Primecuts – This Week In The Journals

May 21, 2013

By Gloria Lan, MD

Faculty Peer Reviewed

This week, Angelina Jolie surprised the world with her confession of having had a prophylactic double mastectomy because of a BRCA-1 mutation. This led to an outpouring of support from breast cancer organizations and celebrities and has landed her on the cover of next month’s Time Magazine entitled “The Angelina Jolie Effect.” Many have predicted that because of Angelina’s brave story, more women will investigate their own family histories and probe further into the issue of genetic testing. News and health organizations have also increased their efforts in educating women about the BRCA-1 mutation and about which women need genetic testing. In other news, the future of Kepler, NASA’s planet-hunting space observatory, which has identified 132 planets since its launch in 2009, has been called into question after a part that aims the spacecraft has stopped working. Kepler had recently discovered three planets that resemble Earth in size and are close enough to the stars they orbit to have liquid water, but not so close that the water is boiling. Many scientists believe that planets with liquid water may harbor life. As we contemplate these new discoveries and the idea of life outside of Earth, we look toward the new discoveries being made in medicine in this week’s Primecuts.

This week, the New England Journal published two articles about sofosbuvir, a nucleotide analogue HCV polymerase inhibitor. The first article looked at sofosbuvir for patient with hepatitis C virus (HCV) genotypes 2 or 3 who could not be treated with standard therapy. A substantial number of patients with HCV genotype 2 or 3 do not receive the standard-of-care treatment, pegylated interferon with ribavirin for 24 weeks, because of contraindications or adverse effects. This article describes two multicenter, randomized trials were done to assess the effect of sofosbuvir with ribavirin in patients with chronic HCV genotype 2 or 3. The POSITRON trial was a placebo-controlled trial that compared 12 weeks of sofosbuvir and ribavirin with placebo in patients who had chosen to discontinue or not initiate interferon treatment because of adverse effects or medical contraindications. The results of this trial were that 78% of patients treated with sofosbuvir and ribavirin had a sustained virologic response (93% of patients with genotype 2 and 61% of patients with genotype 3) compared to 0% of patients on placebo. The FUSION trial was an active-control study that looked at patients who had not previously had a response to interferon treatment and compared 12 weeks of sofosbuvir and ribavirin and 4 weeks of placebo with 16 weeks of sofosbuvir and ribavirin. The results were a statistically significant higher rate of sustained virologic response in the patient treated for 16 weeks. (1)

The second article studied patients who had high levels of HCV RNA during screening and had never been started on HCV treatment. This article also reports two multicenter trials to assess efficacy of sofosbuvir. The NEUTRINO trial was a single-group, open-label study that included patients with HCV genotype 1, 4, 5, or 6. All patients received sofosbuvir, ribavirin, and peginterferon alfa-2a for 12 weeks. The study showed a 90% sustained virologic response rate. The FISSION trial was a randomized, open-label, active-control study of patients with genotype 2 or 3 that assigned patients to 12 weeks of sofosbuvir plus ribavirin or 24 weeks of peginterferon alfa-2a plus ribavirin. This study showed that the sofosbuvir group was noninferior to the peginterferon group. (2) These two articles represent exciting new advancements for HCV patients, especially those who are unable to tolerate interferon treatment. The current data show that sofosbuvir causes a higher percentage of sustained virologic response in genotype 2 than genotype 3, thus better regimens must be explored for genotype 3. Currently, other drugs being tested include protease inhibitors and host-targeting antiviral agents. Given the many side effects with interferon treatment, many studies are also combining the various medications to achieve the highest potency without using interferon. (3)

From a fairly well established infection to a new infection, we turn to Asia. Human infections with avian influenza A viruses usually occur after contact with poultry and can cause a wide array of illness, from conjunctivitis to multiorgan failure. H7 viruses usually cause milder disease such as conjunctivitis or mild respiratory symptoms. In February and March 2013, three patients were hospitalized with severe lower respiratory tract infections of unknown etiology. Throat swabs were collected from these three patients and genomic sequencing revealed a novel H7N9 avian influenza. All three patients developed ARDS and eventually expired due to refractory hypoxemia. Genomic studies have shown the H7N9 strain to have certain mutations that may increase its affinity towards humans and enhance viral replication within the respiratory tract. As of now, no vaccine exists for this strain of avian influenza, and more research is currently being done regarding this potentially fatal disease. (4) The consequences of a new influenza A that is different from known human influenza A strains is hard to predict. It is unclear whether this strain is will cause sporadic infection from an animal source or whether it has the possibility for human-to-human spread. In addition, the scope of the illness is still unknown, as patients who currently have the disease may have undetected or asymptomatic diseases. There is even more concern caused by the fact that this strain has genetic mutations that make it likely to be asymptomatic in zoonotic infection and have higher affinity towards mammals. (5) These facts have increased media attention throughout the world and have caused high degrees of worry, leading many to avoid travels to China for the time being.

In other news, the BRUISE CONTROL study was done comparing continuing Coumadin to bridging with unfractionated heparin before cardiac pacemaker or ICD implantation. The study was a multicenter, single-blind, randomized, controlled trial. Patients were eligible if they were on Coumadin and had a greater than 5% annual predicted thromboembolism risk. In the continued-warfarin group, 3.5% of patients had a pocket hematoma as compared to 16% in the heparin-bridging group. There were no significant differences in incidence of thromboembolism or death. (6) This study suggests that patients may not need bridging with heparin before ICD or pacemaker implantations, as bridging with heparin may cause increased morbidity than continuing Coumadin.

And finally, the USPSTF updated their guidelines regarding the use of calcium and vitamin d in the primary prevention of fractures. Two systematic evidence reviews and a meta-analysis were done to assess the efficacy of calcium and vitamin d supplementation on bone health. The conclusions were that the evidence is currently insufficient to assess the risks and benefits of calcium and vitamin d supplementation for primary prevention of fractures, there is insufficient evidence to assess the risks of benefits of daily supplementation if vitamin D3 400 IU or greater and calcium 1000 mg or higher. However, the USPSTF recommends against doses of vitamin d3 lower than 400 IU and calcium lower than 1000 mg. (7)

A few more interesting reads from the week:

1. Sandra M Swain, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. The Lancet Oncology, Volume 14, Issue 6, Pages 461 – 471, May 2013  http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70130-X/abstract

This double-blind randomized trial assigned patients to receive either pertuzumab, trastuzumab, and docetaxel or the same regimen with pertuzumab replaced by placebo. The study showed a significant improvement in overall survival in patients who were in the pertuzumab group, with no increase in adverse events.

2. Matthew Shirley, et al. Sturge-Weber Syndrome and Port-Wine Stains Caused by Somatic Mutation in GNAQ. http://www.nejm.org/doi/full/10.1056/NEJMoa1213507

Whole genome sequencing of DNA was done on paired samples of affected and normal tissue from patients with Sturge-Weber Syndrome, a single-nucleotide variant in GNAQ was discovered in both the affected and non-affected tissues of patient with Sturge-Weber, but not in any of the controls.

3. American Urological Association Guidelines: PSA

The AUA recommends against PSA screening for men under the age of 40, does not recommend screening for men 40-54 at average risk, and recommends shared decision making for men 55-69. The panel also recommends screening every two years instead of annually.

Dr. Gloria Lan is a 2nd year resident, Internal Medicine, at NYU Langone Medical Center

Peer reviewed by Neil Shapiro, Editor-In-Chief, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

1. Ira M. Jacobson, et al. Sofosbuvir for Hepatitis C Genotype 2 or 3 in Patients without Treatment options. N Engl J Med 2013; 368:1867-1877  http://www.natap.org/2013/EASL/EASL_08.htm

2. Eric Lawitz, et al. Sofosbuvir for Previously Untreated Chronic Hepatitis C Infection. N Engl J Med 2013; 368:1878-1887 http://www.natap.org/2013/EASL/nejmoa1214853.pdf

3. T. Jake Liang and Marc G. Ghany. Current and Future Therapies for Hepatitis C Infection. N Engl J Med 2013; 368: 1907-1917

4. Rongbao Gao, et al. Human Infection with a Novel Avian-Origin Influenza A (H7N9) Virus. N Engl J Med 2013; 368: 1888-1897

5. Timothy Uyeki, Global Concerns Regarding Novel Influenza A (H7N9) Virus Infections. N Engl J Med 2013; 368: 1862-1864

6. David H. Birnie, Pacemaker or Defibrillator Surgery without Interruption of Anticoagulation. http://www.nejm.org/doi/full/10.1056/NEJMoa1302946

7. Virginia A. Moyer, Vitamin D and Calcium Supplementation to Prevent Fractures in Adults: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2013;158(9):691-696

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