Levels of adherence required for virologic suppression among newer antiretroviral medications.

OBJECTIVE: To determine the adherence levels needed for HIV virologic suppression with newer antiretroviral (ARV) medications, including darunavir, etravirine, and raltegravir. DATA SOURCES: Literature searches of PubMed, MEDLINE (1950-October 2010), and Google Scholar were performed using the following key words in multiple combinations: antiretroviral, HIV, AIDS, adherence, darunavir, raltegravir, and etravirine. A review of the bibliographies of retrieved articles was performed to identify additional references. STUDY SELECTION AND DATA EXTRACTION: All articles in English were identified from the data sources and evaluated. Studies that did not state names of medications or drug classes studied were excluded. DATA SYNTHESIS: There are differing levels of adherence needed to maintain virologic suppression, depending on the ARV class used. The adherence level needed for unboosted protease inhibitors (PIs) has been established as greater than 95%, but recent studies have shown that greater than 80% adherence to boosted PIs may be sufficient. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) could require lower adherence rates than boosted PIs; however, study results are varied and NNRTIs carry a potential for developing resistance with nonadherence. Studies assessing the adherence needed for raltegravir have yet to be performed. CONCLUSIONS: Studies have shown differing levels of adherence needed among ARV classes of medications. With the advent of boosted PIs and potent medications, the amount of adherence needed has dropped since the 1990s. Although the current data are useful, there are discrepancies in the results due to the methods of adherence measurement. Knowing what adherence levels are needed is valuable in helping to determine the optimal ARV regimen for patients, given their adherence barriers. This knowledge can also help determine which patients require in-depth adherence counseling. Further research with a reliable method of measuring adherence is essential to determine adherence levels needed for newer ARV medications, including darunavir, etravirine, and raltegravir.

Antiretroviral therapy : pharmacokinetic considerations in patients with renal or hepatic impairment.

Hepatic and renal insufficiency due to co-infection, alcoholism, diabetes mellitus, family history, adverse effects of antiretrovirals and other factors are commonly seen in HIV-infected patients. Therefore, the use of antiretrovirals in this patient setting requires attention to the pharmacokinetic issues that clinicians must consider when prescribing highly active antiretroviral therapy for these patients. This review summarizes the current knowledge of the use of antiretrovirals in patients with hepatic or renal impairment, and makes dosing recommendations for this subpopulation of HIV-infected patients.

Randomized, double-masked, placebo-controlled study to assess the ocular safety of mirabegron in healthy volunteers.

PURPOSE: This study assessed the effect of mirabegron on ocular safety in healthy volunteers. METHODS: This was an 8-week, randomized, double-masked, placebo-controlled study. PARTICIPANTS: Consenting adults aged ≥18 years with a normal intraocular pressure (IOP, ≥10 to ≤21 mmHg) were eligible to enter the study. Of the 321 randomized subjects, 305 completed the study. Subjects were randomized 1:1 to a supratherapeutic dose of oral mirabegron 100 mg or placebo once daily for 56 days. The IOP was measured at screening, baseline, day 10, and day 56/end of treatment using Goldmann applanation tonometry. Visual acuity and biomicroscopy were also evaluated. The primary endpoint was the mean change from baseline in the IOP at 56 days or end of treatment with mirabegron versus placebo. Secondary outcome variables included change from baseline to day 10 in the IOP, and increases in the IOP of ≥6 mmHg and ≥10 mmHg in either eye from baseline to day 10 and day 56. RESULTS: The mean (standard error, SE) IOP at baseline was 15.3 (0.16) mmHg for mirabegron and 15.4 (0.16) mmHg for placebo; values at day 56 were 15.0 (0.16) mmHg and 15.2 (0.17) mmHg, respectively. The adjusted mean IOP change from baseline to day 56 was -0.3 mmHg for mirabegron and -0.2 mmHg for placebo (-0.1 mmHg difference [95% confidence interval, CI, -0.4 to 0.3]). For the primary endpoint, mirabegron was noninferior to placebo, based on the prespecified limit of 1.5 mmHg. No statistically significant treatment effects on the IOP were seen at day 10. No subject discontinued due to increased IOP. Clinically significant increases from baseline in the IOP occurred rarely and only with placebo treatment. Changes in the visual acuity and biomicroscopy were not suggestive of a mirabegron effect. No treatment-emergent adverse event (AE) of glaucoma was reported. CONCLUSIONS: Mirabegron 100 mg orally once daily for 8 weeks of treatment does not increase the IOP, and was generally safe and well tolerated.

Essentials for starting a pediatric clinical study (4): Clinical pediatric safety planning based on preclinical toxicity studies and pediatric pharmacovigilance guidance.

Juvenile toxicology studies in animals provide useful information to guide monitoring of potential adverse effects in children especially on growth and development. In order to continue to gain knowledge and build upon these preclinical studies, recent experience has suggested that additional approaches for monitoring of safety concerns in the pediatric population may be required. Recently, pediatric guidance has become available from the health authorities which provide pharmacovigilance concepts as they specifically relate to drugs being developed for pediatric indications. Clinical trials are typically not robust enough to detect rare or delayed safety effects as the pediatric trials are relatively short-term. Furthermore, such long term or rare effects may not be detected via standard voluntary postmarketing surveillance. Safety monitoring of children with Juvenile Inflammatory Arthritis (JIA) taking nonsteroid anti-inflammatory drug (NSAID)s will be used as an example to describe a post-marketing risk management and pharmacovigilance program that serves to better evaluate safety data from various sources. The intent of this program is to identify adverse events (AE), including events with longer latency, which may be associated with NSAID use in a pediatric population. In this presentation, the 4 major components of the program are to be addressed. Such a program may serve as a model to proactively generate and monitor safety data in order to identify AEs that may be associated with new therapeutics for a pediatric population.