Defining optimal treatment for recurrent Clostridioides difficile infection (OpTION study): A randomized, double-blind comparison of three antibiotic regimens for patients with a first or second recurrence.

BACKGROUND: Although many large, randomized controlled trials (RCT) have been conducted on antibiotic therapy for patients with primary C. difficile infections (CDI), few RCTs have been performed for patients with recurrent CDI (rCDI). In addition, fecal microbial transplant (FMT) is neither FDA-approved or guideline-recommended for patients with pauci-rCDI (first or second recurrences). Therefore, a rigorous RCT of sufficient size was designed to determine the optimal treatment among three antibiotic regimens in current practice for treatment of pauci-rCDI. METHODS: VA Cooperative Studies Program (CSP) #596 is a prospective, double-blind, multi-center clinical trial of veteran patients with pauci-rCDI comparing fidaxomicin (FDX) 200 mg twice daily for 10 days and vancomycin (VAN) 125 mg four times daily for 10 days followed by a 3-week vancomycin taper and pulse (VAN-T/P) regimen to a standard course of VAN 125 mg four times daily for 10 days. The primary endpoint is sustained clinical response at day 59, with sustained response measured as a diarrhea composite outcome (D-COM) that includes symptom resolution during treatment (before day 10) without recurrence of diarrhea or other clinically important outcomes through day 59. DISCUSSION: CSP study 596 is designed to compare three current antibiotic treatments for recurrent CDI that are in clinical practice, but which lack high-quality evidence to support strong guideline recommendations. The design of the study which included a pilot phase initiated at six sites with expansion to 24 sites is described along with protocol modifications based on early trial experience and clinical realities including the COVID-19 pandemic. TRIAL REGISTRATION: This study is registered with clinicaltrials.gov (Identifier: NCT02667418).

Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Since the 1918 influenza pandemic, non-randomised studies and small clinical trials have suggested that convalescent plasma or anti-influenza hyperimmune intravenous immunoglobulin (hIVIG) might have clinical benefit for patients with influenza infection, but definitive data do not exist. We aimed to evaluate the safety and efficacy of hIVIG in a randomised controlled trial. METHODS: This randomised, double-blind, placebo-controlled trial was planned for 45 hospitals in Argentina, Australia, Denmark, Greece, Mexico, Spain, Thailand, UK, and the USA over five influenza seasons from 2013-14 to 2017-18. Adults (≥18 years of age) were admitted for hospital treatment with laboratory-confirmed influenza A or B infection and were randomly assigned (1:1) to receive standard care plus either a single 500-mL infusion of high-titre hIVIG (0·25 g/kg bodyweight, 24·75 g maximum; hIVIG group) or saline placebo (placebo group). Eligible patients had a National Early Warning score of 2 points or greater at the time of screening and their symptoms began no more than 7 days before randomisation. Pregnant and breastfeeding women were excluded, as well as any patients for whom the treatment would present a health risk. Separate randomisation schedules were generated for each participating clinical site using permuted block randomisation. Treatment assignments were obtained using a web-based application by the site pharmacist who then masked the solution for infusion. Patients and investigators were masked to study treatment. The primary endpoint was a six-category ordinal outcome of clinical status at day 7, ranging in severity from death to resumption of normal activities after discharge. The choice of day 7 was based on haemagglutination inhibition titres from a pilot study. It was analysed with a proportional odds model, using all six categories to estimate a common odds ratio (OR). An OR greater than 1 indicated that, for a given category, patients in the hIVIG group were more likely to be in a better category than those in the placebo group. Prespecified primary analyses for safety and efficacy were based on patients who received an infusion and for whom eligibility could be confirmed. This trial is registered with ClinicalTrials.gov, NCT02287467. FINDINGS: 313 patients were enrolled in 34 sites between Dec 11, 2014, and May 28, 2018. We also used data from 16 patients enrolled at seven of the 34 sites during the pilot study between Jan 15, 2014, and April 10, 2014. 168 patients were randomly assigned to the hIVIG group and 161 to the placebo group. 21 patients were excluded (12 from the hIVIG group and 9 from the placebo group) because they did not receive an infusion or their eligibility could not be confirmed. Thus, 308 were included in the primary analysis. hIVIG treatment produced a robust rise in haemagglutination inhibition titres against influenza A and smaller rises in influenza B titres. Based on the proportional odds model, the OR on day 7 was 1·25 (95% CI 0·79-1·97; p=0·33). In subgroup analyses for the primary outcome, the OR in patients with influenza A was 0·94 (0·55-1·59) and was 3·19 (1·21-8·42) for those with influenza B (interaction p=0·023). Through 28 days of follow-up, 47 (30%) of 156 patients in the hIVIG group and in 45 (30%) of 152 patients in the placebo group had the composite safety outcome of death, a serious adverse event, or a grade 3 or 4 adverse event (hazard ratio [HR] 1·06, 95% CI 0·70-1·60; p=0·79). Six (4%) patients in the hIVIG group and five (3%) in the placebo group died, but these deaths were not necessarily related to treatment. INTERPRETATION: When administered alongside standard care (most commonly oseltamivir), hIVIG was not superior to placebo for adults hospitalised with influenza infection. By contrast with our prespecified subgroup hypothesis that hIVIG would result in more favourable responses in patients with influenza A than B, we found the opposite effect. The clinical benefit of hIVIG for patients with influenza B is supported by antibody affinity analyses, but confirmation is warranted. FUNDING: NIAID and NIH. Partial support was provided by the Medical Research Council (MRC_UU_12023/23) and the Danish National Research Foundation.

Benefit of Early versus Deferred Antiretroviral Therapy on Progression of Liver Fibrosis among People with HIV in the START Randomized Trial.

The role of antiretroviral therapy (ART) in reducing or contributing to liver fibrosis in persons with human immunodeficiency virus (HIV) is unclear. We evaluated participants in the Strategic Timing of AntiRetroviral Treatment (START) trial for liver fibrosis using the AST to Platelet Ratio Index (APRI) and Fibrosis-4 Index (FIB-4), and assessed for a benefit of early versus delayed ART on liver fibrosis progression. ART-naïve persons with high CD4 counts (>500 cells/µL) from 222 clinical sites in 35 countries were randomized to receive ART either at study enrollment (immediate treatment arm) or when their CD4 count fell below 350 cells/µL (deferred treatment arm). The following outcomes were evaluated: fibrosis (APRI > 0.5 or FIB-4 > 1.45), significant fibrosis (APRI > 1.5 or FIB-4 > 3.25), hepatic flare, and resolution of elevated APRI and FIB-4 scores. Of the 4,684 enrolled into the START study, 104 did not have APRI or FIB-4 results and were excluded. Among 4,580 participants (2,273 immediate treatment; 2,307 deferred treatment), the median age was 36 years, 26.9% were female, and 30.4% were black. Three percent had an alcoholism or substance abuse history, 6.4% had hepatitis B and/or C, and 1.1% had significant fibrosis at baseline. The median CD4 count was 651, and 5.3% had HIV RNA ≤ 200. Immediate arm participants were at lower risk of developing increased fibrosis scores than deferred arm participants (hazard ratio [HR] = 0.66; 95% confidence interval [CI] = 0.57-0.78; P < 0.001) and more likely to have resolution of elevated baseline scores (HR 1.6; 95% CI 1.3-1.9; P < 0.001). Conclusions: Significant liver fibrosis was rare among ART-naïve HIV-positive persons with high CD4 counts. Our findings suggest a benefit of early ART in preventing the development of liver fibrosis.

Which HIV-infected adults with high CD4 T-cell counts benefit most from immediate initiation of antiretroviral therapy? A post-hoc subgroup analysis of the START trial.

BACKGROUND: Immediate initiation of antiretroviral therapy (ART) in asymptomatic adults with CD4 counts higher than 500 cells per µL, as recommended, might not always be possible in resource-limited settings. We aimed to identify subgroups of individuals who would benefit most from immediate treatment. METHODS: The START trial was a randomised controlled trial in asymptomatic, HIV-positive adults previously untreated with ART. Participants with CD4 counts higher than 500 cells per µL were randomly assigned to receive immediate ART or to defer ART until CD4 counts were lower than 350 cells per µL. The primary endpoint of the study was serious AIDS-defining illnesses or death from AIDS and serious non-AIDS illnesses or non-AIDS-related death. In this post-hoc analysis, we estimated event rates and absolute risk reduction with immediate versus deferred ART, overall and by subgroup. Subgroups were prespecified in the study protocol or formed post hoc on the basis of baseline characteristics associated with morbidity and mortality in people with HIV. For continuous characteristics, approximate terciles were chosen as subgroup cutoff points, unless different cutoffs were clinically meaningful (eg, age ≥50 years). We estimated the number needed to treat immediately with ART for 1 year to prevent one primary event. Heterogeneity in the absolute risk reduction between subgroups was assessed with bootstrap tests. The START trial is registered with ClinicalTrials.gov, number NCT00867048. FINDINGS: Between April 15, 2009, and Dec 23, 2013, we enrolled 4684 participants from 35 countries across five continents, of whom 2325 were assigned to immediate ART and 2359 were assigned to deferred ART. The primary endpoint occurred in 42 participants in the immediate ART group (0·58 events per 100 person-years) and 100 participants in the deferred ART group (1·37 events per 100 person-years). The absolute risk reduction was 0·80 (95% CI 0·48-1·13) per 100 person-years with immediate treatment, and the number needed to treat immediately to prevent one event was 126 (95% CI 89-208). Significant heterogeneity in absolute risk reduction with immediate ART was found across subgroups according to age (p=0·0022), CD4 to CD8 ratio (p=0·0007), and plasma HIV RNA viral load (p=0·033) at baseline. The highest absolute risk reductions and the lowest numbers needed to treat were found in participants aged 50 years or older, those with CD4 to CD8 ratios of less than 0·5, and those with plasma HIV RNA viral loads of 50 000 copies per mL or higher. INTERPRETATION: Asymptomatic, ART-naive adults with CD4 counts higher than 500 cells per µL who are older, have a low CD4 to CD8 ratio, or a high plasma HIV RNA viral load benefit most from immediate initiation of ART and should be prioritised for treatment. FUNDING: US National Institute of Allergy and Infectious Diseases.

Financial Incentives for Linkage to Care and Viral Suppression Among HIV-Positive Patients: A Randomized Clinical Trial (HPTN 065).

Importance: Achieving linkage to care and viral suppression in human immunodeficiency virus (HIV)-positive patients improves their well-being and prevents new infections. Current gaps in the HIV care continuum substantially limit such benefits. Objective: To evaluate the effectiveness of financial incentives on linkage to care and viral suppression in HIV-positive patients. Design, Setting, and Participants: A large community-based clinical trial that randomized 37 HIV test and 39 HIV care sites in the Bronx, New York, and Washington, DC, to financial incentives or standard of care. Interventions: Participants at financial incentive test sites who had positive test results for HIV received coupons redeemable for $125 cash-equivalent gift cards upon linkage to care. HIV-positive patients receiving antiretroviral therapy at financial incentive care sites received $70 gift cards quarterly, if virally suppressed. Main Outcomes and Measures: Linkage to care: proportion of HIV-positive persons at the test site who linked to care within 3 months, as indicated by CD4+ and/or viral load test results done at a care site. Viral suppression: proportion of established patients at HIV care sites with suppressed viral load (<400 copies/mL), assessed at each calendar quarter. Outcomes assessed through laboratory test results reported to the National HIV Surveillance System. Results: A total of 1061 coupons were dispensed for linkage to care at 18 financial incentive test sites and 39 359 gift cards were dispensed to 9641 HIV-positive patients eligible for gift cards at 17 financial incentive care sites. Financial incentives did not increase linkage to care (adjusted odds ratio, 1.10; 95% CI, 0.73-1.67; P = .65). However, financial incentives significantly increased viral suppression. The overall proportion of patients with viral suppression was 3.8% higher (95% CI, 0.7%-6.8%; P = .01) at financial incentive sites compared with standard of care sites. Among patients not previously consistently virally suppressed, the proportion virally suppressed was 4.9% higher (95% CI, 1.4%-8.5%; P = .007) at financial incentive sites. In addition, continuity in care was 8.7% higher (95% CI, 4.2%-13.2%; P < .001) at financial incentive sites. Conclusions and Relevance: Financial incentives, as used in this study (HPTN 065), significantly increased viral suppression and regular clinic attendance among HIV-positive patients in care. No effect was noted on linkage to care. Financial incentives offer promise for improving adherence to treatment and viral suppression among HIV-positive patients. Trial Registration: clinicaltrials.gov Identifier: NCT01152918.

Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per µL: secondary outcome results from a randomised controlled trial.

BACKGROUND: The effects of antiretroviral therapy on risk of severe bacterial infections in people with high CD4 cell counts have not been well described. In this study, we aimed to quantify the effects of immediate versus deferred ART on the risk of severe bacterial infection in people with high CD4 cell counts in a preplanned analysis of the START trial. METHODS: The START trial was a randomised controlled trial in ART-naive HIV-positive patients with CD4 cell count of more than 500 cells per µL assigned to immediate ART or deferral until their CD4 cell counts were lower than 350 cells per µL. We used Cox proportional hazards regression to model time to severe bacterial infection, which was defined as a composite endpoint of bacterial pneumonia (confirmed by the endpoint review committee), pulmonary or extrapulmonary tuberculosis, or any bacterial infectious disorder of grade 4 severity, that required unscheduled hospital admissions, or caused death. This study is registered with ClinicalTrials.gov, number NCT00867048. FINDINGS: Patients were recruited from April 15, 2009, to Dec 23, 2013. The data cutoff for follow-up was May 26, 2015. Of 4685 HIV-positive people enrolled, 120 had severe bacterial infections (immediate-initiation group n=34, deferred-initiation group n=86; median 2·8 years of follow-up). Immediate ART was associated with a reduced risk of severe bacterial infection compared with deferred ART (hazard ratio [HR] 0·39, 95% CI 0·26-0·57, p<0·0001). In the immediate-initiation group, average neutrophil count over follow-up was 321 cells per µL higher, and average CD4 cell count 194 cells per µL higher than the deferred-initiation group (p<0·0001). In univariable analysis, higher time-updated CD4 cell count (0·78, 0·71-0·85, p=0·0001) was associated with reduced risk of severe bacterial infection. Time-updated neutrophil count was not associated with severe bacterial infection. After adjustment for time-updated factors in multivariable analysis, particularly the CD4 cell count, the HR for immediate-initiation group moved closer to 1 (HR 0·84, 0·50-1·41, p=0·52). These results were consistent when subgroups of the severe bacterial infection composite were analysed separately. INTERPRETATION: Immediate ART reduces the risk of several severe bacterial infections in HIV-positive people with high CD4 cell count. This is partly explained by ART-induced increases in CD4 cell count, but not by increases in neutrophil count. FUNDING: National Institute of Allergy and Infectious Diseases National Institutes of Health, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales, Bundesministerium für Bildung und Forschung, European AIDS Treatment Network, Australian National Health and Medical Research Council, UK National Institute for Health Research and Medical Research Council, Danish National Research Foundation.

Comparison of the Outcomes of Individuals With Medically Attended Influenza A and B Virus Infections Enrolled in 2 International Cohort Studies Over a 6-Year Period: 2009-2015.

BACKGROUND: Outcome data from prospective follow-up studies comparing infections with different influenza virus types/subtypes are limited. METHODS: Demographic, clinical characteristics and follow-up outcomes for adults with laboratory-confirmed influenza A(H1N1)pdm09, A(H3N2), or B virus infections were compared in 2 prospective cohorts enrolled globally from 2009 through 2015. Logistic regression was used to compare outcomes among influenza virus type/subtypes. RESULTS: Of 3952 outpatients, 1290 (32.6%) had A(H1N1)pdm09 virus infection, 1857 (47.0%) had A(H3N2), and 805 (20.4%) had influenza B. Of 1398 inpatients, 641 (45.8%) had A(H1N1)pdm09, 532 (38.1%) had A(H3N2), and 225 (16.1%) had influenza B. Outpatients with A(H1N1)pdm09 were younger with fewer comorbidities and were more likely to be hospitalized during the 14-day follow-up (3.3%) than influenza B (2.2%) or A(H3N2) (0.7%; P < .0001). Hospitalized patients with A(H1N1)pdm09 (20.3%) were more likely to be enrolled from intensive care units (ICUs) than those with A(H3N2) (11.3%) or B (9.8%; P < .0001). However, 60-day follow-up of discharged inpatients showed no difference in disease progression (P = .32) or all-cause mortality (P = .30) among influenza types/subtypes. These findings were consistent after covariate adjustment, in sensitivity analyses, and for subgroups defined by age, enrollment location, and comorbidities. CONCLUSIONS: Outpatients infected with influenza A(H1N1)pdm09 or influenza B were more likely to be hospitalized than those with A(H3N2). Hospitalized patients infected with A(H1N1)pdm09 were younger and more likely to have severe disease at study entry (measured by ICU enrollment), but did not have worse 60-day outcomes.

Changing Clinician Practices and Attitudes Regarding the Use of Antiretroviral Therapy for HIV Treatment and Prevention.

As part of the HPTN 065 study in the Bronx, New York and Washington, the authors, we surveyed clinicians to assess for shifts in their practices and attitudes around HIV treatment and prevention. Antiretroviral therapy (ART)-prescribing clinicians at 39 HIV care sites were offered an anonymous Web-based survey at baseline (2010-2011) and at follow-up (2013). The 165 respondents at baseline and 141 respondents at follow-up had similar characteristics-almost 60% were female, median age was 47 years, two-thirds were physicians, and nearly 80% were HIV specialists. The percentage who reported recommending ART irrespective of CD4 count was higher at follow-up (15% versus 68%), as was the percentage who would initiate ART earlier for patients having unprotected sex with partners of unknown HIV status (64% versus 82%), and for those in HIV-discordant partnerships (75% versus 87%). In line with changing HIV treatment guidelines during 2010 to 2013, clinicians increasingly supported early ART for treatment and prevention.

Three months of weekly rifapentine and isoniazid for treatment of Mycobacterium tuberculosis infection in HIV-coinfected persons.

OBJECTIVE: Compare the effectiveness, tolerability, and safety of 3 months of weekly rifapentine and isoniazid under direct observation (3HP) versus 9 months of daily isoniazid (9H) in HIV-infected persons. DESIGN: Prospective, randomized, and open-label noninferiority trial. SETTING: The United States , Brazil, Spain, Peru, Canada, and Hong Kong. PARTICIPANTS: HIV-infected persons who were tuberculin skin test positive or close contacts of tuberculosis cases. INTERVENTION: 3HP versus 9H. MAIN OUTCOME MEASURES: The effectiveness endpoint was tuberculosis; the noninferiority margin was 0.75%. The tolerability endpoint was treatment completion; the safety endpoint was drug discontinuation because of adverse drug reaction. RESULTS: Median baseline CD4 cell counts were 495 (IQR 389-675) and 538 (IQR 418-729) cells/µl in the 3HP and 9H arms, respectively (P = 0.09). In the modified intention-to-treat analysis, there were two tuberculosis cases among 206 persons [517 person-years (p-y) of follow-up] in the 3HP arm (0.39 per 100 p-y) and six tuberculosis cases among 193 persons (481 p-y of follow-up) in the 9H arm (1.25 per 100 p-y). Cumulative tuberculosis rates were 1.01 versus 3.50% in the 3HP and 9H arms, respectively (rate difference: -2.49%; upper bound of the 95% confidence interval of the difference: 0.60%). Treatment completion was higher with 3HP (89%) than 9H (64%) (P < 0.001), and drug discontinuation because of an adverse drug reaction was similar (3 vs. 4%; P = 0.79) in 3HP and 9H, respectively. CONCLUSION: Among HIV-infected persons with median CD4 cell count of approximately 500 cells/µl, 3HP was as effective and safe for treatment of latent Mycobacterium tuberculosis infection as 9H, and better tolerated.

Lessons learned: Infrastructure development and financial management for large, publicly funded, international trials.

BACKGROUND/AIMS: Randomized clinical trials are widely recognized as essential to address worldwide clinical and public health research questions. However, their size and duration can overwhelm available public and private resources. To remain competitive in international research settings, advocates and practitioners of clinical trials must implement practices that reduce their cost. We identify approaches and practices for large, publicly funded, international trials that reduce cost without compromising data integrity and recommend an approach to cost reporting that permits comparison of clinical trials. METHODS: We describe the organizational and financial characteristics of The International Network for Strategic Initiatives in Global HIV Trials, an infectious disease research network that conducts multiple, large, long-term, international trials, and examine challenges associated with simple and streamlined governance and an infrastructure and financial management model that is based on performance, transparency, and accountability. RESULTS: It is possible to reduce costs of participants' follow-up and not compromise clinical trial quality or integrity. The International Network for Strategic Initiatives in Global HIV Trials network has successfully completed three large HIV trials using cost-efficient practices that have not adversely affected investigator enthusiasm, accrual rates, loss-to-follow-up, adherence to the protocol, and completion of data collection. This experience is relevant to the conduct of large, publicly funded trials in other disease areas, particularly trials dependent on international collaborations. CONCLUSION: New approaches, or creative adaption of traditional clinical trial infrastructure and financial management tools, can render large, international clinical trials more cost-efficient by emphasizing structural simplicity, minimal up-front costs, payments for performance, and uniform algorithms and fees-for-service, irrespective of location. However, challenges remain. They include institutional resistance to financial change, growing trial complexity, and the difficulty of sustaining network infrastructure absent stable research work. There is also a need for more central monitoring, improved and harmonized regulations, and a widely applied metric for measuring and comparing cost efficiency in clinical trials. ClinicalTrials.gov is recommended as a location where standardized trial cost information could be made publicly accessible.

Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection.

BACKGROUND: Data from randomized trials are lacking on the benefits and risks of initiating antiretroviral therapy in patients with asymptomatic human immunodeficiency virus (HIV) infection who have a CD4+ count of more than 350 cells per cubic millimeter. METHODS: We randomly assigned HIV-positive adults who had a CD4+ count of more than 500 cells per cubic millimeter to start antiretroviral therapy immediately (immediate-initiation group) or to defer it until the CD4+ count decreased to 350 cells per cubic millimeter or until the development of the acquired immunodeficiency syndrome (AIDS) or another condition that dictated the use of antiretroviral therapy (deferred-initiation group). The primary composite end point was any serious AIDS-related event, serious non-AIDS-related event, or death from any cause. RESULTS: A total of 4685 patients were followed for a mean of 3.0 years. At study entry, the median HIV viral load was 12,759 copies per milliliter, and the median CD4+ count was 651 cells per cubic millimeter. On May 15, 2015, on the basis of an interim analysis, the data and safety monitoring board determined that the study question had been answered and recommended that patients in the deferred-initiation group be offered antiretroviral therapy. The primary end point occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 person-years), as compared with 96 patients in the deferred-initiation group (4.1%; 1.38 events per 100 person-years), for a hazard ratio of 0.43 (95% confidence interval [CI], 0.30 to 0.62; P<0.001). Hazard ratios for serious AIDS-related and serious non-AIDS-related events were 0.28 (95% CI, 0.15 to 0.50; P<0.001) and 0.61 (95% CI, 0.38 to 0.97; P=0.04), respectively. More than two thirds of the primary end points (68%) occurred in patients with a CD4+ count of more than 500 cells per cubic millimeter. The risks of a grade 4 event were similar in the two groups, as were the risks of unscheduled hospital admissions. CONCLUSIONS: The initiation of antiretroviral therapy in HIV-positive adults with a CD4+ count of more than 500 cells per cubic millimeter provided net benefits over starting such therapy in patients after the CD4+ count had declined to 350 cells per cubic millimeter. (Funded by the National Institute of Allergy and Infectious Diseases and others; START ClinicalTrials.gov number, NCT00867048.).

Risk assessment for healthcare workers after a sentinel case of rabies and review of the literature.

BACKGROUND: After a case of rabies, healthcare workers (HCWs) had fear of contagion from the infected patient. Although transmission of rabies to HCWs has never been documented, high-risk exposures theoretically include direct contact of broken skin and/or mucosa with saliva, tears, oropharyngeal secretions, cerebrospinal fluid, and neural tissue. Urine/kidney exposure posed a concern, as our patient's renal transplant was identified as the infection source. METHODS: Our risk assessment included (1) identification of exposed HCWs; (2) notification of HCWs; (3) risk assessment using a tool from the local health department; (4) supplemental screening for urine/kidney exposure; and (5) postexposure prophylaxis (PEP) when indicated. RESULTS: A total of 222 HCWs including diverse hospital staff and medical trainees from university affiliates were evaluated. Risk screening was initiated within 2 hours of rabies confirmation, and 95% of HCWs were assessed within the first 8 days. There were 8 high-risk exposures related to broken skin contact or mucosal splash with the patient's secretions, and 1 person without high-risk contact sought and received PEP outside our hospital. Nine HCWs (4%) received PEP with good tolerance. Due to fear of rabies transmission, additional HCWs without direct patient contact required counseling. There have been no secondary cases after our sentinel rabies patient. CONCLUSIONS: Rabies exposure represents a major concern for HCWs and requires rapid, comprehensive risk screening and counseling of staff and timely PEP. Given the lack of human-to-human rabies transmission from our own experience and the literature, a conservative approach seems appropriate for providing PEP to HCWs.

When to start antiretroviral therapy: the need for an evidence base during early HIV infection.

BACKGROUND: Strategies for use of antiretroviral therapy (ART) have traditionally focused on providing treatment to persons who stand to benefit immediately from initiating the therapy. There is global consensus that any HIV+ person with CD4 counts less than 350 cells/µl should initiate ART. However, it remains controversial whether ART is indicated in asymptomatic HIV-infected persons with CD4 counts above 350 cells/µl, or whether it is more advisable to defer initiation until the CD4 count has dropped to 350 cells/µl. The question of when the best time is to initiate ART during early HIV infection has always been vigorously debated. The lack of an evidence base from randomized trials, in conjunction with varying degrees of therapeutic aggressiveness and optimism tempered by the risks of drug resistance and side effects, has resulted in divided expert opinion and inconsistencies among treatment guidelines. DISCUSSION: On the basis of recent data showing that early ART initiation reduces heterosexual HIV transmission, some countries are considering adopting a strategy of universal treatment of all HIV+ persons irrespective of their CD4 count and whether ART is of benefit to the individual or not, in order to reduce onward HIV transmission. Since ART has been found to be associated with both short-term and long-term toxicity, defining the benefit:risk ratio is the critical missing link in the discussion on earlier use of ART. For early ART initiation to be justified, this ratio must favor benefit over risk. An unfavorable ratio would argue against using early ART. SUMMARY: There is currently no evidence from randomized controlled trials to suggest that a strategy of initiating ART when the CD4 count is above 350 cells/µl (versus deferring initiation to around 350 cells/µl) results in benefit to the HIV+ person and data from observational studies are inconsistent. Large, clinical endpoint-driven randomized studies to determine the individual health benefits versus risks of earlier ART initiation are sorely needed.

The association between symptoms and microbiologically defined response to tuberculosis treatment.

RATIONALE: The lack of consistent associations between clinical outcomes and microbiological responses to therapy for some infectious diseases has raised questions about the adequacy of microbiological endpoints for tuberculosis treatment trials. OBJECTIVES: To evaluate the association between symptoms and microbiological response to tuberculosis treatment. METHODS: We performed a retrospective analysis of four clinical trials in which participants had culture-positive tuberculosis, standardized symptom assessment, and follow-up mycobacterial cultures. Two trials (studies 22 and 23) followed participants to identify recurrent tuberculosis; participants in studies 27 and 28 were only followed to treatment completion. MEASUREMENTS AND MAIN RESULTS: This analysis included 1,978 participants; 39 (2.0%) had culture-confirmed treatment failure, and 75 (3.9%) had culture-confirmed recurrence. Productive cough was associated with indices of increased mycobacterial burden at diagnosis (acid-fast smear grade, severity of radiographic abnormalities). Fever and sweats improved rapidly with treatment, whereas productive cough decreased more slowly and was present in 20% of visits after treatment completion. During treatment, study participants with productive cough more often had concurrent culture positivity compared with those without productive cough (studies 22 and 23: adjusted odds ratio, 1.80; 95% confidence interval [CI], 1.33-2.44). Finally, symptoms during the latter part of treatment and follow-up were associated with culture-confirmed treatment failure and recurrence in studies 22 and 23 (for cough: adjusted hazard ratio, 2.07; 95% CI, 1.23-3.49; for fever: adjusted hazard ratio, 5.05; 95% CI, 2.76-9.19). CONCLUSIONS: There are consistent relationships between symptoms and microbiological indices of tuberculosis, including measures of mycobacterial burden at baseline, culture positivity during treatment, and time to culture-confirmed treatment failure and recurrence.

Biomarkers and bacterial pneumonia risk in patients with treated HIV infection: a case-control study.

BACKGROUND: Despite advances in HIV treatment, bacterial pneumonia continues to cause considerable morbidity and mortality in patients with HIV infection. Studies of biomarker associations with bacterial pneumonia risk in treated HIV-infected patients do not currently exist. METHODS: We performed a nested, matched, case-control study among participants randomized to continuous combination antiretroviral therapy (cART) in the Strategies for Management of Antiretroviral Therapy trial. Patients who developed bacterial pneumonia (cases) and patients without bacterial pneumonia (controls) were matched 1∶1 on clinical center, smoking status, age, and baseline cART use. Baseline levels of Club Cell Secretory Protein 16 (CC16), Surfactant Protein D (SP-D), C-reactive protein (hsCRP), interleukin-6 (IL-6), and d-dimer were compared between cases and controls. RESULTS: Cases (n = 72) and controls (n = 72) were 25.7% female, 51.4% black, 65.3% current smokers, 9.7% diabetic, 36.1% co-infected with Hepatitis B/C, and 75.0% were on cART at baseline. Median (IQR) age was 45 (41, 51) years with CD4+ count of 553 (436, 690) cells/mm(3). Baseline CC16 and SP-D were similar between cases and controls, but hsCRP was significantly higher in cases than controls (2.94 µg/mL in cases vs. 1.93 µg/mL in controls; p = 0.02). IL-6 and d-dimer levels were also higher in cases compared to controls, though differences were not statistically significant (p-value 0.06 and 0.10, respectively). CONCLUSIONS: In patients with cART-treated HIV infection, higher levels of systemic inflammatory markers were associated with increased bacterial pneumonia risk, while two pulmonary-specific inflammatory biomarkers, CC16 and SP-D, were not associated with bacterial pneumonia risk.

Progress realized: trends in HIV-1 viral load and CD4 cell count in a tertiary-care center from 1999 through 2011.

BACKGROUND: HIV-1 RNA and CD4 cell counts are important parameters for HIV care. The objective of this study was to assess the overall trends in HIV-1 viral load and CD4 cell counts within our clinic. METHODS: Patients with at least one of each test performed by the Infectious Diseases Laboratory from 1999 through 2011 were included in this analysis. By adapting a novel statistical model, log(10) HIV-1 RNA means were estimated by month, and log(10)-transformed HIV-1 RNA means were estimated by calendar year. Geometric means were calculated for CD4 cell counts by month and calendar year. Log(10) HIV-1 RNA and CD4 cell count monthly means were also examined with polynomial regression. RESULTS: There were 1,814 individuals with approximately 25,000 paired tests over the 13-year observation period. Based on each patient's final value of the year, the percentage of patients with viral loads below the lower limit of quantitation rose from 29% in 1999 to 72% in 2011, while the percentage with CD4 counts <200 cells/µL fell from 31% to 11%. On average annually, the mean HIV-1 RNA decreased by 86 copies/mL and the mean CD4 counts increased by 16 cells/µL. For the monthly means, the correlations (R(2)) from second-order polynomial regressions were 0.944 for log(10) HIV-1 RNA and 0.840 for CD4 cell counts. CONCLUSIONS: Marked improvements in HIV-1 RNA suppression and CD4 cell counts were achieved in a large inner-city population from 1999 through 2011. This success demonstrates that sustained viral control with improved immunologic status can be a realistic goal for most individuals in clinical care.

Is frequent CD4+ T-lymphocyte count monitoring necessary for persons with counts >=300 cells/µL and HIV-1 suppression?

Among patients infected with human immunodeficiency virus (HIV), those with HIV-1 RNA <200 copies/mL and CD4 counts ≥300 cells/µL had a 97.1% probability of maintaining durable CD4 ≥200 cells/µL for 4 years. When non-HIV causes of CD4 lymphopenia were excluded, the probability rose to 99.2%. Our data support less frequent CD4 monitoring during viral suppression.

Considerations in the rationale, design and methods of the Strategic Timing of AntiRetroviral Treatment (START) study.

BACKGROUND: Untreated human immunodeficiency virus (HIV) infection is characterized by progressive depletion of CD4+ T lymphocyte (CD4) count leading to the development of opportunistic diseases (acquired immunodeficiency syndrome (AIDS)), and more recent data suggest that HIV is also associated with an increased risk of serious non-AIDS (SNA) diseases including cardiovascular, renal, and liver diseases and non-AIDS-defining cancers. Although combination antiretroviral treatment (ART) has resulted in a substantial decrease in morbidity and mortality in persons with HIV infection, viral eradication is not feasible with currently available drugs. The optimal time to start ART for asymptomatic HIV infection is controversial and remains one of the key unanswered questions in the clinical management of HIV-infected individuals. PURPOSE: In this article, we outline the rationale and methods of the Strategic Timing of AntiRetroviral Treatment (START) study, an ongoing multicenter international trial designed to assess the risks and benefits of initiating ART earlier than is currently practiced. We also describe some of the challenges encountered in the design and implementation of the study and how these challenges were addressed. METHODS: A total of 4000 study participants who are HIV type 1 (HIV-1) infected, ART naïve with CD4 count > 500 cells/µL are to be randomly allocated in a 1:1 ratio to start ART immediately (early ART) or defer treatment until CD4 count is <350 cells/µL (deferred ART) and followed for a minimum of 3 years. The primary outcome is time to AIDS, SNA, or death. The study had a pilot phase to establish feasibility of accrual, which was set as the enrollment of at least 900 participants in the first year. RESULTS: Challenges encountered in the design and implementation of the study included the limited amount of data on the risk of a major component of the primary endpoint (SNA) in the study population, changes in treatment guidelines when the pilot phase was well underway, and the complexities of conducting the trial in a geographically wide population with diverse regulatory requirements. With the successful completion of the pilot phase, more than 1000 participants from 100 sites in 23 countries have been enrolled. The study will expand to include 237 sites in 36 countries to reach the target accrual of 4000 participants. CONCLUSIONS: START is addressing one of the most important questions in the clinical management of ART. The randomization provided a platform for the conduct of several substudies aimed at increasing our understanding of HIV disease and the effects of antiretroviral therapy beyond the primary question of the trial. The lessons learned from its design and implementation will hopefully be of use to future publicly funded international trials.

Current approaches to tuberculosis in the United States.

Tuberculosis is a major threat to global health, infecting a third of the world's population. In the United States, however, control of tuberculosis has been increasingly successful. Only 3.2% of the US population is estimated to have latent tuberculosis and there are only 11,000 cases annually of active disease. More than half the cases in this country occur in individuals born outside the United States. Human immunodeficiency virus coinfection is not a major factor in the United States, since only approximately 10% of cases are coinfected. Drug resistance is also uncommon in this country. Because the United States has more resources for the diagnosis, therapy, and public health control of tuberculosis than many regions of the world, and because many hospitals have more cases of clinically significant nontuberculous mycobacteria than tuberculosis, the management approaches to tuberculosis need to be quite different in this country than in other regions. The resurgence in interest in developing new tools and the investment in public health infrastructure will hopefully be sustained in the United States so that the effect of tuberculosis on the US population will continue to diminish, and these new tools and approaches can be adapted to both high and low prevalence areas to meet the global challenge.