Journal of Advanced Research (2016) 7, 391–402

Cairo University

Journal of Advanced Research

ORIGINAL ARTICLE

Antiviral treatment prioritization in HCV-infected

patients with extrahepatic manifestations – An

Egyptian perspective

* Corresponding author. Tel./fax: +20 25790267, mobile: +20 1222107182.

E-mail address: Rashad.barsoum@gmail.com (R. Barsoum).

Peer review under responsibility of Cairo University.

Production and hosting by Elsevier

http://dx.doi.org/10.1016/j.jare.2016.02.0062090-1232 � 2016 Production and hosting by Elsevier B.V. on behalf of Cairo University.

Hussein El-Fishawya, Gamal Saadi

a, May Hassaballa

a, Mohamed Hussein

b,

Wahid Doss c, Gaafar Ragab b, Rashad Barsoum a,*

aKasr-El-Aini Nephrology and Dialysis Center, Cairo University, EgyptbRheumatology Unit, Department of Internal Medicine, Cairo University, EgyptcDepartment of Tropical Medicine, Cairo University, Egypt

G R A P H I C A L A B S T R A C T

392 H. El-Fishawy et al.

A R T I C L E I N F O

Article history:

Received 12 December 2015

Received in revised form 19 February

2016

Accepted 23 February 2016

Available online 2 March 2016

Keywords:

DAAs

Cryoglobulinemia

Chronic kidney Disease

Dialysis

Transplantation

A B S T R A C T

Egypt, the single country with highest incidence of HCV infection in the world, has embarked

on a government-sponsored mass treatment program using several combinations of DAAs.

Recognizing the importance of extrahepatic manifestations, independently of the hepatic, a sub-

committee was assigned to develop national guidelines for respective prioritizing indications and

protocols. It evaluated the benefit of treating patients with different extrahepatic manifestations,

and reviewed relevant clinical trials and guidelines concerning DAA combinations available in

Egypt. The latter included Sofosbuvir plus either peg-interferon, Simeprevir, Ledipasvir or

daclatasvir, and the Viekera family comprising paritaprevir/ritonavir + ombitasvir with (GT-

1) or without (GT-4) Dasabuvir. Any of these protocols may be used with or without Ribavirin

according to indication. A blueprint was subjected to peer debate in dedicated workshops in two

national meetings and subsequently to an online professional review, eventually leading to a

final report that was adopted by the health authorities. Seven compelling and 10 optional indi-

cations were identified for treating patients with predominantly extrahepatic manifestations.

The former include kidney disease at different stages, cryoglobulinemic vasculitis and non-

Hodgkin lymphoma. Selected treatment protocols, were encoded and their use was prioritized

on the basis of evidence of efficacy and safety. We concluded that any of the studied protocols

may be used, preferably with ribavirin, for 12-week treatment in all patients with extrahepatic

manifestations without cirrhosis and with eGFR above 30 ml/min/1.73 sqm. Ribavirin should

be included in protocols for treating patients with compensated cirrhosis. Daclatasvir-based

protocols are recommended for decompensated cirrhosis, while the Viekera family is recom-

mended in patients with eGFR< 30 ml/min/1.73 sqm, including those on dialysis. In kidney-

transplanted patents, caution is due to avoidance of the pharmacokinetic interaction with the

Cytochrome-P450 enzyme system, in-between immunosuppressive agents and most DAAs, par-

ticularly the Viekera family.

� 2016 Production and hosting by Elsevier B.V. on behalf of Cairo University.

Introduction

The remarkable success of the current wave of Direct AntiviralAgents (DAAs) against Hepatitis C virus (HCV) offers an

unprecedented cure opportunity for millions of patients world-wide. Sustained viral response 12 weeks after completion oftreatment (SVR12) is currently achievable in the vast majority,

which predicts viral eradication in 98% of patients. This isassociated with recovery from most clinical sequelae of HCVinfection [1], and provides a survival advantage to many sub-

sets of patients, including reduction of cardiovascular mortal-ity. This imposes a moral responsibility on the healthauthorities to offer treatment to all infected patients, regardlessof the extent of clinical disease.

Meeting this goal in Egypt is a hard challenge, because; (a)it is a unique country where the virus has its highest impact inthe world (serological prevalence of 13.9–15.5% (14.7%) [2];

positive nucleic acid test in 7.0–12.2% (9.8%) [3]); (b) theprevalent viral strain in 90% of patients is Genotype-4 (GT-4) [4], which is typically difficult to treat, and on which only

a few therapeutic trials have been published; and (c) the avail-able health budget cannot accommodate the high demand formass treatment.

Nevertheless, the ambitious strategic decision in Egypt is totreat millions of infected patients in successive stages, whichrequires a comprehensive prioritization system. This was devel-oped according to the extent of liver damage and according to

Child-Pugh criteria and MELD score, and implemented for thetreatment of the first 60,000 patients. But it was soon realizedthat prioritization according to hepatic criteria refutes many

patients with predominantly extrahepatic manifestations,

which may be even more life threatening despite relativelylow liver scores. Accordingly, a subcommittee of the EgyptianNational Commission for Viral Hepatitis was assigned the task

of developing a prioritization system for patients with extra-hepatic manifestations regardless of the extent of liver affec-tion. The subcommittee was also required to prioritize the

treatment protocols for those patients, limiting the choices tothose available in the country.

Process

The subcommittee was composed of 7 members: 4 nephrolo-gists, 2 rheumatologists and a hepatologist. They were pro-vided with a list of approved DAAs, as well as those under

local clinical trial, pending registration in Egypt.A five-step action plan was developed and completed in

9 months.

1. Literature survey for evidence of:a. Benefit from treatment of different extrahepatic

manifestationsb. Preferred treatment protocols for extrahepatic

manifestations

2. Selecting evidence-based protocols that meet the localneeds

3. Peer debate

4. Online professional survey5. Preparation of the final documents for publishing and

governmental implementation.

Antiviral treatment prioritization in HCV-infected patients 393

Literature survey

� The basic pharmacokinetics of each drug on the avail-

ability list provided by the Egyptian National Commis-sion for Viral Hepatitis (ENCVH) were reviewed, withemphasis on its protein binding, metabolism, excretion,

half-life with normal or impaired glomerular filtrationrate, dialyzability, major drug–drug interactions and tar-get viral proteins.

� Randomized Clinical Trials (RCTs) on each DAA werescreened by Medline search and manufacturers’ websites.These were tabulated and shortlisted according to theirrelevance.

� Approval status of individual drugs as well as combinationprotocols by regulatory authorities in the USA (FDA)and Europe (EMA) was obtained from their respective

websites.� Recommendations made by the following guideline initia-tives were reviewed and integrated. The respective terms

for the strength of evidence and recommendations wereused where applicable.

Table 1 Rating by AASLD-IDSA classification and level of eviden

Description

AASLD classification

AASLD Class I Conditions for wh

evaluation, proced

AASLD Class II Conditions for wh

the usefulness and

AASLD Class IIa Weight of evidenc

AASLD Class IIb Usefulness and effi

AASLD Class III Conditions for wh

evaluation, proced

be harmful

Level of Evidence

Level A Data derived from

Level B Data derived from

Level C Consensus opinion

Table 2 Evidence grading used by the European Society of Liver D

Notes

Evidence quality

High Further research is very unli

confidence in the estimate of

Moderate Further research is likely to h

on our confidence in the esti

change the estimate

Low Further research is very like

impact on our confidence in

is likely to change the estima

estimate is uncertain

Recommendation

Strong Factors influencing the stren

recommendation included th

presumed patient-important

Weak Variability in preferences an

uncertainty. Recommendatio

certainty, higher cost or reso

� American Association for the Study of Liver Disease

(AASLD) and Infectious Diseases Society of America(IDSA) issued in August 2015 [5] (Table 1).

� European Association for the Study of the Liver (EASL),

June 2015 [6] (Table 2).� Kidney Disease: Improvement of Global Outcomes(KDIGO), April 2008 [7] (Table 3).

� ‘‘Real Life” observational data of the Hepatitis C Therapeu-

tic Registry and Research Network (HCV-TARGET) [8].

Protocol prioritization

Four factors were taken into consideration while prioritizing

DAA combinations in different clinical settings.

Genotype

1. Higher priority to documented efficacy against GT-4.2. Approved anti-GT-1 combinations including pangenotypic

agents, usually targeting NS5B nucleoside inhibitors.

ce [AASLD-IDSA 2015] [15].

ich there is evidence and/or general agreement that a given diagnostic

ure, or treatment is beneficial, useful, and effective

ich there is conflicting evidence and/or a divergence of opinion about

efficacy of a diagnostic evaluation, procedure, or treatment

e and/or opinion is in favor of usefulness and efficacy

cacy are less well established by evidence and/or opinion

ich there is evidence and/or general agreement that a diagnostic

ure, or treatment is not useful and effective or if it in some cases may

multiple randomized clinical trials, meta-analyses, or equivalent

a single randomized trial, nonrandomized studies, or equivalent

of experts, case studies, or standard of care

isease [EASL 2015] [16].

Grading

kely to change our

effect

A

ave an important impact

mate of effect and may

B

ly to have an important

the estimate of effect and

te. Any change of

C

gth of the

e quality of the evidence,

outcomes, and cost

1

d values, or more

n is made with less

urce consumption

2

Table 3 Levels of strength of recommendations used by the Kidney Disease: Improvement of Global Outcomes [KDIGO 2008] [17].

Strength of recommendation Wording of recommendation Basis for strength of recommendation

Strong An intervention ‘should’ be done High’ quality evidence and/or other considerations support a

strong guideline

Moderate An intervention ‘should be considered’ ‘Moderate’ quality evidence and/or other considerations support a

moderate guideline

Weak An intervention ‘is suggested’ ‘Low’ or ‘Very Low’ quality evidence; predominantly based on

expert judgment for good clinical practice

394 H. El-Fishawy et al.

Evidence

1. Proven efficacy in RCTs.

2. Approved combinations by credible regulatory authoritiesfor specific clinical settings.

3. Higher grading in recognized guideline recommendations.

Efficacy, toxicity and duration of therapy

1. Higher SVR 12 in respective clinical settings.

2. Lower incidence and significance of reported adverse drugreactions.

3. Preference of Interferon-free regimens.

4. Preference of Ribavirin-free regimens in the absence of cir-rhosis and in patients with Stages IV–V CKD(eGFR < 30 ml/min/1.73 sqm).

5. Shorter duration of treatment

Table 4 Scoring of patients with CKD for DAA treatment

priority.

Positive points

Post-renal transplant 5 points

Regular Dialysis 5 points

Cryoglobulinemic vasculitis 5 points

Non-Hodgkin B-cell lymphoma 5 points

Biopsy confirmed MCGN

with hypocomplementemia

4 points

Biopsy-confirmed MCGN without

hypocomplementemia

3 points

Nephrotic syndrome regardless

of histological type

2 points

Previous treatment failure 2 points

HBV/HIV/CMV co-infection 2 points

Stage of kidney disease (MDRD-4) 1 point/stage

Stage of liver disease (Fibroscan) 1 point/stage

Negative points

Age >70 �1 point/5 years

Decompensated cirrhosis �3 points

Concurrent drug–drug interaction

with selected Protocol

�3 points

Concomitant heart disease �1 point/NYHA score

Concomitant pulmonary disease �1 point/�10% FVC1

Concomitant CNS disease �1 point/10% disability

Pharmacokinetics

In the absence of credible evidence in certain clinical settings,the pharmacokinetic and pharmacodynamic features of indi-vidual drugs were the basis of suggestion for clinical use, par-

ticularly with regard to the following:

1. Pharmacokinetics in impaired kidney function.

2. Dialyzability and/or extent of protein-binding (when usedin dialysis patients).

3. Drug–drug interaction with immunosuppressive agents

(when used post-transplantation).4. Drug–drug interaction with common medications for co-

morbid conditions.

5. Spectrum of antiviral action in multiple viral co-infection.

Peer debate

The first blueprint was distributed, presented and discussed in2 dedicated workshops at the 34th national congress of theEgyptian Society of Nephrology and Renal Transplantation,

and the 7th Annual Congress of The National Hepatologyand Tropical Medicine Research Institute, both in Cairo(2015), leading to an amended version, approved by respective

national societies.

Online professional review

The amended version was subject to public review using the free‘‘SurveyMonkey” online tool for one month starting 1stMarch

2015. Participants included a selected cohort of experts,as well as those who requested participation following

the congress discussions. Comments were reviewed by thesubcommittee and incorporated, where applicable, into thefinal document.

Final documents

1. An official report was submitted to the National Commis-sion for Viral Hepatitis, along with a scoring list (Table 4),

for prioritizing patients according to relative urgency andexpected benefit of treatment in different clinical settings,score 5 being the highest. Relative limitations were

expressed as ‘‘negative points” in order to boot the priorityof those who are more likely to benefit from treatment. Anarbitrary acceptance threshold of 10 points was set as abeginning, based on the estimated numbers of patients in

relation to the immediately available budget. This thresholdwould be lowered as funds become available for treatingmore patients.

2. The report was reformatted into this article for formal sci-entific publication.

Antiviral treatment prioritization in HCV-infected patients 395

3. Given the rapid evolution of knowledge and experience

with the use of DAAs in HCV, and the long list of neweragents in the pipeline, the committee is aware of the needfor frequent updating of its recommendations, which shall

be available through a website designed for easy reference(under construction).

Guidelines

Based on the mentioned criteria, the subcommittee developedthe following clinical guidelines for Egyptian patients,

expressed as either ‘‘recommendations” or ‘‘suggestions”according to the strength of evidence and level in referenceguidelines. For suggested items, treatment decision should be

made on individual case to case basis, granting priority tohigher severity scores and life threatening co-morbid condi-tions that are likely to tolerate and benefit from eradication

of HCV infection.

Section I. Indications for treatment

I. We suggest evaluating HCV-infected patients according to six

factors, namely:

1. The stage of liver disease.

2. Estimated glomerular filtration rate, and nature of chronickidney disease (CKD) if present.

3. Nature and severity of extrahepatic manifestations.

4. Presence of co-morbid conditions and related chronic drugadministration.

5. Previous antiviral treatment with interferon or direct anti-

viral agents.6. HCV genotyping only prior to prescribing the Viekera

family.

Stage of liver disease

II. We recommend that patients indicated for the treatment

due to their liver condition be treated according to standard

indications [9], implemented by the Egyptian NationalHCV Control Program, based on fibrosis stage (determinedby Fib4 calculation and fibroscans when available) and

compensation of hepatocellular function (according toChild-Pugh criteria and the Model for End-stage LiverDisease (MELD)) scores.

Glomerular filtration rate

III. We recommend estimating the glomerular filtration rate

(eGFR) by the Modified Diet in Renal Disease (MDRD)

formula-4 [10] or Chronic Kidney Disease Epidemiology Col-laboration (CKD-EPI) [11] for appropriate choice and dosingof DAA combinations.

Nature of chronic kidney disease

IV. We recommend treatment of all HCV-infected patients with

any of the following conditions even in the absence of a com-

pelling liver indication or cryoglobulinemia:

(a) Kidney transplant recipients [AASLD-IDSA-I, LB].

(b) Patients on the waiting list for kidney transplantation[AASLD-IDSA-I, LB]; EASL-A1.

(c) Patients on regular dialysis [AASLD-IDSA-IIa, LC].

(d) Patents with mesangiocapillary (Membranoprolifera-tive) glomerulonephritis [AASLD-IDSA-IIa, LB].

(e) Patients with the nephrotic syndrome due to anyhistopathological type of glomerulonephritis [AASLD-

IDSA-IIa, LB].

V. We suggest treatment of patients with the following HCV-

related kidney disorders:

(a) Patients in CKD stages 3–5 (eGFR < 60 ml/

min/1.73 sqm), regardless of etiology [not graded)].(b) De-novo HCV infection persisting for over 12 weeks

in patients with any grade CKD. (KDIGO 2008[Weak]).

Extrahepatic manifestations

VI. We recommend DAA treatment for cryoglobulinemic

vasculitis with end-organ manifestations (joints, peripheralnerves, skin, kidneys, lungs, eyes, gut, brain, etc.)[AASLD-IDSA-I, LB], graded according to severity[opinion].

VII. We recommend DAA treatment for HCV-associated

Non-Hodgkin B-cell lymphoma [12] [opinion].VIII. We suggest DAA treatment for the following conditions

in the context of HCV infection, even in the absence of

cryoglobulinemia.

� Type 2 Diabetes mellitus (insulin resistant) [AASLD-IDSA-IIa, LB].

� Debilitating fatigue [AASLD-IDSA-IIa, LB].

� Porphyria cutanea tarda. [13] [AASLD-IDSA-IIb, LC].� Hodgkin’s lymphoma [14] and other lymphoproliferativedisorders [15] [not graded].

� Chronic arthritis of undetermined etiology [16] [not

graded].� Autoimmune thrombocytopenia [not graded] [17].� Oral [18] and cutaneous [19] Lichen planus [not graded].

� Low C4, positive rheumatoid factor, negative Anti-CCP,yet with negative cryoglobulins [20] [opinion].

Co-morbid conditions

IX. We suggest investigating all patients before prescribing

DAAs for the presence of co-infection with HBV, HIV, or other

co-morbid conditions that may require modifications inrecommended treatment protocols [Opinion] (see guidelineXIV).

Previous antiviral treatment

X. We recommend reviewing each patient’s history for previous

anti-HCV therapy with interferon, ribavirin or other DAAs

[EASL-A1], since this predicts viral non-structural proteinmutations and guides the selection of re-treatment protocols(see guideline XIII).

396 H. El-Fishawy et al.

Genotyping prior to treatment with Viekera family

XI. We recommend genotyping only prior to treatment with the

Viekera family owing to the protocol variance in the treatmentof either GT-4 or GT-1 infection (see later). These constitutethe only genotypes reported in Egypt in a proportion of 9:1

respectively [4]. Genotyping is not recommended in candidatesfor other protocols, which are equally effective in both

genotypes.

Section II. Treatment protocols

XII. We recommend individualization of the use of DAA proto-

cols for treatment-naive patients guided by the priorities shown

in Table 5

Selected protocols

Selected DAA combinations in this section are chronologicallyordered according to their availability in Egypt. Other DAAs,

even with better pharmacokinetics, FDA approval and inclu-sion in international guidelines, are omitted. Selected protocolsare identified by letters A–E. Numbers following the letters dif-ferentiate additional antiviral agents as follows: (1) no addi-

tions; (2) ribavirin in a weight-based fixed dose; (3) ribavirinin a reduced dose; and (4) interferon. The target non-structural viral protein, the market name and manufacturer

are provided following each drug. A suffixed asterisk indicatesmodification of a standard protocol. The common side effectsassociated with their use are appended to each protocol. Rec-

ommendations for their use in different clinical conditions areprovided in Table 5.

Protocol A: Sofosbuvir (NS5B-Sovaldi)-based protocols

A2: Sofosbuvir (400 mg) and weight-based RBV (1000 mg[<75 kg] to 1200 mg [>75 kg]) for 12 weeks [FDAapproved for GT-1] or 24 weeks [FDA approved for

GT-1 & GT-3], [Egyptian Ancestry Study in GT-4] [21].A4: Sofosbuvir (400 mg) and weight-based RBV (1000 mg

[<75 kg] to 1200 mg [>75 kg]) plus weekly PEG-IFNAlpha 2A (180 mcg subcutaneously) or PEG-IFN Alpha

2B (1.5 mcg/kg subcutaneously) for 12 weeks (NeutrinoStudy [22], FDA approved for GT-1 & GT-4].

Adverse reactions. Over one-third of patients using Sofosbuvirwill complain of headache, fatigue and nausea; and 10–20%will have insomnia, irritability, anemia, shortness of breath,

diarrhea, dermatitis and muscle aches. Some patients maydevelop transient increase in serum bilirubin and lipase, whichresolve spontaneously.

Protocol B: Ledipasvir (NS5A)/sofosbuvir (NS5B) [Harvoni]-based protocols

B1: Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir

(400 mg) for 12 weeks in GT-1 (ION studies [23–25]), orGT-4 or GT-5 (GS-US-337-1119, O056 trial [26]); FDAapproved for 12-week treatment in GT-1 without cirrhosis,

or treatment-naıve patients with cirrhosis; or for 24 weeksGT-1 in treatment-experienced patients with cirrhosis];NAID SYNERGY study for 12 weeks in GT-4 [27].

B2: Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir

(400 mg) plus weight-based Ribavirin (1000 mg [<75 kg]

to 1200 mg [>75 kg]) for 12 weeks in GT-1 (ION studies[23–25]), and GT-4 (SOLAR studies [28,29]).

Adverse reactions. Since Ledipasvir is invariably used withSofosbuvir, it is not possible to figure out the former’s inde-pendent side effects. However, the reported frequency and

severity of adverse reactions with this protocol are much lessthan with Protocol A combinations. They include headacheand fatigue in 15%, nausea in 8% and diarrhea in 5% of

patients. Transient elevation of serum lipase and bilirubinhas also been reported.

Protocol C: Simeprevir (NS3-Olysio) + sofosbuvir (NS5B)-

based protocols

C1: Simeprevir (150 mg) plus sofosbuvir (400 mg) for12 weeks. (FDA approved for GT-1 without

(OPTIMIST-1) [30] or with (OPTIMIST-2) [31]cirrhosis].

C1*: Simeprevir (150 mg) plus half-dose sofosbuvir (200 mg)for 12 weeks (in GT-1 infection with renal insufficiency

[32]).C2: Simeprevir (150 mg) plus sofosbuvir (400 mg) plus

weight-based RBV (1000 mg [<75 kg] to 1200 mg

[>75 kg]) for 12 weeks in GT-1 (COSMOS Study [33]).C4: Simeprevir (150 mg) plus weight-based RBV (1000 mg

[<75 kg] to 1200 mg [>75 kg]) plus peg-interferon for

12 weeks (FDA approved for GT-1).

Adverse reactions. Much of the side effects of this protocol are

attributed to Sofosbuvir rather than Simeprevir. Fatigue,headache and nausea occur in 20–25% of patients, insomnia,diarrhea and muscle pains in about 15%, and dyspnea andpruritus in 10%. Transient hyperbilirubinemia has been

reported in a minority.

Protocol D: Daclatasvir (NS5A-Daklinza, Clatazev)-based

protocols

D1: Daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks[Study AI444040 for GT-1,2,3; FDA-approved for GT-3][34].

D2: Daclatasvir (60 mg) plus sofosbuvir (400 mg) plus weight-based RBV for 12 weeks [European Multicenter Compas-sionate Use Program [35] for Genotypes 1,2,3,4].

D3: Daclatasvir (60 mg) plus sofosbuvir (400 mg) plus fixeddose RBV (600 mg) for 12 weeks (ALLY-I trial [36]).

D4: Daclatasvir (60 mg) plus weight-based RBV plus Inter-

feron for 24 weeks [COMMAND-4 Study in GT-4 [37]).

Adverse reactions. Daclatasvir is well tolerated, even in combi-nation with Sofosbuvir. Fatigue and headache occur in less

than 15%, and nausea and diarrhea in less than 10% of cases.Transient increase in serum lipase has been reported.

Protocol E: Paritaprevir (NS3)/ritonavir (CYP450 inhibitor)+ ombitasvir (NS5A)-based protocols

E1: Paritaprevir (NS3)/ritonavir (CY450), ombitasvir (NS5A)(AbbVie 2D, Viekerax, Technivie, Qurevo)] (PEARL-1

study [38], FDA approved for GT-4 with cirrhosis).E1*: Paritaprevir (NS3)/ritonavir (CY450), ombitasvir

(NS5A) and dasabuvir (NS5B-Exviera) (AbbVie 3D,

Viekera Pack) (FDA approved for GT-1).

Table 5 Selected DAA treatment protocols for HCV-extrahepatic manifestations. Refer to text for protocol codes and citations of

RCTs and guideline recommendations. eGFR = estimated glomerular filtration rate; RBV = Ribavirin; CyA = Cyclosporin-A;

TAC= Tacrolimus; SIR = Sirolimus; EVE = Everolimus.

eGFR [1]

>30ml/min/1.73sqm <30ml/min/1.73sqm

Na�ve Kidneys Transplanted

On Conserva�ve Rx or Dialysis Transplanted

No Cirrhosis

Compensated Cirrhosis [2]

Decompensated Cirrhosis [3]

No Cirrhosis

Compensated Cirrhosis [2]

Decompensated Cirrhosis [3]

Selected Protocol E2:Paritaprevir (150 mg)/ritonavir (100 mg) and ombitasvir (25mg) (Querevo)*+ Ribavirin

B2: Ledipasvir 90mg+ Sofosbuvir 400mg (Harvoni)+ Ribavirin

E2: Paritaprevir (150 mg)/ritonavir (100 mg) and ombitasvir (25mg) (Querevo*)+ Ribavirin

D3: Daclatasvir 60mg (Daklinza)+ Sofodbuvir (Sovaldi) 400mg + Ribavirin

D3: Daclatasvir (Daklinza) 60mg + Sofodbuvir(Sovaldi) 400mg + Ribavirin

Basis of recommenda�on

PEARL-I (GT-4); AASLD-I-LB

SOLAR-2 (GT-4); AASLD-I-LB; EASL A1

RUBY-I (GT-1); AASLD-Iib-LB; EASL A1

ALLY-1 (GT-I) ; AASLD-I-LB; EASL A1

ALLY-1 (GT-I) ; AASLD-I-LB; EASL A1

Alterna�ve Protocol 1

B2: Ledipasvir90mg+ Sofosbuvir 400mg (Harvoni)+ Ribavirin

D3:Daclatasvir (Daklinza)60mg+ Sofodbuvir (Sovaldi)400mg + Ribavirin

C1*: Simeprevir (Olysio)150mg+ Sofosbuvir (Sovaldi) 200mg without Ribavirin

E2: Paritaprevir (150 mg)/ritonavir (100 mg) and ombitasvir (25mg) (Querevo)* + Ribavirin

Basis of recommenda�on

SYNERGY (GT-4); ION-

1 (GT-1); AASLD IIb-

LB

ALLY-1 (GT-1); AASLD-I-

LB;EASL A1 Ram et al (Ref 32) CORAL-1 (GT-1); AASLD-I-LB

Alterna�ve Protocol 2

C2: Simeprevir (Olysio)150mg+ Sofosbuvir (Sovaldi) 400mg + Ribavirin in the presence of cirrhosis

Basis of recommenda�on

COSMOS (GT1); EASL B2

EASL B2

Ribavirin dose [4]

Protocols B,C,E 2: Body weight-based 1000 mg [<75 kg] or 1200 mg [>75 kg] daily; Protocol D3: Daily fixed dose 600mg

200 mg daily to be reduced if not tolerated to 200mg 3 �mes weekly. If on dialysis, 200mg 4

hours before dialysis 3 �mes weekly

200 mg daily to be reduced if not tolerated to 200mg 3 �mes weekly. If on dialysis, 200mg 4

hours before dialysis 3 �mes weekly

Treatment dura�on with RBV

12 weeks 12 weeks 12 weeks

Treatment dura�on without RBV

12 weeks OR 24 weeks in the presence of cirrhosis

24 weeks 12 weeks

24 weeks 12 weeks 24 weeks

Remarks

(*) For GT-4 only. Add Dasabuvir 250mg b.i.d. for GT-1

Modify doses of CyA, TAC, SIR, EVE according to desired blood levels

(*) For GT-4 only. Add Dasabuvir 250mg b.i.d. for GT-1

Reduce doses of CyA, TAC, SIR, EVE accordingto desired blood levels

Use cau�onwith Protocol

E [5]

AvoidProtocol E

Use cau�onwith Protocol E [5]

AvoidProtocol E

1 Estimated by MDRD(4) equation.2 >F3 by Fibroscan or equivalent chemical model.3 Child Pugh score Class B-7 or higher.4 Withdraw if not tolerated or hemoglobin level drops by 2 g/dl despite Erythropoietin treatment.5 Use only by a transplant expert.

Antiviral treatment prioritization in HCV-infected patients 397

398 H. El-Fishawy et al.

E2: Fixed-dose combination of paritaprevir (150 mg)/ritonavir(100 mg) and ombitasvir (25 mg) (Viekerax, Technivie,Qurevo) and weight-based ribavirin (1000 mg [<75 kg]

to 1200 mg [>75 kg]) for 12 weeks (PEARL-1 Study[38], FDA approved for GT-4 without cirrhosis or hepato-cellular failure).

E2*: Fixed-dose combination of paritaprevir (NS3)/ritonavir(CY450), ombitasvir (NS5A) and dasabuvir (NS5B-Exviera) (AbbVie 3D, Viekera Pack) and weight-based

Ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) for12 weeks (CORAL-I trial post-transplant [39]).

E3*: Fixed-dose combination of paritaprevir (NS3)/ritonavir(CY450), ombitasvir (NS5A) and dasabuvir (NS5B-

Exviera) (AbbVie 3D, Viekera Pack) and ribavirin inadjusted doses for renal insufficiency (RUBY-I trial inGT-1 [40]).

Adverse reactions. This protocol is well tolerated. One-third ofpatients complain of fatigue, up to asthenia in half of them.

Less common side effects include skin reactions, myalgias,nausea and insomnia. Hyperbilirubinemia with >5 fold-elevation of hepatic transaminases occurs in 1% of cases, yet

up to 25% in women receiving estrogen therapy. While thisis usually transient, progression to severe hepatic failure hasbeen reported in patients with advanced cirrhosis, which war-ranted a relevant FDA warning.

Ribavirin adverse reactions. Since many protocols includeRibavirin, its significant side effects may be superadded to

those of the individual protocols. Ribavirin administration,by its own right, is associated with fatigue in about two-thirds of cases, headache in one half and insomnia, irritability,

fever, nausea and dermatitis in one-third. Less common sideeffects include arthralgias and myalgias, dizziness, diarrheaand shortness of breath. Owing to its retention in patients with

impaired kidney function, many of these side effects are aug-mented, in addition to the development of Coombs negativehemolytic anemia that can be very severe in CKD StagesIV–V.

Re-treatment protocols

XIII. We recommend re-treatment of patients that do not

achieve a SVR or recur after treatment. The choice of re-treatment protocol depends on the failed initial protocol asfollows:

� Those with failed Interferon + Ribavirin protocol shouldbe treated according to the same recommendations fortreatment-naıve patients (AASDL-IIa, L-B; EASL-A1).

� Patients with failed second-wave DAAs and that have nourgent indication for retreatment, may wait until more reli-able data are obtained by randomized clinical trials (EASL-

A1).� Those who are indicated for treatment may use a differentprotocol that includes ribavirin, for 12 weeks. This may

be extended to 24 weeks if the liver pathology is moreadvanced (F4) or the platelet count persists below 75,000/cmm, which is a predictor of poor response (EASL-B1).

The following successful re-treatment protocols have beenreported in small clinical trials:

� Protocol C2 for failure with any of Protocols B or D.

� Protocol B2 or D2 for failure with any Protocol C.� Protocol B2, C2 or D2 for failure with any Protocol E.

Viral co-infection

XIV. Patients with viral co-infection should be granted high

priority for treatment, regardless of the stage of liver disease,

owing to the rapidly progressive organ damage and potentialof infectivity to the community [AASLD-IDSA-I, LB].

HBV co-infection

Patients should be treated with the same protocols as HCVmono-infected patients (Protocol-B1) [AASLD-IDSA-IIa-LC]. If HBV replicates at a significant rate, concurrent HBV

nucleoside/nucleotide analogue therapy is indicated [41](Protocol-B1) (EASL-2015).

HIV co-infection

Patients co-infected with HCV and HIV have higher HCV-RNA levels, higher rate of HCV persistence and faster progres-sion to cirrhosis and end stage liver disease. The same IFN-free

HCV treatment recommendations for HIV/HCV co-infectedpersons as for those with HCV-only infection, as the virologi-cal results of therapy are identical [42]. However diligence is

due for potential drug–drug interactions with HIV medications(EASL-A1) and (I-B, AASLD-IDSA-2015).

Drug–drug interactions

XV. We suggest using an automated drug compatibility checker

for identifying potential drug–drug interactions in between theselected DAA protocol and contemporary medications for co-

morbid conditions [Opinion].Historically, the interaction in between sofosbuvir and

amiodarone was the earliest life threatening complication, hall-

marked by bradycardia and cardiac arrest. Interaction wassubsequently reported in between DAAs and amlodipine, betablockers, psychoactive drugs, proton pump inhibitors,

substrates or for Cytochrome P450 and P-glycoprotein andmany others [43]. Adverse reactions to other drugs areupdated, by law, in different online databases as well as

drug inserts. As mentioned earlier, we recommend checkingfor such interactions through an automated resource, in orderto keep pace with the rapid expansion of information in thisarea.

Discussion

Extrahepatic manifestations of HCV infection constitute a

broad spectrum of multisystem involvement due to a combina-tion of cytotoxic and immunologically-mediated injury. Thelatter may be propagated by autoimmune mechanisms, which

may not be cured by merely eradicating the infection. We havelimited our prioritization to conditions that have proved byevidence to respond to HCV treatment. This does not deny

potential benefit in many other extrahepatic manifestations,whether the infection is causal or associated, yet they need evi-dence to claim priority.

Antiviral treatment prioritization in HCV-infected patients 399

Owing to the complexity of extrahepatic manifestations,and the frequency of associated renal damage, we opted toprovide multiple choices for different clinical settings (Table 5),

which provides room for enlightened individualization oftreatment on case-to-case basis.

Liver disease

Many clinical trials have shaped the preferred protocolsaccording to three levels of structural and functional liver

damage, namely chronic liver disease without cirrhosis, thatwith cirrhosis, and decompensated cirrhosis. All protocolsincluded in our recommendations achieve a SVR12 over

90% following 12-week treatment in patients without cirrhosis.While most protocols include ribavirin, they can still be usedwithout it for a price of slightly reduced SVR12 and higherpossibility of recurrence.

The presence of cirrhosis calls for obligatory inclusion ofribavirin to improve efficacy of the 12-week protocols andreduce the chance of NS protein mutation. Treatment may

be extended to 24 weeks if the parameters of response areunsatisfactory. Fortunately some ribavirin-free protocols arestill effective when used for 24 weeks in ribavirin-intolerant

patients (Table 5).Decompensated cirrhosis constitutes a significant challenge,

since most patients are ribavirin-intolerant, and many wouldfurther decompensate with the initiation of treatment. Of our

selected protocols, daclatasvir offers a significant step forwardwhen combined with sofosbuvir even without ribavirin (Proto-col D – Table 5). By way of contrast, Protocol E is contraindi-

cated owing to the risk of hepatic failure or death, according toa recent FDA warning.

Kidney disease

Since most DAAs are metabolized by the Cytochrome P450 inthe liver and intestinal wall, the kidney has a minimal role in

their excretion, ranging from 1% to 13%. So, even moderatedegrees of renal insufficiency do not require modification ofprotocol priorities or drug doses. This is in sharp contrast toolder treatment protocols including interferon and ribavirin.

Both are mainly metabolized in the kidneys, which are respon-sible for elimination of 90% [44] and 61% [45] respectively ofadministered single doses, hence the need for caution if the

eGFR is less than 50% of normal.Severe impairment of kidney function, defined as

eGFR < 30 ml/min/1.73 sqm (CKD stages IV and V) consti-

tutes a barrier to using Interferon or ribavirin, as well as a sig-nificant constraint to using several DAAs, which tend to buildup significantly high blood levels along the course of treat-

ment. Sofosbuvir-containing regimens were reported in theHCV-TARGET study [8] to impair kidney function in 5 of17 (29%) patients with eGFR < 30 ml/min/1.73 sqm and 6of 56 (11%) of those with eGFR 30–45 ml/min/1.73 sqm.

The manufacturer of Harvoni (Protocol B) explicitly doesnot recommend using it with severe renal impairment due tolack of data [46]. Despite favorable pharmacokinetics, there

are no RCTs on daclatasvir in this subset of patients. On theother hand, the sofosbuvir-free protocol E, with or without asmall dose of ribavirin, has been FDA approved for patients

with severe renal impairment, on the basis of the RUBY-1

trial. Although the latter included only patients with GT-1infection, it proves the concept of safety with very low eGFR.The earlier proof of efficacy in GT-4, provided in the PEARL-

1 trial makes Protocol E most appropriate for Egyptianpatients with eGFR < 30 ml/min/1.73 sqm. It is importantto note the genotype constraint on using this protocol, where

dasabuvir is included only for GT-1. This imposes the necessityof genotyping prior to embarking on a Viekera familyprotocol.

While the drug pharmacokinetics in severe renal impair-ment apply to those on regular dialysis, the latter adds con-founding factors including drug dialyzability and unstableinternal environment. Dialyzability is the complex outcome

of the drug’s molecular size, configuration and charge, andthe extent of its protein binding. Differences in these factorsin between DAAs make it difficult to predict the pharmacoki-

netic skewing imposed by dialysis, which reflects on efficacy aswell as safety. Unfortunately very few pharmacokinetic studiesand even fewer clinical observations have been made in the

dialysis population. Yet, on the basis of available data, themost appropriate for hemodialysis patients seems to be Proto-col E, achieving 100% SVR12 in the RUBY-1 trial. Slightly

inferior results (10/13) have been reported in a small numberof patients receiving full dose simeprevir with either daily halfdose or alternate day full dose sofosbuvir (Protocol C1*) [32].

Kidney transplant recipients

The pharmacokinetics of antiviral agents in kidney transplantrecipients are influenced by two factors: graft function and

drug–drug interactions.The impact of graft function is the same as that of native

kidneys. So, recipients in stages I–III CKD can be treated

according to the general recommendations, with due consider-ation only to drug–drug interactions. In those with moreadvanced graft dysfunction, the recommendations for severe

renal impairment apply.Drug–drug interactions impose a lot of noise in choosing

protocols for transplant recipients. Since four of the mainimmunosuppressive drugs used in transplantation, namely

cyclosporine, tacrolimus, sirolimus and everolimus are metab-olized by Cytochrome P450 (CYP450), as most DAAs do, sub-strate competition is expected to play a significant role in the

metabolism of both. There is considerable variation in thistype of interaction. For example, the interaction in betweenCyclosporine and simeprevir is so clinically relevant that it is

recommended to avoid this combination all together (EASL-B1). On the other hand, simeprevir may be used concomitantlywith Tacrolimus or Sirolimus, yet with frequent monitoring oftheir blood levels. No dose adjustment is required for tacroli-

mus or cyclosporine with Sofosbuvir plus ribavirin, ledipasviror daclatasvir (EASL-A2).

The CYP450 interaction becomes even more relevant when

the enzyme is inhibited, leading to accumulation of bothimmunosuppressive and antiviral drugs. The list of CYP450inhibitors is immense, which constitutes the main challenge

in the selection of treatment protocol, as well as in monitoringtherapy. Of particular importance is ritonavir, included in Eprotocols with the specific objective of protecting paritaprevir

by inhibiting CYP450. By essence of this effect, Protocol Edrugs are bound to augment the blood levels of the mentioned

400 H. El-Fishawy et al.

immunosuppressive agents, which requires avoiding the use ofmTOR inhibitors all-together, dramatic dose reduction ofTacrolimus to 0.5 mg weekly and Cyclosporine to one-fifth

its dose before initiating HCV treatment (EASL-A2).Clinical data obtained from liver transplants have shown

excellent results with B and D protocols, hence their

prioritization in this guideline. No dose adjustment is requiredfor tacrolimus or cyclosporine with either protocol (EASL-A2).

While pre-transplant HCV eradication was highly desirablein the interferon era, owing to the risk of graft loss if the dugwas administered after transplantation, this policy becamequestionable with the availability of safe DAAs. This provides

considerable relief if transplantation becomes an urgent neces-sity, including that from deceased donors. However, when itcan wait, we strongly recommend treating patients on the wait-

ing list to avoid the HCV-associated many-fold increased riskof thrombotic microangiopathy and acute transplant glomeru-lopathy in the early post-transplant period. Since pre-

transplant patients are essentially in severe renal failure, oftenalready on dialysis, respective recommendations in protocolselection and drug doses apply.

Non-renal extrahepatic manifestations

There is no evidence that any of the currently available DAAsis preferred specifically for the treatment of extrahepatic man-

ifestations of HCV infection. The choice of a treatment proto-col should follow the same recommendations based on thestages of liver and kidney disease. However, the integration

of antiviral treatment within the overall management strategyin individual conditions warrants due consideration in themanagement of cryoglobulinemia.

Cryoglobulinemia

Circulating cryoglobulins are frequently detected in patientswith chronic HCV infection, but the clinical syndrome of

Cryoglobulinemic Vasculitis as defined in the AASLD Classi-fication [20] occurs only in 1–2.5% [47] of patients. It is thissubgroup that requires treatment before receiving DAAs.

Patients with asymptomatic cryoglobulinemia, and those withmild manifestations as arthralgia, fatigue or purpuric skineruptions (Meltzer triad) may be treated according to the gen-eral recommendations as described above.

Patients with minor intermittent inflammatory signs, suchas arthritis, without major organ involvement rapidly respondto low-dose steroids, without undue delay in starting antiviral

treatment. It is noteworthy that HCV-associated peripheralarthritis can also occur without cryoglobulinemia. Whileresponse of this form to interferon-based treatment is conflict-

ing [48], the effect of virological cure by DAAs has not beenspecifically addressed in any randomized trials.

On the other hand, in those with significant organ involve-

ment as the heart, brain or kidneys, induction treatment isindicated with intravenous pulses of methyl prednisolone(10–15 mg/kg/dose for 3–5 consecutive days) followed by IVCyclophosphamide (10 mg/kg). Maintenance immunosuppres-

sion is required following successful induction [49].Alternatively, Rituximab may be used to eliminate the

active B-lymphocyte clone producing the cryoglobulins. We

recommend a weekly dose of 375 mg/m2 for four doses. The

same monoclonal antibody may be used for maintenance ofremission in a fixed dose of 200–500 mg every 6–9 months [50].

Therapeutic plasma exchange (TPE) may be needed to

induce remission in patients with more fulminant or catas-trophic cryoglobulinemic vasculitis [51]. Double-filtrationplasmapheresis is preferable, where available, for the selective

removal of pathogenic immunoglobulins while preservingother, essential components [52]. Maintenance immunosup-pression remains essential following this induction course.

Antiviral treatment may be initiated upon induction of ini-tial remission of the manifestations of cryoglobulinemic vas-culitis. Interferon is not preferable since it may exacerbatedisease activity, and the virological response rate is modest

[53]. DAAs may be used according to the general recommen-dations based on liver and kidney staging. Unfortunately,there are no published data on the outcome of such treatment

in cryoglobulinemia. An Egyptian study is underway to answerthis question in GT-4, including SVR-12 in the face ofimmunosuppressive therapy and the potential of recurrence

of cryoglobulinemia (Egyptian STDF, protocol 15083).

Malignant lymphomas

There is convincing evidence that chronic HCV infection is

causally related to B-Cell Non-Hodgkin lymphoma. Severalreports have shown regression of the lymphoma upon success-ful viral elimination, which justifies our recommendation to

prioritize treatment of this condition despite the lack of RCTs.We also suggest treatment of other lymphomas on the basisstatistical evidence of their reduced incidence after interferon

treatment [15] or case reports of clinical regression [14].

Other extrahepatic manifestations

Despite the evidence of a causal role of HCV in the pathogen-

esis of other extrahepatic manifestations (as outlined in Section ‘Indications for treatment’ above), there is no hard evidenceof their regression following HCV elimination. Accordingly,the strength of treatment recommendation in these conditions

remains meager, stopping short at the level of ‘‘suggestion”whether in this set of guidelines, or in other internationalguidelines as the EASL or AASLD.

Conclusions

Recognizing the clinical and epidemiological impact of extra-

hepatic manifestations of HCV infection, independently fromthe extent of liver injury, we identified 7 compelling and 10indications for antiviral treatment. The former include HCV-

associated and certain other glomerulopathies, dialysis andpre- and post-renal transplantation, cryoglobulinemic vasculi-tis and Non-Hodgkin’s lymphoma. We reviewed different

treatment protocols based on the available DAAs in Egypt,encoded and prioritized their use according to specific criteriato optimize their benefit. We concluded that any of the men-tioned protocols can be effectively and safely used for 12-

week treatment in all patients with extrahepatic manifestationswithout cirrhosis and with eGFR above 30 ml/min/1.73 sqm.Ledipasvir–Sofosbuvir or Simeprevir–sofosbuvir protocols

are readily available in the country and lead to impressivelyhigh SVR12. Patients with compensated cirrhosis usuallyrespond to a ribavirin-containing protocol, and yet they may

need to extend the duration of treatment to 24 weeks.

Antiviral treatment prioritization in HCV-infected patients 401

Daclatasvir-based protocols are recommended for those withdecompensated cirrhosis, while the paritaprevir/ritonavir+ ombitasvir ± Dasabuvir protocol (Viekera family) is con-

traindicated. The choices are much more limited in patientswith eGFR < 30 ml/min/1.73 sqm, including those on dialy-sis, where the Viekera family protocols are currently the most

suitable. In transplanted patents, caution is due to avoidanceof the pharmacokinetic interaction with the Cytochrome-P450 enzyme system, in-between immunosuppressive agents

and most DAAs, particularly the Viekera family. Factors thatmodify the choice of DAAs include previous treatment failure,co-infection with other viruses, and the concomitant adminis-tration of other medications for comorbid conditions. Patients

with significant immune-mediated injury as cryoglobulinemicvasculitis may need concomitant treatment with immunosup-pressive agents.

Funding

The authors have volunteered to produce this set of recom-

mendations. The office work was offered for free by the lastauthor. No additional funding was needed.

Conflict of Interest

The authors have declared no conflict of interest.

Compliance with Ethics Requirements

This article does not contain any studies with human or animal

subjects.

References

[1] van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF,

Lammert F, et al. Association between sustained virological

response and all-cause mortality among patients with chronic

hepatitis C and advanced hepatic fibrosis. JAMA 2012;308

(24):2584–93.

[2] Cuadros DF, Branscum AJ, Miller FD, Abu-Raddad LJ.

Spatial epidemiology of hepatitis C virus infection in Egypt:

analyses and implications. Hepatology 2014;60:1150–9.

[3] Gower E, Estes C, Blach S, Razavi-Shearer K, Razavi HGJ.

Global epidemiology and genotype distribution of the hepatitis

C virus infection. J Hepatol 2014;61(1 Suppl.):S45–57.

[4] Kamal SM, Nasser IA. Hepatitis C Genotype 4: what we know

and what we don’t yet know. Hepatology 2008;47:1371–83.

[5] AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance:

AASLD-IDSA recommendations for testing, managing, and

treating adults infected with hepatitis C virus. Hepatology

2015;62:932–54.

[6] European Association for the Study of the Liver. (EASL)

recommendations on treatment of hepatitis C 2015. J Hepatol

2015;63(1):199–236.

[7] KDIGO. Clinical practice guidelines for the prevention,

diagnosis, evaluation, and treatment of hepatitis C in chronic

kidney disease. Kidney Int 2008(Suppl. 109):S1–S99.

[8] Hepatitis C therapeutic registry and research network (HCV-

TARGET). <http://www.hcvtarget.org/> [accessed 15th Sep

2015].

[9] Øvrehus ALH, Blach S, Christensen PB, Gerstoft J, Weis N,

Krarup H, et al. P0714: impact of prioritizing treatment in a

high resource setting-minimizing the burden of HCV related

disease in 15 years. J Hepatol 2015;62:S591–2.

[10] Fadem SZ. MDRD GFR calculator. <http://nephron.org/

mdrd_gfr_si> [accessed 10th Feb 2016].

[11] (No authors listed). eGFR using CKD-EPI. <https://

qxmd.com/calculate/egfr-using-ckd-epi> [accessed 10th Feb

2016].

[12] Arcaini L, Vallisa D, Rattotti S, et al. Antiviral treatment in

patients with indolent B-cell lymphomas associated with HCV

infection: a study of the Fondazione Italiana Linfomi. Ann

Oncol 2014;25(7):1404–10.

[13] Gisbert JP, Garcıa-Buey L, Pajares JM, Moreno-Otero R.

Prevalence of hepatitis C virus infection in porphyria

cutaneatarda: systematic review and meta-analysis. J Hepatol

2003;39(4):620.

[14] Takahashi K, Nishida N, Kawabata H, Haga H, Chiba T.

Regression of Hodgkin lymphoma in response to antiviral

therapy for hepatitis C virus infection. Intern Med 2012;51

(19):2745–7.

[15] Kawamura Y, Ikeda K, Arase Y, Yatsuji H, Sezaki H, Hosaka

T, et al. Viral elimination reduces incidence of malignant

lymphoma in patients with hepatitis C. Am J Med 2007;120

(12):1034–41.

[16] Sayiner ZA, Haque U, Malik MU, Gurakar A. Hepatitis C virus

infection and its rheumatologic implications. Gastroenterol

Hepatol (NY) 2014;10(5):287–93.

[17] Chiao EY, Engels EA, Kramer JR, Pietz K, Henderson L,

Giordano TP, Landgren O. Risk of immune thrombocytopenic

purpura and autoimmune hemolytic anemia among 120 908 US

veterans with hepatitis C virus infection. Arch Intern Med

2009;169(4):357–63.

[18] Carrozzo M, Scally K. Oral manifestations of hepatitis C virus

infection. World J Gastroenterol 2014;20:7534–43.

[19] Baccaglini L, Thongprasom K, Carrozzo M, Bigby M. Urban

legends series: lichen planus. Oral Dis 2013;19:128–43.

[20] Quartuccio L, Isola M, Corazza L, Ramos-Casals M, Retamozo

S, Ragab GM, et al. Validation of the AASLD-classification

criteria for cryoglobulinaemic vasculitis. Rheumatology

(Oxford) 2014;53(12):2209–13.

[21] Doss W, Shiha G, Hassany M, Soliman R, Fouad R, Khairy M,

et al. Sofosbuvir plus ribavirin for treating Egyptian patients

with hepatitis C genotype 4. J Hepatol 2015;63(3):581–5.

[22] Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M,

Hassanein T, Gordon SC, et al. Sofosbuvir for previously

untreated chronic hepatitis C infection. N Engl J Med

2013;368:1878–87.

[23] Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M,

et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1

infection. N Engl J Med 2014;370:1889–98.

[24] Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff

E, et al. Ledipasvir and sofosbuvir for previously treated HCV

genotype 1 infection. N Engl J Med 2014;370:1483–93.

[25] Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein

DE, Lawitz E, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks

for chronic HCV without cirrhosis. N Engl J Med

2014;370:1879–88.

[26] Abergel A, Loustaud-Ratti V, Metivier S, Jiang D, Kersey K,

Knox SJ, et al. High SVR12 in ledipasvir/sofosbuvir treatment

in patients with chronic genotype 4 and 5 HCV infection. J

Hepatol 2015;S2:S219–20.

[27] Kohli A, Kapoor R, Sims Z, Nelson A, Sidharthan S, Lam B,

et al. Ledipasvir and sofosbuvir for hepatitis C genotype 4: a

proof of concept phase 2a cohort study (NIAID SYNERGY

(Genotype 4). Lancet Infect Dis 2015;15(9):1049–54.

[28] Charlton M, Everson GT, Flamm SL, Kumar P, Landis C,

Brown Jr RS, et al. Ledipasvir and sofosbuvir plus ribavirin for

treatment of HCV infection in patients with advanced liver

disease. Gastroenterology 2015;149:649–59.

402 H. El-Fishawy et al.

[29] Manns M, Forns X, Samuel D, Denning J, Arterburn S, Brandt-

Sarif T, et al. G02: ledipasvir/sofosbuvir with ribavirin is safe

and efficacious in decompensated and post liver transplantation

patients with HCV infection: preliminary results of the

prospective solar 2 trial. J Hepatol 2015;62:S187–8.

[30] Kwo P, Gitlin N, Nahass R, Bernstein D, Rojter S, Schiff E,

et al. A phase 3, randomised, open-label study to evaluate the

efficacy and safety of 12 and 8 weeks of simeprevir (SMV) plus

sofosbuvir (SOF) in treatment-naıve and-experienced patients

with chronic HCV genotype 1 infection without cirrhosis:

OPTIMIST-1. J Hepatol 2015;62(Suppl. 2):S270.

[31] Lawitz E, Matusow G, DeJesus E, Yoshida E, Felizarta F,

Ghalib R, et al. LP04: a phase 3, open-label, single-arm study to

evaluate the efficacy and safety of 12 weeks of simeprevir (SMV)

plus sofosbuvir (SOF) in treatment-naıve or-experienced

patients with chronic HCV genotype 1 infection and cirrhosis:

Optimist-2. J Hepatol 2015;62:S264–5, 39.

[32] Ram BK, Frank C, Adam P, Cynthia L, Maria H, Lennox J,

David R, et al. Efficacy and tolerability of half-dose sofosbuvir

plus simeprevir in management of hepatitis C in patients with

end-stage renal disease. J Hepatol 2015;63:763–73.

[33] Lawitz E, Sulkowski MS, Ghalib R, Rodriguez-Torres M,

Younossi ZM, Corregidor A, et al. Simeprevir plus sofosbuvir,

with or without ribavirin, to treat chronic infection with

hepatitis C virus genotype 1 in non-responders to pegylated

interferon and ribavirin and treatment-naive patients: the

COSMOS randomized study. Lancet 2014;384(9956):1756–65.

[34] Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR,

Hassanein T, Jacobson I, et al. (AI444040 Study Group).

Daclatasvir plus sofosbuvir for previously treated or untreated

chronic HCV infection. N Engl J Med 2014;370(3):211–21.

[35] Welzel TM, Herzer K, Ferenci P, Petersen J, Gschwantler M,

Cornberg M, et al. Daclatasvir plus sofosbuvir with or without

ribavirin for the treatment of HCV in patients with severe liver

disease: interim results of a multicenter compassionate use

program. J Hepatol 2015;62:S619–20.

[36] Poordad F, Schiff ER, Vierling JM, Landis C, Fontana RJ,

Yang R, et al. Daclatasvir, sofosbuvir, and ribavirin

combination for HCV patients with advanced cirrhosis or

posttransplant recurrence: phase 3 ALLY-1 study. J Hepatol

2015;62(Suppl. 2):S261–2.

[37] Hezode C, Alric L, Brown A, Hassanein M, Rizzetto M, Buti M,

et al. Randomized controlled trial of the NS5A inhibitor

daclatasvir plus peginterferon and ribavirin for HCV

genotype-4 (COMMAND-4). Antivir Ther 2015.

[38] Pol S, Reddy KR, Baykal T, Hezode C, Hassanein T, Marcellin

P, et al. Interferon-free regimens of ombitasvir and ABT-450/r

with or without ribavirin in patients with HCV genotype 4

infection: PEARL-I study results. Hepatology 2014;60:1129A.

[39] Kwo PY, Mantry PS, Coakley E, Te HS, Vargas HE, Brown Jr

R, et al. An interferon-free antiviral regimen for HCV after liver

transplantation. N Engl J Med 2014;371(25):2375–82.

[40] Pockros PJ, Reddy KR, Mantry PS, Cohen E, Bennett M,

Sulkowski MS, et al. Safety of ombitasvir/paritaprevir/ritonavir

plus dasabuvir for treating HCV GT-1 infection in patients with

severe renal impairment or end-stage renal disease: the RUBY-1

study. In: 50th Annual meeting of the European association for

the study of the liver (EASL), Vienna, Austriam, vol. S257;

2015. p. 22–6.

[41] Potthoff A, Berg T, Wedemeyer H. Late hepatitis B virus relapse

in patients co-infected with hepatitis B virus and hepatitis C

virus after antiviral treatment with pegylated interferon-a2b and

ribavirin. Scand J Gastroenterol 2009;44:1487–90.

[42] Molina JM, Orkin C, Iser DM, Zamora FX, Nelson M, Stephan

C, et al. Sofosbuvir plus ribavirin for treatment of hepatitis C

virus in patients co-infected with HIV (PHOTON-2): a

multicentre, open-label, non-randomised, phase 3 study.

Lancet 2015;385:1098–106.

[43] Kiser JJ, Burton Jr JR, Everson GT. Drug–drug interactions

during antiviral therapy for chronic hepatitis C. Nat Rev

Gastroenterol Hepatol 2013;10(10):596–606.

[44] Scott GM. Interferon: pharmacokinetics and toxicity. Philos

Trans Roy Soc Lond B Biol Sci 1982;299(1094):91–107.

[45] University of Liverpool: Ribavirin PK fact sheet. <http://

www.hivdruginteractions.org/data/FactSheetImages/FactSheet_

DrugID_112.pdf> [last accessed 16th October 2015].

[46] Full prescribing information for HARVONI. FDA-approved

patient labeling issued: 2015. Reference ID: 3642283. U.S.

<www.gilead.com>; 2015[Last reviewed on RxList: 4/7/2015].

[47] Mangia A, Clemente R, Musto P, Cascavilla I, La Floresta P,

Sanpaolo G, et al. Hepatitis C virus infection and monoclonal

gammopathies not associated with cryoglobulinemia. Leukemia

1996;10:1209–13.

[48] Khattab MA, Eslam M, Alavian SM. Hepatitis C virus as a

multifaceted disease: a simple and updated approach for

extrahepatic manifestations of hepatitis C virus infection.

Hepatitis Mon 2010;10(4):258–69.

[49] Shahin AA, El-Desouky SM, Zayed HS. A retrospective

analysis of treatment outcomes in patients with hepatitis C

related systemic vasculitis receiving intravenous

methylprednisolone and cyclophosphamide. Clin Rheumatol

2011;30:607–14.

[50] Sansonno D, Dammacco F. Hepatitis C virus,

cryoglobulinaemia, and vasculitis: immune complex relations.

Lancet Infect Dis 2005;5:227–36.

[51] Cacoub P, Terrier B, Saadoun D. Hepatitis C virus-induced

vasculitis: therapeutic options. Ann Rheum Dis 2014;73:24–30.

[52] Ramunni A, Brescia P. Double filtration plasmapheresis: an

effective treatment of cryoglobulinemia. In: Dammacco F,

editor. HCV infection and cryoglobulinemia. New

York: Springer; 2012. p. 337–41.

[53] Dammacco F, Sansonn D. Therapy for hepatitis C virus-related

cryoglobulinemic vasculitis. N Engl J Med 2013;369:1035–45.