Biomedical subjects

B Conway

Publications and source records attributed to B Conway.

At least 55 records · Page 3Linked to original sources

PubMed1998

Association of phenotypic changes in B cell lymphocytes and plasma viral load in human immunodeficiency virus-infected patients.

Many B cell abnormalities have been reported in human immunodeficiency virus (HIV)-infected patients, including changes in the expression of mu, gamma, and CD22 molecules on the cell surface. Phenotypic changes in these markers on B cells isolated from HIV-seropositive patients with high or low levels of plasma viremia were measured. The phenotypic changes in B cells isolated from such patients were compared with the markers on B cells isolated from HIV-seronegative individuals using three-color flow cytometry. HIV patients showed a reduction in the proportion of mature B cells isolated from peripheral blood mononuclear cells compared with B cells isolated from HIV-seronegative individuals. An increase in the proportion of B cells expressing both mu and gamma molecules on the cell surface was also seen in association with high-HIV plasma viremia. A low plasma viral load was accompanied by a reduction in the proportion of B cells expressing both mu and gamma molecules to a level comparable to those seen in HIV-seronegative individuals. HIV-seropositive individuals demonstrated an increase in the proportion of committed B cells, as indicated by an increase in the proportion of B cells expressing gamma molecules. This observation may explain the poor humoral response of HIV seropositive patients to neo-antigens. Our results demonstrate that phenotypic changes indicative of in vivo B cell activation and an increase in immature cells are associated with HIV infection, particularly with a high plasma viral load. Phenotypic changes in B cell markers may correlate with functional deficits of B cells.

Antigens, CD↗

PubMed1998

A pilot study of nevirapine, indinavir, and lamivudine among patients with advanced human immunodeficiency virus disease who have had failure of combination nucleoside therapy.

The effects of nevirapine, indinavir, and lamivudine in combination were studied among 22 human immunodeficiency virus (HIV)-infected patients with CD4 cell counts < or =50/mm3, whose options for antiretroviral therapy were limited by clinical or laboratory failure or toxicity with previous regimens. Median plasma HIV RNA was 5.16 log10 copies/mL at baseline, decreasing by a median of 3.12 log10 copies/mL at 24 weeks. Median baseline CD4 cell count was 30/mm3, increasing by a median of 95/mm3 at week 24. Adverse reactions led to drug discontinuation in 4 cases. Steady-state pharmacokinetic analysis in 17 patients was consistent with an interaction between nevirapine and indinavir. Nevirapine plasma levels were within the expected range, while indinavir levels were lower than expected. Despite this interaction, the combination of nevirapine, indinavir, and lamivudine was safe and well-tolerated and had substantial antiviral and immunologic effects lasting for the 24-week study.

Anti-HIV Agents↗

PubMed1998

Do dual nucleoside regimens have a role in an era of plasma viral load-driven antiretroviral therapy?

This study was undertaken to characterize predictors of response to double nucleoside combinations among 245 human immunodeficiency virus-infected persons initiating antiretroviral therapy. The median time for receiving antiretroviral therapy in this group was 6 months, and the plasma virus load was 58,000 copies/mL. The most commonly prescribed regimens were zidovudine/lamivudine (154 subjects, 63%) and stavudine/lamivudine (46 subjects, 19%). A total of 96 (39%) subjects had their virus load decrease to < 500 copies/mL after the initiation of therapy. Of the 245 study subjects, 102 (41.6%) had > or = 5 months of follow-up and two or more consecutive virus load determinations performed after the start of antiretroviral therapy. Multivariate analysis demonstrated that baseline virus load was the only significant factor associated with obtaining two or more plasma virus loads of < 500 copies/mL. Overall, these data demonstrate that dual nucleoside therapy (using currently licensed agents) cannot reliably achieve a high level of suppression of plasma virus load.

Adult↗

PubMed1998

Comparison of costs of strategies for measuring levels of human immunodeficiency virus type 1 RNA in plasma by using Amplicor and Ultra Direct assays.

The costs of four algorithms for monitoring plasma human immunodeficiency virus type 1 RNA were compared. For patients with strong virologic responses, the use of Ultra Direct exclusively was the cheapest strategy. For patients with weak virologic responses, small savings could be obtained by using Amplicor and retesting only samples with values below 500 copies/ml with Ultra Direct.

Algorithms↗

PubMed1998

Outpatient angiography: a prospective study of 3 French catheters in unselected patients.

Financial constraints and bed shortages led to a re-evaluation of the policy of routine hospital admission for angiography. All patients referred for peripheral and renal angiography over an 8 month period had the procedure performed as an outpatient with a 3 F catheter. Patients were kept supine for 1 h and discharged 2 h after the angiogram. No significant complications resulted from the early mobilization of 219 patients who had outpatient 3 F angiography. It was a safe, well tolerated procedure, resulting in images of consistently adequate quality.

Adolescent↗

PubMed1998

Combination therapy for HIV: towards long term control of disease progression.

The difficulty of curing HIV patients with currently available agents has now been demonstrated and the model of care has returned to the long-term use of antiretroviral therapy. As such, the current minimum standard of care is triple drug therapy, with two nucleoside analogues,along with either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRT). Such regimens induce long-term virologic suppression in only 50 - 67% cases, so new approaches are needed. The most promising of these includes the use of two protease inhibitors,particularly in drug-naive patients, with the addition of one or two nucleoside analogues. Newer agents that merit further study include hydroxyurea,abacavir, adefovir, amprenavir and efavirenz. Their role in clinical practice remains to be defined. More complex regimens (including six drugs) are also under consideration. Although they may be more effective, long-term adherence to therapy may be problematic, and such approaches may be more appropriate for short-term use to 'induce' a virologic remission that could then be 'maintained' using a much simpler regimen. Preliminary data generated using such an approach have been disappointing, but this may relate to the specific selection of patients and regimens rather than a basic conceptual flaw with the approach itself. Although much progress has been made in the field of antiretroviral therapy, there is still a long way to go. The insightful study of new combinations of older and newer agents will help us to get closer to our goal of long-term control of HIV infection in all patients.

Journal Article↗

PubMed1997

Bestatin-mediated inhibition of leucine aminopeptidase may hinder HIV infection.

Bestatin, an inhibitor of leucine aminopeptidase (LAPase), significantly decreased HIV infection as reflected by a reduced number of positive immunofluorescent cells, p24 levels, reverse transcriptase activity and the number of proviral copies found in Bestatin-treated cells. Cellular and extracellular LAPase activity in infected cells was higher than the LAPase activity found in uninfected cells. However, cellular and extracellular LAPase activity as well as total protein kinase C activity was lower in Bestatin-treated cells. Conversely, the incubation of human lymphocytic HUT78 cells with LAPase promotes HIV infectivity. The possible role of LAPase in the pathophysiology of HIV was assessed by determining LAPase serum levels in HIV infected patients. LAPase activity levels were three orders of magnitude greater in sera obtained from HIV patients than those detected in sera of uninfected individuals. Although Bestatin reduced HIV infection, a moderate decrease in the reverse transcriptase activity of chronically-infected H9 human T-lymphocytic cells was observed. Based on the higher levels of LAPase present in the serum of HIV patients and on the combined inhibitory effect of Bestatin on LAPase and on protein kinase C activities, we suggest that LAPase may play an important role in the early events of HIV infection such as viral entry.

Anti-HIV Agents↗

PubMed1997

A pilot study of hydroxyurea among patients with advanced human immunodeficiency virus (HIV) disease receiving chronic didanosine therapy: Canadian HIV trials network protocol 080.

To assess the in vivo short-term antiretroviral effect of hydroxyurea in human immunodeficiency virus (HIV)-infected persons chronically treated with didanosine (ddI), 26 patients with CD4 cell counts between 100 and 350 were enrolled in a 12-week, open-label pilot study and randomly assigned to receive 500 or 1000 mg/day hydroxyurea. Clinical status, laboratory toxicities, CD4 lymphocyte count, and HIV RNA plasma virus load were assessed weekly. Median declines from baseline of 0.02 and 0.63 log10 HIV-1 RNA copies/mL of plasma were observed for the 500- and 1000-mg/day groups, respectively (P = .02). CD4 cell counts did not change significantly with the addition of hydroxyurea; however, a small but statistically significant decrease in counts was observed during the washout phase. Both doses of hydroxyurea were well-tolerated. These results demonstrate a substantial decrease in plasma virus load when 1000 mg of hydroxyurea is administered over 1 month as adjunctive therapy to ddI among HIV-infected persons with 100-350 CD4 cells/mm3.

Adult↗

PubMed1997

Stavudine plus lamivudine in advanced human immunodeficiency virus disease: a short-term pilot study.

The short-term effects of stavudine (d4T) plus lamivudine (3TC) were evaluated among 48 human immunodeficiency virus-infected patients for whom zidovudine therapy had failed or who could not tolerate zidovudine. Patients were followed for 8 weeks after initiation of open-label d4T plus 3TC. Four patients discontinued therapy, because of neutropenia (1), hepatitis (1), or neuropathy (2). Reduction in virus load was -0.86 (+0.3 to -3.4) log10 copies/mL and CD4 cell increase was 30 (-100 to +290) cells/mm3. Virologic response was associated with a higher CD4 cell count, no prior exposure to d4T and 3TC, and no previous AIDS-defining illness. Virus load reduction for patients naive to 3TC and d4T was -1.47 (-0.14 to -3.37) log10 copies/mL. Short-term use of d4T plus 3TC is safe, well-tolerated, and associated with virologic and substantial immunologic benefits. Further evaluation of d4T and 3TC in combination is warranted.

Adult↗

PubMed1997

Correlation of virus load in plasma and lymph node tissue in human immunodeficiency virus infection. INCAS Study Group. Italy, Netherlands, Canada, Australia, and (United) States.

The impact of long-term changes in plasma viremia, produced by effective combination antiretroviral therapy, on human immunodeficiency virus (HIV) burden within tissue reservoirs is unknown. Fifteen patients who had received at least 1 year of therapy with two or three drug combinations of zidovudine, didanosine, and nevirapine had suitable samples of lymph node tissue obtained by ultrasound-guided core needle biopsy. HIV RNA was extracted from homogenized tissue samples and quantitated using a modified branched DNA assay. Results were correlated with antiretroviral treatment effect on the basis of plasma virus load measurements over the preceding 12-18 months. A statistically significant negative correlation was observed between magnitude of treatment effect on plasma viremia and lymph node virus load. These data suggest that combinations of antiretroviral drugs that produce sustained suppression of plasma HIV RNA may also be able to reduce the virus burden in lymphoid tissues.

Biopsy↗

PubMed1997

Issues in the design of trials of therapies for subjects with human immunodeficiency virus infection that use plasma RNA level as an outcome.

Longitudinal plasma RNA levels were examined in 326 persons infected with human immunodeficiency virus (HIV), who were participating in 4 clinical trials and 1 observational study. Variations in plasma RNA levels among individuals were analyzed, and correlations were made of replicate and longitudinal measurements, plasma RNA levels, CD4 cell counts, and plasma RNA levels at enrollment. Sample sizes were calculated for detection of differences between treatment groups in mean plasma RNA level at one time point, the average change over time, and the area under the curve. On the basis of study findings, study eligibility criteria should specify a minimum plasma RNA level at least as high as the expected size of the treatment effect, and all longitudinal data should be used when determining the effect of treatment on plasma RNA level. Duplicating plasma RNA levels resulted in a decrease in the required sample size of 14%-41%.

Anti-HIV Agents↗

PubMed1997

Selective cytotoxicity of lithium gamma-linolenic acid in human T cells chronically and productively infected with HIV.

We sought to extend observations of lithium gamma-linolenic acid (LiGLA)-associated selective cytotoxicity in different models of chronic HIV infection in vitro. In our initial experiments, 8E5, 8E5L and A3.01 cells were allowed to proliferate in the presence of 0-20 microg/ml LiGLA for 4 days. Similarly, OM-10.1 cells (with or without prior stimulation with tumour necrosis factor-alpha (TNF-alpha)) were grown with 0-5 microg/ml LiGLA for 10 days. Significant cytotoxicity was observed in productively infected 8E5 cells (100% cell death by day 2 at the highest concentration) as compared with latently infected 8E5L cells (50% cell death on days 2-4) and uninfected A3.01 cells. No drug-induced viral stimulation was observed in surviving cells. In fact, a mild direct antiviral effect may be present, independent of cytotoxicity. Maximum cytotoxicity to OM-10.1 cells was only observed when active viral replication was induced by TNF-alpha. Our preliminary results are encouraging and suggest that LiGLA should be retained as a candidate antiretroviral agent. Further work is underway to identify the specific mechanism underlying our observations.

Anti-HIV Agents↗

PubMed1996

Variation in plasma RNA levels, CD4 cell counts, and p24 antigen levels in clinically stable men with human immunodeficiency virus infection.

Short-term variability in CD4 cell counts, plasma RNA levels, and p24 antigenemia was measured in clinically stable men with human immunodeficiency virus infection. Blood samples were obtained three times in each of 2 weeks 4 weeks apart. Differences between duplicate assays were considered to be due to technical factors; variation among visits was attributed to physiologic factors. Median enrollment values of CD4 cell counts, plasma RNA levels, and immune complex-dissociated (ICD) p24 antigenemia were 400 cells/mm3, 3.4 log10 copies/mL, and 38 pg/mL, respectively. Median absolute differences between duplicate CD4 cell counts, plasma RNA levels, and ICD p24 antigen were 16 cells/mm3, 0.21 log10 copies/mL, and 9.3 pg/mL. Median intraindividual ranges were 119 cells/mm3, 0.83 log10 copies/mL, and 18 pg/mL. Above 500 copies/mL, plasma RNA levels have a variability of 0.5 log10; the test is unreliable below this level.

CD4 Lymphocyte Count↗

PubMed1996

Effect of low-dose gamma radiation of HIV replication in human peripheral blood mononuclear cells.

Recent studies have demonstrated that UV light and x-irradiation enhance human immunodeficiency virus (HIV) gene expression. There are few published data on related effects of gamma-radiation. This may be of clinical relevance, as radiotherapy has been used extensively for the treatment of acquired immunodeficiency syndrome associated conditions. With this in mind, we have studied the effects of gamma-radiation on HIV replication in mononuclear cells (MC). These cells were obtained from five seronegative healthy donors, exposed to 0-200 cGy gamma-radiation, stimulated with phytohemagglutinin-P (PHA-P) for 24 h, infected with a laboratory strain of HIV (HTLV-IIIB, multiplicity of infection = 0.001), then carried in culture for 14 days. Overall, when considering p24 antigen levels on days 7 and 11 in cultures established from cells exposed to 50 cGy, the maximal levels were significantly higher than those measured in the parallel control cultures taken as a whole (P < 0.05), with viral replication enhanced as much as 1000-fold in one case. No significant cytotoxicity was observed following exposure to doses up to 50 cGy. The mechanism of the observed effect remains unknown but may relate to direct gene activation and/or free radical generation, leading to such activation. To date, there is no evidence that viral stimulation occurs following therapeutic radiation in a clinical setting.

Dose-Response Relationship, Radiation↗

PubMed1995

Quantitative PCR for the measurement of circulating proviral load in HIV-infected individuals.

BACKGROUND: PCR has been applied extensively as a tool for the detection of HIV. We have previously developed a semi-quantitative microtiter plate assay for the specific detection of HIV PCR products. OBJECTIVE: To develop and evaluate a novel quantitative assay for the measurement of circulating proviral load in HIV-infected individuals. STUDY DESIGN: We evaluated 70 consecutive, unselected HIV-infected patients, divided into 3 groups, according to their CD4 cell count: greater than 500 cells/microl (10 subjects); 200-500 cells/microl (31 subjects); less than 200 cells/microl (29 subjects). Peripheral blood mononuclear cell lysates were amplified, and a portion of the product was added to streptavidin-coated wells with a biotinylated capture probe and a horseradish peroxidase-linked reporter probe, complementary to separate regions of the amplified product. Following incubation, readings were taken with an automated plate reader. Products were quantitated by interpolation into a standard curve of serial dilutions of an HIV-containing plasmid, included in each assay. RESULTS: HIV sequences were detected in all 70 clinical samples. Within each patient category, a wide range of proviral loads were observed. However, proviral load/10(6) CD4 cells was associated with disease progression when the patient groups were considered (up to 9.6% infected cells in subjects with CD4 cell counts below 200/microl). CONCLUSIONS: This quantitative PCR assay will allow the measurement of proviral load in clinical samples. It may be useful in the managment of HIV-infected individuals and the evaluation of the efficacy of antiretroviral therapy.

Journal Article↗

PubMed1995

Double-blind 1-year follow-up of 1540 infants with respiratory distress syndrome randomized to rescue treatment with two doses of synthetic surfactant or air in four clinical trials. American and Canadian Exosurf Neonatal Study Groups.

Synthetic surfactant has been shown to reduce neonatal and 1-year mortality and neonatal morbidity in infants with respiratory distress syndrome. However, less is known about the effects of synthetic surfactant on developmental outcome and long-term morbidity. Four multicenter, randomized, placebo-controlled trials of synthetic surfactant administered as rescue therapy were conducted in the United States and Canada, with a total enrollment of 2224 patients. Double-blind developmental evaluations of survivors were conducted at 1 year of age (adjusted for prematurity) in all four trials. Of the 1802 patients enrolled in the placebo-controlled rescue trials who survived to 1 year, 1540 (85%) completed the 1-year follow-up evaluation. Height, weight, and head circumference measurements were not different in the treatment and control groups. Mean and median Bayley Scores of Infant Development for both the Mental Development Index and the Psychomotor Development Index were also equivalent. The incidence of impairments was not different in the two groups (mild to moderate impairment, 12% (92 of 745) for the air placebo group vs 11% (86 of 771) for the synthetic surfactant group; severe impairment, 15% (114 of 745) for the air placebo group vs 13% (102 of 771) for the synthetic surfactant group). No differences in rates of retinopathy of prematurity or hearing impairment were found in the treatment groups. The need for surgery after day 28 of life (relative risk, 0.779; 95% confidence interval, 0.665, 0.927) and the need for respiratory support at 1 year (relative risk, 0.525; 95% confidence intervals, 0.303, 0.911) were both reduced in the synthetic surfactant group. These results indicate that developmental outcome at 1 year of age is at least as good among infants with respiratory distress syndrome who received rescue therapy with synthetic surfactant as it is in infants who received air placebo; the results also indicate that the incidence of long-term morbidity is reduced.

Air↗

PubMed1995

Immune response to sulfamethoxazole in patients with AIDS.

Antibody- and cell-mediated responses to sulfamethoxazole (SMX) were analyzed in AIDS patients with or without a history of hypersensitivity and in negative controls. In 20 of 20 (P < 0.01) human immunodeficiency virus (HIV)-seropositive patients with skin reactions to cotrimoxazole, we found SMX-specific antibodies, while only 9 of 20 and 17 of 20 HIV-seropositive patients without a history of hypersensitivity to cotrimoxazole had SMX-specific immunoglobulin M (IgM) and IgG, respectively. The levels of specific IgM and IgG were higher in patients with skin reactions than in patients without reactions (IgM, 1.0 +/- 0.19 versus 0.47 +/- 0.23 [P < 0.001]; IgG, 0.68 +/- 0.15 versus 0.47 +/- 0.14 [P < 0.001] [mean optical density values +/- standard deviations]). Seronegative controls with no history of exposure to sulfa compounds did not have SMX-specific IgG or IgM antibodies, and controls with a history of intake of SMX with or without reactions had low levels of IgG and IgM. The SMX-specific IgG subclasses were exclusively IgG1 and IgG3. None of the patients had detectable SMX-specific IgE or IgA antibodies nor did they exhibit a cell-mediated response as measured by a lymphocyte proliferation assay. Antibodies to SMX recognized N-acetyl-sulfonamide, N-(2-thiazolyl)-sulfanilamide, sulfadiazine, and sulfisoxazole but did not recognize sulfanilamide or 3-amino-5-methyl isoxazole in an inhibition assay. It is not known whether the SMX-specific antibodies associated with hypersensitivity reactions to SMX in HIV-seropositive patients have a pathogenic role in these reactions. Sulfanilamide or 3-amino-5-methyl isoxazole, on the other hand, could be potential alternative therapies in HIV-seropositive patients with a history of skin reactions to SMX.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Potential applications of proviral load measurement in clinical retrovirology.

We have previously noted an association between proviral load and the severity of immune disease in individuals with a wide range of CD4 cell counts. Using the quantitative DNA polymerase chain reaction technology developed in our laboratory, we sought to extend these observations, with a view to establishing guidelines for the use of proviral load in a clinical context. We studied 199 patients with a range of CD4 cell counts attending an urban tertiary care center. Proviral load/10(6) peripheral blood mononuclear cells (PBMCs) was measured using a microtiter plate assay designed specifically for this purpose. Human immunodeficiency virus proviral DNA was detected in 193 of 199 clinical samples. Levels of proviral load were tabulated for patients and evaluated in seven categories defined by CD4 cell counts. Although a wide range of proviral loads was observed in each category of patients, there was a trend toward increasing proviral load with decreasing CD4 cell count. Statistically significant relationships were observed between proviral load and the CD4 cell count and the CD4 cell percentage (Spearman's correlation coefficient -0.19, p = 0.01 for both absolute CD4 and CD4 percentage). These relationships were quite weak and could not be taken to explain disease progression in isolation. If we defined a cutoff between low and high proviral loads at 100 copies/10(6) PBMCs, we noted that 52% (24 of 46) of patients with CD4 cell counts > 400/microliters had lower loads, as compared with 16% (24 of 143) of those with more advanced disease (p < 0.01). There is a weak, but statistically significant association between proviral load and CD4 cell depletion.(ABSTRACT TRUNCATED AT 250 WORDS)

CD4 Lymphocyte Count↗