Effectiveness, tolerability and safety of Direct Acting Antivirals in Mexican individuals with Hepatitis C virus genotype-1 and previous pegylated interferon and ribavirin therapy

Introduction

In 2015, the World Health Organization (WHO) estimated 1.75 million new hepatitis C virus (HCV) infections and that 71 million people in the world were living with chronic hepatitis C (CHC). Approximately 400,000 people died from CHC related liver diseases mainly cirrhosis and hepatocellular carcinoma (HCC) in that year (World Health Organization, 2017).

For nearly a decade, the first-line therapy against CHC was pegylated interferon alpha (pegIFNα) with ribavirin (RBV), but sustained virological response (SVR) was observed only in 40–50% of patients infected with viral genotype 1 and in 70% of those with genotypes 2 or 3 (Hofmann et al., 2015). In the last five years, the direct-acting antiviral agents (DAAs), have revolutionized CHC treatment (Elbaz, El-Kassas & Esmat, 2015). The first generation DAAs (boceprevir and telaprevir) were serine protease inhibitors used in triple combination with interferon and RBV that had low tolerability (Watanabe et al., 2016). New DAA combinations without interferon (i.e., sofosbuvir, simeprevir and ombitasvir), that target several viral-cycle proteins, like NS3/4A (protease), NS5A and NS5B (RNA polymerase), were introduced in 2013–2014 and show enhanced efficacy and tolerability. These second generation DAAs, have increased SVR rates to over 90% and effectively treat all HCV genotypes (Gotte & Feld, 2016) even in patients with advanced cirrhosis (Mizokami et al., 2015), making them efficient curative therapies. However, access to DAAs varies greatly among countries. According to WHO, only around half of patients with CHC that started treatment in 2015 received DAAs, and they concentrated in high income countries (World Health Organization, 2017). Thus, data on real-world safety and effectiveness of DAA regimens are still emerging for the middle- and low-income countries that harbor most of the CHC patients. There is limited data on real-world DAA treatments administered through public health systems in Latin America (LA), which are crucial in the efforts to eradicate HCV. Delivering DAA treatments to patients in need is now a main challenge worldwide. The high costs of DAA regimens are restrictive even for patients in high-income countries. This results in a portion of patients being treated only after liver fibrosis/cirrhosis have emerged, and highlights the need to understand the effects of DAAs on liver fibrosis and inflammation.

In Mexico the most frequent HCV genotype is 1. Treatment for this genotype with pegIFNα+RBV has a low SVR rate of around 38% (Sandoval-Ramirez et al., 2015), while the SVR with DAAs has not been reported in this country and few reports exist for LA (Cheinquer et al., 2017). Large public health systems such as the Mexican Institute of Social Security (IMSS) that currently tends to ≈60% of the Mexican population (Instituto Mexicano del Seguro Social, 2018), introduced DAA regimens in 2017, initially treating patients who received and did not respond to pegIFNα2a+RBV. We studied Mexican adults with CHC that were treated with pegIFNα2a+RBV between 2005 and 2014. The non-responders from that cohort were among the first treated with DAAs in a real-world, public health setting in Mexico between 2017 and 2019 and their results are reported here.

Materials & Methods

Results

Discussion

SVR is attained only in about half of CHC patients treated with pegIFNα+RBV but in over 90% of those treated with DAAs. Widespread access to DAAs was initially delayed by drug costs and accessibility, especially in some world regions that harbor most of the CHC patients (World Health Organization, 2017). The switch to the new treatments in those regions has been slow and relies importantly on public health systems. Mexico and Brazil are the countries in Latin America with the highest rates of cirrhosis, related to alcoholism and CHC (Mendez-Sanchez et al., 2018). Mexican public health institutions, such as IMSS, included DAAs in their list of essential medicines in June 2017, initially treating patients who had failed pegIFNα2a+RBV. This is the first report of the outcome of a Mexican cohort treated this way and followed long-term.

We found 36% SVR with the initial pegIFNα2a+RBV regimen (Table 2), similar to previous reports in Mexico of 32.5% (Sandoval-Ramirez et al., 2015). Fifty one percent of the non-cirrhotic patients, and 68% of those with low baseline viral load achieved SVR with pegIFNα2a+RBV (Table 3), similar to other publications (Enomoto & Nishiguchi, 2015; Naing et al., 2015). Diabetes did not associate with failure of pegIFNα2a+RBV treatment: 34.2% of diabetic patients achieved SVR (Table 3), similar to SVR of all the cohort. The original cohort included equivalent amounts of patients with HCV subtypes 1a and 1b (Table 1), which had similar SVR rates with pegIFNα2a+RBV (Table 2).

Not all patients that displayed some initial response to pegIFNα2a+RBV (RVR, cEVR or pEVR) achieved SVR: 14.6% (38/261) relapsed (Table S1), comparable to previous reports of 16% and 14.4% relapse (15,17). Thus, RVR, cEVR, pEVR were not predictors of SVR or relapse with pegIFNα2a+RBV (Table 3). The low SVR rate with this treatment was likely associated to the high frequency of cirrhosis and the high viral load present in our initial cohort (Table 1). This was expected, as virus elimination is difficult with pegIFNα2a+RBV when the viral load is high, in particular for genotype 1 (Enomoto & Nishiguchi, 2015).

Of the 167 non-responder patients to pegIFNα2a+RBV, only 83 returned for DAA treatment and all of them concluded therapy with either OBV/PTV/r/DSV ± RBV or SOF/LDV ± RBV. DAA treatment happened on average 7 years after pegIFNα2a+RBV treatment, thus the sub-cohort with DAA treatment was older (56.2 vs 49.5 years), had a higher cirrhosis rate (60% vs 29%) and a lower basal average viral load, when they received DAAs than at pegIFNα2a+RBV treatment.

Women were 74.6% of the patients treated with DAAs, which is a high percentage compared to other DAA real-world studies that report 35% (Perello et al., 2017), 45% (Flisiak et al., 2016) 54% (Mendizabal et al., 2017), and 44.4% (Holzmann et al., 2018) females (the last two in Latin America). The high proportion of women in our cohort likely reflects that in Mexico an important risk factor for CHC is the history of blood transfusion prior to 1995 (Lopez-Colombo et al., 2014) likely during obstetric or gynecological procedures. Females had a higher mean age than men in our DAA sub-cohort (Table 4).

SVR in the group treated with OBV/PTV/r/DSV ± RBV was 94.8%, similar to other studies that have reported 96% (Welzel et al., 2017), 99% (MALACHITE II trial) (Dore et al., 2016), and 98.7% (AMBER study) (Flisiak et al., 2016), in patients with previous treatment; or 96.8% (Mendizabal et al., 2017) and 96.2% (Perello et al., 2017) including both treatment-naïve and previously treated patients respectively. Two patients presented failure to OBV/PTV/r/DSV ± RBV, that did not associate with any of the studied factors (Table S2), similar to previous reports (Flisiak et al., 2016). However non-responders were 2/10 men in contrast to 0/29 women, and 2/21 patients without cirrhosis, in contrast to 0/18 patients with cirrhosis (Table S2).

SVR in the group treated with SOF/LDV ± RBV was 100%, similar to two multicenter studies that have reported 95.8%, and 92.5 to 100%, respectively (Calleja et al., 2017; Terrault et al., 2016) in patients with previous treatment; 99% in cirrhotic patients with viral subtype 1b (Ogawa et al., 2017), and a meta-analysis reported ≥ 95% (Rezaee-Zavareh et al., 2017). Our SOF/LDV ± RBV group had 72.7% of cirrhotic patients and viral subtype 1a predominated over 1b (Table 2). Male gender (Ogawa et al., 2017), basal albumin <3.5 g/dL, and basal total bilirubin >2.0 mg/dL have been associated with failure to SOF/LDV ± RBV treatment (Calleja et al., 2017; Terrault et al., 2016). In contrast, in our study 75% of patients with SOF/LDV ± RBV were women; 47.8% had basal albumin >3.5 g/dL and 68% had basal total bilirubin <2.0 mg/dL, likely favoring SVR (Table 4).

Biochemical improvement was observed after both DAA treatments, particularly 10% increase in albumin levels, up to 3-fold decrease in ALT and AST levels, and no decrease in hemoglobin despite 79% of patients with SOF/LDV receiving RBV. In agreement with lack of change in hemoglobin, indirect bilirubin did not increase with DAAs either (Table 6). An AFP concentration above 10 ng/mL was found in 28.9% of patients pretreatment and the concentrations decreased by 50% after DAA treatment (Table 5). Only one patient (4.16%) showed an increase in AFP levels after treatment, in contrast to 22.9% found in another study (Fouad et al., 2019). Biochemical improvement translated into better CPS: 12 cirrhotic patients improved the CPS post-DAAs (Table 5). Other studies report changes in CPS at 36 weeks (El-Sherif et al., 2018), and at 6 months (Essa et al., 2019) post DAAs.

Ninety eight percent of our patients eradicated HCV after 12 weeks of treatment, but we detected residual HCV RNA at treatment end (12 weeks), in 8 patients that became undetectable in the following months (Table S2), A study reported that normalization of albumin, AST, and ALT levels after DAA treatment is associated with the restoration of immune activity (Kostadinova et al., 2018), suggesting that the immune response may clear the residual virus in the following weeks.

Still, not all patients showed biochemical improvement. For example, elevated ALT persisted post-treatment in 8 (9.8%) of patients, corresponding to patients with cirrhosis. This suggests the persistence of chronic liver inflammation despite SVR with DAAs in some cirrhotic patients, as has been observed (Enomoto et al., 2018).

The serological fibrosis markers FIB-4 and APRI showed a significant decrease after DAA treatment (p <  0.05) (Table 5). However, their values suggest that cirrhosis and liver fibrosis were not eliminated by DAA treatments (Table 5). A recent study with non-cirrhotic patients reported that APRI and FIB-4 rates decrease rapidly and steadily from week 2 to week 12 post-DAA treatment (Hsu et al., 2019). Another study reported a decrease in transient elastography 18 months after treatment, but the authors discuss that it remains to be examined whether this indicates a true regression of fibrosis or simply the resolution of chronic liver inflammation (Bachofner et al., 2017). A study with liver biopsies of patients that reached SVR, reported a decrease in the Knodell inflammatory score, and did not observe short-term improvement in fibrosis post-DAA treatment (41 ± 20 weeks after treatment end) (Enomoto et al., 2018). Thus, our observation on FIB-4 and APRI decrease wit treatment, could be due more to an improvement in chronic liver inflammation, which is supported by the significant decrease in liver transaminases (Table 5).

The biochemical and hepatic-fibrosis characterization of patients treated with DAAs, is instrumental to understand details beyond SVR, in particular related to liver inflammation and its contribution to long-term outcomes, like HCC. Several studies report that patients with cirrhosis remain at risk of HCC despite SVR, irrespective of the treatment (even with DAAs) (Chinchilla-Lopez et al., 2017; Waziry et al., 2017). In contrast, in patients without cirrhosis, a decrease in liver inflammation reduces the risk of cirrhosis and HCC (Hsu et al., 2019). This suggests that the best window for DAA treatment is before the onset of cirrhosis.

Conclusions

DAA treatment showed good tolerability and safety, as well as excellent SVR rates in Mexican patients who had been unsuccessfully treated with pegIFNα2a+RBV several years earlier. Child-Pugh-Score improved in some patients with cirrhosis. Treatment with DAA did not correct cirrhosis, but FIB-4 and APRI suggest a reduction in chronic liver inflammation.

Supplemental Information