Module 6. Co-Infections and Their Effects on HIV Therapy

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Module 6.Co-Infections and Their Effects on HIV
Therapy

• TB Screening
• Hepatitis C

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Tuberculosis Screening Guidelines

• On admission
• Mandatory symptom screening
• Symptoms isolate evaluate

• No previous positive test
• Tuberculin skin test

• TST
• HIV (or high risk) 5 mm induration at 48-72 hrs
  
• Chest radiograph
• Sputum analysis for HIV with respiratory symptoms

Annual screening recommended
As recommended by the National Commission for
Correctional Health Care.
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Tuberculosis and the HIV Incarcerated

• HIV infection ? risk of active TB
• HIV/active TB may be TST negative
• Chest x-ray atypical or normal
• Complicates TB treatment
• Drug interaction risk
• Effective ART may result in
• Immune reconstitution syndrome, resulting in
  temporary worsening of TB

Consult an HIV/TB expert for management of
HIV-related TB disease. CDC. MMWR. 200049(No.
RR-6)8. CDC. MMWR. 200049(46)1041-1044. Burman
WJ et al. Clin Infect Dis. 199928419-429.
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TuberculosisLatent or Active in Prisoners on
HAART

• Latent TB
• In practice, TST/HIV cases gtgtgt active TB/HIV
  cases
• Preferred regimen
• Isoniazid (INH) (300 mg) daily for 9 months - or
  900 mg B6 (50 mg) twice a week
• INH may be concurrent with NRTIs, PIs, NNRTIs

• Active TB (AIDS-defining)
• Preferred regimen
• 4-drug incl rifampin or rifabutin INH,
  pyrazinamide ethambutol
• Rifampin and rifabutin interact with PIs NNRTIs

Hepatotoxicity risk from TB treatment also test
for HBV, HCV, follow LFTs
New Jersey Medical School National TB Center
(NTBC) Pocket Guide. CDC Treatment Guidelines for
the Concurrent Treatment of HIV and TB.
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Hepatitis C and BScreening and Treatment

• National Commission for Correctional Health Care
  recommends all prisoners be tested for HBV, HCV
• Combination therapy for HCV usually includes
• Daily treatment with ribavirin and weekly
  PEG-interferon injections

Criteria for HCV treatment may vary slightly
from one correctional system to another.National
Commission on Correctional Health Care Clinical
Guideline. http//www.ncchc.org/hiv.pdf .De
Groot AS. HEPP News (Brown Medical School), April
2001.Paar D. HEPP News (Brown Medical School),
June/July 2001.
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Hepatitis C and BConsequences of Co-Infection
With HIV

• HBV infection ? HIV replication (? VL)
• HIV
• ? Hepatic fibrosis (chronic HCV)
• ? Hepatic failure (HBV)
• Most HBV co-infected patients (vs HBV alone) have
  
• ? HBV DNA
• ? Serum ALT
• ? Liver inflammation/cirrhosis
• Chronic HIV, HBV/HCV patients are more likely to
  have clinically significant hepatotoxicity on
  HAART
• Co-infection with HIV/HCV ? risk of developing
  hepatocellular carcinoma by 12-300 x over
  HIV-/HCV

Hadler SC et al. J Infec Dis. 1991163454-459.
McNair ANB et al. Semin Liver Dis.
199212188-196. NIH Consensus Development
Conference Panel. Hepatology. 199726(Suppl
1)2S-10S.
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HIV and Hepatitis C Coinfection
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Outline of coinfection talk

• HCV manifestation
• epidemiology
• natural history
• treatment
• HCV coinfection
• epidemiology
• natural history
• treatment

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Worldwide prevalence of hepatitis and HIV
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Risk factors for Hepatitis C infection
IVDU
Cocaine
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Exposure to infected sex partner or multiple
partners
10
20
Occupational, hemodialysis, household, perinatal
55
5
No recognized source
http//www.cdc.gov/ncidod/diseases/hepatitis/c_tra
ining/edu/transmission modes 2000
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(No Transcript)
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Cocaine use as a risk factor for HCV

• 5 of HCV infected people have cocaine use as
  their only risk factor

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Natural history of hepatitis C
70 Chronic hepatitis (abnormal liver biopsy)
85 Chronic hepatitis C
Acute hepatitis C
1 Hepatocellular CA
20 Cirrhosis
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Hepatitis C--the facts

• 1.8 of Americans are infected
• approximately 4 million Americans are infected
• leading cause of liver transplantation in the
  United States

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Likelihood of progression to cirrhosis based on
fibrosis
100
90
80
70
Stage 3 - 4
60
50
Stage 2 - 2.9
progression to cirrhosis
40
Stage 0 - 1.9
30
20
10
0
0
2
4
6
8
10
12
14
16
18
20
Years
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Hepatitis C Patterns of Response to Treatment
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HCV Elisa AB
Qualitative PCR ?
yes
no
Chronic hepatitis C Refer for staging of liver
disease
Cleared hepatitis C Repeat Elisa Ab
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False negative antibody results

• 6 of patients have HCV viremia and negative
  antibody results-- most often in patients with
  median cd4 361
• A recent study of 100 HIV patients seronegative
  for HCV
• 6 by commercial assay
• 9 by modified commercial assay (RNA extracted
  from a larger volume of whole blood)
• 19 in-house assay2

1Bonacini, et al. JAIDS 200126340-4. 2George,
et al. JAIDS 200231154-162.
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Screening for HCV in HIV patients

• False negative antibody results can occur,
  particularly in patients with low CD4 counts
• Current recommendation is to screen with HCV RNA
  in seronegative patients with elevated LFTs or
  risk factors for HCV, particularly if CD4 count
  is low

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Evolution of treatment for hepatitis C
McHutchinson, et al. NEJM 19983391485-92
Zeuzem, et al. NEJM 20003431666-1672
Manns, MP et al. Lancet 2001358958-865
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Pegylated interferon Schematic
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Pegylated interferon study Results
Manns, MP et al. Lancet 2001358958-865
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Standard interferon vs pegylated interferon

• STANDARD
• 3x/week
• monthly cost 1500
• response rates
• 33 genotype 1
• 79 genotypes 2 3

• PEGYLATED
• 1x/week
• monthly cost 2500
• response rates
• 42 genotype 1
• 82 genotypes 2 3

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Pegasys versus Peg-Intron--------
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PEG (40 kDa) IFN alfa-2a--SVR by Genotype
IFN alfa-2b RBV
PEG (40 kDa) IFN alfa-2a RBV
P .008
80
76
P .016
70
61
60
(n 140)
46
50

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Patients ()
40
(n 145)
(n 298)
30
(n 285)
20
10
0
Genotype 1
Genotype 2, 3
Fried et al. DDW May 20-23, 2001 Atlanta, Ga.
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Roche product (Pegasys) Adverse Events gt10
PEG IFN alfa-2a
IFN alfa-2b 3 MIU
(40 kDa, 180 µg)RBV (n
451) (n 443) (n 223) Fatigue
44 55 Headache 52 52 Pyrexia
38 56 Myalgia
42 50 Rigors 23 35 Insomnia
23 39 Nausea 25 33
Arthralgia 29 25 Depression
20 30 Injection site reaction
23 15-36

• IFN interferon PEG polyethylene glycol RBV
  ribavirin.
• Treatment period of 48 weeks safety data
  collected through week 72.
• Fried et al. DDW May 20-23, 2001 Atlanta, Ga.
• Roche. Data on file.

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Contraindications to Treatment

• IFN-related risk
• Significant psychiatric disease especially
  depression
• Autoimmune disease (including psoriasis)
• Decompensated liver disease
• Severe comorbid conditions
• RBV-related risk
• Significant cardiovascular disease
• Anemia ( lt12 g/dL in women, lt13 g/dL in men)
• Unable to be compliant with contraception
• Renal failure
• Hemoglobinopathy

Maddrey. Semin Liver Dis. 19991967-75.
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Side Effects of IFN

• Flu-like symptoms
• Headache
• Fatigue or asthenia
• Myalgia, arthralgia
• Fever, chills
• Nausea
• Diarrhea
• Alopecia
• Thyroiditis

• Psychiatric symptoms
• Depression
• Mood lability
• Injection site reaction
• Autoimmunity
• Lab alterations
• Neutropenia
• Anemia
• Thrombocytopenia

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Side Effects of RBV

• Hemolytic anemia
• Teratogenicity
• Cough and dyspnea
• Rash and pruritus
• Insomnia
• Anorexia

Rebetron? package insert. Kenilworth, NJ
Schering Corp 1999.
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Managing Depression

• Take psychiatric history
• Depression, mania
• Develop relationship with mental-health providers
• Treat preexisting depression before starting
  (PEG) IFN
• Evaluate patients for development of depression
  at least every 2 weeks after initiation of IFN
  therapy

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HCV Treatment Side Effect Management

• Prepare patient for IFN/RBV side effects
• Important to realize that side effects are
  manageable
• Possible ancillary medications include
• Granulocyte colony stimulating factor for
  neutropenia (not considered standard of care)
• Antidepressants for depression and irritability
• Consider Epoetin alfa for anemia (not considered
  standard of care)
• Acetaminophen, nonsteroidal antiinflammatory
  drugs, histamine 2 blockers, antidiarrheal
  agents, etc
• Emphasize positive aspects of treatment

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Tools to evaluate severity of liver disease

• ALT level
• liver synthetic function--albumin, PT
• ultrasound examination of liver
• liver biopsy (necessary in genotypes 2 and 3?)

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Factors predicting sustained response to
interferon

• Low HCV RNA level lt 2 million
• Absence of fibrosis on liver biopsy
• Viral genotype other than type 1
• Lighter patients

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2002 NIH Consensus Conference

• All HIV infected persons should be screened for
  HCV
• HIV infection may accelerate the course of HCV
  infection
• Preliminary data from treatment trials suggest
  that pegylated interferon may be better than
  standard interferon to treat coinfection

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Prevalence of HCV infection

• 1.8 in general population
• HIV infected individuals 9-40
• Injection drug users 52-90
• Hemophiliacs 60-85
• incarcerated HIV 50
• MSM 4-8

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100,000 to 400,000 coinfected individuals in the
United States
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HIV infection accelerates the natural history of
HCV infection in paired liver biopsy study
Fibrosis grade
Years
Benhamou V, et al. Hepatology1999301054
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Risk of HCV complications in coinfected patients

• RR 2.07 for cirrhosis in HIV individuals
  compared to HIV-1
• RR 6.14 for decompensated liver disease1
• RR 4.0 for death from liver disease2
• ESLD is the leading cause of mortality in
  HIV-infected inpatients with gt 200 CD4 cells/mm3

1Graham CS, Baden LR, Ye E, et al. Influence of
human immunodeficiency virus infection on the
course of hepatitis C virus infection a
meta-analysis. Clin Infect Dis 200133562569. 2D
i Martino V, Ezenfis J, Tainturier Y, et al.
Impact of HIV coinfection on the long-term
outcome of HCV cirrhosis abstract 567.
Presented at the 8th Conference on Retroviruses
and Opportunistic Infections February 4-8, 2001
Chicago Ill. 3Jain M, Cloud J, Jain C, Skiest D,
Berggren RE. Inpatient deaths among HIV-infected
persons in Dallas, Texas 1995 compared to
1999/2000 abstract 723. Presented at
Infectious Disease Society of America Annual
Meeting October 27, 2001 San Francisco, CA.
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Mortality in HCV-infected HIV patients compared
to those without HCV coinfection
Lancet 20013571361-1362
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HCV effect on ART
No apparent effect of HCV on response to ART,
although HCV-coinfected patients may be less
likely to receive ART1
1Sulkowski MS, Moore R, Mehta S, Thomas D. Effect
of HCV coinfection on HIV disease progression and
survival in HIV-infected adults abstract 34.
Presented at 8th Conference on Retroviruses and
Opportunistic Infections February 4-8,
2001Chicago, Il.
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HCV in coinfected patients interferon/ribavirin
treatment trials
non-coinfected Manns et al. Lancet
2001358958-865 Bochet, et al. 8th
CROI,2001abstract1574 Landau, et al. AIDS
2001152149-2155 Sauleda, et al. Hepatology
2001341035-40 Perez, et al. 9th
CROI,2002abstract 1653
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Why would anyone use interferon???
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Liver transplantation in HIV/HCV

• 16 coinfected patients have undergone LT
• 9 have survived after 4 years
• 7 deaths all due to recurrent HCV
• early mortality associated with HCV, termination
  of HAART
• 16 survivors have tolerated HAART post LT

Ragri M et al, 9th CROI, abstract 125
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Which coinfected patients should be treated?

• Well-controlled HIV disease (?)
• No or stable depression
• No alcohol use
• No IDU
• No serious comorbid cardiopulmonary disease,
  uncontrolled seizures, autoimmune disease