New Paradigms in the management of HIV/HCV co- infected patients Sanjay Bhagani Royal Free Hospital 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 Hep C

Prevalence of Hepatitis C (1685/4957 patients = 33.9%) South: 623 = 44,9 % North: 346 = 24,5 % Central: 280 = 22,9 % East: 412 = 47,7 % Rockstroh J et al., EACS 2003; F12/4

Significant increase in new acute HCV infections amongst HIV+MSM since 2001 Test for trend p-value using Poisson regression p<0.001 Error bars = 95% CI Incidence of acute HCV infection/1000 pt yrs Browne RE, et al. 2nd IAS 2003; Abstract 972

Acute HCV among HIV+ - beyond Europe 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 :

Van der Laas et al. Gastroenterology 2009

Summary Group Sex Sexual practice Drug practice High-risk practices Internet Shared implements Club drugs STI Danta et al, AIDS 2007

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 grade

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

Physiology of hepatic fibrosis Liver cell injury Chronic necroinflammatory response HSC (activated) HSC (quiescent) PDGF TGF- ECM HSC proliferation Progressive fibrosis HCV TNF- IL-1 KC

HIV & Hepatic Stellate Cells: implications for fibrosis in HIV/HCV co-infected patients Friedman SL and Arthur, Science and Medicine 2002; Tuyama AC, et al., Hepatology 2010; 52: Hypothesis: Hepatic Stellate Cells are a cellular target of HIV Activated HSC with fibrosisNormal liver

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

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

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

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:

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

Hepatotoxicity 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

Reduced risk of ART-induced hepatotoxicity after HCV clearance Labarga P et al. JID 2007;196:670– Follow-up (months) Number of patients No: Yes: Cumulative incidence of hepatic events (%) Sustained HCV clearance No Yes Log Rank: (p <0.001)

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/NASH and hepatic fibrosis in HIV/HCV co-infected patients Merchante N, et al., Gut 2009 Sterling R, at al. Hepatology 2008

Main reasons to treat chronic HCV in HIV-infected patients HAART treated HIV patients live longer Faster progression to liver cirrhosis Increased mortality due to end stage liver disease Higher risk of hepatotoxicity following treatment with ART drugs

HCV/HIV HCV/HIV TREATMENT OUTCOMES SVR 14-38%SVR 44-73% Genotype 1Genotype 3

Acute HCV/HIV: Overall virological responses: 133 = Bhagani et al. 3 rd Int HIV/Hepatitis co-infection meeting, Paris 2007

Acute HCV in HIV: finding the balance Waiting long enough to reliably identify those that will clear virus spontaneously Not delaying treatment for those going on to develop chronic infection

Acute HCV in HIV+ patients management: NEAT consensus 2010 (1) 1) HCV RNA levels should be measured at initial presentation and 4 weeks later. (BII) 2) Treatment should be offered to a) Patients without a decrease of 2 log of HCV RNA at 4 weeks when compared with HCV RNA at diagnosis. (BII) b) Patients with persistent serum HCV RNA 12 weeks after diagnosis of acute hepatitis C. (AII) 3) Patients showing spontaneous HCV RNA clearance before and after 12 weeks should be followed with serial HCVRNA assay until 48 weeks after onset in order to confirm resolution of acute hepatitis C. (AIII)

Acute HCV in HIV+ patients management: NEAT consensus 2010 (2) I) Pegylated-interferon and weight-based ribavirin is recommended for the treatment of acute HCV in HIV-infected patients. (AII) II) Duration of treatment should be based on RVR (negative HCV RNA at week 4). a) In patients with RVR treatment duration should be limited to 24 weeks. (AII) b) In patients without RVR treatment duration of 48 weeks should be considered. (BIII) c) In non-RVR patients who do not show a 2log drop in HCV RNA at week 12 treatment can be discontinued. (BIII)

APRICOT – Peg IFN 2a + Ribavirin arm SVR by genotype and viral load High > iu/l Low < iu/l Torriani et al, NEJM 2004

APRICOT: SVR rates according to exposure Genotype 1 recipients of peginterferon alfa-2a plus ribavirin 39% SVR rate (%) 80/80/80 exposure % <80/80/80 exposure* 62 29% All patients n = *Patients violated the rule if 1 of the three targets were not achieved Opravil M, et al. 45th ICAAC 2005; Abstract 2038

Gt 1 (n = 150) Gt 2/3 (n = 78) APRICOT: Baseline CD4+ Count and Efficacy of Peg-IFN alpha-2a Plus RBV Retrospective analysis of HIV/HCV-coinfected patients treated with peg-IFN alpha-2a + RBV in APRICOT SVR rates analyzed in overall population and within genotypes according to baseline CD4+ cell count quartiles (Q1-Q4) Rate of SVR varied according to CD4+ cell percentage quartile in genotype 1 but not in genotypes 2/3 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%)

Predictors of response Host Acute infection Younger age Lack of stage 3/4 fibrosis Ethnicity – genetic?? Low BMI Lack of hepatic steatosis High CD4 % Lack of insulin resistance? Virus Genotypes 2/3 Low viral loads

Thio C, Thomas D. Gastroenterology 2010

IL28B SNPs and SVR in HIV/HCV Pineda, et al. CID 2010 (in Press)

Chromosome 20 SNPs and Ribivirin associated Anaemia

Viral Dynamic response to interferon and ribavirin Pawlotsky Hepatology 2002; 32(4)

Does RVR predict response? (week 4 undetectable HCV RNA) APRICOT –PPV 82% –NPV 79% RIBAVIC –PPV 97.5% –NPV 81.3% PRESCO –Lack of RVR independent predictor of relapse Crespo M et al. –G3 patients with RVR low rates of relapse with 24 weeks of therapy ROMANCE –G2/3 patients without RVR need longer Rx (48 weeks)

How can we maximise response to therapy?

Zidovudine: impact on HCV treatment Alvarez D et al. 12th Conference on Retroviruses and Opportunistic Infections (Abstract #: P-192). Boston, MA USA, February 22–25, 2005

Cost Effectiveness of EPO Therapy Medical Intervention Primary angioplasty vs. thrombolysis PegIFN/RBV vs. IFN/RBV EPO vs. STD Care Incremental cost/QALY $ 13,100 $ 15,000 – 55,000 $ 16,433 Spiegel BR, Chen K, Chiou C-F, et al. Clin Gastro and Hepatology 2005;3:

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 Mira JA, et al. J Antimicrob Chemother 2008; 62(6): 1365–1373 Medscape ® ABC ABV-MP Adenylosuccinate synthase-lyase RBV RBV-MPCBV-MP Adenylate kinase Guanylate kinase RBV-DPCBV-DP Nucleoside diphospho-kinase RBV-TPCBV-TP p=0.02p=0.03p=0.4

Dose of Ribavirin?

High-Dose Ribavirin and Epoetin Alfa Virologic Response PegIFN WB-RBV Response (%) ETR SVR * P <.05 vs group 1 and 2 EVR PegIFN WB-RBV EPO PegIFN HD-RBV EPO * Shiffman ML, et al. Hepatolgy 2007; 46: 371-9

Importance of weight-based Ribavirin (1000mg 75kg) Soriano, et al. AIDS :

Extended duration of therapy?

Utilising kinetics to determine length of therapy – mathematical model Genotype 1 End Rx HCV RNA 36 weeks < 50 c/ml Drusano & Preston. JID 2004; 189:

Retrospective analysis of genotype 1 patients receiving 48 weeks of pegIFN alfa-2a + RBV (N = 453) Longer Duration of Undetectability on Treatment Increases Chance for SVR HCV RNA Positive at Week Week Became HCV RNA Negative Ferenci P, et al. J Hepatol. 2005;43: SVR (%) 0

Treatment of Chronic HCV Extending Therapy Weeks of Treatment % HCV RNA (-) EOT SVR Extending the duration of therapy reduced relapse from 47% to 13% Sanchez-Tapias et al. AASLD Abstract 126.

Results (On Treatment analysis) (8%) 36 (80%) 9 (16%) Voluntary withdrawals (64) 4 (4%) Short arm Extended arm PRESCO No. of patients (389) 31% 53% 67% 82% G 1/4 G 2/ p=0.004 p=0.04

Induction or higher doses of Peg-IFN?

270 mcg vs. 180 mcg PegIFN – alpha 2a + R (1000mg/1200mg) for 4 weeks followed by 180mcg + R No difference in RVR or EVR

Untreated Follow-up SLAM-C trial in HIV–HCV co-infected non-responders (Sherman) Peg-IFNα-2a 180 µg plus RBV 800–1200 mg HCV RNA 2 log drop NR and naïve n=200 HCV RNA <2 log drop 12 weeks Peg-IFNα-2a 180 µg plus RBV 800–1200 mg Peg-IFNα-2a 180 µg Stop treatment, observation period 60 weeks 72 weeks 24 weeks Randomisation

Slam-C results Interim analysis April 2007 –45 patients with paired liver biopsies in the non- EVR arm Insufficient fibrosis progression to determine a difference between the groups BUT – HALT-C results –No sig. reduction in fibrosis or diff between arms –No reduction in primary end-points Sherman et al, CROI 2008

Anti-HCV drugs in development

Slide courtesy Tracy Swann 2010

NS5A inhibitors Slide courtesy Tracy Swann 2010

Nitazoxinide Slide courtesy Tracy Swann 2010

New Interferons Slide courtesy Tracy Swann 2010

Even the best are only human……

Pertinent issues with the Stat-Cs NS3/NS4 PIs – cytochrome P450 metabolised – anti-HIV PIs/NNRTIs NS5b – Nucleosides – potential interaction with anti-HIV NAs NS5b – Non-nucleosides – Cyp450 interactions? Very high HCV mutation rates – rapid emergence of drug resistance Potential for X-resistance amongst classes Mutations not archived but continued circulation dependent on fitness

Take home messages: HIV/HCV co-infection is common Increasing incidence of acute HCV ESLD major cause of morbidity/mortality Early HAART beneficial –Avoid d-thymidine analogues/AZT Treat HCV with PegIFN and Ribavirin –Best results if HCV treated in the acute phase –Maximal doses of Ribavirin (1000/1200mg) –Avoid AZT, d4T and DDI, –?Avoid Abcavir –EPO and G-CSF – avoid dose reductions

Take home messages: Duration of therapy individualised –Genotype –Pre-Rx viral load –Fibrosis stage –RVR/EVR No role for maintenance low-dose IFN Give some thought to hepatic steatosis New anti-HCV drugs (STAT-Cs!) will be available in the future… …be careful out there….!!!

Proposed optimal duration of HCV therapy in 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, Bhagani, Bruno et al, EACS Guidelines 2008