Psychotherapeutic and Psychiatric Intervention in Patients With COVID-19 and Their Relatives: Protocol for the DigiCOVID Trial

BackgroundThe COVID-19 pandemic is negatively impacting the mental health of both patients with COVID-19 and the general population. As current guidelines are limiting in-person contacts to reduce the spread of the virus, the development of a digital approach to implement in psychiatric and psychological consultations is needed. In this paper, we present the DigiCOVID protocol, a digital approach to offer remote, personalized psychological and psychiatric support to former or current patients with COVID-19 and their relatives.ObjectiveThe main goal of this project is to evaluate the feasibility, acceptability, and usability of the DigiCOVID protocol. Furthermore, we also aim to assess the impact of the abovementioned protocol by means of pre-post changes in psychological clinical variables.MethodsParticipants undergo an initial telephonic screening to ensure inclusion criteria are met. Secondly, participants complete a video-assisted neuropsychological IQ test as well as web-based self-reports of health and general well-being. Participants are then assigned to a psychotherapist who offers 8 teletherapy sessions. At the end of the therapy cycle, the web-based questionnaires are administered for a posttreatment evaluation.ResultsAs of April 2022, we enrolled a total of 122 participants, of which 94 have completed neuropsychological tests and web-based questionnaires.ConclusionsOur study aims at testing the feasibility and preliminary efficacy of DigiCOVID, a remote telemedicine protocol for the improvement of psychological and psychiatric health in patients with COVID-19 and their relatives. To date, the approach used seems to be feasible and highly customizable to patients’ needs, and therefore, the DigiCOVID protocol might pave the way for future telepsychiatry-based interventions.Trial RegistrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT05231018","term_id":"NCT05231018"}}NCT05231018; https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT05231018","term_id":"NCT05231018"}}NCT05231018?term={"type":"clinical-trial","attrs":{"text":"NCT05231018","term_id":"NCT05231018"}}NCT05231018 &draw=2&rank=1International Registered Report Identifier (IRRID)DERR1-10.2196/39080     

Preliminary Study of Colistin versus Colistin plus Fosfomycin for Treatment of Carbapenem-Resistant Acinetobacter baumannii Infections

Ninety-four patients infected with carbapenem-resistant Acinetobacter baumannii were randomized to receive colistin alone or colistin plus fosfomycin for 7 to 14 days. The patients who received combination therapy had a significantly more favorable microbiological response and a trend toward more favorable clinical outcomes and lower mortality than those who received colistin alone. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01297894","term_id":"NCT01297894"}}NCT01297894.)     

Pharmacokinetics of Tedizolid in Subjects with Renal or Hepatic Impairment

Two open-label, single-dose, parallel-group studies were conducted to characterize the pharmacokinetics of the novel antibacterial tedizolid and the safety of tedizolid phosphate, its prodrug, in renally or hepatically impaired subjects. Tedizolid pharmacokinetics in subjects with severe renal impairment without dialysis support was compared with that of matched control subjects with normal renal function. Effects of hemodialysis on tedizolid pharmacokinetics were determined in a separate cohort of subjects undergoing long-term hemodialysis. Effects of hepatic impairment on tedizolid pharmacokinetics were determined in subjects with moderate or severe hepatic impairment and compared with those of matched control subjects with normal hepatic function. Each participant received a single oral (hepatic impairment) or intravenous (renal impairment) dose of tedizolid phosphate at 200 mg; hemodialysis subjects received two doses (separated by 7 days), before and after dialysis, in a crossover fashion. The pharmacokinetics of tedizolid was similar in subjects with severe renal impairment and controls (∼8% lower area under the concentration-time curve [AUC], with a nearly identical peak concentration) and in subjects undergoing hemodialysis before and after tedizolid phosphate administration (∼9% lower AUC, with a 15% higher peak concentration); <10% of the dose was removed during 4 h of hemodialysis. Tedizolid pharmacokinetics was only minimally altered in subjects with moderate or severe hepatic impairment; the AUC was increased approximately 22% and 34%, respectively, compared with that of subjects in the control group. Tedizolid phosphate was generally well tolerated in all participants. These results suggest that tedizolid phosphate dose adjustments are not necessary in patients with any degree of renal or hepatic impairment. (This study has been registered at ClinicalTrials.gov under registration numbers {"type":"clinical-trial","attrs":{"text":"NCT01452828","term_id":"NCT01452828"}}NCT01452828 [renal study] and {"type":"clinical-trial","attrs":{"text":"NCT01431833","term_id":"NCT01431833"}}NCT01431833 [hepatic study].)     

Beijing Genotype of Mycobacterium tuberculosis Is Significantly Associated with High-Level Fluoroquinolone Resistance in Vietnam

Consecutive fluoroquinolone (FQ)-resistant isolates (n = 109) identified at the Pham Ngoc Thach Hospital for Tuberculosis, Ho Chi Minh City, Vietnam, were sequenced in the quinolone resistance-determining regions of the gyrA and gyrB genes and typed by large sequence polymorphism typing and spoligotyping to identify the Beijing genotype of Mycobacterium tuberculosis. Beijing genotype prevalence was compared with 109 consecutive isolates from newly presenting patients with pulmonary tuberculosis from the hospital outpatient department. Overall, 82.6% (n = 90/109) of isolates had mutations in gyrAB. Nine novel mutations were identified in gyrB (S486F, N538T, T539P, D500A, D500H, D500N, G509A, E540V, and E540D). The influence of these novel gyrB mutations on FQ resistance is not proven. The Beijing genotype was significantly associated with FQ resistance (odds ratio [OR], 2.39 [95% confidence interval {CI}, 1.34 to 4.25]; P = 0.003). Furthermore, Beijing genotype FQ-resistant isolates were significantly more likely than FQ-resistant isolates of other genotypes to have gyrA mutations (OR, 7.75 [95% CI, 2.84 to 21.15]; P = 0.0001) and high-level (>8 μg/ml) FQ resistance (OR, 11.0 [95% CI, 2.6 to 47.0]; P = 0.001). The underlying mechanism of the association of the Beijing genotype with high-level FQ resistance in this setting remains to be determined. The association of the Beijing genotype with relatively high-level FQ resistance conferred by specific gyrA mutations reported here is of grave concern given the epidemic spread of the Beijing genotype and the current hopes for shorter first-line treatment regimens based on FQs.Fluoroquinolones (FQs) are the most promising antituberculous therapeutic agents to be developed in 40 years (9, 31). They are widely used for the treatment of multidrug-resistant (MDR) tuberculosis (TB) despite the lack of clinical trials evaluating optimal doses, duration, and combinations (10, 28, 31). Gatifloxacin is currently in phase III trials as a first-line agent to shorten existing treatment regimens from 6 to 4 months (ClinicalTrials.gov identification number {"type":"clinical-trial","attrs":{"text":"NCT00216385","term_id":"NCT00216385"}}NCT00216385 [http://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT00216385","term_id":"NCT00216385"}}NCT00216385]), and moxifloxacin is in phase III trials as a first-line substitute for either ethambutol (ETH) (ClinicalTrials.gov identification number {"type":"clinical-trial","attrs":{"text":"NCT00082173","term_id":"NCT00082173"}}NCT00082173 [http://clinicaltrials.gov/show/{"type":"clinical-trial","attrs":{"text":"NCT00082173","term_id":"NCT00082173"}}NCT00082173]) or isoniazid (INH) (ISRCTN register number 85595810 [http://www.controlled-trials.com/ISRCTN85595810]; ClinicalTrials.gov identification number {"type":"clinical-trial","attrs":{"text":"NCT00144417","term_id":"NCT00144417"}}NCT00144417 [www.clinicaltrials.gov/show/{"type":"clinical-trial","attrs":{"text":"NCT00144417","term_id":"NCT00144417"}}NCT00144417]).There is concern about levels of preexisting FQ-resistant TB in regions with high drug resistance rates because these drugs are often available over the counter and are additionally prescribed as broad-spectrum antibiotics for the treatment of undiagnosed respiratory infections (4, 5, 11, 17, 23, 27, 29).Vietnam has some of the highest primary drug resistance rates for Mycobacterium tuberculosis in the world, with over 35% of primary isolates being resistant to one or more first-line drugs (21, 26). Despite this, MDR TB rates remain relatively low, at 2.7% nationally, and the National Tuberculosis Program has achieved World Health Organization (WHO) targets for the detection and cure of TB for the last 10 years (14). An expanded MDR TB management program (formally DOTS-PLUS) will be piloted in the near future; however, the success of standardized regimens will depend heavily on preexisting levels of resistance to the most effective second-line agents, the FQs. At present, no data exist on FQ-resistant TB in Vietnam.In mycobacteria, the FQs bind to DNA gyrase and inhibit DNA replication. Reports in the literature show that the majority (approximately 60%) of FQ-resistant M. tuberculosis isolates carry mutations in the quinolone resistance-determining region (QRDR) of the gyrA gene, and a small number have mutations in the gyrB gene (10). It was previously postulated that efflux pump mechanisms account for FQ resistance in isolates with wild-type gyrAB genes (6).While adherence remains the single most important factor in the emergence of drug-resistant TB, a factor contributing to the high prevalence of INH and streptomycin (STR) resistance in the region may be the high prevalence of strains of Mycobacterium tuberculosis of the Beijing genotype (1-3). The Beijing genotype first attracted attention as being the genotype of the strain responsible (W strain) for several large outbreaks of MDR TB in the United States in the early 1990s (28). It is associated with drug resistance and MDR in Vietnam (1, 3).This study investigated the prevalence of the Beijing genotype among FQ-resistant isolates from southern Vietnam and the associated genotypic mutations and MICs of ofloxacin.     

Association of Higher Plasma Vitamin D Binding Protein and Lower Free Calcitriol Levels with Tenofovir Disoproxil Fumarate Use and Plasma and Intracellular Tenofovir Pharmacokinetics: Cause of a Functional Vitamin D Deficiency?

Tenofovir disoproxil fumarate (TDF) causes bone, endocrine, and renal changes by an unknown mechanism(s). Data are limited on tenofovir pharmacokinetics and these effects. Using baseline data from a multicenter study of HIV-infected youth on stable treatment with regimens containing TDF (n = 118) or lacking TDF (n = 85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium-parathyroid hormone balance, phosphate metabolism (tubular reabsorption of phosphate and fibroblast growth factor 23 [FGF23]), and bone turnover. Pharmacokinetic-pharmacodynamic associations with plasma tenofovir and intracellular tenofovir diphosphate concentrations were explored among those receiving TDF. The mean age was 20.9 (standard deviation [SD], 2.0) years; 63% were male; and 52% were African American. Compared to the no-TDF group, the TDF group showed lower mean estimated glomerular filtration rates and tubular reabsorption of phosphate, as well as higher parathyroid hormone and 1,25-dihydroxy vitamin D [1,25-OH(2)D] levels. The highest quintile of plasma tenofovir concentrations was associated with higher vitamin D binding protein, lower free 1,25-OH(2)D, higher 25-OH vitamin D, and higher serum calcium. The highest quintile of intracellular tenofovir diphosphate concentration was associated with lower FGF23. Higher plasma tenofovir concentrations were associated with higher vitamin D binding protein and lower free 1,25-OH(2)D, suggesting a functional vitamin D deficiency explaining TDF-associated increased parathyroid hormone. The finding of lower FGF23 accompanying higher intracellular tenofovir diphosphate suggests that different mechanisms mediate TDF-associated changes in phosphate handling. Separate pharmacokinetic properties may be associated with distinct TDF toxicities: tenofovir with parathyroid hormone and altered calcium balance and tenofovir diphosphate with hypophosphatemia and FGF23 regulation.(The clinical trial registration number for this study is {"type":"clinical-trial","attrs":{"text":"NCT00490412","term_id":"NCT00490412"}}NCT00490412 and is available online at http://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT00490412","term_id":"NCT00490412"}}NCT00490412.)     

Tracking tDCS induced grey matter changes in episodic migraine: a randomized controlled trial

BackgroundOccipital transcranial direct current stimulation (tDCS) is an effective and safe treatment for migraine attack prevention. Structural brain alterations have been found in migraineurs in regions related to pain modulation and perception, including occipital areas. However, whether these structural alterations can be dynamically modulated through tDCS treatment is understudied.ObjectiveTo track longitudinally grey matter volume changes in occipital areas in episodic migraineurs during and up to five months after occipital tDCS treatment in a single-blind, and sham-controlled study.Methods24 episodic migraineurs were randomized to either receive verum or sham occipital tDCS treatment for 28 days. To investigate dynamic grey matter volume changes patients underwent structural MRI at baseline (prior to treatment), 1.5 months and 5.5 months (after completion of treatment). 31 healthy controls were scanned with the same MRI protocol. Morphometry measures assessed rate of changes over time and between groups by means of tensor-based morphometry.ResultsBefore treatment, migraineurs reported 5.6 monthly migraine days on average. A cross-sectional analysis revealed grey matter volume increases in the left lingual gyrus in migraineurs compared to controls. Four weeks of tDCS application led to a reduction of 1.9 migraine days/month and was paralleled by grey matter volume decreases in the left lingual gyrus in the treatment group; its extent overlapping with that seen at baseline.ConclusionThis study shows that migraineurs have increased grey matter volume in the lingual gyrus, which can be modified by tDCS. Tracking structural plasticity in migraineurs provides a potential neuroimaging biomarker for treatment monitoring.Trial registrationClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT03237754","term_id":"NCT03237754"}}NCT03237754. Registered 03 August 2017 – retrospectively registered, https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT03237754","term_id":"NCT03237754"}}NCT03237754.     

Platelet Profile in Patients with Acute Bacterial Skin and Skin Structure Infections Receiving Tedizolid or Linezolid: Findings from the Phase 3 ESTABLISH Clinical Trials

Tedizolid, the active moiety of tedizolid phosphate, is a recently approved oxazolidinone antibacterial with activity against a wide range of Gram-positive pathogens, including resistant strains such as methicillin-resistant Staphylococcus aureus. To date, 6 days of 200 mg tedizolid once daily has been shown to be noninferior to 10 days of 600 mg linezolid twice daily in two randomized, double-blind phase 3 trials (ESTABLISH-1 and ESTABLISH-2) for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs). The intent of this study was to characterize the platelet profiles of patients receiving tedizolid relative to linezolid over the course of treatment using pooled data from these two trials. The occurrences of clinically defined and statistical analysis plan–specified reduced platelet counts were assessed at the study days 7 to 9 visit, the study days 11 to 13 visit, and the posttherapy evaluation (PTE) visit. At the study days 7 to 9 visit, incidences of reduced platelet counts were low and largely similar between the groups. The only notable difference was a lower incidence of thrombocytopenia (platelet counts, <150,000 cells/mm³) among patients who received tedizolid (3.2%) relative to those who received linezolid (5.6%). At the study days 11 to 13 visit, patients who received tedizolid had lower incidences of platelet counts of <150,000 cells/mm³ (−5.9%), <112,500 cells/mm³ (−2.4%), and <100,000 cells/mm³ (−1.9%) than patients in the linezolid group. Similar differences were noted at the PTE visit. Findings across the two phase 3 ABSSSI trials suggest that 6 days of 200 mg tedizolid daily confers a low potential for reduced platelet counts among patients with ABSSSIs. (The ESTABLISH-1 and ESTABLISH-2 trials have been registered at ClinicalTrials.gov under registration numbers {"type":"clinical-trial","attrs":{"text":"NCT01170221","term_id":"NCT01170221"}}NCT01170221 and {"type":"clinical-trial","attrs":{"text":"NCT01421511","term_id":"NCT01421511"}}NCT01421511, respectively.)     

Nutrition intervention for migraine: a randomized crossover trial

Background

Limited evidence suggests that dietary interventions may offer a promising approach for migraine. The purpose of this study was to determine the effects of a low-fat plant-based diet intervention on migraine severity and frequency.

Methods

Forty-two adult migraine sufferers were recruited from the general community in Washington, DC, and divided randomly into two groups. This 36-week crossover study included two treatments: dietary instruction and placebo supplement. Each treatment period was 16 weeks, with a 4-week washout between. During the diet period, a low-fat vegan diet was prescribed for 4 weeks, after which an elimination diet was used. Participants were assessed at the beginning, midpoint, and end of each period. Significance was determined using student’s t-tests.

Results

Worst headache pain in last 2 weeks, as measured by visual analog scale, was initially 6.4/10 cm (SD 2.1 cm), and declined 2.1 cm during the diet period and 0.7 cm during the supplement period (p=0.03). Average headache intensity (0–10 scale) was initially 4.2 (SD 1.4) per week, and this declined by 1.0 during the diet period and by 0.5 during the supplement period (p=0.20). Average headache frequency was initially 2.3 (SD 1.8) per week, and this declined by 0.3 during the diet period and by 0.4 during the supplement period (p=0.61). The Patient’s Global Impression of Change showed greater improvement in pain during the diet period (p<0.001).

Conclusions

These results suggest that a nutritional approach may be a useful part of migraine treatment, but that methodologic issues necessitate further research.

Trial registration

Clinicaltrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT01699009","term_id":"NCT01699009"}}NCT01699009 and {"type":"clinical-trial","attrs":{"text":"NCT01547494","term_id":"NCT01547494"}}NCT01547494.     

Effects of Rosuvastatin and Atorvastatin on LDL and HDL Particle Concentrations in Patients With Metabolic Syndrome: A randomized, double-blind, controlled study

OBJECTIVE

The purpose of this study was to examine the effects of statin therapy on lipoprotein particle concentrations in patients with the metabolic syndrome. Changes in lipoprotein particle concentration may predict the risk of coronary heart disease more accurately than lipoprotein cholesterol levels.

RESEARCH DESIGN AND METHODS

Patients with dyslipidemia and the metabolic syndrome (n = 318) were randomly assigned in a double-blind study comparing 10 mg rosuvastatin (RSV), 10 mg atorvastatin, or placebo daily for 6 weeks. From weeks 6 to 12, patients in the RSV and placebo groups received 20 mg RSV, whereas the ATV group increased their dose to 20 mg daily. Lipoprotein particle concentrations were measured by nuclear magnetic resonance spectroscopy, LDL cholesterol was measured by β-quantification, and other lipoproteins were measured by standard methods at baseline, 6 weeks, and 12 weeks. Lipoprotein levels were compared by analysis of covariance.

RESULTS

Statins reduced LDL particle concentration less than LDL cholesterol (−30 to −38 vs. −38 to −51%). Reductions were greater with RSV than with ATV (P < 0.05 for LDL particle concentration and P < 0.001 for LDL cholesterol). Most patients attained LDL cholesterol <2.59 mmol/l (100 mg/dl) at 12 weeks (80% with RSV and 59% with ATV; P = 0.003), but only 27% of patients receiving RSV and 19% receiving ATV attained the goal of LDL particle concentration <1,000 nmol/l (P = 0.07).

CONCLUSIONS

In patients with the metabolic syndrome, statin-induced changes in LDL cholesterol do not accurately reflect changes in LDL particle concentration. Consequently, despite attainment of LDL cholesterol goals, these patients may retain considerable residual coronary heart disease risk.Although LDL cholesterol reduction serves as a cornerstone of prevention of coronary disease (1), the coronary heart disease (CHD) risk may be better predicted by measures of atherogenic particles, such as non–HDL cholesterol (2), apolipoprotein B (apoB) (3), or LDL particle concentration (4–6).Patients with the metabolic syndrome may have relatively normal LDL cholesterol when LDL particle concentration is elevated because these patients have a preponderance of small, cholesterol-poor LDL particles (7). Thus, LDL cholesterol may underestimate risk in patients with the metabolic syndrome (2,8). Likewise, in men with CHD, low HDL cholesterol (≤1.04 mmol/l [40 mg/dl]), and often many other characteristics of the metabolic syndrome, new CHD events were correlated with high LDL particle concentration but not LDL cholesterol, and a low HDL particle concentration was more strongly inversely correlated with CHD events than was HDL cholesterol (5).This exploratory analysis of the Comparative Study with Rosuvastatin in Subjects with Metabolic Syndrome (COMETS, 4522IL/0069) (9) compares the effects of rosuvastatin (RSV) and atorvastatin (ATV) on lipoprotein particle concentrations and cholesterol levels in patients with the metabolic syndrome. We sought to determine the efficacy of statin therapy in achieving LDL cholesterol targets set by the National Cholesterol Education Program Adult Treatment Panel III (ATP III) and the corresponding numbers of patients who achieved LDL particle concentration targets below the 50th percentile (<1,300 nmol/l) and below the 20th percentile (<1,000 nmol/l) based on values established by the Multi-Ethnic Study of Atherosclerosis (MESA) (10).     

Temporal and Seasonal Changes of Genetic Polymorphisms Associated with Altered Drug Susceptibility to Chloroquine,Lumefantrine, and Quinine in Guinea-Bissau between 2003 and 2012

In 2008, artemether-lumefantrine was introduced in Guinea-Bissau, West Africa, but quinine has also been commonly prescribed for the treatment of uncomplicated Plasmodium falciparum malaria. An efficacious high-dose chloroquine treatment regimen was used previously. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine, and quinine have been described. P. falciparum chloroquine resistance transporter (pfcrt) K76T, pfmdr1 gene copy numbers, pfmdr1 polymorphisms N86Y and Y184F, and pfmdr1 sequences 1034 to 1246 were determined using PCR-based methods. Blood samples came from virtually all (n = 1,806) children <15 years of age who had uncomplicated P. falciparum monoinfection and presented at a health center in suburban Bissau (from 2003 to 2012). The pfcrt K76T and pfmdr1 N86Y frequencies were stable, and seasonal changes were not seen from 2003 to 2007. Since 2007, the mean annual frequencies increased (P < 0.001) for pfcrt 76T (24% to 57%), pfmdr1 N86 (72% to 83%), and pfcrt 76 + pfmdr1 86 TN (10% to 27%), and pfcrt 76T accumulated during the high transmission season (P = 0.001). The pfmdr1 86 + 184 NF frequency increased from 39% to 66% (from 2003 to 2011; P = 0.004). One sample had two pfmdr1 gene copies. pfcrt 76T was associated with a lower parasite density (P < 0.001). Following the discontinuation of an effective chloroquine regimen, probably highly artemether-lumefantrine-susceptible P. falciparum (with pfcrt 76T) accumulated, possibly due to suboptimal use of quinine and despite a fitness cost linked to pfcrt 76T. (The studies reported here were registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT00137514","term_id":"NCT00137514"}}NCT00137514 [PSB-2001-chl-amo], {"type":"clinical-trial","attrs":{"text":"NCT00137566","term_id":"NCT00137566"}}NCT00137566 [PSB-2004-paracetamol], {"type":"clinical-trial","attrs":{"text":"NCT00426439","term_id":"NCT00426439"}}NCT00426439 [PSB-2006-coartem], {"type":"clinical-trial","attrs":{"text":"NCT01157689","term_id":"NCT01157689"}}NCT01157689 [AL-eff 2010], and {"type":"clinical-trial","attrs":{"text":"NCT01704508","term_id":"NCT01704508"}}NCT01704508 [Eurartesim 2012].)     

Genotypic and Phenotypic Analyses of Hepatitis C Virus Variants Observed in Clinical Studies of VX-222, a Nonnucleoside NS5B Polymerase Inhibitor

VX-222, a thiophene-2-carboxylic acid derivative, is a selective nonnucleoside inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. In phase 1 and 2 clinical studies, VX-222 demonstrated effective antiviral efficacy, with substantial reductions in plasma HCV RNA in patients chronically infected with genotype 1 HCV. To characterize the potential for selection of VX-222-resistant variants in HCV-infected patients, the HCV NS5B gene was sequenced at baseline and during and after 3 days of VX-222 dosing (monotherapy) in a phase 1 study. Variants with the substitutions L419C/I/M/P/S/V, R422K, M423I/T/V, I482L/N/T, A486S/T/V, and V494A were selected during VX-222 dosing, and their levels declined over time after the end of dosing. Phenotypic analysis of these variants was conducted using HCV replicons carrying site-directed mutations. Of the 17 variants, 14 showed reduced susceptibility to VX-222 compared with the wild type, with the L419C/S and R422K variants having higher levels of resistance (>200-fold) than the rest of the variants (6.8- to 76-fold). The M423I and A486S variants remained susceptible to VX-222. The 50% effective concentration (EC₅₀) for the L419P variant could not be obtained due to the poor replication of this replicon. The majority of the variants (15/17) were less fit than the wild type. A subset of the variants, predominately the L419S and R422K variants, were observed when the efficacy and safety of VX-222- and telaprevir-based regimens given for 12 weeks were investigated in genotype 1 HCV-infected patients in a phase 2 study. The NS3 and NS5B variants selected during the dual combination therapy showed reduced susceptibility to both telaprevir and VX-222 and had a lower replication capacity than the wild type. The phase 1b study has the ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00911963","term_id":"NCT00911963"}}NCT00911963, and the phase 2a study has ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT01080222","term_id":"NCT01080222"}}NCT01080222.     

Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes

BACKGROUND. Mutational inactivation in cancer of key apoptotic pathway components, such as TP53/p53, undermines cytotoxic therapies that aim to increase apoptosis. Accordingly, TP53 mutations are reproducibly associated with poor treatment outcomes. Moreover, cytotoxic treatments destroy normal stem cells with intact p53 systems, a problem especially for myeloid neoplasms, as these cells reverse the low blood counts that cause morbidity and death. Preclinical studies suggest that noncytotoxic concentrations of the DNA methyltransferase 1 (DNMT1) inhibitor decitabine produce p53-independent cell-cycle exits by reversing aberrant epigenetic repression of proliferation-terminating (MYC-antagonizing) differentiation genes in cancer cells.METHODS. In this clinical trial, patients with myelodysplastic syndrome (n = 25) received reduced decitabine dosages (0.1–0.2 mg/kg/day compared with the FDA-approved 20–45 mg/m²/day dosage, a 75%–90% reduction) to avoid cytotoxicity. These well-tolerated doses were frequently administered 1–3 days per week, instead of pulse cycled for 3 to 5 days over a 4- to 6-week period, to increase the probability that cancer S-phase entries would coincide with drug exposure, which is required for S-phase–dependent DNMT1 depletion.RESULTS. The median subject age was 73 years (range, 46–85 years), 9 subjects had relapsed disease or were refractory to 5-azacytidine and/or lenalidomide, and 3 had received intensive chemoradiation to treat other cancers. Adverse events were related to neutropenia present at baseline: neutropenic fever (13 of 25 subjects) and septic death (1 of 25 subjects). Blood count improvements meeting the International Working Group criteria for response occurred in 11 of 25 (44%) subjects and were highly durable. Treatment-induced freedom from transfusion lasted a median of 1,025 days (range, 186–1,152 days; 3 ongoing), and 20% of subjects were treated for more than 3 years. Mutations and/or deletions of key apoptosis genes were frequent (present in 55% of responders and in 36% of nonresponders). Noncytotoxic DNMT1 depletion was confirmed by serial BM γ-H2AX (DNA repair/damage marker) and DNMT1 analyses. MYC master oncoprotein levels were markedly decreased.CONCLUSION. Decitabine regimens can be redesigned to minimize cytotoxicity and increase exposure time for DNMT1 depletion, to safely and effectively circumvent mutational apoptotic defects.TRIAL REGISTRATION. Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01165996","term_id":"NCT01165996"}}NCT01165996.FUNDING. NIH (R01CA138858, {"type":"entrez-nucleotide","attrs":{"text":"CA043703","term_id":"24344623","term_text":"CA043703"}}CA043703); Department of Defense (PR081404); Clinical and Translational Science Award (CTSA) (UL1RR024989); and the Leukemia and Lymphoma Society (Translational Research Program).     

Clinical and In Vitro Resistance to GS-9669, a Thumb Site II Nonnucleoside Inhibitor of the Hepatitis C Virus NS5B Polymerase

Treatment with GS-9669, a novel nonnucleoside inhibitor (site II) of hepatitis C virus (HCV) nonstructural 5B (NS5B) polymerase, resulted in significant antiviral activity in HCV genotype (GT) 1 patients dosed at 50 and 500 mg once daily (QD) and at 50, 100, and 500 mg twice daily (BID) for 3 days. This report characterizes the virologic resistance to GS-9669 in vitro and in GT1 HCV-infected patients from a phase I clinical study. An in vitro resistance selection study with GS-9669 revealed substitutions at several NS5B residues that conferred resistance. The M423 variants were selected at low drug concentrations (5× the 50% effective concentration [EC₅₀]), and the L419, R422, and I482 variants were selected at higher drug concentrations (20× the EC₅₀). During the phase I clinical study, substitutions at NS5B residues 419, 422, and 486 were the predominant changes associated with GS-9669 monotherapy. Substitutions at position 423 were observed only in GT1a patients in the low-dose groups (50 and 100 mg BID). Interestingly, four HCV patients had substitutions at position 423 at baseline. Consistent with the low resistance level at this position, three patients with M423I or M423V at baseline achieved >2-log₁₀ reductions of HCV RNA when treated with 100 mg BID or with 500 mg QD or BID of GS-9669. The fourth patient, who had the M423V substitution at baseline, had a 4.4-log₁₀ reduction of HCV RNA with 500 mg BID of GS-9669. Phenotypic analyses demonstrated that the viral isolates with multiple GS-9669 resistance-associated variants have reduced susceptibility to GS-9669 and lomibuvir (VX-222) but are not cross-resistant to other classes of HCV inhibitors. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01431898","term_id":"NCT01431898"}}NCT01431898.)     

Depot Medroxyprogesterone Acetate in Combination with a Twice-Daily Lopinavir-Ritonavir-Based Regimen in HIV-Infected Women Showed Effective Contraception and a Lack of Clinically Significant Interactions,with Good Safety and Tolerability: Results of the ACTG 5283 Study

We conducted an open-label, steady-state pharmacokinetic (PK) study of drug-drug interactions between depot medroxyprogesterone acetate (DMPA) and twice-daily lopinavir (LPV) plus low-dose ritonavir (RTV) (LPV/r) among 24 HIV-infected women and compared the results to those for HIV-infected women receiving DMPA while on no antiretroviral therapy or on nucleosides only (n = 14 subjects from the control arm of AIDS Clinical Trials Group [ACTG] study 5093). The objectives of the study were to address the effect of LPV/r on DMPA and to address the effect of DMPA on LPV/r therapy. PK parameters were estimated using noncompartmental analysis with between-group comparisons of medroxyprogesterone acetate (MPA) PKs and within-subject comparisons of LPV and RTV PKs before and 4 weeks after DMPA dosing. Plasma progesterone concentrations were measured every 2 weeks after DMPA dosing through week 12. Although the MPA area under the concentration-time curve and maximum concentration of drug in plasma were statistically significantly increased in the study women on LPV/r compared to those in the historical controls, these increases were not considered clinically significant. There were no changes in LPV or RTV exposure after DMPA. DMPA was well tolerated, and suppression of ovulation was maintained. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01296152","term_id":"NCT01296152"}}NCT01296152.)     

A Smartphone-Based Intervention for Anxiety and Depression in Racially and Ethnically Diverse Adults (EASE): Protocol for a Randomized Controlled Trial

BackgroundClear health disparities have emerged in the rates of COVID-19 exposure, hospitalization, and death among Black, Hispanic, and American Indian (BHAI) individuals, relative to non-Hispanic White (NHW) individuals. BHAI populations have been disproportionately affected by lower behavioral health access and heightened negative mental health outcomes during the pandemic.ObjectiveThis project directly addresses health disparities in access to behavioral health care during the COVID-19 pandemic among BHAI populations via an adaptation of the established, initially validated, low-cost, mobile app Easing Anxiety Sensitivity for Everyone (EASE) among individuals with symptoms of elevated anxiety or depression or both.MethodsThe EASE trial is a 2-arm, prospective, randomized, blinded-assessor study with intention-to-treat analysis. Participants (N=800; n=200, 25%, Black; n=200, 25%, Hispanic; n=200, 25%, American Indian; and n=200, 25%, NHW) are randomized to receive either EASE or an active comparison condition for anxiety and depression. Participants compete an online prescreener, an enrollment call to provide informed consent, a baseline survey, a 6-month intervention period, and 3- and 6-month postbaseline assessments. Select participants also complete a 3- and 6-month postbaseline qualitative interview via phone or an online platform (eg, Zoom). Participants complete 2 scheduled daily ecological momentary assessments (EMAs) during the 6-month study period. These twice-daily EMAs guide a just-in-time approach to immediate, personalized behavioral health care.ResultsOutcomes include reductions in anxiety and depressive symptoms and functional impairment at 3 and 6 months postrandomization. We also will examine putative mechanisms (eg, anxiety sensitivity [AS] and COVID-19–specific stress and fear) of the intervention effects. Further, as treatment effects may differ across sociocultural factors, perceived discrimination, social support, and socioeconomic status (SES) will be evaluated as potential moderators of treatment effects on the primary outcomes. Process evaluation using data collected during the study, as well as individual interviews with participants, will complement quantitative data.ConclusionsData from this efficacy trial will determine whether EASE successfully improves symptoms of anxiety and depression and whether these improvements outperform an active comparison control app. If successful, findings from this study have the potential to decrease anxiety and depression symptoms among vulnerable populations determined to be most at risk of exacerbated, long-lasting negative health sequelae. Data from this study may be used to support an implementation and dissemination trial of EASE within real-world behavioral health and social service settings.Trial RegistrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT05074693","term_id":"NCT05074693"}}NCT05074693; https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT05074693","term_id":"NCT05074693"}}NCT05074693International Registered Report Identifier (IRRID)DERR1-10.2196/40713     

Evaluation of Intravenous Anthrax Immune Globulin for Treatment of Inhalation Anthrax

Bacillus anthracis toxins can be neutralized by antibodies against protective antigen (PA), a component of anthrax toxins. Anthrivig (human anthrax immunoglobulin), also known as AIGIV, derived from plasma of humans immunized with BioThrax (anthrax vaccine adsorbed), is under development for the treatment of toxemia following exposure to anthrax spores. The pharmacokinetics (PK) of AIGIV was assessed in naive animals and healthy human volunteers, and the efficacy of AIGIV was assessed in animals exposed via inhalation to aerosolized B. anthracis spores. In the clinical study, safety, tolerability, and PK were evaluated in three dose cohorts (3.5, 7.1, and 14.2 mg/kg of body weight of anti-PA IgG) with 30 volunteers per cohort. The elimination half-life of AIGIV in rabbits, nonhuman primates (NHPs), and humans following intravenous infusion was estimated to be approximately 4, 12, and 24 days, respectively, and dose proportionality was observed. In a time-based treatment study, AIGIV protected 89 to 100% of animals when administered 12 h postexposure; however, a lower survival rate of 39% was observed when animals were treated 24 h postexposure, underscoring the need for early intervention. In a separate set of studies, animals were treated on an individual basis upon detection of a clinical sign or biomarker of disease, namely, a significant increase in body temperature (SIBT) in rabbits and presence of PA in the serum of NHPs. In these trigger-based intervention studies, AIGIV induced up to 75% survival in rabbits depending on the dose and severity of toxemia at the time of treatment. In NHPs, up to 33% survival was observed in AIGIV-treated animals. (The clinical study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT00845650","term_id":"NCT00845650"}}NCT00845650.)     

Randomized Noninferiority Trial of Dihydroartemisinin-Piperaquine Compared with Sulfadoxine-Pyrimethamine plus Amodiaquine for Seasonal Malaria Chemoprevention in Burkina Faso

The WHO recommends that children living in areas of highly seasonal malaria transmission in the Sahel subregion should receive seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine plus amodiaquine (SPAQ). We evaluated the use of dihydroartemisinin-piperaquine (DHAPQ) as an alternative drug that could be used if SPAQ starts to lose efficacy. A total of 1,499 children 3 to 59 months old were randomized to receive SMC with SPAQ or DHAPQ over 3 months. The primary outcome measure was the risk of clinical malaria (fever or a history of fever with a parasite density of at least 3,000/μl). A cohort of 250 children outside the trial was followed up as a control group. Molecular markers of drug resistance were assessed. The risk of a malaria attack was 0.19 in the DHAPQ group and 0.15 in the SPAQ group, an odds ratio of 1.33 (95% confidence interval [CI], 1.02 to 1.72). Efficacy of SMC compared to the control group was 77% (67% to 84%) for DHAPQ and 83% (74% to 89%) for SPAQ. pfdhfr and pfdhps mutations associated with antifolate resistance were more prevalent in parasites from children who received SPAQ than in children who received DHAPQ. Both regimens were highly efficacious and well tolerated. DHAPQ is a potential alternative drug for SMC. (This trial is registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT00941785","term_id":"NCT00941785"}}NCT00941785.)     

Clinical Pharmacodynamic Index Identification for Micafungin in Esophageal Candidiasis: Dosing Strategy Optimization

Echinocandins exhibit concentration-dependent effects on Candida species, and preclinical studies support the administration of large, infrequent doses. The current report examines the pharmacokinetics/pharmacodynamics of two multicenter, randomized trials of micafungin dosing regimens that differed in both dose level and dosing interval. Analysis demonstrates the clinical relevance of the dose level and area under the concentration-time curve (AUC). Better, although not statistically significant (P = 0.056), outcomes were seen with higher maximum concentrations of drug in serum (C_max) and large, infrequent doses. The results support further clinical investigation of novel micafungin dosing regimens with large doses but less than daily administration. (These studies have been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT00666185","term_id":"NCT00666185"}}NCT00666185 and {"type":"clinical-trial","attrs":{"text":"NCT00665639","term_id":"NCT00665639"}}NCT00665639.)     

Functionality,satisfaction, and global impression of change with ubrogepant for the acute treatment of migraine in triptan insufficient responders: a post hoc analysis of the ACHIEVE I and ACHIEVE II randomized trials

BackgroundTriptans are the first-line option for the acute treatment of migraine attacks; however, triptans are contraindicated in people with certain underlying cardiovascular risk factors and are associated with inadequate efficacy or poor tolerability in some individuals. Ubrogepant is an oral calcitonin gene–related peptide receptor antagonist approved for the acute treatment of migraine.MethodsThis post hoc analysis of the phase 3 ACHIEVE trials examined the impact of ubrogepant on the Functional Disability Scale (FDS), satisfaction with medication, and Patient Global Impression of Change (PGIC) in participants who were self-reported triptan insufficient responders (TIRs), defined as those who are unable to take triptans due to contraindications, tolerability issues, or insufficient efficacy. Responder definitions for the FDS, satisfaction measures, and PGIC were based on qualitative interpretation of the respective response options for the pooled ubrogepant 50 mg and placebo groups.ResultsIn the pooled analysis population (n = 1799), 451 (25%) participants were TIRs, with most (80%) reporting insufficient efficacy with triptan use. A significantly higher proportion of TIRs treated with ubrogepant vs placebo reported being able to function normally from 2 to 8 h post dose (P < 0.05). Notably, significance was demonstrated at the time of the primary outcome assessments (2 h post dose), where rates of normal function were 38% for ubrogepant vs 29% for placebo (P = 0.048). A greater proportion of TIRs in the ubrogepant arm vs the placebo arm were satisfied with treatment at 2 (33% vs 21%, P = 0.006) and 24 h (58% vs 28%, P < 0.001) and indicated that their migraine improved at 2 h vs placebo (30% vs 18%, P = 0.006). Results were generally similar in the insufficient efficacy subpopulation of TIRs as in the overall TIRs group. Ubrogepant was safe and well tolerated in TIRs, with no new safety signals identified.ConclusionsIn people with migraine who are TIRs, individuals treated with ubrogepant had favorable 2-h outcomes, as measured by the FDS, satisfaction with medication, and PGIC, compared with placebo.Trial registrationClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT02828020","term_id":"NCT02828020"}}NCT02828020 (ACHIEVE I), registered July 11, 2016; {"type":"clinical-trial","attrs":{"text":"NCT02867709","term_id":"NCT02867709"}}NCT02867709 (ACHIEVE II), registered August 16, 2016.