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Rilpivirine (RPV, TMC278, Edurant®) is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), which demonstrated high virologic response rates and non-inferiority versus efavirenz in two Phase III trials in HIV-infected patients through 96 weeks [,]. RPV has been shown to inhibit P-glycoprotein (P-gp) in vitro with an apparent IC50 of 9.2 µM (3.4 µg/mL). This study evaluated the in-vivo effect of steady-state RPV 25 mg once daily (qd) on the single-dose pharmacokinetics of the probe P-gp substrate digoxin. This was a Phase I, open-label, randomised, crossover trial in 22 HIV-negative volunteers. Participants received in one session a single 0.5 mg dose of digoxin, and in another session RPV 25 mg qd for 16 days with a single 0.5 mg dose of digoxin in the morning of Day 11. All study drugs were taken with a breakfast. Pharmacokinetic profiles of digoxin in plasma and urine were determined over 144 hours after dosing in each session. Steady-state RPV 24-hour pharmacokinetic profiles in plasma were determined on Day 11. Plasma and urine samples were analysed using validated LC-MS/MS methods. Pharmacokinetic parameters were calculated with non-compartmental methods. The least square (LS) means and associated 90% confidence intervals (CI) of treatment ratios were calculated based on log-transformed pharmacokinetic parameters. Safety and tolerability were assessed throughout the trial. Digoxin pharmacokinetic parameters and statistical results are summarised in . [ABSTRACT FROM AUTHOR]

Background: Currently available antiretroviral 2-drug regimen (2DR) fixed dose combinations may not be suitable for specific situations including the presence of resistance associated mutations (RAM) or drug − drug interactions (DDI). The data on the use of the non-nucleoside reverse transcriptase inhibitor doravirine (DOR) and the integrase inhibitor dolutegravir (DTG) as an alternative 2DR remain scarce. Methods: People living with HIV with DOR + DTG as a 2DR are being followed in a prospective observational study. Results: This analysis describes 85 participants with a median age of 57 years. Median CD4-nadir was 173/µl and a majority (66%) had a history of HIV-associated or AIDS-defining conditions. Antiretroviral history was mostly extensive, and documentation of RAM was frequent. The main reasons for choosing DOR + DTG were DDI (29%), tolerability (25%), and cardiovascular risk reduction (21%). Plasma viral load at switch was < 50 copies/ml in all but 3 instances, median CD4 count was 600/µl. DOR + DTG was later changed to another regimen in 10 participants after a median of 265 days, the other 75 participants have remained on DOR + DTG for a median of 947 days. Conclusion: DOR + DTG as a 2DR proved to be a durable treatment option even in extensively pretreated individuals. [ABSTRACT FROM AUTHOR]

Background Previously reported post hoc multivariable analyses exploring predictors of confirmed virologic failure (CVF) with cabotegravir + rilpivirine long-acting (CAB + RPV LA) were expanded to include data beyond week 48, additional covariates, and additional participants. Methods Pooled data from 1651 participants were used to explore dosing regimen (every 4 or every 8 weeks), demographic, viral, and pharmacokinetic covariates as potential predictors of CVF. Prior dosing regimen experience was accounted for using 2 populations. Two models were conducted in each population—baseline factor analyses exploring factors known at baseline and multivariable analyses exploring baseline factors plus postbaseline model-predicted CAB/RPV trough concentrations (4 and 44 weeks postinjection). Retained factors were evaluated to understand their contribution to CVF (alone or in combination). Results Overall, 1.4% (n = 23/1651) of participants had CVF through 152 weeks. The presence of RPV resistance-associated mutations, human immunodeficiency virus-1 subtype A6/A1, and body mass index ≥30 kg/m2 were associated with an increased risk of CVF (P <.05 adjusted incidence rate ratio), with participants with ≥2 of these baseline factors having a higher risk of CVF. Lower model-predicted CAB/RPV troughs were additional factors retained for multivariable analyses. Conclusions The presence of ≥2 baseline factors (RPV resistance-associated mutations, A6/A1 subtype, and/or body mass index ≥30 kg/m2) was associated with increased CVF risk, consistent with prior analyses. Inclusion of initial model-predicted CAB/RPV trough concentrations (≤first quartile) did not improve the prediction of CVF beyond the presence of a combination of ≥2 baseline factors, reinforcing the clinical utility of the baseline factors in the appropriate use of CAB + RPV LA. [ABSTRACT FROM AUTHOR]

NK-4 plays a key role in the treatment of various diseases, such as in hay fever to expect anti-allergic effects, in bacterial infections and gum abscesses to expect anti-inflammatory effects, in scratches, cuts, and mouth sores from bites inside the mouth for enhanced wound healing, in herpes simplex virus (HSV)-1 infections for antiviral effects, and in peripheral nerve disease that causes tingling pain and numbness in hands and feet, while NK-4 is used also to expect antioxidative and neuroprotective effects. We review all therapeutic directions for the cyanine dye NK-4, as well as the pharmacological mechanism of NK-4 in animal models of related diseases. Currently, NK-4, which is sold as an over-the-counter drug in drugstores, is approved for treating allergic diseases, loss of appetite, sleepiness, anemia, peripheral neuropathy, acute suppurative diseases, wounds, heat injuries, frostbite, and tinea pedis in Japan. The therapeutic effects of NK-4's antioxidative and neuroprotective properties in animal models are now under development, and we hope to apply these pharmacological effects of NK-4 to the treatment of more diseases. All experimental data suggest that different kinds of utility of NK-4 in the treatment of diseases can be developed based on the various pharmacological properties of NK-4. It is expected that NK-4 could be developed in more therapeutic strategies to treat many types of diseases, such as neurodegenerative and retinal degenerative diseases. [ABSTRACT FROM AUTHOR]

The article presents guidelines given by the British HIV Association (BHIVA) on best clinical practice for antiretroviral therapy (ART) and management of adults living with human immunodeficiency virus (HIV). Topics discussed include involvement of people living with HIV, primary aim of ART, and considerations when managing people with spontaneous HIV viral control.

Recent clinical trial data showed that injectable long-acting antiretroviral treatment (LA-ART) every four or eight weeks could become an alternative option for HIV treatment or prevention. The purpose of our study was to explore perceptions and potential users' points of views of this new mode of administration through individuals' therapeutic itinerary and their singular history with ART. Between 2018 and 2019, a qualitative study was conducted in two University Hospitals in Paris, France. In-depth interviews were conducted with 15 virologically controlled People Living with HIV (PLWH) and 13 men on pre-exposure prophylaxis (PrEP) for at least six months. Interviews, focused on the daily experience with ART, were recorded, transcribed, and analyzed using thematic content analysis. Collected discourses were organized around three emergent concerns: social, material and experimental. Each of these concerns was perceived as ambivalent, balanced by skepticism and hope. It revealed the complexity of each individual's relationship to their HIV treatment or PrEP, leading to balance the injectable LA-ART popularity reported within clinical trials. This new mode of administration may be a suitable alternative for some PLWH and PrEP users, a "simplification" compared to the oral route. It opens a window for "customizable" ART-treatment according to individuals' lives. [ABSTRACT FROM AUTHOR]

Recently, the US Food and Drug Administration and European Medicines Agency issued warnings on the use of dolutegravir and darunavir/cobicistat for treatment of pregnant women living with human immunodeficiency virus (HIV). It took 3–5 years to identify the risks associated with the use of these antiretroviral drugs, during which time pregnant women were exposed to these drugs in clinical care, outside of controlled clinical trial settings. Across all antiretroviral drugs, the interval between registration of new drugs and first data on pharmacokinetics and safety in pregnancy becoming available is around 6 years. In this viewpoint, we provide considerations for clinical pharmacology research to provide safe and effective treatment of pregnant and breastfeeding women living with HIV and their children. These recommendations will lead to timelier availability of safety and pharmacokinetic information needed to develop safe treatment strategies for pregnant and breastfeeding women living with HIV, and are applicable to other chronic disease areas requiring medication during pregnancy. [ABSTRACT FROM AUTHOR]

Introduction: The number of older HIV-infected people is growing due to increasing life expectancies resulting from the use of antiretroviral therapy (ART). Both HIV and aging increase the risk of other comorbidities, such as cardiovascular disease, osteoporosis, and some malignancies, leading to greater challenges in managing HIV with other conditions. This results in complex medication regimens with the potential for significant drug-drug interactions and increased morbidity and mortality. Area covered: We review the metabolic pathways of ART and other medications used to treat medical co-morbidities, highlight potential areas of concern for drug-drug interactions, and where feasible, suggest alternative approaches for treating these conditions as suggested from national guidelines or articles published in the English language. Expert commentary: There is limited evidence-based data on ART drug interactions, pharmacokinetics and pharmacodynamics in the older HIV-infected population. Choosing and maintaining effective ART regimens for older adults requires consideration of side effect profile, individual comorbidities, interactions with concurrent prescriptions and non-prescription medications and supplements, dietary patterns with respect to dosing, pill burden and ease of dosing, cost and affordability, patient preferences, social situation, and ART resistance history. Practitioners must remain vigilant for potential drug interactions and intervene when there is a potential for harm. [ABSTRACT FROM PUBLISHER]

Introduction: People at high risk for HIV acquisition should be offered pre-exposure prophylaxis (PrEP). Tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) is currently the only medication recommended for pre-exposure prophylaxis (PrEP) by the Centers for Disease Control and Prevention (CDC) in people at high risk for HIV acquisition. This article will review medications currently under investigation and the future landscape of PrEP therapy. Areas covered: This article will review clinical trials that have investigated nontraditional regimens of TDF/FTC, antiretroviral agents from different drug classes such as integrase strand transfer inhibitors (INSTI), nucleoside reverse transcriptase inhibitors (NRTI), and non-nucleoside reverse transcriptase inhibitors (NNRTI) as potential PrEP therapies. Expert commentary: Currently, there are several investigational drugs in the pipeline for PrEP against HIV infection. Increased utilization of PrEP therapy depends on provider identification of people at high risk for HIV transmission. Advances in PrEP development will expand options and access for people and reduce the risk of HIV acquisition. [ABSTRACT FROM AUTHOR]

Current antiretroviral therapy reaches and maintains viral suppression over the years in more than 90% of treated HIV-infected individuals. Although integrase inhibitors are the preferred third agent in antiretroviral therapy in the current guidelines, rilpivirine, a non-nucleoside reverse transcriptase inhibitor, and darunavir (DRV), a second-generation protease inhibitor, are the preferred third companion to be used along with a backbone of two nucleos(t)ide reverse transcriptase inhibitors as first-line triple HIV combination treatment. However, rilpivirine is not recommended in patients with plasma HIV-RNA above 100,000 copies/mL. Raltegravir requires uncomfortably twice daily dosing, whereas dolutegravir is often given as coformulation with abacavir, a drug that requires prior HLA-B5701 testing. Antiretroviral combinations based on DRV provide a unique robustness in terms of antiviral potency and resistance barrier, rendering this drug pivotal as part of rescue regimens for the treatment failures. Furthermore, dual antiretroviral therapy with DRV plus lamivudine has been tested with success as maintenance therapy. Finally, DRV has demonstrated its safety and efficacy in special patient populations, including pregnant women, pediatrics, HIV-2 infection, and individuals coinfected with viral hepatitis. Single-tablet regimens containing DRV coformulated with cobicistat alone or with other antiretrovirals should improve drug adherence. These fixed-dose combinations represent a step forward universal antiretroviral regimen, ensuring maximal efficacy, tolerability, and convenience. [ABSTRACT FROM AUTHOR]

Introduction: Tuberculosis (TB) is the most prevalent opportunistic infection among HIV patients, and the leading cause of death among HIV patients worldwide. Simultaneous treatment of both diseases is recommended by current guidelines, but can be challenging due to the potential for drug-drug interactions, overlapping toxicities, difficulty adhering to medications, and an increased risk for immune reconstitution inflammatory syndrome (IRIS). Clinical manifestations of TB can also vary between HIV-infected patients and uninfected patients, which can increase the risk for delayed diagnosis. Areas covered: Topics covered in this review include the following: the inter-related pathophysiology of HIV and TB; clinical manifestations and diagnosis; drug-drug interactions, particularly the rifamycins with the antiretrovirals; IRIS presentation and treatment, as well as a discussion on overlapping toxicity between the two disease states. Expert commentary: The complexity of managing these two disease states simultaneously requires a multidisciplinary approach to care and dedicated resources. If properly funded, TB/HIV co-infection will continue to decline over the coming years. [ABSTRACT FROM AUTHOR]

Introduction: Co-formulated rilpivirine, emtricitabine and tenofovir alafenamide (RPV/F/TAF) is the 6th single-tablet combination antiretroviral medication approved within the past decade for the treatment of HIV-1 infection. It was approved based on positive bioequivalence studies with already approved drugs with its component compounds, RPV and the single tablet regimen- elvitegravir, cobicistat, F/TAF. Areas covered: This article reviews the chemical, pharmacodynamic and pharmacokinetic properties, key drug interactions, and the efficacy, safety, tolerability and optimal clinical uses of the medication and/or its components in different patient populations. The article incorporates pre-clinical and clinical trial data available from Google, Google scholar, PubMed database, conference abstracts as well as US FDA approved drug prescribing information up till September 30, 2016. Expert commentary: RPV/F/TAF is a once-daily administered, well tolerated, and effective antiretroviral regimen that should be taken with a meal. Desirable properties include less neuropsychiatric toxicity than 1st generation non-nucleoside reverse transcriptase inhibitors, better bone and renal safety than tenofovir disoproxil fumarate containing regimens and it may be used in individuals with a creatinine clearance >30 mL/min. A five-year future view of the role of oral antiretroviral drug therapy as well as evolving treatment options for HIV-infected patients are also discussed in the article. [ABSTRACT FROM AUTHOR]

Introduction: Little information is available on the efficacy and safety of the dual combination of ripivirine plus dolutegravir. This work aims at beginning to fill this gap. Methods: All HIV-1 infected subjects treated with ripivirine plus dolutegravir between October 2014 and September 2015 in eight Italian centres were included in an observational cohort. Data were collected at baseline and at weeks 4, 12, 24 and 48. Results: One hundred and thirty-two subjects were followed for a median of 24 months, mean 33 months. One subject discontinued the study drug at week 24 for headache, one for drug interaction and one died after week 24 of illicit drug abuse. The mean age was 51.8, females 31.7% and non-caucasians 10%. Fifty-seven (43.2%) had at least one failure in their treatment history. Reasons for switching were simplification (53.0%), toxicity (34.8%), drug interactions (n = 7), persistent low-level viremia (n = 4), non-adherence (n = 3) and viral failure (n = 2). Sixty patients (45.5%) had reverse transcriptase (RT) mutations and 69 (44,7%) had protease (PR) mutations. Sixteen had baseline viral replication, 27 had < 50 HIV-1 RNA copies/mL and in 89 (67.4%) no virus was detected (NVD, 0 copies/mL). At w4, 114 (86.4%) had NVD, 15 had 1 to 49 HIV-1 RNA copies/mL and 3 had 50 to 57 copies/mL. At week 24 one subject had viral rebound without mutations due to missed drug refill, 19 had 1 to 49 copies/mL, and 112 had NVD. All 132 subjects were tested at weeks 4 and 24. Of the 50 subjects who had a 48-week follow-up, one had a treatment interruption, four had 1 to 49 copies/mL and 45 had NVD. Among the entire population, one subject had low-level, one intermediate and 4 high-level resistance to rilpivirine: none failed by week 48. Mean serum creatinine increased by +0.1 mg/dL. During the follow-up one patient reported headache and insomnia. Conclusions: Ripivirine plus dolutegravir proved safe and effective in this cohort of non-naïve HIV-1 infected subjects. [ABSTRACT FROM AUTHOR]

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Drug-drug interactions between antiretroviral therapy and other drugs are well described. Gastric acid-reducing agents are one such class. However, few data exist regarding the frequency of and indications for prescription, nor risk assessment in the setting of an HIV cohort receiving antiretroviral therapy. To assess prevalence of prescription of gastric acid-reducing agents and drug-drug interaction within a UK HIV cohort, we reviewed patient records for the whole cohort, assessing demographic data, frequency and reason for prescription of gastric acid-reducing therapy. Furthermore, we noted potential drug-drug interaction and whether risk had been documented and mitigated. Of 701 patients on antiretroviral therapy, 67 (9.6%) were prescribed gastric acid-reducing therapy. Of these, the majority (59/67 [88.1%]) were prescribed proton pump inhibitors. We identified four potential drug-drug interactions, which were appropriately managed by temporally separating the administration of gastric acid-reducing agent and antiretroviral therapy, and all four of these patients remained virally suppressed. Gastric acid-reducing therapy, in particular proton pump inhibitor therapy, appears common in patients prescribed antiretroviral therapy. Whilst there remains a paucity of published data, our findings are comparable to those in other European cohorts. Pharmacovigilance of drug-drug interactions in HIV-positive patients is vital. Education of patients and staff, and accurate data-gathering tools, will enhance patient safety. [ABSTRACT FROM AUTHOR]

Background: Paliperidone (9-hydroxyrisperidone), the major active metabolite of risperidone, has been introduced as a novel atypical antipsychotic agent in many countries. It is available both as an oral extended-release (ER) formulation and as a long-acting injection (paliperidone palmitate, PP), which have been approved for treating schizophrenia in the People's Republic of China since 2009 and 2012, respectively. This systematic review summarizes the efficacy, effectiveness, and safety of paliperidone in the treatment of schizophrenia in the Chinese population. Methods: A systematic literature search was conducted on the databases covering international and Chinese core journals, published from January 1, 2008, to May 22, 2015. Results: A total of 122 publications were retrieved, of which 63 studies were identified for inclusion; most studies were related to paliperidone ER (n=53), nine were related to PP, and one study was related to both agents. Paliperidone ER demonstrated at least comparable efficacy with active comparators, including risperidone, olanzapine, ziprasidone, or aripiprazole, and was found to be superior with respect to the onset of action and improvement in the Personal and Social Performance Scale score. Paliperidone ER appeared to be associated with a lower risk of metabolic syndromes; the most common treatment-emergent adverse events were extrapyramidal symptoms, akathisia, insomnia, and somnolence. Results from interventional and observational studies showed that PP was also an effective and well-tolerated treatment for Chinese patients with schizophrenia. The findings were generally consistent with those observed in non-Chinese populations. Conclusion: Both paliperidone ER and PP were effective and well-tolerated agents for the treatment of schizophrenia in the Chinese population according to the data we reviewed. No new safety signals specific for the Chinese population were raised for paliperidone. Further studies may be needed to collect more data on long-term treatment of schizophrenia in the People's Republic of China. [ABSTRACT FROM AUTHOR]

A number of antiviral agents used against Human Immunodeficiency Virus (HIV) infection and hepatitis B virus (HBV) mono or co-infection have been associated with real nephrotoxicity (including tenofovir disoproxil fumarate (TDF), atazanavir, indinavir and lopinavir) or apparent changes in renal function (e.g. cobicistat, ritonavir, rilpivirine and dolutegravir). Patients with HIV are at higher risk of acute and chronic renal dysfunction, so baseline assessment and ongoing monitoring of renal function is an important part of routine management of patients with HIV. Given the paucity of evidence in this area, we sought to establish a consensus view on how routine monitoring could be performed in Australian patients on ART regimens, especially those involving TDF. A group of nephrologists and prescribers (an HIV physician and a hepatologist) were assembled by Gilead to discuss practical and reasonable renal management strategies for patients particularly those on TDF-based combination regimens (in the case of those with HIV-infection) or on TDF-monotherapy (in the case of HBV-mono infection). The group considered which investigations should be performed as part of routine practice, their frequency, and when specialist renal referral is warranted. The algorithm presented suggests testing for serum creatinine along with plasma phosphate and an assessment of urinary protein (rather than albumin) and glucose. Here we advocate baseline tests of renal function at initiation of therapy. If creatinine excretion inhibitors (e.g. cobicistat or rilpivirine) are used as part of the ART regimen, we suggest creatinine is rechecked at 4 weeks and this value used as the new baseline. Repeat testing is suggested at 3-monthly intervals for a year and then at least yearly thereafter if no abnormalities are detected. In patients with abnormal baseline results, renal function assessment should be performed at least 6 monthly. In HBV mono-infected patients advocate that a similar testing protocol may be logical. [ABSTRACT FROM AUTHOR]

There is an urgent need for technologies to prevent sexual acquisition of HIV infection in young women in sub-Saharan Africa. After two decades of 11 pivotal trials of seven products, anti-retroviral-based topical microbicides are showing promise. Building on the CAPRISA 004 trial findings, several trials of new anti-viral agents, novel delivery mechanisms and combination/multipurpose products that address challenges of adherence and meet the sexual and reproductive health needs of men and women, including preventing HIV infection, are underway. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) causes approximately 2.5 million new infections every year, and nearly 1.6 million patients succumb to HIV each year. Several factors, including cross-species transmission and error-prone replication have resulted in extraordinary genetic diversity of HIV groups. One of these groups, known as group M (main) contains nine subtypes (A-D, F-H and J-K) and causes ~95% of all HIV infections. Most reported data on susceptibility and resistance to anti-HIV therapies are from subtype B HIV infections, which are prevalent in developed countries but account for only ~12% of all global HIV infections, whereas non-B subtype HIV infections that account for ~88% of all HIV infections are prevalent primarily in low and middle-income countries. Although the treatments for subtype B infections are generally effective against non-B subtype infections, there are differences in response to therapies. Here, we review how polymorphisms, transmission efficiency of drug-resistant strains, and differences in genetic barrier for drug resistance can differentially alter the response to reverse transcriptase-targeting therapies in various subtypes. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) and HIV continue to be two of the major causes of morbidity and mortality in the world, and together are responsible for the death of millions of people every year. There is overwhelming evidence to recommend that patients with TB and HIV co-infection should receive concomitant therapy of both conditions regardless of the CD4 cell count level. The principles for treatment of active TB disease in HIV-infected patients are the same as in HIV-uninfected patients. However, concomitant treatment of both conditions is complex, mainly due to significant drug-drug interactions between TB and HIV drugs. Rifamycins are potent inducers of the cytochrome P450 (CYP) pathway, leading to reduced (frequently sub-therapeutic) plasma concentrations of some classes of antiretrovirals. Rifampicin is also an inducer of the uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzymes and interferes with drugs, such as integrase inhibitors, that are metabolized by this metabolic pathway. Rifampicin is also an inducer of the adenosine triphosphate (ATP) binding cassette transporter P-glycoprotein, which may also lead to decreased bioavailability of concomitantly administered antiretrovirals. On the other side, rifabutin concentrations are affected by the antiretrovirals that induce or inhibit CYP enzymes. In this review, the pharmacokinetic interactions, and the relevant clinical consequences, of the rifamycins-rifampicin, rifabutin, and rifapentine-with antiretroviral drugs are reviewed and discussed. A rifampicin-based antitubercular regimen and an efavirenz-based antiretroviral regimen is the first choice for treatment of TB/HIV co-infected patients. Rifabutin is the preferred rifamycin to use in HIV-infected patients on a protease inhibitor-based regimen; however, the dose of rifabutin needs to be reduced to 150 mg daily. More information is required to select optimal treatment regimens for TB/HIV co-infected patients whenever efavirenz cannot be used and rifabutin is not available. Despite significant pharmacokinetic interactions between antiretrovirals and antitubercular drugs, adequate clinical response of both infections can be achieved with an acceptable safety profile when the pharmacological characteristics of drugs are known, and appropriate combination regimens, dosing, and timing of initiation are used. However, more clinical research is needed for newer drugs, such as rifapentine and the recently introduced integrase inhibitor antiretrovirals, and for specific population groups, such as children, pregnant women, and patients affected by multidrug-resistant TB. [ABSTRACT FROM AUTHOR]

Objective We investigated the relationship between the plasma concentration of paliperidone (PAL) and clinical and drug-induced extrapyramidal symptoms (EPS) in elderly patients with schizophrenia. Methods In this study, 15 patients with schizophrenia receiving risperidone were switched to PAL and treated for 12 weeks. Their clinical symptoms were assessed using the Positive and Negative Syndrome Scale and the Clinical Global Impression-Severity of Illness Scale. Their EPS were assessed using the Drug-induced EPS Scale, Abnormal Involuntary Movement Scale, and Barnes Akathisia Scale at baseline and 12 weeks. Plasma concentrations were measured by the liquid chromatography-mass spectrometry/mass spectrometry method. Results The results revealed that there were significant correlations between the plasma concentration of PAL and improved Positive and Negative Syndrome Scale total, negative, and general psychopathology scores ( p < 0.05). However, the efficacy did not improve linearly with plasma level. No significant correlations were found between the PAL plasma concentration and the mean change from baseline in the Drug-induced EPS Scale total score, Barnes Akathisia Scale, or Abnormal Involuntary Movement Scale. Conclusions The results of this research suggested that, in elderly patients, although none of an increased plasma concentration of PAL, a worsening of EPS, or an increase in prolactin level occurs, linear clinical efficacy may not be obtained. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective. This study was to evaluate the effects on clinical symptoms and cognitive function of switching the treatment of elderly patients with schizophrenia from risperidone to paliperidone (PAL). Methods. This study was a 12-weeks, preliminary open-label trial. The subjects were 17 inpatients. Their extrapyramidal symptoms (EPS) were assessed using the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS), Abnormal Involuntary Movement Scale (AIMS), and Barnes Akathisia Scale (BAS), and their cognitive function was assessed using the Brief Assessment Cognition in Schizophrenia: Japanese language version (BACS-J), and their clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity of illness scale (CGI-S) at the 0 and 12 weeks. Results. The DIEPSS and BAS significantly improved after switching from risperidone to PAL. Furthermore, improvement was found on AIMS. The mean change from baseline in z-score of the digit sequencing task was significantly increased. All items on the PANSS and CGI-S were not significant; however, changes in some cognitive function were correlated with changes in EPS. Conclusions. The results of this study suggest the possibility that switching elderly patients from risperidone to PAL may have improved pre-existing EPS, and may also have helped improve working memory. [ABSTRACT FROM AUTHOR]

The combination rilpivirine (RPV)/emtricitabine (FTC)/tenofovir (TDF) is a oncedaily, single-tablet regimen (STR) containing one nonnucleoside reverse-transcriptase inhibitor associated with two nucleos(t)ide reverse transcriptase inhibitors. It is approved by regulatory agencies (eg, US Food and Drug Association, European Medicines Agency) in all countries in which it is manufactured, except Switzerland, as first-line highly active antiretroviral therapy (HAART) for the treatment of naïve patients with HIV infection and a viral load HIV-RNA level of ⩽100,000 copies/mL. Two large trials (ECHO and THRIVE) comparing RPV with efavirenz, along with different background regimens, led to approval of the drug, while a more recent trial (STaR) explored the use of STR. RPV showed noninferiority to efavirenz in all the studies, including superiority as an STR in patients with HIV-RNA ⩽100,000 copies/mL in the STaR study. A positive CD4 cell response was observed in all the studies, both in the RPV and efavirenz groups. The incidence of virologic failures was higher for RPV, but was mostly referred to patients with HIV-RNA ⩽100,000 copies/mL. There were fewer adverse events (AEs) with the RPV-based regimens versus efavirenz-based regimens, with a lower discontinuation rate because of AEs, especially psychiatric-neurological AEs, and a significantly lower rate of bloodlipid abnormalities. In the SPIRIT study (a switch study), significantly greater improvements from baseline in serum total cholesterol, low-density lipoprotein cholesterol, and trygliceride were demonstrated in patients switching to RPV/FTC/TDF from a ritonavir-boosted protease inhibitor (PI/r)-based regimen, than in those who continued treatment with a PI/r regimen. RPV's better tolerability, associated with its once-daily STR formulation, is key to improving patients' adherence and quality of life, which are among the most important factors affecting the therapeutic efficacy of an antiretroviral regimen. In summary, RPV/FTC/TDF STR is a valuable treatment option for the majority of antiretroviral-naïve HIV-infected patients. Furthermore, the use of this STR in the therapeutic switch, like in the SPIRIT study, can result in another valuable option by which to reduce AEs and improve patients' quality of life. [ABSTRACT FROM AUTHOR]

Global access to opioid agonist therapy and HIV/hepatitis C virus (HCV) treatment is expanding but when used concurrently, problematic pharmacokinetic and pharmacodynamic interactions may occur. Articles published from 1966 to 2012 in Medline were reviewed using the following keywords: HIV, AIDS, HIV therapy, HCV, HCV therapy, antiretroviral therapy, highly active antiretroviral therapy, drug interactions, methadone and buprenorphine. In addition, a review of abstracts from national and international meetings and conference proceedings was conducted; selected reports were reviewed as well. The metabolism of both opioid and antiretroviral therapies, description of their known interactions and clinical implications and management of these interactions were reviewed. Important pharmacokinetic and pharmacodynamic drug interactions affecting either methadone or HIV medications have been demonstrated within each class of antiretroviral agents. Drug interactions between methadone, buprenorphine and HIV medications are known and may have important clinical consequences. Clinicians must be alert to these interactions and have a basic knowledge regarding their management. [ABSTRACT FROM AUTHOR]

Fixed-dose combination tablets have become an important therapy option for patients infected with the human immunodeficiency virus. Fixed-dose combination rilpivirine-tenofoviremtricitabine is a recently approved therapy option that has been extensively studied within the treatment-naïve population. When compared with efavirenz-based therapy, improved tolerability with rilpivirine-based therapy was balanced by higher rates of virologic failure to provide similar overall efficacy rates within the intention-to-treat analysis. As a result, providers will need to balance the potential for improved tolerability with fixed-dose combination rilpivirine-tenofoviremtricitabine against a higher potential for virologic failure, particularly among patients with baseline viral loads above 100,000 copies/mL. Current treatment guidelines have recommended that fixed-dose combination rilpivirine-tenofovir-emtricitabine be an alternative therapy option for treatment-naïve patients and advise caution in those patients with high viral loads at baseline. Similar to other non-nucleoside reverse transcriptase inhibitor-based regimens, there are a number of drug interaction concerns with fixed-dose combination rilpivirine-tenofovir-emtricitabine that will necessitate monitoring and, in some cases, appropriate management. Additionally, the emergence of drug resistance to fixed-dose combination rilpivirine-tenofovir-emtricitabine has been well documented in clinical studies and close attention will be necessary in order to protect current and future therapy options. Overall, fixed-dose combination rilpivirine-tenofoviremtricitabine is poised to provide an important therapy option for patients when appropriately applied. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder (BD) is a chronic, relapsing, episodic mental illness associated with other psychiatric comorbidities. There is a substantial economic burden with BD, which makes it challenging to treat. The aim of this review is to evaluate the pharmacology, clinical efficacy, and safety data related to paliperidone extended release (ER) for the treatment of BD. Methods: A literature search was performed from January 1966 through January 2012 using PreMEDLINE, MEDLINE, EMBASE, IPA, and ClinicalTrials.gov to identify articles in English regarding the pharmacology, clinical efficacy, and safety of paliperidone ER in acute mania or mixed episodes or in the maintenance treatment of BD I. Results: There are currently three published studies relating to the use of paliperidone ER for the treatment of BD. Two of these evaluated paliperidone ER as monotherapy for acute mania, while the other assessed its role as adjunct with a mood stabilizer. Conclusion: According to the limited available evidence, paliperidone at higher doses of ER 9-12 mg/day may be a safe and efficacious treatment option for acute episodes of mania in BD. A once-daily dose formulation may improve patient adherence to treatment; however, the cost of paliperidone ER, which is higher than that of generically available second-generation antipsychotics (such as olanzapine and risperidone), and a lack of alternative dosage forms (ie, liquid, intramuscular) compared with other agents may limit its usefulness in the treatment of BD. The role of paliperidone ER as an adjunctive agent or for long-term use requires further investigation. [ABSTRACT FROM AUTHOR]

Clinical Pharmacology & Therapeutics (2008) 83, S101-S107. doi: [ABSTRACT FROM AUTHOR]

One of the major factors contributing to HIV-1 drug resistance is suboptimal adherence to combination antiretroviral therapy (cART). Currently, recommended cART for HIV-1 treatment is a three-drug combination, whereas the pre-exposure prophylaxis (PrEP) regimens consist of one or two antivirals. Treatment regimens require adherence to a once or twice (in a subset of patients) daily dose. Long-acting formulations such as injections administered monthly could improve adherence and convenience, and thereby have potential to enhance the chances of expected outcomes, although long-lasting drug concentrations can also contribute to clinical issues like adverse events and development of drug resistance. Globally, two long-acting antivirals have been approved, and fifteen are in clinical trials. More than half of investigational long-acting antivirals target HIV-1 reverse transcriptase (HIV-1 RT) and/or integrase (HIV-1 IN). Here, we discuss the status and potential of long-acting inhibitors, including rilpivirine (RPV), dapivirine (DPV), and 4-ethynyl-2-fluoro-2-deoxyadenosine (EFdA; also known as MK-8591), which target RT, and cabotegravir (CAB), which targets IN. The outcomes of various clinical trials appear quite satisfactory, and the future of long-acting HIV-1 regimens appears bright. [ABSTRACT FROM AUTHOR]

Background: Dyslipidemia represents a significant non-infectious comorbidity among people living with HIV. The aim of this study is to evaluate the impact on lipid profile of switches from an efavirenz (EFV) or protease inhibitor/ritonavir (PI/r)-based regimen to a rilpivirine (RPV) or a once-daily integrase inhibitor-based regimen.Methods: We analyzed data from SCOLTA prospective database. All patients with HIV-RNA < 50 copies/ml in therapy with two NRTI + EFV or PI/r were included if they switched from EFV to dolutegravir (group EFV-DTG), elvitegravir (EFV-EVG), or RPV (EFV-RPV) and from PI/r to DTG (PI/r-DTG), PI/r to EVG (PI/r-EVG), or PI/r to RPV (PI/r-RPV). Total cholesterol (TC), TC/HDL ratio, LDL-cholesterol (LDL) and triglycerides (TG) were compared at baseline, six months and one year. Comparisons among groups were performed by a general linear model.Results: Four hundred and ninety patients were enrolled, 24.9% female, mean age 47.3 years (±10.1). According to ART switch, 11.4% were classified in group EFV-DTG, 3.9% in EFV-EVG, 23.9% in EFV-RPV, 17.6% in PI/r-DTG, 17.8% in PI/r-EVG, and 25.5% in PI/r-RPV. After adjusted analysis, TC significantly decreased in all groups but EFV-EVG, TC/HDL in all but EFV-DTG and EFV-EVG, while the reduction of TG was significant only in switches to RPV (EFV-RPV and PI/r-RPV). The one year decrease of TC, TC/HDL, LDL and TG was higher in patients with higher baseline levels of the same variable (p < .0001 for all).Conclusions: In SCOLTA, all switches from PI/r regimens gave advantages on lipid profile, while stopping EFV had consistently favorable lipid effects only if replaced by RPV. [ABSTRACT FROM AUTHOR]