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BORDERNETwork Training on. HIV and HCV Co-Infections. Dr. med. Wolfgang Güthoff / Alexander Leffers, M.A. www.bordernet.eu. www.aidshilfe-potsdam.de.

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Bordernetwork training on

BORDERNETwork Training on

HIV and HCV

Co-Infections

Dr. med. Wolfgang Güthoff /

Alexander Leffers, M.A.

www.bordernet.eu

www.aidshilfe-potsdam.de


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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.)


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Table of Contents

Epidemiology

Natural Course

Therapy

Treatment


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HIV/HCV Co-infections

  • 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


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Rate of HIV / HCV Coinfection

In Northern America, Europe and Asia together the rate of co-infections amounts about 30%!

Sulkowski Ann Intern Med 2003; Sherman Clin Infect Dis 2002; Rockstroh J; D 2005; Dore J ClinVirol


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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 %

Central: 293 = 19,6 %

South: 695 = 41,4 %


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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%


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Hepatitis C is Common in HIV-infected IDUs

  • HCV transmission in HIV positive IDUs amounts about 80%

Rockstroh JID 2005; Sulkowski Ann Intern Med 2003; Danta J AIDS 2007; Fierer J Infect Dis 2008


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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%)

Distribution of HCV by genotype (1–4) in European regions

60

40

20

0

Genotype

1

2

3

4

1

2

3

4

1

2

3

4

1

2

3

4

Eastern

Europe

Southern

Europe

Northern

Europe

Central

Europe

Soriano et al. 11th EACS,Madrid 2007. PS8/1


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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


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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 2009. / (2) Peters,L.:JAcquir Immune DeficSyndr. 2009, 15;457-63.


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Natural Course of HIV / HCV CoinfectionInfluence of HIV on HCV-Infection

  • HIV infection influences all stages of hepatitis C in different ways:

Correlates of Hepatitis C Virus Clearance from HIV Status

  • HIV increases the rate of hepatitis c persistence, the spontaneous recovery of acute HCV infection is decreased

Thomas, D.L.; The Natural History of Hepatitis C Virus Infection; JAMA 2000; 284:450-456


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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, 128-33


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Natural Course of HIV / HCV CoinfectionInfluence 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, 2349-54


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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


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    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), or 1200mg per day (>75kg body weight


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    Treatment outcome in HIV/HCV:

    PegIFN and Ribavirin

    PRESCO

    ACTG5071

    Laguno

    APRICOT

    RIBAVIC

    389

    n with PEG-IFN-2a + RBV

    66

    289

    205

    52

    2a

    2a

    2a

    2b

    2b

    Type PEG-IFN-

    90%

    Patients with IVDA

    62%

    80%

    75%

    -

    28% (F3-F4)

    11%

    15%

    39% (F3-F4)

    19%

    Patients with cirrhosis

    61%

    77%

    67%

    61%

    63%

    Genotype 1-4

    0

    0

    16%

    0

    normal ALT

    34%

    546

    520

    477

    570

    mean CD4+

    495

    74%

    on HAART*

    83%

    83%

    94%

    85%

    8%

    25%

    17%*

    17%

    12%

    Therapy discont. (AE or L)

    67%

    EOT (ITT)

    49%

    35%

    52%

    41%

    50%

    SVR (ITT)

    40%

    27%

    44%

    27%

    Carratet 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


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    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 rs12979860 polymorphism in acute and chronic hepatitis C in HIV-positive patients

    HIV(+)/acute hepatitis C

    HIV(+)/chronic hepatitis C

    HIV(-)/HCV(+)

    100

    100

    100

    P=n.s.

    P=0.039

    P=0.008

    75

    75

    75

    %SVR

    %SVR

    %SVR

    50

    50a

    50

    25

    25

    25

    0

    0

    0

    C/C

    C/T

    T/T

    C/C

    C/T

    T/T

    C/C

    C/T

    T/T

    IL28B genotype

    IL28B genotype

    IL28B genotype

    Natterman J, et al. . 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 164; JID 2011 in press;

    Source: Rockstroh 2011 Potsdam


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    Proposed optimal duration of HCV therapy inHCV/HIV coinfectedpatients

    W 4

    W 12

    W 24

    W 48

    W 72

    24 weeks‘ therapy*

    G 2/3

    HCV-RNA negative

    48 weeks‘ therapy

    G 1/4

    G 2/3

    HCV-RNA negative

    72 weeks‘ therapy

    >2 log drop in HCV-RNA

    G 1/4

    HCV-RNA positive

    STOP

    HCV-RNA positive

    <2log drop in HCV-RNA

    STOP

    * In patients with baseline low viral load and minimal fibrosis

    Rockstroh: HIV Medicine 2008; update EACS Conference in Cologne November 2009,

    update 2011 Belgrade EACS Conference


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    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


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    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


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    Telaprevir – Drug Interaction with ARVs

    (6) Van HeeswijkR et al.: Pharmacokineticinteractionsbetween ARV agentsandtheinvestigational HCV

    proteaseinhibitorTVR in healthyvolunteers. 18th Conference on RetrovirusesandOpportunisticInfections.

    February27 – March 2, 2011,Boston, USA. Session 34, Abstract 119


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    Boceprevir – Drug Interactions with ARVs

    Boceprevir and PIs:

    • Boceprevir reduced mean trough concentrations of boosted Atazanavir, Lopinavirand Darunavirby 49%, 43% and 59%

    • Boosted Lopinavirand Darunavirdecreased the exposure of Boceprevir by 45% and 32%


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    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:

      • Tenofovirwith Emtricitabineor lamivudine, or Abacavir/Lamivudine.

  • Use of boosted PIs together with Telaprevirand especially with Bocepreviris problematic

  • Use of Raltegraviris possible

  • Excellent management of combination therapy is necessary for success of treatment


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    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: 399 - 409


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    Acute Hepatitis C in HIV Patients –

    Criteria for Case Definition

    • Positive anti HCV and positive HCVRNA and da documented negative antiHCV in the last 12 month (grade A, Level II)

    • Positive HCVRNA and a documented negative HCVRNA and negative antiHCV in the previous 12 month (grade A, Level II)

    • 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 and B have to be excluded


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    Antiviral Therapy of Acute Hepatitis C in HIV PatientsStart treatment if HCVRNA is positive yet at week 12

    Week 4

    Week 12

    HCV-RNAnegative*

    24 weeksAII

    peg-IFN + RBV (AII)

    HCV-RNApositive*

    Drop HCV-RNA 2 log10

    48 weeksBIII

    < 2 log10

    StoptherapyBIII

    *Evidence based on using a 615 IU/ml cutoff to define negative HCV-RNA; NEAT Consensus statement AIDS 2011Vogel M, et al., HIV 10; Glasgow; November 7-11, 2010; Abst. O313.


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    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


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    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


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