CD4+ T-cell count increases in the Randomized Cohort were analysed by prespecified baseline characteristics (age, race, sex, region, HIV-1 RNA, CD4+ T-cell count) and viral susceptibility to OBT. Safety results were analysed by baseline characteristics for combined cohorts (post hoc). RESULTS: In the Randomized Cohort, virologic response rates increased between Weeks 24 and 96 across most subgroups. Virologic response rates over time were most clearly associated with overall susceptibility scores for new OBT agents (OSS-new). CD4+ T-cell count increases were comparable across subgroups. Participants with baseline CD4+ T-cell counts less than 20 cells/µl had a mean increase of 240 cells/µl. In the safety population, more participants with baseline CD4+ T-cell counts less than 20 vs. at least 200 cells/µl had grade 3/4 adverse events [53/107 (50%) vs. 24/96 (25%)], serious adverse events [58/107 (54%) vs. 25/96 (26%)] and deaths [16/107 (15%) vs. 2/96 (2%)]. There were no safety differences by other subgroups. CONCLUSION: Week 96 results for BRIGHTE demonstrate comparable rates of virologic and immunologic response (Randomized Cohort) and safety (combined cohorts) across subgroups. OSS-new is an important consideration when constructing optimized antiretroviral regimens for heavily treatment-experienced individuals with limited remaining treatment options.

Same-day discharge for pediatric laparoscopic gastrostomy.

BACKGROUND: Laparoscopic gastrostomy is a common procedure in children. We developed a same-day discharge (SDD) protocol for laparoscopic button gastrostomy. METHODS: We performed a prospective observational study of children undergoing laparoscopic button gastrostomy and were eligible for SDD from August 2017-September 2019. Patients were eligible if: 1) the family was comfortable with eliminating overnight admission and were suitable candidates for outpatient surgery (absence of major co-morbidities), 2) they were not undergoing additional procedures requiring admission, and 3) they received pre-operative education. RESULTS: Sixty-two patients who underwent laparoscopic button gastrostomy were eligible for SDD. The median age was 2.1 years [IQR 0.9-4.1], and the median weight was 10.5 kg [IQR 7.6-15.5]. Forty-one (66%) were previously nasogastric fed. The median operative time was 22 min [IQR 16-29]. The median time to initiation of feeds was 4.4 h [IQR 3.4-5.5]. Fifty-one (82%) were discharged the same day with a median length of stay of 9 h [IQR 7-10]. Eleven were admitted, most commonly for further teaching. Eleven SDD patients were seen in the emergency room <30 days at a median 5 days [IQR 3-12] post-operatively, primarily for mechanical complications. CONCLUSION: Same-day discharge following laparoscopic gastrostomy is safe and feasible for select pediatric patients who undergo pre-operative education. The SDD pathway results in a low admission rate and relatively low ER visits. TYPE OF STUDY: Prospective Observational Study. LEVEL OF EVIDENCE: Level II.

Susceptibility of global HIV-1 clinical isolates to fostemsavir using the PhenoSense® Entry assay.

BACKGROUND: Fostemsavir is a prodrug of a first-in-class HIV-1 attachment inhibitor, temsavir, that binds to gp120 and blocks attachment to the host-cell CD4 receptor, preventing entry and infection of the target cell. Previous studies using a limited number of clinical isolates showed that there was intrinsic variability in their susceptibility to temsavir. OBJECTIVES: Here, an analysis was performed using all clinical isolates analysed in the Monogram Biosciences PhenoSense® Entry assay as part of the development programme. METHODS: In total, 1337 individual envelopes encompassing 20 different HIV-1 subtypes were examined for their susceptibility to temsavir. However, only seven subtypes (B, C, F1, A, [B, F1], BF and A1) were present more than five times, with subtype B (881 isolates) and subtype C (156 isolates) having the largest numbers. RESULTS: As expected, variability in susceptibility was observed within all subtypes. However, for the great majority of these viruses, temsavir was highly potent, with most viruses exhibiting IC50s <10 nM. One exception was CRF01_AE viruses, where all five isolates exhibited IC50s >100 nM. For the 607 isolates where tropism data were available, geometric mean temsavir IC50 values were remarkably similar for CCR5-, CXCR4- and dual mixed-tropic envelopes from infected individuals. CONCLUSIONS: These data show that HIV-1 viruses from most subtypes are highly susceptible to temsavir and that temsavir susceptibility is independent of tropism.

Mortality and adverse events of special interest with intravenous belimumab for adults with active, autoantibody-positive systemic lupus erythematosus (BASE): a multicentre, double-blind, randomised, placebo-controlled, phase 4 trial.

BACKGROUND: Belimumab is approved for the treatment of active systemic lupus erythematosus (SLE). Although clinical trials showed a favourable benefit-risk profile, numerical differences in the incidence of mortality and adverse events of special interest (AESIs) have been reported. We assessed the frequency of these events in patients with SLE receiving belimumab or placebo plus standard therapy. METHODS: BASE was a double-blind, randomised, placebo-controlled, phase 4 trial done in 33 countries. Adults with active SLE were randomly assigned (1:1) to receive intravenous belimumab (10 mg/kg) or placebo, plus standard therapy, for 48 weeks. The primary endpoints were incidences of all-cause mortality and AESIs during the on-treatment period (first-to-last study drug dose + 28 days). Safety analyses were done in the as-treated population (patients grouped by actual treatment received >50% of the time). This study was registered with ClinicalTrials.gov (NCT01705977). FINDINGS: Between Nov 27, 2012, and July 28, 2017, we randomly assigned 4018 patients. The as-treated population included 2002 patients in the belimumab group versus 2001 in the placebo group. Ten (0·50%) patients in the belimumab group died versus eight (0·40%) in the placebo group (difference 0·10%, 95% CI -0·31 to 0·51). Incidences were similar in the belimumab and placebo groups for serious infections (75 [3·75%] of 2002 vs 82 [4·10%] of 2001; difference -0·35%, 95% CI -1·55 to 0·85), opportunistic infections and other infections of interest (36 [1·80%] vs 50 [2·50%]; -0·70%, -1·60 to 0·20), non-melanoma skin cancers (4 [0·20%] vs 3 [0·15%]; 0·05%, -0·21 to 0·31) and other malignancies (5 [0·25%] vs 5 [0·25%]; 0·00%, -0·31 to 0·31). A higher proportion of patients in the belimumab group than in the placebo group had infusion and hypersensitivity reactions (8 [0·40%] vs 2 [0·10%]; 0·30%, -0·01 to 0·61), serious depression (7 [0·35%] vs 1 [0·05%]; 0·30%, 0·02 to 0·58), treatment-emergent suicidality (28 [1·42%] of 1972 patients vs 23 [1·16%] of 1986; 0·26%, -0·44 to 0·96), and sponsor-adjudicated serious suicide or self-injury (15 [0·75%] of 1972 patients vs 5 [0·25%] of 1986; post hoc difference 0·50%, 0·06 to 0·94). INTERPRETATION: In line with previously published data, incidences of all-cause mortality and AESIs were similar in patients given belimumab and placebo, except for serious infusion or hypersensitivity reactions, serious depression, treatment-emergent suicidality, and sponsor-adjudicated serious suicide or self-injury events. FUNDING: GSK.

Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals: week 96 results of the phase 3 BRIGHTE study.

BACKGROUND: Fostemsavir, a prodrug of the first-in-class attachment inhibitor, temsavir, is indicated for heavily treatment-experienced individuals with multidrug-resistant HIV-1. We previously reported superior efficacy of fostemsavir versus placebo in the randomised cohort of the BRIGHTE study after 8-day functional monotherapy (primary endpoint); here we report planned interim analyses through week 96. METHODS: BRIGHTE (NCT02362503) is an ongoing multicentre, two-cohort, phase 3 trial, done at 108 centres in 22 countries. We enrolled heavily treatment-experienced adults (≥18 years) failing antiretroviral therapy (HIV-1 RNA ≥400 copies per mL) into two cohorts: the randomised cohort, in which patients with one or two fully active antiretrovirals remaining received oral fostemsavir (600 mg twice a day) or placebo in combination with their failing regimen for 8 days, followed by fostemsavir plus optimised background therapy; or the non-randomised cohort, in which patients with no remaining antiretroviral options received oral fostemsavir (600 mg twice a day) plus optimised background therapy from day 1. Endpoints for the week 96 interim analyses included the proportions of participants with plasma HIV-1 RNA of less than 40 copies per mL, changes from baseline in CD4 cell counts, and the frequency of adverse events, adverse events leading to discontinuation, and deaths. The intention-to-treat exposed population and the safety population both included all participants who received at least one dose of study treatment. The response rates (proportion of participants with HIV-1 RNA <40 copies per mL) in the intention-to-treat exposed population were calculated via snapshot analysis at weeks 24, 48, and 96. FINDINGS: Between Feb 23, 2015, and Aug 11, 2016, 371 participants were enrolled and treated, of which 272 participants were in the randomised cohort and 99 in the non-randomised cohort. 320 (86%) of 371 reported a history of AIDS. In the randomised cohort, rates of virological suppression (HIV-1 RNA <40 copies per mL) increased from 53% (144 of 272) at week 24 to 60% (163 of 272) at week 96. Response rates in the non-randomised cohort were 37% (37 of 99) at week 24 and week 96. Mean increases in CD4 counts from baseline at week 96 were 205 cells per µL (SD 191) in the randomised cohort and 119 cells per µL (202) in the non-randomised cohort. Mean CD4/CD8 ratio increased from 0·20 at baseline to 0·44 at week 96 in the randomised cohort. Few adverse events led to discontinuation (26 [7%] of 371). 12 (4%) of 272 people in the randomised cohort and 17 (17%) of 99 in the non-randomised cohort died; the median baseline CD4 count for participants who died was 11 cells per µL. INTERPRETATION: In heavily treatment-experienced individuals with advanced HIV-1 disease and limited treatment options, fostemsavir-based antiretroviral regimens were generally well tolerated and showed a distinctive trend of increasing virological and immunological response rates through 96 weeks; these findings support fostemsavir as a treatment option for this vulnerable population. FUNDING: ViiV Healthcare.

Fostemsavir in Adults with Multidrug-Resistant HIV-1 Infection.

BACKGROUND: Among some patients with human immunodeficiency virus type 1 (HIV-1) infection who have undergone multiple antiretroviral therapies and have limited options for treatment, new classes of antiretroviral drugs with novel mechanisms of action are needed. Fostemsavir is the prodrug of temsavir, a first-in-class investigational HIV-1 attachment inhibitor. METHODS: In this ongoing phase 3 trial in 23 countries, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to their remaining treatment options. In the first cohort, we assigned (in a 3:1 ratio) patients who had the option of using at least one fully active, approved antiretroviral drug in at least one but no more than two antiretroviral classes to add either fostemsavir (at a dose of 600 mg twice daily) or placebo to their failing regimen for 8 days, followed by open-label fostemsavir plus optimized background therapy (randomized cohort). In the second cohort, patients who had no remaining antiretroviral options were started on open-label fostemsavir plus optimized background therapy on day 1 (nonrandomized cohort). The primary end point was the mean change in the HIV-1 RNA level from day 1 through day 8 in the randomized cohort. RESULTS: A total of 371 patients were treated, including 272 in the randomized cohort and 99 in the nonrandomized cohort. At day 8, the mean decrease in the HIV-1 RNA level was 0.79 log10 copies per milliliter in the fostemsavir group and 0.17 log10 copies in the placebo group (P<0.001). At week 48, a virologic response (HIV-1 RNA level, <40 copies per milliliter) had occurred in 54% of the patients in the randomized cohort and in 38% of those in the nonrandomized cohort; the mean increase in the CD4+ T-cell count was 139 cells per cubic millimeter and 64 cells per cubic millimeter, respectively. Adverse events led to the discontinuation of fostemsavir in 7% of the patients. In the randomized cohort, glycoprotein 120 (gp120) substitutions were found in 20 of 47 patients (43%) with virologic failure. CONCLUSIONS: In patients with multidrug-resistant HIV-1 infection with limited therapy options, those who received fostemsavir had a significantly greater decrease in the HIV-1 RNA level than those who received placebo during the first 8 days. Efficacy was sustained through 48 weeks. (Funded by Bristol-Myers Squibb and GSK/ViiV Healthcare; BRIGHTE ClinicalTrials.gov number, NCT02362503.).

Outcomes Following Dynamic Compression Bracing for Pectus Carinatum.

Introduction: Children with pectus carinatum (PC) are particularly vulnerable to psychosocial effects of poor body image, even though they may not experience physical symptoms. Nonoperative treatment with orthotic bracing is effective in PC correction. We describe our experience with dynamic compression bracing (DCB) for PC patients and their satisfaction with bracing. Materials and Methods: Prospective institutional data of patients undergoing DCB from July 2011 to June 2018 were reviewed and analyzed for those who entered the retainer mode after correction, defined by a correction pressure of <1 psi. A telephone survey was conducted regarding their bracing experience and satisfaction with the outcome on a scale of 1-10. Results: Of 460 PC patients, 144 reached the retainer mode. Median time to retainer mode was 5.5 months. There was no statistically significant relationship between initial correction pressure or carinatum height and time to retainer mode (P = .08 and P = .10, respectively). Fifty-seven percent were compliant with brace use, and median time to retainer mode in this subset was significantly shorter than noncompliant patients (3.5 months versus 10 months, P < .001). Fifty-three percent responded to the survey 13 months [interquartile ratios 3, 33] after the last clinic visit. The main barrier to compliance with wearing the brace was discomfort (37%), while the main motivation for compliance was appearance (58%). All endorsed bracing as worthwhile, with 94% reporting a satisfaction rating of 8 or greater for the correction outcome. Conclusion: DCB is effective in achieving correction of PC in compliant patients. Regardless of time to retainer mode, patients reported high satisfaction with bracing.

Successful Brace Treatment of Pectus Carinatum in Osteogenesis Imperfecta Using the Dynamic Compression System.

Osteogenesis imperfecta (OI) is a genetic disorder of collagen resulting in a "fragile" skeleton with increased fracture risk and other complications, dependent on the specific variant. Pectus deformities of the chest wall, while not common, can be associated with OI. The use of a pectus carinatum brace in a patient with OI poses unknown risks for fractures and adverse treatment outcomes. We successfully applied external compression bracing using the dynamic compression system to one such patient. This case illustrates the ability to treat an OI patient with pectus carinatum using a nonsurgical brace, without complications, resulting in an excellent cosmetic result.

Using Microphone Technology to Improve Speech Perception in Noise in Children with Cochlear Implants.

BACKGROUND: Cochlear implant (CI) users are affected more than their normal hearing (NH) peers by the negative consequences of background noise on speech understanding. Research has shown that adult CI users can improve their speech recognition in challenging listening environments by using dual-microphone beamformers, such as adaptive directional microphones (ADMs) and wireless remote microphones (RMs). The suitability of these microphone technologies for use in children with CIs is not well-understood nor widely accepted. PURPOSE: To assess the benefit of ADM or RM technology on speech perception in background noise in children and adolescents with cochlear implants (CIs) with no previous or current use of ADM or RM. RESEARCH DESIGN: Mixed, repeated measures design. STUDY SAMPLE: Twenty (20) children, ten (10) CI users (mean age 14.3 yrs) who used Advanced Bionics HiRes90K implants with research Naida processors, and ten (10) NH age-matched controls participated in this prospective study. INTERVENTION: CI users listened with an ear-canal level microphone, T-Mic (TM), an ADM, and a wireless RM at different audio-mixing ratios. Speech understanding with five microphone settings (TM 100%, ADM, RM + TM 50/50, RM + TM 75/25, RM 100%) was evaluated in quiet and in noise. DATA COLLECTION AND ANALYSIS: Speech perception ability was measured using children's spondee words to obtain a speech recognition threshold for 80% accuracy (SRT80%) in 20-talker babble where the listener sat in a sound booth 1 m (3.28') from the target speech (front) and noise (behind) to test five microphone settings (TM 100%, ADM, RM + TM 50/50, RM + TM 75/25, RM 100%). Group performance-intensity functions were computed for each listening condition to show the effects of microphone configuration with respect to signal-to-noise ratio (SNR). A difference score (CI Group minus NH Group) was computed to show the effect of microphone technology at different SNRs relative to NH. Statistical analysis using a repeated-measures analysis of variance evaluated the effects of the microphone configurations on SRT80% and performance at SNRs. Between-groups analysis of variance was used to compare the CI group with the NH group. RESULTS: The speech recognition was significantly poorer for children with CI than children with NH in quiet and in noise when using the TM alone. Adding the ADM or RM provided a significant improvement in speech recognition for the CI group over use of the TM alone in noise (mean dB advantage ranged from 5.8 for ADM to 16 for RM100). When children with CI used the RM75 or RM100 in background babble, speech recognition was not statistically different from the group with NH. CONCLUSION: Speech recognition in noise performance improved with the use of ADM and RM100 or RM75 over TM-only for children with CIs. Alhough children with CI remain at a disadvantage as compared with NH children in quiet and more favorable SNRs, microphone technology can enhance performance for some children with CI to match that of NH peers in contexts with negative SNRs.

A Single-Center Experience with Dynamic Compression Bracing for Children with Pectus Carinatum.

OBJECTIVE: Bracing for pectus carinatum (PC) has emerged as an alternative to surgical correction. However, predictive factors for bracing remain poorly understood, as much of the data have been reported from small series. MATERIALS AND METHODS: We reviewed a prospective dataset in patients with PC who underwent dynamic compression bracing (DCB) from July 2011 to July 2016. Bracing was initiated in patients > 10 years of age with a significant PC and desire for bracing. Data were analyzed for those observed two or more times after the brace was fitted to the patient. RESULTS: A total of 503 patients were evaluated for PC and 340 (68%) underwent DCB. Eighty-five percent were males with an average age of 14 ± 2 years. There was a positive correlation of age with pressure of initial correction (PIC, r = 0.2). One patient underwent operative correction as the initial therapy. Two hundred seventeen patients had two or more visits after the patient was fitted for the brace. The mean PIC in this cohort was 4 psi (range: 1.5-7.8), and the median duration of bracing in this group was 16 months (IQR: 7-23 months). One hundred three patients (47%) achieved complete correction after an average bracing time of 7.5 months and were then placed in the retainer mode. Thirty patients successfully completed bracing therapy and required an average of 23 months of therapy (2 months-4 years). No patient recurred after bracing was completed, but one failed bracing and required operative correction. Complications included mechanical problems (8%), skin complications (10%), complaints of tightness (3%), and pain (2%). CONCLUSION: DCB has both early and lasting effects in the correction of PC with minimal complications. Predictive factors for successful resolution of the PC include increased duration of DCB and lower initial PIC.

Clinical evaluation of pazopanib eye drops versus ranibizumab intravitreal injections in subjects with neovascular age-related macular degeneration.

PURPOSE: To evaluate pazopanib eye drops in subjects with active subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). DESIGN: Multicountry, randomized, parallel-group, double-masked, active and placebo-controlled, dose-ranging study of eye drops. PARTICIPANTS: A total of 510 subjects (93% white; 58% female; mean age, 75.3 years) whose AMD was previously managed by anti-vascular endothelial growth factor intravitreal injections. METHODS: Treatments administered for 52 weeks included placebo eye drops instilled 4 times daily (n=73); pazopanib 5 mg/ml instilled 3 (n=72) or 4 times daily (n=74); pazopanib 10 mg/ml instilled 2 (n=73), 3 (n=73), or 4 times daily (n=72); or ranibizumab injection administered once every 4 weeks (n=73). In addition, for all eye drop treatment groups, open-label ranibizumab was administered as needed. MAIN OUTCOME MEASURES: The main outcome measures were best-corrected visual acuity (BCVA) and injection frequency assessed at week 52. Safety was assessed every 4 weeks and pazopanib plasma concentrations were determined at weeks 4 and 24. RESULTS: At week 52, pazopanib, with allowance for as-needed ranibizumab injections, was noninferior to monthly ranibizumab as well as to as-needed ranibizumab administered with placebo eye drops in maintaining BCVA (estimated BCVA gains of 0.3-1.8 vs. 1.4 vs. 0.2 letters, respectively). Pazopanib treatment did not reduce as-needed ranibizumab injections by ≥50% (prespecified efficacy criterion). At week 52, there were no clinically meaningful changes from baseline in retinal thickness or morphology, CNV size, or lesion characteristics on optical coherence tomography or fluorescein angiography. Complement factor H genotype had no effect on the responses to pazopanib and/or ranibizumab (BCVA, injection rate, or optical coherence tomography/fluorescein angiography changes). Steady-state concentrations of pazopanib in plasma seemed to be reached by week 4. The most common ocular adverse events related to pazopanib and ranibizumab were application site pain (3%) and injection site hemorrhage (1%), respectively. No treatment-related serious adverse events were reported. CONCLUSIONS: Pazopanib was well tolerated. Daily pazopanib eye drops in neovascular AMD subjects did not result in therapeutic benefit beyond that obtained with ranibizumab alone.