What Every Pharmacist Should Know About Tenofovir Alafenamide

Tenofovir is an antiretroviral (ARV) medication used to prevent and treat HIV and to treat chronic hepatitis B. Tenofovir disoproxil fumarate (TDF), approved in 2001 for HIV and 2008 for chronic hepatitis B, is historically one of the most commonly used ARV agents for these conditions.

On November 5, 2015, the FDA approved Genvoya, the first ARV regimen with tenofovir alafenamide (TAF), a new and improved formulation of tenofovir. The following year, the FDA approved 2 additional TAF formulations, Odefsey and Descovy.

This article will highlight several key therapeutics areas with TAF that every pharmacist should know.

Issues with TDF

Despite TDF’s being the most commonly prescribed ARV and a recommended component of most HIV treatment regimens, TDF presents several safety concerns.^1,2 First, all ARVs formulated with TDF have warnings in their prescribing information for new-onset or worsening renal impairment. How this occurs is still debated, but it’s believed to be due to TDF’s toxicity to mitochondria in the proximal tubule, which leads to impaired reabsorption of low-molecular-weight proteins and other solutes.¹

Consequently, physicians should assess creatinine clearance in all individuals prior to initiating therapy and assess additional lab parameters in those with previous renal events. TDF isn’t recommended for concurrent or recent use of nephrotoxic drugs (eg, high-dose or multiple NSAIDs, or aminoglycosides).

The incidence of renal toxicity with TDF use is relatively low and it’s seen to be comparable with other nucleotide reverse transcriptase inhibitors (NRTI) in clinical trials.³ Despite this, there are many case studies and small case series of renal dysfunction with TDF.

A second safety concern with TDF involves its effects on reducing bone mineral density (BMD). The potential mechanism for this effect is unclear; however, it may result from proximal renal tubular dysfunction causing hypophosphatemia. More recently, TDF was reported to alter both osteoblast gene expression and function.⁴

In clinical trials in HIV-1 infected adults and in a clinical trial of HIV-1 uninfected individuals, TDF was found to be associated with slightly greater decreases in BMD and increases in other biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparator. The long-term effects of TDF on bone health and fracture risk is unknown.

According to the prescribing information for TDF products, assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.

How TAF Works

Like TDF, TAF is a, NRTI. It's a pro-drug of tenofovir, specifically designed to circulate systemically and undergo most of its conversion to tenofovir intracellularly. This results in higher active metabolite levels within HIV-infected cells and lower plasma levels. Within the cells, it inhibits the activity of HIV reverse transcriptase by competing with natural substrates and causing DNA chain termination after being incorporated into viral DNA.⁵

The major difference with TDF is that it has much higher plasma tenofovir exposure, which leads to some of the safety concerns. In fact, TAF in Genvoya is formulated as one-tenth the dose of TDF in Stribild, which results in a 90% lower circulating tenofovir plasma concentration. This results in less renal dysfunction and issues with BMD.⁶

TAF Formulations

TAF is currently available as a component of 3 ARVs as shown in Table 1.

TABLE 1: TAF FORMULATIONS

Brand Name

Active Components

TDF Comparator

FDA Approval Date

Genvoya

Emtricitabine, elvitegravir, cobicistat, TAF

Stribild

11/5/2015

Odefsey

Emtricitabine, rilpivirine, TAF

Complera

3/1/2016

Descovy

Emtricitabine, TAF

Truvada

4/4/2016

FDA-Approved Indications

Genvoya and Odefsey are indicated as complete regimens for the treatment of HIV-1 infection in patients 12 years of age and older who have no antiretroviral treatment history or to replace the current antiretroviral regimen in patients who are virologically-suppressed on a stable antiretroviral regimen for at least 6 months. Like Complera, Odefsey is only indicated in those with HIV-1 RNA less than or equal to 100,000 copies per mL.

Descovy is indicated for combination use with other antiretroviral agents for the treatment of HIV-1 in patients 12 years of age and older. Of note, Descovy isn’t indicated for use as pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk.

Clinical Studies

The efficacy of Genvoya was demonstrated in 5 published studies evaluating safety and efficacy in treatment-naïve adults, virologically-suppressed adults, virologically-suppressed adults with renal impairment, and treatment-naïve adolescents between the ages of 12 to 18. The treatment duration ranged from 24 to 96 weeks.⁷

In the 2 studies that evaluated whether Genvoya was non-inferior to Stribild in treatment-naïve adults, at week 96, Genvoya was found to be non-inferior to Stribild for the combined efficacy outcome and for each individual study.

In the study that evaluated whether Genvoya was safe and effective when patients were switched from (1) Atripla, (2) Truvada plus atazanavir and cobicistat, or (3) Stribild, Genvoya demonstrated that there was a statistically significant increase in maintained virologic success at week 48 in patients who switched to Genvoya compared to patients who continued a TDF-based regimen. Additionally, switching to Genvoya was associated with favorable changes in BMD and significant improvements in serum creatinine and eGFR.

In the study of those with renal impairment, 95% of virologically suppressed subjects maintained HIV-1 RNA less than 50 copies/mL after switching to Genvoya^. In the pediatric study, at 24 weeks, the virologic response rate to Genvoya in treatment naïve HIV-1 infected adolescents was similar to response rates in trials of treatment naïve HIV-1 infected adults.

These studies were also the basis of the approvals for Odefsey and Descovy.

Adverse Reactions

In clinical trials, Genvoya was found to be well tolerated with a 1% discontinuation rate due to adverse events through 96 weeks. Possible adverse reactions are similar to those seen with TDF, including gastrointestinal symptoms, fatigue, diarrhea, nausea, rash, and headache.

In clinical studies, patients in the Genvoya group experienced smaller creatinine increases from baseline than patients in the Stribild group. Additionally, patients on Genvoya experienced statistically significant smaller decreases in BMD than patients on Stribild. Cases of Fanconi syndrome and proximal renal tubulopathy, which have occurred with use of TDF, weren’t reported in clinical trials in patients taking TAF through 96 weeks.

TAF has been shown to have slightly less favorable lipid effects than TDF, likely due to lower tenofovir plasma concentrations with TAF.

As with all nucleoside analogs, Genvoya, Odefsey, and Descovy have boxed warnings in their prescribing information due to the risk of lactic acidosis and severe hepatomegaly.⁷

Drug Interactions

TAF is a weak inhibitor of CYP3A and a substrate of P-gp, BCRP, OATP1B1, and OATP1B3 and a weak inhibitor of both OCT1 and MATE1. Drugs that inhibit P-gp or BCRP may increase the absorption of TAF, whereas drugs that induce P-gp activity may decrease the absorption of TAF. TAF isn’t recommended with any rifamycin containing regimen.⁵ Due to the lower plasma concentrations with TAF, it may be implicated in few drug interactions than TDF, especially when used with certain hepatitis C antivirals.

Specific drug interactions vary by product based on individual ARV ingredients. A cost comparison is presented in Table 2.

TABLE 2: COST COMPARISON

TAF-Regimen

AWP ($ per 30 tab)*

TDF-Regimen

AWP ($ per 30 tab)*

Genvoya

3093

Stribild

3469

Odefsey

2815

Complera

3009

Descovy

1760

Truvada

1760

*Cost based on AWP, per Lexi-Drugs. Cost to the patient will vary based on individual insurance coverage.

Guideline Recommendations

HIV treatment guidelines from the Department of Health and Human Services, updated in July 2016, include Genvoya and Odefsey as complete regimen options for the treatment of HIV-1.

Descovy is recommended as a component of initial therapy. Descovy isn’t currently indicated for use as pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk.² In general, TAF-based regimens may be preferable in those who present with, or at risk for, impaired renal function or concerns with BMD.

References

• Tourret J, et al. Tenofovir effect on the kidneys of HIV-infected patients: a double-edged sword? J Am Soc Nephrol. 2013;24(10):1519-1527.
• Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
• Patel K, et al. Tenofovir-associated renal dysfunction in clinical practice: An observational cohort from western India. Indian J Sex Transm Dis. 2010;31(1):30—34.
• Gill US, et al. Assessment of bone mineral density in tenofovir-treated patients with chronic hepatitis b: can the fracture risk assessment tool identify those at greatest risk? J Infect Dis. 2015;211(3):374-382.
• AIDsinfo Drug Database: Tenofovir Alafenamide Audio icon. AIDsinfo. aidsinfo.nih.gov/drugs/514/tenofovir-alafenamide/0/professional.
• Coffey S. Tenofovir alafenamide (TAF). University of California, San Francisco. hivinsite.ucsf.edu/InSite?page=ar-01-09.
• Genvoya [Prescribing Information]. Gilead Sciences, LLC. September 2016.