Cardiometabolic Parameters 3 Years After Switch to Dolutegravir/Lamivudine vs Maintenance of Tenofovir Alafenamide-Based Regimens.

Background: Cardiometabolic outcomes were investigated 3 years after switching to the 2-drug regimen dolutegravir/lamivudine (DTG/3TC) vs continuing 3-/4-drug tenofovir alafenamide (TAF)-based regimens in a multicenter phase 3 noninferiority study based on an open-label randomized design. Method: Adults with virologically suppressed HIV-1 switched to once-daily DTG/3TC (n = 369) or continued TAF-based regimens (n = 372). Cardiometabolic health parameters were assessed through week 144 via mixed-model repeated measures or logistic regression analyses, adjusting for baseline variables. Results: At week 144, 13% (42/316) of the DTG/3TC group and 12% (37/303) of the TAF-based regimen group had ≥10% weight gain from baseline (adjusted odds ratio, 1.11; 95% CI, .68-1.80). Adjusted change from baseline in serum leptin, a surrogate marker of adiposity, was similar between groups (treatment ratio, 1.00; 95% CI, .89-1.13). The lipid profile generally favored DTG/3TC in the baseline boosted subgroup. Adjusted odds revealed no clinically meaningful differences between groups: homeostatic model assessment of insulin resistance ≥2 (adjusted odds ratio, 0.79; 95% CI, .50-1.26), metabolic syndrome (International Diabetes Federation criteria, 0.99; .59-1.68), hepatic fibrosis (fibrosis-4 index score ≥1.45, 1.39; .63-3.06), and coronary artery disease risk (Framingham risk score ≥10%, 0.92; .56-1.49). Baseline variables and characteristics associated with odds of each cardiometabolic parameter outcome were consistent with known risk factors, including age, sex, race, and some disease characteristics. Conclusions: Cardiometabolic health 3 years after switching to DTG/3TC was comparable to that for individuals continuing TAF-based regimens, further supporting DTG/3TC as a robust switch option with a stable metabolic profile. Trial registration: ClinicalTrials.gov NCT03446573.

Quantitative Benefit-Risk Assessment of P-gp-Mediated Drug-Drug Interactions of Dabigatran Coadministered With Pharmacokinetic Enhancers in Patients With Renal Impairment.

Drug-drug interactions (DDIs) between dabigatran and ritonavir/cobicistat are of major concern in people living with HIV, particularly in those with impaired renal function, because they can result in increased dabigatran exposure and thus an increased risk of major bleeding events. However, the extent of this interaction and subsequent need for dose adjustment in subjects with varying degrees of renal function is currently not yet fully understood. To close this knowledge gap, we conducted an integrated population physiologically-based pharmacokinetic/pharmacodynamic analysis linking changes in dabigatran exposure due to DDIs and varying degrees of renal function to the probability of experiencing an ischemic stroke or major bleeding event within 1 year. The results of our analysis suggest that coadministration of dabigatran etexilate (dabigatran prodrug) and ritonavir/cobicistat should be avoided in subjects with severe renal impairment. A 2-hour dose separation or dabigatran etexilate dose reduction to 110 mg b.i.d. (twice daily) should be considered in subjects with moderate renal impairment when coadministered with ritonavir, while the dabigatran etexilate dose should be further reduced to 75 mg b.i.d. when coadministered with cobicistat. No dabigatran etexilate dose adjustment is needed in subjects with normal renal function receiving ritonavir, but dabigatran etexilate dose reduction to 110 mg b.i.d. should be considered when coadministered with cobicistat.

Assessment of the benefits of and barriers to HIV pharmacist credentialing.

OBJECTIVES: To ascertain the reasons for, benefits of, and barriers to pursuing the American Academy of HIV Medicine (AAHIVM) HIV Pharmacist (AAHIVP) credential. METHODS: A cross-sectional study using an electronic self-administered survey was used. Two separate invitations to participate in online surveys were sent to pharmacists who practice in HIV-related settings: 1 to pharmacists with the AAHIVP credential and 1 to members of key pharmacy organizations and employers without the credential. The surveys assessed demographics, concurrent credentials and certifications, and factors influencing the pursuit of and benefits gained from having the AAHIVP credential (credentialed population) or barriers to pursuing the AAHIVP credential (credentialed and noncredentialed populations). RESULTS: There were 192 participants (survey response rate 38.8%) in the credentialed population and 212 participants in the noncredentialed population. Perceived recognition as an HIV expert from pharmacist (n = 174; 90.6%) and physician (n = 162; 84.4%) peers was the main reason for credentialing; only 20.4% (n = 23/113) of participants' employers reimbursed for the credential. Common reasons for nonpursuit included lack of employer incentive (n = 46; 26.6%) and lack of fee reimbursement (n = 38; 21.9%) in those aware of the credential. However, a majority of these noncredentialed participants reported they would be interested in pursuing credentialing (n = 152; 80.4%). CONCLUSION: AAHIVP credentialing is sought and maintained on the basis of perceived intangible benefits, such as peer recognition, over tangible benefits, such as increased salary and reimbursement by third-party payers. Despite interest, a lack of employer reimbursement is perceived to be a barrier to AAHIVP credentialing among those who have not yet been credentialed.

Differential Influence of the Antiretroviral Pharmacokinetic Enhancers Ritonavir and Cobicistat on Intestinal P-Glycoprotein Transport and the Pharmacokinetic/Pharmacodynamic Disposition of Dabigatran.

Dabigatran etexilate (DE) is a P-glycoprotein (P-gp) probe substrate, and its active anticoagulant moiety, dabigatran, is a substrate of the multidrug and toxin extrusion protein-1 (MATE-1) transporter. The antiretroviral pharmacokinetic enhancers, ritonavir and cobicistat, inhibit both these transporters. Healthy volunteers received single doses of DE at 150 mg alone, followed by ritonavir at 100 mg or cobicistat at 150 mg daily for 2 weeks. DE was then given 2 h before ritonavir or cobicistat. One week later, DE was given simultaneously with ritonavir or cobicistat. No significant increases in dabigatran pharmacokinetic (PK) exposure or thrombin time (TT) measures were observed with the simultaneous administration of ritonavir. Separated administration of ritonavir resulted in a mean decrease in dabigatran PK exposure of 29% (90% confidence interval [CI], 18 to 40%) but did not significantly change TT measures. However, cobicistat increased dabigatran PK exposure (area under the concentration-versus-time curve from time zero to infinity and maximum plasma concentration) by 127% each (90% CI, 81 to 173% and 59 to 196%, respectively) and increased TT measures (33% for the area-under-the-effect curve from time zero to 24 h [90% CI, 22 to 44%] and 51% for TT at 24 h [90% CI, 22 to 78%]) when given simultaneously with dabigatran. Similar increases were observed when cobicistat was administered separately by 2 h from the administration of dabigatran. In all comparisons, no significant increase in the dabigatran elimination half-life was observed. Therefore, it is likely safe to coadminister ritonavir with DE, while there is a potential need for reduced dosing and prudent clinical monitoring with the coadministration of cobicistat due to the greater net inhibition of intestinal P-gp transport and increased bioavailability. (This study has been registered at ClinicalTrials.gov under identifier NCT01896622.).

Lack of an Effect of Ritonavir Alone and Lopinavir-Ritonavir on the Pharmacokinetics of Fenofibric Acid in Healthy Volunteers.

STUDY OBJECTIVE: Because we previously observed a significant 41% reduction in gemfibrozil exposure after 2 weeks of lopinavir-ritonavir administration, we sought to determine the influence of lopinavir-ritonavir and ritonavir alone on the pharmacokinetics of fenofibric acid, an alternative to gemfibrozil for the treatment of elevated triglyceride levels. DESIGN: Open-label, single-sequence pharmacokinetic study. SETTING: Clinical Research Center at the National Institutes of Health. SUBJECTS: Thirteen healthy adult volunteers. INTERVENTION: Subjects received a single oral dose of fenofibrate 145 mg during three study phases: before ritonavir administration, after 2 weeks of administration of ritonavir 100 mg twice/day, and after 2 weeks of administration of lopinavir 400 mg-ritonavir 100 mg twice/day. MEASUREMENTS AND MAIN RESULTS: Serial blood samples were collected over 120 hours for determination of fenofibric acid concentrations. Fenofibric acid pharmacokinetic parameter values were compared before and after concomitant ritonavir or lopinavir-ritonavir administration. The geometric mean ratios (90% confidence intervals) for fenofibric acid area under the plasma concentration-time curve were 0.89 (0.77-1.01) after 14 days of ritonavir alone compared with baseline (p>0.05) and 0.87 (0.69-1.05) after 14 days of lopinavir-ritonavir compared with baseline (p>0.05). Study drugs were generally well tolerated; all adverse events were mild or moderate, transient, and resolved without intervention. CONCLUSION: In contrast to a significant interaction between gemfibrozil and lopinavir-ritonavir, neither lopinavir-ritonavir nor ritonavir alone altered the pharmacokinetics of fenofibric acid in healthy volunteers. These data suggest that fenofibrate remains an important option in human immunodeficiency virus-infected patients receiving common ritonavir-boosted therapy.

High adherence to all-oral directly acting antiviral HCV therapy among an inner-city patient population in a phase 2a study.

BACKGROUND: As treatment for chronic hepatitis C (HCV) virus has evolved to all-oral, interferon-free directly acting antiviral (DAA) therapy, the impact of these improvements on patient adherence has not been described. METHODS: Medication adherence was measured in 60 HCV, genotype-1, treatment-naïve participants enrolled in a phase 2a clinical trial at the National Institutes of Health and community clinics. Participants received either ledipasvir/sofosbuvir (LDV/SOF) (90 mg/400 mg) (one pill) daily for 12 weeks, LDV/SOF + GS-9451 (80 mg/day) (two pills) daily for 6 weeks, or LDV/SOF + GS-9669 (500 mg twice daily; three pills, two in the morning, one in the evening) for 6 weeks. Adherence was measured using medication event monitoring system (MEMS) caps, pill counts and patient report. RESULTS: Overall adherence to DAAs was high. Adherence declined over the course of the 12-week treatment (p = 0.04). While controlled psychiatric disease or symptoms of depression did not influence adherence, recent drug use was a risk factor for non-adherence to 12-week (p = 0.01), but not 6-week regimens. Adherence as measured by MEMS was lower than by patient report. CONCLUSIONS: Adherence to short courses of DAA therapy with 1-3 pills a day was excellent in an urban population with multiple risk factors for non-adherence.

Effect of HIV co-infection on adherence to a 12-week regimen of hepatitis C virus therapy with ledipasvir and sofosbuvir.

OBJECTIVE: As the treatment of hepatitis C virus (HCV) infection has evolved to directly acting antiviral agents, the impact of these directly acting antiviral-only regimens on improving adherence to HCV treatment in HIV/HCV coinfected populations has not been evaluated. The study compared adherence to ledipasvir/sofosbuvir (LDV/SOF) in HCV monoinfected and HIV/HCV coinfected individuals. DESIGN: Adherence was measured from participants in two phase 2 open-label studies (NCT01805882 and NCT01878799). METHODS: HCV treatment-naive, genotype 1 study individuals [HCV monoinfected participants (N = 20) and HIV/HCV coinfected participants, antiretroviral untreated (N = 13) or on combination antiretroviral therapy (N = 37)] were treated with LDV (90 mg) and SOF (400 mg) administered as one tablet once daily for 12 weeks. Adherence was measured using three tools: medication event monitoring system cap, pill count, and patient report. RESULTS: Participants were predominately African American (83%) and male (73%), with a median age of 59 years. Participants had prompt HCV viral load decline and high adherence rates (97 ±â€Š0.5% by medication event monitoring system). Participant adherence decreased significantly from early (baseline week 4) as compared with late (weeks 8-12) in therapy in all three groups - HCV monoinfected (P = 0.01), HIV/HCV antiretroviral untreated (P = 0.02), and HIV/HCV antiretroviral treated participants (P = 0.01). CONCLUSION: Adherence to LDV/SOF in this urban population was high and comparable between HCV monoinfected and HIV/HCV coinfected participants regardless of antiretroviral use.

Emerging drugs and vaccines for candidemia.

Candidemia and other forms of invasive candidiasis are important causes of morbidity and mortality. The evolving challenge of antimicrobial resistance among fungal pathogens continues to highlight the need for potent, new antifungal agents. MEDLINE, EMBASE, Scopus and Web of Science searches (up to January 2014) of the English-language literature were performed with the keywords 'Candida' or 'Candidemia' or 'Candidiasis' and terms describing investigational drugs with activity against Candida spp. Conference abstracts and the bibliographies of pertinent articles were also reviewed for relevant reports. ClinicalTrials.gov was searched for relevant clinical trials. Currently available antifungal agents for the treatment of candidemia are summarised. Investigational antifungal agents with potential activity against Candida bloodstream infections and other forms of invasive candidiasis and vaccines for prevention of Candida infections are also reviewed as are selected antifungal agents no longer in development. Antifungal agents currently in clinical trials include isavuconazole, albaconazole, SCY-078, VT-1161 and T-2307. Further data are needed to determine the role of these compounds in the treatment of candidemia and other forms of invasive candidiasis. The progressive reduction in antimicrobial drug development may result in a decline in antifungal drug discovery. Still, there remains a critical need for new antifungal agents to treat and prevent invasive candidiasis and other life-threatening mycoses.

Influence of Panax ginseng on the steady state pharmacokinetic profile of lopinavir-ritonavir in healthy volunteers.

STUDY OBJECTIVE: Panax ginseng has been shown in preclinical studies to modulate cytochrome P450 enzymes involved in the metabolism of HIV protease inhibitors. Therefore, the purpose of this study was to determine the influence of P. ginseng on the pharmacokinetics of the HIV protease inhibitor combination lopinavir-ritonavir (LPV-r) in healthy volunteers. DESIGN: Single-sequence, open-label, single-center pharmacokinetic investigation. SETTING: Government health care facility. SUBJECTS: Twelve healthy human volunteers. MEASUREMENTS AND MAIN RESULTS: Twelve healthy volunteers received LPV-r (400-100 mg) twice/day for 29.5 days. On day 15 of LPV-r administration, serial blood samples were collected over 12 hours for determination of lopinavir and ritonavir concentrations. On study day 16, subjects began taking P. ginseng 500 mg twice/day, which they continued for 2 weeks in combination with LPV-r. On day 30 of LPV-r administration, serial blood samples were again collected over 12 hours for determination of lopinavir and ritonavir concentrations. Lopinavir and ritonavir pharmacokinetic parameter values were determined using noncompartmental methods, and preadministration and postadministration ginseng values were compared using a Student t test, where p<0.05 was accepted as statistically significant. CONCLUSION: Neither lopinavir nor ritonavir steady-state pharmacokinetics were altered by 2 weeks of P. ginseng administration to healthy human volunteers. Thus, a clinically significant interaction between P. ginseng and LPV-r is unlikely to occur in HIV-infected patients who choose to take these agents concurrently. It is also unlikely that P. ginseng will interact with other ritonavir-boosted protease inhibitor combinations, although confirmatory data are necessary.

Boceprevir: a protease inhibitor for the treatment of hepatitis C.

BACKGROUND: Boceprevir is a protease inhibitor indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in combination with peginterferon and ribavirin for treatment-naive patients and those who previously failed to improve with interferon and ribavirin treatment. OBJECTIVE: This article provides an overview of the mechanism of action, pharmacologic and pharmacokinetic properties, clinical efficacy, and tolerability of boceprevir. METHODS: Relevant information was identified through a search of PubMed (1990-July 2012), EMBASE (1990-July 2012), International Pharmaceutical Abstracts (1970-July 2012), and Google Scholar using the key words boceprevir, SCH 503034, non-structural protein 3 (NS3) serine protease inhibitor, and direct-acting antiviral agent (DAA). Additional information was obtained from the US Food and Drug Administration's Web site, review of the reference lists of identified articles, and posters and abstracts from scientific meetings. RESULTS: Clinical efficacy of boceprevir was assessed in 2 Phase III trials, Serine Protease Inhibitor Therapy-2 (SPRINT-2) for treatment-naive patients and Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2 (RESPOND-2) for treatment-experienced patients. In SPRINT-2, patients were randomized to receive peginterferon + ribavirin (PR) or peginterferon + ribavirin + boceprevir (PRB); duration of boceprevir therapy varied from 24, 32, to 44 weeks on the basis of HCV RNA results. The primary endpoint was achievement of sustained virologic response (SVR; lower limit of detection, 9.3 IU/mL). The addition of boceprevir was shown to be superior, with overall SVR rates ranging from 63% to 66% compared with 38% with PR (P < 0.001). Results of SVR in SPRINT-2 were also reorganized to monitor SVRs in black and non-black patients. Treatment-experienced patients were assessed in RESPOND-2; however, null responders were excluded. Patients were again randomized to PR or PRB; duration of boceprevir therapy varied from 32 to 44 weeks on the basis of HCV RNA results. SVR was significantly higher in patients receiving boceprevir (59%-66% vs 21% with PR; P < 0.001). This benefit was seen in both previous nonresponders (SVR, 40%-52% vs 7% with PR), as well as previous relapsers (SVR, 69%-75% vs 29% with PR). Importantly, SVR could be attained with a shortened course of therapy in almost one half of all treated patients in SPRINT-2 (44%) and RESPOND-2 (46%). CONCLUSIONS: Boceprevir was well tolerated in clinical trials and a welcomed addition to our HCV armamentarium.