Ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic hepatitis C and bleeding disorders.

INTRODUCTION: Chronic hepatitis C virus (HCV) infection is prevalent among patients with inherited bleeding disorders and is a leading cause of mortality in those with haemophilia. AIM: We evaluated the efficacy and safety of ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic HCV genotype 1-4 infection and an inherited bleeding disorder. METHODS: Ledipasvir-sofosbuvir was administered for 12 weeks to patients with genotype 1 or 4 infection and for 12 or 24 weeks to treatment-experienced cirrhotic patients with genotype 1 infection. Patients with genotype 2 and 3 infection received sofosbuvir plus ribavirin for 12 and 24 weeks respectively. RESULTS: The majority of the 120 treated patients had a severe bleeding disorder (55%); overall, 65% of patients had haemophilia A and 26% of patients had haemophilia B; 22% were HIV coinfected. Sustained virologic response at 12 weeks posttreatment was 99% (98/99) in patients with genotype 1 or 4 infection; 100% (5/5) in treatment-experienced cirrhotic patients with genotype 1 infection; 100% (10/10) in patients with genotype 2 infection; and 83% (5/6) in patients with genotype 3 infection. There were no treatment discontinuations due to adverse events (AEs). The most frequent non-bleeding AEs were fatigue, headache, diarrhoea, nausea and insomnia. Bleeding AEs occurred in 22 patients, of which all but one were considered unrelated to treatment. CONCLUSION: Treatment with ledipasvir-sofosbuvir for patients with HCV genotype 1 or 4 infection or sofosbuvir plus ribavirin for patients with genotype 2 or 3 infection was highly effective and well tolerated among those with inherited bleeding disorders.

Quantifying and documenting prior beliefs in clinical trials.

Collecting and documenting subjective prior beliefs from knowledgeable clinicians about the potential results of a clinical trial has many advantages. Two large trials of prophylactic treatments in an HIV-positive population are used as examples. The trials recruited patients of primary care physicians and compared treatments which were in use in clinical practice. Opinions about these trials were elicited from 58 practising HIV clinicians. It is shown how the documented opinions can be used to augment the monitoring process; the prior opinions are updated with interim data using approximate Bayesian methods to give posterior opinions incorporating interim results. These posterior opinions can be used by the monitoring board to anticipate the clinicians' reaction to the results. Eliciting prior beliefs is also ethically important for documenting the nature of the uncertainty or equipoise. Important information is provided for the informed consent process and Institutional Review Board (IRB).

Pharmacological basis for concentration-controlled therapy with zidovudine, lamivudine, and indinavir.

Conventional antiretroviral therapy involves administration of standard fixed doses to adults and adolescents. This approach ignores interindividual variability in pharmacokinetics and results in substantial differences in systemic concentrations among patients. Thus, variability in systemic concentrations contributes to variability in response to therapy. This study was designed to evaluate the feasibility and safety of a regimen of zidovudine, lamivudine, and indinavir designed to achieve select target concentrations versus standard dose therapy. Twenty-four antiretroviral-naïve subjects completed the 24-week study; 13 received standard therapy, and 11 received concentration-controlled therapy. There were no differences in baseline characteristics. Oral clearance for all three drugs was not different between weeks 2 and 28; average ratios of week 2 oral clearance to week 28 oral clearance were 0.95, 1.09, and 1.06 for zidovudine, lamivudine, and indinavir, respectively, with 95% confidence intervals including 1. The selected target concentrations were average steady-state concentrations of 0.19 mg/liter for zidovudine and 0.44 mg/liter for lamivudine and a trough concentration of 0.15 mg/liter for indinavir; mean concentrations achieved at week 28 in the concentration-controlled arm were 0.20, 0.54, and 0.19 mg/liter, respectively. Concentration-controlled therapy significantly reduced interpatient variability in zidovudine concentrations and significantly increased indinavir concentrations. There was no difference in adverse drug effects or adherence. This investigation has provided a pharmacologic basis for concentration-controlled therapy by demonstrating that it is feasible and has a safety profile no different from that of standard therapy. Additional studies to evaluate the virologic effect of the concentration-controlled approach to antiretroviral therapy are warranted.

Phase III study of granulocyte-macrophage colony-stimulating factor in advanced HIV disease: effect on infections, CD4 cell counts and HIV suppression. Leukine/HIV Study Group.

OBJECTIVE: To evaluate the effect of adjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF) (sargramostim, yeast-derived recombinant human GM-CSF) on incidence and time to opportunistic infection or death, plasma HIV-RNA, and CD4 cell count in patients with advanced HIV disease. METHODS: This Phase III randomized, double-blind, placebo-controlled trial enrolled subjects with CD4 cell counts < or = 50 x 10(6)/l or < or = 100 x 10(6)/l with a prior AIDS-defining illness on stable antiretroviral therapy. Subjects were stratified by baseline HIV-RNA level (> or = or < 30,000 copies/ml) and randomized to receive subcutaneous injections of GM-CSF 250 microg or placebo three times per week for 24 weeks. Subjects were permitted to continue on blinded drug for up to 20 months. Subjects were evaluated for infections, plasma HIV-RNA, lymphocyte counts, changes in antiretroviral therapy, toxicity, and survival. RESULTS: Three-hundred and nine subjects received at least one dose of study drug, 70% completed 24 weeks of therapy. Groups were well matched at baseline. Significant increases in CD4 cell and neutrophil counts were observed at 1, 3, and 6 months in the GM-CSF group. GM-CSF significantly reduced the incidence of overall infections (78% placebo versus 67% GM-CSF; P = 0.03) and delayed time to first infection (56 days placebo versus 97 days GM-CSF; P = 0.04). No statistical difference in cumulative opportunistic infections was observed between groups; however, among subjects without an opportunistic infection prior to study, the GM-CSF group demonstrated a trend towards fewer subjects with an opportunistic infection on study (26% placebo versus 8% GM-CSF; P = 0.08). Change in HIV-RNA was not significantly different between groups, but significantly fewer GM-CSF subjects with baseline viral load < 30,000 copies/ml had changes in antiretroviral therapy for increased viral load (42% placebo versus 21% GM-CSF; P = 0.01). In patients with HIV-RNA levels below the limit of detection at baseline, more GM-CSF patients maintained an undetectable viral load at 24 weeks (54% placebo versus 83% GM-CSF; P = 0.02). GM-CSF was well tolerated. CONCLUSIONS: GM-CSF significantly increased CD4 cell count and decreased virological breakthrough and overall infection rate in subjects with advanced HIV disease.

The use of a transscrotal testosterone delivery system in the treatment of patients with weight loss related to human immunodeficiency virus infection.

PURPOSE: Weight loss is a strong predictor of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients. Men with acquired immunodeficiency syndrome (AIDS) lose body cell mass. Hypogonadism is also common. This study tested the efficacy of a testosterone transscrotal patch (6 mg/day) in improving body cell mass and treating hypogonadism in these patients. SUBJECTS AND METHODS: This multicenter, randomized, double-blinded, placebo-controlled trial was conducted from August 1995 to October 1996 in 133 men, 18 years of age and older, who had AIDS, 5% to 20% weight loss, and either a low morning serum total testosterone level (<400 ng/dL) or a low free testosterone level (<16 pg/mL). Outcomes included weight, body cell mass as measured using bioelectrical impedance analysis, quality of life, and morning measurements of serum testosterone and dihydrotestosterone levels, lymphocyte subsets, and HIV quantification. RESULTS: There were no significant differences in baseline weight, CD4 cell counts, or HIV serum viral quantification between treatment arms. Morning total and free testosterone levels increased in those treated with testosterone, but not with placebo. Following 12 weeks of treatment there were no differences (testosterone-placebo) in mean weight change (-0.3 kg [95% confidence interval (CI): -1.4 to 0.8]) or body cell mass (-0.2 kg [95% CI: -1.0 to 0.6]) in the two groups. There were also no changes in quality of life in either group. CONCLUSION: Hypogonadal men with AIDS and weight loss can achieve adequate morning serum sex hormone levels using a transscrotal testosterone patch. However, this system of replacement does not improve weight, body cell mass, or quality of life.

Experience with a cross-study endpoint review committee for AIDS clinical trials. Terry Beirn Community Programs for Clinical Research on AIDS.

OBJECTIVES: To describe the methods and results of a standardized system for clinical endpoint determination for defining and reviewing endpoints in clinical trials for HIV-infected individuals. DESIGN: A system was developed utilizing standard definitions for the 24 diagnoses or clinical events that serve as trial endpoints and together define the combined endpoint 'progression of HIV disease. A common set of case report forms were used for all trials. Thus, an event of Pneumocystis carinii pneumonia (PCP), for example, for a subject co-enrolled in an antiretroviral trial and a PCP prophylaxis trial was only reported once. METHODS: A central committee was established to define clinical events and review endpoints across all studies. Events were classified according to established criteria for confirmed, probable and possible levels of certainty. RESULTS: This report describes the methods used to ascertain and review endpoints, and summarized 2299 clinical events for 8097 subjects enrolled in one or more of nine clinical trials. Data on the diagnostic certainty of events and agreement between site clinicians and the endpoint committee are presented. CONCLUSIONS: Uniform classification of endpoints across AIDS clinical trials can be accomplished by multicenter, multitrial organizations with standardized definitions and review of endpoint documentation. Our experience suggests that nurse coordinators reviewing all submitted endpoints for every trial are warranted and the need for external review by a clinical events committee may depend on the type of trial conducted.

Pharmacokinetics of hyperimmune anti-human immunodeficiency virus immunoglobulin in persons with AIDS.

Hyperimmune anti-human immunodeficiency virus immunoglobulin (HIVIG) is an intravenous immunoglobulin prepared from HIV-infected asymptomatic donors with a CD4 cell count greater than 400 cells/microl and a high titer of antibody to HIV-1 p24 protein. Twelve persons with AIDS received four doses of HMG (two at 50 mg/kg of body weight and then two at 200 mg/kg) every 28 days. Pharmacokinetics were evaluated by measurement of anti-p24 antibody. HIVIG was well tolerated, and all participants completed the study. Three subjects who were not receiving Pneumocystis carinii pneumonia (PCP) prophylaxis developed PCP. The mean value for HIVIG clearance was 3.02 ml/kg/day at 50 mg/kg and 3.65 ml/kg/day at 200 mg/kg (P = 0.027); the mean trough antibody titers (reciprocal units) were 1,442 and 4,428, respectively. This study indicates that high titers of anti-p24 antibody can be maintained with a monthly administration schedule of HIVIG and that short-term safety is acceptable. Comparisons to evaluate the therapeutic potential of HIVIG are justified.

Povidone-iodine (betadine) in the treatment of experimental Pseudomonas aeruginosa keratitis.

Topical 5% povidone-iodine for the treatment of corneal ulcers was observed in Sierra Leone, West Africa by one of us (D.J.D.). To test the efficacy of topical 5% povidone-iodine for infectious keratitis, experimental Pseudomonas aeruginosa keratitis was induced in 12 rabbits by first abrading the central 3 mm of corneal epithelium. Thirty milliliters of broth of P. aeruginosa strain ATCC 27835 (1.8 x 10(7) viable bacteria) was dropped twice on the wounded cornea. After 22 h, all corneas were clinically infected. Eight rabbits were treated with 5% povidone-iodine solution and four with 0.9% NaCl solution. All were given hourly drops. Twenty-four hours after treatment began, the central 8-mm button of the infected cornea was excised, homogenized, and serial dilutions plated onto MacConkey agar. The total number of viable Pseudomonas organisms was calculated. The treatment group had 5.2 +/- 0.4 CFUs (colony-forming units) per cornea. The control group had 4.8 +/- 0.4 CFUs per cornea (p = 0.11). The clinical scores (Hobden grading system) were 6.9 +/- 1.5 for the treated group and 7.3 +/- 2.5 for the control group (p = 0.74). There was no statistical difference between the treated and control groups. Povidone-iodine (5%) is not effective in the acute treatment of P. aeruginosa keratitis in this rabbit model.

Routine HIV testing of hospital patients and pregnant women: informed consent in the real world.

The Centers for Disease Control and Prevention (CDC) has recommended that HIV testing be routinely offered to certain patients in hospitals with a high prevalence of HIV infection and on all pregnant women. The CDC does not, however, offer implementation level guidelines for obtaining informed consent. We provide a moral justification for requiring informed consent for HIV testing and propose guidelines for securing such consent. In particular we argue that genuine informed consent can be secured without elaborate counseling, such as that currently used at Counseling and Testing Sites, provided that sufficient written notice is given to the patients before testing and that they are specifically asked for permission.

Synergy, activity and tolerability of zidovudine and interferon-alpha in patients with symptomatic HIV-1 infection: AIDS Clincal Trial Group 068.

Thirty-four subjects with symptomatic HIV-1 infection, p24 antigenaemia, and CD4 cell counts > 200/mm3 were randomly assigned to receive treatment with either zidovudine (ZDV) orally, interferon-alpha (IFN-alpha) subcutaneously, or both at respective low (200 mg ZDV/ 2 million international units IFN-alpha (MIU)), middle (400 mg/4 MIU) or high (600 mg/6 MIU) daily dose levels for 12 weeks. Thereafter, all patients received combination therapy at the initially assigned dose level to a total of 96 weeks. This design permitted analysis by the combination index (CI) method, which demonstrated antiretroviral synergy between ZDV and IFN-alpha with respect to p24 antigen suppression. Over the first 12 weeks, combination therapy was acceptably tolerated, more so than IFN-alpha monotherapy, and it was significantly more active in suppressing antigenaemia than either of the monotherapies. Similarly, the high-dose combination was the most active dose level over weeks 12 to 96. Combination ZDV/IFN-alpha at the optimal dose level defined by this trial merits further study. In addition, the CI design strategy employed here may be useful for the investigation of new antiretroviral combinations.

CD4+ T lymphocyte counts and patterns of mortality among patients infected with human immunodeficiency virus who were enrolled in community programs for clinical research on AIDS.

CD4+ T lymphocyte measurements are used frequently in clinical practice and have important prognostic implications. In this study, we describe mortality patterns for 5,204 human immunodeficiency virus (HIV)-infected patients classified in different CD4+ cell strata; patients with and patients without a history of disease progression were included. Patients were enrolled in studies sponsored by the Terry Beirn Community Programs for Clinical Research on AIDS of the National Institute of Allergy and Infectious Diseases between September 1990 and December 1993. Over a median follow-up period of 23.6 months, 1,703 of the 5,204 patients died. For those with CD4+ cell counts (/mm3) of < 25, 25-49, 50-99, 100-199, and 200-499, the cumulative mortality rates after 24 months were 72%, 58%, 47%, 27%, and 10%, respectively. The median survival time was 15 months for those with CD4+ cell counts of < 25 cells/mm3; 21 months for those with CD4+ cell counts of 25-49 cells/mm3; and 40 months for patients with CD4+ cell counts of 100-199/mm3. In each CD4+ cell stratum, mortality rates were higher for those with a history of disease progression at entry into the study; across all CD4+ cell strata, mortality was 60% greater (relative risk = 1.6; 95% confidence interval = 1.5-1.8). These data should be useful in planning clinical trials, and they have implications in terms of the frequency with which CD4+ cell counts should be measured to monitor the progression of HIV infection.

Strategies for control of zidovudine concentrations in serum.

There are several clinical scenarios in which knowledge of zidovudine disposition may be important. This study evaluated the clinical utility of pharmacokinetic parameters for zidovudine derived from sparse serum concentration data obtained in an outpatient setting. Twelve human immunodeficiency virus-infected participants had two serum zidovudine concentrations determinations obtained on two different clinic visits, 2 to 38 days apart. Zidovudine concentrations were measured by radioimmunoassay. A one-compartment oral absorption model was used to describe zidovudine disposition. Three different approaches were used to estimate pharmacokinetic parameters: Bayesian estimation with one or two concentrations and least squares with one concentration. The ability of these parameters to predict concentrations measured during the second clinic visit was assessed by calculation of precision and bias and compared with predictions using standard fixed or weight-adjusted parameters. Estimated pharmacokinetic parameters for zidovudine were consistent with literature values; there was no statistically significant difference among the parameters calculated with the three estimation strategies. Absorptive phase concentrations were poorly predicted by all methods (mean percent bias, 157 to 249%; mean percent precision, 389 to 537%). Predictive ability for concentrations obtained in the elimination phase was strikingly improved: mean percent bias, -17 to 70%; mean percent precision, 40 to 95%. Bayesian and least-squares estimated parameters were statistically better than fixed-parameter values for predicting concentrations in the elimination phase. These observations provide a modeling framework to determine pharmacokinetic disposition of zidovudine in an individual, screen for the existence of a drug interaction, and conduct concentration-controlled clinical trials.

The effect of cimetidine and ranitidine administration with zidovudine.

STUDY OBJECTIVE: To evaluate the possibility of a drug interaction with zidovudine and histamine2-receptor antagonists in individuals infected with the human immunodeficiency virus. DESIGN: Randomized crossover study. SETTING: University-affiliated research center. PATIENTS: Six HIV-infected individuals. INTERVENTIONS: The subjects received 7-day regimens of zidovudine 600 mg/day alone, zidovudine with cimetidine 1200 mg/day, and zidovudine with ranitidine 300 mg/day. MEASUREMENTS AND MAIN RESULTS: The renal clearance of zidovudine when given alone was 0.41 L/kg/hour, and was reduced to 0.18 L/kg/hour (p = 0.002) when given with cimetidine. In the presence of cimetidine the urinary excretion of zidovudine decreased from 89.5 to 53.7 microM (p = 0.01), the urinary ratio of metabolite to parent increased from 5.16 to 9.96 (p = 0.0001), and the fraction of zidovudine converted to metabolite increased from 0.86 to 0.92 (p = 0.0025). CONCLUSION: Cimetidine presumably inhibits the renal clearance of zidovudine by competing for tubular secretion. Based on the observation that neither cimetidine nor ranitidine had a significant effect on serum concentrations of zidovudine or zidovudine glucuronide, a change in the dosage of zidovudine is not warranted.

Stool carriage, clinical isolation, and mortality during an outbreak of vancomycin-resistant enterococci in hospitalized medical and/or surgical patients.

During a nosocomial outbreak of infection due to vancomycin-resistant enterococci (VRE), rectal swabs that were collected weekly were used to identify and isolate VRE carriers. Over 6 months, 1,458 stool specimens from 724 high-risk patients were cultured, and 187 VRE isolates were recovered from 61 patients; 96% of the isolates were Enterococcus faecium. VRE tended to be isolated from clinical specimens from patients identified as VRE carriers by stool surveillance (P < .01). However, isolation of VRE from surveillance cultures preceded clinical isolation for only approximately 50% of the patients from whom a clinical VRE isolate was recovered. Mortality was greater (P < .05) among patients from whom a clinical VRE isolate was recovered than among patients from whom VRE was isolated only by stool surveillance. The mortality (1[17%] of 6) among patients for whom VRE was isolated from blood was similar to that (10 [27%] of 37) among patients for whom vancomycin-susceptible enterococcus was isolated from blood (P = .97). Despite prompt initiation of contact precautions for VRE carriers, the incidence of fecal carriage of VRE remained approximately 8% among this patient population for the 6-month period of the study.

Considerations in choice of a clinical endpoint for AIDS clinical trials. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA).

In most clinical trials of antiretroviral therapy for patients infected with HIV, the major outcome variable has been the combined clinical endpoint of any new or recurrent AIDS defining event. We review features of combined endpoints and use data from the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) to evaluate this outcome measure in terms of relevance, diagnostic certainty and sensitivity. We conclude that this endpoint is not relevant because: (i) the 19 different events constituting the combined endpoint are equally weighted in analyses even though they vary considerably in terms of risk of death; and (ii) events after the first are ignored, thus the event profile of patients is not taken into account in making treatment comparisons. We also conclude that power may be low with use of this endpoint if treatments under study do not have an immediate impact on disease progression, if some events which occur soon after randomization represent a disease process that has already begun to incubate, or if treatment differences for the various events constituting the combined endpoint are differentially effected by treatment. Since the ease and certainty of diagnosis of each of the 19 events also vary, we recommend that survival be the primary endpoint of antiretroviral trials, and that all opportunistic events experienced by patients, not just the first, be collected and summarized. Trial reports should include comparisons of incidence of each event by treatment group so that readers can rank events as they please. A single summary measure which considers severity and the entire event profile, as described here, would also be useful for assessing the impact of treatments on quality of life. Further research on approaches for weighting and combining multiple outcome measures is needed.

Value of routine pressure monitoring system changes after 72 hours of continuous use.

OBJECTIVE: To assess the infection potential of not routinely changing invasive monitoring kits and associated plasticware. DESIGN: A prospective, observational study of microbiological contamination of a cohort of pressure monitoring infusion systems. SETTING: Adult intensive care units in a university tertiary care center. PATIENTS: Patients who had invasively monitored arterial, central venous, or pulmonary artery catheters in place for > or = 96 hrs without a change to the system were entered into the study. INTERVENTIONS: Fluid samples were obtained from the proximal stopcock of the monitoring kits every 24 hrs, beginning with a sample at 72 hrs and continuing until either the plasticware or catheter was changed or discontinued. Fluid samples were placed in tryptic soy broth and spread on blood agar plates within 24 hrs. MEASUREMENTS AND MAIN RESULTS: Of 451 intervals in which the system remained unviolated for > or = 96 hrs except for sampling, no positive cultures were found. Of the 333 monitoring kits/lines in the study, four cultures became positive within 48 hrs of a violation of the system (flush bag change). Positive cultures were obtained from two different patients, one patient having positive fluid cultures from arterial, central venous, and pulmonary arterial kits. This bacterial growth would not have been eliminated with routine system changes as it occurred within a 48-hr timeframe. CONCLUSIONS: Invasive hemodynamic pressure monitoring systems including tubing and plasticware need not be changed routinely as these changes may cause a higher incidence of contamination due to increased violations of the systems.