HIV and hepatitis coinfection

1
HIV and hepatitis coinfection

• Josip Begovac
• University Hospital of Infectous Diseases, Zagreb
  Croatia
• HIV/AIDS Curriculum for the Training of
  Infectious Disease Specialists from the Western
  Balkans
• Zagreb, Croatia
• November 3-5, 2006

2
Epidemiology of HCV, HBV and HIV

• Global estimates

3
Prevalence of Hepatitis C (1960/5957 patients
33)
Regions south central north east
Rockstroh J et al., J Inf Dis 2005

• Croatia Slovenia
• 15

4
Cause of death in HIV-infected patients
Unknown
Other
MI, Stroke, CV event
Lactic acidosis, diabetes, pancreatitis, renal
failure
Liver related
HIV-related
Suicide/drug OD
0
10
20
30
40
50

More than one cause of death allowed per patient
p-values from chi-squared test
Konopnicki D, for the EuroSIDA group, AIDS 2005
5
Causes of deaths in the era of HAART (french data
base, year 2000)
all deaths n964, patients n64,000
Lewden et al.Int J Epidemol 200534121-30.
6
Progression to Cirrhosis
1.00
4682 patients
0.83
180 HIV-HCV 701 Alcohol 812 HBV 382
Hemochromatosis 2313 HCV 93 Steatosis BMIgt25 200
PBC
0.67
0.50
Hazard function
0.33
0.17
0.00
0
20
40
60
80
Age in years
Poynard et al J Hepatol 200338 257-65
7
Natural History of HCV Infection
Years
Exposure (Acute phase)
15(15)
85(85)
Resolved
Chronic
10-20 years
20(17)
80(68)
Cirrhosis
Stable
75(13)
25(4)
Slowly Progressive
End stage disease Cancer Transplant Death
8
Interaction of HIV and HCV

• Impact of HIV on HCV infection
• Accelerates HCV-associated liver disease
• Increases risk of HCV transmission
• MTCT (from 6 to 20)
• Sexual transmission (from 0 to 3)
• Significantly lowers clearance of HCV
• Liver disease leading cause of morbidity and
  mortality
• Impact of HCV on HIV infection
• Little or no effect on response to ART or on
  immunological, virological or clinical HIV
  disease progression

9
Case 1.

• Born 1975.y.
• HIV diagnosed in 2002
• Should the patient be tested for HCV and HBV
  antibodies?
• HBsAg neg. AntiHBs neg., AntiHBc poz., AntiHCV
  poz, antiHAV neg.
• What should we do next concerning the HCV status?
• HCV RNA and HCV genotype

10
HIV Hepatitis C

• All HIV infected patients should be tested for
  HCV antibodies
• When HCV antibody is positive, detection of HCV
  RNA should be performed to confirm or exclude
  active replication
• Use HCV genotype determination in predicting
  therapy response

11
Case 1. cont.

• TB (disseminated form) may 2002
• Nadir CD4 cell count 1 per microL (May 02)
• VL 189 000 copies/ml (May 2002)
• Treated for TB with good response
• ART started in June 2002 (d4T3TC EFV)
• ART modified to ZDV3TCefavirenz (Dec 2003)

12
Case 1. cont.

• His HIV VL lt50 copies/ml CD4 cell count 459 (Sept
  2004)
• Should the patient be considered for HCV
  treatment?
• How do we evaluate HCV disease severity?

13
Evaluation of HCV disease severity

• Clinical evaluation of liver disease
• Biochemical parameters
• Child Pugh Score
• Ultrasound
• Histological evaluation (including noninvasive)

14
Non-invasive markers of liver fibrosis

• Non-invasive tools for assessing liver fibrosis,
  such as those based on serum markers (for
  example, FibroTest) or image technique (for
  example, FibroScan) are available.
• Recently, alternatives to biopsies have become
  available for coinfected patients, including a
  combination of biochemical tests indicating the
  degree of liver inflammation and fibrosis (such
  as the Forns index which has been recently
  validated for HIV/HCV coinfected patients) and an
  elastometric method reflecting the degree of
  fibrosis

15
Clinical situations not requiring liver biopsy

• The 1st European Consensus Conference did not
  consider biopsy mandatory when a decision to
  treat is imperative regardless of the result.
  Treatment is recommended, without biopsy or other
  liver assessment in the following situations
• infection with HCV genotype 2 or 3
• infection with HCV genotype 1 with a low viral
  load
• absence of major contraindications and patient
  willingness to undergo therapy the SVR is on the
  order of 40 to 60 in such cases
• Given the limitations of biopsy and the faster
  progression of fibrosis in HCV/HIV patients,
  treatment should also be offered when candidates
  for biopsy decline it or lack access to it

16
Evaluation of Comorbidities and Co-Conditions

• Psychiatric disorders
• Alcohol abuse
• Drug use

17
Case 1. cont

• HCV genotype 1
• HCV RNA 543 000 iu/ml (2004)
• HBV DNA undetectable
• Liver biopsy (Oct 2005)
• fibrosis 2/6
• piecemiel necrosis 2
• focal necrosis and inflamation 1
• portal inflamation 2

18
Case 1. cont.

• The patient is receiving zdv 3tc efavirenz
• What would you do?
• Nothing
• Discontinue HAART
• Change HAART

19
Consideration for Choice of HAART Regimen

• adherence (once daily regimen has to be
  favoured)
• hepatotoxicity of NNRTI (either and acute such
  as with NVP)
• drug interaction d4T, ddI and ZDV with RBV, EFV
  and PEG-IFN (severe depression)
• use of opioid substitution therapy (OST)
  pharmacokinetic interaction between NNRTI and
  methadone or buprenorphine (does adjustments)
• coexistent medical/psychiatric conditions

20
Contraindications for Hepatitis C treatment

• pregnancy, because of risk of IFN and RBV
• cardiopathy, such as ischemic disease and cardiac
  insufficiency
• psychiatric disorders or history of same
• active alcohol intake (gt 50g/day)
• decompensated cirrhosis (Child Pugh C)
• Since RBV may cause abnormalities in sperm, men
  taking it should wait six months after
  discontinuing use before attempting to impregnate
  a woman

21
Case 1. cont

• Abacavir lamivudin efavirenz

22
Case 1. summary

• A 31-year-old HIV and HCV co-infected man is
  evaluated for treatment of HCV. Labs- CD4 cell
  count 486 cells/mm3 (on ART)- HCV genotype 1-
  HCV RNA level of 380 687 iu/ml- Liver Bx 2
  fibrosis
• What would be the preferred therapy for his
  hepatitis C?1. Interferon ribavirin x 24
  weeks2. Peginterferon ribavirin x 24 weeks 3.
  Peginterferon ribavirin x 48 weeks4.
  Peginterferon ribavirin x 96 weeks

23
HIV/HCV Co-infection Study
AIDS PEGASYS Ribavirin International CO-Infection
Trial
24
Key Inclusion Criteria

• HCV criteria
• Naive to IFN and ribavirin
• HCV antibody positive
• Quantifiable HCV RNA (Amplicor MONITOR)
• Elevated serum ALT
• Liver biopsy (?15 months) consistent with HCV
  infection
• Non-cirrhotic or cirrhotic
• If cirrhotic, Child-Pugh Grade A

25
Key Inclusion Criteria

• HIV criteria
• HIV antibody or quantifiable HIV RNA
• CD4 cell count
• ?200/µL or
• ?100/µL to ?200/µL with ?5000 copies/mL HIV RNA
• Stable HIV disease with or without antiretroviral
  treatment

26
Treatment of HCV in HIV-Infected PersonsAPRICOT
TRIAL (Pegasys)
Study Design
SVR 24 Week Post-Treatment

• Background - N 868 - All with baseline
  biopsy
• Evaluation - SVR HCV RNAlt50 IU/ml at week 72
• Regimens (48 Weeks of Therapy) - INF alpha-2a
  Ribavirin - PEG-IFN alpha-2a - PEG-IFN
  alpha-2a Ribavirin

• Dosing- Interferon alpha-2a 3 million IU sq
  3x/week - Peginterferon alpha-2a 180 ug sq q
  week- Ribavirin 800 mg PO qd

DHS/PP
From Torriani FJ, et al. N Engl J Med
2004351438-50.
27
Treatment of HCV in HIV-Infected PersonsACTG
A5071 Study (Pegasys)
Study Design
SVR 24 Week Post-Treatment

• Background - N 133 - All with baseline
  biopsy
• Evaluation - SVR HCV RNA lt60 IU/ml at week 72
• Regimens (48 Weeks of Therapy) - INF alpha-2a
  Ribavirin - PEG-IFN alpha-2a Ribavirin

Dosing- Interferon alpha-2a 6 million IU sq
3x/week x 12 weeks, then 3 million IU sq
3x/week- Peginterferon alpha-2a 180 ug sq q
week- Ribavirin 800 mg PO qd
From Chung R, et al. N Engl J Med
2004351451-9.
DHS/PP
28
Summary HCV HIV Co-Infection Treatment Trials
SVR with Peginterferon Ribavirin x 48 Weeks
Peginterferon-2a
Peginterferon-2a
Peginterferon-2b
DHS/PP
29
Cross-study comparison of HCV treatment in HIV
patients (SVR, ITT)
non-GT1 GT 2 3 GT 1 4
SVR lt50 IU/mL at Wk 72
1. Torriani FJ, et al. 11th CROI, San Francisco
2004, 112 2. Perronne C, et al. ibid, 117LB
3. Chung R, et al. ibid, 110
30
Case 1. summary

• A 31-year-old HIV and HCV co-infected man is
  evaluated for treatment of HCV. Labs- CD4 cell
  count 486 cells/mm3 (on ART)- HCV genotype 1-
  HCV RNA level of 380687 iu/ml- Liver Bx 2
  fibrosis
• What would be the preferred therapy for his
  hepatitis C?1. Interferon ribavirin x 24
  weeks2. Peginterferon ribavirin x 24 weeks 3.
  Peginterferon ribavirin x 48 weeks4.
  Peginterferon ribavirin x 96 weeks

31
Case 1. cont.

• The patient (HCV Genotype 1) is started on
  peginterferon alpha-2b (120 ug once weekly) plus
  ribavirin (2x 400 mg). His 12 week HCV RNA level
  is 74 400 copies/ml (baseline pretreatment HCV
  RNA was 380 687).
• What can we predict regarding the sustained
  virologic response (SVR) based on this 12 week
  HCV RNA value? 1. The 12 week early virologic
  response (EVR) does NOT reliably predict SVR in
  HIV-infected patients2. He has approximately a
  30 chance of having a SVR 3. He has
  approximately a 15 chance of having a SVR4. He
  has less than 10 chance of having a SVR

32
12 Week Early Virologic Response (EVR) Predicts
SVR APRICOT TRIAL (Pegasys)
12 Week EVR- HCV RNA lt50 copies/ml OR- HCV
RNA decrease gt2 log
From Torriani FJ, et al. N Engl J Med
2004351438-50.
DHS/PP
33
Case 1. cont.

• The patient (HCV Genotype 1) is started on
  peginterferon alpha-2b (120 ug once weekly) plus
  ribavirin (2x 400 mg). His 12 week HCV RNA level
  is 74 400 copies/ml (baseline pretreatment HCV
  RNA was 380 687).
• What can we predict regarding the sustained
  virologic response (SVR) based on this 12 week
  HCV RNA value? 1. The 12 week early virologic
  response (EVR) does NOT reliably predict SVR in
  HIV-infected patients2. He has approximately a
  30 chance of having a SVR 3. He has
  approximately a 15 chance of having a SVR4. He
  has less than 10 chance of having a SVR

34
Case 2.

• A 41-year-old HIV and HCV co-infected woman is
  evaluated for treatment of HCV. Labs- CD4 cell
  count 362 cells/mm3 (no ARV)- HCV genotype
  2b- HCV RNA level 711 994 iu/ml- Liver Bx
  Stage 3 fibrosis
• What would recommend for therapy in this
  HIV-infected patient with HCV genotype 3?1.
  Peginterferon ribavirin x 12 weeks 2.
  Peginterferon ribavirin x 24 weeks 3.
  Peginterferon ribavirin x 48 weeks4.
  Peginterferon ribavirin x 72 weeks

35
Peginterferon Ribavirin for HCV Genotypes 2 or
3 48 Weeks versus 28 Weeks (Romance 2 Trial)
Study Design
SVR 24 Week Post-Treatment

• Background - N 128 - HCV HIV co-Infected
  - All with HCV genotype 2 or 3 - CD4 gt200 and
  HIV RNA lt10,000
• Regimen - Peginterferon alpha-2a ribavirin
• Evaluation - Week 24 HCV RNA (57 HCV RNA -)
  - Those with (-) HCV RNA randomized to stop
  therapy or receive 24 more weeks

From Zanini B, et al. 3rd IAS Path Treatment.
2005 MoPpLB0103.
DHS/PP
36
Case 3.

• A 29-year-old HCV and HIV co-infected woman is
  started on peginterferon alpha-2a (180 ug sq once
  weekly) plus ribavirin (400 mg bid) for HCV
  genotype 1. After 6 weeks of therapy, her Hb
  decreases from 14 to 10 g/dL. All other labs
  without a significant change. She weighs 71 kg.
• What would you recommend doing regarding the
  patients development of anemia? 1. No change
  needed Hb likely will improve in next 4 weeks2.
  Decrease ribavirin dose to 600 mg3. Start
  recombinant erythropoetin 40,000 units sq
  weekly4. Decrease peginterferon to 150 uq sq
  once weekly

37
Ribavirin Dosing During Therapy

• Impact of ribavirin dosing on SVR- Near or
  optimal ribavirin dose associated with better SVR
• Ribavirin target dosing- Dose gt800 mg/d OR gt10.6
  mg/kg/d- Most critical in first 20 weeks
• Use recombinant erythropoeitin/epotin alpha
  (EpogenProcrit)- Initiate for Hb lt12 g/dL-
  Dose 40,000 units sq once weekly increase to
  60,000 units sq once weekly if needed

38
Case 3.

• A 29-year-old HCV and HIV co-infected woman is
  started on peginterferon alpha-2a (180 ug sq once
  weekly) plus ribavirin (400 mg bid) for HCV
  genotype 1. After 6 weeks of therapy, her Hb
  decreases from 14 to 10 g/dL. All other labs
  without a significant change. She weighs 71 kg.
• What would you recommend doing regarding the
  patients development of anemia? 1. No change
  needed Hb likely will improve in next 4 weeks2.
  Decrease ribavirin dose to 600 mg3. Start
  recombinant erythropoetin 40,000 units sq
  weekly4. Decrease peginterferon to 150 uq sq
  once weekly

39
Side Effects of Interferon

• Flu-like symptoms
• Headache
• Fatigue or asthenia
• Myalgia, arthralgia
• Fever, chills
• Neuropsychiatric disorders
• Depression
• Mood lability
• Brain Fog

• Other effects
• Alopecia
• Thyroiditis
• Nausea
• Diarrhea
• Injection-site reaction
• Lab alterations
• Neutropenia
• Anemia
• Thrombocytopenia

PEGASYS (peginterferon alfa-2a) package
insert. Nutley, NJ Hoffmann-La Roche 2002.
PEG-Intron (peginterferon alfa-2b) package
insert. Kenilworth, NJ Schering Corporation
2001.
40
Side Effects of Ribavirin

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

COPEGUS (ribavirin, USP) package insert.
Nutley, NJ Hoffmann-La Roche 2002.
41
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42
Key issues in HCV/HIV patients

• not requiring hepatitis C or HIV/AIDS treatment
• requiring only hepatitis C treatment
• requiring only HIV/AIDS treatment
• requiring both hepatitis C and HIV/AIDS
  treatment

43
Key issues in HCV/HIV patients

• Coinfected patients not requiring any treatment
  have the following status
• CD4 count gt350 cells/mm3, absence of HIV related
  symptoms and
• HCV antibodies, but absence of HCV RNA
  replication.
• Coinfected patients requiring only HCV treatment
• CD4 count gt350 cells/mm3, absence of HIV related
  symptoms and
• Active or chronic hepatitis C.

44
Key issues in HCV/HIV patients

• Coinfected patients requiring only HIV/AIDS
  treatment
• CD4 count 350 cells/mm3 in symptomatic patients
  or those with viral load gt100 000 cop/ml or CD4
  count 200 cells/mm3 irrespective of symptoms and
• HCV antibodies but no HCV RNA replication or
• Hepatitis C with contraindications to treatment

45
Key issues in HCV/HIV patients

• Coinfected patients requiring both hepatitis C
  and HIV/AIDS treatment
• CD4 count 350 cells/mm3 in symptomatic patients
  or in those with viral load gt100 000 cop/ml or
  CD4 count 200 cells/mm3 irrespective of symptoms
  and
• Acute or chronic hepatitis C

46
Predicators of SVR Probability

• infection with genotype 2 or 3
• viral load 800 000 IU/ml
• absence of cirrhosis
• age lt40 years
• ALT levels gt3x ULN

47
Duration of treatment 48 weeks
48
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49
HIV and Hepatitis B
50
Evolutionary phases of chronic hepatitis B
infection
51
Classification of chronic hepatitis B virus
infection based on laboratory determinants
52
Interaction of HIV and HBV

• Impact of HIV on HBV infection
• HBV infection is more severe
• Higher HBV replication, more severe liver
  fibrosis, greater risk of cirrhosis and rapid
  progression to ESLD
• More aggressive HCC, and develops at earlier age
• HIV risk factor for reactivation of hepatitis B
  in patients who have developed HBsAb
• Increased risk for liver-related mortality
• No proof of HBV impact on HIV disease progression

53
Treatment of HBV in HIV coinfected patients

• Since no large-scale randomized controlled trials
  have been conducted to determine the efficacy of
  anti-HBV drugs in HBV/HIV coinfected patients,
  recommendations for treatment and monitoring need
  to be derived from the data that is available
  plus what is already known about the treatment of
  HBV mono-infected patients

54
Treatment options in HIV/HBV coinfected patients

• Interferon
• Peg
• Standard
• Lamivudine
• Adefovir
• Tenofovir
• Emtricitabine
• Entecavir

55
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56
Symptomatic patients with a CD4 count of 200350
cells/mm3

• The decision to treat for HBV is mainly based on
  HBV DNA levels.
• In HBeAg-positive patients with HBV DNA gt20 000
  IU/ml and HBeAg-negative patients with HBV DNA
  gt20 000 IU/ml, the ART regimen must include two
  dual-activity drugs (anti-HBV and anti-HIV)
• In patients with low levels of HBV DNA, an ART
  regimen containing two dual-activity drugs is
  optional but highly recommended in anticipation
  of an early switch due to a reactivation of
  hepatitis

57
HBV treatment in patients with CD4 count lt200
cells/mm3

• ART regimen for these patients should include two
  dual-activity drugs in order to minimize the risk
  of HBV reactivation.