Borja Mora-Peris

Rilpivirine exposure in plasma and sanctuary site compartments after switching from nevirapine-containing combined antiretroviral therapy

OBJECTIVES Pharmacokinetic parameters following modifications to antiretroviral therapy and sanctuary site exposure are often unknown for recently licensed antiretrovirals. We assessed plasma, CSF and seminal plasma (SP) exposure of rilpivirine after switching from nevirapine. METHODS HIV-infected male subjects receiving tenofovir/emtricitabine/nevirapine (245/200/400 mg) once daily switched to tenofovir/emtricitabine/rilpivirine (245/200/25 mg) once daily for 60 days when CSF and semen samples were collected. Mean and individual plasma concentrations of nevirapine and rilpivirine were compared with the proposed plasma target concentration for nevirapine (3000 ng/mL) and the protein binding-adjusted EC90 for rilpivirine (12.1 ng/mL). Mean rilpivirine CSF and SP concentrations were calculated and individual values compared with the EC50 and EC90 for wild-type virus (0.27 and 0.66 ng/mL, respectively). RESULTS Of 13 subjects completing study procedures including CSF examination, 8 provided seminal samples. By day 3, the mean plasma rilpivirine trough concentration was 29.7 ng/mL (95% CI: 23.8-37). No patient presented rilpivirine plasma concentrations under the proposed threshold. The mean rilpivirine concentration in CSF was 0.8 ng/mL (95% CI: 0.7-1.0), representing a CSF : plasma ratio of 1.4%, with concentrations above the EC90 in 85% (11/13) of patients. In SP, the mean rilpivirine concentration was 4.9 ng/mL (95% CI: 3.3-7.2), representing an SP : plasma ratio of 9.5%, with all concentrations above the EC90. CONCLUSIONS Switching from nevirapine- to rilpivirine-containing antiretroviral therapy was safe and well tolerated, with plasma rilpivirine concentrations above the protein binding-adjusted EC90 in all subjects. Rilpivirine concentrations were always above the EC50 in the CSF and the EC90 in SP.

Pharmacokinetic profile and safety of 150 mg of maraviroc dosed with 800/100 mg of darunavir/ritonavir all once daily, with and without nucleoside analogues, in HIV-infected subjects

BACKGROUND Once-daily nucleoside-sparing combination antiretroviral therapy regimens are attractive options for the treatment of HIV infection. However, the pharmacokinetic profiles of such regimens are often not established. METHODS HIV-infected subjects receiving 245/200 mg of tenofovir/emtricitabine plus 800/100 mg of darunavir/ritonavir once daily with plasma HIV RNA <50 copies/mL were eligible. On day 1 (period 1), 150 mg of maraviroc daily was added and on day 11 (period 2), tenofovir/emtricitabine discontinued. At steady-state (days 10 and 20), intensive pharmacokinetic sampling was undertaken. We assessed (i) the number of subjects with trough (C(trough)) and average (C(avg)) maraviroc concentrations <25 and <75 ng/mL, respectively; (ii) geometric mean (GM) ratios for pharmacokinetic parameters for period 2 versus period 1; and (iii) factors associated with total maraviroc exposure. RESULTS Eleven subjects completed the study procedures (mean age 49 years; range 35-59 years). In three subjects, maraviroc C(trough) and C(avg) were <25 and <75 ng/mL, respectively (C(avg), 68 ng/mL and C(trough), 14 and 21 ng/mL). Although not statistically significant, a trend was observed towards lower maraviroc, darunavir and ritonavir concentrations in period 2 versus period 1; total maraviroc exposure was 3579 ng· h/mL (95% CI: 2983-4294) and 2996 ng· h/mL (95% CI: 2374-3782) in periods 1 and 2, respectively, and the GM ratio was 0.84 (95% CI: 0.67-1.05). Only total ritonavir exposure was significantly associated with total maraviroc exposure (P=0.049; 95% CI: 0.01-0.91). No clinical safety concerns were observed. CONCLUSIONS Within this novel nucleoside-sparing regimen, maraviroc exposure is dependent on ritonavir exposure, which was slightly reduced in the absence of tenofovir/emtricitabine.

A comparison of two post-processing analysis methods to quantify cerebral metabolites measured via proton magnetic resonance spectroscopy in HIV disease

OBJECTIVE Non-invasive biomarkers to monitor cerebral function in treated human immunodeficiency virus (HIV) disease are required. Cerebral metabolite ratios (CMRs) measured by proton-MR spectroscopy ((1)H-MRS) are a potential biomarker. Here, we compare two post-processing software packages to quantify CMRs. METHODS Cerebral (1)H-MRS data from 11 HIV-positive subjects before and after antiretroviral therapy intensification with maraviroc were quantified using a java-based version of the MR user interface package (jMRUI) and the totally automatic robust quantitation in nuclear MR (TARQUIN). (1)H-MRS data included N-acetylaspartate (NAA), creatine (Cr), choline (Cho) and myo-inositol (mI) from three cerebral locations. Differences in quantification and clinical associations of CMRs measured by the two packages were evaluated. RESULTS Mean CMRs were generally lower when measured by TARQUIN than by jMRUI (NAA/Cr, Cho/Cr, mI/Cr ratios of 1.78, 0.83, 0.81 for jMRUI, and 1.27, 0.25, 0.81 for TARQUIN). Longitudinal changes were observed in CMRs in the basal ganglia voxel although these changes were not statistically significant [+7.1% (p = 0.18), +0.0% (p = 0.91) and -6.6% (p = 0.61) and +14.8% (p = 0.18), +17.9% (p = 0.07) and +34.8% (p = 0.17) for NAA/Cr, Cho/Cr and mI/Cr ratios measured by TARQUIN and jMRUI, respectively]. Plasma maraviroc concentration was associated with a decrease in mI/Cr ratio measured via TARQUIN (p = 0.049). CONCLUSION Although CMRs differed when quantified by jMRUI vs TARQUIN, these differences were consistently observed across three cerebral locations, and clinical associations were evident by both methods. ADVANCES IN KNOWLEDGE TARQUIN and jMRUI are viable options to use in the post-processing of cerebral MRS data acquired in HIV disease.

The pharmacokinetic profile of raltegravir-containing antiretroviral therapy in HIV-infected individuals over 60 years of age

Abstract Background: Antiretroviral safety and efficacy and may differ in older versus younger HIV-infected patients. The objective of this study was to assess the pharmacokinetic (PK) profile in older HIV-infected subjects (>60 years) switching combination antiretroviral therapy (cART) to a raltegravir (RAL) containing regimen. Methods: Nineteen HIV-infected patients over 60 years of age on effective cART (HIV-RNA < 50 copies/ml) were enrolled in this prospective 24-week study. On day 1, patients switched to tenofovir/emtricitabine (245/200 mg once daily) and RAL (400 mg twice daily). On day 28, intensive PK sampling was undertaken in a fasted state and RAL plasma concentrations determined. Neurocognitive function was assessed at baseline and week 24 using a neuropsychological battery. RAL PK parameters were compared to those of two younger historical HIV-infected control groups that received twice-daily RAL co-administered with darunavir/ritonavir (DRV/r) 800/100 once daily by nonlinear mixed effects modelling. Results: In HIV-infected subjects over the age of 60 (mean ± SD age: 66 ± 3.4 years, n = 19) switching to a RAL containing regimen, we observed no safety concerns, no plasma virological rebounds, and no differences in RAL apparent oral clearance when compared to younger HIV-infected populations (mean ± SD age: 41 ± 9.2 years, n = 38) based on population pharmacokinetic analysis. After 24 weeks of study therapy a decline in cognitive function was observed [change in (SD) global score of (0.91 (1.3), P = 0.018]. Conclusions: No significant changes in RAL exposure associated with age were observed.

HIV-1 CNS in vitro infectivity models based on clinical CSF samples

BACKGROUND The concentration of antiretrovirals in CSF is often utilized as a surrogate for CNS drug exposure. This measurement does not consider pharmacodynamic or combinative effects of ART. We have developed a novel endpoint measurement to assess antiretroviral activity of CSF from subjects on ART. METHODS CSF samples were obtained from patients receiving tenofovir/emtricitabine (245/200 mg once daily) with either rilpivirine (25 mg once daily) or lopinavir/ritonavir/maraviroc (400/100/150 mg twice daily) and HIV-uninfected controls. Antiviral activity of ART-containing CSF was assessed in cell cultures using PBMCs and neuro-derived glial (U87) and astrocyte (373) cell lines. Infectivity model half-maximal inhibitory concentration (IMIC50) values were calculated and expressed as -log2IMIC50. Results were correlated with CSF antiretroviral concentrations. RESULTS Compared with controls, CSF from both ART studies demonstrated in vitro antiretroviral activity in all models. CSF antiretroviral activity of patients on lopinavir/ritonavir/maraviroc was significantly greater than that of patients on rilpivirine [-log2IMIC50 (95% CI) 4.82 (4.74-4.89) versus 3.43 (3.33-3.54) in PBMCs, 3.06 (2.98-3.15) versus 2.56 (2.46-2.65) in U87 cells and 6.00 (6.11-5.88) versus 4.90 (5.09-4.72) in 373 cells, respectively]. Positive correlations were observed for individual CSF antiretroviral activity in different cellular models with CSF concentrations of rilpivirine (P = 0.040 in 373 cells) and lopinavir (P = 0.048 in 373 cells), but not maraviroc. CONCLUSIONS Antiviral activity of CSF from patients on ART was successfully calculated and was greater with a regimen containing four active drugs compared with three active drugs. The use of neuro-derived cell lines alongside PBMCs to assess the effect of ART on CSF may act as a useful future clinical research tool.

Evolution of changes in cognitive function after the initiation of antiretroviral therapy

Cognitive function is reported to improve after the initiation of combination antiretroviral therapy (cART). Data on the evolution of such changes are limited. We assessed the dynamics of changes in cognitive parameters, in HIV-positive subjects initiating cART. Cognitive function in seven domains was evaluated for HIV-infected patients without clinically significant cognitive impairment prior to the initiation of cART, and 24 and 48 weeks after. Cognitive scores were transformed using standardised z-scores according to the pooled baseline standard deviation. Global, speed, and accuracy composite z-scores were calculated with changes calculated using a paired t test. In 14 subjects, change in global cognitive z-scores from baseline was by 0.08 at week 24 (p = 0.59) and 0.15 at week 48 (p = 0.43). Change in composite speed and accuracy z-scores from baseline at weeks 24/48 were 0.07/0.05 (p = 0.45/0.82) and 0.13/0.23 (p = 0.47/0.45), respectively. In two of the cognitive domains assessing speed (learning and monitoring time), a continued improvement from baseline to weeks 24 and 48 was observed (changes of 0.06–0.08 and 0.10–0.19, respectively), whereas in two domains (detection and identification) an initial improvement at week 24 (changes of −0.10 and 0.04 from baseline, respectively) was followed by a deterioration in score at week 48 (changes of −0.12 and −0.08 from baseline, respectively). None of these changes were statistically significant. A trend for improvement in cognitive function was observed in naïve HIV-positive patients starting cART. The dynamics of this improvement differed both between cognitive domains and the time-points assessed.

A Phase I study to assess the safety, tolerability and pharmacokinetic profile of boceprevir and sildenafil when dosed separately and together, in healthy male volunteers

OBJECTIVES Boceprevir is a first-generation direct-acting antiviral licensed for the treatment of hepatitis C infection. Sildenafil is an oral therapy for erectile dysfunction. As boceprevir is a potent inhibitor of CYP3A4, potential pharmacokinetic interactions may occur when it is coadministered with sildenafil. The aim of this study was to assess the pharmacokinetic profile of sildenafil and boceprevir when dosed separately and together in healthy volunteers. METHODS Thirteen male subjects completed the following study procedures: phase 1 (Day 0), a single dose of 25 mg of sildenafil was administered; washout period (Days 1-9); phase 2 (Days 10-15), 800 mg of boceprevir three times a day was administered; and phase 3 (Day 16), 800 mg of boceprevir and 25 mg of sildenafil were administered. All drugs were administered in the fed state. Intensive pharmacokinetic sampling was undertaken on Days 0, 15 and 16. Differences in the pharmacokinetic parameters of sildenafil, N-desmethyl-sildenafil and boceprevir between phase 3 and the earlier phases were evaluated by changes in the geometric mean ratios (GMRs). RESULTS All the drugs were well tolerated with no safety concerns arising. In the presence of boceprevir (phase 3 versus phase 1), the GMR for the plasma Cmax and the AUC24 for sildenafil increased by 1.9-fold (95% CI 1.5-2.4) and 2.7-fold (95% CI 2.1-3.4), respectively, whereas a reduction in the Cmax of N-desmethyl-sildenafil was observed (GMR 0.5, 95% CI 0.4-0.7). No significant changes in boceprevir exposure were observed between phases 3 and 2. CONCLUSIONS Exposure of sildenafil is increased in the presence of boceprevir. A dose adjustment of sildenafil is therefore necessary. An initial dose of 25 mg of sildenafil is suggested.

Apparent spontaneous clearance of chronic hepatitis C virus infection in a HIV co-infected patient with decompensated cirrhosis: a case report.

Spontaneous clearance of chronic hepatitis C virus (HCV) infection is unusual, once chronic disease is established, particularly in HIV/HCV co-infected individuals [1]. In cirrhotic patients, pegylated interferon-based regimens achieve lower sustained virological response (SVR) rates and increase the likelihood of decompensation [2]. However, interferon-sparing regimens using novel direct-acting antivirals (DAAs) are now becoming available and have dramatically increased the SVR rates among cirrhotic patients, minimizing the risk of hepatic decompensation [3,4]. We report a patient with HIV/HCV co-infection and decompensated cirrhosis who appeared to have cleared HCV spontaneously on intensive investigation and, therefore, was not offered interferon-free treatment. A 43-year-old heterosexual man with a history of prior intravenous drug use was initially diagnosed with HIV-1 infection in 2008 in the context of Pneumocystis jirovecii pneumonia. At baseline, he had a CD4+ cell count of 30 cells/μl, plasma HIV RNA of 39 911 copies/ml, positive anti-HCV (Abbott Architect; Abbott Diagnostics, Abbott Park, Illinois, USA) and confirmed HCV genotype 4 infection by sequencing (Micropathology Ltd, Coventry, UK) with a plasma HCV RNA level of 602 745 IU/ml (Abbott Real Time HCV PCR, M2000 system; Abbott Diagnostics). He was later shown to be IL28B-CC genotype. Screening demonstrated past hepatitis B virus (HBV) infection with negative surface antigen and undetectable HBV DNA. Combination antiretroviral therapy (cART) with emtricitabine/tenofovir/efavirenz (200/300/600 mg) once daily was initiated shortly after HIV diagnosis and, by 1 year of treatment, his CD4+ cell count had improved to 310 cells/μl. Soon afterwards, he developed decompensation of his chronic liver infection in the form of ascites, jaundice and mild encephalopathy (Child–Pugh B). A liver biopsy showed florid periportal bile duct reaction, marked lobular inflammation and fibrosis scoring 4/6. A decision for HCV treatment was deferred whilst the patient attempted to reduce his high BMI. Regular alpha-fetoprotein levels, liver ultrasound and MRI scans were performed without evidence of hepatocellular carcinoma. His cirrhosis progressed to Child–Pugh C and the patient was referred for liver transplantation, which was turned down due to a low predicted 5-year survival, an assessment influenced by the patients refusal to receive blood products according to his beliefs as a Jehovahs witness. His liver function deteriorated further despite medical management. To minimize drug interactions in case of transplantation and/or HCV treatment, efavirenz was switched to raltegravir 400 mg twice daily in January 2013. Around that time, plasma HCV RNA levels experienced a downward trend, achieving values of less than 15 HCV RNA IU/ml (Roche Cobas TaqMan; Roche Molecular Diagnostics, Pleasanton, California, USA) in January 2014. At that time, he was considered for early access to DAA therapy (sofosbuvir with either ledipasvir or daclatasvir). Subsequently, no HCV RNA was detected on three occasions (February, April and June 2014). In parallel, CD4+ cell count increased from 370 cells/ml (21%) in April 2012, to 955 cells/ml (31%) in June 2014 (Fig. ​(Fig.11). Fig. 1 Time trends from HIV presentation in May 2008 for antiretroviral regimes (with fixed nuke-backbone maintained throughout regimes) and laboratory results: ALT, HCV RNA, HIV RNA, absolute CD4+ cell count and CD4+ percentage. A transjugular liver biopsy was performed showing evidence of inactive cirrhosis, mild portal and nodular inflammation, no large cell or fatty change, negative stains for iron and alpha-1 antitrypsin consistent with resolved infection and no evidence of HCV RNA on PCR (Micropathology Ltd). An HCV-specific enzyme-linked ImmunoSpot that assessed interferon-γ production in peripheral blood mononuclear cells (stimulated by gt1 and gt4 HCV peptides) at this time was not reactive, suggesting recovery of CD8+ and CD4+ T-cell immunity was not responsible for his HCV clearance. Spontaneous clearances of established HCV infection have been previously described in absence of specific anti-HCV CD4+ responses [5]. Although rare, HCV clearance among HIV–HCV co-infected patients on cART is mainly described in patients with IL-28B CC genotype, suggesting this subset of patients might benefit from an earlier initiation of cART [1,6–9]. The initial period of HCV undetectability coincided with a switch to raltegravir and a marked increase in peripheral CD4+ cell count. Whether this was causal is unclear. However, maintained HIV viral suppression [10] and improvements in drug-associated hepatotoxicity have been described in cirrhotic HCV–HIV co-infected patients after switching to raltegravir [11]. What makes this case more unusual is that, given the potential availability of novel DAAs to a limited number of patients, invasive liver investigation was undertaken, which not only failed to find virus, but also showed little evidence of active infection. Cases such as this one raise important implications for patients with very advanced disease being considered for DAA therapy. The potential for low-level viraemia, and even prolonged periods of aviraemia, is well recognized [12]. Whether in these patients more invasive investigations are helpful to exclude the possibility for a hidden focus of HCV infection is unclear. It remains uncertain as to whether, in the absence of viraemia, the likelihood of persistent viral reservoirs should be sufficient to justify treatment.

Changes in cerebral function parameters with maraviroc-intensified antiretroviral therapy in treatment naive Hiv-positive individuals

Background: Maraviroc-intensified antiretroviral therapy (ART) may be associated with cognitive benefits. Methods: Therapy-naive, cognitively asymptomatic, HIV-positive individuals were randomly allocated on a 1 : 1 basis to standard ART (Arm1: tenofovir-emtricitabine and atazanavir/ritonavir) or maraviroc intensified ART (Arm2: abacavir-lamivudine and darunavir/ritonavir/maraviroc). Over 48 weeks, detailed assessments of cognitive function tests were undertaken and cerebral metabolites measured using proton magnetic resonance spectroscopy. Our primary endpoint was mean change in cognitive function across treatment arms with factors associated with cognitive function changes also assessed. Results: Of 60 individuals randomized (30 Arm1 and 30 Arm2), 58 were men and 44 of white ethnicity. Treatment groups had similar disease characteristics including overall mean (SD) baseline CD4+ cell count 428 (209) and 414 (229) cells/&mgr;l, Arms1 and 2, respectively. At week 48, plasma HIV RNA was less than 50 copies/ml in 55 of 56 of those completing study procedures. Cognitive function improved over 48 weeks [mean change z-score (SD) 0.16 (0.09) Arm1 and 0.25 (0.08) Arm2, P = 0.96 for differences between study arms]. A greater increase in frontal grey matter N-acetyl aspartate/creatine ratio was observed in Arm1 [ratio change of 0.071 (SD 0.16)] versus Arm2 [change −0.097 (SD 0.18), P = 0.009], although this was not associated with changes in cognitive function (P = 0.17). Conclusion: Maraviroc-intensified ART had no demonstrable benefit on cognitive function in individuals initiating ART. Greater improvement in neuronal metabolites (N-acetyl aspartate/creatine) was observed with standard ART. Future work should focus on maraviroc-intensified ART in individuals with cognitive impairment.