Brief Review of HIV and Hepatitis C Virus (HCV)...
Transcript of Brief Review of HIV and Hepatitis C Virus (HCV)...
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Brief Review of HIV and Hepatitis C Virus (HCV) Infection
(with focus on HCV)
James Morrill, MD, PhD
MGH Charlestown HealthCare Center
Massachusetts General Hospital
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Disclosures
Neither I nor my spouse/partner has a relevant financial relationship with a commercial interest
to disclose.
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Medical toll of illicit opioid use
Intranasal IV
Tentative Compulsive
Acute Illness • Overdose • Violence / trauma
First-initiated substances
Source: SAMHSA, National Survey on Drug Use and Health, 2010.
Subacute Effects • Soft tissue infection • Endocarditis • Losses / legal issues
Chronic Effects • Chronic viral hepatitis, liver disease • HIV infection • Malnutrition • Smoking related illnesses • Premature CHD, cancer • Homelessness
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Medical toll of illicit opioid use
Graphic from “Heroin’s Small-Town Toll, and a Mother’s Grief” New York Times, 2/10/2014
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HIV (and HCV) outbreak among injection drug users in Indiana
• 135 cases as of report
• Investigation triggered by HIV
surveillance
• Injection of oxymorphone
• Multigenerational use of injection
drugs
• 84.4% (114/135) also diagnosed
with new HCV infection
HIV and HCV: Quick Comparison
Epidemiology
Vaccine available?
Whom to screen?
HIV HCV
• 33 million worldwide • 1.2 million in US • Up to 25% coinfected w/ HCV • Affects 9% of chronic IDUs • Mortality decreasing in US (now 12K/yr) • Less efficient needle transmission (0.3%) • More efficient sexual / perinatal transmission
• 150 million worldwide • 3.4-4.9 million in US • Affects 60-70% of chronic IDUs • Mortality increasing in US (now 15K/yr) • More efficient needle transmission (3%) • Less efficient sexual / perinatal transmission
NO NO
• HIV Ab / p24 Ag immunoassay • HIV viral load • CD4 lymphocyte count • Antiviral resistance testing • Assessment for opportunistic infections
Workup
1X testing for all adults age 15- 65 Risk factor based: • High-risk sexual practices or partner • IVDU • Other STIs • Pregnant women
1X testing for birth cohort 1945-1965 Risk factor based: • IVDU • Transfusion before July, 1992 • Chronic hemodialysis • Healthcare worker w/ needlestick
• HCV Ab immunoassay • HCV viral load • HCV Genotype • Hepatic staging • Assessment for extrahepatic manifestations
HIV and HCV: Quick Comparison
Epidemiology
Vaccine available?
Whom to screen?
HIV HCV
• 33 million worldwide • 1.2 million in US • Up to 25% coinfected w/ HCV • Affects 9% of chronic IDUs • Mortality decreasing (12K/yr) • Less efficient needle transmission (0.3%) • More efficient sexual / perinatal transmission
• 170 million worldwide • 3.4-4.9 million in US • Affects 60-70% of chronic IDUs • Mortality increasing (15K/yr) • More efficient needle transmission (3%) • Less efficient sexual / perinatal transmission
NO NO
• HIV Ab / p24 Ag immunoassay • HIV viral load • CD4 lymphocyte count • Antiviral resistance testing • Assessment for opportunistic infections
Workup
1X testing for all adults age 15- 65 Risk factor based: • High-risk sexual practices or partner • IVDU • Other STIs • Pregnant women
1X testing for birth cohort 1945-1965 Risk factor based: • IVDU • Transfusion before July, 1992 • Chronic hemodialysis • Healthcare worker w/ needlestick
• HCV Ab immunoassay • HCV viral load • HCV Genotype • Hepatic staging • Assessment for extrahepatic manifestations
HIV and HCV: Quick Comparison
Whom to treat?
How to treat?
Curative treatment?
Long-term challenges
Any patient, regardless of CD4 count More urgent w/ OI or high risk of Xmission PREP: High risk sexual partner (or drug use?)
Treatment rationale
Advanced liver fibrosis Those at high risk of Xmission
Restore / preserve immune function Reduce HIV-related end-organ damage Reduce HIV transmission
Prevent HCV-related chronic liver disease Reduce HCV transmission
Four primary med categories: (NRTIs, NNRTIs, PIs, IIs) Recommended treatment: 2-NRTI backbone + NNRTI, PI, or II 1-pill regimens available: (e.g., Atripla, Complera, Stribild) PREP: Truvada = 2-NRTI combo (Emtricitabine + Tenofovir)
Three types of DAAs: (PIs, polymerase inhibitors, NS5A inhibitors) Recommended treatment: 2 or 3 DAAs combined, based on genotype Combination products available: (e.g., Harvoni, Viekira pak, Zepatier)
NO YES
Treatment adherence Surveillance for non-AIDS morbidity (CV disease, liver disease, renal disease, cancers, osteoporosis, neurocognitive effects, frailty)
Treatment uptake (cascade of care) High cost of drug regimens Prevention of reinfection HCC screening (in those with fibrosis)
HIV HCV
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• RNA virus that infects liver cells, causing inflammation and damage.
• Most common and most deadly blood-borne infection in the U.S.
• Transmitted by direct blood to blood contact– primarily needles
Source: Ly et al. (2012) Ann Int Med 156: 271. * Includes cases contracted in the hospital or during childbirth
Source: Centers for Disease Control and Prevention
Sexual 17%
Unknown 10%
Past transfusion 3% Occupational 4%
Other 9%* Injecting drug use 57%
Hepatitis C Virus Structure
Electron micrograph (bar = 50 nm)
Viral particle layers
Mortality due to Hepatitis viruses and HIV
Hepatitis C: Key Facts
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• Highest prevalence 3-4% among “baby boomers” (1945 to 1965 birth cohort)– who should now be screened routinely regardless of risk factors
• New, rising population of infected young adults.
• More than half of patients with Hepatitis C are unaware of their infection
Source: Onofrey et al. (2011) MMWR 60: 537.
The “Baby Boomer” Hepatitis C cohort
Two Hepatitis C cohorts at MGH Charlestown Rise of young adults with Hepatitis C in Massachusetts
Source: Armstrong et al. (2006) Ann Int Med 144: 705.
Hepatitis C: Key Facts
Why treat Hepatitis C?
Acute infection Ab + or -, VL +, ALT ↑↑
Chronic infection (75-85%) Ab +, VL +, ALT ↑
Cirrhosis (30%/30yrs)
Decompensation or Hepatocellular carcinoma
(1-4% per year)
2-12 wk incubation period
More common with: • Young patients • Females • Icteric acute infection Promoted by:
• Alcohol use • Older age, male gender • HBV or HIV infection • High BMI, DM, or fatty liver
Exposure
Viral clearance (15-25%): Ab +, VL -, ALT nl
Natural history of untreated HCV
80% asymptomatic
X
Chronic infection Ab +, VL +, ALT ↑
Decompensation or Hepatocellular carcinoma
(1-4% per year)
New infection
X New infection
New infection
X
X
X
New infection X
Why treat Hepatitis C?
Cirrhosis (30%/30yrs)
Why treat Hepatitis C?
R0 = C * P * D
• C = # of contacts per unit of time
• P = probability of transmission per contact with infectious person
• D = duration that patient is infectious to others
R0 = Basic Reproductive Number
Addiction Care, Needle exchange
Safer injection practices, equipment
Effective antviral treatment
Workup of Hepatitis C
1) Diagnose and characterize infection:
• Hepatitis C virus (HCV)Antibody
• HCV RNA (= viral load)
• HCV genotype (1-6)
2) Assess for HCV-related liver disease:
• Physical exam
• Liver function tests (LFTs), CBC, APRI, AFP
• HCV Fibrosure
• Liver ultrasound
• Fibroscan
• Liver biopsy
HCV Fibrosure (Labcorp): Input:
Total bilirubin GGT ALT Alpha-2-macroglobulin Haptoglobin Apolipoprotein A-1
Output: • Fibrosis score (F0-F4) • Necroinflammatory score (A0-A3)
Workup of Hepatitis C
3) Assess for HCV-related conditions:
• HIV, Hepatitis B, Hepatitis A serologies
• Cholesterol, blood sugar, BMI
• “Extrahepatic” manifestations of HCV
• Cryoglobulinemia (50%)
• Low platelets (40%)
• Autoimmune arthritis (25%)
• Pruritus, porphyria cutanea tarda (20%)
• Lymphoma (risk increased by 20%)
• Diabetes
Source: www.aafp.org
Source: Dartmouth medical photo library
History of Hepatitis C Treatment
“SVR” = Sustained Virologic Response = Negative HCV viral load 24 weeks after treatment = predictor of a CURE.
1990s Interferon-a (IFN) SC + Ribavirin PO
48 wks 10-30% SVR*
2002 - 2011
Pegylated (PEG-) IFN + Ribavirin
G1: 48 G2/3: 24
G1: 44% G2/3: 80%
2011 FDA approval of the first direct acting antivirals (DAAs) against Hepatitis C: the protease inhibitors Telaprevir and Boceprevir.
2011 - 2013
G1: PEG-IFN + Ribavirin + Telaprevir or Boceprevir) G2/3: PEG-IFN + Ribavirin
24-48 24
62-80% 80%
Late 2013
FDA approval of two new direct acting antivirals (DAAs): - Simeprevir (another oral PI) - Sofosbuvir (an oral polymerase inhibitor) Allowing the first all-oral, IFN-free treatment!
Three main types of antivirals
as of 2015
Protease inhibitors Suffix: -previr Examples: - Telaprevir (Incivek) - Boceprevir (Victrelis) - Simeprevir (Olysio)
Polymerase inhibitors Suffix: -buvir Examples: - Sofosbuvir (Sovaldi) - Dasabuvir (part of Viekira Pak)
NS5A inhibitors Suffix: -asvir Examples: - Ledipasvir (part of Harvoni) - Ombitasvir (part of Viekira Pak)
Source: Garber (2011) Nature Biotechnology 29: 963.
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• 39 yo F manager at CVS.
• H/o morbid obesity (BMI 47 – 49), chronic lower extremity edema, well-controlled anxiety and depression.
• H/o skin grafting for severe burn injury as a child.
• No h/o illicit drug use drug use; minimal alcohol use.
• Viral load 270,000, Genotype 1b
• Liver biopsy (8/2014): mild-moderate inflammation; stage 6/6 fibrosis (= cirrhosis).
• Previous virologic relapse on Peginterferon + Ribavirin + Telaprevir
Case 1: Tinamarie M.
Genotype 1
Options
Duration SVR for tx naïve
pts
SVR for tx experienced or cirrhotic
pts
Cost Side Effects
Harvoni (Sofosbuvir / Ledipasvir)
• 8 wks (no cirrhosis, low VL)
• 12 wks (high VL) • 24 wks (cirrhosis)
98-99% 97% (24 wks) $94,500 Fatigue (18%) Headache (17%) Nausea (9%) Diarrhea (7%) Insomnia (6%)
Viekira Pak (Peritaprevir / Ombitasvir / Dasabuvir / Ribavirin)
• 12 wks (no cirrhosis) • 24 wks (cirrhosis)
97% 95% (24 wks) $83,319 Fatigue (34%) Nausea (22%) Pruritus (18%) Insomnia (14%) Asthenia (14%)
Daclatasvir/ Sofosbuvir
• 12 wks (no cirrhosis) • 24 wks (cirrhosis)
96% 76-100% (24 wks)
$63,000 (12 wks)
Fatigue (14%) Headache (14%) Nausea (8%) Diarrhea (5%)
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Hematocrit
Platelets
Viral load
Started Harvoni on 11/15/2014
Case 1: Tinamarie M.
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• 56 yo M on disability for chronic pain.
• Long h/o opioid use disorder with IV heroin and unsupervised opioid pain med use.
• Strong bond with PCP, but uneven clinic compliance and poor follow-up with “wraparound” SUD care.
• Viral load 987,000, Genotype 2b
• HCV Fibrosure (8/2013): no inflammatory activity, no fibrosis.
• No previous HCV treatment
Case 2: Robert T.
Genotype 2
Options
Duration SVR for tx naïve
pts
SVR for tx experienced or cirrhotic
pts
Cost Side Effects
Sofosbuvir / Ribavirin
• 12 wks (no cirrhosis) • 16 wks (cirrhosis)
92-98% 91-96% $86,000 (12 wks)
Fatigue (36%) Headache (25%) Nausea (18%) Insomnia (12%) Anemia (8%)
Daclatasvir/ Sofosbuvir
• 12 wks (w/ or w/out cirrhosis)
>95% >95% $63,000 Fatigue (14%) Headache (14%) Nausea (8%) Diarrhea (5%)
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Hematocrit
Viral load
Started Sofosbuvir / Ribavirin on 12/26/2013
Completed tx on 3/20/2014
Case 2: Robert T.
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• 63 yo former construction worker, doing well on long term Methadone for opioid use disorder.
• H/o significant PVD w/ claudication, requiring stenting, followed by Vascular Medicine.
• Viral load 5.03 million, Genotype 3
• Liver biopsy (2011): moderate inflammatory activity, stage 6/6 fibrosis (= cirrhosis).
• Previously treated with Peginterferon / Ribavirin, with virologic relapse after treatment.
Case 3: James M.
Genotype 3
Options
Duration SVR for tx naïve pts
SVR for tx experienced or cirrhotic
pts
Cost Side Effects
Sofosbuvir / Ribavirin / Peginterferon
12 wks 97% 87% $94,000 Fatigue (59%) Headache (36%) Nausea (34%) Insomnia (25%) Anemia (21%) Anorexia (18%) Neutropenia (17%) Flu-like sx (16%) Irritability (13%)
Sofosbuvir / Ribavirin
24 wks
93% • 77% (tx experienced)
• 92% (cirrhosis, tx naïve)
$169,000 Fatigue (36%) Headache (25%) Nausea (18%) Insomnia (12%) Anemia (8%)
Daclatasvir/ Sofosbuvir
• 12 wks (no cirrhosis)
• 24 wks (cirrhosis)
97% 88% $63,000 (12 wks)
Fatigue (14%) Headache (14%) Nausea (8%) Diarrhea (5%)
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Hematocrit
Platelets
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Started Sofosbuvir / Ribavirin on 6/2/2014
Ended tx on 11/17/2014
VL 5.03 million VL 4.71 million
Case 3: James M.
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• Hepatitis C now surpasses HIV as the most common and deadly blood-borne infection in the U.S.
• Two main populations with Hepatitis C in the U.S.: a) “baby boomers” and b) a rising cohort of young adults with OUD.
• Hepatitis C should be treated to prevent the development of severe liver disease and prevent viral transmission.
• Highly effective oral treatment with few side-effects now exists for all Hepatitis C genotypes.
• The new treatments are costly, and insurance companies are struggling with the decision of when to approve them.
HCV Treatment in 2015: Take-Home Points
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And the beat goes on…
FDA approved 1/28/2016
Toward a pan-genotypic regimen