In this retrospective observational study, we analyzed data from chronic hepatitis C patients who were treated in six centers in the South of Brazil, located in five different cities of the State of Paraná: Curitiba, Londrina, Cascavel, Ponta Grossa, and Maringá. The study was carried out in accordance with the ethical principles of the Declaration of Helsinki and was approved by the local Ethics Committee on Human Research.

Data were collected from databases from each center, which contain all the individual patient records. The sample comprised adult patients (≥18 years) diagnosed with chronic HCV infection who concluded or discontinued any second generation DAA treatment before April 2017. Patients were included regardless of genotype, prior treatment, or liver fibrosis stage. The choice, administration, and management of each patient's treatment was the responsibility of the centers, according to the national guidelines.4

The primary effectiveness outcome was SVR 12 weeks or more after the end of treatment (SVR12), which is defined as undetectable HCV by polymerase chain reaction (PCR). Secondary effectiveness outcomes included rapid virological response (RVR; defined as undetectable HCV RNA after four weeks of therapy) and end of treatment response (EOTr; defined as undetectable HCV RNA at treatment completion), both measured using PCR tests. Patients that completed therapy but did not have any SVR results (i.e., missing data or lost to follow up) were excluded from the analysis.

Clinical information collected at baseline included age, sex, weight, presence/absence of cirrhosis, prior treatment information, HCV genotype, viral load, liver biopsy information, intended treatment, comorbidities (hepatitis B, HIV), other clinical information (prior transplantation or hepatocarcinoma), and treatment discontinuation due to adverse events (tolerability outcome).

Baseline categorical variables are described as absolute and relative frequencies, while continuous variables are reported as medians and standard deviations. Analysis was carried out using the chi-square test and logistic regression to identify variables significantly associated with SVR (e.g., baseline parameters: treatment option, duration, sex, age, cirrhosis, prior treatment, and others). Bivariate logistic regression results are presented as odds ratios (OR) and their 95% confidence intervals (CI). A p-value less than 0.05 was considered statistically significant in all cases. Analysis was performed using SPSS Statistics version 24 (IBM SPSS, Chicago, IL, USA) and StatSoft Statistica version 10.

In the six centers, 363 patients were retrieved for this observational study, although 61 were excluded due to lost follow-up and another six due to missing data (e.g., no treatment information). Data from 296 patients were used for per protocol analysis. The mean age of the participants was 57.8±10.8 years and 56% of the sample were males. In terms of treatment, 59% of patients were treated with sofosbuvir plus daclatasvir, 26% received sofosbuvir plus simeprevir, and 15% received other DAA therapy options. In total, 34% of patients received ribavirin together with the DAA treatment. Genotypes 1 (GT1; 66%) and 3 (GT3; 27%) were the most frequent genotypes observed, and 48% of the patients were treatment experienced. Baseline characteristics of patients that received the two most prevalent treatments (n=255), sofosbuvir with daclatasvir, and sofosbuvir with simeprevir, are shown in Table 1.

SVR was achieved by 160 patients (90%) of the 176 patients who were treated with sofosbuvir and daclatasvir (Fig. 1A and Table 2). This treatment was recommended for patients with GT 1 and 3; GT3 had lower SVR rates compared to patients infected with GT1 (95% versus 84%, p<0.05). All GT3 patients treated for 24 weeks achieved treatment response, compared to only 85% of GT3 patients treated for 12 weeks achieved SVR (although in this case p>0.05, more details in Supplementary Material 1). However, there was no statistically significant difference (p>0.05) in SVR rates in any of the other sub-analysis, including the use of sofosbuvir and daclatasvir with or without ribavirin (94% versus 88%), presence or absence of cirrhosis (92% versus 89%), prior treatment (95% versus 86%, respectively for treatment naïve and experienced patients), and treatment duration (95% versus 89%, respectively for 24 and 12 weeks of treatment).

Fig. 1.

Sustained virological response rates (SVR) for treatment with (A) sofosbuvir and daclatasvir; and (B) sofosbuvir and simeprevir: overall results, and rates according to clinical characteristics. Abbreviations: GT, genotype; RBV, ribavirin.

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RVR was obtained by 74 of 78 patients (94%), while EOTr was achieved by 90% (64 of 71). More detail regarding secondary outcomes is available in Supplementary Material 3.

Of the 79 patients that received sofosbuvir with simeprevir, 73 (92%) achieved SVR (Fig. 1B and Table 2). This DAA combination was only administered to HCV GT 1 patients; SVR rate was 94% for subtype 1a, 90% for subtype 1b, and 87% for unspecified GT 1 subtype. Other sub-analysis included prior treatment (97% versus 85% for treatment naïve and experienced patients). Use or non-use of ribavirin (87% versus 94%), and presence or absence of cirrhosis (90% versus 93%). There were no statistically significant differences (p>0.05), except for treatment duration (93% versus 50%, respectively for 12 and 24 weeks of treatment); however, this finding should be interpreted with caution as only two patients received treatment for 24 weeks.

RVR was achieved by 42 of 47 patients (89%), while EOTr was obtained by 100% of the patients where data was available (19 of 19). More detail regarding secondary outcomes is available in Supplementary Material 3.

Overall SVR rates were similar for both treatments (Table 2). For GT 1, sofosbuvir with daclatasvir had an SVR rate of 95%, compared to 92% for sofosbuvir with simeprevir (p>0.05), however, for GT 1b, sofosbuvir with daclatasvir was more effective (p<0.05). No statistically significant differences between therapies were observed in terms of prior treatment, cirrhosis (Supplementary Material 2 presents more details about SVR regarding genotype and presence/absence of cirrhosis), or additional use of ribavirin. Further, the sub-analyses did not produce statistically significant results (p>0.05 in all analysis). Treatment in patients receiving therapy for 24 weeks was more effective in those who received sofosbuvir with daclatasvir; however, as only two patients received sofosbuvir with simeprevir for 24 weeks, this result should again be interpreted with caution.

In total, 41 patients were treated with different DAAs from those previously described; 18 received daclatasvir with simeprevir, 12 received sofosbuvir with ribavirin, two were treated with pegylated interferon with sofosbuvir and ribavirin, eight were treated with ledipasvir with sofosbuvir, and one received pegylated interferon with daclatasvir and ribavirin. Three of these patients did not achieve SVR (one treated with daclatasvir and simeprevir, and two with sofosbuvir with ribavirin). Baseline data and results for these patients are detailed in Table 3.

Bivariate logistic regression was used to assess the influence of several baseline parameters on treatment response (Fig. 2). Sex, age, cirrhosis, prior treatment, treatment duration, use of ribavirin, baseline viral load, and therapy choice were not associated with treatment success (p>0.05). The only two statistically significant predictors of treatment response (both p<0.05) were genotype 1 compared with genotype 3 (OR 0.41 [CI 0.17–0.98]) and RVR response (OR 0.16 [CI 0.03–0.72]).

Fig. 2.

Predictors of sustained virological response (SVR). Abbreviations: DAC, daclatasvir; GT, genotype; RBV, ribavirin; RVR, rapid virological response. SOF, sofosbuvir; SMV, simeprevir; w, weeks.

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Regarding tolerability, only three patients (1%) discontinued treatment due to adverse events, but all achieved SVR. The first was treated with pegylated interferon with sofosbuvir and ribavirin, and discontinued treatment due to epigastralgia. The second received sofosbuvir with daclatasvir, and suspended treatment due to gastric hemorrhage. The third also received sofosbuvir with daclatasvir but the reason for treatment discontinuation was not described.