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.
Treatment of Symptomatic Congenital CMV: Is Six Months Better Than Six Weeks?
Reviewed by Terri Stillwell, MD
Cytomegalovirus (CMV) is the most common cause of congenital viral infection. Many neonates with congenital CMV are asymptomatic, with only about 10 percent exhibiting symptoms at birth. However, despite being asymptomatic, some infected neonates can go on to develop hearing loss. Additionally, those that are symptomatic at birth can have progression of existing symptoms or development of additional complications later in life.
Previous studies have found that, for symptomatic neonates with central nervous system (CNS) involvement treated within the first month of life, six weeks of antiviral therapy led to improved hearing and neurologic outcomes. A recent New England Journal of Medicine article goes a step further, evaluating the benefit of six months of treatment in comparison to six weeks of treatment.
From June 2008 through May 2011, investigators randomized 96 infants with symptomatic congenital CMV infection to one of two arms: 47 received six weeks of valganciclovir plus four and a half months of placebo; 49 received six months of valganciclovir. The study’s primary endpoint evaluated change in “best-ear” hearing at six months. Secondary end points included change in hearing and neurologic outcomes at 12 and 24 months; medication side effects were also assessed.
While the change in six-month best-ear hearing was the same for both treatment groups, significant differences were seen when assessing the secondary endpoints. When adjusting for baseline CNS involvement, total-ear hearing at 12 months was more likely maintained or improved in those treated with six months of valganciclovir. Also, with CNS-adjusted results, those treated with six months of valganciclovir had significantly higher scores on neurologic testing at 24 months. No significant medication side effects were seen between the two groups.
This study suggests that six months of valganciclovir in symptomatic congenital CMV infection has a positive effect on long-term outcomes. Additional studies are needed to determine if comparable benefit can be achieved in asymptomatic infections.
(Kimberlin et al. N Engl J Med. 2015;372:933-943.)
A New Tenofovir Formulation: Fewer Renal and Bone Effects?
Tenofovir disoproxil fumarate is included in four of the five regimens currently recommended for HIV-infected patients naïve to antiretroviral therapy. Although highly potent, safe, and widely used, tenofovir disoproxil fumarate causes nephrotoxicity (including proximal tubular injury) in a small but significant number of patients, and has also been linked to decreases in bone mineral density.
Reviewed by George R. Thompson III, MD
Tenofovir disoproxil fumarate is metabolized to tenofovir and thereafter metabolized in cells to tenofovir-diphosphate (the active drug). High plasma levels of tenofovir have been associated with the toxicities mentioned above, and thus a novel tenofovir prodrug, tenofovir alafenamide, was developed. This formulation results in four times higher intracellular concentrations allowing for much lower doses to be administered, potentially reducing side-effects.
In a recent article published online in The Lancet, researchers reported the results of two phase 3, double-blind comparative trials of tenofovir alafenamide versus tenofovir disoproxil fumarate (both coformulated with elvitegravir, cobicistat, and emtricitabine). The findings showed similar antiviral activity of both formulations with a significant reduced effect of tenofovir alafenamide compared to tenofovir disoproxil fumarate on patient glomerular filtration rate (p<0.0001), tubular proteinuria (p<0.0001), and bone mineral density (p<0.0001).
The high rate of virologic success in these trials, with a concurrent reduction in both renal and bone effects observed in patients treated with tenofovir alafenamide, suggests this may become the preferred formulation.
(Sax et al. Lancet. published online: April 15, 2015.)
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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: June 15
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