Tenofovir alafenamide: A novel prodrug of tenofovir for the treatment of Human Immunodeficiency Virus

Abstract

Despite substantial progress in the development of antiretroviral regimens that durably suppress Human Immunodeficiency Virus (HIV) infection, new agents that maintain high efficacy while further optimizing the safety of lifelong, chronic therapy are needed. Tenofovir alafenamide (TAF; formerly known as GS-7340) is a novel prodrug of the antiviral acyclic nucleoside phosphonate tenofovir (TFV) with improved properties relative to tenofovir disoproxil fumarate (TDF). Although potent and generally well tolerated, TDF therapy has been associated with changes in markers of renal function, decreases in bone mineral density and a rare occurrence of serious renal adverse events, including Fanconi's Syndrome. The renal and bone toxicity observed with TDF is associated with high circulating plasma levels of TFV. TAF was discovered to be a more efficient prodrug able to further refine HIV therapy and better address life-long therapy in an older and increasingly comorbid HIV infected population. By enhancing stability in biological matrices while being rapidly activated in cells, TAF produces higher levels of intracellular TFV diphosphate, the pharmacologically active metabolite, in HIV-target cells at substantially reduced oral doses of TFV equivalents. All TFV released in the body is eventually eliminated renally; therefore, lowering the TFV equivalents administered reduces off-target kidney exposure. Effective therapy is thus achieved at approximately 90% lower systemic exposure to TFV, translating to statistically and clinically significant improvement in safety parameters associated with bone mineral density and markers of renal function.

Drug Interactions in the Treatment of Malignancy in HIV-Infected Patients

“…TAF produces higher levels of intracellular TFV in HIV-infected target cells at much lower oral doses of TFV equivalent. This allows effective HIV therapy with 90% lower systemic exposure to TFV, thereby reducing renal and bone toxicity [43]. Patients with mild to moderate renal impairment on TDF who were switched to TAF showed significant improvements in proteinuria, albuminuria and tubular proteinuria [44].…”

“…ritonavir, cobicistat, cyclosporine, and itraconazole, increase the plasma concentration of TAF and a lower dose is required. TAF is therefore dosed (10 mg or 25 mg) according to the presence or absence of such drugs [43].Based on the above, the use of chemotherapy with the most commonly prescribed singletablet NRTI combinations (TDF with emtricitabine, TAF with emtricitabine or abacavir with lamivudine) is relatively uncomplicated.…”

Sindrome di Fanconi Tenofovir-correlata in paziente con coinfezione HIV/HBV: un problema di gestione clinica

“…Tenofovir Alafenamide (TAF) è un nuovo profarmaco di TFV che, rispetto a tenofovir-disoproxil-fumarato (TDF) consente di ottenere adeguate concentrazioni intracellulari del metabolita attivo tenofovir-difosfato (TFV-DP) a fronte di concentrazioni plasmatiche significativamente ridotte (2)(3). Anche a livello epatico, TAF consente il raggiungimento di concentrazioni più elevate di TFV-DP, con una emivita superiore alle 24 ore (4).…”

Protease inhibitor monotherapy was non-inferior and cost-effective as maintenance therapy compared to triple therapy in viral load suppressed patients with HIV-1 infection

“…PI-mono is not expected to play a major role for the maintenance strategy of HIV infection over the next few years, as the PI-based dual strategies2 3 compared similarly to triple regimens and it is cheaper, while the next-coming tenofovir alafenamide4 will increase the appeal of widely used three-drug single tablet regimens.…”