HCV Treatment IDSA Friday 10.25.2002 by SCQ5Du

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									  Hepatitis B, Hepatitis C, and
Human Immunodeficiency Virus:
Epidemics on a Collision Course

         Gerald Pierone Jr, MD
   AIDS Research & Treatment Center
         of the Treasure Coast
             Fort Pierce, FL
                  Outline
•   HIV, HBV, HCV Epidemiology
•   Natural history of HIV, HBV, and HCV
•   Interactions between the infections
•   Management of HBV and HCV in HIV-
    infected patients
    Three Worldwide Pandemics
•   40 million infected with HIV
•   170 million infected with HCV
•   400 million infected with HBV
•   Regional epidemics with wide variation in
    prevalence
Adults and children estimated to be
  living with HIV as of end 2004
                                  Western & Central     Eastern Europe
                                      Europe            & Central Asia
       North America                  610 000            1.4 million
       1.0 million                                                        East Asia
                                                                         1.1 million
          Caribbean            North Africa & Middle East
          440 000                      540 000
                                                            South & South-East Asia
                                                                7.1 million
                                      Sub-Saharan Africa
               Latin America             25.4 million                     Oceania
               1.7 million                                                35 000




    Total: 39.4 (35.9 – 44.3) million
              Worldwide Prevalence of
                Chronic Hepatitis B



                                              HBsAg Prevalence (%)
                                                    8: High

                                                    2-7: Intermediate

                                                    <2: Low




World Health Organization
Centers for Disease Control and Prevention.
         Prevalence of HCV/HIV Co-infection
                         100
                                      90%

                         80
            Percentage




                                                                                                           IVDU
                         60
                                                                                                           MSM
                                                                                                           All HIV+
                         40                                        33%                                     US Pop

                         20                        10%
                                                                                1.9%
                          0
                                                       Population

Sulkowski MS, Mast EE, Seeff, LB et al. Hepatitis C Virus Infection as an Opportunistic Disease in Persons infected with Human
Immunodeficiency Virus. Clin Infect Dis. 2000;30:577-84.
      Natural History of HCV
• After primary infection 60-85% develop
  chronic viremia
• Disease progression is measured in
  decades
• Variable rates of progression
• Disconnect between HCV level in blood
  and liver histology
      Natural History of HBV
• After primary infection 5-10% develop
  chronic viremia
• Disease progression is measured in
  decades in those with active infection
• Variable rates of progression
• 25-30% of chronically infected go on to
  develop decompensated liver disease or
  cirrhosis
        Acute HBV Infection with Recovery
            Typical Serologic Course
                                Symptoms
                         HBeAg                            anti-HBe


titer                                                     Total anti-HBc




              HBsAg                             IgM anti-HBc                    anti-HBs




             0      4     8     12   16    20   24   28    32    36        52        100

Source: US CDC and Prevention             weeks of exposure
   Progression to Chronic HBV Infection
         Typical Serologic Course
                       Acute                          Chronic
                    (6 months)                        (Years)
                                    HBeAg                                   anti-HBe
                                            HBsAg
                                            Total anti-HBc
titer




                                  IgM anti-HBc




        0   4   8    12 16 20 24 28 32 36        52                    Years
                weeks of exposure                     Source: US CDC and Prevention
     Liver Biopsy for Staging
• Very helpful in predicting prognosis and
  assisting treatment decision analysis.
• METAVIR Grade 0-3 for scoring of
  inflammation.
• METAVIR Stage 0-4 for scoring of fibrosis
  (cirrhosis is stage 4).
• Knodell histologic activity index and
  Ishak fibrosis score (0-6) are also used
   Liver Biopsy for Staging (HCV)
 • Some controversy among experts
 • F0, F1 follow with re-biopsy
 • Some would recommend blanket
   treatment of all co-infected without biopsy
 • Normal LFT’s – biopsy before treating


Soriano et al. J Viral Hepatology 2004; 11:2-17
    Hepatocellular Carcinoma
• Rarely occurs in absence of cirrhosis or
  advanced fibrosis
• Rate of HCC after after development of
  cirrhosis occurs at a rate of 0-3% per year
• Co-infection with HBV seems to increase
  risk of hepatocellular carcinoma
• Screening cirrhotic patients with periodic
  ultrasound +/- AFP seems to be a sensible
  approach
HIV, HBV, and HCV

    Interactions
       Clinical effect of HIV on HCV
  •   Accelerated course to cirrhosis & HCC1
  •   Greater probability of HCV transmission2
  •   Greater chance of chronic HCV viremia3,4
  •   Decreased efficacy of PEG-IFN and RBV5




1. Benhamou Y. Hepatology 1999;30:1054; 2. Gibb, et al. Lancet 2000;356:904-907
3. Bonacini et al. JAIDS 2001;26:340-344; 4. Sherman et al. Clin Infect Dis 2002;34:831-837
5. Torriani et al. N Engl J Med. 2004;351:438-450.
  Clinical effect of HIV on HBV
• Accelerated course to cirrhosis & HCC
• Greater probability of HBV transmission?
• Greater chance of chronic HBV viremia
  – Less initial clearance
  – Lower rate of later spontaneous reversion



  Soriano, et al. AIDS 2005, 19:221-240
     Clinical effect of HCV on HIV
• More rapid progression of genotype 1 to
  AIDS1
• Greater risk of HAART liver toxicity
• Poorer clinical outcomes – AIDS, death?
• Higher risk of insulin resistance &
  diabetes mellitus


1. Sabin et al. J Infect Dis 1997; 175:164-68 2. Soriano et al. AIDS 2004, 18; 1-12
  Clinical effect of HBV on HIV
• Greater probability of HAART associated
  hepatotoxicity
• Co-factor for HIV disease progression?
                 Liver Fibrosis Progression Rate

                          4
(METAVR scoring system)




                          3
    Fibrosis Grades




                          2
                                                          HIV positive (n=122)
                          1                               Matched controls (n=122)
                                                          Simulated controls (n=122)
                          0
                              0          10           20           30                  40
                                  HCV - infection duration (years)
   Benhamou Y. Hepatology 1999;30:1054
      Perinatal Transmission of
             Hepatitis C
• Maternal-infant ranges from 5-6 %.
• HIV/HCV co-infected mothers 14-19%
• Transmission risk related to HCV RNA
  levels of mother.
• Elective C-section may prevent transfer
   – 491 mother-infant pairs had overall 6.4% rate
   – No transmission with elective C-section
 (Gibb DM,et al. Lancet 2000;356:904-907)
     Increasing Mortality From ESLD
           in Patients With HIV
• One third of 1998 cohort
  had recent history of
  discontinuing HAART                                                                         50




                                                     ESLD-Related Deaths (%)
                                                                               50
  secondary to                                                                                     1991
  hepatotoxicity                                                               40
                                                                                                   1996

• More than 1/2 who died                                                       30                  1998

  with ESLD had either
                                                                               20
  NDVL or CD4 >200/mm3                                                                   14
                                                                                    11
  6 months prior to death                                                      10

                                                                               0

ESLD = end stage liver disease; NDVL = no detectable viral load.
Bica et al. Clin Infect Dis. 2001;32:492-497.
 HIV coinfection increases the risk
       of ESLD due to HBV
• MACS, 4,967 men                    Liver Mortaility by HIV
   – HIV, 47%                           and HBV Status
   – HBV, 6% (n=326)
                                                            14.1
   – HIV/HBV, 4.3% (n=213)      15

                                10
• HIV/HBV - 19-fold higher
  risk of liver death           5
                                              0.8    1.7
  compared to HBV alone                0
                                0
   – Alcohol
                                     No HIV   HBV     HIV   HIV
   – Low CD4
                                     or HBV   only   only   and
   – Increase risk after 1996                               HBV
HCV and ART-associated Hepatotoxicity
    Probability of Hepatotoxicity - free Survival



                                                    1.00
                                                                                    HCV negative


                                                    0.75
                                                                     HCV positive


                                                    0.50



                                                    0.25



                                                    0.00
                                                           0     5                     10          15
                                                               Months since start of NNRTI

 Sulkowski MS et al. Hepatology 2002
Evaluation of Viral Hepatitis
        Hepatitis Evaluation
Routine antibody testing to test for infection
  and immunity to HAV, HBV, HCV
• Hepatitis A antibody (total or IgG)
• Hepatitis B Surface antibody
• Hepatitis B Surface antigen
• Hepatitis B Core antibody (total or IgG)
• Hepatitis C antibody
        Hepatitis A Vaccine
• If HAV antibody negative, offer Hepatitis A
  vaccine
• If inadequate response, may revaccinate
  (particularly if CD4 rising with HAART)
                Hepatitis B Vaccine
• Routine HBV vaccine 20ug (0,1, 6-12 m)
• If CD4 count <500 cells consider intensified
  regimen (0,1, 2, 6-12 m)
• Measure HBsAb titers to confirm response
  (>100 IU/ml)
• If suboptimal response, boost or re-vaccinate
  with 40ug (0,1, 2, 6-12m)
• Consider periodic re-assessment of immune
  status

  Soriano, et al. AIDS 2005, 19:221-240
  What is a “pre-core mutant””
• Following early phase of HBV most
  patients revert to HBeAg negative status
• Some patients have ongoing viral
  replication due to selection of HBeAg-
  defective viral variants in the pre-core
  region
  – HBsAg positive
  – HbeAg negative
  – HBV-DNA positive
 “Seronegative” HBV and HCV
• Hepatitis B
  – HBcAb + only
    • May rarely reactivate
  – HBsAg negative – rare HBV DNA +
• Hepatitis C
  – Ab negative, HCV RNA positive
  – Usually low CD4 counts
  – 0-5% range
HBV Management
            HBV Treatment
• Parameters commonly used to guide
  treatment decisions and response
  – HBV-DNA
  – HBeAg
  – HBsAg
  – ALT (alanine aminotransferase)
  – Liver histology
 HBV Treatment in Co-infected
• Treatment decisions informed by need for
  HAART
• If HAART is indicated - agents that treat
  HBV are best
  – Lamivudine (3TC, Epivir)+ tenofovir (Viread)
  – Emtricitabine (FTC, Emtriva) + tenofovir
    (Viread)
• If HAART not yet necessary – individulaize
  therapy
    HBV Treatment if HAART Optional
• Individual stratification depending on
     –   HBV DNA level
     –   Liver histology
     –   LFT’s
     –   Non-invasive fibrosis surrogate testing?
•   Adefovir
•   Entecavir (Baraclude)?
•   Interferon monotherapy?
•   Use HAART sooner than customary
•   Not lamivudine or tenofovir (resistance to HIV)
Treatment of HCV
 Goals of HCV Therapy in HIV +
• Eradicate HCV RNA
• Delay or reverse hepatic fibrosis.
• Prevent clinical outcomes:
  – Hepatic decompensation
  – Hepatocellular carcinoma
  – Death
           HCV Treatment
• Standard of care is combination therapy
  with Pegylated interferon + ribavirin
• Pegylated interferon is once weekly
  injection
• Ribavirin is typically weight based for
  genotype 1
  – 1000mg <75 kg; 1200 mg >75 kg
• Therapy is 48 weeks for genotype 1 and
  24 weeks for genotype 2,3 (mono-infected)
Fibrosis Change After IFN Treatment
           Paired Liver Biopsy

    0.8
                 0.59                                    <3-year follow-up
    0.6
                                                         >3-year follow-up
    0.4
          0.23
    0.2                                   0.15              Sustained Virologic
                                   0.01                     Response
     0
   –0.2   Untreated                Unsustained
                                   Virologic
   –0.4                            Response
   –0.6
                                                            –0.6
   –0.8
                                                                   –0.88

                        Shiratori. Ann Intern Med. 2000;132:517; with permission.
            HCV Treatment
• Outcomes for HCV mono-infected:
  – Sustained virologic results (SVR) 44-46% for
    genotype 1 (48 weeks)
  – Sustained virologic results (SVR) 75-80% for
    genotype 2,3 (24 weeks)
     HCV Infection - HRN Study
• Randomized study of qd vs TIW Interferon
  in HIV infected
• 180 patients randomized to qd or TIW IFN
  with ribavirin 800mg
• Sustained response 9.3% qd
                       4.3% TIW


Sulkowski M, et al. 10th CROI, 2003 Boston Abstract 841
         Summary: Sustained virologic
         response to PEG-IFN + RBV vs
              standard IFN + RBV
                                  ACTG 5071[1]                          APRICOT[2]            RIBAVIC[3]

Response (%)                      PEG-                                PEG-          PEG-
                                                     IFN                      IFN           IFN
                                   IFN                                 IFN           IFN
                                                    n = 67                   n=285         n=205
                                  n = 66                             n = 289       n = 207

SVR                               27% *               12%             40% *            12%   27% *   19%
Genotype 1
                                   14%                  6%            29% *            7%    15% *   5%
  SVR
Genotypes
                                  73% *               33%             62% *            20%   43%     41%
  2/3 SVR
 1. Chung R, et al. #110. 2. Torriani FJ, et al. #112. 3. Perronne C, et al. #117LB.
Impact of Genotype and HCV Viral
       Load in Coinfected
Apricot Trial
• GT 2/3 - SVR 62% (high and low)
• GT 1 HCV <800,000 IU/mL – 61% SVR (no
  different from GT 2/3)
• GT 1 HCV > 800,000 IU/mL – 18% SVR



Torriani et al. N Engl J Med. 2004; 351:438-450
 APRICOT: Effect of HCV therapy
      on CD4+ cell counts
                                                IFN/RBV                 PEG-IFN                 PEG-IFN/RBV

                                   60
    Median Change (cells/mm3)




                                   40
                                   20
                                    0
                                  -20
                                  -40
                                  -60
                                  -80
                                -100
                                -120
                                -140
                                -160
                                   BL 0   4   8 12            24           36           48 52     60          72
                                                                      Time (Weeks)
* Patients receiving 48 weeks of treatment
8/7/2012                                                                                                      46
                                          Torriani et al. N Engl J Med. 2004; 351:438-450
       HCV Treatment Decision
•   Age, medical co-morbiditiy
•   Psychiatric co-morbidity
•   Liver biopsy result
•   HCV RNA level and genotype
•   Status of HIV - CD4 count
•   Patient preferences
            HCV Treatment
• If HIV disease is stable, consider therapy
• If no fibrosis, may follow
• If cirrhotic, but not decompensated,
  consider treatment
• If decompensated (Childs B or C), do not
  treat (consider referral for transplant)
          Child-Pugh Score
• Bilirubin < 2mg/dL
• Albumin >3.5 mg/dL
• INR <1.7
• Ascites – none
• Hepatic encephalopathy – none
Child Class A – can still have of these out of
  range
                  Case Study
• 57 year old male
  – CD4 count 50, viral load 50,000, multi-drug
    resistant virus
  – Chronic stable angina, known CAD
  – Stable bipolar disease on lithium/depakote
  – Liver biopsy 2002 - stage 2 fibrosis
  – HCV genotype 1, HCV RNA - 4,000,000 IU

  Treat or not?
                  Case Study
• 38 year old male
  – CD4 count 500, viral load < 75 on Combivir +
    Sustiva
  – Previous depression, not on meds currently
  – Liver biopsy 2004 - stage 3 fibrosis
  – HCV genotype 1, HCV RNA – 400,000 IU

  Treat or not?
                Case Study
• 48 year old male
• CD4 count 150, viral load <75 copies on Viread,
  Epivir, Viramune
• No liver biopsy, but ascites off and on,
  splenomegally and gastric varices noted on CT
  abdomen, platelet count 60,000
• Genotype 1, HCV RNA 100,000 IU/mL
• Chronic drug-resistant depression

Treat or not?
                Case Study
• 32 year old female
• CD4 count 450, viral load <75 on Truvada
  + Sustiva
• LFT’s twice upper limit normal range
• Refuses liver biopsy
• Genotype 2, HCV RNA 1.8 million IU/mL

Treat or not?
Treatment Primer
      Baseline Evaluation
– HCV RNA quantitative, CBC, comprehensive
  metabolic profile, thyroid profile, (bHCG
  females)
– Referral to ophthalmology for baseline
  retinal examination
– Educational session to include self-infection
  technique, potential side effects, birth
  control, and adherence counseling
– Baseline mental health screen (MHS)
               Baseline Evaluation
•       Adjust antiretroviral therapy if necessary
    –       Didanosine (Videx EC, ddI) contraindicated due to
            lactic acidosis, pancreatitis, mitochondrial toxicity
    –       Zidovudine (AZT, Retrovir, Combivir, Trizivir)
            relatively contraindicated due to greater rate of
            anemia
    –       Stavudine (Zerit, d4T) relatively contraindicated
            due to greater risk of neuropathy, mitochondrial
            toxicity
        •     Consider switching above nucleosides to either tenofovir
              (Viread) or abacavir (Ziagen) prior to therapy
                     Starting Therapy
•       Schedule treatment initiation date with
        supervised injection of first Pegylated
        interferon dose
    –       Combination therapy with Pegylated interferon
            and ribavirin is current standard of care
        •        Pegasys 180 mcg sq weekly (or Peg-Intron weight based
                 dosing)
        •        Ribavirin BID
             –     Genotype 2,3 – 800mg per day
             –     Genotype 1,4 - 1000 (<75kg) - 1200mg (>75kg) per day
        Maintaining Therapy
•       Follow up visit at week 2, CBC, MHS
•       Follow up at week 4, CBC, CMP, HCV RNA
        quantitative, MHS
•       Follow up visit week 8, CBC, MHS
•       Follow up visit week 12, CBC, CMP, HCV RNA,
        TSH, MHS
    –     If > 2 log reduction in HCV RNA continue therapy
    –     If < 2 log reduction in HCV RNA – “non-responder” -
          stop therapy
        Maintaining Therapy
•       Follow up on-treatment visits week 16, 20, 24,
        28, 32, 36, 40, 44, 48 (end of treatment)
    –     CBC, MHS every visit
    –     CMP week 24, 36, 48
    –     TSH week 24, 48
•       Follow up after-treatment visits week 52, 56, 72
    –     CBC, CMP, MHS week 52
    –     HCV RNA week 56 - Almost all relapses occur within 8
          weeks of therapy discontinuation
    –     HCV RNA week 72
          » HCV RNA undetectable = sustained virologic
             response
          »   HCV RNA detectable = relapse
Side Effects of Therapy
        Managing Side Effects
–       Depression
    •    If history of depression prior to therapy
         consider pre-emptive initiation of SSRI
         (fluoxetine - Prozac 20mg, escitalopram -
         Lexapro 10mg, citalopram – Celexa 20mg)
    •    If depressive symptoms develop on therapy
         start therapy and refer to mental health services
    •    If suicidal ideation, intent, or plan develop, stop
         interferon and ribavirin and refer immediately to
         mental health services
          Managing Side Effects
•       Anemia
    –    If hemoglobin drops below 11 grams (male) or 10
         grams (female) start weekly epoitan alfa (Procrit)
         40,000 units sq, adjust dose to maintain
         hemoglobin above these levels
    –    If epoitan alfa is not available, reduce ribavirin
         dose to maintain hemoglobin level above 9 grams
         (female), 10 grams (male).
    –    If hemoglobin rapidly drops below 9 grams/dL
         suspend dosing of ribavirin and reintroduce at ½
         original dose when hemoglobin level stabilizes
         (preferably with epoitan alfa)
            Managing Side Effects
•       Leucopenia
    –       If absolute neutrophil count (ANC) drops below
            750 cells/mm3 consider g-CSF (neupogen) 300mcg
            sq TIW
        •     Recheck CBC in one week
        •     After stabilization of ANC, may be able to maintain with g-
              CSF dose of 150mcg sq TIW
    –       If g-CSF is unavailable, reduce dose of Pegylated
            interferon to ¾ of initial dose in order to maintain
            ANC >750 cells/mm3
        •     If initial dose titration is insufficient, may temporarily
              suspend therapy and/or lower dose to ½ initial dose
        •     Check CBC weekly until stable ANC is achieved
     Orthotopic Liver Transplantation
  • 23 HIV + compared to
                                                               Survivial after OLT
    UNOS (11,453 HIV -)
       – HCV, 14 and HBV, 9                              100
       – CD4, 200 (range 76 – 506)
                                                          90
       – MELD 16




                                                     %
  • HCV worse than HBV                                    80

  • Drug-drug interaction                                 70
    (tacrolimus)                                                   12           24   36

  • Outcome not associated                                                Months

    with HIV RNA or CD4                                  HIV negative       HIV positive

Ragni M. Survival in HIV-infected Liver Transplant Recipients. 10th CROI #155
            Conclusions
• HBV and HCV commonly found in HIV-
  infected patients
• Co-infection with these viruses
  complicate management and contribute to
  morbidity and mortality
• Active consideration and treatment of
  these co-infections has become an
  integral part of comprehensive HIV
  management
                                            Consensus Interferon vs IFN- 2b
                                                             Patients: HCV Genotype 1, Naïve, Caucasian
                                                       CIFN: 9-15 µg Daily1                         IFN- 2b: 5-15 MU Daily2
Mean HCV RNA decline (log copies/mL)




                                       0


                                       -1


                                       -2


                                       -3

                                                                          9 µg     15 µg            5 MU       10 MU           15 MU
                                       -4
                                            0                      7                       14   0             7                        14
                                                                  Days                                       Days
                                            1. Neumann et al. Hepatology. AASLD. 2000.
                                            2. Neumann et al. Science. 1998;282:103-107.

								
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