Pharmacology of TAF
Tenofovir alafenamide is a phosphonamidate prodrug of tenofovir. After oral absorption, it is hydrolyzed in the hepatocytes to tenofovir, which is then phosphorylated to the active metabolite, TFV-DP. Incorporation of TFV-DP into the HBV DNA, results in termination of HBV replication [
50‐
52].
The recommended dosage of TAF is 25 mg once daily, to be taken orally with food. No dosage adjustment is required in patients with estimated creatinine clearance (CrCl) ≥ 15 mL/min, in patients with CrCl < 15 mL/min who are receiving hemodialysis or in those with hepatic impairment. There are no dosing recommendations for TAF in patients with CrCl < 15 mL/min who are not receiving hemodialysis [
53,
54]. The use of TAF may be considered in pregnancy, only if necessary, as there is limited or no data on the use of TAF in this population. The use of TAF is not recommended during breast feeding [
54].
Tenofovir alafenamide is transported by P-glycoprotein (P-gp) and breast cancer resistance protein (BRCP). Co-administration of TAF with inhibitors of P-gp and BRCP may increase the plasma concentration of TAF, and concomitant administration of TAF with P-gp inducers may decrease the plasma concentrations of TAF, resulting in loss of therapeutic activity. Therefore, administration of TAF with inhibitors of P-gp or BRCP, or P-gp inducers should be avoided [
53,
54].
Although both TAF and TDF are prodrugs of tenofovir and are metabolized to TFV-DP [
53,
54], TAF results in more than 90% lower systemic exposure of tenofovir and provides higher intracellular levels of TFV-DP to target cells than TDF at therapeutic doses [
55,
56]. Hence, TAF has fewer renal and bone safety issues compared to TDF.
Clinical Efficacy of TAF
Evidence for the clinical efficacy of TAF comes from (1) two large, phase 3 clinical trials (study 0108 in HBeAg-negative, and study 0110 in HBeAg-positive chronic HBV patients) with endpoints evaluated at 48 weeks [
57,
58]; (2) pooled analysis of studies 108 and 110 conducted at 96 and 144 weeks [
43,
59]; and (3) open-label extension phase of studies 108 and 110 (144 weeks of TAF therapy) [
60,
61]. A majority of patients in both 108 and 110 studies belonged to the Asian ethnicity. Apart from these two studies, few other real-world studies conducted in Asia have also evaluated the efficacy and safety of TAF for the management of HBV infection.
Design and endpoints in studies 0108 and 0110
Studies 0108 and 0110 were randomized, double-blind, multinational, non-inferiority studies. Inclusion criteria were treatment-naïve and treatment-experienced patients aged ≥ 18 years with chronic HBV infection with plasma HBV DNA > 20,000 IU/mL, serum ALT > 60 U/L in men or > 38 U/L in women (and not more than ten times ULN), and estimated creatinine clearance of at least 50 mL/min. Randomization in both the studies was done in a 2:1 ratio in a double-blind manner to TAF 25 mg or TDF 300 mg orally, once daily, each with a matching placebo for up to 96 weeks [
57,
58]. After 96 weeks, following a protocol amendment, the double-blind phase was extended for an additional year in about half of the patients and the remaining half received open-label therapy with TAF 25 mg orally once daily until week 144 [
59].
Both the studies had the same primary efficacy endpoint, viz. the proportion of patients who had HBV DNA < 29 IU/mL at week 48. Other pre-specified efficacy endpoints included the following: (1) percentage of patients with ALT normalization at week 48 (ALT > ULN of ≤ 43 U/L for men and ≤ 34 U/L for women younger than 69 years of age; ≤ 35 U/L for men and ≤ 32 U/L for women older than 69 years of age; at no more than ten times the ULN by central laboratory normal range; or 30 U/L for men and 19 U/L for women as per AASLD); and (2) proportion of patients with HBsAg loss and seroconversion to anti-HBs at week 48. Bone and renal safety were the secondary safety endpoints [
57,
58].
Efficacy of TAF through 144 weeks in studies 108 and 110
While 426 eligible HBeAg-negative chronic HBV patients were randomized to TAF (
n = 285) or TDF (
n = 141) at 105 sites in study 108, study 110 was conducted at 161 centers across 19 countries in 873 eligible HBeAg-positive chronic HBV patients who were randomized to TAF (
n = 581) or TDF (
n = 292) [
57,
58]. The pooled analysis of both the studies at 96 weeks included 866 patients on TAF and 432 patients on TDF [
43]. About 1118 patients were included in the analysis of the double-blind extension phase [759 HBeAg-positive and 359 HBeAg-negative chronic HBV patients; 866 in the TAF group (both double-blind extension and open-label phases), and 252 in the TDF group (double-blind extension phase)] [
59]. About 72% in each group in study 108, 83% in the TAF group and 79% in the TDF group in study 110, 79% in the TAF group and 77% in the TDF group in the pooled analysis at 96 weeks, and 78% in the double-blind extension phase of both the studies were Asians [
43,
57‐
59].
Treatment with TAF was found to be non-inferior to TDF at 48, 96, and 144 weeks in both HBeAg-negative and HBeAg-positive chronic HBV-infected patients (Tables
1,
2). Further, a pre-defined subgroup analysis revealed no significant difference in the proportion of patients achieving the primary endpoint between Asians and non-Asians in both the studies at both 48 and 96 weeks. Normalization of ALT levels was found to be significantly high in patients treated with TAF vs. TDF at week 96, by central laboratory criteria and AASLD criteria, and at week 144 by AASLD criteria in both the studies (Tables
1,
2) [
43,
57‐
59]. There was no significant difference between the two groups in terms of HBeAg or HBsAg seroconversion or loss, at weeks 48, 96, and 144 in both the studies [
43,
57‐
59].
Table 1
Efficacy of TAF vs. TDF at 48, 96 and 144 weeks in HBeAg-negative, chronic HBV patients [
43,
57,
59]
HBV DNA < 29 IU/mL | 94 | 93 | 1.8% (–3.6 to 7.2) | 0.47 | 90 | 91 | –0.6% (–7.0% to 5.8%) | 0.84 | 87% | 85% | NS |
Normalized ALT by central laboratory criteria | 83 | 75 | 8.0% (–1.3 to 17.2) | 0.076 | 81 | 71 | 9.8% (0.2% to 19.3%) | 0.038 | NA | NA | NA |
Normalized ALT by AASLD criteria | 50 | 32 | 17.9% (8.0 to 27.7) | 0.0005 | 50 | 40 | 10.9% (0.8% to 21.0%) | 0.035 | 71% | 59% | 0.052 |
Table 2
Efficacy of TAF vs. TDF at 48, 96 and 144 weeks in HBeAg-positive, chronic HBV patients [
43,
58,
59]
HBV DNA < 29 IU/mL | 64 | 67 | –3.6% (–9.8 to 2.6%) | 0.25 | 73 | 75 | –2.2% (–8.3 to 3.9%) | 0.47 | 74% | 71% | NS |
Normalized ALT by central laboratory criteria | 72 | 67 | 4.6% (–2.3 to 11.4%) | 0.18 | 75 | 68 | 8.0% (1.2 to 14.7%) | 0.017 | NA | NA | NA |
Normalized ALT by AASLD criteria | 45 | 36 | 8.7% (1.8% to 1.6%) | 0.014 | 52 | 42 | 10.6% (3.6 to 17.6%) | 0.003 | 64% | 53% | 0.010 |
Efficacy of TAF in real-world settings in Asia
Studies evaluating the efficacy and safety of TAF in real-world settings in Asia are limited. A recent study by Kaneko et al
. compared the efficacy and safety of TAF (
n = 67) versus TDF (
n = 117) and investigated the efficacy of switch-over from TDF to TAF therapy (
n = 36). The percentage of patients with ALT normalization was numerically higher in the TAF versus TDF group at week 48 of treatment by both hospital-based criteria (100% vs. 83.3%, respectively) and AASLD laboratory criteria (57.1% and 45.2%, respectively). The decline in HBV DNA and HBsAg levels was comparable between both the groups at week 48 [
62].
Furthermore, in a recent systematic review and network meta-analysis of 42 randomized controlled trials, while both TAF and TDF were found to be the best antiviral agents for virologic response, TAF was noted to be the best for ALT normalization among the assessed antiviral agents for the treatment of chronic HBV infection in both HBeAg-positive and HBeAg-negative patient population [
63].
Resistance with TAF
In the pooled analysis of studies 108 and 110 at 96 weeks, overall, no resistant isolates were detected in the TAF group [
43,
64]. In the phenotypic analysis at week 144 of the double-blind extension phase in 49 patients, no isolates showed resistance to TAF [
65]. Further, in vitro studies have revealed potent antiviral activity of TAF against LAM-, ETV-, and ADV-resistant isolates when compared to the wild-type HBV clinical isolates [
66].
Switch-over from TDF to TAF
The one-year results of the open-label extension phase of studies 108 and 110 revealed maintenance of viral suppression, with significantly higher normalization of ALT levels with 144 weeks of TAF therapy [
67,
68]. A significant increase was noted in the proportion of patients with normalization of ALT levels after 48 weeks of switch-over (week 144 of TAF therapy), both as per the AASLD and central laboratory criteria [
60,
61].
The preliminary results of switch-over from TDF to TAF at 12 and 24 weeks in the open-label extension phase of studies 108 and 110 revealed improved bone and renal parameters with TAF therapy [
67]. These results were sustained up to one-year of the open-label extension phase (viz., after 48 weeks of switch over or after up to 144 weeks of TAF therapy). There was an improvement in markers of tubular dysfunction with TAF therapy (overall decrease in serum creatinine: − 0.018 ± 0.064;
p = 0.008). Further, there was a significant decline in all markers of bone turnover and improvement in hip and spine BMD after 48 weeks of switch-over (hip BMD: + 0.97 ± 2.88,
p = 0.002; spine BMD: + 2.18 ± 3.36;
p < 0.001) [
60,
65].
A comparison of the safety results between the TDF double-blind extension group (
n = 211) and TDF to TAF switch-over group (
n = 180) at week 144 revealed significantly improved bone and renal safety in the latter group. The median changes in eGFR in both the groups were − 0.9 mL/min and + 4.2 mL/min, respectively (
p < 0.001). The corresponding changes in hip BMD were − 0.02 and + 0.98 (
p < 0.001) and spine BMD were + 0.26 and + 2.04 (
p < 0.001), respectively [
69].
Considering the high proportion of Asians in studies 108 and 110, these findings suggest that TAF may be an alternative to TDF with better bone and renal safety for the treatment of Asian patients with HBV infection. The outcomes from studies 108 and 110 in favor of better safety with TAF therapy can be further substantiated by the findings from another recent, randomized, double-blind, phase 3, multicenter, non-inferiority study. A total of 490 patients with chronic HBV infection who had received TDF for ≥ 48 weeks were randomized to receive TAF 25 mg or TDF 300 mg once daily. Out of the 243 patients randomized to TAF, 80% (
n = 195) were Asians and 84% of 245 patients treated with TDF (
n = 205) were Asians. Forty-eight weeks after switch-over, TAF was found to be non-inferior to TDF for antiviral efficacy (96% in both groups had HBV DNA < 20 IU/mL). The proportion of patients with ALT normalization was numerically high in patients receiving TAF versus TDF therapy. Furthermore, while patients on TAF had a significant increase in BMD at hip and spine from baseline, the TDF group experienced decline in BMD at week 48. The study concluded that TAF, with a comparable efficacy and better safety profile, can be substituted for TDF in patients with chronic HBV infection [
70].
Studies in real-world settings in Asia have also assessed the efficacy of switch-over from TDF to TAF in patients with chronic HBV infection. In the study by Kaneko et al
., there was no elevation in HBV DNA or HBsAg levels after 24 weeks of switch-over from TDF to TAF. Further, the significant decline in eGFR with TDF was inhibited by switch-over to TAF. The improvement in eGFR with switch-over from TDF to TAF was observed for up to 24 weeks, regardless of the duration of prior TDF therapy. A significant decline was also noted in the urinary β2MG/Cre ratio, a marker of renal tubular disorder, at 12 and 24 weeks of switch-over from TDF to TAF, thus indicating significant improvement in renal function with TDF to TAF switch-over [
62].
The improved bone and renal safety with TAF vs. TDF may be substantiated with the findings from a recent single-arm, prospective, non-randomized, crossover, pharmacokinetic study. In this study, switch-over from TDF to TAF resulted in a significant 90% decrease in plasma tenofovir concentrations (TDF: 99.98 ± 2.24 ng/mL vs. TAF: 10.2 ± 1.6 ng/mL;
p < 0.001), and 2.41-fold increase in cell-associated TFV-DP concentration (TAF: 834.7 ± 2.49 vs. TDF: 346.85 ± 3.75 fmol/10
6 cells;
p = 0.004) [
71].
While switch-over from TDF to TAF may be associated with an improvement in bone and renal safety in HBV-infected patients, changes in lipid profile have also been noted with TDF to TAF switch-over in people living with HIV. A significant increase in total and low-density lipoprotein cholesterol and decrease in high-density lipoprotein cholesterol has been noted with switch-over from TDF- to TAF-based regimen in HIV-infected individuals [
72‐
74]. However, these results have not been confirmed in HIV-infected individuals with baseline hypercholesterolemia [
72]. The clinical relevance of these findings, if any to HBV-infected individuals, remains to be established.
Outcomes with TAF in patients with decompensated liver disease and liver transplant recipients
While there are no studies comparing the efficacy and safety of TDF versus TAF in HBV-infected patients with decompensated liver disease, the AASLD guidelines recommend TAF as a safe alternative to TDF in these patients with underlying renal dysfunction and/or bone disease [
15]. Studies assessing the efficacy and safety of TDF in chronic hepatitis B-related decompensated cirrhosis also suggest careful monitoring of renal function in these patients [
77]. Regarding HBV-infected liver transplant recipients, in a recent retrospective analysis (that included 72% Asians/Pacific Islanders), the use of TAF was associated with less deterioration of renal function when compared to other antiviral agents [
78]. In another registry-based study conducted in Asia, switch-over from TDF to TAF prophylaxis in HBV-infected liver transplant recipients was associated with increased normalization of ALT levels and improvement in renal function [
79].