TOPIC

Infectious diseases, HIV

HIV/AIDS

The Italian National Institute of Health (ISS) is at the forefront in the fight against infectious agents which, constantly changing over time, make it necessary the frequent updating  of priority actions.

The ISS implements surveillance, prevention and control measures against emerging diseases such as those deriving from the spread of antibiotic-resistant biological agents commonly found in hospital environment, and those transmitted by vectors, such as chikungunya, dengue and West Nile.

Vaccine preventable diseases, although they have been reduced due to effective interventions, represent a significant burden of diseases which require to maintain a high level of attention.

Viral hepatitis and sexually transmitted infections, as human papillomavirus (HPV) infection, are a paradigmatic example of how chronic infections can result in degenerative diseases and even cancers. A vaccine is available for hepatitis B virus (HBV) and HPV infection.

Infectious diseases include also neglected tropical diseases, as intestinal parasitosis and echinococcosis, found in many parts of the world.

With regard to HIV / AIDS, the antiretroviral therapy (ART), although it has saved millions of lives, does not eliminate the HIV from the body nor restore the immune system completely back to normal. Furthermore, it has limited effects if started late or not taken regularly.

In order to stop the HIV epidemic and assure those living with the infection (about 38 million people with HIV / AIDS in the world, including 20.6 million in Africa) better quality of life and life expectancy, the ISS develops surveillance, prevention and treatment strategies, working in cooperation with the National Health Service (SSN), Regions, developing countries and international bodies.

General aims of ISS research activities on HIV/AIDS include:

  • study and surveillance of the spread of HIV and its variants, and of co-infections in general and vulnerable populations
  • study of the mechanisms of infection, of development of AIDS and associated diseases
  • facilitating ART adherence by improving its effectiveness and reducing its side effects
  • development of new strategies capable of preventing infection, reducing its progression and enhancing the effectiveness of ART, in particular preventive and therapeutic vaccines
     

Experimental therapies for Kaposi's sarcoma - Treatment of Kaposi's sarcoma with HIV protease inhibitors 

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").