apricitabine and HIV-Infections

Apricitabine is a novel deoxycytidine nucleoside reverse transcriptase inhibitor (NRTI) currently in clinical development for the treatment of HIV infection. Apricitabine shows antiviral activity in vitro against HIV-1 strains and clinical isolates with mutations in the reverse transcriptase that confer resistance to other NRTIs, including M184V, thymidine analogue mutations (TAMs), nucleoside-associated mutations such as L74V and certain mutations at codon 69. Apricitabine has shown activity in treatment-experienced HIV-1-infected patients with NRTI resistance (with M184V and up to five TAMs) as well as in treatment-naive patients. Resistance to apricitabine is slow to develop in vitro and there has been little evidence of development of resistance to apricitabine in clinical use thus far, including patients receiving apricitabine for up to 48 weeks. The resistance profile of apricitabine suggests there is a low potential for cross-resistance with the currently available NRTIs and, thus, apricitabine may provide a treatment option for treatment-experienced HIV-1-infected patients with resistance to other NRTIs. In particular, the activity of apricitabine in the presence of the M184V mutation, which confers high-level resistance to lamivudine and emtricitabine, lends it to being used as a replacement for deoxycytidine analogues in patients who have failed treatment with lamivudine or emtricitabine.

Topics: Anti-HIV Agents; Deoxycytidine; Drug Resistance, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Mutation, Missense

Apricitabine (ATC) is a nucleoside reverse transcriptase inhibitor (NRTI) being developed for the treatment of HIV. ATC has promising antiviral activity, including against HIV-1 containing reverse transcriptase mutations that confer resistance to other NRTIs.. This paper describes the development of ATC, including its in vitro activity, pharmacokinetics and clinical efficacy and safety.. The current literature on ATC was reviewed.. ATC is a novel deoxycytidine NRTI with good antiviral activity, both in vitro and in treatment-naïve and treatment-experienced HIV-1-infected patients, including those with resistance to other NRTIs. This activity is accompanied by a favourable safety profile and a low propensity to select for resistance. ATC may have a place in the treatment of patients who have failed previous treatment regimens due to the development of NRTI resistance as a replacement for existing drugs.

Topics: Animals; Anti-HIV Agents; Deoxycytidine; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Reverse Transcriptase Inhibitors

To review the pharmacology, pharmacokinetics, efficacy, and safety of apricitabine, a nucleoside reverse transcriptase inhibitor that is currently under investigation and has fast-track approval status with the Food and Drug Administration.. A literature search was conducted using PubMed (1966-June 2009) to retrieve relevant material using the search terms apricitabine, SPD754, and AVX754. References from selected articles were evaluated to identify other pertinent trials. Information was also obtained from the manufacturer.. All English-language in vitro and in vivo studies and abstracts evaluating apricitabine were reviewed and considered for inclusion. Preference was given to human data.. Apricitabine is a prodrug that is phosphorylated to its active triphosphate form intracellularly, which ultimately results in chain termination and inhibition of reverse transcription. Apricitabine is administered orally, displays linear pharmacokinetics, and is renally excreted with minimal to no hepatic metabolism. It has demonstrated antiretroviral activity against drug-resistant strains both in vitro and in vivo. In clinical studies, in both antiretroviral-naïve and treatment-experienced patients, apricitabine achieved the primary endpoint of significant reductions in plasma viral load versus comparator. Further Phase 2 and 3 studies are currently enrolling. Safety analysis indicates that apricitabine is well tolerated and has a low potential for causing mitochondrial damage. The most common adverse events reported include headache and rhinitis. Development of resistance or further gene mutations has not been shown in clinical studies to date.. Although the role of apricitabine in the treatment of HIV-1 infection has yet to be established, its activity against resistant HIV-1 strains and its tolerability profile will likely make it a viable second-line treatment option in patients who have failed regimens containing lamivudine or emtricitabine.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Deoxycytidine; Drug Approval; Drug Resistance, Viral; HIV Infections; Humans; Prodrugs; United States; United States Food and Drug Administration

Existing nucleoside reverse transcriptase inhibitors for HIV disease are limited by problems of resistance and, in some cases, long-term toxicity. Apricitabine (ATC; formerly BCH10618, SPD754 and AVX754) is a deoxycytidine analogue nucleoside reverse transcriptase inhibitor in clinical development. ATC retains substantial in vitro activity against HIV-1 containing many mutations associated with nucleoside reverse transcriptase inhibitor resistance, showing a less than twofold reduction in susceptibility in the presence of either up to five thymidine analogue mutations or the M184V mutation. ATC showed a low potential for cellular or mitochondrial toxicity in vitro. ATC is well absorbed orally, with a bioavailability of 65-80%. Its plasma elimination half-life (approximately 3 h), and the intracellular half-life of its triphosphate (TP) metabolite (6-7 h) support twice-daily dosing. Intracellular ATC-TP levels are markedly reduced in the presence of lamivudine or emtricitabine, indicating that clinical co-administration of ATC together with these agents will not be possible. The drug is renally eliminated, giving a low potential for hepatic drug interactions. In a double-blind, randomized, placebo-controlled Phase II monotherapy trial in antiretroviral-naive patients, ATC doses of 1,200 and 1,600 mg/day reduced plasma viral load levels by 1.65 and 1.58 log10 HIV RNA copies/ml, respectively, after 10 days of treatment (P<0.0001 versus placebo). ATC showed a low propensity to select for resistance mutants in vitro and during clinical monotherapy. ATC was well tolerated in volunteers and in HIV-infected patients. This promising profile suggests that ATC may be useful in treating patients who have failed previous lamivudine- or emtricitabine-containing regimens. Further studies to evaluate the long-term efficacy and tolerability of ATC are underway.

Topics: Anti-HIV Agents; Deoxycytidine; Drug Resistance, Viral; HIV Infections; Humans

Apricitabine (ATC) is a novel deoxycytidine analogue nucleoside reverse transcriptase inhibitor (NRTI) with significant antiviral activity in vitro, including activity against HIV-1 with reverse transcriptase mutations that confer resistance to other NRTIs. ATC has shown promising antiviral activity and good tolerability when given as monotherapy for 10 days in treatment-naïve HIV-1-infected patients.. In this Phase II randomized, double-blind study, 51 treatment-experienced HIV-1-infected patients with the reverse transcriptase mutation M184V who were failing therapy which included lamivudine (3TC) were randomized to receive twice-daily 600 mg ATC, 800 mg ATC or 150 mg 3TC for 21 days. Patients remained on their existing background regimen until day 21, when background therapy could be optimized according to genotype at screening.. At day 21, the mean change in viral load was -0.71 and -0.90 log(10) HIV-1 RNA copies/mL in the 600 and 800 mg ATC groups, respectively, compared with a -0.03 log(10) change in the 3TC group. In patients with at least three thymidine analogue mutations (TAMs) at baseline, greater reductions in viral load were observed in the 800 mg ATC group at day 21 than in the 600 mg ATC group. Few genotypic changes were detected at day 21 [two patients (600 mg ATC) lost and three patients (800 mg ATC) gained a TAM] and all patients with detectable virus retained the M184V mutation. The safety profiles of the two ATC doses were similar to that of 3TC.. Over the 21-day treatment period, ATC showed promising antiviral activity and was well tolerated in treatment-experienced patients with M184V, with or without additional TAMs.

Topics: Adult; Anti-HIV Agents; Argentina; Australia; Deoxycytidine; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Male; Middle Aged; Mutation; Treatment Outcome; Viral Load; Virus Replication; Young Adult

This study aimed to investigate the multiple-dose pharmacokinetics of apricitabine, a novel deoxycytidine analogue reverse transcriptase inhibitor, in antiretroviral-naive patients with HIV-1 infection.. This was an international, randomized, double-blind, placebo-controlled, multicentre, dose-ranging study. Patients received 10 days' oral placebo or apricitabine 200, 400, 600 or 800 mg twice daily or 800 or 1200 mg once daily. On days 1 and 8, blood and urine samples were collected over 24 hours for pharmacokinetic analysis. Apricitabine triphosphate pharmacokinetics were investigated in peripheral blood mononuclear cells (PBMCs) on day 8.. Overall, 63 patients (mean age 33.9 +/- 8.7 years; mean weight 71.6 +/- 15.4 kg) were randomized, and 62 patients completed the study. Apricitabine was rapidly absorbed, with peak plasma concentrations attained within approximately 1.5-2.5 hours. Pharmacokinetics were linear over the range 200-800 mg twice daily. Apricitabine was predominantly excreted via the kidneys, with no significant accumulation during repeated administration. Steady-state conditions were attained by day 8. Apricitabine triphosphate exposure in PBMCs was roughly proportional to the dose of apricitabine across the dose range 200-800 mg twice daily, with adequate correlations between plasma exposure to apricitabine (9910 ng/mL per 65 kg for 800-mg twice-daily administration) and PBMC exposure to apricitabine triphosphate (maximum concentration [C(max)] = 5.55 +/- 1.94 pmol/million cells for 800-mg twice-daily administration). Apri-citabine was well tolerated.. Apricitabine shows essentially linear pharmacokinetics during repeated administration in patients with HIV-1 infection.

Topics: Administration, Oral; Adult; Amylases; Area Under Curve; Biological Availability; Capsules; CD4 Lymphocyte Count; Deoxycytidine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Half-Life; Headache; HIV Infections; HIV-1; Humans; Nasal Obstruction; Nucleosides; Reverse Transcriptase Inhibitors; Stereoisomerism

Apricitabine (formerly AVX754 and SPD754) is a deoxycytidine analogue nucleoside reverse transcriptase inhibitor in clinical development for patients with HIV disease. This study evaluated the antiretroviral efficacy, tolerability and safety of apricitabine monotherapy, administered for 10 days in antiretroviral-naive, HIV-1 infected adults.. Adult patients (> or = 18 years) with HIV infection (CD4 count > or = 250 cells/microl; plasma HIV-1 RNA level 5000-100 000 copies/ml) were randomized to 10 days' double-blind oral therapy with placebo or apricitabine 400 mg/day, 800 mg/day, 1200 mg/day, or 1600 mg/day.. At 7 days, all apricitabine doses produced statistically significant log10 reductions in plasma HIV RNA levels from baseline relative to placebo (n = 13; P < 0.0001), as follows: -1.16 (400 mg; n = 11), -1.28 (800 mg; n = 12), -1.44 (1200 mg; n = 14), -1.30 (1600 mg; n = 13). After 10 days, the log10 viral load reductions with apricitabine 1200 mg (-1.65; P = 0.01) and 1600 mg/day (-1.58; P = 0.04) were significantly greater than that with the 400-mg dose (-1.18). No clinically relevant changes were observed in CD4 or CD8 cell indices. Apricitabine was well tolerated and showed no tendency to select any particular resistance mutation.. Apricitabine monotherapy showed promising antiretroviral efficacy, good tolerability and a low propensity for resistance selection in antiretroviral-naive HIV-infected patients treated for 10 days. These results warrant further evaluation of the long-term clinical efficacy and tolerability of apricitabine.

Topics: Administration, Oral; Adult; Argentina; Deoxycytidine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; HIV Infections; HIV-1; Humans; Lymphocyte Count; Male; Mutation; Reverse Transcriptase Inhibitors; RNA, Viral; South Africa; Thailand; Viral Load

Topics: Animals; Anti-HIV Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Deoxycytidine; Drug Resistance, Multiple, Viral; HIV Antibodies; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Mutation; Nitriles; Nucleosides; Pyrimidines; Reverse Transcriptase Inhibitors; Rilpivirine; Succinates; Triterpenes; Virus Internalization

Topics: Deoxycytidine; HIV Infections; Humans; Reverse Transcriptase Inhibitors; Treatment Outcome

Mutations in the RNase H domain of human immunodeficiency virus type 1 RT have been reported to cause resistance to zidovudine (ZDV) in vitro. However, very limited data on the in vivo relevance of these mutations in patients exist to date. This study was designed to determine the relationship between mutations in the RNase H domain and viral susceptibility to nucleoside analogues. Viruses harboring complex thymidine analogue mutation (TAM) and nucleoside analogue mutation (NAM) profiles were evaluated for their phenotypic susceptibilities to ZDV, tenofovir (TNF), and the nonapproved nucleoside reverse transcriptase inhibitors (NRTIs) beta-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (Reverset), beta-D-5-fluorodioxolane-cytosine, and apricitabine. As controls, viruses from NRTI-naïve patients were also studied. The pol RT region (codons 21 to 250) of the viruses were sequenced and evaluated for mutations in the RNase H domain (codons 441 to 560) and the connection domain (codons 289 to 400). The results showed that viruses from patients failing multiple NRTI-containing regimens had distinct TAM and NAM profiles that conferred various degrees of resistance to ZDV (0.9- to >300-fold). Sequencing of the RNase H domain identified five positions (positions 460,468, 483, 512, and 519) at which extensive amino acid polymorphisms common in both wild-type viruses and viruses from treated patients were identified. No mutations were observed at positions 539 and 549, which have previously been associated with ZDV resistance. Mutations in the RNase H domain did not appear to correlate with the levels of phenotypic resistance to ZDV. Although some mutations were also observed in the connection domain, the simultaneous presence of the L74V and M184V mutations was the most significant determinant of phenotypic resistance to ZDV in patients infected with viruses with TAMs.

Topics: Adenine; Amino Acid Sequence; Deoxycytidine; Drug Resistance, Multiple, Viral; Genetic Variation; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutation; Organophosphonates; Phenotype; Ribonuclease H; RNA-Directed DNA Polymerase; Sequence Homology, Amino Acid; Tenofovir; Zidovudine