Pharmacokinetics of recombinant interleukin 2 in humans.

This report summarizes the pharmacokinetics in humans of recombinant interleukin 2 (IL-2) given as an i.v. bolus, i.v. or i.p. infusion, and i.m. or s.c. injection. Immediately after an i.v. bolus the serum IL-2 level equals the dose divided by the plasma volume, in a typical human 650 units/ml for a dose of 10(6) units/m2. The level initially decreases with a half-life of 12.9 min, followed by a slower phase with a half-life of 85 min out to 4 h after the bolus. The median steady state level during an i.v. infusion of 10(6) units/m2 over 6 h is 41 units/ml. A clearance rate of approximately 120 ml/min is obtained from either the i.v. bolus or infusion data and is consistent with the renal filtration being the major route of clearance. Serum levels remain fairly constant for about 8 h after s.c. or i.m. injection but are approximately 2% of the level seen immediately after an i.v. bolus. The area under the time-concentration curve suggests that about 30% of the IL-2 activity is transported from the site of an i.m. injection to the blood. After i.p. infusion IL-2 is only slowly transported to the blood. The median serum IL-2 levels are 430-fold lower than levels in the i.p. fluid and decrease with a median half-life of 6.3 h.

A multicenter clinical trial of oral ribavirin in HIV-infected patients with lymphadenopathy. The Ribavirin-LAS Collaborative Group.

A double-blind, randomized, placebo-controlled trial comparing two daily doses of oral ribavirin and placebo was conducted at four medical centers. One hundred sixty-four adult men with lymphadenopathy were enrolled over a 2-month period and randomized to receive ribavirin 800 mg (53 subjects), ribavirin 600 mg (55 subjects), or placebo (56 subjects). Active treatment was administered for 24 weeks followed by a 4-week washout period. Nine subjects receiving placebo, four receiving ribavirin 600 mg, and none in the 800 mg group developed AIDS during the 24 weeks of active treatment. One patient randomized to the 800 mg group had Kaposi's sarcoma at study entry and was included in the intent-to-treat analysis. An overall significant difference in progression to AIDS was observed among the three treatment groups (p = 0.028) with patients randomized to receive 800 mg having a significantly longer time to AIDS than placebo patients (p = 0.012; relative risk, 9.0; 95% confidence interval, 1.1 to 70.8). There was no significant difference between the 600 mg and placebo groups (p = 0.15; relative risk, 2.3; 95% confidence interval, 0.7 to 7.6). Baseline CD4 cell count and hematocrit made independent contributions and formed a multivariate prognostic set for these progression data. The significant treatment superiority of 800 mg compared to placebo remained after adjustment for these factors (p = 0.019). After deletion of patients with major protocol violations at entry, the difference between the 800 mg and placebo treatment remained significant (p = 0.021).(ABSTRACT TRUNCATED AT 250 WORDS)

A pilot study of diethyldithiocarbamate in patients with acquired immune deficiency syndrome (AIDS) and the AIDS-related complex.

We investigated the use of diethyldithiocarbamate (DTC, or Imuthiolr, Merieux Institute) as a therapeutic agent in patients with Acquired Immune Deficiency Syndrome (AIDS) and AIDS-Related Complex (ARC). Patients were prospectively stratified and randomized to receive DTC 200 mg/m2 intravenously weekly for 16 weeks or no therapy, followed by crossover to the opposite arm for an equal period. Forty-four patients were entered and forty were evaluable. There was a statistically significant decrease in symptoms in the DTC treated patients compared to the controls (p = .002). There was a significant improvement in lymphadenopathy in the treated patients compared to the controls (p = .005). One patient showed disappearance of splenomegaly, one clearing of antifungal agent-resistant perianal moniliasis, and one clearing of hairy leukoplakia. No significant differences in progression were noted. No changes were seen in any of the immunological parameters measured. There was no significant toxicity. Because of the changes in symptoms and in lymphadenopathy, we suggest that further study of DTC, both alone and in combination with other agents, may be indicated.

Progressive disseminated histoplasmosis in patients with acquired immunodeficiency syndrome.

PURPOSE: Progressive disseminated histoplasmosis is now diagnosed frequently in patients with the acquired immunodeficiency syndrome (AIDS) living in the central United States. Previous review articles of AIDS have failed to mention this infection. Herein, we describe 48 AIDS patients with progressive disseminated histoplasmosis in an effort to better understand the clinical presentation and diagnosis of the condition in this setting and to assess the efficacy of antifungal chemotherapy. PATIENTS AND METHODS: In the Houston metropolitan area, there were 66 cases of progressive disseminated histoplasmosis among 1,300 confirmed cases of AIDS from January 1983 to July 1987. Of AIDS patients in East Texas with histoplasmosis, 16 patients were available for follow-up by one of us, and the histories of 32 were obtained by examination of hospital charts and physician records. RESULTS: Fever, weight loss, and splenomegaly were the most common presenting signs and symptoms, occurring in 81, 52, and 31 percent, respectively. One-third of the patients had hematologic abnormalities. Infiltrates on chest roentgenograms were observed in 52 percent. Progressive disseminated histoplasmosis was the initial manifestation of AIDS in almost three-fourths of our patients. Biopsy and culture of the bone marrow established the diagnosis of progressive disseminated histoplasmosis in 69 percent. Clinical or autopsy proof of relapse occurred in three patients despite an initial course of more than 2 g of amphotericin B chemotherapy followed by ketoconazole suppression. CONCLUSION: Progressive disseminated histoplasmosis is often the first sign of immunodeficiency in patients with AIDS, and the diagnosis of this condition is most often established by bone marrow biopsy and culture. Because of the permanence of the immunodeficient state in these patients, progressive disseminated histoplasmosis is resistant to treatment.

Glucan-induced keratoderma in acquired immunodeficiency syndrome.

Six of 20 patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex receiving intravenous infusions of soluble glucan (beta-1-3 polyglucose) developed a keratoderma of the palms and soles. The eruption began during the first two weeks of therapy and resolved two to four weeks after its discontinuation. The eruption was different in appearance from our previously reported keratoderma blennorrhagica in AIDS-associated psoriasis. None of the other 735 patients with AIDS or AIDS-related complex not treated with soluble glucan developed a similar keratoderma. The correlation between receiving glucan and the hyperkeratosis is highly significant. Since glucan is a naturally occurring component of the cell walls of yeast, fungus, and some bacterial organisms, recognition of its ability to induce such a striking reaction pattern may be of general significance and interest, although the reaction itself may be limited to patients with AIDS.

Decreased 5'-nucleotidase activity in suppressor (OKT8) T lymphocytes from homosexuals with AIDS-related complex: nonassociation with enhanced deoxynucleoside toxicity.

The purine metabolic enzymes adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and 5'nucleotidase (5NT) have been shown to be important for normal lymphocyte maturation. Abnormalities of these enzymes have been associated with hereditary as well as acquired immunodeficiency states. Enzyme activity was measured in helper (OKT4) and suppressor (OKT8) lymphocyte subsets from 10 homosexuals with AIDS-related complex (ARC) and in 10 healthy controls. There were no significant differences in either mean ADA activity or mean PNP activity between ARC OKT4 cells and control OKT4 cells and between ARC OKT8 cells and control OKT8 cells. By contrast, mean 5NT activity was slightly decreased in OKT4 cells from ARC patients compared with that of controls and more significantly diminished in ARC OKT8 cells compared with that of controls. Both deoxyadenosine and deoxyguanosine, when incubated separately with OKT4 and OKT8 cells in the presence of EHNA, an ADA inhibitor, did not significantly inhibit lymphocyte blastogenesis to a greater extent in ARC patients than in controls. Hence, the decreases in 5NT activity most likely reflect lymphocyte immaturity and are not associated with biochemical abnormalities leading to increased deoxynucleoside toxicity.

Enhanced serological and virological findings of Epstein-Barr virus in patients with AIDS and AIDS-related complex.

The potential involvement of Epstein-Barr virus (EBV) in AIDS was examined by determining the type of EBV-specific antibody responses and the EBV content or lymphoproliferative ability present in selected body fluids of patients with AIDS or AIDS-related complex. The results were compared with two control groups. An enhanced antibody response to a broad spectrum of EBV antigens was found in patients with AIDS or AIDS-related complex. The pattern of virus-specific antibody responses resembled that associated with a persistent or reactivated infection. The content of EBV in oropharyngeal secretions and the lymphoproliferative ability in peripheral blood from patients with AIDS or AIDS-related complex was significantly greater than that from healthy controls and approached levels detected in the control group with infectious mononucleosis. These findings, together with recent reports of cellular-level interaction between EBV and human T lymphotropic virus type III, suggest that EBV may have a contributory role in these disorders.

Relationship of exposure to human T lymphotropic virus and T helper cells in homosexual men.

The detection of serum antibodies (Ab) against HTLV-III in individuals with AIDS and related symptoms (ARC) has unambiguously defined the association of the virus infection to AIDS. This study was done to determine the extent of exposure to HTLV-III in homosexual men by measuring (Ab) and relating it to the stage of disease and T cell subsets. We found Ab in 89.5% of the 492 men with the median titers by stage of disease being 1600 for symptom-free, 6400 for ARC or Kaposi's sarcoma, and 4800 for opportunistic infection (OI), respectively. There was no correlation between Ab titers and either absolute or relative T helper cells (T4+), even though these cells decreased with disease severity. More specifically, however, symptom free patients had a normal distribution of the helpers of suppression (T4+/Leu8+), whereas, in symptomatic men, there was a significant decrease suggesting that the target cell for the virus is a subpopulation of the T helper cell.

Aggressive non-Hodgkin's lymphomas in immunocompromised homosexual males.

During the period from 1981 through 1984, 14 immunocompromised homosexual males with intermediate or high-grade non-Hodgkin's lymphoma were seen at University of Texas M.D. Anderson Hospital and Tumor Institute. Six patients had diffuse large-cell lymphoma, seven had diffuse undifferentiated lymphoma, and one had unclassifiable lymphoma that suggested large-cell lymphoma. Eight patients had the acquired immunodeficiency syndrome (AIDS) and five had the AIDS-related complex. Kaposi's sarcoma was initially present in four patients and developed later in two others. The patients with diffuse large-cell lymphoma were characterized by more severely altered immune parameters, multicentric brain mass lesions, pretherapy opportunistic infections, lower performance status, poor response to therapy, and death in all within six months. The undifferentiated lymphoma group had preceding generalized reactive lymphadenopathy, less severe immune dysfunction, and excellent response to combination chemotherapy, with survival time greater than 19 months in three patients. Twelve of the patients had extranodal sites of lymphoma at presentation. There is a definite trend for the development of aggressive non-Hodgkin's lymphomas with unusual sites of extranodal involvement in immunocompromised homosexual males, with the potential for good tolerance to combination chemotherapy and improved survival in the subgroup without severe concomitant opportunistic infections.

Elevated adenosine deaminase and purine nucleoside phosphorylase activity in peripheral blood null lymphocytes from patients with acquired immune deficiency syndrome.

The purine metabolic enzymes adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) are important in lymphocyte differentiation, and genetic deficiencies of either enzyme have been associated with hereditary immunodeficiency states. Both ADA and PNP activity were measured in null cell-enriched and T cell-enriched peripheral blood lymphocytes from 16 patients with the acquired immune deficiency syndrome (AIDS), seven patients with the AIDS-related symptom complex (ARC), and seven asymptomatic homosexuals. ADA activity in nmol/10(6) lymphocytes/h was significantly elevated in null lymphocytes from AIDS (161 +/- 12) as compared with 23 healthy heterosexual controls (127 +/- 8;P less than .025). PNP activity was also significantly increased in null lymphocytes from AIDS patients (96 +/- 10;P less than .005) as well as those from ARC patients (84 +/- 11:P less than .025) relative to controls (61 +/- 5). No significant differences in enzyme activity were noted in T cell-enriched cells in any group. Along with elevated enzyme activity, AIDS patients had small yet significant increases in the percentages of HLA-DR (P less than .025), terminal deoxynucleotidyl transferase (TdT) (P less than .0001), and peanut agglutinin receptor (P less than .0001) positive lymphocytes in the null fraction compared with controls. TdT-positive cells appeared morphologically as large lymphoblasts with irregular nuclei. The data imply that the cellular immune deficiency in AIDS is not a result of deficiencies in lymphocyte ADA or PNP activity, but is more likely associated with an increase in an immature and/or activated lymphocyte subset.

Volatile nitrites. Use and adverse effects related to the current epidemic of the acquired immune deficiency syndrome.

Early reports of the acquired immune deficiency syndrome (AIDS) in homosexual men suggested that the cause might be related to homosexual life-style practices, including use of recreational drugs. Inhalation of volatile nitrites is a possible contributing factor in AIDS because their pharmacologic properties lead to toxicity. Metabolism of N-nitroso compounds produces mutagens, teratogens, and potent carcinogens in 39 different animal species, and volatile nitrites have deleterious effects on human lymphocytes in vitro and in vivo. In relation to the current AIDS epidemic, the timing of production and sales of volatile nitrites for recreational use is the only new life-style factor that might answer the question "why AIDS now?" Prevalence of nitrite use among male homosexuals is very high, and almost every reported case of Kaposi's sarcoma during the past three years includes a history of prior nitrite use. The age of the group of patients in whom Kaposi's sarcoma and AIDS are developing is consistent with a cohort initially exposed seven to 10 years ago. Cessation of nitrite use could reduce the epidemic.

Treatment of acquired immunodeficiency syndrome--related Kaposi's sarcoma with lymphoblastoid interferon.

Twelve homosexual patients with Kaposi's sarcoma associated with the acquired immune deficiency syndrome (AIDS) were treated with a preparation of purified human lymphoblastoid interferon (Wellferon [Burroughs Wellcome, Research Triangle Park, NC]). They were given a dose of 20 X 10(6) U/m2 intramuscularly daily for approximately two months. Responders continued their treatment on a maintenance schedule of 20 X 10(6) U/m2 three times a week. Four patients experienced complete remissions, and four experienced partial remissions that resulted in a total response rate of 67%. The median duration of treatment was 14 weeks (7 to 28+ weeks), and the median response duration was 28+ weeks (19 to 29+ weeks). Of the four patients in complete remission, one relapsed at 25 weeks and one at 26 weeks; the other two remained in complete remission at 28 and 29+ weeks. The clinical toxicity consisted of chills, fever, fatigue, and asthenia. Hematologic toxicity was similar to that previously described for other preparations of alpha-interferon and consisted of moderate leukopenia and thrombocytopenia. Asthenia, a condition present in all 12 patients, was severe in 50%. A minimal tumor burden, the absence of circulating interferon before treatment, and a performance status of greater than or equal to 90% on the Karnofsky scale were related to an improved response rate. Measurement of immunologic parameters showed significant declines in the already impaired T cell levels, lymphocyte blastogenic response to concanavalin A, monocyte-mediated antibody-dependent cellular cytotoxicity, and monocyte-adherence. Activation of natural killer cells was not noted, and no life-threatening infections occurred during treatment. These data suggest that human lymphoblastoid interferon is an active agent in the treatment of Kaposi's sarcoma, and its use warrants further study in a larger number of patients.

IL-2 production and response in vitro by the leukocytes of patients with acquired immune deficiency syndrome.

In order to investigate the nature of the T cell defect associated with the acquired immune deficiency syndrome (AIDS) we studied the ability of peripheral blood mononuclear cells from 8 patients with Kaposi's sarcoma (KS), 2 with opportunistic infection (OI), 23 with AIDS-related symptoms complex (ARC) without KS or OI (ARC), and 29 heterosexual controls to produce interleukin II (IL-2) on phytohemagglutinin (PHA) stimulation and to respond to exogenously supplied IL-2. Patients with AIDS as well as those with ARC produced adequate levels of IL-2 in response to lectin stimulation when compared to controls (AIDS, 3.07 +/- 1.98 units; ARC, 3.03 +/- 1.89 units; controls, 3.75 +/- 1.52 units). However, the ability of these patients' cells to respond in vitro to exogenously supplied IL-2 as measured on short-term PHA-stimulated T cell blasts, was found to be severely impaired in patients with AIDS and ARC (AIDS, 22.4 +/- 6.0 X 10(-3) cpm; ARC, 20.1 +/- 4.2 X 10(-3) cpm; control, 41.4 +/- 4.2 X 10(-3) cpm). This impairment was associated with diminished expression of the IL-2 receptor on 7-day-old lectin-stimulated T cells from both patient groups (AIDS, 17.7 +/- 5.7; ARC, 36.8 +/- 4.4; control 71.8 +/- 1.7). These results should be considered when IL-2 is proposed as potential therapy in the treatment of AIDS. They also suggest that the nature of the AIDS defect is related to impaired hormone receptor expression.

Impaired in vitro interferon, blastogenic, and natural killer cell responses to viral stimulation in acquired immune deficiency syndrome.

The in vitro immune response to herpes simplex virus (HSV), type 1, strain 539, HSV type 2, strain 316D, and cytomegalovirus was studied in 20 patients (14 with acquired immune deficiency syndrome, four with the acquired immune deficiency syndrome-related symptom complex, and two sexually active asymptomatic homosexuals) and 18 heterosexual healthy controls. Peripheral blood mononuclear cells were cultured with 2 X 10(5) plaque-forming units of heat-inactivated viruses, their lymphocyte blastogenic responses were measured after 5 days in culture by [3H]-thymidine incorporation, their interferon production was measured after 24 hr and 5 days, and natural killer (NK) cell activation was measured after 24 hr and 5 days of culture. Blastogenic responses to viruses were significantly low for only HSV, type 1:1.75 X 10(3) cpm in patients' cells compared to 6.36 for controls. Interferon responses to all three viruses were significantly low at both 24 hr and 5 days; e.g., HSV, type 1:139 IU/ml in patients' cells compared to 777 for controls at 24 hr. NK cell responses of patients were lower than those of controls when tested fresh and after 24 hr of incubation: 6.1 versus 11.7% and 9.2 versus 16.8% target cell lysis, respectively. Exposure to viruses boosted NK cell responses of both patients' and controls' cells, but boosting was generally greater among the normal rather than the patients' cells. The abnormalities of response were present in all three patient groups. Addition of interleukin-2 in vitro increased the patient and control blastogenic and NK responses but did not augment the interferon responses. The in vitro responses to both HSV, type 1, and HSV, type 2, correlated significantly with our conventional assays of the percentage and absolute level of T4+-helper lymphocytes in the blood and the blastogenic responses to mitogens, such as phytohemagglutinin, pokeweed mitogen, and concanavalin A. This system should be useful for the study of host defense in acquired immune deficiency syndrome patients and those in high-risk groups, and also for the in vitro evaluation of immunomodulators.

Risk factor analysis among men referred for possible acquired immune deficiency syndrome.

Responses to a lifestyle questionnaire among 13 patients with Kaposi's sarcoma and 18 with an opportunistic infection were compared with those of 29 symptom-free referred individuals. Odds ratios (OR) with 95% confidence limits were calculated as an estimate of risk. Significantly elevated odds ratios (P less than 0.05) were found for cigarette smoking (OR = 3.4), marijuana use (OR = 3.7), nitrite use (OR = 5.5), frequenting bathhouses (OR = 7.6), prior syphilis (OR = 3.4), and fist-rectal sexual practices (OR = 3.5). A response gradient for the risk estimates was found for marijuana use (OR = 2.7 for occasional, OR = 4.3 for frequent use); nitrites (OR = 4.0 for occasional; OR = 6.3 for frequent use); and prior syphilis (OR = 2.9 for one to two previous infections and 9.0 for three or more). We believe the evidence is now sufficient to recommend preventive practices which may reduce the male homosexual's risk for developing acquired immune deficiency syndrome, Kaposi's sarcoma, and/or opportunistic infections. These include cessation of cigarette smoking, marijuana use, and nitrite inhalation; reduction in number of anonymous sexual partners to decrease risk of sexually transmitted diseases; and avoidance of fisting.

In vitro modulation of purine enzyme metabolism and lymphocyte surface marker expression by thymosin fraction 5 in homosexual males.

Thymosin fraction 5 (Thymosin) has numerous immunoregulatory activities including modulation of enzymes involved in lymphocyte maturation. The effect of Thymosin on the purine metabolic enzymes adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and 5' nucleotidase (5'NT) in null and T-enriched peripheral blood lymphocytes from sexually active asymptomatic homosexual males (AS), patients with the AIDS-related symptom complex (ARC), and those with acquired immune deficiency syndrome (AIDS) was examined and compared to its effect on lymphocytes from healthy heterosexual controls. Mean ADA activity was significantly higher in null cells from fourteen AIDS patients than in five asymptomatic homosexuals, ten ARC patients, or 27 controls. Mean PNP activity was significantly elevated in null-enriched lymphocytes from ten ARC and fourteen AIDS patients compared to controls. No differences in these enzymes were found in T-enriched cells from any group. 5'NT was markedly decreased in both null and T lymphocytes in all homosexual groups relative to controls. Homosexuals had significantly elevated percentages of OKT10 positive and Ia positive lymphocytes compared to controls. Thymosin at an optimal concentration of 150 micrograms/ml caused significant decreases in mean ADA and PNP activity in null lymphocytes from ARC + AIDS patients along with a significant decrease in the percentage of OKT10 positive lymphocytes. No phenotypic changes were seen in AS or control lymphocytes. The data suggest that Thymosin has a maturational effect in vitro on immature T cells from symptomatic homosexuals.