Editorial Commentary: Interferon-free Hepatitis C Treatment Efficacy From Clinical Trials Will Translate to “Real World” Outcomes

(See the HIV/AIDS Major Article by Saeed et al on pages 919–26.) Treatment of chronic hepatitis C virus (HCV) infection was interferon (IFN) based for 2 decades, with the addition of ribavirin, pegylated IFN, and first-generation protease inhibitor direct-acting antiviral (DAA) therapies (telaprevir, boceprevir), providing stepwise improvements in efficacy [1]. Despite increases in sustained virological response (SVR) with these IFN-containing regimens, treatment uptake remained low in most countries, with <1%–5% of people with chronic HCV initiating therapy each year [2]. Fortunately, recent years have seen a revolution in HCV therapeutic development, with the advent of DAA therapy and a move toward potent IFN-free regimens, with SVR consistently above 90% [3]. In the near future, simple (single-pill once-daily oral regimens), highly tolerable, short-duration (8–12 weeks) therapy with pangenotypic potency and extremely high efficacy should be the norm [3]. The broad implementation of such therapeutic regimens has the potential to produce one of the greatest shifts in disease burden seen in public health and clinical medicine to date. The capacity to scale-up IFN-free DAA therapy and the subsequent impact on HCV disease burden will depend on several factors. First, high regimen costs coupled with markedly increased demand for HCV treatment are translating into potential budget impacts that have driven liver disease stage–based restrictions in most settings. However, further drug discounting, particularly in the context of a competitive pharmaceuticals market, should ensure that these restrictions are loosened or completely removed over the coming decade. Second, relatively low levels of HCV screening and diagnosis in most settings will need to be addressed to enhance potential population-level impacts of HCV treatment. Third, development of a range of models of healthcare delivery that facilitate linkage to care will be required to enable higher rates of treatment assessment and initiation. In this issue of Clinical Infectious Diseases, Saeed and colleagues identify an additional key issue that is related to the potential impact of IFN-free DAA therapy. They pose the question as to how generalizable are the results from trials of DAAs to patients coinfected with human immunodeficiency virus (HIV)–HCV in the real world. Through a systematic review of DAA-based clinical trial eligibility and demographic, behavioral, and clinical characteristics of patients within the Canadian Coinfection Cohort, they clearly demonstrate that a minority (6%–43%), often a small minority (6%–10% in most trials), of patients would have been eligible for enrollment in the specific clinical trials. The major reasons for lack of trial eligibility were prescription of specific antiretroviral agents (based on concerns around drug–drug interactions) and active illicit drug use. The study is important in highlighting the potential gap between clinical trial–based outcomes and “real-world” efficacy and impact. Although focused on HIV–HCV coinfection, there are clearly implications for the HCV monoinfected population, particularly with regard to active illicit drug use exclusion. However, there are several factors that provide reassurance that clinical trial–based IFN-free DAA efficacy will translate to high efficacy and impact beyond the restricted clinical space that phase 2 and 3 clinical trials generally work within. First, although there are specific drug–drug interaction issues with HCV regimens and some antiretroviral therapies (ART), the broad ART eligibility and high efficacy (sustained virologic response at post-treatment week 12 [SVR12] 96%) in the ALLY-2 HIV–HCV coinfection trial of sofosbuvir and daclatasvir for 12 weeks is encouraging [4]. The ION-4 HIV–HCV coinfection trial of sofosbuvir and ledipasvir for 12 weeks demonstrated the same efficacy (SVR12 96%) [5]. Although considerably more ART restrictive, drug–drug interaction studies indicate that this regimen can be used in a broader population, specifically those receiving ritonavir-boosted HIV protease inhibitors [6]. Even where there are specific drug–drug interaction-based contraindications, presumably most HIV–HCV patients should be able to switch ART regimens, even if temporarily for the duration of HCV treatment. Second, although active drug use was an exclusion criterion for the HIV–HCV clinical trials reviewed, evidence from trials with IFN-containing regimens indicate that active drug use does not compromise HCV treatment outcomes [7]. Recent data also indicate that active drug use does not compromise IFN-free DAA treatment outcomes. In the ALLY-2 trial, drug and alcohol use per se was not an exclusion criteria, with “active substance abuse” only regarded as exclusionary if the investigator deemed it “inappropriate.” On subgroup analysis, SVR12 was 93%–95% in individuals who received 12 weeks of sofosbuvir and daclatasvir and reported injection drug use as the mode of HIV and/or HCV acquisition, although no data were reported on active drug use and outcomes. The C-EDGE CO-STAR study evaluated a 12-week regimen of grazoprevir (second-generation NS3/4A protease inhibitor) and elbasvir (second-generation NS5A inhibitor) in a population on stable opioid substitution therapy (OST), of whom the majority reported ongoing active drug use and demonstrated high treatment efficacy (SVR12 92%) and no impact of active drug use [8]. In addition, treatment adherence and efficacy were similar to that of the other C-EDGE phase 3 studies that excluded people who were actively using drugs [9, 10]. Ongoing CO-STAR study follow-up will be important to characterize the rate of HCV reinfection and its impact on long-term viral clearance. Further studies are required within HIV–HCV and HCV monoinfected populations to evaluate IFN-free DAA regimens among people who inject drugs, particularly those not on OST. Third, observational cohorts that have evaluated IFN-free DAA regimens among broader populations in the real world have generally shown favorable HCV treatment outcomes. The TRIO network in the United States revealed real-world treatment efficacy with IFN-free DAA regimens with or without ribavirin, which is similar to that seen in phase 3 clinical trials of HCV genotype 1–infected adults: sofosbuvir/ledipasvir, SVR12 97% (n = 1225); ombitasvir/paritaprevir/ritonavir and dasabuvir, SVR12 95% (n = 39); and sofosbuvir and simeprevir, SVR12 93% (n = 27) [11]. Within this cohort, SVR12 was 100% in those with HIV–HCV coinfection (n = 70) [11]. Similarly, pooled data from 4 real-world cohorts (GECCO, IFI, TRIO, and TARGET, n = 590), including a small number of HIV–HCV-coinfected individuals (n = 32), demonstrated high SVR (97%) following 8 weeks of sofosbuvir/ledipasvir [12]. Within the HCV TARGET cohort, SVR12 was 95%–97% in those who received sofosbuvir/ledipasvir (n = 942) [13] and 84% in those who received sofosbuvir and simeprevir with or without ribavirin (n = 802) [14]. Even the modestly lower SVR reported in some real-world cohorts may relate more to lack of data availability rather than lower efficacy, which is not surprising given the considerable resources available in phase 2 and 3 trials to ensure patient follow-up and that data collection is optimized. Ultimately, the population-level impact of IFN-free DAA therapy will relate more to factors previously mentioned, such as HCV drug pricing and restrictions, HCV screening and diagnosis, and linkage to treatment and care, rather than a differential treatment efficacy in the broadened or real world. Potential conflicts of interest.