Managing DAA treatment failure and Drug Resistance in Clinical Practice

Transcription

1 Managing DAA treatment failure and Drug Resistance in Clinical Practice Vicente Soriano Infectious Diseases Unit La Paz University Hospital Madrid, Spain

2 The HCV cure equation SVR Viral replication suppression Immune response trigger = + X Time length Activity 95% DAA 40% time

3 Differences in the replication life cycle of HIV and HCV HIV HCV RNA RT Provirus Pro Nucleus Integration RNA Cytosol Pol Pro CD4+ T-lymphocyte Hepatocyte

4 Classification of recommended DAA (2016) NS3 protease inhibitors NS5A inhibitors Nucleos(t)ide polymerase inhibitors Non-nucleoside polymerase inhibitors Simeprevir Asunaprevir Paritaprevir Grazoprevir Ledipasvir Daclatasvir Ombitasvir Elbasvir Velpatasvir Sofosbuvir Beclabuvir Dasabuvir Squares record co-formulations or co-packaged medications. Velpatasvir will soon replace ledipasvir.

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7 Real-World Experience with LDV-SOF in G1 Treatment Naïve, Non-Cirrhotics with HCV-RNA <6 million IU/mL N=1014 N=808 N=131 N=192 N=254 N=456 8-wks eligible but received 12 wks Backus L, Abstract 93 Terrault, Abstract 94 42% 60% 50% Curry M, Abstract 1108

8 DAA real world experience TRIO (n=1685) Spain (n=363) Male 58% 75% Advanced liver fibrosis 30% (cirrhosis) 48% Elevated ALT? 83% Baseline HCV-RNA > 6 log 21% (>6 million) 59% HCV genotype 4 0 (67% G1a ) 15% HIV coinfection 7% 31% Ribavirin added 5% 38% Prior interferon failure? 49% SOF+LDV 88% 80% SVR 96% 97%* *Analysis per protocol (no ITT) Afdhal et al. AASLD 2015 Arias et al. AVT (in press)

9 Main characteristics of the study population according to treatment outcome. Sustained virological response (n=352) Treatment failure (n=11) Male gender, n (%) 255 (73.1) 9 (81.8) 0.7 Elevated ALT, n (%) 311 (81.2) 10 (90.9) 0.8 IL28B-CC, n (%) 97 (27.1) 2 (18.2) 0.9 Advanced liver fibrosis, n (%) 146 (42.8) 10 (90.9) Baseline HCV-RNA >6 log IU/mL, n (%) 225 (62.4) 6 (54.5) 0.7 Prior interferon exposure, n (%) 164 (47.2) 6 (54.5) 0.7 HIV coinfection, n (%) 91 (27.2) 7 (63.6) 0.04 HCV genotype 4, n (%) 46 (13.1) 4 (36.4) 0.05 Ribavirin added, n (%) 120 (34) 5 (45.4) 0.4 p *Analysis per protocol (no ITT) Arias et al. AVT (in press)

10 Main baseline characteristics of chronic hepatitis C patients that experienced DAA treatment failure Age (years) Gender male male male male male male mal e female ALT (IU/L) Serum HCV-RNA (log IU/mL) mal e male female HCV genotype 1a 4 1b 1a 4 1a 1b b Liver fibrosis stage (Metavir) F4 F4 F4 F1 F4 F3 F4 F4 F4 F3 F3 IL28B polymorphisms CC CT CT CT CT CT CC CT CT TT CT Prior interferon exposure no no no no yes yes yes no yes yes yes HIV coinfection yes yes no yes yes no yes yes no no yes DAA regimen SOF/L DV/R BV SOF/L DV/R BV SOF/ LDV/ RBV SOF/L DV SOF/ LDV/ RBV SOF/ LDV SOF/ SMV SOF/S MV SOF/ RBV SOF/ LDV SOF/L DV Arias et al. AVT (in press)

11 Predictors of DAA treatment failure in the study population. Multivariate analysis. Male gender (73%) 1.7 HIV coinfection (27%) p= Advanced liver fibrosis (F3-F4) (43%) p=0.01 Serum HCV-RNA >10 6 IU/mL (63%) Interferon experience (47%) HCV genotype 4 (13%) Ribavirin added (34%) sustained virological response treatment failure odds ratio Arias et al. AVT (In press)

12 Predictors of DAA failure Baseline On-treatment Cirrhosis Genotype 3 RAVs Prior interferon failure Elevated serum HCV-RNA IFNL4 unfavorable AA ethnicity Drug adherence Side effects Drug interactions

13 Anecdotal SAEs with DAA Bradyarrithmias (and syncope) Pulmonary arterial hypertension Lung toxicity Hepatotoxicity Photosensitivity Hyperbilirrubinemia Hypoglycemia in diabetics on insulin Hepatitis B reactivation Rapid HCV drop Fontaine et al. NEJM 2015; 373: Ahmad et al. Hepatology 2015; 62: Dyson et al. J Hepatol 2016; 64: Soriano et al. Hepatology (in press) Stine et al. Dig Dis Sci 2015; 60: Shibata et al. Hepatology (in press) Marchan et al. J Hepatol (in press) Helmers et al. Mayo Clin Proc 2015; 90: Renard et al. Chest 2016; 149: e Soriano et al. Antivir Ther (in press)

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15 HBV reactivation during DAA for hep C * Collins et al. Clin Infect Dis 2016 Ende et al. J Med Case Rep 2015 Takayama et al. Hepatol Res 2016 *De Monte J Clin Virol 2016

16 Difficult-to-cure HCV populations End-stage renal disease Decompensated cirrhosis Prior DAA failures Potential drug interactions: HIV, psychiatric, elder, etc Difficult drug adherence: homeless, illegal immigrants, jail, active IDU, psychiatric Insufficient data: Alcoholics, NASH-obese-diabetics, HBsAg+

17 Considerations for HCV re-treatment How urgent is it? Any chance to wait for better DAA? Virologic challenges: Presence of RAVs (prior DAA failure) Exclude HCV genotype shift (misinterpretation) Exclude HCV re-infection (risk behaviors) Strategic management: Adding ribavirin Extent the length of therapy Maximize drug benefit: Avoid drug interactions (co-morbidities) Prevent and manage side effects Ensure drug adherence

18 Principles guiding selection of HCV regimens for re-treatment of prior DAA failures Prior DAA failure Re-treatment options PegIFN+RBV o Sofosbuvir NS3 protease inhibitors Telaprevir Boceprevir Simeprevir + Sofosbuvir + NS5A inhibitors Ledipasvir Daclatasvir Sofosbuvir + NS5A inhibitors Ledipasvir Daclatasvir Sofosbuvir + NS3 protease inhibitors Simeprevir NS3 protease inhibitors plus NS5A inhibitors Paritaprevir + Ombitasvir Grazoprevir + Elbasvir Sofosbuvir +?

19 HCV Drug Resistance (RAVs) Prevalence vary by geno/subtype and geographic region. Baseline RAVs may reduce SVR in some patients: NS3 Q80K reduced SVR in G1a cirrhotics NS5A reduced SVR in cirrhotics with prior IFN failure Extending the length of DAA therapy may overcome the harmful impact of baseline RAVs Not all RAVs are equal, some are more equal than others NS3 protease D168X NS5A Y93H NS5B S282T

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21 GT 1 NS5A RAV Prevalence by Region * Based on 1% cut-off North America 25% (870/3440) USA Canada Puerto Rico Europe 25% (235/933) Belgium Switzerland Czech Republic Germany Spain France United Kingdom Italy Netherlands Poland Asia Pacific 26% (154/597) China India Japan Korea Russia Taiwan Oceania 27% (115/427) Australia New Zealand Using a 15% cut-off, the prevalence of NS5A RAVs was 14% in North America, 15% in Europe, 20% in Asia Pacific, and 17% in Oceania Zeuzem S, AASLD Abstract 91 21

22 SVR12 (%) No cirrhosis LDV-SOF in Patients with and without Baseline NS5A RAVs Naïve & VL<6M Naive Experienced Zeuzem S, AASLD Abstract 91

23 SVR12 (%) LDV-SOF in Patients with and without Baseline NS5A RAVs With cirrhosis 26/27 65/68 7/7 10/10 8/9 27/27 19/19 12 weeks 24 weeks Treatment Naive 12 weeks 24 weeks Treatment Experience Zeuzem S, AASLD Abstract 91

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28 Estimated clearance time for RAVs selected upon treatment failure RAVs (%) 10% days months years Benitez et al. Exp Op Pharmacother (in press)

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32 Drug Resistance Tests Commercially available methods not available in most countries. Population sequencing (Sanger) of the NS3 protease, NS5A domain I and NS5B by homemade methods. Sensitivity for RAVs: 20% Potential interest of NGS, but thresholds for clinical significance should be set up at 10%.

33 HCV resistance testing At baseline Q80K in G1a if simeprevir to be used At failure RAVs selected to most agents on board but sofosbuvir At re-treatment persistence of RAVs mostly for NS5A inhibitors and NS5B non-nuc inhibitors and less frequently for NS3 protease inhibitors

34 Prospects for HCV resistance testing Interesting academically to learn mechanisms of failure and potential cross-resistance. Avoid short lengths and close monitoring in cirrhotics However, the pace of development of better treatments and broader options would overcome the need to require individual resistance information for most re-treatments. Reminds what has happened in HIV.

35 Summary Failure to current DAA combinations occurs in 5-15% of chronic hepatitis C patients outside clinical trials. Most failures to oral DAA combinations are relapses instead of viral breakthroughs on therapy. Failures occur more frequently in treatment-experienced patients, those with advanced cirrhosis and infection with HCV genotypes 3 or 1a. In non-cirrhotics patients, DAA failure is rare and generally seen only when therapy is given for less than 12 weeks. Virologic breakthrough during DAA therapy generally reflects poor drug adherence. DAA failure is frequently associated with emergence of RAVs but to sofosbuvir. HCV drug resistance testing should be recommended for choosing the most convenient salvage DAA regimen as re-treatment for prior DAA failures.