medRxiv (Cold Spring Harbor Laboratory), Jun 2, 2022
Background: Prognostic markers for COVID-19 disease outcome are currently lacking. Plasma gelsoli... more Background: Prognostic markers for COVID-19 disease outcome are currently lacking. Plasma gelsolin (pGSN) is an actin-binding protein and an innate immune marker involved in disease pathogenesis and viral infections. Here, we demonstrate the utility of pGSN as a prognostic marker for COVID-19 disease outcome; a test performance that is significantly improved when combined with cytokines and antibodies compared to other conventional markers such as CRP and ferritin. Methods: Blood samples were longitudinally collected from hospitalized COVID-19 patients as well as COVID-19 negative controls and the levels of pGSN in μg/mL, cytokines and anti-SARS-CoV-2 spike protein antibodies assayed. Mean±SEM values were correlated with clinical parameters to develop a prognostic platform. Results: pGSN levels were significantly reduced in COVID-19 patients compared to healthy individuals. Additionally, pGSN levels combined with plasma IL-6, IP-10 and M-CSF significantly distinguished COVID-19 patients from healthy individuals. While pGSN and antispike IgG titers together strongly predict COVID-19 severity and death, the combination of pGSN and IL-6 was a significant predictor of milder disease and favorable outcomes. Conclusion: Taken together, these findings suggest that multi-parameter analysis of pGSN, cytokines and antibodies could predict COVID-19 hospitalization outcomes with greater certainty compared with conventional clinical laboratory markers such as CRP and ferritin. This research will inform and improve clinical management and health system interventions in response to SARS-CoV-2 infection.
Purpose: Given the increasing use of intravenous immunoglobulin for various neurological conditio... more Purpose: Given the increasing use of intravenous immunoglobulin for various neurological conditions, its significant cost and the uncertainty pertaining to its benefits and harms, we conducted a systematic review of randomized controlled trials that compared intravenous immunoglobulin to other current therapies. Methods: A systematic search strategy of Medline (1966-June 2003) and the Cochrane Registry of Controlled Trials (June 2003 edition) was developed to identify randomised controlled trials. Two authors (BH, DF) independently reviewed all citations retrieved from the electronic search to identify all potentially relevant trials for this review. In cases where a unanimous decision could not be reached, a third party was consulted. To be eligible, studies had to be randomised controlled trials comparing intravenous immunoglobulin to either placebo or an active control and evaluating clinical outcomes. Measures of effect were calculated for each trial independently, and studies were pooled based on clinical and methodologic judgment as to its appropriateness. Fixed effects and random effects models were selected for each meta-analysis based on appraisal of the clinical homogeneity of patients across studies, as well as from testing for heterogeneity between studies. In circumstances where pooling of trials was inappropriate or not feasible, a qualitative discussion of the findings was developed. Results: Thirty-seven trials representing 14 conditions were identified. Results from meta-analysis suggest that intravenous immunoglobulin therapy is effective for the treatment of multiple sclerosis (pooled 1-year EDSS change −0.46, 95% CI [−0.92,0.01] in favor of IVIG; pooled change in annual exacerbation rate −0.82, 95% CI [−1.54, −0.11] in favor of IVIG; pooled odds of remaining exacerbation free 0.24, 95% CI [0.12, 0.50] in favor of IVIG ) and idiopathic chronic inflammatory demyelinating polyneuropathy (pooled change in disability score −0.67, 95% CI [−1.04, −0.30] in favor of IVIG; pooled odds of achieving treatment response 4.43, 95% CI [2.20, 8.91] in favor of IVIG). There was insufficient evidence to determine whether this therapy was more effective for Guillain-Barré Syndrome than plasma exchange (pooled change in disability score −0.11, 95% CI [−0.37,0.14]; pooled odds of improving by 1 or more grades on the Hughes disability scale 1.91, 95% CI [1.11, 3.28] in favor of IVIG; pooled odds of mortality 0.84, 95% CI [0.31, 2.29]). There was also insufficient evidence regarding paraprotein-associated chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. No evidence of benefit was observed for inclusion body myositis and myasthenia gravis. Based on evidence from lone randomised trials, there also exists evidence indicating that IVIG may be useful for treatment of dermatomyositis, stiff person syndrome and Lambert-Eaton Syndrome.
Canadian Journal of Anesthesia/Journal canadien d'anesthésie, 2021
This national survey evaluated the perceived efficacy and safety of intravenous immune globulin (... more This national survey evaluated the perceived efficacy and safety of intravenous immune globulin (IVIG) in septic shock, self-reported utilization patterns, barriers to use, the population of interest for further trials and willingness to participate in future research of IVIG in septic shock. We conducted a cross-sectional survey of critical care and infectious diseases physicians across Canada. We summarized categorical item responses as counts and proportions. We developed a multivariable logistic regression model to identify physician-level predictors of IVIG use in septic shock. Our survey was disseminated to 674 eligible respondents with a final response rate of 60%. Most (91%) respondents reported having prescribed IVIG to patients with septic shock at least once, 86% for septic shock due to necrotizing fasciitis, 52% for other bacterial toxin-mediated causes of septic shock, and 5% for undifferentiated septic shock. The majority of respondents expressed uncertainty regarding the impact of IVIG on mortality (97%) and safety (95%) in septic shock. Respondents were willing to participate in further IVIG research with 98% stating they would consider enrolling their patients into a trial of IVIG in septic shock. Familiarity with published evidence was the single greatest predictor of IVIG use in septic shock (odds ratio, 10.2; 95% confidence interval, 3.4 to 30.5; P < 0.001). Most Canadian critical care and infectious diseases specialist physicians reported previous experience using IVIG in septic shock. Respondents identified inadequacy of existing research as the greatest barrier to routine use of IVIG in septic shock. Most respondents support the need for further studies on IVIG in septic shock, and would consider enrolling their own patients into a trial of IVIG in septic shock.
JAIDS Journal of Acquired Immune Deficiency Syndromes, 2017
CONTENTS Click on any content title to link to that section. 03 Program Information and Acknowled... more CONTENTS Click on any content title to link to that section. 03 Program Information and Acknowledgements* *as of press time 13 Events Schedule 16 Speaker Schedule
We are pleased to present peer reviewed forum proceedings of the 2 nd synchronicity forum of GHRI... more We are pleased to present peer reviewed forum proceedings of the 2 nd synchronicity forum of GHRI/CHVIfunded Canadian and African HIV prevention and vaccine teams Forum objectives GHRI-funded capacity building and HIV prevention research teams presented highlights of achievements Teams discussed how to jointly build on achievements for sustainability Provided an opportunity for inter-team collaboration, synchronize best approach to capacity building, mentoring of new researchers and building leadership Provided opportunities for informal discussions and networking among the teams. Teams learnt about recent advances in the area of African regulatory and ethics review process The forum proceedings was a special supplement in an openaccess journal was produced Forum partners
To study the mechanisms of inducible immunity to Haemophilus ducreyi infection in the temperature... more To study the mechanisms of inducible immunity to Haemophilus ducreyi infection in the temperature-dependent rabbit model of chancroid, we conducted passive immunization experiments and characterized the inflammatory infiltrate of chancroidal lesions. Polyclonal immunoglobulin G was purified from immune sera raised against H. ducreyi 35000 whole-cell lysate or a pilus preparation and from naive control rabbits. Rabbits were passively immunized with 24 or 48 mg of purified polyclonal immunoglobulin G intravenously, followed 24 h after infusion by homologous titered infectious challenge. Despite titratable antibody, no significant difference in infection or disease was observed. We then evaluated the immunohistology of lesions produced by homologous-strain challenge in sham-immunized rabbits and those protectively vaccinated by pilus preparation immunization. Immunohistochemical stains for CD5 and CD4 T-lymphocyte markers were performed on lesion sections 4, 10, 15, and 21 days from in...
Using the temperature-dependent rabbit model of Haemophilus ducreyi infection as a quantitative v... more Using the temperature-dependent rabbit model of Haemophilus ducreyi infection as a quantitative virulence assay, we tested the abilities of two bacterial antigen preparations to induce protection against subsequent infection and disease. Lipooligosaccharide (LOS) and a pilus preparation were purified from H. ducreyi 35000 and were used in a booster immunization procedure. The serologic response to each immunogen was monitored by enzyme immunoassay. H. ducreyi virulence was assayed by intraepithelial inoculation and subsequent measurement of disease for homologous strain 35000 or clinical isolate RO-34. LOS and the pilus preparation induced humoral responses. The kinetics of the LOS antibody response suggest a type 1 T-independent response, whereas the pilus preparation induced an anamnestic response. An inoculum of 10(5) CFU of H. ducreyi 35000 or RO-34 consistently produced ulcerative chancroidal lesions in naive rabbit controls. Immunization with LOS did not modify the virulence o...
Background: Guidance is needed on best medical management for advanced HIV disease with multidrug... more Background: Guidance is needed on best medical management for advanced HIV disease with multidrug resistance (MDR) and limited retreatment options. We assessed two novel antiretroviral (ARV) treatment approaches in this setting. Methods and Findings: We conducted a 262 factorial randomized open label controlled trial in patients with a CD4 count #300 cells/ml who had ARV treatment (ART) failure requiring retreatment, to two options (a) re-treatment with either standard (#4 ARVs) or intensive ($5 ARVs) ART and b) either treatment starting immediately or after a 12-week monitored ART interruption. Primary outcome was time to developing a first AIDS-defining event (ADE) or death from any cause. Analysis was by intention to treat. From 2001 to 2006, 368 patients were randomized. At baseline, mean age was 48 years, 2% were women, median CD4 count was 106/ml, mean viral load was 4.74 log 10 copies/ml, and 59% had a prior AIDS diagnosis. Median follow-up was 4.0 years in 1249 person-years of observation. There were no statistically significant differences in the primary composite outcome of ADE or death between re-treatment options of standard versus intensive ART (hazard ratio 1.17; CI 0.86-1.59), or between immediate retreatment initiation versus interruption before re-treatment (hazard ratio 0.93; CI 0.68-1.30), or in the rate of non-HIV associated serious adverse events between re-treatment options. Conclusions: We did not observe clinical benefit or harm assessed by the primary outcome in this largest and longest trial exploring both ART interruption and intensification in advanced MDR HIV infection with poor retreatment options.
Research has revealed differences on scales measuring HIV knowledge between individuals from vari... more Research has revealed differences on scales measuring HIV knowledge between individuals from various ethnic backgrounds and cultures. Few studies have examined this knowledge with immigrant populations and persons living with HIV. This study examined HIV knowledge among persons living with HIV who were either born in Canada or in sub-Saharan Africa and, for comparison, in a sample of college students. All participants were residing in Canada. Participants completed questionnaires measuring demographic variables, sexual health behaviour, and HIV status, treatment, and knowledge. Canadian-born patients living with HIV were more likely to be older and male than the other groups. On average, patients living with HIV were diagnosed 6.4 years ago, and 80% reported having current or previous experience taking HIV medications. After adjusting for age and gender, significant differences were found between the groups on the Brief HIV Knowledge Questionnaire. Canadian-born persons living with HIV (n = 110) scored higher than sub-Saharan African-born patients (n = 23) and college students (n = 81); mean percentage correct was 86, 70, and 62%, respectively (P \ .01). These results suggested that ongoing HIV education is needed for all groups, and that additional tailored and targeted educational interventions are needed to address important gaps in knowledge among persons living with HIV patients originating from Africa and among college students.
SUMMARY Infection of immune cells with HIV induces dysregulation of cytokines which may play a vi... more SUMMARY Infection of immune cells with HIV induces dysregulation of cytokines which may play a vital role in HIV pathogenesis. We analysed the expression of T helper type I (Th1) (interferon-gamma (IFN-γ)) and Th2 (IL-4, IL-10) type cytokines in peripheral blood lymphocytes (PBL) from HIV patients. The semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed that IFN-γ mRNA in unstimulated PBL was significantly decreased and IL-10 mRNA was significantly upregulated in patients with < 400 CD4+ T cells/mm3 (n= 30) as compared to patients with > 400 CD4+ T cells/mm3 (n= 6) and normal controls (n= 16). In addition. IL-10 mRNA levels were inversely associated with IFN-γ expression. Similar results were obtained by measuring IL-10 production in the supernatants of PBL cultured in vitro without stimulation by employing an enzyme immunosorbent assay (ELISA). However, the levels of IL-4 and IFN-7 produced by unstimulated PBL were undetectable by ELISA...
β-Carotene supplements are often taken by individuals living with HIV-1. Contradictory results fr... more β-Carotene supplements are often taken by individuals living with HIV-1. Contradictory results from in vitro studies suggest that β-carotene may inhibit or induce cytochrome P450 enzymes and transporters. The study objective was to investigate the effect of β-carotene on the steady-state pharmacokinetics of nelfinavir and its active metabolite M8 in HIV-1 infected individuals. Twelve hour nelfinavir pharmacokinetic analysis was conducted at baseline and after 28 days of β-carotene supplementation (25,000 IU twice daily). Nelfinavir and M8 concentrations were measured with validated assays. Non-compartmental methods were used to calculate the pharmacokinetic parameters. Geometric mean ratios comparing day 28 to day 1 area under the plasma concentration-time curve (AUC 0-12 h), maximum (C max) and minimum (C min) concentrations of nelfinavir and M8 are presented with 90% confidence intervals. Eleven subjects completed the study and were included in the analysis. There were no significant differences in nelfinavir AUC 0-12 h and C min (−10%, +4%) after β-carotene supplementation. The M8 C min was increased by 31% while the M8 AUC 0-12 h and C max were unchanged. During the 28 day period, mean CD4 + % and CD4 + :CD8 + ratio increased significantly (p < 0.01). β-carotene supplementation increased serum carotene levels but did not cause any clinically significant difference in the nelfinavir and M8 exposure.
To compare the pharmacokinetics of lopinavir/ritonavir (LPV/r) 800/200 mg administered once daily... more To compare the pharmacokinetics of lopinavir/ritonavir (LPV/r) 800/200 mg administered once daily in the morning compared with the evening.
The pharmacokinetics of zidovudine in 10 symptomatic HIV-infected men were assessed after adminis... more The pharmacokinetics of zidovudine in 10 symptomatic HIV-infected men were assessed after administration of the initial 200 mg oral dose at the start of therapy (day 1) and on one occasion during non steady-state conditions of chronic-dose therapy (200 mg every 4 h while awake on day 21-66; 5 doses per day). The following mean (± s.d.) pharmacokinetic parameters were determined on day 1 and during chronic therapy, respectively: Cmax (4.09 ± 2.54 vs 3.82 ± 1.03 FLmol 1-1), oral clearance (40.7 ± 12.9 vs 41.1 ± 8.4 ml min-' kg-1) and terminal half-life (68.4 ± 29.4 vs 65.1 ± 13.1 min). Mean pharmacokinetic parameters on day 1 were < 10% different (P > 0.34) from those determined during chronic therapy. Differences in means of 21% for clearance and 36% for Cmax could be detected with a power of 80% at the 5% significance level. Intra-subject coefficients of variation were 17% for clearance and 32% for Cmax, respectively. This study suggests that within a group of patients whose stage of HIV infection and general health are relatively stable, first-dose pharmacokinetic parameters provide a good estimate of multiple-dose pharmacokinetic parameters.
Background: The role of oral antibiotic therapy in treating infective endocarditis (IE) is not we... more Background: The role of oral antibiotic therapy in treating infective endocarditis (IE) is not well established. Methods: We searched MEDLINE, EMBASE and Scopus for studies in which oral antibiotic therapy was used for the treatment of IE. Results: Seven observational studies evaluating the use oral beta-lactams (five), oral ciprofloxacin in combination with rifampin (one), and linezolid (one) for the treatment of IE caused by susceptible bacteria reported cure rates between 77% and 100%. Two other observational studies using aureomycin or sulfonamide, however, had failure rates >75%. One clinical trial comparing oral amoxicillin versus intravenous ceftriaxone for streptococcal IE reported 100% cure in both arms but its reporting had serious methodological limitations. One small clinical trial (n = 85) comparing oral ciprofloxacin and rifampin versus conventional intravenous antibiotic therapy for uncomplicated right-sided S. aureus IE in intravenous drug users (IVDUs) reported cure rates of 89% and 90% in each arm, respectively (P =0.9); however, drug toxicities were more common in the latter group (62% versus 3%; P <0.01). Major limitations of this trial were lack of allocation concealment and blinding at the delivery of the study drug(s) and assessment of outcomes.
Haemophilus ducreyi, a gram-negative and heme-dependent bacterium, is the causative agent of chan... more Haemophilus ducreyi, a gram-negative and heme-dependent bacterium, is the causative agent of chancroid, a genital ulcer sexually transmitted infection. Heme acquisition in H. ducreyi proceeds via a receptor mediated process in which the initial event involves binding of hemoglobin and heme to their cognate outer membrane proteins, HgbA and TdhA, respectively. Following this specific interaction, the fate of the periplasmic deposited heme is unclear. Using protein expression profiling of the H. ducreyi periplasmic proteome, a periplasmic-binding protein, termed hHbp, was identified whose expression was enhanced under heme-limited conditions. The gene encoding this protein was situated in a locus displaying genetic characteristics of an ABC transporter. The purified protein bound heme in a dose-dependent and saturable manner and this binding was specifically competitively inhibited by heme. The hhbp gene functionally complemented an Escherichia coli heme uptake mutant. Expression of the heme periplasmic-binding protein was detected in a limited survey of H. ducreyi and H. influenzae clinical strains. These results indicate that the passage of heme into the cytoplasm of H. ducreyi involves a heme dedicated ABC transporter.
Previously it has been shown that tipranavir-ritonavir (TPV/r) does not affect efavirenz (EFV) pl... more Previously it has been shown that tipranavir-ritonavir (TPV/r) does not affect efavirenz (EFV) plasma concentrations. This study investigates the effect of steady-state EFV on steady-state TPV/r pharmacokinetics. This was a single-center, open-label, multiple-dose study of healthy adult female and male volunteers. TPV/r 500/200 mg twice a day (BID) was given with food for 24 days. After dosing with TPV/r for 10 days, EFV 600 mg once a day was added to the regimen. Intensive pharmacokinetic (PK) sampling was done on days 10 and 24. Validated bioanalytical high-pressure liquid chromatography-tandem mass spectrometry methods were used to determine plasma tipranavir (TPV), ritonavir (RTV), and EFV concentrations. Thirty-four subjects were entered into the study, and 16 subjects completed it. The geometric mean ratios (90% confidence intervals) for TPV and RTV area under the curves, C max s, and C min s comparing TPV/r alone and in combination with EFV were 0.97 (0.87 to 1.09), 0.92 (0.81 to 1.03), and 1.19 (0.93 to 1.54) for TPV and 1.03 (0.78 to 1.38), 0.92 (0.65 to 1.30), and 1.04 (0.72 to 1.48) for RTV. Frequently observed adverse events were diarrhea, headache, dizziness, abnormal dreams, and rash. EFV had no effect on the steady-state PK of TPV or RTV, with the exception of a 19% increase in the TPV C min , which is not clinically relevant. TPV/r can be safely coadministered with EFV and without the need for a dose adjustment.
medRxiv (Cold Spring Harbor Laboratory), Jun 2, 2022
Background: Prognostic markers for COVID-19 disease outcome are currently lacking. Plasma gelsoli... more Background: Prognostic markers for COVID-19 disease outcome are currently lacking. Plasma gelsolin (pGSN) is an actin-binding protein and an innate immune marker involved in disease pathogenesis and viral infections. Here, we demonstrate the utility of pGSN as a prognostic marker for COVID-19 disease outcome; a test performance that is significantly improved when combined with cytokines and antibodies compared to other conventional markers such as CRP and ferritin. Methods: Blood samples were longitudinally collected from hospitalized COVID-19 patients as well as COVID-19 negative controls and the levels of pGSN in μg/mL, cytokines and anti-SARS-CoV-2 spike protein antibodies assayed. Mean±SEM values were correlated with clinical parameters to develop a prognostic platform. Results: pGSN levels were significantly reduced in COVID-19 patients compared to healthy individuals. Additionally, pGSN levels combined with plasma IL-6, IP-10 and M-CSF significantly distinguished COVID-19 patients from healthy individuals. While pGSN and antispike IgG titers together strongly predict COVID-19 severity and death, the combination of pGSN and IL-6 was a significant predictor of milder disease and favorable outcomes. Conclusion: Taken together, these findings suggest that multi-parameter analysis of pGSN, cytokines and antibodies could predict COVID-19 hospitalization outcomes with greater certainty compared with conventional clinical laboratory markers such as CRP and ferritin. This research will inform and improve clinical management and health system interventions in response to SARS-CoV-2 infection.
Purpose: Given the increasing use of intravenous immunoglobulin for various neurological conditio... more Purpose: Given the increasing use of intravenous immunoglobulin for various neurological conditions, its significant cost and the uncertainty pertaining to its benefits and harms, we conducted a systematic review of randomized controlled trials that compared intravenous immunoglobulin to other current therapies. Methods: A systematic search strategy of Medline (1966-June 2003) and the Cochrane Registry of Controlled Trials (June 2003 edition) was developed to identify randomised controlled trials. Two authors (BH, DF) independently reviewed all citations retrieved from the electronic search to identify all potentially relevant trials for this review. In cases where a unanimous decision could not be reached, a third party was consulted. To be eligible, studies had to be randomised controlled trials comparing intravenous immunoglobulin to either placebo or an active control and evaluating clinical outcomes. Measures of effect were calculated for each trial independently, and studies were pooled based on clinical and methodologic judgment as to its appropriateness. Fixed effects and random effects models were selected for each meta-analysis based on appraisal of the clinical homogeneity of patients across studies, as well as from testing for heterogeneity between studies. In circumstances where pooling of trials was inappropriate or not feasible, a qualitative discussion of the findings was developed. Results: Thirty-seven trials representing 14 conditions were identified. Results from meta-analysis suggest that intravenous immunoglobulin therapy is effective for the treatment of multiple sclerosis (pooled 1-year EDSS change −0.46, 95% CI [−0.92,0.01] in favor of IVIG; pooled change in annual exacerbation rate −0.82, 95% CI [−1.54, −0.11] in favor of IVIG; pooled odds of remaining exacerbation free 0.24, 95% CI [0.12, 0.50] in favor of IVIG ) and idiopathic chronic inflammatory demyelinating polyneuropathy (pooled change in disability score −0.67, 95% CI [−1.04, −0.30] in favor of IVIG; pooled odds of achieving treatment response 4.43, 95% CI [2.20, 8.91] in favor of IVIG). There was insufficient evidence to determine whether this therapy was more effective for Guillain-Barré Syndrome than plasma exchange (pooled change in disability score −0.11, 95% CI [−0.37,0.14]; pooled odds of improving by 1 or more grades on the Hughes disability scale 1.91, 95% CI [1.11, 3.28] in favor of IVIG; pooled odds of mortality 0.84, 95% CI [0.31, 2.29]). There was also insufficient evidence regarding paraprotein-associated chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. No evidence of benefit was observed for inclusion body myositis and myasthenia gravis. Based on evidence from lone randomised trials, there also exists evidence indicating that IVIG may be useful for treatment of dermatomyositis, stiff person syndrome and Lambert-Eaton Syndrome.
Canadian Journal of Anesthesia/Journal canadien d'anesthésie, 2021
This national survey evaluated the perceived efficacy and safety of intravenous immune globulin (... more This national survey evaluated the perceived efficacy and safety of intravenous immune globulin (IVIG) in septic shock, self-reported utilization patterns, barriers to use, the population of interest for further trials and willingness to participate in future research of IVIG in septic shock. We conducted a cross-sectional survey of critical care and infectious diseases physicians across Canada. We summarized categorical item responses as counts and proportions. We developed a multivariable logistic regression model to identify physician-level predictors of IVIG use in septic shock. Our survey was disseminated to 674 eligible respondents with a final response rate of 60%. Most (91%) respondents reported having prescribed IVIG to patients with septic shock at least once, 86% for septic shock due to necrotizing fasciitis, 52% for other bacterial toxin-mediated causes of septic shock, and 5% for undifferentiated septic shock. The majority of respondents expressed uncertainty regarding the impact of IVIG on mortality (97%) and safety (95%) in septic shock. Respondents were willing to participate in further IVIG research with 98% stating they would consider enrolling their patients into a trial of IVIG in septic shock. Familiarity with published evidence was the single greatest predictor of IVIG use in septic shock (odds ratio, 10.2; 95% confidence interval, 3.4 to 30.5; P < 0.001). Most Canadian critical care and infectious diseases specialist physicians reported previous experience using IVIG in septic shock. Respondents identified inadequacy of existing research as the greatest barrier to routine use of IVIG in septic shock. Most respondents support the need for further studies on IVIG in septic shock, and would consider enrolling their own patients into a trial of IVIG in septic shock.
JAIDS Journal of Acquired Immune Deficiency Syndromes, 2017
CONTENTS Click on any content title to link to that section. 03 Program Information and Acknowled... more CONTENTS Click on any content title to link to that section. 03 Program Information and Acknowledgements* *as of press time 13 Events Schedule 16 Speaker Schedule
We are pleased to present peer reviewed forum proceedings of the 2 nd synchronicity forum of GHRI... more We are pleased to present peer reviewed forum proceedings of the 2 nd synchronicity forum of GHRI/CHVIfunded Canadian and African HIV prevention and vaccine teams Forum objectives GHRI-funded capacity building and HIV prevention research teams presented highlights of achievements Teams discussed how to jointly build on achievements for sustainability Provided an opportunity for inter-team collaboration, synchronize best approach to capacity building, mentoring of new researchers and building leadership Provided opportunities for informal discussions and networking among the teams. Teams learnt about recent advances in the area of African regulatory and ethics review process The forum proceedings was a special supplement in an openaccess journal was produced Forum partners
To study the mechanisms of inducible immunity to Haemophilus ducreyi infection in the temperature... more To study the mechanisms of inducible immunity to Haemophilus ducreyi infection in the temperature-dependent rabbit model of chancroid, we conducted passive immunization experiments and characterized the inflammatory infiltrate of chancroidal lesions. Polyclonal immunoglobulin G was purified from immune sera raised against H. ducreyi 35000 whole-cell lysate or a pilus preparation and from naive control rabbits. Rabbits were passively immunized with 24 or 48 mg of purified polyclonal immunoglobulin G intravenously, followed 24 h after infusion by homologous titered infectious challenge. Despite titratable antibody, no significant difference in infection or disease was observed. We then evaluated the immunohistology of lesions produced by homologous-strain challenge in sham-immunized rabbits and those protectively vaccinated by pilus preparation immunization. Immunohistochemical stains for CD5 and CD4 T-lymphocyte markers were performed on lesion sections 4, 10, 15, and 21 days from in...
Using the temperature-dependent rabbit model of Haemophilus ducreyi infection as a quantitative v... more Using the temperature-dependent rabbit model of Haemophilus ducreyi infection as a quantitative virulence assay, we tested the abilities of two bacterial antigen preparations to induce protection against subsequent infection and disease. Lipooligosaccharide (LOS) and a pilus preparation were purified from H. ducreyi 35000 and were used in a booster immunization procedure. The serologic response to each immunogen was monitored by enzyme immunoassay. H. ducreyi virulence was assayed by intraepithelial inoculation and subsequent measurement of disease for homologous strain 35000 or clinical isolate RO-34. LOS and the pilus preparation induced humoral responses. The kinetics of the LOS antibody response suggest a type 1 T-independent response, whereas the pilus preparation induced an anamnestic response. An inoculum of 10(5) CFU of H. ducreyi 35000 or RO-34 consistently produced ulcerative chancroidal lesions in naive rabbit controls. Immunization with LOS did not modify the virulence o...
Background: Guidance is needed on best medical management for advanced HIV disease with multidrug... more Background: Guidance is needed on best medical management for advanced HIV disease with multidrug resistance (MDR) and limited retreatment options. We assessed two novel antiretroviral (ARV) treatment approaches in this setting. Methods and Findings: We conducted a 262 factorial randomized open label controlled trial in patients with a CD4 count #300 cells/ml who had ARV treatment (ART) failure requiring retreatment, to two options (a) re-treatment with either standard (#4 ARVs) or intensive ($5 ARVs) ART and b) either treatment starting immediately or after a 12-week monitored ART interruption. Primary outcome was time to developing a first AIDS-defining event (ADE) or death from any cause. Analysis was by intention to treat. From 2001 to 2006, 368 patients were randomized. At baseline, mean age was 48 years, 2% were women, median CD4 count was 106/ml, mean viral load was 4.74 log 10 copies/ml, and 59% had a prior AIDS diagnosis. Median follow-up was 4.0 years in 1249 person-years of observation. There were no statistically significant differences in the primary composite outcome of ADE or death between re-treatment options of standard versus intensive ART (hazard ratio 1.17; CI 0.86-1.59), or between immediate retreatment initiation versus interruption before re-treatment (hazard ratio 0.93; CI 0.68-1.30), or in the rate of non-HIV associated serious adverse events between re-treatment options. Conclusions: We did not observe clinical benefit or harm assessed by the primary outcome in this largest and longest trial exploring both ART interruption and intensification in advanced MDR HIV infection with poor retreatment options.
Research has revealed differences on scales measuring HIV knowledge between individuals from vari... more Research has revealed differences on scales measuring HIV knowledge between individuals from various ethnic backgrounds and cultures. Few studies have examined this knowledge with immigrant populations and persons living with HIV. This study examined HIV knowledge among persons living with HIV who were either born in Canada or in sub-Saharan Africa and, for comparison, in a sample of college students. All participants were residing in Canada. Participants completed questionnaires measuring demographic variables, sexual health behaviour, and HIV status, treatment, and knowledge. Canadian-born patients living with HIV were more likely to be older and male than the other groups. On average, patients living with HIV were diagnosed 6.4 years ago, and 80% reported having current or previous experience taking HIV medications. After adjusting for age and gender, significant differences were found between the groups on the Brief HIV Knowledge Questionnaire. Canadian-born persons living with HIV (n = 110) scored higher than sub-Saharan African-born patients (n = 23) and college students (n = 81); mean percentage correct was 86, 70, and 62%, respectively (P \ .01). These results suggested that ongoing HIV education is needed for all groups, and that additional tailored and targeted educational interventions are needed to address important gaps in knowledge among persons living with HIV patients originating from Africa and among college students.
SUMMARY Infection of immune cells with HIV induces dysregulation of cytokines which may play a vi... more SUMMARY Infection of immune cells with HIV induces dysregulation of cytokines which may play a vital role in HIV pathogenesis. We analysed the expression of T helper type I (Th1) (interferon-gamma (IFN-γ)) and Th2 (IL-4, IL-10) type cytokines in peripheral blood lymphocytes (PBL) from HIV patients. The semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed that IFN-γ mRNA in unstimulated PBL was significantly decreased and IL-10 mRNA was significantly upregulated in patients with < 400 CD4+ T cells/mm3 (n= 30) as compared to patients with > 400 CD4+ T cells/mm3 (n= 6) and normal controls (n= 16). In addition. IL-10 mRNA levels were inversely associated with IFN-γ expression. Similar results were obtained by measuring IL-10 production in the supernatants of PBL cultured in vitro without stimulation by employing an enzyme immunosorbent assay (ELISA). However, the levels of IL-4 and IFN-7 produced by unstimulated PBL were undetectable by ELISA...
β-Carotene supplements are often taken by individuals living with HIV-1. Contradictory results fr... more β-Carotene supplements are often taken by individuals living with HIV-1. Contradictory results from in vitro studies suggest that β-carotene may inhibit or induce cytochrome P450 enzymes and transporters. The study objective was to investigate the effect of β-carotene on the steady-state pharmacokinetics of nelfinavir and its active metabolite M8 in HIV-1 infected individuals. Twelve hour nelfinavir pharmacokinetic analysis was conducted at baseline and after 28 days of β-carotene supplementation (25,000 IU twice daily). Nelfinavir and M8 concentrations were measured with validated assays. Non-compartmental methods were used to calculate the pharmacokinetic parameters. Geometric mean ratios comparing day 28 to day 1 area under the plasma concentration-time curve (AUC 0-12 h), maximum (C max) and minimum (C min) concentrations of nelfinavir and M8 are presented with 90% confidence intervals. Eleven subjects completed the study and were included in the analysis. There were no significant differences in nelfinavir AUC 0-12 h and C min (−10%, +4%) after β-carotene supplementation. The M8 C min was increased by 31% while the M8 AUC 0-12 h and C max were unchanged. During the 28 day period, mean CD4 + % and CD4 + :CD8 + ratio increased significantly (p < 0.01). β-carotene supplementation increased serum carotene levels but did not cause any clinically significant difference in the nelfinavir and M8 exposure.
To compare the pharmacokinetics of lopinavir/ritonavir (LPV/r) 800/200 mg administered once daily... more To compare the pharmacokinetics of lopinavir/ritonavir (LPV/r) 800/200 mg administered once daily in the morning compared with the evening.
The pharmacokinetics of zidovudine in 10 symptomatic HIV-infected men were assessed after adminis... more The pharmacokinetics of zidovudine in 10 symptomatic HIV-infected men were assessed after administration of the initial 200 mg oral dose at the start of therapy (day 1) and on one occasion during non steady-state conditions of chronic-dose therapy (200 mg every 4 h while awake on day 21-66; 5 doses per day). The following mean (± s.d.) pharmacokinetic parameters were determined on day 1 and during chronic therapy, respectively: Cmax (4.09 ± 2.54 vs 3.82 ± 1.03 FLmol 1-1), oral clearance (40.7 ± 12.9 vs 41.1 ± 8.4 ml min-' kg-1) and terminal half-life (68.4 ± 29.4 vs 65.1 ± 13.1 min). Mean pharmacokinetic parameters on day 1 were < 10% different (P > 0.34) from those determined during chronic therapy. Differences in means of 21% for clearance and 36% for Cmax could be detected with a power of 80% at the 5% significance level. Intra-subject coefficients of variation were 17% for clearance and 32% for Cmax, respectively. This study suggests that within a group of patients whose stage of HIV infection and general health are relatively stable, first-dose pharmacokinetic parameters provide a good estimate of multiple-dose pharmacokinetic parameters.
Background: The role of oral antibiotic therapy in treating infective endocarditis (IE) is not we... more Background: The role of oral antibiotic therapy in treating infective endocarditis (IE) is not well established. Methods: We searched MEDLINE, EMBASE and Scopus for studies in which oral antibiotic therapy was used for the treatment of IE. Results: Seven observational studies evaluating the use oral beta-lactams (five), oral ciprofloxacin in combination with rifampin (one), and linezolid (one) for the treatment of IE caused by susceptible bacteria reported cure rates between 77% and 100%. Two other observational studies using aureomycin or sulfonamide, however, had failure rates >75%. One clinical trial comparing oral amoxicillin versus intravenous ceftriaxone for streptococcal IE reported 100% cure in both arms but its reporting had serious methodological limitations. One small clinical trial (n = 85) comparing oral ciprofloxacin and rifampin versus conventional intravenous antibiotic therapy for uncomplicated right-sided S. aureus IE in intravenous drug users (IVDUs) reported cure rates of 89% and 90% in each arm, respectively (P =0.9); however, drug toxicities were more common in the latter group (62% versus 3%; P <0.01). Major limitations of this trial were lack of allocation concealment and blinding at the delivery of the study drug(s) and assessment of outcomes.
Haemophilus ducreyi, a gram-negative and heme-dependent bacterium, is the causative agent of chan... more Haemophilus ducreyi, a gram-negative and heme-dependent bacterium, is the causative agent of chancroid, a genital ulcer sexually transmitted infection. Heme acquisition in H. ducreyi proceeds via a receptor mediated process in which the initial event involves binding of hemoglobin and heme to their cognate outer membrane proteins, HgbA and TdhA, respectively. Following this specific interaction, the fate of the periplasmic deposited heme is unclear. Using protein expression profiling of the H. ducreyi periplasmic proteome, a periplasmic-binding protein, termed hHbp, was identified whose expression was enhanced under heme-limited conditions. The gene encoding this protein was situated in a locus displaying genetic characteristics of an ABC transporter. The purified protein bound heme in a dose-dependent and saturable manner and this binding was specifically competitively inhibited by heme. The hhbp gene functionally complemented an Escherichia coli heme uptake mutant. Expression of the heme periplasmic-binding protein was detected in a limited survey of H. ducreyi and H. influenzae clinical strains. These results indicate that the passage of heme into the cytoplasm of H. ducreyi involves a heme dedicated ABC transporter.
Previously it has been shown that tipranavir-ritonavir (TPV/r) does not affect efavirenz (EFV) pl... more Previously it has been shown that tipranavir-ritonavir (TPV/r) does not affect efavirenz (EFV) plasma concentrations. This study investigates the effect of steady-state EFV on steady-state TPV/r pharmacokinetics. This was a single-center, open-label, multiple-dose study of healthy adult female and male volunteers. TPV/r 500/200 mg twice a day (BID) was given with food for 24 days. After dosing with TPV/r for 10 days, EFV 600 mg once a day was added to the regimen. Intensive pharmacokinetic (PK) sampling was done on days 10 and 24. Validated bioanalytical high-pressure liquid chromatography-tandem mass spectrometry methods were used to determine plasma tipranavir (TPV), ritonavir (RTV), and EFV concentrations. Thirty-four subjects were entered into the study, and 16 subjects completed it. The geometric mean ratios (90% confidence intervals) for TPV and RTV area under the curves, C max s, and C min s comparing TPV/r alone and in combination with EFV were 0.97 (0.87 to 1.09), 0.92 (0.81 to 1.03), and 1.19 (0.93 to 1.54) for TPV and 1.03 (0.78 to 1.38), 0.92 (0.65 to 1.30), and 1.04 (0.72 to 1.48) for RTV. Frequently observed adverse events were diarrhea, headache, dizziness, abnormal dreams, and rash. EFV had no effect on the steady-state PK of TPV or RTV, with the exception of a 19% increase in the TPV C min , which is not clinically relevant. TPV/r can be safely coadministered with EFV and without the need for a dose adjustment.
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