Primecuts – This Week In The Journals

July 9, 2012

Jenny Gartshteyn, MD

Faculty Peer Reviewed

It’s the week of July 4th 2012, people gather on the boardwalks and rooftops, fireworks light up the sky – silent tribute to how far art and science have advanced since the first discovery of fireworks in China in the 10th century. Paralleling the advancement in pyrotechnics from year to year is the growing body of medical research and knowledge. In this spirit of progress, let’s review some of the more exciting medical findings from this week.

In this week’s issue of The Lancet, a new once-daily combination pill for initial treatment of HIV was evaluated in a phase 3, non-inferiority trial. [1] Today, the preferred initial therapy for HIV consists of two nucleoside/nucleotide reverse transcriptase inhibitors (generally emtricitabine and tenofovir) combined with a third agent (a non-nucleoside reverse transcriptase inhibitor vs a protease or integrase inhibitor). This controlled, randomized, double-blinded phase 3 trial compared the gold-standard, emtricitabine(FTC)/tenofovir(TDF)/efavirenz(EFV) – sold under the brand name Atripla – with an experimental regimen of emtricitabine (FTC)/tenofovir(TDF)/ elvitegravir(EVG, new integrase inhibitor) and an investigational CYP3A4 inhibitor cobicistat (COBI). 707 North American patients with non-resistant HIV-1 (and >5000 RNA copies/mL) that have never before been treated, with preserved eGFR>70ml/min, were randomized to receive one of the two medication regimens with the primary endpoint of viral suppression (HIV RNA<50 copies/mL) at week 48. Intention to treat analysis was performed with a pre-specified inferiority margin of 12%, the primary endpoint was achieved in 84.1% of patients in the atripla group and 87.6% in the experimental group, with a 3.6% difference (95% CI -1.6 to 8.8%). The virologic response was seen earlier in the experimental group and persisted up to week 16, with no significant difference seen after week 16. 2% of patients developed resistance to the antiretroviral regimen in each of the two groups. Meanwhile, discontinuation rates were similar (12% in experimental group and 15% in the control group) with side-effects of nausea being more common in the experimental drug group (23% vs 19%), whereas side-effects dizziness, headace and rash were more common in the control group (likely 2/2 efavirenz). This study suggests that there may soon be a new one-tablet regimen for the initial treatment of HIV infection in patients with non-resistant HIV and a preserved renal function.

On the topic of new, experimental medications the New England Journal of Medicine this week published a phase 2 study by Olnes et. al. evaluating the effect of a thrombopoietin mimetic (eltrombopag, or Promacta) in patients with aplastic anemia. [2] Twenty five consecutive adults with aplastic anemia refractory to immunosuppresion with anti-thymocyte globulin (ATG)/cyclosporin were recruited in a non-blinded study to receive a 12 week course of daily eltrombopag with primary end-points of response in one or more lineages at 12 weeks (pre-defined increase of either +20,000 platelets, +1.5 g/dl hemoglobin (hgb), or +500 absolute neutrophil count (ANC) , or a reduction in the required number of transfusions for Hgb of 9 g/dl or platelets<10,000). Eleven of the 25 patients met the primary response criteria (9 pts had a platelet response, 6 had an erythroid response, 9 eventually had a neutrophil response). Seven of 11 patients with a response continued to receive eltrombopag (150mg daily), and 6 patients eventually met response criteria in three lineages. This study is important because for most patients with refractory aplastic anemia, stem-cell transplantation remains the only hope – and if a suitable donor is not found, more than 40% will die from bleeding or infection within 5 yrs after diagnosis.[2] Thrombopoietin regulates platelet production via the c-MPL receptor on megakaryocytes, however hematopoietic stem cells and progenitor cells also express c-MPL and thrombopoietin modulated activation of these receptors may open up new therapeutic opportunities in the treatment of aplastic anemia.

Switching gears, a Nature Medicine article by Breen et al proposes a new physiological explanation for the rapid glucose-lowering effects of bariatric surgery in type 2 diabetes. [3] This group suggests that nutrient delivery to the small bowel activates a neurocircuit via the brain that ultimately innervates the liver to reduce its glucose production, thus improving hyperglycemia in diabetes. Direct intrajejunal glucose and lipid administration in rats increased overall glucose metabolism and decreased endogenous glucose production; the same effect was not seen with an equal amount of glucose infused directly into the hepatic portal vein. A diabetic model in rats (by administering beta-cell toxin streptozotocin), was used in a 4×4 design with control and diabetes induced rats randomized to duodenal-jejunal bypass surgery (DJB) or sham surgery – the group found that as early as day 2 DJB-operated diabetic rats had reduced plasma glucose levels as compared to sham-treated diabetic rats or control group rats. This finding was not associated with any changes in weight or food intake. By 14 days after the surgery, plasma glucose levels of DJB-operated rats remained normal (with no significant difference from the non-diabetic control groups), whereas glucose concentrations in the sham-operated diabetic rats remained at presurgical glucose values (~400mg/dL). Although still controversial and of unknown duration of benefit, this early work may pave a road for bariatric surgery in more than just weight loss. Specifically it may have its own niche in the treatment of both type I and type II DM.

Another common problem of the aging population is osteoporosis, and the optimal treatment against fractures is still encased in some mystery. A NEJM meta-analysis by Bischoff-Ferrari et al evaluated the effect of vitamin D supplementation based on pooled data from 11 double-blind, randomized, controlled trials involving 31,022 persons 65 years or older that received oral vitamin D supplementation, alone or in combination with calcium, as compared to with a control (placebo or calcium alone). [4] Primary end points were risk of hip fracture and any nonvertebral fracture. Although the intention-to -treat analysis showed a nonsignificant reduction of 10% in hip and 7% in any non-vertebral fracture, an alternate primary analysis (which looked at the actual intake of vitamin D in treated participants vs controls, with adjustment for adherence) found a 30% reduction in hip fractures (hazard ratio 0.70; 95%CI .58-.87) and a 14% reduction in any non-vertebral fracture (hazard ratio 0.86; 95%CI 0.76-0.96) at vitamin D intake levels of 792-2000 IU per day. Notably, there was no reduction in fractures at any vitamin D intake levels lower than 792 IU per day. A limitation to the findings was that any significant effect of vitamin D independent of calcium could not be assessed because all trials that gave higher doses of vitamin D (>800 IU/day) also gave calcium. In summary, it appears that to be effective – vitamin D needs to be given in doses of at least 800 IU per day, with the exact therapeutic dose and effect of calcium supplementation still unknown.

Another popular treatment for osteoporosis are the bisphosphonates, whose safety has recently been brought into question as well. A case-control study from the Archives of Internal Medicine by Meier et al. evaluated the correlation of recent rise in new, atypical femoral fractures (unlike the classic osteoporosis-related femoral fractures) with the use of bisphosphonates. [5] Retrospective analysis of 477 patients aged 50 years or older, that initially presented with either a femoral or a subtrochanteric fracture not related to trauma, tumor or other conditions that affect bone integrity, were radiographically evaluated (by blinded analysis) to have either atypical fracture lines (cases) or classic fracture lines (controls). Of these 477 patients with fractures, 39 were found to have atypical fractures as compared to the 438 with classic fractures. Among the patients with atypical fractures, 82.1% were taking a bisphosphonate, as compared to the 6.4% in the controls (Odds Ratio, adjusted for vit D, corticosteroids, PPI, sex and age, was 69.1; 95%CI 22.8-209.5). The correlation of atypical fractures and bisphosphonate use increased with increasing durations of bisphosphonate use, OR 46.9 at 2-5 years of use (95% CI, 14.2154.4), OR 117 at 5-9 years of use (95% CI, 34.2-401.7), and OR of 175.7 at >9yrs of use (95% CI, 30.0-1027.6). This study implies a strong correlation between prolonged bisphosphonate use and atypical fracture risk. However, given the small incidence of atypical fractures as compared to classic fractures – the benefits of bisphosphonate use are still likely to outweigh the risks, although shortening duration of treatment may be warranted given the long half life of bisphosphonates and the above mentioned risk with extended use.

So as the smoke of the fireworks clears, we are left with several more medical advancement and with a lot more unsolved puzzles on the horizon. Stay tuned for next week’s prime-cuts!

Dr. Jenny Gartshteyn is a 2nd year resident at NYU Langone Medical Center

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

Image courtesy of Wikimedia Commons

References:

1. Paul E Sax, Edwin DeJesus, Anthony Mills, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. The Lancet 2012; 379:2439-2448 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2960917-9/fulltext

2. Matthew J Olnes, Phillip Scheinberg, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. New England Journal of Medicine 2012; 367(1):11-19 http://www.nejm.org/doi/full/10.1056/NEJMoa1200931

3. Danna Breen, Brittany Rasmussen, et al. Jejunal nutrient sensing is required for duodenal-jejunal bypass surgery to rapidly lower glucose concentrations in uncontrolled diabetes. Nature Medicine 2012; 18(6):950-956 http://www.nature.com/nm/journal/v18/n6/full/nm.2745.html

4. Heike A. Bischoff-Ferrari, Walter C Willett, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. New England Journal of Medicine 2012; 367(1):40-49 http://www.nejm.org/doi/full/10.1056/NEJMoa1109617

5. Raphael P.H. Meier, Thomas V Perneger, et al. Increased occurence of atypical femoral fractures associated with bisphosphonae use. Archives Internal Medicine 2012; 172(12):930-936 http://archinte.jamanetwork.com/article.aspx?articleid=1160668

Other Noteworthy Publications:

1. Lesley A Inker et al. Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C. NEJM 2012; 367(1):20-29. As a substitute for serum creatinine as a measurement of eGFR, GFR calculations based on cystatin C levels may be more accurate.

2. Anjan Debnath et al. A high-throughput drug screen for Entamoeba histolytica identifies a new lead and target. Nature Medicine 2012; 18:956960 Anjan Debnath and colleagues now report their identification of auranofin, an approved treatment for rheumatoid arthritis, as a candidate new drug for combating E. histolytica infection.

3. Vanessa D Alphonse et al. Mechanisms of Eye Injuries From Fireworks. JAMA 2012; 308(1):33-34. Cadaver eyes were procured within 55 days of death and exposed to simulated fireworks with the only observed injuries being corneal abrasions caused by projected material.

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