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
Phase: PHASE2
Conditions: Kaposi Sarcoma, Human Immunodeficiency Virus, Immune Reconstitution Syndrome
Sponsor: National Institute of Cancerología

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TITLE: 
 Valganciclovir Four Weeks Prior to cART Initiation Compared to 
Standard Therapy for Disseminated Kaposi Sarcoma 
 
 
NCT NUMBER: NCT03296553 
 
DATE : JULY 23, 2015. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

STUDY PROTOCOL 
 
Objective: 
To evaluate the occurrence of severe immune reconstitution inflammatory syndrome 
associated to Kaposi Sarcoma (S-IRIS –KS) and it´s attributable mortality in patients with 
AIDS and disseminated KS (dKS) (pulmonary and/or skin disseminated, and/or 
lymphadenopathic, and/or generalized lymphedema, and/or gastrointestinal tract 
involvement) with the use of valganciclovir  (ganciclovir prodrug, oral formulation) prior to 
the initiation of combined antiretroviral therapy (cART) compared with the standard 
management of immediate cART initiation. 
 
Hypothesis: 
In patients with AIDS and disseminated KS administration of valganciclovir as an anti-HHV-
8 agent can diminish viral replication prior to administration of cART, and thus decrease 
the frequency of S-IRIS-KS with a subsequent reduction on S-IRIS-KS attributable mortality.  
 
Methodology: 
Open randomized clinical assay. Will include patients with AIDS and disseminated KS who 
accept to participate and sign informed consent.  
  
Inclusion criteria:   
Patients >18 years old, HIV+ naïve to cART with dKS, able and willing to provide written 
informed consent.  
DKS was defined as the presence of KS pulmonary disease and/or ≥30 KS skin lesions, with 
or without lymphedema, and/or lymph node involvement, and/or gastrointestinal tract KS 
involvement (biopsy-proven at least in one site).  
 
Exclusion criteria:   
Another concomitant malignancy, Multicentric Castleman Disease (MCD), steroid 
treatment two months prior to screening, active Hepatitis B, Hepatitis C  or CMV end-
organ disease infection, and/or severely ill patients with APACHE II score >15 points. 
 
The study will comprise two study groups: 
1. 
Group 1: Patients will receive treatment with valganciclovir during 4 weeks prior to 
initiation of cART and/or continue for 48 weeks 
2. 
Group 2: Patients will initiate standard treatment with cART.  
Both groups receive chemotherapy with bleomycin/vincristine; according to treating 
physician.  
 
Randomization 
Patients will be randomized by blocks of ten; the assigned group written in closed 
envelopes:  
Experimental Group 1 (EG) will receive valganciclovir 900 mg twice daily for 48 weeks and 
initiate cART at week 4 after randomization. 

Control Group 2 (CG) will start cART immediately according to current Mexican Guidelines. 
 
Blinding: 
No blinding was considered feasible for personnel or patients; this is an open label study.  
 
Sample Size 
Sample size was calculated for a study power of 80% and an alpha of 0.05. Event rate in 
the control group was estimated as 40%, while that in the treated group was considered 
5%. The number of resulting patients in each group is 19 for as total sample of 38 patients.  
This assumes a significant impact of treatment impact on S-IRIS-KS occurrence and its 
mortality.   
 
The antiretroviral scheme will be assigned according to the criteria of the “The 
Antiretroviral Management Guide of Persons with HIV” in effect in Mexico. 
 
Candidates will have an initial thorough clinical evaluation including a work-up to diagnose 
coinfections and rule out other neoplasms that comprise: ophthalmologic evaluation, 
computed tomography (CT) scan (neck, thorax, and abdomen), bone marrow culture with 
bone biopsy, Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) serology, venereal 
disease research laboratory (VDRL) test and if indicated lumbar puncture to rule-out 
neurosyphilis, Histoplasma urinary antigen and serology, and GenXpert MTB/RIF test.  
Upper gastrointestinal tract (GIT) endoscopy with biopsy of lesions; colonoscopy will be 
performed only on patients with diarrhea or lower-GIT bleeding. Biopsies of enlarged 
lymph nodes will be obtained and process for histopathological analysis and culture. If 
indicated, bronchoscopy with bronchoalveolar lavage (BAL) will be performed as well as a 
thoracic Gallium 67 Spect-CT Scan or PET-FDG scans.  
 
Criteria for Non-severe-IRIS KS and Severe-IRIS-KS 
 
Non-severe-IRIS-KS: Is defined as an increase in the number of KS lesions plus ≥one log10 
of HIV-1 RNA VL decrease or ≥50 cells/mm3 or ≥2-fold from baseline CD4+ cells increase 
after cART initiation.  
 
Severe-IRIS-KS: Is defined as an abrupt clinical deterioration after cART initiation 
alongside the presence of at least two clinical and at least three laboratory criteria.  
Clinical criteria:  1) Fever (no identified concomitant infection), 2) increase in the size or 
number of KS lesions, 3) exacerbation of lymphedema, 4) appearance or increase of 
otherwise unexplained lung opacities on the chest images with a negative Gallium-Scan 
negative and 4) appearance or increase of pleural effusion. 
Laboratory criteria:  1) Thrombocytopenia <100,000 platelets/ml; 2) Anemia (decrease of 
at least 1 g/dl from previous measure and no obvious bleeding), 3) Hyponatremia <135 
mEq/L and 4) Hypoalbuminemia <3.5 g/dL.  This is the clinical picture associated with 
death. 
 

Classification of KS evolution: 
 
Complete Response (CR): when all of the KS lesions disappear, according to physician´s 
criteria documented by pictures taken in each visit.  
Partial Response (PR): when there was a diminution of >50% in number and/or size of 
original lesions without the appearance of new lesions, according to physician´s criteria 
documented by pictures taken in each visit. 
Stable Disease (SD): was when there was a reduction of <50% of lesions and new lesions 
have not appeared, according to physician´s criteria documented by pictures taken in each 
visit. 
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. 
 
Visits will be performed at baseline, week 1, 2, 4, 8, 12, 16, 24, and 48. At each visit, an 
Infectious Diseases specialist will perform a clinical evaluation, and pictures of skin lesions 
will photograph. Blood samples will be obtained for: WBC count, complete blood 
chemistry, urine analysis, CRP, D-Dimer, HIV VL with Abbott Real-time, HHV-8, CMV, and 
Epstein-Barr Virus (EBV) VL ELITe MGB KIT by ELITe InGenius Software, CD4+ and CD8+ 
cells count and percentage, (flow cytometry, Facs Canto II, Becton Dickinson) CD4/CD8 
ratio and plasma levels of interleukin 6, 10 (IL-6, IL-10), tumor necrosis factor (TNF) and 
interferon-gamma (IFN-ɤ) were measured using a sandwich-type immunoassay, ELISA 
(Biolegend). Serology for syphilis, HBV, and HCV will be repeated at week 24 and 48. If 
patients had an exacerbation of KS outside the scheduled visit they will be reevaluated 
with laboratory tests and study images.  
A qualified phlebotomist will carry out blood sampling. 
 
 
Primary outcome: 
Mortality by all causes at end of follow-up, 48 weeks, adjusted at least by age, gender, 
CD4, and viral load of HHV-8, primarily with a survival analysis by a Cox regression, but 
also with a logistic regression model.   
 
Secondary outcomes: 
Total number of SIRI events (S-IRIS-KS and Non-S-IRIS-KS) in treated and control group.  
This is going to be done by a Poisson´s models analysis adjusted by age, gender, 
coinfections, basleine: CD4, and viral load of HV8, C reactive protein, HIV VL, IL6, IL10, 
TNF, and IFN. We will compare mortality in patients with pulmonary KS between groups. 
 
 
Vigilance of adverse events: 
Adverse events in treated and control group will be reported. 
 

Statistical analysis: 
The primary analysis is going to be as intention to treat, but as a secondary analysis also as 
per protocol analysis is going to be performed for mortality, and S-IRIS-KS. 
 
 
Ethical issues: 
Protocol and informed consent were reviewed and accepted by IRB form Instituto 
Nacional de Cancerología. (CEI/950/15No.15/03/INI) 
First submission: 14 October 2014  
First amendment:  July 22, 2016 
Second amendment.  25 April 2018