Efficacy of Generic Oral Directly Acting Agents in Patients With Hepatitis C Virus Infection

S. Gupta; G. Rout; A. H. Patel; M. Mahanta; N. Kalra; P. Sahu; R. Sethia; A. Agarwal; G. Ranjan; S. Kedia; S. K. Acharya; B. Nayak; Shalimar


J Viral Hepat. 2018;25(7):771-778. 

In This Article


In this study, we observed an overall SVR12 of 95.9%; with higher rates in treatment–naïve patients as compared to those who were treatment–experienced. This study includes a large number of patients who received generic DAA treatment for HCV genotype 3 infection, which is highly prevalent in India. A paradigm shift from interferon–based therapies to interferon–free regimens has occurred in the management of HCV due to the introduction of oral DAAs. Recent guidelines advocate treatment with oral DAAs for all HCV patients who have no contraindications.[2,3] Moreover, the World Health Organization recently launched a drive to eliminate viral hepatitis by 2030.[13] Hepatitis C eradication can be best achieved globally by treatment with DAAs; however, the major barrier continues to remain the cost of treatment. The cost of treatment largely depends on the region of treatment and the availability of brand–name patented drugs; branded drugs are generally expensive.[14] Several generic low–cost drugs of these DAAs are now available in developing countries. The introduction of low–cost generic brands—including sofosbuvir, ledipasvir and daclatasvir—has led to a reduction in the overall cost of therapy to as little as $300 USD for a 12–week course of therapy.

Irrespective of underlying cirrhosis, SVR12 was very high in treatment–naïve patients, while rates of SVR12 in treatment–experienced patients were lower. We previously reported an SVR (24 weeks) rate of 64% in patients treated with peginterferon and ribavirin in combination.[15] In this present study, overall SVR12 was 95.9% (470/490), which is similar to those reported previously from other studies performed in the Indian subcontinent.[16–18] Prior multicenter studies evaluating the efficacy of branded DAA have reported similar high SVR12 rates.[5–7,19] Our study supports the fact that generic DAAs are associated with high efficacy.

A recent review on efficacy and safety of oral DAA reported an overall SVR12 of 92% in cirrhosis patients treated with sofosbuvir/ledipasvir combination therapy.[20] Other real–life observational studies have reported an SVR12 between 94% and 98% in treatment–naïve genotype 1 patients treated with combination of sofosbuvir and ledipasvir;[21,22] including a study by Zeng et al, wherein naïve genotype 1 patients were treated with a combination of generic sofosbuvir and ledipasvir, SVR12 among cirrhotic and noncirrhotic patients was 96.8% and 96.9%, respectively. The overall SVR12 in our study in genotype 1 (90.3%) was lower than that reported from other studies. This may have been due, in part, to small sample size in this subgroup and classification of patients who were lost to follow–up as treatment failures. After excluding such patients, our SVR12 rates were similar to those reported in other studies.

A study from Spain reported an overall SVR12 of 93.8% in genotype 3 patients treated with sofosbuvir and daclatasvir combination therapy.[23] Another study in Asian American patients with CHC and advanced liver disease (genotypes 1, 2, 3 and 6), treated with multiple oral DAA combinations, reported a similar overall SVR.[24] The SVR12 in CHC patients treated with sofosbuvir plus daclatasvir and ribavirin was lower than that of other combinations, possibly due to a small sample size of eight patients in this subgroup. The SVR12 in compensated cirrhosis and decompensated cirrhosis in our study was similar to that reported in previous studies.[25]

We used various oral DAA drug combinations, as per the AASLD HCV management guidelines.[3] Our data reinforce that the drug regimens recommended by AASLD are associated with high SVR. Prior treatment exposure was the only factor associated with virological failure, corroborating a previous study that involved genotype 4 patients and showed that male gender and prior treatment–experience (with peginterferon) were predictors of nonresponse.[26]

Our patients did not develop any major complications requiring stoppage of therapy. Anaemia developed in 10% of the patients and was secondary to ribavirin therapy. Prior studies have reported minor side effects with oral DAAs, most of which are not significant and do not mandate cessation of therapy.[10] These observations provide reassurance that generic DAAs are associated with a similar safety profile as the branded DAAs. To provide cost–conscious care, HCV patients can be prescribed a complete course of therapy during the initial patient encounter without the need for repeated blood tests, as was the case with an interferon–based regimen.

We did not find any significant difference in the MELD score after 12 weeks of therapy as compared with baseline. This may be because the mean MELD score at baseline was low, and therefore, the fractional change was not significant. Prospective studies need to evaluate the effect of oral DAAs on the change in MELD and Child–Pugh–Turcotte scores.

Seven patients had relapse on sofosbuvir–based therapies. The aetiology of this is unclear as these patients had different treatment regimens. We did not assess for resistance associated variants in these patients.

Similar to the paradigm shift in the management of human immunodeficiency virus (HIV) infection, where the use of generic drugs has led to significant reduction of cost of therapy, the use of generic medications for HCV infection will make drugs more affordable, especially in developing countries, where treatment costs are borne by the patients themselves. The availability of generics with good efficacy and tolerability has the potential to redefine the management and outcomes of HCV infection, and in the future, potentially eradicate it.

This study has a few limitations. The data were from a single tertiary care centre, which is associated with a referral bias. Another limitation is the observational design of the study, which was not randomized for drug regimens or HCV genotypes. Therefore, there is a selection bias for patient enrollment such as inclusion of larger numbers of HCV genotype 3 patients and differences in patient enrollment for the various generic drug combinations. Generic drugs have certain limitations, as compared to branded drugs. Branded drugs undergo extensive testing for quality, safety and efficacy. There is no post–marketing surveillance for generics. We used multiple generic brands; however, we did not compare head–to–head outcomes with different manufacturers. We included both treatment–naïve and treatment–experienced patients, as well as a spectrum of liver disease including chronic hepatitis C, compensated and decompensated cirrhosis. We assessed virologic relapse by repeat documentation of the same genotype by real time PCR and not by phylogenetic analysis of nucleotide sequence, which would have accurately differentiated relapse from reinfection. In conclusion, generic oral directly acting agents are associated with high SVR rates in patients with HCV infection in a real–life clinical scenario.