The Management of Medical Comorbidities in Opioid Dependent Patients

1
The Management of Medical Comorbidities in Opioid
Dependent Patients

• Lynn E. Sullivan, M.D.
• NIDA Physician Scientist

2

• Opioid dependent patients who present for
  treatment often have other medical problems
• There are special management issues that must be
  addressed in patients who have comorbid medical
  conditions and are being treated for concurrent
  opioid dependence
• The purpose of this section is to provide the
  clinician with an overview of the common comorbid
  medical conditions found in opioid dependent
  patients, and to review the features of opioid
  agonist therapy and preventive health care in
  these patients

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Outline for this talk

• Hepatitis C
• HIV/AIDS
• III. Opioid agonist therapies
• IV. Preventive health care for opioid dependent
  patients
• V. Summary

4
Outline for this talk

• I. Hepatitis C
• HIV/AIDS
• Opioid agonist therapies
• IV. Preventive health care for opioid dependent
  patients
• V. Summary

5
Hepatitis C

• Most common blood-borne infection in the U.S.
• Incidence 30,000 new cases per year in U.S.
• Seroprevalence studies reveal that approximately
  1.8 of the U.S. population are infected with HCV
• IDU is the major risk factor for HCV
• 60 of new cases
• 20-50 or chronic infections
• Greater than 90 of injection drug users (IDUs)
  have antibodies to HCV

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Hepatitis C

• Sexual transmission
• Efficiency low
• Rare, but not absentestimated 0.03-0.6 per year
  between long-term monogamous discordant
  partnersno change in sexual practices
  recommended
• Risk amongst those with multiple sexual partners
  is 1 per yearbarrier methods or abstinence
  recommended
• Presence of other sexually transmitted diseases
  increases risk of transmission

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Hepatitis C

• Clinical course
• Incubation period averages 6-8 weeks during which
  time antibodies are undetectable
• 85 with acute infection develop persistent
  infection
• Most patients are asymptomatic
• Serum transaminases Persistently elevated in
  43, intermittently elevated in 42, normal in
  15
• Risk factors for disease progression include
• Alcohol use
• Co-infection with hepatitis B virus and/or HIV
• Early onset infection (lt40 years old)
• Male sex

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30 year progression of chronic hepatitis C
Acute hepatitis C
gt85 (10 years)
Chronic hepatitis C
20 - gt50 (20 years)
Cirrhosis
lt 20 Hepatic failure
lt 20 HCC (30 years)
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Hepatitis C

• HCV and HIV co-infection
• 30 of HIV-positive patients in the U.S. are
  co-infected with HCV
• In HIV-infected IDUs, the prevalence of
  HCV50-90
• HIV has a significant effect on progression of
  liver disease in HCV-infected patients
• Must balance hepatotoxicity of HIV therapy with
  need to treat HIV in HCV-infected patients, while
  HIV therapy can worsen the symptoms of HCV

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Hepatitis C

• Pre-treatment assessment
• HCV RNA
• Lower viral RNA levels (viral load) appear to
  predict better treatment response
• HCV genotyping
• 70 of HCV-infected in U.S. have genotype 1,
  rest are genotypes 2, 3, and 4 (genotype 1
  has less favorable prognosis--requires
  longer duration of therapy)
• Liver biopsy
• Provides information regarding degree of
  inflammation, fibrosis, or cirrhosis

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Hepatitis C

• Treatment
• Sustained virological response (SVR)absence of
  detectable RNA at end of treatment and 24 weeks
  after end of treatment
• Pegylated interferon plus ribavirin produced
  SVR54-56 after 48 weeks of therapy (82 in
  genotypes 2 and 3, 42 in genotype 1)
• Side effects
• Interferon Flu-like syndrome
• Depressionseen in 10-40 of patients
• 5-10 of patients with these side effects
  require discontinuation of therapy
• Ribavirin Hemolytic anemia

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Hepatitis C

• IDUs and HCV treatment
• Standard recommendation gt 6 mos clean
• Arguments for not treating poor adherence, side
  effects, re-infection, non- urgent treatment
• Data supporting these arguments is lacking
• Some drug users may do well
• Treatment should be based on individual
  risk-benefit assessments
• Edlin BR, Seal KH, Lorvick J, et al. Is it
  justifiable to withhold treatment for hepatitis C
  from illicit drug users? New England Journal of
  Medicine. 345211-214, 2001.

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Hepatitis C

• IDUs and HCV treatment (continued)2002 NIH
  guidelines on treatment of hepatitis C
• Management of HCV-infected IDUs is enhanced by
  linkage to drug treatment programs
• Promotion of collaboration between HCV experts
  and providers specializing in substance abuse
  treatment
• HCV treatment of active IDU should be considered
  on a case-by-case basis
• Active IDU should not exclude patients from HCV
  treatment

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Outline for this talk

• I. Hepatitis C
• HIV/AIDS
• Opioid agonist therapies
• Preventive health care for opioid dependent
  patients
• Summary

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HIV/AIDS

• A blood-borne retroviral infection caused by the
  human immunodeficiency virus (HIV)
• Transmission is through sexual contact,
  parenteral exposure, and perinatal or postpartum
  contact
• Twenty-five percent of the approximately 40,000
  new HIV infections per year are through IDU
• From 1993-1999 the number of IDUs living with
  AIDS increased from 48,244 to 88,540
• IDUs with HIV are less likely to receive
  antiretroviral treatment
• IDUs less adherent to antiretroviral therapy, but
  substance abuse treatment found to increase
  medication adherence

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Risk of disease progression

• Course followed clinically with CD4 lymphocyte
  counts and viral RNA (viral load)
• Low CD4 is the strongest predictor of the
  development of opportunistic infections (OIs)
• Most OIs occur at CD4lt50 HIV RNA gt20,000 confers
  greater OI risk for any given CD4 count
• High HIV RNA is an independent predictor of
  disease progression

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Natural history of HIV-1 infection
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HIV/AIDS treatment

• Standard is at least a three-drug regimen
  frequently called highly active antiretroviral
  therapy (HAART
• Medication classes
• a) Reverse transcriptase inhibitors (e.g.,
  Zidovudine or AZT)
• b) Non-nucleoside reverse transcriptase
  inhibitors (e.g., Efavirenz or
• Sustiva)
• c) Protease inhibitors (e.g., Indinavir or
  Crixivan)
• d) Non-nucleotide reverse transcriptase inhibitor
  (e.g., Tenofovir or
• Viread)
• e) Membrane fusion inhibitor (e.g., enfuvirtide
  or Fuzeon or T-20)

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Outline for this talk

• I. Hepatitis C
• HIV/AIDS
• Opioid agonist therapies
• Preventive health care for opioid dependent
• Summary

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Pharmacologic treatment of opioid dependence

• Pharmacologic withdrawal - detoxification
• Opioid antagonist treatment
• Naltrexone
• Opioid agonist treatment
• Methadone
• LAAM (levo-alpha acetylmethadol)
• Buprenorphine

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Buprenorphine

• Partial agonist at mu receptor (methadone is a
  full mu agonist)
• Low abuse and diversion potential, especially
  when combined with naloxone
• Sub-lingual tablet, buprenorphine/naloxone, 41
• Daily or thrice weekly dosing
• Effective therapy for opioid dependence
• Approved for use in office-based settings

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Buprenorphine, Methadone, LAAMOpioid Urine
Results
100
All Subjects
80
LAAM
49
60
Bup
40
Hi Meth
Mean Negative
40
39
Lo Meth
20
19
0
1
3
5
7
9
11
13
15
17
Study Week
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Methadone treatment and HCV

• Patients receiving methadone and HCV treatment
  36 achieved SVR and no cases of reinfection
  after 24 weeks of treatment (Backmund et al,
  2001)
• Another study of methadone-maintained patients
  receiving HCV treatment 78 of patients
  completed treatment with an SVR of 64
  (Sylvestre, 2002)
• Studies have shown methadone has little effect on
  hepatic function in patients with or without
  underlying liver disease

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Buprenorphine treatment and HCV

• Hepatitis
• Case reports (4)
• Transaminase increased, 30-50 times normal, with
  intravenous buprenorphine in patients infected
  with hepatitis C
• Mechanism
• Buprenorphine inhibits hepatic mitochondrial
  function at high concentrations
• Should not occur with sublingual administration
• Berson A, Gervais A, Cazals D, et al. Hepatitis
  after intravenous buprenorphine misuse in heroin
  addicts.comment. Journal of Hepatology.200134(2
  )346-350.

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Buprenorphine treatment and HCV

• Hepatitis (continued)
• 120 patients treated with buprenorphine gt 40 days
• 72 with hepatitis
• Median increase in ALT 8.5 (-12 to 54)
• AST 9.5 (-8 to 32)
• 48 without hepatitis
• Median increase in ALT 0 (-7 to 8)
• AST 1 (-6 to 4.5)
• Petry NM, Bickel WK, Piasecki D, et al. Elevated
  liver enzyme levels in opioid dependent patients
  with hepatitis treated with buprenorphine.
  American Journal on Addictions. 9(3) 265-9, 2000.

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Opioid agonist treatment and HIV seroconversion

• Opioid agonist treatment reduces HIV transmission
  among IDUs
• Metzger, 1993
• 2 cohorts of patients
• 103 out-of-treatment intravenous opiate users
• 152 subjects receiving methadone treatment
• HIV antibody conversion, 18-months
• 22 of those out-of-treatment
• 3.5 of those receiving methadone treatment
• Opioid agonist treatment integrated with HIV care
  is associated with increased adherence to HIV
  treatment protocols

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Buprenorphine treatment in HIV IDUs

• MANIF 2000 cohort (France )
• Enrollment 1995-98, 467 HIV patients with IDU
  risk factor, gt18 y.o., CD4 gt 300, no prior
  opportunistic infections
• 164 receiving HAART
• 32 receiving buprenorphine
• 113 no current IDU
• 19 active IDU
• Moatti JP, Carrieri MP, Spire B, et al. Adherence
  to HAART in French HIV-infected injecting drug
  users the contribution of buprenorphine drug
  maintenance treatment. AIDS. 14(2) 151-5, 2000.

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Buprenorphine treatment in HIV IDUs

• MANIF 2000 cohort--(continued)--risk for HAART
  non-adherence
• Non-adherent Adherent OR (adjusted)
• Buprenorphine 7(21) 25 (78) 1.00
• No current IDU 39 (35) 74 (65) 2.32 (0.8-6.5)
• Active IDU 11 (58) 8 (42) 5.1 (1.3-20.1)

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Buprenorphine treatment in HIV IDUs

• MANIF 2000 cohort (France )
• 129 initiating HAART
• 22 receiving buprenorphine
• 89 no current IDU
• 11 methadone
• 7 active IDU
• Carrieri MP, Vlahov D, Dellamonica P, et al. Use
  of buprenorphine in HIV-infected injection drug
  users negligible impact on virologic response to
  HAART. Drug and Alcohol Dependence. 6051-4,
  2000.

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Buprenorphine treatment in HIV IDUs

• MANIF 2000 cohort, 6 month follow-up, Median
  values
• Buprenorphine (n20) Ex-IDU (n83) P
• Age 32 34 .04
• CD4 (pre) 287 347 .16
• CD4 (post) 344 457 .17
• Viral Load (pre) 4.8 4.4 .17
• Viral Load (post) 2.7 3.3 .91
• Months on HAART 3.7 4.0 .34
• Months on Buprenorphine 10 NA
  NA

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Methadone interactions with antiretrovirals

• NRTIs
• Methadone increases AZT concentrations but
  decreases concentrations of DDI and D4T NRTIs do
  not significantly effect methadone levels
• NNRTIs
• Significantly decrease methadone concentrations
• PIs
• Some studies found that PIs lead to higher
  methadone levels, while recent studies indicate a
  reduction of the AUC of methadone, but that it
  was not clinically significant

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Medication interactions with buprenorphine/naloxon
e

• Buprenorphine is metabolized via the cytochrome
  P450 3A4 system
• Cytochrome P450 3A4 inhibitorsincrease
  buprenorphine levels
• Azole anti-fungals
• Macrolide antibiotics
• Protease inhibitors
• In vitro study of buprenorphine
• 13 human liver microsomes
• RitonavirgtIndinavirgtSaquinavir inhibited
  buprenorphine N- dealkylation
• Of less concern given safety profile of
  buprenorphine and decreased likelihood of
  respiratory depression and coma
• 1 NNRTI (Delavirdine)

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Medication interactions with buprenorphine/naloxon
e

• Zidovudine (AZT)
• No significant impact on AZT AUC, Cmax, T1/2
  between buprenorphine maintained patients and
  controls
• (McCance-Katz EF, Rainey PM, Friedland GF, et
  al. Effect of opioid dependence pharmacotherapies
  on zidovudine disposition. Am J Addict.
  10(4)296-307, 2001)

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Outline for this talk

• I. Hepatitis C
• HIV/AIDS
• Opioid agonist therapies
• Preventive health care for opioid dependent
  patients
• V. Summary

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Other medical conditions

• Alcoholic hepatitis
• Hepatitis A, Delta agent
• Nicotine dependence
• Tuberculosis
• Bacterial infections (soft tissue infections,
  pneumonia, endovascular infections
  (endocarditis))
• Sexually transmitted diseases (e.g., syphilis,
  human papillomavirus)
• Psychiatric conditions
• Cervical cancer
• Respiratory tract cancers including lung,
  oropharynx, and larynx

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Preventive health care

• Routine screening activities for patients with
  opioid dependence
• Viral Hepatitis A, B, C Screening antibody
  tests and liver enzymes. HIV antibody testing to
  be offered initially and repeatedly as indicated
• Tuberculosis Annual screening with PPD and/or
  chest x-ray
• Syphilis Annual VDRL or RPR
• Cervical cancer Yearly screening PAP smear,
  more frequent (q6month) in those with prior
  abnormalities or very high risk

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Preventive health care

• Routine vaccinations to be considered in patients
  with opioid dependence
• Pneumococcal vaccine
• Influenza vaccine
• Hepatitis A
• Hepatitis B
• Tetanus

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Outline for this talk

• I. Hepatitis C
• HIV/AIDS
• Opioid agonist therapies
• Preventive health care for opioid dependent
  patients
• Summary

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Summary

• Patients with opioid dependence frequently have
  comorbid medical conditions, most significantly
  HCV and HIV
• Linkage of substance abuse treatment with medical
  treatments will enhance outcomes in the treatment
  of opioid dependence and its medical
  comorbidities
• Important to screen for these disorders, and to
  provide treatment, preventive services, or
  referral