Hepatitis and HIV

1
Hepatitis and HIV

• Catherine Creticos, M.D.
• August, 2007

2
Case study 1

• D. M. is a 38 y.o. man who has recently
  immigrated from India to join his wife who works
  as a nurse in the U.S. As part of the
  immigration process, he was tested for HIV and
  found to be positive. He has a history of
  multiple dental surgeries in India, but otherwise
  no medical problems. He denies a history of any
  sexual partners except his wife, who is HIV
  negative. Upon initial evaluation in the U.S.
  liver enzymes are minimally elevated. Further
  studies reveal HAV IgG, HBsAg, HBsAb-,
  HBcAb(IgG), HBeAg, HBeAb-, HCVAb-

3
Hepatitis B Virus Infection

• gt300 million chronically infected worldwide
• Established cause of chronic hepatitis and
  cirrhosis
• Human carcinogencause of up to 80 of
  hepatocellular carcinomas

4
Hepatitis B Clinical Features

• Incubation period 60-150 days (average 90 days)
• Nonspecific prodrome of malaise, fever, headache,
  myalgia
• Illness not specific for hepatitis B
• At least 50 of infections asymptomatic

5
Hepatitis B Complications

• Fulminant hepatitis
• Hospitalization
• Cirrhosis
• Hepatocellular carcinoma
• Death

6
Chronic Hepatitis B Virus Infection

• Chronic viremia
• Responsible for most mortality
• Overall risk 10
• Higher risk with early infection

7
High Viral Load Predicts Poor Outcomes

• Large, long-term, prospective cohort studies have
  linked high viral load with poor outcomes
• Haimen City Cohort Chen G, et al. Am J
  Gastroenterol. 20061011797-1803.
• Fox Chase Cancer Center Cohort Study Evans AA,
  et al. AASLD 2004. Abstract 144.
• R.E.V.E.A.L Study GroupChen CJ, et al. JAMA.
  200629565-73.Iloeje UH, et al.
  Gastroenterology. 2006130678-686.

8
Haimen City Cohort Viral Load and Mortality From
Liver Disease

• 10-year prospective cohort study in Haimen City
• Permanent cohort of 83,794 subjects established
  1992-1993
• 2354 subjects included in HBV mortality analysis
• Serum HBV DNA tested on baseline samples
• Mortality information from death certificate
  records
• 448 deaths (231 HCC, 85 CLD, and 132 nonliver
  deaths)

CLD, chronic liver disease HCC, hepatocellular
carcinoma.
Chen G, et al. Am J Gastroenterol.
20061011797-1803.
9
Haimen City Increased RR of HCC and CLD
Mortality With High Viral Load
Baseline HBV DNA (copies/mL)
Low ( 1. 6 x 103 - lt 105)
High ( 105)
1.2 (0.6-2.3)
Nonliver (n 132)
1.0 (0.5-1.8)
15.2 (2.1-109.8)
CLD (n 85)
Cause of Death
1.5 (0.2-12.1)
11.2 (3.6-35.0)
HCC (n 231)
1.7 (0.5-5.7)
0
5
10
15
20
Relative Risk (95 CI)
P trend lt .001Reference HBV DNA lt 1.6 x 103
copies/mL, adjusted for age and sex
Chen G, et al. Am J Gastroenterol.
20061011797-1803.
10
Fox Chase Center Cohort Association Between
Viral Load and HCC

• 3754 HBV-infected Asian American adults in
  Philadelphia
• Nested case-control study
• 27 case subjects diagnosed with HCC
• Median age 54 years (range 42-74)
• Case entry lt 1-17 years (median 3) prior to HCC
  diagnosis
• 51 control subjects
• Median age 56 years (range 44-77)
• HBV DNA quantified with real-time PCR

Randomly selected from non-HCC subjects and
matched for age, sex, and year of study entry but
not race
Evans AA, et al. AASLD 2004. Abstract 144.
11
Fox Chase High HBV DNA Associated With Increased
Risk of HCC
Relative Risk of HCC According to Baseline Viral
Load (n 51 controls n 27 cases)
High HBV DNA ( 105 copies/mL)
9.8 (2.3-42.7)
Low HBV DNA (104 - lt 105 copies/mL)
2.1 (0.4-10.0)
Undetectable (lt 104 copies/mL)
Reference
0
5
10
15
Relative Risk (95 CI) of HCC
Conditional on the matching variables
Evans AA, et al. AASLD 2004. Abstract 144.
12
Risk Evaluation of Viral Load Elevation
Associated Liver Disease/Cancer Study

• REVEAL prospective, multicenter, observational
  cohort study

7 Taiwanese townships individuals aged 30-65
years eligible (N 89,293)
1991-1992 recruitment
HCC-free individuals enrolled (N 23,820)
Insufficient serum for tests or HBsAg(-)
HBsAg() with adequatebaseline HBV DNA sample (N
3851)
HCV seropositive or diagnosed with cirrhosis or
died within 6 months of entry
HCV seropositive
Cirrhosis analysis (n 3582)
HCC analysis (n 3653)
HCC follow-up 41,779 PYs Cirrhosis follow-up
40,038 PYs
Chen CJ, et al. JAMA. 200629565-73. Iloeje UH,
et al. Gastroenterology. 2006130678-686.
13
REVEAL High HBV DNA Associated With Increased
HCC Incidence
Relationship Between Baseline HBV DNA and HCC
IncidenceAll Participants (N 3653)
50
40
30
Cumulative Incidence of HCC at Year 13 Follow-up
()
20
14.89
12.17
10
3.57
1.37
1.30
0
300- 999
1000- 9999
10,000- 99,999
lt 300
100,000
HBV DNA at Baseline (copies/mL)
Chen CJ, et al. JAMA. 200629565-73.
14
REVEAL High HBV DNA Associated With Increased
Incidence of Cirrhosis
Relationship Between Baseline HBV DNA and
Cirrhosis Incidence All Participants (N 3582)
50
40
36.2
30
23.5
Cumulative Incidence of Cirrhosis at Year 13
Follow-up ()
20
9.8
10
5.9
4.5
0
10,000- 99,999
300- 9999
100,000- 999,999
1,000,000
lt 300
HBV DNA at Baseline (copies/mL)
Iloeje UH, et al. Gastroenterology.
2006130678-686.
15
HBV viral load and disease progression - summary

• The higher the viral load, the greater the risk
  for development of cirrhosis, its complications,
  and HCC
• Disease can progress even when HBV DNA is lt 104
  copies/mL ( 2000 IU/mL)
• Continued suppression of HBV DNA decreases
  fibrosis and delays disease progression

16
Goals of Hepatitis B Therapy

• Primary goal suppress HBV DNA to the lowest
  possible level to achieve
• Prevention of liver disease progression to
  cirrhosis
• Prevention of liver failure and HCC
• Prevention of liver diseaserelated
  transplantation or death
• HBV DNA suppression leads to
• Histologic improvement
• ALT normalization
• HBeAg loss and seroconversion
• HBsAg loss and seroconversion

17
Goals of Therapy 2 Distinct Patient Populations

• HBeAg positive (wild type)
• HBeAg loss ? seroconversion
• Durable suppression of HBV DNA to lowest possible
  levels
• Therapy discontinued after seroconversion
  durability of response 80
• HBeAg negative (precore and core promoter
  mutants)
• HBeAg seroconversion not an endpoint
• Durable suppression of HBV DNA to lowest possible
  levels
• Relapse common after stopping oral therapy
  therapy usually administered long term

18
Reversal of Fibrosis With Long-termNucleos(t)ide
Analogue Therapy

• Paired biopsies from before, after 3 years of
  lamivudine(N 63)
• HAI necroinflammatory scores
• 56 improved by 2 points
• 33 had no change
• 11 had worsening (YMDD mutations blunted the
  response)
• Fibrosis
• 63 (12/19) had improvement in bridging fibrosis
  by 1
• 73 (8/11) had improvement in cirrhosis (score 4
  ? 3)
• Only 2 (1/52) had progression to cirrhosis and
  9 (3/34) to bridging fibrosisall with YMDD
  mutations

Dienstag J, et al. Gastroenterology.
2003124105-117.
19
Reversal of Fibrosis With Long-termNucleos(t)ide
Analogue Therapy

• 47 HBeAg-negative patients treated with up to 2
  years of adefovir
• Fibrosis by rank assessment at Week 96
• Mean reduction with continued adefovir 0.63
  1.07 (P .031 compared with adefovir ? placebo
  group)

96 Wks Continued Adefovir (n 19) 96 Wks Continued Adefovir (n 19) 48 Wks Adefovir ? 48 Wks Placebo (n 8) 48 Wks Adefovir ? 48 Wks Placebo (n 8) 48 Wks Placebo ? 48 Wks Adefovir (n 20) 48 Wks Placebo ? 48 Wks Adefovir (n 20)
Wk 48 Wk 96 Wk 48 Wk 96 Wk 48 Wk 96
Inflammation change - 4.2 - 4.3 - 3.8 - 0.9 - 0.6 - 2.3
Hadziyannis SJ, et al. N Engl J Med.
20053522673-2681.
20
Delayed Disease Progression With Continued
Suppression Cirrhotics

• 651 cirrhosis patients with evidence of viral
  replication

Placebo (n 215) Lamivudine (n 436)
P .001
25
21
20
15
Patients With Disease Progression at Follow-up
9
10

• Child-Pugh score P .02 HCC P .047
• Benefit reduced with YMDD emergence

5
0
5 cases of HCC in Year 1 excluded, P .052
Liaw YF, et al. N Engl J Med. 20043511521-1531.
21
Delayed Disease Progression With Continued
Suppression Noncirrhotics

• 142 noncirrhotic patients on continuous
  lamivudine for a median of 89.9 months vs 124
  untreated controls

Placebo Lamivudine
P .005
14
12
10
8
Percentage of Patients With Cirrhosis/HCC
6
4
2
0
Yuen MF, et al. AASLD 2005. Abstract 985.
22
Conclusions

• Prolonged viral suppression with nucleos(t)ide
  analogues
• Reduces necroinflammation
• Reverses fibrosis and cirrhosis
• Decreases cirrhotic complications and HCC in both
  cirrhotic and precirrhotic patients

23
HBV DNA as a Marker of Efficacy During Treatment
of HBV

• Literature analysis of 26 prospective studies
• Investigation of the relationship between
  treatment-induced changes in HBV DNA, histology,
  other disease activity markers
• Results
• Statistically significant and consistent
  correlations between HBV DNA, histology,
  biochemical and serologic responses
• HBV DNA had broader dynamic range than histology
• Conclusion
• Treatment-induced reduction in HBV DNA can be
  used to assess efficacy
• Treatment goal should be profound and durable
  suppression of HBV DNA

Mommeja-Marin H, et al. Hepatology.
2003371309-1319.
24
Correlation Between HBV DNA Levels and Markers of
Liver Disease (contd)

• Necroinflammation correlated with
• HBV DNA levels in untreated patients (r 0.78 P
  .001)
• HBV DNA levels at the end of treatment (r 0.71
  P .003)
• HBeAg seroconversion correlate with change in
  median HBV DNA from baseline to end of treatment
  (r 0.72, P lt .0002)
• Normalized ALT post treatment correlated with HBV
  DNA level (r 0.62, P .0004)

Mommeja-Marin H, et al. Hepatology.
2003371309-1319.
25
Entecavir Superior to Lamivudine in
HBeAg-Positive Patients
Entecavir (n 354)
Lamivudine (n 355)
Histologic Improvement Through Week 48
HBV DNA lt 300 copies/mL Through Week 96
HBeAg Seroconversion Through Week 96
100
100
100
P lt .0001
P .009
80
80
80
80
72
62
60
60
60
P NS
Patients ()
39
40
40
40
31
26
20
20
20
(n 354)
(n 355)
(n 354)
(n 355)
(n 314)
(n 314)
0
0
0
Cumulative confirmed data 2 data points or last
observation on therapy. Cumulative confirmed
data through last observation and 6 months off
treatment.
Gish RG, et al. Hepatology. 200542267A.
26
Long-term Entecavir in HBeAg-Negative Patients
Entecavir
Lamivudine
Histologic Improvement Through Week 48
HBV DNA lt 300 copies/mL Through Week 96
P lt .0001
100
100
94
P .01
77
80
80
70
61
60
60
Patients ()
40
40
20
20
(n 287)
(n 325)
(n 313)
(n 296)
0
0
Cumulative confirmed data 2 data points or last
observation on therapy.
Shouval D, et al. EASL 2006. Abstract 45. Lai C,
et al. N Engl J Med. 20063541011-1020.
27
Clinical Efficacy 2-Year ResultsTelbivudine vs
Lamivudine
HBeAg() HBeAg() HBeAg(-) HBeAg(-)
Response LdT (n 458) LAM (n 463) LdT (n 222) LAM (n 224)
Mean HBV DNA reduction, log10 copies/mL -5.7 -4.4 -5.0 -4.2
HBV DNA undetectable, 56 39 82 57
ALT normalization, 70 62 78 70
Therapeutic response, 64 48 78 66
HBeAg loss, 35 29 - -
HBeAg seroconversion, 30 25 - -
Primary treatment failure, 4.0 12.3 0 2.7
P .05 vs lamivudine.
Lai C, et al. AASLD 2006. Abstract 91.
28
Week 52 Histologic OutcomesTelbivudine vs
Lamivudine
HBeAg Positive Patients
HBeAg Negative Patients
100
7
8
12
15
Missing Week 52
23
25
80
19
biopsy
26
Histologic Response ()
60
No improvement
40
69
69
68
60
Improvement
20
0
LdT
LdT
LAM
LAM
Lai C, et al. AASLD 2006. Abstract 91.
29
Peginterferon alfa-2a in HBeAg-Positive Chronic
Hepatitis B Patients
HBV DNA Levels 1 Year Post treatment According to
Type of Initial Response
100
HBV DNA 1 year post treatment (copies/mL)
21
29
80
7
60
29
33
gt 100,000
Patients ()
96
10,001-100,000
40
21
401-10,000
20
39
400
21
0
Early, Sustained HBeAg Seroconversion
Late HBeAg Seroconversion
No HBeAg Seroconversion
(n61)
(n15)
(n88)
Lau GK, et al. EASL 2006. Abstract 50.
30
Histologic Improvement With Peginterferon Therapy
HBeAg-Positive Patients
HBeAg-Negative Patients
100
80
59
58
PegIFN
52
60
51
49
48
Histologic Improvement ()
PegIFN LAM
40
LAM
20
0
Lau GK, Piratvisuth T, Luo KX, et al. N Engl J
Med. 2005. 303522682-2695. Marcellin P, Lau
GK, Bonino F, et al. N Engl J Med. 2004.
163511206-1217.
31
HBV DNA and HBeAg Seroconversion at Year 1 in
HBeAg() Patients
Data from individual studies, not direct
comparisons (different populations, baseline
values, HBV DNA assays)
PegIFN
LAM
ADV
ETV
LdT
30
27
23
21
HBeAg Seroconversion,
18
20
12
10
0
0
Log10 Decrease in HBV DNA
-3.6
-4.0
-5.8
-6.5
-6.9
-10
Lau et al. N Engl J Med. 20053522682-2695.
Dienstag et al. N Engl J Med. 19993411256-1263.
Marcellin et al. EASL 2005. Abstract 73. Lai et
al. AASLD 2005. Abstract 72404. Chang et al.
AASLD 2004. Abstract 70. Entecavir package
insert. Telbivudine package insert.
32
Emtricitabine impact on HBV in HBV/HIV coinfection

• Data analyzed from HIV/HBV coinfected individuals
  enrolled in three Gilead studies designed to
  evaluate the safety and efficacy of FTC as part
  of HAART in treatment-naïve patients
• Anti-HIV and anti-HBV effects of FTC in these
  individuals evaluated

33
Emtricitabine effective against HBV

• 39 patients from 3 studies
• Baseline median HBV viral load gt500,000 copies/mL
  
• Week 24 HBV viral load undetectable in 45 59
  at week 48
• HIV viral load undetectable at week 24 in 97,
  94 at week 48
• In a separate study, undetectable HBV viral load
  was achieved in 59 of monoinfected individuals
  at 48 weeks.
• 12 incidence of drug-resistant HBV at week 48 in
  coinfected individuals with detectable HBV viral
  load at baseline

Snow A, Harris J, Borroto-Esoda K, et al. CROI
2004 Poster 836
34
Tenofovir active against HBV in coinfected
individuals

• Tenofovir has potent activity against HBV in
  vitro and in retrospectively analyzed
  HIV/HBV-coinfected patients
• Study to assess long-term HBV dynamics and
  influence of baseline factors on HBV load in
  HIV/HBV-coinfected patients beginning
  tenofovir-based HAART

Lacombe K, Gozlan J, Boelle PY, et al. AIDS.
200519907-915
35
Summary of Study Design

• Subgroup of patients enrolled in French
  multicenter prospective HIV-HBV Cohort Study used
  in analysis
• Child-Pugh score determined in cirrhotic patients
  at beginning and end of follow-up
• HBV DNA and biochemical data measured at least
  once during first month and then at least once
  every 3 months thereafter

36
Baseline Characteristics

• N 28
• Median duration HIV infection, 11.1 years (range,
  0.01-17.7 years)
• Median duration HBV infection, 7.0 years (range,
  0.01-16.9 years)
• Median HIV-1 RNA, 3.81 log10 copies/mL (range,
  1.4-5.7 log10 copies/mL)
• Median HBV DNA, 7.75 log10 copies/mL (range, 3-10
  log10 copies/mL)

37
Main Findings

• HBV DNA declined from baseline by mean of 4.6
  log10 copies/mL with tenofovir treatment (P lt
  .001)
• HBV DNA undetectable (lt 200 copies/mL) in 21
  (87.5) patients
• Median time until undetectable, 272.5 days (95
  confidence interval CI, 203.5-416.0)
• 4 of 24 (16.7) HBeAg-positive patients at
  baseline lost HBeAg and seroconverted to
  hepatitis B antibodies
• No incidence of grade 3/4 adverse events

38
Main Findings

• Tenofovir-based HAART also had significant impact
  on HIV-1 RNA, ALT
• HIV-1 RNA declined from baseline by mean of 1.4
  log10 copies/mL (P lt .0001)
• Undetectable HIV-1 RNA (lt 50 copies/mL) increased
  from 22 of patients at baseline to 75
• Mean ALT declined from 125 to 50 IU/mL (P lt .05)

39
Key Conclusions

• Tenofovir demonstrates potent activity against
  HBV in HIV/HBV-coinfected patients and shows
  marked impact on liver function by decreasing ALT
  activity
• Significant decline in HIV-1 RNA also observed
• Tenofovir well tolerated
• Long-term HBV dynamics not affected by
  concomitant receipt of lamivudine, HBV genotype,
  or HIV-related immunosuppression

40
Treatment of HBV with TDF or ADV

• Nonrandomized, open label study of TDF vs. ADV in
  85 HIV-HBV co-infected patients
• ADV (n29), TDF (n56)
• Tx-naive, except for past or current 3TC as part
  of ARV regimen.
• TDF superior regarding antiviral and biochemical
  responses
• More rapid HBV DNA decline and a greater decline
  at 12 mos. (plt0.0001)
• Greater decreases in transaminases
• After adjustment of HBeAg status, HBV-DNA at
  baseline and level of ALT at baseline, TDF
  associated with a higher rate of patients
  achieving undetectable HBV-DNA levels

1.00
P0.04
0.75
Proportion with lt200 copies/mL
0.50
TDF
.025
ADV
0.00
0
1
0
2
0
3
0
4
0
Time to HBV-DNA undetectability (months)
Lacombe Burman W, et al. 14th CROI, Los Angeles,
CA, February 25-28, 2007. Abst. 945.
41
Conclusions

• HBV DNA suppression with anti-HBV therapy
  improves patient outcomes
• Continued benefits are observed with long-term
  HBV therapy
• Resistance diminishes the benefits of treatment
• More potent viral suppression can lead to greater
  patient outcomes
• HBeAg seroconversion
• ALT normalization
• Long-term virologic response
• Lower risk of resistance

42
HBV Resistance

• HBV resistance can be delayed
• By using highly potent antivirals
• By improving adherence
• By using combination therapies
• When resistance occurs
• Consider add-on therapy rather than switching to
  second monotherapy
• Consider using the most potent available
  antiviral combination

43
2006 NIH Workshop on the Management of CHBWho
Should Receive Treatment?
HBsAg Positive
HBeAg
Decompensated cirrhosis
Inactive carrier/mild chronic hepatitis
Pos
Neg
HBV DNA lt 104 IU/mL ALT normal 3-6 months
Grey zone
HBV DNA gt 104 IU/mL elevated ALT 3-6 months
Consider antiviral therapy/ refer for OLT
Consider Liver biopsy
Consider antiviral therapy
Monitor every 3-6 months
44
Interferon Therapy

• Pros
• Finite duration of therapy
• Durable response
• No resistance or cross resistance
• Cons
• Route of administrationinjection
• Frequent side effects
• Cost

45
Ideal Clinical Situation for IFN Therapy

• High ALT (gt 5 x ULN) and low HBV DNA level (lt
  200,000 IU/mL)
• Younger patient
• Black
• Well-compensated cirrhosis
• No contraindications to use of interferon
• ? Genotype A or B
• ?HIV/HBV with high CD4, low HIV-RNA

46
Lamivudine

• Pros
• Oral
• Negligible side effects
• Excellent safety profile
• Low cost
• Cons
• High rate of resistance and cross-resistance with
  other nucleoside analogues
• Long/indefinite duration of therapy
• Cannot be used as monotherapy in HIV/HBV

47
Ideal Clinical Situation for Lamivudine Use

• Short duration of therapy
• Prevention of disease flares/reactivation during
  chemotherapy
• Protracted or severe acute hepatitis
• Safety a concern
• During pregnancy
• Cost a concern
• HBeAg-negative CHB in developing countries

48
Lamivudine in HAART Regimen

• Lamivudine used in HAART regimen for coinfected
  individual may result in the development of HBV
  resistance mutations
• If HAART interrupted or changed, anticipate flare
  in HBV/hepatitis if lamivudine also stopped

49
Adefovir

• Pros
• Route of administration oral
• Low rate of resistance
• Effective against lamivudine resistant virus
• Can be used as monotherapy in HIV/HBV without
  inducing HIV resistance mutations
• Cons
• Slow response and high rate of primary
  nonresponse
• ? Renal toxicity with long-term use
• Long/indefinite duration of therapy

50
Ideal Clinical Situation for Adefovir Use

• HBeAg-positive and HBeAg-negative chronic
  hepatitis B with low HBV DNA
• Management of lamivudine-resistant chronic
  hepatitis B
• HIV/HBV coinfected individual not requiring HAART

51
Entecavir

• Pros
• Route of administration oral
• Potent with low rate of resistance
• Effective against LAM-R
• Cons
• Long-term safety unknown
• Long/indefinite duration of therapy
• Cannot be used in HIV/HBV coinfected patient not
  on HAART will select for M184V mutation

52
Ideal Clinical Situation for Entecavir Use

• HBeAg-positive or HBeAg-negative chronic
  hepatitis B with high viral load
• Management of lamivudine resistance
• Can be used in HIV/HBV coinfection in patients
  who are on HAART if preferable to other HBV agents

53
FTC and TDF for HIV/HBV Coinfected Individuals

• Evidence supports benefit of this combination for
  coinfected individuals requiring both HIV and HBV
  treatment
• Should be used in combination with a fully HIV
  suppressive regimen
• If HAART regimen interrupted or altered,
  anticipate potential HBV flare if FTC and/or TDF
  withdrawn without continued HBV suppression

54
Case Study 1 cont.

• Additional laboratories
• CD4 372
• HIV RNA 86,000
• HBV DNA gt500,000
• Treatment options
• Treat HBV, not HIV
• Adefovir
• Telbivudine
• Interferon
• Treat both HBV and HIV
• Tenofovir and epivir or emtricitabine in a HAART
  regimen
• Monitor both HBV and HIV off treatment

55
Case Study 2

• C. T. is a 53 y.o. man with a history of paranoid
  schizophrenia and alcohol and cocaine use. He
  continues to actively use both substances, but
  not IV cocaine. He has been HIV and HCV positive
  for the last 10 years CD4 nadir at time of
  diagnosis was 125. He has been extremely
  adherent to HAART over the last 10 years,
  including a difficult indinavir-containing
  regimen, maintaining an undetectable HIV RNA for
  the last 9 years, and CD4 above 600 for most of
  that time. He has had 2 liver biopsies for
  staging of liver disease (3 and 1 year ago), that
  have both show stage 1 fibrosis. His
  transaminases fluctuate in the 80-100 range. He
  is anxious to treat his hepatitis C, but although
  he is extremely adherent to his HAART regimen,
  refuses to take any psychiatric medications.

56
Hepatitis C

• Identified in 1989
• Now recognized as the primary cause of
  non-A/non-B hepatitis
• Most common blood borne infection in the US
• 3.9 million people infected
• 36,000 new cases annually
• 10,000 deaths annually
• Causes 40 of chronic liver disease in the US
• Leading indication for liver transplantation -
  10,000 per year

57
Screening for HCV disease

• EVERYONE who is HIV positive should be screened
  for HCV - similar risk factors
• Children born to women with suspected chronic HCV
  infection at the time of the delivery should be
  screened for HCV infection (risk approximately
  5)
• History of acute hepatitis - HAV, HBV, and HCV
• Injection drug users

58
Serologic Tests for HCV

• Anti-HCV by EIA-3
• May be negative in immunocompromised patients or
  acute HCV infection
• HCV RNA by PCR
• Recombinant Immunoblot Assay (RIBA)
• Quantitative PCR and branched DNA (bDNA)

59
Acute HCV Infection

• Asymptomatic - 60-70
• Jaundice - 20-30
• Non-specific symptoms - 20-30
• Anorexia, malaise, or abdominal pain
• Time from exposure to symptoms - 6-7 weeks
• Time from exposure to seroconversion 8-9 weeks
• Anti-HCV can be detected in 80 of patients
  within 15 weeks after exposure
• gt90 within 5 months
• gt97 within 6 months
• Rarely is seroconversion delayed gt9 months

60
Serologic Pattern of Acute HCV Infection with
Recovery
61
Chronic HCV Infection

• HCV RNA detectable in the blood for gt 6 months
• 60-85 of acutely infected will become chronic
• Most do not have symptoms
• Some may experience fatigue, mild RUQ
  discomfort or tenderness, nausea, poor appetite,
  muscle and joint pains

62
Serologic Pattern of Acute HCV Infection with
Progression to Chronic Infection
anti-HCV
Symptoms /-
HCV RNA
Titer
ALT
Normal
6
1
2
3
4
0
1
2
3
4
5
Years
Months
Time after Exposure
63
Factors Influencing the Progression of HCV

• Older age at time of infection
• Male gender
• Immunocompromised state
• Concurrent infection with HBV
• Alcohol intake
• Men - 30 g/day (2 beers, 2 glasses of wine, 2
  mixed drinks)
• Women - 20 g/day
• Other - iron overload, nonalcoholic fatty liver
  disease, schistosomal co-infection, hepatotoxic
  medications, environmental contaminants

64
Prognosis of Untreated HCVVariable Course and
Outcome

• No symptoms - 50-80
• Liver biopsy with some chronic hepatitis changes
• Good prognosis
• Severe hepatitis - 20-50
• HCV RNA detectable
• Elevated liver enzymes
• Within 10-20 years, 15 will develop cirrhosis
  and ESLD
• 1-4 will develop hepatocellular carcinoma

65
Epidemiology and Natural History of HIV/HCV
Co-infection

• Prevalence - 33 of all HIV infected persons have
  HCV
• Injection drug users - 60 - 90
• Persons with hemophilia - 85 (blood products
  prior to 1985)
• Homosexual men - 4 - 8

66
Natural History of HCV disease in HIV-infected
persons

• HIV infection - significant co-factor for
  HCV-related liver disease and mortality
• HCV-related fibrosis is accelerated in persons
  with HIV-infection
• Impact of HCV disease will increase as
  HIV-related mortality declines due to the use of
  HAART and OI prophylaxis

67
Effect of HCV on HIV

• HCV may hasten progression to AIDS or death
• May impair immune reconstitution following
  initiation of HAART
• More frequent vertical transmission
• Increased risk of hepatotoxicity from HAART

68
Effect of HIV on HCV

• May have false negative anti-HCV EIA results
• Vertical transmission of HCV in increased
• May increase sexual transmission of HCV
• Higher HCV viremia
• Associated with higher HIV RNA levels and lower
  CD4 counts
• Increases rate of fibrosis
• Increased rate of HCV-related liver disease
  (cirrhosis, ESLD, HCC)

69
In the Co-Infected Patient

• Higher risk of toxicity associated with IFN
  therapy with patients on HAART
• Early treatment is key to successful management
• HCV must be evaluated and treated before the
  development of ESLD

70
Goals of HCV Therapy

• Eliminate HCV RNA
• Delay progression of fibrosis
• Prevent liver decompensation, HCC, and death
• Improve tolerance and effectiveness of HAART
• Permit aggressive ART
• Potentially enhance immune reconstitution

71
HAART reduces liver fibrosis progression in
HIV/HCV coinfected individuals

• Liver biopsies performed on 296 coinfected
  patients who had not received therapy for HCV
• Data analyzed from 213 patients on whom date of
  HCV infection could be ascertained
• Logistic regression analysis done to assess the
  association between time on HAART and fibrosis
  progression index (ratio of fibrosis stage to
  years of HCV infection)
• Results HAART reduces the fibrosis progression
  rate and the development of bridging fibrosis and
  cirrhosis in HIV-HCV coinfected patients

S Resino, J Berenguer, P Miralles et al., CROI
2007, Abstract 935
72
In the Co-Infected Patient

• Higher risk of toxicity associated with IFN
  therapy with patients on HAART
• Early treatment is key to successful management
• HCV must be evaluated and treated before the
  development of ESLD

73
HCV/HIV Co-infection Who should be treated?

• All patients with HIV and HCV should be
  considered for treatment
• Patients with well controlled HIV disease
• HIV RNA undetectable and CD4 count gt 200
  cells/mm3
• Patients with advanced liver disease by biopsy

74
HCV Treatment Options

• Interferon alfa monotherapy
• Interferon alfa-2b (Intron A)
• Interferon alfa-2a (Roferon-A)
• Interferon alfacon-1 (Infergen)
• Pegylated interferon monotherapy
• Peginterferon alfa-2b (PEG-Intron)
• Peginterferon alfa-2a (PEGASYS)
• Pegylated interferon combination therapy
• Peginterferon alfa-2b plus ribavirin
• Peginterferon alfa-2a plus ribavirin

75
HIV/HCV Coinfection TrialsPEG IFN and RBV
Study Treatment Regimen
RIBAVIC France (N 412) PEG IFN alfa-2b 1.5 µg/kg RBV 800 mg IFN alfa-2b 3 MIU RBV 800 mg
ACTG 5071 USA (N 133) PEG IFN alfa-2a 180 µg RBV 600 mg x 4 wks, then 800mg x 4 wks, then 1 g/d IFN alfa-2a 6 MIU x 12 wks ? 3 MIU RBV 600 mg x 4wks, then 800mg x 4wks, then 1 g/d
APRICOT International (N 868) PEG IFN alfa-2a 180 µg RBV 800 mg IFN alfa-2a 3 MIU RBV 800 mg PEG IFN alfa-2a 180 µg RBV placebo 800 mg
ACTG, AIDS Clinical Trials Group APRICOT, AIDS
PEGASYS Ribavirin International CO-Infection
Trial. Chung et al. N Engl J Med.
2004351451-459. Perronne et al. 11th CROI.
February 8-11, 2004 San Francisco, Calif.
Abstract 117LB. Torriani et al. N Engl J Med.
2004351438-450.
76
ACTG 5071 Overall Results
(N133)


SVR HCVlt60 IU/mL 24 weeks after end of therapy
(EOT). P.0001 versus IFN 2a RBV. Plt.03
versus IFN 2a RBV.
Chung R et al. Presented at 11th Conference of
Retroviruses and Opportunistic Infections No.
110.
77
ACTG 5071 PEG a-2a RBV Arm by Genotype


P.0007 vs Genotype 1.
Chung R et al. Presented at 11th Conference of
Retroviruses and Opportunistic Infections No.
110.
78
ACTG 5071 Summary

• Predictors of sustained virologic response
  included PEG a-2a RBV treatment, HCV genotype
  non-1, no previous IDU, and detectable HIV-1 RNA
  at entry
• PEG-IFN a-2a RBV was more effective treatment
  than standard IFN RBV
• Even in virologic nonresponders, 36 had a
  histological response

IDU injection drug use. Chung R et al.
Presented at 11th Conference of Retroviruses and
Opportunistic Infections No. 110.
79
APRICOT Virologic ResponseEnd of Treatment
Versus End of Follow-up (Genotype 1)
Response
PEG-IFN a-2a(40 kDa) Placebo
PEG-IFN a-2a (40 kDa) RBV
IFN a-2a RBV
Defined as lt50 IU/mL HCV RNA. Torriani FJ et al.
Presented at 11th Conference of Retroviruses and
Opportunistic Infections No. 112.
80
APRICOT Virologic ResponseEnd of Treatment
Versus End of Follow-up (Genotypes 2 and 3)
Defined as lt50 IU/mL HCV RNA.
Torriani FJ et al. Presented at 11th Conference
of Retroviruses and Opportunistic Infections No.
112.
81
APRICOT Median Change in CD4 Counts From
Baseline
?
?
?g
?
?g
Median Change From Baseline in CD4 Count
(cells/?L)
BL
Time (Weeks)
Patients receiving 48 weeks of treatment.
Torriani FJ et al. Presented at 11th Conference
of Retroviruses and Opportunistic Infections No.
112.
82
APRICOT Change in HIV RNA From Baseline All
Patients Treated
?
?g
?
?
?g
Change in Log10 HIV RNA
BL
Time (Weeks)
Patients receiving 48 weeks of treatment.
Torriani FJ et al. Presented at 11th Conference
of Retroviruses and Opportunistic Infections No.
112.
83
APRICOT Summary

• SVR was significantly higher for PEG-IFN a-2a (40
  kDa) RBV compared with conventional
  combination therapy
• Overall 40 versus 12 P lt.0001
• Genotype 1 29 versus 7
• Genotype 2/3 62 versus 20
• Adverse event profile of PEG-IFN a-2a (40kDa)
  RBV is generally similar to IFN RBV therapy
• Only 15 to 16 of patients discontinued for
  adverse events or laboratory abnormalities

Torriani FJ et al. Presented at 11th Conference
of Retroviruses and Opportunistic Infections No.
112.
84
French ANRS RIBAVIC Study

• Randomized, multicenter, open-label study in
  HIV-HCV coinfected patients with CD4gt200 and
  stable HIV RNA for 48 weeks on
• PEG-IFN a-2b 1.5 ?g/kg/wk RBV (n205), or
• Standard IFN-2b 3 MIU tiw RBV 800 mg QD (n207)
• Primary efficacy end point was SVR (undetectable
  HCV RNA) at week 72

Perronne C et al. Presented at 11th Conference
of Retroviruses and Opportunistic Infections No.
117LB.
85
RIBAVIC SVR at Week 72
P.031
Perronne C et al. Presented at 11th Conference
of Retroviruses and Opportunistic Infections No.
117LB.
86
RIBAVIC Response Rates Patients Who Did Not
Discontinue Treatment
Perronne C et al. Presented at 11th Conference
of Retroviruses and Opportunistic Infections No.
117LB.
87
HIV/HCV Infection TrialsSVR (combined genotypes)

• RIBAVIC
• PEG IFN-alfa-2b and RBV SVR 26
• ACTG 5071
• PEG IFN alfa 2-a/RBV SVR 27
• APRICOT
• PEG IFN alfa-2a/RBV SVR 40

Chung et al. N Engl J Med. 2004351451-459.
Perronne et al. 11th CROI. February 8-11, 2004
San Francisco, Calif. Abstract 117LB.
Torriani et al. N Engl J Med. 2004351438-450.
88
Contraindications to Peginterferon/Ribavirin

• Hypersensitivity to peginterferon or ribavirin
• Pregnancy
• Hemoglobinopathies
• Active OI
• Decompensated liver disease
• Autoimmune disease

89
Adverse Effects of Combination Therapy

• Interferon
• Fatigue (70)
• Flu-like symptoms - self limited after initial
  doses
• Bone marrow suppression
• Depression, anxiety, insomnia, and irritability
• Alopecia
• Weight loss
• Potential exacerbation of autoimmune conditions
• Thyroid dysfunction (4)

• Ribavirin
• Teratogenicity
• Hemolytic anemia
• Dose-dependent and completely reversible
• Average 2-3 grams hemoglobin over the first four
  weeks of therapy
• Nausea - take with food

90
Managing Side Effects

• Evening injections
• Increase fluid intake
• Aerobic exercise
• Prophylactic acetaminophen or ibuprofen
• Support groups
• Psychiatric medications
• Erythropoetin and G-CSF

91
International, US, and Canadian Guidelines

• Test ALL HIV-infected patients for HCV antibodies
• To treat HCV consider
• Liver biopsy score
• CD4 cell count
• HIV RNA viral load
• Substance abuse
• History of depression
• Active Opportunistic Infection
• Treatment of choice is PEG IFN/RBV

92
AASLD Practice Guidelines

• HCV RNA testing for
• confirmation of HCV infection in HIV-infected
  persons who are positive for anti-HCV
• those who are negative and have evidence of
  unexplained liver disease
• HCV treatment for the HIV/HCV coinfected person
• in whom the likelihood of serious liver disease
  and a treatment response are judged to outweigh
  the risk of morbidity from the adverse effects of
  therapy
• Initial treatment of HCV in most HIV-infected
  persons is PEG IFN alfa/RBV for 48 weeks

93
AASLD Practice Guidelines (cont)

• Monitor coinfected patients on HCV treatment
  closely
• Use RBV with caution in persons with limited
  myeloid reserves and in those taking AZT and D4T
• Patients receiving ddI should be switched to an
  equivalent ART before beginning therapy with RBV
  if possible
• HIV-infected patients with decompensated liver
  disease may be candidates for OLT

AZT, zidovudine OLT, orthotopic liver
transplantation.
Strader et al. Hepatology. 2004391147-1171.
94
International Guidelines
Parameter HCV Treatment Recommendation
Elevated ALT, CD4 gt350 cells/mm3, HIV RNA lt50,000 copies/mL Begin therapy
Normal ALT, fibrosis Begin therapy
CD4 lt350 cells/mm3 Treat with caution
CD4 lt200 cells/mm3 Hold treatment
Cirrhosis without hepatic decompensation Begin therapy
Hepatic decompensation Liver transplant
ALT, alanine aminotrasferase. Soriano et al. J
Viral Hepat. 2004112-17.
95
New International Guidelines for Management of
HIV/HCV Coinfection

• 25-40 of coinfected patients with persistently
  normal ALT may have fibrosis and thus should be
  considered for HCV treatment regardless of ALT
• Non-invasive methods for assessing liver fibrosis
  accurately predict fibrosis in most cases, so
  that liver biopsy is not necessary for
  considering HCV treatment

96
New International Guidelines cont.

• RVR at week 4 predicts SVR in coinfected
  individuals as it does in monoinfected
• Coinfected patients on treatment who do not
  achieve EVR by week 12 or who still have
  detectable HCV RNA at week 24 should stop
  treatment early

97
Guidelines cont.

• Weight-based RBV superior to fixed dose
• 48 weeks PEG IFN RBV for all HCV genotypes 24
  weeks may be adequate for HCV 2 or 3
• Slow responders may benefit from 60-72 week
  courses of therapy

98
Guidelines cont.

• Coinfected non-responders and relapsers must be
  evaluated on and individual basis and considered
  for retreatment or interferon maintenance
  monotherapy to slow liver disease
• HAART may benefit patients with ESLD

99
Acute HCV in HIV-infected Individuals
International Guidelines

• Outbreaks in Europe among MSM presumably
  sexually transmitted
• HIV infected individuals less likely to clear
  acute hepatitis C
• Early treatment especially indicated in patients
  with HIV
• Treatment should be initiated after 12 weeks to
  allow for possible spontaneous clearance, then
  initiated with PEG IFN and weight-based RBV for
  24 weeks

100
Case Study 2

• C.T. is a candidate for Peg IFN and RBV therapy,
  but active substance use and psychiatric issues
  may complicate treatment
• Lack of progression in liver fibrosis on 2
  consecutive biopsies reassuring
• Non-invasive studies to monitor fibrosis may be
  helpful