Baseline and acquired resistance to bedaquiline, linezolid and pretomanid, and impact on treatment outcomes in four tuberculosis clinical trials containing pretomanid.

Bedaquiline (B), pretomanid (Pa) and linezolid (L) are key components of new regimens for treating rifampicin-resistant tuberculosis (TB). However, there is limited information on the global prevalence of resistance to these drugs and the impact of resistance on treatment outcomes. Mycobacterium tuberculosis (MTB) phenotypic drug susceptibility and whole-genome sequence (WGS) data, as well as patient profiles from 4 pretomanid-containing trials-STAND, Nix-TB, ZeNix and SimpliciTB-were used to investigate the rates of baseline resistance (BR) and acquired resistance (AR) to BPaL drugs, as well as their genetic basis, risk factors and impact on treatment outcomes. Data from >1,000 TB patients enrolled from 2015 to 2020 in 12 countries was assessed. We identified 2 (0.3%) participants with linezolid BR. Pretomanid BR was also rare, with similar rates across TB drug resistance types (0-2.1%). In contrast, bedaquiline BR was more prevalent among participants with highly resistant TB or longer prior treatment histories than those with newly diagnosed disease (5.2-6.3% vs. 0-0.3%). Bedaquiline BR was a risk factor for bacteriological failure or relapse in Nix-TB/ZeNix; 3/12 (25%, 95% CI 5-57%) participants with vs. 6/185 (3.2%, 1.2-6.9%) without bedaquiline BR. Across trials, we observed no linezolid AR, and only 3 cases of bedaquiline AR, including 2 participants with poor adherence. Overall, pretomanid AR was also rare, except in ZeNix patients with bedaquiline BR. WGS analyses revealed novel mutations in canonical resistant genes and, in 7 MTB isolates, the genetic determinants could not be identified. The overall low rates of BR to linezolid and pretomanid, and to a lesser extent to bedaquiline, observed in the pretomanid trials are in support of the worldwide implementation of BPaL-based regimens. Similarly, the overall low AR rates observed suggest BPaL drugs are better protected in the regimens trialed here than in other regimens combining bedaquiline with more, but less effective drugs.

Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis.

BACKGROUND: The bedaquiline-pretomanid-linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear. METHODS: We enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated. RESULTS: A total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline-pretomanid-linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups. CONCLUSIONS: A total of 84 to 93% of the participants across all four bedaquiline-pretomanid-linezolid treatment groups had a favorable outcome. The overall risk-benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.).

Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid.

OBJECTIVES: To develop a robust phenotypic antimicrobial susceptibility testing (AST) method with a correctly set breakpoint for pretomanid (Pa), the most recently approved anti-tuberculosis drug. METHODS: The Becton Dickinson Mycobacterial Growth Indicator Tube™ (MGIT) system was used at six laboratories to determine the MICs of a phylogenetically diverse collection of 356 Mycobacterium tuberculosis complex (MTBC) strains to establish the epidemiological cut-off value for pretomanid. MICs were correlated with WGS data to study the genetic basis of differences in the susceptibility to pretomanid. RESULTS: We observed ancient differences in the susceptibility to pretomanid among various members of MTBC. Most notably, lineage 1 of M. tuberculosis, which is estimated to account for 28% of tuberculosis cases globally, was less susceptible than lineages 2, 3, 4 and 7 of M. tuberculosis, resulting in a 99th percentile of 2 mg/L for lineage 1 compared with 0.5 mg/L for the remaining M. tuberculosis lineages. Moreover, we observed that higher MICs (≥8 mg/L), which probably confer resistance, had recently evolved independently in six different M. tuberculosis strains. Unlike the aforementioned ancient differences in susceptibility, these recent differences were likely caused by mutations in the known pretomanid resistance genes. CONCLUSIONS: In light of these findings, the provisional critical concentration of 1 mg/L for MGIT set by EMA must be re-evaluated. More broadly, these findings underline the importance of considering the global diversity of MTBC during clinical development of drugs and when defining breakpoints for AST.

Leveraging longitudinal clinical laboratory results to improve prenatal care.

OBJECTIVES: To assess the impact of providing laboratory-generated near-real-time clinical insights for pregnant Medicaid members to managed care organization (MCO) care coordinators. STUDY DESIGN: A prospective, nonrandomized feasibility study was conducted over 11 months to examine the benefits of laboratory-generated clinical insights on prenatal care quality metrics and clinical outcomes. Measures included early identification of pregnancy and births to facilitate care, care gaps with prenatal laboratory testing, emergency department (ED) visits, preterm births, and neonatal intensive care unit (NICU) admissions and length of stay. METHODS: Weekly MCO care coordinators were provided a laboratory-generated prenatal targeted intervention module (TIM) to supplement their existing systems in a longitudinal, patient-centric format. Care coordinators contacted patients for enrollment in prenatal or postpartum services based on the TIM, which identified concomitant health conditions, missing prenatal care, and risks. RESULTS: The prenatal TIM identified 1355 pregnant members, 77% (n = 1040) of whom were detected in the first trimester. A total of 488 births were identified within 24 hours of parturition. Sixty-four percent of women had at least 80% of prenatal care gaps associated with laboratory testing closed. Women with ongoing prenatal care had fewer ED visits (17% vs 23%) and NICU admissions (11% vs 18%) compared with those without prenatal care. After adjusting for confounders, ongoing prenatal care had a borderline effect at decreasing the probability of having an ED visit and a NICU admission. CONCLUSIONS: An innovative collaboration between an MCO and a clinical laboratory improved quality measures for prenatal members enrolled in Medicaid.

Safety, Tolerability, and Pharmacokinetic Properties of Intravenous Delafloxacin After Single and Multiple Doses in Healthy Volunteers.

PURPOSE: The objective of this report was to determine the pharmacokinetic properties, safety, and tolerability of single and multiple doses of intravenous delafloxacin. In addition, the absolute bioavailability (BA) of the 450-mg tablet formulation of delafloxacin was determined. METHODS: Three clinical trials are summarized. The first study was a randomized, double-blind, placebo-controlled, single- (300, 450, 600, 750, 900, and 1200 mg) ascending-dose study of IV delafloxacin in 62 (52 active, 10 placebo) healthy volunteers. The second study was a randomized, double-blind, placebo-controlled study of IV delafloxacin (300 mg) given as a single dose on day 1, followed by twice-daily dosing on days 2 through 14; 12 (8 active, 4 placebo) healthy volunteers were enrolled. The third study was an open-label, randomized, 2-period, 2-sequence crossover study in which 56 healthy volunteers were randomly assigned to 1 of 2 sequences of a single oral dose of delafloxacin (450-mg tablet) or IV delafloxacin (300 mg). Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were calculated. FINDINGS: Delafloxacin Cmax values increased proportionally with increasing single IV dose for the dose range of 300 to 1200 mg, whereas the AUC values increased more than proportionally to dose for the same dose range. The mean terminal half-life of delafloxacin was approximately 12 hours (ranging from 8 to 17 hours). The volume of distribution (Vd) at steady state was approximately 35 L, which is similar to the volume of total body water. There was minimal accumulation of delafloxacin after twice-daily IV administration of 300 mg with an accumulation ratio of 1.09. The delafloxacin total exposure after a single 1-hour IV infusion of 300 mg and a single oral dose of a 450-mg tablet were equivalent with geometric least square mean ratio (90% CI) of 0.8768 (0.8356-0.9200) for AUC0-∞ and 0.8445 (0.8090-0.8815) for AUC0-t, respectively. The Cmax values of delafloxacin were not equivalent for the 2 formulations with a ratio (90% CI) of 0.5516 (0.5150-0.5908), respectively. The mean absolute bioavailability of delafloxacin was 58.8%. IMPLICATIONS: Delafloxacin was well tolerated in healthy volunteers after single and multiple IV doses. The total systemic exposure to IV (300 mg) and oral (450 mg) delafloxacin is comparable, supporting that a switch between the 2 formulations is appropriate.

Single and Multiple Ascending-dose Studies of Oral Delafloxacin: Effects of Food, Sex, and Age.

PURPOSE: The objective of this report is describe the results of 2 studies that examined the pharmacokinetic parameters, safety profile, and tolerability of single and multiple ascending doses of oral delafloxacin and the effects of food, sex, and age on oral delafloxacin pharmacokinetic parameters, safety profile, and tolerability. METHODS: The first study contained 3 parts and used unformulated delafloxacin in a capsule. Part 1 was a randomized, double-blind, placebo-controlled, single (50, 100, 200, 400, 800, 1200, and 1600 mg) ascending-dose study of oral delafloxacin in healthy men. Part 2 was a single-dose crossover study in which 20 men received 250 mg delafloxacin with or without food. Part 2 also included a parallel group, double-blind, placebo-controlled study in 16 women and 16 elderly men and women who were randomized (3:1) to receive 250 mg delafloxacin or placebo. Part 3 was a randomized, double-blind, placebo-controlled, multiple (100, 200, 400, 800, 1200 mg once daily for 5 days) ascending-dose study of oral delafloxacin in healthy men. The second study was a single-dose, randomized, 3-period crossover study in which participants received 900 mg delafloxacin (2 × 450-mg tablets) under fasted conditions, with a high-fat meal, or fasted with a high-fat meal 2 hours after dosing. Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were determined. FINDINGS: Delafloxacin Cmax and AUC0-∞ increased with increasing oral dose over the dose range of 50 to 1600 mg. The increases in delafloxacin AUC0-∞ were dose proportional at doses of ≥200 mg. Steady state was reached by day 3 of dosing with minimal accumulation of delafloxacin. The Cmax of delafloxacin was decreased slightly in the presence of food. No sex difference in delafloxacin pharmacokinetic parameters was observed. In the elderly men and women, mean delafloxacin Cmax and AUC0-∞ were 35% higher than observed for young adults, which could be partially explained by a decrease in the creatinine clearance in the elderly men and women. Delafloxacin was well tolerated at the tested doses, with gastrointestinal adverse effects observed more commonly at doses ≥1200 mg. IMPLICATIONS: Delafloxacin exhibits linear pharmacokinetic parameters that reached steady state after 3 days of daily oral dosing with minimal accumulation. Delafloxacin was well tolerated throughout both studies, with gastrointestinal effects observed at the higher doses (≥1200 mg).

A thorough QT study to evaluate the effects of therapeutic and supratherapeutic doses of delafloxacin on cardiac repolarization.

A randomized, double-blind, placebo-controlled, 4-period crossover study was conducted in 52 healthy adults to assess the effect of delafloxacin on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using Fridericia's formula (QTcF), was determined predose and at 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 12, 18, and 24 h after dosing with delafloxacin at 300 mg intravenously (i.v.; therapeutic), delafloxacin at 900 mg i.v. (supratherapeutic), moxifloxacin at 400 mg orally (p.o.; positive control), and placebo. The pharmacokinetic profile of delafloxacin was also evaluated. At each time point after delafloxacin administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from the predose baseline in QTcF (ΔΔQTcF) was less than 10 ms (maximum, 3.9 ms at 18 h after dosing), indicating an absence of a clinically meaningful increase in the QTc interval. The lower limit of the 90% CI of ΔΔQTcF for moxifloxacin versus placebo was longer than 5 ms at all 5 time points selected for assay sensitivity analysis, demonstrating that the study was adequately sensitive to assess QTc prolongation. There was no positive relationship between delafloxacin plasma concentrations and ΔΔQTcF. Treatment-emergent adverse events (AEs) were more frequent among subjects receiving a single supratherapeutic dose of 900 mg delafloxacin. There were no deaths, serious AEs, or AEs leading to study discontinuation and no clinically meaningful abnormalities in laboratory values or vital signs observed at any time point after any dose of the study drug.

Community health workers and medicaid managed care in New Mexico.

We describe the impact of community health workers (CHWs) providing community-based support services to enrollees who are high consumers of health resources in a Medicaid managed care system. We conducted a retrospective study on a sample of 448 enrollees who were assigned to field-based CHWs in 11 of New Mexico's 33 counties. The CHWs provided patients education, advocacy and social support for a period up to 6 months. Data was collected on services provided, and community resources accessed. Utilization and payments in the emergency department, inpatient service, non-narcotic and narcotic prescriptions as well as outpatient primary care and specialty care were collected on each patient for a 6 month period before, for 6 months during and for 6 months after the intervention. For comparison, data was collected on another group of 448 enrollees who were also high consumers of health resources but who did not receive CHW intervention. For all measures, there was a significant reduction in both numbers of claims and payments after the community health worker intervention. Costs also declined in the non-CHW group on all measures, but to a more modest degree, with a greater reduction than in the CHW group in use of ambulatory services. The incorporation of field-based, community health workers as part of Medicaid managed care to provide supportive services to high resource-consuming enrollees can improve access to preventive and social services and may reduce resource utilization and cost.

Factors associated with risk of surgical wound infections.

Surgical wound infections are the most common hospital-acquired infections among patients who undergo inpatient surgery. Risk of infection is a function of both patient susceptibility and exposure. The authors studied all discharges in Pennsylvania from October 1, 2004, through September 30, 2005, in which a circulatory (n= 65 940), neurological (n= 6706), or orthopedic (n = 107 825) procedure was performed using data from the Pennsylvania Health Care Cost Containment Council. They estimated the impact of patient-specific factors on risk of infection and compared the ability of these factors to predict infections relative to hospital effects. Results suggested that for all 3 types of procedures, patient-specific factors were a significant determinant of risk of surgical wound infection. However, prediction of infection was improved by 23% to 33% when hospital fixed effects were included. Although patient-specific factors had a statistically significant association with risk of infections, much of the risk of surgical wound infections is determined by hospital factors.

Cost-effectiveness of lopinavir/ritonavir versus nelfinavir as the first-line highly active antiretroviral therapy regimen for HIV infection.

PURPOSE: Selecting the optimal treatment regimen for antiviral-naive patients may be difficult, given the concern about the antiviral activity, the development of drug resistance, and the increase in drug costs. This study evaluates the costs and effectiveness of using lopinavir/ritonavir (LPV/r) vs. nelfinavir (NFV), both coadministered with stavudine and lamivudine, as the first HAART regimen in treating HIV patients, based on the results from the published clinical trial M98-863. METHOD: A Markov model was developed using a combination of viral load (VL) and CD4 count as surrogate markers to define health states. VL and CD4 count data from the 48-week analysis of the clinical trial were used as measures of effect. The impact of resistance difference between NFV and LPV/r was also examined. RESULTS: Over the first 5 years, the model estimated that LPV/r could save $3,461 USD per patient in total HIV care costs compared with NFV. If the resistance advantage of LPV/r was taken into account, the cost savings by LPV/r increased to $5,546 USD. For longer term projection, without considering the resistance difference, the incremental cost-effectiveness ratio (CER) for LPV/r vs. NFV was $6,653 USD per quality-adjusted life-year (QALY). This CER compares favorably to therapies for HIV disease and for common drug treatments for other conditions and is well within accepted thresholds for health policy makers. CONCLUSION: When treatment options are being considered, this study suggests that use of LPV/r in the first antiretroviral regimen, as compared to NFV, is cost-effective based on improved efficacy and resistance.

Metabolism and disposition of the HIV-1 protease inhibitor lopinavir (ABT-378) given in combination with ritonavir in rats, dogs, and humans.

PURPOSE: The objective of this study was to examine the metabolism and disposition of the HIV protease inhibitor lopinavir in humans and animal models. METHODS: The plasma protein binding of [14C]lopinavir was examined in vitro via equilibrium dialysis technique. The tissue distribution of radioactivity was examined in rats dosed with [14C]lopinavir in combination with ritonavir. The metabolism and disposition of [14C]lopinavir was examined in rats, dogs, and humans given alone (in rats only) or in combination with ritonavir. RESULTS: The plasma protein binding of lopinavir was high in all species (97.4-99.7% in human plasma), with a concentration-dependent decrease in binding. Radioactivity was extensively distributed into tissues, except brain, in rats. On oral dosing to rats, ritonavir was found to increase the exposure of lopinavir-derived radioactivity 13-fold. Radioactivity was primarily cleared via the hepato-biliary route in all species (>82% of radioactive dose excreted via fecal route), with urinary route of elimination being significant only in humans (10.4% of radioactive dose). Oxidative metabolites were the predominant components of excreted radioactivity. The predominant site of metabolism was found to be the carbon-4 of the cyclic urea moiety, with subsequent secondary metabolism occurring on the diphenyl core moiety. In all the three species examined, the primary component of plasma radioactivity was unchanged lopinavir (>88%) with small amounts of oxidative metabolites. CONCLUSIONS: Lopinavir was subject to extensive metabolism in vivo. Co-administered ritonavir markedly enhanced the pharmacokinetics of lopinavir-derived radioactivity in rats, probably due to inhibition of presystemic and systemic metabolism, leading to an increased exposure to this potent HIV protease inhibitor.

Baseline HIV-1 RNA level and CD4 cell count predict time to loss of virologic response to nelfinavir, but not lopinavir/ritonavir, in antiretroviral therapy-naive patients.

Baseline CD4 cell counts and human immunodeficiency virus (HIV)-1 RNA levels have been shown to predict immunologic and virologic responses in HIV-infected patients receiving antiretroviral therapy. In our randomized, double-blind, comparative trial, 653 antiretroviral therapy-naive patients received lopinavir/ritonavir or nelfinavir, plus stavudine and lamivudine, for up to 96 weeks. The risk of loss of virologic response was significantly higher for nelfinavir-treated patients than for lopinavir/ritonavir-treated patients (Cox model hazard ratio, 2.2; 95% confidence interval, 1.7-3.0; P<.001). For nelfinavir-treated patients, but not for lopinavir/ritonavir-treated patients, higher baseline HIV-1 RNA levels and lower baseline CD4 cell counts were associated with a higher risk of loss of virologic response.

Incidence of resistance in a double-blind study comparing lopinavir/ritonavir plus stavudine and lamivudine to nelfinavir plus stavudine and lamivudine.

Study M98-863 was a double-blind, randomized, phase 3 study that compared lopinavir/ritonavir with nelfinavir, each coadministered with stavudine and lamivudine, in 653 antiretroviral therapy-naive human immunodeficiency virus (HIV) type 1-infected subjects. The incidence of HIV drug resistance was analyzed using baseline and rebound virus isolates from subjects with plasma HIV RNA >400 copies/mL from weeks 24 to 108 of therapy. No evidence of genotypic or phenotypic resistance to lopinavir/ritonavir, defined as any active site or primary mutation in HIV protease, was detected in virus isolates from 51 lopinavir/ritonavir-treated subjects with available genotypes. Primary mutations related to nelfinavir resistance (D30N and/or L90M) were observed in 43 (45%) of 96 nelfinavir-treated subjects. Resistance to lamivudine and stavudine was also significantly higher in nelfinavir-treated versus lopinavir/ritonavir-treated subjects. These differences suggest substantially different genetic and pharmacological barriers to resistance for these 2 protease inhibitors and may have implications for strategies for initiating antiretroviral therapy.

Once-daily versus twice-daily lopinavir/ritonavir in antiretroviral-naive HIV-positive patients: a 48-week randomized clinical trial.

The safety, pharmacokinetics, and antiviral activity of lopinavir, a human immunodeficiency virus (HIV) protease inhibitor, coformulated with ritonavir as a pharmacokinetic enhancer were evaluated in 38 antiretroviral-naive patients randomized 1:1 to receive open-label lopinavir/ritonavir at a dose of 800/200 mg once daily or 400/100 mg twice daily, each in combination with stavudine and lamivudine twice daily, for 48 weeks. Over the course of 48 weeks, median predose concentrations of lopinavir exceeded the protein-binding corrected concentration required to inhibit replication of wild-type HIV by 50% in vitro by 40- and 84-fold in the once- and twice-daily groups, respectively. Predose concentrations of lopinavir were more variable in the once-daily group (mean +/- SD, 3.62+/-3.38 microg/mL for the once-daily group and 7.13+/-2.93 microg/mL for the twice-daily group). At week 48, in an intent-to-treat (missing = failure) analysis, 74% of patients in the once-daily group and 79% of patients in the twice-daily group had HIV RNA levels of <50 copies/mL (P=.70). Study drug-related discontinuations occurred in 1 patient in each treatment group. Genotypic resistance testing of 4 patients with HIV RNA levels >400 copies/mL between weeks 24 and 48 demonstrated no protease inhibitor-resistance mutations.

Characterization of resistant HIV variants generated by in vitro passage with lopinavir/ritonavir.

Lopinavir (LPV, formerly ABT-378) is an HIV protease inhibitor (PI) that is co-administered with a small amount of ritonavir (RTV), which greatly increases and sustains the plasma levels of LPV. Lopinavir/ritonavir (LPV/r) has shown potent antiviral activity in both therapy-nai;ve and PI-experienced patients. To assess the effect of pharmacologically relevant ratios of LPV/RTV (LPV/r) on the emergence of resistant HIV in vitro, HIV-1 pNL4-3 was passaged in the presence of increasing concentrations of LPV alone and LPV/r. Passages with fixed 5/1 and 15/1 concentration ratios of LPV/r initially selected I84V and I50V/M46I mutants, respectively. Selection with LPV alone also generated the same initial mutants (I50V/M46I) as the 15/1 LPV/r passage. Further passage produced other mutations previously found to be associated with PI-resistance. Phenotypic susceptibility to both LPV and RTV decreased with successive passages, irrespective of whether RTV was present in the selection experiment. Furthermore, in the two selection experiments that included RTV (at either 5/1 or 15/1 LPV/r ratio), the IC(50) of RTV at each passage evaluated was at least five-fold higher than the concentration of RTV employed at that passage, while the IC(50) of LPV toward the passaged virus was similar to the concentration of LPV used at that passage, indicating that the selective pressure was attributable to LPV and not RTV.

Determining the relative efficacy of highly active antiretroviral therapy.

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.

A novel antiviral intervention results in more accurate assessment of human immunodeficiency virus type 1 replication dynamics and T-cell decay in vivo.

Mathematical models provide an understanding of in vivo replication kinetics of human immunodeficiency virus type 1 (HIV-1). With a novel intervention designed for increased potency, we have more accurately deduced the half-lives of virus-producing CD4(+) T cells, 0.7 day, and the generation time of HIV-1 in vivo, approximately 2 days, confirming the dynamic nature of HIV-1 replication.

Forty-eight-week evaluation of lopinavir/ritonavir, a new protease inhibitor, in human immunodeficiency virus-infected children.

BACKGROUND: Lopinavir/ritonavir has demonstrated antiviral activity in the HIV-infected adult. SUBJECTS: The objective of this study was to investigate a liquid coformulation of lopinavir/ritonavir, in combination with reverse transcriptase inhibitors, in HIV-infected children. METHODS: One hundred antiretroviral (ARV)-naive and ARV-experienced, nonnucleoside reverse transcriptase inhibitor-naive children between 6 months and 12 years of age participated in this Phase I/II, open label, multicenter trial. Subjects initially received either 230/57.5 mg/m(2) or 300/75 mg/m(2) lopinavir/ritonavir twice daily; ARV-naive subjects also received stavudine and lamivudine, whereas ARV-experienced subjects also received nevirapine and one or two nucleoside reverse transcriptase inhibitors. Lopinavir/ritonavir pharmacokinetics, safety and efficacy were evaluated. RESULTS: All subjects were escalated to the 300/75 mg/m(2) twice daily dose based on results from an interim pharmacokinetic and safety evaluation. The pharmacokinetics of lopinavir did not appear to be dependent on age when dosing was based on body surface area but were decreased on coadministration with nevirapine. Overall 79% of subjects had HIV RNA levels <400 copies/ml at Week 48 (intent-to-treat: missing = failure). Mean increases in absolute and relative (percent) CD4 counts from baseline to Week 48 were observed in both ARV-naive subjects (404 cells/mm(3); 10.3%) and ARV-experienced subjects (284 cells/mm(3); 5.9%). Only one subject prematurely discontinued the study because of a study drug-related adverse event. CONCLUSIONS: The liquid coformulation of lopinavir/ritonavir demonstrated durable antiviral activity and was safe and well-tolerated after 48 weeks of treatment in HIV-infected children.

Pharmacokinetic-pharmacodynamic analysis of lopinavir-ritonavir in combination with efavirenz and two nucleoside reverse transcriptase inhibitors in extensively pretreated human immunodeficiency virus-infected patients.

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.