
==== Front
J Virus Erad
J Virus Erad
Journal of Virus Eradication
2055-6640
2055-6659
Elsevier

S2055-6640(24)00025-6
10.1016/j.jve.2024.100388
100388
Original Research
A comparison of sofosbuvir/velpatasvir and glecaprevir/pibrentasvir for the treatment of hepatitis C infection among people who inject drugs
Yi Shana a
Truong David a
Conway Brian brian.conway@vidc.ca
ab⁎
a Vancouver Infectious Diseases Centre, Vancouver, British Columbia, Canada
b Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada
⁎ Corresponding author. Faculty of Health Sciences, Simon Fraser University, 8888 University Dr W, Burnaby, British Columbia, V5A 1S6, Canada. brian.conway@vidc.ca
31 8 2024
9 2024
31 8 2024
10 3 1003888 7 2024
14 8 2024
29 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

To eliminate hepatitis C (HCV) infection as a public health concern by 2030, there is a need to develop comprehensive programs among key populations such as people who use drugs (PWUD). Two highly effective regimens are available for initial therapy: glecaprevir/pibrentasvir (G/P) given as 3 tablets/day for 8 weeks and sofosbuvir/velpatasvir (S/V) given as 1 tablet/day for 12 weeks. Data evaluating the safety and efficacy comparing one regimen over another in a population of PWUD is limited.

Methods

Patients were identified through outreach events. Viremic patients were offered HCV treatment within a multidisciplinary program. This retrospective comparison analysis focuses on the first 120 sequential individuals who chose either treatment and in whom a definitive outcome of treatment was available between March 1, 2019 and February 29, 2024. The primary outcomes of the analysis were cure of HCV infection and its corelates, as well as safety of the individual regimens.

Results

We successfully identified 120 within each of the G/P and S/V treatment groups. Of those on G/P, we note 28.3 % female, 20.9 % Indigenous, 70.8 % using fentanyl, and 51.3 % with unstable housing. Of those on S/V, we note 25.8 % female, 20.8 % Indigenous, and 75 % using fentanyl and 56.7 % with unstable housing. Overall, 118 and 115 patients completed therapy on G/P and S/V, respectively. A total of 118 and 115 completed therapy on G/P and S/V, with virologic relapse documented in 3 and 2 participants on G/P and S/V, respectively. The ITT/mITT cure rates for G/P and S/V were 95.0 %/97.4 % and 94.2 %/98.3 %, respectively. There were 5 drug overdose deaths among those who initiated treatment, one on G/P and 4 on S/V. Conclusion: We have evaluated two highly effective regimens in a group of inner-city PWUD, with comparable success rates well in excess of 90 %. Our data supports the offer of both options for the treatment of PWUD with HCV infection.

Keywords

DAA
Hepatitis C
Glecaprevir/pibrentasvir
Sofosbuvir/velpatasvir
People who inject drugs
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pmc1 Introduction

In 2016, the World Health Organization (WHO) put forward the ambitious goal to eliminate HCV infection as a public health concern by 2030. To do so, 90 % of infected individuals would need to be diagnosed and 80 % successfully treated.1 In this way, incident infections would be reduced by 90 % and disease-associated mortality would be reduced by 65 %. Globally, an estimated 71 million people are living with chronic HCV infection, including at least 5.8 million people who use or inject drugs (PWUD).1 In addition, approximately 1.5 million new infections are recorded per year.2 Treatment coverage among PWUD is still challenging with less than 20 % HCV treatment coverage for this marginalized population in Canada,3 confirming that this issue will remain a significant public health burden for years to come.

Several population-specific approaches will be required to increase the rate of diagnosis and treatment of HCV infection. This is particularly true for vulnerable inner-city residents, many of whom are active drug users. This key population encounters specific challenges that limit meaningful engagement in care which reduces their HCV treatment uptake.4 Meaningful provision of services to marginalized populations needs to be addressed via focused outreach programs to provide point-of-care interventions linked to strategies to immediately engage viremic individuals in care to receive treatment.

With effective development of direct-acting antiviral agents (DAA), HCV is almost universally curable,5,6 We are fortunate, in many countries (including Canada), to have equal, low-barrier access to two different regimens to achieve this goal. The combination of sofosbuvir and velpatasvir (S/V) is given as one pill once a day for 12 weeks.5,7, 8, 9, 10 Its use has led to cure rates exceeding 95 % in a broad range of previously untreated individuals, including all patients with cirrhosis. Among PWUD, the SIMPLIFY study was conducted, with 97/103 (94 %) participants cured with S/V.10 The combination of glecaprevir and pibrentasvir (G/P) is given as 3 pills once a day with food for 8 weeks.11, 12, 13 Its use has led to cure rates exceeding 95 % in a broad range of previously untreated individuals, including all patients with compensated cirrhosis.14 Among PWUD, the GRAND PLAN study was conducted, with 108/111 (97 %) participants cured with G/P.15

The HCV management guidelines highlight crucial differences between the DAA regimens of G/P and S/V, particularly in terms of drug-drug interactions, pharmacokinetics, and patient-specific factors, such as possible interactions between G/P and statins and anticonvulsants. Conversely, there remains some concern about the interaction between S/V and proton pump inhibitors as well as other acid-reducing agents. For a given patient, the selection of a specific regimen should be made to maximize both safety and efficacy. As such, the discussion on the use of DAAs in treating HCV infection must be fully aligned with these considerations.

There has not been a head-to-head comparison of S/V and G/P as first line therapy, among PWUD or otherwise. It is unlikely that such a study would ever be conducted. Given the high degree of efficacy for each regimen individually demonstrated in a broad range of clinical trials and no demonstration of reduced efficacy of one or the other in any specific group (other than G/P being contraindicated in patients with decompensated cirrhosis) many would argue that it is not needed. However, there would be some value in comparing their relative efficacies in a real-world setting, where both therapies are offered equally to large numbers of individuals over time. With this in mind, we undertook a retrospective evaluation of the efficacy of S/V and G/P among PWUD offered therapy in the context of a specific high-volume community-based program designed to promote diagnosis and engagement in care.

2 Methods

2.1 Study design

This is a retrospective chart review-based study to evaluate the efficacy and safety of two antiviral regimens, G/P and S/V, prescribed for the treatment of HCV infection at the Vancouver Infectious Diseases Centre (VIDC) in Vancouver, Canada. Individuals with HCV infection living in the inner-city were identified through dedicated outreach programs conducted at their place of residence. Point-of-care testing for HCV antibodies was performed, If positive, phlebotomy was immediately done on site for HCV RNA testing, with results available within one week. In some cases, historical positive HCV RNA tests were identified in the provincial laboratory database and used to confirm the presence of viremia. An offer of treatment was then made within the context of a multidisciplinary program to address medical, social, mental health and addiction-related needs. With the exception of patients with decompensated cirrhosis, an offer of both S/V and G/P therapy was made. Both are fully funded by governmental authorities. Patient preference generally guided the therapeutic selection, with approximately equal preference for either treatment. Among the prescribers within the program, there was no evidence, in clinical practice, of preference of one regimen over the other. Participants were 19 years or older, documented to be viremic with any HCV genotype at the time of enrollment, previously untreated for HCV infection and actively using or injecting drugs or having been documented to be doing so in the previous 3 months. Individuals with a specific contraindication to the use of S/V or G/P were excluded. Antiviral medications were dispensed weekly, with the possibility of daily dispensing if there were adherence concerns. Additionally, during treatment, a participant could be evaluated by a physician for acute medical conditions, to discuss issues of side effects or adherence or to assess any other concerns. Additional clinical and laboratory evaluations were completed as indicated, as part of routine medical care. After treatment was completed, individuals remained within the multidisciplinary care program to ensure that the outcome of HCV therapy could be ascertained.

Counting back from August 2022, the chart review was conducted in the first 120 sequential individuals receiving either G/P or S/V regimens in whom a definitive outcome of HCV treatment had been ascertained. The primary endpoint of the study was the proportion of participants achieving cure of HCV infection (undetectable HCV RNA 12 or more weeks after the end of S/V or G/P treatment, or SVR12). Secondary endpoints of interest included comparability of subjects selecting either S/V or G/P as their preferred regimen, correlates of not achieving SVR12 with either regimen, rate of premature treatment discontinuation, loss to follow up during the study, and mortality.

Relapse and reinfection were differentiated through review of HCV RNA measures at the end of treatment (EOT), as well as 4 and 12 weeks later. In the absence of sequencing and genotypic data, relapse or virologic failure was the assumed outcome if HCV RNA was detected at the end of treatment or within 12 weeks thereafter. Reinfection was identified when the HCV RNA bloodwork at EOT, SVR 4, and/or SVR 12 showed negative results, but subsequently indicated a positive HCV RNA result.

3 Statistical analysis

For this retrospective comparison study, descriptive statistics were utilized to report on the primary and secondary outcomes.

3.1 Patient consent

The study protocol was approved by Advarra and was conducted according to the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice guidelines. In addition, all participants provided specific written consent for the utilization of their demographic information in this research study.

4 Results

By pre-established design, 240 subjects were included, 120 each in the S/V and G/P treatment groups. To generate this dataset, treatment outcomes confirmed between March 1, 2019 and February 29, 2024 were considered among all participants. In our subjects, we noted a median age of 47 (IQR 38–55, range 22–77) years, 27 % female and 20.8 % Indigenous (Table 1). 72.9 % of the participants in this study were active fentanyl users and 53.3 % experiencing unstable housing defined by living in shelters, temporary single room accommodation centers (SRAs), or experiencing homelessness. In comparing demographic characteristics between participant in the G/P treatment group or in the S/V treatment group (Table 1), age, and sex were comparable. The median age at the time of enrollment was 45 years (IQR: 36.5–54) for the G/P group and 50 years (IQR: 39–56) for the S/V group, with age ranging from a minimum of 22 to a maximum of 75 years for G/P and 27 to 77 years for S/V, respectively (Table 1). We noted 34 (28.3 %) and 31 (25.8 %) of the participants were female in G/P and S/V groups, respectively. Additionally, 20.9 % of participants in G/P group and 20.8 % of participants in S/V group self-identified as Indigenous. Participants' drug use profiles, ascertained through self-reports, revealed a predominant utilization of fentanyl in both groups, 85 (70.8 %) and 90 (75 %) of participants on G/P and S/V. Lower rates of stimulant (amphetamine/cocaine) use were noted in subjects receiving G/P, as well as lower rates of alcohol use. The prevalence of HCV genotype 1 infection was predominant in both treatment cohorts, accounting for 64 (54.7 %) in the G/P treatment group and 62 (51.7 %) in the S/V treatment group, with genotype 3 being the second most prevalent one, representing 38 (32.5 %) in the G/P group and 49 (40.8 %) in the S/V group. Notably, higher FibroScan scores indicating stages F3-F4 were prevalent in the S/V group 25 (29.2 %).Table 1 Baseline characteristics of participants who completed either G/P or S/V treatment regimens.

Table 1Characteristics		G/P	S/V	All	
N = 120	N = 120	N = 240	
Age (years)	Median	45	50	47	
	Min	22	27	22	
	Max	75	77	77	
	IQR	36.5–54	39–56	38–55	
Sex	Female	34 (28.3 %)	31 (25.8 %)	65 (27 %)	
	Male	86 (71.7 %)	89 (74.2 %)	175 (72.9 %)	
Ethnicity	Caucasian	90 (75.0 %)	90 (75 %)	180 (75 %)	
	Indigenous	25 (20.9 %)	25 (20.8 %)	50 (20.8 %)	
	Others	5 (4.1 %)	5 (4.2 %)	10 (4.2 %)	
Genotype	1	64 (54.7 %)	62 (51.7 %)	126 (52.5 %)	
	2	13 (11.1 %)	4 (3.3 %)	17 (7 %)	
	3	38 (32.5 %)	49 (40.8 %)	87 (36.2 %)	
	N/A	5 (4.2 %)	5 (4.2 %)	10 (4.2 %)	
Fibrosis Stage	F0-F2	109 (91.6 %)	82 (68.3 %)	191 (79.6 %)	
	F3-F4	10 (8.4 %)	35 (29.2 %)	45 (18.8 %)	
	N/A	1 (0.8 %)	3 (2.5 %)	4 (1.6 %)	
Drug use profile	Amphetamine	47 (39.2 %)	77 (64.2 %)	124 (51.6 %)	
	Benzodiazepine	5 (4.2 %)	21 (17.5 %)	26 (10.8 %)	
	Cocaine	19 (15.8 %)	59 (49.2 %)	78 (32.5 %)	
	Fentanyl	85 (70.8 %)	90 (75 %)	175 (72.9 %)
87 (36.2 %)	
	Methadone	34 (28.3 %)	53 (44.2 %)	
Alcohol	Yes	36 (30 %)	59 (49.2 %)
59 (49.2 %)	95 (39.5 %)
140 (58.3 %)	
	No	81 (69.2 %)	
Unstable housing	Yes	60 (51.3 %)	68 (56.7 %)	128 (53.3)	
	No	54 (46.1 %)	52 (43.3 %)	106 (44.2 %)	

A focused examination of the indigenous subset within our study revealed a total of 26 subjects receiving treatment with G/P and 25 subjects receiving treatment with S/V (Table 2). In our total indigenous cohort, the median age was 47 (IQR = 38–55.5, range 23–69) years. The distribution of sex at birth resulted in 15 (29.4 %) females and 36 (70.6 %) males. More specifically, more females were enrolled in the G/P treatment group, with 10 (38.4 %) females compared to 5 (20 %) females in the S/V group. The prevalence of FibroScan scores denoting stages F3-F4 was notably higher in the S/V treatment group, accounting for 10 (40 %), as opposed to 2 (8 %) in the G/P group. Fentanyl emerged as the predominant drug of choice in both treatment groups, with rates of 18 (72 %) and 17 (68 %) for G/P and S/V, respectively. The indigenous subset exhibited elevated levels of amphetamine and cocaine use in the S/V treatment groups, registering at 48 % cocaine use, in contrast to 28 % for G/P, and 60 % amphetamine use in the S/V group, in contrast to 44 % for G/P, respectively. Furthermore, similar to the broader demographic cohort, unstable housing conditions were prevalent among over half of the indigenous participants, with proportions of 64 % and 68 % for G/P and S/V, respectively.Table 2 Baseline characteristics of participants who self identified as Indigenous who completed G/P or S/V treatment regimens.

Table 2		G/P	S/V	All	
Indigenouscharacteristics	N=26	N=25	N=51	
Age (years)	Median	46	51	47	
	Min	23	31	23	
	Max	63	69	69	
	IQR	38–52	38–57	38–55.5	
Sex	Female	10 (38.4 %)	5 (20 %)	15 (29.4 %)	
	Male	16 (64 %)	20 (80 %)	36 (70.6 %)	
Genotype	1	14 (56 %)	17 (68 %)	31 (60.8 %)	
	2	5 (20 %)	2(8 %)	7 (13.7 %)	
	3	6 (24 %)	6 (24 %)	12 (23.5 %)	
	N/A	1 (3.85 %)		1 (1.2 %)	
Fibrosis Stage	F0-F2	24 (96 %)	14 (56 %)	38 (74.5 %)	
	F3-F4	2 (8 %)	10 (40 %)	12 (23.5 %)	
	N/A		1 (4 %)	1 (1.2 %)	
Drug use profile	Amphetamine	11 (44 %)	15 (60 %)	26 (51 %)	
	Benzodiazepine	4 (16 %)	3 (12 %)	7 (13.7 %)	
	Cocaine	7 (28 %)	12 (48 %)	19 (37.2 %)	
	Fentanyl	18 (72 %)	17 (68 %)	35 (68.6 %)	
	Methadone	11 (44 %)	10 (40 %)	21 (41.2 %)	
Alcohol	Yes	10 (40 %)	18 (72 %)	28 (54.9 %)	
	No	15 (60 %)	7 (28 %)	22 (43.1 %)	
Unstable housing	Yes	16 (64 %)	17 (68 %)	33 (64.7 %)	
	No	10 (40 %)	8 (32 %)	18 (35.3 %)	

Next, we investigated the cascades of care for each treatment group (Fig. 1A and B). Out of 120 subjects who initiated G/P treatment, 118 completed the 8 weeks treatment, while one participant was lost to follow up during treatment and one withdrew from the study. Out of 118 subject who completed the G/P treatment, 114 achieved HCV cure, 1 subject died due to overdose, and 3 showed relapse (Fig. 1A). The G/P treatment resulted in 95.0 % (114/120) cure rate by ITT, 97.4 % (114/117) by mITT. We also investigated the cascade of care for the S/V treatment group (Fig. 1B). Out of 120 subjects who were enrolled in the S/V treatment group, 118 initiated treatment and 2 subjects died due to drug-related causes before initiating treatment. Out of 118 subjects who initiated S/V treatment, 115 completed 12 weeks treatment with 2 subjects dying due to overdose after initiating treatment and 1 subject withdrawing from the study. Out of 115 subjects who completed the S/V treatment, 113 achieved SVR12 and were cured, 2 subjects showed relapse (Fig. 1B). The S/V treatment resulted in 94.2 % (113/120) cure rate by ITT, 98.3 % (113/115) by mITT. These results indicate that both treatment regimens, G/P and S/V, show high efficacy in achieving SVR12 with no significant differences among marginalized population such as PWUD.Fig. 1 HCV cascade of care for G/P and S/V treatments. A) Cascade of care for G/P. B) Cascade of care for S/V. LTFU: Lost to follow up.

Fig. 1

Instances of virologic relapse are summarized in Table 3. We have investigated the characteristics of 5 documented cases: 3 were on G/P, and 2 on S/V. The 5 individuals were aged between 33 and 56 years at enrollment, comprising 4 males and 1 female, all with unstable housing and actively utilizing fentanyl. FibroScan scores ranged from F0 to F2, and HCV genotypes included 1A, 2, and 3A. For those in whom a virologic relapse was documented, second-line HCV treatment with the combination of sofosbuvir, velpatasvir, and voxilaprevir was offered as retreatment, free of charge. To date, 3 individuals have achieved SVR12 through successful retreatment (see Table 4).Table 3 Participants with documented virological relapse.

Table 3Treatment	ID	Age at baseline	Sex	Ethnicity	Genotype	Fibrescore	Active Drug Use	Type of Drug	Unstable Housing	Baseline Viral Load (IU/ml)	Confirmation Viral Load at Point of Relapse	
	22	44	M	Caucasian	1A	F0	Y	F,M	Y	3,038,030	61,826	
G/P	99	52	M	Caucasian	3A	F0	Y	A,F	y	10,969,093	14,858,439	
	124	40	F	Indigenous	2	F2	Y	C,F	Y	2,942,871	8,479,148	
S/V	5	56	M	Caucasian	1A	F1	Y	A,C	Y	1277837	566997	
	87	33	M	Indigenous	1A	F1	Y	A,C,O	Y	399678	370532	
Baseline characteristics of participants with documented virologic relapse and their baseline and confirmation viral loads at point of relapse. All patients were active drug users and had unstable housing.

aA, Amphetamines; B, Benzodiaspan; C, Cocaine; M, Methadone; O, Opiates; F, Fentanyl; CAN, Cannabis.

Table 4 Participants with documented viral re-infection.

Table 4Treatment	ID	Age at baseline	Sex	Ethnicity	Genotype	Fibrescore	Active Drug Use	Type of Drug	Unstable Housing	Re-infected confirmation viral load (IU/ml)	Current RNA status	
	16	63	M	Indigenous	3A	F1	Y	O	Y	245	2591	
	38	29	M	Caucasian	1A	F0	Y	A,B,C,CAN,M,O	Y	79090	50	
G/P	43	29	M	Caucasian	3A	F0	Y	A,M,O	Y	552987	Undetectable -Cured by S/V	
	51	38	M	Indigenous	2B	F0	Y	A,B,M,O	Y	7688	Undetectable -Cured by S/V	
	52	27	M	Caucasian	1A	F1	Y	M	Y	3911	94890	
	2	56	M	Caucasian	3A	F4	Y	A,M,O	Y	103	104151	
	11	35	F	Caucasian	1A	F0	Y	O	Y	275760	2295924	
S/V	32	49	M	Caucasian	1A	F1	Y	C,CAN,M,O	Y	11521881	14331977	
	38	57	M	Caucasian	1A	F1	Y	A,C,O	Y	160096	Undetectable -Cured by S/V	
	90	29	M	Caucasian	1A	F0	Y	A,C,CAN,O	Y	850263	Undetectable -Cured by G/P	
	120	51	F	Caucasian	1B	F0	Y	A,C,CAN,M,O	Y	2281	Undetectable -Cured by S/V	
Baseline characteristics of participants with documented virologic re-infection. All patients were active drug users and had unstable housing.

aA, Amphetamines; B, Benzodiazepine; C, Cocaine; M, Methadone; O, Opiates; F, Fentanyl; CAN, Cannabis.

5 Discussion

Numerous studies have substantiated the effectiveness and safety of DAA therapy in the treatment of HCV within populations characterized as PWUD, even when concurrent substance use persists.10,15, 16, 17, 18, 19, 20 Interventions using currently available regimens have demonstrated high sustained virologic cure rates, comparable to those observed in cohorts without a history of drug use.21,22 This is true of both S/V and G/P in clinical trials of PWUD with HIV infection. As such, both are commonly offered in parallel to each other, especially in high volume centers such as ours. There is no comparative data for G/P vs. S/V in clinical trials or otherwise. We therefore aimed to address this issue by identifying large numbers of treated patients in whom the result of treatment was known to attempt to discern if outcomes were comparable in a setting where patients were identified and treated in a uniform and systematic way. In addition, this analysis should allow us to evaluate whether our perceived practice of offering both treatments equally (excluding decompensated cirrhotic individuals) was borne out in clinical practice, or whether a more directed assignment of patients with certain characteristics to one regimen or the other should be implemented.

Baseline characteristics were quite comparable between those who received either G/P or S/V. It is not expected that minor difference in non-opiate drug use pattern and sex distribution between the two groups (most noted among indigenous women) would have affected treatment outcomes. Similarly, an imbalance with a slight excess of those with more advanced fibrosis on S/V had no impact on our findings, given that all virologic relapses were documented among individuals with mild liver fibrosis. By strict ITT analysis, cure rate among PWUD undergoing treatment with G/P was 95.0 % (114/120), 97.4 % (114/117) by mITT analysis. This compares to 94.2 % (113/120) and 98.3 % (113/115) on S/V. These figures are consistent to those reported in the medical literature, including among PWUD.15,21,22,23, 24, 25, 26, 27, 28 The results from this retrospective comparison study seem to indicate that both G/P and S/V are highly effective in treating PWUD cohorts and neither is inherently superior to this other.

In our study, among our cohort of PWUD, treatment adherence was high in subjects enrolled in both treatment regimens, with 118 out of 120 completing the G/P treatment course and 115 out of 120 the S/V treatment course. This aligns with prior studies demonstrating low treatment discontinuation rates in people who inject drugs,29, 30, 31,32 especially if they are treated in appropriate settings. Out of a total of 240 subjects in this retrospective study, we documented only five overdose deaths in the setting of an opioid crisis where three deaths/day are reported within the inner city of Vancouver, with a population of about 15,000 individuals.33 There was one from the G/P treatment group and four from the S/V treatment group. This data suggests that engagement in care may play a role in reducing opioid-related mortality and reassures us about the use of G/P in this population, where there was a concern about a drug interaction with fentanyl, possibly increasing its toxicity. A recent observational study observed no link between recorded adverse events and any specific drug administration regimen among PWUD who use fentanyl.34

The lower withdrawal and lost-to-follow-up (LTFU) rates in the present study compared to other cohorts can be largely attributed to the model of care and the multidisciplinary approach employed in our program. This approach plays a crucial role in enhancing participant engagement and retention by providing comprehensive longitudinal support. The multidisciplinary team, which includes physicians, nurses, and outreach workers, offers holistic care that addresses not only the medical needs of participants but also their social, psychological, and substance use-related challenges. This comprehensive support structure is likely a significant factor in keeping withdrawal and LTFU rates low. Another key aspect is the emphasis on personalized care plans tailored to each participant's unique needs. This approach helps build trust with participants, making them more likely to stay engaged in care, complete treatment and remain engaged so that the outcome of HCV therapy can be ascertained. If an individual is not present for a scheduled follow-up visit, strategies for engagement through our outreach programs are immediately implemented. Lastly, culturally sensitive care, which considers the cultural and social context of PWUD, plays a significant role in fostering a sense of belonging and reducing stigma.

To achieve the WHO goal of HCV elimination by 2030, a systematic approach to the diagnosis and treatment of infection in all target populations will be needed, including among PWUD. In many cases, the availability of different individualized therapeutic options will be important. We have evaluated two highly effective regimens in a group of inner-city PWUD enriched for fentanyl use and unstable housing. Although this was not a randomized trial, we will note that among 240 subjects included in this analysis (120 per treatment arm), baseline demographic and disease characteristics were highly comparable, as noted above. Our data supports the offer of both G/P and S/V regimens within the setting of a multidisciplinary program for the treatment of PWUD with HCV infection, irrespective of the level of stability.

6 Limitations

One of the limitations of our findings is that they were generated as part of a retrospective chart review, not a randomized clinical trial. We are therefore relying on non-directed prescribing of either regimen in a way that could affect the outcome. This is not a major concern here, as the groups were comparable according to key parameters of interest. Further, very high success rates were observed in all cases. The key predictors of failure were factors of vulnerability (ongoing fentanyl use and unstable housing), issues completely unrelated to the choice of treatment. Secondly, the reporting and collection of patient-level data in self-reported drug use, history of overdose, and alcohol use are subject to considerable bias arising from incomplete information or stigma associated with substance use and may underestimate vulnerability. In our experience, our low-threshold community-based program mitigates this risk, as reflected in the very high reported rates of drug use here. Studies conducted at centers similar to ours have suggested that collection of substance use data and other stigmatized behaviors yield reliable results.31 Thirdly, the scope and comprehensive nature of the services we offer would yield higher success rates and reduce our ability to detect any differences in treatment efficacy should they exist. As an example, without adherence support (which may not be available in all clinics treating PWUD with HCV infection), treatment discontinuations would be more frequent and disproportionately reduce the measured cure rates for individuals receiving a longer course of treatment. If this is correct, it backs the need to have such adherence support in place to ensure that the benefits of intervention are maximized and that something approaching the infrastructure that we provide should be the standard for health care delivery to inner city populations.

7 Conclusion

We have demonstrated that high and consistent treatment outcomes can be achieved with either treatment option (G/P or S/V) in individuals who are active drug users and who are committed to starting HCV treatment. With appropriate support, treatment completion rates were equally high with both approaches, and there were no concerns about the safety of G/P or S/V in this population.

Funding statements

The funder had no role in the analysis or interpretation of the study results and did not have access to the raw data. VIDC staff designed and implemented the study and evaluated its outcome under the supervision of Brian Conway<a name = "Line_manuscript_53">

Informed consent statement

All cohort participants provided written informed consent to the access of their personal health numbers, linkage to vaccination status and history, and the questionnaire survey.

CRediT authorship contribution statement

Shana Yi: Writing – review & editing, Writing – original draft, Visualization, Formal analysis, Data curation, Conceptualization. David Truong: Writing – review & editing, Supervision, Investigation. Brian Conway: Writing – review & editing, Writing – original draft, Supervision, Investigation, Conceptualization.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests.- SY has no conflict of interest to declare.

- DT has received honoraria and/or acted as remunerated advisor for AbbVie and Gilead Sciences.

- BC has received research grants, honoraria and/or acted as a remunerated advisor for AbbVie, Astra Zeneca, Gilead Sciences, GSK, Indivior Canada, Merck, Moderna, Sanofi Pasteur, Seqirus, and ViiV Healthcare. In particular, AbbVie and Gilead Sciences have funded the community pop-up clinic program in a direct way.

Data availability

Data will be made available on request.
==== Refs
References

1 World Health Organisation. Hepatitis C Fact sheet.
2 Brunner N. Bruggmann P. Trends of the global hepatitis C disease burden: strategies to achieve elimination J Prev Med Public Health 54 4 2021 Jul 251 258 34370938
3 Hajarizadeh B. Kairouz A. Ottaviano S. Global, regional, and country-level coverage of testing and treatment for HIV and hepatitis C infection among people who inject drugs: a systematic review Lancet Glob Health 11 12 2023 Dec e1885 e1898 37973339
4 Falade‐Nwulia O. Gicquelais R.E. Astemborski J. Hepatitis C treatment uptake among people who inject drugs in the oral direct‐acting antiviral era Liver Int 40 10 2020 Oct 23 2407 2416 32770638
5 Flamm S. Lawitz E. Borg B. Efficacy and safety of sofosbuvir/velpatasvir plus ribavirin in patients with hepatitis C virus-related decompensated cirrhosis Viruses 15 10 2023 Sep 29 2026 37896803
6 Alimohammadi A. Holeksa J. Thiam A. Truong D. Conway B. Real-world efficacy of direct-acting antiviral therapy for HCV infection affecting people who inject drugs delivered in a multidisciplinary setting Open Forum Infect Dis 5 6 2018 ofy120
7 Grebely J. Feld J.J. Wyles D. Sofosbuvir-based direct-acting antiviral therapies for HCV in people receiving opioid substitution therapy: an analysis of phase 3 studies Open Forum Infect Dis 5 2 2018 Feb 1
8 Takehara T. Izumi N. Mochida S. Sofosbuvir–velpatasvir in adults with hepatitis C virus infection and compensated cirrhosis in Japan Hepatol Res 52 10 2022 Oct 8 833 840 35802063
9 Suzuki H. Sato K. Takezawa J. Yamada S. Uraoka T. Okamoto H. Successful prolonged treatment with sofosbuvir/velpatasvir for a hepatitis C patient with decompensated cirrhosis and treatment failure after 12-week therapy Clin J Gastroenterol 17 2024 106 111 37792179
10 Grebely J. Dalgard O. Conway B. Sofosbuvir and velpatasvir for hepatitis C virus infection in people with recent injection drug use (SIMPLIFY): an open-label, single-arm, phase 4, multicentre trial Lancet Gastroenterol Hepatol 3 3 2018 Mar 153 161 29310928
11 Zeuzem S. Foster G.R. Wang S. Glecaprevir–pibrentasvir for 8 or 12 weeks in HCV genotype 1 or 3 infection N Engl J Med 378 4 2018 Jan 25 354 369 29365309
12 Aghemo A. Persico M. D'Ambrosio R. Safety and effectiveness of 8 weeks of Glecaprevir/Pibrentasvir in challenging HCV patients: Italian data from the CREST study PLoS One 18 2 2023 Feb 2 e0280165
13 Pugliese N. Calvaruso V. Masarone M. Glecaprevir/Pibrentasvir is safe and effective in Italian patients with chronic hepatitis C aged 75 years or older: a multicentre study Liver Int 43 7 2023 Jul 30 1440 1445 37122194
14 Vera J. Gomes A. Póvoas D. Real-world effectiveness and safety of glecaprevir/pibrentasvir for the treatment of chronic hepatitis C: a prospective cohort study in Portugal Acta Med Port 37 5 2024 Feb 7 323 333 38325411
15 Conway B. Yi S. Yung R. Sharma S. GRAND PLAN: safety and efficacy of glecaprevir/pibrentasvir for the treatment of hepatitis C virus infection among people initially disengaged from health care who use drugs—a systematic multidisciplinary approach Open Forum Infect Dis 11 3 2024 Feb 29
16 Alimohammadi A. Holeksa J. Parsons R. Diagnosis and treatment of hepatitis C virus infection: a tool for engagement with people who inject drugs in Vancouver's Downtown Eastside Canadian Liver Journal 1 2 2018 Jul 14 33 35990714
17 Asher A.K. Portillo C.J. Cooper B.A. Dawson-Rose C. Vlahov D. Page K.A. Clinicians' views of hepatitis C virus treatment candidacy with direct-acting antiviral regimens for people who inject drugs Subst Use Misuse 51 9 2016 Jul 28 1218 1223 27219274
18 Graf C. Mücke M.M. Dultz G. Efficacy of direct-acting antivirals for chronic hepatitis C virus infection in people who inject drugs or receive opioid substitution therapy: a systematic review and meta-analysis Clin Infect Dis 70 11 2020 May 23 2355 2365 31513710
19 Grebely J. Gilliver R. McNaughton T. Single-visit hepatitis C point-of-care testing, linkage to nursing care, and peer-supported treatment among people with recent injecting drug use at a peer-led needle and syringe program: the TEMPO Pilot Study Int J Drug Pol 114 2023 Apr 103982
20 Grebely J. Hajarizadeh B. Dore G.J. Direct-acting antiviral agents for HCV infection affecting people who inject drugs Nat Rev Gastroenterol Hepatol 14 11 2017 Nov 23 641 651 28831184
21 Graf C. Mücke M.M. Dultz G. Efficacy of direct-acting antivirals for chronic hepatitis C virus infection in people who inject drugs or receive opioid substitution therapy: a systematic review and meta-analysis Clin Infect Dis 70 11 2020 May 23 2355 2365 31513710
22 Hajarizadeh B. Cunningham E.B. Reid H. Law M. Dore G.J. Grebely J. Direct-acting antiviral treatment for hepatitis C among people who use or inject drugs: a systematic review and meta-analysis Lancet Gastroenterol Hepatol 3 11 2018 Nov 754 767 30245064
23 Grebely J. Dalgard O. Conway B. Sofosbuvir and velpatasvir for hepatitis C virus infection in people with recent injection drug use (SIMPLIFY): an open-label, single-arm, phase 4, multicentre trial Lancet Gastroenterol Hepatol 3 3 2018 Mar 153 161 29310928
24 Kwo P.Y. Poordad F. Asatryan A. Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1–6 without cirrhosis J Hepatol 67 2 2017 Aug 263 271 28412293
25 Gane E. Poordad F. Wang S. High efficacy of ABT-493 and ABT-530 treatment in patients with HCV genotype 1 or 3 infection and compensated cirrhosis Gastroenterology 151 4 2016 Oct 651 659.e1 27456384
26 Gountas I. Sypsa V. Blach S. Razavi H. Hatzakis A. HCV elimination among people who inject drugs. Modelling pre- and post–WHO elimination era PLoS One 13 8 2018 Aug 16 e0202109
27 O'Sullivan M. Jones A. Mourad A. Haddadin Y. Verma S. Excellent hepatitis C virus cure rates despite increasing complexity of people who use drugs: integrated‐Test‐stage Treat study final outcomes J Viral Hepat 31 2 2024 Feb 28 66 77 38018328
28 Mangia A. Rina M.F. Canosa A. Increased Hepatitis C virus screening, diagnosis and linkage to care rates among people who use drugs through a patient‐centered program from Italy United European Gastroenterol J 9 10 2021 Dec 26 1109 1118
29 Holeksa J. Magel T. Alimohammadi A. Low rate of reinfection among a cohort of people who use drugs successfully treated for hepatitis C virus infection in Vancouver, Canada Int J Drug Pol 72 2019 Oct 177 180
30 Akiyama M.J. Cleland C.M. Lizcano J.A. Cherutich P. Kurth A.E. Prevalence, estimated incidence, risk behaviours, and genotypic distribution of hepatitis C virus among people who inject drugs accessing harm-reduction services in Kenya: a retrospective cohort study Lancet Infect Dis 19 11 2019 Nov 1255 1263 31540840
31 Jenkins W.D. Bolinski R. Bresett J. COVID‐19 during the opioid epidemic – exacerbation of stigma and vulnerabilities J Rural Health 37 1 2021 Jan 172 174 32277731
32 Mukherjee D. Collins M. Dylla D.E. Assessment of drug–drug interaction risk between intravenous fentanyl and the glecaprevir/pibrentasvir combination regimen in hepatitis C patients using physiologically based pharmacokinetic modeling and simulations Infect Dis Ther 12 8 2023 Aug 20 2057 2070 37470926
33 BC Government More than 2,500 lives lost to toxic drugs in 2023 2024
34 Martinez A. Khan T. Dylla D.E. Reported adverse events related to use of hepatitis C virus direct-acting antivirals with opioids: 2017–2021 Harm Reduct J 20 1 2023 Oct 1 142 37779203
