Valganciclovir Four Weeks Prior to cART Initiation Compared to Standard Therapy for Disseminated Kaposi Sarcoma

Kaposi sarcoma (KS) is an angioproliferative disease associated with infection by the Human Immune Deficiency virus (HIV), mediated by cytokines, in which the presence of Human Herpes-Virus 8 (HHV-8) and immunosuppression are essential for the disease process. It has an unpredictable course and can be indolent or can entertain a progressive and fulminant disease course. Patients with severe KS can have pulmonary involvement and/or disseminated cutaneous disease and/or lymphadenopathic involvement, generally associated with low CD4 counts (<100 cells); this patients are at risk of Immune Reconstitution Syndrome (IRIS) after the initiation of cART aggravating the clinical status of the patient.

Ganciclovir and Foscarnet (antivirals) are active in vitro against HHV-8. Our work group documented, in a retrospective study with patients treated with Ganciclovir for the management of organ-end infection due to Cytomegalovirus (CMV) in the era pre-cART that they developed complete remission.

Patients with infections such as meningeal tuberculosis, cryptococcal meningitis, or CMV-related chorioretinitis, and low CD4 are at a greater risk of developing Immune Reconstitution Inflammatory Syndrome (IRIS), and, as a consequence of IRIS, of developing severe complications that cause death or irreversible sequel. In these cases, it has been demonstrated that treating the opportunistic infection and delay 4 weeks the initiation of cART; usually avoids these complications.

Objective:

To evaluate the presence of IRIS and it attributable mortality in patients with HIV and severe KS (pulmonary and/or disseminated, and/or lymphadenopathic, and/or generalized lymphedema, and/or intestinal tract compromise) with the use of Ganciclovir or the prodrug Valganciclovir prior to the initiation of cART compared with the standard management of immediate cART initiation.

Hypothesis:

Administration of Ganciclovir and the suppression of HHV-8 replication prior to administration of cART, with or without chemotherapy in patients with Acquired Immunodeficiency Syndrome (AIDS) and disseminated KS will diminish the frequency of IRIS and will exert an impact on diminishing mortality attributable to KS.

Methodology:

Open randomized clinical assay. Will include patients with AIDS and disseminated KS who accept to participate and who sign the letter of informed consent.

A disseminated case of KS is considered when it presents one or more of the following involvements: pulmonary compromise, and/or disseminated cutaneous KS, and/or lymphadenopathic and/or generalized lymphedema, and digestive tract compromise documented in at least two segments (oral cavity, esophagus, stomach, large intestine).

Exclusion criteria are patients who present another synchronic neoplasm, those receiving corticosteroids, those with replicative co-infection with hepatitis B or hepatitis C and patients with an APACHE score ≥ 15.

The study will comprise two study groups:

1. Group 1 (randomized): Patients with HIV and disseminated KS, who will receive treatment with Ganciclovir during 4 weeks prior to initiation of cART and/or until suppression of HHV-8 or 12 weeks (whichever comes first).

2. Group 2 (randomized): Patients with HIV and disseminated KS, who initiate standard treatment with cART.

Sample size was calculated for a study power of 80% and an alpha of 0.05. Event rate in the control group was 40%, while that in the treated group was 5%. The number of patients in each group will be 19 for as total sample of 38 patients.

The antiretroviral scheme will be assigned according to the criteria of the "The Antiretroviral Management Guide of Persons with HIV" in effect in Mexico.

A baseline clinical evaluation will be carried out to define the extension of KS (on skin, at the gastrointestinal level by means of upper-gastrointestinal endoscopy and colonoscopy), at the pulmonary and lymphatic levels (Computerized tomography scan [CT] of the thorax and abdomen. In case of suspicion of pulmonary compromise a Gallium 67 Spect-CT Scan will be performed, in the case of suspicion of lymphadenopathic compromise; lymph node biopsy will be performed. Investigation will be conducted to document or rule out other active infections and treatment will be given if necessary including bone marrow culture.

IRIS criteria: Patients with 2 weeks of cART initiation according to their presenting one laboratory criterion and two laboratory criteria:

A reduction of at least 1 log10 of HIV-1 in viral load levels and an increase of ≥50 cells/mm3 or an increase of at least ≥2 times in the baseline levels of the CD4+ cell count

Exacerbation of KS by at least two of the following clinical criteria:

Increase in size of KS lesions Increase in number of KS lesions Appearance or exacerbation of lymphedema Appearance or increase of otherwise inexplicable pulmonary opacities in the thoracic x-ray or Computerized tomography (CT) of the thorax with negative Gallium-67 Spect-scan.

Classification of the evolution of KS:

Complete Response (CR) when all of the KS lesions disappear Partial Response (PR) when there was a diminution of >50% in number and/or size of original lesions without the appearance of new lesions Stable Disease (SD) was when there was a reduction of <50% of lesions and new lesions have not appeared Disease Progression (DP) when an increase is documented of the number and size of the KS lesions during follow-up periods Relapse when new lesions appeared in patients with CR or documented CR in previous evaluations.

Ten ml. will be obtained of anticoagulated peripheral blood with EDTA. This routine procedure will be carried out by the Attending Physician of the patients and by a qualified Phlebotomist.

At baseline and at weeks 1, 2, 4, 8, 12, 16, 24, and 48 weeks, inflammation markers will be measured related with the response of the cytosines, known in KS, such as the following: C reactive protein; D-dimer; IL-6; Il-10, Tumor Necrosis Factor (TNF) and Gamma Interferon (IFNγ). Serum and plasma will be obtained for the HIV viral load, the HHV-8 viral load, and a complete blood count will be performed, as well as the CD4 lymphocyte count, and liver function and blood chemistry tests. From the plasma samples, the absolute amount of each analyte will be quantified, and we will analyze the Luminex methodology (Bio-Rad). The plasma will be incubated with monoclonal antibody-coated spheres directed against each analyte and to a specific fluorochrome, and fluorescence will be read in Bio-Plex 2000 equipment (Bio-Rad). Absolute readings will be obtained in μg/mL for each analyte.