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Progressive histological liver improvement after sustained
virological response to therapy in HCV / HIV coinfected patients.
Jose L. Casado, Paloma Martí-Belda, Carmen Quereda, María del Palacio, Ana Moreno, María Pumares, María J Perez-Elías,
Santiago Moreno.
Dept of Infectious Diseases
Spain
WEAB0104
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Background• Liver fibrosis is a dynamic, bi-directional process, wherein recovery with
remodelling of scar tissue is possible.
• Histological improvement after HCV therapy has been previously described– Around 25-50% of HCV monoinfected patients– Few data in HCV/HIV coinfected patients (10% of patients included in the
RIBAVIC study)
• Fibrosis improvement could explain the clinical benefit and prolonged survival in HCV/HIV coinfected patients achieving sustained virological response (Berenguer et al. Hepatology 2009, 50: 407-13)
• However, there are no long-term data on duration and grade of improvement, if any, taking into account the differences in viral kinetics, fibrogenesis, and the existence of immunodepression
• In addition, most studies are based in paired liver biopsy samples– No data on the usefulness of succesive transient elastographies (TE)
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Aim of the study
• To evaluate the long-term outcome of HCV/HIV coinfected patients in terms of fibrosis improvement after HCV therapy
• To establish the factors associated with histological improvement
• To determine the usefulness of transient elastography in this indication
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Study Design
• Prospective follow-up of HCV/HIV coinfected patients who received HCV therapy from 2002 to 2010
Inclusion criteria1. HCV RNA positive2. Baseline fibrosis determination3. HCV therapy4. At least 2 consecutive TE measurements after therapy
1st TE measurement
2nd TE measurement
• HCV/HIV coinfection(n=236)
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Study Design
• Transient elastography (FibroScan®, Echosense, Paris, France) was performed starting in 2007 and repeated anually during follow-up.
– Up to 10 stiffness measurements were performed on each patient, considering as valid measurement if IQR <30% and the success rate was ≥80%. The cutoff values for fibrosis stages were established according to Castera et al (J Hepatol 2008; 48: 835 - 847 ):• < 7,2 kPa ------------ F1• 7,2 to 9,4 ------------ F2 (PPV 95%, NPV 48%)
• 9,5 to 12.5 ---------- F3 (PPV 87%, NPV 91%)
• > 12.5 KPa ---------- F4 (PPV 77%, NPV 95%)
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Study Design
• Definitions:
– Fibrosis regression: reduction of at least 1 point in fibrosis METAVIR score.
– Confirmed improvement: reduction of at least 2 points in fibrosis (i.e, from fibrosis 3 to fibrosis 1), OR continued improvement in the two consecutive TE (at 2nd TE)
• Univariate and multivariate analysis (survival analysis and Cox multivariate model) for identifying predictive factors associated to fibrosis changes.
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Baseline characteristics
Inclusion criteria: Baseline fibrosis HCV therapy TE (2) during follow up
HCV / HIV
coinfection
n=236
Mean age 42 yrs (34-51)
Sex male 80%
Former IDUs 90%
HIV infection:Nadir CD4+ countHAART PI-based NNRTI-basedBaseline CD4+ countHIV RNA <50 copies/mlPrior AIDS diagnosis
171 (14-548)100%72%28%
499 (150-1226)85%29%
Time of HCV infection* 21.4 yrs (11-30)
Median RNA-HCV (log) 5.9 (4.35-7.14)
Genotype1234
50%2%
32%16%
HBsAg (+) 2%
Time of HCV infection: Median estimated time since 1 year after IDU or first HCV positive serology
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Baseline characteristics: Histological data at biopsy
HCV / HIV
coinfection
n=236
TE baseline 69 patients
Mean HAI* 5.52 (1-11)
Fibrosis (METAVIR scoring system) 1234
24%21%20%35%
Fibrosis progression rate** (MU/yr)
0.15 (.04-.28)
*HAI, histological activity index; **Fibrosis progression rate= Fibrosis (Metavir)/Time of HCV, expressed as Metavir Units per year
Inclusion criteria: Baseline fibrosis HCV therapy TE (2) during follow up
In 26 patients with concomitant TE and liver biopsy, correlation was 0.86, p< 0.01
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Results: SVR
1st TE measurement
2nd TE measurement
• HCV/HIV coinfection(n=236)
Inclusion criteria:Baseline fibrosisHCV therapyTE (2) during follow up
40% Sustained Virological Response
(SVR)
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Sustained virological responseVariable SVR
(95, 40%)No SVR
(141, 60%)p value
Age, mean, yrs 43 41 .04
Nadir CD4+ count 225 187 .09
HCV RNA (log) 5.69 6.02 <.001
Genotype 2-31-4
61%30%
39%70%
<.001
Fibrosis (METAVIR)1-23-4
36%45%
64%55%
.12
Fibrosis progression rate 0.10 0.14 .04
Time on HCV therapy, median (mo)
11.57 8.48 <.01
No differences in gender, HIV RNA level, antiretroviral therapy, CD4+ count at therapy, time of HCV infection, HAI, or date of HCV therapy.
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Results: Follow up
1st TE measurement
2nd TE measurement
• HCV/HIV coinfection(n=236)
Inclusion criteria:Baseline fibrosis HCV therapyTE (2) during follow up
40% Sustained Virological Response (SVR)
Median 30.1 mo (2-87.6) after tx
Median 47.2 mo (15-103)
after tx
Median follow up: 61 mo (33-98.1) after HCV therapy
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Fibrosis changes
Mean fibrosis score change -0.26 -0.33Median stiffness, Kpa 8.8 (4-45.5) 8.7 (3.9-37.2)
%
Confirmed improvement: defined as reduction of 2 points on fibrosis score (1st TE) or/and consecutive reduction in fibrosis score (2nd TE)
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Fibrosis changes
1st TE 2nd TE
SVR Non SVR P value SVR Non SVR p value
TE value* 7.05
(3.6-25.7)10.2
(4.3-48)<.01
6.8 (3.3-38.5)
9.35 (4.2-39.8)
0.01
< 7.2 kpa 52 28 <.01 52 35 <.01
7.2-9.4 15 18 0.12 16 15 0.45
9.5-12.5 12 12 0.6 10 15 .13
>12.5 21 42 .02 22 35 .02
Fibrosis regression
53 17 <.01 56 24 <.01
Confirmed ** 23 5 <.01 48 15 <.01
*median, IQR
** defined as reduction of 2 points on fibrosis score (1st TE) or/and consecutive reduction in fibrosis score (2nd TE)
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Time to histological improvement after HCV therapy
SVR
Non SVR
P<0.01, log-rank test
In a K-M analysis, probability of improvement for SVR-patients was 22% and 41% at 1 and 3 yrs, respectively. For non-SVR, it was 4% and 15% at the same time points
Time to improvement (days)
40003000200010000
Cum
ulati
ve h
azar
d5
4
3
2
1
0
SVR
No SVR
P<.01, log-rank test
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Fibrosis regression: Predictive factors
In a Cox multivariate model, only SVR was associated with fibrosis regression
(HR 1.94; 95%CI 1.18-3.2)
Without changes after controlling for:
HCV related variables (HCV RNA level, genotype, baseline fibrosis, duration of HCV therapy, Histological Activity Index).
HIV related variables (HIV RNA level, nadir or baseline CD4+ count, type of antiretroviral therapy, virological failure during follow up, CD4+ count increase) .
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TE results for patients with fibrosis 4 (n=82)
Mean fibrosis score change -0.56 -0.97Median stiffness, Kpa 16.9 (5.3-56) 14.3 (4.1-44.7)
%
Confirmed improvement: defined as reduction of 2 points on fibrosis score (1st TE) or/and consecutive reduction in fibrosis score (2nd TE)
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Time to improvement for patients with F4
In a K-M analysis, probability of improvement for SVR-patients was 26% and 48% at 1 and 3 yrs, respectively. For non-SVR, it was 7% and 21% at the same time points
SVR
No SVR
p=0.01
Time to improvement (days)
40003000200010000
Cum
ulati
ve h
azar
d
5,0
4,0
3,0
2,0
1,0
0,0
p=0.01, log-rank test
SVR
No SVR
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TE results for patients with fibrosis 2-3 (n=95)
Mean fibrosis score change -0.41 -0.34Median stiffness, Kpa 7.8 (4.2-48) 8 (3.4-43.5)
%
Confirmed improvement: defined as reduction of 2 points on fibrosis score (1st TE) or/and consecutive reduction in fibrosis score (2nd TE)
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Time to improvement for patients with F2-F3
In a K-M analysis, probability of improvement for SVR-patients was 22% and 42% at 1 and 3 yrs, respectively. For non-SVR, it was 5% and 15% at the same time points
Time (days)
40003000200010000
Cum
ulati
ve H
azar
d
4,0
3,0
2,0
1,0
0,0
SVR
No SVR
p<0.01, log-rank test
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Limitations of the study (bias)
• High variability in TE results (specially in F2-3). However, in our study
– Most of the TE performed by the same, highly trained, operator in all cases (> 1500 TE experienced),
– 28% of patients have reduction of at least 2 points in fibrosis score, – a second TE confirming improvement (more than 1 year later), and – there was a statistically significant association with SVR, as
described in biopsy-based studies
• Influence of immunity or maintained HAART?– similar CD4+ count at inclusion– most patients with HIV RNA levels below 50 copies/ml (8% of
patients had virological failure during follow up, and they were quickly changed to an effective therapy)
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Conclusions
• Our study demonstrates the high probability of fibrosis improvement after HCV therapy in an important proportion of coinfected HCV/HIV patients, in case of achieving sustained virological response.
• Our data confirm that liver histological regression is progressive during the follow up after successful HCV therapy, and therefore it is expected an increase in the number of patients improving.
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Acknowledgments
To our patients
To my colleagues at the HIV Unit
A Moreno
MJ Perez Elías
F Dronda
S Moreno
And special thanks to
C Quereda (HCV/HIV specialist)
P Martí Belda (TE)