Hepatitis C Virus (HCV)

OVERVIEW: What every clinician needs to know

Pathogen name and classification

The Hepatitis C virus (HCV) is a single stranded, positive sense, RNA virus belonging to the family Flaviviridae and is the only member of the genus Hepacivirus.

What patients should be treated?

The FDA approval of multiple direct-acting antiviral regimens for HCV has ushered in the interferon-free HCV treatment era. Pegylated interferon-based therapy is no longer indicated for any patients with HCV, save a very limited potential role in those with genotype 3 HCV, cirrhosis and prior treatment failure. In scenarios where treatment with pegylated interferon (PEG)-based therapies are still utilized, clinicians must keep the serious, potentially life-threatening side effects in mind when assessing the risks and benefits of therapy. HCV treatment efficacy is no longer a major consideration as direct acting antiviral (DAA) therapies offer high cure rates (>95% in most cases, though still slightly lower in treatment-experienced GT3 patients with cirrhosis).

A thorough evaluation of the patient’s readiness for therapy remains important before embarking on a course of therapy. A major shift has occurred in the wake of DAA therapies and current guidelines recommend treatment of all patients with HCV engaged in care unless faced with an extremely limited lifespan due to non-HCV related co-morbid conditions.

All IFN-free DAA genotype 1 treatment regimens drastically improve response rates and side-effects over prior IFN-based therapies. A careful pre-treatment evaluation remains critical to identify those with cirrhosis who require additional medical care and screening for HCC. Also, given the cost and limitations payers are placing on medication approvals in some locations, staging is likely to be required to obtain medication approval.

NOTE: In the remainder of the document HCV therapy or DAA therapy refers to interferon-free therapy unless specifically stated otherwise.

Treatment recommended

Treatment is recommended for all patients found to have chronic HCV infection
Studies suggest even patients with minimal fibrosis are likely to benefit from HCV eradication (PMID 24316172).

If treatment is postponed, fibrosis progression should be evaluated in the future.

Populations that deserve special attention in order to expedite treatment include:

Advanced fibrosis or cirrhosis (equivalent to Metavir stage 3 or 4)
Patients with any current or prior evidence of decompensation (i.e. Childs-Pugh-Turcotte B or C) should only be treated by practitioners experienced in HCV therapy; preferably in association with a transplantation center.

Active/severe extra-hepatic manifestations of HCV disease (See section on extrahepatic manifestations)
Populations at risk for faster disease progression and poor outcomes (e.g. HIV-1 co-infection)
Patients diagnosed during acute infection
Arbitrarily defined as within 6 months of initial infection

Approaches to treatment with DAAs are generally the same as for chronic HCV infection.

Absolute contraindications to therapy with DAA regimens

There are no true absolute contraindications to HCV therapy
Rare exception may be a documents severe allergic reaction
Patients with a very limited lifespan, arbitrarily defined as <12 months, due to non-HCV related comorbidities are generally not considered candidates for HCV therapy.

Factors which may delay start of HCV therapy

Uncontrolled psychiatric disease
Medical management of psychiatric disease in consultation with a mental health professional
Ongoing substance abuse that interferes with compliance and follow-up
Attempt to engage patients in care

Medical management of addiction (e.g., Opiate Substitution Therapy)

Ongoing substance use is NOT an absolute contraindication to therapy

Careful consideration of patient’s ability to adhere to the HCV medical regimen required.
Active infections (opportunistic infections in those with HIV)
Decompensated liver disease
Should be treated in conjunction with liver specialists

Certain DAA medications are contraindicated in patients with decompensated liver disease

HCV protease inhibitors should be avoided

There are now a number of DAA HCV treatment regimens approved; however treatment approaches are expected to continue to evolve.

Treatment for chronic HCV genotype 1 infection continues to evolve. Currently there are multiple HCV DAA regimens approved for treatment of GT1 HCV. All of these regimens offer outstanding efficacy (>90% success rates) and vastly improved side effect profiles compared to treatment with interferon-based regimens. Cure rates in HCV are defined by a sustained virologic response (SVR) measured at various time points after completion of therapy. The standard definition for cure is now SVR12- sustained virologic response (HCV RNA below the limit of quantification) 12 weeks after completion of therapy.

The relative merits of one regimen versus another surround:

the need for RBV
treatment duration (8 vs. 12 vs. 24 weeks)
pill burden and dosing schedules
drug interaction potential.

When used as recommended, efficacy differences between regimens are minimal. Ultimately, insurance coverage and access are often the major determinant of which regimen will be used in a given patient. Although access is improving- this remains the major impediment to treating diagnosed patients engaged in care.

HCV DAAs target several viral non-structural (NS) proteins including the NS3 protease, NS5A protein and the NS5B RNA polymerase. HCV NS3 and NS5B have well defined functions and DAAs act by inhibiting protease cleavage of the viral polyprotein or interfering with RNA replication by NS5B. NS5B polymerase inhibitors have two mechanisms of action- nucleotide polymerase inhibitors (e.g., sofosbuvir) are incorporated by the polymerase and then stop further elongation of the viral RNA (chain-termination). Non-nucleoside inhibitors of NS5B (e.g., dasabuvir) bind to allosteric sites on the polymerase and inhibit RNA replication indirectly.

While the NS5A protein does not have a defined enzymatic function it is critical for viral replication and assembly/release from cells. NS5A proteins exist as homodimers and NS5A inhibitors bind to these dimers, possibly disrupting its association with the viral replication complex.

NS3 protease inhibitors

Simeprevir (SMV, Olysio)

Stand-alone agent
Dose 150 mg PO QD
Used in combination with sofosbuvir
Should be avoided in decompensated cirrhosis (CPT B/C)

Paritaprevir (PTV, component of Viekira Pak)

Only in combination
Dose 100 mg PO QD (boosted with ritonavir)
Used in FDC with ombitasvir and separate dasabuvir
Should be avoided in decompensated cirrhosis (CPT B/C)

Grazoprevir (GZR, component of Zepatier)

Only in combination
Dose 100 mg PO QD
Used in FDC with elbasvir
Should be avoided in decompensated cirrhosis (CPT B/C)

NS5B RNA-dependent RNA polymerase inhibitors

Nucleotide inhibitors

Sofosbuvir (SOF, Sovaldi and component of Harvoni)

Stand-alone agent and in combination
Dose 400 mg PO QD
Used in FDC with ledipasvir; combined as stand alone agent other DAAs
Should be avoided in ESRD (eGFR <30 ml/min/1.73 m²)

Non-nucleoside inhibitors
Dasabuvir (DSV, component of Viekira Pak)

Only in combination
Dose 250 mg PO BID
Used in combination with the FDC PTV/r/ombitasvir
Should be avoided in decompensated cirrhosis (CPT B/C) due to combination with PTV

NS5A inhibitors

Ledipasvir (LDV, component of Harvoni)

Only in combination
Dose 90 mg PO QD
Used in FDC with sofosbuvir
Should be avoided in ESRD (eGFR <30 ml/min/1.73 m²) due to FDC with SOF

Daclatasvir (DCV, Daklinza)

Stand-alone agent
Dose 60 mg PO QD (dose can be adjusted 30-90 mg QD)
Used in combination with sofosbuvir

Ombitasvir (OBT, component of Viekira Pak)

Only in combination
Dose 25 mg PO QD
Used in FDC with PTV/r and additional DSV
Should be avoided in decompensated cirrhosis (CPT B/C) due to combination with PTV

Elbasvir (EBR, component of Zepatier)

Only in combination
Dose 50 mg PO QD
Used in FDC with grazoprevir
Should be avoided in decompensated cirrhosis (CPT B/C) due to combination with GZR

Velpatasvir (VEL, component of Epclusa)

Only in combination
Dose 100 mg PO QD
Used in FDC with sofosbuvir
Should be avoided in ESRD (eGFR <30 ml/min/1.73 m²) due to FDC with SOF
Improved resistance profile compared to other currently available NS5A inhibitors

Genotype 1 HCV

The following regimens are listed in alphabetical order. Regimens are noted to be alternatives in certain circumstances if features of the patient or regimen make it less attractive in a given setting but it may still be used safely and efficaciously if other issues such as medication access or cost make it the only option.

Preferred regimens:

Preferred regimen: Elbasvir 50 mg (EBR)/Grazoprevir 100 mg (GZR) FDC (ZepatierTM, Merck)
General regimen consideration and treatment approaches.
NOTE: Regimen not recommend for those with CPT B or C cirrhosis.

Drug interactions

Both EBR and GZR are CYP3A substrates

Coadministration with CYP3A inducers or inhibitors is not recommended

See package insert for details

Medications that should not be co-administered include:

Ritonavir-boosted HIV PIs

cobisistat

Efavirenz or nevirapine

St John’s wort

Phenytoin or carbamazepine

Rifamycins

Use with caution with statins and in general use lowest dose possible.

This regimen combines a next-generation protease inhibitor (grazoprevir, improved non-genotype 1 activity and better resistance profile) with an NS5A inhibitor (elbasvir) in a FDC pill taken once daily. Data from phase 3 studies indicate excellent efficacy and tolerability; unique features of this regimen include phase 3 data in patients with end-stage renal disease and the recommendation for NS5A resistance testing in genotype 1a patients.

Treatment naïve patients, including 22% with cirrhosis
12 weeks no RBV (n=316): 95% SVR12

Genotype 1a: 92% SVR12

1a with RAVs (n=19): 58% SVR12

Genotype 1b: 99% SVR12
Treatment experienced patients, including 35% with cirrhosis
12 weeks no RBV (n=105): 92% SVR12

1a with baseline RAVs: 29% SVR12

16 weeks plus RBV (n=106): 97% SVR12

1a with baseline RAVs: 100% SVR12
End-stage renal disease patients
12 weeks no RBV (n=116): 99% SVR12
HIV co-infection study, treatment naïve only, 16% with cirrhosis
Allowed ARV: Raltegravir, rilpivirine, or dolutegravir plus nucleosides

12 weeks no RBV (n=218): 96% SVR12
Dosing: 1 tablet PO QD
Duration and use of RBV is determined by genotype 1 subtype (1a vs. 1b) and the presence of baseline NS5A resistance associated variants (RAVs)

The presence of certain baseline NS5A RAVs are the best determinant of treatment response in patients with GT1a treated for 12 weeks no RBV

SVR12 with RAVs: 89%

SVR12 without RAVs: 99%

Only a subset of NS5A RAVs impact EBR/GZR response

Positions M28, Q30, L31M, and Y93

Found in 5-10% of GT1a by population sequencing

Commercially available HCV NS5A resistance testing

LabCorp: CPT/test code: 87902/550705

Quest: CPT/test code: 87902/92447

Genotype 1a without baseline NS5A RAVs

12 weeks no RBV

Regardless of treatment experience or presence of cirrhosis

This regimen is particularly attractive in TE, cirrhotic patients as RBV is not needed and only a 12 week duration

Genotype 1a with baseline NS5A RAVs

16 weeks plus RBV

Regardless of treatment experience or presence of cirrhosis

Standard weight-based RBV is recommended (1000/1200 mg)

Genotype 1b (no RAV testing required)

12 weeks no RBV

Regardless of treatment experience or presence of cirrhosis

Preferred regimen: Ledipasvir/Sofosbuvir fixed dose combination (FDC, Harvoni^TM, Gilead)

This regimen is composed of an NS5B nucleotide polymerase inhibitor (SOF) plus an NS5A inhibitor in a single FDC tablet. Data from phase 3 trials demonstrated high SVR12 rates in most populations and subgroups studied with excellent tolerability.

Treatment naïve patients, including 16% with cirrhosis
12 weeks no RBV (n=214): 99% SVR12

12 weeks plus RBV (n=217): 97% SVR12

24 weeks no RBV (n=217): 98% SVR12

24 weeks plus RBV (n=217): 99% SVR12
In a follow-up phase 3 study 8 weeks of treatment with or without RBV was compared to 12 weeks without RBV
Treatment naïve, non-cirrhotic patients

8 weeks no RBV (n= 215): 94% SVR12

8 weeks plus RBV (n= 216): 93% SVR12

12 weeks no RBV (n= 216): 95% SVR12

Relapse rates were higher in 8 weeks arms and a post-hoc analysis identified the viral load cutoff of 6 million.

Other studies have found female sex and IL28B CC status improved responses with 8 weeks
Treatment experienced patients, including 20% with cirrhosis
12 weeks no RBV (n=109): 94% SVR12

12 weeks plus RBV (n=111): 96% SVR12

24 weeks no RBV (n=109): 99% SVR12

24 weeks plus RBV (n=111): 99% SVR12

All viral relapses were in the 12 week arms
A follow up randomized trial in treatment experienced patients with cirrhosis showed equivalent responses in this population with 12 weeks plus RBV and 24 weeks
12 weeks plus RBV (n=77): 96% SVR12

24 weeks no RBV (n=77): 97% SVR12
HIV co-infection, treatment naïve and experienced, 20% with cirrhosis
Allowed ARVs included: efavirenz, raltegravir or rilpivirine.

12 weeks no RBV (n=335): 96% SVR12

10 viral relapses all in Black patients

8/10 were on efavirenz based regimens

General regimen consideration and treatment approaches.
Drug interactions

Proton pump inhibitors: increase in gastric pH decreases the absorption of LDV

Discontinue proton pump inhibitors (PPIs) unless absolutely medically necessary

Dosing if co-administered:

Maximum dose: omeprazole 20 mg QD (or equivalent)

Taken at the same time as LDV

H2 blockers

Discontinue unless medically necessary

Dosing if co-administered

Maximum dose: famotidine 40 mg BID (or equivalent)

Taken 12 hours apart from LDV

Potent P-gp inducers

Potential to decrease SOF exposure

Avoid co-administration:

Carbamazapine/Oxcarbamazapine

Phenytoin

Phenobarbital

St. John’s Wart

Rifampin (and other rifamycins)

Tipranavir

Statins

Avoid rosuvastatin

Co-administer with caution:

Ritonavir-boosted HIV protease inhibitors when also given with TDF

SOF and LDV increase tenofovir (TFV) levels when co-administered with tenofovir disoproxil fumarate (TDF)

Ritonavir boosted HIV protease inhibitors increase LDV levels and are may also increase TFV levels.

Consider alternative therapy for HCV if possible

If co-administered, close monitoring for TDF-associated toxicity suggested

Creatinine and U/A at week 2 and 4 of therapy and then monthly till complete

See Harvoni package insert for complete list of drug interactions

Metabolism and elimination

Sofosbuvir

primarily renal elimination in the form of inactive metabolite GS-33007

Metabolite accumulates up to 20x in those with ESRD

Not recommended in those with an eGFR <30 ml/min/1.73 m²

Pgp substrate: levels decreased when coadministered with potent

Not a CYP isoenzyme substrate

Ledipasvir

Pgp inhibitor and substrate

Absorption optimal in low gastric pH

Food effect: may be taken without regard to food intake

Take with food if given with RBV

Side effects and tolerability

Bradycardia has been reported when LDV/SOF was given to patients on amiodarone (frequently in conjunction with a b-blocker)

LDV/SOF is contraindicated in persons on amiodarone

Dosing 1 table PO QD (Ledipasvir 90 mg/Sofosbuvr 400 mg)
Duration and use of RBV is dictated by cirrhosis status and prior treatment experience

Important drug interaction (see section on drug interactions):

Acid-reducing agents

Potent P-gp inducers

Treatment naïve (regardless of cirrhosis status)

LDV/SOF 1 PO QD x 12 weeks

Alternative for non-cirrhotic patients with HCV RNA <6 million IU/mL

LDV/SOF 1 PO QD x 8 weeks

NOT recommended in those with HIV co-infection

NOTE: Viral load assessments are not equivalent across different platforms

Cutoff based on Roche COBAS 2.0

12 weeks should be used in patients with other unfavorable characteristic, examples include:

Men with advanced fibrosis (e.g., Metavir F3)

African-American males

Extremely elevated BMI (e.g., >40)

Treatment experienced without cirrhosis

LDV/SOF 1 PO QD x 12 weeks

Includes patients treated with an HCV PI + PEG/RBV

Includes patients treated with SOF + PEG/RBV

RBV should be added if no contraindications

Treatment experienced with cirrhosis (CPT-A)

Two equally efficacious options

Includes patients treated with an HCV PI + PEG/RBV

Includes patients treated with SOF + PEG/RBV

LDV/SOF 1 PO QD x 12 weeks PLUS weight based RBV

RBV 1000 mg (<75 kg), 1200 mg (>75 kg)

This regimen is generally preferred given the significantly lower cost

Contraindications to RBV include:

Absolute:

Hemoglobinopathies

Other severe pre-existing anemia

Relative:

Coronary artery disease

Prior intolerance

Anemia due to RBV is significantly potentiated by interferon but not DAA therapies

LDV/SOF 1 PO QD x 24 weeks

Preferred regimen: Paritaprevir/ritonavir/Ombitasvir 75 mg/50 mg/12.5 mg FDC 2 tablets QD plus Dasabuvir 250 mg BID (Viekira Pak^TM, AbbVie) +/- RBV.
General regimen consideration and treatment approaches.
NOTE: Regimen contraindicated in those with CPT B or C cirrhosis

NOTE: Use with caution in those with CPT A (compensated) cirrhosis

Recent case reports of potential drug induced liver injury occurring early in therapy with this regimen have been reported.

Drug interactions

Given the use of ritonavir-boosting significant potential for drug interaction exit

Consult package insert for full details.

Oral contraceptives

Ethinyl estradiol products

Increased risk of ALT elevations

Should not be co-administered with Viekira Pak.

This regimen combines a ritonavir-boosted NS3 PI (paritaprevir) plus an NS5A inhibitor (ombitasvir) in a FDC with a NS5B non-nucleoside inhibitor (dasabuvir). Differentiating factors for this regimen include a larger pill burden, components with BID dosing (DSV), and the need to always use RBV in patients with GT1a. In contrast for GT1b no RBV is needed and all patients can be treated with 12 weeks of therapy.

Treatment naïve patients, no cirrhosis
12 weeks plus RBV (n=473): 96% SVR12
Treatment experienced patients, no cirrhosis
12 weeks plus RBV (n=297): 96% SVR12
Treatment naïve and experienced patients with cirrhosis
12 weeks plus RBV (n=208): 92% SVR12

GT1a: 89% SVR12 (80% in 1a, prior null responders)

24 weeks plus RBV (n=172): 96% SVR12
HIV co-infection study, treatment naïve and experienced, 16% with cirrhosis
Allowed ARV: Atazanavir or raltegravir

12 weeks plus RBV (n=31): 94% SVR12

24 weeks plus RBV (n=32): 91% SVR12

2 reinfections occurred after SVR4
Dosing: 2 PTV/r/OBV tablets PO QD plus 1 DSV tablet BID
Duration and use of RBV is determined by genotype 1 subtype and the presence of cirrhosis

Genotype 1a without cirrhosis (treatment naïve or experienced)

NOTE: not recommend in those with prior HCV PI treatment

12 weeks plus weight-based RBV
Genotype 1a with cirrhosis (treatment naïve or experienced)
24 weeks plus RBV

Regardless of treatment experience or presence of cirrhosis

Weight-based RBV is recommended
Genotype 1b regardless of treatment history or cirrhosis status
12 weeks no RBV

Omission of RBV in cirrhotis patients treated for 12 weeks.

SVR12 no RBV (n=60): 100% SVR12

Preferred regimen: Velpatasvir/Sofosbuvir fixed dose combination (FDC, Epclusa^TM, Gilead)

This regimen is composed of an NS5B nucleotide polymerase inhibitor (SOF) plus an NS5A inhibitor (VEL) in a single FDC tablet.

It is the first FDC with pangenotypic activity and single duration (12 weeks) for all groups (naïve or experienced, cirrhosis or not) and genotypes (1-6).
Prescribing information only recommends RBV in decompensated cirrhosis

Guidelines endorse use of RBV in additional select populations

GT3 cirrhosis with prior treatment experience

GT3 treatment experienced with Y93H mutation

GT3 treatment naïve with cirrhosis and Y93H mutation

Data from phase 3 trials demonstrated high SVR12 rates all populations and subgroups studied with excellent tolerability.

SVR12 rates are slightly lower in GT3 patients with either prior treatment or cirrhosis (~90%)
Treatment naïve or experienced patients GT1, 2, 4-6
12 weeks no RBV is recommended for all subgroups (note exception for decompensated cirrhosis)

SVR12 rates for select subgroups:

Overall = 99% (618/624)

GT1a = 98% (206/210)

1a cirrhosis = 100% (49/49)

GT1b = 99% (117/118)

GT2 = 100% (104/104)

GT4 = 100% (116/116)

GT6 = 100% (41/41)

<1% discontinued therapy due to an adverse event

In a follow-up phase 3 of patients with GT2, VEL/SOF 12 weeks without RBV was compared to SOF/RBV 12 weeks

VEL/SOF SVR12 = 99% (133/134)

No virologic failures

SOF/RBV SVR12 = 94% (124/132)

6 virologic failures

VEL/SOF was superior to SOF/RBV (p=0.02)

Genotype 3-12 weeks of VEL/SOF is recommended

RBV is added for select groups including:

Treatment experienced patients with cirrhosis

Treatment experienced patients with the NS5A Y93H RAV

Treatment naïve patients with cirrhosis AND the NS5A Y93H RAV

Dedicated phase 3 study in GT3, VEL/SOF 12 weeks without RBV was compared to SOF/RBV 24 weeks

VEL/SOF SVR12 = 95%

11 virologic failures

SVR12 in key subgroups with VEL/SOF 12 weeks:

Treatment experienced = 90% (64/71)

Cirrhosis = 91% (73/80)

SOF/RBV SVR12 = 80%

38 virologic failures

VEL/SOF was superior to SOF/RBV

Treatment approaches with VEL/SOF in patients with HIV co-infection are the same as for those without HIV.

VEL/SOF was studied in HIV/HCV patients in a phase 3 study:

Allowed ARVs included:

Ritonavir-boosted protease inhibitors

Cobicistat-boosted integrase inhibitors

ARVs not studied with VEL/SOF included:

Efavirenz

Nevirapine

Etravirine

Tipranavir

General regimen consideration and treatment approaches.

Drug interactions

VEL is a substrate of CYP3A4, 2B6, and 2C8

AVOID potent CYP inducers

Efavirenz, Nevirapine, Etravirine

Rifamycins

Proton pump inhibitors: increase in gastric pH decreases the absorption of VEL

Discontinue proton pump inhibitors (PPIs) unless absolutely medically necessary

Dosing if co-administered:

Maximum dose: omeprazole 20 mg QD (or equivalent)

Take VEL/SOF with food 4 hours prior to PPI

(NOTE: this adjustment is different than what is recommended for LDV/SOF)

H2 blockers

Discontinue unless medically necessary

Dosing if co-administered

Maximum dose: famotidine 40 mg BID (or equivalent)

Taken 12 hours apart from LDV

Potent P-gp inducers

Potential to decrease SOF exposure

Avoid co-administration:

Carbamazapine/Oxcarbamazapine

Phenytoin

Phenobarbital

St. John’s Wart

Rifampin (and other rifamycins)

Tipranavir

Statins

Rosuvastatin- dose should not exceed 10 mg

Atorvastatin- monitor patients for adverse reactions related to increased atorvastatin exposure (e.g., myopathy)

Co-administer with caution:

Ritonavir-boosted HIV protease inhibitors when also given with TDF

SOF and VEL increase tenofovir (TFV) levels when co-administered with tenofovir disoproxil fumarate (TDF)

Ritonavir boosted HIV protease inhibitors increase VEL levels and are may also increase TFV levels.

When co-administered, close monitoring for TDF-associated toxicity suggested

Creatinine and U/A at week 2 and 4 of therapy and then monthly till complete

See Epclusa package insert for complete list of drug interactions

Metabolism and elimination

Sofosbuvir

primarily renal elimination in the form of inactive metabolite GS-33007

Metabolite accumulates up to 20x in those with ESRD

Not recommended in those with an eGFR <30 ml/min/1.73 m²

Pgp substrate: levels decreased when coadministered with potent

Not a CYP isoenzyme substrate

Velpatasvir

Substrate of CYP2B6, 2C8 and 3A4

Pgp inhibitor and substrate

BCRP substrate

OATP1B1 and 1B3 substrate

Absorption optimal in low gastric pH

Food effect: may be taken without regard to food intake

Take with food if given with RBV

Side effects and tolerability

Bradycardia has been reported with the related regimen LDV/SOF when given to patients on amiodarone (frequently in conjunction with a b-blocker)

VEL/SOF (due to SOF component) is contraindicated in persons on amiodarone

Dosing 1 table PO QD (Velpatasvir 100 mg/Sofosbuvr 400 mg)

Duration is 12 weeks regardless of genotype or patient characteristics

RBV use varies by genotype and patient characteristics

Important drug interaction (see section on drug interactions):

Acid-reducing agents

Strong to moderate CYP inducer (3A4, 2B6, 2C8)

Potent P-gp inducers

Genotypes 1, 2, 4-6 (all patient groups)

VEL/SOF 1 PO QD x 12 weeks

Genotype 3 treatment naïve, no cirrhosis

VEL/SOF 1 PO QD x 12 weeks

Genotype 3 with treatment experienced with cirrhosis (naïve or experienced)

12 weeks VEL/SOF plus weight-based RBV

RBV 1000 mg (<75 kg), 1200 mg (>75 kg)

Genotype 3, treatment naïve patients with cirrhosis

Baseline NS5A resistance testing recommended

No Y93H

12 weeks VEL/SOF

With Y93H

12 weeks VEL/SOF plus weight-based RBV

RBV 1000 mg (<75 kg), 1200 mg (>75 kg)

Genotype 3, treatment experienced, non-cirrhotic patients

Baseline NS5A resistance testing recommended

No Y93H

12 weeks VEL/SOF

With Y93H

12 weeks VEL/SOF plus weight-based RBV

RBV 1000 mg (<75 kg), 1200 mg (>75 kg)

Decompensated cirrhosis (all genotypes)

12 weeks VEL/SOF plus weight-based RBV

RBV 1000 mg (<75 kg), 1200 mg (>75 kg)

Two alternative regimens are listed below. While highly efficacious and well tolerated these regimens are significantly more expensive in the United States and are not likely to be approved by insurers unless unique situations exist requiring one of these regimens over those listed as preferred above.

Alternative regimen: Sofosbuvir (Sovaldi^TM, Gilead) plus Simeprevir (Olysio^TM, Janssen Pharmaceuticals).
NOTE: Simeprevir is not recommend in patients with CPT B or C cirrhosis.

Drug interactions: SMV is a CYP3A4 substrate

Do not co-administer with potent CYP3A4 inducers or inhibitors

See package insert for details.

This regimen is unique in that it does not contain an NS5A inhibitor and thus may be uniquely situated for use in those with prior NS5A failure and resistance. Two phase 3 studies of SOF plus SMV have been completed. Data for use of 24 weeks are incomplete.

Treatment naïve and experienced patients, no cirrhosis (PMID: 26799692)
12 weeks no RBV (n=155): 97% SVR12

8 weeks no RBV (n=155): 83% SVR12
Treatment naïve and experienced patients, with cirrhosis (PMID: 26704148)
12 weeks no RBV (n=103): 83% SVR12

based on low SVR12, 24 weeks of treatment is recommended though not studied in phase 3.
Dosing: Administered as SOF (400 mg) 1 tablet PO QD plus SMV (150 mg) 1 tablet PO QD.
Duration is guided by the presence of cirrhosis.

RBV is recommended based in select settings based on incomplete data.

Patients without cirrhosis (treatment naïve or experienced NO prior PI exposure)

SOF plus SMV for 12 weeks

SVR12 96%

Patients with cirrhosis (No prior PI exposure)

SOF plus SMV for 24 weeks

Data with 12 weeks and indicate a suboptimal response

SVR12

SVR12 with 24 weeks of therapy:

The role of RBV is unknown

RBV can be considered in treatment experienced patients or those with baseline Q80K.

Largely based on expert opinion

Alternative regimen: Sofosbuvir (Sovaldi^TM, Gilead) plus daclatasvir (Daklinza^TM, Bristol-Myers Squibb).
Drug interactions: DCV is a CYP3A4 substrate

Dose adjustment is required in the presence of CYP3A4 inducers (90 mg) or inhibitors (30 mg). Examples include:

Efavirenz- dose DCV at 90 mg PO QD

Atazanavir/ritonavir- dose DCV at 30 mg PO QD

NOTE- the DCV dose is NOT decreased when used in combination with lopinavir/ritonavir or darunavir/ritonavir (DCV 60 mg PO QD)

See package insert for details.

This regimen combines SOF with an NS5A inhibitor, daclatasvir, and is unique in that it is not a FDC and the dose of DCV can be adjusted to accommodate many drug-interactions. This aspect provides some flexibility compared to SOF/LDV. Perhaps more importantly, DCV is more pangenotypic with good activity against HCV GT2 and GT3 making this the preferred regimen for most patients with GT3 (see corresponding sections for treatment approaches).

Limited data are available for this regimen in GT1 with 12 weeks of therapy.
HIV co-infected treatment naïve and experienced patients, with and without cirrhosis
Treatment naïve 12 weeks no RBV (n=83): 96% SVR12

Treatment naïve 8 weeks no RBV (n=41): 76% SVR12

Treatment experienced 12 weeks no RBV (n=44): 98% SVR12
Dosing: Administered as SOF (400 mg) 1 tablet PO QD plus DCV (60 mg) 1 tablet PO QD. Duration is guided by the presence of cirrhosis, though data are insufficient for definitive guidance.
Patients without cirrhosis (treatment naïve or experienced including prior PI exposure)

SOF plus DCV for 12 weeks

Patients with cirrhosis

SOF plus DCV for 24 weeks

Data are limited in cirrhotic patients treated for either 12 or 24 weeks with this combination. A 24 week duration represents the conservative approach and is based on phase 2 study data.

NOTE: A 12 week duration is recommended in the label

The role of RBV is unknown

RBV can be considered in treatment experienced patients or those with baseline NS5A resistance (if tested for).

Largely based on expert opinion

RBV should be added in those with CPT B or C cirrhosis

Patients with CPT B and C cirrhosis should be treated in conjunction with a liver specialist/Hepatologist

RBV dosed at 600 mg

Increase as tolerated

Regimens no longer recommended for GT1:

Sofosbuvir plus RBV or SOF plus PEG/RBV are no longer recommended due to inferior efficacy and tolerability compared to current DAA regimens.
Simeprevir plus PEG/RBV is not recommended due to lower response rates and longer duration of PEG/RBV required (24-48 weeks)
Boceprevir and Telaprevir are no longer recommended due to poor tolerance, lower efficacy and prolonged durations of PEG-RBV exposure
Similarly PEG/RBV alone is not recommended for GT1 patients.

General considerations:

Classification of prior treatment responses
Relapser: undetectable HCV RNA at end of interferon-based therapy with subsequent recurrence

Partial responder: greater than 2log10 HCV RNA decrease by week 12 on interferon but never undetectable

Null responder: less than 2log10 HCV RNA decrease on interferon by week 12

A less than 1log10 decrease at week 4 may also be used
Patient assistance programs:
Sovaldi and Harvoni: www.mysupportpath.com

Viekira Pak: www.viekira.com/proceed-support

Zapatier: www.merckaccessprogram-zepatier.com

Daklinza: www.daklinza.bmscustomerconnect.com/patient-support

Simeprevir: www.Olysio.com

Current standard of care therapy for non-genotype 1 chronic hepatitis C infection differs depending on the specific viral genotype. Treatments for genotypes 2 and 3 are no longer lumped together as different regimens, durations and efficacy rates are seen. Genotypes 4, 5, and 6 are treated in a similar fashion to genotype 1, though not all genotype 1 regimens are appropriate for genotype 4-6 patients (see below).

In phase 3 studies cure rates of >95% are seen in treatment naïve patients with genotype 2 infection treated for 12 weeks. Cure rates drop modestly in treatment experienced GT2 patients, particularly those with cirrhosis, and thus treatment is extended in these patients. Sofosbuvir plus DCV is an option for GT2 patients who cannot take RBV though data are limited.

Genotype 3 infected patients have lower response rates with SOF/RBV, particularly in the setting of cirrhosis (SVR12 ~60%) thus this regimen is no longer recommended for GT3 patients. Sofosbuvir plus DCV has emerged as the current preferred regimen for patients with GT3 infection. Sofosbuvir plus PEG/RBV may be an option for some GT3 patients and offers high SVR12 rates, though patient and provider acceptance is limited.

Genotype 2

Regimen 1

Sofosbuvir 400 mg PO QD plus RBV 1000/1200 mg per day.
SOF as single 400 mg tablet

RBV divided BID by body weight

>75 kg: 1200 mg RBV

<75 kg: 1000 mg RBV
Duration 12 weeks
Extension to 16 weeks in those with cirrhosis

Further extension to 24 weeks in those with both treatment experience and cirrhosis may be considered
No response guided therapy and no established futility rules

Regimen 2- for patients with contraindications to RBV

Sofosbuvir 400 mg PO QD plus DCV 60mg PO QD.
Drug interactions and other dosing consideration same as listed under genotype 1 treatment

SOF as single 400 mg tablet

DCV as a single 60 mg tablet
Duration 12 weeks
Extension to 16-24 weeks can be considered in treatment experienced patients with cirrhosis
No response guided therapy and no established futility rules

Genotype 3

Sofosbuvir plus RBV is no longer recommended for treatment of GT3 patients.

Regimen 1

Sofosbuvir 400 mg PO QD plus DCV 60 mg PO QD.
Drug interactions and other dosing consideration same as listed under genotype 1 treatment

SOF as single 400 mg tablet

DCV as a single 60 mg tablet
Treatment naïve or experienced without cirrhosis
Duration 12 weeks

SVR12: 96-97%

Addition of RBV for those with NS5A RAV Y93H
Treatment naïve or experienced with cirrhosis
Duration 16-24 weeks

PLUS weight-based RBV

SVR12: 88-89%
No response guided therapy and no established futility rules

Regimen 2

For treatment naïve and experienced patients with cirrhosis who can tolerate and are willing to take interferon
SOF 400 mg QD plus PEG 180 mcg week plus RBV 1000/1200 mg QD

SVR12: 93%

Advantages

Shorter treatment duration

Improved efficacy over SOF/RBV for 24 weeks

NOTE: Interferon therapy is associated with significant side effects and a risk of hepatic decompensation in those with cirrhosis. Treatment should only be undertaken by those experienced with interferon therapy, preferable in a transplant center.

Genotypes 4, 5, and 6

Genotypes 4

Regimens recommended for GT1 are generally effective in treating GT4.
Key differences for each regimen in GT4 are noted.

Drug interactions and other dosing considerations remain the same
SOF/LDV (Harvoni)
1 tablet PO QD

Treatment naïve with or without cirrhosis

12 weeks

Treatment experience with cirrhosis

12 weeks plus weight-based RBV

24 weeks without RBV
EBR/GZR (Zepatier)
1 tablet PO QD

NS5A RAV testing not commercially available for GT4

Treatment duration is based on prior treatment history

Treatment naïve or relapse

12 weeks

Partial or null responder

16 weeks plus weight-based RBV
PTV/r/OBV plus weight-based RBV (NOTE Dasabuvir is omitted in GT4)
2 tablets PO QD plus RBV divided BID

12 weeks

same duration regardless of cirrhosis or prior treatment

Genotypes 5 and 6

Extremely limited data exists
Should be treated as recommended for GT1 patients with SOF/LDV regimen

Historical section on use of interferon:

Specifics on the use and dosing of PEG and RBV:

Pegylated interferon alpha-2a (Pegasys^®) contains a 40 kD branched PEG.
Small volume of distribution (roughly the blood volume)

Standard dose: 180 μg subcutaneously once a week

No dose adjustment based on body weight

Dose adjustment only for severe renal impairment or hemodialysis

CrCl<30 mL/min or hemodialysis:135 mcg week
Pegylated interferon alpha-2b (Peg-intron^®) contains a 12 kD linear PEG.
Larger volume of distribution.

Standard dose: 1.5 micrograms per kilogram subcutaneously once a week

Dose adjustment is required for renal impairment.

CrCl 30-50 mL/min: 25% dose reduction

CrCl 10-29 mL/min: 50% dose reduction

Hemodialysis: 50% dose reduction

Ribavirin is most commonly dosed using 200 mg tablets.
Dosing recommendations vary by the HCV genotype and the patient’s body weight.

Dose adjustment for renal impairment

CrCl 30-50 mL/min: 200 mg QD alternating with 400 mg QD

CrCl <30 mL/min or hemodialysis: 200 mg QD

Consider further decrease to 200 mg QOD

Titrate up to 200 mg QD as tolerated

Monitoring on therapy

Preferred DAA regimens

Minimal monitoring on therapy is required.

Week 4 on therapy
CBC, basic metabolic panel (creatinine) and LFTs

HCV RNA

Primarily to ensure compliance

Most patients should have low or undetectable HCV RNA levels

No established futility rules

Consider discontinuation if HCV RNA >1000 IU/mL
Patients with cirrhosis should have additional monitoring if on Viekira Pak or Zepatier
LFTs at weeks 2 and 4.

Any patients with ALT/AST > 10x ULN should immediately stop therapy

Persistent ALT/AST elevations combined with elevated direct bilirubin, INR from baseline should also stop therapy.
Based on week 4 results additional monitoring may be needed.
Repeat HCV RNA until undetectable or therapy stopped
Patients on SOF/LDV who are also on tenofovir disoproxil fumarate may require more intensive monitoring for renal dysfunction/tubular damage related to elevated tenofovir levels.

Monitoring for interferon and ribavirin is primarily of historical significance

Pegylated interferon and ribavirin are associated with multiple side effects, including but not limited to:

Hematologic: anemia, thrombocytopenia, and leukopenia/neutropenia
Psychiatric: depression, suicide, and mania
Endocrine: hypo or hyperthyroidism
Dermatologic: rash and pruritus

Additionally, therapy may precipitate a flare of hepatitis.

Rare progressive hepatitis with hepatic decompensation
More common in those with advanced liver fibrosis

Given the availability of IFN-free treatment option only patients treated with IFN-containing regimens require intensive monitoring for side effects and laboratory abnormalities.

Toxicity laboratory assessments
CBC

Weeks 2 and 4, then approximately monthly

Patients requiring dose reductions and/or growth factors need more frequent monitoring

Chemistry and liver function tests

Weeks 2 and 4, then approximately monthly

TSH at baseline and every 12 weeks on therapy

HCV treatment approaches and responses with interferon-freee DAA therapies are similar in those co-infected with HIV with several important caveats.

Treatment of genotype 1 HCV

Drug interactions are the major consideration and specific to each regimen
Refer to package inserts

The University of Liverpool drug interaction website is a good resource

http://www.hep-druginteractions.org
A recent review summarized the drug interactions with HCV PI and many classes of medications (Kiser Clinical Infectious Diseases 2016 in press).

The following is a list of HIV drugs to avoid with specific DAAs:

Simeprevir

All HIV PIs
Efavirenz
Cobicistat

Paritaprevir/ritonavir/ombitasvir plus dasabuvir

Rilpivirine
Efavirenz or nevirapine
Lopinavir/ritonavir
Caution with darunavir/ritonavir
Cobicistat

Sofosbuvir

Tipranavir

Ledipasvir/sofosbuvir

Tipranavir
Cobicistat
Caution with ritonavir-boosted HIV PIs in patients also on tenofovir disoproxil fumarate

Elbasvir/Grazoprevir

All HIV PIs
Efavirenz or nevirapine
Cobicistat

Daclatasvir

Can be used with all ART but dose adjustment may be required
30 mg with Atazanavir/ritonavir or cobicistat
90 mg with efavirenz or nevirapine

Side-effect management ()

Side effects frequently encountered during interferon-based HCV therapy include flu-like symptoms (fatigue, fever, myalgia), cytopenias, depression, thyroid abnormalities, and weight loss. Effective management of treatment-induced side effects is key to optimizing the dose and duration of antiviral therapy received.

Interferon contributes to all cytopenias through its suppressive effect on hematopoiesis. Anemia is primarily related to ribavirin induced hemolysis, which is exacerbated by both interferon and HCV protease inhibitors. Neutropenia and thrombocytopenia are primarily side effects of interferon therapy.

Anemia
Development of anemia on therapy is associated with improved SVR rates.

Ribavirin dose reduction is the primary method for dealing with anemia, particularly in the setting of HCV PI use.

Specific recommendations vary

Ribavirin dose reduction does not adversely impact treatment outcomes for PI based therapy

Hgb less than 10 g/dL

Decrease RBV by 200-400 mg per day

Magnitude of decrease will depend on rapidity and amount of the drop

More aggressive dose reductions (50%) should be undertaken in those with cardiovascular disease.

Consider earlier dose reduction in this population (Hgb <12 g/dL).

Hgb less than 8.5 g/dL

Hold ribavirin

Caution: patients being treated with an HCV PI must also stop the PI.

Ribavirin therapy may be restarted once hemoglobin has recovered (>10-11 g/dL).

Start at 600 mg; slow titration (200 mg every 2 weeks) up as tolerated

Recombinant erythropoietin (epoetin alfa) may be used in place of or in addition to dose RBV dose reduction.

Careful consideration of the risk/benefits must be considered.

A meta-analysis examining the impact of epoetin alpha suggested improved adherence and SVR rates.

The value of adding erythropoietin to PI-based therapy is not established.

Side effects include

Hypertension

Cardiovascular events (stroke, myocardial infarction)

Thrombosis

Pure red cell aplasia

Adequate iron stores should be verified prior to initiating therapy.

Hgb less than 10 g/dL

40,000 units sc q week: complete blood count (CBC) and blood pressure minimum of every 2 weeks; dose may be increase if poor response (<1 g/dL rise) after 4 weeks

Hold for Hgb greater than 12 g/dL: restart at 25-50% of original dose for Hgb less than 11 g/dL

Neutropenia
ANC less than 750 per mm³

Occurs in 10-15% of patients with PEG/RBV.

20% with boceprevir or telaprevir

ANC less than 500 per mm³

4-5% with PEG/RBV

7% with boceprevir

Increased rates of infections attributed to treatment induced neutropenia have not been described.

Interferon therapy itself does predispose to bacterial infections.

Primary management is interferon dose reduction.

ANC less than 750 per mm³

25% dose reduction in pegylated interferon

ANC less than 500 per mm³

50% dose reduction

Repeat CBC in 1-2 weeks: low threshold to discontinue interferon if ANC still <500/mm³; consider GCSF

GCSF (filgrastim) administration may be considered

Not of proven benefit

Consider in patients whose HCV RNA is not yet undetectable (dose reductions may have negative impact on SVR) and inadequate response to dose reduction alone (to avoid therapy discontinuation)

300 mcg SC q week: Goal ANC greater than 1000/mm³; CBC should be checked before next injection (nadir); frequency can be increased to achieve goal ANC

Side effects

Common: bony pain

Severe/rare: splenic rupture, ARDS, alveolar hemorrhage

Precipitation of sickle cell crisis

Allergic reactions and Sweet’s syndrome (neutrophilic dermatosis)

Thrombocytopenia
Less than 50,000

25-50% dose reduction in pegylated interferon

Magnitude related to rapidity and magnitude of reduction

Repeat CBC in 1-2 weeks

Less than 25,000

Discontinue interferon

Constitutional symptoms
Best managed by adjustments in dosing schedule and premedication

Pegylated interferon injections at bedtime

Premedication with ibuprofen or acetaminophen

Total dose of acetaminophen must be closely monitored in cirrhotics.

Less than 2000 mg per day

Depression/central nervous system
Central nervous system side effects, including depression, irritability, and difficulty with concentration, are extremely common during interferon-based HCV therapy.

Major depressive disorder report in about 30% of patients.

Depression may be severe, and suicide has been reported.

Patients with a history of severe depression (hospitalization, suicide attempts) or poorly controlled depression should be managed in conjunction with a psychiatrist.

Patients with a history of depression not currently on treatment

Initiation of an selective serotonin reuptake inhibitor (SSRI) at least 2 weeks prior to therapy

Clinical trials suggest that pre-treatment can decrease the severity of depression during treatment (may improve medication adherence and improve SVR rates).

The majority of clinical trial data is with citalopram and paroxetine.

Citalopram 20 mg PO QD

Low potential for significant drug-drug interactions

Start at 10 mg PO QD in cirrhotics

Escitalopram is also unlikely to significantly impact HCV PI pharmacokinetics.

10 mg PO QD

Dose dependent QT prolongation with both citalopram and escitalopram

Do not co-administer with other drugs which can impact QT

Do not co-administer CYP 2C19 inhibitors (e.g., efavirenz)

Paroxetine 20 mg PO QD

Other SSRIs may be used

Patients with bipolar disorder or other psychotic disorders may be treated if psychiatric disease is stable.

Should be managed in conjunction with a psychiatrist or other mental health professional in all cases

Treatment failure and resistance

Treatment failure (non-response, breakthrough, or relapse) with pegylated interferon and ribavirin is not associated with specific viral resistance mutations.
PEG/RBV ineffectiveness is associated with a number of viral and patient characteristics, including:

HCV genotype 1 or 4

HCV Viral load (>800,000 IU/L)

Chronic infection (vs acute)

IL28B genotype CT or TT (rs12979860)

Advanced stages of liver disease (cirrhosis)

Retreatment of patient who previously failed PEG/RBV is extremely effective using current DAA regimens
Specific resistance mutations within the protease gene are found after failure with PI containing regimens.
In vitro these mutations are associated with decreased antiviral activity of the PI.

Resistance mutations for telaprevir, boceprevir, simeprevir and paritaprevir overlap, and cross-resistance is expected.

Patients failing a PI-containing regimen should not be re-treated with the another PI-based regimen.

Grazoprevir has a higher barrier to resistance and slightly different resistance profile compared the above mentioned PIs

GZR retains activity against the R155K variant in GT1a

Cross resistance with other PIs does occur at positions 156 and 168

Limited data with GZR/EBR suggest efficacy in patients previously failing PEG/RBV + PI

Given excellent results with non-PI containing regimens in re-treating PEG/RBV + PI treatment failures EBR/GZR is not recommended in those failing a prior PI containing regimen.
NS5A resistance is frequently selected after failing an NS5A inhibitor containing regimen
NS5A resistance persists for >2 years

NS5A resistance also appears to impact re-treatment responses.
Patients who have failed an interferon-free DAA regimen should have resistance testing done including:
NS3 protease and NS5A resistance genotyping
Optimal re-treatment approaches are not well studied
Re-treatment should be undertaken in consultation with an HCV expert

Treatment of acute HCV

The majority of persons infected with HCV go on to develop chronic infection (70-80%). However, because of its mild and often non-specific symptoms, acute HCV infection is difficult to diagnose. Given the excellent responses now seen with treatment using DAAs in chronic HCV infection, there is no benefit in treating early to improve response rates. A benefit in terms of prevention of future transmission (treatment as prevention) may be realized, however, this remains largely theoretical at this point.

Limited data suggest that treatment during acute infection may not have the same impact on responses with DAAs as was seen with interferon-based therapies.

Acute HCV diagnosis
HCV RNA is the preferred diagnostic test for acute HCV infection and monitoring

Positive 1-2 weeks after infection

Requires a high index of suspicion or known high-risk exposure

Monitored to determine spontaneous clearance

The majority who clear do so within 12 weeks

A 2 log decrease in HCV RNA over first 4 weeks of infection is associated with spontaneous clearance.

A negative HCV RNA should be repeated 3-6 months later (relapse has been reported especially in those with HIV).

If HCV RNA remains detectable at or after 12 weeks, treatment should be considered.

HCV antibody is not reliable for diagnosis of acute HCV infection.

HCV antibody generally appears within 2-3 months.

Antibody appearance can be delayed out to 1 year, particularly in HIV co-infected patients.

Appearance of HCV antibody is not associated with clearance.

Hepatic transaminases (ALT, AST)

Elevated in nearly all case of acute HCV infection

Greater than 10 times the upper limit of normal is frequent during acute infection

New or dramatic elevation should trigger an evaluation for acute HCV
Acute HCV treatment
Treatment of acute HCV infection should be strongly considered in patients who do not clear HCV infection spontaneously within 12 weeks of the estimated date of infection.

Efficacy is no longer a major consideration to treat during the acute stage

Patients with acute HCV infection may be more likely to engage in risk behaviors and are a reservoir for ongoing forward transmission of HCV

Prompt treatment of HCV may prevent further transmissions

Treatment approaches are the same as for chronic HCV

Sufficient data are not yet available to truncate DAA therapy in the acute setting.

How do patients contract this infection, and how do I prevent spread to other patients?

HCV Epidemiology

Prevalence
Worldwide: 170-200 million persons infected

United States: 3-4 million with chronic infection (1.3%)

As high as 5-7 million accounting for high risk populations (2%)

Highest prevalence: Egypt 15-20%

Presumed largely due to iatrogenic transmission/unsafe injection practices

Lowest prevalence: Scandinavia/Northern Europe less than 1%
Incidence
An alarming trend of increased HCV incidence has been seen in United States over the last 3 years

The increase has been most dramatic in young age groups

20-29 and 30-39 years old

Outbreaks of acute HCV are also increasingly seen in non-urban areas

Estimated 30,000 new (acute) infections in 2013 (cdc.gov, viral hepatitis surveillance 2013)

Increasing incidence presumed due to

Increased injection drug use

Transition from prescription opiates to injection drug use

Much publicized outbreak of HIV and HCV in rural Indiana.

>90% in that outbreak with HCV infection

The problem does not appear to be isolated to the Midwest

Multiple states have seen a >200% increase in incident HCV cases from 2006-2012

States include:

New York

California

Florida

Illinois

HCV transmission

The routes via which the exposure occurs differ based on the risk factors for a given population and influence the frequency with which infection is established following exposure.

The primary mode is percutaneous exposure to blood or blood-products containing HCV RNA.

Intravenous drug use is the primary means of HCV transmission in the United States.
HCV can survive for more than 1 week in blood in syringes.

Implements used in drug preparation may also play a role in transmission (cotton swabs, etc.).
Infection by transfusion is exceedingly rare in the United States (<1 in a million)
Predominate mode of transmission in the United States prior to 1991

Sequential implementation of HCV antibody and nucleic acid testing screening essentially eliminated transmission via transfusion.

Less than 0.5 in a million per unit transfused

Remains an issue in the developing world
Medical procedures/other injections
Sporadic case reports in the United States

Improper use of multi-use injectable medication vials

Poor sterilization technique

A major source of transmission in the developing world
Healthcare-associated needle-stick exposures
1-3% transmission rate

No post-exposure prophylaxis available
Vertical transmission
Occurs in roughly 5% of infants born to mother with detectable HCV RNA

15-20% transmission rate if the mother is HIV infected

Diagnosis in infants

HCV antibody may remain positive for 12-18 months because of placental transfer of maternal IgG antibody.

Diagnosis relies on HCV RNA with testing at:

2-6 months of age

Repeated 3-6 months later or after 18 months old

Spontaneous clearance may occur

Prevention

Cesarean section is not recommended to prevent HCV transmission

Exception if mother is also HIV-positive

Breast feeding is not known to transmit HCV

Invasive scalp monitoring should be avoided

Sexual transmission

HCV is NOT readily transmitted by sexual contact under most circumstances. However, sexual transmission of HCV serves as a major source of incident HCV infection in HIV-positive men who have sex with men (MSM).

Exceedingly rare for heterosexual couples in long-term relationships
No transmission was observed over 10 years in a study of heterosexual couples.

No specific recommendation for measures to prevent HCV sexual transmission in this population

HIV-positive partner seems to increase the rate of transmission of HCV in heterosexual couples.

3% HCV infection rate in long-term female partners of HCV/HIV+ men
Sexual transmission in HIV-positive MSM
Increasing over the last decade

Has been described in major urban centers of Europe and North America

Incidence estimate in the United States from 1996 to 2008 (5.1 cases per 1000 patient-years)

Risk factors

Unprotected receptive anal intercourse

Group sex

Traumatic sexual practices (fisting, use of sex toys)

Non-injection drug use (methamphetamines, GHB)

Concomitant STIs

Majority (60-75%) have few or no symptoms

Dramatic increases in HCV incidence in HIV negative MSM have not been noted, although the HCV prevalence in this population is higher than the general population.

Annual HCV antibody screening should be performed in high-risk HIV-positive populations.

MSM with high-risk sexual practices

Injection drug user

Hepatic transaminases (ALT, AST) semi-annually

Inexpensive and readily available

May facilitate earlier diagnosis

Diagnosis and treatment during acute infection results in improved cure rates.

Infection control issues

Standard universal precautions should be followed.
No special personal protective equipment or precautions are required.

Prevention

No HCV vaccine is currently available.
Prophylactic therapy is not recommended.
A significant proportion of acutely infected persons may clear HCV on their own (20-30%).

Clearance rates appear to be higher with symptomatic acute infection (50%).

Clearance rate depends on a number of factors, including:

IL28B genotype: CC genotype resulted in a greater than 50% clearance rate

Age: younger age at infection favors clearance

Sex: females clear more frequently

Co-morbid conditions (e.g., HIV): spontaneous clearance rates of roughly 10%

Patients who have not cleared within 12 weeks of infection should be considered for therapy. (See chapter on Treatment of Acute HCV Infection.)

What host factors protect against this infection?

Establishment of infection with HCV is largely determined by the type and intensity of exposure.

Host factors are not known to be involved with the risk of developing initial infection.
Host factors play a significant role in:
Outcome of acute infection (resolution vs. chronic)

Response to antiviral therapy
Immune system factors that protect from chronic HCV infection
Neutralizing antibodies have a limited role in controlling or resolving HCV infection.

Reinfection is possible following treatment induced HCV clearance.

Immunoglobulin preparations are not effective as post-exposure prophylaxis.

Strong and sustained multi-specific T-cell responses are associated with clearance.

Single nucleotide polymorphisms near the IL28B (interferon lambda) gene

rs12979860 C/C genotype (vs C/T or T/T): three times more likely to clear

Human leukocyte antigens

HLA B27

Natural Killer cell immunoglobulin-like receptors

KIR2DL3/HLA-C1

Histopathology of HCV infection

HCV diagnosis is based on antibody and viral RNA detection.
Histopathology is used for grading the severity of liver disease and fibrosis staging.
Stage of liver disease is the best prognostic factor for future complications.
Typical HCV histopathology
Portal inflammation with lymphocytic infiltrates (nodular)

Interface hepatitis

Lymphocytic infiltration at the border between portal tracts and parenchyma

Hepatocyte apoptosis/dropout

Lobular hepatitis

Steatosis is typically present.

Macrovesicular

More pronounced with genotype 3 infection

Should be differentiated from concomitant steatohepatitis

Mild bile duct damage

Fibrosis (if present)

Starts in portal tracts

Progression with septa

Bridging fibrosis- connection of septa

Cirrhosis: bridging fibrosis with regenerative nodules

Additional (often unsuspected) diagnoses may be found in up to 20% of biopsies.

Three most common additional diagnoses

Steatosis +/- steatohepatitis

Hemosiderosis

Hepatocellular carcinoma

What are the clinical manifestations of infection with this organism?

HCV infection is now the leading cause of mortality from chronic viral infections in the United States, recently surpassing HIV infection.

Liver-related manifestations

Chronic hepatitis
Develops in 60-80% of those infected

Those more likely to clear acute infection include:

Women

IL28CC genotype

Young age at infection

Most are asymptomatic until end-stage liver disease develops.

Chronic fatigue may be noted.

Transaminitis on routine laboratory studies

ALT/AST elevations

ALT/AST may be normal in up to 1/3.

Does not preclude the development of progressive fibrosis

Progressive hepatic fibrosis
End Stage Liver Disease
Clinical manifestation of cirrhosis on liver histology

Develops over the course of 20-40 years

Estimated to develop in 20% of those chronically infected

Accelerated by alcohol abuse and HIV co-infection

Progression is NOT associated with the level of HCV viremia or viral genotype.

May be clinically silent until decompensation occurs

Signs of decompensation

Jaundice

Ascites

Esophageal varices with bleeding

Coagulopathy (elevated INR)

Encephalopathy
Hepatocellular Carcinoma
Incidence of 1-4% per year in those with cirrhosis

Chronic HCV is most common cause in the United States.

Screening for hepatocellular carcinoma

Initiated once cirrhosis is diagnosed or suspected

Abdominal ultrasound every 6-12 months is preferred in guidelines

CT (Quad-phase) or MRI are likely more sensitive

Not validated as screening tools

Cost and radiation exposure are concerns

Serum alpha-feto protein is not recommended as a screening tool.

Use remains common in clinical practice.

Role in evaluation of suspicious lesions identified on imaging

Extra-hepatic manifestations
Cryoglobulinemia- type II and III mixed cryoglobulinemia

40-50% of persons with chronic HCV will have circulating cryoglobulins

Majority will not have clinical symptoms

Up to 95% of patients with clinically symptomatic cryoglobulinemia will have chronic HCV

Clinical symptoms

Vasculitis

Palpable purpura

Nonspecific symptoms such as fatigue and arthralgias

Neuropathy

Renal disease: membranoproliferative glomerulonephritis

Patients presenting with symptoms suggestive of or diagnosed with mixed cryoglobulinemia should be screened for HCV.

Clinically active cryoglobulinemia due to chronic HCV is an indication for HCV treatment.

NOTE: Patients presenting with severe clinical manifestations due to cryoglobulinemia (renal failure/vasculitis) will require treatment to control disease prior to HCV therapy.

Rituximab plus pegylated interferon and ribavirin has shown promising early trial results.

Porphyria cutanea tarda
Photosensitivity and skin lesions (bullae and vesicles) in sun exposed areas

Roughly 50% of sporadic cases will have evidence of HCV infection

Treatment of HCV may result in improvement.
Diabetes mellitus
Strong epidemiologic association between HCV infection and the development of diabetes

Three time more likely to develop diabetes mellitus than those without HCV

Improvements in insulin sensitivity have been described with effective HCV therapy.
Other extra-hepatic manifestations/complications
B-cell lymphoproliferative disorders

B-cell Non-Hodgkin’s lymphoma

Central nervous system effects

Fatigue, depression, and reduced health-related quality of life

Cognitive-impairment
Sicca syndrome
Oral and ocular dryness

Sialadenitis does not appear to improve with effective HCV therapy.
Vitiligo
Lichen planus

How should I identify the organism?

The Hepatitis C virus is a positive-strand RNA virus with the primary site of replication being hepatocytes. The entire virus life cycle takes place within the cellular cytoplasm. Unlike retroviruses, such as HIV-1, there is no DNA intermediate or integrated form of HCV from which to create a viral archive.

Testing for the virus relies on two techniques: detection of antibody to the virus and direct detection of viral RNA.

HCV serologic testing

Testing for the presence of HCV antibodies in blood is the first step is assessing a patient for possible HCV infection.

HCV antibody (AB) detection via enzyme immunoassay (EIA) is the standard screening test
Greater than 98% sensitivity for third-generation assays

Detectable about 2 months after infection

False negatives during early acute infection and severely immunosuppressed

False positives if low risk populations (low pre-test probability) are screened

DOES NOT indicate active infection (HCV viremia)

Appearance of HCV AB may be delayed in immunosuppressed persons.

Mean time to detectability about 6 months in HIV co-infected

Reports of antibody appearance delayed out to greater than 1 year

HCV RIBA (recombinant immunoblot) is a confirmatory test that detects antibody to specific HCV antigens.

Historically used to confirm a positive HCV EIA (e.g., rule out a false-positive EIA in low risk persons)

Limited role now with widely available HCV RNA assays

DOES NOT indicate active infection

HCV ribonucleic acid detection

HCV RNA detection
Detection of HCV RNA via RT-PCR (or other similar nucleic acid amplification techniques)

Mainstay of diagnosis for chronic HCV infection

Diagnosis of acute infection prior to appearance of antibody

positive within 1-2 weeks of infection

A number of commercial quantitative RT-PCR assays are available.

Critical to following viral response during therapy

The same assay should be used for serial measurements

HCV is difficult to grow in cell culture, and cell culture is not used clinically for virus isolation/diagnosis.

Liver disease staging

The clinical course of chronic HCV infection is highly variable with some persons developing significant fibrosis within a few decades, whereas others may never develop clinically significant fibrosis or complication related to HCV. Accurate disease staging remains a key component of the management of HCV infection from both a treatment decision standpoint, as well as for monitoring of complications related to cirrhosis, such as HCC.

Individual routine blood tests (e.g., ALT, bilirubin, INR or platelets) cannot accurately stage liver disease.
Indices composed of several common clinical laboratory parameters:
Simple and can be calculated from readily available patient data

Can identify advanced fibrosis/cirrhosis reasonably well.

APRI: AUROC 0.88-0.94 for identifying advanced fibrosis/cirrhosis

FIB-4: AUROC 0.85-0.91 for identifying advanced fibrosis/cirrhosis

FORNS: AUROC 0.81-0.86 for excluding significant fibrosis/cirrhosis

May eliminate the need for biopsy in a subset of patients
Specialized assays
FibroSure (also called FibroTest in Europe)

Combines routine and specialized blood tests in a proprietary algorithm

Haptoglobin, total bilirubin, alpha-2 macroglobulin, apolipoprotein A1, and GGT

AUROC 0.85 (0.82-0.87) for distinguishing F0/1 versus F2-4 (meta-analysis)

Decreased AUROC (about 0.65) for distinguishing adjacent stage of fibrosis

20-25% discordance with biopsy

Roughly one-half due to biopsy failure (inadequate sample)

Better than biopsy at predicting HCV-related complication and death over 5 years

Limitations

Situations that significantly limit the diagnostic accuracy

Gilbert syndrome

Medications which raise bilirubin (e.g., atazanavir)

Acute inflammation (alters haptoglobin)

Increased cost

Requires specialized testing (compared to APRI or FIB-4)

Imaging techniques

Ultrasound

Routine ultrasound is not a reliable measure of hepatic fibrosis.

Portal venous pressures/flows may improve sensitivity

Transient Elastography (FibroScan™)

Specialized ultrasound technique for assessing fibrosis

FDA-approved in May 2013

AUROC 0.94 for discriminating between cirrhosis and mild fibrosis

Sensitivity 85% for detecting greater than or equal to F2 fibrosis

Limitations

Cannot discriminate between acute inflammation and fibrosis

Is not yet widely available

Liver biopsy: the accepted standard for staging of liver disease (see histopathology section)

Advantages

Direct assessment of:

Fibrosis and inflammation

Iron stores

Steatosis

Diagnosis or suggestion of other liver pathology

Steatohepatitis

Alcoholic hepatitis

Drug-induced injury

Auto-immune hepatitis

Limitations

Invasive

Pain is common but generally mild to moderate

Complication rate: 1 in 1,000 to 10,000

Bleeding most common

Mortality: less than or equal to 1 in 10,000

Primarily due to hemorrhage

Sampling error or inadequate sampling

Paired biopsies from left and right lobe

33% with greater than or equal to 1 stage difference in fibrosis

Ideally16-gauge needle or wider

Minimum criteria for an adequate biopsy

Greater than 2cm total length

11 portal tracts

Inter-observer variability

Approaches

Ultrasound guided, percutaneous

Trans-jugular

Reserved for those with contraindications to percutaneous biopsy

Morbid obesity

Ascites

Coagulopathy

Biopsy assessment- grading/staging systems

Grade: assessment of disease activity and inflammation

Stage: evaluation of the extent of fibrosis

Common grading systems

Simple systems: largely descriptive

Metavir

Activity: A0-A3

Fibrosis: F0-F4

F4 equals cirrhosis

Other examples include IASL and Batts-Ludwig

Complex numerical scoring systems

Histology Activity Index (HAI or Knodell)

Modified HAI (mHAI or Ishak)

Grade: numerical score from 0-18 with discrete categories

Stage: 0-6

5/6 equals incomplete/complete cirrhosis

How does this organism cause disease?

Liver inflammation and fibrosis

Liver disease progression is highly variable and non-linear in chronic HCV infection. It is estimated that, after 30 years, 20% of patients will have had progressive fibrosis to the point of cirrhosis. Following the development of cirrhosis clinical events, such as the development of ascites, encephalopathy, variceal bleeding, and hepatocellular carcinoma, occur leading to appreciable morbidity and mortality. Antiviral therapy can cure HCV and is associated with not only improved clinical outcomes, but reversal of liver fibrosis.

HCV is not directly cytopathic for hepatocytes.
Liver disease with progressive fibrosis is related to chronic inflammation and the immune response.
Progression of liver disease is NOT correlated with the level of viremia.

Viral genotype is not a strong predictor of disease progression.

Genotype 3 HCV is associated with steatosis, which may accelerate disease progression.

Non-viral factors associated with more rapid liver disease progression include:

Male gender

Alcohol use

Duration of infection

Establishment of chronic infection

HCV has evolved a number of strategies leading to efficient establishment of chronic infection.
Viral characteristics favoring chronic infection

Error prone viral RNA polymerase allows rapid viral mutation

Mutation in hypervariable region 1 (HVR 1) of the second envelope protein

Escape from neutralizing antibody

Subversion of innate immune responses and interferon signaling by viral proteins

Viral NS3 protease

Inhibition of TLR3 signaling (sensing of ssRNA)

Inhibition of RIG-I signaling (sensing of dsRNA)

Other viral proteins, including core, E2, and NS5A, have been associated with subverting antiviral immune responses

Up regulation of Programmed Death receptor-1 (PD-1) on HCV-specific CD8 cells

Increase in non-functional cytotoxic T cells (immune exhaustion)

Direct cell-to-cell spread of virus

Avoidance of neutralizing antibody

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