Original article Liver fibrosis progression despite HCV cure with antiviral therapy in HIV HCV-coinfected patients

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1 Antiviral Therapy 2015; 20: (doi: /IMP2909) Original article Liver fibrosis progression despite HCV cure with antiviral therapy in HIV HCV-coinfected patients Pablo Labarga 1,2, Jose V Fernandez-Montero 1, Carmen de Mendoza 3, Pablo Barreiro 1,4, Javier Pinilla 5, Vincent Soriano 1,4 * 1 Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain 2 Department of Internal Medicine, Clínica La Luz, Madrid, Spain 3 Department of Internal Medicine, Puerta de Hierro Research Institute & University Hospital, Majadahonda, Spain 4 Department of Internal Medicine, La Paz University Hospital, Madrid, Spain 5 HIV Unit, Hospital San Pedro, Logroño, Spain *Corresponding author vsoriano@dragonet.es Background: Accelerated liver fibrosis and more frequent hepatic decompensation events and liver-related deaths are characteristically seen in chronic hepatitis C patients coinfected with HIV compared with HCV-monoinfected individuals. Quantitative estimates of long-term clinical benefits derived from curing HCV with antiviral therapy in coinfected patients are scarce, despite being needed for accurate cost-effectiveness decisions using expensive direct-acting antivirals in this population. Methods: We retrospectively examined all HIV HCVcoinfected patients followed at one reference clinic in Madrid since Liver fibrosis was measured longitudinally using elastometry; changes above 30% in kilopascal units were considered as significant. Results: A total of 568 HIV HCV-coinfected patients were examined. Pegylated interferon/ribavirin therapy had been given to 396 (69.7%) of whom 138 (34.8%) had achieved sustained virological response (SVR). Mean follow-up was of 6.8 (±1.5) years for hepatic events and 4.4 (±0.8) years for liver fibrosis. Hepatic decompensation events, liver-related deaths and significant liver fibrosis progression occurred less frequently in SVR than in non-treated/treatment failures. Although regression of liver fibrosis occurred in most SVR patients, fibrosis significantly progressed in 7.2% of them, in association with higher plasma HIV RNA (P=0.005) and longer exposure to HIV protease inhibitors (P=0.009). Conclusions: Achievement of SVR dramatically reduces the risk of hepatic decompensation events and liver-related deaths in HIV HCV-coinfected patients. Although liver fibrosis generally improves following HCV cure, worsening may occur in association with uncontrolled HIV replication and prolonged exposure to protease inhibitors. Thus, periodic assessment of liver fibrosis is warranted after SVR and screening for liver cancer should continue in coinfected patients with advanced liver fibrosis. Introduction Chronic HCV infection is frequently recognized in HIVinfected individuals with prior exposure to contaminated needles (that is, injecting drug users) or recipients of blood products (that is, haemophiliacs) [1]. It is estimated that around 5 million people worldwide are coinfected with HIV and HCV [2]. Liver disease is accelerated in the HIV setting, with faster progression to cirrhosis, and ultimately to end-stage liver disease, including the development of hepatocellular carcinoma [2 4]. Not surprisingly, HCV-related liver disease is currently a major cause of clinical complications and mortality in HIV HCVcoinfected patients [5 7], because dramatic declines in opportunistic infections and cancers have been seen as a result of the widespread use of potent antiretroviral therapy. For this reason, the advent of new oral directacting antivirals (DAAs) that provide very high rates of HCV cure are eagerly awaited for HIV HCV-coinfected individuals [2]. The assessment of antiviral treatment response in chronic hepatitis C is generally based on the achievement of sustained virological response (SVR). Patients that remain with undetectable serum HCV RNA 24 weeks or even 12 weeks after discontinuation of a course of antiviral therapy are considered to be cured from HCV infection, since less than 1% experience late relapses [8 10]. SVR has been associated with 2015 International Medical Press (print) (online) 329

2 P Labarga et al. improvements in liver fibrosis, including regression of cirrhosis [11,12] and lower rates of liver cancer, transplant and all-cause mortality [13,14]. Similar benefits have been reported in HIV HCV-coinfected patients that attain SVR [15 19]. However, quantitative estimates of the impact of SVR on liver fibrosis progression and clinical events in the HIV HCV-coinfected population are scarce. This information is particularly valuable for allowing accurate cost-effectiveness analyses of using expensive DAA regimens in this population, as it is being addressed in HCV monoinfection [20 22]. Methods Study design Retrospective analysis of hepatic fibrosis changes and liver-related clinical end points in a large cohort of HIV HCV-coinfected patients with compensated liver disease who attended since 2004 at one reference HIV clinic in Madrid. Hepatic events were defined as follows: ascites, oesophageal variceal bleeding, spontaneous acute peritonitis, hepatic encephalopathy, hepatocellular carcinoma or liver transplantation. Patients were stratified into three groups: treated and cured, treatment failures and non-treated. Follow-up began after completion of pegylated interferon/ribavirin (PEG-IFN/RBV) in treated patients and since the first elastometry examination in untreated individuals. SVR was defined for negative serum HCV RNA 6 months after treatment discontinuation. Follow-up ended at the time of first liver decompensation event or death, or at last visit either in year 2012 (when the database was closed) or earlier if lost to follow-up. None of these patients had received DAAs for HCV at the time the study was closed. Data recording Main demographics (age, gender, alcohol intake, body mass index), haematological variables (haemoglobin, leukocyte and platelet counts), biochemistry (glucose, aspartate transaminase, alanine aminotransferase, gamma-glutamyl transpeptidase, alkaline phosphatase, total bilirubin, total cholesterol, low-density lipoprotein-cholesterol, triglycerides and creatinine), HIV parameters (current and nadir CD4 + T-cell count, plasma HIV RNA, current and prior antiretroviral drugs), hepatitis C variables (HCV genotype, HCV RNA, prior PEG-IFN/RBV therapy) and hepatitis B (HBV) serostatus were examined. All patients were followed regularly at around 4-month intervals. At every visit they were evaluated for clinical manifestations potentially associated with either HIV or HCV infections. Likewise, patients were interviewed for consumption of alcohol and/or other medications. Standard haematological, immunological, virological and biochemical examinations were performed at each time point. Prescription of antiretroviral therapy was made following international guidelines [23 25]. Liver fibrosis assessment Transient elastometry (FibroScan ; EchoSens, Paris, France) was performed by experienced operators using a single machine. The right lobe of the liver was explored through intercostal spaces on patients lying on their back, with the right arm at maximal abduction. At least 10 valid measurements were required before producing a result. Examinations with a success rate (ratio between number of validated and total measurements) <0.7 were excluded, as previously recommended [26]. Final liver stiffness was reported as the median value of all valid measurements, expressed as kilopascals (kpa). Values <7.5 kpa were considered as equivalent to histological Metavir stages F0 F1, values 7.5 to 9.4 kpa reflected F2, values 9.5 to 14.4 kpa were considered as F3 and values >14.5 kpa were equivalent to F4. Advanced liver fibrosis was considered for Metavir F3 or F4 estimates. Study end points The primary clinical end point of the study was the development of a first hepatic decompensation event or liverrelated death in the three groups. The association between the primary end point and other variables, including age, gender, body mass index, alcohol abuse, hepatitis B surface antigen, baseline liver stiffness, CD4 + T-cell counts, CD4 + T-cell nadir, plasma HIV RNA and baseline HCV RNA was examined using Cox logistic regression. Significant liver fibrosis progression was defined as a shift from baseline Metavir estimates F0 F2 to F3 F4, or by >30% increase in liver stiffness if baseline F3 F4. Conversely, significant liver fibrosis regression was defined as a shift from F3 F4 to F0 F2, or by >30% reduction in liver stiffness if baseline F0 F2. Statistical analysis Continuous variables are expressed as mean and standard deviations (sd), while categorical variables are recorded as percentages and 95% CI. The Student s t-test was used for the comparison of continuous variables whereas categorical variables were compared using the c 2 test. Univariate and multivariate analyses were performed using logistic regression. Variables with P-values <0.25 in the univariate analysis were included in the multivariate analysis. The SPSS version 17.0 software (SPSS Inc., Chicago, IL, USA) was used for calculations. Results A total of 568 HIV HCV-coinfected patients were examined. PEG-IFN/RBV therapy had been given International Medical Press

3 Liver fibrosis despite HCV cure to 396 patients (69.7%) of whom 138 (34.8%) had achieved SVR. Table 1 records the main characteristics of the study population. Briefly, mean age was 41 years old; 72% were male; 86% were former injecting drug users; 9.6% acknowledged alcohol abuse; mean baseline CD4 + T-cell count was 489 cells/µl, and 32% had baseline F3 F4 Metavir estimates. Mean body mass index was 23.1 ±3.9 kg/m 2. Favourable IL28B alleles CC (rs ) were present in 44% of 406 tested individuals. Compared to patients untreated or treatment failures, individuals that achieved SVR with PEG-IFN/RBV therapy had significantly lower baseline serum HCV RNA, were more frequently infected by HCV genotypes 2 or 3, harboured IL28B- CC alleles more often and admitted alcohol abuse less frequently. Mean follow-up was 6.8 (±1.5) years for hepatic events and survival. Liver decompensation episodes occurred in one SVR patient, eight untreated individuals and six prior treatment failures. The only subject with SVR that progressed clinically had cirrhosis and was diagnosed with liver cancer 2.5 years after achieving HCV cure. Globally there were 11 liver-related deaths, 9 in untreated patients and 2 in previous treatment failures (Table 2). The mean interval between the first and latest elastometry measurements was 4.4 (±0.8) years. As shown in Figure 1, significant liver fibrosis progression, as previously defined empirically, was frequently seen in HIV HCV-coinfected patients with treatment failure (26.2%) or those who remained untreated (19.7%). In contrast, most SVR patients experienced liver fibrosis regression, which was particularly recognizable in those with advanced liver fibrosis stages. However, 10 out of 138 (7.2%) SVR patients experienced more than 30% increase in elastometry values during the study period. Factors determining the paradoxical worsening of liver fibrosis despite SVR were investigated using multivariate analysis. Greater mean plasma HIV RNA (P=0.005) and longer exposure to HIV protease inhibitors (P=0.009) during the study period were found to independently predict significant liver fibrosis progression in SVR patients (Table 3). It should be noted that overall antiretroviral therapy had been given to 527 patients (92.8%) and the most frequently prescribed third agents along with a nucleoside backbone had been ritonavir-boosted atazanavir (n=104, 19.7%), efavirenz (n=84, 15.9%), ritonavir-boosted lopinavir (n=69, 13.1%), nevirapine (n=38, 7.2%) and ritonavirboosted fosamprenavir (n=17, 3.2%). The proportion of patients treated with darunavir, raltegravir or other third agents for long periods was still low at the time the study was conducted. The most frequently prescribed nucleoside backbone had been tenofovir/emtricitabine followed by abacavir/lamivudine. Table 1. Mean baseline characteristics of the HIV HCV-coinfected population Non-treated (n=258) Treatment failure (n=172) SVR (n=138) P-value a Mean age, years Male gender, % Mean body mass index, kg/m Intravenous drug use, % Alcohol abuse, % Baseline mean CD4 + T-cell count, cells/ml Baseline undetectable plasma HIV RNA, % Baseline advanced liver fibrosis, % HCV genotypes 1 or 4, % Baseline serum HCV RNA>800,000 IU/ml, % IL28B-CC, % Antiretroviral therapy, % a Comparisons made between patients with sustained virological response (SVR) and the rest. Table 2. Hepatic decompensation events and liver-related deaths in HIV HCV-coinfected patients a Study population n Total hepatic events, n Liver decompensation episodes, n Liver-related deaths, n n/1,000 patient-years follow-up Non-treated Treatment failure SVR a Mean follow-up 6.2 ±1.5 years. SVR, sustained virological response. Antiviral Therapy

4 P Labarga et al. Discussion The achievement of SVR has been associated with significant improvements in liver fibrosis and lower rates of hepatic decompensation events and liverrelated deaths in patients with chronic hepatitis C treated with PEG-IFN/RBV [11 14]. Similar observational data has been recorded in HIV HCV-coinfected patients [15 19]. Our study was performed in a large coinfected population followed for the longest period so far. Observational data were collected from 568 coinfected individuals followed over an average of 4.4 years for liver fibrosis and 6.8 years for clinical hepatic Figure 1. Significant changes in liver fibrosis in HIV HCVcoinfected patients a Population Untreated (n=258) Treatment failures (n=172) SVR (n=138) Improvement % Worsening Values within the black boxes are n numbers. a Mean follow-up of 4.4 ±0.8 years. SVR, sustained virological response. episodes and survival. The achievement of SVR was associated with a ninefold reduction in hepatic decompensation events and liver-related deaths compared with untreated individuals and with a sixfold decline compared with patients that failed PEG-IFN/RBV treatment. The only subject with SVR that progressed clinically had cirrhosis and was diagnosed with liver cancer 2.5 years after achieving HCV cure. This observation stresses that chronic hepatitis C patients with advanced liver disease should continue on periodic follow-up even after achieving SVR with antiviral therapy [27]. At present it is unclear for how long screening for hepatocellular carcinoma should be maintained in these patients but given the heterogeneity of fibrosis deposition in the liver and the potential for malignancy in any hepatic scar regions, it would be desirable to keep visits for years regardless of regression to milder hepatic fibrosis stages. Although liver fibrosis improved in most cases following HCV cure, a significant worsening, defined as more than 30% increase in kpa units, was seen in 10 (7.2%) out 138 SVR patients. It is noteworthy that this subset of individuals did not exhibit other well-known causes of liver disease, such as chronic hepatitis B or delta [28], alcohol abuse or autoimmune hepatitis. However, most of them had incomplete HIV suppression despite being on antiretroviral therapy and had been exposed to ritonavir-boosted protease inhibitors for longer periods than SVR patients that experienced liver fibrosis improvements. A role of HIV replication on liver fibrosis progression has been demonstrated in patients with HIV HCV coinfection [29] but to our knowledge not following HCV cure with antiviral therapy. As a limitation of our study, we should acknowledge that our analysis of predictors of liver fibrosis Table 3. Predictors of significant changes in liver fibrosis in HIV HCV-coinfected patients following sustained virological response Parameter Progression (n=10) Regression (n=36) P-value Mean age, years Male gender, n (%) 8 (80) 28 (69.4) 0.4 Mean body mass index, kg/m Alcohol abuse (>60 g/day), n (%) 1 (10) 1 (2.8) 0.3 IL28B CC, n (%) 4 (40) 24 (66.7) 0.2 HCV genotypes 1 or 4, n (%) 7 (70) 18 (50) 0.3 Mean serum HCV RNA, log IU/ml Metavir stage F3 F4, n (%) 5 (50) 34 (94.4) Mean CD4 + T-cell count, cells/µl Mean nadir CD4 + T-cell count, cells/µl Median plasma HIV RNA during the study period, log copies/ml Any detectable plasma HIV RNA, n (%) 8 (80) 7 (19.4) Antiretroviral therapy, n (%) 10 (100) 34 (94.4) 0.8 Median exposure to PI/r, months Median exposure to NNRTI, months NNRTI, non-nucleoside reverse transcriptase inhibitor; PI/r, ritonavir-boosted protease inhibitor International Medical Press

5 Liver fibrosis despite HCV cure progression in SVR patients did not account for interventions and/or drugs used for controlling elevated triglycerides, cholesterol, glucose or insulin resistance during the study period. Its consideration might have enlightened the presumed metabolic abnormalities associated with ritonavir-boosted protease inhibitors that hypothetically could have mediated fatty liver disease and progression of liver fibrosis despite curing HCV in our population. Although dyslipidaemia and diabetes have been associated with accelerated liver fibrosis progression in both HCV-monoinfected individuals [30] and HIV HCV-coinfected patients [31 33], their impact following SVR has not been well assessed following HCV eradication with antiviral therapy. In summary, this study shows that the achievement of SVR dramatically reduces the long-term risk of hepatic decompensation events and liver-related deaths in HIV HCV-coinfected patients. This benefit is accompanied by regression of liver fibrosis in most SVR patients. However, worsening of hepatic fibrosis may still occur in association with uncontrolled HIV replication and prolonged exposure to protease inhibitors. Thus, periodic assessment of liver fibrosis and screening for liver cancer should continue following HCV cure in coinfected patients with advanced liver fibrosis. Acknowledgements This work was supported in part by grants from Fundación Investigación y Educación en SIDA (FIES); European Community s Seventh Framework Programs NEAT (European AIDS Treatment Network; LSHM-CT ) and CHAIN (Collaborative HIV and Anti-HIV Drug Resistance Network; FP7/ ). PL and VS designed the study. 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