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Subcutaneous (SC) injections can be associated with local pain and discomfort that is subjective and may affect treatment adherence and overall patient experience. With innovations increasingly focused on finding ways to deliver higher doses and volumes (≥2 mL), there is a need to better understand the multiple intertwined factors that influence pain upon SC injection. As a priority for the SC Drug Development & Delivery Consortium, this manuscript provides a comprehensive review of known attributes from published literature that contribute to pain/discomfort upon SC injection from three perspectives: (1) device and delivery factors that cause physical pain, (2) formulation factors that trigger pain responses, and (3) human factors impacting pain perception. Leveraging the Consortium's collective expertise, we provide an assessment of the comparative and interdependent factors likely to impact SC injection pain. In addition, we offer expert insights and future perspectives to fill identified gaps in knowledge to help advance the development of patient-centric and well tolerated high-dose/high-volume SC drug delivery solutions.
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Dor , Humanos , Injeções Subcutâneas , Dor/tratamento farmacológico , Sistemas de Liberação de MedicamentosRESUMO
BACKGROUND: In the Prehospital Tranexamic Acid (TXA) for TBI Trial, TXA administered within two hours of injury in the out-of-hospital setting did not reduce mortality in all patients with moderate/severe traumatic brain injury (TBI). We examined the association between TXA dosing arms, neurologic outcome, and mortality in patients with intracranial hemorrhage (ICH) on computed tomography (CT). METHODS: This was a secondary analysis of the Prehospital Tranexamic Acid for TBI Trial (ClinicalTrials.gov [NCT01990768]) that randomized adults with moderate/severe TBI (Glasgow Coma Scale<13) and systolic blood pressure > =90 mmHg within two hours of injury to a 2-gram out-of-hospital TXA bolus followed by an in-hospital saline infusion, a 1-gram out-of-hospital TXA bolus/1-gram in-hospital TXA infusion, or an out-of-hospital saline bolus/in-hospital saline infusion (placebo). This analysis included the subgroup with ICH on initial CT. Primary outcomes included 28-day mortality, 6-month Glasgow Outcome Scale-Extended (GOSE) < = 4, and 6-month Disability Rating Scale (DRS). Outcomes were modeled using linear regression with robust standard errors. RESULTS: The primary trial included 966 patients. Among 541 participants with ICH, 28-day mortality was lower in the 2-gram TXA bolus group (17%) compared to the other two groups (1-gram bolus/1-gram infusion 26%, placebo 27%). The estimated adjusted difference between the 2-gram bolus and placebo groups was -8·5 percentage points (95% CI, -15.9 to -1.0) and between the 2-gram bolus and 1-gram bolus/1-gram infusion groups was -10.2 percentage points (95% CI, -17.6 to -2.9). DRS at 6 months was lower in the 2-gram TXA bolus group than the 1-gram bolus/1-gram infusion (estimated difference -2.1 [95% CI, -4.2 to -0.02]) and placebo groups (-2.2 [95% CI, -4.3, -0.2]). Six-month GOSE did not differ among groups. CONCLUSIONS: A 2-gram out-of-hospital TXA bolus in patients with moderate/severe TBI and ICH resulted in lower 28-day mortality and lower 6-month DRS than placebo and standard TXA dosing. LEVEL OF EVIDENCE: Therapeutic/Care Management, Level II.
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HIV-1 infection greatly alters the NK cell phenotypic and functional repertoire. This is highlighted by the expansion of a rare population of FcRγ- NK cells exhibiting characteristics of traditional immunologic memory in people with HIV (PWH). Although current antiretroviral therapy (ART) effectively controls HIV-1 viremia and disease progression, its impact on HIV-1-associated NK cell abnormalities remains unclear. To address this, we performed a longitudinal analysis detailing conventional and memory-like NK cell characteristics in n = 60 PWH during the first 4 y of ART. Throughout this regimen, a skewed repertoire of cytokine unresponsive FcRγ- memory-like NK cells persisted and accompanied an overall increase in NK surface expression of CD57 and KLRG1, suggestive of progression toward immune senescence. These traits were linked to elevated serum inflammatory biomarkers and increasing Ab titers to human CMV, with human CMV viremia detected in approximately one-third of PWH at years 1-4 of ART. Interestingly, 40% of PWH displayed atypical NK cell subsets, representing intermediate stages of NK-poiesis based on single-cell multiomic trajectory analysis. Our findings indicate that NK cell irregularities persist in PWH despite long-term ART, underscoring the need to better understand the causative mechanisms that prevent full restoration of immune health in PWH.
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Antígenos CD57 , Infecções por HIV , HIV-1 , Células Matadoras Naturais , Humanos , Células Matadoras Naturais/imunologia , Infecções por HIV/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/imunologia , Masculino , Feminino , Antígenos CD57/imunologia , Adulto , Pessoa de Meia-Idade , Memória Imunológica/imunologia , Lectinas Tipo C/imunologia , Receptores Imunológicos , Viremia/imunologia , Viremia/tratamento farmacológico , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/tratamento farmacológico , Receptores de IgG/imunologia , Estudos Longitudinais , Antirretrovirais/uso terapêuticoRESUMO
BACKGROUND: The Joint Commission reports that at least half of communication breakdowns occur during handovers or transitions of care. There is no consensus on how best to approach the transfer of care within acute care surgery (ACS). We conduct a systematic review and meta-analysis of the current data on handoffs and transitions of care in ACS patients and evaluate the impact of standardization and formalized communication processes. METHODS: Clinically relevant questions regarding handoffs and transitions of care with clearly defined patient Population(s), Intervention(s), Comparison(s), and appropriately selected Outcomes were determined. These centered around specific transitions of care within the setting of ACS, specifically perioperative interactions, emergency medical services and trauma team interactions, and intra/interfloor and intensive care unit (ICU) interactions. A systematic literature review and meta-analysis were conducted using the Grading of Recommendations Assessment, Development, and Evaluation methodology. RESULTS: A total of 10 studies were identified for analysis. These included 5,113 patients in the standardized handoff group and 5,293 in the current process group. Standardized handoffs reduced handover errors for perioperative interactions and preventable adverse events for intra/interfloor and ICU interactions. There were insufficient data to evaluate outcomes of clinical complications and medical errors. CONCLUSION: We conditionally recommend a standardized handoff in the field of ACS, including perioperative interactions, emergency medical services and trauma team interactions, and intra/interfloor and ICU interactions. LEVEL OF EVIDENCE: Systematic Review/Meta-analysis; Level III.
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Transferência da Responsabilidade pelo Paciente , Humanos , Equipe de Assistência ao Paciente/organização & administração , Equipe de Assistência ao Paciente/normas , Transferência da Responsabilidade pelo Paciente/normas , Transferência da Responsabilidade pelo Paciente/organização & administração , Transferência de Pacientes/normas , Ferimentos e Lesões/cirurgia , Ferimentos e Lesões/terapiaRESUMO
BACKGROUNDIdentifying factors that predict the timing of HIV rebound after treatment interruption will be crucial for designing and evaluating interventions for HIV remission.METHODSWe performed a broad evaluation of viral and immune factors that predict viral rebound (AIDS Clinical Trials Group A5345). Participants initiated antiretroviral therapy (ART) during chronic (N = 33) or early (N = 12) HIV infection with ≥ 2 years of suppressive ART and restarted ART if they had 2 viral loads ≥ 1,000 copies/mL after treatment interruption.RESULTSCompared with chronic-treated participants, early-treated individuals had smaller and fewer transcriptionally active HIV reservoirs. A higher percentage of HIV Gag-specific CD8+ T cell cytotoxic response was associated with lower intact proviral DNA. Predictors of HIV rebound timing differed between early- versus chronic-treated participants, as the strongest reservoir predictor of time to HIV rebound was level of residual viremia in early-treated participants and intact DNA level in chronic-treated individuals. We also identified distinct sets of pre-treatment interruption viral, immune, and inflammatory markers that differentiated participants who had rapid versus slow rebound.CONCLUSIONThe results provide an in-depth overview of the complex interplay of viral, immunologic, and inflammatory predictors of viral rebound and demonstrate that the timing of ART initiation modifies the features of rapid and slow viral rebound.TRIAL REGISTRATIONClinicalTrials.gov NCT03001128FUNDINGNIH National Institute of Allergy and Infectious Diseases, Merck.
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Infecções por HIV , Humanos , Provírus/genética , Linfócitos T CD8-Positivos , Carga Viral , DNARESUMO
CD4+ T cells with latent HIV-1 infection persist despite treatment with antiretroviral agents and represent the main barrier to a cure of HIV-1 infection. Pharmacological disruption of viral latency may expose HIV-1-infected cells to host immune activity, but the clinical efficacy of latency-reversing agents for reducing HIV-1 persistence remains to be proven. Here, we show in a randomized-controlled human clinical trial that the histone deacetylase inhibitor panobinostat, when administered in combination with pegylated interferon-α2a, induces a structural transformation of the HIV-1 reservoir cell pool, characterized by a disproportionate overrepresentation of HIV-1 proviruses integrated in ZNF genes and in chromatin regions with reduced H3K27ac marks, the molecular target sites for panobinostat. By contrast, proviruses near H3K27ac marks were actively selected against, likely due to increased susceptibility to panobinostat. These data suggest that latency-reversing treatment can increase the immunological vulnerability of HIV-1 reservoir cells and accelerate the selection of epigenetically privileged HIV-1 proviruses.
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Infecções por HIV , HIV-1 , Inibidores de Histona Desacetilases , Interferon-alfa , Panobinostat , Provírus , Humanos , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Panobinostat/uso terapêutico , Provírus/efeitos dos fármacos , Latência Viral , Inibidores de Histona Desacetilases/uso terapêutico , Interferon-alfa/uso terapêuticoRESUMO
The treatment for COVID-19 has evolved rapidly since the start of the pandemic and now consists mainly of antiviral and immunomodulatory agents. Antivirals, such as remdesivir and nirmatrelvir-ritonavir, have proved to be most useful earlier in illness (e.g., as outpatient therapy) and for less severe disease. Immunomodulatory therapies, such as dexamethasone and interleukin-6 or Janus kinase inhibitors, are most useful in severe disease or critical illness. The role of anti-SARS-CoV-2 monoclonal antibodies has diminished because of the emergence of viral variants that are not anticipated to be susceptible to these treatments, and there still is not a consensus on the use of convalescent plasma. COVID-19 has been associated with increased rates of venous thromboembolism, but the role of antithrombotic therapy is limited. Multiple investigational agents continue to be studied, which will alter current treatment paradigms as new data are released.
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COVID-19 , Inibidores de Janus Quinases , Humanos , Soroterapia para COVID-19 , Imunomodulação , Interleucina-6 , Inibidores de Janus Quinases/uso terapêuticoAssuntos
Tosse , Dispneia , Idoso , Feminino , Humanos , Tosse/etiologia , Diagnóstico Diferencial , Dispneia/etiologiaRESUMO
Objectives: The risk factors for anastomotic leak (AL) after resection and primary anastomosis for traumatic bucket handle injury (BHI) have not been previously defined. This multicenter study was conducted to address this knowledge gap. Methods: This is a multicenter retrospective study on small intestine and colonic BHIs from blunt trauma between 2010 and 2021. Baseline patient characteristics, risk factors, presence of shock and transfusion, operative details, and clinical outcomes were compared using R. Results: Data on 395 subjects were submitted by 12 trauma centers, of whom 33 (8.1%) patients developed AL. Baseline details were similar, except for a higher proportion of patients in the AL group who had medical comorbidities such as diabetes, hypertension, and obesity (60.6% vs. 37.3%, p=0.015). AL had higher rates of surgical site infections (13.4% vs. 5.3%, p=0.004) and organ space infections (65.2% vs. 11.7%, p<0.001), along with higher readmission and reoperation rates (48.4% vs. 9.1%, p<0.001, and 39.4% vs. 11.6%, p<0.001, respectively). There was no difference in intensive care unit length of stay or mortality (p>0.05). More patients with AL were discharged with an ostomy (69.7% vs. 7.3%, p<0.001), and the mean duration until ostomy reversal was 5.85±3 months (range 2-12.4 months). The risk of AL significantly increased when the initial operation was a damage control procedure, after adjusting for age, sex, injury severity, presence of one or more comorbidities, shock, transfusion of >6 units of packed red blood cells, and site of injury (adjusted RR=2.32 (1.13, 5.17)), none of which were independent risk factors in themselves. Conclusion: Damage control surgery performed as the initial operation appears to double the risk of AL after intestinal BHI, even after controlling for other markers of injury severity. Level of evidence: III.
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In this Viewpoint, the authors summarize the therapeutic landscape for COVID-19, discuss who is most likely to benefit from treatment, provide an update on managing illness in immunocompromised individuals, and highlight how to improve COVID-19 treatment.
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IL-15 is under clinical investigation toward the goal of curing HIV infection because of its abilities to reverse HIV latency and enhance immune effector function. However, increased potency through combination with other agents may be needed. 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) enhances IL-15-mediated latency reversal and NK cell function by increasing STAT5 activation. We hypothesized that HODHBt would also synergize with IL-15, via STAT5, to directly enhance HIV-specific cytotoxic T cell responses. We showed that ex vivo IL-15 + HODHBt treatment markedly enhanced HIV-specific granzyme B-releasing T cell responses in PBMCs from antiretroviral therapy-suppressed (ART-suppressed) donors. We also observed upregulation of antigen processing and presentation in CD4+ T cells and increased surface MHC-I. In ex vivo PBMCs, IL-15 + HODHBt was sufficient to reduce intact proviruses in 1 of 3 ART-suppressed donors. Our findings reveal the potential for second-generation IL-15 studies incorporating HODHBt-like therapeutics. Iterative studies layering on additional latency reversal or other agents are needed to achieve consistent ex vivo reservoir reductions.
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Antineoplásicos , Infecções por HIV , Humanos , Fator de Transcrição STAT5/metabolismo , Interleucina-15/farmacologia , Interleucina-15/metabolismo , Latência Viral , Linfócitos T Citotóxicos , Antineoplásicos/uso terapêuticoRESUMO
BACKGROUND: Antiretroviral treatment improves health related quality of life (HRQoL) of people with human immunodeficiency virus (PWH). However, one third initiating first-line treatment experience virological failure and the determinants of HRQoL in this key population are unknown. Our study aims to identify determinants of among PWH failing antiretroviral treatment in sub-Saharan Africa. METHODS: We analysed data from a cohort of PWH having virological failure (> 1,000 copies/mL) on first-line ART in South Africa and Uganda. We measured HRQoL using the EuroQOL EQ-5D-3L and used a two-part regression model to obtain by-country analyses for South Africa and Uganda. The first part identifies risk factors that were associated with the likelihood of participants reporting perfect health (utility = 1) versus non-perfect health (utility < 1). The second part identifies risk factors that were associated with the EQ-5 L-3L utility scores for participants reporting non-perfect health. We performed sensitivity analyses to compare the results between the two-part model using tobit models and ordinary least squares regression. RESULTS: In both countries, males were more likely to report perfect health and participants with at least one comorbidity were less likely to report perfect health. In South Africa, participants with side effects and in Uganda those with opportunistic infections were also less likely to report perfect health. In Uganda, participants with 100% ART adherence were more likely to report perfect health. In South Africa, high HIV viral load, experiencing ART side effects, and the presence of opportunistic infections were each associated with lower HRQoL, whereas participants with 100% ART adherence reported higher HRQoL. In Uganda participants with lower CD4 count had lower HRQoL. CONCLUSION: Markers of advanced disease (opportunistic infection, high viral load, low CD4), side effects, comorbidities and lack of ART adherence negatively impacted HRQoL for PWH experiencing virological failure. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02787499.
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Infecções por HIV , Infecções Oportunistas , Masculino , Humanos , HIV , Qualidade de Vida , África do Sul/epidemiologia , Antirretrovirais , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologiaRESUMO
While the coronavirus disease 2019 (COVID-19) pandemic continues to present global challenges, sufficient time has passed to reflect on lessons learned and use those insights to inform policy and approaches to prepare for the next pandemic. In May 2022, the Duke Clinical Research Institute convened a think tank with thought leaders from academia, clinical practice, the pharmaceutical industry, patient advocacy, the National Institutes of Health, the US Food and Drug Administration, and the Centers for Disease Control and Prevention to share, firsthand, expert knowledge of the insights gained from the COVID-19 pandemic and how this acquired knowledge can help inform the next pandemic response. The think tank focused on pandemic preparedness, therapeutics, vaccines, and challenges related to clinical trial design and scale-up during the early phase of a pandemic. Based on the multi-faceted discussions, we outline 10 key steps to an improved and equitable pandemic response.
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COVID-19 , Estados Unidos , Humanos , Pandemias/prevenção & controle , National Institutes of Health (U.S.)RESUMO
BACKGROUND: Primary aim was to assess the relative risk (RR) of anastomotic leak (AL) in intestinal bucket-handle (BH) compared to non-BH injury. METHODS: Multi-center study comparing AL in BH from blunt trauma 2010-2021 compared to non-BH intestinal injuries. RR was calculated for small bowel and colonic injury using R. RESULTS: AL occurred in 20/385 (5.2%) of BH vs. 4/225 (1.8%) of non-BH small intestine injury. AL was diagnosed 11.6 ± 5.6 days from index operation in small intestine BH and 9.7 ± 4.3 days in colonic BH. Adjusted RR for AL was 2.32 [0.77-6.95] for small intestinal and 4.83 [1.47-15.89] for colonic injuries. AL increased infections, ventilator days, ICU & total length of stay, reoperation, and readmission rates, although mortality was unchanged. CONCLUSION: BH carries a significantly higher risk of AL, particularly in the colon, than other blunt intestinal injuries.
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Traumatismos Abdominais , Ferimentos não Penetrantes , Humanos , Fístula Anastomótica/epidemiologia , Fístula Anastomótica/etiologia , Estudos Retrospectivos , Colo/cirurgia , Colo/lesões , Intestinos/lesões , Ferimentos não Penetrantes/cirurgia , Traumatismos Abdominais/cirurgia , Anastomose CirúrgicaRESUMO
Burn injury causes a coagulopathy that is poorly understood. After severe burns, significant fluid losses are managed by aggressive resuscitation that can lead to hemodilution. These injuries are managed by early excision and grafting, which can cause significant bleeding and further decrease blood cell concentration. Tranexamic acid (TXA) is an anti-fibrinolytic that has been shown to reduce surgical blood losses; however, its use in burn surgery is not well established. We performed a systematic review and meta-analysis to investigate the influence TXA may have on burn surgery outcomes. Eight papers were included, with outcomes considered in a random-effects model meta-analysis. Overall, when compared to the control group, TXA significantly reduced total volume blood loss (mean difference (MD) = -192.44; 95% confidence interval (CI) = -297.73 to - 87.14; P = 0.0003), the ratio of blood loss to burn injury total body surface area (TBSA) (MD = -7.31; 95% CI = -10.77 to -3.84; P 0.0001), blood loss per unit area treated (MD = -0.59; 95% CI = -0.97 to -0.20; P = 0.003), and the number of patients receiving a transfusion intraoperatively (risk difference (RD) = -0.16; 95% CI = -0.32 to - 0.01; P = 0.04). Additionally, there were no noticeable differences in venous thromboembolism (VTE) events (RD = 0.00; 95% CI = -0.03 to 0.03; P = 0.98) and mortality (RD = 0.00; 95% CI = -0.03 to 0.04; P = 0.86). In conclusion, TXA can potentially be a pharmacologic intervention that reduces blood losses and transfusions in burn surgery without increasing the risk of VTE events or mortality.
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Antifibrinolíticos , Queimaduras , Ácido Tranexâmico , Tromboembolia Venosa , Humanos , Ácido Tranexâmico/uso terapêutico , Antifibrinolíticos/uso terapêutico , Tromboembolia Venosa/prevenção & controle , Queimaduras/cirurgia , Queimaduras/tratamento farmacológico , Perda Sanguínea Cirúrgica/prevenção & controleRESUMO
PURPOSE OF REVIEW: We review the intersection between the HIV and COVID-19 pandemics, particularly the impact of HIV infection on the development of severe COVID-19. RECENT FINDINGS: Studies early in the COVID-19 pandemic did not find a clear link between HIV infection and increased COVID-19 severity or mortality. People with HIV (PWH) were more likely to have severe COVID-19, but much of the risk for worse outcomes was related to high rates of comorbidities and social determinants of health. Although comorbidities and social determinants of health are certainly critically important reasons for severe COVID-19 among PWH, recent large studies have found HIV infection - particularly when the CD4 cell count is low or HIV RNA is not suppressed - is an independent risk factor for COVID-19 severity. The link between HIV and severe COVID-19 highlights the need to diagnose and treat HIV as well as the importance of COVID-19 vaccination and treatment among PWH. SUMMARY: People with HIV have faced increased challenges during the COVID-19 pandemic because of high rates of comorbidities and social determinants of health as well as the impact of HIV on COVID-19 severity. Information on the intersection of the two pandemics has been crucial to improving care for people with HIV.
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COVID-19 , Infecções por HIV , Humanos , Infecções por HIV/complicações , COVID-19/epidemiologia , Vacinas contra COVID-19 , Pandemias , Fatores de RiscoRESUMO
OBJECTIVE: This study aimed to evaluate the 9-month cost and health-related quality of life (HRQOL) outcomes of resistance versus viral load testing strategies to manage virological failure in low-middle income countries. METHODS: We analyzed secondary outcomes from the REVAMP clinical trial: a pragmatic, open label, parallel-arm randomized trial investigating resistance versus viral load testing for individuals failing first-line treatment in South Africa and Uganda. We collected resource data, valued according to local cost data and used the 3-level version of EQ-5D to measure HRQOL at baseline and 9 months. We applied seemingly unrelated regression equations to account for the correlation between cost and HRQOL. We conducted intention-to-treat analyses with multiple imputation using chained equations for missing data and performed sensitivity analyses using complete cases. RESULTS: For South Africa, resistance testing and opportunistic infections were associated with statistically significantly higher total costs, and virological suppression was associated with lower total cost. Higher baseline utility, higher cluster of differentiation 4 (CD4) count, and virological suppression were associated with better HRQOL. For Uganda, resistance testing and switching to second-line treatment were associated with higher total cost, and higher CD4 was associated with lower total cost. Higher baseline utility, higher CD4 count, and virological suppression were associated with better HRQOL. Sensitivity analyses of the complete-case analysis confirmed the overall results. CONCLUSION: Resistance testing showed no cost or HRQOL advantage in South Africa or Uganda over the 9-month REVAMP clinical trial.
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Fármacos Anti-HIV , Humanos , Fármacos Anti-HIV/uso terapêutico , Qualidade de Vida , África do SulRESUMO
HIV post-treatment controllers (PTCs) are rare individuals who maintain low levels of viremia after stopping antiretroviral therapy (ART). Understanding the mechanisms of HIV post-treatment control will inform development of strategies aiming at achieving HIV functional cure. In this study, we evaluated 22 PTCs from 8 AIDS Clinical Trials Group (ACTG) analytical treatment interruption (ATI) studies who maintained viral loads ≤400 copies/mL for ≥24 wk. There were no significant differences in demographics or frequency of protective and susceptible human leukocyte antigen (HLA) alleles between PTCs and post-treatment noncontrollers (NCs, n = 37). Unlike NCs, PTCs demonstrated a stable HIV reservoir measured by cell-associated RNA (CA-RNA) and intact proviral DNA assay (IPDA) during analytical treatment interruption (ATI). Immunologically, PTCs demonstrated significantly lower CD4+ and CD8+ T cell activation, lower CD4+ T cell exhaustion, and more robust Gag-specific CD4+ T cell responses and natural killer (NK) cell responses. Sparse partial least squares discriminant analysis (sPLS-DA) identified a set of features enriched in PTCs, including a higher CD4+ T cell% and CD4+/CD8+ ratio, more functional NK cells, and a lower CD4+ T cell exhaustion level. These results provide insights into the key viral reservoir features and immunological profiles for HIV PTCs and have implications for future studies evaluating interventions to achieve an HIV functional cure.
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Linfócitos T CD8-Positivos , Infecções por HIV , Humanos , Células Matadoras Naturais , Ativação Linfocitária , RNA , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , ViremiaRESUMO
Fourteen people with human immunodeficiency virus type 1 had longitudinal measurements of intact, defective, and total proviral DNA over the course of two decades of antiretroviral therapy. Three patterns of intact proviral DNA decay were revealed: (1) biphasic decline with markedly slower second-phase decline, (2) initial decline that transitions to a zero-slope plateau, and (3) initial decline followed by later increases in intact proviral DNA. Defective proviral DNA levels were essentially stable. Mechanisms of slowing or reversal of second-phase decay of intact proviral DNA may include the inability to clear cells with intact but transcriptionally silent proviruses and clonal expansion of cells with intact proviruses.