A Two-Faced Gut Microbiome: Butyrogenic and Proinflammatory Bacteria Predominate in the Intestinal Milieu of People Living with HIV from Western Mexico.

HIV infection results in marked alterations in the gut microbiota (GM), such as the loss of microbial diversity and different taxonomic and metabolic profiles. Despite antiretroviral therapy (ART) partially ablating gastrointestinal alterations, the taxonomic profile after successful new ART has shown wide variations. Our objective was to determine the GM composition and functions in people living with HIV (PLWHIV) under ART in comparison to seronegative controls (SC). Fecal samples from 21 subjects (treated with integrase strand-transfer inhibitors, INSTIs) and 18 SC were included. We employed 16S rRNA amplicon sequencing, coupled with PICRUSt2 and fecal short-chain fatty acid (SCFA) quantification by gas chromatography. The INSTI group showed a decreased α-diversity (p < 0.001) compared to the SC group, at the expense of increased amounts of Pseudomonadota (Proteobacteria), Segatella copri, Lactobacillus, and Gram-negative bacteria. Concurrently, we observed an enrichment in Megasphaera and Butyricicoccus, both SCFA-producing bacteria, and significant elevations in fecal butyrate in this group (p < 0.001). Interestingly, gut dysbiosis in PLWHIV was characterized by a proinflammatory environment orchestrated by Pseudomonadota and elevated levels of butyrate associated with bacterial metabolic pathways, as well as the evident presence of butyrogenic bacteria. The role of this unique GM in PLWHIV should be evaluated, as well as the use of butyrate-based supplements and ART regimens that contain succinate, such as tenofovir disoproxil succinate. This mixed profile is described for the first time in PLWHIV from Mexico.

Pilot study on the efficacy and safety of berberine in people with metabolic syndrome and human immunodeficiency virus infection.

BACKGROUND: Antiretroviral therapy has increased the life expectancy of people living with HIV. However, this increase is not free of comorbidities, and metabolic syndrome is one of the most prevalent. Berberine is an alkaloid nutraceutical that has been shown to ameliorate metabolic disorders such as prediabetes, polycystic ovary syndrome, and non-alcoholic fatty liver disease. However, it has not been tested in HIV infection. Therefore, we conducted a randomized controlled trial to evaluate the efficacy of berberine in improving metabolic syndrome. METHODS AND RESULTS: In this double-blind, placebo-controlled trial, adults living with HIV under virological suppression and metabolic syndrome received either berberine 500 mg TID or placebo for 20 weeks. The primary outcomes were a composite of weight reduction, insulin resistance decrease, and lipid profile improvement. A total of 43 participants were randomized (22 in the berberine group and 21 in the placebo group); 36 participants completed the follow-up and were analyzed. The berberine group showed a reduction in weight and body mass index, lower insulin resistance, and a reduction in TNF-alpha. The control group had higher total cholesterol, c-LDL, and IL-6 concentration. CONCLUSION: In people living with HIV under virological suppression, berberine was safe and improves clinical and biochemical components of metabolic syndrome. However, further studies with more participants and longer intervention periods need to be explored.

Gut Bacterial Communities in HIV-Infected Individuals with Metabolic Syndrome: Effects of the Therapy with Integrase Strand Transfer Inhibitor-Based and Protease Inhibitor-Based Regimens.

Antiretroviral therapies (ART) are strongly associated with weight gain and metabolic syndrome (MetS) development in HIV-infected patients. Few studies have evaluated the association between gut microbiota and integrase strand transfer inhibitor (INSTI)-based and protease inhibitor (PI)-based regimens in HIV-infected patients with MetS. To assess this, fecal samples were obtained from HIV-infected patients treated with different regimens (16 PI + MetS or 30 INSTI + MetS) and 18 healthy controls (HCs). The microbial composition was characterized using 16S rRNA amplicon sequencing. The INSTI-based and PI-based regimens were associated with a significant decrease in α-diversity compared to HCs. The INSTI + MetS group showed the lowest α-diversity between both regimens. A significant increase in the abundance of short-chain fatty acid (SCFA)-producing genera (Roseburia, Dorea, Ruminococcus torques, and Coprococcus) was observed in the PI + MetS group, while Prevotella, Fusobacterium, and Succinivibrio were significantly increased in the INSTI + MetS group. Moreover, the Proteobacteria/Firmicutes ratio was overrepresented, and functional pathways related to the biosynthesis of LPS components were increased in the INSTI + MetS group. The gut microbiota of patients receiving INSTIs showed a more pronounced dysbiosis orchestrated by decreased bacterial richness and diversity, with an almost complete absence of SCFA-producing bacteria and alterations in gut microbiota functional pathways. These findings have not been previously observed.

Effect of antiretroviral therapy on decreasing arterial stiffness, metabolic profile, vascular and systemic inflammatory cytokines in treatment-naïve HIV: A one-year prospective study.

INTRODUCTION: Cardiovascular disease is a major cause of death among people living with HIV (PLH). Non-treated PLH show increased levels of inflammation and biomarkers of vascular activation, and arterial stiffness as a prognostic cardiovascular disease risk factor. We investigated the effect of one year of ART on treatment-naïve HIV(+) individuals on arterial stiffness and inflammatory and vascular cytokines. METHODS: We cross-sectionally compared aortic stiffness via tonometry, inflammatory, and vascular serum cytokines on treatment-naïve (n = 20) and HIV (-) (n = 9) matched by age, sex, metabolic profile, and Framingham score. We subsequently followed young, treatment-naïve individuals after 1-year of ART and compared aortic stiffness, metabolic profile, and inflammatory and vascular serum biomarkers to baseline. Inflammatory biomarkers included: hs-CRP, D-Dimer, SAA, sCD163s, MCP-1, IL-8, IL-18, MRP8/14. Vascular cytokines included: myoglobin, NGAL, MPO, Cystatin C, ICAM-1, VCAM-1, and MMP9. RESULTS: Treatment-naïve individuals were 34.8 years old, mostly males (95%), and with high smoking prevalence (70%). Baseline T CD4+ was 512±324 cells/mcL. cfPWV was similar between HIV(-) and treatment-naïve (6.8 vs 7.3 m/s; p = 0.16) but significantly decreased after ART (-0.52 m/s; 95% CI -0.87 to -0.16; p0.006). Almost all the determined cytokines were significantly higher compared to controls, except for MCP-1, myoglobin, NGAL, cystatin C, and MMP-9. At follow-up, only total cholesterol and triglycerides increased and all inflammatory cytokines significantly decreased. Regarding vascular cytokines, MPO, ICAM-1, and VCAM-1 showed a reduction. D-Dimer tended to decrease (p = 0.06) and hs-CRP did not show a significant reduction (p = 0.17). CONCLUSION: One year of ART had a positive effect on reducing inflammatory and vascular cytokines and arterial stiffness.

A randomized clinical trial of lipid metabolism modulation with fenofibrate for acute coronavirus disease 2019.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cytotoxicity may involve inhibition of peroxisome proliferator-activated receptor alpha. Fenofibrate activates peroxisome proliferator-activated receptor alpha and inhibits SARS-CoV-2 replication in vitro. Whether fenofibrate can be used to treat coronavirus disease 2019 (COVID-19) infection in humans remains unknown. Here, we randomly assigned inpatients and outpatients with COVID-19 within 14 d of symptom onset to 145 mg of oral fenofibrate nanocrystal formulation versus placebo for 10 d, in a double-blinded fashion. The primary endpoint was a severity score whereby participants were ranked across hierarchical tiers incorporating time to death, mechanical ventilation duration, oxygenation, hospitalization and symptom severity and duration. In total, 701 participants were randomized to fenofibrate (n = 351) or placebo (n = 350). The mean age of participants was 49 ± 16 years, 330 (47%) were female, mean body mass index was 28 ± 6 kg/m2 and 102 (15%) had diabetes. Death occurred in 41 participants. Compared with placebo, fenofibrate had no effect on the primary endpoint. The median (interquartile range) rank in the placebo arm was 347 (172, 453) versus 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in secondary and exploratory endpoints, including all-cause death, across arms. There were 61 (17%) adverse events in the placebo arm compared with 46 (13%) in the fenofibrate arm, with slightly higher incidence of gastrointestinal side effects in the fenofibrate group. Overall, among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes ( NCT04517396 ).

Ghrelin level as a biomarker for knee osteoarthritis severity and appearance in HIV + patients.

BACKGROUND: Knee Osteoarthritis (KOA) is a multifactorial disease with several mechanisms to promote articular cartilage damage. New molecules, such as ghrelin, have been recently reported to participate in the pathogenesis and progression of KOA. In HIV + patients, arthralgias are the most frequent musculoskeletal manifestations, mainly affecting joints such as the knee. Also, it has been reported that HIV + patients have a reduction of ghrelin even with treatment compared to HIV- patients. However, there is no report in the literature evaluating ghrelin and KOA in the HIV + population. We aimed to evaluate whether serum ghrelin levels can function as a biomarker for OA in HIV + patients. METHODS: We recruited 40 patients, 20 HIV+, and 20 HIV- controls, and grouped as follows: HIV+/KOA+; HIV+/KOA-; HIV-/KOA+; HIV-/KOA-. Clinical features were obtained during clinical visits. Peripheral blood samples were acquired to measure serum ghrelin levels. RESULTS: The HIV+/KOA + group significantly reduced serum ghrelin levels when compared with the other groups. Comparing the ghrelin levels with the patients' nadir of CD4+ T-cells count, we identified a statistically significant negative correlation in the KOA- group (r = -0.80, P < 0.007). An ROC curve analysis, for the accuracy of ghrelin levels to identified HIV+/KOA + from HIV+/KOA- patients, found an area under the curve of 0.83 (95 % CI 0.65-0.10; P = 0.017), with a cut-off < 4026 pg/mL serum ghrelin levels, with a sensitivity of 0.62 (95 % CI 0.32-0.86), and a specificity of 0.10 (95 % CI 0.59-0.10). CONCLUSION: This study shows the potential use of ghrelin levels as a biomarker for KOA in the high-risk HIV population that should be further analyzed.

Oral Manifestations Associated with HIV/AIDS Patients.

Oral manifestations are early and important clinical indicators of Human Immunodeficiency Virus (HIV) infection since they can occur in up to 50% of HIV-infected patients and in up to 80% of patients at the AIDS stage (<200 CD4+ T lymphocytes). Oral health is related to physical and mental well-being because the presence of some lesions can compromise dental aesthetics, and alter speech, chewing, and swallowing, thus impacting the quality of life of patients. For this reason, it is necessary to integrate, as part of the medical treatment of HIV-positive patients, the prevention, diagnosis, and control of oral health. It is essential that health professionals have the power to identify, diagnose, and treat oral pathologies through clinical characteristics, etiological agents, and risk factors, both local and systemic. A diagnosis at an early stage of injury allows optimizing and prioritizing oral treatments, especially in acute pathologies, such as gingivitis and necrotizing periodontitis. In this group of patients, the development of strategies for the prevention, control, and reduction of these pathologies must be prioritized in order to reduce morbidity and mortality in this group of patients.

A Randomized Trial of Lipid Metabolism Modulation with Fenofibrate for Acute Coronavirus Disease 2019.

Background Abnormal cellular lipid metabolism appears to underlie SARS-CoV-2 cytotoxicity and may involve inhibition of peroxisome proliferator activated receptor alpha (PPARα). Fenofibrate, a PPAR-α activator, modulates cellular lipid metabolism. Fenofibric acid has also been shown to affect the dimerization of angiotensin-converting enzyme 2, the cellular receptor for SARS-CoV-2. Fenofibrate and fenofibric acid have been shown to inhibit SARS-CoV-2 replication in cell culture systems in vitro . Methods We randomly assigned 701 participants with COVID-19 within 14 days of symptom onset to 145 mg of fenofibrate (nanocrystal formulation with dose adjustment for renal function or dose-equivalent preparations of micronized fenofibrate or fenofibric acid) vs. placebo for 10 days, in a double-blinded fashion. The primary endpoint was a ranked severity score in which participants were ranked across hierarchical tiers incorporating time to death, duration of mechanical ventilation, oxygenation parameters, subsequent hospitalizations and symptom severity and duration. ClinicalTrials.gov registration: NCT04517396. Findings: Mean age of participants was 49 ± 16 years, 330 (47%) were female, mean BMI was 28 ± 6 kg/m 2 , and 102 (15%) had diabetes mellitus. A total of 41 deaths occurred. Compared with placebo, fenofibrate administration had no effect on the primary endpoint. The median (interquartile range [IQR]) rank in the placebo arm was 347 (172, 453) vs. 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in various secondary and exploratory endpoints, including all-cause death, across randomization arms. These results were highly consistent across pre-specified sensitivity and subgroup analyses. Conclusion Among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes.

Gut microbiota from Mexican patients with metabolic syndrome and HIV infection: An inflammatory profile.

AIM: A remarkable increase in metabolic syndrome (MetS) has occurred in HIV-infected subjects. Gut dysbiosis is involved in the pathogenesis of metabolic disorders. Therefore, the aim is to explore the profile of the gut microbiota in Mexican population with HIV infection and MetS. METHODS AND RESULTS: In all, 30 HIV-infected patients with MetS were compared to a group of 30 patients without MetS, treated with integrase inhibitors and undetectable viral load were included in the study. Stool samples were analysed by 16S rRNA next-generation sequencing. High-sensitivity C-reactive protein >3 mg L-1 and higher scores in cardiometabolic indices were associated with MetS. The group with MetS was characterized by a decrease in α-diversity, higher abundance of Enterobacteriaceae and Prevotella, as well as a dramatic decrease in bacteria producing short-chain fatty acids. Prevotella negatively correlated with Akkermansia, Lactobacillus and Anaerostipes. Interestingly, the group without MetS presented higher abundance of Faecalibacterium, Ruminococcus, Anaerofilum, Oscillospira and Anaerostipes. Functional pathways related to energy metabolism and inflammation were increased in the group with MetS. CONCLUSIONS: HIV-infected patients with MetS present a strong inflammatory microbiota profile; therefore, future strategies to balance intestinal dysbiosis should be implemented.

Clinical features associated with neurosyphilis in people living with HIV and late latent syphilis.

BACKGROUND: The diagnosis of neurosyphilis is a challenge, and the criteria for deciding when to perform a lumbar puncture are still controversial, especially in people living with HIV with a late latent syphilis diagnosis. METHODS: Retrospective analysis of demographic, clinical, and laboratory data of people with HIV and documented late latent syphilis or syphilis of unknown duration with a cerebrospinal fluid VDRL test. RESULTS: 122 patients were evaluated, of whom 52 had the diagnosis of neurosyphilis. Patients with and without neurosyphilis presented a similar viral load and lymphocyte CD4+ T-cell count. Neurological symptoms (OR 6.4, 95% CI 2.1-22.4; p < 0.01), serum VDRL titers of 1:32 (p<0.01), 1:64 (p = 0.055), and ≥1:128 (p < 0.001) were associated with neurosyphilis. Furthermore, serum VDRL ≥1:32 were associated with (OR 24.9, 95% CI 5.45-154.9; p < 0.001) or without (OR 6.5, 95% CI 2.0-29.2; p = 0.004) neurological symptoms with neurosyphilis; however, VDRL ≤1:16 with neurological symptoms can be associated with neurosyphilis (OR 7.6, 95% CI 1.03-64.3; p = 0.046). CONCLUSION: Neurological symptoms, particularly headache, were predictors of neurosyphilis in people with HIV irrespective of their viral load and lymphocyte CD4+ T-cell count in late latent syphilis. A serum VDRL ≥1:32 increased the risk of neurosyphilis in patients with or without any symptoms.

Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 96-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study.

BACKGROUND: Long-acting cabotegravir and rilpivirine administered monthly or every 2 months might address the challenges associated with daily oral antiretroviral therapy. The ATLAS-2M week 48 results showed non-inferiority of long-acting cabotegravir and rilpivirine administered every 8 weeks compared with that of every 4 weeks. In this study, we report the efficacy, safety, and tolerability results from the week 96 analysis. METHODS: ATLAS-2M is a randomised, multicentre, open-label, phase 3b, non-inferiority trial conducted in 13 countries, evaluating the safety and efficacy of maintenance treatment with intramuscular injections of long-acting cabotegravir and rilpivirine, administered every 8 weeks versus every 4 weeks, to people living with HIV-1. Virologically suppressed adults with HIV-1, either already receiving intramuscular long-acting cabotegravir and rilpivirine every 4 weeks (ie, ATLAS study rollover participants) or oral standard of care, were randomly assigned (1:1), in an unblinded fashion, to receive either intramuscular long-acting cabotegravir (600 mg) and rilpivirine (900 mg) every 8 weeks (ie, the every 8-week dosing group) or intramuscular long-acting cabotegravir (400 mg) and rilpivirine (600 mg) every 4 weeks (ie, the every 4-week dosing group). Randomisation was generated using the GlaxoSmithKline-validated randomisation software RANDALL NG (version 1.3.3). The primary endpoint at week 48 was the proportion of participants with plasma HIV-1 RNA measurements of 50 copies per mL or more (ie, the US Food and Drug Administration [FDA] Snapshot algorithm), which has been published previously. Here, we present the week 96 results: the proportion of participants with plasma HIV-1 RNA measurements of less than 50 copies per mL (FDA Snapshot algorithm), with a non-inferiority margin of -10%; the proportion of participants with plasma HIV-1 RNA measurements of 50 copies per mL or more (FDA Snapshot algorithm), with a non-inferiority margin of 4%; the proportion of participants with protocol-defined confirmed virological failure (ie, two consecutive plasma HIV-1 RNA measurements ≥200 copies per mL); safety; pharmacokinetics; and tolerability. This study is registered with ClinicalTrials.gov, number NCT03299049, and is currently ongoing. FINDINGS: Between Oct 27, 2017, and May 31, 2018, a total of 1149 participants were screened; of whom, 1049 (91%) were randomly assigned and 1045 (91%) initiated treatment (522 in the every 8-week dosing group and 523 in the every 4-week dosing group). The median age was 42 years (IQR 34-50). 280 (27%) of 1045 participants were assigned female at birth and 764 (73%) were white. At week 96 (FDA Snapshot algorithm), 11 (2%) of 522 participants in the every 8-week dosing group and six (1%) of 523 in the every 4-week dosing group had an HIV-1 RNA measurement of 50 copies per mL or more, with an adjusted treatment difference of 1·0 (95% CI -0·6 to 2·5), meeting the prespecified non-inferiority threshold of 4%; 475 (91%) of 522 participants in the every 8-week dosing group and 472 (90%) of 523 in the every 4-week dosing group maintained an HIV-1 RNA measurement of less than 50 copies per mL, with an adjusted treatment difference of 0·8 (95% CI -2·8 to 4·3), which met the prespecified non-inferiority threshold of -10%. One participant in the every 8-week dosing group met the confirmed virological failure criterion since the week 48 analysis at week 88, resulting in a total of nine participants in the every 8-week dosing group and two in the every 4-week dosing group having confirmed virological failure. No new safety signals were identified, and no treatment-related deaths occurred. Injection site reactions were the most common adverse event, occurring in 412 (79%) of 522 participants in the every 8-week dosing group and 400 (76%) of 523 in the every 4-week dosing group. Most injection site reactions were grade 1 or 2 (7453 [99%] of 7557 in both groups), with a median duration of 3 days (IQR 2-5). INTERPRETATION: Long-acting cabotegravir and rilpivirine dosed every 8 weeks had non-inferior efficacy compared with that of every 4 weeks through the 96-week analysis, with both regimens maintaining high levels of virological suppression. These results show the durable safety, efficacy, and acceptability of dosing long-acting cabotegravir and rilpivirine monthly and every 2 months as maintenance therapy for people living with HIV-1. FUNDING: ViiV Healthcare and Janssen Research & Development.

Prevalence and risk factors of chronic kidney disease in an HIV positive Mexican cohort.

BACKGROUND: HIV subjects have several kidney pathologies, like HIV-associated nephropathy or antiretroviral therapy injury, among others. The global prevalence of Chronic Kidney Disease (CKD) is 8-16%; however, in HIV subjects, the prevalence varies between geographic regions (2-38%). The aim was to determine the prevalence of CKD and identify the associated risk factors. METHODS: A longitudinal descriptive study was carried out at the 'Hospital Civil de Guadalajara' Feb'18 - Jan'19. Basal clinical, demographic, opportunistic infections (OI), and laboratory data were obtained at months 0 and 3; inclusion criteria were ≥ 18 years old, naïve HIV + , urine albumin/creatinine ratio, serum creatinine & urine test, and signed informed consent. Descriptive and multiple logistic regression statistical analyses were made. RESULTS: One hundred twenty subjects were included; 92.5% were male, 33 ± 9.5 years, 60% consumed tobacco, 73% alcohol, and 59% some type of drug. The CKD prevalence was 15.8%. CKD patients had a higher risk of hepatitis C virus coinfection, Relative Risk (RR):5.9; HCV infection, RR:4.3; ≥ 30 years old, RR:3.9; C clinical-stage, RR:3.5; CD4+ T cells count < 200 cells/µL, RR: 2.4; and HIV-1 viral load ≥ 100,000 cop/mL, RR: 2.7. CONCLUSIONS: Our study showed a higher CKD prevalence in patients with HIV; higher CKD development with coinfections as Hepatitis C Virus and Mycobacterium tuberculosis. The identification and prompt management of CKD and coinfections should be considered to avoid the progression and to delay renal replacement therapy as long as possible.

Diagnostic accuracy of antigen detection in urine and molecular assays testing in different clinical samples for the diagnosis of progressive disseminated histoplasmosis in patients living with HIV/AIDS: A prospective multicenter study in Mexico.

BACKGROUND: The progressive disseminated histoplasmosis (PDH) has been associated with severe disease and high risk of death among people living with HIV (PLWHIV). Therefore, the purpose of this multicenter, prospective, double-blinded study done in ten Mexican hospitals was to determine the diagnostic accuracy of detecting Histoplasma capsulatum antigen in urine using the IMMY ALPHA Histoplasma EIA kit (IAHE), clarus Histoplasma GM Enzyme Immunoassay (cHGEI IMMY) and MiraVista Histoplasma Urine Antigen LFA (MVHUALFA); as well as the Hcp100 and 1281-1283220SCAR nested PCRs in blood, bone-marrow, tissue biopsies and urine. METHODOLOGY/PRINCIPAL FINDINGS: We included 415 PLWHIV older than 18 years of age with suspicion of PDH. Using as diagnostic standard recovery of H. capsulatum in blood, bone marrow or tissue cultures, or histopathological exam compatible, detected 108 patients (26%, [95%CI, 21.78-30.22]) with proven-PDH. We analyzed 391 urine samples by the IAHE, cHGEI IMMY and MVHUALFA; the sensitivity/specificity values obtained were 67.3% (95% CI, 57.4-76.2) / 96.2% (95% CI, 93.2-98.0) for IAHE, 91.3% (95% CI, 84.2-96.0) / 90.9% (95% CI, 87.0-94.0) for cHGEI IMMY and 90.4% (95% CI, 83.0-95.3) / 92.3% (95% CI, 88.6-95.1) for MVHUALFA. The Hcp100 nested PCR was performed on 393, 343, 75 and 297, blood, bone marrow, tissue and urine samples respectively; the sensitivity/specificity values obtained were 62.9% (95%CI, 53.3-72.5)/ 89.5% (95%CI, 86.0-93.0), 65.9% (95%CI, 56.0-75.8)/ 89.0% (95%CI, 85.2-92.9), 62.1% (95%CI, 44.4-79.7)/ 82.6% (95%CI, 71.7-93.6) and 34.9% (95%CI, 24.8-46.2)/ 67.3% (95%CI, 60.6-73.5) respectively; and 1281-1283220SCAR nested PCR was performed on 392, 344, 75 and 291, respectively; the sensitivity/specificity values obtained were 65.3% (95% CI, 55.9-74.7)/ 58.8% (95%CI, 53.2-64.5), 70.8% (95%CI, 61.3-80.2)/ 52.9% (95%CI, 46.8-59.1), 71.4% (95%CI, 54.7-88.2)/ 40.4% (95%CI, 26.4-54.5) and 18.1% (95%CI, 10.5-28.1)/ 90.4% (95%CI, 85.5-94.0), respectively. CONCLUSIONS/SIGNIFICANCE: The cHGEI IMMY and MVHUALFA tests showed excellent performance for the diagnosis of PDH in PLWHIV. The integration of these tests in clinical laboratories will certainly impact on early diagnosis and treatment.

Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial.

BACKGROUND: Biological considerations suggest that renin-angiotensin system inhibitors might influence the severity of COVID-19. We aimed to evaluate whether continuing versus discontinuing renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) affects outcomes in patients admitted to hospital with COVID-19. METHODS: The REPLACE COVID trial was a prospective, randomised, open-label trial done at 20 large referral hospitals in seven countries worldwide. Eligible participants were aged 18 years and older who were admitted to hospital with COVID-19 and were receiving a renin-angiotensin system inhibitor before admission. Individuals with contraindications to continuation or discontinuation of renin-angiotensin system inhibitor therapy were excluded. Participants were randomly assigned (1:1) to continuation or discontinuation of their renin-angiotensin system inhibitor using permuted block randomisation, with allocation concealed using a secure web-based randomisation system. The primary outcome was a global rank score in which participants were ranked across four hierarchical tiers incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during the hospitalisation. Primary analyses were done in the intention-to-treat population. The REPLACE COVID trial is registered with ClinicalTrials.gov, NCT04338009. FINDINGS: Between March 31 and Aug 20, 2020, 152 participants were enrolled and randomly assigned to either continue or discontinue renin-angiotensin system inhibitor therapy (continuation group n=75; discontinuation group n=77). Mean age of participants was 62 years (SD 12), 68 (45%) were female, mean body-mass index was 33 kg/m2 (SD 8), and 79 (52%) had diabetes. Compared with discontinuation of renin-angiotensin system inhibitors, continuation had no effect on the global rank score (median rank 73 [IQR 40-110] for continuation vs 81 [38-117] for discontinuation; ß-coefficient 8 [95% CI -13 to 29]). There were 16 (21%) of 75 participants in the continuation arm versus 14 (18%) of 77 in the discontinuation arm who required intensive care unit admission or invasive mechanical ventilation, and 11 (15%) of 75 participants in the continuation group versus ten (13%) of 77 in the discontinuation group died. 29 (39%) participants in the continuation group and 28 (36%) participants in the discontinuation group had at least one adverse event (χ2 test of adverse events between treatment groups p=0·77). There was no difference in blood pressure, serum potassium, or creatinine during follow-up across the two groups. INTERPRETATION: Consistent with international society recommendations, renin-angiotensin system inhibitors can be safely continued in patients admitted to hospital with COVID-19. FUNDING: REPLACE COVID Investigators, REPLACE COVID Trial Social Fundraising Campaign, and FastGrants.

Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study.

BACKGROUND: Phase 3 clinical studies showed non-inferiority of long-acting intramuscular cabotegravir and rilpivirine dosed every 4 weeks to oral antiretroviral therapy. Important phase 2 results of every 8 weeks dosing, and supportive modelling, underpin further evaluation of every 8 weeks dosing in this trial, which has the potential to offer greater convenience. Our objective was to compare the week 48 antiviral efficacy of cabotegravir plus rilpivirine long-acting dosed every 8 weeks with that of every 4 weeks dosing. METHODS: ATLAS-2M is an ongoing, randomised, multicentre (13 countries; Australia, Argentina, Canada, France, Germany, Italy, Mexico, Russia, South Africa, South Korea, Spain, Sweden, and the USA), open-label, phase 3b, non-inferiority study of cabotegravir plus rilpivirine long-acting maintenance therapy administered intramuscularly every 8 weeks (cabotegravir 600 mg plus rilpivirine 900 mg) or every 4 weeks (cabotegravir 400 mg plus rilpivirine 600 mg) to treatment-experienced adults living with HIV-1. Eligible newly recruited individuals must have received an uninterrupted first or second oral standard-of-care regimen for at least 6 months without virological failure and be aged 18 years or older. Eligible participants from the ATLAS trial, from both the oral standard-of-care and long-acting groups, must have completed the 52-week comparative phase with an ATLAS-2M screening plasma HIV-1 RNA less than 50 copies per mL. Participants were randomly assigned 1:1 to receive cabotegravir plus rilpivirine long-acting every 8 weeks or every 4 weeks. The randomisation schedule was generated by means of the GlaxoSmithKline validated randomisation software RANDALL NG. The primary endpoint at week 48 was HIV-1 RNA ≥50 copies per mL (Snapshot, intention-to-treat exposed), with a non-inferiority margin of 4%. The trial is registered at ClinicalTrials.gov, NCT03299049 and is ongoing. FINDINGS: Screening occurred between Oct 27, 2017, and May 31, 2018. Of 1149 individuals screened, 1045 participants were randomised to the every 8 weeks (n=522) or every 4 weeks (n=523) groups; 37% (n=391) transitioned from every 4 weeks cabotegravir plus rilpivirine long-acting in ATLAS. Median participant age was 42 years (IQR 34-50); 27% (n=280) female at birth; 73% (n=763) white race. Cabotegravir plus rilpivirine long-acting every 8 weeks was non-inferior to dosing every 4 weeks (HIV-1 RNA ≥50 copies per mL; 2% vs 1%) with an adjusted treatment difference of 0·8 (95% CI -0·6-2·2). There were eight (2%, every 8 weeks group) and two (<1%, every 4 weeks group) confirmed virological failures (two sequential measures ≥200 copies per mL). For the every 8 weeks group, five (63%) of eight had archived non-nucleoside reverse transcriptase inhibitor resistance-associated mutations to rilpivirine at baseline. The safety profile was similar between dosing groups, with 844 (81%) of 1045 participants having adverse events (excluding injection site reactions); no treatment-related deaths occurred. INTERPRETATION: The efficacy and safety profiles of dosing every 8 weeks and dosing every 4 weeks were similar. These results support the use of cabotegravir plus rilpivirine long-acting administered every 2 months as a therapeutic option for people living with HIV-1. FUNDING: ViiV Healthcare and Janssen.

ZBTB gene expression in HIV patients: a possible new molecular mechanism of viral control.

HIV infects its target cell and integrates into its genome as an essential step in its replication cycle. Proviral DNA is also subjected to the same transcriptional regulation as the host cell genome by its own transcriptional factors, with activating or repressive activity. There is a clear interaction between the presence of transcriptional repressors and a decrease in the rate of HIV replication, promoting gene silencing in infected cells, which serve as viral reservoirs. This represents a major obstacle for HIV eradication. The ZBTB gene family comprises 49 genes that encode transcription factors that have a repressor function in differentiation and development of cells of the lymphopoietic lineage, including the main target cells of HIV, CD4+ T cells. In this cross-sectional study, we evaluated the expression profile of ZBTB genes in CD4+ T cells of HIV-positive individuals with different levels of infection control. We found upregulation of gene expression of ZBTB4 (p < 0.01), ZBTB7B (p < 0.001), and ZBTB38 (p < 0.05) and downregulation of ZBTB16 (p < 0.01) in HIV-positive patients compared to HIV-negative individuals. Interestingly, in a deeper analysis, we observed that elite controllers had the highest levels of expression of the ZBTB38, ZBTB2, HIC1, ZBTB7A, ZBTB7B (ThPOK) and ZBTB4 genes, showing 2.56- to 7.60-fold upregulation compare to the ART-naïve group. These results suggest a possible contribution of these ZBTB transcriptional repressors in HIV-positive patients and a possible new molecular mechanism of viral control.

Long-Acting Injectable Cabotegravir + Rilpivirine for HIV Maintenance Therapy: Week 48 Pooled Analysis of Phase 3 ATLAS and FLAIR Trials.

BACKGROUND: Long-acting (LA) injectable regimens are a potential therapeutic option in people living with HIV-1. SETTING: ATLAS (NCT02951052) and FLAIR (NCT02938520) were 2 randomized, open-label, multicenter, multinational phase 3 studies. METHODS: Adult participants with virologic suppression (plasma HIV-1 RNA <50 copies/mL) were randomized (1:1) to continue with their current antiretroviral regimen (CAR) or switch to the long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). In the LA arm, participants initially received oral CAB + RPV once-daily for 4 weeks to assess individual safety and tolerability, before starting monthly injectable therapy. The primary endpoint of this combined analysis was antiviral efficacy at week 48 (FDA Snapshot algorithm: noninferiority margin of 4% for HIV-1 RNA ≥50 copies/mL). Safety, tolerability, and confirmed virologic failure (2 consecutive plasma HIV-1 RNA ≥200 copies/mL) were secondary endpoints. RESULTS: The pooled intention-to-treat exposed population included 591 participants in each arm [28% women (sex at birth), 19% aged ≥50 years]. Noninferiority criteria at week 48 were met for the primary (HIV-1 RNA ≥50 copies/mL) and key secondary (HIV-1 RNA <50 copies/mL) efficacy endpoints. Seven individuals in each arm (1.2%) developed confirmed virologic failure; 6/7 (LA) and 3/7 (CAR) had resistance-associated mutations. Most LA recipients (83%) experienced injection site reactions, which decreased in incidence over time. Injection site reactions led to the withdrawal of 6 (1%) participants. The serious adverse event rate was 4% in each arm. CONCLUSION: This combined analysis demonstrates monthly injections of CAB + RPV LA were noninferior to daily oral CAR for maintaining HIV-1 suppression.

Aortic stiffness and central hemodynamics in treatment-naïve HIV infection: a cross-sectional study.

BACKGROUND: Human immunodeficiency virus (HIV) infection is associated with a greater risk of cardiovascular disease (CVD). HIV infection causes a chronic inflammatory state and increases oxidative stress which can cause endothelial dysfunction and arterial stiffness. Aortic stiffness measured by carotid femoral-pulse wave velocity (cfPWV) and central hemodynamics are independent cardiovascular risk factors and have the prognostic ability for CVD. We assessed cfPWV and central hemodynamics in young individuals with recent HIV infection diagnosis and without antiretroviral therapy. We hypothesized that individuals living with HIV would present greater cfPWV and central hemodynamics (central systolic blood pressure and pulse pressure) compared to uninfected controls. METHODS: We recruited 51 treatment-naïve individuals living with HIV (HIV(+)) without previous CVD and 51 age- and sex-matched controls (HIV negative (-)). We evaluated traditional CVD risk factors including metabolic profile, blood pressure (BP), smoking, HIV viral load, and CD4+ T-cells count. Arterial stiffness and central hemodynamics were evaluated by cfPWV, central systolic BP, and central pulse pressure (cPP) via applanation tonometry. RESULTS: HIV(+) individuals presented a greater prevalence of smoking, reduced high-density lipoprotein cholesterol, and body mass index. 65.9% of HIV(+) individuals exhibited lymphocyte CD4+ T-cells count < 500 cells/µL. There was no difference in brachial or central BP between groups; however, HIV(+) individuals showed significantly lower cPP. We observed a greater cfPWV (mean difference = 0.5 m/s; p < 0.01) in HIV(+) compared to controls, even after adjusting for heart rate, mean arterial pressure and smoking. CONCLUSION: In the early stages of infection, non-treated HIV individuals present a greater prevalence of traditional CVD risk factors, arterial stiffness, and normal or in some cases central hemodynamics.

Correction to: Alterations in bacterial communities, SCFA and biomarkers in an elderly HIV-positive and HIV-negative population in western Mexico.

An amendment to this paper has been published and can be accessed via the original article.

Association of intestinal and systemic inflammatory biomarkers with immune reconstitution in HIV+ patients on ART.

BACKGROUND: HIV infection is characterized by CD4+ T-cells depletion related to gut damage, microbial translocation, immune activation and intestinal and systemic low-grade inflammation. With the use of antiretroviral treatment, these alterations in HIV+ patients reach similar levels to HIV- controls. However, almost 20% patients have deficient immune reconstitution of CD4+ T-cells, which make them more susceptible to develop non-AIDS and AIDS comorbidities. METHODS: HIV+ patients on ART, with sustained virologic control were grouped according to their immune reconstitution as: immunological responders (n = 18) and immunological non-responders (n = 18); also, HIV- controls were enrolled (n = 14). CD4+ and CD8+ T-cell activation (HLA-DR+ and CD38+ single and co-expression) were measured by flow cytometry. Serum levels of sCD14, sCD163, lipopolysaccharide, I-FABP, sST2, as well as fecal levels of calprotectin, lactoferrin and secretory IgA were evaluated by ELISA. Levels of C-reactive protein were determined by a high sensibility singleplex bead-based immunoassay. Serum and fecal concentrations of proinflammatory cytokines were quantified by multiplex bead-based immunoassay. RESULTS: HLA-DR+ and CD38+ co-expression, as well as median fluorescence intensity in CD4+ and CD8+ T-cells subpopulations was greater in immunological non-responders group, after normalization and fold change calculation. Similarly, this group presented higher levels of sCD14, C-reactive protein, as well as fecal calprotectin and lactoferrin. Furthermore, both HIV+ groups showed elevated levels of proinflammatory cytokines in stool. CONCLUSIONS: Our data suggests that despite the virologic control, HIV+ patients under treatment with deficient immune reconstitution showed elevation of both innate and T-cells immune activation, as well as intestinal and systemic inflammation. However, some patients with CD4+ T-cells count above 350 cells/µL also presented these alterations. Future studies are necessary to evaluate the dynamics of multiple systemic and intestinal biomarkers in diverse types of HIV+ patients, as such as their clinical impact.