Short Course Therapy With Glecaprevir/Pibrentasvir for Early Hepatitis C Virus Infection: PURGE-C

Abstract

Background

Shorter treatment courses for early hepatitis C virus (HCV) infection could simplify treatment approaches, particularly in key populations.

Methods

PURGE-C (A5380) was a single-arm, multicenter trial evaluating the treatment of early HCV (primary or reinfection) with 4 weeks of glecaprevir/pibrentasvir (G/P). Early HCV was defined as new detectable HCV RNA or alanine aminotransferase (ALT) elevation within 24 weeks of study entry. The primary endpoint was sustained virologic response (SVR) 12 weeks after prescribed treatment completion (SVR12). Re-treatment outcomes were also collected.

Results

Forty-five participants (98% male, 51% White, 31% Hispanic, median age 36 years, 51% with human immunodeficiency virus [HIV], 27% self-reported injecting drugs) were enrolled from the United States and Brazil between November 2019 and January 2023. Median time from HCV diagnosis to entry was 31 days (Q1–Q3: 15–49). Median baseline HCV RNA was 5.3 log₁₀ IU/mL (Q1–Q3: 3.3–6.0) and ALT 146 U/L (min–max: 22–3866). Overall, 38 of 45 (84%) participants (90% confidence interval [CI]: 74%–91%) achieved SVR12. All 4 participants who were retreated and had outcome data achieved SVR12.

Conclusions

In this population with elevated risk of onward HCV transmission, 84% were cured with 4 weeks of G/P. Failing this short-course treatment did not compromise retreatment. This study suggests that people with early HCV infection can achieve moderately high cure rates with abbreviated courses of direct-acting antivirals (DAA). Simplified approaches to treatment are critical for HCV elimination and are particularly relevant for populations difficult to retain in care.

Clinical Trial Registration

NCT04042740.

This study shows that people with early hepatitis C virus (HCV) infection can achieve moderately high cure rates with a short course of 4 weeks of glecaprevir/pibrentasvir. The study informs novel approaches to achieve HCV elimination.

Graphical Abstract

Graphical Abstract.

https://tidbitapp.io/institutional-portal/clinical-infectious-diseases/tidbits/short-course-therapy-with-glecaprevir-pibrentasvir-for-early-hepatitis-c-virus-infection-purge-c/update

With the availability of safe and effective hepatitis C virus (HCV) treatment with direct-acting antiviral agents (DAA), the World Health Organization (WHO) has proposed that HCV could be eliminated as a public health threat by 2030. However, with over 67 000 new HCV infections yearly [1], the United States is not on target to achieve the WHO elimination goal despite almost a decade of availability of curative therapies [2]. Most incident infections occur in marginalized populations who face substantial barriers to cure [3].

Treatment of HCV infection in the acute/early phase decreases the risk of onward transmission and overall cost from a payer perspective [4]. Numerous studies have tested the hypothesis that HCV treatment may be shortened in the early stages of infection [5], when HCV RNA may be low and/or fluctuating [6, 7], indicative of active immune responses. The shortest treatment course among approved regimens includes 8 weeks with a fixed-dose combination regimen of glecaprevir/pibrentasvir (G/P). A 4-week treatment course is attractive to treat early phase infection in populations for whom engagement and retention in care can be challenging. A previous trial with 23 participants receiving 4 weeks of G/P during early HCV reported a sustained virologic response (SVR) 12 weeks after cessation of therapy (SVR12) of 78%, with a wide confidence interval (CI) (95% CI: 56–93%) [8]. Additional data to confirm the efficacy of shortened regimens in populations with early HCV could inform elimination efforts.

The Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG) Network 5380 PURGE-C study's objectives were to evaluate the efficacy, safety, and tolerability of oral G/P for 4 weeks in adults with early HCV primary infection or reinfection, regardless of HCV genotype (Protocol Step 1). The primary efficacy endpoint was defined as HCV RNA less than lower limit of quantification (LLQ) 12 weeks after cessation of therapy (SVR12). To ensure access to curative therapy, the trial included a retreatment option (Protocol Step 2) for participants not achieving SVR12 with the investigational 4-week treatment.

METHODS

Study Design

A5380 was a phase II, open-label, single-arm multicenter clinical trial evaluating the efficacy, safety, and tolerability of 4 weeks of an orally administered fixed-dose combination (FDC) of glecaprevir (300 mg) and pibrentasvir (120 mg) once daily for early HCV infection. The sample size of 44 participants was determined to provide 90% power to conclude a SVR12 proportion >80%, based on a 2-sided 90% CI. The 80% SVR threshold was chosen based on 3 prior studies that halved the treatment durations from those recommended for chronic HCV [9–11]. Participants with HCV viremia at any time from the end of treatment through SVR12 determination could be retreated with a salvage regimen as part of the study (Step 2) or through their provider.

We obtained approval from all relevant regulatory and ethical committees. All participants provided written informed consent. An independent study monitoring committee reviewed safety and progress of the study. The study was registered with clinicaltrials.gov (NCT04042740).

Participant Population

Eligible participants were adults (aged ≥18 years) with confirmed early HCV infection within 24 weeks prior to entry. Participants were recruited from 11 ACTG Clinical Research Sites (CRSs) in the United States and 1 in Brazil. Early HCV infection was defined per the European AIDS Treatment Network (NEAT) Acute Hepatitis C Infection Consensus Panel [12].

For participants with no history of prior HCV infection:

• (1) New (<24 weeks prior to study entry) alanine aminotransferase (ALT) elevation to ≥5× upper limit of normal (ULN); OR >250 U/L in participants with documented normal ALT in the preceding 12 months or ≥10× ULN; OR >500U/L in participants with abnormal or no measured ALT baseline in the preceding 12 months prior to study entry with detectable HCV RNA;

OR

• (2) Detectable HCV RNA with prior negative anti-HCV antibody or undetectable HCV RNA within the preceding 6 months.

For participants with a history of prior HCV infection, reinfection was defined by meeting the definition of early infection and having documentation of clearance of prior infection (as evidenced by positive anti-HCV Ab) either spontaneously or after treatment with 2 negative HCV RNA a minimum of 12 weeks apart. All HCV genotypes were included. People with HIV (PWH) on antiretroviral therapy (ART) at screening were required to have evidence of HIV RNA suppression (human immunodeficiency virus type 1 [HIV-1] RNA <50 copies/mL or less than LLQ if the LLQ was >50 copies/mL) and CD4⁺ cell count >100 cells/mm³. ART regimens containing efavirenz, etravirine, and boosted protease inhibitors except darunavir were excluded due to potential drug-drug interactions with G/P. Participants with known preexisting cirrhosis, whether compensated or decompensated and those with evidence of concurrent hepatitis B infection or acute hepatitis A infection, or other causes of chronic liver disease were excluded. Full eligibility criteria are provided in the study protocol (see Supplementary Materials).

Study Endpoints and Procedures

The primary efficacy endpoint was sustained virologic response (SVR), defined as HCV RNA less than LLQ, either target detected (TD) or target not detected (TND) (Roche COBAS Taqman HCV Test 2.0 with LLQ of 15 IU/mL), 12 weeks after prescribed treatment completion (SVR12). For the participants affected by coronavirus disease 2019 (COVID-19) pandemic restrictions who missed the SVR12 visit, the HCV RNA obtained at the subsequent visit was allowed for SVR12 determination following a protocol amendment. The primary safety endpoint was the occurrence during treatment or within 28 days after prescribed treatment completion of Grade ≥2 adverse events (AE) as defined by the Division of AIDS, including clinical and laboratory, serious AEs according to ICH criteria, or treatment-limiting AEs. Secondary endpoints included HCV RNA measurements at other study visits.

Study visits occurred at entry (baseline), weeks 1, 2, 4 (on-treatment), and weeks 8, 12, 16, 28 (corresponding to 4, 8, 12, and 24 weeks after the end of scheduled treatment). On study HCV RNA and HIV RNA testing (Abbott reverse transcription polymerase chain reaction [RT-PCR]) was performed centrally at Quest Diagnostics. Adherence was assessed during on-treatment visits via pill counts and participant self-report of missed doses within the prior 4 days. A risk factor questionnaire captured use of specific drugs and sexual risks.

Viral Recurrence, Post-Treatment Viremia, and Step 2

Viral recurrence was defined as HCV RNA less than LLQ after achieving HCV RNA less than LLQ (TD or TND), and post-treatment viremia as HCV RNA greater than LLQ at the end of treatment or follow-up. To recommend a regimen for retreatment, the protocol co-chairs and virologist reviewed results from HCV genotype testing, and, if genotype 1 or 3, sequencing of the NS3 and NS5A genes for detection of resistance-associated substitutions (RAS) (Quest Diagnostics) [13]. The recommended Step 2 regimen for re-infection was G/P for 8 weeks and for relapse was G/P ± ribavirin for 16 weeks or sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) for 12 weeks [14, 15]. If participants underwent retreatment as part of usual care, the regimen was at the discretion of the treating provider.

Statistical Analysis

The primary efficacy endpoint was assessed by estimating the proportion of participants who achieved SVR12 with a 2-sided 90% CI using the Wilson score method. A CI entirely above 80% would support that the true underlying SVR12 proportion was > 80%. We pre-specified imputation of missing SVR12 endpoint as response if there were preceding and subsequent HCV RNA measurements less than LLQ around the missed SVR12 visit. For the participants who missed all visits between the end of treatment and the final study visit due to COVID-19 pandemic restrictions, the requirement of preceding HCV RNA measurement less than LLQ was removed. Otherwise, it was imputed as nonresponse in the primary analysis, consistent with the SVR12 definition in other studies. We pre-specified a supplementary SVR12 analysis to exclude participants who discontinued prior to the SVR12 visit for reasons unrelated to study treatment (eg, incarceration), assuming missing at random rather than imputing as nonresponse. Secondary analyses included SVR12 proportion by HIV status. The primary safety outcome was assessed by estimating the proportion of participants with Grade ≥2 adverse events with a 2-sided 95% CI.

The analysis was conducted using SAS software (Version 9.4 for Linux. Copyright © 2016 SAS Institute Inc., Cary, North Carolina, USA).

RESULTS

Participants

Sixty-eight participants were screened, and 45 participants enrolled between November 2019 and January 2023 (Figure 1). Among the enrolled population, 1 was assigned female sex at birth, the median age was 36 years (Q1–Q3: 29–43 years), 31% were Hispanic, 27% were Black, 51% were White, and 51% were PWH (Table 1). The majority (n = 38, 84%) of infections were primary HCV infections; 7 (16%) were reinfections. The median time from the current HCV diagnosis to enrollment was 31 days (min–max: 5 to 157 days). At the start of treatment, the median ALT was 146 U/L (min–max: 22–3866 U/L) and the median HCV RNA was 5.3 log₁₀ IU/mL (min–max: 1.0–7.5 log₁₀ IU/mL). Three enrolled participants had detectable HCV RNA < LLQ at study entry. Most participants (n = 32, 71%) had genotype 1 infection, although for 5 (11%) participants the baseline genotype was unable to be determined.

Figure 1.

Consort participant flow diagram.

Table 1.

A5380 Participants’ Baseline Demographic, Behavioral and Virologic Characteristics

Characteristic	Category or Statistic	Total (N = 45)
Age (y)	Median (Q1–Q3)	36 (29–43)
Sex assigned at birth	Female	1 (2%)
	Male	44 (98%)
Gender identity	Cisgender woman	1 (2%)
	Cisgender man	43 (96%)
	Non-Binary	1 (2%)
Race	Asian	3 (7%)
	Black	12 (27%)
	White	23 (51%)
	Other/Unknown	7 (16%)
Ethnicity	Hispanic or Latino	14 (31%)
	Not Hispanic or Latino	30 (67%)
History of injection drug use	Yes	12 (27%)
	No	33 (73%)
HIV-1 status	Present	23 (51%)
HIV-1 RNA (copies/mL)a	<40	23 (100%)
CD4 count (cells/mm3)a	Median (Q1–Q3)	545 (348–820)
ART regimena	BIC/FTC/TAF	8 (35%)
	DTG/ABC/3TC	4 (17%)
	EVG/COBI/FTC/TAF	3 (13%)
	DTG/FTC/TAF	2 (9%)
	Otherb	6 (26%)
HCV history	None	38 (84%)
	Previous	7 (16%)
Time since acute HCV diagnosis (d)	Median (Q1–Q3)	31 (15–49)
	Min–Max	5–157
Alanine aminotransferase (U/L)	Median (Min–Max)	146 (22–3866)
HCV genotype	1	32 (71%)
	2	2 (4%)
	3	1 (2%)
	4	5 (11%)
	Unable to determine	5 (11%)
HCV RNA (log10 IU/mL)	Median (Q1–Q3)	5.3 (3.3–6.0)
	Min–Max	1.0–7.5

Abbreviations: ABC, abacavir; ART, antiretroviral therapy; BIC, bictegravir; COBI, cobicistat; DRV, darunavir; DTG, dolutegravir; EVG, elvitegravir; FTC, emtricitabine; HCV, hepatitis C virus; HIV-1, human immunodeficiency virus type 1; min, minimum; max, maximum; Q1, lower quartile; Q3, upper quartile; RAL, raltegravir; RTV, ritonavir; 3TC, lamivudine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

^aSummaries of HIV-1 RNA, CD4 cell count, and ART regimen are among the 23 participants with HIV.

^bOne participant each was on the following antiretroviral regimens, respectively: DRV/RTC/3TC/TDF, RPV/FTC/TAF, RAL/DRV/RTV, DRV/COBI/FTC/TAF, DTG/3TC/TDF, EVG/COBI/FTC/TDF.

Twelve participants (27%) reported a history of ever injecting drugs. Data on additional risk factors were limited due to incomplete questionnaires, partly due to interruptions related to the COVID-19 pandemic. Among the 22 participants without HIV, 11 (50%) reported receiving pre-exposure prophylaxis (PrEP). All PWH were on ART with HIV-1 RNA <50 copies/mL (ART regimens are provided in Table 1). The median baseline CD4⁺ cell count was 545 cells/mm³ (Q1–Q3: 348–820 cells/mm³).

Efficacy

Among the 45 participants in the primary analysis, 38 (84%) achieved SVR12. The 90% CI (74%–91%) did not exclude 80% (Figure 2). The 38 participants with SVR12 included 4 participants who missed the SVR12 visit due to COVID-19 disruptions but had HCV RNA less than LLQ (TD or TND) at their subsequent visit. SVR12 was 19/23, 83% (CI: 66%–92%) in PWH and 19/22, 86% (CI: 70%–94%) in those without HIV. SVR12 was 31/38, 82% (CI: 69%–90%) in those with primary HCV infection and 7/7, 100% (CI: 72%–100%) in those with re-infection. SVR12 was 9/12, 75.0% (CI: 51.3%, 89.5%) in those who reported history of injecting drugs and 29/33, 87.9% (CI: 75.6%, 94.4%) in those who did not. One participant prematurely discontinued the study due to incarceration after achieving SVR4 and was excluded from the planned supplementary analysis that resulted in SVR12 of 38/44, 86% (90% CI: 76–93%).

Figure 2.

SVR12 proportion for the overall study, and by HIV-1 status, HCV history, and injection drug use history. The primary analysis approach included all participants who initiated study treatment. The planned supplementary approach excluded participants who discontinued study prematurely for reasons unrelated to study treatment. Proportions by HIV-1 status (HIV-1 present/HIV-1 absent), HCV history (no prior infection/previous infection), and injection drug use history (yes/no) are provided for all participants who initiated study treatment. Point estimates with 90% 2-sided Wilson confidence intervals are shown.

Virologic Failures

HCV RNA results for the 6 participants who exhibited virologic failure are shown in Figure 3. Of those, none had prior HCV infection; 5 (83%) self-identified as men who have sex with men (MSM); and 4 (67%) were PWH (Table 2). Four of the 6 participants achieved HCV RNA less than LLQ by the end of treatment; the participant with the highest baseline HCV RNA, had quantifiable HCV RNA at the end of treatment; and for another on-treatment HCV RNA measurements were missing due to the pandemic. The timing of detection of recurrent viremia was after the participants achieved SVR4 in 2 and at the first available timepoint after completion of treatment in 4 (Figure 3). The median HCV RNA among virologic failures was higher at baseline (6.3 log₁₀ IU/mL) than among those not experiencing virologic failure (Figure 4). Missing data and the small sample size prevented meaningful analysis of on-treatment viral suppression. All 6 participants for whom viral genotypes were available at both baseline and after recurrent viremia had the same genotype by commercial assay.

Figure 3.

HCV RNA over time of Step 1 participants with virologic failure. LLQ is 15 IU/mL. Participants who entered Step 2 for HCV retreatment are shown with black outlines around the last HCV RNA result; × represents loss to follow-up. Participant A did not have on-treatment testing due to reduced visits during the pandemic. Participant B had HCV RNA of 7950 IU/mL at recurrence, followed by less than LLQ (TD) at confirmatory testing; the participant subsequently withdrew from the study. Participant C, with the highest HCV RNA at baseline, did not achieve HCV RNA less than LLQ by week 4 of treatment.

Table 2.

Characteristics and HCV Re-treatment Outcomes for Participants Experiencing Viral Recurrence or Failure by SVR12 Visit

Participant	Age/Sex	IDU	MSM	HIV	Peak ALT/baseline ALT (u/L)	Baseline HCV RNA (IU/mL)	HCV RNA at Recurrence/failure (IU/mL)	GT at Baseline/GT at Recurrence	Re-treatment Regimen	Re-treatment Outcome
A	53/M	Former	Yes	Yes	252/116	564 000	6 137 600	1a/1a	G/P × 16w	SVR12
B	42/M	Former	No	No	1322/1088	3 200 000	7950	2/2	LTFU	Unknown
C	51/M	Never	Yes	Yes	127/75	28 900 000	3 160 000a	1a/1a	SOF/VEL/VOX × 12w	SVR12b
D	55/M	Never	Yes	Yes	485/69	11 500 000	46 183 638	1/1a	G/P × 16w	Unknownc
E	35/M	Never	Yes	Yes	1344/76	228	48 500d	1a/1a	SOF/VEL/VOX × 12w	SVR12
F	41/M	Never	Yes	No	465/801	1 460 000	5 010d	4d/4d	G/P × 16w	SVR12

All participants with viral recurrence or failure were experiencing their first HCV infections. Adherence by returned pill count was considered excellent for all 6 participants.

Only samples with genotypes 1 or 3 were analyzed in real-time by commercial resistance assays; notably no RAS were detected in any available baseline or recurrent viremia timepoint.

Abbreviations: HCV, hepatitis C virus; HIV, human immunodeficiency virus; MSM, men who have sex with men; IDU, injection drug use.

^aThis participant's end-of-treatment HCV RNA result was target detected 27 IU/mL.

^bThis participant received HCV retreatment outside the study, through clinical care.

^cThis participant's baseline genotyping result was 1 with an unknown subtype, stopped retreatment during his third week after hospitalization with cellulitis, and withdrew from the study. No HCV RNA results after HCV retreatment initiation were captured.

^dFor each of these participants at week 4 after treatment cessation HCV RNA was <15 IU/mL target not detected.

Figure 4.

Baseline HCV RNA by Outcome. Each bar represents a participant's HCV RNA at baseline in ascending order; colored according to the treatment outcome. *The participant was lost to follow-up after SVR4 and included as non-virologic failure in the primary analysis of SVR12.

Risk factor questionnaire data indicated that none of the 6 participants experiencing virologic failure reported snorting or injecting substances after entry, although some questionnaires were missing. Four of the 5 MSM reported condomless receptive anal intercourse at 1 or more visits during the study period. Adherence by self-report or by pill count in those with HCV RNA recurrence was excellent (Supplementary Tables 1 and 2).

Resistance and Re-treatment (Step 2)

No resistance mutations were identified in the post-treatment samples of those with genotypes 1 and 3. Four participants entered Step 2 with three prescribed G/P for 16 weeks without ribavirin and one prescribed SOF/VEL/VOX for 12 weeks (Table 2) through standard of care. Three participants achieved SVR12, whereas 1 participant discontinued Step 2 after <3 weeks of treatment following an adverse event (cellulitis) judged unrelated to study treatment and withdrew from the study; SVR12 status is unknown. Another participant was prescribed SOF/VEL/VOX × 12 weeks outside of Step 2 and had SVR12 after retreatment. One participant withdrew from the study before retreatment; no further information about the outcome of the infection is available.

Safety

Twenty-seven of the 45 participants (60%, 95% CI: 46%–73%) had a Grade 2 or higher AEs from treatment initiation through 4 weeks after prescribed treatment completion (Supplementary Table 3); 33 participants (73%, 95% CI: 59%–84%) experienced Grade 2 or higher AEs through the entirety of Step 1 (Supplementary Table 4). Overall, 4 SAEs were reported during Step 2; none were considered related to study treatment. AEs during Step 2 are summarized in Supplementary Table 5.

DISCUSSION

Four weeks of glecaprevir/pibrentasvir for early HCV infection was safe, well tolerated, and cured approximately 85% of participants, including in PWH. The SVR was lower than those that used G/P for 6–8 weeks for early infection [5, 16, 17]. Most viral failures occurred in those with higher baseline HCV RNA titers, no new resistance-associated substitutions were detected, and for those able to complete retreatment SVR12 was achieved.

Treating early HCV infection allows for cure as soon as possible after diagnosis, reducing the risk of loss to follow-up associated with treatment delay and shortening the period of infectiousness, providing benefits through a treatment-as-prevention approach. Despite increasing availability of DAAs, a recent examination of Medicaid recipients showed only 20% received DAAs within 6 months of their HCV diagnosis [18 ]. One report indicated no change in prevalence of HCV viremia in the United States between 2013–2016 and 2017–2020 [19], suggesting that new infections and reinfections may offset DAA treatment cures [20]. More attention to prompt provision of DAAs is warranted for vulnerable and marginalized populations at elevated risk for transmission, as incident infections represent a primary barrier to HCV elimination in the United States.

With a larger sample size, we observed a slightly higher point estimate of SVR12 compared to a smaller multinational study from the United Kingdom, Australia, and New Zealand, where the intention-to-treat (ITT) SVR12 proportion was 78% (95% CI: 56%–93%) [8]. A randomized trial of 6 weeks versus 12 weeks of SOF/VEL also showed a decrement in SVR12 with a shorter course (82% vs 91% ITT rate, respectively) [21]. Halving the duration of treatment from that approved in chronic infection may come at a trade-off of lower SVR. Questions remain: what is the acceptable loss in SVR to achieve higher treatment uptake in the most marginalized and difficult-to-retain populations? How does access to highly effective retreatment strategies impact this risk-benefit decision?

Ideally, patients with early HCV would be prescribed and dispensed entire courses for the standard 8 (for G/P) or 12 weeks (for SOF/VEL) to increase the probability of cure, such as in the MINMON trial [22]. However, DAAs in the United States are usually dispensed in 4-week increments and delivered by specialty pharmacies. People who use drugs (PWUD) are a population who often have fragmented care and face barriers such as housing instability. PWUD are also a high incidence population for reinfection, a subgroup in which 7 out of 7 participants achieved SVR12 in our study. Providers may be reluctant to prescribe DAAs when social situations may compromise the provision of complete courses [23]. Treatment completion of 12 weeks of sofosbuvir/velpatasvir for people who are recently or actively injecting drugs was ∼82% in the recent HERO trial [24]; even if treatment is completed, many do not return for visits to document cure [25]. In a program aimed at enhancing treatment completion rates for PWUD, refills of DAAs were incomplete for almost 36% prescribed a 12-week DAA treatment course [26]. Strategic and novel approaches aimed at increasing DAA access are needed to achieve elimination.

One approach is to identify subgroups of patients who may achieve high cure rates with shortened courses of therapy. Other trials of DAAs showed that shortened courses may be effective in those with lower baseline HCV RNA titers, as most relapses or recurrences occurred in those with HCV RNA >10⁶ log₁₀ IU/mL [8, 10, 21, 27]. Factors such as younger age, sex at birth, viral genotype, and/or host genetics such as IFN-λ4 genotype could add predictive value as they did in studies examining 8 weeks of ledipasvir/sofosbuvir for chronic HCV [28, 29]; however, further conclusions are limited for early HCV by the small sample sizes of these studies.

Does exposure to shorter courses compromise future treatment by emergence of resistance-associated substitutions (RAS)? Reassuringly, no treatment-emergent RAS were detected by commercial assays. Although our sample size is small, this result contrasts with the prevalence of RAS of 79% following virologic failure following initial G/P treatment in patients with chronic infection [30]. Rates of developing RAS may increase with greater selection pressure associated with longer treatment lengths, as shown in an analysis of exposure to ledipasvir/sofosbuvir [31]. Despite the lack of known resistance in those with viral recurrence, salvage regimens such as G/P for 16 weeks or SOF/VEL/VOX for 12 weeks were deployed to optimize SVR.

Limitations of this study include the sample size and generalizability. Only 1 participant assigned female sex at birth was enrolled, and only about a quarter of study participants reported injecting drugs. A dedicated study would be ideal to inform specific recommendations for these subgroups. We included participants who had quantifiable viral load at screening regardless of the viral load at treatment initiation to replicate real-world settings where, once treatment decisions are made, repeat measurements at the time of initiation are not performed.

In the absence of an effective vaccine to prevent HCV, prompt treatment of people with recent HCV infection will be necessary to achieve HCV elimination, especially among populations at high risk of transmission such as MSM and PWUD. Although an 8-week course is ideal to maximize SVR [16], many with early HCV who receive 4 weeks of G/P may be cured; those who relapse do not appear to exhibit resistance and can be successfully retreated. Shorter courses may be pragmatic when a longer course is unlikely to be completed, especially in the context of treatment as prevention. Providers should immediately treat those in the early phase of HCV to reduce transmission and promote elimination goals.

Supplementary Data

Supplementary materials are available at Clinical 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

Acknowledgments. The study team would like to thank all of the participants who enrolled in this study, the Advancing Clinical Therapeutics Globally Network (formerly the AIDS Clinical Trials Group), the Statistical Data and Management Center, participating CRSs, and Specialty Laboratories. They also thank AbbVie, Inc., for providing glecaprevir-pibrentasvir. AbbVie, Inc., had no role in gathering or preparation of data or in the writing of the manuscript.

Financial support. This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers UM1 AI068634, UM1 AI068636, and UM1 AI106701. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The research has also been supported in part by AbbVie, Inc.

Additional A5380 study team members. Shahadah Bailey, Stephanie Caruso, Allegra Cermak, Nuntisa Chotirosniramit, Nickson Chepkwony, Jagpreet Chhatwal, Dichaba Siane, Austin Glick, Cherisse Heirs, Laura Hovind, Faye Landsman, Kacey Matecki, Jennifer McClaren, Esmelda Montalban, Aspara Nair, Cynthia Parker, Michelle Seamann, Katherine Shin, Shannon Sloan, Dean Soko, Heather Sprenger, Vincent Vu, and Frances Whalen.

A5380 site investigators. Gabriela Lisseth Umana Robleda, MD, and Lucimar Salgado, RN, Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS (Site 12101), grant number UM1 AI069476; Jay Dwyer, RN, Dennis Dentoni-Lasofsky, and Cecilia Rivas Alfaro, UCSF AIDS CRS (Site 801), grant number UM1 AI069496; Rebecca Fry, FNP, and Celine Arar, Weill Cornell Uptown CRS (Site 7803), grant numbers UM1 AI069419 and UL1 TR000457; Todd Stroberg, RN, and Shaun Barcavage, Weill Cornell Chelsea CRS (Site 7804), grant numbers UM1 AI069419 and UL1 TR000457; Sarah Henn and Megan Dieterich, PA-C, Whitman-Walker Health (Site 31791), grant number UM1 AI069465; Teri Flynn, ANP-BC, and Amy Sbrolla, RN BSN, Massachusetts General Hospital (Site 101), grant number UM1 AI069412; Nina Kim, MD, and Rachel Bender Ignacio, MD, University of Washington Positive Research CRS (Site 1401), grant number UM1 AI069481; Mark Sulkowski, MD, Juhi Moon, MD, Becky Becker, RN, and Sara Mekhael, RN, Johns Hopkins University CRS (Site 201), grant number UM1 AI069465; Michael T Yin, MD, and Ariana Pazmino, MS, RN, Miriam Chicurel-Bayard, and Jaclyn Leone, Chapel Hill CRS (Site 3201), grant number 5UM1 AI069423; Columbia P&S CRS (Site 30329), grant number UM1 AI069470, Vanessa Sutton, NP, and Nicola Haakonsen, University of Colorado Hospital CRS (Site 6101), grant number UM1 AI069432; George Lara-Paez and Steven Hendrickx, UCSD AVRC (Site 701), grant number UM1 AI069432; James B. Pendleton Charitable Trust.

Potential conflicts of interest. A. Y. K. has served on a data monitoring committee for Shionogi, Inc.(Osaka, Japan). K. M. M. reports serving on a data monitoring committee for Immorna and Novo Nordisk and grants to her institution from Gilead and GlaxoSmithKline. A. F. L. reports grants to her institution from Gilead, GlaxoSmithKline, Merck, and Cepheid. D. S. F. reports grants to his institution from Merck and Gilead Pharmaceuticals. S. S. S. reports grants to his institution and honoraria from Abbott Laboratories and Gilead Sciences. J. K. is an employee and shareholder of AbbVie, Inc. (North Chicago, Illinois, USA). J. J. K. is an employee and shareholder of Merck & Co. Inc. (Rahway, New Jersey, USA). R. T. C. reports grants to his institution from Bristol-Myers Squibb, AbbVie, Boehringer, Janssen, Gilead, Merck, Roche, GSK, and Salix. L. A. S. is a former employee and current shareholder of Gilead Sciences (Foster City, California, USA). S. N. has grants to her institution from Abbott Laboratories and Gilead Sciences and is a current shareholder in Vir (San Francisco, California, USA). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.