title: Rapamycin with antiretroviral therapy in AIDS-associated Kaposi sarcoma: an AIDS Malignancy Consortium study.
abstract: OBJECTIVE
  The mammalian target of rapamycin is activated in Kaposi sarcoma (KS) and its inhibitor, rapamycin, has induced KS regression in transplant-associated KS. This study aimed to evaluate rapamycin's safety and toxicity in HIV-infected individuals with KS receiving antiretroviral therapy (ART), investigate rapamycin interactions with both protease inhibitor (PI)-containing and nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing ART regimens, and assess clinical and biological endpoints including KS response and mammalian target of rapamycin-dependent signaling.
  
  
  METHODS
  Seven participants, 4 on PI-based and 3 on NNRTI-based ART, had rapamycin titrated to achieve trough concentrations of 5-10 ng/mL. Patients were monitored for safety and KS response. KS biopsies were evaluated for changes in phosphoribosomal S6 protein, and phospho-Akt expression. Interleukin 6 and vascular endothelial growth factor levels, HIV and KS-associated herpesvirus viral loads, and CD4 counts were monitored.
  
  
  RESULTS
  Despite pharmacokinetic interactions resulting in >200-fold differences in cumulative weekly rapamycin doses between participants on PI-containing and NNRTI-containing regimens, treatment was well tolerated. There were no significant changes in viral loads or cytokine levels; modest initial decreases in CD4 counts occurred in some patients. Three participants, all on PI-containing regimens and with higher rapamycin exposure, showed partial KS responses. Three of 4 subjects whose biopsies were studied at ≥day 50 showed decreased phosphoribosomal S6 protein staining.
  
  
  CONCLUSIONS
  Rapamycin seems safe in HIV-infected individuals with KS and can, in some cases, induce tumor regression and affect its molecular targets. Significant pharmacokinetic interactions require careful titration to achieve target drug trough concentrations but may be exploited to achieve therapeutic benefit.
authors: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. krowns@mskcc.org
authors: Susan E
authors: SE
authors: Krown
authors: Debasmita
authors: D
authors: Roy
authors: Jeannette Y
authors: JY
authors: Lee
authors: Bruce J
authors: BJ
authors: Dezube
authors: Erin G
authors: EG
authors: Reid
authors: Raman
authors: R
authors: Venkataramanan
authors: Kelong
authors: K
authors: Han
authors: Ethel
authors: E
authors: Cesarman
authors: Dirk P
authors: DP
authors: Dittmer
mesh_terms: D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D000956:Antigens, Viral / Q000032:analysis; D014408:Biomarkers, Tumor / Q000097:blood; D016207:Cytokines / Q000097:blood; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D012514:Sarcoma, Kaposi / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D020123:Sirolimus / Q000009:adverse effects / Q000627:therapeutic use*; D019562:Viral Load
chemical_list: D000903:Antibiotics, Antineoplastic; D000956:Antigens, Viral; D014408:Biomarkers, Tumor; D016207:Cytokines; D020123:Sirolimus