One Week of Oral Camostat Versus Placebo in Nonhospitalized Adults With Mild-to-Moderate Coronavirus Disease 2019: A Randomized Controlled Phase 2 Trial.

BACKGROUND: Camostat inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vitro. We studied the safety and efficacy of camostat in ACTIV-2/A5401, a phase 2/3 platform trial of therapeutics for COVID-19 in nonhospitalized adults. METHODS: We conducted a phase 2 study in adults with mild-to-moderate COVID-19 randomized to oral camostat for 7 days or a pooled placebo arm. Primary outcomes were time to improvement in COVID-19 symptoms through day 28, proportion of participants with SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) from nasopharyngeal swabs through day 14, and grade ≥3 treatment-emergent adverse events (TEAEs) through day 28. RESULTS: Of 216 participants (109 randomized to camostat, 107 to placebo) who initiated study intervention, 45% reported ≤5 days of symptoms at study entry and 26% met the protocol definition of higher risk of progression to severe COVID-19. Median age was 37 years. Median time to symptom improvement was 9 days in both arms (P = .99). There were no significant differences in the proportion of participants with SARS-CoV-2 RNA

Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2022 Recommendations of the International Antiviral Society-USA Panel.

Importance: Recent advances in treatment and prevention of HIV warrant updated recommendations to guide optimal practice. Objective: Based on a critical evaluation of new data, to provide clinicians with recommendations on use of antiretroviral drugs for the treatment and prevention of HIV, laboratory monitoring, care of people aging with HIV, substance use disorder and HIV, and new challenges in people with HIV, including COVID-19 and monkeypox virus infection. Evidence Review: A panel of volunteer expert physician scientists were appointed to update the 2020 consensus recommendations. Relevant evidence in the literature (PubMed and Embase searches, which initially yielded 7891 unique citations, of which 834 were considered relevant) and studies presented at peer-reviewed scientific conferences between January 2020 and October 2022 were considered. Findings: Initiation of antiretroviral therapy (ART) is recommended as soon as possible after diagnosis of HIV. Barriers to care should be addressed, including ensuring access to ART and adherence support. Integrase strand transfer inhibitor-containing regimens remain the mainstay of initial therapy. For people who have achieved viral suppression with a daily oral regimen, long-acting injectable therapy with cabotegravir plus rilpivirine given as infrequently as every 2 months is now an option. Weight gain and metabolic complications have been linked to certain antiretroviral medications; novel strategies to ameliorate these complications are needed. Management of comorbidities throughout the life span is increasingly important, because people with HIV are living longer and confronting the health challenges of aging. In addition, management of substance use disorder in people with HIV requires an evidence-based, integrated approach. Options for preexposure prophylaxis include oral medications (tenofovir disoproxil fumarate or tenofovir alafenamide plus emtricitabine) and, for the first time, a long-acting injectable agent, cabotegravir. Recent global health emergencies, like the SARS-CoV-2 pandemic and monkeypox virus outbreak, continue to have a major effect on people with HIV and the delivery of services. To address these and other challenges, an equity-based approach is essential. Conclusions and Relevance: Advances in treatment and prevention of HIV continue to improve outcomes, but challenges and opportunities remain.

Ending the evidence gap for pregnancy, HIV and co-infections: ethics guidance from the PHASES project.

INTRODUCTION: While pregnant people have been an important focus for HIV research, critical evidence gaps remain regarding prevention, co-infection, and safety and efficacy of new antiretroviral therapies in pregnancy. Such gaps can result in harm: without safety data, drugs used may carry unacceptable risks to the foetus or pregnant person; without pregnancy-specific dosing data, pregnant people face risks of both toxicity and undertreatment; and delays in gathering evidence can limit access to beneficial next-generation drugs. Despite recognition of the need, numerous barriers and ethical complexities have limited progress. We describe the process, ethical foundations, recommendations and applications of guidance for advancing responsible inclusion of pregnant people in HIV/co-infections research. DISCUSSION: The 26-member international and interdisciplinary Pregnancy and HIV/AIDS: Seeking Equitable Study (PHASES) Working Group was convened to develop ethics-centred guidance for advancing timely, responsible HIV/co-infections research with pregnant people. Deliberations over 3 years drew on extensive qualitative research, stakeholder engagement, expert consultation and a series of workshops. The guidance, initially issued in July 2020, highlights conceptual shifts needed in framing research with pregnant people, and articulates three ethical foundations to ground recommendations: equitable protection from drug-related risks, timely access to biomedical advances and equitable respect for pregnant people's health interests. The guidance advances 12 specific recommendations, actionable within the current regulatory environment, addressing multiple stakeholders across drug development and post-approval research, and organized around four themes: building capacity, supporting inclusion, achieving priority research and ensuring respect. The recommendations describe strategies towards ethically redressing the evidence gap for pregnant people around HIV and co-infections. The guidance has informed key efforts of leading organizations working to advance needed research, and identifies further opportunities for impact by a range of stakeholder groups. CONCLUSIONS: There are clear pathways towards ethical inclusion of pregnant people in the biomedical research agenda, and strong agreement across the HIV research community about the need for - and the promise of - advancing them. Those who fund, conduct, oversee and advocate for research can use the PHASES guidance to facilitate more, better and earlier evidence to optimize the health and wellbeing of pregnant people and their children.

Severe postvaccinia encephalitis with acute disseminated encephalomyelitis: recovery with early intravenous immunoglobulin, high-dose steroids, and vaccinia immunoglobulin.

We report the second case of severe postvaccinial encephalitis with acute disseminated encephalomyelitis since smallpox vaccination was reintroduced in 2002. Both affected patients responded dramatically with early intervention of intravenous immunoglobulin. Our patient, who also received concurrent vaccinia immunoglobulin and corticosteroids, demonstrated full recovery.

Barriers and facilitators to HIV testing and linkage to primary care: narratives of people with advanced HIV in the Southeast.

Persons with unrecognized HIV infection forgo timely clinical intervention and may unknowingly transmit HIV to partners. However, in the USA, unrecognized infection and late diagnosis are common. To understand barriers and facilitators to HIV testing and care, we conducted a qualitative study of 24 HIV infected persons attending a Southeastern HIV clinic who presented with clinically advanced illness. The primary barrier to HIV testing prior to diagnosis was perception of risk; consequently, most participants were diagnosed after the onset of clinical symptoms. While most patients were anxious to initiate care rapidly after diagnosis, some felt frustrated by the passive process of connecting to specialty care. The first visit with an HIV care provider was identified as critical in the coping process for many patients. Implications for the implementation of Centers for Disease Control and Prevention HIV routine screening guidelines are discussed.

Simplifying antiretroviral therapy.

The substantial benefits conferred by HAART require strict patient adherence. Many of the initial HAART regimens consisted of a number of large pills that needed to be taken several times daily, sometimes with meal restrictions. The development of once-daily antiretroviral agents has eased some of the burden associated with the intense, difficult schedules of early HAART regimens.. The majority of regimens currently used in treatment-naive HIV-positive patients contain a mixture of agents that are taken on a once- and twice-daily basis. Although this is an improvement over past regimens, the asynchronous administration of pills throughout the day still presents a scheduling challenge for most patients. The newest advance in simplifying antiretroviral therapy is the use of regimens in which all pills are taken at the same time once a day. Choosing drugs for a fully once-daily regimen requires awareness of a number of factors, including pharmacokinetics, potency, durability of response, resistance and safety. At this time, there are a limited number of combinations that can be used as a fully once-daily regimen and few clinical trials evaluating such combinations. Results from initial clinical trials using simplified, once-daily regimens in treatment-naive patients have been promising. Additional studies should add to this experience and provide guidance on the role and timing of such regimens in the management of patients with HIV disease.

Unexpected finding of delayed-onset seizures in HIV-positive, treatment-experienced subjects in the Phase IIb evaluation of fosdevirine (GSK2248761).

BACKGROUND: Fosdevirine (GSK2248761) is a non-nucleoside reverse transcriptase inhibitor with HIV-1 activity against common efavirenz-resistant strains. Two partially blind, randomized, Phase IIb studies were initiated (1 in treatment-naive and 1 in treatment-experienced subjects with HIV) to select a once-daily dose of fosdevirine for Phase III trials. METHODS: In the SIGNET study, treatment-naive subjects were randomized 1:1:1 to receive once-daily fosdevirine 100 or 200 mg or efavirenz 600 mg, each along with tenofovir disoproxil fumarate/emtricitabine 300 mg/200 mg or abacavir/lamivudine 600 mg/300 mg. In the SONNET study, treatment-experienced subjects with non-nucleoside reverse transcriptase inhibitor-resistant HIV-1 were randomized 1:1:1 to treatment with fosdevirine 100 or 200 mg once daily or etravirine 200 mg twice daily, each along with twice-daily darunavir/ritonavir 600/100 mg and raltegravir 400 mg. The primary efficacy end point was the proportion of subjects with HIV-1 RNA<50 copies/ml. Safety and pharmacokinetics were also addressed. RESULTS: A total of 35 subjects were exposed to fosdevirine 100 or 200 mg. Trials were halted when 5 treatment-experienced subjects (1 receiving fosdevirine 100 mg, 4 receiving fosdevirine 200 mg) developed new-onset seizures after ≥4 weeks of exposure to fosdevirine. There was no clear association between seizures and fosdevirine plasma drug levels. Time to seizure onset ranged from 28 to 81 days, and all 5 subjects experienced ≥1 seizure after drug discontinuation. CONCLUSIONS: The delayed onset of seizures after fosdevirine exposure and persistence after discontinuation is without precedent in antiretroviral drug development, leading to additional investigation and underscoring the need for careful subject monitoring.

Evaluating nurses' implementation of an infant-feeding counseling protocol for HIV-infected mothers: The Ban Study in Lilongwe, Malawi.

A process evaluation of nurses' implementation of an infant-feeding counseling protocol was conducted for the Breastfeeding, Antiretroviral and Nutrition (BAN) Study, a prevention of mother-to-child transmission of HIV clinical trial in Lilongwe, Malawi. Six trained nurses counseled HIV-infected mothers to exclusively breastfeed for 24 weeks postpartum and to stop breastfeeding within an additional four weeks. Implementation data were collected via direct observations of 123 infant feeding counseling sessions (30 antenatal and 93 postnatal) and interviews with each nurse. Analysis included calculating a percent adherence to checklists and conducting a content analysis for the observation and interview data. Nurses were implementing the protocol at an average adherence level of 90% or above. Although not detailed in the protocol, nurses appropriately counseled mothers on their actual or intended formula milk usage after weaning. Results indicate that nurses implemented the protocol as designed. Results will help to interpret the BAN Study's outcomes.

Factors associated with fewer visits for HIV primary care at a tertiary care center in the Southeastern U.S.

In this study we sought to evaluate sociodemographic and clinical characteristics associated with decreased access to HIV outpatient care in a University-based clinic in the Southeastern U.S. The number of HIV outpatient clinic visits per person-year was estimated among 1,404 HIV-infected individuals participating in a large observational clinical cohort study. On average, participants attended 3.38 visits per person-year (95% CI = 3.32, 3.44), with 71% attending fewer than 4 visits per year. Younger persons, of Black race/ethnicity, with less advanced HIV disease, and a shorter time from entry to HIV care, had poorer access to care, as did participants without health insurance and residing a greater distance from care. Vulnerable subgroups of HIV-infected patients in the South have decreased access to ongoing HIV health care. Interventions including more intensive counseling and active outreach for newly HIV diagnosed individuals and support with obtaining health insurance and transportation may lead to improved outcomes.

An HIV self-care symptom management intervention for African American mothers.

BACKGROUND: Human immunodeficiency virus (HIV) infection has become a serious health problem for low-income African American women in their childbearing years. Interventions that help them cope with feelings about having HIV and increase their understanding of HIV as a chronic disease in which self-care practices, regular health visits, and medications can improve the quality of life can lead to better health outcomes. OBJECTIVE: This study aimed to determine the efficacy of an HIV self-care symptom management intervention for emotional distress and perceptions of health among low-income African American mothers with HIV. METHOD: Women caregivers of young children were randomly assigned to self-care symptom management intervention or usual care. The intervention, based on a conceptual model related to HIV in African American women, involved six home visits by registered nurses. A baseline pretest and two posttests were conducted with the mothers in both groups. Emotional distress was assessed as depressive symptoms, affective state, stigma, and worry about HIV. Health, self-reported by the mothers, included the number of infections and aspects of health-related quality of life (i.e., perception of health, physical function, energy, health distress, and role function). RESULTS: Regarding emotional distress, the mothers in the experimental group reported fewer feelings of stigma than the mothers in the control group. Outcome assessments of health indicated that the mothers in the experimental group reported higher physical function scores than the control mothers. Within group analysis over time showed a reduction in negative affective state (depression/dejection and tension/anxiety) and stigma as well as infections in the intervention group mothers, whereas a decline in physical and role function was found in the control group. CONCLUSIONS: The HIV symptom management intervention has potential as a case management or clinical intervention model for use by public health nurses visiting the home or by advanced practice nurses who see HIV-infected women in primary care or specialty clinics.