Hepatitis C virus (HCV) infection is highly prevalent in Egypt.[1,2] Genotype 4 (and in particular subtype 4a) dominates the HCV epidemic in Egypt.[1–6] The prevalence of chronic kidney disease (CKD) including end stage renal disease (ESRD) is recognized to be significantly higher in HCV-seropositive patients than in HCV-seronegative subjects.[7–9]
In the past, treating HCV infection in patients with CKD was difficult because of toxicities associated with the use of interferon (IFN) and reduced its renal clearance; so that, the risk of IFN-related toxicity might increase.[10,11] This toxicity was aggravated by the concomitant use of renal excreted ribavirin (RBV), which is minimally eliminated by hemodialysis including hematologic toxicity in a population already at risk for anemia.
Ombitasvir/paritaprevir/ritonavir plus dasabuvir (OBV/PTV/ r+DSV) are mainly metabolized by the liver. They have got FDA approval for the treatment of HCV patients with severe renal disease. This regimen was associated with high sustained virological response (SVR) at post-treatment week 12 (SVR12) in patients with genotype 1 infection, synonymous with viral cure. Pharmacokinetics of these DAAs were evaluated in HCV seronegative persons with mild (creatinine clearance 60–89 mL/min), moderate (creatinine clearance 30–59 mL/min), and severe (creatinine clearance 15–29 mL/min) renal impairment. The plasma exposures observed support the use of this regimen in HCV-infected patients with renal impairment with no need for dose adjustments. This study aimed to evaluate the antiviral efficacy, safety, and tolerability of ombitasvir/paritaprevir/ritonavir/ribavirin in CKD patients infected with chronic HCV infection.
2 Patients and methods
This observational, open-label prospective study was carried in the national hepatology and tropical medicine research institute; outpatient clinics in internal medicine and tropical medicine departments in Tanta University Hospital and El-obour clinic in Kafr-Elsheikh during the period between January and September 2018 on 103 chronic HCV infected patients with varying degrees of renal impairment with estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m2. Institutional ethical committee approval was obtained and a written consent was taken from every participant.
Patients younger than 18 years old, with decompensated cirrhosis, organ transplantation, severe anemia (Hb level less than 10 g\dl), and severe uncontrolled morbidity e.g. cardiac disease, malignant tumors, HIV, or hepatitis B virus co-infection were excluded from the study. Moreover, pregnant and lactating females and patients receiving contraindicated concomitant drugs for ombitasvir/paritaprevir/ritonavir were excluded from the study.
All patients enrolled in this study were evaluated by Complete blood count (CBC), liver function tests, liver enzymes including alanine transferase (ALT) and aspartate transferase (AST), Fasting blood sugar, serum creatinine and estimated glomular filtration rate, HBs-Ag testing, α-fetoprotein as well as abdominal ultrasonography.
Renal function was assessed in our patients by estimating serum creatinine, blood urea and eGFR calculation for all patients with serum creatinine more than 1.2 mg/dL by CKD-EPI equation as eGFR is considered to be an important indicator of kidney function that is vital for recognition, assessment and management of CKD.[17–20] All patients received paritaprevir/ritonavir and ombitasvir (75/50/12.5 mg) film-coated table twice daily plus ribavirin for 12 weeks. RBV was given 200 mg 4 hours before dialysis 3 times weekly. In patients without dialysis, the dose of ribavirin was calculated according to eGFR with eGFR < 30 ml/min; RBV dose was 200 mg daily. RBV was stopped in patients who developed severe anemia or intolerant to it.
Patients were followed up routinely every 4 weeks. Side effects were recorded. Complete blood count, liver, and kidney function tests (serum creatinine and blood urea), quantitative PCR for HCV RNA and eGFR were performed before the start of therapy and at weeks 4, 8, and 12 during antiviral treatment. The primary end point was a SVR at 12 weeks after end of treatment determined by quantitative PCR for HCV RNA that was also estimated at weeks 4, 12 (end of therapy). The secondary end point was to evaluate the side effects and the safety of this regimen in our patient groups.
2.1 Statistical analysis
Results were statistically analyzed using SPSS statistical package version 23 (SPSS Inc. Released 2015. IBM SPSS statistics for windows, version 23.0, Armnok, NY: IBM Corp.). Number (No), percentage (%) means and standard deviation was used for description of data. Repeated measures ANOVA (with Bonferoni correction) with Mauchly test for sphereicty test were used for comparison among 3 or more consecutive measures in the same group of quantitative variables. Assumed spherecity was used for normally distributed data while Greenhouse-Geisser was used for not normally distributed data.
The mean age of the patients included in the study was 58.49 ± 6.92 years; fifty- four (52.4%) patients were males and fifty- five (53.4%) patients were on dialysis. Baseline demographic and clinical characteristics are shown in (Table 1).
No significant change was observed in the level of follow up of serum creatinine (p value = 0.11), white blood cells (p value = 0.10), platelets (p value = 0.067), total bilirubin (p value = 0.54), and eGFR (p value = 0.076); while, there was a significant decrease in ALT and AST (P value < 0.001) (Table 2).
One hundred patients (97.1%) had undetectable PCR for HCV-RNA at week 4; meanwhile; at the end of treatment; the response reached 100%. However; 12 week after treatment; (SVR) occurred in 101 patients (98.1%) while 2 patients had viral relapse.
Regarding the safety of antiviral treatment; Side effects were observed in 62 patients. Forty-eight patients had anemia: (44 patients had reduction of RBV dose, 48 patients received erythropiotein and 4 patients received packed RBCs), while 3 patients presented by pruritus and insomnia. GIT disturbances were noticed in 3 patients also. However, no serious adverse events were observed in any patient (Tables 3 and 4).
The treatment of HCV in patients with renal impairment was a challenge till the last few years because these patients could not benefit from INF containing regimen and they were at risk of liver disease progression. However, this is changed by the era of IFN-free treatment regimen as these drugs offered a chance for the cure of these patients.
In this study; 103 patients with chronic HCV infection and severe renal impairment were enrolled, all these patients had received ombitasvir/paritaprevir/ritonavir plus ribavirin for 12 weeks, only 3 patients did not achieve virologic response; However; all our patients were PCR negative at week 12 of treatment; then ultimately; 2 patients had relapsed at 12 weeks post treatment (SVR 98.1%).
This was similar to the results obtained by Atsukawa et al., who studied 31 patients suffering from HCV infection and ESRD and concluded that rates of rapid virologic response, end-of-treatment response, and SVR12 were 93.5% (29/31), 100% (31/31), and 96.8% (30/31), respectively. Also, Pockros et al., 2016 concluded that 18 of 20 HCV positive patients with CKD who received ombitasvir co-formulated with paritaprevir and ritonavir, administered with dasabuvir for 12 weeks have achieved SVR with 1 patient relapsed after treatment. In addition, “Muñoz-Gómez et al., 2017” stated that 46 patients suffering from CKD stage 4 and 5 who received ombitasvir/paritaprevir/ritonavir(OBV/PTV/r) ± dasabuvir (DSV) ± ribavirin (RBV) had 95.7% SVR12.
However, as dasabuvir is not available in Egypt. The Egyptian protocol recommends ombitasvir/paritaprevir/ritonavir with ribavirin in management of HCV patients with renal impairment. As this study was a real life experience in daily HCV management practice in Egypt, it reported that Paritaprevir/ritonavir and ombitasvir plus ribavirin for 12 weeks was considered to be safe and effective in the treatment of chronic HCV infected patients with varying degrees of renal impairment.
There was a significant decline in hemoglobin in our patient group. This could be explained as patients with ESRD suffer from anemia due to inadequate erythropoietin production and hemolysis due to decreased RBV excretion. Most of hemoglobin decline occurred during the first month of treatment. Despite, 48 patients had erythropoietin from the start of therapy they showed significant decline in hemoglobin. No 1 had to stop RBV and 4 patients had packed RBCs transfusion. Our results were similar to “Muñoz-Gómez et al, 2017” who concluded that the overall incidence of anaemia in their 2 studied groups was 47.8% either they were taking RBV or not. On the other hand 9 of the patients enrolled by Pockros et al, 2016 had to stop RBV as they reached prespecified values for its stoppage.
Both ALT and AST can be considered as surrogate markers of hepatocellular injury. It was demonstrated that persistent elevation of ALT and AST was associated with progression of CHC and increasing risk for cirrhosis.[25–27] So that, follow up of liver enzymes had been done and there was significant decrease in ALT and AST until reaching base line at 12 week of therapy and this decrease was sustained at week 12 post treatment. This was in agreement with results obtained by Huynh et al, 2018 who studied 115 HCV patients and found that 85.5% and 83.9% of patients had normal ALT and AST as early as week 2 of therapy and this percentage increased to 90.8% at post treatment weeks 12 (18). In addition, the study done by Atsukawa et al, showed marked decrease in patients ALT at 12 weeks post treatment. Additionally, Khan et al, 2017 had concluded that enzyme levels (particularly AST and AST:ALT ratio) were a viable alternative to HCV RNA, with strong predictive value in determining treatment success of DAA therapies.
Renal function tests were stable during treatment and at 12 weeks after therapy. Our results were in accordance with the results of Muñoz-Gómez et al.; On the contrary, previous studies showed that SOF-based therapies in patients suffering from renal function impairment (eGFR < 45 mL/min) were associated with high risk of renal function deterioration and adverse events.
While recent Egyptian study conducted by Eleterby et al had studied the efficacy of sofosbuvir based regimen in chronic HCV patients with CKD with eGFR of less than 60 mL/min/1.73 m2, and they concluded that SVR was achieved in 97.5% of their study population, and that 18 patients of their patients had improved renal function at end of therapy, they also documented that patients group with more severe renal disease and those on dialysis showed lower SVR (80%) and they concluded that these regimens are safe and effective in treating patients suffering from chronic HCV with moderate to severe renal impairment.
In all our recovered patients who are on dialysis precautions are taken to prevent reinfection of those patients according to CDC recommendations to prevent transmission of HCV which is available since 2001.
One of the strength points of our study is that it was a prospective study that allowed us to directly follow our patients’ renal function.
The limitation of the study is the limited sample size. So, larger studies on larger number of patients are recommended to document these findings.
In conclusion, The use of paritaprevir/ritonavir and ombitasvir (75/50/12.5 mg) daily plus ribavirin for 12 weeks was safe and effective in the treatment of chronic HCV genotype 4 infected patients with varying degrees of renal impairment.
We would like to acknowledge the contributions of Egypt's national committee for control of viral hepatitis for the great efforts for control of hepatitis C in Egypt. Special thanks to Dr. Manal Negm consultant of nephrology in Tanta University and Prof. Mohammad Safi Ullah for their commitment and support.
S.A.-E., Y.A.-A and M.E.-A designed the study. S.A.-E., M. U. and R.B. developed the methodology. S.A.-E., M.U. and A.M. A. E wrote the article. S.A-E., Y. E-A., M.E-A., S. A. E, H.F.E., R.A, M.E., N.H., S. S, R. B, M. Y. S., A.A.M and L. M collected the data. S.S., S.A.-E. and A.M. A. E performed the analysis. All the authors participated sufficiently in the work and approved the final version of the article.
. Blach S, Zeuzem S, Manns M, et al. global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modeling study. Lancet GastroenterolHepatol 2017;2:161–76.
. Ahmed OA, Kaisar HH, Hawash N, et al. Efficacy of sofosbuvir plus ribavirin with or without peginterferon-alfa in treatment of a cohort of Egyptian patients with hepatitis C virus infection. Infect Disord Drug Targets 2017;17:95–100.
. Abd-Elsalam S, Sharaf-Eldin M, Soliman S, et al. Efficacy and safety of sofosbuvir plus ribavirin for treatment of cirrhotic patients with genotype 4 hepatitis C virus in real-life clinical practice. Arch Virol 2018;163:51–66.
. Ahmed OA, Kaisar HH, Badawi R, et al. Efficacy and safety of sofosbuvir-ledipasvir for treatment of a cohort of Egyptian patients with chronic hepatitis C genotype 4 infection. Infect Drug Resist 2018;11:295–8.
. Ahmed OA, Elsebaey MA, Fouad MHA, et al. Outcomes and predictors of treatment response with sofosbuvir plus daclatasvir with or without ribavirin in Egyptian patients with genotype 4 hepatitis C virus infection. Infect Drug Resist 2018;11:441–5.
. Ahmed OA, Safwat E, Khalifa MO, et al. Sofosbuvir plus daclatasvir in treatment of chronic hepatitis C genotype 4 infection in a cohort of Egyptian patients: an experiment the size of Egyptian village. Int J Hepatol 2018;2018:9616234.
. Satapathy SK, Lingisetty CS, Williams S. Higher prevalence of chronic kidney disease and shorter renal survival in patients with chronic hepatitis C virus infection. Hepatol Int 2012;6:369–78.
. Tsui JI, Vittinghoff E, ShlipakMG, et al. Association of hepatitis C seropositivity with increased risk for developing end-stage renal disease. Arch Intern Med 2007;167:1271–6.
. Goodkin DA, Bieber B, Gillespie B, et al. Hepatitis C infection is very rarely treated among hemodialysis patients. Am J Nephrol 2013;38:405–12.
. Fabrizi F, Dulai G, Dixit V, et al. Meta-analysis: interferon for the treatment of chronic hepatitis C in dialysis patients. Aliment Pharmacol Ther 2003;18:1071–81.
. Russo MW, Goldsweig CD, Jacobson IM, et al. Interferon monotherapy for dialysis patients with chronic hepatitis C: an analysis of the literature on efficacy and safety. Am J Gastroenterol 2003;98:1610–5.
. Rebetol (ribavirin USP) capsules, for oral use [package insert]. Whitehouse Station, NJ: Merck. Revised on May 2015. Available at: https://www.merck.com/product/usa/pi_circulars/r/rebetol/rebetol_mg.pdf
. American Association for the study of Liver Disease/Infectious Disease Society of America/International Antiviral Society.Recommendations for testing, managing, and treating hepatitis C virus. 2015. Available at: https://www.hcvguidelines.org/
. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research(CDER). Guidance for Industry Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Drugs for Treatment. Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm225333.pdf
. Khatri A, Dutta S, Marbury TC, et al. The pharmacokinetics and safety of the direct acting antiviral regimen of ABT-450/r, ombitasvir with/without dasabuvir in subjects with mild, moderate and severe renal impairment compared to subjects with normal renal function. Hepatology 2014;60:320A.
. National kidney foundation. CKD-EPI CREATININE EQUATION, 2009. Available at: https://www.kidney.org/conte nt/ckd-epi-creatinine-equation-2009
, Accessed in January 2018.
. National Kidney, Foundation,. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1–266.
. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604–12.
. Stevens LA, Schmid CH, Zhang Y, et al. Development and validation of GFR-estimating equations using diabetes, transplant and weight. Nephrol Dial Transplant 2009;25:449–57.
. Abdelmoemen G, Khodeir SA, Abou-Saif S, et al. Prevalence of occult hepatitis C virus among hemodialysis patients in Tanta university hospitals: a single-center study. Environ Sci Pollut Res Int 2018;25:5459–64.
. Atsukawa M, Tsubota A, Koushima Y, et al. Efficacy and safety of ombitasvir/paritaprevir/ritonavir in dialysis patients with genotype 1b chronic hepatitis C. Hepatol Res 2017;47:1429–37.
. Pockros PJ, Reddy KR, Mantry PS, et al. Efficacy of direct-acting antiviral combination for patients with hepatitis C virus genotype 1 infection and severe renal impairment or end-stage renal disease. Gastroenterology 2016;150:1590–8.
. Muñoz-Gómez R, Rincón D, Ahumada A, et al. Therapy with ombitasvir/paritaprevir/ritonavir plus dasabuvir is effective and safe for the treatment of genotypes 1 and 4 hepatitis C virus (HCV) infection in patients with severe renal impairment: a multicentre experience. J Viral Hepat 2017;24:464–71.
. El-Gendy NA, EL-Raey FM, Nassibi SA, et al. Efficacy of ombitasvir/paritaprevir/ritonavir plus ribavirin in treatment of chronic hepatitis C patients with end stage renal disease on regular hemodialysis. IJMA 2020;2:313–9.
. Lynch SM, Wu GY. Hepatitis C virus: a review of treatment guidelines, cost effectiveness, and access to therapy. J ClinTranslHepatol 2016;4:310–9.
. González-Grande R, Jiménez-Pérez M, González Arjona C, et al. New approaches in the treatment of hepatitis C. World J Gastroenterol 2016;22:1421–32.
. Zampino R, Marrone A, Restivo L, et al. Chronic HCV infection and inflammation: clinical impact on hepatic and extra-hepatic manifestations. World J Hepatol 2013;5:528–40.
. Huynh T, Zhang J, Hu K. Hepatitis C virus clearance by direct-acting antiviral results in rapid resolution of hepatocytic injury as indicated by both alanine aminotransferase and aspartate aminotransferase normalization. J Clin Transl Hepatol 2018;6:258–63.
. Khan ST, McGuinty M, Corsi DJ, et al. Liver enzyme normalization predicts success of Hepatitis C oral directacting antiviral treatment. Clin Invest Med 2017;40:E73–80.
. Saxena V, Koraishy FM, Sise ME, et al. Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function. Liver Int 2016;36:807–16.
. Eletreby R, El-Serafy M, Anees M, et al. Sofosbuvir-containing regimens are safe and effective in the treatment of HCV patients with moderate to severe renal impairment. Liver Int 2020;40:797–805.
. Centers for Disease Control, Prevention,. Recommendations for preventing transmission of infections among chronic hemodialysis patients. MMWR Recomm Rep 2001;50(RR–5):1–43.