Primecuts – This Week In The Journals

July 31, 2012

By Benjamin P. Geisler, MD, MPH

Faculty peer-reviewed

July 28th was World Hepatitis Day. Just three days prior, a group of researchers from Johns Hopkins published a paper in JAMA on HCV/HIV co-infected patients.[1] This study demonstrated an independent correlation between hepatic fibrosis stage and a composite endpoint of end-stage liver disease, hepatocellular carcinoma, or death. As the authors note, these results support starting highly active antiretroviral treatment (HAART) for HIV in “most coinfected” patients.

Also last week, the 19th International AIDS Conference took place in Washington, D.C. Speakers included Hillary Rodham Clinton, Laura Bush, Bill Gates, and Elton John. Coincidentally, The Lancet started a series of papers on HIV-positive men who have sex with men [2] and JAMA also featured the 2012 Recommendations of the International Antiviral  Society-USA Panel  for the treatment of adult HIV patients based on systematic PubMed and Embase searches.[3] The recommendations include offering HAART to all patients regardless of CD4 count while monitoring not just CD4 count and viral load, but also engagement in care, HAART adherence and drug resistance. The recommended initial regimens are two nucleosides/nucleotides (tenofovir/emtricitabine or abacavir/lamivudine) plus a nonnucleoside reverse transcriptase inhibitor (efavirenz), a ritonavir-boosted protease inhibitor (atazanavir or darunavir), or an integrase strand transfer inhibitor (raltegravir).

In clinic, you might be asked about Preexposure Prophylaxis for HIV Prevention (PrEP), another hot topic these days. Krakower and Mayer reviewed PrEP in an on online-first Annals article.[4] They conclude that PrEP does not provide complete protection (44 to 75% depending on the setting). This narrative review underlines a currently controversial option for prevention. Importantly, there are no “real world” data yet. If you need to know more, I recommend reading the entire article, for this is a topic that will continue to be heavily discussed.

Meet the newest targeted therapy on the oncology block: dabrafenib for BRAFV600E-mutated metastasized melanoma. Hauschild et al. published a randomized controlled trial [5] in The Lancet with a total of 250 previously untreated stage IV or unresectable stage III melanoma patients. The trial compared dabrafenib to a standard chemo regimen (dacarbazine) and was non-blinded and randomized in a 3:1 fashion, an often recurring trial design for new oncology agents thought to have great potential. After a median follow-up of 4.9 months, there were not enough deaths in either group to calculate median overall survival (mortality 11 vs. 14%; hazard ratio [HR] 0.6 with a 95% confidence interval [95%CI] of 0.3-1.5). Median progression-free survival was 5.1 vs. 2.7 months (HR 0.3; 95%; CI: 0.2 to 0.1).
Dabrafenib selectively inhibits the gene product of the BRAFV600E mutation, a supposedly oncogenic variant of the B-RAF kinase. This mutation was present in 48% of the screened patients in this trial (own calculation). However, there is already a targeted therapy for the exact same indication, vemurafenib, which in contrast to dabrafenib is already FDA-approved. The pivotal trial [6] comparing vemurafenib to the same chemo as the present trial, demonstrated 84 vs 64% overall survival (HR: 0.4; 95% CI: 0.3 to 0.6) and median progression-free survival of 5.3 vs 1.6 months (HR: 0.3; 95% CI: 0.2-0.3). Taken together, the results of these two phase-III trials warrant a head-to-head trial or at least an indirect treatment comparison meta-analysis. However, neither agent might provide more than a temporary relief as tumor cells might, analogous to the HIV virus, adapt to the therapy.

Staying in Europe and on the same topic, a systematic review with meta-analysis in BMJ estimated the burden of cutaneous melanoma that can be attributed to tanning salons.[7] Boniol, Autier, and Boyle pooled the results of case-control, cohort, and cross-sectional studies and found a relative risk of 1.2 for squamous cell carcinoma, and 1.1 for basal cell carcinoma. They fitted a mixed model to quantify the effect of each indoor tanning session per year, which came out as almost 0.02 additional melanomas per session. Initiating indoor tanning before 35 years of age almost doubled the risk. The attributable burden of indoor tanning in Europe was estimated as 3,418 cases per year – 5.4% of all melanoma cases. What this study adds to previous research is proof of a dose-dependent relationship and that age of initiation seems to play a role. In conclusion, sun-deprived young doctors and everybody else should refrain from using sunbeds.

Two studies in this week’s Archives highlighted the importance of taking a social history; they investigated the role of loneliness in functional decline and death in a nationally representative study of people age 60 and older and the effect of living alone at age 45 years and above on the cardiovascular event and death risk.[8, 9] In the two studies, 43% reported feeling lonely and 19% were living alone, respectively. Unsurprisingly, loneliness was a predictor of functional decline – less activities of daily living, and same or less mobility – and death. Living alone was associated with higher four-year mortality (14 vs 11%; p<0.01) and cardiovascular death (9 vs 7%; p<0.01). However, living alone was only associated with increased mortality among middle-aged and not among elderly patients.

Next, Primecuts heads to the emergency department: Mass General’s cardiac imaging program published the results of a multi-center trial of coronary CT angiography for low-to-intermediate risk acute coronary syndrome (ACS) in this week’s New England Journal.[10] ED patients with signs and symptoms suggestive of ACS but without a history of coronary disease, acute ischemic EKG changes, or initially positive troponins were randomly assigned to either coronary CT angiography or standard of care. The comparator strategy may or may not include cycling troponins, repeating rest or doing a stress EKG, treadmill testing, other advanced imaging such as SPECT, referring for a conventional angiography, or just “watchful waiting” which occurred in 2% of CT and 22% of standard of care patients. The study’s endpoints were length of stay, disposition, cardiovascular complications at day 28, and costs. CT angiography was associated with a shorter stay (mean 23 vs 31 hours; p<0.001), shorter time to diagnosis (10 vs 19 hours, p<0.001), and higher discharge rates from the main ED (most patients in the comparison group left from the observation unit, which was not defined as belonging to the ED or to inpatient wards). Interestingly, there was no statistically significant difference in costs ($4,289 vs. $4,060; p=0.65). ACS was only confirmed in 2% of cases. An editorialist sees no role for CT-based angiography for this patient group, in fact sees no role for testing in the ED or observation at all.[11] Short-fused New Yorkers demanding a CT for faster discharge should be informed about the additional radiation of CT angiography.

One last thing: In a special paper in this week’s New England Journal, a group at Harvard examined whether mortality rates changed after a Medicaid expansion in Arizona, New York, and Maine in 2001 and 2002.[12] They compared mortality rates of these States from the Centers for Disease Control and Prevention to four neighboring States without any changes in their Medicaid eligibility (Nevada and New Mexico combined, Pennsylvania, and New Hampshire). Over five years post-enactment (compared to five years prior), Medicaid’s enrollees increased by almost one forth or 2% of the overall sample of childless adults aged 19-64 years. Associated with this was a 6% decrease in mortality rates. The decrease was strongest in non-whites, in people 35 years and over, and in counties with higher levels of poverty. While the mortality rates decreased in New York, there was no statistically significant difference in Arizona and Maine. Comment: this study was obviously motivated by the Affordable Care Act’s intended Medicaid expansion which, as the Supreme Court ruled, cannot be forced upon the States by threatening to cut their existing Medicaid funding. What the study teaches us is that Medicaid expansion might, on the whole, reduce mortality rates, but that your mileage will be likely to vary from state to state.

Benjamin P. Geisler, MD, MPH is an intern in NYU’s Categorical Residency Program in Internal Medicine

Peer reviewed by Danise Schiliro-Chuang, MD Assistant Professor of Medicine and Contributing Editor Clnical Correlations,

Image courtesy of Wikimedia Commons

References

  1. Limketkai, B.N., et al., Relationship of liver disease stage and antiviral therapy with liver-related events and death in adults coinfected with HIV/HCV. JAMA, 2012. 308(4): p. 370-8.
    http://jama.jamanetwork.com/article.aspx?articleid=1221699
  2. http://www.thelancet.com/series/hiv-in-men-who-have-sex-with-men
  3. Thompson, M.A., et al., Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA, 2012. 308(4): p. 387-402.
    http://jama.jamanetwork.com/article.aspx?articleid=1221704
  4. Krakower, D. and K.H. Mayer, What Primary Care Providers Need to Know About Preexposure Prophylaxis for HIV Prevention: A Narrative Review. Ann Intern Med, 2012.
    http://annals.org/article.aspx?articleID=1221642
  5. Hauschild, A., et al., Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet, 2012.
    http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60868-X/fulltext
  6. Chapman, P.B., et al., Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med, 2011. 364(26): p. 2507-16.
    http://www.nejm.org/doi/full/10.1056/NEJMoa1103782
  7. Boniol, M., et al., Cutaneous melanoma attributable to sunbed use: systematic review and meta-analysis. BMJ, 2012. 345: p. e4757.
    http://www.bmj.com/content/345/bmj.e4757?view=long&pmid=22833605
  8. Perissinotto, C.M., I. Stijacic Cenzer, and K.E. Covinsky, Loneliness in older persons: a predictor of functional decline and death. Arch Intern Med, 2012. 172(14): p. 1078-84.
    http://archinte.jamanetwork.com/article.aspx?articleid=1188033
  9. Udell, J.A., et al., Living Alone and Cardiovascular Risk in Outpatients at Risk of or With Atherothrombosis. Arch Intern Med, 2012. 172(14): p. 1086-1095.
    http://archinte.jamanetwork.com/article.aspx?articleid=1188041
  10. Hoffmann, U., et al., Coronary CT angiography versus standard evaluation in acute chest pain. N Engl J Med, 2012. 367(4): p. 299-308.
    http://www.nejm.org/doi/full/10.1056/NEJMe1206040
  11. Redberg, R.F., Coronary CT Angiography for Acute Chest Pain. N Engl J Med, 2012. 367(4): p. 375-6.
    http://www.nejm.org/doi/full/10.1056/NEJMe1206040
  12. Sommers, B.D., K. Baicker, and A.M. Epstein. Mortality and Access to Care among Adults after State Medicaid Expansions. N Engl J Med, 2012.
    http://www.nejm.org/doi/full/10.1056/NEJMsa1202099

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