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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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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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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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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