Tenofovir Disoproxil Fumarate Co-administration Research Articles

S3176 Tenofovir Disoproxil Fumarate-Related Metabolic Syndrome and Steatohepatitis in a Case of Chronic Hepatitis B

Introduction: Tenofovir disoproxil fumarate (TDF) is a nucleotide analog used in the treatment of chronic hepatitis B virus infection (HBV). TDF is considered to have no direct hepatotoxicity. Herein we present a patient with HBV developing liver test abnormalities and biopsy-proven steatohepatitis (SH) after starting TDF, and the resolution of liver tests and SH after switching TDF to entecavir (ETV). Case Description/Methods: A 48-year-old female patient was admitted to our clinic with positive HBsAg and HBV-DNA level of 21600 copies/mL. Her Anti-HBe was positive and Anti-HDV was negative. Abdominal ultrasonography revealed 2 cm hepatomegaly; her AST was 74 U/L (5-40 U/L) and ALT 125 U/L (10-40 U/L). Her BMI was within normal limits, she had no comorbidities and was not on any medication. Her lipid panel was within the normal range. She was prescribed 245 mg/day TDF, and was scheduled for regular clinical follow-up. Six months later, her AST was 113 U/L, ALT 148 U/L, and her HBV-DNA was negative. The patient was advised to follow-up closely. Eighteen months after the initiation of TDF, her AST increased to 211 U/L and ALT to 216 U/L. Her HbA1c was 6.1% and HOMA-IR was 4.0. MRI showed fat accumulation in the liver, and a liver needle biopsy was performed. Histological evaluation revealed grade 2 steatosis with moderate ballooning degeneration and stage 3/4 fibrosis (Figure 1). Autoimmune serologies including antinuclear antibody and anti-smooth muscle antibody were negative, and ceruloplasmin phenotype was normal. The causation of TDF was hypothesized. TDF was stopped, and ETV 0.5 mg/day was initiated. Her follow-up at month 3 revealed a decreased trend in transaminase levels. The patient lost to follow-up for 2 years, but she used ETV regularly. Her control HbA1c was 5.5% at this last visit and a control abdominal ultrasonography showed no fat accumulation. Discussion: While it is known that TDF co-administration with other nucleoside analogs (e.g., didanosine, stavudine) can cause fatty infiltration of the liver, we present a rare case of metabolic syndrome and SH related with TDF monotherapy. Despite some reports suggesting tenofovir, specifically tenofovir alafenamide, might be associated with adverse metabolic changes in patients with HIV, our patient with HBV developed these changes while she was on TDF. We show that hepatic steatosis associated with TDF can be reversible with the medication change to ETV.Figure 1.: A: Hematoxylin-eosin staining shows 50% steatosis (grade 2), portal and lobular inflammation and moderate hepatocyte ballooning. B: Masson-trichrome staining shows portocentral and pericellular fibrosis (stage 3/4).

No Meaningful Drug Interactions with Doravirine, Lamivudine and Tenofovir Disoproxil Fumarate Coadministration

Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor available as a single tablet and a three-drug combination with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF) to treat HIV-1 infection. These analyses assessed pharmacokinetic (PK) interactions with coadministration. Two trials were conducted. Study 1: two-period, fixed-sequence; eight healthy participants; Period 1, DOR 100 mg followed by ≥7-day washout; Period 2, TDF 300 mg once daily for 18 days, coadministration of DOR 100 mg on day 14. Study 2: three-period, crossover, 15 healthy participants; Treatment A, DOR 100 mg; Treatment B, 3TC 300 mg + TDF 300 mg; Treatment C, DOR 100 mg + 3TC 300 mg + TDF 300 mg; ≥7-day washout between periods. Study 1: geometric mean ratios (GMRs; 90% confidence interval [CI]) of DOR area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) and observed plasma concentrations at 24 h post-dose (C24 h; DOR+TDF/DOR) were 0.95 (0.80, 1.12) and 0.94 (0.78, 1.12), respectively. Study 2: GMRs (90% CI) of DOR AUC0-∞ and C24 h (DOR+3TC+TDF/DOR) were 0.96 (0.87, 1.06) and 0.94 (0.83, 1.06), respectively. GMRs (90% CI) of 3TC and tenofovir AUC0-∞ (DOR+3TC+TDF/3TC+TDF) were 0.94 (0.88, 1.00) and 1.11 (0.97, 1.28), respectively. Study drugs were generally well tolerated. Multiple doses of TDF did not have a clinically meaningful effect on DOR PK. The PK of DOR were similar when administered alone or in combination with 3TC and TDF. DOR had no meaningful effect on the PK of 3TC and tenofovir.

Protease Inhibitors and Renal Function in Patients with HIV Infection: a Systematic Review.

IntroductionDespite antiretroviral (ARV) therapy reducing renal disease in human immunodeficiency virus overall, there is concern that certain ARVs, particularly tenofovir disoproxil fumarate (TDF) with or without a boosted protease inhibitor (PI), may reduce renal function over time. It is not known whether effects seen with PI-based regimens are independent, result from interactions with TDF coadministration, or are artefactual owing to inhibition of renal tubular creatinine transport by ritonavir or cobicistat pharmacoenhancement. The aim of this review was to conduct a systematic review of studies, weighted toward high-quality evidence, examining changes in renal function over time with PI-based regimens.MethodsPubMed, Embase, and Medline databases and conference abstracts were searched using pre-defined terms for English language articles, published up to and including August 12, 2013, describing changes in renal function over time with PI-based regimens. All available randomized controlled trials (RCTs) were selected; however, to reduce bias, only observational studies recruiting from more than one center and analyzing data from more than 1,000 patients were included. Evidence was qualitatively evaluated according to levels established by the Oxford Centre for Evidence-Based Medicine (OCEBM).ResultsA total of 2,322 articles were retrieved by the initial search. Of these, 37 were selected for full review, comprising 24 RCTs (OCEBM Level 1 evidence: 4 reports of fully double-blinded or blinded with respect to the PI component). The remaining 20 RCTs and 13 observational studies qualified as OCEBM Level 2 evidence. Level 1 evidence showed initial but non-progressive increases in serum creatinine and corresponding decreases in estimated glomerular filtration rate (eGFR), suggesting an effect on renal tubular transport of creatinine. Level 2 evidence suggested that atazanavir and lopinavir especially in combination with TDF were associated with non-progressive reductions in eGFR over time, with a decreased risk for the development of chronic kidney disease (CKD) on cessation and without the development of advanced CKD or end-stage renal disease (ESRD); whether these reductions were independent or associated with interactions with coadministered TDF could not be established with certainty. Data on darunavir were insufficient to draw any conclusions. The principal limitation of the reviewed studies was the lack of standardization of creatinine measurements in virtually all studies and the lack of corroborative data on changes in proteinuria or other indices of renal function.DiscussionIn this review, there was little evidence for progressive changes in eGFR, or the development of advanced CKD, or ESRD with lopinavir or atazanavir. Further long-term studies, employing a wide range of validated renal function assessments, are required to fully evaluate potential association of PIs with CKD.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-014-0056-4) contains supplementary material, which is available to authorized users.

Role of Drug Efflux and Uptake Transporters in Atazanavir Intestinal Permeability and Drug-Drug Interactions

To investigate the role of membrane-associated drug transporters in regulating the intestinal absorption of the HIV-1 protease inhibitor, atazanavir, and assess the potential contribution of these transporters in clinical interactions of atazanavir with other protease inhibitors and tenofovir disoproxil fumarate (TDF). Intestinal permeability of atazanavir was investigated in vitro, using the Caco-2 cell line system grown on Transwell inserts, and in situ, by single-pass perfusion of rat intestinal segments, jejunum and ileum, in the absence or presence of standard transporter inhibitors or antiretroviral drugs. Atazanavir accumulation by Caco-2 cells was susceptible to inhibition by P-glycoprotein and organic anion transporting polypeptide (OATP) family inhibitors and several antiretroviral drugs (protease inhibitors, TDF). The secretory flux of atazanavir (basolateral-to-apical Papp) was 11.7-fold higher than its absorptive flux. This efflux ratio was reduced to 1.5-1.7 in the presence of P-glycoprotein inhibitors or ritonavir. P-glycoprotein inhibition also resulted in 1.5-2.5-fold increase in atazanavir absorption in situ. Co-administration of TDF, however, reduced atazanavir intestinal permeability by 13-49%, similar to the effect observed clinically. Drug transporters such as P-glycoprotein and OATPs regulate intestinal permeability of atazanavir and may contribute to its poor oral bioavailability and drug-drug interactions with other protease inhibitors and TDF.

Renal function in HIV-infected children and adolescents treated with tenofovir disoproxil fumarate and protease inhibitors

BackgroundKidney disease is an important complication in HIV infected people, and this may be related to infection or antiretroviral therapy (ART). Our aim is to assess renal function in HIV infected paediatric patients, who may be particularly affected and are likely to take ART for longer than adults, and investigate the long term role of Tenofovir Disoproxil Fumarate (TDF) alone or co-administered with Ritonavir-boosted Protease Inhibitors (PI).MethodsSerum creatinine, phosphate and potassium levels, with estimated Glomerular Filtration Rate (eGFR), had been prospectively evaluated for 2 years in a cohort of HIV infected children and adolescents (age 9-18) on ART, and data analyzed according to the exposure to TDF or simultaneous TDF and PI.ResultsForty-nine patients were studied (57% female, mean age 14). Sixty-three percent were treated with ART containing TDF (Group A), and 37% without TDF (Group B); 47% with concomitant use of TDF and PI (Group C) and 53% without this combination (Group D). The groups didn't differ for age, gender or ethnicity. The median creatinine increased in the entire cohort and in all the groups analyzed; eGFR decreased from 143.6 mL/min/1.73 m2 at baseline to 128.9 after 2 years (p = 0.006) in the entire cohort. Three patients presented a mild eGFR reduction, all were on TDF+PI. Phosphatemia decreased significantly in the entire cohort (p = 0.0003) and in TDF+PI group (p = 0.0128) after 2 years. Five patients (10%) developed hypophosphatemia (Division of Acquired Immune Deficiency AE grade 1 or 2), and four of them were on TDF+PI.ConclusionsRenal function decrease and hypophosphatemia occur over time in HIV infected children and adolescents on ART. The association with co-administration of TDF and PI appears weak, and further studies are warranted.

Intracellular Nucleotide Levels during Coadministration of Tenofovir Disoproxil Fumarate and Didanosine in HIV-1-Infected Patients

Studies were conducted to determine if there is a mechanistic basis for reports of suboptimal virologic responses and concerns regarding the safety of regimens containing the combination of tenofovir (TFV) disoproxil fumarate (TDF) and didanosine (ddI) by assessing the pharmacokinetic consequences of coadministration of these drugs on intracellular nucleotides. This was a prospective and longitudinal study in HIV-1-infected patients of adding either TDF or ddI to a stable antiretroviral regimen containing the other drug. Intracellular concentrations of the nucleotide analogs TFV diphosphate (TFV-DP) and ddATP and the endogenous purine nucleotides dATP and 2'-dGTP in peripheral blood mononuclear cells were measured. A total of 16 patients were enrolled into the two study arms and a study extension. Intracellular TFV-DP concentrations (median, 120 fmol/10(6) cells) and ddATP concentrations (range, 1.50 to 7.54 fmol/10(6) cells in two patients) were unaffected following addition of ddI or TDF to a stable regimen containing the other drug. While coadministration of ddI and TDF for 4 weeks did not appear to impact dATP or dGTP concentrations, cross-sectional analysis suggested that extended therapy with ddI-containing regimens, irrespective of TDF coadministration, may decrease dATP and ddATP concentrations. Addition of TDF or ddI to a stable regimen including the other drug, in the context of ddI dose reduction, did not adversely affect the concentration of dATP, dGTP, TFV-DP, or ddATP. The association between longer-term ddI therapy and reduced intracellular nucleotide concentrations and this observation's implication for the efficacy and toxicity of ddI-containing regimens deserve further study.

Steady‐state amprenavir and tenofovir pharmacokinetics after coadministration of unboosted or ritonavir‐boosted fosamprenavir with tenofovir disoproxil fumarate in healthy volunteers

Objective An open-label, three-period pharmacokinetic study was conducted to investigate the drug interaction potential between fosamprenavir (FPV) and tenofovir disoproxil fumarate (TDF). Methods Thirty-six healthy subjects received TDF 300 mg once daily (qd) for 7 days (period 1), and then were randomized to 14 days of either FPV 1400 mg twice daily (bid) or FPV/ritonavir (RTV) 700/100 mg bid alone or with TDF (period 2). Subjects continued their randomized dose of FPV for 14 more days, adding or removing TDF based upon its receipt in period 2 (period 3). Twenty-four-hour pharmacokinetic sampling was carried out on day 7 of period 1 and on day 14 of periods 2 and 3. Steady-state plasma amprenavir (APV) and tenofovir (TFV) pharmacokinetics were assessed by noncompartmental analysis and parameter values observed with each regimen were compared using geometric mean ratios with 90% confidence intervals. Results After TDF coadministration, APV geometric mean minimum concentration (C(min)), maximum concentration (C(max)), and area under the plasma concentration-time curve (AUC) increased by 31, 3 and 7% above values observed with unboosted FPV alone; they also increased by 31, 4 and 16% above values observed with FPV/RTV alone. TFV C(min), C(max) and AUC decreased by 12, 25 and 15% after FPV coadministration and by 9, 18 and 7% after FPV/RTV coadministration. No significant changes in RTV pharmacokinetics were observed. No differences were noted in adverse events among dosing periods. Conclusions In this evaluation of the interaction between FPV and TDF, increases in APV exposures and modest decreases in TFV exposures were observed. These were unlikely to be clinically significant.

Pharmacokinetics and Safety of Tenofovir Disoproxil Fumarate on Coadministration With Lopinavir/Ritonavir

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. 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. 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 (Ctau) were 32%, 15%, and 51% higher, respectively, when TDF was coadministered with LPV/r (n = 24). LPV and RTV pharmacokinetics, including Ctau, were unaffected by TDF (n = 24). Clinical estimates of renal function were unaffected by administration of TDF alone or with LPV/r. 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.

Absence of Clinically Relevant Pharmacokinetic Interaction Between Ribavirin and Tenofovir in Healthy Subjects

This was a 36-day, open-label, fixed-sequence, multiple-dose drug interaction study in 23 healthy subjects to evaluate the effects of multiple doses of tenofovir disoproxil fumarate on the single-dose pharmacokinetics of ribavirin. Subjects received a 600-mg once-daily oral dose of ribavirin on days 1 and 22 and 300-mg once-daily oral doses of tenofovir disoproxil fumarate on days 17 through 24. Pharmacokinetic sampling was performed on days 1 through 4 and 22 through 25. Pharmacokinetics of ribavirin was not altered by its coadministration with tenofovir disoproxil fumarate as the point estimates (day 22 [test treatment]/day 1 [reference treatment]), and the 90% confidence interval for maximum observed concentration (0.95; 88.7-101) and area under the plasma concentration-time curve up to time of last measurable concentration (1.12; 106-117) were within the equivalence bounds of 80% to 125%. Tenofovir pharmacokinetics after ribavirin coadministration was similar to that observed in previous studies. These results indicate that coadministration of tenofovir disoproxil fumarate and ribavirin does not result in substantial changes to their individual pharmacokinetic profiles.

Systemic and Renal Pharmacokinetics of Adefovir and Tenofovir Upon Coadministration

Adefovir and tenofovir are nucleotide analogs that undergo renal secretion by the human renal organic anion transporter. The pharmacokinetics of tenofovir and adefovir following the administration of tenofovir disoproxil fumarate and adefovir dipivoxil alone and together were determined in 24 healthy subjects in an 8-day, open-label, fixed-sequence study. Subjects received oral doses of adefovir dipivoxil on days 1 and 8 and oral doses of tenofovir disoproxil fumarate on days 2 to 8. Pharmacokinetic sampling was performed on days 1, 7, and 8. The plasma pharmacokinetics of tenofovir and adefovir were unaltered upon coadministration. Furthermore, the renal clearances (CLrenal) of tenofovir and adefovir were unaffected by their coadministration. The plasma Cmax values of tenofovir and adefovir were 33-fold and 340-fold lower than their Km values for the human renal organic anion transporter. These results demonstrate that coadministration of tenofovir disoproxil fumarate and adefovir dipivoxil does not result in substantial changes to their individual pharmacokinetic profiles.

In VitroCombination Studies of Tenofovir and Other Nucleoside Analogues with Ribavirin against HIV-1

In patients coinfected and treated for both HIV-1 and hepatitis C virus (HCV), administration of ribavirin (RBV) may result in altered intracellular drug levels of nucleoside reverse transcriptase inhibitors through inhibition of inosine 5′-monophosphate dehydrogenase. Drug interactions between tenofovir and RBV were studied in vitro in order to provide insights into the safety of co-administration of tenofovir disoproxil fumarate (DF) and RBV in HCV/HIV-1-coinfected patients. In accordance with previous in vitro studies, strongly increased anti-HIV activity was observed when RBV was combined with didanosine (ddI). In contrast, low-level anti-HIV antagonism was observed when RBV was combined with either tenofovir or abacavir. Significantly stronger anti-HIV antagonism was observed when RBV was combined with either zidovudine, stavudine, emtricitabine or lamivudine. Thus, although tenofovir and ddI are both adenosine analogues, their in vitro interactions with RBV are markedly different. These results suggest a low potential for increased toxicity upon co-administration of teno-fovir DF with RBV in patients.

Concomitant intake of tenofovir disoproxil fumarate (TDF) does not impair plasma exposure of ritonavir (RTV) boosted atazanavir (ATV) in HIV-1 infected adults

Background Recent data showed contradictory results on pharmacokinetic drug interactions of the protease inhibitor ATV and the nucleotide reverse transcriptase inhibitor TDF in HIV-1 infected adults. TDF co-administration decreases plasma levels of ATV 400mg QD alone, but has no impact on plasma trough levels of ATV 300mg QD when boosted with low-dose RTV. Methods We compared steady state plasma pharmacokinetics (PK) of ATV/RTV in a cohort of 53 (34male/19female) outpatients of comparable baseline characteristics, taking ATV/RTV 300/100mg QD+ 2–4 nucleoside reverse transcriptase inhibitors (NRTI) either with TDF (n=39) or without TDF (n=14). Following a standardized PK protocol, plasma drug levels were measured by LC/MS/MS after at least 4 weeks on the regimen prior to and 1,2,4,6,9,12,24h after drug intake. Noncompartmental AUCss, Cmin, Cmax and CLtot were subject to statistical analysis. Results see Table. Conclusions Co-administration of TDF does not impair the steady state plasma exposure of ATV or RTV in a limited number of HIV-1 infected patients. ATV/RTV 300/100mg+TDF/NRTI appears to be a pharmacokinetically suitable once-daily therapy regimen. Further clinical and PK data are obtained in this observational cohort. Clinical Pharmacology & Therapeutics (2005) 77, P18–P18; doi: 10.1016/j.clpt.2004.11.072 Table 1. ATV/RTV 300/100mg QD +NRTI with TDF mean (±SD) +NRTI without TDF mean (±SD) Mann-Whitney U-Test: p-value AUCss(ng24h/mL) ATV 40461 (±20824) 42193 (±19376) .68 RTV 11006 (±7623) 8774 (±3819) .55 Cmin(ng/mL) ATV 522 (±441) 663 (±444) .14 RTV 75 (±74) 61 (±35) .75 Cmax(ng/mL) ATV 3582 (±1877) 3772 (±2008) .86 RTV 1275 (±896) 1015 (±453) .39 CLtot(mL/min) ATV 174 (±127) 145 (±72) .67 RTV 231 (±161) 232 (±117) .57