Efficacy and tolerability of sofosbuvir and daclatasvir for treatment of hepatitis C genotype 1 & 3 in patients undergoing hemodialysis- a prospective interventional clinical trial

The prevalence of HCV in patients on MHD ranges from 6 to 60% in different parts of the world [1]. Nosocomial transmission and spread through blood and its components are important factors that affect HCV incidence [2, 3]. Patients on dialysis are at a greater risk for progression to cirrhosis, hepatocellular carcinoma and liver-related mortality. HCV also increases the risk of serious infections in renal transplantation recipients [4]. Pegylated- interferon alone or in combination with ribavirin (RBV) have been the mainstay of treatment for HCV infection in hemodialysis patients but is associated with longer treatment duration, poor virologic response, low efficacy, lesser tolerability, high frequency of adverse effects, and requires close supportive care [5]. Direct acting antiviral (DAAs) have revolutionized the treatment of HCV infection with superior cure rates (SVR > 90%), tolerable adverse event profiles and short treatment durations but clinical data on efficacy and safety in the treatment of hemodialysis patients have been limited [6]. Direct acting antivirals including Sofosbuvir in combination with Daclatasvir, with or without ribavirin is highly effective in treating HCV infection in patients with or without cirrhosis [7‐11, and]. Even immunocompromised patients can now be treated safely by interferon-free therapies, resulting in potential reduction of HCV disease [12, 13]. Certain approved options for ESRD patients includes pegylated interferon, which previously provided lower SVR rates and higher side effects [14‐16, and]. Dialysis patients have been negatively impacted by HCV infection in terms of morbidity and mortality compared to non-HCV dialysis patients, this demands effective treatment option [17]. Sofosbuvir based therapy leads to high rates of SVR with few side effects [18], however use is restricted to patients who have eGFR of ≥30 ml/min per 1.73 m². The active metabolite of sofosbuvir is eliminated by the kidneys and levels of sofosbuvir are substantially higher in patients with severe renal impairment [19]. Premarket testing has raised concerns for cardiovascular and hepatobiliary toxicity at higher levels of sofosbuvir dosing, but toxicity of the drug and metabolites in humans remains unknown [20]. Daclatasvir has been recommended for treatment of patients with severe renal disease, as its components are metabolized mainly by the liver. Currently, little data on the treatment of HCV in hemodialysis patients with DAAs (sofosbuvir based regimens) are available [21]. Therefore, this study was intended to assess the efficacy and tolerability of sofosbuvir based regimen in treatment of HCV in hemodialysis patients.

This study comprised of a total of 36 patients divided into 2 equal groups depending upon the treatment. Three (n = 3) patients in group 1, while one (n = 1) patient in group 2 left treatment due to non-compliance and rash respectively. Baseline characteristics of included patients are shown in Table 1.

After treatment all patients had significant reductions in AST and ALT values in group 1 & 2 respectively. AST & ALT values in group 1 at baseline were 57.06 ± 48.71 U/L & 50.89 ± 44.08 U/L respectively, and reduced to 20.17 ± 7.70 U/L & 20.78 ± 10.81 U/L at week 24. In group 2, baseline AST & ALT values were 34.5 ± 25.27 U/L & 40.5 ± 34.85 and at 24 week were 21.61 ± 8.23 U/L & 22.28 ± 11.92 U/L (Table 2). Three patients in group 1 had AST & ALT level greater than 100 U/L each. No significant difference was observed in complete blood indices from baseline to 24th week in both groups 1 & 2 respectively except hemoglobin level in group 2 patients (Table 2).

As per ITT analysis Rapid Virological Response; RVR (Undetectable HCV-RNA after 4 weeks of therapy) was achieved in 14/18 patients (77.7%) in group 1 compared to 15/18 patients (83.3%) in group 2. End of Treatment response; ETR (undetectable HCV-RNA at completion of therapy) was achieved in 15/18 patients in group 1 (83.3%) and 17/18 patients in  group 2 (94.4%) respectively. SVR (undetectable HCV-RNA 12 weeks after end of treatment) was achieved in 15/18 patients (83.3%) in group 1 compared to 14/18 patients (77.7%) in group 2 (Table 3).

As per PP population, RVR was achieved in 14/15 patients (93.4%) in group 1 compared to 15/17 patients (88.3%) in group 2. ETR was achieved in all patients in group 1 (15/15; 100%) and group 2 (17/17; 100%) respectively. SVR was achieved in 15/15 patients (100%) in group 1 compared to 14/17 patients (82.35%) in group 2 (Table 4, Figs. 2 and 3). One patient with cirrhosis in group 2 did not achieve RVR but all cirrhotic patients in both groups achieved ETR and SVR. Three patients in group 2 who did not achieved SVR were all infected by genotype 1 and two of them had previously received treatment with interferon (Table 5).

As per published data, HCV is endemic in Pakistan and around 6.8% of Pakistani population might be infected with HCV which is almost a 40% increase in HCV sero-prevalence in recent years [22]. It appears that SOF based regimens are currently the choice to treat hepatitis-C and once-daily oral sofosbuvir plus daclatasvir is associated with high rates of SVR among patients infected with HCV genotype 1, 2, or 3 [11]. Patients who have advanced CKD are less likely to receive treatment for HCV despite of safety and efficacy data [23]. There are various published studies that report the efficacy & safety of DAAs in Hepatitis-C patients with advanced chronic kidney disease in Japan; daclatasvir & asunaprevir in genotype 1 patients [24], glecaprevir & pibrentasvir combination in genotype 1, 2 & 3 patients [25], ombitasvir, paritaprevir & ritonavir in genotype 1 b dialysis patients [26]. Certain newer DAAs as mentioned earlier are not yet available in Pakistan that could be safely used in patients with advanced CKD [22]. So considering the situation, this study is by far the largest from Pakistan reporting that SOF based therapy can be safely and effectively used to treat HCV in patients undergoing MHD.

In recently published meta-analysis using DAAs in MHD, the SVR in all these studies ranged from 66.7 to 98.3% but in a subgroup with SOF-based therapy, SVR was 89.4% [27]. This is consistent with our study results showing overall SVR of 80.55% in intention to treat population and SVR of 90.62% in per-protocol population. In one of the meta-analysis nineteen patients in 2 studies were treated with half dose of SOF and 4 of them failed to achieve SVR. Similarly, in our study, all patients who did not achieve SVR were from the group in which 3 times per week SOF was used (SVR; 77.7% in ITT population & SVR; 82.3% in PP population) indicating the dose to be an important variable to achieve SVR. In most studies SOF was well tolerated like in our study, where only one patient left the study due to rash which improved after DAAs were stopped. In the meta-analysis, genotype 1 was the most common, unlike in our study where genotype 3 was most prevalent. In our study cohort, we had 12 patients (33.3%) with genotype 1, 01 patient (2.7%) with genotype 2 and 23 patients (63.8%) with genotype 3, which remains to be the most prevalent genotype in Pakistan [22].

In a recent study from India [28], that included treatment-naïve haemodialysis, HCV infected patients. Most patients had genotype 1 (64.5%), followed by genotype 3(29%). Patients were treated with different frequency of drug usage, like daily SOF/Ribavirin, every other day SOF /ribavirin, daily SOF/daclatasvir and every other day SOF/daclatasvir for 12 weeks. 95.2% achieved SVR. There was no impact of genotype on SVR. Treatment with daily daclatasvir and daily sofosbuvir yielded a 93.3% (14/15) SVR, compared to 100% (6/6) SVR with daily daclatasvir and alternate day sofosbuvir. Our study reported a 100% SVR in daily SOF/daclatasvir group and 82.35% in thrice weeklySOF/daclatasvir group. The characteristics of group 2 patients who achieved ETR but not SVR12 are shown in Table 2.

In our study population most common genotype was 3 (63.8% of study population) and all patients with genotype 3 achieved SVR with either daily sofosbuvir or thrice/ week Sofosbuvir based regimen. This is also comparable to Agarwal et al. study [28] in which 29% of hemodialysis patients treated for hepatitis-C had genotype 3 and overall 95.9% of patients had achieved SVR.

In one prospective study [29], two dosing regimen were compared. One group received daily sofosbuvir (N = 7) and other group received three times a week sofosbuvir (N = 5) along with simeprevir, daclastavir, ledipavir or ribavirin. Both groups showed higher SOF-007 plasma concentrations. Sofosbuvir or its inactive metabolite was not accumulated with either regimen, irrespective of hemodialysis sessions or treatment course. Study participants experience no serious adverse event. SVR was achieved in 10 out of 12 patients (83%). Two relapses occurred with 3 times a week regimen and none with the daily regimen. In our study overall SVR was 90.62% and all 3 relapses occurred only in thrice weekly regimen.

Gane et al. [30] presented results of 10 patients with severe renal impairment (9 infected with HCV genotype 1, and one with genotype 3) receiving 200 mg daily sofosbuvir, combined with 200 mg daily RBV. Although, the dose was safe, the regimen was not efficacious and resulted in an SVR of only 40%.This regimen resulted in 6 relapses in HCV genotype 1 infected patients who had previously achieved SVR. This emphasizes the fact that full dose of SOF is an important variable to achieve SVR.

Similarly, Bhamidimarri et al. [31] evaluated 2 different schedules in 15 patients with severe renal impairment (n = 3) or requiring hemodialysis (n = 12). Eleven patients received sofosbuvir, 200 mg daily, and 4 patients received sofosbuvir 400 mg three times weekly, all with simeprevir at a standard dose. Results demonstrated an overall SVR of 87% with no major toxicity observed in either group. Two relapses occurred, one in each group.

Our study like few others have shown that even in patients with ESRD on MHD who usually have eGFR of less than 10 ml/min/1.73m², SOF based regimen are not only effective but tolerable as well. Given higher SVR with daily SOF based regimen at full dosages, this approach appears preferred in this patient population. Further studies on a larger scale are pivotal especially in developing countries where there is higher prevalence of HCV in MHD patients.

Hepatitis C virus infection is endemic in Pakistan like some other developing courtiers and its burden is expected to increase in patients with hemodialysis in coming years owing mainly to widespread use of unsafe medical procedures. Daily Full dose sofosbuvir in combination with daclatasvir is very effective and appears tolerable in ESRD patients with genotype 1 & 3 undergoing maintenance hemodialysis. Decreasing the dose or frequency of SOF may lead to decreased SVR or higher relapses. Larger scale studies are warranted since sofosbuvir is backbone of direct acting antivirals in developing world not only because of its efficacy but due to its low cost as well.