Abstract

Background. The objective of this study was to determine the efficacy of pegylated interferon (peg-IFN) plus ribavirin (RBV) in human immunodeficiency virus (HIV)–infected patients with hepatitis C virus (HCV)–related compensated liver cirrhosis, as well as the predictors of response in these individuals.

Methods. All subjects enrolled in a prospective cohort of 841 HIV/HCV-coinfected patients who received peg-IFN and RBV and who had a liver biopsy or a liver stiffness measurement within the year before starting peg-IFN plus RBV were included in this study. The sustained virologic response (SVR) rate and predictors of SVR response were analyzed.

Results. A total of 629 patients were included in this study; 175 (28%) had cirrhosis. In an intention-to-treat analysis, 44 (25%) patients with cirrhosis and 177 (39%) without cirrhosis achieved SVR (P = .001). Among patients with cirrhosis, SVR was observed in 14%, 47%, and 30% of individuals with HCV genotypes 1, 2–3, and 4, respectively. Discontinuation of therapy owing to adverse events was observed in 30 (17%) individuals with cirrhosis and 37 (8%) subjects without cirrhosis (P = .001).

Conclusions. The efficacy of peg-IFN plus RBV among HIV/HCV-coinfected patients with cirrhosis is lower than in those without cirrhosis, although this antiviral combination still leads to a substantial rate of SVR in those carrying HCV genotype 3. A higher rate of discontinuations of HCV therapy due to adverse events among cirrhotic patients could partially explain the differences in the SVR rate between both populations.

Hepatitis C virus (HCV)–related liver disease is a major cause of morbidity and mortality in human immunodeficiency virus (HIV)–infected patients, given that HCV infection shows a more aggressive behavior in the coinfected population [1–3]. In fact, progression to advanced chronic hepatitis C and cirrhosis is faster and, once decompensated cirrhosis emerges, death due to liver failure occurs in the short term [4–6]. HCV eradication is considered to be the best tool to control the progression of liver disease in HIV/HCV-coinfected individuals. Thus, the achievement of a sustained virologic response (SVR) after treatment with pegylated interferon (peg-IFN) plus ribavirin (RBV) reduces the risk of hepatocellular carcinoma, end-stage liver disease, and mortality due to liver failure in these patients [7]. Consequently, therapy against HCV infection is a priority among HIV-infected individuals with advanced liver fibrosis.

It is known that compensated liver cirrhosis is a predictor of worse response to peg-IFN plus RBV in HCV-monoinfected patients [8, 9]. Nevertheless, the information regarding treatment with peg-IFN plus RBV in HIV/HCV-coinfected individuals with compensated cirrhosis is very limited. Indeed, only 1 study has specifically assessed this topic [10]. This study included only 41 HIV-coinfected individuals with cirrhosis assessed using transient elastometry (TE). Surprisingly, this study showed similar SVR rates between patients with and without cirrhosis [10]. On the other hand, the influence of several potential predictors of response, such as liver stiffness (LS) values at baseline or interleukin 28B (IL-28B) genotype on the likelihood of SVR in HIV-infected patients with cirrhosis treated with peg-IFN plus RBV is unknown, as they were not analyzed in the above-mentioned survey [10]. Therefore, larger studies are needed to clarify these issues in order to improve the management of HCV therapy in HIV-infected individuals with compensated liver cirrhosis.

We conducted this study whose objective was to determine the efficacy of peg-IFN plus RBV in HIV-infected patients with HCV-related compensated liver cirrhosis, as well as the predictors of response to such a therapy in these individuals.

PATIENTS AND METHODS

Study Population and Follow-up

From December 2001 to December 2011, a prospective cohort of 841 HIV/HCV-coinfected individuals treated with peg-IFN plus RBV as their first therapy against HCV infection was followed in 10 centers from Spain. All individuals included in this cohort were followed at least every 4 weeks during the first 24 weeks of treatment and every 2 months during the remaining treatment period. Evaluations of adverse events were carried out at every visit. Plasma HCV RNA was assessed at least at weeks 12, 24, and 48 during treatment, as well as at week 24 after treatment completion.

To accomplish the goals of our study, patients from this cohort who fulfilled the following criteria were included: (1) age >18 years; (2) available liver biopsy or LS measurement within the year before starting HCV therapy; (3) evaluable response to therapy against HCV infection.

Treatment Modality

All subjects were treated with peg-IFN alfa-2a (180 µg/week) or peg-IFN alfa-2b (1.5 µg/kg/week) along with oral RBV (800 to 1200 mg/day). Treatment duration was 48 weeks for carriers of HCV genotype 1 or 4. Those patients bearing HCV genotype 2 or 3 received therapy during 24 weeks if they showed undetectable plasma HCV RNA load at week 4, and 48 weeks if otherwise. At weeks 12 and 24, peg-IFN and RBV treatment was prematurely discontinued in nonresponders. Rapid virological response (RVR) was defined as undetectable serum HCV-RNA at week 4 of therapy. Nonresponse was defined as a failure to reach a decline of at least 2 log10 in HCV-RNA levels at week 12 of therapy or detectable serum HCV-RNA 24 weeks after beginning therapy. Relapse was defined as detectable plasma HCV-RNA concentration after having reached undetectable serum HCV-RNA at the end of therapy. Dose adjustments for peg-IFN and RBV and the use of growth factors were done according to the criteria of the physician who was in charge of the patient.

Laboratory Determinations

Plasma HCV-RNA load was measured using a quantitative polymerase chain reaction assay (Cobas Amplicor HCV Monitor, Roche Diagnostic Systems, Branchburg, New Jersey: detection limit of 600 IU/mL; Cobas AmpliPrep-Cobas TaqMan, Roche Diagnostic Systems, Meylan, France: detection limit of 50 IU/mL; Cobas TaqMan, Roche Diagnostic Systems, Pleasanton, California: detection limit of 10 IU/mL, according to the time when the determination was carried out). The IL-28B single nucleotide polymorphism rs12979860 was genotyped using a custom TaqMan assay (Applied Biosystems, Foster City, California) on DNA isolated from whole blood samples, following the manufactureŕs instructions, on a Stratagene MX3005 thermocycler using MXpro software (Stratagene, La Jolla, California). IL-28B genotype determination was performed retrospectively on frozen (−80°C) serum samples.

Liver Fibrosis Assessment

The determination of baseline liver fibrosis could be based on either histology or TE performed 1 year before starting HCV treatment. A single experienced pathologist at each center evaluated liver biopsy specimens, whereas TE was performed according to a standardized technique [11]. Liver biopsy that showed fibrosis stage 4 (F4), according to the Scheuer scoring system [12], or LS values ≥14.6 kPa measured by TE (FibroScan, Echosens, Paris, France) were considered as cirrhosis [11].

Statistical Analysis

The primary endpoint of this study was SVR, defined as undetectable serum HCV-RNA 6 months after the end of peg-IFN plus RBV. The efficacy analysis of HCV therapy was done according to the principle of intention to treat (ITT), considering missing values as failures, and by per-protocol analysis. Additionally, we determined the association between SVR rate and the following variables: age, sex, risk factor for HCV transmission, baseline plasma HCV-RNA load, alanine aminotransferase and low-density lipoprotein (LDL) cholesterol levels at baseline, IL-28B genotype (CC vs non-CC), Centers for Disease Control and Prevention clinical category, CD4+ cell count and HIV-RNA at baseline, antiretroviral therapy, self-reported compliance to therapy, type of peg-IFN, daily RBV by weight, and LS values at baseline.

Continuous variables were expressed as median (interquartile range) and categorical variables as number (percentage; 95% confidence interval [CI]). Continuous variables were compared using the Student t test if a normal distribution was proven and the Mann-Whitney U test otherwise, whereas the categorical variables were analyzed applying the χ2 test or the Fisher exact test, when applicable. Those factors that were considered clinically relevant were entered into a logistic regression model to identify independent predictive factors for SVR in the study population and in the subgroup of individuals with cirrhosis. The adjusted odds ratio (AOR) and the respective 95% CI were calculated. All P values < .05 were considered statistically significant. Data were analyzed using the SPSS statistical software package release 19.0 (SPSS Inc, Chicago, Illinois) and Stata software, version 9.0 (StataCorp, College Station, Texas).

Ethical Aspects

The study was designed and performed according to the Helsinki declaration. The ethics committee of the Hospital Universitario de Valme (Spain) approved the study.

RESULTS

Characteristics of the Study Population

A total of 629 patients were included in this study (Figure 1). There were no individuals excluded from this study because response to peg-IFN plus RBV was unknown. One hundred seventy-five (28%) subjects had compensated cirrhosis and 454 (72%) individuals were noncirrhotic patients (Figure 1). Diagnosis of cirrhosis was proven by biopsy in 98 (56%) patients and by TE in 77 (44%) individuals. Ninety (51%) cirrhotic patients had an LS measurement. One hundred twenty-eight (73%) individuals with cirrhosis harbored HCV genotype 1 or 4 vs 323 (71%) of those without cirrhosis (P = .6). Among the 104 (60%) cirrhotic patients and 222 (49%) noncirrhotic subjects with rs12979860 single-nucleotide polymorphism genotype available (P = .01), 51 (49%) and 74 (33%), respectively, were identified as IL-28B CC carriers (P = .007). The remaining baseline characteristics of both groups are summarized in Table 1.

Table 1.

Features of the Study Population (N = 629)

Variables Cirrhosis (n = 175) Noncirrhosis (n = 454) P Value 
Age, yearsa 43 (39–46) 41 (37–44) .01 
Male sex 150 (86) 358 (79) .05 
Baseline body weight, kga 70 (62–79) 68 (59–75) .03 
Former IDU 157 (89) 389 (86) .2 
HCV genotype   .5 
 1 101 (58) 249 (55)  
 2 5 (3) 6 (1)  
 3 42 (24) 125 (28)  
 4 27 (15) 74 (16)  
Baseline serum ALT, IU/La 79 (51–116) 69 (47–105) .4 
rs12979860 genotypeb   .02 
 CC 51 (49) 74 (33)  
 CT 43 (41) 120 (54)  
 TT 10 (10) 28 (13)  
Available LS at baseline 90 (51) 190 (42) .03 
Baseline LS values, kPa 26.8 (18.1–36) 8.3 (6.5–10.2) <.001 
Baseline HCV-RNA load, log IU/mLa 5.9 (5.5–6.4) 5.9 (5.2–6.4) .7 
Use of peg-IFN alfa-2a 152 (87) 344 (76) .002 
RBV dose/weight, mg/kg/da 14.8 (13.3–16.2) 14.7 (13.1–16.6) .3 
Baseline hemoglobin level, g/dLa 14.3 (13.1–15.7) 15.1 (14–16.1) <.001 
Baseline neutrophil count, cells/μLa 2600 (1760–3500) 3060 (2350–4080) <.001 
Baseline platelet count, cells/μLa 115 000 (84 000–149 000) 182 000 (145 000–226 000) <.001 
Compliance with HCV therapy ≥80% 157 (90) 397 (87) .4 
CDC C clinical category 58 (33) 148 (33) 0.9 
Baseline CD4 cell count/μLa 422 (278–597) 499 (366–676) .001 
Baseline undetectable HIV load 153 (87) 346 (76) .002 
Baseline LDL cholesterol, mg/dLa,c 78 (60–100) 85 (63–110) .05 
Antiretroviral therapy 168 (96) 389 (86) <.001 
Use of abacavir 36 (21) 80 (18) .4 
Use of growth factors 43 (25) 82 (18) .06 
Dose reduction of peg-IFN or RBV 52 (30) 89 (20) .03 
Variables Cirrhosis (n = 175) Noncirrhosis (n = 454) P Value 
Age, yearsa 43 (39–46) 41 (37–44) .01 
Male sex 150 (86) 358 (79) .05 
Baseline body weight, kga 70 (62–79) 68 (59–75) .03 
Former IDU 157 (89) 389 (86) .2 
HCV genotype   .5 
 1 101 (58) 249 (55)  
 2 5 (3) 6 (1)  
 3 42 (24) 125 (28)  
 4 27 (15) 74 (16)  
Baseline serum ALT, IU/La 79 (51–116) 69 (47–105) .4 
rs12979860 genotypeb   .02 
 CC 51 (49) 74 (33)  
 CT 43 (41) 120 (54)  
 TT 10 (10) 28 (13)  
Available LS at baseline 90 (51) 190 (42) .03 
Baseline LS values, kPa 26.8 (18.1–36) 8.3 (6.5–10.2) <.001 
Baseline HCV-RNA load, log IU/mLa 5.9 (5.5–6.4) 5.9 (5.2–6.4) .7 
Use of peg-IFN alfa-2a 152 (87) 344 (76) .002 
RBV dose/weight, mg/kg/da 14.8 (13.3–16.2) 14.7 (13.1–16.6) .3 
Baseline hemoglobin level, g/dLa 14.3 (13.1–15.7) 15.1 (14–16.1) <.001 
Baseline neutrophil count, cells/μLa 2600 (1760–3500) 3060 (2350–4080) <.001 
Baseline platelet count, cells/μLa 115 000 (84 000–149 000) 182 000 (145 000–226 000) <.001 
Compliance with HCV therapy ≥80% 157 (90) 397 (87) .4 
CDC C clinical category 58 (33) 148 (33) 0.9 
Baseline CD4 cell count/μLa 422 (278–597) 499 (366–676) .001 
Baseline undetectable HIV load 153 (87) 346 (76) .002 
Baseline LDL cholesterol, mg/dLa,c 78 (60–100) 85 (63–110) .05 
Antiretroviral therapy 168 (96) 389 (86) <.001 
Use of abacavir 36 (21) 80 (18) .4 
Use of growth factors 43 (25) 82 (18) .06 
Dose reduction of peg-IFN or RBV 52 (30) 89 (20) .03 

Data are presented as No. (%) unless otherwise specified.

Abbreviations: ALT, alanine aminotransferase; CDC, Centers for Disease Control and Prevention; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IDU, intravenous drug user; LDL, low-density lipoprotein; LS, liver stiffness; peg-IFN, pegylated interferon; RBV, ribavirin.

a Median (Q1–Q3).

b Available in 104 cirrhotic and 222 noncirrhotic patients.

c Available in 131 cirrhotic and 339 noncirrhotic patients.

Figure 1.

Study flow chart. Abbreviations: HCV, hepatitis C virus; HIV, human immunodeficiency virus; peg-IFN, pegylated interferon; RBV, ribavirin; SVR, sustained virological response.

Figure 1.

Study flow chart. Abbreviations: HCV, hepatitis C virus; HIV, human immunodeficiency virus; peg-IFN, pegylated interferon; RBV, ribavirin; SVR, sustained virological response.

Response to HCV Therapy

In the ITT analysis, a total of 221 (35.1%; 95% CI, 32%–39%) individuals presented SVR in the overall study population. Forty-four (25.1%; 95% CI, 19%–33%) patients with cirrhosis achieved SVR compared to 177 (38.9%; 95% CI, 35%–44%) of those without cirrhosis (P = .001). SVR rates were significantly lower in cirrhotic patients harboring HCV genotype 1 or genotype 2–3 than in noncirrhotic subjects, whereas there were no differences in HCV genotype 4 carriers between the 2 groups (Figure 2). Nonresponse was observed in 58 (33%) and 133 (29%) patients with and without cirrhosis, respectively (P = .3). Other virological responses in both groups are depicted in Figures 1 and 3. In the subgroup of 74 cirrhotic patients in whom a HCV viral load determination had been carried out at week 4 of therapy, 14 (82%) individuals with RVR showed SVR compared with 10 (17.5%) subjects without RVR (P < .0001). Among 12 cirrhotic patients with genotype 2 or 3 and RVR who received peg-IFN plus RBV during 24 weeks, 8 (66%) patients reached SVR, 2 (16%) individuals had relapse, and 2 (16%) subjects discontinued HCV therapy by their own decision.

Figure 2.

Sustained virological response rates to pegylated interferon plus ribavirin in cirrhotic and noncirrhotic patients according to hepatitis C virus genotype (intention-to-treat analysis). Abbreviation: SVR, sustained virological response.

Figure 2.

Sustained virological response rates to pegylated interferon plus ribavirin in cirrhotic and noncirrhotic patients according to hepatitis C virus genotype (intention-to-treat analysis). Abbreviation: SVR, sustained virological response.

Figure 3.

Virological responses at different time points in cirrhotic and noncirrhotic patients. Abbreviations: ETR, end of treatment response; RVR, rapid virological response.

Figure 3.

Virological responses at different time points in cirrhotic and noncirrhotic patients. Abbreviations: ETR, end of treatment response; RVR, rapid virological response.

Among the 521 patients included in the per-protocol analysis, 44 (33%) cirrhotic patients showed SVR compared with 177 (46%) subjects without cirrhosis (P = .007). In the same analysis efficacy, 91 (67.4%) individuals with cirrhosis presented lack of SVR (including nonresponse, viral breakthrough, and relapse) vs 208 (53.9%) subjects without cirrhosis (P = .006).

Discontinuation of therapy due to adverse events was observed in 30 (17%) and 37 (8%) individuals with and without cirrhosis, respectively (P = .001). Nine (5%) subjects with cirrhosis were prematurely withdrawn from HCV treatment because of liver decompensation. Among these patients who developed hepatic decompensation, 7 (78%) and 2 (22%) individuals had a Child-Turcotte-Pugh score A and B, respectively, whereas 1 (11%) subject was treated with didanosine during HCV therapy. One (25%) patient of 4 cirrhotic subjects with available LS who developed liver decompensation had an LS >30 kPa. The frequency of dose reductions of peg-IFN or RBV and use of growth factors were higher in patients with cirrhosis (Table 1).

In the multivariate analysis, noncirrhosis (AOR, 2.02; 95% CI, 1.1–3.4; P = .009) was a predictor of better SVR in the study population, independently of HCV genotype 2 or 3, lower baseline plasma HCV-RNA load, IL-28B genotype CC, baseline LDL cholesterol levels ≥100 mg/dL and adherence to therapy >80%.

Predictors of SVR in HIV/HCV-Coinfected Patients With Cirrhosis

In the ITT analysis, 17 (33.3%) individuals with cirrhosis who were IL-28B genotype CC carriers reached SVR vs 9 (17%) subjects with IL-28B genotype CT or TT (P = .054). SVR rates were 42.5% in CC patients and 19.6% in CT/TT subjects in the per-protocol analysis (P = .02). The median (Q1–Q3) LS at baseline in patients with and without SVR was 25 (17–30) kPa and 28 (20–38) kPa (P = .1), respectively. Twenty of 57 individuals (35.1%) with an LS value <30 kPa achieved SVR compared with 6 of 33 subjects (18.2%) with an LS value ≥30 kPa (P = .08). There were no statistically significant differences in the main features related to HCV therapy according to baseline LS value categorized as <30 kPa and ≥30 kPa (Table 2).

Table 2.

Main Features Related to Hepatitis C Virus Therapy Among Patients with Compensated Cirrhosis According to Baseline Liver Stiffness Value Categorized as <30 kPa and ≥30 kPa (n = 90)

Parameter LS <30 kPa Group (n = 57) LS ≥30 kPa Group (n = 33) P Value 
HCV genotype 1 or 4 37 (65) 26 (79) .1 
Baseline HCV-RNA >600 000 IU/mL 34 (59) 20 (61) .9 
Nonresponse 20 (35) 16 (48) .2 
Relapses 3 (5) 4 (12) .2 
Withdrawal due to adverse events 9 (16) 4 (12) .6 
Voluntary dropout 3 (5) 3 (9) .4 
Use of growth factors 18 (32) 12 (36) .6 
Dose reduction of peg-IFN or RBV 13 (23) 7 (21) .9 
Parameter LS <30 kPa Group (n = 57) LS ≥30 kPa Group (n = 33) P Value 
HCV genotype 1 or 4 37 (65) 26 (79) .1 
Baseline HCV-RNA >600 000 IU/mL 34 (59) 20 (61) .9 
Nonresponse 20 (35) 16 (48) .2 
Relapses 3 (5) 4 (12) .2 
Withdrawal due to adverse events 9 (16) 4 (12) .6 
Voluntary dropout 3 (5) 3 (9) .4 
Use of growth factors 18 (32) 12 (36) .6 
Dose reduction of peg-IFN or RBV 13 (23) 7 (21) .9 

All data are presented as No. (%).

Abbreviations: HCV, hepatitis C virus; LS, liver stiffness; peg-IFN, pegylated interferon; RBV, ribavirin.

In the multivariate analysis, HCV genotype 2 or 3, lower baseline plasma HCV-RNA load and a baseline LS value <30 kPa were independent predictors of SVR among HIV/HCV-coinfected patients with compensated cirrhosis (Table 3). Given that LS value at baseline was not available in all patients, a multivariate analysis was performed excluding this variable. In this analysis, only HCV genotype 2 or 3 (AOR, 5.0; 95% CI, 1.5–16.8; P = .008) and baseline plasma HCV-RNA load ≤600 000 IU/mL (AOR, 3.6; 95% CI, 1.3–10.1; P = .012) were associated with SVR. Likewise, when we performed the multivariate analysis excluding those patients in whom the HCV course of therapy were not completed due to causes other than nonresponse or virological breakthrough (per-protocol analysis), IL-28B CC genotype (AOR, 3.7; 95% CI, 1.1–12.6; P = .035) was associated with SVR along with the same predictors observed in the ITT analysis.

Table 3.

Predictors of Sustained Virologic Response in HIV-Infected Patients With Cirrhosis in the Intention-to-Treat Analysis

Variables SVR, No. (%) P Value (Univariate) Adjusted OR(95% CI) P Value (Multivariate) 
Age, yearsa 
 <42.8 23 (26) .7 … … 
 ≥42.8 21 (24)    
Sex 
 Male 38 (25) .8 … … 
 Female 6 (23)    
Injecting drug user 
 Yes 41 (26) .2 … … 
 No 3 (14)    
CDC clinical category 
 A–B 31 (28) .5 … … 
 C 13 (23)    
LS values at baseline 
 <30 kPa 20 (35) .08 4.1 (1.02–16.7) .045 
 ≥30 kPa 6 (18)    
IL-28 genotype 
 CC 17 (33) .06 2.3 (.8–6.6) .09 
 Non-CC 9 (17)    
Baseline HCV viral load 
 ≤600 000 IU/mL 27 (40) <.001 6.0 (1.8–20) .004 
 >600 000 IU/mL 17 (16)    
HCV genotype 
 1–4 22 (17) <.001 8.9 (2.7–29) <.001 
 2–3 22 (44)    
Type of peg-IFN 
 Alfa-2a 40 (26) .3 … … 
 Alfa-2b 4 (17)    
Exposure to HCV therapy 
 <80% 1 (10) .2 … … 
 ≥80% 43 (26)    
Baseline undetectable plasma HIV-RNA 
 Yes 42 (27) .05  4.9 (.56–43) .15 
 No 2 (9)    
Baseline CD4 cell count/μLa 
 ≥422 26 (29) .2 … … 
 <422 18 (21)    
Baseline LDL cholesterol (mg/L) 
 ≥100 11 (32) .2 … … 
 <100 21 (22)    
Antiretroviral therapy 
 Yes 42 (25) .8 … … 
 No 2 (29)    
Variables SVR, No. (%) P Value (Univariate) Adjusted OR(95% CI) P Value (Multivariate) 
Age, yearsa 
 <42.8 23 (26) .7 … … 
 ≥42.8 21 (24)    
Sex 
 Male 38 (25) .8 … … 
 Female 6 (23)    
Injecting drug user 
 Yes 41 (26) .2 … … 
 No 3 (14)    
CDC clinical category 
 A–B 31 (28) .5 … … 
 C 13 (23)    
LS values at baseline 
 <30 kPa 20 (35) .08 4.1 (1.02–16.7) .045 
 ≥30 kPa 6 (18)    
IL-28 genotype 
 CC 17 (33) .06 2.3 (.8–6.6) .09 
 Non-CC 9 (17)    
Baseline HCV viral load 
 ≤600 000 IU/mL 27 (40) <.001 6.0 (1.8–20) .004 
 >600 000 IU/mL 17 (16)    
HCV genotype 
 1–4 22 (17) <.001 8.9 (2.7–29) <.001 
 2–3 22 (44)    
Type of peg-IFN 
 Alfa-2a 40 (26) .3 … … 
 Alfa-2b 4 (17)    
Exposure to HCV therapy 
 <80% 1 (10) .2 … … 
 ≥80% 43 (26)    
Baseline undetectable plasma HIV-RNA 
 Yes 42 (27) .05  4.9 (.56–43) .15 
 No 2 (9)    
Baseline CD4 cell count/μLa 
 ≥422 26 (29) .2 … … 
 <422 18 (21)    
Baseline LDL cholesterol (mg/L) 
 ≥100 11 (32) .2 … … 
 <100 21 (22)    
Antiretroviral therapy 
 Yes 42 (25) .8 … … 
 No 2 (29)    

Abbreviations: CDC, Centers for Disease Control and Prevention; CI, confidence interval; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IL-28, interleukin 28; LDL, low-density lipoprotein; LS, liver stiffness; OR, odds ratio; peg-IFN, pegylated interferon; SVR, sustained virological response.

a Categorized by median.

DISCUSSION

The results reported here demonstrate that the efficacy of peg-IFN plus RBV among HIV-infected patients with HCV-related compensated liver cirrhosis is lower than among individuals without cirrhosis. Despite this fact, this antiviral combination still leads to an appreciable rate of SVR in cirrhotic patients carrying HCV genotype 3, whereas the impact of cirrhosis on the likelihood of SVR in patients bearing HCV genotype 4 seems to be lower than in patients with other genotypes.

To date, information on the efficacy of peg-IFN plus RBV in HIV-infected patients with compensated HCV-related cirrhosis is scarce. Moreover, available data about the response to HCV therapy in these patients come from clinical trials that included a limited number of patients and from one cohort study carried out also with a small population [10, 13–16]. In fact, to our knowledge, the largest study had included 41 subjects with compensated cirrhosis diagnosed by TE. This study did not find differences in SVR rates between cirrhotic patients and those individuals without cirrhosis [10]. Thus, the results of the present study, including 175 cirrhotic patients, clarify the true impact of cirrhosis on the efficacy of peg-IFN plus RBV in HIV/HCV-coinfected individuals. Our data strongly support a negative influence of cirrhosis on the SVR likelihood in the coinfected population independently of other known predictors of poorer response to HCV therapy, such as HCV genotype, IL-28B genotype, baseline plasma LDL cholesterol levels, and HCV-RNA load at baseline.

As it has been observed in our study, a higher rate of discontinuations of peg-IFN plus RBV due to adverse events could partially explain a lower SVR rate among HIV/HCV-coinfected patients with cirrhosis. Other reasons why patients with cirrhosis respond worse to HCV therapy are unclear. It has been shown that disease severity is the factor that impaired virological response to a greater extent in patients with advanced chronic hepatitis C [17]. Data from the HALT-C trial suggested that several potential factors present in patients with more advanced disease could decrease SVR rate, such as impaired uptake or metabolism of antiviral medications, interference with immune mechanisms of viral clearance by cytokines or other factors mediating fibrosis, and refractoriness to the interferon signaling pathway [17]. In our study, a higher rate of lack of SVR was observed in those patients with cirrhosis in the per-protocol analysis. This finding suggests that other factors, probably related to antiviral mechanisms, could contribute to explain the lower efficacy achieved in cirrhotic patients. Specific studies are required in order to determine the mechanism that explains the effect of disease severity on virologic response in patients with HCV infection.

According to the results obtained in this study, LS at baseline is a predictive factor of SVR in patients with compensated cirrhosis receiving peg-IFN plus RBV treatment, a finding that has not been previously reported in this subgroup of patients. Thus, the efficacy of HCV therapy was lower in cirrhotic patients with LS values ≥30 kPa. This result is probably reflecting a lower SVR rate to peg-IFN plus RBV in those cirrhotic patients with higher severe disease, which is a known factor of worse response in subjects with chronic hepatitis C considered as a whole [17]. For this reason, a measurement of LS by TE is an excellent tool for the early identification of those patients with advanced fibrosis who should preferentially be evaluated for HCV treatment. Larger prospective studies are needed in order to determine the utility of this cutoff value, specifically 30 kPa, in clinical practice.

In the per-protocol analysis, we found that the rs12979860 genotype CC is associated with a better response to peg-IFN plus RBV treatment in HIV-infected patients with cirrhosis. Interestingly, in our study the rs12979860 CC was more common in cirrhotic patients than in individuals without cirrhosis. These results are similar to those reported in a recent study performed in HIV-infected patients [18], which suggested that IL-28B CC carriers may show a more rapid progression of HCV-related liver fibrosis. In contrast, other studies assessing this topic did not find a greater prevalence of IL-28B genotype CC in subjects with HCV-related cirrhosis with and without HIV infection [19–21]. Due to these contradictory results, further studies are required in order to clarify the impact of IL-28B genotype on fibrosis progression.

This study has some limitations. First, the diagnosis of cirrhosis was performed using TE instead of biopsy in a considerable percentage of patients. Nevertheless, different studies have showed that TE is highly reliable for the diagnosis of cirrhosis in HIV/HCV-coinfected individuals [11]. Second, IL-28B genotype determination was performed retrospectively. Thus, the proportion of patients with available IL-28B genotype was significantly higher in the cirrhosis group than in the noncirrhosis group, which could influence on the results found in this study about the relationship between the polymorphism rs12979860 and the response to peg-IFN plus RBV. In fact, in our study, we cannot exclude that IL-28B genotype was mainly performed in patients with more advanced liver disease.

According to our results, decisions in specific subgroups of coinfected patients regarding therapy with peg-IFN and RBV should not be modified due to the presence or not of cirrhosis. In our study, SVR rates observed in individuals with HCV genotype 3 receiving peg-IFN plus RBV were considerable. Likewise, there were no differences in the rate of response to this therapy between coinfected patients bore HCV genotype 4 with and without cirrhosis, although we cannot exclude that these results were due to low number of patients with genotype 4 included in this study. Therefore, currently, cirrhotic patients with HCV genotype non-1 must be evaluated for HCV treatment with peg-IFN plus RBV. Regarding treatment among genotype 1–coinfected patients with compensated cirrhosis, in our study, the efficacy of peg-IFN plus RBV found in this population was very low. Based on the available information in HCV-monoinfected patients and interim data reported in the coinfected population, these patients are the best candidates for triple therapy with a first-generation protease inhibitor against HCV infection, such as telaprevir or boceprevir, along with peg-IFN plus RBV [22–25].

In summary, although HIV-infected patients with compensated HCV-related cirrhosis are a hard-to-cure population, HCV therapy is a priority in these patients. Because of this, HCV therapy with peg-IFN plus RBV should be recommended to patients with genotype non-1 until more effective drugs are available. New drugs are needed to improve the efficacy of HCV therapy in HIV/HCV-coinfected patients with compensated liver cirrhosis.

Notes

Financial support. This work was supported in part by grants from the Ministerio de Sanidad (ISCIII-RETIC RD06/006), the Servicio Andaluz de Salud (Reference SAS/111239) and the Fundación para la Investigación y la Prevención del Sida en España (360799/09). J. A. P. has received an intensification grant from the Consejería de Salud of the Junta de Andalucía (Reference: AI-0021). A. R. is the recipient of a research grant from the Fundación Progreso y Salud, Consejería de Salud de la Junta de Andalucía (Reference AI-0011-2010). J. A. G. has received an intensification grant from the Instituto de Salud Carlos III.

Potential conflicts of interest. A. R. and J. A. P. have received consulting fees from GlaxoSmithKline, Bristol-Myers Squibb, Abbott Pharmaceuticals, Gilead, Merck Sharp & Dohme, Janssen-Cilag, and Boehringer Ingelheim. Both A. R. and J. A. P. have received research support from GlaxoSmithKline, Roche, Bristol-Myers Squibb, Schering-Plough, Abbott Pharmaceuticals, and Boehringer Ingelheim, and have received lecture fees from GlaxoSmithKline, Roche, Abbott Pharmaceuticals, Bristol-Myers Squibb, Gilead, Merck Sharp & Dohme, Janssen-Cilag, and Boehringer Ingelheim. J. M. has been an investigator in clinical trials supported by Roche, Bristol-Myers Squibb, and Abbott Pharmaceuticals. He has received lecture fees from Roche, Gilead, Boehringer Ingelheim, and Bristol-Myers Squibb, and consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb, and Merck Sharp & Dohme. All other authors report no potential conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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Author notes

a
Members of the Grupo HEPAVIR de la Sociedad Andaluza de Enfermedades Infecciosas.

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