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Neurpoathy Predictors in HIV in CHARTER Group
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April 2015 - PAIN
Malvar, Jemilya; Vaida, Florinb; Sanders, Chelsea Fitzsimonsb; Atkinson, J. Hamptonb; Bohannon, Williamb; Keltner, Johnb; Robinson-Papp, Jessicac; Simpson, David M.c; Marra, Christina M.d; Clifford, David B.e; Gelman, Benjaminf; Fan, Juanjuanh; Grant, Igorb; Ellis, Ronald J.b,* for the CHARTER Group
from Jules: diabetes can cause neuropathy although in this study they did not find that & authors said it because the # with diabetes in the study was too small. Studies find diabetes rates are increased in HIV+ and even greater rates as they age in older HIV+.
The average age was 42 years (range, 18 to 66)
Abstract
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. Standardized, semi-annual clinical evaluations were administered at six U.S. sites.
DNP was defined by using a clinician-administered instrument standardized across sites. All participants analyzed were free of DNP at study entry. New onset DNP was recorded at the first follow-up visit at which it was reported. Mixed effects logistic regression was used to evaluate potential predictors including HIV disease and treatment factors, demographics, medical comorbidities and neuropsychiatric factors.
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. During follow-up, more severe depression symptoms conferred a significantly elevated risk.
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. Delineating such risk factors might help target emerging preventive strategies, for example, to individuals with a prior history of opioid use disorder, or might lead to new treatment approaches such as the use of tools to ameliorate depressed mood.
Neuropsychiatric factors, specifically opioid use disorders and worsening depressed mood, were associated with increased rates of new DNP. Sensitivity analyses demonstrated that these risk factors were robust to model assumptions, since they remained significant when limited only to individuals with clear clinical evidence of sensory neuropathy and when the endpoint was limited to those moderate or severe DNP. DNP was associated with past opioid abuse, rather than recent use of opioids. This implies that new onset DNP reflects a shared vulnerability, perhaps mediated by brain reward circuits. Indeed, reciprocal projections between the nucleus accumbens, a key brain reward hub, and prefrontal cortex subserve important aspects of both pain and addiction [2; 4; 6; 18]. For example, opioid addiction is associated with increased dopaminergic tone between the ventral tegmental area and nucleus accumbens, leading to long-term downregulation of dopamine receptors in the accumbens and enhanced glutamatergic transmission in prefrontal-accumbens pathways [5]. These same circuits process emotional and cognitive aspects of sensory information [1; 35]. Thus in individuals with SN and a past history of opioid abuse, aberrant sensory input from damaged peripheral nerves might be processed differently by brain reward circuits in vulnerable individuals, predisposing to the clinical phenotype of DNP.
older age was associated with higher rates of new DNP. Since DNP is the principal reason for seeking medical attention among patients with HIV-SN, and since pain contributes significantly to reduced quality of life [17], and to medical costs [26], our findings have substantial implications for an aging population of HIV-infected men and women on long-term ART.....Neuropsychiatric factors, specifically opioid use disorders and worsening depressed mood, were associated with increased rates of new DNP......We found also that during follow-up worse depressive symptoms predicted new DNP.....HIV disease and treatment status significantly affected new DNP rates in this study-history of more advanced immunosuppression, as indexed by lower nadir CD4 counts.....individuals with detectable plasma HIV viral loads at entry had a higher risk of new DNP.
Table 3 shows the final selected multivariable model. No variables interacted with time. Significant predictors of new onset DNP after adjusting for other variables in the model were current (OR 2.44 versus naive) and past (OR 4.59 versus naive) CART use at study entry, detectable plasma viral load during follow-up (OR 1.54 versus undetectable), lifetime history of opioid use disorders (OR 2.31 versus no opioid use disorder) and more severe depression symptoms at follow-up (OR 1.66, 1.89, and 2.99 for mild, intermediate, and severe depression versus no depression). Participant age and sex were retained in the model based on the AIC criterion; older age had higher risk than younger age (OR 1.20 for 50 years versus 45 years, p-value = 0.064); men (81% of the cohort) had lower risk than women, at a p-value (0.15). Variables not included in the multivariable model were race/ethnicity, history of d-drug use, current and nadir CD4, estimated duration of HIV infection at study entry, hepatitis C serostatus, diabetes mellitus, serum triglycerides [7; 43], and lifetime history of alcohol or other non-opioid substance use disorders.
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]. In a previously reported, prospective, cross-sectional analysis [17] of data collected at six US academic medical centers between 2002-2007, we found prevalent HIV-associated sensory neuropathy (HIV-SN) in 881 of 1539 participants (57%). Of these, 38% reported DNP. DNP was significantly associated with disability in daily activities, unemployment, and reduced quality of life, even when rated mild in severity. Risk factors for neuropathic pain were use of specific, neurotoxic, dideoxynucleoside analogue antiretrovirals ("D-drugs") and higher CD4 nadir.
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 (IQR 290-639) cells/mm3. Among the 156 not taking CART, 106 were CART naïve and the remainder had some prior exposure to ART but had discontinued it.
Predictors of New Onset Distal Neuropathic Pain in HIV-infected Individuals in the Era of Combination Antiretroviral Therapy
Among the 493 participants initially free of pain, 131 (27%) participants reported new DNP over a median follow-up of 24 months [IQR 12-42] (1,961 visits). Among these 131, only 1 (0.76%) took opioid analgesics at the new onset visit. The rate of new DNP in the entire cohort was 16.4 per 100 person-years of follow-up (PYFU); among those on CART with undetectable VL at study entry, the rate was 14.8 per 100 PYFU. The duration of DNP reported at the new onset visit was more than one year in 59 participants (45%), one month to one year in 59 (45%) and less than one month for 13 (10%). Of the 131 participants with new DNP, 85 (65%) had one or more signs of neuropathy (symmetric distal reduction in reflexes or in pin or vibration sensation) at the new DNP visit.
Multivariable Analysis
Table 3 shows the final selected multivariable model. No variables interacted with time. Significant predictors of new onset DNP after adjusting for other variables in the model were current (OR 2.44 versus naive) and past (OR 4.59 versus naive) CART use at study entry, detectable plasma viral load during follow-up (OR 1.54 versus undetectable), lifetime history of opioid use disorders (OR 2.31 versus no opioid use disorder) and more severe depression symptoms at follow-up (OR 1.66, 1.89, and 2.99 for mild, intermediate, and severe depression versus no depression). Participant age and sex were retained in the model based on the AIC criterion; older age had higher risk than younger age (OR 1.20 for 50 years versus 45 years, p-value = 0.064); men (81% of the cohort) had lower risk than women, at a p-value (0.15). Variables not included in the multivariable model were race/ethnicity, history of d-drug use, current and nadir CD4, estimated duration of HIV infection at study entry, hepatitis C serostatus, diabetes mellitus, serum triglycerides [7; 43], and lifetime history of alcohol or other non-opioid substance use disorders.
One third (167; 34%) had a history of prior exposure to potentially neurotoxic drugs (stavudine, didanosine); 71 (14%) took these medications at entry. 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. Among those meeting criteria for lifetime disorders, most were remote (333; 94%) rather than current (in the last 30 days; N=23; 6%). 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.
Characterizing predictors of new DNP is important since some of these individuals will ultimately transition to chronic pain, a condition which affects tens of millions of people in the United States, 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. A recent opinion piece highlighted the tension between the challenges of chronic pain and addiction[34]. This paper and ours together point to the dilemma faced by clinicians managing DNP of whether to use opiates for pain in patients with a prior history of opioid abuse. Imaging of brain structure and function as well as characterization of peripheral nerve function in participants before and after new HIV DNP might help to clarify brain influences on DNP and identify potential new therapeutic targets.
Discussion
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. Independent of other risk factors, older age was associated with higher rates of new DNP. Since DNP is the principal reason for seeking medical attention among patients with HIV-SN, and since pain contributes significantly to reduced quality of life [17], and to medical costs [26], our findings have substantial implications for an aging population of HIV-infected men and women on long-term ART.
Neuropsychiatric factors, specifically opioid use disorders and worsening depressed mood, were associated with increased rates of new DNP. Sensitivity analyses demonstrated that these risk factors were robust to model assumptions, since they remained significant when limited only to individuals with clear clinical evidence of sensory neuropathy and when the endpoint was limited to those moderate or severe DNP. DNP was associated with past opioid abuse, rather than recent use of opioids. This implies that new onset DNP reflects a shared vulnerability, perhaps mediated by brain reward circuits. Indeed, reciprocal projections between the nucleus accumbens, a key brain reward hub, and prefrontal cortex subserve important aspects of both pain and addiction [2; 4; 6; 18]. For example, opioid addiction is associated with increased dopaminergic tone between the ventral tegmental area and nucleus accumbens, leading to long-term downregulation of dopamine receptors in the accumbens and enhanced glutamatergic transmission in prefrontal-accumbens pathways [5]. These same circuits process emotional and cognitive aspects of sensory information [1; 35]. Thus in individuals with SN and a past history of opioid abuse, aberrant sensory input from damaged peripheral nerves might be processed differently by brain reward circuits in vulnerable individuals, predisposing to the clinical phenotype of DNP.
We found also that during follow-up worse depressive symptoms predicted new DNP. This was not simply due to depressed individuals having poorer antiretroviral medication adherence [16; 32], since multivariable regression showed that depression remained significant after adjusting for adherence. Previous studies have demonstrated that, regardless of the cause of the underlying pain state, pain and depression are reciprocally reinforcing [3; 13; 26]. In depression, altered brain activity in the insular cortex may impair the ability to modulate pain experience [41; 42] leading to allodynia, the experience of pain in response to stimuli that are not ordinarily painful.
HIV disease and treatment status significantly affected new DNP rates in this study. Thus the highest rate occurred in a relatively small group of individuals (N=50) who had prior CART exposure, but had discontinued antiretroviral therapy. These individuals had a history of more advanced immunosuppression, as indexed by lower nadir CD4 counts, than ART-naïve participants. Also they had lower current CD4s than those with virologic suppression on CART. The lowest rate was seen in ARV naïve individuals, likely reflecting their less advanced HIV disease. Among those taking CART, rates of new DNP were intermediate between the two previously mentioned groups. Additionally, individuals with detectable plasma HIV viral loads at entry had a higher risk of new DNP. Since 30 to 40% of HIV-infected persons on CART in the U.S. do not maintain durable virologic suppression due to transfer of care, poor antiretroviral adherence, and other factors [24], our findings suggest that DNP will be a persistent or increasing clinical problem.
Overall these findings indicate that the determinants of new onset DNP in the current treatment era are different from those for DNP as described in previous studies. For example, whereas in previous studies CD4 nadir was a robust correlate of DNP [17; 40], we did not find it to correlate with new onset DNP in the present study. Also, previous studies have demonstrated that exposure to neurotoxic antiretroviral agents such as stavudine increased the risk of DNP [12; 33], but we did not find such exposure to predict new DNP in the current era. In previous studies taller stature [11] and comorbid diabetes mellitus [30] correlated with DNP. Although height was a significant predictor in our univariable analysis, it was no longer significant when the multivariable analysis adjusted for other predictors. Although we did not find diabetes mellitus to be a significant predictor, the number of diabetics in this cohort was relatively small (39; 7.8%). Alcohol is a peripheral neurotoxin that can cause DNP; nutritional deficiencies are known to amplify alcohol's neurotoxicity [10; 29]. Although we did not observe an association between alcohol use disorders and DNP, the magnitude of alcohol-related effects may have been attenuated in these community dwelling U.S. participants in care who were unlikely to suffer from substantial nutritional deficiencies.
This study has several limitations. Clinicians were trained to assess whether subjects' pain was likely to be neuropathic by virtue of the use of descriptors such as "stabbing", "aching" and "burning". These particular descriptors were chosen from a much longer list of adjectives often used by individuals with pain due to distal neuropathy. Although these terms were presented as guidelines, rather than formal definitions, the limitation to this particular short list of descriptors was otherwise expedient and it is possible that under-ascertainment of neuropathic occurred, since some patients use alternative descriptors. All prospective cohort studies are subject to bias related to factors not observed or measured. A strength of the present analysis was its extensive characterization of disease and treatment indicators and comorbid conditions. Nevertheless it remains possible that important factors were not assessed. In our study, some of those with incident DNP did not have objective findings of distal sensory loss or reduced tendon reflexes. However, the clinical neurological examination is incompletely sensitive to the presence of neuropathy, and in clinical practice neuropathy is frequently diagnosed by using more sensitive measures of nerve function such as quantitative sensory testing (QST) and nerve conduction studies (NCS). One reason for the lesser sensitivity of the clinical examination is that it does not adequately assess the function of small fibers, including C and delta fibers, which subserve pain perception [19]. Ancillary testing improves sensitivity to small fiber injury. While ancillary testing is prohibitively expensive to carry out in a large cohort such as this one, we did perform QST and NCS on a subset of these same study participants. In a previous analysis published in Pain [37], we demonstrated that the presence of DNP and paresthesias had 95% sensitivity for detecting objective evidence of neuropathy with such tests. Indeed, early reviews that included autopsy studies found evidence of peripheral nerve damage in more than half of those dying with AIDS - even though only 40% had symptoms [23; 44]. Notwithstanding these considerations, we performed a sensitivity analysis limiting the sample at risk to those who did show signs of neuropathy on examination. This sensitivity analysis demonstrated that the predictors were robust to model assumptions.
It might be argued that DNP in some of our subjects was relatively mild therefore of questionable clinical significance. However, we have previously shown in this same cohort that DPN intensity is not as strongly related to quality of life as is commonly assumed [28]. Thus even mild pain was associated with substantial distress and reductions in life quality. To further address the concern that milder degrees of DNP were "driving" the observed relationships, we re-analyzed our data after excluding cases with clinician-rated "mild" DNP. In the remaining subjects with moderate or severe DNP, we found the same significant predictors.
Neuropathic pain can wax and wane in severity [38]. Also, DNP can remit, either spontaneously or as a result of treatment, and might even recur at a later time. The present study was not designed to distinguish between recurrent and incident DNP. However, 90% of participants reported that the duration of their neuropathic pain was at least one month, and almost half indicated that it had been present for longer than a year. Future work is needed to develop instruments to carefully discriminate between recurrent and incident neuropathic pain.
Characterizing predictors of new DNP is important since some of these individuals will ultimately transition to chronic pain, a condition which affects tens of millions of people in the United States, 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. A recent opinion piece highlighted the tension between the challenges of chronic pain and addiction[34]. This paper and ours together point to the dilemma faced by clinicians managing DNP of whether to use opiates for pain in patients with a prior history of opioid abuse. Imaging of brain structure and function as well as characterization of peripheral nerve function in participants before and after new HIV DNP might help to clarify brain influences on DNP and identify potential new therapeutic targets.
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