Antiviral Therapy 2015; 20:65 72 (doi: /IMP2827)

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1 Antiviral Therapy 2015; 20:65 72 (doi: /IMP2827) Original article Long-term survival and liver-related events after pegylated interferon/ribavirin therapy in HIV infected patients with chronic hepatitis C Pablo Labarga 1,2, José V Fernández-Montero 1, Carmen de Mendoza 3, Pablo Barreiro 1,4, 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 *Corresponding author vsoriano@dragonet.es Background: Sustained HCV clearance after hepatitis C therapy is associated with reduced liver-related complications and death. It is unknown if treatment may provide any clinical benefit in patients that fail therapy. This could be particularly relevant in HIV HCV-coinfected patients, in whom liver disease progresses more rapidly. Methods: This was a retrospective study of clinical end points in a large cohort of HIV HCV-coinfected patients with compensated liver disease followed since Patients were stratified into three groups: treated and cured, treatment failures and non-treated. Follow-up ended at the time of last visit, first liver decompensation event or death. Results: A total of 527 HIV HCV-coinfected patients were examined, of whom 339 (64.3%) had been treated with pegylated interferon/ribavirin. During a mean follow-up of 70.5 months, hepatic decompensation events or liver-related deaths occurred less frequently in cured patients (4/138; 2.9%) than in treatment failures (28/201; 13.9%) or untreated (25/188; 13.3%) patients (P<01). Interestingly, in the subset of patients with baseline advanced liver fibrosis (Metavir F3 F4), those with treatment failure experienced less hepatic decompensation events or deaths than untreated patients (19% versus 42%; P=05) and this finding was more pronounced in patients harbouring IL28B-CC alleles (15.8% versus 47.4%; P=2). Conclusions: Sustained HCV clearance following pegylated interferon/ribavirin therapy is associated with a reduced incidence of liver complications and death in HIV HCVcoinfected patients. In the subset of patients with baseline advanced liver fibrosis, treatment provides clinical benefit despite lack of sustained virological response. The transient antiviral and/or anti-inflammatory effect of interferon, more recognizable in IL28B-CC carriers, could explain this finding. Introduction Sustained HCV clearance following hepatitis C therapy with interferon-based regimens has been associated with regression of liver fibrosis, even in patients with cirrhosis [1] or HIV coinfection [2]. This histological benefit has been shown to translate into a reduced incidence of liver-related complications and mortality in both HCV-monoinfected individuals [3,4] and HIV HCV-coinfected patients [5,6]. It is unknown if antiviral treatment may provide any recognizable clinical benefit in patients that fail therapy. This could be particularly relevant in HIV HCVcoinfected patients, in whom liver disease progresses more rapidly [7,8]. New oral antivirals to treat hepatitis C have raised enormous expectations [9]. However, many of these agents are and will be given for a while as part of triple combinations along with pegylated interferon/ribavirin. Furthermore, a few are active mainly against HCV genotype 1, exhibiting null or poor activity against other HCV genotypes, particularly to HCV genotype 3. Finally, the high price of these drugs is becoming an important obstacle to their broader use. In this regard, considerations are given to prioritization of treatment with new oral antivirals only for patients with more advanced liver disease and/or those more difficult-tocure. A course of pegylated interferon/ribavirin dual 2015 International Medical Press (print) (online) 65

2 P Labarga et al. therapy is encouraged as a first option when treatment does not need to be deferred. Alternatively, this latest group might defer therapy and wait for cheaper new drugs and/or progression of liver disease fibrosis [10]. Treatment of hepatitis C in HIV-coinfected patients does not escape from this debate [11]. In this regard updated information on the long-term clinical benefit of antiviral therapy in this population is of much interest. Methods Study design Retrospective analysis of clinical end points in a large cohort of HIV HCV-coinfected patients with compensated liver disease who have attended our institution since 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 in treated patients and since the first elastometry examination in untreated individuals. Sustained virological response (SVR) was defined as 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 due to loss of follow-up. None of these patients had received direct-acting antivirals 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 aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transpeptidase, alkaline phosphatase, total bilirubin, total cholesterol, lowdensity lipoprotein [LDL]-cholesterol, triglycerides and creatinine), HIV parameters (current and nadir CD4 + T-cell counts, plasma HIV RNA, current and prior antiretroviral drugs), hepatitis C variables (HCV genotype, HCV RNA, prior pegylated interferon/ribavirin 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 [12 14]. 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 [15]. 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 end point of the study was the development of a first hepatic decompensation event or liver-related 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 [HBsAg], baseline liver stiffness, CD4 + T-cell counts, CD4 + T-cell nadir, plasma HIV RNA and baseline HCV RNA was examined using Cox logistic regression. Statistical analyses Continuous variables are expressed as mean and standard deviations (sd), while categorical variables are recorded as percentages and 95% CIs. 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 <5 in the univariate analysis were included in the multivariate analysis. SPSS version 17.0 software (SPSS Inc., Chicago, IL, USA) was used for calculations. Results A total of 527 HIV HCV-coinfected patients were included in the study. Table 1 summarizes the main characteristics of the study population. The mean age was 41.4 ±5.2 years, 72% were male, 86% had prior history of injection drug use and 9.6% of alcohol abuse. Mean body mass index was 23.3 ±3.9 kg/m 2 and mean CD4 + T-cell count was 517 ±273 cells/ml. Overall 35% had advanced liver fibrosis (Metavir F3 F4 estimates) at baseline. Favourable IL28B alleles CC (rs ) were present in 44% of 406 tested individuals International Medical Press

3 Hepatitis C outcome after treatment Table 1. Main characteristics of the study population Treatment Untreated Total (n=527) SVR (n=138) failure (n=201) (n=188) P-value Mean age, years NS Male gender, n (%) 379 (72) 102 (74) 151 (75) 126 (67) NS Mean body mass index, kg/m NS Injecting drug users, n (%) 427 (86) 116 (86) 164 (85) 147 (86) NS Mean baseline CD4 + T-cell count, cells/µl a ; 07 b Mean CD4 + T-cell count nadir, cells/µl NS On antiretroviral therapy at baseline, n (%) 487 (92.4) 130 (94.2) 186 (92.5) 171 (91) NS Plasma HIV RNA<50 copies/ml at baseline, n (%) 342 (68.7) 130 (97) 132 (69.5) 113 (63.5) 3 c HCV genotypes 1 or 4, n (%) 391 (77) 68 (50.7) 179 (9) 144 (81) <01 a,c ; 08 b Mean baseline serum HCV RNA, log IU/ml NS Baseline advanced liver fibrosis (Metavir F3 F4), n (%) 183 (35) 46 (33.3) 88 (43.8) 49 (26.1) 5 a ; <01 b IL28B CC (data for only 406 patients), n (%) 186 (44.1) 65 (64.4) 43 (27.2) 67 (45.6) 04 c ; <01 a ; 01 b Positive serum HBsAg, n (%) 21 (4.8) 6 (4.7) 4 (2.4) 11 (7.6) 2 b Delta hepatitis, n (%) 7 (1.3) 1 (0.7) 0 (0) 6 (3.2) 1 b Alcohol intake >60 g/day, n (%) 45 (9.6) 5 (3.7) 17 (9.2) 23 (15.3) 01 c ; 5 a a Sustained virological response (SVR) versus treatment failure. b Treatment failure versus untreated. c SVR versus untreated. HBsAg, hepatitis B surface antigen; NS, not significant. Of 201 patients that had failed prior hepatitis C therapy, 40 (19.9%) were relapsers, 61 (30.3%) were partial responders, 71 (35.3%) were null responders and 29 (14.4%) had discontinued therapy prematurely due to serious adverse events. Clinical benefit in patients treated and cured Patients were followed for a mean of 70.5 months but this was significantly lower in untreated patients compared to the rest (65.2 versus 73.4 months; P<01), which was explained by the development of more rapid and frequent end points in the former group. The mean time to liver decompensation events or death was shorter in untreated patients compared to the rest (42.1 versus 54.5 months; P=02). Table 2 summarizes the number of deaths and hepatic decompensation events in the whole study population and in each of the three groups. Overall, patients with SVR after successful hepatitis C treatment experienced significantly less frequent episodes of hepatic decompensation and/or mortality (both all causes and liver-related deaths). Variables associated with the development of liverrelated events (decompensation events or hepatic deaths) were assessed using univariate and multivariate analysis. As shown in Table 3, the lack of achievement of SVR, the presence of advanced liver fibrosis at baseline and low CD4 + T-cell counts were the major and independent predictors of liver decompensation events or death in this cohort. During the entire follow-up, for more than 5 years in all groups, the rate of hepatic decompensation events or deaths was reduced between three- and fivefold in HIV HCV-coinfected individuals that cleared the virus with antiviral therapy, compared with the rest (Table 4). Interestingly, there was a lower rate of events in the treatment failure group compared with the untreated population. Therefore, a sub-analysis was conducted in this specific group of patients with persistent HCV viraemia. Comparison of treatment failures versus untreated patients A total of 389 coinfected patients remained positive for HCV RNA during the study period, of whom 201 (52%) had failed pegylated interferon/ribavirin therapy and 188 (48%) had not been treated. As shown in Table 1, the two groups were comparable for mean age (41 years old), male gender (72%), injection drug user (86%), use of antiretroviral therapy (92%), mean CD4 + T-cell count (480 cells/ml) and mean serum HCV RNA (5.5 log IU/ml). However, there were differences comparing treatment failures and untreated patients for the proportion of HCV genotypes 1 or 4 (90% versus 81%; P=08), baseline Metavir F3 F4 (44% versus 26%; P<01), IL28B CC alleles (27% versus 46%; P=01), positive HBsAg (2.4% versus 7.6%; P=2) and alcohol abuse (9.2% versus 15.3%; P=8). After a mean follow-up of 68 months, treatment failures versus untreated patients experienced similar rates of liver decompensation events (12% versus 13.5%; P=) and deaths (2% versus 0%; P=0.1). Interestingly, there were no significant differences in the rate of hepatic events or deaths when comparing patients with different treatment failure modalities, such as relapsers, partial responders and null responders (10%, 12.7% and 11.5%, respectively). Antiviral Therapy

4 P Labarga et al. Table 2. Clinical outcomes in the study population Treatment Untreated Total (n=527) SVR (n=138) failure (n=201) (n=188) P-value Mean follow-up, months <01 a,b Deaths (all causes), n (%) 12 (2.2) 1 (0.7) 9 (4.5) 2 (1.1) 4 c,b Liver-related deaths d, n (%) 4 (0.75) 0 4 (2) 0 NS Liver decompensation events, n (%) 53 (10) 4 (3) 24 (12) 25 (13.5) 01 a ; 03 c Deaths (all causes) or liver decompensation events, n (%) 60 (11) 5 (3) 29 (11.9) 26 (13.5) 02 a ; 01 c Liver-related deaths or hepatic decompensation events, n (%) 57 (1) 4 (3) 28 (13.9) 25 (13.3) 01 a ; 03 c Mean time to liver decompensation events or death, months a,c a Sustained virological response (SVR) versus untreated. b Treatment failure versus untreated. c SVR versus treatment failure. d The four liver-related deaths were due to hepatocellualr carcinoma (one), hepato-renal syndrome (one) and variceal bleeding (two). NS, not significant. Table 3. Predictors of liver-related deaths or hepatic decompensation events in the study population Adjusted hazard ratio 95% CI P-value Older age , Male gender 4 4, Baseline CD4 + T-cell count <200 cells/µl , Plasma HIV RNA>50 copies/ml 5 8, Baseline liver fibrosis F3 F , <01 IL28B-CC alleles , Positive serum HBsAg , SVR , Multivariate analysis by Cox regression. P-values with statistical significance are shown in bold. HBsAg, hepatitis B surface antigen; SVR, sustained virological response. Table 4. Rate of events in the study population (liver-related deaths or hepatic decompensation events/100 patient-years) SVR (n=138) Treatment failure (n=201) Untreated (n=188) P-value Deaths (all causes) a,b Liver-related deaths b Liver decompensation events c ; 03 a Deaths (all causes) or liver decompensation events c ; 01 a Liver-related deaths or decompensation events c ; 03 a a Sustained virological response (SVR) versus treatment failure. b Treatment failure versus untreated. c SVR versus untreated. Overall, in the subset of patients with baseline Metavir F3 F4, decompensation events or deaths were less frequent among treatment failures than in non-treated patients (19% versus 42%; P=05). This finding was confirmed after adjusting for other variables, including baseline haemoglobin, platelets or CD4 + T-cell counts (Table 5). The incidence of hepatic decompensation episodes or liver-related deaths in the study population is represented in Figure 1. It is noteworthy that hepatitis C treatment exposure, despite not being curative, was associated with a reduced incidence of hepatic events in the subset of patients with advanced liver fibrosis. Interestingly, the protective effect of treatment exposure on hepatic outcomes in treatment failures versus untreated individuals in the subset of patients with advanced liver fibrosis was significantly greater in those with IL28B-CC alleles (15.8% versus 47.4%; P=2) than in non-cc carriers (16.3% versus 35.7%; P=0.1; Figure 2). Discussion Clinical complications of liver disease are currently major causes of hospitalization and death in HIVinfected individuals in Western countries [16,17] where the widespread use of antiretroviral therapy has dramatically reduced the incidence of classical opportunistic conditions. Chronic hepatitis C is the most frequent cause of advanced cirrhosis in HIV-infected persons [18], International Medical Press

5 Hepatitis C outcome after treatment Table 5. Predictors of liver-related events (decompensation episodes or death) in HIV-infected patients viraemic for HCV during the study period Adjusted hazard ratio 95% CI P-value Untreated versus treatment failure 1.57, Advanced liver fibrosis (Metavir F3 F4) , 3.52 <01 HCV genotypes 1 or 4 7 6, 1.69 Baseline CD4 + T-cell count, cells/µl , 0 7 Positive serum HBsAg , 5.03 Plasma HIV RNA<50 copies/ml , 2.32 Multivariate analysis by Cox regression. HBsAg, hepatitis B surface antigen. in whom the pace of liver fibrosis, hepatic decompensation events and liver-related deaths is accelerated in comparison with HCV-monoinfected individuals [19]. Thus, the prompt availability of new potent oral regimens as hepatitis C therapy is eagerly awaited for this population [11]. In our study, SVR following pegylated interferon/ ribavirin therapy was associated on average with a fourfold reduction in hepatic complications and mortality in HIV HCV-coinfected patients followed for over 5 years. This observation confirms prior findings [5,6] highlighting that the achievement of SVR is associated with improved survival and reduced incidence of hepatic events in HIV HCV-coinfected patients. However, none of those studies showed any benefit in patients that had been treated and failed, which was one of our major findings. In the subset of patients with baseline advanced liver fibrosis (Metavir F3 F4), the clinical benefit of antiviral therapy was recognized even in patients that did not achieve SVR in comparison with untreated individuals. The longer follow-up of our cohort in comparison with that of Berenguer et al. [6] could explain it (70.5 versus 2 months, respectively). Although it might be argued that untreated patients experienced faster liver disease progression due to the presence of other comorbidities, some of which might have deferred them from HCV treatment and contribute to liver disease progression (for example, alcohol abuse, low CD4 + T-cell counts, active injection drug use, neuropsychiatric illness), we adjusted for these variables in a multivariate model. On the other hand, more patients that failed therapy had baseline advanced liver fibrosis with respect to untreated individuals, reflecting that HCV treatment was prioritized in patients with Metavir F3 F4 estimates. Despite the negative impact of advanced liver fibrosis on clinical outcomes, untreated patients decompensated or died more frequently of liver complications than patients that failed therapy. A large study conducted in HIV HCV-coinfected patients in the United States also pointed out the strong predictive value of baseline liver fibrosis staging on the subsequent rate of liver-related events and deaths but could not find any significant difference between treatment failures and untreated patients [20]. Among other differences, distinct patient demographics (80% were Black and 47% abused alcohol) and very low SVR rates with large heterogeneity among non-responders could have limited the accuracy of that study to explore the impact of non-curative hepatitis C therapy on clinical outcomes with more refinement. By contrast, one study conducted in HIV HCVcoinfected patients acknowledged that relapses after a course of pegylated interferon/ribavirin therapy provided a significant clinical benefit over 4 years in comparison with treatment failure [21]. However, this study did not include, as comparator, a group of untreated patients and therefore could not assess the contribution of antiviral treatment exposure per se. Our results suggest that benefits of interferon-based therapy may be seen in failing patients other than relapsers. Our results point out that interferon exposure might improve the natural history of HIV HCV-coinfected patients even when HCV eradication is not achieved, reducing per se the incidence of hepatic decompensation episodes and liver-related deaths. We should acknowledge several limitations of our study. Because only four hepatic events occurred in the cured group, we could not examine differences between groups in individual outcomes (for example, liver cancer). Likewise, we could not compare with enough power differences between distinct subsets of patients with prior treatment failure modalities, such as relapse, partial response and null response. In addition, the study was retrospective, and therefore unaccounted selection and survival biases could have influenced estimates of effects. Finally, the benefit of antiviral therapy despite lack of SVR was found only in the subset of patients with advanced liver fibrosis and adjustment for other variables such as Model of End-Stage Liver Disease (MELD) was not taken into account. Overall, however, the population size in our study is one of the largest and had one of the longest follow-ups examined so far in HIV HCV-coinfected patients with compensated liver disease that tested the impact of hepatitis C therapy on clinical end points. It would be of Antiviral Therapy

6 P Labarga et al. Figure 1. Incidence of hepatic decompensation events or death A P=02 SVR (n=138) Treatment failure (n=201) Untreated (n=185) B Metavir F0 F2 C Metavir F3 F4 P=4 SVR (n=92) Treatment failure (n=113) Untreated (n=137) SVR (n=46) Treatment failure (n=88) Untreated (n=48) P=02 P<01 Incidence of hepatic decompensation events or death in (A) the study population and (B&C) split out by baseline liver fibrosis staging. SVR, sustained virological response. interest to examine if the new oral direct-acting antivirals against HCV may retain a similar residual clinical benefit compared with interferon when HCV is not eliminated. In summary, the achievement of SVR following pegylated interferon/ribavirin therapy was associated with a fourfold reduction in hepatic complications and mortality in HIV HCV-coinfected patients followed for over 5 years. More interestingly, in the subset of patients with advanced liver fibrosis, the clinical benefit of treatment was recognized even in patients that did not achieve SVR in comparison with untreated individuals. This effect was mainly noticed in patients harbouring International Medical Press

7 Hepatitis C outcome after treatment Figure 2. Incidence of liver-related deaths and/or hepatic decompensation events in patients with baseline Metavir F3-F4 according to IL28B alleles IL28B non-cc IL28B CC P=0.1 P= P=0.1 P=2 P=2 SVR (n=12) Treatment failure (n=43) Untreated (n=14) SVR (n=23) Treatment failure (n=19) Untreated (n=19) P=01 SVR, sustained virological response. IL28B-CC alleles, suggesting that transient antiviral and/or anti-inflammatory effects of exogenous interferon, which are more pronounced in IL2B-CC carriers, might account for this residual benefit of interferon in the absence of SVR in this population. Acknowledgements This work was supported in part by grants from Fundación Investigación y Educación en SIDA (FIES); and European Community s Seventh Framework Programs NEAT (European AIDS Treatment Network; LSHM-CT ) and CHAIN (Collaborative HIV and Anti-HIV Drug Resistance Network; FP7/ ). Disclosure statement The authors declare no competing interests. References 1. Mallet V, Gilgenkrantz H, Serpaggi J, et al. The relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann Intern Med 2008; 149: Fernández-Montero JV, Barreiro P, Vispo E, et al. Liver fibrosis progression in HIV HCV-coinfected patients treated with distinct antiretroviral drugs and impact of pegylated interferon/ribavirin therapy. Antivir Ther 2014; 19: Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med 2007; 147: van der Meer AJ, Veldt B, Feld J, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 2012; 308: Soriano V, Maida I, Núñez M, et al. Long-term follow-up of HIV-infected patients with chronic hepatitis C virus infection treated with interferon-based therapies. Antivir Ther 2004; 9: Berenguer J, Alvarez-Pellicer J, Martín P, et al. Sustained virological response to interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with HIV and hepatitis C virus. Hepatology 2009; 50: Macías J, Berenguer J, Japón MA, et al. Fast fibrosis progression between repeated liver biopsies in patients coinfected with HIV/hepatitis C virus. Hepatology 2009; 50: Konerman MA, Mehta S, Sutcliffe C, et al. Fibrosis progression in HIV/hepatitis C virus coinfected adults: prospective analysis of 435 liver biopsy pairs. Hepatology 2014; 59: Thomas DL. Cure of hepatitis C virus infection without interferon alfa: scientific basis and current clinical evidence. Top Antivir Med 2014; 21: Shiffman ML, Benhamou Y. HCV F1/2 patients: treat now or continue to wait. Liver Int 2014; 34 Suppl 1: Barreiro P, Fernández-Montero JV, de Mendoza C, Labarga P, Soriano V. Towards hepatitis C eradication from the HIV-infected population. Antiviral Res 2014; 105: Thompson MA, Aberg J, Hoy J, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA 2012; 308: Antiviral Therapy

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