Article

The case for expanding access to highly active antiretroviral therapy to curb the growth of the HIV epidemic

British Columbia Centre for Excellence in HIV/AIDS, Providence Health Care, University of British Columbia, Vancouver, Canada.
The Lancet (Impact Factor: 39.21). 09/2006; 368(9534):531-6. DOI: 10.1016/S0140-6736(06)69162-9
Source: PubMed
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    ABSTRACT: Realizing the full individual and population-wide benefits of antiretroviral therapy for human immunodeficiency virus (HIV) infection requires an efficient mechanism of HIV-related health service delivery. We developed a system dynamics model of the continuum of HIV care in Vancouver, Canada, which reflects key activities and decisions in the delivery of antiretroviral therapy, including HIV testing, linkage to care, and long-term retention in care and treatment. To measure the influence of operational interventions on population health outcomes, we incorporated an HIV transmission component into the model. We determined optimal resource allocations among targeted and routine testing programs to minimize new HIV infections over five years in Vancouver. Simulation scenarios assumed various constraints informed by the local health policy. The project was conducted in close collaboration with the local health care providers, Vancouver Coastal Health Authority and Providence Health Care.
    Health Care Management Science 01/2015; DOI:10.1007/s10729-014-9312-0 · 1.05 Impact Factor
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    ABSTRACT: Sequencing human immunodeficiency virus type 1 (HIV-1) for drug resistance mutations and viral tropism is crucial to the current HIV/AIDS personalized treatment approach. This thesis addresses particular areas where clinical utility data is lacking: First, current methods were validated as clinically useful with plasma viral RNA primarily from patients infected with subtype B HIV-1, the dominant strain in developed countries; however, globally most patients are infected with non-subtype B variants. Secondly, there is insufficient data available with respect to the newest classes of antiretroviral drugs (i.e. CCR5-antagonist and integrase inhibitors). Finally, modern antiretroviral therapies often lead to “undetectable plasma viremia” (i.e. successful ongoing treatment) which make plasma-based genotypic testing impossible; the utility of examining alternative sample types is being actively explored. The overall objective of this thesis is to evaluate genotypic assessment of HIV-1 using standard and “second generation” DNA sequencing methods for guiding clinical decisions in nonconventional sample types. Specifically, it is hypothesized that genotypic assessment of subtype A, C and D HIV-1, plasma viral RNA collected pre-therapy, and viral DNA archived in blood cells are useful predictors of in vitro phenotype and/or clinical outcomes. Chapter 1 and 2 examine the clinical utility of current genotyping approaches when applied to non-subtype-B HIV-1. Results suggest that (1) transmitted genotypic drug resistance predicted small but negative treatment outcomes in non-B infections, and (2) current genotypic tools for predicting viral tropism had poor sensitivities and/or specificities in subtypes A and D, but not C HIV-1. Chapter 3 and 4 examine the clinical utility of current genotypic approaches coupled with alternative sample types. Results suggest that (3) pre-therapy plasma sample tropism results predicted post-therapy post-suppression tropism in 90% of subjects, and (4) viral DNA archived in blood and plasma RNA had similar integrase inhibitor-associated mutations, but mutations in DNA were detected substantially later and were substantially less prevalent. In conclusion, genotypic assessment of HIV-1 using nonconventional sample types is clinically relevant, but has specific limitations. Further methodological research and clinical validation studies are needed to ensure proper interpretation of results.
    01/2015, Degree: PhD, Supervisor: Dr. Richard Harrigan
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    ABSTRACT: This randomised, open label, phase I, immunotherapeutic study investigated the effects of interleukin (IL)-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), recombinant human growth hormone (rhGH), and therapeutic immunisation (a Clade B DNA vaccine) on combination antiretroviral therapy (cART)-treated HIV-1-infected individuals, with the objective to reverse residual T-cell dysfunction.Methods Twelve HIV-1+ patients on suppressive cART with baseline CD4 T-cell counts >400 cells/mm3 blood were randomised into one of three groups: (1) vaccine, IL-2, GM-CSF and rhGH (n = 3); (2) vaccine alone (n = 4); or (3) IL-2, GM-CSF and rhGH (n = 5). Samples were collected at weeks 0, 1, 2, 4, 6, 8, 12, 16, 24 and 48. Interferon (IFN)-γ, IL-2, IL-4 and perforin ELISpot assays performed at each time point quantified functional responses to Gag p17/p24, Nef, Rev, and Tat peptides; and detailed T-cell immunophenotyping was undertaken by flow cytometry. Proviral DNA was also measured.ResultsMedian baseline CD4 T-cell count was 757 cells/mm3 (interquartile range [IQR] 567–886 cells/mm3), median age 48 years (IQR 42–51 years), and plasma HIV-1-RNA <50 copies/ml for all subjects. Patients who received vaccine plus IL-2, GM-CSF and rhGH (group 1) showed the most marked changes. Assessing mean changes from baseline to week 48 revealed significantly elevated numbers of CD4 T cells (p = 0.0083) and improved CD4/CD8 T-cell ratios (p = 0.0033). This was accompanied by a significant reduction in expression of CD38 on CD4 T cells (p = 0.0194), significantly increased IFN-γ and IL-2 production in response to Gag (p = 0.0122) and elevated IFN-γ production in response to Tat (p = 0.041) at week 48 compared to baseline. Subjects in all treatment groups showed significantly reduced PD-1 expression at week 48 compared to baseline, with some reductions in proviral DNA.Conclusions Multifarious immunotherapeutic approaches in the context of fully suppressive cART further reduce immune activation, and improve both CD4 T-lymphocyte counts and HIV-1-specific T-cell responses (NCT01130376).
    Vaccine 10/2014; DOI:10.1016/j.vaccine.2014.09.072 · 3.49 Impact Factor

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