It is well known that HIV promotes a faster progression of liver disease among patients with hepatitis C virus (HCV) infection . This effect is translated into an accelerated fibrosis progression, and a higher risk of developing cirrhosis, liver decompensation , hepatocellular carcinoma (HCC) , and liver-related mortality . The consequences of HIV coinfection on the outcome of HCV-related liver disease are not completely reverted by antiretroviral therapy .
Sustained virological response (SVR) achievement with anti-HCV therapy significantly changes the natural history of HCV-related liver disease. Thus, liver fibrosis may, at least partially, subside and liver stiffness decreases, reaching even normal values in some patients [6,7]. In addition, SVR is associated with a reduced risk of liver decompensation [8,9], a decrease in the incidence of HCC [10,11], and a reduction of liver-related and all-cause mortality [12–15], However, among patients with advanced liver disease, the risk of HCC and liver decompensation is not entirely eliminated after SVR [16,17]. As a consequence of this, these patients should undergo surveillance for liver complications, as HCC, indefinitely .
As HIV coinfection negatively impacts on the outcome of liver disease related with active HCV infection, it is reasonable to speculate that it could also modify the natural history of liver damage after SVR and the risk of residual complications. In fact, HIV infection leads to a chronic activation of the immune system, as well as to an earlier immune senescence , which may prevent fibrosis regression and increase the risk of HCC. However, little is known about whether HIV/HCV coinfection modifies the outcome of HCV-related liver disease after achieving SVR. As a high number of patients, both HCV-monoinfected and HIV/HCV-coinfected, are currently achieving SVR with direct-acting antiviral (DAA) therapy, we have a chance to clarify this issue. Therefore, the aim of this study was to assess the impact of HIV coinfection on the risk of developing liver-related complications in HCV-infected patients with advanced liver disease treated with DAA who achieved SVR.
Study design and patients
This was a prospective multisite study of two parallel cohorts. All individuals with HCV monoinfection (GEHEP-MONO Cohort, ClinicalTrials.gov ID: NCT02333292) or HIV/HCV co-infection (HEPAVIR-DAA Cohort, ClinicalTrials.gov ID: NCT02057003) who initiated therapy with one or more DAA after October 2011 at the Infectious Diseases Units of 14 institutions throughout Spain were enrolled in these cohorts. For this study, patients recruited in these cohorts were selected, if they fulfilled the following criteria: treatment against HCV with all oral DAA combination; SVR achievement, defined as undetectable plasma HCV RNA 12 weeks after the end of therapy; Pretreatment liver stiffness equal to or higher than 9.5 kPa; liver stiffness measurement at the time of SVR. Patients with concomitant hepatitis B virus (HBV) infection were excluded.
The date of SVR was considered as the baseline time point. Patients were followed until the occurrence of death, loss to follow-up, liver transplantation, HCV reinfection or the censoring date (30 November 2017). All participants were evaluated in the same manner at least every 6 months with a clinical exam and a blood test for routine virologic, immunologic, and biochemical determinations. Patients with cirrhosis were followed according to a protocol reported in detail elsewhere . HCC screening was done in all patients by ultrasound at least every 6 months and that of esophageal varices with periodic upper gastrointestinal endoscopies in patients with liver stiffness at least 21 kPa.
Endpoint and other definitions
The primary study end-point was the emergence of a liver complication (i.e. hepatic decompensation or HCC) or requiring liver transplant, whatever happened first. The diagnosis of different types of decompensation (ascites, portal hypertensive gastrointestinal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, and acute on chronic liver failure) was made as reported in previous studies [21,22]. HCC was diagnosed according to the American Association for the Study of Liver Diseases (AASLD) criteria [23,24]. The vital status in patients lost to follow-up was established by contacting them or with close relatives. Death was considered to be because of liver disease when the medical record or death certificate stated that the cause of death was one of the previous liver complications. As a secondary end-point, overall survival was also compared between HCV-monoinfected and HIV/HCV-coinfected patients.
Continuous variables are expressed as median (Q1–Q3) and categorical variables as frequencies (percentage). The comparisons of variables were carried out using the χ2 test or the Fisher's exact test for categorical variables and the Student's t-test or the Mann–Whitney U test for continuous variables. Continuous variables were categorized according to the median value or clinically relevant cut-off points. Differences were considered significant for P values 0.05 or less. The time-to-event was calculated as the months elapsed from SVR time point to the primary end-point. Proportions of patients surviving at specific time points were computed by life tables. Estimated survival functions were calculated using the Kaplan–Meier method, and survival curves were compared by the log-rank test. Baseline variables that were significantly different in HIV-negative and HIV-positive patients, as well as those associated with the main end-point in the bivariate analysis were entered in a Cox regression model for competitive risks, using the enter method. Variables included were: sex, age, drug use as the risk factor for HCV infection, Model for End-stage Liver Disease (MELD) score prior to treatment, prior liver decompensation, MELD score at SVR, CPT at SVR, platelets count at SVR, liver stiffness prior to treatment, and at SVR. Nonliver-related death was considered as the competitive event with the primary end-point. All data analyses were performed using the SPSS statistical software package release 24.0 (IBM, Armonk, New York, USA) and Stata 12.0 Statistics/Data Analysis (StataCorp, College Station, Texas, USA).
This study was designed and performed according to the Helsinki declaration and was approved by the local ethics committee. All patients gave written informed consent before being included in the cohorts.
Characteristics of the study population
Seven hundred and seventeen HCV patients were included in this study. Of them, 507 (71%) were coinfected with HIV. The most relevant characteristics of the study population are shown in Tables 1 and 2. There were a greater proportion of men and people who injected drugs (PWID) among HIV/HCV-coinfected individuals. The Child–Pugh–Turcotte (CPT) class and the pretreatment MELD score were slightly worse in HIV-positive patients. Also, at SVR, MELD score was higher, and platelet count lower among coinfected patients.
All HIV/HCV-coinfected patients were undergoing antiretroviral therapy and, in 94% of them, plasma HIV-RNA was lower than 50 copies/ml. Median (Q1–Q3) CD4+ cell counts were 579 (369–805) cells/μl. The overall median follow-up time (Q1–Q3) was 21 (14–25) months, 21 (10–25) months among HCV-monoinfected patients and 21 (15–25) months among HIV/HCV-coinfected patients. Forty-three (6.0%) patients, 15 (2.1%) HCV-monoinfected and 28 (3.9%) HCV-coinfected, were lost to follow-up.
Fifteen patients (2.1%) developed a liver complication during the follow-up, 5 (2.4%) among HCV-monoinfected individuals and 10 (2.0%) among the HIV/HCV-coinfected group. Only one coinfected patient (0.2%) underwent a liver transplant before developing a liver complication, basically because of a MELD score progression over 16. The median time to the occurrence of liver complication or transplant was 8 (5–20) months. The probability of developing a hepatic complication or requiring transplant at 1 and 2 years was, respectively, 1% [95% confidence intervals (95% CI) (0–4%)] and 4% (2–9%) among HCV-monoinfected individuals and 1% (1–3%) and 2% (1–4%) in HIV/HCV-coinfected patients (Fig. 1; P = 0.648).
Fifteen patients died during the follow-up, 12 (2.4%) of them were HIV positive and 3 (1.4%) HIV negative. The clinical events observed, by HIV-coinfection status, are shown in Table 3.
Association between HIV infection and clinical outcome
HIV/HCV-coinfection was not associated with the emergence of a liver complication or requiring a liver transplant in the univariate analysis (Table 4). Having developed a liver decompensation before SVR, higher MELD score prior to treatment, greater liver stiffness before starting treatment, as well as higher CPT, MELD scores and liver stiffness, and lower platelet counts at SVR were significantly associated with the occurrence of the primary endpoint in the univariate analysis (Table 4). After multivariate analysis adjusted for those covariates for which both populations were different at baseline and for those who impacted on clinical outcome in the univariate analysis, HIV coinfection and the main endpoint were again not associated (P = 0.181). In this analysis, liver decompensation before SVR, liver stiffness at SVR and drug use as the risk factor for HCV infection were independently associated with the occurrence of a hepatic complication or requiring a liver transplant (Table 4).
Overall survival was also similar between HIV/HCV-coinfected and HCV-monoinfected patients. Thus, the probability (95% CI) of survival at 12 and 24 months was, respectively, 100 and 98% (93–100%) for HCV-monoinfected patients. The corresponding figures for HIV/HCV-coinfected individuals were 99% (97–99%) and 97 (96–98%; P = 0.528).
This study shows that HIV coinfection does not lead to a poorer liver outcome in HCV-infected patients with advanced fibrosis who achieve SVR after interferon-free, DAA-based treatment.
Immune dysregulation and activation caused by HIV infection, the interaction of HIV itself with cells in the liver and microbial translocation promote liver fibrosis progression and lead to an accelerated evolution of liver damage associated with HCV [18,25]. SVR prompts a reduction in the levels of immune activation, inflammation and microbial translocation markers in HIV/HCV-coinfected patients . However, after HCV eradication, the effects of HIV on the immune system and on liver cells still remain. In addition, HCV also causes chronic inflammation, immune activation and immune senescence, which may partly persist after SVR even in patients without HIV coinfection . Because of this, it was conceivable to hypothesize that HIV coinfection might interfere liver damage recovering after SVR, increasing the residual risk of mid-term and long-term liver complications. With this regards, it has been recently reported that noninvasive liver fibrosis markers experience a similar decrease in HCV-monoinfected and HIV-coinfected patients . In addition, comparable declines in liver function parameters are seen with SVR in both populations . All these results are in line with the findings of the present study. Altogether, these results suggest that, once HCV is eradicated, the deleterious effect of HIV coinfection on liver damage would disappear.
To date, studies assessing the risk of residual liver complications after SVR have been reported in separated cohorts of HIV/HCV-coinfected patients [8,12,30] and HCV-monoinfected individuals [9,17,31]. In addtition, up to our knowledge, data on this topic in HIV/HCV-coinfection are restricted to patients treated with interferon-based combinations. Because of this, we cannot make comparisons of the figures reported in these studies, as they were carried out in very different populations, with unequal follow-ups and completely different managements. Thus, this is the first study that allows us comparing the hepatic outcome of HIV/HCV-coinfected patients with that of HCV-monoinfected individuals.
Predictors of liver complications in this study were not surprising. Thus, prior liver decompensation and higher liver stiffness, both indicating a more advanced liver disease, were associated with a greater risk of hepatic complications. Likewise, patients who acquired HCV infection through intravenous drug use were at higher risk of complications. Lower adherence to healthcare and active use of toxics might underlie this finding. Particular interest could have the predictive value of liver stiffness to identify patients with no risk of long-term liver complications, in whom surveillance examinations could be given up. Since, occasionally, some complications, particularly hepatocellular carcinoma, may emerge several years after SVR , studies with longer follow-ups will be required to assess this topic.
The main limitation of this study is that the follow-up period could have not been long enough to detect some complications, which might emerge later on. However, most hepatic complications occur early at the follow-up [32,33]. In addition, the follow-up was long enough to identify predictors of clinical outcomes, such as liver stiffness at SVR time point and liver decompensation prior to treatment. Because of this, if HIV coinfection had any impact on the liver outcome after SVR, at least a trend to a worse evolution in HIV/HCV-coinfected patients would have been observed at this study. In addition, as stated above, to our knowledge, this is the first study that has demonstrated that HIV-coinfection is not associated with a higher risk of developing clinical liver events after HCV eradication with DAA, and this is a strength of this study.
In conclusion, the incidence of liver complications and the survival of HIV/HCV-coinfected patients after SVR with DAA are similar to that HCV-monoinfected patients, at least in the short-term and mid-term. Consequently, the management of liver disease in HIV/HCV-coinfected patients with advanced fibrosis who achieve SVR with DAA should not differ from that of HCV-monoinfected individuals.
This work was funded in part by the Instituto de Salud Carlos III (Project ‘PI16/01443’), integrated in the national I+D+i 2013–2016 and co-funded by the European Union (ERDF/ESF, ‘Investing in your future’), by the Spanish Network for AIDS investigation (RIS) (www.red.es/redes/inicio) (RD16/0025/0040), as a part of the Nacional I+ D+I, ISCIII Subdirección General de Evaluación and the European Fund for Development of Regions (FEDER) and by GEHEP-SEIMC (GEHEP-011 project). J.A.P. has received a research extension grant from the Programa de Intensificación de la Actividad de Investigación del Servicio Nacional de Salud Carlos III (I3SNS).
Author contributions: J.A.P. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: J.A.P. Acquisition, analysis, or interpretation of data: J.A.P., A.C.G., L.M.A., F.T., A.R.J., L.M.R., J.C.A., M.J.R., F.J.V.M. R.P., P.G., J.M. Statistical analysis: A.C.G and J.A.P. Drafting of the manuscript: A.C.G. and J.A.P. Critical revision of the manuscript for important intellectual content: J.A.P., A.C.G., L.M.A., F.T., A.R.J., L.M.R., J.C.A., M.J.R., F.J.V.M., R.P., P.G., J.M.
Obtained funding: J.M, and J.A.P. Study supervision: J.A.P.
Conflicts of interest
J.M. has been an investigator in clinical trials supported by Bristol-Myers Squibb, Gilead and Merck Sharp & Dohme, He has received lectures fees from Gilead, Bristol-Myers Squibb, and Merck Sharp & Dohme, and consulting fees from Bristol Myers-Squibb, Gilead, and Merck Sharp & Dohme. J.A.P. reports having received consulting fees from Bristol-Myers Squibb, Abbvie, Gilead, Merck Sharp & Dohme, and Janssen Cilag. He has received research support from Bristol-Myers Squibb, Abbvie and Gilead and has received lecture fees from Abbvie, Bristol-Myers Squibb, Janssen Cilag, and Gilead. D.M. has received lecture fees from Abbvie, Gilead, ViiV Healthcare, Janssen Cilag, and Merck Sharp & Dohme, and consulting fees from Janssen Cilag. R.G. has received lecture fees from Abbvie, Gilead, MSD and Janssen Cilag, and consulting fees from Abbvie and Janssen Cilag. R.P. has received lectures fees and consulting fees from ViiV Healthcare, Gilead Sciences, Merck Sharp and Dohme, Janssen-Cilag. The remaining authors report no conflict of interest.
1. Macías J, Berenguer J, Japón MA, Girón JA, Rivero A, López-Cortés LF, et al. Fast fibrosis progression between repeated liver biopsies in patients coinfected with human immunodeficiency virus/hepatitis C virus
2. Macias J, Marquez M, Tellez F, Merino D, Jimenez-Aguilar P, Lopez-Cortes LF, et al. Risk of liver decompensation among HIV/hepatitis C virus-coinfected individuals with advanced fibrosis: implications for the timing of therapy
. Clin Infect Dis
3. Merchante N, Merino E, López-Aldeguer J, Jover F, Delgado-Fernández M, Galindo MJ, et al. Increasing incidence of hepatocellular carcinoma in HIV-infected patients in Spain
. Clin Infect Dis
4. Hernando V, Perez-Cachafeiro S, Lewden C, Gonzalez J, Segura F, Oteo JA, et al. CoRIS. All-cause and liver-related mortality in HIV positive subjects compared to the general population: differences by HCV co-infection
. J Hepatol
5. Klein MB, Althoff KN, Jing Y, Lau B, Kitahata M, Lo Re V, et al. North American AIDS Cohort Collaboration on Research and Design of IeDEA; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA. Risk of end-stage liver disease in HIV-viral hepatitis coinfected persons in North America from the early to modern antiretroviral therapy eras
. Clin Infect Dis
6. Macias J, del Valle J, Rivero A, Mira JA, Camacho A, Merchante N, et al. Grupo para el Estudio de las Hepatitis Víricas de la Sociedad Andaluza de Enfermedades Infecciosas. Changes in liver stiffness in patients with chronic hepatitis C with and without HIV co-infection treated with pegylated interferon plus ribavirin
. J Antimicrob Chemother
7. Macías J, Rivero A, Cifuentes C, Camacho A, Neukam K, Rivero-Juárez A, et al. Sustained virological response to pegylated interferon plus ribavirin leads to normalization of liver stiffness in hepatitis C virus-infected patients
. Enferm Infecc Microbiol Clin
8. Mira JA, Rivero-Juárez A, López-Cortés LF, Girón-González JA, Téllez F, Santos-Gil I de los, et al. Grupo Andaluz para el Estudio de las Hepatitis Víricas de la Sociedad Andaluza de Enfermedades Infecciosas. Benefits from sustained virologic response to pegylated interferon plus ribavirin in HIV/hepatitis C virus-coinfected patients with compensated cirrhosis
. Clin Infect Dis
9. Nahon P, Bourcier V, Layese R, Audureau E, Cagnot C, Marcellin P, et al. ANRS CO12 CirVir Group. Eradication of hepatitis C virus infection in patients with cirrhosis reduces risk of liver and non-liver complications
10. Bang CS, Song IH. Impact of antiviral therapy on hepatocellular carcinoma and mortality in patients with chronic hepatitis C: systematic review and meta-analysis
. BMC Gastroenterol
11. Ioannou GN, Green PK, Berry K. HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma
. J Hepatol
12. Van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour J-F, Lammert F, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis
13. Simmons B, Saleem J, Heath K, Cooke GS, Hill A. Long-term treatment outcomes of patients infected with hepatitis C virus: a systematic review and meta-analysis of the survival benefit of achieving a sustained virological response
. Clin Infect Dis
14. Bruno S, Di Marco V, Iavarone M, Roffi L, Crosignani A, Calvaruso V, et al. Survival of patients with HCV cirrhosis and sustained virologic response is similar to the general population
. J Hepatol
15. Hepatitis C Working Group for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord. Is response to antihepatitis C virus treatment predictive of mortality in hepatitis C virus/HIV-positive patients?
16. Merchante N, Merino E, Rodríguez-Arrondo F, Tural C, Muñoz J, Delgado-Fernández M, et al. HIV/hepatitis C virus-coinfected patients who achieved sustained virological response are still at risk of developing hepatocellular carcinoma
17. Van der Meer AJ, Feld JJ, Hofer H, Almasio PL, Calvaruso V, Fernández-Rodríguez CM, et al. Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication
. J Hepatol
18. European Association for the Study of the Liver (EASL). EASL Recommendations on Treatment of Hepatitis C 2018
. J Hepatol
19. Paiardini M, Müller-Trutwin M. HIV-associated chronic immune activation
. Immunol Rev
20. Merchante N, Rivero-Juárez A, Téllez F, Merino D, Ríos-Villegas MJ, Ojeda-Burgos G, et al. Grupo Andaluz para el Estudio de las Hepatitis Víricas (HEPAVIR) de la Sociedad Andaluza de Enfermedades Infecciosas (SAEI). Liver stiffness predicts variceal bleeding in HIV/HCV-coinfected patients with compensated cirrhosis
21. Pineda JA, García-García JA, Aguilar-Guisado M, Ríos-Villegas MJ, Ruiz-Morales J, Rivero A, et al. Grupo para el Estudio de las Hepatitis Víricas de la Sociedad Andaluza de Enfermedades Infecciosas (SAEI). Clinical progression of hepatitis C virus-related chronic liver disease in human immunodeficiency virus-infected patients undergoing highly active antiretroviral therapy
22. Pineda JA, Romero-Gómez M, Díaz-García F, Girón-González JA, Montero JL, Torre-Cisneros J, et al. Grupo Andaluz para el Estudio de las Enfermedades Infecciosas; Grupo Andaluz para el Estudio del Hígado. HIV coinfection shortens the survival of patients with hepatitis C virus-related decompensated cirrhosis
23. Bruix J, Sherman M. Practice Guidelines Committee; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma
24. Bruix J, Sherman M. American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update
25. Chew KW, Bhattacharya D. Virologic and immunologic aspects of HIV-hepatitis C virus coinfection
26. López-Cortés LF, Trujillo-Rodríguez M, Báez-Palomo A, Benmarzouk-Hidalgo OJ, Dominguez-Molina B, Milanés-Guisado Y, et al. Eradication of hepatitis C virus (HCV) reduces immune activation, microbial translocation, and the HIV DNA level in HIV/HCV-coinfected patients
. J Infect Dis
27. Naggie S. Hepatitis C virus, inflammation, and cellular aging: turning back time
. Top Antivir Med
28. Lledó GM, Carrasco I, Benítez-Gutiérrez LM, Arias A, Royuela A, Requena S, et al. Regression of liver fibrosis after curing chronic hepatitis C with oral antivirals in patients with and without HIV coinfection
29. Macías J, Granados R, Téllez F, Merino D, Pérez M, Morano LE, et al. Similar recovery of liver function after response to all oral HCV therapy in patients with cirrhosis with and without HIV coinfection
. J Viral Hepatol
30. Pineda JA, Aguilar-Guisado M, Rivero A, Girón-González JA, Ruiz-Morales J, Merino D, et al. Grupo para el Estudio de las Hepatitis Víricas (HEPAVIR) de la Sociedad Andaluza de Enfermedades Infecciosas. Natural history of compensated hepatitis C virus-related cirrhosis in HIV-infected patients
. Clin Infect Dis
31. Xu F, Moorman AC, Tong X, Gordon SC, Rupp LB, Lu M, et al. All-cause mortality and progression risks to hepatic decompensation and hepatocellular carcinoma in patients infected with hepatitis C virus
. Clin Infect Dis
32. Fierer DS, Dieterich DT, Fiel MI, Branch AD, Marks KM, Fusco DN, et al. Rapid progression to decompensated cirrhosis, liver transplant, and death in HIV-infected men after primary hepatitis C virus infection
. Clin Infect Dis
33. Butt AA, Yan P, Lo Re V, Rimland D, Goetz MB, Leaf D, et al. Liver fibrosis progression in hepatitis C virus infection after seroconversion
. JAMA Intern Med