John F. Flaherty

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.

Randomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B.

BACKGROUND & AIMS Tenofovir disoproxil fumarate (TDF) is active against lamivudine-resistant hepatitis B virus (HBV) infection, but data to support its clinical efficacy in this setting are limited. METHODS In a prospective, double-blind, 96-week trial, patients were randomly assigned (1:1) to groups given TDF (300 mg, n = 141) or a combination of emtricitabine (FTC, 200 mg; n = 139) and TDF (300 mg, FTC/TDF). Patients were hepatitis B e antigen (HBeAg)-positive or HBeAg-negative, with levels of HBV DNA ≥3 log10 IU/mL and lamivudine resistance mutations (HBV polymerase or reverse transcriptase amino acid substitutions rtM204I/V ± rtL180M by INNO-LiPA Multi-DR v3; Innogenetics, Inc, Alpharetta, GA). The primary end point was proportion with HBV DNA <69 IU/mL (Roche COBAS Taqman assay; Roche Molecular Systems, Inc, Pleasanton, CA). RESULTS Patient groups were well matched for demographic and disease characteristics, including region (60% from Europe), HBV genotype (45% genotype D), HBeAg status (47% HBeAg-positive), and duration of lamivudine treatment (mean, 3.8 years). At week 96 of treatment, 89.4% of patients in the TDF group and 86.3% in the FTC/TDF group had levels of HBV DNA <69 IU/mL (P = .43). HBeAg loss and seroconversion did not differ between groups; only 1 patient (0.7%) in the FTC/TDF group lost hepatitis B surface antigen. Treatment was well tolerated; confirmed renal events (creatinine increase of ≥0.5 mg/dL [>44 umol/L], creatinine clearance <50 mL/min, or level of PO4 <2 mg/dL [<0.65 mmol/L]) were generally mild and infrequent (<1%). Small reductions (<2%) in mean bone mineral density of hip and spine were detected by dual-energy x-ray absorptiometry in both groups. No TDF resistance developed through 96 weeks of treatment. CONCLUSIONS TDF alone is safe and effective for treatment of patients with lamivudine-resistant, chronic HBV infection. Clinical Trials.gov No, NCT00737568.

Tenofovir Disoproxil Fumarate and an Optimized Background Regimen of Antiretroviral Agents as Salvage Therapy for Pediatric HIV Infection

Objectives. Highly active antiretroviral therapy has altered the course of HIV infection among children, but new antiretroviral agents are needed for treatment-experienced children with drug-resistant virus. Tenofovir disoproxil fumarate (DF) is a promising agent for use in pediatric salvage therapy, because of its tolerability, efficacy, and resistance profile. We designed this study to provide preliminary pediatric safety and dosing information on tenofovir DF, while also providing potentially efficacious salvage therapy for heavily treatment-experienced, HIV-infected children. Methods. Tenofovir DF, alone and in combination with optimized background antiretroviral regimens, was studied among 18 HIV-infected children (age range: 8.3–16.2 years) who had progressive disease with ≥2 prior antiretroviral regimens, in a single-center, open-label trial. Tenofovir DF monotherapy for 6 days was followed by the addition of individualized antiretroviral regimens. Subjects were monitored with HIV RNA reverse transcription-polymerase chain reaction, flow cytometry, and routine laboratory studies; monitoring for bone toxicity included measurement of lumbar spine bone mineral density (BMD) with dual-energy x-ray absorptiometry. Subjects were monitored through 48 weeks. Results. Two subjects developed grade 3 elevated hepatic transaminase levels during monotherapy and were removed from the study. The remaining 16 subjects had a median of 4 antiretroviral agents (range: 3–5 agents) added to tenofovir DF. HIV plasma RNA levels decreased from a median pretreatment level of 5.4 log10 copies per mL (range: 4.1–5.9 log10 copies per mL) to 4.21 log10 copies per mL at week 48 (n = 15), with 6 subjects having <400 copies per mL, including 4 with <50 copies per mL. The overall median increases in CD4+ T cell counts were 58 cells per mm3 (range: −64 to 589 cells per mm3) at week 24 and 0 cells per mm3 (range: −274 to 768 cells per mm3) at week 48. The CD4+ cell responses among the virologic responders were high and sustained. The major toxicity attributed to tenofovir DF was a >6% decrease in BMD for 5 of 15 subjects evaluated at week 48, necessitating the discontinuation of tenofovir DF therapy for 2; all 5 subjects experienced >2 log10 copies per mL decreases in HIV plasma RNA levels. Conclusions. Tenofovir DF-containing, individualized, highly active antiretroviral therapy regimens were well tolerated and effective among heavily treatment-experienced, HIV-infected children. Loss of BMD may limit tenofovir DF use among prepubertal patients.

Efficacy of tenofovir disoproxil fumarate at 240 weeks in patients with chronic hepatitis B with high baseline viral load

We evaluated the antiviral response of patients with chronic hepatitis B (CHB) who had baseline high viral load (HVL), defined as having hepatitis B virus (HBV) DNA ≥9 log10 copies/mL, after 240 weeks of tenofovir disoproxil fumarate (TDF) treatment. A total of 641 hepatitis B e antigen (HBeAg)‐negative and HBeAg‐positive patients (129 with HVL) received 48 weeks of TDF 300 mg (HVL n = 82) or adefovir dipivoxil (ADV) 10 mg (HVL n = 47), followed by open‐label TDF for an additional 192 weeks. Patients with confirmed HBV DNA ≥400 copies/mL on or after week 72 had the option of adding emtricitabine (FTC). By week 240, 98.3% of HVL and 99.2% of non‐HVL patients on treatment achieved HBV DNA <400 copies/mL. Both groups had similar rates of histologic regression between baseline and week 240. Patients with HVL generally took longer to achieve HBV DNA <400 copies/mL than non‐HVL patients, but by week 96, the percentages of patients with HBV DNA <400 copies/mL were similar in both groups. Among HVL patients, time to achieving HBV DNA <400 copies/mL was shorter among those initially receiving TDF, compared to ADV. No patient with baseline HVL had persistent viremia at week 240 or amino acid substitutions associated with TDF resistance. Conclusion: CHB patients with HVL can achieve HBV DNA negativity with long‐term TDF treatment, although time to HBV DNA <400 copies/mL may be longer, relative to patients with non‐HVL. (Hepatology 2013;58:505–513)

Effects of Tenofovir Disoproxil Fumarate in Hepatitis B e Antigen-Positive Patients With Normal Levels of Alanine Aminotransferase and High Levels of Hepatitis B Virus DNA

BACKGROUND & AIMS Little is known about the benefit of antiviral therapy for hepatitis B e antigen (HBeAg)-positive patients with high viral load and normal levels of alanine aminotransferase. We evaluated the effects of single and combination therapies in immune-tolerant patients with chronic hepatitis B. METHODS In a double-blind study, nucleos(t)ide-naïve patients with high levels of hepatitis B virus (HBV) DNA who were positive for HBeAg and had normal levels of alanine aminotransferase were randomly assigned to groups given either oral tenofovir disoproxil fumarate (TDF, 300 mg) and placebo (n = 64) or a combination of TDF (300 mg) and emtricitabine (200 mg, n = 62) for 192 weeks. The primary end point was proportion of patients with serum levels of HBV DNA <69 IU/mL at week 192. RESULTS The study population (mean age was 33 years; 89% were Asian) was predominantly infected with HBV genotypes B and C (93%), 99% were HBeAg positive with a mean baseline level of HBV DNA of 8.41 log10 IU/mL. At week 192, 55% of patients (35 of 64) in the TDF+placebo group and 76% of patients (47 of 62) in the TDF+emtricitabine group had levels of HBV DNA <69 IU/mL (P = .016). No patients were found to have viral resistance to therapy. HBeAg seroconversion occurred in 3 patients (5%), all in the TDF+placebo group; no patient had loss of hepatitis B surface antigen. In multivariate analysis, female sex (odds ratio = 7.05; P = .002) and TDF+emtricitabine treatment (odds ratio = 3.9; P = .01) were associated with a favorable response. Both regimens were well tolerated. CONCLUSIONS In HBeAg-positive patients with chronic HBV infection, high viral loads, normal levels of alanine aminotransferase, and therapy with the combination of TDF and emtricitabine provided better viral suppression than TDF alone, although rates of HBeAg seroconversion and hepatitis B surface antigen loss were low.

Twenty-eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection

BACKGROUND & AIMS Tenofovir alafenamide, a phosphonate prodrug of tenofovir with greater plasma stability than tenofovir disoproxil fumarate, provides efficient delivery of active drug to hepatocytes at reduced systemic tenofovir exposures. METHODS Non-cirrhotic, treatment-naïve subjects with chronic hepatitis B were randomized (1:1:1:1:1) to receive tenofovir alafenamide 8, 25, 40, or 120 mg, or tenofovir disoproxil fumarate 300 mg for 28 days and assessed for safety, antiviral response, and pharmacokinetics, followed-up by off-treatment for 4 weeks. RESULTS 51 subjects were randomized and all completed study treatment. Groups were generally well matched (67% male, 57% Asian, 53% HBeAg-negative, mean HBV DNA approximately 6.0 log10 IU/ml) with HBV genotypes reflective of the population. No subject experienced an adverse event that was serious or severe (grade 3/4). Across the tenofovir alafenamide groups, similar mean changes in serum HBV DNA were found at Week 4 (-2.81, -2.55, -2.19, and -2.76 log10 IU/ml for the 8, 25, 40, and 120 mg groups, respectively) which were also comparable to the control (-2.68 log10 IU/ml for tenofovir disoproxil fumarate 300 mg). Kinetics of viral decline were also similar among groups. Tenofovir alafenamide pharmacokinetics were linear and proportional to the dose; doses⩽25 mg were associated with ⩾92% reductions in mean tenofovir area under the curve relative to tenofovir disoproxil fumarate 300 mg. CONCLUSIONS Tenofovir alafenamide was safe and well tolerated; declines in HBV DNA were similar to tenofovir disoproxil fumarate at all doses evaluated. Tenofovir alafenamide 25 mg has been selected for further hepatitis B clinical development.

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.

Impact of long‐term tenofovir disoproxil fumarate on incidence of hepatocellular carcinoma in patients with chronic hepatitis B

Efficacy trials have shown that antiviral therapy improves the outcomes of patients with chronic hepatitis B virus (HBV) infection. However, prospective data regarding the effect of antiviral therapy on the incidence of hepatocellular carcinoma (HCC), especially among patients without cirrhosis, are limited. The authors examined the impact of tenofovir disoproxil fumarate (TDF) on the incidence of HCC using a validated prediction model.

Tenofovir disoproxil fumarate (TDF) vs. emtricitabine (FTC)/TDF in lamivudine resistant hepatitis B: A 5-year randomised study.

BACKGROUND & AIMS Long-term treatment with tenofovir disoproxil fumarate (TDF) alone, or in combination with emtricitabine (FTC) is associated with sustained viral suppression in patients with lamivudine resistant (LAM-R) chronic hepatitis B (CHB). METHODS LAM-R CHB patients were randomised 1:1 to receive TDF 300mg or FTC 200mg and TDF 300mg once daily in a prospective, double blind, study. The proportion of patients with plasma hepatitis B virus (HBV) DNA<69IU/ml (<400copies/ml) at week 96 (primary efficacy endpoint) was reported previously. Here we present week 240 follow-up data. RESULTS Overall, 280 patients were randomised to receive TDF (n=141) or FTC/TDF (n=139), and 85.4% completed 240weeks of treatment. At week 240, 83.0% of patients in the TDF arm, and 82.7% of patients in the FTC/TDF treatment arm had HBV DNA<69IU/ml (p=0.96). Rates of normal alanine aminotransferase (ALT) and normalised ALT were similar between groups (p=0.41 and p=0.97 respectively). Hepatitis B e antigen loss and seroconversion at week 240 were similar between groups, (p=0.41 and p=0.67 respectively). Overall, six patients achieved hepatitis B surface antigen (HBsAg) loss and one patient (FTC/TDF arm) had HBsAg seroconversion by week 240. No TDF resistance was observed up to week 240. Treatment was generally well tolerated, and renal events were mild and infrequent (∼8.6%). The mean change in bone mineral density at week 240 was -0.98% and -2.54% at the spine and hip, respectively. CONCLUSIONS TDF monotherapy was effective and well tolerated in LAM-R CHB patients for up to 240weeks. LAY SUMMARY The goal of oral antiviral treatment for chronic hepatitis B (CHB) is to achieve and maintain undetectable HBV DNA levels. Treatment options with enhanced potency, and low risk of resistance development for patients infected with lamivudine resistant (LAM-R) HBV are required. Tenofovir disoproxil fumarate (TDF) monotherapy was effective and well tolerated without TDF resistance development in CHB patients with LAM-R, for up to 240weeks. Clinical trial number: NCT00737568.

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

ABSTRACT 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/106 cells) and ddATP concentrations (range, 1.50 to 7.54 fmol/106 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 observations implication for the efficacy and toxicity of ddI-containing regimens deserve further study.