Tenofovir Alafenamide Fumarate: A New Tenofovir Prodrug for the Treatment of Chronic Hepatitis B Infection

Abstract

Tenofovir alafenamide fumarate (TAF), a new prodrug of tenofovir and a potential successor of tenofovir disoproxil fumarate (TDF), has been approved in the United States and Europe for treating adolescents and adults with chronic hepatitis B infection. TAF is formulated to deliver the active metabolite to target cells more efficiently than TDF at lower doses, thereby reducing systemic exposure to tenofovir. In patients with chronic hepatitis B, TAF appears to be as effective as TDF, with lower bone and renal toxicity. TAF has the potential advantages that dose adjustment is not required in patients with renal impairment, and monitoring can be less intense because of the better safety profile. Results from 2 large, randomized, phase 3 studies after 48 weeks of therapy have shown that TAF may be a good alternative to TDF for treating chronic hepatitis B. Whether the short-term benefits observed in these 48-week trials will translate into improvements in bone and renal health in patients receiving long-term treatment remains to be seen.

Chronic hepatitis B (CHB) infection is a serious global health problem and one of the main causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). It has been estimated that 250–350 million individuals are positive to hepatitis B surface antigen (HBsAg), yielding a worldwide prevalence of 3.6%, with considerable geographic variability [1, 2].

Individuals who develop CHB are at substantial risk of cirrhosis, hepatic decompensation, and HCC, which afflicts 15%–40% of patients with CHB in the absence of effective treatment [3–6]. Globally, HCC is the third leading cause of cancer deaths, and the highest burden of disease is found in regions where hepatitis B virus (HBV) is endemic [7]. In 2013, an estimated 686 000 deaths were due to HBV infection and associated complications, placing it among the top 20 causes of mortality worldwide [7]. Despite the implementation of HBV vaccination programs in many countries, new cases of HBV infection are still common, even in areas of low prevalence. The World Health Organization estimates that there are >4 million acute clinical cases of HBV infection worldwide every year [1, 3–5].

Currently, there are 2 options for treating CHB: interferons and oral antiviral agents. Of these, treatment with oral antiviral agents has been more successful in achieving maintained viral suppression in CHB patients, an effect associated with a decrease in long-term complications [4]. Two oral antivirals, entecavir (ETV) and tenofovir disoproxil fumarate (TDF), are currently the HBV standard of care because of their high antiviral potency and minimal or absent risk for the development of resistant HBV strains. In naive hepatitis B e antigen (HBeAg)–positive and HBeAg-negative patients with CHB, both drugs achieve high viral suppression rates, but in those previously treated with lamivudine, ETV therapy has been associated with the development of resistance and low rates of maintained virological suppression [3–5, 8–11]. Although both drugs have a satisfactory safety profile, an ongoing long-term safety study has been requested by the US Food and Drug Administration (FDA) for ETV, and TDF use is associated with nephrotoxicity and reductions in bone mineral density (BMD) in some patients. Thus, alternative therapies with high antiviral potency, a high genetic barrier to resistance, and improved long-term safety and tolerability are needed for further advances in CHB treatment. Tenofovir alafenamide fumarate (TAF) is a new drug recently approved by the FDA and the European Medicines Agency for this purpose.

TAF is a phosphonamidate prodrug of tenofovir, a nucleotide analogue with limited oral bioavailability that inhibits HBV and human immunodeficiency virus type 1 (HIV-1) reverse transcription. TAF and TDF are both prodrugs of tenofovir that share the same intracellular active metabolite (tenofovir diphosphate [TFV-DP]) [12]. TAF is more stable in plasma than TDF, provides higher intracellular levels of the active phosphorylated metabolite TFV-DP to target cells (HBV-infected hepatocytes and HIV-infected lymphoid cells), and is associated with approximately 90% lower circulating tenofovir levels relative to TDF at therapeutically active doses [13]. TAF metabolism differs from that of TDF and offers the potential for a better safety profile; that is, fewer adverse effects on renal function and BMD due to the lower systemic tenofovir exposure [14].

MECHANISM OF ACTION

Tenofovir alafenamide enters primary hepatocytes by passive diffusion and by the hepatic uptake transporters OATP1B1 and OATP1B3, and is then primarily hydrolyzed by carboxylesterase 1 to form tenofovir. Intracellular tenofovir is subsequently phosphorylated to the pharmacologically active metabolite TFV-DP. This metabolite is a weak inhibitor of mammalian DNA polymerases, including mitochondrial DNA polymerase γ, and there has been no evidence of mitochondrial toxicity in vitro based on several assays, including mitochondrial DNA analysis [13].

TAF is a potent inhibitor of HBV replication, exhibiting in vitro activity comparable to that of TDF, with a half-maximal effective concentration (EC₅₀) value of 18 nM. TAF also exhibits potent anti-HIV activity in lymphoid T cells, primary human peripheral blood mononuclear cells, and macrophages, with EC₅₀ values ranging from 3 nM to 14 nM [13]. In vitro, TAF has shown excellent anti-HBV activity against all LAM-resistant and ETV-resistant recombinants and most ADV-resistant recombinants, with mean changes in EC₅₀ values of <2.0-fold compared with the wild type [14].

TENOFOVIR ALAFENAMIDE FUMARATE IN HIV PATIENTS

TAF was initially evaluated in HIV-1–infected patients. It has been coformulated with other antiretrovirals for treatment of HIV disease, including novel fixed-dose combinations. In 2 controlled, double-blind, phase 3 studies, 1744 patients were randomly assigned (1:1) to receive oral tablets containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg TAF (E/C/F/TAF) or 300 mg TDF (E/C/F/TDF). The 2 treatments showed similar efficacy at week 48, but the incidence of renal and bone adverse effects was significantly lower in patients receiving E/C/F/TAF than in those given the TDF-containing regimen [15]. Similar reductions in renal and bone effects after 48 weeks of treatment were observed in HIV-1–infected, treatment-experienced patients randomized to receive either F/TAF (n = 333) or E/C/F/TAF (n = 959) therapy, compared with those receiving a TDF-containing regimen [16, 17].

CLINICAL STUDIES IN CHRONIC HEPATITIS B

Early-Phase Studies

In a phase 1b study, 51 noncirrhotic treatment-naive patients with CHB infection were randomized (1:1:1:1:1) to receive different doses of TAF (8, 25, 40, or 120 mg) or TDF 300 mg for 28 days and assessed for safety, antiviral response, and pharmacokinetics, with an off-treatment follow-up of 4 weeks [18]. Groups were generally well matched (67% male, 57% Asian, 53% HBeAg negative, mean HBV DNA approximately 6.0 log₁₀ IU/mL) and had HBV genotypes reflective of the general population. None of the participants experienced serious or severe (grade 3/4) adverse events. Across the TAF groups, similar mean changes in serum HBV DNA were found at week 4 of the study (–2.81, –2.55, –2.19, and –2.76 log₁₀ IU/mL for the 8-, 25-, 40-, and 120-mg groups, respectively), and these were also comparable to the TDF control values (–2.68 log₁₀ IU/mL). The kinetics of viral decline was also similar across the groups. TAF pharmacokinetics were linear and proportional to the dose; doses ≤25 mg were associated with ≥92% reductions in the mean tenofovir area under the curve relative to TDF 300 mg [18]. Based on the magnitude of HBV DNA decline, systemic tenofovir exposure, and safety profile of the drug seen in this study, a 25-mg TAF dose was selected for use in 2 phase 3 trials.

Phase 3 Studies

The TAF clinical development program for CHB includes 2 ongoing phase 3 studies in HBeAg-negative and HBeAg-positive CHB patients. The 2 studies have similar designs. Patients were randomly assigned (2:1) to receive once-daily oral doses of TAF 25 mg or TDF 300 mg for 3 years, and are invited to participate in an open-label phase with TAF up to year 8 [19, 20].

Study in HBeAg-Negative Patients With CHB

There is an ongoing randomized, double-blind, phase 3, noninferiority study including patients with HBeAg-negative CHB. In total, 426 patients stratified by plasma HBV DNA concentration and previous treatment status were randomly assigned (2:1) to receive once-daily oral doses of TAF 25 mg (n = 285) or TDF 300 mg (n = 141) [19]. Eligible patients were at least 18 years of age and had plasma HBV DNA levels >20 000 IU/mL, serum alanine aminotransferase (ALT) levels >60 U/L in men or >38 U/L in women, and estimated creatinine clearance of ≥50 mL/minute (Cockcroft-Gault method) [19].

The primary endpoint of TAF noninferiority to TDF was based on the percentage of patients with plasma HBV DNA <29 IU/mL at week 48, which was achieved in 94% of patients in the TAF arm and 93% in the TDF arm (difference in percentages adjusted by baseline stratum was 1.8%; 95% confidence interval [CI], −3.6% to 7.2%). Furthermore, the percentage of patients with HBV DNA <29 IU/mL at week 48 did not differ statistically between TAF and TDF treatment across all the major subgroup evaluations, including age (<50 years vs ≥50 years), sex, race (Asian vs non-Asian), baseline HBV DNA level (<7 log₁₀ IU/mL vs ≥7 log₁₀ IU/mL), treatment status (treatment-experienced vs treatment-naive), region (East Asia, Europe, North America, other), HBV genotype, or baseline ALT level (≤ vs > the upper limit of normal [ULN] according to the central laboratory normal range, defined as ALT ≤43 U/L for men and ≤34 U/L for women aged <69 years and ≤35 U/L for men and ≤32 U/L for women aged ≥69 years).

Regarding the biochemical response, a consistently higher percentage of patients achieved ALT normalization by central laboratory criteria over 48 weeks in the TAF group compared with the TDF group (83.1% vs 75.2%, respectively; P = .076) [19]. When patients were evaluated using the American Association for the Study of Liver Diseases (AASLD) criteria (ULN ≤30 U/L for males and ≤19 U/L for females) (ALT levels) (2), the percentage with normalized ALT at week 48 was significantly higher in the TAF group (49.6%) than in those receiving TDF (31.9%) (P < .001). Data regarding efficacy and safety of TAF vs TDF in HBeAg-negative and -positive patients are summarized in Table 1.

None of the patients in either treatment group experienced HBsAg loss by week 48. The study is ongoing and the virologic response results have been maintained at week 72.

Study in HBeAg-Positive Patients With CHB

There is an ongoing phase 3, randomized, double-blind, noninferiority, international, multicenter study in HBeAg-positive CHB. In total, 873 patients were randomly assigned (2:1) to receive either 25 mg TAF (n = 581) or 300 mg TDF (n = 292). Randomization was stratified by plasma HBV DNA level (<8 log₁₀ IU/mL vs ≥8 log₁₀ IU/mL) and oral antiviral treatment status (treatment-naive vs treatment-experienced) at screening [20].

The primary endpoint, HBV DNA level <29 IU/mL at week 48, was achieved in 371 (64%) patients receiving TAF and 195 (67%) patients receiving TDF (adjusted difference, –3.6%; 95% CI, –9.8 to 2.6; P = .25), which showed noninferiority between the 2 treatments [20]. In addition, the percentage of patients receiving TAF or TDF with HBV DNA <29 IU/mL showed no significant differences in all the major subgroup evaluations, including age (<50 years vs ≥50 years), sex, race (Asian vs non-Asian), baseline HBV DNA level (<8 log₁₀ IU/mL vs ≥8 log₁₀ IU/mL), treatment status (treatment-experienced vs treatment-naive), region (East Asia, Europe, North America, other), HBV genotype, or baseline ALT level (≤ULN vs >ULN according to the central laboratory normal range). In a manner similar to what occurred in the HBeAg-negative study, a higher percentage of patients achieved ALT normalization at week 48 in the TAF group than in the TDF group according to the central laboratory criteria (71.5% vs 66.8%; P = .18) and the AASLD criteria (ULN ≤30 U/L for males and ≤19 U/L for females: TAF 44.9%, TDF 36.2%; P = .014) [20]. Patients with elevated ALT at week 48 had a higher prevalence of overweight (45% vs 29%; P < .001), hypertension (15% vs 10%; P = .007), dyslipidemia (11% vs 6%; P = .003), and diabetes (8% vs 5%; P = .062) compared with those with normal ALT. In a multivariate analysis, TAF treatment (odds ratio [OR], 0.60; 95% CI, .44–.82; P = .002) and virologic suppression (OR, 0.33; 95% CI, .22–.49; P < .001) were associated with a lower likelihood of ALT elevation at week 48. Additional independent predictors of ALT elevation included female sex, higher body mass index, diabetes, cirrhosis, and lower baseline ALT, suggesting that patients with metabolic risk factors are less likely to normalize ALT, which could occur due to underlying hepatic steatosis [21].

Seventy-eight (14%) and 34 (12%) patients in the TAF and TDF groups, respectively, experienced HBeAg loss, and 58 (10.3%) and 23 (8.1%) patients experienced seroconversion to anti-HBe at week 48. Only 4 patients (0.7%) in the TAF group and 1 (0.3%) in the TDF group experienced HBsAg loss.

In an integrated analysis of the 2 studies, 24 patients (2.8%) receiving TAF and 14 (3.2%) receiving TDF qualified for study of tenofovir resistance by population-based sequence analysis. No HBV pol/RT amino acid substitutions associated with resistance to tenofovir were detected in either treatment group through 48 weeks of study [22].

Safety

The most important finding from these studies was the safety profile of the drugs, particularly bone and renal safety. From this perspective, the 2 registrational phase 3 studies demonstrated a superiority of TAF over TDF treatment according to renal and bone parameters. Significant differences between the groups were seen in the laboratory results reflecting renal function and BMD in both groups of patients at week 48 [19, 20].

Renal Safety

There were no cases of proximal renal tubulopathy (including Fanconi syndrome) or renal failure in either treatment group. None of the participants experienced a severe renal adverse event or an event leading to discontinuation of the study drugs during the first 48 weeks. Decreases in the estimated glomerular filtration rate showed significant differences between the TAF- and TDF-treated groups in both studies: –0.6 mL/minute vs –5.4 mL/minute in HBeAg-positive patients (P < .0001), –1.8 mL/minute vs –4.8 mL/minute in HBeAg-negative patients (P = .004). The 2 treatment groups showed similar mean serum creatinine changes in HBeAg-positive patients (0.01 mg/dL in the TAF group vs 0.03 mg/dL in the TDF group; P = .02) and in HBeAg-negative patients (0.01 mg/dL vs 0.02 mg/dL; P = .32). A similar percentage of participants in each treatment group had at least 1 recorded graded proteinuria event by dipstick while on study (TAF: 24.7% [212/859] patients; TDF: 21.4% [91/426] patients; P = .26), most of which were grade 1 [19, 20, 23].

A significant difference between the 2 treatment groups at week 48 was found in the median percentage changes from baseline of one of the quantitative markers of proteinuria—the urinary protein to creatinine ratio (UPCR). The median UPCR percentage change was 6.0 mg/g in the TAF group and 16.5 mg/g in the TDF group (P = .010). Although the difference was not statistically significant, the median percentage change from baseline in the urinary albumin to creatinine ratio was lower in the TAF group than in the TDF group.

Given the known specificity of tenofovir nephrotoxicity for the proximal tubule cells, changes in tubular proteinuria were assessed using the urinary retinol-binding protein to creatinine ratio and the β-2-microglobulin to creatinine ratio. Median percentage changes from baseline in these parameters were smaller in the TAF group than the TDF group (P < .001 for differences between the 2 groups at week 48).

BONE SAFETY

Decreases in BMD and mineralization defects have been seen in patients treated with TDF; hence, bone safety was assessed in the phase 3 TAF studies. The incidence of fracture events was low in both studies (TAF: 0.7% [6/866] and TDF: 0.2% [1/432]; P = .44). Six of the 7 fractures recorded were associated with trauma, and all fractures were considered unrelated to the study drugs. There was a significantly greater percentage of BMD decline in TDF-treated patients than in those receiving TAF at the hip (–0.10% vs 1.72% in HBeAg-positive patients, P < .0001; and –0.29% vs –2.16% in HBeAg-negative patients, P < .0001) and at the spine (–0.42% vs –2.29% in HBeAg-positive patients and –0.88% vs –2.51% in HBeAg-negative patients). In addition, a lower percentage of TAF patients had a >3% decrease in hip BMD than TDF patients (8.4% vs 26.7%, respectively). Similarly, a lower percentage of patients in the TAF group had a >3% decrease in spine BMD compared with the TDF group (19.5% vs 38.1%, respectively) [24]. Additional data in biomarkers of bone turnover (eg, C-type collagen sequence) and bone formation (eg, procollagen type 1 N-terminal propeptide and bone-specific alkaline phosphatase) suggest less marked systemic effects with TAF treatment than with TDF [25].

The studies are ongoing and they will compare the safety of TAF vs TDF for 3 years. However, it is still too soon to evaluate the impact of these changes on the patients’ clinical outcomes; longer follow-up is needed to formulate clinical recommendations. If the efficacy and safety results are confirmed with longer therapy, TAF will be a first-line option. In the meantime, TAF could be particularly useful in the aging population, in patients with important comorbidities, and in those with renal impairment or under hemodialysis [19, 20, 23, 24].

As compared with other antiretroviral agents, TDF administration has been associated with lower fasting direct low-density lipoprotein (LDL) cholesterol levels and higher fasting high-density lipoprotein (HDL) cholesterol, and this effect generally correlates with the tenofovir plasma levels [17]. Consistent with the lower plasma tenofovir concentration associated with TAF, fasting lipid concentrations remained relatively stable through week 48 in the TAF group, whereas TDF administration resulted in the expected lipid-lowering effect, with decreases from baseline. Overall, the changes in the median total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride values in the TAF group were not clinically relevant.

In summary, TAF has a more favorable safety profile than TDF: Adverse bone and renal laboratory parameters were significantly less marked with TAF treatment than those seen with TDF treatment after 48 weeks.

DOSE ADJUSTMENT

TAF dose adjustment is not required in patients aged ≥65, patients with hepatic impairment, patients with renal impairment and an estimated creatinine clearance (CrCl) ≥15 mL/minute, or patients receiving hemodialysis with CrCl <15 mL/minute. TAF should be administered after completion of hemodialysis in patients undergoing this treatment. No dosing recommendations can be given for patients with CrCl <15 mL/minute who are not receiving hemodialysis.

The safety and efficacy of TAF have not yet been established in HBV-infected patients with decompensated liver disease or Child-Pugh score >9 (Child-Pugh class C), or in children <12 years of age.

COSTS

The cost of the drug may be taken into account when ETV and TDF become generics. TAF in the United States has been approved with a similar price as TDF. In Europe, there is still no price. The majority of HBV-infected patients require lifelong therapy and therefore cost of drugs would be an important issue.

In summary, TAF is a new drug approved for treatment of adults and adolescents with chronic hepatitis B. The efficacy of TAF is similar to that of TDF, and TAF is associated with a better renal and bone safety profile. Taken together, all of these data support the use of TAF for patients as a substitute for TDF. However, longer follow-up results on safety are needed.

Notes

Supplement sponsorship. This work is part of a supplement sponsored by the Hepatitis Research Center at the National Taiwan University Hospital.

Potential conflicts of interest.  M. B., M. R.-B., and R. E. have received grants from Gilead. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References