3 Rate of death according to calendar year and specific cause of death D:A:D: Liver-related death is a frequent cause of non-AIDS death in HIV-infected patientsAnalysis of 2,482 deaths in 180,176 person-years among 33,308 individualsAIDS remains the primary cause of death amongst HIV-positive individualsRate of death according to calendar year and specific cause of death1234561999–20002001–20022003–2004Rate per 1,000 person years2005–20062007–2008The cause of death mirrored the incidence rates as shown previously with reduction in AIDS-defining Ois and cancers and an increase in non-AD diseases.However, although the overall rate has decreased and is much lower than that observed in the pre-cART era, AIDS-related illness remains the most common cause of death although the differential between AIDS-deaths and those from non-AIDS defining malignancies and chronic viral hepatitis was less marked.Rates of death also fell for chronic viral hepatitis, liver failure, myocardial infarctionHIV/AIDSStrokeChronic viral hepatitisLiver failureNon-AIDS malignancyComplications due to diabetesMyocardial infarction, definite or possibleOther cardiovascular diseaseOther heart diseaseAdapted from D:A:D Study Group. AIDS. 2010;24:1537–48.3
4 Prevalence of HBV: Global Estimates HBsAg +ve, (%)Taiwan10.0–13.8Vietnam5.7–10.0China5.3–12.0Africa5.0–19.0Philippines5.0–16.0Thailand4.6–8.0Japan4.4–13.0Indonesia4.0South Korea2.6–5.1India2.4–4.7Russia1.4–8.0US0.2–0.5HBsAg, hepatitis B surface antigen.This slide illustrates the prevalence of hepatitis B using global estimates by region and country. As seen on this slide, there are wide ranges of hepatitis B surface antigen (HBsAg) prevalence in different countries. However, some information on this slide may not fully reflect the current situation. For instance, in some communities in Vietnam and China, the prevalence is as high as 30%. Fortunately, in a number of countries that instituted vaccination, which will also be discussed later, there has been a declining prevalence of hepatitis B, especially in babies, infants, and young children.HBsAg PrevalenceHigh (≥8%)Intermediate (2% to 8%)Low (<2%)Mast EE, et al. MMWR Recomm Rep. 2006;55:1–33 Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl):S158-S168444
5 Global HIV/HBVThio, C. Hepatology 2009; 49(5): s138
6 HIV/HBV Co-infection: Increased risk of ESLD due to HBV P<0.0001Liver-related Mortality Rate (per 1000 person-years)P<0.001P=0.04Thio CL, et al. Lancet. 2002:360:6
7 Immune activation and liver disease CirrhosisHCV/HBVAlcoholAltered 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 of S. Lewin
9 Natural history of HBV infection – where does co-infection fit in? > 95%< 5%Early childhoodImmune toleranceAdulthoodHBeAg– Chronic Hepatitis BHBV DNA +HIV/HBVIncreased likelihoodHBeAg+ Chronic Hepatitis BHIV/HBVHigherviral loadsHIV/HBV:Increased viral loadsLower ALTIncreased fibrosisHCCInactive carrierHBs+HBe-HBV DNA lowHBeAg, hepatitis B e antigen; HCC, hepatocellular carcinoma.This slide highlights the risk of cancer. A patient can progress to cancer from any of the 4 highlighted states.HIV/HBVReduced seroconversionAdapted from: Chen DS, et al. J Gastroenterol Hepatol 1993;8:470–5; Seeff L, et al. N Engl J Med 1987;316:965–70; Thio CL, et al. Lancet 2002;360:1921–6; Gilson RJ, et al. AIDS 1997;11:597–606; Colin JF, et al. Hepatology 1999;29:1306–10.99
11 Anti-HBV drugs PegIFN ETV* TDF* TBV LAM* FTC* Potency ADV NucleosidesADVNucleotidesOral drugs against HBV all share the same target, viral DNA polymerase. Two main families of inhibitors may be distinguished, nucleoside and nucleotide analogs. It is also important to notice that some of these drugs have antiHBV and antiHIV activity (LAM, FTC, ETV, TDF), while others are only active against HBV polymerase (TBV and CLV). AntiHBV drugs may also be classified according to antiviral potency and genetic barrier. TDF and ETV have the best profile, while LAM and FTC are weak and rapidly affected by the selection of mutants. The case of ADV is a little different, as its limitations in potency and genetic barrier mainly derive from the low doses used to avoid kidney toxicity.*Anti-HIV activityGenetic barrier11
13 Agbaji et al, (CROI, 2013) HBV in the resource-poor setting; how useful is FibroScan? HBV/HIV co-infectedUnivariate Multivariate OR, 95% CIp valueAge ≥30 yrs0.83 (0.26,3.03)0.740.50 (0.14,1.87)0.30Male gender1.52 (0.50,4.51)0.401.18 (0.35,3.92)0.79HBV DNA >3.3 log IU/mL 1,2 6.5 (1.99, 22.97) 0.00036.09 (1.96,18.91)0.002HBeAg reactive2.50 (0.69, 8.41)0.10-Married1.1 (0.37, 3.46) 0.86Current alcohol use2.62 (0.81, 8.19)0.062.38 (0.74,7.60)0.15ALT ≥3030.80 (0.27, 2.46)0.66BMI >250.44 ( )0.170.52 (0.14,1.82)0.29CD4 <2001.72 (0.53,5.30)1.26 (0.37,4.29)0.71HIV VL >400,0001.16 (0.18, 5.35)0.83Platelets <150 2.18 (0.45, 9.76) 0.24HIV mono-infectedNigerian study (Abuja)Pre-cART comparison of FibroScans and other parameters between HIV mono and HBV co-infected patientsA high elastography reading (>9.3 kPa) was associated with an HBV DNA >3.3 Log10 Iu/ml, immaterial of eAg status and ALT.
14 Pertinent issues in HIV/HBV co-infection management TDF +/- 3TC/FTC worksWhat options for patients NOT needing HAARTPegIFNWhat about hepatic ‘flares’ with anti-HBV therapy?What about ‘slow’ responders to TDF?For patients needing HAARTWhat to do with patients developing Tenofovir toxicity?Global implications of lamivudine resistance
15 Pertinent issues in HIV/HBV co-infection management TDF +/- 3TC/FTC worksWhat options for patients NOT needing HAARTPegIFNWhat about hepatic ‘flares’ with anti-HBV therapy?What about ‘slow’ responders to TDF?For patients needing HAARTWhat to do with patients developing Tenofovir toxicity?Global implications of lamivudine resistance
16 High rates of HBeAg seroconversion following HBV active HAART Longitudinal Thai cohort (n=47); HBeAg-positive (n=30); median follow up = 27 monthsHBeAg loss = 46%; HBsAg loss = 13%Avahingson et al., 5th IAS Conference, Capetown 2009, Poster # WEPEB226
20 MORTAVIC: Causes of death in HIV-infected adults in France in 2010 Patients (%)Patients (%)Cause of deathCause of underlying cirrhosisNumber of documented deaths=230Patients (%)Created from Rosenthal E, et al. EASL Barcelona Spain. Oral presentation 26.Liver-related cause of death
21 Pertinent issues in HIV/HBV co-infection management TDF +/- 3TC/FTC worksWhat options for patients NOT needing HAARTPegIFNWhat about hepatic ‘flares’ with anti-HBV therapy?What about ‘slow’ responders to TDF?For patients needing HAARTWhat to do with patients developing Tenofovir toxicity?Global implications of lamivudine resistance
22 PegIFN and HIV/HBV Very little data in HIV/HBV co-infected patients Ingiliz P et al. (combination with adefovir)No e-seroconversion after 48 weeksHBV DNA levels not maintained post-RxPredictors of response in mono-infected patientsGenotype A/BHigh ALT (>3 × ULN)Low HBV DNA (<2 × 106 IU/L)Risk of de-compensation/complications in cirrhotic CP-B/C patientsEASL Practice Guidelines. J Hepatol 2009;50:227–42; Ingiliz P, et al. Antivir Ther 2008;13:895–900.
23 Can pegIFN intensification help clear HBeAg in TDF treated HBV/HIV co-infection? .CROI 2013: Anders Boyd et al.Case control from larger French HIV/HBV prospective cohortPeg-IFN-INTS during TDF-treatment was associated with accelerated HBeAg-lossBut no effect on qHBeAg/qHBsAg decline or long-term serological outcomes.Adding peg-IFN to a TDF-containing regimen may not be a beneficial option in co-infectionCROI 2013: Patrick Miailhes et al.The ANRS HB01 EMVIPEG StudyN=51, no control groupaddition of pegIFN did not allow to increase the rate of HBe seroconversion in HBeAg+ HIV co-infected patients1030pegIFN 7/12controlsMedian 39/12 TDF based cART alreadyKaplan-Meier of cummulative loss of HBeAgMatched qHBeAg at baseline37 months TDF + 3TC/FTCpegIFN126on pegIFN24/52 post pegIFNHBeAg loss12/51 (24%)8/51 (16%)HBeAb seroconversion6 (12%)4 (8%)HBsAg loss2 (4%)1.00HBV DNA Undetectable?pegINF 1/10 (10%)Ctrl /30 (7%)0.400.000/1212/1224/1236/12
24 Pertinent issues in HIV/HBV co-infection management TDF +/- 3TC/FTC worksWhat options for patients NOT needing HAARTPegIFNWhat about hepatic ‘flares’ with anti-HBV therapy?What about ‘slow’ responders to TDF?For patients needing HAARTWhat to do with patients developing Tenofovir toxicity?Global implications of lamivudine resistance
25 Hepatic flares post-starting TDF-based cART in co-infected patients Avihingasanon, et al AIDS Research Therapy 2012
26 Co-relates of hepatic flares Avihingasanon, et al AIDS Research Therapy 2012
27 Hepatic flares in HBV/HIV Usually in the first 12 weeks post-cARTAssociated with high HBV DNA levels and high baseline ALTsRestoration of innate and adaptive anti-HBV response in the presence of high HBV DNADe-compensation rare BUT caution with cirrhosis
28 Pertinent issues in HIV/HBV co-infection management TDF +/- 3TC/FTC worksWhat options for patients NOT needing HAARTPegIFNWhat about hepatic ‘flares’ with anti-HBV therapy?What about ‘slow’ responders to TDF?For patients needing HAARTWhat to do with patients developing Tenofovir toxicity?Global implications of lamivudine resistance
30 Delayed response with TDF How long is ‘delayed’?In this small study almost all ‘delayed’ responders suppressed by a median of 49 months.No TDF associated mutationsX1 new lam-associated polymormphismChilds, et al AIDS 2013
31 Pertinent issues in HIV/HBV co-infection management TDF +/- 3TC/FTC worksWhat options for patients NOT needing HAARTPegIFNWhat about hepatic ‘flares’ with anti-HBV therapy?What about ‘slow’ responders to TDF?For patients needing HAARTWhat to do with patients developing Tenofovir toxicity?Global implications of lamivudine resistance
32 Renal impairment with TDF – watch this space…. 240 patients with a 3year-time follow-up, normal eGFR at baseline1>400 HIV+ patients receiving TDFFigure 1: MDRD clearance over timePune:RFH:Retrospective cohort review of two cohorts of HIV patients (Royal Free – predominantly caucasian, Pune – all asian).In patients with a normal eGFR, incidence of eGFR <60ml/min higher in Indian patients.Increased co-morbidities, concomitant therapies and boosted-PI use associated with risk of eGFR <60ml/minPujari, et al, CROI 2013
33 What about tenofovir toxicity or HIV resistance to tenofovir or 3TC/FTC?BHIVA Guidelines 2010; HIV Medicine 2010
34 Care with patients who have previously been exposed to Lam mono-therapy 6 patients switched from TDF to ETVLam maintained in 5/6Rapid rebound in HBV viraemia – median 2 months (range 1-11 months)All had baseline L180M + M204V
35 Cumulative probability of virological breakthrough with entecavir Mutations: (M204V, L180M) + T184, S202 and/or M250Colonno, AASLD 2006; Colonno EASL 2007; Colonno Hepatology 2006; Tenney et al Antiimicrob.Agents Chemother 2007
37 Pertinent issues in HIV/HBV co-infection management TDF +/- 3TC/FTC worksWhat options for patients NOT needing HAARTPegIFNWhat about hepatic ‘flares’ with anti-HBV therapy?What about ‘slow’ responders to TDF?For patients needing HAARTWhat to do with patients developing Tenofovir toxicity?Global implications of lamivudine resistance
38 Triple HBV mutation twice as common in HIV/HBV3 Incidence of HBV Resistance in Patients Treated with LAM in HBV infection vs. HIV/HBV co-infectionLAM1(YMDD )LAM2(YMDD in HIV/HBV)100%90%Triple HBV mutation twice as common in HIV/HBV380%70%60%53%Incidence of Resistance47%42%40%24%20%0%year 1year 2year 3year 41. Lai C.L., et al., Clinical Infectious Diseases (2003) 36:6872. Benhamou Y et al. Hepatology 1999; 30:1302-63. Matthews GV, et al. AIDS 2006;20(6):38
39 Impact of lamivudine resistance on progression of liver disease Patients with severe fibrosis or cirrhosis25Placebo (n = 215)YMDDm (n = 209) (49%)20Wild-Type (n = 221)Placebo21%1513%Disease Progression, %YMDDm105%5WT61218243036Time after Randomization (months)Liaw, N Engl J Med. 200439
40 More than just ‘drug resistance’ Overlapping Pol and SMutations in Pol – changes in SADASMs – Antiviral Drug-Associated S mutationsADAPVEMS – Antiviral Drug Associated Potentially Vaccine (and detection) Escape MutationsAssociated with L-nucleosides and Entacavir, possibly with adefovir
41 Ag–Ab binding [IC50 (μg/ml)] Envelope/Polymerase Mutations and the Antigen/Antibody Binding Capacity in Genotype A and D HBV/HIV Co-infected Subjects (n=9) with LAM ResistanceEnvelope changesPolymerase changesAg–Ab binding [IC50 (μg/ml)]Wild type1.09HBIG escapesG145RAnti-viral drug resistantsE164DsW196SsI195MsM198IsE164D/I195MrtW153GrtV173LrtM204IrtM204VrtV207IrtV173/rtL180/rtM204V>55.014.868.295.2612.554.53Cooley L et al. AIDS 2003;17:1649–57.41
43 ARV Rollout AZT/d4T+LAM+NNRTI ?Global Impact HBsAg, hepatitis B surface antigen.This slide illustrates the prevalence of hepatitis B using global estimates by region and country. As seen on this slide, there are wide ranges of hepatitis B surface antigen (HBsAg) prevalence in different countries. However, some information on this slide may not fully reflect the current situation. For instance, in some communities in Vietnam and China, the prevalence is as high as 30%. Fortunately, in a number of countries that instituted vaccination, which will also be discussed later, there has been a declining prevalence of hepatitis B, especially in babies, infants, and young children.434343
44 HIV/HBV co-infection: mortality in the resource rich setting 353025Liver related mortality rate/100 py20Hoffman et al., AIDS 2009HAARTHBV-active (95%)15105HBV<1996Thio et al Lancet 2002
48 WHO: Global HIV and HCV infection Global HIV infection1 (% adult prevalence)Global chronic HCV infection2 (% adult prevalence)Asia Pacific up to 1.3%Asia Pacific up to and over 10%North America up to 3.1%Europe up to 1.2%North America up to 2.49%Europe up to 2.49%Africa and Middle East up to 25.9%Africa and Middle East up to and over 10%Latin America up to and over 10%Latin America up to 2.3%Estimated total HIV infections worldwide:33.3 millionEstimated total chronic HCV infections worldwide:170 millionHCV genotypes 1–3 have a worldwide distributionGenotypes 1a and 1b are most common and account for 60% of global infectionsWHO=World Health Organisation1. Adapted from UNAIDS Global View of HIV infection Available at _2010_HIV_Prevalence_Map_em.pdf. Accessed September 2012; 2. Adapted from WHO Hepatitis C Guide Available at Accessed September 2012BMS CONFIDENTIAL: for internal use only. Not for distribution
49 EuroSIDA: Prevalence of HIV/HCV co-infection and distribution of HCV genotypes NorthGenotype60%40%20%0%1234CentralGenotype60%40%20%0%1234North: 18.3%Central: 15.0%East: 31.3%SouthGenotype60%40%20%0%1234EastGenotype123460%40%20%0%Distribution of hepatitis C virus genotypes in the distinct EuroSIDA regions.South: 35.5%Map shows prevalence of HIV/HCV coinfection by region in N=5,957 HIV-infected patients with an HCV antibody test available1Bar charts shows prevalence of HCV genotype in n=1,940 HIV/HCV-coinfected patients by region2Created from: 1. Rockstroh J, et al. J Infect Dis. 2005;192:992–1002; 2. Soriano V, et al. J Infect Dis. 2008;198:1337–44.
50 Swiss HIV Cohort Study: Changing patterns of HCV incidence HCV incidence in MSM:Reached 4.1 cases per 100 PY in 2011 (18‐fold increase since 1998)HCV incidence in IDU:Decreased from 13.9 to 2.2 cases per 100 PYHCV incidence in heterosexualsRemained <1 per 100 PY throughout the study periodSwiss HIV Cohort Study: HCV yearly incidence rate by transmission group*HETIDUMSM20151051Incidence rate (per 100 py)0.1Predictors of HCV seroconversion in MSM1,2:History of UAI, multiple partners, use of sex-toys and fistingSTIs, especially syphilis and LGV1998200020022004200620082010Calendar year*Shaded: 95% confidence intervalsPY=patient years; IDU=intravenous drug users; UAI=unprotected anal intercourse; STIs=sexually transmitted infections; LGV=lymphogranuloma venereum; HET=heterosexual1. Adapted from Wandeler G, et al. CROI Seattle USA. Poster Q106; 2. Van de Laar T, et al. JID 2007;196:230–8.
51 HIV/HCV coinfection may result in multi-systemic disorders Diabetes mellitusInsulin resistanceMicrobial translocationSteatosisFibrosisCirrhosisEnd-stage liver diseaseLiver-related deathGlobal cognitive impairmentCognitive-motor impairmentDementiaPeripheral neuropathyCerebrovascular diseaseAcute myocardial infarctionOpportunistic infectionsWasting syndromeProteinuriaAcute renal failureChronic kidney diseaseOsteonecrosisOsteoporosisBone fractureLiver diseaseHIV disease progressionMetabolic disordersGI tractNeurologic diseaseCardio-vascularKidney diseaseBone disordersCD4 apoptosisAbnormal T-cell responses and cytokine productionCytotoxic T-cell accumulation in liverImpaired CD4 recovery post-HAARTSevere immunodeficiencyImmune activationImmune dysfunctionHIV/HCVAdapted from Operskalski EA and Kovacs A. Curr HIV/AIDS Rep. 2011;8:12–22.
52 Impact of chronic HCV in patients with AIDS in the cART era Chronic HCV infection is independently associated with a 50% increase in mortality among patients with an AIDS diagnosis0.50w/o HCV markersCleared HCVChronic HCVCumulative probability of mortality0.25Years of follow upNumber at riskw/o HCV markersClearedChronicAdapted from Branch A, et al. Clin Infect Dis 2012;55:137–44.
53 HAART reduces mortality in HIV/HCV-co-infected patients Overall MortalityBonn cohort (1990–2002)285 HIV/HCV-coinfected patientsLiver-related mortality rates per 100 PY:HAART: 0.45ART: 0.69No therapy: 1.70Predictors of liver-related mortality:No HAARTLow CD4 cell countIncreasing ageHAART*Cumulative SurvivalART*p<0.001No therapyDaysLiver-Related MortalityHAART*ARTNo therapyCumulative Survival*p=0.018DaysAdapted from Qurishi N, et al. Lancet. 2003:362:1708–13.53
54 Effective treatment of HIV infection reduces fibrosis risk in HIV/HCV-coinfected patients Predictive factors of fibrosis progression (≥1 stage) (multivariate analysis)Relative risk (95% CI)0.51.01.52.02.53.0p multivariateAge, years(≥37 vs <37)0.900.720.0280.870.580.0090.0110.023HAART during the follow-up(Yes vs No)Undetectable HIV viraemia*(Yes vs No)CD4 cell counts change(Per 25 cell increase)Genotype 3(Yes vs No)Baseline ALT, IU/mL(≥66 vs <66)Baseline necroinflammatory activity(L2–4 vs L0–1)Time between liver biopsies(Per 1 year increase)Response to anti-HCV treatment(ETR vs no ETR)Data collected from 135 coinfected patients with 2 liver biopsies >1 year apart.Specimens were centrally read and scored blindly by 2 independent pathologists using the Scheuer classification.RR (95% CI)=relative risk (95% confidence interval); ETR=end-of-treatment response;HAART=highly active antiretroviral therapy; *Undetectable HIV RNA in ≥70% determinations during the follow up.Created from Macias J, et al. Hepatology 2009;50:1056–63.
55 HCV/HIV treatment outcomes with pegIFN and Ribavirin Genotype 1 SVR 14–38%Genotype 3 SVR 44–73%10075MonoinfectionAPRICOTSVR (%)ACTG50RIBAVICLaguno et al.PRESCOOutline studies25G1G2/3GenotypeFried 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: 45:5555
56 Rallón et al, CROI 2010, J Hepatology 2012 READ AS STATED.Rallón et al, CROI 2010, J Hepatology 2012565656
57 HCV Life Cycle and DAA Targets – essential knowledge 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;6:57
60 Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC) Telaprevir (TVR) in combination with pegylated interferon-α-2a (P) + ribavirin (R) in HCV/HIV-coinfected patientsPart A: No ARTSVR 12 follow upSVRTVR+PRPRT/PR 1:1 PR48 (control)SVR 12 follow upSVRPbo+PRPRPart B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC)SVR 12 follow upSVRTVR+PRPRT/PR 1:1 PR48 (control)SVR 12 follow upPbo+PRPRSVRWeeks122436486072Telaprevir dose was 1,125 mg every 8 hours when the ART regimen included EFVPart A, patients had no concurrent ARTPart B, patients were on stable, predefined ART with either an EFV- or an ATV/r-based regimenAdapted from Dieterich D, et al CROI Seattle USA. Oral Presentation 46.
61 Boceprevir (BOC) + pegylated interferon-α-2b + ribavirin for the treatment of HCV/HIV-coinfected patientsPEG2b+RBV 4wkBocepravir + PEG2b + RBV44wkFollow up SVR-24wkPlacebo + PEG2b + RBV2412284872WeeksArm 1Arm 2Futility rulesTwo-arm study, double blinded for BOC, open-label for PEG2b/RBV2:1 randomisation (experimental: control)BOC dose 800 mg TID4-week lead-in with PEG2b/RBV for all patientsPEG-2b 1.5µg/kg QW; RBV 600–1,400 mg/day divided BIDAdapted from Sulkowski M, et al CROI Seattle USA. Oral Presentation 47.
62 SVR12 with TVR or BOC + pegylated interferon and ribavirin (PR) vs PR alone in HIV/HCV coinfection SVR12: TVR + PR vs PR1*SVR12: BOC + PR vs PR2**2040608010020406080100No ART80EFV-based ART747169ATV-based ART60.7Total5050Patients with SVR12 (%)Patients with SVR12 (%)453326.511/ 1612/ 1528/3810/225/72/64/84/837/619/34So what do we see in coinfected patients? These are data looking at SVR12 (12 weeks after the end of therapy) If the patient’s hepatitis C viral load suppressed at this point, SVR12 is a good predictor of SVR24.On the left are the results of telaprevir combined with peginterferon and ribavirin Response rates were approximately 20% to 30% higher in patients that also received telaprevir compared with those that only took pegylated interferon and ribavirin. When boceprevir plus pegylated interferon and ribavirin was compared with placebo you see more than a doubling of the response rate.These are relatively small studies; that’s important to note. Again, this is SVR12 not SVR24, but the data suggest that these HCV protease inhibitors not only are a great benefit to monoinfected patients, but are also likely to be a great benefit for our coinfected patients. The challenge, of course, is that there are, as you might guess, quite a few drug-drug interactions.TVR + PRPlacebo + PRBOC + PRPlacebo + PRRebound in HIV-1 RNA not observed in any patientHIV-1 RNA breakthrough observed in 7 patientsDC due to AEsPR (n=22)0%TVR + PR (n=38)8%DC due to AEsPR (n=34)9%BOC + PR (n=64)20%Primary endpoint=SVR at 12 weeks; interim analysis presented; TVR=telaprevirPrimary endpoint=SVR at 44 weeks; interim analysis presented*Pegylated interferon-α-2a; **Pegylated interferon-α-2b.Adapted from: 1. Dieterich DT, et al. CROI Seattle USA. Oral Presentation 46; 2. Sulkowski MS, et al. CROI Seattle USA. Oral Presentation 47.62
63 Tolerability and safety signals from the pilot studies
64 NB: HCV PIs, cyp450 metabolised, so important DDIs
65 Kinetic Guided Rx length TVR W4W8W12W24W48P + ReRVR+RxNaïve/RelapsersPIFN + R + TVRP + ReRVR-PartialResponders/Non-Responders/Cirrhotics?HIVPIFN + R + TVRP + RStopping RulesWeek 4 or week 12 HCV RNA >1000 U/l
66 BOV- kinetic guided Rx length W4W8W12W28W36W48eRVR+PIFN + R + BOVRxNaïveP + ReRVR-PIFN + R + BOVP + RPartialResponders/RelapsersPIFN + R + BOVP + RP + RCirrhotics(and ?HIV+)PIFN + R + BOVStopping Rulesweek 12 >100 U/l
67 Stopping Rules for BOC and TVR Established as ‘futility’ rule in PegIFN/RibReduce exposure to potentially toxic drugsCost-benefitIn DAAs, also helpful to stop emergence of further Resistance Associated VariantsBoceprevirWeek 12 HCV RNA >100 IU/lWeek 12 detectable HCV RNATelaprevirWeek 4 HCV RNA >1000 IU/lWeek 8 HCV RNA >1000 IU/lWeek 12 detectable HCV RNA
68 So what’s on the horizon? New once daily new generation PIs with pIFN and RibavirinPegIFN-lamda in combination with NS5a inhibitor and ribavirinIFN-free therapies
69 Management of HIV/HCV Co-infected Genotype 1 Patients Management of newly diagnosed HIV-HCV coinfected genotype-1 patientsManagement of HIV/HCV Co-infected Genotype 1 PatientsNewly diagnosed chronicHCV GT 1 infectionPerform transient elastography and/or serum marker and/or liver biopsyF0F1aF2F3aF4aIn general, treatment can be deferred. Consider treatment with Peg/RBV and an HCV protease inhibitor or Peg/RBV alone if low HCV viral load, IL28B CC genotype, absence of insulin resistance and high CD4+ cell count.Treatment with Peg/RBV and an HCV protease inhibitor.Treatment with Peg/RBV and an HCV protease inhibitor if compensated disease.Treatment should be undergone in specialised centres.aMetavir fibrosis score: F0=no fibrosis; F1= portal fibrosis, no septae;F2= portal fibrosis, few septae, F3=bridging fibrosis, F4=cirrhosis.EACS Heptitis/HIV Guidelines 2012