Effectiveness of generic direct-acting agents for the treatment of hepatitis C: systematic review and meta-analysis

Abstract Objective To compare the efficacy of generic direct-acting agents and brand-name medicines for treating hepatitis C virus (HCV) infection by conducting a systematic review and meta-analysis. Methods We searched online databases for studies that reported sustained virological responses 12 weeks after the end of HCV treatment with generic direct-acting agents. We derived pooled proportions of treated patients with a sustained virological response from intention-to-treat and per-protocol analyses. In addition, we calculated the pooled relative risk (RR) of a sustained virological response brand-name versus generic direct-acting agents using a random-effects model (DerSimonian–Laird) from the data available. Between-study heterogeneity was assessed using the I2 statistic. Findings We identified 19 studies involving a total of 57 433 individuals from eight territories or regions. The pooled overall proportions of patients with a sustained virological response were 98% (95% confidence interval, CI: 97–99; 18 studies; I2 = 94.1%) in per-protocol analyses and 96% (95% CI: 93–98; 8 studies; I2 = 68.1%) in intention-to-treat analyses. The likelihood of a sustained virological response with brand-name medicines was similar to that with generic direct-acting agents (RR: 1.00; 95% CI: 0.98–1.02; I2 = 0.0%). The likelihood of a sustained virological response was significantly higher in patients without than with cirrhosis (RR:1.03; 95% CI: 1.01–1.06; 7 studies) but was not significantly affected by either previous treatment (3 studies) or human immunodeficiency virus coinfection (3 studies). Conclusion Generic direct-acting agents are highly effective for treating hepatitis C. Generic agents should be considered in resource-constrained settings for decreasing the burden of liver disease in HCV-infected patients.


Introduction
An estimated 70 million people worldwide are chronically infected by the hepatitis C virus (HCV). 1 The clinical presentation of HCV infection can vary from minimal fibrosis to cirrhosis and its complications. 2 The disease is one of the most frequent reasons for liver transplantation and more than 1 million deaths were due to HCV infection in 2013, 3 most of which were related to cirrhosis and hepatocellular carcinoma. 4 A sustained virological response to treatment has been associated with lower rates of liver-related complications, 5 better quality of life, 6 and a shorter waiting list for liver transplantation among patients with chronic hepatitis C. 7 The introduction of direct-acting antiviral agents has revolutionized the treatment of chronic hepatitis C -alloral, interferon-free regimens have been shown to be highly effective. 8 In 2016, the World Health Organization (WHO) outlined strategies for eliminating HCV infection and for reducing the number of viral hepatitis-related deaths by 65% by 2030. 4 However, the use of direct-acting agents has had a substantial economic impact in several countries due to high drug costs. Nevertheless, the adoption of a test-and-treat-all strategy is cost-effective and has been shown to be essential for reaching global treatment goals. 9 Access to direct-acting agents varies widely across the world. 10 Several countries have provided access with minimal co-payments or have negotiated large discounts with the pharmaceutical industry to provide universal treatment for everyone living with HCV. 11 Despite the availability of highly effective therapeutic regimens, however, WHO's target of eliminating HCV infection by 2030 will probably be difficult to achieve for several reasons, including: (i) the high rate of new infections; (ii) HCV-infected individuals remaining untreated due to a lack of screening; (iii) patent restrictions that affect generic medicines; and (iv) the high price of direct-acting agents in middle-income countries with large HCV epidemics. 12 Generic versions of direct-acting agents could be provided at a much lower cost than brandname medicines and could contribute to eradicating HCV infection in coming years. Optimally, generic HCV directacting agents should be prequalified by WHO. 13 Our hypothesis was that generic direct-acting agents are highly effective for the treatment of HCV infection. Although observational studies have reported on the effectiveness and safety of generic direct-acting agents in recent years, pooled effectiveness data from published studies is lacking. In this analysis, we estimated the pooled proportions of patients treated with generic direct-acting agents who had a sustained virological response, both with and without comparison with brand-name medicines.

Effectiveness of generic direct-acting agents for the treatment of hepatitis C: systematic review and meta-analysis
criteria. The search strategy is described in detail in the data repository. 14 Briefly, we searched for randomized or openlabel clinical trials or real-life cohort studies that evaluated the effectiveness of generic direct-acting agents in people chronically infected by HCV, with or without comparison with brand-name medicines. In addition, we manually searched the reference lists of included articles and relevant systematic reviews. This systematic review and metaanalysis was registered on PROSPERO (CRD42019117610). 15 Two i nd e p e nd e nt re v i e we rs screened the titles and abstracts of all articles identified for eligibility using the Rayyan QRCI web application and a list of inclusion and exclusion criteria. 16 A response to treatment was defined as a sustained virological response 12 weeks after the end of treatment. We excluded conference papers, editorials, published letters, studies in children or adolescents younger than 18 years, studies that exclusively evaluated the effectiveness of brand-name direct-acting agents and studies that did not report sustained virological response data.
Two investigators extracted the following data from the full text of each included study and entered them in a case report form using the database application REDCap (Research Electronic Data Capture): 17 study design, study country, period of recruitment, participants' demographic characteristics, directacting agent regimens used, duration of direct-acting agent treatment, previous treatment, presence of cirrhosis, presence of human immunodeficiency virus (HIV) coinfection, country of manufacture of generic direct-acting agents, trade names of generic direct-acting agents and the proportions of patients with sustained virological response from per-protocol or intention-to-treat analyses or both. This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. 18 The quality of the studies included was appraised using the National Institute of Health's quality assessment tool for observational cohort and crosssectional studies. 19 This tool's 14-item checklist was designed to focus on factors important for evaluating a study's internal validity. Studies were rated as being of good, fair or poor quality. Those with 0 to 6, 7 to 10, or 11 or more "yes" responses to the 14 items were considered as having a high, moderate or low risk of bias, respectively.

Statistical analysis
Our primary outcome was the pooled proportions of treated patients with sustained virological response for generic direct-acting agents, reported with a 95% confidence interval (CI). In addition, where data were available, we performed a meta-analysis of proportions using a random-effects model (i.e. the DerSimonian-Laird Table 1. Study inclusion criteria, systematic review and meta-analysis of generic directacting agents for treating hepatitis C Characteristic

Study population
People living with a chronic HCV infection None

Study intervention
Treatment of HCV infection using generic direct-acting agents  Between-study heterogeneity was assessed using the I 2 statistic: an I 2 value of 25-< 50%, 50-75%, and > 75% was considered to indicate mild, moderate or severe heterogeneity, respectively. 20 We performed subgroup analyses to explore how the following variables affected the pooled proportions of sustained virological response and heterogeneity: (i) the presence of cirrhosis; (ii) previous treatment; and (iii) the presence of an HIV-HCV coinfection. In addition, we performed sensitivity analyses to evaluate the impact of the study's geographical location and quality on the sustained virological response proportions and heterogeneity. A P-value ≤ 0.05 was regarded as significant. All statistical analyses were conducted using the metan and metaprop procedures in Stata v.14 (StataCorp LP., College Station, United States of America). 21,22

Subgroups
A single study exclusively included individuals with cirrhosis, 33 11 studies included patients with and without cirrhosis, two excluded cirrhotic patients and five did not report the prevalence of cirrhosis. Of the eight studies that reported proportions of sustained virological response in patients with cirrhosis, seven reported proportions for cirrhotic and noncirrhotic patients separately. 23

Fig. 2. Sustained virological response to hepatitis C treatment by generic direct-acting agents, per-protocol analysis, systematic review and meta-analysis, 2019
Author, year Treated (no.)

Fig. 3. Sustained virological response to hepatitis C treatment by generic direct-acting agents, intention-to-treat analysis, systematic review and meta-analysis, 2019
Author, year Treated (no.)

Sensitivity analysis
Our sensitivity analysis showed that heterogeneity was lower in studies performed in Asia than in Egypt (Fig. 12).
In addition, we found that heterogeneity was lower in studies of patients with cirrhosis ( Fig. 8) and when studies were stratified by quality ( Fig. 13

Discussion
Through a systematic review and metaanalysis approach, we derived pooled proportions of sustained virological response in patients treated for HCV infection using generic direct-acting agents. We found that generic directacting agents were highly effective. The overall pooled proportion of patients with a sustained virological response was 98% in real-life observational studies that included over 57 000 individuals, which was similar to that reported for brand-name direct-acting agents in large, real-life, observational cohort studies around the world. 8,44,45 In particular, we found that a sustained virological response with generic direct-acting agents was similar to brand-name medicines. Additionally, in sensitivity analyses, we found that sustained virological response was also high with specific regimens, such as sofosbuvir with daclatasvir and sofosbuvir with ledipasvir. Although neither an HIV coinfection nor previous treatment was associated with a high treatment failure, the presence of cirrhosis at baseline was associated with a significantly lower sustained virological response in patients treated

Fig. 4. Relative risk of a sustained virological response to hepatitis C treatment by brand-name versus generic direct-acting agents, systematic review and meta-analysis, 2019
Author, year % Weight RR (95%CI) Vargas   with generic direct-acting agents. The results of this study can help in the elaboration of public health strategies for using generic direct-acting agents to treat HCV infection.
Our study findings have implications for achieving the goal of eliminating HCV infection by 2030. 4 Universal access to direct-acting agents is essential for decreasing viral transmission as well as for reducing mortality and the risk of liver-related complications associated with chronic hepatitis C worldwide. However, HCV treatment has entailed a substantial financial burden, especially as direct-acting agents are expensive. 46 The nominal price of 12-week course of sofosbuvir ranges from 6 766 United States dollars (US$) in Brazil to US$ 64 680 in the United States. 11,47 In contrast, a course of a generic directacting agent regimen can be produced for approximately US$ 200 per patient in countries such as Egypt and India. 27 The production of generic directacting agents has been challenged in various local intellectual property jurisdictions because some pharmaceutical components may still be patented. In most countries, local drug regulatory authorities can approve the marketing of a generic version of a patented drug only after the relevant patent has expired, generally after 20 years. 48 In several countries, local intellectual property offices have evaluated requests to cancel patent claims previously granted to pharmaceutical companies, thereby opening up the possibility that affordable generic versions of directacting agents could be produced. 49 In opposition, pharmaceutical companies have defended their patents and, in the meantime, have collaborated with local companies to produce authorized versions of generic medicines for HCV treatment. The cost of these authorized versions will most likely exceed that of generic direct-acting agents produced by independent companies. Authorized, generic versions of sofosbuvir-ledipasvir and sofosbuvir-velpatasvir combi-nations were expected to be available in the United States in 2019 at a cost of US$ 24 000 per treatment course. 50 Our study has limitations. First, there was high between-study heterogeneity for pooled overall proportions of sustained virological response. High heterogeneity might have resulted from differences in the ethnic or clinical characteristics of study participants. Most studies were conducted either in Egypt, where most patients have an HCV genoype-4 infection, or in various parts of Asia. Our sensitivity analysis showed that the region where the study took place and characteristics of patients and study design influenced the heterogeneity. Second, there was a lack of a pooled proportion of patients with a sustained virological response for pan-genotypic interferon-free regimens. We acknowledge that few studies included patients treated with sofosbuvir and velpatasvir or patients with an HIV-HCV coinfection. 30,31 Most studies included in our analysis were real-life cohort studies in-

Fig. 12. Sustained virological response to hepatitis C treatment with generic direct-acting agents, by geographical location, systematic review and meta-analysis, 2019
Author The main strength of our study is the large number of patients in real-life scenarios included in the meta-analysis. This large sample size enabled us to estimate the pooled overall proportion of patients with a sustained virological response rates and proportions for different direct-acting agent regimens and for the presence of conditions such as cirrhosis. Moreover, we were able to perform sensitivity analyses that explored the effect on pooled estimates of geographical location, study quality and clinical and demographic characteristics.
In conclusion, we found that the proportion of patients treated with generic direct-acting agents with a sustained virological response was high. The proportion was also high in patients treated with sofosbuvir and daclatasvir, and with sofosbuvir and ledipasvir, and in those with cirrhosis or an HIV coinfection. Recent cost-effectiveness studies of generic direct-acting agents in India suggest that their use can reduce costs, 51 especially if pan-genotypic regimens are used (though efficacy estimates for brand-name medicines were used in these studies). 52

Resumen
Eficacia de los antivirales genéricos de acción directa para el tratamiento de la hepatitis C: revisión sistemática y metaanálisis Objetivo Comparar la eficacia de los antivirales genéricos de acción directa y los medicamentos de marca para el tratamiento de la infección por el virus de la hepatitis C (VHC) mediante la realización de una revisión sistemática y un metaanálisis. Métodos Se realizaron búsquedas en las bases de datos en línea de estudios que notificaron respuestas virológicas sostenidas 12 semanas después del final del tratamiento contra el VHC con antivirales genéricos de acción directa. Se derivaron las proporciones agrupadas de los pacientes tratados con una respuesta virológica sostenida de los análisis por intención de tratar y por protocolo.      29 study was not included in this subanalysis because it involved only patients with an HIV-HCV coinfection. c The I 2 value for between-study heterogeneity was 0.0% (P = 0.842).