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

IntroductionHigh 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. MethodsOpen-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 [≥]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 number of lesions plus [≥]one log10 HIV-VL decrease or [≥]50 cells/mm3 increase or [≥]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. Results40 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 >80% remission. No difference was found between groups in the number of non-S-IRIS-KS events. ConclusionsValganciclovir 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. NIH Clinical Trails ID NCT03296553.