3 Mortality of HIV-infected patients in France (GERMIVIC Study Group) Rosenthal et al. AASLD 2004; Abstract 572.
4 Overlapping HCV & HIV epidemics 40 million175 million10 millionHIVHCV
5 Epidemic of Acute HCV among HIV+ MSM-beyond Europe...and continuing..... – UK2,3,4– Germany5– France6,7– Netherlands8– Switzerland9– Italy10– Belgium11USA1,2: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. pers.com.; 12. Matthews , CID 20095
6 HCV-seroconversion may be delayed Median time from HCV RNA to Ab(+) = 91 days (0-1206)10% Ab(-) after 9 months5% Ab(-) after 12 monthsLow ALT/low nadir CD4 associated with delayed/null AB responseThomson 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 withHost 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 patientsWeek 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 control2 log drop of HCV-RNA at week 4cRVC complete rapid virological control HCV-RNA < 615 IU/ml at week 4cEVC complete early virological control HCV-RNA < 615 IU/ml at week 12ClearanceHCV-RNA < 615 IU/ml week 24Clearancechronic HCVpredictive valuepRVC223PPV 88%no pRVC423NPV 85%cEVC32PPV 89%no cEVC2NPV 92%Vogel et al. CROI 2010, Poster 640
10 EACS Guidelines 2011 Screening and counselling All HIV+ patients should be screened for HCV at diagnosis, and then on an annual basisHCV RNA in those with a high index of suspicion and a negative HCV-AB testThose at high risk of HCV-infection (ongoing IVDU, unprotected mucosal traumatic sex, unprotected anal intercourse, recent STD) with unexplained rise in hepatic serum aminotransferasesHCV-AbIf HCV-Ab negative – test for HCV RNA for early identificationSince 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 mortalityEffect of HAARTResponse rates to PegIFN-alpha and ribavirinPredictors of responseCurrent guidelines – who to treat and when to start?Future…..
12 Effect of HIV/HCV co-infection on fibrosis rate (Benhamou et al 1999) Fibrosis ScoreFibrosis progression influenced byCD4 cell count (< 200 cells/microlitre)Age at infection ( > 25 years)Male sexAlcohol consumption ( > 50g/d)
13 Impact of HIV RNA, CD4, or Both on Liver Fibrosis Progression Rate 0.196P=0.005P=0.0050.1620.1550.145Slide #34: Impact of HIV RNA, CD4, or Both on Liver Fibrosis Progression RateBrau 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).ReferenceBrau 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/YearP=0.040.1220.1210.123P=0.53< K >100K > < < >400HIV RNA(copies/mL)CD4(cells/mm3)HIV RNA (copies/mL) +<500 CD4 cells/mm3Brau 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 CirrhosisHCVAlcoholAltered portal vein circulationMathurin et al., Hepatology 2000; 32: ; Paik et al., Hepatology 2003; 37: ;Balagopal et al., Gastroenterology 2008; 135:IL-1TNF-aIFN-aIL-12Hepatic fibrosisHSC activationHIV -> GIT CD4+ T-cell depletionMicrobial translocationLPSImmune activationDCsmacrophageSlide Courtesy Prof S Lewin
16 Progression to cirrhosis 1.004682 patients0.83HIV-HCVAlcoholHBVHaemochromatosisHCVSteatosis BMI>252PBC0.670.50Hazard function0.33Fibrosis 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.0.170.0020406080Age in yearsPoynard, 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 biopsyn = 5160Median (IQR) time between bxs, 2.84 yrs (2.05–3.41)28% with more than 2 stage progression45%40Patients (%)23%2014%10%8%123 or 45 or 6Fibrosis stage at second biopsySulkowski 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
20 Overall and Liver-related Mortality - effect of HAART A) Overall-MortalityB) Liver-related-Mortality1,11,1P<0.0001P<0.018Patients with HAARTPatients with HAART,9,9Patients with ARTuntreated PatientsCumulative survival,7Cumulative survival,7,5Patients with ART,5untreated Patients,3,3100020003000400050006000100020003000400050006000Observation 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 <5050-99All-cause mortality>500<5050-99Liver-related mortality>500DAD, Arch Intern Med 2006; 166: 1632
22 Effect of HAART on progression to ESLD – a meta-analysis PRE-HAARTPOST-HAARTThien, 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 armsN patients10203040NNRTIPIMixedBPINRTIOverallDrug Class% Patients with LEEAll PatientsHCV CoinfHIV OnlyReferencesBenhamou 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;#88Benhamou 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 obesityBreast enlargementLipoatrophy (fat wasting or loss)Arms and/or legs ( prominence of veins)FaceButtocksInsulin Resistance and HyperlipidaemiaDiabetes and impaired GTTHypercholesterolaemia and hyperlipidaemiaLipodystrophyLipodystrophy, 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): 57-76John 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
27 HCV/HIV treatment outcomes Genotype 1 SVR 14–38%Genotype 3 SVR 44–73%10075MonoinfectionAPRICOTSVR (%)ACTG50RIBAVICLaguno et al.PRESCO25Outline studiesG1G2/3GenotypeFried 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: 45:2727
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%)807360Q4 (32.1% to 69.3%)6962Pts With SVR (%)404710034202927Gt, 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.16Gt 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%SVREarly D/C AllSevere Anemia (Hb < 8.5 g/dL)Early D/C AnemiaRBV Dose Reduction For AnemiaEPOTorriani F, et al, N Engl J Med. 2004;351:438.
32 Interactions between RBV & nucleoside analogues AZT ddI d4Tanemia hepatic pancreatitis weightdecomp & lactic acidosis loss mitochondrial DNA synthesis lactateBlanco et al. NEJM 2002; 347: 1287
33 Abacavir and SVR SVR predicted by GenotypeViral loadRBV trough concentrationsAbcavir use associated with NR/NSR in patients with low rbavirin trough concentrationsVispo et al, 3rd Int. HIV/hepatitis Conference, Paris Abs 46
34 EACS HCV treatmentPatients with acute HCV – treat if HCV RNA persistently detectable 12 weeks after putative time of infectionChronic HCV – offer treatment to ALL (biopsy/staging/grading NOT essential)Those with CD4 <350 – reasonable to give HAART firstUse HAART with low potential for hepatotoxicityManage insulin resistance activelyThose with F0/F1 fibrosis, especially if G1/G4If CD4 <500 – early HAARTreasonable to wait in terms of Anti-HCV Rx – but frequent monitoring
35 Proposed optimal duration of HCV therapy in chronic HCV/HIV-coinfected patients. W4W12W24W48W72G2/324 weekstherapy *HCV-RNAnegG1/448 weekstherapyG2/3HCV-RNAneg> 2 log dropin HCV-RNAG1/472 weekstherapyHCV-RNAposHCV-RNAposStop< 2 log dropin HCV-RNAStop* 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 4Week 12HCV-RNAnegative*24 weeks of therapyPeg-IFN +RBV (AII)HCV-RNApositive*Drop HCV-RNA 2 log1048 weeks of therapy< 2 log10Stop Therapy*evidence based on using a 615 IU/ml cut-off to define negative HCV-RNA
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 endocytosisTransport and releaseFusion and uncoatingER lumen(+) RNAVirion assemblyLDLDNS3/4 protease inhibitorsTranslation and polyprotein processingDAAs, 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.LDMembranous webNS5B polymerase inhibitorsNucleoside/nucleotideNonnucleosideRNA replicationER lumen*Role in HCV life cycle not well definedNS5A* inhibitorsAdapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:42
43 Select DAAs in Clinical Development Phase IPhase IIPhase IIIProtease InhibitorsABT-450ACH-1625GS 9451MK-5172VX-985BMSCTS-1027DanoprevirGS 9256IDX320VaniprevirBIBoceprevirTelaprevirTMC435Nonnucleoside polymerase inhibitorsBIIDX375ABT-333ABT-072ANA598BMSFilibuvirTegobuvirVX-759VX-222Nucleoside polymerase inhibitorsIDX184PSI-7977RG7128NS5A inhibitorsA-831PPI-461BMSBMSCF102DAAs, 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 100Current Standard of Care100SOC + Protease Inhibitors (Approved in 2011)808063-75[1-2]59-66[3-4]6060SVR (%)38-44[1-2]SVR (%)4040BOC, 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]2020Treatment-Naive PtsTreatment-ExperiencedTreatment-Naive PtsTreatment-Experienced1. 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)1004-wk PR + 44-wk BOC + PR (n = 161)8075666948-wk PR (n = 80)59*6052SVR (%)40*46% of patients in response-guided arm eligible for shorter duration of therapy, with 86% SVR rate.4029BOC, 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:21207OverallPrior NonrespondersPrior RelapsersBacon 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 RVRSVRRelapse1009397868880756055Patients (%)414037262420HCV, 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/ 256/ 233 (1/29)n=21192516762728Prior 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
50 Other issues with NS3/4 inhibitors Side-effect profilesTVR – rashBOC - anaemiaPotential for drug-drug interactions with anti-HIV drugsTVR – ONLY use with Atazanir/R and EFVBOC – significant interaction with EFV, ?interaction with boosted-PIsGenotype 1 specific activityResistance
51 Activity of PIs by HCV Genotype AgentPotential ActivityProtease InhibitorsBoceprevir[1,2]1, 2Telaprevir[3,4]BI 1, 2?DanoprevirMK-51721-6TMC4351, 2, 4, 5, 6VaniprevirDAAs, 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 ClassGeneticBarrierCrossResistancePersistenceNS3/4Low (1b>>1a)yesYes but at low levelNS5b NucshighProb. nounlikelyNS5b Non-nucLowNoYes - ?high levelNS5aHigh (1b>1a)??Cyclophilininhibitors
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 interactionsPredictors of response to triple therapyWhat is the significance of HCV resistance mutationsHow 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 + R2DAAs + P2DAAs + R2DAAs + P+R3 or more DAAsInduction/consolidationRegimensShort duration of RxpIFN + R + PIpIFN + R(g3/g2 + acute HCV)20112012201320142015201620172018HCV resistance testing- Rx failure/rebound- baselineUse of other SNPs toPredict side-effectsIFN-lambda – IFN of choice?Use of IL28BP/R lead-in phaseResponse guided therapyIFN-alphaHistorical therapy!
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