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, in each issue of Clinical Infectious Diseases.
Standardized CMV Viral Load Testing in Solid-Organ Transplant Recipients
Reviewed by Sheila Mitsuma, MD
Cytomegalovirus (CMV) is a significant cause of morbidity and mortality in solid-organ transplant recipients. CMV viral load testing, performed using quantitative PCR, is routinely used for diagnosis and to help guide therapy. Until recently, viral load testing has not been standardized and performance characteristics of available assays varied, precluding meaningful comparison of test results among transplantation centers.
In November 2010, the World Health Organization (WHO) approved an international standard for CMV nucleic acid amplification techniques, composed of a standard quantity of virus. Investigators present the results of the first clinical study using an assay calibrated to this standard in the June 1, 2013 issue of Clinical Infectious Diseases.
In this study, 1,522 plasma samples from 267 solid-organ transplant recipients with non-severe CMV disease obtained in a prior international, randomized trial, were retested using the first Food and Drug Administration-approved CMV quantitative PCR platform and calibrated to the WHO standard. The primary outcome measured was time to resolution of disease. Pretreatment viral loads < 18,200 IU/ml were associated with faster resolution of disease (median 7 vs. 12 days; AHR 1.56, p = 0.001). Mean baseline viral loads were higher in those diagnosed with tissue invasive disease compared to those with CMV syndrome (20,893 IU/ml vs. 9120 IU/ml). The association between pretreatment viral load and disease resolution remained significant for both those with known tissue invasive disease and CMV syndrome. No association between the rate of viral load decline and disease resolution was found.
While these associations are not novel, this study represents a step forward. Calibration to the international standard and reporting test results in international units will facilitate comparison of test results among institutions and aid in determining the predictive value of viral load measures. Clinicians will need to remain mindful that specimen type, specimen handling, DNA extraction techniques, and other features of testing platforms may continue to vary among centers.
(Razonable et al. Clin Infect Dis. 2013;56(11):1546-1553.)
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HCV Therapy: At the Threshold of Interferon-Free Options?
Reviewed by Ed Dominguez, MD
Boceprevir and telaprevir were approved in the U.S. in 2011 for use in combination with interferon alfa-2a and ribavirin in hepatitis C virus (HCV) genotype 1 infection. Patients infected with this genotype account for at least 70 percent of chronic U.S. cases. However, up to 40 percent who complete this triple-therapy regimen may relapse, and there is a low genetic barrier to resistance with the approved protease inhibitors. These drugs are also narrow spectrum. Two articles in the May 16 issue of The New England Journal of Medicine describe four phase III multicenter trials of sofosbuvir, a nucleotide polymerase inhibitor with pan-genotypic activity.
In the first article, researchers describe two trials evaluating sofosbuvir in patients naïve to prior HCV therapy. One trial, NEUTRINO, was a 12-week single-group, open-label trial of patients infected with genotypes 1, 4, 5, or 6 who received sofosbuvir plus peginterferon alfa-2a and ribavirin. The sustained virologic response (SVR) at 12 weeks after the end of treatment in 327 patients was 90 percent. Importantly, 89 percent of the patients were infected with genotype 1 and 9 percent with genotype 4. The other trial, FISSION, was a non-inferiority trial comparing 12 weeks of sofosbuvir plus ribavirin (n=256) to 24 weeks of peginterferon alfa-2a plus ribavirin (n=243) in patients infected with genotypes 2 or 3. For the 499 patients in this trial, SVR was 67 percent. In sofosbuvir patients with genotype 3, SVR was 56 percent; in those with genotype 2, SVR was 97 percent.
In the other journal article, investigators in two additional trials evaluated sofosbuvir in patients infected with genotypes 2 or 3 for whom peginterferon was not an option. The POSITRON trial, a 12-week randomized trial, compared sofosbuvir plus ribavirin (n=207) to matching placebo (n=71). SVR in the sofosbuvir arm was 78 percent versus 0 percent in the placebo arm. FUSION was a blinded, active-control trial of peginterferon non-responders that evaluated two treatment durations: 12 weeks of sofosbuvir plus ribavirin followed by four weeks of matching placebo (n=103), and 16 weeks of sofosbuvir plus ribavirin (n=98). SVR was higher in the 16 week sofosbuvir arm compared to the 12 week arm (73 percent versus 50 percent).
Importantly, in all four trials, which were also drug-company funded, the attrition rate was 2 percent or less in patients receiving sofosbuvir. Common side effects (>25 percent) included fatigue, headache, nausea, and insomnia. An accompanying editorial noted the strong “selling points” of a sofosbuvir-ribavirin regimen: pan-genotypic activity, manageable side effects of low incidence, and short duration of treatment. While it is too soon to proclaim the demise of interferon, HCV therapy is at the threshold of interferon-free options.
(Jacobson et al. N Engl J Med. 2013; 368:1867-1877; Lawitz et al. N Engl J Med. 2013; 368:1878-1887; and Holmberg et al. N Engl J Med. 2013; 368:1859-1861.)
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An Argument for Less Frequent CD4 Monitoring in HIV-Infected Patients on HAART
Reviewed by Nina Kim, MD, MSc
The Department of Health and Human Services currently advises extending the interval of CD4 cell count testing to 6-12 months in clinically stable patients whose CD4 counts have reached a safer range (generally agreed to be >200 cells/mm3) and whose HIV viral level remains effectively suppressed on highly active antiretroviral therapy (HAART). A study from the Veterans Affairs Medical Center in Washington, D.C., in the May 1 issue of Clinical Infectious Diseases not only bolsters this recommendation but suggests frequent CD4 monitoring is superfluous in some patients with high baseline CD4 counts.
The authors identified 832 patients who had two or more paired viral level and CD4 counts with initial values <200 copies/ml and >200 cells/mm3 respectively, with no more than 390 days between consecutive results. Most of these patients (93 percent) maintained their CD4 ≥200 cells/mm3 during a median period of 7.7 years. Those whose initial CD4 counts were 200-299 cells/mm3 were more likely to experience a CD4 dip to <200 cells/mm3 compared to those with higher baseline CD4; the group with the lower baseline accounted for 70 percent of the 61 patients who dipped. Chemotherapy, interferon treatment, surgery, and severe infection were among the main non-HIV causes of CD4 lymphopenia. Notably, the Kaplan-Meier probability of maintaining CD4 ≥200 cells/mm3 was 97.1 percent at year four for those with initial CD4 ≥300 cells/mm3 and when non-HIV lymphopenic events were excluded, this probability rose to 99.2 percent.
These findings clearly call into question our custom of repeated CD4 monitoring on HAART in those with robust CD4 counts. The authors make a persuasive argument for simplifying to annual CD4 testing, which would not only result in cost savings (estimated at >$40,000 for their center alone) but also reduce episodes of anxiety when patients encounter minor fluctuations in CD4, particularly when such variations are unlikely to influence our clinical management.
(Gale et. al. Clin Infect Dis. 2013;56: 1340-43.)
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Penicillin to Prevent Recurrent Cellulitis: More Questions than Answers?
Reviewed by Christopher J. Graber, MD, MPH
In a recent randomized trial published in The New England Journal of Medicine, penicillin was demonstrated to be more effective than placebo as prophylaxis against recurrent cellulitis of the lower extremity, but issues related to exactly which patients would benefit from prophylaxis limit the study’s application to clinical practice.
The study randomized 274 patients in the United Kingdom and Ireland who had had at least two episodes of lower extremity cellulitis within the prior 24 months to receive penicillin 250 mg twice a day or placebo for 12 months, with a primary endpoint of cellulitis recurrence.
During the first year of follow-up (i.e., while patients were taking study medication), 22 percent of participants in the penicillin arm experienced cellulitis recurrence, compared to 37 percent in the placebo arm (hazard ratio 0.55, 95 percent confidence interval 0.35-0.86, p=0.01). The risk reduction (measured out to three years) did not persist past the time of prophylaxis. Factors that were associated with failure of prophylaxis included many characteristics that would suggest one consider prophylaxis in the first place: at least three prior episodes of cellulitis (OR 3.23), pre-existing edema (OR 1.83), and body mass index (BMI) greater than 33 (OR 2.05). No comparison was made between the treatment and placebo arms for these specific risk factors. Adverse events were similar in both arms; while rates of Clostridium difficile-associated diarrhea were not specifically determined, overall rates of diarrhea were similar in the two arms.
This study provides some hope for improvement in our management of a particularly difficult clinical problem, but questions remain before antibiotic prophylaxis for recurrent cellulitis can be routinely practiced. In particular, the effects of higher doses on efficacy and the side effect profile in patients with the risk factors for prophylaxis failure in this study deserve further exploration.
(Thomas et al. New Engl J Med. 2013;368(18):1695-703)
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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:
- Cutaneous Leishmaniasis Acquired in the United States: A Slow Northward Creep
- Vulvovaginal Candidiasis Recalcitrant to Fluconazole Therapy
- Cerebrospinal Fluid Pleocytosis After Fever-Associated Status Epilepticus
- Prehospital Management of Sepsis
- Left Ventricular Assist Device Infections
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