nephrology case conference 報告日期 : 2011/10/05 指導老師 : 方基存教授報告醫師 :...

Nephrology Case Conference

報告日期 : 2011/10/05指導老師 : 方基存教授報告醫師 : R3 陳惠湘

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Outlines

Case Presentation

HCV and CKD

HCV Treatment in CKD patient

Side effects of antiviral treatment

Review the case

Discussion

Case Presentation


Patient Profiles

Name: 徐 O 緯Gender: MaleBirthday: 1954/08/25 (57y/o)

Ethnic: TaiwaneseOccupation: sales, retiredMarital status: marriedTraveling history: nilAdmission during

2011/04/23~2011/04/29 at GI ward


Chief Complaint

Progressive depressive mood and behavior change since about one month ago


Present Illness -1

This 57 y/o male patient is a case with histories of ESRD under regular HD and HCV carrier who follow up at our GI OPD.

Since one month before admission, he was noted with agitation, depressive mood, insomnia and suicide ideation.

According to his wife, he has received Interferon + Ribavirin treatment for hepatitis C since about one and half month ago.


Present Illness -2

He denied constipation and high protein diet. No bloody or tarry stool noted, no fever checked.

No other medication taken except those from OPD.

General malaise but no focal limb weakness.


Past history

End stage renal disease under regular hemodialysis via left AVG for about 13 years

Hepatitis C carrier Known when screening for HD History of tooth retraction with bleeding,

blood transfusion(+)Secondary hyperparathyroidism

status post total parathyroidectomy with autotransplantation in 2008

NephrolithiasisHypertension known for 13 years


Personal history

Allergy: no known allergy historySmoking: deniedAlcohol: deniedBetel nut: denied


Family history

Family history:

Colon cancer

GN


Physical Examination -1

Vital signs: BT:36.3’C, BP:120/82mmHg, HR:75/min,

RR:16/minGeneral appearance: chronic ill lookingConsciousness: oriented, E4V5M6HEENT:

Conjunctiva: pale, Sclera: anicteric Neck: no stiffness, no lymphadenopathy

Chest: Smooth respiratory pattern Breathing sound: bilateral coarse Heart sound: regular heart beat, murmur(-)


Physical Examination -2

Abdomen: soft, no tenderness normoactive bowel sound Bruit(?)

Extremities Freely movable No pitting edema Left AVG bruit/thrill(?)

Skin: Intact, no rashes


Lab data when admitted (4/22-4/23)

WBC 2200 /uL

RBC 2.50 x106/uL

Hb 7.2 g/dL

HCT 22.6 %

MCV 90.4 fL

MCH 28.8 pg/cell

MCHC 31.9 gHb/dL

RDW 16.6 %

PLT 99 x103/uL

Seg 74.0 %

Lym 12.0 %

Mono 14.0 %

Eos 0.0 %

Baso 0.0 %

PT(INR) 1.1

Leukopenia with lymphopenia

ThrombocytopeniaNormocytic anemia


Lab data when admitted (4/22-4/23)

CRP 30.86 mg/L

BUN 57.7 mg/dL

Cr 5.08 mg/dL

Na 138 mEg/L

K 3.9 mEg/L

AST 47 U/L

ALT 26 U/L

Bil(T) 0.6 mg/dL

Bil(D)

Alk-p 77 U/L

R-GT

Ca 9.9 mg/dL

P 3.2 mg/dL

Alb 3.21 g/dL

Ammonia 118 ug/dL

TnI 0.07 ng/mL

68 (4/23) 68 (4/25)


CXR (4/22)

No definite active lung lesion


Brain CT (4/22)

No definite evidence of infarction


Current medications at OPD

2011/2/15 Nephrology OPD: Fosinopril(10mg) 0.5# QD Silymarin(150mg) 1# QD Carvedilol(6.25mg) 0.5# QD

2011/4/11 GI OPD Ribavirin(200mg) 1# QD Peginterferon alfa-2b(100mcg) 1pc QW Mefenamic acid(250mg) 1# QID

2011/04/20 HD room Epoetin beta (2000iu) 1pc TIW Atenolol(100mg) 1# QD


Impression

Suspect Interferon induced mood disorder

Leukopenia/Thrombocytopenia and Anemia, suspect Interferon/Ribavirin related

ESRD under hemodialysisHCV carrierSecondary hyperparathyroidism

status post total parathyroidectomy with autotransplantation

Nephrolithiasis


Admission course -1

Hold IFN+RBV since 4/22

(s/p 6th injection)

1st suicide at ER

2nd suicide at ward

c/s Psychi doctor


Admission course -2


Review this patient’s history

PegIFN 100mcg/QW

RBV 200mg 3#BID

RBV 200mg 1#QD

HCV-RNA

15.2 million IU/ml

Genotype 1b

HCV-RNA

(-)

HCV-RNA

(-)

HCV-RNA

0.006 million IU/ml

EPO 2000iu TIW 5000

HBV(-)

P’t want to withdraw the Tx…

HCV and CKD


Epidemiology of HCV

Hepatitis C virus is a blood-borne pathogen that appears to be endemic in most parts of the world.

WHO estimates that the global prevalence of HCV infection averages 3%, or around 170 million infected persons worldwide.

World J Gastroenterol 2007 May 7; 13(17): 2436-2441


Epidemiology of HCV in CKD P’t -1

The reported prevalence of HCV infection in haemodialysis units of developed countries has ranged from 2.6-22.9% (with a mean of 13.5%)

But prevalence may be as high as 70% in developing countries.

Postgrad Med J 2010;86:486-492


Epidemiology of HCV in CKD P’t -2

High rate of HCV transmission among CKD patients direct exposure to infectious blood and/or

blood products because of inadequate infection control.

• improving since 1992 with regular screening Cross contamination between patients

can occur in dialysis units • lack of disinfection of commonly utilised

medication equipment and supplies• the use of shared vials of heparin• blood spills which are not immediately cleaned



Natural history of HCV in CKD P’t -1

ALT values may not be a useful indicator of liver damage among CKD patients Suppression of ALT synthesis in hepatocytes,

inhibition of its release into the bloodstream and accelerated clearance from serum have been proposed as probable mechanisms of low ALT values in CKD patients

Liver biopsy may be required for CKD patients to assess the degree of liver damage and to plan antiviral therapy. Transjugular biopsy Elastography



Natural history of HCV in CKD P’t -2

In renal transplant patient renal transplant recipients with HCV

infection had higher mortality rates (RR 2.23)

graft losses were higher (RR 1.96) Risk for development of post-transplant

diabetes mellitus and MGN was also higher



HCV vs. CKD

Chronic infection with hepatitis C could be both the main cause and the complication of CKD.

Probable association between HCV infection and renal disease was first reported in 1990. Hepatitis C virus in patients with cryoglobulinemia type II. J Infect Dis 1990;162:569-70


HCV vs. CKD -- associated

Study Design: National cohort study. Setting & Participants: HCV-infected and -

uninfected veterans in ERCHIVES (Electronically Retrieved Cohort of HCV Infected Veterans) in 2001-2006.

Outcomes: Incident CKD stages 3-5. Conclusions: HCV infection is associated with

higher risk and shorter time to CKD despite having a lower prevalence of many CKD risk factors. HCV-infected persons should have targeted monitoring for the development and progression of CKD.



Study Design: Cross-sectional study. Setting & Participants: A large-scale

community study with 54,966 adults in a Taiwanese county endemic for HBV and HCV infection.

Conclusions: HCV infection, but not HBV infection, was associated significantly with prevalence and disease severity of CKD in this HBV and HCV endemic area


HCV vs. CKD -- not associated

METHODS: We conducted a cohort study of 167,569 patients included in a national health care claims database from January 1, 2003–December 31, 2006, with a mean follow-up of 25.3 months. We used multivariable logistic regression analyses to measure the independent effect of HCV status on the baseline prevalence of and progression to CKD

CONCLUSIONS: We found no association between HCV and risk of development of CKD.


HCV vs. CKD – not associated


Mechanism and Pathogenesis of HCV induced renal injury -1

Hepat Mon. 2010; 10(4): 258-269



Hepat Mon. 2010; 10(4): 258-269



Mixed cryoglobulinemia induced GN The most documented extrahepatic

manifestation of hepatitis C virus (HCV) infection is mixed cryoglobulinemia (MC).

MC is characterised by the presence of temperature-sensitive protein complexes

• precipitates when the serum is incubated at a temperature lower than 37C.

• in type II MC, cryoglobulins are composed of a monoclonal rheumatoid factor (usually, IgMk) against polyclonal IgG

Lupus (2000) 9, 83±91



Lupus (2000) 9, 83±91



Nephrol Dial Transplant (2007) 22: 1840–1848



(B) Non-cryoglobulinaemic membranoproliferative glomerulonephritis (C) Membranous nephropathy (D) Focal and segmental sclerosis (E) Amyloidosis (F) Fibrillary glomerulonephritis. (G) Post-transplant thrombotic microangiopathy (H) Transplant glomerulopathy

Treatment of HCV in CKD Patients


Antiviral therapy -- Interferon

Interferons are an important part of the innate antiviral immune response. They induce interferon-stimulated genes

(ISGs) that help establish an antiviral state within cells

Act by binding to cell surface receptors, activating a response cascade that culminates in the expression of multiple ISGs, some of which block viral protein synthesis. In addition, it may lead to a decrease in viral RNA stability.


Antiviral therapy -- Interferon

Alpha interferons also interact with the adaptive immune system. It promote the proliferation of memory T-

cells, prevent T-cell apoptosis, stimulate natural killer cell activation, and stimulate dendritic cell maturation.

It also upregulate the production of major histocompatibility complex class-I and class-II peptides and may promote a T-helper-1 phenotype over a T-helper-2 phenotype.

Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature 2005; 436:967.


Antiviral therapy -- PEG-Interferon

The attachment of polyethylene glycol to a protein (pegylation) reduces its rate of absorption following subcutaneous injection, reduces renal and cellular clearance, and decreases the immunogenicity of the protein.

All of these effects tend to enhance the half-life of the pegylated versus the native protein.

On the other hand, pegylation may interfere with the ability of a protein to bind to its receptor, thereby decreasing its biologic effect. Thus, the true biologic effect of the pegylated protein is determined by the balance of these competing properties

Two formulations of peginterferon alfa have been developed: peginterferon alfa-2a (Pegasys, Roche Pharmaceuticals), and peginterferon alfa-2b (Peg-Intron, Schering-Plough Corporation).

Immunogenicity of recombinant IL-2 modified by covalent attachment of polyethylene glycol. J Immunol 1990; 144:209


Antiviral therapy -- Ribavirin

Ribavirin is a nucleoside analog which has a broad spectrum of antiviral activity

It inhibits the replication of RNA viruses in cell culture. Ribavirin appears to decrease hepatitis C virus infectivity in a dose-dependent manner

Several mechanisms may be involved: Depletion of intracellular triphosphate pools through

direct inhibition of inosine monophosphate dehydrogenase

Inhibition of the 5'-cap structure of viral mRNA Inhibition of the viral-dependent RNA polymerases Altering the balance between proinflammatory (Th1-

like) and antiinflammatory (Th2-like) cytokines Inducing mutations into viral RNA Potentiating interferon action

Modelling how ribavirin improves interferon response rates in hepatitis C virus infection. Nature 2004; 432:922


Treatment of HCV -1

HEPATOLOGY, Vol. 49, No. 4, 2009


Treatment of HCV -2



Treatment of HCV -3



Treatment of HCV -4

SVR (sustained virological response) defined as the absence of HCV RNA from

serum by a sensitive PCR assay 24 weeks following discontinuation of therapy

ETR (end-of treatment response) Undetectable virus at the end of either a

24-week or 48-week course of therapy An ETR does not accurately predict that

an SVR will be achieved but is necessary for it to occur.



Treatment of HCV -5

EVR (early virological response) EVR is defined as a 2 log reduction or

complete absence of serum HCV RNA at week 12 of therapy compared with the baseline level.

97~100% of treatment-naive patients with HCV genotype 1 infection who did not reach an EVR failed to achieve an SVR.

RVR (Rapid virology response) defined as undetectable HCV RNA at

week 4 of treatment predicts a high likelihood of achieving an

SVR. HEPATOLOGY, Vol. 49, No. 4, 2009


Treatment of HCV -6

Important predictors of a treatment response include: HCV genotype (genotypes 2 and 3 are more

responsive to treatment than genotypes 1 and 4)

Baseline viral load (≤600,000 to 800,000 IU/mL)

Race (whites have higher response rates than African Americans and Latino whites)

Host genetic factors (eg, IL28B polymorphisms) Use of combination therapy with Peginterferon

and Ribavirin Treatment adherence


Treatment of HCV -6

American Journal of Kidney Diseases, Vol 42, No 4 (October), 2003


Treatment of HCV -7



Treatment of HCV -8

Genotype 1


American Associationfor the Study of Liver Diseases’ (AASLD) guideline


Treatment of HCV -9

Genotype 2 or 3




KDIGO guideline

Kidney Disease: Improving Global Outcomes (KDIGO) is an independently incorporated nonprofit foundation, governed by an international board of directors, that was established in 2003 with the stated mission to ‘improve the care and outcomes of kidney disease patients worldwide through promoting coordination, collaboration, and integration of initiatives to develop and implement clinical practice guidelines.’


Evaluation for treatment -1

It is suggested that CKD patients with HCV infection be evaluated for antiviral treatment. (Weak) Biopsy is recommended in patients infected

with HCV genotypes 1 and 4, it may not be necessary in patients infected with genotypes 2 and 3 in whom the response rate to treatment is quite high (~80%)

patients who have chronic hepatitis C with significant fibrosis (predictive of progression to more advanced histology) should receive antiviral therapy


It is suggested that the decision to treat be based on the potential benefits and risks of therapy, including life expectancy, candidacy for kidney transplantation, and comorbidities. (Weak) treatment is not recommended for the

patient with less than a 5-year estimated survival due to comorbidities such as cardiovascular disease

5-year mortality:• CKD stage 2 (19.5%), stage 3 (24%), stage 4

(46%)




Genotypes: Geographical and racial variability


Genotypes: Genotypes 1 and 4 are less responsive to IFN-

based therapy and require 48 weeks of treatment Genotypes 2 and 3 are far more responsive to

treatment and require only 24 weeks of therapy to achieve SVR.

• In patients with HCV genotype 3 who did not reach HCV RNA clearance within 24 weeks of therapy, a prolonged treatment (up to 48 weeks) is recommended at present, especially in those patients with high viral load.

HCV genotype 5 appears to have a response similar to genotypes 2 and 3 but requires 48 weeks of therapy.

Genotype 6 responds better than genotype 1 but not so well as genotypes 2 and 3.



It is suggested that in CKD patients—except kidney transplant recipients—who develop an acute HCV infection, a waiting period beyond 12 weeks to observe spontaneous clearance (by NAT) is not justified and that antiviral treatment should be started. (Weak) the rate of spontaneous SVR is lower in

dialysis patients (5–30%) than in the general population (up to 50%)



It is suggested that HCV-infected patients accepted for kidney transplantation be treated. (Weak) Positive anti-HCV serologic status after

kidney transplantation is implicated in the • pathogenesis of acute glomerulopathy• de novo graft HCV-associated nephropathy• NODAT (new onset diabetes after

transplantation)• a higher incidence of chronic allograft

nephropathy



It is suggested that treatment of HCV-infected kidney transplant recipients be considered only when the benefits of treatment clearly outweigh the risk of allograft rejection due to IFN-based therapy (for example, fibrosing cholestatic hepatitis, life-threatening vasculitis). (Weak) Graft dysfunction and failure are frequent

side effects of IFN therapy administered after transplant

Dropouts during antiviral therapy are mostly related to IFN-induced acute rejection, which is frequently steroid resistant and irreversible



It is suggested that antiviral therapy be considered for patients with HCV-related GN (Weak)



The level of kidney function in the CKD population plays a crucial role on the pharmacokinetics of antiviral drugs targeted at HCV.

Basing Treatment in CKD patient


For HCV-infected patients with CKD Stages 1 and 2, combined antiviral treatment using pegylated IFN and ribavirin is suggested, as in the general population. (Weak). It is suggested that the ribavirin dose be

titrated according to patient tolerance. (Weak).

Basing Treatment – in CKD stage 1&2


For HCV-infected patients with CKD Stages 3–5 not yet on dialysis, monotherapy with pegylated IFN with doses adjusted to the level of kidney function is suggested. (Weak). The use of ribavirin in patients with a GFR

<50 ml per min per 1.73m2 is not recommended in other guidelines

Recent data support ribavirin use in CKD patients with GFR<50 ml per min per 1.73m2 in a cautious and very well-monitored setting.

Basing Treatment – in CKD stage 3-5


For HCV-infected patients with CKD Stage 5D on maintenance hemodialysis, monotherapy with standard IFN that is dose-adjusted for a GFR <15 ml per min per 1.73m2 is suggested.(Weak). There are limited data on monotherapy with

pegylated IFN for HCV-infected patients on maintenance hemodialysis

Basing Treatment – in CKD stage 5D


The viral response to monotherapy with standard IFN in maintenance hemodialysis patients (summary estimate of 37%), is higher than patients with normal kidney function (7–16%) who received standard IFN monotherapy.

However, the viral response to monotherapy with standard IFN in dialysis patients is lower than that observed in patients with chronic hepatitis C treated with combined therapy (conventional or pegylated IFN plus ribavirin) in the general population.



Mechanisms account for the relatively higher response to IFN in patients receiving maintenance hemodialysis: Dialysis patients with HCV usually have a lower viral

load The infection is frequently associated with milder

forms of histologic liver disease clearance of IFN is lower in dialysis patients an increase in endogenous IFN release from

circulating white blood cells during hemodialysis sessions

A marked and prolonged release of hepatocyte growth factor (or other cytokines) caused by hemodialysis could play an additional role



Although response rates to conventional IFN are better in the dialysis population, tolerance to IFN monotherapy appears lower in patients on maintenance hemodialysis than in non-CKD individuals

The summary estimate of dropout rate was 17% in dialysis patients who received standard IFN monotherapy, whereas the frequency of side effects requiring IFN discontinuation ranged between 5~9% in non-CKD patients



Few studies have evaluated combined therapy in patients on maintenance hemodialysis

Ribavirin therapy in this setting is not recommended.

The Work Group feels that if a decision is made to use ribavirin in patients on maintenance hemodialysis, it should be used very cautiously Very low ribavirin dose (about 200 mg day1

or 200 mg thrice weekly) weekly monitoring of hemoglobin levels high doses of erythropoietin to treat anemia.



Basing Treatment – in transplant recipients

For HCV-infected kidney transplant recipients in whom the benefits of antiviral treatment clearly outweigh the risks, monotherapy with standard IFN is suggested. (Weak) IFN-based regimens are contraindicated

after kidney transplantation (allograft loss occurred in 6–15%)

Treatment is indicated in fibrosing cholestatic hepatitis and life-threatening vasculitis.


Basing Treatment – Summary


If SVR is achieved, it is suggested that testing with NAT be performed annually to ensure that the patient remains nonviremic. (Weak). For patients on maintenance hemodialysis, repeat

testing with NAT every 6 months is suggested. (Weak)

All patients with HCV infection, regardless of treatment or treatment response, should be followed for HCV-associated comorbidities. (Strong). Patients who have evidence of clinical or histologic

cirrhosis should have follow-up every 6 months. (Strong)

Annual follow-up for patients without cirrhosis is suggested.(Weak)

Monitor the response -1


In a long-term follow-up on 20 HCV-infected patients on maintenance hemodialysis for a period of 6 years, 15 (75%) showed HCV RNA clearance at the end of treatment, but 7 of them (47%) had viral relapse and only 8 (40%) had SVR at final follow-up.

Recent data indicate that pretransplant SVR is well sustained after transplantation despite intense immunosuppressive therapy.


A six-year follow-up after interferonalpha monotherapy for chronic hepatitis C infection in hemodialysis patients. Ren Fail 2004; 26


patients who have received antiviral therapy and are on the waiting list for kidney transplantation annual assessment of HCV viremia is

especially important Those who relapse should receive antiviral

treatment for at least 1 year.


Side effects of antiviral treatment


Side effects are observed in almost

80% of patients receiving

P eginterferon andRibavirin combination therapy for chronic HCV.

Flu-like symptoms Anemia Neutropenia Thrombocytopenia Rashes Hair loss Thyroid dysfunction Depression Fatigue Irritability and mania Insomnia Nonproductive cough Dyspnea Ophthalmologic disorders such

as retinal hemorrhages Teratogenicity Exacerbations of autoimmune

diseases


Pharmacologic therapy should be considered before beginning IFN in patients with risk factors for a mood disturbance.

In other patients it can be started after development of its initial features. We generally suggest beginning antidepressant

treatment in such patients if they have had seven or more days of continuous depressive symptoms of mild or greater severity.

Patient at greatest risk for treatment-emergent symptoms are also those most likely to benefit from antidepressant pretreatment.

When to treat


Pretreatment -1

A randomized trial of Paroxetine to prevent interferon-alpha-induced depression in patients with hepatitis C.

METHODS: In a double-blind, placebo-controlled study, 33 patients with HCV were randomly assigned to paroxetine or placebo prior to antiviral therapy. Patients were evaluated for psychiatric symptoms prior, during, and six months after antiviral therapy.

Group assignment did not appear to impact antiviral therapy completion rates, as a similar proportion of patients from each group completed treatment.

CONCLUSION: A prophylactic approach to interferon-alpha-induced depression may not be indicated in patients with HCV infection.


Pretreatment -2

To investigate the use of Paroxetine in a prospective, double-blind, placebo-controlled study for this indication.

Sixty-one hepatitis C virus-infected patients were randomly assigned to the antidepressant, paroxetine (n = 28), or placebo (n = 33), begun 2 weeks before and continued for 24 weeks during interferon-alpha/ribavirin treatment. Primary endpoints included development of major depression and severity of depressive symptoms measured by the Montgomery Asberg Depression Rating Scale (MADRS).

Result: Assignment to Paroxetine was also associated with significantly reduced depressive symptom severity.

This double-blind, placebo-controlled trial provides preliminary data in support of antidepressant pre-treatment in hepatitis C virus patients with elevated depressive symptoms at baseline.


Treatment of interferon-alfa-induced depression

Review the case


A case of ESRD under regular HD with chronic HCV infection

No previous mood disturbance historyNo liver biopsy dataReceived anti-viral treatment

Peginterferon alfa-2b(100mcg) 1pc QW x 6 injections (2011/3/7~2011/4/22)

Ribavirin(200mg) (2011/3/7 1200mg 2011/4/7 200mg)

Discontinue treatment on 2011/4/22 due to neuropsychiatric side effects


According to KDIGO guideline:

Regimen of this patient: Peginterferon alfa-2b(100mcg) 1pc QW x 6 injections

(2011/3/7~2011/4/22) Ribavirin(200mg) (2011/3/7 1200mg 2011/4/7 200mg)

Adequate?


Patient with neuropsychiatric side effects as agitation, depressive mood, insomnia and suicide ideation. Improving after cease the treatment With still mild fatigue and headache

sometimes now felt worse than the condition before treatment

GI doctor consider further treatment due to HCV-RNA(+) rechecked, but patient worried about the side effects.

Discussion


Q: Is the regimen rational for this patient?

Peg-IFN and Ribavirin usage in the CKD patient has higher risk of side effects incidence.

Aspect of GI doctor?


Q: What is the next step of this patient?

The HCV genotype of this patient is genotype 1b. Liver biopsy maybe indicated to decide

whether further treatment should be restarted.

Previous psychiatric underlying disease is not contraindication for antiviral treatment. But if previous treatment related

neuropsychiatric problems predict high risk of recurrence if the treatment restarted? no data found


If the treatment restart was decided after benefit-risk evaluation: Regimen/Dose by the guideline Close monitor the hemogram and titrate

EPO dose Close monitor neuropsychiatric side effects,

prescribed medication if progressive s/sIf the further treatment was not

considered Close monitor liver function, HCV-RNA,

liver echo and AFP


The newer and investigational therapies for chronic HCV infection can be divided conceptually into: Derivatives of current treatments Treatments targeting HCV-encoded

proteins Treatments targeting host-encoded

proteins Therapeutic and preventive vaccines Complementary/Alternative medicine

Q: Is there other treatment choice?


Derivatives of current treatments Albinterferon

• A form of interferon alfa genetically fused to albumin

• Lower dosing frequency (every two weeks rather than every week)

• no longer being developed because of toxicity concerns

Ribavirin derivatives• Levovirin• Taribavirin


Treatments targeting HCV-encoded proteins

Specifically Targeted Antiviral Therapy for HCV (STAT-C)


NS3/4A protease inhibitors • Telaprevir: Telaprevir monotherapy found that

while the majority of subjects had marked declines in HCV RNA over the 14-day dosing period.

• Boceprevir: Boceprevir is another protease inhibitor for the treatment of chronic HCV infection. Boceprevir is a competitive inhibitor of the NS3 protease complex of HCV genotype 1. As such, it does not have significant activity against other HCV genotypes


While protease inhibitors substantially increase SVR rates in genotype 1 chronic HCV, patients should be made aware that approximately 20 to 30 percent of treatment-naïve individuals with genotype 1 infection will not achieve an SVR with combination protease inhibitor/peginterferon/ribavirin. This is even more significant for null responders to prior peginterferon/ribavirin treatment, of whom only 30 to 40 percent will likely attain an SVR even with the addition of a protease inhibitor.


Inhibitors of the NS5B RNA-dependent RNA polymerase (RdRp) fall into two broad classes: nucleoside analogs and non-nucleoside inhibitors (NNIs).

• Nucleoside analogs bind to the NS5B active site, while NNIs bind to one of at least three allosteric binding pockets outside the active site.

• Development of a number of promising HCV polymerase inhibitors has been halted due to toxicity

NS5A inhibitors — The HCV NS5A protein is essential for viral replication and for the assembly of infectious virions, although the precise molecular mechanisms by which NS5A accomplishes these functions are uncertain.


Treatments targeting host-encoded proteins HCV depends upon host proteins for all phases

of its life cycle: entry, replication, and virion assembly/secretion.

Cyclophilin inhibitors• Cyclosporin A, an immunosuppressant, inhibits HCV

replication in cell culture replicon models.• cyclosporin A inhibits the cellular protein cyclophilin B

which interacts with NS5B and appears to promote its RNA binding activity.

Nitazoxanide • An antiprotozoal drug. • The mechanism of nitazoxanide activity against HCV

may be mediated by phosphorylation of the host proteins kinase R and eIF2alpha, which in turn inhibits HCV replication.


HCV vaccines There are substantial challenges to the development of

an effective HCV vaccine. • There is extensive sequence diversity among the six

different known genotypes of HCV. • A large number of viral quasispecies in infected

individuals. • Result in the rapid selection of viral escape mutants.

Vaccines to elicit both CD4+ and CD8+ T-cell responses• Spontaneous HCV clearance in acutely infected

individuals is associated with broad and early T-cell responses to HCV.

• lack of a small animal model


A hepatitis C immune globulin (Civacir) is being studied in a phase II trial to evaluate its effect on recurrent hepatitis C following liver transplantation.

A DNA-based vaccine

• a gene encoding the HCV NS3/4A protein is introduced into the patient's skeletal muscle by a technique called DNA electroporation. The muscle tissue then expresses the HCV NS3/4A protein with the goal of stimulating HCV-specific immune responses.

Although some of these vaccines have shown promise in preclinical models, more study is needed.


Complementary/Alternative treatment Silybum marianum (milk thistle)

• The extract of milk thistle seeds is called Silymarin and contains a number of flavonoid compounds, of which the dominant compound is called silibinin (also known as silybin).

• Decrease serum aminotransferases • Antiviral activity

There is no firm evidence

supporting medicinal herbs

for HCV infection


HCV, with more than 170 million cases documented worldwide, is associated with chronic liver and kidney disease.

Always be aware of the benefit-risk evaluation while anti-HCV treatment was considered, especially in patient with impaired renal function.

Most important of all, Prevention of HCV dissemination is the major work.

Take home message


Psychi consultant’s note

<MSE> Conscious: clear and oriented Appearance: kempt Attention: focus and sustain Attitude: cooperative Affect: worrisome Mood: somehow anxious, depressed mood improving much Behavior: no psychomotor retardation, normoactivity, appropriate Speech: coherent and relevant Thought: less blocking

• worry and fear of IFN treatment• no active delusion• less worthless feeling• no current suicidal ideation

Perception: no auditory/visual hallucination Sleep: intermittent initial insomnia Appetite: improving

<Impression> Interferon induced mood disorder with melancholic feature


Ribavirin is a nucleoside analog (1-b-D-ribofuranosyl- 1H-1,2,3-triazole-3-carboxamide) with an antiviral mechanism of action

when used in combination with interferon, it has a key role in maintaining antiviral response following completion of therapy and increases SVR rates compared to interferon monotherapy.

Despite caution about the use of ribavirin, results from small uncontrolled trials in patients with CKDon maintenance hemodialysis using fixed low doses or individualized dosing of ribavirin to target specific ribavirin plasma levels are encouragin (200mg QD~QOD)


Treatment related Depression

Incidence: 20~40% (as high as 82% have been described)

Developed in the first 3 months of therapy with highest incidence in the first 4~8 weeks and prevalence rates continuing to increase during the first 6 months.

Management: Selective serotonin reuptake inhibitors (SSRIs),

especially Paroxetine and Citalopram, have been most extensively studied.

Combined serotonin-norepinephrine reuptake inhibitors (SNRIs).

Other options include Bupropion (an agent with norepinephrine and dopamine activity) and Mirtazapine (a novel agent with effects on norepinephrine and serotonin).


Treatment related Fatigue

The most common neuropsychiatric side effect Begins within the 1~2 week of treatment, is maximal

between 4~8 weeks. Management:

SRI Paroxetine was significantly effective Behavioral strategies (conserve energy by taking

frequent rest periods, napping) Adequate fluid balance (IFN can affect the hypothalamic

temperature center, which leads to low-grade fevers and fatigue)

Growth factors used to maintain adequate hemoglobin levels

Psychostimulants The non-stimulant wake promoter Modafinil Ondansetron, a serotonin 5-HT3 receptor antagonist

improved fatigue The activating antidepressant bupropion Dopamine agonists (ie, Ropinirole and Pramipexole)


Treatment related Irritability and mania

Management: Benefit from the initiation of an antidepressant with

serotonergic activity (ie, an SRI or SNRI) Benzodiazepines were also found to be effective Mood stabilizer: Lithium, Valproic acid,

carbamazepine and Haloperidol Antipsychotic drugs such as Olanzapine,

Risperidone, Quetiapine, Ziprasidone, and Aripiprazole


Treatment related Insomnia

Management: Frequently prescribed agents include the non-

benzodiazepine hypnotics (ie, Zolpidem) Trazodone, a sleep promoting antidepressant Diphenhydramine was not suggested because that

have the potential to add to the side effect Novel melatonin modulating sleep agent Ramelteon


Aims: Oral Silibinin (SIL) is widely used for treatment of hepatitis C, but its efficacy is unclear. Substantially higher doses can be administered intravenously (IV).

Methods: Pedigreed nonresponders to full-dose pegylated (Peg)-interferon/ ribavirin (PegIFN/RBV) were studied.

Result: Unexpectedly, in the first study, HCV-RNA declined on IV SIL by 1.32 +/- 0.55 log (mean SD), P < 0.001 but increased again in spite of PegIFN/RBV after the infusion

period. The viral load decrease was dose dependent

Conclusions: IV SIL is well tolerated and shows substantial antiviral effect against HCV in nonresponders.


Method: The databases of the Cochrane Collaboration,

MEDLINE, EMBASE, and BIOSIS were searched combined with manual searches of five Chinese and one Japanese journals.

Conclusion: There is no firm evidence supporting medicinal

herbs for HCV infection, and further randomized trials are justified.


Chronic viral hepatitis and CKD

Chronic viral hepatitis is a major public health issue that affects about 500 million people worldwide.

Only HBV and HCV usually become chronic.

Chronic HBV and chronic HCV have significant association with chronic kidney disease

Extrahepatic diseases are more common in HCV infection patient than HBV.

Postgrad Med J 2010;86:486-492.


HBV associated CKD -1

HBV, a common cause of liver disease and liver cancer, infects more than 300 million people worldwide.

Renal injury caused by: direct cytopathic effect of the virus on cells

of the kidney glomerular deposition of immune

complexes virus induced specific immunological

effector mechanisms

Postgrad Med J 2010;86:486-492.



Pathology:

Postgrad Med J 2010;86:486-492.

Most common 1/3 CKD

10% dialysis or transplantation



Treatment of HBV related MGN: Steroid was not found useful Benefit of using interferon α Lamivudine: improve renal outcome and

seroconversion rate Entecavir, Tenofovir: improve viral

suppression and less resistanceTreatment in other nephropathy?

Steroid: vasculitis secondary to HBV associated PAN

Postgrad Med J 2010;86:486-492.



HBV infection among CKD patients prevalence of HBV infection among

patients on haemodialysis in the developed world is currently low (0-10%) but remains higher (2-20%) in developing countries.

HBV infection among CKD patients is associated with higher morbidity and mortality rates.

Postgrad Med J 2010;86:486-492.



HBV infection among CKD patients Patients with CKD may be more likely to

develop chronic infection once exposed to HBV

• uraemia is associated with dysfunction of the immune system

• Haemodialysis exacerbates the oxidative stress and impaired granulocyte phagocytic activity

• anaemia• malnutrition

Postgrad Med J 2010;86:486-492.



HBV infection among CKD patients For renal transplant recipient:

• associated with decreased survival after renal transplantation

• More frequent need for re-transplantation• all renal allograft recipients with HBV infection

should receive long term antiviral treatment

Postgrad Med J 2010;86:486-492.


Review this patient’s history

2011/03/24 Abdominal echo: Parenchymal liver disease, score 6; Rt.

renal cyst.

2011/03/24 Kidney echo: Left Kidney Length: 8.0 cm

Right Kidney Length: 11.1 cm 1. Left small and contracted kidney

2. Right chronic parenchymal renal disease 3. Bilateral renal cysts and renal stones

4. Incomplete urinary bladder study

Hepatitis C


HCV -1

a small double-shelled virus consisting of: a lipid envelope (E)

with virally encoded glycoproteins (E1 and E2)

an inner nucleocapsid (core) that contains a positive-sense single stranded RNA genome consisting of 9,500 nucleotides

AJKD, Vol 42, 2003

http://trialx.com/curebyte/2011/05/22/hcv-photos-and-related-clinical-trials/


HCV -2

HCV has well-defined structural (core, E1, and E2) and nonstructural ([NS]; P7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) components. The nonstructural proteins encode several

proteases, a virus-specific helicase, and an RNA dependent RNA polymerase responsible for replication of the genome.


HCV -3

http://www.biken.osaka-u.ac.jp/act/act_matsuura_e.php


HCV -4

HCV isolates are classified into 6 distinct clades (genotypes 1 to 6) based on sequence homology.

HCV does not replicate in cell culture studies of infectivity have relied on the

Chimpanzee (the only reliable animal model for HCV infection and disease)

Recovery from infection has correlated best with an early, vigorous, and broadly based CD4 and CD8 immune response against HCV peptides

AJKD, Vol 42, 2003

Vaccine?!


HCV -5

Exposure of chimpanzees to infectious inocula

• appearance of HCV RNA in serum within 1 to 2 weeks

• Viral levels increase rapidly and serum ALT values become abnormal peak 4 to 8 weeks after exposure

• Antibody to HCV (anti-HCV) arises (initial antibody response is targeted mostly against HCV core, NS3, and NS4 proteins; low level of anti-E1 and anti-E2 generally arise later)

• Recovery is marked by loss of HCV RNA and resolution of disease activity

• Chronicity is marked by persistence of viremia

AJKD, Vol 42, 2003


Epidemiology of HCV

Hepatitis C virus is a blood-borne pathogen that appears to be endemic in most parts of the world.

WHO estimates that the global prevalence of HCV infection averages 3%, or around 170 million infected persons worldwide.

World J Gastroenterol 2007 May 7; 13(17): 2436-2441


Epidemiology of HCV – in Taiwan

Journal of Medical Virology 65:30±34 (2001)


Natural history and course of HCV -1

Acute hepatitis C is often mild and associated with few symptoms. Fulminant or severe cases are rare.

Major complication of acute HCV infection is chronic hepatitis Continued presence of HCV RNA for 6

months after (estimated) onset defines chronic infection

subsequent spontaneous loss of virus is unusual

AJKD, Vol 42, 2003



Overall chronicity rate of hepatitis C is 70% Lower in children and young healthy

women (50% to 60%) Higher in older individuals and African

Americans (greater than 90% in African-American men)

Long-term complications: hepatic fibrosis, eventuate in cirrhosis(5-

20%), portal hypertension, and hepatic failure

Hepatocellular carcinoma(1-4%)AJKD, Vol 42, 2003



Factors correlate with a greater rate of fibrosis progression: Viral factors (less important):

• HCV RNA level, viral genotype, quasispecies diversity

Host factors (more improtant):• older age, older age at onset of infection, male

sex, white race, coinfection HIV or HBV, hemochromatosis, nonalcoholic steatohepatitis, obesity, and diabetes

Environmental factors• Chronic alcoholism

AJKD, Vol 42, 2003


Treatment of HCV -1



Treatment of HCV -2



Treatment of HCV -3



Treatment of HCV -4

SVR (sustained virological response) defined as the absence of HCV RNA from

serum by a sensitive PCR assay 24 weeks following discontinuation of therapy

ETR (end-of treatment response) Undetectable virus at the end of either a

24-week or 48-week course of therapy An ETR does not accurately predict that

an SVR will be achieved but is necessary for it to occur.



Treatment of HCV -5

EVR (early virological response) EVR is defined as a 2 log reduction or

complete absence of serum HCV RNA at week 12 of therapy compared with the baseline level.

97~100% of treatment-naive patients with HCV genotype 1 infection who did not reach an EVR failed to achieve an SVR.

RVR (Rapid virology response) defined as undetectable HCV RNA at

week 4 of treatment predicts a high likelihood of achieving an

SVR. HEPATOLOGY, Vol. 49, No. 4, 2009


Treatment of HCV -6

Important predictors of a treatment response include: HCV genotype (genotypes 2 and 3 are more

responsive to treatment than genotypes 1 and 4)

Baseline viral load (≤600,000 to 800,000 IU/mL)

Race (whites have higher response rates than African Americans and Latino whites)

Host genetic factors (eg, IL28B polymorphisms) Use of combination therapy with Peginterferon

and Ribavirin Treatment adherence


Treatment of HCV -6



Treatment of HCV -7



Treatment of HCV -8

Genotype 1




Treatment of HCV -9

Genotype 2 or 3





Nephrol Dial Transplant (2007) 22: 1840–1848


KDIGO guideline

nephrology case conference 報告日期 : 2011/10/05 指導老師 : 方基存教授 報告醫師 :...

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nephrology case conference 報告日期 : 2011/10/05 指導老師 : 方基存教授報告醫師 :...