W G Powderly

University College Dublin, Dublin, L, Ireland

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Publications (223)1586.15 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: OBJECTIVE:: The objective of this study was to define the test characteristics of plasma beta-glucan for diagnosis of Pneumocystis jirovecii pneumonia (PCP) in AIDS patients with respiratory symptoms. DESIGN:: Analysis of baseline blood samples in a randomized strategy study of patients with acute opportunistic infections, limited to participants with respiratory symptoms. METHODS:: Participants in the 282-person ACTG A5164 trial had baseline plasma samples assayed for beta-glucan testing. As part of A5164 trial, two study investigators independently adjudicated the diagnosis of PCP. Respiratory symptoms were identified by investigators from a list of all signs and symptoms with an onset or resolution in the 21 days prior to or 14 days following study entry. Beta-glucan was defined as positive if at least 80 pg/ml and negative if less than 80 pg/ml. RESULTS:: Of 252 study participants with a beta-glucan result, 159 had at least one respiratory symptom, 139 of whom had a diagnosis of PCP. The sensitivity of beta-glucan for PCP in participants with respiratory symptoms was 92.8% [95% confidence interval (CI) 87.2-96.5], and specificity 75.0% (95% CI 50.9-91.3). Among 134 individuals with positive beta-glucan and respiratory symptoms, 129 had PCP, for a positive predictive value of 96.3% (95% CI 91.5-98.8). Fifteen of 25 patients with a normal beta-glucan did not have PCP, for a negative predictive value of 60% (95% CI 38.7-78.9). CONCLUSION:: Elevated plasma beta-glucan has a high predictive value for diagnosis of PCP in AIDS patients with respiratory symptoms. We propose an algorithm for the use of beta-glucan as a diagnostic tool on the basis of the pretest probability of PCP in such patients.
    AIDS (London, England) 03/2013; 27(6):967-972. · 4.91 Impact Factor
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    ABSTRACT: The success of antiretroviral therapy in HIV disease comes currently with the realization that patients are committed to life-long treatment, which raises the possibility of long-term toxicity. Such long-term side effects may not be identified in initial clinical trials requiring, therefore, a different approach to monitoring patients over time - a pharmacovigilance approach. Several key issues in long-term management of HIV infection have been addressed by a pharmacovigilance approach - including unusual and rare side effects and elucidation of emerging toxicities such as cardiovascular, bone and renal disease. Recent changes in legislation in the USA and Europe are aimed to strengthen pharmacovigilance in developed countries. HIV infection and its treatment provide an important example of the role of pharmacovigilance. As clinical trials can rarely address the question of long-term tolerability, effective pharmacovigilance programs are and will remain essential.
    Current opinion in HIV and AIDS 05/2012; 7(4):292-8. · 4.75 Impact Factor
  • William G Powderly
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    ABSTRACT: Patients with HIV can develop several complications that involve bone including low bone mineral density and osteoporosis, osteonecrosis, and rarely osteomalacia. Low bone mineral density leading to osteoporosis is the most common bone pathology. This may result from HIV infection (directly or indirectly), antiretroviral toxicity, or as a consequence of other co-morbidities. The clinical relevance of osteoporosis in HIV infection has been uncertain; however, fragility fractures are increasingly reported in HIV-infected patients. Further research is required to understand the pathogenesis of osteoporosis in HIV-infected patients and determine effective management; however, initiation of antiretroviral therapy seems to accelerate (in the short-term) bone demineralization. Tenofovir may be associated with a greater degree of short-term loss of bone density than other antiviral agents and the potential long-term bone dysfunction is unclear. As the HIV-infected population ages, screening for low bone mineral density will become increasingly important.
    Current HIV/AIDS Reports 05/2012; 9(3):218-22.
  • William G. Powderly
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    ABSTRACT: Cryptococcosis is a fungal infection that is potentially deadly for and common among AIDS patients, in the United States and worldwide. Subacute meningitis and meningoencephalitis are typical, clinically. This article will review relevant aspects of cryptococcal meningitis in AIDS, focusing on the most recent information pertaining to pathogenesis, epidemiology, clinical syndromes, and treatment of this devastating disease.
    Current Infectious Disease Reports 04/2012; 2(4):352-357.
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    ABSTRACT: HIV genetic diversity may have an impact on viral pathogenesis, transmission, response to treatment, and vaccine development. Public health surveillance that monitors the frequency and variety of HIV subtypes in a particular region or patient group is vital to successfully control the pandemic. We present the first comprehensive report on HIV diversity in Ireland. This study comprised all new HIV-1 diagnoses that were confirmed in the National Virus Reference Laboratory, University College Dublin, from January 2004 to December 2008. HIV 1 protease and reverse transcriptase sequences were generated using the Siemens Trugene HIV 1 Genotyping System. Subtypes were determined using web-based genotyping tools. There were 1579 new diagnoses [615 (39%) female and 964 (61%) male], of which 1060 had HIV-1 RNA specimens available for sequencing. Of sequenced samples, HIV-1 subtype B accounted for 50% overall, decreasing from 55.1% in 2004 to 49.5% in 2008. In addition, subtype B accounted for more than 80% of Irish-born individuals and more than 90% of Irish-born injection drug users and men who have sex with men. Subtype C was the second most prevalent in the overall cohort, accounting for 25%, although it accounted for only 6.1% of Irish-born individuals, with no evidence of in country transmission. The prevalence of non-subtype B HIV-1 infection in Ireland is increasing. However, these appear primarily to be imported infections not yet circulating within traditional Irish risk groups. Enhanced HIV-1 molecular epidemiology surveillance is required to monitor the spread of HIV-1, to inform future public health policy, and to ultimately control the HIV-1 epidemic in Ireland.
    AIDS research and human retroviruses 12/2011; 28(9):1073-81. · 2.18 Impact Factor
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    ABSTRACT: HIV-1-infected individuals with transmitted HIV drug resistance (TDR) begin antiretroviral therapy (ART) with a lower genetic barrier to resistance and a higher risk of both virological failure and of developing further resistance. TDR surveillance informs HIV-1 public health strategies and first line ART. TDR has not been studied nationally in an Irish population. This study includes all new HIV diagnoses from January 2004 to September 2008 from the National Virus Reference Laboratory, University College Dublin. HIV-1 protease and reverse transcriptase sequences were generated, and resistance mutations identified using the Siemens TRUGENE HIV-1 Genotyping System. Subtypes were determined using web-based genotyping tools. The study comprised 1579 patients. There were 305 new diagnoses in 2004 (173 male; 132 female), 298 in 2005 (175M; 123F), 321 in 2006 (197M; 124F), 297 in 2007 (184M; 113F), and 358 (235M; 123F) in 2008. HIV-1 RNA was sequenced from 158/305 patients in 2004, 199/298 in 2005, 225/321 in 2006, 203/297 in 2007, and 275/358 in 2008. The overall TDR rate was 6.3%, peaking in 2006 at 10.4% and declining to 5.3% in 2008. The majority of TDR was seen in Irish born individuals with HIV-1 subtype B infection. The TDR rate in Ireland is comparatively low. Thus, a health technology assessment is required to ascertain the most cost effective use of genotypic antiretroviral resistance testing (GART) in the future: the current approach of performing baseline GART on all new diagnoses, or perhaps a more targeted approach that focuses on patients commencing nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART.
    AIDS research and human retroviruses 07/2011; 28(3):276-81. · 2.18 Impact Factor
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    ABSTRACT: (See the editorial commentary by Morris and Masur, on pages 203-204.) Improved noninvasive diagnostic tests for Pneumocystis jirovecii pneumonia (PCP) are needed. We evaluated the test characteristics of plasma (1 → 3)-β-D-glucan (β-glucan) for HIV-related PCP among a large group of patients presenting with diverse opportunistic infections (OIs). The study population included all 282 participants in AIDS Clinical Trials Group A5164, a study of early versus deferred antiretroviral therapy in conjunction with initial therapy of acute OIs. Baseline plasma samples were assayed for β-glucan, with standard assay reference values defining ≥ 80 pg/mL as positive. Before this analysis, diagnosis of PCP was independently adjudicated by 2 study investigators after reviewing reports from study sites. A total of 252 persons had a β-glucan result that could be analyzed, 173 (69%) of whom had received a diagnosis of PCP. Median β-glucan with PCP was 408 pg/mL (interquartile range [IQR], 209-500 pg/mL), compared with 37 pg/mL (IQR, 31-235 pg/mL) without PCP (P < .001). The sensitivity of β-glucan dichotomized at 80 pg/mL for the diagnosis of PCP was 92% (95% confidence interval [CI], 87%-96%), and the specificity was 65% (95% CI, 53%-75%); positive and negative predictive values were 85% (95% CI, 79%-90%) and 80% (95% CI, 68%-89%) respectively, based on the study prevalence of 69% of patients with PCP. Rates of abnormal lactate dehyrogenase levels did not differ significantly between those with and without PCP. Blood (1 → 3)-β-D-glucan is strongly correlated with HIV-related PCP. In some clinical centers, this may be a more sensitive test than the induced sputum examination and could reduce the need for both bronchoscopy and empirical therapy of PCP.
    Clinical Infectious Diseases 07/2011; 53(2):197-202. · 9.37 Impact Factor
  • Aoife G Cotter, William G Powderly
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    ABSTRACT: Treatment with highly active antiretroviral therapy (HAART) has revolutionized care of patients with HIV infection. The cost of increased survival has been antiretroviral toxicity and increasing age-related co-morbidities that include significant metabolic issues. Hypogonadism was first described in the setting of advanced AIDS and can be primary or secondary. Data regarding treatment largely concern patients with wasting. Varied syndromes involving bone have been described in patients with HIV including osteonecrosis, low bone mineral density (BMD) and osteoporosis, and rarely osteomalacia. Low BMD leading to osteoporosis is the most common bone pathology and may be as a result of HIV infection, drug toxicity or co-morbidities. However, increasingly fragility fractures are reported in HIV-infected patients, suggesting bone demineralization in this population is of clinical relevance. Further research is required to understand its pathogenesis and determine effective management; however, initiation of antiretroviral therapy seems to accelerate (in the short-term) bone demineralization. One particular antiretroviral agent, tenofovir is widely used and is potentially implicated as having a greater role in long-term bone and renal dysfunction. As this population ages, screening for low BMD will become increasingly more important.
    Best practice & research. Clinical endocrinology & metabolism 06/2011; 25(3):501-15. · 3.89 Impact Factor
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    ABSTRACT: Unintentional loss of weight and muscle due to aging and disease has been associated with increased mortality. Wasting and weight loss occur in HIV infection even in the modern era of effective antiretroviral therapy. We determined the association of MRI-measured regional and total skeletal muscle and adipose tissue with 5-year, all-cause mortality in 922 HIV-infected persons in the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). After 5 years of follow-up, HIV-infected participants with arm skeletal muscle in the lowest tertile had a mortality rate of 23%, compared with 11 and 8% for those in the middle and highest tertiles. After multivariable adjustment for demographics, cardiovascular risk factors, HIV-related factors, inflammatory markers, and renal disease, we found that lower arm skeletal muscle, lower leg skeletal muscle and higher visceral adipose tissue (VAT) were each independently associated with increased mortality. Those in the lowest tertile of arm or leg skeletal muscle had higher odds of death [arm: odds ratio (OR) = 2.0, 95% confidence interval (CI) 0.96-4.0; leg: OR = 2.4, 95% CI 1.2-4.8] compared with the highest respective tertiles. Those in the highest tertile of VAT had 2.1-fold higher odds of death (95% CI 1.1-4.0) compared with the lowest VAT tertile. Lower muscle mass and central adiposity appear to be important risk factors for mortality in HIV-infected individuals. A substantial proportion of this risk may be unrecognized because of the current reliance on body mass index in clinical practice.
    AIDS (London, England) 05/2011; 25(11):1405-14. · 4.91 Impact Factor
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    ABSTRACT: Hepatitis B (HBV) vaccination is an important preventive intervention for HIV-infected population. Data regarding booster HBV vaccine for persons with low HBV surface antibody (sAb) titers after vaccination in this immunocompromised population is lacking. We randomized 60 HIV-infected subjects lacking HBV protection after completion of 3 doses of HBV vaccine to receive a booster dose of HBV vaccine with 250mcg GM-CSF as an adjuvant or booster vaccine alone. GM-CSF was safe with expected side effects. However, only 35% of persons receiving GM-CSF developed protective sAb while 50% in vaccine only arm developed protection (P = 0.47). Overall, only 28% of subjects maintained protective sAb 1 year after vaccination. GM-CSF failed to improve responses to the booster HBV vaccination. Overall, response was poor with only 42% of persons responding at one month post-vaccination confirming booster vaccination with the current HBV vaccine has poor immunogenicity among HIV-infected persons. Further research is needed to develop optimal vaccination strategies in HIV-infected persons.
    The Open Virology Journal 01/2011; 5:109-13.
  • William G Powderly
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    ABSTRACT: Agents active against HIV type 1 (HIV-1) that target the viral integrase by inhibiting the strand transfer step of integration have now entered the clinical arena. Raltegravir is the first in this new class. Clinical trials in treatment-experienced and in treatment-naive patients have shown that raltegravir-containing regimens have potent antiretroviral activity and are well tolerated. Drug resistance emerges relatively frequently in patients who fail therapy and is associated with mutations in the gene encoding the integrase enzyme. Although such mutations often confer cross-resistance to other integrase inhibitors, newer agents in development, such as S/GSK1349572, show promise as potential second-generation integrase inhibitors. Given their potency, safety and novel mechanism of action, integrase inhibitors represent an important advance in HIV-1 therapy.
    Journal of Antimicrobial Chemotherapy 12/2010; 65(12):2485-8. · 5.34 Impact Factor
  • Eoin J Cotter, Nicholas Chew, William G Powderly, Peter P Doran
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    ABSTRACT: An increased incidence of bone and lipid toxicities is associated with HIV-1 infection and its treatment. Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into both osteoblasts (OB) and adipocytes (AC). We hypothesize that the interaction of MSC and HIV-1 underlie these toxicities. Serum was collected from uninfected control and HIV-infected, antiviral-naive patients. Sera were divided into three groups: HIV-negative sera (n = 5), HIV-positive low viral load (LVL) (VL range 120; 4000, n = 5) or high viral load (HVL) (VL range 100,000; 500,000, n = 5). MSCs were exposed to these sera (5%) in an adipogenic/osteogenic condition and in nondifferentiating conditions in acute and chronic exposure models. Markers of adipogenesis/osteogenesis were examined in both MSCs induced to differentiated and nondifferentiating cells. Sera from HVL HIV-1-infected individuals induced a clear proadipogenic phenotype, as evidenced by an increase in adipocyte formation and the induction of increased expression of adipogenic markers including LPL and PPARγ. Both CD4 receptor blockade and treatment with the antiretroviral AZT attenuated these proadipogenic effects, suggesting that an infection event may underlie the observed phenomena. Finally, inhibition of COUP TF-1 by HIV-1 TAT was identified as a potential molecular mechanism for these effects. These results suggest that HIV-1 directly interacts with and may infect MSCs resulting in alterations of their differentiation potential, findings that significantly enhance our understanding of HIV-1-associated bone and fat toxicities.
    AIDS research and human retroviruses 10/2010; 27(2):187-99. · 2.18 Impact Factor
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    ABSTRACT: Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality. These guidelines for its management have been built on the previous Infectious Diseases Society of America guidelines from 2000 and include new sections. There is a discussion of the management of cryptococcal meningoencephalitis in 3 risk groups: (1) human immunodeficiency virus (HIV)-infected individuals, (2) organ transplant recipients, and (3) non-HIV-infected and nontransplant hosts. There are specific recommendations for other unique risk populations, such as children, pregnant women, persons in resource-limited environments, and those with Cryptococcus gattii infection. Recommendations for management also include other sites of infection, including strategies for pulmonary cryptococcosis. Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and cryptococcomas. Three key management principles have been articulated: (1) induction therapy for meningoencephalitis using fungicidal regimens, such as a polyene and flucytosine, followed by suppressive regimens using fluconazole; (2) importance of early recognition and treatment of increased intracranial pressure and/or IRIS; and (3) the use of lipid formulations of amphotericin B regimens in patients with renal impairment. Cryptococcosis remains a challenging management issue, with little new drug development or recent definitive studies. However, if the diagnosis is made early, if clinicians adhere to the basic principles of these guidelines, and if the underlying disease is controlled, then cryptococcosis can be managed successfully in the vast majority of patients.
    Clinical Infectious Diseases 02/2010; 50(3):291-322. · 9.37 Impact Factor
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    Judith Aberg, William Powderly
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    ABSTRACT: Opportunistic infections can occur in up to 40% of people with HIV infection and a CD4 count less than 250/mm(3), although the risks are much lower with use of highly active antiretroviral treatment. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of prophylaxis for Pneumocystis jirovecii pneumonia (PCP) and toxoplasmosis? What are the effects of antituberculosis prophylaxis in people with HIV infection? What are the effects of prophylaxis for disseminated Mycobacterium avium complex (MAC) disease for people with, and without, previous MAC disease? What are the effects of prophylaxis for cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella zoster virus (VZV)? What are the effects of prophylaxis for invasive fungal disease in people with, and without, previous fungal disease? What are the effects of discontinuing prophylaxis against opportunistic pathogens in people on highly active antiretroviral treatment (HAART)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 43 systematic reviews, RCTs, or observational studies that met our inclusion criteria. In this systematic review we present information relating to the effectiveness and safety of the following interventions: aciclovir; antituberculosis prophylaxis; atovaquone; azithromycin (alone or plus rifabutin); clarithromycin (alone, or plus rifabutin and ethambutol); discontinuing prophylaxis for CMV, MAC, and PCP; ethambutol added to clarithromycin; famciclovir; fluconazole; isoniazid; itraconazole; oral ganciclovir; rifabutin (alone or plus macrolides); trimethoprim-sulfamethoxazole; and valaciclovir.
    Clinical evidence 01/2010; 2010.
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    ABSTRACT: ACTG A5164 demonstrated that early antiretroviral therapy (ART) in HIV-infected patients with acute opportunistic infections (OIs) reduced death and AIDS progression compared to ART initiation 1 month later. We project the life expectancies, costs, and incremental cost-effectiveness ratios (ICERs) of these strategies. using an HIV simulation model, we compared 2 strategies for patients with acute OIs: (1) an intervention to deliver early ART, and (2) deferred ART. Parameters from ACTG A5164 included initial mean CD4 count (47/microL), linkage to outpatient care (87%), and immune reconstitution inflammatory syndrome 1 month after ART initiation (7%). The estimated intervention cost was $1,650/patient. early ART lowered projected 1-year mortality from 10.4% to 8.2% and increased life expectancy from 10.07 to 10.39 quality-adjusted life-years (QALYs). Lifetime costs increased from $385,220 with deferred ART to $397,500 with early ART, primarily because life expectancy increased, producing an ICER of $38,600/QALY. Results were most sensitive to increased intervention cost and decreased virologic efficacy in the early ART strategy. an intervention to initiate ART early in patients with acute OIs improves survival and meets US cost-effectiveness thresholds. Programs should be developed to implement this strategy at sites where HIV-infected patients present with OIs.
    HIV Clinical Trials 01/2010; 11(5):248-59. · 2.30 Impact Factor
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    ABSTRACT: Immune reconstitution inflammatory syndrome (IRIS) is reported widely in patients initiating antiretroviral therapy (ART). However, few studies are prospective, and no study has evaluated the impact of the timing of ART when allocated randomly during an acute opportunistic infection (OI). A5164 randomized 282 subjects with AIDS-related OIs (tuberculosis excluded), to early or deferred ART. IRIS was identified prospectively using pre-defined criteria. We evaluated associations between IRIS and baseline variables in subjects with follow-up on ART using Wilcoxon and Fisher's exact tests, logistic regression, and Cox models with time-varying covariates. Twenty of 262 (7.6%) subjects developed IRIS after a median of 33 days on ART. Subjects with fungal infections (other than pneumocystis) developed IRIS somewhat more frequently (OR = 2.7; 95% CI: 1.02, 7.2; p-value = 0.06 (using Fisher's exact test)). In Cox models, lower baseline and higher on-treatment CD4+ T-cell counts and percentage were associated with IRIS. Additionally, higher baseline and lower on-treatment HIV RNA levels were associated with IRIS. Corticosteroids during OI management and the timing of ART were not associated with the development of IRIS. In patients with advanced immunosuppression and non-tuberculous OIs, the presence of a fungal infection, lower CD4+ T-cell counts and higher HIV RNA levels at baseline, and higher CD4+ T-cell counts and lower HIV RNA levels on treatment are associated with IRIS. Early initiation of ART does not increase the incidence of IRIS, and concern about IRIS should not prompt deferral of ART. ClinicalTrials.gov NCT00055120.
    PLoS ONE 01/2010; 5(7):e11416. · 3.73 Impact Factor
  • E J Cotter, P P Doran, W G Powderly
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    ABSTRACT: HIV-1 exerts its most profound effects through destruction of the host's immune responses specifically through targeting of the T-lymphocyte populations. In addition to its primary immune target, HIV-1 also targets cells of the nervous, skeletal and vascular system. There is emerging evidence to suggest that HIV-1 may, in part at least, affect these diverse tissues by impairing the homeostatic production of terminally differentiated cells from stem and progenitor cell populations. The interaction between HIV-1 and stem cell populations may serve to underpin the diverse non-immunological effects of HIV-1. This review deals with the effect of HIV-1 infection on a number of progenitor cell types, with emphasis on delineating mechanisms of HIV's destructive effect on the body. Modification of these effects may represent novel avenues for exploration in our search for clinical interventions.
    Current HIV research 10/2009; 7(5):508-18. · 1.98 Impact Factor
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    ABSTRACT: The metabolic effects of initial therapy for HIV-1 infection are important determinants of regimen selection. Open-label study in 753 subjects randomized equally to efavirenz or lopinavir/ritonavir(r) plus two nucleoside reverse-transcriptase inhibitor (NRTI) vs. the NRTI-sparing regimen of lopinavir/r plus efavirenz. Zidovudine, stavudine, or tenofovir with lamivudine was selected prior to randomization. Metabolic outcomes through 96 weeks were lipoatrophy, defined as at least 20% loss in extremity fat, and fasting serum lipids. Lipoatrophy by dual-energy X-ray absorptiometry at week 96 occurred in 32% [95% confidence interval (CI) 25-39%] of subjects in the efavirenz plus two NRTIs arm, 17% (95% CI 12-24) in the lopinavir/r plus two NRTIs arm, and 9% (95% CI 5-14) in the NRTI-sparing arm (P < or = 0.023 for all comparisons). Varying the definition of lipoatrophy (> or =10 to > or =40% fat loss) and correction for baseline risk factors did not affect the significant difference in lipoatrophy between the NRTI-containing regimens. Lipoatrophy was most frequent with stavudine-containing regimens and least frequent with tenofovir-containing regimens (P < 0.001), which were not significantly different from the NRTI-sparing regimen. Total cholesterol increases at week 96 were greatest in the NRTI-sparing arm (median +57 mg/dl) compared with the other two arms (+32-33 mg/dl; P < 0.001). Use of lipid-lowering agents was more common (25 vs. 11-13%) in the NRTI-sparing arm. Lipoatrophy was more frequent with efavirenz than lopinavir/r when combined with stavudine or zidovudine, and less frequent when either drug was combined with tenofovir. Lipoatrophy was least frequent with the NRTI-sparing regimen, but this benefit was offset by greater cholesterol elevations and the need for lipid-lowering agents.
    AIDS (London, England) 06/2009; 23(9):1109-18. · 4.91 Impact Factor
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    ABSTRACT: To examine risk factors for sub-optimal CD4 recovery on suppressive highly active antiretroviral therapy (HAART) and assess long-term clinical and immunological outcomes. Retrospective analysis of 286 HIV-positive patients from a university clinic who initiated HAART with CD4 count <350 cells/microL between January 1996 and July 2006 and achieved > or =52 weeks of viral suppression (VS). Sub-optimal and optimal CD4 count recovery were defined by gains of <150 and > or =150 cells/microL during the first year of VS, respectively. Risk factors were analysed by multivariate logistic regression and markers of immune maturation and activation were evaluated prospectively for a sub-group of patients with prolonged (>5 years) VS. One hundred and two (36%) patients had sub-optimal CD4 recovery. Male gender, lower pre-HAART viral load, HAART toxicity and use of opportunistic infection (OI) prophylaxis were independent risk factors on multivariate analysis (P<0.05). Outcomes of duration of VS on HAART (4 years), new OI events (1%) and mortality (5%) were similar between groups. Markers of immune maturation and activation were higher among patients with sub-optimal CD4 recovery (P<0.05). Among HIV-positive patients with long-term VS, sub-optimal CD4 recovery was common but morbidity and mortality remained low. In addition, persistent CD4 T-cell activation appeared to blunt long-term CD4 gains.
    HIV Medicine 06/2009; 10(7):439-46. · 3.16 Impact Factor
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    ABSTRACT: Optimal timing of ART initiation for individuals presenting with AIDS-related OIs has not been defined. A5164 was a randomized strategy trial of "early ART"--given within 14 days of starting acute OI treatment versus "deferred ART"--given after acute OI treatment is completed. Randomization was stratified by presenting OI and entry CD4 count. The primary week 48 endpoint was 3-level ordered categorical variable: 1. Death/AIDS progression; 2. No progression with incomplete viral suppression (ie HIV viral load (VL) >or=50 copies/ml); 3. No progression with optimal viral suppression (ie HIV VL <50 copies/ml). Secondary endpoints included: AIDS progression/death; plasma HIV RNA and CD4 responses and safety parameters including IRIS. 282 subjects were evaluable; 141 per arm. Entry OIs included Pneumocytis jirovecii pneumonia 63%, cryptococcal meningitis 12%, and bacterial infections 12%. The early and deferred arms started ART a median of 12 and 45 days after start of OI treatment, respectively. THE DIFFERENCE IN THE PRIMARY ENDPOINT DID NOT REACH STATISTICAL SIGNIFICANCE: AIDS progression/death was seen in 20 (14%) vs. 34 (24%); whereas no progression but with incomplete viral suppression was seen in 54 (38%) vs. 44 (31%); and no progression with optimal viral suppression in 67 (48%) vs 63 (45%) in the early vs. deferred arm, respectively (p = 0.22). However, the early ART arm had fewer AIDS progression/deaths (OR = 0.51; 95% CI = 0.27-0.94) and a longer time to AIDS progression/death (stratified HR = 0.53; 95% CI = 0.30-0.92). The early ART had shorter time to achieving a CD4 count above 50 cells/mL (p<0.001) and no increase in adverse events. Early ART resulted in less AIDS progression/death with no increase in adverse events or loss of virologic response compared to deferred ART. These results support the early initiation of ART in patients presenting with acute AIDS-related OIs, absent major contraindications. ClinicalTrials.gov NCT00055120.
    PLoS ONE 02/2009; 4(5):e5575. · 3.73 Impact Factor

Publication Stats

8k Citations
1,586.15 Total Impact Points

Institutions

  • 2006–2012
    • University College Dublin
      • • School of Medicine & Medical Science
      • • Clinical Research Centre
      Dublin, L, Ireland
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
  • 1988–2012
    • University of Washington Seattle
      • • Division of Allergy and Infectious Diseases
      • • Department of Medicine
      • • Division of General Internal Medicine
      Seattle, WA, United States
  • 2007–2008
    • Mater Misericordiae University Hospital
      Dublin, Leinster, Ireland
  • 1988–2008
    • Washington University in St. Louis
      • Department of Medicine
      San Luis, Missouri, United States
  • 2005
    • The University of Edinburgh
      Edinburgh, Scotland, United Kingdom
  • 2003
    • St. Vincent's Hospital Sydney
      Sydney, New South Wales, Australia
  • 1994–2003
    • University of Alabama at Birmingham
      • • Division of Infectious Diseases
      • • Department of Pathology
      Birmingham, Alabama, United States
  • 2000
    • Hospital Universitario La Paz
      • Servicio de Medicina Interna
      Madrid, Madrid, Spain
  • 1999
    • University of Cincinnati
      • Division of Infectious Diseases
      Cincinnati, OH, United States
    • University of California, San Francisco
      • Division of Hospital Medicine
      San Francisco, California, United States
  • 1997
    • Albert Einstein College of Medicine
      New York City, New York, United States
  • 1995–1997
    • Indiana University-Purdue University Indianapolis
      • Department of Medicine
      Indianapolis, Indiana, United States
    • University of Miami Miller School of Medicine
      • Division of Hospital Medicine
      Miami, FL, United States
    • Centers for Disease Control and Prevention
      • National Center for Emerging and Zoonotic Infectious Diseases
      Druid Hills, GA, United States