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April 25, 2018


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.

Christopher J. Graber, MD, MPH, FIDSA

Taking the Pulse of Pulse-Dose Fidaxomicin

Reviewed by Christopher J. Graber, MD, MPH, FIDSA

The new IDSA/SHEA clinical practice guidelines for the management of Clostridium difficile infection (CDI) now recommend a 10-day course of either oral vancomycin 125 mg four times daily or fidaxomicin 200 mg twice daily in the management of an initial episode of CDI and no longer recommend metronidazole for milder presentations. For recurrent episodes, a tapering dose of oral vancomycin followed by a pulsed-dose (i.e., every 2-3 day) regimen is recommended as a potential option, with the thought that pulse dosing balances anti-CDI activity with microbiome reconstitution. The standard 10-day dose of fidaxomicin is also mentioned as an option for recurrent CDI, but no mention is made of fidaxomicin pulse dosing. 

A recent randomized open-label study published in The Lancet Infectious Diseases evaluated an innovative pulse-dosed regimen of fidaxomicin (200 mg twice daily on days 1-5, then once daily on alternate days from day 7 to 25) in comparison to the standard 10-day oral vancomycin 125 mg four times daily course among 364 hospitalized adults with CDI age 60 and older across 86 European hospitals. It was the first episode of CDI within the prior three months for approximately 80 percent of patients (second episode for ~15 percent). Sustained clinical cure 30, 40, 55, and 90 days after treatment was higher in the fidaxomicin arm: 70 percent versus 59 percent sustained clinical cure at 30 days, odds ratio 1.62 (95 percent confidence interval 1.04-2.54). Time to CDI recurrence was longer after the end of treatment with fidaxomicin with no difference in adverse events. There was a trend, however, to longer time to resolution of diarrhea with fidaxomicin (34 versus 22 hours, P = 0.068).

The accompanying editorial notes that this is the third randomized study in which fidaxomicin has been observed to have an approximately 10 percent higher sustained clinical cure rate for CDI than vancomycin. One of the primary barriers to increased use of fidaxomicin has been cost, though oral vancomycin capsules are also relatively expensive in most markets. Interestingly, the pulse-dosed fidaxomicin regimen used in this study is the equivalent amount of medication in the standard 10-day regimen, thus partially balancing out cost differences between pulse-dosed regimens of fidaxomicin and vancomycin.  

(Guery et al. Lancet Infect Dis. 2018;18:296-307.)

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Brian R. Wood, MDIs Dual ART the Future of HIV Treatment?

Reviewed by Brian R. Wood, MD

Two-drug (dual) antiretroviral therapy (ART) may offer reduced side effects and dramatic cost savings over three-drug ART, and the first two-drug combination for maintenance therapy (the combination tablet dolutegravir/rilpivirine) was recently approved by the Food and Drug Administration (FDA). Numerous studies of other two-drug combinations are ongoing. One such option, which also may be co-formulated into a single tablet in the future, is dolutegravir with lamivudine. Two recent pilot trials, both published in Clinical Infectious Diseases, assessed this option for initial and for maintenance therapy.

In ACTG 5353, a phase II, single-arm study, investigators enrolled treatment-naïve adults with HIV RNA below 500,000 copies/mL, no nucleoside reverse-transcriptase inhibitor (NRTI) or integrase resistance, and no hepatitis B. Participants (n = 120) received daily dolutegravir plus lamivudine. At 24 weeks, 90 percent had HIV RNA below 50 copies/mL, with no significant difference between those with pre-treatment HIV RNA above versus below 100,000 copies/mL. Three individuals developed virologic failure, all of whom had evidence of poor adherence based on dolutegravir drug levels. In one of these cases, the NRTI mutation M184V and the integrase mutation mixture R263R/K were detected at the time of virologic failure. While resistance only occurred in this one individual and the R263K mutation has minimal impact on dolutegravirsusceptibility, this finding is notable because it is a glaring difference between these results and results of the large phase III clinical trials of dolutegravir plus two NRTIs, in which zero instances of resistance occurred.

As a contrast, in the ASPIRE study, investigators recruited adults living with HIV who had routinely suppressed HIV RNA levels on standard three-drug ART; participants also had creatinine clearance above 50 mL/min, no history of virologic failure, no NRTI or integrase resistance, and no hepatitis B. They were randomized to continue their three-drug regimen or to switch to dolutegravir plus lamivudine. Of 89 individuals included in the analysis, there was no significant difference in treatment failure (which included virologic failure, loss to follow-up, or treatment discontinuation) at 24 weeks (6.8 percent in the dual ART arm versus 6.7 percent in the triple ART arm). Additionally, the proportion with HIV RNA below 50 copies/mL by FDA snapshot analysis at 24 or 48 weeks was not statistically different. Unlike in the above trial, the one person with virologic failure did not develop resistance mutations.

So, is two-drug ART the future? Accumulating evidence suggests that two-drug ART may be effective, especially with a drug that has a relatively high barrier to resistance (dolutegravir or boosted darunavir) combined with a once-daily, well-tolerated second drug (such as lamivudine or rilpivirine). The data for dual ART as maintenance therapy for select patients is stronger than the data for initial therapy, and the one case of resistance in the treatment-naïve trial indicates that further study on the risk of resistance in this setting is needed. The necessity of two-drug options for initial therapy could be debated now that we have effective and generally well-tolerated options that include tenofovir alafenamide. However, evaluations of ART regimens that may be less toxic and less costly are welcome, and more two-drug oral and also injectable options are anticipated in the future (e.g., a phase III study of long-acting injectable rilpivirine plus long-acting injectable cabotegravir as maintenance therapy recently launched).

(Taiwo et al. Clin Infect Dis. 2017 Dec 14.

(Taiwo et al. Clin Infect Dis. 2017 Dec 21.)

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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

April 15

  • Cutibacterium (Propionibacterium) Prosthetic Valve Endocarditis
  • Case Vignette: Aseptic Hepatic Abscesses
  • Case Vignette: Varicella Zoster Transmission via a Transplanted Lung

April 1

  • The Human Archaeome: Opening a New Door to Our Understanding of Patients and Their Microbial Partners and Adversaries
  • Therapeutic Drug Monitoring May Not Be of Value in Patients Receiving Isavuconazonium, the Prodrug of Isavuconazole
  • The Flint River, Chlorine, and Legionnaires’ Disease

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