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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 1  |  Page : 103-111

Assessment of new hepatitis C virus therapy in patients with chronic kidney disease


1 Internal Medicine Department, Faculty of Medicine, Menofia University, Egypt
2 Department of Nephrology, Damanhour National Medical Institute, Damanhour, Behera, Egypt

Date of Submission19-Apr-2019
Date of Decision09-Jul-2019
Date of Acceptance14-Jul-2019
Date of Web Publication27-Mar-2021

Correspondence Address:
Sarah E. H. El-Kabany
Address: Damanhour, Behera
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_159_19

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  Abstract 


Objective
To evaluate efficacy and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) and ribavirin (RBV) therapy in hepatitis C virus (HCV)-infected patients with chronic kidney disease (CKD).
Background
In the era of new direct-acting antiviral drugs for HCV, data about their efficacy and safety in different renal situations are still under evaluation especially in Egypt.
Patients and methods
Between June 2017 and August 2018, a prospective study at Damanhour Medical National Institute was designed to enroll 50 patients with chronic HCV and CKD grades 4, 5, and 5D. Patients were given OBV/PTV/r (25/150/100 mg) plus RBV (200 mg) once daily for 12 weeks. Sustained virologic response (SVR12) was the primary end point.
Results
All patients achieved SVR12 (100%). Hemoglobin levels were significantly reduced during treatment (P < 0.001), with partial improvement 12 weeks after treatment; however, they were significantly lower than the baseline levels (P < 0.001). Serum bilirubin and liver enzymes levels were significantly increased during treatment (P = 0.046 and 0.021, respectively). After 12 weeks, bilirubin levels were normalized, whereas liver enzymes were significantly reduced (P < 0.001). Following a nonsignificant deterioration in serum creatinine and estimated glomerular filtration rates during treatment, a significant improvement was achieved 12 weeks after treatment in nonhemodialysis patients (P = 0.010). No serious adverse events occurred. Only three patients discontinued treatment; however, they achieved SVR12.
Conclusion
This study concluded that the combination of OBV/PTV/r and RBV for 12 weeks is an effective and relatively safe option for patients with HCV and CKD grades 4, 5, and 5D, which was even associated with improved estimated glomerular filtration rates after treatment in nonhemodialysis patients.

Keywords: chronic kidney disease, hemoglobin concentration, hepatitis C virus


How to cite this article:
Ragheb A, Kora MA, El-Zorkany KM, El-Kabany SE. Assessment of new hepatitis C virus therapy in patients with chronic kidney disease. Menoufia Med J 2021;34:103-11

How to cite this URL:
Ragheb A, Kora MA, El-Zorkany KM, El-Kabany SE. Assessment of new hepatitis C virus therapy in patients with chronic kidney disease. Menoufia Med J [serial online] 2021 [cited 2021 Jun 15];34:103-11. Available from: http://www.mmj.eg.net/text.asp?2021/34/1/103/311997




  Introduction Top


Hepatitis C virus (HCV) infection is a major health problem worldwide [1]. It has become evident that patients with renal disease and/or on hemodialysis are among those with a higher risk of HCV infection [2],[3]. It is well known that HCV infection in patients with renal dysfunction increases morbidity and mortality owing to liver disease, whereas chronic HCV infection contributes to deteriorate renal function [4].

The use of conventional interferon-based therapies in patients with advanced chronic kidney disease (CKD) has been associated with low efficacy and high toxicity [5]. The widely accepted standard of care (SoC) for HCV therapy is pegylated IFN in combination with ribavirin (RBV) [6]. Using this SoC in renal impaired patients has several limitations mainly owing to aggravated adverse effects resulting in premature discontinuation of therapy, higher dropout rates, and treatment-related mortality. Consequently, only few hemodialysis patients infected with HCV are treated [3].

Recent development of direct-acting antiviral agents (DAAs) has dramatically changed the treatment of chronic hepatitis C, and interferon-free regimes have become the treatment of choice in clinical practice [7]. Information on the efficacy and safety of DAAs in patients with renal failure is limited. As sofosbuvir and its metabolites (GS-331007) are excreted by the kidney, available data do not support its use when estimated glomerular filtration rates (eGFR) are less than 30 ml/min [5],[8].

A regimen of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) is indicated to treat infection by HCV genotype 4 (GT4), with 91–100% sustained virological response (SVR12) in RBV-free and RBV-containing combinations for treatment-naive and treatment-experienced patients. However, few studies in real-life clinical experience with OBV/PTV/r combined with RBV in advanced CKD population especially in Egypt have been published, and data on the efficacy and safety of OBV/PTV/r in HCV-infected patients with advanced CKD are still lacking [9]. So we conducted this prospective study to evaluate the efficacy and safety of this combination in patients with advanced CKD.


  Patients and methods Top


Between June 2017 and August 2018, an open-label nonrandomized prospective study was designed to enroll 50 patients who had CKD grades 4, 5, and 5D and chronically infected with HCV receiving treatment under the Egyptian National HCV Control program at Damanhour Medical National Institute.

All enrolled patients in this study provided written informed consents before any study-related procedures. Furthermore, Ethics Committee of Menoufia University in Egypt approved the study protocol, which conformed to Egyptian guidelines.

Patients who were eligible for this study received 25-mg ombitasvir, 150-mg paritaprevir, and 100-mg ritonavir (2 capsules Qurevo, AbbVie Inc. North Chicago, Illinois, U.S.A.) plus RBV 200 mg once daily for 12 weeks (based on the patient eGFR and tolerability). Planned treatment duration was 12 weeks.

If on hemodialysis, 200-mg RBV was given 4 h before session. Phosphorus-binding drugs where administered at least 4 h before or after antiviral therapy to avoid interference with drug absorption. Erythropoietin was given in titrated dose according to hemoglobin (Hb) for all patients. On regular follow-up of our patients, a decrease of Hb 2 g, or less than 10 g/dl, with respect to baseline Hb, necessitates intervention by dose reduction, close monitoring, possible use of erythropoietin, and/or possible discontinuation.

Inclusion criteria were patients with CKD grades 4, 5, and 5D who had eGFR less than 30 ml/min/1.73 m2 and were HCV RNA positive, with an age range from 18 to 75 years, provided the following: patients had compensated liver (Child-A cirrhosis or no cirrhosis), Hb level at least 10 g/dl, and had no associated uncontrolled comorbidity.

Abdominal ultrasonography was carried out on each patient to detect the echo pattern of the liver (ultrasonographic features of cirrhosis) and to exclude hepatocellular carcinoma. Presence of compensated liver cirrhosis was documented by ultrasonographic examination, Child–Turcotte–Pugh score, and laboratory biomarkers, and was also confirmed by clinical characteristics such as lower limb edema, splenomegaly, and esophageal varices. Presence of liver stiffness was evaluated by FIB-4 score calculation.

Cardiac evaluation of patients who are 65 years or older was done by ECG and ECHO.

Exclusion criteria were any of the following: total serum bilirubin more than 3 mg/dl, serum albumin less than 2.8 g/dl, International Normalized Ratio (INR) more than 1.7, and platelet count less than 50 000/mm (provided that, if any of these mentioned criteria were not caused by liver disease, patients were able to be included in the treatment protocol); hepatocellular carcinoma, except 4 weeks after intervention aiming at cure with no evidence of activity by dynamic imaging (computed tomography or MRI); extrahepatic malignancy except after 2 years of disease-free interval; in cases of lymphomas and chronic lymphocytic leukemia, patients was able to be included in the treatment protocol immediately after remission based on the treating oncologist report; pregnancy or inability to use effective contraception and lactation; and inadequately controlled DM (HbA1c > 9%).

All patients were evaluated at the beginning of study, at 4-week interval (during the treatment), and at 12 weeks after treatment by the following: full medical history (on the first visit); general examination; and clinical biomarkers such as complete blood count, liver profile [serum albumin, serum bilirubin, aspartate aminotransferase, alanine aminotransferase (ALT), prothrombin activity, INR, and α-fetoprotein (AFP)], renal profile (blood urea, serum creatinine, eGFR calculated with CKD EPI formula, serum calcium, and serum phosphorus) and HCV RNA level by PCR.

Efficacy of the regimen was assessed by measuring HCV RNA levels using QIAcube one-step ABS (Qiagen, Hilden, Germany/Applied Biosystems, Foster City, California, USA; lower limit of detection 12 IU/ml) real-time PCR-based assay for all patients before-treatment and at 4 and 12 weeks after end of treatment (SVR12). Virological failure was defined as detectable HCV RNA more than 12 IU/ml after achieving an HCV RNA concentration of lower than 12 IU/ml.

Safety of the regimen was assessed by laboratory changes that occurred during and 12 weeks after treatment and were compared with pretreatment values in addition to detecting the adverse effects for patients receiving at least first dose of the study medication (during treatment period, average duration 3 months).

Serious adverse events were defined as any life-threatening event, an event leading to hospital admission, prolonging an existing hospital stay or resulting in death, or any event considered serious in the opinion of the treating physician.

Significant anemia was defined as Hb level less than 10 g/dl. Leukopenia was defined as white blood cell count below reference range according to laboratory findings, and thrombocytopenia was defined as platelet count below reference range according to laboratory findings.

Discontinuation of therapy was required when Hb levels were less than 6.5 g/dl, ALT levels were above 10 times normal (if not already present at the time of starting treatment), or severe bacterial infection regardless of the neutrophil count.

Hepatic decompensation was defined as the presence of variceal hemorrhage, ascites, spontaneous bacterial peritonitis, and/or hepatic encephalopathy.

Statistical analysis

Data were fed to the computer and analyzed using IBM SPSS software package version 20.0. (IBM Corp., Armonk, New York, USA). Qualitative data were described using number and percent. The Kolmogorov–Smirnov test was used to verify the normality of distribution. Normally quantitative data were expressed in mean ± SD, whereas abnormally distributed data were expressed in median (minimum–maximum). Significance of the obtained results was judged at the 5% level (sample size = 50 patients). Significance between periods was done by post-hoc test, adjusted Bonferroni, and Dunn's. Test of significance was done by Friedman test and F test (analysis of variance) with repeated measures. P value of 0.05 was considered statistically significant.


  Results Top


The baseline data of the patients are summarized in [Table 1]. Our patients included 15 (30%) patients with CKD4; 35 (70%) patients with CKD5, where seven (14%) of them were not on hemodialysis; and 28 (56%) were CKD5D (on hemodialysis), as shown in [Figure 1]. Twelve (24%) cases had liver cirrhosis by ultrasonography. Thirty-one (62%) were classified as class A5 by Child scoring and the other 19 (38%) patients were classified as class A6. By using FIB-4 score, 42 (84%) of our patients were less than 3.25 (no or moderate fibrosis), whereas the other eight (16%) were at least 3.45 (advanced fibrosis).
Table 1: Baseline criteria of the studied cases

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Figure 1: Distribution of cases of the study according to the chronic kidney disease stage

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Regarding efficacy of antiviral therapy, all patients achieved SVR12 (100%), regardless of CKD stage, hemodialysis, liver cirrhosis, or liver fibrosis stage.

Regarding safety of the antiviral therapy, mean Hb levels were significantly reduced during treatment (P < 0.001) with partial improvement 12 weeks after treatment; however, they were significantly lower than the baseline levels (P < 0.001). Mean change in Hb levels from baseline to end of treatment was 3.55 ± 1.71. WBC count was not changed significantly during treatment; however, it was significantly increased 12 weeks after treatment (P = 0.004) when compared with pretreatment level. Platelet count was not significantly changed during treatment but was significantly increased 12 weeks after treatment (P < 0.001) when compared with pretreatment level [Table 2].
Table 2: Laboratory investigations before, during, and 12 weeks after therapy

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Albumin, INR, prothrombin activity, and AFP were not significantly changed during and after treatment when compared with before-treatment levels. Aspartate aminotransferase and ALT were significantly increased during treatment (P = 0.021) and significantly decreased 12 weeks after treatment (P < 0.001) when compared with baseline levels. Total bilirubin was significantly increased during treatment (P = 0.046) but not changed after treatment when compared with before-treatment levels [Table 2].

In nonhemodialysis patients, blood urea, serum calcium, and serum phosphorus levels were not significantly changed when compared among before, during, and after treatment levels, whereas serum creatinine and eGFR improved significantly after treatment (P = 0.010) without significant deterioration during therapy [Table 3].
Table 3: Renal profile before, during, and after therapy in nonhemodialysis patients

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Regarding safety profile, no serious adverse events were detected and only three patients discontinued all treatment after 8 weeks owing to severe Hb decline; however, they achieved SVR12 as shown in [Table 4]. Common adverse events were Hb reduction (90%); general disorders such as fatigue, myalgia and headache (46%); gastrointestinal complications (28%); elevated blood urea (28%); and other less common adverse events which were either self-limited or managed by therapy modifications, as shown in [Table 5].
Table 4: Safety summary

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Table 5: Laboratory and clinical adverse events during treatment

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During therapy, reduced Hb concentration developed where patients complained of anemia manifestations. They were managed by RBV dose reduction in 37 (74%) patients, RBV discontinuation or interruption in 25 (50%) patients, three (6%) patients discontinued all treatment after 8 weeks (and all achieved SVR12), increase of the erythropoietin dose in 37 (74%) patients, and blood transfusion was initiated in 17 (34%) patients, as shown in [Figure 2]. CKD5D was the most significant CKD grade that needed RBV dose reduction, RBV discontinuation, increased EPO dose, or increased need for blood transfusion [Figure 3] and [Table 6].
Table 6: Comparison among chronic kidney disease grades regarding modalities owing to changes to hemoglobin levels

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Figure 2: Management of hemoglobin declines in all cases of the study.

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Figure 3: Comparison among chronic kidney disease stages regarding modalities of management owing to changes in hemoglobin levels.

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  Discussion Top


HCV infection significantly impairs the life expectancy of patients with chronic renal failure and adversely affects prognosis after renal transplantation [10].

Thus, cure of HCV infection in patients with CKD or those on dialysis is deemed highly important. The use of interferon-based therapies for HCV eradication, in this group of patients, was hampered by the high frequency of adverse events related to therapy, especially anemia and infections [3].

Recent development of DAAs has dramatically changed the treatment of chronic hepatitis C, and interferon-free regimes have become the treatment of choice in clinical practice [7].

Till now, pooled data about the safety and efficacy of different DAAs regimens in different renal situations are still under evaluation [11], especially in Egypt, where HCV GT4 is the most dominating genotype [12]. In Egypt, there were two adopted protocols for patients with HCV and CKD: the sofosbuvir-based combinations and the OBV/PTV/r plus RBV based combination; therefore, we performed an open-label nonrandomized prospective study on 50 patients who were treated by OBV/PTV/r plus RBV for 12 weeks to evaluate the second combination in patients with CKD grades 4, 5, and 5D.

Sofosbuvir was proved to be contraindicated in patients with end-stage renal diseases, as its elimination was based mainly on renal route that may affect its bioavailability [8]. On the contrary, OBV/PTV/r plus RBV regimen was proved to be a well-tolerated protocol in noncirrhotic patients with CKD [13],[14].

Regarding efficacy, all patients in our study achieved SVR12 (100%), whatever CKD grade, hemodialysis, liver cirrhosis, or fibrosis stage.

Said et al. [10] conducted an open cohort study on patients with chronic GT4 HCV and CKD (grades 3–5 with or without hemodialysis) who were treated with 12 weeks of OBV/PTV/r plus RBV. Their study achieved SVR of 100% at post-treatment week 12, and no virological failures were reported, which was in agreement with our results.

Sanai et al. [15] performed an observational cohort study to evaluate the efficacy of co-formulated OBV/PTV/r in the treatment of GT4 HCV, and combined with dasabuvir (DSV) in GT1 patients, with CKD stages 4–5. They achieved SVR12 of 100%. Moreover, Abad et al. [16] carried out a multicenter study to analyze the efficacy and safety of OBV/PTV/r and DSV with/without RBV in 35 HCV-infected patients who were on HD and achieved the same results.

Welzel et al. [17] conducted a cohort study that investigated the effectiveness and safety of OBV/PTV/r ± DSV ± RBV for treatment of HCV GT1 and GT4 infection in 505 patients. They found in their study that the overall SVR12 was 96%, and in patients with severe renal impairment (34 patients), it was 100%, which was in agreement with our results.

Arai et al. [18], in their retrospective, multicenter study of 12-week (OBT/PTV/r) therapy that included GT1b patients with or without CKD found that the SVR12 among the patients with CKD was 98.1%, with only one patient experiencing failure of antiviral treatment, which runs in line with our results. Moreover, Atsukawa et al. [19] in their retrospective, multicenter study that evaluated the outcome of 12 weeks of OBV/PTV/r therapy on 35 dialysis patients found that SVR12 was 96.8%. Both studies achieved high efficacy rate, but these results were obtained using OBV/PTV/r regimen without RBV [18],[19].

Regarding safety of the antiviral therapy, mean Hb levels were significantly reduced during treatment with partial improvement 12 weeks after treatment; however, they were significantly lower than the baseline levels.

Mekkey et al. [20] found in their study a significant decrease in Hb concentration which improved after either reduction of RBV dose, iron supplementation, erythropoietin injection, or blood transfusion, which was in agreement with our results.

Sanai et al. [15] in their study found that there was no overall difference in the baseline and post-treatment week 12 Hb levels, although patients receiving RBV experienced greater reductions in Hb levels, which was in agreement with our results.

Lawitz et al. [21] in their RUBY-II study that enrolled 23 with stage 4 or 5 CKD or ESRD, including those on dialysis, who had chronic HCV GT1a or 4 infection treated with (OBV/PTV/r) found that there was no significant affection of Hb concentration in their RBV-free regimen study.

In this study, albumin, INR, prothrombin activity, and AFP were not significantly changed. Serum bilirubin and liver enzymes levels were significantly increased during treatment. At 12 weeks after treatment, bilirubin levels were normalized, whereas liver enzymes were significantly reduced.

Petta et al. [22], in their prospective study that used OBV/PTV/r, with or without DSV, plus RBV for treatment of patients with HCV GT1 or GT4 infection with cirrhosis, found that there were increases in the serum bilirubin levels, which was probably owing to inhibition of the bilirubin transporters OATP1B1 and 1B3 by paritaprevir and RBV-induced hemolysis, rather than hepatotoxicity caused by OBV/PTV/r treatment, in addition to significant improvement of liver functions 12 weeks after treatment, with no significant change in INR, and these findings were in agreement with our results.

Atsukawa et al. [19] found in their study that ALT levels significantly decreased from baseline versus 12 weeks after treatment, whereas albumin levels did not change between the baseline and 12 weeks after treatment, and these findings were in agreement with our results.

In this study, following a nonsignificant deterioration in serum creatinine and eGFR during treatment, a significant improvement was achieved 12 weeks after treatment in nonhemodialysis patients, whereas blood urea, serum calcium, and serum phosphorus levels were not changed.

Said et al. [10], in their study that included patients who were CKD grades 3, 4, and 5, found that the median eGFR significantly improved and also reported that the use of OBV/PTV/r for treatment of HCV-infected patients with advanced renal disease was safe and effective and was associated with significantly improved eGFR.

Petta et al. [22] found in their study that estimated creatinine clearance decreased slightly during treatment with OBV/PTV/r, with or without DSV, plus RBV. This effect is consistent with that shown in patients with normal renal function in previous safety analyses of OBV/PTV/r with DSV plus RBV in phase 2 and 3 clinical trials. Conversely, mean eGFR increased in patients with baseline renal impairment, which is in parallel with our results.

No serious adverse events were detected in our study. Only three patients discontinued treatment after 8 weeks owing to severe Hb decline; however, they achieved SVR12.

In agreement with this study, Lawitz et al. [21] and Sanai et al. [15] found in their studies that most patients experienced mild to moderate adverse events, and 2 (3%) patients stopped treatment, but they achieved SVR12.

In this study, common adverse events were Hb reduction (90%); general disorders such as fatigue, myalgia, and headache (46%); gastrointestinal complications (28%); elevated blood urea (28%); and other less common adverse events, which were either self-limited or managed by therapy modifications.

Mekkey et al. [20] found in their study that there were no reported serious adverse events, and anemia was reported in most of their hemodialysis patients in addition to headache, epigastric pain, fatigue/myalgia, pruritus, and raised ALT, which was in agreement with our results. Moreover, Said et al. [10] found in their study that the most frequently detected laboratory abnormality was anemia. Grade 3 and 4 Hb abnormalities, blood transfusions plus interruption of RBV therapy were also observed. However, anemia that was found in only 25.15% of their patients was only confined to grade 3 and 4 Hb abnormalities.

Abdel-Moneim et al. [23] in their study found that the most common adverse effects observed across all treatment arms during and after follow-up were headache, fatigue, asthenia, nausea, and abdominal troubles in addition to a decrease in Hb concentration, which was in agreement with our study.

Moreover, RUBY-I, cohort 2, and RUBY-II studies that enrolled 66 patients, including 50 (76%) on dialysis, had three discontinuations owing to adverse events, and 73% of patients receiving RBV had adverse events managed by dose modification [21].

Current guidelines recommend 2 RBV-free regimens for patients with HCV infection and CKD grade 4, 5 or 5 D; elbasvir/grazoprevir, which is approved for the treatment of patients with GT1 or 4 infection; and glecaprevir/pibrentasvir, which has pangenotypic activity [24].

Our study is the first prospective Egyptian study that tackles the efficacy and safety profile of OBV/PTV/r and RBV on different laboratory profiles during and after therapy including patients with severe grades of renal impairment and hemodialysis. Limitations of this study included lack of genotype testing and assuming that more than 90% of Egyptian patients with chronic HCV are infected with GT4, in addition to lack of randomization and blindness, which were difficult to apply because of the fixed regimen adopted by our nation-wide protocol.


  Conclusion Top


The combination of OBV/PTV/r and RBV for 12 weeks used for treatment of patients with HCV and CKD grades 4, 5, and 5D is a highly effective with a relatively safe treatment option associated with relatively well-tolerated adverse events and was even associated with improvement of eGFR after treatment in nonhemodialysis patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
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