[Show abstract][Hide abstract] ABSTRACT: HIV-1 tropism assays play a crucial role in determining the response to CCR5 receptor antagonists. Initially, phenotypic tests were used, but limited access to these tests prompted the development of alternative strategies. Recently, genotyping tropism has been validated using a Canadian technology in clinical trials investigating the use of maraviroc in both experienced and treatment-naive patients. The present guidelines review the evidence supporting the use of genotypic assays and provide recommendations regarding tropism testing in daily clinical management.
Full-text · Article · Dec 2013 · The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale / AMMI Canada
[Show abstract][Hide abstract] ABSTRACT: : It is recommended to boost atazanavir with ritonavir (ATV/r) when it is combined with tenofovir disoproxil fumarate (TDF) because of drug interactions. For tolerability, unboosted atazanavir (ATV) is sometimes coadministered with TDF. The objective of this study was to evaluate the impact of this interaction on the proportion of patients achieving target ATV Ctroughs and genotypic inhibitory quotients (GIQ).
: A therapeutic drug monitoring database was screened to evaluate ATV concentrations. Differences in Ctrough and GIQ values among 4 antiretroviral drug combinations were evaluated.
: Three hundred eight Ctroughs, 91 GIQs, and 92 viral loads were evaluated for 238, 68, and 69 patients, respectively. Patients receiving ATV/r and TDF compared with ATV and TDF were more likely to have a therapeutic Ctrough (odds ratio, 2.27; 95% confidence interval: 1.46-3.52; P < 0.001). Among patients on unboosted ATV, the odds of having a therapeutic ATV Ctrough did not differ between groups with TDF versus without TDF. Although ritonavir increased the GIQ in patients receiving TDF (odds ratio, 3.38; 95% confidence interval: 1.30-8.81; P = 0.013), a similar proportion of patients on TDF and either ATV/r or ATV achieved a therapeutic GIQ.
: In patients receiving TDF, ritonavir increased the ATV Ctrough and GIQ and patients on ATV/r were more likely to have therapeutic Ctroughs. However, among subjects without ritonavir boosting, TDF compared with other nucleosides did not influence the odds of achieving a therapeutic ATV Ctrough. These data suggest that ritonavir boosting of ATV is prudent, particularly in patients with resistance mutations.
No preview · Article · Apr 2013 · Therapeutic drug monitoring
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Data collected from 224 women living with HIV were analyzed to study quality of life. Quality of life was operationalized as mental health and physical functioning. A structural equation model was tested. The final model demonstrates good fit to data (χ = 17.63, p = .48). Mental health was directly and positively associated with being born outside of Canada, social support, and physical functioning but negatively associated with the proportion of people aware of serostatus and experienced discrimination. Physical functioning was directly and positively associated with being born outside of Canada and social support; however, it was negatively associated with time since diagnosis. The proportion of people aware of serostatus was negatively associated with being born outside of Canada and being a mother. Social work interventions aimed at improving quality of life in women living with HIV should target contexts of serostatus disclosure to minimize HIV discrimination and to improve social support sources without compromising existing ones.
No preview · Article · Jul 2012 · Journal of HIV/AIDS & Social Services
[Show abstract][Hide abstract] ABSTRACT: The management and treatment of HIV and hepatitis B virus (HBV)-coinfected patients present specific challenges for clinicians. The morbidity and mortality related to these concomitant infections are growing concerns, while the use of antiviral drugs effective against both viruses complicates therapeutic decision making. The present document provides guidelines for physicians regarding care and treatment of patients coinfected with HIV and HBV. Primary prevention of HBV in HIV-positive patients is achieved through appropriate vaccination schedules. Follow-up before treatment of HBV may include liver biopsy, screening for hepatocellular carcinoma and testing for esophageal varicies in cases of cirrhosis. In HBV-infected patients requiring treatment, recommendations regarding initiation, duration and choice of first-line drugs are made. Finally, in the case of resistance, appropriate alternative therapies are necessary.
Full-text · Article · Sep 2011 · The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale / AMMI Canada
[Show abstract][Hide abstract] ABSTRACT: The appropriate use of antiretrovirals reduces morbidity and mortality caused by HIV infection. The present article provides health care professionals with a practical guide for the use of antiretrovirals. Therapy should be initiated based predominantly on clinical presentation and CD4 count, and should consist of three active drugs or at least two active drugs when this is not possible, as in cases of some treatment-experienced patients. This is the most effective way to achieve long-term suppression of viral replication. Selection of individual drugs in the regimen should consider the weight of the evidence supporting these choices, as well as their tolerability profiles and ease of use, the patients' comorbidities and treatment history. Treatment interruption is not recommended, either in aviremic patients or in those who have experienced virological failure. Instead, the therapeutic regimen should be adjusted to minimize side effects, promote adherence and suppress viral replication.
Full-text · Article · Jun 2011 · The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale / AMMI Canada
[Show abstract][Hide abstract] ABSTRACT: A Canadian group, consisting of six physicians and an HIV researcher with significant experience and knowledge in HIV management, reviewed the available data and developed guidelines for Canadian health care providers (who treat HIV infection) on the appropriate use of maraviroc (UK-427,857) in HIV-infected adults.
Evidence from the published literature and conference presentations, as well as the expert opinions of the group members were considered and evaluated to develop the recommendations. Feedback on the draft recommendations was obtained from this core group, as well as from four other physicians across Canada with expertise in HIV treatment and experience with the use of maraviroc. The final recommendations represent the core group's consensus agreement once all feedback was considered.
Recommendations were developed to guide physicians and other health care providers in the optimal use of maraviroc. The recommendations were considered in light of the fact that the decision to include maraviroc in an antiretroviral regimen depends not only on issues that concern all antiretroviral agents, such as efficacy, safety, resistance and drug interactions, but also on the issue of viral tropism, which is unique to maraviroc and other CCR5 inhibitors.
Full-text · Article · Dec 2010 · The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale / AMMI Canada
[Show abstract][Hide abstract] ABSTRACT: HIV infection increases the risk of reactivation of latent tuberculosis (TB). The present study evaluates how latent TB is detected and treated to determine the effectiveness of screening in HIV-infected patients with diverse risk profiles.
A retrospective medical record database review (1988 to 2007) was conducted at a tertiary care HIV clinic. The proportion of patients receiving tuberculin skin tests (TSTs) and the rate of active TB at each stage of screening and prevention were estimated. Predictors of receiving a TST at baseline, testing positive by TST and developing active TB were evaluated.
In the present study, 2123 patients were observed for a total of 9412 person-years. Four hundred seventy-six (22.4%) patients were tested by TST within 90 days of first clinic visit. Having a first clinic visit during the highly active antiretroviral therapy era (OR 3.64; 95% CI 2.66 to 4.99), country of birth (ORs: Africa 3.11, Asia 2.79, Haiti 3.14, and Latin America and the Caribbean 2.38), time between HIV diagnosis and first visit (OR per one-year change 0.97; 95% CI 0.94 to 0.99) and previous antiretroviral exposure (OR 0.61; 95% CI 0.45 to 0.81) were independent predictors of receiving a TST at baseline. Of the 17 patients who developed active TB during follow-up, nine (53%) had no documented TSTs at baseline or during follow-up. Forty-one per cent of all TB patients and 56% of TB patients who were not screened were born in Canada.
The administration of TSTs to newly diagnosed HIV patients was inconsistent and differential according to country of birth, among other factors, resulting in missed opportunities for TB prevention.
Full-text · Article · Jun 2009 · The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale / AMMI Canada
[Show abstract][Hide abstract] ABSTRACT: The influence of viral subtype on the natural history of HIV is unclear and confounded by socioeconomic and host factors that vary between groups harboring different clades. We compared Canadians (clade B), with recent immigrants from Haiti (clade B) and sub-Saharan Africa (clades non-B) to determine whether there were differences in disease progression attributable to viral subtype.
We conducted a retrospective cohort study in a universal healthcare setting between 1996 and 2007. The rate of CD4+ T-lymphocyte decline prior to initiation of antiretroviral therapy was determined in all participants with at least two CD4+ T-lymphocyte measures using mixed linear regression models. Time to first AIDS-defining illness was compared using adjusted Cox proportional hazards models.
Two hundred and eighty-nine Canadians, 44 Haitians, and 123 Africans were studied for a median of 260 days (2 days-11 years). Africans and Haitians were demographically and clinically similar. However, the adjusted slope of square root CD4+ T-lymphocyte decline was significantly lower in Africans [-0.04/year; 95% confidence interval (CI) = -0.08 to -0.003] compared with Canadians (-0.07/year; 95% CI = -0.11 to -0.03; P = 0.02), and Haitians (-0.10/year; 95% CI = -0.12 to -0.07; P = 0.001). Africans were also less likely to develop AIDS.
Despite having similar demographic, socioeconomic, and nutritional status to Haitians, Africans infected with non-B clade HIV had slower rates of disease progression compared with both Haitians and Canadians, with both groups being infected by the clade B virus. Our findings suggest that viral subtype may be an important predictor of HIV natural history in a developed medical setting.
No preview · Article · Apr 2009 · AIDS (London, England)
[Show abstract][Hide abstract] ABSTRACT: Mutations in the RNase H domain of human immunodeficiency virus type 1 RT have been reported to cause resistance to zidovudine (ZDV) in vitro. However, very limited data on the in vivo relevance of these mutations in patients exist to date. This study was designed to determine the relationship between mutations in the RNase H domain and viral susceptibility to nucleoside analogues. Viruses harboring complex thymidine analogue mutation (TAM) and nucleoside analogue mutation (NAM) profiles were evaluated for their phenotypic susceptibilities to ZDV, tenofovir (TNF), and the nonapproved nucleoside reverse transcriptase inhibitors (NRTIs) beta-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (Reverset), beta-D-5-fluorodioxolane-cytosine, and apricitabine. As controls, viruses from NRTI-naïve patients were also studied. The pol RT region (codons 21 to 250) of the viruses were sequenced and evaluated for mutations in the RNase H domain (codons 441 to 560) and the connection domain (codons 289 to 400). The results showed that viruses from patients failing multiple NRTI-containing regimens had distinct TAM and NAM profiles that conferred various degrees of resistance to ZDV (0.9- to >300-fold). Sequencing of the RNase H domain identified five positions (positions 460,468, 483, 512, and 519) at which extensive amino acid polymorphisms common in both wild-type viruses and viruses from treated patients were identified. No mutations were observed at positions 539 and 549, which have previously been associated with ZDV resistance. Mutations in the RNase H domain did not appear to correlate with the levels of phenotypic resistance to ZDV. Although some mutations were also observed in the connection domain, the simultaneous presence of the L74V and M184V mutations was the most significant determinant of phenotypic resistance to ZDV in patients infected with viruses with TAMs.
Full-text · Article · Nov 2007 · Antimicrobial Agents and Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: Concomitant HIV and hepatitis C virus (HCV) is a common yet complex coinfection. The present document is a practical guide for treating HCV infection in people coinfected with HIV. Effective antiretroviral therapies have prolonged survival rates for HIV-infected people over the past decade, which have made latent complications of HCV major causes of morbidity and mortality in these patients. Advances in the treatment of HCV (eg, combined pegylated interferon and ribavirin) offer the possibility of eradicating HCV infection in coinfected persons. The treatment of HCV must be considered in all cases. Intensive management of the adverse effects of HCV treatment is one of the factors for the success of these therapies. HCV eradication is predicted to decrease the mortality associated with coinfection and reduce the toxicity of HIV treatment.
Preview · Article · Oct 2007 · The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale / AMMI Canada
[Show abstract][Hide abstract] ABSTRACT: The effects of highly active antiretroviral therapy (HAART) on progression of hepatic fibrosis in hepatitis C virus (HCV) coinfection with HIV are not well understood and are difficult to measure because of the need for repeated liver biopsy. We evaluated the evolution of a noninvasive measure of liver fibrosis, the alanine aspartyl transferase (AST)-to-platelet ratio index (APRI), longitudinally and determined its predictive value for hepatic outcomes in HIV-positive patients with and without HCV coinfection. A total of 673 HIV-positive patients without liver complications at baseline (540 with HIV only, 133 with HIV-HCV coinfection) were followed between 1991 and 2004 for a median of 4.6 years (3524 person-years). At baseline, HIV-HCV coinfection had a higher median APRI compared with HIV infection alone (0.59 vs. 0.33; P < 0.0001). The natural logarithm of the APRI [ln(APRI)] changed significantly over time, particularly among patients with HIV-HCV coinfection. The baseline ln(APRI) was predictive of liver complications (hazard ratio [HR] = 4.0, 95% confidence interval [CI]: 2.5 to 6.4 per log), as was HCV (HR = 4.5, 95% CI: 1.5 to 14). Cumulative HAART did not protect against liver complications, although it was significantly associated with progression of APRI scores in HIV-HCV coinfection and in HIV alone. In conclusion, the APRI may be a useful marker for longitudinal evaluation of the progression of liver disease in HIV-HCV coinfection.
No preview · Article · May 2007 · JAIDS Journal of Acquired Immune Deficiency Syndromes
[Show abstract][Hide abstract] ABSTRACT: HLA-B*5701 strongly predicts abacavir hypersensitivity (HSR), but implementation of effective routine screening into clinical practice requires testing be practical and accurate. We tested the proficiency of HLA-B*5701 typing among laboratories using sequence-specific primer PCR.
DNA panels (1 and 2) were distributed to seven laboratories (A to G) for blinded typing of the HLA-B*5701 allele. Panel 1 (n = 10 samples; n = 7 laboratories) included 3 positives and other closely related B17 subtypes (B*5702, B*5703, B*5704 and B*5801). Panel 2 (n = 96 samples; n = 4 laboratories) included 36 positives among a broad spectrum of other B alleles. Two laboratories (A and B) also submitted 96 routine samples, typed by the same methodology, to the reference centre for additional analysis by sequence-based typing.
All laboratories correctly typed panel 1 for HLA-B*5701 carriage. Laboratories A, B and C identified HLA-B*5701 alleles in panel 2 with 100% sensitivity and 100% specificity. Laboratory D reported one false negative, reportedly due to a sampling error. The results obtained for routine samples typed by laboratories A and B and those generated by the reference laboratory using sequencing were fully concordant.
Detection of HLA-B*5701 alleles among laboratories was 100% specific and 99.4% sensitive, indicating that participating HIV testing laboratories were currently offering effective primary screening to identify individuals at high risk of abacavir HSR. Accurate reporting of HLA-B*5701 status is critical for the safe administration of this drug and participation in quality assurance programmes by all sites who report HLA-B*5701 status should be promoted.
Full-text · Article · Feb 2007 · Antiviral therapy
[Show abstract][Hide abstract] ABSTRACT: The efficacy, safety, and pharmacokinetics of three doses of tipranavir/ritonavir (TPV/r) in highly treatment-experienced human immunodeficiency virus (HIV)-1-infected patients with protease inhibitor (PI)-resistant isolates were evaluated. A 24-week multicenter, double-blind, randomized, dose-finding trial was conducted. All patients were three-drug class experienced and had taken at least two PI-based regimens. All had at least one primary PI mutation and had plasma HIV-RNA > 1000 copies/ml. Patients remained on their background non-PI antiretroviral medications for the first 14 days. After this 14-day period of functional TPV/r monotherapy, the background antiretroviral medications were optimized based on treatment history and the screening genotype. A total of 216 patients were randomized. All groups [TPV/r 500 mg/100 mg (n = 73), 500 mg/200 mg (n = 72), and 750 mg/200 mg (n = 71) twice daily] achieved an approximate 1 log10 reduction in the median HIV-RNA at week 2. A significant reduction was sustained through 24 weeks in the TPV/r 500 mg/200 mg and 750 mg/200 mg groups. The 500 mg/200 mg dose achieved optimal median TPV trough concentrations and lower interpatient variability. The most frequently reported adverse events (AEs) were diarrhea, nausea, vomiting, fatigue, and headache. The TPV/r 750 mg/200 mg group had the highest rate of grade 3 or 4 laboratory abnormalities and study discontinuations due to AEs. All doses of TPV/r tested in this study were associated with HIV-1 viral load reductions through 24 weeks. The 500 mg/200 mg dose achieved the best efficacy, safety, and pharmacokinetic profile in this highly treatment-experienced population and was selected for the pivotal phase 3 studies.
Full-text · Article · Feb 2007 · AIDS Research and Human Retroviruses
[Show abstract][Hide abstract] ABSTRACT: Gender differences in a large population-based cohort of HIV-1 infected patients (245 women and 723 men) were examined with respect to the incidence of metabolic and morphologic alterations after initiation of highly active antiretroviral therapy (HAART). Patients initiated HAART between January 1996 and December 2003. The outcome measures were the incidence of hyperglycemia, hypercholesterolemia, symptomatic lactic acidosis, treatment-limiting lipodystrophy, and hypersensitivity reaction. Cox proportional hazards models were used to estimate the crude and adjusted hazard ratios of reaching the endpoints for exposures and covariates. Women were younger than men (35 +/- 9.8 vs. 40 +/- 8.2 years, P < 0.001) and more frequently from Haiti or Africa (59%), whereas 76% of men were Canadian-born. Type of initial HAART regimen did not differ between women and men. There were no gender differences in the overall incidence of hyperglycemia, hypercholesterolemia, or treatment-limiting lipodystrophy, even after adjusting for age, CD4 cell count, viral load, time since HIV diagnosis, history of AIDS-defining illness and year of HAART initiation. In contrast, women had significantly higher risk of developing lactic acidosis than men (P = 0.0009). Hypersensitivity reactions were also more frequent in women than men (adjusted hazard ratio = 4.4 (95% CI: 2.1-9.3)). Collectively, these data suggest that metabolic toxicities after HAART do not differ by gender but that lactic acidosis and hypersensitivity reactions are more frequent in women than men.
No preview · Article · Sep 2006 · Journal of Medical Virology
[Show abstract][Hide abstract] ABSTRACT: An eight-member group consisting of Canadian infectious disease and immunology specialists and a family physician with significant experience in HIV management was convened to update existing recommendations, specifically intended for use by Canadian HIV-treating physicians, on the appropriate use of enfuvirtide in HIV/AIDS patients with resistance to other antiretroviral drugs.
Evidence from the literature and expert opinions of the group members formed the basis of the guidelines. Comments on the draft guidelines were obtained from other physicians across Canada with HIV expertise. The final guidelines represent the group's consensus agreement.
The recommendations were developed to guide physicians in optimal practices in patient selection for enfuvirtide treatment and subsequent patient management. The issues considered include positive predictors of response to enfuvirtide, stage of disease, optimization of the background regimen, early indicators of enfuvirtide response, and patient education and support.
Full-text · Article · Jun 2006 · The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale / AMMI Canada
[Show abstract][Hide abstract] ABSTRACT: To illustrate the progressive loss of cross-echinocandin activity on Candida albicans isolates with strong clonal homology from a patient with advanced HIV infection and chronic oesophagitis progressively resistant to uninterrupted micafungin treatment.
Antifungal susceptibility profiles for different antifungal agents were determined against serial C. albicans isolates retrieved before and during therapy. Multilocus sequencing typing (MLST) was performed on each of the isolates. FKS1 mutations conferring reduced susceptibility to echinocandin drugs were determined by DNA sequence analysis.
Four C. albicans isolates showing identical allelic homology were retrieved from the patient at the initiation and during therapy with micafungin. The progressive lack of clinical response to micafungin therapy was associated with increased MICs of all three echinocandin drugs (caspofungin, micafungin and anidulafungin) in association with the acquisition of mutations in the FKS1 gene.
This report documents for the first time a progressive loss of activity of all three echinocandin drugs against clonally related C. albicans isolates following long-term clinical exposure to this new class of antifungal agents.
Full-text · Article · May 2006 · Journal of Antimicrobial Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: We studied HIV genetic diversity in a cohort of 127 pregnant, HIV-infected women who received prenatal care at Sainte-Justine Hospital in Montreal, Canada, between 1999 and 2003. Clade assignments were derived by phylogenetic analysis of amplified pol sequences. Genotyping was successful in 103 of 127 women, 59 (57.3%) of whom were infected with clade B HIV-1, and 44 (42.7%) with nonclade B viruses, including subtypes A, C, D, F, G, and H. Four sequences remained unassigned. Forty-three of 44 women infected with non-clade B viruses were newcomers from sub-Saharan Africa, and subtype identity was consistent with those circulating in their countries of origin. These results highlight the epidemiologic importance of non-B HIV-1 in antenatal populations in a large North American urban center, underscore the influence of population movements on clade intermixing, and identify a group of patients who could be targeted for surveillance and drug therapy followup.
[Show abstract][Hide abstract] ABSTRACT: Approximately two years after the introduction of highly active antiretroviral therapy for the treatment of HIV infection, body shape changes and metabolic abnormalities were increasingly observed. Initially, these were ascribed to protease inhibitors, but it is now clear that nucleoside reverse transcriptase inhibitors also contribute to lipodystrophy syndrome. The syndrome groups together clinical conditions describing changes in body fat distribution that include lipoatrophy, lipoaccumulation or both. However, there does not appear to be a direct link between lipoatrophy and lipoaccumulation that would support a single mechanism for the redistribution of body fat. Currently, there is no clear definition of lipodystrophy, which explains the difficulty in determining its prevalence and etiology. There are no current guidelines for the treatment of fat distribution abnormalities that occur in the absence of other metabolic complications. The present article reviews the current state of knowledge of the definition, symptoms, risk factors, pathogenesis, diagnosis and treatment of the morphological changes associated with lipodystrophy syndrome.
Full-text · Article · Aug 2005 · The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale / AMMI Canada