HIV

1
HIV Viral Hepatitis How to Educate Clients
PhysiciansCare, Treatment Policy Issues

• Tracy Swan
• Treatment Action Group ADAP TA Meeting
• July 2008

2
HIV/ Hepatitis Coinfection Hepatitis B (HBV)
Hepatitis C (HCV)

• Epidemiology Implications
• Transmission Prevention
• Diagnostics
• Natural History
• Treatment Treatment Issues
• New Treatments Planning for the Future
• Role of ADAPs

3
HBV Epidemiology

• HBV (chronic)
• US 2 million people
• Worldwide 350 million people
• HIV HBV
• US 10 of HIV-positive people also have HBV
• Worldwide 2-4 million are HIV/HBV coinfected

4
HCV Epidemiology

• HCV (chronic)
• US 45 million people
• Worldwide 120170 million people
• HIV HCV
• US30 of HIV-positive people also have HCV
• Worldwide 4-5 million are HIV/HCV coinfected

5
Who Are We Talking About?

• HBV HCV testing recommended for all
  HIV people
• (DHHS Guidelines for Prevention and Treatment of
  Opportunistic Infections
• in HIV-1 Infected Adults and Adolescents June
  2008)
• HBV coinfection prevalent among MSM
• current and former IDUs
• HCV coinfection prevalent among current
• former IDUs up to 90 are coinfected
• Coinfected people more likely to be poor,
  African American, have multiple co-morbidities,
  a history of incarceration

6
HBV Transmission

• HBV is 100x more infectious than HIV
• Mainly transmitted through blood, also semen
• vaginal fluid same as HIV unprotected sex
• with an infected person, IDU with shared
  equipment,
• birth from an infected mother, needlesticks
• Lives outside the body for up to 7 days
• Bleach is effective

7
What Can Be Done HBV Prevention

• HBV is vaccine-preventable All susceptible HIV
  people
• should be vaccinated against HBV (but not with
  twinrx)
• HBV vaccine more effective with CD4 count gt500
  HIV RNA is undetectable recommended when CD4
  cell count is gt350 less effective with nadir CD4
  count of lt 200
• (DHHS Guidelines for Prevention and
  Treatment of Opportunistic Infections in
• HIV-1 Infected Adults and Adolescents June
  2008 Laurence Am J Med 2005
• Overton et al CID 2005 Tedaldi et al CID
  2004)
• Doubled dosing and adjuvants may increase
  response rate
• (Brook J Hepatol 2005 Cooper et al CID
  2008 Rey et al Vaccine 2000)
• HIV people need anti-HBs titer 1 month after
  completing the
• HBV vaccination series re-vaccination should be
  considered for
• non-responders annual boosters for people at
  ongoing risk
• (CDC 2008 DHHS Guidelines for Prevention and
  Treatment of Opportunistic Infections in HIV-1
  Infected Adults and Adolescents June 2008)

8
HBV Prevention

• There is PEP for HBV
• HBV vaccination HBIG (considered after
• assessment of source)
• MTCT can be prevented
• with HBIG and vaccination (for infant)

9
HCV Transmission

• HCV is 10x more infectious than HIV
• Bloodborne, mainly transmitted through IDU, blood
• transfusion/products before 1992, needlestick
• accidents, dialysis other invasive medical
• procedures w/o adequate infection control
  also
• sexually (less common but increasing reports
• among HIV MSM), MTIT (increased risk if
• mother is HIV)
• Lives outside the body for up to 4 days
• Bleach is not effective

10
HCV Prevention

• No preventive vaccine available
• No recommended PEP (but HCV TX is more effective
  during acute infection)
• ART and elective C-section reduce risk of MTIT

11
HCV Prevention

• Outbreaks of new, sexually transmitted HCV
• infections recently reported among HIV MSM
• in US, UK, Europe Australia
• HCV may be even more aggressive in people who are
  already HIV
• Important to discuss risk factors, and risk
  reduction
• Ongoing testing for people at risk
• Prevention for IDUs is important -- so they
• can avoid HCV HCV reinfection,
• exposure to other bloodborne pathogens
• Refer to NEP, provide information on safer
  injection, offer buprenorphine refer to drug
  treatment upon request

12
Hepatitis A Virus (HAV)

• Can cause sudden liver failure in people
• with hepatitis C
• Vaccination against HAV recommended for
• people w/ chronic liver disease, MSM, IDUs
• susceptible HIV people who are at risk
• Vaccination more effective when CD4 cell count
  
• is gt200
• Response should be checked, revaccination is
• recommended for non-responders
• (DHHS Guidelines for Prevention and Treatment
  of Opportunistic Infections
• in HIV-1 Infected Adults and Adolescents June
  2008)

13
Survival After AIDS Diagnosis in 2002
Mode of transmission 12 months 24 months 36 months
MSM 0.93 0.90 0.88
IDU (male only) 0.89 0.84 0.81
CDC 2008
14
Why is Viral Hepatitis Coinfection a Problem?

• HIV worsens liver disease from
• HBV HCV
• Liver damage from viral hepatitis more likely and
  more rapid in HIV people
• HCV-associated cirrhosis can develop in lt10
  years (vs.15 to 50 years in HIV-negative people)
• People with lt200 CD4 cells at greatest risk
• Viral hepatitis coinfection can complicate HIV
  treatment

15

• In places where HIV treatment
• is widely available
• (US Western Europe),
• end-stage liver disease from
• viral hepatitis coinfection is the
• leading cause of non AIDS-
• related death among PLWHA
• (Weber et al Arch Intern Med 2006)

16
HBV Natural History

• Acute, chronic or cleared?
• Not always chronic gt95 of HIV-negative adults
  will clear hepatitis B without treatment within
  months spontaneous viral clearance
• More likely to become chronic in HIV people
• Can only be infected once

17
HBV Range of Outcomes

• Causes mild to serious liver damage
• 25 of people infected as adults will develop
  serious liver damage
• Cirrhosis
• Hepatocellular carcinoma (HCC often initially
  asymptomatic) develops in lt1 year--cirrhosis not
  always a precursor
• Liver failure
• HIV coinfection accelerates HBV progression
• HCC is more aggressive more difficult to treat
• HIV coinfection increases liver related mortality
  
• (Braü et al J Hepatol 2007 Puoti et al
  AIDS 2004 Puoti et al J Hepatol 2006 Thio et
  al Lancet 2002)

18
HBV Progression Cofactors

• HIV coinfection
• HCV coinfection
• HDV coinfection (limits treatment options,
  increases risk for HCC)
• High HBV viral load
• HBV genotype
• Alcohol consumption
• Being male

19
HCV Natural History

• Acute, chronic or cleared?
• Some people spontaneously clear hepatitis C
  without treatment (15 to 45) within a year
• Young people, especially females, and Caucasians
  more likely to clear HCV
• HIV people are less likely to clear hepatitis C,
  although some do (25)
• A person can be reinfected with HCV

20
HCVRange of Outcomes

• No symptoms, no liver damage
• Symptoms (fatigue depression) some liver
  damage
• Fat in the liver (steatosis)
• Liver scarring (fibrosis)
• Cirrhosis (serious liver scarring, making it
  difficult for the liver to function) 20-30,
  occurs 15 to 50 years after infection for HIV
  negative people can develop in lt10 years in HIV
  people
• Liver cancer (1 to 5 per year)
• Liver failure (3 to 4 per year)

21
HCV Progression Cofactors

• HIV coinfection
• Age gt40 at infection
• Insulin resistance, obesity, steatosis
• Aging/duration of HCV infection
• Chronic HBV coinfection
• Being male
• Alcohol (accelerates HCV progression,
• especially gt50 grams/day)
• Many physicians wont treat people who drink,
  despite their
• increased risk for cirrhosis (imagine this
  happening with HIV)

22
Viral Hepatitis Diagnostics

• Diagnostic, monitoring and screening tests
  provide some information about liver disease
  progression, likelihood of response to
  treatment
• These tests also create additional barriers to
  care and treatment, because some are expensive
  and/or invasive

23
Liver Biopsy

• Described as the CD4 count of HCV
• Only test that grades (assesses
• inflammation) stages (identifies
• extent of scarring) liver disease
• Can identify other causes
• of liver disease
• Can detect additional liver damage,
• such as steatosis (fatty liver) and
• drug-induced liver injury

24
BUT..

• Biopsy is expensive
• Invasive/painful
• Carries risk of complications
• Very small (lt1 in 10,000) mortality risk
• Not always accurate--or interpreted accurately
• Not always necessary for HCV or HBV treatment
  decisions, although some providers may require
  one before initiating treatment

25
HBV Diagnostics 1

• Chronic HBV diagnosed with a combination
• of blood tests
• HBsAg anti-HBc (both tests needed if
  anti-HBc alone, result may be false positive, or
  indicate latent infection HBV DNA testing should
  be done before vaccination or ART)
• 53 45
• OR
• HBsAg HBV DNA 53 499
• OR
• HBeAg (twice in six months) 149
• (DHHS Guidelines for Prevention and Treatment of
  Opportunistic Infections
• in HIV-1 Infected Adults and Adolescents
  June 2008)

26
HBV Diagnostics 2

• There are 8 viral strains, or genotypes of HBV
• Hepatitis B genotype linked with susceptibility
  to some treatments HBV disease progression
• Distributed geographically genotypes A G are
  most common in US

27
HBV Diagnostics 3

• For HIV people with chronic HBV
• Test for HBeAg HBV DNA, HBV genotype and HDV
  make treatment plan accordingly
• Hepatic imaging or ultrasound with AFP to screen
  for HCC every 6 months, since cirrhosis is not
  always a precursor
• Consider liver biopsy
• If no HBV or HIV treatment (unusual), monitor
  every six
• months with liver panel, CBC
• If current or prior ART Do HBV resistance
  testing (some drugs active against both viruses)

28
HCV Diagnostics 1

• Antibody testing screening, not diagnostic
• Viral load testing (HCV RNA) Confirms or rules
  out
• chronic HCV, helps predict likelihood of response
  to TX, but does
• not indicate/predict disease progression or liver
  damage
• (665 for Super Quant 765 for qualitative PCR)
  check super quant
• Liver Panel Blood tests part of a routine
  physical exam,
• includes liver enzyme levels (ALT, AST)
• Liver enzymes can be elevated by medication,
  toxic fumes, heavy drinking, viral hepatitis or
  other infections, during detox, and from other
  causes-so they dont indicate or predict liver
  disease severity
• Many ARVs can cause liver enzyme elevations-
  coinfected people on ART should have regular
  monitoring

29
HCV Diagnostics 2

• More than 6 different viral strains of HCV,
  called
• genotypes numbered in order of discovery
• HCV genotype can be determined by a blood test
• Genotype is not linked to HCV progression or
• severity of liver damage
• Key factor in determining length predicting
• outcome of HCV treatment
• Genotype 1 is most common in the US harder
• to treat than genotype 2 or 3

30
Viral Load Testing

• In HBV, viral load testing is necessary for
• Predicting disease progression
• Predicting response to treatment
• Deciding to initiate treatment
• Monitoring response to treatment / possible
  development of resistance
• In HCV, viral load testing is necessary for
• Diagnosis
• Predicting response to treatment
• Monitoring response to treatment
• Lack of access to viral load testing is a major
• barrier for both mono-and coinfected people

31
Non-Invasive Testing

• Serum markers not ready for prime time yet
• Good for detecting cirrhosis, but not as good for
  identifying mild to moderate liver damage
• Less reliable in HIV people, because of
  inflammation and certain ARVs
• Expensive gt450
• Elastometry (Fibroscan) may be more precise
• More research on accuracy in HIV people needed
• Not reliable in overweight people
• Machine is very expensive, thus access is limited

32
Who Needs HBV Treatment?

• HBV treatment should be considered earlier for
• HIV/HBV coinfected people treatment initiation
• based on
• HBV DNA (gt2000 IU/mL)
• ALT (if elevated)
• Extent of liver fibrosis
• (No treatment needed when HBV DNA lt2000 IU/mL,
  or HBV
• DNA gt2000 IU/mL with normal ALT mild liver
  damage)
• (Soriano et al AIDS 2008)

33
HBV Treatment

• HBV treatment is also HIV treatment
• Upcoming HIV treatment guidelines will recommend
• ART for all coinfected people (regardless of
  CD4 count)
• ARV regimen should contain tenofovir 3TC or
• FTC, since both are also active against HBV
• In cases where ART is not indicated, or refused,
  the
• only HBV treatment options are PEG-IFN for 12
  months,
• or LdT/adefovir (because of dual activity)

34
HBV Drug Resistance

• Cross-resistance is a big problem
• If lamivudine (3TC) resistance develops, FTC
  LdT may not be effective, since one HBV mutation
  can confer resistance
• Resistance to other anti-HBV drugs may also
  develop
• Lamivudine should be discontinued treatment
• with new drug (s) initiated (entecavir,
  adefovir,
• tenofovir)
• Monitoring HBV DNA is crucial to detect
  resistance

35
Who Needs HCV Treatment?

• Patients with an increased risk of developing
• cirrhosis
• NIH Consensus Statement 2002
• Consider HCV treatment in all HIV/HCV-
• coinfected patients
• Veterans Administration 2005

36
HCV Treatment1

• Reports of rapid (gt2 stage, in lt3 years) liver
  disease
• progression, benefits of ART prompting more
• aggressive treatment strategies for HIV/HCV
• coinfected people
• HCV can be treated regardless of HIV status
• SVR (sustained virological response to HCV TX,
  meaning no detectable HCV in the bloodstream 6
  months after treatment) associated with decreased
  morbidity and mortality
• Treat to cure HCV--benefit of maintenance therapy
  is uncertain
• ART may slow liver disease progression by
  maintaining immune health

37
HCV Treatment2

• Hepatitis C is treated with a combination of two
  agents interferon and ribavirin
• These were not designed to treat HCV (but may new
  drugs that specifically target HCV are in
  development)
• Duration of treatment depends on genotype, HCV
  viral load, early response to treatment, HIV
  status--anywhere from 12 to 72 weeks

38
Interferon

• A synthetic version of a chemical messenger made
• by the human body it stimulates the immune
• system fights viruses
• Pegylated Interferon (PEG-IFN) is standard of
  care
• Pegylation means that a small molecule has been
• attached to interferon to keep it in the body
  longer
• increase efficacy
• Pegylated interferon is injected 1 X per week

39
IFN Side Effects

• Flu-like fever, aches, nausea, appetite loss,
• weakness, fatigue
• Lab Abnormalities anemia, neutropenia,
• thrombocytopenia
• Neuropsychiatric suicidal ideation/suicide(rare),
  
• depression, insomnia, anxiety, irritability, mood
  
• swings, mania, psychosis
• Other hair loss, optic nerve damage, etc

40
Ribavirin (RBV)

• Pill or capsule, taken 2 X a day
• Same family (NRTI) as some HIV drugs but it does
  not work against HIV
• Prevents relapse, enhances SVR
• RBV dosing is usually based on weight and genotype

41
RBV Side Effects

• Anemia is a major, sometimes treatment-limiting
• side effect
• Cardiac events
• Shortness of breath, coughing
• Itchy skin/rash
• May also cause depression

42
Managing Side Effects

• Flu-like symptoms evening/Friday night shot,
  tylenol,
• anti-nausea medication
• Appetite/weight loss many small, light meals,
  marinol
• Anemia growth factor, dose reduction
• Neutropenia growth factor, dose reduction
• Thrombocytopenia if severe, dose reduction or
  d/c
• treatment

43
Neuropsychiatric Side Effects

• A pre-treatment psychiatric assessment ongoing
• mental health care and screening for depression
• should be standard of care
• Depression, anxiety manage with mental health
  care, support system from peers, family and
  friends
• anti-depressants
• Irritability/insomnia/mood swings/mania manage
  with mental health care, mood stabilizers,
  sleeping aids

44
HCV Treatment Less Effective For Coinfected
People
SVR, overall SVR, genotype 1 SVR, genotypes 2 3
HIV-negative 56 to 61 42 to 44 70 to 82
HIV/HCV coinfected 27 to 44 14 to 38 53 to 73
45
Predicting Response

• HCV genotype (2,3,4,1)
• Race (WhitegtAfrican American)
• Hepatitis C viral load lt400,000 IU/mL
• HIV status (not CD4 count or viral load)
• Amount of liver damage/steatosis
• Weight, insulin resistance, diabetes
• Adequate dose/duration of TX adherence
  (80/80/80)
• Maintaining full ribavirin dose
• Education and support
• Effective side effects management

46
HIV HCV Whats Happening?

• 845 coinfected patients at
• a Baltimore HIV clinic

277 referred for HCV care TX
125 completed pre-TX evaluation
69 eligible for TX
29 treated
6 had SVR
(Mehta et al AIDS 2006)
47

• Withholding an
• effective treatment
• from the highest
• prevalence
• population is
• unacceptable
• for any other
• medical condition

48
Multidisciplinary Care

• Provide mental health care peer
• support/education
• Offer drug/alcohol treatment on request
• OST, pharmacotherapy, counseling,
• in/out patient treatment
• Explain HCV natural history,
• assessment process for treatment,
• risks/benefits of treatment

49
Flexible Eligibility Criteria

• No abstinence requirements
• Willingness/interest in HCV TX
• Reasonable adherence to clinic visits
• Engagement in psychiatric care,
• when indicated

50
HCV TX GUIDELINES

• it is recommended that treatment
• of active injection drug users be
• considered on a case-by-case
• basis
• NIH, 2002

51
The good news.

• Robust HCV pipeline many drugs have entered
  clinical trials some already in phase 3 more
  in preclinical development, including
• Anti-virals (HCV protease polymerase
  inhibitors, among
• others)
• Immune-based therapies (monoclonal antibodies,
• TLR 7 antagonists, among others)
• Vaccines (therapeutic and preventive)
• Anti-fibrotics (to stave off liver disease
  progression)
• New formulations of interferon (more
  convenient,
• possibly less toxic)
• Ribavirin substitute (less toxic)

52
The Not-As-Good News

• Interferon ribavirin will continue as the
• backbone of hepatitis C therapy until there are
• enough sufficiently potent new agents to
• construct regimens without them
• (but IFN may still be necessary)
• BUT..
• Adding new drugs may increase
• efficacy shorten duration of HCV
• therapy

53
Cost Associated With New HCV TX

• Resistance testing (when, how often?)
• Other tests/monitoring may be necessary
  (additional HCV RNA)
• Pharmacokinetic boosting
• High drug prices -- dont expect new agents to be
  a bargain
• Management of new types of side effects
• Scaling up preparing infrastructure for
  increased treatment uptake

54
ADAP Coverage

• 22 State ADAPs covered HCV TX as of
• June 2007 (down from 25 in 2006)
• 28 cover HAV and HBV vaccines
• Low TX uptake---clients cite difficulty of
  treatment, or are not interested
• Lack of providers to prescribe HCV TX

55
What Can ADAPs Do?

• One drug from each ARV class must be in
• ADAP formulary
• HBV escape clause for inclusion of tenofovir
• HCV TX escape clause to avoid drug-drug
• interactions during HCV treatment
• (tenofovir and FTC/3TC only usable nukes due
• to drug interactions)

56
ADAP Breaking Down Barriers

• 12 week early stopping rule (vs RVR), no
  maintenance TX
• Add lab work HBV DNA genotyping, HCV RNA
  genotyping, biopsy?
• Add drugs to formulary buprenorphine, entecavir,
  LdT, adefovir, pharmacotherapy for alcohol
  cessation