pyrimidinones and efavirenz

HIV-positive children are at high risk of drug resistance, which is of particular concern in settings where antiretroviral options are limited. In this Review we explore resistance rates and patterns among children in developing countries in whom antiretroviral treatment has failed. We did a systematic search of online databases and conference abstracts and included studies reporting HIV-1 drug resistance after failure of first-line paediatric regimens in children (<18 years) in resource-poor regions (Latin America, Africa, and Asia). We retrieved 1312 citations, of which 30 studies reporting outcomes in 3241 children were eligible. Viruses with resistance-associated mutations were isolated from 90% (95% CI 88-93%) of children. The prevalence of mutations associated with nucleoside reverse transcriptase inhibitors was 80%, with non-nucleoside reverse transcriptase inhibitors was 88%, and with protease inhibitors was 54%. Methods to prevent treatment failure, including adequate paediatric formulations and affordable salvage treatment options are urgently needed.

Topics: Adolescent; Africa; Alkynes; Anti-HIV Agents; Asia; Benzoxazines; Child; Child, Preschool; Cross-Sectional Studies; Cyclopropanes; Developing Countries; Drug Resistance, Viral; Female; Health Resources; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Latin America; Lopinavir; Male; Mutation; Nevirapine; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Treatment Failure; Viral Load; Zidovudine

The strategy of induction-maintenance therapy with lopinavir-ritonavir (LPV7r) consists of initiating antiretroviral therapy in a treatment-naïve patient with two nucleosides plus LPV/r. When the patient has achieved an undetectable HIV RNA viral load of < 50 copies/mL for a specified time period, the nucleosides are withdrawn and the patient continues to receive antiretroviral therapy with LPV/r monotherapy. The induction-maintenance strategy with LPV/r has been analyzed in the M03-613 clinical trial. In this trial, antiretroviral-naïve patients were randomized to receive zidovudine/lamivudine plus LPV/r (n = 104) or efavirenz (n = 51). In patients randomized to receive LPV/r who achieved an HIV RNA viral load of < 50 copies/mL for 3 consecutive months, nucleoside therapy was suspended. In an intention-to-treat analysis (missing equals failure), 60% of the patients randomized to receive LPV/r and 63% of those randomized to receive efavirenz maintained an HIV RNA viral load of < 50 copies/mL at 96 weeks of follow-up (p = 0.73; 95% confidence interval for the difference -19% to 13%). Moreover, this study showed that patients randomized to LPV/r experienced less lipoatrophy than those randomized to efavirenz. The M03-613 trial suggests that the induction-maintenance strategy with LPV/r is safe in most patients. However, rates of virological efficacy are lower than those achieved with the simplification strategy. Moreover, this trial demonstrates that LPV/r monotherapy may have major benefits in peripheral fat preservation.

Topics: Adipose Tissue; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Lamivudine; Lopinavir; Pyrimidinones; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome; Viral Load; Virus Replication; Zidovudine

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Didanosine; Drug Prescriptions; Drug Therapy, Combination; Humans; Lopinavir; Protease Inhibitors; Pyrimidinones; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine

In the current era of HIV treatment, the toxicity profiles of antiretroviral drugs have increasingly emerged as a basis for selecting initial antiretroviral regimens as well as a reason for switching therapy in treatment-experienced patients. In this respect, an intensive research effort involving clinical research as well as basic science research over the past six years, has focused on the cluster of metabolic and body composition abnormalities that have come to be termed the 'lipodystrophy syndrome'. These data have now provided a clear and clinically relevant understanding of the individual profiles of drugs within the nucleoside analogue reverse transcriptase inhibitor , HIV protease inhibitor and non-nucleoside analogue reverse transcriptase inhibitor drug classes, and have provided a rational basis for assessing and monitoring these adverse effects in clinical practice. In this review, current and emerging drug toxicities are considered with an emphasis on lipodystrophy complications.

Topics: Adenine; Alkynes; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cardiovascular Diseases; Cyclopropanes; Drug Monitoring; Drug Therapy, Combination; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Kidney Diseases; Lopinavir; Metabolic Syndrome; Nevirapine; Organophosphonates; Oxazines; Pyrimidinones; Risk Factors; Tenofovir

The aim of the study was to compare changes in bone mineral density (BMD) over 144 weeks in HIV-infected patients initiating nucleoside reverse transcriptase inhibitor (NRTI)-sparing or protease inhibitor-sparing highly active antiretroviral therapy (HAART).. Sixty-three HAART-naïve patients were randomized to zidovudine/lamivudine+efavirenz or lopinavir/ritonavir+efavirenz. We performed dual energy X-ray absorptiometry (DEXA) at baseline and at weeks 24, 48, 96 and 144 to evaluate lumbar spine and femoral neck (hip) BMD.. At baseline, 33 patients (55.9%) had low BMD (T-score < -1.0) and of these eight had osteoporosis (T-score < -2.5). Spine BMD declined in both arms until week 24, before stabilizing. In the NRTI-sparing arm, the mean percentage change from baseline was -2.7% [95% confidence interval (CI) -3.9 to -1.4] at week 24 and -2.5% (95% CI -5.4 to 0.3) at week 144, compared with -3.2% (95% CI -4.4 to -2.1) and -1.9% (95% CI -3.5 to -0.3) in the protease inhibitor-sparing arm. Hip BMD declined until week 48 before stabilizing. In the NRTI-sparing arm, BMD had decreased by -5.1% (95% CI -7.1 to -3.1) at week 48 and -4.5% (95% CI -6.9 to -2.1) at week 144, compared with -6.1% (95% CI -8.2 to -4.0) and -5.0% (95% CI -6.8 to -3.1) in the protease inhibitor-sparing arm. There were no significant differences between arms. Low baseline CD4 cell count was independently associated with spine (P=0.007) and hip (P=0.04) BMD loss and low body mass index with hip BMD loss (P=0.03).. Spine and hip BMD declined rapidly 24 to 48 weeks after initiating HAART, independent of the assigned drug class, but thereafter BMD values remained stable.

Topics: Absorptiometry, Photon; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Bone Density; Cyclopropanes; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lopinavir; Male; Pyrimidinones; Ritonavir; Zidovudine

Although efavirenz and lopinavir/ritonavir(r) are both recommended antiretroviral agents in antiretroviral-naïve HIV-infected patients, there are few randomized comparisons of their efficacy and tolerability.. A multicenter and randomized study was performed including 126 antiretroviral-naïve patients, randomly assigned to efavirenz+Kivexa (n=63) or lopinavir/r+Kivexa (n=63). Efficacy endpoints were the percentage of patients with HIV-RNA < or =50 copies/mL at week 48 and CD4 recovery. Safety was assessed by comparing toxicity and discontinuations. Statistical analyses were performed on an intention-to-treat (ITT) basis (Missing=Failure).. At week 48, 56.7% of patients in the efavirenz and 63.2% in the lopinavir/r groups showed HIV-1 RNA <50 copies/mL (P=0.770) (intention-to-treat analysis; Missing=Failure). Only 1 (1.53%) patient from each group experienced virological failure. CD4 values increased in both groups (298 cells in the efavirenz group, P=0.001; 249 cells in the lopinavir/r group, P=0.002; P=0.126 between groups). HDL-cholesterol only increased in the efavirenz group (from 39+/-12 mg/dL to 49+/-11; P=0.001). Discontinuations were more frequent in the lopinavir/r group (36.5% versus 28.5%; P=0.193), but more patients with efavirenz interrupted due to toxicity (11.1% versus 6.3%); most of them were attributed to hypersensitivity reaction.. Similar virological efficacy was observed for efavirenz and lopinavir/r, when administered with Kivexa in antiretroviral-naïve patients, while immunological improvement was slightly superior for efavirenz. The higher rate of discontinuation due to toxicity in the efavirenz group was related to a higher incidence of hypersensitivity reaction. Nowadays, the use of the new formulation of lopinavir/r and the HLA-B*5701 genotype test before starting abacavir should improve the safety profiles of these regimens.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Drug Combinations; Drug Hypersensitivity; Female; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load; Withholding Treatment

To compare the efficacy of efavirenz (EFV) vs lopinavir/ritonavir (LPV/r) in combination with azidothymidine/lamivudine in antiretroviral therapy naive, HIV+ individuals presenting for care with CD4 counts <200/mm.. Prospective, randomized, open label, multicenter trial in Mexico. HIV-infected subjects with CD4 <200/mm were randomized to receive open label EFV or LPV/r plus azidothymidine/lamivudine (fixed-dose combination) for 48 weeks. Randomization was stratified by baseline CD4 cell count (< or =100 or >100/mm). The primary endpoint was the percentage of patients with plasma HIV-1 RNA <50 copies/mL at 48 weeks by intention-to-treat analysis.. A total of 189 patients (85% men) were randomized to receive EFV (95) or LPV/r (94). Median baseline CD4 were 64 and 52/mm, respectively (P = not significant). At week 48, by intention-to-treat analysis, 70% of EFV and 53% of LPV/r patients achieved HIV-1 RNA <50 copies/mL [estimated difference 17% (95% confidence interval 3.5 to 31), P = 0.013]. The proportion with HIV-1 RNA <400 copies/mL was 73% with EFV and 65% with LPV/r (P = 0.25). Virologic failure occurred in 7 patients on EFV and 17 on LPV/r. Mean CD4 count increases (cells/mm) were 234 for EFV and 239 for LPV/r. Mean change in total cholesterol and triglyceride levels were 50 and 48 mg/dL in EFV and 63 and 116 mg/dL in LPV/r (P = 0.24 and P < 0.01).. In these very advanced HIV-infected ARV-naive subjects, EFV-based highly active antiretroviral therapy had superior virologic efficacy than LPV/r-based highly active antiretroviral therapy, with a more favorable lipid profile.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cyclopropanes; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Mexico; Prospective Studies; Pyrimidinones; Ritonavir; RNA, Viral

We evaluated the pharmacokinetics of lopinavir-ritonavir with and without nonnucleoside reverse transcriptase inhibitors (NNRTIs) in Ugandan adults. The study design was a three-period crossover study (3 tablets [600 mg of lopinavir/150 mg of ritonavir {600/150 mg}], 4 capsules [533/133 mg], and 2 tablets [400/100 mg] twice a day [BD]; n = 40) of lopinavir-ritonavir with NNRTIs and a parallel one-period study (2 tablets BD; n = 20) without NNRTIs. Six-point pharmacokinetic sampling (0, 2, 4, 6, 8, and 12 h) was undertaken after observed intake with a standardized breakfast. Ugandan DART trial participants receiving efavirenz (n = 20), nevirapine (n = 18), and no NNRTI (n = 20) had median ages of 41, 35, and 37 years, respectively, and median weights of 60, 64, and 63 kg, respectively. For the no-NNRTI group, the geometric mean (percent coefficient of variation [%CV]) lopinavir area under the concentration-time curve from 0 to 12 h (AUC(0-12)) was 110.1 (34%) microg x h/liter. For efavirenz, the geometric mean lopinavir AUC(0-12) (%CV) values were 91.8 microg x h/liter (58%), 65.7 microg x h/liter (39%), and 54.0 microg x h/liter (65%) with 3 tablets, 4 capsules, and 2 tablets BD, respectively, with corresponding (within-individual) geometric mean ratios (GMR) for 3 and 2 tablets versus 4 capsules of 1.40 (90% confidence interval [CI], 1.18 to 1.65; P = 0.002) and 0.82 (90% CI, 0.68 to 0.99; P = 0.09), respectively, and the apparent oral clearance (CL/F) values were reduced by 58% and 1%, respectively. For nevirapine, the geometric mean lopinavir AUC(0-12) (%CV) values were 112.9 microg x h/liter (30%), 68.1 microg x h/liter (53%), and 61.5 microg x h/liter (52%), respectively, with corresponding GMR values of 1.66 (90% CI, 1.46 to 1.88; P < 0.001) and 0.90 (90% CI, 0.77 to 1.06; P = 0.27), respectively, and the CL/F was reduced by 57% and 7%, respectively. Higher values for the lopinavir concentration at 12 h (C(12)) were observed with 3 tablets and efavirenz-nevirapine (P = 0.04 and P = 0.0005, respectively), and marginally lower C(12) values were observed with 2 tablets and efavirenz-nevirapine (P = 0.08 and P = 0.26, respectively). These data suggest that 2 tablets of lopinavir-ritonavir BD may be inadequate when dosed with NNRTIs in Ugandan adults, and the dosage should be increased by the addition of an additional adult tablet or a half-dose tablet (100/25 mg), where available.

Topics: Adult; Aged; Alkynes; Benzoxazines; Chromatography, High Pressure Liquid; Cyclopropanes; Female; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Nevirapine; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Uganda

Initial viral decay rate may be useful when comparing the relative potency of antiretroviral regimens. Two hundred twenty-seven ART-naïve patients were randomized to receive efavirenz (EFV) (n = 74), lopinavir/ritonavir (LPV/r) (n = 77), or atazanavir/ritonavir (ATV/r) (n = 79) in combination with two NRTIs. The most frequently used NRTI combinations in the EFV and ATV/r groups were the nonthymidine analogues tenofovir and emtricitabine or lamivudine (70% and 68%, respectively) and, in the LPV/r group, lamivudine and the thymidine analogue zidovudine (89%). HIV-1 RNA was monitored during the first 28 days after treatment initiation. Phase 1 and 2 decay rate was estimated in a subset of 157 patients by RNA decrease from days 0 to 7, and days 14 to 28. One-way ANOVA and subsequent Tukey's post hoc tests were used for groupwise comparisons. Mean (95% CI) HIV-1 RNA reductions from days 0 to 28 were 2.59 (2.45-2.73), 2.42 (2.27-2.57), and 2.13 (2.01-2.25) log(10) copies/ml for the EFV-, LPV/r-, and ATV/r-based treatment groups, respectively, with a significantly larger decrease in the EFV-based group at all time points compared with ATV/r (p < 0.0001), and with LPV/r at days 7-21 (p < 0.0001-0.03). LPV/r gave a greater RNA decrease compared with ATV/r from day 14 (p = 0.02). Phase 1 decay rate was significantly higher in the EFV group compared with LPV/r (p = 0.003) or ATV/r (p < 0.0001). No difference was found in phase 2 decrease. EFV-based treatment gave a more rapid decline in HIV-1 RNA than did either of the boosted protease inhibitor-based regimens. The observed differences may reflect different inherent regimen potencies.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome

Few randomized trials comparing antiretroviral therapy (ART) regimens have been conducted in resource-limited settings.. In the Republic of South Africa, antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals >14 years old with a CD4 cell count <200 cells/μL or a prior AIDS diagnosis were randomized to receive efavirenz (EFV) or lopinavir/ritonavir (LPV/r) with either zidovudine (ZDV) plus didanosine (ddI) or stavudine (d4T) plus lamivudine (3TC) in an open-label, 2-by-2 factorial study and followed up for the primary outcome of AIDS or death and prespecified secondary outcomes, including CD4 cell count and viral load changes, treatment discontinuation, and grade 4 events.. In total, 1771 persons were randomized and followed up for a median of 24.7 months. AIDS or death occurred in (1) 163 participants assigned EFV and 157 assigned LPV/r (hazard ratio [HR], 1.04 [95% confidence interval {CI}, 0.84-1.30]) and in (2) 170 participants assigned ZDV+ddI and 150 assigned d4T+3TC (HR, 1.15 [95% CI, 0.93-1.44]). HIV RNA levels were lower (P < .001) and CD4 cell counts were greater (P < .01) over follow-up for d4T+3TC versus ZDV+ddI. Rates of potentially life-threatening adverse events and overall treatment discontinuation were similar for d4T+3TC and ZDV+ddI; however, more participants discontinued d4T because of toxicity (12.6%) than other treatments (<5%).. EFV and LPV/r are effective components of first-line ART. The poorer viral and immune responses with ZDV+ddI and the greater toxicity-associated discontinuation rate with d4T+3TC suggest that these treatments be used cautiously as initial therapy.. ClinicalTrials.gov identifier: NCT00342355.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Didanosine; Drug Therapy, Combination; Female; HIV; Humans; Lamivudine; Lopinavir; Male; Pyrimidinones; Ritonavir; RNA, Viral; South Africa; Stavudine; Treatment Outcome; Zidovudine

The pharmacokinetics of lopinavir/ritonavir (LPV/RTV) 300 mg/m twice daily and efavirenz (EFV) 350 mg/m once daily were evaluated in HIV-infected children. The minimum concentrations for LPV contained values above the target range, and the estimated minimum concentrations for EFV contained values below the range. Our data support the current LPV/RTV dose, but EFV 350 mg/m may not be sufficient.

Topics: Adolescent; Alkynes; Anti-HIV Agents; Benzoxazines; Child; Child, Preschool; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir

The metabolic effects of initial therapy for HIV-1 infection are important determinants of regimen selection.. Open-label study in 753 subjects randomized equally to efavirenz or lopinavir/ritonavir(r) plus two nucleoside reverse-transcriptase inhibitor (NRTI) vs. the NRTI-sparing regimen of lopinavir/r plus efavirenz. Zidovudine, stavudine, or tenofovir with lamivudine was selected prior to randomization. Metabolic outcomes through 96 weeks were lipoatrophy, defined as at least 20% loss in extremity fat, and fasting serum lipids.. Lipoatrophy by dual-energy X-ray absorptiometry at week 96 occurred in 32% [95% confidence interval (CI) 25-39%] of subjects in the efavirenz plus two NRTIs arm, 17% (95% CI 12-24) in the lopinavir/r plus two NRTIs arm, and 9% (95% CI 5-14) in the NRTI-sparing arm (P < or = 0.023 for all comparisons). Varying the definition of lipoatrophy (> or =10 to > or =40% fat loss) and correction for baseline risk factors did not affect the significant difference in lipoatrophy between the NRTI-containing regimens. Lipoatrophy was most frequent with stavudine-containing regimens and least frequent with tenofovir-containing regimens (P < 0.001), which were not significantly different from the NRTI-sparing regimen. Total cholesterol increases at week 96 were greatest in the NRTI-sparing arm (median +57 mg/dl) compared with the other two arms (+32-33 mg/dl; P < 0.001). Use of lipid-lowering agents was more common (25 vs. 11-13%) in the NRTI-sparing arm.. Lipoatrophy was more frequent with efavirenz than lopinavir/r when combined with stavudine or zidovudine, and less frequent when either drug was combined with tenofovir. Lipoatrophy was least frequent with the NRTI-sparing regimen, but this benefit was offset by greater cholesterol elevations and the need for lipid-lowering agents.

Topics: Absorptiometry, Photon; Adult; Alkynes; Benzoxazines; Cyclopropanes; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Lipid Metabolism; Lopinavir; Male; Pyrimidinones; Ritonavir

Decreased bone mineral density (BMD) has been described in HIV-infected patients initiating antiretroviral therapy (ART), but the contributions of ART and immunologic and/or virologic factors remain unclear.. We compared total BMD changes over 96 weeks in 106 ART-naive HIV-infected subjects who were randomized to receive efavirenz (EFV) + zidovudine/lamivudine (n = 32) or lopinavir/ritonavir (LPV/r) + zidovudine/lamivudine induction (n = 74) for 24-48 weeks followed by LPV/r monotherapy. We also sought to identify factors associated with BMD loss, including markers of systemic inflammation [soluble tumor necrosis factor-alpha receptors (sTNFR I and II)].. After 96 weeks, the mean percent change from baseline in total BMD was -2.5% (LPV/r) and -2.3% (EFV) (P < 0.01 for within-group changes in either arm; P = 0.86 for between-group differences). No alteration in the rate of BMD change was observed upon simplification to LPV/r monotherapy. Although soluble tumor necrosis factor-alpha receptor II concentrations at baseline and 24 weeks were at least marginally associated with subsequent changes in BMD (P = 0.06 and P = 0.028, respectively), these associations were no longer significant after adjustment for CD4 T cell count. Subjects with lower baseline CD4 T cell count, non-black race, and higher baseline glucose demonstrated a higher risk for >5% decrease in BMD.. Similar decreases in BMD over 96 weeks occurred in ART-naive subjects receiving either EFV-based regimen or LPV/r-based regimen, which was not altered by simplification to LPV/r monotherapy and was unrelated to markers of tumor necrosis factor-alpha activity.

Topics: Absorptiometry, Photon; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Bone Density; Cyclopropanes; Female; HIV Infections; Humans; Inflammation Mediators; Lamivudine; Lopinavir; Male; Middle Aged; Osteoporosis; Prospective Studies; Pyrimidinones; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Risk Factors; Ritonavir; Zidovudine

Efavirenz and lopinavir boosted with ritonavir are both recommended as first-line therapies for patients with HIV when combined with two nucleoside reverse transcriptase inhibitors. It is uncertain which therapy is more effective for patients starting therapy with an advanced infection.. We estimated the relative effect of these two therapies on rates of virological and immunological failure within the Swiss HIV Cohort Study and considered whether estimates depended on the CD4(+) T-cell count when starting therapy. We defined virological failure as either an incomplete virological response or viral rebound after viral suppression and immunological failure as failure to achieve an expected CD4(+) T-cell increase calculated from EuroSIDA statistics.. Patients starting efavirenz (n=660) and lopinavir (n=541) were followed for a median of 4.5 and 3.1 years, respectively. Virological failure was less likely for patients on efavirenz, with the adjusted hazard ratio (95% confidence interval) of 0.63 (0.50-0.78) then multiplied by a factor of 1.00 (0.90-1.12) for each 100 cells/mm(3) decrease in CD4(+) T-cell count below the mean when starting therapy. Immunological failure was also less likely for patients on efavirenz, with the adjusted hazard ratio of 0.68 (0.51-0.91) then multiplied by a factor of 1.29 (1.14-1.46) for each 100 cells/mm(3) decrease in CD4(+) T-cell count below the mean when starting therapy.. Virological failure is less likely with efavirenz regardless of the CD4(+) T-cell count when starting therapy. Immunological failure is also less likely with efavirenz; however, this advantage disappears if patients start therapy with a low CD4(+) T-cell count.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cohort Studies; Cyclopropanes; Female; HIV Infections; Humans; Lopinavir; Male; Prospective Studies; Pyrimidinones

Antiretroviral-naive HIV-1-infected volunteers received zidovudine/lamivudine plus either lopinavir/ritonavir (n=104) or efavirenz (n=51). Lopinavir/ritonavir-treated subjects demonstrating 3 consecutive monthly HIV-1 RNA levels <50 copies/mL started lopinavir/ritonavir monotherapy. In previous-failure=failure analysis, 48% (lopinavir/ritonavir) and 61% (efavirenz) maintained HIV-1 RNA at <50 copies/mL through week 96, (P= .17; 95% confidence interval [CI] for the difference, -29% to 4%); in noncompletion=failure analysis, 60% (lopinavir/ritonavir) and 63% (efavirenz) maintained HIV-1 RNA at <50 copies/mL at week 96 (P= .73; 95% CI for the difference, -19% to 13%). Significant sparing of peripheral lipoatrophy was noted in the lopinavir/ritonavir simplification strategy. This study has provided important information for future studies using treatment simplified to lopinavir/ritonavir monotherapy.

Topics: Acquired Immunodeficiency Syndrome; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Diarrhea; Drug Therapy, Combination; Glucose Tolerance Test; HIV Protease Inhibitors; Humans; Lopinavir; Nausea; Pyrimidinones; Ritonavir; RNA, Viral; Time Factors; Treatment Outcome; Viral Load

This study evaluated the effects of 3 class-sparing antiretroviral therapy (ART) regimens on endothelial function in human immunodeficiency virus (HIV)-infected subjects participating in a randomized trial.. Endothelial dysfunction has been observed in patients receiving ART for HIV infection.. This was a prospective, multicenter study of treatment-naive subjects who were randomly assigned to receive a protease inhibitor-sparing regimen of nucleoside reverse transcriptase inhibitors (NRTIs) + efavirenz, a non-nucleoside reverse transcriptase inhibitor-sparing regimen of NRTIs + lopinavir/ritonavir, or a NRTI-sparing regimen of efavirenz + lopinavir/ritonavir. The NRTIs were lamivudine + stavudine, zidovudine, or tenofovir. Brachial artery flow-mediated dilation (FMD) was determined by B-mode ultrasound before starting on ART, then after 4 and 24 weeks.. There were 82 subjects (median age 35 years, 91% men, 54% white). Baseline CD4 cell counts and plasma HIV ribonucleic acid (RNA) values were 245 cells/mm(3) and 4.8 log(10) copies/ml, respectively. At baseline, FMD was 3.68% (interquartile range [IQR] 1.98% to 5.51%). After 4 and 24 weeks of ART, plasma HIV RNA decreased by 2.1 and 3.0 log(10) copies/ml, respectively. FMD increased by 0.74% (IQR -0.62% to +2.74%, p = 0.003) and 1.48% (IQR -0.20% to +4.30%, p < 0.001), respectively, with similar changes in each arm (Kruskal-Wallis p value >0.600). The decrease in plasma HIV RNA at 24 weeks was associated with greater FMD (r(s) = -0.30, p = 0.017).. Among treatment-naive individuals with HIV, 3 different ART regimens rapidly improved endothelial function. Benefits were similar for all ART regimens, appeared quickly, and persisted at 24 weeks.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Brachial Artery; CD4 Lymphocyte Count; Cyclopropanes; Endothelium, Vascular; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Male; Organophosphonates; Prospective Studies; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Tenofovir; Time Factors; Zidovudine

Induction-maintenance strategies were associated with a low response rate. We compared the virological response with two different induction regimens with trizivir plus efavirenz or lopinavir/ritonavir.. A randomized, multicentre, open-label clinical trial with 209 antiretroviral-naive HIV-infected patients assigned to trizivir plus either efavirenz or lopinavir/ritonavir during 24-36 weeks. Patients reaching undetectable plasma viral loads during induction entered a 48-week maintenance on trizivir alone. The primary endpoint was the proportion of patients without treatment failure at 72 weeks using an intent to treat (ITT) analysis (switching equals failure).. Patients were randomly assigned (efavirenz 104; lopinavir/ritonavir 105), and 114 (55%) entered the maintenance phase (efavirenz 54; lopinavir/ritonavir 60). Baseline characteristics were balanced between groups. The response rate at 72 weeks was 31 and 43% (ITT analysis, P = 0.076) and 63 and 75% (on-treatment analysis, P = 0.172) in the efavirenz and lopinavir/ritonavir arms, respectively. Virological failure occurred in 27 patients: six during induction (efavirenz, three; lopinavir/ritonavir, three; P = 1.0) and 21 during maintenance (efavirenz, 14; lopinavir/ritonavir, seven; P = 0.057). Thirty-four patients in the efavirenz arm switched treatment because of adverse events compared with 25 in the lopinavir/ritonavir arm (P = 0.17).. Trizivir plus either efavirenz or lopinavir/ritonavir followed by maintenance with trizivir achieved a low but similar response at 72 weeks, with a high incidence of adverse events leading to drug discontinuation during the induction phase in both arms. The study showed a trend towards an increased virological failure rate in the efavirenz arm during the maintenance phase.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Failure; Treatment Outcome; Zidovudine

Efavirenz and lopinavir/ritonavir are both recommended antiretroviral agents for combination first-line therapy, although information on direct comparisons between them is scarce. A retrospective longitudinal study from the VACH cohort comparing both regimens was performed.. Efficacy was examined comparing time to virological failure, CD4 recovery and clinical progression. Tolerability was examined comparing time to treatment discontinuation for any reason and for toxicity. Survival analysis was conducted using the Kaplan-Meier method, and standard and weighted Cox regression models.. A total of 1550 antiretroviral-naive patients starting a two-nucleoside reverse transcriptase inhibitor regimen plus either efavirenz (n = 1159) or lopinavir/ritonavir (n = 391) were included in the study. At baseline, patients starting lopinavir/ritonavir had higher HIV-1 RNA and lower CD4+ cell counts. There was no difference in the adjusted hazards of virological failure [efavirenz versus lopinavir/ritonavir hazard ratio (HR) = 0.93, 95% confidence interval (CI): 0.77-1.12, P = 0.43], CD4 recovery (HR = 1.11, 95% CI: 0.95-1.30, P = 0.19) and clinical progression (HR = 0.71, 95% CI: 0.39-1.31, P = 0.27). There was an increased risk of discontinuation for any reason or for toxicity for lopinavir/ritonavir (HR = 2.10, 95% CI: 1.40-3.15, P = 0.0003). CD4 recovery with both drugs was also similar in the lowest CD4 strata. A higher risk of early hypertriglyceridaemia was associated with lopinavir/ritonavir-based regimens.. Our study suggests similar virological efficacy for efavirenz- or lopinavir/ritonavir-based first-line antiretroviral regimens, but an increased risk of discontinuation because of toxicity in case of lopinavir/ritonavir-based therapy. Immunological outcome appeared similar with both regimens.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Female; HIV Infections; HIV-1; Humans; Hypertriglyceridemia; Kaplan-Meier Estimate; Longitudinal Studies; Lopinavir; Male; Pyrimidinones; Retrospective Studies; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load; Withholding Treatment

A member of the major human cytochrome P450 superfamily of hemoproteins, CYP3A4/5, converts cholesterol into 4beta-hydroxycholesterol. We studied plasma 4beta-hydroxycholesterol levels prior to and 4 weeks after initiating antiretroviral therapy that included efavirenz, ritonavir-boosted atazanavir or ritonavir-boosted lopinavir with the aim of exploring the usefulness of plasma 4beta-hydroxycholesterol levels as an endogenous biomarker of CYP3A activity. Efavirenz is an inducer of CYP3A, whereas the ritonavir-boosted regimens are net inhibitors of CYP3A.. In patients treated with efavirenz, the median plasma 4beta-hydroxycholesterol level increased by 46 ng/mL (p = 0.004; n = 11). In contrast, patients given ritonavir-boosted atazanavir showed a median decrease in plasma 4beta-hydroxycholesterol of -9.4 ng/mL (p = 0.0003; n = 22), and those given ritonavir-boosted lopinavir showed a median change from baseline of -5.8 ng/mL (p = 0.38; n = 19). There were significant between-group differences in the effects of antiretroviral treatment on plasma 4beta-hydroxycholesterol levels (p < 0.0001).. Changes in plasma 4beta-hydroxycholesterol following the initiation of efavirenz- or atazanavir/ritonavir-based antiretroviral therapy reflected the respective net increase and decrease of CYP3A activity of these regimens. The plasma 4beta-hydroxycholesterol level did not indicate a net CYP3A inhibition in the lopinavir/ritonavir arm, possibly because of concomitant enzyme induction.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP3A; Drug Therapy, Combination; Enzyme Induction; Enzyme Inhibitors; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxycholesterols; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; Young Adult

The use of either efavirenz or lopinavir-ritonavir plus two nucleoside reverse-transcriptase inhibitors (NRTIs) is recommended for initial therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection, but which of the two regimens has greater efficacy is not known. The alternative regimen of lopinavir-ritonavir plus efavirenz may prevent toxic effects associated with NRTIs.. In an open-label study, we compared three regimens for initial therapy: efavirenz plus two NRTIs (efavirenz group), lopinavir-ritonavir plus two NRTIs (lopinavir-ritonavir group), and lopinavir-ritonavir plus efavirenz (NRTI-sparing group). We randomly assigned 757 patients with a median CD4 count of 191 cells per cubic millimeter and a median HIV-1 RNA level of 4.8 log10 copies per milliliter to the three groups.. At a median follow-up of 112 weeks, the time to virologic failure was longer in the efavirenz group than in the lopinavir-ritonavir group (P=0.006) but was not significantly different in the NRTI-sparing group from the time in either of the other two groups. At week 96, the proportion of patients with fewer than 50 copies of plasma HIV-1 RNA per milliliter was 89% in the efavirenz group, 77% in the lopinavir-ritonavir group, and 83% in the NRTI-sparing group (P=0.003 for the comparison between the efavirenz group and the lopinavir-ritonavir group). The groups did not differ significantly in the time to discontinuation because of toxic effects. At virologic failure, antiretroviral resistance mutations were more frequent in the NRTI-sparing group than in the other two groups.. Virologic failure was less likely in the efavirenz group than in the lopinavir-ritonavir group. The virologic efficacy of the NRTI-sparing regimen was similar to that of the efavirenz regimen but was more likely to be associated with drug resistance. (ClinicalTrials.gov number, NCT00050895 [ClinicalTrials.gov].).

Topics: Adolescent; Adult; Alkynes; Benzoxazines; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Kaplan-Meier Estimate; Lopinavir; Male; Middle Aged; Mutation; Prospective Studies; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Treatment Failure

Complex antiretroviral regimens can be associated with increased toxicity and poor adherence. Our aim was to compare the efficacy and safety of switching to two simplified, class-sparing antiretroviral regimens.. We conducted a randomized, open-label study in 236 patients with virologic suppression who were taking a three- or four-drug protease inhibitor or non-nucleoside reverse transcriptase inhibitor regimen for > or = 18 months. Patients received lopinavir/ritonavir (LPV/r) 533 mg/133 mg twice daily + efavirenz (EFV) 600 mg once daily or EFV + two nucleoside reverse transcriptase inhibitors (NRTI). Primary study endpoint was time to first virologic failure (VF, confirmed HIV-1 RNA > 200 copies/ml) or discontinuation because of study drug-related toxicity.. After 2.1 years of follow up, patients receiving LPV/r + EFV discontinued treatment at a greater rate than patients receiving EFV + NRTI (P < 0.001). Twenty-one patients developed VF (14 receiving LPV/r + EFV and seven receiving EFV + NRTI) and 26 discontinued because of a study drug-related toxicity (20 receiving LPV/r + EFV and six receiving EFV + NRTI). Time to VF or study drug related-toxicity discontinuation was significantly shorter for LPV/r + EFV than EFV + NRTIs (P = 0.0015). A significantly higher risk of drug-related toxicity occurred with LPV/r + EFV, mainly for increased triglycerides (P = 0021). A trend toward a higher VF rate occurred with LPV/r + EFV in an intent-to-treat and as-treated analyses (P = 0.088 and P = 0.063 respectively).. Switching to EFV + NRTI resulted in better outcomes, fewer drug-related toxicity discontinuations and a trend to fewer virologic failures compared to switching to LPV/r + EFV.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Resistance, Viral; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome

To develop a computer-based system for modelling and interpreting plasma antiretroviral concentrations for therapeutic drug monitoring (TDM).. Data were extracted from a prospective TDM study of 199 HIV-infected patients (CCTG 578). Lopinavir (LPV) and efavirenz (EFV) pharmacokinetic (PK) parameters were modelled using a Bayesian method and interpreted by an expert committee of HIV specialists and pharmacologists who made TDM recommendations. These PK models and recommendations formed the knowledge base to develop an artificial intelligence (AI) system that could estimate drug exposure, interpret PK data and generate TDM recommendations. The modelled PK exposures and expert committee TDM recommendations were considered optimum and used to validate results obtained by the AI system.. A group of patients, 67 on LPV, 46 on EFV and three on both drugs, were included in this analysis. Correlations were high for LPV and EFV estimated trough and 4 h post-dose concentrations between the Al estimates and modelled values (r > 0.79 for all comparisons; P < 0.0001). Although trough concentrations were similar, significant differences were seen for mean predicted 4 h concentrations for EFV (4.16 microg/ml versus 3.89 microg/ml; P = 0.02) and LPV (7.99 microg/ml versus 8.79 microg/ml; P < 0.001). The AI and expert committee TDM recommendations agreed in 53 out of 69 LPV cases [kappa (kappa) = 0.53; P < 0.001] and 47 out of 49 EFV cases (kappa = 0.91; P < 0.001).. The AI system successfully estimated LPV and EFV trough concentrations and achieved good agreement with expert committee TDM recommendations for EFV- and LPV-treated patients.

Topics: Adult; Algorithms; Alkynes; Anti-Retroviral Agents; Artificial Intelligence; Bayes Theorem; Benzoxazines; California; Computer Systems; Cyclopropanes; Drug Monitoring; Drug Therapy, Combination; Expert Systems; Female; Fuzzy Logic; HIV Infections; Humans; Lopinavir; Male; Models, Biological; Practice Guidelines as Topic; Prospective Studies; Pyrimidinones; Reproducibility of Results

Subcutaneous limb fat loss continues to be one the most troubling side effects of long-term antiretroviral regimens. Nucleoside analogues and protease inhibitors (PIs) have been linked to the development of this complication.. We evaluated the effects of nucleoside-sparing and PI-sparing regimens on fat distribution, bone mineral density, and metabolic parameters in 62 subjects, who were not selected for lipoatrophy, with advanced HIV (nadir CD4 count or=80,000 copies/mL) and an undetectable HIV viral load. Participants were randomized to switch their initial successful antiretroviral regimen to open-label lopinavir/ritonavir (LPV/r) at a dose of 533/133 mg twice a day and efavirenz (EFV) at a dose of 600 mg/d (the nucleoside-sparing arm) versus EFV and 2 nucleoside analogues (the PI-sparing arm).. At week 48, the median change in limb fat in the nucleoside-sparing arm was 562 g (6%, interquartile range [IQR]: -218-1186 g) versus a loss of -242 g (-4%, IQR: -539-452 g) in the nucleoside-containing PI-sparing arm (P = 0.086). At the time of last observation (median = 102 weeks, IQR: 73-152 weeks), a median gain of 782 g (10%, IQR: -380-1168 g) of limb fat was noted in the nonnucleoside arm (n = 22) versus a loss of 850 g (-15%, IQR: -1270 to -526 g) in the nucleoside-containing arm (n = 25; P = 0.002).. The switch to a nucleoside-sparing combination antiretroviral regimen (LPV/r + EFV) was associated with significant improvement in limb fat. These results provide additional evidence that nucleoside analogues are important in the progressive limb fat loss that characterizes antiretroviral treatment and that switching medications can significantly improve this complication. This option has to be carefully balanced with the potential to increase serum lipid levels and the trend to increase virologic failure.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Body Fat Distribution; Cyclopropanes; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir; Time Factors

To characterise the interactions between tacrolimus and antiretroviral drug combinations in hepatitis C virus-HIV co-infected patients who had received a liver transplant.. An observational, open-label, multiple-dose, two-period, one-sequence design clinical trial in which patients received tacrolimus as an immunosuppressive therapy during the postoperative period and then had an antiretroviral drug regimen added. Tacrolimus pharmacokinetics were evaluated at steady state during these two periods.. Fourteen patients participated in the study and seven participated in the intensified pharmacokinetic protocol. Patients were included if they had undergone liver transplantation for end-stage chronic hepatitis C, absence of opportunistic infection, a CD4 cell count of >150 cells/microL and an undetectable HIV plasma viral load (<50 copies/mL) under highly active antiretroviral therapy. During the posttransplantation period, the tacrolimus dose was adjusted according to blood concentrations. When liver function and the tacrolimus dose were stable, antiretroviral therapy was reintroduced.. When lopinavir/ritonavir were added to the tacrolimus regimen (seven patients), the tacrolimus dose was reduced by 99% to maintain the tacrolimus concentration within the therapeutic range. Only two patients were treated with nelfinavir, which led to a wide variation in inhibition of tacrolimus metabolism. When efavirenz (four patients) or a nucleoside analogue combination (one patient) was added, very little change in tacrolimus dosing was required.. The lopinavir/ritonavir combination markedly inhibited tacrolimus metabolism, whereas the effect of efavirenz was small. Tacrolimus dosing must be optimised according to therapeutic drug monitoring and the antiretroviral drug combination.

Topics: Adult; Aged; Alkynes; Antiretroviral Therapy, Highly Active; Area Under Curve; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dose-Response Relationship, Drug; Female; Graft Rejection; Half-Life; Hepatitis C; HIV; HIV Infections; Humans; Liver Transplantation; Lopinavir; Male; Middle Aged; Nelfinavir; Pyrimidinones; Ritonavir; Tacrolimus; Viral Load

Amprenavir (APV), fosamprenavir (FPV), lopinavir (LPV), ritonavir (RTV) and efavirenz (EFV) are to varying degrees substrates, inducers and inhibitors of CYP3A4. Coadministration of these drugs might result in complex pharmacokinetic drug-drug interactions.. Two prospective, open-label, non-randomized studies evaluated APV and LPV steady-state pharmacokinetics in HIV-infected patients on APV 750 mg twice daily + LPV/RTV 533/133 mg twice daily with EFV (n=7) or without EFV (n=12) + background nucleosides (Study 1) and after switching FPV 1,400 mg twice daily for APV (n=10) (Study 2).. In Study 1 EFV and non-EFV groups did not differ in APV minimum plasma concentration (Cmin; 1.10 versus 1.06 microg/ml, P = 0.89), area under the concentration-time curve (AUC; 17.46 versus 24.34 microg x h/ml, P = 0.22) or maximum concentration (Cmax; 2.61 versus 4.33 microg/ml, P = 0.08); for LPV there was no difference in Cmin, (median: 3.66 versus 6.18 microg/ml, P = 0.20), AUC (81.84 versus 93.75 microg x h/ml, P = 0.37) or Cmax (10.36 versus 10.93 microg/ml, P = 0.61). In Study 2, after switching from APV to FPV, APV Cmin increased by 58% (0.83 versus 1.30 microg/ml, P = 0.0001), AUC by 76% (19.41 versus 34.24 micorg x h/ml, P = 0.0001), and Cmax by 75% (3.50 versus 6.14, P = 0.001). Compared with historical controls, LPV and RTV pharmacokinetics were not changed. All treatment regimens were well tolerated. Seven of eight completers (88%) maintained HIV-1 RNA <400 copies/ml 12 weeks after the switch (1 lost to follow up).. EFV did not appear to significantly alter APV and LPV pharmacokinetic parameters in HIV-infected patients taking APV 750 mg twice daily + LPV 533/133 mg twice daily. Switching FPV 1400 mg twice daily for APV 750 mg twice daily resulted in an increase in APV Cmin, AUC, and Cmax without changing LPV or RTV pharmacokinetics or overall tolerability.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Organophosphates; Pyrimidinones; Ritonavir; Sulfonamides

To assess if enfuvirtide (ENF) increases antiviral activity of a highly active four-drug antiretroviral (ARV) regimen containing lopinavir/ritonavir, efavirenz, lamivudine and tenofovir in ARV-naive, HIV-infected patients.. Pilot study in ARV-naive, HIV-infected patients with viral load (VL) >10,000 copies/ml and no documented resistance to any of the study drugs. Patients were randomized to receive ENF (ENF Group) or not (Control Group) in combination with lopinavir/ritonavir, efavirenz, lamivudine and tenofovir as a backbone. The primary endpoint was to assess differences in the HIV-1 RNA decay rate during the first phase of viral decay. VL and treatment adherence were measured at baseline, every 6 h during the first 3 days, and once daily from day 3 to 6. Individual HIV-1 RNA decay rates were obtained using a non-linear least squares regression model.. Eight subjects were included in each study group. Mean (SD) baseline VL was 4.98 (0.38) log10 copies/ml in the ENF Group and 5.10 (0.49) log10 copies/ml in the Control Group (P=0.607). Baseline CD4+ cell count was 463 (306) and 362 (225) cells/mm3 in the ENF and the Control Group, respectively (P=0.484). First phase HIV-1 RNA decay rate was 0.802 (0.127) d(-1) in the ENF Group and 0.624 (0.182) d(-1) in the Control Group (P=0.045). By day 6, VL was 3.55 (0.40) and 3.92 (0.36) log10 copies/ml in the ENF and the Control Group, respectively (P=0.079).. The addition of ENF increased the antiviral potency of a highly active four-drug ARV regimen by 28.5% in ARV-naive, HIV-infected patients. The clinical impact of this finding should be assessed.

Topics: Adenine; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Drug Synergism; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Lamivudine; Lopinavir; Organophosphonates; Oxazines; Patient Compliance; Peptide Fragments; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Tenofovir; Treatment Outcome

To describe the occurrence of a high early virological failure (VF) rate and development of resistance mutations in antiretroviral-naive patients receiving tenofovir, didanosine and efavirenz.. HIV-infected antiretroviral-naive patients with viral load > or =30 000 copies/ml were enrolled in a pilot randomized trial of tenofovir/didanosine (250 mg)/ efavirenz with (arm A) or without (arm B) lopinavir/r for the first 12 weeks. As six cases of early VF (a drop of <2 log at month 3, or a rebound of >1 log from the nadir) were detected (five in arm B and one in arm A who had previously stopped lopinavir/r) an unplanned interim analysis was performed.. A total of 29 out of 36 enrolled patients completed at least 3 months of follow-up and were included in the interim analysis. An intent-to-treat analysis showed treatment failure in 7/15 (46.7%) patients in arm B (five VF, one lost, one switched) versus 2/14 (14.3%) in arm A (one lost, one switched) (P=0.109). The patient in arm A who interrupted lopinavir/r at day 3 and continued with tenofovir/didanosine/efavirenz later developed VF. At baseline, 6/6 VF patients had VL >100000 copies/ml and an advanced stage of disease (CD4 <200 plus CDC stage C or B3) versus 0/8 non-VF patients taking the triple drug regimen (P<0.001). At failure, G190S/E alone or associated with K103N and K101R mutations was detected in five patients, and K103N/L1001/V108l in the sixth patient. Additionally, L74V/I and K65R were detected in four and two patients, respectively.. A high early virological failure rate and the occurrence of resistance mutations were detected in a group of antiretroviral-naive patients treated with tenofovir/didanosine/efavirenz.

Topics: Adenine; Adult; Aged; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Didanosine; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Mutation; Organophosphonates; Oxazines; Pyrimidinones; RNA, Viral; Tenofovir; Time Factors; Treatment Failure; Viremia

Nucleoside reverse transcriptase inhibitor-sparing regimens have not yet been systematically evaluated in children. The nonnucleoside reverse transcriptase inhibitors nevirapine and efavirenz lower plasma levels of protease inhibitors in adults and children. Therefore, coadministration of lopinavir/ritonavir with nevirapine and efavirenz necessitates a 30% increase in the dose of lopinavir/ritonavir in adults. In children, the extent of the pharmacokinetic interaction between efavirenz and lopinavir/ritonavir has not yet been studied.. To investigate the pharmacokinetics of increased-dose (300/75 mg/m2 twice-daily) lopinavir/ritonavir with normal-dose (14 mg/kg once-daily) efavirenz in HIV-1-infected children.. Steady-state pharmacokinetics of lopinavir and efavirenz were determined and compared with historical data.. Fifteen children of median age 11.8 (range, 5.7-16.3) years were included. Area under the plasma concentration-time curve (AUC0-12), peak levels (Cmax), and trough levels (Cmin) of lopinavir were similar to historical data in adults and children. Medians (interquartile range) were 92.3 (43.5-138.5) mg/L.h, 12.5 (6.9-16.7) mg/L, and 5.7 (1.3-8.0) mg/L, respectively. Efavirenz pharmacokinetics approximated previous data in adults and children.. The increased dose of 300/75 mg/m2 twice-daily lopinavir/ritonavir compensates for the enzyme-inducing effect of efavirenz in HIV-infected children.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Alkynes; Anti-HIV Agents; Area Under Curve; Benzoxazines; Child; Child, Preschool; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Female; HIV Protease Inhibitors; Humans; Lopinavir; Male; Oxazines; Pyrimidinones; Ritonavir; Safety

The influence of efavirenz on lopinavir pharmacokinetics was investigated using a population approach.. Forty-five HIV patients treated with lopinavir/ritonavir plus efavirenz (A) and 24 patients treated with lopinavir/ritonavir plus nucleoside/nucleotide reverse transcriptase inhibitors (B) were studied.. A relationship (P < 0.01) was established between the elimination rate constant of lopinavir (k(10)) and treatment with efavirenz. Mean k(10) was higher in group A than in group B (0.3838 vs 0.2810 h(-1)) (P < 0.001, 95% confidence interval for difference between means 0.1004, 0.1052).. These results suggest that lopinavir metabolism is induced by efavirenz.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Combinations; Drug Interactions; Female; HIV Protease Inhibitors; Humans; Lopinavir; Male; Oxazines; Pyrimidinones; Ritonavir

Recommended antiretroviral regimens include a nucleoside reverse transcriptase inhibitor (NRTI) component. Class cross-resistance and mitochondrial toxicity are recognized as problems with this class of antiretrovirals.. In a pilot open-label study, 65 antiretroviral-naive and 21 experienced but nonnucleoside reverse transcriptase inhibitor-naive HIV-1-infected adults were given a combination of lopinavir/ritonavir (533.3/133.3 mg twice daily) and efavirenz (600 mg once daily) for 48 weeks.. At baseline, the mean viral load was 4.84 log10 copies/mL and the mean CD4 count was 311 cells/mm. At week 24, the proportions of patients with a viral load <400 copies/mL were 78% and 93% using an intent-to-treat and on-treatment analysis, respectively. At week 48, proportions were 73% and 97%, respectively. Treatment discontinuation occurred in 21 patients during the 48-week period, with 33% of those attributable to drug-related adverse effects. A viral load >400 copies/mL at week 24 or 48 was associated with nonadherence in 3 patients and virologic failure in 1 patient. After an increase during the first 8 weeks, fasting lipid levels remained stable up to 48 weeks.. The lopinavir/ritonavir-efavirenz combination is associated with a high rate of virologic response and should be compared with more classic NRTI-containing regimens in randomized and controlled clinical trials.

Topics: Adolescent; Adult; Aged; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Resistance, Viral; Drug Tolerance; Female; France; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oxazines; Prospective Studies; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Safety

We studied a nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimen for the treatment of children infected with NRTI-resistant HIV-1. The combination of lopinavir/ritonavir and efavirenz suppressed HIV-1 levels for a prolonged period and resulted in a significant increase in CD4+ T cell numbers despite an extensive prior treatment with NRTI (>4 years). Observed side effects were transient with the exception of dyslipidaemia.

Topics: Adolescent; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Child; Child, Preschool; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lopinavir; Oxazines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome

The steady-state pharmacokinetics and pharmacodynamics of two oral doses of lopinavir-ritonavir (lopinavir/r; 400/100 and 533/133 mg) twice daily (BID) when dosed in combination with efavirenz, plus two nucleoside reverse transcriptase inhibitors, were assessed in a phase II, open-label, randomized, parallel arm study in 57 multiple protease inhibitor-experienced but non-nucleoside reverse transcriptase inhibitor-naive human immunodeficiency virus (HIV)-infected subjects. All subjects began dosing of lopinavir/r at 400/100 mg BID; subjects in one arm increased the lopinavir/r dose to 533/133 mg BID on day 14. When codosed with efavirenz, the lopinavir/r 400/100 mg BID regimen resulted in lower lopinavir concentrations in plasma, particularly C(min), than were observed in previous studies of lopinavir/r administered without efavirenz. Increasing the lopinavir/r dose to 533/133 mg increased the lopinavir area under the concentration-time curve over a 12-h dosing interval (AUC(12)), C(predose), and C(min) by 46, 70, and 141%, respectively. The increase in lopinavir C(max) (33%,) did not reach statistical significance. Ritonavir AUC(12), C(max), C(predose), and C(min) values were increased 46 to 63%. The lopinavir predose concentrations achieved with the 533/133-mg BID dose were similar to those observed with lopinavir/r 400/100 mg BID in the absence of efavirenz. Results from univariate logistic regression analyses identified lopinavir and efavirenz inhibitory quotient (IQ) parameters, as well as the baseline lopinavir phenotypic susceptibility, as predictors of antiviral response (HIV RNA < 400 copies/ml at week 24); however, no lopinavir or efavirenz concentration parameter was identified as a predictor. Multiple stepwise logistic regressions confirmed the significance of the IQ parameters, as well as other baseline characteristics, in predicting virologic response at 24 weeks in this patient population.

Topics: Adult; Alkynes; Area Under Curve; Benzoxazines; Biological Availability; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV Reverse Transcriptase; Humans; Logistic Models; Lopinavir; Oxazines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir

Despite the clinical benefits of combination antiviral therapy, whether maximal antiviral potency has been achieved with current drug combinations remains unclear. We studied the first phase of decay of human immunodeficiency virus type 1 (HIV-1) RNA in plasma, one early indicator of antiviral activity, after the administration of a novel combination of lopinavir/ritonavir, efavirenz, tenofovir disoproxil fumarate, and lamivudine and compared it with that observed in matched cohorts treated with alternative combination regimens. On the basis of these comparisons, we conclude that the relative potency of highly active antiretroviral therapy may be augmented by as much as 25%-30%. However, it is important to emphasize that further study is warranted to explore whether these early measurements of relative efficacy provide long-term virologic and clinical benefits. Nevertheless, we believe that optimal treatment regimens for HIV-1 have yet to be identified and that continued research to achieve this goal is warranted.

Topics: Adenine; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cohort Studies; Cyclopropanes; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Organophosphonates; Organophosphorus Compounds; Oxazines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Tenofovir; Treatment Outcome

Emerging data indicate that the reverse transcriptase (RT) protein encoded by LINE-1 transposable elements is a promising cancer target. Nonnucleoside RT inhibitors, e.g. efavirenz (EFV) and SPV122.2, reduce proliferation and promote differentiation of cancer cells, concomitant with a global reprogramming of the transcription profile. Both inhibitors have therapeutic anticancer efficacy in animal models. Here we have sought to clarify the mechanisms of RT inhibitors in cancer cells. We report that exposure of PC3 metastatic prostate carcinoma cells to both RT inhibitors results in decreased proliferation, and concomitantly induces genome damage. This is associated with rearrangements of the nuclear architecture, particularly at peripheral chromatin, disruption of the nuclear lamina, and budding of micronuclei. These changes are reversible upon discontinuation of the RT-inhibitory treatment, with reconsititution of the lamina and resumption of the cancer cell original features. The use of pharmacological autophagy inhibitors proves that autophagy is largely responsible for the antiproliferative effect of RT inhibitors. These alterations are not induced in non-cancer cell lines exposed to RT inhibitors. These data provide novel insight in the molecular pathways targeted by RT inhibitors in cancer cells.

Topics: Alkynes; Autophagy; Benzoxazines; Cell Differentiation; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Cyclopropanes; DNA Damage; Humans; Male; PC-3 Cells; Prostatic Neoplasms; Pyrimidinones; Reverse Transcriptase Inhibitors

The durability of combination antiretroviral therapy (cART) regimens can be measured as time to discontinuation because of toxicity or treatment failure, development of clinical disease or serious long-term adverse events. The aim of this analysis was to compare the durability of nevirapine, efavirenz and lopinavir regimens based on these measures.. Patients starting a nevirapine, efavirenz or lopinavir-based cART regimen for the first time after 1 January 2000 were included in the analysis. Follow-up started ≥ 3 months after initiation of treatment if viral load was <500 HIV-1 RNA copies/mL. Durability was measured as discontinuation rate or development/worsening of clinical markers.. A total of 603 patients (21%) started nevirapine-based cART, 1465 (51%) efavirenz, and 818 (28%) lopinavir. After adjustment there was no significant difference in the risk of discontinuation for any reason between the groups on nevirapine and efavirenz (P=0.43) or lopinavir (P=0.13). Compared with the nevirapine group, those on efavirenz had a 48% (P=0.0002) and those on lopinavir a 63% (P<0.0001) lower risk of discontinuation because of treatment failure and a 31% (P=0.01) and 66% (P<.0001) higher risk, respectively, of discontinuation because of toxicities or patient/physician choice. There were no significant differences in the incidence of non-AIDS-related events, worsening anaemia, severe weight loss, increased aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels or increased total cholesterol. Compared with patients on nevirapine, those on lopinavir had an 80% higher incidence of high-density lipoprotein (HDL) cholesterol decreasing below 0.9 mmol/L (P=0.003), but there was no significant difference in this variable between those on nevirapine and those on efavirenz (P=0.39).. The long-term durability of nevirapine-based cART, based on risk of all-cause discontinuation and development of long-term adverse events, was comparable to that of efavirenz or lopinavir, in patients in routine clinical practice across Europe who initially tolerated and virologically responded to their regimen.

Topics: Alkynes; Argentina; Benzoxazines; Cyclopropanes; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Europe; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Israel; Lopinavir; Male; Nevirapine; Prospective Studies; Pyrimidinones; Reverse Transcriptase Inhibitors; Treatment Outcome; Viral Load

Topics: Adenine; Aged; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cote d'Ivoire; Cyclopropanes; Drug Therapy, Combination; Enterobacter aerogenes; Enterobacteriaceae Infections; Fanconi Syndrome; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lopinavir; Malaria; Male; Middle Aged; Organophosphonates; Pyelonephritis; Pyrimidinones; Ritonavir; Tenofovir

Therapeutic drug monitoring (TDM) is recommended in several international HIV treatment guidelines. The adherence of clinicians to these recommendations is unknown. The authors evaluated the adherence to the Dutch TDM guideline of 2005.. From the ATHENA cohort study, three scenarios were selected for which the guideline recommended TDM: 1) start of a combination of lopinavir/ritonavir + efavirenz or nevirapine (drug-drug interaction); 2) start of efavirenz (routine TDM); and 3) use of nelfinavir during pregnancy. For each scenario, we determined the proportion of patients for whom TDM was performed. Multivariable logistic regression modeling was used to identify determinants for the use of TDM.. The adherence to the TDM guideline was 46.7% in patients who started lopinavir/ritonavir plus efavirenz or nevirapine; 9.5% for patients who started efavirenz; and 58.5% for patients who used nelfinavir during pregnancy. Patients treated in clinics that had a TDM assay available locally and patients treated in academic clinics were more likely to receive TDM. A higher baseline HIV viral load was another significant predictor for the performing TDM.. The adherence of clinicians to the Dutch TDM guidelines varied from low to moderate for the three investigated TDM scenarios. This study identifies several determinants for the use of TDM, which may be useful information for those responsible for generating TDM guidelines.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Guideline Adherence; HIV Infections; Humans; Lopinavir; Netherlands; Nevirapine; Pregnancy; Pyrimidinones; Randomized Controlled Trials as Topic

To evaluate the effect of antiretroviral treatment on aminotransferase serum levels in treatment-naïve patients infected with human immunodeficiency virus (HIV).. We conducted a longitudinal study in treatment-nanaïve patients infected with HIV. Patients were excluded if they had consumed alcohol during the last three months or had an opportunistic disease or co-infection. All 54 enrolled patients were evaluated and those having a CD4+ cell count <350 cells/ml (41/54) were allocated to the treatment group (TG), while those with CD4+ counts >350 cells/ml (13/54) did not receive any anti-retroviral treatment (ART). TG patients received either efavirenz (EFV) (21/41) or lopinavir/ritonavir (LPV/RTV) (20/41), each with zidovudine/lamivudine (ZDV/LMV).. During the trial, 2 subjects in the EFV group were excluded due to rash and 1 subject in the LPV/RTV group due to gastric intolerance. The remaining 51 subjects (13 (25.5%) in the NTG and 38 (74.5%) in the TG) were included in the data analysis. Overall, 43 (84%) of analyzed patients were male and 8 (16%) female with an overall mean age of 33 ± 9 years. Of the 38 treated patients, 19 received LPV/RTV and 19 received EFV. Patients in the TG showed an increase in their CD4+ cell count, a decrease in aspartate aminotransferase (AST) from 39.3 ± 28 IU/ml to 22.7 ± 6 IU/ml (p = 0.02), and a decrease in alanine aminotransferase (ALT) from 52.0 ± 25 IU/ml to 23.8 ± 13 IU/ml (p < 0.01). Patients in the NTG showed no statistically significant differences in these measurements. Positive correlation was found between HIV viral load, AST (r = 0.31, p = 0.001) and ALT (r = 0.40, p = 0.04).. There is a significant decrease in aminotransferase serum levels following the initiation of antiretroviral treatment in HIV infected patients.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Combinations; Female; HIV Infections; Humans; Lamivudine; Longitudinal Studies; Lopinavir; Male; Pyrimidinones; Ritonavir; Serum; Transaminases; Zidovudine

To evaluate the effect of a previous single dose of nevirapine given to prevent mother-to-child transmission of human immunodeficiency virus (HIV) on virologic and immunologic measures after months of an antiretroviral regimen containing either efavirenz or lopinavir-ritonavir.. Retrospective subgroup analysis of data from the Phidisa II trial.. Six South African research clinics. Patients. A total of 394 women with HIV who completed 6 months of combination antiretroviral regimen containing either efavirenz or lopinavirritonavir as part of the Phidisa II trial.. During the screening process for the Phidisa II study, 478 women were asked about previous nevirapine use: 392 women (82%) were nevirapine naïve, and 86 (18%) had received nevirapine. During the study, patients received either an efavirenz-based or lopinavir-ritonavir- based antiretroviral regimen. After 6 months of treatment, virologic (HIV RNA levels) and immunologic (CD4(+) cell count) responses were measured. These data were compared between women with or without previous nevirapine exposure, and between women who received efavirenz versus lopinavirritonavir. After 6 months of treatment, 394 women (324 nevirapine naïve, 70 exposed to nevirapine) had follow-up HIV RNA results. Two hundred twenty-seven (70.1%) of the nevirapine-naïve patients and 48 (68.6%) of the nevirapine-exposed patients achieved HIV RNA levels lower than 400 copies/ml (p=0.89), with CD4(+) cell count increases of 115.5 and 120.4 cells/mm(3), respectively (p=0. 7). Among the nevirapine-exposed women, 27 (75%) of 36 efavirenz-treated and 21 (61.8%) of 34 lopinavir-ritonavir-treated patients had HIV RNA levels lower than 400 copies/ml at months (p=0.31).. In this retrospective analysis of a small cohort, previous exposure to a single dose of nevirapine did not affect virologic outcomes after 6 months of either an efavirenz-based or lopinavir-ritonavir-based antiretroviral regimen. As efavirenz is one of the first-line combination antiretroviral therapies administered in Africa, it remains an option for women who received single-dose nevirapine.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Clinical Trials, Phase II as Topic; Cyclopropanes; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; HIV; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Lopinavir; Nevirapine; Pyrimidinones; Randomized Controlled Trials as Topic; Retrospective Studies; Ritonavir; RNA, Viral; South Africa; Young Adult

There have been no data presented on the relative rates of the development of renal stones in those receiving ritonavir-boosted atazanavir (ATZ/r) when compared with other commonly used antiretrovirals (ARVs). We compared the rate of development of renal stones in a cohort of HIV-infected individuals attending the Chelsea and Westminster Hospital Foundation Trust exposed to ATZ/r with those exposed to efavirenz (EFV)/ritonavir-boosted lopinavir (LPV/r) and ritonavir-boosted darunavir (DRV/r) over a 45-month study period. The rate of development of renal stones in the ATZ/r group (n = 1206) compared with the EFV/LPV/r/DRV/r combined group (n = 4449) was 7.3 [95% confidence interval (CI) 4.7-10.8] per 1000 patient-years and 1.9 (95% CI 1.2-2.8) per 1000 patient-years (P < 0.001), respectively. The renal stones rate remained significantly higher in the ATZ/r group after adjusting for prior ATZ/r/indinavir (IND) exposure. When choosing a boosted protease inhibitor, ATZ/r renal stones should be considered as a potential comorbidity.

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Bilirubin; Cohort Studies; Cyclopropanes; Darunavir; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Nephrolithiasis; Oligopeptides; Pyridines; Pyrimidinones; Retrospective Studies; Ritonavir; Sulfonamides

The protease inhibitors lopinavir and atazanavir are both recommended for treatment of HIV-infected patients. Considerable inter-individual variability in plasma concentration has been observed for both drugs. The aim of this study was to evaluate which demographic factors and concomitant drugs are associated with lopinavir and atazanavir plasma concentration.. Data from the Liverpool TDM (therapeutic drug monitoring) Registry were linked with the UK Collaborative HIV Cohort (CHIC) study. For each patient, the first measurement of lopinavir (twice daily) or atazanavir [once daily, ritonavir boosted (/r) or unboosted] plasma concentration was included. Linear regression was used to evaluate the association of dose, gender, age, weight, ethnicity and concomitant antiretroviral drugs or rifabutin with log-transformed drug concentration, adjusted for time since last intake.. Data from 439 patients on lopinavir (69% 400 mg/r, 31% 533 mg/r; 3% concomitant rifabutin) and 313 on atazanavir (60% 300 mg/r, 32% 400 mg/r, 8% 400 mg) were included. Multivariable models revealed the following predictors for lopinavir concentration: weight (11% decrease per additional 10 kg; P = 0.001); dose (25% increase for 533 mg/r; P = 0.024); and rifabutin (116% increase; P < 0.001). For atazanavir the predictors were dose (compared with 300 mg/r: 40% increase for 400 mg/r, 67% decrease for 400 mg; overall P < 0.001) and efavirenz (32% decrease; P = 0.016) but not tenofovir (P = 0.54).. This analysis confirms that efavirenz decreases atazanavir concentrations, and there was a negative association of weight and lopinavir concentrations. The strong impact of rifabutin on lopinavir concentration should be studied further.

Topics: Adult; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Body Weight; Cyclopropanes; Female; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Plasma; Pyridines; Pyrimidinones; Rifabutin; United Kingdom

The relation between treatment outcome and trough plasma concentrations of efavirenz (EFV), atazanavir (ATV) and lopinavir (LPV) was studied in a pharmacokinetic/pharmacodynamic substudy of the NORTHIV trial-a randomised phase IV efficacy trial comparing antiretroviral-naïve human immunodeficiency virus-1-infected patients treated with (1) EFV + 2 nucleoside reverse transcriptase inhibitors (2NRTI) once daily, (2) ritonavir-boosted ATV + 2NRTI once daily or (3) ritonavir-boosted LPV + 2NRTI twice daily. The findings were related to the generally cited minimum effective concentration levels for the respective drugs (EFV 1,000 ng/ml, ATV 150 ng/ml, LPV 1,000 ng/ml). The relation between atazanavir-induced hyperbilirubinemia and virological efficacy was also studied.. Drug concentrations were sampled at weeks 4 and 48 and optionally at week 12 and analysed by high-performance liquid chromatography with UV detector. When necessary, trough values were imputed by assuming the reported average half-lives for the respective drugs. Outcomes up to week 48 are reported.. No relation between plasma concentrations of EFV, ATV or LPV and virological failure, treatment withdrawal due to adverse effects or antiviral potency (viral load decline from baseline to week 4) was demonstrated. Very few samples were below the suggested minimum efficacy cut-offs, and their predictive value for treatment failure could not be validated. There was a trend toward an increased risk of virological failure in patients on ATV who had an average increase of serum bilirubin from baseline of <25 micromol/l.. The great majority of treatment-naïve and adherent patients on standard doses of EFV, ritonavir-boosted ATV and ritonavir-boosted LPV have drug concentrations above that considered to deliver the maximum effect for the respective drug. The results do not support the use of routine therapeutic drug monitoring (TDM) for efficacy optimisation in treatment-naïve patients on these drugs, although TDM may still be of value in some cases of altered pharmacokinetics, adverse events or drug interactions. Serum bilirubin may be a useful marker of adherence to ATV therapy.

Topics: Alkynes; Atazanavir Sulfate; Benzoxazines; Bilirubin; Chromatography, High Pressure Liquid; Clinical Trials as Topic; Cyclopropanes; Drug Interactions; HIV-1; Humans; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Failure; Treatment Outcome; Viral Load

Adverse effects of combination antiretroviral therapy (CART) commonly result in treatment modification and poor adherence.. We investigated predictors of toxicity-related treatment modification during the first year of CART in 1318 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from the Swiss HIV Cohort Study who began treatment between January 1, 2005, and June 30, 2008.. The total rate of treatment modification was 41.5 (95% confidence interval [CI], 37.6-45.8) per 100 person-years. Of these, switches or discontinuations because of drug toxicity occurred at a rate of 22.4 (95% CI, 19.5-25.6) per 100 person-years. The most frequent toxic effects were gastrointestinal tract intolerance (28.9%), hypersensitivity (18.3%), central nervous system adverse events (17.3%), and hepatic events (11.5%). In the multivariate analysis, combined zidovudine and lamivudine (hazard ratio [HR], 2.71 [95% CI, 1.95-3.83]; P < .001), nevirapine (1.95 [1.01-3.81]; P = .050), comedication for an opportunistic infection (2.24 [1.19-4.21]; P = .01), advanced age (1.21 [1.03-1.40] per 10-year increase; P = .02), female sex (1.68 [1.14-2.48]; P = .009), nonwhite ethnicity (1.71 [1.18-2.47]; P = .005), higher baseline CD4 cell count (1.19 [1.10-1.28] per 100/microL increase; P < .001), and HIV-RNA of more than 5.0 log(10) copies/mL (1.47 [1.10-1.97]; P = .009) were associated with higher rates of treatment modification. Almost 90% of individuals with treatment-limiting toxic effects were switched to a new regimen, and 85% achieved virologic suppression to less than 50 copies/mL at 12 months compared with 87% of those continuing CART (P = .56).. Drug toxicity remains a frequent reason for treatment modification; however, it does not affect treatment success. Close monitoring and management of adverse effects and drug-drug interactions are crucial for the durability of CART.

Topics: Adenine; Adult; AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Deoxycytidine; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Nevirapine; Oligopeptides; Organophosphonates; Proportional Hazards Models; Prospective Studies; Pyridines; Pyrimidinones; Risk Factors; Switzerland; Tenofovir; Zidovudine

HIV-infected travellers frequently use atovaquone/proguanil as malaria prophylaxis. We compared atovaquone/proguanil pharmacokinetics between healthy volunteers and HIV-infected patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir. The geometric mean ratio (95% confidence interval) area under the curve (AUC)0-->t for atovaquone relative to the healthy volunteers was 0.25 (0.16-0.38), 0.26 (0.17-0.41) and 0.54 (0.35-0.83) for patients on efavirenz, lopinavir/ritonavir and atazanavir/ritonavir, respectively. Proguanil plasma concentrations were also significantly lower (38-43%). Physicians should be alert for atovaquone/proguanil prophylaxis failures in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir.

Topics: Adolescent; Adult; Aged; Alkynes; Atazanavir Sulfate; Atovaquone; Benzoxazines; Cyclopropanes; Drug Administration Schedule; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Proguanil; Pyridines; Pyrimidinones; Ritonavir; Young Adult

Free ritonavir, lopinavir and efavirenz injected intraperitoneally were compared with antiretroviral (AR) nanoparticles (NPs).. This is a prospective study in BALB/c mice comparing the pharmacokinetics of free drugs with AR NPs. All animals received free drugs or AR NPs (20 mg/kg) in PBS. In vitro replication assays were used for determination of the anti-HIV efficacy of NP formulations. At specific times (free drugs 0.08, 0.125, 0.25, 0.33, 1, 2 and 3 days; AR NPs 0.125, 0.33, 1, 2, 4, 7, 14, 21, 28, 35 and 42 days) mice were euthanized and serum and organs were harvested for determination of AR concentrations by HPLC. Single treatment of monocyte-derived macrophages (MDMs) infected with HIV-1(ada) compared AR NPs (0.005-0.05 mg/mL) with free efavirenz or lopinavir/ritonavir (0.01-0.1 mg/mL), blank NPs and controls. Results are presented as means ± SEM.. Serum free AR drug concentrations peaked 4 h post-injection (ritonavir 3.9 ± 3.05, lopinavir 3.4 ± 2.5 and efavirenz 1.8 ± 0.63 µg/mL) and were eliminated by 72 h. Poly(dl-lactide-co-glycolide) NP animals had detectable ritonavir, lopinavir and efavirenz concentrations in all tissues for 28 days. Treatment of MDMs with AR NPs resulted in sustained inhibition of HIV-1(ada) replication.. AR drug concentrations from NPs are sustained for 28 days in vivo and anti-HIV inhibition was comparable to that of free drugs in vitro and could be a sustained treatment for delivery of AR drugs.

Topics: Alkynes; Animal Structures; Animals; Anti-HIV Agents; Benzoxazines; Chromatography, High Pressure Liquid; Cyclopropanes; Drug Delivery Systems; Injections, Intraperitoneal; Lopinavir; Mice; Mice, Inbred BALB C; Monocytes; Nanoparticles; Polyesters; Pyrimidinones; Ritonavir; Serum; Time Factors

To compare plasma antiretroviral concentrations in HIV-HCV co-infected and in matched HIV mono-infected patients.. This was a cross-sectional, observational study. Antiretroviral trough concentrations (C(min)) in plasma were measured in HIV-HCV co-infected patients with liver disease documented by liver biopsy, matched with HIV mono-infected patients according to gender and antiretroviral treatment. C(min) values in serum were measured using an HPLC method. Statistical analysis was performed using the Wilcoxon test.. Seventy-three HIV-HCV co-infected patients and 66 HIV-infected patients were enrolled; 70% of patients were receiving a protease inhibitor (PI)- and 30% a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. Among the 73 co-infected patients, 27 had a fibrosis score (Fibrotest(®)) of F4. Abacavir was the only nucleoside reverse transcriptase inhibitor whose trough concentrations differed between the co-infected and mono-infected groups. PI median plasma C(min) values were not different in the two groups, except for lopinavir, with a lower C(min) in the co-infected group than in the HIV-infected group (median 3673 versus 5990 ng/mL, P=0.04), and nelfinavir, with significantly higher concentrations in the co-infected group. Seventy-five percent of co-infected patients scoring F4, 33% of those scoring F0-F3 and 12% of HIV-infected patients were underdosed (P=0.02). Co-infected patients receiving an NNRTI had a higher plasma C(min) than HIV-infected patients; median C(min) was 3583 versus 1494 ng/mL (P=0.025) and 5331 versus 3954 ng/mL (P=0.10) for efavirenz and nevirapine, respectively. Overall, there was a greater proportion of co-infected patients with high concentrations of both NNRTIs (15/23) compared with HIV mono-infected patients (5/21) (P=0.008), especially in co-infected patients with an advanced liver fibrosis stage.. Median plasma C(min) values differed significantly between HIV and HIV-HCV co-infected patients for abacavir, lopinavir and efavirenz. NNRTIs were strongly overdosed in HIV-HCV co-infected patients.

Topics: Adult; Aged; Alkynes; Anti-Retroviral Agents; Benzoxazines; Case-Control Studies; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Cyclopropanes; Dideoxynucleosides; Female; Hepatitis C, Chronic; HIV Infections; Humans; Liver Cirrhosis; Lopinavir; Male; Middle Aged; Plasma; Pyrimidinones

In the present study, a comparative assessment of the effects of efavirenz (EFV) and lopinavir/ritonavir (LPV/r; 4:1) on human adipocytes in culture has been performed. Human pre-adipocytes were treated with EFV or LPV/r during or after adipogenic differentiation. Acquisition of adipocyte morphology, expression of gene markers of mitochondrial toxicity, adipogenesis and inflammation, and release of adipokines and cytokines to the medium were measured. Results indicated that EFV and LPV/r impaired adipocyte differentiation in association with a reduction in transcript levels for adipogenic differentiation genes (adiponectin, lipoprotein lipase, leptin) and master regulators of adipogenesis (PPAR, C/EBP). The effects were greater with EFV than LPV/r. Both LPV/r and EFV induced increases in monocytechemoattactant protein-1 (MCP-1) mRNA levels, but the effect was greater with EFV. Similarly, the release of proinflammatory cytokines and other inflammation-related molecules (interleukins 6 and 8, MCP-1, PAI-1) was enhanced to a much higher degree by EFV than by LPV/r. Adiponectin and leptin release by adipocytes was reduced by both drugs, although to a higher extent by EFV. Neither drug affected mitochondrial DNA levels, transcripts encoding mitochondrial proteins or lactate release by adipocytes. In previously differentiated adipocytes, EFV caused a significant reduction in PPARγ and adiponectin expression, whereas LPV/r did not. We conclude that both EFV and LPV/r impair human adipogenesis, reduce adipokine release and increase the expression and release of inflammation-related cytokines, but the overall effects are greater with EFV. These findings may have implications for the pathogenesis of HIV-1-associated lipodystrophy and the development of HIV-1 therapies.

Topics: Adipocytes; Adipogenesis; Adipokines; Adiponectin; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cells, Cultured; Cyclopropanes; Cytokines; Female; Gene Expression; Humans; Lopinavir; Mitochondria; PPAR gamma; Pyrimidinones; Reverse Transcriptase Polymerase Chain Reaction; Ritonavir; RNA, Messenger

Most HPLC-UV methods for therapeutic drug monitoring of anti-HIV drugs have long run times, which reduce their applicability for high-throughput analysis. We developed an ultra-performance liquid chromatography (UPLC)-diode array detection method for the simultaneous quantification of the HIV-protease inhibitors (PIs) amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir (TPV), and the nonnucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine.. Solid-phase extraction of 1 mL plasma was performed with Waters HLB cartridges. After 3 wash steps, we eluted the drugs with methanol, evaporated the alcohol, and reconstituted the residue with 50 microL methanol. We injected a 4-microL volume into the UPLC system (Waters ACQUITY UPLC BEH C8 column maintained at 60 degrees C) and used a linear gradient of 50 mmol/L ammonium acetate and 50 mmol/L formic acid in water versus acetonitrile to achieve chromatographic separation of the drugs and internal standard (A-86093). Three wavelengths (215, 240, and 260 nm) were monitored.. All drugs were eluted within 15 min. Calibration curves with concentrations of 0.025-10 mg/L (1.875-75 mg/L for TPV) showed coefficients of determination (r(2)) between 0.993 and 0.999. The lower limits of quantification were well below the trough concentrations reported in the literature. Inter- and intraassay CVs and the deviations between the nominal and measured concentrations were <15%. The method was validated by successful participation in an international interlaboratory QC program.. This method allows fast and simultaneous quantification of all commercially available PIs and NNRTIs for therapeutic drug monitoring.

Topics: Alkynes; Atazanavir Sulfate; Benzoxazines; Carbamates; Chromatography, High Pressure Liquid; Cyclopropanes; Furans; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Nevirapine; Oligopeptides; Pyridines; Pyrimidinones; Pyrones; Reproducibility of Results; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Sensitivity and Specificity; Solid Phase Extraction; Sulfonamides

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Clinical Trials, Phase III as Topic; Cyclopropanes; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Treatment Outcome

Topics: Adenine; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis D, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Lopinavir; Male; Nephrolithiasis; Oligopeptides; Organophosphonates; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Tenofovir

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; HIV Infections; Humans; Lopinavir; Pyrimidinones; Ritonavir; Treatment Outcome; Viral Load; Viremia

Combination antiretroviral (AR) therapy continues to be the mainstay for HIV treatment. However, antiretroviral drug nonadherence can lead to the development of resistance and treatment failure. We have designed nanoparticles (NP) that contain three AR drugs and characterized the size, shape, and surface charge. Additionally, we investigated the in vitro release of the AR drugs from the NP using peripheral blood mononuclear cells (PBMCs).. Poly-(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing ritonavir (RTV), lopinavir (LPV), and efavirenz (EFV) were fabricated using multiple emulsion-solvent evaporation procedure. The nanoparticles were characterized by electron microscopy and zeta potential for size, shape, and charge. The intracellular concentration of AR drugs was determined over 28 days from NPs incubated with PBMCs. Macrophages were imaged by fluorescent microscopy and flow cytometry after incubation with fluorescent NPs. Finally, macrophage cytotoxicity was determined by MTT assay.. Nanoparticle size averaged 262 +/- 83.9 nm and zeta potential -11.4 +/- 2.4. AR loading averaged 4% (w/v). Antiretroviral drug levels were determined in PBMCs after 100 microg of NP in 75 microL PBS was added to media. Intracellular peak AR levels from NPs (day 4) were RTV 2.5 +/- 1.1; LPV 4.1 +/- 2.0; and EFV 10.6 +/- 2.7 microg and continued until day 28 (all AR >or= 0.9 microg). Free drugs (25 microg of each drug in 25 microL ethanol) added to PBMCs served as control were eliminated by 2 days. Fluorescence microscopy and flow cytometry demonstrated phagocytosis of NP into monocytes-derived macrophages (MDMs). Cellular MTT assay performed on MDMs demonstrated that NPs are not significantly cytotoxic.. These results demonstrated AR NPs could be fabricated containing three antiretroviral drugs (RTV, LPV, EFV). Sustained release of AR from PLGA NP show high drug levels in PBMCs until day 28 without cytotoxicity.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Carriers; Drug Combinations; Drug Compounding; HIV Infections; Humans; Lactic Acid; Lopinavir; Macrophages; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Pyrimidinones; Ritonavir

Corticosteroids are cytochrome P450 3A4 substrates, which have been associated with toxicities in patients receiving cytochrome P450 3A4 inhibitors such as human immunodeficiency virus protease inhibitors. In a study in healthy volunteers, ritonavir significantly increased prednisolone exposure.. We investigated the influence of antiretroviral (ARV) medications on prednisolone pharmacokinetics in 3 groups of 10 human immunodeficiency virus-infected subjects. One group received lopinavir/ritonavir, and another efavirenz, as part of their ARV regimen; a third group did not receive ARV medications. Each subject received a single 20-mg prednisone dose followed by serial blood sampling for prednisolone. Prednisolone pharmacokinetics were compared among the groups.. Area under the concentration-time curve was significantly lower in efavirenz recipients versus subjects receiving lopinavir/ritonavir (geometric mean ratio = 0.60, P = 0.01). Average prednisolone area under the concentration-time curve was higher in subjects taking lopinavir/ritonavir versus subjects not on ARVs; however, this difference was not significant (P > 0.05).. These data indicate that prednisolone concentrations may fluctuate widely when human immunodeficiency virus-positive individuals established on efavirenz therapy change to lopinavir/ritonavir or vice versa.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Prednisolone; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir

Topics: Alkynes; Benzoxazines; Cause of Death; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir

Topics: Alkynes; Anti-Retroviral Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lopinavir; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Failure

To evaluate the pharmacokinetics and pharmacogenomics of efavirenz (EFV) and lopinavir/ritonavir (LPV/RTV) in HIV-infected persons requiring hemodialysis.. Prospective, observational study of HIV-infected hemodialysis patients receiving one 600 mg tablet daily of EFV (N = 13) or three 133.3/33.3 mg capsules twice daily of LPV/RTV (N = 13).. Twenty-four-hour EFV and 12-h LPV/RTV pharmacokinetics were assessed. Geometric mean ratios were calculated using historical controls with normal renal function. The effects of several candidate gene polymorphisms were also explored.. The geometric mean [95% confidence interval (CI); percentage of coefficient of variation (% CV)] Cmin, Cmax, and area under the curve (AUC) for the EFV group were 1.81 microg/ml (0.93, 3.53; 103%), 5.04 microg/ml (3.48, 7.29; 72%), and 71.5 microg h/ml (43.2, 118.3; 93%), respectively. These parameters were 2.76 microg/ml (1.86, 4.11; 53%), 8.45 microg/ml (6.41, 11.15; 52%), and 69.6 microg h/ml (55.6, 87.2; 37%) for LPV and 0.08 microg/ml (0.05, 0.14; 63%), 0.58 microg/ml (0.44, 0.76; 41%), and 3.74 microg h/ml (2.91, 4.80; 37%) for RTV. The AUC geometric mean ratios (90% CI) for EFV, LPV, and RTV were 132% (89, 197), 81% (67, 97), and 92% (76, 111), respectively. LPV Cmin was lower than expected in the hemodialysis group. Higher EFV concentrations were associated with the CYP2B6 516G>T polymorphism.. The pharmacokinetics of EFV and LPV/RTV in hemodialysis suggests that no dosing adjustments are necessary in treatment-naive patients. As HIV-infected hemodialysis patients are disproportionately black, the increased frequency of the CYP2B6 516G>T polymorphism may lead to higher EFV levels. The potentially lower LPV trough levels in this population suggest that LPV/RTV should be used with caution in protease-inhibitor-experienced patients.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Kidney Failure, Chronic; Lopinavir; Male; Middle Aged; Polymorphism, Single Nucleotide; Prospective Studies; Pyrimidinones; Renal Dialysis; Reverse Transcriptase Inhibitors; Ritonavir

A highly sensitive and selective method using liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) was developed and validated for the measurement of three antiretroviral agents, efavirenz, lopinavir and ritonavir, in human hair. Hair samples from adherent HIV-infected patients on antiretroviral therapies were cut into about 1 mm length segments and drugs were extracted by first shaking the samples with methanol in a 37 degrees C water bath overnight (>14 h), followed by methyl tert-butyl ether/ethyl acetate (1:1) extraction under weak alkaline conditions. The extracted lopinavir and ritonavir were separated by reversed-phase chromatography and detected by tandem mass spectrometry in electrospray positive ionization mode with multiple reaction monitoring (MRM), while efavirenz was monitored in negative ionization MRM mode. This method was validated from 0.01 to 4.0 ng/mg hair for ritonavir and 0.05-20 ng/mg hair for lopinavir and efavirenz by using 2 mg of a human hair sample. The interday and intraday assay precision (coefficients of variation, CV) for spiked quality control (QC) samples at low, medium and high concentrations were within 15% and accuracy ranged from 89% to 110%. Assay reproducibility was also demonstrated by analysis of incurred hair QC samples (CV <14%). No significant matrix ionization suppression was observed. This developed method allowed for the monitoring of these target medications in the hair samples of HIV-infected women on antiretroviral therapy in an observational study using small amounts of hair.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Case-Control Studies; Chromatography, Liquid; Cyclopropanes; Dose-Response Relationship, Drug; Hair; Humans; Lopinavir; Pyrimidinones; Quality Control; Reference Standards; Reproducibility of Results; Ritonavir; Sensitivity and Specificity; Solutions; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

Topics: Adult; Aged; Alkynes; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP2C9; Drug Interactions; Female; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir; Warfarin

Topics: Alkynes; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir

An efficient, isocratic high performance liquid chromatography (HPLC) method for determining human immunodeficiency virus (HIV) non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) in plasma is advantageous for laboratories participating in clinical trials and therapeutic drug monitoring (TDM) programs, or conducting small animal research. The combination of isocratic reversed phase chromatography using an S-3, 3.0 mm x 150 mm column along with low plasma volume (200 microl), rapid liquid-liquid extraction, and detection at a single wavelength (212 nm) over a short run time makes this method valuable. Within and between assay variability ranges from 0.8 to 3.5% and 1.2-6.2%, respectively. Accuracy ranges from 91.0 to 112.8% for four quality controls (50, 100, 1000, and 10,000 ng/ml) for all drugs measured (efavirenz, nevirapine, amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir).

Topics: Alkynes; Atazanavir Sulfate; Benzoxazines; Carbamates; Chromatography, High Pressure Liquid; Cyclopropanes; Furans; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Nevirapine; Oligopeptides; Pyridines; Pyrimidinones; Reproducibility of Results; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Spectrophotometry, Ultraviolet; Sulfonamides

An accurate, sensitive and simple reverse-phase (RP) high-performance liquid chromatography (HPLC) assay has been developed and validated for the simultaneous quantitative determination of tipranavir with nine other antiretroviral drugs in plasma. A liquid-liquid extraction of the drugs in tert-butylmethylether (TBME) from 200 microL of plasma is followed by a reversed phase gradient HPLC assay with UV detection at 210 nm. The standard curve for the drug was linear in the range of 80-80,000 ng/mL for tipranavir; 10-10,000 ng/mL for nevirapine, indinavir, efavirenz, and saquinavir; and 25-10,000 ng/mL for amprenavir, atazanavir, ritonavir, lopinavir, and nelfinavir. The regression coefficient (r(2)) was greater than 0.998 for all analytes. This method has been fully validated and shown to be specific, accurate and precise. Due to an excellent extraction procedure giving good recovery and a clean baseline, this method is simple, rapid, accurate and provides excellent resolution and peak shape for all analytes. Thus this method is very suitable for therapeutic drug monitoring.

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Carbamates; Chromatography, High Pressure Liquid; Cyclopropanes; Drug Stability; Furans; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Molecular Structure; Nelfinavir; Nevirapine; Oligopeptides; Oxazines; Pyridines; Pyrimidinones; Pyrones; Reproducibility of Results; Ritonavir; Saquinavir; Sensitivity and Specificity; Spectrophotometry, Ultraviolet; Sulfonamides; Time Factors

Most antiretrovirals are metabolized in the liver, and lower dosing could be advisable in patients with severe liver insufficiency.. Plasma drug levels were measured in hepatitis C virus (HCV)/human immunodeficiency virus (HIV)-coinfected patients receiving nevirapine (NVP), efavirenz (EFV), lopinavir/ritonavir (LPV/r), or atazanavir (ATV) with or without ritonavir. Liver fibrosis was measured using elastometry.. A total of 268 coinfected patients with compensated liver disease were analyzed. Mean plasma levels were 6.1 micro g/mL for NVP (35 patients), 2.8 micro g/mL for EFV (46 patients), 5.8 micro g/mL for LPV (56 patients), 0.4 micro g/mL for ATV (58 patients), and 0.7 micro g/mL for ATV/r (73 patients). Overall, drug levels were higher in patients with cirrhosis than in those without cirrhosis for EFV (median, 3.4 vs. 1.9 micro g/mL; P<.01) and NVP (median, 6.6 vs. 5.8 micro g/mL; P=.33). EFV plasma levels above the toxic threshold (>4 micro g/mL) were more frequent in patients with cirrhosis than in those without (31% vs. 3%; P<.001). The same trend was seen for NVP levels >8 micro g/mL (50% vs. 27%; P=.27). By contrast, plasma levels of protease inhibitors (PIs) did not differ significantly between patients with and those without cirrhosis.. Liver clearance of nonnucleoside reverse-transcriptase inhibitors, particularly EFV, is impaired in patients with cirrhosis. No similar effect is seen for PIs. Assessment of liver fibrosis by noninvasive tools may identify HCV/HIV-coinfected patients who might benefit from therapeutic drug monitoring to avoid drug overexposure.

Topics: Adult; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Drug Monitoring; Female; Hepatitis C, Chronic; HIV Infections; Humans; Liver Cirrhosis; Lopinavir; Male; Nevirapine; Oligopeptides; Oxazines; Pyridines; Pyrimidinones; Ritonavir; Severity of Illness Index

Metabolism of the antimalarial drug amodiaquine (AQ) into its primary metabolite, N-desethylamodiaquine, is mediated by CYP2C8. We studied the frequency of CYP2C8 variants in 275 malaria-infected patients in Burkina Faso, the metabolism of AQ by CYP2C8 variants, and the impact of other drugs on AQ metabolism. The allele frequencies of CYP2C8*2 and CYP2C8*3 were 0.155 and 0.003, respectively. No evidence was seen for influence of CYP2C8 genotype on AQ efficacy or toxicity, but sample size limited these assessments. The variant most common in Africans, CYP2C8(*)2, showed defective metabolism of AQ (threefold higher K(m) and sixfold lower intrinsic clearance), and CYP2C8(*)3 had markedly decreased activity. Considering drugs likely to be coadministered with AQ, the antiretroviral drugs efavirenz, saquinavir, lopinavir, and tipranavir were potent CYP2C8 inhibitors at clinically relevant concentrations. Variable CYP2C8 activity owing to genetic variation and drug interactions may have important clinical implications for the efficacy and toxicity of AQ.

Topics: Alkynes; Amodiaquine; Antimalarials; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Burkina Faso; Chromatography, High Pressure Liquid; Cyclopropanes; Cytochrome P-450 CYP2C8; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Genotype; HIV Protease Inhibitors; Humans; Lopinavir; Malaria, Falciparum; Models, Biological; Polymorphism, Genetic; Pyridines; Pyrimidinones; Pyrones; Reverse Transcriptase Inhibitors; Saquinavir; Spectrophotometry, Ultraviolet; Sulfonamides; Treatment Outcome; Trimethoprim

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Civil Disorders; Cyclopropanes; Drug Industry; Drugs, Generic; France; Health Services Accessibility; Humans; Intellectual Property; Legislation, Drug; Lopinavir; Pyrimidinones; Thailand

A 38-year-old Caucasian woman with uncontrolled human immunodeficiency virus (HIV) infection was treated with highly active antiretroviral therapy (HAART) consisting of zidovudine, lamivudine, and nevirapine. Because her therapeutic response was inadequate, the HAART regimen was changed to abacavir, lamivudine, and lopinavir-ritonavir. Three months after this therapy was started, the patient developed progressive and notable hair loss. Her hair became fair and thin, and her appearance deteriorated considerably. Hair loss due to HAART was diagnosed. Lopinavir-ritonavir was stopped, and efavirenz was substituted; abacavir and lamivudine were continued. After 4 weeks, her hair growth substantially improved, as evidenced by rapid growth of new hair. Her general condition also improved. No relapse was observed with the new HAART regimen, and the patient's hair loss completely reversed in 8 weeks. Alopecia is a possible adverse event in HIV-infected patients treated with protease inhibitors, particularly indinavir. Our patient's severe and generalized alopecia was temporally related to the initiation and discontinuation of lopinavir-ritonavir. On the basis of the Naranjo adverse drug reaction probability scale, the adverse reaction was considered probable. Although generalized hair loss due to lopinavir-ritonavir is rare, clinicians should be aware of this potential adverse reaction of this widely used drug. If alopecia is severe or particularly distressing to the patient, the offending drug should be discontinued, and therapy with another HIV drug should be started.

Topics: Adult; Alkynes; Alopecia; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Lopinavir; Probability; Pyrimidinones; Ritonavir

To assess the presence of insulin resistance in human immunodeficiency virus (HIV)-infected patients receiving long-term antiretroviral therapy.. Cross-sectional study in consecutive HIV-infected patients treated with regimens containing efavirenz, lopinavir/ritonavir or atazanavir. Insulin resistance was assessed by HOMA (Homeostasis Model Assessment).. We analyzed 47 patients, 18 on treatment with efavirenz, 17 with lopinavir/ritonavir and 12 with atazanavir. Patients treated with lopinavir/ritonavir had higher insulinemia than those treated with efavirenz (p = 0.007) or atazanavir (p = 0.020). The HOMA index was also higher in subjects treated with lopinavir/ritonavir than in those receiving efavirenz (p = 0.07) or atazanavir (p = 0.028). Insulin resistance was found in 5 (10.6%) patients, 4 among those receiving lopinavir/ritonavir, one among those treated with efavirenz and none among subjects receiving atazanavir (p = 0.065). In the logistic regression analysis, the antiretroviral regimen was associated with risk of insulin resistance.. A substantial number of patients on antiretroviral therapy may have insulin resistance according to the HOMA index. Alterations of the hydrocarbonated metabolism appear to be more likely to occur in patients receiving regimens with lopinavir/ritonavir.

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cross-Sectional Studies; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Metabolic Syndrome; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; Time Factors

To describe first dose and steady state antiretroviral drug exposure in the female genital tract.. Non-blinded, single center, open-label pharmacokinetic study in HIV-infected women.. Twenty-seven women initiating combination antiretroviral therapy underwent comprehensive blood plasma and cervicovaginal fluid sampling for drug concentrations during the first dose of antiretroviral therapy and at steady-state. Drug concentrations were measured by validated HPLC/UV or HPLC-MS/MS methods. Pharmacokinetic parameters were estimated for 11 drugs by non-compartmental analysis. Descriptive statistics and 95% confidence intervals were generated using Intercooled STATA Release 8.0 (Stata Corporation, College Station, Texas, USA).. For all antiretroviral drugs, genital tract concentrations were detected rapidly after the first dose. Drugs were stratified according to the genital tract concentrations achieved relative to blood plasma. Median rank order of highest to lowest genital tract concentrations relative to blood plasma at steady state were: lamivudine (concentrations achieved were 411% greater than blood plasma), emtricitabine (395%), zidovudine (235%) tenofovir (75%), ritonavir (26%), didanosine (21%), atazanavir (18%), lopinavir (8%), abacavir (8%), stavudine (5%), and efavirenz (0.4%).. This is the first study to comprehensively evaluate antiretroviral drug exposure in the female genital tract. These findings support the use of lamivudine, zidovudine, tenofovir and emtricitabine as excellent pre-exposure/post-exposure prophylaxis (PrEP/PEP) candidates. Atazanavir and lopinavir might be useful agents for these applications due to favorable therapeutic indices, despite lower genital tract concentrations. Agents such as stavudine, abacavir, and efavirenz that achieve genital tract exposures less than 10% of blood plasma are less attractive PrEP/PEP candidates.

Topics: Adenine; Administration, Oral; Adult; Alkynes; Anti-Retroviral Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Deoxycytidine; Drug Therapy, Combination; Emtricitabine; Female; Genitalia, Female; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Lopinavir; Oligopeptides; Organophosphonates; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Tenofovir; Zidovudine

Consensus on the interpretation of mutations in the human immunodeficiency virus (HIV)-1 reverse transcriptase (RT) gene that predict the response to didanosine treatment is needed.. Baseline HIV-1 RT genotypes and 12-week virological outcomes for patients undergoing didanosine-containing salvage regimens were extracted from prospective studies. Existing didanosine genotypic-resistance interpretation rules were validated in the entire-patient data set. Mutations were given weighted positive or negative scores according to their coefficient of correlation with virological response in a derivation set. The score resulting from the algebraic sum of the mutations was then validated in an independent data set.. A total of 485 patients were analyzed. The didanosine-resistance scores derived from the Jaguar and Gesca studies predicted virological outcome. The best correlation with response was found with the derived score (M41L x 2) + E44D/A/G + T69D/S/N/A + (L210W x 2) + T215Y or revertants + L228H/R - D123E/N/G/S, by use of which viruses were categorized as being susceptible (score < or =0), as having intermediate resistance (1-3), and as being resistant (> or =4) to didanosine. In the validation set, the adjusted mean difference in 12-week virological response was +0.34 log(10) copies/mL (95% confidence interval, +0.11 to +0.57; P=.004) per higher resistance category. Correlation with virological response constantly outperformed that obtained with the previous interpretation.. The improved genotypic-resistance interpretation score can be applied to better guide the use of didanosine in treatment-experienced individuals.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Didanosine; Female; Genotype; HIV Reverse Transcriptase; HIV-1; Humans; Lopinavir; Male; Middle Aged; Mutation; Nelfinavir; Nevirapine; Pyrimidinones; Reverse Transcriptase Inhibitors; RNA, Viral; Salvage Therapy

To examine the effect of antiretroviral agents and clinical factors on the development of elevated blood pressure (BP).. Observational cohort study of patients initiating their first HAART regimen. We evaluated mean BP prior to HAART and while receiving HAART in relation to antiretroviral classes and individual agents, and demographic and clinical characteristics including change in body mass index (BMI) while on HAART. We used logistic regression analysis to examine factors associated with elevated BP [> or = 10 mmHg increase in systolic BP (SBP), diastolic BP (DBP) or new diagnosis of hypertension].. Among 444 patients who had 4592 BP readings, 95 patients developed elevated SBP (n = 83), elevated DBP (n = 33), or a new diagnosis of hypertension (n = 11) after initiating HAART. In multivariate analysis, patients on lopinavir/ritonavir had the highest risk of developing elevated BP [odds ratio (OR), 2.5; P = 0.03] compared with efavirenz-based regimens. When change in BMI was added to the model, increased BMI was significantly associated with elevated BP (OR, 1.3; P = 0.02), and the association between lopinavir/ritonavir and elevated BP was no longer present. Compared with lopinavir/ritonavir-based regimens, patients receiving atazanavir (OR, 0.2; P = 0.03), efavirenz (OR, 0.4; P = 0.02), nelfinavir (OR, 0.3; P = 0.02), or indinavir (OR, 0.3; P = 0.01) had significantly lower odds of developing elevated BP.. Treatment with lopinavir/ritonavir is significantly associated with elevated BP, an effect that appears to be mediated through an increase in BMI. Patients receiving atazanavir were least likely to develop elevated BP. The impact of antiretroviral medications on cardiovascular disease risk factors will increasingly influence treatment decisions.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Blood Pressure; Body Mass Index; CD4 Lymphocyte Count; Cyclopropanes; Female; HIV Protease Inhibitors; Humans; Hypertension; Indinavir; Longitudinal Studies; Lopinavir; Male; Middle Aged; Nelfinavir; Oligopeptides; Oxazines; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir

The efficacy and safety of a combination regimen including either efavirenz or lopinavir-ritonavir was examined in a cohort of 65 patients positive for human immunodeficiency virus-1 (HIV-1). Both the efavirenz (n = 33, 18 anti-retroviral naive) and lopinavir-ritonavir (n = 32, 15 naive) regimens achieved significant changes from baseline CD4 cell counts and HIV RNA levels after 108 weeks (p < 0.01). Despite diminished immunological and virological parameters at study entry, the lopinavir-ritonavir group showed greater virological effects than the efavirenz group after 108 weeks (median change 3.3 log(10), interquartile range (IQR) 2.2-3.8 log(10) vs. 2.4 log(10), IQR 0.9-3.3 log(10), respectively, p 0.004). Use of lopinavir-ritonavir, in contrast to use of efavirenz, was associated with significant hypertriglyceridaemia.

Topics: Adult; Aged; Alkynes; Benzoxazines; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Lopinavir; Male; Middle Aged; Oxazines; Pyrimidinones; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Triglycerides; Viral Load

We present a case with important pharmacogenetic and pharmacokinetic aspects of antiretroviral therapy in a patient with high efavirenz concentrations, severe CNS side-effects and low lopinavir concentrations. Despite therapeutic drug monitoring and subsequent efavirenz dosage reductions, side-effects did not resolve completely and lopinavir concentrations remained relatively low.

Topics: Adult; Alkynes; Anti-HIV Agents; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Central Nervous System Diseases; Cyclopropanes; Cytochrome P-450 CYP2B6; Drug Monitoring; Genotype; HIV; HIV Infections; Humans; Lopinavir; Male; Oxazines; Oxidoreductases, N-Demethylating; Pyrimidinones

Although efavirenz (EFV) and lopinavir/ ritonavir (LPV/r) are both recommended antiretroviral agents for combination therapy in drug-naive HIV-infected patients, no randomized comparison of their efficacy and tolerability is available yet. A multi-cohort prospective observational comparative study was performed.. Efficacy was examined comparing time to virological failure, CD4 recovery and clinical progression. Tolerability was examined comparing time to treatment discontinuation for any reason and for toxicity and time to liver enzymes or lipid alterations. Survival analysis was conducted by an intent-to-treat principle using the Kaplan-Meier method, and standard and weighted Cox regression models.. A total of 674 antiretroviral-naive patients starting a two nucleoside reverse transcriptase inhibitor regimen plus either EFV (n = 481) or LPV/r (n = 193) were examined. At baseline, patients starting LPV/r had higher HIV RNA and lower CD4+ T-cell counts. There was no difference in the adjusted hazards of virological failure (LPV/r versus EFV relative hazard [RH] 1.16, 95% confidence intervals [CI]: 0.58-2.32, P = 0.67), CD4 recovery (RH = 0.93, 95% CI: 0.66-1.30, P = 0.66), clinical progression (RH = 1.64, 95% CI: 0.70-3.84, P = 0.25), drug discontinuation for toxicity (RH = 0.92, 95% CI: 0.51-1.64, P = 0.76) and for any reason, and rates of liver enzyme and total/low density lipoprotein (LDL) cholesterol elevation. In contrast, the rate of triglycerides elevations (> 1 NCEP Adult Treatment Panel III category increase) was higher in the LPV/r group (RH = 1.69, 95% CI: 1.14-2.50; P = 0.01). Models weighted for the inverse of conditional probability of receiving either drug applied to the efficacy endpoints yielded similar results. CD4 recovery with both drugs was also similar in the lowest CD4 strata.. Our analysis suggests similar efficacy and tolerability for EFV- or LPV/r-based first-line antiretroviral regimens. LPV/r was associated with higher rates of hypertriglyceridaemia.

Topics: Adult; Aged; Alkynes; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Disease Progression; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hypertriglyceridemia; Italy; Lopinavir; Male; Middle Aged; Nucleosides; Prospective Studies; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Failure; Viral Load

Protease inhibitors are highly bound to orosomucoid (ORM) (alpha1-acid glycoprotein), an acute-phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir, lopinavir, and nelfinavir apparent clearance (CL(app)) and cellular accumulation. Efavirenz, mainly bound to albumin, was included as a control drug.. Plasma and cells samples were collected from 434 human immunodeficiency virus-infected patients. Total plasma and cellular drug concentrations and ORM concentrations and phenotypes were determined.. Indinavir CL(app) was strongly influenced by ORM concentration (n = 36) (r2 = 0.47 [P = .00004]), particularly in the presence of ritonavir (r2 = 0.54 [P = .004]). Lopinavir CL(app) was weakly influenced by ORM concentration (n = 81) (r2 = 0.18 [P = .0001]). For both drugs, the ORM1 S variant concentration mainly explained this influence (r2 = 0.55 [P = .00004] and r2 = 0.23 [P = .0002], respectively). Indinavir CL(app) was significantly higher in F1F1 individuals than in F1S and SS patients (41.3, 23.4, and 10.3 L/h [P = .0004] without ritonavir and 21.1, 13.2, and 10.1 L/h [P = .05] with ritonavir, respectively). Lopinavir cellular exposure was not influenced by ORM abundance and phenotype. Finally, ORM concentration or phenotype did not influence nelfinavir (n = 153) or efavirenz (n = 198) pharmacokinetics.. ORM concentration and phenotype modulate indinavir pharmacokinetics and, to a lesser extent, lopinavir pharmacokinetics but without influencing their cellular exposure. This confounding influence of ORM should be taken into account for appropriate interpretation of therapeutic drug monitoring results. Further studies are needed to investigate whether the measure of unbound drug plasma concentration gives more meaningful information than total drug concentration for indinavir and lopinavir.

Topics: Adult; Alkynes; Benzoxazines; Cohort Studies; Cyclopropanes; Female; Genetic Variation; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Male; Middle Aged; Nelfinavir; Orosomucoid; Oxazines; Phenotype; Pyrimidinones; Ritonavir; Switzerland

Chronic viral hepatitis is common among persons with HIV-1 infection, because of shared modes of transmission, and coinfection results in accelerated liver damage, compared with persons with chronic viral hepatitis alone. The use of highly active antiretroviral therapy (HAART) has led to a significant decrease in the morbidity and mortality associated with HIV-1 infection. A number of the medications that are commonly used in HAART regimens are metabolized by the hepatic CYP enzymes, which raises the possibility of significant interactions between antiretroviral medications and hepatic impairment induced by chronic viral hepatitis. Although the data are still very scant, the pharmacokinetics of several antiretroviral medications have been shown to be significantly altered in the presence of liver disease. In the present report, we review the available data and consider potential options, such as dose adjustment and therapeutic drug monitoring, for the administration of antiretroviral therapy to patients with significant hepatic impairment.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Hepatitis; HIV Infections; Humans; Indinavir; Liver Function Tests; Lopinavir; Nelfinavir; Nevirapine; Oxazines; Protease Inhibitors; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Zidovudine

Several studies suggest that therapeutic drug monitoring of protease inhibitors and nonnucleoside reverse transcriptase inhibitors may contribute to the clinical outcome of HIV-infected patients. Because of the growing number of antiretroviral drugs and of drug combinations than can be administered to these patients, an accurate high-performance liquid chromatographic (HPLC) method allowing the simultaneous determination of these drugs may be useful. To date, the authors present the first simultaneous HPLC determination of the new protease inhibitor atazanavir with all the others currently in use (M8 nelfinavir metabolite included) and the 2 widely used nonnucleoside reverse transcriptase inhibitors efavirenz and nevirapine. This simple HPLC method allows the analysis all these drugs at a single ultraviolet wavelength following a 1-step liquid-liquid extraction procedure. A 500-muL plasma sample was spiked with internal standard and subjected to liquid-liquid extraction using by diethyl ether at pH 10. HPLC was performed using a Symmetry Shield RP18 and gradient elution. All the drugs of interest and internal standard were detected with ultraviolet detection at 210 nm. Calibration curves were linear in the range 50-10,000 ng/mL. The observed concentrations of the quality controls at plasma concentrations ranging from 50 to 5000 ng/mL for these drugs showed that the overall accuracy varied from 92% to 104% and 92% to 106% for intraday and day-to-day analysis, respectively. No metabolites of the assayed compounds or other drugs commonly coadministered to HIV-positive patients were found to coelute with the drugs of interest or with the internal standard. This assay was developed for the purpose of therapeutic monitoring (TDM) in HIV-infected patients.

Topics: Alkynes; Atazanavir Sulfate; Benzoxazines; Calibration; Carbamates; Chromatography, Liquid; Cyclopropanes; Drug Stability; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Nevirapine; Oligopeptides; Oxazines; Pyridines; Pyrimidinones; Reproducibility of Results; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Specimen Handling; Spectrophotometry, Ultraviolet; Sulfonamides

This retrospective longitudinal cohort study compared the virological and immunological responses to highly active antiretroviral therapy containing either efavirenz or lopinavir/ritonavir in previously antiretroviral-naive HIV-infected patients.. A total of 472 patients were selected (348 efavirenz and 124 lopinavir/ritonavir). The primary endpoint of this study was virological success (HIV RNA <50 copies/mL). The immunological response was assessed on the basis of either CD4+ T cell count variations (absolute and percentage) with respect to baseline values or categorical endpoints (defined as either a CD4+ T cell increase of > or =1;50 cells/mm(3) at week 24 or of > or =1;75 cells/mm(3) at week 48).. At intention-to-treat (ITT) analysis, the adjusted odds ratio of virological success for patients who started lopinavir/ritonavir, compared with those who started efavirenz, was 0.54 (95% CI: 0.33-0.89, P = 0.016) at week 24 and 0.40 (95% CI: 0.33-0.89, P = 0.002) at week 48. However, patients receiving lopinavir/ritonavir had a more pronounced CD4+ T cell recovery, demonstrating both a mean absolute and percentage increase up to week 48 (MANOVA P < 0.0001).. Although comparisons of drug efficacy in non-randomized studies should be viewed with caution, from a virological point of view efavirenz-containing regimens performed as well (on-treatment analysis) or better (ITT analysis) than those containing lopinavir/ritonavir. In contrast, immunological outcome appeared to favour lopinavir/ritonavir.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Seropositivity; Humans; Longitudinal Studies; Lopinavir; Male; Middle Aged; Oxazines; Pyrimidinones; Retrospective Studies; Ritonavir

Researchers reported on the benefits of once-daily tenofovir + FTC + efavirenz as initial therapy, described a needle-free injection system for T-20, and announced the impending availability of lopinavir/ritonavir in tablet formulation.

Topics: Alkynes; Anti-HIV Agents; Atenolol; Benzoxazines; Brazil; Congresses as Topic; Cyclopropanes; Deoxycytidine; Drug Therapy, Combination; HIV Infections; Humans; Lopinavir; Oxazines; Pyrimidinones; Ritonavir

Topics: Adolescent; Alkynes; Anti-Retroviral Agents; Benzoxazines; CD4 Lymphocyte Count; Child; Child, Preschool; Cyclopropanes; HIV Infections; Humans; Infant; Lamivudine; Lopinavir; Nevirapine; Oxazines; Pyrimidinones; Ritonavir; South Africa; Stavudine; Viral Load

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Drug Resistance, Viral; HIV Infections; Humans; Lopinavir; Nevirapine; Oxazines; Pyrimidinones; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Treatment Outcome; Viral Load

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Clinical Trials as Topic; Cyclopropanes; Drug Synergism; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Long-Term Care; Lopinavir; Organophosphonates; Oxazines; Pyrimidinones; Ritonavir; Tenofovir; Viral Load

Valproic acid (VPA) has the potential to benefit patients suffering from human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine if VPA affects the plasma concentration of efavirenz (EFV) or lopinavir. HIV type 1 (HIV-1)-infected patients receiving EFV or lopinavir-ritonavir (LPV/r) had 9 or 10 blood samples drawn over 8 to 24 h of a dosing interval at steady state before and after receiving 250 mg of VPA twice daily for 7 days. VPA blood samples drawn before (C(0)) and 8 h after the morning dose (8 h) were compared to blood samples from a group of HIV-1-infected subjects who were taking either combined nucleoside reverse transcriptase inhibitors alone or had discontinued antiretroviral therapy. Pharmacokinetic parameters were calculated by noncompartmental analysis, and tests of bioequivalence were based on 90% confidence intervals (CIs) for ratios or differences. The geometric mean ratio (GMR) (90% CI) of the areas under the concentration-time curve from 0 to 24 h (AUC(0-24)s) of EFV (n = 11) with and without VPA was 1.00 (0.85, 1.17). The GMR (90% CI) of the AUC(0-8)s of LPV (n = 8) with and without VPA was 1.38 (0.98, 1.94). The differences (90% CI) in mean C(0) and 8-h VPA concentrations versus the control (n = 11) were -1.0 (-9.4, 7.4) microg/ml and -2.1 (-11.1, 6.9) microg/ml for EFV (n = 10) and -5.0 (-13.2, 3.3) microg/ml and -6.7 (-17.6, 4.2) microg/ml for LPV/r (n = 11), respectively. EFV administration alone is bioequivalent to EFV and VPA coadministration. LPV concentrations tended to be higher when the drug was combined with VPA. Results of VPA comparisons fail to raise concern that coadministration with EFV or LPV/r will significantly influence trough concentrations of VPA.

Topics: Adult; Alkynes; Anti-HIV Agents; Anticonvulsants; Area Under Curve; Benzoxazines; Cognition Disorders; Cyclopropanes; Drug Interactions; Female; Half-Life; HIV Infections; Humans; Lopinavir; Male; Oxazines; Pyrimidinones; Reverse Transcriptase Inhibitors; Valproic Acid

Ninety-seven consecutive patients started anti-HIV therapy based on efavirenz (46) or lopinavir-ritonavir (51) in an observational study. Despite the significantly more compromised immunological-clinical baseline conditions of patients starting lopinavir-ritonavir, a mean clinical-laboratory follow-up of 17 months showed a comparable laboratory response and therapy interruption or change rate, although the toxicity profile of the two compounds proved significantly different. Randomized studies comparing these two recommended first-line treatments are warranted, particularly from a pharmacoeconomic viewpoint.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Oxazines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome; Viral Load

Since 1999 an ongoing international interlaboratory quality control program has analyzed antiretroviral drugs in plasma. Results of the third round of this program are presented. Quality control samples were prepared by spiking drug-free plasma with varying concentrations of the currently available protease inhibitors and the nonnucleoside reverse transcriptase inhibitors efavirenz and nevirapine. Thirty-three laboratories participated in the program and were requested to analyze the quality control samples. Results were from 30 laboratories. Of all measurements, 82% were performed within 80%-120% accuracy limits. Only 3 laboratories performed all their measurements within these limits, and 12 participants reported at least 90% of their analyses within the acceptance range. Mean accuracy for low drug concentrations was worse than for medium and high concentrations. The percentage of satisfactory measurements for the 6 laboratories that participated for the third time in the program increased from 54% in the first round to 85% in the third round. The program revealed a large variability in the laboratories' ability to measure antiretroviral drugs accurately. This variability may have important implications for therapeutic drug monitoring of these drugs and for pharmacokinetic studies. Interlaboratory testing is useful to alert laboratories to previously undetected analytical problems.

Topics: Alkynes; Australia; Benzoxazines; Canada; Carbamates; Cyclopropanes; Europe; Furans; HIV Protease Inhibitors; Humans; International Cooperation; Laboratories; Lopinavir; Nevirapine; Oxazines; Pyrimidinones; Quality Control; Reference Standards; Reproducibility of Results; Reverse Transcriptase Inhibitors; Sulfonamides; United States

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.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Chromatography, High Pressure Liquid; Cyclopropanes; Furans; Heparin; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Oxazines; Pyrimidinones; Ritonavir; Saquinavir; Sulfonamides

We developed a simple HPLC method for the simultaneous determination of lopinavir (LPV), ritonavir (RTV) and efavirenz (EFV) to evaluate the efficiency of co-administration of LPV/RTV and EFV in Japanese patients enrolled in a clinical study. The monitoring of LPV plasma concentration is important because co-administration of LPV/RTV with EFV sometimes decreases plasma concentrations of LPV caused by EFV activation of cytochrome P-450 3A. A solution of acetonitrile, methanol and tetramethylammonium perchlorate (TMAP) in dilute aqueous trifluoroacetic acid (TFA) has been used as the mobile phase in a HPLC method to elute LPV and RTV. We found that a solvent ratio of 45 : 5 : 50 (v/v/v) of acetonitrile/methanol/0.02 M TMAP in 0.2% TFA optimized separation of LPV, RTV and EFV. A column temperature of 30 degrees C was necessary for the reproducibility of the analyses. Standard curves were linear in the range 0.060 to 24.06 micro g/ml for LPV, 0.010 to 4.16 micro g/ml for RTV, and 0.047 to 37.44 micro g/ml for EFV. Coefficients of variation (CVs) of LPV, RTV and EFV in intraday and interday assays ranged from 1.5 to 4.0%, 2.5 to 16.8% and 1.0 to 7.7%, respectively. Accuracies ranged from 100 to 110%, 101 to 116% and 99 to 106% for LPV, RTV and EFV, respectively. The extraction recoveries were 77-87, 77-83 and 81-91% for LPV, RTV and EFV, respectively.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Chromatography, High Pressure Liquid; Cyclopropanes; Drug Monitoring; Humans; Lopinavir; Oxazines; Pyrimidinones; Reference Standards; Reproducibility of Results; Ritonavir; Sensitivity and Specificity

Topics: Alkynes; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Male; Oxazines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Viral Load

In a retrospective study of HIV patients under antiretroviral therapy, we investigated the influence of the MDR1 genotype (C3435T) on plasma levels of lopinavir (LPV) and efavirenz (EFV).. The MDR1 genotype was analysed from 67 patients who were treated with LPV (n = 32; mean treatment period 53 weeks) and/or EFV (n = 43, mean treatment period 105 weeks) between 1999 and 2003. Plasma levels of LPV (trough levels) and EFV (12-h-levels) were determined every three months. Data were analysed by the Kruskal-Wallis test.. There were no significant differences in the LPV and EFV plasma levels with respect to the MDR1 3435 genotype.. We did not find evidence for an influence of the MDR1 3435 genotype on plasma levels of LPV and EFV.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzoxazines; Cyclopropanes; Female; Genotype; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oxazines; Polymorphism, Genetic; Pyrimidinones; Retrospective Studies

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.

Topics: Alkynes; Benzoxazines; Carbamates; Chromatography, Liquid; Cyclopropanes; Drug Monitoring; Furans; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Oxazines; Pyrimidinones; Reproducibility of Results; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Sulfonamides

A selective and sensitive high-performance liquid chromatographic (HPLC) method has been developed for the determination of the six human immunodeficiency virus (HIV)-protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) and the non-nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine) in a single run. After a liquid-liquid extraction with diethyl ether, the six protease inhibitors and the two non-nucleoside reverse transcriptase inhibitors are separated on a Stability RP18 column eluted with a gradient of acetonitrile and phosphate buffer 50 mmol/L pH 5.65. A sequential ultraviolet detection (5-minute sequence set at 240 nm for nevirapine acquisition, 22-minute sequence set at 215 nm for other antiretroviral drugs acquisition followed by a sequence set at 260 nm for internal standard acquisition) allowed for simultaneous quantitation of the six protease inhibitors, nevirapine, and efavirenz. Calibration curves were linear in the range 100 ng/mL to 10,000 ng/mL. The limit of quantitation was 50 ng/mL for all drugs except nevirapine (100 ng/mL). Average accuracy at four concentrations ranged from 88.2% to 110.9%. Both interday and intraday coefficients of variation were less than 11% for all drugs. The extraction recoveries were greater than 62%. This method is simple and shows a good specificity with respect to commonly co-prescribed drugs. This method allows accurate therapeutic monitoring of amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, efavirenz, and nevirapine.

Topics: Alkynes; Benzoxazines; Carbamates; Chromatography, High Pressure Liquid; Cyclopropanes; Drug Monitoring; Furans; HIV Infections; Humans; Indinavir; Lopinavir; Nelfinavir; Nevirapine; Oxazines; Protease Inhibitors; Pyrimidinones; Reproducibility of Results; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Sulfonamides

Current treatment strategies need to be planned carefully, because there is an inadequate supply of new types of drugs available to treat people who have failed previous therapies. It is important to fully use existing therapies so as not to limit future options. Drugs in development include: ABT-378, a protease inhibitor from Abbott Laboratories; tipranavir (PNU-140690), a protease inhibitor by Pharmacia & Upjohn; and S-1153, a non-nucleoside reverse transcriptase inhibitor from Agouron Pharmaceuticals. All were effective and well-tolerated in recent trials. A warning was issued for adefovir, a nucleoside reverse transcriptase inhibitor, regarding the development of kidney toxicity for people taking the drug more than 20 weeks. Information on expanded access programs for abacavir, adefovir, amprenavir, and efavirenz is provided.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; CD4 Lymphocyte Count; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Imidazoles; Kidney Diseases; Lopinavir; Oxazines; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Sulfonamides; Viral Load

The 12th World AIDS Conference in Geneva brought together AIDS researchers, medical care providers, advocates, and people living with HIV to discuss implications related to providing global access to care. New drugs have decreased deaths and opportunistic infections in developed countries, but developing countries are becoming overwhelmed by the number of new patients. The World Health Organization estimates that the majority of the 30.6 million people infected with HIV/AIDS worldwide will die within a decade unless a cure is found or treatments are made accessible to them. Researchers are no longer optimistic about the feasibility of viral eradication, and instead are looking for strategies to overcome the virus that continues to live in latent reservoirs in the body. Descriptions are given of several new drugs currently being studied, including abacavir, amprenavir, efavirenz, ABT 378, and Hydroxyurea. Progress is also highlighted about dosing regimens, antiretroviral resistance, and reconstitution of the immune system.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; CD4-Positive T-Lymphocytes; Clinical Trials as Topic; Congresses as Topic; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Enzyme Inhibitors; Furans; Health Services Accessibility; HIV Protease Inhibitors; Humans; Hydroxyurea; Lopinavir; Oxazines; Patient Care Planning; Pyrimidinones; Remission Induction; Reverse Transcriptase Inhibitors; Sulfonamides; Switzerland; Virus Replication