María J. Ríos-Villegas

Clinical progression of hepatitis C virus–related chronic liver disease in human immunodeficiency virus–infected patients undergoing highly active antiretroviral therapy

Little is known about the natural history of liver disease in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)‐coinfected subjects under highly active antiretroviral therapy (HAART). The objectives of this study were to obtain information about the mortality, the incidence of hepatic decompensations, and the predictors thereof in this population. In a multicenter cohort study, the time to the first hepatic decompensation and the survival of 1,011 antiretroviral naïve, HIV/HCV‐coinfected patients who started HAART and who were followed prospectively were analyzed. After a median (Q1‐Q3) follow‐up of 5.3 (2.9–7.1) years, 59(5.83%) patients developed a hepatic decompensation and 69 (6.82%) died, 30 (43%) of them because of liver disease. The factors independently associated [HR (95% CI)] with the occurrence of hepatic decompensations were age older than 33 years [2.11 (1.18–3.78)], female sex [2.11 (1.07–4.15)], Centers for Disease Control stage C [2.14 (1.24–3.70)], a diagnosis of cirrhosis at baseline [10.86 (6.02–19.6)], CD4 cell gain lower than 100/mm3 [4.10 (2.18–7.69)] and less than 60% of the follow‐up with undetectable HIV viral load [5.23 (2.5–10.93)]. Older age [2.97 (1.18–7.50)], lack of HCV therapy [11.32 (1.44–89.05)], hepatitis D virus coinfection [16.15 (2.45–106.48)], a diagnosis of cirrhosis at recruitment [13.69 (5.55–34.48)], hepatic encephalopathy [62.5 (21.27–200)] and lower CD4 cell gain [3.63 (1.45–9.09)] were associated with mortality due to liver failure. Conclusion: End‐stage liver disease is the primary cause of death in HIV/HCV‐coinfected patients under HAART. Higher increase of CD4 cell counts, lack of markers of serious liver disease and therapy against HCV are factors associated with better hepatic outcome. (HEPATOLOGY 2007.)

Benefits From Sustained Virologic Response to Pegylated Interferon Plus Ribavirin in HIV/Hepatitis C Virus–Coinfected Patients With Compensated Cirrhosis

BACKGROUND The objective of this study was to determine the impact of sustained virologic response (SVR) to pegylated interferon (peg-IFN) plus ribavirin (RBV) on the incidence of liver-related complications and overall mortality in human immunodeficiency virus (HIV)-infected patients with compensated hepatitis C virus (HCV)-related cirrhosis. METHODS We included in this prospective cohort study 166 coinfected patients with compensated cirrhosis, who received peg-IFN plus RBV, to assess the time from the starting date of HCV therapy to the first hepatic decompensation and death due to any cause. RESULTS SVR was observed in 43 (25%) individuals. Two (4.6%) patients with SVR developed liver decompensation vs 33 (26.8%) individuals without SVR (P = .002). The incidence of liver-related complications was 0.89 cases per 100 person-years (95% confidence interval [CI], .11-3.1) in SVR patients and 6.4 cases per 100 person-years (95% CI, 4.5-8.9) in non-SVR patients. Factors independently associated with liver decompensation were non-SVR (hazard ratio [HR], 8.1; 95% CI, 1.08-61.5; P = .042) and MELD score ≥9 at baseline (HR, 2.9; 95% CI, 1.2-7.2; P = .016). Two (4.6%) patients with SVR died due to any cause compared with 22 (17.9%) individuals without SVR (P = .02). MELD score ≥9 (HR, 3.1; 95% CI, 1.3-7.7; P = .011) and non-SVR (HR, 8.0; 95% CI, 1.07-61; P = .043) were independently associated with overall mortality. CONCLUSIONS The achievement of SVR following peg-IFN plus RBV markedly reduces the incidence of liver-related decompensation and the overall mortality in HIV/HCV-coinfected patients with compensated cirrhosis.

Natural History of Compensated Hepatitis C Virus-Related Cirrhosis in HIV-Infected Patients

OBJECTIVE To provide information about the incidence and predictors of liver decompensation and death due to liver failure in human immunodeficiency virus (HIV)-infected patients with compensated hepatitis C virus (HCV)-related cirrhosis. METHODS Prospective cohort study of 154 HIV-HCV-coinfected patients with a new diagnosis of Child-Pugh-Turcotte (CPT) class A compensated cirrhosis. We evaluated time from diagnosis to the first liver decompensation and death from liver disease, as well as predictors of these outcomes. RESULTS Thirty-six patients (23.4%) developed liver decompensation. The incidence of liver decompensation was 6.40 cases per 100 person-years (95% confidence interval [CI], 4.18-9.38 cases per 100 person-years). Factors independently associated with liver decompensation were lack of HCV therapy (hazard ratio [HR], 3.38; 95% CI, 1.09-10.53; P = .035), baseline CD4 cell counts <or=300 cells/mm3 (HR, 2.12; 95% CI, 1.14-5.04; P = .021), CPT score 6 versus 5 (HR, 3.33; 95% CI, 1.39-7.69; P = .007), and a diagnosis of cirrhosis based on data other than biopsy or transient elastography (HR, 2.09; 95% CI, 1.05-4.16; P = .036 ). Fifteen patients (9.7%) died; 11 (73%) of these 15 died from liver disease (mortality due to liver failure, 2.44 deaths per 100 person-years; 95% CI, 1.21-4.36 deaths per 100 person-years). Hepatic encephalopathy as the first liver decompensation (HR, 20.67; 95% CI, 2.71-157.57; P = .003), baseline CD4 count <or=300/mm3 (HR, 0.24; 95% CI, 0.07-0.78; P = 0.17), and baseline CPT score 6 (HR, 4.50; 95% CI, 1.63-12.37; P = .004) were independently associated with liver-related death. CONCLUSIONS The incidence of clinical liver events in HIV-HCV-coinfected patients with CPT class A compensated cirrhosis is close to that previously reported in HCV-monoinfected patients. Lower baseline CD4 cell counts, lack of therapy against HCV, and higher CPT score are the factors related to the occurrence of clinical liver events. Minimal changes in CPT score have strong impact in the prognosis of this population.

Liver stiffness predicts clinical outcome in human immunodeficiency virus/hepatitis C virus-coinfected patients with compensated liver cirrhosis†

Our aim was to assess the predictive value of liver stiffness (LS), measured by transient elastography (TE), for clinical outcome in human immunodeficiency virus / hepatitis C virus (HIV/HCV)‐coinfected patients with compensated liver cirrhosis. This was a prospective cohort study of 239 consecutive HIV/HCV‐coinfected patients with a new diagnosis of cirrhosis, done by TE, and no previous decompensation of liver disease. The time from diagnosis to the first liver decompensation and death from liver disease, as well as the predictors of these outcomes, were evaluated. After a median (Q1‐Q3) follow‐up of 20 (9‐34) months, 31 (13%, 95% confidence interval [CI]: 9%‐17%) patients developed a decompensation. The incidence of decompensation was 6.7 cases per 100 person‐years (95% CI, 4.7‐9‐6). Fourteen (8%) out of 181 patients with a baseline LS < 40 kPa developed a decompensation versus 17 (29%) out of 58 with LS ≥ 40 kPa (P = 0.001). Factors independently associated with decompensation were Child‐Turcotte‐Pugh (CTP) class B versus A (hazard ratio [HR] 7.7; 95% CI 3.3‐18.5; P < 0.0001), log‐plasma HCV RNA load (HR 2.1; 95% CI 1.2‐3.6; P = 0.01), hepatitis B virus coinfection (HR, 10.3; 95% CI, 2.1‐50.4; P = 0.004) and baseline LS (HR 1.03; 95% CI 1.01‐1.05; P = 0.02). Fifteen (6%, 95% CI: 3.5%‐9.9%) patients died, 10 of them due to liver disease, and one underwent liver transplantation. CTP class B (HR 16.5; 95% CI 3.4‐68.2; P < 0.0001) and previous exposure to HCV therapy (HR 7.4; 95% CI 1.7‐32.4, P = 0.007) were independently associated with liver‐related death; baseline LS (HR 1.03; 95% CI 0.98‐1.07; P = 0.08) was of borderline significance. Conclusion: LS predicts the development of hepatic decompensations and liver‐related mortality in HIV/HCV‐coinfection with compensated cirrhosis and provides additional prognostic information to that provided by the CTP score. (HEPATOLOGY 2012;56:228–238)

Efficacy of pegylated interferon plus ribavirin treatment in HIV/hepatitis C virus co-infected patients receiving abacavir plus lamivudine or tenofovir plus either lamivudine or emtricitabine as nucleoside analogue backbone

OBJECTIVES To compare the response to hepatitis C virus (HCV) therapy among human immunodeficiency virus (HIV)/HCV co-infected patients receiving a nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] backbone consisting of abacavir plus lamivudine with that observed in subjects who receive tenofovir plus lamivudine or emtricitabine. METHODS A total of 256 subjects, enrolled in a cohort of 948 HIV-infected patients who received pegylated interferon and ribavirin from October 2001 to January 2006, were included in this study. All patients were taking one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor and abacavir plus lamivudine or tenofovir plus lamivudine or emtricitabine as N(t)RTI backbone during HCV therapy. Sustained virological response (SVR) rates in both backbone groups were compared. RESULTS In an intention-to-treat analysis, 20 out of 70 (29%) individuals under abacavir and 83 out of 186 (45%) under tenofovir showed SVR (P = 0.02). N(t)RTI backbone containing tenofovir was an independent predictor of SVR in the multivariate analysis [adjusted odds ratio (95% CI), 2.6 (1.05-6.9); P = 0.03]. The association between abacavir use and lower SVR was chiefly seen in patients with plasma HCV-RNA load higher than 600 000 IU/mL and genotype 1 or 4. Among patients treated with ribavirin dose <13.2 mg/kg/day, 3 (20%) of those under abacavir versus 22 (52%) under tenofovir reached SVR (P = 0.03), whereas the rates were 31% and 38% (P = 0.4), respectively, in those receiving >/=13.2 mg/kg/day. CONCLUSIONS HIV-infected patients who receive abacavir plus lamivudine respond worse to pegylated interferon plus ribavirin than those who are given tenofovir plus lamivudine or emtricitabine as N(t)RTI backbone, especially in those receiving lower ribavirin doses.

Increasing Incidence of Hepatocellular Carcinoma in HIV-Infected Patients in Spain

BACKGROUND To report the clinical and epidemiological characteristics of hepatocellular carcinoma (HCC) diagnosed in a cohort of human immunodeficiency virus (HIV)-infected patients in Spain. METHODS All HIV-infected patients diagnosed of HCC in 18 hospitals in Spain before 31 December 2010 were included. The main characteristics of HCC cases are described and comparisons between cases according to the year of diagnosis are presented. RESULTS Eighty-two cases of HCC in HIV-infected patients were included, all of them related to viral hepatitis coinfection: hepatitis C virus (HCV) in 66 (81%), hepatitis B virus (HBV) in 6 (7%), and HBV/HCV in 10 (12%). From 1999, when the first case of HCC was diagnosed, a progressive increment in the incidence of HCC in the cohort has occurred. In patients coinfected with HIV/HCV-coinfected patients, the incidence HCC increased from 0.2 to 2.8 cases per 1000 person-years between 2000 and 2009. Death occurred in 65 patients (79%), with a median survival of 91 days (interquartile range, 31-227 days). Three of 11 patients (28%) who received potentially curative therapy died, compared with 62 of 71 patients (87%) who did not receive curative therapy (P = .0001). Compared with cases of HCC diagnosed before 2005, cases diagnosed later did not show a higher survival rate. CONCLUSIONS HCC is an emerging complication of cirrhosis in HIV-infected patients. A sharp increase in its incidence has occurred in those also infected by HCV in the recent years. Unfortunately, HCC is frequently diagnosed at an advanced stage, and mortality continues to be very high, with no significant changes in recent years. Earlier diagnosis, which may allow potentially curative therapy, is necessary.

Baseline serum low-density lipoprotein cholesterol levels predict response to hepatitis C virus therapy in HIV/hepatitis C virus coinfected patients.

Background:High levels of serum low-density lipoprotein cholesterol are associated with better response to pegylated interferon and ribavirin in hepatitis C virus monoinfected patients. There are no data concerning this topic in HIV/hepatitis C virus coinfected patients in whom lipid disorders are particularly common. Objective:To assess the association between baseline lipid levels and sustained virologic response to pegylated interferon and ribavirin in coinfected patients. Methods:A total of 260 HIV/hepatitis C virus coinfected patients under treatment with pegylated interferon and ribavirin and who had a baseline serum lipid profile were included in this retrospective study. Results:Thirty-eight (24%) patients with genotypes 1–4 and 64 (63%) with genotypes 2–3 achieved sustained virologic response. Forty-nine (44%) patients with serum low-density lipoprotein cholesterol levels 100 mg/dl or more showed sustained virologic response compared with 53 (36%) with lower values [adjusted odds ratio: 2.51; 95% confidence interval: 1.40–4.87; P = 0.003]. This association was independent of the remaining predictors of sustained virologic response which were genotypes 2–3, plasma hepatitis C virus RNA 600 000 IU/ml or less, exposure to at least 80% of the planned therapy and lack of concomitant antiretroviral therapy. The rate of sustained virologic response in patients with genotype 1 and low-density lipoprotein cholesterol at least 100 mg/ml was 31% compared with 17% in those with lower values (adjusted odds ratio: 2.19; 95% confidence interval: 1.04–4.66; P = 0.040). The corresponding figures in subjects with genotypes 2–3 were 73 and 58% [2.71 (0.99–7.46); P = 0.054]. No other lipid was associated with response. Conclusion:Higher low-density lipoprotein cholesterol levels predict sustained virologic response to pegylated interferon and ribavirin in HIV/hepatitis C virus coinfected patients. This might be used to improve the rate of sustained virologic response in this setting.

Response to Pegylated Interferon Plus Ribavirin Among HIV/Hepatitis C Virus–Coinfected Patients With Compensated Liver Cirrhosis

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.

Efficacy of pegylated interferon and ribavirin for retreatment of chronic HCV infection in HIV co-infected patients failing a previous standard interferon-based regimen

BACKGROUND Combination of pegylated interferon (Peg-IFN) and ribavirin is the standard treatment for HCV infection in HIV co-infected patients. However, data available on the efficacy of this therapy in co-infected patients who failed a former interferon-based regimen are limited. METHODS We analysed the efficacy and safety of the Peg-IFN alfa-2a or alfa-2b plus ribavirin combination in a multicentre observational cohort study including 54 HCV/HIV co-infected patients who had failed to respond to or relapsed on interferon-based treatment. The primary efficacy endpoint was the proportion of patients who achieved a sustained virological response (SVR), defined as HCV RNA <50 IU/mL 24 weeks after completion of therapy. RESULTS By intention-to-treat analysis, 30% of the patients achieved an SVR. Viral eradication by genotype was 18.9% (7/37) genotype 1; 57.1% (8/14) genotype 3 and 33.3% (1/3) genotype 4. The only independent predictor of SVR was genotype 3 (odds ratio: 5.3; 95% confidence interval: 1.4-19.8). Fourteen (38%) patients with genotype 1 had undetectable viral load at week 48 of treatment. Nevertheless, 50% of them relapsed during the follow-up period. Severe adverse events or progression of HIV infection did not occur during the study; however, 39% of the patients required Peg-IFN dose reduction because of intolerance or haematological toxicity. CONCLUSIONS Combined Peg-IFN and ribavirin achieved a substantial rate of SVR in HCV/HIV co-infected patients who failed a prior standard interferon-based regimen. The decision to retreat any co-infected patient should be individual-based. More aggressive strategies may be necessary to avoid the high relapse rate observed among patients with genotype 1.

Hepatitis C virus genotype 4 responds better to pegylated interferon with ribavirin than genotype 1 in HIV-infected patients.

We assess the efficacy of pegylated interferon (peg-IFN) with ribavirin (RBV) and the predictors of sustained virological response (SVR) among HIV/hepatitis C virus genotype 4 (HCV-4)-coinfected patients. Thirty-nine (31.5%) of 124 individuals with HCV-4 achieved SVR compared with 103 (22.7%) of 453 individuals with HCV genotype 1 (P=0.046). Only interleukin-28B (IL28B) genotype CC was independently associated with SVR in HIV/HCV-4-coinfected patients. The efficacy of peg-IFN with RBV in coinfected individuals with genotype 4 is significantly higher than in those with genotype 1. IL28B CC genotype is the main predictor of response in this population.