Primecuts – This Week in the Journals

July 31, 2017

primecuts 7.31.17By Jiwoon Chang, MD

Peer Reviewed

This past week at the International AIDS Society Conference in Paris, investigators of the mosaic HIV vaccination trial called APPROACH shared their early findings of healthy adults developing immunological responses against HIV after vaccinations [1]. Results from this NIH-funded clinical trial are expected in late 2017, but the preliminary report provides a new hope to protect those at risk of acquiring HIV. This week, our first article evaluates enhanced antimicrobial prophylaxis for HIV patients with low CD4+ count. The second article reviews the duration of targeted temperature management in unconscious patients with out-of-hospital cardiac arrest. Next, we will explore the effects of E-cigarette use with smoking cessation in the current US population. Finally, we will discuss the use of idarucizumab to reverse the anticoagulation effect of dabigatran.

Enhanced Prophylaxis plus Antiretroviral Therapy for Advanced HIV Infection in Africa

According to the World Health Organization, 36.7 million people lived with HIV/AIDS and 1.1 million people died of complications from AIDS worldwide in 2015 [2]. In sub-Saharan Africa, about 25% of patients with HIV have a CD4+ count of less than 100 cells per cubic millimeter, and 10% of these individuals die in the first 3 months of starting antiretroviral therapy (ART) [3,4].

In a NEJM study published this week, investigators of the Reduction of Early Mortality in HIV-Infected Adults and Children Starting Antiretroviral Therapy (REALITY) conducted an open-label, randomized trial to compare enhanced antimicrobial prophylaxis and standard prophylaxis (5). The study included 1805 HIV-infected patients with CD4+ count of less than 100 cells per cubit millimeter in Africa without any previous ART. Patients were randomized to enhanced therapy with continuous trimethoprim-sulfamethoxazole, 12 weeks of isoniazid-pyridoxine, 12 weeks of fluconazole, 5 days of azithromycin, and 1 dose of albendazole, or standard therapy with continuous trimethoprim-sulfamethoxazole at the initiation of ART. The primary outcome included death at 24 weeks after enrollment. Other outcomes included death at 48 weeks, incidences of opportunistic infections, and serious adverse events from prophylactic drugs.

Investigators found that the rate of death at 24 weeks was significantly less with enhanced prophylaxis compared to standard prophylaxis (8.9% vs. 12.2%, p=0.03, CI 0.55-0.98). The enhanced prophylaxis group had a lower rate of death at 48 weeks as well (11.0% vs. 14.4%, p=0.04, CI 0.58-0.99). Notable findings in secondary outcomes include lower rates of new tuberculosis (7.1% vs. 10.2%, p=0.02, CI 0.49-0.93), cryptococcal infection (1.0% vs. 2.6%, p=0.01, CI 0.18-0.83) in enhanced prophylaxis group. There was no significant difference in the rate of presumed severe bacterial infections (4.6% vs. 3.7%, p=0.32, CI 0.80-1.99). The rate of adverse events due to prophylactic drugs did not differ significantly between the two groups (6.8% vs. 7.7%, p=0.50, CI 0.63-1.26).

In this study, enhanced prophylaxis resulted in lower rates of death at 24 and 48 weeks in severely immunocompromised patients with AIDS compared to standard prophylactic therapy. These findings advocate for enhanced prophylactic treatment to prevent tuberculosis and cryptococcal disease at the initiation of ART. Limitations of this trial included the lack of microbiologic analyses at participating centers, causing many bacterial infections to be diagnosed presumptively. Given limited screening test availability in many African regions, benefits of enhanced prophylactic treatment may outweigh harms of potential antimicrobial resistance in patients with AIDS, and guidelines for prophylactic antimicrobial regimen in AIDS patients may be updated for resource-limited areas.

Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest

To prevent a neurologic deficit and death in unconscious patients who had out-of-hospital cardiac arrest, current international guidelines recommend targeted temperature management (TTM) [6]. A clinical trial in 2013 showed similar benefits of TTM at 33°C and at 36°C, and investigators from the study recommended at least 24 hours of TTM, but the optimal duration of cooling is unclear [7].

A pragmatic, multicenter, randomized trial conducted in Europe was published this week in JAMA to address the question of whether or not TTM for 48 hours results in better neurologic outcome compared to 24-hour TTM. [8]. 355 adults between the age of 17 and 80 with out-of-hospital cardiac arrest who had sustained return of spontaneous circulation for more than 20 minutes and Glasgow Coma Scale score less than 8 were randomized to 24 or 48 hours of TTM at 33°C. The primary outcome was 6-month neurologic outcome, and secondary outcomes were 6-month mortality, adverse events, and ICU resource use.

Study authors found no significant difference in favorable functional neurologic outcome in 6 months between 24-hour and 48-hour groups (64% vs. 69%, p=0.33, CI 0.93-1.25). There was also no difference in mortality at 6 months (34% vs. 27%, p=0.19, CI 0.59-1.11). There was a modest but significant decrease in adverse events in the 24-hour cooling group compared to the 48-hour group (91% vs. 97%, p=0.03, CI 1.01-1.12). The median ICU length of stay was shorter in the 24-hour group compared to the 48-hour group (117 hours vs. 151 hours, p<0.001, CI 1.14-1.47). Authors concluded that there was no scientific evidence to support 48 hours of TTM compared to 24 hours, and longer TTM may cause more adverse events and a longer ICU stay. This study had limited power given a small number of subjects, and the 5% difference in 6-month neurologic outcome should be re-evaluated in a larger trial. While this trial addressed one variable of TTM, larger and more sophisticated studies are required to address the optimal temperature, duration, and onset of TTM for unconscious patients after cardiac arrest.

E-cigarette use and associated changes in population smoking cessation: evidence from US current population surveys
Use of electronic cigarettes has increased worldwide, but there is a debate regarding its utility for cigarette smoking cessation. Some countries like the United Kingdom allow e-cigarettes to be licensed for nicotine replacement therapy, whereas Australia does not allow the sale of nicotine-containing e-cigarettes. In a BMJ study published this week, a group of investigators from UCSD examined if the increase in use of e-cigarettes in the US was associated with a smoking cessation rate at the population level [9]. This study used the US Current Population Surveys about tobacco use supplement between 2001 and 2015 and included 161,054 respondents from the 2014-15 survey to analyze the prevalence of e-cigarette use. Measured outcomes included the number of current smokers and quitters, the rate of attempt to quit cigarette smoking, and the rate of successful quitting. Investigators found 22,548 active smokers and 2,136 recent quitters from the 161,054 people who completed the 2014-15 survey. 38.2% of active smokers and 49.3% of recent quitters had tried e-cigarettes in the past, and 11.5% and 19.0% of them reported active e-cigarette use. E-cigarette users were more likely to try to quit smoking (65.1% vs. 40.1%, change=25.0%, CI 23.2-26.9%) and more likely to succeed in quitting (8.2% vs. 4.8%, change=3.5%, CI 2.5-4.5%). This study shows a correlation between increased e-cigarette use and increased overall smoking cessation for the US population. Limitations include recall biases from self-reporting and absence of randomization. We should consider using e-cigarettes for smoking cessation in addition to other nicotine replacement therapy and varenicline. Future studies may examine the health impact of long-term e-cigarette use and initiation of e-cigarettes among teenagers to analyze the effect on public health.

Idarucizumab for Dabigatran Reversal — Full Cohort Analysis

Dabigatran is an oral anticoagulation that works by directly inhibiting thrombin. Idarucizumab is a monoclonal antibody fragment that binds dabigatran to reverse its anticoagulation effect, and it was approved by the FDA after interim analysis with the first 90 patients enrolled in the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) study in 2015 [10].

This past week in NEJM, investigators reported the full cohort analysis of the RE-VERSE AD trial to validate the interim findings and assess the use of idarucizumab in patients with uncontrolled bleeding or those with an urgent procedure [11]. In this pragmatic, multicenter, prospective, single-cohort study, 301 patients received idarucizumab for uncontrolled bleeding, such as gastrointestinal bleeding and intracranial hemorrhage, and 202 patients received idarucizumab for urgent surgery or intervention. Primary outcome was the maximum percentage reversal of dabigatran’s anticoagulation effect, which was measured by the diluated thrombin time or the ecarin clotting time. Clinical outcomes such as thrombotic complications and mortality were also measured.

Investigators found that the median maximum percentage reversal at 4 hours after idarucizumab administration was 100% in all patients. Among patients who received idarucizumab for uncontrolled bleeding, 67.7% had bleeding cessation within 24 hours with the median time to hemostasis 2.5 hours after administration (CI 2.2 to 3.9). Authors reported that the rest of patients in this group did not have any evidence of bleeding on physical examination or imaging.
Among those who received idarucizumab prior to undergoing a procedure, 93.4% had periprocedural hemostasis. Thrombotic events at 90 days occurred in 6.3% in the uncontrolled bleeding group and 7.4% in the procedural group, and the mortality rate was 18.8% and 18.9%, respectively.

Although this study was conducted without a control group or randomization, this full cohort analysis validates the interim report of effective anticoagulation reversal of idarucizumab and advocates for its usage for patients on dabigatran who have uncontrolled bleeding or require urgent interventions. It is encouraging to see the effectiveness of idarucizumab as providers wait for the approval of monoclonal antibody fragments that reverse Factor Xa inhibitors, such as apixaban and rivaroxaban.

Minicuts
Sorafenib and TACE in Hepatocellular Carcinoma
Administration of Sorafenib with transarterial chemoembolization (TACE) did not improve progression-free survival in patients with unresectable hepatocellular carcinoma compared to TACE alone [12].

Calcium Correlation with Coronary Artery Disease
In a JAMA study published this week, investigators reported that a genetic predisposition to high serum calcium levels was associated with higher incidences of coronary artery disease and myocardial infarction [13].

Chronic Traumatic Encephalopathy in American Football Players
A case series of 202 American football players whose brains were donated for research showed that almost all of them had neuropathological evidence of chronic traumatic encephalopathy, or CTE [14]. This study also suggested that a high level of play might cause more extensive disease.

Dr. Jiwoon Chang is a 3rd year Internal Medicine Resident at NYU Langone Health

Peer reviewed by Amar Parikh, MD, Associate Editor, Clinical Correlations and Chief Resident in Internal Medicine at NYU Langone Health

Image courtesy of the National Institutes of Health

References

1. NIH News Releases. Experimental HIV vaccine regimen is well-tolerated, elicits immune responses. . National Institute on Health. https://www.nih.gov/news-events/news-releases/experimental-hiv-vaccine-regimen-well-tolerated-elicits-immune-responses. Published July 2017. Accessed July 28, 2017.

2. World Health Organization. Global Health Observatory (GHO) data. World Health Organization. http://www.who.int/gho/hiv/en/. Accessed July 28, 2017.

3. The IeDEA and ART Cohort Collaborations. Immunodeficiency at the start of combination antiretroviral therapy in low-, middle-, and high-income countries. J Acquir Immune Defic Syndr. 2014;65(1):e8-16. https://www.ncbi.nlm.nih.gov/pubmed/24419071

4. Boulle A, Schomaker M, May MT, et al. Mortality in patients with HIV-1 infection starting antiretroviral therapy in South Africa, Europe, or North America: a collaborative analysis of prospective studies. PLoS Med. 2014;11(9):e1001718.

5. Hakim J, Musiime V, Szubert AJ. Enhanced Prophylaxis plus Antiretroviral Therapy for Advanced HIV Infection in Africa. NEJM. 2017;377:233-245. doi: 10.1056/NEJMoa1615822 https://www.ncbi.nlm.nih.gov/pubmed/28723333

6. Callaway CW, Donnino MW, Fink EL, et al. Part 8: post-cardiac arrest care: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015;132(18)(suppl 2):S465-S482. https://www.ncbi.nlm.nih.gov/pubmed/26472996

7. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33 degrees C vs 36 degrees C after cardiac arrest. NEJM. 2013;369:2197-2206. http://www.nejm.org/doi/full/10.1056/NEJMoa1310519#t=article

8. Kirkegaard, H, Soreide, E, Haas, I. Targeted Temperature Management for 48 vs 24 hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest: A randomized clinical trial. JAMA. 2017;318(4):341-350. doi:10.1001/jama.2017.8978

9. Zhu, SH, Zhuang YL, Wong S, Cummins SE, Tedeschi GJ. E-cigarette use and associated changes in population smoking cessation: evidence from US current population surveys. BMJ. 2017;358. doi: https://doi.org/10.1136/bmj.j3262.

10. Pollack, CV, Reilly PA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal. NEJM. 2015;373:511-520. https://www.ncbi.nlm.nih.gov/pubmed/26095746

11. Pollack, CV, Reilly PA, van Ryn J, et al. Idarucizumab for Dabigatran Reversal — Full Cohort Analysis. NEJM. 2017. doi: 10.1056/NEJMoa1707278

12. Meyer T, Fox R, Ma YT et al. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2017;2(8):565-575. doi: 10.1016/S2468-1253(17)30156-5. http://www.thelancet.com/pdfs/journals/langas/PIIS2468-1253(17)30156-5.pdf

13. Larsson SC, Burgess S, Michaëlsson K. Association of Genetic Variants Related to Serum Calcium Levels With Coronary Artery Disease and Myocardial Infarction. JAMA. 2017;318(4):371-380. doi:10.1001/jama.2017.8981. http://paper.medlive.cn/literature/2630059

14. Mez J, Daneshvar DH, Kiernan PT. Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football. JAMA. 2017;318(4):360-370. doi:10.1001/jama.2017.8334. file:///C:/Users/smitha11/Downloads/JOI170072supp1_prod.pdf

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