Long-term safety and efficacy results of once-daily emtricitabine-based highly active antiretroviral therapy regimens in human immunodeficiency virus-infected pediatric subjects.

OBJECTIVES: The purpose of this work was to obtain long-term safety and efficacy data for antiretroviral regimens containing emtricitabine in HIV-infected pediatric subjects and confirm that a pediatric dose of 6 mg/kg once daily would provide steady-state emtricitabine concentrations comparable to those observed in adults given 200 mg of emtricitabine once daily. PATIENTS AND METHODS: HIV-infected subjects between 3 months and 16 years of age were enrolled, including 71 antiretroviral-naïve subjects and 45 antiretroviral-experienced subjects. Naive subjects received emtricitabine plus stavudine plus lopinavir or ritonavir. Experienced subjects replaced the lamivudine in their existing regimens with emtricitabine. Tolerance, safety, disease progression, and virologic and immunologic responses were evaluated. RESULTS: The Kaplan-Meier probability of persistent virologic response in the intent-to-treat population through week 164 at < or = 400 copies per mL and < or = 50 copies per mL was 74% and 62%, respectively. Three subjects (3%) discontinued the study for adverse events, 8 (7%) for virologic failure, and 1 died through a median follow-up of 164 weeks. The annualized incidence rate of grade 3 to 4 adverse events and grade 3 to 4 laboratory abnormalities was 6% and 3%, respectively. The annualized incidence rate of serious adverse events was 9%, with 1% attributed as related to emtricitabine. Genotypic analysis showed the emergence of the M184V mutation in 4 of the 15 subjects who experienced virologic failure through week 164. Pharmacokinetic evaluation demonstrated plasma drug exposures in these children comparable to adults receiving the approved dose of 200 mg once daily. CONCLUSIONS: These results demonstrate the safety and efficacy of emtricitabine in pediatric patients. They also support that the safety and efficacy profile of emtricitabine in children is similar to that demonstrated in adults.

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.

A phase II dose-escalating trial of clevudine in patients with chronic hepatitis B.

Current therapies available for the treatment of chronic hepatitis B are limited in their ability to result in a cure. Clevudine is a new pyrimidine analog with potent anti-hepatitis B virus (HBV) activity in vitro. A multicenter dose-escalation study evaluated clevudine at 10, 50, 100, and 200 mg once daily for 28 days. Eligible patients had HBV DNA levels of 3 x 10(6) copies/mL or more, had not undergone nucleoside treatment, and were without human immunodeficiency or hepatitis C virus coinfection. Thirty-two patients were enrolled (5, 10, 10, and 7 patients in the 10-, 50-, 100-, and 200-mg dose groups, respectively), 81% were male, 81% Asian, and 88% were hepatitis Be antigen (HBeAg) positive at baseline. Median pretreatment serum HBV DNA levels ranged from 7.3 to 8.8 log(10) copies/mL. After 28 days, the median HBV DNA log(10) change from baseline was -2.5, -2.7, -3.0, and -2.6 log(10). Six months after dosing, median changes from baseline were -1.2, -1.4, -2.7 and -1.7 log(10) in the 10-, 50-, 100-, and 200-mg cohorts, respectively. Six of 27 patients lost HBeAg, and 3 of 27 patients seroconverted to HBe antibody. Clevudine was well tolerated, with no dose-limiting toxicities. A transient increase in alanine aminotransferase of up to 7.8 times the upper limit of normal (increase ranged from 20 to 186 IU/L) was observed in six patients in the 100-mg cohort, without signs of liver failure. These increases were associated with improved viral suppression. The pharmacokinetic profile of clevudine was proportional to the dose. In conclusion, these results demonstrate the tolerability and potent activity of clevudine in HBV-infected patients and support further clinical study.

Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: analysis and review of the literature.

Currently, compounds under evaluation for treatment of chronic hepatitis B virus (HBV) infection are evaluated with liver histology as the primary end point for efficacy. However, because of practical limitations in serial liver biopsies, there is a need for alternate markers to assess efficacy over shorter periods of time. Considering the direct correlation between viral replication and disease progression during human immunodeficiency virus and hepatitis C virus infection, we explored whether such a correlation exists for HBV infection. We reviewed the literature and conducted an analysis to investigate the relationship between absolute or treatment-induced changes in HBV DNA levels and other accepted markers of disease activity. A total of 26 prospective studies met our selection criteria, including 33 evaluable treatment arms. The study treatments consisted of nucleosides and/or interferon regimens and control arms. We found statistically significant and consistent correlations between viral load level or change and histologic grading and biochemical and serologic response. Our analysis suggests that a treatment-induced reduction in HBV DNA level can be used for assessing efficacy of treatment regimens. Further, we observed that quantitative HBV DNA has a broader dynamic range than histology, allowing demonstration of differences between 2 active treatments of unequal potency. The analysis showed stronger results in studies using nucleoside regimens and in hepatitis B e antigen (HBeAg)-positive patients. In conclusion, the goal of anti-HBV therapy should be profound and durable viral suppression, as defined by very sensitive assays. Additional prospective studies are needed to precisely determine the desirable level of viremia to attain.