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September 2014
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IDSA Journal Club
In this feature, a panel of IDSA members identifies and critiques important new studies in the current literature that have a significant impact on the practice of infectious diseases medicine.

Click here for the previous edition of Journal Club. For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, MD, FIDSA, in each issue of Clinical Infectious Diseases.

The Era of Interferon-Free Therapy Arrives for HIV-infected Patients with Chronic HCV
Reviewed by Nina Kim, MD, MSc

Death from end-stage liver disease is a major cause of non-AIDS-related mortality among HIV-infected individuals, with an overwhelming majority of these deaths attributable to chronic hepatitis C virus (HCV) infection. However, treatment of HCV in HIV/HCV co-infected patients has historically been infrequent due to the poor efficacy as well as complexity and toxicity of interferon-based therapy. The advent of direct-acting antiviral (DAA) combination therapy for HCV has changed this history. The PHOTON-1 study of the all-oral regimen of sofosbuvir plus ribavirin, published in the July 19 HIV-themed issue of the Journal of the American Medical Association, is the first to prove the concept that interferon-free therapy is safe and efficacious in this population.

In this open-label phase 3 trial, patients received sofosbuvir, a nucleotide NS5B polymerase inhibitor, with ribavirin (weight-based dosing). The majority (n=114) were treatment-naive patients with genotype 1 HCV infection who received 24 weeks of therapy. The remainder had genotype 2 or 3 infection and received either 12 weeks (treatment-naive, n=68) or 24 weeks (treatment-experienced, n=41). The median CD4 count ranged from 562 to 581 cells/mm3 and 95 percent were on antiretroviral therapy. Ultimately this regimen was safe, well-tolerated, and achieved high rates of sustained virologic response (SVR, HCV viral level <25 IU/ml 12 weeks post-treatment): 76 percent for genotype 1 and 67-94 percent for genotype 2 or 3 patients – success rates that are notably comparable to those observed in the mono-infection trials.

This study heralds the beginning of the end of the interferon era and hopefully more widespread treatment of co-infected patients. But as impressive as 76 percent may be compared with the historic 25-30 percent SVR with 48 weeks of peginterferon and ribavirin in genotype 1 co-infected patients, the promise of greater than 90 percent efficacy with multi-class DAA combinations of 12 weeks or shorter is just around the corner.

(Sulkowski et al. JAMA. 2014;312:353-61.)

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 Impact of Time to Antibiotic Administration on Mortality in Patients with Febrile Neutropenia
Reviewed by Zeina Kanafani, MD, MS

Febrile neutropenia is a significant cause of mortality in patients on chemotoxic drugs. The time to antibiotic administration (TTA) is a known determinant of mortality in patients with sepsis, with current guidelines recommending a TTA of one hour or less with appropriate antibiotics. However the impact of TTA on mortality and the optimal TTA for patients on chemotherapy with febrile neutropenia is still not well established.

In the July 2014 issue of Antimicrobial Agents and Chemotherapy, researchers prospectively analyzed 307 febrile neutropenia episodes in 169 subjects. Bloodstream infections were the most common cause of fever (37.4 percent) with E. coli accounting for 41.7 percent of infections followed by coagulase negative staphylococci (31.3 percent). During the study period, 29 patients died (9.4 percent). Cox regression was used to determine predictors of mortality at 28 days. There was a statistically significant association between TTA and mortality (1.66 hours in the mortality group vs. 0.33 hours in the survival group; p < 0.001). Each hour of delay in TTA was associated with an 18 percent increase in mortality (hazard ratio, 1.19; 95 percent confidence interval, 1.10-1.26). Additional independent predictors of mortality included a relapsing underlying disease, bloodstream infection, and high-risk Multinational Association for Supportive Care in Cancer (MASCC) score.

The authors also performed a subgroup analysis comparing mortality in patients with a TTA of < 30 minutes to those with a TTA between 31 and 60 minutes. They found that 28-day mortality was significantly decreased in those with a TTA of < 30 minutes (3.0 percent vs. 18.1 percent; log-rank p = 0.0002).

The study highlights that early treatment with antibiotics in patients with febrile neutropenia significantly decreases mortality. These findings suggest that having a target TTA of less than 30 minutes could have a favorable impact on the survival rate of these patients.

(Rosa and Goldani. Antimicrob Agents Chemother. 2014;58(7):3799-3803.)

The Good (Reduced Mortality), the Bad (One More Metric), and the Timely: Antibiotic Timing and Severe Sepsis

Reviewed by Nirav Patel, MD

Timely administration of antibiotic therapy in the setting of sepsis is intuitive and evidence-based, however a large confirmatory study had not yet been performed. In the August 2014 issue of Critical Care Medicine, researchers describe a retrospective analysis of a large dataset to ascertain the association between the timing of antibiotic administration and mortality.

The study was performed using the large Surviving Sepsis Campaign (SSC) database. After excluding patients who did not receive antibiotics, who were previously on antibiotics prior to the development of sepsis, and those missing antibiotic administration time, 17,990 patients were included in the study. Investigators reviewed the time of first antibiotic dose compared to the time of presentation. The statistical analysis used risk factor modeling to determine 51 covariates considered by the investigators as possible confounders.

The results showed that hospital mortality was 32 percent in the first hour, dropped to 28.1 percent in the second hour, and then increased to 39.6 percent in those receiving antibiotics after six hours. Adjusting for Sepsis Severity Score, ICU admission source, and geographic region, the odds ratio for mortality increased to 1.52 (1.36-1.70, p<0.001) if antibiotics were administered more than six hours after presentation, with a probability of mortality linearly increasing from 24.6 percent to 33.1 percent.

Clear strengths of the study include the sample size and the robust dataset, however there are concerns regarding the inclusion criteria used in the SSC as well as potentially missed confounders in the final analysis. Additionally, the focus on administration of the first antibiotic only and the lack of consideration of bug-drug mismatches is somewhat limiting to the practicing clinician. More broadly, there is concern about the use of such data to generate quality metrics that may lead to inappropriate antibiotic use. Timely use of antibiotics in patients with sepsis clearly reduces mortality; how it translates into the current quality and regulatory domains remains to be seen.

(Ferrer et al. Crit Care Med. 2014;42(8):1749–1755.)

Cefazolin: A More Tolerable Option than Nafcillin for Outpatient Parenteral Therapy for S. aureus Disease?
Reviewed by Christopher J. Graber, MD, MPH, FIDSA

The optimal antibiotic for completing treatment for complicated methicillin-sensitive Staphylococcus aureus (MSSA) infections via outpatient parenteral therapy (OPAT) is a matter of debate. Some experts suggest that the semisynthetic penicillins (e.g., oxacillin or nafcillin) should be preferred over cefazolin due to the fact that some MSSA strains produce type A β-lactamase (which degrades cefazolin more than semisynthetic penicillins) that may lead to an inoculum effect, though it is not clear if this phenomenon leads to worse outcomes clinically. Cefazolin is typically much more inexpensive, requires less frequent dosing, and is generally well-tolerated.

A recently published article in Clinical Infectious Diseases compares the tolerability of cefazolin to nafcillin in the outpatient setting in the treatment of MSSA infection. In an analysis of 509 OPAT episodes (366 nafcillin, 119 cefazolin) from 2007 to 2011, the authors found a significantly higher premature discontinuation rate with nafcillin as compared to cefazolin (hazard ratio, 2.81; 95 percent confidence interval, 1.26-3.68), although the Kaplan-Meier curves did not diverge until after about two weeks of therapy. A significantly higher proportion of patients on nafcillin developed rash (13.9 percent vs. 4.2 percent), renal dysfunction (11.4 percent vs. 3.3 percent), and liver function abnormalities (8.1 percent vs. 1.6 percent). Clinical cure rates were not specifically assessed.

While this article suggests that cefazolin is more tolerable in the outpatient setting than nafcillin, semisynthetic penicillins should still be considered (at least in the initial phases of management) as primary options in cases involving a deep focus of infection and high bacterial load (e.g., endocarditis) or in cases involving the central nervous system, as cefazolin penetrates the blood-brain barrier poorly.

(Youngster et al. Clin Infect Dis. 2014;59(3):369-75.)

Patience Matters: Reduction in Mortality with Delayed ART in Treatment-Naive AIDS Patients with Cryptococcal Meningitis
Reviewed by Manie Beheshti, MD

Current data generally supports early initiation of antiretroviral therapy (ART) in all HIV-infected patients. However, due to the challenge of balancing the benefits of ART with the potentially fatal risks of immune reconstitution inflammatory syndrome (IRIS), the optimal time to start ART in newly diagnosed AIDS patients with cryptococcal meningitis has been unclear. The 2010 IDSA guidelines for treatment of cryptococcal meningitis highlight the uncertainty but broadly recommend initiating ART “2–10 weeks after commencement of initial antifungal treatment (B-III).”

In the June 26 issue of the New England Journal of Medicine, investigators evaluated the difference between early and late ART in AIDS patients with cryptococcal meningitis. Their study included 177 treatment-naive HIV-infected adults in Uganda and South Africa with cryptococcal meningitis randomly assigned to two groups: early ART (started one-to-two weeks after diagnosis) and delayed ART (started five weeks after diagnosis). Due to the limited availability of flucytosine, all patients were treated with 14 days amphotericin B and high-dose fluconazole (800 mg), followed by consolidation fluconazole therapy.

Mortality at 26 weeks (the primary end point) was significantly higher in the early versus delayed ART group: 45 percent versus 30 percent (hazard ratio [HR], 1.73; 95 percent confidence interval [CI], 1.06-2.82; P=0.03). The gap was most notable two-to-five weeks after diagnosis (HR, 3.10; 95 percent CI, 1.37-7.00; P=0.007). In the subgroup analysis, mortality was significantly higher in patients with cerebrospinal fluid (CSF) white blood cell (WBC) counts less than 5 cells/mm3 (HR, 3.87). Due to the substantial mortality difference, study enrollment was stopped early. All other outcomes were similar between the two groups.

These findings shed light on an area of previous uncertainty and strongly support the delay of ART until five weeks after start of amphotericin B-based therapy for cryptococcal meningitis, especially in those without significant CSF pleocytosis (<5 WBCs/mm3) at the time of presentation.

(Boulware et al. New Eng J Med. 2014;370:2487-2498.)

Double the Risk of Suicidality with Efavirenz-Containing ART

Reviewed by Brian R. Wood, MD

Efavirenz, a frequent component of initial antiretroviral therapy (ART) for HIV-1 infection around the world (often as part of the single-tablet regimen tenofovir-emtricitabine-efavirenz), frequently causes central nervous side effects such as insomnia, dizziness, and vivid dreams. For most, those effects are mild and short-lived. More concerning are post-marketing reports of psychiatric adverse events, which have led to warnings about worsening depression and suicidality. New data recently published in the Annals of Internal Medicine support a causal relationship between efavirenz and suicidality and suggest caution when prescribing the medication.

Investigators pooled data from four AIDS Clinical Trials Group randomized controlled trials of efavirenz-containing versus efavirenz-free regimens (most of the efavirenz-free regimens were protease inhibitor-based). They performed a retrospective comparison of reported suicidality, defined as documented suicidal ideation, attempt, or completion. Overall, 3,241 participants were randomized to an efavirenz-containing regimen and 2,091 to an efavirenz-free regimen. Participants were primarily young men, and one-third had documented psychiatric history or pre-study psychoactive medication use. Median follow-up was 96 weeks.

The primary intent-to-treat analysis demonstrated higher likelihood of suicidality in the efavirenz group (hazard ratio, 2.28; 95 percent confidence interval, 1.27 to 4.10; P = 0.006) as well as shorter time to suicidality (highest risk occurred in the first 24 weeks after ART initiation). Eight of nine completed suicides occurred in the efavirenz group. In multivariate analysis, additional factors associated with suicidality included: history of injection drug use, psychiatric history or recent psychoactive medication use, and low body weight.

This new robust data demonstrate that suicidality, although uncommon overall, is twice as frequent with efavirenz-containing as compared to efavirenz-free ART. Ideally, efavirenz should be avoided in individuals with a history of psychiatric illness or at high risk for depression or suicidality; if other options are not readily available, close monitoring for worsening psychiatric symptoms is warranted.

(Mollan et al. Ann Intern Med. 2014;161(1):1-10.)

For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, MD, in each issue of Clinical Infectious Diseases:

August 15

  • Rhizopus on the Linen
  • Transmission of Hepatitis E Virus Infection by Transfusion

August 1

  • Nebulized Colistin Treatment of Bronchiectasis Patients With Chronic Pseudomonas Infection
  • Cats, Humans, and Bovine Tuberculosis

July 15

  • Chronic Granulomatous Disease: A Potentially Lethal Combination of Immunodeficiency and Excess Inflammation
  • Tissue Destruction in Amebiasis: Chew on It
  • Streptococcus Pyogenes: The Path to Enhanced Virulence

July 1

  • Influenza C Virus

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