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Disconcerting data from analysis of the Women’s Interagency HIV Study database
 
Gretchen L. Birbeck, MD, MPH, Without Borders Editor, Rochester, NY
 
In this issue of Neurology, Rubin and colleagues report disconcerting data from their analysis of the Women’s Interagency HIV Study database. In longitudinal assessments of cognitive and motor function in women with and without HIV infection, even among women with continuous viral suppression HIV-associated differences were evident. Perhaps even more disturbingly, in some domains women with continuous suppression performed more poorly than those with HIV who were not suppressed.
 
This cohort data is from 2009-2013 so many of the participants would have an antiretroviral therapy initiated only after some significant period of viral suppression and possibly with a very low CD4 nadir—both recognized as underlying risk factors for adverse neurologic outcomes in HIV. One can hope that with earlier treatment initiation long term cognitive outcomes in women with HIV will cease to differ from their HIV uninfected counterparts. Nonetheless, the women with continuous viral suppression had longer antiretroviral therapy duration and greater use of efavirenz and this report may offer some fuel to the fire of concerns regarding the neurotoxicity of antiretrovirals, particularly efavirenz.1 The strongest HIV-related predictor of neurocognitive performance remains the proportion of time with undetectable viral load. Within the context of HIV as a chronic condition, balancing the toxicity and neurologic protective aspects of antiretroviral use appears to be one of the bigger challenges that lies ahead.
 

1. Ma Q, Vaida F, Wong J, et al. Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients. J Neurovirol 2016;22:170-178.

 
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Sickle cell and neurologic complications
 
Gretchen L. Birbeck, MD, MPH, Without Borders Editor, Rochester, NY
 
A newly published systematic review and meta-analysis in Neurology looks at the complications of sickle cell disease in Africa. In an accompanying editorial, Dr. Ralph Green and I consider the unmet challenges of these neurologic complications. As we note in the editorial, “Sometimes an important scientific report is more notable for what it cannot tell us than for what it can”.
 
 
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Inflammation, anxiety and depression
 
Gretchen L. Birbeck, MD, MPH, Without Borders Editor, Rochester, NY
 
Rossi and colleagues have published an interesting report on CNS inflammation in multiple sclerosis as it relates to anxiety and depression that may be more relevant to resource-limited tropical settings than one might imagine. Their paper makes an important contribution to the growing body of clinical data supporting the importance of CNS inflammation-induced anxiety and depression in persons with neurologic disorders. The potential for these psychiatric symptoms to serve as a possible warning sign of ongoing CNS inflammation warrants further study and the range of conditions for which this might be relevant is extensive.
 
In 2006 during the antiretroviral therapy (ART) roll out in rural Zambia, we undertook a study of the neurologic and psychiatric status of people initiating ART and patient outcomes at 1 year1. Mortality was 20% at a median of 80 days (IQR 44-139) after treatment initiation. After adjusting for World Health Organization HIV Disease Stage, the only predictor of mortality was the Shona Symptom Score, an instrument developed in Zimbabwe to quantify anxiety and depression symptoms. More recently, we evaluated predictors of mortality among people with HIV and new onset seizure. After advanced imaging, EEG and extensive cerebrospinal fluid (CSF) studies to identify opportunistic infections2, the highest mortality was seen among those patients in who we could find no cause for the underlying seizure. Clearly CSF studies of CNS inflammation in this population, and likely others, are needed.
 
References:
 
1. Birbeck GL, Kvalsund MP, Byers PA, et al. Neuropsychiatric and socioeconomic status impact antiretroviral adherence and mortality in rural Zambia. Am J Trop Med Hyg 2011;85:782-789.
2. Siddiqi OK, Elafros MA, Bositis CM, et al. New-onset seizure in HIV-infected adult Zambians: A search for causes and consequences. Neurology 2017;88:477-482.
 
 
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As Summer Peaks, the US House of Representative Appropriations Committee Proposes Budget that Keeps Fogarty International Center Intact
 
Gretchen L. Birbeck, MD, MPH, Without Borders Editor, Rochester, NY
 
Most in the ‘global know’ were dumbfounded in March when both President Trump’s “skinny” budget and the subsequent detailed one explicitly targeted the Fogarty International Center (FIC) for closure.1 Happy news arrived earlier this month when the appropriations committee for the House of Representatives approved a bill that did not close Fogarty but in fact allocated FIC a 1.5% increase ($73.4 million total budget).2 Despite its teeny, tiny budget (described by some as amounting to “less than pencil dust” in the overall NIH budget, Fogarty’s work yields serious benefits to U.S citizens and the global community alike including Fogarty’s leadership in the Brain Disorders programme which has played such a central role in the globalization of US Neurology.3 A disclosure—as an investigator funded through the Brain Disorders program and a Fogarty International Center Advisory Board member, I am seriously conflicted here. So don’t take my word for it—you can read any number of Op Eds and commentaries testifying to the critical nature of the FIC.1, 4-6 The Senate appropriations committee take this up in September. We certainly live in interesting times. Stay tuned.
 

References:

1. McNeil DG. Muffling an early warning system. New York Times 2017 March 21, 2017;Sect. 4.
2. US House of Representatives proposal preserves Fogarty, boosts NIH by $1B. In: NIH Fogerty International Center [online]. Available at: www.fic.nih.gov/News/GlobalHealthMatters/july-august-2017/Pages/house-ap.... Accessed August 14, 2017.
3. Birbeck GL, Meyer AC, Ogunniyi A. Nervous system disorders across the life course in resource-limited settings. Nature 2015;527:S167-171.
4. Drain PK, Subbaraman R, Heimburger DC. Preserving the Fogarty International Center - Benefits for Americans and the World. N Engl J Med 2017;377:9-11.
5. Green A. US stands to lose as much as Africa if Fogarty closes. University World News 2017 16June17.
6. Karim SSA, Karim QA, Abimiku A, et al. Closing the NIH Fogarty Center threatens US and global health. Lancet 2017;390:451.

                                                  
 

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Disclaimer: Blogs constitute the opinion of the author and do not reflect the views of the AAN or of Neurology ®

 

 

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  • HIV-associated motor neuron disease HERV-K activation and response to antiretroviral therapy In this small case series Bowen and colleagues report activation of human endogenous retrovirus-K (HERV-K) in people with HIV who developed motor neuron disease that subsequently improved with antiretroviral therapy. For neurologists caring for HIV patients in HIV endemic areas, this may be the silver lining on a heavy cloud. ​
    Lauren N. Bowen, MD, Richa Tyagi, MS, Wenxue Li, PhD, Tariq Alfahad, MD, Bryan Smith, MD, Mary Wright, MD, MPH, Elyse J. Singer, MD and Avindra Nath, MD  Published September 24, 2016
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    Soo Joo Lee, MD, PhD, Yong-Jin Cho, MD, PhD, Jae Guk Kim, MD, et al. on behalf of the CRCS-5 Investigators | Published December 1, 2015

Extra! Extra! Read all about it!

The September issue of the American Academy of Neurology's Global Health Section has posted: 
This issue includes information on the Foundation for African Medicine & Education (FAME), Iceland's health care system, experiences in an observership at the Neuroscience Center of All India Institute of Medical Sciences, and The International AIDS Society Conference on HIV Science in Paris.

AAN International Scholarship Award - There are travel bursaries available for young neurologists living outside of the US to attend the 2018 AAN meeting. Please share this opportunity with any appropriate colleagues.

US Immigration Policy Update - An update to the original letter of January 2017 has been published on the American Academy of Neurology website, regarding a recent decision by the Supreme Court and announcements by the U.S. Department of Homeland Security.

Neurology®: Clinical Practice has just launched their next Practice Current survey on a very globally relevant topic—How do you treat epilepsy in pregnancy? Given the broad range of approaches to managing this problem in diverse settings with varying resources, this survey promises to provide interesting insights. If you care for epilepsy patients, please consider completing the survey to add your own perspective.

Check out Dr. Omar Siddiqi’s most recent blog on his work in Zambia. Read about “The Broken File” effect. Quite an insightful commentary on what we need to do to improve patient care wherever we work.

2017 ANA Meeting features Global Neurology - This year the ANA has included a Presidential Symposium dedicated to Global Neurology titled, Translational Neuroscience Research to Improve Outcomes for the "Bottom Billion" as part of the 2017 Annual Meeting. The Scientific Program Advisory Committee has also added a special interest group dedicated to Global Neurology, which will enable those in the global neurology community an ideal opportunity to showcase their research.
     The upcoming American Neurological Association (ANA) annual meeting will be held in San Diego, CA from October 15-17, 2017. This is a meeting at which you can meet and network with experienced and successful neurologist investigators from academic medical centers around the US, senior leadership from NIH and other neuroscience research sponsors, and peers/colleagues at every career stage. It will be a valuable and worthwhile experience. Hope to see you there. ~ Gretchen Birbeck

Global Stuff you should know

On The Road

 

International AIDS Society 2017 Conference Report

Omar K. Siddiqi, MD, Beth Israel Deaconess Medical Center, Boston 

Siddiqi_2017

The International AIDS Society Conference on HIV Science was held in Paris, France from the 23-26 of July. As a first-time attendee of the conference, I was struck at how almost every lecture provided some take home lessons on global health in general, reinforcing the idea that HIV helped to invent the field of global health. There was no shortage of topics that touched on neurological issues of HIV.

Dolutegravir is an integrase inhibitor that has started to be scaled up as a first line treatment option in all settings because of its shorter duration to viral suppression, lower risk of drug resistance, and favorable side effect profile. The main side effect mentioned in multiple sessions was CNS in nature, specifically chronic insomnia and sleep disturbances. The overall CNS complaints are still less in comparison to Efavirenz. In addition, there are important interactions between Dolutegravir and the most commonly used anti-epileptics in resource limited settings (RLS), phenobarbital and carbamazepine. Carbamazepine and phenobarbital may increase metabolism of Dolutegravir resulting in decreased serum levels. The suggestion is to avoid this combination, if possible, or potentially increase the baseline dose of Dolutegravir. This has important implications for HIV patients with co-morbid epilepsy.

Results were presented from the ACTA trial--a randomized controlled, non-inferiority trial from 9 centers in Malawi, Zambia, Cameroon, and Tanzania for patients presenting with their first episode of cryptococcal meningitis. The aim of the trial was to see if alternatives to two weeks of IV amphotericin B (AmB) were feasible given its lack of availability and difficulty of administration in RLS. Participants were randomized to:

1) oral regimen of high dose fluconazole (1200mg/day) plus flucytosine (100mg/kg/day) for 14 days.
2) one week regimen of IV AmB (1mg/kg/d) plus high dose fluconazole followed by 7 days of high dose fluconazole.
3) one week regimen of IV AmB plus flucytosine, followed by 7 days of high dose fluconazole.
4) IV AmB plus high dose fluconazole for 14 days.
5) IV AmB plus flucytosine for 14 days (gold standard).

The outcome measured was 2 and 10 week mortality. The most interesting findings were that short course 1 wk AmB-based therapy and the exclusively oral regimen or high dose fluconazole/flucytosine were non-inferior to 2wks AmB-based therapy. In addition, 1 wk AmB + flucytosine was associated with better survival compared with all other arms. This study indicates the urgent need to make flucytosine widely available in sub-Saharan Africa where it is currently not registered in the majority of countries.

Dr. Felicia Chow, Assistant Professor of Neurology at UCSF, had an oral presentation “Higher HDL, better brain? Higher HDL is associated with better cognition in a cohort of older persons living with HIV infection”. Her group looked at data from 988 patients from a prospective cohort of older patients in the AIDS Clinical Trials Group A5322 study looking an association between cardiovascular risk and performance on a brief neurocognitive screen. In a multivariate regression analysis, her group demonstrated that longer ART duration and HDL was associated with better cognition in an older cohort of HIV patients. The study suggests that modifying HDL cholesterol may be one way of improving cognitive outcomes in older HIV patients.

Finally, there was a lot of time dedicated to the idea of differentiated care meaning a patient-centered approach to adapt HIV care based on where a patient falls in the treatment cascade. For example, the approach to children, adolescents, pregnant women, and adult males should be different rather than one size fits all. One interesting model of differentiated care is ART adherence clubs. It reduces the burden that stable patients place on healthcare facilities, increasing available clinical human resources for new patients and those clinically unstable who are at risk of failing treatment. In the model, 30 patients are allocated to an ART club. The group meets either at a facility or community venue for less than an hour every 2 months. Group meetings are facilitated by a lay club facilitator who provides a quick clinical assessment, referral when necessary, and dispenses pre-packed ART.1 I immediately thought this model could apply to well controlled epilepsy patients in RLS. I have a large group of stable epilepsy patients who wait hour and hours in my clinic just to get a medication refill. I think the adherence club model would lend itself well to this group. There are countless lessons from HIV care that can improve neurological services in RLS.

1. Wilkinson LS.. ART adherence clubs: A long-term retention strategy for clinically stable patients receiving antiretroviral therapy. SAJHIVMED. 2013 Jul; 14(2):48-50.

 

Conference Report from the Conference on Retroviruses and Opportunistic Infections

David Bearden, MD, Assistant Professor of Neurology and Pediatrics, Rochester, NY -- USA, MD, PhD 

The Conference on Retroviruses and Opportunistic Infections (CROI) is an annual scientific meeting devoted to the science around the pathophysiology, prevention, and treatment of Human Immunodeficiency Virus (HIV) and opportunistic infections in patients living with HIV. Given that patients with HIV are living longer and are less likely to develop opportunistic infections, there has been growing interest in non-communicable disorders associated with HIV, such as HIV-associated Neurocognitive Disorders (HAND) and HIV-associated stroke. This year at CROI (held February 13-16 in Seattle), the primary emphasis was on the possibility of HIV cure, but there were a number of interesting presentations related to CNS complications of HIV. There were several epidemiologic studies demonstrating that cognitive complications of HIV remain a major issue, even in the era of combined antiretroviral therapy (cART). In IMPAACT P1104s, longitudinal neurocognitive testing was performed in cART-treated children with HIV ages 5-11 in 6 countries in Sub-Saharan Africa. Children with HIV demonstrated significantly worse neurocognitive performance compared to controls, and longitudinal testing demonstrated that these differences persisted or worsened over time. One exciting aspect of CROI this year was that we are beginning to see results from treatment studies. For example, The SABES study randomized patients with very early HIV infection to immediate vs. deferred treatment, and found significant improvements in cognition with early treatment. There were also two interesting studies presented looking at a treatment intensification strategy for treatment of HAND. The first, using the CCR5 antagonist maraviroc, failed to meet the primary endpoint of decreased CSF inflammatory markers, but did show a statistically significant improvement in executive function. The second trial, using the novel CCR5/CCR2 antagonist cenicriviroc, demonstrated a significant improvement in global cognitive function as well as a decrease in CSF inflammatory markers. Both studies were small, open label, uncontrolled trials, and so should be viewed with some skepticism, but treatment intensification appears to be a promising strategy for treatment of cognitive complications of HIV

 A R C H I V E 

Neurology Podcasts

March 27, 2017: Dr. Kiran T. Thakur interviews Dr. Tarun Dua, Medical Officer at the World Health Organization working on the Program for Neurological Diseases and Neuroscience, Management of Mental and Brain Disorders in the Department of Mental Health and Substance Abuse, Geneva, Switzerland Find it here.

February 6, 2017: Dr. Omar Siddiqi interviews Dr. Victor Valcour, Associate Professor of Geriatric Medicine and Neurology at the UCSF Memory and Aging Center and Deputy Director of the Global Brain Health Institute. Find it here.

Without Borders Podcast Archive


Current Neurology Podcast
Dr. Stephen Donahue interviews Dr. Aaron Berkowitz

Dr. Stephen Donahue interviews Dr. Aaron Berkowitz about his paper on Zika virus-associated Guillain-Barre syndrome variant in Haiti. Dr. Ilena George is reading our e-Pearl of the week about juvenile Huntington disease. Dr. Alberto Espay interviews Dr. Alireza Atri about his Clinical Trials Plenary Session at the AAN meeting about 5-HT6 antagonist as adjunctive therapy to cholinesterase inhibitors in patients with mild-to-moderate Alzheimer disease.

Disclosures