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HIV/HCV co-infection current and future management

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1 HIV/HCV co-infection current and future management
Sanjay Bhagani Consultant Physician/Senior Lecturer Dept of Infectious Diseases/HIV Medicine Royal Free Hospital/University College London


3 Mortality of HIV-infected patients in France (GERMIVIC Study Group)
Rosenthal et al. AASLD 2004; Abstract 572.

4 Overlapping HCV & HIV epidemics
40 million 175 million 10 million HIV HCV

5 Epidemic of Acute HCV among HIV+ MSM-beyond Europe...and continuing.....
– UK2,3,4 – Germany5 – France6,7 – Netherlands8 – Switzerland9 – Italy10 – Belgium11 USA1,2: Australia12: 1. Luetkemeyer JAIDS 2006; 2. Danta AASLD 2008; 3. Jones 4th Works. HIV & Hep. Coinf. 2008; 4. Fisher CROI 2007; 5. Stand 01/2009; 6.Gambotti Euro Surveill 2005; 7. Larsen AASLD 2007; 8. van de Laar JID 2007; 9. Rauch CID 2005; 10. Gallotta 4th Works. HIV & Hep. Coinf. 2008; 11.; 12. Matthews , CID 2009 5

6 HCV-seroconversion may be delayed
Median time from HCV RNA to Ab(+) = 91 days (0-1206) 10% Ab(-) after 9 months 5% Ab(-) after 12 months Low ALT/low nadir CD4 associated with delayed/null AB response Thomson E, et al. AIDS 2009; 23: 89-93

7 Natural course of acute HCV infection
Acute Hepatitis C takes a chronic course more frequently in HIV infected individuals (II) Spontaneous clearance of acute HCV in HIV patients occurs in 0 – 40% (III) and is associated with Host genetic factors (IL28b-CC genotype) and stronger adaptive immune responses. (II) Female sex, exposure group (sexual transmission vs. IVDU), HBsAg+, jaundice and higher peak ALT (II) Early decline of HCV-RNA 4-8 weeks after presentation (III)

8 Natural Course AHC in HIV-positive C
Natural Course AHC in HIV-positive C.NEAT Cohort, 92 untreated patients Week 4 HCV-RNA may be predictive for negative HCV-RNA at week 24 (=spontaneous clearance) Sensitivity analysis classifying missing = failure reduced NPV of a pRVC to 78% pRVC partial rapid virological control 2 log drop of HCV-RNA at week 4 cRVC complete rapid virological control HCV-RNA < 615 IU/ml at week 4 cEVC complete early virological control HCV-RNA < 615 IU/ml at week 12 Clearance HCV-RNA < 615 IU/ml week 24 Clearance chronic HCV predictive value pRVC 22 3 PPV 88% no pRVC 4 23 NPV 85% cEVC 32 PPV 89% no cEVC 2 NPV 92% Vogel et al. CROI 2010, Poster 640

9 Managing Acute HCV in HIV+ The NEAT consensus
Initial presentation acute HCV Week 4 Decay HCV-RNA < 2 log10 Treatment  2 log10 Week 12 HCV-RNA positive Treatment negative wait: cont´d controls throughout week 48

10 EACS Guidelines 2011 Screening and counselling
All HIV+ patients should be screened for HCV at diagnosis, and then on an annual basis HCV RNA in those with a high index of suspicion and a negative HCV-AB test Those at high risk of HCV-infection (ongoing IVDU, unprotected mucosal traumatic sex, unprotected anal intercourse, recent STD) with unexplained rise in hepatic serum aminotransferases HCV-Ab If HCV-Ab negative – test for HCV RNA for early identification Since HIV and HBV and occasionally HCV are sexually transmitted counselling regarding safe-sex practices should be provided

11 Consideration for treatment with anti-HCV therapy in HIV/HCV co-infected patients Pertinent issues:
Natural history of liver disease and liver associated mortality Effect of HAART Response rates to PegIFN-alpha and ribavirin Predictors of response Current guidelines – who to treat and when to start? Future…..

12 Effect of HIV/HCV co-infection on fibrosis rate (Benhamou et al 1999)
Fibrosis Score Fibrosis progression influenced by CD4 cell count (< 200 cells/microlitre) Age at infection ( > 25 years) Male sex Alcohol consumption ( > 50g/d)

13 Impact of HIV RNA, CD4, or Both on Liver Fibrosis Progression Rate
0.196 P=0.005 P=0.005 0.162 0.155 0.145 Slide #34: Impact of HIV RNA, CD4, or Both on Liver Fibrosis Progression Rate Brau and colleagues found that in HIV/HCV-coinfected patients, fibrosis progression rate was: Strongly correlated with HIV RNA levels. Increased with CD4 cell counts <500 cells/mm3 combined with HIV RNA>400 copies/mL (P=0.005). Reference Brau N, Rogdriquez-Torres M, Salatore M, et al. Control of viral HIV load through highly active antiretroviral therapy (HAART) slows down liver fibrosis in HIV/HCV-coinfection and makes it the same as in HCV-monoinfection. Program and abstracts of the 39th Annual Meeting of the European Association for the Study of the Liver. April 14-19, Berlin, Germany. Abstract 91. Ishak Fibrosis Units/Year P=0.04 0.122 0.121 0.123 P=0.53 < K >100K > < < >400 HIV RNA (copies/mL) CD4 (cells/mm3) HIV RNA (copies/mL) + <500 CD4 cells/mm3 Brau N, et al. 39th EASL. Berlin, Abstract 99.

14 HIV/HCV – complex immune interactions
Klenerman P, Kim A. PLOS Med 2007; 4:

15 Immune activation and liver disease
Cirrhosis HCV Alcohol Altered portal vein circulation Mathurin et al., Hepatology 2000; 32: ; Paik et al., Hepatology 2003; 37: ; Balagopal et al., Gastroenterology 2008; 135: IL-1 TNF-a IFN-a IL-12 Hepatic fibrosis HSC activation HIV -> GIT CD4+ T-cell depletion Microbial translocation LPS Immune activation DCs macrophage Slide Courtesy Prof S Lewin

16 Progression to cirrhosis
1.00 4682 patients 0.83 HIV-HCV Alcohol HBV Haemochromatosis HCV Steatosis BMI>25 2PBC 0.67 0.50 Hazard function 0.33 Fibrosis progression to cirrhosis varies by cause and population. This large retrospective analysis shows that in this cohort of over4500 patients progression to cirrhosis was fastest in HIV/HCV co-infected patients. Not only did progression vary by disease, but also there was acceleration of fibrosis progression by aging. Therefore, staging helps identify level of fibrosis and helps in prognosis and individual treatment decision-making in patients with HIV/HCV. 0.17 0.00 20 40 60 80 Age in years Poynard, T. et al., (2003) A comparison of fibrosis progression in chronic liver disease. Journal of Hepatology 38:

17 Fibrosis stage at second biopsy
Ishak fibrosis stage on second biopsy among persons with little or no fibrosis on first biopsy n = 51 60 Median (IQR) time between bxs, 2.84 yrs (2.05–3.41) 28% with more than 2 stage progression 45% 40 Patients (%) 23% 20 14% 10% 8% 1 2 3 or 4 5 or 6 Fibrosis stage at second biopsy Sulkowski MS et al. 12th Conference on Retroviruses and Opportunistic Infections (Abstract #: P-172). Boston, MA USA, February 22–25, 2005

18 HIV/HCV - Cirrhosis and survival
Pineda et al. Hepatology 2005

19 So what effect does HAART have?

20 Overall and Liver-related Mortality - effect of HAART
A) Overall-Mortality B) Liver-related-Mortality 1,1 1,1 P<0.0001 P<0.018 Patients with HAART Patients with HAART ,9 ,9 Patients with ART untreated Patients Cumulative survival ,7 Cumulative survival ,7 ,5 Patients with ART ,5 untreated Patients ,3 ,3 1000 2000 3000 4000 5000 6000 1000 2000 3000 4000 5000 6000 Observation time[days]] Observation time[days]] Patients under observation: HAART-group: ART-group: Untreated-group: Patients under observation: HAART-group: ART-group: Untreated-group: Qurishi N et al. Lancet, 2004

21 Deaths in D:A:D Multivariable relationships with death rate Latest CD4 count
<50 50-99 All-cause mortality >500 <50 50-99 Liver-related mortality >500 DAD, Arch Intern Med 2006; 166: 1632

22 Effect of HAART on progression to ESLD – a meta-analysis
PRE-HAART POST-HAART Thien, H et al. AIDS 2008; 22:

23 Hepatotoxicty by co-infection status
Interactions were not significant between drug CLASS and CO (p=0.800) N arms N patients 10 20 30 40 NNRTI PI Mixed BPI NRTI Overall Drug Class % Patients with LEE All Patients HCV Coinf HIV Only References Benhamou Y, Mats V, Walcak D. Systemic overview of HAART associated liver enzyme elevations in patients infected with HIV and co-infected with HCV. CROI 2006;#88 Benhamou Y, Mats V, Walcak D. Systemic overview of HAART associated liver enzyme elevations in patients infected with HIV and co-infected with HCV. CROI 2006;#88

24 Lipodystrophy Lipohypertrophy (fat accumulation)
Dorsocervical fat pad enlargement (buffalo hump) Central or abdominal obesity Breast enlargement Lipoatrophy (fat wasting or loss) Arms and/or legs ( prominence of veins) Face Buttocks Insulin Resistance and Hyperlipidaemia Diabetes and impaired GTT Hypercholesterolaemia and hyperlipidaemia Lipodystrophy Lipodystrophy, is one of the long-term adverse events associated with prolonged antiretroviral therapy. This acetate summarises the physical changes associated with lipodystrophy. Long-term treatment with antiretroviral therapy is only one factor in the development of lipodystrophy. Weight loss and altered lipid levels are also seen in therapy naïve patients i.e. with the natural progression of HIV and AIDS. John M, Nolan D, Mallal S. Antiviral Therapy 2001; 6: 9-20. JIAPAC Supplement, Winter 2001. Behrens GMN, Stoll M, Schmidt RE. Drug Safety 2000; 23(1): 57-76 John M, Nolan D, Mallal S. Antiviral Therapy 2001; 6: 9-20. JIAPAC Supplement, Winter 2001. Behrens GMN, Stoll M, Schmidt RE. Drug Safety 2000; 23(1):

25 Insulin Resistance and hepatic fibrosis in HIV/HCV co-infected patients
Merchante N, et al. Gut 2009

26 What about response to anti-HCV therapy?

27 HCV/HIV treatment outcomes
Genotype 1 SVR 14–38% Genotype 3 SVR 44–73% 100 75 Monoinfection APRICOT SVR (%) ACTG 50 RIBAVIC Laguno et al. PRESCO 25 Outline studies G1 G2/3 Genotype Fried et al, NEJM 2002, 347: , Torriani et al, NEJM 2004; 351: , Chung R, et al, NEJM 2004: 351; 451-9, Carrat F, et al, JAMA 2004: 292: , Laguno et al, AIDS 2004; 18: F27-F36, Nunez et al, JAIDS 2007: 45: 27 27

28 Acute HCV/HIV: Overall virological responses:
133 = Bhagani et al. 3rd Int HIV/Hepatitis co-infection meeting, Paris 2007, Vogel et al Antiviral Therapy (in press) 2010

29 Predictors of response to PegIFN and Ribavirin in co-infected patients

30 CD4+ Count and Efficacy of Peg-IFN alpha and RBV
Q1 (2.5% to 19%) Q2 (19.1% to 25.0%) Q3 (25.0% to 32.1%) 80 73 60 Q4 (32.1% to 69.3%) 69 62 Pts With SVR (%) 40 47 100 34 20 29 27 Gt, genotype; HCV, hepatitis C virus; IFN, interferon; RBV, ribavirin; SVR, sustained virologic response. The APRICOT study prospectively evaluated a large cohort of HIV/hepatitis C virus–coinfected patients who were treated with peginterferon alfa‑2a and ribavirin. This analysis looks at sustained virologic response according to CD4+ cell count quartile. The graph shows an apparent relationship between sustained virologic response and CD4+ cell count quartile for hepatitis C virus genotype 1 patients, meaning that patients within the lower CD4+ cell count quartiles tended to have the worst response and those in the higher count quartiles tended to do better. On the other hand, patients with genotypes 2 and 3 had good responses for all 3 CD4+ cell count quartiles. 16 Gt 1 (n = 150) Gt 2/3 (n = 78) APRICOT: Dieterich D, et al. ICAAC Abstract H-1888. Avidal, et al. JAIDS 2009

31 Ribavirin-Related Anaemia: HIV Coinfection
PEG-IFN 2a (180 µg/wk) + RBV (800 mg/d) 40% 25% 3.80% 16% 10% 0% 20% 60% SVR Early D/C All Severe Anemia (Hb < 8.5 g/dL) Early D/C Anemia RBV Dose Reduction For Anemia EPO Torriani F, et al, N Engl J Med. 2004;351:438.

32 Interactions between RBV & nucleoside analogues
AZT ddI d4T anemia hepatic pancreatitis weight decomp & lactic acidosis loss  mitochondrial DNA synthesis  lactate Blanco et al. NEJM 2002; 347: 1287

33 Abacavir and SVR SVR predicted by
Genotype Viral load RBV trough concentrations Abcavir use associated with NR/NSR in patients with low rbavirin trough concentrations Vispo et al, 3rd Int. HIV/hepatitis Conference, Paris Abs 46

34 EACS HCV treatment Patients with acute HCV – treat if HCV RNA persistently detectable 12 weeks after putative time of infection Chronic HCV – offer treatment to ALL (biopsy/staging/grading NOT essential) Those with CD4 <350 – reasonable to give HAART first Use HAART with low potential for hepatotoxicity Manage insulin resistance actively Those with F0/F1 fibrosis, especially if G1/G4 If CD4 <500 – early HAART reasonable to wait in terms of Anti-HCV Rx – but frequent monitoring

35 Proposed optimal duration of HCV therapy in chronic HCV/HIV-coinfected patients.
W4 W12 W24 W48 W72 G2/3 24 weeks therapy * HCV-RNA neg G1/4 48 weeks therapy G2/3 HCV-RNA neg > 2 log drop in HCV-RNA G1/4 72 weeks therapy HCV-RNA pos HCV-RNA pos Stop < 2 log drop in HCV-RNA Stop * In patients with baseline low viral load and minimal liver fibrosis. Rockstroh, et al, EACS Guidelines 2011

36 Rx algorithm for acute HCV in HIV+ NEAT Consensus 2010
Week 4 Week 12 HCV-RNA negative* 24 weeks of therapy Peg-IFN + RBV (AII) HCV-RNA positive* Drop HCV-RNA  2 log10 48 weeks of therapy < 2 log10 Stop Therapy *evidence based on using a 615 IU/ml cut-off to define negative HCV-RNA

37 HIV/HCV 2011 HIV/HCV co-infection Chronic HCV- Rx: Early reversal of
Patient Education – avoid infection HIV/HCV co-infection Early reversal of Immune suppression Use non-toxic agents Identify early Rx – ‘early’/acute Chronic HCV- Rx: Max dose Ribavirin Interactions Avoid dose-reductions Kinetics based Rx length Address Co-factors: Alcohol Hepatic Steatosis Insulin Resistance


39 Ge D et al. Nature 2009; 461(7262):

40 Sampling locations, allele frequencies and degree of
regional differentiation of the rs C allele. DL Thomas et al. Nature 461, (2009) doi: /nature08463

41 IL28B SNPs and HIV/HCV co-infection
Pineda et al, CROI 2010

42 HCV Life Cycle and DAA Targets
Receptor binding and endocytosis Transport and release Fusion and uncoating ER lumen (+) RNA Virion assembly LD LD NS3/4 protease inhibitors Translation and polyprotein processing DAAs, direct-acting antivirals; ER, endoplasmic reticulum; HCV, hepatitis C virus; LD, luminal domain. The elucidation of the life cycle of the hepatitis C virus (HCV) allowed for the identification of potential targets of antivirals that directly interrupt HCV replication. From the binding of the virus to the plasma membrane and its endocytosis through the membrane, all the way through uncoating and generating the membranous web to translation and replication, viral assembly, and transport and release again into the extracellular space, one may envision a variety of potential targets. The most obvious targets are the NS3/4 serine protease and the NS5B HCV polymerase. Therefore, our first DAAs have been protease inhibitors and nucleoside or nonnucleoside polymerase inhibitors. Also interesting was the recent discovery of NS5A inhibitors that are inhibitors of the NS5A protein. However, the function of this protein in the hepatitis C life cycle is not yet well understood. Therefore, the inhibitory drugs may help to elucidate the involvement of this protein in the HCV life cycle rather than vice versa. LD Membranous web NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside RNA replication ER lumen *Role in HCV life cycle not well defined NS5A* inhibitors Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6: 42

43 Select DAAs in Clinical Development
Phase I Phase II Phase III Protease Inhibitors ABT-450 ACH-1625 GS 9451 MK-5172 VX-985 BMS CTS-1027 Danoprevir GS 9256 IDX320 Vaniprevir BI Boceprevir Telaprevir TMC435 Nonnucleoside polymerase inhibitors BI IDX375 ABT-333 ABT-072 ANA598 BMS Filibuvir Tegobuvir VX-759 VX-222 Nucleoside polymerase inhibitors IDX184 PSI-7977 RG7128 NS5A inhibitors A-831 PPI-461 BMS BMS CF102 DAAs, direct-acting antivirals. This is a list of some of the newly developed antivirals. It is not a complete list but includes many of the compounds with reported data at the major international meetings. They are listed by their clinical phase of development, from phase I to phase III. The majority of these different compounds in development can be categorized into classes of protease inhibitors, nucleoside or nonnucleoside polymerase inhibitors, and the NS5A inhibitors. Two drugs—the protease inhibitors boceprevir and telaprevir—that are in pivotal phase III programs are expected to be approved in 2011 in Europe and the United States. 43

44 SVR Rates With BOC and TPV in GT1 Treatment-Naive and -Experienced mono-infected Pts
100 Current Standard of Care 100 SOC + Protease Inhibitors (Approved in 2011) 80 80 63-75[1-2] 59-66[3-4] 60 60 SVR (%) 38-44[1-2] SVR (%) 40 40 BOC, boceprevir; GT1, genotype 1; SOC, standard of care; SVR, sustained virologic response; TPV, telaprevir. This slide is a summary of data. It is clearly not a head-to-head comparison but an illustration of the data for boceprevir and telaprevir in patients who were treatment naive or previous nonresponders. If one compares the blue box on the left with the blue box on the right, one can see that in treatment-naive patients, approximately 30% more patients can be cured with the addition of either boceprevir or telaprevir to peginterferon/ribavirin. The difference is even more pronounced in previous nonresponders. Here one can see success rates of 17% to 21% with repeat peginterferon/ribavirin treatment; however, a 59% to 66% SVR rate can be attained in these previous nonresponders when a protease inhibitor is added. So you clearly see how important, especially for patients who have been previously unsuccessfully treated, the addition of a protease inhibitor will be. 17-21[3-4] 20 20 Treatment-Naive Pts Treatment-Experienced Treatment-Naive Pts Treatment-Experienced 1. Poordad F, et al. AASLD Abstract LB Jacobson IM, et al. AASLD Abstract Bacon BR, et al. AASLD Abstract Foster GR, et al. APASL Abstract 1529. 44

45 RESPOND-2: SVR Rates According to Treatment Arm and Prior Response
P < vs control (both arms) 4-wk PR + response-guided BOC + PR (n = 162) 100 4-wk PR + 44-wk BOC + PR (n = 161) 80 75 66 69 48-wk PR (n = 80) 59* 60 52 SVR (%)[1] 40 *46% of patients in response-guided arm eligible for shorter duration of therapy, with 86% SVR rate.[2] 40 29 BOC, boceprevir; PR, peginterferon/ribavirin; SVR, sustained virological response. The results of RESPOND-2 are shown on this graph. The overall SVR rates in the response-guided therapy and standard-duration therapy arms were 59% and 66%, respectively; both of these SVR rates were significantly higher than in the control arm, at 21% (P < .0001). When analyzed by type of previous nonresponse, relapsers achieved higher SVR rates of 69% to 75% vs 29% in the control arm. Previous nonresponders also achieved higher SVR rates of 40% to 52% vs 7% in the control arm. In the response-guided arm, 46% of patients were eligible for a shorter duration of therapy; those individuals achieved a very high SVR rate of 86%. For more information, go online to: 21 20 7 Overall Prior Nonresponders Prior Relapsers Bacon BR, et al. AASLD Abstract 216. 45

46 Study 107: TVR Re-treatment of Pts With PegIFN/RBV Failure in PROVE 1/2/3 Trials
RVR SVR Relapse 100 93 97 86 88 80 75 60 55 Patients (%) 41 40 37 26 24 20 HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response; TVR, telaprevir. The Study 107 rollover trial revealed various response rates based on the previous response; previous null responders achieved an SVR of 37%, and those that had a partial response to interferon had an SVR rate of 55%. Those who were previous relapsers had very high SVR rates of 93% to 97%, and these individuals had a very low likelihood of relapse of just 3%. Hence, it was noted that previous interferon responsiveness dictated the likelihood of cure. Patients who responded poorly to interferon during their first course of therapy had the lowest likelihood of SVR, and patients experiencing intermediate levels of response were more likely to achieve SVR upon retreatment. 6/ 25 6/ 23 3 (1/29) n= 21 19 25 16 7 6 27 28 Prior Null Responders* (n = 51) Prior Partial Responders† (n = 29) Prior Virologic Breakthrough (n = 8) Prior Relapsers (n = 29) *Null responders: Wk 4 HCV RNA reduced by < 1 log10 IU/mL; Wk 12 HCV RNA reduced by < 2 log10 IU/mL. †Partial responders: HCV RNA reduced by ≥ 2 log10 IU/mL at Wk 12, but HCV RNA detectable at Wk 24. Berg T, et al. EASL Abstract 4. 46


48 Complex Kinetic Guided Rx lengths with TVR and BOC
P + R eRVR+ Rx Naïve/ Relapsers PIFN + Ribavirin + TVR P + R eRVR- Partial Responders/ Non-Responders (and HIV+) PIFN + Ribavirin + TVR P + R Stopping Rules Week 4 or week 12 HCV RNA >1000 U/l ?week 12 detectable

49 BOV- kinetic guided Rx length
W4 W8 W12 W28 W36 W48 eRVR+ PIFN + Ribavirin + BOV Rx Naïve P + R eRVR- PIFN + Ribavirin + BOV P + R eRVR+ PIFN + Ribavirin + BOV Partial Responders/ Relapsers P + R eRVR- (and ?HIV+) PIFN + Ribavirin + BOV P + R Stopping Rules Week 4 HCV RNA <1 log drop week 12 >100 U/l

50 Other issues with NS3/4 inhibitors
Side-effect profiles TVR – rash BOC - anaemia Potential for drug-drug interactions with anti-HIV drugs TVR – ONLY use with Atazanir/R and EFV BOC – significant interaction with EFV, ?interaction with boosted-PIs Genotype 1 specific activity Resistance

51 Activity of PIs by HCV Genotype
Agent Potential Activity Protease Inhibitors Boceprevir[1,2] 1, 2 Telaprevir[3,4] BI [5] 1, 2? Danoprevir[6] MK-5172[7] 1-6 TMC435[8] 1, 2, 4, 5, 6 Vaniprevir[9] DAAs, direct-acting antivirals; HCV, hepatitis C virus. It is important to realize that not all DAAs have activity against each HCV genotype. The protease inhibitors that are expected to be approved in 2011, boceprevir and telaprevir, have their major activity against genotype 1. They both have activity against genotype 2; however, for patients with genotype 2 HCV, response rates to peginterferon/ribavirin are so high that an additional drug may not be necessary. Boceprevir and telaprevir clearly have no activity against HCV genotypes 3 and 4, but no data are available for other genotypes, such as 5 and 6. Some of the next-generation protease inhibitors, such as some of the ones indicated here (MK-5172 and TMC435), may have an extended spectrum of activity. I hope that future drug candidates in the protease inhibitor class have potent activity against all genotypic subtypes so that we may not need to subtype our patients before starting therapy. I would also like to remind you that with current technology, genotyping is not performed in the region where protease inhibitors act. We typically classify the genotype by assaying the 5’ noncoding region of HCV. However, we are not quite sure whether there are patients in our treatment populations who may have chimera genotypes, that is, they may have a different genotype in the 5’ noncoding region than they have in the protease region. If this is the case, a patient may be classified as HCV genotype 1, but in the protease region he may have another genotype. Therefore, in the future, if you have patients not responding to a protease inhibitor, you may need to consider sequencing the protease region to confirm that the genotype against which these compounds are active is indeed prevalent. 1. Poordad F, et al. AASLD Abstract LB Pawlotsky JM, et al. Gastroenterology. 2011[epub ahead of print]. Abstract Jacobson IM, et al. AASLD Abstract Foster G, et al. EASL Abstract Sulkowski M, et al. EASL Abstract Terrault N, et al. AASLD Abstract Petry A, et al. AASLD Abstract Fried M, et al. AASLD Abstract LB Manns MP, et al. AASLD Abstract 82. 51

52 Resistance to DAAs - summary
Class Genetic Barrier Cross Resistance Persistence NS3/4 Low (1b>>1a) yes Yes but at low level NS5b Nucs high Prob. no unlikely NS5b Non-nuc Low No Yes - ?high level NS5a High (1b>1a) ?? Cyclophilin inhibitors

53 What do we need to think about in the coming months
Treat now with PegIFN and Ribavirin or wait? Who should we prioritise for Rx with available DAAs? Characterisation of drug-drug interactions Predictors of response to triple therapy What is the significance of HCV resistance mutations How can we encourage Pharma to prioritise trials in HIV/HCV and patients to take part in clinical trials

54 HCV Rx landscape – the future?
DAA + P + R 2DAAs + P 2DAAs + R 2DAAs + P+R 3 or more DAAs Induction/consolidation Regimens Short duration of Rx pIFN + R + PI pIFN + R (g3/g2 + acute HCV) 2011 2012 2013 2014 2015 2016 2017 2018 HCV resistance testing - Rx failure/rebound - baseline Use of other SNPs to Predict side-effects IFN-lambda – IFN of choice? Use of IL28B P/R lead-in phase Response guided therapy IFN-alpha Historical therapy!


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