Presentation on theme: "HIV/HCV co-infection current and future management Sanjay Bhagani Consultant Physician/Senior Lecturer Dept of Infectious Diseases/HIV Medicine Royal Free."— Presentation transcript:
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
Mortality of HIV-infected patients in France (GERMIVIC Study Group) Rosenthal et al. AASLD 2004; Abstract 572.
Overlapping HCV & HIV epidemics 40 million 175 million 10 million HIV HCV
Epidemic of Acute HCV among HIV+ MSM-beyond Europe...and continuing 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. pers.com.; 12. Matthews, CID 2009 Europe: – UK 2,3,4 – Germany 5 – France 6,7 – Netherlands 8 – Switzerland 9 – Italy 10 – Belgium 11 Australia 12 :USA 1,2 :
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
Natural course of acute HCV infection 1.Acute Hepatitis C takes a chronic course more frequently in HIV infected individuals (II) 2.Spontaneous clearance of acute HCV in HIV patients occurs in 0 – 40% (III) and is associated with a)Host genetic factors (IL28b-CC genotype) and stronger adaptive immune responses. (II) b)Female sex, exposure group (sexual transmission vs. IVDU), HBsAg+, jaundice and higher peak ALT (II) c)Early decline of HCV-RNA 4-8 weeks after presentation (III)
Natural Course AHC in HIV-positive C.NEAT Cohort, 92 untreated patients Vogel et al. CROI 2010, Poster 640 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 Clearancechronic HCV predictiv e value pRVC223PPV 88% no pRVC423NPV 85% cEVC324PPV 89% no cEVC223NPV 92%
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
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…..
Effect of HIV/HCV co-infection on fibrosis rate Effect of HIV/HCV co-infection on fibrosis rate ( Benhamou et al 1999 ) Fibrosis progression influenced by CD4 cell count (< 200 cells/microlitre) Age at infection ( > 25 years) Male sex Alcohol consumption ( > 50g/d) Fibrosis Score
Impact of HIV RNA, CD4, or Both on Liver Fibrosis Progression Rate HIV RNA (copies/mL) Ishak Fibrosis Units/Year Brau N, et al. 39 th EASL. Berlin, Abstract P=0.53 P=0.04 P= K > K > CD4 (cells/mm 3 ) HIV RNA (copies/mL) + <500 CD4 cells/mm 3
HIV/HCV – complex immune interactions Klenerman P, Kim A. PLOS Med 2007; 4:
Immune activation and liver disease HIV -> GIT CD4+ T-cell depletion Immune activation IL-1 TNF- IFN- IL-12 Hepatic fibrosis HSC activation Microbial translocationLPS DCs macrophage 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: Slide Courtesy Prof S Lewin
HIV-HCV Alcohol HBV Haemochromatosis HCV Steatosis BMI>25 2PBC Hazard function 4682 patients Poynard, T. et al., (2003) A comparison of fibrosis progression in chronic liver disease. Journal of Hepatology 38: Age in years Progression to cirrhosis
Ishak fibrosis stage on second biopsy among persons with little or no fibrosis on first biopsy Sulkowski MS et al. 12th Conference on Retroviruses and Opportunistic Infections (Abstract #: P-172). Boston, MA USA, February 22–25, 2005 Median (IQR) time between bxs, 2.84 yrs (2.05–3.41) 28% with more than 2 stage progression n = 51 45% 23% 10% 14% 8% or 45 or 6 Fibrosis stage at second biopsy Patients (%)
HIV/HCV - Cirrhosis and survival Pineda et al. Hepatology 2005
So what effect does HAART have?
A) Overall-Mortality Observation time[days]] Cumulative survival 1,1,9,7,5,3 P< Patients with HAART Patients with ART untreated Patients 6000 Patients under observation: HAART-group: ART-group: Untreated-group: ,1,9,7,5,3 B) Liver-related-Mortality P<0.018 Patients with HAART Patients with ART untreated Patients Overall and Liver-related Mortality - effect of HAART Qurishi N et al. Lancet, 2004 Cumulative survival Observation time[days]] Patients under observation: HAART-group: ART-group: Untreated-group:
Deaths in D:A:D Multivariable relationships with death rate Latest CD4 count > < > < All-cause mortality Liver-related mortality Latest CD4 count DAD, Arch Intern Med 2006; 166: 1632
Effect of HAART on progression to ESLD – a meta-analysis PRE-HAART POST-HAART Thien, H et al. AIDS 2008; 22:
Hepatotoxicty by co-infection status 1.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 Interactions were not significant between drug CLASS and CO (p=0.800) N arms N patients NNRTIPIMixedBPINRTIOverall Drug Class % Patients with LEE All PatientsHCV CoinfHIV Only
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 John M, Nolan D, Mallal S. Antiviral Therapy 2001; 6: JIAPAC Supplement, Winter Behrens GMN, Stoll M, Schmidt RE. Drug Safety 2000; 23(1): Lipodystrophy
Insulin Resistance and hepatic fibrosis in HIV/HCV co-infected patients Merchante N, et al. Gut 2009
What about response to anti-HCV therapy?
HCV/HIV treatment outcomes G1G2/3 Monoinfection APRICOT ACTG RIBAVIC Laguno et al. PRESCO Genotype 1 SVR 14–38% Genotype 3 SVR 44–73% Genotype SVR (%) 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:
Acute HCV/HIV: Overall virological responses: 133 = Bhagani et al. 3 rd Int HIV/Hepatitis co-infection meeting, Paris 2007, Vogel et al Antiviral Therapy (in press) 2010
Predictors of response to PegIFN and Ribavirin in co-infected patients
Gt 1 (n = 150) Gt 2/3 (n = 78) CD4+ Count and Efficacy of Peg-IFN alpha and RBV APRICOT: Dieterich D, et al. ICAAC Abstract H Pts With SVR (%) Q4 (32.1% to 69.3%) Q1 (2.5% to 19%) Q2 (19.1% to 25.0%) Q3 (25.0% to 32.1%) Avidal, et al. JAIDS 2009
Ribavirin-Related Anaemia: HIV Coinfection Torriani F, et al, N Engl J Med. 2004;351:438. PEG-IFN 2a (180 µg/wk) + RBV (800 mg/d) 40% 25% 3.80% 16% 10% 0% 20% 40% 60% SVREarly D/C All Severe Anemia (Hb < 8.5 g/dL) Early D/C Anemia RBV Dose Reduction For Anemia EPO
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
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, 3 rd Int. HIV/hepatitis Conference, Paris Abs 46
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
Proposed optimal duration of HCV therapy in chronic HCV/HIV-coinfected patients. W4 W12 W24 W48W72 HCV-RNA neg HCV-RNA pos > 2 log drop in HCV-RNA < 2 log drop in HCV-RNA HCV-RNA neg HCV-RNA pos G2/3 G1/4 Stop G2/3 G1/4 24 weeks therapy * 48 weeks therapy 72 weeks therapy * In patients with baseline low viral load and minimal liver fibrosis. Rockstroh, et al, EACS Guidelines 2011
Rx algorithm for acute HCV in HIV+ NEAT Consensus 2010 *evidence based on using a 615 IU/ml cut-off to define negative HCV-RNA HCV-RNA negative* HCV-RNA negative* Stop Therapy Peg-IFN + RBV (AII) Peg-IFN + RBV (AII) < 2 log weeks of therapy Drop HCV-RNA 2 log 10 Drop HCV-RNA 2 log 10 Week 4 Week 12 HCV-RNA positive* HCV-RNA positive* 48 weeks of therapy
HIV/HCV 2011 HIV/HCV co-infection Early reversal of Immune suppression Use non-toxic agents Address Co-factors: Alcohol Hepatic Steatosis Insulin Resistance Identify early Rx – early/acute Chronic HCV- Rx: Max dose Ribavirin Interactions Avoid dose-reductions Kinetics based Rx length Patient Education – avoid infection
Ge D et al. Nature 2009; 461(7262):
DL Thomas et al. Nature 461, (2009) doi: /nature08463 Sampling locations, allele frequencies and degree of regional differentiation of the rs C allele.
Pineda et al, CROI 2010 IL28B SNPs and HIV/HCV co-infection
HCV Life Cycle and DAA Targets Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6: Receptor binding and endocytosis Fusion and uncoating Transport and release (+) RNA Translation and polyprotein processing RNA replication Virion assembly Membranous web ER lumen LD ER lumen LD NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside *Role in HCV life cycle not well defined NS5A* inhibitors
SVR Rates With BOC and TPV in GT1 Treatment-Naive and -Experienced mono- infected Pts SVR (%) Treatment-Naive Pts Treatment- Experienced [1-2] [3-4] Current Standard of Care SVR (%) [1-2] [3-4] SOC + Protease Inhibitors (Approved in 2011) 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 Treatment-Naive Pts Treatment- Experienced
RESPOND-2: SVR Rates According to Treatment Arm and Prior Response Overall SVR (%)  4-wk PR + 44-wk BOC + PR (n = 161) 59* Prior Nonresponders Prior Relapsers 48-wk PR (n = 80) 4-wk PR + response-guided BOC + PR (n = 162) P <.0001 vs control (both arms) *46% of patients in response-guided arm eligible for shorter duration of therapy, with 86% SVR rate.  Bacon BR, et al. AASLD Abstract 216.
Study 107: TVR Re-treatment of Pts With PegIFN/RBV Failure in PROVE 1/2/3 Trials Berg T, et al. EASL Abstract 4. RelapseSVRRVR Prior Null Responders* (n = 51) Patients (%) 41 Prior Partial Responders (n = 29) Prior Virologic Breakthrough (n = 8) (1/29) 97 Prior Relapsers (n = 29) * Null responders: Wk 4 HCV RNA reduced by < 1 log 10 IU/mL; Wk 12 HCV RNA reduced by < 2 log 10 IU/mL. Partial responders: HCV RNA reduced by 2 log 10 IU/mL at Wk 12, but HCV RNA detectable at Wk 24. n= / /
Complex Kinetic Guided Rx lengths with TVR and BOC Stopping Rules –Week 4 or week 12 HCV RNA >1000 U/l –?week 12 detectable W4W8W12W24W48 Rx Naïve/ Relapsers Partial Responders/ Non-Responders (and HIV+) PIFN + Ribavirin + TVR P + R eRVR+ eRVR-
BOV- kinetic guided Rx length Stopping Rules –Week 4 HCV RNA <1 log drop –week 12 >100 U/l W4W8W12W28W36W48 Rx Naïve Partial Responders/ Relapsers P + R PIFN + Ribavirin + BOV P + R PIFN + Ribavirin + BOV P + R eRVR+ eRVR- eRVR- (and ?HIV+) eRVR+
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
Activity of PIs by HCV Genotype AgentPotential Activity Protease Inhibitors Boceprevir [1,2] 1, 2 Telaprevir [3,4] 1, 2 BI  1, 2? Danoprevir  1, 2? MK-5172  1-6 TMC435  1, 2, 4, 5, 6 Vaniprevir  1, 2? 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.
Resistance to DAAs - summary ClassGenetic Barrier Cross Resistance Persistence NS3/4Low (1b>>1a)yesYes but at low level NS5b NucshighProb. nounlikely NS5b Non-nucLowNoYes - ?high level NS5aHigh (1b>1a)yes?? Cyclophilin inhibitors highyesunlikely
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
HCV Rx landscape – the future? pIFN + R + PI pIFN + R (g3/g2 + acute HCV) Use of IL28B P/R lead-in phase Response guided therapy DAA + P + R 2DAAs + P 2DAAs + R 2DAAs + P+R HCV resistance testing - Rx failure/rebound - baseline Use of other SNPs to Predict side-effects IFN-lambda – IFN of choice? 3 or more DAAs Induction/consolidation Regimens Short duration of Rx IFN-alpha Historical therapy!