HCV Treatment in Special

Population

Difficult to treat cases

Point to discussed
HCV treatment in patients with :-
1. Decompensated cirrhosis
2. Kidney disease
3. Pregnancy
4. HIV/HCV Coinfection
Treatment of HCV in decompensated Cirrhosis
 Ascites

If treatment is considered in
decompensated cirrhosis, then it
should be in;
 Experienced center
 Transplant evaluation

Bleeding varices

 Decompensated cirrhosis
 Ascites
 Hepatic hydrothorax
 Bleeding varices
 Hepatic encephalopathy

Hepatic hydrothorax
 Impact on Treatment Outcomes

Patients with low levels of F <3 have high likelihood of

treatment success with DAAs in less than 12 weeks
Patients with F-3 and above have slower responses to
treatment, especially when previously treated, requiring:
Longer treatment durations or
Addition of ribavirin, which increases side effects
Patients with very high levels of fibrosis (F-4 ) are;
 less likely to reach treatment success (SVR12)
more likely to have signs of decompensated cirrhosis
more likely to require extra-care to manage their illness
Patients With Decompensated Cirrhosis
• most patients(including CTP-C) receiving DAA therapy experience
improvement in clinical and biochemical indicators of liver disease
• Improvements, however, may be insufficient to avoid liver-related death or the
need for liver transplantation
• highlighting that not everyone benefits from DAA therapy
• Most deaths among those receiving DAA therapy relate to the severity of
underlying liver disease
• (MELD) score >20 or severe portal hypertension complications
• In a more recent large, multicenter, real-world cohort of 642 patients with
advanced cirrhosis (defined as cirrhosis and MELD score ≥10) treated with a
variety of DAA regimens, the overall SVR12 rate was 90.5%.

www.HCVGuidance.org on January 27, 2021

 Ledipasvir/sofosbuvir
in decompensated cirrhosis

12 weeks 24 weeks
SOLAR study 100
Patients 87 89 90
86
108 GT 1 or 4
80
treatment naïve or
experienced
CPT class B or C 60

SVR12 (%)
Inclusion/exclusion
Total bili <10 mg/dL
40
Creatinine clearance >40 26 24 19 18
mL/min 30 27 22 20
Platelets >30,000 x 103/uL 20
Design: RCT
Regimen 0
CPT B CPT C
Ledipasvir/sofosbuvir +
ribavirin for 12 or 24
weeks Charlton M. Gastroenterology 2015.
 Ledipasvir/sofosbuvir
in decompensated cirrhosis
SOLAR study Pre-transplant
Patients Child Pugh B & C
n = 108
108 GT 1 or 4
treatment naïve or
Any adverse event 106 (98%)
experienced
CPT class B or C Serious adverse 30 (28%)
Inclusion/exclusion event
Total bili <10 mg/dL Adverse event 5 (5%)
Creatinine clearance >40 leading to
mL/min discontinuation
Platelets >30,000 x 103/uL
Design: RCT Death 1 (1%)
Regimen Liver transplantation 4 (4%)
Ledipasvir/sofosbuvir +
ribavirin for 12 or 24
weeks
Charlton M. Gastroenterology 2015.
AVOID in
 Decompensated Cirrhosis……

No
No
protease
interferon
inhibitors

Not recommended OK to use

 Simeprevir  Daclatasvir + Sofosbuvir
 Paritaprevir/r, ombitasvir, +/- ribavirin
dasabuvir  Ledipasvir + Sofosbuvir
 Grazoprevir/elbasvir +/- ribavirin
 Peginterferon  Sofosbuvir + Ribavirin
Decompensated cirrhosis…
Decompensated cirrhosis…
…..cont’d
 Decompensated cirrhosis…………
Genotype 1 or 4
AASLD/IDSA Recommendations for patients with DC
Daclatasvir + Sofosbuvir
Ribavirin eligible Recommended for 12 weeks with RBV 600 mg starting dose and
increased as tolerated
Ribavirin ineligible Recommended for 24 weeks

Genotype 2 or 3
AASLD/IDSA Recommendations for patients with Decompensated cirrhosis

hcvguidelines.org
 Daclatasvir/sofosbuvir
in decompensated cirrhosis

ALLY-1 study
Patients
60 advanced cirrhosis
53 post-transplant
CPT class A, B or C
MELD 4
Design: open-label
Regimen
Daclatasvir +
sofosbuvir + ribavirin
(600 mg and raised to
1000 mg if tolerated)

Poordad F. EASL 2015

 Daclatasvir/sofosbuvir
in decompensated cirrhosis

100 94
ALLY-1 study 83
80
Patients
60 advanced cirrhosis 60

53 post-transplant 40

SVR12 (%)
CPT class A, B or C
20
MELD 4
Design: open-label 500
50
53

sis

t
an
60
Regimen

pl
rh

ns
cir

tra
Daclatasvir +

st-
ce
an

Po
sofosbuvir + ribavirin

v
Ad
(600 mg and rasied to 9 relapses
100 mg if tolerated) Poordad F. EASL 2015
 Daclatasvir/sofosbuvir
in decompensated cirrhosis
100 94
92
ALLY-1 study 80
Patients
60 advanced cirrhosis 60 56

SVR12 (%)
53 post-transplant
CPT class A, B or C 40
MELD 4
20
Design: open-label 11 30 9
12 32 16
Regimen 0
A B C
Daclatasvir +
sofosbuvir + ribavirin Child Pugh score
(600 mg and raised to
1000mg if tolerated) Poordad F. EASL 2015
 What does cure of HCV mean?

Decompensated cirrhosis:
Is there a threshold where we cannot avoid liver failure and a transplant?
 Decompensated cirrhosis and HCV

Summary
Patients with decompensated cirrhosis can be cured with
direct acting antiviral regimens
Current protease inhibitors are not recommended for
patients with decompensated cirrhosis due to risk of toxicity
Ribavirin should be used carefully in patients with
decompensated cirrhosis
Patients ineligible to take ribavirin require longer courses of
therapy
The degree of improvement in portal hypertension and long
term clinical outcomes are unknown in patients with
decompensated cirrhosis cured of HCV
HCV Treatment in CKD and ESKD
 Treatment of HCV in Kidney Disease
HCV-associated immune complex disorders can cause renal disease
HCV infection was associated with a
 51% increase in the risk of proteinuria and
 43% increase in the incidence of CKD
More common
• Glomerulonephritis (membranoproliferative (MPGN) =>most common
• Mixed cryoglobulinemia
• Polyarteritis nodosa(PAN)
Less common
• Focal segmental glomerular sclerosis(FSGS)
• Proliferative glomerulonephritis(PGN)
• Membranous glomerulonephritis(MGN)
Possible indication for treatment regardless of stage of disease
Successful HCV antiviral treatment improves clinical outcomes
Ozkok A, Gastroenterol 2014. Peters L, AIDS 2012
Fabrizi, 2015; Rogal2016; Sὄderholm,2018
 Risk of HCV infection in hemodialysis
 Rates of HCV in patients on hemodialysis

 HCV is 5 times greater in hemodialysis patients than US general population

 Risk factors for HCV infection among hemodialysis patients include;

•  years on dialysis
• Blood product transfusions
• Injection drug use
• Organ transplantation

Finelli L. Semin Dial 2005

 Renal Clearance of HCV Medicines
Renal Supporting
HCV antiviral Clearance FDA Guidance Data

Ribavirin YES extensive

Sofosbuvir YES No use if GFR<30 limited
Simeprevir NO No dose change limited

Ledipasvir NO No use if GFR<30 none

ml/min

Paritaprevir/r/ombitasvir + NO No dose change limited

dasabuvir
Daclatasvir NO No dose change none
 Renal Clearance of HCV Medicines
Peginterferon and ribavirin
Dose Adjustments Needed for Patients with Renal Impairment

Renal Glomerular filtration PEG-IFN PEG-IFN Ribavirin

Impairment rate/ 2a 2b
Creatinine clearance
(mL/min)
Mild 50-80 180 µg 1.5 1000 mg or 1200 mg
µg/kg
Moderate 30-50 180 µg 1 µg/kg Alternating doses
200 mg and 400 mg
every other day
Severe <30 135 µg 1 µg/kg 200 mg/day
ESRD with HD 135 µg 1 µg/kg 200 mg/day

hcvguidelines.org
 Ribavirin in Kidney Disease
Major adverse event: hemolytic anemia
Hemoglobin 8.5 -10 g/dL
in patients
without cardiac disease,
or
Decrease in hemoglobin of ≥2
g/dL during any 4 week period
in patients
with stable cardiac disease
Ribavirin dose Reduce to 600 mg
Hemoglobin <8.5 g/dL
in patients
without cardiac disease,
or
Hemoglobin <12 g/dL despite 4
weeks at reduced dose
in patients
with stable cardiac disease
Discontinue

AASLD/IDSA recommendation if chronic kidney disease:

Discontinue ribavirin if hemoglobin level  by > 2 g/dL despite erythropoietin
hcvguidelines.org
 Chronic kidney disease and HCV Treatment
Genotype 1 or 4
AASLD/IDSA Recommendations for patients with chronic kidney disease

Daclatasvir Ledipasvir Sofosbuvir

Paritaprevir/r Peginterfer Grazoprevir
Sofosbuvir Sofosbuvir ribavirin
Ombitasvir on Elbasvir
Dasabuvir ribavirin
Mild- Recom- Recom- Not recom- Recommended Not recom- Recom-
moderate, mended. mended mended Ribavirin dose mended mended
GFR 30-80 No dose No dose adjustment No dose
ml/min adjustment adjustment if GFR < 50 adjustment
ml/min

Severe & Not reco- Not reco- Not Reco- Recom- Not recom- Recom-
ESRD, mmended mmended mmended mended 1b mended mended
GFR < 30 Alternative 1a No dose
ml/min Ribavirin dose adjustment
adjustment
if GFR < 50
ml/min

hcvguidelines.org
 Chronic kidney disease and HCV Treatment
Genotype 2, 3, 5, 6
AASLD/IDSA Recommendations for patients with chronic kidney
disease
Daclatasvir Ledipasvir Sofosbuvir Peginterferon
Sofosbuvir Sofosbuvir ribavirin ribavirin
Mild- Recom- Recom- Recommended Not recom-
moderate, mended mended for for 2 mended Note:
GFR 30-80 No dose 5 and 6 Alternative for
ml/min adjustment No dose 3 grazoprevir/
adjustment Ribavirin dose elbasvir
adjustment
if GFR < 50 effective
ml/min against
Severe & Not recom- Not recom- Not recom- Recommended genotype 6
ESRD, mended mended mended if urgency is
GFR < 30 high but did not
ml/min receive FDA
approval

hcvguidelines.org
 RUBY-1: PrOD in Chronic Kidney Disease
 Patients
 Genotype total no 20. 100
 1a (n=13) and 1b (n=7) 100
95
 Chronic kidney disease
 CKD stage 4 80
 eGFR 15-29 ml/min
 CKD stage 5
 eGFR < 15 ml/min on hemodialysis 60

HCV RNA TND (%)

 Design: open label
 Regimen
40
Paritaprevir/r, ombitasvir +
dasabuvir
 Ribavirin for 1a only (Q80K pol) 20
20 19
• Patients not on hemodialysis: 200 mg once 20 20
daily
on hemodialysis: 200 mg given 4 hours before
each hemodialysis session 0
End of SVR12
treatment

Pockros et al. AASLD 2015

 C-SURFER: Grazoprevir/Elbasvir in kidney disease
Patients Grazoprevir Placebo
 Genotype 1 Elbasvir
n=111 n=113
 Chronic kidney disease
 CKD stage 4 Serious adverse events 14% 17%
 eGFR 15-29 ml/min Discontinued for adverse events 0% 4%
 CKD stage 5 Deaths 1% 3%
 eGFR < 15 ml/min or
hemodialysis
 75% hemodialysis
 Design: RCT, placebo controlled
 Regimen
• Grazoprevir + elbasvir x 12 weeks, no
ribavirin

Roth D. EASL 2015

safety and efficacy of GP at week 12

EXPEDITION-4 Study

• 104 patients enrolled in the study

• 76% male
• 25% black
• 19% compensated cirrhosis
• 40% treatment experienced; and
• 82% hemodialysis dependent.
• The genotype distribution
• genotype 1a: 22%
• genotype 1b: 28%
• genotype 2: 16%
• genotype 3: 11%
• genotype 4: 19%
• genotype 5 & genotype 6= 1% each
• The daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120mg)
• three 100 mg/40 mg fixed-dose combination pills.
EXPEDITION-5 , Efficacy and safety of FD-GP

• Non-cirrhotic or with compensated

cirrhosis and stage 3b, 4, or 5 CKD
• 101 study participants
• 76% (n=77) were on dialysis and
• 24% (n=24) had predialysis CKD.
• Genotypes
• GT-1: 55%
• GT-2: 27%
• GT-3: 15%
• GT-4: 4%
• GT-5& 6: None
• 84 patients were treated for 8 weeks
• 13 patients for 12 weeks, and
• 4 patients for 16 weeks.
• The overall SVR12 was 97% (98/101)
with no reported virologic failures
Current management of HCV in Renal D.

M Jadoul et al., Kidney International (2018) 94, 663Ð673

 Chronic Kidney Disease and HCV
Summary
Excellent options for patients with mild to moderate chronic kidney
disease
Limited options for patients with severe kidney disease and ESRD on
dialysis
Ribavirin-containing regimes have increased risk of hemolytic anemia
Sofosbuvir-containing regimens not recommended if GFR less than 30
ml/min
Grazoprevir/elbasvir great option for genotypes 1, 4, 6
Peginterferon/ribavirin first line for severe kidney disease in
genotypes 2, 3, 5, 6
Pregnancy and HCV
 Pregnancy and HCV
• For women of reproductive age with HCV infection antiviral therapy should be
given before considering pregnancy.

• Women's should wait for 4 weeks after treatment before becoming pregnant and
6 months for ribavirin

• Breastfeeding is not contraindicated in women with HCV, except in the case of

bleeding or cracked nipples.

• Viral RNA should be checked postpartum since there is chance spontaneous viral
clearance
 Pregnancy and HCV
Meta-analysis of risk of vertical transmission from
mother to baby
Viral load
 The higher the viral load the greater is the risk of MTCT
Factor associated with transmission
• HIV status
Mothers Risk of vertical transmission

HCV antibody + HCV RNA + HIV - 5.8% (4.2-7.8%)

HCV antibody + HCV RNA + HIV + 10.8% (7.6-15.2%)

Not associated with transmission

 Genotype
 Mode of delivery
Benova L. Clin Infect Dis 2014
 Breastfeeding
 DAA- Safety in Pregnancy

*Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

There is currently no HCV treatment approved for use during pregnancy. ACOG, 2021

AASLD. Hepatology. 2020;[Epub]. Slide credit: clinicaloptions.com

 Safety in Pregnancy………..

Direct Acting Antiviral Teratogenic/ Pregnancy Class FDA Guidance

embryocidal
Ribavirin YES (animals) X – pregnancy Dual contraception during
testing prior to and for 6 months after
and during use use in female or male

Simeprevir Yes (animals) C No adequate studies

Paritaprevir/r/ No (animals) B only if no RBV No adequate studies
ombitasvir + dasabuvir

Daclatasvir Yes (animals) C No adequate studies

“At this time benefit of treatment is unlikely to outweigh any possible unforeseen risk”
 ….cont’d

HCV Guidance: AASLD and IDSA,2021

 Pregnancy

Risk of
Low risk of
birth
HCV Do not
defects
transmissio treat
with
n to baby
treatment

• Pregnancy offers an opportunity to identify patients

and prepare for treatment after delivery
Last update: 
August 27, 2020