Research Article: Trend of estimated glomerular filtration rate during ombistasvir/paritaprevir/ritonavir plus dasabuvir ± ribavirin in HIV/HCV co-infected patients

Date Published: February 20, 2018

Publisher: Public Library of Science

Author(s): Lucia Taramasso, Antonio Di Biagio, Francesca Bovis, Laura Ambra Nicolini, Andrea Antinori, Laura Milazzo, Salvatore Sollima, Guido Gubertini, Fosca Niero, Annalisa Saracino, Raffaele Bruno, Vanni Borghi, Francesca Montagnani, Annamaria Cattelan, Hamid Hasson, Gloria Taliani, Antonella D’Arminio Monforte, Claudio Mastroianni, Giovanni Di Perri, Sara Bigoni, Massimo Puoti, Angiola Spinetti, Andrea Gori, Nicola Boffa, Bruno Cacopardo, Andrea Giacometti, Giustino Parruti, Vincenzo Vullo, Antonio Chirianni, Elisabetta Teti, Caterina Pasquazzi, Daniela Segala, Massimo Andreoni, Chen-Hua Liu.

http://doi.org/10.1371/journal.pone.0192627

Abstract

The renal function is a key-issue in HIV/HCV co-infected patients, nevertheless, it has not established so far whether HCV treatment with new direct acting agents could impact on estimated glomerular filtration rate (eGFR) variations. In the present work, we examined the real-life data on renal function that have been prospectively collected in the SIMIT compassionate-use program of ombitasvir/paritaprevir/ritonavir plus dasabuvir (OBV/PTV/r + DSV) in 144 HIV/HCV genotype 1 co-infected patients. The population was 74% male, 30.5% in CDC stage C, with median age of 52 years (48.0–56.5) and median liver stiffness of 7.8 kPa (6.7–9.2). Median baseline eGFR was 102.0 (90.8–108.1), changing to 99.8 (83.5–104.8) at the end of treatment (EoT), and 100.0 (87.3–105.6) 12 weeks after the EoT (FU12), p<0.0001. No patient had grade 3–4 increase of creatinine. At EoT 60/144 (41.7%) patients had ≥ 5% reduction in their eGFR, confirmed at FU12 in 39/60 (65.0%) cases. Longer duration of HCV infection (cut-off 12.9 years), lower HCV-RNA viral load (cut-off 1,970,160 IU/ml) and lower platelet count (cut-off 167,000 x106/L) were significantly associated with eGFR decline at logistic analysis (adjOR 2.9, 95%CI 1.0–8.8, p = 0.05; adjOR 3.5, 95%CI 1.2–10.4, p = 0.02; adjOR 2.8, 95%CI 1.1–6.8, p = 0.03, respectively). After repeating the analysis throughout a mixed model, a higher eGFR decline was highlighted in patients concomitantly treated with tenofovir (p = 0.0001), ribavirin (p = 0.0001), or integrase inhibitors (p <0.0001), with longer duration of HIV (p = 0.0002) and HCV infection (p = 0.035), lower baseline HCV RNA (p <0.0001), previous HCV treatment (p<0.0001), and older age (p<0.0001). In conclusion, our study confirms a good renal safety profile of OBV/PTV/r + DSV treatment in HIV/HCV patients, and the median decline of 2 ml/min in eGFR, albeit statistically significant, is of doubtful clinical significance. The role of aging, concomitant therapies and duration of HIV/HCV infection needs to be further investigated.

Partial Text

New direct-acting antiviral (DAA) agents have radically changed the therapeutic scenario of chronic HCV infection in both mono-infected and HIV co-infected patients [1, 2]. The 3-DAA regimen of ombitasvir, paritaprevir plus ritonavir, and dasabuvir (OBV/PTV/r + DSV) has showed high efficacy in clinical trials in HIV/HCV co-infected patients [3, 4] and recent data on compassionate-use program for OBV/PTV/r + DSV, coordinated by the Italian Society of Infectious and Tropical Diseases (SIMIT), have confirmed high efficacy in real-life setting in HCV genotype 1 infected patients [5]. Moreover, good tolerability without major adverse events attributable to the study drugs has been reported in the same context [5], but an analysis focalized on the trend of the renal function has not been performed yet. In patients co-infected with HIV/HCV the renal safety is an issue of primary interest, as HCV and HIV both constitute risk factors for renal disease. HIV infection may be linked to HIV-associated nephropathy (HIVAN) or favour renal thrombotic microangiopathy, focal segmental glomerulosclerosis and immunecomplexes deposition in the glomerulus [6]. Moreover, some of the drugs used in combined antiretroviral therapy (cART) have possible renal side effects or long-term toxicity [7]. On the same time, HCV infection is linked to a series of immune-mediated glomerulopathies as well as to possible cryoglobulinemia-linked renal vasculitis [8] and hepatorenal syndromes in more advanced stages of liver disease [9]. Nevertheless, little is known on the trend of estimated glomerular filtration rate (eGFR) in patients who clear HCV infection during and after treatment with new DAAs, especially in real life settings [10, 11]. A worsening of renal function after DAA treatment has been reported in patients with cirrhosis, and in those treated with OBV/PTV/r + DSV [10]. Nevertheless, it has not established so far whether HCV clearance is related or not with an improvement in GFR, or if, on the contrary, the combination of antiretroviral drugs and DAAs can even cause a reduction of GFR, throughout a direct mechanism or indirectly, for drug-drug interactions (DDI).

The SIMIT compassionate-use program provided access to treatment for patients co-infected with HIV and HCV genotype 1 or 4, with or without compensated cirrhosis.

Among patients included in the SIMIT compassionate-use program, 144 HIV/HCV co-infected people satisfied inclusion criteria. The population was 74% male (107/144 patients), with median age of 52 years (48.0–56.5), and median CD4+T-cell count of 658 cells /μl (480–929).The median CD4+T cell nadir was 190 cells /μl (74–314). All but three (2.1%) patients had HIV-RNA load <50 copies/ml. According to Centers for Disease Control and Prevention (CDC) definition, 66 (45.8%) patients were stage A, 44 (30.5%) stage B and 29 (30.5%) stage C. All patients had documented HCV genotype 1 infection (1a in 94, 1b in 44, 1a/b in five and 1 not further characterized in one). Median liver stiffness was 7.8 kPa (6.7–9.2) at baseline. Regarding the route of HIV/HCV transmission, the majority of patients (n = 107, 74.3%) reported previous intravenous drug use, 26 (18.1%) unprotected sexual intercourse (5.6% homo/bi-sexual and 12.5% eterosexual), five (3.4%) transfusions of blood components, while in the remaining seven (4.9%) it was unknown. Three patients had more than one risk factor: two patients with previous intravenous drug use and one with previous transfusions of blood components, that also reported unprotected sexual intercourse. Demographic and clinic characteristics of the study population are summarized in Table 1. This study analyses the eGFR trend in a large and homogeneous cohort of patients with HIV/HCV genotype 1 co-infection and mild fibrosis prospectively treated with OBV/PTV/r + DSV.   Source: http://doi.org/10.1371/journal.pone.0192627

 

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