Safety and efficacy of grazoprevir/elbasvir in the treatment of acute hepatitis C in hemodialysis patients

Abstract Treatment of hepatitis C virus (HCV) infection with direct‐acting antiviral agents (DAAs) in hemodialysis patients requires extensive consideration. At present, studies regarding DAAs for acute HCV infection in such patients are limited. The present study aims to evaluate the efficacy and safety of grazoprevir (GZR) plus elbasvir (EBR) treatment in acute hepatitis C (AHC) patients undergoing hemodialysis. Patients undergoing hemodialysis who had a nosocomial acute HCV infection were enrolled. All patients received GZR 100 mg/EBR 50 mg once daily for 12 weeks and were followed up for 12 weeks. Serum alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and HCV RNA levels were monitored during treatment and follow‐up periods. Sustained virologic response at 12 weeks after treatment cessation and treatment‐emergent adverse events (AEs) were assessed. A total of 68 AHC patients were enrolled. All patients were infected with HCV genotype 1b and achieved SVR12. Decreasing ALT, AST, and TBIL were observed over time in the first 4 weeks and became steady thereafter. Forty‐eight (70.59%) patients reported at least one AEs. The most common AEs were fatigue, headache, and nausea. Two AHC patients discontinued treatment due to serious but drug‐unrelated AEs. In conclusion, GZR/EBR has a high efficacy and safety profile in hemodialysis‐dependent patients with genotype 1b AHC.


| INTRODUCTION
Hepatitis C virus (HCV) infection is associated with morbidity and mortality of patients with cirrhosis and hepatocellular carcinoma caused by chronic hepatitis C (CHC). 1 The World Health Organization estimates that in 2015, there were 71 million people living with HCV infections worldwide, accounting for 1% of the global population, and there were 1.75 million new HCV infections diagnosed. 2 In 2015, HCV infections were responsible for approximately 0.4 million deaths, mainly due to cirrhosis and hepatocellular carcinoma. 2 HCV is transmitted primarily by parenteral routes, including unsafe healthcare practices in developing countries (unsterile healthcare injections, blood transfusions, and other invasive medical procedures) and intravenous drug use in developed countries. 1 Patients undergoing hemodialysis are at high risk for HCV infection as they are commonly exposed to blood-borne pathogens because of frequent intravenous access and catheter manipulation. 3 The prevalence of HCV infection in hemodialysis-dependent patients has been reported to be between 3.8% and 7.6%, while the data in China are 9.9% from the DOPPS study, which was dependent on economic development and is substantially higher than in the general population. 4 Moreover, acute HCV infections in hemodialysis-dependent patients are always silent and asymptomatic, and 65%-92% of the patients with acute hepatitis C (AHC) can develop CHC without treatment. 5 HCV seropositive patients with advanced kidney disease may experience an increased risk of death and reduced access to renal transplantation. [6][7][8] Cirrhosis is also a concern in such patients with long-term HCV infection. Although the management of AHC has not reached a consensus, early treatment may be helpful to prevent chronic infection and avoid the risk factors that accelerate disease progression.
Until the introduction of direct-acting antiviral agents (DAAs), the recommended treatment for HCV infection was a regimen of Peg-interferon with ribavirin, which achieved a sustained virologic response (SVR) in 54.4%-87.0% of patients, even after optimization. 9,10 Hemodialysis was considered a contradiction of HCV treatment due to the severe side effects of Peg-interferon and ribavirin before the DAA era. The development of DAAs in 2011 has revolutionized hepatitis C management. 11 At present, available oral regimens are based on the combination of DAAs with or without ribavirin, which has excellent efficacy and safety profiles for most CHC patients according to clinical trials and real-world studies. 1,11 However, data on the efficacy of DAAs in acute or recent HCV-infected patients vary with different treatment regimens and durations. Several clinical trials and cohort studies were conducted to describe the optimal management for acute or recent HCV infection. Altogether, the regime containing sofosbuvir plus ribavirin showed suboptimal efficacy with the SVR12 rate ranging from 32% to 92% and it is not recommended in current guidelines, [12][13][14] whereas the second generation DAA regimes had promising results. The DAHHS2 study showed that treatment of 80 patients with genotypes 1 and 4 AHC using grazoprevir (GZR) plus elbasvir (EBR) for 8 weeks can achieve an SVR12 rate of 99%. 15 Martinello et al. 16 also reported that treatment of 30 patients with recent HCV genotype 1 infection using ombitasvir/paritaprevir/ ritonavir plus dasabuvir (ProD) for 8 weeks can achieve an SVR12 rate of 97%. 16 Treatment of 20 patients with an acute HCV genotype 1 monoinfection using ledipasvir plus sofosbuvir resulted in an SVR12 rate of 100%. 17 Another study also reported an SVR12 rate of 100% with interferon-free therapy for AHC in V-positive patients. 14 The C-SURFER study first investigated the efficacy and safety of EBR/GZR in 224 HCV genotype 1 infected CHC patients with Stage 4 or 5 chronic kidney disease (CKD). They found that the SVR12 was 99% with only one relapse 12 weeks after the end of treatment and the adverse events (AEs) (headache, nausea, and fatigue) were comparable to those in the placebo-control group. 18,19 Several other Phase III trials and real-world studies also reported comparable results in the same population with regimens containing protease inhibitors (PI) such as EBR/GZR, ProD, asunaprevir/daclatasvir, or glecaprevir/ pibrentasvir. [20][21][22][23][24][25] However, studies on acute HCV-infected patients undergoing hemodialysis are limited. One study in 19 patients reported that sofosbuvir-containing regimens were effective and safe for the treatment of acute HCV in patients undergoing hemodialysis. 26 In May 2019, nosocomial HCV infections among hemodialysisdependent patients occurred in Dongtai People's Hospital of Jiangsu Province, and 68 patients were diagnosed with AHC. We evaluated the efficacy and safety of GZR plus EBR treatment for 12 weeks in these patients. Then all of the patients undergoing hemodialysis were screened for anti-HCV and HCV RNA.
Baseline information including age, sex, baseline HCV RNA levels, genotype, and certain laboratory data was collected from the records.

| GZR/EBR treatment
All patients received GZR 100 mg/EBR 50 mg once daily for 12 weeks and were followed up for an additional 12 weeks.

| Assessments
Serum alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and HCV RNA levels were detected at baseline, during treatment at 1 week, 2 weeks, 4 weeks, and 12 weeks, as well as at the final follow-up 12 weeks after the end of treatment (EOT).
HCV RNA levels were quantified using real-time polymerase chain reaction using the Roche Cobas Ampliprep/Cobas Taqman HCV test V.2.0 (Roche) with a lower detection limit of 15 IU/ml. Virologic response (VR) and SVR were defined as undetectable HCV RNA levels during the treatment and follow-up period, respectively. The efficacy was evaluated using SVR12.

| Adverse events (AEs)
Safety was assessed by monitoring the AEs. AEs of all patients were recorded during the 12-week treatment. Common AEs in the present study included itching, fatigue, headache, nausea, vomiting, insomnia, dizziness, diarrhea, and so forth.

| Statistical analysis
All data are presented as n (%) or mean ± standard deviation. To evaluate the efficacy analysis, a univariate analysis was performed using the χ 2 test, and factors with p values less than 0.1 were entered into the multivariate analysis, which was performed to identify independent prognostic factors.
A p value less than 0.05 was considered statistically significant.

| Efficacy
All patients achieved virologic responses at EOT and SVR12 both in the AHC and CHC groups, (Figure 1) and no patients were lost to follow-up.
All patients showed a decrease in ALT and AST levels over time within the first 4 weeks and normal levels were maintained thereafter ( Figure 2).
Early virologic response was defined as undetected HCV-RNA at treatment weeks 1, 2, and 4 (VR1, VR2, and VR4; Figure 1). At Week 4, almost all patients achieved viral eradication. All CHC patients (11/11) and 95.6% of AHC patients (65/68) achieved VR4. The risk factors that affected early virologic response were calculated in the AHC group, but those in the CHC group were not analyzed due to the small sample size. Early treatment viral kinetics were related to baseline HCV-RNA levels. Patients with a high baseline viral load had significantly lower rates of VR1 and VR2 than those with a low baseline viral load (Table 2).
Moreover, multivariate analysis showed baseline HCV levels can predict VR1 (Table 3). However, due to all patient with lower RNA level achieved VR2, the number of patients without VR2 was 0 in the lower group, multivariate analysis cannot be performed for VR2.

| Safety
The safety profile of EBR/GZR is summarized in In addition, these two patients still achieved SVR12.
The most common laboratory abnormality was mild and moderate ALT/AST elevation. In this study, elevated ALT and AST levels were observed in 23.5% (16/68) and 8.8% (6/68) of AHC patients, and 9.1% (1/11) and 18.2% (2/11) of CHC patients, respectively ( proportion of hemodialysis patients who had acute HCV infections will develop chronic hepatitis and the incidence of spontaneous viral clearance is lower than that in the general population. 27,28 Early anti-HCV treatment is an alternative option in such patients. In most cases, the anti-HCV antibody can be detected 12 weeks after exposure. 29 Interestingly, in the present study, anti-HCV was detected in only 58% of acute patients even after the 12-week follow-up period. The prolonged seroconversion time was consistent with that reported in immuno-compromised individuals. 30 Our data also showed that most patients had only mild AEs during treatment. The most common AEs were fatigue, headache, and nausea. All AEs were tolerated, but two patients discontinued treatment due to serious AEs unrelated to the drugs, which were similar to previous reports in the C-SUFER study and were comparable to those in the placebo control group. 19 For patients with advanced CKD with or without hemodialysis, sofosbuvir-based DAA  35,36 However, PI-containing regimes carry potential risks of liver toxicity. As such, treatment-emergent liver injury is a major concern when using EBR/GZR therapy. We found that in the CHC group, only 9.09% (1/11) and 18.18% (2/11) patients experienced mild ALT or AST elevation, respectively. All treatment-emergent ALT/AST elevations improved and were levels were restored to normal after cessation of treatment. The frequency of ALT/AST fluctuation in the AHC group was higher than that in the CHC group.
We suspect that this may be caused by the disease progression of AHC. Most AHC patients also had restored ALT/AST levels after treatment, but the remaining ALT abnormalities in two patients who discontinued treatment early and achieved SVR12 still require further assessment. The inflammatory response triggered by HCV is a complicated procedure and the HCV infection is only the initiator of the pathophysiological processes, while persistent inflammatory cytokine storms caused by the interaction between the virus and host immune system exacerbate the progression of liver inflammation. 41 Therefore, transaminase changes during anti-HCV treatment are related to many factors. Additional studies should be performed to investigate the underlying mechanisms. Taken together, these data indicate that GZR/EBR is well-tolerated for AHC and CHC patients undergoing hemodialysis.
There were some limitations in the present study.

| CONCLUSIONS
In conclusion, our data confirmed that 12 weeks of the EBR/GZR regimen is efficient and tolerable for the treatment of genotype 1b AHC in hemodialysis-dependent patients. Our study provides evidence that supports the use of GZR plus EBR to treat acute HCV infection in patients undergoing hemodialysis.

ACKNOWLEDGMENTS
Medical writing and editorial assistance were provided by Medjaden Bioscience Limited. This assistance was funded by MSD China.