Brian P. Kearney

Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks

BACKGROUND The integrase inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) in a single tablet given once daily. We compared the efficacy and safety of EVG/COBI/FTC/TDF with standard of care-co-formulated efavirenz (EFV)/FTC/TDF-as initial treatment for HIV infection. METHODS In this phase 3 trial, treatment-naive patients from outpatient clinics in North America were randomly assigned by computer-generated allocation sequence with a block size of four in a 1:1 ratio to receive EVG/COBI/FTC/TDF or EFV/FTC/TDF, once daily, plus matching placebo. Patients and study staff involved in giving study treatment, assessing outcomes, and collecting and analysing data were masked to treatment allocation. Eligibility criteria included screening HIV RNA concentration of 5000 copies per mL or more, and susceptibility to efavirenz, emtricitabine, and tenofovir. The primary endpoint was HIV RNA concentration of fewer than 50 copies per mL at week 48. The study is registered with ClinicalTrials.gov, number NCT01095796. FINDINGS 700 patients were randomly assigned and treated (348 with EVG/COBI/FTC/TDF, 352 with EFV/FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to EFV/FTC/TDF; 305/348 (87·6%) versus 296/352 (84·1%) of patients had HIV RNA concentrations of fewer than 50 copies per mL at week 48 (difference 3·6%, 95% CI -1·6% to 8·8%). Proportions of patients discontinuing drugs for adverse events did not differ substantially (13/348 in the EVG/COBI/FTC/TDF group vs 18/352 in the EFV/FTC/TDF group). Nausea was more common with EVG/COBI/FTC/TDF than with EFV/FTC/TDF (72/348 vs 48/352) and dizziness (23/348 vs 86/352), abnormal dreams (53/348 vs 95/352), insomnia (30/348 vs 49/352), and rash (22/348 vs 43/352) were less common. Serum creatinine concentration increased more by week 48 in the EVG/COBI/FTC/TDF group than in the EFV/FTC/TDF group (median 13 μmol/L, IQR 5 to 20 vs 1 μmol/L, -6 to 8; p<0·001). INTERPRETATION If regulatory approval is given, EVG/COBI/FTC/TDF would be the only single-tablet, once-daily, integrase-inhibitor-based regimen for initial treatment of HIV infection. FUNDING Gilead Sciences.

Tenofovir disoproxil fumarate: Clinical pharmacology and pharmacokinetics

Tenofovir disoproxil fumarate (tenofovir DF) is an oral prodrug of tenofovir, a nucleotide (nucleoside monophosphate) analogue with activity against retroviruses, including HIV-1, HIV-2 and hepadnaviruses. Following absorption, tenofovir DF is rapidly converted to tenofovir, which is metabolised intracellularly to its active anabolite tenofovir diphosphate, which is a competitive inhibitor of HIV-1 reverse transcriptase and terminates the growing DNA chain. Tenofovir exerts antiviral effects in a variety of cell types, including resting cells.Tenofovir exhibits longer serum (17 hours) and intracellular (≥60 hours) half-lives than those of nucleoside analogues, which supports a flexible once-daily administration schedule. The pharmacokinetics of tenofovir are dose-proportional and similar in healthy volunteers and HIV-infected individuals. The oral bioavailability of tenofovir is enhanced by administration with a high-fat meal, but is similar at steady state when administered with or without a typical meal.Tenofovir is not a substrate, inducer or inhibitor of human cytochrome P450 enzymes in vitro or in vivo. Tenofovir DF has been studied with 15 other antiretroviral and other concomitant medications frequently used in the HIV-1-infected population. With the exception of didanosine and atazanavir, which require dosage modifications, no clinically significant drug interactions have been observed with tenofovir DF.The recommended oral dosage of tenofovir DF in adults is 300 mg/day. Tenofovir is eliminated by renal elimination, including tubular secretion; dose-interval adjustments are necessary for tenofovir DF in patients with significant renal impairment. No dosage adjustment of tenofovir DF is necessary in patients with liver disease.

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.

Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial.

BACKGROUND The HIV integrase strand transfer inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) into a once-daily, single tablet. We compared EVG/COBI/FTC/TDF with a ritonavir-boosted (RTV) protease inhibitor regimen of atazanavir (ATV)/RTV+FTC/TDF as initial therapy for HIV-1 infection. METHODS This phase 3, non-inferiority study enrolled treatment-naive patients with an HIV-1 RNA concentration of 5000 copies per mL or more and susceptibility to atazanavir, emtricitabine, and tenofovir. Patients were randomly assigned (1:1) to receive EVG/COBI/FTC/TDF or ATV/RTV+FTC/TDF plus matching placebos, administered once daily. Randomisation was by a computer-generated random sequence, accessed via an interactive telephone and web response system. Patients, and investigators and study staff who gave treatments, assessed outcomes, or analysed data were masked to the assignment. The primary endpoint was HIV RNA concentration of 50 copies per mL or less after 48 weeks (according to the US FDA snapshot algorithm), with a 12% non-inferiority margin. This trial is registered with ClinicalTrials.gov, number NCT01106586. FINDINGS 1017 patients were screened, 715 were enrolled, and 708 were treated (353 with EVG/COBI/FTC/TDF and 355 with ATV/RTV+FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to ATV/RTV+FTC/TDF for the primary outcome (316 patients [89·5%] vs 308 patients [86·8%], adjusted difference 3·0%, 95% CI -1·9% to 7·8%). Both regimens had favourable safety and tolerability; 13 (3·7%) versus 18 (5·1%) patients discontinued treatment because of adverse events. Fewer patients receiving EVG/COBI/FTC/TDF had abnormal results in liver function tests than did those receiving ATV/RTV+FTC/TDF and had smaller median increases in fasting triglyceride concentration (90 μmol/L vs 260 μmol/L, p=0·006). Small median increases in serum creatinine concentration with accompanying decreases in estimated glomerular filtration rate occurred in both study groups by week 2; they generally stabilised by week 8 and did not change up to week 48 (median change 11 μmol/L vs 7 μmol/L). INTERPRETATION If regulatory approval is given, EVG/COBI/FTC/TDF would be the first integrase-inhibitor-based regimen given once daily and the only one formulated as a single tablet for initial HIV treatment. FUNDING Gilead Sciences.

Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients

Background: GS-9137 is a potent low-nanomolar strand transfer inhibitor of HIV-1 integrase. Methods: The antiviral activity, tolerability, pharmacokinetics, and pharmacodynamics of GS-9137 were evaluated in a randomized, double-blind, placebo-controlled monotherapy study in 40 HIV-1- infected patients not receiving antiretroviral therapy with an HIV-1 RNA between 10,000 and 300,000 copies/mL and a CD4 count of 200 cells/&mgr;L or greater. GS-9137 or matching placebo was administered with food for 10 days at 5 dosage regimens (200, 400, or 800 mg BID, 800 mg QD, or 50 mg + 100 mg ritonavir QD; 6 active, 2 placebo per dose level). The primary end point was the maximum reduction from baseline in log10 HIV-1 RNA. Results: Forty patients were enrolled, with a mean baseline viral load of 4.75 log10 copies/mL and a CD4 count of 442 cells/&mgr;L. Each GS-9137 dosing regimen exhibited significant, exposure-dependent (mean reductions, −0.98 to −1.99 log10 copies/mL) antiviral activity compared with placebo (P < 0.01). Twice-daily administrations of GS-9137 at doses of 400 or 800 mg or once-daily dosing of 50 mg with ritonavir demonstrated mean reductions from baseline in HIV-1 RNA of 1.91 log10 copies/mL or greater, with all patients exhibiting 1 log10 or greater and 50% having 2 log10 or greater reductions. No patient developed evidence of integrase resistance. GS-9137 showed an adverse event profile similar to placebo, and there were no study drug discontinuations. Conclusions: GS-9137 demonstrated substantial short-term antiviral activity and was well tolerated as monotherapy, thus warranting further study.

Intracellular pharmacokinetics of tenofovir diphosphate, carbovir triphosphate, and lamivudine triphosphate in patients receiving triple-nucleoside regimens.

Objective:To evaluate the potential for a pharmacologic mechanism to explain suboptimal virologic responses observed in a triple-nucleoside only regimen containing tenofovir disoproxil fumarate (TDF), abacavir (ABC), and lamivudine (3TC). Methods:This was a prospective evaluation of intracellular concentrations and pharmacokinetics of tenofovir diphosphate (TFV-DP), carbovir triphosphate (CBV-TP), and lamivudine triphosphate (3TC-TP) in patients on triple-nucleoside regimens. Fifteen patients on a stable TDF plus ABC plus a third nucleoside reverse transcriptase (RT) inhibitor (3TC [n = 13], stavudine [n = 2]) regimen discontinued TDF or ABC, replacing it with a nonnucleoside RT inhibitor or protease inhibitor. Peripheral blood mononuclear cells were collected after the last dose of TDF or ABC at baseline and over 12 to 96 hours as well as at days 14 and 28 after discontinuation. Nucleotide concentrations were measured directly using liquid chromatography with tandem mass spectrometry; changes after ABC or TDF discontinuation would provide evidence of an intracellular drug interaction. Results:Intracellular nucleotide concentrations of the continued drugs were unaffected when TDF or ABC was discontinued. Intracellular levels of TFV-DP exhibited less inter- and intrapatient variability than CBV-TP or 3TC-TP. TFV-DP also had persistent intracellular levels on TDF discontinuation (median half-life of 150 hours, range: 60 to >175 hours). CBV-TP concentrations fell to below the limit of detection in all patients by 72 hours after the last ABC dose in accordance with a median half-life of 18 hours (range: 12-19 hours). Conclusions:An intracellular drug interaction does not explain the suboptimal viral response in patients treated with the nucleoside-only regimen of TDF, ABC, and 3TC.

Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy: impact on bone mineral density in HIV-infected children.

OBJECTIVE. Tenofovir disoproxil fumarate, a nucleotide analog HIV reverse transcriptase inhibitor with demonstrated activity against nucleoside-resistant HIV, is approved for use in adults but not children. Metabolic bone abnormalities have been seen in young animals given high-dose tenofovir and HIV-infected adults that were treated with oral tenofovir disoproxil fumarate. However, tenofovir disoproxil fumarate is being used in children despite a lack of bone safety data. We hypothesized that, given the higher rate of bone turnover that is associated with normal skeletal growth, the potential for TDF-related bone toxicity may be greater in children than in adults. METHODS. Fifteen highly antiretroviral-experienced HIV-infected children who were 8 to 16 years of age (mean ± SD: 12 ± 2) and required a change in therapy received tenofovir disoproxil fumarate 175 to 300 mg/m2 per day (adult dose equivalent) as part of highly active antiretroviral therapy for up to 96 weeks. Bone mineral density of the lumbar spine, femoral neck, and total hip by dual-energy x-ray absorptiometry and blood and urine markers of bone metabolism were measured at 0, 24, 48, 72, and 96 weeks. RESULTS. Median z score (SD score compared with age, gender, and ethnicity-matched control subjects) of the lumbar spine, femoral neck, and total hip were decreased from baseline at 24 weeks and 48 weeks and then stabilized. Lumbar spine bone mineral apparent density (which estimates volumetric bone mineral density independent of bone size) z scores also decreased at 24 weeks. Absolute decreases in bone mineral density were observed in 6 children; the mean age of these children was significantly younger than the bone mineral density stable group (10.2 ± 1.1 vs 13.2 ± 1.8 years). The change in lumbar spine bone mineral density correlated with decreases in HIV plasma RNA during treatment. Metabolic markers of bone formation and resorption were variable. Two children in whom tenofovir disoproxil fumarate was discontinued because of bone loss that exceeded protocol allowances demonstrated partial or complete recovery of bone mineral density by 96 weeks. CONCLUSIONS. Tenofovir disoproxil fumarate use in children seems to be associated with decreases in bone mineral density that, in some children, stabilize after 24 weeks. Increases in bone markers and calcium excretion suggest that tenofovir disoproxil fumarate may stimulate bone resorption. Bone turnover is higher in children than in older adolescents and adults because of skeletal growth, potentially explaining the greater effect seen in young children. Decreases in bone mineral density correlate with decreases in viral load and young age, suggesting that young responders may be at greater risk for bone toxicity.

Pharmacokinetics and Pharmacodynamics of GS‐9350: A Novel Pharmacokinetic Enhancer Without Anti‐HIV Activity

GS‐9350 is a new chemical entity under development as a potent, mechanism‐based inhibitor of human cytochrome P450 3A (CYP3A) isoforms. Its intended use is to increase the systemic exposure of coadministered agents that are metabolized by CYP3A enzymes. Unlike ritonavir, which is in current clinical use for this purpose, GS‐9350 is devoid of anti‐HIV activity. The pharmacokinetics of GS‐9350 and its efficacy in increasing systemic exposure of the probe CYP3A substrate midazolam were examined in a study involving single‐ and multiple‐dose escalations of GS‐9350 from 50 to 400 mg. Single‐dose escalation from 50 to 400 mg resulted in a 164‐fold increase in GS‐9350 exposure, whereas multiple‐dose escalation in the dosage range of 50–300 mg resulted in a 47‐fold increase in exposure. GS‐9350 potently inhibited midazolam apparent clearance (95% reduction), similar in effect to ritonavir 100 mg. GS‐9350 was generally well tolerated at all doses, and there was no evidence of dose‐limiting toxicity. Establishing proof‐of‐concept, GS‐9350 is currently under phase II development as a potential alternative to ritonavir for use with antiretroviral agents (including the HIV integrase inhibitor elvitegravir) that are often prescribed along with a “booster” drug.

Pharmacokinetics and safety of tenofovir disoproxil fumarate on coadministration with lopinavir/ritonavir.

Objective:Lopinavir/ritonavir (LPV/r) and tenofovir disoproxil fumarate (TDF) are frequently used antiretrovirals. A pharmacokinetic study in healthy volunteers was conducted to assess the potential for a drug interaction between these agents. Methods:This was a 36-day, multiple-dose, drug-drug interaction study of TDF and lopinavir/ritonavir (LPV/r). Subjects received TDF alone for 7 days, followed by 14 days each of TDF plus LPV/r and LPV/r alone in a randomized manner. Pharmacokinetic assessments were performed over 24 hours on days 7, 21, and 35. LPV/r and tenofovir plasma/serum concentrations were measured by high-performance liquid chromatography/mass spectometry (MS)/MS. Geometric mean ratios and 90% confidence intervals of pharmacokinetic parameters for tenofovir, LPV, and ritonavir (RTV) were estimated using analysis of variance and compared with the no-effect criterion for pharmacokinetic equivalence. Results:Tenofovir measurements with an area under the concentration-time curve over the dosing interval, maximum concentration, and concentration at the end of the dosing interval (Cτ) were 32%, 15%, and 51% higher, respectively, when TDF was coadministered with LPV/r (n = 24). LPV and RTV pharmacokinetics, including Cτ, were unaffected by TDF (n = 24). Clinical estimates of renal function were unaffected by administration of TDF alone or with LPV/r. Discussion:Coadministration of TDF with LPV/r resulted in increased tenofovir exposures at steady state, possibly through increased absorption. This increase is not believed to be clinically relevant based on the safety and efficacy of TDF plus LPV/r-containing regimens in HIV-infected patients in long-term controlled clinical trials.

Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function.

Objective:This study evaluated the effect of cobicistat (COBI) on glomerular filtration rate in subjects with normal renal function (RF) or with mild/moderate renal impairment, by comparing creatinine clearance [estimated glomerular filtration rate (eGFR)] with actual GFR (aGFR) using iohexol, a probe drug excreted by glomerular filtration. COBI is a potent CYP3A inhibitor (pharmacoenhancer) currently in phase 3 testing with elvitegravir, atazanavir, and darunavir. Methods:Normal RF subjects received COBI 150 mg QD, ritonavir (RTV) 100 mg QD, or placebo for 7 days; subjects with mild/moderate renal impairment received COBI 150 mg QD. The eGFR and aGFR were measured on days 0, 7, and 14 and within-subject changes calculated relative to day 0. COBI and RTV pharmacokinetics were analyzed on day 7. Results:All 36 subjects in cohort 1 and 17 of 18 subjects in cohort 2 completed all study treatments. Study treatments were well tolerated. Small increases in serum creatinine with corresponding mean decreases in eGFR (∼10 mL/min or mL/min per 1.73 m2) were observed on day 7 relative to day 0 in subjects receiving COBI (P < 0.05). The decreases were reversible on COBI discontinuation; mean eGFR values returned to baseline on day 14 (P > 0.05). No statistically significant changes in aGFR on days 7 or 14 relative to day 0 were seen with COBI (P > 0.05). No statistically significant decreases in aGFR or eGFR were observed with RTV or placebo. Conclusions:COBI affects eGFR but not the actual GFR. The time to onset, magnitude, and time to resolution of changes in eGFR are consistent with altered proximal tubular secretion of creatinine through inhibition of drug transporters.