• Thalidomide Pharmacokinetics (PK), Safety and Effect on HIV Viral Load and Immune Parameters (Poster 352)
  Authored by D. Wohl, R. Pomerantz, J. Schmitz, F. Aweeka, L. Fox, D. Weng, J. Spritzler, W. Robinson, M. Holohan, H. Teppler, and the ACTG 267 Team
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Thalidomide, a selective inhibitor of monocyte TNF-alpha production, is used in HIV-infected patients to treat aphthous ulcers and wasting. It has also been studied for its use as an immunomodulator to augment HIV therapies.

This study, ACTG 267, a multicenter, randomized, controlled, dose-escalating study of thalidomide, was designed to assess the safety and tolerability, as well as pharmacokinetic properties. In addition, the study assessed the effect of thalidomide on induceable PBMC TNF-alpha production and plasma TNF-alpha levels. The effect on CD4 cell count, HIV RNA levels, neopterin and ß2 microglobulin was also assessed. Earlier studies had shown increases in the amount of HIV RNA after administration of thalidomide.

The study enrolled 36 patients (9 per cohort). Patients were recruited beginning in 1994, so the majority of patients were on nucleoside analog therapy only at accrual. All had CD4 counts 200-500 cells/µL (median 338) and median plasma HIV PCR RNA 3.64log10 copies/mL. Patients were randomized 3:1 to thalidomide (50mg qd, 100mg qd or 150mg qd) or placebo. Study drug was given for 8 weeks, with evaluations at baseline, weeks 2, 4, 8, and 10. 24-hour PK studies were done after first dose and at weeks 2 and 8.

In this dose-ranging study, the maximum tolerated dose was not achieved, although dose-limiting toxicity did occur in 4 patients. (Greater than Grade 2 somnolence was seen in 2 patients who received the 150mg dose and in 1 patient on placebo. Grade 2 peripheral neuropathy was seen in 1 patient on placebo.) There were no significant differences between the groups in terms of adverse events, which were rare in both groups.

Thalidomide concentrations in plasma did show a dose response with regard to Tmax and clearance across the cohorts.

Thalidomide did not have a significant effect on HIV RNA (contrary to prior reports), CD4 counts, induceable PBMC TNF-alpha production or plasma TNF-alpha levels. There were decreases in the ß2 microglobulin levels in all treatment arms including placebo. Neopterin levels increased only in the lower dose cohorts in an unpredictable pattern, and at no time in the highest dose cohort or in the placebo arm.

In contrast to ACTG 251 and Celgene wasting studies, in this study of patients with HIV, but not AIDS, thalidomide did not have a significant effect on HIV RNA levels. The results of this study may be due to the relatively better health and immune function of the patients in this cohort compared to those in other cohorts studied.

This study was designed and powered to assess the safety and pharmacokinetic profile of thalidomide when administered to patients with HIV. This study did show that thalidomide is safe, well tolerated, and does show dose-dependent pharmacokinetics. No measurable changes in immune function were found.

Further studies of the use of thalidomide to treat wasting and cachexia, for instance in the treatment of active tuberculosis or other opportunistic infections, could still be pursued. It may be more likely that thalidomide's effect on TNF-alpha and other markers of immune activation would be more pronounced in a more advanced population.