Hepatitis and HIV CoInfection - PowerPoint PPT Presentation

Loading...

PPT – Hepatitis and HIV CoInfection PowerPoint presentation | free to view - id: 814c3-ZDc1Z



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Hepatitis and HIV CoInfection

Description:

SVR with PEG IFN ribavirin reduces cirrhosis, HCCA, transplant, death by 9-fold ... Liver transplantation may be a viable option in selected HIV individuals ... – PowerPoint PPT presentation

Number of Views:115
Avg rating:3.0/5.0
Slides: 60
Provided by: DEL5160
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Hepatitis and HIV CoInfection


1
Hepatitis and HIV Co-Infection
  • Sandra G. Gompf, MD, FACP, FIDSA
  • Associate Professor, Infectious Diseases and
    International Medicine
  • University of South Florida College of Medicine

2
Disclosure of Financial Relationships
  • This speaker has no significant financial
    relationships with commercial entities to
    disclose.

This slide set has been peer-reviewed to ensure
that there areno conflicts of interest
represented in the presentation.
3
The Big Picture of Hepatitis
  • Damage to liver cells caused by inflammation or
    cell death
  • Can be caused by infections, drug toxicity,
    poisoning, biliary tract obstruction
  • If persists, can lead to progressive scarring of
    the liver (cirrhosis) and end-stage liver
    dysfunction

4
Causes of Hepatitis in the HIV Patient
  • Drugs
  • HAART
  • Metabolic complications
  • Treatment of opportunistic infection
  • Viral pathogens
  • Hepatitis A, B, C
  • CMV
  • Overlap is common

5
Drug-Induced Hepatotoxicity, Besides HAART
  • trimethoprim-sulfamethoxazole, antituberculars,
    azole antifungals
  • anabolic steroids
  • acetaminophen
  • statins fibrates

6
HAART-Associated Hepatotoxicity
  • Elevated transaminases mostly with PIs, but also
    w/ NNRTIs
  • Probably hyperimmunity or immune restoration
    syndrome
  • Often subsides over several months
  • HIV/HCV 3-5-fold more likely to develop severe
    transaminitis

7
HAART-Associated Immune Restoration
  • Ofotokun et al. Am J Med Sci 11/07, HAART-naïve
    pts
  • Elevated liver enzymes were associated with HBV
    or HCV co-infection, stavudine
  • Robust rise in CD4 count/month associated with
    co-infection abnormal LFTs
  • HIV/HCV or HBV abnormal LFTs 99/mm3
  • HIV/HCV or HBV normal LFTs 62/mm3
  • HIV normal LFTs 59/mm3
  • HIV abnormal LFTs 36/mm3

8
Viral Hepatitis in HIV Patients
  • Acute viral hepatitis may be severe or fatal
  • Acute viral hepatitis may add to liver damage
    already present from other causes
  • e.g. Acute hepatitis A on chronic hepatitis C may
    be deadly

9
Viral Hepatitis Overview
10
GBV-C Infection the Role ofHepatitis G
  • may reduce mortality in late HIV
  • may reduce HIV viral loads

W Zhang, et al. Effect of Early and Late GB Virus
C (GBV-C) on the Survival of HIV-infected
Individuals a Meta-analysis. HIV Med 7(3)
173-180. April 2006. KS Howard, et al. No
observed effect of GB virus C coinfection on
disease progression in a cohort of African woman
infected with HIV-1 or HIV-2. Clin Infect Dis
40(6)876-8. February 2005. H L Tillmann, et al.
Infection with GB Virus C and Reduced Mortality
among HIV-Infected Patients N Engl J Med 345(10)
715 - 724. September 2001. JXiang S et al.
Effect of Coinfection with GB Virus C on Survival
among Patients with HIV Infection N Engl J Med
345(10) 707 - 714. September 2001.
11
Hepatitis A HIV, in Brief
  • role seems significant
  • 35 HIV with acute HAV
  • 80 treatment interrupted X 2 months
  • 25 lost efficacy on resuming HAART
  • safe, effective VACCINE available

Berggren RE et al. 39th ICAAC, 9/26-29/99, San
Francisco, CA. Abstract 97.
12
Hepatitis C
  • Transmitted via IVDU/blood, less often sex (more
    likely for MSM)
  • In U.S., 4 million HCV ? 85 chronic
  • If chronic ? 20 cirrhotic _at_ 20 years
  • Once cirrhotic ? 25 hepatocellular CA
  • (0.5 of total HCV)
  • Alcohol HIV worsen prognosis
  • Usually no symptoms
  • sometimes fatigue, RUQ ache, difficulty
    concentrating

13
Hepatitis C
  • 6 Genotypes
  • Genotypes 1-3 are commonest in US, WEurope
  • 75 are 1
  • 25 are Non-1
  • Most are 2 3
  • 4-6 Middle East/Africa/?Spain
  • African Americans less likely to achieve
    sustained virologic response (SVR) to treatment
  • 28 AA
  • 52 Cauc

H S Conjeevaram, M W Fried, L J Jeffers, et al.
Gastroenterology. 131(2) 470-477. August
2006. SM Martinez, et al. Clin Microbiol. 43(10)
54035404 October 2005.
14
Hepatitis C
  • Like HIV, antigenic variation occurs
  • ? Hepatitis C antibody is not protective
  • ? no vaccine
  • Unlike HIV HBV, does not integrate into the
    host genome
  • ? eradication is possible / more likely with
    treatment

15
Sources of Infection for Persons with Hepatitis C
  • 30-50 HIV have chronic HCV
  • HIV/HCV
  • IVDU 90
  • hemophilia 80
  • MSM 4-8

CDC
16
HIV/HCV Co-Infection is Clearly Associated with
More Rapid Progression to Cirrhosis
  • Soto, et al. J Hepat 1997
  • compared 547 HIV- with 116 HIV
  • all with chronic hepatitis C
  • Incidence of cirrhosis
  • HIV-
  • 2.6 (mean HCV duration 23.2 years)
  • HIV
  • 14.9 (mean HCV duration 6.9 years)

17
Other Possible Interactions between Hepatitis C
HIV
  • HCV does not appear to consistently affect
    progression of HIV disease
  • chronic HCV does not appear to consistently
    affect CD4 response to HAART
  • cirrhosis suppresses immunitymay affect CD4

N Soriano-Sarabia, A Vallejo, S Molina-Pinelo.
AIDS 21(2) 253-255. January 11, 2007. B H
McGovern, Y Golan, M Lopez, et al. Clinical
Infectious Diseases 44(3) 431-437. February 1,
2007. Daar ES, et al. 7th Conference on
Retroviruses and Opportunistic Infections,
1/30-2/2/00, San Francisco, CA. Abstract 280.
18
Diagnosing HCV in HIV
  • Do not rely on transaminases! There is no
    correlation between transaminase levels and
    disease severity.
  • HCV ELISA antibody screening
  • Antibody means infected at some point, need to
    determine if active or chronic infection
  • in advanced HIV, may be falsely negative
  • HCV RNA PCR confirms or excludes active disease
  • Viral load means active hepatitis

19
Diagnosing HCV in HIV
  • HCV ELISA antibody (low-threshold, sensitive)
  • If (or advanced HIV)? HCV RNA quantitative PCR.
  • If HCV ELISA or RNA PCR -, no further
    intervention.
  • If HCV RNA PCR ? active hepatitis is present

20
Doc, so I have chronic hepatitis, now what?
  • STOP ALL ETHANOL
  • Genotyping is helpful in predicting response to
    therapy
  • 1 ( 4) is more refractory to treatment
  • 2 3 are very responsive
  • Rule out other causes of liver disease if liver
    enzymes are abnormal
  • Autoimmune hepatitis, biliary disease,
    hemochromatosis

21
Look for Complications of Chronic Hepatitis
  • Liver biopsy? Gold standard in evaluating
    hepatitis and cirrhosishow close to cirrhosis
    is your patient?
  • Fibrosure Fibroscan not validated in HIV yet,
    but non-invasive measures of fibrosis
  • Cannot rule concurrent diseases, over-diagnoses
    fibrosis
  • Fibrosure may be affected by elevated bilirubin
    due to atazanavir or indinavir
  • Sonogram screen for other liver disease, CA
  • Alpha-fetoprotein alone is not enough to screen
    out CA

22
Look for Complications of Chronic Hepatitis
  • Extra-hepatic manifestations of Hepatitis C
  • Mixed cryoglobulinemia (rash, joint pain)
  • Membranous glomerulonephritis (proteinuria)
  • These may be reasons to treat BUT
  • extrahepatic manifestations may differ in HIV-HCV
  • may or may not improve

23
Talking to Your Patient Benefits Goals of
Treating Chronic Hepatitis C
  • Viral eradication (sustained viral remission,
    SVR)
  • Delay progression of fibrosis
  • Prevent/delay bad clinical outcomes of cirrhosis
  • Liver decompensation
  • Hepatocellular carcinoma
  • Death
  • Improve tolerance and effectiveness of HAART
  • Allows aggressive antiretroviral drug therapy
  • Enhanced immune reconstitution?
  • Increases survival

24
Note BeneWhich Hepatitis Drugs are Which??
  • aINF 2b, PEG aINF 2b
  • Schering-Plough
  • Intron A, PEG-Intron A
  • ribavirin (Rebetol)
  • aINF 2a, PEG aINF 2a
  • Roche
  • Roferon-A, Pegasys
  • ribavirin (Copegus)
  • lamivudine
  • Epivir-HBV, 50mg
  • Epivir, 150mg (HIV)
  • Adefovir
  • Hepsera
  • Entecavir, Baraclude
  • Telbivudine, Tyzeka

Approved by European Union for use in
co-infected patients in 2007
25
Talking to Your Patient Benefits Goals of
Treating Chronic Hepatitis C
  • In studies, sustained viral remission w/ newer
    treatments PEG ?IFN ribavirin
  • Genotype 1 4 ( 30 -70 SVR)
  • Genotype 2 3 (gt80 SVR)
  • SVR with PEG ?IFN ribavirin reduces cirrhosis,
    HCCA, transplant, death by 9-fold
  • HIV disease is not affected by ?IFN or ribavirin

L Martin-Carbonero, et al. CROI 2008. Abstract
1052.
26
Talking to Your Patient Risks, Problems,
Adverse Effects of Treating Chronic Hepatitis C
in HIV
  • Theres still more to talk about..

27
Hepatitis C Treatment Toxicities
  • Pegylated aINF 2a or 2b
  • flu-like symptoms
  • depression/suicidal
  • fatigue, dizziness
  • anorexia, nausea/diarrhea
  • bone marrow suppression
  • serious infections
  • autoimmune disease
  • thyroid, diabetes
  • hair loss, oral ulcers
  • pulmonary fibrosis
  • Stevens-Johnson, hypersensitivity
  • Ribavirin
  • anemia/hemolysis
  • dose dependent
  • 2.5-3g ? within 4 weeks
  • erythopoietin
  • bone marrow depression
  • embryocidal / Category X
  • teratogenic for up to 6 months after treatment
  • FDA Ribavirin Pregnancy Registry

28
Talking to Your Patient Whom NOT to Treat
  • Major contraindications
  • pregnant or planning
  • untreated/severe depression or psych disease
  • significant ischemic cardiovascular disease
  • decompensated cirrhosis before/during treatment
  • hemoglobinopathies (thalassemia/sickle cell)
  • significant asthma, lung disease
  • malignancy
  • end-stage renal disease

29
Talking to Your Patient Whom to Delay or
Re-Consider Treating
  • Relative contraindications
  • untreated depression or psych disease
  • street drug or ethanol abuse
  • uncontrolled diabetes or thyroid disease
  • seizure disorders
  • infections
  • poor ADHERENCE (predicts poor adherence to
    treatment, BIRTH CONTROL, follow-up visits)

30
HIV Infected Veterans with Co-morbid
Conditions, 2006 (22,638 Total)
Data from VHA HIV Clinical Case Registry
31
Talking to Your Patient Best Odds and Best
Reasons to Treat
  • Stable HIV disease with intact immune function
  • (to eradicate virus, delay cirrhosis/CA)
  • Advanced hepatic fibrosis
  • (to delay cirrhosis/CA)
  • Starting HAART
  • (to limit HAART interruptions by hepatotoxicity )

Sulkowski MS, 8th Conf on Retrov and OI, 2000,
Abstract S11
32
Talking with Your Patient Which to Treat First?
HIV or HCV?
  • CD4 lt 350 ? treat HIV
  • Higher risk of HIV morbidity/mortality
  • CD4 gt 350 ? treat HCV
  • HCV response is better _at_ higher CD4s
  • lower pressure to start HAART
  • possibly avoid HAART interruptions due to
    hepatotoxicity

33
Talking to Your Patient Other Issues
  • ex-IVDU needle-aversions, needle-fixations

McBride, A.J., Pates, R.M., Arnold, K. and Ball,
N. (2001), Needle fixation, the drug users
perspective a qualitative study, Addiction, 96,
(7) pp 1051 -1060.
34
Ribavirin Interacts with HAART
  • Didanosine (DDI) should be replaced before
    treatment
  • Ribavirin will markedly increase DDI
  • Increased lactic acidosis, mitochondrial
    toxicity, peripheral neuropathy pancreatitis
  • Zidovudine, stavudine therapy should be monitored
    for failure, toxicity
  • RBV inhibits phosphorylation of pyrimidine
    nucleoside analogs and raises ZDV levels
  • Bone marrow inhibition by ZDV RBV may be
    additive

35
Other HAART Considerations with Hepatitis C
  • NNRTIs (efavirenz, nevirapine)
  • Increased severe hepatotoxicity is 1 w/ NNRTIs
  • NNRTIs need not be withheld in HCV/HIV
  • Tenofovir vs. ZDV or abacavir (?)
  • Better HCV treatment responses with tenofovir?
  • Confounders lower RBV doses
  • Sulkowski, et al, 8th COROI, 618 Dieterich et
    al, 2002
  • JJ Gonzalez-Garcia, et al. GESIDA 05/06 Study
    Group. CROI 2008. Abstract 1076
  • J Mira, et al. CROI 2008. Abstract 1074.

36
Treatment of HCV
  • PEG aINF 2a (fixed 180 mcg) or 2b (wgt-based)
    subcutaneously every week X 48 weeks
  • Ribavirin 800mg PO daily (1000-1200mg preferable
    for genotype 1 or 4) X 48 weeks
  • If HCV undetectable _at_ 12 weeks (EVR)? continue
  • If HCV undetectable _at_ end of tx (ETR)? repeat _at_
    72 weeks
  • if still undetectable ?SVR!!

Off-label in HIV/HCV. Wgt-based regimens may be
more effective in morbidly obese patients.
37
Prescreening and Monitoring During Treatment
  • Monitoring
  • Monthly
  • CBC diff ( (_at_ 2 weeks of start)
  • lytes, FBS, creatinine, liver enzymes
  • serum or urine ß HCG
  • _at_ 12, 48, 72 weeks
  • HCV RNA PCR
  • Every 12 weeks
  • serum TSH
  • Prescreening tests
  • serum or urine ß HCG
  • serum TSH
  • serum ANA
  • iron, ferritin
  • HAV HBV serology
  • CBC differential
  • PT, PTT
  • fasting blood glucose, lytes, creatinine, liver
    enzymes

38
Managing Adverse Effects
  • Avoid dose reductions where feasible
  • Moderate depression reduce PEG STOP if severe
    or suicidal
  • Neutropenia thrombocytopenia
  • G-CSF 300 mcg SC TIW to keep ANC gt 750
  • ANC lt 750 reduce PEG
  • ANC gt 750 hold PEG, resume at lower dose once
    over 750
  • PLT lt 50K reduce PEG at lt 25K, D/C PEG
  • Anemia
  • Reduce RBV if Hgb lt10 mg/dL, D/C if lt 8 mg/dL
  • ?Erythropoietin alfa 40K IU SC weekly if Hgb lt12
    mg/dL
  • Risks of tumor growth, vascular disease, etc?

39
The Future of HIV/HCV?
  • Longer courses of pegylated INF ribavirin
  • 72 weeks (indefinite maintenance found of ?
    benefit in HIV/HCV who relapse)
  • maximize ribavirin dose
  • Non-invasive fibrosis markers?
  • eltrombopag for thrombocytopenia?
  • HCV protease polymerase inhibitors?
  • Liver transplantation?...

M Nunez, J Garcia-Samaniego, M Romero, and
others. Abstract 365. The PRESCO trial. AASLD.
October, 2006. H Al-Mohri, T Murphy, Y Lu, and
others. JAIDS. January 4, 2007 K Sherman, and
others. CROI 2008. Abstract 59.
40
What happens after ESLD?
  • Liver transplantation may be a viable option in
    selected HIV individuals
  • Experimental, outcomes similar to HIV-/HCV
  • need good HIV control, adherence
  • HCV recurrence is common in new liver
  • re-treatment x 3 months after transplant
  • 5-year survival is 51 (vs.81 in HIV-/HCV)

L Castells, J I Esteban, I Bilbao, and others.
Antiviral Therapy 11(8) 1061-1070. 2006.
41
Key Points about HCV/HIV
  • HCV is worse in HIV/HCV
  • Treat based on individual benefits vs. risks
  • If you or patient in doubt, hold off
  • Patient must be committed to birth control
  • Be aware of HAART interactions
  • Be alert to toxicities revisit contraception!
  • PEG aIFN ribavirin x 48 weeks is standard
  • Vaccinate all co-infected patients against HAV
    and HBV if seronegative

42
Viral Hepatitis Overview
43
Hepatitis B
  • Hepatitis B
  • sex, perinatal, IVDU, blood
  • gt300,000/year in U.S.
  • Only 25 symptomatic acute jaundice, elevated
    liver enzymes, fatigue, NVD
  • Lifetime risk up to 100 if risks (avg U.S. 5)
  • 10 become chronic ? cirrhosis/CA in 20-30 yrs
  • Ethanol, HIV, other hepatitis viruses

44
Serology of Chronic HBV
  • HBsAg HBsAb HBeAg HBV DNA
  • - /-
  • Pre-core protein/core promoter mutation
  • dont express HBeAg, DNA ??
  • severe inflammation?cirrhosis
  • longer duration of disease?older
  • more resistant to therapy
  • non-A genotypes, Asia/Europe

45
Serology in Chronic HBV, cont.
  • YMDD mutation lamivudine resistance
  • 1000x rise in resistance
  • Up to 90 resistance _at_ 4 years lamivudine
  • Mutations in RT region of HBV DNA pol
  • YMDD motif tyrosine, methionine, aspartic acid,
    aspartic acid
  • 2 forms M ? valine or M ? isoleucine

46
Hepatitis B HIV
  • acute HBV may be more severe
  • 10 of HIV
  • 5-6x gt chronicity than HBV alone
  • impaired cell-mediated immunity can cause chronic
    HBV
  • HIV/HBV 19x gt liver deaths than HBV alone
  • 8x gt liver deaths than HIV
    alone

Thio C, Seaburg E, Skolasky Jr. R, et al.
Multicenter Cohort Study MACS. Lancet
20023601921-26.
47
Hepatitis B HIV
  • 7 genotypes (data evolving)
  • A commonest in HIV/HBV in U.S. 75
  • may respond best
  • G least common 25
  • marker of rapid fibrosis
  • efavirenz exposure
  • duration of HIV

K Lacombe and others. AIDS 20(3) 419-427,
February 14, 2006.
48
Hepatitis B HIV Occult HBV
  • Isolated HBcAb and DNA low level
  • HBsAg HBsAb HBcAg HBV DNA
  • - - -
  • commoner in HIV

Gandhi RT, Wurcel A, Lee H, et al. J Infect Dis
20051911435-41.
49
Hepatitis B HIV Occult HBV
  • may account for acute hepatitis in
  • HAART initiation/immune reconstitution
  • Immune suppression (CD4? or chemo-tx)
  • probably need HBV vaccine
  • Poor anamnestic response, HBcAb
  • commonest in HIV/HCV/HBV

Gandhi RT, Wurcel A, Lee H, et al. J Infect Dis
20051911435-41.
50
Therapies for Chronic HBV in HIV
  • First line
  • lamivudine (Epivir)NOT Epivir-HBV
  • emtricitabine (Emtriva, off-label for HBV)
  • inhibit HBV DNA pol
  • YMDD resistance with lamivudine
  • 15 _at_ 1 yr
  • 30-40 _at_ 2 yr
  • 70-90 _at_ 4 yrs
  • emtricitabine is equivalent, delayed
    resistance/may overcome YMDD

HEP DART 2003. December 14-18, 2003. Kauai,
Hawaii.
51
Therapies for Chronic HBV in HIV
  • Unlike HAART, combination therapy is no better
    than sequential monotherapy in HBV
  • lamivudine tenofovir/lamivudine
  • sequencing or combo depends on HIV HAART

S Maus and others. Abstract 964. American
Association for the Study of Liver Diseases.
November, 2005.
52
Therapies for Chronic HBV in HIV
  • Second line interferon
  • aINF 2b x 48 wk
  • 30 SVR (Schering)
  • PEG aINF 2a x 48 wk
  • 30 SVR
  • Roche, 1st PEG FDA approved for HIV/HBV, 2005
  • Schering PEG aINF 2b used off-label, more data
    for HIV/HCV but not HIV/HBV

53
Therapies for Chronic HBV in HIVOther Agents?
  • adefovir (Hepsera) NO
  • dosing for HBV is too low to suppress HIV
  • promotes tenofovir resistance
  • entecavir (Baraclude)with CAUTION
  • may be associated with M184V resistance mutation,
    use only with effective HAART
  • severe hepatomegaly, lactic acidosis

54
Therapies for Chronic HBV in HIVOther Agents?
  • telbivudine (Tyzeka)maybe?
  • nucleoside analog
  • more effective than lamivudine, adefovir
  • may have additive benefit with other
    agentscombination therapy?
  • no HIV-1 activity, no apparent NRTI antagonism in
    vitro, but no data in HIV
  • Canadian govt warning peripheral neuropathy
    with INFs

55
When to Treat with What
  • Ready for HAART?
  • lamivudine emtricitabine/tenofovir backbones
  • indefinite tx
  • FLARES with stopping meds or onset of YMDD
    resistance USE CAUTION
  • Not ready for HAART?
  • Consider PEG aINF 2a ribavirin x 48 weeks
  • advanced fibrosis
  • HIV/HBV/HCV
  • improves fibrosis
  • may clear virus
  • Consider earlier HAART w/ HBV-active agent
    (telbivudine?)

56
Treatment Options for Lamivudine-Resistant HBV
(YMDD Mutants)
  • emtricitabine may still work in YMDD
  • tenofovir (off-label for HBV)
  • entecavir with caution?
  • telbivudine?
  • consider PEG aINF 2a ribavirin
  • expectant management

57
Last words about Hepatitis A, B, C HIV
  • Liver transplantation may be a viable option in
    selected HIV individuals
  • Experimental, outcomes similar to HIV-/HCV
  • need good HIV control, adherence
  • HCV recurrence is common in new liver
  • re-treatment x 3 months after transplant
  • 5-year survival is 51 (vs.81 in HIV-/HCV)

L Castells, J I Esteban, I Bilbao, and others.
Antiviral Therapy 11(8) 1061-1070. 2006.
58
Last words Hepatitis A, B, C HIV
  • Prevention is KEY
  • Screen vaccinate early
  • Lower CD4s will lower antibody response
  • CD4 lt 200 15-40 antibody
  • CD4 gt500 90 antibody
  • ?Re-vaccinate w/ double-dose (50.7 response in
    previous non-responders in Dutch prospective
    open-label study)
  • Counsel about risk factors

TE De Vries-Sluijs, et al. JID 197(2) 292-94.
January 2008.
59
(No Transcript)
About PowerShow.com