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Biomedical subjects

M S Hirsch

Publications and source records attributed to M S Hirsch.

At least 73 records · Page 4Linked to original sources
PubMed1995

Potential clinical implications of interlaboratory variability in CD4+ T-lymphocyte counts of patients infected with human immunodeficiency virus.

The CD4+ T-lymphocyte count is an important factor in the management of patients infected with human immunodeficiency virus. Previous studies have found significant variability among the counts determined by different laboratories. We conducted a study of lymphocyte phenotyping in four laboratories to assess this variability and its possible clinical implications. One laboratory was situated at the study site; the other three were selected randomly from a total of 11 commercial and hospital laboratories available locally. Blood specimens were obtained from 24 patients and were sent to the four laboratories for a complete blood count and a lymphocyte subset analysis. Using the Kruskall-Wallis test, we found that the laboratories' ranks of four individual components of the CD4 cell count differed significantly: total white blood cell count (P < .0001), lymphocyte percentage (P = .003), lymphocyte count (P = .002), and CD4 percentage (P = .0004). Of the 24 patients in this survey, 14 (58.3%) had CD4-count results with enough variation to have led to conflicting treatment recommendations; three of the 24 patients fulfilled the revised Centers for Disease Control and Prevention case definition of AIDS on the basis of results from some but not all laboratories. In addition, the laboratories disagreed on whether CD4 cell counts of nine patients (37.5%) had increased or decreased since the previous determination. We conclude that when strict thresholds of CD4 cell counts are used as a basis for treatment recommendations or for diagnosis of AIDS, interlaboratory variability may be sufficient to alter the decisions made.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Ex vivo expansion of CD4 lymphocytes from human immunodeficiency virus type 1-infected persons in the presence of combination antiretroviral agents.

Expansion of CD4 lymphocytes from human immunodeficiency virus type 1 (HIV-1)-infected persons ex vivo has been limited by enhanced virus replication and cell death. The successful expansion of functional CD4 lymphocytes from HIV-1-infected persons has now been accomplished using a bispecific monoclonal antibody to CD3 and CD8 in combination with three antiretroviral agents. CD4 lymphocytes were polyclonally expanded by a factor of 10(3)-10(7) during 4-8 weeks in culture. Supernatants from most cultures were persistently HIV-1 p24 antigen-negative by day 14 and remained negative despite removal of antiretroviral agents at day 28. In such cultures, HIV-1 could not be recovered by cocultivation, and amounts of HIV-1 DNA declined or remained stable at low levels, eventually becoming undetectable in 2 cases. This approach establishes the feasibility of CD4 lymphocyte expansion in persons with HIV disease and may be useful for immune-based or gene therapies.

Acquired Immunodeficiency Syndrome↗
PubMed1995

The predictive value of changes in serologic and cell markers of HIV activity for subsequent clinical outcome in patients with asymptomatic HIV disease treated with zidovudine.

OBJECTIVE: To determine if serologic marker responses to zidovudine treatment during the first year of antiretroviral therapy could predict subsequent HIV disease progression independently of absolute CD4 lymphocyte responses. METHODS: We conducted a case-control study in patients with asymptomatic HIV disease, who were initiating zidovudine therapy in a randomized, prospective trial. A total of 102 patients who progressed to AIDS or advanced AIDS-related complex and 177 randomly selected controls matched by baseline CD4 cell count and duration of follow-up had serum samples (from prior to and at 8, 16, 32 and 48 weeks of zidovudine treatment) assayed for acid-disassociated HIV p24 antigen, beta 2-microglobulin (beta 2M), neopterin, soluble interleukin (IL)-2 receptor, soluble CD4 protein and soluble CD8 protein. RESULTS: Median time to event for cases was 20.2 months; median follow-up on study was 35.4 months for controls. After controlling for absolute CD4 count at baseline, increased baseline serum concentrations of HIV p24 antigen, beta 2M, neopterin, and soluble IL-2 receptor were highly predictive of increased risk of HIV disease progression. In a multiple logistic regression model, controlling for baseline marker values, change in beta 2M consistently added independent value to change in CD4 count in predicting subsequent risk of disease progression. CONCLUSIONS: Monitoring serum immunologic markers, in particular beta 2M, in addition to absolute CD4 lymphocyte counts prior to and within the first 4 months after initiating dideoxynucleoside therapy can increase the accuracy of estimations of subsequent long-term risk of clinical HIV disease progression. This information may be useful to clinicians and patients who are making decisions about initiating or changing antiretroviral therapy.

AIDS-Related Complex↗
PubMed1995

Persistence of attenuated rev genes in a human immunodeficiency virus type 1-infected asymptomatic individual.

With the goal of examining the functional diversity of human immunodeficiency virus type 1 (HIV-1) env genes within the peripheral blood mononuclear cells of an asymptomatic individual, we substituted four complete env genes into the replication-competent NL4-3 provirus. Despite encoding full-length open reading frames for gp120 and gp41 and the second coding exon of tat and rev, each chimera was replication defective. Site-directed mutagenesis of codon 78 in the Rev activation domain (from a hitherto unique Ile to the subtype B consensus Leu) partially restored infectivity for two of three chimeras tested. Similarly, mutagenesis of rev codon 78 of NL4-3 from Leu to Ile partially attenuated this virus. Ile-78 was found in all 13 clones examined from samples taken from this asymptomatic subject 4.5 years after infection, including 9 from peripheral blood mononuclear cells and 4 from a virus isolate, as well as 4 additional clones each from peripheral blood mononuclear cells sampled 37 and 51 months later. We next examined conservation of the Rev activation domain within and among long-term survivors (LTS) and patients with AIDS, as well as T-cell-line-adapted strains of HIV-1. Putative attenuating mutations were found in a minority of sequences from all five LTS and two of four patients with AIDS. Of the 11 T-cell-line-adapted viruses examined, none had these changes. Among and within LTS virus population had marginally higher levels of diversity in Rev than in Env; patients with AIDS had similar levels of diversity in the two reading frames; and T-cell-line-adapted viruses had higher levels of diversity in Env. These results are consistent with the hypothesis that asymptomatic individuals harbor attenuated variants of HIV-1 which correlate with and contribute to their lack of disease progression.

Acquired Immunodeficiency Syndrome↗
PubMed1994

The duration of zidovudine benefit in persons with asymptomatic HIV infection. Prolonged evaluation of protocol 019 of the AIDS Clinical Trials Group.

OBJECTIVE: To determine the durability of zidovudine-induced delay in clinical progression of asymptomatic human immunodeficiency virus (HIV) disease and to assess the relationship between this effect and the entry CD4+ cell count. DESIGN AND INTERVENTIONS: Extended follow-up data from subjects participating in protocol 019 of the AIDS [acquired immunodeficiency syndrome] Clinical Trials Group were examined. Subjects were offered a total daily dose of 500 mg of open-label zidovudine after the unblinding of the original randomized trial in 1989. Original treatment groups included placebo, 500 mg of zidovudine, or 1500 mg of zidovudine daily in divided doses. Three distinct analyses were conducted to assess the duration of zidovudine's effect on progression to AIDS or death: (1) analysis of all follow-up information from all subjects, (2) analysis of all subjects but with follow-up of original placebo-assigned subjects censored at the time open-label zidovudine was initiated, and (3) analysis of the effect of initiating zidovudine in subjects initially assigned to receive placebo. SETTING: University-based and university-affiliated AIDS research clinics participating in AIDS Clinical Trials Group protocol 019. PATIENTS: A total of 1565 asymptomatic HIV-infected subjects with entry CD4+ cell counts less than 0.50 x 10(9)/L (500/microL). MAIN OUTCOME MEASURE: Time to progression to AIDS or death. RESULTS: During follow-up of up to 4.5 years (mean, 2.6 years), 232 subjects progressed to AIDS or died. In each of the three analyses described herein, zidovudine was associated with a significant (P = .008, .004, .007) decrease in the risk of such progression. However, each of these analyses also indicated a decreasing placebo:zidovudine relative risk with duration of use (P = .002, .08, .04), suggesting a nonpermanent effect. The duration of benefit appeared to be related to entry CD4+ cell count, with greater benefit in those with higher counts at entry. No significant differences in survival were found between those originally randomized to zidovudine or placebo. CONCLUSIONS: Zidovudine at 500 mg/d caused a significant delay in progression to AIDS or death, but its earlier use in asymptomatic disease was not associated with an additional prolongation of survival compared with delayed initiation. The delay in progression diminished over time especially in subjects with entry CD4+ cell counts less than 0.30 x 10(9)/L (300/microL). Treatment strategies that alter drug regimens before the loss of zidovudine benefit should be explored.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Combination therapy for infection due to human immunodeficiency virus type 1.

The preliminary results of the Concorde trial demonstrated the transient clinical benefit of monotherapy with zidovudine (AZT) in asymptomatic persons infected with human immunodeficiency virus type 1 (HIV-1). This result, which has been widely disseminated and discussed, was predictable given the previous demonstration of the development of resistance to AZT in isolates from individuals receiving prolonged treatment with the drug and given the finding that didanosine (ddI) is more efficacious than continued therapy with AZT in individuals who have received > or = 6 months of AZT monotherapy. On the basis of these findings, interest in combinations of antiretroviral agents has continued to grow. Many in vitro studies of nucleoside and nonnucleoside inhibitors of reverse transcriptase combined with interferon-alpha or inhibitors of protease have been published. In addition, numerous clinical trials of various combinations have been completed or are under way. Dr. Martin Hirsch and his colleagues at the Massachusetts General Hospital have been among the leaders of this effort. He and Dr. Angela Caliendo review, in this AIDS Commentary, the current state of our knowledge regarding the potential utility of combination therapy for infection with HIV-1.

Acyclovir↗
PubMed1994

Inhibition of human immunodeficiency virus type 1 replication in cytokine-stimulated monocytes/macrophages by combination therapy.

Combination regimens against human immunodeficiency virus type 1 (HIV-1) were studied in granulocyte-macrophage colony-stimulating factor (GM-CSF)-stimulated monocyte/macrophage cultures. Regimens included those that inhibited the same target (reverse transcriptase) or multiple targets. Treatment conditions assessed efficacy during prophylaxis and ongoing infection. Drugs included zidovudine, didanosine, nevirapine, foscarnet, pyridinone, the protease inhibitor RO31-8959 (also known as saquinavir), interferon-alpha A, the Tat inhibitor RO24-7429, and N-butyl-deoxynojirimycin. Two-, three-, and four-drug combinations were tested. Drugs were tested at individually inhibitory concentrations of IC99, IC95, IC75, and IC50. All prophylactic regimens prevented HIV-1 replication at IC99. As drug concentrations were reduced, differences among the regimens became apparent. Regimens that acted at both single and multiple targets were effective in prophylactic settings and less so in acute infection. In ongoing infections, only modest reductions in viral replication were seen, even at IC99.

Antiviral Agents↗
PubMed1994

Resistance to 2',3'-dideoxycytidine conferred by a mutation in codon 65 of the human immunodeficiency virus type 1 reverse transcriptase.

A human immunodeficiency virus type 1 variant resistant to zalcitabine (2',3'-dideoxycytidine [ddC]) was selected by sequential passage in the presence of increasing concentrations of ddC in peripheral blood mononuclear cell cultures. A mutation causing a lysine-to-arginine substitution was noted in reverse transcriptase (RT) codon 65 of this ddC-selected virus. A cloned mutant virus with this codon 65 mutation was constructed by using a novel PCR approach for site-directed mutagenesis. Characterization of this virus confirmed that the RT Lys-65-->Arg substitution was necessary and sufficient for a fourfold increase in the ddC 50% inhibitory concentration, as well as for resistance to didanosine (2',3'-dideoxyinosine [ddI]). Lys-65-->Arg and virus resistance to ddC and ddI also developed during therapy in isolates from one ddC-treated patient and two ddI-treated patients. Recombinant-expressed codon 65 mutant RT enzyme was resistant to ddCTP and ddATP in cell-free polymerase assays. Results of mutant enzyme studies are consistent with Lys-65-->Arg leading to changes in binding of the triphosphate forms of these nucleoside analogs to the RT. These data have implications for future studies of ddC resistance, particularly those aimed at defining its clinical relevance.

Arginine↗
PubMed1994

Alternating versus continuous drug regimens in combination chemotherapy of human immunodeficiency virus type 1 infection in vitro.

We compared the in vitro efficacies of two-, three-, and four-drug combinations given continuously or in alternating regimens against a clinical isolate of human immunodeficiency virus type 1. In H9 cells and peripheral blood mononuclear cells, at the drug concentrations used in this study, there was greater suppression of human immunodeficiency virus type 1 infection as the number of drugs in the regimen was increased from one to four simultaneously administered agents. Although alternating drug regimens were effective, they were not better than continuous administration of either single drugs or combinations of agents and were less effective than giving all drugs of an alternating regimen simultaneously.

Antiviral Agents↗
PubMed1994

Therapy other than reverse transcriptase inhibitors for HIV infection.

Antiretroviral drugs against HIV infection have been developed that inhibit various stages of the HIV replication cycle. Agents other than reverse transcriptase inhibitors are reviewed with particular attention to those under study in clinical trials, including inhibitors of the virus-encoded protease enzyme. In addition, innovative strategies using gene therapy are described. It is concluded that combinations of agents may be the best approach for minimizing toxicity and reducing or delaying the emergence of drug-resistant virus during therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Alternating and intermittent regimens of zidovudine and dideoxycytidine in patients with AIDS or AIDS-related complex.

OBJECTIVE: To determine whether alternating regimens consisting of zidovudine and 2',3'-dideoxycytidine (ddC) reduce the toxicity and maintain or increase the antiretroviral effect associated with each drug alone. DESIGN: An unblinded, randomized (phase II) clinical trial in which seven treatment regimens were compared. SETTING: Outpatient clinics of 12 AIDS Clinical Trials Units. PATIENTS: One hundred thirty-one patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and serum p24 antigenemia (> or = 70 pg/mL). INTERVENTION: Treatments included weekly or monthly alternating zidovudine (200 mg every 4 hours) and ddC (0.01 or 0.03 mg/kg body weight every 4 hours); weekly intermittent zidovudine, 200 mg every 4 hours, or ddC, 0.03 mg/kg every 4 hours; and continuous zidovudine. MEASUREMENTS: Toxicity, CD4 cell counts, serum p24 antigen levels, and clinical end points. Data were analyzed for the first 48 weeks of therapy (median follow-up, 40 weeks). RESULTS: Hematologic toxicity was significantly less frequent in patients who received zidovudine therapy every other week (11% to 15%) or every other month (11% to 14%) than in those who received continuous zidovudine therapy (33%) (P < 0.02). Weekly alternating therapy with zidovudine and ddC, 0.03 mg/kg, or intermittent therapy with ddC, 0.03 mg/kg, produced high rates of peripheral neuropathy (41% and 50%, respectively). Neuropathy occurred in 10% to 21% of patients in the other three alternating-therapy limbs and in 17% of patients receiving zidovudine alone (intermittently or continuously). Initial increases in CD4 cell counts were sustained in three alternating-therapy limbs, but counts returned to baseline by week 28 in the remaining limbs. The median weight gain at week 48 was significantly greater in patients treated with alternating regimens (0.9 to 3.8 kg) compared with those treated with continuous zidovudine therapy (-0.7 kg) (P = 0.008). Patients treated with alternating regimens and those treated with continuous zidovudine had similarly sustained decreases in p24 antigen levels. CONCLUSIONS: These findings suggest that alternating therapy with zidovudine and ddC reduces the toxicity associated with each drug alone while maintaining strong antiretroviral activity.

AIDS-Related Complex↗
PubMed1993

Use of evolutionary limitations of HIV-1 multidrug resistance to optimize therapy.

Wild-type reverse transcriptase has evolved for the survival of human immunodeficiency virus type 1 (HIV-1) by natural selection. In contrast, therapy relying on inhibitors of reverse transcriptase by nucleosides like zidovudine (AZT) or dideoxyinosine (ddI), and by non-nucleosides like pyridinones or nevirapine, may exert different selection pressures on this enzyme. Therefore the acquisition of resistance to reverse transcriptase inhibitors by selection of mutations in the pol gene may require compromises in enzyme function that affect viral replication. As single mutations are unlikely to confer broad resistance when combinations of reverse transcriptase inhibitors are used, multiple mutations may occur that result in further compromises. Certain drug combinations may prevent the co-existence of adequate reverse transcription function and multi-drug resistance (MDR). Unlike bacterial or eukaryotic drug resistance, retroviral drug resistance is conferred only by mutations in its own genome and is limited by genome size. Combining drugs directed against the same essential viral protein may thus prevent HIV-1 MDR, whereas the conventional approach of targeting different HIV-1 proteins for combination therapy may not, because genomes with resistance mutations in different HIV-1 genes might recombine to develop MDR. Here we show that several mutations in the HIV-1 reverse transcriptase gene that confer resistance to inhibitors of this enzyme can attenuate viral replication. We tested whether combinations of mutations giving rise to single-agent resistance might further compromise or even abolish viral replication, and if multidrug-resistant viruses could be constructed. Certain combinations of mutations conferring resistance to AZT, ddI and pyridinone are incompatible with viral replication. These results indicate that evolutionary limitations exist to restrict development of MDR. Furthermore, a therapeutic strategy exploiting these limitations by using selected multidrug regimens directed against the same target may prevent development of MDR. This approach, which we call convergent combination therapy, eliminated HIV-1 replication and virus breakthrough in vitro, and may be applicable to other viral targets. Moreover, elimination of reverse transcription by convergent combination therapy may also limit MDR.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Zidovudine treatment of the AIDS dementia complex: results of a placebo-controlled trial. AIDS Clinical Trials Group.

The efficacy of two doses of zidovudine was examined for the treatment of the acquired immunodeficiency syndrome (AIDS) dementia complex in a randomized, double-blinded, placebo-controlled trial conducted at nine study centers. For the initial 16 weeks, 40 subjects with mild to moderate AIDS dementia complex were randomized to one of three treatment arms: 400 mg of zidovudine five times daily, 200 mg of zidovudine five times daily, or placebo five times daily. After week 16, patients initially randomized to the placebo group were rerandomized to one of the two zidovudine treatment arms. The primary efficacy end point was improvement in performance on a battery of seven neuropsychological tests; the secondary end point was improvement on a protocol neurological evaluation directed at the cardinal features of the AIDS dementia complex. For the initial 16-week period, average z scores based on the neuropsychological test battery revealed a significant improvement in the combined treatment groups compared to the placebo group; however, when the two treatment groups were compared separately to the placebo group, only the group receiving the higher zidovudine dose exhibited significant improvement. After rerandomization of the placebo patients to one of the two treatment arms at week 16, this group also showed significant improvement in the average neuropsychological z score by week 32. These results extend previous observations that indicate a therapeutic benefit of zidovudine for the treatment of AIDS dementia complex.

AIDS Dementia Complex↗
PubMed1993

Interactions between HIV-1 and cytomegalovirus in human osteosarcoma cells carrying both viruses.

Cytomegalovirus (CMV) and the human immunodeficiency virus type 1 (HIV-1) may interact in the pathogenesis of AIDS. We compared CMV replication in human osteosarcoma (HOS) cells to that in HOS cells genetically engineered to contain an envelope-deficient HIV-1 proviral construct (designated HOS-HXG). Following acute CMV infection of each cell line, HOS-HXG cells contained higher numbers of intranuclear CMV nucleocapsids than did HOS cells. Infectious CMV could be persistently detected in culture supernatant fluids of the CMV-infected HOS-HXG cells, whereas CMV was lost over several weeks from HOS cells infected with CMV in parallel. HIV-1 CMV pseudotypes were not detected in supernatant fluids from CMV-infected HOS-HXG cells. On day 119 after CMV infection, these cultures were superinfected with HIV-1. These dually infected HOS-HXG cells produced infectious HIV-1 and exhibited markedly enhanced CMV replication compared to parental CMV-infected HOS-HXG cells. Two different HIV-1 tat gene function antagonists, Ro24-7429 and chemically modified antibodies to the Tat protein, did not inhibit the replication of CMV in either acute or persistent infections of HOS-HXG cells at concentrations that inhibited HIV-1 replication.

Antiviral Agents↗