Safety and Virologic Impact of Haploidentical NK Cells Plus Interleukin 2 or N-803 in HIV Infection.

BACKGROUND: Natural killer (NK) cells are dysfunctional in chronic human immunodeficiency virus (HIV) infection as they are not able to clear virus. We hypothesized that an infusion of NK cells, supported by interleukin 2 (IL-2) or IL-15, could decrease virus-producing cells in the lymphatic tissues. METHODS: We conducted a phase 1 pilot study in 6 persons with HIV (PWH), where a single infusion of haploidentical related donor NK cells was given plus either IL-2 or N-803 (an IL-15 superagonist). RESULTS: The approach was well tolerated with no unexpected adverse events. We did not pretreat recipients with cyclophosphamide or fludarabine to "make immunologic space," reasoning that PWH on stable antiretroviral treatment remain T-cell depleted in lymphatic tissues. We found donor cells remained detectable in blood for up to 8 days (similar to what is seen in cancer pretreatment with lymphodepleting chemotherapy) and in the lymph nodes and rectum up to 28 days. There was a moderate decrease in the frequency of viral RNA-positive cells in lymph nodes. CONCLUSIONS: There was a moderate decrease in HIV-producing cells in lymph nodes. Further studies are warranted to determine the impact of healthy NK cells on HIV reservoirs and if restoring NK-cell function could be part of an HIV cure strategy. Clinical Trials Registration. NCT03346499 and NCT03899480.

Prevalencia y caracterización de las neoplasias malignas en personas viviendo con VIH en Colombia

Introducción: En el síndrome de inmunodeficiencia adquirida las neoplasias han jugado un papel preponderante, y con el advenimiento del tratamiento antirretroviral (TAR), la infección por VIH se ha transformado en una enfermedad crónica, siendo los tumores malignos una causa importante de morbilidad y mortalidad. Objetivo: Describir las características demográficas, clínicas y de laboratorio de las personas que viven con VIH (PVVIH) y han sido diagnosticadas con cáncer en Colombia y comparar los grupos de neoplasias definitorias y no definitorias de Sida. Métodos: Revisión multicéntrica retrospectiva, en la que se recolectó y analizó datos relacionados con la infección por VIH y de diagnóstico de cáncer y tipo. Incluyó PVVIH diagnosticadas con neoplasias malignas atendidas en 23 centros de atención de pacientes con VIH en 11 ciudades de Colombia desde 1986 hasta 2018. Resultados: En 23.189 pacientes, se identificaron 650 casos de malignidad (prevalencia de 2,8 % [IC de 95%: 2,6-2,9]). La neoplasia definitoria de Sida (NDS) sigue siendo el tipo de cáncer prevalente (71,1%), las neoplasias malignas más frecuentes fueron sarcoma de Kaposi (n: 330; 50,8%), linfoma no Hodgkin (n: 110; 16,9%), cáncer de piel (n: 48; 7,4%) y linfoma de Hodgkin (n: 25; 3,8%). Los pacientes con NDS tenían más probabilidades de ser HSH y estar en un estadio CDC 3, un recuento de linfocitos T CD4 < 200/μL y una carga viral del VIH ≥ 50 copias/mL al momento del diagnóstico de malignidad. Las personas con neoplasias no definitorias de Sida (NNDS) eran significativamente mayores y tenían más probabilidades de ser fumadores. Conclusiones: Estos hallazgos son relevantes considerando la creciente carga de cáncer en las PVVIH que envejecen y las causas cambiantes de morbilidad y mortalidad. La presentación tardía a la atención del VIH y el retraso en el inicio del TAR son probablemente factores que contribuyen al cambio más lento hacia NNDS en comparación con las regiones de altos ingresos donde hay un acceso más rápido y temprano al TAR. El conocimiento de las tendencias epidemiológicas actuales y el perfil del cáncer en las PVVIH es fundamental para mejorar los esfuerzos de prevención y tratamiento del cáncer en el contexto de la atención integral del VIH.

Background: In the acquired immunodeficiency syndrome, neoplasms have played a preponderant role, and with the advent of antiretroviral treatment (ART), HIV has become a chronic disease, with malignant tumors being an important cause of morbidity and mortality. Aim: To describe the demographic, clinical, and laboratory characteristics of people living with HIV (PLHIV) who have been diagnosed with cancer in Colombia and to compare the groups of AIDS-defining (ADC) and non-AIDS-defining neoplasms (NADC). Methods: Retrospective, multicenter study that included people living with HIV/AIDS (PLHIV) diagnosed with malignancies treated at 23 HIV care centers located in 11 Colombian cities from 1986 to 2018. Data related to HIV infection and cancer diagnosis were collected and analyzed. Results: Among 23,189 patients, 650 malignancy cases were identified (prevalence of 2.8% [95% CI 2.6-2.9]). AIDS-defining neoplasm remains the most prevalent type of cancer (71.1%), The most frequent individual malignancies were Kaposi sarcoma (n: 330; 50.8%), non-Hodgkin lymphoma (n: 110; 16.9%), skin cancer (n: 48; 7.4%), and Hodgkin lymphoma (n: 25; 3.8%). Compared people with NADC, with ADC were more likely to be MSM and have a CDC HIV stage 3, CD4 T cell count < 200/μL, and HIV viral load ≥ 50 copies/mL at the time of malignancy diagnosis. PLHIV and with NADC were significantly older and were more likely to be smokers. Conclusions: These findings are relevant considering the increasing burden of cancer in the aging PLHIV and the changing causes of morbidity and mortality. Late presentation to HIV care and delayed ART initiation are likely factors contributing to the slower shift toward NADCs compared with high-income regions where access to ART is better. Knowledge of the current epidemiological trends and profile of cancer in PLWHA is critical to improve cancer prevention and treatment efforts in the context of comprehensive HIV care.

Impact of antimicrobial stewardship programs on antibiotic consumption and antimicrobial resistance in four Colombian healthcare institutions.

BACKGROUND: Antimicrobial stewardship programs (ASPs) have become a fundamental pillar in optimizing antimicrobial usage, improving patient care, and reducing antimicrobial resistance (AMR). Herein we evaluated the impact of an ASP on antimicrobial consumption and AMR in Colombia. METHODS: We designed a retrospective observational study and measured trends in antibiotic consumption and AMR before and after the implementation of an ASP using interrupted time series analysis over a 4-year period (24 months before and 24 months after ASP implementation). RESULTS: ASPs were implemented according to the available resources in each of the institutions. Before ASP implementation, there was a trend toward an increase in the antibiotic consumption of all measured antimicrobials selected. Afterward, an overall decrease in antibiotic consumption was observed. The use of ertapenem and meropenem decreased in hospital wards, while a decrease in the use of ceftriaxone, cefepime, piperacillin/tazobactam, meropenem, and vancomycin was observed in intensive care units. After ASP implementation, the trend toward an increase of oxacillin-resistant Staphylococcus aureus, ceftriaxone-resistant Escherichia coli, and meropenem-resistant Pseudomonas aeruginosa was reversed. CONCLUSIONS: In our study, we showed that ASPs are a key strategy in tackling the emerging threat of AMR and have a positive impact on antibiotic consumption and resistance.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Dose, Infection, and Disease Outcomes for Coronavirus Disease 2019 (COVID-19): A Review.

The relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) dose, infection, and coronavirus disease 2019 (COVID-19) outcomes remains poorly understood. This review summarizes the existing literature regarding this issue, identifies gaps in current knowledge, and suggests opportunities for future research. In humans, host characteristics, including age, sex, comorbidities, smoking, and pregnancy, are associated with severe COVID-19. Similarly, in animals, host factors are strong determinants of disease severity, although most animal infection models manifest clinically with mild to moderate respiratory disease. The influence of variants of concern as it relates to infectious dose, consequence of overall pathogenicity, and disease outcome in dose-response remains unknown. Epidemiologic data suggest a dose-response relationship for infection contrasting with limited and inconsistent surrogate-based evidence between dose and disease severity. Recommendations include the design of future infection studies in animal models to investigate inoculating dose on outcomes and the use of better proxies for dose in human epidemiology studies.

Revisiting COVID-19 policies: 10 evidence-based recommendations for where to go from here.

BACKGROUND: Strategies to control coronavirus 2019 disease (COVID-19) have often been based on preliminary and limited data and have tended to be slow to evolve as new evidence emerges. Yet knowledge about COVID-19 has grown exponentially, and the expanding rollout of vaccines presents further opportunity to reassess the response to the pandemic more broadly. MAIN TEXT: We review the latest evidence concerning 10 key COVID-19 policy and strategic areas, specifically addressing: 1) the expansion of equitable vaccine distribution, 2) the need to ease restrictions as hospitalization and mortality rates eventually fall, 3) the advantages of emphasizing educational and harm reduction approaches over coercive and punitive measures, 4) the need to encourage outdoor activities, 5) the imperative to reopen schools, 6) the far-reaching and long-term economic and psychosocial consequences of sustained lockdowns, 7) the excessive focus on surface disinfection and other ineffective measures, 8) the importance of reassessing testing policies and practices, 9) the need for increasing access to outpatient therapies and prophylactics, and 10) the necessity to better prepare for future pandemics. CONCLUSIONS: While remarkably effective vaccines have engendered great hope, some widely held assumptions underlying current policy approaches call for an evidence-based reassessment. COVID-19 will require ongoing mitigation for the foreseeable future as it transforms from a pandemic into an endemic infection, but maintaining a constant state of emergency is not viable. A more realistic public health approach is to adjust current mitigation goals to be more data-driven and to minimize unintended harms associated with unfocused or ineffective control efforts. Based on the latest evidence, we therefore present recommendations for refining 10 key policy areas, and for applying lessons learned from COVID-19 to prevent and prepare for future pandemics.

COVID-19 false dichotomies and a comprehensive review of the evidence regarding public health, COVID-19 symptomatology, SARS-CoV-2 transmission, mask wearing, and reinfection.

Scientists across disciplines, policymakers, and journalists have voiced frustration at the unprecedented polarization and misinformation around coronavirus disease 2019 (COVID-19) pandemic. Several false dichotomies have been used to polarize debates while oversimplifying complex issues. In this comprehensive narrative review, we deconstruct six common COVID-19 false dichotomies, address the evidence on these topics, identify insights relevant to effective pandemic responses, and highlight knowledge gaps and uncertainties. The topics of this review are: 1) Health and lives vs. economy and livelihoods, 2) Indefinite lockdown vs. unlimited reopening, 3) Symptomatic vs. asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, 4) Droplet vs. aerosol transmission of SARS-CoV-2, 5) Masks for all vs. no masking, and 6) SARS-CoV-2 reinfection vs. no reinfection. We discuss the importance of multidisciplinary integration (health, social, and physical sciences), multilayered approaches to reducing risk ("Emmentaler cheese model"), harm reduction, smart masking, relaxation of interventions, and context-sensitive policymaking for COVID-19 response plans. We also address the challenges in understanding the broad clinical presentation of COVID-19, SARS-CoV-2 transmission, and SARS-CoV-2 reinfection. These key issues of science and public health policy have been presented as false dichotomies during the pandemic. However, they are hardly binary, simple, or uniform, and therefore should not be framed as polar extremes. We urge a nuanced understanding of the science and caution against black-or-white messaging, all-or-nothing guidance, and one-size-fits-all approaches. There is a need for meaningful public health communication and science-informed policies that recognize shades of gray, uncertainties, local context, and social determinants of health.