BORDERNETwork Training on HIV and HCV Co-Infections Dr. med. Wolfgang Güthoff / Alexander Leffers, M.A.

This presentation arises from the BORDERNETwork project which has received funding from the European Union, in the framework of the Health Program, and co- funding of the Ministry of Environment, Health and Consumer Protection of the Federal State of Brandenburg. The sole responsibility of any use that may be made of the information lies with the authors (SPI, AIDS-Hilfe Potsdam e.V.)

Table of Contents Epidemiology Natural Course Therapy Treatment

 Chronic Hepatitis C infection is one of the major co morbidities in people with HIV infection  Worldwide about 5 million of the 33 million HIV infected people are co-infected with HCV, but there are differences between several regions  High rate of co-infection in different countries depends on the common blood borne transmission pathway, especially to high occurrence of intravenous drug use HIV/HCV Co-infections

Rate of HIV / HCV Coinfection Sulkowski Ann Intern Med 2003; Sherman Clin Infect Dis 2002; Rockstroh J; D 2005; Dore J Clin Virol In Northern America, Europe and Asia together the rate of co-infections amounts about 30%!

Prevalence of hepatitis C in the HIV population (1960/5957 patients = 33%) Regions: South Central North East North: 359 = 23,2 % East: 613 = 46,9 % South: 695 = 41,4 % Central: 293 = 19,6 %

Different Routes of HCV Transmission in HIV patients  Rates of vertical HCV transmission are low (3-6%), but in HIV infection it increases 5-fold  Rates of sexual HCV transmission are below 1%  Transmission with blood to blood contact (intravenous drug users) is very high and amounts about 80 to 90%

Hepatitis C is Common in HIV-infected IDUs Rockstroh JID 2005; Sulkowski Ann Intern Med 2003; Danta J AIDS 2007; Fierer J Infect Dis 2008  HCV transmission in HIV positive IDUs amounts about 80%

Hepatitis C co-infection in EuroSIDA  HCV genotype distribution and percentage of naturally cleared HCV infection within EuroSIDA  Results: Of 2263 HCVAb+ patients, 1677 (74%) were serum HCV RNA+ (95% CI:71–78%) Northern Europe Southern Europe Central Europe Eastern Europe Distribution of HCV by genotype (1–4) in European regions Genotype Soriano et al. 11 th EACS, Madrid PS8/1

Diagnostic in patients with HIV/HCV Coinfection  All HIV patients have to be screened for hepatitis C. If HCV antibody test is negative in progressive stage of HIV infection and if there is further suspicion of possible HCV infection, a measurement of HCVRNA with PCR should be done.  HCV genotype and viral concentration before starting therapy  Liver fibrosis staging (liver biopsy as the best method but not mandatory for considering treatment)  All necessary laboratory measurements for excluding possible contraindications of combination therapy with pegylated interferon and ribavirin

Natural Course of HIV / HCV Coinfection Influence of HCV on HIV-Infection  HCV infection does not have a relevant influence on the course of HIV infection There was no difference in the EuroSIDA cohort regarding CD4 cell recovery after starting ART in mono-infected HIV patients in comparison to HCV co-infected patients (1) Hepatitis coinfection does not influence the virological and immunologic response to ART (2) (1) Rockstroh / (2) Peters,L.:J Acquir Immune Defic Syndr. 2009, 15;

Natural Course of HIV / HCV Coinfection Influence of HIV on HCV-Infection  HIV infection influences all stages of hepatitis C in different ways: 1.HIV increases the rate of hepatitis c persistence, the spontaneous recovery of acute HCV infection is decreased Correlates of Hepatitis C Virus Clearance from HIV Status FactorNo. (% Clearence) HIV negative420 (13,8) HIV positive CD4 > (8,3) HIV positive CD4 200 – (8,6) HIV positive CD4 < (5,0) Thomas, D.L.; The Natural History of Hepatitis C Virus Infection; JAMA 2000; 284:

Natural Course of HIV / HCV Coinfection Influence of HIV on HCV-Infection 2. There is a rapid progression of liver fibrosis in HIV / HCV co-infected patients in contrast to hepatitis C mono-infected patients. Probably this is due to the lack of CD4-T cell response against hepatitis C virus. The Time of development to liver cirrhosis is shorter in co-infected patients than in mono-infected HCV patients. Martin-Carbonero, L. et al.: Incidence and predictors of severe liver fibrosis in HIV infected patients with chronic hepatitis C. Clin Infect Dis 2004,

Natural Course of HIV / HCV Coinfection Influence of HIV on HCV-Infection 3. As a result of faster progression of liver fibrosis and faster development of cirrhosis the incidence of hepatocellular carcinoma is also higher in HIV/HCV co-infected patients than in HCV mono-infected patients Giordano, TP et al.: Cirrhosis and HCC in HIV infected veterans with and without the hepatitis C virus. Arch Intern Med 2004,

Therapeutic Challenges in co-infected patients with hepatitis C and HIV  Treatment of chronic Hepatitis C: Access to treatment, costs of therapy, Duration of therapy depends on HCV genotype, baseline HCV viral load and virological response and can take 72 weeks  In co-infected patients the sustained virological response is lower then in HCV mono-infected patients  Choice of ART together with concomitant HCV therapy regarding side effects and interactions  Challenges in treatment of HCV with the new oral agents Telaprevir and Boceprevir

Treatment of Hepatitis C in HIV infected People 1.Pegylated interferon alfa 2a Standard dosage: 180  g sc once weekly independent of body weight or Pegylated interferon alfa 2b Standard dosage: 1.5  g / kg body weight once weekly combined with 2.Ribavirin Standard dosage of ribavirin for HCV genotype 1 is 1000mg per day ( 75kg body weight

Treatment outcome in HIV/HCV: PegIFN and Ribavirin Carrat et al. JAMA 2004, Laguno et al. AIDS 2004, Nunez et al. AIDS Res Hum Retroviruses 2007 Chung et al. NEJM 2004, Torriani et al. NEJM 2004, Alvarez et al. CROI 2005, Abstract 927 ACTG n with PEG-IFN-  2a + RBV Type PEG-IFN-  Patients with IVDA Patients with cirrhosis Genotype 1-4 normal ALT mean CD4 + on HAART* Therapy discont. (AE or L) 66 EOT (ITT) SVR (ITT) 52 2a2b2a2b 62%80% - 75% 15%39% (F3-F4)11%19% 67%61%77%63% 016% 34% % 85% 94% 25%17%* 12% 17% 49%35% 41% 52% 40%27% 44% APRICOTRIBAVIC Laguno 389 2a 90% 28% (F3-F4) 61% % 8% 67% 50% PRESCO

IL-28B Genotypes and SVR Rates  Recent studies demonstrate polymorphisms near interleukin 28 B (IL28B) gen predict sustained virological response (SVR) to treatment with Peg-IFN + RBV in HCV-mono-infected patients harbouring genotype 1  Study assessing potential role of the IL-28B treatment induced clearance of rs polymorphism in acute and chronic hepatitis C in HIV-positive patients C/CC/TT/T IL28B genotype P=0.008 %SVR HIV(-)/HCV(+) P=0.039 IL28B genotype HIV(+)/chronic hepatitis C C/CC/TT/T a %SVR P=n.s. IL28B genotype HIV(+)/acute hepatitis C C/CC/TT/T %SVR Natterman J, et al.. 17th CROI; San Francisco, CA; February 16-19, Abst. 164; JID 2011 in press; Source: Rockstroh 2011 Potsdam

Proposed optimal duration of HCV therapy in HCV/HIV coinfected patients Rockstroh: HIV Medicine 2008; update EACS Conference in Cologne November 2009, update 2011 Belgrade EACS Conference * In patients with baseline low viral load and minimal fibrosis W 4W 12W 24W 48W 72 HCV-RNA negative HCV-RNA positive G 2/3 G 1/4 >2 log drop in HCV-RNA <2log drop in HCV-RNA STOP 24 weeks‘ therapy* 48 weeks‘ therapy 72 weeks‘ therapy HCV-RNA positive HCV-RNA negative STOP G 1/4 G 2/3

HIV Medication with HCV Therapy  Didanosine (ddI) is contraindicated  Use of AZT and d4T should be avoided due to increased risk of toxicity  Increasing side effects of combination Atazanavir – Ribavirine is possible  Combination of Efavirenz and PEG-IFN – high risk of severe depression

PIs in the treatment of HIV/HCV Co-infected Patients  New directly acting agents (DAAs)  Two groups of protease inhibitors (PI) linear and macrocylic PI  First two linear PI are approved in US and Europe: Telaprevir Boceprevir  Triple therapy (PEG-IFN, Ribavirine + PI) is an additional challenge for clinicians

Telaprevir – Drug Interaction with ARVs (6) Van Heeswijk R et al.: Pharmacokinetic interactions between ARV agents and the investigational HCV protease inhibitor TVR in healthy volunteers. 18th Conference on Retroviruses and Opportunistic Infections. February 27 – March 2, 2011,Boston, USA. Session 34, Abstract 119 TVR doseARVTVR AUCTVR CminARV AUCARVCmin TVR 750 mg TIDATV/r0.80 ( )0.85 ( )1.17 ( )1.85 ( ) DRV/r0.65 ( )0.68 ( )0.60 ( )0.58 ( ) FPV/r0.68 ( )0.70 ( )0.53 ( )0.44 ( ) LPV/r0.46 ( )0.48 ( )1.06 ( )1.14 ( ) TVR 1250 mg TID EFV 0.82 ( )0.75 ( ) 0.82 ( )0.90 ( ) TDF1.10 ( )1.17 ( ) TVR 1500 mg BID EFV 0.80 ( )0.52 ( ) 0.85 ( )0.89 ( ) TDF1.10 ( )1.06 ( )

Boceprevir – Drug Interactions with ARVs Boceprevir and PIs:  Boceprevir reduced mean trough concentrations of boosted Atazanavir, Lopinavir and Darunavir by 49%, 43% and 59%  Boosted Lopinavir and Darunavir decreased the exposure of Boceprevir by 45% and 32%

Treatment of HIV/HCV Coinfection with PI containing therapy - Conclusions  New options for therapy also in setting of HIV/HCV co-infected patients, especially for patients with detected liver fibrosis  Recommended backbone: Tenofovir with Emtricitabine or lamivudine, or Abacavir/Lamivudine.  Use of boosted PIs together with Telaprevir and especially with Boceprevir is problematic  Use of Raltegravir is possible  Excellent management of combination therapy is necessary for success of treatment

Antiviral Therapy of Acute Hepatitis C in HIV Patients Recommendations from the European AIDS TreatmentNetwork (NEAT) for acute hepatitis C in HIV infected individuals The European AIDS Treatment Network Acute Hepatitis C Consensus Panel AIDS 2011, 25:

Acute Hepatitis C in HIV Patients – Criteria for Case Definition 1.Positive anti HCV and positive HCVRNA and da documented negative antiHCV in the last 12 month (grade A, Level II) 2.Positive HCVRNA and a documented negative HCVRNA and negative antiHCV in the previous 12 month (grade A, Level II) 3.If there do not exist serological data for HCV in the past: Positive HCVRNA with acute rise of ALAT more than 10 times the upper limits of normal (ULN) (B III) Positive HCVRNA with acute rise more than 5 times the ULN, with documented normal ALAT within 12 month (B III) In these cases acute Hepatitis A, B and E have to be excluded

Antiviral Therapy of Acute Hepatitis C in HIV Patients Start treatment if HCVRNA is positive yet at week 12 *Evidence based on using a 615 IU/ml cutoff to define negative HCV-RNA; NEAT Consensus statement AIDS 2011 Vogel M, et al., HIV 10; Glasgow; November 7-11, 2010; Abst. O313. HCV-RNA negative* Stop therapy BIII peg-IFN + RBV (AII) < 2 log weeks AII Drop HCV-RNA  2 log 10 Week 4 Week 12 HCV-RNA positive* 48 weeks BIII

Summary 1  HCV/HIV co-infected patients show an accelerate progression to cirrhosis and increased liver-related mortality  Every co-infected patient should be evaluated for combination therapy with pegylated interferon + ribavirin  Duration of therapy depends on the HCV genotype, baseline HCV concentration and treatment response  Higher CD4 cell counts are associated with higher treatment response, so ART should not be withheld in coinfected patients  ART needs to be adapted to concomitant HCV therapy

Summary 2  The new protease inhibitors in HCV therapy induce better chances of cure in HIV/HCV co-infected patients, but the use of Telaprevir and Boceprevir together with ART causes additional challenges.  Further studies regarding drug interactions optimizing therapy are necessary  Treatment of co-infections should be carried out only in special treatment centres