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Pain among individuals with HCV and substance use disorders: Impact of direct-acting antiviral treatment
Joseph L. Goulet, PhD, MS
Jeanette M. Tetrault, MD
Amy C. Justice, MD, PhD
William C. Becker, MD
For the Veterans Aging Cohort Study project team
Yale School of Medicine
Veterans Health Administration
Bonjour and good afternoon.

2. HCV Hepatitis C is a blood-borne virus US prevalence ~5M
IDU most common risk factor in the US
US prevalence ~5M
40%-85% unaware of their HCV infection status
HCV related morbidity and mortality:
Cirrhosis/Hepatocellular carcinoma/ ↑ mortality
Currently no vaccine for HCV
15-30% clear the infection
infected persons might not be aware of their infection because they are not clinically ill
Deaths will peak in , ~36,000 per year

3. HCV and Pain Persons with HCV have 3x risk for persistent pain
The mechanism(s) are not well understood
Cryoglobulinemia - Proteins which restrict blood flow to joints, muscles, and organs, ~40%
HCV viremia associated inflammation: arthralgia and arthritis are common manifestations, up to 74%
However, hypothesized mechanisms include:
abnormal proteins that clump together which can lead to
Viremia is a condition where viruses enter the bloodstream and have access to the rest of the body. May lead to sites of infection other than the liver
Patients with OUD, which is associated with IDU, are also at risk for chronic pain
In a large prospective study of 1612 patients with chronic HCV infection, the MULTIVIRC group reported a 74% prevalence of extrahepatic manifestations.6

4. DAA Direct-acting antiviral (DAA) therapies in 2013
e.g. Sofosbuvir
Expanded access in VHA
Compared to prior treatments:
Shorter duration
Fewer side effects
Higher success rate
>90% achieve sustained viral response wks
Veterans Health Administration

5. Aim Examine whether DAA treatment is associated with decreased pain
Hypothesized mechanism through decreased viremia/cryoglobulins
Gain insight into mechanism(s) of pain in HCV
And may promote testing and treatment rates

6. Study design Observational cohort in VHA
Data source: Veterans Aging Cohort Study
EHR database: including labs, ICD, pharmacy
1:2 matched HIV-infected and HIV-uninfected
128 VHA facilities in USA
Identified
THE STUDY DESIGN WAS A
Case series nested within an observational cohort
Our data source was
The Veterans Aging Cohort Study (VACS)-Virtual Cohort
Which is an Electronic database of administrative, laboratory and pharmacy data of HIV-infected veterans and HIV-uninfected matched controls
It represents over 40,000 HIV infected patients from
128 sites nationwide who were
Identified from 10/97-9/08
**don’t say**
33,420 HIV-infected veterans from VHA records between 10/1/97-9/30/04
Construct of cohort has 100% sensitivity, 96.1% specificity, 97.2% PPV, and 100% NPV to identify HIV-infected patients in care
2 HIV-uninfected comparators matched to each case

7. Methods Identified patients with an HCV diagnosis/RNA
Limited to patients :
Who initiated DAA treatment
Had three or more pain numeric rating scale (NRS) scores in the year prior to DAA that averaged ≥ 4
Had 12 weeks or more dispensed DAA
Had three or more post-DAA pain NRS scores
Within VACS, we identified….
≥ 4, indicating moderate-to-severe pain, since the test is on reductions in pain

8. Data analyses Descriptive statistics Matched t-test
pre- and post DAA pain NRS score averages
Compare by important clinical characteristics
OUR DATA ANALYSES included
Descriptive statistics
And Mixed model random intercept regression
Examining ALT, AST, CD4, and VL
For the 365 days Before, during, and 365 days after naltrexone exposure
Data were log transformed to normalize distribution
We also specifically looked at cases of Liver enzyme elevation within our sample

9. Patient flow diagram 4,122 HCV-infected patients received 1+ DAA
599 patients in analytic sample
1,444 <3 pre- and post-DAA NRS
544 <84 days DAA
1,535 pre-DAA NRS average <4
Here we show the PATIENT FLOW DIAGRAM
Initially we identified 4122 HCV infected patients in the VACS study who initiated at least 1 DAA in the study period.
# patients were excluded ….
Leaving ### patients for analysis

10. Sample characteristics, N=599
Value
Male
98%
Age, years, mean 61
White
33%
HIV-infected
48%
Alcohol use disorder
27%
Drug use disorder*
34%
Cirrhosis
Duration of DAA, days, median 84
* May not include distal drug use disorders (e.g. 40 years ago)

11. NRS pre- and post-DAA Mean 95% CI Pre- 5.57 5.47-5.66 Post- 4.95
Pre-post mean difference=0.62, p<0.0001

12. Change scores

13. Proportions with 20% or more improved pain
Reduction of 2 or more points is considered the minimal clinical important difference in many trials
Pain scores of 4-6 are generally considered moderate, while 7+ are severe
19% in those with pre-scores <7, 32% with those above
Chi-Square=5.12, p=0.024

14. NRS scores by clinical characteristics
Note consistency
Mention comorbidity, not mutually exclusive

15. Summary
DAA is associated with a statistically significant decrease in pain among patients with HCV
A clinically important difference (2+ NRS points) was observed in 21% of HCV patients
Greater proportion among those with high pre-DAA pain
Results suggest that improvement is consistent across comorbid conditions
In SUMMARY,
Hepatotoxicity in HIV-infected patients receiving naltrexone is rare and reversible
Liver enzyme elevation occurred in 5/114 cases
only one of which was temporally related to naltrexone
HIV biomarkers do not appear to be affected, and may be improved, during naltrexone administration
**don’t say**
95% confidence interval of that ONE case…is up to 5%.

16. Limitations Currently lack SVR data Regression to the mean?
Predominantly male, older sample

17. Conclusions
These data add to the evidence for the benefits of treating chronic HCV patients
Pain relief may be a motivator for increasing acceptance of HCV screening and treatment
Indirect support for viremia/cryoglobulin and pain hypothesis

18. Thank you