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HIV-Hepatitis C Treatment in 2016 Shobha Swaminathan, MD Associate Professor of Medicine Rutgers New Jersey Medical School Disclosure • Grant funding and advisory board from Gilead Sciences Overview • Background • Benefits and data to support all oral treatment for HCV • Case discussion Epidemiology • 3.6 million cases in the United States1 • 1.3 % of the United States population1 • 13,000 deaths annually in the United States • HCV is the leading cause of liver transplant in the US2 1 Denniston NM et al, Ann Intern Med 2014; 160(5):293 2 Verna EC, Brown RS, Clin Liver Dis 2006; 10(4) 919 Reported number of acute hepatitis C cases — United States, 2000–2014 3,500 Number of cases 3,000 2,500 2,000 1,500 1,000 500 0 Year Source: CDC, National Notifiable Diseases Surveillance System (NNDSS) Incidence of acute hepatitis C, by age group — United States, 2000–2014 3 Reported cases/100,000 population 0-19 yrs 20-29 yrs 2.5 30-39 yrs 2 40-49 yrs 50-59 yrs 1.5 > 60 yrs 1 0.5 0 Year Source: CDC, National Notifiable Diseases Surveillance System (NNDSS) 702 328 Injection-drug use Yes No 1,164 Missing§ 27 203 Men who have sex with men¶ 937 3 32 Sexual contact 2,159 150 344 Multiple sex partners 1,700 0 200 400 600 800 Source: CDC, National Notifiable Diseases Surveillance System (NNDSS) *A total of 2,194 case reports of acute hepatitis C were received in 2014. † More than one risk exposure/behavior may be indicated on each case-report. §Risk data not reported. ¶A total of 1,174 acute hepatitis C cases were reported among males in 2014. 1,000 1,200 1,400 1,600 1,800 2,000 2,200 Epidemiology of HIV-HCV Infection Liver disease associated with HCV infection has become a leading cause of morbidity and mortality among HCV/HIV-coinfected patients1 HIV/HCV epidemiology2 – Approximately 25% of HIV+ patients are coinfected with HCV – Approximately 80% of HIV+ patients who inject drugs are coinfected with HCV – All patients with HIV infection should be tested for HCV HIV+ patients are at 4.1 times the risk of HCV as HIV- patients3 1. Weber R, et al. Arch Intern Med. 2006;166:1632-1641. 2. CDC. HIV and viral hepatitis. May 2013. 3. Yaphe S, et al. Sex Transm Infect. 2012;88:558-564. Distribution of HCV Worldwide Fang J. Clin. Liver Dis 1997 Natural History of HCV Infection Acute HCV Resolved 15% to 45% Chronic HCV 55% to 85% Cirrhosis 5% to 25% Stable 75% to 95% Stable 97% to 99%/yr HCC or Decompensation 1% to 3%/yr Infection with HCV can also cause extrahepatic diseases: mixed cryoglobulinemia, types II and III 1. 2. 3. Thomas DL, et al. Clin Liver Dis. 2005;9:383-398, Strader DB, et al. Eur J Gastroenterol Hepatol 1996;8:324-328 Seeff LB, et al. Hepatology. 2002;36(suppl):S1-S2, 4. Seeff LB, et al. Hepatology. 2002;36(suppl):S35-S46, 5. Liang TJ, et al. Ann Intern Med. 2000;132:296-305, 6. Fattovich G, et al. Gastroenterology. 1997;112:463-472. Impact of HIV on HCV-related Disease • Coinfected pts have a faster (almost twice as fast) rate of progression to fibrosis • Accelerated rate of liver failure • Cirrhotic patients with HIV do worse • Hepatocellular carcinoma occurs at a younger age • Increasing mortality from liver disease related to HCV in HIV-infected patients • Serum HCV-RNA titers are 1.5-2 fold higher • People with lower CD4 count have faster progression of HCV Hepatitis C Screening • Birth Cohort (1945-1965) • Injection drug users (current or past) • received clotting factor concentrates produced before 1987 • long-term hemodialysis • persistently abnormal alanine aminotransferase levels (ALT) • HIV infection • Received blood products or transplant before 1992 USPSTF, CDC HCV Antibody Positive Negative HCV RNA Stop Not Detected No current HCV infection Additional Testing as needed Detected Link to care Treatment Objectives and Outcomes • Goal of HCV therapy • To prevent complications and death from HCV infection • Treatment responses currently defined by short-term surrogate parameters rather than clinical endpoints • Biochemical (normalization of serum ALT levels) • Virologic (undetectable serum HCV RNA by PCR) • Histologic (> 2 point improvement in necroinflammatory score with no worsening in fibrosis score) Ghany MG, et al. Hepatology. 2009;49:1335-1374. HCV Treatment Landscape in 2016: All-Oral Therapy for Genotype 1 HCV Infection • NS5B Polymerase Inhibitors (“buvir”) • Sofosbuvir • Dasabuvir • NS5A Inhibitors (“asvir”) • Ledipasvir • Ombitasvir • Daclatasvir • Elbasvir • Velpatasvir (Non-approved: Investigational Use) • Protease Inhibitors (“previr”) • Simeprevir • Paritaprevir • Grazoprevir AASLD Guidance on HCV/HIV DDIs Atazanavir + RTV Darunavir + RTV Lopinavir/RTV Tipranavir + RTV Efavirenz Rilpivirine Etravirine Raltegravir Elvitegravir + COBI Dolutegravir Maraviroc Tenofovir DF SMV + SOF SOF LDV/SOF DCV + SOF nephrotoxicity No clinically significant interaction expected AASLD/IDSA. HCV guidelines. December 2015. Potential interaction may require adjustment to dosage, timing of administration, or monitoring OMV/PTV/RTV + DSV Do not coadminister AASLD/IDSA Guidance for HCV/HIV Coinfection • Use same regimens as in HCV-monoinfected pts, but consider drug–drug interactions – Avoid combination of LDV and tenofovir DF if CrCl < 60 mL/min or if receiving tenofovir DF with RTV-boosted PIs – When LDV/SOF and tenofovir DF are coadministered with antiretrovirals, monitor for nephrotoxicity – Tenofovir levels increased with efavirenz, rilpivirine, or dolutegravir, when administered with LDV/SOF and tenofovir DF – Adjust/withhold RTV if receiving a boosted PI with OMV/PTV/RTV + DSV – Adjust DCV with atazanavir/RTV, efavirenz, or etravirine • DCV + SOF ± RBV recommended when ART regimen changes cannot be made to accommodate other DAAs AASLD/IDSA. HCV guidelines. April 2016 Sofosbuvir • NS5B Nucleotide Polymerase Inhibitor • 400 mg daily • A/E: fatigue, headache, nausea, rash, and irritability. • Active against genotype 1,2,3,4 • ARV: ALL except tipranavir; didanosine, zidovudine, (if given with ribavirin) • No response guided therapy Simeprevir • NS3/4A protease inhibitor • 150 mg daily • Genotype 1 and 4 • A/E: rash, pruritus, nausea • ARV: LIMITED to raltegravir, rilpivirine, maraviroc, enfuvirtide, tenofovir, emtricitabine, lamivudine, abacavir • *For genotype 1a, baseline resistance testing for Q80K should be performed and alternative treatments should be considered if this mutation is present. Ledipasvir • NS5A inhibitor • Available co-formulated with sofosbuvir • Generally well tolerated • Risk of Serious Symptomatic Bradycardia When Coadministered with Amiodarone • Risk of Reduced Therapeutic Effect of HARVONI Due to P-gp Inducers • Genotype 1, 4,5,6 • Can increase levels of tenofovir when co-administered with ritonavir Genotype 1 Genotype 4, 5, or 6 Patient Population Duration Treatment-naïve with or without cirrhosis 12 weeks Treatmentexperienced without cirrhosis 12 weeks Treatmentexperienced with cirrhosis 24 weeks Treatment-naïve 12 weeks and treatment experienced, with or without cirrhosis ION-4: LDV/SOF for 12 Wks in GT1/4 HCV/ HIV–Coinfected Pts 100 95 97 321/ 335 142/ 150 179/ 185 Overall Naive Exp’d 96 96 94 258/ 268 63/ 67 98 90 99 SVR12 (%) 80 60 40 20 n/N = 0 103/ 115 No Cirrhosis Exp’d + Black Cirrhosis Cirrhosis • Permitted ARTs: TDF/FTC plus efavirenz, raltegravir, or rilpivirine • Effective across subgroups, but with lowered SVR in black pts Cooper C, et al. EASL 2015. Abstract P1353. 46/ 47 215/ 217 Nonblack • • • • • • Daclatasvir NS5A inhibitor FDA approval for GT 1, 3 Genotype 1 Recommended in the guidelines for GT1, 2,3 CYP3A4 substrate 60 mg PO daily with sofosbuvir for 12 weeks Dose modification: Reduce dosage to 30 mg once daily with strong CYP3A inhibitors and increase dosage to 90 mg once daily with moderate CYP3A inducers • Daclatasvir requires dose adjustment with Genotype 3 ritonavir-boosted atazanavir (a decrease to 30 mg daily) and efavirenz or etravirine (an increase to 90 mg daily). • CONTRAINDICATIONS • Strong inducers of CYP3A, including phenytoin, carbamazepine, rifampin, and St. John’s wort Patient Population Duration Without cirrhosis DCV + SOF for 12 weeks Compensated (Child-Pugh A) cirrhosis Decompensated (Child-Pugh B or C) cirrhosis DCV + SOF+ RBV for 12 weeks Post-transplant Without cirrhosis With cirrhosis (including decompensated) Post-transplant DCV + SOF for 12 weeks DCV + SOF+ RBV for 12 weeks ALLY-2: DCV + SOF for 12 Wks in GT1-4 HCV/HIV–Coinfected Pts SVR12 (%) 100 96 98 97 98 80/ 83 43/ 44 98/ 101 51/ 52 Naive, 12 wks of DCV + SOF Exp’d 12 wks of DCV + SOF 80 60 40 20 n/N = 0 GT1 All Treated • Permitted ARTs: atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, efavirenz, nevirapine, rilpivirine, dolutegravir, raltegravir, enfuvirtide, maraviroc, zidovudine, lamivudine, abacavir, tenofovir DF, emtricitabine • Cirrhosis: 8.9% of naive pts, 28.8% of experienced pts • No significant difference in SVR12 rates among black vs nonblack pts (92% vs 97%, respectively) Wyles DL, et al. EASL 2015. Abstract LP01. Paritaprevir/Ritonavir/Ombitasvir/Dasabuvir (PrOD) • PI/NS5A/NS5B combination • Activity against GT1, 4 • atazanavir, dolutegravir, emtricitabine, enfuvirtide, lamivudine, raltegravir, and tenofovir • Adjust dose of ritonavir if part of HIV combo • HIV PI should be given at the same time • 2 tab P/r/O daily plus 1 tab Dasabuvir BID with ribavirin PATIENT POPULATION TREATMENT* DURATION Genotype 1a, without cirrhosis PrOD + ribavirin 12 weeks Genotype 1a, with cirrhosis PrOD + ribavirin 24 weeks** PrOD 12 weeks PrOD + ribavirin 12 weeks Genotype 1b, without cirrhosis Genotype 1b, with cirrhosis TURQUOISE-I: Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV in HIV/GT1 HCV Pts • Open-label phase II/III trial; compensated cirrhosis (Child-Pugh A) allowed; DAA naive but pegIFN/RBV naive or experienced Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV (n = 31) DAA-naive HIV-infected pts with GT1 HCV infection (N = 63) 100 Wk 12 Wk 24 Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV (n = 32) 93.5 90.6 93.8 100 93.3 29/ 29/ 31 32 15/ 12/ 16 12 14/ 17/ 15 20 Overall Atazanavir Raltegravir 85.0 SVR12 (%) 80 60 40 20 n/N = 0 Sulkowski MS, et al. JAMA. 2015;313:1223-1231. Eron JJ, et al. Glasgow HIV. Abstract O222. Slide credit: clinicaloptions.com Elbasvir/Grazoprevir • NS5A/protease inhibitor • GT1, 4 • 1a test for polymorphism • 1 tab daily +/- food • Approved for renal impairment including HD • Fatigue, headache, nausea • Monitor for DDI Patient Population Duration Genotype 1a: Treatment-naïve or PegIFN/RBVexperienced* without baseline NS5A polymorphisms† 12 weeks Genotype 1a: Treatment-naïve or PegIFN/RBVexperienced* with baseline NS5A polymorphisms† 16 weeks Genotype 1b: Treatment-naïve or PegIFN/RBVexperienced* 12 weeks Genotype 1a or 1b: PegIFN/RBV/PI-experienced‡ 12 weeks Genotype 4: Treatment-naïve 12 weeks Genotype 4: PegIFN/RBV-experienced* 16 weeks C-EDGE Coinfection: Grazoprevir/Elbasvir for 12 Wks in GT1-4 HCV/HIV–Coinfection 100 93 93 93 93 203/ 218 134/ 144 41/ 44 26/ 28 All Pts GT1a GT1b GT4 SVR24 (%) 80 60 40 20 n/N = 0 • SVR rates similar across pt subgroups, including in black pts and pts with cirrhosis • Tx failure in 2 pts attributable to posttreatment reinfection with GT3 HCV Rockstroh JK, et al. AASLD 2015. Abstract 210. C-EDGE TN: Impact of Baseline NS5A RAVs SVR12 With 12 Wks of Grazoprevir/Elbasvir 92 99 99 SVR12 (%) 100 58 80 60 40 20 n/N = 0 144/ 157 129/ 131 133/ 135 11/ 19 GT1a GT1b GT1a, No BL NS5A RAVs GT1a, BL NS5A RAVs Zeuzem Z, et al. Ann Intern Med. 2015;163:1-13. Slide credit: clinicaloptions.com HCV Treatment Terms • RVR- HCV negative at week 4 of treatment • EOT_ HCV negative at the end of treatment course • SVR 4- HCV negative at week 4 after completion of therapy • SVR12- HCV negative at week 12 after completion of therapy-”Cured” Monitoring of Patients • Within 12 weeks before treatment • CBC, INR, CMP • Any time prior • HCV GT • HCV Viral load • NS3 resistance • PI therapy • RAV testing • Per guidelines • During therapy • Monitor adherence • CBC, GFR, LFT at week 4 • HCV PCR at week 4, EOT, 12 weeks after t/t • Closer monitoring for cirrhotics • Discontinuation of treatment • HCV RNA at wk 4 if detectable, repeat at wk 6, if higher, discontinue Case Presentation-1 • A 54 year old male with HIV HCV • HIV VL < 20, CD4- 554 • HCV, GT 1a, VL- 6 million • Fibrosure: F2 • ARV: TDF/FTC, ATV/r • What are your treatment considerations • ARV • Pill burden • Drug interaction GT 1 a Preferred Alternative Cirrhosis EBV/GZV 12 WKS (no RAVs) DCV SOF 12 WKS LDV/SOF 12 WKS PrOD RBV 12 WKS SOF/SMV 12 WKS EBV/GZV 16 WKS (high NS5A RAVs) Cirrhosis + EBV/GZV 12 WKS LDV/SOF 12 WKS PrOD RBV 24 WKS SOF/SMV 24 WKS DCV SOF 24 +/- RBV EBV/GZV 16 WKS (high NS5A RAVs) Genotype 1b GT 1 b Preferred Cirrhosis EBV/GZV 12 WKS Cirrhosis + EBV/GZV 12 WKS DCV SOF 12 WKS LDV/SOF 12 WKS LDV/SOF 12 WKS PrOD RBV 12 WKS SOF/SMV 12 WKS Alternative PrOD RBV 12 WKS SOF/SMV 24 WKS DCV SOF 24 +/- RBV Case Presentation -2 • A 45 year old injection drug user with HIV-HCV, (GT2) was previously successfully treated with pegylated interferon and RBV. He comes back for a routine visit and is found to have elevated LFTs and found to have HCV infection again with GT2. • Further questioning reveals that he has been sharing needles with his girlfriend who also has HCV. She does not have HIV • His HIV is well controlled, VL < 50, CD4- 450, on Atripla Case Presentation -2 Contd • What are the issues that come up: • HIV PrEP • Risk reduction messaging • Would you treat him again • What different would you do Genotype 2 GT Cirrhosis - Cirrhosis + 2 DCV SOF 12 WKS Consider 16-24 weeks SOF RBV 12 WKS Genotype 3 GT3 Recommended Alternative Cirrhosis DCV SOF 12 WKS SOF RBV IFN 12 WKS SOF/RBV 24 WKS Cirrhosis + DCV SOF 24 +/RBV SOF RBV IFN 12 WKS Genotype 4 GT 4 Recommended Alternative Cirrhosis LDV/SOF 12 WKS Cirrhosis + LDV/SOF 12 WKS PrOD RBV 12 WKS EBV/GZV 12 WKS PrOD RBV 12 WKs EBV/GZV 12 WKS SOF RBV IFN 12 WKS SOF RBV IFN 12 WKS Genotype 5,6, Naïve • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks • Daily sofosbuvir (400 mg) and weight-based RBV plus weekly PEG-IFN for 12 weeks Case Presentation-3 • A 55 year old woman with compensated cirrhosis, HIV • HIV VL <20, CD4: 356 • HCV, GT 1a, HCV VL- 4 million • Treatment experienced with Peg IFN • TDF/FTC, RAL • ARV • HCV treatment option • Duration of therapy GT 1 a Preferred Alternative Cirrhosis EBV/GZV 12 WKS (no RAVs) DCV SOF 12 WKS LDV/SOF 12 WKS PrOD RBV 12 WKS SOF/SMV 12 WKS EBV/GZV 16 WKS (high NS5A RAVs) Cirrhosis + EBV/GZV 12 WKS LDV/SOF 12 WKS PrOD RBV 24 WKS SOF/SMV 24 WKS DCV SOF 24 +/- RBV EBV/GZV 16 WKS (high NS5A RAVs) What if the patient has ESRD Case Presentation-4 • A 55 year old woman with HIV and HCV and compensated cirrhosis was successfully treated with LDV/SOF for 12 weeks. • Does she require any future monitoring for her liver disease? 1. None required she is cured 2. Repeat HCV PCR every 6 months to ensure that she remains negative 3. She will require ongoing surveillance for hepatocellular carcinoma Case Presentation-5 • A 56 year old male with HIV/HCV treated with LDV/SOF for 12 weeks. However, his HCV PCR was positive 4 weeks after treatment completion. • What should you do now: • Defer treatment • Retreat with same regimen but now for 24 weeks • Retreat with another combo Case Presentation- 6 • A 60 year old AA male with HIV (VL <20, CD4 of 564) • Has HCV GT1a, compensated cirrhosis • Treated with LDV/SOF for 24 weeks • Now relapsed • What will you do next • Defer • Retreat with LDV/SOF/RBV for 24 weeks • Treat with SOF/SMV/RBV for 24 weeks Prior NS5b Failure • Deferral of treatment is recommended, for those who do not have cirrhosis, and do not have reasons for urgent retreatment. • Testing for resistance-associated variants that confer decreased susceptibility to NS3 protease inhibitors and to NS5A inhibitors is recommended • When using nucleotide-based (eg, sofosbuvir) dual DAA therapy a treatment duration of 24 weeks is recommended, and weight-based RBV, unless contraindicated, should be added. • If available, quadruple DAA regimens may be considered. In these settings treatment duration ranges from 12 weeks to 24 and weight-based ribavirin, unless contraindicated, are recommended. Case Presentation-7 • A 56 year old male with HIV, HCV (GT1a), ESRD on HD • ARV: Dolutegravir, Lamivudine, Darunavir/r (h/o NNRTI resistance) • No cirrhosis • What can you treat him with • • • • • LDV/SOF PrOD DCV/SOF SOF/RBV Elbasvir/grazoprevir Dosing Considerations for Pts With Renal Impairment eGFR/CrCl SOF/LDV[2] SOF + SIM[3,4] SOF + DCV[3,5] RBV[6] GZR/EBV[7] No adjustment needed No adjustment needed No adjustment needed No adjustment needed Alternating 200 mg and 400 mg every other day 15-30 mL/min No adjustment needed Safety and efficacy not established SMV/DCV: no adjustment needed; SOF: safety and efficacy not established 200 mg/day No adjustment needed < 15 mL/min or hemodialysis Safety and efficacy not established Safety and efficacy not established Safety and efficacy not established 200 mg/day No adjustment needed 30-50 mL/min PTV/RTV/OBV + DSV[1] In pts with CrCl < 30 mL/min for whom treatment is urgent and renal transplant not an immediate option: [3] – Recommended: 12 wks GZR/EBV (GT1a or GT1b); 12 wks PTV/RTV/OBV + DSV (GT1b) – Alternative: 12 wks PTV/RTV/OBV + DSV + reduced-dose RBV (GT1a) Slide credit: clinicaloptions.com SUMMARY • All patients should be considered for treatment • Priority for those with more advanced liver disease • Treatment will likely be expanded for all with additional medications being approved which will hopefully drive the costs down • In general HIV/HCV co-infected patients respond similar to HCV mono-infected patients • Ongoing risk reduction is necessary to reduce likelihood of reinfection