Abstract
Background
Pradefovir is a liver-targeted prodrug of adefovir, a nucleoside/nucleotide analogue with antiviral activity against hepatitis B virus (HBV) DNA polymerase. This phase 2 study compared the efficacy and safety of oral pradefovir (30, 45, 60, or 75 mg) versus tenofovir disoproxil fumarate (TDF; 300 mg) and aimed to identify the most appropriate dose of pradefovir for the forthcoming phase 3 study.
Methods
Treatment-naive and experienced (not on treatment >6 months) patients with chronic hepatitis B were eligible.
Results
A total of 240 participants were randomized and treated in the study (48 per group). Approximately 80% were hepatitis B e antigen (HBeAg) positive, and 10% had liver cirrhosis. The reductions from baseline in HBV DNA levels achieved at week 24 were 5.40, 5.34, 5.33, and 5.40 log10 IU/mL, with pradefovir doses of 30-, 45-, 60-, and 75-mg, respectively, compared with 5.12 log10 IU/mL with TDF. However, HBeAg loss was attained by more participants who received 45-, 60-, or 75-mg pradefovir than by those receiving TDF (12%, 6%, and 9% vs 3%). The TDF group exhibited a more significant increase in serum creatinine than the pradefovir 30- and 45-mg groups, and serum phosphate levels were comparable among all groups. Most adverse events (AEs) were mild (grade 1). No treatment-related severe AEs were reported. Overall, AEs and laboratory abnormalities were comparable to those in the TDF group.
Conclusions
Pradefovir and TDF exhibited comparable reductions in HBV DNA levels. All treatments were safe and well tolerated.
Clinical Trials registration
NCT00230503 and China Drug Trials CTR2018042
Keywords: pradefovir, tenofovir disoproxil fumarate, hepatitis B, efficacy, safety
In a phase 2 trial, pradefovir—a liver-targeted prodrug of adefovir, a nucleoside/nucleotide analogue with antiviral activity against hepatitis B virus (HBV) DNA—exhibited good efficacy in reducing HBV DNA levels and an acceptable safety profile, comparable to tenofovir disoproxil fumarate.
Hepatitis B virus (HBV) infection is a global health problem, but its prevalence shows considerable geographic variability. According to the World Health Organization, nearly 257 million people are chronically infected with HBV, and 68% of cases occur in Africa and the Western Pacific [1]. Worldwide, approximately 887 000 people die of HBV infection–related diseases annually [2]. The prevalence of HBV surface antigen (HBsAg) is 2% (39 million) in Southeast Asia and 6.0% (1.15 billion) in the Western Pacific. In China, the current prevalence of HBsAg is estimated to be 5%–6%, representing approximately 70 million patients, including 20–30 million with chronic hepatitis B (CHB). Therefore, liver disease caused by CHB represents a major burden in China [3–5].
Antiviral drugs can effectively inhibit HBV replication, reduce liver inflammation and cirrhosis, and delay the occurrence of liver failure, decompensated cirrhosis, liver cancer, and other complications [6–8]. Currently, the antiviral drugs primarily used in clinical practice are nucleoside/nucleotide analogues (NAs) and interferon [2, 9]. Lamivudine was the first approved oral therapy for HBV infection, but its efficacy is limited by the high incidence of drug resistance [10]. Adefovir dipivoxil exhibits activity against wild-type and lamivudine-resistant HBV [11], but dose-limiting renal and bone toxic effects, as well as the risk of resistance, limit its clinical use [12, 13]. Entecavir, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF) are currently recommended as first-line treatments for CHB.
Pradefovir is a liver-targeted prodrug of oral bioequivalent adefovir, which is converted to drug-active 9-(2-phosphonomethoxyethyl)adenine (PMEA; adefovir) via catalysis by liver CYP3A4 enzyme [14, 15]. Adefovir dipivoxil is metabolized in vivo, with a 1:1 kidney to liver ratio of PMEA levels; thus, the drug has a high risk of nephrotoxicity. However, pradefovir mesylate targets the liver and leads to a kidney-to-liver PMEA ratio of 1:20 after activation, which greatly reduces its nephrotoxicity. In HBV-infected transgenic mouse models, this drug significantly inhibits HBV replication. In addition, pradefovir has shown good antiviral activity and safety in phase 1 clinical trials, both in China and elsewhere [16].
The results of the phase 2 clinical trial of pradefovir are presented herein. For this clinical trial, a randomized, double-blind, noninferiority, positive drug parallel contrast research design was applied, with TDF as the control drug for evaluating the efficacy and safety of pradefovir.
METHODS
Study Design
This randomized, double-blind, noninferiority trial was conducted across 23 centers in China and is registered with ClinicalTrials.gov (NCT00230503) and ChinaDrugTrials.org.cn (CTR20180426). The primary objectives were to evaluate the safety and tolerability of multiple oral doses of pradefovir (30, 45, 60, or 75 mg), compared with 300-mg TDF given once daily for 24 weeks and to identify the most appropriate pradefovir dose for the forthcoming phase 3 study. The study protocol was approved by the institutional review board or independent ethics committee at each participating site, and the study was designed and conducted according to the principles of the Declaration of Helsinki and Good Clinical Practice. Written informed consent was obtained from all participants before enrollment.
Participants
Patients (male or female) were eligible if they met the following inclusion criteria: age 18–65 years; CHB with plasma HBV DNA level >20 000 IU/mL if hepatitis B e antigen (HBeAg) positive or >2000 IU/mL if HBeAg negative; and high serum alanine aminotransferase (ALT) level (1.2–10 times the upper limit of normal [ULN]), except in patients with confirmed liver inflammation or hepatic fibrosis of grade 2 or above. Treatment-naive and treatment-experienced patients (previous treatment with interferon or NAs if stopped ≥6 months before screening), as well as those with advanced fibrosis (stage F3) or compensated cirrhosis (stage F4) (≤10%), were included.
The following exclusion criteria were applied: allergy to NAs, liver failure, decompensated cirrhosis, hepatocellular carcinoma, or any severe liver disorder other than HBV infection; total bilirubin >2 times the ULN; chronic kidney disorder or estimated glomerular filtration rate ≤70 mL/min; or positive results for human immunodeficiency virus or hepatitis C virus. Patients with adefovir or TDF resistance also were excluded.
Procedures
Patients were screened 14 days before enrollment, and eligible patients were stratified according to HBeAg status (180 were HBeAg positive; 60, HBeAg negative) and randomly assigned (1:1:1:1:1) to receive pradefovir (30, 45, 60, or 75 mg) or TDF (300 mg) once daily for 24 weeks, after which all patients switched to or continued TDF for an additional 4 weeks of observation. After that, patients either continued the treatment or started alternative therapies. Participants returned to the clinic every 4 weeks for laboratory assessments of serum biochemical and hematological profiles, liver function, renal function (eg, serum creatinine level, glomerular filtration rate, and proteinuria), and HBV DNA levels.
HBV DNA testing was performed using the Roche COBAS AmpliPrep/Taqman assay (Roche Molecular Systems), with lower and upper limits of quantitation of 20 and 108 IU/mL, respectively. Hepatitis B serological markers (HBsAg, HBeAg, etc) were assessed every 12 weeks in a central laboratory (Teddy Clinical Research Laboratory). Resistance surveillance and genotypic analysis of HBV polymerases were conducted for all participants at baseline and for participants whose HBV DNA viral load decreased by <1 log10 IU/L from baseline to week 12. Safety and tolerability assessments were conducted throughout the study, and all adverse events (AEs), treatment discontinuations, and patient deaths were recorded.
End Points
The primary efficacy end point was defined as the reduction in serum HBV DNA level from baseline to after 24 weeks of treatment. Secondary end points included the proportions of participants with undetectable HBV DNA (<29 IU/mL), with ALT normalization, and with HBeAg loss or seroconversion at week 24.
Safety was assessed at every study visit by monitoring AEs, vital signs, physical examination findings, clinical laboratory test results, 12-lead electrocardiography, and upper abdominal ultrasonographic scans from the start of treatment up to 4 weeks after the last dose of study drug. AEs were coded using the Medical Dictionary for Regulatory Activities, version 17.1 (MedDRA MSSO) and graded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. The attribution of causality for any AE to the study drug was at the discretion of the investigator according to a national adverse drug reaction vigilance procedure. An adverse drug reaction is defined as any AE that is definitely, probably, or possibly caused by the use of the study drug, as assessed by the investigator.
Statistical Analysis
The planned study enrollment was 180 HBeAg-positive and 60 HBeAg-negative patients with CHB, for a total of 240 randomized patients. The proportion with compensated liver cirrhosis was intended to be <20%, and the proportion of treatment-experienced patients, <35%. Serum HBV DNA levels were analyzed after logarithmic transformation. For the primary efficacy analysis, HBV DNA levels <20 IU/mL were considered to be 20 IU/mL, and the change from baseline to week 24 in HBV DNA (log10 IU/mL) was analyzed using the Bonferroni method for multiple comparisons, with significance set at P < .05/10 = .005. The proportions of participants with undetectable HBV DNA within patient subsets and the potential effects of HBV DNA e antigen presentation (HBeAg positive or negative) were analyzed using Pearson χ 2 or Fisher exact tests. Safety results were descriptively summarized and compared, also using Pearson χ 2 or Fisher exact tests. Differences were considered statistically significant at P ≤.05 (2 sided). All statistical summaries and analyses were performed using the SAS software package, version 9.4 (SAS Institute).
RESULTS
Study Population
From 31 May 2018 through 9 January 2019, a total of 330 patients were screened. Of these, 90 patients were excluded for not meeting the eligibility criteria, leaving 240 participants for randomization (48 per group). All 240 randomized participants received ≥1 dose of the assigned drugs. A total of 13 participants did not complete the study. One patient withdrew from the pradefovir 45-mg group at week 8 owing to a serious AE (SAE) that was determined to be unrelated to the study drug (hepatocellular carcinoma). Three patients did not complete the treatment owing to AEs determined to be likely related to the study drugs: 1 patient in the pradefovir 75-mg group who withdrew at week 20 because of gastritis, 1 in the pradefovir 30-mg group who experienced proteinuria and withdrew at week 16, and 1 in the TDF group who experienced increased creatinine and withdrew at week 14. Another 6 patients withdrew from the study for unknown reasons. Three participants were lost to follow-up. No participants discontinued the study due to lack of efficacy (Figure 1).
Figure 1.
Study flow chart. Abbreviations: AE, adverse event; SAE, serious AE.
The demographic and other baseline characteristics of the randomized participants were similar across the 5 groups (Table 1). The participants included 183 men and 57 women and had a mean age of 34 years (range, 18–65 years). The proportion of HBeAg-positive participants was 72% (172 of 240). Fifty-four participants had received nucleoside/nucleotide analogues treatments previously, including adefovir dipivoxil (5%), entecavir (14%), telbivudine (10%), lamivudine (3%), and TDF (4%), and 13 (2%) had a history of interferon use. At the time of screening, the mean liver stiffness measurement was 10.68 kPa, and 21 (9%) participants had liver cirrhosis. The mean baseline ALT concentration was 156.5 IU/L (range, 18–476 IU/L). However, the pradefovir 30-mg group had a significantly higher mean serum HBV DNA level (7.54 log10 IU/mL) and a higher proportion of patients with HBV DNA levels ≥8 log10 IU/mL than the other 4 groups.
Table 1.
Demographics and Baseline Characteristics of Study Participants by Treatment Group
| Characteristic | Participants, No. (%)a | P Value | ||||
|---|---|---|---|---|---|---|
| TDF Group (300 mg) (n = 48) | Pradefovir Groups | |||||
| 30 mg (n = 48) | 45 mg (n = 48) | 60 mg (n = 48) | 75 mg (n = 48) | |||
| Sex | ||||||
| Male | 38 (79) | 38 (79) | 34 (71) | 37 (77) | 36 (75) | .86 |
| Female | 10 (21%) | 10 (21) | 14 (29) | 11 (22) | 12 (25) | |
| Age, mean (SD) y | 35 (11) | 35 (10) | 35 (9) | 37 (9) | 36 (10) | .53 |
| HBV DNA level, mean (SD), log10 IU/mL | 7.00 (1.50) | 7.54 (1.35) | 7.08 (1.49) | 6.97 (1.48) | 6.81 (1.63) | .17 |
| ALT concentration, mean (SD), IU/L | 185 (179) | 177 (186) | 162 (136) | 152 (119) | 139 (128) | .35 |
| HBeAg | ||||||
| Negative | 13 (27) | 13 (27) | 12 (25) | 15 (31) | 14 (29) | .65 |
| Positive | 35 (73) | 35 (73) | 36 (75) | 33 (69) | 34 (71) | |
| Previous NA use | 11 (23) | 10 (21) | 12 (25) | 10 (21) | 11 (23) | .99 |
| Previous interferon use | 2 (4) | 2 (4) | 2 (4) | 2 (4) | 5 (10) | .63 |
| Compensated liver cirrhosis | ||||||
| No | 5 (10) | 3 (6) | 4 (8) | 5 (10) | 4 (8) | .98 |
| Yes | 43 (90) | 45 (94) | 44 (92) | 43 (90) | 44 (92) | |
| LSM, mean (SD, kPa | 9.9 (4.3) | 11.3 (7.6) | 10.7 (9.7) | 10.9 (6.3) | 10.6 (6.6) | .83 |
Abbreviations: ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; LSM, liver stiffness measurement; NA, nucleoside/nucleotide analogue; SD, standard deviation; TDF, tenofovir disoproxil fumarate.
aData represent no. (%) of study participants unless otherwise specified.
Virologic and Biochemical Responses
At week 24, all 5 treatment groups exhibited significant reductions in serum HBV DNA levels from baseline (Figure 2A). The reductions from baseline were 5.40, 5.34, 5.33, and 5.40 log10 IU/mL for the pradefovir 30-, 45-, 60-, and 75-mg groups, respectively, compared with 5.12 log10 IU/mL for the TDF group (Table 2). The proportions of participants with HBV DNA levels <29 IU/mL were 27%, 54%, 48%, and 58%, respectively, for the 4 pradefovir groups, compared with 42% for TDF (Figure 2B). A dose–response relationship was demonstrated among the pradefovir treatment groups. HBeAg loss rates did not differ significantly among the pradefovir 30-, 45-, 60-, and 75-mg groups (3%, 12%, 6%, 9%, respectively) and the TDF group (3%; Table 2). The HBeAg seroconversion rates were 0%, 10%, 0%, and 4%. respectively, for the 4 pradefovir groups, compared with 3% for the TDF group. No statistically significant differences were identified between the groups. No HBsAg loss or HBsAg seroconversion was observed throughout the study.
Figure 2.
Hepatitis B virus (HBV) DNA levels in study participants during 24-week treatment by group and visit. A, HBV DNA levels. B, Proportion of participants with undetectable HBV DNA (<29 IU/mL). C, Proportion who achieved alanine aminotransferase (ALT) normalization. Abbreviation: TDF, tenofovir disoproxil fumarate.
Table 2.
Virologic Response in Study Participants at Week 24 by Treatment Group
| Pradefovir | P Value | |||||
|---|---|---|---|---|---|---|
| Response | TDF (300 mg) | 30 mg | 45 mg | 60 mg | 75 mg | |
| Change from baseline in HBV DNA level, mean, log10 IU/mL | 5.12 | 5.40 | 5.34 | 5.33 | 5.40 | .85 |
| Proportion of participants, no./total (%) | ||||||
| With HBV DNA <29 IU/mL | 17/40 (43) | 11/43 (26) | 24/44 (55) | 14/38 (37) | 23/41 (56) | .02 |
| With HBeAg loss | 1/33 (3) | 1/35 (3) | 4/33 (12) | 2/31 (6) | 3/33 (9) | .53 |
| With HBeAg seroconversion | 1/30 (3) | 0/30 (0%) | 3/30 (10) | 0/26 (0%) | 1/24 (4) | .23 |
Abbreviations: HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; TDF, tenofovir disoproxil fumarate.
At week 24, the mean reductions in serum ALT were 141.8, 119.1, 107.5, and 83.2 IU/L for the pradefovir 30-, 45-, 60-, and 75-mg groups, respectively, compared with 145.5 IU/L for the TDF group. The proportions of participants who achieved ALT normalization were 83%, 68%, 65%, and 51%, respectively, for the 4 pradefovir groups, compared with 69% for the TDF group (Figure 2C); no statistically significant differences between treatment groups were observed.
Safety
The rates of AEs in the pradefovir 30-, 45-, 60-, and 75-mg groups and the TDF group were 96%, 90%, 90%, 96%, and 98%, respectively. Most AEs were classified as grade 1 or 2 (Table 3). Fourteen SAEs were reported, and none were judged to be related to the study drugs. The rates of SAEs that occurred in the pradefovir 30-, 45-, 60-, and 75-mg groups and the TDF 300-mg group were 6%, 6%, 8%, 4%, and 4%, respectively. Three patients were discontinued from the study owing to drug-related grade 3 AEs. The AEs resolved thereafter. No grade 4 AEs or deaths were reported. Overall, the treatments were well tolerated, and the safety profiles were similar among the groups, with no relationships between dose and AEs observed.
Table 3.
Adverse Events and Laboratory Abnormalities in Study Participants by Treatment Group
| Participants, No. (%) | |||||
|---|---|---|---|---|---|
| Pradefovir | |||||
| AEs and Abnormalities | TDF 300 mg (n = 48) | 30 mg (n = 48) | 45 mg (n = 48) | 60 mg (n = 48) | 75 mg (n = 48) |
| Any AE | 47 (98) | 46 (96) | 43 (90) | 43 (90) | 46 (96) |
| Death | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| SAE | 2 (4) | 3 (6) | 3 (6) | 4 (8) | 2 (4) |
| AE leading to drug discontinuation | 1 (2) | 1 (2) | 0 (0) | 0 (0) | 1 (2) |
| Grade 3 AE | 4 (8) | 4 (8) | 5 (10) | 4 (8) | 7 (15) |
| AEs occurring in ≥5% | |||||
| Upper respiratory tract infection | 7 (15) | 8 (17) | 8 (17) | 2 (4) | 7 (15) |
| Urinary tract infection | 0 (0) | 3 (6) | 5 (10) | 1 (2) | 1 (2) |
| Nausea | 5 (10) | 1 (2) | 0 (0) | 3 (6) | 1 (2) |
| Diarrhea | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 3 (6) |
| Abdominal distention | 0 (0) | 1 (2) | 1 (2) | 2 (4) | 5 (10) |
| Abnormal liver function | 4 (8) | 3 (6) | 4 (8) | 5 (10) | 9 (19) |
| Malaise | 3 (6) | 0 (0) | 1 (2) | 1 (2) | 0 (0) |
| Laboratory abnormalities occurring in >5% | |||||
| Increased CK-MB | 26 (54) | 12 (25) | 14 (29) | 14 (29) | 17 (35) |
| Increased CK | 10 (21) | 8 (17) | 5 (10) | 5 (10) | 2 (4) |
| Hypophosphatemia | 2 (4) | 5 (10) | 2 (4) | 6 (13) | 5 (10) |
| Increased ALT | 3 (6) | 4 (8) | 0 (0) | 5 (10) | 6 (13) |
| Increased bilirubin | 5 (10) | 1 (2) | 0 (0) | 4 (8) | 5 (10) |
| Decreased neutrophil count | 2 (4) | 4 (8) | 1 (2) | 3 (6) | 4 (8) |
| Increased GGT | 1 (2) | 2 (4) | 3 (6) | 2 (4) | 9 (19) |
| Increased transaminase | 3 (6) | 3 (6) | 4 (8) | 3 (6) | 1 (2) |
| Increased AST | 1 (2) | 2 (4) | 0 (0) | 3 (6) | 4 (8) |
| Leukopenia | 1 (2) | 3 (6) | 1 (2) | 2 (4) | 3 (6) |
| Prolonged APTT | 1 (2) | 2 (4) | 0 (0) | 4 (8) | 0 (0) |
| Proteinuria | 4 (8) | 3 (6) | 4 (8) | 2 (4) | 1 (2) |
| Hematuria | 1 (2) | 3 (6) | 4 (8) | 1 (2) | 2 (4) |
| Urine erythrocytes | 4 (8) | 2 (4) | 1 (2) | 1 (2) | 0 (0) |
| Amylase increases | 2 (4) | 3 (6) | 0 (0) | 1 (2) | 2 (4) |
| Elevated blood uric acid | 4 (8) | 2 (4) | 2 (4) | 2 (4) | 1 (2) |
| Total bile acids increase | 0 (0) | 1 (2) | 4 (8) | 1 (2) | 1 (2) |
| Increased creatinine | 1 (2) | 1 (2) | 1 (2) | 1 (2) | 2 (4) |
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; CK-MB, creatine kinase MB; GGT, γ-glutamyl transpeptidase; SAE, serious AE; TDF, tenofovir disoproxil fumarate.
The most frequently reported AEs were upper respiratory infection (15%), nausea (10%), abnormal liver function (8%), and malaise (6%) in the TDF group and upper respiratory infection (13%), abdominal distention (5%), and abnormal liver function (11%) in the pradefovir groups (Table 3). The most common laboratory abnormalities (>5%) in the pradefovir groups were decreased cholinesterase (56%), increased creatine kinase MB (30%), hypophosphatemia (10%), increased ALT (10%), increased bilirubin (8%), increased γ-glutamyl transferase (7%), neutropenia (7%), increased aspartate aminotransferase (5%), and increased transaminase (5%).
ALT levels increased to >10 times the ULN were observed in 13 participants, including 3 in the TDF group and 10 in pradefovir groups (3 each treated with 30, 60, or 75 mg and 1 treated with 45 mg). No relationship between dose and ALT increased was observed. In all cases, the ALT level improved to <2 times the ULN. By week 12, normalization was achieved in 11 participants (85%), despite continuation of treatment. During the study period, 8 participants experienced an ALT flare (defined as serum ALT >2 times the baseline and >10 times the ULN, with or without associated symptoms). Most of these events occurred early in the treatment period (within the first 1–2 months). They resolved without sequelae and were judged to be associated with the underlying CHB. Among these 8 participants, 2 were in the TDF group and 6 in the pradefovir groups (2 treated with 30 mg, 1 with 45 mg, 2 with 60 mg, and 1 with 75 mg; Table 4).
Table 4.
Alanine Aminotransferase (ALT) Concentrations in Study Participants Who Experienced ALT Flare
| ALT, IU/L | ||||||||
|---|---|---|---|---|---|---|---|---|
| Treatment Group | Participant number | Baseline | wk 4 | wk 8 | wk 12 | wk 16 | wk 20 | wk 24 |
| TDF (300 mg) | 9 | 245 | 679 | 69 | 23 | 18 | 22 | 18 |
| 102 | 119 | 243 | 555 | 99 | 41 | 33 | 23 | |
| Pradefovir | ||||||||
| 30 mg | 10 | 276 | 842 | 50 | 30 | 31 | 27 | 26 |
| 166 | 120 | 920 | 170 | 79 | 33 | ND | 24 | |
| 45 mg | 83 | 131 | 494 | 25 | 22 | 28 | 23 | 19 |
| 60 mg | 153 | 236 | 609 | 50 | 37 | 52 | 37 | 40 |
| 223 | 221 | 621 | 27 | 26 | 19 | 40 | 46 | |
| 75 mg | 105 | 255 | 565 | 42 | 68 | 83 | 75 | 29 |
Abbreviations: ALT, alanine aminotransferase; ND, not done; TDF, tenofovir disoproxil fumarate.
Drug-related, mild serum creatinine increases were recorded in 3 patients. One in the TDF group discontinued treatment at week 14. The other 2 cases (1 in the TDF group and 1 in the pradefovir 75-mg group) resolved without intervention, despite continuation of the treatment. Furthermore, higher mean increases in the serum creatinine level from baseline to 24 weeks were observed in the TDF group than in the pradefovir groups (Figure 3A). Similarly, intermittent serum phosphate fluctuations were observed among the 5 treatment groups (Figure 3B), but no clinical meaningful trends were identified.
Figure 3.
Changes in serum creatinine and phosphate levels in study participants during 24-week treatment by group and visit. A, Changes in serum creatinine levels in the tenofovir disoproxil fumarate (TDF) and pradefovir (30- and 45-mg) groups. B, Changes in phosphate levels in the TDF and pradefovir (30- and 45-mg) groups.
DISCUSSION
In this phase 2 clinical trial, pradefovir showed good efficacy and an acceptable safety profile compared with TDF. These findings indicate that pradefovir is a promising novel NA for the treatment of CHB.
Regarding HBV DNA viral suppression, our results indicate that pradefovir doses of 30–75 mg proved noninferior to TDF at 300 mg. The response rates did not differ significantly among the treatment groups. The rates of HBeAg loss and serum serological conversion appeared to be better in the pradefovir 45-mg group than in the TDF group (12% vs 3% and 10% vs 3%, respectively), but these differences were not statistically significant. The proportions of participants who achieved ALT normalization were similar among the groups, with very close percentages noted for the pradefovir 45-mg (68%) and the TDF 300-mg (69%) groups.
All treatments were safe and well tolerated, and most AEs were mild. Discontinuation of treatment drugs owing to AEs was very rare (<1% overall), and there were no significant differences in the rates of AEs, SAEs, or laboratory abnormalities among the 5 groups. The rate of drug-related AEs in the pradefovir 45-mg group was almost identical to that in the TDF 300-mg group (both 71%).
ALT flares in CHB are common and may be caused by cell-mediated immune system against HBV-infected hepatocytes [17, 18]. It has been reported during entecavir, TDF, and TAF therapy [19, 20]. In this study, the ALT flares accompanied reductions of ≥3 log10 UL/mL in serum HBV DNA level, and serum ALT levels achieved normalization despite continuation of treatment. Therefore, the serum ALT flares may indicate recovery of the host immune response against HBV.
Long-term treatment with tenofovir has been linked with kidney injury, including acute renal failure, proximal tubulopathy, and, in rare instances, Fanconi syndrome [12, 21–25]. In addition, TDF treatment can cause modest declines in glomerular filtration rates, which may result from subclinical tubular injury [26, 27]. In the current study, the change trend for serum creatinine was analyzed. Participants given pradefovir exhibited smaller increases in serum creatinine levels than those given TDF, particularly patients who received lower pradefovir doses (30 or 45 mg). Notably, serum creatinine levels showed minimal increases and remained within the normal ULN range. In addition, no cases of serious renal injury were observed.
The current guidance from the American Association for the Study of Liver Diseases recommends entecavir, TDF, and TAF as first-line treatments for CHB [28]. Dohyeong Lee suggested that serum phosphate measurement is a sensitive method for predicting kidney injury in patients taking NAs; however, the use of hypophosphatemia as a predictor of kidney injury and the characteristics of patients who experience this condition when taking TDF have yet to be clearly established [29]. In the current study, serum phosphate levels were closely monitored, and similar intermittent serum phosphate fluctuations were observed among the 5 treatment groups (Figure 3B). However, no clinically meaningful trends were identified.
Although the rates of virological response did not differ significantly among the groups, the proportion of patients with an HBV DNA level <29 IU/mL at week 24 was numerically higher in the pradefovir 45-mg group than in the pradefovir 30-mg and TDF groups. The pradefovir 45-mg group also showed numerical advantages in the rates of HBeAg loss and serum serological conversion compared with the pradefovir 30-mg and TDF groups. Although the rates of AEs were similar among all groups, the pradefovir 45-mg group showed the best profile overall. Most importantly, the pradefovir 30-mg and 45-mg groups showed safer trends in serum creatinine changes, suggesting a better renal safety profile. Considering the safety and efficacy profiles of the treatment groups and the risk–benefit balance, once-daily use of pradefovir at 45 mg may be recommended for forthcoming phase 3 studies to further investigate the efficacy and safety of pradefovir for the long-term treatment of patients with CHB.
The possible limitation of this study is that the treatment period was only 24 weeks. However, viral resistance to long-term adefovir therapy is rare, with reported cumulative rates of resistance of 0%, 3%, 11%, 18%, and 28%, respectively, at 1, 2, 3, 4, and 5 years of treatment [30]. No drug-resistant HBV mutant was observed in this study. However, the 24-week duration might not be long enough to conclusively show that pradefovir will lead to a lower incidence of bone and renal events. A randomized, double-blind, multicenter, phase 3 trial is now recruiting participants to compare long-term efficacy and safety of pradefovir versus TDF in patients with CHB in China (NCT04543565). The study will enroll 900 participants to be randomly assigned (2:1) to receive pradefovir (45 mg) or TDF (300 mg) once daily for 144 weeks.
Notes
Financial support. This work was supported by Xi’an Xintong Pharmaceutical Research Co., Ltd. and national major project funding of the 13th Five-Year Plan of China (code 2016ZX09101008‐001).
Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
Contributor Information
Yanhang Gao, Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China.
Fei Kong, Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China.
Xinwen Song, Department of Infectious Diseases, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
Jia Shang, Department of Infectious Diseases, Henan Provincial People’s Hospital, Zhengzhou, Henan, China.
Lvfeng Yao, Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China.
Jinyu Xia, Department of Infectious Diseases, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China.
Yanzhong Peng, Department of Infectious Diseases, Peking University Shenzhen Hospital, Shenzhen, China.
Weidong Liu, Department of Hepatology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Huanyu Gong, Department of Infectious Diseases, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Mao Mu, Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
Hesong Cui, Department of Infectious Diseases, Yanbian University Affiliated Hospital, Yanji, Jilin, China.
Tao Han, Department of Hepatology, Tianjin Third Central Hospital, Tianjin, China.
Wen Chen, Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
Xiaolu Wu, Department of Infectious Diseases, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China.
Yongfeng Yang, Department of Hepatology, The Second Hospital of Nanjing, Nanjing, Jiangsu, China.
Xuebing Yan, Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
Zhenjing Jin, Department of Hepatology, The Second Hospital of Jilin University, Changchun, China.
Peng Wang, Department of Infectious Diseases, Shunde Hospital of Southern Medical University, Foshan, Guangdong, China.
Qingjing Zhu, Department of Hepatology, Wuhan Hospital for Infectious Diseases, Wuhan, Hubei, China.
Liang Chen, Department of Infectious Diseases, Shanghai Public Health Clinical Center, Shanghai, China.
Caiyan Zhao, Department of Infectious Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Dengke Zhang, Xi’an Xintong Pharmaceutical Research, Xi’an, Shanxi, China.
Weili Jin, Xi’an Xintong Pharmaceutical Research, Xi’an, Shanxi, China.
Daidi Wang, Xi’an Xintong Pharmaceutical Research, Xi’an, Shanxi, China.
Xiuhong Wen, Xi’an Xintong Pharmaceutical Research, Xi’an, Shanxi, China.
Chunmei Liu, Xi’an Xintong Pharmaceutical Research, Xi’an, Shanxi, China.
Jidong Jia, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Qing Mao, Institute of Infectious Diseases, First Affiliated Hospital of People’s Liberation Army Medical University, Chongqing, China.
Yanhua Ding, Department of Phase I Clinical Trial, The First Hospital of Jilin University, Changchun, Jilin, China.
Xueyuan Jin, Department of Quality Management, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
Zong Zhang, Department of Hepatology, Jinan Hospital for Infectious Disease, Jinan, Shandong, China.
Qianguo Mao, Department of Hepatology, Chinese Medicine Xiamen Hospital, Xiamen, Fujian, China.
Guangming Li, Cirrhosis Department, Zhengzhou Sixth Municipal People’s Hospital, Zhengzhou, Henan, China.
Junqi Niu, Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China.
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