Daily versus thrice-weekly interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C in HIV-infected persons: a multicenter randomized controlled trial

Among HIV-infected persons, chronic hepatitis C virus (HCV) infection causes substantial morbidity and mortality. However, few studies have evaluated the safety and efficacy of interferon alfa (IFN) and ribavirin (RBV) therapy in co-infected persons. Accordingly, a randomized, controlled, open-label, multicenter trial was conducted to establish the safety, tolerability, and efficacy of IFN alfa-2b 3 mIU daily plus RBV 800 mg/d compared with IFN alfa-2b 3 mIU thrice weekly (TIW) plus RBV 800 mg/d in HCV treatment-naive, HIV-infected subjects with compensated liver disease and stable HIV disease. The primary endpoint was sustained virologic response (SVR), defined as an undetectable HCV RNA level 24 weeks after discontinuation of HCV therapy. At study entry, subjects in both groups were similar with respect to age, gender, HCV genotype, and HIV disease status. Of 180 randomized subjects, 162 received at least 1 dose of study medication, constituting the modified intention-to-treat population. After 12 weeks of therapy, 122 (75%) had serum HCV RNA levels assessed; of these subjects, early virologic response (undetectable HCV RNA or >2 log10 decrease from baseline) was observed in 33 (42%) and 13 (16%) of subjects taking daily and TIW IFN, respectively (P < 0.001). SVR was observed in 15 (19.0%) and 7 (8.4%) of subjects taking daily and TIW IFN, respectively (P = 0.05). Adverse events were similar in both groups. However, while no deaths or opportunistic infections were observed, nearly 30% of subjects stopped treatment due to adverse events and 7 subjects experienced a serious adverse event. In conclusion, SVR was achieved in 19% of HIV/HCV coinfected subjects treated with daily IFN plus RBV, but the effectiveness of therapy was substantially diminished by relatively high rates of treatment-related toxicity.     

Phase II studies of Elsamitrucin in breast cancer, colorectal cancer, non-small cell lung cancer and ovarian cancer

PURPOSE:: To test the antitumor activity of Elsamitrucin in metastaticcancer of the breast, colon and rectum, non-small cell lungand ovary. PATIENTS AND METHODS:: Eligibility required histologically proven cancer. Patientswith colorectal or non-small cell lung cancer could not havereceived prior chemotherapy. Patients were entered if WHO PSwas 2 and organ functions were normal. Treatment consisted ofElsamitrucin 25 mg/m²/week given as a 5–10 min infusionfor at least 3–6 weekly doses. RESULTS:: One hundred and five patients entered the studies, 97 were eligible,94 are evaluable for toxicity and 75 for response. Toxicitymainly consisted of mild nausea/vomiting, and less frequentlyreversible hepatotoxicity and malaise. No objective responseswere seen. CONCLUSION:: Elsamitrucin at this dose and schedule is not an active drugin metastatic breast cancer, colorectal cancer, non-small celllung cancer or ovarian cancer. Elsamitrucin, phase II, breast, colorectum, nonsmall cell lung, ovary     

Pharmacokinetics of Saquinavir-SGC in HIV-Infected Pregnant Women

Abstract

Purpose: To evaluate saquinavir (SQV) pharmacokinetics, tolerance, and safety in 10 HIV-infected pregnant women between 14-32 weeks gestation. Method: This was a phase I, prospective, area-under-the-curve (AUC) targeted study. Antepartum treatment consisted of SQV 1200 mg tid, lamivudine 150 mg bid, and zidovudine 200 mg tid. The SQV targeted exposure was an 8-hour AUC (AUC₈) of 3000 ng · h/mL; the study was to be halted if the first 4 participants did not achieve this AUC₈. Cord blood and plasma samples were collected in neonates at birth. Results: Four women completed the SQV pharmacokinetic assessments. Exposure in all 4 patients was below the target AUC₈. Median (range) AUC₈ and trough (C8H) were 1672 (738-2614) ng · h/mL and 60 (<15-332) ng/mL, respectively. Oral clearance (CL/F) was 9.3 (5.1-16.6) L/h/kg and C_max was 599 (177–953) ng/mL. Cord and neonate plasma concentrations were mostly undetectable; 1 of 5 infants was HIV-infected at 24 weeks. Conclusion: These data suggest highly variable SQV pharmacokinetics in pregnant women, and exposure at 1200 mg tid may not be adequate for longer term therapy; both the AUC₈ and C8H were considerably below average. Because ritonavir has been shown to significantly increase SQV concentrations, this combination should be further explored in this population.     

Comparative effectiveness and safety of the novel oral anticoagulants: do the pivotal clinical trials point to a new paradigm?

Spyropoulos AC, Goldenberg NA, Kessler CM, Kittelson J, Schulman S, Turpie AGG, Cutler NR, Hiatt WR, Halperin JL. Comparative effectiveness and safety of the novel oral anticoagulants: do the pivotal clinical trials point to a new paradigm? J Thromb Haemost 2012; 10: 2621–4.     

A Randomized Controlled Trial of the Clinical Utility of Genotypic Resistance Testing in Patients with Limited Prior Exposure to Antiretroviral Drugs

Abstract

Purpose: To assess the clinical utility of genotypic resistance testing among HIV-1-infected patients with limited prior exposure to antiretroviral drugs. Method: Patients experiencing virological failure were randomly allocated to either centralized genotypic resistance testing or to no testing and were followed for a minimum of 1 year. Results: 55 patients were recruited from 14 centers in the United Kingdom. There were no demonstrable differences between the groups in terms of virological or immunological response. For patients allocated to resistance testing, there was an increased tendency to recycle previously used drugs. Conclusion: The study did not demonstrate a benefit of genotypic resistance testing in this population, although statistical power was low. However, testing did alter prescribing behavior, and clinical effects may become manifest in the longer term.     

The blossoming of evidence-based clinical rheumatology: The Arthritis Research Campaign's Clinical Trials Collaboration in association with the MRC Clinical Trials Unit,BSR and BOA

Competing demands for scarce healthcare resources have accentuatedthe requirement for routine clinical practice to be evidence-based.One of the benchmarks for evidence-based medicine is the appropriatelyconducted randomized controlled trial (RCT). Although epidemiologicalstudies, whether case–control or cohort in design, havecontributed enormously to the generation of hypotheses and permitthe controlled evaluation of therapeutic interventions, theyare susceptible to biases through selection, information ascertainmentand confounding. While RCTs are also susceptible to such biases,the process of randomization and of blinded evaluation of outcomespermits the closest approximation in clinical research to theconduct of a hypothesis-testing laboratory experiment. Historically,there have been several obstacles to the execution of high-qualityRCTs to address important rheumatological questions. One     

Low isoniazid concentrations and outcome of tuberculosis treatment with once-weekly isoniazid and rifapentine

To understand why once-weekly isoniazid/rifapentine therapy for tuberculosis was less effective than twice-weekly isoniazid/rifampin, we studied human immunodeficiency virus-seronegative patients with either failure (n = 4), relapse (n = 35), or cure (n = 94), recruited from a comparative treatment trial. In multivariate analyses that were adjusted for severity of disease, low plasma concentrations of isoniazid were associated with failure/relapse with once-weekly isoniazid/rifapentine (median isoniazid area under the concentration-time curve for 12 hours after the dose [AUC(0-12)] was 36 microg x hour/ml in failure/relapse versus 56 microg x hour/ml in control cases p = 0.005), but not with twice-weekly isoniazid/rifampin. Furthermore, two patients who relapsed with Mycobacterium tuberculosis monoresistant to rifamycin had very low concentrations of isoniazid. Finally, isoniazid acetylator status determined by N-acetyltransferase type 2 genotype was associated with outcome with once-weekly isoniazid/rifapentine (p = 0.03) but not twice-weekly isoniazid/rifampin. No rifamycin pharmacokinetic parameter was consistently and significantly associated with outcome (p > 0.10). Because low isoniazid concentrations were associated with failure/relapse, a drug with consistently greater area under the concentration-time curve than isoniazid may be needed to achieve highly active once-weekly therapy with rifapentine.