HIV

1
HIV The Other Players

• Jeffrey Beal, MD
• Medical Director
• Florida/Caribbean AIDS Education and Training
  Center

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 are no conflicts of interest
represented in the presentation.
3
HIV is not Alone!

• TB was on its way to obliteration prior to the
  arrival of HIV as a new host

4
Reported TB Cases United States, 19822004
No. of Cases
1982
1987
1991
1995
1999
2004
Year
All case counts and rates for 19932003 have been
revised based on updates received by CDC as of
April 1, 2005.
5
TB Case Rates, United States, 2004
D.C.
lt 3.5 (year 2000 target)
3.64.9
gt 4.9 (national average)
Cases per 100,000.
6
HIV TB Trouble

• In HIV negative patients, 10 will develop active
  TB in a LIFETIME
• Among patients with HIV, one in ten per YEAR will
  develop active TB that is a 100 fold increase!!
• One in two or three tuberculin test positive AIDS
  patients will develop active TB

7
HIV makes TB worse

• Without T cells get immature response
• Host response can no longer contain TB organisms
  that may be present
• Taken to Lymph Nodes causing adenopathy and
  dissemination
• May lose innate resistance so have the ability to
  get re-infected if exposed again
• Recent infection with post primary TB more common
  in HIV infected patients as shown in Genotyping
  studies from NY and SF
• Changes way TB presents-lower lobe, hilar
  adenopathy, pleural TB, extrapulmonary
  disseminated disease
• With severe immunosuppression may get no response
• CT and CXR negative

8
TB HIV Trouble

• Tuberculosis also negatively impacts HIV Disease
• Associated with a higher plasma HIV RNA viral
  Load level
• More rapid progression of HIV Disease

Whalen, 1995 Jones, 1993
9
Definitions

• Latent tuberculosis infection (LTBI) is the
  presence of M. tuberculosis without symptoms or
  evidence of active TB disease
• Positive tuberculin skin test (TST) or
  QuantiFERON-TB Gold test (QFT-G)
• Active tuberculosis (TB)
• Clinical signs and symptoms of active TB
• Positive tuberculin skin test TST or QFT-G
  usually positive

10
When to Treat

• Non Incarcerated
• PPD gt 15 mm
• Incarcerated
• PPD gt 10 mm
• HIV
• PPD gt 5 mm

11
Treatment of Latent Tuberculosis Infection
(Formerly Known as Preventive Therapy)

• Treatment of latent TB infection for HIV
• INH 300 mg pyridoxine 50 mg qd x 9 mo., or
• INH 900 mg pyridoxine 100 mg 2x/wk x 9 mo.
• Short Course Treatment of LTBI no longer
  routinely recommended
• RIF for 4 months as effective as INH for 9 months

12
Infection Control

• THINK TB, ISOLATE START MEDS
• 6-8 air exchanges/hr
• Negative Pressure
• Doors Closed
• All entering room wear N95 mask
• Keep in isolation until 3 negative smears, on
  medications and responding clinically

13
(No Transcript)
14
DIAGNOSIS OF TB DISEASE

• Chest X-Ray
• 95 of HIV(-) cases with upper lobe infiltrates
  and/or cavities

15
DIAGNOSIS OF TB DISEASE

• Up to 30 of HIV (), active TB cases will have
  no infiltrates or cavities

16
TB Disease Diagnosis

• Culture
• Positive 80 of active TB cases
• Takes 6-8 weeks by conventional
• Takes 1-3 weeks by liquid media
• Sensitivity
• Takes 1-2 weeks after positive culture
• Nucleic Acid Amplification
• Results available in 4-6 hours
• Specificity 98 on smear() specimens
• Sensitivity 70-80 on multiple respiratory
  specimens

17
Treatment of active TB in Patients on
Antiretroviral Therapy

• Rifabutin (RBT-T1/245 hours) preferred over
  rifampin (Rif-T1/25 hours) due to less p450
  interactions
• Must adjust dosages of ARV and RBT if given
  concurrently (see handout)
• Alternative regimens is not to use a rifamycin or
  delay ARV therapy

18
TREATMENT OF ACTIVE TB DISEASE

• Start with 4 drugs in all patients
• INH, RIF (RBT), PZA and EMB or SM until
  sensitivities return
• If pansensitive, D/C EMB or SM
• After 2 months of therapy, D/C PZA
• Continue INH RIF(RBT) for 4 more mths-total 6
  mths
• Must have culture conversion by 2 months
• 6 month regimen good for HIV(-) and ()
• Can use BIW regimen if CD4gt100 (? RIF
  Monoresistance in HIV pts with CD4lt100 use TIW)
• Monitor adherence and toxicity
• DOT preferred, Combination pills for self
  administered

19
TB Treatment Monitoring

• Observe for response-weight gain, coughing less,
  improved appetite, decreased fevers, AFB smears
  decreasing
• Repeat cultures at two months
• Observe for drug toxicities
• INH
• hepatitis with transaminase elevation-monitor for
  clinical signs of hepatitis and at least monthly
  LFTs
• Peripheral neuropathy-monitor clinically, give B6
• Rifampin
• Red color to urine, sweat, tears
• Myalgias-NSAIDS prn
• Cholestatic hepatitis-monitor for clinical signs
  of hepatitis and at least monthly LFTs
• Pancytopenia-CBC monthly
• Rifabutin-same as rifampin except uveitis more
  common
• Ethambutol
• GI upset-? Metoclopramide (try not to give TB
  meds with food)
• optic neuritis (esp in pts with decreased renal
  function)-monitor clinically, monthly color
  vision and visually acuity
• Pyrazinamide
• hepatitis with transaminase elevation-monitor for
  clinical signs of hepatitis and at least monthly
  LFTs
• Increased uric acid (gout)-monitor clinically and
  if symptomatic and elevated uric acid-allupurinol
  
• CXRs not routinely recommended for f/u

20
Baseline and Clinical Monitoring

• Baseline
• CBC, Platelets, creatinine, uric acid, bilirubin,
  hepatic enzymes (ALT or AST)
• Visual acuity and red-green color perception
  (ethambutol)
• Audiogram (Streptomycin)
• Susceptibility drug testing of M. TB isolate

American Thoracic Society, 2003
21
Baseline and Clinical Monitoring

• Follow-Up Monitoring
• Monthly clinic visit
• Monthly AST or ALT if elevated at baseline
• Monthly creatinine and audiogram if using
  streptomycin
• Monthly visual acuity and red-green perception if
  using ethambutol
• f/u sputums monthly collection of 3 consecutive
  daily morning sputum specimens for AFB smear and
  culture until negative for 2 consecutive months
• Drug susceptibility if patient remains culture
  positive after 3 months of TB Treatment
• At the end of Treatment
• Obtain CXR and sputum for AFB smear and culture

American Thoracic Society, 2003 Federal Bureau of
Prisons, 2001
22
MultiDrugResistant TB

• Definition strains of tuberculosis that are
  resistant to at least the two main first-line TB
  drugs
• MDRTB in the HIV setting is associated with very
  rapid spread and high mortality
• Treatment interruption or poor adherence are risk
  factors for developing MDRTB

23
XDR TB

• Extensive Drug Resistant TB (also referred to as
  Extreme Drug Resistance) is MDR-TB that is also
  resistant to three or more of the six classes of
  second-line drugs.

24
Clinical Significance of Resistance

• If pansensitivegt95 chance of cure
• If resistant to INHgt90 chance of cure
• If resistant to rifampingt70 chance of cure
• If resistant to INH and RIF50 chance of cure
• Before chemotherapy50 chance of cure
• Note MDR more common in HIV pt.

25
A.G. HOLLEY TB HOTLINE
1-800-4TB-INF0 Or www.FAETC.org Clinical
Consultation Link
26
Paradoxical Responses
27
Paradoxical Response

• Soon after ARVs are started (2-6 weeks) in
  patients with HIV and TB, paradoxical responses
  (Immune Reconstitution with Inflammatory Response
  Syndrome-IRIS) may frequently be seen ( 25 esp.
  in patients with an initially high HIV viral load
  who experience a marked drop post ARVs)
• These paradoxical responses frequently arouse
  concerns of uncontrolled TB due to drug
  resistance and/or noncompliance, drug fever or
  alternative diagnosis, they are distinct from
  these and may represent an enhanced
  antituberculous immune response after the
  initiation of anti-retroviral therapy
• Clinicians should be aware of this phenomenon
  although other possibilities for a worsening
  clinical state must first be excluded
• Potentially many will regain their ability to
  react to PPD

28
Hepatitis C No Vaccine Available
29
HIV is not Alone!

• An estimated 4.1 million (1.6) Americans have
  been infected with Hepatitis C of which 3.2
  million are chronically infected
• 1.0 1.2 million Americans are infected with
  HIV
• CDC estimates the prevalence of HCV infection at
  25 of the HIV people in the US
• HCV co-infection prevalence among HIV people may
  be as high as 50-90 in IDUs and hemophiliacs in
  the US

• Shah, M., Paul, Sindy, Bishburg, E., Martin, E.
  Update on HIV and Hepatitis C Virus
  Co-Infection,. New Jersey AIDSline. Volume 2
  Number 2, December 2005

30
HCV Background

• HCV is an RNA virus of the flavivirdae family.
• There are 6 HCV genotypes and more than 50
  subtypes which explains part of the difficulty in
  vaccine development and a lack of response to
  therapy.
• Genotype I accounts for 70 75 of all HCV cases
  in the U.S.
• This genotype is associated with a lower response
  rate to therapy.

31
HCV Transmission

• Occurs primarily through infected blood exposure
• Injected drug use (Sharing of Needles)
• Accounts for more than 60 of new cases in
  Western countries.
• Blood transfusion before 1992
• Today the chance is less than 1 chance in 2
  million units of transfused blood.
• High-risk sexual practices or sex with an
  infected person.

http//www.gicare.com/pated/ecdlv42.htm
32
Prevalence of HCV

• Hepatitis C infection outweighs HIV in
  correctional settings in terms of sheer numbers
  of inmates living with this infection
• The prevalence of HCV infection among US
  prisoners is at least 10-fold higher than the
  estimated prevalence of 2 in the general
  population

Dr. Ted Hammett (Abt Associates, Cambridge
Massachusetts
33
Why do we need to treat HCV in those coinfected?

• HCV is a more serious disease in coinfected
  patients than in monoinfected.

34
Clinical effect of HIV on HCV

• Accelerated course to cirrhosis HCC1,6
• Greater probability of HCV transmission2
• Greater chance of chronic HCV viremia3,4
• Higher HCV viral loads6
• Decreased efficacy of PEG-IFN and RBV5

1. Benhamou Y. Hepatology 1999301054 2. Gibb,
et al. Lancet 2000356904-907 3. Bonacini et al.
JAIDS 200126340-344 4. Sherman et al. Clin
Infect Dis 200234831-837 5. Torriani et al. N
Engl J Med. 2004351438-450. 6. Sulkowski,
clinicaloptions.com/ccohiv2006 Management Update
on Hepatitis/HIV Coinfection
35
Clinical effect of HIV on HCV

• 16 year cumulative incidence of ESLD
• 14 if HIV positive
• 2.6 is HIV negative
• Increased risk ESLD
• Hep B Surface Ag
• CD4 lt 200 cells/mm3
• for each year of age
• Sulkowski, clinicaloptions.com/ccohiv2006
  Management Update on Hepatitis/HIV Coinfection

36
Why do we need to treat HCV in those coinfected?

• HCV has become one of the leading causes of death
  in the HIV population.

37
HIV Outpatient Study (HOPS)
N5561
Nonopportunistic Illnesses Contributing to Death
as a Percentage () of All Deaths Between 2000
and 2002
Proportion () of Deaths Due to Nonopportunistic
Causes
Plt.0001 for trend
Palella FJ et al. Presented at 11th Conference
on Retroviruses and Opportunistic Infections,
2004 Abstract 872.
38
HCV/HIV-related Morbidity Mortality

• Johns Hopkins University 1995-2000 admissions for
  liver-related complications in HIV/HCV pts.
• Increased nearly 5-fold from 5.4 to 26.7
  admissions per 100 person-years
• Related to longer life of patients with HAART
• Sulkowski, clinicaloptions.com/ccohiv2006
  Management Update on Hepatitis/HIV Coinfection

39
Prognosis Effect of HAART on HCV

• PIs have no activity against HCV
• Control of HIV to lt 400 copies/ml does not affect
  HCV RNA levels
• May see transient elevation of ALT after
  initiation
• PI vs NNRTI, no difference in rate of liver
  fibrosis (Deitrich, CROI 2005)

40
Clinical effect of HCV on HIV

• More rapid progression of genotype 1 to AIDS1
• Greater risk of HAART liver toxicity
• Poorer clinical outcomes AIDS, death?
• Higher risk of insulin resistance diabetes
  mellitus

• Sabin et al. J Infect Dis 1997 175164-68
• 2. Soriano et al. AIDS 2004, 18 1-12

41
Why do we need to treat HCV in those coinfected?

• HCV coinfection carries significant morbidity,
  limits ARV options, decreases QOL.

42
Does Treating Hepatitis C Help?
43
Potential Benefits of HCV Therapy in Patients
Infected With HIV

• Viral eradication
• Delay fibrosis progression
• Prevent/delay bad clinical outcomes
• Liver decompensation
• Hepatocellular carcinoma
• Death
• Improve tolerance and effectiveness of HAART
• Permit aggressive antiretroviral drug therapy
• Enhance immune reconstitution?

44
Screening and Diagnosis

• Test all HIV patients for anti-HCV EIA ab.1
• If IDU and neg HCV ab, check HCV PCR.
• (False-neg ab has been reported, 3.4 in one
• HIV cohort).2
• If HCV pos., check PCR to confirm active
  infection (10-15 spontaneous clearance in
  monoinfected).

1. USPHS Guidelines for Preventing OI in PWHIV,
1999. 2. Boyle B and Vaamonde C. DDW, May 2002,
San Francisco, Abs 106665.
45
HCV Genotypes

• Simmonds Classification
• Six Genotypes (1-6) with subtypes (a,b,c)
• Genotypes 1,2,3 90 worldwide
• Genotype 1a,b 80 North America
• Type 4 Middle East, Central Africa
• Type 5a South Africa
• Type 6 Asia

46
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

47
Whom Do We Treat?

• HIV stable (No AZT/ ddI in regimen. Avoid d4T and
  Nevirapine)
• If HIV not stable, needs to be addressed first
  (judgment call!)
• Treatment/follow-up adherence
• Mostly drug alcohol free (methadone okay)
• Willing to undergo treatment
• Pre-treatment liver biopsy?

48
International Guidelines for Mangement of HIV-HCV
Coinfection

• Updated May 31, 2007
• -Given improved rate of response to anti-HCV
  therapy,
• -the faster rate of fibrosis progression in HIV
• -the ability to assess early virologic response,
  the panel stated that in most cases, liver
  biopsy is not mandatory for considering the
  treatment of chronic HCV infection adding that a
  combination of non-invasive methods accurately
  predicts hepatic fibrosis in most cases.
• www.hivandhepatitis.com/hiv_co_inf/2007/060107_a.h
  tml

49
Whom Do We Treat (2)

• Depression under control
• No other contraindications for treatment (renal
  failure, severe cardiac disease, severe
  anemia/neutropenia/thrombocytopenia uncontrolled
  diabetes, autoimmune diseases)
• Compensated liver disease
• Pretreatment vaccine for Hep A/Hep B

50
When to Delay or Avoid Treatment

• CD4 cells lt 100/mm³, active opportunistic
  infections
• Uncontrolled HIV viral load
• Decompensated liver disease
• Untreated depression
• Ongoing substance abuse
• Nonadherence
• Active ischemic heart disease
• Untreatable malignancy
• Severe autoimmune disease
• Pregnancy plans

51
HCV Treatment

• Standard of care is combination therapy with
  Pegylated interferon ribavirin
• Pegylated interferon is once weekly injection
• 180 mcg/week pegylated interferon alfa-2a
• 1.5 mcg/kg/week of pegylated interferon alfa-2b
• Ribavirin is typically weight based for genotype
  1
• 1000mg lt75 kg 1200 mg gt75 kg
• Therapy is 48 weeks for all genotypes, but 24
  weeks may be adequate for genotype 2 or 3

52
Defining Success

• RVR Rapid viral response (undetectable VL) at
  week 4 predicts SVR
• EVR Early viral response, 12 week viral load is
  undetectable or decreased by 2 logs.
• ETR End of treatment response, undetectable
  viral load at end of treatment.
• SVR Sustained viral response, undetectable 6
  or more months after therapy.

53
Defining Response in HIV/HCV

• Lack of Early Virologic Response (lt2 log10 IU/mL
  decrease in HCV RNA from baseline or
  undetectable) at wk 12 is highly predictive of
  virologic failure.
• Current guideline discontinue treatment if EVR
  not seen (some experts would disagree)

54
HCV Treatment

• Those individuals with Genotype 1 or 4 who
  achieve EVR, but not RVR might benefit from
  extended (60-72 weeks) of therapy.
• www.hivandhepatitis.com/hiv_co_inf/2007/060107_a.h
  tml

55
Results AEs
Only those w/ detectable virus
56
Does Rx Improve Liver Health if No SVR?

• Retrospective analysis of APRICOT
• N 64 pts with paired pre and post -Rx bx
• Histologic response defined as ? at least 2 pts
  in index
• 1/3 of pts without SVR had histologic response
• Lissen, E. et al, 3rd IAS Conf., Rio de Janeiro,
  7/05 Abstract TuPel1C21

57
HEPC/HIV

• Screen all patients and vaccinate those Hep A or
  B negative
• Consider treating as a part of HIV care and
  within HIV practice
• Aggressively pursue treatment and treat early in
  course of HIV infection
• Supportive measures increase success

58
(No Transcript)
59
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

60
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

61
HEPATITIS B/ HIV COINFECTION
62
Natural History of HBV

• After primary infection 5-10 develop chronic
  viremia
• Disease progression is measured in decades in
  those with active infection
• Variable rates of progression
• 25-30 of chronically infected go on to develop
  decompensated liver disease or cirrhosis

63
Transmission Hepatitis B in US

• Sexual intercourse (Heterosexual and MSM)
• IDU
• Percutaneous exposure
• Vertical

64
Relative Risk of Infection Rule of Three

• HBV contaminated needle
• eAg 30 risk of transmission
• eAg- 10 risk
• HCV contaminated needle
• 3 risk
• HIV contaminated needle
• 0.3 risk
• Sexual transmission HBVgtHIVgtHCV

65
Clinical effect of HIV on HBV

• Accelerated course to cirrhosis HCC
• Greater probability of HBV transmission?
• Greater chance of chronic HBV viremia
• Less initial clearance
• Lower rate of later spontaneous reversion

Soriano, et al. AIDS 2005, 19221-240
66
Clinical effect of HBV on HIV

• Greater probability of HAART associated
  hepatotoxicity
• Co-factor for HIV disease progression?

67
HIV coinfection increases the risk of ESLD due to
HBV

• MACS, 4,967 men
• HIV, 47
• HBV, 6 (n326)
• HIV/HBV, 4.3 (n213)
• HIV/HBV - 19-fold higher risk of liver death
  compared to HBV alone
• Alcohol
• Low CD4
• Increase risk after 1996

68
HBV Treatment in Co-infected

• Treatment decisions informed by need for HAART
• If HAART is indicated - agents that treat HBV are
  best
• Lamivudine (3TC, Epivir) tenofovir (Viread)
• Emtricitabine (FTC, Emtriva) tenofovir (Viread)
• Entecavir HAART
• If HAART not yet necessary individulaize
  therapy

69
HBV Treatment if HAART Optional

• Individual stratification depending on
• HBV DNA level
• Liver histology
• LFTs
• Non-invasive fibrosis surrogate testing?
• pegylated interferon alfa-2a
• Use HAART sooner than customary
• Not lamivudine or tenofovir (resistance to HIV)
• Telbivudine no data in HIV
• Future Clevudine

70
Goals of Therapy Treatment Endpoints for HBV

• Goals of therapy
• Prevent long-term clinical outcomes by inducing
  sustained suppression of HBV replication.
• (chronic HBV infection is currently not readily
  eradicable)
• - Objective is to slow liver disease progression
• Treatment endpoints
• Biochemical normalization
• Serological (HBeAg /or HBsAg seroconversion)
• Virological (serum HBV-DNA suppression)
• Histological improvement

1 Lok, et al. J Hepatology 2003 38 S90-S103.
71
Sulkowski, clinicaloptions.com/ccohiv2006
Management Update on Hepatitis/HIV Coinfection
72
indicated for tx. Chronic HBV in HIV Sulkowski,
clinicaloptions.com/ccohiv2006 Management Update
on Hepatitis/HIV Coinfection
73
(No Transcript)
74
Conclusions

• HBV and HCV commonly found in HIV-infected
  patients
• Co-infection with these viruses complicate
  management and contribute to morbidity and
  mortality
• Active consideration and treatment of these
  co-infections has become an integral part of
  comprehensive HIV management

75
Questions?