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Korean J Gastroenterol  <  Volume 83(3); 2024 <  Articles

Korean J Gastroenterol 2024; 83(3): 111-118  https://doi.org/10.4166/kjg.2023.141
Comparison of Glecaprevir/Pibrentasvir and Sofosbuvir/Ledipasvir in Patients with Hepatitis C Virus Genotype 1 and 2 in South Korea
Hyun Deok Shin1, Il Han Song1, Sae Hwan Lee2, Hong Soo Kim2, Tae Hee Lee3, Hyuk Soo Eun4, Seok Hyun Kim4, Byung Seok Lee4, Hee Bok Chae5, Seok Hwan Kim6, Myung Joon Song6, Soon Yeong Ko7, Suk Bae Kim1
1Department of Gastroenterology, Dankook University College of Medicine, Cheonan; 2Department of Gastroenterology, Soonchunhyang University College of Medicine, Cheonan; 3Department of Gastroenterology, Konyang University College of Medicine, Daejeon; 4Department of Gastroenterology, Chungnam University College of Medicine, Daejeon; 5Department of Gastroenterology, Chungbuk University College of Medicine, Cheongju; 6Department of Gastroenterology, College of Medicine, The Catholic University of Korea, Daejeon; 7Department of Gastroenterology, Konkuk University College of Medicine, Chungju; Korea
Correspondence to: Suk Bae Kim, Department of Gastroenterology, Dankook University College of Medicine, 119 Dandae-ro, Dongnam-gu, Cheonan 31116, Korea. Tel: +82-41-550-3910, Fax: +82-41-556-3256, E-mail: dryakson@hanmail.net, ORCID: https://orcid.org/0000-0002-6857-9624
Received: November 23, 2023; Revised: January 15, 2024; Accepted: February 4, 2024; Published online: March 25, 2024.
© The Korean Journal of Gastroenterology. All rights reserved.

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Abstract
Background/Aims: This study compared the effectiveness and safety of glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/ledipasvir (SOF/LDV) in real-life clinical practice.
Methods: The data from genotype 1 or 2 chronic hepatitis C patients treated with GLE/PIB or sofosbuvir + ribavirin or SOF/LDV in South Korea were collected retrospectively. The analysis included the treatment completion rate, sustained virologic response at 12 weeks (SVR12) test rate, treatment effectiveness, and adverse events.
Results: Seven hundred and eighty-two patients with genotype 1 or 2 chronic hepatitis C who were treated with GLE/PIB (n=575) or SOF/LDV (n=207) were included in this retrospective study. The baseline demographic and clinical characteristics revealed significant statistical differences in age, genotype, ascites, liver cirrhosis, and hepatocellular carcinoma between the GLE/PIB and SOF/LDV groups. Twenty-two patients did not complete the treatment protocol. The treatment completion rate was high for both regimens without statistical significance (97.7% vs. 95.7%, p=0.08). The overall SVR12 of intention-to-treat analysis was 81.2% vs. 80.7% without statistical significance (p=0.87). The overall SVR12 of per protocol analysis was 98.7% vs. 100% without statistical significance (p=0.14). Six patients treated with GLE/PIB experienced treatment failure. They were all male, genotype 2, and showed a negative hepatitis C virus RNA level at the end of treatment. Two patients treated with GLE/PIB stopped medication because of fever and abdominal discomfort.
Conclusions: Both regimens had similar treatment completion rates, effectiveness, and safety profiles. Therefore, the SOF/LDV regimen can also be considered a viable DAA for the treatment of patients with genotype 1 or 2 chronic hepatitis C.
Keywords: Glecaprevir; Pibrentasvir; Harvoni; Chronic hepatitis C; Korea
INTRODUCTION

Direct antiviral agents (DAAs) have become the standard treatment for chronic hepatitis C since the first Food and Drug Administration (FDA) approval of Boceprevir and Telaprevir in 2011. The high cure rate of DAAs gave hope that the eradication of chronic hepatitis C would become possible. The early guidelines for using DAAs were complicated according to the resistance- associated substitutions (RASs) mutation, viral genotypes, renal function, liver function, and treatment experience. Fortunately, the guidelines have been simplified with the development of pan-genotypic agents, such as glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL). The American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) guidelines recommend these pan-genotypic agents as the primary treatment for chronic hepatitis C.1,2 On the other hand, the use of DAAs in clinical practice may vary from country to country because of insurance policies and the main genotypes prevalent in each country. South Korea also had limitations on the use of SOF/VEL until the South Korean government approved its use in November 2022.

Hepatitis C virus (HCV) genotype 2 accounts for approximately 13% of cases worldwide and is most common in East Asia, sub-Saharan Africa, and Latin America.3 In Korea, genotype 2 accounts for approximately half of all cases. The AASLD and EASL guidelines recommend the use of SOF/VEL for 12 weeks or GLE/PIB for 8–12 weeks as the primary treatments for genotype 2.1,2 On the other hand, SOF + ribavirin or SOF/LDV is used in countries where these drugs are not available.4 In Korea, SOF + ribavirin was the primary treatment until GLE/PIB was approved by health insurance. Although SOF + ribavirin had a relatively high sustained virologic response at 12 weeks (SVR12), its use was limited because of ribavirin-induced anemia. Therefore, since the approval of GLE/PIB and SOF/LDV, both drugs have been mainly used to treat HCV genotype 2. Currently, in Korea, SOF/LDV is recommended for chronic hepatitis C, excluding genotype 3.

Although SOF/LDV was not initially recommended for HCV genotype 2 because of the laboratory results, clinical studies later obtained the treatment indications for this genotype. Nevertheless, GLE/PIB has been primarily used to treat this genotype as SOF/LDV indication for genotype 2 was approved relatively late, meaning there has been a lack of studies on the effectiveness of SOF/LDV for genotype 2 worldwide. Consequently, small study results have led to hesitation in using SOF/LDV for HCV genotype 2.

Compared to GLE/PIB, SOF/LDV needs to be used for 12 weeks instead of eight weeks. Nevertheless, it has the advantage of requiring only one tablet per day and is suitable for Child-Pugh class B and C patients. Furthermore, rescue treatment with GLE/PIB is an option if treatment fails. While salvage treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) is also possible, it may be difficult to use in countries where it is unavailable. Despite these advantages and disadvantages, there has been a paucity of research on the effectiveness of SOF/LDV for genotype 2. Therefore, this study compared the treatment completion rate, effectiveness, and side effects of SOF/LDV and GLE/PIB in treating patients with genotype 1 and 2 chronic hepatitis C in South Korea. The aim was to provide evidence-based insights for clinicians to make informed decisions when selecting more suitable treatment options for these patients.

SUBJECTS AND METHODS

A retrospective study was conducted using the data from seven university hospitals in the Daejeon-Chungcheong area of South Korea. All patients treated with GLE/PIB or SOF/LDV between January 2016 and July 2022 were included; those with genotypes 3–6 or undetermined genotypes were excluded. In the GLE/PIB group, patients received either an eight- or 12-week course of a fixed-dose combination of GLE 300 mg and PIB 120 mg once daily (Maviret®). In the SOF/LDV group, patients received an eight-week (in patients without cirrhosis + HCV RNA <6,000,000 IU/mL) or 12-week course of a fixed-dose combination of LDV 90 mg and SOF 400 mg once daily (Harvoni®) ± ribavirin (in patients with decompensated cirrhosis).

The Institutional Review Board of each hospital approved this study. Informed consent was waived owing to the retrospective nature of the study. Medical information was collected from the electronic medical records, including sex, age, baseline laboratory test results, genotype, HCV RNA, cirrhosis, hepatocellular carcinoma (HCC), and HCV treatment history. Cirrhosis was diagnosed using abdominal sonography, computed tomography, transient elastography (FibroScan®; Echosens, Paris, France), or histology. Cirrhosis was classified as either compensated or decompensated using the patient’s Child-Pugh score. The KASL (Korean Association for the Study of Liver Diseases) guidelines were followed to define virologic response, and the adverse events, treatment persistence, and SVR12 were analyzed.5 SVR12 was defined when HCV RNA was not detected at week 12 after treatment.

SPSS software version 25.0 for Windows was used for statistical analysis, expressing the data as mean ± standard deviation or as a percentage of patients. A student’s t-test or the Mann-Whitney U test was used for the continuous data, and a chi-square test or Fisher’s exact test was used for the categorical data to compare the two groups (GLE/PIB vs. SOF/LDV). SVR12 was measured in both intention-to-treat (ITT) and per protocol (PP) analyses, excluding patients who were lost to follow-up, non-virologic failure, or did not undergo the SVR12 test. P-values less than 0.05 were considered significant.

RESULTS

1. Baseline characteristics of the patients

Seven hundred and eighty-two patients were prescribed GLE/PIB (n=575) or SOF/LDV (n=207) between January 2016 and July 2022 (Fig. 1). The study population comprised 344 (44.0%) male patients and 438 (56.0%) female patients, with a mean age of 59.8±13.1 years. The prevalence of type 2 genotype was higher than that of type 1 (59.1% vs. 40.9%). Cirrhosis and ascites were present in 17.8% and 2.8% of the study participants, respectively. Nine patients in the SOF/LDV group were diagnosed with decompensated cirrhosis (Child-Pugh score 7–8) and were treated with SOF/LDV + ribavirin. In the SOF/LDV group, 124 patients showed non-cirrhosis and HCV RNA levels <6,000,000 IU/mL. Among them, seven patients were treated with SOF/LDV for eight weeks. Seventeen (2.2%) and 32 patients (4.1%) had a history of HCC and HCV treatment, respectively (Table 1).

Table 1 . Baseline Characteristics of the Patients treated with GLE/PIB or SOF/LDV

VariableAll patients (n=782)GLE/PIB group (n=575)SOF/LDV group (n=207)p-values
Age59.8±13.160.7±13.157.5±12.9<0.01
Male344 (44.0)246 (42.8)98 (47.3)0.26
Genotype 1320 (40.9)155 (27.0)165 (79.7)<0.01
Liver cirrhosis139 (17.8)90 (15.7)49 (23.7)0.01
Decompensated cirrhosis9 (1.2)0 (0)9 (4.3)<0.01
Ascites22 (2.8)9a (1.6)13 (6.3)<0.01
HCC history17 (2.2)7 (1.2)10 (4.8)<0.01
HCV Tx history32 (4.1)11 (1.9)21 (10.1)<0.01
AST (U/L)62.9±68.362.8±74.263.0±48.50.97
ALT (U/L)65.3±95.965.4±104.665.0±66.30.96
Albumin (g/dL)4.3±1.14.3±1.24.2±0.50.69
Total bilirubin (mg/dL)0.8±0.90.8±1.00.8±0.50.68
INR1.1±0.11.0±0.11.1±0.10.10
HCV RNA × 6log10 (IU/mL)3.5±5.53.6±5.93.3±4.50.44

Values are presented as mean±standard deviation or number (%).

GLE/PIB, glecaprevir/pibrentasvir; SOF/LDV, sofosbuvir/ledipasvir; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; Tx, treatment; AST, aspartate aminotransferase; ALT, alanine aminotransferase; INR, international normalized ratio.

aAll of them showed compensated cirrhosis.



Figure 1. Flow chart summarizing patient selection. GLE/PIB, glecaprevir/pibrentasvir; SOF/LDV, sofosbuvir/ledipasvir; SVR12, sustained virologic response at post-treatment week 12.

The baseline characteristics of the GLE/PIB and SOF/LDV groups were compared. The mean age was significantly higher in the GLE/PIB group than in the SOF/LDV group (60.7±13.1 vs. 57.5±12.9, p<0.01). The proportion of patients with genotype 1 was significantly higher in the SOF/LDV group than in the GLE/PIB group (79.7% vs. 27.0%, p<0.01). The prevalence of liver cirrhosis (23.7% vs. 15.7%, p=0.01), decompensated cirrhosis (4.3% vs. 0%, p<0.01), ascites (6.3% vs. 1.6%, p<0.01), HCC history (4.8% vs. 1.2%, p<0.01), and HCV treatment history (10.1% vs. 1.9%, p<0.01) were all significantly higher in the SOF/LDV group than the GLE/PIB group. On the other hand, there was no statistically significant difference in the patient characteristics, including aspartate aminotransferase, alanine aminotransferase, albumin, total bilirubin, international normalized ratio, and HCV RNA levels between the two groups (Table 1).

2. Treatment completion and SVR12 test

During the study, 13 patients (2.3%) from the GLE/PIB group did not complete the treatment protocol. Eleven patients were lost to follow-up, and two patients stopped the treatment due to drug side effects, including fever and abdominal discomfort. On the other hand, nine patients from the SOF/LDV group did not complete the treatment protocol. Eight patients were lost to follow-up, and one patient expired due to non-liver-related causes. The treatment completion rate was similar in the two groups (97.7% vs. 95.7%, p=0.08) (Fig. 2).

Figure 2. Treatment completion and SVR12 test rate in the glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/ledipasvir (SOF/LDV) groups.

Among the 760 patients who completed the treatment schedule, 120 did not undergo the SVR12 test. The SVR12 test rate was 84.2% and 84.3% in the GLE/PIB and SOF/LDV groups, respectively, without statistical significance (p=0.61) (Fig. 2). Male patients showed a higher tendency not to undergo the SVR12 test (p=0.01). Other factors, including age, liver cirrhosis, ascites, HCC history, and HCV treatment history, showed no statistical difference in the SVR12 test rate (Table 2).

Table 2 . Comparison of the SVR12 Test Group and No Test Group

VariableAll patients (n=760)SVR12 test group (n=640)SVR12 no test group (n=120)p-values
Age59.8±13.160.1±12.958.2±13.90.14
Male334 (43.9)268 (41.9)66 (54.5)0.01
Liver cirrhosis134 (17.6)115 (18.0)19 (15.7)0.55
Ascites20 (2.6)17 (2.7)3 (2.5)0.91
HCC history14 (1.8)13 (2.0)1 (0.8)0.37
HCV Tx history31 (4.1)29 (4.5)2 (1.7)0.14

Values are presented as mean±standard deviation or number (%).

SVR, sustained virologic response; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; Tx, treatment.



3. Treatment effectiveness

Six patients failed to achieve SVR12. All were male patients without cirrhosis and treated with GLE/PIB. Their HCV genotype was 2. They did not have a history of HCC and HCV treatment. They all showed undetectable levels of HCV RNA after treatment (Table 3).

Table 3 . Analysis of Treatment Failure Patients in the GLE/PIB Group

Patient123456
SexMaleMaleMaleMaleMaleMale
Age414458637480
Genotype222222
LCNoNoNoNoNoNo
HCC historyNoNoNoNoNoNo
HCV Tx historyNoNoNoYesaNoNo
Drug complianceGoodGoodGoodGoodGoodGood
HCV RNA × 6log10 (IU/mL)Initial19.77.354.335.552.253.39
8 weeks000000
Post-Tx week 1210.313.72.145.20.895.73

GLE/PIB, glecaprevir/pibrentasvir; LC, liver cirrhosis; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; Tx, treatment.

aHe was treated with sofosbuvir + ribavirin in the past but failed to achieve SVR12.



The treatment effectiveness was evaluated using the SVR12 rate. ITT analysis showed that the overall SVR12 was achieved in 81.2% (467/575) and 80.7% (167/207) of patients who received GLE/PIB and SOF/LDV, respectively. No significant differences were observed between the two groups (p=0.87). When analyzing SVR12 based on the HCV genotype, in genotype 1, the GLE/PIB and SOF/LDV groups showed a rate of 80.0% and 81.8%, respectively, without statistical significance (p=0.68). In HCV genotype 2, the GLE/PIB and SOF/LDV groups had a rate of 81.7% and 76.2%, respectively, showing no significant difference (p=0.39) (Fig. 3).

Figure 3. SVR12 according to ITT analysis of the glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/ledipasvir (SOF/LDV) groups. SVR12, sustained viral response 12 weeks after treatment; ITT, intention-to-treat.

Further analysis using the PP approach, which excluded patients with non-virologic failure and those lost to follow-up, showed that the overall SVR12 rate was achieved in 98.7% (467/473) and 100% (167/167) of patients receiving GLE/PIB and SOF/LDV, respectively. There was no statistical significance between the two groups (p=0.14). PP analysis was conducted based on the HCV genotype. In genotype 1, both drug groups showed 100% SVR12. In genotype 2, the GLE/PIB group demonstrated 98.3%, whereas the SOF/LDV group showed 100% SVR12, with no significant difference between the two groups (p=0.48) (Fig. 4).

Figure 4. SVR12 according to PP analysis of the glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/ledipasvir (SOF/LDV) groups. SVR12, sustained viral response 12 weeks after treatment; PP, per protocol (excluded patients with non-virologic failure, lost to follow-up).

4. Adverse events

Overall, the incidence of adverse events was similar in the two groups, with 3.5% and 6.3% of patients in the GLE/PIB and SOF/LDV groups, respectively (p=0.09). The most common adverse events reported were gastrointestinal discomfort, pruritus, headache, and fatigue. Other symptoms reported included chest pain, leg edema, urticaria, hair loss, and thirst (Table 4). The frequency and severity of adverse events were generally mild to moderate but were manageable without serious complications.

Table 4 . Adverse Events during Treatment according to the Treatment Regimen

AEsGLE/PIB group (n=575)SOF/LDV group (n=207)
Any AE20 (3.5)13 (6.3)
Any serious AE00
Drug discontinuation due to AE2 (0.3)0
AEs occurred in patients
GI discomfort7 (1.2)6 (2.9)
Pruritus4 (0.7)1 (0.5)
Headache2 (0.3)4 (1.9)
Fatigue1 (0.2)1 (0.5)
Chest pain01 (0.5)
Leg edema1 (0.2)0
Urticaria1 (0.2)0
Hair loss1 (0.2)0
Thirst1 (0.2)0
Fever1 (0.2)0

Values are presented as number (%).

GLE/PIB, glecaprevir/pibrentasvir; SOF/LDV, sofosbuvir/ledipasvir; AE, adverse events; GI, gastrointestinal.



In the GLE/PIB group, two patients (0.3%) stopped treatment because of adverse events. One patient was an 84-year-old female who complained of a high fever. She stopped taking the medication and was subsequently lost to follow- up. The other patient was a 58-year-old male who complained of abdominal discomfort and the large size of the drug tablet two days after beginning the medication. He had a history of treatment failure with PEG-interferon + ribavirin. No patient stopped treatment due to adverse events in the SOF/LDV group. The drug discontinuation rate due to adverse events was similar in the two groups, with a rate of 0.3% and 0% in the GLE/PIB and SOF/LDV groups, respectively (p=0.40).

DISCUSSION

This retrospective study conducted across multiple centers in Korea found that the sustained virologic response (SVR) rates were similar in patients with HCV genotypes 1 and 2 who were treated with SOF/LDV or GLE/PIB. Furthermore, SOF/LDV was well-tolerated compared to GLE/PIB, with no patients discontinuing treatment due to side effects.

The treatment completion and SVR12 test rates were also analyzed. In Korea, due to insurance criteria, patients can be prescribed DAA agents once in their lifetime as an initial treatment. Therefore, completing treatment during the initial therapy is crucial. Factors like the duration and number of medication doses can influence the treatment completion rate. Although the SOF/LDV regimen requires taking a single tablet for 12 weeks, the GLE/PIB regimen has the advantage of a shorter treatment duration (eight weeks) but involves taking three pills. Nevertheless, both regimens demonstrated a more than 95% treatment completion rate, suggesting that the duration or number of doses may not significantly affect the treatment completion rate.

The SVR12 test rates for both drugs were relatively low (~84%). These SVR12 test rates are relatively lower than anticipated, considering the short treatment duration and the high cost of the DAAs. Educating patients about the significance of SVR12 testing is necessary, considering the importance of achieving a cure for chronic hepatitis C and the high success rate of retreatment as a secondary option in cases of initial treatment failure. The reason is uncertain, but among the causes of the low SVR12 testing rate, the male sex was the only statistically significant sole factor. Hence, education for this group is essential.

The proportion of patients with liver cirrhosis, ascites, and a history of HCC was high in the SOF/LDV group, possibly because the SOF/LDV regimen may be prescribed for patients with decompensated liver cirrhosis. The proportion of patients with a HCV treatment history was also higher in the SOF/LDV group. This is likely because the SOF/LDV regimen was released earlier than the GLE/PIB regimen and was prescribed more commonly to patients who had previously experienced Peg-interferon-based HCV treatment. The average age of the patients in the GLE/PIB group was higher. The reason for this is unclear. Patients with genotype 2 may have delayed treatment with sofosbuvir + ribavirin because of concerns about side effects, such as anemia.

SOF/LDV was initially developed and approved for patients with HCV genotype 1, which has resulted in numerous clinical trials and real-life data. In a study conducted in South Korea, Japan, and Taiwan, the overall SVR12 rate for patients with genotype 1 HCV was 99%, which decreased slightly to 98% for those with a prior HCV treatment history.6-9 GLE/PIB demonstrated a similarly high SVR12 rate for genotype 1 HCV, ranging from 97% to 100%, with only slight variations according to the HCV treatment history or the presence of cirrhosis.10-14 In the present study, both regimens exhibited very high SVR12 rates without treatment failures for patients with genotype 1 HCV.

According to studies conducted in Korea, the treatment effectiveness of GLE/PIB for patients with genotype 2 HCV was lower than that for HCV genotype 1. In these studies, the SVR12 rates for genotype 1 HCV were 99.2–100%, while those for genotype 2 HCV were 96.6–98.5%.15,16 In the present study, however, the SVR12 (PP) rate for patients with genotype 2 HCV was 98.3% and 100% in the GLE/PIB and SOF/LDV groups, respectively. This is slightly different from a study conducted in Japan that compared SOF/LDV with GLE/PIB and found that the SVR12 rate for GLE/PIB was superior to that for SOF/LDV but without statistical significance (98.0% vs. 96.1%, mITT, p=0.57).17 Previous phase 2/3 trials of LDV/SOF for patients with HCV genotype 2 revealed good SVR12 results, with an overall SVR rate of 98.5% for patients treated with SOF/LDV for 12 weeks.18-20 Therefore, the effectiveness of SOF/LDV is not inferior to that of GLE/PIB for patients with HCV genotype 2.

Concerns were raised that the potent NS5A inhibition of ledipasvir might limit the therapeutic effectiveness of SOF/LDV in patients with NS5A RAS. Furthermore, recent RAS analysis showed that most of the patients with HCV GT2a (94–97%) and GT2b (39–89%) had the NS5A L31 mutation, which is associated with a low half-maximal effective concentration (EC50) and low SVR rate.21 Nevertheless, real data showed different results despite these concerns. For example, in a recent Taiwanese study evaluating the effectiveness and safety of LDV/SOF for HCV genotype 2, all 39 patients achieved SVR12. Japanese data also showed an overall SVR rate of 98.5% (262/266) in mITT analysis.18,20 These real-world data show that SOF/LDV can achieve a high SVR rate if given for a sufficient treatment period, regardless of the RAS status.

Some countries with a high prevalence of HCV GT2 are middle- or low-income countries that have not yet approved these SOF/VEL and GLE/PIB regimens. In contrast, SOF/LDV was initially approved by the FDA in 2014 and is relatively more available in many other countries.22 Therefore, SOF/LDV can be a viable alternative where new DAAs, such as SOF/VEL and GLE/PIB, are unavailable.

This study had several limitations that should be acknowledged. First, it was a retrospective study, which may introduce potential biases and limit the generalizability of the findings. Second, the number of patients treated with each drug was not distributed evenly by genotype, which may affect the comparison of the treatment effectiveness between the two groups. Third, many patients did not undergo the SVR12 test, potentially influencing the accuracy of the treatment effectiveness evaluation. This may limit the generalizability of the results.

In conclusion, the rates of sustained virologic responses (SVRs) were similar in patients with HCV genotypes 1 and 2 treated with SOF/LDV or GLE/PIB. Both regimens were well-tolerated and showed high SVR12 rates. The study supports SOF/LDV as a viable alternative to GLE/PIB in countries where new DAAs are unavailable.

Financial support

None.

Conflict of interest

None.

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