Elimination of hepatitis C in the Middle East: a narrative review of the efficacy of direct-acting antiviral therapies

Introduction

Hepatitis C virus (HCV), is a major health concern in the Middle East, with the region categorised as having a high prevalence of HCV infection (>3.5%) (1). New treatment strategies provide an opportunity to eliminate HCV infection globally, particularly in the Middle East (2,3). This review focuses on UK National Institute for Health and Care Excellence (NICE) guidance as these interventions have been through rigorous cost-effectiveness analysis and are applicable to a global population.

HCV is an RNA virus (4) primarily spread through the transmission of contaminated blood (5). If left untreated, the associated hepatic damage results in 20–30% of patients developing cirrhosis (6), and a 1–4% annual risk of developing hepatocellular carcinoma (5). However, effective treatment can eliminate this risk (7,8).

Previously, the mainstay of treatment was a combination of interferon and ribavirin, but the average success rate was 40–50% (9) and many patients discontinued regimens due to adverse events (AEs) and long treatment durations ranging from 24 to 48 weeks (10,11). Currently, this combination has largely been replaced by direct-acting antivirals (DAAs) which inhibit different stages of the HCV replication cycle. DAAs target specific non-structural proteins of the HCV to disrupt viral replication and infection. These DAAs can be divided into NS3/4A protease inhibitors, NS5A inhibitors and NS5B polymerase inhibitors (3). To reduce the development of viral resistance, and increase treatment efficacy, DAAs from different classes are often combined to simultaneously target multiple aspects of the HCV life cycle (12).

Several combinations of DAAs are currently recommended for HCV treatment (Table 1). The choice of the drug, treatment duration and decision to add other agents, such as the CYP3A4 inhibitor ritonavir, depends largely on three patient factors. Firstly, the genotype (GT) of HCV a patient has been infected with is identified. NICE guidelines focus on six specific GTs of HCV (GT1 to GT6) (13), with GT1 and GT3 being the most prevalent (14,15). Some treatments are only effective against specific GTs whereas others can be used for all GTs (pan-genotypic) which is preferred due to its simplicity. Sofosbuvir-velpatasvir (SOF-VEL), glecaprevir-pibrentasvir (GLE-PIB), and sofosbuvir-velpatasvir-voxilaprevir (SOF-VEL-VOX) are pan-genotypic options. Secondly, the presence and severity of any existing cirrhosis is assessed. Finally, it is considered whether this is a first attempt at treating the patient’s HCV (treatment-naïve) or whether previous treatments were attempted and were unsuccessful (treatment-experienced).

The primary goal of treatment is to achieve a sustained viral response (SVR) 12 or 24 weeks (SVR12 or SVR24) after completion of therapy. This indicates HCV RNA levels are too low to be detected with a sensitive assay (lower limit of detection ≤15 IU/mL) (12).

In HCV patients coinfected with hepatitis B virus (HBV), DAAs are effective and tolerable. So, these patients should be treated with the same anti-HCV regimens as HCV-monoinfected patients (14). However, with DAA treatment there is a risk of HBV reactivation so these patients should be monitored throughout treatment (15). Chronic kidney disease (CKD) and human immunodeficiency virus (HIV) are common comorbidities, treatment options with HIV co-infection are outlined in Table 2 (16) and considerations for renal impairment are noted in the results section below (17,18).

Our objective is to review and appraise evidence on the efficacy and safety of the DAAs and combinations recommended for the treatment of HCV infection in adults. We present this article in accordance with the Narrative Review reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-87/rc).

Methods

This study used manual searches of NICE and European Association for the Study of the Liver (EASL) guidelines to identify important trials for recommending DAAs.

To ensure a comprehensive scope, the keywords ‘HCV’, ‘clinical trial’, and the seven DAA combinations recommended by NICE (glecaprevir-pibrentasvir, sofosbuvir, sofosbuvir-velpatasvir, sofosbuvir-velpatasvir-voxilaprevir, sofosbuvir-ledipasvir, grazoprevir-elbasvir, and paritaprevir-ombitasvir-ritonavir) were used in a literature search of PubMed, MEDLINE, Cochrane Library, and EMBASE databases (Table 3).

The inclusion criteria for publications were clinical trials, adult human participants, English language, papers within 5 years and seminal papers (no date limit). Papers excluded were those addressing paediatrics and obstetrics.

After screening the title and abstract of the 390 publications identified, 62 studies were deemed relevant. Additionally, bibliographies of literature, including seminal systematic reviews and meta-analyses were manually searched.

Results

GLE-PIB

A combination of the protease inhibitor glecaprevir (300 mg) paired with the NS5A inhibitor pibrentasvir (100 mg) is a pan-genotypic once-daily oral tablet as per NICE guidelines since 2017 (12,19).

In non-cirrhotic patients, an 8-week regimen is recommended, as trials have demonstrated SVR12 rates of 99% (20), 98% (21), 95% (22), 93%, 100%, and 90% in GT1–6 respectively (23). Several studies and meta-analyses have shown that GT3 treatment-experienced patients display higher relapse rates on a 12-week regimen than treatment-naïve patients (8% vs. 0%) (21,24,25). However, the SURVEYOR-2 study has shown that high efficacy can be achieved by a 12-week regimen in treatment-naïve patients (SVR12 =98%) or a 16-week regimen in treatment-experienced GT3 patients (SVR12 =96%) (21).

Studies containing both treatment-naïve and treatment-experienced compensated (Child-Pugh A) cirrhotic patients, demonstrated an 8-week regimen of GLE-PIB achieved SVR12 rates of 98% for GT1, 95% GT3, and 100% for all other GTs (26,27).

A real-world meta-analysis involving 11,101 adults showed GLE-PIB achieves SVR12 rates of 97–98% in non-cirrhotic and compensated cirrhotic patients on 8- or 12-week regimens (25).

Amongst the trials explored, the most common AEs of GLE-PIB were asthenia, diarrhoea, headache and nausea. A meta-analysis of 13 studies involving 3082 participants showed the rate of AEs was 1.6% and no serious AEs (SAEs) were reported (27). Furthermore, its safety and efficacy are well evidenced in patients with CKD4/5 (28). Additionally, ENDURANCE-1&3 demonstrated 100% SVR12 rates in HIV co-infection for GT1 and GT3 (29). However, protease inhibitors such as glecaprevir are contraindicated in decompensated (Child-Pugh B or C) cirrhosis and those with previous episodes of decompensation due to high serum levels and related risk of toxicity (30).

Sofosbuvir

Sofosbuvir is a polymerase inhibitor to be taken once daily orally (400 mg), alongside ribavirin twice daily (400 or 800 mg depending on body weight) and/or PEG (subcutaneously) as per NICE guidelines since 2013 (12,19). A combination of the three is recommended in all GTs (except GT2), whilst sofosbuvir with ribavirin (SOF + RBV) is recommended for GT2 and GT3 (12,19).

Sofosbuvir in combination with peginterferon alfa and ribavirin (SOF + PEG + RBV) is recommended for 12 weeks in GT1 and GT4–6 cirrhotic patients (12,19). This is supported by the phase III NEUTRINO trial which showed this combination confers high efficacy in GT1 (SVR12 =90%) and GT4–6 (SVR12 =97%) treatment-naïve patients (31). Meanwhile, the phase II ATOMIC trial showed this 12-week regimen was matched in efficacy to one of 24 weeks (SVR24 =89%) (32).

In GT2 treatment-naïve patients, despite high SVR12 rates demonstrated in ELECTRON (100%) (33), PROTON (93%) (34), and LONESTAR-2 (96%) (35) trials, SOF + PEF + RBV lacks market authorisation for use in this cohort (36).

In GT2 treatment-experienced patients, SOF + RBV was shown to be efficacious by FUSION (SVR12 =86%) (37). However, in GT2 patients who are treatment-naïve, this combination is only recommended in those intolerant to interferons (33). FISSION supports this, as SOF + RBV displayed high efficacy in both non-cirrhotic (SVR12 =91%) and compensated cirrhotic patients (SVR12 =98%) (32).

For GT3 patients, SOF + PEG + RBV is recommended in cirrhotic patients (12,19). Evidence comes from trials with treatment-naïve patients in PROTON and ELECTRON (SVR12 =90%, 100%) and LONESTAR-2 which included treatment-experienced patients (SVR12 =83%) (33,34).

For GT3 treatment-naïve cirrhotic patients intolerant to peginterferon alfa-interferon, SOF + RBV alone can be used (19). FISSION showed this combination has equal efficacy compared to peginterferon alfa and ribavirin (PEG + RBV) (SVR12 =67%) (32). The phase III FUSION and VALENCE trials have shown benefits from lengthened SOF + RBV treatment as higher SVR12 rates were seen with 16- and 24-week regimens (62%, 85%, respectively) (32,34,35,37).

Amongst the trials explored, the most common AEs of sofosbuvir were fatigue, headache and nausea (33-38). However, the most common AEs causing the discontinuation of treatment were anaemia and neutropenia associated with PEG + RBV, rather than sofosbuvir. ATOMIC suggests anaemia, which resulted in dose adjustment or interruption, was more common in cohorts with RBV for 24 weeks (20%, 23%) than in cohorts with RBV for only 12 weeks (10%, 11%) (32). Recent trials have shown sofosbuvir remains safe in advanced CKD; only 0.1% of cases experienced SAEs (39). Additionally, the phase III PHOTON-1 trial demonstrated high efficacy in treatment-experienced GT2 and GT3 HCV/HIV co-infected patients (SVR12 =92%, 94%) (40).

SOF-VEL

A fixed-dose combination of sofosbuvir (400 mg) with the NS5A inhibitor velpatasvir (100 mg) is a pan-genotypic once-daily tablet recommended by NICE in 2016 for 12 or 24 weeks (41). Notably, SOF-VEL with ribavirin (SOF-VEL + RBV) is recommended in decompensated cirrhotic patients (Child-Pugh B and C) (42). All evidence for these guidelines comes from the phase III ASTRAL trial series.

SOF-VEL combination is recommended for all HCV GTs with or without compensated cirrhosis (12,19). In ASTRAL-1, in GT1, GT2, GT4–6 patients, SOF-VEL conferred higher efficacy than a placebo (SVR12 =99% vs. 0%) (43). In ASTRAL-3, in GT3 patients, SOF-VEL was superior to SOF + RBV (SVR12 =95% vs. 80%) (43).

However, the exception is in GT2 treatment-naïve, non-cirrhotic patients; SOF-VEL is recommended if they are intolerant to interferons (19). ASTRAL-2 demonstrated excellent efficacy for GT2 patients with SOF-VEL compared with SOF + RBV (SVR12 =99% vs. 94%) (43).

Evidence for the addition of ribavirin in decompensated cirrhotic patients arises from ASTRAL-4, where a 12-week regimen of SOF-VEL + RBV showed higher efficacy compared to SOF-VEL alone in GT1 (SVR12 =96% vs. 88%) and GT3 (SVR12 =85% vs. 50%). Matched efficacy was seen in GT2, GT4, and GT6 (SVR12 =100%) (43,44).

Amongst all trials explored, the most common AEs of SOF-VEL were fatigue, nausea and headache; ASTRAL-1 demonstrates no significant difference in AE rates between SOF-VEL and placebo (78%, 77%) (43). Furthermore, ASTRAL-4 found anaemia is associated with adding ribavirin (43). However, RBV-associated anaemia was successfully managed by RBV dose adjustment in all but one patient who necessitated erythropoietin treatment. SOF-VEL displays high efficacy in patients with end-stage renal disease (SVR12 =95%), where SAEs reported were deemed unrelated (45). Additionally, ASTRAL-5 has shown GT1–4 and GT6 HCV/HIV coinfected patients respond successfully to SOF-VEL (SVR12 =95%) (46).

SOF-VEL-VOX

SOF-VEL-VOX is a pan-genotypic fixed-dose combination of sofosbuvir (400 mg), velpatasvir (100 mg) with the protease inhibitor voxilaprevir (100 mg), available as a once-daily tablet first recommended by NICE in 2017 for those refractory to previous DAA treatment (47).

In POLARIS-1, the SVR12 for treatment-experienced GT1 patients after a 12-week regimen of SOF-VEL-VOX was 96% whereas no patients who received a placebo obtained an SVR12 (48). In POLARIS-4, the efficacy of this regimen in treatment-experienced GT1–3 patients was shown to be statistically significant compared to the trial’s prespecified performance goal (SVR12 =98% vs. 85%, P<0.001) (48). However, this did not occur with SOF-VEL (SVR12 =90% vs. 85%, P=0.09). The use of SOF-VEL-VOX in real-world treatment-experienced cohorts has shown similar rates of efficacy (49,50).

In GT3 treatment-naïve patients, SOF-VEL-VOX is recommended as an 8-week regimen regardless of cirrhosis status. This regimen was shown to be non-inferior to a standard 12-week SOF-VEL regimen in non-cirrhotic patients in POLARIS-2 (SVR12 =99% vs. 97%) and in cirrhotic patients in POLARIS-3 (SVR12 =96% for both arms) (51).

POLARIS-1, 3, and 4 demonstrated no increased risk of SAEs with SOF-VEL-VOX vs. placebo (51). In POLARIS-2, SAEs with 8 weeks of SOF-VEL-VOX occurred in 3% of patients compared to 2% for 12 weeks of SOF-VEL (51). The most common AEs were headache, fatigue, diarrhoea and nausea (48,51).

Advanced CKD has no bearing on the pharmacokinetics clinically (50). Finally, the RESOLVE STUDY showed a 12-week regimen of SOF-VEL-VOX to be efficacious in GT1 patients with HIV co-infection (SVR12 =82.4%) (52).

Sofosbuvir-ledipasvir (SOF-LDV)

A fixed-dose combination of sofosbuvir (400 mg) with the polymerase inhibitor ledipasvir (90 mg) is a once-daily tablet (12). Since 2014 NICE has recommended this for treatment of GT1 and GT4 in those without decompensated cirrhosis, regardless of prior treatment experience.

ION-1 concluded that in treatment-naïve GT1 and four patients, SOF-LDV was equally effective in cirrhotic and non-cirrhotic patients (SVR12 =99% vs. 99%) (53). In GT1 patients with no cirrhosis, an 8-week regimen is used, as ION-3 showed this to be non-inferior to the standard 12 weeks of treatment (SVR12 =94% vs. 95%) (54).

Meanwhile, the ION-2 trial evidenced the high efficacy of SOF-LDV in treatment-experienced patients (both in non-cirrhotic and cirrhotic patients) (SVR12 =94%) (55).

Recommendations for SOF-LDV in GT4 are evidenced by the phase IIa SYNERGY study. A 12-week regime of SOF-LDV was found to be highly efficacious (SVR12 =95%) regardless of cirrhosis status or previous treatment exposure (56).

Across these trials, the most common AEs reported with SOF-LDV were fatigue and headache. In the ION series, SOF-LDV also conferred lower AE rates than SOF-LDV with ribavirin (SOF-LDV + RBV). Only two patients (ION-3) discontinued the SOF-LDV regimen discussed owing to an AE (12).

In a recent phase IIb study, a 12-week regimen of SOF-LDV was shown to be efficacious in GT1 individuals with stage CKD4/5 who were not on dialysis (SVR12 =100%) (57). The ION-4 study showed SOF-LDV is also efficacious in those with HIV co-infection (SVR12 =96%) (58).

Grazoprevir-elbasvir (GZR-EBR)

A combination of the NS5A inhibitor elbasvir (50 mg) and the protease inhibitor grazoprevir (100 mg) is available as a once-daily tablet (59). Since 2016 a 12-week regimen of GZR-EBR has been recommended for GT1 and 4, in those without decompensated cirrhosis. A 16-week regimen of GZR-EBR in conjunction with ribavirin (GZR-EBR + RBV) is recommended for GT1a and GT4 patients with an HCV RNA level of >800,000 IU/mL and GT1a patients with resistance-associated NS5A polymorphisms (59).

In GT1a, evidence for recommendations arose from the phase III C-EDGE trial, where GZR-EBR was shown to be efficacious in both treatment-naïve (59). and treatment-experienced patients (60) (SVR12 =92%, 95%, respectively). In GT1b patients, high efficacy was observed in C-SALVAGE64 and pooled analysis (61) (SVR12 =96%, 97%, respectively).

In GT4, pooled analysis revealed the high efficacy of GZR-EBR in both treatment-naïve and treatment-experienced patients (SVR12 =96%, 89%) (61). Furthermore, a pooled analysis of GT1, GT4, and GT6 has shown this to be retained in cirrhotic patients (SVR12 =89–100%) (21). Whilst a shorter 8-week regimen in this cohort was trialled in C-WORTHY, it was found to be inferior to the standard 12-week regimen (SVR12 =80% vs. 98%) (62).

In GT1a patients with resistance-associated NS5A polymorphisms, a 16-week regimen of GZR-EBR + RBV was shown to be highly efficacious (SVR12 =100%). This trial also showed that the 16-week regimen of GZR-EBR + RBV had high efficacy in patients with a high baseline viral load of >2,000,000 IU/mL (SVR12 =100%) (63).

Among all trials, the most common AEs reported were fatigue, headache and nausea. 0.8% of patients experienced significant, yet asymptomatic elevation of ALT (>5 times upper limit)—this resolved spontaneously during or after the treatment (21).

GZR-EBR requires no dose adjustment in CKD4/5; evidenced by C-SURFER, where GZR-EBR showed improved efficacy vs. historical reference values from a meta-analysis of interferon-based regimens (SVR12 =99% vs. 45%) (64). Patient tolerance was 98%, no SAEs were observed and a similar safety profile was seen in non-CKD patients (65). Additionally, CO-STAR has shown that intravenous (IV) drug users (a historically hard-to-treat population) respond better to GZR-EBR than PEG (SVR12 =91% vs. 67%) (66). Elsewhere, C-EDGE-CO-INFXN showed high efficacy in patients with HIV co-infection (SVR12 =96%) (67).

Paritaprevir-ombitasvir-ritonavir (PTV-OBV-RIT) ± dasabuvir ± ribavirin

In 2014, NICE recommended a fixed-dose combination with 75 mg the protease inhibitor paritaprevir (75 mg), the NS5A inhibitor ombitasvir (12.5 mg) and the boosting agent ritonavir (50 mg) as two tablets once-daily (68). Dasabuvir is a polymerase inhibitor taken twice daily. PTV-OBV-RIT with dasabuvir and ribavirin is recommended for GT1, except in GT1b without cirrhosis where ribavirin is omitted (69). In GT4, PTB-OBV-RIT with ribavirin is recommended for all patients.

In GT1a non-cirrhotic, treatment-naïve patients, evidence of this combination’s efficacy comes from the phase III PEARL-III/IV and MALACHITE-I (70) trials where patients receiving PTV-OBV-RIT with dasabuvir and ribavirin showed effective responses (SVR12 =90%, 97%, respectively). In GT1b treatment-naïve patients, these studies also showed comparative efficacy (SVR12 =99%, 98%, respectively). In GT1b non-cirrhotic treatment-naïve patients, PTV-OBV-RIT with dasabuvir is recommended for a shorter 8-week regimen; supported by the phase III GARNET trial (SVR12 =98%) (71).

Elsewhere, GT1 treatment-experienced patients in phase III PEARL-II and MALACHITE-II (69,70) trials have also shown high efficacy with ribavirin in per-protocol analysis (SVR12 =100%, 96.6%, respectively). However, GT1b non-cirrhotic patients in PEARL-II showed non-inferiority without ribavirin (SVR12 =100% vs. 96.6%), evidencing the current guidelines in this group (69).

In GT4 non-cirrhotic patients, recommendations outline the use of PTV-OBV-RIT with ribavirin due to the phase IIb PEARL-I trial showing improved efficacy across all patient groups when ribavirin was taken vs. placebo (SVR12 =100% vs. 91%) (72).

Lastly, in cirrhotic patients, evidence which comes from individual (73) and pooled (74) analysis of the TURQUOISE-III, PEARL-II/III, TOPAZ-II, and MALACHITE-I studies shows similar efficacy in cirrhotic (SVR12 =100%) and non-cirrhotic patients (SVR12 =99%). Several real-world reports confirm such results (75-77).

Amongst all trials, the most common AEs were fatigue and nausea, with a pooled analysis (73) showing low rates of SAEs (2%) across all patients receiving PTV-OBV-RIT with dasabuvir. Additionally, PTV-OBV-RIT ± dasabuvir ± ribavirin is as effective in CKD4/5 (SVR12 =100%) (74). Here, 19.6% of patients reported SAEs across all arms, although none were drug-related (75). Elsewhere, the phase II/III trial TURQUOISE-I (78) has shown GT1a-HIV coinfected patients (darunavir-treated) respond successfully to PTV-OBV-RIT + ribavirin (SVR12 =100%).

Discussion

Viral hepatitis, particularly HCV, remains a major cause of mortality worldwide that World Health Organisation (WHO) attributed 242,000 deaths to HCV in 2020 (79). The Middle East remains one of the most affected regions (80) in particular Egypt and Pakistan (81). The introduction of DAAs provides effective treatment of HCV infection to meet the WHO’s global target to eliminate HCV infection by 2030 (82).

All DDAs demonstrated high efficacy in their recommended cohorts accounting for viral GT, cirrhosis status and previous HCV treatment attempts. There are examples of therapies with good trial data that aren’t recommended by NICE. For example, SOF + PEG + RBV has shown high efficacy against GT2 in the ELECTRON (SVR12 =100%) and LONESTAR-2 (SVR12 =96%) (35,36) trials, yet, it doesn’t have market authorisation for this cohort. This is likely due to cost implications but this discrepancy is not explained in the supporting evidence. Furthermore, low efficacy is reported for SOF + RBV in GT3 non-cirrhotic (SVR12 =57%) and cirrhotic patients (SVR12 =34%) compared to other treatments demonstrating SVR12 rates ≥95% (23). Despite this, SOF + RBV is still recommended by NICE in these patients.

DAAs were found to be generally safe and well-tolerated. The most common AEs were headache and nausea. This is an improvement on the previous standard of treatment (PEG + RBV) which was associated with more SAEs (9).

Due to the numerous complex drug interactions with DAAs, a range of effective combinations must be licensed to provide treatment options for those with concurrent medications as well as “hard-to-treat” populations. The list of all drug-specific interactions is available online (83) and options for HIV co-infection are outlined in Table 2.

The interpretation of these studies should be considered in light of their limitations and strengths. Firstly, the sample size of GT4–6 patients was often small. Trials rarely included GT5, with those doing so only including one or two patients (22). Despite results being less applicable to GT5-infected patients, this does reflect the natural GT prevalence (14). The exclusion of IV drug users in studies such as NEUTRINO (33) omits a large proportion of HCV patients seen in everyday practice.

Moreover, several studies had different patient demographics (33,74,75). There was a lack of consistency in defining decompensated cirrhosis, with some studies using scoring systems such as Child-Pugh (25) whilst others used clinical features (33). Both within the scope of this review, but also as clinicians utilising multiple sources of research to make educated prescribing decisions, in the absence of meta-analyses with statistical comparison, this can make it more challenging to draw conclusions on efficacy in this patient group.

Another substantial limitation is the consistent lack of statistical comparison between treatment arms. In place of statistical comparisons, there was a pre-determined SVR12 rate that the lower boundary of the 95% confidence interval (CI) had to be achieved for the drug to be deemed ‘non-inferior’. It was often unclear how the threshold SVR12 rate had been calculated: some studies used a threshold of 6% (22,23) above SVR12 rates achieved by conventional therapies, but others chose different thresholds (19). Other studies lack analysis of non-inferiority (20) or compare DAAs to a placebo, rather than the previous standard of care (interferon-based treatments). These factors make it difficult to conclude which treatment is superior.

Many studies were open-labelled and industry-funded which may introduce bias (19,32). Moreover, the repeated use of modified intention to treat (mITT) analysis raises questions as this has shown to be overwhelmingly associated with industry funding and author conflicts of interest, which is linked to pro-industry results (83,84).

There were notable strengths of the trials, most remarkably the large sample sizes; trials included as many as 4,944 participants (37). Additionally, they all utilised SVR, a well-validated outcome measure for HCV treatment success and an objective endpoint. The consistent use of this endpoint makes comparisons easier (85).

Our narrative review included an extensive database search. The most cited, high-impact papers were included to ensure we did not miss any important or controversial findings. However, the review focused on trials of adults and non-obstetric cases; thus, future reviews should focus on paediatric and obstetric research as it is equally necessary to discuss research in these groups.

The aims-directed inclusion and exclusion criteria for the literature search minimised selection bias by ensuring a consistently neutral methodology. Additionally, we included trials with HIV-coinfection and renal impairment for each drug; which are important and common ‘hard-to-treat’ HCV populations (86,87).

Given the novelty of DAAs, there are significant gaps in the literature. There is little evidence of long-term adverse effects, especially in important subpopulations such as IV drug users and prisoners (88). Therefore, monitoring of patients post-treatment is crucial, particularly in these subpopulations. Additionally, in decompensated cirrhotic patients, future studies to evaluate novel dose adjustments are required, such as that shown in C-SALT (21). Finally, more data is needed for GT7 and GT8, as these newly discovered GTs lack research.

Shorter regimens could prove vital for HCV patients unlikely to complete a 12-week course. Several trials are currently underway to this effect; TARGET3D (NCT02634008) is researching GLE/PIB for 4 and 6 weeks and REACT (NCT02625909) is investigating a 6-week regimen of sofosbuvir.

Despite the existence of efficacious and safe treatments, the elimination of HCV in the Middle East remains challenging. Progress is hampered by low diagnostic rates, treatment availability and adherence, alongside high reinfection rates (89). Hence, further efforts are necessary for the most at-risk subpopulations, such as IV drug users and prisoners. These include accessible community-based screening, diagnostics and treatments. Furthermore, needle exchange programmes, addiction support, and post-treatment surveillance will help offer the best chance of HCV elimination.

Conclusions

In conclusion, a range of DAAs for HCV are recommended, based upon an extensive pool of research that evidences high efficacy and safety among a diverse patient cohort. This narrative review synthesises the current understanding of DAAs and treatment regimens based on virus GT, cirrhosis status and treatment experience. Future efforts should focus on diagnosing and screening for HCV, ultimately working towards the WHO goal of eliminating the virus by 2030.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-87/rc

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-87/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-87/coif). L.A. serves as an unpaid editorial board member of Translational Gastroenterology and Hepatology from May 2023 to April 2025. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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