Hepatitis and HIV CoInfection - PowerPoint PPT Presentation


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


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation

Hepatitis and HIV CoInfection


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


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

Title: Hepatitis and HIV CoInfection

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

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

This slide set has been peer-reviewed to ensure
that there areno conflicts of interest
represented in the presentation.
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

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

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

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

HAART-Associated Immune Restoration
  • Ofotokun et al. Am J Med Sci 11/07, HAART-naïve
  • 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

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

Viral Hepatitis Overview
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.
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.
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

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.
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

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

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)

Other Possible Interactions between Hepatitis C
  • 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.
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

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
  • If HCV RNA PCR ? active hepatitis is present

Doc, so I have chronic hepatitis, now what?
  • Genotyping is helpful in predicting response to
  • 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,

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
  • 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

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

Talking to Your Patient Benefits Goals of
Treating Chronic Hepatitis C
  • Viral eradication (sustained viral remission,
  • 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

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
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
Talking to Your Patient Risks, Problems,
Adverse Effects of Treating Chronic Hepatitis C
in HIV
  • Theres still more to talk about..

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

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

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)

HIV Infected Veterans with Co-morbid
Conditions, 2006 (22,638 Total)
Data from VHA HIV Clinical Case Registry
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
Talking with Your Patient Which to Treat First?
  • 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

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.
Ribavirin Interacts with HAART
  • Didanosine (DDI) should be replaced before
  • 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

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.

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.
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
  • 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

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
  • Risks of tumor growth, vascular disease, etc?

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.
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.
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

Viral Hepatitis Overview
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

Serology of Chronic HBV
  • - /-
  • 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

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

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
  • HIV/HBV 19x gt liver deaths than HBV alone
  • 8x gt liver deaths than HIV

Thio C, Seaburg E, Skolasky Jr. R, et al.
Multicenter Cohort Study MACS. Lancet
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.
Hepatitis B HIV Occult HBV
  • Isolated HBcAb and DNA low level
  • - - -
  • commoner in HIV

Gandhi RT, Wurcel A, Lee H, et al. J Infect Dis
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
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,
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.
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

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

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

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
  • improves fibrosis
  • may clear virus
  • Consider earlier HAART w/ HBV-active agent

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

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.
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.
(No Transcript)
About PowerShow.com