Search Results (849)

HIV reservoir size and decay represent distinct dimensions of viral persistence, yet whether they are governed by shared or separable immunological mechanisms during early antiretroviral therapy (ART) remains unclear. In this study, we employed multiparameter flow cytometry and bulk RNA sequencing to analyze longitudinal immune profiles across 21 treatment-naïve people living with HIV before ART initiation and at 1 and 5 months thereafter. Our findings revealed an apparent dissociation between HIV-1 DNA levels and decay rates in peripheral blood, and the two indicators appear to be relatively independent dimensions of viral persistence. Specifically, lower HIV-1 DNA levels were associated with higher frequencies of cytotoxic and adaptive-like natural killer (NK) cell subsets, whereas faster HIV-1 DNA decay was linked to restored HIV-specific CD4+ and CD8+ T-cell responses during treatment. Notably, transcriptomic analyses uncovered divergent gene expression signatures related to B cell-associated immunity and type I interferon pathways, with individuals with higher HIV-1 DNA levels exhibiting elevated expression of immunoglobulin and interferon-stimulated genes, while faster decay correlated with enrichment of antiviral and complement-related genes. Collectively, these findings provide a preliminary characterization of immune correlates of peripheral blood total HIV-1 DNA dynamics in the early phase following ART initiation. This work offers potential immune clues for exploring the viral reservoir and generates testable hypotheses for validation in future large cohorts. Full article

Background: Torque teno virus (TTV) is a ubiquitous, non-pathogenic component of the human virome whose role in people living with HIV (PLWH), particularly during antiretroviral therapy (ART)-mediated immune reconstitution, remains unclear. This systematic review aimed to synthesize available evidence on TTV viral load in PLWH, focusing on its relationship with immunological markers. Methods: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. A comprehensive literature search was conducted in MEDLINE, Web of Science, and Scopus in January 2026 to identify studies assessing plasma TTV viral load before and/or during ART and reporting immunological outcomes. Eligible studies included prospective and retrospective longitudinal studies, cross-sectional studies, and mixed designs assessing plasma TTV viral load in relation to ART status and immune recovery markers. Results: Thirteen studies (n = 1700 PLWH) were included, predominantly observational and conducted in adult populations. Most studies (76.9%) reported a significant inverse association between TTV viral load and CD4 T-cell count, while all studies assessing HIV viral load found a direct correlation with TTV levels. An inverse relationship with the CD4/CD8 ratio was consistently observed where evaluated. Higher TTV loads were reported in ART-naïve individuals and in those with advanced immunosuppression, with longitudinal studies indicating a general decline during ART. Overall, methodological heterogeneity and moderate risk of bias were common. Conclusions: TTV viral load shows a consistent inverse association with CD4 cell count and may reflect global immune dysfunction in PLWH beyond conventional markers. However, its clinical utility remains investigational due to the heterogeneity in the study design, limited data on longitudinal dynamics, and lack of standardized assays and thresholds. Full article

Background/Objectives: Despite widespread antiretroviral therapy (ART) use, whether the expected transition from AIDS-defining to non-AIDS-defining cancers has occurred in settings with persistent late HIV presentation remains unclear. We examined long-term cancer patterns, determinants, and survival outcomes in a large HIV cohort. Methods: This retrospective, single-center cohort included 1419 people living with HIV followed between 2006 and 2024. Patients who developed malignancy were classified as AIDS-defining cancers (ADC) or non-AIDS-defining cancers (NADC). Immuno-virological parameters were assessed at HIV and cancer diagnosis. Survival was analyzed using Kaplan–Meier methods, and predictors of mortality were evaluated using Cox proportional hazards regression. Determinants of ADC development were assessed using multivariable logistic regression. Temporal changes were evaluated by trend analysis. Results: Sixty-six patients (4.6%) developed malignancy (31 ADC, 35 NADC). Late HIV presentation was common, with 72.7% having CD4+ T-lymphocyte counts < 350 cells/mm³ at cancer diagnosis, particularly among ADC cases. Most ADCs (93.5%) occurred within 24 months of HIV diagnosis. Overall survival did not differ between ADC and NADC groups (log-rank p = 0.14). Although mortality declined after 2015, temporal changes in ADC and NADC proportions did not reach statistical significance (p = 0.14). In Cox regression analysis, viral suppression before death or last follow-up was independently associated with lower mortality risk (HR 0.12; 95% CI 0.05–0.31). Lower CD4+ T-lymphocyte counts were associated with ADC development, and a CD4+ T-lymphocyte threshold of 295 cells/mm³ showed good discriminative performance (AUC = 0.83), although this cutoff should be interpreted cautiously due to the lack of external validation. Conclusions: In this long-term cohort from Türkiye, a clear epidemiological transition from ADC to NADC could not be demonstrated. The cancer spectrum remained strongly influenced by late HIV presentation and advanced immunodeficiency. Sustained viral suppression was independently associated with lower mortality risk, supporting the importance of early HIV diagnosis, timely ART initiation, and sustained virological control. Full article

Background: Infectious diseases remain a leading cause of mortality in South Africa, compounded by a high HIV prevalence. This study aimed to delineate the spectrum and clinicopathological characteristics of fatal infectious diseases through a postmortem audit to inform clinical practice and public health strategy. Methods: A retrospective, cross-sectional descriptive study was conducted on all autopsies with a final cause of death attributed to infectious disease at a National Health Laboratory Service, in Northern Pretoria, Gauteng, South Africa, from 2012 to 2021. Using the Systematised Nomenclature of Medicine Clinical Terms (SNOMED) code and word search engines codes, 55 cases were identified. Data on demographics, clinical presentation, HIV status, antiretroviral therapy (ART), comorbidities, and final autopsy diagnosis were extracted from the laboratory information system. Histological confirmation was performed using standard stains. Descriptive statistical analysis was conducted using STATA-18. Results: The cohort (n = 55) had a median age of 31 years (IQR 19–45) and was predominantly female (67%). HIV prevalence was 35%, with 68% of those on ART. The leading cause of death was multilobar pneumonia (36%), followed by bronchopneumonia (22%). AIDS-defining illnesses were present in 27% of cases, with disseminated tuberculosis being the most common (46%). Septic shock was identified in 18% of decedents. A significant proportion (60%) of the cohort was HIV-negative. Conclusions: This autopsy series reveals a high burden of fatal community-acquired pneumonias and HIV-associated opportunistic infections, with a notable proportion of deaths occurring in HIV-negative individuals. The findings underscore diagnostic gaps and highlight the critical role of autopsy in accurate mortality surveillance, advocating for enhanced antemortem diagnostic protocols and targeted public health interventions. Full article

Objective: This retrospective cross-sectional study aimed to characterize HIV-1 genotypes, assess drug resistance, and analyze molecular transmission networks in Zhongwei City to inform prevention strategies. Methods: Plasma samples were collected from antiretroviral therapy (ART)-treated patients (2007–2024) with viral load ≥ 200 copies/mL. HIV-1 pol was amplified by nested PCR; successful sequences were genotyped by maximum likelihood (ML) (IQ-TREE, TVM+F+I+G4, 1000 bootstrap). Drug resistance (DR) was interpreted using Stanford HIV Drug Resistance Database (HIVDB) v9.0; detected mutations represent acquired drug resistance (ADR). Pairwise genetic distances (GD) (TN93 model) were calculated; transmission networks were constructed in Cytoscape 3.10.3. Results: 75 sequences were obtained. Males (84.00%), and heterosexual transmission (64.00%) predominated. CRF07_BC (46.67%) and CRF01_AE (38.67%) were the major subtypes; the overall ADR rate was 40.00%, mainly NNRTIs-associated (30.67% of all participants, including 16.00% single-class NNRTIs and 14.67% dual-class NRTIs-NNRTIs). Network inclusion rate was 40.00% of the 75 sequences; CRF07_BC showed higher betweenness centrality (p = 0.028), while CRF01_AE and CRF85_BC showed higher closeness centrality (p < 0.001). Occupation significantly affected network enrollment (p ≤ 0.05). Conclusion: HIV-1 subtypes are diverse with high ADR. CRF07_BC may act as a transmission bridge, whereas CRF01_AE and CRF85_BC exhibit faster potential spread. Baseline DR testing and network-guided interventions are recommended. Full article

Background and Objectives: Human immunodeficiency virus (HIV) infection is associated with immune dysregulation, which may influence the development of autoimmune diseases. However, population-based evidence on the prevalence of autoimmune diseases in individuals living with HIV remains limited, particularly in Asian populations. This study aimed to evaluate the prevalence of autoimmune diseases in individuals living with HIV in Korea using nationwide population-based data. Materials and Methods: We conducted a cross-sectional analysis using the Health Insurance Review and Assessment Service National Patient Samples from 2012 to 2015, including 4,851,064 individuals aged ≥15 years. HIV infection and autoimmune diseases were identified using ICD-10 codes. The prevalence of autoimmune diseases in individuals with HIV infection was compared with that in the general population. Antiretroviral therapy (ART) status was determined based on prescription records. Results: A total of 1023 individuals were identified with HIV infection, all of whom were receiving antiretroviral therapy. The overall prevalence of autoimmune diseases was 4.4% in males and 3.6% in females with HIV, without significant differences compared to controls. However, the prevalence of ulcerative colitis in males (p = 0.030) and of dermatomyositis in females (p = 0.011) was higher in individuals with HIV. Conclusions: Although the overall prevalence of autoimmune diseases was not significantly increased in individuals living with HIV, certain autoimmune diseases—particularly ulcerative colitis in men and dermatomyositis in women—showed a higher prevalence. As these findings were based on small case numbers, they should be approached with caution. The results are best regarded as hypothesis-generative observations that warrant further investigation rather than findings on which clinical practice should currently be based. Further research using large datasets is warranted to confirm these associations and clarify the underlying immunological mechanisms. Full article

Latently infected resting CD4+ T cells represent the principal barrier to HIV eradication. Their immunological quiescence renders them invisible to combination antiretroviral therapy (cART) and host immune surveillance, sustaining a reservoir that mandates lifelong treatment. The ‘shock and kill’ strategy seeks to reverse this latency using pharmacological latency-reversing agents (LRAs) so that immune effectors and cART can eliminate reactivated cells. In this narrative, structured review, we examine histone deacetylase inhibitors (HDACis) as LRAs from a medicinal chemistry perspective. The review places particular emphasis on structure–activity relationship (SAR), isoform selectivity, and the mechanistic basis of differential clinical performance, synthesizing evidence from preclinical, ex vivo, and clinical studies published between 2010 and 2026. Four structural classes of HDACis—hydroxamic acids, benzamides, cyclic depsipeptides, and short-chain fatty acids—differ substantially in isoform selectivity, potency, pharmacokinetics, and tolerability. No single agent has achieved statistically significant reservoir reduction in clinical trials, highlighting the apparent inadequacy of the ‘shock’ phase alone and suggesting a need for complementary ‘kill’ strategies. Rational design of HDACis informed by isoform-selective SAR, combined with emerging combination LRA strategies and immunological ‘kill’ components, represents a promising direction toward a functional HIV cure, though substantial translational hurdles remain. Full article

Background: Virological suppression is a key outcome of antiretroviral therapy. Despite progress in HIV treatment in Kazakhstan, virological non-suppression remains a relevant clinical and public health issue requiring further analysis. This study aimed to assess the prevalence of virological suppression (VS) and to identify factors associated with the absence of VS among people living with human immunodeficiency virus (HIV) who are receiving antiretroviral therapy (ART) in Kazakhstan. Methods: A retrospective cross-sectional analytical study was conducted using secondary analysis of a de-identified national registry database of people living with HIV (PLHIV) receiving ART in the Republic of Kazakhstan as of 30 September 2025. The primary outcome was virological non-suppression (VNS), defined as the last viral load (VL) value of at least 200 copies per milliliter. The analysis included sex, age, presumed route of HIV transmission, the first available cluster of differentiation 4 (CD4) cell count recorded in the registry, the last recorded percentage category of adherence to ART, and the aggregated category of ART regimen. The main descriptive, bivariate, and multivariable analyses were performed using a complete-case approach. Independent associations were assessed using multivariable logistic regression, and the results were presented as adjusted odds ratios (aORs) with 95 percent confidence intervals (CIs). Results: The initial registry extraction included 33,614 records, of which 32,130 patients were included in the final analytical sample. VS was achieved in 29,454 (91.7%) patients, whereas VNS was observed in 2676 (8.3%) patients. In the multivariable model, higher adjusted odds of VNS were observed among men compared with women (aOR 1.14; 95% CI 1.02–1.26), as well as among patients with a first CD4 count < 200 cells/μL compared with those with a first CD4 count of ≥500 cells/μL (aOR 1.25; 95% CI 1.09–1.44). The strongest association was found for reduced adherence to therapy. Compared with adherence of at least 95%, the adjusted odds of VNS were markedly higher among patients with adherence of 85–94% (aOR 28.66; 95% CI 25.85–31.77) and among those with adherence below 85% (aOR 61.05; 95% CI 50.50–73.81). In all age groups older than 25 years, the adjusted odds of VNS were lower than among patients younger than 25 years. Lower adjusted odds of VNS were also observed among patients with homosexual transmission, vertical transmission, and other or unspecified transmission routes compared with heterosexual transmission. Among ART regimens, regimens containing non-nucleoside reverse transcriptase inhibitors (NNRTIs) were associated with lower adjusted odds of VNS than dolutegravir-containing regimens (DTG-containing regimens) (aOR 0.68; 95% CI 0.52–0.88), whereas no statistically significant differences were identified for regimens containing protease inhibitors (PIs). Conclusions: Despite the high overall level of VS among PLHIV receiving ART in Kazakhstan, VNS remains concentrated in clinically and programmatically important subgroups. It was most strongly associated with reduced adherence and was also associated with younger age, marked baseline immunosuppression, and male sex in the primary model. These findings support the need for targeted interventions focused on adherence support, early diagnosis, and differentiated long-term follow-up of patients. Full article

People with HIV (PWH) experience higher rates of depression compared with the general population. Inflammation has been associated with depressive symptoms and may be associated with a subtype of depression, but the relationship between inflammation and depressive symptoms in PWH on antiretroviral therapy (ART) is unclear. In this study, inflammation biomarkers (IFN-γ, IL-1β, IL-6, IL-8, IL-12p70, IL-15, IP-10, MCP-1, VEGF, CRP) were measured in plasma from 195 PWH on ART and depressive symptoms were assessed using Beck Depression Inventory-II (BDI-II) scores. Logistic regression and mixed-effects models were used to examine the associations between inflammation biomarkers and depressive symptoms at baseline and over 18 months of follow-up. PWH had a median age of 52 years, with 95% being virally suppressed below 200 copies/mL, 33% having high depressive symptoms, and 62% having ≥1 medical comorbidity (HCV, cardiovascular disease, diabetes, chronic kidney disease, chronic lung disease). VEGF levels were increased in PWH with high vs. low depressive symptoms (p = 0.01). The association between VEGF and depressive symptoms remained significant in covariate-adjusted models (p = 0.005) and was augmented in PWH with medical comorbidities (p = 0.002). Other inflammation biomarkers were increased in PWH with medical comorbidities, but not significantly different between groups stratified by depressive symptoms. Among PWH with high depressive symptoms, biomarker clustering identified inflammatory and noninflammatory subgroups distinguished by levels of VEGF/MCP-1/IL-8 or IL-6/CRP and prevalence of HCV, cardiovascular disease, and diabetes. These findings suggest that VEGF is a biomarker associated with depressive symptoms in PWH on ART and may identify a subtype of depression for targeted interventions. Full article

Combined antiretroviral therapy (cART) has transformed HIV into a manageable chronic disease. However, people living with HIV (PLWH) experience a 16-year reduction in comorbidity-free life expectancy compared to HIV-negative individuals, driven by persistent chronic immune activation despite virological suppression. Serious non-AIDS events (SNAEs)—including cardiovascular disease, metabolic disorders, and malignancies—now represent the predominant cause of morbidity. This narrative review provides a clinician-oriented synthesis of immunopathophysiological mechanisms driving chronic inflammation in treated HIV infection, focusing on the gut–immune axis, restriction factors, trained immunity, biomarker-guided risk stratification, and therapeutic strategies. We searched PubMed/MEDLINE, Embase, and Web of Science through April 2026 using terms related to HIV chronic immune activation, gut-associated lymphoid tissue, microbial translocation, inflammaging, restriction factors, trained immunity, and biomarkers. This review followed the SANRA checklist. Irreversible destruction of gut-associated lymphoid tissue (GALT), intestinal barrier dysfunction, microbial translocation, maladaptive trained immunity, persistent myeloid activation with NLRP3 inflammasome signaling and cellular senescence, and viral reservoir persistence collectively perpetuate systemic inflammation. Biomarkers, including sCD14, IL-6, and suPAR, independently predict mortality but are not pathogen-specific. The REPRIEVE trial demonstrated a 36% reduction in cardiovascular risk with pitavastatin (HR 0.64, 95% CI 0.48–0.84), validating inflammation as a therapeutic target. Integration of early cART, statin therapy, optimal antiretroviral selection, and emerging strategies—including GLP-1 receptor agonists and gut-directed therapies—offers a practical framework for reducing inflammation-associated comorbidities in virologically suppressed PLWH. Full article

Background/Objectives: Adolescents living with HIV (ALHIV) face compounded health and psychosocial challenges while managing lifelong antiretroviral therapy (ART). Mental health difficulties among ALHIV are strongly associated with suboptimal adherence and disengagement from care. While mental illness is well documented, limited empirical evidence exists on the influence of positive mental wellness on adherence self-efficacy among ALHIV. This study assessed mental wellness among ALHIV and identified key psychosocial predictors of adherence self-efficacy in public healthcare facilities in Cape Town, South Africa. Methods: A cross-sectional survey was conducted among ALHIV (N = 251) aged 10–19 years who were receiving ART at public healthcare facilities across the Cape Town metropole. Participants completed an electronic questionnaire that assessed ten mental wellness domains and adherence self-efficacy. Descriptive statistics were calculated to summarise participant characteristics and mental wellness scores, while Pearson correlations and multiple linear regression were done to identify associations and independent predictors of adherence self-efficacy using SPSS v29. Results: Most participants were aged 15–19 years (76.9%) and diagnosed with HIV at birth (68.9%). Mental wellness scores were high across all domains (M = 3.14–3.71). Hope (M = 3.71), spirituality (M = 3.58), and purpose in life (M = 3.52) were the highest-rated domains. All mental wellness domains were positively correlated with adherence self-efficacy (p < 0.001), with the strongest associations being purpose in life (r = 0.66), self-acceptance (r = 0.66) and resilience (r = 0.66). Hope (p < 0.001), resilience (p = 0.001), purpose in life (p = 0.03) and self-acceptance (p = 0.012) emerged as significant independent predictors. Conclusions: Positive mental wellness and adolescent-centred psychosocial support in routine HIV care may strengthen adherence self-efficacy and support adolescents’ confidence in managing treatment. Full article

The human gut microbiome is essential for immune regulation and mucosal homeostasis, functions that are profoundly disrupted during HIV infection. Early viral replication in the gut-associated lymphoid tissue (GALT) triggers a self-reinforcing cycle of CD4⁺ T-cell depletion, epithelial barrier breakdown, and increased microbial translocation. This persistent immune activation continues even under effective antiretroviral therapy (ART). A growing body of evidence indicates that HIV infection is consistently associated with alterations in gut microbial communities. This dysbiosis is typically characterized by fewer beneficial butyrate-producing commensal bacteria and an enrichment of pro-inflammatory microbial taxa. It also involves disturbances in key microbial metabolites, including short-chain fatty acids (SCFAs) and tryptophan catabolites. Such changes not only exacerbate systemic inflammation but may also contribute to incomplete immune reconstitution and the persistence of latent viral reservoirs despite long-term ART. In this review, we summarize current knowledge of microbiome–HIV interactions, with particular emphasis on the mechanisms through which gut dysbiosis contributes to immune dysfunction and viral persistence. We discuss recent advances in multi-omics technologies, as well as experimental systems such as gnotobiotic and humanized mouse models and intestinal organoid platforms that are helping to elucidate these complex interactions. Furthermore, we evaluate emerging microbiome-targeted interventions—including probiotics, prebiotics, fecal microbiota transplantation, and engineered bacterial therapeutics—and consider their potential role as adjunctive strategies in HIV treatment and cure research. By integrating microbiological, immunological, and clinical perspectives, this review highlights key knowledge gaps and outlines future research directions aimed at harnessing the gut microbiome as a novel therapeutic avenue in HIV management and eradication. Full article

Background: Durable virological suppression is achieved in the majority of people living with HIV (PLWH) receiving contemporary antiretroviral therapy (ART). However, a subset of patients experience persistent low-level viremia (LLV), the clinical relevance and underlying determinants of which remain incompletely understood. Methods: Adult PLWH followed between 1 January 2005 and 31 December 2025 were retrospectively evaluated. LLV was defined as detectable HIV-1 RNA < 200 copies/mL on at least two consecutive measurements during follow-up in individuals receiving ART for at least 6 months. Patients with sustained virological suppression served as controls. Propensity score matching (1:1) was performed using variables associated with LLV in univariate analyses. Multivariable logistic regression analysis was applied to identify factors independently associated with LLV, and a p value < 0.05 was considered statistically significant. Results: Among 880 PLWH, 45 patients with LLV and 113 virologically suppressed controls were included. LLV was associated with lower baseline CD4+ T-cell counts, higher baseline HIV-1 RNA levels, delayed virological suppression at weeks 8 and 24, increased frequency of AIDS-defining illnesses and a higher prevalence of metabolic comorbidities, including hypertension, diabetes mellitus or dyslipidemia in univariate analysis. After propensity score matching, 32 patients remained in each group, with no clear association between low-level viremia and antiretroviral regimen class. Multivariable regression analysis showed baseline CD4+ T-cell count < 200 cells/µL, and the presence of ≥1 metabolic comorbidity (hypertension, diabetes mellitus or dyslipidemia) remained independently associated with LLV. Conclusions: Our findings suggest that LLV is associated with host-related factors rather than antiretroviral regimen failure. The coexistence of immunological impairment and metabolic comorbidities in patients with LLV underscores the importance of comprehensive clinical evaluation. Full article

Antiretroviral therapy (ART) effectively suppresses HIV-1 replication but does not purge the latent HIV-1 reservoir. Strategies aimed at HIV-1 latency reversal and subsequent elimination of infected cells are being explored. Targeting the inhibitor of apoptosis proteins (IAP) and DEAD-box polypeptide 3 (DDX3) RNA helicase reduces the HIV-1 reservoir ex vivo. However, the mechanisms driving apoptosis of HIV-1 infected cells remain unclear. Here, we uncovered the mechanism regarding HIV-1 transcriptional activation and induction of apoptosis specific for HIV-1 infected cells using an acute in vitro infection model. Inhibition of IAP by second mitochondrial-derived activator of caspases mimetic (SMACm; AZD5582) resulted in activation of non-canonical NF-κB pathway (RelB/p52) that induced HIV-1 transcription, confirming previous reports, whereas inhibition of DDX3 sensitized HIV-1 infected cells for apoptosis (DDX3i; FH1321). Transcriptome analysis revealed that HIV-1 actively suppressed apoptosis-related genes in HIV-1 infected cells. SMACm treatment resulted in a broad induction of these genes irrespective of infection. Notably, DDX3 inhibition specifically restored the expression of the majority of HIV-1 suppressed genes, and when combined with SMACm, restored almost all HIV-1 downregulated genes, thereby rendering HIV-1 infected cells sensitive to apoptosis. Thus, our data strongly suggest that inhibition of host factors IAP and DDX3 not only induces activation of HIV-1 transcription but also restores HIV-1 suppressed apoptotic processes in infected cells. Full article

HIV-associated neurocognitive disorders (HAND) arise from HIV infection of the central nervous system, resulting in chronic neuroinflammation and progressive neuronal damage that impair cognitive, motor, and behavioral functions. Clinically, HAND encompasses a spectrum of neurological impairments ranging from asymptomatic neurocognitive impairment to severe HIV-associated dementia. Despite the widespread use of combination antiretroviral therapy (cART) and significant improvements in the life expectancy of people living with HIV, HAND remains prevalent and continues to pose a major clinical challenge. One of the primary limitations of cART is the limited penetration of many antiretroviral drugs across the blood–brain barrier (BBB), thereby allowing the persistence of viral reservoirs within the CNS and contributing to sustained neuroinflammation and neuronal damage. To address these challenges, novel nanotherapeutic strategies have been developed to enhance the delivery of antiretroviral agents to the brain. These approaches include targeted delivery systems and the co-delivery of therapeutics across the BBB through mechanisms such as receptor-mediated transcytosis and other transport pathways. In this review, we discuss the pathophysiological challenges associated with HAND and recent advances in nanotherapeutic approaches designed to improve treatment efficacy. We also discuss the current state of the art in vitro and in vivo models used to test the efficacy of these advanced therapeutics. Finally, we outline the remaining challenges and future prospects for the development of nanotherapeutics to improve the treatment of HAND. Full article