Search PubMed⌕ Search

Biomedical subjects

M S Hirsch

Publications and source records attributed to M S Hirsch.

At least 91 records · Page 5Linked to original sources
PubMed1993

pol mutations conferring zidovudine and didanosine resistance with different effects in vitro yield multiply resistant human immunodeficiency virus type 1 isolates in vivo.

Specific mutations in the human immunodeficiency virus type 1 (HIV-1) pol gene that cause zidovudine (3'-azido-2',3'-dideoxythymidine; AZT) and didanosine (2',3'-dideoxyinosine; ddI) resistance were studied. The 50% inhibitory concentrations (IC50s) of nucleosides for cloned viruses containing these mutations were compared with the IC50s of the corresponding triphosphate analogs for mutant recombinant-expressed reverse transcriptases (RTs). Changes in ddATP inhibition of RNA-dependent DNA polymerase activity fully accounted for the ddI resistance of the virus caused by a Leu-74-->Val substitution in RT, including an augmentation by the AZT-selected substitutions Thr-215-->Tyr and Lys-219-->Gln in RT. In contrast, the AZT-selected substitutions studied did not cause as great a change in the IC50 of AZT-triphosphate (AZT-TP) for polymerase as they did in the IC50 of AZT for mutant virus. In addition, the mutation at codon 74 suppressed AZT resistance in the virus caused by the mutations at codons 215 and 219 but did not suppress the AZT-TP resistance of enzyme containing these same mutations in RT. The mutation at codon 74 was found in clinical isolates whether or not the patient had received AZT prior to starting ddI therapy. AZT resistance coexisted with ddI resistance following acquisition of Leu-74-->Val in three clinical isolates, indicating that the suppressive effect of Val-74 on the AZT resistance of the virus does not occur in all genetic contexts. When this suppression of AZT resistance was seen in the virus, Val-74 did not appear to cause mutually exclusive changes in AZT-TP and ddATP binding to RT in vitro. The results of the in vitro experiments and characterization of clinical isolates suggest that there are differences in the functional effects of these AZT and ddI resistance mutations.

AIDS-Related Complex↗
PubMed1993

Cytomegalovirus antigenemia: clinical correlations in transplant recipients and in persons with AIDS.

We evaluated a rapid immunoperoxidase technique for the detection of cytomegalovirus (CMV) antigenemia in peripheral blood neutrophils of 56 transplant recipients (117 specimens) and 36 persons with AIDS (59 specimens). Antigenemia was 92% sensitive and 98% specific for the detection of clinical CMV infection in transplant recipients and 100% sensitive and 86% specific in persons with AIDS. Overall, CMV antigenemia was a more rapid and sensitive method for the detection of clinical CMV infection than either shell vial culture or conventional tube culture of blood.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Eosinophils as host cells for HIV-1.

Transient expression of HIV-1 p24 antigen was observed in eosinophils acutely infected with the HTLV-IIIB strain of HIV-1. PCR analysis of eosinophils isolated from 18 seropositive individuals showed HIV-1 sequences to be present in 2 subjects. These data suggest that eosinophils may act as host cells for HIV-1.

DNA, Viral↗
PubMed1992

Comparison of spot-blot and microtitre plate methods for the detection of HIV-1 PCR products.

We have compared spot-blot methodology with a recently developed rapid microtitre plate assay for the specific detection of HIV-1 PCR products. We have studied blood specimens isolated from HIV-1 infected individuals (48 asymptomatic and 56 symptomatic patients). Mononuclear cells were isolated, lysed and processed for PCR. Both PCR product detection methods were carried out in parallel on all amplified samples. HIV-1 sequences were detected by spot-blot or microtitre plate hybridization in samples taken from 42/48 asymptomatic and 53/56 symptomatic subjects. Concordant results between the two detection methods were observed for 90 samples, with 81 positive and nine negative assays. On repeat evaluation of the 14 discordant samples, nine showed concordant positive results, near the limit of detection of the assay. Serial dilutions of ACH-2 cells were amplified, and the PCR products were detected using the microtitre plate assay, yielding semi-quantitative results. The sensitivity of this simple, rapid assay compares with that of more laborious DNA detection systems. This may become a useful tool in HIV-1 research and in the clinical care of seropositive individuals.

DNA, Viral↗
PubMed1992

Human immunodeficiency virus type 1 (HIV-1) inhibitory interactions between protease inhibitor Ro 31-8959 and zidovudine, 2',3'-dideoxycytidine, or recombinant interferon-alpha A against zidovudine-sensitive or -resistant HIV-1 in vitro.

Protease inhibitor Ro 31-8959, a compound that interrupts human immunodeficiency virus (HIV)-specific formation of infectious virions, was evaluated in two-drug combined regimens with zidovudine, 2',3'-dideoxycytidine (ddC), or recombinant interferon-alpha A (rIFN-alpha A) against HIV-1 replication in vitro. By using peripheral blood mononuclear cells infected with HIV-1, drug interactions were evaluated by the median-effect principle and the isobologram technique. A zidovudine-sensitive and -resistant HIV-1 isolate pair was studied. Additive to synergistic anti-HIV-1 interactions were seen with 7.5-30 nM Ro 31-8959 and 0.005-0.02 microM zidovudine (for the zidovudine-sensitive HIV-1 isolate), 0.25-1.0 microM zidovudine (for the zidovudine-resistant HIV-1 isolate), 0.025-0.1 microM ddC, and 8-32 units/mL rIFN-alpha A, without additive toxicity. Phase I/II clinical trials of Ro 31-8959 for therapy of HIV-1 infection are in progress. If results are favorable, combined regimens including Ro 31-8959 deserve consideration for future clinical trials.

Cells, Cultured↗
PubMed1992

Synergistic inhibition of replication of human immunodeficiency virus type 1, including that of a zidovudine-resistant isolate, by zidovudine and 2',3'-dideoxycytidine in vitro.

The combination of zidovudine (AZT) and 2',3'-dideoxycytidine synergistically inhibits human immunodeficiency virus type 1 (HIV-1) replication in vitro with AZT-sensitive and AZT-resistant clinical isolates and HIV-1IIIB. Synergy was determined by the median-effect principle and isobologram techniques. Cytotoxicity of the agents was not observed. Clinical trials are ongoing to define the combination's role in HIV-1 therapy.

Drug Combinations↗
PubMed1991

Enhancement of human immunodeficiency virus 1 replication in monocytes by 1,25-dihydroxycholecalciferol.

Human immunodeficiency virus (HIV) expression and replication are under tight regulatory control. We demonstrate that 1,25-dihydroxycholecalciferol [1,25-(OH)2D3] enhances the replication of monocyte- and lymphocyte-tropic strains of HIV-1 up to 10,000-fold in monocyte cell lines, peripheral blood monocytes, and unfractionated peripheral blood mononuclear cells. 1,25(OH)2D3 is therefore one of the most potent regulators of HIV-1 replication described to date. Precursors of 1,25(OH)2D3 enhance HIV-1 replication in proportion to their affinity for the 1,25(OH)2D3 intracellular receptor, suggesting that 1,25(OH)2D3 influences HIV-1 replication by mechanisms involving this receptor. These studies may have important implications for the design of effective therapy of HIV-1 infection.

Antigens, CD↗
PubMed1991

Two-drug combinations of zidovudine, didanosine, and recombinant interferon-alpha A inhibit replication of zidovudine-resistant human immunodeficiency virus type 1 synergistically in vitro.

Optimal management of human immunodeficiency virus type 1 (HIV-1) infections may require combinations of anti-HIV-1 agents. Zidovudine (AZT, 3'-azido-3'-deoxythymidine), didanosine (ddI, 2',3'-dideoxyinosine), and recombinant interferon-alpha A (rIFN-alpha A) were evaluated in two-drug regimens against replication of AZT-resistant HIV-1 in vitro. AZT-sensitive and AZT-resistant isolate pairs derived from two individuals before and after extended AZT monotherapy were studied. Drug interactions using peripheral blood mononuclear cells infected with HIV-1 were evaluated mathematically. Synergistic interactions were seen among AZT, ddI, and rIFN-alpha A in two-drug regimens against AZT-resistant HIV-1 in vitro, even when AZT was included in the treatment regimen. Mixtures of wild-type and mutant reverse transcriptase genes were found in one of the late-AZT therapy isolates, suggesting that the mechanism of synergy of AZT-containing regimens may involve inhibition of AZT-sensitive viruses in the viral pool. These studies suggest that AZT may be useful in drug combination regimens, even when AZT-resistant viruses are isolated in vitro.

Base Sequence↗
PubMed1990

A randomized controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome. The AIDS Clinical Trials Group.

BACKGROUND: The initially tested dose of zidovudine for the treatment of patients with advanced disease caused by the human immunodeficiency virus type 1 (HIV) was 1500 mg. Although this dose is effective, it is associated with substantial toxicity. METHODS: To evaluate the efficacy and safety of a reduced dose, we conducted a randomized controlled trial in 524 subjects who had had a first episode of Pneumocystis carinii pneumonia. The subjects were assigned to receive zidovudine in either a dose of 250 mg taken orally every four hours (the standard-treatment group, n = 262) or a dose of 200 mg taken orally every four hours for four weeks and thereafter 100 mg taken every four hours (the low-dose group, n = 262). RESULTS: The median length of follow-up was 25.6 months. At 18 months the estimated survival rates were 52 percent for the standard-treatment group and 63 percent for the low-dose group (P = 0.012 by the log-rank test). At 24 months the estimated survival rates were 27 percent for the standard-treatment group and 34 percent for the low-dose group (P = 0.033). In both groups, 82 percent of the subjects had another opportunistic infection, and the length of time to that infection was similar in the two groups (P = 0.56 by the log-rank test). CD4 T-lymphocyte counts improved transiently in both groups, and serum levels of HIV antigen decreased in the subjects with antigenemia. The hemoglobin level declined to less than 5 mmol per liter (80 g per liter) in 101 subjects in the standard-treatment group and in 77 in the low-dose group (39 vs. 29 percent, P = 0.0009 by the log-rank test). The neutrophil count declined to less than 0.750 x 10(9) per liter in 134 subjects in the standard-treatment group and in 96 in the low-dose group (51 vs. 37 percent, P = 0.0001). CONCLUSIONS: The reduced daily dose of zidovudine used in this study was at least as effective as the standard dose and was less toxic; however, with the use of a four-week induction period with a high dose followed by low-dose treatment, severe anemia and neutropenia were common complications of treatment with zidovudine.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. The AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases.

Zidovudine (AZT) is a potent inhibitor of the replication of the human immunodeficiency virus (HIV), and it has been shown to improve survival in advanced HIV disease. We conducted a randomized, double-blind trial in adults with asymptomatic HIV infection who had CD4+ cell counts of fewer than 500 per cubic millimeter on entry into the study. The subjects (92 percent male) were randomly assigned to one of three treatment groups: placebo (428 subjects); zidovudine, 500 mg per day (453); or zidovudine, 1500 mg per day (457). After a mean follow-up of 55 weeks (range, 19 to 107), 33 of the subjects assigned to placebo had the acquired immunodeficiency syndrome (AIDS), as compared with 11 of those assigned to receive 500 mg of zidovudine (P = 0.002; relative risk, 2.8; 95 percent confidence interval, 1.4 to 5.6) and 14 of those assigned to receive 1500 mg of zidovudine (P = 0.05; relative risk, 1.9; 95 percent confidence interval, 1.0 to 3.5). In the three treatment groups, the rates of progression (per 100 person-years) to either AIDS or advanced AIDS-related complex were 7.6, 3.6, and 4.3, respectively. As compared with those assigned to placebo, the subjects in the zidovudine groups had significant increases in the number of CD4+ cells and significant declines in p24 antigen levels. In the 1500-mg zidovudine group, severe hematologic toxicity (anemia or neutropenia) was more frequent than in the other groups (P less than 0.0001). In the 500-mg zidovudine group, nausea was the only toxicity that was significantly more frequent (in 3.3 percent) than in the placebo group (P = 0.001). We conclude that zidovudine is safe and effective in persons with asymptomatic HIV infection and fewer than 500 CD4+ cells per cubic millimeter. Additional study will be required to determine whether such treatment will ultimately improve survival for persons infected with HIV.

AIDS-Related Complex↗
PubMed1990

Recombinant soluble CD4 therapy in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. A phase I-II escalating dosage trial.

STUDY OBJECTIVE: To study the safety and pharmacokinetics and to derive preliminary evidence on surrogate indicators of efficacy of recombinant soluble CD4 (rsCD4) in patients with the acquired immunodeficiency syndrome (AIDS) and advanced AIDS-related complex. DESIGN: Open label, escalating dosage, phase I-II tolerance trial. SETTING: Massachusetts General Hospital, Cedars-Sinai Medical Center, and Stanford University Medical School, three tertiary care institutions and members of the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. INSTRUCTIONS: Cohorts of 3 to 11 patients received rsCD4 by intravenous infusion or intramuscular injection in dosages of up to 30 mg per day for 28 days. MEASUREMENTS AND MAIN RESULTS: Recombinant soluble CD4 was tolerated by these patients with no significant clinical or immunologic toxicities. Serum levels of rsCD4 in patients receiving doses of 9 or 30 mg per day administered intramuscularly were in the range of rsCD4 concentrations required to inhibit replication of human immunodeficiency virus 1 (HIV-1) in vitro. A decline in serum HIV-1 p24 antigen was seen in patients receiving 30 mg of rsCD4 daily, but no such changes were noted at lower dosages. CONCLUSIONS: Recombinant soluble CD4 is well tolerated by patients with AIDS or advanced AIDS-related complex. Our study has also provided preliminary evidence of antiviral activity of rsCD4 in vivo. Our data suggest that further trials of receptor-based therapies against HIV-1 are warranted.

AIDS-Related Complex↗
PubMed1990

A double-blind, placebo-controlled study of oral acyclovir in postherpetic neuralgia.

Twenty-one patients with postherpetic neuralgia of two- to 84-months duration participated in a double-blind, placebo-controlled study of oral acyclovir. Pain perception was assessed with the Melzack Pain Questionnaire at baseline and at two-to six-week intervals during the ensuing six months. Clinically significant pain reduction occurred in eight patients: four received acyclovir, and four received a placebo. Several treatment strategies have been advocated for relief of postherpetic neuralgia. Results of the present study demonstrate the need for a double-blind, placebo-controlled paradigm to substantiate the efficacy of new clinical approaches. The same caveat applies to the more common syndromes encountered in psychiatric practice.

Acyclovir↗
PubMed1990

Chemotherapy of human immunodeficiency virus infections: current practice and future prospects.

As human immunodeficiency virus type 1 (HIV-1) has become better understood, numerous drugs have been developed that act at virus-specific sites. These are challenging our ability to evaluate them thoroughly and rapidly. Zidovudine (AZT) remains the mainstay of anti-HIV-1 drugs. Recent controlled trials indicate it should be used early in infection (in those with CD4 cell counts less than 500/mm3) and in lower doses (500-600 mg/day). Prolonged AZT treatment in patients with AIDS, however, is often associated with viral resistance. Newer reverse transcriptase-inhibiting nucleoside derivatives are currently in phase II-III clinical trials. Other HIV-1 replicative sites under attack in clinical studies include binding and entry of virus, envelope protein glycosylation, and viral assembly and release. Agents that target HIV-1 proteinase, integrase, ribonuclease H, and products of regulatory genes such as tat are under development. Combination therapies that target different viral replicative sites likely will allow use of individual agents below their toxic concentrations and help prevent drug resistance. Innovative programs for expanded access to experimental drugs are needed that will permit expeditious clinical trials, optimize the gathering of useful information, and permit the widest access to promising treatments.

Animals↗
PubMed1990

Three-drug synergistic inhibition of HIV-1 replication in vitro by zidovudine, recombinant soluble CD4, and recombinant interferon-alpha A.

Optimal management of human immunodeficiency virus type 1 (HIV-1) infections may require combinations of agents that attack different targets in the viral replicative cycle. Zidovudine (AZT), recombinant soluble CD4 (rsCD4), and recombinant interferon-alpha A (rIFN-alpha A) were evaluated in 2- and 3-drug regimens against HIV-1 replication in vitro. Peripheral blood mononuclear cells and a CD4+ T cell line (H9) were studied using multiple HIV-1 replicative end points. Drug interactions were evaluated by the median-effect principle and the isobologram technique. AZT, rsCD4, and rIFN-alpha A inhibited HIV-1 synergistically in 2- and 3-drug combinations. The 3-drug regimen provided more complete virus suppression than the 2-drug regimens. In H9 cells, single-drug regimens lost effectiveness at 10-14 days and 2-drug regimens lost effectiveness at 14-18 days. In contrast, the 3-drug regimen showed nearly complete suppression over 28 days in culture without toxicity. Clinical trials of these 3 drugs in combination should be considered.

CD4 Antigens↗