Pentoxifylline for the Treatment of HIV Infection and Its Complications

Abstract

The increased levels of tumor necrosis factor-alpha (TNF-alpha) seen in patients with acquired immune deficiency syndrome (AIDS) may contribute to the AIDS-related wasting syndrome. TNF also induces expression of human immunodeficiency virus (HIV) through activation of the transcription factor NF-kappa B, which binds to the viral long terminal repeat (LTR). Because TNF can decrease the antiretroviral activity of zidovudine (AZT) in vitro, pentoxifylline (PTX) may increase the efficacy of AZT. PTX decreases HIV replication in acutely infected cells and inhibits gene expression controlled by the HIV-1 LTR. The antiretroviral activity of PTX is associated with decreased binding of NF-kappa B to its recognition sequences. Therefore, PTX may inhibit HIV expression indirectly by diminishing TNF production and directly, by decreasing activity of NF-kappa B. PTX, and an inhibitor of the viral transactivator TAT, Ro24-7429, may inhibit HIV gene expression in a cooperative fashion. The first clinical study of PTX in AIDS patients was conducted by us through the AIDS Clinical Trial Group of the National Institutes of Health. AIDS patients on antiretroviral therapy received PTX 400 or 800 mg three times daily for 8 weeks. TNF assays included TNF mRNA levels in peripheral blood mononuclear cells (PBMCs) and inducible TNF protein levels in the supernatant of PBMCs cultured in the presence of 0.1 microgram/ml lipopolysaccharide (LPS). The median change in TNF mRNA was a 30% decrease. There was a median and significant 40% decrease in the production of inducible TNF protein. HIV load decreased in 10 patients and increased in four patients, but did not change in the group as a whole. Others have extended our initial observations in HIV-infected patients. In a placebo-controlled trial, TNF production by unstimulated PBMCs decreased by 52% in the PTX arm and increased by 7.2% in the placebo arm. In a study comparing AZT, PTX, or a combination of the two, viral load after treatment was ninefold above baseline in the AZT or PTX alone arm, compared to only twofold in the combination arm. In a quality of life trial, PTX was associated with improvement in depression, anger, and social and cognitive function: a placebo effect, however, was not ruled out. PTX 400 mg three times daily is safe and well tolerated. PTX decreases PBMC TNF expression in HIV-infected patients, measured as protein in culture supernatant or as mRNA, and may decrease viral replication. Further studies of HIV-infected persons are needed to ascertain the benefit of PTX as an adjunct either to inhibitors of reverse transcriptase (e.g., AZT) or of transcription (e.g., TAT inhibitor).