Combination Antiretroviral Therapy Research Articles

A retrospective study of Kaposi's sarcoma in Hotan region of Xinjiang, China.

Kaposi sarcoma (KS) is the most common cancer in patients with human immunodeficiency virus/acquired immunodeficiency syndrome (AIDS). In 1994, Chang and Moore discovered Kaposi sarcoma associated herpesvirus for the first time in KS lesions in AIDS patients. KS is a low-grade mesenchymal neoplasm of blood and lymphatic vessels that primarily affects the skin, although the disease may become disseminated to the lymphatic system, lungs, airways, or abdominal viscera. In this research, clinical characteristics and treatment of patients of Kaposi sarcoma were retrospectively analyzed in Hotan District, Xinjiang China. We look into the clinical traits, prognosis, and therapy of Kaposi sarcoma. From May 2017 to August 2022, 32 patients were treated in the People's Hospital of Hotan District, Xinjiang Uygur Autonomous Region, China. Twenty-two of these were classic Kaposi sarcomas (cKS), and 10 of these were Kaposi sarcomas linked to AIDS (AIDS-KS). The majority of KS patients were Uyghur. In terms of age at onset, AIDS-KS patients were younger than cKS patients. cKS and AIDS-KS are most frequently manifested in the feet and lower limbs. Ten patients with AIDS-KS have treated with combination antiretroviral therapy (combination antiretroviral therapy) combination chemotherapy, 5 of 10 patients had a complete response, 2 patients achieved partial response, the overall effective rate was 70%, and CD4 + T cells were greater than before. For cKS and AIDS-KS, the median overall survival was 56 and 50.8 months, respectively (P > .05). As a result, antiviral combination chemotherapy can also improve the prognosis of AIDS-KS patients.

HIV cure: Are we going to make history?

At present, combination antiretroviral therapy (cART) is the mainstay for the treatment of people living with HIV/AIDS. cART can suppress the viral load to a minimal level; however, the possibility of the emergence of full-blown AIDS is always there. In the latter part of the first decade of the 21st century, an HIV-positive person received stem cell transplantation (SCT) for treatment of his haematological malignancy. The patient was able to achieve remission of the haematological condition as well as of HIV following SCT. Thorough investigations of various samples including blood and biopsy could not detect the virus in the person's body. The person was declared to be the first cured case of HIV. Over the next decade, a few more similar cases were observed and have recently been declared cured of the infection. A comprehensive search was performed in PubMed, Cochrane library and Google Scholar. Four such additional cases were found in literature. These cases all share a common proposed mechanism for the HIV cure, that is, transplantation of stem cells from donors carrying a homozygous mutation in a gene encoding for CCR5 (receptor utilized by HIV for entry into the host cell), denoted as CCR5△32. This mutation makes the host immune cells devoid of CCR5, causing the host to acquire resistance against HIV. To the best of our knowledge, this is the first review to look at relevant and updated information of all cured cases of HIV as well as the related landmarks in history and discusses the underlying mechanism(s).

Metabolic and mitochondrial dysregulation in CD4+ T cells from HIV-positive women on combination anti-retroviral therapy.

For optimal functionality, immune cells require a robust and adaptable metabolic program that is fueled by dynamic mitochondrial activity. In this study, we investigate the metabolic alterations occurring in immune cells during HIV infection and antiretroviral therapy by analyzing the uptake of metabolic substrates and mitochondrial phenotypes. By delineating changes in immune cell metabolic programming during HIV, we may identify novel potential therapeutic targets to improve anti-viral immune responses. After consent and voluntary participation was confirmed, whole blood was drawn from HIV uninfected women and women with chronic HIV infection on long-term combination antiretroviral therapy (HIV/cART). Peripheral blood mononuclear cells-derived immune cells were directly incubated with different fluorescently tagged metabolites and markers of mitochondrial activity: FITC-2-NBDG (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose), FITC-BODIPY (4,4-Difluoro-5,7-Dimethyl-4-Bora-3a,4a-Diaza-s-Indacene-3-Hexadecanoic Acid), FITC-MitoTracker Green and APC-MitoTracker Deep Red. The uptake of glucose and fats and the mitochondrial mass and potential were measured using flow cytometry. All values are reported quantitatively as geometric means of fluorescence intensity. During chronic HIV infection, cellular uptake of glucose increases in HIV+ dendritic cells in particular. CD4+ T cells had the lowest uptake of glucose and fats compared to all other cells regardless of HIV status, while CD8+ T cells took up more fatty acids. Interestingly, despite the lower utilization of glucose and fats in CD4+ T cells, mitochondrial mass increased in HIV+ CD4+ T cells compared to HIV negative CD4+ T-cells. HIV+ CD4+ T cells also had the highest mitochondrial potential. Significant disparities in the utilization of substrates by leukocytes during chronic HIV/cART exist. Innate immune cells increased utilization of sugars and fats while adaptive immune cells displayed lower glucose and fat utilization despite having a higher mitochondrial activity. Our findings suggest that cART treated HIV-infected CD4+ T cells be dysfunctional or may prefer alternative fuel sources not included in these studies. This underscores the importance of understanding the metabolic effects of HIV treatment on immune function.

HIV-1 drug resistance in people on dolutegravir-based antiretroviral therapy: a collaborative cohort analysis

The widespread use of the integrase strand transfer inhibitor (INSTI) dolutegravir in first-line and second-line antiretroviral therapy (ART) might facilitate emerging resistance. The DTG RESIST study combined data from HIV cohorts to examine patterns of drug resistance mutations (DRMs) and identify risk factors for dolutegravir resistance. We included cohorts with INSTI resistance data from two collaborations (ART Cohort Collaboration, International epidemiology Databases to Evaluate AIDS in Southern Africa), and the UK Collaborative HIV Cohort. Eight cohorts from Canada, France, Germany, Italy, the Netherlands, Switzerland, South Africa, and the UK contributed data on individuals who were viraemic on dolutegravir-based ART and underwent genotypic resistance testing. Individuals with unknown dolutegravir initiation date were excluded. Resistance levels were categorised using the Stanford algorithm. We identified risk factors for resistance using mixed-effects ordinal logistic regression models. We included 599 people with genotypic resistance testing on dolutegravir-based ART between May 22, 2013, and Dec 20, 2021. Most had HIV-1 subtype B (n=351, 59%), a third had been exposed to first-generation INSTIs (n=193, 32%), 70 (12%) were on dolutegravir dual therapy, and 18 (3%) were on dolutegravir monotherapy. INSTI DRMs were detected in 86 (14%) individuals; 20 (3%) had more than one mutation. Most (n=563, 94%) were susceptible to dolutegravir, seven (1%) had potential low, six (1%) low, 17 (3%) intermediate, and six (1%) high-level dolutegravir resistance. The risk of dolutegravir resistance was higher on dolutegravir monotherapy (adjusted odds ratio [aOR] 34·1, 95% CI 9·93-117) and dolutegravir plus lamivudine dual therapy (aOR 9·21, 2·20-38·6) compared with combination ART, and in the presence of potential low or low (aOR 5·23, 1·32-20·7) or intermediate or high-level (aOR 13·4, 4·55-39·7) nucleoside reverse transcriptase inhibitor (NRTI) resistance. Among people with viraemia on dolutegravir-based ART, INSTI DRMs and dolutegravir resistance were rare. NRTI resistance substantially increased the risk of dolutegravir resistance, which is of concern, notably in resource-limited settings. Monitoring is important to prevent resistance at the individual and population level and ensure the long-term sustainability of ART. US National Institutes of Health, Swiss National Science Foundation.

CD4 dim CD8 bright T cells are inversely associated with neuro-inflammatory markers among people with HIV.

HIV-associated neuroinflammation persists in the brain despite suppressive combination antiretroviral therapy (cART). We evaluated associations between a subset of CD8 + T cells, termed CD4 dim CD8 bright T cells, and soluble markers of immune activation and/or neuroinflammation in the cerebrospinal fluid (CSF) and plasma of people with HIV (PWH). Fifteen cART-naive PWH were enrolled and underwent blood draw, lumbar puncture for CSF collection, and neuropsychological tests at week 0 (pre-cART) and 24 weeks after cART initiation. CSF and peripheral blood T cells were evaluated with flow cytometry and soluble markers of immune activation were measured by multiplex and singleplex assays. Spearman bootstrap correlation coefficients with 10 000 resamples were computed and reported with corresponding 95% confidence intervals (CIs) for each marker of interest and T-cell type. The frequency of CSF CD4 dim CD8 bright T cells at week 0 was inversely related with CSF neopterin. In contrast, at week 24, CSF CD4 - CD8 + T cells were positively correlated with CSF s100β, a marker of brain injury. In the blood, at week 0, CD4 dim CD8 bright T cells were inversely correlated with MCP-1, IP-10, IL-8, IL-6, G-CSF, and APRIL and positively correlated with plasma RANTES and MMP1. At week 0, the frequency of blood CD4 - CD8 + were positively correlated with CRP and BAFF. CD4 dim CD8 bright T cells are associated with some anti-inflammatory properties, whereas CD4 - CD8 + T cells may contribute to inflammation and injury. Assessing the contrast between these two cell populations in neuroHIV may inform targeted therapeutic intervention to reduce neuroinflammation and associated neurocognitive impairment.

Acquired immunodeficiency syndrome-related progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome: prevalence, main characteristics, and outcomes in a Brazilian center.

Progressive multifocal leukoencephalopathy (PML) - immune reconstitution inflammatory syndrome (IRIS) in people living with HIV/AIDS (PLWHA) has been rarely described in low- and middle-income countries. To describe the prevalence of PML-IRIS among PLWHA with PML and its main features in a tertiary hospital in Brazil. We performed a retrospective cohort study. We included PLWHA with PML-IRIS patients admitted at Instituto de Infectologia Emílio Ribas, São Paulo, Brazil, between 2011 and 2021. We retrieved information on neurological manifestations, neuroimaging findings, treatments, and outcomes. We identified 11 (11.8%) PML-IRIS cases among 93 patients with definite PML. Eight (73%) cases were men and had a median (IQR) age of 41 (27-50) years. Seven (63.6%) patients developed unmasking PML-IRIS and 4 (36.4%) had paradoxical PML-IRIS. The median (IQR) time from initiation of combined antiretroviral therapy (cART) to IRIS diagnosis was 49 (30-70) days. Ten (90.9%) patients received corticosteroids. There were 4 (36%) in-hospital deaths and 3 were associated with hospital-acquired pneumonia. Among the 7 (64%) patients who survived, 5 (71.5%) had sequelae at discharge. One year after the PML-IRIS diagnosis, 6 (54.5%) patients were alive. The prevalence of PML-IRIS was 11.8%. Most patients had unmasking PML-IRIS. In-hospital mortality and morbidity were high. One-year survival was similar to that described in some high-income countries.

All-cause hospitalisation among people living with HIV according to gender, mode of HIV acquisition, ethnicity, and geographical origin in Europe and North America: findings from the ART-CC cohort collaboration

Understanding demographic disparities in hospitalisation is crucial for the identification of vulnerable populations, interventions, and resource planning. Data were from the Antiretroviral Therapy Cohort Collaboration (ART-CC) on people living with HIV in Europe and North America, followed up between January, 2007 and December, 2020. We investigated differences in all-cause hospitalisation according to gender and mode of HIV acquisition, ethnicity, and combined geographical origin and ethnicity, in people living with HIV on modern combination antiretroviral therapy (cART). Analyses were performed separately for European and North American cohorts. Hospitalisation rates were assessed using negative binomial multilevel regression, adjusted for age, time since cART intitiaion, and calendar year. Among 23 594 people living with HIV in Europe and 9612 in North America, hospitalisation rates per 100 person-years were 16·2 (95% CI 16·0-16·4) and 13·1 (12·8-13·5). Compared with gay, bisexual, and other men who have sex with men, rates were higher for heterosexual men and women, and much higher for men and women who acquired HIV through injection drug use (adjusted incidence rate ratios ranged from 1·2 to 2·5 in Europe and from 1·2 to 3·3 in North America). In both regions, individuals with geographical origin other than the region of study generally had lower hospitalisation rates compared with those with geographical origin of the study country. In North America, Indigenous people and Black or African American individuals had higher rates than White individuals (adjusted incidence rate ratios 1·9 and 1·2), whereas Asian and Hispanic people living with HIV had somewhat lower rates. In Europe there was a lower rate in Asian individuals compared with White individuals. Substantial disparities exist in all-cause hospitalisation between demographic groups of people living with HIV in the current cART era in high-income settings, highlighting the need for targeted support. Royal Free Charity and the National Institute on Alcohol Abuse and Alcoholism.

HIV and an Ageing Population-What Are the Medical, Psychosocial, and Palliative Care Challenges in Healthcare Provisions.

The continuing increase in patient numbers and improvement in healthcare provisions of HIV services in the UK, alongside the effectiveness of combined antiretroviral therapy (cART), has resulted in increasing numbers of the ageing population among people living with HIV (PLWH). It is expected that geriatricians will need to deal with many older people living with HIV (OPLWH) as life expectancy increases. Therefore, geriatric syndromes in OPLWH will be similar to the normal population, such as falls, cognitive decline, frailty, dementia, hypertension, diabetes and polypharmacy. The increase in the long-term use of cART, diabetes, dyslipidaemia and hypertension may lead to high prevalence of cardiovascular disease (CVD). The treatment of such conditions may lead to polypharmacy and may increase the risk of cART drug-drug interactions. In addition, the risk of developing infection and cancer is high. OPLWH may develop an early onset of low bone mineral density (BMD), osteoporosis and fractures. In this review, we have also provided potential psychosocial aspects of an ageing population with HIV, addressing issues such as depression, stigma, isolation and the need for comprehensive medical and psychosocial care through an interdisciplinary team in a hospital or community setting. OPLWH have a relatively high burden of physical, psychological, and spiritual needs and social difficulties, which require palliative care. The holistic type of palliative care that will improve physical, emotional and psychological wellbeing is discussed in this review.

Liver Transplantation in People Living with HIV: Still an Experimental Procedure or Standard of Care?

Liver transplantation (LT) is the only curative treatment for various liver diseases, including acute liver failure, end-stage liver disease, and selected unresectable liver malignancies. Combination antiretroviral therapy has improved outcomes for people living with HIV (PLWH), transforming the status of acquired immune deficiency syndrome from a fatal disease to a chronic and manageable condition. These powerful antiviral therapies have not only increased the number of HIV+ enlisted patients by improving their survival but also made the use of HIV+ organs a viable option. In this review, we summarise current knowledge on the peculiarities of liver transplantation in PLWH. In particular, we focus on the indications, contraindications, specific considerations for treatment, and outcomes of LT in PLWH. Finally, we present available preliminary data on the use of HIV+ liver allografts.

Strategies in the Design and Development of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs).

AIDS (acquired immunodeficiency syndrome) is a potentially life-threatening infectious disease caused by human immunodeficiency virus (HIV). To date, thousands of people have lost their lives annually due to HIV infection, and it continues to be a big public health issue globally. Since the discovery of the first drug, Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI), to date, 30 drugs have been approved by the FDA, primarily targeting reverse transcriptase, integrase, and/or protease enzymes. The majority of these drugs target the catalytic and allosteric sites of the HIV enzyme reverse transcriptase. Compared to the NRTI family of drugs, the diverse chemical class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) has special anti-HIV activity with high specificity and low toxicity. However, current clinical usage of NRTI and NNRTI drugs has limited therapeutic value due to their adverse drug reactions and the emergence of multidrug-resistant (MDR) strains. To overcome drug resistance and efficacy issues, combination therapy is widely prescribed for HIV patients. Combination antiretroviral therapy (cART) includes more than one antiretroviral agent targeting two or more enzymes in the life cycle of the virus. Medicinal chemistry researchers apply different optimization strategies including structure- and fragment-based drug design, prodrug approach, scaffold hopping, molecular/fragment hybridization, bioisosterism, high-throughput screening, covalent-binding, targeting highly hydrophobic channel, targeting dual site, and multi-target-directed ligand to identify and develop novel NNRTIs with high antiviral activity against wild-type (WT) and mutant strains. The formulation experts design various delivery systems with single or combination therapies and long-acting regimens of NNRTIs to improve pharmacokinetic profiles and provide sustained therapeutic effects.

Highly sensitive and rapid point-of-care testing for HIV-1 infection based on CRISPR-Cas13a system

BackgroundHuman immunodeficiency virus type one (HIV-1) is the leading cause of acquired immunodeficiency syndrome (AIDS). AIDS remains a global public health concern but can be effectively suppressed by life-long administration of combination antiretroviral therapy. Early detection and diagnosis are two key strategies for the prevention and control of HIV/AIDS. Rapid and accurate point-of-care testing (POCT) provides critical tools for managing HIV-1 epidemic in high-risk areas and populations.MethodsIn this study, a POCT for HIV-1 RNA was developed by CRISPR-Cas13a lateral flow strip combined with reverse transcriptase recombinase-aided amplification (RT-RAA) technology, the results can be directly observed by naked eyes.ResultsMoreover, with the degenerate base-binding CRISPR-Cas13a system was introduced into the RT-RAA primer designing, the technology developed in this study can be used to test majority of HIV-1 RNA with limit of detection (LOD) 1 copy/μL, while no obvious cross-reaction with other pathogens. We evaluated this method for detecting HIV-1 RNA of clinical samples, the results showed that the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were 91.81% (85.03- 96.19%), 100% (92.60–100%), 100% (96.41–100%), 39.14% (25.59–54.60%) and 92.22% (86.89–95.88%), respectively. The lowest viral load detectable by this method was 112copies/mL.ConclusionAbove all, this method provides a point-of-care detection of HIV-1 RNA, which is stable, simple and with good sensitivity and specificity. This method has potential to be developed for promoting early diagnosis and treatment effect monitoring of HIV patients in clinical.

The New Era of Long-Acting Antiretroviral Therapy: When and Why to Make the Switch.

Despite the availability of safe and effective oral combination antiretroviral therapy, barriers to maintaining viral suppression remain a challenge to ending the HIV epidemic. Long-acting injectable antiretroviral therapy was developed as an alternative to daily oral therapy. This review summarizes the current literature on the efficacy of long-acting cabotegravir plus rilpivirine for the treatment of HIV-1, reasons to switch to injectable therapy, and barriers to switching. Long-acting cabotegravir plus rilpivirine is safe and effective in maintaining HIV-1 virologic suppression. Ideal candidates for switching to long-acting cabotegravir plus rilpivirine are virologically suppressed on oral regimens with good adherence and no history of virologic failure or baseline resistance. Indications to switch to injectable therapy include patient preference, the potential for improved adherence, and avoidance of adverse effects. Implementation research is needed to assess and overcome system barriers. Long-acting cabotegravir plus rilpivirine is a novel alternative to oral antiretrovirals, with the potential to improve adherence and quality of life in people with HIV.

Norovirus infection among HIV-infected patients in Abuja, Nigeria: impact of combination antiretroviral therapy status

BackgroundNorovirus is now recognized to be major cause of gastroenteritis worldwide, with significantly higher disease burden among immunocompromised patients. This study aimed to determine the prevalence of Norovirus among HIV-infected patients and to evaluate the impact of combination antiretroviral therapy (cART) status on Norovirus prevalence in a sub-urban area of Abuja, Nigeria.MethodsThis study included a total of Two hundred and fifteen subjects (85 cART-naïve and 130 cART-exposed) HIV-infected patients. Age range of study participants was 18 to 60 years. Faecal specimens where collected in screw capped containers and analyzed for Norovirus using Accupower Norovirus real-time PCR Test kit. CD4 + cell count was determined using flow cytometry.ResultsThe prevalence of Norovirus among cART-naïve HIV-infected patients was 10.6%. Age and gender was not associated with norovirus infection. cART –naïve HIV-infected patients with CD4 + cell count < 200 was significantly more infected with Norovirus as compared to those with CD4 + count ≥ 200 (OR: 28.000, 95% CI 3.2237, 243.2007, P = 0.0025). Norovirus was also found to be significantly higher in cART-naïve HIV-infected patients than amongst cART-exposed counterparts (OR: 6.882, 95% CI: 1.4514, 32.6343, P = 0.015).ConclusionsThe prevalence of Norovirus among cART-naïve HIV-infected patients was high; and was significantly higher in subjects with low CD4 + counts. Screening for Norovirus among cART-naïve HIV-infected patients is however emphasized to allow for effective Norovirus disease management.

The safety and efficacy of PD-1 inhibitors in patients with advanced cancers and HIV/AIDS in China.

Purpose-Immunotherapy has revolutionizedcancertherapy, becoming the standardofcare for various malignancy treatments. Human immunodeficiency virus (HIV) patients, however, are an underserved group with limited access to clinical trials and cancer therapy. This study was to evaluate the safety and efficacy of programmed cell death 1 (PD - 1) inhibitors in patients with advanced cancer and HIV/acquired immunodeficiency syndrome (AIDS). Methods and Materials-We performed a prospective, open-label, nonrandomized, phase 1 single center study. Patients with advanced cancer and HIV/AIDS received the treatment of PD - 1 inhibitors (camrelizumab, 200 mg, administered intravenously every 3 weeks), along with combination antiretroviral therapy (cART) for HIV. Results-Sixteen participants (12 men and 4 women; median age, 46.5 (29 - 78) years) were enrolled; 1 had non - Hodgkin lymphoma (NHL), and 15 had non - AIDS - defining cancers. Safety was observed over 130 cycles of treatment with camrelizumab. Most treatment-emergent adverse events at least possibly attributed to camrelizumab were grade 1 or 2, including reactive cutaneous capillary endothelial proliferation (RCCEP) (9 participants), hearing loss (1 participant), hypophysitis (1 participant). 3 participants experienced hemorrhage due to poor performance status. HIV was controlled in all participants. Best tumor responses included 3 complete response, 5 partial response, 2 stable disease, and 6 progressive disease. The 2 years progression-free survival (PFS) was 67.0% (95% CI: -0.05, 0.00) and overall survival (OS) was 55.3% (95% CI: -0.05, 0.01) for the 16 patients who had received camrelizumab. Conclusions-This study demonstrates that camrelizumab treatment in patients with advanced cancers and HIV/AIDS was feasible and the clinical outcomes were acceptable.

Implication of the Autophagy-Related Protein Beclin1 in the Regulation of EcoHIV Replication and Inflammatory Responses.

The protein Beclin1 (BECN1, a mammalian homologue of ATG6 in yeast) plays an important role in the initiation and the normal process of autophagy in cells. Moreover, we and others have shown that Beclin1 plays an important role in viral replication and the innate immune signaling pathways. We previously used the cationic polymer polyethyleneimine (PEI) conjugated to mannose (Man) as a non-viral tool for the delivery of a small interfering (si) Beclin1-PEI-Man nanoplex, which specifically targets mannose receptor-expressing glia (microglia and astrocytes) in the brain when administered intranasally to conventional mice. To expand our previous reports, first we used C57BL/6J mice infected with EcoHIV and exposed them to combined antiretroviral therapy (cART). We show that EcoHIV enters the mouse brain, while intranasal delivery of the nanocomplex significantly reduces the secretion of HIV-induced inflammatory molecules and downregulates the expression of the transcription factor nuclear factor (NF)-kB. Since a spectrum of neurocognitive and motor problems can develop in people living with HIV (PLWH) despite suppressive antiretroviral therapy, we subsequently measured the role of Beclin1 in locomotor activities using EcoHIV-infected BECN1 knockout mice exposed to cART. Viral replication and cytokine secretion were reduced in the postmortem brains recovered from EcoHIV-infected Becn1+/- mice when compared to EcoHIV-infected Becn1+/+ mice, although the impairment in locomotor activities based on muscle strength were comparable. This further highlights the importance of Beclin1 in the regulation of HIV replication and in viral-induced cytokine secretion but not in HIV-induced locomotor impairments. Moreover, the cause of HIV-induced locomotor impairments remains speculative, as we show that this may not be entirely due to viral load and/or HIV-induced inflammatory cytokines.

Association between the gut microbiome and organic acid profiles in a Japanese population with HIV infection

IntroductionAn increased incidence of metabolic syndrome has been observed in human immunodeficiency virus (HIV)-infected individuals. In contrast, gut dysbiosis is involved in various pathogeneses, including vascular endothelial disorders. Organic acids, including short-chain fatty acids (SCFAs), are essential for maintaining gut homeostasis. Therefore, this study aimed to explore the gut microbiome profile and organic acids in a Japanese population infected with HIV. MethodsForty-nine patients with HIV infection on combination antiretroviral therapy (cART) were enrolled and divided into the high and low CD4 groups based on a CD4 cutoff of 350 cells/μL. Stool samples were analyzed by 16S ribosomal RNA next-generation sequencing and high-performance liquid chromatography. The association between the gut microbiome, including bacterial taxa and organic acids, was statistically analyzed. ResultsThe fecal microbial community composition was significantly different between HIV patients with CD4 counts above and below 350 cells/μL. The relative abundance of Roseburia, Prevotella, Prevotella_9, and [Clostridium]_methylpentosum_group were significantly enriched in the high CD4 group. Fecal succinic acid tended to be more abundant in the low CD4 group, and acetic, propionic, and butyric acids tended to be more abundant in the high CD4 group. Roseburia was positively correlated with butyric acid levels. Prevotella_9 and Prevotella were negatively correlated with succinic acid levels and positively correlated with acetic and propionic acid levels. ConclusionsThis study showed intestinal dysbiosis bordering on a CD4 count of 350 in patients with HIV infection undergoing cART. These findings might help in understanding intestinal damage and systemic inflammation in HIV infection.

Human immunodeficiency virus transmission-Mechanisms underlying the cell-to-cell spread of human immunodeficiency virus.

Despite the success of combined antiretroviral therapy in controlling viral load and reducing the risk of human immunodeficiency virus (HIV) transmission, an estimated 1.5 million new infections occurred worldwide in 2021. These new infections are mainly the result of sexual intercourse and thus involve cells present on the genital mucosa, such as dendritic cells (DCs), macrophages (Mø) and CD4+ T lymphocytes. Understanding the mechanisms by which HIV interacts with these cells and how HIV exploits these interactions to establish infection in a new human host is critical to the development of strategies to prevent and control HIV transmission. In this review, we explore how HIV has evolved to manipulate some of the physiological roles of these cells, thereby gaining access to strategic cellular niches that are critical for the spread and pathogenesis of HIV infection. The interaction of HIV with DCs, Mø and CD4+ T lymphocytes, and the role of the intercellular transfer of viral particles through the establishment of the infectious or virological synapses, but also through membrane protrusions such as filopodia and tunnelling nanotubes (TNTs), and cell fusion or cell engulfment processes are presented and discussed.

Association between Combination Antiretroviral Therapy and Telomere Length in People Living with Human Immunodeficiency Virus.

Long-term exposure to combination antiretroviral therapy (cART) may be associated with accelerated ageing. Telomere length is considered to be reliable aging biomarker. The aim of this study was to compare patients' relative telomere length (RTL) between and within different cART classes and to estimate the impact of certain HIV-related variables on RTL. The study was conducted in 176 HIV-infected male patients receiving cART, with ≤50 copies HIV RNA/mL plasma. RTL was determined from mononuclear cells by quantitative polymerase chain reaction. Standard statistical tests and unsupervised machine learning were performed. The mean RTL was 2.50 ± 1.87. There was no difference (p = 0.761) in RTL between therapeutic groups: two nucleoside reverse transcriptase inhibitors as the backbone treatment, combined with either integrase inhibitor, protease inhibitor, or non-nucleoside reverse transcriptase inhibitor (NNRTI). Machine learning results suggested duration of HIV infection, CD4+ T-cell count, and cART, including NNRTI, as potentially significant variables impacting RTL. Kendall's correlation test excluded duration of HIV infection (p = 0.220) and CD4+ T-cell count (p = 0.536) as significant. The Mann-Whitney test confirmed that cART containing NNRTI impacted RTL (p = 0.018). This was the first study to show that patients using efavirenz within cART had significantly shorter telomeres than patients using nevirapine.

Effectiveness of Linkage to Care and Prevention Interventions Following HIV Self-Testing: A Global Systematic Review and Meta-analysis.

Over 38.4million people were living with HIV globally in 2021. The HIV continuum includes HIV testing, diagnosis, linkage to combined antiretroviral therapy (cART), and retention in care. An important innovation in the HIV care continuum is HIV self-testing. There is a paucity of evidence regarding the effectiveness of interventions aimed at linking self-testers to care and prevention, including pre-exposure prophylaxis (PrEP). To bridge this gap, we carried out a global systematic review and meta-analysis to ascertain the effectiveness of interventions post-HIV self-testing regarding: (1) linkage to care or ART, (2) linkage to PrEP, and (3) the impact of HIV self-test (HIVST) interventions on sexual behaviors. We searched PubMed, Web of Science, SCOPUS, Cochrane Library, CINAHL Plus (EBSCO), MEDLINE (Ovid), Google Scholar, and ResearchGate. We included only published randomized controlled trials (RCTs) and quasi-experiment that compared HIVST to the standard of care (SoC). Studies with sufficient data were aggregated using meta-analysis on RevMan 5.4 at a 95% confidence interval. Cochrane's Q test was used to assess heterogeneity between the studies, while Higgins and Thompson's I2 was used to quantify heterogeneity. Subgroup analyses were conducted to identify the source of heterogeneity. Of the 2669 articles obtained from the databases, only 15 studies were eligible for this review, and eight were included in the final meta-analysis. Overall, linkage to care was similar between the HIVST arm and SoC (effect size: 0.92 [0.45-1.86]; I2: 51%; p: 0.04). In the population subgroup analysis, female sex workers (FSWs) in the HIVST arm were significantly linked to care compared to the SoC arm (effect size: 0.53 [0.30-0.94]; I2: 0%; p: 0.41). HIVST interventions did not significantly improve ART initiation in the HIVST arm compared to the SoC arm (effect size: 0.90 [0.45-1.79]; I2: 74%; p: < 0.001). We found that more male partners of women living with HIV in the SoC arm initiated PrEP compared to partners in the HIVST arm. The meta-analysis showed no difference between the HIVST and SoC arm regarding the number of clients (effect size: - 0.66 [1.35-0.02]; I2: 64%; p: 0.09) and non-clients FSWs see per night (effect size: - 1.45 [- 1.45 to 1.38]; I2: 93%; p: < 0.001). HIVST did not reduce the use of condoms during insertive or receptive condomless anal intercourse among MSM. HIVST does not improve linkage to care in the general population but does among FSWs. HIVST intervention does not improve linkage to ART nor significantly stimulate healthy sexual behaviors among priority groups. The only RCT that linked HIVST to PrEP found that PrEP uptake was higher among partners of women living with HIV in the SoC arm than in the HIVST arm. More RCTs among priority groups are needed, and the influence of HIVST on PrEP uptake should be further investigated.

Myocardial extracellular volume fraction is positively associated with activated monocyte subsets among cART-treated persons living with HIV in South Africa

BackgroundDespite treatment with combination antiretroviral therapy (cART), persons living with HIV (PLWH) are at higher risk of cardiac structural abnormalities that may presage clinical heart failure, including myocardial fibrosis. This study assessed whether circulating cellular and soluble protein markers of immune activation cross-sectionally associate with myocardial fibrosis among cART-treated PLWH in South Africa. MethodsParticipants were enrolled in Khayelitsha township near Cape Town, SA. Cardiac magnetic resonance imaging was performed. Plasma protein biomarkers were measured using enzyme-linked immunoassays and monocyte phenotypes were evaluated using flow cytometry. Associations were assessed using multivariable linear and logistic regression. ResultsAmong 69 cART-treated PLWH, mean (SD) age was 48 (10) years, 71% were female, and time since HIV diagnosis was 9 (6) years. Evidence of left ventricular fibrosis by late gadolinium enhancement was present in 74% of participants and mean (SD) extracellular volume fraction (ECV) was 30.9 (5.9)%. Degree of myocardial fibrosis/inflammation measured by ECV was positively associated with percentages of circulating non-classical and intermediate monocyte phenotypes reflecting inflammation and tissue injury. ConclusionThese data generate hypotheses on possible immune mechanisms of HIV-associated non-ischemic myocardial disease, specifically among cART-treated PLWH in sub-Saharan Africa, where the majority of the HIV burden exists globally.