Hepatitis C virus (HCV) infection is one of the main causes of acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The World Health Organization estimates that during 2019, 58 million people worldwide are living with hepatitis C and 1.5 million people were newly infected with chronic hepatitis C. HCV patients frequently have kidney disorders, which is one of the most common extrahepatic manifestations associated with HCV infection, appearing in 10% to 60% of patients.[3–5] HCV infection is the most common viral infection that affects patients on maintenance hemodialysis (MHD). Its prevalence in patients on MHD ranges from 6% to 60% in different parts of the world.[6,7] In Libya, report from 37 hemodialysis (HD) centers have shown a prevalence of HCV in HD was 16.7%, ranging from 0% to 26.3%. Chronic HCV infection can cause various types of renal diseases. The most common renal manifestations of HCV infection are essential mixed cryoglobulinemia leading to membranoproliferative glomerulonephritis (MPGN) and MPGN without cryoglobulinemia and membranous glomerulonephritis (GN). Chronic hepatitis C represents a common blood-borne disease, and the HCV infection rate is higher in HD patients compared with the general patient population due to factors such as blood transfusion and HD treatment.[10–12] As an additional source of infection, HCV in HD patients not only further increases the exposure risk of other patients and medical workers, but also causes kidney deterioration and liver diseases in the patients themselves, significantly increasing all-cause mortality. Indeed, liver disease-related mortality, cardiovascular mortality, and infection-related mortality are all significantly increased in HD patients complicated with HCV infection.[13–16] Therefore, antiviral treatment must be timely administered to HD patients with HCV infection. The availability of Direct acting antivirals (DAAs) has sparked major enthusiasm for treating persons with HCV who have chronic renal impairment, especially since many of these individuals historically have not been eligible for treatment given the toxicities associated with interferon (IFN) and ribavirin-based therapies. However, there are two issues related to DAAs. First, various DAA drugs are not universally available in all countries. Second, doses and safety for all DAAs, particularly sofosbuvir (SOF) in Stages IV and V chronic kidney disease (CKD), are unclear. SOF, a nonstructural protein 5B (NS5B) polymerase inhibitor, has been approved in 2013 and is now the backbone of many DAA treatment regimens. SOF has large renal excretion and has been initially licensed for patients with a glomerular filtration rate (GFR) more than 30 mL/min. The SOF-free combination therapies: grazoprevir (GZR)/elbasvir (EBR) and glecaprevir/pibrentasvir proved to be effective and safe in patients with advanced CKD, based on C-SURFER (Hepatitis C: Study to Understand Renal Failure’s Effect on Responses) and EXPEDITION-4 trials, respectively.[18,19] Numerous “real-life” studies have suggested the efficacy and safety of SOF-based regimens in those with an estimated GFR (eGFR) ≤30 mL/min. American Association of Liver Diseases (AASLD) now recommends all DAAs for GFR ≤30 mL/min. In Libya, only SOF and ledipasvir (LDV), daclatasvir (DAC), and subsequently velpatasvir (VEL) were available in 2016–2018 and later, EBR/GZR was introduced in HCV treatment for CKD patients. Because of suboptimal sustained virological response (SVR) and the moderate degree of adverse effects (AEs) of IFN-based therapy, there was an intense interest in using DAAs in patients with end-stage renal disease (ESRD) and patients on MHD. We report the first experience of DAA therapy in patients in Libya who were on MHD and who were awaiting renal transplants. However, to the best of our knowledge, there is still a lack of reports assessing DAAs in Libyan patients. The objective of this article is to describe our experience using SOF-based and other direct antiviral agents (DAA) therapy in MHD patients and to assess the efficacy and tolerability of these therapies in the setting of ESRD in our MHD patients complicated with chronic hepatitis C.
MATERIALS AND METHODS
Patient selection and study design
We performed a multicenter retrospective analysis of 155 patients with treatment-naive and pegylated IFN (PEG IFNα 2a, 2b) experienced chronic hepatitis C who have positive HCV antibodies and detectable RNA by polymerase chain reaction (PCR) with ESRD (patients with GFR <15 ml/min) who underwent MHD therapy and who treated with DAAs from five centers in the eastern part of Libya between October 2016 and January 2020. The patients were collected from the following centers; the Clinic of Infectious Disease Department at Benghazi Medical Center, Benghazi Nephrology Center, and dialysis units at Al Bada, Al Marj, and Ajdabiya Hospitals.
DAA regimens were administered at the discretion of the treating physician depending on the drug availability at the time of treatment. Five regimens were adopted: Daily fixed-dose combinations of EBR 50 mg/GZR 100 mg (n = 49 patients, [31.6%]); SOF 400 mg and LDV 90 mg (n = 43 patients, [27.7%]); SOF 400 mg and DAC 60 mg (n = 48 patients [30.9%]), SOF 400 mg and VEL 100 mg (n = 8 patients, [5.1%]), and ombitasvir 25 mg + paritaprevir 150 mg + ritonavir 100 mg (n = 7 patients [4.5%]).
The age, sex, comorbidities, and duration of dialysis were evaluated. Hemoglobin, creatinine, alanine aminotransferase (ALT), aspartate aminotransferase, bilirubin, albumin, and international normalized ratio were assessed in all patients before and after the end of treatment. Cirrhosis was diagnosed according to the clinical findings and by abdominal ultrasound imaging reports of the treating clinician. In response to the initial safety, all patients were asked to contact their treating physicians if they had any adverse symptoms. Plasma HCV RNA levels were measured using the real-time HCV PCR assay, with the lower limit of quantitation of 15 IU/ml done at the end of therapy, and 12 weeks after the stoppage of treatment for SVR.
Patients with CKD not in dialysis, patients with liver cirrhosis (Child–Pugh B or C), hepatitis B, or HIV co-infected patients, and patients with age <18 years were excluded from the study. The study was approved by the Research Ethics of Local Committee.
In the statistical analysis, the quantitative variables were described by mean and standard deviation. Baseline and endpoint data were summarized by descriptive statistics. To compare means before and after treatment, the paired Student’s t-test was applied. The significance level adopted was 5% (P < 0.05), and the analyzes were performed in the SPSS version 28 (International Business Machines Corporation (IBM), USA).
Characteristics of participant
One hundred and fifty-five patients were analyzed. Table 1 shows the baseline characteristics of these patients. There was a light predominance of males 96 (61.9%), and the mean age was 48.2 ± 12.6 years (18–73 years). Regarding the etiology of ESRD, 40 (25.8%) had no diagnosis and GN was found in 21 patients (13.5%). Systemic lupus erythematosus, diabetes mellitus (DM), systemic arterial hypertension, polycystic kidney disease, and vasculitis syndrome were responsible for the etiology in the rest of patients. The prevalent comorbidities were DM in 46 (31%) patients, systemic arterial hypertension in 25 (16.8%) patients, ischemic heart disease in 9 (6%) patients, and bronchial asthma in 3 (2%). The mean duration of dialysis before HCV therapy was 15 ± 8.4 years. The mean ALT value was 57.73 ± 34.185 IU/dl (range: 11–234 IU/dl), mean creatinine was 7.74 ± 2.23 mg/dl (range; 3.4–12.3 IU/dl), mean hemoglobin value was 9.178 ± 1.196 g% (range; 5.5–11.2 IU/dl), and mean baseline HCV RNA was 4.772 ± 1.0456log10 (range; 2.4–7.02 log10). Ninety-six percentage of patients were noncirrhotic and six patients (3.8%) were compensated cirrhotic (Child–Pugh A).
Laboratory data following completion of the antiviral therapy showed mean hemoglobin of 9.204 g/dL (±1.036), no rise in serum total bilirubin (0.7 ± 0.2 mg/dL), and overall improvement in liver enzymes [P < 0.05, Table 2]. None of the dialysis-dependent patients demonstrated deterioration in renal function posttreatment. There were no significant differences in laboratory parameters before and after antiviral therapy for patients in all used treatment regimens, except for the normalization of liver enzymes in patients with SVR-12. SVR was evaluated in all patients who completed the treatment, and 153 (98.7%) patients achieved SVR-12. Only 2 (1.2%) patients presented HCV recurrence after treatment both from EBR/GZR arm.
Minor AEs were observed in 12 (8.1%) patients. Headache, mild gastrointestinal (GI) upset, fatigue, and dizziness were the most common side effects. None of the patients developed severe AEs or drug–drug interactions with their concomitant underlying comorbid illness medications. There were no treatment interruptions due to AE as well as no hospitalizations, lost to follow-up, and/or death [Table 3].
Considering the abundant evidence demonstrating worse outcomes in patients who suffer from both CKD/HCV, and the high efficacy and tolerability of DAAs, curing HCV should be prioritized in patients with kidney disease. Treatment recommendations for patients with mild-to-moderate renal impairment, with eGFR ≥30 mL/min/1.7 m2 do not differ from the general population with no dose adjustment needed for any of the approved DAAs.[16,21] SOF was first among its class of NS5B polymerase inhibitors to be introduced and revolutionized treatment changed to HCV treatment CHC treatment. Invivo, SOF undergoes intrahepatic metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which eventually results in ultimate metabolite GS-331007 through dephosphorylation. SOF and GS-331007 are mainly eliminated through kidney. Compared with subjects of normal renal function, area under the curve of SOF and GS-331007 is 171 and 451% higher for patients with eGFR <30 ml/min (not receiving HD).[17,23,24] Protease inhibitors containing regimens may be used in advanced CKD, as they are metabolized mainly in liver and do not need dose adjustment for renal function. Similarly, NS5A inhibitors are also metabolized in liver and can be used in CKD Stage 4, 5 and dialysis patients.[18,19,25] Earlier in 2017, only two DAA regimens were approved by the Food and Drug Administration (FDA) to treat HCV infection in Stage 4, 5 CKD patients on HD: EBR/GZR and glecaprevir/pibrentasvir. Although these fixed dose combinations are effective and safe for the treatment of patients with CKD Stage 4–5, a need for safety and efficacy data on SOF-containing DAAs remained, due to limited access to these regimens in some parts of the world and the risks associated with the use of protease inhibitor-containing regimens in patients with advanced fibrosis or cirrhosis.[16,21] Initial data suggested that the use of SOF in patients with advanced renal impairment was associated with serious adverse events, worsening of renal function, and higher rates of anemia. Despite early concerns about the accumulation of SOF and its active metabolite, multiple “real-world” studies showed that SOF-based DAAs were effective and well tolerated in the dialysis populations,[28,29] and other analyses showed extremely low rates of kidney injury in patients receiving SOF-based DAAs.[30,31] In November 2019, based on the submission of safety and efficacy data from postmarketing clinical studies, the US FDA granted three SOF-containing regimens (SOF-LED, SOF-VEL, and SOF-VEL–voxilaprevir [VOX]) approval for use in patients with eGFR <30 mL/min/1.73 m2 including those undergoing dialysis. The multitude of studies confirming the safety and efficacy profile of full-dose SOF in patients with severe CKD and on HD was accepted by the most recent European Association for the Study of the Liver HCV guidelines which now endorse the use of SOF-based regimens in CKD patients. Moreover, sofosbuvir is available through access programs and affordable prices to patients in low- and middle-income countries. This is the first report on the experience of DAAs in patients on MHD from Libyan largest multi-center experience on SOF-based and other direct antiviral agents (DAA) therapy in HD patients. This study confirms that various DAA therapies are effective in patients with CKD/HD. In this series of 155 cases, the SVR-12 was reached in 153 (98.6%) patients. Only two patients (1.4%) developed HCV recurrence after treatment; the present study also showed excellent safety, with an increase in GI upset, dizziness, and fatigue being the most frequent side effects. In patients on HD, these side effects might not always be attributed to drug therapy. We found that DAAs could be successfully applied to treat MHD patients complicated with chronic hepatitis C, with an impressive viral response rate of nearly 100% and no overt adverse reactions. It was shown that the most common HCV genotype in the eastern part of Libya is Type 4 accounting for 85% of patients, followed by Type 1, accounting for < 15% of all HCV infections.[35,36] Although genotyping was not performed at baseline, this genotyping report can thus be taken to represent the results of HCVG4 treatment in CKD patients on HD and to less extent to HCVG1. Available literature and our own experience showed excellent efficacy of various DAAs, including SOF-based therapy in HCV patients on HD, with an SVR of more than 90% in most studies. According to the meta-analysis of observational studies (30 studies, n = 1537 patients) conducted by Fabrizi et al., the pooled SVR-12 rate was 99% and this meta-analysis showed an excellent efficacy of SOF-based combination therapy in patients with Grade 4–5 CKD. Tolerance to SOF was satisfactory in this population – severe adverse events and treatment discontinuations were uncommon. Li et al. reviewed 21 studies totaling 717 HCV-infected patients with CKD Stage 4 or 5 (58.4% on dialysis). Pooled SVR-12/24 was 97.1%. There was no significant difference at SVR-12/24 (97.1% vs. 96.2%, P = 0.72) between subgroups applying full or decreased doses of SOF. The 98.6.0% cure rate of our study is comparable to those studies. In the systematic review conducted by Majd Jabbari et al. which included 27 relevant studies, comprising 1464 patients in this meta-analysis. The pooled SVR-12 rate was 97%, which was also compatible with our findings. Desnoyer et al. observed that SOF was well tolerated in 13 dialysis patients. However, SVR-12 was 100% in patients who used SOF full dose and 60% in those who received three times a week.
In a single-center, prospective, open-label study in India, 21 noncirrhotic patients on HD were treated with LDV-SOF every other day for 12 weeks. SVR-12 was achieved in 90% (19/21) of patients, neither virologic failures nor Severe adverse effects severe AEs (SAEs) were reported and none of the patients experienced cardiac events. Fadili et al. reported 61 Moroccan dialysis patients treated with full-dose SOF-based regimens, the rate of treatment success was 75,6% in these patients with no need for dose adjustment and no major adverse events were observed. In a real-life experience study, Pawlotsky showed that patients with kidney dysfunction did not experience significant changes in renal parameters after full-dose SOF-based therapy in patients with eGFR <45 ml/min/173 m2. Our results were in accordance to this study, as we did not notice any significant alteration of renal function in our HD patients. None of the patients experienced worsening of kidney function. On the contrary, in most cases, the use of DAAs and the achievement of SVR resulted in important amelioration of renal function. Moreover, evidence found in previous similar studies states that both eGFR and serum creatinine improved by the end of treatment in patients with CKD Stage 2 or 3, revealing the fact that this antiviral regimen does not produce alterations in renal function.[42,43] Full-dose SOF with LDV or DCV was evaluated at a single center in India in an analysis including 47 patients with an eGFR <30 mL/min/1.73 m2, including 39 undergoing HD, 96% of patients had reached SVR-12. In the study population, mean hemoglobin and eGFR did not change appreciably during treatment, which is quite similar to our results as no significant difference was observed in hemoglobin levels before and after treatment. The current study shows some shortcomings. It is a multicenter study with retrospective design and the information was collected from follow-up files. However, the treating clinicians engaged at ESRD/HCV care followed patients very closely and that assured the accuracy of data. The number of studied patients with cirrhosis was small, and the safety and outcome of therapy in these patients are lacking.
Many studies in the literature that evaluate the use of DAA in CKD presented with encouraging results. The results of this study showed satisfactory and novel findings regarding the usage of full-dose SOF-based and other DAAS regimens in HCV-infected patients with advanced CKD at national setting. Strategies to eradicate HCV from dialysis units should consider DAA treatment as prevention along with improvements in the practice of standard precautions that prevent nosocomial HCV infection. By combining these two approaches, it is possible to eradicate HCV from HD units. Indeed, reports of targeted outreach efforts to screen and treat HCV in dialysis have resulted in the reduction of HCV entirely from many dialysis units in Libya, demonstrating these efforts can be successful. Future studies will be needed to determine the effect of HCV eradication on the risk of progression to ESRD and mortality risk in patients with kidney disease.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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