High prevalence of human papillomavirus infections in urine samples from human immunodeficiency virus-infected men.

Infection with human immunodeficiency virus (HIV) and the resulting immunosuppression are associated with an increased risk for human papillomavirus (HPV) persistence and related malignancies. In the present study we investigated the prevalence of HPV in urine samples from 104 HIV-infected men with low CD4+ cell counts (<100 per mm(3)) and 115 urine samples from HIV-negative men. A high prevalence of HPV DNA (39.4%) was found in the HIV patients. Most of the HPV types were high risk (81.4%), with HPV 52 as the most prevalent type (12.5%), followed by HPV 18 (6.7%), HPV 35 (5.8%), and HPV 70 (4.8%). Multiple HPV genotypes were observed in 17 (41%) of the 41 HPV- and HIV-positive men. In contrast, only 11 (9.6%) HPV DNA-positive cases were observed among the 115 HIV-uninfected men, and 3 (27.3%) contained multiple genotypes. Quantitative analyses indicated that the HPV viral load, as measured in urine samples, is significantly higher in HIV-positive men compared to HIV-negative men. In the present study we show that urine samples are useful for detecting HPV DNA, there is a high prevalence of HPV in HIV-positive men, and the HPV viral load is substantially higher in HIV-positive than in HIV-negative men. More studies are needed to evaluate the risk and natural development of HPV-related malignancies in HIV-positive men.

Population pharmacokinetics of indinavir alone and in combination with ritonavir in HIV-1-infected patients.

AIMS: The aim of the study was to characterize the population pharmacokinetics of indinavir, define the relationship between the pharmacokinetics of indinavir and ritonavir, and to identify the factors influencing the pharmacokinetics of indinavir alone or when given with ritonavir. METHODS: HIV-1-infected patients being treated with an indinavir-containing regimen were included. During regular visits, 102 blood samples were collected for the determination of plasma indinavir and ritonavir concentrations. Full pharmacokinetic curves were available from 45 patients. Concentrations of indinavir and ritonavir were determined by liquid chromatography coupled with electrospray tandem mass spectrometry. Pharmacokinetic analysis was performed using nonlinear mixed effect modelling (NONMEM). RESULTS: The disposition of indinavir was best described by a single compartment model with first order absorption and elimination. Values for the clearance, volume of distribution and the absorption rate constant were 46.8 l h(-1) (24.2% IIV), 82.3 l (24.6% IIV) and 02.62 h(-1), respectively. An absorption lag-time of 0.485 h was detected in patients also taking ritonavir. Furthermore this drug, independent of dose (100-400 mg) or plasma concentration, decreased the clearance of indinavir by 64.6%. In contrast, co-administration of efavirenz or nevirapine increased the clearance of indinavir by 41%, irrespective of the presence or absence of ritonavir. Female patients had a 48% higher apparent bioavailability of indinavir than males. CONCLUSIONS: The pharmacokinetic parameters of indinavir were adequately described by our population model. Female gender and concomitant use of ritonavir and non-nucleoside reverse transcriptase inhibitors strongly influenced the pharmacokinetics of this drug. The results support the concept of ritonavir boosting, maximum inhibition of indinavir metabolized being observed at 100 mg.

Population pharmacokinetics of efavirenz in an unselected cohort of HIV-1-infected individuals.

OBJECTIVE: The aim of this study was to characterise the population pharmacokinetics of efavirenz in a representative patient population and to identify patient characteristics influencing the pharmacokinetics of efavirenz, with the ultimate goal of further developing techniques that can be applied to optimise therapeutic drug monitoring of antiretroviral agents. METHODS: Ambulatory HIV-1-infected patients using an efavirenz-containing regimen were included. During regular visits, blood samples were collected for efavirenz plasma concentrations and clinical chemistry parameters. Concentrations of efavirenz were quantitatively assessed by a validated high-performance liquid chromatographic with ultraviolet detection method. Using nonlinear mixed-effect modelling (NONMEM), the pharmacokinetics of efavirenz were described. Disposition of efavirenz was described by a two-compartment model and absorption was modelled using a chain of three transition compartments. Apparent clearance (CL/F), volume of distribution after oral administration (V(d)/F), intercompartmental clearance, the peripheral volume of distribution and the intercompartmental transition rate constant (k(tr)) were estimated. Furthermore, interindividual, interoccasion and residual variability were estimated. The influence of patient characteristics on the pharmacokinetic parameters of efavirenz was explored. RESULTS: From 172 patients, 40 full pharmacokinetic curves and 315 efavirenz plasma concentrations at a single timepoint were available, resulting in a database of 1009 efavirenz plasma concentrations. CL/F, V(d)/F, and k(tr) were 11.7 L/h (4.3% relative standard error [RSE]), 189L (14.6% RSE) and 3.07 h(-1) (11.2% RSE), respectively. Residual variability in the model was composed of 0.14 mg/L additive error and 8.85% proportional error. Asian race and baseline total bilirubin (TBR) increased the relative bioavailability of efavirenz by 56% and 57%, respectively. No significant covariates were found for CL/F or V(d)/F. CONCLUSION: The pharmacokinetic parameters of efavirenz were adequately described with the developed population pharmacokinetic model. Asian race and baseline TBR were found to be significantly correlated with the bioavailability of efavirenz. The described model will be an essential tool in further optimisation of efavirenz-containing antiretroviral therapy, e.g. by the use of Bayesian estimation of individual pharmacokinetic parameters.

Development and validation of a population pharmacokinetic model for ritonavir used as a booster or as an antiviral agent in HIV-1-infected patients.

AIMS: The aim of this study was to develop and validate a population pharmacokinetic model of ritonavir, used as an antiviral agent or as a booster, in a large patient population and to identify factors influencing its pharmacokinetics. METHODS: Ambulatory HIV-1-infected patients from the outpatient clinic of the Slotervaart Hospital, Amsterdam, the Netherlands, who were being treated with a ritonavir-containing regimen were included. During regular visits, blood samples were collected for the determination of ritonavir plasma concentrations and several clinical chemistry parameters. Furthermore, complete pharmacokinetic curves were available in some patients. Single and multiple compartment models with zero-order and first-order absorption, with and without absorption lag-time, with linear and nonlinear elimination were tested, using nonlinear mixed effect modelling (NONMEM). Pharmacokinetic parameters and interindividual, interoccasion and residual variability were estimated. In addition, the influence of several factors (e.g. patient characteristics, comedication) on the pharmacokinetics of ritonavir was explored. RESULTS: From 186 patients 505 ritonavir plasma concentrations at a single time-point and 55 full pharmacokinetic profiles were available, resulting in a database of 1228 plasma ritonavir concentrations. In total 62% of the patients used ritonavir as a booster of their protease inhibitor containing antiretroviral regimen. First order absorption in combination with one-compartment disposition best described the pharmacokinetics of ritonavir. Clearance, volume of distribution and absorption rate constant were 10.5 l h(-1) (95% prediction interval (95% PI) 9.38-11.7), 96.6 l (95% PI 67.2-121) and 0.871 h(-1) (95% PI 0.429-1.47), respectively, with 38.3%, 80.0% and 169% interindividual variability, respectively. The interoccasion variability in the apparent bioavailability was 59.1%. The concomitant use of lopinavir resulted in a 2.7-fold increase in the clearance of ritonavir (P value < 0.001). No patients characteristics influenced the pharmacokinetics of ritonavir. CONCLUSIONS: The pharmacokinetic parameters of ritonavir were adequately described by our population pharmacokinetic model. Concomitant use of the protease inhibitor lopinavir strongly influenced the pharmacokinetics of ritonavir. The model has been validated and can be used for further investigation of the interaction between ritonavir and other protease inhibitors.

The plasma and intracellular steady-state pharmacokinetics of lopinavir/ritonavir in HIV-1-infected patients.

Therapeutic drug monitoring of protease inhibitors (PIs) is usually performed on plasma samples although their antiretroviral effect takes place inside cells. Little is known, however, about the intracellular accumulation and related plasma pharmacokinetics of PIs such as lopinavir/ritonavir (LPV/RTV). Therefore, we studied the plasma and intracellular (cell-associated) steady-state pharmacokinetics of this PI combination in a dosage of 400/100 mg twice daily in a non-randomized cohort of HIV-1-infected individuals. Plasma (0-12 h) and peripheral blood mononuclear cell (PBMC; 0-8 h) samples were drawn during a 12-h dosing interval in 11 subjects. The plasma concentrations versus time curves of LPV and RTV were characterized by an irregular absorption phase showing double-peaks (Cmax) in most subjects and single-peaks in the remaining patients between 1 and 3 h after drug intake. Pre-dose concentrations of both agents in plasma were significantly higher than the concentrations at the end of the dosing interval indicating the presence of a circadian rhythm in their pharmacokinetics. The course of the intracellular concentrations versus time curves appeared to be similar to the plasma concentration curves, with the highest intracellular concentration measured 3 h after drug intake. The intracellular RTV concentrations were higher than reported in vitro EC50 values and might therefore contribute to the antiretroviral effect of LPV/RTV. The median intracellular-to-plasma concentration ratios (interquartile range) were 1.18 (0.74-2.06) and 4.59 (3.20-7.70) for LPV and RTV, respectively. In conclusion, both LPV and RTV accumulate to potential therapeutic concentrations in PBMCs. Irregular absorption and circadian plasma clearance patterns were observed for the PI combination LPV/RTV.

Photophobia in a patient with high indinavir plasma concentrations.

An HIV-infected male patient experienced photophobia after a change in dosing regimen that resulted in substantially higher indinavir plasma levels as compared with a reference population. High indinavir levels were suspected to be the cause of photophobia in this patient.

Incidence and risk factors for nevirapine-associated rash.

OBJECTIVE: To determine the incidence of rash in HIV-1 infected individuals starting a nevirapine-containing regimen in an unselected outpatient clinic population. Possible risk factors including plasma concentrations of nevirapine were evaluated for their relationship with the occurrence of a rash. METHODS: The occurrence of rash was extracted from the outpatient medical records or based on a prescription of the antihistaminic cetirizine as documented by the community pharmacy within the first 90 days of nevirapine use. During regular visits to the clinic blood samples were collected for the determination of nevirapine plasma concentrations. Possible risk factors such as demographics, immunology, virology, clinical chemistry and antiretroviral pretreatment were collected at baseline for each patient. In addition, concomitantly used drugs during the nevirapine-based regimen were recorded. The association between these factors and the occurrence of rash was studied. Primary outcome was the onset of rash within the first 90 days after initiation of a nevirapine-containing regimen. RESULTS: Data from 216 HIV-1-infected patients were used in this study. Thirty-eight patients (17.6%) developed a rash of some grade that led to discontinuation of nevirapine in seven patients (3.2% of the included patients). The median time to occurrence of rash was 26 days (interquartile range 17-46 days). The multivariate analysis showed that patients pretreated with antiretroviral drugs less than 12 months before the initiation of a nevirapine-containing regimen had a more than 2.5-fold increased risk of developing rash. Furthermore, nevirapine plasma concentrations were also significantly related to the occurrence of rash. A more than twofold increased risk for developing rash was observed for patients with nevirapine plasma concentrations above 5.3 mg/l. CONCLUSIONS: This is the first study demonstrating that patients with antiretroviral pretreatment less than 12 months and with nevirapine plasma concentrations above 5.3 mg/l during the first 90 days of treatment are at a higher risk for the development of rash. It is therefore advised to monitor this group of patients carefully when initiating nevirapine-containing therapy.

Subtherapeutic antiretroviral plasma concentrations in routine clinical outpatient HIV care.

The objective of this study was to evaluate plasma concentrations of nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) within several dosing schemes in a cohort of HIV-infected patients in routine clinical practice and to find possible explanations for subtherapeutic plasma concentrations. Patients were included if a PI or NNRTI was part of their antiretroviral regimen, at least one plasma concentration was obtained, and a complete medication overview from community pharmacy records was available. The study period was from January 1998 to September 2001. Each plasma concentration was related to median plasma concentrations of a pharmacokinetic reference curve, yielding a concentration ratio (CR). A cutoff CR was defined for each antiretroviral drug per specific regimen, discriminating between >or=therapeutic and subtherapeutic concentrations. For the patients with subtherapeutic concentrations, it was sorted out whether drug interactions, adverse events and self-reported symptoms, or nonadherence could be the cause of the lower than expected plasma concentration. Ninety-seven HIV-infected patients fulfilled the criteria. During the defined period, 1145 plasma concentrations were available (median, 11; interquartile range, 8-14). Three hundred fourteen (27.4%) plasma concentrations were classified subtherapeutic. Drug interactions (2; 0.6%), adverse events and self-reported symptoms (67; 21.3%), and nonadherence (14; 4.5%) could only partly explain the subtherapeutic drug levels. Consequently, a large number of the subtherapeutic plasma concentrations (73.6%) remained inexplicable. A high number of subtherapeutic plasma concentrations were observed. No clear causes were found; thus, corrective measures will be difficult to employ. Therefore, therapeutic drug monitoring (TDM) must maintain its crucial place in routine clinical care to be able to identify patients who need extra attention so that therapeutic plasma concentrations are achieved.

Drug Interaction of Fluvoxamine and Fluoxetine with Nevirapine in HIV-1-Infected Individuals.

OBJECTIVE: To evaluate the possible pharmacokinetic interactions between nevirapine and fluvoxamine or fluoxetine in patients with HIV-1 infection. PATIENTS AND METHODS: Patients who were using fluvoxamine or fluoxetine concomitantly were chosen from an unselected cohort (n = 173) of HIV-1-infected individuals using a nevirapine-containing regimen (study group). HIV-1-infected patients using nevirapine without fluvoxamine or fluoxetine and non-HIV-infected individuals who were using fluvoxamine and fluoxetine were included as controls. The influence of fluvoxamine and fluoxetine on the pharmacokinetics of nevirapine was investigated with a previously developed population pharmacokinetic model. Concomitant use of fluvoxamine or fluoxetine was tested independently as covariate for apparent clearance (CL/F) of nevirapine using nonlinear mixed-effect modelling (NONMEM). Furthermore, to explore the influence of nevirapine on the pharmacokinetics of fluvoxamine and fluoxetine, dose-normalised concentrations of fluvoxamine and fluoxetine from the study group were compared with those of the controls. RESULTS: Of the 173 HIV-1-infected individuals, 14 were using fluoxetine (n = 7) or fluvoxamine (n = 7) simultaneously with nevirapine. In addition, 17 and 29 individuals were identified as controls for the fluoxetine- and fluvoxamine-group, respectively. Concomitant use of fluvoxamine resulted in a significant reduction of 33.7% in CL/F of nevirapine; this reduction in CL/F appeared to be dose-dependent. Concomitant use of fluoxetine had no influence on the pharmacokinetics of nevirapine. Conversely, nevirapine significantly lowered plasma levels of fluoxetine plus norfluoxetine (seproxetine). In contrast, no significant difference was observed in dose-normalised concentrations of fluvoxamine when the controls were compared with the study group. CONCLUSION: We advise that special attention is paid to HIV-1-infected indivi-duals using a nevirapine-containing regimen and fluvoxamine or fluoxetine con-comitantly, since pharmacokinetic interactions have been observed.

Pharmacotherapy of Hospitalised HIV-Infected Patients in a General Hospital during 1990, 1997 and 2001.

OBJECTIVE: To describe the changes over time in drug therapy (antiretroviral as well as co-administered drugs) in HIV-infected patients who required hospitalisation during the period 1990-2001. In addition, we wanted to evaluate and compare the characteristics of these patients. DESIGN/SETTING: Retrospective review of hospitalisations of HIV-infected patients in a general hospital. RESULTS: During specified periods in 1990, 1997 and 2001, 22 patients out of 130 outpatients, 29 out of 394 outpatients, and 19 out of 570 outpatients, respectively, who were treated at the outpatient clinic were admitted 30, 38 and 27 times, respectively. The mean duration of these hospitalisations was 18.8, 14.2 and 16.7 days, respectively. The percentage of women and the mean age of the hospitalised patients increased over the studied time period. AIDS-related diagnoses decreased when comparing 1997 with 2001. The type of co-administered drugs of patients who required hospitalisation was fairly stable, but the total volume (defined as the mean volume of drugs per patient per bed-day) increased dramatically from 5.3 in 1990 to 6.8 in 1997 and to 15.5 in 2001. Dual and triple antiretroviral therapy decreased and became quadruple or greater therapy when 1997 and 2001 were compared. In addition, the number of hospitalised patients not treated with antiretroviral drugs increased from 1997 to 2001. CONCLUSION: The incidence of hospital admissions decreased but the volume of co-administered drugs increased from 1990 to 2001, suggesting extensive co-morbidity in the patients who still require hospitalisation.

Population pharmacokinetics of nevirapine in an unselected cohort of HIV-1-infected individuals.

AIMS: To study the population pharmacokinetics of nevirapine and to identify relationships between patient characteristics and pharmacokinetics in an unselected population of patients attending our outpatient clinic. METHODS: Ambulatory HIV-1-infected patients from the outpatient clinic of the Slotervaart Hospital who were being treated with a nevirapine-containing regimen were included. During each visit, blood samples were collected for the determination of nevirapine plasma concentrations and clinical chemistry parameters. Variables that were collected at baseline were serology for hepatitis B (HBV) and C (HCV) viruses, liver enzymes, and total bilirubin (TBR). In addition, information about concomitant use of St John's wort and patient demographics were included. The pharmacokinetics of nevirapine were described by first-order absorption and elimination using nonlinear mixed effect modelling (NONMEM V1.1). Population pharmacokinetic parameters (apparent clearance (CL/F), volume of distribution (V/F), absorption rate constant (k a)) were estimated, as were interindividual, interoccasion, and residual variability in the pharmacokinetics. The influence of patient characteristics on the pharmacokinetics of nevirapine was determined. RESULTS: From 173 outpatients a total number of 757 nevirapine plasma concentrations at a single random time point and full pharmacokinetic curves for 13 patients were available resulting in a database of 1329 nevirapine plasma concentrations. Mean CL/F, V/F, and k a were 3.27 l h-1, 106 l, and 01.66 h-1, respectively. CL/F of nevirapine was correlated with weight, chronic HCV infection, and baseline aspartate aminotransferase (ASAT). Chronic HCV and baseline ASAT> 1.5 x upper limit of normal (ULN) decreased CL/F by 27.4% and 13.2%, respectively, whereas an increase in body weight of 10 kg increased CL/F by 0.14 l h-1. A trend towards a lower CL/F in patients of the Negroid race was observed. No significant covariates were found for V/F. CONCLUSIONS: The pharmacokinetics of nevirapine were adequately described by our population pharmacokinetic model. Weight, chronic HCV infection, and baseline ASAT were found to be significant covariates for CL/F of nevirapine. The model incorporating these significant covariates may be an important aid in further optimizing nevirapine-containing therapy.

Hepatotoxicity following nevirapine-containing regimens in HIV-1-infected individuals.

To determine the incidence of hepatotoxicity and to investigate whether plasma concentrations of nevirapine, in addition to other risk factors, could predict hepatotoxicity during treatment with nevirapine-containing regimens, we conducted a retrospective analysis with data from 174 individuals infected with human immunodeficiency virus-1 (HIV-1). During regular visits to the clinic, blood samples were collected for the determination of nevirapine plasma concentrations and clinical chemistry parameters including liver enzymes (LEs) and total bilirubin (TBR). Severe hepatotoxicity was defined as a grade > or =3 elevation in at least one of the tested LEs or TBR levels while on therapy. Analysis of predictive factors was focused on increases in aspartate aminotransferase (ASAT) and/or alanine aminotransferase (ALAT) to grade > or =2. Grade > or =3 elevation developed with an incidence of 0.15 per patient year (PY); only 3.4% of the patients developed grade > or =3 values for ASAT and/or ALAT (incidence 0.03 per PY). We found that patients who use a protease inhibitor (PI) in a nevirapine-containing regimen and patients who have chronic hepatitis B (HBV) infection are at a higher risk for the development of increases in ASAT and/or ALAT to grade > or =2. In contrast, the plasma concentration of nevirapine does not appear to be a predictive factor in this study population.

High Epstein-Barr virus (EBV) DNA loads in HIV-infected patients: correlation with antiretroviral therapy and quantitative EBV serology.

OBJECTIVE: To study Epstein-Barr virus (EBV) DNA loads in peripheral blood of HIV carriers to determine base-line values and diagnostic relevance of viral load in relation to quantitative serology; to compare EBV presence in parallel plasma and unfractionated whole blood samples; and to correlate EBV DNA load to HIV, CD4 T-cell counts and HAART. DESIGN: One-hundred and nine random patients receiving highly active antiretroviral therapy (HAART) during 1999 and 99 patients on anti-HIV monotherapy during 1993-1996 were included. METHODS: EBV DNA load was determined by quantitative competitive PCR. EBV serology was determined by immunoblot profile and quantitative enzyme-linked immunosorbent assay for responses against VCA-p18 and EBNA-1. RESULTS: Twenty-two out of 109 patients receiving HAART and 28 out of 99 of patients on anti-HIV monotherapy showed elevated EBV DNA loads in whole blood (> 2000 copies/ml), without elevated loads in parallel plasma. EBV DNA load distribution did not differ between the two groups (P = 0.78) and did not correlate with HIV or CD4 T-cell count. In three patients with high EBV DNA loads EBV RNA was virtually absent. Patients with high EBV DNA loads (3610-89 400 copies/ml) had higher anti-VCA-p18 IgG levels than patients with undetectable EBV DNA (P < 0.0001) but lower anti-EBNA-1 IgG levels (P = 0.005). CONCLUSION: Absolute values of EBV DNA load may have poor diagnostic value for defining HIV patients at risk for developing EBV-associated disease. Elevated EBV DNA loads are cell-associated and are not influenced by HAART. Increased anti-p18-VCA and decreased anti-EBNA-1 IgG levels in patients with high EBV loads indicate impaired latency control and increased lytic replication suggesting disturbed overall immunosurveillance against EBV.

Discrepancies between medical and pharmacy records for patients on anti-HIV drugs.

OBJECTIVE: To compare and evaluate drug notations in outpatient medical records and in pharmacy records in a cohort of HIV-1-infected patients treated with antiretroviral drugs. METHODS: Data on 103 patients were obtained from January 1, 1998, through December 31, 1999, by medical chart review and collection of pharmacy records. Two analyses were performed. First, antiretroviral drugs and comedication in the pharmacy records were documented and compared with their appearance in the outpatient medical records. Second, a detailed comparison was performed at 5 time points during the study period for the antiretroviral drugs. Generic name, formulation, strength, and frequency of dosing as registered in the outpatient medical records were compared with those registered in the pharmacy records. RESULTS: Total drug dispensation was 1607 (366 and 1241 antiretroviral drugs and comedication, respectively). The first screening resulted in a total discrepancy of 55.1% (n = 885), of which 97.1% (n = 859) was attributed to the comedication and 2.9% (n = 26) to the antiretroviral drugs. The discrepancy for the antiretroviral drugs at the specific time points ranged from 5.1% to 12.6% when the generic name only was used, and from 7.1% to 17% when formulation, strength, and frequency of dosing were also taken into account. CONCLUSIONS: The observed discrepancy between outpatient medical records and pharmacy records mainly concerns the comedication. For the antiretroviral drugs fewer, but still substantial, discrepancies were observed. These results indicate that full exchange of information conceming drug use in this population between general practitioners and specialists (infectious disease) is lacking.