Slide 1 of 8 From MG Peters, MD, at Los Angeles, CA: April 22, 2013, IAS-USA. IAS–USA Marion G. Peters, MD John V. Carbone, MD, Endowed Chair Professor of Medicine Chief of Hepatology Research University of California San Francisco Hepatitis C Virus (HCV) Coinfection: New Drugs, New Strategies From MG Peters, MD, at Los Angeles, CA: April 22, 2013, IAS-USA.

Slide 2 of 8 From MG Peters, MD, at Los Angeles, CA: April 22, 2013, IAS-USA. The Long-Awaited New Era: Protease Inhibitors for HCV Genotype 1 SVR >70% Genotype 1 Response-guided therapy (RGT) Side effectsResistance April 27-28, 2011: FDA Advisory Panel voted 18-0 for approval of boceprevir and telaprevir Both drugs approved by FDA May 2011 Drug-drug interactions

Slide 3 of 8 From MG Peters, MD, at Los Angeles, CA: April 22, 2013, IAS-USA Week of Treatment HCV RNA (log IU/ml) Different Types of “Non-Response” Null Partial Breakthrough Relapse Adapted from M. Shiffman

Slide 4 of 8 From MG Peters, MD, at Los Angeles, CA: April 22, 2013, IAS-USA Viral RNA (–) EVR: Partial versus Complete RGT= response guided therapy Wks of Therapy HCV RNA (log copies/mL) 6 cEVR RVR eRVR: ud at weeks 4 and 12

Slide 5 of 8 From MG Peters, MD, at Los Angeles, CA: April 22, 2013, IAS-USA. Similarities/ Differences in Phase III Studies of TVR and BOC in GT1 Naive Mono Pts ParameterTVR [1] BOC [2] PR lead-in?NoYes: 4 wks PegIFN alfa formulation2a2b PI dosing requirements TID; administer with fatty meal TID with food not low fat Duration of PI triple therapy 8-12 wks followed by wks PR wks after 4 wks PR lead-in Qualification for shortened therapy (response guided) Undetectable HCV RNA Wk 4 and 12 of triple therapy Undetectable HCV RNA w8 and w24 of triple therapy Qualified for shortened therapy, % 58 (24 wks)44 (28 wks) SVR, % Relapse, %99 Adverse events more frequent in PI arms Rash, anemia, pruritus, nausea Anemia, dysgeusia 1. Jacobson IM, et al. AASLD Abstract Poordad F, et al. AASLD Abstract LB-4. ccoptions.com, Zeuzem

Slide 6 of 8 From MG Peters, MD, at Los Angeles, CA: April 22, 2013, IAS-USA. Various Paradigms Being Developed Simultaneously PEG IFN + Ribavirin + Single DAA PIs Nucs NS5A Cyclophilin antagonist PEG IFN + Ribavirin + DAA-1 + DAA-2 IFN-free regimens Some trials involve more than one of these designs PEG IFN lambda being evaluated Proof of concept for curative potential of IFN-free regimens had been established

Slide 7 of 8 From MG Peters, MD, at Los Angeles, CA: April 22, 2013, IAS-USA. Issues in HCV therapy Genotype differences – 2 versus 3 versus 1 – 1a poorer response than 1b Easier to develop resistance IL28b response – CC versus TT Prior exposure to IFN and DAA Extent of liver disease DDI

Slide 8 of 8 From MG Peters, MD, at Los Angeles, CA: April 22, 2013, IAS-USA. HCV and HIV coinfected Select who to treat –Moderate to severe fibrosis F3-4 Assess fibrosis –Liver biopsy –Serum tests APRI FIB-4 –Transient elastography Control HIV Encourage adherence Avoid alcohol