BackgroundChronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a severely debilitating disease of unknown pathogenesis consisting of a variety of symptoms including severe fatigue. The objective of the study was to examine the efficacy and safety of a TLR-3 agonist, rintatolimod (Poly I: C12U), in patients with debilitating CFS/ME.Methods and FindingsA Phase III prospective, double-blind, randomized, placebo-controlled trial comparing twice weekly IV rintatolimod versus placebo was conducted in 234 subjects with long-standing, debilitating CFS/ME at 12 sites. The primary endpoint was the intra-patient change from baseline at Week 40 in exercise tolerance (ET). Secondary endpoints included concomitant drug usage, the Karnofsky Performance Score (KPS), Activities of Daily Living (ADL), and Vitality Score (SF 36). Subjects receiving rintatolimod for 40 weeks improved intra-patient placebo-adjusted ET 21.3% (p = 0.047) from baseline in an intention-to-treat analysis. Correction for subjects with reduced dosing compliance increased placebo-adjusted ET improvement to 28% (p = 0.022). The improvement observed represents approximately twice the minimum considered medically significant by regulatory agencies. The rintatolimod cohort vs. placebo also reduced dependence on drugs commonly used by patients in an attempt to alleviate the symptoms of CFS/ME (p = 0.048). Placebo subjects crossed-over to receive rintatolimod demonstrated an intra-patient improvement in ET performance at 24 weeks of 39% (p = 0.04). Rintatolimod at 400 mg twice weekly was generally well-tolerated.Conclusions/SignificanceRintatolimod produced objective improvement in ET and a reduction in CFS/ME related concomitant medication usage as well as other secondary outcomes.Trial RegistrationClinicalTrials.gov NCT00215800

The aim of this study was to determine whether oral ganciclovir interacted pharmacokinetically with zidovudine (AZT), didanosine (ddI), or probenecid. A multicenter, open-label, randomized, crossover pharmacokinetic study with four phases was undertaken at an outpatient private research center and at university research clinics. Twenty-six HIV-infected adults (23 men, 3 women) with cytomegalovirus (CMV) seropositivity and CD4+ T-lymphocyte count > or =100 cells/microl were studied. Patients had to be stable on antiretroviral therapy for at least 4 weeks. Patients with a history of opportunistic infection or gastrointestinal symptoms were excluded. Measurements included serial blood and urine samples during the dosing intervals at steady state. The steady-state pharmacokinetics of ganciclovir were determined after the participants had stabilized and were tolerating AZT or ddI therapy. When a 1000-mg dose of oral ganciclovir was taken every 8 hours, there was a significant mean increase in Cmax and dosing interval area under the serum concentration time curve over a dosing interval (AUC) for the two antiretroviral drugs: for AZT, 61.6% and 19.5%, respectively; for ddI when administered sequentially (2 hours before ganciclovir), 116.0% and 114.6%; and for ddI administered simultaneously with ganciclovir, 107.9% and 107.1%, respectively. There was no significant change in renal clearance for either antiretroviral drug, suggesting that the interaction did not occur through a renal mechanism. There was no significant change in mean ganciclovir Cmax and AUC(0-8) when coadministered with AZT. Mean increases in Cmax and AUC(0-8) of oral ganciclovir averaged 40.1% and 52.5%, respectively, when coadministered with probenecid, but decreased by 22.1% and 22.7%, respectively, when oral ganciclovir was administered 2 hours after ddI. There was no change in the mean ganciclovir Cmax or AUC(0-8) when administered simultaneously with ddI. The mean renal clearance of oral ganciclovir was not affected by AZT or ddI coadministration intake, but there was a mean decrease of 19% when coadministered with probenecid. We conclude the increased serum concentration and reduced renal clearance of ganciclovir suggests competition with probenecid for secretion at the renal tubule. The mechanism of the interaction of oral ganciclovir with either AZT or ddI remains to be determined. The magnitude of the effect of oral ganciclovir on ddI pharmacokinetics may result in an increase in ddI concentration-related toxicities. Similarly, the small but significant decrease in ganciclovir concentration with sequential combination ddl therapy may impair the efficacy of oral ganciclovir. For HIV-infected patients receiving ganciclovir and ddI, clinicians should recommend administering the two drugs simultaneously, and patients should be monitored closely for ddI-associated toxicities.

This phase IIb study explored the antiviral activity and safety of the investigational CC chemokine receptor 5 (CCR5) antagonist aplaviroc (APL) in antiretroviral-naïve patients harbouring R5-or R5X4-tropic virus. MethodsA total of 191 patients were randomized 2:2:2:1 to one of three APL dosing regimens or to lamivudine (3TC)/zidovudine (ZDV) twice daily (bid), each in combination with lopinavir/ritonavir (LPV/r) 400 mg/100 mg bid. Efficacy, safety and pharmacokinetic parameters were assessed. ResultsThis study was terminated prematurely because of APL-associated idiosyncratic hepatotoxicity. A total of 141 patients initiated treatment early enough to have been able to complete 12 weeks on treatment [modified intent-to-treat (M-ITT) population]; of these, 133 completed the 12-week treatment phase. The proportion of subjects in the M-ITT population with HIV-1 RNA o400 copies/mL at week 12 was 50, 48, 54 and 75% in the APL 200 mg bid, APL 400 mg bid, APL 800 mg once a day (qd) and 3TC/ZDV arms, respectively. Similar responses were seen in the few subjects harbouring R5X4-tropic virus (n 5 17). Common clinical adverse events (AEs) were diarrhoea, nausea, fatigue and headache. APL demonstrated nonlinear pharmacokinetics with high interpatient variability. ConclusionsWhile target plasma concentrations of APL were achieved, the antiviral activity of APL 1 LPV/r did not appear to be comparable to that of 3TC/ZDV 1 LPV/r. IntroductionUnlike currently available agents which inhibit HIV after infection of the target cell, aplaviroc (APL; 873140), a novel spirodiketopiperazine CC chemokine receptor 5 (CCR5) antagonist, inhibits HIV entry into cells, blocking a critical step in the fusion process [1]. For this reason, CCR5 is an attractive potential target for the treatment of HIV infection [2,3].APL demonstrated significant anti-HIV activity in in vitro and severe combined immunodeficiency (SCID) mouse studies [4,5]. In a phase I/II randomized dose-ranging study of APL monotherapy in R5-tropic antiretroviral (ARV)-naïve (n 5 19) and ARV-experienced (n 5 21) patients, 10 days of APL led to dose-dependent decreases in HIV-1 *Data were presented in part at the 10th European AIDS Conference, Dublin, Ireland,[17][18][19][20] DOI: 10.1111/j.1468-1293.2008.00660.x HIV Medicine (2009 (RTV). In a drug interaction study in healthy volunteers, repeat-dose coadministration of APL with lopinavir/ritonavir (LPV/r) increased the plasma APL area under the curve (AUC) by 7.7-fold without significant changes in LPV or RTV plasma exposure [8]. The combination of APL and LPV/r was well tolerated over the 7-day dosing interval of this study.Triple-drug antiretroviral therapy (ART) regimens that contain LPV/r are potent, durable and associated with a high barrier to genetic resistance when used in ARV-naïve patients [9,10]. In a pilot study, Gathe et al. reported that LPV/r may be effective as monotherapy in some ARV-naïve patients [11]. Thus, the nucleoside-sparing, two-drug combination of APL with LPV/r merited study in HIVinfected pati...