New Developments in Hepatitis C - Steven L. Flamm MD Professor of Medicine and Surgery Chief, Liver Transplantation Northwestern Feinberg School ...
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New Developments in
Hepatitis C
NATAP Program
Steven L. Flamm MD
Professor of Medicine and Surgery
Chief, Liver Transplantation
Northwestern Feinberg School of Medicine
Hepatitis C Is a Global Disease
• ~ 170 million people currently infected
• 3 to 4 million people newly infected annually
• 75% of cases in US are Genotype 1
World Health Organization (WHO) website: http://www.who.int/vaccine_research/diseases/viral_cancers/en/print.html
Reprinted from Alter MJ, et al. World J Gastroenterol. 2007;13:2436-2441.
Universal HCV Screening for American
Adults
Screening for Hepatitis C Virus (HCV) Number of newly reported chronic HCV
Infection 4,000
by sex and age, 2018
3,500
Chronic HCV is a common infection in the United States that
can lead to liver failure, liver transplantation, and death. 3,000
Antiviral treatment for HCV is highly effective in curing it
2,500
No. of cases
2,000
Population
Adults aged 18 to 79 years (including pregnant
persons) who do not have any signs or symptoms 1,500
of HCV infection and who do not have known liver
disease
1,000
500
USPSTF recommendation
The USPSTF recommends screening for HCV 0
infection in adults aged 18 to 79 years
Male Female
All persons with risk factors (eg, persons with HIV, prior recipients of blood transfusions,
persons who ever injected drugs and shared needles, and persons who are born to an
HCV-infected mother) should be tested for HCV, with periodic testing while risk factors persist
MMWR April 10, 2020 / 69(14);399–404; US Preventive Services Task Force. JAMA. 2020;323(10):970–975AMA 2020
How the Epidemic of Drug Overdose Deaths Rippled
Across America
Drug Poisoning Mortality in the United States, 1994–2015” by Lauren M. Rossen, Brigham Bastian, Margaret Warner, Diba Khan and Yinong Chong, National Center for Health Statistics, Centers for Disease Control and Prevention
Drug Overdose Death in the US,
1999 - 2018
National Drug Overdose Deaths National Drug Overdose Deaths
Number Among All Ages, by Gender, Number Among All Ages, 1999-2018
1999-2018
Other Synthetic Narcotics
Other Than Methadone
Mainly Fentanyl), 31,335
Prescription Opioids,
14,975
Heroin, 14,996
Cocaine, 14,666
Psychostimulants with
Abuse Potential (Including
Methamphetamine),
12,676
Benzodiazepines, 10,724
Antidepressants, 5,064
Source: Centers for Disease Control and Prevention, National Center for Health Statistics, Multiple Cause of Death 1999-2018 on CDC WONDER Online Database, released January 2019
https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates
NEW CASES OF ACUTE HCV AND OVERDOSE DEATHS RELATED
TO OPIOID USE HAVE BOTH INCREASED OVER TIME
NEW CASES OF ACUTE HCV AND OVERDOSE DEATHS RELATED TO
OPIOID USE HAVE BOTH INCREASED OVER TIME
Opioid-related Overdose Deaths and Acute Cases of HCV
Number of acute HCV cases2-4
50,000 5000
Overdose deaths1
35,000 3500
20,000 2000
5000 500
2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
Opioid overdose deathsa Reported acute cases of HCV
• New cases of acute HCV are on the rise due to the opioid epidemic and injection drug use2
• People who are current and former injection drug users comprise more than half of the chronic HCV
population in developed countries5
aIncludes people with or without HCV. 7
1. CDC. National health and statistics data brief. Accessed January 22, 2020. https://www.cdc.gov/nchs/data/databriefs/db329_tables-508.pdf#page=4 2. CDC. Surveillance for
viral hepatitis – United States, 2017. Accessed January 22, 2020. https://www.cdc.gov/hepatitis/statistics/2017surveillance/pdfs/2017HepSurveillanceRpt.pdf 3. CDC.
Surveillance for viral hepatitis – United States, 2016. Accessed January 17, 2020. https://www.cdc.gov/hepatitis/statistics/2016surveillance/commentary.htm 4. CDC.
Surveillance for viral hepatitis – United States, 2011. Accessed January 17, 2020. https://www.cdc.gov/hepatitis/statistics/2016surveillance/commentary.htm 5. Grebely J, et al.
Clin Infect Dis. 2013;57(7):1014-1020.
Risk Factors for Sexual HCV Transmission
of Hepatitis C Virus Among HIV-infected
MSM
MOSAIC study at 5 large HIV outpatient clinics in the Netherlands: Case-control
SEXUAL BEHAVIOR6M
receptive UAI
sharing sex toys
unprotected fisting
SEX-RELATED VARIABLES6M
no. of casual sex partners (per doubling)
anal rinsing
rectal bleeding
meeting casual sex partner(s) at sex party
DRUG USE BEFORE/DURING SEX6M
injected drugs
NADs used, straws shared
CLINICAL CHARACTERISTICS
CD4 cell count (per cubic root lower)
ulcerative STI6M
0.1 1 10 100
Adjusted odds ratio
Vanhommerig JW et al. Open Forum Infect Dis, Volume 2, Issue 3, Summer 2015, ofv115
High Burden of HCV Among Incarcerated
• 2.2 million Populations
people
incarcerated at
end of 2016 in
United States
• Nearly 1/3
Americans with
HCV spend at
least part of
the year in a
correctional 6.0 – 10.0%
facility 10.1% - 12.4%
12.5% - 17.9%
• Major 18.0 – 20.0%
opportunity to 20.1 – 39.7%
N/A
provide HCV
screening and
linkage to care
www.hepcorrections.org/. Bureau of Justice Statistics. www.hepCorrections.org.
Varan, et al. Public Health Report. 2014. 129:187-195.
Universal HCV Screening for ALL Adults
Ages 18 to 79
Draft: Recommendation Summary
Population Recommendation Grade
The USPSTF recommends screening for
Adults ages 18-79
years
hepatitis C virus (HCV) infection in adults ages B
18-79 years
https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/hepatitis-c-screening1Natural History of HCV Infection
Acute HCV
Resolved Chronic Hepatitis C
25% − 30% 70% − 75%
20 yrs
Cirrhosis
10% − 20%
Hepatocellular carcinoma
(1% − 4%/yr)
Liver failure
Santantonio T et al, J Hepatology. 2008;49:625-33.
NIH Consensus Conference Statement, June 2002.
John-Baptiste A et al, J Hepatology. 2010;53:245-51.
Seeff LB, Liver International. 2009;29(suppl 1):89-99.HCV/HIV-1 Co-infection
HCV/HIV-1 Co-infection in the United States
• In the United States, HCV/HIV co-infected persons account for
approximately 25% of all HIV-infected persons and 8% of HCV-infected
persons1
• Injection drug use remains the leading cause for HCV and HIV infection,1
while an increase in HCV co-infection among HIV-positive MSM has
recently been described2
Prevalence of anti-HCV in HIV-infected persons
(Johns Hopkins HIV clinic)1
Percent
Injection Drug Heterosexual Male Homosexual
Use Contact Contact
Self-reported HIV Exposure Risk Category
MSM = men who have sex with men.
1. Thomas DL. Annu Rev Med. 2008;59:473-485; 2. Witt MD, et al. Clin Infect Dis. 2013;57:77-84.Impact of HIV Infection on CHC
• A recent study of large HIV-infected patient cohorts showed that the liver-related
mortality rate was among the highest compared to other causes of non-AIDS mortality1,a
• HCV co-infection with HIV-1 is associated with accelerated hepatic fibrosis progression
and with higher rates of liver decompensation and death2,3
Figure adapted from Chen JY, et al.
a Study consisted of 65,121 HIV-1 positive patients in 16 cohorts from Europe and North America who were followed from starting ART.1
1. Ingle SM, et al. Clin Infect Dis. 2014;59:287-297; 2. Chen JY, et al. Nat Rev Gastroenterol Hepatol. 2014;11:362-371;
3. Kang W, et al. Expert Rev Gastroenterol Hepatol. 2014;8:247-266.Accelerated Fibrosis Progression in
HCV/HIV-1 Co-infection
• A recent observational study of HCV seropositive current and former injection-drug users
showed that fibrosis progression was accelerated in HCV/HIV-1 co-infected subjects
‒ The median age difference was approximately 9.2 years at any fibrosis stage
(FibroScan score)
14
Predicted FibroScan score
Predicted FibroScan Score (kPa)
HCV mono-infection
12 HCV/HIV co-infection
10
8
9.2 yr
6
30 35 40 45 50 55 60
Age (yr)
This was an observational cohort study of HCV seropositive current and former injection-drug users (N=1176) from the ALIVE
(AIDS Linker to the Intravenous Experience) study in Baltimore, Maryland.
For each age, predicted liver fibrosis scores were calculated using a regression equation that included the race, sex, alcohol
use, body mass index, hepatitis B virus surface antigen (HBsAg) level status, and HCV RNA level values for a representative
participant (overweight black male who has no regular alcohol use, is HBsAg–negative, and has high HCV viral load).
Kirk GD, et al. Ann Intern Med. 2013;3158:658-666.Annual Mortality Rate Due to HCV-related vs HIV-related
Deaths in the United States, 2000-20171-8,a • In 2018, ~2.7 million
HIV HCV people were living with
HCV in the United States9
Mortality rate per 100,000 persons
• The HCV mortality rate
surpassed that of HIV
in 20071-8
• In 2017, 61 years was
the mean age at which
patients with HCV died.10
This is ~18 years earlier
than the average
US lifespan11
Year
CDC=Centers for Disease Control and Prevention.
a Adapted from: Ly KN, et al. Ann Intern Med. 2012;156(4):271-278.
1. Ly KN, et al. Ann Intern Med. 2012;156(4):271-278. 2. Holmberg S, et al. Paper presented at: American College of Gastroenterology Annual
Scientific Meeting and Postgraduate Course; October 16-21, 2015; Honolulu, HI. 3. CDC. Accessed January 22, 2019.
https://www.cdc.gov/hepatitis/statistics/2016surveillance/pdfs/2016HepSurveillanceRpt.pdf 4. Kochanek KD, et al. Nat Vital Stat Rep.
2016;65(4):1-122. 5. Murphy SL, et al. Nat Vital Stat Rep. 2017;66(6):1-75. 6. Xu J, et al. Nat Vital Stat Rep. 2018;67(5):1-76. 7. CDC.
Accessed April 10, 2020. https://www.cdc.gov/hepatitis/policy/NationalProgressReport-HepC-ReduceDeaths.htm 8. Kochanek KD, et al. Nat
Vital Stat Rep. 2019;68(9):1-77. 9. Chhatwal J, et al. Aliment Pharmacol Ther. 2019;50(1):66-74. 10. Ly KN, et al. Clin Infect Dis. 2019. [Epub
ahead of print]. 11. Arias E, et al. Natl Vital Stat Rep. 2019;68(7):1-66.Chronic HCV Therapy (Genotype 1):
Advances in Raising Cure Rates
>2013
2nd Generation DAAs
PegIFN-Free Regimens
2011 >90%
Telaprevir or
Boceprevir +
PegIFN/RBV
~70%
2001
SVR (%)
1998 PegIFN/RBV
IFN/RBV 44%
1991 35%
IFN
16%
Schaefer EA, et al. Gastroenterology. 2012;142:1340-1350.
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
Ghany MG, et al. Hepatology. 2011;54:1433-1444.Current Standard of Care Therapies • Sofosbuvir and Velpatasvir (HCV HIV co- infected patients) • Glecaprevir and Pibrentasvir (all genotypes and DAA treatment failure) • Sofosbuvir, Velpatasvir and Voxilaprevir (DAA treatment failure)
Persons With HCV Genotype 1, 2, 3, 4, 5, or
6 Infection Can Be Effectively Treated With
One Tablet Daily for 12 Weeks Sofosbuvir/Velpatasvir
1015 323 237 264 116 34 41
1035 328 238 277 116 35 41
Total 1 2 3 4 5 6
Feld JJ et al. NEJM 2016; Foster G et al NEJM 2016Persons with HCV Genotype 1, 2, 3, 4, 5, or 6 Infection Can Be
Effectively Treated with Three Tablets Daily for 8 Weeks
Glecaprevir/Pibrentasivir
Puoti M et al. Journal of Hepatology (2018); Brown RS et al. Journal of Hepatology (2019)HIV/HCV Co-infected Individuals Have Similar
Cure Rates
Sofosbuvir/Velpatasvir x 12 weeks
95 95 92 100 92 100 94 100 93 97
100
80
SVR12 (%)
60
40
20
n/N = 99/ 62/ 11/ 11/ 11/ 4/ 80/ 19/ 71/ 28/
n/N = 104 65 12 11 12 4 85 19 75 29
0
Total 1a 1b 2 3 4 No Yes No Yes
Genotype Cirrhosis Tx Experienced
Glecaprevir/Pibrentasvir for 8 weeks
1 LTFU
136 136
137 136
Wyles D, et al. EASL 2016. Abstract PS104. Reproduced with permission.Overall Cure Rates in NS5A inhibitor –
Experienced patients
Sofosbuvir/Velpatasvir/Voxilaprevir
(Genotypes 1-6)
99%
96% 93%
SVR12 (%)
Breakthrough (n=1) Breakthrough (n=1)
Relapse (n=6) Relapse (n=6)
253 140 113
263 142 121
Overall No Cirrhosis Cirrhosis
No placebo patients achieved an SVR12.
*PHBV Testing/Monitoring During HCV DAA
Therapy to Prevent Reactivation
• Cases of Hepatitis B reactivation have been reported in predominantly
HBsAg+/HCV coinfected with extremely rare HCV/Anti HBc individuals
developing reactivation
• Test all pts initiating HCV therapy for HBsAg, anti-HBc, and anti-HBs
– Vaccinate if no HBV markers; follow flow chart below if HBV markers present
HBsAg positive HBsAg negative;
anti-HBc positive
Low or HBV DNA ( anti-HBs)
HBV DNA detectable undetectable
“Insufficient data
HBV DNA meets criteria to provide
for treatment in AASLD Monitor for reactivation; recommendations”
HBV treat if HBV DNA level
meets AASLD HBV guideline (Consider HBV
guidelines reactivation if clinical
treatment criteria
Or initiate HBV therapy, symptoms or ALT rise)
stop 12 weeks post rx
Treat with HBV drug
AASLD/IDSA. HCV Guidelines 2017. Graphic adapted from Ira M. Jacobson, MD.HCV HIV Co-infection
Drug-drug interactions between HCV medications
and HIV antiretroviral medications need to be
recognized and managed
The same regimens are used as for mono-infected
people, and the results are equivalent
HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C AASLD , IDSA, 2017HCV HIV Co-infection
Important Counseling
• Successful treatment does NOT prevent re-
infection
• If patients are re-exposed, they will get HCV
again
• It is important to eliminate risk factors for re-
exposure (unprotected sexual intercourse,
sharing needles)HCV Eradication
THE World Health Organization (WHO) HAS OUTLINED
STEPS NEEDED TO ELIMINATE HCV AS A PUBLIC
HEALTH THREAT BY 2030
According to the WHO, the elimination of HCV as a public health threat by 2030
will require:
of HCV cases of people diagnosed
diagnosed with HCV treated
HCV=hepatitis C virus; WHO=World Health Organization.
WHO. Accessed June 14, 2020. https://apps.who.int/iris/bitstream/handle/10665/273174/9789241550345-eng.pdf?ua=1HCV Eradication
We are failing
• Lack of diagnosis
• Poor linkage to medical care
• Lack of access to medical therapy
• Somewhat complicated therapeutic
recommendations
• Simplify
• Challenges to provide therapy
• PWID
• PregnancyUnder-Diagnosis:
The Largest Gap in the Cascade of Care
Complete
Access to Linkage to
Confirmatory Access to Treatment
Antibody HCV
Testing DAAs Retained
Testing Provider
in Care
Terrault NA. Hepatitis C elimination: challenges with under-diagnosis and under-treatment [version 1; peer review: 2 approved]. F1000Research 2019, 8(F1000 Faculty Rev):54
(https://doi.org/10.12688/f1000research.15892.1)How Simple Can Treatment Become
for Most Patients?
HCV Viremia
History, Exam, Labs*
Assess for cirrhosis with
platelets (>150x109/L)
Assess for DDI**
SOF/VEL 1 tab daily w/ or w/o GLE/PIB 3 tabs daily
food for 12 Weeks w/ food for 8 or 12 Weeks
*Assessment labs: CBC, AST, ALT, bilirubin, albumin, creatinine, HBV, HIV, HAV; eGFR
**HCPs should consult prescribing information, their local pharmacist and/or online tools (eg, HEP Drug Interactions; http://www.hep-druginteractions.org) to confirm interaction or lack of
interaction for specific drugs within a class, as exceptions may exist.
Dieterich et al, Gastroenterology & Hepatology; volume 15, issue 5, supplement 3, May 2019Simplified Algorithm for Management
of Hepatitis C Infection
1 2 3
Pretreatment Treatment and
Screening and diagnosis assessment and testing monitoring
Initial assessment Assess for potential DDI
Physical exam, stigmata of
• Universal screening optimal cirrhosis, clinical and prior Treatment with
or treatment history, extrahepatic pan-genotypic therapy:
• Risk factors/age screening manifestations GLE/PIB or SOF/VEL
Blood tests
HCV antibody test CBC, AST, ALT, bilirubin, Assessment of cure (SVR12)
with reflex to PCR albumin, creatinine; HCV RNA, ALT
HBV, HIV, HAV; eGFR
Positive (+)
HCV RNA-
PCR
Active HCV infection Platelets >150x109/L Cured
Refer to post-cure management
Dieterich et al, Gastroenterology & Hepatology; volume 15, issue 5, supplement 3, May 2019Treatment Simplification – ACTG A5360 Study
SOF/VEL Minimal Monitoring (MinMon)
Strategy for HCV treatment
Phase IV multi-national, open-label, prospective, single-arm, interventional study
A broad population of 399 participants from 5 countries Treatment with SOF/VEL for 12 weeks in a simplified,
minimal monitoring approach
X
GT
USA FIB-4 liver
N=131 FIB-4
assessment and no
Thailand
1–6 pre-treatment
N=110 genotyping
Uganda
N=15
SOF/VEL All 84 tablets
Brazil 12 weeks dispensed at initiation
N=131
South Africa
X
N=12 Remote contact
2x at Week 4 and 22
Compensated PWID Women HIV (SVR scheduling) –
cirrhosis (former/current) coinfection no on-treatment clinic
9% 34% 35% 42% visits/labs
ACTG=AIDS Clinical Trials Group
Solomon S, et al. AASLD 2020. LO7Treatment Simplification – ACTG A5360 Study
SOF/VEL Minimal Monitoring (MinMon)
Strategy for HCV treatment
MINMON
1
Clinic visits or telephone contact are recommended as clinically indicated during
treatment to ensure medication adherence and to monitor for adverse events and
potential drug-drug interactions, especially with newly prescribed medications
GT
2
3 Patients receiving a DAA-containing regimen should be assessed for clinical side
effects at each visit. ALT levels should be assessed at least at baseline and at
12- (or 24-) weeks post-treatment, and in case of suggestive symptoms. AL
Renal function should be checked monthly in patients with reduced eGFR. T
GT
Week 0 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24
ACTG=AIDS Clinical Trials Group
1. AASLD/IDSA. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Available at:
https://www.hcvguidelines.org/evaluate/monitoring. (Accessed November 2020); 2. EASL CPG HCV. J Hepatol
2020; https://doi.org/10.1016/j.jhep.2020.08.018; 3. Solomon S, et al. AASLD 2020. L07.Treatment Simplification – ACTG A5360 Study
SOF/VEL Minimal Monitoring (MinMon)
Strategy for HCV treatment
Sustained virological response* Remote contact:
2x • Week 4: 99% (396/399)
• Week 22: 84% (335/399)
Unplanned visits
• 15 (3.8%) participants recorded
95% 21 unplanned visits†
Adverse and serious adverse events
379/399
• 23 participants (5.8%) reported AEs
AE • 5 attributed to SOF/VEL
• 1 resulted in SOF/VEL discontinuation
• 17 with virological non-response**
• 1 sample prior to SVR window opening and no follow-up • 14 participants (3.5%) reported SAEs
after SAE • 0 attributed to SOF/VEL
• 2 lost to follow-up • 0 resulted in SOF/VEL discontinuation
The MINMON approach to HCV treatment delivery with SOF/VEL was simple, safe and achieved SVR comparable
to current clinical standards in treatment naïve persons without decompensated cirrhosis
*SVR defined as HCV ≤LLOQ in the first sample obtained from participant from Week 22–Week 76; †8=abnormal lab values at baseline; 6=non-AE clinical events; 3=adverse events. **Investigator reinfection
analysis pending. ACTG=AIDS Clinical Trial Group
Solomon S, et al. AASLD 2020. L07Who Is Eligible for Simplified Treatment? • Adults with chronic HCV infection (all genotypes) who do not have cirrhosis and who have not previously been treated • Not eligible per guidelines (but not necessarily complicated) – Prior HCV therapy – Cirrhosis – End-stage renal disease – HIV infection – Chronic HBV infection (HBsAg+) – Current pregnancy – Prior liver transplantation
WHAT ARE SOME OF THE CHALLENGES PROVIDERS FACE WHEN
MANAGING HCV-INFECTED PATIENTS WHO INJECT DRUGS?
In a 2019 study of a group of people with HCV who had a history of injection drug use
in Baltimore, Maryland (PWID cohort study):
~29% had recent (within the previous 6 months) or ongoing injection drug use
~51% had recent (within the previous 6 months) or ongoing alcohol use
~41% had ever been prescribed methadone
~12% had ever been prescribed buprenorphine
~11% experienced homelessness in the past 6 months
.
Falade-Nwulia O, et al. Int J Drug Policy. 2020;78:102714.PWIDs
SOME PROVIDERS MAY VIEW PEOPLE WITH HCV WHO INJECT
DRUGS AS POOR CANDIDATES FOR HCV TREATMENT
Concerns regarding patient adherence1,2
Perception that substance use may affect treatment outcomes2
Concerns about the risk of HCV reinfection1,2
1. Zeremski M, et al. World J Gastroenterol. 2013;19(44):7846-7851. 2. Grebely J, et al. J Infect Dis. 2013;207(Suppl 1):S19-S25.THE SAFETY AND EFFICACY OF SOF/VEL WERE STUDIED IN A
PROSPECTIVE CLINICAL TRIAL IN PEOPLE WHO INJECT DRUGS
SIMPLIFY1
GT 1, 2, 3, 4 | TN/TE | NC/CC
SOF/VEL
N=103 SVR12
0 12 24 36
Study Weeks
International, multicenter, single-arm, open-label, Phase 4 trial
The Phase 4 SIMPLIFY clinical trial evaluated the efficacy and safety of Sof/Vel for 12 weeks in adults with HCV and
recent injection drug use (within the past 6 months) who were naïve to NS5A-based HCV therapy.1
• Active injection drug users (within 12 months)a were excluded from the ASTRAL pivotal trials2
• SVR12 was the primary endpoint in SIMPLIFY and was defined as HCV RNASIMPLIFY INCLUDED SUBJECTS WITH
CHALLENGES THAT ARE COMMON AMONG
PEOPLE WHO INJECT DRUGS
Baseline Characteristics N=103
At baseline:
Mean age, years (SD) 48 (41-53)
Male sex, n (%) 74 (72) 74% had injected drugs in the past 30 days
1 36 (35)
2 5 (5)
GT, n (%)
3 60 (58) 26% had injected drugs at least daily in the
4 2 (2)
past 30 days
F4 (cirrhosis), n (%) 9 (9)
Any injection drug use in the past 6 months, n (%) 103 (100)
Any injection drug use in the past 30 days, n (%) 76 (74) 60% had used alcohol in the past 30 days
At least daily injection drug use in the past 30 days, n
27 (26)
(%)
Alcohol use in the past 30 days, n (%) 62 (60)
59% were receiving MAT
History of MAT, n (%) 84 (82)
Methadone 45 (44)
Current MAT, n Buprenorphine 4 (4)
(%)
Buprenorphine–naloxone 12 (12) 23% had unstable housing
Unstable housing, n (%) 24 (23)
MAT=medication-assisted treatment.
Grebely J, et al. Lancet Gastroenterol Hepatol. 2018;3(3):153-161.SOF/VEL SAFETY PROFILE IN SIMPLIFY
ADVERSE REACTIONS (ALL GRADES) REPORTED
IN ≥5% OF SUBJECTS IN SIMPLIFY
EPCLUSA
• The majority of subjects reported experiencing a mild or
12 WEEKS
ADVERSE REACTIONS moderate (Grades 1-2) adverse reaction up to 28 days
(N=103) following the last dose
FATIGUE 22% • Seven (7%) subjects had at least 1 serious AE; 1 (1%) was
HEADACHE 18% possibly treatment-related (rhabdomyolysis, resolved)
NAUSEA 14%
INSOMNIA 9%
ARTHRALGIA
DIZZINESS
NASOPHARYNGITIS
6%
5%
5%
1 (n=1/103)
% Discontinuations due to AEs
Grebely J, et al. Lancet Gastroenterol Hepatol. 2018;3(3):153-161.ILLICIT DRUG USE AND TREATMENT
ADHERENCE IN SIMPLIFY
Self-reported injecting drug
use during therapy Overall Treatment Adherence2,a
100 98% 99%
94%
80
60
40
20
0
Daily blister Weekly blister Self-reported
pack pack
Adherence
Sof/Vel has no known interaction with opioids fentanyl and oxycodone3
aData is from the SIMPLIFY trial, an open-label, single-arm Phase 4 trial of 103 participants with recent injection drug use (past 6 months)
and chronic HCV GT 1-6 infection from 7 countries (19 sites). Participants received Sof/Vel once daily for 12 weeks.
1. Grebely J, et al. Lancet Gastroenterol Hepatol. 2018;3(3):153-161. 2. Cunningham EB, et al. Int J Drug Policy. 2018;62:14-23. 3.
University of Liverpool. Updated December 3, 2019. Accessed March 4, 2020. https://www.hep-druginteractions.org/checkerANCHOR STUDIED SOF/VEL IN PEOPLE
WHO INJECT DRUGS WITH REAL
CHALLENGES IN A REAL-WORLD SETTING
ANCHOR evaluated the efficacy of Sof/Vel for 12 weeks in
adults with opioid use disorder and reported ongoing ANCHOR
injection drug use (within 3 months of screening visit) GT 1, 2, 3, 4 | NC/CC
treated at a harm-reduction center in Washington, DC SOF/VEL
(N=100)
• The primary endpoint was the proportion of participants with SVR12. Adherence N=100 SVR12
was assessed by monthly pill count, HCV viral load, number of bottles completed,
interruptions on treatment (3 or more days with subsequent resumption), and date
of last pill taken relative to planned end-of-treatment date. Imperfect daily
adherence was defined as finishing treatment >7 days after the anticipated
treatment end date 0 12 24 36
• Patients with decompensated liver disease and those who were pregnant or
Study Weeks
breastfeeding were excluded
Prospective, open-label, observational, single-site trial
• Participants were offered optional buprenorphine initiation
Rosenthal ES, et al. Clin Infect Dis. 2020 Feb 3. [Epub ahead of print].ANCHOR INCLUDED PATIENTS WITH CHALLENGES
THAT COMMONLY OCCUR IN PEOPLE WHO INJECT
DRUGS
Select Baseline Characteristics N=100
At baseline:
Median age, years (IQR) 58 (53-62)
Men, n (%) 76 (76)
Black race, n (%) 93 (93)
59% had daily or more
frequent injection drug use
Cirrhosis, n (%) 33 (33)
Unstably housed, n (%) 51 (51)
Prior incarceration, n (%) 92 (92) 40% had hazardous drinking
Baseline Drug Use Factors N=100
Median age at first injection drug use, years (IQR) 21 (17-31) 33% were receiving MAT
Daily or more frequent injection drug use, n (%) 59 (59)
MAT, n (%) 33 (33)
Receptive sharing of injection drug use equipment
29 (29)
51% had unstable housing
within 3 months, n (%)
Hazardous drinking (AUDIT-C), n (%) 40 (40)
IQR=interquartile range.
Rosenthal E, et al. Clin Infect Dis. 2020 Feb 3. [Epub ahead of print].SOF/VEL EFFICACY WAS STUDIED IN A UNIQUE PROSPECTIVE
CLINICAL STUDY FOCUSED SOLELY ON PEOPLE WHO INJECT
DRUGS
88%
overall cure rate (PP)
80% cure rate
in adults with
hazardous alcohol use
88% cure rate in
adults with
baseline MAT
75% cure rate
in adults with
unstable housing
in the real world • Real-world data are observational in nature and are not based on controlled clinical studies.
(n=82/93; ANCHOR) Results from these studies may differ from those observed in clinical practice
• Study Limitations: MAT status groups were non-randomized and self-selected. Factors
For the total patient associated with non-uptake or discontinuation of MAT may have been the same factors that
led to HCV treatment failure or LTFU. Results may not be generalizable to the larger HCV
population, the cure rate population
was 82% (82/100).
LTFU=loss to follow-up; PP=per-protocol.
Rosenthal E, et al. Clin Infect Dis. 2020 Feb 3. [Epub ahead of print].PWID
Real-World Adherence to DAAs and SVR Among PWID
Retrospective chart review for outpatients with co-localized HCV and opioid dependence treatment
from 2014 to 2020
Distribution of Prescribed DAAs
Full Adherence Variable Adherence
Regimen N=749 p=0.67
8 Weeks
GLE/PIB 292 p=0.77
LDV/SOF 61
12 Weeks
LDV/SOF 173
SOF/VEL 107
ELB/GRZ 73
GLE/PIB 43 8 Week DAA 12 Week 341/ 385/
DAA 353 396
Real-world adherence was not different for 12 week regimens compared to 8 week regimens
PWID have high SVR and adherence to HCV treatment
Variable adherence=documentation of >5 doses missed or a >5 day lapse in treatment.
Moga T, et al. AASLD 2020. P945PWID
SOF/VEL in Persons Actively Injecting Drugs
Real-world care management of SOF/VEL for 12 weeks in 25 clinical cohorts across 7 countries
Effectiveness Population*
Baseline Demographics N=254
Age, years (SD) 44 (10)
Male, n (%) 214 (84)
Fibrosis stage, n (%)
F0-F2, n (%) 150 (59)
F3, n (%) 46 (18)
F4, n (%) 42 (17)
TN, n (%) 231 (91)
42 / 4 / 43
HCV GT 1 / 2 / 3 /
/
4-6 / mixed/unknown, %
4/8
≥1 mental health disorder, n
186 (73)
(%)
249/ 40/ 67/ 53/ 181/ 41/
Use of ≥1 antipsychotic 254 42 67 53 186 43
68 (27)
drug, n (%)
In prison, n (%) 53 (21) †
Homeless, n (%) 67 (26)
Regardless of challenging baseline characteristics, SOF/VEL achieved high SVR rates in Persons Actively Injecting Drugs
*Effectiveness population included all patients with a valid SVR12/24 result available. †Advanced fibrosis was defined as F3 and F4, according to the treating physician.
Teti E, et al. AASLD 2020. P915PWID
HCV Reinfection and Retreatment in a Cohort of PWID
ANCHOR Study
Two year follow-up of patients who achieved SVR with SOF/VEL in a prospective study evaluating
active PWID with chronic HCV, OUD, and IDU in a syringe service program
Reinfecte Reinfection-Free Survival
Overall Not Reinfected
Baseline Characteristics d
N=82 n=73
n=9
Age, years, median (range) 58 (53, 62) 60 (52, 61) 57 (53, 65)
Male, n (%) 61 (74) 9 (100) 52 (71)
Black, n (%) 75 (92) 8 (89) 67 (92)
Cirrhosis, n (%) 26 (32) 3 (33) 23 (32) Rate of reinfection:
Hazardous alcohol use, n 6.5/100 person-years
33 (40) 4 (44) 29 (40)
(%)
Receiving an income, n
44 (54) 2 (22) 42 (58)
(%) Weeks
Stable housing, n (%) 44 (54) 5 (55) 39 (54) § High rates of HCV reinfection were not associated
with risk factors
Moderately high rates of HCV reinfection can occur in
high-risk PWID; longitudinal follow-up and retreatment in high-risk individuals is essential
IDU=injection drug use; OAT=opioid agonist therapy; OUD=opioid use disorder
Kattakuzhy S, et al. AASLD 2020. P968HCV Reinfection and Retreatment in a Cohort of PWID
ANCHOR Study
Two year follow-up of patients who achieved SVR with SOF/VEL in a prospective study evaluating
active PWID with chronic HCV, OUD, and IDU in a syringe service program
Reinfection-Free Survival
Overall Reinfected Not Reinfected
Baseline Characteristics
N=82 n=9 n=73
Age, years, median (range) 58 (53, 62) 60 (52, 61) 57 (53, 65)
Male, n (%) 61 (74) 9 (100) 52 (71)
Black, n (%) 75 (92) 8 (89) 67 (92)
Rate of reinfection:
Cirrhosis, n (%) 26 (32) 3 (33) 23 (32) 6.5/100 person-years
Hazardous alcohol use, n
33 (40) 4 (44) 29 (40)
(%)
Receiving an income, n Weeks
44 (54) 2 (22) 42 (58)
(%) § High rates of HCV reinfection were not associated
Stable housing, n (%) 44 (54) 5 (55) 39 (54) with risk factors
HCV reinfection can occur in
high-risk PWID; longitudinal follow-up and retreatment in high-risk individuals is essential
IDU=injection drug use; OAT=opioid agonist therapy; OUD=opioid use disorder
Kattakuzhy S, et al. AASLD 2020. P968MAJOR ORGANIZATIONS CONSIDER HCV TREATMENT FOR
PEOPLE WITH HCV WHO INJECT DRUGS CRITICAL1-4
AASLD/IDSA
“Scale up of HCV treatment in persons who inject drugs is necessary to positively impact the HCV epidemic in the
United States and globally”1
American Society of Addiction Medicine (ASAM)
“Active alcohol and/or drug use should not in itself exclude any person from receiving treatment for their HCV infection”2
WHO
“Treatment for HCV infection is both efficacious and cost-effective in PWID and therefore WHO recommends that all adults and
children with chronic HCV infection, including PWID, should be assessed for antiviral treatment”3
Gastroenterological Society of Australia (GESA) / Hepatitis Australia / EC Australia / AIVL / Kirby Institute
“Although some practitioners previously excluded current PWID from treatment, there is clear evidence of equivalent treatment
outcomes, albeit with a low risk of reinfection.4 Holistic care therefore includes harm reduction strategies, such as opioid
substitution therapy, together with access to needle and syringe programs and education on safer injecting practices.”5
AASLD=American Association for the Study of Liver Diseases; IDSA=Infectious Diseases Society of America.
1. AASLD/IDSA. Updated May 24, 2018. Accessed August 24, 2018. http://www.hcvguidelines.org 2. ASAM. April 5, 2017. Accessed October 11, 2018.
https://www.asam.org/docs/default-source/public-policy-statements/pdff5b01a9472bc604ca5b7ff000030b21a.pdf?sfvrsn=780c7ac2_0 3. WHO. Accessed June 14, 2020.
https://apps.who.int/iris/bitstream/handle/10665/205035/9789241549615_eng.pdf?sequence=1 4. Aspinall EJ, Corson S, Doyle JS, et al Treatment of hepatitis C virus
infection among people who are actively injecting drugs: a systematic review and metaanalysis. Clin Infect Dis 2013; 57 Suppl 2: S80-S89 5. Hepatitis C Virus Infection
Consensus Statement Working Group. Australian recommendations for the management of hepatitis C virus infection: a consensus statement (June 2020). Melbourne:
Gastroenterological Society of Australia, 2020.Pregnancy
Reported Prevalence of Maternal Hepatitis C
Virus Infection in the United States
Rossi, Robert M.; Wolfe, Christopher; Brokamp, Richard; McAllister, Jennifer M.; Wexelblatt, Scott; Warshak, Carri R.; Hall, Eric S.
Obstetrics & Gynecology135(2):387-395, February 2020.AASLD/IDSA Guidance HCV and Pregnancy
Recommendation for Universal Recommendations for Monitoring
Hepatitis C Screening Pregnancy HCV-Infected Women During Pregnancy
RECOMMENDED RATING
RECOMMENDED RATING
As part of prenatal care, all pregnant women should be
tested for HCV infection, ideally at the initial visit HCV RNA and routine liver function are recommended at initiation of
(See Recommendations for Initial HCV Testing and Follow-
II, B prenatal care for HCV-antibody-positive pregnant women to assess the I, B
risk of mother-to-child transmission (MTCT) and degree of liver disease
Up)
All pregnant women with HCV infection should receive prenatal and
intrapartum care that is appropriate for their individual obstetric risk(s) as I, B
Recommendation Regarding there is no currently known intervention to reduce MTCT
HCV Treatment and Pregnancy
In HCV-infected pregnant women with pruritus or jaundice, there should
be a high index of suspicion for intrahepatic cholestasis of pregnancy
I, B
RECOMMENDED RATING (ICP) with subsequent assessment of alanine aminotransferase (ALT),
aspartate aminotransferase (AST), and serum bile acids
For women of reproductive age with known HCV infection, HCV-infected women with cirrhosis should be counseled about the
increased risk of adverse maternal and perinatal outcomes. Antenatal
antiviral therapy is recommended before considering I, B
pregnancy, whenever practical and feasible, to reduce the
II, B and perinatal care should be coordinated with a maternal-fetal medicine
(ie, high-risk pregnancy) obstetrician
risk of HCV transmission to future offspring
Recommendations Regarding Breastfeeding and
Postpartum Care for HCV-Infected Women
RECOMMENDED RATING
Breastfeeding is not contraindicated in women with HCV infection, except when the mother has cracked, damaged, or
I, B
bleeding nipples, or in the context of HIV coinfection
Women with HCV infection should have their HCV RNA reevaluated after delivery to assess for spontaneous
I, B
clearance
https://www.hcvguidelines.org/Conclusions • Untreated HCV can cause cirrhosis, liver failure, liver cancer and death • All people at least 18 years of age should be screened for HCV • Highly effective therapies for HCV are currently available with cure rates of approximately 99% • The WHO has strategies to eliminate HCV worldwide, although we are failing in the US • Attempts to simplify medical therapy for appropriate patients are ongoing • HCV patients currently present challenges to provide effective therapy, but many can be overcome • Aggressive treatment of PWIDs is now recommended • Screening for HCV of pregnant women is now recommended
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