Impact of valganciclovir therapy on severe IRIS-Kaposi Sarcoma mortality: an open-label, parallel, randomized controlled-trial

Abstract

High HHV-8 viral load (VL) in Kaposi Sarcoma (KS) has been associated with severe Immune reconstitution inflammatory syndrome (S-IRIS-KS), which can occur after initiating cART, and is linked with high mortality particularly in patients with pulmonary involvement. We investigate if valganciclovir initiated before cART decreases HHV-8 VL and assess if it reduces the incidence of S-IRIS-KS and its attributable mortality. Methods: Open-label parallel-group randomized clinical trial in AIDS cART naive patients with disseminated KS (DKS) as defined by at least two of the following: pulmonary, lymph-node or gastrointestinal involvement, lymphedema, or equal or more 30 skin lesions. In the experimental group (EG), patients were randomized to valganciclovir 900 mg BID four weeks before cART and continued until week-48; in the control group (CG), cART was initiated on week-0. Non-severe-IRIS-KS was defined as: increase in the number of lesions plus equal or more than one log10 HIV-VL decrease or equal or more than 50 cells/mm3 increase or equal or more than 2-fold rise in baseline CD4+ cells. S-IRIS-KS was defined as abrupt clinical worsening of KS lesions and/or fever after ruling out another infection following cART initiation, and at least three of the following: thrombocytopenia, anemia, hyponatremia, or hypoalbuminemia. Results: 40 patients were randomized and 37 completed the study. In the ITT analysis, the overall mortality did not differ between groups. In the per-protocol analyses, the difference showed a trend for higher S-IRIS-KS mortality in the CG 3/19 (15.7%), compared to EG 0/18 (p=0.07). The incidence of S-IRIS KS was significantly lower in the EG; two patients, one each had S-IRIS-KS episode (0.038 per 100 patient-days) compared to CG group, four patients developed 12 S-IRIS-KS episodes (0.21 per 100 patient-days); incidence rate of 0.09 (95% CI 0.02-0.5 p=0.006). Mortality in patients with pulmonary KS was significantly lower in EG, 3/4 in CG vs 0/5 in EG. S-IRIS-KS was associated with higher HHV-8-VL; IL6 and CRP; valganciclovir was protective. Of survivors at week 48, 82% achieved more than 80% remission. No difference was found between groups in the number of non-S-IRIS-KS events. Conclusions: Valganciclovir significantly reduced the episodes of S-IRIS-KS although attributable KS mortality was lower in the EG the difference was not significant (p=0.07). Mortality was significantly lower in EG patients with pulmonary KS.

Treatment of Skin Oncological Disease Using an Immunosuppressive Medication

“…Volkow et al (9) note the following in their article on the mortality in severe Kaposi's syndrome: In HIV-infected patients who receive ART, the HIV RNA in the blood plasma may not be detectable using the simple laboratory tests, but there is still a reservoir of potentially HIVinfected cells that can reappear after stopping ART. Maintenance of the HIV reservoir may depend on the duration of the existence of the CD4+ T-cell memory that is in the resting phase (G0).…”

Valganciclovir modulates the tumor necrosis factor axis molecules expression and CD4+ T-cell subsets in disseminated Kaposi Sarcoma patients

“…The DKS/HIV patients are part of a cohort nested in a clinical trial recruited and followed up at Instituto Nacional de Cancerología, Mexico City (ClinicalTrials.gov, NCT03296553, registered 28 September 2017); patients were enrolled during 2017–19 [ 15 ]. Twenty men > 18 years old with disseminated KS, cART naïve, were randomly assigned to two groups; 10 patients received CT at week 0 (W 0 ), according to current Mexican Guidelines, the cART consists of a triple combination of Efavirenz/emtricitabine/tenofovir.…”

“…In this regard, valganciclovir (VGC) has been proposed as an HHV-8 therapy to diminish viral replication in disseminated KS/HIV+ (DKS/HIV) patients and decrease mortality attributable to severe immune reconstitution inflammatory syndrome KS (S-IRIS-KS) episodes [ 13 , 14 ]. A phase II clinical trial conducted by the Instituto Nacional de Cancerología at Mexico City (NCT03296553) established a novel therapy scheme using VGC, delaying 4 weeks of the cART administration, in order to decrease HHV-8 viral load (VL) before initiating cART [ 15 ].…”

Immune Reconstitution Inflammatory Syndrome Associated Kaposi Sarcoma

“…The randomized clinical trial conducted by Volkow et al on 38 ART naïve patients with disseminated KS found a reduction of severe KS-IRIS events and in the number of patients with at least one severe KS-IRIS episode. Valganciclovir treatment was administered at 900 mg BID, initiated four weeks before ART and maintained for 48 weeks [ 106 ]. This result remains to be confirmed in a larger number of patients, and the benefits and risks of such a prophylaxis weighed, particularly due to valganciclovir’s haematological toxicities.…”