Deming Mi

Bacterial Communities of the Coronal Sulcus and Distal Urethra of Adolescent Males

Lactobacillus-dominated vaginal microbiotas are associated with reproductive health and STI resistance in women, whereas altered microbiotas are associated with bacterial vaginosis (BV), STI risk and poor reproductive outcomes. Putative vaginal taxa have been observed in male first-catch urine, urethral swab and coronal sulcus (CS) specimens but the significance of these observations is unclear. We used 16 S rRNA sequencing to characterize the microbiota of the CS and urine collected from 18 adolescent men over three consecutive months. CS microbiotas of most participants were more stable than their urine microbiotas and the composition of CS microbiotas were strongly influenced by circumcision. BV-associated taxa, including Atopobium, Megasphaera, Mobiluncus, Prevotella and Gemella, were detected in CS specimens from sexually experienced and inexperienced participants. In contrast, urine primarily contained taxa that were not abundant in CS specimens. Lactobacilllus and Streptococcus were major urine taxa but their abundance was inversely correlated. In contrast, Sneathia, Mycoplasma and Ureaplasma were only found in urine from sexually active participants. Thus, the CS and urine support stable and distinct bacterial communities. Finally, our results suggest that the penis and the urethra can be colonized by a variety of BV-associated taxa and that some of these colonizations result from partnered sexual activity.

Progressive cerebral injury in the setting of chronic HIV infection and antiretroviral therapy

Emerging evidence suggests that CNS injury and neurocognitive impairment persist in the setting of chronic HIV infection and combination antiretroviral therapy (CART). Yet, whether neurological injury can progress in this setting remains uncertain. Magnetic resonance spectroscopy and neurocognitive and clinical assessments were performed over 2xa0years in 226 HIV-infected individuals on stable CART, including 138 individuals who were neurocognitively asymptomatic (NA). Concentrations of N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myoinositol, and glutamate/glutamine (Glx) were measured in the midfrontal cortex (MFC), frontal white matter (FWM), and basal ganglia (BG). Longitudinal changes in metabolite levels were determined using linear mixed effect models, as were metabolite changes in relation to global neurocognitive function. HIV-infected subjects showed significant annual decreases in brain metabolite levels in all regions examined, including NAA (2.95xa0%) and Cho (2.61xa0%) in the FWM; NAA (1.89xa0%), Cr (1.84xa0%), Cho (2.19xa0%), and Glx (6.05xa0%) in the MFC; and Glx (2.80xa0%) in the BG. Similar metabolite decreases were observed in the NA and subclinically impaired subgroups, including subjects with virologic suppression in plasma and CSF. Neurocognitive decline was associated with longitudinal decreases in Glx in the FWM and the BG, and in NAA in the BG. Widespread progressive changes in the brain, including neuronal injury, occur in chronically HIV-infected persons despite stable antiretroviral treatment and virologic suppression and can lead to neurocognitive declines. The basis for these findings is poorly understood and warrants further study.

Effects of switching from efavirenz to raltegravir on endothelial function, bone mineral metabolism, inflammation, and renal function: a randomized, controlled trial.

Abstract:We performed a randomized controlled trial in 30 HIV-infected participants to either continue tenofovir/emtricitabine/efavirenz (Continuation Group) or switch to tenofovir/emtricitabine/raltegravir (Switch Group) for 24 weeks. There were no significant differences in the changes in flow-mediated dilation, 25(OH) vitamin D, or parathyroid hormone levels. Total cholesterol, high sensitivity C-reactive protein, serum alkaline phosphatase, sCD14 levels, and renal function significantly declined in the Switch Group compared with the Continuation Group; however, sCD163 levels significantly increased in the Switch Group. These findings suggest that raltegravir is not inherently more beneficial to endothelial function compared with efavirenz but may impact renal function and monocyte activation.

Effect of Advanced HIV Infection on the Respiratory Microbiome

RATIONALEnPrevious work found the lung microbiome in healthy subjects infected with HIV was similar to that in uninfected subjects. We hypothesized the lung microbiome from subjects infected with HIV with more advanced disease would differ from that of an uninfected control population.nnnOBJECTIVESnTo measure the lung microbiome in an HIV-infected population with advanced disease.nnnMETHODSn16s RNA gene sequencing was performed on acellular bronchoalveolar lavage (BAL) fluid from 30 subjects infected with HIV with advanced disease (baseline mean CD4 count, 262 cells/mm(3)) before and up to 3 years after starting highly active antiretroviral therapy (HAART) and compared with 22 uninfected control subjects.nnnMEASUREMENTS AND MAIN RESULTSnThe lung microbiome in subjects infected with HIV with advanced disease demonstrated decreased alpha diversity (richness and diversity) and greater beta diversity compared with uninfected BAL. Differences improved with HAART, but still persisted up to 3 years after starting therapy. Population dispersion in the group infected with HIV was significantly greater than in the uninfected cohort and declined after treatment. There were differences in the relative abundance of some bacteria between the two groups at baseline and after 1 year of therapy. After 1 year on HAART, HIV BAL contained an increased abundance of Prevotella and Veillonella, bacteria previously associated with lung inflammation.nnnCONCLUSIONSnThe lung microbiome in subjects infected with HIV with advanced disease is altered compared with an uninfected population both in diversity and bacterial composition. Differences remain up to 3 years after starting HAART. We speculate an altered lung microbiome in HIV infection may contribute to chronic inflammation and lung complications seen in the HAART era.

Plasma and Cerebrospinal Fluid Biomarkers Predict Cerebral Injury in HIV-Infected Individuals on Stable Combination Antiretroviral Therapy.

Objectives:HIV-associated brain injury persists despite combination antiretroviral therapy, but contributing factors remain poorly understood. We postulated that inflammation-associated biomarkers will be associated with cerebral injury on proton magnetic resonance spectroscopy in chronically HIV-infected subjects. Methods:Five biomarkers were measured in 197 HIV-infected subjects: soluble CD14, MCP-1, IP-10, MIP-1&bgr;, and fractalkine. Levels of N-acetyl aspartate (NAA), Choline (Cho), Myoinositol (MI), Glutamate + Glutamine (Glx), and Creatine (Cr) were acquired in the midfrontal cortex (MFC), frontal white matter, and basal ganglia (BG). Predictive models were built through linear regression, and the best models were chosen using the Akaike Information Criterion. Results:Increases in plasma or CSF MCP-1 were associated with lower NAA/Cr in the MFC and BG, whereas metabolite changes in the frontal white matter for NAA/Cr, GlxCr, and Cho/Cr were explained almost exclusively by a single factor, sCD14. Plasma and CSF levels of this factor were also significantly associated with Glx/Cr in MFC and BG. Higher CSF FKN was associated with higher NAA/Cr in BG. Best predictors for higher Cho/Cr in BG and MFC were CSF sCD14 and CSF MIP-1&bgr;. Plasma and CSF IP-10 were only associated with Cho/Cr in MFC. Of the 3 models that simultaneously accounted for both plasma and CSF, there were more associations between CSF biomarkers and magnetic resonance spectroscopy metabolites. Conclusions:Markers of inflammation and immune activation, in particular MCP-1 and sCD14, predominantly reflecting CNS sources, contribute to the persistence of brain injury in a metabolite and region-dependent manner in chronically HIV-infected patients on stable combination antiretroviral therapy.

Pentoxifylline, Inflammation, and Endothelial Function in HIV-Infected Persons: A Randomized, Placebo-Controlled Trial

Background Untreated HIV may increase the risk of cardiovascular events. Our preliminary in vitro and in vivo research suggests that pentoxifylline (PTX) reduces vascular inflammation and improves endothelial function in HIV-infected persons not requiring antiretroviral therapy. Methods We performed a randomized, placebo-controlled trial of PTX 400 mg orally thrice daily for 8 weeks in 26 participants. The primary endpoint was change in flow-mediated dilation (FMD) of the brachial artery after 8 weeks. Nitroglycerin-mediated dilation (NTGMD) and circulating markers of inflammation, cellular immune activation, coagulation, and metabolism were also assessed. Results The difference in mean absolute change (SD) in FMD after 8 weeks between the placebo [−1.06 (1.45)%] and PTX [−1.93 (3.03)%] groups was not significant (Pu200a=u200a0.44). No differences in NTGMD were observed. The only significant between-group difference in the changes in biomarkers from baseline to week 8 was in soluble tumor necrosis factor receptor-1 (sTNFRI) [−83.2 pg/mL in the placebo group vs. +65.9 pg/mL in the PTX group; Pu200a=u200a0.03]. PTX was generally well-tolerated. Conclusions PTX did not improve endothelial function and unexpectedly increased the inflammatory biomarker sTNFRI in HIV-infected participants not requiring antiretroviral therapy. Additional interventional research is needed to reduce inflammation and cardiovascular risk in this population. Trial Registration ClinicalTrials.gov NCT00796822

Endothelial, inflammatory, coagulation, metabolic effects and safety of etravirine in HIV-uninfected volunteers.

The innate proatherosclerotic properties of non-nucleoside reverse transcriptase inhibitors have not previously been examined. Therefore, we performed a pilot study of etravirine (ETR) in healthy volunteers over 28 days. This investigation also allowed us to evaluate the safety of ETR over a period commonly used for HIV postexposure prophylaxis. ETR 200 mg twice daily was given to 28 healthy HIV-uninfected volunteers over 28 days. Flow-mediated dilation (FMD) of the brachial artery and circulating markers of inflammation, coagulation, and metabolism were measured at entry and at day 28. These circulating markers were also measured at day 35. Of the initial 28 subjects, 23 completed both entry and day 28 procedures. Two subjects were discontinued due to development of rash. No other major toxicities developed. The change in FMD over 28 days was minimal and not significant (0.03 [-3.21, 0.97] %; p=0.36). The post hoc estimated detectable absolute change in FMD with the 23 subjects in our study was 2.26%, which is an effect size that has been associated with future cardiovascular event rates in the general population; thus our study had sufficient power to find clinically relevant changes in FMD. In addition, there were no significant changes in any of the circulating markers from entry to day 28 or from day 28 to day 35. ETR did not demonstrate any innate proatherosclerotic properties over 28 days in these HIV-uninfected volunteers. ETR was generally well tolerated. Larger studies are warranted to confirm that ETR can be used safely as part of HIV postexposure prophylaxis regimens.

P3.061 Mycoplasma Genitalium DNA Detected from Adolescent Males in a Longitudinal Cohort

Background Mycoplasma genitalium (MG) causes non-gonococcal urethritis as well as asymptomatic infections although most data on the incidence and natural history of MG is from adults. Methods Participants were 14–17 year old men in a longitudinal study of STI and the urethral microbiome. Urine samples were collected monthly and batch tested retrospectively for MG DNA using PCR. Urine samples were tested in real-time for chlamydia, gonorrhoea, trichomonas and white blood cells (WBC): infections by these organisms were treated. White blood cell count (WBC) was measured by automated cell count of fresh urine. Dysuria and urethral discharge were self-reported on cell phone diaries. Results Among 75 participants (mean age 16.0 at enrollment), 6 (8.0%) men have at least one MG positive sample, with a total of 14 MG positive monthly urine samples. The prevalence of Chlamydia or gonorrhoea infection was 19/75 (25.3%) and 1/75 (1.3%), respectively. All but one participant was positive for at least two consecutive months, and one participant was positive for 4 consecutive months. One participant was positive only once, was co-infected with chlamydia, but treatment could not be confirmed. No other MG positive visits occurred simultaneously with other STI. None of the participants reported symptoms or sexual behaviours within a 15 day window of the positive visit. Average urine WBC was 21.8 WBC/ml urine although only 3/14 MG positive samples were associated with urine WBC > 28.5/ml (commonly used as a diagnostic threshold for pyuria). Conclusions MG in adolescent men is more common than gonorrhoea, persistent without treatment for up to 120 days, and is typically not associated with symptoms or pyuria. These data add to emerging understanding of the prevalence and natural history of sexually transmitted MG and support the importance of more detailed understanding of sexual and reproductive health morbidity associated with these infections.