This is management of hep c infection in ckd patients….

1. MANAGEMENT OF HEPATITIS C
INFECTION IN CKD PATIENTS
PRESENTER:
DR IRFAN UL HAQ
PG RESIDENT INTERNAL
MEDICINE

2. INTRODUCTION
• Hepatitis C virus (HCV) infection is associated with high rates of liver-related
morbidities and mortality.
• More than 180 million people, 2.8% of the global population, are infected with HCV.
• The hepatic complications of HCV infection including liver cirrhosis, hepatic
decompensation,and hepatocellular carcinoma are well documented.
• 40% to 70% of cases of HCV infection are accompanied by extrahepatic
manifestations such as autoimmune, metabolic, renal, cardiovascular, central
nervous system, and lymphoproliferative disorders

3. • Kidney disease in particular is a common extrahepatic manifestation of HCV
infection. Chronic HCV infection is related not only to chronic kidney disease
(CKD) but also accelerates renal deterioration, leading to end-stage renal
disease (ESRD).

4. ABOUT THE BUG
• Linear, single-strand, positive-sense, 9600-nucleotide RNA virus.
• The HCV genome contains a single, large open reading frame (ORF) (gene) that codes
for a virus polyprotein of ~3000 amino acids, which is cleaved after translation to yield 10
viral proteins.
• The 5′ end of the genome consists of an untranslated region (containing an internal
ribosomal entry site [IRES]) adjacent to the genes for three structural proteins, the
nucleocapsid core protein, C, and two envelope glycoproteins,E1 and E2.
• The 3′ end of the genome also includes an untranslated region and contains the genes
for seven nonstructural (NS) proteins: p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B.

5. • p7 is a membrane ion channel protein necessary for efficient assembly and
release of HCV.
• Important NS proteins involved in virus replication include the NS3 helicase;
NS3-4A serine protease; the multifunctional membrane-associated
phosphoprotein NS5A, an essential component of the viral replication
membranous web (along with NS4B); and the NS5B RNA-dependent RNA
polymerase.

6. • At least six distinct major genotypes (and a minor genotype 7), as well as >50
subtypes within genotypes, of HCV have been identified by nucleotide
sequencing.

7. LIFE CYCLE

8. ABOUT THE SAVIOUR
• PegINF/RBV was the Standard of Care (SOC) for HCV treatment.
• However Sustained virologic response (SVR) was only seen in 50-60 percent.
• About 50% of patients infected with HCV genotype 1 and 20% of patients
infected with HCV genotype 2 or 3 still fail to achieve SVR with SOC.
• The current concept of HCV treatment is to achieve SVR [SVR 12] as it is
associated with permanent eradication of the virus and diminished long term
risks of HCV.

9. SAVIOURS: DIRECT ACTING ANTIVIRALS
• A greater understanding of the hepatitis C virus (HCV) genome and proteins has enabled
efforts to improve efficacy and tolerability of HCV treatment.
• Directly Acting Antivirals (DAAs) are molecules that target specific nonstructural proteins
of the virus and results in disruption of viral replication and infection.
• There are four classes of DAAs, which are defined by their mechanism of action and
therapeutic target.
• The four classes are nonstructural proteins 3/4A (NS3/4A) protease inhibitors (PIs),
NS5B nucleoside polymerase inhibitors (NPIs), NS5B non-nucleoside polymerase
inhibitors (NNPIs), and NS5A inhibitors.

11. • NS3/4A PROTEASE INHIBITORS:
NS3/4A protease inhibitors are inhibitors of the NS3/4A serine protease, an
enzyme involved in post-translational processing and replication of HCV.
Protease inhibitors disrupt HCV by blocking the NS3 catalytic site or the
NS3/NS4A interaction. Glecaprevir , Glecaprevir are pangenotypic antivirals.
• NS5A INHIBITORS:
The NS5A protein plays a role in both viral replication and the assembly of the
hepatitis C virus. Daclatasvir ,Elbasvir ,Ledipasvir , Ombitasvir , Pibrentasvir
Velpatasvir are the drugs in this category wherein Pibrentasvir and Velpatasvir
are the pangenotypic antivirals among this class.

12. • NS5B RNA-DEPENDENT RNA POLYMERASE INHIBITORS:
NS5B is an RNA-dependent RNA polymerase involved in post-translational
processing that is necessary for replication of HCV. The enzyme’s structure is
highly conserved across all HCV genotypes, giving agents that inhibit NS5B
efficacy against all six genotypes.
There are two classes of polymerase inhibitors: nucleoside/ nucleotide
analogues (NPIs) and non-nucleoside analogues (NNPIs).
Sofosbuvir is NPI and Dasabuvir is among NNPI.

14. TREATMENT
• WHAT IS THE RATIONALE:
o The primary rationale for antiviral treatment in patients with chronic HCV infection is to
prevent liver-related morbidity and mortality.
o The patient with advanced chronic kidney disease (CKD) who is a potential kidney candidate,
an additional reason is to prevent kidney transplant-related complications specific to HCV
infection.
o Less common scenario of HCV-associated vasculitis and/or glomerulonephritis (such as
mixed cryoglobulinemia), an additional objective is to eradicate the immunologic stimulus (ie,
HCV itself) for the vasculitis and/or glomerulonephritis.

15. o For patients with HCV-associated renal disease, cure of HCV confers additional
benefits. As examples, in several studies of patients with membranoproliferative
glomerulonephritis and/or mixed cryoglobulinemia, improvements in the cutaneous
vasculitis, cryoglobulin titers, proteinuria, and the plasma creatinine concentration
were observed in the majority patients who achieved HCV viral suppression during
interferon-based treatment.

16. GOALS OF THERAPY
• The goal of antiviral therapy in patients with chronic hepatitis C virus (HCV) is to
eradicate HCV RNA, which is predicted by attainment of a sustained virologic
response (SVR), defined as an undetectable RNA level 12 weeks following the
completion of therapy.
• An SVR is associated with a 97 to 100 percent chance of being HCV RNA
negative during long-term follow-up and can therefore be considered cure of the
HCV infection.

17. PATIENT SELECTION:
• American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases
Society of America (IDSA) recommends treatment for all patients with chronic HCV
infection who have access to DAA therapies, including those who have renal impairment
and/or are on dialysis; the main exceptions to universal treatment are patients with short
life expectancies due to comorbidities.
• For patients with HCV-related renal disease, successful antiviral treatment is likely to
result in improved renal function and symptoms related to renal failure. Thus, antiviral
treatment is warranted in such patients, even if life expectancy may otherwise be limited
due to other comorbities.

18. • For patients who have severe renal impairment or are on dialysis and have incidental
HCV infection (ie, the renal disease is not associated with HCV), the decision on
antiviral treatment should be undertaken on a case-by-case basis and take into
account the potential for kidney transplant candidacy in addition to the anticipated
benefits of HCV therapy, comorbidities, and life expectancy.

19. Regimen selection and dosing
• The selection of the antiviral regimen among patients with renal disease is largely the
same as that among patients without renal disease and depends on genotype, extent of
underlying liver disease, and treatment history.
• In general, glecaprevir-pibrentasvir and sofosbuvir-velpatasvir are the preferred
pangenotypic options. Ledipasvir-sofosbuvir is another preferred option for genotype 1, 4,
5, and 6 infections.
• Dose adjustments of the DAAs that can be used in advanced renal disease and
hemodialysis are not necessary. However, sofosbuvir-containing regimens are cleared by
dialysis and should be administered after the session on hemodialysis days.

21. ANTIVIRAL EFFICACY AND SAFETY
• Glecaprevir-pibrentasvir and sofosbuvir-containing regimens are the primary
treatment options for most patients with HCV infection.
• Glecaprevir-pibrentasvir – Both glecaprevir and pibrentasvir undergo hepatic
metabolism and clearance, and levels are largely unaffected by renal
impairment. In a study (EXPEDITION-4) of 104 patients with genotypes 1
through 6 infection and estimated glomerular filtration rate (eGFR) <30 mL/min
per 1.73 m , 82 percent of whom were on dialysis, 98 percent achieved
sustained virologic response (SVR) with glecaprevir-pibrentasvir for 12 weeks.

22. • The regimen was generally well tolerated. None of the severe adverse events were
considered drug related, but four percent of patients discontinued the regimen
because of adverse events.

23. • Sofosbuvir-containing combinations – The major elimination pathway for
sofosbuvir is renal, so exposure to the drug is increased in patients with severe
renal impairment [41]. Because of this and some data suggesting worsening
renal function with sofosbuvir, sofosbuvir-containing regimens were previously
only recommended for patients with eGFR >30 mL/min per 1.73 m.
• However, based on subsequent evidence indicating safety, the US Food and
Drug Administration approved sofosbuvir-containing regimens for use in severe
renal impairment and dialysis in 2019.

24. • It does not appear that the dose of sofosbuvir needs to be adjusted for renal
function.
• Other antiviral agents that are used in combination with sofosbuvir(eg, velpatasvir,
ledipasvir, and voxilaprevir) are all hepatically cleared, and their levels are largely
unaffected by renal impairment.

25. • In a study of 59 patients with end-stage kidney diseases on dialysis and
genotypes 1 to 6 HCV infection, sofosbuvir-velpatasvir (400 mg to 100 mg) for
12 weeks resulted in an SVR rate of 95 percent.
• Other regimens that are less frequently used but have documented efficacy and
safety in the setting of renal impairment include:
o Elbasvir-grazoprevir: 94 percent achieved SVR with elbasvir-grazoprevir
for 12 weeks in HCV genotype 1 infected patients with eGFR <30 mL/min per
1.73 m.
o Ombitasvir-paritaprevir-ritonavir plus dasabuvir – This regimen also
appears effective and safe in severe renal impairment. SVR12 of 90 percent
has been achieved genotype 1-infected patients with eGFR <30 mL/min per
1.73 m , including those on dialysis and without cirrhosis.

26. • Daclatasvir – Daclatasvir is primarily metabolized by the liver, and renal
elimination is minor. Daclatasvir is usually given with sofosbuvir in locations with
limited access to more commonly used regimens.
• Ribavirin — Ribavirin is not commonly used in HCV antiviral therapy, although
there are certain indications for adding it to a DAA regimen. The main adverse
effect of ribavirin is hemolytic anemia, and the risk is predicted by ribavirin
plasma concentration.

27. MONITORING DURING ANTIVIRAL THERAPY
• Interferon-free regimens:
o Clinical assessment during treatment with an interferon-free, direct-acting
antiviral (DAA) regimen focuses on adherence to the regimen and
identification of adverse effects. DAAs are generally well tolerated.
• Viral monitoring:
o Monitoring viral levels during treatment with interferon-free regimens has
minimal prognostic value, as almost all patients without cirrhosis in the large
clinical trials of interferon-free regimens achieve an undetectable hepatitis C
virus (HCV) viral level by four weeks of treatment.

28. o Failure to achieve that threshold does not accurately predict failure to
achieve a sustained virologic response (SVR).
o HCV RNA quantitative testing is done at week 4.
o The joint guidelines from the American Association for the Study of Liver
Diseases (AASLD) and the Infectious Diseases Society of America (IDSA)
additionally recommend rechecking HCV RNA quantitative testing at week 6
if the week 4 level is detectable and discontinuing therapy if the level has
increased by >1 log.
o Virologic response to treatment should be assessed by checking the viral
load at 12 weeks following the cessation of therapy.

29. Other monitoring:
o AASLD/IDSA recommends to check basic laboratory tests (complete blood
count, creatinine with estimated glomerular filtration rate (eGFR) calculation,
and liver enzyme and bilirubin levels) at week 4 of treatment with any
regimen, with more frequent monitoring for concerning results or trends.
o Additional indications for laboratory testing are regimen specific:

30. • Elbasvir-grazoprevir – Additionally, checking liver enzyme and bilirubin levels
at week 8 (and week 12, if treatment duration is 16 weeks) is recommended.
• Paritaprevir-ritonavir-ombitasvir-based regimens – For those patients who
have compensated cirrhosis, close monitoring for hepatic decompensation is
warranted during therapy with these regimens.
• Ribavirin-containing regimens – We check the complete blood count at weeks
4, 8, and 12 to evaluate for anemia. For those who develop anemia, the dose of
ribavirin can be adjusted based on the severity and comorbidities.

31. FOLLOW-UP AFTER ANTIVIRAL THERAPY
• Virologic response to treatment should be assessed by checking the viral load at
12 weeks following the cessation of therapy.
• Sustained virologic response (SVR) is defined by an undetectable viral level at
this time point, which is generally maintained through 24 weeks following the
cessation of therapy and beyond.
• A very small proportion of patients (less than 1 percent in studies of direct-acting
antivirals) experience virologic relapse between weeks 12 and 24, and some of
those cases may be reinfection rather than true relapse.

32. • Although SVR reflects effective cure of hepatitis C virus (HCV) infection, it does
not confer immunity to HCV, and patients should be counseled that they are at
risk for reinfection with future exposure.
• Patients who fail to achieve an SVR should continue to be followed for signs of
progression of liver disease and assessed for retreatment of HCV infection.
• Patients with advanced fibrosis or cirrhosis, regardless of whether they attain an
SVR, require ongoing monitoring (including liver ultrasonography every six
months) because they continue to be at risk of hepatocellular carcinoma and
other complications.

33. THANK YOU