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Kinetics of emergence of liver complications in HCV-infected patients and advanced fibrosis, with and without HIV-coinfection, after SVR
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life-long surveillance for liver complications is recommended in individuals with pre-treatment cirrhosis
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Prevalence and Predictors of Hepatic Steatosis in Patients with HIV/HCV Coinfection and the Impact of HCV Eradication
Ultimately, it remains to be established if HIV patients with elevated CAP values and LDL levels after HCV eradication are at higher risk of HS and its associated metabolic and cardiovascular events.
we evaluated HS prior and after HCV eradication in an HIV/HCV-coinfected cohort at the Medical University of Vienna between January 2014 and June 2017. Two hundred forty-seven patients underwent liver stiffness measurement and controlled attenuation parameter (CAP)-based steatosis assessment. A subcohort of 138 patients also had follow-up CAP measurement after HCV eradication by direct-acting antivirals (DAAs). A CAP value ≥248 dB/m defined HS and all CAP values were adapted to compensate for body mass index (BMI) and diabetes mellitus. Among all 247 HIV/HCV-coinfected patients, HS was prevalent in 31%, mean age was 43.3 years, 75% were male, the main ethnicity was Caucasian (96%), and mean BMI was 23.33 kg/m2. Independent risk factors for HS were BMI, years exposed to HIV, PNPLA3 G-alleles, and protease inhibitor (PI) intake. Notably, a significant increase in CAP (from 225 ± 52.9 to 235 ± 50.7 dB/m; p = 0.047) was observed after HCV eradication, whereas patients on PI-containing ART experienced a significant decrease in CAP. Overall, one-third of HIV/HCV-coinfected patients are affected by HS with PI-based ART and PNPLA3 impacting on HS prevalence. While HCV eradication by DAAs increased HS, as assessed by CAP, future studies should account for metabolic syndrome and evaluate whether changes in CAP-based steatosis assessments correspond to a clinically relevant outcome.
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AIDS: May 27, 2021 Corma-Gomez, Anaïsa; Macías, Juana; Téllez, Franciscob; Morano, Luisc; Rivero, Antoniod; Serrano, Miriame; Ríos, María Joséf; Vera-Méndez, Francisco Jesusg; Santos, Martah; Real, Luis Migueli; Palacios, Rosarioj; Santos, Ignacio de Losk; Geijo, Palomal; Imaz, Arkaitzm; Merino, Doloresn; Galindo, Maria Joséo; Reus-Banuls, Sergiop; Lopez-Ruz, Miguel Ángelq; Galera, Carlosr; Pineda, Juan A.a on belhaf of RIS-HEP13 and GEHEP 011 study groups
Abstract
Objective:
There is scarce available evidence on the distribution over time of liver complications emergence in hepatitis C virus (HCV)-infected patients who achieve sustained virological response (SVR) with direct-acting antiviral (DAA)-based therapy. Therefore, we aimed at describing the kinetics of liver-related events appearance in this setting.
Design:
Multicentric prospective cohort study.
Methods:
HCV-monoinfected and HIV/HCV-coinfected patients from GEHEP-011 cohort, whose inclusion criteria were: 1) Had achieved SVR with DAA-based therapy; 2) Liver stiffness (LS) prior to starting treatment≥ 9.5 kPa; 3) Available LS measurement at SVR. SVR was considered as the baseline time-point.
Results:
1035 patients were included, 664 (64%) coinfected with HIV.
After a median (Q1-Q3) follow-up time of 43 (30-49) months, 49 (4.7%) patients had died: 16 (32.7%) were classified as liver-related deaths, 28 (57.1%) as non-liver related and 5 (10.2%) deaths were unclassified. Nine (0.9%) individuals underwent a liver transplant, 20 (1.9%) patients were lost to follow-up and 5 (0.5%) were reinfected with HCV after SVR.
Before DAA-based therapy, 63 (6.1%) individuals showed decompensated cirrhosis.
After SVR, 51 (4.9%) patients developed liver complications. Forty- nine (96.1%) out of the 51 patients who developed a hepatic complication after SVR were cirrhotic before starting DAA-based therapy. HCC was the most frequently observed one.
Almost all patients had achieved SVR with interferon-free regimens (n=973; 94%). At SVR time point, 435 (42%) had a liver stiffness value equal to or above 14 kPa. Regarding HIV-coinfection, all participants living with HIV were receiving antiretroviral therapy at the time of SVR and 610 (92%) had an undetectable plasma HIV-RNA load. The median (Q1-Q3) CD4 cell count was 571 (353-793) cells/ml.
Median (Q1-Q3) time to the emergence of hepatic events was: hepatic encephalopathy 11 (7-24) months, ascites 14 (6-29) months, hepatocellular carcinoma (HCC) 17 (11-42) months and portal hypertension gastrointestinal bleeding (PHGB) 28 (22-38) months (p = 0.152).
We define two profiles of liver complications: those emerging earlier (encephalopathy and ascites) and, those occurring continuously during the follow-up (HCC, PHGB) [median (Q1-Q3) time to emergence 12.7 (6.6-28.2) months vs. 25.4 (12.5-41.53) months, respectively (p = 0.026)].
Conclusions:
The vast majority of HCV-infected patients who develop liver complications after reaching SVR with DAA do it within three years after SVR time-point. Specifically, hepatic encephalopathy and ascites do not usually emerge after this period. Conversely, HCC and PHGB may occur in longer term. It is critical to identify patients at risk of developing hepatic events to continue performing surveillance for them.
Introduction
In patients with hepatitis C virus (HCV) chronic infection, the benefits of sustained virological response (SVR) achievement, in terms of global survival and survival free from liver-related complications, have been demonstrated in several studies. Thus, viral clearance is related to a decrease in the incidence of liver decompensations [1], hepatocellular carcinoma (HCC) [2-5] and all-cause mortality [5-9]. However, even after attaining SVR, the risk of developing HCC and other hepatic decompensations is not zero, mainly among patients with cirrhosis [2,10-13]. As a result, life-long surveillance for liver complications is recommended in individuals with pre-treatment cirrhosis [14]. Furthermore, according to some experts, after achieving virologic cure, patients with advanced fibrosis should be included in HCC surveillance programs as well [15,16].
In the last few years, research about the development of liver events after HCV cure with direct acting antivirals (DAA)-therapy has mostly focused on HCC emergence. In this sense, some studies have assessed the incidence of HCC after SVR [17,18]. Recently, the incidence of liver-related events after HCV cure has been assessed in compensated cirrhotic patients, both in HCV-monoinfected and HIV/HCV-coinfected individual [19,20]. However, there is little available evidence of the distribution of liver complications over time. Understanding the patterns of hepatic-related events appearance over time in HCV cured individuals is of best interest to accurately design surveillance programs and therapeutic strategies. Therefore, the aim of this study was to describe the kinetics of appearance of liver complications in HCV-infected patients, with advanced fibrosis, who attain SVR after DAA-based therapy.
The underlying causes for these differences in liver events kinetic after SVR remain uncertain. Once HCV is eradicated, patients experience a rapid improvement of the synthetic (albumin level, prothrombin time) and purifying (bilirubin) liver functions [31-33]. This might justify the prompt decline in the incidence of hepatic encephalopathy. Ascites, hepatorenal syndrome and, more importantly, PHGB are closely related to portal hypertension. Even if SVR achievement is associated with a reduction of hepatic venous pressure gradient, clinical significant portal hypertension persists in long-tern among a considerable proportion of patients [34] and might explain latter PHGB episodes in the follow-up. Finally, HCV eradication reduces the risk of HCC [3-5,29]. However, the epigenetic alterations induced by HCV, which are maintained after SVR [35], might explain late carcinogenesis and the emergence of HCC in the medium-long term. The coexistence of additionally factors leading to liver injury, such as alcoholic or non-alcoholic fatty liver disease, might have an impact on the kinetic of hepatic complications occurrence. The effect of such factors on the latter appearance of liver complications cannot be entirely ruled out.
Liver complications during follow-up
At the end of the study, 51 (4.9%) individuals had developed a liver complication after SVR. Liver event cumulative incidence after SVR, according to the severity of liver disease is depicted in supplementary table 1, http://links.lww.com/QAD/C161. When specifically evaluating the first hepatic complication emerging after SVR, globally, HCC was the most frequently observed one, with an incidence rate (95% CI) of 0.6 (0.4-1.0) per 100 person-years. Regarding to hepatic decompensations other than HCC, 32 [3.1% (2.1%-4.3%)] patients developed a liver decompensation, accounting for an incidence rate of 1.0 (0.7-1.4) per 100 person-years. Table 2 shows cumulative incidences and incidence rates of first liver complications after SVR, by type of event. Ascites was the most frequent first decompensation occurred after SVR, followed by PHGB, and hepatic encephalopathy. Only one patient presented with a hepatorenal syndrome (table 2). Forty- nine (96.1%) out of the 51 patients who developed a hepatic complication after SVR were cirrhotic before starting DAA-based therapy.
Considering patients with no prior liver complications, 38 (3.9%) of the 972 individuals developed a liver event after achieving SVR, with an incidence rate of 1.2 (0.9-1.2) per 100 person-years. Similarly, HCC and ascites were the most frequently observed complications (table 2). Among the 63 patients who had developed a liver event before SVR, 13 (20.6%) individuals also experienced complications related to their liver disease after HCV cure [incidence rate 7.5 (4.4-12.9) per 100 person-years]. Likewise, ascites was the most commonly first event developed in this setting, followed by HCC (table 2).
Kinetics of liver complications emergence
The overall median (Q1-Q3) time between SVR assessment and diagnosis of liver complication was 16.8 (10.2-37.1) months. Thirty eight out of 51 (74.5%) of the liver events observed during the study period emerged within the first 36 months after SVR (figure 1). The median time to HCC occurrence was 17 (11-42) months and 16.8 (9.8-35.1) months to the emergence of hepatic decompensation other than HCC (p=0.123). Concerning liver decompensations, ascites (range 0.6-58.1 months) and hepatic encephalopathy (range 5.6-35.8 months) were the earliest events to emerge after SVR. PHGB (range 12.8-48.4 months) was more prone to be developed throughout the entire follow-up. The median time to the emergence of specific liver events are shown in table 2. Additionally, no episode of hepatic encephalopathy was diagnosed after 36 months of follow-up. Likewise, the vast majority of ascites events (n=17; 89%) occurred within this period. Conversely, HCC, PHGB and hepatorenal syndrome appeared in the late follow-up as well. Thus, we could define two patterns of liver complications, those which tended to appear earlier (ascites and hepatic encephalopathy) and those also emerging continuously during the follow-up (HCC, PHGB and hepatorenal syndrome). Median (Q1-Q3) time to appearance of earlier complications was significantly shorter than that of continuous events [12.7 (6.6-28.2) months vs. 25.4 (12.5-41.53) months, respectively (p=0.026; figure 2)]. The distribution of liver complications is displayed in figure 1, altogether and by the kind of event.
When specifically evaluating individuals without episodes of hepatic complications prior to HCV cure, the pattern of liver events emergence after SVR was very similar (figure 3a). Twenty-six out of the 38 (68.4%) patients who developed liver complications did it within the first 36 months after SVR time-point. Again, complications of the earlier profile appeared sooner in the follow-up. HCC and PHGB emerged throughout the whole study period (table 2). Considering patients with liver complications before SVR, practically all individuals developed liver events in the first 36 months after achieving SVR (n=12; 92.3%). Only one individual showed an episode of HCC latter during the follow-up. The distribution of liver events appearance post-SVR among this subgroup is showed in figure 3b. The median time to liver complication in this subset is depicted in table 2.
Sensitivity analyses by HIV-coinfection were conducted. Again, ascites and hepatic encephalopathy were developed earlier than HCC and PHGB, regardless of HIV-coinfection [HIV/HCV-coinfected individuals: median (Q1-Q3) time 11.1 (6.1-27.4) months vs. 24.4 (12.8-39.4) months, respectively (p=0.057); HCV-monoinfected patients 15.2 (6.8-32.0) months vs. 26.5 (11.8-46.4) months, respectively (p=0.252)]. The kinetics of liver complications after SVR by HIV coinfection status are depicted in supplementary figures 1a and 1b, http://links.lww.com/QAD/C160.
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