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Brian Gazzard

Publications and source records attributed to Brian Gazzard.

At least 73 records · Page 4Linked to original sources
PubMed2004

Intracellular and plasma pharmacokinetics of saquinavir-ritonavir, administered at 1,600/100 milligrams once daily in human immunodeficiency virus-infected patients.

Ritonavir-boosted saquinavir (SQV/r) is currently licensed as a twice-daily regimen. Reducing the pill burden with once-daily dosing may improve adherence. Intracellular concentrations of drugs must be related to the clinical efficacy of protease inhibitors. The aims of the study were to determine the cellular and plasma saquinavir and ritonavir concentrations, to determine the half-lives (t(1/2)s) of the drugs in each compartment, and to examine relationships between drug accumulation and lymphocyte subset P glycoprotein (P-gp) expression. Venous blood samples from 12 human immunodeficiency virus-infected patients receiving a hard-gel formulation of SQV/r (1,600/100 mg once daily) were collected at 2, 6, 12, and 24 h after dosing. Peripheral blood mononuclear cells were separated by density gradient centrifugation, and P-gp expression was measured by dual-color flow cytometry. Plasma and intracellular (cell-associated) drug concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. The ratio of the intracellular drug area under the concentration-time curve from 0 to 24 h (AUC(0-24 h)) to plasma drug AUC(0-24 h) was calculated to determine cellular drug accumulation. The median (range) AUC(0-24 h) of saquinavir in plasma was 16.2 (5.7 to 39.3) mg. h. liter(-1), and that in cells was 46.3 (24.7 to 114.6) mg. h. liter(-1). Corresponding ritonavir values were 7.5 (1.5 to 14.6) mg. h. liter(-1) and 10.4 (3.2 to 13.7) mg. h. liter(-1), respectively. The median accumulation ratios of cellular AUC to plasma AUC for saquinavir and ritonavir were 3.31 (range, 1.49 to 6.69) and 1.46 (range, 0.83 to 4.15), respectively. Significant differences between the plasma and intracellular saquinavir t(1/2)s (4.5 h [range, 2.5 to 9.3 h] and 5.9 h [range, 4.0 to 17.7 h]; P = 0.034) and between the plasma and intracellular ritonavir t(1/2)s (4.1 h [range, 2.6 to 8.3 h] and 6.2 h [range, 3.9 to 18.6 h]; P = 0.032) were observed. No relationship was observed between the accumulation of saquinavir or ritonavir and lymphocyte subset P-gp expression. The intracellular t(1/2)s of saquinavir and ritonavir were longer than the plasma t(1/2)s, indicating that intracellular drug may be available at a time when concentrations in plasma are below the minimum effective concentration.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Enhanced T-cell maturation, differentiation and function in HIV-1-infected individuals after growth hormone and highly active antiretroviral therapy.

BACKGROUND: Strong virus-specific helper and cytotoxic T-cell responses correlate with non-progression during HIV-1 infection. Administration of antiretroviral therapy (ART) during the chronic phases of HIV-1 infection fails to restore these responses in most patients. DESIGN AND METHODS: We assessed the changes in immune function of 12 HIV-1-positive individuals treated with ART for over 4 years, who received 4 mg/day of recombinant human growth hormone (rhGH) for 12 weeks and were then randomized into groups receiving either placebo, twice weekly or alternate day dosing of rhGH. Peripheral blood was drawn for phenotypic analysis and functional assays at time points 0, 12 and 24 weeks. RESULTS: At week 12, we observed significant increases in naive CD4 T cells (P<0.01) and effector CD8 T cells based on CD45RA and CCR7 expression (P<0.02). In addition, we observed a rise in HIV-1 antigen-specific CD4 (P<0.005) and CD8 (P<0.05) T-cell responses. Twelve weeks post-randomization into placebo, alternate day or twice weekly dosing (24 weeks post-baseline), the phenotype and function of the virus-specific effector CD8 T cells seen at week 12 was maintained in most patients regardless of randomization arm and despite the disappearance of HIV-1-specific CD4 T-cell responses. CONCLUSIONS: Concomitant administration of rhGH at 4 mg/day with highly active ART appears to partially reverse some of the defects exerted on the immune system by HIV-1. This combination may represent a valuable immunotherapeutic intervention aiding in the treatment of chronic HIV-1 infection.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Pharmacokinetics of once-daily saquinavir/ritonavir in HIV-infected subjects: comparison with the standard twice-daily regimen.

OBJECTIVE: To evaluate the steady-state pharmacokinetics and safety of two once-daily saquinavir/ritonavir (SQV/RTV) regimens, 1600/100 and 2000/100 mg, in HIV-positive patients. METHODS: Eighteen HIV-infected adults treated with the standard twice-daily SQV/RTV 1000/100 mg regimen were enrolled in this open-label, two-phase, crossover pharmacokinetic study. The steady-state pharmacokinetics of SQV administered with 100 mg RTV were investigated following once-daily doses of 1600 mg or 2000 mg or a twice-daily dose of 1000 mg. Plasma drug concentrations were determined by high performance liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were calculated using a non-compartmental model. RESULTS: Compared with SQV 1000 mg twice daily, the Cmax of SQV following a 1600 mg and 2000 mg dose increased in a dose-proportional manner [geometric mean (95% CI) 1915 (1656-2850) ng/ml for 1000 mg, 2782 (2249-4330) ng/ml for 1600 mg and 4179 (3429-6105) ng/ml for 2000 mg doses, respectively]. SQV Ctrough values were 539 (453-1011), 106 (76-223) and 231 (75-822) ng/ml, respectively. A SQV Ctrough value greater than 100 ng/ml was achieved in all subjects on the twice-daily regimen, in 9/18 (50%) subjects on the 1600/100 mg once-daily regimen, and in 14/17 (82%) subjects on the 2000/100 mg once-daily regimen. The once-daily regimens were well tolerated, with mild-to-moderate gastrointestinal symptoms being the only events reported by a small number of patients. CONCLUSION: This is the first study to evaluate the pharmacokinetics of once-daily SQV/RTV 2000/100 mg in HIV-infected subjects. Our findings suggest that this regimen may be an alternative to twice-daily 1000/100 mg doses and should be further evaluated in efficacy studies. The data indicate that most patients (14/17) on once-daily 2000/100 mg achieve trough concentrations above target values (determined for HIV wild-type) for efficacy of SQV with the use of just 100 mg RTV/day and with good tolerability.

Adult↗
PubMed2003

All for CD91 and CD91 for all.

Heat shock proteins interact with antigen-presenting cells through their receptor, CD91, eliciting a cascade of events including maturation, activation and representation of chaperoned foreign peptides with class I molecules on their surface. In turn, this facilitates recognition of non-self leading to induction of a cytotoxic T cell response. The abundance of heat shock proteins in tumours and their presence in virion coats makes them attractive propositions for use in antitumour and antiviral strategies.

Animals↗
PubMed2003

Antibody-targeted MHC complex-directed expansion of HIV-1- and KSHV-specific CD8+ lymphocytes: a new approach to therapeutic vaccination.

The ability of therapeutic vaccines to generate large numbers of CD8+ T lymphocytes that have specificity for HIV-1 or other virally infected cells has enormous potential clinical value. However, approaches to produce cytotoxic T lymphocytes (CTLs) in vivo via vaccine technology have thus far been disappointing and the ex vivo production of cells for adoptive transfer is labor intensive and expensive. We describe the results of a 2-step antibody-targeting system for the production of CD8+ T lymphocytes specific for HIV-1 and Kaposi sarcoma-associated herpesvirus (KSHV), suitable for use in vivo. In 8 consecutive human leukocyte antigen-A2 (HLA-A2)-positive HIV-1-infected individuals with Kaposi sarcoma, 2 cycles of this system resulted in more than 1 Log increases of specific anti-HIV and anti-KSHV CD8+ lymphocytes. These expanded cells have an effector phenotype that includes the ability to produce interferon-gamma and CD45Ra+/CD69+ staining. We have shown that antibody-targeted B cells can function as effective antigen-presenting molecules and lead to sustained specific T-lymphocyte expansion from peripheral blood mononuclear cells (PBMCs) of immunosuppressed individuals. This approach, which offers an easy and effective protocol for the amplification of specific antiviral and antitumor CTLs, may offer significant advances for in vivo T-cell immunotherapeutic protocols.

Antigens, CD↗
PubMed2003

Natural killer cells are not infected by Kaposi's sarcoma-associated herpesvirus in vivo, and natural killer cell counts do not correlate with the risk of developing Kaposi's sarcoma.

Although the innate immune system is implicated in the control of Kaposi's sarcoma (KS), the risk of developing KS is not associated with the nadir natural killer (NK) cell count, and NK cell counts do not significantly increase or decrease during KS resolution. KS-associated herpesvirus replication was not demonstrated in vivo or in vitro within NK cells, suggesting that NK cells do not contribute to the resolution of KS. Their role appears limited to events occurring during early infection.

Antiretroviral Therapy, Highly Active↗
PubMed2003

A comparison of regimens based on non-nucleoside reverse transcriptase inhibitors or protease inhibitors in preventing Kaposi's sarcoma.

OBJECTIVE: To determine the incidence of Kaposi's sarcoma (KS) in a prospective longitudinal cohort of HIV-1-infected individuals before during and after the introduction of highly active antiretroviral therapy (HAART) and to compare the incidence of KS between specific HAART regimens. DESIGN: Univariate and multivariate analysis of 8640 HIV-1-infected individuals. METHODS: The protective effect of HAART regimens based on either protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI) on the development of KS was examined in prospectively recorded data to determine whether treatments based on the two types of drug were comparable with regard to a reduction in the incidence of KS. RESULTS: A total of 1204 patients with KS were identified. The incidence of KS decreased from 30/1000 patient-years prior to 1995 to 0.03/1000 patient-years in 2001. Multivariate analysis showed that age, nadir CD4 cell count and antiretroviral class exposure were significant independent predictors of KS. NNRTI-based HAART (adjusted rate ratio, 0.42; 95% confidence interval 0.24-0.37) had a similar protective effect to PI-based HAART (adjusted rate ratio, 0.47; 95% confidence interval 0.38-0.58). Most patients who develop KS on HAART [30/35 (86%)] had evidence of virological treatment failure. CONCLUSION: PI- and NNRTI-based HAART regimens are equally effective as protection against KS. This is the first study to demonstrate a decreased incidence of an AIDS-defining disease with NNRTI-based therapy.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Disease-associated dendritic cells respond to disease-specific antigens through the common heat shock protein receptor.

The most abundant intracellular proteins, heat shock proteins (HSPs), serve as molecular chaperones for regulatory and maturation pathways. Diverse families of HSPs have been shown to bind antigenic peptides and to play major roles in innate and adaptive immune responses through the common HSP receptor, CD91. HIV-1+ patients with Kaposi sarcoma (KS) were matched for CD4 count and HIV-1 RNA viral load to HIV-1+ patients without Kaposi sarcoma (and negative for Kaposisarcoma-associated herpesvirus). We then investigated the pathways used by tumor lysates, viral lysates, and viral particles in their activation. In particular, we observed immune responses after HSP depletion using antitumor antibiotics and blockade of the common HSP receptor, CD91. Despite the impaired functional capacity of dendritic cells (DCs) derived from patients with KS, DCs retain the ability to prime the adaptive arm of the immune system through the common HSP receptor, leading to phenotypic activation and stimulation of tetramer-positive CD8+ cytotoxic T cells. We also show that interferon-producing plasmacytoid DCs are selectively depleted in KS-positive compared with matched KS-negative HIV-1-infected patients. Functionally impaired DCs can effectively cross-present immune responses through the common HSP receptor. These results have important implications for the etiopathogenesis of KS and for the development and design of any compounds, including vaccines, derived from cellular lysates.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Leptomeningeal disease in AIDS-related non-Hodgkin's lymphoma.

OBJECTIVE: To evaluate clinicopathological features associated with leptomeningeal disease in systemic AIDS-related non-Hodgkin's lymphoma (NHL) and to compare outcomes to those without leptomeningeal disease. In addition to evaluate intrathecal chemoprophylaxis for patients with good immunological parameters and high risk of meningeal relapse (bone marrow, paraspinal or paranasal involvement or Burkitt's lymphoma histology). DESIGN AND METHODS: Prospective data, which has been collected on our cohort of 8640 HIV seropositive patients treated at the Chelsea and Westminster Hospital includes 176 patients with systemic AIDS-related NHL, was analysed. RESULTS: At presentation, 18 (10%) patients had meningeal involvement. There were significant associations between meningeal disease and both Burkitt's lymphoma and paraspinal or paranasal involvement. There was no difference in the overall survival between patients with or without meningeal involvement at presentation (Kaplan-Meier log-rank, P = 0.35) and the 1-year actuarial survivals are 25% [95% confidence interval (CI), 3-47%] for patients with meningeal involvement and 33% (95% CI, 26-41%) for those without. Prophylactic intrathecal chemotherapy was administered to 21 high-risk patients and four (19%) relapsed with meningeal disease. CONCLUSIONS: This single-centre experience of a large cohort has demonstrated that meningeal involvement at presentation correlates with Burkitt's lymphoma histology and paraspinal or paranasal space disease, but not with bone marrow lymphoma. It also documents that long-term survival is achievable rarely in patients who present with meningeal disease and in patients with isolated meningeal relapse.

Adult↗
PubMed2003

Identification of two mutually exclusive groups after long-term monitoring of HIV DNA 2-LTR circle copy number in patients on HAART.

BACKGROUND: Anti-retroviral drug therapy reduces but does not abolish HIV transmission and replication throughout the body. HIV DNA 2-long terminal repeat (2-LTR) circles have been shown in point-based studies to persist in some patients whose plasma HIV RNA was undetectable. However, the degree of fluctuation of circle copy number over time has not been determined. METHODS: A reliable, reproducible and robust quantitative LightCycler (LC qPCR)-based assay for HIV DNA 2-LTR circles in peripheral blood mononuclear (PBMN) cells was established. A prospective, longitudinal study of these circles was undertaken in HIV-1-positive patients on anti-retroviral therapy whose plasma HIV RNA was undetectable at < 50 copies/ml. Patients starting therapy for the first time were also monitored. RESULTS: A cohort of 60 patients whose plasma HIV RNA was undetectable for 32 +/- 2 months were monitored for circles for 15 +/- 2 months. The circle copy number ranged from < 10 to 620 copies/106 PBMN cells. The circle-negative (< 10 copies/1 x 106 PBMN) cells group of 36 patients and the circle-positive (> 10 copies/106 PBMN cells) group of 24 patients were mutually exclusive (P < 0.0001). The mean circle half-life in seven of the 10 patients starting anti-retroviral therapy for the first time was 5.7 days. CONCLUSION: The circle assay is useful for identifying those patients in whom transmission of infectious virus continues despite prolonged periods of time during which plasma HIV RNA is undetectable. New drug combinations and new therapeutic approaches should be aimed at those patients whose plasma HIV RNA is undetectable but who remain positive for 2-LTR circles.

Anti-HIV Agents↗
PubMed2003

HIV-related lung cancer in the era of highly active antiretroviral therapy.

OBJECTIVES: To address the impact of highly active antiretroviral therapy (HAART) on the incidence and outcome of patients with HIV-related lung cancer. DESIGN AND SUBJECTS: Patients with HIV-related lung cancer were identified from a prospective HIV data base of 8400 patients diagnosed between 1986 and 2001. Patients diagnosed with HIV-related lung cancer before 1996 were in the pre-HAART cohort whereas the remainder were in the post-HAART cohort. METHODS: The incidence of HIV-related lung cancer in the pre- and post-HAART cohorts was compared with the age and sex-matched population of south east England. Clinicopathological features, treatments and outcomes were also recorded. RESULTS: The incidence of HIV-related lung cancer increased from 0.8 (95% CI 0.2-3.2)/10(5) patient-years follow-up in the pre-HAART era to 6.7 (95% CI 3.1-13.9)/10(5) patient-years follow-up in the post-HAART era. The age and sex-matched incidence of lung cancer in south east England was 0.75 (95% CI 0.63-0.87)/10(5) patient-years, suggesting that HIV-related lung cancer only occurred more frequently in the post-HAART era (relative risk 8.93, 95% CI 4.92-19.98). The patient characteristics and outcomes were similar in the pre- and post-HAART eras, although the time interval between testing HIV positive and developing HIV-related lung cancer was longer in post-HAART patients. CONCLUSION: In this study HIV-related lung cancer occurred more frequently in the post-HAART era, when compared with the HIV-negative population. Unfortunately, the outcome of these patients remains poor despite HAART.

Antiretroviral Therapy, Highly Active↗
PubMed2003

Dysfunction and infection of freshly isolated blood myeloid and plasmacytoid dendritic cells in patients infected with HIV-1.

Recently it has been shown that the 2 populations of blood dendritic cells (DCs), termed plasmacytoid (pcDCs) and myeloid (myDCs), are reduced in HIV-1 infection. This study aimed to determine whether these 2 populations are targets for HIV-1 infection and whether their ability to stimulate T-lymphocyte proliferation is affected. Highly purified populations of myDCs and pcDCs were isolated from the blood of antiretroviral treatment-naive patients and assessed for the level of HIV provirus by polymerase chain reaction (PCR). We show that both populations are targets for HIV-1 infection as indicated by the presence of provirus in 12 of 14 pcDC and 13 of 14 myDC samples tested. A proportion of this provirus is integrated in myDCs. The ability of both myDCs and pcDCs from HIV-1-infected patients to stimulate allogeneic T-lymphocyte proliferation in a 6-day mixed leukocyte reaction was severely impaired, but was not mediated by secondary infection of T lymphocytes. Thus, in addition to depletion, both myeloid and plasmacytoid DCs are infected and show impaired functional capacity. These findings suggest that infection, depletion, and dysfunction of dendritic cells may contribute to the immunosuppression associated with HIV-1 disease.

Blood Cells↗
PubMed2003

The heat-shock protein receptor CD91 is up-regulated in monocytes of HIV-1-infected "true" long-term nonprogressors.

A small proportion of patients with human immunodeficiency virus type 1 (HIV-1) remains asymptomatic for a long period after infection. It is thought that a vigorous immune response may contribute to long-term nonprogression, though studies are confounded by heterogeneity among patients. We studied the levels of HIV-1 receptors, costimulatory T-cell molecules, and dendritic cell (DC) numbers in 18 patients with long-term infection, CD4 counts greater than 400 cells/mm(3), and HIV-1 viral loads lower than 50 copies/mL. These patients were further differentiated through the presence or absence of 2-LTR DNA circles, a possible marker for residual ongoing HIV-1 replication. A statistically significant increase in levels of CD91, the heat-shock protein (HSP) receptor, was observed in therapy-naive patients who had no evidence of ongoing viral replication (P =.01). This difference was most notable on their monocytes. High levels of CD91 may be a host factor that contributes to the maintenance of long-term nonprogression. The ability of CD91 to internalize alpha-defensins and to cross-present exogenous antigen to cytotoxic T lymphocytes through major histocompatibility complex (MHC) class 1 may maintain CD8(+) responses in these patients.

Antigens, CD↗
PubMed2003

An open-label randomized clinical trial of novel therapeutic strategies for HIV-infected patients in whom antiretroviral therapy has failed: rationale and design of the OPTIMA Trial.

OPTIMA (OPTions In Management with Antiretrovirals) is a clinical trial with a factorial randomization to evaluate the hypotheses that mega-antiretroviral therapy (ART) consisting of five or more anti-HIV drugs compared to standard-ART consisting of four or fewer anti-HIV drugs and a 3-month antiretroviral drug-free period (ARDFP) compared to no ARDFP will delay the occurrence of new or recurrent acquired immunodeficiency syndrome events or death, and prove to be more cost-effective in treating human immunodeficiency virus-infected individuals previously exposed to ART drugs from the current three main classes. The aim is to randomize 1,700 participants to four treatment strategy arms: (1) ARDFP+standard-ART; (2) ARDFP+mega-ART; (3) no ARDFP+standard-ART; (4) no ARDFP+mega-ART. The planned study duration is 3.5 years with 2.5 years of intake and a minimum 1 year of follow-up. The OPTIMA Trial was initiated in June 2001 at 30 U.S. Department of Veterans' Affairs hospitals, 22 hospitals in Canada, and 25 hospitals in the United Kingdom. This is the first large-scale, multicenter, randomized controlled trial to compare the relative efficacy of these different therapeutic strategies. We discuss the rationale behind the OPTIMA Trial design as well as the issues arising from the conduct of a trial that involves three national clinical trial agencies.

Adult↗