However, in a Phase I/II trial, BMS-275291, a more specific oral nonpeptidic MMPI, was poorly tolerated and did not show any meaningful responses [121]. Similarly, interleukin 12 was administered to patients on HAART with KS and the response rate was 71% [122]. Valproic acid has properties of an HDAC inhibitor with some activity in vitro, but a pilot study in 18 patients did not show any promising efficacy [123]. PI3K/AKT/mTOR signalling is a common pathway downstream of many growth factor and cytokine receptors and is upregulated by KSHV encoded proteins. Rapamycin,

an oral immunosuppressant used to prevent rejection in solid organ transplantation, has activity in AIDS-KS but has significant pharmacokinetic interactions with HAART [124]. Topoisomerase

I and II enzymes play a critical role in KSHV DNA replication, and type I inhibitors click here such as irinotecan and topotecan, and type II poisons, such as etoposide [125,126] and doxorubicin have significant cytotoxic activity but with dose-limiting toxicities including myelosuppression. Topoisomerase II catalytic inhibitors such as novobiocin, in contrast, show marked inhibition of KSHV replication AZD2281 in vivo and minimal cytotoxicity and may be a promising therapeutic alternative [127]. A number of antiherpes virus agents have been studied in AIDS-related KS; none has demonstrated significant activity, although they have been shown to prevent KS in one cohort study [39]. KSHV stimulates expression of angiopoietin-2 in KS via upregulation of the Ras/Raf/MEK/ERK

pathway. Selumetinib is an oral selective inhibitor of MEK1/2 with anticancer activity in a variety of tumour models [128] and is being tested in a Phase I/II study for AIDS-KS patients. Where possible, patients should be considered for appropriate clinical trials. We recommend that KS should be confirmed histologically (level of evidence 1C). We suggest that CT scans, bronchoscopy and endoscopy are not warranted in the absence of symptoms (level of evidence 2D). We recommend that HAART should be started in all patients diagnosed with KS (level of evidence 1B) We suggest local radiotherapy or intralesional Interleukin-3 receptor vinblastine for symptomatic or cosmetic improvement in early stage T0 KS (level of evidence 2C) We recommend that patients with T1 advanced stage KS, should receive chemotherapy along with HAART (level of evidence 1B). We recommend that liposomal anthracyclines (either DaunoXome 40 mg/m2 q14d or Caelyx 20 mg/m2 q21d) are first-line chemotherapy for advanced KS (level of evidence 1A). We recommend paclitaxel chemotherapy (100 mg/m2 q14d) for second-line treatment of anthracycline refractory KS (level of evidence 1C). All patients should be considered for clinical trial enrolment if eligible (GPP). 1 Amerson E, Buziba N, Wabinga H et al.