Adenosine nucleotide analogue
| Clinical Use|
| Use in Initial vs Subsequent Therapy|
Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services (DHHS) designate several TAF-containing regimens as "recommended" regimens for initial therapy, and others as "alternative" regimen options.
TAF has been studied primarily as part of the fixed-dose combination of elvitegravir/cobicistat/emtricitabine/TAF, which includes 10 mg of TAF. In the Phase 3 studies of initial therapy mentioned above, TAF in this single-pill combination was compared with TDF in the fixed-dose combination of elvitegravir/cobicistat/emtricitabine/TDF.(1) In combined analysis of the two studies, by FDA snapshot analysis, 92% and 90% of study subjects, respectively, had HIV RNA levels of <50 copies/mL at 48 weeks; the difference was not statistically significant. The two ARV regimens yielded similar rates of HIV suppression in patients with pretreatment HIV RNA levels of >100,000 copies/mL and those with ≤100,000 copies/mL. CD4 cell increases were 230 cells/µL for the TAF group and 211 cells/µL for the TDF group.
In treatment-naive patients, a Phase 2 placebo-controlled trial compared a single pill combination of darunavir/cobicistat/emtricitabine/TAF to darunavir + cobicistat + emtricitabine/TDF, each given once daily. After 48 weeks of treatment, HIV RNA was <50 copies/mL in 77% and 84% of the groups, respectively; the difference was driven by a higher rate of treatment discontinuation in the TAF arm rather than by disparities in virologic efficacy.(2)
In a randomized double blind Phase 3 study, patients on a virologically suppressive regimen of TDF/FTC + a third agent either switched to TAF/FTC or remained on TDF/FTC; all continued their third agent. After 48 weeks, HIV RNA was maintained at <50 copies/mL in 94% of the switch group and 93% of the continuation group; the difference was not statistically significant.(3)
An open-label study randomized patients to switch from one of three specific TDF-containing regimens to the TAF-containing regimen elvitegravir/cobicistat/emtricitabine/TAF or to continue their baseline regimens. At study entry, patients had suppressed HIV viral loads and no significant HIV resistance. At 48 weeks, HIV RNA remained <50 copies/mL in 97% of the TAF group vs 93% of the other group (p < .001); the difference appeared to be driven by an excess of study discontinuations in the comparator (TDF-containing) group.(4)
TAF has not been studied extensively in subsequent therapy for patients with resistance to nucleoside/nucleotide analogues. One small open-label study examined the efficacy of elvitegravir/cobicistat/emtricitabine/TAF + darunavir (800 mg once daily) in patients with HIV RNA suppression on a darunavir-containing treatment regimen. These patients had HIV resistance to at least 2 classes of antiretroviral medications (but without resistance to integrase inhibitors or darunavir). They were randomized to switch to the study regimen immediately or to continue their baseline ART. At 24 weeks, HIV RNA was <50 copies/mL in 97% of the switch group vs 91% of the baseline regimen group; at 48 weeks, 96% vs 76% had HIV RNA <20 copies/mL (p = .012).(5)
| Potential Adverse Effects|
In the Phase 3 studies described above,(1) symptomatic adverse effects attributable to TAF were uncommon, but included gastrointestinal symptoms and headache. Laboratory abnormalities included increases in serum creatinine and urinary protein.
TDF has been associated with renal impairment, both as slowly progressive kidney disease and as acute renal failure and Fanconi syndrome.(6) The effect of TAF on renal function is under investigation. In the Phase 3 studies of TAF (as part of the elvitegravir/cobicistat/emtricitabine/TAF coformulation), decreases in estimated glomerular filtration rate (eGFR) and worsening of markers of tubular function (eg, urinary protein and albumin) were smaller at 48 weeks than those in the elvitegravir/cobicistat/emtricitabine/TDF comparator group.(1) In the switch study mentioned above, creatinine increased slightly but proteinuria and albuminuria improved in patients switched from TDF-containing treatment regimens to elvitegravir/cobicistat/emtricitabine/TAF; albuminuria, proteinuria, and other markers of tubular function worsened in those who continued their baseline TDF-containing ART; differences were statistically significant.(4) The clinical significance of these differences in markers of renal function between the TAF-containing and TDF-containing regimens is not clear.
In patients with chronic kidney disease (estimated GFR 30-69 mL/min), an open-label study switched patients from stable ARV regimens (with or without TDF) to elvitegravir/cobicistat/emtricitabine/TAF. After 48 weeks, there appeared to be no significant changes in eGFR, though persons who were not previously on TDF appeared to have slight worsening of eGFR after the switch to elvitegravir/cobicistat/emtricitabine/TAF; proteinuria and albuminuria improved in those switched from TDF-containing regimens.(7)
Renal safety of TAF will require further study. Renal function should be assessed before treatment with TAF, and regular monitoring should be performed for patients receiving any form of tenofovir.
TDF is associated with decreases in bone mineral density.(8) In studies comparing TAF and TDF in initial treatment, patients treated with TAF also had decreases in bone density at the hip and the spine, but these were less than those seen in the TDF groups.(1,2) In the switch studies of patients on TDF-containing regimens described above (see Use in Initial vs Subsequent Therapy), slight increases in hip and spine bone mineral density were seen at 48 weeks in those who changed to TAF-containing regimens while slight decreases in bone mineral density at those sites occurred in patients who continued to receive TDF with their background regimens; differences between the groups were statistically significant.(4,3) Similar differences between TAF and TDF in their effects on bone mineral density have been noted in other studies.(9,7) The clinical relevance of the effect of TAF on bone mineral density is not clear, and optimal monitoring and management are not certain.
| Interactions with Other Drugs|
TAF is a substrate of p-glycoprotein, and levels of tenofovir can be affected by inhibitors or inducers of p-glycoprotein. Ritonavir and cobicistat can increase plasma concentrations of tenofovir, while darunavir can decrease tenofovir concentrations. In HIV-uninfected subjects, coadministration of TAF with atazanavir + ritonavir, darunavir + ritonavir, or lopinavir/ritonavir significantly increased plasma levels of tenofovir; levels of the protease inhibitors were not affected. No significant interactions between TAF and dolutegravir or rilpivirine were noted.(10) In studies of TAF, a dose of 10 mg daily was used when it was coadministered with ritonavir, cobicistat, or protease inhibitors, and 25 mg daily when coadministered with integrase inhibitors or nonnucleoside reverse transcriptase inhibitors. Based on pharmacokinetic data, the FDA has approved the fixed-dose combination of TAF 25 mg/emtricitabine 200 mg for use once daily with all other ARV agents (except tipranavir, which is contraindicated with TAF).
Drugs that induce p-glycoprotein may decrease plasma tenofovir concentrations. For this reason, rifampin, rifabutin; certain anticonvulsants including phenytoin and phenobarbital; St John's Wort; and boosted tipranavir should not be coadministered with TAF.
Resistance to TAF is associated with the selection of one or more of several resistance mutations.
| Implications of tenofovir alafenamide resistance for treatment with other antiretrovirals|
The K65R mutation, which may be selected by tenofovir, is associated with resistance to most other nucleoside analogues. Zidovudine, however, retains activity in the presence of this mutation.
| Implications of resistance to other antiretrovirals for treatment with tenofovir alafenamide|
In the setting of resistance, TAF would be expected to perform the same as TDF.
|Single- and some double-thymidine analogue resistance mutations do not appear to confer significant resistance to tenofovir. However, in clinical trials of TDF, the presence of 3 or more thymidine analogue resistance mutations is associated with a decreased response to tenofovir, particularly if these mutations include M41L or L210W.(11)|
|The presence of the M184V reverse transcriptase mutation, associated with resistance to lamivudine and emtricitabine, does not reduce sensitivity to tenofovir, and when it occurs with thymidine analogue mutations, it may increase the susceptibility of HIV to tenofovir.|
|The K65R mutation, which may be selected by prior nucleoside analogue therapy, is associated with a decrease in sensitivity to tenofovir. |
|The T69S insertion mutations, associated with resistance to multiple nucleoside analogues, are associated with resistance to tenofovir as well.|
| Special Uses|
| Treatment of hepatitis B|
TAF is approved by the FDA for the treatment of hepatitis B. In a small single-arm, open-label study of patients coinfected with HIV and hepatitis B, substitution of TAF (in the coformulation with elvitegravir, cobicistat, and emtricitabine) for TDF was associated with improvement in the rate of HBV DNA suppression at 48 weeks, from 86% to 92% of the group.(9)
DHHS guidelines recommend inclusion of TAF or TDF plus either lamivudine or emtricitabine in the antiretroviral regimens of patients coinfected with HIV and hepatitis B. This will result in treatment of both HIV and hepatitis B infections.
For patients with hepatitis B, there is a risk of hepatitis B exacerbation upon discontinuation of TAF.
| Preexposure prophylaxis|
TDF in combination with emtricitabine is approved for preexposure prophylaxis (PrEP) against HIV infection. TAF has not been studied for this purpose and is not approved for use as PrEP; until supporting data are available, it should not be used to prevent HIV infection.
|| || Sax PE, Wohl D, Yin MT, et al; GS-US-292-0104/0111 Study Team. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 2015 Jun 27;385(9987):2606-15.|
|| || Mills A, Crofoot G Jr, McDonald C, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate in the first protease inhibitor-based single-tablet regimen for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr. 2015 Aug 1;69(4):439-45.|
|| || Gallant JE, Daar ES, Raffi F, et al. Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled phase 3 trial. Lancet HIV. 2016 Apr;3(4):e158-65.|
|| ||Mills A, Andrade-Billanueva J, DiPerri G, et al. Switching from a tenofovir disoproxil fumarate (TDF)-based regimen to a tenofovir alafenamide (TAF)-based regimen: data in virologically suppressed adults through 48 weeks of treatment. In: Program and abstracts of the 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2015; Vancouver, BC, Canada. Abstract TUAB0102.|
|| ||Huhn G, Tebas P, Gallant J, et al. Strategic simplification: the efficacy and safety of switching to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) plus darunavir (DRV) in treatment-experienced HIV-1 infected adults (NCT01968551). In: Program and abstracts of ID Week 2015; October 7-11, 2015; San Diego, CA. Abstract 726.|
|| || Hall AM, Hendry BM, Nitsch D, et al. Tenofovir-associated kidney toxicity in HIV-infected patients: a review of the evidence. Am J Kidney Dis. 2011 May;57(5):773-80.|
|| || Pozniak A, Arribas JR, Gathe J, et al; GS-US-292-1249 Study Investigators. Switching to tenofovir alafenamide, coformulated with elvitegravir, cobicistat, and emtricitabine, in HIV-infected patients with renal impairment: 48 week results from a single-arm, multi-center, open-label, phase 3 study. J Acquir Immune Defic Syndr. 2015 Nov 30. [Epub ahead of print]|
|| || McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011 Jun 15;203(12):1791-801.|
|| || Gallant J, Brunetta J, Crofoot G, et al. Efficacy and safety of switching to a single-tablet regimen of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) in HIV-1/hepatitis B coinfected adults. J Acquir Immune Defic Syndr. 2016 May 11. [Epub ahead of print]|
|| ||Lawson EB, Martin H, McCallister S, et al; GS-US-292-0112 Study Team.. Drug interactions between tenofovir alafenamide and HIV antiretroviral agents. In: Program and abstracts of the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 5-9, 2014; Washington, DC. Abstract H-1012.|
|| || Margot NA, Isaacson E, McGowan I, et al. Extended treatment with tenofovir disoproxil fumarate in treatment-experienced HIV-1-infected patients: genotypic, phenotypic, and rebound analyses. J Acquir Immune Defic Syndr. 2003 May 1;33(1):15-21.|