Sofosbuvir-Based Regimens in HIV/HCV Coinfected Patients... : Transplantation (original) (raw)

Original Clinical Science—Liver

Results From the ANRS CO23 CUPILT Study

Antonini, Teresa Maria MD1,2,3,4; Coilly, Audrey1,2,3,4; Rossignol, Emilie5,6; Fougerou-Leurent, Claire5,6; Dumortier, Jérôme7,8; Leroy, Vincent9,10; Veislinger, Aurélie5,6; Radenne, Sylvie11; Botta-Fridlund, Danielle12; Durand, François13; Houssel-Debry, Pauline14; Kamar, Nassim15,16,17; Canva, Valérie18; Perré, Philippe19; De Ledinghen, Victor20; Rohel, Alexandra21; Diallo, Alpha21; Taburet, Anne-Marie4,22,23; Samuel, Didier1,2,3,4; Pageaux, Georges-Philippe24,25; Duclos-Vallée, Jean-Charles1,2,3,4 for the ANRS C023 CUPILT study group

1 AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, France.

2 Université Paris-Sud, Villejuif, France.

3 INSERM, Unité 1193, Villejuif, France.

4 DHU Hepatinov, Villejuif, France.

5 Rennes 1 University, Pontchaillou University Hospital, Service de Pharmacologie, Rennes, France.

6 INSERM, CIC 1414 Clinical Investigation Centre, Rennes, France.

7 Unité de Transplantation, Hôpital Edouard Herriot, Hépatique, Lyon, France.

8 Université Claude Bernard Lyon 1, Lyon, France.

9 Clinique Universitaire d’Hépato-Gastroentérologie, Pôle Digidune, CHU de Grenoble, France.

10 Unité INSERM/Université Grenoble Alpes U823, IAPC Institut Albert Bonniot, Grenoble, France.

11 Hôpital de la Croix Rousse, Service de Transplantation Hépatique, Lyon, France.

12 CHU Conception, Service d’Hépato-gastroentérologie, Marseille, France.

13 Service d'Hépatologie et Réanimation Hépato-Digestive INSERM U773, Université Paris VII, Hôpital Beaujon, Clichy, France.

14 Université de Rennes 1, Service des Maladies du Foie, INSERM U991, Rennes, France.

15 Department of Organ Transplantation, CHU Rangueil, Toulouse, France.

16 INSERM U1043, CHU Rangueil, Toulouse, France.

17 IFR–BMT, Université Paul Sabatier, Toulouse, France.

18 CHRU de Lille, Service d’Hépatologie, Hôpital Huriez, Lille, France.

19 Service de MPU Infectiologie CHD Vendée, La Roche sur Yon, France.

20 Service d’Hépato-Gastroentérologie, Hôpital Haut-Lévêque, CHU Bordeaux, France.

21 Unit for Basic and Clinical Research on Viral Hepatitis, ANRS (France REcherche Nord&Sud Sida-HIV Hépatites) Paris, France.

22 AP-HP, Hôpital Bicêtre, HUPS, Pharmacie Clinique, Le Kremlin-Bicêtre, France.

23 Université Paris-Sud, CEA, INSERM UMR 1184, Kremlin Bicêtre, France.

24 Département d’Hépato-gastroentérologie et de Transplantation Hépatique, CHU Saint-Eloi, Montpellier, France.

25 Université Montpellier 1, Montpellier, France.

Received 22 May 2017. Revision received 30 June 2017.

Accepted 27 July 2017.

Clinical Trial Notation NCT01944527.

The study was sponsored and funded by INSERM-ANRS (France REcherche Nord&sud Sida-HIV Hepatites).

T.M.A. has been a clinical investigator and/or speaker for Abbvie, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck Sharp & Dohme, and Roche. A.C. has been a clinical investigator, speaker and/or consultant for Astellas, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Novartis, Merck Sharp & Dohme and Abbvie. F.D. has been a clinical investigator, speaker and/or consultant for Astellas, Bristol-Myers Squibb, Gilead Sciences and Novartis, and received a research grant from Gilead. Pauline Houssel-Debry has been speaker and/or consultant for Astellas, Novartis and Gilead Sciences. N.K. has been a clinical investigator, speaker and/or consultant for Astellas, Bristol-Myers Squibb, Gilead Sciences, Novartis, Alexion, Fresenius, Amgen and Roche. V.D.L. has been a clinical investigator, speaker and/or consultant for Abbvie, Bristol-Myers Squibb, Gilead Sciences, Jansen Pharmaceuticals, Merck Sharp & Dohme. J.D. has been a clinical investigator, speaker and/or consultant for Astellas, Gilead Sciences, Janssen Pharmaceuticals, Novartis and Roche. V.L. has been a clinical investigator, speaker and/or consultant for Abbvie, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck Sharp & Dohme, and Roche. D.S. has been a consultant for Astellas, Bristol-Myers Squibb, LFB, Merck Sharp & Dohme, Novartis, Roche, Biotest. G.-P.P. has been a clinical investigator, speaker and/or consultant for Astellas, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck Sharp & Dohme, Novartis and Roche. J.-C.D.-V. has been a clinical investigator, speaker and/or consultant for Astellas, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Abbvie, Novartis, and Roche. All the other authors declare no conflicts of interest.

T.M.A., A.C., J.D., V.L., G-P.P., and J-C.D-V. contributed to the conception and design of this study and to the preparation and finalization of the manuscript. T.M.A., A.C., S.R., D.B-F., F.D., P.H-D., N.K., V.C., P.P., V.D.L., D.S., G-P.P., and J-C.D-V. recruited patients into the study and participated in data collection and data analysis. C.F-L., E.R., and A.V. contributed to data analysis. A.R. was responsible for regulatory aspects on behalf of the sponsor. A.D. contributed to the safety analysis. All authors critically reviewed the article for important intellectual content and approved the final draft for submission.

Correspondence: Teresa Maria Antonini, MD, Centre Hépato-Biliaire, DHU Hepatinov, Hôpital Paul-Brousse 12, avenue Paul Vaillant Couturier, 94800 Villejuif, France. ([email protected]).

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Background

A recurrence of hepatitis C virus (HCV) after liver transplantation affects survival in human immunodeficiency virus (HIV)/HCV coinfected patients. This study assessed the efficacy and safety of sofosbuvir (SOF)-based regimens in HIV/HCV coinfected patients after liver transplantation.

Methods

Twenty-nine HIV/HCV coinfected transplanted patients receiving tacrolimus-, cyclosporine-, or everolimus-based immunosuppressive therapy were enrolled in the Compassionate Use of Protease Inhibitors in Viral C Liver Transplantation cohort. Their antiviral treatment combined SOF, daclatasvir with or without ribavirin (n = 10/n = 6), or SOF, ledipasvir with or without ribavirin (n = 2/n = 11).

Results

The median delay between liver transplantation and treatment initiation was 37.5 months (interquartile range [IQR], 14.4-99.2). The breakdown of HCV genotypes was G1, 22 patients (75.9%); G3, 3 patients (10.3%); and G4, 4 patients (13.8%). The treatment indications were HCV recurrence (≥ F1 n = 23) or fibrosing cholestatic hepatitis (n = 6). Before starting SOF, the HCV viral load and CD4 count were 6.7 log10 IU/mL (IQR, 5.9-7.2) and 342 cells/mm3 (IQR, 172-483), respectively. At week 4, the HCV viral load was less than 15 IU/mL in 12 (42.9%) patients. The overall sustained virological response 12 was 96.6%. No significant drug-drug interactions were observed.

Conclusions

SOF-based treatment regimens produced excellent results in HIV/HCV coinfected patients after liver transplantation, suggesting an important change in their prognosis.

Liver transplantation (LT) in human immunodeficiency virus (HIV)-infected patients is a feasible procedure,1-4 but the 2- and 5-year survival rates of HIV/hepatitis C virus (HCV) coinfected patients are poorer than those of HCV monoinfected patients (73% and 51% in HIV/HCV coinfected patients vs 91% and 81% in HCV monoinfected patients, respectively).2 This is the consequence of a more rapid progression of fibrosis on the graft and severe forms of recurrence, such as fibrosing cholestatic hepatitis (FCH) in a significant number of patients (up to 20%), associated with a 15% survival rate at 3 years.2-5 Standard anti-HCV therapy with pegylated interferon (Peg-IFN) and ribavirin (RBV) enables a sustained virological response (SVR) in about 20% of patients who experience an HCV recurrence after LT.5-7 Triple therapy combining Peg-IFN/RBV and first generation protease inhibitors (telaprevir) after LT has greatly improved treatment efficacy (60%) despite poor tolerability, severe adverse events and potent drug-drug interactions in all patients.8

Data from clinical trials on interferon-free direct-acting antiviral (DAA) combinations have suggested very high rates of viral eradication.9-12 In the field of LT, encouraging results have been obtained with new anti-HCV drugs,13-17 even in patients with a severe HCV recurrence such as FCH.18-20 Few series are available in liver transplanted HIV/HCV coinfected patients treated with DAA.21-24

The France REcherches Nord&sud Sida-HIV Hépatites C023 study entitled “Compassionate use of Protease Inhibitors in viral C Liver Transplantation” (CUPILT) is being funded and sponsored by France REcherche Nord&sud Sida-HIV Hépatites. The aim of the present study was to describe the clinical, biochemical, virological outcomes and perform a pharmacokinetic analysis of calcineurin inhibitors (CNI) in HIV-HCV coinfected recipients included in the CUPILT cohort and treated with sofosbuvir (SOF)/NS5A inhibitor therapy for a recurrence of HCV after liver transplantation.

MATERIALS AND METHODS

Patients

CUPILT is a multicentre prospective cohort study being implemented in 25 French and Belgian LT centres (ClinicalTrials.gov number NCT01944527). Between October 2013 and December 2015, 699 liver transplant patients experiencing a recurrence of HCV were included in the cohort, among whom 38 were HIV/HCV coinfected patients. Only patients receiving a combination of SOF and daclatasvir (DCV), or SOF and ledipasvir (LDV), with or without RBV (n = 29), were enrolled in the present study, whatever their genotype or fibrosis stage. No modifications to immunosuppressive therapy or combined antiretroviral therapy (cART) were required to be enrolled in this study.

Written informed consent was obtained from each patient before the enrolment in the study. The protocol was implemented in accordance with the Declaration of Helsinki and French laws on biomedical research and was approved by the "Sud Méditerranée" Ethics Committee (France).

The indication for antiviral therapy was based on the investigator’s decision, considering that patients with HIV infection could have access to interferon-free regimens as soon as they became available in France.

Study Design

The treatment regimens were administered at the discretion of the investigators.

Four regimens were used during the present study: SOF, DCV with or without RBV (n = 10/n = 6), or SOF, LDV with or without RBV (n = 2/n = 11).

A once-daily oral dose of SOF (400 mg) and LDV (90 mg) was prescribed. A once-daily dose of DCV (30, 60, or 90 mg) was adjusted for concomitant cART per current guidelines as a function of their inhibiting (ritonavir-based protease inhibitors) or inducing (efavirenz [EFV]) properties. The RBV dosage was at the investigator’s discretion, depending on the patient's weight and renal function. The planned duration of treatment was 12 weeks in 9 (31%) patients and 24 weeks in 20 (69%) patients, for all regimens. However, the investigators could extend the treatment duration per their clinical judgement in the event of a suboptimal response. The patients were not randomized, so this study did not allow for any comparisons between the treatment regimens. Immunosuppressive therapy, depending on the time elapsing since LT, was adjusted to therapeutic target ranges. Any modifications to the dosages of calcineurin and mTOR inhibitors were left to the discretion of the investigator.

Fibrosis Assessment and Histological Examination

Chronic hepatitis was evaluated using the METAVIR scoring system25 or Fibroscan (Echosens, Paris, France).

FCH was defined per the recently refined histological criteria originally described by Davies et al, which include the presence of dense portal fibrosis with immature fibrous bands extending into the sinusoidal spaces, ductular proliferation, cholestasis and hepatocyte ballooning with lobular disarray.26-28

Study Assessment

Clinical evaluation, including general and nutritional status (body mass index [BMI]), clinical signs of decompensated liver disease (ascites), laboratory tests (including CNI assays), and HCV viral load (VL) were collected at baseline and at each scheduled visit throughout treatment (week [W]1, W2, W3, W4, W6, W8, W12, W16, W20, W24) and follow-up (4 and 12 weeks posttreatment). Creatinine clearance was calculated per the Modified Diet in Renal Disease-6 equation.29

Virological Monitoring

HCV RNA was quantified using the Abbott Real Time HCV polymerase chain reaction assay (lower limit of quantification (LLOQ) of 12 IU/mL, Abbott Diagnostics, USA, Abbott, IL), COBAS AmpliPrep or COBAS TaqMan (both with an LLOQ of 15 IU/mL, Roche Molecular Systems, Pleasanton, CA). The plasma HIV VL was quantified using Cobas Taqman AmpliPrep/Cobas Taqman v2 (LLOQ of 20 cp/mL, Roche Molecular Diagnostics, Mannheim, Germany) or the Abbott Real Time assay (LLOQ of 40 cp/mL, Abbott Diagnostics, USA). Direct sequencing of the NS5B region was used to determine the HCV genotype, as described elsewhere.30

End Points

The main goal of the study was to evaluate the SVR 12 rate in HIV/HCV recipients, defined as an undetectable HCV RNA VL at the end of treatment (EOT) and for 12 weeks after its discontinuation. Secondary endpoints included an evaluation of viral kinetics, safety throughout the duration of treatment (including laboratory liver tests), a BMI evaluation, and an assessment of drug-drug interactions between CNI and the combined antiviral drugs (cART and DAAs).

Pharmacokinetic Study of CNIs

Cyclosporine and tacrolimus blood concentrations were measured at regular time intervals to optimise dosing. To assess the impact of combined antiviral therapy, apparent oral blood clearance (Cl/F) was estimated if a steady state level had been reached and that trough concentrations (C0) were close to the average. The following equation was therefore applied at different periods of the study: baseline (D0 before DAA initiation), after 4 weeks of DAA treatment, at the EOT and 4 weeks after DAA discontinuation: Cl/F = D/(C0. [INCREMENT]t), where D is the dose per intake and [INCREMENT]t the time interval between 2 administrations; 12 hours for cyclosporine and 12 or 24 hours for tacrolimus, depending on the pharmaceutical formulation prescribed.

Safety

Data on the following adverse events were collected: serious adverse events, clinical and laboratory grade 3 or 4 adverse events and any grade of adverse event related to neutrophils, platelets, prothrombin time, bilirubin, creatinine, hemoglobin, or infections. All adverse events were managed per the guidelines issued by the French Association for the Study of the Liver.31

Statistical Analysis

No sample size was predefined. Statistical analyses were performed on an intent-to-treat basis using SAS statistical software (SAS Institute, Cary, NC). Continuous variables were expressed in terms of medians and interquartile ranges (IQR). Categorical variables were expressed as the numbers of patients and percentages. Given the small sample and the abnormality of the data, differences in baseline characteristics for continuous data were evaluated using the Wilcoxon-Mann-Whitney test between 2 groups and the Kruskal-Wallis test between more than 2 groups. A Wilcoxon signed rank sum test was used to test for changes over time (ie, W0 and EOT or W0 and FUW12) in continuous variables.

RESULTS

Patient Characteristics at Baseline

The characteristics of patients at the initiation of anti-HCV therapy are described in Table 1.

TABLE 1:

Clinical and biological characteristics of HIV/HCV coinfected patients at baseline

The breakdown of HCV genotypes was as follows: 1 (n = 22 patients, 75.9%), 3 (n = 3 patients, 10.3%), and 4 (n = 4 patients, 13.8%). Eleven (37.9%) patients had not responded to previous anti-HCV therapy with Peg-IFN and RBV (n = 9) or to a first-generation anti-HCV protease inhibitor-based regimen (n = 2) after LT.

The immunosuppressive regimen was based on tacrolimus (n = 15; 51.7%), cyclosporine (n = 13; 44.8%), and everolimus (n = 1; 3.4%). Mycophenolate mofetil was associated with tacrolimus in 9 patients (31.0%) and with cyclosporine in 9 other patients (31.0%).

Anti-HCV therapy was initiated because of HCV recurrence in the graft (F1-F2, n = 13; F3-F4, n = 10), or a diagnosis of FCH (n = 6). The median delay between LT and DAA initiation was 37 months (14-99 months) and was significantly shorter in the group of patients treated with RBV (18.9 months; 3.5-40.0 months) than in those who had not received RBV (82.7 months; 17.5-102.9 months), (P = 0.02). The median HCV VL at baseline in patients with and without FCH was 7.4 log10 IU/mL (IQR, 6.9-8.0) and 6.6 log10 IU/mL (IQR, 5.9-6.8), respectively (P = 0.04). In patients treated with or without RBV, the median HCV VL at baseline was 6.1 (5.8-6.7) versus 7.1 (6.8-7.6) log10 IU/mL (P = 0.0004). Refractory ascites and depleted nutritional state (BMI <20 kg/m2) were present in 3 (10%) and 7 (29%) patients, respectively.

HIV Management

At W0, the plasma HIV VL was below LLOQ (50 cp/mL) in all patients. cART therapy included raltegravir in 20 patients (69%). Details of cART are described in Table 2.

TABLE 2:

Type of cART associated to direct anti-HCV viral agents

The median CD4 cell count at W0 was 342 cells/mm3 (IQR, 222-459). A rise in the CD4 cell count was observed at FUW12 (450 cells/mm3; IQR, 227-598) (P = 0.04). The plasma HIV VL was below LLOQ throughout the study period.

Anti-HCV Therapy Regimens

The following antiviral regimens were used: SOF + DCV ± RBV, SOF + LDV ± RBV. The median initial dose of RBV (Copegus from Roche, or Rebetol from Schering-Plough) adjusted to renal function was 700 mg/d (IQR, 400-800 mg/d). The daily dosages were as follows: 200 mg (n = 2), 400 mg (n = 3), 600 mg (n = 1), 800 mg (n = 4), and 1000 mg (n = 2). The once-daily DCV dose was 60 mg in 14 (88%) patients or was adjusted to concomitant cART (30 mg in 1 patient [6%] and 90 mg in 1 patient [6%] who were on atazanavir-based or EFV-based cART therapy, respectively) (Table 2).

Treatment was given for 12 weeks in 7 patients (24%), 24 weeks in 19 patients (66%), 28 weeks in 2 patients (7%) and 42 weeks in 1 patient (3%) who achieved a late virological response at W24.

Virological Responses

A rapid fall in HCV RNA levels was observed in all patients after the initiation of treatment. The median time necessary to achieve HCV RNA < LLOQ was 6 weeks (range, 3-8 weeks). The median times required to achieve HCV RNA < LLOQ were 6, 4, and 9 weeks in F1-F2, F3-F4 and FCH patients, respectively. Figure 1 summarizes the virological response rates observed during therapy. At W4 and W12, HCV RNA was < LLOQ in 12 (43%) and 24 (83%) patients, respectively. All patients had undetectable HCV RNA levels at EOT. SVR12 was observed in 12 (92%) patients receiving SOF/LDV ± RBV and in 16 (100%) patients receiving SOF/DCV ± RBV.

FIGURE 1:

On-treatment and posttreatment HCV virological responses.

The median times necessary to achieve HCV RNA < LLOQ in patients treated with and without RBV were 7 and 3 weeks, respectively (P = 0.003) (Figure 2).

FIGURE 2:

Kinetics of HCV VL in patients treated with or without RBV.

Clinical and Biological Evolution of Liver Function

The median Model of End-stage Liver Disease (MELD) scores at baseline and FUW12 were 12 (IQR, 8-13) and 10 (IQR, 8-12), respectively. A fall in the MELD score was observed in 7 (30%) patients (between 1 and 11 points), whereas 8 (38%) patients increased their MELD score (between 1 and 4 points), as shown in Figure 3. Significant decreases in liver test parameters were observed between baseline and FUW12 with respect to bilirubin (P = 0.001), aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl-transpeptidase (P < 0.001). Refractory ascites disappeared in 3 of 3 affected patients (100%) (FUW12) and an improvement in the BMI was observed (P = 0.03).

FIGURE 3:

Evolution of MELD scores during anti-HCV therapy.

Safety

DAA was not discontinued in any of the patients because of adverse effects. All the adverse events collected are described in Table 3. Four (14.0%) patients developed grade 3/4 infections. All these patients experienced a severe recurrence of HCV on the graft: 3 had FCH and 1 had cirrhosis. In the FCH group, the infections occurred during the first month of treatment. The first patient developed aspergillosis, cytomegalovirus reactivation, and cholangitis, the second experienced spontaneous bacterial peritonitis and cytomegalovirus reactivation; and the third patient developed a urinary tract infection and cholangitis. As for the cirrhotic patient, he developed aortic valve endocarditis and enterococcus faecalis septicemia.

TABLE 3:

Details of adverse events during SOF-based therapy

One cirrhotic patient developed pulmonary arterial hypertension 8 weeks after the initiation of DAA (SOF/LDV). Thirteen (44.8%) patients developed anemia (7 patients, <10 g/dL and 3 patients, <8 g/dL). This event was more frequent in the group of patients treated with RBV (66.7% vs 29.4%, P = ns) The median hemoglobin nadir was 11.6 g/dL (IQR, 9.4-13.1). RBV doses were reduced in 4 patients (14%) by an average of 38% (25.0%-60.0%). Six (20.7%) patients required EPO and 5 (17%) patients required red blood cell transfusions.

A slight reduction in the glomerular filtration rate was observed between W0 and EOT (−6 mL/min; IQR, −23 to −1). Baseline creatinine clearance values were 73 mL/min (IQR, 61-105) and 67 mL/min (IQR, 50-91) in patients treated with (n = 13; 45%) and without (n = 16; 55%) tenofovir, respectively. At EOT, the creatinine clearance values were 58 mL/min (IQR, 44-90) and 58 mL/min (49-78) in patients treated with and without tenofovir, respectively (P = 0.11). One (3.4%) patient died of multiorgan failure in the presence of metastatic pancreatic cancer, 4 weeks after treatment completion.

Pharmacokinetics of Immunosuppressive Drugs

Only a minimal dose modification of CNI therapy was required in 8 (53.3%) of 15 patients receiving tacrolimus (16.8% increase between W0 and EOT) and 6 (46.2%) of 13 patients under cyclosporine (−5.6% reduction). The median tacrolimus Cl/F before DAA initiation was 6.3 (IQR, 0.6-8.9) L/h. Two patients on ritonavir-boosted darunavir had a very low tacrolimus Cl/F (0.22 and 0.57 L/h), and the patient on EFV the highest (109 L/h). One month after the initiation of DAA, the median tacrolimus Cl/F was 10.7 (0.7-15.3) L/h, indicative of little change. The cyclosporine Cl/F remained unchanged between W0 and W4, at 48 (39-71) L/h versus 60 (29-80) L/h). Again, 1 patient on darunavir/ritonavir displayed a cyclosporine Cl/F in the lower range (16 L/h). No patients experienced any biopsy-proven graft rejection during DAA therapy or lactic acidosis.32

DISCUSSION

This study confirms the effectiveness and satisfactory safety of a SOF-based regimen in HIV-HCV coinfected patients after LT.

All patients had undetectable HCV RNA levels at EOT, and 28 (96.6%) of 29 patients achieved SVR12. These results regarding a high SVR were in accordance with those recently published elsewhere.21-24,33

Such exceptional SVR12 rates had never previously been reported in this subgroup of patients receiving the standard Peg-IFN/RBV combination or first-generation DAA combined with Peg-IFN/RBV.5-7 The results were particularly impressive in patients with FCH, because they all achieved SVR12 (100%) when compared with the historical SVR rates obtained with Peg-IFN/RBV (only 18%).6 The SVR12 rates were not influenced by genotype, the degree of fibrosis, or the presence of FCH, but the number of patients studied was limited.

These results were like those observed in HCV monoinfected liver transplant recipients. Recent data with SOF/NS5A have shown SVR rates higher than 90% in liver transplant patients.15-17

In this cohort, the median time required to achieve HCV RNA < LLOQ was 6 weeks; interestingly, this was higher in patients treated with RBV than without (7 weeks vs 3 weeks, respectively; P = 0.003). This was probably the consequence of a higher HCV VL at baseline in the former group (7.1 vs 6.0 log10 IU/mL; P = 0.0004).

Although not significant, HCV viral clearance was slower in patients with FCH (9 weeks) than in other patients (F1-F2, 6 weeks; F3-F4, 4 weeks). These results could perhaps be explained by the higher HCV VL at baseline in FCH patients; moreover, the degree of fibrosis may influence the kinetics of HCV VL during therapy, as has been demonstrated with other combinations of DAA.17

Concerning treatment duration, only 6 (20.6%) of 29 patients received 12 weeks of the SOF and DCV or LDV combination without RBV, but even in this group, the SVR reached 100%.

The clinical status of these patients improved markedly: the MELD score fell in 30% of patients, ascites disappeared, and there was a significant improvement in BMI values.

Importantly, in these HIV/HCV coinfected patients, the CD4 cell count rose significantly during the study (P = 0.04). These results emphasize the point that achieving an SVR involves not only an improvement in clinical condition but also a restoration of the immune defences.

As well as the exceptional SVR12 rates and clinical improvements observed, the most important result of this study was the tolerability of this therapy: all patients reached the end of the therapeutic regimen, none had to be hospitalized for reasons related to their anti-HCV treatment, and the global survival rate was 96.6%. One (3.4%) patient died, but this event was not linked to the antiviral drugs under investigation.

However, 37.9% of the patients in this study developed infections. Interestingly, severe infections were only observed in patients with cirrhosis or FCH during the first month of SOF-based therapy, suggesting that these infections were more closely related to clinical status than to the anti-HCV therapy. Consequently, attention needs to be paid to this adverse event in this subgroup of patients.

Concerning the single patient who developed pulmonary arterial hypertension, this event has already been reported in literature (6 patients).34,35 The authors concluded that healthcare professionals and drug regulatory agencies need to be aware of the potential involvement of DAA in pulmonary vascular adverse effects. However, the presence in our patient of cirrhosis, portal hypertension, and HIV coinfection (which are well-known risk factors for pulmonary arterial hypertension) did not allow us to attribute this pulmonary vascular complication to DAA therapy.

As anticipated in this difficult-to-treat population, the most common adverse event was RBV-related anemia, which was treated by reducing the RBV dosage and administering EPO or red blood cell transfusions, depending on its severity.

Despite marked interpatient differences in tacrolimus or cyclosporine clearance, there was little change in Cl/F values after the initiation of DAA, indicating an absence of potent drug-drug interactions. Interpatient variability of CNI Cl/F values was strongly dependent on the ARVs administered concomitantly, which inhibited (ritonavir) or induced (EFV) the CYP3A-mediated biotransformation pathway of tacrolimus and cyclosporine. Considerable intrapatient variability of tacrolimus Cl/F values have been reported elsewhere, and there are several factors that might be involved, such as diarrhea, anemia, food intake, and a decline in Cl/F over time after LT.36 Interestingly, 1 patient treated with SOF/RBV displayed an increased tacrolimus Cl/F concomitantly with severe anemia induced by RBV, the hemoglobin level falling from 11.5 to 6.8 g/dL.

No modifications to cART were required before the introduction of DAA. The levels of DAA or cART were not measured in this cohort of patients. However, no drug-drug interactions between SOF and cART were reported. The DCV dosage was reduced, as is recommended during its concomitant administration with ritonavir-boosted darunavir. However, although the dosage was not increased in the patient on EFV-based antiretroviral therapy, this had no consequences on efficacy because this patient achieved an SVR12. Indeed, the effectiveness and safety of the DAA regimen in these difficult-to-treat patients suggested an absence of potent drug-drug interactions. Because a more aggressive recurrence is now acknowledged in these patients, treatment should be initiated soon after LT without waiting for its onset.

In conclusion, SOF-based DAA therapy in HIV/HCV coinfected patients was associated with high SVR12 rates and high tolerability. These excellent results in terms of SVR will have a major impact on the long-term survival of HIV/HCV coinfected patients after LT.

ACKNOWLEDGMENTS

The authors thank Clementine Retter for the assistance in preparing the article and Vicky Hawken for correcting the English text.

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