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
Mortality trends in HIV HIV Outpatient Study
(HOPS)
Palella FJ et al. Presented at 11th Conference
on Retroviruses and Opportunistic Infections,
2004 Abstract 872.
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-induced hepatotoxicity

• Elevated transaminases mostly with PIs, but also
  w/ NNRTIs
• May be related to hyperimmunity or immune
  restoration syndrome
• Often subsides over several months
• HIV/HCV are 3-5-fold more likely to develop
  severe transaminitis

7
Viral Hepatitis in HIV patients

• Acute viral hepatitis be severe or fatal
• Acute viral hepatitis can add to liver damage
  already present from other causes
• E.g. Acute hepatitis A on chronic hepatitis C may
  be deadly

8
Viral Hepatitis Overview
9
GBV-C infection the role ofHepatitis G

• may reduce mortality in late HIV
• may reduce HIV viral loads

W Zhang and others. Effect of Early and Late GB
Virus C (GBV-C) on the Survival of HIV-infected
Individuals a Meta-analysis. HIV Medicine 7(3)
173-180. April 2006.
10
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.
11
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

12
Hepatitis C

• 6 Genotypes
• 1, 2, 3 are commonest in US/W Europe
• 75 Genotype 1
• 25 Non-1
• Most are 2 3
• 4 occurs less often
• African Americans less likely to have sustained
  response to treatment
• SVR 28 AA vs. 52 Cauc

H S Conjeevaram, M W Fried, L J Jeffers, and
others. Gastroenterology. 131(2) 470-477. August
2006.
13
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

14
Sources of Infection for Persons with Hepatitis C

• 30-50 HIV have chronic HCV
• HIV/HCV
• IVDU 90
• hemophilia 8
• MSM 4-8

CDC
15
Sources of Infection for Persons with Hepatitis C

• Sexual/household exposure to HCV contact
• Sexual transmission in monogamous couples
  1-5
• Razors
• Multiple sex partners
• Sexual practices that may damage mucosa
• Birth to HCV-infected mother
• Acute maternal infection during pregnancy
• Vietnam-era veterans (7 vs. 2 general US pop.)

16
HIV/HCV Co-infection is associated with 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 interactions between Hepatitis C HIV

• chronic HCV is more likely in advanced HIV (low
  CD4 high HIV viral load)
• high HCV viral load predicts progression to AIDS
  regardless of HIV viral load
• chronic HCV blunts CD4 response to HAART
• cirrhosis suppresses immunity
• May affect total 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, I have chronic hepatitis, now what?

• STOP ALL ETHANOL
• Genotyping is helpful in predicting response to
  therapy
• 1 is more refractory to treatment
• Non-1 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?
• 1 serious bleed
• Fibrosure(blood) Fibroscan (liver stiffness)
  not validated in HIV yet, but non-invasive
  measures of fibrosis
• 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 in HIV

• 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
• Enhance immune reconstitution?

24
Note beneWhich hepatitis drugs are which??

• PEG aINF 2b
• Schering-Plough
• PEG-Intron A
• ribavirin (Rebetol)
• PEG aINF 2a
• Roche
• Pegasys
• ribavirin (Copegus)

• lamivudine
• Epivir-HBV, 50mg
• Epivir, 150mg (HIV)
• adefovir, Hepsera
• entecavir, Baraclude
• telbivudine, Tyzeka

25
Talking to your patient Benefits goals of
treating chronic hepatitis C in HIV

• In studies, sustained viral remission w/ newer
  treatments PEG ?IFN ribavirin
• Genotype 1 4 ( 30 - 70 SVR)
• Genotype 2 3 (gt80 SVR)
• HIV disease is not worsened by ?IFN or ribavirin

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
• immune suppression, infection
• autoimmune disease
• thyroid, diabetes
• hair loss, oral ulcers
• pulmonary fibrosis

• 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 to be
• 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)

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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 improve response )

Sulkowski MS, 8th Conf on Retrov and OI, 2000,
Abstract S11
31
Talking with your patient Which to treat first?
HIV or HCV?

• CD4 lt 350 ? treat HIV
• Higher risk of HIV morbidity/mortality
• Lower HCV response to tx
• CD4 gt 350 ? treat HCV
• HCV response is better _at_ higher CD4s
• lower pressure to start HAART
• possibly avoid HAART interruptions due to
  hepatotoxicity

32
Talking to your patient Other Issues

• ex-IVDU needle aversions
• Needle fixation
• Ritual of injecting
• Injection euphoric experience
• Risk of recidivism

33
Ribavirin interacts with HAART

• Didanosine (DDI) should be replaced before
  treatment
• Ribavirin will markedly increase DDI
• Increased lactic acidosis/mitochondrial toxicity,
  neuropathy pancreatitis
• Zidovudine, stavudine therapy should be monitored
  for failure/toxicity
• Ribavirin inhibits phosphorylation of pyrimidine
  nucleoside analogs
• Bone marrow inhibition by zidovudine ribavirin
  may be additive

34
Other HAART considerations with Hepatitis C

• NNRTIs (efavirenz, nevirapine)
• Nevirapine has been associated with liver
  toxicity
• Increased severe hepatotoxicity 1 w/ NNRTIs
• No indication for avoidance
• NNRTIs need not be withheld in HCV/HIV

Sulkowski, et al, 8th COROI, 618 Dieterich et
al, 2002
35
Treatment of HCV in HIV

• PEG aINF 2a (fixed 180 mcg) or 2b (wgt-based)
  subcutaneously every week X 48 weeks
• Ribavirin 800mg PO daily (up to 1200mg for
  genotype 1 or 4) X 48 weeks
• If HCV undetectable _at_ 12 weeks ? continue
• if not, D/C
• If HCV undetectable _at_ 48 weeks ? repeat _at_ 72
  weeks
• if still undetectable ? SVR!!

36
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

37
Managing adverse effects

• Avoid dose reductions where possible
• Moderate depression MH care, reduce PEG D/C 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
• Erythropoietin alfa 40K IU SC weekly if Hgb lt12
  mg/dL
• Reduce RBV if Hgb lt10 mg/dL, D/C if lt 8 mg/dL

38
The future of HIV/HCV?

• Longer courses of pegylated INF ribavirin
• 72 weeks
• maximum ribavirin dose
• Improved SVR, reduced relapse
• AST-to-platelet ratio index (APRI) may prove
  useful as a non-invasive marker for fibrosis

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
39
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
• PEG aIFN ribavirin x 48 wks is standard
• Vaccinate all co-infected patients against HAV
  and HBV if seronegative

40
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

41
Hepatitis B HIV

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

Thio C, Seaburg E, Skolasky Jr. R, et al.
Multicenter Cohort Study MACS. Lancet
20023601921-26.
42
Hepatitis B HIV

• 7 genotypes (data evolving)
• A commonest in HIV/HBV/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.
43
Serology Mutations in 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

44
Serology Mutations in Chronic HBV

• 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

45
Hepatitis B HIV Occult HBV

• Isolated HBcAb and DNA low level
• HBsAg HBsAb HBV DNA
• - -
• commoner in HIV

Gandhi RT, Wurcel A, Lee H, et al. J Infect Dis
20051911435-41.
46
Hepatitis B HIV Occult HBV

• may account for acute flare in
• HAART initiation/immune reconstitution
• With immune suppression (CD4? or chemo-therapy)
• Should get HBV vaccine
• Poor anamnestic response

Gandhi RT, Wurcel A, Lee H, et al. J Infect Dis
20051911435-41.
47
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.
48
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.
49
Therapies for Chronic HBV in HIV

• Second line interferon
• 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

50
Therapies for Chronic HBV in HIVOther agents?

• adefovir (Hepsera) NO
• dosing for HBV is too low to suppress HIV
• promotes tenofovir resistance
• entecavir (Baraclude)CAUTION
• may be associated with M184V (FDA MedWatch 2/2007)

51
Therapies for Chronic HBV in HIVOther agents?

• telbivudine (Tyzeka)maybe??
• nucleoside analog
• alternative to lamivudine, tenofovir pre-HAART?
• may have additive benefit with other
  agentscombination therapy?
• no HIV-1 activity, no apparent NRTI antagonism in
  vitro
• but no data in HIV

52
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 agents

53
Earlier HAART?

• 79 HBsAg (39 also HBeAg)
• 37 lamivudine experienced
• 58 lamivudine tenofovir experienced
• Followed on HAART that included HBV agents
• _at_ 52 wks, undetectable HBV PCR was most likely in
  those with greater CD4 increases undetectable
  HIV ? will starting HAART earlier be beneficial?

M Nunez, B Ramos, B Diaz-Pollan, and others. AIDS
Res Human Retroviruses 22(9) 842-848. September
2006.
54
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

55
What about the patient with end-stage liver
disease?

• Liver transplantation may be a viable option in
  selected HIV individuals
• Experimental, outcomes non-HIV
• good HIV control
• good adherence/compliance
• HCV recurrence is common in new liver
• Re-treatment may need to be longer

L Castells, J I Esteban, I Bilbao, and others.
Antiviral Therapy 11(8) 1061-1070. 2006.
56
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
• Counsel about risk factors

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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 are no conflicts of interest
represented in the presentation.