HCV therapeutics


37

Antiviral Treatment for Hepatitis C Virus in HIV/HCV Coinfected Patients

George N. Ioannou1,2, John D. Scot2, Yin Yang1, Pamela Green1, Lauren A. Beste1

1Veterans Affairs Puget Sound Health Care System, Seattle, WA; 2University of Washinqfon, Seattle, WA

Objectives We aimed to determine the rates and predictors of sustained virologic response (SVR) to antiviral treatment for hepatitis C virus (HCV) with pegylated interferon and ribavirin in HIV/HCV co-infected patients. Methods We identified all HIV/HCV co-infected patients who received antiviral treatment with pegylated interferon and ribavirin, the current standard of care, in the Veterans Affairs healthcare system nationally between 2002-2009 (n=665). Results Among 619 patients with available data, SVR was achieved in 21.6% overall, 16.7% among patients with genotype 1 HCV (n=491), and 44% among patients with genotype 2 or 3 HCV (n = 116). Among genotype 1 infected patients, characteristics that independently predicted failure to achieve SVR included baseline HCV viral load >2 million IU/ml (adjusted odds ratio [AOR] 0.41, 95% CI 0.2-0.7), Black race (AOR 0.56 [0.3-0.96]), diabetes (AOR 0.42 [0.2-0.9]), baseline anemia (AOR 0.42 [0.2-0.97]), serum AST/ALT ratio >1.2 (AOR 0.48 [0.2-0.97]) and use of zidovudine (AOR 0.41 [0.2-0.9]). Treatment characteristics that independently predicted achieving SVR in genotype 1-infected patients included a starting dose of ribavirin ≥1200mg/day, if weight ≥75Kg, or ≥1000mg/day, if weight <75Kg, (AOR 2.0 [1.1-3.7]) and erythropoietin use during treatment (AOR 2.9 [1.6-5.0]). Among genotype 2 or 3 infected patients, only erythropoietin use was an independent predictor of achieving SVR (AOR 3.1[1.2-7.8]), while a starting dose of ribavirin >800 mg/day was not associated with SVR. Conclusions SVR rates achieved with pegylated interferon and ribavirin in HIV/HCV co-infected patients are low in clinical practice. Erythropoietin use was the most important, modifiable factor associated with SVR. Higher starting ribavirin doses are necessary to achieve SVR for genotype 1 HCV (1000-1200 mg/day) than for genotype 2 and 3 HCV (800 mg/day).

Disclosures:

John D. Scott - Advisory Committees or Review Panels: Vertex; Grant/Research Support: Gilead, Merck, Genentech, Vertex, Janssen; Speaking and Teaching: Gilead, Genentech, Vertex; Stock Shareholder: Merck

The following people have nothing to disclose: George N. Ioannou, Yin Yang, Pamela Green, Lauren A. Beste

38

Telaprevir combination therapy in treatmenl-naϊve and experienced patients co-infected with HCV and HIV

Marisa Montes1, Mark Nelson2, Marie Girard3, Joe Sasadeusz4, Andrzej Horban5, Beatriz Grinsztejn6, Natalia Zakharova7, Karolin Falconer8, Inge Dierynck9, Donghan Luo10, Yi-Wen Ma10, James Witek10

1Hospital La Paz, Madrid, Spain; 2Chelsea and Westminster Hospital, London, United Kingdom; 3Hôpital St Antoine, Paris, France; 4Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne, VIC, Australia; 5Hospital of Infectious Diseases, Warsaw, Poland; 6STD/AIDS Clinical Research Laboratory, Instituto de Pesquisa Clίnica Evandro Chagas, Rio de Janeiro, Brazil; 7Saint-Petersburg AIDS Center, St. Petersburg, Russian Federation; 8Karolinska University Hospital, Stockholm, Sweden; 9Janssen Infectious Diseases BVBA, Beerse, Belgium; 10Janssen Research & Development LLC, Titusville, NJ

Background: A Phase 2 study in HCV treatment naϊve patients co-infected with genotype 1 HCV/HIV previously showed substantially higher SVR24 rates with a telaprevir (TVR)-based regimen (74%) compared with placebo (45%). We report the Week 12 interim analysis of INSIGHT: a Phase 3 study of TVR in combination with peginterferon (P)/ribavirin (R) in genotype 1 HCV treatment-naϊve and -experienced patients with HCV/HIV co-infection. Methods: Patients who were on stable, suppressive HIV antiretroviral therapy (ARV) including atazanavir (ATZ)/ritonavir (r), efavirenz (EFV), darunavir (DRV)/r, raltegravir (RAL), etravirine (ETR) or rilpivirine received TVR 750mg q8h (1125mg q8h if on EFV) plus P (180μg onceweekly) and R (800mg/day) for 12 weeks, followed by an additional 12 weeks (HCV treatment-naϊve and relapse patients with extended rapid viral response [eRVR]) or 36 weeks (all others) of PR alone. Analysis was performed when all patients had completed Week 12 or discontinued earlier. Results: 162 patients were enrolled and treated (ARV: 65 EFV, 58 ATZ/r, 17 DRV/r, 16 RAL, 4 ETR, 2 other). Mean age was 45 years, 78% were male, 92% were Caucasian; mean CD4 count was 687cells/mm3.64 patients were HCV treatment naϊve and 98 were HCV treatment experienced (29 relapsers, 18 partial responders and 51 null responders). 64% had subtype 1a and 30% had bridging fibrosis (17%) or cirrhosis (13%). 19% of patients discontinued TVR, including 9% due to an AE and 8% reaching a virologic endpoint. Treatment responses are shown by HCV treatment experience groups (Table). There were no HIV RNA breakthroughs. Absolute CD4 counts declined from baseline, although CD4% was unchanged. Most frequently reported (≥20% patients) AEs were pruritis (41%), fatigue (27%), rash (26%) and influenza-like illness (21%); rash was Grade >3 in 2% of patients. Anemia was reported in 13% of patients, with 3% reporting Grade >3 anemia. Hemoglobin decrease Grade >3 occurred in 2% of patients.6% of patients had serious AEs. Conclusions: In this first Phase 3 study of HIVinfected, HCV treatment-naīve and -experienced patients, 49% of patients achieved eRVR and 72% had undetectable HCV RNA at Week 12.Safety and tolerability of TVR/PR was comparable with that previously observed in HCV monoinfected patients, but with less frequent occurrence of anemia using R 800mg/day.

Undetectable HCV RNA*, n (%) Treatment naϊve (N=64)Priorrelapse (N=29)Prior partial responder (N=18)Prior null responder (N=51)Overall (N=162)
  1. *HPS COBAS® Taqman® (v2.0, Roche): lower limit of quantification of 25 IU/mL, limit of detection of 15 IU/mL (genotype 1).

At Week 4 (RVR)38 (59)17(59)10(56)19 (37)84 (52)
At Week 12 (cEVR)51(80)21(72)15 (83)29 (57)116(72)
At Weeks 4 and 12 (eRVR)36 (56)14 (48)10(56)19(37)79 (49)

Disclosures:

Mark Nelson - Advisory Committees or Review Panels: Boehringer Ingelheim, Janssen, MSD, BMS, Abbott, Viiv, Gilead; Consulting: Boehringer Ingelheim, Janssen, MSD, BMS, Abbott, Viiv, Gilead; Grant/Research Support: Boehringer Ingelheim, Janssen, MSD, BMS, Abbott, Viiv, Gilead, Roche; Speaking and Teaching: Boehringer Ingelheim, Janssen, MSD, BMS, Abbott, Viiv, Gilead

Joe Sasadeusz - Grant/Research Support: Gilead Sciences, BMS, Roche, Janssen; Speaking and Teaching: Gilead Sciences, Roche, BMS

Karolin Falconer - Advisory Committees or Review Panels: Roche, Roche, Roche, Roche

Inge Dierynck - Employment: Janssen Infectious Diseases, Johnson & Johnson; Stock Shareholder: Janssen Infectious Diseases, Johnson & Johnson

Donghan Luo - Employment: Tibotec Inc.; Stock Shareholder: Johnson & Johnson

James Witek - Employment: Johnson & Johnson; Stock Shareholder: Johnson & Johnson

The following people have nothing to disclose: Marisa Montes, Marie Girard, Andrzej Horban, Beatriz Grinsztejn, Natalia Zakharova, Yi-Wen Ma

39

Differential Impact of Type 1 Interferon on Chronic Hepatitis C Infection in HIV Co-infection, Pre- and PostHAART

Ashwin Balagopal, Abraham J. Kandathil, Johnanathan Wood, Fuat Kurbanov, Jeffrey Quinn, Justin Richer, Yvonne M. Higgins, Lois Eldred, Zhiping Li, Mark S. Sulkowski, David L. Thomas

Johns Hopkins, Baltimore, MD

Viral dynamic studies were performed pre- and post- antiretroviral therapy (ART) in HIV-HCV co-infected persons to test whether HIV suppression would improve the response of HCV to interferon alfa. Persons with chronic HIV-HCV co-infection were recruited if they were treatment naϊve for HCV and had no ART for HIV within 12 months AND cumulatively for <24 months, were HBsAg negative, and had CD4+ T cell counts >200/mm3.A baseline viral dynamic study (pre-ART) was performed at the Johns Hopkins Hospital Clinical Research Unit; HCV RNA was measured at baseline (time-zero) and at 12, 24, 48, and 72 hours after 1.5μg/kg of peginterferon (IFN) alfa 2b. After 14 days, ART consisting of raltegravir, tenofovir, and emtricitabine was given. When HIV RNA levels were <400 c/ml for ≥12 weeks, subjects were restudied in an identical IFN study (post-ART). Liver biopsies were performed by minilaparoscopy 2-4 hours before each IFN dose. of a planned 20 participants, 20 gave informed consent and were enrolled; one did not complete the study. At baseline, median (range) age was 49.1 years (21.4-60.6), 4/19 (21%) were female, and 12/19 (63.2%) were black. Median (IQR) CD4+ T cell count and HIV RNA level were 425 cells/μL (219-690) and 4.27 log10 cp/mL (2.91-5.44), respectively. Most subjects had HCV genotype 1a infection (15/19) with median (IQR) HCV RNA levels of 6.83 log10 IU/mL (6.04-7.62); 14/19 (73.7%) had Metavir scores<2, and none had cirrhosis. The post-ART IFN study commenced after a median (IQR) of 175 days (112-217) of ART. Within 12 weeks of ART a transient increase in HCV RNA was seen in 18 of 19 patients, followed by a decrease such that the time-zero HCV RNA was lower in the post-ART study by a median (IQR) of 0.21 log10 IU/mL (0.06-0.56; p=0.002). Both pre- and post-ART, the HCV RNA nadir occurred 48 to 72 hours after IFN. The IFN response pre- and post-ART were closely correlated (at 72 hours: r=0.87; p<0.001) and both were associated with IL28B genotype (before p=0.02 and after p=0.005). The IFN response was not associated with baseline HIV RNA level, CD4+ T cell count, or T cell recovery. As hypothesized, the IFN response post-ART was greater than pre-ART; the difference was small and only significant at 72 hours (median (IQR) 0.11 log10 IU/mL; 0.000.40; p<0.05). Intrahepatic IFIT1 levels were inversely correlated with IFN response (r=-0.78; p<0.001) and its improvement post-ART (r=-0.56; p<0.05). While these data support the preference to begin ART before IFN based HCV treatment, the small improvement in early IFN response might also support withholding ART when interactions between HCV protease inhibitors and ART cannot safely be overcome.

Disclosures:

Mark S. Sulkowski - Advisory Committees or Review Panels: Pfizer; Consulting: Merck, AbbVie, BIPI, Vertex, Janssen, Gilead, BMS, BMS; Grant/Research Support: Merck, AbbVie, BIPI, Vertex, Janssen, Gilead

David L. Thomas - Grant/Research Support: Merck, Gilead

The following people have nothing to disclose: Ashwin Balagopal, Abraham J. Kandathil, Johnanathan Wood, Fuat Kurbanov, Jeffrey Quinn, Justin Richer, Yvonne M. Higgins, Lois Eldred, Zhiping Li

40

Telaprevir in the Treatment of Acute HCV Infection in HIV-infected Men: SVR 12 Results

Daniel S. Fierer1, Douglas T Dieterich2, Michael P. Mullen1, Andrea D. Branch2, Alison J. Uriel2, Damaris C. Carriero2, Woufer O. van Seggelen1, Rosanne M. Hijdra1, David Cassagnol1

1Infectious Diseases, Mount Sinai School of Medicine, New York, NY; 2Liver Diseases, Mount Sinai School of Medicine, New York, NY

Background: Sustained virological response (SVR) rates with pegylated interferon (pIFN) + ribavirin (RBV) in HIV-infected men are significantly higher in acute HCV (∼65%) than in chronic HCV (∼35%), but treatment is lengthy (24-48 wks) and SVR rates are suboptimal. We hypothesized that adding telaprevir (TVR) to pIFN+RBV would both shorten treatment and increase the SVR rates in acute HCV in HIV-infected men. Methods: This is an IRB-approved, open-label, consecutive enrollment pilot study of TVR 750 mg/8 hr + pIFN-α 180 μg/wk + weight-based RBV for 12 wks in HIV-infected men with acute gt 1 HCV infection. Stopping rule was HCV VL > 1,000 IU/mL at wk 4.Allowed ARVs were tenofovir+emtricitabine, efavirenz (with TVR dose adjustment), rilpivirine, atazanavir/ritonavir, and raltegravir. HCV VL was measured by transcription-mediated amplification (TMA, LLOD 5 IU/mL). The comparator group was HIV-infected men with acute gt 1 HCV treated during the 3 yrs prior to the FDA approval of TVR and those ineligible for TVR. The primary endpoint, SVR 12, is reported without statistical analysis due to the small sample sizes. Results: In the TVR-based triple therapy group, 84% (16/19) achieved the primary endpoint, SVR 12, compared to 63% (31/49) in the comparator group. Among men with SVR, the median time to VL < 5 was wk 2 in the TVR group vs wk 4 in the comparator group, and 94% vs 55% had VL < 5 by wk 4.In the TVR group there were no relapses after ETR, and 13 men (81% of SVR 12) have achieved SVR 24 so far. Two of the 3 patients in the TVR group who failed therapy had non-response (gt 1b, white, CT; gt 1a, black, TT), and one had rebound at wk 12 (gt 1a, Hispanic, CT). Most (81%) in the TVR group received ≤ 12 weeks of therapy–3 were treated 4-8 wks and 3 were treated with an additional 12 wks pIFN+RBV–while all in the comparator group received ≥ 24 weeks of therapy. A higher percentage of men in the TVR vs comparator group had IL28B CC (63% vs 42%), which may have contributed to the higher SVR rate. No one in the TVR group had HIV VL break-through and the overall safety profile was similar to that known for the TVR+pIFN+RBV regimen. Conclusions: Incorporating TVR into treatment of acute gt 1 HCV in HIV-infected men reduced treatment duration to 12 wks in most patients while maintaining a very high SVR rate. The absence of relapses suggests that 12 wks triple therapy is sufficient if HCV VL < 5 by wk 4.Larger studies should be done to confirm these findings. Nonetheless, this triple drug regimen appears to be a substantive improvement in the treatment of acute gt 1 HCV in HIV-infected men.

Disclosures:

Douglas T. Dieterich - Advisory Committees or Review Panels: Gilead, Genentech, Janssen, achillion, idenix, Merck, Tobira, Boehringer Ingelheim, TIbotec, Inhibitex, Roche, Vertex

Michael P. Mullen - Advisory Committees or Review Panels: GILEAD; Speaking and Teaching: GILEAD

Andrea D. Branch - Grant/Research Support: Kadmon, Gilead, Janssen

Damaris C. Carriero - Consulting: Genentech, Gilead, Vertex; Speaking and Teaching: Genentech, Vertex

The following people have nothing to disclose: Daniel S. Fierer, Alison J. Uriel, Wouter O. van Seggelen, Rosanne M. Hijdra, David Cassagnol

41

Virologic Outcomes and Adherence to Treatment Algorithms in a Longitudinal Study of Patients with Chronic Hepatitis C Treated with Boceprevir (BOC) or Telaprevir (TVR) in the United States (HCV-TARGET)

Adrian M. Di Bisceglie1, Alexander Kuo2, Vinod K. Rustgi3, Mark S. Sulkowski4, Richard K. Sterling10, Thomas Stewart8, Michael W. Fried8, Jonathan M. Fenkel5, Hisham ElGenaidi6, Mitchell A. Mah'moud7, George M. Abraham9

1Saint Louis University, St. Louis, MO; 2UC San Diego Medical Center, San Diego, CA; 3Metropolitan Liver Diseases/Gastroenterology Center, Fairfax, VA; 4Johns Hopkins University, Baltimore, MA; 5Thomas Jefferson University, Philadelphia, PA; 6Our Lady of Lourdes Medical Center, Camden, NJ; 7Duke School of Medicine/Boice-Willis Clinic, Rocky Mount, NC; 8University of North Carolina, Chapel Hill, NC; 9Saint Vincent Hospital, Worcester, MA; 10Virginia Commonwealth University Health System, Richmond, VA

BACKGROUND: Since 2011 recommended treatment for HCV genotype 1 has been pegIFN/RBV combined with TVR or BOC. However, adherence to current response guided therapy (RGT) and the effectiveness of triple therapy outside of registration trials are poorly defined. AIMS: To assess utilization of RGT and virologic responses for a large cohort of pts treated within the U. S. based upon local practice and HCV RNA determinations. METHODS: HCV-TARGET is an ongoing longitudinal observational study at 44 academic and 59 community centers. Demographic, clinical and virologic data and adverse events are collected throughout treatment and follow-up on sequentially enrolled pts, together with information on adherence to treatment futility rules at key time points. RESULTS: Of 2,212 pts enrolled in TARGET, 709 have been followed for at least 1 yr, of whom 524 had a determination of virologic outcome within a window up to 6 wks after stopping therapy (SVR6). Of 524 pts, 61% were male, 77% Caucasian (17% Black). Their mean age was 56 yrs (range 18-76), 41% were treatment naive and 44% cirrhotic. Adherence to futility rules was evaluated: an HCV RNA result was available at wk 4 in 84% of pts on TVR and in 73% of pts on BOC by wk 12.Among pts on TVR, 19/457 (4%) had HCV RNA >1000 IU at treatment wk 4; 7 (37%) promptly discontinued treatment, 9 (47%) discontinued later (mean −7.8 wks) but 3 remained on treatment and 1 achieved SVR6.Of pts with a planned BOC regimen, 12 had an inadequate viral response to pegIFN/RBV by wk 4 so treatment was discontinued. By wk 8, HCV RNA declined <3 log10 from baseline in 12/142 (8%) on BOC; 5 (42%) promptly discontinued treatment, while 7 (68%) continued. By wk 12 on BOC, 16/123 (13%) met the futility rule (residual HCV RNA >100 IU). Of these, 7 (58%) stopped therapy within 2 wks, 6 continued (mean +5.5 wks; range 3-12 wks), 3 completed a full course of treatment, although only 1 achieved SVR6.Table shows rates of SVR6.CONCLUSIONS: RGT virologic milestones appeared to be managed appropriately in most pts. Preliminary SVR results were lower than in published pivotal studies, possibly because pts in this large cohort had difficult-totreat characteristics (cirrhosis, genotype 1a, prior null response).

FeatureTelaprevir (n=392)Boceprevir (n=132)
Disease Characteristics Cirrhosis Genotype la/lb/lNOS Prior null response49%49%/21%/25% 15% 31% 47%/25%/24% 25%
Treatment naϊve SVR6 (Cirrhosis/Non-cirrhosis)63% (100/158) 47% (36/76); 78% (64/82)66% (31/47) 45% (5/11); 72% (26/36)
Treatment experienced SVR 6 (Cirrhosis/Non-Cirrhosis) 60% (140/234) 56% (70/124); 64% (70/110)29% (25/85) 20% (6/30); 35% (19/55)
V irologic breakthrough 9% 8%

Disclosure:

Adrian M. Di Bisceglie - Advisory Committees or Review Panels: Genentech, Vertex, Janssen, BMS, Salix; Consulting: Vertex; Grant/Research Support: Genentech, Gilead, Idenix, Vertex, Abbott, Janssen, GlobeImmune

Alexander Kuo - Advisory Committees or Review Panels: Gilead; Grant/Research Support: Gilead, Roche, Vertex

Vinod K. Rustgi - Grant/Research Support: gilead, bristol myers squibb, abbott, achillion; Speaking and Teaching: merck, genentech, vertex

Mark S. Sulkowski - Advisory Committees or Review Panels: Pfizer; Consulting: Merck, AbbVie, BIPI, Vertex, Janssen, Gilead, BMS, BMS; Grant/Research Sup port: Merck, AbbVie, BIPI, Vertex, Janssen, Gilead

Richard K. Sterling - Advisory Committees or Review Panels: Merck, Vertex, Salix, Bayer, BMS, Abbott; Grant/Research Support: Merck, Roche/Genentech, Pfizer, Medtronic, Boehringer Ingelheim, Bayer, BMS, Abbott

Michael W. Fried - Consulting: Genentech, Merck, Abbvie, Vertex, Janssen, Bristol Myers Squibb, Gilead; Grant/Research Support: Genentech, Merck, AbbVie, Vertex, Janssen, Bristol Myers Squibb, Gilead; Patent Held/Filed: HCCPlex

Jonathan M. Fenkel - Consulting: Vertex Pharmaceuticals, Idenix Pharmaceuticals, Janssen Therapeutics

Hisham ElGenaidi - Speaking and Teaching: Genentech, Merck, Bayer/Onyx, Kadmon, Vertex, BMS, Salix

George M. Abraham - Consulting: Kadmon; Grant/Research Support: Gilead, Genentech; Speaking and Teaching: Vertex, Merck

The following people have nothing to disclose: Thomas Stewart, Mitchell A. Mah'moud

42

Serious Adverse Drug Reactions Related to Boceprevir: Analysis of Food and Drug Administration Reported Events

Bryan L. Love1, Vishvas Garg2, Rasha Arabyat2, Dennis W. Raisch2, Charles L. Bennett1

1SC College of Pharmacy, Columbia' SC; 2The University of New Mexico College of Pharmacy, Albuquerque, NM

BACKGROUND: The approval of Hepatitis C (HCV) protease inhibitors has ushered in a new era of therapy for chronic HCV infection. Boceprevir, in combination with peginterferon and ribavirin, is approved for treatment of both naϊve and previously treated patients. The purpose of this study was to examine the frequency of serious adverse drug reactions (SADRs) associated with boceprevir from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: We searched FAERS for boceprevir-associated SADRs between May 13, 2011 and June 30, 2012.Empirical Bayes geometric means (EBGM) were estimated to investigate the disproportionality reporting signals for specific SADRs from boceprevir administration. SADRs of interest included thromboembolic events [myocardial infarction (MI), deep vein thrombosis (DVT), pulmonary embolism (PE), cerebrovascular accident (CVA)], severe cutaneous reactions, anemia, thrombocytopenia, neutropenia, and hepatic failure. Duplicate case reports were matched (based on age, sex, race, and event date) and excluded from the analysis. A significant signal was defined as EBGM 0.05 lower boundary confidence interval (CI) >2 and number of events >3.RESULTS: A total of 334 SADRs of interest were reported in 295 patients while receiving a boceprevirbased treatment regimen(table 1). Hematologic toxicities were the most frequently reported events. Significant signals were found for boceprevir-associated anemia, thrombocytopenia, and neutropenia. A total of 13 cases of hepatic failure were reported with 8 of these resulting in death; however, this did not meet the pre-specified criteria to be a significant signal. CONCLUSIONS: Hematologic toxicity was disproportionately reported with boceprevir, which is consistent with adverse events observed during clinical trials. Additionally, the EBGM signal for hepatic failure was nearly significant. This finding was unexpected and distinct from clinical trial data. Additional investigation into these cases of hepatic failure is warranted and may provide further insight into underlying risk factors.

Table 1: Summary of FDA Reported Cases

Adverse EventReported CasesEBGM (95% CI)
MI90.38 (0.19 to 0.68)
CVA130.44 (0.24 to 0.72)
Severe Cutaneous Reactions130.46 (0.12 to 1.85)
DVT/PE40.65 (0.21 to 1.50)
Hepatic Failure133.53 (1.96 to 6.14)
Thrombocytopenia805.71 (4.89 to 7.03)
Neutropenia1687.78 (6.54 to 8.93)
Anemia4617.95 (10.56 to 22.79)

Disclosures:

Bryan L. Love - Grant/Research Support: Bristol-Myers-Squibb

The following people have nothing to disclose: Vishvas Garg, Rasha Arabyat, Dennis W. Raisch, Charles L. Bennett

Ancillary