1. Advances in Hepatitis C Virus Treatment for HIV-Infected Persons: Have We Reached the End of the Rainbow?
Kara W. Chew, MD, MS
Assistant Clinical Professor of Medicine
David Geffen School of Medicine at UCLA
Los Angeles, California
FLOWED: 04/18/2016
Los Angeles, California: April 25, 2016
From KW Chew, MD, MS, at Los Angeles, CA: April 25, 2016, IAS-USA.

2. After attending this presentation, participants will be able to:
Learning Objectives
After attending this presentation, participants will be able to:
Conduct the initial evaluation for hepatitis C virus (HCV) including hepatic fibrosis assessment
Select between treatment options for genotype 1 HCV in HIV/HCV-coinfected patients
List treatment options for genotype 2, 3, or 4 HCV infection

3. Evaluation for advanced fibrosis is recommended for all
Necessary to determine the appropriate HCV treatment strategy
Impacts treatment options
Depending on the genotype and regimen:
Treatment duration may need to be extended
Addition of ribavirin may need to be considered
Additional management necessary for advanced fibrosis/cirrhosis
Screening for hepatocellular carcinoma
Screening for esophageal varices
Monitoring of hepatic function
Counseling to avoid NSAIDs, limit acetaminophen use, avoid raw shellfish

4. Recommended approach for fibrosis assessment
Combining direct biomarkers and transient elastography is most efficient
If discordant, consider liver biopsy
If direct biomarkers or transient elastography not available, combine indirect serum biomarkers
If indeterminate, consider liver biopsy
Use multiple measures. Clinical evaluation + indirect and direct, TE next, and then liver biopsy if needed – if it would impact treatment decisions/management
AASLD/IDSA, hcvguidelines.org, Boursier Hepatology 2012

5. Key considerations when choosing between HCV treatment regimens
Drug interactions between ART and HCV DAAs
Drug interactions between HCV DAAs and drugs for comorbidities
E.g. PPIs, statins, anticonvulsants, dihydropyridines, rifampin, digoxin
Comorbidities:
Cardiac disease (anemia with RBV, drug interactions with cardiac meds)
Renal insufficiency (limited data for most DAAs with advanced kidney disease/ESRD, increased tenofovir levels with coadministration of ledipasvir with TDF)
Potent p-gp inhibitors-sofosbuvir levels decreased – rifampin, St. John’s wort
CYP3A inhibitors and inducers - daclatasvir dose adjustment
Daclatasvir is an inhibitor of P-gp, OATP1B1 And 1. B3, BCRP increased atorvastatin (OATP and BCRP). Max 20 mg atorva with elbasvir/grazoprevir. Ledipasvir inhibitos P-gp and/or BCRP- atorvastain levels may increase. May get increased amlodipine through P-gp inhibitiron
CYP3A4 inhibition (weak) by grazoprevir and mild P-gp inhibition by elbasvir may increase amlodipine.
Ritonavir in PrOD inhibits CYP3A4 and paritaprevir OATP1B1 - > increased atorvastatin levels. European advice no coadministration
Amlodipine inhibits CYP3A4- may increase daclatasvir concentrations
CYP3A4 inhibition by ProD – consider dose reduction of amlodipine
Statins, buprenorphine- monitor for toxicity, digoxin levels may increase
Beta-blocker levels may increase (P-gp inhibition by DAAs)

6. Drug-drug interactions between ART and HCV treatment
HCV regimen
Allowed ART
Comments
Ledipasvir/sofosbuvir (LDV/SOF)
Most ART allowed
Interaction between ledipasvir and TDF, ledipasvir and cobicistat
LDV increases tenofovir levels – avoid coadmin with TDF if CrCL <60 mL/min and avoid LDV + TDF with ritonavir- or cobicistat-boosted ART
Elbasvir/grazoprevir
Raltegravir, dolutegravir, rilpivirine, tenofovir, abacavir, emtricitabine, enfuvirtide, lamivudine,
NO HIV-1 protease inhibitors or efavirenz
Paritaprevir/ritonavir/ombitasvir + dasabuvir
Atazanavir, dolutegravir, raltegravir, emtricitabine, lamivudine, tenofovir, enfuvirtide
NO efavirenz
If ritonavir in ART regimen, hold ritonavir in ART for dose due with HCV treatment
Simeprevir
Raltegravir, (dolutegravir), rilpivirine, maraviroc, abacavir, emtricitabine, tenofovir, lamivudine, enfuvirtide
Daclatasvir (DCV)
-Note standard DCV dose is 60 mg
No restrictions
Dose adjustment with select ART
DCV dose to 30 mg with r/ATV, IDV, NFV, SQV, cobi-containing ART (except DRV-cobi).  DCV dose to 90 mg with efavirenz, etravirine, nevirapine
With the addition of ledipasvir/sofosbuvir, tenofovir levels (when given as TDF) are increased with efavirenz, rilpivirine, DTG, r/ATV, r/DRV. With HIV PIs, TDF levels exceed what’s felt to be safe
TAF may be OK – 20% of levels seen with TDF in healthy volunteers
Doyle 16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, May 26-28, 2015, Washington, DC, USA - R/F/TAF or E/C/F/TAF may be coadministered with LDV/SOF without dose modification
Cobicistat trough levels increased 4-fold by ledipasvir – Stribild contraindicated on label
Elbasvir/grazoprevir – no efavirenz. With CYP3A induction, decreased EBV/GZR levels No HIV Pis - May increase the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition.
PrOD – label no DRV. May get decreased DRV levels. European recs OK if no extensive PI resistance. May need to do BID DRV.
Daclatasvir dose modification – reduced to 30 mg with strong CYP3A inhibitors, increase to 90mg with moderate CYP3A inducers

7. Treatment recommendations - HCV genotype 3
Treatment naïve and PEG-IFN/RBV experienced non-cirrhotic
Treatment naïve compensated cirrhotic
PEG-IFN/RBV treatment experienced compensated cirrhotic
Sofosbuvir/RBV experienced non-cirrhotic or cirrhotic
Daclatasvir + sofosbuvir x 12 weeks (IA)
Sofosbuvir + WBR + PEG-IFN x 12 weeks (IA)
Sofosbuvir + WBR + PEG-IFN x 12 weeks (IIaC)
Daclatasvir + sofosbuvir +/- WBR x 24 weeks (IIaB)
Daclatasvir + sofosbuvir + WBR x 24 weeks (IIaB)
Daclatasvir + sofosbuvir + WBR x 24 weeks (IIaC)
WBR = weight-based ribavirin, RBV = ribavirin; Strength of recommendation provided by Class (I, IIa/b, III) and Level (A, B, C), PEG-IFN= pegylated interferon
ALLY-2 SVR 12 GT 3 10/10
ALLY-3 – 12 weeks daily DCV + SOF naïve – SVR12 90%
Naïve non-cirrhotic 97% SVR12
Naïve with cirrhosis 58% SVR12
Experienced with cirrhosis – limited data. 12 weeks of SOF+DCV = SVR12 69%
SOF-experienced treated with SOF/DCV x 12 weeks = 71% (n=7) SVR12. Extend duration + add RBV.
European compassionate use – SVR12 cirrhotics - 86% with 24 weeks vs 70% 12 weeks
Role of RBV not clear. Adding to 24 weeks doesn’t seem to increase SVR12 rates.
Duration for naïve GT 3 compensated cirrhosis not known:
ALLY-3+ SOF+DCV+ RBV 12 vs 16 weeks in naïve and experienced with stage 3 and compensated cirrhosis. SVR12 86% in cirrhotics, most experienced. Extending to 16 weeks not much difference 88% vs 89% n=17 and 18)
FDA label –SOF/DCV + RBV x 12 weeks for GT 1 and 3 cirrhotics
In ALLY-1,2,3, HCV GT1a and 3presence of NS5A polymorphisms Y93H associated with reduced SVR12 – very few N =6 1a and n=4 GT3.
BOSON study: TN and TE GT3 to SOF/RBV x 16 vs 24 weeks or SOF+PEG+RBV x 12 weeks. SVR12 naïve 77% vs 88% vs 95%. In cirrhotics n=23 SVR12=91% with PEG
C-SWIFT Elbasvir/GZR + SOF x 8-12 week TN w/ and w/o cirrhosis. 93% SVR12 with 8 weeks non-cirrhotics. 100% SVR 12 with 12 weeks. Cirrhotics 91% with 12 weeks (n=11)
AASLD/IDSA HCV Guidance

8. Determining treatment response and post-treatment follow-up
Quantitative HCV RNA at week 4 on treatment and 12 weeks after treatment completion (SVR12 determination)
Can consider HCV RNA at end of treatment and 24 weeks after end of treatment (SVR24)
>99% concordance between SVR12 and SVR24
Remind patients that treatment cure does not = HCV immunity
High rates of reinfection in HIV/HCV co-infected persons
HIV+ MSM without IDU, 2-year cumulative reinfection rates 25-33%
Continue to review risk factors
Ongoing cirrhosis/chronic liver disease management
Positive VL at week 4- repeat at week 6. If increased >1 log (10-fold), d/c treatment
The significance of a positive HCV RNA test result at week 4 that remains positive, but lower, at week 6 or week 8 is unknown. No recommendation to stop therapy or extend therapy can be provided at this time.
Yoshida et al, Hepatology 2015, Martin et al, AIDS 2013, Lambers et al, AIDS 2011, AASLD/IDSA HCV guidance

9. Management of treatment failures
Optimal retreatment strategy unknown
If urgent to retreat:
Resistance testing for NS3 and NS5A resistance mutations
Include RBV on retreatment
Consider PEG-IFN
Consider a clinical trial
RAVs make a difference.
NS5A inhibitor RAVs on retreatment with longer duration LDV/SOF = more failures. Also then developed S282T/NS5B RAVs
AASLD/IDSA HCV Guidance, hcvguidelines.org