Transcript Document

Abstract
Background: Liver fibrosis is accelerated in HCV/HIV-coinfected patients.
The reasons for this faster liver disease progression are unclear, although
higher plasma HCV-RNA levels and distinct HCV genotype distribution in
this population compared to HCV-monoinfected subjects could play a role.
Patients and Methods: Liver fibrosis was assessed using elastometry in all
consecutive HIV-infected patients with chronic hepatitis C attended at our
institution during the last 12 months. Hepatic stiffness was measured in
KiloPascal (KPa) units and interpreted according to the Metavir score: no or
mild fibrosis (F-F1) when ≤7.1 KPa and fibrosis with septa or cirrhosis (F2F4) when >7.1 KPa.
Results: A total of 283 patients (71% males; mean age 42 years-old; 94% iv
drug users; 94% on antiretrovirals; mean CD4 count 554 cells/l, and 72%
with plasma HIV-RNA <50 copies/mL) were analysed. Mean ALT was 68
IU/L and mean plasma HCV-RNA was 5.9 log IU/mL. HCV genotype
distribution was as follows: 1 (60%), 2 (2%), 3 (26%) and 4 (12%). Overall,
164 (58%) patients scored with advanced liver fibrosis (F2-F4) using
elastometry.
In the univariate and multivariate analyses, respectively, significant OR [95%
CI] for F2-F4 stages was found for HCV genotype 3 versus others (1.9 [1.13.4] and 4.3 [1.4-13.3]), older age (1.1 [1.03-1.17] and 1.1 [1.01-1.25]), and
elevated ALT levels (1.02 [1.01-1.03] and 1.03 [1.01-1.04]). Although
patients with HCV genotype 1 had higher mean serum HCV-RNA levels than
those with HCV genotype 3 (6.1 vs 5.7 log IU/mL; p=0.01), F2-F4 tended to
be more frequent in patients with HCV genotype 3 than in those with HCV
genotype 1 (69% vs 58%; p=ns).
Conclusions: HCV genotype 3, older age and elevated ALT levels are
independent predictors of advanced liver fibrosis in HCV/HIV-coinfected
patients.
Introduction
Liver fibrosis leads to most clinical
complications in patients with chronic HCV
infection. Several factors, such as male gender,
older age, longer duration of HCV infection
and/or high alcohol consumption, have
classically been associated to more severe liver
damage in patients with chronic hepatitis C.
More recently, HIV coinfection has been
demonstrated to be an strong independent
predictor of accelerated HCV-related liver
fibrosis. HCV genotypes were considered to
cause liver fibrosis with similar frequency;
however, patients infected with HCV genotype
1 seem to show higher HCV-RNA levels both
plasma and the liver, with more rapid
progression to end-stage liver disease than
patients carrying other HCV genotypes. On the
other hand, patients infected with HCV
genotype 3 show frequently liver steatosis,
which ultimately accelerates liver fibrosis.
Liver biopsy has been for many years the most
reliable procedure to assess hepatic fibrosis.
However, this tool is not free of complications
and may not always be accurate. Transient
elastometry (FibroScan) is a new non-invasive
procedure to measure the stiffness of the liver
tissue. The accuracy of the method for
measuring liver fibrosis has been successfully
compared with that of liver biopsy (figure 1).
The factors associated with more advanced
liver fibrosis according to elastometry were
examined in a cohort of HIV/HCV coinfected
patients.
Figure 1. Correlation between FibroScan and liver biopsy in HIV/HCV
coinfected patients De Ledinghen, et al. JAIDS 2006;41:175
868
Predictors of liver fibrosis in HIV-infected patients with chronic hepatitis C
Pablo Barreiro, Luz Martín-Carbonero, Marina Núñez, Pablo Rivas, Adolfo Morente, Nuria Simarro, Pablo Labarga, Juan González-Lahoz and Vincent Soriano.
Department of Infectious Diseases, Hospital Carlos III. Madrid, Spain.
Patients and Methods
Study population
All patients with HIV/HCV coinfection (reactive HCV serology and detectable HCVRNA in plasma) attending at our institution in a 12-month period were identified and
invited to undergo transient elastometry. Laboratory parameters (ALT, CD4 count,
HIV-RNA and HCV load) were recorded at the last control; there were no lags greater
than 4 months between elastometry and laboratory testing.
HCV load was measured using a commercial real-time PCR assay (Cobas Taqman;
Roche Diagnostic Systems, Pleasanton, CA). HCV genotypes were assessed using a
commercial reverse hybridisation method (InnoLiPA HCV II; Innogenetics, Ghent,
Belgium).
Assessment of liver fibrosis using elastometry
Liver stiffness was determined using transient elastometry (figure 2). Briefly, the
hepatic region of the patients was explored with an ultrasound transducer that was
placed in the right intercostal spaces. When the echography window showed the
characteristic image of liver tissue, an elastic shear wave was emitted by the vibration
of the ultrasound probe. The speed of propagation of this vibration through the liver
parenchyma was calculated according to ultrasound scanning. On the basis of
physical principles, the stiffer the liver the faster the vibration would pass through the
organ. It has been shown that the PPV of advanced liver fibrosis (fibrosis with septa
to overt cirrhosis (F2-F4 in the Metavir score) was 95% when elastometry rendered
liver stiffness values >7.1 KPa.
Statistical analyses
Descriptive values are expressed as percentages, mean (+SD) or median (+range).
Given the cross-sectional nature of the study, the association of multiple variables
with the two distinct groups, patients with minimal (F0-F1) and advanced liver
fibrosis (F2-F4), were analysed in uni- and multivariate analyses. Comparisons were
made using the Chi square test for proportions, and parametric or non-parametric
tests, as required, for continuous variables. Finally, all variables included in the
univariate analysis that had p values ≤0.5 were considered for a logistic regression
analysis. All data were recorded and analysed using SPSS (version 11.01) software
package (SPSS Inc, Chicago, IL, USA).
Overall, 119 (42%) patients had median elastometric values compatible with
no or mild liver fibrosis (<7.1 KPa); the remaining 164 patients (58%) had
advanced liver fibrosis (>7.1 KPa). The accuracy of elastometry in terms of
mean number of valid measures and success rates was comparable when
comparing fibrotic and non-fibrotic patients. The distribution of patients
according to estimated Metavir scores for liver fibrosis (mean elastometric
values) was as follows: F0-F1 (5.4±0.95 KPa) in 69 patients (42%), F2
(8.2±0.6 KPa) in 36 (22 %), F3 (10.6±0.7 KPa) in 16 (10%), and F4
(23.9±13.3 KPa) in 43 (26%).
Comparisons between HCV genotypes
No significant differences between patients with HCV genotype 3 versus
other genotypes were found when comparing demographics or main
laboratory parameters, except for a lower proportion of men (57% versus
76%, p=0.004) and higher mean ALT values (75±78 IU/L versus 65±46
IU/L; p<0.001) (Table 2). Likewise, no significant differences in plasma
HIV-RNA or CD4 counts were noticed when comparing patients with
distinct HCV genotypes. Although subjects with HCV genotype 3 tended
to have been exposed more frequently to anti-HCV therapy in the past than
the rest, the difference did not reach statistical significance (56.3% versus
45.9%; p=ns). However, as expected, sustained viral clearance had been
obtained by a greater proportion of them compared to others (19.6% versus
7.7%; p=0.01).
The success rate of elastometry was similar in patients with HCV genotype
3 compared to the rest (0.88±0.17 vs 0.87±0.14, respectively). The
proportion of patients with significant liver stiffness (>7.1 KPa, Metavir
F2-F4) was significantly higher in the group infected by HCV genotype 3
as compared with other genotypes (69% versus 54%, p=0.02).
Figure 2
Results
Main characteristics of the study population
A total of 285 HCV/HIV-coinfected patients were identified. In two cases invalid
elastometric measures were obtained due to severe obesity. Analyses were carried
out on the remaining 283 patients (Table 1). Mean laboratory parameters were ALT
68±56 IU/L, CD4 count 554±287 cells/l, and viral load 2±0.9 HIV-RNA log
copies/ml. Most patients (94%) were under HAART and 72% had less than 50 HIVRNA copies/ml. The distribution of patients according to the type of antiretroviral
regimen being received at the time of examination was fairly heterogeneous.
Mean HCV viremia was 5.9±0.9 HCV-RNA log IU/ml, and the distribution of
genotypes was as follows: genotype 1 in 60%, genotype 2 in 2%, genotype 3 in
25%, genotype 4 in 12% and mixed genotypes (2 and 3) in two patients. Nearly half
of the study population (49%) had been exposed to anti-HCV therapy in the past (37
patients to IFN monotherapy, 32 to IFN+RBV, and 65 to pegylated IFN+RBV).
However, only 17% of them had attained sustained virological response. Given that
no definitive information exists regarding a possible reversion of liver fibrosis in
patients who have cleared HCV infection with anti-HCV therapy, we decided to
keep this small group of patients in our analysis.
Predictors of advanced liver fibrosis
A total of 164 (58%) patients were found to show advanced liver fibrosis
(Metavir F2-F4) according to elastometry (>7.1 KPa). Older age was the only
demographic variable which could be associated to a greater liver stiffness
(p=0.001). No differences were found with respect to gender, BMI or risk
behaviour (Table 3).
Mean ALT values were higher in patients with advanced liver fibrosis as
compared with those with F0-F1 (81±66 versus 48±27 IU/L; p<0.001).
Likewise, the proportion of patients with ALT levels above the upper limit of
normality (>55 IU/L) was higher in subjects with >7.1 KPa compared to those
with ≤7.1 KPa (56% versus 29%, p<0.001). Of note, the positive predictive
value for significant liver stiffness (Metavir F2-F4) in subjects with elevated
ALT levels was particularly high for HCV genotype 3 (87% [95% CI, 75%99%]), while it was lower (68% [95% CI, 59%-78%]) for patients with other
HCV genotypes. These differences persisted when the subset of patients cured
from chronic hepatitis C with anti-HCV therapy were excluded from the
analysis (data not shown).
Mean plasma HIV-RNA and CD4 counts, as well as the proportion of patients on
HAART and time on antiretroviral therapy did not differ significantly when
comparing patients with F2-F4 and F0-F1 liver fibrosis stages. Likewise, plasma
HCV-RNA and prior experience to IFN-based therapies did not different either.
As previously mentioned, the proportion of patients with estimates of advanced
liver fibrosis was higher in subjects with HCV genotype 3 (50 out of 72; 69%) as
compared with other genotypes (114 out of 211; 54%) [p=0.02]. While no
differences in liver fibrosis were observed with respect to alcohol consumption,
all 6 patients with positive HBsAg were in the group with advanced liver
fibrosis.
The multivariate analysis was performed including in the model all variables
with a p value ≤0.5 in the univariate analysis (Table 3). Then, infection with
HCV genotype 3 becomes the stronger independent predictor of advanced liver
fibrosis (OR 4.3 [95% CI, 1.4-13.3]), being older age (OR 1.12 [95% CI, 1.011.25] and elevated ALT (OR 1.03 [95% CI, 1.01-1.04]) the other two variables
independently associated with it.
Discussion
We found an association between HCV genotype 3 and advanced liver fibrosis
stages. This observation has significant clinical implications, since patients with
HCV genotype 3 are amongst the best responders to current anti-HCV therapy, and
therefore reinforces that treatment should particularly be pursued in them. HCV
genotype 3 infection has been associated with higher rates of liver steatosis. More
recently a link between hepatic steatosis and inflammation has been reported, which
may explain a faster progression to liver fibrosis in patients with chronic hepatitis C
due to genotype 3. In the setting of HIV infection, other factors might as well
contribute to explain the greater fibrogenic effect of HCV genotype 3. Firstly, the
risk of hepatotoxicity following initiation of antiretroviral drugs is greater in patients
with HCV genotype 3 than with other genotypes. Secondly, the use of some
antiretrovirals could favour steatosis of the liver.
In agreement with prior studies, we found that patients carrying HCV genotype 1
presented higher plasma HCV-RNA levels than those infected with HCV genotype 3.
In HCV/HIV-coinfected hemophiliacs, this finding has been associated with more
rapid CD4 declines and faster HIV disease progression . However, in our knowledge
no studies have found a significant correlation between HCV-RNA levels and the
extent of liver fibrosis. Our results using elastometry confirm that there is no
significant correlation between HCV load and the extent of liver fibrosis.
ALT elevations are not a good marker of liver fibrosis. This is particularly true in
HIV-infected patients in whom other factors besides chronic hepatitis C, such as
antiretroviral drugs, may also contribute to ALT abnormalities [22]. However, the
probability of having F2-F4 estimates using elastometry in our patients with elevated
ALT was as high as 87% for HCV genotype 3 and 68% for other genotypes.
Conversely, it was below 40% in patients with normal ALT.
The simplicity and indulgence of transient elastometry as compared with liver biopsy
may probably facilitate in the near future a better understanding of the role of other
factors involved in the progression of liver fibrosis in the HCV/HIV-coinfected
population.
Conclusions
HCV genotype 3, older age and elevated ALT levels are independent predictors of
advanced liver fibrosis in HCV/HIV-coinfected patients.
Transient elastometry seems to be a valid method to study liver fibrosis in
HIV/HCV coinfected patients.
Contact: [email protected]
Abstract
Background: Chronic hepatitis C leads to progressive liver fibrosis, which is
accelerated in HCV/HIV-coinfected patients. Therapy with interferon (IFN) +/- ribavirin
(RBV) for 6 to 12 months allows reaching sustained virological response (SVR) in less
than half of coinfected patients. An improvement in liver fibrosis should be expected in
the subset of patients attaining SVR. However, this benefit has not been proven in
HCV/HIV-coinfected patients.
Material and Methods: All HIV/HCV-coinfected patients who had completed a full
course of HCV therapy with IFN (or pegylated IFN) +/- RBV in the past at our
institution and were seen during the last 12 months were identified. All had elevated
liver enzymes before receiving HCV therapy and some extent of hepatic fibrosis (F1F4) in the liver biopsy. Current liver fibrosis was measured in all using elastometry by
FibroScan.
Results: A total of 112 HIV/HCV-coinfected patients were analysed (76% males,
mean age 36±7 years, 67% on HAART). HCV genotype distribution was: 1 (70%), 3
(24%) and 4 (6%). A total of 44 had SVR while the remaining 68 were non-responders
or relapsers. The main demographic features were comparable between both groups.
Information for other variables is recorded in the table.
F3-F4 estimates were less frequent in SVR than in non-SVR (OR 2.6; p=0.04).
Interestingly, in patients with SVR the mean lag between the end of HCV therapy and
elastometry assessment was longer in patients showing F0-F1 as compared with
those with F2-F4 (38 vs 22 months; p=0.06). Moreover, all 3 patients cured ≥10 years
earlier were F0-F1.
Conclusions: SVR after IFN-based therapies may lead to regression of HCV-related
liver fibrosis in HIV-coinfected patients. However, long periods of time seem to be
required to show this benefit.
P. Barreiro, P. Labarga, N. Simarro, M. Núñez, L. Martín-Carbonero, M. Romero, P. Rivas, J. García-Samaniego, J. González-Lahoz and V. Soriano
Service of Infectious Diseases. Hospital Carlos III, Madrid, Spain
Table 1. Main characteristics of the HCV/HIV co-infected population examined
with FibroScan following a prior course of IFN (or pegylated IFN) ± RBV therapy.
Table 3. Factors associated with less liver stiffness (F0-F2 vs F3-F4) by FibroScan in
HCV/HIV co-infected patients who attained sustained virological response after a prior
course of IFN (or pegylated IFN) ± RBV therapy.
Figure 2
Results
A total of 106 consecutive HIV/HCV coinfected
patients that had received a full course of
(peg)IFN±RBV were examined with FibroScan
between September 2004 and December 2005. In
three instances elastometry was not available due to
severe obesity, so that the analyses were performed
in 103 patients. Among these, 69 did not respond to
therapy and 34 were sustained virological
responders. The main characteristics of the study
population are depicted in Table 1. As shown, most
of them were males (67%) and mean age was 43
years; ALT values were normal in responders and,
on average, elevated in non-responders (24 vs 80
IU/L, p<0.001). There were no differences between
responders and non responders regarding HIVrelated parameters (viral load (1.87 log copies/ml),
CD4 count (597 cells/L), proportion under HAART
(83%), or HAART modality). Non-responders had a
mean HCV load of 5.68 log IU/mL, while all
responders presented undetectable values; the
distribution of HCV genotypes was different between
these two groups, there were more genotypes 1 in
non-responders (75 vs 37%, p<0.001) and more
genotypes 3 in responders (56 vs 17%, p<0.001).
Importantly, the lag between the end of (peg)IFN
±RBV therapy and FibroScan examination was long
and comparable between the two groups (40
months). Mean liver stiffness resulted significantly
lower in responders as compared with nonresponders (6.6 vs 11.7 KPa, p<0.001); the
distribution of patients according to estimated
Metavir scores is shown in the next figure:
Table 2. Factors associated with less liver stiffness (F0-F2 vs F3-F4) by FibroScan in HCV/HIV
co-infected patients who had received a prior course of IFN (or pegylated IFN) ± RBV therapy.
Table 4. Factors associated with less liver stiffness (F0-F2 vs F3-F4) by FibroScan
in HCV/HIV co-infected patients who did not attained sustained virological response
after a prior course of IFN (or pegylated IFN) ± RBV therapy.
1,2
50
1,0
40
100%
,8
80%
F4 (>12 KPa)
F3 (9.5-12 KPa)
F2 (7.1-9.4 KPa)
F0-F1 (<7.1 KPa)
60%
40%
20%
Sustained virological response
after IFN±RBV:
,6
OR 3.94 (95% CI, 1.39-11.11)
[p=0.01]
,4
No
,2
SV- non-responders
20
rho: 0.25 (95% CI, 0.04 – 0.96) [p=0.03]
Sustained virological response
after IFN±RBV:
Conclusion:
Sustained virological response to anti-HCV therapy seems to be
associated with regression in liver fibrosis.
0,0
Yes
-,2
rho: -0.39 (-0.64 – -0.06) [p=0.02]
0
40
20
SV-responders
30
10
0
0%
Yes
80
60
120
100
160
0
140
Figure 2
Time (months)
The comparison between patients with F0-F2 and those with F3-F4
estimates at FibroScan is shown in Table 2. No differences were
found regarding demographic parameters. Patients with higher grades
of fibrosis presented with higher ALT levels (83 vs 47 IU/L, p=0.001)
and lower platelet counts (169 vs 199 per L, p=0.01). While HIV
related parameters were comparable, in patients with ≥F3 vs <F3, the
HCV load was greater (5.1 vs 3.2 log IU/mL, p=0.002) and the
proportion of genotypes 1 was higher (76 vs 54%, p=0.03). The
proportion of responders was higher in the group of patients with <F3
vs ≥F3 (48 vs 10%, p<0.001). The lag between the end of anti-HCV
therapy and FibroScan assessment was comparable between the two
groups. Only attaining SVR after anti-HCV therapy was related with
lower liver fibrosis in the univariate analysis. We also analyzed the
influence of different variables on the degree of liver stiffness in
patients that had attained SVR and in non-responders. We found no
significant differences in the group of responders (Table 3); however,
patients with lower grades of liver fibrosis had a longer duration of
sustained anti-HCV treatment response (40 months) than those with
more fibrosis (18 months).
In patients with persistent HCV viremia, if more advanced liver fibrosis
was detected, ALT values were greater (91 vs 68 IU/L, p=0.06) and
platelet counts were lower (169 vs 196 per L, p=0.05) (Table 4).
Interestingly, the length of persistent viremia after the end of anti-HCV
therapy was higher as the degree of liver stiffness was greater (50
months in F3-F4 and 30 months in F0-F2, p=0.02). The lag between
anti-HCV therapy and FibroScan was the only variable associated
with the extent of liver fibrosis in the multivariate analysis.
We performed a survival analysis to compare, between responders
and non-responders, the detection of F3-F4 along time after end of
anti-HCV therapy (Figure 2). As shown, an accumulation of advanced
fibrosis was observed in patients with persistent HCV viremia, while
the incidence of this adverse outcome remained were stable in
patients that had attained SVR. The difference between the curves
obtained was statistically significant (p=0.01). Finally, a correlation
analysis was done, in responders and in non-responders, in order to
estimate the influence of time after anti-HCV therapy on the
progression of liver fibrosis (Figure 3). In patients with persistent
viremia a direct and significant correlation was observed between
time after therapy and the degree of liver fibrosis (rho: 0.25, p=0.03).
Conversely, the longer the time after therapy in patients that had
attained SVR to (peg)IFN±RBV, the less intense the degree of liver
stiffness detected by FibroScan (rho: -0.39, p=0.02).
Discussion:
We have evaluated the long-term impact on liver fibrosis of sustained
HCV clearance. Patients attaining SVR to anti-HCV regimens were
compared with those that had viral rebound after therapy. The most
striking finding was that, responders presented significantly lower liver
stiffness than those with persistent HCV replication. These results
underscore the importance of pegIFN-RBV therapy in patients with
chronic hepatitis C as the benefits of long-term viral clearance on liver
fibrosis worth the effort. This affirmation is probably more valid for
HIV/HCV coinfected patients in whom the progression of liver fibrosis
is accelerated with respect to HCV monoinfected patients.
BMI, body mass index; PI, protease inhibitors; NAN, non-nucleoside analogs; NA, nucleoside analogs; ddX;
dideoxy-nucleosides; FS, FibroScan; OR, odds ratio; CI, confidence interval; ns, not significant; na, not applicable.
Median liver stiffness (KPa)
Patients and Methods
All patients with HIV/HCV coinfection that had received a
full course of (peg)IFN ±RBV therapy were identified and
invited to undergo transient elastometry. Main laboratory
parameters (ALT, CD4 count, HIV-RNA, HCV load, etc.)
were recorded at the last control; there were no lags
greater than 4 months between elastometry and
laboratory testing. HCV load was measured using a
commercial real-time PCR assay (Cobas Taqman; Roche
Diagnostic Systems, Pleasanton, CA). HCV genotypes
were assessed using a commercial reverse hybridisation
method (InnoLiPA HCV II; Innogenetics, Ghent, Belgium).
Liver stiffness was determined using transient elastometry
(figure 1). Briefly, the hepatic region of the patients was
explored with an ultrasound transducer that was placed in
the right intercostal spaces. When the echography
window showed the characteristic image of liver tissue, an
elastic shear wave was emitted by the vibration of the
ultrasound probe. The speed of propagation of this
vibration through the liver parenchyma was calculated
according to ultrasound scanning. On the basis of
physical principles, the stiffer the liver the faster the
vibration would pass through the organ. It has been
shown that the AUROC curve for advanced liver fibrosis
(bridging fibrosis to overt cirrhosis (F3-F4 in the Metavir
score) was 97% when elastometry rendered liver stiffness
values >9.5 KPa.
Given the cross-sectional nature of the study, the
association of multiple variables with the two distinct
groups, patients with minor/moderate (F0-F2) and
advanced liver fibrosis (F3-F4), were analysed in uni- and
multivariate analyses.
859
Risk for liver stiffness >9.5 KPa (Metavir F3-F4)
Introduction
Chronic hepatitis C is a relevant cause of morbidity and
mortality in patients with HIV infection. Treatment with the
combination of (peg)interferon (IFN) plus ribavirin (RBV) for
6 to 12 months may provide sustained clearance of HCV
from the plasmatic compartment in a significant number of
patients, 30-45% across studies. Some studies have shown
that patients attaining sustained virological response to antiHCV therapy present fewer liver complications than nonresponders in the long term. There are other reports
showing a regression in liver fibrosis years after the
achievement of HCV sustained clearance. Herein, we have
examined the degree of liver fibrosis according to transient
elastometry in a group of HIV/HCV coinfected patients that
received treatment with (peg)IFN±RBV in order to analyze
the impact of HCV clearance on liver histology.
Sustained Virological Response Following HCV Therapy is Associated
with Regression of Liver Fibrosis in HCV/HIV-Coinfected Patients
40
20
80
60
No
120
100
160
140
Figure 3
Time (months)
Contact: [email protected]