Impact of Valganciclovir on Severe IRIS-Kaposi Sarcoma Mortality: an Open-label, Parallel, Randomized Controlled-trial.
Condition: Kaposi Sarcoma; Human Immunodeficiency Virus; Immune Reconstitution Syndrome
MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections; Sarcoma, Kaposi; Sarcoma; Immune Reconstitution Inflammatory Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      Kaposi sarcoma (KS) has an unpredictable course, patients with disseminated KS starting
      combined Antiretroviral Therapy can develop Immune Reconstitution Syndrome (IRIS), with a
      severe clinical presentation and high mortality (severe-IRIS-KS). The objective of this study
      is to evaluate the presence of Severe IRIS-KS and it´s attributable mortality in patients
      with AIDS and disseminated KS with the use of valganciclovir prior to the initiation of cART
      compared with the standard management of immediate cART initiation.
    

Detailed description: 
      Kaposi sarcoma (KS) is a Human Herpes-8 disease, it has been described as an
      angioproliferative disease mediated by cytokines in an environment of immunodeficiency and
      thus associated with HIV infection. Its course has been described as unpredictable; it can be
      indolent or can be progressive with a fulminant course. Patients with disseminated KS can
      have an extensive disseminated cutaneous disease with lymphedema and/or lymph node,
      gastrointestinal or pulmonary involvement, usually associated with low CD4 T cell counts
      (<100 cells).

      High early mortality in patients starting cART has been described in different settings, and
      it has been attributed to the development of Immune Reconstitution Syndrome KS (IRIS-KS).

      In patients developing IRIS-KS the clinical event until now recognized as IRIS-KS: increase
      in KS lesion, lymphedema or pleural effusion that is associated with CD4 cells increase and
      the decrease of at least one log of HIV VL does not fully express what threatens patients
      life. The clinical picture of IRIS-KS that threatens the patient's life is the abrupt
      development of fever with no other infection recognized, rapid clinical deterioration with
      thrombocytopenia, anemia, hyponatremia, and hypoalbuminemia together with an increase in KS
      lesion, lymphedema, or pleural effusion, this clinical picture we have named Severe-Iris-KS.

      Patients with AIDS and disseminated KS are at risk of developing severe Immune Reconstitution
      Syndrome KS (S-IRIS-KS) after the initiation of cART and this has been associated with high
      mortality.

      Ganciclovir and Foscarnet (antivirals) are active in vitro against HHV-8; valganciclovir is a
      prodrug of ganciclovir, it is an oral formulation.

      Our group documented, in a retrospective study that patients that were treated with
      ganciclovir for the management of Cytomegalovirus (CMV) end-organ disease in the pre-cART era
      achieve KS complete remission.

      Patients with infections such as meningeal tuberculosis, cryptococcal meningitis, or
      CMV-related chorioretinitis, are also at a greater risk of developing IRIS, and as a
      consequence of it, deteriorate their clinical conditions that can even lead to death or
      irreversible sequel. In these cases, it has been demonstrated that starting treatment for the
      opportunistic infection and delays two or four weeks cART initiation; is possible to avoid or
      diminish these complications.

      Objective:

      To evaluate the occurrence of S-IRIS-KS and it attributable mortality in patients with HIV
      and disseminated KS (pulmonary and/or disseminated, and/or lymphadenopathic, and/or
      generalized lymphedema, and/or intestinal tract compromise) with the use of valganciclovir
      (ganciclovir prodrug, oral formulation) prior to the initiation of 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 and will exert an impact on diminishing 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 GIT 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 HBV or HCV or CMV end-organ disease, or severely ill
      patients with APACHE II score >15.

      The study will comprise two study groups:

        1. Group 1:Patients will receive treatment with valanciclovir 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 recieve
           bleomycin/vincristine; according to treating physician.

      Randomization Patients will be randomized by blocks of ten; the assigned group written in
      closed envelopes: either to Experimental Group 1 (EG) to receive valganciclovir 900 mg twice
      daily for 48 weeks and initiate cART at week 4 after randomization.

      Or to the Control Group 2(CG) to 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 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-svere-IRIS KS and Severe-IRIS-KS

      Non-severe-IRIS-KS: si 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 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.

      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 repeat 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 HV8, 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.

      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 Severe-IRIS. KS..

      Ethical issues:

      Protocol and informed consent were reviewed and accepted by IRB form Intsituto Nacional de
      Cancerología. CEI/950/15No.15/03/INI) First submission: 14 October 2014 First amendment: July
      22, 2016 Second amendment. 25 April 2018
    

Intervention name(s): Valganciclovir; Antiretroviral Combinations
Intervention type(s): Drug; Drug
Intervention description(s): 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.; Patients will receive standard antiretroviral treatment as recommended
Other intervention name(s): Valcyte; cART
Intervention MeSH terms: Anti-Retroviral Agents; Valganciclovir
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment