Characteristics and Outcomes of Direct-Acting Antiviral Experienced Patients with Hepatitis C Undergoing Retreatment at an Essential Hospital in the United States

Abstract

The introduction of effective direct-acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) infection was a milestone in the fields of infectious diseases, gastroenterology, and primary care. DAAs are >90% effective in achieving a sustained virologic response at 12 weeks (SVR12) in patients with previously untreated HCV and are highly efficacious among patients previously treated with ribavirin, peginterferon, and/or DAAs [1, 2]. With these data, the World Health Organization set the objective of eliminating HCV by 2030 [3]. However, reinfection and treatment failure remain barriers to the elimination of HCV, particularly among priority populations such as people who inject drugs (PWID) [4].

Treatment failure is common in patients with advanced liver disease and those with low adherence to medications [5]. The latter scenario is more frequent among PWID and often rooted in social determinants of health and other structural barriers to consistent medication access and administration [6]. Reinfection is also more frequent in PWID, as well as in men who have sex with men and patients with other sexually transmitted infections [7]. Current guidelines informed by randomized trial data recommend treating patients with a history of treatment failure with a rescue regimen such as sofosbuvir/velpatasvir/voxilaprevir (SVV) for 12 weeks or glecaprevir/pibrentasvir (GP) for 16 weeks [8], whereas retreatment with first-line regimens, such as sofosbuvir/ledipasvir (SL) or sofosbuvir/velpatasvir (SV), is recommended for patients with reinfection [9].

There is a subset of patients who are DAA experienced with HCV viremia who have an indeterminate prior treatment outcome, typically due to barriers to completion of treatment and SVR12 laboratory testing. Recent studies suggest that up to 25% of people treated with DAA do not have SVR12 assessment [10, 11]. In these cases, it is difficult to discern if current HCV viremia is the result of treatment failure or reinfection. Patients in these circumstances, owing to the inability to rule out prior DAA treatment failure, are often treated with more complex rescue DAA regimens, which are associated with increased cost. However, outcomes of each regimen in this clinical scenario have not been well described. The goal of the present study is to describe a cohort of patients who were DAA experienced and undergoing HCV retreatment at an academic essential hospital in the United States and to evaluate the outcomes of first-line vs rescue DAA regimens in the subset of patients with an indeterminate prior treatment outcome.

METHODS

Study Design and Selection Criteria

We performed a retrospective cohort study with manual data abstraction to evaluate the clinical characteristics and outcomes of DAA treatment experienced patients with HCV who were undergoing retreatment with DAAs. We included patients who were ≥18 years of age, had detectable HCV RNA, and initiated retreatment with DAAs at one of the clinics of the Boston Medical Center (BMC) Health System between 1 January 2016 and 31 May 2022. We excluded those patients who did not take at least one dose of DAA.

Setting

This study took place in Boston, Massachusetts, a high-prevalence area for HCV. A recent study analyzing data from the BMC Health System reported >1600 new HCV cases in a 2-year period, with the highest prevalence in the 26- to 65-year-old group [10]. This same study demonstrated a cascade of care with high prevalence of HCV but significant fall-off for treatment completion and SVR12 rates. This exposes the complexity of caring for a population with multilevel social and medical barriers to care [10].

BMC Treatment Pathways

BMC patients can access HCV screening and treatment in a variety of general medicine and subspecialty care settings, including general internal medicine primary care, family medicine, the Center for Infectious Diseases, gastroenterology, and several addiction medicine programs. Navigators contact patients who test positive for HCV RNA and assist with linkage to care if they meet certain criteria. Subsequently, patients are followed throughout the treatment by the medical team and navigator until an SVR12 test is obtained.

Data Collection

We identified patients who initiated DAA treatment during the study period via a central clinical database used for HCV treatment tracking, managed by the hospital's pharmacy team. The first author subsequently reviewed the electronic health records and central clinical database of all included patients to identify those with prior DAA treatment with or without interferon or ribavirin. For patients who initiated DAA retreatment more than once during the study period, we included only the first retreatment episode. We abstracted demographic and clinical variables from the electronic health records, such as comorbidities, stage of liver fibrosis and cirrhosis, history of substance use, and history of psychiatric disorders. Patient baseline characteristics were obtained from the index visit ±6 months prior to starting retreatment if these were not available at that visit. Data on previous and current HCV treatments, including genotype, type of treatment, and outcomes, were extracted from the central clinical database. All data were entered into REDCap. A list of definitions is provided in the Supplementary material.

Outcomes

We described the demographic and clinical characteristics of patients undergoing retreatment for HCV, including the outcome of the current treatment episode. Possible treatment outcomes were as follows: SVR12, defined as a negative RNA at 12 to 16 weeks after discontinuing DAA therapy; treatment failure, defined as a detectable RNA 12 to 16 weeks after discontinuing DAA therapy; and indeterminate, defined as either complete loss to follow-up or noncompletion of an HCV RNA test 12 to 16 weeks after discontinuing DAA therapy.

We performed additional analyses for the subset of patients with an indeterminate prior DAA treatment outcome. Among this subset of patients, we compared the clinical characteristics and outcomes of those retreated with first-line vs rescue therapy. There is no standard therapeutic regimen protocol at our institution for these patients; regimens are selected by the clinicians caring for the patients. First-line therapy was defined as GP (for 8 weeks), SV, or SL. All other regimens were considered rescue therapies.

Data Analysis

We used descriptive statistics to summarize the patients’ demographic variables, clinical characteristics, and outcomes. We used means and standard deviations. Clinical characteristics and comparative outcomes were analyzed by Fisher exact test and analysis of variance. Tests were 2-tailed, and P < .05 was considered statistically significant. We utilized a convenience sample size for this study due to its retrospective nature. Data analysis was performed with Stata (version 18.0; Stata Corporation).

Ethical Approval

This study was approved by the institutional review board at Boston University Medical Center (H-42862). We obtained a waiver for informed consent given the retrospective and observational nature of the project and the use of deidentified data.

RESULTS

Out of 186 treatment experienced patients with HCV who were retreated during the study period, 184 had available information about prior treatments. A minority of patients were previously treated with interferon (with or without ribavirin), and the majority (60.2% n = 112) were previously treated with DAAs. Demographic and clinical characteristics of patients with prior DAA treatment are summarized in Table 1. The mean age was 52 years (SD, 12.2), and patients were mostly male (80.4%) and White (42.9%), followed by African American (34.8%) and Hispanic/Latinx (21.4%). Most patients had a history of substance use (88.4%), predominantly heroin (71.4%) and cocaine (65.2%), including 25% reporting active substance use and 10.7% reporting active injection drug use. Half (51.8%) were prescribed medications for opioid use disorder, mostly buprenorphine/naloxone (33.9%) and methadone (12.5%). Rates of HIV coinfection (13.4%) and psychiatric comorbidities, particularly major depression (47.3%), were high. A third of patients were diagnosed with cirrhosis (27.7%).

In terms of prior treatment outcomes, 39.3% (n = 44) were being treated for reinfection and 27.7% (n = 31) for prior failed therapy, and for 33% (n = 37) it was indeterminate whether their present viremia was due to treatment failure or reinfection. Most patients had been treated with SL (56.1%) or SV (24.9%; Table 2). The most common current genotype was 1a (56.2%), followed by 3 (14.3%) and 1b (12.5%). Resistance testing (NS5a) was performed in 46 cases. After retreatment, most patients had SVR12 (74.1%, n = 83), 18.8% (n = 21) were lost to follow-up, and 7.1% (n = 8) failed retreatment.

Patients with SVR12 after retreatment had a significantly lower frequency of active substance use vs those with treatment failure and indeterminate outcome (21.7% vs 62.5% and 33.3%, P = .03) and a nonsignificant lower frequency of active injection drug use vs those with treatment failure and indeterminate outcome (7.2% vs 12.5% and 26%, P = .066). Housing instability was also lower in patients with SVR12 as compared with the other two groups (33.7% vs 37.5% and 61.9%, P = .070; Supplementary Table 1). Supplementary Table 2 describes the treatment characteristics of patients stratified by current treatment outcome.

A total of 37 patients had an indeterminate prior treatment outcome and were eligible for additional analyses comparing first-line vs rescue therapy. Of these 37 patients, 24 had resistance-associated substitution testing, and only 8 had mutations that could predict resistance to NS5A inhibitors. Subgroup analyses of the eligible group (Table 3) showed that 18 patients were treated with first-line regimens, including GP for 8 weeks, SL, or SV, and 19 patients received rescue regimens with SVV or GP for 16 weeks. Outcomes including failure (0% vs 10.5%), SVR12 (66.7% vs 52.7%), and indeterminate (33.3% vs 36.8%) were similar in both groups (P = .502). Prior treatment completion and frequency of resistant mutations were higher in the rescue therapy group.

DISCUSSION

Our study describes the outcomes after retreatment of DAA experienced patients at an essential hospital during the opioid and polysubstance crises in the United States. This observational study found that patients who were DAA experienced and undergoing retreatment for HCV had good SVR12 rates, even among those with active substance use. This supports the need for low-barrier access to HCV treatment, including for PWID and other populations who face barriers to follow-up and risk of reinfection. Additionally, we observed that patients with an indeterminate prior DAA treatment outcome had similar outcomes when retreated with first-line regimens as compared with rescue ones.

This study addresses a common clinical dilemma that has not been well described in the literature to date: how to approach HCV retreatment in DAA experienced patients and an indeterminate prior treatment outcome. This is a common scenario at institutions that serve patients with active substance use disorder and profound structural barriers to care. Current guidelines recommend retreating patients with reinfection using a first-line regimen, based on studies showing excellent outcomes with these medications [9]. For instance, the REACH-C study reported an SVR12 rate of 95% in patients with reinfection retreated with DAAs, which is similar to the efficacy seen in randomized controlled trials [12]. By contrast, a rescue regimen is recommended for those with documented treatment failure. However, guidelines provide no clear recommendations for retreatment of patients who are DAA experienced and have an indeterminate outcome of prior treatment owing to the scarcity of data on this specific group, leading to variability in clinical practice.

Some observational studies have evaluated the effectiveness of retreatment with first-line regimens in patients nonrespondent to DAAs, including patients with treatment failure, describing acceptable SVR12 rates [13–19]. Elhence et al described their experience retreating patients who were DAA experienced and had prior treatment failure with first-line regimens, mostly SV, finding that 10 of 11 (90.9%) had SVR12 [13]. In a similar study, Zarȩbska-Michaluk et al reported a 78% SVR12 rate in patients previously nonrespondent after retreatment with first-line regimens [14]. A larger study from Brazil describing retreatment outcomes with first-line and rescue regimens in patients who did not respond to a first treatment showed SVR12 rates ranging from 82.6% to 100% with first-line regimens such as SV, SL, sofosbuvir/simeprevir, and sofosbuvir/daclatasvir [19]. However, in the absence of guideline recommendations, many patients with an indeterminate prior treatment outcome are assumed to have treatment failure and are therefore retreated with rescue regimens, which are associated with greater cost and potential side effect burden.

Our results demonstrated similar outcomes for patients with an indeterminate prior treatment outcome who were retreated with first-line vs rescue regimens (P = .502). These findings provide support for the consideration of first-line regimens when retreating patients in whom the outcome of a previous treatment is unknown, potentially mitigating cost and side effect barriers associated with rescue regimens. However, this should not be extrapolated to patients who completed a prior regimen or those with resistance mutations, given that the likelihood of failure may be higher.

Notably, despite the high SVR12 rates in the cohort overall, we observed that active substance use, housing instability, and active injection drug use were more frequent in patients whose retreatment failed or were lost to follow-up, indicating opportunities to improve structural support and treatment access for unhoused individuals with substance use disorder during and after HCV treatment. The SVR12 rate in the subset of patients with prior reinfection was lower when compared with published benchmarks (74.1%). This could be attributed to the high frequency of active injection drug use, active substance use, and housing instability at the time of retreatment. In addition, we included all patients who were lost to follow-up in the denominator, whereas many studies exclude this group when reporting treatment outcomes. Yet, the subset of patients with previous treatment failure had a higher SVR12 (90.3%) comparable to other real-world cohorts and randomized controlled trials [8, 20–23].

Results should be considered in the context of several limitations. First, the retrospective observational study design limits the possibility of capturing additional variables relevant to our outcomes, such as the number of DAA doses taken and resistance testing results for all patients, as well as our ability to rule out whether unmeasured differences between patients retreated with first-line and rescue regimens influenced study results. Our small sample size also limits the strength of conclusions that can be drawn from the work, as it is possible, though unlikely, that all indeterminate patients represented reinfection rather than treatment failure. A future randomized trial design can provide more definitive evidence of the relative efficacy of these treatment approaches in patients with an indeterminate prior treatment outcome. However, this exploratory and descriptive study is one of few describing the outcomes of individuals with an indeterminate outcome retreated with first-line vs rescue treatments and, as such, offers important context for providers facing a clinical scenario not well covered by HCV treatment guidelines.

In conclusion, patients with HCV undergoing retreatment at an essential hospital had acceptable SVR12 rates. This was true for patients with reinfection and prior treatment failure. Most importantly, we observed the use of first-line and rescue DAA regimens among patients with an indeterminate prior treatment outcome, with similar SVR12 rates in both groups. Treating this population with first-line medications and augmenting housing stability and substance use treatment could reduce barriers and contribute to the elimination of HCV in the United States.

Supplementary Data

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Data availability. Data are available upon request to the corresponding author.

Patient consent statement. The design of this work has been approved by the institutional review board at Boston University Medical Center (H-42862), which conforms to standards currently applied in the United States. A waiver of informed consent was given by the board.

Financial support. This work did not receive specific funding.

References

Author notes