Raltegravir with Optimized Background Therapy for Resistant HIV-1 Infection

Background: Raltegravir (MK-0518) is an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase active against HIV-1 susceptible or resistant to older antiretroviral drugs. Methods: We conducted two identical trials in different geographic regions to evaluate the safety and efficacy of raltegravir, as compared with placebo, in combination with optimized background therapy, in patients infected with HIV-1 that has triple-class drug resistance in whom antiretroviral therapy had failed. Patients were randomly assigned to raltegravir or placebo in a 2:1 ratio. Results: In the combined studies, 699 of 703 randomized patients (462 and 237 in the raltegravir and placebo groups, respectively) received the study drug. Seventeen of the 699 patients (2.4%) discontinued the study before week 16. Discontinuation was related to the study treatment in 13 of these 17 patients: 7 of the 462 raltegravir recipients (1.5%) and 6 of the 237 placebo recipients (2.5%). The results of the two studies were consistent. At week 16, counting noncompletion as treatment failure, 355 of 458 raltegravir recipients (77.5%) had HIV-1 RNA levels below 400 copies per milliliter, as compared with 99 of 236 placebo recipients (41.9%, P<0.001). Suppression of HIV-1 RNA to a level below 50 copies per milliliter was achieved at week 16 in 61.8% of the raltegravir recipients, as compared with 34.7% of placebo recipients, and at week 48 in 62.1% as compared with 32.9% (P<0.001 for both comparisons). Without adjustment for the length of follow-up, cancers were detected in 3.5% of raltegravir recipients and in 1.7% of placebo recipients. The overall frequencies of drug-related adverse events were similar in the raltegravir and placebo groups. Conclusions: In HIV-infected patients with limited treatment options, raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.

Subgroup and Resistance Analyses of Raltegravir for Resistant HIV-1 Infection

Background: We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral therapy had failed. Methods: We conducted subgroup analyses of the data from week 48 in both studies according to baseline prognostic factors. Genotyping of the integrase gene was performed in raltegravir recipients who had virologic failure. Results: Virologic responses to raltegravir were consistently superior to responses to placebo, regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in optimized background therapy; or demographic characteristics. Among patients in the two studies combined who were using both enfuvirtide and darunavir for the first time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and in 47% and 57% of the placebo recipients using either darunavir or enfuvirtide for the first time, respectively. At 48 weeks, 105 of the 462 raltegravir recipients (23%) had virologic failure. Genotyping was performed in 94 raltegravir recipients with virologic failure. Integrase mutations known to be associated with phenotypic resistance to raltegravir arose during treatment in 64 patients (68%). Forty-eight of these 64 patients (75%) had two or more resistance-associated mutations. Conclusions: When combined with an optimized background regimen in both studies, a consistently favorable treatment effect of raltegravir over placebo was shown in clinically relevant subgroups of patients, including those with baseline characteristics that typically predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.

Pentacyclic Nitrofurans with <i>In Vivo</i> Efficacy and Activity against Nonreplicating <i>Mycobacterium tuberculosis</i>

<div><p>The reductively activated nitroaromatic class of antimicrobials, which include nitroimidazole and the more metabolically labile nitrofuran antitubercular agents, have demonstrated some potential for development as therapeutics against dormant TB bacilli. In previous studies, the pharmacokinetic properties of nitrofuranyl isoxazolines were improved by incorporation of the outer ring elements of the antitubercular nitroimidazole OPC-67683. This successfully increased stability of the resulting pentacyclic nitrofuran lead compound Lee1106 (referred to herein as <b>9a</b>). In the current study, we report the synthesis and antimicrobial properties of <b>9a</b> and panel of <b>9a</b> analogs, which were developed to increase oral bioavailability. These hybrid nitrofurans remained potent inhibitors of <i>Mycobacterium tuberculosis</i> with favorable selectivity indices (>150) and a narrow spectrum of activity. <i>In vivo</i>, the pentacyclic nitrofuran compounds showed long half-lives and high volumes of distribution. Based on pharmacokinetic testing and lack of toxicity <i>in vivo,</i><b>9a</b> remained the series lead. <b>9a</b> exerted a lengthy post antibiotic effect and was highly active against nonreplicating <i>M. tuberculosis</i> grown under hypoxia. <b>9a</b> showed a low potential for cross resistance to current antitubercular agents, and a mechanism of activation distinct from pre-clinical tuberculosis candidates PA-824 and OPC-67683. Together these studies show that <b>9a</b> is a nanomolar inhibitor of actively growing as well as nonreplicating <i>M. tuberculosis</i>.</p></div

In vitro activity against NRP bacteria grown under hypoxic conditions.

<p>Viability of hypoxic <i>M. tuberculosis</i> cultures was assessed using the rapid anaerobic dormancy model.</p

Cross Resistance Profiles for Compounds 9a Resistant Clones.

<p>Abbreviations: S, susceptible; <b>R</b>, resistant.</p

Murine model of acute tuberculosis infection.

<p>Log₁₀ reduction provided by compound <b>9a</b> in lungs (black bars) and spleen (grey bars) after 9 days of daily oral administration of 300 mg/kg was determined by calculating the difference between bacillary loads in organs from the untreated group and <b>9a</b> dissolved in (<b>1</b>) 0.5% methylcellulose in DI-H₂O (<b>2</b>) 30% captisol in DI-H₂O (<b>3</b>) 10% vitamin E TPGS in DI-H₂O (<b>4</b>) 0.5% Tween 80 in DI-H₂O (<b>5</b>) 20% cyclodextrin in DI-H₂O or (<b>6</b>) cold PEG (50∶35∶15 H₂O:PEG300:PG). Error bars indicate SEM within treatment groups of 5–7 mice per group.</p

Nutrient starvation model of nonreplicating persisters.

<p>The viability of mid-log phase (black bars) or nutrient-starved (gray bars) after exposure to DMSO carrier (1% v/v), 1 µg/mL of isoniazid (INH), or 1 µg/mL of <b>9a</b>. Averaged results and SEM from two biologically independent experiments are presented.</p

MIC and MBCs for select nitrofurans and controls.

<p>Treatments were considered cidal when the MBC_99.9 for <i>M. tuberculosis</i> H37Rv was less than 4X the MIC.</p

Known nitroaromatic antimicrobial drugs and nitrofurans explored in this study.

<p>Known nitroaromatic antimicrobial drugs and nitrofurans explored in this study.</p

<i>In vivo</i> pharmacokinetic parameters.

<p>Pharmacokinetic analysis of experimental compounds in rats.</p><p>Values represent means (% coefficient of variation).</p><p>Abbreviations: t_½: half life; CL: clearance; Vd: volume of distribution; fe: fraction excreted unchanged in urine; C_max: maximum plasma concentration; C_{min,24<b> </b>h}: minimum plasma concentration within 24 hours after dosing; AUC_0-∞: systematic exposure; F: oral bioavailability.</p