While many in the field of infectious disease research and medicine have noted the decline in new investigators and practitioners entering the workforce, the HIV Medicine Association and the Infectious Diseases Society of America Foundation have teamed up to do something about it. In Summer 2018, they announced a program to fund 15 medical students in the U.S. for clinical learning and research projects, each to be paired with an experienced mentor to support the student's research area of interest. This is one of a series of interviews with a mentor/mentee pair.
We spoke with Ronald Ellis, M.D., Ph.D., co-director of the HIV Neurobehavioral Research Center and principal investigator of its Neuromedical Core as well as co-director of the Translational Methamphetamine AIDS Research Center at University of California, San Diego (UCSD). His mentee, Jennie Xu, is a second-year medical student at UCSD. Before medical school, she received her undergraduate degree in neuroscience at Duke University and worked at the University of California, San Francisco Alliance Health Project.
Jeanine Barone: How common is peripheral neuropathy among HIV-positive individuals?
Ronald Ellis: In our experience, distal sensory polyneuropathy affects approximately 50% of persons living with HIV (PLWH). Reports vary depending upon different definitions of neuropathy and specific study populations, with respect to exposure to antiretrovirals and varying levels of immunosuppression due to progression of disease.
JB: In the U.S., what are the most common types of neuropathy in this population?
RE: Overwhelmingly, the most common type of neuropathy is a distal sensory predominant polyneuropathy. Thirty to forty percent of these are symptomatic, with the remainder reporting no symptoms. Our study defines the objective physical signs of neuropathy to be a diminished ability to recognize vibration bilaterally in the toes, reduced sharp-dull discrimination in the feet and toes, and reduced bilateral ankle reflexes. Neuropathy symptoms include bilateral loss of sensation, paresthesias [pins and needles sensation], and distal neuropathic pain. Of the signs, diminished vibration is the most common, and of the symptoms, paresthesias are the most common. HIV itself is believed to be the primary etiology. Various other contributors to polyneuropathies in HIV are common. These include diabetes and toxic exposure (especially with some of the older antiretroviral medications). These conditions are clinically indistinguishable from HIV itself.
JB: What are the risk factors?
RE: Risk factors pertinent to our study of HIV peripheral neuropathy include older age, taller height, d-drug exposure (toxicity from drugs such as stavudine [d4T, Zerit], didanosine [ddI, Videx], and zalcitabine [ddC, Hivid]), hypertriglyceridemia, alcohol use, and diabetes. Depression is associated with an increased risk of neuropathic pain. Autoimmune disease, vitamin deficiency, and hereditary diseases cause neuropathy but are much less likely to be present in the context of HIV.
JB: What do we know about preventing or reducing the risk for this condition?
RE: Managing comorbid medical conditions, such as diabetes, alcohol abuse, and hypertriglyceridemia, are potential strategies for reducing the risk for neuropathy. Neurotoxic medications must be avoided. However, the contribution of HIV and its associated medications to the progression of neuropathy is unpredictable. Therefore, one of the goals of our study is to identify a genetic risk factor that may help us better predict an individual's susceptibility to painful neuropathy.
JB: What treatments are recommended?
RE: Management of peripheral neuropathy is two-fold: treatment of the underlying condition and symptom abatement. Axonal polyneuropathies can be slowed by removing exposure to toxic substances like alcohol and drugs and better managing blood glucose levels in diabetes. Diseases causing demyelinating neuropathies might be treated with steroids or other disease-specific therapies. The primary pharmacologic treatments for pain symptoms are gabapentin and tricyclic antidepressants, and a number of other drugs (duloxetine and pregabalin) may have varying efficacy as well. Tramadol, NSAIDs [nonsteroidal anti-inflammatory drugs], and low-dose narcotics can help with management of breakthrough pain. Opiates should be avoided. Physical therapy can help address weakness and disability.
JB: How does the genetic variant that you are studying affect whether HIV-positive individuals with peripheral neuropathy have symptoms or not?
RE: The genetic variant we are interested in is a polymorphism of catechol-O-methyltransferase (COMT) known as Val158Met. Prior studies have implicated this specific variant in a variety of pain conditions, and the pathophysiology is believed to be related to COMT metabolism of dopamine -- an important neurotransmitter in the brain's reward and punishment pathways. Our data show that Val158Met significantly predisposes HIV-[positive] individuals to distal neuropathic pain, but not a higher incidence of non-painful neuropathic signs or symptoms (e.g., paresthesias or numbness).
JB: What other differences are there between patients who have or do not have symptoms?
RE: Neuropathy symptoms, particularly pain, are debilitating and have been shown by previous studies to affect mood, function in daily activities, and quality of life. In this study, we did not investigate the difference between symptomatic and non-symptomatic neuropathy generally; rather, we focused on the presence of neuropathic pain specifically. Some of the risk factors that are more common in patients with neuropathy are age, female gender, diabetes, lifetime depression, d-drug exposure, and CD4 nadir.
JB: If HIV treatment is successful in terms of improving CD4 count, is there less of a risk of neuropathy?
RE: In the pre-ART [antiretroviral] era, CD4 count and HIV viral load were strong predictors of peripheral neuropathy. Unfortunately, CD4 recovery with cART (combination antiretroviral therapy) does not reliably result in improvement. Additionally, with more successful current treatments, HIV-[positive] individuals are living longer, and advancing age, metabolic conditions, and prolonged duration of cART actually tend to increase the prevalence of neuropathy.
Jeanine Barone: What attracted you to working with Dr. Ellis?
Jennie Xu: The work that Dr. Ellis does in HIV neurology was a good fit for my interests. In college, I studied neuroscience and worked on a research project investigating the neurobiology of pain. After I graduated, I had the opportunity to work at an HIV clinic in San Francisco. Through these experiences prior to medical school, I developed an interest in both topics, and particularly in the intersection of neuroscience and HIV. I originally met Dr. Ellis at a neurology interest group networking event at UCSD, where I first heard a little about his work.
JB: Are there any findings that you can discuss?
JX: The Val158Met polymorphism of COMT results in reduced enzymatic activity and in higher synaptic dopamine levels. The role of this genetic variant has been previously studied in a number of different pain conditions, but never in HIV-related neuropathic pain. Our preliminary findings suggest that Val158Met may serve as a genetic marker for susceptibility to distal neuropathic pain without an increased risk for neuropathy at large. Interestingly, this finding is only significant in those of European genetic ancestry, but not in those of African ancestry. Val158Met still significantly predisposes HIV-[positive] individuals to neuropathic pain even after controlling for a multitude of other factors known to influence neuropathy. Despite the efficacy of cART in viral suppression and immune recovery in HIV, distal neuropathic pain remains a debilitating complication that is increasingly relevant in an aging HIV population. ¬
JB: What do you think would get more medical students interested in working in HIV, either clinically or research-wise?
JX: I think that emphasizing to medical students the interdisciplinary nature of HIV work may generate more interest. My first experience working in the HIV realm was with the UCSF Alliance Health Project, a division of the psychiatry department that served as a community clinic to provide HIV testing and counseling services to the San Francisco community. I worked alongside social workers and psychiatrists and public health workers who introduced me to each of their unique approaches to supporting HIV patients and stopping the spread of HIV. Then, in medical school after meeting Dr. Ellis, an HIV-focused neurologist, I realized how there is room for a contribution from every medical specialty to the treatment and research of HIV, a multisystem and multidimensional disease. The landscape of HIV is fast-evolving, and there is room for us as medical students to make a significant impact on HIV research and management at this pivotal point in time.