Quality of life assessment among HIV-positive persons entering the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: With HIV treatment prolonging survival and HIV infection now managed as a chronic illness, quality of life (QOL) is important to evaluate in persons living with HIV (PLWH). We assessed at study entry the QOL of antiretroviral-naïve PLWH with CD4 counts > 500 cells/µL in the Strategic Timing of AntiRetroviral Treatment (START) clinical trial. METHODS: QOL was assessed with: (1) a visual analogue scale (VAS) for self-assessment of overall current health; (2) the Short-Form 12-Item Version 2 Health Survey(®) (SF-12V2), for which responses are summarized into eight individual QOL domains plus component summary scores for physical health [the Physical Health Component Summary (PCS)] and mental health [the Mental Health Component Summary (MCS)]. The VAS and eight domain scores were scaled from 0 to 100. Mean QOL measures were calculated overall and by demographic, clinical and behavioural factors. RESULTS: A total of 4631 participants completed the VAS and 4119 the SF-12. The mean VAS score (with standard deviation) was 80.9 ± 15.7. Mean SF-12 domain scores were lowest for vitality (66.3 ± 26.4) and mental health (68.6 ± 21.4), and highest for physical functioning (89.3 ± 23.0) and bodily pain (88.0 ± 21.4). Using multiple linear regression, PCS scores were lower (P < 0.001) for Asians, North Americans, female participants, older participants, and those with less education, longer duration of known HIV infection, alcoholism/substance dependence and body mass index ≥ 30 kg/m(2) . MCS scores were highest (P < 0.001) for Africans, South Americans and older participants, and lowest for female participants, current smokers and those with alcoholism/substance dependence. CONCLUSIONS: In this primarily healthy population, QOL was mostly favourable, emphasizing that it is important that HIV treatments do not negatively impact QOL. Self-assessed physical health summary scores were higher than mental health scores. Factors such as older age and geographical region had different effects on perceived physical and mental health.

Transmission risk behaviour at enrolment in participants in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: A proportion of HIV-positive people have condomless sex. Antiretroviral treatment (ART) reduces infectiousness, but a substantial proportion of HIV-diagnosed people are not yet on ART. We describe baseline self-reported risk behaviours in ART-naïve Strategic Timing of AntiRetroviral Treatment (START) trial participants. METHODS: All START participants completed a risk behaviour questionnaire. Data were collected on sociodemographics, lifestyle factors, health and wellbeing status and clinical status. Recent sexual behaviour and HIV transmission beliefs in the context of ART were also assessed. The primary interest was in condomless sex with serodifferent partners (CLS-D) in the past two months. RESULTS: A total of 4601 of 4685 HIV-positive participants (98%) completed the questionnaire [2559 men who have sex with men (MSM), 803 heterosexual men and 1239 women]. Region of recruitment was Europe/Israel, 33%; South America/Mexico, 25%; Africa, 22%; other, 21%. Median age was 36 years [interquartile range (IQR) 29, 44 years]. Forty-five per cent reported white ethnicity and 31% black ethnicity. Two per cent had HIV viral load < 50 HIV-1 RNA copies/mL. Seventeen per cent (767 of 4601) reported CLS-D; 20% of MSM compared with 10% of heterosexual men and 14% of women. MSM were also more likely to report multiple CLS-D partners. Possible risk limitation measures (reported by more than half of those who had CLS-D) were seropositioning (receptive anal CLS-D only) or withdrawal (insertive anal CLS-D always without ejaculation). CLS-D was more commonly reported by participants from South America/Mexico and North America compared with Europe; among heterosexual men and women CLS-D was also more commonly reported among participants from Africa compared with Europe. Knowledge of ART impact on transmission risk was low. CONCLUSIONS: A substantial minority recruited to the START study reported CLS-D at baseline. CLS-D reporting was higher in MSM than heterosexuals and varied significantly according to region of recruitment. A substantial proportion of MSM reporting CLS-D appear to take transmission risk limitation measures.

Requirements for the clinical evaluation of new anti-tuberculosis agents in children.

The ultimate goal of evidence-based drug treatment is to produce a desired pharmacological response in a predictable manner and also to minimise adverse effects. This goal requires not only an increased awareness of the need to provide specific dosing recommendations aimed at specific patient groups, but also the implementation of a consistent integrative approach to recognise all factors contributing to the within- and between-subject variability in drug disposition and response. The assessment of new anti-tuberculosis agents and regimens in children requires a specific programme of investigation, and should be included early in human drug evaluation programmes. Appreciation of this principle is an important step forward towards the full integration of children into the tuberculosis research agenda and control programmes. The development of anti-tuberculosis drug formulations and regimens tailored to the requirements of children needs to consider physiological age-related differences for pharmacokinetics and toxicity between adults and children. Research based on these principles will create an evidence base that will inform the appropriate treatment of children with novel agents and regimens and will also inform future research, including the use of chemoprophylaxis and treatment-shortening strategies in children.

Targets for antibiotic and healthcare resource stewardship in inpatient community-acquired pneumonia: a comparison of management practices with National Guideline Recommendations.

PURPOSE: Community-acquired pneumonia (CAP) is the most common infection leading to hospitalization in the USA. The objective of this study was to evaluate management practices for inpatient CAP in relation to Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) guidelines to identify opportunities for antibiotic and health care resource stewardship. METHODS: This was a retrospective cohort study of adults hospitalized for CAP at a single institution from 15 April 2008 to 31 May 2009. RESULTS: Of the 209 patients with CAP who presented to Denver Health Medical Center during the study period and were hospitalized, 166 (79 %) and 43 (21 %) were admitted to a medical ward and the intensive care unit (ICU), respectively. Sixty-one (29 %) patients were candidates for outpatient therapy per IDSA/ATS guidance with a CURB-65 score of 0 or 1 and absence of hypoxemia. Sputum cultures were ordered for 110 specimens; however, an evaluable sample was obtained in only 49 (45 %) cases. Median time from antibiotic initiation to specimen collection was 11 [interquartile range (IQR) 6-19] h, and a potential pathogen was identified in only 18 (16 %) cultures. Blood cultures were routinely obtained for both non-ICU (81 %) and ICU (95 %) cases, but 15 of 36 (42 %) positive cultures were false-positive results. The most common antibiotic regimen was ceftriaxone + azithromycin (182, 87 % cases). Discordant with IDSA/ATS recommendations, oral step-down therapy consisted of a new antibiotic class in 120 (66 %), most commonly levofloxacin (101, 55 %). Treatment durations were typically longer than suggested with a median of 10 (IQR 8-12) days. CONCLUSIONS: In this cohort of patients hospitalized for CAP, management was frequently inconsistent with IDSA/ATS guideline recommendations, revealing potential targets to reduce unnecessary antibiotic and healthcare resource utilization.

Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers.

Rifapentine (RP T) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RI F).The maximal tolerated daily dose of RP T and its potential for cytochrome 3A4 induction and autoinduction at clinically relevant doses are unknown. In this phase I, dose-escalation study among healthy volunteers, daily doses as high asa prespecified maximum of 20 mg/kg/day were well tolerated. Steady-state RP T concentrations increased with dose from 5 to 15 mg/kg, but area under the plasma concentration­time curve (AU C0­24) and maximum concentration (Cmax)were similar in the 15- and 20-mg/kg cohorts. Although RP T pharmacokinetics (PK) appeared to be time-dependent,accumulation occurred with daily dosing. The mean AU C0­12 of oral midazolam (MDZ), a cytochrome 3A (CYP 3A) probe drug, was reduced by 93% with the coadministration of RPT and by 74% with the coadministration of RIF (P < 0.01).Changes in the oral clearance of MDZ did not vary by RP T dose. In conclusion, RP T was tolerated at doses as high as20 mg/kg/day, its PK were less than dose-proportional, and its CYP 3A induction was robust.

Effect of HIV infection on tolerability and bacteriologic outcomes of tuberculosis treatment.

SETTING: Two international, multicenter Phase 2 clinical trials examining fluoroquinolone-containing regimens in adults with smear-positive pulmonary tuberculosis (TB), conducted from July 2003 to March 2007. Both trials enrolled human immunodeficiency virus (HIV) infected participants who were not receiving antiretroviral therapy (ART) at TB treatment initiation. OBJECTIVE: To assess the impact of HIV infection on TB treatment outcomes in Phase 2 clinical trials. DESIGN: Cross-protocol analysis comparing the safety, tolerability and outcomes of anti-tuberculosis treatment by HIV status. RESULTS: Of 750 participants who received at least one dose of study treatment, 123 (16%) were HIV-infected. Treatment completion rates were similar by HIV status (81% infected vs. 85% non-infected), as were rates of week 8 culture conversion (66% infected vs. 63% non-infected), and treatment failure (5% infected vs. 3% non-infected). Among HIV-infected participants, treatment failure detected using liquid media was more frequent in those treated thrice weekly (14% thrice weekly vs. 2% daily, P = 0.03). HIV-infected participants more frequently experienced an adverse event during the intensive phase treatment than non-HIV-infected participants (30% vs. 15%, P < 0.01). CONCLUSION: HIV-infected persons not receiving ART had more adverse events during the intensive phase of anti-tuberculosis treatment, but tolerated treatment well. Failure rates were higher among HIV-infected persons treated with thrice-weekly intensive phase therapy.

Management of HIV-infected patients with MDR- and XDR-TB in resource-limited settings.

The emergence of extensively drug-resistant tuberculosis (XDR-TB) poses a significant public health threat for human immunodeficiency virus (HIV) programmes and tuberculosis (TB) control efforts. Recent reports demonstrate high mortality rates among HIV-infected multidrug-resistant (MDR) and XDR-TB patients compared to those without HIV infection. Transmission of these highly resistant TB strains is occurring both within health facilities and in the community. We review the principles of a sound public health approach to this problem, including early diagnosis, treatment for suspected disease, patient support and adherence and sound infection control measures. In the context of drug-resistant TB, we elaborate on current World Health Organization antiretroviral guidelines addressing management issues related to timing of antiretroviral treatment (ART), drug interactions and drug toxicities among patients receiving both ART and second-line TB regimens. We highlight the important research agenda that exists at the intersection of MDR- and XDR-TB and HIV disease.

Frequency, severity and duration of immune reconstitution events in HIV-related tuberculosis.

SETTING: Patients were enrolled in a prospective trial of rifabutin-based tuberculosis (TB) treatment for human immunodeficiency virus related TB. Antiretroviral therapy (ART) was encouraged, but not required. OBJECTIVE: To evaluate the frequency, risk factors and duration of immune reconstitution events. DESIGN: Patients were prospectively evaluated for immune reconstitution events, and all adverse event reports were reviewed to identify possible unrecognized events. RESULTS: Of 169 patients, 25 (15%) developed immune reconstitution events related to TB. All 25 were among the 137 patients who received ART during TB treatment, so the frequency in this subgroup was 18% (25/137). Risk factors for an immune reconstitution event in multivariate analysis were Black race, the presence of extra-pulmonary TB and a shorter interval from initiation of TB treatment to initiation of ART. The most common clinical manifestations were fever (64%), new or worsening adenopathy (52%) and worsening pulmonary infiltrates (40%). Twelve patients (48%) were hospitalized for a median of 7 days, six underwent surgery and 11 had needle aspiration. The median duration of events was 60 days (range 11-442). CONCLUSION: Immune reconstitution events were common among patients receiving ART during TB treatment, produced substantial morbidity and had a median duration of 2 months.

CD4+ count-guided interruption of antiretroviral treatment.

BACKGROUND: Despite declines in morbidity and mortality with the use of combination antiretroviral therapy, its effectiveness is limited by adverse events, problems with adherence, and resistance of the human immunodeficiency virus (HIV). METHODS: We randomly assigned persons infected with HIV who had a CD4+ cell count of more than 350 per cubic millimeter to the continuous use of antiretroviral therapy (the viral suppression group) or the episodic use of antiretroviral therapy (the drug conservation group). Episodic use involved the deferral of therapy until the CD4+ count decreased to less than 250 per cubic millimeter and then the use of therapy until the CD4+ count increased to more than 350 per cubic millimeter. The primary end point was the development of an opportunistic disease or death from any cause. An important secondary end point was major cardiovascular, renal, or hepatic disease. RESULTS: A total of 5472 participants (2720 assigned to drug conservation and 2752 to viral suppression) were followed for an average of 16 months before the protocol was modified for the drug conservation group. At baseline, the median and nadir CD4+ counts were 597 per cubic millimeter and 250 per cubic millimeter, respectively, and 71.7% of participants had plasma HIV RNA levels of 400 copies or less per milliliter. Opportunistic disease or death from any cause occurred in 120 participants (3.3 events per 100 person-years) in the drug conservation group and 47 participants (1.3 per 100 person-years) in the viral suppression group (hazard ratio for the drug conservation group vs. the viral suppression group, 2.6; 95% confidence interval [CI], 1.9 to 3.7; P<0.001). Hazard ratios for death from any cause and for major cardiovascular, renal, and hepatic disease were 1.8 (95% CI, 1.2 to 2.9; P=0.007) and 1.7 (95% CI, 1.1 to 2.5; P=0.009), respectively. Adjustment for the latest CD4+ count and HIV RNA level (as time-updated covariates) reduced the hazard ratio for the primary end point from 2.6 to 1.5 (95% CI, 1.0 to 2.1). CONCLUSIONS: Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load. Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy. (ClinicalTrials.gov number, NCT00027352 [ClinicalTrials.gov].).

Pharmacokinetics of ethambutol in children and adults with tuberculosis.

SETTING: Five hospitals in the United States. OBJECTIVE: To describe ethambutol pharmacokinetics in children and adults with active tuberculosis (TB). DESIGN: Prospective, open-labeled study in 56 adults and 14 children with active tuberculosis who received ethambutol as part of their multidrug TB regimens. RESULTS: Most serum samples were collected up to 10 h post dose and assayed using a validated gas chromatography assay with mass selective detection (GC/MS). Concentration data were analyzed using non-compartmental and population pharmacokinetic methods. Drug exposure increased with dose, but less than proportionally at doses >3000 mg. Lower than expected maximum serum concentrations (Cmax <2 microg/ml) were common in adults. Very low Cmax (<1 microg/ml) were common in children, as was delayed absorption (time to Cmax >3 h). Many Cmax were at or below typical TB minimal inhibitory concentrations. Cmax values for HIV-positive patients were 20% lower than HIV-negative patients with daily doses, but were similar with larger twice-weekly doses. CONCLUSIONS: Adult TB patients often had lower than expected ethambutol serum concentrations, and most pediatric TB patients had very low ethambutol serum concentrations. Higher doses and therapeutic drug monitoring may be indicated for many of these patients.

Lack of toxicity from concomitant directly observed disulfiram and isoniazid-containing therapy for active tuberculosis.

We retrospectively evaluated the use of disulfiram among alcoholic patients being treated for active tuberculosis. There were 13 alcoholics treated with disulfiram, 105 alcoholics not on disulfiram, and 249 non-alcoholics. Rates of toxicity were higher among alcoholics than among non-alcoholics (58% vs. 32%), but there was no difference between alcoholics taking and those not taking disulfiram (61% vs. 57%). There were no neurological side effects in the disulfiram group. Disulfiram appeared to be safe when added to intermittent, directly observed isoniazid-containing tuberculosis treatment, and was useful in managing complications of alcohol abuse. However, the small number of patients on disulfiram limits the strength of this negative finding.

Population pharmacokinetics of intravenous and intramuscular streptomycin in patients with tuberculosis.

STUDY OBJECTIVES: To determine population pharmacokinetic parameters of streptomycin after administration of multiple intramuscular and intravenous doses. DESIGN: Prospective, unblinded clinical study. SETTING: Two medical centers in Denver, Colorado. PATIENTS: Thirty patients with tuberculosis. INTERVENTION: Patients received multiple doses of streptomycin as part of their tuberculosis treatment. They received concurrent drugs based on in vitro susceptibility data. MEASUREMENTS AND MAIN RESULTS: Serum samples were collected over a 10-hour period and assayed by validated high-performance liquid chromatography Concentration-time data were analyzed using population methods. Streptomycin concentrations increased linearly with increasing intravenous doses. The intramuscular doses did not produce as linear a relationship, presumably because of variability in rates of and, potentially, completeness of absorption. Streptomycin elimination decreased with declining renal function. Higher, intermittent doses were well tolerated and appeared to maximize the peak concentration:minimal inhibitory concentration ratio. CONCLUSION: Overall, pharmacokinetic parameters of streptomycin were comparable with those previously published for streptomycin and other aminoglycosides. Higher, intermittent doses maximize pharmacodynamic parameter estimates and might have advantages for treatment of tuberculosis.

The effect of changes in laboratory practices on the rate of false-positive cultures for Mycobacterium tuberculosis.

CONTEXT: False-positive cultures for Mycobacterium tuberculosis have been found in nearly all DNA fingerprinting studies, but the effectiveness of interventions to reduce cross-contamination has not been evaluated. OBJECTIVE: To evaluate whether changes in laboratory policies and procedures reduced the rate of false-positive cultures. DESIGN: Retrospective study of isolates with matching DNA fingerprints. SETTING: A mycobacteriology laboratory serving an urban tuberculosis control program and public hospital system. PATIENTS: All M tuberculosis isolates processed from July 1994 to December 1999. METHODS: Isolates were fingerprinted using IS6110; pTBN12 was used to fingerprint isolates having fewer than 6 copies of IS6110. We further evaluated all patients having only one positive culture whose DNA fingerprint matched that of another isolate processed in the laboratory within 42 days. INTERVENTIONS: We changed laboratory policy to reduce the number of smear-positive specimens processed and changed laboratory procedures to minimize the risk of cross-contamination during batch processing. MAIN OUTCOME MEASURE: The rate of false-positive cultures. RESULTS: Of 13 940 specimens processed during the study period, 630 (4.5%) from 184 patients and 48 laboratory proficiency specimens grew M tuberculosis. There were no cases (0/184) of probable or definite cross-contamination, compared with the 4% rate (8/199) identified in our previous study (P =.008). We also fingerprinted a convenience sample of isolates from other laboratories in Denver; 13.6% (3/22) of these were false-positive, a rate similar to the 11.9% rate (5/42) identified for other laboratories in our previous study (P =.84). CONCLUSIONS: Laboratory cross-contamination decreased significantly after relatively simple, inexpensive changes in laboratory policies and practices. Cross-contamination continued to occur in other laboratories in Denver.

Comparative pharmacokinetics and pharmacodynamics of the rifamycin antibacterials.

The rifamycin antibacterials, rifampicin (rifampin), rifabutin and rifapentine, are uniquely potent in the treatment of patients with tuberculosis and chronic staphylococcal infections. Absorption is variably affected by food; the maximal concentration of rifampicin is decreased by food, whereas rifapentine absorption is increased in the presence of food. The rifamycins are well-known inducers of enzyme systems involved in the metabolism of many drugs, most notably those metabolised by cytochrome P450 (CYP) 3A. The relative potency of the rifamycins as CYP3A inducers is rifampin > rifapentine > rifabutin; rifabutin is also a CYP3A substrate. The antituberculosis activity of rifampicin is decreased by a modest dose reduction from 600 to 450mg. This somewhat surprising finding may be due to the binding of rifampicin to serum proteins, limiting free, active concentrations of the drug. However, increasing the administration interval (after the first 2 to 8 weeks of therapy) has little effect on the sterilising activity of rifampicin, suggesting that relatively brief exposures to a critical concentration of rifampicin are sufficient to kill intermittently metabolising mycobacterial populations. The high protein binding of rifapentine (97%) may explain the suboptimal efficacy of the currently recommended dose of this drug. The toxicity of rifampicin is related to dose and administration interval, with increasing rates of presumed hypersensitivity with higher doses combined with administration frequency of once weekly or less. Rifabutin toxicity is related to dose and concomitant use of CYP3A inhibitors. The rifamycins illustrate the complexity of predicting the pharmacodynamics of treatment of an intracellular pathogen with the capacity for dormancy.

Inactivated pronase as the cause of false-positive results of serum cryptococcal antigen tests.

Four patients who had acquired immunodeficiency syndrome and who were evaluated for headache within a 3-week period had false-positive results of serum cryptococcal antigen tests. This cluster of false-positive test results appeared to be due to inactivation of the pronase vial in the test kit, a cause that has not been reported previously.

Breaking the camel's back: multicenter clinical trials and local institutional review boards.

Clinical research has undergone remarkable and beneficial expansion in the past 25 years, but with this growth has come an unprecedented increase in workload for the human subjects protection system. Recently, a major change in federal oversight of local institutional review boards (IRBs) became evident. Although it was not announced publicly, in 1998 and 1999 federal regulatory actions against local IRBs increased threefold. Particularly notable was the marked increase in regulatory actions taken against the IRBs of academic medical centers (1 in 1997 compared with 14 in 1999). Ironically, this apparent federal crackdown began at the same time that two federal review panels called for major changes in the regulations governing local IRBs. A key factor in the current crisis in the function of local IRBs is the ascendance of multicenter clinical trials as the dominant form of clinical research. Local IRBs were not designed to handle the initial evaluation and ongoing review required by the rapidly increasing number of multicenter clinical trials. Furthermore, local IRB review of the thousands of safety reports from multicenter clinical trials monopolizes resources without promoting patient safety. Instead of rigid enforcement of outmoded regulations that do not contribute to patient safety, the responsibilities of the local IRB in the oversight of multicenter clinical trials must be systematically evaluated.