AEGiS-11IAC: A placebo controlled phase II trial of thalidomide in asymptomatic HIV-positive patients; clinical tolerance and effect on activation markers and cytokines.

11th International AIDS Conference

Vancouver, British Columbia — July 7-12, 1996

A placebo controlled phase II trial of thalidomide in asymptomatic HIV-positive patients; clinical tolerance and effect on activation markers and cytokines.

Int Conf AIDS 1996 Jul 7-12; 11:221 (abstract no. Th.B.176)
Marriott JB, Cookson S, Carlin E, Youle M, Hawkins D, Nelson M, Pearson M, Vaughan A, Gazzard B, Dalgleish A; Division of Oncology, CMS, St. George's Hospital Medical School, London, UK. Fax: +44-181-725-2992. E-mail: jmarriot@sghms.ac.uk.

OBJECTIVE: To determine the safety, efficacy and effect on a variety of immunological and biochemical parameters of thalidomide when given to human immunodeficiency virus positive asymptomatic positive patients.

METHODS: Nineteen male patients who had to satisfy criteria for inclusion in groups II, III, IVA or IVE of the CDC classification, have elevated markers of immune activation, have a mean CD4+ T cell count above 400/mm3 in the absence of acute infection from two separate samples taken at least two weeks apart within six months of enrolment and not taking antiretroviral treatment. Patients were randomised to either placebo or thalidomide (100mg/day) for 24 weeks. A clinical assessment and analysis of blood samples were performed prior to treatment and at four week intervals. Blood/serum/plasma was used to determine levels of CD4+/CD8+ T cells, activation markers, biochemical markers and TNF-alpha. PBMC were isolated and cytokine mRNA levels determined ex vivo and cytokine mRNA and protein levels determined after in vitro stimulation with mitogen. Total RNA was extracted from PBMC, reverse transcribed and amplified, using DNA polymerase, in the presence of a heterologous competitor fragment specific for each cytokine of interest. Input cDNA was normalised to the beta-actin signal for each sample.

RESULTS: Only three patients (of 10) receiving thalidomide completed the study, the main clinical effect being somnolence. Blood thalidomide levels were very low or undetectable. Levels of CD4+/CD8+ T cells, activation markers, biochemical markers, TNF-alpha, and TNFRI in blood/serum/plasma and TNF-alpha, IL-4, IL-10 and IFN-gamma in PBMC supernatants were not significantly different, although reduction in mitogen-induced TNF-alpha production at week 24 compared to week 0 bordered on significance. A cessation of chronic diarrhea was noted in two patients not fulfilling inclusion criteria but taking thalidomide off study.

CONCLUSIONS: This study indicates the need to include pharmacokinetic studies with this type of agent to address the problem of absorption in relation to dose needed to achieve a systemic effect rather than one localised to the gut.

Keywords: AEGIS, Thalidomide, Cytokines, HIV Infections, HIV, Biological Markers, HIV Seropositivity, Placebos, Antigens, CD8, Antigens, CD4, Interleukin-10, T-Lymphocytes, Receptors, Tumor Necrosis Factor, Tumor Necrosis Factor, Interleukin-4, Anti-HIV Agents, Antigens, CD, Immunosuppressive Agents, tumor necrosis factor receptor 55, Human, In Vitro, Male, ICA11

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ThB176