Updated Guidelines for Managing HIV/HCV Co-Infection John J Faragon, PharmD, BCPS, AAHIV-P Regional Pharmacy Director, NY/NJ AIDS Education and Training Center Pharmacist, HIV Medicine, Albany Medical Center

Released 1/29/14!

Abbreviations  BOC – boceprevir  DAA – direct acting antiviral  IFN – interferon  PEG – pegylated interferon  RBV WB – ribavirin, weight based dosing  RGT – response guided therapy  SMV – simeprevir  SOF – sofosbuvir  TVR – telaprevir

IFN Ineligible Definitions  Intolerance to IFN  Autoimmune hepatitis and other autoimmune disorders  Hypersensitivity to PEG or any of its components  Decompensated hepatic disease  History of depression, or clinical features consistent with depression  A baseline neutrophil count below 1500/μL, a baseline platelet count below 90,000/μL or baseline hemoglobin below 10 g/dL  A history of preexisting cardiac disease

Standard Dosing  Sofosbuvir – 400mg once daily  Simeprevir – 150mg once daily  Peg Interferon – 180mcg once weekly  Ribavirin – weight based dosing  <75kg – 1000mg daily in divided doses  ≥75 kg – 1200mg daily in divided doses

Drug Interactions Considerations  Sofosbuvir  Substrate for P-glycoprotein and breast cancer resistance protein  Intracellular metabolism mediated by hydrolase and nucleotide phosphorylation pathways  Minimal drug interactions expected  Simeprevir  Mild inhibitor of CYP1A2 activity and intestinal CYP3A4  Does not affect hepatic CYP3A4 activity  Inhibits OATP1B1/3 and P-glycoprotein  Multiple drug interactions expected

Sofosbuvir and HIV Medications (1 of 2) Concurrent MedicationRecommendation HIV Protease Inhibitors All HIV PIs, with or without ritonavir, except tipranavir  Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism of sofosbuvir. Tipranavir (Aptivus®)  Co-administration not recommended HIV Non Nucleoside Reverse Transcriptase Inhibitors All NNRTIs  Concurrent use at standard doses acceptable.

Sofosbuvir and HIV Medications (2 of 2) Concurrent MedicationRecommendation HIV Integrase Strand Transfer Inhibitors Dolutegravir (Tivicay®)  Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism of sofosbuvir. Elvitegravir (contained in Stribild®)  Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism of sofosbuvir. Raltegravir (Isentress®)  Concurrent use at standard doses acceptable. HIV Entry Inhibitors Maraviroc (Selzentry®)  Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism of sofosbuvir. HIV Nucleoside/Nucleotide Reverse Transcriptase Inhibitors All NRTIs  Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism of sofosbuvir.

Simeprevir and HIV Medications (1 of 2) Concurrent MedicationRecommendation HIV Protease Inhibitors All HIV PIs  Significant increases or decreases in simeprevir levels expected when used with any HIV protease inhibitor, when used with or without ritonavir. Co-administration not recommended HIV Non Nucleoside Reverse Transcriptase Inhibitors Efavirenz (Sustiva®), Etravirine (Intelence®), Nevirapine (Viramune®)  Significant reductions in simeprevir levels and reduced simeprevir efficacy due to CYP3A4 induction. Co- administration not recommended. Rilpivirine (Edurant®)  Concurrent use at standard doses acceptable.

Simeprevir and HIV Medications (2 of 2) Concurrent MedicationRecommendation HIV Integrase Strand Transfer Inhibitors Dolutegravir (Tivicay®)  Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism of simeprevir. Elvitegravir (contained in Stribild®)  Significant increase in simeprevir levels expected when used with a cobicistat containing regimen. Co-administration not recommended. Raltegravir (Isentress®)  Concurrent use at standard doses acceptable. HIV Entry Inhibitors Maraviroc (Selzentry®)  Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism of simeprevir. HIV Nucleoside/Nucelotide Reverse Transcriptase Inhibitors All NRTIs  Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism of simeprevir.

HIV/HCV Co-Infection, GT1 PreferredAlternative Treatment-naïve, prior PEG/RBV relapsers, IFN eligible: SOF + PEG/RBV(WB) x 12 weeks IFN ineligible: SOF + RBV(WB) x 24 weeks SOF + SMV ± RBV(WB) x 12 weeks Treatment experienced, prior PEG/RBV nonresponders, regardless of IFN eligibility: SOF + SMV ± RBV(WB) x 12 weeks Treatment-naïve, prior PEG/RBV relapsers, IFN eligible: SMV x 12 weeks + PEG/RBV(WB) x 24 weeks IFN ineligible: None Treatment experienced, prior PEG/RBV nonresponders IFN eligible: SOF + PEG/RBV(WB) x 12 Weeks IFN ineligible: SOF + RBV(WB) x 24 Weeks Not Recommended: TVR + PEG/RBV x 24 or 48 weeks (RGT), BOC + PEG/RBV x 28 or 48 weeks (RGT) PEG/RBV x 48 weeks, SMV x 12 weeks + PEG/RBV x 48 wks

HIV/HCV Co-Infection, GT2 PreferredAlternative All patients, regardless of treatment history: SOF + RBV(WB) x 12 weeks Treatment naive and prior PEG/RBV relapsers: None Treatment experienced, prior PEG/RBV Nonresponders: IFN eligible: SOF + PEG/RBV(WB) X 12 Weeks IFN ineligible: None Not Recommended: PEG/RBV x weeks, or any regimen with TVR, BOC, or SMV

HIV/HCV Co-Infection, GT3 PreferredAlternative All patients, regardless of treatment history: SOF + RBV(WB) x 24 weeks Treatment naïve, PEG/RBV relapsers: None Treatment experienced, prior PEG/RBV Nonresponders: IFN eligible: SOF + PEG/RBV(WB) X 12 weeks IFN ineligible: None Not Recommended: PEG/RBV x weeks, Any regimen with TVR, BOC, or SMV

HIV/HCV Coinfection, GT4 PreferredAlternative All patients, regardless of treatment history: IFN eligible: SOF + PEG/RBV(WB) x 12 weeks IFN ineligible: SOF + RBV(WB) x 24 weeks None Not Recommended: PEG/RBV x 48 weeks, any regimen with TVR or BOC

HIV/HCV Coinfection, GT 5,6 PreferredAlternative All patients, regardless of treatment history: SOF + PEG/RBV(WB) x 12 weeks None Not Recommended: PEG/RBV x 48 weeks, any regimen with TVR, BOC, or SMV

HIV/HCV NOT Recommended Not Recommended for treatment-naïve or treatment-experienced patients: PEG/RBV with or without telaprevir or boceprevir for 24 to 48 weeks Monotherapy with PEG, RBV, or a DAA

Other Drug Interactions with Sofosbuvir Medication and or ClassRationale for Avoiding with Sofosbuvir Anticonvulsants – carbamazepine, oxcarbazepine, phenobarbital, phenytoin  Co-administration with these medications is likely to reduce concentrations of sofosbuvir leading to reduced sofosbuvir efficacy. Co-administration not recommended. Antimycobacterials – rifampin, rifabutin, rifapentin  Co-administration with these medications is likely to reduce concentrations of sofosbuvir leading to reduced sofosbuvir efficacy due to intestinal P-glycoprotein (P-gp) induction from rifampin. Herbal products – St. John’s Wort  Co-administration with these medications is likely to reduce concentrations of sofosbuvir leading to reduced sofosbuvir efficacy due to intestinal P-glycoprotein (P-gp) induction associated with St. John’s Wort.

Other Drug Interactions with Simeprevir (1 of 2) Medication and or ClassRationale for Avoiding with Simeprevir Anticonvulsants - carbamazepine, oxcarbazepine, phenobarbital, phenytoin  Co-administration with these medications is likely to reduce concentrations of simeprevir and lead to reduced simeprevir efficacy. Co-administration not recommended. Antibiotics – clarithromycin, erythromycin, telithromycin  Co-administration with these medications is likely to increase concentrations of either simeprevir or the antibiotic due to CYP3A4 and P-glycoprotein (P-gp) inhibition. Co-administration not recommended. Antifungals – fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole  Co-administration with these medications is likely to increase concentrations of simeprevir due to CYP3A4 inhibition from the antifungals. Co-administration not recommended. Antimycobacterials – rifampin, rifabutin, rifapentine  Co-administration with these medications is likely to reduce concentrations of simeprevir and lead to reduced simeprevir efficacy. Co-administration not recommended.

Other Drug Interactions with Simeprevir (2 of 2) Medication and or ClassRationale for Avoiding with Simeprevir Corticosteroids – dexamethasone  Co-administration with dexamethasone is likely to decrease concentrations of simeprevir and lead to reduced simeprevir efficacy. Co-administration not recommended. Propulsive – cisapride  Co-administration with cisapride may result in increased concentrations of cisapride leading to potential cardiac arrhythmias. Herbal products – Milk Thistle, St. John’s Wort  Co-administration with milk thistle is likely to increase concentrations of simeprevir. Co-administration not recommended.  Co-administration with St. John’s Wort is likely to reduce concentrations of simeprevir leading to reduced simeprevir efficacy, due to intestinal P-glycoprotein (P-gp) induction associated with St. John’s Wort.

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