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

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: ) 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)

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

Study Design Prospective follow-up of HCV/HIV coinfected patients who received HCV therapy from 2002 to 2010 Inclusion criteria 1.HCV RNA positive 2.Baseline fibrosis determination 3.HCV therapy 4.At least 2 consecutive TE measurements after therapy 1st TE measurement 2nd TE measurement HCV/HIV coinfection (n=236)

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: ): < 7,2 kPa F1 7,2 to 9, F2 (PPV 95%, NPV 48%) 9,5 to F3 (PPV 87%, NPV 91%) > 12.5 KPa F4 (PPV 77%, NPV 95%)

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.

Baseline characteristics Inclusion criteria: Baseline fibrosis HCV therapy TE (2) during follow up HCV / HIV coinfection n=236 Mean age42 yrs (34-51) Sex male80% Former IDUs90% HIV infection: Nadir CD4+ count HAART PI-based NNRTI-based Baseline CD4+ count HIV RNA <50 copies/ml Prior AIDS diagnosis 171 (14-548) 100% 72% 28% 499 ( ) 85% 29% Time of HCV infection*21.4 yrs (11-30) Median RNA-HCV (log)5.9 ( ) Genotype % 2% 32% 16% HBsAg (+)2% Time of HCV infection: Median estimated time since 1 year after IDU or first HCV positive serology

Baseline characteristics: Histological data at biopsy HCV / HIV coinfection n=236 TE baseline69 patients Mean HAI*5.52 (1-11) Fibrosis (METAVIR scoring system) % 21% 20% 35% Fibrosis progression rate** (MU/yr) 0.15 ( ) *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

Results: SVR 1st TE measurement 2nd TE measurement HCV/HIV coinfection (n=236) Inclusion criteria: Baseline fibrosis HCV therapy TE (2) during follow up 40% Sustained Virological Response (SVR)

Sustained virological response VariableSVR (95, 40%) No SVR (141, 60%) p value Age, mean, yrs Nadir CD4+ count HCV RNA (log) <.001 Genotype % 30% 39% 70% <.001 Fibrosis (METAVIR) % 45% 64% 55%.12 Fibrosis progression rate Time on HCV therapy, median (mo) <.01 No differences in gender, HIV RNA level, antiretroviral therapy, CD4+ count at therapy, time of HCV infection, HAI, or date of HCV therapy.

Results: Follow up 1st TE measurement 2nd TE measurement HCV/HIV coinfection (n=236) Inclusion criteria: Baseline fibrosis HCV therapy TE (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 ( ) after HCV therapy

Fibrosis changes Mean fibrosis score change Median stiffness, Kpa 8.8 (4-45.5) 8.7 ( ) % Confirmed improvement: defined as reduction of 2 points on fibrosis score (1st TE) or/and consecutive reduction in fibrosis score (2nd TE)

Fibrosis changes 1st TE2nd TE SVRNon SVRP valueSVRNon SVRp value TE value* 7.05 ( ) 10.2 (4.3-48) < ( ) 9.35 ( ) 0.01 < 7.2 kpa5228< < > Fibrosis regression 5317< <.01 Confirmed **235< <.01 *median, IQR ** defined as reduction of 2 points on fibrosis score (1st TE) or/and consecutive reduction in fibrosis score (2nd TE)

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 SVR No SVR P<.01, log-rank test

Fibrosis regression: Predictive factors In a Cox multivariate model, only SVR was associated with fibrosis regression (HR 1.94; 95%CI ) 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).

TE results for patients with fibrosis 4 (n=82) Mean fibrosis score change Median stiffness, Kpa 16.9 (5.3-56) 14.3 ( ) % Confirmed improvement: defined as reduction of 2 points on fibrosis score (1st TE) or/and consecutive reduction in fibrosis score (2nd TE)

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 p=0.01, log-rank test SVR No SVR

TE results for patients with fibrosis 2-3 (n=95) Mean fibrosis score change Median stiffness, Kpa 7.8 (4.2-48) 8 ( ) % Confirmed improvement: defined as reduction of 2 points on fibrosis score (1st TE) or/and consecutive reduction in fibrosis score (2nd TE)

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 SVR No SVR p<0.01, log-rank test

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)

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.

Acknowledgments To our patientsTo my colleagues at the HIV Unit A MorenoMJ Perez ElíasF DrondaS Moreno And special thanks to C Quereda (HCV/HIV specialist)P Martí Belda (TE)