User Experience of Persons Using Ingestible Sensor-Enabled Pre-Exposure Prophylaxis to Prevent HIV Infection: Cross-Sectional Survey Study.

Background: A digital health technology's success or failure depends on how it is received by users. objectives: We conducted a user experience (UX) evaluation among persons who used the Food and Drug Administration-approved Digital Health Feedback System incorporating ingestible sensors (ISs) to capture medication adherence, after they were prescribed oral pre-exposure prophylaxis (PrEP) to prevent HIV infection. We performed an association analysis with baseline participant characteristics, to see if "personas" associated with positive or negative UX emerged. Methods: UX data were collected upon exit from a prospective intervention study of adults who were HIV negative, prescribed oral PrEP, and used the Digital Health Feedback System with IS-enabled tenofovir disoproxil fumarate plus emtricitabine (IS-Truvada). Baseline demographics; urine toxicology; and self-report questionnaires evaluating sleep (Pittsburgh Sleep Quality Index), self-efficacy, habitual self-control, HIV risk perception (Perceived Risk of HIV Scale 8-item), and depressive symptoms (Patient Health Questionnaire-8) were collected. Participants with ≥28 days in the study completed a Likert-scale UX questionnaire of 27 questions grouped into 4 domain categories: overall experience, ease of use, intention of future use, and perceived utility. Means and IQRs were computed for participant total and domain subscores, and linear regressions modeled baseline participant characteristics associated with UX responses. Demographic characteristics of responders versus nonresponders were compared using the Fisher exact and Wilcoxon rank-sum tests. Results: Overall, 71 participants were enrolled (age: mean 37.6, range 18-69 years; n=64, 90% male; n=55, 77% White; n=24, 34% Hispanic; n=68, 96% housed; and n=53, 75% employed). No demographic differences were observed in the 63 participants who used the intervention for ≥28 days. Participants who completed the questionnaire were more likely to be housed (52/53, 98% vs 8/10, 80%; P=.06) and less likely to have a positive urine toxicology (18/51, 35% vs 7/10, 70%; P=.08), particularly methamphetamine (4/51, 8% vs 4/10, 40%; P=.02), than noncompleters. Based on IQR values, ≥75% of participants had a favorable UX based on the total score (median 3.78, IQR 3.17-4.20), overall experience (median 4.00, IQR 3.50-4.50), ease of use (median 3.72, IQR 3.33-4.22), and perceived utility (median 3.72, IQR 3.22-4.25), and ≥50% had favorable intention of future use (median 3.80, IQR 2.80-4.40). Following multipredictor modeling, self-efficacy was significantly associated with the total score (0.822, 95% CI 0.405-1.240; P<.001) and all subscores (all P<.05). Persons with more depressive symptoms reported better perceived utility (P=.01). Poor sleep was associated with a worse overall experience (-0.07, 95% CI -0.133 to -0.006; P=.03). Conclusions: The UX among persons using IS-enabled PrEP (IS-Truvada) to prevent HIV infection was positive. Association analysis of baseline participant characteristics linked higher self-efficacy with positive UX, more depressive symptoms with higher perceived utility, and poor sleep with negative UX.

Asynchronous Video Directly Observed Therapy to Monitor Short-Course Latent Tuberculosis Infection Treatment: Results of a Randomized Controlled Trial.

Background: Observing medication ingestion through self-recorded videos (video directly observed therapy [VDOT]) has been shown to be a cost-effective alternative to in-person directly observed therapy (DOT) for monitoring adherence to treatment for tuberculosis disease. VDOT could be a useful tool to monitor short-course latent tuberculosis infection (LTBI) treatment. Methods: We conducted a prospective randomized controlled trial comparing VDOT (intervention) and clinic-based DOT (control) among patients newly diagnosed with LTBI who agreed to a once-weekly 3-month treatment regimen of isoniazid and rifapentine. Study outcomes were treatment completion and patient satisfaction. We also assessed costs. Pre- and posttreatment interviews were conducted. Results: Between March 2016 and December 2019, 130 participants were assigned to VDOT (n = 68) or DOT (n = 62). Treatment completion (73.5% vs 69.4%, P = .70) and satisfaction with treatment monitoring (92.1% vs 86.7%, P = .39) were slightly higher in the intervention group than the control group, but neither was statistically significant. VDOT cost less per patient (median, $230; range, $182-$393) vs DOT (median, $312; range, $246-$592) if participants used their own smartphone. Conclusions: While both groups reported high treatment satisfaction, VDOT was not associated with higher LTBI treatment completion. However, VDOT cost less than DOT. Volunteer bias might have reduced the observed effect since patients opposed to any treatment monitoring could have opted for alternative unobserved regimens. Given similar outcomes and lower cost, VDOT may be useful for treatment monitoring when in-person observation is prohibited or unavailable (eg, during a respiratory disease outbreak). The trial was registered at the National Institutes of Health (ClinicalTrials.gov NTC02641106). Clinical Trials Registration: ClinicalTrials.gov NTC02641106; registered 24 October 2016.

SARS-CoV-2 RNA and nucleocapsid antigen are blood biomarkers associated with severe disease outcomes that improve in response to remdesivir.

BACKGROUND: Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter ACTT-1 clinical trial that randomized patients to remdesivir or placebo. METHODS: Longitudinal specimens collected during hospitalization from a substudy of 642 COVID-19 patients were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed. RESULTS: Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95%CI 1.40-2.71) for levels >245 pg/ml vs 1.04 (95%CI 0.76-1.42) for levels < 245 pg/ml. Remdesivir also accelerated the rate of viral RNA and antigen clearance in blood, and patients whose blood levels decreased were more likely to recover and survive. CONCLUSIONS: Reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from antiviral therapy.

Safety and Immune Responses Following Anti-PD-1 Monoclonal Antibody Infusions in Healthy Persons With Human Immunodeficiency Virus on Antiretroviral Therapy.

Background: T cells in people with human immunodeficiency virus (HIV) demonstrate an exhausted phenotype, and HIV-specific CD4+ T cells expressing programmed cell death 1 (PD-1) are enriched for latent HIV, making antibody to PD-1 a potential strategy to target the latent reservoir. Methods: This was a phase 1/2, randomized (4:1), double-blind, placebo-controlled study in adults with suppressed HIV on antiretroviral therapy with CD4+ counts ≥350 cells/µL who received 2 infusions of cemiplimab versus placebo. The primary outcome was safety, defined as any grade 3 or higher adverse event (AE) or any immune-related AE (irAE). Changes in HIV-1-specific polyfunctional CD4+ and CD8+ T-cell responses were evaluated. Results: Five men were enrolled (median CD4+ count, 911 cells/µL; median age, 51 years); 2 received 1 dose of cemiplimab, 2 received 2 doses, and 1 received placebo. One participant had a probable irAE (thyroiditis, grade 2); another had a possible irAE (hepatitis, grade 3), both after a single low-dose (0.3 mg/kg) infusion. The Safety Monitoring Committee recommended no further enrollment or infusions. All 4 cemiplimab recipients were followed for 48 weeks. No other cemiplimab-related serious AEs, irAEs, or grade 3 or higher AEs occurred. One 2-dose recipient of cemiplimab had a 6.2-fold increase in polyfunctional, Gag-specific CD8+ T-cell frequency with supportive increases in plasma HIV RNA and decreases in total HIV DNA. Conclusions: One of 4 participants exhibited increased HIV-1-specific T-cell responses and transiently increased HIV-1 expression following 2 cemiplimab infusions. The occurrence of irAEs after a single, low dose may limit translating the promising therapeutic results of cemiplimab for cancer to immunotherapeutic and latency reversal strategies for HIV. Clinical Trials Registration. NCT03787095.

A Risk Profile Using Simple Hematologic Parameters to Assess Benefits From Baricitinib in Patients Hospitalized With COVID-19: A Post Hoc Analysis of the Adaptive COVID-19 Treatment Trial-2.

BACKGROUND: The ACTT risk profile, which was developed from ACTT-1 (Adaptive COVID-19 Treatment Trial-1), demonstrated that hospitalized patients with COVID-19 in the high-risk quartile (characterized by low absolute lymphocyte count [ALC], high absolute neutrophil count [ANC], and low platelet count at baseline) benefited most from treatment with the antiviral remdesivir. It is unknown which patient characteristics are associated with benefit from treatment with the immunomodulator baricitinib. OBJECTIVE: To apply the ACTT risk profile to the ACTT-2 cohort to investigate potential baricitinib-related treatment effects by risk quartile. DESIGN: Post hoc analysis of ACTT-2, a randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT04401579). SETTING: Sixty-seven trial sites in 8 countries. PARTICIPANTS: Adults hospitalized with COVID-19 (n = 999; 85% U.S. participants). INTERVENTION: Baricitinib+remdesivir versus placebo+remdesivir. MEASUREMENTS: Mortality, progression to invasive mechanical ventilation (IMV) or death, and recovery, all within 28 days; ALC, ANC, and platelet count trajectories. RESULTS: In the high-risk quartile, baricitinib+remdesivir was associated with reduced risk for death (hazard ratio [HR], 0.38 [95% CI, 0.16 to 0.86]; P = 0.020), decreased progression to IMV or death (HR, 0.57 [CI, 0.35 to 0.93]; P = 0.024), and improved recovery rate (HR, 1.53 [CI, 1.16 to 2.02]; P = 0.002) compared with placebo+remdesivir. After 5 days, participants receiving baricitinib+remdesivir had significantly larger increases in ALC and significantly larger decreases in ANC compared with control participants, with the largest effects observed in the high-risk quartile. LIMITATION: Secondary analysis of data collected before circulation of current SARS-CoV-2 variants. CONCLUSION: The ACTT risk profile identifies a subgroup of hospitalized patients who benefit most from baricitinib treatment and captures a patient phenotype of treatment response to an immunomodulator and an antiviral. Changes in ALC and ANC trajectory suggest a mechanism whereby an immunomodulator limits severe COVID-19. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases.

A Cross Sectional Study on the Bidirectional Interactions Between Leptospirosis and HIV Infection Among Patients from Maputo Central Hospital, Mozambique.

Introduction: This study aims to determine the baseline seroprevalence of leptospirosis, a zoonotic and neglected disease, in people living with HIV (PWH) in Maputo, Mozambique, and to evaluate the relationship between selected HIV-related factors that might influence risk of coinfection with leptospirosis, such as degree of immunosuppression, as assessed by CD4 cell count, World Health Organization (WHO) HIV/AIDS clinical stage and antiretroviral therapy (ART) intake. Methods: This was a descriptive cross-sectional analysis of 157 PWH, aged over 18 years old, admitted to the Maputo Central Hospital, in Maputo, Mozambique, between March 2020 and October 2021. The study participants were recruited as a convenience sample regardless of the reasons for their admission. We collected sociodemographic and clinical data, including ART and WHO HIV/AIDS clinical stage, and blood for CD4 cell count and detection of Leptospira IgG antibodies using a commercial Kit ab247199 Leptospira IgG ELISA (www.abcam.com/ab247199) with sensitivity and specificity of 100% and 97.3%, respectively. Laboratory testing was performed at the Faculty of Medicine, Eduardo Mondlane University and Laboratory of Clinical Analysis, in Maputo. Results: Participants were aged 18 to 72 years (median age 39 years; SD ± 10.5), the majority were female 100 (63.7%), from urban areas 138 (87.9%), with secondary-level education 80 (51%). The overall seroprevalence of Leptospira IgG antibodies was 40.1%. The median CD4 cell count was 385 cells/µl (02 to 2297; SD ± 378.47). Higher seroprevalence of Leptospira antibodies was found among participants with CD4 cell counts <250 cells/µl (54.8%), WHO HIV/AIDS stage IV (70.2%) and those on ART (92%), though there were no statistically significant differences between groups with and without Leptospira antibodies. Conclusion: Our study confirmed that Leptospira antibodies are highly prevalent in PWH in Maputo; however, Leptospira infection was not associated with the degree of immunosuppression, WHO HIV/AIDS clinical stage, or the use of ART. Our data support the need for routine screening for leptospirosis in PWH in Mozambique. Future studies are warranted to characterize the incidence and outcomes of symptomatic leptospirosis in this patient population and to identify circulating serovars and species in the country and region, as well as the implicated reservoirs.

Adverse Pregnancy Outcomes Among Women with Human Immunodeficiency Virus Taking Isoniazid Preventive Therapy During the First Trimester.

BACKGROUND: Isoniazid preventive therapy (IPT) is recommended for tuberculosis prevention yet data on the safety of first-trimester pregnancy exposure are limited. METHODS: Planned secondary analysis in a TB prevention trial of adverse pregnancy outcomes among participants assigned to 9-month IPT who became pregnant during (IPT-exposed) or after (unexposed) IPT. Regression models compared binary outcomes of a composite adverse outcome (any non-live birth, excluding induced abortion); preterm delivery <37 weeks; and low birth weight <2500 g) among exposure groups. Models were adjusted for latent TB infection, maternal age, CD4 count, and antiretroviral therapy (ART). RESULTS: In total, 128 participants had a known pregnancy outcome; 39 IPT-exposed and 89 unexposed. At pregnancy outcome, ART use was lower in IPT-exposed (79%) than unexposed women (98%). Overall, 29 pregnancies ended in a composite adverse outcome (25 spontaneous abortions, 2 stillbirths and 2 ectopic pregnancies), 15 preterm deliveries, and 10 infants with low birth weight. IPT was associated with the composite adverse outcome adjusting for covariates at enrollment (adjusted relative risk [aRR] 1.98; 95% confidence interval [CI] 1.15, 3.41), but the effect was attenuated when adjusted for covariates at pregnancy outcome (aRR 1.47; 95% CI .84, 2.55); IPT was not associated with preterm delivery (relative risk [RR] 0.87; 95% CI .32-2.42) or low birth weight (RR 1.01; 95% CI .29, 3.56). CONCLUSIONS: First-trimester IPT exposure was associated with nearly two-fold increased risk of fetal demise, mostly spontaneous abortion, though the association was attenuated when adjusted for covariates proximal to pregnancy outcome including ART use. Further study is needed to inform TB prevention guidelines.

Inclusion, Diversity, Access, and Equity in Infectious Diseases Fellowship Training: Tools for Program Directors.

The Infectious Diseases Society of America (IDSA) has set clear priorities in recent years to promote inclusion, diversity, access, and equity (IDA&E) in infectious disease (ID) clinical practice, medical education, and research. The IDSA IDA&E Task Force was launched in 2018 to ensure implementation of these principles. The IDSA Training Program Directors Committee met in 2021 and discussed IDA&E best practices as they pertain to the education of ID fellows. Committee members sought to develop specific goals and strategies related to recruitment, clinical training, didactics, and faculty development. This article represents a presentation of ideas brought forth at the meeting in those spheres and is meant to serve as a reference document for ID training program directors seeking guidance in this area.

Evaluating Demographic Representation in Clinical Trials: Use of the Adaptive Coronavirus Disease 2019 Treatment Trial (ACTT) as a Test Case.

Background: Clinical trials initiated during emerging infectious disease outbreaks must quickly enroll participants to identify treatments to reduce morbidity and mortality. This may be at odds with enrolling a representative study population, especially when the population affected is undefined. Methods: We evaluated the utility of the Centers for Disease Control and Prevention's COVID-19-Associated Hospitalization Surveillance Network (COVID-NET), the COVID-19 Case Surveillance System (CCSS), and 2020 United States (US) Census data to determine demographic representation in the 4 stages of the Adaptive COVID-19 Treatment Trial (ACTT). We compared the cumulative proportion of participants by sex, race, ethnicity, and age enrolled at US ACTT sites, with respective 95% confidence intervals, to the reference data in forest plots. Results: US ACTT sites enrolled 3509 adults hospitalized with COVID-19. When compared with COVID-NET, ACTT enrolled a similar or higher proportion of Hispanic/Latino and White participants depending on the stage, and a similar proportion of African American participants in all stages. In contrast, ACTT enrolled a higher proportion of these groups when compared with US Census and CCSS. The proportion of participants aged ≥65 years was either similar or lower than COVID-NET and higher than CCSS and the US Census. The proportion of females enrolled in ACTT was lower than the proportion of females in the reference datasets. Conclusions: Although surveillance data of hospitalized cases may not be available early in an outbreak, they are a better comparator than US Census data and surveillance of all cases, which may not reflect the population affected and at higher risk of severe disease.

Microbiological assessment reveals that Salmonella, Shigella and Campylobacter infections are widespread in HIV infected and uninfected patients with diarrhea in Mozambique.

Diarrhea is an important cause of hospitalizations in Mozambique. However, little attention has been paid to the impact HIV infection on the prevalence or clinical manifestations of enteric bacterial infections. This study aimed to determine the prevalence of Salmonella spp., Shigella spp. and Campylobacter spp. in HIV-infected and HIV-uninfected patients with diarrhea, identify risk factors for infection, and explore the association between HIV status, viral load, and bacterial prevalence. We conducted a case-control study at the Centro de Saúde de Mavalane and Centro de Saúde 1° de Maio in Maputo, Mozambique, from November 2021 to May 2022. We recruited 300 patients, including 150 HIV-infected (cases) and 150 HIV-uninfected patients (controls), aged between 0-88 years, presenting with diarrhea. Stool samples were collected for bacterial isolation through culture, and for each HIV-infected patient, 4 ml of venous blood were obtained for viral load detection through PCR. A total of 129 patients (43.0%) had at least one bacterial infection. The prevalence of Salmonella spp., Shigella spp. and Campylobacter spp. was 33.0% (n = 99), 15.0% (n = 45) and 4.3% (n = 13), respectively. The prevalence of any bacterial infection did not differ significantly between HIV-infected (45.3%, n = 68) and HIV-uninfected patients (40.7%, = 61) (p = 0.414). Overall, having 2-3 symptoms of enteric disease (p = 0.008) and a basic education (p = 0.030) were factors associated with bacterial infection. Of the 148 patients for whom HIV-1 RNA levels were available, 115 had copy numbers ≤ 75. Another 13 had levels between 76 and 1,000 and the remaining 20 had an average of 327,218.45 copies/ml. Bivariate logistic regression found that Shigella spp. were associated with HIV (p = 0.038), although no association was found in the multivariate analysis. Enteric infections are common in both HIV-infected and -uninfected patients. Low schooling influences the occurrence of enteric infections, which highlights the need to raise awareness about their prevention.

Susceptibility antibiotic screening reveals high rates of multidrug resistance of Salmonella, Shigella and Campylobacter in HIV infected and uninfected patients from Mozambique.

BACKGROUND: Antibacterial resistance is a growing concern worldwide, including in Mozambique. Diarrhea is an important cause of mortality in Mozambique, yet few local studies have reported on the resistance of bacterial pathogens in this context. Therefore, this study aims to characterize antibiotic susceptibility patterns of Salmonella, Shigella and Campylobacter spp. among patients with diarrhea, including those who are HIV-infected and-uninfected. METHODS: We conducted antibiotic susceptibility testing on 157 stool isolates recovered from 129 patients aged between 0 and 80 years with diarrhea, including HIV infected (n = 68) and-uninfected individuals (n = 61), assisted at two health centers in Maputo city. The isolates comprised of 99 Salmonella, 45 Shigella and 13 Campylobacter strains. The Kirby-Bauer disk diffusion method was used on Mueller-Hinton II agar for Salmonella and Shigella spp., while Mueller-Hinton II agar with 5% defibrinated sheep blood was used for Campylobacter spp. We tested six antibiotics listed on the national essential medicines list, including ciprofloxacin, erythromycin, azithromycin, trimethoprim-sulfamethoxazole, gentamicin, and tetracycline. RESULTS: All isolates were resistant to at least one antibiotic. A high percentage of Salmonella spp. isolates were found to be resistant to trimethoprim-sulfamethoxazole (89.9%, n = 89), erythromycin (88.9%, n = 88) and tetracycline (76.8%, n = 76). In addition, 86.6% (n = 39) and 68.9% (n = 31) of Shigella isolates were resistant to trimethoprim-sulfamethoxazole and tetracycline, respectively. The majority of Campylobacter isolates (92.3%, n = 12) were resistant to erythromycin, azithromycin and tetracycline. Multidrug resistance (MDR) was observed in 79.8% of Salmonella spp., 76.9% of Campylobacter spp., and 57.8% of Shigella spp. Drug susceptibility profiles for Salmonella spp. and Campylobacter were similar in both HIV-1 infected and uninfected patients. However, Shigella spp. isolates obtained from patients without HIV infection were significantly more likely to be resistant to erythromycin, azithromycin or to exhibit multidrug resistance than those obtained from patients with HIV-1 infection (p < 0.05). All Shigella spp. and Campylobacter spp. isolates were susceptible to gentamicin. CONCLUSION: Our study highlights concerning rates of antibiotic resistance and MDR among diarrheal bacterial pathogens in Mozambique. Further research is needed to understand the impact of HIV, ART therapy and immunosuppression on antibiotic resistance. Urgent interventions are essential to prevent the spread of resistant strains.

Phage Therapy of Mycobacterium Infections: Compassionate Use of Phages in 20 Patients With Drug-Resistant Mycobacterial Disease.

BACKGROUND: Nontuberculous Mycobacterium infections, particularly Mycobacterium abscessus, are increasingly common among patients with cystic fibrosis and chronic bronchiectatic lung diseases. Treatment is challenging due to intrinsic antibiotic resistance. Bacteriophage therapy represents a potentially novel approach. Relatively few active lytic phages are available and there is great variation in phage susceptibilities among M. abscessus isolates, requiring personalized phage identification. METHODS: Mycobacterium isolates from 200 culture-positive patients with symptomatic disease were screened for phage susceptibilities. One or more lytic phages were identified for 55 isolates. Phages were administered intravenously, by aerosolization, or both to 20 patients on a compassionate use basis and patients were monitored for adverse reactions, clinical and microbiologic responses, the emergence of phage resistance, and phage neutralization in serum, sputum, or bronchoalveolar lavage fluid. RESULTS: No adverse reactions attributed to therapy were seen in any patient regardless of the pathogen, phages administered, or the route of delivery. Favorable clinical or microbiological responses were observed in 11 patients. Neutralizing antibodies were identified in serum after initiation of phage delivery intravenously in 8 patients, potentially contributing to lack of treatment response in 4 cases, but were not consistently associated with unfavorable responses in others. Eleven patients were treated with only a single phage, and no phage resistance was observed in any of these. CONCLUSIONS: Phage treatment of Mycobacterium infections is challenging due to the limited repertoire of therapeutically useful phages, but favorable clinical outcomes in patients lacking any other treatment options support continued development of adjunctive phage therapy for some mycobacterial infections.

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.

Supporting the Art: Medication Adherence Patterns in Persons Prescribed Ingestible Sensor-enabled Oral Pre-Exposure Prophylaxis to Prevent Human Immunodeficiency Virus Infection.

BACKGROUND: Timely, accurate adherence data may support oral pre-exposure prophylaxis (PrEP) success and inform prophylaxis choice. We evaluated a Food and Drug Administration (FDA)-approved digital health feedback system (DHFS) with ingestible-sensor-enabled (IS) tenofovir-disoproxil-fumarate plus emtricitabine (Truvada®) in persons starting oral PrEP. METHODS: Human immunodeficiency virus (HIV)-negative adults were prescribed IS-Truvada® with DHFS for 12 weeks to observe medication taking behavior. Baseline demographics, urine toxicology, and self-report questionnaires were obtained. Positive detection accuracy and adverse events were computed as percentages, with Kaplan Meier Estimate for persistence-of-use. In participants persisting ≥28 days, adherence patterns (taking and timing) were analyzed, and mixed-effects logistic regression modeled characteristics associated with treatment adherence. RESULTS: Seventy-one participants were enrolled, mean age 37.6 years (range 18-69), 90.1% male, 77.5% White, 33.8% Hispanic, 95.8% housed, and 74.6% employed. Sixty-three participants (88.7%) persisted ≥28 days, generating 4987 observation days, average 79.2 (29-105). Total confirmed doses were 86.2% (95% confidence interval [CI] 82.5, 89.4), decreasing over time, odds ratio (OR) 0.899 (95% CI .876, .923) per week, P < .001; 79.4% (95% CI 66.7%, 87.3%) of participants had ≥80% adherence. Pattern analysis showed days without confirmed doses clustered (P = .003); regular dose timing was higher among participants with ≥80% confirmed doses (0.828, 95% CI .796 to .859) than among those with <80% (0.542, 95% CI95 .405 to .679) P < .001. In multi-predictor models, better adherence was associated with older age, OR 1.060 (95% CI 1.033, 1.091) per year, P < .001; negative vs positive methamphetamine screen, OR 5.051 (95% CI 2.252, 11.494), P < .001. CONCLUSIONS: DHFS with IS-Truvada® distinguished adherent persons from those potentially at risk of prophylactic failure. Ongoing methamphetamine substance use may impact oral PrEP success.

A systematic review and meta-analysis of the epidemiology of Leptospirosis in HIV uninfected and in people living with HIV from the Southern African Development Community.

BACKGROUND: Leptospirosis is an occupational, neglected febrile disease of bacterial origin transmitted between humans and animals. In this manuscript we summarize available data on Leptospira infection in HIV uninfected and in people living with HIV from the Southern African Development Community (SADC) countries, identifying gaps in knowledge and recommend future research priorities. METHODOLOGY: Articles published between 1990 and 2021 were accessed by an online search of Google Scholar and Medline/PubMed performed between February 2020 and July 2022. The STATA program was used for the Meta-analysis. Pooled prevalence values with 95% confidence intervals and heterogeneity were determined. RESULTS: Thirty studies from eight SADC countries, reporting the prevalence on Leptospira were reviewed. A pooled prevalence of 19% (CI: 13-25%), a heterogeneity level of 96% and index score ranging from 2 to 9 was determined. Only four (4) studies reported HIV co-infection status. Three species of Leptospira (Leptospira interrogans (4), L. kirschneri (3), Leptospira borgpetersenii (1) and 23 serogroups were identified. The most frequently reported serogroups were Icterohaemorrhagiae (13), Grippotyphosa and Australis (10) followed by Sejroe (8). CONCLUSION: Studies on human leptospirosis in the SADC region are scarce, especially in people living with HIV. Additional studies aimed at determining the prevalence and the role of the pathogen in people living with HIV, including detailed clinical, molecular and demographic data are recommended.

Temporal Improvements in COVID-19 Outcomes for Hospitalized Adults: A Post Hoc Observational Study of Remdesivir Group Participants in the Adaptive COVID-19 Treatment Trial.

BACKGROUND: The COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear. OBJECTIVE: To evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial). DESIGN: ACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4]). SETTING: 94 hospitals in 10 countries (86% U.S. participants). PARTICIPANTS: Adults hospitalized with COVID-19. INTERVENTION: SOC. MEASUREMENTS: 28-day mortality and recovery. RESULTS: Although outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages. LIMITATION: Unmeasured confounding. CONCLUSION: Changes in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases.

Fostering Sustainable Biomedical Research Training in Mozambique: A Spin-Off of the Medical Education Partnership Initiative.

Background: The further development of research capacity in low- and middle-income countries is critical to the delivery of evidence-based healthcare, the design of sound health policy and effective resource allocation. Research capacity is also critical for the retention of highly skilled faculty and staff and for institutional internationalization. Objectives: We summarize the accomplishments, challenges and legacy of a five-year program to train biomedical researchers entitled "Enhanced Advanced Biomedical Research Training for Mozambique (EABRTM)". Methods: A program conducted from 2015-2021 built upon the Medical Education Partnership Initiative to develop research capacity at Eduardo Mondlane University (UEM) and allied institutions. The project included design and implementation of postgraduate training programs and bolstered physical and human research infrastructure. Findings: The program supported development and implementation of UEM's first doctoral (Bioscience and Public Health) and master (Biosciences) programs with 31 and 23 students enrolled to date, respectively. Three master programs were established at Lúrio University from which 176/202 (87.1%) and 107/202 (53.0%) students obtained a Postgraduate Diploma or master's degree, respectively. Scholarships were awarded to 39 biomedical researchers; 13 completed master degrees, one completed a PhD and five remain in doctoral studies. Thirteen administrative staff and four biomedical researchers were trained in research administration and in biostatistics, respectively. A total of 119 courses and seminars benefited 2,142 participants. Thirty-five manuscripts have been published to date in peer-reviewed international journals of which 77% are first-authored by Mozambicans and 44% last-authored by Africans. Sustainability was achieved through 59 research projects awarded by international agencies, totaling $16,363,656.42 and funds ($ 7,319,366.11) secured through 2025. Conclusions: The EABRTM program substantially increased research and mentorship capacity and trained a new generation of biostatisticians and research administrators. These programmatic outcomes significantly increased the confidence of early stage Mozambican researchers in their ability to successfully pursue their career goals.

Population Pharmacokinetic Modeling and Simulation of Rifapentine Supports Concomitant Antiretroviral Therapy with Efavirenz and Non-Weight Based Dosing.

The Brief Rifapentine-Isoniazid Efficacy for TB Prevention/A5279 trial demonstrated a 1-month daily regimen of rifapentine and isoniazid was noninferior to 9 months of isoniazid alone for preventing TB in persons living with HIV (PLWH). Our objective was to evaluate rifapentine pharmacokinetics in trial participants receiving antiretroviral therapy (ART) and perform simulations to compare weight-based rifapentine dosing with a standard, fixed dose. Nonlinear mixed effect modeling was used to estimate rifapentine and 25-desacetyl rifapentine population pharmacokinetic characteristics. The pharmacokinetic model was validated using a nonparametric bootstrap and visual predictive checks. Monte Carlo simulations were performed to compare weight-based and fixed dose regimens. Rifapentine and 25-desacetyl rifapentine concentrations (347 of each; 185 participants) were each described with a one-compartment model with one-way conversion between rifapentine and 25-desacetyl rifapentine. The absorption rate was nearly doubled in fed versus fasting states. Rifapentine clearance was increased 31% in those receiving efavirenz (EFV)-based versus nevirapine-based ART. Metabolite clearance was allometrically scaled with fat-free mass. Simulations showed lower rifapentine exposures with weight-based compared with fixed dosing. With 10 mg/kg weight-based regimens, 26% and 62% of simulated exposures in <35 kg and 35-45 kg weight classes were above target (AUC0 to 24 h of 257 mg*hr/L); 85% of simulated exposures across all weight classes with fixed dosing were above target. These data support fixed dosing with rifapentine 600 mg daily for TB prevention regardless of weight for PLWH 13 years or older receiving the 4-week regimen and no need for dose adjustment when given with EFV-based ART. Clinical Trials Registration. NCT01404312.

Unraveling the Treatment Effect of Baricitinib on Clinical Progression and Resource Utilization in Hospitalized COVID-19 Patients: Secondary Analysis of the Adaptive COVID-19 Treatment Randomized Trial-2.

Background: The Adaptive COVID Treatment Trial-2 (ACTT-2) found that baricitinib in combination with remdesivir therapy (BCT) sped recovery in hospitalized coronavirus disease 2019 (COVID-19) patients vs remdesivir monotherapy (RMT). We examined how BCT affected progression throughout hospitalization and utilization of intensive respiratory therapies. Methods: We characterized the clinical trajectories of 891 ACTT-2 participants requiring supplemental oxygen or higher levels of respiratory support at enrollment. We estimated the effect of BCT on cumulative incidence of clinical improvement and deterioration using competing risks models. We developed multistate models to estimate the effect of BCT on clinical improvement and deterioration and on utilization of respiratory therapies. Results: BCT resulted in more linear improvement and lower incidence of clinical deterioration compared with RMT (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.95). The benefit was pronounced among participants enrolled on high-flow oxygen or noninvasive positive-pressure ventilation. In this group, BCT sped clinical improvement (HR, 1.21; 95% CI, 0.99 to 1.51) while slowing clinical deterioration (HR, 0.71; 95% CI, 0.48 to 1.02), which reduced the expected days in ordinal score (OS) 6 per 100 patients by 74 days (95% CI, -8 to 154 days) and the expected days in OS 7 per 100 patients by 161 days (95% CI, 46 to 291 days) compared with RMT. BCT did not benefit participants who were mechanically ventilated at enrollment. Conclusions: Compared with RMT, BCT reduces the clinical burden and utilization of intensive respiratory therapies for patients requiring low-flow oxygen or noninvasive positive-pressure ventilation compared with RMT and may thereby improve care for this patient population.

Bacteriophage treatment of disseminated cutaneous Mycobacterium chelonae infection.

Mycobacterium chelonae is a rare cause of chronic disseminated cutaneous infections in immunocompromised patients. Multidrug-resistant M. chelonae infections present a challenge for treatment, and prolonged antimicrobial courses lead to significant toxicities and further antimicrobial resistance. We report a case of refractory cutaneous disseminated M. chelonae infection in a patient with seronegative arthritis on immunotherapy with tofacitinib that was treated with combination antimicrobial, surgical, and single bacteriophage therapy with excellent clinical response. The patient developed neutralizing antibodies against the bacteriophage but continues to have stable improvement of disease with negative biopsies and no evidence of bacterial resistance to the phage.