Cerebrospinal fluid drug concentrations and viral suppression in HIV-1-infected patients receiving ritonavir-boosted atazanavir plus lamivudine dual antiretroviral therapy (Spanish HIV/AIDS Research Network, PreEC/RIS 39).

This study aimed to assess cerebrospinal fluid (CSF) drug concentrations and viral suppression in HIV-1-infected patients on ritonavir-boosted atazanavir (ATV/r) plus lamivudine (3TC) dual therapy. HIV-1-infected adults with suppressed plasma HIV-1 RNA who switched to ATV/r plus 3TC were studied. Total ATV and 3TC concentrations at the end of the dosing interval (C24h), using a validated LC-MS/MS method, and HIV-1 RNA were measured in paired CSF and plasma samples 12 weeks after switching. Ten individuals were included. Median (range) age was 42.5 (33-70) years, time on ART was 39.5 (11-197) months, and time with plasma HIV-1 RNA < 40 copies/mL was 15.5 (6-46) months. At baseline, CSF HIV-1 RNA was < 40 copies/mL in all patients. Twelve weeks after switching to ATV/r plus 3TC, HIV-1 RNA remained at < 40 copies/mL in both plasma and CSF in 9/10 patients. One patient with suboptimal adherence to ART had HIV-1 RNA rebound in both plasma and CSF. The median CSF-to-plasma concentration ratios of ATV and 3TC were 0.013 and 0.417, respectively. Median ATV C24h in CSF was 10.4 (3.7-33.4) ng/mL (in vitro ATV IC50 range, 1-11 ng/mL). Median 3TC C24h in CSF was 43.4 (16.2-99.3) ng/mL (in vitro 3TC IC50 range, 0.68-20.6 ng/mL). Most patients maintained HIV-1 RNA in CSF < 40 copies/mL despite CSF ATV C24h close to or within the IC50 range in the majority. ATV PK data in CSF should be considered and rigorous patient selection is advisable to assure effective CSF viral suppression with this two-drug simplification regimen.

HIV-1-RNA Decay and Dolutegravir Concentrations in Semen of Patients Starting a First Antiretroviral Regimen.

BACKGROUND: The objective of this study was to quantify human immunodeficiency virus (HIV) type 1 RNA decay and dolutegravir (DTG) concentrations in the semen of HIV-infected patients receiving DTG-based first-line therapy. METHODS: This was a prospective, single-arm, open-label study including 15 HIV-1-infected, antiretroviral therapy-naive men starting once-daily treatment with DTG (50 mg) plus abacavir-lamivudine (600/300 mg). HIV-1 RNA was measured in seminal plasma (SP) and blood plasma (BP) at baseline, on days 3, 7, and 14, and at weeks 4, 12, and 24. The HIV-1 RNA decay rate was assessed using nonlinear mixed-effects models. Total and free DTG concentrations were quantified 24 hours after the dose at weeks 4 and 24 by means of a validated liquid chromatography-tandem mass spectrometry method. RESULTS: Viral decay was faster in BP than in SP in the first decay phase (half-life, 4.5 vs 8.6 days; P = .001) with no statistically significant differences in the second phase. HIV-1 RNA suppression (<40 copies/mL) was reached earlier in SP (4 vs 12 weeks; P = .008) due to lower baseline HIV-1 RNA levels. The median total DTG 24 hours after the dose in SP was 119.1 ng/mL (range, 27.2-377 ng/mL), which represents 7.8% of BP exposure. The median DTG free-fraction in SP was 48% of the total drug. Seminal protein-unbound DTG concentrations exceeded the in vitro 50% inhibitory concentration (0.21 ng/mL) by a median of 214-fold. CONCLUSIONS: DTG concentrations in SP are sufficient to contribute to rapid seminal HIV-1 RNA suppression.

Randomized trial of a multidisciplinary lifestyle intervention in HIV-infected patients with moderate-high cardiovascular risk.

OBJECTIVE: To assess the impact of a multidisciplinary lifestyle intervention on cardiovascular risk and carotid intima-media thickness (c-IMT) in HIV-infected patients with Framingham scores (FS) > 10%. DESIGN: Randomized pilot study; follow-up 36 months. METHODS: Virologically suppressed adult HIV-1-infected patients with FS >10% were randomized 1:1 to the intervention group (multidisciplinary lifestyle intervention) or control group (routine care). At baseline and months 12, 24 and 36, lipid parameters were analyzed and carotid ultrasound was performed to determine c-IMT and presence of plaques. Biomarkers were measured at baseline and month 36. The primary endpoints were lipid and FS changes at 36 months. RESULTS: Fifty-four patients were included, 27 in each arm. Median age was 50.5 years, all patients but one were men, and FS was 16.5%. Relative to controls, total and LDL cholesterol had significantly decreased in the intervention group at 24 months (p = 0.039, p = 0.011, respectively). However, no differences between groups were found at month 36 in lipid variables, neither in FS. Tobacco use decreased in the intervention group (p = 0.031). At baseline, 74.5% of patients had subclinical atherosclerosis, and at month 36, we observed a progression in c-IMT that was greater in the intervention group (p = 0.030). D-dimer increased (p = 0.027) and soluble intercellular adhesion molecule-1 decreased (p = 0.018) at 36 months. CONCLUSIONS: In this cohort of HIV-infected patients with FS>10% and a high percentage of subclinical atherosclerosis, a multidisciplinary lifestyle intervention resulted in a slight improvement in some cardiovascular risk factors and the FS during the first 2 years, but did not prevent c-IMT progression.

Cerebrospinal fluid and plasma lopinavir concentrations and viral response in virologically suppressed patients switching to lopinavir/ritonavir monotherapy once daily.

BACKGROUND: Lopinavir/ritonavir (LPV/r) monotherapy is used in selected virologically suppressed HIV-infected patients. Some would prefer a once-daily (OD) dose instead of the usual twice-daily dose to favour adherence. However, trough concentrations of the drug in blood and particularly in cerebrospinal fluid (CSF) may not be adequate to maintain viral suppression. METHODS: Prospective, open-label pilot study to evaluate the efficacy and safety of LPV/r monotherapy OD. HIV-1-infected patients, virologically suppressed for at least 6 months were enrolled. HIV viral load (VL) was determined at baseline and at weeks 4, 8, 12, 16, 24, 36 and 48. Lumbar puncture was performed in a subgroup of patients to evaluate CSF VL and CSF LPV concentrations. RESULTS: A total of 21 patients were included. At week 48, 85.7% (n=18) showed viral suppression (VL<40 copies/ml). Two patients had viral failure (9.5%) and a third was withdrawn from the study because of gastrointestinal symptoms. Nine patients were enrolled in the substudy. CSF VL was <40 copies/ml in all cases. Median (range) LPV concentration was 9.78 ng/ml (1.93-78.3) in CSF and 1,970 (154-16,700) ng/ml in plasma; the CSF/plasma ratio was 0.004 (0.001-0.186). CONCLUSIONS: In this small pilot study, LPV/r monotherapy OD maintained plasma HIV RNA suppression at 48 weeks in most patients, with no cases of CSF viral escape. However, CSF LPV concentrations were close to the 50% inhibitory concentration threshold in several patients; hence, this intervention should be avoided in patients with advanced immune suppression and/or those individuals presenting with significant comorbidities such as hepatitis C coinfection.

Prevalence of methicillin-resistant Staphylococcus aureus colonization in HIV-infected patients in Barcelona, Spain: a cross-sectional study.

BACKGROUND: Colonization by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has been found to be markedly more common in HIV-infected individuals in the USA. Studies evaluating the prevalence MRSA colonization in HIV-infected populations in Europe are scarce. The aim of this study was to investigate the prevalence of MRSA colonization in a cohort of HIV-infected patients in Barcelona, Spain. METHODS: Nasal and pharyngeal S. aureus carriage was assessed in a random sample of 190 patients from an outpatient HIV clinic. Nasal and pharyngeal swab specimens were obtained for staphylococcal culture from 190 and 110 patients respectively. All MRSA isolates were screened for Panton-Valentine leukocidin (PVL) genes by PCR. Molecular characterization of MRSA isolates was performed by multilocus sequence typing. Data related to HIV infection, healthcare exposure, and previously described risk factors for MRSA were collected from medical records and a questionnaire administered to each patient. RESULTS: The patients' characteristics were as follows: male, 83 %; median (IQR) age, 45 (39-49) years; intravenous drug users, 39 %; men who have sex with men, 32 %; heterosexual, 26 %; CD4 count, 528/µL (IQR 351-740); on antiretroviral therapy, 96 %; and undetectable plasma viral load, 80 %. Sixty-five patients (34 %) were colonized by S. aureus. MRSA colonization was found in 1 % and 2 % of nasal and pharyngeal samples respectively. No PVL positive MRSA strains were detected and all the MRSA isolates belonged to typical hospital-acquired clones. CONCLUSIONS: Our data suggest that CA-MRSA colonization is not currently a problem in HIV-infected individuals in our area.

Telaprevir decreases estimated glomerular filtration rate in HIV-hepatitis C virus coinfected patients.

We investigated kidney function outcome in 24 chronic hepatitis C genotype 1 patients coinfected with HIV receiving telaprevir in a single tertiary care hospital in Spain. A statistically significant median (interquartile range) decrease in estimated glomerular filtration rate (eGFR, ml/min/1.73 m) relative to baseline [93.6 (73.0-109.0)] was seen at weeks 4 [86.5 (34.0-112.0), P = 0.014], 8 [90.0 (49.0-111.0), P = 0.026] and 12 [89.5 (54.0-113.0), P = 0.017]. These changes reversed after telaprevir discontinuation. Patients presenting an eGFR decrease had a higher risk of haematological toxicity.

Antiviral activity and CSF concentrations of 600/100 mg of darunavir/ritonavir once daily in HIV-1 patients with plasma viral suppression.

OBJECTIVES: The objective of this study was to assess whether a lower dose than the currently used one of darunavir/ritonavir might achieve good CSF concentrations and contribute to inhibition of CNS viral replication. PATIENTS AND METHODS: This was a substudy of a randomized, open, multicentre study (eudraCT 2011-006272-39), comparing the efficacy and safety of 800/100 mg of darunavir/ritonavir (darunavir 800) versus 600/100 mg of darunavir/ritonavir (darunavir 600) once daily plus tenofovir/emtricitabine or abacavir/lamivudine in 100 virologically suppressed patients. Paired blood and CSF samples were obtained. Total plasma darunavir concentrations were determined by HPLC, and CSF concentrations by liquid chromatography-tandem MS. Viral load (VL) was determined in plasma and CSF (limit of detection = 40 copies/mL) by PCR. RESULTS: Sixteen patients were enrolled. The median (range) of darunavir CSF concentrations in darunavir 600 (n = 8) and darunavir 800 (n = 8) patients was 17.08 (5.79-30.19) and 13.23 (3.47-32.98) ng/mL, respectively (P = 0.916). The median (range) darunavir CSF:plasma ratio was 0.010 (0.005-0.022) in darunavir 600 patients and 0.008 (0.004-0.017) in the darunavir 800 arm (P = 0.370). All 16 patients had a VL < 40 copies/mL in plasma and 14 had a VL < 40 copies/mL in CSF. Of the two patients with detectable CSF VL (280 copies/mL and 159 copies/mL), one was receiving darunavir 600 and the other darunavir 800 plus tenofovir/emtricitabine. Of note, these patients had the lowest CSF darunavir concentrations in their respective groups: 5.79 ng/mL (802 ng/mL in plasma) and 3.47 ng/mL (958 ng/mL in plasma). CONCLUSIONS: Darunavir CSF and plasma concentrations were comparable between the two arms. However, one patient from each group (with the lowest CSF darunavir concentrations in their respective groups) had detectable CSF VL despite undetectable plasma VL.

CSF LPV concentrations and viral load in viral suppressed patients on LPV/r monotherapy given once daily.

INTRODUCTION: Plasma trough concentrations of lopinavir (LPV) given as LPV/r 800/200 mg once daily (OD) are reduced in comparison with 400/100 mg twice daily (BID). While OD dosage of LPV/r is sufficient to achieve viral suppression in plasma, data about drug penetration and viral suppression in central nervous system (CNS) is needed, mainly if LPVr is used as maintenance monotherapy strategy in selected patients. The objective of this study was to evaluate CSF HIV-1 RNA and CSF LPV concentrations in patients receiving LPV/r monotherapy OD (LPVrMOD). MATERIAL AND METHODS: This is a cross-sectional sub-study within a prospective, open-label pilot simplification study to evaluate the efficacy and safety of LPV/rMOD in virologically suppressed patients previously receiving a BID LPV/r monotherapy regimen (LPV/rMBID), the "Kmon study" (NCT01581853). To assess LPV concentrations and HIV-1 RNA in CSF, a lumbar puncture (LP) was performed in a subgroup of patients after at least one month of LPVrMOD treatment. Plasma-paired samples of all patients were also obtained. HIV-1 RNA was determined by real-time PCR (limit of detection 40 copies/mL). Liquid chromatography-tandem mass spectrometry (Tandem labs, NJ) was used to determine CSF and blood plasma LPV concentrations. RESULTS: Nine patients were included. Median (range) age was 48 (34-56) years, median CD4 cell count 672 (252-1,408) cells/mL, median nadir CD4 count 125 (35-537) cells/mL and 40% of subjects were HCV-positive. Before starting LPV/rMOD median time on a LPV/r-containing regimen and on LPV/rMBID were 9 (4-11) years and 15 (7-24) months respectively, median time with undetectable HIV viral load was 5 (3-12) years and 2 patients had a previous documented blip. LP was performed a median of 24 (8-36) weeks after starting LPV/rMOD and 24 (11-28) hours after the last LPV/rMOD dose CSF and plasma HIV RNA was 40 copies/mL in all patients. Median LPV CSF concentration was 9.78 (1.93-78.3) ng/mL, median LPV plasma concentration 1,103 (377-16,700) ng/mL and median LPV CSF/plasma ratio 0.3% (0.1-1.2). CONCLUSIONS: No CSF viral escape was detected and LPV concentrations were above the IC50 for wtHIV-1 (1.9 ng/mL). However, as concentrations were close to IC50 in some patients, a careful clinical follow up of patients receiving this regimen would be advisable. Larger longitudinal studies will be helpful for a better understanding of the CNS antiviral activity of LPVr monotherapy.

DRV concentrations and viral load in CSF in patients on DRV/r 600/100 or 800/100mg once daily plus two NRTI.

INTRODUCTION: Darunavir/r (DRV/r) is currently used at a dose of 800/100 mg once daily (OD) in a high proportion of patients. Pharmacokinetic data suggest that 600/100 OD may be effective, reducing toxicity and cost. However, drug concentrations in reservoirs such as cerebrospinal fluid (CSF) might not be adequate to inhibit viral replication. We aimed to evaluate concentrations of DRV and HIV-1 viral load (VL) in CSF patients receiving DRV 600/100 mg OD. METHODS: DRV600 is an ongoing randomized open study comparing DRV/r 800/100 mg (DRV800) vs 600/100 mg (DRV600) OD plus TDF/FTC or ABC/3TC in 100 virologically suppressed patients (eudraCT 2011-006272-39). Here we present the results of a CSF sub-study. A lumbar puncture (LP) was performed in participating patients after at least six months of inclusion in the study, 20-28 hours after a dose of DRV/r. VL (PCR, LOD 40 copies/mL) was determined in CSF and in plasma. DRV concentrations were quantified in CSF by liquid chromatography mass spectrometry (LC/MS/MS) and in plasma using high-performance liquid chromatography (HPLC). RESULTS: Sixteen patients were included (eight in each arm). All DRV600 patients and four out of eight DRV800 patients received TDF/FTC, and the other four ABC/3TC. 75% were males, median (range) age was 48 (17-71) years, CD4 cell count 532 cells/mL (190-1,394). Median total time on DRV/r was 30 (11-57) months, and since the beginning of the study 8 (6-12) months in DRV800 and 10 (7-12) months in DRV600 patients. LP was performed a median of 26 (24-28) hours after the last DRV/r+TVD or KVX dose. In DRV600 patients the median DRV plasma levels were 1,674 (326-3,742) ng/mL, CSF levels 17.08 (5.79-30.19) ng/mL and DRV CSF:plasma ratio 0.0084 (0.0028-0.0388), while in the DRV800 arm, median DRV plasma levels were 1,707 (958-3,910) ng/mL, CSF levels 13.23 (3.47-32.98) ng/mL and DRV CSF:plasma ratio 0.0104 (0.0018-0.0262). All patients had VL<40 copies/mL in plasma and 14 patients VL<40 copies/mL in CSF. Two patients (1 in each arm, and taking TDF/FTC) had detectable VL in CSF (280 and 159 c/mL). These patients had the lowest CSF DRV concentrations (5.47 and 3.47 ng/mL), with plasma DRV concentrations of 802 and 958 ng/mL respectively. CONCLUSIONS: CSF DRV concentrations and CSF VL were similar between patients receiving DRV/r 800/100 mg or 600/100 mg OD. Low CSF DRV concentrations might be associated with viral escape in CNS. This may be taken into account in patients receiving OD DRV/r. Larger studies should confirm these findings.