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
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