European Journal of Cardiovascular Medicine

Hepatitis C virus (HCV) infection is one of the most common chronic viral infections worldwide and in many cases leads to end-stage liver disease, liver transplantation, or death. HCV infection is also associated with the development of several extrahepatic manifestations, including chronic kidney disease (CKD). Multiple studies have suggested that HCV infection leads to accelerated CKD progression and increased incidence of end-stage renal disease¹

The number of individuals with chronic HCV all over the world is approximately 185 million In the last few years, antiviral therapy for HCV has been rapidly evolving with the introduction of direct-acting antiviral (DAA) therapies. They revolutionized the therapy of HCV infection with higher efficacy and sustained virological response (SVR) rates, shortened and simplified regimens, and minimal adverse effects. However, achieving sustained SVR does not instantly reverse HCV-related hepatic fibrosis or cirrhosis²

Public interest in HCV is growing, especially since the virus can also induce extrahepatic manifestations (in 40–70% of cases) including autoimmunity-related symptoms, metabolic, renal, cardiovascular, central nervous system or lymphoproliferative disorders. Renal complications often appear in the context of cryoglobulinemia. Due to the persistence of the virus in the organism, an overstimulation of B lymphocytes occurs, leading to the production of mixed cryoglobulins (a group of globulins with the property of reversible precipitation at low temperatures). Recently, toll-like receptors (TLRs) – important components of the innate immune system, have been attributed a role in HCV associated renal injury. Chronic HCV infection exacerbates renal deterioration, resulting in end-stage renal disease (ESRD) and increasing morbidity and mortality in patients undergoing dialysis, as well as in kidney transplant recipients (KT). Therefore, HCV therapeutic approach has always represented a challenging topic. Interferon-based therapies have demonstrated frequent and severe side-effects. The development of direct acting antivirals (DAAs) has led to a new era, showing promising effects, even in patients with chronic kidney disease (CKD)³

HCV infection leads to a number of extra-hepatic manifestations resulting in morbidity and mortality, including renal dysfunction. [There is a well-established association between HCV infection and increased incidence of chronic kidney disease. HCV infection is also associated with increased incidence of end stage renal disease as well as mortality among patients with existing end-stage renal disease. Renal impairment in HCV usually manifests as membranoproliferative glomerulonephropathy, most commonly in association with mixed cryoglobinemia. Other forms of glomerular injury with or without cryoglobinemia have been reported as well.⁴

Those infected with chronic hepatitis C are 70% more likely to develop chronic kidney disease (CKD) as compared to HCV seronegative patients. In addition, the presence of hepatitis C is associated with more rapid progression to end stage renal disease.2,3 Hepatitis C has also been shown to increase all cause mortality for those on dialysis, and in the kidney transplant population, HCV also accelerates graft loss. While the introduction of direct acting antiviral (DAA) agents has changed the treatment landscape of HCV, with highly efficacious treatment and few difficult to treat populations, patients with advanced renal disease were not among those who initially benefitted from these therapeutic options⁵

THE AIM & OBJECTIVE of the present study is to study the Virological response among hepatitis C infected patients treated with DAA with CKD and without CKD

STUDY SETTING after ontaining institutional ethical committee clearance, the study was conducted in the Department of Medicine, Silchar Medical College and Hospital, Silchar, Assam. Located in the district of Cachar, in the south western part of Assam, it is the only tertiary care hospital in the Barak Valley, catering to the health care of not only the patients of this valley but also patients from the neighbouring states of Tripura, Mizoram, Manipur and Meghalaya

PERIOD OF STUDY The present study was done be for a period of two months as data was collected from previous records of patients admitted in SMCH during last one year

SAMPLE SIZE the sample size was 100

STUDY DESIGN The study is a hospital based comparative retrospective study

METHOD OF COLLECTION OF DATA

All the patients attending the outdoor and indoor of the Department of Medicine of Silchar Medical College & Hospital with HCV reactive infection with and without CKD. Data including age, sex, HCV viral load was recorded. Diabetes melllitus was recorded from documentation in medical chart or blood values of random glucose more than 11.0mmol / L or HbA1c more than 6.5%.  Pretreatment and post treatment blood levels of liver enzymes, (ALT, AST) Platelet, Hemoglobin, WBC, Bilirubin , Albumin, Serum Creatinine ,HCV RNA, eGFR, APRI ,FIB 4 SCORE,USG W/A,PT -INR  Was recorded. Viral infection was evaluated by quantitative HCV RNA determination pre and post treatment . Patient infected with HCV received DAA therapy for 12 weeks and combination of sofosbuvir-velpatasvir and sofosbuvir- daclatasvir. Diabetes mellitus was selected from fasting blood sugar more than 126mg/dl and post prandial blood sugar more than 200 mg /dl.

CRITERIA

INCLUSION CRITERIA

HCV infection with CKD who have completed treatment with DAA for 12 weeks

HCV infection without CKD who have completed treatment with DAA for 12 weeks

Age more than 18years

EXCLUSION CRITERIA

Malignancies Coinfection with other viruses

Organ failure

Those who have not completed DAA

STATISTICAL ANALYSIS Data was entered using Microsoft Excel and exported to SPSS version 26.0. Analysis of data will be collected on the basis of descriptive statistics. Values will be expressed as mean +/- SD or proportion (percentage) with statistical significance set at P- value less than 0.005 (p < 0.05) to be considered statistically significant.

A total of 100 adults commenced direct–acting antiviral therapy; 50% had CKD . Median age was 42 years (IQR 25) and 82% were male.

Table 1 summarises baseline characteristics by CKD status. Apart from renal indices and age, groups were comparable.

Table 1: Baseline characteristics by CKD status

Overall SVR12 was 81% with no difference between CKD and non-CKD groups (Fisher’s p = 1.00) (Table 2).

Table 2: SVR12 outcomes overall and by CKD status

Table 3: SVR12 and viral-load reduction by CKD stage

Creatinine and eGFR remained stable after therapy (Supplementary Table ??), and ALT and AST reductions were consistent across CKD stages (Supplementary Tables ??–??).

In multivariable logistic regression (Table 4), CKD status was not significantly associated with SVR12 (OR 0.50, 95 % CI 0.04–6.67, p = 0.601), and hypertension did not modify outcomes. Higher AST (OR 1.05, 95 % CI 1.01–1.09, p = 0.025) and lower ALT (OR 0.97, 95 % CI 0.95–0.99, p = 0.018) were independently associated with failure to achieve SVR12. Finally, an exploratory random-forest model achieved an optimism-corrected AUC of 0.73 (Figure 3); this AUC denotes the model’s ability to discriminate between patients who achieve SVR12 and those who do not (0.5 = no better than chance; 1.0 = perfect discrim- ination). Body-mass index, age, AST and ALT emerged as the top predictors (Figure 4; Supplementary Table: S4).

Figure 1: SVR12 by CKD stage with Wilson 95% CIs.

Figure 2: Viral-load reduction across CKD stages (boxen + strip; outlier removed).

Table 4: Multivariable logistic regression for SVR12

Figure 3: ROC curve from 500-bootstrap OOB predictions (optimism-corrected AUC = 0.73).

Figure 4: Relative importance of the ten strongest predictors in the random-forest model.

In our study we find that DAA administered CKD patients show no worsening of renal function. We did not find any AKI event in CKD related to DAA. In non CKD patients SVR is 82% and in CKD patients it is 80% . Within CKD, sustained virological response in stage I and 2 is 80%, stage 3a is 80%, 3 b is 100 % and stage 5 is 80%.

A previous study that suggested higher rates of “worsening renal function” in patients with CKD treated with sofosbuvir-based DAAs found a 15% rate of worsening renal function in those with eGFR < 45 ml/min per 1.73 m2 compared with 1% in patients with eGFR > 45 ml/min per 1.73 m⁶

Previous studies also did not attempt to attribute cause or determine reversibility of AKI events. They found that although AKI events were slightly more common in patients with eGFR < 60 ml/min per 1.73 m2 compared with those with normal eGFR, there were no stage 2 or 3 AKI events in patients with stage 3 CKD and most AKI episodes were unrelated to DAAs and resolved without the need to discontinue DAAs. CKD itself is a known risk factor for AKI⁷

The introduction of DAA regimens marks the first time we can comprehensively evaluate the effect of HCV eradication on kidney function, because large numbers of patients are now undergoing safe and effective treatment of HCV. Small studies of patients treated with DAAs suggest they may be beneficial for kidney function⁸.

In our study we find that DAA administered CKD patients show no worsening of renal function. We did not find any AKI event in CKD related to DAA. In non CKD patients SVR is 82% and in CKD patients it is 80%

1. Sise E Meghan, Chute F Donald, Oppong Yaa et al.Direct acting antiviral therapy shows kidney function decline in patients with Hepatitis C virus infection and chronic kidney disease. Kidney International .2020;97: 193-201.
2. Agwa H. Ramy, Elgazzar H. Mohamed, El Zayyadi Islam A et al. Effect of virological response after direct acting anti virals on liver fibrosis in patients with chronic HCV infection. The Egyptian Journal of Internal Medicine.2022;34:18
3. Illescu L. Elena, Mercan S. Adriana, Letitia Toma. Safety and efficacy of direct acting antivirals for chronic Hepatitis C in patients with chronic kidney disease. BMC Nephrology,2020;21:21
4. Driedger M, Galanakis C, Cooper C et al. Direct acting antiviral HCV treatment does not influence renal function. Medicine ,2020;99:22
5. Kwo Paul, Dronamraju Deepti. More evidence that direct acting anti retroviral therapy is safe and effective in chirrosis and chronic kidney disease including peritoneal dialysis. Clinical and Molecular Hepatology,2020;26:489-491
6. Su FH, Su CT, Chang SN, et al. Association of hepatitis C virus infection with risk of ESRD: a population-based study. Am J Kidney Dis. 2012;60:553–560.
7. Hsu CY, Ordonez JD, Chertow GM, et al. The risk of acute renal failure in patients with chronic kidney disease. Kidney Int. 2008;74:101–107.
8. Blé M, Aguilera V, Rubín A, et al. Improved renal function in liver transplant recipients treated for hepatitis C virus with a sustained virological response and mild chronic kidney disease. Liver Transpl. 2014;20:25–34.