The microbiome as a biomarker of anal precancerous lesions in people with HIV.

PURPOSE OF REVIEW: Early detection and treatment of human papillomavirus (HPV)-related anal dysplasia in some high-risk groups can help anal cancer prevention, but new tools to improve diagnostic and risk assessment are needed. Here, we aim to discuss the evidence on the role of the microbiome as a potential biomarker for anal high-grade squamous intraepithelial lesions (HSILs) in people with HIV (PWH). RECENT FINDINGS: This review covers relevant studies on the links between the microbiome and HPV infection, cervical dysplasia/cancer, and anal HPV disease. It focuses on anal samples and precancerous lesions. SUMMARY: The review highlights the promising potential of the anal microbiome as a novel biomarker for precancerous lesions in people with HIV, while also discussing limitations and future research needs.

Expanding HIV clinical monitoring: the role of CD4, CD8, and CD4/CD8 ratio in predicting non-AIDS events.

BACKGROUND: While a low CD4/CD8 ratio during HIV treatment correlates with immunosenescence, its value in identifying patients at an increased risk for clinical events remains unclear. METHODS: We analyzed data from the CoRIS cohort to determine whether CD4 count, CD8 count, and CD4/CD8 ratio at year two of antiretroviral therapy (ART) could predict the risk of serious non-AIDS events (SNAEs) during the next five years. These included major adverse cardiovascular events, non-AIDS-defining malignancies, and non-accidental deaths. We used pooled logistic regression with inverse probability weighting to estimate the survival curves and cumulative risk of clinical events. FINDINGS: The study included 4625 participants, 83% male, of whom 200 (4.3%) experienced an SNAE during the follow-up period. A CD4/CD8 ratio <0.3 predicted an increased risk of SNAEs during the next five years (OR 1.63, 95% CI 1.03-2.58). The effect was stronger at a CD4/CD8 ratio cut-off of <0.2 (OR 3.09, 95% CI 1.57-6.07). Additionally, low CD4 count at cut-offs of <500 cells/µL predicted an increased risk of clinical events. Among participants with a CD4 count ≥500 cells/µL, a CD8 count ≥1500 cells/µL or a CD4/CD8 ratio <0.4 predicted increased SNAE risk. INTERPRETATION: Our results support the use of the CD4/CD8 ratio and CD8 count as predictors of clinical progression. Patients with CD4/CD8 ratio <0.3 or CD8 count ≥1500/µL, regardless of their CD4 count, may benefit from closer monitoring and targeted preventive interventions. FUNDING: This work was supported by CIBER (CB 2021), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea-NextGenerationEU; by the Spanish AIDS Research Network (RIS) RD16/0025/0001 project as part of the Plan Nacional R + D + I, and cofinanced by Instituto de Salud Carlos III (ISCIII)- Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER), ISCIII projects PI18/00154, PI21/00141, and ERDF, "A way to make Europe", ICI20/00058.

CD4/CD8 Ratio During Human Immunodeficiency Virus Treatment: Time for Routine Monitoring?

In the last decade, studies in persons with HIV (PWH) on antiretroviral therapy (ART) have shed light on the significance of persistently high CD8 counts and low CD4/CD8 ratios. A low CD4/CD8 ratio reflects increased immune activation and is associated with an increased risk of severe non-AIDS events. As a result, many clinicians now believe that the CD4/CD8 ratio can help in HIV monitoring, and many researchers now report it as an efficacy marker in interventional studies. However, the topic is more complex. Recent studies have not yielded unanimous conclusions on the ability of the CD4/CD8 ratio to predict adverse outcomes, and only some clinical guidelines recommend monitoring it. Knowledge gaps remain on the best cutoff points, associated clinical events, effects of treatments, and how the CD4/CD8 ratio could improve decision making in the clinic. Here, we critically review the literature, identify knowledge gaps, and discuss the role of the CD4/CD8 ratio as a marker for HIV monitoring.

The microbiota as a modulator of mucosal inflammation and HIV/HPV pathogenesis: From association to causation.

Although the microbiota has largely been associated with the pathogenesis of viral infections, most studies using omics techniques are correlational and hypothesis-generating. The mechanisms affecting the immune responses to viral infections are still being fully understood. Here we focus on the two most important sexually transmitted persistent viruses, HPV and HIV. Sophisticated omics techniques are boosting our ability to understand microbiota-pathogen-host interactions from a functional perspective by surveying the host and bacterial protein and metabolite production using systems biology approaches. However, while these strategies have allowed describing interaction networks to identify potential novel microbiota-associated biomarkers or therapeutic targets to prevent or treat infectious diseases, the analyses are typically based on highly dimensional datasets -thousands of features in small cohorts of patients-. As a result, we are far from getting to their clinical use. Here we provide a broad overview of how the microbiota influences the immune responses to HIV and HPV disease. Furthermore, we highlight experimental approaches to understand better the microbiota-host-virus interactions that might increase our potential to identify biomarkers and therapeutic agents with clinical applications.

Implementation of a lung cancer screening initiative in HIV-infected subjects.

In this pilot program of low-dose computed tomography (LDCT) for the screening of lung cancer (LC) in a targeted population of people with HIV (PWH), its prevalence was 3.6%; the number needed to screen in order to detect one case of lung cancer was 28, clearly outweighing the risks associated with lung cancer screening. While data from additional cohorts with longitudinal measurements are needed, PWH are a target population for lung cancer screening with LDCT.

Exploiting the Microbiota for the Diagnosis of Anal Precancerous Lesions in Men Who Have Sex With Men.

BACKGROUND: While the microbiota has been associated with human papillomavirus malignant transformation, it is unclear whether anal bacteria could improve the low specificity of anal cytology for the screening of high-grade intraepithelial squamous neoplasia (HSIL). METHODS: We recruited men who have sex with men undergoing anal cytology and high-resolution anoscopy. We assessed the microbiota composition from fecal samples and cytobrush anal samples using 16S ribosomal DNA sequencing in participants with or without biopsy-proven HSIL (bHSIL). We selected bacterial biomarkers based on their linear discriminant analysis. We assessed their predictive performance using logistic regression and bootstrap resampling. RESULTS: We included 128 individuals, 47 (36.7%) with bHSIL and 99 (77.3%) with human immunodeficiency virus. We detected 40 potential predictors of bHSIL. Ruminococcaceae NK4A214 group, Alloprevotella genus, Prevotella melanonigenica, and Ruminococcaceae UCG-014 were the most predictive of bHSIL. From 35 false-positive cytologic results, the combination of these 4 biomarkers with the anal cytology reclassified to true-negative 33 individuals (94%) and showed good diagnostic performance (area under the receiver operating characteristic curve, 0.805; 95% confidence interval, .728-.882). CONCLUSIONS: We found anal-associated bacteria indicative of a higher risk of precancerous anal lesions, which combination was highly specific. The microbiota could be developed as a complementary diagnostic tool to overcome the limitations of the current screening strategy for anal cancer.