Dion F. Coakley

Phase i/ii trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults.

ABSTRACT Tenofovir DF is an antiviral nucleotide with activity against human immunodeficiency virus type 1 (HIV-1). The pharmacokinetics, safety, and activity of oral tenofovir DF in HIV-1-infected adults were evaluated in a randomized, double-blind, placebo-controlled, escalating-dose study of four doses (75, 150, 300, and 600 mg given once daily). Subjects received a single dose of tenofovir DF or a placebo, followed by a 7-day washout period. Thereafter, subjects received their assigned study drug once daily for 28 days. Pharmacokinetic parameters were dose proportional and demonstrated no change with repeated dosing. Reductions in plasma HIV-1 RNA were dose related at tenofovir DF doses of 75 to 300 mg, but there was no increase in virus suppression between the 300- and 600-mg dose cohorts, despite dose-proportional increases in drug exposure. Grade III or IV adverse events were limited to laboratory abnormalities, including elevated creatine phosphokinase and liver function tests, which resolved with or without drug discontinuation and without sequelae. No patients developed detectable sequence changes in the reverse transcriptase gene.

Tenofovir Disoproxil Fumarate in Nucleoside-Resistant HIV-1 Infection: A Randomized Trial

Context Resistance to antiretroviral drugs is a leading cause of treatment failure in HIV-1infected patients. Contribution In this multicenter, double-blind trial, 552 treatment-experienced patients with detectable RNA levels despite continuing antiretroviral therapy were randomly assigned to receive tenofovir DF (a nucleotide analogue) or placebo. At 6 months, patients given tenofovir DF had greater reductions in HIV-1 RNA levels than those given placebo. Nearly 15% of patients in both groups had clinical adverse events, such as severe diarrhea, pain, or depression. Implications In HIV-infected patients with suboptimal viral suppression, adding tenofovir DF to ongoing antiretroviral therapy reduces viral loads. The Editors Combination antiretroviral therapy has decreased mortality rates for patients with HIV-1 infection (1, 2). Suppression of HIV-1 viral load has been shown to be highly predictive of slower clinical disease progression (3). However, the clinical utility of a combination antiretroviral regimen typically wanes, often because of one or more factors such as drug resistance or poor adherence (4). These factors are even more important for patients who have previously used antiretroviral drugs. This difficult-to-treat population has limited treatment options and often experiences drug-related adverse effects due to previous antiretroviral therapy regimens (5-7). Given these limitations, novel potent agents that combine ease of dosing with favorable safety and resistance profiles are needed to increase the long-term durability of combination antiretroviral therapy (8, 9). Simplifying HIV treatment regimens using once-daily antiretroviral drugs may improve adherence and therapeutic outcomes (10, 11). Tenofovir disoproxil fumarate (tenofovir DF) is an oral prodrug of tenofovir, a novel, acyclic nucleotide analogue with in vitro activity against HIV-1 and HIV-2 (12, 13). Unlike nucleoside analogues, tenofovir is active in both active and resting lymphoid cells and macrophages (13). In rhesus macaques acutely infected with simian immunodeficiency virus, tenofovir administered as monotherapy 24 hours after inoculation eradicated viral DNA from lymph nodes, plasma, and leukocytes (14). Tenofovir has also demonstrated in vitro activity against wild-type and lamivudine-resistant hepatitis B virus (15). In a 186-patient phase II dose-ranging study, Schooley and colleagues (16) demonstrated the potency and favorable safety profile of tenofovir DF, 300 mg, highlighting its potential for further study in larger phase III trials. Tenofovir has a favorable resistance profile with activity against most nucleoside analogueresistant viruses and infrequent (3%) emergence of the K65R resistance mutation through 96 weeks (17-21). Our study was designed to confirm the antiviral efficacy and safety of tenofovir DF compared with placebo in treatment-experienced patients who had detectable HIV-1 RNA levels despite combination antiretroviral therapy. Methods Study Sample Institutional review boards at all study sites approved the study protocol and informed consent statements. Recruitment began in October 1999 and continued until June 2000 at 75 HIV clinics in western Europe, North America, and Australia. All patients gave written informed consent. Patients 18 to 65 years of age were eligible if they had received antiretroviral therapy (four agents or fewer) for at least 8 weeks before randomization and had stable plasma HIV-1 RNA levels of 400 to 10 000 copies/mL on the Roche Amplicor HIV-1 Monitor UltraSensitive test, version 1.0 (Roche Diagnostics, Branchburg, New Jersey). The lower limit of quantification for this test was 50 copies/mL. We placed no entry restrictions on CD4 cell count. Additional inclusion criteria were serum creatinine concentration of 133 mol/L or less ( 1.5 mg/dL), calculated creatinine clearance (using the CockcroftGault formula [22]) of at least 1.00 mL/s ( 60 mL/min), absolute neutrophil count of at least 1.000 109 cells/L, platelet count of at least 50.0 109 cells/L, hemoglobin level of at least 80 g/L, total bilirubin level of 26 mol/L or less ( 1.5 mg/dL), serum phosphorus level of at least 0.71 mmol/L ( 2.2 mg/dL), alanine aminotransferase level less than 108 U/L, aspartate aminotransferase level less than 90 U/L, negative results on a serum pregnancy test for women of childbearing potential, and life expectancy of more than 1 year. We excluded patients who had previously participated in clinical trials with intravenous tenofovir, tenofovir DF, or adefovir dipivoxil; had been immunized within 30 days of baseline; had an active AIDS-defining condition within 30 days of baseline; or were receiving aminoglycoside antibiotics, amphotericin B, cidofovir, cisplatin, foscarnet, intravenous pentamidine, vancomycin, ganciclovir, systemic chemotherapeutic agents, oral corticosteroids, probenecid, or other investigational agents on an ongoing basis. Patients who were receiving their first antiretroviral regimen were not excluded. We assessed 976 patients for eligibility and randomly assigned 552 to study groups (Figure). Four hundred twenty-four patients were excluded. Of the 380 who did not meet inclusion criteria, the most common reason (n = 269) was HIV-1 RNA levels outside the range of 400 to 10 000 copies/mL. Among the remaining 44 patients, 22 elected not to participate in the study and the other 22 were excluded because of investigator decision, concomitant participation in other investigational studies, screening after the cutoff date for enrollment, incomplete laboratory values, lack of follow-up, or family emergency. No statistical analyses were performed for patients who were not randomly assigned to a study group. Figure. Recruitment and disposition flow chart. Design Through an interactive voice response system that centralized patient randomization, Interactive Clinical Technologies, Inc. (San Francisco, California), generated the random allocation sequence, assigned patients to their treatment groups, and blinded kit numbers to conceal the allocation sequence. Patients were stratified according to HIV-1 RNA level (<5000 copies/mL or 5000 copies/mL), CD4 cell count (<0.2 109 cells/L or 0.2 109 cells/L), and number of antiretroviral drugs taken before study entry (fewer than four or at least four). Patients were then randomly assigned in a 2-to-1 ratio to add tenofovir DF, 300 mg, or identical-appearing placebo to their existing antiretroviral regimen. Randomization was not stratified by study center. Changes to the background regimen were discouraged during the first 24 weeks. After week 24, all patients received open-label tenofovir DF for the remainder of the 48-week study. As predefined in both the study protocol and the statistical analysis plan, the single end point for primary efficacy was the time-weighted average change in HIV-1 RNA level from baseline to week 24. Secondary efficacy end points included the proportion of patients with HIV-1 RNA levels of 50 copies/mL or less and 400 copies/mL or less at weeks 24 and 48, the time-weighted average change in HIV-1 RNA level from baseline to week 48, and CD4 cell count at weeks 24 and 48. Adherence to treatment was measured by using pill counts at each study visit, but pill counts were not formally analyzed and drug concentrations were not measured during routine study visits. Approximately half of the patients (n = 274) were randomly assigned to a virologic genotyping substudy at baseline. HIV-1 reverse transcriptase nucleotides 1 to 1200 and all of the HIV-1 protease gene were sequenced by following the reverse transcriptase polymerase chain reaction from plasma HIV-1 RNA (Vircogen, Virco, Mechelen, Belgium). All plasma HIV-1 samples that were obtained at baseline, at week 24 or 48, or at early study termination and had more than 50 copies of HIV-1 RNA per mL were analyzed in a blinded fashion. A polymerase chain reaction product could not be obtained from 21 patients at baseline (14 in the tenofovir DF group, 7 in the placebo group). Plasma HIV-1 RNA was insufficient for genotypic analysis in 58 patients at week 24 (43 patients in the tenofovir DF group, 15 in the placebo group) and 129 patients at week 48. Assessments The incidences of grade 3 or 4 clinical adverse events or laboratory abnormalities were evaluated as safety end points. At each postbaseline study visit (weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48), the investigator assessed and recorded all adverse events found during history and physical examination as well as laboratory toxicities found on chemical and hematologic tests and urinalysis, including date of onset and resolution, severity, relationship to study drug, outcome, and action taken with study medication. Severity was recorded and graded according to the modified severity grading for adult adverse experiences outlined by the National Institutes of Allergy and Infectious Diseases, Division of AIDS. Plasma levels of HIV-1 RNA and CD4 cell counts were measured at all study visits except weeks 28, 36, and 44. Statistical Analysis Data were analyzed for the intention-to-treat sample and the as-treated sample. The intention-to-treat sample included all enrolled patients who received at least one dose of study medication and was the primary sample for analyses of efficacy. The as-treated sample included patients who received at least one dose of study medication but excluded all data obtained after permanent discontinuation of assigned study medication or addition of other antiretroviral medication. The safety analysis sample included all patients who received at least one dose of study medication. As the primary efficacy end point, the time-weighted average change in HIV-1 RNA level from baseline to week 24 represents the difference between the time-weighted average postbaseline values and values at baseline. This difference is defined as follows (23, 24). If the area under the curve (AUC) at week 24 (

Phase I/II study of the pharmacokinetics, safety and antiretroviral activity of tenofovir alafenamide, a new prodrug of the HIV reverse transcriptase inhibitor tenofovir, in HIV-infected adults

BACKGROUND Tenofovir alafenamide (formerly GS-7340) is a new oral prodrug of tenofovir, a nucleotide analogue that inhibits HIV-1 reverse transcription. Unlike the currently marketed tenofovir prodrug, tenofovir disoproxil fumarate, tenofovir alafenamide is stable in plasma and then rapidly converted into tenofovir once inside cells. METHODS The pharmacokinetics, safety and antiviral activity of 40 or 120 mg of tenofovir alafenamide compared with 300 mg of tenofovir disoproxil fumarate when administered as monotherapy once daily for 14 days in HIV-1-infected, treatment-naive subjects was studied. RESULTS Administration of 40 mg of tenofovir alafenamide for 14 days resulted in lower tenofovir Cmax (13 versus 207 ng/mL) and lower systemic exposures (AUC0-t, 383 versus 1810 ng · h/mL) compared with subjects who received tenofovir disoproxil fumarate. There were higher intracellular tenofovir concentrations within peripheral blood mononuclear cells with both 40 mg of tenofovir alafenamide (8.2 μM) and 120 mg of tenofovir alafenamide (16.9 μM) compared with 300 mg of tenofovir disoproxil fumarate (0.9 μM). The most commonly observed adverse events were headache, nausea and flatulence, which occurred similarly across the three groups. After 14 days, the mean changes in HIV-1 RNA were -0.94 log₁₀copies/mL for the tenofovir disoproxil fumarate group, -1.57 log₁₀ copies/mL for the 40 mg of tenofovir alafenamide group and -1.71 log₁₀ copies/mL for the 120 mg of tenofovir alafenamide group. The mean first-phase HIV-1 RNA decay slopes were -0.36, -0.63 and -0.64 for the tenofovir disoproxil fumarate group, the 40 mg of tenofovir alafenamide group and the 120 mg of tenofovir alafenamide group, respectively. No resistance mutations to either tenofovir alafenamide or tenofovir disoproxil fumarate were detected. CONCLUSIONS Tenofovir alafenamide, a new once-daily oral prodrug of tenofovir, showed more potent anti-HIV-1 activity and higher intracellular tenofovir levels compared with tenofovir disoproxil fumarate, while maintaining lower plasma tenofovir exposure at 40 mg with good tolerability over 14 days of monotherapy.

Single-Dose and Steady-State Pharmacokinetics of Tenofovir Disoproxil Fumarate in Human Immunodeficiency Virus-Infected Children

ABSTRACT Tenofovir disoproxil fumarate (DF) is a potent nucleotide analog reverse transcriptase inhibitor approved for the treatment of human immunodeficiency virus (HIV)-infected adults. The single-dose and steady-state pharmacokinetics of tenofovir were evaluated following administration of tenofovir DF in treatment-experienced HIV-infected children requiring a change in antiretroviral therapy. Using increments of tenofovir DF 75-mg tablets, the target dose was 175 mg/m2; the median administered dose was 208 mg/m2. Single-dose pharmacokinetics were evaluated in 18 subjects, and the geometric mean area under the concentration-time curve from 0 h to ∞ (AUC0-∞) was 2,150 ng · h/ml and the geometric mean maximum concentration (Cmax) was 266 ng/ml. Subsequently, other antiretrovirals were added to each patients regimen based upon treatment history and baseline viral resistance results. Steady-state pharmacokinetics were evaluated in 16 subjects at week 4. The steady-state, geometric mean AUC for the 24-h dosing interval was 2,920 ng · h/ml and was significantly higher than the AUC0-∞ after the first dose (P = 0.0004). The geometric mean Cmax at steady state was 302 ng/ml. Tenofovir DF was generally very well tolerated. Steady-state tenofovir exposures in children receiving tenofovir DF-containing combination antiretroviral therapy approached values seen in HIV-infected adults (AUC, ∼3,000 ng · h/ml; Cmax, ∼300 ng/ml) treated with tenofovir DF at 300 mg.

Patterns of resistance emerging in HIV-1 from antiretroviral-experienced patients undergoing intensification therapy with tenofovir disoproxil fumarate.

Study GS-99-907 was a 48-week, phase 3, double-blind, placebo-controlled intensification trial of tenofovir disoproxil fumarate (tenofovir DF). Antiretroviral-experienced patients added tenofovir DF 300 mg once daily to their existing regimen. The patterns of HIV-1 resistance development and the corresponding virologic responses were evaluated in a virology substudy at week 48. Although 94% of these treatment-experienced patients had nucleoside-associated resistance mutations (NAMs) at baseline, addition of tenofovir DF resulted in a mean reduction in viral load of −0.59 log10 copies/mL after 24 weeks that was durable through 48 weeks. Relative to the placebo-controlled arm, patients in the tenofovir DF arm had a reduced frequency of development of resistance mutations to all classes of HIV-1 inhibitors, with reduction in new protease inhibitor (PI)-associated mutations achieving statistical significance. The K65R mutation, which occurred in 8 patients (3%), was the only emergent mutation directly associated with tenofovir DF therapy. New thymidine analogue–associated mutations (TAMs) emerged in 19% of patients by week 48. Other than K65R, the patterns of mutations that developed were not significantly different between the tenofovir DF and placebo control arms, suggesting that the background therapies caused their development. The K65R mutation emerged only in patients with no detectable TAMs at baseline, whereas new TAMs developed similarly between patients with or without TAMs at baseline. Development of K65R was associated with mostly low-level changes in phenotypic susceptibility to tenofovir DF and other nucleoside reverse transcriptase inhibitors and was not associated with viral load rebound. No novel patterns of genotypic or phenotypic resistance to tenofovir were identified. Therefore, intensification with once-daily tenofovir DF therapy resulted in a sustained reduction in HIV-1 viral load and a low risk for development of the K65R mutation in this treatment-experienced patient population.

Effect of Tenofovir Disoproxil Fumarate on the Pharmacokinetics and Pharmacodynamics of Total, R-, and S-Methadone

Study Objective. To evaluate the potential effect of tenofovir disoproxil fumarate (DF) on the pharmacokinetics of methadone.

Single-Dose Pharmacokinetics and Safety of the Oral Antiviral Compound Adefovir Dipivoxil in Children Infected with Human Immunodeficiency Virus Type 1

ABSTRACT The acyclic phosphonate analog adefovir is a potent inhibitor of retroviruses, including human immunodeficiency virus (HIV) type 1, and, unlike some antiviral nucleosides, does not require the initial phosphorylation step for its activity. Two oral dosages of the adefovir prodrug adefovir dipivoxil were evaluated in a phase I study with children with HIV infection. A total of 14 patients were stratified into age groups ranging from 6 months to 18 years of age. Eight patients received 1.5 mg of adefovir dipivoxil per kg of body weight, and six patients received 3.0 mg of adefovir dipivoxil per kg. Serum samples were obtained at intervals during the 8 h postdosing and were analyzed for adefovir concentrations. Patients were monitored for adverse effects. All samples collected resulted in quantifiable levels of adefovir (lower limit of quantitation, 25 ng/ml) from each patient. The areas under the concentration-versus-time curves (AUCs) were similar (P = 0.85) for the 1.5- and 3.0-mg/kg doses, while the apparent oral clearance (CL/F) was significantly higher (P = 0.05) for the 3-mg/kg dose. Pharmacokinetic parameters differed by patient age. In comparing those children older and younger than the median age of 5.1 years, AUC (P = 0.03), maximum concentration of drug in serum (P = 0.004), and the concentration at 8 h postdosing (P = 0.02) were significantly lower for the younger children. There were no significant differences for apparent volume of distribution and CL/F normalized to body surface area, but there was a suggestive difference in half-life (P = 0.07) among the subjects in the older and younger age groups. No significant adverse events were encountered. These data provide the basis for a multidose phase II study of adefovir dipivoxil in HIV-infected infants and children.

Hydroxyurea does not enhance the anti-HIV activity of low-dose tenofovir disoproxil fumarate.

Tenofovir disoproxil fumarate (DF) is an adenosine analogue with significant activity against HIV-1. Hydroxyurea decreases the intracellular concentrations of deoxyadenosine triphosphate, the active metabolite of adenosine. We therefore tested the hypothesis that hydroxyurea could enhance the anti-HIV activity of low-dose tenofovir in vivo. Eight patients received tenofovir DF, 75 mg, plus hydroxyurea, 500 mg bid, for 28 days. Changes in plasma HIV RNA levels were compared with a previously studied cohort of patients treated with tenofovir DF, 75 mg once daily ( n = 8), or tenofovir placebo ( n = 12). The median change in HIV RNA levels after 28 days of continuous treatment was -0.01 log(10) copies/ml for tenofovir placebo, -0.33 log(10) copies/ml for tenofovir 75 mg once daily, and -0.22 log(10) copies RNA/ml for tenofovir plus hydroxyurea. The difference between placebo and tenofovir-treated groups was significant ( p <.05); however, the difference between the tenofovir and tenofovir plus hydroxyurea groups was not significant ( p =.90). We conclude that hydroxyurea does not significantly enhance the antiviral activity of low-dose tenofovir.