Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy.

Importance: Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis. Objective: To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy. Design, Setting, and Participants: NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013-November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo ("placebo") group. Interventions: Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60). Main Outcomes and Measures: Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, -22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, -4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights. Results: Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was -81.7% with eplontersen and -11.2% with placebo (difference, -70.4% [95% CI, -75.2% to -65.7%]; P < .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, -24.8 [95% CI, -31.0 to -18.6; P < .001) and for Norfolk QoL-DN (-5.5 vs 14.2; difference, -19.7 [95% CI, -25.6 to -13.8]; P < .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group. Conclusions and Relevance: In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10.

Liver-directed drugs for transthyretin-mediated amyloidosis.

Transthyretin-mediated amyloidosis (ATTR) is a rare, under-recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition of amyloid transthyretin (TTR) fibrils in multiple organs and tissues throughout the body. TTR is predominantly synthesized by the liver and normally circulates as a homotetramer, while misfolded monomers aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to reduce the amount of TTR produced by the liver using drugs that directly target the TTR mRNA or gene. This narrative review focuses on how TTR gene silencing tools act to reduce TTR production, describing strategies for improved targeted delivery of these agents to hepatocytes where TTR is preferentially expressed. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed RNA silencers, cause selective degradation of TTR mRNA, while a TTR gene editing tool reduces TTR expression by introducing nonsense mutations into the TTR gene. Two strategies to facilitate tissue-specific delivery of these nucleic acid-based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low-density lipoprotein receptor-mediated uptake of unconjugated siRNA and are now used for CRISPR gene editing tools. Additionally, conjugating N-acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor-mediated uptake by the asialoglycoprotein receptor. In summary, ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor-targeted ligands (eg, GalNAc) and nanoparticle encapsulation (eg, LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis.

Enabling patient-reported outcome measures in clinical trials, exemplified by cardiovascular trials.

OBJECTIVES: There has been limited success in achieving integration of patient-reported outcomes (PROs) in clinical trials. We describe how stakeholders envision a solution to this challenge. METHODS: Stakeholders from academia, industry, non-profits, insurers, clinicians, and the Food and Drug Administration convened at a Think Tank meeting funded by the Duke Clinical Research Institute to discuss the challenges of incorporating PROs into clinical trials and how to address those challenges. Using examples from cardiovascular trials, this article describes a potential path forward with a focus on applications in the United States. RESULTS: Think Tank members identified one key challenge: a common understanding of the level of evidence that is necessary to support patient-reported outcome measures (PROMs) in trials. Think Tank participants discussed the possibility of creating general evidentiary standards depending upon contextual factors, but such guidelines could not be feasibly developed because many contextual factors are at play. The attendees posited that a more informative approach to PROM evidentiary standards would be to develop validity arguments akin to courtroom briefs, which would emphasize a compelling rationale (interpretation/use argument) to support a PROM within a specific context. Participants envisioned a future in which validity arguments would be publicly available via a repository, which would be indexed by contextual factors, clinical populations, and types of claims. CONCLUSIONS: A publicly available repository would help stakeholders better understand what a community believes constitutes compelling support for a specific PROM in a trial. Our proposed strategy is expected to facilitate the incorporation of PROMs into cardiovascular clinical trials and trials in general.

Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-LRx (ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy.

INTRODUCTION: AKCEA-TTR-LRx is a ligand-conjugated antisense (LICA) drug in development for the treatment of hereditary transthyretin amyloidosis (hATTR), a fatal disease caused by mutations in the transthyretin (TTR) gene. AKCEA-TTR-LRx shares the same nucleotide sequence as inotersen, an antisense medicine approved for use in hATTR polyneuropathy (hATTR-PN). Unlike inotersen, AKCEA-TTR-LRx is conjugated to a triantennary N-acetylgalactosamine moiety that supports receptor-mediated uptake by hepatocytes, the primary source of circulating TTR. This advanced design increases drug potency to allow for lower and less frequent dosing. The NEURO-TTRansform study will investigate whether AKCEA-TTR-LRx is safe and efficacious, with the aim of improving neurologic function and quality of life in hATTR-PN patients. METHODS/DESIGN: Approximately 140 adults with stage 1 (independent ambulation) or 2 (requires ambulatory support) hATTR-PN are anticipated to enroll in this multicenter, open-label, randomized, phase 3 study. Patients will be assigned 6:1 to AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks or inotersen 300 mg once weekly until the prespecified week 35 interim efficacy analysis, after which patients receiving inotersen will receive AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks. All patients will then receive AKCEA-TTR-LRx through the remainder of the study treatment period. The final efficacy analysis at week 66 will compare the AKCEA-TTR-LRx arm with the historical placebo arm from the phase 3 trial of inotersen (NEURO-TTR). The primary outcome measures are between-group differences in the change from baseline in serum TTR, modified Neuropathy Impairment Score + 7, and Norfolk Quality of Life-Diabetic Neuropathy questionnaire. CONCLUSION: NEURO-TTRansform is designed to determine whether targeted delivery of AKCEA-TTR-LRx to hepatocytes with lower and less frequent doses will translate into clinical and quality-of-life benefits for patients with hATTR-PN. TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov (NCT04136184) and EudraCT (2019-001698-10).

Hereditary transthyretin amyloidosis with peripheral neuropathy (hATTR-PN for short) is a rare inherited condition. In hATTR-PN, a protein called transthyretin (TTR for short) builds up and damages nerves throughout the body. This neuropathy causes symptoms such as weakness, loss of sensation, and pain. Currently available medicines can slow disease progression, but researchers are looking for more effective treatments with fewer side effects. AKCEA-TTR-L_Rx is an investigational treatment for hATTR-PN. AKCEA-TTR-L_Rx prevents the liver from making TTR, reducing the amount that causes disease progression. It is similar to an existing treatment called inotersen, but designed for better delivery to the liver and is more potent. This article describes the NEURO-TTRansform study that will evaluate how effective AKCEA-TTR-L_Rx is for treating hATTR-PN. Around 140 adults with hATTR-PN from the USA, Canada, and Europe will be able to take part in this study. The study treatment period will be 85 weeks long. People will receive injections underneath the skin of either: AKCEA-TTR-L_Rx every 4 weeks, or Inotersen once a week for 35 weeks, followed by a switch to AKCEA-TTR-L_Rx every 4 weeks. People may continue to receive AKCEA-TTR-L_Rx after the study treatment period ends. In this study, researchers will compare results from people who received AKCEA-TTR-L_Rx to results from people who received no active ingredients (called placebo) in a similar study (called NEURO-TTR). Researchers will measure the differences in peoples': Neuropathy symptoms. Quality of life. TTR protein levels in the blood.

Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data.

AIMS: Amyloidogenic transthyretin (ATTR) amyloidosis is a fatal disease characterized by progressive cardiomyopathy and/or polyneuropathy. AKCEA-TTR-LRx (ION-682884) is a ligand-conjugated antisense drug designed for receptor-mediated uptake by hepatocytes, the primary source of circulating transthyretin (TTR). Enhanced delivery of the antisense pharmacophore is expected to increase drug potency and support lower, less frequent dosing in treatment. METHODS AND RESULTS: AKCEA-TTR-LRx demonstrated an approximate 50-fold and 30-fold increase in potency compared with the unconjugated antisense drug, inotersen, in human hepatocyte cell culture and mice expressing a mutated human genomic TTR sequence, respectively. This increase in potency was supported by a preferential distribution of AKCEA-TTR-LRx to liver hepatocytes in the transgenic hTTR mouse model. A randomized, placebo-controlled, phase 1 study was conducted to evaluate AKCEA-TTR-LRx in healthy volunteers (ClinicalTrials.gov: NCT03728634). Eligible participants were assigned to one of three multiple-dose cohorts (45, 60, and 90 mg) or a single-dose cohort (120 mg), and then randomized 10:2 (active : placebo) to receive a total of 4 SC doses (Day 1, 29, 57, and 85) in the multiple-dose cohorts or 1 SC dose in the single-dose cohort. The primary endpoint was safety and tolerability; pharmacokinetics and pharmacodynamics were secondary endpoints. All randomized participants completed treatment. No serious adverse events were reported. In the multiple-dose cohorts, AKCEA-TTR-LRx reduced TTR levels from baseline to 2 weeks after the last dose of 45, 60, or 90 mg by a mean (SD) of -85.7% (8.0), -90.5% (7.4), and -93.8% (3.4), compared with -5.9% (14.0) for pooled placebo (P < 0.001). A maximum mean (SD) reduction in TTR levels of -86.3% (6.5) from baseline was achieved after a single dose of 120 mg AKCEA-TTR-LRx . CONCLUSIONS: These findings suggest an improved safety and tolerability profile with the increase in potency achieved by productive receptor-mediated uptake of AKCEA-TTR-LRx by hepatocytes and supports further development of AKCEA-TTR-LRx for the treatment of ATTR polyneuropathy and cardiomyopathy.

Omecamtiv Mecarbil in Chronic Heart Failure With Reduced Ejection Fraction: Rationale and Design of GALACTIC-HF.

A central factor in the pathogenesis of heart failure (HF) with reduced ejection fraction is the initial decrease in systolic function. Prior attempts at increasing cardiac contractility with oral drugs have uniformly resulted in signals of increased mortality at pharmacologically effective doses. Omecamtiv mecarbil is a novel, selective cardiac myosin activator that has been shown to improve cardiac function and to decrease ventricular volumes, heart rate, and N-terminal pro-B-type natriuretic peptide in patients with chronic HF. The GALACTIC-HF (Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure) trial tests the hypotheses that omecamtiv mecarbil can safely improve symptoms, prevent clinical HF events, and delay CV death in patients with chronic HF. The GALACTIC-HF trial is an international, multicenter, randomized, double-blind, placebo-controlled, event-driven cardiovascular outcomes trial. More than 8,000 patients with chronic symptomatic (New York Heart Association functional class II to IV) HF, left ventricular ejection fraction ≤35%, elevated natriuretic peptides, and either current hospitalization for HF or history of hospitalization or emergency department visit for HF within a year of screening will be randomized to either oral placebo or omecamtiv mecarbil employing a pharmacokinetic-guided dose titration strategy using doses of 25, 37.5, or 50 mg twice daily. The primary efficacy outcome is the time to cardiovascular death or first HF event. The study has 90% power to assess a final hazard ratio of approximately 0.80 in cardiovascular death, the first secondary outcome. The GALACTIC-HF trial is the first trial examining whether selectively increasing cardiac contractility in patients with HF with reduced ejection fraction will result in improved clinical outcomes. (Registrational Study With Omecamtiv Mecarbil/AMG 423 to Treat Chronic Heart Failure With Reduced Ejection Fraction [GALACTIC-HF]; NCT02929329).

Effects of fluids on microvascular perfusion in patients with severe sepsis.

PURPOSE: To evaluate the effects of fluid administration on microcirculatory alterations in sepsis. METHODS: With a Sidestream Dark Field device, we evaluated the effects of fluids on the sublingual microcirculation in 60 patients with severe sepsis. These patients were investigated either within 24 h (early, n = 37) or more than 48 h (late, n = 23) after a diagnosis of severe sepsis. Hemodynamic and microcirculatory measurements were obtained before and 30 min after administration of 1,000 ml Ringer's lactate (n = 29) or 400 ml 4% albumin (n = 31) solutions. RESULTS: Fluid administration increased perfused small vessel density from 3.5 (2.9-4.3) to 4.4 (3.7-4.9) n/mm (p < 0.01), through a combined increase in the proportion of perfused small vessels from 69 (62-76) to 79 (71-83) %, p < 0.01) and in small vessel density from 5.3 (4.4-5.9) to 5.6 (4.8-6.3) n/mm (p < 0.01). Importantly, microvascular perfusion increased in the early but not in the late phase of sepsis: the proportion of perfused small vessels increased from 65 (60-72) to 80 (75-84) % (p < 0.01) in the early phase and from 75 (66-80) to 74 (67-81) (p = ns) in the late phase. These microvascular effects of fluids were not related to changes in cardiac index (R(2) = 0.05, p = ns) or mean arterial pressure (R(2) = 0.04, p = ns). CONCLUSIONS: In this non-randomized trial, fluid administration improved microvascular perfusion in the early but not late phase of sepsis. This effect is independent of global hemodynamic effects and of the type of solution.

Effects of hydrocortisone on microcirculatory alterations in patients with septic shock.

OBJECTIVE: To evaluate the effects of hydrocortisone on microcirculatory blood flow alterations in patients with septic shock. DESIGN: Prospective, open-label study. SETTING: A 31-bed, medico-surgical intensive care unit of a university hospital. PATIENTS: Twenty patients with septic shock. INTERVENTIONS: Intravenous hydrocortisone (50 mg/6 hr). MEASUREMENTS AND MAIN RESULTS: An orthogonal polarization spectral device (Cytoscan ARII, Cytometrics; Philadelphia, PA) was used to investigate the sublingual microcirculation in 20 patients who received so-called "stress doses" of hydrocortisone as part of their management for septic shock. Hemodynamic measurements and orthogonal polarization spectral images were obtained before administration of the first dose (50 mg) of hydrocortisone and 1, 2, 4, and 24 hours later. Measurements were also made before an adrenocorticotropic hormone (ACTH) test, whenever performed. Global hemodynamic variables were similar at all study time points. Microcirculatory variables improved slightly already at 1 hour after the start of hydrocortisone administration. In particular, perfused vessel density increased from 5.7 (4.8-6.4) to 7.2 (6.5-9.0)n/mm, p < 0.01, which was due to combined increases in small vessel density from 5.2 (4.6-6.2) to 6.0 (5.1-7.5)n/mm, p < 0.01, and in the proportion of perfused vessels from 82.1 (68.7-88.0) to 89.2 (83.4-92.6)%, p < 0.01. There were no differences in microcirculatory variables during hydrocortisone administration between ACTH test responders and nonresponders. CONCLUSIONS: The administration of moderate doses of hydrocortisone in septic shock results in a modest but consistent improvement in capillary perfusion, independent of the response to the ACTH test. The mechanisms underlying this effect need to be elucidated.

Multicenter, randomized, controlled trials evaluating mortality in intensive care: doomed to fail?

OBJECTIVES: To determine how many multicenter, randomized controlled trials have been published that assess mortality as a primary outcome in the adult intensive care unit population, and to evaluate their methodologic quality. DATA SOURCE: A sensitive search strategy for randomized controlled trials was conducted in the Cochrane Central Register of Controlled Trials and in MedLine using the PubMed interface. STUDY SELECTION: All publications of adult, multicenter randomized controlled trials carried out in the intensive care unit, with mortality as a primary outcome, and including >50 patients were selected. DATA EXTRACTION: Seventy-two randomized controlled trials were retrieved and were classified according to their effect on mortality: beneficial, detrimental, or neutral. DATA SYNTHESIS: Ten of the studies reported a positive impact of the studied intervention on mortality, seven studies reported a detrimental effect of the intervention, and 55 studies showed no effect on mortality. CONCLUSIONS: This literature search demonstrates that relatively few of the randomized controlled trials conducted in intensive care units and using mortality as a primary outcome show a beneficial impact of the intervention on the survival of critically ill patients. Methodological limitations of some of the randomized controlled trials may have prevented positive results. Other forms of evidence and end points other than mortality need to be considered when evaluating interventions in critically ill patients.

How to evaluate the microcirculation: report of a round table conference.

INTRODUCTION: Microvascular alterations may play an important role in the development of organ failure in critically ill patients and especially in sepsis. Recent advances in technology have allowed visualization of the microcirculation, but several scoring systems have been used so it is sometimes difficult to compare studies. This paper reports the results of a round table conference that was organized in Amsterdam in November 2006 in order to achieve consensus on image acquisition and analysis. METHODS: The participants convened to discuss the various aspects of image acquisition and the different scores, and a consensus statement was drafted using the Delphi methodology. RESULTS: The participants identified the following five key points for optimal image acquisition: five sites per organ, avoidance of pressure artifacts, elimination of secretions, adequate focus and contrast adjustment, and recording quality. The scores that can be used to describe numerically the microcirculatory images consist of the following: a measure of vessel density (total and perfused vessel density; two indices of perfusion of the vessels (proportion of perfused vessels and microcirculatory flow index); and a heterogeneity index. In addition, this information should be provided for all vessels and for small vessels (mostly capillaries) identified as smaller than 20 microm. Venular perfusion should be reported as a quality control index, because venules should always be perfused in the absence of pressure artifact. It is anticipated that although this information is currently obtained manually, it is likely that image analysis software will ease analysis in the future. CONCLUSION: We proposed that scoring of the microcirculation should include an index of vascular density, assessment of capillary perfusion and a heterogeneity index.

The prognostic value of muscle StO2 in septic patients.

OBJECTIVE: To quantify sepsis-induced alterations in changes in muscle tissue oxygenation (StO(2)) after an ischemic challenge using near-infrared spectroscopy (NIRS), and to test the hypothesis that these alterations are related to outcome. DESIGN: Prospective study. SETTING: Thirty-one-bed, university hospital Department of Intensive Care. PATIENTS: Seventy-two patients with severe sepsis or septic shock, 18 hemodynamically stable, acutely ill patients without infection, and 18 healthy volunteers. INTERVENTIONS: Three-minute occlusion of the brachial artery using a cuff inflated 50[Symbol: see text]mmHg above systolic arterial pressure. MEASUREMENTS AND MAIN RESULTS: Thenar eminence StO(2) was measured continuously by NIRS before (StO(2)baseline), during, and after the 3-min occlusion. Changes in StO(2) were assessed by the slope of increase in StO(2) during the first 14 s following the ischemic period and by the difference between the maximum StO(2) and StO(2)baseline (Delta). The slope was lower in septic patients than in controls and volunteers [2.3 (1.3-3.6), 4.8 (3.5-6.0), and 4.7 (3.2-6.3) %/s, p < 0.001]. Delta was also significantly lower in septic patients than in the other groups. Slopes were lower in septic patients with than without shock [2.0 (1.2-2.9) vs 3.2 (1.8-4.5) %/s, p < 0.05]. In 52 septic patients, in whom the slope was obtained every 24 h for 48 h, slopes were higher in survivors than in non-survivors and tended to increase in survivors but not in non-survivors. CONCLUSIONS: Altered recovery in StO(2) after an ischemic challenge is frequent in septic patients and more pronounced in the presence of shock. The presence and persistence of these alterations in the first 24[Symbol: see text]h of sepsis are associated with worse outcome.

How microcirculation data have changed my clinical practice.

PURPOSE OF REVIEW: The present review discusses how microcirculation assessment, which was recently made feasible, has altered clinical practice. RECENT FINDINGS: Experimental data have provided important information on microcirculation alterations in disease states. Recent advances in imaging techniques have allowed microcirculation studies in critically ill patients. Derangements in microcirculation are variable and unpredictable, associated with organ dysfunction and outcome, and can be improved by therapeutic interventions. Recent studies not only confirm the beneficial effects of some drugs on the microcirculation, but also suggest new mechanisms of actions of these drugs. In particular, the interaction between the endothelial surface and circulating cells, and especially white blood cells, seems to be crucial. Although these imaging techniques provide important information, these remain difficult to implement at the bedside. Assessment of vasoreactivity using transient occlusion tests and indirect measurements of microvascular blood flow with laser Doppler or near infrared spectroscopy may be good alternatives. SUMMARY: Microcirculation alterations are present in shock states, mainly septic shock, and can have a prognostic role and be the target of therapeutic interventions. To date, microcirculation analysis remains in the field of clinical investigation, but recently interesting clinical data have encouraged assessment of the microcirculation at the bedside.

Apresentaçäo atípica de sífilis em um paciente com o vírus da imunodeficiência humana: relato de caso e revisäo da literatura / Atypical presentation of syphilis in a patient with virus of the human: case report and literature review

Introdução: A incidência da infecção pelo Treponema pallidum tem aumentado significativamente na última década, e a co-infecção com o vírus da imunodeficiência humana (HIV) é um achado freqüente. O HIV parece modificar a apresentação clínica da sífilis, e formas anômalas e malignas têm sido descritas na literatura. Objetivo: Relatar um caso de paciente com Aids e uma apresentação atípica de sífilis. Relato do caso: G.R.S.P., sexo masculino, 38 anos, branco, homossexual, com diagnóstico de HIV em 1991, foi admitido em nosso serviço com queixa de dor retal, obstipação e apresentando lesões de pele papulares eritematosas e descamativas disseminadas por toda a superfície corporal, excetuando-se a face. Ausência de manifestações neurológicas e exame liquórico inconclusivo para sífilis. A retossigmoidoscopia mostrou exulcerações na borda e canal anal. Contagem de CD4 428 cel./mmü, carga viral para o HIV 73.000 cópias, VDRL 1:256, FTA-ABS positivo para IgC e IgM. A citologia por coloração pela prata foi positiva para Treponema pallidum, tanto em lesões de pele quanto em ânus. Três meses antes apresentava carga viral de 25.000 cópias e era assintomático. Foi tratado com ceftriaxona 2g por 10 dias e evoluiu com resolução do quadro. Conclusão: Esta caso mostra uma apresentação inicial atípica da sífilis em paciente com Aids, mostrando que a co-infecção altera a história natural da sífilis; a presença destas duas patologias deve sempre ser lembrada em pacientes de risco. Existe uma correlação no caso descrito entre infecção pelo T.pallidum e um aumento significativo da carga viral do HIV