Brincidofovir for Asymptomatic Adenovirus Viremia in Pediatric and Adult Allogeneic Hematopoietic Cell Transplant Recipients: A Randomized Placebo-Controlled Phase II Trial.

Adenovirus infection in immunocompromised patients contributes to significant morbidity and mortality, especially after allogeneic hematopoietic cell transplantation (HCT). Brincidofovir (BCV, CMX001) is an orally bioavailable lipid conjugate of cidofovir that has in vitro activity against adenoviruses and other double-stranded DNA viruses. This randomized placebo-controlled phase II trial evaluated pre-emptive treatment with BCV for the prevention of adenovirus disease in pediatric and adult allogeneic HCT recipients with asymptomatic adenovirus viremia. Allogeneic HCT recipients with adenovirus viremia were randomized 1:1:1 to receive oral BCV 100 mg (2 mg/kg if <50 kg) twice weekly (BIW), BCV 200 mg (4 mg/kg if <50 kg) once weekly (QW), or placebo for 6 to 12 weeks, followed by 4 weeks of post-treatment follow-up. For randomization, subjects were stratified by screening absolute lymphocyte count (<300 cells/mm3 versus ≥300 cells/mm3). Assignment to BCV or placebo was double blinded; dose frequency was unblinded. The primary endpoint was the proportion of subjects experiencing treatment failure, defined as either progression to probable or definitive adenovirus disease or confirmed increasing adenovirus viremia (≥1 log10 copies/mL) during randomized therapy. Between June 2011 and December 2012, 48 subjects were randomized to the BCV BIW (n = 14), BCV QW (n = 16), or placebo (n = 18) groups. The proportion of subjects with treatment failure in the BCV BIW group was 21% (odds ratio, .53; 95% confidence interval [CI], .11 to 2.71; P = .45), 38% (odds ratio, 1.23; 95% CI, .30 to 5.05, P = .779) in the BCV QW group, and 33% in the placebo group. All-cause mortality was lower in the BCV BIW (14%) and BCV QW groups (31%) relative to the placebo group (39%), but these differences were not statistically significant. After 1 week of therapy, 8 of 12 subjects (67%) randomized to BCV BIW had undetectable adenovirus viremia (<100 copies/mL), compared with 4 of 14 subjects (29%) randomized to BCV QW and 5 of 15 subjects (33%) randomized to placebo. In a post hoc analysis of subjects with viremia ≥1000 copies/mL at baseline, 6 of 7 BCV BIW subjects (86%) achieved undetectable viremia compared with 2 of 8 placebo subjects (25%; P = .04). Early treatment discontinuation because of adverse events was more common in subjects treated with BCV than with placebo. Diarrhea was the most common event in all groups (57% BCV BIW, 38% BCV QW, 28% placebo), but it led to treatment discontinuation in only 1 subject receiving BCV QW. Events diagnosed as acute graft-versus-host disease, primarily of the gastrointestinal tract, were more frequent in the BCV BIW group (50%) than in the BCV QW (25%) and placebo (17%) groups. There was no evidence of myelotoxicity or nephrotoxicity in BCV-treated subjects. The results of this trial confirm the antiviral activity of BCV against adenoviruses. Further investigation is ongoing to define the optimal treatment strategy for HCT recipients with serious adenovirus infection and disease.

Brincidofovir for polyomavirus-associated nephropathy after allogeneic hematopoietic stem cell transplantation.

Polyomavirus-associated nephropathy (PVAN) is common in patients who have undergone kidney transplantation and has been reported in hematopoietic stem cell (HSC) transplant recipients. Aside from reduction of immunosuppression, few therapeutic options exist for treatment of PVAN. We report a case of PVAN in a severely immunocompromised allogeneic HSC transplant recipient that was treated with brincidofovir without reduction of immunosuppression. We review our institutional experience of PVAN in HSC transplantation and discuss the potential use of brincidofovir for treatment.

Long-term safety and efficacy of a once-daily regimen of emtricitabine, didanosine, and efavirenz in HIV-infected, therapy-naive children and adolescents: Pediatric AIDS Clinical Trials Group Protocol P1021.

BACKGROUND: Compliance with complex antiretroviral therapy regimens is a problem for HIV-1-infected children and their families. Simple, safe, and effective regimens are important for long-term therapeutic success. METHODS: A novel, once-daily dosing regimen of 3 antiretroviral drugs, emtricitabine, didanosine, and efavirenz, was tested in 37 therapy-naive HIV-infected children and adolescents between 3 and 21 years of age (inclusive). Subjects were followed for > or = 96 weeks on an intention-to-treat basis. Signs, symptoms, plasma HIV-1 RNA viral load, CD4 counts, and safety laboratories were followed regularly. End points were the proportion of subjects with plasma HIV < 400 or 50 HIV copies per mL and safety and tolerability of the regimen. RESULTS: Thirty-seven subjects enrolled at 16 sites. Two subjects with rashes during the first 2 weeks of therapy were the only adverse events leading to study-drug discontinuation. Other early (before protocol-scheduled conclusion) study discontinuations included 3 viral failures on treatment and 5 patients who stopped therapy for apparently nonmedical reasons. Possible drug-related adverse events included 1 grade 4 low-glucose and 5 varied grade 3 events. There were no deaths. Virologic outcomes demonstrated that 32 (85%) of 37 subjects achieved viral suppression to < 400 RNA copies per mL, and 26 (72%) of 37 subjects maintained sustained suppression at < 50 copies per mL through week 96. The median baseline CD4 count was 310 per microL (17%), which increased at week 96 by a median of +329 cells per microL (by +18% CD4). Pharmacokinetic results were as predicted for emtricitabine, didanosine, and efavirenz capsules, whereas efavirenz concentrations in children receiving efavirenz oral solution were lower than anticipated, requiring a dose escalation after the planned assessment point. CONCLUSIONS: A once-daily regimen of emtricitabine, didanosine, and efavirenz proved to be safe and tolerable and demonstrated good immunologic and virologic efficacy in this 2-year study.

Pharmacokinetic evaluation of emtricitabine in combination with other nucleoside antivirals in healthy volunteers.

Emtricitabine is a potent nucleoside reverse transcriptase inhibitor approved as a once-daily drug in combination with other antiretroviral agents for the treatment of HIV infection. Several phase I studies were conducted in healthy volunteers over the course of clinical development to evaluate whether pharmacokinetic drug-drug interactions exist between emtricitabine and other nucleoside antivirals that are extensively eliminated by renal excretion. Potential interactions with stavudine and famciclovir were evaluated in single-dose studies, whereas interactions with zidovudine and its major metabolite, zidovudine glucuronide, were evaluated in a multiple-dose study. Plasma pharmacokinetic profiles and, in some studies, urinary excretion data were evaluated when each drug was administered alone and in combination with emtricitabine. Safety and plasma pharmacokinetic profiles of each drug administered alone or with emtricitabine were consistent with historical data. Statistical analyses indicated that there were no significant interactions between emtricitabine and these 3 nucleoside antivirals.

Steady-state pharmacokinetics of emtricitabine and tenofovir disoproxil fumarate administered alone and in combination in healthy volunteers.

The approved antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate, were considered good candidates for a fixed-dose combination product that could be administered as a single pill once daily (qd), thereby simplifying existing treatment regimens and promoting patient adherence. As both drugs are extensively renally eliminated, a randomized, 3-way crossover study was conducted in 19 healthy volunteers to formally evaluate the potential pharmacokinetic interaction when the drugs are administered alone and together (ie, 200 mg emtricitabine qd for 7 days, 300 mg tenofovir disoproxil fumarate qd for 7 days, and 200 mg emtricitabine plus 300 mg tenofovir disoproxil fumarate qd for 7 days) with no washout between treatments. Steady-state pharmacokinetic parameters (AUC(tau), C(max), and C(min)) of emtricitabine and tenofovir (as tenofovir disoproxil fumarate) in combination were essentially equivalent versus each drug alone, providing a pharmacokinetic rationale for combining these products in emtricitabine/tenofovir disoproxil fumarate fixed-dose tablets.

Pharmacokinetics of tenofovir disoproxil fumarate and ritonavir-boosted saquinavir mesylate administered alone or in combination at steady state.

A phase I study was conducted to formally evaluate the steady-state pharmacokinetics (PK) of tenofovir disoproxil fumarate (TDF) and ritonavir (RTV)-boosted saquinavir mesylate (SQV) when coadministered in healthy volunteers. Forty subjects received multiple doses of TDF (300 mg, once daily) and SQV/RTV (1,000 mg/100 mg, twice daily) alone and together under steady-state conditions in an open-label, fixed sequence design. Blood samples for tenofovir (TFV) and SQV/RTV PK were drawn over respective 24- and 12-h dosing intervals, and drug concentrations were measured by liquid chromatography-tandem mass spectrometry. Safety was assessed periodically by clinical and laboratory monitoring. Thirty-two subjects completed the study and were fully evaluable; three subjects discontinued participation in the study due to adverse events, three subjects withdrew for personal reasons, and two subjects withdrew because of inadequate venous access for blood sampling. Steady-state TFV PK were not significantly altered upon coadministration with SQV/RTV. Steady-state SQV (administered as SQV/RTV) AUCtau, Cmax, and Ctau increased 29, 22, and 47%, respectively, upon coadministration with TDF, and all subjects achieved a Ctau of >100 ng/ml. These modestly increased SQV exposures are not clinically meaningful given its clinical use with RTV already results in >10-fold-higher SQV levels. Steady-state RTV AUCtau and Cmax levels were not significantly altered, whereas Ctau was 23% higher upon coadministration of SQV/RTV and TDF. Thus, no clinically relevant interactions between TDF and RTV-boosted SQV were observed under conditions simulating clinical practice.

Pharmacokinetics and safety of single oral doses of emtricitabine in human immunodeficiency virus-infected children.

Emtricitabine (FTC; Emtriva), a potent deoxycytidine nucleoside reverse transcriptase inhibitor, has recently been approved by the U.S. Food and Drug Administration for the treatment of human immunodeficiency virus (HIV) infection. In adults, FTC has demonstrated linear kinetics over a wide dose range, and FTC 200 mg once a day (QD) is the recommended therapeutic dose. A phase I open-label trial was conducted in children to identify an FTC dosing regimen that would provide comparable plasma exposure to that observed in adults at 200 mg QD. Two single oral doses of FTC (60 and 120 mg/m(2), up to a maximum of 200 mg, in solutions) were evaluated in HIV-infected children aged <18 years old. Children >/=6 years old also received a third dose of approximately 120 mg/m(2) in capsules. A total of 25 children (two <2 years old, eight 2 to 5 years old, eight 6 to 12 years old, and seven 13 to 17 years old) received at least two doses of FTC. Single escalating oral doses of FTC were well tolerated and produced dose-proportional plasma drug concentrations in children. The FTC pharmacokinetics was comparable between adults and children 22 months to 17 years of age. The capsule formulation provided approximately 20% higher plasma FTC exposure than the solution formulation. Using plasma area under the concentration-time curve (AUC) data at the 120-mg/m(2) dose, it is projected (based on dose proportionality) that a 6-mg/kg dose (up to a maximum of 200 mg) of FTC would produce plasma AUCs in children comparable to those in adults given a 200-mg dose (i.e., median of approximately 10 h. micro g/ml). This pediatric FTC dose is being evaluated in long-term phase II therapeutic trials in HIV-infected children.