Tenofovir: A Nucleotide Analog for The Management of Human Immunodeficiency Virus Infection

Abstract

Tenofovir disoproxil fumarate, an acyclic nucleotide analog of adenosine monophosphate, is the most recent addition to the antiretroviral arsenal. After conversion to tenofovir by diester hydrolysis, subsequent phosphorylation by cellular enzymes to form the active tenofovir diphosphate is necessary for antiretroviral activity. Preliminary data suggest that tenofovir is as safe and efficacious as stavudine when given in combination with lamivudine and efavirenz for the treatment of antiretroviral-naïve patients. In antiretroviral-experienced patients, the addition of tenofovir to stable background antiretroviral therapy resulted in approximately a 0.6 log10 copies/ml reduction in viral load relative to placebo. Extended follow-up suggests that such virologic gains may be durable. In vitro, recombinant human immunodeficiency virus (HIV) expressing the K65R mutation showed a 3-4-fold increase in the 50% inhibitory concentrations of tenofovir when compared with wild type. In vivo, this mutation thus far appears to occur infrequently and is associated with variable virologic responses. Response rates to tenofovir vary with the number and pattern of thymidine analog mutations present before starting treatment with this agent. Tenofovir appears to be a well-tolerated agent in patients who are heavily pretreated and who have advanced disease. The main adverse effects appear to be gastrointestinal in nature and include nausea, vomiting, and diarrhea. In animals, osteomalacia and nephrotoxicity have occurred with tenofovir at exposures much higher than those observed in humans. Although no patient had to discontinue therapy as a result of elevated creatinine levels or hypophosphatemia through 58 weeks of treatment, the toxicities associated with long-term tenofovir therapy in humans are unknown. Concomitant administration of tenofovir and didanosine increases the area under the concentration-time curve of the latter by 44-60%; monitoring for signs and symptoms of didanosine toxicity is recommended. The approved dosage of tenofovir is 300 mg (one tablet) once/day with meals. Given the ease of administration and relative safety from the perspectives of adverse effects and drug interactions, tenofovir has the potential to assume a large role in the treatment of patients with HIV infection.

The development of hypophosphataemic osteomalacia with myopathy in two patients with HIV infection receiving tenofovir therapy

“…Moreover, both patients reported here were taking ritonavir/lopinavir concurrently with tenofovir. Ritonavir use has been shown to increase the concentrations of tenofovir by 30-40% [26,27] and has been anecdotally linked to tenofovir-related renal tubular disease [5]. NSAIDs appear to have simply resulted in a further deterioration in renal function in both cases, as would be expected in incipient renal failure [21,28].…”

Simultaneous Delivery of Tenofovir and Acyclovir via an Intravaginal Ring

“…It has demonstrated the ability to inhibit retroviral replication in animals and humans and was well tolerated when administered orally as its disoproxil fumarate prodrug (4,14,24). Parikh et al evaluated a topical gel containing two long-acting antiretroviral drugs, TFV and emtricitabine (FTC), in a repeat challenge macaque model (31).…”

Cathepsin A Is the Major Hydrolase Catalyzing the Intracellular Hydrolysis of the Antiretroviral Nucleotide Phosphonoamidate Prodrugs GS-7340 and GS-9131

“…Tenofovir disoproxil fumarate (TDF) is a bis-isopropoxycarbonyloxymethyl ester prodrug of TFV approved for the treatment of HIV. TDF is well tolerated, with infrequent development of resistance and a favorable long-term toxicity profile (2,8, 16). The oral administration of TDF results in high systemic levels of TFV (5); however, the rapid systemic degradation of TDF to TFV limits its uptake into target cells.…”

“…Tenofovir {9-R-[(2-phosphonomethoxy)propyl]adenine} (TFV), an acyclic nucleotide analog of dAMP, is a potent in vitro and in vivo inhibitor of human immunodeficiency virus type 1 (HIV-1) replication (2). TFV is sequentially phosphorylated in the cell by AMP kinase and nucleoside diphosphate kinase to the active species, tenofovir diphosphate (23,39), which acts as a potent inhibitor of HIV-1 reverse transcriptase (7,49).…”