www.ias2011.org

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

www.ias2011.org

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)

www.ias2011.org

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

www.ias2011.org

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)

www.ias2011.org

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%)

www.ias2011.org

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.

www.ias2011.org

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

www.ias2011.org

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

www.ias2011.org

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)

www.ias2011.org

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.

www.ias2011.org

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

www.ias2011.org

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)

www.ias2011.org

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)

www.ias2011.org

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

www.ias2011.org

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) .

www.ias2011.org

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)

www.ias2011.org

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

www.ias2011.org

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)

www.ias2011.org

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

www.ias2011.org

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)

www.ias2011.org

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.

www.ias2011.org

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)