**3. Results**

A total of 236 patients with liver cirrhosis infected with GT3 with mean age 52.3 ± 11.3 years and male predominance (72%) treated with pangenotypic regimens were included in the analysis. One hundred and seven (45%) were assigned to GLE/PIB, whereas the remaining 129 patients received SOF/VEL including 58 on the regimen with RBV. The choice of the therapeutic option was made by treating physicians in line with guidelines of the Polish Group of Experts for HCV and the recommendations of the National Health Fund, taking into consideration patients' characteristics and drug labels.

No significant differences in demographic variables, as well as rates of comorbidities and concomitant medications, were observed between patients treated with two pangenotypic regimens (Table 1).

**Table 1.** Baseline characteristics of GT3 HCV infected patients with liver cirrhosis treated with pangenotypic regimens.


HCV, hepatitis C virus; GLE, glecaprevir; PIB, pibrentasvir; SOF, sofosbuvir; VEL, velpatasvir; RBV, ribavirin; SD, standard deviation; BMI, body mass index; ALT, alanine transaminase; HCV RNA, ribonucleic acid of hepatitis C virus.

Significantly higher bilirubin concentration, lower albumin level, and platelet count were found among patients treated with SOF/VEL + RBV. In addition, in this subpopulation, a significantly higher percentage of those with past and present hepatic decompensation were observed, and a higher rate of individuals in category B of the Child-Pugh scale (Table 2).

**Table 2.** Characteristics of the liver disease in GT3 HCV infected patients with liver cirrhosis treated with pangenotypic regimens.


HCV, hepatitis C virus; GLE, glecaprevir; PIB, pibrentasvir; SOF, sofosbuvir; VEL, velpatasvir; RBV, ribavirin; hepatocellular carcinoma; OLTx, orthotopic liver transplantation; MELD, Model End-Stage Liver Disease; HBV, hepatitis B virus; HBsAg+, hepatitis B surface antigen; HIV, human immunodeficiency virus.

> The significantly lower percentage of patients treated with SOF/VEL+RBV were treatment-naïve as compared to SOF/VEL and GLE/PIB regimens, 55.2%, 77.5%, and 77.6%, respectively. The relapse rate was the highest among those assigned to SOF/VEL + RBV option, and SOF + RBV was the most frequently used previous regimen in all subpopulations. A total of 30 patients were nonresponders to previous DAA-containing therapy without IFN, and eight of them were treated in the past with NS5A inhibitors. Six of those who previously failed NS5A-containing regimens were treated with SOF/VEL + RBV; the remaining two patients received GLE/PIB in re-therapy.

> The majority of patients on the GLE/PIB option received a 12-weeks regimen (60.7%); more than half (55%) of those assigned to SOF/VEL therapy were treated for 12 weeks without RBV (Table 3).

> A total of 211 patients achieved an SVR corresponding to 89.4% in the ITT analysis, and after exclusion of four patients lost to follow-up, 91% in the PP analysis. The SVR rate was significantly higher among patients treated with GLE/PIB compared to those receiving SOF/VEL ± RBV both in ITT and PP analyses, 94.4% vs. 85.3% (*p* = 0.03), and 96.2% vs. 86.6%, (*p* = 0.01), respectively (Figure 1).



HCV, hepatitis C virus; GLE, glecaprevir; PIB, pibrentasvir; SOF, sofosbuvir; VEL, velpatasvir; RBV, ribavirin; PegIFN<sup>α</sup>, pegylated interferon alpha; LDV, ledipasvir. \* IFNα + RBV, Uprifosbuvir + Grazoprevir + Elbasvir/Ruzasvir.

**Figure 1.** The comparison of the SVR rates between GT3 HCV infected patients with liver cirrhosis treated with GLE/PIB and SOF/VEL ± RBV regimens.

The detailed comparison of an SVR rates revealed no significant difference between GLE/PIB and SOF/VEL regimens, whereas cirrhotics on SOV/VEL + RBV option had significantly lower SVR as compared to both remaining options, 77.6% vs. 91.5% (*p* = 0.04), vs. 94.4% (*p* = 0.002), and 78.9% vs. 92.9% (*p* = 0.003), vs. 96.2% (*p* = 0.001), in ITT and PP analysis, respectively (Figure 2).

**Figure 2.** The effectiveness of the GLE/PIB, SOF/VEL, and SOF/VEL + RBV options in GT3 infected patients with liver cirrhosis.

A total of twenty-three virologic failures were documented, 6 on GLE/PIB and 17 on SOF/VEL ± RBV regimen (Tables 4 and 5).


**Table 4.** Characteristics of 6 virologic failures to GLE/PIB regimen.

GLE, glecaprevir; PIB, pibrentasvir; CP, Child-Pugh scale; HCV RNA, ribonucleic acid of hepatitis C virus; EOT, end of treatment; TD, target detected; TND, target not detected; SOF, sofosbuvir; RBV, ribavirin; DAA, direct-acting antivirals.

> All of them were scored as category A on the CP scale; one experienced RBV dose reduction, and another one discontinued therapy by his own decision. Twenty-one of them were males, and nine were nonresponders to previous DAA-containing therapy, of whom two were treated in the past with pegylated IFN alpha (pegIFNα) + RBV + SOF, 4 received SOF + RBV, two another with GLE/PIB and one patient as a participant of the clinical trial did not respond to uprifosbuvir + grazoprevir + elbasvir/ruzasvir.

> A significantly higher rate of males (91.3% vs. 69.4%, *p* = 0.03) was documented in GT3-infected nonresponders to pangenotypic regimens than those who achieved an SVR (Table 6).

> The univariate analysis demonstrated the significantly lower SVR in males, in patients with baseline HCV RNA ≥ 1,000,000 IU/mL compared to <1,000,000 IU/mL, and among those who failed previous DAA-based therapy (Table 7).

> The multivariate logistic regression analysis recognized the male gender and presence of ascites at baseline as the independent factors of non-response to pangenotypic treatment (Table 8).


**Table 5.** Characteristics of 17 virologic failures to SOF/VEL ± RBV regimen.

SOF, sofosbuvir; VEL, velpatasvir; RBV, ribavirin; CP, Child-Pugh scale; HCV RNA, ribonucleic acid of hepatitis C virus; EOT, end of treatment; TD, target detected; TND, target not detected; DAA, direct-acting antivirals; PR, PegIFNα + RBV; GLE, glecaprevir; PIB, pibrentasvir.

**Table 6.** Virologic nonresponders vs. responders to pangenotypic regimens.


BMI, body mass index; SD, standard deviation; HBV, hepatitis B virus; HBsAg+, hepatitis B surface antigen; HIV, human immunodeficiency virus; HCC, hepatocellular carcinoma; IFN, interferon; DAA, direct-acting antivirals; ALT, alanine transaminase; HCV RNA, ribonucleic acid of hepatitis C virus.


**Table 7.** Treatment effectiveness in subpopulations.

SVR, sustained virologic response; ITT, intent to treat; PP, per protocol; HCV RNA, ribonucleic acid of hepatitis C virus; IFN, interferon; DAA, direct-acting antivirals; SOF, sofosbuvir; BMI, body mass index; The bold represent the same level as gender.

> **Table 8.** Baseline factors associated with SVR based on the logistic regression model.


HCV RNA, ribonucleic acid of hepatitis C virus.

The majority of patients completed the treatment course according to schedule, 98.2% in GLE/PIB and 93% in SOF/VEL ± RBV, 6.2% of patients receiving RBV experienced dose modification, three patients discontinued treatment, two due to adverse events (AE), and one by his own decision. A similar proportion of patients in both subpopulations reported at least one AE, with the most common pruritus/skin changes in the course of GLE/PIB treatment and weakness/fatigue during SOF/VEL ± RBV therapy (Table 9).

**Table 9.** Safety of GLE/PIB and SOF/VEL ± RBV in GT3 infected patients with liver cirrhosis.



**Table 9.** *Cont.*

\* patient's decision; \*\* hepatic decompensation, HCC, pneumonia; \*\*\* worsening of depression, exacerbation of heart failure; GLE, glecaprevir; PIB, pibrentasvir; SOF, sofosbuvir; VEL, velpatasvir; RBV, ribavirin; AE, adverse event.

> Three serious AE in patients treated with SOF/VEL + RBV, but not related to this regimen, were documented. In addition, seven AEs of particular interest related to the deterioration of the liver function were reported, including ascites in 4 patients, gastrointestinal bleeding in 2 individuals, and hepatic encephalopathy in one person.
