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Biomedical subjects

S Swindells

Publications and source records attributed to S Swindells.

At least 19 recordsLinked to original sources
PubMed2007

Lopinavir/ritonavir reduces bupropion plasma concentrations in healthy subjects.

Limited data are available about the effect of steady-state lopinavir and ritonavir (LPV/r) on bupropion pharmacokinetics. As patients may benefit by using these two agents in combination, this study determined the extent and direction of this drug-drug interaction. Twelve healthy volunteers received a single 100 mg dose of sustained-release bupropion before and after 2 weeks of treatment with LPV/r 400 mg/100 mg twice daily. Pharmacokinetics profiles were determined on days 1 and 30 for bupropion and hydroxybupropion and days 29 and 30 for LPV/r. LPV/r administration significantly decreased bupropion maximum plasma concentration (C(max)) by 57% (90% confidence interval (CI), 38-76%; P<0.01) and area under the curve (AUC) infinity by 57% (90% CI, 32-83%; P<0.01). Hydroxybupropion C(max) and AUC infinity decreased by 31% (90% CI, 7-55%; P<0.01) and by 50% (90% CI, 34-65%; P<0.01), respectively. No significant changes in the pharmacokinetics of LPV/r were found following administration of a single dose of bupropion. Concurrent use of LPV/r and bupropion resulted in decreased exposure to bupropion and its active metabolite hydroxybupropion that may necessitate as much as a 100% dose increase of bupropion. A probable mechanism for this interaction is the concurrent induction of cytochrome P450 2B6 and UDP-glucuronosyltransferase enzymes. LPV/r exposure is unaffected by a single dose of bupropion.

Adult↗
PubMed2006

Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy.

Changes in fat distribution, dyslipidemia, disordered glucose metabolism, and lactic acidosis have emerged as significant challenges to the treatment of human immunodeficiency virus (HIV) infection. Over the past decade, numerous investigations have been conducted to better define these conditions, identify risk factors associated with their development, and test potential therapeutic interventions. The lack of standardized diagnostic criteria, as well as disparate study populations and research methods, have led to conflicting data regarding the diagnosis and treatment of metabolic and body shape disorders associated with HIV infection. On the basis of a review of the medical literature published and/or data presented before April 2006, we have prepared a guide to assist the clinician in the detection and management of these complications.

Dyslipidemias↗
PubMed2001

The regulation of alpha chemokines during HIV-1 infection and leukocyte activation: relevance for HIV-1-associated dementia.

Cellular immunity against human immunodeficiency virus type 1 (HIV-1)-infected brain macrophages serves to prevent productive viral replication in the nervous system. Inevitably, during advanced disease, this antiretroviral response breaks down. This could occur through virus-induced dysregulation of lymphocyte trafficking. Thus, we studied the production of non-ELR-containing alpha-chemokines and their receptor (CXCR3) expression in relevant virus target cells. Macrophages, lymphocytes, and astrocytes secreted alpha-chemokines after HIV-1 infection and/or immune activation. Lymphocyte CXCR3-mediated chemotactic responses were operative. In all, alpha-chemokine-mediated T cell migration continued after HIV-1 infection and the neuroinflammatory events operative during productive viral replication in brain.

AIDS Dementia Complex↗
PubMed2001

Plasma levels of soluble CD14 and tumor necrosis factor-alpha type II receptor correlate with cognitive dysfunction during human immunodeficiency virus type 1 infection.

The relationship between monocyte immune responses and cognitive impairment during progressive human immunodeficiency virus type 1 (HIV-1) infection was investigated in 28 subjects receiving highly active antiretroviral therapy. The mean+/-SEM CD4(+) T lymphocyte count and virus load for all patients were 237+/-41 cells/mm(3) and 77,091+/-195,372 HIV-1 RNA copies/mL, respectively. Levels of soluble tumor necrosis factor-alpha type II receptor (sTNF-RII) and soluble CD14 (sCD14) were measured in plasma by ELISA and were correlated with results from neuropsychological, magnetic resonance imaging, and magnetic resonance spectroscopy tests. Plasma sCD14 and sTNF-RII levels were elevated in subjects with cognitive impairment and in those with brain atrophy. Furthermore, both factors were correlated with spectroscopic choline:creatine ratios. These findings support the idea that peripheral immune responses are linked to cognitive dysfunction during advanced HIV-1 disease.

Adult↗
PubMed2001

Dyslipidaemia in HIV-infected patients: association with adherence to potent antiretroviral therapy.

Metabolic complications are being increasingly recognized among HIV-infected patients treated with potent combination antiretroviral therapies. We sought to assess the association of dyslipidaemia with adherence to protease inhibitor (PI) therapy and with the markers of clinical response to antiretroviral therapy (CD4 count, HIV RNA viral level) through a prospective, cross-sectional cohort study. Fifty-six HIV-infected patients who were already on, or who were started on PI-containing antiretroviral therapy were monitored for the development of dyslipidaemias. Therapy with PI-containing antiretroviral therapy was significantly associated with elevated serum triglyceride level (>250 mg/dl) (52% vs 8%, P=0.001). Patients with an adherence rate of at least 80% to a PI-containing regimen were significantly more likely to have elevated low density lipoprotein (LDL) cholesterol level as compared to patients with an adherence rate of <80% (79% vs 26%, P=0.03). Patients with an adherence rate of at least 80% to a PI-containing regimen were also significantly more likely to have severe hypertriglyceridaemia (>800 mg/dl) as compared to patients with an adherence rate of <80% (21% vs 4%, P=0.04). Viral load at the last study visit did not correlate with total cholesterol (r=-0.39, P=0.30), LDL cholesterol (r=0.57, P=0.30), or triglyceride level (r=0.55, P=0.20). However, there was a significant correlation between the last viral load and high density lipoprotein (HDL) cholesterol (r=0.79, P=0.035), i.e. lower viral load was associated with higher HDL cholesterol level. In conclusion, dyslipidaemia in patients with HIV infection was significantly associated with adherence to PI-containing antiretroviral therapy. Patients who are adherent to PI-containing regimens at least 80% of the time warrant close monitoring for the development of dyslipidaemia.

Adult↗
PubMed2000

A comparison of stavudine, didanosine and indinavir with zidovudine, lamivudine and indinavir for the initial treatment of HIV-1 infected individuals: selection of thymidine analog regimen therapy (START II).

OBJECTIVE: Comparison of stavudine (d4T), didanosine (ddI) and indinavir (IDV) with zidovudine (ZDV), lamivudine (3TC) and IDV in HIV-1 infected patients. DESIGN: Randomized, open-label. SETTING: Fourteen HIV Clinical Research Centers. PATIENTS: Two-hundred and five patients with less than 4 weeks antiretroviral treatment, naive to 3TC and protease inhibitors and with CD4 cell counts > or = 200 x 10(6)/l and plasma HIV-1 RNA levels > or = 10,000 copies/ml. INTERVENTIONS: Stavudine 40 mg and ddI 200 mg twice daily plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h or 300 mg twice daily, 3TC 150 mg twice daily plus IDV. MAIN OUTCOME MEASURES: The proportion of patients with plasma HIV-1 RNA levels < 500 copies/ml and < or = 50 copies/ml and changes in CD4 cell counts were compared. RESULTS: In an analysis of the primary endpoint, 61% of patients on d4T + ddI + IDV and 45% of patients on ZDV + 3TC + IDV had all HIV-1 RNA values obtained between weeks 40 and 48 < 500 copies/ml [95% confidence interval (CI) for the difference between proportions, 1.7-30.3%; P = 0.038]. In an intent-to-treat analysis, the percentage of all patients randomized with all HIV-1 RNA levels < 500 copies/ml between 40 and 48 weeks were 53% for the d4T + ddI + IDV arm and 41% for the ZDV + 3TC + IDV arm (95% CI, -1.4% to 25.7%; P = 0.068). At 48 weeks 41% and 35% were < or = 50 copies/ml for the stavudine- and ZDV-containing arms respectively (P > 0.2). The median time-weighted average increases in CD4 cells count over 48 weeks were 150 x 10(6)/l cells for the d4T arm and 106 x 10(6)/l cells for the ZDV arm (P= 0.001). The occurrence of serious adverse events was not significantly different between arms. CONCLUSION: The combination of stavudine, ddl and IDV resulted in potent antiretroviral effects over a 48-week period, comparable or superior to zidovudine, 3TC and IDV supporting the use of stavudine, ddI and a protease inhibitor as an initial antiretroviral treatment.

Adolescent↗
PubMed2000

Adherence to protease inhibitor therapy and outcomes in patients with HIV infection.

BACKGROUND: Combination antiretroviral therapy with protease inhibitors has transformed HIV infection from a terminal condition into one that is manageable. However, the complexity of regimens makes adherence to therapy difficult. OBJECTIVE: To assess the effects of different levels of adherence to therapy on virologic, immunologic, and clinical outcome; to determine modifiable conditions associated with suboptimal adherence; and to determine how well clinicians predict patient adherence. DESIGN: Prospective, observational study. SETTING: HIV clinics in a Veterans Affairs medical center and a university medical center. PATIENTS: 99 HIV-infected patients who were prescribed a protease inhibitor and who neither used a medication organizer nor received their medications in an observed setting (such as a jail or nursing home). MEASUREMENTS: Adherence was measured by using a microelectronic monitoring system. The adherence rate was calculated as the number of doses taken divided by the number prescribed. Patients were followed for a median of 6 months (range, 3 to 15 months). RESULTS: During the study period, 45,397 doses of protease inhibitor were monitored in 81 evaluable patients. Adherence was significantly associated with successful virologic outcome (P < 0.001) and increase in CD4 lymphocyte count (P = 0.006). Virologic failure was documented in 22% of patients with adherence of 95% or greater, 61% of those with 80% to 94.9% adherence, and 80% of those with less than 80% adherence. Patients with adherence of 95% or greater had fewer days in the hospital (2.6 days per 1000 days of follow-up) than those with less than 95% adherence (12.9 days per 1000 days of follow-up; P = 0.001). No opportunistic infections or deaths occurred in patients with 95% or greater adherence. Active psychiatric illness was an independent risk factor for adherence less than 95% (P = 0.04). Physicians predicted adherence incorrectly for 41% of patients, and clinic nurses predicted it incorrectly for 30% of patients. CONCLUSIONS: Adherence to protease inhibitor therapy of 95% or greater optimized virologic outcome for patients with HIV infection. Diagnosis and treatment of psychiatric illness should be further investigated as a means to improve adherence to therapy.

Adult↗
PubMed1999

Joint effects of HIV-1 RNA levels and CD4 lymphocyte cells on the risk of specific opportunistic infections.

OBJECTIVES: To evaluate the predictive value of baseline plasma HIV-1 RNA levels and CD4 lymphocyte counts and early changes in these markers after initiating antiretroviral therapy on the risk of development of specific opportunistic infections (OIs). DESIGN: Patient data from four antiretroviral therapy studies were combined for a retrospective analysis. The analysis included 842 participants from the virology substudies of these trials who had baseline measurements for both HIV-1 RNA levels and CD4 cell counts. METHODS: Cox proportional hazards models were used to assess the joint effects of baseline CD4 cell count and HIV-1 RNA level and early treatment-associated changes in these values on the risk of development of Pneumocystis carinii pneumonia (PCP), cytomegalovirus (CMV), or Mycobacterium avium complex (MAC). The effects of potential confounders such as prior prophylaxis and previous OIs were also addressed. RESULTS: Baseline CD4 cell counts and HIV-1 RNA measurements showed significant associations with the risk of PCP, CMV, and MAC. Patients with higher levels of HIV-1 RNA were estimated to have three to six times the risk of these OIs than those with lower levels. Reductions in viral load were linked to significantly reduced risks of PCP, CMV, and MAC. Early decreases in RNA were generally more predictive of risk than were early increases in CD4 cell counts. CONCLUSIONS: Baseline viral load and reductions in viral load during therapy appeared to influence the risk of these OIs independently of the CD4 cell count. Future guidelines for the initiation of prophylaxis for these OIs may be improved by incorporating information on viral load.

AIDS-Related Opportunistic Infections↗
PubMed1999

Adherence of human immunodeficiency virus-infected patients to antiretroviral therapy.

The impact of demographic, psychosocial, and medical regimen-related variables on adherence of 123 human immunodeficiency virus (HIV)-infected patients to antiretroviral therapy was assessed by means of refill methodology. Satisfaction with social support (P = .029), problem-focused coping (P = .027), and active-behavioral coping (P = .011) correlated significantly with adherence, whereas loss of motivation (P = .006), hopelessness (P = .16), and avoidant coping (p = .015) correlated with nonadherence. At the 6-month follow-up, the mean CD4 cell count differed significantly among adherent versus nonadherent patients (a mean increase of 78/mm3 vs. a mean decrease of 5/mm3; P = .018). Adherence did not correlate with the number of antiretroviral medications consumed per day (mean, 3.0 vs. 2.5). Non-Caucasian patients were more likely to be nonadherent than Caucasian patients (relative risk, 2.5; 95% confidence interval, 1.2-5.3; P = .013); this difference was not explained by age, education, employment, income, history of intravenous drug use, or medical regimen. Non-Caucasian patients, however, were less satisfied with their social support (P = .04) and informational support (P = .016) and were more likely to utilize emotion-focused coping (P = .01). Thus, satisfaction with social support and coping style significantly impacted adherence and likely accounted for the observed racial difference in adherence among HIV-infected patients.

Adaptation, Psychological↗
PubMed1999

HIV-associated dementia: new insights into disease pathogenesis and therapeutic interventions.

Remarkable progress was made in recent years in the therapeutics of HIV-1-associated dementia (HAD) and in unraveling the complex pathophysiology that follows viral invasion of the central nervous system (CNS). Viral replication in and outside of the CNS was significantly reduced in HIV-1 infected subjects by new potent antiretroviral therapies. This has resulted in partial repair of cellular immune function with improvement in, and the prevention of, neurologic deficits associated with progressive HIV-1 disease. In regard to HAD pathophysiology, it is now known that CNS damage induced by HIV-1 infection occurs indirectly. Neuronal loss is mediated through immune activation and viral infection of mononuclear phagocytes (MPs) (brain macrophages and microglia). Cellular and viral factors secreted by brain MPs produce, over time, neuronal damage and drop out. Viral growth in the brain appears necessary, but not sufficient, to produce cognitive and motor impairments in affected individuals. Indeed, the best predictor for neurologic impairment following HIV-1 infection is the absolute number of immune-competent macrophages; not the level of viral production in affected brain tissue. As yet, an understanding of macrophage-related neurodegeneration has not translated into significant improvements in the treatment of this devastating complication of HIV disease. Nonetheless, adjunctive antiinflammatory and neuroprotective therapies are being developed. New ideas regarding HAD neuropathogenesis, and implications for the diagnosis and treatment of HAD are summarized in this article.

AIDS Dementia Complex↗
PubMed1999

Quality of life in patients with human immunodeficiency virus infection: impact of social support, coping style and hopelessness.

We aimed to determine whether the quality of life (QOL) in the patients infected with human immunodeficiency virus (HIV) infection was influenced by satisfaction with social support, coping style and hopelessness. One hundred and thirty-eight HIV-infected patients were prospectively studied in this multicentre, longitudinal study. The QOL was assessed by Medical Outcome Study Health Survey SF-36, social support by Sarason Social Support Questionnaire, hopelessness by Beck Hopelessness Scale, and coping by Billing and Moos Inventory of coping with illness. The QOL did not correlate with age, sex, race, HIV risk factor, education or marital status. Employment (P = 0.0001), higher income (P = 0.03), satisfaction with social support (P = 0.04), regardless of the source of that support, and problem-focused coping (P = 0.03) were associated with a significantly better QOL, while, emotion-focused coping (r = -0.19, P = 0.04), avoidant coping (r = 0.40, P = 0.0001), hopelessness (r = -0.64, P = 0.0001) and AIDS (P = 0.09) were predictors of poorer QOL. Physical functioning correlated positively with employment (P = 0.0001), and inversely with AIDS (P = 0.0002), hopelessness (P = 0.03), avoidant coping (P = 0.03), and age (P = 0.10). At 6 months follow up, QOL score had changed in 20% of the patients; older age (P = 0.01), and lesser satisfaction with social support (P = 0.15) were associated with a decline in QOL, while adherence with antiretroviral therapy (P = 0.006) was associated with an increase in QOL score. Seven of 138 patients died during follow up; these patients had significantly lower QOL at baseline than all other patients (P = 0.003). Interventions to alleviate hopelessness, maladaptive coping, and enhancement of satisfaction with social support may improve overall QOL in HIV-infected patients. Older patients with HIV were less satisfied with their social support, were more likely to utilize unhealthy coping styles, and experienced a greater decline in QOL over time.

Adult↗
PubMed1998

Suppression of inflammatory neurotoxins by highly active antiretroviral therapy in human immunodeficiency virus-associated dementia.

A human immunodeficiency virus type 1 (HIV)-seropositive, antiretroviral-naive patient presented with significant cognitive dysfunction. Neuropsychologic, neuroradiologic, immunologic, and virologic studies confirmed HIV-associated dementia (HAD). After 12 weeks of highly active antiretroviral therapy (HAART) with ibuprofen, dramatic improvements were demonstrated in neurologic function and were sustained for > 1 year. HIV-1 RNA in cerebrospinal fluid (CSF) decreased from 10(5) to 10(4) copies/mL after 4 weeks. After 20 weeks of therapy, plasma viremia decreased from 10(6) copies/mL to undetectable (< 96 copies/mL). Assays of neurotoxins (tumor necrosis factor-alpha, quinolinic acid, and nitric oxide) in plasma and CSF were considerably elevated at presentation and significantly decreased after therapy. Baseline plasma and CSF demonstrated neurotoxic activities in vitro, which also reduced markedly. These data, taken together, support the notion that HAD is a reversible metabolic encephalopathy fueled by viral replication. HAART used with nonsteroidal antiinflammatory agents leads to the suppression of inflammatory neurotoxins and can markedly improve neurologic function in HAD.

AIDS Dementia Complex↗
PubMed1997

Characterization of thyroglobulin-directed and polyreactive catalytic antibodies in autoimmune disease.

Polyreactive and thyroglobulin (Tg)-directed proteolytic activities present in the serum IgG of healthy controls and patients with autoimmune disease were studied by electrophoretic separation of 125I-labeled Tg reaction products and spectrofluorometric measurement of Pro-Phe-Arg-methylcoumarinamide cleavage at the Arg-methylcoumarinamide bond. A decrease of the polyreactive proteolytic activity accompanying an increase of the Tg-cleaving activity in IgG from autoimmune thyroiditis (ATh) and systemic lupus erythematosus (SLE) patients was evident. The Tg, a known target of autoimmune reactions in ATh, was cleaved at lower levels by Abs from patients with this disease than from SLE patients. The Tg-cleaving and Tg-binding activities of the autoantibody preparations were not correlated. Enhanced rates of cleavage at saturating substrate concentrations (Vmax), not increased Tg-binding affinities, were evident in IgG preparations with the greatest Tg-cleaving activity. Similarly, diminution of the polyreactive proteolytic activity in IgG from the autoimmune disease patients was due to decreased Vmax values, not decreased substrate-binding affinities. No cleavage of Tg by IgG from subjects with HIV-1 infection, or from mice hyperimmunized with an albumin-hapten conjugate was evident, suggesting that generation of Tg-cleaving Abs does not accompany V region affinity maturation in response to unrelated Ags. These observations establish Tg as a target of catalytic autoantibodies in SLE and ATh, suggest a transition from polyreactive proteolytic activity to autoantigen-directed activity in autoimmune disease, and open the possibility that combining site chemical reactivity is a factor driving the expression of catalytic activity by autoantibodies.

Autoantibodies↗
PubMed1996

Idiopathic genital ulcers in women infected with human immunodeficiency virus.

A national survey of investigators caring for human immunodeficiency virus (HIV)-infected women was undertaken to describe the clinical presentation of idiopathic genital ulcer disease. Patients with negative syphilis and herpes simplex testing and/or negative genital ulcer biopsy were included in this study. Study participants (n = 29) were generally severely immunocompromised (median CD4 cell count was 50/mm3, and 68% had an acquired immunodeficiency syndrome [AIDS]-defining opportunistic process). Thirty-seven percent had coexistent oral ulcers and 19% had their genital ulcer progress to fistula formation (four rectovaginal and one vaginal-perineal). There was generally a favorable response to topical, systemic, and intralesional steroid treatment. This study suggests that idiopathic or probable aphthous genital ulcers in women have similar clinical characteristics to aphthous oroesophageal ulcers. Although infrequent, these genital ulcers can cause severe morbidity. Further research is warranted to better define the pathophysiology and optimal management.

Adult↗
PubMed1996

Mechanisms for the transendothelial migration of HIV-1-infected monocytes into brain.

HIV-1 penetration of the brain is a pivotal event in the neuropathogenesis of AIDS-associated dementia. The establishment of productive viral replication or up-regulation of adhesion molecule expression on brain microvascular endothelial cells (BMVEC) could permit entry of HIV into the central nervous system. To investigate the contribution of both, we inoculated primary human BMVEC with high titer macrophage-tropic HIV-1 or cocultured them with virus-infected monocytes. In both instances, BMVEC failed to demonstrate productive viral replication. Cell to cell contact between monocytes and microvascular endothelium resulted in E-selectin expression on BMVEC. BMVEC. cocultured with LPS-activated HIV-infected monocytes expressed even higher levels of E-selectin and vascular cell adhesion molecule-1 (VCAM-1). Transwell assays supported a role of soluble factors, from virus-infected monocytes, for the induction of adhesion molecules on BMVEC. To verify the in vivo relevance of these findings, levels of adhesion molecules were compared with those of proinflammatory cytokines and HIV-1 gene products in brain tissue of AIDS patients with or without encephalitis and HIV-seronegative controls. E-Selectin, and to a lesser degree VCAM-1, paralleled the levels of HIV-1 gene products and proinflammatory cytokines in brain tissue of subjects with encephalitis. Most importantly, an association between macrophage infiltration and increased endothelial cell adhesion molecules was observed in encephalitic brains. Monocyte binding to encephalitic brain tissue was blocked with Abs to VCAM-1 and E-selectin. These data, taken together, suggest that HIV entry into brain is, in part, a consequence of the ability of virus-infected and immune-activated monocytes to induce adhesion molecules on brain endothelium.

Base Sequence↗