The implementation of rifapentine and isoniazid (3HP) in two remote Arctic communities with a predominantly Inuit population, the Taima TB 3HP study.

Background: The incidence of TB among Inuit is the highest in Canada. A significantly shorter latent TB infection (LTBI) treatment with rifapentine and isoniazid once weekly for 12 weeks (3HP) is now available in limited settings in Canada.Methods: A prospective open-label 2-year observational postmarketing study was conducted introducing 3HP for the first time in Canada in Iqaluit followed by a program rollout in Qikiqtarjuaq, Nunavut.Results: A total of 247 people were offered 3HP, 102 in the Iqaluit postmarketing study and 145 in the Qikiqtarjuaq program roll out. Although statistical significance was not reached, more people who started treatment completed treatment in the 3HP group (Iqaluit, 60/73 (82.2%) and Qikiqtarjuaq, 89/115 (77.4%)) than in the historical control 9INHgroup (306/420 = 72.9%) (p = 0.2). Most of the adverse events in 3HP treated patients were associated with mild discomfort but no disruption of normal daily activity. Not drinking alcohol was associated with increased 3HP completion (OR 13.33, 95% CI, 2.27-78.20) as was not taking concomitant medications (OR 7.19, 95% CI, 1.47-35.30).Conclusions: The present study supports the feasibility and safety profile of 3HP for the treatment of LTBI in Nunavut.

A drug interaction study investigating the effect of Rifabutin on the pharmacokinetics of Maraviroc in healthy subjects.

Effects of steady-state rifabutin on the pharmacokinetics of steady-state maraviroc were investigated in fourteen healthy adult female and male volunteers. Maraviroc 300 mg twice daily (BID) was given orally with food for fifteen days. On day six, rifabutin 300 mg once daily (QD, P.O.) was added to the regimen. Formal pharmacokinetic (PK) sampling was performed on days five and fifteen. Individual plasma drug concentration-time data for maraviroc, and rifabutin on day fifteen, were obtained using validated High Performance Liquid Chromatography (HPLC) tandem Mass Spectrometry (MS/MS). Rifabutin steady state exposure was comparable to data in the literature. Maraviroc area under the curve (AUC) and minimum plasma concentration (Clast or Cmin) were reduced by 17% and 30% respectively when co-administered with rifabutin. No unexpected or serious adverse eventsoccurred. Based on the reduced exposure of maraviroc observed in this study, increasing the dose of maraviroc may be studied to normalize its moderately reduced exposure following rifabutin co-administration, a moderate inducer of CYP3A4.

Protocol for updating a systematic review of randomised controlled trials on the prophylactic use of intravenous immunoglobulin for patients undergoing haematopoietic stem cell transplantation.

INTRODUCTION: Haematopoietic stem cell transplantation (HSCT) is commonly employed in the management of haematological malignancies. This intervention results in an increased risk of infectious and immune-related complications. Prophylactic immunoglobulin therapy has been used to prevent post-HSCT complications, including infections, with varying efficacy. We sought to update the current evidence supporting the use of immunoglobulins in the modern HSCT era. METHODS/ANALYSIS: Using a structured search strategy, we will perform a systematic review of the literature from MEDLINE, EMBASE and all EBM Reviews databases. We will include randomised clinical trials investigating clinical outcomes of prophylactic polyvalent immunoglobulin or cytomegalovirus (CMV)-specific immunoglobulin or plasma in patients undergoing HSCT. Clinical outcomes will include overall survival, transplant-related mortality, CMV infection, CMV disease, graft-versus-host disease, interstitial pneumonitis/fibrosis and hepatic veno-occlusive disease. Studies that only reported the results of biochemical tests will be excluded. Data will be extracted by two investigators independently. Study quality assessment will be evaluated using a validated five-point system as proposed by Jadad. Trial quality will be further assessed by identifying whether there was adequate allocation concealment. Where appropriate, a meta-analysis will be performed where relative risk will be used as the primary summary measure with 95% CIs. Pooled measures will be calculated for randomised clinical trials using a random-effects model. The Cochrane Q/χ(2) test and I(2) statistic will also be calculated to evaluate heterogeneity. We will also use a visual inspection of a funnel plot to assess potential publication bias. DISCUSSION: This systematic review aims to provide current evidence to justify the use of immunoglobulin prophylaxis in HSCT recipients. We will discuss whether current HSCT guidelines are supported by the current evidence, and whether further trials are needed, given the changing landscape of patients undergoing HSCT and the immunoglobulin manufacturing process. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015016684.

A model to rule out smear-negative tuberculosis among symptomatic HIV patients using C-reactive protein.

SETTING: Improved diagnostic algorithms for sputum smear-negative tuberculosis (SNTB) are needed to address the dramatic increase in SNTB in regions with high human immunodeficiency virus (HIV) prevalence. OBJECTIVE: To determine whether the addition of C-reactive protein (CRP) to a prediction model using simple clinical criteria improves the diagnosis of SNTB among mostly antiretroviral-naïve adult HIV TB suspects in an out-patient setting. DESIGN: A multiple logistic regression model was derived from a database of 228 HIV patients to predict the risk of SNTB using data from a previous prospective study. RESULTS: The derived model demonstrated that male sex, night sweats, fever, low body mass index and anemia increased the probability of having SNTB. CRP improved the accuracy of the model (without CRP, area under the curve [AUC] 0.75, 95%CI 0.68-0.81 vs. model with CRP, AUC 0.81, 95%CI 0.76-0.87, P = 0.0014) to predict SNTB. Using reclassification tables, CRP correctly reclassified 27.9% of the patients (net reclassification improvement, P = 0.0005) into higher or lower risk categories. The strongest effect was seen in the reclassification improvement among patients with no TB, which was 20.6% (P = 0.0023). CONCLUSION: CRP improved the performance of the prediction model in the diagnosis of SNTB in HIV patients, and may play a role in ruling out SNTB in this population. Prospective validation of this model is needed.

Comparison of interferon-γ-, interleukin (IL)-17- and IL-22-expressing CD4 T cells, IL-22-expressing granulocytes and proinflammatory cytokines during latent and active tuberculosis infection.

In this study, we investigated the role and expression of T helper type 17 (Th17) cells and Th17 cytokines in human tuberculosis. We show that the basal proportion of interferon (IFN)-γ-, interleukin (IL)-17- and IL-22-expressing CD4(+) T cells and IL-22-expressing granulocytes in peripheral blood were significantly lower in latently infected healthy individuals and active tuberculosis patients compared to healthy controls. In contrast, CD4(+) T cells expressing IL-17, IL-22 and IFN-γ were increased significantly following mycobacterial antigens stimulation in both latent and actively infected patients. Interestingly, proinflammatory IFN-γ and tumour necrosis factor (TNF)-α were increased following antigen stimulation in latent infection. Similarly, IL-1ß, IL-4, IL-8, IL-22 and TNF-α were increased in the serum of latently infected individuals, whereas IL-6 and TNF-α were increased significantly in actively infected patients. Overall, we observed differential induction of IL-17-, IL-22- and IFN-γ-expressing CD4(+) T cells, IL-22-expressing granulocytes and proinflammatory cytokines in circulation and following antigenic stimulation in latent and active tuberculosis.

HIV knowledge among Canadian-born and sub-Saharan African-born patients living with HIV.

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.

Tuberculosis retreatment category predicts resistance in hospitalized retreatment patients in a high HIV prevalence area.

SETTING: Rates of multidrug-resistant tuberculosis (MDR-TB) are currently as high as 7.7% in retreatment cases in KwaZulu-Natal, South Africa. MDR-TB prevalence is known to be high in patients categorized as treatment failures. Recent reports have questioned the effectiveness of the World Health Organization (WHO) Category II regimen in retreatment TB cases. OBJECTIVE: To determine whether treatment category predicts susceptibility patterns and outcomes in a hospitalized population of retreatment TB cases. DESIGN: Retrospective cohort of 197 pulmonary retreatment cases. RESULTS: Retreatment cases treated with the standard retreatment regimen had a high in-hospital mortality (19.8%), or poor outcome (26.4%) and a high rate of MDR-TB (16.2%). The 'treatment failure' category predicted resistance, with 57.1% of patients exhibiting any resistance compared to other treatment categories (P = 0.02); 53.8% of patients with any resistance experienced poor outcomes, compared to 16.6% of pan-susceptible cases (P = 0.02). There was a trend towards poor outcome in the treatment failure category (42.9%, P = 0.13). CONCLUSION: The retreatment category 'treatment failure' is associated with a high prevalence of resistance in an area of high human immunodeficiency virus (HIV) prevalence. The 'treatment failure' category should be used to identify patients who may benefit from alternative regimens using directed, intensified therapy or second-line agents instead of the current standard retreatment regimen.

Lack of effect of efavirenz on the pharmacokinetics of tipranavir-ritonavir in healthy volunteers.

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.

Differential effects of tipranavir plus ritonavir on atorvastatin or rosuvastatin pharmacokinetics in healthy volunteers.

To identify pharmacokinetic (PK) drug-drug interactions between tipranavir-ritonavir (TPV/r) and rosuvastatin and atorvastatin, we conducted two prospective, open-label, single-arm, two-period studies. The geometric mean (GM) ratio was 1.37 (90% confidence interval [CI], 1.15 to 1.62) for the area under the concentration-time curve (AUC) for rosuvastatin and 2.23 (90% CI, 1.83 to 2.72) for the maximum concentration of drug in serum (Cmax) for rosuvastatin with TPV/r at steady state versus alone. The GM ratio was 9.36 (90% CI, 8.02 to 10.94) for the AUC of atorvastatin and 8.61 (90% CI, 7.25 to 10.21) for the Cmax of atorvastatin with TPV/r at steady state versus alone. Tipranavir PK parameters were not affected by single-dose rosuvastatin or atorvastatin. Mild gastrointestinal intolerance, headache, and mild reversible liver enzyme elevations (grade 1 and 2) were the most commonly reported adverse drug reactions. Based on these interactions, we recommend low initial doses of rosuvastatin (5 mg) and atorvastatin (10 mg), with careful clinical monitoring of rosuvastatin- or atorvastatin-related adverse events when combined with TPV/r.

CPG 7909 adjuvant plus hepatitis B virus vaccination in HIV-infected adults achieves long-term seroprotection for up to 5 years.

BACKGROUND: Human immunodeficiency virus (HIV)-infected persons are hyporesponsive to hepatitis B virus (HBV) vaccination. CPG 7909 is an oligodeoxynucleotide containing immunostimulatory CpG motifs that activate human B and plasmacytoid dendritic cells via Toll-like receptor 9. We previously reported that addition of CPG 7909 to a commercial HBV vaccine enhanced the kinetics, magnitude, and longevity of the seroprotective response over 48 weeks. We now report data for the 5-year period following vaccination. METHODS: A randomized, double-blind, controlled trial was conducted to determine clinical safety and immunogenicity of HBV vaccine in adult HIV-infected subjects receiving effective antiretroviral therapy. HBV-susceptible subjects, one-half of whom had experienced previous vaccination failure, were vaccinated at 0, 1, and 2 months with a double adult dose of recombinant HBV vaccine, with or without 1 mg of CPG 7909 (19 subjects per arm). Titers of antibody to HBV surface antigen (anti-HBs) were measured at 6-month intervals for up to 60 months. RESULTS: The proportion of participants achieving and retaining seroprotection (surface antibody titers, > or =10 mIU/mL) was greater in CPG 7909 recipients (P < .05 at all time points). Geometric mean anti-HBs titers were higher in the CPG 7909 group than in the control group (without CPG 7909 adjuvant) at all measured time points. CONCLUSIONS: The immunostimulatory properties of CPG 7909 present an important strategy in achieving long-term protection in HIV-infected patients and other HBV vaccine-hyporesponsive populations.

Development and psychometric validation of the HIV Treatment Knowledge Scale.

Accurate treatment knowledge is required for patients to successfully manage complex medical conditions. Existing HIV knowledge scales focus on disease transmission and risk factors. This is the first study to develop and validate a scale to measure HIV treatment knowledge about complex treatment issues such as adherence, side-effects and drug resistance. A total of 346 participants were recruited into this cross-sectional study. Participants included HIV-positive patients (n=130), HIV-hepatitis C co-infected patients (n=22), hepatitis C patients, (n=78), community healthcare providers (n=35) and college students (n=81). Participants completed the proposed HIV Treatment Knowledge Scale and a validated measure of general knowledge about HIV transmission and risk factors. Two-week test-retest data were collected. Results demonstrated that the HIV Treatment Knowledge Scale was significantly correlated with general HIV knowledge across all samples. Among HIV-positive patients, the HIV Treatment Knowledge Scale was positively associated with time since HIV diagnosis. HAART-experienced patients had significantly higher treatment knowledge than HAART-naïve patients. HIV-positive patients scored significantly higher than hepatitis C patients and college students on HIV treatment knowledge. Test-retest reliability (r=0.83) and internal consistency (reliability coefficient=0.90) were both satisfactory. The HIV Treatment Knowledge Scale is a novel, easy-to-administer measure demonstrating high levels of validity and reliability. It has important applications as a clinical teaching tool with patients and healthcare workers and it could be used as an outcome indicator in HIV educational intervention studies.

Combining social network analysis and cluster analysis to identify sexual network types.

Increases in the rates of sexually transmitted infections (STIs) suggest that control programmes may not be effectively targeting diverse subpopulations. The objective of this investigation was to examine STI transmission within different groups, using both social network analysis and cluster analysis. Routine partner notification data were analysed from individuals diagnosed with, or exposed to an STI in Manitoba. Groups were identified and characterized. Three different clusters of groups were identified, comprised of demographically and clinically distinct individuals. A greater understanding of disease transmission patterns within these groups will aid in the development of targeted education and prevention programmes for all STIs.

The effect of ABCB1 polymorphism on the pharmacokinetics of saquinavir alone and in combination with ritonavir.

This genotype panel study investigated the effect of ABCB1 polymorphism in exon 26 (C3435T), exon 21 (G2677T/A), and exon 12 (C1236T) on saquinavir pharmacokinetics and on the expression and activity of P-glycoprotein (P-gp) in peripheral blood monocytic cells (PBMCs). One hundred and fifty healthy volunteers were genotyped to identify 15 TT3435 and 15 CC3435 individuals. In these individuals, saquinavir pharmacokinetics were assessed after administration of a single oral dose of saquinavir 1,000 mg and saquinavir/ritonavir 1,000/100 mg. PBMC P-gp expression and activity were assessed in 15 and 19 subjects. The co-administration of ritonavir on study day 2 caused a significant increase in saquinavir exposure, in both TT3435 and CC3435 individuals. No correlation was observed between the ABCB1 C3435T, G2677T/A, and C1236T polymorphisms, separately and in haplotypes, with saquinavir pharmacokinetics, administered with or without ritonavir and with PBMC P-gp expression and activity. In conclusion, ABCB1 polymorphism has no pronounced effect on saquinavir exposure.

Blastomycosis in a young African man presenting with a pleural effusion.

Blastomyces dermatitidis is a dimorphic fungus endemic to north-western Ontario, Manitoba and some parts of the United States. The fungus is also endemic to parts of Africa. Pulmonary and extrapulmonary findings of a 24-year-old African man who presented with weight loss, dry cough and chronic pneumonia not resolving with antibiotic treatment are presented. The unusual occurrence of pulmonary blastomycosis associated with skin lesions and a moderate pleural effusion is reported.

A randomized controlled psycho-education intervention trial: Improving psychological readiness for successful HIV medication adherence and reducing depression before initiating HAART.

The purpose of this study was to evaluate a novel psycho-educational intervention intended to increase patients' medication preparedness and treatment adherence skills before initiating highly active antiretroviral therapy (HAART). Sixty-three HIV-positive patients not currently on antiretroviral therapy participated in a randomized controlled trial of a standardized, four-session psycho-educational intervention (Supportive Therapy for Adherence to Antiretroviral Treatment; STAART). Session topics included learning techniques to increase medication adherence and learning effective strategies to cope with stress and depression. Patients completed psychological questionnaires assessing psychological readiness to initiate HAART and depressed mood. They completed both measures at study baseline and at four-weeks post-baseline. After controlling for baseline medication readiness scores, intervention patients (n = 30) reported significantly higher mean medication readiness following the STAART intervention (four-weeks post-baseline) (27.3+/-6.9) compared to controls (n = 33; 24.6+/-9.9; p < 0.05). Among depressed patients (n = 27), those receiving the intervention (n = 15) reported significantly lower mean depression scores at four-weeks post-baseline (22.5+/-12.9) compared to controls (n = 12; 27+/-9.9; p < 0.05). The STAART intervention enhanced HIV treatment readiness by better preparing patients prior to initiating HAART. It was also beneficial for reducing depressive symptoms in depressed, HIV-positive patients.

A community randomized controlled clinical trial of mixed carotenoids and micronutrient supplementation of patients with acquired immunodeficiency syndrome.

OBJECTIVE: This clinical trial aims to evaluate if natural mixed carotenoids supplementation can improve the health and survival of acquired immunodeficiency syndrome (AIDS) patients. DESIGN: A placebo-controlled, prospective, randomized, double-blind, multicenter clinical trial. SETTING: Community, tertiary care human immunodeficiency virus (HIV) clinics of the Canadian HIV Trials Network (CTN). PARTICIPANTS: Three hundred and thirty-one adults with advanced AIDS on conventional management were recruited during routine clinic visits. INTERVENTIONS: All participants, including 166 controls, received daily oral specially formulated multivitamins including vitamin A and trace elements; 165 treatment group participants received additional daily oral natural mixed carotenoids, equivalent to 120,000 IU (72 mg) of beta-carotene daily. Follow-up was quarterly at routine clinic visits. RESULTS: Mean (s.d.) follow-up was for 13 (6) months. Thirty-six participants died by 18 months. Serum carotene concentration <1.0 micromol/l was present in 16% participants at baseline. Despite variation in carotene content of the treatment medication, serum carotene concentrations increased significantly to twice the baseline levels to 18 months follow-up in participants who received carotenoids treatment compared with controls (P < 0.0001). Although not statistically significant, mortality was increased in participants who did not receive carotenoids treatment compared with those who did (HR time to death 1.76, 95% CI 0.89, 3.47, P = 0.11). In multivariate analysis, survival was significantly and independently improved in those with higher baseline serum carotene concentrations (P = 0.04) or higher baseline CD4 T-lymphocyte counts (P = 0.005). Adjusted mortality was also significantly and independently increased in those who did not receive carotenoids treatment compared with those who did (HR time to death 3.15, 95% CI 1.10, 8.98, P = 0.03). CONCLUSIONS: Low serum carotene concentration is common in AIDS patients and predicts death. Supplementation with micronutrients and natural mixed carotenoids may improve survival by correction of a micronutrient deficiency. Further studies are needed to corroborate findings and elucidate mechanism of action.

Absence of circadian variation in the pharmacokinetics of lopinavir/ritonavir given as a once daily dosing regimen in HIV-1-infected patients.

AIMS: To compare the pharmacokinetics of lopinavir/ritonavir (LPV/r) 800/200 mg administered once daily in the morning compared with the evening. METHODS: This was a randomized, two-way, cross-over study in HIV+ subjects. In each subject the pharmacokinetics of each drug were characterized after 2 weeks of LPV/r 800/200 mg administered once daily at 08.00 h and 19.00 h. On study days, LPV/r was taken with a standardized meal (800 kCal, 25% from fat) after fasting for at least 5 h. LPV/r concentrations were measured by LC-MS/MS, and the data were analyzed by noncompartmental pharmacokinetic analysis. RESULTS: Fourteen subjects completed the study (all men, mean age/weight 44 year/81 kg). The median (interquartile range) LPV AUC(0,24 h), maximum plasma concentration (C(max)) and concentration at the end of the dosing interval (C(24 h)) after am and pm dosing was, respectively, 143 (116-214) mg l(-1) h, 12.8 (10.3-17.2) mg l(-1), 1.34 (0.58-3.25) mg l(-1), and 171 (120-232) mg l(-1) h, 12.9 (8.22-16.3) mg l(-1), 1.15 (0.59-1.98) mg l(-1). The geometric mean ratio (GMR, am : pm) and 95% CI of the LPV AUC(0,24 h), C(max), and C(24 h) was 0.91 (0.79, 1.06), 1.11 (0.94, 1.32), and 1.19 (0.72, 1.96), respectively. The median ritonavir C(max) after am and pm dosing was 1.05 and 0.90 mg l(-1), respectively. The GMR (95% CI) of the RTV AUC(0,24 h), C(max), and C(24 h) was 0.93 (0.80, 1.08), 1.27 (1.00, 1.63), and 1.04 (0.68, 1.60), respectively. Administration of LPV/r in a once-daily regimen was generally well tolerated. CONCLUSIONS: No differences were observed in the pharmacokinetics of LPV/r after am or pm dosing with food, which suggests that this once daily combination, can be taken in the morning or evening. Such flexibility in dosing may improve adherence.