Michael S. Gottlieb

The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double blind, placebo-controlled trial

We conducted a double-blind, placebo-controlled trial of the efficacy of oral azidothymidine (AZT) in 282 patients with the acquired immunodeficiency syndrome (AIDS) manifested by Pneumocystis carinii pneumonia alone, or with advanced AIDS-related complex. The subjects were stratified according to numbers of T cells with CD4 surface markers and were randomly assigned to receive either 250 mg of AZT or placebo by mouth every four hours for a total of 24 weeks. One hundred forty-five subjects received AZT, and 137 received placebo. When the study was terminated, 27 subjects had completed 24 weeks of the study, 152 had completed 16 weeks, and the remainder had completed at least 8 weeks. Nineteen placebo recipients and 1 AZT recipient died during the study (P less than 0.001). Opportunistic infections developed in 45 subjects receiving placebo, as compared with 24 receiving AZT. The base-line Karnofsky performance score and weight increased significantly among AZT recipients (P less than 0.001). A statistically significant increase in the number of CD4 cells was noted in subjects receiving AZT (P less than 0.001). After 12 weeks, the number of CD4 cells declined to pretreatment values among AZT recipients with AIDS but not amonG AZT recipients with AIDS-related complex. Skin-test anergy was partially reversed in 29 percent of subjects receiving AZT, as compared with 9 percent of those receiving placebo (P less than 0.001). These data demonstrate that AZT administration can decrease mortality and the frequency of opportunistic infections in a selected group of subjects with AIDS or AIDS-related complex, at least over the 8 to 24 weeks of observation in this study.

Pneumocystis carinii Pneumonia and Mucosal Candidiasis in Previously Healthy Homosexual Men

Four previously healthy homosexual men contracted Pneumocystis carinii pneumonia, extensive mucosal candidiasis, and multiple viral infections. In three of the patients these infections followed prolonged fevers of unknown origin. In all four cytomegalovirus was recovered from secretions. Kaposis sarcoma developed in one patient eight months after he presented with esophageal candidiasis. All patients were anergic and lymphopenic; they had no lymphocyte proliferative responses to soluble antigens, and their responses to phytohemagglutinin were markedly reduced. Monoclonal-antibody analysis of peripheral-blood T-cell subpopulations revealed virtual elimination of the Leu-3 / helper/inducer subset, an increased percentage of the Leu-2 + suppressor/cytoxic subset, and an increased percentage of cells bearing the thymocyte-associated antigen T10. The inversion of the T/ helper to suppressor/cytotoxic ratio suggested that cytomegalovirus infection was an important factor in the pathogenesis of the immunodeficient state. A high level of exposure of male homosexuals to cytomegalovirus-infected secretions may account for the occurrence of this immune deficiency.

Pulmonary Complications of the Acquired Immunodeficiency Syndrome: Report of a National Heart, Lung, and Blood Institute Workshop

Under the sponsorship of the Division of Lung Diseases of the National Heart, Lung, and Blood Institute, a two-day workshop on the pulmonary complications of the acquired immunodeficiency syndrome ...

Acquired Immune Deficiency Syndrome: Ocular Manifestations

The acquired immune deficiency syndrome (AIDS) is a recently described disorder of cellular immunity in homosexuals, intravenous drug abusers, and Haitians. Manifestations include Kaposis sarcoma, Pneumocystis carinii pneumonia, and other opportunistic infections. Ophthalmic and autopsy examinations of 30 patients at UCLA revealed frequent ocular abnormalities. Findings included cotton-wool spots (16 patients), cytomegalovirus retinitis (eight patients), conjunctivitis and keratitis (four patients), conjunctival Kaposis sarcoma (three patients), Mycobacterium avium intracellulare choroidal granulomas (one patient), and retinal periphlebitis (one patient). We feel that the presence of cotton-wool spots in patients with this syndrome indicates a poor prognosis. Immunologic and electronmicroscopic studies of cotton-wool spots revealed no infectious agents or immunoglobulin deposition. Cytomegalovirus retinitis always was associated with a fatal outcome. The retinitis was characterized by an acute inflammatory reaction in 50% of patients. Ophthalmologists should be aware of the syndrome and its ocular manifestations.

The Acquired Immunodeficiency Syndrome

Abstract Recently, a new epidemic illness, the acquired immunodeficiency syndrome, has dramatically emerged in the United States, Europe, and Haiti. The syndrome represents an unprecedented epidemi...

Recombinant Alpha-2 Interferon Therapy for Kaposi's Sarcoma Associated with the Acquired Immunodeficiency Syndrome

In a randomized prospective study we tested the toxicity and efficacy of recombinant alpha-2 interferon in the treatment of Kaposis sarcoma associated with the acquired immunodeficiency syndrome. High doses (50 X 10(6) U/m2 body surface area, intravenously) or low doses (1 X 10(6) U/m2, subcutaneously) of recombinant alpha-2 interferon were administered to 20 patients for 5 days/wk, every other week, for four treatment cycles. Therapy was well tolerated subjectively and caused only mild hematologic and hepatic toxicity at both dose levels. No consistent or sustained changes were seen in immunologic variables during or after treatment. Six patients with Kaposis sarcoma, four at high dose and two at low dose, had objective responses (complete or partial) to treatment. However, therapy did not appear to eradicate cytomegalovirus carriage or prevent opportunistic infections related to cytomegalovirus.

Ocular Disorders Associated with a new Severe Acquired Cellular Immunodeficiency Syndrome

Among the prominent features of a newly described acquired cellular immunodeficiency syndrome that affects previously healthy male homosexuals are multiple opportunistic infections and Kaposis sarcoma. Immunosuppression induced by cytomegalovirus infection may play a major role in the pathogenesis of this disorder. We have performed ophthalmic examinations on seven such patients and found ocular abnormalities in all cases. Six patients were examined during the course of their illness and one patient at autopsy only. Each patient had several cotton-wool spots in the affected eye. Other ocular findings included cytomegalovirus retinitis, severe retinal periphlebitis, and conjunctival Kaposis sarcoma (one case each).

Immunological studies of homosexual men with immunodeficiency and Kaposi's sarcoma☆

Acquired immunodeficiency and Kaposis sarcoma are epidemic among homosexual men in the United States. We have identified three clinically distinct disease syndromes in homosexually active men: a syndrome of severe cellular immunodeficiency including infection with Pneumocystis carinii and other opportunistic pathogens, a syndrome of chronic benign lymphadenopathy without severe opportunistic infections, and Kaposis sarcoma. All 46 patients which we have studied with these three disease syndromes shared a common immune abnormality, that being a reduction in the circulating T-lymphocyte subpopulation bearing the Leu-3/OKT-4 antigen. The second major T-lymphocyte subpopulation, which bears the Leu-2/OKT-8 antigen, was numerically normal in all the disease syndromes, but increased as a percentage of all circulating lymphocytes. These abnormalities resulted in an inversion of the normal ratio of these two lymphocyte subpopulations. A similar, but less pronounced imbalance in circulating T-lymphocyte subpopulations was observed in a group of healthy homosexual men. The immune deficiency in these patients was most evident in the T-cell component of the immune system. Percentages of B cells, circulating immunoglobulin levels, and natural killer (NK) and antibody-dependent cell-mediated cytoxic (ADCC) functions were normal. Proliferative responses to antigen and mitogen were typically decreased in patients with the acquired immunodeficiency syndrome and some Kaposis sarcoma patients, but not those with the prolonged lymphadenopathy syndrome or a control group of healthy homosexual men. Possible causes or factors contributing to the immunodeficiency and interrelationships among the three disease manifestations are discussed.

Treatment of Cytomegalovirus Retinopathy with Ganciclovir

Ganciclovir is an experimental antiviral drug with activity against human cytomegalovirus (CMV). Forty patients with acquired immune deficiency syndrome (AIDS) and CMV retinopathy were treated with ganciclovir on a compassionate protocol basis. Initial treatment doses ranged from 5.0 to 14.0 mg/kg/day for 9 to 26 days. Signs of drug response were a halt to enlargement of lesions, decreased opacification of retinal tissue, and resolution of hemorrhage and vasculitis. Complete response was seen in 88% of patients and incomplete response was seen in 9%. Vision improved or remained stable in 88% of patients. Initial treatment did not eradicate live virus from the eye. To prevent reactivation of disease, 26 patients received low-dose maintenance therapy ranging from 1.5 to 7.5 mg/kg/day, once or twice daily, 3 to 7 days per week. Reactivation of disease developed for unknown reasons in 50% of patients on continuous, uninterrupted maintenance therapy for longer than 3 weeks. Reversible neutropenia, requiring cessation of treatment, developed in 30% of patients on initial treatment and in 38% of patients on maintenance therapy. Rhegmatogenous retinal detachment was a late complication in seven patients. By reducing or delaying visual loss, ganciclovir appears to be useful in the management of CMV retinopathy in patients with AIDS.

Recombinant Human Erythropoietin in the Treatment of Anemia Associated with Human Immunodeficiency Virus (HIV) Infection and Zidovudine Therapy: Overview of Four Clinical Trials

OBJECTIVE To assess the effect of recombinant human erythropoietin (r-HuEPO) on anemia in patients with the acquired immunodeficiency syndrome (AIDS) who are receiving zidovudine therapy. DESIGN Combined analysis of four 12-week, randomized, double-blind, controlled clinical trials. SETTING Multiple centers in the United States. PATIENTS Two hundred and ninety-seven anemic (hematocrit < 30%) patients with AIDS who were receiving zidovudine therapy. Of the 297 patients, 255 were evaluable for efficacy, but all patients were included in analysis of safety. INTERVENTION Patients were randomly assigned to receive either r-HuEPO (100 to 200 U/kg body weight) or placebo, intravenously or subcutaneously, three times per week for up to 12 weeks. MEASUREMENTS Changes in mean hematocrit, transfusion requirement, and quality of life. RESULTS Sixty-nine percent of patients had endogenous serum erythropoietin levels less than or equal to 500 IU/L, and 31% had erythropoietin levels greater than 500 IU/L. In patients with low erythropoietin levels (< or equal to 500 IU/l), r-HuEPO therapy decreased the mean number of units of blood transfused per patient when compared with placebo (3.2 units and 5.3 units, respectively; P = 0.003) and increased the mean hematocrit from the baseline level (4.6 percentage points and 0.5 percentage points, respectively; P <0.001). Overall quality of life improved in patients on r-HuEPO therapy (P = 0.13). Patients with erythropoietin levels greater than 500 IU/L showed no benefit from r-HuEPO in any outcome variable. Placebo and r-HuEPO recipients did not differ in the incidence of adverse effects or opportunistic infections. CONCLUSION Therapy with r-HuEPO can increase the mean hematocrit and decrease the mean transfusion requirement in anemic patients with AIDS who are receiving zidovudine and have endogenous low erythropoietin levels (< or equal to 500 IU/L). Such therapy is of no apparent benefit in patients whose endogenous erythropoietin levels are higher than 500 IU/L.