Antiviral Therapy 2014; 19:799 803 (doi: 10.3851/IMP2816) Original article Progression to advanced liver fibrosis in HIV HCV coinfected patients and prioritization of new hepatitis C therapies Pablo Labarga 1, Jose V Fernández-Montero 1, Mariola López 1, Pablo Barreiro 1, Carmen de Mendoza 1,2, Rocío Sierra-Enguita 1, Ana Treviño 1, Vincent Soriano 1 * 1 Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain 2 Department of Internal Medicine, Puerta de Hierro Research Institute and Hospital Universitario Puerta de Hierro, Madrid, Spain *Corresponding author e-mail: vsoriano@dragonet.es Background: Because of their high cost, the use of directacting antivirals (DAAs) is being restricted by many governments to chronic HCV-infected individuals with advanced liver fibrosis. However, response rates are lower and toxicities more frequent in this subset of patients. Methods: All HIV HCV-coinfected patients followed for at least 3 years at one reference clinic were identified. Liver fibrosis progression (LFP) was defined as a shift from Metavir F0 F2 to F3 F4 estimates (>9.5 KPa) using elastometry. Results: A total of 527 HIV HCV-coinfected patients were identified, of whom 344 had F0 F2 at baseline. Pegylated interferon/ribavirin therapy was given to 205 patients with null/mild fibrosis, of whom 92 (44.9%) achieved sustained virological response (SVR). After a mean follow-up of 53 months, LFP occurred in 5.4% SVR, 25.7% non-svr and 18% untreated patients (P=0.005). In multivariate analysis, only achievement of SVR prevented LFP (adjusted hazard ratio 2.1; 95% CI 1.1, 4.1; P=0.01). In 139 untreated patients, only greater baseline elastometry values predicted LFP in multivariate analysis (adjusted hazard ratio 1.84; 95% CI 1.03, 3.3; P=0.03). The area under the receiver operating characteristic (AUROC) curve was 79%. A discriminant threshold of 7.1 kpa gave 68% sensitivity and 82% specificity. Conclusions: In the absence of successful treatment, more than 20% of HIV HCV-coinfected patients with null/mild liver fibrosis progress to advanced fibrosis within 5 years. Patients with >7.1 kpa (Metavir F2) display the highest risk. Therefore, all coinfected patients with any significant liver fibrosis should be considered as candidates for new DAA-based therapies. Introduction Until recently the current standard of care for patients with chronic HCV genotype 1 infection was a combination of either boceprevir or telaprevir with pegylated interferon (PEG-IFN) and ribavirin (RBV) [1]. Although triple therapy is effective in a high proportion of these patients, including those with HIV coinfection [2,3], this treatment is associated with high pill burden and significant adverse events [4,5]. The second wave of HCV protease inhibitors simeprevir [6,7] and faldaprevir [8,9] are also given in combination with PEG-IFN/RBV. IFNfree therapies with sofosbuvir [10] appear much more promising and have recently been approved by the FDA, extending its use to HIV HCV coinfection. However, the elevated price of this medication may preclude its wide and rapid prescription. The likelihood of treatment response and the risk of liver fibrosis progression (LFP) are amongst the most important variables that guide when to treat chronic hepatitis C patients. In the absence of significant risk for liver disease progression, treatment could be deferred until more effective, well-tolerated and cheaper drugs became available. In this regard, European guidelines have recommended the Prometheus index [11] to assist treatment decisions in HIV HCV-coinfected patients [12]. Because of the global financial crisis, many European governments have released specific requirements asking to restrict new direct-acting antivirals (DAAs) only to patients with advanced liver fibrosis in order to save costs. However, response rates are lower and side effects more frequent and severe in this subset of patients [4,13]. Therefore, there is a need to re-assess the 2014 International Medical Press 1359-6535 (print) 2040-2058 (online) 799
P Labarga et al. indication of hepatitis C therapy in patients with null/ mild liver fibrosis, considering their likelihood of cure, their risk for LFP and the medication cost [14,15]. This debate is particularly relevant for HIV HCV coinfection, given that disease progression is accelerated and access to DAAs may be delayed in this population [16]. Methods Study population This was a retrospective study in which clinical and laboratory data were examined in all HIV HCV-coinfected patients on regular follow-up at our institution since 2004 that had longitudinal assessment of liver fibrosis staging. For the purpose of this study all consecutive individuals who underwent periodic transient elastometry evaluations for longer than 3 years were chosen. Patients had been followed regularly at around 4-month intervals on average. Prescription of antiretroviral therapy was made following international guidelines [12,17,18]. The baseline time point was defined as the date of the first transient elastometry examination, whereas the follow-up period corresponded to the months lapsed until the last elastometry evaluation. Liver fibrosis assessment 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 7.0 kpa were considered as Metavir stages F0 F1 (null fibrosis), 7.1 9.4 kpa as F2 (mild fibrosis), 9.5 14.4 kpa as F3 (pre-cirrhosis) and 14.5 kpa as F4 (cirrhosis). Advanced liver fibrosis was considered for Metavir F3 or F4 estimates [19]. LFP was defined as a shift from baseline F0 F2 Metavir estimates (null/mild fibrosis) to F3 F4 (advanced fibrosis). Statistical analyses Overall results are presented as means for continuous variables, and as frequencies and percentages for categorical data. Analysis of normality was performed using the Kolmogorov Smirnov test. Categorical data and proportions were analysed using the c 2 test or Fisher s exact test, as required. The Student s t-test and ANOVA were used to compare variables with normal distributions among two or three groups respectively, while the Mann Whitney and Kruskal Wallis tests were used to compare variables with non-normal distributions among two or three groups, respectively. Multiple association tests were conducted using univariate logistic regression to identify independent variables associated with LFP, the primary outcome. In the last analysis we included all variables with P-values <0.25 in the univariate analysis. Then, a forward stepwise logistic regression analysis was conducted. Thereafter, the accuracy of different baseline liver stiffness values to predict LFP was tested calculating area under the receiver operating characteristic (AUROC) curve. For obtaining the highest sensitivity and negative predictive value (NPV), the lowest threshold was established at quartile 0.25. Conversely, for obtaining the highest specificity and positive predictive value (PPV), the highest threshold was established at quartile 0.75. Finally, from the receiver operating characteristic (ROC) curve, the Youden index, equal to the sensitivity + specificity -1, was maximized to quantify the cutoff value for baseline liver stiffness. All tests were two-tailed with P-values <0.05 considered as significant. All statistical analyses were performed using the SPSS v20.0 software (SPSS Inc., Chicago, IL, USA) and Optimal Cut points package in R was performed to compute the optimal cutoff for baseline liver stiffness to predict LFP. Results A total of 527 HIV HCV-coinfected patients were identified, of whom 344 (65.3%) had baseline F0 F2 Metavir estimates using elastometry. Hepatitis C therapy with PEG-IFN/RBV was given to 205 patients with null/mild fibrosis, of whom 92 (44.9%) achieved sustained virological response (SVR). Figure 1 records patients disposition and Table 1 summarizes the main characteristics of the study population, considering separately SVR patients, treatment failures and untreated individuals with null/mild liver fibrosis. After an average follow-up of 53 months, HIV HCVcoinfected patients with baseline null/mild liver fibrosis experienced LFP at rates of 5.4% for SVR, 25.7% for non-svr and 18% for untreated patients (P=0.005). It should be highlighted that patients who failed treatment had significantly longer follow-up than those that reached SVR or were untreated (Figure 2). In multivariate analysis, only achievement of SVR independently prevented LFP (adjusted hazard ratio 2.1 [95% CI 1.1, 4.1]; P=0.01) in HIV HCV-coinfected individuals with baseline null/mild liver fibrosis. A sensitivity analysis was conducted in the subset of 139 untreated HIV HCV-coinfected patients. As mentioned above, LFP occurred in 18% of them during an average of 50.4 months. Compared to patients that remained with null/mild liver fibrosis during the whole follow-up period, individuals that experienced LFP had significantly lower baseline CD4 + T-cell counts, liver stiffness and low-density lipoprotein (LDL) cholesterol, and conversely greater alanine aminotransferase and gamma-glutamyl transpeptidase (GGT; Table 2). 800 2014 International Medical Press
Liver fibrosis progression in HIV HCV coinfection In multivariate analysis, however, only greater baseline elastometry values predicted LFP in this subset of patients (Table 3). In an attempt to find a threshold in liver stiffness that might help to identify individuals with null/ mild liver fibrosis with the highest likelihood of LFP, a ROC curve was produced. The AUROC was 79% (95% CI 69%, 0.89%; P<0.001) and the optimal threshold in liver stiffness to discriminate between Figure 1. Patient treatment status Not treated 139 Null/mild fibrosis 344 Failure 113 SVR, sustained virological response. HIV HCV coinfection 527 Treated 205 Advanced fibrosis 183 SVR 92 LFP and not was 7.1 kpa. This threshold gave 82% specificity and 68% sensitivity, with a NPV of 92% and PPV of 45% (P<0.001). Discussion Progression to advanced fibrosis and cirrhosis represents a significant step in the natural history of patients with chronic hepatitis C. Once advanced liver fibrosis is recognized in a given patient, there is a need to begin periodic screening for hepatocellular carcinoma and diagnosis of oesophageal varices to prevent upper gastrointestinal bleeding [1]. In our study, the risk of progression to advanced fibrosis was examined in 344 chronic hepatitis C patients with HIV coinfection, a population in whom hepatic fibrosis typically progresses faster [20 22]. In 344 individuals with baseline null/mild fibrosis as assessed by elastometry, progression to Metavir F3 F4 estimates occurred in 18% after an average follow-up of 4.5 years. It is noteworthy that LFP only occurred in 5% of subjects treated and cured with IFN-based therapies. In contrast, hepatic fibrosis progression occurred in 21% of untreated patients and those with treatment failure within a similar time frame. Our results are in agreement with those from a recent study that examined 162 HIV HCV-coinfected patients with baseline null/mild liver fibrosis on liver biopsy [23]. Progression to advanced liver fibrosis, also measured using transient elastometry, occurred in 47 patients (29%) after a median follow-up of 7.8 years. Older age, hepatitis B surface antigen (HBsAg)-positivity and baseline F2 predicted LFP. Based on their results, the authors concluded that HCV antiviral therapy should not be denied to HIV HCV-coinfected patients with early liver Table 1. Main characteristics of HIV HCV-coinfected patients with null/mild liver fibrosis SVR patients Treatment failure patients Untreated patients (n=92; 26.7%) (n=113; 32.8%) (n=139; 40.4%) P-value Mean age, years (sd) 41.1 (4.5) 40.9 (4.8) 41.1 (4.3) NS Male gender, % 73.9 73.5 61.9 NS Mean body mass index, kg/m 2 (sd) 23.2 (3.9) 23.6 (4.2) 22.6 (3.6) NS Intravenous drug use, % 84.6 85.2 84.7 NS Mean baseline CD4 + T-cell count, cells/µl (sd) 503.5 (245.1) 586.1 (293.9) 504.8 (292.1) NS Mean CD4 + T-cell count nadir, cells/µl (sd) 238.7 (137.4) 264.8 (176.2) 257.9 (197.5) NS On antiretroviral therapy, % 94.6 92.9 91.4 NS Baseline plasma HIV RNA<50 copies/ml, % 72.7 68.8 67.2 NS HCV genotype 1 or 4, % 52.8 90.2 81.1 <0.001 a,b ; 0.008 c Mean baseline serum HCV RNA, log IU/ml (sd) 3.5 (2.5) 5.3 (1.9) 5.4 (1.8) <0.001 a ; <0.001 a IL28B CC alleles, n (%) d 42 (63.6) 24 (25) 47 (41.6) 0.004 a ; <0.001 b ; 0.001 c Positive HBsAg, % 2.4 1 4.9 NS Hepatitis delta, % 0 0 1.4 NS Alcohol intake >60 g/day, % 3.4 9.4 15.9 0.004 a a Sustained virological response (SVR) versus untreated. b SVR versus treatment failure. c Treatment failure versus untreated. d Data only for 275 patients. HBsAg, hepatitis B surface antigen; NS, not significant. Antiviral Therapy 19.8 801
P Labarga et al. fibrosis stages. It is noteworthy that in our study LFP was significantly increased in patients with baseline elastometry values >7.1 kpa than in those with null liver fibrosis (45% versus 8%; P<0.003), supporting that coinfected patients with any significant liver fibrosis (Metavir F2 Figure 2. Progression to advanced liver fibrosis in HIV HCVcoinfected patients with baseline null/mild fibrosis LFP, % Mean follow-up, months 5.4 SVR (n=92) 25.7 Treatment failures (n=113) 18 Untreated (n=139) 52.5 58.3 50.4 LFP, liver fibrosis progression; SVR, sustained virological response. estimates) should be prioritized for treatment and be considered as candidates for new DAA-based therapies. As we are rapidly moving to an era of new all-oral IFNfree regimens, expecting cure rates above 90% with very few side effects [24], controversies about the cost-effectiveness of hepatitis C treatment will steadily vanish [25]. In other words, all hepatitis C patients will benefit from HCV eradication and therefore treatment should be given as soon as possible. However, the current number of potential candidates for antiviral treatment is so huge and the cost of medications so high that it would be difficult to give access to the new antivirals in a short period to everyone. Moreover, data derived from HIV-positive persons is still scarce and strong pressure should exist for prioritizing access to the new drugs in HIV HCV coinfection, at least in some countries, if not everywhere. In this context, our results highlight that any evidence of hepatic fibrosis and not just the presence of advanced fibrosis should lead to a push for antiviral treatment in this population. Otherwise, at least 20% of HIV HCV-coinfected patients will progress to advanced fibrosis within 5 years. Then, implementation of additional medical procedures would be required to minimize the risk of gastrointestinal bleeding and/or liver cancer [1]. Finally, this study confirms in the largest population examined so far (344 coinfected individuals) and for the longest mean follow-up (4.5 years) the benefit of HCV eradication on LFP in HIV HCV-coinfected patients, previously noticed by others [26 28]. Among the limitations of the study we should acknowledge the lack of consideration of a differential impact of distinct Table 2. Main characteristics of untreated HIV HCV-coinfected patients with baseline null/mild liver fibrosis LFP (n=25) No LFP (n=114) P-value Mean age, years (sd) 41.1 (4.7) 41.1 (6.7) 0.9 Male gender, % 64 61 0.8 Mean body mass index, kg/m 2 (sd) 22.3 (4.4) 22.7 (3.3) 0.6 Intravenous drug use, % 96 81.8 0.1 Mean CD4 + T-cell count, cells/µl (sd) 391.7 (174.1) 532.2 (308.6) 0.003 Mean CD4 + T-cell nadir, cells/µl (sd) 186.6 (117.4) 274.2 (208.5) 0.006 Antiretroviral therapy, % 96 90.4 0.3 Plasma HIV RNA<50 copies/ml, % 56 69.8 0.1 HCV genotypes 1 or 4, % 81.8 80.9 0.4 Mean serum HCV RNA, log IU/ml (sd) 6.6 (0.7) 5.2 (1.9) 0.04 Mean baseline liver stiffness, kpa (sd) 7.4 (1.4) 5.8 (1.4) <0.001 IL28B CC alleles, % 47.4 40.4 0.5 Mean LDL cholesterol, mg/dl (sd) 86.2 (27.2) 104.9 (31.4) 0.007 Mean AST, IU/ml (sd) 80 (55) 44 (26) 0.004 Mean GGT, IU/ml (sd) 123.4 (142.8) 78.2 (89.6) 0.04 Positive HBsAg, % 15.4 3.4 0.1 Alcohol intake >60 g/day, % 22.7 14.3 0.2 Mean follow-up, months (sd) 49.7 (15.7) 50.6 (16.6) 0.8 AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase; HBsAg, hepatitis B surface antigen; LDL, low-density lipoprotein; LFP, liver fibrosis progression. 802 2014 International Medical Press
Liver fibrosis progression in HIV HCV coinfection Table 3. Baseline predictors of liver fibrosis progression in untreated HIV HCV-coinfected patients with null/mild fibrosis antiretroviral regimens, some of which might have influenced hepatic fibrosis (for example, dideoxynucleosides) during the long study period (almost 10 years). Furthermore, hepatic fibrosis was only assessed using transient elastometry with no information available on its correlation with liver biopsies or serum fibrosis indexes, which could have provided further strength. Disclosure statement The authors declare no competing interests. References Adjusted hazard ratio 95% CI P-value Baseline liver stiffness, kpa 1.84 1.03, 3.3 0.03 Serum HCV RNA, log IU/ml 3.32 0.68, 16.16 0.13 ALT, IU/ml 1.02 0.99, 1.05 0.18 Nadir CD4 + T-cell count, 1 0.99, 1 0.54 cells/mm 3 LDL cholesterol, mg/dl 0.99 0.99, 1 0.69 Alcohol intake >60 g/day 0.9 0.91, 1.1 0.9 ALT, alanine aminotransferase; LDL, low-density lipoprotein. 1. EASL clinical practice guidelines: management of hepatitis C virus infection. J Hepatol 2014; 61:373 395. 2. Sulkowski M, Pol S, Mallolas J, et al. Boceprevir versus placebo with pegylated interferon alfa-2b and ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a randomised, double blind, controlled Phase 2 trial. Lancet Infect Dis 2013; 13:597 605. 3. Sulkowski M, Sherman K, Dieterich D, et al. Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIV: a randomized trial. Ann Intern Med 2013; 159:86 96. 4. Hézode C, Fontaine H, Dorival C, et al. Triple therapy in treatment-experienced patients with HCV cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC). J Hepatol 2013; 59:434 441. 5. Cachay E, Wyles D, Torriani F, et al. High incidence of serious adverse events in HIV-infected patients treated with a telaprevir based HCV treatment regimen. AIDS 2013; 27:2893 2897. 6. Fried MW, Buti M, Dore G, et al. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naive genotype 1 hepatitis C - the randomized PILLAR study. Hepatology 2013; 58:1918 1929. 7. Zeuzem S, Berg T, Gane E, et al. Simeprevir increases the rate of sustained virological response among treatmentexperienced patients with HCV genotype 1 infection a Phase IIb trial. Gastroenterology 2014; 146:430 441. 8. Sulkowski MS, Asselah T, Lalezari J, et al. Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naive patients with chronic genotype 1 HCV: SILEN-C1 trial. Hepatology 2013; 57:2143 2154. 9. Sulkowski M, Bourliere M, Bronowicki JP, et al. Faldaprevir combined with peginterferon alfa-2a and ribavirin in chronic hepatitis C virus genotype 1 patients with prior nonresponse: SILEN-C2 trial. Hepatology 2013; 57:2155 2163. 10. Soriano V, Vispo E, de Mendoza C, et al. Hepatitis C therapy with HCV NS5B polymerase inhibitors. Expert Opin Pharmacother 2013; 14:1161 1170. 11. Medrano J, Neukam K, Rallon N, et al. Modeling the probability of SVR to therapy with pegylated interferon plus ribavirin in patients coinfected with HCV and HIV. Clin Infect Dis 2010; 51:1209 1216. 12. European AIDS Clinical Society Guidelines (EACS). Version 7.0. October 2013. (Accessed 31 January 2014.) Available from http://www.europeanaidsclinicalsociety.org 13. Bichoupan K, Schwartz JM, Martel-Laferriere V, et al. Effect of fibrosis on adverse events in patients with hepatitis C treated with telaprevir. Aliment Pharmacol Ther 2014; 39:209 216. 14. Shiffman ML, Benhamou Y. Patients with HCV and F1 and F2 fibrosis stage: treat now or wait? Liver Int 2013; 33 Suppl 1:105 110. 15. EASL. EASL recommendations on treatment of hepatitis C 2014. J Hepatol 2014; 61:373 395. 16. Soriano V, Vispo E, Fernandez-Montero JV, Labarga P, Barreiro P. Update on HIV/HCV coinfection. Curr HIV/ AIDS Rep 2013; 10:226 234. 17. 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; 308:387 402. 18. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. (Accessed 31 January 2014.) Available from http://aidsinfo.nih.gov/contentfiles/ lvguidelines/adultandadolescentgl.pdf 19. Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol 2008; 48:835 847. 20. Sulkowski MS, Mehta S, Torbenson M, et al. Rapid fibrosis progression among HIV/HCV coinfected adults. AIDS 2007; 21:2209 2216. 21. Macías J, Berenguer J, Japón M, et al. Fast fibrosis progression between repeated liver biopsies in patients coinfected with HIV and HCV. Hepatology 2009; 50:1056 1063. 22. 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; 19:287 292. 23. Sanmartín R, Tor J, Sanvisens A, et al. Progression of liver fibrosis in HIV/HCV-coinfected individuals on antiretroviral therapy with early stages of liver fibrosis at baseline. HIV Med 2014; 15:203 212. 24. Soriano V, Labarga P, Fernández-Montero JV, et al. The changing face of hepatitis C in the new era of direct-acting antivirals. Antiviral Res 2013; 97:36 40. 25. Younossi ZM, Singer M, Mir H, Henry L, Hunt S. Impact of interferon-free regimens on clinical and cost outcomes for chronic hepatitis C genotype 1 patients. J Hepatol 2014; 60:530 537. 26. Barreiro P, Labarga P, Martín-Carbonero L, et al. Sustained virological response following HCV therapy is associated with non-progression of liver fibrosis in HCV/HIVcoinfected patients. Antivir Ther 2006; 11:869 877. 27. Loko MA, Bani-Sadr F, Valantin MA, et al. Antiretroviral therapy and sustained virological response to HCV therapy are associated with slower liver fibrosis progression in HIV-HCV-coinfected patients: study from the ANRS CO 13 HEPAVIH cohort. Antivir Ther 2012; 17:1335 1343. 28. Konerman MA, Mehta S, Sutcliffe C, et al. Fibrosis progression in human immunodeficiency virus/hepatitis C virus coinfected adults: Prospective analysis of 435 liver biopsy pairs. Hepatology 2014; 59:767 775. Accepted 28 April 2014; published online 25 June 2014 Antiviral Therapy 19.8 803