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HIV Neuropathy: Women & Men/Prevalence-Risk Factors
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"DNP [neuropathy]....is often refractory to medical therapy, and is associated with disability, reduced quality-of-life, high health care costs and premature death.
"African American women were more likely to have HIV-DSPN even after multivariable adjustment"
"men (81% of the cohort) had lower risk than women, at a p-value (0.15)."
Prevalence: 57% to 36%
"Aging is a risk factor for peripheral neuropathy/SPN"
"Key predictors....neuropathic pain in HIV+ individuals during follow-up were past opioid use disorders.....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.
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ALLERT: 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)."
(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
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.
Demographics and baseline characteristics. Two thousand one hundred and forty-one ART-naıve 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/ml at cARTinitiation) were analyzed (Table 1.
"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.
.......54.1% (44.8%, 63.2%) of patients continued to have peripheral neuropathy during all remaining follow-up,
"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].
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Predictors of New Onset Distal Neuropathic Pain in HIV-infected Individuals in the Era of Combination Antiretroviral Therapy
Peripheral Neuropathy, a severe comorbidity for Aging Older HIV+
http://www.natap.org/2016/HIV/080616_04.htm/
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).
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.
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). .....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. ....
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).
This implies that new onset DNP reflects a shared vulnerability, perhaps mediated by brain reward circuits.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299869/
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The Relationship Between Race and HIV-Distal Sensory Polyneuropathy in a Large Cohort of US Women
Yaacov Anziska, MD, MS, Elizabeth P. Helzner, PhD, [...], and Pamela Burian, PA
Abstract
Introduction
HIV-distal sensory polyneuropathy (HIV-DSPN) is a common complication of HIV infection, yet race as a potential risk factor is not known.
Methods
Between April and October 2009, as part of the NIH Women's Interagency HIV Study (WIHS), 1414 women, 973 of whom were HIV-infected, were clinically evaluated for peripheral neuropathy. Utilizing available clinical, laboratory, and sociodemographic variables, we conducted a cross-sectional analysis of factors associated with HIV-DSPN. Multivariable logistic regression was used to examine factors independently associated with HIV-DSPN.
Results
36% of HIV-infected women met our definition of HIV-DSPN. 41.3% of African Americans, 34.8% of Whites and 24.7% of Hispanics had DSPN. Age, Hepatitis C-co-infection, and diabetes were each significantly associated with HIV-DSPN. After controlling for age, diabetes, Hepatitis C co-infection, alcohol use, current dideoxy-nucleoside reverse transcriptase inhibitor use, current CD4 count, and plasma HIV viral load, HIV-DSPN was significantly associated with ethnicity; the odds ratio was 1.67 (p=0.001) in African-Americans compared to other racial groups.
Conclusion
The prevalence of HIV-DSPN in women was lower than reported in prior studies. The likelihood of HIV-DSPN was higher in African-Americans compared to other racial groups. HIV-DSPN was more common in those co-infected with Hepatitis C, older individuals, and diabetics. Further prospective studies are needed to explore the relationship between gender, race, and HIV-DSPN, and the mechanistic basis for racial differences.
Discussion
In this study, the first involving only women, we found that age, diabetes, and chronic co-infection with Hepatitis C were significantly associated with HIV-DSPN, confirming findings from other studies [7]. As described in a recent study [15], African-American race was associated with significantly higher rates of HIV-DSPN compared to other racial groups. CD4 count, HIV viral load, and the use of d-NRTI drugs were not significantly associated with HIV-DSPN, as in previous studies [1]. This may be due to the low percentages of subjects using d-NRTI drugs and the relatively high median CD4 count of 523 cells/mm3. Furthermore, increasing height was not associated with HIV-DSPN, as in previous studies [8,16], but these studies had larger mean heights with both sexes represented. In this study of women, the mean height was smaller, only 159 centimeters, and HIV-DSPN might rely on a "threshold affect", or affecting subjects above a certain height.
Within the 973 HIV-infected subjects, the frequency of HIV-DSPN was 36.4%. In the 378 uninfected subjects, the frequency of neuropathy was only 19%. The HIV-infected subjects were 20.4% Hispanic, 64.3% African-American, 9% White, and 5.1% Other. 17.3 % of the infected subjects were infected with Hepatitis C, 20.5% had diabetes, and 17.4% had heavy alcohol use. The mean age was 42 years, with a standard deviation of 9.9.
Within the 973 HIV-infected subjects tested for neuropathy, there was no significant difference between the HIV-DSPN+ (n=354) and HIV-DSPN− (n=619) groups as to alcohol use, height, CD4 count, viral load, and age. Both groups had similar percentages of white and Asian participants, although the HIV-DSPN+ group had a smaller percentage of Hispanics (20.6 versus 31.2, p<0.001) and greater percentage of African-Americans (66.7 versus 52.5, p<0.001). Diabetics comprised 26.3% of HIV-DSPN+ group and 16% of HIV-DSPN− group (p<0.001). Co-infectivity with Hepatitis C was found in 39.3% of HIV-DSPN+ participants and 21.6% of HIV-DSPN− participants (p<0.001). The high CD4 counts and low viral loads in both groups, as well as the mean duration of HIV infection and use of d-NRTI drugs, are shown in Table 1.
We found a frequency of HIV-DSPN of 36%, lower than previous studies, most of which contained male subjects. In the one prior study with a majority of female subjects, the prevalence of HIV-DSPN was 57%, and the median age of these women was 35, younger than in our study [16]. The presence of an entirely black-African cohort may explain this cited study's increased prevalence of HIV-DSPN, as compared to our own study. From our data, it appears that although our participants share similar risk factors for HIV-DSPN as in other studies, our study's women are less affected by HIV-DSPN. The lower prevalence of neuropathy in our study's HIV-infected women was not due to the lack of known risk factors for neuropathy; 28% of these women possessed chronic co-infection with hepatitis C, 19.4% had diabetes, and 9% drank 3 or more times/week. Furthermore, one would have expected higher rates of HIV-DPSN because of the study's expansive definition of neuropathy: one (or more) clinical signs, not two signs, as in other studies.
We found a frequency of HIV-DSPN of 36%, lower than previous studies, most of which contained male subjects. In the one prior study with a majority of female subjects, the prevalence of HIV-DSPN was 57%, and the median age of these women was 35, younger than in our study [16]. The presence of an entirely black-African cohort may explain this cited study's increased prevalence of HIV-DSPN, as compared to our own study. From our data, it appears that although our participants share similar risk factors for HIV-DSPN as in other studies, our study's women are less affected by HIV-DSPN. The lower prevalence of neuropathy in our study's HIV-infected women was not due to the lack of known risk factors for neuropathy; 28% of these women possessed chronic co-infection with hepatitis C, 19.4% had diabetes, and 9% drank 3 or more times/week. Furthermore, one would have expected higher rates of HIV-DPSN because of the study's expansive definition of neuropathy: one (or more) clinical signs, not two signs, as in other studies.
Compared to others women, African American women were more likely to have HIV-DSPN even after multivariable adjustment. Although it is possible that African-Americans might suffer more from risk factors for neuropathy, such as Hepatitis C co-infection, the multivariable model controlled for these factors, and the increased odds for HIV neuropathy in African American women still persists. There may be other, as yet, uncharacterized confounders more common in African Americans that predispose them to neuropathy. This possibility is suggested by the results of a recent study, Evans et al, in which African-American race was positively associated with HIV-DSPN [15].
Study biases could have contributed to the higher incidence of HIV-DSPN in African-American subjects. There could be selection bias, with more African-American women possessing signs and symptoms of neuropathy enrolling in our cohort; they might have done so because of over-representation of African-Americans in study neighborhoods. A significant study limitation was the lack of data on cumulative antiretroviral exposure, especially of the d-NRTI drugs. Neuropathy was only evaluated recently in this cohort, much later than initial enrollment, so the cross-sectional and retrospective nature of the study prevents evaluation of causation.
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