2017: HIV, STD, HBV, and HCV Update David Spach, MD Professor of Medicine, Division of Infectious Diseases University of Washington Last Updated: August 6, 2017

HIV, HBV, HCV: Update 2017 HIV HBV HCV Questions

HIV Update

HIV Testing

Estimated HIV Prevalence in U.S. ? Number of Persons Living with HIV in US * *

Estimated HIV Prevalence in U.S. * * Estimated 1,250,000 living with HIV in United States

Estimated Incidence of HIV Infection in U.S. by Year, 2006-2013 Source: Song R, et al. J Acquir Immune Defic Syndr. 2017;74:3-9. 1

Estimated Incidence of HIV Infection in U.S. by Year, 2008-2013 Source: Hall HI, et al. JMIR Public Health Surveill. 2017;3:e8.

Estimated Incidence of HIV Infection in U.S. by Year, 2008-2013 Why? Source: Hall HI, et al. JMIR Public Health Surveill. 2017;3:e8.

Decreasing New HIV Infections Reduce HIV undiagnosed fraction Treatment as Prevention (TasP) Preexposure Prophylaxis (PrEP)

Proportion with Undiagnosed HIV in U.S., by Year, 2007-2013 Source: CDC. HIV Surveillance Supplemental Report. 2016;21(No. 4):1-87. July 2016 1

Using Marks Model and 2008 CDC Data Estimating Impact of Knowledge of HIV Infection on Sexual Transmission of New HIV Infections Using Marks Model & 2008 CDC Estimates of Awareness of HIV Status Knowledge of HIV Infection New HIV Infections 21% 48% Unaware of HIV Infection 79% 52% Aware of HIV Infection Estimates Based on: Marks G, et al. AIDS. 2006;20:1447-50. 1

HIV Prevention Trials Network (HPTN) Study 052 1,763 HIV Serodiscordant Couples (97% heterosexual) + - + - + - + - n = 872 n = 853 n = 37 n = 1 Source: Cohen M, et al. N Engl J Med. 2011;36:493-505.

HIV Prevention Trials Network (HPTN) Study 052 550 Early Therapy CD4 350-550 cells/mm3 350 250 Deferred Therapy CD4 <250 cells/mm3 or AIDS-Related Event Source: Cohen M, et al. N Engl J Med. 2011;36:493-505.

HIV Prevention Trials Network (HPTN) Study 052 96% Reduction P < 0.001 Source: Cohen M, et al. N Engl J Med. 2011;36:493-505.

+ - + - + - Heterosexual Couples MSM Couples n = 279 n = 269 n = 340 HIV Transmission with Condomless Sex if HIV-Infected with Suppressed HIV European PARTNER Study Heterosexual Couples MSM Couples + - + - + - n = 279 n = 269 n = 340 767 HIV-serodiscordant couples in 14 European Countries Partner with HIV taking ART and HIV RNA <200 copies/mL Couples having condomless sex Source: Rodger AJ, et al. JAMA 2016;316:171-81.

HIV Transmission with Condomless Sex if HIV-Infected with Suppressed HIV European PARTNER Study Couples reported condomless sex meNo linked HIV transmissions during follow-up of 894 couple years Uncertainty remains for upper limit of risk, particularly with receptive anal sex with ejaculation Source: Rodger AJ, et al. JAMA 2016;316:171-81.

Preexposure Prophylaxis (PrEP) Time Preexposure Prophylaxis

Preexposure Prophylaxis (PrEP) HIV Exposure Events Time Preexposure Prophylaxis

Tenofovir DF-Emtricitabine as Sexual PrEP for HIV Prevention Estimated Protection in Adherent Patients Source: Marrazzo JM, et al. JAMA. 2014;312:390-409 1

Antiretroviral Update

CDC and Association of Public Health Laboratories 2014 Laboratory Testing for the Diagnosis of HIV Infection HIV-1/2 Antigen/Antibody Immunoassay (+) (-) Negative for HIV-1 and HIV-2 antibodies and p24 Ag HIV-1/HIV-2 Ab Differentiation Immunoassay HIV-1 (+) HIV-2 (-) HIV-1 (-) HIV-2 (+) HIV-1 (+) HIV-2 (+) HIV-1 (-) or Indeterminate HIV-2 (-) HIV-1 antibodies detected HIV-2 antibodies detected HIV antibodies detected HIV-1 NAT HIV-1 NAT (+) HIV-1 NAT (-) Acute HIV-1 infection Negative for HIV-1 Source: Centers for Disease Control and Prevention. June 27, 2014.

CDC and Association of Public Health Laboratories 2014 Laboratory Testing for the Diagnosis of HIV Infection HIV-1/2 Antigen/Antibody Immunoassay HIV p24 Antigen HIV Antibodies (+) (-) Negative for HIV-1 and HIV-2 antibodies and p24 Ag HIV-1/HIV-2 Ab Differentiation Immunoassay HIV-1 (+) HIV-2 (-) HIV-1 (-) HIV-2 (+) HIV-1 (+) HIV-2 (+) HIV-1 (-) or Indeterminate HIV-2 (-) HIV-1 antibodies detected HIV-2 antibodies detected HIV antibodies detected HIV-1 NAT Detects HIV-1 p24 antigen and antibodies to HIV-1 and HIV-2 HIV-1 NAT (+) HIV-1 NAT (-) Acute HIV-1 infection Negative for HIV-1 Source: Centers for Disease Control and Prevention. June 27, 2014.

CDC and Association of Public Health Laboratories 2014 Laboratory Testing for the Diagnosis of HIV Infection HIV-1/2 Antigen/Antibody Immunoassay (+) (-) Negative for HIV-1 and HIV-2 antibodies and p24 Ag HIV-1/HIV-2 Ab Differentiation Immunoassay HIV-1 (+) HIV-2 (-) HIV-1 (-) HIV-2 (+) HIV-1 (+) HIV-2 (+) HIV-1 (-) or Indeterminate HIV-2 (-) HIV-1 antibodies detected HIV-2 antibodies detected HIV antibodies detected HIV-1 NAT HIV-1 NAT (+) HIV-1 NAT (-) Acute HIV-1 infection Negative for HIV-1 Source: Centers for Disease Control and Prevention. June 27, 2014.

Geenius HIV-1/HIV-2 Supplemental Assay

Geenius HIV-1/HIV-2 Supplemental Assay Immunochromographic Assay: Detects HIV-1 and HIV-2 Antibodies HIV-2 Bands HIV-1 Bands Control gp36 gp140 p31 gp160 p24 gp41 Source: Fernández-McPhee C, et al. J Clin Virol. 2015;63:66-9.

Geenius HIV-1/HIV-2 Supplemental Assay Software Interpretation Source: Geenius Product Information

Antiretroviral Update

HHS Antiretroviral Therapy Guidelines: January 28, 2016 Initiating Therapy in Treatment-Naïve Patients 2017 HHS Recommendation for Initiating ART Therapy in Treatment-Naïve Patients Antiretroviral Therapy is Recommended for: All HIV-infected individuals, regardless of CD4 T lymphocyte cell count, to reduce the morbidity and mortality associated with HIV infection. AI For HIV-infected individuals to prevent HIV transmission. Source: HHS Antiretroviral Therapy Guidelines. January 28, 2016. AIDS Info

HHS Recommended Initial Antiretroviral Therapy Backbone Anchor Drug Integrase Inhibitor 2 Nucleoside RTIs + Protease Inhibitor (Boosted)

Hepatitis B

Hepatitis B Reactivation During HCV Treatment Reports Reports of HBV reactivation in persons coinfected with HCV-HBV coninfection Cases have involved active (HBsAg+) and resolved (HBsAg- and HBcAb+) Some cases severe: fulminant hepatitis, liver failure, death FDA warning October 4, 2016

Hepatitis B Reactivation During HCV Treatment AASLD/IDSA HCV Guideance: Recommendation Test all patients for HBsAg, HBcAb, and HBsAb prior to treating HCV Patients with active HBV should receive HBV therapy if indicated If HBsAg positive and not receiving therapy, obtain HBV DNA levels at baseline and monitor during therapy Note: some experts would treat HBV in all persons with HBsAg prior to starting HCV therapy, regardless of HBV DNA level

Hepatitis C Update

Hepatitis C: Progression of Disease Time 20-25 years 25-30 years Normal Liver Chronic Hepatitis Cirrhosis HCC ESLD Death HCV Infection

2005 Forecast of HCV-Associated Deaths in U.S. Number Year 2010 Deaths 2014 2018 2022 2026 2030 2034 2038 2042 2046 2050 2054 2058 40,000 35,000 30,000 25,000 20,000 15,000 10,000 5,000 45,000 Source: Rein DR, et al. Dig Liver Dis. 2011:43:66-72.

Hepatitis C Virus Structural and Nonstructural Proteins Hepatitis C Proteins C NS4B NS5A NS2 NS3 E1 NS4A p7 E2 NS5B Structural Proteins Nonstructural (NS) Proteins Cysteine Protease Serine Protease Cofactors RNA binding and assembly recognition complex Vioporin Serine Protease RNA Helicase Membranous Web Induction RNA-Dependent RNA Polymerase

Hepatitis C Virus Structural and Nonstructural Proteins Hepatitis C Protein Targets for Direct Acting Antiviral Agents (DAAs) NS3 NS4A NS5A NS5B Serine Protease Serine Protease Cofactors RNA binding and assembly recognition complex RNA-Dependent RNA Polymerase

Categories of Direct Acting Antiviral Agents Hepatitis C Direct Acting Antiviral Agent (DAA) Categories NS3/4A Protease Inhibitor NS5A Inhibitor NS5B Polymerase Inhibitor NS3 NS4A NS5A NS5B Serine Protease Serine Protease Cofactors RNA binding and assembly recognition complex RNA-Dependent RNA Polymerase

HCV Direct Acting Agents (DAAs) NS3 NS4A NS5A NS5B Protease Inhibitors NS5A Inhibitors Polymerase Inhibitors Glecaprevir Daclatasvir Dasabuvir Grazoprevir Elbasvir Sofosbuvir Simeprevir Ledipasvir Voxilaprevir Ombitasvir Pibrentasvir Velpatasvir

Glecaprevir-Pibrentasvir Approval Status: Approval by United States FDA on August 3, 2017 Indications and Usage - Treatment-naïve patients with HCV genotypes 1-6 in without cirrhosis and with compensated cirrhosis (Child-Pugh A) - HCV genotype 1 previously treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor, but not both Class & Mechanism - Glecaprevir: HCV NS3/4A protease inhibitor - Pibrentasvir: HCV NS5A inhibitor Doseage Form (Tablet): 100 mg Glecaprevir and 40 mg Pibrentasvir Dosing: Three tablets orally once daily, with food (total daily dose of Glecaprevir (300 mg)-Pibrentasvir 120 mg) Adverse Effects (AE): most common headache and fatigue Source: Mavyret Prescribing Information. AbbVie., Inc.

Glecaprevir-Pibrentasvir Indications: Treatment-Naïve Patients Glecaprevir-Pibrentasvir in HCV Treatment-Naïve Patients HCV Genotype Treatment Duration No Cirrhosis Compensated Cirrhosis (Child-Pugh Class A) Genotype 1 8 weeks 12 weeks Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Source: Mavyret Prescribing Information. AbbVie.

Glecaprevir/Pibrentasvir in Cirrhotic Genotype 1, 2, 4, 5, and 6 EXPEDITION-1: Results with 12-Week Treatment 145/146 89/90 31/31 16/16 2/2 7/7 SVR12 by intent-to-treat analysis. N=1 patient with GT1A experienced viral relapse at week 8 post-treatment; had Y93N detected at baseline & at time of failure. Source: Forns X, et. al, EASL 2017. Abstract GS-006.

SVR12 (ITT analysis), Overall and by Genotype Glecaprevir-Pibrentasvir in Non-Cirrhotic Genotype 4, 5 and 6 ENDURANCE-4: Results SVR12 (ITT analysis), Overall and by Genotype 50/51 51/51 50/51 50/51 120/121 75/76 26/26 19/19 Source: Asselah T, et al. AASLD 2016, Abstract 114.

Glecaprevir-Pibrentasvir in Treatment-Naïve Non-Cirrhotic GT 3 ENDURANCE-3 Study: Results ION-3: SVR 12 by Treatment Duration and Regimen (ITT Analysis) 222/233 111/115 149/157 12-Week Regimens 8-Week Regimen GLE-PIB = glecaprevir-pibrentasvir; SOF = sofosbuvir; DCV = daclatasvir ITT = Intent-to-treat Source: Foster G, et al. EASL 2017, Abstract GS-007.

Hepatitis C Genotype 1a Costs of Different Regimens for Treatment of Genotype 1a Estimated Cost* for Initial Recommend Treatment of Genotype 1a HCV Regimen and Duration of Therapy^ Cost of Regimen* Elbasvir-Grazoprevir for 12 weeks $54,600 Elbasvir-Grazoprevir for 16 weeks $72,800 Glecaprevir-Pibrentasvir for 8 weeks $26,400 Ledipasvir-Sofosbuvir for 12 weeks $94,500 Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir + Ribavirin for 12 weeks $83,819 Sofosbuvir + Simeprevir for 12 weeks $150,000 Sofosbuvir-Velpatasvir for 12 weeks $74,760 Sofosbuvir + Daclatasvir x 12 weeks $147,000 ^Regimen and Duration of therapy for Initial treatment of patients with Genotype 1a without cirrhosis *Cost of regimen estimated based on Wholesale Acquisition Cost (WAC)

Sofosbuvir-Velpatasvir-Voxilaprevir Indications: Treatment-Experienced Only Sofosbuvir-Velpatasvir-Voxilaprevir for Adults with Chronic HCV without Cirrhosis or with Compensated Cirrhosis (Child-Pugh A) HCV Genotype Patient Previously Treated With an HCV Regimen Containing: Treatment Duration 1, 2, 3, 4, 5, or 6 An NS5A inhibitora 12 weeks 1a or 3 Sofosbuvir without an NS5A inhibitorb aIn clinical trials, prior NS5A inhibitor experience included daclatasvir, elbasvir, ledipasvir, ombitasvir, or velpatasvir. bIn clinical trials, prior treatment experience included sofosbuvir with or without any of the following: peginterferon alfa/ribavirin, ribavirin, HCV NS3/4A protease inhibitor (boceprevir, simeprevir or telaprevir). Source: Vosevi Prescribing Information, Gilead Sciences.

Sofosbuvir-Velpatasvir- Sofosbuvir-Velpatasvir-Voxilaprevir in NS5A-Experienced GT 1-6 POLARIS-1: Study Design 12 24 Week GT 1-6 with NS5A inhibitor experience* n = 415 Sofosbuvir-Velpatasvir- Voxilaprevir N=263 SVR12 Placebo N=152 SVR12 GT 1 patients randomized 2:1 ratio (active:placebo). Stratified by presence of cirrhosis (target ≥30%). Genotypes 2-6 were assigned to active arm (and not randomized). Placebo recipients were eligible for deferred treatment with sofosbuvir-velpatasvir-voxilaprevir Drug Dosing Sofosbuvir-Velpatasvir-Voxilaprevir (400/100/100 mg): fixed dose combination; one pill once daily Placebo: one pill once daily Source: Bourlière M, et al. N Engl J Med. 2017;376:2134-46.

Sofosbuvir-Velpatasvir-Voxilaprevir in NS5A-Experienced GT 1-6 POLARIS-1: Prior NS5A Treatment 133/263 70/263 30/263 33/263 Source: Bourlière M, et al. N Engl J Med. 2017;376:2134-46.

Sofosbuvir-Velpatasvir-Voxilaprevir in NS5A-Experienced GT 1-6 POLARIS-1: Results by Genotype 97/101 45/45 5/5 74/78 20/22 1/1 6/6 Source: Bourlière M, et al. N Engl J Med. 2017;376:2134-46.

HIV, HBV, HCV: Update 2017 HIV HBV HCV Questions