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PubMed2004

Tolerability of postexposure prophylaxis with the combination of zidovudine-lamivudine and lopinavir-ritonavir for HIV infection.

Tolerability of the combination of zidovudine-lamivudine and lopinavir-ritonavir as postexposure prophylaxis (PEP) for human immunodeficiency virus infection was prospectively assessed. A total of 121 patients were enrolled in the study; 23 patients discontinued PEP prematurely for reasons other than adverse events. Of the other 98 patients, 58 (59%) experienced adverse effects, which led to premature PEP discontinuation in 20 cases (20%).

Adult↗
PubMed2002

Genotypic and phenotypic cross-resistance patterns to lopinavir and amprenavir in protease inhibitor-experienced patients with HIV viremia.

Genotypic correlates of reduced phenotypic susceptibility to amprenavir (APV) and lopinavir (LPV) were examined in 271 HIV isolates from 207 protease inhibitor (PI)-experienced subjects. All samples were from LPV-naive subjects; two were from APV-experienced subjects. Using a fold resistance (FR) of <2.5, 179 (66%) were APV susceptible. Using FRs of <2.5 and <10, 107 (39%) and 194 (72%), respectively, were LPV susceptible. The I84V mutation was the strongest APV resistance marker in PI-experienced subjects in both univariate and multivariate analyses, with an increased relative incidence (RI) of 6.9 with >2.5 FR. Mutations L10I (RI, 1.7), M46I (RI, 2.3), and L90M (RI, 1.9, but 65% linked with the I84V) were associated with decreased APV susceptibility in the univariate analysis (p < 0.001). Mutations L10I, G48V, I54T, I54V, and V82A were significantly associated with decreased LPV susceptibility (p < 0.001 for each) and had increased RIs of 2.2, 4.4, 13, 4.6, and 3.2, respectively. Decreased susceptibility to LPV (FR, >or=10) was significantly associated with prior exposure to the following PIs: ritonavir (RTV) (p < 0.001), saquinavir (SQV) (p < 0.001), nelfinavir (NFV) (p = 0.008), and indinavir (IDV) (p = 0.028). Decreased APV susceptibility (FR, >or=2.5) was significantly associated with prior exposure to RTV (p = 0.009), NFV (p = 0.003), and IDV (p = 0.021) but not with prior SQV (p = 0.103). These results suggest that APV and LPV have different cross-resistance mutation patterns that may help determine choice of PI therapy after therapy failure.

Carbamates↗
PubMed2004

Short communication: liver toxicity of lopinavir-containing regimens in HIV-infected patients with or without hepatitis C coinfection.

Liver toxicity is a common side effect of antiretroviral therapy, particularly in subjects coinfected with the hepatitis C virus (HCV). The incidence of severe liver toxicity after initiation of treatment with lopinavir (LPV) as well as its possible association with LPV plasma levels were assessed in 120 HIV-infected patients (52% coinfected by HCV). The incidence of severe liver toxicity at 3 months was 1.7% and the cumulative incidence at 12 months was 4%. The development of severe liver toxicity was associated with HCV coinfection but not with LPV plasma levels.

Adult↗
PubMed2003

Correlation between lopinavir plasma levels and lipid abnormalities in patients taking lopinavir/ritonavir.

Lopinavir (LPV)/ritonavir (RTV) used in combination, is a potent antiretroviral drug. However, its benefit is limited by its inherent effect on lipid metabolism, causing dislypemia in a large proportion of treated patients. Fasting triglyceride (TG) and cholesterol levels were assessed in 126 HIV-infected patients who initiated salvage therapy based on LPV/RTV. Both TG and cholesterol significantly increased from baseline to month 3. A positive correlation was found between the percentage increase in TG and LPV trough levels (r = 0.32; p = 0.003). Moreover, patients with TG elevations above the median (27%) showed higher LPV Ctrough levels than those with lower TG elevations (7.1 vs. 4.7 microg/ml, p = 0.004). In contrast, no correlation was found between LPV Ctrough and increases in cholesterol levels. Cholesterol elevations were positively correlated with RTV Ctrough concentrations (r = 0.32; p = 0.003).

Adult↗
PubMed2004

Lopinavir plasma levels in salvage regimes by a population of highly active antiretroviral therapy-treated HIV-1-positive patients.

Increased lopinavir (LPV) exposure obtained in vivo through combination with low-dose ritonavir may overcome a certain grade of resistance but not all. We sought to analyze LPV variability and possible risk factors. LPV trough plasma concentrations were determined by high-performance liquid chromatography after 1, 4, and 12 weeks from salvage regimens and tested in both univariate and multivariate regression analyses with age, gender, weight, risk factors for HIV acquisition, hepatitis C virus reactivity, hepatitis B surface antigen positivity, baseline aspartate transferase (AST) or alanine transferase (ALT) levels, creatinine, non-nucleoside reverse transcriptase inhibitors (NNRTIs) or tenofovir as concomitant drugs, and NNRTIs administered in the previous regimen. Fifty-six patients were included into the study. Among them, 8 of 56 (14.3%) at week 1, 12 of 56 (21.4%) at week 4, and 9 of 56 (16.1%) at week 12 had suboptimal LPV plasma concentrations, defined as trough concentration less than 4 microg/mL. No correlation was found between LPV trough concentrations and assessed variables. In conclusion, pharmacokinetic variability and low LPV concentrations have been found, supporting the use of therapeutic drug monitoring in those starting this drug.

Adult↗
PubMed2003

Improving lopinavir genotype algorithm through phenotype correlations: novel mutation patterns and amprenavir cross-resistance.

BACKGROUND: Current genotypic algorithms suggest that the HIV-1 protease inhibitors (PI) lopinavir (LPV) and amprenavir (APV) have distinct resistance profiles. However, phenotypic data indicate that cross-resistance is more common than expected. METHODS: Protease genotype (GT) and phenotype (PT) from 1418 patient viruses with reduced PI susceptibility and/or resistance-associated mutations (training data) were analyzed. Samples were classified as LPV resistant by GT (GT-R) if six or more LPV mutations were present, and by PT (PT-R) if the 50% inhibitory concentration (IC(50)) fold-change (FC) was over 10. RESULTS: There were 182 samples (13%) that were GT-S but PT-R for LPV. A comparison of the mutation prevalence in PT-R/GT-S samples with that in PT-S/GT-S samples identified mutations associated with LPV PT-R. Several previously defined LPV mutations were found to have a stronger than average effect (e.g., M46I/L, I54V/T, V82A/F), and new variants at known positions (e.g., I54A/M/S, V82S) were identified. Other mutations, including known APV resistance mutations, were found to contribute to reduced LPV susceptibility. A new LPV genotypic interpretation algorithm was constructed that improved overall genotypic/phenotypic concordance from 80% to 91%. The algorithm demonstrated a concordance rate of 90% when tested on 523 new samples. Cross-resistance between APV and LPV was greater in samples with primary APV resistance mutations than in those lacking them. CONCLUSIONS: The current LPV mutation score does not fully account for many resistant viruses. Consequently, cross-resistance between LPV and APV is underappreciated. Phenotypic results from large and diverse patient virus populations should be used to guide the development of more accurate GT interpretation algorithms.

Algorithms↗
PubMed2003

Distinct cross-resistance profiles of the new protease inhibitors amprenavir, lopinavir, and atazanavir in a panel of clinical samples.

A panel of 245 clinical samples with known treatment histories was retrospectively evaluated for cross-resistance to new protease inhibitors (PI). Samples with resistance to previously approved PI displayed high cross-resistance to atazanavir, whereas cross-resistance to amprenavir was considerably lower. A similar cross-resistance profile was observed for lopinavir, if a higher cut-off for resistance (9.5-fold) was applied. The enhanced efficacy of boosted PI is discussed with respect to clinically relevant cut-offs for drug resistance.

Atazanavir Sulfate↗
PubMed2005

Combining fosamprenavir with lopinavir/ritonavir substantially reduces amprenavir and lopinavir exposure: ACTG protocol A5143 results.

OBJECTIVE: To evaluate fosamprenavir/lopinavir (LPV)/ritonavir (RTV), fosamprenavir/RTV, or LPV/RTV in antiretroviral treatment-experienced patients. Lack of drug interaction data prompted a pharmacokinetic substudy to minimize subject risk. DESIGN: Multi-center, open-label, selectively randomized, steady-state pharmacokinetic study in HIV-infected subjects. METHODS: A planned independent interim review occurred after at least eight subjects were randomized to each arm. Subjects received twice daily LPV/RTV 400/100 mg (arm A; n = 8); fosamprenavir/RTV 700/100 mg (arm B; n = 8) or LPV/RTV/fosamprenavir 400/100/700 mg (arm C; n = 17). Plasma samples were collected over 12 h between study weeks 2 and 4. Pharmacokinetic parameters were compared based on a one-sided t-test on log-transformed data with a Peto stopping boundary (P < 0.001). RESULTS: Amprenavir mean area under the curve over 12 h (AUC0-12 h) and concentration at 12 h (C12 h) (microg/ml) were, respectively, 42.7 microg x h/ml (range, 33.1-55.1) and 2.4 microg/ml (range, 1.4-3.2) in arm B and 17.4 microg x h/ml (range, 4.6-41.3) and 0.9 microg/ml (range, 0.2-2.7) in arm C: geometric mean ratio (GMR) arm C:B was 0.36 [99.9% upper confidence boundary (UCB), 0.64] and 0.31 (99.9% h UCB, 0.61), respectively (P < or = 0.0001). Lopinavir AUC0-12 h and C12 h were, respectively, 95.3 microg x h/ml (range, 60.3-119.3) and 6.3 microg/ml (range, 2.2-9.2) in arm A and 54.4 microg x h/ml (range, 23.5-112.2) and 3.0 microg/ml (range, 0.4-7.9) in arm C: GMR arm C:A of 0.52 (99.9% UCB, 0.89) and 0.39 (99.9% UCB, 0.98), respectively (P < or = 0.0008). Ritonavir exposure was not significantly different between arms. CONCLUSION: APV and LPV exposures are significantly reduced using LPV/RTV/fosamprenavir, possibly increasing the risk of virologic failure. Consequently, A5143 was closed to enrollment.

Adult↗
PubMed2002

Simultaneous determination of the six HIV protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) plus M8 nelfinavir metabolite and the nonnucleoside reverse transcription inhibitor efavirenz in human plasma by solid-phase extraction and column liquid chromatography.

A sensitive and selective liquid chromatographic assay has been developed for the determination of the six currently protease inhibitors approved by the U.S. Food & Drug Administration (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) plus the M8 active metabolite of nelfinavir and the nonnucleoside reverse transcription inhibitor efavirenz in a single run. Pretreatment of 1-mL plasma sample spiked with internal standard was made by a solid-phase extraction procedure using a polymeric reversed-phase sorbent. Liquid chromatography was performed using a narrow-bore C18 reversed-phase column and gradient elution. Double ultraviolet detection at 265 nm (amprenavir) and at 210 nm (all other assayed drugs and internal standard) was used. Calibration curves were linear in the range 25 to 10,000 ng/mL, and the assay has been validated over the range 25 to 5,000 ng/mL. Average accuracies at four concentrations were in the range 92.4% to 103.0% and 94.4% to 103.0% for within-day and between-day, respectively, and the coefficients of variation were less than 8%. Mean absolute recoveries varied from 72.8% (ritonavir) to 93.7% (indinavir). No metabolite of the protease inhibitors was found to coelute with the drugs of interest or with the internal standard. At this time, among the tested drugs, especially all the currently licensed nucleosides and the other nonnucleoside reverse transcription inhibitor nevirapine that can be used in combination with the protease inhibitors, none was found to interfere with the assay.

Alkynes↗
PubMed2003

Reverse phase high-performance liquid chromatography method for the analysis of amprenavir, efavirenz, indinavir, lopinavir, nelfinavir and its active metabolite (M8), ritonavir, and saquinavir in heparinized human plasma.

The increasing interest in applying therapeutic drug monitoring (TDM) to antiretroviral therapy is related to the observed interindividual variation in antiretroviral pharmacokinetics that results in a wide range of drug exposure from fixed-dosing regimens and the rapid evolution in the availability of phenotypic assays that generate a target 50% inhibitory concentration (e.g., IC(50)) as a basis for adjusting individual antiretroviral dosages. To facilitate the application of TDM, a method for the simultaneous determination of eight species has been developed. This method is used to quantitate efavirenz and the following protease inhibitors: amprenavir, indinavir, lopinavir, nelfinavir and its active metabolite (M8), ritonavir, and saquinavir. The method using reversed-phase high-performance liquid chromatography (RP-HPLC) was validated. Detection is effected using a photodiode-array detector (PDA) scanning at four different wavelengths. This method allows for detection of all analytes to a lower limit of quantitation of 0.1 to 0.2 microg/mL with an interday variation in CV ranging from 3.5% to 10.4%. The method is being applied to a TDM program that is currently being implemented in the authors' laboratory.

Alkynes↗
PubMed2004

Lopinavir protein binding in vivo through the 12-hour dosing interval.

Most protease inhibitors available for the treatment of human immunodeficiency virus (HIV) infection are highly bound to plasma proteins, mainly alpha-1 acid glycoprotein. Therapeutic drug monitoring (TDM) of total protease inhibitor (PI) concentrations has been increasing in the past few years; however, the pharmacological activity of the PIs is dependent on unbound drug entering cells harboring HIV. There is little information available on unbound drug concentrations of these drugs in vivo. The aim of the study was to measure unbound plasma concentrations of lopinavir (LPV) and to relate them to the total plasma concentrations to establish the unbound percentage in vivo during a full dosage interval. A pharmacokinetic study was performed in HIV-infected subjects (n = 23; median CD4 cell count = 290 x 10(6) cells x L(-1); viral load < 50 copies x mL(-1)) treated with a LPV/ritonavir (RTV)-containing regimen. Ultrafiltration was used to separate unbound LPV in all plasma samples (n = 115). Equilibrium dialysis was also used to compare with ultrafiltration measurements in 10/23 patients at baseline and 2 hours after drug intake. Total and unbound LPV concentrations were measured by a fully validated method using high-performance liquid chromatography-mass spectometry (HPLC-MS/MS). Based on a comparison of AUC(unbound)AUC(total), the mean (+/- SD) unbound percentage of LPV from all the samples studied (n = 115) was 0.92% (+/- 0.22) when measured with ultrafiltration and 1.32% (+/- 0.44) when equilibrium dialysis was used (n = 20), showing a higher drug recovery (P = 0.048). The unbound percentage of LPV was found to be significantly higher after 2 h than at baseline (P < 0.05 with both methods), suggesting a concentration-dependent binding of LPV that has not been observed in vitro. However, the clinical significance of such phenomena is still unclear.

Adult↗
PubMed2003

HIV-1 phenotypic susceptibility to lopinavir (LPV) and genotypic analysis in LPV/r-naive subjects with prior protease inhibitor experience.

The relationship between phenotypic susceptibility to lopinavir (LPV) and genotypic pattern was investigated in LPV-naive, protease inhibitor (PI)-experienced subjects. Protease sequences of 100 HIV isolates with ascertained susceptibility (determined by Antivirogram) to LPV were analyzed (VircoGen). Two different thresholds (2.5- and 10-fold) were used for defining reduced susceptibility. Mutations were classified as LPV/r (the actual formulation of LPV that combines LPV with low-dose ritonavir) mutations according to the International AIDS Society-USA. Thirty-four isolates showed reduced LPV susceptibility (2.6- to 75.9-fold). Fold resistance to LPV correlated with the number of total and LPV/r mutations (Spearman coefficient = 0.62 and 0.74, respectively; P < 0.001). Current PI therapy (P = 0.002) and indinavir administration (P < 0.001), >5 LPV/r mutations (P < 0.0012), and detection of L10FIRV, K20MR, M46IL, I54VL, A71VT, G73SA, V82AFTS, I84V, and M90L were associated with LPV resistance in univariate analysis. Factors independently associated with LPV resistance were K20MR (odds ratio [OR], 13.9; 95% confidence interval [CI], 1.3-145.1; P = 0.028), I54VL (OR, 131.7; 95% CI, 10.5-1654.7; P < 0.001), G73SA (OR, 19.2; 95% CI, 1.4-273.7; P = 0.029), and I84V (OR, 177.5; 95% CI, 6.0-5232.5; P = 0.003) mutations and >9 protease mutations (OR, 18.6; 95% CI, 1.6-213.0; P = 0.019). Sixteen of 34 and 18 of 34 isolates with reduced LPV susceptibility showed >10-fold or <10-fold LPV resistance, respectively. Linear regression analysis demonstrated that each additional LPV mutation and I54VL accounted for much of the fold resistance to LPV (adjusted R2 = 0.70). In conclusion, for PI-experienced patients requiring salvage therapy, switching to LPV should be based on the number of baseline mutations and the presence of mutation 54.

Adult↗
PubMed2003

Lopinavir plasma concentrations and changes in lipid levels during salvage therapy with lopinavir/ritonavir-containing regimens.

OBJECTIVE: To determine whether an association existed between lopinavir (LPV) plasma concentrations and changes in lipid levels. DESIGN: A prospective, nonrandomized study. SUBJECTS: HIV-infected subjects with virologic failure on protease inhibitor-containing regimens. Twenty-two consecutive patients were enrolled, 19 completed 24 weeks of treatment, and 16 completed the full 48-week study period. INTERVENTION Patients were treated with LPV/ritonavir (LPV/r) in combination with other antiretroviral agents. Subjects were evaluated at baseline and weeks 4, 8, 12, 24, 36, and 48. LPV trough plasma concentrations and lipid levels were measured. RESULTS: LPV trough concentrations were higher in patients experiencing grade 3 or higher lipid elevations (mean [SD]: 9.71 microg/mL (5.62) vs. 6.09 microg/mL (3.83); P = 0.002) and in those developing grade 2 or higher hypercholesterolemia (mean [SD]: 8.48 microg/mL [4.64] vs. 5.71 microg/mL [3.94]; P = 0.003). All patients developing grade 2 or higher cholesterol elevation had an LPV trough concentration at week 4 greater than 8 microg/mL. Significant positive correlations were found between LPV trough concentrations and changes in triglyceride and cholesterol levels. CONCLUSIONS: In patients receiving salvage therapy with LPV/r, there is an association between LPV plasma concentrations and lipid changes. Patients achieving higher LPV trough concentrations may be at greater risk of experiencing dyslipidemia. Further investigations are warranted to support a direct cause and effect relationship.

Adult↗
PubMed2006

High rate of proV47A selection in HIV-2 patients failing lopinavir-based HAART.

We describe the emergence of the proV47A mutation in three out of five HIV-2-infected individuals failing lopinavir/ritonavir-based HAART. The appearance of such mutated variants resulted in high levels of phenotypic resistance to lopinavir, cross-resistance to indinavir, amprenavir, and hypersusceptibility to saquinavir. A search in HIV-2 databases revealed that proV47A is present in 8.6% of protease inhibitor (PI)-experienced patients but absent in all PI-naive patients. Its selection may be a common mutational pathway for developing resistance to lopinavir/ritonavir in HIV-2.

Adolescent↗
PubMed2006

The genotypic inhibitory quotient and the (cumulative) number of mutations predict the response to lopinavir therapy.

For 95 protease inhibitor-experienced HIV-1-infected patients, the genotypic inhibitory quotient (GIQ; trough level/number of mutations) was calculated for lopinavir. Three different sets of mutations showed equal predictive value. However, the use of cumulative numbers of mutations for calculation of the GIQ showed significantly better association with the virological response. Furthermore, the predictive value of the GIQ was no different from that of the number of mutations alone.

Drug Resistance, Viral↗
PubMed2006

Placental transfer and pharmacokinetics of lopinavir and other protease inhibitors in combination with nevirapine at delivery.

BACKGROUND: Antiretroviral combination therapies, including nevirapine (NVP) and protease inhibitors (PI), are increasingly used in the treatment and for the prophylaxis of vertical HIV-1 transmission in HIV-1 infected pregnant women. OBJECTIVE: To determine pharmacokinetics and placental transfer of NVP and different PI in pregnancy we measured drug levels in maternal and foetal compartments at the day of delivery. DESIGN AND METHODS: We conducted a prospective study in 40 eligible HIV-1 infected pregnant women who gave birth in our hospital. A pre-dose to 6 h post-dose steady-state pharmacokinetic analysis (n = 35) of the drugs on the day of the scheduled Caesarean section was performed. In addition cord blood and amniotic fluid drug levels were measured (n = 40). RESULTS: In all women NVP plasma concentrations (n = 20) were below the recommended level. PI plasma concentrations (nelfinavir, n = 5; saquinavir, n = 3; lopinavir, n = 10; ritonavir, n = 13) were extremely variable. Cord blood and amniotic fluid drug levels suggested that NVP passes the placenta unrestricted whereas PI were detected in smaller concentrations in the foetal compartment. CONCLUSIONS: Because of the changed pharmacokinetics of antiretroviral drugs in pregnancy therapeutic drug monitoring could be important and dose adjustment should be considered. The minimal placental transfer of PI is desirable from the perspective that the foetus is protected from potentially teratogenic agents. However, it is not known if antiretroviral compounds in the foetal compartment contribute to the risk reduction of vertical HIV-1 transmission, and whether the property of missing placental transfer is in fact beneficial for the newborn.

Amniotic Fluid↗
PubMed2005

Steady-state pharmacokinetics and tolerability of indinavir-lopinavir/r combination therapy in antiretroviral-experienced patients.

Six HIV-positive antiretroviral experienced patients initiating therapy with a regimen including lopinavir/ritonavir (400/100 mg twice per day) and indinavir (800 mg twice per day) underwent steady-state pharmacokinetic analysis. The AUC0-12 h of indinavir when combined with lopinavir/ritonavir was comparable with previously published data on indinavir/ritonavir 800/100 mg twice per day in HIV-infected individuals. However, lopinavir AUC0-12 h, Cmax, and C12 h were lower than previously reported in the absence of indinavir. The regimen was well tolerated, although 2 patients developed grade 3 hypertriglyceridemia. No patient discontinued the regimen because of indinavir-related urologic or retinoid-type adverse effects. Further study of the regimen with larger cohorts of patients is necessary.

Adult↗
PubMed2004

Salvage lopinavir-ritonavir therapy in human immunodeficiency virus-infected children.

OBJECTIVE: To study the control of viral replication in human immunodeficiency virus (HIV)-infected children on different salvage therapies. DESIGN AND SETTING: A retrospective observational study in 120 HIV-infected children was conducted. The children were divided into 3 groups according to their salvage therapies: (1) children receiving first line highly active antiretroviral therapy (HAART); (2) protease inhibitor-experienced children receiving second line HAART; (3) protease inhibitor-experienced children receiving HAART including lopinavir-ritonavir (LPV/r). The outcome variables examined were time to achieve viral load (VL) < or =400 copies/mL, success in achieving VL < or =400 copies/mL and time to virologic failure (VL >400 copies/mL). METHODS: VL (HIV-RNA copies/mL) was quantified with reverse transcription-polymerase chain reaction molecular assay. For each protocol, survival analyses were conducted to determine the probability of achieving VL < or =400 copies/mL and rebound of VL. RESULTS: VL < or =400 copies/mL was achieved by 52.4% of children receiving first line HAART, 48.3% receiving second line HAART and 71.5% receiving HAART including LPV/r. Children receiving HAART including LPV/r reached VL < or =400 copies/mL in a shorter time than children receiving second line HAART (P = 0.017), but quite similar to children receiving first line HAART. In terms of adjusted relative risk, children receiving HAART including LPV/r were 3.36 [95% confidence interval (95% CI), 1.59, 7.07] more likely to achieve VL < or =400 copies/mL than children receiving a different second line HAART. VL rebound occurred in 68.2% children receiving first line HAART, 73.4% receiving second line HAART and 32.4% receiving HAART including LPV/r. Children receiving HAART that includes LPV/r has less incidence of VL rebound (P=0.013) and 3.29 (95% CI 1.04, 10.3) times less risk to achieve a VL rebound than children receiving a different second line HAART. CONCLUSIONS: HAART that includes LPV/r is able to control HIV replication more efficiently than other classic salvage antiretroviral therapies.

Amino Acid Sequence↗