Valganciclovir Four Weeks Prior to cART Initiation Compared to Standard Therapy for Disseminated Kaposi Sarcoma
National Institute of Cancerología
Instituto Nacional de Enfermedades Respiratorias
Information provided by (Responsible Party)
Volkow Fernandez Patricia Amalia, National Institute of Cancerología
First received: September 20, 2017
Last updated: March 13, 2019
Last Verified: March 2019
History of Changes
Kaposi sarcoma (KS) has an unpredictable course, patients with severe KS and low CD4 counts (<100 cells) can develop Immune Reconstitution Syndrome (IRIS) after the initiation of combined Antiretroviral Therapy (cART). The objective of this study is to evaluate the presence of IRIS and its attributable mortality in patients with HIV and severe KS with the use of Ganciclovir or the prodrug Valganciclovir prior to the initiation of cART compared with the standard management of immediate cART initiation.
Human Immunodeficiency Virus
Immune Reconstitution Syndrome
Drug : Valganciclovir
Drug : Antiretroviral Combinations
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||Valganciclovir for Suppression of HHV-8 Four Weeks Prior to Initiation of cART in Patients With Disseminated Kaposi Sarcoma Compare With Standard Therapy, Its Impact on the Development of IRIS and Attributable Mortality|
Further study details as provided by Volkow Fernandez Patricia Amalia, National Institute of Cancerología:
Primary Outcome Measures
[ Time Frame: 24 weeks ]
Measure mortality attributable to IRIS-KS in all the groups
|Study Start Date:||October 1, 2015|
|Estimated Study Completion Date:||August 10, 2019|
|Estimated Primary Completion Date:||August 10, 2019 (Final data collection date for primary outcome measure)|
Oral Valgancyclovir 900 mg twice in a day during 4 weeks prior to initiation of cART (combined antirretroviral therapy) until suppression of HHV-8.
The experimental group will receive Valganciclovir 900 mg twice in a day before the initiation of cART until viral load of HHV-8 is undetectable.
Other Name: Valcyte
Standard treatment with cART according to current HIV Therapy Mexican guidelines.
Patients will receive standard antiretroviral treatment as recommended
Other Name: cART
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.
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.
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.
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:
- 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).
- Group 2 (randomized): Patients with HIV and disseminated KS, who initiate standard
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. Eligibility
|Ages Eligible for Study:||18 Years to 70 Years|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- Patients will be included with AIDS naïve to antiretroviral therapy and severe KS, who accept to participate and who sign the letter of informed consent.
- The following are the KS severity criteria: pulmonary compromise, and/or digestive tract compromise, and/or disseminated cutaneous, and/or lymphadenopathic compromise with generalized lymphedema.
- Patients with another synchronic malignant neoplasm
- Patients receiving corticosteroids
- Patients with active hepatitis B and/or hepatitis C
- Patients with KS limited to skin with less than 30 lesions.
- Patients with APACHE II score ≥15 points.
Contacts and LocationsChoosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT03296553
Locations Show More
|Instituto Nacional de Cancerologia|
|Mexico city, Mexico, 14080|
Sponsors and CollaboratorsNational Institute of Cancerología
Instituto Nacional de Enfermedades Respiratorias
|Responsible Party:||Volkow Fernandez Patricia Amalia, Infectious disease consultant, Clinical Professor, National Institute of Cancerología|
|ClinicalTrials.gov Identifier:||NCT03296553 History of Changes|
|Other Study ID Numbers:||(015/031/INI) (CEI/950/15)|
|Study First Received:||September 20, 2017|
|Last Updated:||March 13, 2019|
|Individual Participant Data|
|Plan to Share IPD:||No|
Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
Immune Reconstitution Inflammatory Syndrome
ClinicalTrials.gov processed this data on June 01, 2020
This information is provided by ClinicalTrials.gov.