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Biomedical subjects

M S Hirsch

Publications and source records attributed to M S Hirsch.

At least 19 recordsLinked to original sources
PubMed2006

ALK expression in pseudosarcomatous myofibroblastic proliferations of the genitourinary tract.

AIMS: Pseudosarcomatous myofibroblastic proliferation of the genitourinary tract is rare and may develop after trauma or spontaneously. The aim of this study was to characterize further the clinicopathological features of these lesions and to examine their relationship to inflammatory myofibroblastic tumour (IMT). METHODS AND RESULTS: Twenty-seven cases of pseudosarcomatous myofibroblastic proliferation were analysed. There were seven males and 20 females; median age was 37 years (range 16-88). Most lesions were from the bladder (n = 21), while others were in the urethra, vulva, vagina, rectum and retrovesical space. Median tumour size was 30 mm (range 6-120 mm). Seven cases (25%) had a history of prior trauma or surgery. Three cases recurred locally but not destructively. The tumours had fasciitis-like features including bland spindle cells with evenly distributed chromatin, admixed inflammatory cells (mainly lymphocytes) and often a myxoid stroma. Immunohistochemistry showed positivity for smooth muscle actin in 14/20 cases, keratin in 8/19, desmin in 7/20 and anaplastic lymphoma kinase (ALK) in 10/21 cases. Fluorescent in situ hybridization was performed in six ALK+ cases; all were negative for ALK gene rearrangement. CONCLUSIONS: Pseudosarcomatous myofibroblastic proliferations of the genitourinary tract may show ALK immunopositivity but do not show consistent ALK rearrangement. Given subtle morphological differences and more consistently benign behaviour, their relationship to inflammatory myofibroblastic tumour at other sites remains uncertain.

Actins↗
PubMed2001

Effects of treatment intensification with hydroxyurea in HIV-infected patients with virologic suppression.

BACKGROUND: Virologic rebound can result from suboptimal antiviral potency in combination antiretroviral therapy. DESIGN: Multicenter, partially blinded, prospective, randomized study of 202 HIV-infected subjects to determine whether therapy intensification improves long-term rates of virologic suppression. METHODS: Subjects had plasma HIV RNA < 200 copies/ml, CD4 cell count of > 200 x 10(6) cells/l, and treatment with indinavir (IDV) + zidovudine (ZDV) + lamivudine (3TC) for at least 6 months before randomization to stay on this regimen or to receive IDV + didanosine (ddI) + stavudine (d4T) plus or minus hydroxyurea (HU) (600 mg twice daily). Treatment failure was defined as either confirmed rebound of HIV RNA level to > 200 copies/ml or a drug toxicity necessitating treatment discontinuation. RESULTS: Treatment failure occurred more frequently in subjects randomized to the HU-containing arm (32.4%), than in those taking IDV + ddI + d4T (17.6%) or IDV + ZDV + 3TC (7.6%). The time to treatment failure was shorter for the HU-containing arm compared with the IDV + ZDV + 3TC (P < 0.0001) or IDV + ddI + d4T arms (P = 0.032). Dose-limiting toxicities rather than virologic rebound accounted for the differences between treatment failure among the study arms. Pancreatitis led to treatment discontinuation in 4% of subjects in treatment arms containing ddI + d4T. Three subjects with pancreatitis died, all randomized to the HU-containing arm. CONCLUSIONS: Switching to IDV + ddI + d4T + HU in patients treated with IDV + ZDV + 3TC was associated with a worse outcome, principally because of drug toxicity.

Adolescent↗
PubMed2001

Prevalence and predictive value of intermittent viremia with combination hiv therapy.

CONTEXT: In HIV-infected patients having virologic suppression (plasma HIV RNA <50 copies/mL) with antiretroviral therapy, intermittent episodes of low-level viremia have been correlated with slower decay rates of latently infected cells and increased levels of viral evolution, but the clinical significance of these episodes is unknown. OBJECTIVE: To determine if HIV-infected patients with intermittent viremia have a higher risk of virologic failure (confirmed HIV RNA >200 copies/mL). DESIGN AND SETTING: Retrospective analysis of subjects in well-characterized cohorts, the AIDS Clinical Trials Group (ACTG) 343 trial of induction-maintenance therapy (August 1997 to November 1998) and the Merck 035 trial (ongoing since March 1995). PATIENTS: Two hundred forty-one ACTG 343 patients, of whom 101 received triple-drug therapy throughout the study, and a small group of 13 patients from Merck 035 having virologic suppression after 6 months of indinavir-zidovudine-lamivudine. MAIN OUTCOME MEASURES: Association of intermittent viremia (plasma HIV RNA >50 copies/mL with a subsequent measure <50 copies/mL) with virologic failure (2 consecutive plasma HIV RNA measures >200 copies/mL) in both study groups; evidence of drug resistance in 7 patients from the small (n = 13) study group with long-term follow-up. RESULTS: Intermittent viremia occurred in 96 (40%) of the 241 ACTG 343 patients of whom 32 (13%) had 2 consecutive HIV RNA values >50 copies/mL during the median 84 weeks of observation (median duration of observation after first intermittent viremia episode was 46 weeks). Of the 101 individuals receiving triple-drug therapy throughout, 29% had intermittent viremia; the proportion of episodes occurring during the maintenance period was 64% for the entire cohort and 68% for the group not receiving triple-drug therapy throughout vs 55% for those who did (P =.25). Intermittent viremia did not predict virologic failure: 10 (10.4%) of 96 patients with and 20 (13.8%) of 145 patients without intermittent viremia had virologic failure (relative risk, 0.76; 95% confidence interval [CI], 0.29-1.72). In a Cox proportional hazards model, the risk for virologic failure was not significantly greater in the ACTG 343 patients with intermittent viremia (hazard ratio, 1.28; 95% CI, 0.59-2.79). Median viral load in 10 ACTG 343 patients assessed between 24 and 60 weeks of therapy using an ultrasensitive 2.5-copies/mL detection level assay was 23 copies/mL in those with intermittent viremia vs <2.5 copies/mL in those without (P =.15). Intermittent viremia occurred in 6 of 13 patients from the small study group assessed after 76 to 260 weeks of therapy (using the 2.5-copies/mL detection level assay) and was associated with a higher steady state of viral replication (P =.03), but not virologic failure over 4.5 years of observation. Viral DNA sequences from 7 patients did not show evolution of drug resistance. CONCLUSIONS: Intermittent viremia occurred frequently and was associated with higher levels of replication (Merck 035), but was not associated with virologic failure in patients receiving initial combination therapy of indinavir-zidovudine-lamivudine (ACTG 343 and Merck 035). In this population, treatment changes may not be necessary to maintain long-term virologic suppression with low-level or intermittent viremia.

Anti-HIV Agents↗
PubMed2001

Alterations in T cell phenotype and human immunodeficiency virus type 1-specific cytotoxicity after potent antiretroviral therapy.

Cytotoxic T lymphocytes (CTLs) are an important defense against human immunodeficiency virus (HIV) type 1 but ultimately fail to control infection. To determine whether more efficient sustained immunity is induced by suppressing replication, the evolution of T cell phenotypes and HIV-specific CD8+ lymphocytes was prospectively investigated in 41 patients initiating combination therapy. Suppression of viremia to <200 copies/mL was associated with increases in naive cells (CD45RA+62L+) and declines in activated T cells (CD95+ cell counts and CD38+ HLA-DR+). HIV-specific tetramer-staining CD8+ T cells were detected in 6 of 10 HLA-A*0201-positive persons, which declined in 5 with treatment. CTL precursor frequencies were markedly consistent before and after treatment. Eight (72%) of 11 recognized > or =1 immunodominant epitope, representing either a new or an increased CTL response after treatment. Thus, activated CD8+ T cells, including those recognizing immunodominant epitopes, decline with combination therapy. However, the overall level of antigen-specific cells that are capable of differentiating into effectors remains stable, and the recognition of new epitopes may occur.

Anti-HIV Agents↗
PubMed2000

Two double-blinded, randomized, comparative trials of 4 human immunodeficiency virus type 1 (HIV-1) envelope vaccines in HIV-1-infected individuals across a spectrum of disease severity: AIDS Clinical Trials Groups 209 and 214.

The potential role of human immunodeficiency virus type 1 (HIV-1)-specific immune responses in controlling viral replication in vivo has stimulated interest in enhancing virus-specific immunity by vaccinating infected individuals with HIV-1 or its components. These studies were undertaken to define patient populations most likely to respond to vaccination, with the induction of novel HIV-1-specific cellular immune responses, and to compare the safety and immunogenicity of several candidate recombinant HIV-1 envelope vaccines and adjuvants. New lymphoproliferative responses (LPRs) developed in <30% of vaccine recipients. LPRs were elicited primarily in study participants with a CD4 cell count >350 cells/mm(3) and were usually strain restricted. Responders tended to be more likely than nonresponders to have an undetectable level of HIV-1 RNA at baseline (P=.067). Induction of new cellular immune responses by HIV-1 envelope vaccines is a function of the immunologic stage of disease and baseline plasma HIV-1 RNA level and exhibits considerable vaccine strain specificity.

AIDS Vaccines↗
PubMed2000

Strong in vitro synergy between the fusion inhibitor T-20 and the CXCR4 blocker AMD-3100.

Attachment and entry of HIV-1 into CD4 cells involve a series of events in which different viral envelope proteins interact with specific cell receptors, culminating in fusion of viral and cell membranes. AMD-3100 is a small molecule inhibitor of HIV-1 attachment to the CXCR4 chemokine receptor, and T-20 is a synthetic peptide corresponding to a region of HIV-1 gp41 that blocks fusion to cell membranes. To evaluate the interaction between agents acting at two different steps of the entry process, we conducted in vitro studies of the combination of T-20 and AMD-3100 against an X4 HIV-1 isolate. Single drugs or multiply diluted fixed ratio combinations of drugs were added to peripheral blood mononuclear cells infected with a clinical isolate, 14aPre. Drug interactions were evaluated using the median-effect principle and the combination index technique. The 50% inhibitory concentration (IC50) for T-20 was 0.10 microg/ml and for AMD-3100 was 0.19 microg/ml. Synergy was observed between T-20 and AMD-3100 and this increased with higher inhibitory concentrations, with combination indices ranging from 0.62 at IC50 to 0.02 at IC95. Whether these synergistic interactions translate into clinical benefit will need to be addressed in the context of clinical trials.

Anti-HIV Agents↗
PubMed2000

Dynamics of HIV-1 viral load rebound among patients with previous suppression of viral replication.

OBJECTIVE: To model the dynamics of HIV-1 rebound in patients receiving suboptimal therapy after suppression of plasma viremia to < 200 copies/ml by triple combination therapy. DESIGN: Mathematical modeling of data from 23 patients switched to indinavir maintenance therapy after viral replication was suppressed with a combination of indinavir, zidovudine and lamivudine. Modeling of HIV-1 rebound among 24 patients on zidovudine/lamivudine maintenance was also performed for comparison. METHODS: Evaluation of slopes of rebound and of their heterogeneity; calculation of the basic reproductive number (Ro, the number of newly infected cells arising from each productively infected cell); regression analyses for predictors of the slope of rebound. RESULTS: Rebound of plasma HIV RNA followed a sigmoid curve with an initial exponential phase. There was significant heterogeneity in the slopes of rebound for individual patients (P < 0.001). In the indinavir maintenance rebounds, the average initial slope was estimated to be 0.587/day (doubling time 1.2 days). The slopes of rebound in patients on zidovudine/lamivudine maintenance tended to be less steep on average (P = 0.025). Among patients taking indinavir maintenance, the average Ro for the initial rebound of viremia was 4.3; in multivariate regressions, the slope of rebound was steeper during early rebound and in patients with higher viral load at the start of triple therapy or a higher CD4 cell count when indinavir monotherapy was initiated. The slope was less steep in patients with a greater increase in the number of CD4 cells during triple therapy. CONCLUSIONS: The rates of viral load increase among patients with viral rebound while receiving less than triple therapy are similar to those reported in patients interrupting therapy. Variability among patients may depend on viral fitness, target cell availability and extent of immune reconstitution.

Adult↗
PubMed2000

Antiretroviral drug resistance testing in adult HIV-1 infection: recommendations of an International AIDS Society-USA Panel.

OBJECTIVE: Assays for drug resistance testing in human immunodeficiency virus type 1 (HIV-1) infection are now available and clinical studies suggest that viral drug resistance is correlated with poor virologic response to new therapy. The International AIDS Society-USA sought to update prior recommendations to provide guidance for clinicians regarding indications for HIV-1 resistance testing. PARTICIPANTS: An International AIDS Society-USA 13-member physician panel with expertise in basic science, clinical research, and patient care involving HIV resistance to antiretroviral drugs was reconvened to provide recommendations for the clinical use of drug resistance testing. EVIDENCE AND CONSENSUS PROCESS: The full panel met regularly between January and October 1999. Resistance and resistance testing data appearing in the last decade through April 2000 and presentations at national and international research conferences were reviewed. Recommendations and considerations were developed by 100% group consensus, acknowledging that definitive data to support final recommendations are not yet available. CONCLUSIONS: Emerging data indicate that despite limitations, resistance testing should be incorporated into patient management in some settings. Resistance testing is recommended to help guide the choice of new regimens after treatment failure and for guiding therapy for pregnant women. It should be considered in treatment-naive patients with established infection, but cannot be firmly recommended in this setting. Testing also should be considered prior to initiating therapy in patients with acute HIV infection, although therapy should not be delayed pending the results. Expert interpretation is recommended given the complexity of results and assay limitations.

Adult↗
PubMed2000

Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USA Panel.

OBJECTIVE: To update recommendations for antiretroviral therapy for adult human immunodeficiency virus type 1 (HIV-1) infection, based on new information and drugs that are available. PARTICIPANTS: A 17-member international physician panel with antiretroviral research and HIV patient care experience initially convened by the International AIDS Society-USA in December 1995. EVIDENCE: Available clinical and basic science data including phase 3 controlled trials; data on clinical, virologic, and immunologic end points; research conference reports; HIV pathogenesis data; and panel expert opinion. Recommendations were limited to therapies available (US Food and Drug Administration approved) in 1999. CONSENSUS PROCESS: The panel assesses new research reports and interim results and regularly meets to consider how the new data affect therapy recommendations. Recommendations are updated via full-panel consensus. Guidelines are presented as recommendations if the supporting evidence warrants routine use in the particular situation and as considerations if data are preliminary or incomplete but suggestive. CONCLUSIONS: The availability of new antiretroviral drugs has expanded treatment choices. The importance of adherence, emerging long-term complications of therapy, recognition and management of antiretroviral failure, and new monitoring tools are addressed. Optimal care requires individualized management and ongoing attention to relevant scientific and clinical information in the field.

Adult↗
PubMed2000

Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens.

CONTEXT: Loss of viral suppression in patients infected with human immunodeficiency virus (HIV), who are receiving potent antiretroviral therapy, has been attributed to outgrowth of drug-resistant virus; however, resistance patterns are not well characterized in patients whose protease inhibitor combination therapy fails afterachieving viral suppression. OBJECTIVE: To characterize drug susceptibility of virus from HIV-infected patients who are failing to sustain suppression while taking an indinavir-containing antiretroviral regimen. DESIGN AND SETTING: Substudy of the AIDS Clinical Trials Group 343, a multicenter clinical research trial conducted between February 1997 and October 1998. PATIENTS: Twenty-six subjects who experienced rebound (HIV RNA level > or =200 copies/mL) during indinavir monotherapy (n = 9) or triple-drug therapy (indinavir, lamivudine, and zidovudine; n = 17) after initially achieving suppression while receiving all 3 drugs, and 10 control subjects who had viral suppression while receiving triple-drug therapy. MAIN OUTCOME MEASURE: Drug susceptibility, determined by a phenotypic assay and genotypic evidence of resistance assessed by nucleotide sequencing of protease and reverse transcriptase, compared among the 3 patient groups. RESULTS: Indinavir resistance was not detected in the 9 subjects with viral rebound during indinavir monotherapy or in the 17 subjects with rebound during triple-drug therapy, despite plasma HIV RNA levels ranging from 10(2) to 10(5) copies/mL. In contrast, lamivudine resistance was detected by phenotypic assay in rebound isolates from 14 of 17 subjects receiving triple-drug therapy, and genotypic analyses showed changes at codon 184 of reverse transcriptase in these 14 isolates. Mean random plasma indinavir concentrations in the 2 groups with rebound were similar to those of a control group with sustained viral suppression, although levels below 50 ng/mL were more frequent in the triple-drug group than in the control group (P = .03). CONCLUSIONS: Loss of viral suppression may be due to suboptimal antiviral potency, and selection of a predominantly indinavir-resistant virus population may be delayed for months even in the presence of ongoing indinavir therapy. The results suggest possible value in assessing strategies using drug components of failing regimens evaluated with resistance testing.

Anti-HIV Agents↗
PubMed2000

Viability and functional activity of cryopreserved mononuclear cells.

Factors that influence viability and function of cryopreserved peripheral blood mononuclear cells (PBMC) were identified on 54 samples from 27 AIDS Clinical Trial Units. PBMC viability ranged from 1 to 96% with a median of 70%, was higher in laboratories with experienced staff, and was not significantly associated with CD4 cell number. Function of cryopreserved PBMC, measured by lymphocyte proliferation, was associated with viability. Preparations with viability greater than or equal to 70% had consistent proliferative responses and were suitable for functional analyses.

Cell Division↗
PubMed2000

Marked differences in quantity of infectious human immunodeficiency virus type 1 detected in persons with controlled plasma viremia by a simple enhanced culture method.

Culture of autologous CD4 lymphocytes from peripheral blood mononuclear cells compared favorably with two other methods for the measurement of cell-associated human immunodeficiency virus type 1 (HIV-1). For subjects with undetectable HIV-1 RNA levels in plasma, there was a 10,000-fold range of cell-associated virus detected. This method provides a simple and reproducible means for monitoring cell-associated HIV-1.

CD4-Positive T-Lymphocytes↗
PubMed2000

Combination of CCR5 and CXCR4 inhibitors in therapy of human immunodeficiency virus type 1 infection: in vitro studies of mixed virus infections.

We studied the combined anti-human immunodeficiency virus type 1 (HIV-1) effects of a derivative of stroma-derived factor 1beta (SDF-1beta), Met-SDF-1beta, and a modified form of RANTES, aminooxypentane (AOP)-RANTES. The antiviral agents were tested singly or in combination at 95 and 99% virus inhibitory concentrations. Clinical R5 and X4 HIV-1 isolates were used. AOP-RANTES inhibited R5 but not X4 viruses, whereas Met-SDF-1beta had the opposite effect. Combinations of these compounds inhibited mixed infections with R5 and X4 viruses (95 to 99%), whereas single drugs were less inhibitory (32 to 61%). Combinations of R5 and X4 inhibitors are promising and deserve further evaluation.

Amino Acid Sequence↗
PubMed2000

In vitro inhibition of HIV-1 by Met-SDF-1beta alone or in combination with antiretroviral drugs.

Compounds that can block the CXCR4 chemokine receptor are a promising new class of antiretroviral agents. In these experiments we studied the effect of a modified form of the native stromal cell-derived factor-1 (SDF-1), Met-SDF-1beta. The in vitro susceptibility of two different CXCR4-tropic HIV-1 strains was determined. Antiviral effect was assessed by the reduction of p24 antigen production in PHA-stimulated peripheral blood mononuclear cells with exposure to the modified SDF-1 molecule. The 50% inhibitory concentrations (IC50) were derived from six separate experiments. The IC50 against the two HIV-1 isolates was in 1.0-2.8 microg/ml range for Met-SDF-1beta. Met-SDF-1beta showed synergy to additivity with either zidovudine or nelfinavir at IC75 IC90 and IC95. Additivity was seen when Met-SDF-1beta was combined with efavirenz. No cellular toxicity was observed at the highest concentrations when these agents were used either singly or in combination. This compound is a promising new candidate in a receptor-based approach to HIV-1 infection in conjunction with currently available combination antiretroviral drug therapies.

Anti-HIV Agents↗