REVIEWS E L I M I N AT I N G V I R A L H E PAT I T I S
Direct-acting antiviral agents for HCV infection affecting people who inject drugs Jason Grebely, Behzad Hajarizadeh and Gregory J. Dore
Abstract | Globally, 12 million people are estimated to have injected drugs in the past year, 50% of whom have chronic HCV infection, with people who have previously injected drugs presenting an additional large reservoir of infection. The availability of simple and tolerable interferon-free direct-acting antiviral agents (DAAs) for HCV infection, which have a cure rate of >95% represents one of the most exciting advances in clinical medicine in the past few decades. Adherence and response to DAA therapy among people who inject drugs (PWID) receiving opioid substitution therapy (OST) in clinical trials are comparable to populations without a history of injecting drugs. Further data are required among current PWID not receiving OST. Given the potential prevention benefits of treatment, DAAs have enhanced cost-effectiveness among PWID. As HCV therapy is expanded to populations of PWID with high-risk behaviours for re‑exposure, acknowledgement that HCV reinfection will occur is crucial, and appropriate strategies must be in place to maximize prevention of reinfection and offer retreatment for reinfection. This Review will also discuss essential components for broadening access to HCV care for PWID as we strive for the global elimination of HCV infection.
The Kirby Institute, UNSW Sydney, Sydney, New South Wales 2052, Australia. Correspondence to J.G. [email protected] doi:10.1038/nrgastro.2017.106 Published online 23 Aug 2017
Globally, HCV infection is a major health issue among people who inject drugs (PWID)1,2. Given the high prevalence of HCV among PWID, and ageing drug user populations, the burden of HCV-related cirrhosis, hepatocellular carcinoma (HCC) and liver-related mortality is growing 1. Although interferon-based HCV treatment in populations of PWID has been shown to be safe and effective3–6, the poor tolerability of interferon-based therapies has limited the uptake of HCV treatment among PWID7–9 and the effect of these treatments on disease burden has been minimal. The advent of simple and well-tolerated oral HCV therapeutic regimens — direct-acting antiviral agents (DAAs) — with a cure rate of >95% offers the potential to reverse the rising burden of advanced liver disease10. However, in some countries (for example, the USA), people with ongoing drug use or people receiving opioid substitution therapy (OST) are still ineligible11 or might not be considered suitable by practitioners12 to receive DAAs. The reluctance to offer HCV therapy to PWID often stems from concerns around treatment adherence, poorer outcomes than in p eople who do not inject drugs and the potential risk of HCV reinfection13.
This Review outlines the epidemiology of HCV among PWID and those receiving OST, clearly defines ‘recent PWID’ and provides updated information on DAAs for HCV infection in these populations. A particular focus is given to HCV reinfection, acknowledging that strategies are required to reduce its incidence and impact. Essential components for broadening access to HCV testing and treatment for PWID will also be discussed within the broader goal of HCV elimination.
Epidemiology and burden People with a history of injecting drug use include those who report injecting an illicit drug at least once in their life, or ‘lifetime PWID’ (FIG. 1). This population includes both former injectors having ceased injecting and ‘recent PWID’ (with definitions for ‘recent’ often varying from 1 month to 12 months depending on the study)14. Among lifetime PWID, a population of people receiving OST also exists, some of whom might also have recently injected drugs. Understanding definitions for different PWID populations is crucial to better define outcomes following DAA-based HCV therapy in different populations.
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY
ADVANCE ONLINE PUBLICATION | 1
. d e v r e s e r s t h g i r l l A . e r u t a N r e g n i r p S f o t r a p , d e t i m i L s r e h s i l b u P n a l l i m c a M 7 1 0 2 ©
REVIEWS Key points • HCV prevalence and incidence among people who inject drugs (PWID) remains high • Direct-acting antiviral agents (DAA) for HCV with cure in >95% provide a tool for addressing HCV-related liver-disease burden among PWID • Adherence and response to DAA therapy among people receiving opioid substitution therapy (OST), including those with ongoing drug use, are comparable to other HCV-infected populations, although more data are required among current PWID who are not on OST • HCV reinfection can occur, so strategies to maximize prevention of reinfection (including OST and needle and syringe programmes) and access to DAA retreatment are crucial • Improved health services for PWID are needed to enhance HCV prevention, testing, access to care and treatment • Continued global leadership and advocacy is required to ensure that HCV prevention, care and treatment for PWID are accessible to all
Globally, in 2014, 12 million people were estimated to have injected illicit drugs in the past year 15, 50% of whom had chronic HCV infection (~6 million people), with former PWID presenting an additional large reservoir of infection (exact size of this population is unknown)2. HCV genotypes 1a, 1b and 3a are common among PWID (>70% among PWID globally)16,17, genotype 4 has been documented among PWID in Europe (8% among PWID globally)17,18, and genotype 6 in Southeast Asia (20% among PWID globally)17,19. HCV infection incidence remains high in many countries9,20,21, particularly in p eople who are more recent initiates to injecting drug use20,22. The development of an HCV vaccine has been challenging 23. One HCV vaccine is being evaluated in a phase II trial to prevent HCV persistence among PWID24,25, but a highly effective HCV vaccine would seem to be more than a decade away in development. However, combined OST and needle and syringe programmes (NSP) with a high-coverage (often defined as one or more sterile needles obtained from a NSP for each injection reported), can reduce HCV incidence by up to 80%26–30, with data suggesting that OST alone can also reduce HCV transmission by up to 60% (through reductions in injecting risk behaviour)6,31–34. Data from mathematical modelling studies suggest that HCV treatment for PWID can lead to substantial reductions in HCV prevalence and reduce transmission35–39, particularly when combined with OST and NSP36. In a setting of 40% coverage OST and NSP, annually treating 1, 2.3 and 4.2 per 100 PWID would halve HCV prevalence over 10 years in settings with a chronic HCV prevalence of 20%, 40%, or 60%, respectively36. Furthermore, given the potential prevention benefits, both interferon-based and interferon-free HCV treatment among PWID is cost-effective40–42. Given that PWID are at a high risk of HCV transmission, and HCV treatment resulting in cure eliminates infectiousness, PWID are a high priority for treatment, as per international guidelines6,43–45. The availability of tolerable, highly effective, all-oral DAA-based regimens has overcome the poor tolerability of interferon-based therapy, which has been a considerable barrier for treatment of HCV. These new regimens provide an important tool to achieve scale‑up of HCV therapy in PWID.
DAA therapy outcomes among PWID DAA regimens for the treatment of HCV infection include combinations of small-molecule inhibitors of HCV proteins that are involved in HCV replication10. Phase III studies of DAA HCV therapies have reported responses in >95% of patients, minimal toxicity, short therapy duration (8–12 weeks) and regimens that can be dosed once-daily 10. Treatment of HCV infection among PWID provides benefits at both the individual and the population level. At an individual level, successful treatment of HCV infection reduces the progression of liver disease46 and reduces all-cause mortality in people with advanced liver disease47. At a population level, treatment of HCV in PWID with ongoing injecting drug use represents a potential tool to prevent onward HCV transmission among PWID37. As such, HCV treatment targeted to people with recent (that is, previous 6–12 months) or ongoing injecting drug use will be required to enable a reduction in HCV transmission. Mathematical modelling also indicates that DAA treatment of PWID who have moderate or mild liver fibrosis is cost-effective compared with delaying until cirrhosis, owing to the additional HCV prevention benefit42. Furthermore, given that the average time from HCV infection to the development of cirrhosis among PWID is 30–40 years48, delaying treatment might also prolong the period of infectiousness. Importantly, international guidelines also support the prioritization of HCV treatment among PWID6,43–45. Among people receiving OST with no recent illicit drug use, post-hoc analyses of phase II and III trials of DAA therapy have demonstrated that the sustained virologic response (SVR) is similar in those receiving and not receiving OST49–56 (TABLE 1; see Supplementary information S1 (table)). According to preliminary data, in people infected with HCV genotype 1 treated with ombitasvir, paritaprevir, ritonavir and dasabuvir with or without ribavirin49,54, or who were treated with sofosbuvir and ledipasvir 53, treatment completion was 96–100% and SVR was 94–96% in people who were receiving OST (TABLE 1; see Supplementary information S1 (table)). In the ION‑1 study, stored blood samples were tested for illicit drugs and 8% (n = 70) of samples showed illicit, noncannabis drug use by participants during therapy 53. SVR was 99% (n = 657) in those patients without illicit drug use, compared with 98% in those with cannabis use alone (n = 126, P = 0.12) and 97% in those with any illicit drug use, with or without cannabis use (n = 70, P = 0.14). As such, among people without drug use at the time of therapy initiation, subsequent illicit drug use during therapy did not have a major effect on SVR. In a post-hoc analysis of people with HCV genotypes 1–6 who received the once-daily fixed-dose combin ation of sofosbuvir and velpatasvir for 12 weeks in the ASTRAL‑1–3 studies, OST did not affect completion, adherence, SVR or safety 52; SVR at 12 weeks was 96% in those receiving OST and was 96% in those receiving OST with HCV genotype 352. In another post-hoc analysis of people on OST with HCV genotypes 1–6 who received sofosbuvir, velpatasvir, and voxilaprevir for 12 weeks in the POLARIS studies, 100% completed
2 | ADVANCE ONLINE PUBLICATION
www.nature.com/nrgastro . d e v r e s e r s t h g i r l l A . e r u t a N r e g n i r p S f o t r a p , d e t i m i L s r e h s i l b u P n a l l i m c a M 7 1 0 2 ©
REVIEWS treatment and SVR12 was 96% according to preliminary data55. Although these post-hoc analyses clearly focus on a restricted PWID population because they have small sample sizes and exclude people with recent drug use at baseline, they provide important data on outcomes following DAA therapy among a subpopulation of people receiving OST. The first clinical trial to specifically evaluate DAA therapy among people receiving OST evaluated the efficacy of ombitasvir, paritaprevir, ritonavir and dasabuvir in combination with ribavirin for 12 weeks in 38 partici pants receiving methadone (n = 19) or buprenorphine (n = 19) OST with HCV genotype 1 (84% genotype 1a) without cirrhosis57. Participants with a positive urine drug screen for noncannabis drugs at screening were excluded. Overall, 97% of participants (37 of 38) completed treatment and 97% (37 of 38) achieved SVR. Notably, people with active drug use at baseline were excluded from participating in these trials, and as such, enrolled participants represented a selected population who are likely to be engaged in care. Consequently, these findings might not be generalizable to other PWID populations (particularly those not receiving stable OST or recent PWID). The C‑EDGE CO‑STAR study was the first phase III trial that evaluated DAA therapy in people receiving OST including those with ongoing drug use56. People with no previous treatment experience with HCV geno types 1, 4 or 6 who were receiving OST with methadone, buprenorphine or buprenorphine–naloxone for at least 3 months before enrolment and who were >80% adherent to OST appointments were randomly assigned to receive either immediate treatment with elbasvir and grazoprevir for 12 weeks (n = 201) or placebo for 12 weeks, followed by deferred treatment with elbasvir and grazoprevir for 12 weeks (n = 100). Participants were provided with an electronic diary to record the time of dosing that also acted as a daily adherence reminder. People with ongoing injecting drug use at screening were eligible to participate in this study. Overall, 96% of patients completed therapy (277 of 296 who initiated therapy) and >97% of participants demonstrated >95% adherence56. In an intentto‑treat analysis, the overall SVR was 91% (269 of 296). Importantly, drug use at baseline (62% all, 47% non cannabinoids) and during treatment (60% all, 47% noncannabinoids) did not affect SVR or adherence. The inclusion of a placebo arm in this trial also enabled an important comparison of safety between those receiving treatment compared with those receiving placebo, with no differences in adverse events between groups. Encouragingly, the proportion of participants reporting fatigue was lower in those receiving DAAs (14%) than in those receiving placebo (20%). A concern among some clinicians is whether the results from clinical trials will be replicated among people receiving OST treated outside of clinical trials. Among people receiving OST treated with DAAs in the real-world, treatment completion was 93–100% and SVR was 84–100%58–63. In a large study from the German Hepatitis C registry, the intent-to‑treat SVR
was lower among people receiving OST (n = 528, 85%) than those not receiving OST (n = 5,582; 91%, P
Direct-acting antiviral agents for HCV infection affecting people who inject drugs Jason Grebely, Behzad Hajarizadeh and Gregory J. Dore
Abstract | Globally, 12 million people are estimated to have injected drugs in the past year, 50% of whom have chronic HCV infection, with people who have previously injected drugs presenting an additional large reservoir of infection. The availability of simple and tolerable interferon-free direct-acting antiviral agents (DAAs) for HCV infection, which have a cure rate of >95% represents one of the most exciting advances in clinical medicine in the past few decades. Adherence and response to DAA therapy among people who inject drugs (PWID) receiving opioid substitution therapy (OST) in clinical trials are comparable to populations without a history of injecting drugs. Further data are required among current PWID not receiving OST. Given the potential prevention benefits of treatment, DAAs have enhanced cost-effectiveness among PWID. As HCV therapy is expanded to populations of PWID with high-risk behaviours for re‑exposure, acknowledgement that HCV reinfection will occur is crucial, and appropriate strategies must be in place to maximize prevention of reinfection and offer retreatment for reinfection. This Review will also discuss essential components for broadening access to HCV care for PWID as we strive for the global elimination of HCV infection.
The Kirby Institute, UNSW Sydney, Sydney, New South Wales 2052, Australia. Correspondence to J.G. [email protected] doi:10.1038/nrgastro.2017.106 Published online 23 Aug 2017
Globally, HCV infection is a major health issue among people who inject drugs (PWID)1,2. Given the high prevalence of HCV among PWID, and ageing drug user populations, the burden of HCV-related cirrhosis, hepatocellular carcinoma (HCC) and liver-related mortality is growing 1. Although interferon-based HCV treatment in populations of PWID has been shown to be safe and effective3–6, the poor tolerability of interferon-based therapies has limited the uptake of HCV treatment among PWID7–9 and the effect of these treatments on disease burden has been minimal. The advent of simple and well-tolerated oral HCV therapeutic regimens — direct-acting antiviral agents (DAAs) — with a cure rate of >95% offers the potential to reverse the rising burden of advanced liver disease10. However, in some countries (for example, the USA), people with ongoing drug use or people receiving opioid substitution therapy (OST) are still ineligible11 or might not be considered suitable by practitioners12 to receive DAAs. The reluctance to offer HCV therapy to PWID often stems from concerns around treatment adherence, poorer outcomes than in p eople who do not inject drugs and the potential risk of HCV reinfection13.
This Review outlines the epidemiology of HCV among PWID and those receiving OST, clearly defines ‘recent PWID’ and provides updated information on DAAs for HCV infection in these populations. A particular focus is given to HCV reinfection, acknowledging that strategies are required to reduce its incidence and impact. Essential components for broadening access to HCV testing and treatment for PWID will also be discussed within the broader goal of HCV elimination.
Epidemiology and burden People with a history of injecting drug use include those who report injecting an illicit drug at least once in their life, or ‘lifetime PWID’ (FIG. 1). This population includes both former injectors having ceased injecting and ‘recent PWID’ (with definitions for ‘recent’ often varying from 1 month to 12 months depending on the study)14. Among lifetime PWID, a population of people receiving OST also exists, some of whom might also have recently injected drugs. Understanding definitions for different PWID populations is crucial to better define outcomes following DAA-based HCV therapy in different populations.
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY
ADVANCE ONLINE PUBLICATION | 1
. d e v r e s e r s t h g i r l l A . e r u t a N r e g n i r p S f o t r a p , d e t i m i L s r e h s i l b u P n a l l i m c a M 7 1 0 2 ©
REVIEWS Key points • HCV prevalence and incidence among people who inject drugs (PWID) remains high • Direct-acting antiviral agents (DAA) for HCV with cure in >95% provide a tool for addressing HCV-related liver-disease burden among PWID • Adherence and response to DAA therapy among people receiving opioid substitution therapy (OST), including those with ongoing drug use, are comparable to other HCV-infected populations, although more data are required among current PWID who are not on OST • HCV reinfection can occur, so strategies to maximize prevention of reinfection (including OST and needle and syringe programmes) and access to DAA retreatment are crucial • Improved health services for PWID are needed to enhance HCV prevention, testing, access to care and treatment • Continued global leadership and advocacy is required to ensure that HCV prevention, care and treatment for PWID are accessible to all
Globally, in 2014, 12 million people were estimated to have injected illicit drugs in the past year 15, 50% of whom had chronic HCV infection (~6 million people), with former PWID presenting an additional large reservoir of infection (exact size of this population is unknown)2. HCV genotypes 1a, 1b and 3a are common among PWID (>70% among PWID globally)16,17, genotype 4 has been documented among PWID in Europe (8% among PWID globally)17,18, and genotype 6 in Southeast Asia (20% among PWID globally)17,19. HCV infection incidence remains high in many countries9,20,21, particularly in p eople who are more recent initiates to injecting drug use20,22. The development of an HCV vaccine has been challenging 23. One HCV vaccine is being evaluated in a phase II trial to prevent HCV persistence among PWID24,25, but a highly effective HCV vaccine would seem to be more than a decade away in development. However, combined OST and needle and syringe programmes (NSP) with a high-coverage (often defined as one or more sterile needles obtained from a NSP for each injection reported), can reduce HCV incidence by up to 80%26–30, with data suggesting that OST alone can also reduce HCV transmission by up to 60% (through reductions in injecting risk behaviour)6,31–34. Data from mathematical modelling studies suggest that HCV treatment for PWID can lead to substantial reductions in HCV prevalence and reduce transmission35–39, particularly when combined with OST and NSP36. In a setting of 40% coverage OST and NSP, annually treating 1, 2.3 and 4.2 per 100 PWID would halve HCV prevalence over 10 years in settings with a chronic HCV prevalence of 20%, 40%, or 60%, respectively36. Furthermore, given the potential prevention benefits, both interferon-based and interferon-free HCV treatment among PWID is cost-effective40–42. Given that PWID are at a high risk of HCV transmission, and HCV treatment resulting in cure eliminates infectiousness, PWID are a high priority for treatment, as per international guidelines6,43–45. The availability of tolerable, highly effective, all-oral DAA-based regimens has overcome the poor tolerability of interferon-based therapy, which has been a considerable barrier for treatment of HCV. These new regimens provide an important tool to achieve scale‑up of HCV therapy in PWID.
DAA therapy outcomes among PWID DAA regimens for the treatment of HCV infection include combinations of small-molecule inhibitors of HCV proteins that are involved in HCV replication10. Phase III studies of DAA HCV therapies have reported responses in >95% of patients, minimal toxicity, short therapy duration (8–12 weeks) and regimens that can be dosed once-daily 10. Treatment of HCV infection among PWID provides benefits at both the individual and the population level. At an individual level, successful treatment of HCV infection reduces the progression of liver disease46 and reduces all-cause mortality in people with advanced liver disease47. At a population level, treatment of HCV in PWID with ongoing injecting drug use represents a potential tool to prevent onward HCV transmission among PWID37. As such, HCV treatment targeted to people with recent (that is, previous 6–12 months) or ongoing injecting drug use will be required to enable a reduction in HCV transmission. Mathematical modelling also indicates that DAA treatment of PWID who have moderate or mild liver fibrosis is cost-effective compared with delaying until cirrhosis, owing to the additional HCV prevention benefit42. Furthermore, given that the average time from HCV infection to the development of cirrhosis among PWID is 30–40 years48, delaying treatment might also prolong the period of infectiousness. Importantly, international guidelines also support the prioritization of HCV treatment among PWID6,43–45. Among people receiving OST with no recent illicit drug use, post-hoc analyses of phase II and III trials of DAA therapy have demonstrated that the sustained virologic response (SVR) is similar in those receiving and not receiving OST49–56 (TABLE 1; see Supplementary information S1 (table)). According to preliminary data, in people infected with HCV genotype 1 treated with ombitasvir, paritaprevir, ritonavir and dasabuvir with or without ribavirin49,54, or who were treated with sofosbuvir and ledipasvir 53, treatment completion was 96–100% and SVR was 94–96% in people who were receiving OST (TABLE 1; see Supplementary information S1 (table)). In the ION‑1 study, stored blood samples were tested for illicit drugs and 8% (n = 70) of samples showed illicit, noncannabis drug use by participants during therapy 53. SVR was 99% (n = 657) in those patients without illicit drug use, compared with 98% in those with cannabis use alone (n = 126, P = 0.12) and 97% in those with any illicit drug use, with or without cannabis use (n = 70, P = 0.14). As such, among people without drug use at the time of therapy initiation, subsequent illicit drug use during therapy did not have a major effect on SVR. In a post-hoc analysis of people with HCV genotypes 1–6 who received the once-daily fixed-dose combin ation of sofosbuvir and velpatasvir for 12 weeks in the ASTRAL‑1–3 studies, OST did not affect completion, adherence, SVR or safety 52; SVR at 12 weeks was 96% in those receiving OST and was 96% in those receiving OST with HCV genotype 352. In another post-hoc analysis of people on OST with HCV genotypes 1–6 who received sofosbuvir, velpatasvir, and voxilaprevir for 12 weeks in the POLARIS studies, 100% completed
2 | ADVANCE ONLINE PUBLICATION
www.nature.com/nrgastro . d e v r e s e r s t h g i r l l A . e r u t a N r e g n i r p S f o t r a p , d e t i m i L s r e h s i l b u P n a l l i m c a M 7 1 0 2 ©
REVIEWS treatment and SVR12 was 96% according to preliminary data55. Although these post-hoc analyses clearly focus on a restricted PWID population because they have small sample sizes and exclude people with recent drug use at baseline, they provide important data on outcomes following DAA therapy among a subpopulation of people receiving OST. The first clinical trial to specifically evaluate DAA therapy among people receiving OST evaluated the efficacy of ombitasvir, paritaprevir, ritonavir and dasabuvir in combination with ribavirin for 12 weeks in 38 partici pants receiving methadone (n = 19) or buprenorphine (n = 19) OST with HCV genotype 1 (84% genotype 1a) without cirrhosis57. Participants with a positive urine drug screen for noncannabis drugs at screening were excluded. Overall, 97% of participants (37 of 38) completed treatment and 97% (37 of 38) achieved SVR. Notably, people with active drug use at baseline were excluded from participating in these trials, and as such, enrolled participants represented a selected population who are likely to be engaged in care. Consequently, these findings might not be generalizable to other PWID populations (particularly those not receiving stable OST or recent PWID). The C‑EDGE CO‑STAR study was the first phase III trial that evaluated DAA therapy in people receiving OST including those with ongoing drug use56. People with no previous treatment experience with HCV geno types 1, 4 or 6 who were receiving OST with methadone, buprenorphine or buprenorphine–naloxone for at least 3 months before enrolment and who were >80% adherent to OST appointments were randomly assigned to receive either immediate treatment with elbasvir and grazoprevir for 12 weeks (n = 201) or placebo for 12 weeks, followed by deferred treatment with elbasvir and grazoprevir for 12 weeks (n = 100). Participants were provided with an electronic diary to record the time of dosing that also acted as a daily adherence reminder. People with ongoing injecting drug use at screening were eligible to participate in this study. Overall, 96% of patients completed therapy (277 of 296 who initiated therapy) and >97% of participants demonstrated >95% adherence56. In an intentto‑treat analysis, the overall SVR was 91% (269 of 296). Importantly, drug use at baseline (62% all, 47% non cannabinoids) and during treatment (60% all, 47% noncannabinoids) did not affect SVR or adherence. The inclusion of a placebo arm in this trial also enabled an important comparison of safety between those receiving treatment compared with those receiving placebo, with no differences in adverse events between groups. Encouragingly, the proportion of participants reporting fatigue was lower in those receiving DAAs (14%) than in those receiving placebo (20%). A concern among some clinicians is whether the results from clinical trials will be replicated among people receiving OST treated outside of clinical trials. Among people receiving OST treated with DAAs in the real-world, treatment completion was 93–100% and SVR was 84–100%58–63. In a large study from the German Hepatitis C registry, the intent-to‑treat SVR
was lower among people receiving OST (n = 528, 85%) than those not receiving OST (n = 5,582; 91%, P
