Darunavir concentrations in CSF of HIV-infected individuals when boosted with cobicistat versus ritonavir.

Objectives: Cobicistat and ritonavir have different inhibitory profiles for drug transporters that could impact the distribution of co-administered drugs. We compared darunavir concentrations in CSF when boosted by cobicistat versus ritonavir relative to plasma concentrations and with WT HIV-1 IC50 and IC90. Methods: An open, single-arm, sequential clinical trial (NCT02503462) where paired CSF and blood samples were taken from seven HIV-infected patients presenting with HIV-associated neurocognitive disorders (HAND) and treated with a darunavir/ritonavir (800/100 mg) once-daily regimen. Ritonavir was subsequently replaced by cobicistat and paired CSF and blood samples were obtained from the same patients after treatment with the darunavir/cobicistat (800/150 mg) once-daily regimen. Darunavir concentrations at the end of the dosing interval were quantified by LC-MS/MS. Results: The median (IQR) darunavir concentrations in CSF with ritonavir and cobicistat boosting were 16.4 ng/mL (8.6-20.3) and 15.9 ng/mL (6.7-31.6), respectively (P = 0.58). The median (IQR) darunavir CSF:plasma ratios with ritonavir and cobicistat boosting were 0.007 (0.006-0.012) and 0.011 (0.007-0.015), respectively (P = 0.16). Darunavir concentrations in CSF exceeded the darunavir IC50 and IC90 by a median of 9.2- and 6.7-fold with ritonavir boosting, and by 8.9- and 6.5-fold with cobicistat boosting, respectively. All patients had darunavir CSF concentrations above the target inhibitory concentrations and remained virologically suppressed in the CSF and plasma. Conclusions: This small study shows that cobicistat and ritonavir give comparable effective darunavir concentrations in CSF, thus suggesting that these boosters can be used interchangeably in once-daily darunavir regimens.

Protease inhibitor monotherapy and the CNS: peace of mind?

Boosted protease inhibitor (bPI) monotherapy has demonstrated high efficacy for maintaining viral suppression in the blood. bPI monotherapy has the theoretical advantage of avoiding the long-term toxicity associated with the use of nucleoside reverse transcriptase inhibitors. Concern about the efficacy of bPI monotherapy in preventing HIV replication in the CNS is one reason that has precluded the widespread use of this therapeutic strategy. In several studies, a low CNS penetration-effectiveness (CPE) score has been associated with a higher risk of virological failure in the CNS and with neurocognitive impairment. Since the CPE score is substantially lower for bPI monotherapy than for triple-drug highly active antiretroviral therapy (HAART), it has been postulated that bPI monotherapy might have a higher risk for CNS virological failure and neurocognitive impairment. However, the available evidence, although limited, does no support this notion. Lopinavir and darunavir achieve CSF drug levels that are sufficient to fully suppress HIV replication. In clinical trials, when compared with triple-drug HAART, patients receiving bPI monotherapy with lopinavir and darunavir who maintain full virological suppression in plasma do not appear to be at a higher risk of discordant HIV replication in the CSF or of neuropsychiatric adverse events. It should be noted that several studies have suggested that nucleoside reverse transcriptase inhibitors might have neurotoxic effects and, consequently, bPI monotherapy might be able to avoid the CNS toxicity induced by nucleosides. It is clear that more studies including detailed neurocognitive testing are needed to completely establish the risk/benefit ratio of bPI monotherapy or triple-drug HAART for preserving neurocognitive function in HIV-infected patients.

Lopinavir cerebrospinal fluid steady-state trough concentrations in HIV-infected adults.

BACKGROUND: The central nervous system may act as a sanctuary site for viral replication in the setting of low antiretroviral penetration. Data on lopinavir cerebrospinal fluid (CSF) trough concentration (C(trough)) values have yet to be reported. OBJECTIVE: To describe lopinavir CSF C(trough) values and compare them with a measure of HIV susceptibility. METHODS: In a prospective, open-label design, HIV-infected adults whose regimen included lopinavir/ritonavir 400/100-mg soft-gel capsules twice daily for at least 4 weeks were enrolled. Each subject had 8 plasma lopinavir concentrations determined over a 12-hour dosing interval and 1 CSF lopinavir C(trough) value determined at the end of the study. Linear regression methods tested for associations between CSF or CSF to plasma concentration ratio and covariates including pharmacokinetic parameters and CSF protein. RESULTS: Ten patients (7 male; median [range] +/- SD age 45.3 +/- 2.8 y) completed the study. Median (intraquartile range [IQR]) lopinavir plasma 0- to 12-hour area under the curve (AUC(0-12)) and minimum concentrations were 71.3 h x microg/mL (48.4-87.6) and 3.82 microg/mL (2.76-5.34). Median (IQR) CSF C(trough), paired plasma concentration, and time since last dose were 11,200 pg/mL (6760-16,400), 5.42 microg/mL (3.88-5.85), and 9.9 hours (9.7-10.2), respectively. Median (IQR) CSF to plasma concentration ratio was 0.225% (0.194-0.324). Lopinavir CSF C(trough) was above the median 50% inhibitory concentration (IC(50)) for wild-type HIV-1 (wtHIV-1) (1900 pg/mL) in all subjects. Lopinavir plasma AUC(0-12) (r(2) = 0.65; p = 0.009) and CSF protein (r(2) = 0.26; p = 0.006) were associated with lopinavir CSF concentration, while CSF protein (r(2) = 0.66; p = 0.008) was associated with CSF to plasma concentration ratio. CONCLUSIONS: Lopinavir CSF C(trough) was above the median IC(50) for wtHIV-1 replication in all patients receiving lopinavir/ritonavir 400/100-mg soft-gel capsules twice daily.

Darunavir concentrations in cerebrospinal fluid and blood in HIV-1-infected individuals.

Darunavir is the most recently licensed protease inhibitor currently used in treatment-experienced HIV-infected individuals. Our objective was to determine darunavir concentrations in cerebrospinal fluid (CSF) and plasma in subjects receiving antiretroviral treatment regimens containing ritonavir-boosted darunavir. Darunavir concentrations were determined by liquid chromatography tandem mass spectrometry in 14 paired CSF and plasma samples from eight HIV-1-infected individuals. The lower limit of quantification was 5.0 ng/ml. All of the 14 CSF samples had detectable darunavir concentrations with a median darunavir concentration of 34.2 ng/ml (range 15.9-212.0 ng/ml). The median (range) plasma darunavir concentration was 3930 (1800-12900) ng/ml. All CSF samples had detectable darunavir concentrations. Most of them exceeded or were in the same range as levels needed to inhibit replication of wild type virus, making it probable that darunavir, at least to some extent, contributes to the suppression of HIV replication in the central nervous system.

Low atazanavir concentrations in cerebrospinal fluid.

OBJECTIVE: Protease inhibitors may not penetrate into the central nervous system in therapeutic concentrations, which may allow ongoing HIV replication and injury. The objective of this study was to determine atazanavir penetration into cerebrospinal fluid (CSF). DESIGN: Single random plasma or paired plasma and CSF samples were drawn from participants enrolled in a multicenter, observational cohort study and taking atazanavir with or without ritonavir between October 2003 and October 2005. METHODS: Plasma samples were assayed by high performance liquid chromatography and immunoassay; lower limit of detection was 45 ng/ml. CSF samples were assayed by immunoassay (ARK ATV-test); lower limit of detection was 5 ng/ml. RESULTS: One hundred and seventeen participants (43 +/- 7.7 years, 79% men, 81 +/- 15 kg) had plasma or plasma and CSF paired samples drawn a median (interquartile range) of 10 (5-17) h postdose. Median (interquartile range) plasma atazanavir concentrations with or without ritonavir were 1278 (525-2265) and 523 (283-1344) ng/ml. The median (interquartile range) CSF concentrations with or without ritonavir were 10.3 (<5-21.1) and 7.9 (6.6-22) ng/ml. Nineteen of 79 (24%) CSF samples were less than 5 ng/ml. CSF concentrations were less than 1% of plasma concentrations and near the atazanavir wild-type IC50 of 1-11 ng/ml. CONCLUSION: Atazanavir CSF concentrations are highly variable and 100-fold lower than plasma concentrations, even with ritonavir boosting. CSF concentrations of atazanavir do not consistently exceed the wild-type IC50 of atazanavir and may not protect against HIV replication in the CSF.

Central nervous system distribution kinetics of indinavir in rats.

The central nervous system (CNS) distribution kinetics of indinavir were extensively evaluated using a combinational in-vivo model comprising the integration plot method (a single-passage approach) and neuropharmacokinetic method (a multiple-passage approach). A 5 mg kg(-1) dose of indinavir was administered intravenously to rats. Blood and cerebrospinal fluid (CSF) samples and whole brain were collected from the animals at specified time points and the drug concentration in each sample was determined using a high-performance liquid chromatography method. For the neuropharmacokinetic study, the simultaneous plasma, CSF and brain concentrations were fitted to an integrated model, which resulted in the estimation of the influx (K(in)) and efflux (K(out)) rate constants of the drug to/from CSF and brain parenchyma. The integration plot method involved plotting the brain-plasma or CSF-plasma concentration ratios (K(p, app)) against AUC(0-->t)/C(p(t)), and estimating the uptake clearance of the drug by brain/CSF from the slope of the initial linear portion of the plot. The K(in) and K(out) values of the drug to/from CSF were estimated to be 2.42 x 10(-2) and 13.26 x 10(-2)min(-1), respectively, and the corresponding values for brain parenchyma were 1.02 x 10(-2) and 1.32 x 10(-2) min(-1), respectively. The uptake clearances of indinavir by CSF and brain parenchyma were 8.89 and 8.38microL min(-1)g(-1), respectively. The permeability surface area products of the drug for the blood-brain barrier and blood-CSF barrier were estimated as 1.05 x 10(-2) and 2.45 x 10(-2) mLmin(-1)g(-1), respectively. The estimated kinetic parameters indicated limited CNS entry of the drug because of the limited blood-brain barrier permeability and the efficient drug efflux from CNS, particularly from CSF.

Inhibition of P-glycoprotein activity at the primate blood-brain barrier increases the distribution of nelfinavir into the brain but not into the cerebrospinal fluid.

P-glycoprotein (P-gp) expression at the rodent blood-brain barrier (BBB) limits the central nervous system (CNS) distribution of anti-human immunodeficiency virus (HIV) protease inhibitors (PIs). However, it is not clear whether P-gp activity at the human BBB is as effective as that in rodents in preventing the distribution of PIs into the CNS. If it is, inhibition of P-gp at the human BBB could increase the distribution of the PIs into the CNS and, therefore, their efficacy against HIV-associated dementia. Because the distribution of the PIs into the human brain cannot be directly measured, we conducted studies in a more representative animal, the nonhuman primate. Specifically we investigated the distribution of nelfinavir (a PI and a P-gp substrate; 6 mg/kg i.v.) into the brain and cerebrospinal fluid (CSF) of nonhuman primates (cynomolgus monkeys, Macaca fascicularis) in the presence and absence of the potent and selective P-gp inhibitor, zosuquidar, and whether changes in brain nelfinavir concentration, after inhibition of P-gp, paralleled those in the CSF. Our data indicate that nelfinavir has poor penetration into the macaque's brain and CSF, and P-gp inhibition at the BBB by zosuquidar enhanced the distribution of nelfinavir into the brain by 146-fold. However, the concentration of nelfinavir in the CSF was unaffected by coadministration of zosuquidar (p > 0.05). In conclusion, P-gp inhibition at the nonhuman primate BBB significantly enhanced the distribution of nelfinavir into the brain, and this effect was not observed in the CSF. Therefore, as is common in human studies investigating P-gp inhibition at the BBB, CSF concentration of a drug should not be used as a surrogate marker for brain drug concentration.

Efficacy of nelfinavir-based treatment in the central nervous system of HIV-1 infected patients.

We studied the HIV-1 load and nelfinavir (NFV) concentrations in cerebrospinal fluid (CSF) after long-term successful NFV-based therapy, using ultrasensitive methods of detection. 19 patients without virological failure in plasma, who had been treated with 2 nucleoside analogue reverse transcripaste inhibitors (NRTI) and NFV for a minimum of 18 months were included. HIV-RNA was determined in plasma and CSF using an ultrasensitive method (<2 copies/ml). Total and free concentrations of NFV were analysed using high liquid chromatography with UV-light detection. 12 out of 19 (63%) patients had <2 copies HIV-RNA/ml in CSF. Seven subjects ranged between 3 and 39 copies/ml, 2 of whom had a slightly higher viral load in CSF than in plasma. NFV was detected in CSF in 16 out of 18 patients analysed and was quantifiable in 8 patients, at concentrations ranging from 6 to 29 nM. There was no correlation between NFV concentration and HIV-RNA levels. Long-term therapy with NFV + 2 NRTI showed no increased rate of virological treatment failure within the central nervous system (CNS) in compliant patients, despite earlier reports of lack of NFV penetration to CNS. Using a highly sensitive method, NFV was detected and quantified in the CSF, although at low values, which could have contributed to the high anti-HIV-1 efficacy of the therapy seen in our subjects.

Simple and sensitive high-performance liquid chromatography method for the quantitation of indinavir in rat plasma and central nervous system.

A simple and sensitive RP-HPLC method using UV detection (215 nm) was developed for the determination of indinavir concentrations in rat plasma, cerebrospinal fluid (CSF), and brain tissue homogenates. Biological samples were processed using a combination of acid pretreatment and liquid-liquid extraction with verapamil used as the internal standard. This method produced a linear response throughout the indinavir concentration range of 0.05-30 microM in plasma and 0.05-2.5 microM in CSF and brain with a LOD of 12.5 nM for plasma and CSF, and 6.25 nM for brain homogenate. Due to its high sensitivity, this assay is particularly useful for the quantitative determination of indinavir concentrations in brain and CSF.

Bioanalysis of HIV protease inhibitors in samples from sanctuary sites.

The human immunodeficiency virus (HIV) is present in several sites inside the human body, which are hardly accessible to antiretroviral drugs, the so-called sanctuary sites. The most important sanctuary sites are cerebrospinal fluid (CSF), peripheral blood mononuclear cells (PBMCs) and seminal plasma. The determination of drug concentrations in these sanctuary sites may form an important step in treatment optimisation of HIV-infected individuals. However, bioanalysis in these sites is hampered by several factors with regard to sample preparation, chromatography and detection. In this review, we will discuss these issues and give an overview of published methods using high-performance liquid chromatography (HPLC) for the bioanalysis of HIV protease inhibitors in CSF, PBMCs and seminal plasma.

Lopinavir concentrations in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV.

INTRODUCTION: Lopinavir (LPV) is highly bound to plasma proteins and is a substrate for active drugs transporters, which may greatly limit the access of LPV to the central nervous system (CNS). However, even low lopinavir concentrations may be sufficient to inhibit HIV replication. Prior anecdotal reports indicated that lopinavir concentrations were below detection in cerebrospinal fluid (CSF). METHODS: LPV was measured by liquid chromatography/mass spectrometry in 31 CSF-plasma pairs from 26 HIV-infected individuals who were taking LPV-containing antiretroviral regimens. The lower limit of quantification was 3.7 microg/l. RESULTS: Seven of the sample pairs had very low plasma (and CSF) LPV concentrations, with a mean estimated plasma trough of 274 microg/l (range, < 3.7 to 608; typical trough values approximately 4000 microg/l), suggesting poor recent adherence. In the remaining 24 sample pairs, the median LPV concentration was 5889 microg/l [interquartile range (IQR), 4805-9620] and all CSF samples had measurable LPV concentrations: median 17.0 microg/l (IQR, 12.1-22.7). The median CSF-plasma ratio was 0.23% (range, 0.12-0.75). All CSF concentrations in these samples were more than double the 50% inhibitory concentration for wild-type HIV virus. CONCLUSIONS: In patients with typical plasma levels of LPV, the drug is detectable in the CSF at concentrations that exceed those needed to inhibit HIV replication. Despite being > 98% bound to plasma proteins, LPV penetrates into the CNS and may contribute to the control of HIV in this potential reservoir.

Lopinavir/ritonavir combined with twice-daily 400 mg indinavir: pharmacokinetics and pharmacodynamics in blood, CSF and semen.

OBJECTIVES: To evaluate the steady-state blood plasma (BP), CSF and seminal plasma (SP) pharmacokinetics (PK) of twice-daily indinavir 400 mg and lopinavir/ritonavir. METHODS: Ten HIV-1-positive men on lopinavir/ritonavir participated in a PK study. PK sampling was performed before and 2 weeks after adding indinavir to lopinavir/ritonavir-containing regimens. BP, CSF and SP RNA levels, CD4 counts and blood chemistry were checked at baseline and 2 weeks after indinavir. RESULTS: At baseline: lopinavir parameters (n=10) in BP were within expected levels. Median lopinavir trough concentrations (n=5) in CSF and SP were below the limit of detection (BLD) (i.e. <10 ng/mL) and 248 ng/mL (range 96-2777), respectively. After indinavir: lopinavir C(max), C(min) and AUC(0-12) increased by 9%, 46% and 20%, respectively (P<0.32, P<0.32 and P<0.20). In two of four men lopinavir concentrations in CSF were detectable at 27 and 29 ng/mL. Median SP lopinavir concentration was 655 ng/mL (20-2734). Median indinavir PK parameters were C(max) 3365 ng/mL (range 2130-5194), C(min) 293 ng/mL (14-766), T(max) 2.25 h (1-3), AUC(0-12) 22452 ng/mL.h (11243-33661), and t(1/2) 2.8 h (1.4-3.7). Median indinavir concentrations in CSF and SP were 39 ng/mL (21-86) and 592 ng/mL (96-983). Two of eight men who initially had detectable BP viral load (VL) became BLD (<50 copies/mL) after the addition of indinavir, and in 2/4 men with low-level viraemia in SP (BPVL BLD) their SPVL became BLD after addition of indinavir. CONCLUSIONS: Adding indinavir 400 mg twice daily to lopinavir/ritonavir-containing regimens did not significantly alter the median lopinavir PK parameters. However, wide interpatient variability in lopinavir concentrations was seen. In contrast plasma indinavir levels were >80 ng/mL in seven of eight plasma samples, and all CSF and semen samples collected.

Effects of ritonavir on indinavir pharmacokinetics in cerebrospinal fluid and plasma.

Therapeutic control of human immunodeficiency virus type 1 (HIV-1) in peripheral compartments does not assure control in the central nervous system. Inadequate drug penetration may provide a sanctuary from which resistant virus can emerge or allow development of psychomotor abnormalities. To characterize the effect of ritonavir on indinavir disposition into cerebrospinal fluid, seven HIV-infected adults underwent intensive sampling at steady-state while receiving twice-daily indinavir (800 mg) and ritonavir (100 mg). Serial cerebrospinal fluid and plasma samples were obtained at 10 time points from each subject. Free indinavir accounted for 98.6% of drug in cerebrospinal fluid and 55.9% in plasma. Mean cerebrospinal fluid C(max), C(min), and area under the concentration-time curve from 0 to 12 h (AUC(0-12)) values for free indinavir were 735 nM, 280 nM, and 6502 nM h(-1), respectively, and the free levels exceeded 100 nM in every sample. The cerebrospinal fluid/plasma AUC(0-12) ratio for free indinavir was 17.5% +/- 6.4%. This ratio was remarkably similar to results obtained in a previous study in which subjects received indinavir without ritonavir, indicating that ritonavir did not have a substantial direct effect on the barrier to indinavir penetration into cerebrospinal fluid. Low-dose ritonavir increases cerebrospinal fluid indinavir concentrations substantially more than 800 mg of indinavir given thrice daily without concomitant ritonavir, despite a lower total daily indinavir dose.

Suppression of cerebrospinal fluid HIV burden in antiretroviral naive patients on a potent four-drug antiretroviral regimen.

OBJECTIVE: To determine the longitudinal response of HIV in the cerebrospinal fluid (CSF) to highly active antiretroviral therapy (HAART) and to investigate the levels of indinavir penetrating into the CSF. DESIGN: Open study of HIV-infected subjects naive to therapy with protease inhibitors. SETTING: Tertiary care referral center. SUBJECTS: Twenty-five participants were begun on indinavir, nevirapine, zidovudine, and lamivudine. INTERVENTIONS: Lumbar punctures were performed prior to therapy and 2 and 6 months after beginning therapy. Plasma and CSF were assayed for routine cell counts, chemistries, HIV load and indinavir levels. RESULTS: Twenty-two subjects had CSF HIV RNA level data available at all three time points, three others at baseline and 2 months. At month 2 of therapy, nine of 25 (36%) subjects had CSF HIV RNA levels > 50 HIV RNA copies/ml. By 6 months, all 22 subjects had CSF HIV RNA levels < 50 HIV RNA copies/ml. CSF white blood cell counts fell from a baseline mean of 5.3 x 10(6)/l to 1.9 x 10(6)/l (P = 0.013) at 6 months. Plasma indinavir levels declined rapidly while CSF levels remained stable throughout the 8-h dosing interval. The median CSF indinavir level was 71 ng/ml, approximating the upper limit of the 95% inhibitory concentration for indinavir against HIV-1. CONCLUSIONS: CSF HIV RNA levels cannot be expected to fall below 50 HIV RNA copies/ml even after 2 months of therapy on HAART. Prolonged therapy may be required to suppress HIV levels within the central nervous system.

Discrepancies between protease inhibitor concentrations and viral load in reservoirs and sanctuary sites in human immunodeficiency virus-infected patients.

The variable penetration of antiretroviral drugs into sanctuary sites may contribute to the differential evolution of human immunodeficiency virus (HIV) and the emergence of drug resistance. We evaluated the penetration of indinavir, nelfinavir, and lopinavir-ritonavir (lopinavir/r) in the central nervous system, genital tract, and lymphoid tissue and assessed the correlation with residual viral replication. Plasma, cerebrospinal fluid (CSF), semen, and lymph node biopsy samples were collected from 41 HIV-infected patients on stable highly active antiretroviral therapy regimens to determine drug concentrations and HIV RNA levels. When HIV RNA was detectable, sequencing of the reverse transcriptase and protease genes was performed. Ratios of the concentration in semen/concentration in plasma were 1.9 for indinavir, 0.08 for nelfinavir, and 0.07 for lopinavir. Only indinavir was detectable in CSF, with a concentration in CSF/concentration in plasma ratio of 0.17. Differential penetration into lymphoid tissue was observed, with concentration in lymph node tissue/concentration in plasma ratios of 2.07, 0.58, and 0.21 for indinavir, nelfinavir, and lopinavir, respectively. HIV RNA levels were <50 copies/ml in all CSF samples of patients in whom HIV RNA was not detectable in plasma. HIV RNA was detectable in the semen of three patients (two patients receiving nelfinavir and one patient receiving lopinavir/r), and its detection was associated with multiple resistance mutations, while the viral load in plasma was undetectable. HIV RNA was detectable in all lymph node tissue samples. Differential drug penetration was observed among the three protease inhibitors in the sanctuary sites, but there was no correlation between drug levels and HIV RNA levels, suggesting that multiple factors are involved in the persistence of viral reservoirs. Further studies are required to clarify the role and clinical relevance of drug penetration in sanctuaries in terms of long-term efficacy and drug resistance.

Differences in the detection of three HIV-1 protease inhibitors in non-blood compartments: clinical correlations.

PURPOSE: To study the presence of three HIV-1 protease inhibitors (PIs) in the cerebrospinal fluid (CSF), semen, and lymph nodes and to assess the correlations with residual viral replication in these compartments. METHOD: We performed a cross-sectional analysis of sanctuary samples from 41 HIV-infected patients on stable highly active antiretroviral therapy (HAART) regimens containing indinavir, nelfinavir, or lopinavir combined with ritonavir (lopinavir/r) and a longitudinal analysis of PI levels and HIV-1 RNA in plasma and CSF of 6 additional patients on nelfinavir or lopinavir/r monotherapy (3 cases each). Plasma, CSF, semen, and a lymph node (LN) biopsy were taken on the same day. Samples were assayed for PI concentrations, HIV-1 RNA levels, and, when detectable, sequencing of the reverse transcriptase and protease genes on seminal viral RNA. RESULTS: In the cross-sectional analysis, the CSF/plasma ratio was 0.14 for indinavir. Nelfinavir and lopinavir/r were consistently undetectable in CSF. The semen/plasma ratio was 1.9 for indinavir, 0.07 for nelfinavir, and 0.07 for lopinavir. The LN/plasma ratio was 2.07 for indinavir, 0.58 for nelfinavir, 0.21 for lopinavir, and 0.64 for ritonavir. Plasma HIV-1 RNA was <50 copies/mL in 28 patients and was detectable in 13 patients. HIV-1 RNA was <50 copies/mL in CSF samples when plasma RNA was undetectable. Three semen samples taken from patients with viremia <50 copies/mL showed detectable HIV-1 RNA with resistance mutations. HIV-1 RNA was detectable in all LNs, with no differences in patients on indinavir compared with those on nelfinavir or lopinavir/r. In the longitudinal analysis, HIV-1 RNA decreased in the plasma of the 6 patients on nelfinavir or lopinavir/r monotherapy, although CSF HIV-1 RNA decreased only in patients on lopinavir/r. CONCLUSION: Major differences exist between PIs in terms of detection in non-blood compartments. An undetectable PI level in CSF does not rule out drug activity in the brain for lopinavir/r, although this is not the case for nelfinavir. Poor penetration of PIs in semen in some patients can lead to double nucleoside therapy in this compartment. The persistence of HIV-1 RNA in LNs does not seem to be related to PI levels in this tissue.

[Indinavir-ritonavir combination: pharmacologic results and tolerance in patients infected by HIV]. / Association indinavir-ritonavir: résultats pharmacologiques et tolérance chez les patients infectés par le VIH.

OBJECTIVES: Ritonavir (RTV) is a powerful inhibitor of P450 3A4 cytochorme. When given in combination with indinavir (IDV) it increases the IDV trough concentrations (Cmin) allowing a lower IDV dosage in a twice a day regimen, independently of meals. We report tolerance data and IDV Cmin levels observed in plasma and cerebrospinal fluid (CSF) in a cohort of HIV-infected patients treated with the IDV-RTV combination at different dosages of IDV and RTV. PATIENTS AND METHODS: IDV Cmin was assayed 56 times in 40 patients (few patients had received different dosages of the IDV-RTV combination). Tolerance was recorded. RESULTS: For patients given the IDV-RTV combination at the doses of 800/100 mg b.i.d., 800/200 mg b.i.d. or 400/400 mg b.i.d., the IDV Cmin was 12 times the median IDV IC95. If the Cmin/IC95 ratio was greater than 10 with the 800/100 mg b.i.d. regimen and virological success was achieved, the IDV dosage was reduced to 400 mg b.i.d. For these patients, the 400/100 mg b.i.d. IDV-RTV regimen always gave a Cmin above the IDV IC95. Median Cmin for IDV in CSF was 146 ng/ml (range 71-881 ng/ml), above the IDV IC95. It was possible to control most of the adverse effects by reducing dosage after obtaining the IDV pharmacological levels. Definitive interruption of treatment was required in only 2 cases at mean follow-up of 7.9 months. DISCUSSION: The IDV-RTV combination should be used to improve observance of antiretroviral treatments and reduce the risk of virological failure related to low plasma levels. The IDV-RTV combination at 800/100 mg b.i.d. is a useful protocol when IDV efficacy alone is the goal. The 400/400 mg b.i.d. IDV-RTV regimen is an interesting alternative when efficacy of both inhibitors is the goal. Drug assays should be systematic to adapt individual dosages and limit the risk of adverse effects.

Steady-state pharmacokinetics of indinavir in cerebrospinal fluid and plasma among adults with human immunodeficiency virus type 1 infection.

To characterize steady-state indinavir pharmacokinetics in cerebrospinal fluid and plasma, 8 adults infected with human immunodeficiency virus underwent intensive cerebrospinal fluid sampling while receiving indinavir (800 mg every 8 hours) plus nucleoside reverse transcriptase inhibitors. Nine and 11 serial cerebrospinal fluid and plasma samples, respectively, were obtained from each subject. Free indinavir accounted for 94.3% of the drug in cerebrospinal fluid and 41.7% in plasma. Mean values of cerebrospinal fluid peak concentration, concentration at 8 hours, and area under the concentration-time profile calculated over the interval 0 to 8 hours [AUC(0-8)] for free indinavir were 294 nmol/L, 122 nmol/L, and 1616 nmol/L x h, respectively. The cerebrospinal fluid-to-plasma AUC(0-8) ratio for free indinavir was 14.7% +/- 2.6% and did not correlate with indexes of blood-brain barrier integrity or intrathecal immune activation. Indinavir achieves levels in cerebrospinal fluid that should contribute to control of human immunodeficiency virus type 1 replication in this compartment. The cerebrospinal fluid-to-plasma AUC(0-8) ratio suggests clearance mechanisms in addition to passive diffusion across the blood-cerebrospinal fluid barrier, perhaps by P-glycoprotein-mediated efflux.