A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS.

OBJECTIVE: To evaluate foscarnet sodium in treating cytomegalovirus retinitis in patients with AIDS. PATIENTS: Twenty-four previously untreated persons with AIDS and cytomegalovirus retinitis who were at low risk for loss of their visual acuity. INTERVENTION: PATIENTS were randomly assigned to receive either no therapy (delayed treatment, control group) or immediate treatment with intravenous foscarnet at a dose of 60 mg/kg body weight three times a day for 3 weeks (induction regimen) followed by a maintenance regimen of 90 mg/kg once a day. MEASUREMENTS: PATIENTS were examined weekly until they reached the primary clinical end point, defined as progression of their retinitis border by 750 microns or the development of a new retinal lesion due to cytomegalovirus. Progression was evaluated using retinal photographs by masked readers. Secondary evaluations included changes in visual acuity, cytomegalovirus shedding in the blood and urine, serum levels of human immunodeficiency virus type 1 (HIV-1) p24 antigen, and total CD4 T lymphocyte counts. RESULTS: The mean time to progression of retinitis was 3.2 weeks in the control group (n = 11) compared with 13.3 weeks in the treatment group (n = 13) (P less than 0.001). Nine of 13 patients in the treatment group had positive blood cultures for cytomegalovirus at entry and all nine cleared their blood of cytomegalovirus by the end of the induction period (P = 0.004) compared with one of six patients in the control group. No reductions in p24 levels were seen in the control patients compared with a reduction of more than 50% in p24 levels for all four patients on treatment for whom follow-up levels were available. The main adverse effects of foscarnet treatment were seizures (2 of 13 patients), hypomagnesemia (9 of 13), hypocalcemia (11 of 13), and elevations in serum creatinine above 176.8 mumol/L (2.0 mg/dL) (3 of 13). The control patients received an average of 0.2 units of blood per week compared with an average of 0.6 units of blood per week for the patients on treatment. CONCLUSIONS: The administration of foscarnet decreases the rate of progression of cytomegalovirus retinitis in persons with AIDS. Its judicious use is likely to prevent loss of vision in these patients. In this study, however, there was little change in visual acuity in patients in either the immediate or delayed treatment group because only patients with non-sight-threatening disease were selected.

A phase I/II trial of zidovudine, interferon-alpha, and granulocyte-macrophage colony-stimulating factor in the treatment of human immunodeficiency virus type 1 infection.

Twenty-four patients infected with human immunodeficiency virus type 1 (HIV-1) who had CD4+ counts of 0.2-0.5 x 10(9) cells/l received granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with zidovudine plus escalating doses of daily subcutaneous interferon-alpha. Mean neutropenia-inducing doses of interferon-alpha were 9.4 x 10(6) and 10.6 x 10(6) IU/day for groups receiving 100 or 200 mg zidovudine every 4 h, respectively. Mean GM-CSF doses used to reverse neutropenia were 0.64 and 0.63 microgram/kg/day for these two groups, respectively, although the mean minimum effective GM-CSF dose for both was only 0.30 microgram/kg/day. Serum p24 antigen declined greater than 70% in all 5 antigenemic patients. Toxicities included a dose-dependent increase in lymphokine-like side effects (100%), anorexia and weight loss (42%), fatigue (42%), and anemia (50%). While toxicities of the combination can be significant, low-dose GM-CSF readily ameliorated neutropenia associated with zidovudine and interferon-alpha therapy without adversely affecting the antiviral properties of the combination.

Immunologic abnormalities in HIV infection.

The progressive decline in the number and function of circulating CD4+ T lymphocytes remains the most characteristic immunologic abnormality found in persons infected with HIV. With the CD4+ cell as the central element in the immunologic cascade of events involved in antigen recognition and host defense, loss of normal CD4 number and function results in impairment of many immune functions that require induction signals by CD4 lymphocytes, including CD8 function, B lymphocyte production of immunoglobulin, NK cell function, and monocyte/macrophage function. Although CD4 cell depletion is a major factor in the pathogenesis of HIV infection, immunologic abnormalities such as impairment of responses to soluble protein antigens appear even before detectable loss of circulating CD4 cells. Progression of clinical disease occurs despite the development of antibodies to HIV proteins. Cellular immune responses have been described in a limited number of individuals, but their exact role is not yet understood. Delineation of the precise nature of the immunologic defects in HIV infection should provide the basis for the continued development of better therapeutic strategies.

Syngeneic bone marrow transplantation and adoptive transfer of peripheral blood lymphocytes combined with zidovudine in human immunodeficiency virus (HIV) infection.

OBJECTIVE: To examine the role of syngeneic bone marrow transplantation and peripheral blood lymphocyte infusions combined with zidovudine in the treatment of patients with human immunodeficiency virus (HIV) infection. DESIGN: A partially randomized outpatient trial. SETTING: Outpatient and inpatient facility of the Clinical Center of the National Institutes of Health, a research-based referral facility. PATIENTS: Sixteen patients with HIV infection (15 symptomatic, 1 asymptomatic). INTERVENTIONS: Symptomatic patients were treated with zidovudine, 500 mg orally every 4 hours for 12 weeks, combined with six peripheral blood lymphocyte infusions (four at week 10, two at week 12) and bone marrow transplantation (at week 12) using HIV-seronegative identical twins as donors. After transplantation, patients were randomly assigned to receive either zidovudine, 100 mg every 4 hours, or placebo for 12 months. The asymptomatic patient received zidovudine for the first 12 weeks, discontinuing therapy after transplantation. Immunologic and virologic monitoring were done monthly. MEASUREMENTS AND MAIN RESULTS: Immediately after lymphocyte infusions and bone marrow transplantation, there was an increase in the mean (+/- SE) CD4 cell percent (19.1% +/- 3.1% to 28.1% +/- 3.0%), an increase in the fraction of patients with delayed-type hypersensitivity responses to tetanus toxoid (4 of 13 to 11 of 13) and the development of delayed-type hypersensitivity to keyhole-limpet hemocyanin (a primary immunogen to which only the donor had been immunized) in 8 of 12 patients tested. No significant clinical improvement was noted, however, and there was no overall sustained immunologic improvement. No differences in CD4 cell percents, delayed-hypersensitivity skin tests, HIV cultures, or p24 antigenemia were seen between patients treated with zidovudine or placebo after transplantation. CONCLUSIONS: Although they establish the feasibility of combining zidovudine with cellular immune reconstitution in treating patients with HIV infection, our results show that any benefits from such combination therapy are at best transient. Future attempts at cellular immune reconstitution may need to use improved antiretroviral regimens as well as immunization of donors with HIV-specific antigens.

The immunology of HIV infection.

A variety of immunologic abnormalities have been reported in patients with human immunodeficiency virus (HIV) infection. The most characteristic is a decrease in the number and function of CD4 helper/inducer T lymphocytes. Patients with HIV infection also have abnormalities in the number and activity of CD8 suppressor/cytotoxic T lymphocytes, defective soluble antigen recognition, polyclonal B cell activation, and decreased cytotoxicity. The CD4 cell defect is the most critical abnormality in the immunopathogenesis of HIV disease. Understanding the relationship of this defect to the appearance of clinical problems can contribute to the management of patients with HIV infection.

Combined zidovudine and interferon-alpha therapy in patients with Kaposi sarcoma and the acquired immunodeficiency syndrome (AIDS)

STUDY OBJECTIVE: To evaluate the toxicity and potential clinical efficacy of combined therapy with zidovudine and interferon-alpha for patients with Kaposi sarcoma and the acquired immunodeficiency syndrome (AIDS). DESIGN: Nonrandomized, open trial study. SETTING: Outpatient clinic of a government referral-based research hospital. PATIENTS: Volunteer sample of 39 patients with human immunodeficiency virus (HIV) infection and Kaposi sarcoma. INTERVENTIONS: Patients received zidovudine, 250, 100, or 50 mg orally every 4 hours; 6 weeks after interferon-alpha was begun at a dose of 5 million U/d, and the dose was increased every 2 weeks until a maximum tolerated dose was determined. Patients then received the maximum tolerated dose of the combination for a minimum of 12 weeks before formal efficacy evaluations. MEASUREMENTS AND MAIN RESULTS: In the dose-escalation phase, the ability to tolerate interferon-alpha was clearly related to the zidovudine dose. Of the 13 patients receiving 250 mg of zidovudine, only 1 patient was able to tolerate at least 10 million U/d of interferon-alpha. Of the 12 patients receiving 100 mg of zidovudine, 8 tolerated 10 million U/d, 5 tolerated 15 million U/d, and none tolerated higher doses. Of the 12 patients receiving 50 mg of zidovudine, 8 tolerated 10 million U/d, 7 tolerated 15 million U/d, and 6 tolerated 20 million U/d or more. Dose-limiting toxicities included neutropenia (57%), fatigue (16%), thrombocytopenia (14%), and hepatic dysfunction (10%). Of the 22 patients who received a stable dose of both drugs for 12 weeks, 11 patients had a complete or partial tumor response and 8 showed an anti-HIV effect. Peak serum levels of interferon-alpha (32 to 250 U/mL) and zidovudine (0.40 to 3.85 microM) were in the ranges previously shown to be synergistic against HIV. CONCLUSIONS: Combination therapy with zidovudine and interferon-alpha can be administered to patients with HIV infection and Kaposi sarcoma in doses that effect antiviral and antitumor responses; it appears to have a potential role in managing such patients.

The effect of theophylline and enprofylline on the late cutaneous response to antigen and compound 48/80.

Theophylline and enprofylline have been demonstrated to reduce mast cell-mediator release, inhibit polymorphonuclear leukocyte activation, and have been reported to reduce the late bronchial response to antigen. The effects of theophylline and enprofylline on the late cutaneous response (LCR) to compound 48/80 and antigen were studied in 29 patients enrolled in a placebo-controlled, double-blind study of the effect of the xanthines in mild asthma. Skin testing to a common environment allergen and compound 48/80 was performed during a baseline period and in the second phase of the study after stable drug levels were achieved, at least 6 weeks later. During baseline, the mean immediate wheal diameter (IWD) with antigen was 15.7 mm +/- 0.5, resulting in 27/29 LCRs with a mean wheal diameter of 37.1 mm +/- 5.2. The mean IWD with compound 48/80 was 16.1 mm +/- 0.7, resulting in 26/29 LCRs with a mean wheal diameter of 19.6 mm +/- 2.8. Repeat skin testing during treatment revealed no statistically significant changes in the LCR elicited by antigen or 48/80 in any of the treatment groups. There was little correlation between the size of the immediate wheal produced by antigen or 48/80 and the resulting size of the late response (r = 0.174 to 0.519). However, for the same IWD, the resulting late response was smaller with 48/80 than with antigen (p = 0.003). We conclude that (1) theophylline and enprofylline have no effect on the LCR to 48/80 and antigen and (2) for equivalent immediate wheal sizes, the resulting late response is smaller with 48/80 than with antigen.

Methionine-enkephalin as immunomodulator therapy in human immunodeficiency virus infections: clinical and immunological effects.

Enkephalins have been shown to enhance T cell-mediated immune responses and natural killer-cell activity in vitro. We have studied the effects of infusions of methionine-enkephalin on immune functions and clinical courses in seven patients with various stages of infection with human immunodeficiency virus (HIV). All patients were clinically stable at the time of entry into the study. Each received 10 micrograms/kg of methionine-enkephalin in an intravenous infusion three times weekly for up to 12 weeks. Evaluation of cellular immunity (T-cell subsets, in vitro interleukin-2 production and interleukin-2 receptor expression, T-cell responses to mitogens and antigens, and delayed-hypersensitivity skin tests) as well as clinical and toxicity monitoring was performed prior to treatment, at 2-week intervals during treatment, and after the cessation of treatment. Increases in interleukin-2 receptor expression were seen on lymphocytes collected on one occasion from each of two patients 30 min postinfusion. Studies done 24 hr after infusions revealed increases in interleukin-2 production in one patient, but when pre- and posttreatment values were compared there were no significant changes in numbers of circulating T cells of any phenotype or in T-cell responses to mitogens or antigens. None of the patients with Kaposi's sarcoma had regression of tumor; one patient dropped out of the study at week 5 because of deteriorating clinical status and progression of tumor. There were no adverse reactions or evidence of toxicity. We conclude that methionine-enkephalin appears to enhance temporarily selected immune responses in patients with HIV infection, however, in the schedule used in this study it was not clinically efficacious.