Fernández-Montero, José Vicente; Barreiro, Pablo; Vispo, Eugenia; Labarga, Pablo; Sánchez-Parra, Clara; Soriano, Vicente
The broad use of highly active antiretroviral therapy has led to a dramatic decrease in opportunistic events and deaths in HIV-infected patients . As the HIV-infected population ages, cardiovascular events and liver-related conditions are becoming frequent causes of hospitalization and death [2–4].
Chronic hepatitis C affects overall 20–25% of the 35 million people currently living with HIV worldwide . Progression of liver fibrosis is accelerated in the coinfected population, especially in those with low CD4 cell counts . Thus, early diagnosis of coinfection and prompt initiation of antiretroviral treatment have become a priority in this subset of patients [6,7]. However, when advanced liver fibrosis is already present the prognosis of HIV/HCV-coinfected individuals may be compromised even after beginning antiretroviral therapy and/or hepatitis C therapy [8,9].
Although liver biopsy has been traditionally considered as the gold standard for liver fibrosis staging, its invasive nature, along with the complications associated with the procedure  have led to an increased use of noninvasive methods for assessing hepatic damage. Transient elastometry is a noninvasive, ultrasound-based technique that allows an accurate and longitudinal assessment of liver fibrosis. It has been validated in HCV-infected patients , including individuals coinfected with HIV [12,13]. Herein, we assessed the prognostic value of transient elastometry for the development of liver-related complications and death in a large cohort of HIV/HCV-coinfected patients.
Patients and methods
Study design and population
This study was designed as an observational, retrospective study, in which data from all HIV/HCV-coinfected patients managed at our institution who underwent a transient elastometry examination and had at least 18 months of follow-up were analysed. Patients with a prior history of decompensated hepatic disease were excluded. Transient elastometry is routinely performed in all HIV/HCV-coinfected individuals at our institution since year 2004.
Main demographics (age, sex, alcohol abuse – defined as an alcohol intake >50 g/day – and BMI), haematologic variables (haemoglobin, leukocyte and platelet counts), biochemistry [glucose, aspartate transaminase, alanine transaminase (ALT), gamma-glutamyl transpeptidase, alkaline phosphatase, total bilirubin, total cholesterol, low-density lipoprotein cholesterol, triglycerides and creatinine], HIV-related variables (CD4 cell count and CD4 nadir, HIV-RNA, current and prior antiretroviral drug regimens), HCV-related data [genotype, HCV-RNA, prior peginterferon (PegIFN)-ribavirin (RBV) therapy and outcome] and hepatitis B virus serostatus were examined.
Transient elastometry values and clinical data regarding liver-related events (defined as development of ascites, encephalopathy, oesophageal varices or hepatocellular carcinoma) were collected from clinical reports. Censoring date was 1 January 2012.
Liver stiffness measurement
Transient elastometry (FibroScan; EchoSens, Paris, France) was performed by experienced operators, using a single machine. Examinations were conducted in at least two different intercostal areas overlying the liver. Values less than 7.5 kPa were considered as Metavir stages F0--F1, 7.5–9.4 kPa as F2, 9.5–12.4 kPa as F3 and more than 14.5 kPa as F4, values adapted from those suggested in prior studies . Advanced liver fibrosis was considered for Metavir F3 or F4 estimates.
Patients had been followed regularly at an average of 4-month intervals. At every visit, patients were assessed for clinical manifestations associated with either HIV or HCV infections, along with routine haematological, immunological, virological and biochemical examinations. Prescription of antiretroviral therapy was made following international guidelines [6,7].
The baseline time-point was defined as the date of transient elastometry examination, whereas the follow-up period was defined as the months lapsed until the development of liver-related events, death or the censoring date (1 January 2012), whichever occurred first. Information regarding liver-related events or death was obtained from clinical records.
The primary end-points of the study were the development of a first manifestation of decompensated liver disease (ascites, encephalopathy, liver cancer or oesophageal varices) or death for any reason. The association between the primary end-point and other variables, such as age, sex, BMI, alcohol abuse, hepatitis B surface antigen (HBsAg), exposure to interferon-based therapy, achievement of sustained virological response (SVR), baseline liver stiffness, CD4 cell count, glucose, total cholesterol, ALT, HIV-RNA and baseline HCV-RNA were assessed using logistic regression.
Continuous variables are expressed as mean and standard deviation (SD), whereas categorical variables are presented as percentages and 95% confidence intervals (95% CIs). Liver event-free survival, defined as the cumulative proportion of patients without developing liver decompensation events at the end of the follow-up period, was calculated using Kaplan--Meier curves. The Student t-test was used for comparing continuous variables, whereas comparisons of categorical variables were performed using the chi-squared test. Univariate and multivariate analysis were performed using logistic regression. Variables with P values less than 0.25 in the univariate analysis were included in the multivariate analysis. Biochemistry and haematological values were analysed as continuous variables. SPSS 17.0 software (SPSS Inc., Chicago, Illinois, USA) was used for calculations.
A total of 545 HIV/HCV-coinfected patients were included in the study. The main baseline characteristics of the study population are recorded in Table 1. Briefly, mean age was 41.5 ± 5.3 years, 71.5% were men, 81% had a prior history of injection drug use and 8.4% of alcohol abuse. Mean BMI was 23.3 ± 3.9 kg/m2 and mean CD4 cell count was 519 ± 284 cells/μl. All patients but three were on antiretroviral therapy. Overall, 88% had undetectable plasma HIV-RNA. Positive serum HBsAg was present in 4.2% and 1.5% had delta antibodies. Mean ALT was 65 ± 54 IU/ml and mean serum HCV-RNA was 4.9 ± 2.2 log10 IU/ml. Mean baseline liver stiffness in the study population was 10.6 ± 9.4 kPa, and 34.2% of patients had F3-F4 Metavir score estimates. The mean follow-up was 70.9 ± 15.7 months.
During follow-up, 335 patients (63%) were treated with PegIFN and RBV and 132 (39.4%) of them achieved SVR. Of note, 63.4% of the whole population was infected with HCV genotype 1.
Twelve patients (2.2%) died during the follow-up period, four of them due to liver-related complications (two due hepatocellular carcinoma and two due to liver failure). The remaining patients died from malignancies (three), cardiovascular disease (two), non-AIDS defining infections (two) and renal failure (one). During the same period, another 53 patients (10.1%) developed liver-related events, such as oesophageal varices (28), ascites (17), encephalopathy (four) and hepatocellular carcinoma (four).
At the end of follow-up, survival rates were 85.6% (95% CI 85.2–86) in patients with null to mild baseline liver fibrosis (F0--F2 Metavir estimates) and 84.2% (95% CI 82.9–85.5) in patients with baseline advanced liver fibrosis (log-rank test, P = 0.02) (Fig. 1).
Liver event-free survival rates were 84.7% (95% CI 84–85.4) in patients with null to mild baseline liver fibrosis and 75.7% (95% CI 72.6–78.8) in patients with advanced liver fibrosis (log-rank test, P < 0.0001) (Fig. 2). After stratification by single baseline METAVIR stages, patients with F0--F1 had significantly higher liver event-free survival rates (85.5%) than individuals with baseline stages F2, F3 or F4 (82.8, 83.1 and 70.6%, respectively; log-rank test, P < 0.0001).
The univariate analysis assessing the predictors of all-cause mortality only showed a significant association for baseline liver stiffness (OR 1.04; 95% CI 1–1.08; P = 0.04). This unique association was confirmed in the multivariate analysis after adjusting for those variables with a significant P value less than 0.25 in the univariate analysis (OR 1.09; 95% CI 1.01–1.19; P = 0.02) (Table 2).
As shown in Table 3, the predictors of liver-related events in the univariate analysis were baseline liver stiffness, CD4 cell count, glucose, total cholesterol and achievement of SVR following hepatitis C therapy during the study period. However, in the multivariate analysis, the variables that were independently and significantly associated with the development of liver-related events were baseline liver stiffness, male sex, CD4 cell count, glucose and the achievement of SVR, with baseline liver fibrosis being the most significant predictor.
The incidence of opportunistic infections and AIDS-related malignancies has dramatically decreased in HIV individuals living in developed countries, whereas cardiovascular and liver-related events have gained preponderance as a major cause of hospitalization and death in this population [2–4]. Hepatic complications in HIV-infected patients are particularly frequent in those coinfected with HCV, in whom progression to end-stage liver disease is accelerated . Inflammatory processes in the liver of chronic hepatitis C patients lead to hepatic fibrosis and ultimately to cirrhosis.
Liver biopsy has been for decades the only procedure available to assess liver fibrosis. However, newer noninvasive tools, including biomarkers and transient elastometry, are being commonly used for this purpose, replacing liver biopsy [11–13]. Several studies have recently pointed out that the extent of liver fibrosis may predict survival in patients with chronic hepatitis C [15,16]. Some of these analyses have also been performed in HIV/HCV-coinfected individuals assessing hepatic fibrosis using either liver biopsies  or biomarkers [18,19]. One study used transient elastometry to predict outcomes in coinfected cirrhotics . However, to our knowledge, no studies have tested so far the value of transient elastometry as a predictor of liver-related complications and death in HIV/HCV-coinfected patients with any degree of baseline hepatic fibrosis. The strength of our study is the large size of the study population that included 545 individuals and the long follow-up, approaching nearly 6 years on average. We found that baseline liver stiffness was the strongest predictor of developing hepatic events and of all-cause of death in HIV/HCV-coinfected patients.
It is noteworthy that baseline liver stiffness was the only predictor of survival in our cohort of HIV/HCV-coinfected patients. As most individuals were on successful antiretroviral therapy, we could not recognize any impact of CD4 cell counts nor plasma HIV-RNA on survival. Along with baseline liver stiffness, the risk of liver-related events was significantly increased with low CD4 cell counts, elevated glucose levels and male sex. This information reassures recent recommendations for earlier initiation of antiretroviral therapy in all patients with HIV/HCV coinfection .
Our study shows some limitations. First, it is a single-centre study. However, the study population is somewhat similar to those enrolled in other studies assessing the predictive value of liver stiffness for clinical outcomes in demographic terms . It would be also expected that the association magnitude of some variables in the multivariate analysis would be higher. This could be potentially explained by the low mortality and liver decompensation rates found (2.2 and 10% at 71 months, respectively), a fact that could have a strong influence in the results of the multivariate analysis. However, and based on similar studies, there is growing evidence supporting the association between higher liver stiffness values and liver morbidity and overall mortality. Another aspect to be kept in mind is that transient elastometry measurements could be overestimated in obese patients. This limitation has somehow been overcome in recent years with the development of a probe specifically designed for such patients.
The subset of individuals in our cohort who cleared HCV following a course of PegIFN and RBV therapy during the study period was further protected from presenting liver-related complications. This fact is consistent with prior studies assessing the clinical outcome of coinfected patients treated for hepatitis C [21,22] and reinforces the need for prioritizing antiviral therapy in this population. This consideration is particularly relevant nowadays, when direct-acting antivirals are revolutionizing hepatitis C therapeutics, and it is expected that its use will become the standard of care for HIV/HCV-coinfected patients .
In summary, baseline liver stiffness is the strongest predictor of liver-related complications and of all-cause mortality in HIV/HCV-coinfected patients on antiretroviral therapy. On the contrary, clearance of HCV with antiviral therapy significantly reduces the risk of developing liver decompensation events in this population.
This work was funded in part by grants from the European Network of AIDS Trials (NEAT), Red de Investigacion en SIDA (RIS, project RD06/0006) and Fundación Investigación y Educación en SIDA (F-IES). The authors would like to thank Dr Luis Parra and Dr Eduardo Delgado-Oliver for helpful comments and assistance.
J.V.F. and V.S. designed the study. J.V.F., P.B., E.V., P.L., C.S.P. and V.S. recorded clinical and demographic information. J.V.F. built the database and performed the statistical analysis. J.V.F. and V.S. wrote the manuscript and all authors provided their suggestions, reviewed and approved it.
Conflicts of interest
There are no conflicts of interest.
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