Long-acting cabotegravir and rilpivirine for HIV-1 suppression: switch to 2-monthly dosing after 5 years of daily oral therapy.

OBJECTIVES: Long-acting formulations of cabotegravir (CAB) and rilpivirine (RPV) have demonstrated efficacy in Phase 3 studies. POLAR (NCT03639311) assessed antiviral activity and safety of CAB+RPV long-acting administered every 2 months (Q2M) in adults living with HIV-1 who previously received daily oral CAB+RPV in LATTE (NCT01641809). DESIGN: A Phase 2b, multicenter, open-label, rollover study. METHODS: LATTE participants with plasma HIV-1 RNA less than 50 copies/ml who completed at least 300 weeks on study were eligible. Participants elected to switch to either CAB+RPV long-acting Q2M or daily oral dolutegravir/RPV for maintenance of virologic suppression. The primary endpoint was the proportion of participants with HIV-1 RNA greater than or equal to 50 copies/ml at Month 12 (M12) per the Food and Drug Administration Snapshot algorithm. The incidence of confirmed virologic failure (CVF, two consecutive HIV-1 RNA measurements greater than or equal to 200 copies/ml), as well as safety, laboratory, and patient-reported outcomes (HIV Treatment Satisfaction and preference questionnaires) were also assessed. RESULTS: Of 97 participants enrolled, 90 chose to receive CAB+RPV long-acting and seven chose dolutegravir/RPV. At M12, no participant had HIV-1 RNA greater than or equal to 50 copies/ml or met the CVF criterion in either treatment group. No new safety signals were identified. Total treatment satisfaction was high at Baseline and remained stable through M12 across both treatment groups. Overall, 88% (n = 77/88) of long-acting arm participants preferred CAB+RPV long-acting to oral CAB+RPV. CONCLUSION: CAB+RPV long-acting maintained virologic suppression in participants who had previously received daily oral CAB+RPV for at least 5 years in LATTE, with a favorable safety profile. Most participants preferred CAB+RPV long-acting to their prior oral CAB+RPV regimen at M12.

Candida urinary tract infections--epidemiology.

Candiduria is rarely present in healthy individuals. In contrast, it is a common finding in hospitalized patients, especially those in intensive care units (ICUs) who often have multiple predisposing factors, including diabetes mellitus, indwelling urinary catheters, and exposure to antimicrobials. Candiduria occurs much less commonly in the community setting. In a majority of episodes in adult patients in critical care facilities candiduria represents colonization, and antifungal therapy is not required. However, the presence of yeast in the urine can be a sign of a disseminated infection. In the critically ill newborn, candiduria often reflects disseminated candidiasis and is accompanied by obstructing fungus ball formation in the urinary tract. In ICU patients, although candiduria is a marker for increased mortality, it is only rarely attributable to Candida urinary tract infection.

Candida urinary tract infection: pathogenesis.

Candida species are unusual causes of urinary tract infection (UTI) in healthy individuals, but common in the hospital setting or among patients with predisposing diseases and structural abnormalities of the kidney and collecting system. The urinary tract may be invaded in either an antegrade fashion from the bloodstream or retrograde via the urethra and bladder. Candida species employ a repertoire of virulence factors, including phenotypic switching, dimorphism, galvano - and thigmotropism, and hydrolytic enzymes, to colonize and then invade the urinary tract. Antegrade infection occurs primarily among patients predisposed to candidemia. The process of adherence to and invasion of the glomerulus, renal blood vessels, and renal tubules by Candida species was elegantly described in early histopathologic studies. Armed with modern molecular biologic techniques, the various virulence factors involved in bloodborne infection of the kidney are gradually being elucidated. Disturbances of urine flow, whether congenital or acquired, instrumentation of the urinary tract, diabetes mellitus, antimicrobial therapy, and immunosuppression underlie most instances of retrograde Candida UTI. In addition, bacterial UTIs caused by Enterobacteriaceae may facilitate the initial step in the process. Ascending infections generally do not result in candidemia in the absence of obstruction.

Candida urinary tract infections--diagnosis.

The finding of candiduria in a patient with or without symptoms should be neither dismissed nor hastily treated, but requires a careful evaluation, which should proceed in a logical fashion. Symptoms of Candida pyelonephritis, cystitis, prostatitis, or epididymo-orchitis are little different from those of the same infections produced by other pathogens. Candiduria occurring in critically ill patients should initially be regarded as a marker for the possibility of invasive candidiasis. The first step in evaluation is to verify funguria by repeating the urinalysis and urine culture. Pyuria is a nonspecific finding; the morphology of the offending yeast may allow separation of Candida glabrata from other species. Candida casts in the urine are indicative of renal candidiasis but are rarely seen. With respect to culture, colony counts have not proved to be diagnostically useful. In symptomatic or critically ill patients with candiduria, ultrasonography of the kidneys and collecting systems is the preferred initial study. However, computed tomography (CT) is better able to discern pyelonephritis or perinephric abscess. The role of magnetic resonance imaging and renal scintigraphy is ill defined, and prudent physicians should consult with colleagues in the departments of radiology and urology to determine the optimal studies in candiduric patients who require in-depth evaluation.

Candida urinary tract infections--treatment.

In many instances a report from the clinical laboratory indicating candiduria represents colonization or procurement contamination of the specimen and not invasive candidiasis. Even if infection of the urinary tract by Candida species can be confirmed, antifungal therapy is not always warranted. Further investigation may reveal predisposing factors, which if corrected or treated, result in the resolution of the infection. For those with symptomatic urinary tract infections (UTIs), the choice of antifungal agent will depend upon the clinical status of the patient, the site of infection, and the pharmacokinetics and pharmacodynamics of the agent. Because of its safety, achievement of high concentrations in the urine, and availability in both an oral and intravenous formulation, fluconazole is preferred for the treatment of Candida UTIs. Flucytosine is concentrated in urine and has broad activity against Candida spp, but its use requires caution because of toxicity. Low-dose amphotericin B may be useful for Candida UTIs in selected patients. The role of echinocandins and azoles that do not achieve measurable concentrations in the urine is not clear. Small case series note some success, but failures have also occurred. Irrigation of the bladder with antifungal agents has limited utility. However, with fungus balls, irrigation of the renal pelvis through a nephrostomy tube can be useful in combination with systemic antifungal agents.

A CD study of uncoupling protein-1 and its transmembrane and matrix-loop domains.

Conformations of the prototypic UCP-1 (uncoupling protein-1) and its TM (transmembrane) and ML (matrix-loop) domains were studied by CD spectroscopy. Recombinant, untagged mouse UCP-1 and a hexahistidine-tagged version of the protein were obtained in high purity following their overexpression in Escherichia coli. The TM and ML domains of hamster UCP-1 were chemically synthesized. Conformations of both recombinant UCP-1 proteins were dominantly helical (40-50%) in digitonin micelles. Binding of the purine nucleotides GDP and GTP to UCP-1, detected in the near-UV CD region, supported the existence of the functional form of the protein in digitonin micelles. All individual TM and ML peptides, except the third ML domain, adopted helical structures in aqueous trifluoroethanol, which implies that, in addition to six TM segments, at least two of the ML domains of the UCP-1 can form helical structures in membrane interface regions. TM and ML domains interacted with vesicles composed of the main phospholipids of the inner membrane of mitochondria, phosphatidylcholine, phosphatidylethanolamine and cardiolipin, to adopt dominantly beta- and/or unordered conformations. Mixtures of UCP-1 peptide domains spontaneously associated in aqueous, phospholipid vesicles and digitonin micelle environments to form ordered conformations, which exhibited common features with the conformations of the full-length proteins. Thermal denaturations of UCP-1 and its nine-peptide-domain assembly in digitonin were co-operative but not reversible. Assembly of six TM domains in lipid bilayers formed ion-conducting units with possible helical bundle conformations. Consequently, covalent connection between peptide domains, tight domain interactions and TM potential are essential for the formation of the functional conformation of UCP-1.

CCL28 effects on periodontal pathogens.

BACKGROUND: Chemokines are small proteins that signal to and attract cells of the immune system; they are vital components in the modulation of immunity and wound healing. A newly described chemokine was reported to have antibacterial and antifungal activity. This chemokine, chemokine (C-C motif) ligand 28 (CCL28; also called mucosae-associated epithelial chemokine), is secreted by mucosal epithelial cells and is found in saliva and in breast milk. The objective of this study was to test whether CCL28 has antibacterial activity against two anaerobic periodontal pathogens: Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans. METHODS: We used a bacterial viability test, in which two fluorescent dyes are bound differentially to living and killed bacteria. We tested the bacteria at concentrations of 2 x 10(7)/ml, exposing them to CCL28 at concentrations from 0.04 to 10 microM. RESULTS: CCL28 was effective at killing both organisms. After 1 hour of exposure to the chemokine under appropriate oxygen conditions, the percentage of living organisms was reduced significantly for each species. We estimated the 50% effective concentration to be approximately 0.7 microM for P. gingivalis and approximately 2.0 microM for A. actinomycetemcomitans (N = five experiments each). We confirmed these observations using standard bacterial plating methods. CONCLUSION: Because this chemokine is secreted into the saliva, a reduction in salivary flow (as in xerostomia) may diminish the oral self-defense mechanisms by also reducing the exposure of bacteria to the antibacterial action of CCL28.

Autotransporter and two-partner secretion: delivery of large-size virulence factors by gram-negative bacterial pathogens.

A number of protein secretion mechanisms have been identified in gram-negative pathogens. Many of these secretion systems are dependent upon the Sec translocase for protein export from the cytoplasm into the periplasm and then utilize other mechanisms for transport from the periplasm through the outer membrane. In this article, we review secretion similarities between autotransporter and two-partner secretion systems, and we report similarities between the autotransporter secretion mechanism with that of intimin/invasins. Considering that many secreted proteins are virulence factors, a better understanding of their secretion mechanisms will aid in the development of disease treatments and new bacterial vaccines.