Brief review of Treatment of hcv infection in patients with renal impairment

1. TreatmentofHepatitisC
in
ChronicKidneyDiseasepatients
PRATAP SAGAR TIWARI
World Hepatitis Day 2021
“Find The Missing Millions.”

2. 1. Squires JE and balistreri WF. Treatment of Hepatitis C: A New Paradigm toward Viral Eradication. Medical progress 2020;221:P12-22.E1
Treatment of Hepatitis C: A New Paradigm toward Viral Eradication

3. TEXT :PREVIOUS SLIDE
 WHO have endorsed the hcv elimination by 2030.
 Since the discovery of HCV in 1989 which was early mentioned as NANB virus, we have come a long way.
 And we know recently in 2020 the researchers ,Harvey, Michael and Charles were awarded with nobel
prize for discovery of HCV.
 Regarding the endorsment of HCV elimation, there are several hurdles, one of them being the so called
“unique population” or special populations are referred to as difficult-to-treat due to unreached SVR,
potential drug side effects or interactions or co-morbidities. And one of the so called unique population
is the group of “HCV patients with renal impairment or kidney disease”.

4. The current scenario
Association of HCV infection and CKD
Initiation of DAAs
Rise of the Sofosbuvir
Management in Pre-DAAs era
Contents

5. 5
1. Cacoub P, et al. Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. The GERMIVIC. Groupe d’Etude et de Recherche
en Medecine Interne et Maladies Infectieuses sur le Virus de l’Hepatite C. Medicine (Baltimore) 2000; 79: 47-56
Background: Association of HCV infection and CKD

6. TEXT :PREVIOUS SLIDE
 Until now, The association between ckd and hcv infection has been well established.
 We know HCV primarily affects the liver causing hepatitis; chronic hepatitis may progress to liver fibrosis
and subsequently cirrhosis and hepatocellular carcinoma.
 However, there are also extra-hepatic manifestations which can present in a milder form as myalgia,
arthralgia or can lead to specific disorder like mixed cryoglobulinemia, and its subsequent features like
vasculitis, glomerulonephritis or even without cryoglobulinema there can be GN, nephrotic features, and
so on. Other extra hepatic manifestation can include insulin resistance, diabetes mellitus, etc.
 Interestingly, HCV infection can cause renal impairment even in the absence of these entities, probably
as a result of systemic inflammation and vascular damage or we can say direct viral effects.
 So, I am here trying to justify is that whether by immune complex formation n deposition, or indirectly
related to insulin resistance, dyslipidemia , diabetes or through a potentially direct viral effects, overall it
seems there is an increase risk of renal disease in a pt with HCV infection..
 There have been several studies done to see this association.

7. Prevalence
Dialysis
Progression
Survival
Renal transplant
The impact

8. Prevalence
Dialysis
Progression
Survival
Renal transplant
 The prevalence of a low GFR (GFR <60 ml/min/1.73 m2 of BSA)
among HCV-positive pts is reported to range from 5.1 to 17.2%,1
 Similarly in CKD pts, HCV infection ↑ the risk of developing ESRD
with an estimated 5-year cumulative incidence rate of 52.6%
compared to 38.4% in those without HCV infection.2
1. Fabrizi F, Verdesca S, Messa P, Martin P. Hepatitis C virus infection increases the risk of developing chronic kidney disease: a systematic review and meta-analysis. Dig Dis Sci 2015;60:3801-3813.
2. Lee JJ, Lin MY, Chang JS, Hung CC, Chang JM, Chen HC, Yu ML, Hwang SJ. Hepatitis C virus infection increases risk of developing end-stage renal disease using competing risk analysis. PLoS One
2014; 9: e100790
The impact

9. Prevalence
Dialysis
Progression
Survival
Renal transplant
 The prevalence of HCV positive among HD pts can vary from <
5% to as high as 60% from different regions in the world.1,2
 In 2004, the Dialysis Outcomes and Practice Patterns Study
(DOPPS) reported that 13.5% of HD pts are infected with HCV.
 Among 10 countries studied within the Asia-Pacific region, the
HCV seroprevalence among HD pts: between 0.7% and 18.1%.3
1. Wreghitt TG. Blood-borne virus infections in dialysis units--a review. Rev Med Virol 1999; 9: 101-109
2. Chan TM, Lok AS, Cheng IK, Chan RT. Prevalence of hepatitis C virus infection in hemodialysis patients: a longitudinal study comparing the results of RNA and antibody assays.
Hepatology 1993; 17: 5-8
3. Johnson DW, Dent H, Yao Q, Tranaeus A, Huang CC, Han DS, Jha V, Wang T, Kawaguchi Y, Qian J. Frequencies of hepatitis B and C infections among haemodialysis and peritoneal
dialysis patients in Asia-Pacific countries: analysis of registry data. Nephrol Dial Transplant 2009; 24: 1598-1603
The impact

10. Text of previous slide
Now, in context of dialyisis patient ; There are mainly two groups of HCV infected patients in the
hemodialysis unit, either the patients already have HCV infection before entering into treatment with
hemodialysis or the HCV infection was acquired during the maintenance hemodialysis. Despite much
improvement in the care of this group of patients, the prevalence of hepatitis C infection in hemodialysis
patients is still higher than the general population.

11. Prevalence
Dialysis
Progression
Survival
Renal transplant
 The presence of anti-HCV antibody is a/with renal disease
progression with a higher rate of positive anti- HCV in those
with more severe stages of CKD.1
A meta-analysis (14 studies; 145 608 pts) on pts receiving mHD,
found that HCV-positive pts have higher mortality compared to
HCV-negative pts. This study showed that liver-related death was
higher than cardiovascular-related death among these groups
[adjusted RR 3.82 (95%CI: 1.92; 7.61) vs 1.26 (95%CI: 1.10; 1.45)
respectively].2
1. Lee JJ, Lin MY, Yang YH, Lu SN, Chen HC, Hwang SJ. Association of hepatitis C and B virus infection with CKD in an endemic area in Taiwan: a cross-sectional study. Am J Kidney Dis
2010; 56: 23-31
2. Fabrizi F, Dixit V, Messa P. Impact of hepatitis C on survival in dialysis patients: a link with cardiovascular mortality? J Viral Hepat 2012; 19: 601-607
The impact

12. Prevalence
Dialysis
Progression
Survival
Renal transplant
 A meta-analysis on 13 studies by Fabrizi et al found that most
studies showed an increase in all-cause mortality and all-cause
renal graft loss among renal transplant recipients with HCV.1
This is likely due to post-transplant immunosuppression and
undiagnosed HCV infection prior to transplant. Hepatitis C infection
in the setting of post renal transplant had been reported to cause
specific diseases in the liver and the transplanted kidney.
1. Fabrizi F, Martin P, Dixit V, Messa P. Meta-analysis of observational studies: hepatitis C and survival after renal transplant. J Viral Hepat 2014; 21: 314-324
The impact

13. Prevalence
Dialysis
Progression
Survival
Renal transplant
 A meta-analysis on 13 studies by Fabrizi et al found that most
studies showed an increase in all-cause mortality and all-cause
renal graft loss among renal transplant recipients with HCV.1
This is likely due to post-transplant immunosuppression and
undiagnosed HCV infection prior to transplant. Hepatitis C infection
in the setting of post renal transplant had been reported to cause
specific diseases in the liver and the transplanted kidney.
1. Fabrizi F, Martin P, Dixit V, Messa P. Meta-analysis of observational studies: hepatitis C and survival after renal transplant. J Viral Hepat 2014; 21: 314-324
The impact
HCV infection in pts with CKD, ESRD or requiring HD is a/with faster renal disease
progression and greater liver-related morbidity/mortality than in pts with normal renal
function . Thus, it is evident that treatment of HCV infection in this “unique population” is
eminent.

14. Treatment: Pre-DAA era
Interferon and RBV are a/with significant toxicity including anemia, infections, depression, anxiety, and other
psychiatric side effects.. 5
Rendina et al.1
2007
ESRD on MHD peg-IFN 𝛼-2a plus Riba Vs Control
35 Vs 35
SVR24: 97% vs. 0%; p < 0.001
DOR: 14%
Liu et al. 2
2013
ESRD on MHD
Gen1-HCV
peg-IFN 𝛼-2a plus Riba Vs peg-IFN 𝛼-2a
103 Vs 102
SVR48: 64% vs. 33%;
P < 0.001
Liu et al.3
2013
ESRD on MHD
Gen2-HCV
peg-IFN 𝛼-2a plus Riba Vs peg-IFN 𝛼-2a
86 Vs 86
SVR24: 74% vs. 44%;
P < 0.001
Fabrizi et al 4
2014
MA of 11 studies
N=287
IFN-based combination therapy SVR24: 60%
DOR: 18 %
References are at the end of the slides

15. Treatment: Pre-DAA era
Rendina et al.1
2007
ESRD on MHD peg-IFN 𝛼-2a plus Riba Vs Control
35 Vs 35
SVR24: 97% vs. 0%; p < 0.001
DOR: 14%
Liu et al. 2
2013
ESRD on MHD
Gen1-HCV
peg-IFN 𝛼-2a plus Riba Vs peg-IFN 𝛼-2a
103 Vs 102
SVR48: 64% vs. 33%;
P < 0.001
Liu et al.3
2013
ESRD on MHD
Gen2-HCV
peg-IFN 𝛼-2a plus Riba Vs peg-IFN 𝛼-2a
86 Vs 86
SVR24: 74% vs. 44%;
P < 0.001
Fabrizi et al 4
2014
MA of 11 studies
N=287
IFN-based combination therapy SVR24: 60%
DOR: 18 %
Summary: Antiviral therapy with peg-IFN with or without RBV was not quite effective and
was a/with several side effects, which raised concerns about its safety.
As a result, the main limitation of interferon-based regimens is their high withdrawal rates.

16. Awakening of the DAAs
1. Mehawej M, Rostaing L, Alric L, Del Bello A, Izopet J, Kamar N. Boceprevir-based triple antiviral therapy for chronic hepatitis c virus infection in kidney-transplant candidates. J
Transplant. 2015;2015:159795.
2. Kaya S, Aksoz S, Baysal B, Ay N, Danis R. Evaluation of telaprevir-containing triple therapy in the treatment of chronic hepatitis C in hemodialysed patients. Infect Dis (Lond)
2015;47:658–661.
3. Dumortier J, Guillaud O, Gagnieu MC, et al. Anti-viral triple therapy with telaprevir in haemodialysed HCV patients: is it feasible? J Clin Virol. 2013;56:146–149.
In summary, sustained viral response rates are suboptimal with either regimen
with reasons unclear.

17. Text of previous slide
 A treatment breakthrough came in 2011 with the approval of two oral DAAs, the protease inhibitors
telaprevir and boceprevir (HCV-NS3/NS4A protease inhibitors).
 These DRUGS were introduced as an adjunctive therapy for patients with chronic HCV but normal kidney
function and have significantly improved the SVR in comparision to ifn mono or combination therapy.
However, scarce data regarding their use in hemodialysis patients have been published.

18. Sofosbuvir: HCV-TARGET study
A paradigm shift occurred in late 2013 with the approval of simeprevir and sofosbuvir .
Saxena et al.1 evaluated the safety and efficacy of SOF containing regimens (PEG-IFN,
Simeprevir, and Ribavirin) in HCV-infected pts with impaired renal dysfunction.
This real-world outcome study [n=1789: genotypes 1(72%), 2(17%) 3(9%), 4–6(2%)]
showed SVR12 rates of 81% to 88% depending on the GFR; however, pts with a GFR of ≤
45 mL/min/1.73 m2 more frequently experienced worsening renal function and ribavirin-
related hemolytic anemia.
1. Saxena V, Koraishy FM, Sise ME, et al. Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function. Liver Int. 2016;36:807–
816.
Based on the renal excretion of sofosbuvir and its metabolites, the use of this DAA agent
is not recommended in pts with a GFR of ≤ 30 mL/min/1.73 m2.

19. Drugs Approval date Studies
LEDIPASVIR/SOFOSBUVIR 2014 ION
SIRIUS
SYNERGY
SOLAR
PARITAPREVIR/RITONAVIR/
OMBITASVIR PLUS
DASABUVIR
Dec 2014 SAPPHIRE
TURQUOISE
PEARL
AGATE
SIMEPREVIR/SOFOSBUVIR Nov 2014 OPTIMIST
DACLATASVIR/SOFOSBUVIR Jul 2015 ALLY
ELBASVIR/GRAZOPREVIR Early 2016 C-EDGE
C-WORTHY
VELPATASVIR/SOFOSBUVIR June 28 2016 ASTRAL

20. Ribavirin
NS5B
NUC inhibitor
NS5B
NON NUC inhibitor
NS5A
Replication complex inhibitor
Boceprevir (BOC)
Telaprevir (TVR)
Simeprevir (SMV)
Paritaprevir (PTV)
Grazoprevir (GRZ)
Voxilaprevir (VOX)
Glecaprevir (GLE)
Dasabuvir (DSB)
Daclatasvir (DSV)
Ledipasvir (LDV)
Ombitasvir (OMV)
Elbasvir
Velpatasvir (VEL)
Pibrentasvir (PIB)
Ruzasvir *
NS3
protease inhibitor
Sofosbuvir (SOF)
Uprifosbuvir *
DAAs in HCV Treatment
Polymerase

21. EXPEDITION-5 trial: Glecaprevir/Pibrentasvir
To evaluate efficacy and safety of Gleca/Pibrenta (300/120 mg) for HCV in adults without
cirrhosis or with compensated cirrhosis and with stage 3b, 4 or 5 CKD. (treatment labelled
for 8, 12, or 16 weeks). The primary efficacy endpoint :SVR12
Among the 101 pts enrolled in the study, 76% were on dialysis. Gen-1; 55%, Gen-2; 27%,
Gen-3: 15%,Gen-4; 4%, Gen-5/6; 0
The SVR12: 97% (98/101).
AEs :5% of the pts were pruritus, bronchitis, HTN. Serious AEs were reported in 12% of
pts; none related to study drug. eGFR remained unchanged through post-treatment week
4 in the pre-dialysis population.
1. Lawitz E, et al. Efficacy and safety of glecaprevir/pibrentasvir in renally impaired patients with chronic HCV infection. Liver Int. 2020;40(5):1032-41.
Conclusions: G/P treatment yielded high SVR12 rates irrespective of the presence of stage of
CKD. No safety signals were detected.

22. The MAGELLAN-2 study
Reau et al.1 was a phase 3, single-arm, open-label, multicenter trial of the efficacy and
safety of Glecaprevir/Pibrentasvir for HCV gen 1-6 who had undergone primary LT or
kidney transplantation (N=20).
The SVR rate was 98% and A/Es were tolerable.
1. Reau N, Kwo PY, Rhee S, et al. Glecaprevir/pibrentasvir treatment in liver or kidney transplant patients with hepatitis C virus infection. Hepatology. 2018 Apr
19; [Epub]

23. C-SURFER trial: Elbasvir/Grazoprevir
The C-SURFER trial1 evaluated the safety and efficacy of 12 weeks of the daily fixed-dose
combination of elbasvir (50 mg)/grazoprevir (100 mg) versus placebo among Gen1-infected
pts ( n=224;111 vs 113) with CKD stage 4 or 5 (eGFR <30 mL/min).
The initial study randomized eligible pts to immediate or deferred RX with
elbasvir/grazoprevir. The delayed RX arm initially received placebo and was later treated
with elbasvir/grazoprevir. 75 % of the study participants were on HD. A small number of pts
with compensated cirrhosis were included.
SVR12 rate was 99%. There were no changes in Hb or other A/Es in the RX groups
compared to placebo.
23
1. Roth D,et al. Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-
SURFER study): a combination phase 3 study. Lancet. 2015 Oct 17;386(10003):1537-45.
Based on these data, daily fixed-dose elbasvir/grazoprevir was recommended for the RX of
HCV-1 infection in pts with severely compromised renal function.

24. 1. Pockros PJ, Reddy KR, Mantry PS, et al. Efficacy of direct-acting antiviral combination for patients with hepatitis C virus genotype 1 infection and severe renal impairment or end-stage renal
disease. Gastroenterology. 2016;150:1590–1598.
The RUBY study
 Pockros et al.1 studied the combination of Ombitasvir, Paritaprevir, Ritonavir, and
Dasabuvir in 20 HCV-1 pts with stage 4 to 5 CKD or ESRD; the SVR12 rate was 90%
and all A/Es were tolerable.

25. Recommended Regimens
25

26. Recommended Regimens

27. Sofosbuvir: variable dosing regime
Multicenter, prospective study of pts receiving SOF, 400mg OD (n=7) or 3 times a week (n=5), after
HD with simeprevir, daclatasvir, ledipasvir or ribavirin was conducted..
Plasma concentrations of SOF or its inactive metabolite SOF-007 did not accumulate with either
regimen between HD sessions or throughout the treatment course.
HD did not remove any other associated anti-HCV agents. Clinical and biological tolerance was good
for all pts.
All of the 7 pts (100%) receiving SOF QD, and 3 pts (60%) receiving SOF TIW:SVR12. Two relapses
occurred in patients receiving SOF TIW.
1. Desnoyer A, et al. Pharmacokinetics, safety and efficacy of a full dose sofosbuvir-based regimen given daily in hemodialysis patients with chronic hepatitis C. 2016 Journal of Hepatology
65(1):40-47
Conclusions: A regimen including SOF, 400mg OD, could be proposed for HCV-infected pts
on HD .

28. Sofosbuvir/velpatasvir as simple, effective HCV
treatment. Mangia A,et al1
In the largest real-world analysis to date, the effectiveness of SOF/VEL (400/100 mg) OD
for 12 weeks was assessed in 12 clinical real-world cohorts from various geographical
areas, settings and treatment practices.
• Of the 5196 pts evaluated for effectiveness, 98.9% achieved SVR12.
• High SVR12/24 rates occurred in all genotypes including those with
compensated cirrhosis (97.9; 1055/1078).
• Only 55 pts did not achieve SVR12/24 due to a virological reason; the only
factor statistically significantly a/with an increased risk of not achieving
SVR12/24 was compensated cirrhosis (P = .002).
Conclusion: a simple 12-week regimen of SOF/VEL without ribavirin resulted in high
SVR12/24 rates in diverse pt populations, even among those with compensated cirrhosis.
1. Mangia A, Milligan S, Khalili M, Fagiuoli S, Shafran S, Carrat F, et al. Global real-world evidence of sofosbuvir/velpatasvir as a simple, effective regimen for the treatment of chronic
hepatitis C patients: integrated analysis of 12 clinical practice cohorts. J Hepatol 2019;70(Suppl.):e2–e3.

29. In HCV-infected pts with ESRD undergoing
dialysis
In this single-arm study1, 59 pts with HCV Gen;1-6 with ESRD undergoing HD/PD received
open-label SOF/VEL (400 mg/100 mg) OD X 12 weeks.
Pts were HCV Rx-naive or Rx-experienced without cirrhosis or with compensated cirrhosis.
Pts previously treated with any HCV NS5A inhibitor were not eligible.
I. The primary efficacy endpoint: proportion of pts achieving SVR 12
II. The primary safety endpoint: proportion of pts who discontinued study due to A/Es.
1. Borgia SM, Dearden J, Yoshida EM, Shafran SD, Brown A, Ben-Ari Z, et al. Sofosbuvir/velpatasvir for 12 weeks in hepatitis C virus-infected patients with end-stage renal disease undergoing
dialysis. J Hepatol 2019;71:660–665.
The most common A/Es were headache (17%), fatigue (14%), nausea (14%), and vomiting (14%). Serious adverse events
were reported for 11 pts (19%), and all were deemed to be unrelated to sofo/velpa.
Results: Overall, 56/59 pts achieved SVR12:95% (95% CI 86-99%).

30. An updated systematic review and meta-analysis on
efficacy of Sofosbuvir in treating HCV pts with
advanced CKD
Jabbari et al conducted an updated literature search from 2013 to June 2020.
Metaanalysis of 27 published articles (n= 1,464 HCV-infected pts treated with SOF based
regime in advanced CKD).
The pooled SVR12 & 24: 97% and 95% respectively.
The pooled incidence of severe A/Es: 0.11.
The pooled SVR12 rate was 98% in cirrhotic pts and 100% (98–100) in non-cirrhotic pts.
1. Majd Jabbari S. An updated systematic review and meta-analysis on efficacy of Sofosbuvir in treating hepatitis C-infected patients with advanced chronic kidney disease. 2021 PLoS ONE
16(2): e0246594.
The endorsement of Sofosbuvir-based regimen can improve the treatment of hepatitis C
virus infection in pts with advanced CKD.

31. 1. Majd Jabbari S. An updated systematic review and meta-analysis on efficacy of Sofosbuvir in treating hepatitis C-infected patients with advanced chronic kidney disease. 2021 PLoS ONE
16(2): e0246594.
Results of subgroup analysis for estimating the pooled SVR12 rate in HCV-infected patients with
advanced CKD.

32. Summary of treatment of HCV in CKD/ESRD/HD

33. Summary
No Cirrhosis or
Compensated Cirrhosis (Child-Pugh A)
All CKD stages including ESRD on HD
B1
Gleca (300 mg)/ Pibrenta (120 mg)
12 weeks, if Comp. cirrhosis
Grazo (100 mg)/ Elbas (50 mg)
HCV 1b only
8 weeks, if no Cirrhosis
 For Treatment experience; Gleca/Pibrenta x 16 weeks regime can be an alternative, except for Gen-3, if SOF was used

34. End of Slides
Thankyou
HCV in CKD patients – Beginning of the
end?
CKD patients: still the “unique population”
group ?
“Find The Missing Millions.”

35. Ref: Treatment: Pre-DAA era
1. Rendina M, Schena A, Castellaneta NM, et al. The treatment of chronic hepatitis C with peginterferon alfa-2a (40 kDa) plus ribavirin in haemodialysed patients awaiting renal
transplant. J Hepatol. 2007;46:768–774.
2. Liu CH, Huang CF, Liu CJ, et al. Pegylated interferon-α2a with or without low-dose ribavirin for treatment-naive patients with hepatitis C virus genotype 1 receiving hemodialysis: a
randomized trial. Ann Intern Med. 2013;159:729–738.
3. Liu CH, Liu CJ, Huang CF, et al. Peginterferon alfa-2a with or without low-dose ribavirin for treatment-naive patients with hepatitis C virus genotype 2 receiving haemodialysis: a
randomised trial. Gut. 2015;64:303–311.
4. Fabrizi F, Dixit V, Messa P, Martin P. Antiviral therapy (pegylated interferon and ribavirin) of hepatitis C in dialysis patients: meta-analysis of clinical studies. J Viral Hepat.
2014;21:681–689.
5. Raison CL,et al. Neuropsychiatric Adverse Effects of Interferon-α Recognition and Management. CNS Drugs. 2005; 19(2): 105–123.

36. Drug interaction with SOF/VEL
Avoid
Anriarrythmic agents : Amiodarone/dronedarone
Anticonvulsants : Carbamazepine/ phenytoin/ phenobarbitol
Rifamycin derivatives : Rifabutin/Rifampicin/Rifapentine
A dose change or additional monitoring is warranted
Acid reducing agents : Antacids/H2RA/PPI
Alpha blocker :Prazosin
Anriarrythmic agents :Digoxin/quinidine
Anticoagulant and antiplatelet agents: Apixaban/Dabigatran/Edoxaban/Rivaroxaban/Ticagrelor/Warfarin
Antihypertensives : Diltiazem
Cholesterol lowering agents: Atorvastatin/Rosuvastatin/Simvastatin

37. Direct Acting Antivirals

40. Resistance-associated substitutions (RASs)
RASs are amino acid substitutions in HCV protein sequences that result in decreased
antiviral efficacy of the HCV DAAs.
Among the HCV RASs, the NS5A RASs were found to effectively modify and decrease
treatment response to NS5A inhibitor-containing regimens.
As a baseline predictor of treatment response, NS5A RAS draws attention for pretreatment
testing in targeted pt groups.

41. Resistance-associated substitutions (RASs)
Given NS5A RASs are either naturally-occurring or DAA-selected, the application of NS5A
RAS testing can be considered in two settings of NS5A inhibitor-naïve pts and NS5A inhibitor-
experienced patients.
Less than 5% of NS5A inhibitor-naïve pts harbor naturally-occurring NS5A RAS with high
resistance level (> 100X resistance fold-change).
In NS5A inhibitor-naïve pts, NS5A RAS testing accompanied by treatment optimization
cannot increase treatment response more than 2%-3%, while in NS5A inhibitor-experienced
patients, > 75% are found to have NS5A RASs > 100X and NS5A RAS testing in this group of
pts seems to be reasonable.

42. Resistance-associated substitutions (RASs)
We are using NS5A inhibitors VEL and LDV.
HCV resistance can be their with these drugs. For eg, for SOF/VEL, in Gen 3, treatment
naive with cirrhosis or treatment experienced without cirrhosis, it is recommended for
NS5A RAS testing. if y93h is present, add weight based ribavirin.
Similarly while using Sof/LDV or Elbas/Grazo in HCV Gen 1, it is is recommended.