Pharmacokinetics and Safety of Remdesivir in Pregnant and Non-Pregnant Women with COVID-19: Results from IMPAACT 2032.

BACKGROUND: Pregnant people with COVID-19 experience higher risk for severe disease and adverse pregnancy outcomes, but no pharmacokinetic (PK) data exist to support dosing of COVID-19 therapeutics during pregnancy. We report PK and safety data for intravenous remdesivir in pregnancy. METHODS: IMPAACT 2032 was a phase IV prospective, open-label, non-randomized opportunistic study of hospitalized pregnant and non-pregnant women receiving intravenous remdesivir as part of clinical care. Intensive PK sampling was performed on infusion days 3, 4, or 5 with collection of plasma and peripheral blood mononuclear cells (PBMCs). Safety data were recorded from first infusion through 4 weeks post-last infusion and at delivery. Geometric mean ratios (GMR) (90% confidence intervals [CI]) of PK parameters between pregnant and non-pregnant women were calculated. RESULTS: Fifty-three participants initiated remdesivir (25 pregnant; median (IQR) gestational age 27.6 (24.9, 31.0) weeks). Plasma exposures of remdesivir, its two major metabolites (GS-704277 and GS-441524), and the free remdesivir fraction were similar between pregnant and non-pregnant participants. Concentrations of the active triphosphate (GS-443902) in PBMCs increased 2.04-fold (90% CI 1.35, 3.03) with each additional infusion in non-pregnant versus pregnant participants. Three adverse events in non-pregnant participants were related to treatment (one Grade 3; two Grade 2 resulting in treatment discontinuation). There were no treatment-related adverse pregnancy outcomes or congenital anomalies detected. CONCLUSIONS: Plasma remdesivir PK parameters were comparable between pregnant and non-pregnant women, and no safety concerns were identified based on our limited data. These findings suggest no dose adjustments are indicated for intravenous remdesivir during pregnancy.

Patient Engagement in and Adaptations to Delivery of Outpatient Care for Opioid Use Disorder During the COVID-19 Pandemic.

OBJECTIVE: The authors investigated adaptations to outpatient care delivery and changes in treatment demand and engagement among patients receiving medications for opioid use disorder (MOUD) in the months after the declaration of the COVID-19 public health emergency in 2020. METHODS: Data were collected through an online survey (June-November 2020) of outpatient MOUD prescribers. The survey obtained information on outpatient practices' adaptations to MOUD treatment and urine drug screening (UDS) and elicited provider views on the effects of the COVID-19 pandemic on patient demand for, and engagement in, treatment. Multivariable regression analyses were used to examine associations among practice characteristics, patient engagement, and service adaptations. RESULTS: Of 516 respondents, 74% reported adaptations to MOUD delivery during the pandemic. Most respondents implemented virtual visits for initial (67%) and follow-up (77%) contacts. Prescribers of buprenorphine were more likely than those who did not prescribe the medication to report MOUD adaptations. Among respondents reporting any MOUD adaptation, 77% made adaptations to their UDS practices. Among 513 respondents who answered COVID-19-related questions, 89% reported that the pandemic had affected the treatment and engagement of their patients. Of these respondents, 30% reported increased difficulty with patient engagement, and 45% reported that their patients preferred virtual visits during this period, whereas 18% endorsed patient preference for in-person visits. CONCLUSIONS: Telehealth and federal regulatory easements in response to the COVID-19 pandemic enabled providers to continue treating patients for opioid use disorder in 2020. The results suggest that care adaptations and changes in patient demand and engagement were common in the practices surveyed.

DSM-5-TR: Rationale, Process, and Overview of Changes.

The DSM-5 text revision (DSM-5-TR) is the first published revision of the DSM-5 since its publication in 2013. Like the previous text revision (DSM-IV-TR), the main goal of the DSM-5-TR is to comprehensively update the descriptive text accompanying each DSM disorder on the basis of reviews of the literature over the past 10 years. In contrast to the DSM-IV-TR, in which updates were confined almost exclusively to the text, the DSM-5-TR includes many other changes and enhancements of interest to practicing clinicians, such as the addition of diagnostic categories (prolonged grief disorder, stimulant-induced mild neurocognitive disorder, unspecified mood disorder, and a category to indicate the absence of a diagnosis); the provision of ICD-10-CM symptom codes for reporting suicidal and nonsuicidal self-injurious behavior; modifications, mostly for clarity, of the diagnostic criteria for more than 70 disorders; and updates in terminology (e.g., replacing "neuroleptic medications" with "antipsychotic medications or other dopamine receptor blocking agents" throughout the text and replacing "desired gender" with "experienced gender" in the text for gender dysphoria). Finally, the entire text was reviewed by an Ethnoracial Equity and Inclusion Work Group to ensure appropriate attention to risk factors such as the experience of racism and discrimination, as well as the use of nonstigmatizing language.

Physiologically-based pharmacokinetic modeling of remdesivir and its metabolites in pregnant women with COVID-19.

Pregnant individuals are at high risk for severe illness from COVID-19, and there is an urgent need to identify safe and effective therapeutics for this population. Remdesivir (RDV) is a SARS-CoV-2 nucleotide analog RNA polymerase inhibitor. Limited RDV pharmacokinetic (PK) and safety data are available for pregnant women receiving RDV. The aims of this study were to translate a previously published nonpregnant adult physiologically based PK (PBPK) model for RDV to pregnancy and evaluate model performance with emerging clinical PK data in pregnant women with COVID-19. The pregnancy model was built in the Open Systems Pharmacology software suite (Version 10) including PK-Sim® and MoBi® with pregnancy-related changes of relevant enzymes applied. PK were predicted in a virtual population of 1000 pregnant subjects, and prediction results were compared with in vivo PK data from the International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network  2032 study. The developed PBPK model successfully captured RDV and its metabolites' plasma concentrations during pregnancy. The ratios of prediction versus observation for RDV area under the curve from time 0 to infinity (AUC0-∞ ) and maximum concentration (Cmax ) were 1.61 and 1.17, respectively. For GS-704277, the ratios of predicted versus observed were 0.94 for AUC0-∞ and 1.20 for Cmax . For GS-441524, the ratios of predicted versus observed were 1.03 for AUC0-24 , 1.05 for Cmax , and 1.07 for concentrations at 24 h. All predictions of AUC and Cmax for RDV and its metabolites were within a twofold error range, and about 60% of predictions were within a 10% error range. These findings demonstrate the feasibility of translating PBPK models to pregnant women to potentially guide trial design, clinical decision making, and drug development.

Screening chimeric GAA variants in preclinical study results in hematopoietic stem cell gene therapy candidate vectors for Pompe disease.

Pompe disease is a rare genetic neuromuscular disorder caused by acid α-glucosidase (GAA) deficiency resulting in lysosomal glycogen accumulation and progressive myopathy. Enzyme replacement therapy, the current standard of care, penetrates poorly into the skeletal muscles and the peripheral and central nervous system (CNS), risks recombinant enzyme immunogenicity, and requires high doses and frequent infusions. Lentiviral vector-mediated hematopoietic stem and progenitor cell (HSPC) gene therapy was investigated in a Pompe mouse model using a clinically relevant promoter driving nine engineered GAA coding sequences incorporating distinct peptide tags and codon optimizations. Vectors solely including glycosylation-independent lysosomal targeting tags enhanced secretion and improved reduction of glycogen, myofiber, and CNS vacuolation in key tissues, although GAA enzyme activity and protein was consistently lower compared with native GAA. Genetically modified microglial cells in brains were detected at low levels but provided robust phenotypic correction. Furthermore, an amino acid substitution introduced in the tag reduced insulin receptor-mediated signaling with no evidence of an effect on blood glucose levels in Pompe mice. This study demonstrated the therapeutic potential of lentiviral HSPC gene therapy exploiting optimized GAA tagged coding sequences to reverse Pompe disease pathology in a preclinical mouse model, providing promising vector candidates for further investigation.

Climate change and mental health research methods, gaps, and priorities: a scoping review.

Research on climate change and mental health is a new but rapidly growing field. To summarise key advances and gaps in the current state of climate change and mental health studies, we conducted a scoping review that comprehensively examined research methodologies using large-scale datasets. We identified 56 eligible articles published in Embase, PubMed, PsycInfo, and Web of Science between Jan 1, 2000, and Aug 9, 2020. The primary data collection method used was surveys, which focused on self-reported mental health effects due to acute and subacute climate events. Other approaches used administrative health records to study the effect of environmental temperature on hospital admissions for mental health conditions, and national vital statistics to assess the relationship between environmental temperature and suicide rates with regression analyses. Our work highlights the need to link population-based mental health outcome databases to weather data for causal inference. Collaborations between mental health providers and data scientists can guide the formation of clinically relevant research questions on climate change.

A Crosswalk Study of DSM-IV and DSM-5 Criteria for PTSD from the DSM-5 Field Trials.

Objective: Posttraumatic stress disorder (PTSD) is prevalent and sometimes severely disabling. Providing effective treatment for PTSD and addressing its social consequences require accurate diagnosis. PTSD criteria have changed in all editions of the American Diagnostic Criteria since introduction of the diagnosis in DSM-III in 1980. The DSM-5 Field Trials demonstrated very good inter-rater reliability for PTSD, but a crosswalk study comparing DSM-IV and DSM-5 criteria has potential to identify diagnostic differences generated by changed criteria. Methods: A DSM-IV to DSM-5 PTSD crosswalk study was conducted in real-world adult clinical treatment settings in two DSM-5 Field Trials sites, the Dallas (N = 93) and Houston (N = 48) Veterans Affairs medical centers. The crosswalk assessment was conducted by trained clinicians who interviewed the patients and rated both sets of criteria on a combined checklist. Results: PTSD prevalence differed insubstantially between criteria sets (42% vs. 45% and 55% vs. 52% in the Dallas and Houston sites, respectively), with moderate to excellent diagnostic agreement (reliability indicated, respectively, by κ = .53 and .93); however, substantial proportions of individuals diagnosed in one criteria set did not meet criteria in the other. Differences in cross-criteria diagnostic reliability were largely a function of differing definitions of criterion A trauma. Conclusions: Reliability across the two criteria sets was generally good to excellent, and diagnostic discrepancy predominantly reflected the elimination of criterion A2 in DSM-5 with a smaller contribution from changes to the avoidance and numbing criteria.

Optimizing Dolutegravir Initiation in Neonates Using Population Pharmacokinetic Modeling and Simulation.

BACKGROUND: A knowledge gap exists for dolutegravir (DTG) pharmacokinetics and safety during the first 4 weeks of life, preventing safe and effective DTG use in neonates. SETTING: Population pharmacokinetic modeling and simulation were used to assess newborn DTG dosing requirements during the first few days of life as a function of maternal DTG dosing history before delivery. METHODS: DTG PK data were obtained from pregnant women and infants enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026S study. Maternal and neonate population pharmacokinetic models were separately developed. Monte Carlo simulations were performed to simulate neonatal concentrations after 2 doses of DTG after birth for infants born to mothers either receiving or not receiving DTG before delivery. RESULTS: In DTG-naïve infants, a 5-mg DTG dose at birth with a second dose after 48 hours maintained median concentrations above the lower bound of the target range (0.77 µg/mL) and below the upper bound of the target range (7.34 µg/mL representing 2-fold above the adult Cmax value). In DTG-exposed infants, a 5-mg DTG dose at 24 hours after birth with a second dose after 48 hours maintained median concentrations within or nearly within the target range, even if the last maternal DTG dose was taken as soon as 6 hours or as long as 24 hours before delivery. CONCLUSIONS: Newborn DTG dosing requirements during the first few days of life depend on maternal DTG dosing history before delivery. These results may help the design of future clinical studies of DTG in the neonatal population.

Climate Change and Mental Health: Implications for the Psychiatric Workforce.

Climate change is a major global public mental health crisis that is expected to increase the need for mental health services. Psychiatrists and other mental health care providers must address workforce needs through recruitment, training and education, prevention and intervention, public policy and advocacy, and direct efforts to reduce climate change. This column discusses concrete steps for the psychiatric workforce to take to prepare for growing mental health needs associated with climate change.

Strategies to aid self-isolation and quarantine for individuals with severe and persistent mental illness during the COVID-19 pandemic: A systematic review.

BACKGROUND: Individuals with severe and persistent mental illness (SPMI) have a higher risk of contracting COVID-19 than individuals without SPMI. In combination with physical distancing, hygiene protocols, and vaccines, quarantine and self-isolation are primary means of viral containment. However, individuals with SPMI may experience more difficulties with mandated quarantine or self-isolation because of their illness(es), stigma, and marginalization. To date, there is a lack of consensus on strategies that could aid such individuals in completing isolation. AIM: This review aimed to synthesize evidence for interventions to support self-isolation and mandated quarantine for COVID-19 among individuals with SPMIs. METHODS: We followed the PRISMA guidelines, searching 19 electronic databases (9 published literature registries and 10 gray literature sources). We looked for relevant randomized controlled trials, quasi-experimental studies, and program evaluations of the effectiveness of relevant psychosocial, pharmacological, harm reduction, and addiction management strategies to support isolation settings or quarantine requirements for individuals with any SPMI (e.g., any mental disorder, substance use disorder, or their combination). FINDINGS: Of 10,298 total records that were located, 5582 were duplicate citations. Upon screening the remaining 4716 unique records by title and abstract, we excluded a further 3562 records. Only one original article met our inclusion criteria after reviewing the full texts of the remaining 1154 citations. To support individuals experiencing homelessness during the COVID-19 pandemic, San Francisco developed an isolation hotel that reduced COVID-19 hospital strain for 1009 participants (25% had a mental health disorder and 26% had a substance use disorder). While 81% completed their hotel stay, 48 patients had behavioral health needs that exceeded the hotel's capabilities. No other studies met our review's eligibility criteria. Most articles located by the search simply proposed solutions or discussed the challenges brought by COVID-19 for people with SPMIs. While some documents went a step further (e.g., shelter guidance documents to support individuals experiencing homelessness), these rarely addressed individuals with SPMIs directly. CONCLUSIONS: This systematic review evaluated evidence from published and gray literature on interventions to support self-isolation and mandated COVID-19 quarantine for individuals with SPMIs. Only one study met our inclusion criteria. This study found a beneficial effect of a dedicated isolation hotel for individuals experiencing homelessness and COVID-19-where approximately 25%-50% of the study sample had a mental or substance use disorder. While there has been an abundance of COVID-19 protocols in general, information for SPMIs is lacking. As the pandemic continues and we better prepare for future pandemics, developing protocols for supporting SPMIs in this context is imperative.

An Ecological Study of a Universal Employee Depression Awareness and Stigma Reduction Intervention: "Right Direction".

Objective: Right Direction (RD) was a component of a universal employee wellness program implemented in 2014 at Kent State University (KSU) to increase employees' awareness of depression, reduce mental health stigma, and encourage help-seeking behaviors to promote mental health. We explored changes in mental health care utilization before and after implementation of RD. Methods: KSU Human Resources census and service use data were used to identify the study cohort and examine the study objectives. A pre-post design was used to explore changes in mental health utilization among KSU employees before and after RD. Three post-intervention periods were examined. A generalized linear mixed model approach was used for logistic regression analysis between each outcome of interest and intervention period, adjusted by age and sex. Logit differences were calculated for post-intervention periods compared to the pre-intervention period. Results: Compared to the pre-intervention period, the predicted proportion of employees seeking treatment for depression and anxiety increased in the first post-intervention period (OR = 2.14, 95% Confidence Interval [CI] = 1.37-3.34), then declined. Outpatient psychiatric treatment utilization increased significantly in the first two post-intervention periods (OR =1.89, 95% CI = 1.23-2.89; OR = 1.75, 95% CI = 1.11-2.76). No difference was noted in inpatient psychiatric treatment utilization across post-intervention periods. Unlike prescription for anxiolytic prescriptions, receipt of antidepressant prescriptions increased in the second (OR = 2.25, 95% CI = 1.56-3.27) and third (OR = 2.16, 95% CI = 1.46-3.20) post-intervention periods. Conclusions: Effects of RD may be realized over the long-term with follow-up enhancements such as workshops/informational sessions on mindfulness, stress management, resiliency training, and self-acceptance.

Addiction Medicine Practice-Based Research Network (AMNet): Assessment Tools and Quality Measures.

INTRODUCTION: The need for innovative approaches to address the opioid epidemic in the United States is widely recognized. Many challenges exist to addressing this epidemic, including the obstacles outpatient substance use treatment practices face in implementing measurement-based care (MBC), quality measurement systems, and evidence-based treatments. Also, there are insufficient opportunities for clinicians in these settings to participate in research, resulting in diminished translation of research findings into community-based practice. To address these challenges, the Addiction Medicine Practice-Based Research Network (AMNet) was developed to facilitate the uptake of MBC in outpatient practices via implementation of patient-reported assessments and quality of care performance measures to improve patient outcomes. This network will offer clinicians in outpatient settings (not incuding opioid treatment programs [OTPs]) the opportunity to participate in future substance use disorder treatment research studies. METHODS: A key step in the development of AMNet was the selection of substance use-specific assessment tools and quality of care performance measures for incorporation into the American Psychiatric Association's mental health patient registry, PsychPRO. A scoping review and multi-step consensus-based process were used to identify, review and select candidate assessment tools and quality of care performance measures for opioid use disorders (OUD) and substance use disorders (SUD). RESULTS: Following a consensus-based methodology, 12 standardized assessment tools and 3 quality of care performance measures for OUD and SUD were selected to help facilitate the implementation of MBC and quality improvement for AMNet participants. These tools were further categorized as core and optional. CONCLUSION: By offering a collection of carefully vetted assessment tools and quality measures through PsychPRO, AMNet will help participating clinicians with the systematic uptake of MBC and delivery of evidence-based treatment for patients with SUD. Also, AMNet will act as a centralized repository of data collected from patients and clinicians in non-OTP outpatient addiction medicine practices and serve as a platform for opioid treatment research.

Addiction Medicine Practice-Based Research Network (AMNet): Building Partnerships.

This column describes the collaboration among the American Psychiatric Association (APA), American Society of Addiction Medicine, Friends Research Institute, and the National Institute on Drug Abuse to create the Addiction Medicine Practice-Based Research Network (AMNet). The collaboration, which aims to address the opioid overdose epidemic in the United States, leverages the APA's clinical data registry (PsychPRO) and is recruiting office-based addiction medicine and addiction psychiatry practices for AMNet. AMNet aims to address knowledge gaps regarding patient care in such practices, facilitate performance improvement efforts, and serve as a research platform.

"Meds-in-Hand" Intervention to Reduce Critical Process Delays in Pediatric Human Immunodeficiency Virus Post-Exposure Prophylaxis.

Pediatric human immunodeficiency virus post-exposure prophylaxis is frequently indicated, but delays in medication receipt are common. Using plan-do-study-act cycles, we developed a multidisciplinary collaboration to reduce critical process delays in our pediatric emergency department. Interruptions decreased from a median 1 per month pre-intervention to zero per month during the intervention.

Suicide in the Time of COVID-19: Review and Recommendations.

The coronavirus (COVID-19) pandemic presents us with unusual challenges to the global health system and economics. The pandemic may not have an immediate impact on suicide rates, however, given that it is likely to result in a confluence of risk factors for suicide and economic crisis, it is highly possibly that it will lead to increases in suicide rates in the long-run. Elderly persons are more likely to live alone, be socially isolated during COVID-19 and have physical health problems, which are risk factors for suicide. Young children and health professionals may also be population at risk. Isolation, quarantine and the economic crisis that follows may impact mental health significantly. The International Academy of Suicide Research (IASR) is an organization dedicated to promote high standards of research and scholarship in the field of suicidal behaviour to support efforts to prevent suicide globally. This IASR's board position paper gives recommendations for suicide research during the COVID-10 pandemic. Clinical research has to be modified due to COVID-19 shutdown.

Impact of Low Birth Weight and Prematurity on Neonatal Raltegravir Pharmacokinetics: Impaact P1097.

BACKGROUND: HIV treatment of neonates requires identifying appropriate antiretroviral dosing regimens. Our aims were to characterize raltegravir elimination kinetics in low birth weight (LBW) neonates after maternal dosing and to develop a pharmacokinetic model to predict raltegravir plasma concentrations for term and preterm neonates. METHODS: Mothers living with HIV who received raltegravir during pregnancy and their LBW neonates participated in IMPAACT P1097 study. Up to 6 serial plasma samples were collected from each infant over the first 2 postnatal weeks to characterize raltegravir elimination. Safety laboratory evaluations were obtained, and infants were monitored for 6 weeks for signs of raltegravir toxicity. An integrated maternal-neonatal pharmacokinetic model was developed to predict neonatal raltegravir plasma concentrations. RESULTS: Sixteen mothers and their 18 LBW neonates were enrolled. The median (range) raltegravir elimination half-life was 24.4 (10.1-83) hours (N = 17 neonates). No adverse events related to raltegravir in utero exposure were observed. Pharmacokinetic modeling revealed that raltegravir clearance in full-term LBW neonates was well described by allometric scaling but clearance in preterm LBW neonates was better described using slower clearance maturation kinetics. Simulations suggest receipt of the current dosing recommendations in a 34-week gestation neonate would result in plasma concentrations up to 2.5-fold higher than those observed in full-term LBW infants. CONCLUSIONS: Modeling suggests that prematurity reduces raltegravir clearance and a modified raltegravir dosing regimen will be necessary to avoid elevated plasma raltegravir concentrations.

Proxy WHO Disability Assessment Schedule 2.0 Is Clinically Useful for Assessing Psychosocial Functioning in Severe Mental Illness.

AIMS: This study explores how well the World Health Organization Disability Assessment Schedule (WHODAS 2.0) assesses problems with psychosocial functioning in patients with severe mental illness (SMI). Further, we assessed the relationships between psychosocial functioning and psychopathology, medication side effects, treatment setting, and quality of life. METHODS: We performed an observational, cross-sectional study on the island of Curaçao to assess psychosocial functioning in 77 patients with SMI; they mainly had psychotic disorders. We interviewed their healthcare providers using the proxy version of the WHODAS 2.0. In addition, patients were examined for psychiatric symptoms, medication side effects (including drug-induced movement disorders), and quality of life. Associations were examined with Spearman's rank correlation (ρ). RESULTS: Difficulties in psychosocial functioning were reported by patients with SMI in the WHODAS 2.0 domains of understanding and communicating [mean (M)=34.5, standard deviation (SD)=18.6), participation in society (M=25.5, SD=15.6), and getting along with people (M=24.1, SD=16.1)]. Notably, outpatients had more problems participating in society than inpatients (M=33.6, SD=18.5 versus M=23.2, SD=14.1, p=0.03). A positive correlation was observed between drug-induced parkinsonism and the WHODAS 2.0 total score (ρ =0.30; p=0.02), as well as with various subscales, getting around, and household activities. CONCLUSION: The proxy version of the WHODAS 2.0 is clinically useful for patients with severe mental illness. The highest scores on the WHODAS 2.0 were found in domains related to interactions with other people and to participation in society. Inpatient status appeared to aid participation in society; this might be due to living in the sheltered clinic environment and its associated daily activities. We further found that drug-induced parkinsonism was associated with a broad spectrum of psychosocial disabilities. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02713672; retrospectively registered in February 2016.

Raltegravir (RAL) in Neonates: Dosing, Pharmacokinetics (PK), and Safety in HIV-1-Exposed Neonates at Risk of Infection (IMPAACT P1110).

BACKGROUND: Adequate pharmacokinetic and safety data in neonates are lacking for most antiretroviral agents. Raltegravir is a selective HIV-1 integrase strand transfer inhibitor available in a granule formulation suitable for use in neonates and young infants as prophylaxis or treatment of HIV infection. METHODS: IMPAACT P1110 is a phase 1, multicenter, noncomparative dose-finding study of raltegravir in infants exposed to HIV-1 infection. A 2-cohort adaptive design was utilized where pharmacokinetic data from infants in cohort 1 who received 2 single doses of raltegravir 3 mg/kg were included in population modeling and simulations to guide selection of a daily dose for infants in cohort 2. RESULTS: A total of 52 infants enrolled in IMPAACT 1110: cohort 1 (N = 16) and cohort 2 (N = 36). Using simulations based on population PK modeling incorporating cohort 1 data, the following daily dosing regimen was selected for study: 1.5 mg/kg daily from birth through day 7; 3 mg/kg twice daily from days 8-28 of life; and 6 mg/kg twice daily after 4 weeks of age through 6 weeks of age. The geometric mean protocol exposure targets for AUC, Ctrough, and Cmax were met or slightly exceeded in all infants. The chosen neonatal raltegravir dosing regimen was safe and well tolerated in full-term neonates during treatment over the first 6 weeks of life and follow-up to age 24 weeks. CONCLUSIONS: Raltegravir can be safely administered to full-term infants using the daily dosing regimen studied. This regimen is not recommended for use in premature infants in a new version of P1110.

Acceptability and Feasibility of Using Raltegravir Oral Granules for the Treatment of Neonates in a Low-resource Setting.

BACKGROUND: Raltegravir granules for oral suspension, now recommended by World Health Organization for use in neonates with HIV infection, may be challenging for caregivers because of the multistep preparation required. METHODS: We evaluated the acceptability and feasibility of preparing granules for oral suspension in a low-to-middle-income country setting. Thirty-four caregivers and 10 health-care workers were enrolled from an HIV clinic in Durban, South Africa. Health-care workers were provided with pictorial instruction booklet, demonstration kit and guidance on preparation of granules for oral suspension. The health-care workers then trained caregivers on the preparation of granules for oral suspension. Caregivers were evaluated during the preparation process and instructed to practice at home with a sample kit and return to the clinic for repeat evaluation 5-7 days later. Caregivers and health-care workers were interviewed and participated in a focus group discussion regarding their experiences. RESULTS: The median age of the caregivers was 31 years (interquartile range: 9.7); 70% had received secondary-level education, 37% were employed. The median preparation time was 7.95 minutes (interquartile range: 5.08 minutes) and 7.48 minutes (3.55 minutes) at initial and repeated observation, respectively. Major errors were insufficient mixing time and incorrect suspension volume. The average number of errors between the 2 observation time points was significantly reduced at the repeat session (2.5 vs. 0.87, P = 0.023). Most participants found the preparation difficult at first but gained confidence over time. CONCLUSION: Despite the complexity involved in the preparation of the granules for oral suspension, with practice, this formulation was found to be acceptable and feasible to majority of participants in this low-resource setting. As a result, this formulation was included in the 2018 World Health Organization recommendations for first line in neonates living with HIV.