Howard S. Jaffe

Recombinant interferon gamma therapy for atopic dermatitis

BACKGROUNDnAtopic dermatitis is characterized by immunologic abnormalities including evidence for reduced interferon gamma production. Therapeutic options for treatment of atopic dermatitis are limited and unsatisfactory. Previous open trials have suggested efficacy for recombinant interferon-gamma (rIFN-gamma) in treatment of severe atopic dermatitis. We describe the results of treatment with rIFN-gamma, assessing clinical, immunologic, and laboratory safety parameters in 83 patients with moderate to severe atopic dermatitis.nnnOBJECTIVEnOur purpose was to determine in a randomized, placebo-controlled, double-blind multicenter study the effects of recombinant human interferon gamma therapy in patients with atopic dermatitis.nnnMETHODSnPatients received 50 micrograms/m2 rIFN-gamma (n = 40) or placebo (n = 43) by daily subcutaneous injection for 12 weeks. Seventy-eight patients completed the treatment course; two patients receiving rIFN-gamma (one because of constitutional side effects) and three receiving placebo discontinued treatment before completion. Physician and patient overall response evaluations, clinical severity scores, body surface area involvement, and laboratory parameters were monitored throughout the trial.nnnRESULTSnPatients in both treatment groups were similar except that the rIFN-gamma group was older and had a longer disease duration. Forty-five percent of rIFN-gamma-treated patients and 21% of placebo-treated patients achieved greater than 50% improvement in physicians overall response evaluations (p = 0.016). As estimated by patients, responses also showed significant improvement in the rIFN-gamma group compared with the placebo group (53% vs 21%, p = 0.002). Significant reductions in erythema (p = 0.035) and in excoriations or erosions (p = 0.045) occurred in rIFN-gamma-treated patients. Other atopic symptoms such as conjunctivitis (p < 0.002) were also reduced in the rIFN-gamma group. Occasional headaches, myalgias, or chills occurred in 30% to 60% of rIFN-gamma-treated patients but were effectively prevented by pretreatment acetaminophen and by dosing at bedtime. Grade II granulocytopenia occurred in five rIFN-gamma patients but normalized with continued treatment. Reduction to alternate-day dosing was necessary for six patients in the rIFN-gamma group and two in the placebo group. Seven had mild elevations of hepatic transaminase levels that did not affect therapy. The mean eosinophil count was significantly reduced (p = 0.003), whereas a nonsignificant increase in serum IgE levels occurred in the active treatment group.nnnCONCLUSIONnThis study demonstrated that rIFN-gamma given by daily subcutaneous injection over a 12-week period was safe, well accepted, and effective in reducing inflammation, clinical symptoms, and eosinophilia in severe atopic dermatitis.

A randomized prospective clinical trial to determine the efficacy of interferon-γ in severely injured patients

Many aspects of the normal immune response are depressed after severe injury. Reduced monocyte human leukocyte antigen-DR (HLA-DR) levels have closely correlated with the development of major infection. After a pilot study with recombinant interferon-gamma (rIFN-gamma) showed restoration of depressed HLA-DR levels after major injury, a multicenter, prospective, randomized, double-blind trial was conducted. Two hundred thirteen trauma patients who were at high risk of infection received either placebo or rIFN-gamma (100 micrograms) subcutaneously each day for 10 days after admission. One hundred ninety-three patients were evaluable with respect to primary end points. Patients treated with rIFN-gamma were older (p = 0.10) and had more severe modes of injury (p = 0.02). By the third day, both monocyte HLA-DR antigen expression and outcome predictive score were significantly better in the rIFN-gamma-treated group than in the placebo group (p = 0.0001 and p = 0.0006, respectively). Nine deaths occurred in patients treated with rIFN-gamma compared with 12 deaths in the placebo group (p = 0.46). Major infections requiring surgical drainage or debridement occurred in 17 patients treated with rIFN-gamma compared with 22 treated with placebo. No difference between treatment arms was noted in overall major or minor infection rates, but there were fewer severe infections that required reoperation or computer tomographic-guided drainage in patients receiving IFN-gamma. While these results suggest that rIFN-gamma may be useful in some aspects of infection in the patient with severe trauma, a larger trial with longer treatment will be needed to prove the comprehensive value of rIFN-gamma.

A Randomized, Double-Blind, Placebo-Controlled Trial of Cidofovir Gel for the Treatment of Acyclovir-Unresponsive Mucocutaneous Herpes Simplex Virus Infection in Patients with AIDS

The safety and efficacy of cidofovir gel for treatment of acyclovir-unresponsive herpes simplex virus infections in AIDS patients was evaluated in a randomized, double-blind, multicenter trial. Cidofovir (0.3% or 1%) or placebo gel was applied once daily for 5 days. Ten of 20 cidofovir-treated and none of 10 placebo-treated patients had complete healing or >50% decreased area (P = .008); 30% of cidofovir-treated patients versus 0 placebo recipients had complete healing (P = .031). Viral shedding ceased in 13 (87%) of 15 cidofovir-treated and 0 of 9 placebo-treated patients (P = .00004). For cidofovir-treated patients, median time to complete or good response was 21 days, and median time to negative viral culture was 2 days (P = .025, P = .0001, respectively). Median lesion area decreases were 58% for cidofovir-treated versus 0 for placebo-treated patients (P = .005), and mean pain score changes were -1.84 versus -0.34 (P = .042). Application site reactions occurred in 25% of cidofovir-treated and 20% of placebo-treated patients; none was dose-limiting. Cidofovir therapy provided significant benefits in lesion healing, virologic effect, and pain reduction.

Clinical uses of cidofovir

Cidofovir is a cytidine nucleotide analogue recently licensed as an intravenous treatment for CMV retinitis in AIDS patients. Three controlled clinical trials have demonstrated efficacy of cidofovir for this indication, and have generated data useful as a guideline to prevent potential toxicity. Although de novo emergence of resistance to cidofovir has not been observed clinically in patients receiving cidofovir, cross‐resistance to cidofovir in ganciclovir‐resistant clinical DNA polymerase mutants has been identified. Cross‐resistance of cidofovir and foscarnet has not been identified to date. A broad spectrum agent with in vitro activity against human herpesviruses, adenovirus, HPV, polyomaviruses and human poxviruses, cidofovir is under clinical investigation for a variety of potential applications. Examples include intravenous administration of cidofovir for treatment of progressive multifocal leukoencephalopathy and Kaposis sarcoma, intraocular injection for treatment of CMV retinitis, intralesional injection for treatment of respiratory papillomatosis, topical application for treatment of molluscum contagiosum, anogenital condyloma acuminata, and recurrent genital herpes, and ophthalmic instillation for treatment of viral keratoconjunctivitis.

Clinical Pharmacokinetics of Cidofovir in Human Immunodeficiency Virus-Infected Patients

The pharmacokinetics of cidofovir (HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine) were examined at five dose levels in three phase I/II studies in a total of 42 human immunodeficiency virus-infected patients (with or without asymptomatic cytomegalovirus infection). Levels of cidofovir in serum following intravenous infusion were dose proportional over the dose range of 1.0 to 10.0 mg/kg of body weight and declined biexponentially with an overall mean +/- standard deviation terminal half-life of 2.6 +/- 1.2 h (n = 25). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 24 h. The overall mean +/- standard deviation total clearance of the drug from serum (148 +/- 25 ml/h/kg; n = 25) approximated renal clearance (129 +/- 42 ml/h/kg; n = 25), which was significantly higher (P < 0.001) than the baseline creatinine clearance in the same patients (83 +/- 21 ml/h/kg; n = 12). These data indicate that active tubular secretion played a significant role in the clearance of cidofovir. The steady-state volume of distribution of cidofovir was approximately 500 ml/kg, suggesting that the drug was distributed in total body water. Repeated dosing with cidofovir at 3.0 and 10.0 mg/kg/week did not alter the pharmacokinetics of the drug. Concomitant administration of intravenous cidofovir and oral probenecid to hydrated patients had no significant effect on the pharmacokinetics of cidofovir at a 3.0-mg/kg dose. At higher cidofovir doses, probenecid appeared to block tubular secretion of cidofovir and reduce its renal clearance to a level approaching glomerular filtration.

Recombinant gamma interferon in treatment of patients with atopic dermatitis and elevated IgE levels

PURPOSEnRecombinant gamma interferon (rIFN-gamma) inhibits IgE synthesis in vitro by human peripheral blood mononuclear cells (PBMC). These data suggest a role for rIFN-gamma in the treatment of patients with severe atopic dermatitis (AD) and elevated IgE levels. The purpose of this study was to determine the effect of rIFN-gamma treatment on IgE production in patients with AD.nnnPATIENTS AND METHODSnTwenty-two patients with chronic severe AD were treated with rIFN-gamma. In part I of the study, 14 patients were treated with daily subcutaneous injections at three successive dose levels (0.01 mg/m2, 0.05 mg/m2, and 0.1 mg/m2) for 5 days with 2 days off between each dose level. In part II, eight patients received rIFN-gamma at 0.05 mg/m2, daily for 6 weeks. One patient from part I and eight patients from part II of the study received three times per week maintenance thereby for up to 14 months. Prior to and at selected times during and after treatment, the clinical and immunologic status of the patients was assessed.nnnRESULTSnIn part I, spontaneous de novo IgE synthesis by PBMC was inhibited in 10 patients receiving rIFN-gamma at 0.01 mg/m2 (p = 0.038) and in nine at 0.1 mg/m2 (p = 0.066). There was no reduction of serum IgE levels at any of the three dose levels. Total clinical severity showed improvement at each dose level (p less than 0.04) with worsening 3 days after discontinuation of treatment. In part II, there was no significant inhibition of spontaneous IgE synthesis by PBMC nor was there any reduction of serum IgE. Nevertheless, there was a progressive and significant reduction (p less than 0.01) in total clinical severity over the 6 weeks of daily rIFN-gamma with a sustained improvement during maintenance therapy.nnnCONCLUSIONnThe results of this pilot study suggest that rIFN-gamma may be efficacious in the treatment of AD and that further clinical trials are warranted.

Anti-Human Immunodeficiency Virus (HIV) Activity, Safety, and Pharmacokinetics of Adefovir Dipivoxil (9-[2-(bis-pivaloyloxymethyl)-phosphonylmethoxyethyl]adenine) in HIV-Infected Patients

A randomized, double-blind, placebo-controlled, dose-escalation study of adefovir dipivoxil, an oral prodrug of adefovir, was conducted in 36 human immunodeficiency virus (HIV)-infected subjects to evaluate its anti-HIV activity, safety, and pharmacokinetics. Subjects received placebo or one of three dosages of adefovir dipivoxil daily for 14 days. Median decreases in serum p24 antigen of 31% (P = .02), 25% (P = .31), and 30% (P = .01) occurred in each drug-treated group, respectively, compared with an increase of 17% in the placebo group. Median decreases in serum HIV RNA of 0.4-0.6 log10 copies/mL occurred in the drug-treated groups (P = .03), compared with no change in the placebo group. Gastrointestinal complaints and reversible liver transaminase elevations were the most frequently noted adverse events. Decreases in serum free carnitine occurred in each drug-treated group during treatment. After 14 days of dosing, adefovir dipivoxil demonstrated anti-HIV activity and was best tolerated at the lowest dosage studied, 125 mg daily.

Use of recombinant human interferon gamma to enhance neutrophil chemotactic responses in Job syndrome of hyperimmunoglobulinemia E and recurrent infections

Recombinant human interferon gamma enhances neutrophil respiratory burst and bactericidal activity in patients with chronic granulomatous disease. Mononuclear leukocytes of patients with the hyperimmunoglobulinemia E syndrome (Job syndrome) produce low or undetectable levels of this lymphokine. For these reasons we have restudied neutrophil chemotaxis in a group of our patients with the syndrome and determined the effect of recombinant human interferon gamma on the responses. Each of the patients had neutrophil chemotactic responses ranging from 22% to 55% of simultaneous control values (p less than 0.001). After incubation with interferon gamma, a significant improvement in chemotactic responsiveness was observed in the neutrophils of each of the patients (mean 301% of baseline chemotaxis; p less than 0.008). These data suggest the need for a double-blind, placebo-controlled trial of interferon gamma in a larger group of patients with the syndrome of hyperimmunoglobulinemia E and recurrent infections.

Treatment of steroid‐dependent asthma with recombinant interferon‐gamma

We have recently reported that treatment of patients with severe atopic dermatitis with recombinanl interferon‐gamma (rIFN‐y) resulted in clinical improvement as well as a reduction of circulating eosinophils. Since IgE‐dependent late phase allergic reactions and eosinophilic infiltration are thought to play an important role in the pathogenesis of asthma, we conducted a two centre randomized double‐blind placebo‐controlled trial of rIFN‐y in the treatment of steroid‐dependent asthma. Patients were treated with daily subcutaneous injections of either 0.05 mg/m2 rIFN‐y (n= 9) or placebo (n=11) for 90 days. All patients completed the study without significant drug toxicity noted. Oral prednisone dose, forced expiratory volume in 1 second (FEV), peak expiratory flow rates (PEFR) and circulating eosinophil counts were monitored throughout the trial. There was no significant difference between the two treatment groups in per cent reduction from baseline of daily prednisone (P=0.51). There was also no significant difference between the two treatment groups in per cent change from baseline in FEV1 (P= 0.54)or in PEFR (P=0.75). Total circulating eosinophil counts decreased by 31% in the rIFN‐y group and increased by 8.5% in the placebo group (P= 0.09). We conclude that this treatment regimen was not effective in patients with steroid‐dependent asthma.

Interferon-gamma in a family with X-linked lymphoproliferative syndrome with acute Epstein-Barr virus infection

A 20-month-old male with fulminant infectious mononucleosis and the X-linked lymphoproliferative syndrome (XLP) was studied. Epstein-Barr virus (EBV)-determined nuclear antigen (EBNA) and EBV DNA were detected in various tissues. Despite a combined treatment with acyclovir, immunoglobulin, and methylprednisolone, the patient deteriorated rapidly. Following treatment with recombinant interferon-gamma (IFN-γ), defervescence occurred and circulating EBNA-positive cells markedly decreased. IFN-γ prior to treatment ranged from 10.8 to 24.5 U/ml in the patients serum and increased linearly post exogenous IFN-γ treatment. His natural killer (NK)-cell activity remained in the normal range throughout his illness but autologous EBV-infected cells were not killedin vitro by his peripheral blood lymphocytes (PBL). These results suggest that patients with the fatal infectious mononucleosis phenotype of XLP may produce endogenous IFN-γ. Defective cytotoxic T cells against EBV-infected cells seem to be responsible for the fulminant infectious mononucleosis in this patient.