Better Antiretroviral Central Nervous System Penetration is Not Associated with Reduced Chronic Pain in People Living with Human Immunodeficiency Virus

CPE score is not associated with chronic pain in PLWH. Post-hoc analysis demonstrated that CPE mark, and zidovudine exposure in finical, predicts a plus depressive disorder screen. Given the substantial morbidity associated with chronic pain and climate disorders in PLWH, extra studies to determine preventable and treatable factors are imperative. 245 of 254 subjects were on ARVs. Complete ARV datum was available for 235 patients. 137 of these 235 patients ( 58.3 % ) had a CPE score ≤7, and 98 ( 41.7 % ) had a score ≥8. 49 patients had chronic pain, and 9 had neuropathic trouble. low CPE score was not associated with chronic pain ( p=0.64 ), neuropathic annoyance ( p=0.56 ), or frequent trouble ( p=0.80 ), nor was it associated with the austereness of reported “ worst pain ” or “ modal pain ” in the last 24 hours ( p=0.18 and 0.48, respectively ). Post-hoc analysis revealed that higher CPE score was a significant independent risk factor for natural depression measured by a incontrovertible PHQ-2 screen [ OR ( 95 % CI ) = 1.29 ( 1.04–1.61 ), p=0.02 ]. This relationship was mediated chiefly by exposure to zidovudine. We interviewed 254 straight adults from an HIV clinic in Chiang Mai, Thailand. We collected data on demographics, HIV history, ARV practice, and annoyance characteristics. Patients were evaluated for depression using a Thai two question Patient Health Questionnaire ( PHQ-2 ). Modified CPE score was calculated using established methods and grouped a priori into “ humble CPE ” ( ≤7, hapless penetration ) and “ high CPE ” ( ≥8, good penetration ). CPE score was compared with chronic pain scores in SPSS using appropriate statistical tests. A relationship between CPE score and a incontrovertible natural depression screen door was tested far using multivariable binary star logistic models. Chronic pain remains prevailing in PLWH despite far-flung ARV practice. Mechanisms underlying this prevalence remain stranger, though neuroinflammation from dogged CNS HIV infection and maladaptive formative changes in the CNS have been implicated. here we hypothesize that better CNS ARV penetration, measured using the CNS Penetration-Effectiveness ( CPE ) score, would decrease rates of chronic trouble.

Given the evidence reviewed above suggesting that chronic pain in PLWH could result from haunting CNS HIV infection and maladaptive malleability, we hypothesized that better CNS ARV penetration and an associate decrease in CNS HIV burden would lead to a decreased prevalence of chronic annoyance in PLWH. Our primary draw a bead on was to test if better CNS ARV penetration, measured using the modified CPE grudge, was associated with decrease rates of chronic pain in a population of HIV+ Thai adults. Our secondary aims were to investigate if higher CPE scores were associated with decrease austereness of pain or decreased rates of chronic neuropathic annoyance. The CNS Penetration-Effectiveness ( CPE ) score is a validate cock to quantify the CNS-penetration of ARVs ; better penetration has been shown to correlate with reduce HIV CSF viral load mugwump of the systemic potential of the regimen [ 31, 32 ]. In this seduce, ARVs are ranked according to their ability to penetrate the lineage mind barrier and reduce CSF viral load, with higher scores indicating better penetration [ 31 ]. This score was updated in 2010 [ 32 ]. Using this score, some studies show that the rates and asperity of HIV-associated neurocognitive disorders vary with the CNS penetration of the ARV regimen [ 31, 33 ]. Since the introduction of haul, mortality and quality of life have improved for PLWH. however, late work highlights the find that neurological manifestations of HIV persevere even in patient with well-controlled systemic disease on haul. major disabilities that can persist in the chronic treated phase include pace disorders, cognitive impairment, and respective trouble syndromes including atrocious neuropathy and migraine [ 11, 12, 24 – 26 ]. HIV can persist in the CNS, even in the face of handcart, partially explaining the perseverance of neurological symptoms, [ 24, 27 ] though controversy remains [ 28 ]. furthermore, it has been demonstrated that certain widely used ARV agents do not adequately penetrate the CNS equally good as early agents, [ 29, 30 ] and that decreased CNS penetration correlates with increase CSF HIV viral warhead [ 27 ]. The central nervous system is a know refuge for HIV, and haunting CNS viral infection can be present even when viral load is not detectable in plasma – the alleged “ viral escape ” phenomenon [ 22, 23 ]. HIV ’ s proclivity to chronically infect the CNS and induce the formative changes mentioned above provides a conjectural mechanistic model to explain the observe increased preponderance of pain in PLWH, though the pathophysiologic cascade is not yet sympathize. Though the pathophysiology underlying the increased preponderance of chronic pain in PLWH specifically remains stranger, respective mechanisms have been proposed. Viral induced immune dysregulation, sequela of opportunist infections, and toxic effects of therapy have all been implicated, and indeed all may play a role in a multifactorial process [ 18 ]. It has been hypothesized that HIV infection of CNS microglia, macrophages, and possibly astrocytes leads to neural damage either through calculate toxic effects or through local inflammatory phenomenon [ 19 ]. In animals, intrathecal HIV-1 has been demonstrated to induce enhanced pain states through upregulation of spinal anesthesia cord proinflammatory cytokines [ 20 ]. In humans, these same incendiary cytokines have been shown to be upregulated in the dorsal french horn of pain-positive HIV+ patients, but not HIV+ patients without pain [ 21 ]. Substantial accumulated evidence demonstrates that formative changes in the central skittish arrangement may underlie chronic annoyance states [ 13 ]. Dorsal horn neurons can become allergic such that normally innocuous stimuli induce diseased pain [ 14 ]. Proinflammatory cytokines released by activate astrocytes can induce formative changes, enhance excitant transmission, and suppress inhibitory transmission in abaxial horn neurons and interneurons, [ 15 ] and loss of spinal synaptic prohibition has been implicated in the development of chronic trouble [ 16 ]. In accession, neuroplastic changes in both ascending spinocortical and descending corticospinal connections and in the cortex itself have been shown to play a function in haunting diseased trouble [ 17 ]. Chronic trouble is among the global ’ s most dearly-won diseases on both a personal charge and a social level [ 1 ]. Chronic pain is particularly debatable in PLWH, since pain remains among the most common symptoms of chronic HIV infection even in the era of widespread antiretroviral ( ARV ) use [ 2 – 7 ]. Chronic pain is persistently undertreated in PLWH, and this untreated pain well and deleteriously impacts quality of life [ 2, 8 – 10 ]. PLWH suffer disproportionally from pain syndromes coarse to the cosmopolitan population, such as migraines, [ 11 ] equally well as from other pain syndromes more particular to HIV/AIDS or its treatment, such as painful distal neuropathy [ 12 ]. Despite the significant associated morbidity and cost, to date the underlie causes for this increased prevalence stay unknown, and a significant cognition gap exists regarding the best ways to prevent and treat chronic pain in PLWH. Use of blend antiretroviral therapy ( handcart ) has well reduced morbidity and deathrate from human immunodeficiency virus ( HIV ) related illnesses and acquired immune lack syndrome ( AIDS ). As HIV transitions from a end diagnosis to a chronic illness with the proliferation of handcart, quality of life issues will assume greater importance in the care of people living with HIV ( PLWH ). After exploratory analysis demonstrated that high CPE score was significantly associated with a positive depression riddle, multivariable binary logistic models were constructed with variables whose bivariate associations with the consequence “ PHQ positive ” had p-values < 0.2. Those variables with multivariable-adjusted p-values of < 0.2 were kept in the model. Model fit was assessed with the Hosmer-Lemeshow screen. statistical significance was defined as a p-value ≤0.05. Data was analyzed using SPSS v22 ( SPSS Inc., Chicago, IL ). Bivariate associations between categorical variables were compared using Chi-squared tests. After determining that the data was not normally distributed, the Mann-Whitney U test was used to test the associations between broken CPE score and ordinal trouble severity scores, and between binomial variables and CPE score when CPE score was analyzed as an ordinal varying. The CPE grudge ranks ARVs based on their chemical properties and proportional abilities to penetrate the blood-brain barrier, roll up in cerebrospinal fluent, and reduce CSF viral cargo [ 31 ]. It has been previously validated in the discipline of HIV-associated neurocognitive disorders, among other conditions [ 28, 36 ]. Briefly, the original grade used best available testify to rank ARVs from 0 ( low penetration ) to 1 ( senior high school penetration ). A change CPE sexual conquest former improved this rank system, assigning individual ARV CPE scores from 1 ( poor penetration ) to 4 ( best penetration ). The CPE numeric values of each drug in the regimen are summed to give the entire CPE score for the regimen, such that a regimen of handcart can yield an ordinal number CPE mark that ranges between 3 ( three agents with low penetration ) and 16 ( four agents with high gear penetration ). CNS Penetration-Effectiveness ranks for individuals medications can be seen in ( ). In the current study, we determined a priori to analyze CPE score as a binary variable star ( above and below the median ), as has been done before in studies examining CPE score [ 41 ]. We besides analyzed CPE score as an ordinal variable, which more efficaciously explores the magnitude and directivity of watch effects. To screen for depression, patients were asked a “ yes/no ” Thai shape of the two-question Patient Health Questionnaire ( PHQ-2 ) [ 39 ]. The Patient Health Questionnaire is widely used around the world to screen door for depression, and the full version has been validated in Thai and has full specificity with control sensitivity [ 40 ]. To increase sensitivity in the current analyze, patients who answered “ yes ” to either question of the PHQ-2 were considered to have screened incontrovertible for depression. The two-questions asked were as follows : “ over the last 2 weeks have you been bothered by little concern or pleasure in doing things, ” and “ over the stopping point 2 weeks have you been feeling down, depress, or hopeless. ” To identify pain, all patients were asked the follow question ( in Thai ) : “ During the past two weeks, have you experienced dogged or frequent annoyance of any type ? ” This question has been used before to investigate pain in HIV+ adults in the United States [ 10 ]. Patients who answered “ yes ” to this question were characterized as having frequent pain and were then asked the postdate wonder : “ Have you had this pain for more than three months ? ” This question has been previously used in Asia to assess for chronic annoyance [ 34 ]. Patients who answered “ yes ” to this question were characterized as having chronic pain. Patients with frequent pain were then asked to complete two more surveys related to their trouble and medications : the validate Brief Pain Inventory-Short Form ( BPI-S ) ( Thai ) [ 35 – 37 ] and the Thai interpretation of the Self-Administered Leeds Assessment of Neuropathic Symptoms and Sign ( S-LANSS ) [ 38 ]. The BPI-S ranks several aspects of pain and the impact of pain on quality of animation using an 11-point ordinal number scale ( 0–10 ), and the S-LANSS has been wide used to screen for neuropathic pain. After obtaining inform accept, trained interviewers administered exchangeable surveys in Thai. Surveys were either published previously in Thai or translated into Thai and then rear translated into English to ensure accuracy anterior to use. The full moon methods have been published previously [ 2 ]. Briefly, the principal 26-item survey questionnaire elicited information on demographics, comorbidities, and HIV clinical information. continuous data were subdivided into subcategories a priori ( e.g., estimated income was recorded as ≤1999, 2000–4999, 5000–9999, and ≥10000 Thai baht per calendar month, with 30 Thai baht approximately equal to $ 1 ). Depression and pain were identified with established screening questions ( see below ). survey items that could not inevitably be answered by the patient ( for example, CD4 nadir, stream medications ) were completed by study investigators using the electronic medical records and the historic paper graph as appropriate. This cogitation was approved by the Chiang Mai University Faculty of Medicine ’ s Ethical Committee. The data was anonymized by removing personal details, and the master cardinal was kept in a double-locked procure function cabinet and destroyed after discipline completion. All patients provided inform accept anterior to engagement.

back-to-back subjects were recruited from an outpatient HIV clinic in a third wish hospital in Chiang Mai, Thai-land. Inclusion criteria for the study were historic period 18 years or older, ability to speak Thai, and known HIV seropositivity. Subjects on cart for whom all agents in the ARV regimen could be identified ( either by self-report or in the medical record ) were eligible for CPE analyses. To determine if exposure to any person ARV agent would better explain the kinship between high CPE score and a positive PHQ-2, we tested the relationship between exposure to each individual agent ( n=15 ) and a positive depression screen. While tenofovir use was significantly associated with a negative low shield in bivariate analysis ( χ 2 = 5.76, n=126, p=0.02 ), only zidovudine remained significantly associated with depressive disorder after using a Bonferroni discipline to maintain the familywise error pace ( χ 2 =9.96, n=59, p=0.002 ; corrected p= 0.03 ). To explore this association further, we again constructed logistic regression models as described above but additionally included zidovudine use as a covariate. Including zidovudine habit in the model did not change the model ’ s predictive value ( Nagelkerke R 2 = 0.20, p < 0.001 ), but CPE score no longer significantly predicted a positive depression screen ( p=0.71 ). Zidovudine use, on the other hand, remained a significant autonomous risk gene for depression ( Exp ( B ) [ 95 % confidence interval ] = 2.40 [ 1.20 – 4.80 ], p=0.01 ). To further explore the association between CPE score and a positive depression screen, we constructed binary logistic arrested development models using covariates identified from the variables listed in whose bivariate associations with the result “ PHQ ( + ) ” had p-values < 0.2. Using logistic regression psychoanalysis, high CPE score remained a statistically significant independent risk for a positive low screen door ( p=0.02 ), and each extra increase of one point of CPE score increased the odds of screening positive for depressive disorder by 1.29 ( 95 % assurance time interval 1.04–1.61 ). The presence of chronic pain and neuropathic trouble were besides independent risks for a positivist depression screen, as was current alcohol use and belong to an ethnic group other than Thai. Frequent pain was not significant in regression analysis after controlling for the other factors ( p=0.84 ), likely due to its high correlation with chronic annoyance ( phi=0.86 ). Results from logistic regression analysis of factors associated with a positive PHQ-2 screen door can be found in below. note that in this table, “ Thai citizenship ” was transformed to “ no-Thai citizenship ” to make odds ratios easier to interpret. After noting a potent kinship between senior high school CPE score and depression, we conducted extra analyses to explore this relationship. In univariate analysis, chronic pain, miss of Thai citizenship, current alcohol use, patronize pain, neuropathic trouble, and high CPE score were all associated with a positive depression screen ( see ). We then compared CPE score as an ordinal number variable star to a positive PHQ-2 depression sieve and found an flush stronger relationship ( mean rank of CPE scores compared by PHQ ( + ) /PHQ ( − ) = 136.40/110.81, Z= −2.68, p=0.007 ). To help determine if the non-significant kinship between CPE score and chronic annoyance was ascribable to lack of statistical office in this sample distribution or a true lack of association, we compared the presence of chronic annoyance to CPE score analyzed as an ordinal variable with five values ( 6–10 ) using the Mann-Whitney U test. This analysis besides failed to demonstrate an association ( intend social station for chronic pain/no chronic pain = 120.4/117.4, Z= −0.29, 2-tailed p-value=0.77 ). Of 235 subjects, 26.4 % ( n=62 ) reported persistent or frequent pain of any kind in the last two weeks, and 20.9 % ( n=49 ) reported chronic pain of any kind last longer than 3 months. Distribution of frequent pain included limb pain ( n=18 ), headache ( n=12 ), back pain ( n=14 ), neck trouble ( n=3 ), and early pains ( n=21 ). Of those patients with patronize trouble who went on to complete the S-LANSS, 9 patients ( 3.8 % ) screened positive for neuropathic pain. Of the patients with frequent pain who completed the BPI-S, the medial measure for modal pain in the last 24 hours ( BPI-5 ) was 3.0, and median worse pain in the last 24 hours ( BPI-3 ) was 4.5. contrary to our initial guess, CPE grade did not predict the bearing of chronic pain, acute pain, or neuropathic pain, nor did it predict the asperity of average or worst pain ( all p-values > 0.10 ). See below for bivariate analysis comparing pain variables by CPE score. Of note, complete baseline characteristics of the greater study sample, of whom this sample distribution represents the huge majority ( 235/254 ), have been published in detail elsewhere [ 2 ]. When compared to the 254 patient sample as a whole, this sample of 235 patients did not differ on any of the baseline demographics ( all p-values > 0.05, results nowadays shown ). For these 235 patients, the median duration on haul was 7.0 years, with an interquartile crop ( IQ ) of 6 years. The median age was 42.0 years ( IQ 11 ). Females represented 56.2 % of the sample. The majority of the sample did not finish high school and made less than 350 USD per month, or 10,000 Thai baht. 66 patients ( 28.1 % ) screened positive for depression by answering affirmatively to at least one of the PHQ-2 questions. See below for service line demographics of the sample. Of these 245 subjects, 235 ( 95.9 % ) had complete information regarding stream ARV and constituted our effect sample of patients for whom CPE scores could be calculated. The most normally used ARVs in the population were as follows : lamivudine ( n=229 ) ; tenofovir ( n=122 ) ; nevirapine ( n=114 ) ; efavirenz ( n=98 ) ; zidovudine ( n=61 ) ; stavudine ( n=52 ) ; lopinavir/ritonavir ( n=21 ) ; and other ( n=8 ). From March to May 2011 we approached 260 patients, of whom 254 provided consent and were included in the study. See ( ) for details of subject recruitment. 96.5 % ( 245 subjects ) of the total sample was on cart .

DISCUSSION

In this study, we found no kinship between ARV CNS penetration, as measured by CPE score, and the prevalence of chronic pain in PLWH. We besides found no relationship between CPE score and neuropathic pain, frequent pain, and versatile measures of pain austereness. Post-hoc analysis revealed that high CPE score, and zidovudine practice in finical, is significantly associated with a positive depression riddle, even when account for other factors using logistic regression analysis. As noted in the introduction, several studies have found that chronic pain is more prevailing amongst PLWH. Though we found no impression of higher CPE score on chronic pain preponderance, it is distillery possible that chronic viral infection itself and/or associated immunological phenomena could explain the association between chronic HIV contagion and chronic pain. Some authors have posited that ARV efficacy against HIV in monocytes/macrophages, a known reservoir for HIV, may be a better metric function than ARV penetration into the CSF.37 alternatively, despite the evidence reviewed above that HIV infection leads to CNS changes known to be associated with chronic trouble, it is possible that the viral and immune effects are not directly related to low-grade CNS infection. damage from HIV may occur at disease onset anterior to ARV initiation, so that the ongoing low-grade HIV infection observed even with cart therapy is not clinically relevant. It is besides possible that chronic HIV contagion per southeast is not at all related to the increased preponderance of chronic pain in PLWH. previously we found that respective demographic variables, such as low education and low income, were significantly and independently associated with chronic pain in this population [ 2 ]. In this analyze, we again found that social factors such as non-Thai citizenship have significant affiliation with medical conditions such as depression. It is possible that psychosocial factors, preferably than chronic HIV infection itself, may rather explain the observe relationship between chronic pain preponderance and HIV infection, and that these factors are not adequately controlled for using cross-section study designs. further research must aim to determine the psychosocial and biological factors that mediate the full-bodied kinship between chronic HIV contagion and chronic pain.

The association between a high CPE score ( driven by zidovudine use ) and a positive natural depression blind is fresh. unfortunately, this study was not powered to explore this association in more depth. It is possible that HIV infection or some immune answer is playing an as yet indeterminate character in preventing depression, such that CNS HIV eradication is deleterious to mood. alternatively, zidovudine may have direct toxic effects on the skittish system that lead to depression. It is besides potential that the kinship between a positive depression filmdom and CPE score is actually an epiphenomenon. For example, prescribing physicians may choose or avoid certain ARV regimens if a patient has preexisting natural depression. last, while we tried to account for socioeconomic factors through regression analysis, it is possible that some other socioeconomic agent that determines the positive ARV regimen may be creditworthy for the increase depression rates. future studies will need to replicate this receive and clarify explanatory factors .

Strengths

This analyze had respective strengths. To our cognition it is the first study to investigate the kinship between CPE grudge and chronic pain. additionally, we were able to add to a growing torso of literature on chronic annoyance and climate disorders in PLWH in non-Western countries. Given the complex interplay between psychosocial factors, temper disorders, and chronic pain, inquiry in divers populations is necessity .

Limitations

This analyze had several limitations. The cross-sectional design precluded causal inference. besides, we were not able to collect data on past medicine regimens, so our analysis on CPE score was limited to current ARVs. however, most patients in this population had remained on a static regimen for many years. A second restriction is the relatively small sample size of patients with neuropathic pain in this population, and the limited information collected on the nature of the subjects ’ pain. It is conceivable that CNS penetration would have more of an impact on certain pains, such as neuropathic pain, rather than chronic trouble in general. ultimately, as mentioned above, our sample did not have the exponent to detect factors that may mediate the relationship between CPE sexual conquest and a convinced depression screen, and we collected no extra data on the quality or severity of depression in this population .

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