Chronic hepatitis C (CHC) is exhibited by 25–30% of European and US–American HIV-positive patients . Although AIDS-related mortality is decreasing, hepatitis C virus (HCV) coinfection has emerged as a major cause of morbidity and mortality in HIV-positive patients .
When compared with HCV monoinfection, HIV/HCV coinfection has been found to be associated with faster liver fibrosis progression  and markedly higher risk of developing cirrhosis . HCV eradication prevents end-stage liver disease, hepatocellular carcinoma, and death, with an even greater impact in HIV-positive than HIV-negative patients .
The efficacy of dual-therapy with pegylated interferon along with ribavirin (PEGIFN/RBV) has improved as a result of treatment individualization over the last decade. However, it still remains unsatisfactory, especially in HIV-positive patients . With the availability of first-generation direct-acting antiviral agents (DAAs), sustained virologic response (SVR) rates comparable to those in HCV-monoinfected patients were demonstrated [7–10]. However, serious adverse events are of particular concern in HIV-positive patients, as this patients group is highly susceptible to severe infectious complications during triple-therapy, even in the absence of cirrhosis . As a consequence, treatment uptake rates with IFN-based regimens have been much lower in this patient population [11,12].
The approval of IFN-free regimens has ushered in a new era in the treatment of CHC. Studies investigating the safety and efficacy of sofosbuvir (SOF)/RBV [13,14], SOF/daclatasvir (DCV) , SOF/ledipasvir (LDV) [16,17], as well as ritonavir-boosted paritaprevir, ombitasvir, and dasabuvir (3D)  in HIV/HCV-coinfected patients have shown promising results. Treatment is therefore indicated in all HIV-positive patients with CHC. Moreover, current European Association for the Study of the Liver (EASL)  and American Association for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA)  guidelines recommend prioritization of HIV/HCV-coinfected patients.
Owing to its pangenotypic efficacy and its favorable drug–drug interaction (DDI) profile, SOF/DCV can be used in nearly all patients with HIV/HCV coinfection . In the phase 3 ALLY-2 study , excellent SVR rates were observed among both treatment-naive (96%) and treatment-experienced (98%) HIV/HCV-genotype (GT)1-coinfected patients who received 12 weeks of SOF/DCV. However, only a small number of non-HIV/HCV-GT1-coinfected patients were included in the ALLY-2 study and patients with cirrhosis were underrepresented (16%) . However, as patients with advanced liver disease are at considerable risk for hepatic decompensation and death , they have an urgent need for effective treatment options.
Liver stiffness, assessed by transient elastrography, is an accurate noninvasive marker of liver fibrosis and commonly used in HIV/HCV-coinfected patients . Importantly, it also predicts the development of hepatic decompensation and hepatocellular carcinoma, as well as liver-related and overall mortality [24–26]. SVR to IFN-based therapies has been shown to induce liver stiffness regression in this special population . However, the effect of HCV eradication with IFN-free therapies has yet to be investigated.
The aim of our study was to investigate the safety and efficacy of SOF/DCV in HIV/HCV-coinfected patients with advanced liver disease. We also assessed the changes in liver stiffness and liver enzymes after HCV therapy.
Patients and methods
Thirty-one HIV/HCV-coinfected patients with advanced liver disease treated with SOF/DCV at the Medical University of Vienna were studied retrospectively.
Epidemiological, HIV, and HCV characteristics were assessed from patients’ medical history. Interleukin 28B rs12979860 single nucleotide polymorphism (SNP) (IL28B) genotyping was performed in house using the StepOnePlus Real Time PCR System and a Custom TaqMan SNP Genotyping Assay (Applied Biosystems, Carlsbad, California, USA) as previously described . HCV-GT was determined using the VERSANT HCV Genotype 2.0 Assay Line Probe Assay (LiPA) (Siemens Healthcare Diagnostics, Tarrytown, New York, USA). HCV-RNA was assessed using the Abbott RealTime HCV assay (Abbott Molecular, Des Plaines, Illinois, USA) with a lower limit of quantification (LLOQ) and detection of 12 IU/ml. SVR4 and SVR12 were defined as undetectable HCV-RNA 4 and 12 weeks after the end of therapy, respectively. Aspartate (AST) and alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), as well as CD4+ T-lymphocyte (CD4+) cell count were assessed using standard laboratory methods.
Hepatitis C virus therapy
SOF [Sovaldi (Gilead, Cambridge, UK) 400 mg once daily] was covered by the Austrian health insurance and provided by the local pharmacy. Bristol-Myers Squibb provided DCV (30–90 mg once daily) within a named patient program. After the approval by the European Medicines Agency, DCV was also provided by the local pharmacy [Daklinza (Bristol-Myers Squibb, Uxbridge, UK) 30–90 mg once daily]. Similar to the ALLY-2 study , adjusted DCV doses of 30 or 90 mg were used in patients who were treated with ritonavir-boosted protease inhibitors or nonnucleoside reverse-transcriptase inhibitors (NNRTIs), respectively. The patient who was on both a NNRTI and a ritonavir-boosted protease inhibitor was treated with a daily DCV dose of 60 mg. None of the patients received RBV. The following treatment durations were applied: HCV-GT1/4 without cirrhosis: 12 weeks; HCV-GT1/4 with cirrhosis: 24 weeks; HCV-GT3: 24 weeks; if HCV-RNA was detectable 4 weeks before the end of treatment, treatment duration was extended by 4 weeks at a time.
Similarly to the ALLY-2 study , adverse events (AEs) and laboratory abnormalities were graded according to the criteria of the Division of AIDS of the National Institute of Allergy and Infectious Diseases.
Liver stiffness and portal hypertension measurement
Measurement of liver stiffness was performed by transient elastography (Fibroscan, Echosens, Paris, France), as previously described . Liver stiffness was assessed before (baseline) and after HCV treatment (follow-up).
The Vienna Hepatic Hemodynamic Laboratory at the Medical University of Vienna performed the portal hypertension (HVPG) measurements in accordance with a standardized operating procedure . At our center, measurement of HVPG is a routine procedure in patients with evidence of advanced chronic liver disease, as recommended by current guidelines [31,32]. Concomitant medications known to have an effect on HVPG, including but not limited to β-blockers and nitrates were paused 5 days prior to HVPG measurements. Portal hypertension and clinically significant portal hypertension were defined as HVPG not less than 6 mmHg and at least 10 mmHg [31,32], respectively.
Advanced liver disease and cirrhosis were diagnosed by transient elastography (baseline liver stiffness >9.5 kPa and >12.5 kPa , respectively), liver biopsy (METAVIR >F2 and F4, respectively), or HVPG measurement (portal hypertension and clinically significant portal hypertension, respectively).
Statistical analyses were performed using IBM SPSS Statistics 23 (IBM, Armonk, New York, USA) and GraphPad Prism 6 (GraphPad Software, La Jolla, California, USA). Continuous variables were reported as mean ± standard error of the mean or median (interquartile range), whereas categorical variables were reported as number of patients with (proportion of patients with) the certain characteristic. Confidence intervals of proportions were calculated using the modified Wald method.
Student's t test was used for group comparisons of continuous variables when applicable. Otherwise, Mann–Whitney U test was applied. Group comparisons of categorical variables were performed using χ2 or Fisher's exact test. Intraindividual comparisons were performed using Wilcoxon matched-pairs signed rank test, or McNemar's test. Spearman's rank correlation coefficient was calculated for correlation analyses. A P value ≤ 0.05 was considered as statistically significant.
This study was conducted in accordance with the Declaration of Helsinki and approved by the local ethics committee of the Medical University of Vienna (no. 1814/2015).
The mean baseline CD4+ T-lymphocyte (CD4+) cell count was 495 ± 46 cells/μl (Table 1). Almost all patients [97% (30/31)] were currently on antiretroviral therapy. Although the majority of patients were on an integrase inhibitor-based regimen [68% (21/31)], there was a wide range of concomitant antiretroviral therapy. Eighty-one percent (25/31) of patients had suppressed HIV-RNA (<50 copies/ml) at baseline.
Fifty-two percent (16/31) of patients were treatment-experienced, including patients with previous first-generation DAA failure [6% (2/31)]. The majority of patients was infected with HCV-GT1 [68% (21/31)], whereas HCV-GT3 and HCV-GT4 were observed in 23% (7/31) and 10% (3/31) of patients, respectively. Seventy-four percent (23/31) of patients had the IL28B non-C/C genotype.
Ninety-four percent (29/31) had liver stiffness greater than 9.5 kPa or METAVIR fibrosis stage higher than F2 and 45% (14/31) had liver stiffness above 12.5 kPa or METAVIR F4. Among 27 patients with information on HVPG, portal hypertension and clinically significant portal hypertension were observed in 67% (18/27) and 26% (7/27) of patients, respectively. All patients had advanced liver disease and 52% (16/31) of patients had cirrhosis.
At treatment week (W)4, 17% (5/29) and 52% (15/32) had undetectable HCV-RNA and HCV-RNA below LLOQ, respectively (Fig. 1). At W8, HCV-RNA was detectable in 31% (4/13) of HCV-GT1/4 patients without cirrhosis. In these patients, treatment duration was extended by 4 weeks at a time to 16 (n = 2), 20 (n = 1), or 24 weeks (n = 1). Only 77% (24/31) achieved undetectable HCV-RNA at W12, whereas HCV-RNA below LLOQ was observed in 97% (30/31) of patients.
HCV-RNA was undetectable in all patients [100% (31/31)] at the end of treatment and all patients [100% (31/31)] achieved SVR4 and SVR12.
Twenty-seven (87%) patients had at least one AE during HCV-therapy and follow-up (Table 2). Grade 3/4 AEs occurred in four (13%) patients. These were influenza (fever grade 3), gastroenteritis (fever grade 3), ulcer bleeding (hemorrhage grade 3), and acute myocardial infarction (grade 4). Serious AEs were observed in only two (6%) patients (ulcer bleeding and acute myocardial infarction). Grade 3/4 AEs and serious AEs were not considered to be treatment-related and there were no treatment discontinuations.
Grade 3/4 laboratory abnormalities were observed in eight (26%) patients. At baseline (before the first administration of SOF/DCV), three (10%) patients had CD4+ cell counts less than 200 cells/μl (grade 3), three (10%) patients had platelet counts below 50 G/l (grade 3), and one patient had an AST elevation greater than 5 × upper limit of normal (grade 3). One additional patient developed a CD4+ cell count below 200 cells/μl (grade 3) during HCV-therapy. To exclude a potential detrimental effect of SOF/DCV on CD4+ and platelet counts, we assessed the course of CD4+ and platelet count during HCV-therapy and follow-up (Supplementary Figure 2).
Changes in liver stiffness and liver enzymes
The mean time periods between baseline liver stiffness measurement and treatment initiation as well as baseline and follow-up liver stiffness measurement were 10 ± 2.2 and 42.7 ± 2.8 weeks, respectively. Thus, the mean time period between treatment initiation and follow-up liver stiffness measurement was 32.7 ± 1.2 weeks.
Liver stiffness decreased in 90% (28/31) of patients, whereas it increased in 10% (3/31) of patients (Fig. 1). There was a decrease in liver stiffness between baseline and follow-up [11.8 (11.5) vs. 6.9 (8.2) kPa; median change: –3.6 (5.2) kPa; P < 0.001]. The median relative change in liver stiffness was −33 (26)%.
The proportion of patients with liver stiffness values greater than 9.5 kPa decreased significantly [baseline: 71% (22/31) vs. follow-up: 35% (11/31); P < 0.001]. Moreover, there was a trend toward a decrease in the proportion of patients with liver stiffness values above 12.5 kPa [baseline: 42% (13/31) vs. follow-up: 26% (8/31); P = 0.059].
Liver enzyme levels decreased statistically significantly after HCV-therapy: AST: 44 (34) vs. 29 (20) U/l; median change: −16 (23) U/l; P < 0.001, ALT: 47 (41) vs. 22 (19) U/l; median change: −22 (27) U/l; P < 0.001, and GGT: 81 (97) vs. 23 (23) U/l; median change: −54 (67) U/l; P < 0.001 (Fig. 1).
Determinants of the change in liver stiffness
There was a statistically significant inverse correlation between the relative changes in liver stiffness and baseline liver stiffness (ρ = −0.462; P = 0.009), indicating more pronounced relative decreases among patients with higher baseline liver stiffness. We did not observe a correlation between the relative changes in liver stiffness and baseline liver enzyme levels [AST (ρ = 0.154; P = 0.409), ALT (ρ=0.088; P = 0.64), and GGT (ρ = 0.131; P = 0.483)], or their change after HCV-therapy [AST (ρ = −0.05; P = 0.788), ALT (ρ = −0.079; P = 0.672), and GGT (ρ = −0.077; P = 0.679)].
Our real-life cohort comprises thoroughly characterized HIV/HCV-coinfected patients with an urgent need for effective HCV-therapy. Several IFN-free regimens have been studied in HIV/HCV-coinfected patients. However, none of these studies aimed to investigate the use of IFN-free regimens in patients with advanced liver disease. The proportions of patients with cirrhosis and clinically significant portal hypertension were 52 and 26%, respectively, which underlines the difficult-to-treat character of our study population. Moreover, more than half of them were treatment-experienced, including patients with previous first-generation DAA failure (6%), and 23% had HIV/HCV-GT3 coinfection.
Two large phase 3 trials investigated the use of 24 weeks of SOF/RBV in HIV-positive patients [13,14]. Combining the HIV/HCV-GT1/4 arms of both studies, SVR was observed in only 81% of patients, although all patients were treatment-naive. The rates of SVR may further decline in treatment-experienced patients and real-life cohorts comprising a higher proportion of patients with cirrhosis. Due to the unprecedented advances in the field of HCV-therapy, these SVR rates are no longer satisfactory and more potent regimens, such as SOF/DCV, should be used for patients with HIV/HCV-GT1/4 coinfection [19,20].
The majority of patients included in the phase 3 ALLY-2 study had HIV/HCV-GT1 coinfection. In patients treated for 12 weeks, the presence of previous negative predictive factors, such as liver cirrhosis, did not affect SVR rates. Although the association between cirrhosis and treatment failure did not attain statistical significance, due to limited statistical power (only 16% of patients had cirrhosis), a clinically relevant impact cannot be ruled out. Thus, current EASL guidelines  recommend either the addition of RBV, or 24 weeks of treatment in patients with cirrhosis. In our study, we adopted the latter approach, which resulted in SVR in all HIV/HCV-GT1/4 patients with cirrhosis (n = 11), despite the high proportion of patients with clinically significant portal hypertension. This is in line with our previous observation , that IFN-free regimens overcome the negative effect of portal hypertension on virologic response.
In HIV/HCV-GT1/4-coinfected patients without cirrhosis, response-guided therapy was used. The concept of response-guided therapy has been validated for PEGIFN/RBV  and first-generation DAAs, such as boceprevir . Although some authors have proposed response-guided algorithms for individualization of IFN-free treatment [35,36], a final appraisal of its practicability has not yet been made. In our study, the adaption of response-guided treatment durations for HIV/HCV-GT1/4 patients without cirrhosis might have led to an overtreatment of four out of 13 patients. Treatment duration was extended to 16–24 weeks in these patients, although according to the excellent results of the ALLY-2 study, 12 weeks might have been sufficient.
Two studies investigated the use of SOF/LDV in HIV-positive patients [16,17], which is another NS5B/NS5A inhibitor combination with a favorable DDI profile. The NIAID ERADICATE study  was restricted to treatment-naive, HIV/HCV-GT1 patients without cirrhosis, which precludes direct comparisons with our study. The second study (ION-4 study ), included a significant proportion of difficult-to-treat HCV-GT1/4 patients, such as patients with cirrhosis (20%), as well as first-generation DAA (29%) and SOF/RBV failures (4%). Patients were treated for 12 weeks, resulting in SVR rates of 95 and 97% among treatment-naive and treatment-experienced patients, respectively. Moreover, the combination of the 3D regimen and RBV has been investigated in the TURQUOISE-1 study  in HIV/HCV-GT1-coinfected patients, including 10% of patients with cirrhosis. Patients were randomized into two arms comparing 12 and 24 weeks of treatment, achieving SVR rates of 94 and 91%, respectively.
However, the 3D regimen is only effective against HCV-GT1/4 and even SOF/LDV is not a pangenotypic regimen, as its efficacy against HCV-GT3 largely relies on the addition of RBV . Accordingly, EASL  and IDSA/AASLD  guidelines recommend against the use of SOF/LDV in patients with HCV-GT3 and suggest the use of SOF/PEGIFN/RBV, SOF/RBV, or SOF/DCV ± RBV.
HIV/HCV-GT3 coinfection is common in Europe and other parts of the world . The prevalence of liver cirrhosis among HIV/HCV-coinfected patients is more than 20% , and might be even higher among HIV/HCV-GT3 patients, as HCV-GT3 accelerates liver fibrosis progression . Thus, both patients with HIV/HCV-GT3 (7%) and with cirrhosis (16%) were underrepresented in the phase 3 ALLY-2 study . Based on the results of the ALLY-3 study , which investigated the same regimen in HCV monoinfection, these patients are considered as one of the remaining difficult-to-treat populations. Current EASL guidelines recommend both the addition of RBV and extended SOF/DCV treatment duration of 24 weeks in patients with HCV-GT3 and cirrhosis , although the currently available evidence for this recommendation is very limited. In our study, all HIV/HCV-GT3-coinfected patients (five out of seven patients had cirrhosis) were treated without RBV for 24 weeks and all patients achieved SVR. Nevertheless, larger studies investigating the optimal treatment strategy for patients with HIV/HCV-GT3 coinfection and cirrhosis are needed.
DDIs were of major concern when first-generation DAAs were used . Even with second-generation DAAs, such as simeprevir or the 3D regimen, DDIs with antiretroviral therapy complicate management in the majority of patients . Similar to the phase 3 ALLY-2 study , patients with ritonavir-boosted protease inhibitors received a reduced DCV dose of 30 mg in our study. Patients with ritonavir-boosted darunavir containing antiretroviral therapy were overrepresented among patients who had a relapse in the ALLY-2 study. Moreover, recent pharmacokinetic data suggests that 60 mg is more appropriate for patients on ritonavir-boosted darunavir or lopinavir containing antiretroviral therapy . As all patients achieved SVR in our study, we did not observe a detrimental effect. Nevertheless, the daily DCV dose should not be reduced to 30 mg in patients on ritonavir-boosted darunavir, as the low number of patients (n = 4) included in our study limits the significance of this finding.
As patients with advanced liver disease are at considerable risk for hepatic decompensation and death , they represent the frontline in the use of IFN-free regimens. Combining treatment-naive and treatment-experienced patients receiving 12 weeks of SOF/DCV in the ALLY-2 study, the SVR rate among patients with advanced liver fibrosis treated for 12 weeks was 97%. Although our study included patients with even more advanced liver disease who would have been excluded from the ALLY-2 study (decompensated cirrhosis; platelet count <50 G/l), SVR was achieved in all patients. However, we can only speculate whether this was by chance or as a result of the use of longer treatment durations.
Although the proportion of patients with at least one AE during HCV-therapy and follow-up (87%) was comparable to the ALLY-2 study (69%), we observed numerically higher proportions of patients with grade 3/4 (13 vs. 4%) and serious AEs (6 vs. 2%), which might be explained by the multimorbidity of our study population. Importantly, none of the grade 3/4 or serious AEs was considered to be treatment-related and there were no treatment discontinuations. Moreover, the majority of grade 3/4 laboratory abnormalities were observed at baseline, before the first administration of SOF/DCV. Low absolute CD4+ and platelet counts at baseline are secondary to portal hypertension  and underline the difficult-to-treat character of our study population. Importantly, both parameters remained stable during HCV-therapy. Thus, SOF/DCV is well tolerated, even in HIV/HCV-coinfected patients with advanced liver disease.
With increasing availability of highly effective and well tolerated regimens, the focus of attention will shift from liver disease progression  to the regression of liver fibrosis and portal hypertension after HCV eradication [21,42]. Achieving SVR with IFN-based therapies has been shown to decrease liver stiffness in HIV/HCV-coinfected patients. In the ANRS CO13 HEPAVIH cohort , the probability of achieving a 30% decrease in liver stiffness among patients with SVR was 51 and 74% at 1 and 2 years after the end of treatment, respectively. In a previous study in HCV-monoinfected patients with cirrhosis under IFN-free treatment, we also observed a decrease in liver stiffness, paralleled by an increase in platelet count shortly after HCV eradication, suggesting an anti-portal hypertensive effect .
This is the first study to provide information on changes in liver stiffness after HCV eradication with IFN-free therapies in the setting of HIV/HCV-coinfection. In our study, the median relative change in liver stiffness between baseline and follow-up was –33%, indicating a rapid, clinically significant effect. We observed more pronounced relative decreases among patients with higher baseline liver stiffness. These findings have strong implications for the long-term management of patients with cirrhosis at baseline, as a decrease in liver stiffness might abolish the need for HCC surveillance and screening endoscopies .
Potential mechanisms for the decrease in liver stiffness after HCV eradication include changes in tissue contraction/relaxation, hepatic necroinflammation, liver fibrosis, and cholestasis [29,42]. Although the improvement in liver stiffness was paralleled by a decrease in liver enzymes, there was no correlation between liver enzymes as a marker of necroinflammation and the relative change in liver stiffness. Moreover, the expected dynamics of liver fibrosis and cholestasis after HCV eradication may rather explain long-term, than short-term changes. Further studies investigating short and long-term changes in liver fibrosis and portal hypertension after IFN-free treatments in HIV/HCV-coinfected patients are highly encouraged, due to their strong clinical implications (e.g. HCC surveillance, screening endoscopies, and prevention of variceal hemorrhage).
The main limitations of our study arise from its retrospective design and the limited number of patients. First, although our results are promising, we cannot draw definite conclusion on the utility of response-guided therapy in the era of IFN-free regimens, or the optimal treatment strategy for patients with HIV/HCV-GT3 and cirrhosis. Second, as we do not have information on changes in liver histology and portal hypertension, the mechanism by which HCV eradication lowers liver stiffness in this short time period remains unclear.
In conclusion, IFN- and RBV-free treatment with SOF/DCV was well tolerated and achieved SVR in all difficult-to-treat HIV/HCV-coinfected patients, including those with HIV/HCV-GT3 coinfection, cirrhosis, and/or portal hypertension. It also improved liver stiffness, suggesting anti-fibrotic and anti-portal hypertensive effects. As IFN-free regimens achieve comparable rates of SVR in HIV-negative and HIV-positive patients, HIV/HCV-coinfected patients should from now on be referred to as a special, rather than a difficult-to-treat population.
Funding: This work was supported by a grant from the Medical Scientific Fund of the Major of the City of Vienna (14033) to M.M.
Contributions: Study concept and design (M.M. and M.P.), acquisition of data (M.M., P.S., S.S., B.S., D.C., T.B., A.F.S., M.C.A, K.G., and T.R.), analysis and interpretation of data (M.M., P.S., M.T., T.R., and M.P.), drafting of the manuscript (M.M., P.S., M.T., T.R., and M.P.), critical revision of the manuscript for important intellectual content (M.M., P.S., S.S., B.S., D.C., T.B., A.F.S., M.C.A, K.G., M.T., T.R., and M.P.).
Conflicts of interest
M.M. received honoraria for consulting from Janssen, payments for lectures from Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, and Roche, as well as travel support from AbbVie, Gilead, MSD, and Roche. P.S. received payments for lectures from Roche and travel support from AbbVie, Gilead, Janssen, and Roche. S.S., B.S. and D.C. have nothing to disclose. T.B. received payments for lectures from Roche and travel support from Bristol-Myers Squibb. A.F.S. received honoraria for consulting from Gilead, payments for lectures from Boehringer Ingelheim, Janssen, and Roche, as well as travel support from Bristol-Myers Squibb, Gilead, Janssen, and Roche. M.C.A. received honoraria for consulting from Gilead and MSD and travel support from AbbVie, Gilead, and MSD. K.G. received honoraria for consulting from Gilead, payments for lectures from Bristol-Myers Squibb and ViiV, as well as travel support from Bristol-Myers Squibb, Gilead, and GlaxoSmithKline. M.T. received grants from MSD, honoraria for consulting from AbbVie, Gilead, Janssen, and MSD, payments for lectures from Gilead, MSD, and Roche, as well as travel support from Gilead. T.R. received payments for lectures from Roche, as well as travel support from Gilead, MSD, and Roche. M.P. received grants from Gilead, MSD, and Roche, honoraria for board membership and consulting from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, and MSD, as well as payments for lectures from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, MSD, and Roche.
1. Alter MJ. Epidemiology of viral hepatitis and HIV co-infection
. J Hepatol
2. Puoti M, Moioli MC, Travi G, Rossotti R. The burden of liver disease in human immunodeficiency virus-infected patients
. Semin Liver Dis
3. Benhamou Y, Bochet M, Di Martino V, Charlotte F, Azria F, Coutellier A, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group
4. Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis
. Clin Infect Dis
5. 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
6. Mandorfer M, Neukam K, Reiberger T, Payer BA, Rivero A, Puoti M, et al. The impact of interleukin 28B rs12979860 single nucleotide polymorphism and liver fibrosis stage on response-guided therapy in HIV/HCV-coinfected patients
7. Sulkowski MS, Sherman KE, Dieterich DT, Bsharat M, Mahnke L, Rockstroh JK, et al. Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIV: a randomized trial
. Ann Intern Med
8. Sulkowski M, Pol S, Mallolas J, Fainboim H, Cooper C, Slim 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
9. Mandorfer M, Steiner S, Schwabl P, Payer BA, Aichelburg MC, Lang G, et al. Response-guided boceprevir-based triple therapy in HIV/HCV-coinfected patients: The HIVCOBOC-RGT study
. J Infect Dis
10. Neukam K, Munteanu DI, Rivero-Juarez A, Lutz T, Fehr J, Mandorfer M, et al. Boceprevir or telaprevir based triple therapy against chronic hepatitis C in HIV coinfection: real-life safety and efficacy
. PLoS ONE
11. Reiberger T, Obermeier M, Payer BA, Baumgarten A, Weitner L, Moll A, et al. Considerable under-treatment of chronic HCV infection in HIV patients despite acceptable sustained virological response rates in a real-life setting
. Antivir Ther
12. Mandorfer M, Payer BA, Niederecker A, Lang G, Aichelburg MC, Strassl R, et al. Therapeutic potential of and treatment with boceprevir/telaprevir-based triple-therapy in HIV/chronic hepatitis C co-infected patients in a real-world setting
. AIDS Patient Care STDS
13. Sulkowski MS, Naggie S, Lalezari J, Fessel WJ, Mounzer K, Shuhart M, et al. Sofosbuvir and ribavirin for hepatitis C in patients with HIV coinfection
14. Molina JM, Orkin C, Iser DM, Zamora FX, Nelson M, Stephan C, et al. Sofosbuvir plus ribavirin for treatment of hepatitis C virus in patients co-infected with HIV (PHOTON-2): a multicentre, open-label, nonrandomised, phase 3 study
15. Wyles DL, Ruane PJ, Sulkowski MS, Dieterich D, Luetkemeyer A, Morgan TR, et al. Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1
. N Engl J Med
16. Osinusi A, Townsend K, Kohli A, Nelson A, Seamon C, Meissner EG, et al. Virologic response following combined ledipasvir and sofosbuvir administration in patients with HCV genotype 1 and HIV co-infection
17. Naggie S, Cooper C, Saag M, Workowski K, Ruane P, Towner WJ, et al. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1
. N Engl J Med
18. Sulkowski MS, Eron JJ, Wyles D, Trinh R, Lalezari J, Wang C, et al. Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1: a randomized trial
19. European Association for Study of Liver. EASL Recommendations on Treatment of Hepatitis C 2015
. J Hepatol
20. AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus
21. Mandorfer M, Schwabl P, Steiner S, Reiberger T, Peck-Radosavljevic M. Advances in the management of HIV/HCV coinfection
. Hepatol Int
22. Macias J, Mancebo M, Marquez M, Merino D, Tellez F, Rivero A, et al. Low risk of liver decompensation among human immunodeficiency virus/hepatitis C virus-coinfected patients with mild fibrosis in the short term
23. de Ledinghen V, Douvin C, Kettaneh A, Ziol M, Roulot D, Marcellin P, et al. Diagnosis of hepatic fibrosis and cirrhosis by transient elastography in HIV/hepatitis C virus-coinfected patients
. J Acquir Immune Defic Syndr
24. Macias J, Camacho A, Von Wichmann MA, Lopez-Cortes LF, Ortega E, Tural C, et al. Liver stiffness measurement versus liver biopsy to predict survival and decompensations of cirrhosis among HIV/hepatitis C virus-coinfected patients
25. Perez-Latorre L, Sanchez-Conde M, Rincon D, Miralles P, Aldamiz-Echevarria T, Carrero A, et al. Prediction of liver complications in patients with hepatitis C virus-related cirrhosis with and without HIV coinfection: comparison of hepatic venous pressure gradient and transient elastography
. Clin Infect Dis
26. Merchante N, Rivero-Juarez A, Tellez F, Merino D, Jose Rios-Villegas M, Marquez-Solero M, et al. Liver stiffness predicts clinical outcome in human immunodeficiency virus/hepatitis C virus-coinfected patients with compensated liver cirrhosis
27. ANRS CO13 HEPAVIH Cohort. Regression of liver stiffness after sustained hepatitis C virus (HCV) virological responses among HIV/HCV-coinfected patients
28. Stattermayer AF, Stauber R, Hofer H, Rutter K, Beinhardt S, Scherzer TM, et al. Impact of IL28B genotype on the early and sustained virologic response in treatment-naive patients with chronic hepatitis C
. Clin Gastroenterol Hepatol
29. Schwabl P, Bota S, Salzl P, Mandorfer M, Payer BA, Ferlitsch A, et al. New reliability criteria for transient elastography increase the number of accurate measurements for screening of cirrhosis and portal hypertension
. Liver Int
30. Reiberger T, Payer BA, Ferlitsch A, Sieghart W, Breitenecker F, Aichelburg MC, et al. A prospective evaluation of pulmonary, systemic and hepatic haemodynamics in HIV-HCV-coinfected patients before and after antiviral therapy with pegylated interferon and ribavirin
. Antivir Ther
31. Peck-Radosavljevic M, Angermayr B, Datz C, Ferlitsch A, Ferlitsch M, Fuhrmann V, et al. Austrian consensus on the definition and treatment of portal hypertension and its complications (Billroth II)
. Wien Klin Wochenschr
32. de Franchis R, Baveno VIF. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension
. J Hepatol
33. Castera L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C
34. Mandorfer M, Kozbial K, Freissmuth C, Schwabl P, Stattermayer AF, Reiberger T, et al. Interferon-free regimens for chronic hepatitis C overcome the effects of portal hypertension on virological responses
. Aliment Pharmacol Ther
35. Ferenci P. Treatment of hepatitis C in difficult-to-treat patients
. Nat Rev Gastroenterol Hepatol
36. Ferenci P, Kozbial K, Mandorfer M, Hofer H. HCV targeting of patients with cirrhosis
. J Hepatol
37. Gane EJ, Hyland RH, An D, Pang PS, Symonds WT, McHutchison JG, et al. Sofosbuvir/ledipasvir fixed dose combination is safe and effective in difficult-to-treat populations including genotype-3 patients, decompensated genotype-1 patients, and genotype-1 patients with prior sofosbuvir treatment experience
. J Hepatol
38. Mandorfer M, Payer BA, Schwabl P, Steiner S, Ferlitsch A, Aichelburg MC, et al. Revisiting liver disease progression in HIV/HCV-coinfected patients: the influence of vitamin D, insulin resistance, immune status, IL28B and PNPLA3
. Liver Int
39. Nelson DR, Cooper JN, Lalezari JP, Lawitz E, Pockros PJ, Gitlin N, et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study
40. Eley T, You X, Wang R, Luo WL, Huang SP, Kandoussi H, et al. Daclatasvir: overview of drug-drug interactions with antiretroviral agents and other common concomitant drugs
. Global Antivir J
41. Mandorfer M, Reiberger T, Payer BA, Peck-Radosavljevic M. The influence of portal pressure on the discordance between absolute CD4+ cell count and CD4+ cell percentage in HIV/hepatitis C virus-coinfected patients
. Clin Infect Dis
42. Pinzani M. Liver fibrosis in the post-HCV era
. Semin Liver Dis