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Biomedical subjects

M A Fischl

Publications and source records attributed to M A Fischl.

At least 73 records · Page 4Linked to original sources
PubMed1992

Combination therapy with zidovudine and dideoxycytidine in patients with advanced human immunodeficiency virus infection. A phase I/II study.

OBJECTIVE: To evaluate the safety and immunologic and antiviral effects of combination therapy with zidovudine and dideoxycytidine (ddC) in patients with advanced human immunodeficiency virus type 1 (HIV) infection. DESIGN: A phase I/II open-label, dose-ranging study. SETTING: Two AIDS Clinical Trials Group units. PATIENTS: Patients (56) with advanced HIV disease. INTERVENTIONS: Patients were randomly assigned to one of three paired regimens of zidovudine and ddC. We evaluated six dosing regimens, each involving oral administration of the study drugs at 8-hour intervals. MEASUREMENTS: Pharmacokinetics, toxicity, CD4 counts, p24 antigenemia and clinical end points. MAIN RESULTS: The median follow-up period was 40.6 weeks (range, 0.3 to 70 weeks). Neither drug affected the pharmacokinetic profile of the other. Episodes of serious hematologic toxicity were infrequent, occurring in only 17.9% of patients, and did not differ among the regimens (P = 0.15). Severe sensory peripheral neuropathy occurred in two patients (one patient each in regimens 1 and 4). One patient receiving regimen 4 died. The mean maximal increase in CD4 counts exceeded 109 cells/mm3, and 69% of patients receiving combinations containing 300 or 600 mg of zidovudine daily had an increase in CD4 counts of 50 cells/mm3 or greater. Regimens containing 600 mg of zidovudine daily (regimens 2 and 5) were also more likely to result in persistent increases in CD4 counts above pretreatment values than were the two lowest dose regimens (P = 0.003). The decline in CD4 counts was more rapid, and the suppression of the p24 antigenemia was less rapid and less sustained in patients receiving the lowest zidovudine dose alone (regimen 6). The addition of ddC to regimen 6 (regimen 3) resulted in a slower decline in the CD4 counts (P = 0.06). CONCLUSIONS: Combination therapy with zidovudine and ddC at the doses tested was well tolerated and did not result in toxicity. A daily oral dose of 150 mg of zidovudine appeared to produce a suboptimal effect on p24 antigenemia and CD4 counts. Combination therapy with ddC and higher doses of zidovudine produced greater and more persistent effects in patients with advanced HIV infection compared with other study regimens and with the results of previous trials of zidovudine monotherapy.

Adult↗
PubMed1992

The effect of zidovudine treatment on serum neopterin and beta 2-microglobulin levels in mildly symptomatic, HIV type 1 seropositive individuals.

Sixty-one subjects with mildly symptomatic human immunodeficiency virus (HIV) infection were included in a double-blind, randomized, placebo-controlled trial of zidovudine (part of AIDS Clinical Trials Group protocol 016, ACTG 016) to evaluate changes in the serum immune activation markers neopterin and beta 2-microglobulin (beta 2M) as early markers of the antiviral effect of zidovudine on HIV type 1 (HIV-1) infection. The mean values of serum neopterin and beta 2M levels in 27 placebo-treated subjects tended to increase with time. The mean value of neopterin in 34 subjects receiving zidovudine decreased at 4 weeks (15.76 nmol/L before treatment to 12.73 nmol/L, p = 0.001). The maximum reduction was seen at 8 weeks of treatment (10.78 nmol/L, p less than 0.0001). Subsequently, the mean value of serum neopterin increased but remained below the pretreatment value for more than a year. Serum beta 2M levels decreased (from 3.01 to 2.69 mg/L at 4 weeks, p = 0.01) and reached the lowest level at 8 weeks (2.45 mg/L, p = 0.0002) in zidovudine recipients. The mean beta 2M level returned to pretreatment value at approximately 24 weeks of the treatment. There was a close correlation between changes from baseline in serum neopterin and beta 2M during the first 16 weeks of the zidovudine therapy, but not later. Subjects with greater reductions of serum neopterin or beta 2M tended to maintain lower levels of these markers with continued zidovudine administration.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS-Related Complex↗
PubMed1991

Effects of zidovudine therapy in minority and other subpopulations with early HIV infection.

UNLABELLED: OBJECTIVE--The purpose of this study was to determine whether the beneficial effects of zidovudine seen overall in two recently completed placebo-controlled clinical trials are also apparent in blacks, Hispanics, women, and intravenous drug users. DESIGN--Two double-blind placebo-controlled randomized clinical trials, protocols 016 and 019, conducted by the AIDS Clinical Trials Group. SETTING--University-based referral centers. PARTICIPANTS--Two thousand forty-eight persons with asymptomatic or mildly symptomatic human immunodeficiency virus infection were analyzed. Of these, 155 were black, 190 were Hispanic, 144 were women, and 221 were intravenous drug users. All randomized subjects were included in the analysis. INTERVENTION--Participants in the AIDS Clinical Trials Group protocol 016 were assigned to receive a placebo or a 1200-mg daily dose of zidovudine. Participants in the AIDS Clinical Trials Group protocol 019 were assigned to receive a placebo, a 500-mg daily dose of zidovudine, or a 1500-mg daily dose of zidovudine. MAIN OUTCOME MEASURE--Progression to AIDS. RESULTS--The rates of progression to AIDS in subjects receiving zidovudine were significantly lower than those in subjects receiving a placebo among blacks (P = .03), whites (relative risk [RR] = 2.3, 95% confidence interval [CI] = 1.5 to 3.6, P less than .0001), Hispanics (RR = 4.4, CI = 1.2 to 16.8, P = .02), non-Hispanics (RR = 2.3, CI = 1.5 to 3.6, P = .0002), men (RR = 2.5, CI = 1.6 to 3.8, P less than .0001), and non-intravenous drug users (RR = 2.5, CI = 1.6 to 4.0, P less than .0001). The rates of disease progression for subjects receiving zidovudine were not statistically different from those receiving placebo for women (RR = 3.3, CI = 0.3 to 36.3, P = .31) or for intravenous drug users (RR = 2.0, CI = 0.7 to 6.2, P = .21); however, in both instances the estimated RRs were similar to those for men and non-intravenous drug users. CONCLUSIONS: -Although the two studies used for this analysis were not specifically designed to assess the effects of zidovudine in each separate subpopulation, the data suggest that the beneficial effects of zidovudine reported for the entire study population also apply to the subpopulations of blacks, Hispanics, women, and intravenous drug users.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Antiretroviral therapy in combination with interferon for AIDS-related Kaposi's sarcoma.

In vitro studies have shown that 3'-azido-3'-deoxythymidine (zidovudine, AZT) and interferon synergistically inhibit the replication of the human immunodeficiency virus type 1 (HIV) in peripheral blood mononuclear cells at concentrations achievable in patients. Interferon alfa can cause lesions to regress in patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma (KS). Although zidovudine has no significant effect on the regression of these lesions, it does have antiviral activity in these patients as manifested by a decline in serum HIV antigen. However, when used separately, the two drugs can have serious side effects in some patients. In addition, the development of zidovudine-resistant strains has been noted in patients with advanced HIV disease receiving zidovudine for nine months or longer. Three in vivo trials have been initiated to assess possible advantages of combination therapy with zidovudine and interferon alfa in patients with AIDS-related KS. The incidence of serious adverse reactions, therapeutic efficacy, and the rate of emergence of zidovudine-resistant strains of HIV were evaluated. Preliminary results indicate that combination therapy with interferon alfa and zidovudine can safely be administered to patients with AIDS-related KS in doses that elicit antitumor and antiviral responses and discourage the potential emergence of zidovudine-resistant HIV strains.

Acquired Immunodeficiency Syndrome↗
PubMed1991

A phase I study of recombinant human interferon-alpha 2a or human lymphoblastoid interferon-alpha n1 and concomitant zidovudine in patients with AIDS-related Kaposi's sarcoma.

To determine the safety, maximum tolerated dose, and preliminary efficacy of concomitant interferon-alpha and zidovudine therapy in AIDS-related Kaposi's sarcoma (KS), 56 patients with biopsy-proven KS and documented human immunodeficiency virus type 1 (HIV) infection were enrolled into a phase I study. Interferon-alpha was given intramuscularly at a dose of 9, 18, or 27 mu once a day and zidovudine was administered as 100 or 200 mg every 4 h for 8 weeks followed by a 48-week maintenance period. The major toxicities were anemia, neutropenia, and hepatotoxicity. Neutropenia was dose limiting with 1,200 mg of zidovudine/day and the lowest dose of interferon-alpha (9 mu/day). Hepatotoxicity was dose limiting with 27 mu of interferon and 600 mg of zidovudine/day. Cumulative dose-related anemia or neutropenia was not seen during long-term follow-up. The maximum tolerated doses for the combination were defined as 18 mu daily for interferon-alpha and 600 mg daily for zidovudine. Variable changes in CD4 lymphocytes occurred during the first 8 weeks of therapy. At higher doses of the combination, sustained increases in median CD4 lymphocyte numbers were noted (p less than 0.001). In HIV antigenemic patients, progressive antigen suppression was seen with increasing doses of the combination (p less than 0.005). The overall antitumor response rate was 47%. Tumor regression was associated with better survival benefits (p less than 0.001) and a pretreatment CD4 cell count greater than or equal to 200 cells/mm3 (p = 0.01). In conclusion, intermediate doses of interferon-alpha and lower doses of zidovudine appear to be relatively well tolerated and associated with disease improvement, including survival benefits.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A double-blind, placebo-controlled trial.

BACKGROUND: Preliminary reports suggest that patients with the acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii pneumonia may benefit from the addition of corticosteroid treatment to antibiotic therapy. METHODS: We conducted a double-blind, placebo-controlled trial to assess the efficacy of adjunctive corticosteroids in patients with AIDS and severe P. carinii pneumonia. Patients with marked abnormalities in gas exchange who had been treated with antibiotics for less than 72 hours were randomly assigned to receive either methylprednisolone (40 mg) or placebo every 6 hours for 7 days, in addition to treatment for 21 days with trimethoprim-sulfamethoxazole. The primary outcome measures were survival until hospital discharge and the development of respiratory failure. RESULTS: Twenty-three patients were enrolled in the study; there were no significant differences in base-line clinical or laboratory measures between the two treatment groups. Of 12 patients treated with corticosteroids, 9 (75 percent) survived until hospital discharge, as compared with only 2 of 11 placebo recipients (18 percent) (P less than 0.008). Respiratory failure developed in nine placebo recipients, as compared with only three patients treated with corticosteroids (P less than 0.008). No patient required the interruption or discontinuation of corticosteroid or antibiotic treatment because of toxicity or a complicating event. Because of the marked difference in survival, it was deemed unethical to continue the trial, and the study was terminated. CONCLUSIONS: Early adjunctive corticosteroid therapy can improve survival and decrease the occurrence of respiratory failure in patients with AIDS and severe P. carinii pneumonia.

Acquired Immunodeficiency Syndrome↗
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

AIDS Clinical Trials Group: phase I/II study of combination 2',3'-dideoxycytidine and zidovudine in patients with acquired immunodeficiency syndrome (AIDS) and advanced AIDS-related complex.

The dideoxynucleosides 3'-azido-3'-deoxythymidine (zidovudine, AZT) and 2',3'-dideoxycytidine (ddC) are potent inhibitors of human immunodeficiency virus (HIV) in vitro and improve surrogate measures of HIV infection in vivo. Long-term administration of AZT has been associated with significant hematologic toxicity and has resulted in virus with reduced in vitro susceptibility. Although ddC does not have significant hematologic toxicity and has not shown cross-resistance with AZT in vitro, ddC has been associated with a severe dose-related peripheral neuropathy. Given the independent activity of each agent, their non-overlapping toxicity profiles, and the absence of cross-resistance, it was hypothesized that concurrent administration of AZT and ddC in low doses might be at least as active as either drug given individually at higher doses in the treatment of HIV infection. It was further hypothesized that combined low doses of both drugs would reduce the incidence of serious side effects and the development of resistance. A phase I/II dose-finding trial of six different regimens of combination AZT and ddC in persons with acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex was initiated to test these hypotheses.

AIDS-Related Complex↗
PubMed1990

The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection. A double-blind, placebo-controlled trial. The AIDS Clinical Trials Group.

OBJECTIVE: To evaluate the efficacy and safety of zidovudine early in the treatment of human immunodeficiency virus type 1 (HIV) infection. DESIGN: A double-blind, randomized, placebo-controlled trial with subject stratification by pretreatment CD4 T lymphocyte counts. SETTING: Multicenter trial at AIDS Clinical Trial units. SUBJECTS: Seven hundred eleven subjects with mildly symptomatic HIV infection. INTERVENTION: Three hundred fifty-one subjects were assigned to placebo and 360 to zidovudine, 200 mg orally every 4 hours. The median duration of follow-up was 11 months. MEASUREMENTS AND MAIN RESULTS: Fifty-one subjects developed the acquired immunodeficiency syndrome (AIDS), advanced AIDS-related complex, or death as a first critical event. For the stratum of subjects with more than 200 but less than 500 CD4 T lymphocytes/mm3 before treatment, 34 events occurred in placebo recipients and 12 in zidovudine recipients (P = 0.0002; relative risk [RR] estimate, 3.23 [95% CI, 1.67 to 6.24]). For the stratum of subjects with 500 to 799 CD4 T lymphocytes/mm3 before treatment, 2 events occurred in placebo recipients and 3 in zidovudine recipients. Candidiasis at study entry independently increased the risk for having an event (P = 0.005; RR estimate, 2.3 [95% CI, 1.29 to 4.12]); HIV antigenemia at study entry also increased this risk (P = 0.01; RR estimate, 2.1 [95% CI, 1.2 to 3.8]). Significant differences between the treatment groups in CD4 T-lymphocyte counts occurred in subjects with more than 200 but less than 500 CD4 T lymphocytes/mm3 after 4 weeks of therapy (P = 0.002). Differences persisted through week 52. Less prominent changes occurred in subjects with 500 or more CD4 T lymphocytes/mm3. Serum levels of HIV antigen decreased significantly in zidovudine recipients. Serious anemia and neutropenia occurred in 5% and 4% of zidovudine recipients, respectively, and in 0% and 1% of placebo recipients, respectively. CONCLUSION: Zidovudine delayed progression of HIV disease and produced little toxicity in subjects with mildly symptomatic HIV disease and less than 500 CD4 T lymphocytes/mm3.

AIDS-Related Complex↗
PubMed1989

Prolonged zidovudine therapy in patients with AIDS and advanced AIDS-related complex. AZT Collaborative Working Group.

We examined the long-term safety and efficacy of zidovudine therapy in 229 subjects with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex who previously participated in a placebo-controlled study of zidovudine. One hundred two placebo recipients (delayed treatment group) and 127 zidovudine recipients (original treatment group) were followed up while receiving zidovudine therapy for a mean of 21 months. Survival rates for the original treatment group were 84.5% and 57.6% at 12 and 21 months, respectively; for the delayed treatment group, 78.8% and 64.6% at 12 and 21 months, respectively, and 78.8% and 47.5% at 12 and 21 months, respectively, for 77 subjects with AIDS and 93.0% and 71.8%, respectively, for 50 subjects with AIDS-related complex in the original treatment group. Adverse reactions decreased over time and newly observed toxic reactions were unusual. The clinical course of these subjects suggests continued survival benefits with long-term zidovudine therapy.

AIDS-Related Complex↗
PubMed1988

Safety and efficacy of sulfamethoxazole and trimethoprim chemoprophylaxis for Pneumocystis carinii pneumonia in AIDS.

The safety and efficacy of sulfamethoxazole and trimethoprim in the prevention of Pneumocystis carinii pneumonia associated with the acquired immunodeficiency syndrome (AIDS) were evaluated. Sixty patients with a new diagnosis of Kaposi's sarcoma and no history of opportunistic infections were randomly assigned to receive 800 mg of sulfamethoxazole and 160 mg of trimethoprim twice per day or no therapy. None of the 30 patients receiving sulfamethoxazole and trimethoprim developed P carinii pneumonia. Sixteen of the 30 patients receiving no suppressive therapy developed P carinii pneumonia. Development of P carinii pneumonia was associated with the stage of Kaposi's sarcoma, B subtype disease, and the presence of 0.20 X 10(9)/L (200/mm3) or fewer CD4 cells at study entry. The proportion of patients surviving and the mean length of survival were significantly greater in the treatment group compared with the control group. Adverse reactions occurred in 15 patients (50%).

Acquired Immunodeficiency Syndrome↗
PubMed1988

Phase I studies of 2',3'-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT).

Five dose regimens of 2',3'-dideoxycytidine (ddC) were administered, intravenously for 2 weeks then orally for 4 or more weeks, to 20 patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). ddC was well absorbed from the gut and crossed the blood-brain barrier. 10 of the 15 patients who received 0.03-0.09 mg/kg every 4 h had increases in their absolute number of T4+ T cells at week 2 (p less than 0.05), though in many these rises were not sustained. 11 of 13 evaluable patients had a fall in their serum human immunodeficiency virus (HIV)p24 antigen by week 2 of therapy (p less than 0.01); in 4 patients the p24 antigen subsequently rose to baseline while in others the decline was sustained. Dose-related toxic effects included cutaneous eruptions, fever, mouth sores, thrombocytopenia, and neutropenia. A reversible painful peripheral neuropathy developed in 10 patients after 6-14 weeks' treatment. These results suggest that ddC has activity against HIV in vivo and has a different toxicity profile from that of zidovudine (AZT). 6 patients with AIDS or ARC were given an alternating regimen of oral AZT (200 mg every 4 h for 7 days) and oral ddC (0.03 mg/kg every 4 h for 7 days). The regimen was well tolerated, and the 5 patients who completed 9 or more weeks of treatment had sustained rises in their T4+ T cells and/or falls in p24 antigen.

AIDS-Related Complex↗
PubMed1988

Tuberculosis and nontuberculous mycobacteriosis in patients with AIDS.

Thirty-six patients with AIDS and culture-proven nontuberculous mycobacteriosis were compared to 20 patients with acquired immunodeficiency syndrome (AIDS) and tuberculosis with regard to clinical signs, symptoms, and diagnostic methods. Patients with nontuberculous mycobacteriosis were more often younger and homosexuals, while patients with tuberculosis were usually Haitian-American or users of intravenous drugs. A majority of patients with tuberculosis presented with fever and weight loss. These symptoms were seen in approximately 50 percent of the patients with nontuberculous mycobacteriosis. A distinct syndrome of dyspnea, chills, hemoptysis, and chest pain was seen in a significant minority of patients with nontuberculous mycobacteriosis. Lymphadenopathy was seen almost exclusively in patients with tuberculosis. Pulmonary sources (expectorated sputum or bronchoscopy specimens) were the most common source of diagnosis in both groups. Patients in both groups in whom the diagnosis was obtained from pulmonary sources frequently had negative chest x-ray films on presentation. Cavitary disease was absent from both groups.

Acquired Immunodeficiency Syndrome↗
PubMed1988

HIV-1 inhibition by azidothymidine in a concurrently randomized placebo-controlled trail.

Two independent measures of human immunodeficiency virus type 1 (HIV-1) infection, virus isolation, and serum levels of p24 antigen were evaluated in a double-blind randomized clinical trial of the safety and efficacy of a nucleoside analogue, 3'-azido-3'-deoxythymidine (AZT) versus placebo in a single center. Pretreatment studies from 38 AIDS and AIDS-related complex (ARC) patients were comparably positive for virus isolation from their lymphocytes; all patients were qualitatively virus positive. Before AZT treatment, there was significantly decreased virus recovery in patients with higher numbers of CD4-positive lymphocytes. Within 1 month of AZT therapy, the time in culture required to register virus positivity was increased markedly in the AZT-treated group, and over the following several months progressive diminution in virus recovery was noted. Similar changes were not seen in patients concurrently receiving placebo treatment. Before treatment, 16 of 20 and 12 of 16 patients in the AZT and placebo groups, respectively, were p24 antigen positive. Marked reduction in serum p24 levels were noted in 11 of 16 (69%) of the p24 antigen-positive AZT-treated patients compared to 3 of 12 (25%) of the p24 antigen-positive placebo-treated patients (p = 0.02). There was a marked virologic response in 14 of 20 (70%) of the AZT-treated patients compared to 4 of 18 (22%) placebo-treated patients (p = 0.004). A higher frequency of positive clinical and immunological effects also were noted in the AZT-treated patients relative to placebo-treated patients (p = 0.02 and p = 0.06, respectively).

Acquired Immunodeficiency Syndrome↗