Elsevier

Biochemical Pharmacology

Volume 153, July 2018, Pages 2-11
Biochemical Pharmacology

Review
Role of tenofovir alafenamide (TAF) in the treatment and prophylaxis of HIV and HBV infections☆

https://doi.org/10.1016/j.bcp.2017.11.023Get rights and content

Abstract

Tenofovir (TFV) is the cornerstone of the treatment and prophylaxis of HIV infections. It has been routinely used in its prodrug form TDF (tenofovir disoproxil fumarate) combined with emtricitabine ((−)FTC) and other antiretroviral agents. TDF has now been replaced by TAF (tenofovir alafenamide) which allows better uptake by the lymphoid tissue. In combination with elvitegravir (E), cobicistat (C), emtricitabine (F), TAF can be advocated as an STR (single tablet regimen, Genvoya®) for the treatment of HIV infections. In this combination, E and C may in the future be replaced by bictegravir. The prophylaxis of HIV infection is momentarily based upon Truvada®, the combination of F with TDF, which in the future may also be replaced by TAF. TAF (Vemlidy®) has also replaced TDF (Viread®) for the treatment of hepatitis B virus (HBV) infections. Both TDF and TAF offer little or no risk for virus-drug resistance. As compared to TDF, TAF limits the risk for nephrotoxicity and loss of bone mineral density. What remains to be settled, however, before the universal use of TAF could be recommended, is its safety during pregnancy and its applicability in the treatment of tuberculosis, in combination with rifampicin.

Introduction

For the treatment of human immunodeficiency virus (HIV) infections, tenofovir alafenamide (TAF) is the successor of tenofovir disoproxil fumarate (TDF). It can be used in different combinations [single-tablet regimens (STRs)], first, together with, i.e. emtricitabine [(−)FTC, F] (Descovy®: 200 mg F + 25 mg TAF), second, together with emtricitabine and rilpivirine (Odefsey®: 200 mg F + 25 mg rilpivirine(R) + 25 mg TAF), and third, together with emtricitabine, cobicistat and elvitegravir (Genvoya®: 200 mg F + 150 mg cobicistat (C) + 150 mg elvitegravir (E) + 10 mg TAF) [1]. TAF (25 mg, Vemlidy®) is also the successor of TDF (Viread®, 300 mg) for the treatment of chronic hepatitis B virus (HBV) infections. For the treatment of HIV-1 infections TAF has an efficacy similar to, but a safety greater than, that of TDF [2]. Its role in current HIV treatment has been addressed in several review articles [3], [4], [5], [6], [7], [8]. A first glance on TAF has been given in Table 1.

That TAF demonstrated more potent antiviral activity, higher intracellular tenofovir (diphosphate) levels, and lower plasma tenofovir concentrations, at approximately 1/10th of the TDF dose, was first mentioned by Ruane et al. [9] and Markowitz et al. [10]. The compound (GS-7340) had been first described as a novel amidate prodrug of PMPA by Ballatore et al. [11] and Eisenberg et al. [12]; and its potential role as an anti-HIV drug, due to its preferential accumulation in lymphatic tissue, was first demonstrated by Lee et al. [13] (for a glimpse on prodrugs, see Rautio et al. [14]).

Section snippets

Metabolism

In CD4+ T-lymphocytes and monocyte-derived macrophages, prepared from peripheral blood mononuclear cells (PBMCs), TAF is converted by the lysosomal protease cathepsin A (CatA) to tenofovir alanine (TFV-Ala) [15] (Fig. 1). In the liver hepatocytes this role is primarily assumed by the liver esterase Ces1 [16]. The hepatitis C virus (HCV) protease inhibitors telaprevir and boceprevir potently inhibit the CatA-mediated TAF activation and reduce the anti-HIV activity of TAF in primary human CD4+

E/C/F/TAF (Genvoya®)

The combination of elvitegravir (E), cobicistat (C), emtricitabine (F) ((−)FTC) and TAF, as a single-tablet regimen (STR) was first introduced by Sax et al. [20] in 2014; compared with those receiving TDF, patients on E/C/F/TAF experienced significantly smaller changes in estimated creatinine clearance, renal tubular proteinuria, and bone mineral density [20]. Through 48 weeks, more than 90% of the patients given E/C/F/TAF had plasma HIV-1 RNA levels less than 50 copies per mL, while the

Switching

Switching from a TDF-containing regimen to one containing TAF was non-inferior for maintenance of viral suppression and led to improved bone mineral density and renal function [30]. Fixed-dose TAF with F was postulated to become an important nucleoside reverse transcriptase inhibitor (NRTI) backbone for HIV-1 treatment [31]. This premise was corroborated upon a long-term (96-week) follow-up [32]. In a meta-analysis, at week 48, viral suppression rates were similar for TAF and TDF (90.2% vs

Bictegravir

Integrase strand transfer inhibitors (INSTIs) represent the latest class of antiretroviral drugs approved for the treatment of HIV-1 infection. They block HIV-1 replication by inhibiting the strand transfer of viral DNA integration into the host genome [40]. The first two INSTIs to be approved for clinical use (as components of combination antiretroviral therapy) were raltegravir and elvitegravir (E), subsequently followed by dolutegravir. INSTI-based regimens offer an important contemporary

Resistance

Resistance development to E/C/F/TDF has been infrequent through 144 weeks of therapy and decreased over time, consistent with durable efficacy. For instance, the emergence of resistance decreased with 8, 2 and 0 patients developing HIV-1 resistance through week 48, post-week 48–96, and post-week 96–144, respectively [49]. Through week 96, resistance development attained no more than 2.8% in both the E/C/F/TAF and E/C/F/TDF arms [50]. Resistance development was rare (<1%) after 48 weeks of

Pre-exposure prophylaxis

Now that TDF has been replaced by TAF for the treatment of HIV-1 infections, the question could be raised whether TAF may also be advocated for the pre-exposure prophylaxis (PrEP) of HIV infections [58], [59]. The combination of TDF with emtricitabine (Truvada®) has been approved by the US Food and Drug Administration for the prophylaxis of HIV infections on 16 July 2012.

Oral chemoprophylaxis with TAF and emtricitabine has been shown to protect rhesus macaques from rectal simian/human

Hepatitis B

In 1965, Blumberg et al. [68] discovered the “Australia” antigen, which in 1967 was identified to be the hepatitis B virus (HBV) surface antigen [69]. For the treatment of HBV infection, the US FDA approved, successively, interferon-α, lamivudine, adefovir dipivoxil, pegylated interferon-α, entecavir, telbivudine, TDF [70], and, in 2016, TAF. Chronic hepatitis B would occur in approximately 350 million people worldwide; they have an increased risk of end-stage liver disease (i.e. cirrhosis)

Nephrotoxicity

Unlike tenofovir, TAF does not interact with renal transporters OAT1 or OAT3 (organic anion transporters), and exhibits no OAT-dependent cytotoxicity; TAF is thus unlikely to actively accumulate in renal proximal tubules in an OAT-dependent manner [87]. This supports the potential for an improved renal safety profile of TAF as compared to TDF. Patients with mild-moderately impaired renal function who switched from TDF- to TAF-containing regimens experienced rapid sustained improvement in

Outlook

Günthard et al. [97] postulated: “Antiretroviral agents remain the cornerstone of HIV treatment and prevention. All HIV-infected individuals with detectable plasma virus should receive treatment with recommended initial regimens consisting of an INSTI plus 2 N(t)RTIs. Preexposure prophylaxis (PrEP) should be considered as part of an HIV prevention strategy for at-risk individuals. When used effectively, currently available antiretrovirals can sustain HIV suppression and can prevent new HIV

Conflict of interest

The author is co-discoverer of tenofovir.

Acknowledgments

I thank Mrs. Christiane Callebaut for her proficient editorial assistance.

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    ☆

    This review article is dedicated to the memory of Dr. Antonín Holý, co-discoverer of tenofovir, who died on 16 July 2012.

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