Search PubMed⌕ Search

Biomedical subjects

S M Hammer

Publications and source records attributed to S M Hammer.

At least 55 records · Page 3Linked to original sources
PubMed1996

The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team.

BACKGROUND: We studied measures of human immunodeficiency virus (HIV) replication, the viral phenotype, and immune function (CD4 cell counts) and the relation of changes in these indicators to clinical outcomes in a subgroup of patients in a controlled trial of early antiretroviral treatment for HIV, the AIDS Clinical Trials Group Study 175. METHODS: The 391 subjects, each of whom entered the study with a single screening CD4 cell count of 200 to 500 per cubic millimeter, were randomly assigned to receive zidovudine alone, didanosine alone, zidovudine plus didanosine, or zidovudine plus zalcitabine. Plasma concentrations of HIV RNA were assessed in 366 subjects, and viral isolates from 332 subjects were assayed for the presence of the syncytium-inducing phenotype. RESULTS: After eight weeks, the mean (+/-SE) decrease from base line in the concentration of HIV RNA, expressed as the change in the base 10 log of the number of copies per milliliter, was 0.26+/-0.06 for patients treated with zidovudine alone, 0.65+/-0.07 for didanosine alone, 0.93+/-0.10 for zidovudine plus didanosine, and 0.89+/-0.06 for zidovudine plus zalcitabine (P<0.001 for each of the pairwise comparisons with zidovudine alone). Multivariate proportional-hazards models showed that higher base-line concentrations of plasma HIV RNA, less suppression of plasma HIV RNA by treatment, and the presence of the syncytium-inducing phenotype were significantly associated with an increased risk of progression to the acquired immunodeficiency syndrome and death. After adjustment for these measures of viral replication and for the viral phenotype, CD4 cell counts were not significant predictors of clinical outcome. CONCLUSIONS: Both the risk of the progression of HIV disease and the efficacy of antiretroviral therapy are strongly associated with the plasma level of HIV RNA and with the viral phenotype. The changes in the plasma concentration of HIV RNA predict the changes in CD4 cell counts and survival after treatment with reverse-transcriptase inhibitors.

Adult↗
PubMed1996

Lack of in vivo effect of granulocyte-macrophage colony-stimulating factor on human immunodeficiency virus type 1.

Neutropenia complicates HIV disease or its treatment in a large proportion of patients. Hematopoietic growth factor support has been tested in a number of clinical settings in HIV disease and has been demonstrated to be of benefit for specific parameters. One consideration regarding the use of hematopoietic growth factors in HIV disease is their potential effect on HIV viral burden, since alterations in HIV expression have been documented with certain cytokines in vitro. It has also been reported that some cytokines, notably GM-CSF, potentiate the antiviral properties of thymidine analogs such as zidovudine (AZT) in vitro. We tested these observations in vivo. Twelve HIV-positive patients with a CD4 cell count < or = 200/mm3 or HIV plasma viremia who were receiving a stable dose of zidovudine were enrolled into three dose cohorts of yeast-derived GM-CSF at 50, 125, or 250 micrograms/m2 daily by subcutaneous self-injection for 28 days. Measurements of HIV activity included serum acid-dissociated HIV p24 antigen levels, plasma and peripheral blood mononuclear cell (PBMC) limiting dilution HIV culture, and plasma HIV quantitative competitive polymerase chain reaction (PCR). Serum and intracellular zidovudine levels were measured as well as hematologic, immunologic, and toxicity parameters. Virologic measures showed neither significant upregulation nor downregulation of serum acid-dissociated HIV p24 antigen, plasma and PBMC HIV culture, or PCR in association with GM-CSF administration. A trend toward increased intracellular AZT levels was noted, but this did not achieve statistical significance (p = 0.073). CD4 and CD8 lymphocytes were essentially unaffected while absolute neutrophil counts increased with GM-CSF administration as expected. These data suggest that administration of GM-CSF does not perturb HIV activity or immunologic parameters in patients receiving AZT for advanced HIV disease. No potentiation of AZT antiviral effect was demonstrated.

Adult↗
PubMed1996

Antiretroviral therapy for HIV infection in 1996. Recommendations of an international panel. International AIDS Society-USA.

OBJECTIVE: To provide clinical recommendations for antiretroviral therapy for human immunodeficiency virus (HIV) disease with currently (mid 1996) available drugs. When to start therapy, what to start with, when to change, and what to change to were addressed. PARTICIPANTS: A 13-member panel representing international expertise in antiretroviral research and HIV patient care was selected by the international AIDS Society-USA. EVIDENCE: Available clinical and basic science data, including phase 3 controlled trials, clinical endpoint data, virologic and immunologic endpoint data, interim analyses, studies of HIV pathophysiology, and expert opinions of panel members were considered. Recommendations were limited to drugs available in mid 1996. PROCESS: For each question posed, 1 or more member(s) reviewed and presented available data. Recommendations were determined by group consensus (January 1996); revisions as warranted by new data were incorporated by group consensus (February-May 1996). CONCLUSIONS: Recent data on HIV pathogenesis, methods to determine plasma HIV RNA, clinical trial data, and availability of new drugs point to the need for new approaches to treatment. Therapy is recommended based on CD4+ cell count, plasma HIV RNA level, or clinical status. Preferred initial drug regimens include nucleoside combinations; at present protease inhibitors are probably best reserved for patients at higher progression risk. For treatment failure or drug intolerance, subsequent regimen considerations include reasons for changing therapy, available drug options, disease stage, underlying conditions, and concomitant medication(s). Therapy for primary (acute) infection, high-risk exposures to HIV, and maternal-to-fetal transmission are also addressed. Therapeutic approaches need to be updated as new data continue to emerge.

Antiviral Agents↗
PubMed1996

Epstein-Barr virus-induced infectious mononucleosis complicated by acute renal failure: case report and review.

Infectious mononucleosis, most commonly caused by Epstein-Barr virus (EBV), is generally a benign, self-limited illness. Occasionally, however, more severe complications may arise such as acute renal insufficiency. While subclinical renal involvement appears to be relatively common in patients with infectious mononucleosis, patients with significant renal parenchymal dysfunction have rarely been described in the English-language literature. In this report, we review 27 previous cases ad present a case of oliguric renal failure complicating heterophil-positive infectious mononucleosis. The patient required hemodialysis but recovered promptly with treatment with the combination of corticosteroids plus acyclovir. Renal biopsy revealed interstitial nephritis, and immunoperoxidase studies demonstrated a predominance of suppressor/cytotoxic T cells, which has been described in only one previous case report. In situ hybridization done on renal biopsy tissue failed to reveal evidence of EBV-encoded RNA-1. Acute renal failure in infectious mononucleosis is rare, often self-limited, and usually caused by interstitial nephritis that is likely the result of immunopathologic injury precipitated by EBV infection.

Acute Kidney Injury↗
PubMed1996

Evaluation of an infectivity standard for real-time quality control of human immunodeficiency virus type 1 quantitative micrococulture assays. Participating Laboratories of The AIDS Clinical Trials Group.

Quantitative microculture assays of cryopreserved human immunodeficiency virus type 1-infected cell suspensions and culture supernatants were compared among seven assays sites. There was no significant change in titer during 1 year of storage. The overall standard deviation for infected cell suspensions was approximately 0.8 log10 virus titer. A method for detecting deviant assay results was developed and was used to identify two donor cell preparations (n = 54) that gave consistently low titers.

Cell Culture Techniques↗
PubMed1996

Advances in antiretroviral therapy and viral load monitoring.

OBJECTIVE: To highlight recent developments in the field of antiretroviral therapy and viral load monitoring. METHODS: Review of studies detailing the efficacy of the antiretroviral agents and combinations furthest along in clinical development and the application of plasma HIV RNA quantification as a disease marker. RESULTS: Developments in the field of antiretroviral therapy have led to substantial advances in the approach to management of HIV-infected persons. These include the end of the zidovudine (ZDV) monotherapy era; the demonstration of a survival benefit conferred by antiretroviral therapy in patients with CD4 counts of 200-500x10(6)/l; the further development of newer nucleoside analog combinations (e.g., ZDV-lamivudine, stavudine-didanosine, stavudine-lamivudine, ZDV-1592U89) and the non-nucleoside reverse transcriptase inhibitor class of compounds; and, perhaps most importantly, the advent of the protease inhibitor era. Trials of ritonavir and saquinavir have proven that clinical benefit can be conferred by protease inhibitors, and three-drug combination regimens, such as indinavir-ZDV-lamivudine, have shown the potential for degrees of viral suppression not previously seen. Newer protease inhibitors, such as nelfinavir and VX-478/GW141W94, hold promise for further advances. The concurrent development of assays to quantitatively measure plasma HIV RNA has provided laboratory tools to improve our understanding of disease pathogenesis, to assess the in vivo potency of treatment regimens and to characterize the risk of disease progression. CONCLUSIONS: Recent progress in HIV disease pathogenesis, antiretroviral therapy and viral load monitoring indicates the interdependence of these factors. The current optimism in the field is warranted but complex challenges must be met if the fulfilment of this hope is to be realized by the world community.

Adult↗
PubMed1995

Major infectious complications after orthotopic liver transplantation and comparison of outcomes in patients receiving cyclosporine or FK506 as primary immunosuppression.

A retrospective cohort study was conducted to determine the incidence of major infectious complications after orthotopic liver transplantation and to compare outcomes in patients receiving either cyclosporine (CsA) or FK506 (tacrolimus) as primary immunosuppression. Of 133 transplants performed in 118 patients, 124 transplant episodes were evaluated. Cytomegalovirus (CMV) infection (INF) and disease (DIS), deep fungal infection (DFI), and intraabdominal bacterial infections (IAI) were catalogued. The overall incidences of major infectious outcomes were: CMV INF = 33%; CMV DIS = 19%; DFI = 15%; and IAI = 25%. Cox proportional hazard analysis identified donor seropositivity, OKT3 as secondary immunosuppression and initial intensive care unit (ICU) duration as risk factors for CMV INF and DIS in the overall population. Fungal colonization was the dominant risk factor associated with deep fungal infection. A choledochojejunostomy anastomosis, the number of cellular blood products transfused at the time of transplantation surgery, and prior CMV INF were independent risk factors for both fungal colonization and deep infection. The single risk factor identified for intraabdominal bacterial infections was the number of cellular blood products transfused at the time of surgery. In the Cox proportional hazards model the relative risk (RR) for each category of infection was lower in the FK506 group (CMV: RR = .87, 95% confidence interval [C.I.] = [.32-2.4]; DFI: .58 [.13-2.6]; IAI: .51 [.15-1.7]), but the effect was not statistically significant. Survival was similar in patients receiving FK506 or CsA. CMV INF and DFI were independent predictors of death for all patients. Risk factors identified for CMV INF and DIS support the findings of others. Higher intraoperative blood product requirements and complicated intraoperative or postoperative courses increase the risk for IAI or DFI. The development of effective strategies to prevent CMV and fungal infections in liver transplant recipients remains a priority for future endeavors.

Bacterial Infections↗
PubMed1995

In vivo effects of interleukin 3 in HIV type 1-infected patients with cytopenia.

OBJECTIVE: To determine the safety, tolerance, and hematological and virological effects of the recombinant hematopoietic growth factor interleukin 3 (IL-3) in HIV-1-infected individuals with cytopenia. DESIGN AND METHODS: A phase I single-center trial was conducted with patients in cohorts of three receiving one of four dose levels of self-administered, subcutaneously injected IL-3 (0.5, 1.0, 2.5, or 5.0 micrograms/kg/day). Toxicities, hematological effects, and virological effects were recorded. Viral studies included serum HIV p24 antigen levels, quantitative plasma and peripheral blood mononuclear cell cultures, and quantitative, competitive polymerase chain reaction of patient plasma. RESULTS: Increases in white blood cell counts (WBC) and absolute neutrophil counts (ANC) were noted at the higher dose levels while absolute eosinophil counts (AEC) increased in all patients. The percent changes in WBC from baseline ranged from 52 to 309 and in ANC from 20 to 262 in the 2.5- and 5.0-micrograms/kg/day groups. The mean AEC change was 17-fold (range, 2- to 59-fold). Hemoglobin, hematocrit, platelets, and CD4 and CD8 counts were generally unaffected although individual patients demonstrated increases in hemoglobin and platelet levels. Toxicities were generally mild, but one patient developed a transient local erythematous rash at the sites of IL-3 injection which pathologically demonstrated hypersensitivity vasculitis. Of note, viral studies did not demonstrate any consistent changes in HIV-1 activity. CONCLUSION: These data demonstrate limited hematological effects of IL-3 monotherapy in HIV-1-infected patients with cytopenia. However, should IL-3 be incorporated into combination cytokine therapies for HIV disease, these data suggest that IL-3 does not enhance in vivo HIV-1 activity.

Adult↗
PubMed1995

HIV-1 Tat modulates invasion by a bacterial enteric pathogen into a human intestinal cell line.

OBJECTIVE: To explore the possibility that an HIV-1 gene product may modulate entry of an invasive enteric pathogen into a terminally differentiated human intestinal cell line. HIV-1 Tat was selected for investigation because of its unique ability to cross cell membranes. METHODS: After transient transfection of HT29-C1 cells with plasmids containing HIV-1 long terminal repeat (LTR)-lacZ plus a Tat expression cassette, or with a pSR-lacZ control plasmid, bacterial invasion assays were performed on both groups of cells utilizing a clinical Salmonella isolate. Assays were performed concurrently on a control group of non-transfected cells. A second series of experiments compared bacterial invasion into cells transfected with the Tat expression vector alone versus cells transfected with either an isogenic expression vector that did not make Tat, or with pSR-lacZ. Finally, the ability of exogenous Tat protein to transactivate an HIV-1 LTR-chloramphenicol acetyltransferase (CAT) plasmid which had been transfected into HT29-C1 cells and to modulate Salmonella invasion was also assessed. RESULTS: HT29-C1 cells transfected with a Tat expression vector, either alone or in combination with another plasmid, were significantly less susceptible to bacterial invasion than cells that either did not undergo transfection, were transfected with an otherwise isogenic expression vector without Tat, or transfected with an unrelated plasmid. Duplicate experiments also demonstrated that exogenous purified Tat protein transactivated an HIV-1 LTR-CAT plasmid which had been transfected into HT29-C1 cells and inhibited Salmonella invasion compared with unexposed cells. CONCLUSION: HIV-1 Tat inhibits Salmonella invasion of a human enterocyte cell line whether the protein is expressed intracellularly or provided exogenously.

Animals↗
PubMed1995

An approach to antiretroviral treatment of HIV disease. Nucleoside monotherapy.

Despite hopes for attack of multiple viral targets, the licensed agents now in use are all of one type: the nucleoside analogue reverse transcriptase inhibitors, of which four, including zidovudine, are available, with a fifth likely to follow. Clinicians and patients are still struggling to learn how best to employ them; but even now, the available trial results can be distilled into rational management plans.

Antiviral Agents↗
PubMed1994

Physiological effects of HIV infection on human intestinal epithelial cells: an in vitro model for HIV enteropathy.

OBJECTIVES: To determine the role of direct infection of intestinal cells with HIV-1 in the pathogenesis of HIV-related enteropathy. METHODS: We infected HT-29-18-C1 intestinal cells with the IIIB strain of HIV and examined the physiologic effects of enterocyte function. Dipeptidase-IV, aminopeptidase-N, gamma glutamic transferase, and alkaline phosphatase were measured in HIV-infected and control cultures. The cellular second messengers intracellular calcium and cyclic adenosine monophosphate were also measured in infected and control cultures. RESULTS: A persistent infection was established for > 95 days with peak supernatant reverse transcriptase and HIV p24 antigen levels of 5.17 log10 c.p.m./ml and 45 ng/ml, respectively. Brush-border enzyme activity (nmol of product/min/mg protein) tended to be lower in infected cell cultures compared with controls early in infection (P < 0.02). Baseline second messenger concentrations were similar but infected cultures responded to stimulation with a calcium ionophore with an exaggerated increase in intracellular calcium (P = 0.03). CONCLUSIONS: These results suggest that absorptive and secretory function of enterocytes may be altered by direct HIV infection and that additional physiologic experiments with this in vitro model may lead to a better understanding of the clinical syndrome of HIV enteropathy.

Alkaline Phosphatase↗
PubMed1994

Dideoxynucleoside resistance emerges with prolonged zidovudine monotherapy. The RV43 Study Group.

Human immunodeficiency virus type 1 (HIV-1) isolates resistant to zidovudine (ZDV) have previously been demonstrated to exhibit in vitro cross-resistance to other similar dideoxynucleoside agents which contain a 3'-azido group. However, cross-resistance to didanosine (ddI) or dideoxycytidine (ddC) has been less well documented. ZDV, ddI, and ddC susceptibility data have been collected from clinical HIV-1 isolates obtained by five clinical centers and their respective retrovirology laboratories. All subjects were treated only with ZDV. Clinical HIV-1 isolates were isolated, amplified, and assayed for drug susceptibility in standardized cultures of phytohemagglutinin-stimulated donor peripheral blood mononuclear cells obtained from healthy seronegative donors. All five cohorts showed a correlation between decreased in vitro susceptibility to ZDV and decreased susceptibility to ddI and ddC. For each 10-fold decrease in ZDV susceptibility, an average corresponding decrease of 2.2-fold in ddI susceptibility was observed (129 isolates studied; P < 0.001, Fisher's test of combined significance). Similarly, susceptibility to ddC decreased 2.0-fold for each 10-fold decrease in ZDV susceptibility (82 isolates studied; P < 0.001, Fisher's test of combined significance). These data indicate that a correlation exists between HIV-1 susceptibilities to ZDV and ddI or ddC for clinical HIV-1 isolates.

AIDS-Related Complex↗
PubMed1994

Cytomegalovirus vasculitis. Case reports and review of the literature.

Cytomegalovirus (CMV) infection is a substantial cause of morbidity and mortality among immunocompromised patients. It may present with a mild, self-limited syndrome, retinitis, colitis, or invasive disease with pneumonitis, hepatitis, and bone marrow suppression. We review another, less common manifestation of CMV disease: CMV-associated vasculitis. CMV may productively infect vascular endothelial cells (25), causing a local vasculitis (3, 14, 19) and ischemia. Alternatively, the host immune response to cells expressing viral antigen may be the stimulus for vasculitis (12, 53). Since there are no pathognomonic appearances to mucosal or cutaneous lesions, biopsy of accessible sites is critical for diagnosis and expeditious initiation of appropriate antiviral therapy. The CMV-associated vasculitides represent a broad spectrum of diseases, with GI vasculitis in nontransplant recipients having the best prognosis. Cutaneous vasculitis associated with CMV seems to be a more fulminant disease, with the majority of cases having a fatal outcome. These differences likely reflect the degree of viral burden and the state of immune competence. Additionally, since the virus itself is immunosuppressive, host defenses may be further compromised by the infection. Although a large collective experience assessing the impact of ganciclovir and foscarnet is not currently available, both the prompt initiation of antiviral treatment and a concurrent reduction in any immunosuppressive regimen, including steroids, should be undertaken since these therapeutic strategies have clearly improved outcome for other CMV syndromes (22, 34, 55). As the number of recipients rises and the HIV pandemic spreads we are likely to see an increase in the number of cases of vasculitis associated with CMV infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Pathogenicity and diversity of HIV and implications for clinical management: a review.

Genetic variation of human immunodeficiency virus (HIV) over time is an important consideration in long-term antiretroviral therapy, in all likelihood affecting the course of HIV disease and its response to antiretroviral therapy. Viral replication persists throughout HIV disease, and viral burden is correlated with disease stage. CD4+ T-helper cells, a prime target for HIV, appear responsible for direct cellular and humoral responses to infection. HIV can be divided into three groups: nonsyncytium-inducing (NSI) isolates with low replicative capacity; high-replicative-capacity NSI isolates; and high-replicative-capacity, syncytium-inducing (SI) isolates. The SI phenotype also is associated with T-helper-cell tropism, rapid CD4+ cell count decline, and rapid HIV disease progression. In some HIV-infected individuals, SI variants evolve from NSI variants at approximate mean CD4+ cell counts of 400 to 500 cells/microliters. Appearance of SI variants may be a useful prognostic marker for decline in cell counts and more rapid progression to AIDS. However, SI variants are not required for HIV disease progression. Only about one-half of AIDS patients harbor SI variants, indicating that HIV that remains NSI can cause AIDS and death. Zidovudine resistance has been found (in ACTG 116B/117) to be an independent predictor of HIV disease progression. Zidovudine resistance and SI phenotype together are closely associated with rapid HIV disease progression.

Antiviral Agents↗
PubMed1994

Issues in combination antiretroviral therapy: a review.

High viral burden and replication persist during all phases of human immunodeficiency virus (HIV) disease. Although monotherapy has yielded considerable benefits, these benefits are neither absolute nor durable. Combination therapy has multiple goals: to reduce viral replication and burden; to relieve drug toxicity; to attenuate viral mutations leading to resistance and possibly to conversion from non-syncytium-inducing to syncytium-inducing virus; and to broaden the spectrum of specific cells and tissues in which antiretroviral agents are active. At present, zidovudine remains the cornerstone of antiretroviral monotherapy and combination therapy. A partial list of agents tried in combinations with and without zidovudine includes the nucleoside analogues zalcitabine and didanosine; non-nucleoside reverse-transcriptase inhibitors (nevirapine, delavirdine, atevirdine, pyridinones, TIBO derivatives); protease inhibitors; inhibitors of viral regulatory functions (tat inhibitors); cytokine antagonists; acyclovir; and colony-stimulating factors. The rationales, the regimens, and the results all vary. We usually recommend combination therapy for treatment-naive patients who are asymptomatic with < 200 CD4+ cells/mm3 or who are symptomatic, and for patients who have been receiving zidovudine monotherapy and who are stable but whose CD4+ counts have fallen to < 300 cells/mm3, or who are progressing. In the absence of definitive results from clinical trials of combination therapy, the decision to embark on this route remains to be made between each individual patient and the practitioner.

AIDS-Related Opportunistic Infections↗
PubMed1992

Zidovudine: five years later.

Zidovudine, a nucleoside analog, was the first agent proved to be effective in the management of human immunodeficiency virus type 1 (HIV-1) infection. After demonstration of zidovudine's in-vitro activity against HIV-1 in 1985, the drug was rapidly evaluated in phase I and phase II clinical trials and was found to be effective in decreasing both mortality and the incidence of opportunistic infections in patients with the acquired immunodeficiency syndrome (AIDS) and advanced AIDS-related complex; the drug was also found to have a substantial but tolerable toxicity profile. Since the licensure of zidovudine in 1987, an intensive clinical research effort has established the drug's efficacy in the prevention of disease progression in asymptomatic and mildly symptomatic HIV-infected persons and has established the success of lower-dose therapy in patients at all stages of disease. The current recommendation is to use zidovudine at a dose of 500 to 600 mg/d in both symptomatic and asymptomatic persons with CD4 counts of less than 500/mm3. The major toxicities of anemia and neutropenia are less frequent at the lower doses presently used and can be managed by dose reduction or by use of hematopoietic growth factors. The inexorable disease progression seen despite zidovudine therapy and the isolation of clinical strains of HIV-1 resistant to zidovudine in vitro highlight the limitations of prolonged monotherapy with this agent. Although alternative dideoxynucleoside agents (for example, didanosine [dideoxyinosine and zalcitabine dideoxycytidine]) are available for the management of HIV-infected persons, zidovudine remains the cornerstone of antiretroviral therapy. Current research efforts are directed at elucidating the clinical relevance of zidovudine resistance and studying regimens in which zidovudine is used in combination with other agents. This latter approach holds great promise for improving efficacy, limiting toxicity, and perhaps preventing the emergence of viral resistance. For the forseeable future, zidovudine will continue to play a role in the development and in our understanding of antiretroviral therapy.

Clinical Trials as Topic↗
PubMed1992

Treatment of HIV infection: the antiretroviral nucleoside analogues. Nucleoside analogues: combination therapy.

Combination antiretroviral therapy is an important development in the management of HIV infection. AZT with ddC is the first such combination to be approved for clinical use. Several issues remain, however, including the precise clinical benefit and toxicity of combination therapy, its effect on drug resistance, and the development of ever more effective therapeutic strategies.

Acquired Immunodeficiency Syndrome↗