CNAIDS has been engaged for years in studies on the pathogenesis of syndromes and tumors associated with HIV infection, such as Kaposi's sarcoma (KS), to develop innovative therapies that could be transferred to the general population. These studies indicate that antiretroviral drugs belonging to the HIV protease inhibitor class can be used for the treatment of KS (and other cancers) in people infected or not infected with HIV.
KS is a tumor associated with human herpesvirus 8 (HHV8) infection and characterized by intense angiogenesis (formation of new blood vessels) and proliferation of "spindle-like" cells of endothelial origin (i.e. the cells lining the vessel wall). KS is a “rare” disease that occurs with increased frequency in elderly subjects of the Mediterranean area (classical KS) or sub-Saharan Africa (endemic or African KS), in organ transplant recipients (post-transplant KS) and in HIV infected patients (AIDS-KS). This latter form is characterized by a particularly aggressive course. KS arises in a context of dysregulation of the immune system characterized by reduced immunological surveillance, increased production of some "diffusible mediators" of inflammation, i.e. inflammatory cytokines, and factors that promote angiogenesis. In addition, KS is characterized by the increased activity of some enzymes responsible for the "remodeling" of the part of tissue not composed of cells (the extracellular matrix). These enzymes, called matrix metalloproteases (MMP), are an important therapeutic target for this tumor since they are responsible for the invasion of the tissues by neoplastic cells. In HIV-infected persons, the HIV-1 Tat protein is responsible for the increased frequency and aggressiveness of AIDS-KS. There is no treatment of choice for KS and conventional therapies show high toxicity and limited or palliative effects.
CNAIDS is committed to studying the factors favoring the onset and progression of KS, in particular AIDS-KS. Studies conducted by CNAIDS also showed that HIV protease inhibitors (HIV-PI) exert anti-angiogenic and anti-tumor effects against several cancers, regardless of their anti-HIV activity, indicating that these drugs may represent new anti-tumor candidates.
As part of this program, CNAIDS conducted two phase 2 clinical trials for the treatment of HIV-negative classical-KS patients with the HIV-PI indinavir used in mono-therapy (for early-stage cancers) or in combination with conventional chemotherapy (for late stage tumors) obtaining efficacy results. We observed that treatment with HIV-PI is well tolerated and induces a high frequency of response in subjects with initial KS. Treatment response requires high plasmatic drug-levels and is associated with a significant stabilization of MMP and angiogenic factors plasmatic-levels, as well as a decrease in the number of circulating endothelial cells, the precursors of KS spindle-cells. In advanced KS, however, HIV-PI treatment is effective when used in combination with conventional chemotherapy, after reduction of the tumor mass.
CNAIDS is trying to raise funds to continue this program with the aim of achieving registration for the use of HIV-PI in classical KS.
These studies will allow the transfer to the National Health Service of HIV-PI used in monotherapy or in combination with cytotoxic drugs for the treatment of early or advanced cancer. Since these drugs are already on the market, their transfer to the clinical practice will be possible in a short time, after the registration of HIV-PI for the new indication ("drug repositioning").