CHARACTERIZING THE ASSOCIATION BETWEEN POSITIVE HCV ANTIBODY AND PAIN AMONG PEOPLE WHO INJECT DRUGS

Abstract

Introduction and Aims:

People who inject drugs (PWID) are a key group within the hepatitis C virus (HCV) pandemic. Chronic pain is a common condition among PWID as these individuals are often exposed to soft tissue infections due to injections, and violence. This study aims to characterize the relationship between HCV exposure and pain among PWID.

Design and Methods:

Data were derived from three prospective cohorts of PWID in Vancouver, Canada, between December 2011 and November 2016. The primary outcome was pain severity, which was defined based on the Euroqol EQ-5D-3L pain subscale. A bivariable and multivariable ordinal generalized estimating equations model was used to quantify the association between HCV exposure and pain among participants.

Results:

One-thousand and twelve of 2038 participants (50%) reported moderate/extreme pain at baseline. In total, 1473 (72%) participants were HCV-antibody positive. In unadjusted analyses, HCV exposure was positively associated with increased pain (Odds Ratio [OR] = 1.47; 95% confidence interval [CI]: 1.20–1.81). However, once adjusted for known confounders in multivariable analyses, HCV exposure did not remain significantly associated with increased pain (Adjusted Odds Ratio [AOR] = 1.00; 95%CI: 0.78–1.28).

Discussion and Conclusions:

In this sample of PWID, HCV exposure was not significantly associated with pain once other factors were considered. These various factors may explain the elevated risk of pain among PWID and should be addressed in future initiatives when managing pain among PWID with HCV exposure. Future studies should also examine whether pain changes with changes in HCV status (i.e., active versus cleared infection).

1. INTRODUCTION

Hepatitis C (HCV) is a viral infection with a significant presence globally, with an estimated 71 million people chronically infected [1]. Although recent years have seen new medications that have greatly improved the cure rate for HCV [2,3], chronic infection remains highly associated with progression to liver cirrhosis, hepatocellular carcinoma, liver failure, and death [4]. The most prominent mode of transmission of HCV is through blood-to-blood contact, putting people who inject drugs (PWID) at high risk of acquiring new infections [5]. Studies have shown that an estimated 66% of people who currently inject drugs, and 28.5% of those who formerly injected drugs are seropositive for HCV [6].

Chronic pain and other pain-related disorders affect over 60% of those living with HCV and are associated with decreased quality of life, increased health care utilization, and increased risk of comorbidities [7–9]. Although the mechanisms and pathways are not clearly known, inflammatory cytokines in HCV are theorized to play a role [7,10]. Additionally, chronic pain is a common condition among PWID, occurring in one-third to half of the population [11,12]. These individuals are often exposed to soft tissue infections due to injections, as well as poor health and nutrition [11]. In both HCV infection and PWID, clinical and behavioural factors (e.g. mental illness, non-medical opioid use) have shown to be strongly associated with chronic pain [12,13].

While there has been considerable literature examining chronic pain in people with HIV and PWID, there is a lack of evidence around the relationship between HCV exposure and pain among PWID. In an effort to better understand and improve pain management among the PWID population, we sought to characterize the relationship between HCV exposure and pain among PWID in British Columbia, Canada.

2. MATERIALS AND METHODS

Data were derived from three ongoing prospective studies: the Vancouver Injection Drug Users Study (VIDUS), the AIDS Care Cohort to evaluate Exposure to Survival Services (ACCESS), and the At-Risk Youth Study (ARYS). VIDUS has been operating since 1996 and consists of HIV-negative people who have used an illicit drug via injection in the past month prior to enrollment. ACCESS consists of people with HIV who have used an illicit drug other than or in addition to cannabis in the past month prior to enrollment. ARYS consists of street-involved youth aged 14–26 years old at baseline who have used an illicit drug other than or in addition to cannabis in the past month prior to enrollment. Details on recruitment and sampling have been reported elsewhere [14–16]. In short, recruitment is through word-of-mouth, street outreach, and self-referral. At baseline and every six months, participants complete a harmonized interviewer-administered questionnaire that elicits information on demographics, drug use patterns, health status, and other social-structural exposures. Additionally, at each study visit, participants provide blood samples for HIV and HCV serologic tests. Participants receive a $40 stipend for each visit. These studies have been approved by The University of British Columbia/Providence Health Care Research Ethics Board.

The study period for the current analysis was from December 2011 to November 2016. Participants were eligible for the present study if they had a history of injection drug use at baseline or initiated injection drug use at some point during follow-up. The primary outcome was current pain severity on the date of the participant’s interview, defined using the Euroqol EQ-5D-3L pain subscale, which is categorized as no pain, moderate pain, or severe pain [17]. The main explanatory variable of interest was HCV exposure, defined as having a positive HCV antibody test result. We included a number of confounders with a known or suspected effect on the relationship between HCV exposure and pain: age at baseline; sex; HIV infection; homelessness; heroin injection; prescription opioid injection; cannabis use; incarceration; diagnosed mental illness; and enrollment in opioid agonist therapy. All variables except for sex and age were time-updated and referred to the six-month period prior to the interview unless otherwise indicated.

First, we compared characteristics of the study participants, stratified by whether they reported moderate/extreme pain at baseline or not: Pearson χ2 test was used for categorical variables and Wilcoxon rank-sum test for continuous variables. Then, bivariate ordinal generalized estimating equations (GEE) regression model was constructed to examine the unadjusted relationship between pain severity and covariates (including HCV exposure). Lastly, a multivariable ordinal GEE regression model was constructed to establish whether there was an independent relationship between HCV exposure and pain severity, after adjusting for all the confounding variables previously described. The proportional odds assumption of logistic regression was checked. All p-values were two-sided. All statistical analyses were performed using R, version 3.2.4 (R Foundation for Statistical Computing, Vienna, Austria).

3. RESULTS

Two thousand and thirty-eight individuals were included in the study from December 2011 to November 2016. The median number of follow-ups per participant during the study period was 6 (interquartile range: 3–9). The majority of participants were HCV positive (1473; 72%). Approximately half (50%) of the participants had reported moderate or extreme pain at baseline. Of the 1012 participants that had reported pain, 81% had moderate pain, while 19% had extreme pain. Baseline characteristics were stratified by pain status (moderate or extreme pain vs no pain; Table 1).

Table 1:

Baseline characteristics of participants, stratified by pain status

Characteristic	Total (%) (n = 2038)	Outcome
		Moderate/extreme Pain (%) (n = 1012)	No Pain (%) (n = 1026)
HCV exposure	1473 (72.3)	775 (76.6)	698 (68.0)
Age at baseline (med, IQR)	42 (30–50)	44 (32–52)	40 (29–49)
Male	1290 (63.3)	627 (62.0)	663 (64.6)
HIV Infection	682 (33.5)	359 (35.5)	323 (31.5)
Homelessness*	566 (27.8)	270 (26.7)	296 (28.8)
Heroin injection*°	403 (19.8)	212 (20.9)	191 (18.6)
Prescription opioid injection*°	85 (4.2)	62 (6.1)	23 (2.2)
Cannabis use*°	502 (24.6)	263 (26.0)	239 (23.3)
Recent incarceration*	199 (9.8)	103 (10.2)	96 (9.4)
Diagnosed mental illness*	89 (4.4)	52 (5.1)	37 (3.6)
Enrolled in opioid agonist therapy*	951 (46.7)	499 (49.3)	452 (44.1)

HCV: hepatitis C virus; med: median; IQR: interquartile range

^*behaviours/activities in last 6 months

^°≥ daily

Shown in Table 2, in unadjusted analyses, HCV was associated with increased pain severity (OR = 1.47; 95% CI 1.20 – 1.81). However, once adjusted for select sociodemographic, behavioural, and clinical confounders in multivariable analyses, HCV did not remain statistically significantly associated with increased pain (AOR = 1.00; 95% CI 0.78 – 1.28).

Table 2.

Bivariable and multivariable ordinal regression analyses of factors associated with pain severity among people who inject drugs (n = 2038)

	Unadjusted		Adjusted°
Characteristic	Odds Ratio (95% CI)	p - value	Odds Ratio (95% CI)	p - value
Main Exposure
HCV exposure
(yes vs. no [ref])	1.47 (1.20–1.81)	<0.001	1.00 (0.78–1.28)	0.994
Confounders
Age at baseline
per 10 years older	1.24 (1.17–1.32)	<0.001	1.36 (1.26–1.47)	<0.001
Sex
Male vs female [ref]	0.82 (0.70 – 0.98)	0.024	0.72 (0.60 – 0.86)	<0.001
HIV infection
(yes vs. no [ref])	1.27 (1.07–1.49)	0.005	1.17 (0.99–1.39)	0.071
Homelessness*
(yes vs. no [ref])	1.00 (0.87–1.14)	0.973	1.12 (0.96–1.30)	0.139
Heroin injection*
(≥ daily vs. < daily [ref])	1.29 (1.13–1.47)	<0.001	1.43 (1.24–1.66)	<0.001
Prescription opioid injection
(≥ daily vs. < daily [ref])	1.91 (1.53–2.39)	<0.001	1.93 (1.48–2.51)	<0.001
Cannabis use*
(≥ daily vs. < daily [ref])	1.15 (1.00–1.31)	0.047	1.29 (1.12–1.49)	<0.001
Recent incarceration*
(yes vs. no [ref])	1.10 (0.92–1.32)	0.307	1.20 (0.96–1.49)	0.104
Diagnosed mental illness*
(yes vs. no [ref])	1.16 (1.02–1.32)	0.028	1.47 (1.17–1.85)	0.001
Enrolled in opioid agonist therapy*
(yes vs. no [ref])	1.16 (1.02–1.32)	0.027	1.14 (0.99–1.31)	0.075

HCV: hepatitis C virus; CI: confidence interval

^°Multivariable model adjusted for all confounders

^*behaviours/activities in past 6 months

4. DISCUSSION

We found that among our study sample of PWID, half of the participants reported experiencing moderate to extreme pain. Among these participants, 77% were positive for HCV. In an unadjusted model, there was a positive association between HCV exposure and pain. However, once adjusted for various factors known to be associated with pain severity, this relationship was not found to be statistically significant. This suggests that other factors play a larger role than merely HCV exposure status in the experience of pain among PWID.

The high prevalence of pain in our study was not surprising, given that PWID are vulnerable to skin infections, venous ulcers, co-morbidities, unstable housing, and poverty, which are directly causal or known risk factors for pain [11,18]. Findings from the present study showed a similar prevalence of pain among PWID with HCV compared to available literature [10,19]. However, the body of literature to date has focused specifically on either HCV or PWID separately as a factor in pain, not the interplay of both. In studies of people with HCV, pain has been reported to occur in 64–83% [7,8,19,20].

Our study is one of few examining the relationship between HCV exposure and pain among PWID. Our findings were similar to one study conducted in the US, which reported an association between HCV and chronic pain in PWID; this association was also not statistically significant when adjusted for known confounders [10]. It appears that the higher risk of pain among PWID living with HCV exposure may be related to co-morbidities, illicit drug use, and other factors beyond chronic HCV exposure. Confounding factors associated with pain in our study were older age, being female, being diagnosed with mental illness and use of cannabis use, heroin injection and prescription opioid injection. It is well known that psychological distress (e.g., depression, anxiety), as well as social isolation and low socioeconomic status is linked to increased pain and poor health [9,18,21]. This has implications in clinical care, calling for a more encompassing and comprehensive strategy to optimize pain management among PWID and HCV. Future initiatives could explore non-pharmacological options in pain management such as behavioural responses to pain (e.g., cognitive-behavioural therapy) or physical exercises to minimize the experience of pain (e.g., physiotherapy) [22,23].

Our study has several limitations. Firstly, we cannot make conclusions about causality based on our findings. For example, our results do not emphasize whether opioid use causes pain, or whether pain causes one to use opioids. As our study collected only HCV antibody testing, it is not known if participants had an active HCV exposure during the study period. Future studies should assess HCV RNA status to examine whether pain changes with changes in HCV status (e.g., active infection versus cleared infection). Our main outcome was current pain severity as defined by the Euroqol EQ-5D-3L pain subscale which, while considered reliable and valid in assessing pain in a variety of health conditions [17], does not measure other pain-related factors such as pain duration, etiology of pain, or other chronic diseases. Future research should consider utilizing other valid measures of pain, such as Brief Pain Inventory [24]. As with other cohort studies, selection of participants was not random, and therefore these findings may not be representative of or generalizable to other PWID. Lastly, much of the data gathered was self-reported, which is subject to recall bias and response bias. However, we did utilize laboratory assays for our main explanatory variable to minimize these biases.

In conclusion, our results show that PWID with HCV experience a high prevalence of pain. However, once adjusted for potential confounders, HCV exposure did not remain significantly associated with pain, which may suggest that factors other than HCV exposure, such as injection drug use and mental illness, may explain the elevated risk of pain among PWID locally. These findings have implications for clinical practice. Future initiatives should focus on addressing these confounding factors when managing chronic pain in those with HCV exposure.