Overview of Current Therapy in Hepatitis C

Overview of current therapy in hepatitis C

Dominique Salmon Paris Descartes University, Paris, France ESCMID Study Group for Viral Hepatitis (ESGVH) ESCMIDECCMID, Madrid, eLibrary April 22, 2018 © by author Plan

• Treatment options in 2018 • Overview of the 2018 EASL recommendations • Patients with and without cirrhosis • Drug-drug interactions • Special groups • Except failures to DDA therapy

ESCMID eLibrary © by author Unlike some chronic conditions, HCV infection can be cured

HCV RNA remains in the cytoplasm, while HBV and HIV DNA are incorporated into the nucleus of the cell HBV HIV HCV

Host cell Viral RNA

cccDNA Proviral DNA

Host DNA

Nucleus

TREATMENT TREATMENT TREATMENT Lifelong suppression Lifelong suppression No reservoir of infection  HCV clearance  CURE Soriano V, et al.ESCMID J Antimicrob Chemother 2008;62:1–4 eLibrary cccDNA: covalently closed circular DNA © by author High SVR Rates with DAA in HCV Genotype 1 Treatment-Naïve Patients 1986 1998 2001 2002 2011 2013 2014* 2016

94-99 100 90 1989 80-81 80 HCV identification 68-75

60 54-56

42 39

40 34 SVR Rate Rate (%) SVR

20 16 6 0 IFN IFN IFN+RBV IFN+RBV PEG PEG+RBV PI+PEG SMV+PEG SOF+PEG DAA without 6 mo 12 mo 6 mo 12 mo 12 mo 12 mo +RBV +RBV +RBV IFN 6-12 mo 6-12 mo 3 mo 2-3mo *Year of data presentation at EASL 2014 and publication in NEJM Adapted from Strader DB, et al. Hepatology 2004;39:1147-71. INCIVEK [PI]. Cambridge, MA: Vertex Pharmaceuticals; 2013. VICTRELIS [PI]. Whitehouse Station, NJ: Merck & Co; 2014. Jacobson I, et al. EASL 2013. Amsterdam. The Netherlands. Poster #1425. Manns M, et al. EASL 2013. Amsterdam. The Netherlands. Oral #1413. Lawitz E, et al. APASL 2013. Singapore. ESCMIDOral #LB-02; Afdhal N, et al. N Engl J Med 2014; 370: 1889 -98eLibrary; Kowdley K, et al. N Engl J Med 2014; 370: 1879-88. © by author Targets for direct-acting antivirals (DAAs)

Structural Non-structural

Viral Capsid Envelope Viral Protease Serine Membranous RNA dependent replication shell glycoproteins assembly protease web formation RNA polymerase or assembly

Protease Inhibitors NS5A Inhibitors Polymerase Inhibitors « …previr » « ….asvir » « …..buvir »

Telaprevir Daclatasvir Nucs Non-Nucs Boceprevir Ledipasvir Simeprevir Ombitasvir Sofosbuvir Dasabuvir Paritaprevir Elbasvir Grazoprevir Velpatasvir GS-9669 Voxilaprevir Pibrentasvir Glecaprevir ESCMID eLibraryFeeney ER, Chung RT. BMJ 2014;349:g3308 © by author Approved DAAs (Europe)

2014 2015 2016 2017

Sofosbuvir Sofosbuvir/ Sofosbuvir/ Glecaprevir/ Ledipasvir Velpatasvir Pibrentasvir Pangenotypic Gen 1, 4, 5, 6 Pangenotypic Pangenotypic

Daclatasvir Ombitasvir/ Grazoprevir Sofosbuvir/ Gen 1, 2, 3, 4 Dasabuvir Paritaprevir/r Elbasvir Velpatasvir/ Voxilaprevir Gen 1 Gen 1, 4 Gen 1, 4 Pangenotypic

ESCMIDEASL Recommendations on Treatment of Hepatitis C 2018 eLibrary © by author Cure rate with 1st generation DAAs combinations

100 > 90-95% . Suboptimal for G3, and for decompensated cirrhosis 90

80 . Complex regimen for non 70 specialist prescribers 60 . 8, 12, 24 weeks 50 . +/- RBV 40

SVR12 (%) rate SVR12 30 . Risk of failure in case of baseline polymorphism or 20 acquired RASs 10

0 DAA ESCMID1 st waveeLibrary © by author Advantages and drawbacks of 1st generation DAAs combinations

SOFOSBUVIR/LEDIPASVIR SOFOSBUVIR/DACLATASVIR GRAZOPREVIR/ELBASVIR PARITAPREVIR/DASABUVIR /OMBITASVIR - GT 1-6 : > 95% efficacy - Less efficient for -GT 1- 6 : > 95% -GT 1, 4: > 95% G3 efficacy efficacy -Efficacy > 95% for - 8 weeks (GT1, non -Less efficient for -Not against GT2, GT1b cirrhosis), to12 G3 GT3 -Complex regimen weeks + RBV or 24 -12 or 24 weeks -Useful for severe - Need ribavirin weeks -Interactions renal impairment - CI: bradycardia, CI in renal impairment

ESCMIDMAV—VHC—MED—164—nov17—R—A—DLU déc18 v1 eLibrary © by author DAA combinations of 2nd generation: pangenotypic and panfibrotypic

SOFOSBUVIR/ SOFOSBUVIR/VELPATASVIR VELPATASVIR GLECAPREVIR/ /VOXILAPREVIR PIBRENTASVIR

ESCMIDMAV—VHC—MED—164—nov17—R—A—DLU déc18 v1 eLibrary © by author In vitro activity of second generation NS5A inhibitors

EC50 (pM) of cellular replication

1a 1b 2a 2b 3a 5 pM 4a 5a 6a

Pibrentasvir Ombitasvir Daclatasvir Ledipasvir Elbasvir Velpatasvir Odalasvir

CE50 : Median efficient concentration Ng T, et al. Hepatology 2014; 60(suppl):1142A (poster presentation); Olysio US Prescribing Information (accessed August 2015); AbbVie data on file; McPhee F, et al. Antimicrob Agents Chemother 2012;56:5387–96; Lahser F, et al. Hepatology 2014; 60 (suppl):1168A (poster presentation); Taylor JG, et al. J Hepatol 2015; 62(suppl):S681 (poster presentation). ESCMIDChase R, et al. IVHD 2013: OA25 (oral presentation); eLibrary*Pawlotsky JM et al., Gastroenterology 2016;-:1–17 © by author In vitro activity of second generation NS3 protease inhibitors

EC50 (nM) of cellular replication

1a 1b 2a 3a 4a 5 nM 5a 6a

Glecaprevir Paritaprevir Grazoprevir Simprevir Asunaprevir Voxilaprevir

CE50 : Median efficient concentration

Ng T, et al. Hepatology 2014; 60(suppl):1142A (poster presentation); Cheng G, et al. J Hepatol 2013; 58(Suppl):S484–S485 (poster presentation); Wang C, et al. Antimicrob Agents Chemother 2014; 58:5155–5163; Zhao Y, et al. J Hepatol 2012; 56(Suppl):S330 (poster presentation); Dousson C, et al. J Hepatol 2011; 54(Suppl):S326–S327 (poster presentation). Harvoni US PrescribingMAV —InformationVHC—MED (accessed—164— Augustnov17 2015);—R—A—DLU déc18 v1 ESCMIDLui R, et al. J Hepatol 2012; 56(Suppl):S334–S335 (poster presentation); eLibrary*Pawlotsky JM et al., Gastroenterology 2016;-:1–17 © by author sofosbuvir/velpatasvir, EPCLUSA, Gilead

Sofosbuvir Velpatasvir NS5b NS5A pangenotypic inhibitor pangenotypic inhibitor 2nd generation

EMEA marketing autorisation on July 6, 2016 • One pill for 12 weeks (with or without cirrhosis) • High pangenotypic efficacy • 98 % for genotypes 1, 2, 4, 5 et 6 • 91-95% for genotype 3 • Good tolerance and resistance profile • Low rate of interactions ESCMID eLibrary © by author Sofosbuvir/Velpatasvir ASTRAL-1– Phase III, TN and TE (32%), Gt 1,2,4,5,6, 19% cirrhosis, 12 wks

99% 100% 100% 100% 100 99% 98% 97%

SVR12 (%) rate SVR12 30

10 N=624 N=210 N=118 N=104 N=116 N=35 N=41 0 Overall GT1a GT1b GT2 GT4 GT5 GT6

FeldESCMID et al., N Engl J Med 2015;373:2599-60 eLibrary © by author Sofosbuvir/Velpatasvir ASTRAL-3– Phase III, TN and TE (26%), Gt 3, 30% cirrhosis, 12 weeks

98% 100 91% 93% 90 89%

SVR12 (%) rate SVR12 30

10 N=163 N=34 N=43 N=37 0 Rx-naïve Rx-experienced Rx-naïve Rx-experienced No cirrhosis Cirrhosis ESCMIDFoster et al., N Engl J Med 2015;373:2608-17 eLibrary © by author Sofosbuvir/Velpatasvir ± RBV Randomized trial in patients with cirrhosis

100 96% 91% 2 relapses 5 relapses 80

40 SVR12 (%) SVR12

N=101 N=103 0 SOF/VEL SOF/VEL+RBV 12 weeks 12 weeks ESCMIDButi et al., EASL 2018 eLibrary © by author Sofosbuvir-Velpatasvir (Epclusa) Indications for Usage

Sofosbuvir-Velpatasvir* for HCV Treatment in Patients with Genotype 1-6

Patient Population Treatment Duration

Patients without cirrhosis/ or with compensated cirrhosis (Child-Pugh A) Sofosbuvir-Velpatasvir 12 weeks

Patients with decompensated cirrhosis Sofosbuvir-Velpatasvir + (Child-Pugh B and C) Ribavirin 12 weeks

Not recommended for patients with severe renal impairment (eGFR <30 mL/min/1.73 m2)

ESCMIDSource: Epclusa Prescribing Information, GileadeLibrary Sciences. © by author Glecaprevir/Pibrentasvir, Maviret®, AbbVie

Glecaprevir Pibrentasvir NS3 protease inhibitor NS5A inhibitor

2nd generation 2nd generation

EMEA marketing autorisation on July 26, 2017 Once daily administration (3 pills) for 8 weeks or 12 weeks (cirrhosis)

In vitro1,2 • Pangenotypic activity • High barrier to resistance (active against common NS3 and NS5a polymorphisms)

Pharmacokinetic • Negligible kidney excretion (< 1 %) =>indicated in severe renal disease metabolism • Minimal liver metabolism, biliary excretion, • Interactions++

Maviret co-formulated in 3 pills of 100 mg/40mg once a day 1. Ng TI, et al. Abstract 636. CROI, 2014. 2. Ng TI, et al. Abstract 639. CROI, 2014. ESCMIDGlecaprevir developed by AbbVie and Enanta. eLibrary3. Pawlotsky, Gastroenterology 2016;-:1– 17 4. EPAR Maviret © by author Glecaprevir/Pibrentasvir 8 weeks in patients without cirrhosis

99% 100 97% 95% 97% 1 breakthrough 2 relapses 5 relapses 90 1 VBT 80

SVR12 (%) rate SVR12 30

10 N=351 N=142 N=157 N=203 0 SURVEYOR-2 ENDURANCE-1 ENDURANCE 2/ ENDURANCE-3 GT4, 5, 6, TN/TE GT1, TN/TE SURVEYOR-2 GT3, TN GT2, TN/TE ESCMIDZeuzem et al., N Engl J Med 2018;378:354-69; Kwo et al.,eLibrary J Hepatol 2017;67:263-71 © by author Glecaprevir/Pibrentasvir 12 weeks in patients with compensated cirrhosis EXPEDITION-1– Phase III, GT1-2-4-5-6, Compensated cirrhosis, 12 weeks

99% 99% 100% 100% 100% 100% 100 1 relapse 1 relapse 90

SVR12 SVR12 (%) rate 30

10 N=146 N=90 N=31 N=16 N=2 N=7 0 All GT1 GT2 GT4 GT5 GT6 ESCMIDForns et al., Lancet Infect Dis 2017;17:1062-8 eLibrary © by author Glecaprevir/Pibrentasvir Integrated analysis in GT3 patients with severe fibrosis/cirrhosis

100% 100 94% 3 virological failures 80

40 SVR12 (%) SVR12

N=63 N=51 0 Rx-naïve Rx-exped 12 weeks 16 weeks ESCMIDKrishnan et al., EASL 2017 eLibrary © by author Glecaprevir/pibentasvir- Maviret® - Duration of therapy

No cirrhosis Cirrhosis

All genotypes 8 weeks 12 weeks Naive or pre treated * ∆16 weeks for G3 pretreated *

Not recommended in case of decompensated cirrhosis

*failure of a previous treatment based peg-IFN + ribavirine +/- sofosbuvir or by sofosbuvir + ribavirine ESCMIDMAV—VHC—MED—164—nov17—R—A—DLU déc18eLibrary v1 © by author Sofosbuvir/velpatasvir/voxilaprevir, VOSEVI

SOFOSBUVIR NS5b inhibitor VOXILAPREVIR NS3 inhibitor Patients naïfs d’AAD VELPATASVIR NS5a inhibitor POLARIS-2 POLARIS-3 n = 941 n = 219 Patients naive of DAA Cirrhose

n = 941 n = 219 G 1 2 3 4 5 6 G 1 2 3 4 5 6 POLARIS-2 POLARIS-3

Cirrhosis 8 semaines 95 % 8 semaines 96 %

G 1 2 3 4 5 6 G 3 5 6 12 semaines 98 % 12 semaines 96 %

SVR12 8 weeks 95% 8 weeks 96 % 12 weeks 98% 12 weeks 96% ESCMID eLibraryBourlière M, Marseille, AASLD 2016, Abs. 194 ; Zeuzem S, Allemagne, AASLD 2016, Abs. 109 updated © by author SOF/VEL/VOX for 8 wks in DAA-Naïve Patients POLARIS-2 and 3, Rx-naïve and –IFN experienced (32%)

98 100 100 100 95 97 97 94 93 92 94

SVR12,(%) 40

583 217 155 61 61 197 59 17 30 2 611 233 169 63 63 202 63 18 30 2 0 Total GT 1 GT 1a GT 1b GT 2 GT 3 GT 4 GT 5 GT 6 Other Total 97% SVR (427/441) in DAA-naïve GT 1b, 2–6 patients treated with SOF/VEL/VOX for 8 weeks. Lower SVR in patients with HCV GT 1a infection. ESCMIDRoberts, EASL 2017, SAT-280 eLibrary © by author Best options for patients with GT3 HCV infection without or with cirrhosis

SVR12 rate 102%

100% 100% 98% 99% 98% 96% 97% 97% 96% 94% 95% 94% 94% 92% 93%

90%

88% 89%

86%

84%

82% SOF/VEL SOF/Velpa/RBV SOF/DCV+/-RBV GLE/PIB SOF/VEL/VOX Non cirrhosis Cirrhosis Cirrhosis pretreated Sof/Vel: Foster ESCMIDGR. N Engl J Med 2015: 373: 2608-17 G/P: Foster G, et al. J Hepatol eLibrary2017, Wyles, Hepatology 2016; Puoti 2018. Sof/vel/ vox: Roberts, EASL 2017, SAT-280 © by author EASL Recommendations on Treatment of Hepatitis C 2018

Chair: Jean-Michel Pawlotsky

EASL Governing Board Representative : Francesco Negro

Panel: Alessio Aghemo , Marina Berenguer, Olav Dalgard, Geoffrey Dusheiko, Fiona Marra, Massimo Puoti, Heiner Wedemeyer

ESCMIDPresented on April 14, 2018eLibrary at EASL, in press in J Hepatology © by author Treatment Indications

• All patients with HCV infection, including: • Treatment-naïve patients • Individuals who failed to achieve SVR after prior treatment

=> UNIVERSAL ACCESS TO THERAPY

ESCMIDEASL Recommendations on Treatment of Hepatitis C 2018 eLibrary © by author General considerations

• DAA based regimen without IFN and without ribavirine • For all patients • Those without and with cirrhosis (Child Pugh A) • Those naive and pretreated • Same regimen for those with HIV infection

ESCMID EASLeLibrary recommandations on Treatment of Hepatitis 2018 © by author Pretreatment initial assessement

• Demonstration of HCV replication

• Non-invasive assessement of the severity of liver disease: FS, APRI, FIB-4

• (HCV genotype determination)

• Drug drug interactions assessement

ESCMIDEASL Recommendations on Treatment of Hepatitis C 2018 eLibrary © by author Drug-Drug Interactions Comedications can influence the choice of a DAA. Online tools can be helpful www.hep-druginteractions.org

ESCMIDEASL Recommendations on Treatment of Hepatitis C 2018 eLibrary © by author Drug-Drug interactions: Summary DAAs can act as inhibitors and/or inducers of metabolic enzymes (CYP3A4) and of transporters. They can increase toxicity or decrease effectiveness of coadministrated drugs and vice versa

SOF/ LDV/ SOF/ GLE/ SOF VEL/ SOF VEL PIB VOX Atorvastatin      No clinically significant interaction  expected Lovastatin     

Pitavastatin      Potential interaction which may require a dosage adjustment, Pravastatin       altered timing of administration or additional monitoring Lipid lowering drugs lowering Lipid Rosuvastatin      Simvastatin      These drugs should not be co- - Amiodarone       administered.

drugs Digoxin

Cardio      vascular vascular

Dabigatran      - Cyclosporine     

Immuno Tacrolimus      + meal suppressants Estradiol    * * Ethinylestradiol      Norethisterone     

(Norethindrone)

replacement

and hormone and Contraceptives Contraceptives IPP. Omeprazole 20 mg simultaneously SOF/VEL + food or before and 4 h before ESCMIDIPP. Omeprazole 40 mg QD eLibrary © by author Drug-Drug interactions: HIV ARVs Summary

SOF/ LDV/ SOF/ GLE/ No clinically significant SOF SOF/DCV VEL/  interaction expected SOF VEL PIB * VOX Abacavir       Potential interaction which may require a dosage Emtricitabine        adjustment, altered timing of administration or additional Lamivudine NRTIs       monitoring Tenofovir       These drugs should not be Efavirenz        co-administered. Etravirine      

NNRTIs Nevirapine       SOF: sofosbuvir; LDV: ledipasvir; VEL: velpatasvir; Rilpivirine       VOX: voxilaprevir OBV: ombitasvir; PTV: paritepravir; ATV,ATV/r       DSV: dasabuvir; GZR: grazoprevir; EBR: elbasvir; DRV/r, DRV/c       GLE: glecaprevir; PIB: Pibrentasvir

Lopinavir/r      

inhibitors Protease Protease Dolutegravir       EFV/c/FTC/TDF       EFV/c/FTC/TAF      

Maraviroc       inhibitors

Entry/Integrase Entry/Integrase Raltegravir      

ESCMIDLiverpool HEP-drug Interactions: http://www.hep-druginteractions.org/ (Accessed AugusteLibrary 2017) © by author Patients without cirrhosis or with compensated cirrhosis

ESCMID eLibrary © by author EASL Recommendations on Treatment of Hepatitis C 2018: no cirrhosis or compensated cirrhosis

Pangenotypic regimens Genotype-specific regimens Genotype SOF/VEL GLE/PIB SOF/VEL/VOX SOF/LDV GZR/EBR 3D

Genotype 1a Yes Yes No* Yesa Yesb No

Genotype 1b Yes Yes No* Yes Yes Yes

Genotype 2 Yes Yes No* No No No

Genotype 3 Yesc Yes Yesd No No No

Genotype 4 Yes Yes No* Yesa Yese No

Genotype 5 Yes Yes No* Yesa No No

Genotype 6 Yes Yes No* Yesa No No

*Triple combination therapy efficacious but not useful due to the efficacy of double combination regimens. aTreatment-naïve patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis. b Treatment-naïve and treatment-experienced patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis with an HCV RNA level ≤800,000 IU/mL (5.9 Log10 IU/mL). cTreatment-naïve and treatment-experienced patients without cirrhosis. dTreatment-naïve and treatment-experienced patients with compensated (Child-Pugh A) cirrhosis. e Treatment-naïve patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis with an HCV RNA level ≤800,000 IU/mL (5.9 Log10 IU/mL) ESCMIDEASL Recommendations on Treatment of Hepatitis C 2018 eLibrary © by author Patients with decompensated cirrhosis

• No protease inhibitors +++

• Sofosbuvir/Ledipasvir + RBV for 12 weeks

• Sofosbuvir/Velpatasvir + RBV for 12 weeks

• Treatment for 24 weeks without ribavirin (contra- indications or poor tolerance to ribavirin)

ESCMIDEASL Recommendations on Treatment of Hepatitis C 2018 eLibrary © by author Improvement in Life Expectancy and QALY in Patients with an Indication for LT

• eGFR ≥30 ml/min/1.73 m2 Treat according to the general recommendations

• eGFR <30 ml/min/1.73 m2 or ESRD on hemodialysis (CKD stage 4 or 5) Glecaprevir/pibrentasvir for 8 or 12 weeks (all genotypes)

Grazoprevir/elbasvir for 12 weeks (genotypes 1a, 1b and 4)

Ombitasvir/paritaprevir/ritonavir + dasabuvir for 12 weeks (genotype 1b)

Sofosbuvir should be used with caution, only if no alternative treatment is available

• Children <12 years: Treatment deferred until DAAS, including pangenotypic regimens, are approved for this age group

• Adolescents aged ≥12 years: Genotypes 1, 4, 5, 6: => Sofosbuvir/ledipasvir for 12 weeks

Genotypes 2, 3 => Other regimens approved for adults, with caution pending more safety data

• Same treatment regimens as for patients with chronic hepatitis C, according to the HCV genotype

• For 8 weeks

• SVR12 and SVR24 must be assessed, as late relapses have been reported

• HBV coinfection

• Extra hepatic manifestations of chronic hepatitis C

• Non-hepatic solid organ transplant recipients

• PWIDs

• Haemoglobinopathies and bleeding disorders

• Pretreatment assessment: Proof of HCV replication Liver disease severity (APRI, FIB4) Assessement of drug-drug interactions

• Treatment Sofosbuvir/velpatasvir for 12 weeks Glecaprevir/pibrentasvir For 8 weeks in patients without cirrhosis For 12 weeks in patients with cirrhosis Generic drugs possible if quality controls met and guaranteed

• Follow-up: Assessment of SVR dispensable HCC surveillance (if treatment for HCC available) ESCMIDEASL Recommendations on Treatment of Hepatitis C 2018 eLibrary © by author Treatment Monitoring

Pangenotypic Treatment

Baseline assessment a SVR12 b

0 2 4 6 8 12 18 20 24 30 32 36

Weeks a Baseline assessment: Proof of HCV replication (+/-genotype) APRI or FIB-4 for liver disease severity b SVR12 is dispensable in the simplified treatment strategy Assessment of drug-drug interactions ESCMIDEASL Recommendations on Treatment of Hepatitis C 2018 eLibrary © by author The Road to Elimination of HCV

. WHO called for Elimination of HCV by 2030 : 90% reduction in new HCV infections . 2016 survey: 210 countries were investigated for their analysis of HCV cures versus new Infections . . An annual net cure of 7% was used as a target to reach the WHO target of elimination of HCV. If 7% of the epidemic is cured each year, > 90% of people infected should be cured in 2030.

• 91/210 countries had in 2016 data on SVR, HCV-related deaths and new infections • Only 8/91 countries had a net cure of >7%

Net Cure = Cures + HCV Related Deaths - New Infections

Based on 2016 epidemiological data from national reports, publications and45 Polaris Observatory ESCMIDHill AM et al J Virus Erad. 2017 Jul; 3(3): 117–123 eLibrary © by author Screening in the general population is a blocking point

How to screen the Those with other risk exposure general population Blood transfusions prior to blood screening Primary healthcare/GPs On long-term dialysis (ever) Medical or dental interventions in settings with poor Community infection control (health) Tatoos, body piercing or scarification procedures with centres unsterilised equipment

Children born to HCV-infected mothers Hospitals/ tertiary setting Systematic screening

WHO. Guidelines on hepatitis B and C testing, February 2017. Available at: http://apps.who.int/iris/bitstream/10665/254621/1/9789241549981-eng.pdf?ua=1; AASLD/IDSA. HCV Guidance: Recommendations for testing, managing, and treating hepatitis C. Available at:ESCMID http://www.hcvguidelines.org/ (both accessed January 2018) eLibraryGP: general practitioner © by author Conclusion

• Potent and simplified therapies for HCV infection • Short duration, > 95% efficacy • No ribavirin • Not affected by genotype, fibrosis, mutations • Resistance rare • Manageable risk of interactions • New perspective : the HCV elimination world wide • Access to therapy needs to optimize the blocking points of the cascade • Screening +++ • Access to affordable drugs and garanteed generics ESCMID eLibrary © by author CLINICAL CASE

• 54-year-old woman, HIV/HCV contaminated in 1998, after short IVDU period. Works as an historian teacher and lives in couple.

• HIV : CD4: 500/mm3, undetectable HIV VL under raltegravir/TDF/FTC • Hypercholesterolemia on rosuvastatin 10 mg QD (primary prevention) • Peptic esophagitis under PPI

• HCV: genotype G3, HCV RNA: 5,6 log, ALAT: 1.5 N, elastometry: 7.1 kpaESCMID, pretreated with PegIFN/RBV eLibrary © by author Question 1- What are the DAA options available in your country?

1. SOFOSBUVIR/LEDIPASVIR 2. SOFOSBUVIR/VELPATASVIR 3. SOFOSBUVIR/DACLATASVIR 4. GLECAPREVIR/PIBRENTASVIR 5. GRAZOPREVIR/ELBASVIR 6. PARITAPREVIR/ELBASVIR +/- DASABUVIR 7. SOFOSBUVIR/VELPATASVIR/VOXILAPREVIR 8. OTHER

1. SOFOSBUVIR/LEDIPASVIR 2. SOFOSBUVIR/VELPATASVIR 3. GRAZOPREVIR/ELBASVIR 4. GLECAPREVIR/PIBRENTASVIR 5. SOFOSBUVIR/DACLATASVIR 6. SOFOSBUVIR/VELPATASVIR/VOXILAPREVIR 7. OTHER

5754 ESCMID eLibrary © by author You have selected glecaprevir/pibrentasvir The patient takes raltegravir/TDF/FTC and rosuvastatin 10 mg QD + PPI

Question 5- How would you take into account the risk of interactions? 1. No change 2. Stop the statin (or reduce at 5 mg if G/P) 3. Give the PPI once daily 4. Change the cART regimen 5. Other

1. 8 weeks 2. 12 weeks 3. 16 weeks 4. 24 weeks

5756 ESCMID eLibrary © by author HIV/HCV coinfection, G3, pretreated with Peg IFN/RBV The patient takes raltegravir/TDF/FTC and rosuvastatin 10 mg QD + PPI You have selected glecaprevir/pibrentasvir for 16 weeks The antiretroviral treatment was maintained Rosuvastatin was decreased to 5 mg QD PPI treatment was maintained => We wait for SVR 12 ESCMID eLibrary © by author