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Update on
Alcohol, Other Drugs,
and Health
November–December 2013
www.aodhealth.org
1
Studies on
Interventions &
Assessments
www.aodhealth.org
2
Chronic Care Management
in Primary Care for Patients
with Substance Dependence
Yields Little Benefit
Saitz R, et al. JAMA. 2013;310(11):1156–1167.
Summary by Darius A. Rastegar, MD
www.aodhealth.org
3
Objectives/Methods

Providing multidisciplinary patient-centered
proactive care in the form of chronic care
management (CCM) may be one way to
reduce the adverse health consequences
and high rates of health care utilization that
are associated with substance use.
www.aodhealth.org
4
Objectives/Methods (cont’d)



This randomized controlled trial included 563
participants with alcohol, stimulant, or opioid
dependence.
Subjects assigned to CCM received care from a
team that included a nurse, a social worker,
internists, and a psychiatrist with addiction
expertise; the CCM visits were separate from
primary care visits.
The control group received primary care at the
same center, without additional services.
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5
Results



There was no significant difference in the primary
outcome measure of 30-day abstinence from stimulants,
opioids, or heavy alcohol use at 12-month follow-up
between the CCM (44%) and control (42%) groups.
There was likewise no significant difference in Addiction
Severity Index scores, quality of life measures, and
hospital or emergency department utilization.
Those assigned to CCM were significantly more likely to
receive addiction pharmacotherapy (21% versus 15% in
the control arm).
www.aodhealth.org
6
Comments



It is disappointing that this model of care failed to show
a significant benefit.
This study does not suggest that primary care
practitioners cannot help patients with substance
dependence; the control group received primary care
services and likely benefited from them.
As the authors point out, a likely explanation for these
results is that their study achieved a “small increase in
use of addiction treatments that are modestly
efficacious for only some subsets of people with
addictions.” More clinical trials are needed to test other
approaches.
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7
Counseling Adds No
Detectable Benefit to
Patients Receiving
Buprenorphine Treatment
and Medical Management for
Opioid Dependence
Ling W, et al. Addiction. 2013:108(10);1788–1798.
Amato L, et al. Cochrane Database Syst Rev. 2011;(10):CD004147.
Summary by Peter D. Friedmann, MD, MPH
www.aodhealth.org
8
Objectives

The Drug Abuse Treatment Act of 2000
requires that physicians prescribing
buprenorphine in the US be able to refer
patients for ancillary counseling, but several
studies have been unable to detect benefit
from psychosocial treatments in addition to
buprenorphine and physician-provided
medical management.
www.aodhealth.org
9
Objectives/Methods (cont’d)

This study randomized 202 outpatients with
opioid dependence receiving buprenorphine
and medical management to 16 weeks of
treatment within one of four groups:

Cognitive behavioral therapy (CBT)

Contingency management (CM)

Both CBT and CM; or

Buprenorphine treatment and medical
management alone (control)
www.aodhealth.org
10
Results


There was no difference across groups during the 16week active treatment phase or over the 52-week followup in the percentage of participants with opioid-negative
urine test results; 71% of the buprenorphine and medical
management control group had three or more
consecutive opioid-negative urine test results compared
with 66% of the CBT group, 74% of the CM group, and
76% of those who received both CBT and CM.
There were no differences between the groups’
treatment retention rates, withdrawal symptoms,
craving, other drug use, or adverse events.
www.aodhealth.org
11
Comments


This study confirms a recent meta-analysis (Amato et al.,
2011), which found that psychosocial counseling delivers
no detected benefit when combined with opioid agonist
treatment and physician-provided medical management
for people with opioid dependence.
The possibility remains that additional counseling may
prove to be beneficial to select subgroups or in
maintaining long-term recovery after the first year;
however, a provider’s inability to arrange for additional
behavioral counseling should not be a barrier to the
provision of effective opioid agonist treatment.
www.aodhealth.org
12
Varenicline a Potential
Treatment Option for Alcohol
Use Disorders in Smokers
and Nonsmokers
Litten RZ, et al. J Addict Med. 2013;7(4):277–286.
Summary by Jeanette M. Tetrault, MD
www.aodhealth.org
13
Objectives/Methods


Varenicline is a partial α4β2 nicotinic acetylcholine agonist
approved for smoking cessation.
Preclinical studies have suggested reduced alcohol intake
in the setting of varenicline; a human laboratory study
suggested reduced drinking, alcohol craving, and
reinforcing effects of alcohol intake in individuals with
heavy smoking and drinking behaviors; and a small
preliminary study of smokers with heavy drinking given
varenicline for 3 weeks suggested a greater reduction in
alcohol craving and fewer heavy drinking days over
placebo.
www.aodhealth.org
14
Objectives/Methods (cont’d)


This is the first reported multi-site clinical
trial of varenicline in smokers and
nonsmokers with alcohol dependence.
Two hundred patients with alcohol
dependence were randomized to receive
double-blind varenicline or placebo plus a
computerized behavioral intervention for 13
weeks.
www.aodhealth.org
15
Results


Patients in the varenicline group reported a
lower weekly percentage of heavy drinking days
over those in the placebo group (38% versus
48%, respectively). Smoking status did not alter
the primary outcome.
The varenicline group had fewer drinks per
drinking day (6 versus 7) and a lower percentage
of very heavy drinking days over placebo (18%
versus 26%).
www.aodhealth.org
16
Results (cont’d)


Abstinence did not differ between the two
groups.
Adverse events were those expected and
varenicline was well tolerated between the
two groups.
www.aodhealth.org
17
Comments

In this study, varenicline reduced alcohol
consumption among smokers and
nonsmokers compared with placebo.
Larger, longer-duration studies are needed
to replicate the data presented in this
proof-of-concept trial.
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18
Screening and Assessment
for Unhealthy Alcohol Use
Can Determine Hospital
Inpatients’ Risk for Alcohol
Withdrawal
Pecoraro A, et al. J Gen Intern Med. 2013
[Epub ahead of print]. PMID: 23959745.
Summary by Peter D. Friedmann, MD, MPH
www.aodhealth.org
19
Objectives/Methods



Screening is intended to identify unhealthy alcohol use for
interventions, but this study examined whether alcohol
screening tools can also stratify hospitalized patients for
their risk of alcohol withdrawal syndrome (AWS).
In a case-control study of all adult medical or surgical
inpatients from a single hospital, investigators identified 223
patients who developed AWS after admission and 466
randomly-selected controls without AWS.
All patients had been screened at admission with the Alcohol
Use Disorders Identification Test-(Piccinelli) Consumption
(AUDIT-PC), which includes five of the ten items from the
full AUDIT.
www.aodhealth.org
20
Results



An AUDIT-PC score of ≥4 proved to be the best cut
point between true and false positives for AWS;
9% of cases would be missed.
For every 17 patients whose screening resulted in a
false positive, one was correctly identified as
having AWS.
Among patients who scored ≥4 on the AUDIT-PC,
the post-test probability of AWS was 5.8%.
www.aodhealth.org
21
Comments


This study suggests that a screening
questionnaire, the AUDIT-PC, might risk-stratify
hospitalized patients for AWS. However,
prospective validation with an independent sample
is necessary before this tool can be recommended
for this purpose.
An implication is that even a rudimentary
assessment of the alcohol history among inpatients
who screen positive for unhealthy drinking can
have important clinical and prognostic implications.
www.aodhealth.org
22
Patients Who Initially
Screen Negative for
Unhealthy Alcohol Use
May Need to be Screened
Again
Lapham GT, et al. Alcohol Clin Exp Res. 2013 [Epub ahead of print].
doi: 10.1111/acer.12260.
Summary by Kevin L. Kraemer, MD, MSc
www.aodhealth.org
23
Objectives/Methods


To determine whether some patients who
screen negative for unhealthy alcohol use have
a risk of converting to a positive screen in the
future, researchers retrospectively examined
Alcohol Use Disorder Identification Test–
Consumption (AUDIT-C) data collected from
462,126 outpatients screened on 2 occasions
(one year apart).
The main outcome was conversion from a
negative AUDIT-C score (0–2 in women and 0–
3 in men) to a positive score (≥3 in women
and ≥4 in men).
www.aodhealth.org
24
Results



Initially, 75% of the patients screened had a negative
AUDIT-C score; 18% had a positive score; and 8% had
addiction treatment or an alcohol use disorder diagnosis in
the year before initial screening or between the initial and
subsequent screens.
Overall, 5% of women and 6% of men with initial negative
screens converted to a positive screen the following year.
In adjusted analyses, younger men with initial scores of 3
were most likely to convert to positive screens. In contrast,
older patients, women, and those with initial scores of 0
were least likely to convert. In no patient subgroup was the
probability of converting to a positive screen below 2% or
greater than 39%.
www.aodhealth.org
25
Comments


This study suggests that the probability of
converting from a negative to a positive
screen for unhealthy alcohol use is high
enough to justify repeating the screen for
all patients after one year.
It does not address whether patients with
more than 2 consecutive negative screens
should be eligible for cessation of
screening.
www.aodhealth.org
26
Emergency Department Brief
Intervention May Decrease
Some Risky Driving and
Drinking Behaviors in Young
Adults
Sommers MS, et al. Alcohol Clin Exp Res. 2013;37(10):1753–1762.
Summary by Kevin L. Kraemer, MD, MSc and Richard Saitz, MD, MPH
www.aodhealth.org
27
Objectives/Methods

The results of alcohol brief
intervention trials in emergency
departments (EDs) have been mixed
and in trauma centers largely
disappointing (i.e., no effect of
intervention).
www.aodhealth.org
28
Objectives/Methods (cont’d)

In this study, researchers targeted a
subpopulation with two risks, randomizing 476
ED patients with risky driving and drinking,*
aged 18 to 44 years, to:



An assessment followed by two brief interventions addressing
both issues
An assessment-only control; or
A no-contact control (no assessment, no intervention)
*Defined by the authors as: within the past month, ≥2 risky driving
behaviors (partial or non-use of a seatbelt; ≥2 occasions of driving 20
mph over the speed limit; ≥2 occasions of driving through a yellow light
as it turns to red), AND ≥2 risky drinking behaviors (≥11 standard
drinks in a week for women and ≥14 for men; ≥4 drinks on a typical
drinking day; ≥5 drinks on one occasion for women and ≥6 for men).
www.aodhealth.org
29
Results



31% of participants were lost to follow-up, more in the brief
intervention group than in the other groups.
At 3, 6, and 9 months, participants in the brief intervention
group were less likely than those in the assessment-only
group to report “not always wearing a seat belt” (39–45%
versus 50–55%), but no less likely to report exceeding the
speed limit by 20 mph.
At 3 and 6 months, participants in the brief intervention
group reported fewer maximum drinks per occasion (median
6 versus 8) and reports of ≥5 drinks in a day (27–30%
versus 40–43%) than did the assessment-only group.
www.aodhealth.org
30
Results (cont’d)



The intervention had no effect on 4 secondary drinking
outcomes or 6 measures of traffic offenses and crashes,
although it was associated with fewer reports of 4 other
risky driving behaviors (e.g., fewer times driving through
yellow light as it turns to red).
The brief intervention group did not differ with either
control group on any risky driving and drinking outcomes
at 12 months.
Outcomes for the assessment-only group were not
substantially different from the no-contact control group.
www.aodhealth.org
31
Comments


The mixed findings on self-report outcomes
and differential loss to follow-up raise
concerns about the validity of the findings,
particularly in the context of prior studies.
Interestingly, assessments—often thought to
explain the many negative studies of brief
intervention—had no effects on outcomes.
www.aodhealth.org
32
Comments (cont’d)


Nonetheless, this study suggests that 2 brief
counseling sessions for a select group of ED
patients with two risky behaviors (risky driving
and drinking) may modestly reduce some
aspects of both in the short term.
But it also suggests that better interventions are
needed for more robust and longer-term success
(e.g., booster interventions using electronic
methods and/or in primary care settings).
www.aodhealth.org
33
Studies on
Health Outcomes
www.aodhealth.org
34
Race and Socioeconomic
Status Affect Emergency
Department Opioid
Prescribing for Pain
Joynt M, et al. J Gen Intern Med. 2013 [Epub ahead of print].
PMID: 23797920.
Summary by Richard Saitz, MD, MPH
www.aodhealth.org
35
Objectives/Methods



Prior research suggests that factors besides pain—
such as patient race and ethnicity—affect opioid
prescribing for pain, but those studies have often not
adjusted for socioeconomic status (SES).
In this study, investigators examined the association
between race, ethnicity, and neighborhood SES on
prescription of an opioid during an emergency
department (ED) visit for moderate or severe pain in
the National Hospital Ambulatory Care Survey.
During 4 years there were over 183 million visits and
opioids were prescribed during 50,264 of them.
www.aodhealth.org
36
Results



Compared with patients living in areas with the highest SES,
patients living in areas with the lowest SES were less likely
to receive opioids (39% versus 49% when neighborhood
poverty was >20%; 41% versus 47% when median income
was <$33,000; and 43% versus 46% when <13% held a
bachelor’s degree).
Black (39% versus 46% for white) and Hispanic (40%
versus 45% for non-Hispanic) patients were less likely to
receive opioids.
All differences were significant in analyses adjusted for race,
ethnicity, SES, sex, pain severity, injury, hospital type, past
ED visits, and geography.
www.aodhealth.org
37
Comments


This study adjusted for neighborhood rather
than individual SES. Nonetheless, it does provide
support for the hypothesis that race, ethnicity,
and SES impact opioid receipt for pain.
Clinicians should be aware that this may happen,
and researchers should attend to discovering
why, with an eye toward eliminating any
inappropriate disparities.
www.aodhealth.org
38
General Population
Preferences Regarding
Treatment for Alcohol Use
Disorders Suggest Pervasive
Stigma
Andréasson S, et al. Alcohol Alcohol. 2013;48(6):694–699.
Summary by Nicolas Bertholet, MD, MSc
www.aodhealth.org
39
Objectives/Methods



To investigate treatment preferences for alcohol use
disorders, researchers conducted a random, crosssectional survey of the Swedish general population
aged 16–80.
A total of 9005 individuals completed the survey
(62% response rate).
Participants were asked which type and source of
treatment they would recommend to a friend or
relative with unhealthy alcohol use.
www.aodhealth.org
40
Objectives/Methods (cont’d)

Treatment types were:
Treatment via internet
 Alcoholics Anonymous or other support
groups
 Psychotherapy
 Pharmacotherapy; and
 Residential treatment

www.aodhealth.org
41
Objectives/Methods (cont’d)

Treatment sources were:
Social services
 Psychiatry or other addiction specialist
treatment
 Primary health care; and
 Occupational health care

www.aodhealth.org
42
Results


Individuals with lower* alcohol use tended to recommend
support groups as their preferred form of treatment, whereas
individuals with higher consumption** favored psychotherapy.
Treatment via the internet was the least preferred option among
the respondents.
More than 50% of participants reported psychiatry or other
addiction specialist treatment as their preferred source of
treatment. Around 10% cited primary health care as their
preferred source of treatment and 20% occupational health
services.
* Defined by the authors as 0–28 drinks in a week for men, or 0–18 drinks in a
week for women (one drink containing 12 g of alcohol).
** Defined as >28 drinks in a week for men, or >18 drinks in a week for women.
www.aodhealth.org
43
Comments



Treatment for alcohol use disorders remains
stigmatized; this study suggests that newer forms of
treatment (pharmacotherapy, internet) are less
commonly recognized as options by the general
population.
The dissemination of information on alcohol use
disorders and available treatments, especially new
medications, seems to be key to disseminating
effective treatments.
Adapting the delivery of treatment for alcohol use
disorders to the reported preferences may reduce
some of the stigma.
www.aodhealth.org
44
Moderate Alcohol Intake
May Lower the Risk of
Rheumatoid Arthritis
Jin Z, et al. Ann Rheum Dis. July 29, 2013 [Epub ahead of print].
doi: 10.1136/annrheumdis-2013-203323.
Summary by R. Curtis Ellison, MD
www.aodhealth.org
45
Objectives/Methods


Few prospective cohort studies have included
an adequate number of cases to test the
association of alcohol consumption with the
development of rheumatoid arthritis (RA).
This large meta-analysis evaluated the
relationship between alcohol consumption and
the diagnosis of RA in 1878 subjects, based on
prospective data from 5 cohort studies and 3
nested case-control studies.
www.aodhealth.org
46
Results



Overall, subjects reporting low-to-moderate alcohol
consumption (<15 g in a day) had a lower risk of RA
(relative risk [RR], 0.86) than abstainers.
Compared with no alcohol consumption, the adjusted
RR was 0.93 for 3 g of alcohol in a day; 0.86 for 9 g in
a day; 0.88 for 12 g in a day; 0.91 for 15 g in a day;
and 1.28 for 30 g in a day, with stronger effects among
women.
Subgroup analysis indicated that consistent low-tomoderate alcohol consumption for a period of at least
10 years was found to have a 17% reduction in RA risk
for both men and women.
www.aodhealth.org
47
Comments



This study concludes that moderate alcohol
consumption is inversely associated with the
development of RA.
It suggests a “J-shaped” curve, with a lowered risk
for an average intake of up to 15 g in a day in
comparison with abstainers, and an increased risk
with heavier drinking.
Down-regulation of the immune response and a
decrease in pro-inflammatory cytokines is the
probable mechanism of alcohol’s protective effect on
the risk of RA, though the increased risk at higher
levels remains unexplained.
www.aodhealth.org
48
Prenatal Cocaine Exposure
Impacts Adolescent
Development, but Clinical
Relevance is Unclear
Buckingham-Howes S, et al. Pediatrics. 2013;131(6):e1917–1936.
Summary by Sarah Bagley, MD† and Judith Tsui, MD, MPH
†Contributing Editorial Intern and Addiction Medicine Fellow, Clinical Addiction Research and
Education (CARE) Unit, Section of General Internal Medicine, Boston University School of Medicine,
Boston, MA.
www.aodhealth.org
49
Objectives/Methods


During the crack cocaine epidemic there was
concern that prenatal cocaine exposure
(PCE) would have long-term adverse effects
on development.
This systematic review examined the impact
of PCE on adolescent outcomes.
www.aodhealth.org
50
Objectives/Methods (cont’d)

Twenty-seven studies representing
nine cohorts were identified and four
outcomes of interest were reported:




Behavior
Cognition/school performance
Brain structure/function; and
Physiologic response
www.aodhealth.org
51
Results



Eleven studies reported behavioral outcomes such as
drug use, victimization, and attention problems. Seven
of those studies had statistically significant findings
consistent with adverse effects.
Eight studies reported cognition/school performance.
Six had statistically significant findings consistent with
adverse effects.
Eight studies reported results about brain morphology
and functioning using neuroimaging. Four studies had
statistically significant findings consistent with adverse
effects.
www.aodhealth.org
52
Results (cont’d)


Three studies reported physiologic response
variability using cortisol levels. The results
were inconsistent but all studies showed
alterations in the cortisol response to stress
in the PCE groups.
Most of the differences between those
exposed and unexposed to cocaine were
small to moderate.
www.aodhealth.org
53
Comments



This systematic review represents the first effort
to synthesize information on studies of PCE
effects in adolescence.
70% of the studies had significant findings;
however, the authors point out that the clinical
relevance of those findings is unclear.
These mixed results are consistent with prior
reviews of PCE and early (pre-adolescent)
development.
www.aodhealth.org
54
Studies on
HIV and HCV
www.aodhealth.org
55
Illicit Substance Use is
Associated with HIV
Medication Non-Adherence
and Risky Behaviors
Mimiaga MJ, et al. Am J Pub Health. 2013;103(8):1457–1467.
Summary by Darius A. Rastegar, MD
www.aodhealth.org
56
Objectives/Methods


Investigators used data from a cohort of 3413
HIV-infected patients to examine illicit substance
use and its association with HIV medication
adherence, psychological distress, and HIV risk
behaviors.
Self-reported substance use within the past 3
months was broken into 6 categories:






Crack-cocaine
Amphetamines
Opiates
Marijuana
Injection drug use (IDU); and
Polydrug use (a combination of crack-cocaine,
amphetamines, opiates, or marijuana)
www.aodhealth.org
57
Results


Overall, 24% of subjects reported marijuana use,
9% amphetamine use, 8.5% crack-cocaine use,
2% opiate use, and 3% IDU; 10% of participants
reported polydrug use.
In multivariable models, non-adherence to HIV
medications in the previous three months was
associated with each of the substance use
categories, except for marijuana. Having a
detectable viral load was associated with crackcocaine use, IDU, and polydrug use.
www.aodhealth.org
58
Results (cont’d)

Engaging in unprotected anal sex was
associated with marijuana, amphetamine,
opiate, polydrug use, and IDU; the
association was strongest for amphetamine
and IDU. Vaginal sex risk behaviors were
associated only with polydrug and crackcocaine use.
www.aodhealth.org
59
Comments




This study supports previous observations of an
association between illicit substance use and HIV
medication non-adherence and risky behaviors.
While substance use may simply be a marker for risktaking behavior, it makes sense to screen patients with
HIV for substance use and provide counseling.
For those who have a substance use disorder, providing
targeted treatment may offer additional benefits.
Counseling alone is probably not sufficient and further
investigation is needed on how to improve adherence
and reduce risky behaviors among this population.
www.aodhealth.org
60
Perceptions of Hepatitis C
Screening and Treatment
among People with Illicit
Drug Use
Jordan AE, et al. Harm Reduct J. 2013;10:10.
Summary by Jeanette M. Tetrault, MD
www.aodhealth.org
61
Objectives/Methods


Despite the existence of effective treatment
options, people with illicit drug use are less
likely to be screened and treated for
hepatitis C virus (HCV) than those without
drug use.
This disparity is especially pronounced
among racial and ethnic minorities.
www.aodhealth.org
62
Objectives/Methods (cont’d)


The purpose of this qualitative study was to
explore attitudes, perceptions, and
experiences regarding HCV testing, referral,
and treatment among racial and ethnic
minorities with drug use.
Ninety-five participants recruited from HIV
primary care clinics, methadone
maintenance programs, and syringe
exchange programs in New York and San
Francisco were included in 14 focus groups.
www.aodhealth.org
63
Results


Many participants reported that they
underwent testing at their treatment facility
but were unaware of other voluntary testing
sites.
Participants reported that receipt of a
positive test was often accompanied by an
unclear message about next steps.
www.aodhealth.org
64
Results (cont’d)


Many participants perceived a lack of need for
treatment due to asymptomatic state, health care
messages minimizing the severity of the disease,
and inadequate recommendations for treatment
by health care professionals.
Social networks and interactions with peers were
a common source of HCV-related information.
www.aodhealth.org
65
Comments


Although people with illicit drug use have a high
prevalence of HCV, testing and treatment are
not always offered to this population.
Perceived inconsistent health care messages
regarding the natural history of the disease
contribute to a lack of understanding among
patients.
www.aodhealth.org
66
Comments (cont’d)

Standardization of public health
messages—including those delivered via
social networking, peer support groups,
and post-test counseling—may improve
the general understanding of the natural
history and treatment of HCV among
people with drug use.
www.aodhealth.org
67
Directly Observed Treatment
for Hepatitis C Virus
Infection among People
with Active Drug Use
Hilsden RJ, et al. Clin Infect Dis. 2013;57 Suppl 2:S90–96.
Summary by Judith Tsui, MD, MPH
www.aodhealth.org
68
Objectives/Methods

This study appears to be the first
randomized controlled trial (RCT) of
treatment for HCV with directly observed
interferon (peg-IFN) alpha-2a plus selfadministered ribavirin (RBV) conducted
exclusively among adults with active*
injection drug or crack cocaine use.
* Defined as use at least once in a month and within 3 months of the date
of randomization.
www.aodhealth.org
69
Objectives/Methods (cont’d)

Subjects were randomized to either
immediate treatment with peg-IFN/RBV or
delayed treatment (after 24–48 weeks).
The original primary outcome was loss to
follow-up and adverse events. The authors
here report on sustained virologic response
(SVR)—defined as undetectable HCV RNA—
24 weeks after completion of treatment.
www.aodhealth.org
70
Results



377 participants were screened and only 66 (18%)
were enrolled. The leading reasons for exclusion
were cessation of drug use (82), loss to follow-up
(72), and HCV RNA-negative status (61). The
study was terminated early as the desired sample
size (100) could not be achieved.
In intention-to-treat analysis, SVR was 65% in the
immediate group and 39% in the delayed group.
Recent drug use in the past month did not impact
treatment completion or SVR.
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Comments

The results of this study suggest a benefit
for immediate treatment over delayed
treatment, although the authors
encourage readers to interpret the
findings with caution as they are observed
in a small number of patents and the
study was not originally designed to
answer a question regarding efficacy via
SVR.
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Comments (cont’d)

The inability of the investigators to recruit
their targeted sample size informs
translation into real-world settings. As
newer therapies for HCV with fewer side
effects and shorter duration of treatment
become available, it may become easier to
treat people with illicit drug use and HCV.
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