Download Hepatitis and HIV

Hepatitis and HIV
Catherine Creticos, M.D.
August, 2007
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-
Hepatitis B Virus Infection



>300 million chronically infected
worldwide
Established cause of chronic hepatitis
and cirrhosis
Human carcinogen—cause of up to
80% of hepatocellular carcinomas
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
Hepatitis B Complications





Fulminant hepatitis
Hospitalization
Cirrhosis
Hepatocellular carcinoma
Death
Chronic Hepatitis B
Virus Infection




Chronic viremia
Responsible for most mortality
Overall risk 10%
Higher risk with early infection
High Viral Load Predicts Poor
Outcomes

Large, long-term, prospective cohort studies have
linked high viral load with poor outcomes
1. Haimen City Cohort
Chen G, et al. Am J Gastroenterol.
2006;101:1797-1803.
2. Fox Chase Cancer Center Cohort Study
Evans AA, et al. AASLD 2004. Abstract 144.
3. R.E.V.E.A.L Study Group
Chen CJ, et al. JAMA. 2006;295:65-73.
Iloeje UH, et al. Gastroenterology.
2006;130:678-686.
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. 2006;101:1797-1803.
Haimen City: Increased RR of HCC and
CLD Mortality With High Viral Load
Baseline HBV DNA (copies/mL)
Cause of Death
High (≥ 105)
Low (≥ 1. 6 x 103 - < 105)
1.2 (0.6-2.3)
1.0 (0.5-1.8)
Nonliver
(n = 132)
15.2* (2.1-109.8)
CLD
(n = 85)
1.5 (0.2-12.1)
11.2* (3.6-35.0)
HCC
(n = 231)
1.7 (0.5-5.7)
0
5
10
Relative Risk† (95% CI)
*P trend < .001
†Reference HBV DNA: < 1.6 x 103 copies/mL, adjusted for age and sex
Chen G, et al. Am J Gastroenterol. 2006;101:1797-1803.
15
20
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 < 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.
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)
(104
9.8 (2.3-42.7)
Low HBV DNA
- < 105 copies/mL)
2.1 (0.4-10.0)
Undetectable
Reference
(< 104 copies/mL)
0
5
10
Relative Risk* (95% CI) of HCC
*Conditional on the matching variables
Evans AA, et al. AASLD 2004. Abstract 144.
15
Risk Evaluation of Viral Load Elevation
& Associated Liver Disease/Cancer
Study

REVEAL: prospective, multicenter, observational cohort study
1991-1992:
recruitment
7 Taiwanese townships;
individuals aged 30-65 years eligible
(N = 89,293)
HCC-free individuals enrolled
(N = 23,820)
HCV
seropositive
HCC follow-up: 41,779 PYs
Cirrhosis follow-up: 40,038 PYs
HBsAg(+) with adequate
baseline HBV DNA sample
(N = 3851)
HCC
analysis
(n = 3653)
Cirrhosis
analysis
(n = 3582)
Chen CJ, et al. JAMA. 2006;295:65-73. Iloeje UH, et al. Gastroenterology. 2006;130:678-686.
Insufficient
serum for tests
or HBsAg(-)
HCV seropositive
or diagnosed with
cirrhosis or died within
6 months of entry
REVEAL: High HBV DNA Associated
With Increased HCC Incidence
Relationship Between Baseline HBV DNA and HCC Incidence:
All Participants (N = 3653)
Cumulative Incidence of HCC
at Year 13 Follow-up (%)
50
40
30
20
14.89
12.17
10
1.30
0
< 300
Chen CJ, et al. JAMA. 2006;295:65-73.
1.37
3.57
100030010,0009999
999
99,999
HBV DNA at Baseline (copies/mL)
≥ 100,000
Cumulative Incidence of Cirrhosis
at Year 13 Follow-up (%)
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
20
10
0
4.5
< 300
5.9
9.8
10,000300100,000- ≥ 1,000,000
99,999
9999
999,999
HBV DNA at Baseline (copies/mL)
Iloeje UH, et al. Gastroenterology. 2006;130:678-686.
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 < 104 copies/mL (~ 2000 IU/mL)

Continued suppression of HBV DNA
decreases fibrosis and delays disease
progression
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 disease–related
transplantation or death
HBV DNA suppression leads to
 Histologic improvement
 ALT normalization
 HBeAg loss and seroconversion
 HBsAg loss and seroconversion
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
Reversal of Fibrosis With Long-term
Nucleos(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 fibrosis—all with YMDD mutations
Dienstag J, et al. Gastroenterology. 2003;124:105-117.
Reversal of Fibrosis With Long-term
Nucleos(t)ide Analogue Therapy

47 HBeAg-negative patients treated with up to 2
years of adefovir
Inflammation
change

96 Wks Continued
Adefovir
(n = 19)
48 Wks Adefovir →
48 Wks Placebo
(n = 8)
48 Wks Placebo →
48 Wks Adefovir
(n = 20)
Wk 48
Wk 96
Wk 48
Wk 96
Wk 48
Wk 96
- 4.2
- 4.3
- 3.8
- 0.9
- 0.6
- 2.3
Fibrosis by rank assessment at Week 96
 Mean reduction with continued adefovir 0.63 ±
1.07
(P = .031 compared with adefovir → placebo
group)
Hadziyannis SJ, et al. N Engl J Med. 2005;352:2673-2681.
Delayed Disease Progression With
Continued Suppression: Cirrhotics
651 cirrhosis patients with evidence of
viral replication
Placebo (n = 215)
Patients With Disease
Progression at Follow-up

P = .001
25
Lamivudine (n = 436)
21
20
15
10
5
0
*5 cases of HCC in Year 1 excluded, P = .052
Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.
9
 Child-Pugh score
P = .02; HCC P = .047*
 Benefit reduced with
YMDD emergence
Delayed Disease Progression With
Continued Suppression: Noncirrhotics
142 noncirrhotic patients on continuous
lamivudine for a median of 89.9 months vs
124 untreated controls
Percentage of Patients
With Cirrhosis/HCC

14
12
10
8
6
4
2
0
Yuen MF, et al. AASLD 2005. Abstract 985.
P = .005
Placebo
Lamivudine
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
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. 2003;37:1309-1319.
Correlation Between HBV DNA Levels
and Markers of Liver Disease (cont’d)



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 < .0002)
Normalized ALT post treatment correlated with HBV
DNA level (r = 0.62, P = .0004)
Mommeja-Marin H, et al. Hepatology. 2003;37:1309-1319.
Entecavir Superior to Lamivudine in
HBeAg-Positive Patients
Entecavir (n = 354)
HBV DNA < 300 copies/mL
Through Week 96*
100
Patients (%)
80
P < .0001
Lamivudine (n = 355)
HBeAg Seroconversion
Through Week 96†
100
Histologic Improvement
Through Week 48
100
P = .009
80
80
80
72
62
60
60
39
40
20
0
60
P = NS
40
31
40
26
20
(n = 354)
(n = 355)
0
20
(n = 354)
(n = 355)
0
(n = 314)
*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. 2005;42:267A.
(n = 314)
Long-term Entecavir in
HBeAg-Negative Patients
Entecavir
Lamivudine
Histologic Improvement
Through Week 48
HBV DNA
< 300 copies/mL Through Week 96*
P < .0001
100
77
80
Patients (%)
100
94
P = .01
80
60
60
40
40
20
20
0
(n = 325)
(n = 313)
0
70
61
(n = 296)
*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. 2006;354:1011-1020.
(n = 287)
Clinical Efficacy 2-Year Results:
Telbivudine vs Lamivudine
HBeAg(+)
Response
Mean HBV DNA reduction,
log10 copies/mL
HBV DNA undetectable, %
HBeAg(-)
LdT
LAM
LdT
LAM
(n = 458) (n = 463) (n = 222) (n = 224)
-5.7*
-4.4
-5.0*
-4.2
56*
39
82*
57
ALT normalization, %
70*
62
78
70
Therapeutic response, %
64*
48
78*
66
HBeAg loss, %
35
29
-
-
HBeAg seroconversion, %
30
25
-
-
4.0*
12.3
0*
2.7
Primary treatment failure, %
*P ≤ .05 vs lamivudine.
Lai C, et al. AASLD 2006. Abstract 91.
Histologic Response (%)
Week 52 Histologic Outcomes:
Telbivudine vs Lamivudine
HBeAg Positive
Patients
100
12
80
HBeAg Negative
Patients
19
7
8
23
15
26
25
60
No improvement
40
69
69
60
68
20
0
Missing Week 52
biopsy
LdT
Lai C, et al. AASLD 2006. Abstract 91.
LAM
LdT
LAM
Improvement
Peginterferon alfa-2a in HBeAgPositive Chronic Hepatitis B Patients
HBV DNA Levels 1 Year Post treatment
According to Type of Initial Response
100
21
Patients (%)
80
60
HBV DNA 1 year
post treatment
(copies/mL)
29
7
33
29
96
10,001-100,000
40
21
20
> 100,000
401-10,000
39
≤ 400
21
0
Early, Sustained
Late HBeAg
HBeAg
Seroconversion
Seroconversion
(n=61)
(n=15)
Lau GK, et al. EASL 2006. Abstract 50.
No HBeAg
Seroconversion
(n=88)
Histologic Improvement (%)
Histologic Improvement With
Peginterferon Therapy
100
HBeAg-Positive
Patients
HBeAg-Negative
Patients
80
60
49
52
59
51
40
20
0
Lau GK, Piratvisuth T, Luo KX, et al. N Engl J Med. 2005. 30;352:2682-2695.
Marcellin P, Lau GK, Bonino F, et al. N Engl J Med. 2004. 16;351:1206-1217.
58
48
PegIFN
PegIFN + LAM
LAM
HBV DNA and HBeAg Seroconversion
at Year 1 in HBeAg(+) Patients
30
27
20
18
21
23
12
10
0
0
-3.6
-4.0
-6.9
-6.5
-5.8
-10
Lau et al. N Engl J Med. 2005;352:2682-2695. Dienstag et al. N Engl J Med. 1999;341:1256-1263.
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.
Log10 Decrease
in HBV DNA
HBeAg
Seroconversion, %
Data from individual studies, not direct comparisons
(different populations, baseline values, HBV DNA assays)
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
Emtricitabine effective against
HBV






39 patients from 3 studies
Baseline median HBV viral load >500,000
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
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/HBVcoinfected patients beginning tenofovirbased HAART
Lacombe K, Gozlan J, Boelle PY, et al. AIDS. 2005;19:907-915
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
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)
Main Findings



HBV DNA declined from baseline by mean of
4.6 log10 copies/mL with tenofovir treatment
(P < .001)
 HBV DNA undetectable (< 200 copies/mL)
in 21 (87.5%) patients
 Median time until undetectable, 272.5
days (95% confidence interval [CI], 203.5416.0)
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
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 < .0001)
Undetectable HIV-1 RNA (< 50
copies/mL) increased from 22% of
patients at baseline to 75%
Mean ALT declined from 125 to 50 IU/mL
(P < .05)
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
Treatment of HBV with TDF or ADV

Proportion
with <200 copies/mL

Nonrandomized, open label study of TDF vs. ADV in 85 HIV-HBV coinfected patients
 ADV (n=29), TDF (n=56)
 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.
(p<0.0001)
 Greater decreases in transaminases
 After adjustment of HBeAg status, HBV-DNA at baseline and level
1.00 of ALT at baseline, TDF associated with a higher rate of patients
achieving undetectable HBV-DNA levels
0.75
P=0.04
0.50
TDF
.025
ADV
0.00
0
10
20
30
Time to HBV-DNA undetectability (months)
Lacombe Burman W, et al. 14th CROI, Los Angeles, CA, February 25-28, 2007. Abst. 945.
40
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
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
2006 NIH Workshop on the
Management of CHB:
Who Should Receive Treatment?
HBsAg Positive
HBeAg
Inactive carrier/mild
chronic hepatitis
Neg
HBV DNA < 104 IU/mL;
ALT normal
3-6 months
Monitor every
3-6 months
Decompensated
cirrhosis
Pos
Grey
zone
Consider Liver
biopsy
HBV DNA > 104 IU/mL;
elevated ALT
3-6 months
Consider antiviral
therapy
Consider
antiviral
therapy/
refer for
OLT
Interferon Therapy

Pros
–
–
–

Finite duration of therapy
Durable response
No resistance or cross resistance
Cons
–
–
–
Route of administration—injection
Frequent side effects
Cost
Ideal Clinical Situation for IFN
Therapy







High ALT (> 5 x ULN) and low HBV DNA
level
(< 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
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
Ideal Clinical Situation for
Lamivudine Use

Short duration of therapy
–
–

Safety a concern
–

Prevention of disease flares/reactivation
during chemotherapy
Protracted or severe acute hepatitis
During pregnancy
Cost a concern
–
HBeAg-negative CHB in developing
countries
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
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
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
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
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
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
Case Study 1 – cont.


Additional laboratories:
 CD4 372
 HIV RNA 86,000
 HBV DNA >500,000
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
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.
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



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
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)
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



>90% within 5 months
>97% within 6 months
Rarely is seroconversion delayed >9 months
Serologic Pattern of Acute HCV Infection
with Recovery
antiHCV
Symptoms +/-
Titer
HCV RNA
ALT
Normal
0
1
2
6
1 2
3
3
4
5
Years
Months
Time after Exposure
4
Chronic HCV Infection

HCV RNA detectable in the blood for > 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
Serologic Pattern of Acute HCV Infection with
Progression to Chronic Infection
antiHCV
Symptoms +/-
Titer
HCV RNA
ALT
Normal
0
1
2
6
1 2
3
3
4
5
Years
Months
Time after Exposure
4
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
Prognosis of Untreated HCV
Variable 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
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%
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
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
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)
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
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
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
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
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 >
200 cells/mm3
Patients with advanced liver disease
by biopsy
HCV Treatment Options

Interferon alfa monotherapy




Pegylated interferon monotherapy



Interferon alfa-2b (Intron A)
Interferon alfa-2a (Roferon-A)
Interferon alfacon-1 (Infergen)
Peginterferon alfa-2b (PEG-Intron)
Peginterferon alfa-2a (PEGASYS)
Pegylated interferon combination therapy


Peginterferon alfa-2b plus ribavirin
Peginterferon alfa-2a plus ribavirin
HIV/HCV Coinfection Trials:
PEG 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. 2004;351:451-459.
Perronne et al. 11th CROI. February 8-11, 2004; San Francisco, Calif. Abstract 117LB.
Torriani et al. N Engl J Med. 2004;351:438-450.
ACTG 5071: Overall Results
(N=133)
Response (%)
*
45
40
35
30
25
20
15
10
5
0
41
EOT
SVR
27
12
**
12
IFN 2a + RBV
PEG 2a + RBV
SVR: HCV<60 IU/mL 24 weeks after end of therapy (EOT).
*P=.0001 versus IFN 2a + RBV.
**P<.03 versus IFN 2a + RBV.
Chung R et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 110.
Response (%)
ACTG 5071: PEG α-2a + RBV
Arm by Genotype
90
80
70
60
50
40
30
20
10
0
80 *
EOT
SVR
73 *
29
14
Genotype 1
Genotype non-1
* P=.0007 vs Genotype 1.
Chung R et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 110.
ACTG 5071: Summary



Predictors of sustained virologic response
included PEG α-2a + RBV treatment, HCV
genotype non-1, no previous IDU, and
detectable HIV-1 RNA at entry
PEG-IFN α-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.
APRICOT: Virologic Response*
End of Treatment Versus End of Follow-up
(Genotype 1)
End of treatment
End of follow-up
60%
% Response
50%
38%
40%
29%
30%
21%
20%
10%
0%
14%
8%
7%
IFN α-2a + RBV
PEG-IFN α-2a
(40 kDa) + Placebo
PEG-IFN α-2a
(40 kDa) + RBV
*Defined as <50 IU/mL HCV RNA.
Torriani FJ et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 112.
APRICOT: Virologic Response*
End of Treatment Versus End of Follow-up
(Genotypes 2 and 3)
70%
End of treatment
64%
57%
60%
% Response
End of follow-up
62%
50%
36%
40%
30%
27%
20%
20%
10%
0%
IFN α-2a + RBV
PEG-IFN α-2a
(40 kDa) + Placebo
PEG-IFN α-2a
(40 kDa) + RBV
*Defined as <50 IU/mL HCV RNA.
Torriani FJ et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 112.
Median Change From Baseline
in CD4+ Count (cells/L)
APRICOT: Median Change in CD4+
Counts From Baseline *

IFN -2a 3 MIU + RBV 800 mg (n=174)
g

PEG-IFN -2a (40 kDa) 180
g + Placebo (n=196)

PEG-IFN -2a (40 kDa) 180
+ RBV 800 mg (n=217)
60
40
20
0
-20
-40
-60
-80
-100
-120
-140
-160
BL
0 4
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76
Time (Weeks)
* Patients receiving 48 weeks of treatment.
Torriani FJ et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 112.
APRICOT: Change in HIV RNA From Baseline –
All Patients Treated*
Change in Log10 HIV RNA
IFN -2a 3 MIU + RBV 800 mg (n=174)
PEG-IFN -2a (40 kDa) 180g + Placebo (n=196)
PEG-IFN -2a (40 kDa) 180g + RBV 800 mg (n=217)
2.0
1.5
1.0
0.5
0.0
-0.5
-1.0
-1.5
-2.0
BL
4
8
* Patients receiving 48 weeks of treatment.
12
24
36
Time (Weeks)
48
52
Torriani FJ et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 112.
60
72
APRICOT: Summary



SVR was significantly higher for PEG-IFN α-2a (40
kDa)
+ RBV compared with conventional combination
therapy
 Overall: 40% versus 12%; P <.0001
 Genotype 1: 29% versus 7%
 Genotype 2/3: 62% versus 20%
Adverse event profile of PEG-IFN α-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.
French ANRS RIBAVIC Study


Randomized, multicenter, open-label study in HIVHCV coinfected patients with CD4>200 and stable
HIV RNA for 48 weeks on:
 PEG-IFN α-2b 1.5 g/kg/wk + RBV (n=205), or
 Standard IFN-2b 3 MIU tiw + RBV 800 mg QD
(n=207)
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.
RIBAVIC: SVR at Week 72
50
P=.031
43
45
SVR (%)
40
35
26
(54/205)
30
25
20
18
(18/207)
15
10
11
5
0
IFN 2b/RBV
PEG
2b/RBV
Genotypes Genotypes
1/4
2/3
Perronne C et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 117LB.
RIBAVIC: Response Rates – Patients Who Did
Not Discontinue Treatment
(n=245)
Response Rates (%)
60
PEG-IFN  -2b + RBV
54
52
IFN 2b + RBV
50
41
40
41
34
34
30
35
26
20
20
12
10
0
4
12
24
48
72 (SVR)
Weeks of Treatment
Perronne C et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 117LB.
HIV/HCV Infection Trials:
SVR (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. 2004;351:451-459.
Perronne et al. 11th CROI. February 8-11, 2004; San Francisco, Calif. Abstract 117LB.
Torriani et al. N Engl J Med. 2004;351:438-450.
Contraindications to
Peginterferon/Ribavirin






Hypersensitivity to peginterferon or
ribavirin
Pregnancy
Hemoglobinopathies
Active OI
Decompensated liver disease
Autoimmune disease
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
Managing Side Effects

Evening injections
Increase fluid intake
Aerobic exercise
Prophylactic acetaminophen or ibuprofen
Support groups
Psychiatric medications

Erythropoetin and G-CSF





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
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
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. 2004;39:1147-1171.
International Guidelines
Parameter
HCV Treatment
Recommendation
Elevated ALT, CD4+
>350 cells/mm3,
HIV RNA <50,000 copies/mL
Begin therapy
Normal ALT, fibrosis
CD4+ <350 cells/mm3
CD4+ <200 cells/mm3
Begin therapy
Treat with caution
Hold treatment
Cirrhosis without hepatic
decompensation
Hepatic decompensation
Begin therapy
ALT, alanine aminotrasferase.
Soriano et al. J Viral Hepat. 2004;11:2-17.
Liver transplant
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
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
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 6072 week courses of therapy
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
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 weightbased RBV for 24 weeks
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