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July/August 2016
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. Isavucanzole as Another Option for Treatment of Mucormycosis 
Reviewed by Lauren Richey, MD, MPH

The prognosis for mucormycosis, an opportunistic fungal infection associated with immunosuppressed patients, is poor, and mortality rates can exceed 90 percent. Present therapy consists of antifungal treatment, generally with amphotericin B, in combination with surgical debridement and treatment of the underlying disorder.  Few other treatment options currently exist. The recent VITAL study, published in Lancet Infectious Diseases, tested the use of isavuconazole, a new triazole antifungal with activity against Mucorales species and high oral bioavailability, in patients with mucormycosis.  The drug has both an oral and intravenous formulation.

In this study, 37 patients with proven or probable mucormycosis were recruited and treated with isavuconazole, including both those with pulmonary and non-pulmonary disease. The majority, 21 (57 percent), were in the primary treatment group, but the total group also included 11 with refractory disease and five patients who were intolerant to other antifungals. An independent data review committee determined the primary efficacy endpoint of overall response at day 42. Four patients (11 percent) had a partial response, 16 (43 percent) had stable disease, one (3 percent) had progression of disease, 13 (35 percent) had died, and three (8 percent) had missing data. A high rate of adverse events was seen (95 percent). The most common were vomiting, diarrhea, nausea, pyrexia, and constipation, with elevated hepatic enzymes seen in less than 10 percent of patients.

A matched case control analysis was also performed using patients from the FungiScope registry. Cases were matched on three variables: hematologic disease, severe disease (defined as central nervous system involvement or dissemination), and surgical treatment within seven days of antifungal treatment initiation. The authors found a similar crude mortality rate between the groups at day 42, 33 percent for cases and 41 percent for controls.

This study provides evidence that isavuconazole has a role in the treatment of both primary and refractory disease with mucormycosis, with outcomes that are likely similar to amphotericin. The study is limited by being single-armed and non-randomized, but it does suggest another treatment option.

(Marty et al. Lancet Infect Dis. 2016;16(7):828–837.)

Neurologic Signs and Symptoms Common in Acute HIV Infection
Reviewed by Kelly Cawcutt, MD

HIV can invade the central nervous system rapidly after infection, but knowledge is limited regarding neurologic manifestations of acute HIV infection beyond fulminant diseases, such as Guillain-Barré syndrome, Bell’s palsy, encephalitis, or myelitis, which may not represent the true spectrum of disease. To better define the neurologic complications, the authors of a recent Neurology article prospectively evaluated adult patients with acute HIV from a single center in Thailand who were started on early antiretroviral therapy (ART) and evaluated via structured neurologic evaluations over 12 weeks.

Of the 197 patients enrolled, 139 had complete data with a median estimated duration of HIV infection of 19 days (range of 3-56). Of these, 73 (53 percent) had at least one positive neurologic finding reported or identified. Only one patient had a fulminant neurologic process identified as Guillain-Barré. There were 245 positive neurologic findings, with 96 percent categorized as mild. The most common findings were defined as cognitive (33 percent) and motor (34 percent). Approximately half (49 percent) of the neurologic findings were noted at the time of HIV diagnosis, prior to initiation of ART, and improved with one month of treatment. Of note, no structural abnormalities were found. Patients with neurologic findings demonstrated a statistically significant higher viral load as compared to those without (p=0.006).

Overall, the study demonstrates that mild neurologic findings are common in the first 12 weeks after acute HIV infection, are correlated with higher viral loads, and usually improve after initiation of ART. Severe manifestations, or fulminant neurologic disease, are rare in acute HIV infection.

The study is limited with the ability to comment on association but not causality. There is a lack of control arms with uninfected controls or infected participants not started on ART, thus the authors cannot attribute neurologic findings directly to HIV or improvements to ART. Illicit drug use may also have confounded the results. The study does however raise important awareness about the possibility of early neurologic manifestations and warrants future studies to better define these associations.

(Hellmuth et al. Neurology. 2016;87(2):148-54.)

Prevention of Mother-to-Child Hepatitis B Transmission with Tenofovir
Reviewed by George R. Thompson III, MD

Vertical transmission of hepatitis B virus (HBV) occurs in 80-90 percent of infants born to mothers who are positive for hepatitis B e antigen (HBeAg). The efficacy of postnatal passive and active immunization reduces the rate of mother-to-child transmission, however this practice fails a significant number of infants. Prenatal antiviral treatment has the potential to further reduce transmission.

The results of a recent study evaluating the efficacy tenofovir disoproxil fumarate (TDF) for the prevention of maternal hepatitis B transmission were recently published in the New England Journal of Medicine. In this study, 200 women were randomly assigned in a 1:1 ratio to an oral dose of 300 mg of TDF or usual care without antiviral therapy beginning 30-32 weeks of gestation until postpartum week 4. Infants in both groups received 200 IU of hepatitis B immune globulin IM and 10 ug of the HBV vaccine within 12 hours of birth. The same dose of active or passive immunization was administered at week 4 and an additional HBV vaccination at week 24.

In the primary outcomes, the rate of mother-to-child transmission was significantly lower in the TDF group than in the control group, in both the intention to treat analysis (5 percent vs. 18 percent, p=0.007) and the per-protocol analysis (0 percent vs. 7 percent, p=0.01). Maternal and infant safety profiles were similar in both groups with no significant differences in birth-defect rates between groups.  Maternal HBV serologic outcomes (loss or seroconversion of HBeAg or HBsAg) did not significantly differ between groups.

This study illustrates the utility of TDF for the prevention of hepatitis B transmission with a favorable side effect profile. Although the serologic status did not differ between groups, this was not unexpected given the relatively short (approximately 12 weeks) duration of therapy.

(Pan et al. N Engl J Med.  2016;374:2324-34.)

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:

August 1
  • Improving Antibiotic Use in Primary Care Outpatients
  • Why Is Candida glabrata More Likely Than Candida albicans to Be Resistant to Antifungal Agents?
July 15
  • Is your Patient Encephalopathic Because of His or Her Antibiotic Therapy?
  • Candidalysin 
July 1
  • Vancomycin Loading Dose: Is it Safe?
  • Case Vignette: Eosinophilic Pnemonia - Do Not Inhale Flies!
  • Case Vignette: Simultaneous Complicated Pasturella multocida and Bartonella henselae Infections?

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