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Biomedical subjects

David A Cooper

Publications and source records attributed to David A Cooper.

At least 91 records · Page 5Linked to original sources
PubMed2003

Pharmacokinetics of lower doses of saquinavir soft-gel caps (800 and 1200 mg twice daily) boosted with itraconazole in HIV-1-positive patients.

OBJECTIVE: The pharmacokinetics of 800 mg and 1200 mg of saquinavir soft-gel caps (SQV-SGC) twice daily plus 100 mg itraconazole once daily were compared to 1400 mg SQV-SGC twice daily without itraconazole. METHODS: The pharmacokinetics of SQV were determined in 17 randomly selected patients on 1400 mg twice daily SQV-SGC without itraconazole and after 2 weeks with lower SQV-SGC doses plus itraconazole. SQV plasma concentrations were determined by HPLC. Pharmacokinetic parameters were calculated by a non-compartmental model. RESULTS: Median (+IQR) area under plasma concentration-versus-time curve (AUC0-12h) were 3.33 (1.96-7.34), 4.29 (3.14-7.67) and 4.07 (2.76-4.49) mg/l x h for SQV 1400 mg without itraconazole, SQV 1200 mg with itraconazole and SQV 800 mg with itraconazole, respectively. These differences were not statistically significant. The median Cmin was above the proposed minimum effective concentration of 0.05 mg/l for all three regimens. CONCLUSION: SQV-SGC 800 mg or 1200 mg twice daily boosted with 100 mg of itraconazole once daily resulted in adequate SQV pharmacokinetics not significantly different from SQV-SGC 1400 mg twice daily.

Adult↗
PubMed2002

Comprehensive analyses of a unique HIV-1-infected nonprogressor reveal a complex association of immunobiological mechanisms in the context of replication-incompetent infection.

We recently demonstrated that a unique HIV-1-infected nonprogressor was infected with a nonevolving replication-incompetent HIV-1 strain, showing a total absence of viral evolution in vivo. Potent immune responses against HIV-1 were observed in his PBMC, despite an apparent lack of viral replication for at least 8 years. His PBMC resisted superinfection with CCR5, CXCR4, and dual-tropic HIV-1 strains, although highly purified CD4+ T cells supported infection, but without any visible cytopathic effect. Potent noncytolytic CD8+ T cell antiviral activity was shown to protect his PBMC from productive infection. This activity was not mediated by several known chemokines or IFN-gamma, which were produced at high levels after PHA activation of his CD8+ T cells, indicating the action of other CAF-like CD8 factors. This antiviral activity was a memory response, induced by HIV-specific stimulation to similar levels observed by PHA stimulation, but absent in ex vivo resting T cells. Immunological mechanisms associated with this antiviral suppressive activity included vigorous Gag-specific helper T cell proliferative responses and high-level IFN-gamma release by both CD4 and CD8 T cells. These responses were broadly directed against multiple Gag epitopes, both previously reported and some novel epitopes. Strong HIV-specific helper T cell function was also associated with strong neutralizing antibodies. Understanding how to induce these protective immune responses in other individuals could provide a major step forward in the design of effective immunotherapies or vaccines against HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed2002

A randomized, double-blind study of gemfibrozil for the treatment of protease inhibitor-associated hypertriglyceridaemia.

BACKGROUND: Hypertriglyceridaemia is common in patients with HIV, especially those taking protease inhibitors or with lipodystrophy, frequently observed at levels associated with accelerated cardiac disease. This study aimed to explore the efficacy and safety of gemfibrozil for hypertriglyceridemia in patients with HIV infection. METHODS: A 16-week, randomized, double-blind, comparative study of low saturated fat diet versus low saturated fat diet with gemfibrozil 600 mg twice daily in patients with triglycerides > or = 3mmol/l receiving protease inhibitor therapy. Following a 4-week period of dietary intervention alone, patients were randomized to gemfibrozil or matching placebo. The primary outcome was the difference in mean change in fasting triglycerides at week 16 between the two groups. RESULTS: 37 men were randomized (17 gemfibrozil, 20 placebo) with median fasting triglycerides 5.6 mmol/l. Mean changes in triglycerides from week 4 to week 16 were -1.22 mmol/l and +0.35 mmol/l for the gemfibrozil and placebo groups respectively (between-group mean difference of 1.57 mmol/l; 95% confidence interval, -6.7 to 3.5; = 0.08). Only one patient treated had triglycerides return to a desirable range (< or = 2.00 mmol/l). No significant changes in the other metabolic parameters were observed. Gemfibrozil was well tolerated, did not appear to induce additional protease inhibitor toxicity, and did not induce changes in CD4 lymphocyte counts or HIV RNA load. CONCLUSIONS: Gemfibrozil is safe and demonstrated at most, modest efficacy for hypertriglyceridemia in HIV-infected patients receiving protease inhibitors. Given the level of response, however, it is unclear whether these reductions will confer clinical benefit, at least in the presence of continued protease inhibitor use.

Diet↗
PubMed2002

Clinical features of acute retroviral syndrome differ by route of infection but not by gender and age.

The rate of HIV disease progression is associated with the severity of the acute retroviral syndrome (ARS). We explored the clinical features of ARS by gender, age and route of infection among 378 individuals with documented ARS enrolled in 5 prospective cohort studies with similar enrollment criteria. No major differences were detected by gender or by age. Several symptoms were reported less frequently in the injecting drug users as compared with infection acquired through sexual contacts (either heterosexual or homosexual). This was observed in particular for fever (50% vs. 77%, p=.001), skin rash (21% vs. 51%, p=.001), pharyngitis (18% vs. 43%, p=.004), and myalgia (29% vs. 52%, p=.01). Genital ulcerations were present only in cases of sexual exposure to HIV. Injecting drug users had or reported symptoms associated with the ARS less frequently than persons acquiring HIV via sexual transmission.

Acute Disease↗
PubMed2002

Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial.

CONTEXT: Peripheral lipoatrophy may complicate antiretroviral therapy of human immunodeficiency virus (HIV) infection, often related to duration and type of nucleoside analog therapy, and may have a mitochondrial pathogenesis. No proven therapy exists for lipoatrophy, but abacavir is a nucleoside analog that may be less toxic to mitochondria. OBJECTIVE: To determine if substitution of stavudine or zidovudine with abacavir improves HIV lipoatrophy without affecting control of HIV replication. DESIGN: Randomized, open-label 24-week study. SETTING: Seventeen hospital HIV outpatient clinics and primary care centers in Australia and England, with randomization from June 2000 through January 2001. PARTICIPANTS: A total of 111 adults (109 men) with moderate or severe lipoatrophy who were receiving stavudine (n = 85) or zidovudine (n = 26) and had stable plasma HIV RNA levels below 400 copies/mL and no prior abacavir therapy. INTERVENTION: Patients were randomly assigned to switch from stavudine or zidovudine to abacavir, 300 mg twice per day, while continuing all other antiretroviral therapy (n = 54) or to continue all antiretroviral therapy (n = 57). MAIN OUTCOME MEASURES: The primary end point was limb fat mass, measured by dual-energy x-ray absorptiometry; key secondary end points were plasma HIV RNA levels, adverse events, physician-assessed (via subjective measures) lipodystrophy severity, total and central fat mass, and fasting metabolic (lipid, glycemic, and lactate) levels. RESULTS: There was a significant increase in limb fat in the abacavir group relative to the stavudine/zidovudine group (0.39 vs 0.08 kg; mean difference, 0.31; 95% confidence interval [CI], 0.06-0.57 kg), as well as significant relative increases in subcutaneous thigh (P =.01), arm (P<.001), and abdominal (P =.001) fat areas on computed tomography. Switching had no significant effect on secondary end points, including plasma HIV RNA (for unadjusted comparison between groups at week 24, odds ratio, 1.38; 95% CI, 0.48-3.96). Change in limb fat mass at week 24 did not correlate with change in subjectively determined perceived lipoatrophy severity (r = -0.06; P =.53 by Spearman correlation). Hypersensitivity to abacavir was seen in 5 patients (10%). CONCLUSIONS: In this sample of lipoatrophic HIV-infected adults, switching from stavudine or zidovudine to abacavir for 24 weeks led to significant, albeit modest, objectively measured increases in limb fat. Clinical lipoatrophy, as assessed subjectively, did not resolve, however, and at the rate of increase observed may take years to resolve with use of this strategy. Longer-term follow-up is needed.

Absorptiometry, Photon↗
PubMed2002

Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel.

OBJECTIVE: New information warrants updated recommendations for the 4 central issues in antiretroviral therapy: when to start, what drugs to start with, when to change, and what to change to. These updated recommendations are intended to guide practicing physicians actively involved in human immunodeficiency virus (HIV)- and acquired immunodeficiency syndrome (AIDS)-related care. PARTICIPANTS: In 1995, physicians with specific expertise in HIV-related basic science and clinical research, antiretroviral therapy, and HIV patient care were invited by the International AIDS Society-USA to serve on a volunteer panel. In 1999, others were invited to broaden international representation. The 17-member panel met regularly in closed meetings between its last report in 2000 and April 2002 to review current data. The effort was sponsored and funded by the International AIDS Society-USA, a not-for-profit physician education organization. EVIDENCE AND CONSENSUS PROCESS: The full panel was convened in late 2000 and assigned 7 section committees. A section writer and 3 to 5 section committee members (each panel member served on numerous sections) identified relevant evidence and prepared draft recommendations. Basic science, clinical research, and epidemiologic data from the published literature and abstracts from recent (within 2 years) scientific conferences were considered by strength of evidence. Extrapolations from basic science data and expert opinion of the panel members were included as evidence. Draft sections were combined and circulated to the entire panel and discussed in a series of full-panel conference calls until consensus was reached. Final recommendations represent full consensus agreement of the panel. CONCLUSIONS: Because of increased awareness of the activity and toxicity of current drugs, the threshold for initiation of therapy has shifted to a later time in the course of HIV disease. However, the optimal time to initiate therapy remains imprecisely defined. Availability of new drugs has broadened options for therapy initiation and management of treatment failure, which remains a difficult challenge.

Adjuvants, Immunologic↗
PubMed2002

Characterization of CD4(+) CTLs ex vivo.

The cytotoxic potential of CD8(+) T cells and NK cells plays a crucial role in the immune response to pathogens. Although in vitro studies have reported that CD4(+) T cells are also able to mediate perforin-mediated killing, the in vivo existence and relevance of cytotoxic CD4(+) T cells have been the subject of debate. Here we show that a population of CD4(+) perforin(+) T cells is present in the circulation at low numbers in healthy donors and is markedly expanded in donors with chronic viral infections, in particular HIV infection, at all stages of the disease, including early primary infection. Ex vivo analysis shows that these cells have cytotoxic potential mediated through the release of perforin. In comparison with more classical CD4(+) T cells, this subset displays a distinct surface phenotype and functional profile most consistent with end-stage differentiated T cells and include Ag experienced CD4(+) T cells. The existence of CD4(+) cytotoxic T cells in vivo at relatively high levels in chronic viral infection suggests a role in the immune response.

CD4 Antigens↗
PubMed2002

Adaptive changes after human immunodeficiency virus type 1 transmission.

Primary HIV-1 infection (PHI) is associated with a period of viremia, the resolution of which generally coincides with the development of both humoral and cellular immune responses. In this study replication-competent quasispecies were derived from virus isolated from an individual before and after seroconversion. Virus was also isolated from the presumed donor. Phenotypic and genotypic analysis of biological clones identified transmission of an R5/M-tropic phenotype. However, the ability of clones derived from the recipient to replicate in primary macrophages and PBMCs was restricted after transmission. This apparent selection process was supported by analysis of molecular clones derived from the isolated virus. Analysis of the ratio of synonymous and nonsynonymous substitutions predicted the existence of selective pressure soon after transmission, coincident with the development of HIV-1-specific antibodies. An Env trans-complementation assay demonstrated that the infectivity of a clone derived from the recipient after seroconversion was enhanced in the presence of a selected neutralizing antibody, indicating that the developing humoral immune response may have at least in part contributed to the selective pressure identified.

Adaptation, Physiological↗
PubMed2002

Dose-escalating study of the safety and pharmacokinetics of nelfinavir in HIV-exposed neonates.

The pharmacokinetics of nelfinavir (NFV) in neonates younger than 4 weeks of age was assessed. Three cohorts of HIV-exposed neonates were enrolled in cohorts to receive 15, 30, and 45 mg of NFV/kg twice daily in combination with stavudine and didanosine for 4 weeks after birth. Trough NFV concentrations (C(min)) were measured at 1 and 7 days of age. Intensive pharmacokinetic evaluations were performed at 14 and 28 days of age. The median NFV C(min) values in the 15 mg/kg (6 patients), 30 mg/kg (5), and 45 mg/kg (11) cohorts at 1, 7, 14, and 28 days of age were 0.19, 1.21, 0.51, and 0.33; 1.02, 3.18, 0.73, and 0.55; and 0.67, 3.21, 0.70, and 0.73 mg/L, respectively. The median area under the plasma concentration-versus-time curve values over 12 hours in the three cohorts at 14 and 28 days of age were 14.4 and 8.7, 19.4 and 15.8, and 23.4 and 18.5 (h. mg)/L, respectively. No serious adverse events were observed. In conclusion, the systemic exposure of NFV decreased after 7 days of age, possibly because of hepatic enzyme maturation, autoinduction of NFV metabolism, and/or changes in NFV absorption. The highly variable systemic exposure observed in the study indicates that therapeutic drug monitoring seems warranted to ensure adequate NFV dosing in this population.

Adult↗
PubMed2002

Simplifying protease inhibitor therapy with once-daily dosing of saquinavir soft-gelatin capsules/ritonavir (1600/100 mg): HIVNAT 001.3 study.

OBJECTIVE: To determine the feasibility of switching therapy for HIV-1-infected patients with plasma viral loads of <50 HIV-1 RNA copies/mL who are receiving twice-daily saquinavir soft-gelatin capsules (SQV-SGC) plus dual nucleoside reverse transcriptase inhibitors (NRTIs) to a regimen containing once-daily SQV-SGC/ritonavir (RTV). DESIGN: Therapy for patients with plasma viral loads of <50 copies/mL after 2 years of treatment with twice-daily SQV-SGC (1400 mg) plus zidovudine/lamivudine or didanosine/stavudine was switched to once-daily SQV-SGC/RTV (1600/100 mg) with continuing NRTI treatment. METHODS: Safety and efficacy (determined by plasma viral load and CD4 cell count) were evaluated (week 24). For 12 patients, steady-state plasma pharmacokinetics of SQV was determined (week 4). RESULTS: Once-daily SQV-SGC/RTV was well tolerated. No patient changed regimens. After 24 weeks, 64 (93%) of 69 patients had plasma viral loads of <50 copies/mL (the remaining 5 patients had plasma viral loads of <300 copies/mL). The median CD4 cell count increased from 534/mL at the start of once-daily SQV-SGCs/RTV to 695/mL after 24 weeks (p <.001). Compared with the preceding 24 weeks of treatment with twice-daily SQV-SGC, the CD4 cell count improved significantly during once-daily SQV-SGC/RTV therapy (p <.001). All patients maintained SQV trough concentrations (C(24h)) of >0.05 mg/L. Median values for the area under the plasma concentration-versus-time curve from 0 to 24 hours (AUC(0-24h)), maximal concentration (C(max)), and C(24h) for SQV were 48.1 (h.mg)/L, 6.98 mg/L, and 0.17 mg/L, respectively. Body weight was inversely correlated with SQV AUC(24h) and C(24h) (p <.01). CONCLUSIONS: Clinical and pharmacokinetic data support once-daily SQV-SGC/RTV (1600/100 mg) with two NRTIs as a convenient and safe therapeutic regimen to maintain viral suppression and immune function in HIV-1-infected patients with plasma viral loads of <50 copies/mL.

Adult↗
PubMed2002

The extent of HIV-1-related immunodeficiency and age predict the long-term CD4 T lymphocyte response to potent antiretroviral therapy.

OBJECTIVE: To study the long-term immunological recovery in HIV-1-infected individuals receiving potent antiretroviral therapy (ART). DESIGN: Prospective, observational study. METHODS: Plasma HIV-1 RNA, CD4 and CD8 T lymphocyte counts were determined at 3-6 monthly intervals in 95 HIV-1-infected subjects receiving ART who suppressed plasma HIV-1 RNA to levels below 400 copies/ml during a median observation period of 45 months. RESULTS: The median CD4 cell count rose from 325 to 624 cells/microl at 48 months, increasing by 22.6 cells/microl per month in the first 3 months, 8.1 cells/microl per month from months 3 to 12, 6.8 cells/microl per month in the second year, 3.3 cells/microl per month in the third, and 1.7 cells/microl per month in the fourth year. At 48 months, 98% of subjects reached CD4 cell counts > 200 cells/microl, 86% > 350 cells/microl, and 74% > 500 cells/microl. A higher nadir CD4 cell count and younger age were independently associated with greater increases in CD4 cell counts, and higher absolute CD4 cell counts at 48 months. Poor immunological responders who did not reach 500 CD4 lymphocytes/microl at 48 months showed lower nadir and baseline CD4 cell counts than good responders (99 versus 300 cells/microl and 160 versus 373 cells/microl, respectively). CONCLUSION: The recovery of CD4 T lymphocytes occurs mainly in the first 2 years after the initiation of ART, and is associated with age and the pre-existing degree of HIV-1-related immunodeficiency, suggesting that the long-term exposure to HIV-1 infection has caused damage to the immune system that is difficult to correct.

Adult↗
PubMed2002

HIV medicine.

Explore the source record for details and available documents.

Australia↗
PubMed2002

HIV-associated lipodystrophy: description, pathogenesis, and molecular pathways.

HIV-infected individuals taking antiretroviral medications may experience changes in body shape and metabolism, commonly known as HIV-associated lipodystrophy (HIVLD). In vitro and in vivo research have revealed numerous effects of both protease inhibitors and nucleoside reverse transcriptase inhibitors on the function of various organs--most importantly adipose tissue, liver, and muscle. The metabolic abnormalities could result in an increased risk of cardiovascular disease in this vulnerable and relatively young population. Treatment strategies, normally successful in the general population, have generally been less effective in this group of people, in which the detrimental effects of the antiretroviral medications are ongoing.

Adipocytes↗
PubMed2002

The evaluation of subcutaneous proleukin (interleukin-2) in a randomized international trial: rationale, design, and methods of ESPRIT.

The Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) is a large ongoing randomized trial of subcutaneous interleukin-2 (IL-2) plus antiretroviral therapy versus antiretroviral therapy alone in patients with HIV (human immunodeficiency virus) disease and CD4 cell counts of at least 300 cells/mm(3). The primary objective is to determine whether the addition of IL-2 to combination antiretroviral therapy improves morbidity and mortality. The aim is to recruit 4000 participants and follow them for an average of 5 years. Eligible subjects will be recruited at 275 investigational sites in 23 countries around the world. Coupled with broad eligibility criteria this will ensure widely applicable results. A range of secondary objectives will also be addressed in this setting that will include the conduct of observational studies and nested substudies with a public health focus. This article describes the rationale supporting the trial in addition to reviewing the study design, coordination, and governance.

Adult↗