Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial.

HIV-1 therapy with single or dual broadly neutralizing antibodies (bNAbs) has shown viral escape, indicating that at least a triple bNAb therapy may be needed for robust suppression of viremia. We performed a two-part study consisting of a single-center, randomized, double-blind, dose-escalation, placebo-controlled first-in-human trial of the HIV-1 V2-glycan-specific antibody PGDM1400 alone or in combination with the V3-glycan-specific antibody PGT121 in 24 adults without HIV in part 1, as well as a multi-center, open-label trial of the combination of PGDM1400, PGT121 and the CD4-binding-site antibody VRC07-523LS in five viremic adults living with HIV not on antiretroviral therapy (ART) in part 2 ( NCT03205917 ). The primary endpoints were safety, tolerability and pharmacokinetics for both parts and antiviral activity among viremic adults living with HIV and not on ART for part 2 of the study. The secondary endpoints were changes in CD4+ T cell counts and development of HIV-1 sequence variations associated with PGDM1400, PGT121 and VRC07-523LS resistance in part 2. Intravenously administered PGDM1400 was safe and well-tolerated at doses up to 30 mg kg-1 and when given in combination with PGT121 and VRC07-523LS. A single intravenous infusion of 20 mg kg-1 of each of the three antibodies reduced plasma HIV RNA levels in viremic individuals by a maximum mean of 2.04 log10 copies per ml; however, viral rebound occurred in all participants within a median of 20 days after nadir. Rebound viruses demonstrated partial to complete resistance to PGDM1400 and PGT121 in vitro, whereas susceptibility to VRC07-523LS was preserved. Viral rebound occurred despite mean VRC07-523LS serum concentrations of 93 µg ml-1. The trial met the pre-specified endpoints. Our data suggest that future bNAb combinations likely need to achieve broad antiviral activity, while also maintaining high serum concentrations, to mediate viral control.

Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial.

Human immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg-1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg-1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load.

Evaluation of Six Weekly Oral Fecal Microbiota Transplants in People with HIV.

BACKGROUND: Reduced microbiota diversity (dysbiosis) in people with HIV (PWH) likely contributes to inflammation, a driver of morbidity and mortality. We aimed to evaluate the safety and tolerability of 6 weekly oral fecal microbiota transplants (FMT) administered to reverse this dysbiosis. METHODS: Six PWH on suppressive antiretroviral therapy (ART) received 6 weekly doses of lyophilized fecal microbiota product from healthy donors. Shotgun sequencing on stool before, after last FMT, and 20 weeks thereafter was performed. Inflammation and gut permeability biomarkers were measured. RESULTS: Median age at week 0 was 39 years, CD4+ T cell count 496 cells/mm3, HIV RNA levels <20 copies/mL. FMT was safe and well-tolerated. α diversity increased in 4 participants from weeks 0 to 6, including the 3 with the lowest α diversity at week 0. At week 26, α diversity more closely resembled week 0 than week 6 in these 4 participants. Metagenomic analysis showed no consistent changes across all participants. One participant had high gut permeability and inflammation biomarker levels and low α diversity that improved between weeks 0 and 6 with a shift in distribution. CONCLUSIONS: Weekly FMT was safe and well-tolerated. α diversity increased in participants with the lowest baseline α diversity during the treatment period. Future randomized, controlled trials of FMT should consider evaluating PWH with greater inflammation, gut damage, or dysbiosis as this population may be most likely to show a significant response.ClinicalTrials.gov Identifier: NCT03329560.

Systemic Inflammation Characterizes Lack of Metabolic Health in Nonobese HIV-Infected Men.

BACKGROUND: Increasing body mass index (BMI) is generally associated with loss of metabolic health, although some obese individuals remain metabolically healthy. Among nonobese men, HIV infection has been associated with a lower prevalence of metabolic health. METHODS: We conducted a cross-sectional analysis of 470 HIV-infected and 368 HIV-uninfected men enrolled in the Multicenter AIDS Cohort Study Cardiovascular substudy. Circulating biomarker levels were compared by BMI category and by HIV serostatus. Poisson regression with robust variance determined associations between metabolic health and circulating inflammatory biomarker levels after adjusting for factors previously associated with metabolic health. RESULTS: HIV-infected men were younger and less likely to be obese. Among HIV-infected, normal weight metabolically healthy men (compared to unhealthy) had significantly lower circulating levels of interleukin- (IL-) 6, soluble tumor necrosis factor receptors (sTNFR) I and II, and homeostatic model assessment of insulin resistance (HOMA-IR), higher adiponectin, less visceral fat, and more subcutaneous fat. Among HIV-uninfected normal weight men and obese men (regardless of HIV serostatus), metabolic health was associated only with higher levels of adiponectin, less visceral fat, and lower HOMA-IR values. In multivariate analyses restricted to HIV-infected men, lower hs-CRP, sTNFRI, sTNFRII, and HOMA-IR and higher adiponectin levels were associated with metabolic health. Additional adjustment for visceral adiposity did not alter results. CONCLUSIONS: Among HIV-infected normal weight men, metabolic health was associated with less systemic inflammation, a relationship that, among normal weight men, was unique to HIV+ men and did not exist among obese men of either HIV serostatus.

Descripción epidemiológica de los episodios de sífilis asistidos en una institución de la Ciudad de Buenos Aires durante el período 2008-2011 / Epidemiological description of episodes of syphilis attending an institution of the city of Buenos Aires during the period 2008-2011

Introducción: se han notificado epidemias de sífilis en di-versas regiones del mundo, la reemergencia de sífilis constituye un problema de salud pública.Objetivos: determinar número de casos de sífilis diagnosticados y asistidos en una institución, analizar características demográficas, pertenencia o no a la población vulnerable de hombres que tienen sexo con hombres (HSH), estadio del episodio en el momento del diagnóstico, coinfección con infección por VIH, estadios clínicos en VIH reactivos y no reactivos. Materiales y métodos: en la base de datos del laboratorio se iden-tificaron VDRL ≥ 1/8 de pacientes mayores de 18 años asistidos en la institución durante 2008-2011. En forma retrospectiva se revisa-ron las historias clínicas de los pacientes con diagnóstico de sífilis. Resultados: se diagnosticaron 356 episodios en 325 pacientes. Edad media 38,6 años(DS 10,47), mediana 37 años, 95,3 % hombres, 65,2 % VIH reactivos; 50,5 % fueron sífilis primaria o secun-daria y 45 % sífilis latente. Estadio de sífilis similar en pacientes VIH reacti-vos y no reactivos (p = 0,41). Se analizó el número total de VDRL procesadas y el porcentaje de posi-tividad de las mismas en los cuatro años estudiados. Se observó aumento de la tasa anual de positividad de VDRL por 1000 VDRL solicitadas, diferencia estadísticamente no significa-tiva (p = 0,1).Discusión: los episodios de sífilis fueron diagnosticados predomi-nantemente en hombres, en HSH y en pacientes VIH reactivos. Los resultados de nuestro estudio sugieren que la implementación ru-tinaria del testeo para sífilis en poblaciones vulnerables permite diagnosticar un número considerable de episodios en pacientes sin-tomáticos y asintomáticos, ofreciendo beneficios clínicos y epide-miológicos.

Introduction: syphilis epidemics have been reported worldwide and currently represent a major reemerging public health problem.Objectives: to determine the number of cases of syphilis diagnosed at one institution, analyzing demographics, subjects belonging to the population of men who have sex with men (MSM), stage of the episode at the time of diagnosis, co infection with HIV infection, clinical stages in HIV reactive and non-reactive patients. Materials and methods: in the database laboratory VDRL ≥ 1/8 of patients over 18 years attended the institution during 2008-2011 were identified. We retrospectively reviewed the medical records of patients with diagnosis of syphilis Results: 356 episodes were diagnosed in 325 patients. Mean age 38.6 years; median age 37 years; 95.3% male, 65.2% HIV reactive; 50.5% were primary or secondary syphilis and 45% latent syphilis. Similar stage syphilis in HIV reactive and non-reactive (p = 0.41). Increase in the annual rate of positive VDRL requested by 1000 VDRL was observed, however, the difference was no statistically significant (p = 0.1).Discussion: episodes of syphilis were diagnosed predominantly in men, MSM and HIV reactive patients. The results of our study suggest that implementation of routine testing for syphilis in vulnerable populations to diagnose symptomatic and asymptomatic syphilis may provide clinical benefits and epidemiological.

Higher transactivation activity associated with LTR and Tat elements from HIV-1 BF intersubtype recombinant variants.

BACKGROUND: HIV-1 is characterized by its rapid genetic evolution and high diversity as a consequence of its error-prone reverse transcriptase and genetic recombination. This latter mechanism is responsible for the creation of circulating recombinant forms (CRFs) found in nature. Previous studies from our lab group have shown that the epidemic in Argentina is characterized by one highly prevalent circulating recombinant form, CRF12_BF, and many related BF recombinant forms. Since transcriptional transactivation of the HIV-1 long terminal repeat (LTR) promoter element requires the essential viral Tat protein, since these genetic structures underwent recombination in variants widely spread in South America, the aim of this work was to study transcriptional activity associated with the recombinant LTR and Tat elements. RESULTS: Differential transcriptional activity was measured for the BF recombinant LTR/Tat complex that is present in widely spread viral variants was demonstrated. This analysis demonstrated a higher activity for the BF complex when compared to its B subtype counterpart. CONCLUSION: This study indicates structural and functional consequences of recombination events within the LTR promoter and Tat transactivator protein of a naturally occurring HIV-1 recombinant form.