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Peripheral Neuropathy, a severe comorbidity for Aging Older HIV+
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Download the PDF here
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- "Signs of peripheral neuropathy remain despite virologic/immunologic control but frequently occurs without symptoms. Aging is a risk factor for peripheral neuropathy/SPN"
- "Severe pain due to damage of the peripheral nerves is one of the most frequent neurological complications of an HIV infection"
- "is often refractory to medical therapy, and is associated with disability, reduced quality-of-life, high health care costs and premature death"
- The Pain in Neuropathy Study-HIV (PINS-HIV) was an observational single cohort cross-sectional study conducted at Chelsea and Westminster Hospital in London....total of 66 HIV-positive subjects participated in the study....The majority of participants were white (86.4%), male (86.4%), and middle-aged (mean ± SD age, 49.2 ± 8.8 years), with 34.2% and 85.7% of participants in the HIV-No SN and HIV-SN groups
- (CHARTER) study - evaluated risk factors for new onset DNP in the CNS Antiretroviral Therapy Effects Research (CHARTER) study - we found prevalent HIV-associated sensory neuropathy (HIV-SN) in 881 of 1539 participants (57%). ......One third (167; 34%) had a history of prior exposure to potentially neurotoxic drugs (stavudine, didanosine); 71 (14%) took these medications at entry - detectable plasma HIV viral loads at entry had a higher risk of new DNP......Alcohol is a peripheral neurotoxin that can cause DNP; nutritional deficiencies are known to amplify alcohol's neurotoxicity.....Neuropsychiatric factors, specifically opioid use disorders and worsening depressed mood, were associated with increased rates of new DNP......NP was associated with past opioid abuse - Comorbid diabetes mellitus was diagnosed in 39 participants (8%) and hepatitis C virus seropositivity in 125 (25%). A lifetime history of substance use disorder (abuse or dependence) by DSM-IV criteria was present for 356 (73%) participants.....Alcohol use disorders were the most common (270, 55%), followed by cocaine (40%), methamphetamine (18%) and opioids (17%).
- ALLERT - AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trial
Two thousand, one hundred and forty-one participants were followed from January 2000 to June 2007. Rates of peripheral neuropathy/SPN at 3 years were 32.1/ 8.6% despite 87.1% with HIV-1RNA 400 copies/ml or less and 70.3% with CD4 greater than 350 cells/ml.
"Of these, 38% reported DNP....Risk factors for neuropathic pain were use of specific, neurotoxic, dideoxynucleoside analogue antiretrovirals ("D-drugs")......Neuropsychiatric conditions such as substance use and mood disorders have been shown to influence the prevalence and incidence of neuropathic pain in other diseases
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from Jules: these days we hear a lot about comorbidities that are becoming a worsening problem for aging HIV like heart disease, neurologic/brain disorders, fractures & falling, increasing kidney disease etc, but we do not hear about peripheral neuropathy in the feet. In the early HIV days many patients were experiencing neuropathy just from HIV, and the early nucleosides caused neuropathy, but we no longer hear about neuropathy, but older aging HIV+ can experience severe worsening neuropathy for which there is no good treatment, so it can be disabling, prescribed opoids treatment can be used but obviously this can be a problem. I am reporting on neuropathy to remind people that discussion about the usual cast of comorbidities these days ignores neuropathy but I hear often about many older patients with insufferable neuropathy that "is often refractory to medical therapy, and is associated with disability, reduced quality-of-life, high health care costs and premature death", so another condition to put on the list of comorbidities for aging HIV+. My recent experiences with federal governmental HIV leadership is they are diminishing their funding & interest in HIV, particularly in the aging area, although this may not be noticeable now. Following a recent congressional hearing last year where the NIH & its director Francis Collins was grilled & warned to reduce HIV funding by a senator on the panel questioning Collins, it appears that perhaps quietly Collins is caving in and finding ways to reduce funding for HIV in favor of what the Senator supported which was alzheimers. Regardless of the reason the HIV leadership, ACTG, NIAID, and NIH are not very interested in this one point - that older aging HIV+ need special support services and we need a national discussion on this issue. Sure some research dollars from the Nih are supporting R&D to look for medical interventions but nothing yet has been found & this is a difficult task, although it does appear even this funding is decreasing, but the special support services patients need is being ignored, as death rates will for sure increase because of the depleted immunity combined with increased severity & worsening of comorbidities o=in older aging HIV+ . The first "class" with HIV :) are those older & aging now & are experiencing severe onset of comorbidities in numbers and severity, but their special needs are being ignored & abandoned by NIH leadership. Industry, doctors, and young advocates need to perk up & pay attention too.
"Severe pain due to damage of the peripheral nerves is one of the most frequent neurological complications of an HIV infection....neuropathic pain affects approximately 30 percent of people with AIDS. Like other serious health issues, such as cancer and diabetes, HIV can cause damage to the peripheral nerves of the body....Symptoms are usually felt in both feet or both hands and can progress up the body in a "stocking and glove" pattern. Minor everyday injuries like a paper cut or sunburn injure these nerves in healthy people. However with a condition like HIV, this nerve damage can lead to burning pain, numbness, or even paralysis. Patients may also feel numbness, tightness, or clumsiness."
http://www.paulchristomd.com/peripheral-neuropathy-and-hiv-associated-nerve-pain/......Treatment of HIV neuropathies depends on the type. Typical HIV polyneuropathy requires good control of HIV infection. Antiretroviral toxic neuropathy may require the cessation of the offending drug. Neuropathic pain due to HIV polyneuropathy can be treated with anti-seizure medications, antidepressants, or analgesics including opiate drugs. In severe painful conditions, patients may be referred to the Blaustein Chronic Pain Clinic for a multidisciplinary approach to pain management. Patients with GBS due to HIV are treated in a similar manner to other GBS patients.
http://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/peripheral_nerve/conditions/hiv_neuropathy.html
3 published studies:
"Key predictors....neuropathic pain in HIV+ individuals during follow-up were past opioid use disorders"
(study 1) The Pain in Neuropathy Study-HIV (PINS-HIV) was an observational single cohort cross-sectional study conducted at Chelsea and Westminster Hospital in London....total of 66 HIV-positive subjects participated in the study....The majority of participants were white (86.4%), male (86.4%), and middle-aged (mean ± SD age, 49.2 ± 8.8 years), broadly reflecting the patient population of the recruitment centre in the current cART era.....Participants were recruited between July 7, 2009, and January 25, 2011.....The population recruited to this deep profiling study had a prevalence of HIV-SN of 43%, with 75% of those reporting pain, which is similar to larger epidemiological studies [12]. In the cART era, HIV-SN prevalence is consistently reported at ∼40% [22], [49], [62] and [67].
......Of those with HIV, 42% fulfilled the case definition for HIV-SN (n = 28), of whom 75% (n = 21) reported pain...... The most frequent QST abnormalities in HIV-SN were loss of function in mechanical and vibration detection......The majority of abnormal parameters were loss of sensory function for any of the QST parameters, with 34.2% and 85.7% of participants in the HIV-No SN and HIV-SN groups, respectively, displaying evidence of at least 1 abnormal value.....Analysis of data from the self-report ISI instrument indicated that both patient groups on average experienced mild subclinical insomnia.....A higher mean triglyceride plasma (TRG) concentration was measured in the HIV-SN group 2.18 ± 1.09 mmol/L compared to that for the HIV-No SN group, at 1.61 ± 0.77 mmol/L (P < .05; Table 6).
.....Established risk factors associated with the development of HIV-SN include advancing age, height, and exposure to the neurotoxic dNRTI (nucleoside reverse transcriptase inhibitor) class of antiretroviral agents [30] and [31]. The dNRTI drugs are zalcitabine (ddC), stavudine (d4T), and didanosine (ddI). Crucially, despite the phasing out of neurotoxic dNRTI drugs, especially in well-resourced countries, the prevalence of HIV-SN has consistently remained at around 40%, even in people who have no history of exposure to dNRTIs, suggesting that drug-induced neurotoxicity may not be a major aetiological factor for HIV-SN in the cART era [12], [22] and [62].
......http://www.sciencedirect.com/science/article/pii/S0304395914003030
"DNP....is often refractory to medical therapy, and is associated with disability, reduced quality-of-life, high health care costs and premature death. Determining the rate at which new DNP still occurs in individuals who are growing older on antiretroviral therapy is important to estimate the likely burden of chronic pain for the US healthcare system. Future studies might address prevention strategies to reduce new DNP among individuals at high-risk, such as those with opioid use disorders or depression.
(study 2)
our findings suggest that DNP will be a persistent or increasing clinical problem......Despite modern combination antiretroviral therapy (CART), distal neuropathic pain (DNP) continues to affect many individuals with HIV infection. We evaluated risk factors for new onset DNP in the CNS Antiretroviral Therapy Effects Research (CHARTER) study, an observational cohort.......at six US academic medical centers between 2002-2007, we found prevalent HIV-associated sensory neuropathy (HIV-SN) in 881 of 1539 participants (57%). ......One third (167; 34%) had a history of prior exposure to potentially neurotoxic drugs (stavudine, didanosine); 71 (14%) took these medications at entry. .....individuals with detectable plasma HIV viral loads at entry had a higher risk of new DNP......Alcohol is a peripheral neurotoxin that can cause DNP; nutritional deficiencies are known to amplify alcohol's neurotoxicity.....Neuropsychiatric factors, specifically opioid use disorders and worsening depressed mood, were associated with increased rates of new DNP......NP was associated with past opioid abuse, rather than recent use of opioids.
........Comorbid diabetes mellitus was diagnosed in 39 participants (8%) and hepatitis C virus seropositivity in 125 (25%). A lifetime history of substance use disorder (abuse or dependence) by DSM-IV criteria was present for 356 (73%) participants.....Alcohol use disorders were the most common (270, 55%), followed by cocaine (40%), methamphetamine (18%) and opioids (17%). Among the 131 participants with a history of opioid use disorders, 13 (9.9%) took opioid medications at study entry. The median study entry BDI-II score was 9 (IQR 4 to 18), indicating minimal current depressive symptomatology on average.....Among 493 participants, 131 (27%) reported new DNP over 2,306 visits during a median follow-up of 24 months [interquartile range (IQR) 12-42]. In multivariable regression, after adjusting for other covariates, significant entry predictors of new DNP were older age, female sex, current and past antiretroviral treatment, lack of virologic suppression, and lifetime history of opioid use disorder.....We observed new onset DNP -- defined as bilateral distal leg and foot pain with neuropathic qualities in participants who did not report this at study entry -- in one quarter of HIV-infected individuals over an average of 2 years.....older age was associated with higher rates of new DNP."
(study 3)
ALLERT - AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trial
Two thousand, one hundred and forty-one participants were followed from January 2000 to June 2007. Rates of peripheral neuropathy/SPN at 3 years were 32.1/ 8.6% despite 87.1% with HIV-1RNA 400 copies/ml or less and 70.3% with CD4 greater than 350 cells/ml.
"Of these, 38% reported DNP....Risk factors for neuropathic pain were use of specific, neurotoxic, dideoxynucleoside analogue antiretrovirals ("D-drugs")......Neuropsychiatric conditions such as substance use and mood disorders have been shown to influence the prevalence and incidence of neuropathic pain in other diseases.....Study entry characteristics of the 493 initially DNP-free study participants are provided in Table 1. Participants were mostly male (81%) and mostly either African-American (44%) or Caucasian (42%). The average age was 42 years (range, 18 to 66). The median nadir CD4 was 192 (interquartile range [IQR] 52 to 342). Most participants (68%) were prescribed CART. Of those on CART, 201 (60%) had an undetectable plasma VL, and the median current CD4 was 442
Sensory neuropathy (SN) is a common cause of chronic neuropathic pain that contributes to disability, unemployment, depression, medication overuse and frequent medical provider visits. HIV frequently leads to SN and attendant distal neuropathic pain (DNP) [17; 22]. DNP typically appears first in the toes and feet and is often described with words such as "stabbing", "burning" and "aching" [9; 36]. DNP is the most frequent source of disability in HIV-SN and often requires daily analgesics or other pain-modifying therapies. HIV-SN persists and can occur de novo even during successful (i.e., virologically suppressive) treatment with modern treatment with combination antiretroviral therapies (CART) [22].
Distal painful sensorimotor polyneuropathy may affect up to 35% of people with HIV.......HIV can cause neuropathy.....The pattern of neuropathy is different for polyneuropathy caused by direct HIV infection, which affects all fibers, compared with that induced by antiretroviral treatment, which affects small fibers......Peripheral neuropathy in HIV patients persists despite improved immunologic function and virologic control associated with cART and decreased nART use. Our data span studies in which nART was initiated to recent studies avoiding nART. nART use has become uncommon in the developed world yet remains in resource-limited settings due to low cost, making these observations relevant. Additionally, this study considers the impact of diabetes, statins, and protease inhibitors, all of which are central issues for HIV care.
"Two thousand, one hundred and forty-one participants were followed from January 2000 to June 2007."
"Signs of peripheral neuropathy remain despite virologic/immunologic control but frequently occurs without symptoms. Aging is a risk factor for peripheral neuropathy/SPN......The following variables were associated with a higher odds of peripheral neuropathy in a model simultaneously evaluating all factors: older patient age [OR = 1.89, 95% CI = (1.73-2.07), P < 0.001], baseline CD4 200 or less compared to CD4 at least 501 [OR = 1.39, 95% CI = (1.02-1.90), P = 0.121], current CD4 200 or less compared to CD4 at least 501 [OR = 1.47, 95% CI = (1.16-1.87), P = 0.007], current nART use [OR = 1.40, 95% CI = (1.20-1.63), P < 0.001], taller height [OR = 1.11, 95% CI = (1.05-1.17), P < 0.001], black race compared to white race [OR = 1.25, 95% CI = (1.03-1.51), P = 0.004], and other race compared to white race [OR = 1.96, 95% CI = (1.21-3.19), P = 0.004]. A history of diabetes [OR = 1.57, 95% CI = (0.96-2.59), P = 0.080] and use of a statin drug [OR = 1.17, 95% CI = (0.98-1.41), P = 0.097] also trended towards significance. Viral suppression (HIV-1 RNA ≤ 400 copies/ml) was not associated with peripheral neuropathy [OR = 0.99, 95% CI = (0.84-1.17), P = 0.902] (Fig. 2a)."
Patients that had peripheral neuropathy (and SPN) while on nART and later withdrew nART were followed to evaluate recovery. A 54.1% (44.8%, 63.2%) of patients continued to have peripheral neuropathy during all remaining follow-up, whereas 18% (11.7%, 26.0%) of patients had no peripheral neuropathy during all remaining follow-up. 36.8% (24.5%, 50.7%) of patients continued to have SPN during all remaining follow-up, whereas 43.9% (30.7%, 57.6%) of patients had no SPN during all remaining follow-up.
Diabetes reflected by insulin use also predicts less chance for reversal of symptomatic neuropathy, suggesting that combining the diabetic risk with nART-induced mitochondrial deficits may be a particularly troublesome neurotoxic situation.
Two thousand one hundred and forty-one ART-naïve participants (81% men, 44% white, 32% black, median age = 39 years, median log10 HIV-1 RNA = 4.90 copies/ml and median CD4 cell count = 206 cell/μl at cART initiation) were analyzed (Table 1)."
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The pattern of neuropathy is different for polyneuropathy caused by direct HIV infection, which affects all fibers, compared with that induced by antiretroviral treatment, which affects small fibers.[4]
Since the advent of HAART, several studies have shown a lack of association between distal painful sensorimotor polyneuropathy and the degree of immunosuppression, including CD4 counts and viral load. Several HAART medications [old D drugs/nukes: d4T, ddI, dec, AZT] may be toxic to mitochondria by inhibiting mitochondrial DNA polymerase.[7, 8, 9] The latest 2013 WHO guidelines have sought to phase out d4T therapy in underdeveloped countries as first-line treatment.
Childs et al. found that HIV-associated distal sensory polyneuropathy was associated with lower CD4 count and higher viral load.[17] This association, however, has not been well characterized since the HAART era. Other risk factors include diabetes, height, statin use, d4T exposure, and substance abuse.[14, 18, 19, 20, 21, 22, 23]
HIV-associated distal painful neuropathy is a progressive disease unless co-existant causes, such as neurotoxic drugs or vitamin deficiencies, can be eliminated.
Distal painful sensorimotor polyneuropathy may affect up to 35% of people with HIV.[12]
At autopsy it is found in almost 100% of patients with AIDS. The prevalence of distal painful sensorimotor polyneuropathy continues to rise because of increased life expectancy.[13, 14]
Distal painful sensorimotor polyneuropathy is more prevalent in males than in females and more common in persons older than 50 years.[15]
There are no FDA-approved treatments. Treatment options fall into 2 groups: causal and symptomatic. In causal treatment, avoid neurotoxic medications, if possible.
Treatment of HIV-associated distal painful sensorimotor polyneuropathy currently focuses on pain management. As in other painful neuropathies drugs from several classes can be used alone or in combination.
In a phase II, double-blind, placebo-controlled, crossover trial by Ellis et al, adjunctive smoked cannabis was generally well tolerated and effective for refractory pain from HIV-associated distal painful sensorimotor polyneuropathy.[36] Regulatory concerns limit the utility of this approach in many parts of the world.
http://emedicine.medscape.com/article/1167783-overview
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Predictors of New Onset Distal Neuropathic Pain in HIV-infected Individuals in the Era of Combination Antiretroviral Therapy
Pain. April 2015
Despite modern combination antiretroviral therapy (CART), distal neuropathic pain (DNP) continues to affect many individuals with HIV infection. We evaluated risk factors for new onset DNP in the CNS Antiretroviral Therapy Effects Research (CHARTER) study, an observational cohort.
In multivariable regression, after adjusting for other covariates, significant entry predictors of new DNP were older age, female sex, current and past antiretroviral treatment, lack of virologic suppression, and lifetime history of opioid use disorder. The associations with opioid use disorders and depression reinforce the view that the clinical expression of neuropathic pain with peripheral nerve disease is strongly influenced by neuropsychiatric factors.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374054/
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Peripheral neuropathy in HIV: prevalence and risk factors
AIDS April 24 2011
Evans, Scott Ra; Ellis, Ronald Jb; Chen, Huichaoa; Yeh, Tzu-mina; Lee, Anthony Ja; Schifitto, Giovannic; Wu, Kunlinga; Bosch, Ronald Ja; McArthur, Justin Cd; Simpson, David Me; Clifford, David Bf
Results:
Two thousand, one hundred and forty-one participants were followed from January 2000 to June 2007.
Study participants had variable length of follow-up and variable timing (relative to initiation of cART) for their first evaluations. Participants from six randomized trials [ACTG trials 347 (n = 19 [31]), 384 (n = 566 [32]), 388 (n = 214 [33]), A5014 (n = 38 [34]), A5095 (n = 771 [35]), and A5142 (n = 533 [36])] were analyzed.
Rates of peripheral neuropathy/SPN at 3 years were 32.1/8.6% despite 87.1% with HIV-1RNA 400 copies/ml or less and 70.3% with CD4 greater than 350 cells/μl.
Associations with higher odds of peripheral neuropathy included older patient age and current nART use. Associations with higher odds of SPN included older patient age, nART use, and history of diabetes mellitus.
Associations with lower odds of recovery after nART discontinuation included older patient age. Associations with higher odds of peripheral neuropathy while on nART included older patient age and current protease inhibitor use. Associations with higher odds of SPN while on nART included older patient age, history of diabetes, taller height, and protease inhibitor use.
Conclusion: Signs of peripheral neuropathy remain despite virologic/immunologic control but frequently occurs without symptoms. Aging is a risk factor for peripheral neuropathy/SPN.
Higher plasma HIV-1 RNA and lower CD4+ cell counts before the initiation of ART increased the risk of HIV-DSP in the pre-cART era [16,17]. Risk factors in the cART era have been investigated [7,18-23]. Data suggest that risk factors include prolonged exposure to cART [24], protease inhibitor exposure [25] and lipid-lowering drugs (statins and fibrates) [26]. Diabetes mellitus is a common cause of sensory neuropathy, and ART therapy, especially protease inhibitors, is associated with diabetes mellitus [27]. Ances et al. [28] reports that the risk for HIV-DSP is associated with diabetes and hypertriglyceridemia but not by other metabolic syndrome components. The interaction between metabolic syndrome and HIV is unclear. Height has been identified as a risk factor for peripheral neuropathy in diabetes [29] and recently in HIV infection when using nARTs [30].
We evaluated potential risk factors for peripheral neuropathy and symptomatic peripheral neuropathy (SPN) using data from more than 2000 ART-naive patients initiating cART in six randomized AIDS Clinical Trials Group (ACTG) trials.
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