A specific natural killer cells phenotypic signature associated to long term elite control of HIV infection.

Elite controllers (ECs) are an exceptional group of people living with HIV (PLWH) that control HIV replication without therapy. Among the mechanisms involved in this ability, natural killer (NK)-cells have recently gained much attention. We performed an in-deep phenotypic analysis of NK-cells to search for surrogate markers associated with the long term spontaneous control of HIV. Forty-seven PLWH (22 long-term EC [PLWH-long-term elite controllers (LTECs)], 15 noncontrollers receiving antiretroviral treatment [ART] [PLWH-onART], and 10 noncontrollers cART-naïve [PLWH-offART]), and 20 uninfected controls were included. NK-cells homeostasis was analyzed by spectral flow cytometry using a panel of 15 different markers. Data were analyzed using FCSExpress and R software for unsupervised multidimensional analysis. Six different subsets of NK-cells were defined on the basis of CD16 and CD56 expression, and the multidimensional analysis revealed the existence of 68 different NK-cells clusters based on the expression levels of the 15 different markers. PLWH-offART presented the highest disturbance of NK-cells homeostasis and this was not completely restored by long-term ART. Interestingly, long term spontaneous control of HIV (PLWH-LTEC group) was associated with a specific profile of NK-cells homeostasis disturbance, characterized by an increase of CD16dimCD56dim subset when compared to uninfected controls (UC) group and also to offART and onART groups (p < 0.0001 for the global comparison), an increase of clusters C16 and C26 when compared to UC and onART groups (adjusted p-value < 0.05 for both comparisons), and a decrease of clusters C10 and C20 when compared to all the other groups (adjusted p-value < 0.05 for all comparisons). These findings may provide clues to elucidate markers of innate immunity with a relevant role in the long-term control of HIV.

O trânsito entre armários: encontros entre ativismo, HIV e arte no Brasil / Transit between closets: encounters between activism, HIV and art in Brazil

Esta tese é resultado de uma investigação com o objetivo geral de compreender os trânsitos entre arte, ativismo e saúde nas narrativas de vida de artistas vivendo com HIV que trazem a temática do HIV e da AIDS para seus trabalhos artísticos. Para o alcance desta finalidade, recorro a narrativas de vida, começando pela minha própria em busca de (des)encontros a partir do trânsito entre diferentes armários sociais, mergulhando em conceitos como a epistemologia do armário (Sedgwick, 2007) e artivismo (Chaia, 2007; Machado, 2019; Baldissera, 2019). Na busca por caminhos metodológicos, trago reflexões sobre pesquisa qualitativa, com a consciência de que me envolvo no que me é familiar (Velho, 1978) e encontro na etnossociologia as narrativas de vida proposta por Bertaux (2010) uma luz a guiar as entrevistas e a análise das informações, produzindo dados por meio de conversas narrativas. As entrevistas ocorreram durante a pandemia de COVID-19 de forma remota no final do ano de 2021 e início de 2022. Essa pesquisa chega a seguintes considerações: a arte, como um antirretroviral social, tem uma força na desconstrução dos vírus ideológicos (Daniel, 2018) e no renascimento de mortes sociais (Daniel, 2018) com produção de deslocamentos e transformações. No processo dos artistas vivendo que aqui chamo de artistas-autores participantes, a ancestralidade é uma fonte artística, em um continuum artístico. Por fim, o campo da saúde tem o desafio de incorporar ainda mais arte em seus processos de pesquisa e produção de conhecimento, de forma a explorar as infinitas possibilidades que o campo saúde e arte pode trazer para o lidar com doenças estigmatizadas.

This thesis results from an investigation with the general objective of understanding the transits between art, activism, and health in the life narratives of artists living with HIV who bring the theme of HIV and AIDS to their artistic works. To achieve this purpose, I resort to life narratives, starting with my own in search of (mis)encounters from the transit between different social closets, diving into concepts such as closet epistemology (Sedgwick, 2007) and artivism (Chaia, 2007; Machado, 2019; Baldissera, 2019). In the search for methodological paths, I bring reflections on qualitative research, with the awareness that I am involved in what is familiar to me (Velho, 1978). I find in ethnosociology the life narratives proposed by Bertaux (2010) a light to guide the interviews and the analysis of information, producing data through narrative conversations. The interviews occurred remotely during the COVID-19 pandemic at the end of 2021 and the beginning of 2022. This research reaches the following considerations: art, as a social antiretroviral, has a force in deconstructing ideological viruses (Daniel, 2018) and in the revival of social deaths (Daniel, 2018) with the production of displacements and transformations. In the process of living artists that I call participating artist-authors here, ancestry is an artistic source in an artistic continuum. Finally, the field of health has the challenge of incorporating even more art into its research processes and production of knowledge to explore the infinite possibilities that the field health and art can bring to response stigmatized diseases.

Two Distinct Mechanisms Leading to Loss of Virological Control in the Rare Group of Antiretroviral Therapy-Naive, Transiently Aviremic Children Living with HIV.

HIV-specific CD8+ T cells play a central role in immune control of adult HIV, but their contribution in pediatric infection is less well characterized. Previously, we identified a group of ART-naive children with persistently undetectable plasma viremia, termed "elite controllers," and a second group who achieved aviremia only transiently. To investigate the mechanisms of failure to maintain aviremia, we characterized in three transient aviremic individuals (TAs), each of whom expressed the disease-protective HLA-B*81:01, longitudinal HIV-specific T-cell activity, and viral sequences. In two TAs, a CD8+ T-cell response targeting the immunodominant epitope TPQDLNTML (Gag-TL9) was associated with viral control, followed by viral rebound and the emergence of escape variants with lower replicative capacity. Both TAs mounted variant-specific responses, but only at low functional avidity, resulting in immunological progression. In contrast, in TA-3, intermittent viremic episodes followed aviremia without virus escape or a diminished CD4+ T-cell count. High quality and magnitude of the CD8+ T-cell response were associated with aviremia. We therefore identify two distinct mechanisms of loss of viral control. In one scenario, CD8+ T-cell responses initially cornered low-replicative-capacity escape variants, but with insufficient avidity to prevent viremia and disease progression. In the other, loss of viral control was associated with neither virus escape nor progression but with a decrease in the quality of the CD8+ T-cell response, followed by recovery of viral control in association with improved antiviral response. These data suggest the potential for a consistently strong and polyfunctional antiviral response to achieve long-term viral control without escape. IMPORTANCE Very early initiation of antiretroviral therapy (ART) in pediatric HIV infection offers a unique opportunity to limit the size and diversity of the viral reservoir. However, only rarely is ART alone sufficient to achieve remission. Additional interventions that likely include contributions from host immunity are therefore required. The HIV-specific T-cell response plays a central role in immune control of adult HIV, often mediated through protective alleles such as HLA-B*57/58:01/81:01. However, due to the tolerogenic and type 2 biased immune response in early life, HLA-I-mediated immune suppression of viremia is seldom observed in children. We assessed a rare group of HLA-B*81:01-positive, ART-naive children who achieved aviremia, albeit only transiently, and investigated the role of the CD8+ T-cell response in the establishment and loss of viral control. We identified a mechanism by which the HIV-specific response can achieve viremic control without viral escape that can be explored in strategies to achieve remission.

Combination Immune Checkpoint Blockade Enhances IL-2 and CD107a Production from HIV-Specific T Cells Ex Vivo in People Living with HIV on Antiretroviral Therapy.

In people with HIV (PWH) on antiretroviral therapy (ART), immune dysfunction persists, including elevated expression of immune checkpoint (IC) proteins on total and HIV-specific T cells. Reversing immune exhaustion is one strategy to enhance the elimination of HIV-infected cells that persist in PWH on ART. We aimed to evaluate whether blocking CTL-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), T cell Ig domain and mucin domain 3 (TIM-3), T cell Ig and ITIM domain (TIGIT) and lymphocyte activation gene-3 (LAG-3) alone or in combination would enhance HIV-specific CD4+ and CD8+ T cell function ex vivo. Intracellular cytokine staining was performed using human PBMCs from PWH on ART (n = 11) and expression of CD107a, IFN-γ, TNF-α, and IL-2 was quantified with HIV peptides and Abs to IC. We found the following: 1) IC blockade enhanced the induction of CD107a and IL-2 but not IFN-γ and TNF-α in response to Gag and Nef peptides; 2) the induction of CD107a and IL-2 was greatest with multiple combinations of two Abs; and 3) Abs to LAG-3, CTLA-4, and TIGIT in combinations showed synergistic induction of IL-2 in HIV-specific CD8+ and CD107a and IL-2 production in HIV-specific CD4+ and CD8+ T cells. These results demonstrate that the combination of Abs to LAG-3, CTLA-4, or TIGIT can increase the frequency of cells expressing CD107a and IL-2 that associated with cytotoxicity and survival of HIV-specific CD4+ and CD8+ T cells in PWH on ART. These combinations should be further explored for an HIV cure.

HIV knowledge and its correlation with the Undetectable = Untransmittable slogan in Brazil

ABSTRACT Knowledge about HIV transmission and prevention is a necessary step for adopting preventive behaviors. We assessed HIV knowledge and its correlation with the perceived accuracy of the "Undetectable = Untransmittable" (U=U) slogan in an online sample with 401 adult Brazilians. Overall, 28% of participants showed high HIV knowledge level. The perceived accuracy of the U=U slogan significantly correlated with HIV knowledge. Younger participants, those reporting lower income or lower education, or who had never tested for HIV showed poorer HIV knowledge. Filling gaps of knowledge among specific populations is urgent in order to increase preventive behaviors and decrease HIV stigma.

Memórias, trajetórias e experiência no campo do cuidado às pessoas vivendo com HIV/AIDS: uma autoetnografia / Memories, trajectories and experience in the field of care for people living with HIV/AIDS: an autoethnography

Essa dissertação comparece entrelaçando produção de conhecimento no campo da atenção e pesquisa dirigida às crianças, adolescentes, jovens e gestantes vivendo com Hiv/aids, e minhas memórias e experiência no campo do cuidado. Para tanto assume a perspectiva metodológica autoetnográfica sustentada pela discussão da Antropologia das Emoções. Isso porque compreendemos que a mobilização das memórias, experiência e trajetória da autora não passa impune pela sensibilização necessária de si própria. E esse processo de sensibilizar invade o texto, que utiliza como dispositivo para mobilizar os leitores, sensibilizando-os, a produção autoral de crônicas, contos e poesias. Partindo desse dispositivo, pretendemos também embaçar possíveis personagens reais, e alcançar figuras que reúnem traços comuns a muitos e muitas que fazem parte das práticas de pesquisa e atenção no campo do Hiv/aids. Alertamos que a dimensão autoetnográfica se revela processo de narrativização da convivência com aqueles e aquelas que durante 20 anos foram atendidos e participantes de pesquisas mediadas pela autora. Organizamos o acervo de crônicas / contos /poesias abrindo cada um dos três núcleos que organizam a produção de conhecimento nessa trajetória: 1) Estigma e Suas Reatualizações; (2) Quando o Segredo Cola com a Doença: Segredo ­ Sigilo ­ Revelação; (3) O Caleidoscópio do Cuidado e a Entrada do Psicólogo no Hospital Geral. Concluímos que para quem ainda está na linha de cuidados de pessoas que vivem com Hiv/aids, essa dissertação é um convite afetivo de refletir sobre esses conceitos encarnados. E ter a oportunidade de pensar criticamente a construção de práticas que cuidam e que incluem, mas também, e principalmente, pensar para transformar as práticas que reproduzem, atualizam e perpetuam práticas violentas de des-cuidado, de opressão e exclusão, e como isso opera como um Sistema naturalizado que se repete como uma estrutura de medicalização da vida e redução da mesma a elementos de controle racional.

This dissertation has come forward intertwining the building up of knowledge from clinical trials with children, adolescents, youngsters, and pregnant women living with Hiv/aids and memories, experiences I have lived as caregiver. It embodies the methodological autoethnographic perspective upheld by the debate of Anthropology of Emotions because we understand that mustering the author's remembrances, assignments and trajectory does not waive the necessary awareness of oneself. And this process pervades the text that utilizes the authorial production of chronicles, short-stories, and poetry to reach out and touch the readers. With ingenuity, we envisage to shadow possible actual characters and engage archetypes with common features to many who are part of HIV/aids researches and attention. We remark that the autoethnographic dimension translates into a narrative about living with those who for 20 years are cared, and study participants mediated by the author. Chronicles, short-stories, poetries were gathered to reflect each one of the three hubs which deploy the production of knowledge in this trajectory: 1) Stigma and its novel updates; 2) When the secret sticks to the disease: Secret ­ Secrecy ­ Disclosure. 3) Kaleidoscope of care and the psychologist arrival at the general hospital. The conclusion we have reached for those who are still caring for persons who live with HIV/aids is that this dissertation is a gentle invitation to reflect about these concepts actually experienced. And embrace the opportunity to review critically the elaboration of caring and inclusive practices but mainly to think in transforming those which replicate, refresh, and perpetuate violent and uncaring conducts of oppression and exclusion and how a naturalized system functions, repeating itself as a medicalization and demeaning life structure to mere rational control.

Instruments to assess adherence to medication in people living with HIV: a scoping review / Instrumentos para avaliar a adesão medicamentosa em pessoas vivendo com HIV: uma revisão de escopo

ABSTRACT OBJECTIVE To compile the instruments validated in Brazil for assessing adherence of people living with HIV to antiretroviral therapy. METHODS Scoping review using the Web of Science, Scopus, Medline (via PubMed), Embase, BDENF, CINAHL and Lilacs databases. In addition, the Preprints bioRxiv, Google Scholar and OpenGrey servers were checked. There was no language restriction for the search, and it considered articles published from the year 1996 onwards. RESULTS Three publications were included in the qualitative synthesis. Following were the instruments identified "Questionário para Avaliação da Adesão ao Tratamento Antirretroviral" (Questionnaire for Assessment of Adherence to Antiretroviral Treatment) developed in Porto Alegre (RS) and published in 2007; the "Escala de autoeficácia para adesão ao tratamento antirretroviral em crianças e adolescentes com HIV/Aids" (Self-efficacy Scale for Adherence to Antiretroviral Treatment in Children and Adolescents with HIV/Aids) developed in São Paulo (SP) and published in 2008; and the "WebAd-Q, um instrumento de autorrelato para monitorar a adesão à terapia antirretroviral em serviços de HIV/Aids no Brasil" (WebAd-Q, a self-report instrument to monitor adherence to antiretroviral therapy in HIV/Aids services in Brazil) developed in São Bernardo do Campo (SP) and published in 2018. The instruments were validated in Brazil, and presented statistically acceptable values for psychometric qualities. CONCLUSION The instruments to assess adherence of people living with HIV to antiretroviral therapy are validated strategies for the Brazilian context. However, their (re)use in different settings and contexts of the nation should be expanded. The use of these instruments by health professionals can improve the understanding of factors that act negatively and positively on antiretroviral therapy adherence, and the proposition of strategies intended to consolidate good adherence and intervene in the treatment of people with low therapeutic engagement.

RESUMO OBJETIVO Compilar os instrumentos validados no Brasil para avaliação da adesão de pessoas vivendo com HIV à terapia antirretroviral. MÉTODOS Revisão de escopo, utilizando as bases de dados Web of Science, Scopus, Medline (via PubMed), Embase, BDENF, CINAHL e Lilacs. Em complementação, os servidores Preprints bioRxiv, Google Scholar e OpenGrey foram verificados. Para a busca, não houve restrição de idioma e considerou artigos publicados a partir do ano de 1996. RESULTADOS Três publicações foram incluídas na síntese qualitativa. Os instrumentos identificados foram o "Questionário para Avaliação da Adesão ao Tratamento Antirretroviral", desenvolvido em Porto Alegre (RS) e publicado em 2007; a "Escala de autoeficácia para adesão ao tratamento antirretroviral em crianças e adolescentes com HIV/Aids", desenvolvida em São Paulo (SP) e publicada em 2008; e o "WebAd-Q, um instrumento de autorrelato para monitorar a adesão à terapia antirretroviral em serviços de HIV/Aids no Brasil", desenvolvido em São Bernardo do Campo (SP) e publicado em 2018. Os instrumentos foram validados no Brasil e apresentaram valores estatisticamente aceitáveis para as qualidades psicométricas. CONCLUSÃO Os instrumentos para avaliar a adesão de pessoas vivendo com HIV à terapia antirretroviral são estratégias validadas para o contexto do Brasil. Todavia há que se expandir a (re)utilização em diferentes cenários e contextos da nação. A utilização desses instrumentos por profissionais da saúde pode melhorar a compreensão dos fatores que atuam negativa e positivamente na adesão à terapia antirretroviral, e a proposição de estratégias com o objetivo de consolidar a boa adesão e intervir no tratamento das pessoas com baixo engajamento terapêutico.

Delayed antiretroviral therapy in HIV-infected individuals leads to irreversible depletion of skin- and mucosa-resident memory T cells.

People living with HIV (PLWH) are at increased risk for developing skin and mucosal malignancies despite systemic reconstitution of CD4+ T cells upon antiretroviral therapy (ART). The underlying mechanism of chronic tissue-related immunodeficiency in HIV is unclear. We found that skin CD4+ tissue-resident memory T (Trm) cells were depleted after HIV infection and replenished only upon early ART initiation. TCR clonal analysis following early ART suggested a systemic origin for reconstituting CD4+ Trm cells. Single-cell RNA sequencing in PLWH that received late ART treatment revealed a loss of CXCR3+ Trm cells and a tolerogenic skin immune environment. Human papilloma virus-induced precancerous lesion biopsies showed reduced CXCR3+ Trm cell frequencies in the mucosa in PLWH versus HIV- individuals. These results reveal an irreversible loss of CXCR3+ Trm cells confined to skin and mucosa in PLWH who received late ART treatment, which may be a precipitating factor in the development of HPV-related cancer.

Tuberculosis preventive therapy for people living with HIV: A systematic review and network meta-analysis.

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) is an essential component of care for people living with HIV (PLHIV). We compared efficacy, safety, completion, and drug-resistant TB risk for currently recommended TPT regimens through a systematic review and network meta-analysis (NMA) of randomized trials. METHODS AND FINDINGS: We searched MEDLINE, Embase, and the Cochrane Library from inception through June 9, 2020 for randomized controlled trials (RCTs) comparing 2 or more TPT regimens (or placebo/no treatment) in PLHIV. Two independent reviewers evaluated eligibility, extracted data, and assessed the risk of bias. We grouped TPT strategies as follows: placebo/no treatment, 6 to 12 months of isoniazid, 24 to 72 months of isoniazid, and rifamycin-containing regimens. A frequentist NMA (using graph theory) was carried out for the outcomes of development of TB disease, all-cause mortality, and grade 3 or worse hepatotoxicity. For other outcomes, graphical descriptions or traditional pairwise meta-analyses were carried out as appropriate. The potential role of confounding variables for TB disease and all-cause mortality was assessed through stratified analyses. A total of 6,466 unique studies were screened, and 157 full texts were assessed for eligibility. Of these, 20 studies (reporting 16 randomized trials) were included. The median sample size was 616 (interquartile range [IQR], 317 to 1,892). Eight were conducted in Africa, 3 in Europe, 3 in the Americas, and 2 included sites in multiple continents. According to the NMA, 6 to 12 months of isoniazid were no more efficacious in preventing microbiologically confirmed TB than rifamycin-containing regimens (incidence rate ratio [IRR] 1.0, 95% CI 0.8 to 1.4, p = 0.8); however, 6 to 12 months of isoniazid were associated with a higher incidence of all-cause mortality (IRR 1.6, 95% CI 1.2 to 2.0, p = 0.02) and a higher risk of grade 3 or higher hepatotoxicity (risk difference [RD] 8.9, 95% CI 2.8 to 14.9, p = 0.004). Finally, shorter regimens were associated with higher completion rates relative to longer regimens, and we did not find statistically significant differences in the risk of drug-resistant TB between regimens. Study limitations include potential confounding due to differences in posttreatment follow-up time and TB incidence in the study setting on the estimates of incidence of TB or all-cause mortality, as well as an underrepresentation of pregnant women and children. CONCLUSIONS: Rifamycin-containing regimens appear safer and at least as effective as isoniazid regimens in preventing TB and death and should be considered part of routine care in PLHIV. Knowledge gaps remain as to which specific rifamycin-containing regimen provides the optimal balance of efficacy, completion, and safety.

Economic and modeling evidence for tuberculosis preventive therapy among people living with HIV: A systematic review and meta-analysis.

BACKGROUND: Human immunodeficiency virus (HIV) is the strongest known risk factor for tuberculosis (TB) through its impairment of T-cell immunity. Tuberculosis preventive treatment (TPT) is recommended for people living with HIV (PLHIV) by the World Health Organization, as it significantly reduces the risk of developing TB disease. We conducted a systematic review and meta-analysis of modeling studies to summarize projected costs, risks, benefits, and impacts of TPT use among PLHIV on TB-related outcomes. METHODS AND FINDINGS: We searched MEDLINE, Embase, and Web of Science from inception until December 31, 2020. Two reviewers independently screened titles, abstracts, and full texts; extracted data; and assessed quality. Extracted data were summarized using descriptive analysis. We performed quantile regression and random effects meta-analysis to describe trends in cost, effectiveness, and cost-effectiveness outcomes across studies and identified key determinants of these outcomes. Our search identified 6,615 titles; 61 full texts were included in the final review. Of the 61 included studies, 31 reported both cost and effectiveness outcomes. A total of 41 were set in low- and middle-income countries (LMICs), while 12 were set in high-income countries (HICs); 2 were set in both. Most studies considered isoniazid (INH)-based regimens 6 to 2 months long (n = 45), or longer than 12 months (n = 11). Model parameters and assumptions varied widely between studies. Despite this, all studies found that providing TPT to PLHIV was predicted to be effective at averting TB disease. No TPT regimen was substantially more effective at averting TB disease than any other. The cost of providing TPT and subsequent downstream costs (e.g. post-TPT health systems costs) were estimated to be less than $1,500 (2020 USD) per person in 85% of studies that reported cost outcomes (n = 36), regardless of study setting. All cost-effectiveness analyses concluded that providing TPT to PLHIV was potentially cost-effective compared to not providing TPT. In quantitative analyses, country income classification, consideration of antiretroviral therapy (ART) use, and TPT regimen use significantly impacted cost-effectiveness. Studies evaluating TPT in HICs suggested that TPT may be more effective at preventing TB disease than studies evaluating TPT in LMICs; pooled incremental net monetary benefit, given a willingness-to-pay threshold of country-level per capita gross domestic product (GDP), was $271 in LMICs (95% confidence interval [CI] -$81 to $622, p = 0.12) and was $2,568 in HICs (-$32,115 to $37,251, p = 0.52). Similarly, TPT appeared to be more effective at averting TB disease in HICs; pooled percent reduction in active TB incidence was 20% (13% to 27%, p < 0.001) in LMICs and 37% (-34% to 100%, p = 0.13) in HICs. Key limitations of this review included the heterogeneity of input parameters and assumptions from included studies, which limited pooling of effect estimates, inconsistent reporting of model parameters, which limited sample sizes of quantitative analyses, and database bias toward English publications. CONCLUSIONS: The body of literature related to modeling TPT among PLHIV is large and heterogeneous, making comparisons across studies difficult. Despite this variability, all studies in all settings concluded that providing TPT to PLHIV is potentially effective and cost-effective for preventing TB disease.

Derivation and external validation of a risk score for predicting HIV-associated tuberculosis to support case finding and preventive therapy scale-up: A cohort study.

BACKGROUND: Among people living with HIV (PLHIV), more flexible and sensitive tuberculosis (TB) screening tools capable of detecting both symptomatic and subclinical active TB are needed to (1) reduce morbidity and mortality from undiagnosed TB; (2) facilitate scale-up of tuberculosis preventive therapy (TPT) while reducing inappropriate prescription of TPT to PLHIV with subclinical active TB; and (3) allow for differentiated HIV-TB care. METHODS AND FINDINGS: We used Botswana XPRES trial data for adult HIV clinic enrollees collected during 2012 to 2015 to develop a parsimonious multivariable prognostic model for active prevalent TB using both logistic regression and random forest machine learning approaches. A clinical score was derived by rescaling final model coefficients. The clinical score was developed using southern Botswana XPRES data and its accuracy validated internally, using northern Botswana data, and externally using 3 diverse cohorts of antiretroviral therapy (ART)-naive and ART-experienced PLHIV enrolled in XPHACTOR, TB Fast Track (TBFT), and Gugulethu studies from South Africa (SA). Predictive accuracy of the clinical score was compared with the World Health Organization (WHO) 4-symptom TB screen. Among 5,418 XPRES enrollees, 2,771 were included in the derivation dataset; 67% were female, median age was 34 years, median CD4 was 240 cells/µL, 189 (7%) had undiagnosed prevalent TB, and characteristics were similar between internal derivation and validation datasets. Among XPHACTOR, TBFT, and Gugulethu cohorts, median CD4 was 400, 73, and 167 cells/µL, and prevalence of TB was 5%, 10%, and 18%, respectively. Factors predictive of TB in the derivation dataset and selected for the clinical score included male sex (1 point), ≥1 WHO TB symptom (7 points), smoking history (1 point), temperature >37.5°C (6 points), body mass index (BMI) <18.5kg/m2 (2 points), and severe anemia (hemoglobin <8g/dL) (3 points). Sensitivity using WHO 4-symptom TB screen was 73%, 80%, 94%, and 94% in XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively, but increased to 88%, 87%, 97%, and 97%, when a clinical score of ≥2 was used. Negative predictive value (NPV) also increased 1%, 0.3%, 1.6%, and 1.7% in XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively, when the clinical score of ≥2 replaced WHO 4-symptom TB screen. Categorizing risk scores into low (<2), moderate (2 to 10), and high-risk categories (>10) yielded TB prevalence of 1%, 1%, 2%, and 6% in the lowest risk group and 33%, 22%, 26%, and 32% in the highest risk group for XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively. At clinical score ≥2, the number needed to screen (NNS) ranged from 5.0 in Gugulethu to 11.0 in XPHACTOR. Limitations include that the risk score has not been validated in resource-rich settings and needs further evaluation and validation in contemporary cohorts in Africa and other resource-constrained settings. CONCLUSIONS: The simple and feasible clinical score allowed for prioritization of sensitivity and NPV, which could facilitate reductions in mortality from undiagnosed TB and safer administration of TPT during proposed global scale-up efforts. Differentiation of risk by clinical score cutoff allows flexibility in designing differentiated HIV-TB care to maximize impact of available resources.

The latent tuberculosis cascade-of-care among people living with HIV: A systematic review and meta-analysis.

BACKGROUND: Tuberculosis preventive therapy (TPT) reduces TB-related morbidity and mortality in people living with HIV (PLHIV). Cascade-of-care analyses help identify gaps and barriers in care and develop targeted solutions. A previous latent tuberculosis infection (LTBI) cascade-of-care analysis showed only 18% of persons in at-risk populations complete TPT, but a similar analysis for TPT among PLHIV has not been completed. We conducted a meta-analysis to provide this evidence. METHODS AND FINDINGS: We first screened potential articles from a LTBI cascade-of-care systematic review published in 2016. From this study, we included cohorts that reported a minimum of 25 PLHIV. To identify new cohorts, we used a similar search strategy restricted to PLHIV. The search was conducted in Medline, Embase, Health Star, and LILACS, from January 2014 to February 2021. Two authors independently screened titles and full text and assessed risk of bias using the Newcastle-Ottawa Scale for cohorts and Cochrane Risk of Bias for cluster randomized trials. We meta-analyzed the proportion of PLHIV completing each step of the LTBI cascade-of-care and estimated the cumulative proportion retained. These results were stratified based on cascades-of-care that used or did not use LTBI testing to determine eligibility for TPT. We also performed a narrative synthesis of enablers and barriers of the cascade-of-care identified at different steps of the cascade. A total of 71 cohorts were included, and 70 were meta-analyzed, comprising 94,011 PLHIV. Among the PLHIV included, 35.3% (33,139/94,011) were from the Americas and 29.2% (27,460/94,011) from Africa. Overall, 49.9% (46,903/94,011) from low- and middle-income countries, median age was 38.0 [interquartile range (IQR) 34.0;43.6], and 65.9% (46,328/70,297) were men, 43.6% (29,629/67,947) were treated with antiretroviral therapy (ART), and the median CD4 count was 390 cell/mm3 (IQR 312;458). Among the cohorts that did not use LTBI tests, the cumulative proportion of PLHIV starting and completing TPT were 40.9% (95% CI: 39.3% to 42.7%) and 33.2% (95% CI: 31.6% to 34.9%). Among cohorts that used LTBI tests, the cumulative proportions of PLHIV starting and completing TPT were 60.4% (95% CI: 58.1% to 62.6%) and 41.9% (95% CI:39.6% to 44.2%), respectively. Completion of TPT was not significantly different in high- compared to low- and middle-income countries. Regardless of LTBI test use, substantial losses in the cascade-of-care occurred before treatment initiation. The integration of HIV and TB care was considered an enabler of the cascade-of-care in multiple cohorts. Key limitations of this systematic review are the observational nature of the included studies, potential selection bias in the population selection, only 14 cohorts reported all steps of the cascade-of-care, and barriers/facilitators were not systematically reported in all cohorts. CONCLUSIONS: Although substantial losses were seen in multiple stages of the cascade-of-care, the cumulative proportion of PLHIV completing TPT was higher than previously reported among other at-risk populations. The use of LTBI testing in PLHIV in low- and middle-income countries was associated with higher proportion of the cohorts initiating TPT and with similar rates of completion of TPT.

Skeletal muscle bioenergetic health and function in people living with HIV: association with glucose tolerance and alcohol use.

At-risk alcohol use is prevalent and increases dysglycemia among people living with human immunodeficiency virus (PLWH). Skeletal muscle (SKM) bioenergetic dysregulation is implicated in dysglycemia and type 2 diabetes. The objective of this study was to determine the relationship between at-risk alcohol, glucose tolerance, and SKM bioenergetic function in PLWH. Thirty-five PLWH (11 females, 24 males, age: 53 ± 9 yr, body mass index: 29.0 ± 6.6 kg/m2) with elevated fasting glucose enrolled in the ALIVE-Ex study provided medical history and alcohol use information [Alcohol Use Disorders Identification Test (AUDIT)], then underwent an oral glucose tolerance test (OGTT) and SKM biopsy. Bioenergetic health and function and mitochondrial volume were measured in isolated myoblasts. Mitochondrial gene expression was measured in SKM. Linear regression adjusting for age, sex, and smoking was performed to examine the relationship between glucose tolerance (2-h glucose post-OGTT), AUDIT, and their interaction with each outcome measure. Negative indicators of bioenergetic health were significantly (P < 0.05) greater with higher 2-h glucose (proton leak) and AUDIT (proton leak, nonmitochondrial oxygen consumption, and bioenergetic health index). Mitochondrial volume was increased with the interaction of higher 2-h glucose and AUDIT. Mitochondrial gene expression decreased with higher 2-h glucose (TFAM, PGC1B, PPARG, MFN1), AUDIT (MFN1, DRP1, MFF), and their interaction (PPARG, PPARD, MFF). Decreased expression of mitochondrial genes were coupled with increased mitochondrial volume and decreased bioenergetic health in SKM of PLWH with higher AUDIT and 2-h glucose. We hypothesize these mechanisms reflect poorer mitochondrial health and may precede overt SKM bioenergetic dysregulation observed in type 2 diabetes.

Combined single-cell transcriptional, translational, and genomic profiling reveals HIV-1 reservoir diversity.

Although understanding the diversity of HIV-1 reservoirs is key to achieving a cure, their study at the single-cell level in primary samples remains challenging. We combine flow cytometric multiplexed fluorescent in situ RNA hybridization for different viral genes with HIV-1 p24 protein detection, cell phenotyping, and downstream near-full-length single-cell vDNA sequencing. Stimulation-induced viral RNA-positive (vRNA+) cells from viremic and antiretroviral-therapy (ART)-suppressed individuals differ in their ability to produce p24. In participants on ART, latency-reversing agents (LRAs) induce a wide variety of viral gene transcription and translation patterns with LRA class-specific differences in reactivation potency. Reactivated proviruses, including in p24+ cells, are mostly defective. Although LRAs efficiently induce transcription in all memory cell subsets, we observe induction of translation mostly in effector memory cells, rather than in the long-lived central memory pool. We identify HIV-1 clones with diverse transcriptional and translational patterns between individual cells, and this finding suggests that cell-intrinsic factors influence reservoir persistence and heterogeneity.

Do people living with HIV face more secondary cancers than general population: From the French CANCERVIH network.

INTRODUCTION: People living with HIV (PLWHIV) are at a higher risk of cancer compared to the general population. With improved cancer treatments and the increased life expectancy of PLWHIV, the incidence of second cancers is also expected to increase. METHODS: We reviewed the cases of PLWHIV with cancer that have been presented to the CANCERVIH national multidisciplinary board since 2014. We included all cases with a history of cancer, and studied the incidence and types of second cancers. RESULTS: In total, 719 cases were reviewed, out of which 94 (13%) had a history of at least one cancer. For the first primary cancers, 46 (49%) were AIDS-defining cancers (ADCs) and 48 (51%) were non-AIDS-defining cancers (NADCs). Kaposi sarcoma (33%) and NHL (15%) occurred most frequently as first cancers. Among the first cancers that were ADCs, 15% of the second cancers were NHL, 11% anal canal cancers, 9% bladder and 9% Hodgkin lymphomas. Among the first cancers that were NADCs, 38% of the second cancers were lung cancers, 8% bladder, 8% head and neck and 8% NHL. DISCUSSION: With the aging of PLWHIV, the incidence of second and subsequent cancers is expected to increase in this population. Immuno-virological control should be maintained. Increased surveillance, early prevention and screening programs should be offered to all PLWHIV, including those with an undetectable HIV viral load and/or immune restoration.

Patterns of HIV Self-Disclosure in the Oncology Setting.

Higher rates of cancer treatment toxicity and uniquely poor outcomes following a cancer diagnosis have been reported for persons living with HIV (PLWH). This highlights the importance of active HIV status ascertainment in the oncology setting. Self-disclosure of HIV via electronic questionnaire at patient intake is a low-cost option that has not been thoroughly evaluated. We examined 10 years (2009-2019) of patient intake questionnaire data at Moffitt Cancer Center. Self-disclosure of an HIV diagnosis was not uniform, with 36.1% (n = 299, 95% confidence interval [CI] = 32.8% to 39.4%) of 828 patients disclosing. Identification of HIV through this method was highest for anal cancer patients (66.7%, 95% CI = 57.8% to 74.7%). Self-disclosure among patients with hematopoietic malignancies, the most common diagnosis among PLWH at our institution, was lower (19.4%, 95% CI = 14.6% to 25.0%). Patient characteristics associated with HIV self-disclosure included cancer site, natal gender, and race and ethnicity. Findings highlight gaps to motivate future efforts to increase HIV ascertainment prior to initiating cancer care.

Menopausal hormone therapy for women living with HIV.

People living with HIV are ageing, and a growing number of women living with HIV are entering menopause. Women living with HIV commonly have bothersome vasomotor symptoms and onset of menopause at earlier ages; both factors go on to affect quality of life and systemic health. Vasomotor symptoms and early menopause are both indications for menopausal hormone therapy; however, current evidence suggests that this therapy is seldom offered to women living with HIV. Additionally, women living with HIV have several risks to bone health and are likely to benefit from the bone-strengthening effects of menopausal hormone therapy. We present an assessment of the benefits and risks of menopausal hormone therapy in the context of HIV care and propose a practical approach to its prescription. If considered in the appropriate clinical context with discussion of risks and benefits, menopausal hormone therapy might provide substantial benefits to symptomatic menopausal women living with HIV and improve health-related quality of life.

Transmethylamine-N-Oxide Is Associated With Diffuse Cardiac Fibrosis in People Living With HIV.

Background People living with HIV are at increased risk of developing diastolic dysfunction, heart failure, and sudden cardiac death, all of which have been characterized by higher levels of myocardial fibrosis. Transmethylamine-N-oxide (TMAO), a dietary gut metabolite, is linked to the development of myocardial fibrosis in animal models. However, it is unclear whether TMAO plays a role in the development of myocardial fibrosis in people living with HIV. Methods and Results The study population consisted of participants enrolled in the multisite cross-sectional study called CHART-HIV (Characterizing Heart Function on Anti-Retroviral Therapy). Participants underwent echocardiography, cardiac magnetic resonance imaging, biomarker analysis, and targeted assessment of gut-related circulating metabolites; diastolic dysfunction was determined by study-specific criteria. Multivariable linear regression models were performed to examine the relationship of gut-related metabolites with serum and imaging measures of myocardial fibrosis. Models were adjusted for traditional cardiovascular, inflammatory, and HIV-related risk factors. Diastolic dysfunction was present in 94 of 195 individuals (48%) in CHART-HIV; this cohort demonstrated higher prevalence of hypertension, hyperlipidemia, and chronic kidney disease as well as higher plasma levels of both TMAO and choline. TMAO levels were associated with parameters reflecting increased left ventricular filling pressures and with a marker of the innate immune system. TMAO levels correlated with diffuse myocardial fibrosis (R=0.35; P<0.05) as characterized by myocardial extracellular volume fraction as well as biomarkers reflective of myocardial fibrosis. Conclusions In this study of people living with HIV, the gut metabolite TMAO was associated with underlying diffuse myocardial fibrosis and found to be a potential marker of early structural heart disease. The mechanistic role of the gut microbiome in HIV-associated cardiovascular disease warrants further investigation. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT02860156.