AIDS RESEARCH AND HUMAN RETROVIRUSES Volume 17, Number 9, 2001, pp. 789–797 Mary Ann Liebert, Inc. A Phase III Study of Recombinant Human Interferon Gamma to Prevent Opportunistic Infections in Advanced HIV Disease LYNN A. RIDDELL, 1 ANTHONY J. PINCHING, 2 SUSAN HILL, 1 TONY T. NG, 2 EMILIO ARBE, 3 GARY P. LAPHAM, 3 STEPHEN ASH, 4 RICHARD HILLMAN, 5 STEPHEN TCHAMOUROFF, 6 DAVID W. DENNING, 7 and JACQUELINE M. PARKIN 2 ABSTRACT The efficacy and safety of recombinant human interferon gamma (rIFN-c ) in the reduction of opportunistic disease in patients with advanced HIV-1 infection are assessed. A 12-month double-blind, placebo-controlled, multicenter, Phase III trial of rIFN-c in HIV-positive patients with CD4 , 100 3 10 9 /liter on stable anti- retroviral therapy. Eighty-four patients were allocated treatment on a 1:1 basis to rIFN-c or placebo. Patients received rIFN-c 0.05 mg/m 2 or 0.9% saline subcutaneously three times weekly for 48 weeks (optional exten- sion to 18 months). The primary end point was the incidence of opportunist infections (CDC categories B/C). Secondary end points included mortality, immunological, and virological parameters. Patients on placebo had a mean of 3.45 opportunist infections (OIs) in the first 48 weeks. Patients treated with rIFN-c had a mean of 1.71 OIs (p 5 0.04). However, the model showed overdispersion and the inclusion of a dispersion factor raised the p value to 0.13. rIFN-c appeared to have a particular effect on the incidence of Candida, herpes simplex, and cytomegalovirus infections. Three-year survival in the rIFN-c arm was 28% compared to 18% in the placebo group (not significant). rIFN-c -associated side-effects of headache, fatigue, rigors, influenza-like symp- toms, depression, myalgia, and granulocytopenia were reversible. There was no evidence for HIV activation. Although not significant, the trend towards decreased opportunistic infections and increased survival war- rants consideration of further trials of rIFN-c . The study gives additional information on the safety profile of this cytokine. 789 INTRODUCTION D ESPITE THE USE of highly active antiretroviral therapy (HAART), HIV-infectedindividualscontinue to show pro- gressive immunodeficiencyand opportunistinfections.This re- flects drug resistance, poor compliance/absorption, or insuffi- cient immunoreconstitution. Immunomodulating agents, such as cytokines, to replace missing factors or stimulate existing immune responses, are attractive adjuvants to drug therapy. These could theoretically accelerate immunoreconstitution or provide protection from opportunist disease during periods of suboptimal immune function. However, there is concern that substances that stimulate the T cell/macrophage immune re- sponse, such as interleukin-2 (IL-2), IL-12, IL-15, interferon gamma (rIFN-g), and granulocyte-macrophage colony-stimu- lating factor (GM-CSF), also activate HIV replication. 1–3 A candidate cytokine for immunotherapy in HIV infection is interferon gamma (IFN-g). This is a lymphokine mainly of T cell origin, distinguished from interferons a and b by sig- nificant immunomodulating activity. The integral role of IFN- g in the eradication of intracellular pathogens has been shown in knockout mice deficient in either the IFN-g receptor or the IFN-g gene itself. The animals develop fulminant infections with mycobacteria,listeria, and vaccinia. 4,5 IFN-g is also an es- 1 Andrewes Unit, Barts and the London NHS Trust, London, UK. 2 Department of Immunology, St. Bartholomew’s and the Royal London School of Medicine and Dentistry, London, UK. 3 Boehringer Ingelheim Ltd., Bracknell, Berkshire, UK. 4 Department of Infectious Diseases, Ealing Hospital NHS Trust, London, UK. 5 Graham Hayton Unit, Barts and the London NHS Trust, London, UK. 6 Claude Nicol Centre, Royal Sussex County Hospital, Brighton, UK. 7 Department of Infectious Diseases, North Manchester General Hospital, Manchester, UK.