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Real-World Effectiveness and Safety of Oral Combination Antiviral Therapy for Hepatitis C Virus Genotype 4 Infection

2017; Elsevier BV; Volume: 15; Issue: 6 Linguagem: Inglês

10.1016/j.cgh.2017.02.020

1542-7714

Javier Crespo, José Luís Calleja, Inmaculada Fernández, Begoña Sacristán, Belén Ruíz‐Antorán, Javier Ampuero, Marta Hernández‐Conde, Javier García‐Samaniego, Francisco Gea, Marı́a Buti, Joaquín Cabezas, Sabela Lens, Rosa M. Morillas, J.R. Salcines, J.M. Pascasio, Juan Turnés, F. Sáez-Royuela, Juan Arenas, Diego Rincón, M. Prieto, Francisco Jorquera, Juan José Sánchez‐Ruano, C.A. Navascués, Esther Molina, Adolfo Gallego, J.M. Moreno Planas, Silvia Montoliu, Miguel A. Serra, Raúl J. Andrade, Conrado Fernández-Rodrı́guez, Miguel Fernández‐Bermejo, Miguel Ángel Simón, Lucía Bonet, Juan de la Vega, M. Diago, J.R. Fernández, Gloria Sánchez‐Antolín,

Hepatitis B Virus Studies

Patients with hepatitis C virus (HCV) genotype 4 infection are poorly represented in clinical trials of second-generation direct-acting antiviral agents (DAAs). More data are needed to help guide treatment decisions. We investigated the effectiveness and safety of DAAs in patients with genotype 4 infection in routine practice. In this cohort study, HCV genotype 4-infected patients treated with ombitasvir/paritaprevir/ritonavir (OMV/PTVr) + ribavirin (RBV) (n=122) or ledipasvir/sofosbuvir (LDV/SOF) ± RBV (n=130) included in a national database were identified and prospectively followed up. Demographic, clinical and virologic data and serious adverse events (SAEs) were analyzed. Differences between treatment groups mean that data cannot be compared directly. Overall sustained virologic response at Week 12 post treatment (SVR12) was 96.2% with OMV/PTVr+RBV and 95.4% with LDV/SOF±RBV. In cirrhotic patients, SVR12 was 91.2% with OMV/PTVr+RBV and 93.2% with LDV/SOF±RBV. There was no significant difference in SVR12 according to degree of fibrosis in either treatment group (P = .243 and P = .244, respectively). On multivariate analysis, baseline albumin 2 mg/dL (both cohorts) were significantly associated with failure to achieve SVR (P < .05). Rates of SAEs and SAE-associated discontinuation were 5.7% and 2.5%, respectively, in the OMV/PTVr subcohort and 4.6% and 0.8%, respectively, in the LDV/SOF subcohort. DAA-based regimens returned high rates of SVR12, comparable to limited data from clinical trials, in cirrhotic and non-cirrhotic HCV genotype 4 patients managed in a realworld setting. Safety profiles of both regimens were good and comparable to those reported for other HCV genotypes. Patients with hepatitis C virus (HCV) genotype 4 infection are poorly represented in clinical trials of second-generation direct-acting antiviral agents (DAAs). More data are needed to help guide treatment decisions. We investigated the effectiveness and safety of DAAs in patients with genotype 4 infection in routine practice. In this cohort study, HCV genotype 4-infected patients treated with ombitasvir/paritaprevir/ritonavir (OMV/PTVr) + ribavirin (RBV) (n=122) or ledipasvir/sofosbuvir (LDV/SOF) ± RBV (n=130) included in a national database were identified and prospectively followed up. Demographic, clinical and virologic data and serious adverse events (SAEs) were analyzed. Differences between treatment groups mean that data cannot be compared directly. Overall sustained virologic response at Week 12 post treatment (SVR12) was 96.2% with OMV/PTVr+RBV and 95.4% with LDV/SOF±RBV. In cirrhotic patients, SVR12 was 91.2% with OMV/PTVr+RBV and 93.2% with LDV/SOF±RBV. There was no significant difference in SVR12 according to degree of fibrosis in either treatment group (P = .243 and P = .244, respectively). On multivariate analysis, baseline albumin 2 mg/dL (both cohorts) were significantly associated with failure to achieve SVR (P < .05). Rates of SAEs and SAE-associated discontinuation were 5.7% and 2.5%, respectively, in the OMV/PTVr subcohort and 4.6% and 0.8%, respectively, in the LDV/SOF subcohort. DAA-based regimens returned high rates of SVR12, comparable to limited data from clinical trials, in cirrhotic and non-cirrhotic HCV genotype 4 patients managed in a realworld setting. Safety profiles of both regimens were good and comparable to those reported for other HCV genotypes. Worldwide, an estimated 15 million people are infected with hepatitis C virus (HCV) genotype 4 (GT 4).1Messina J.P. Humphreys I. Flaxman A. et al.Global distribution and prevalence of hepatitis C virus genotypes.Hepatology. 2015; 61: 77-87Crossref PubMed Scopus (1140) Google Scholar Because there is only moderate response to interferon-based therapy in these patients, this infection has been considered more difficult to treat. Although scarcer than for GT 1 patients, data from clinical trials on the efficacy of direct-acting antiviral agents (DAAs) in GT 4 patients suggest that interferon-free regimens with DAAs have the potential to achieve high rates of sustained virologic response (SVR) in GT 4 patients. SVR rates of 100% were achieved in the phase 2b PEARL-1 study in 135 treatment-naive and treatment-experienced non-cirrhotic GT 4 patients treated with ombitasvir/paritaprevir/ritonavir (OMV/PTVr) ± ribavirin (RBV).2Hézode C. Asselah T. Reddy K.R. et al.Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial.Lancet. 2015; 385: 2502-2509Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar SVR was similarly achieved in all 20 patients, including 7 with cirrhosis, included in a phase 2 study and treated with ledipasvir/sofosbuvir (LDV/SOF).3Kohli A. Kapoor R. Sims Z. et al.Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label phase 2a cohort studyLancet Infect Dis. 2015; 15: 1049-1054Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar Evaluation of drugs in the real-world setting is critical, particularly in patients such as those with HCV GT 4 infection where clinical trial data are more limited. Therefore, we evaluated the clinical effectiveness and safety of 2 interferon-free DAA regimens, OMV/PTVr and LDV/SOF, in a cohort of HCV GT 4 patients treated in routine practice across Spain. Data were collected through a National Registry (HEPA-C) under the auspices of the Spanish Association for the Study of the Liver and the Networked Biomedical Research Centre for the Study of the Liver and Digestive Diseases in Spain. All data recorded between April 1, 2015 and February 28, 2016 in treatment-naive or treatment-experienced patients chronically infected with HCV GT 4 and treated with OMV/PTVr + RBV or LDV/SOF ± RBV in 35 Spanish centers were analyzed retrospectively. The study was approved in advance by the Research Ethics Committee of Hospital Universitario Puerta de Hierro of Majadahonda (Madrid, Spain). Treatment was entirely at the discretion of the physician. Recommended treatment regimens were OMV 25 mg/PTV 150 mg/ritonavir 100 mg as 2 tablets once daily plus RBV or a single tablet fixed-dose regimen containing LDV 90 mg/SOF 400 mg given once daily ± RBV. Both regimens were administered for 12–24 weeks as determined by individual patient clinical characteristics. Demographic, clinical, virologic, and safety data were collected. Virologic response, defined as undetectable HCV RNA determined by using either the COBAS AmpliPrep/COBAS TaqMan (Roche Molecular Systems, Pleasanton, CA; lower limit of detection, 15 IU/mL) or the m2000SP/m2000RT (Abbott Molecular, Des Moines, IL; lower limit of detection, 12 IU/mL) real-time polymerase chain reaction–based assays, was assessed at week 4 of treatment, at end of treatment (EOT), and at week 4 (SVR4) and week 12 (SVR12) after treatment. Virologic failure was defined as detectable HCV RNA at any time during treatment (with the exception of week 4 of treatment) or post-treatment follow-up. Change in renal function was assessed at week 12 after treatment. Details of all recorded serious adverse events (SAEs) were collected from the time of first drug administration to week 12 after the planned EOT. Results for each treatment group are presented separately and are not directly comparable. Data from 122 patients treated with OMV/PTVr were included in the analysis (Table 1). Overall, 96.2% of those with available data achieved SVR12 (modified intent-to-treat). SVR12 was numerically lower in patients with cirrhosis, but overall there was no statistical difference in SVR12 according to degree of fibrosis (P = .243). The majority of patients without cirrhosis (88.5%) received the recommended 12 weeks of treatment with OMV/PTVr + RBV, and 98.4% achieved SVR12. In patients with cirrhosis, SVR12 rates were 93.3% after 12 weeks of treatment and 89.5% after 24 weeks of treatment. Among those with data, 92.2% had an on-treatment week 4 response, 98.4% had an EOT response, and 98.4% achieved SVR4. There was no significant difference between non-cirrhotic and cirrhotic patients in on-treatment response at week 4 (P = .291). Four patients experienced treatment failure; 2 patients withdrew early because of an adverse event, 1 patient experienced virologic failure (relapse), and 1 patient discontinued treatment voluntarily. Baseline factors significantly associated with failure to achieve SVR12 on multivariate analysis were platelets ≤70,000/mm3, bilirubin >2 mg/dL, and albumin <3.5 g/dL (both P < .05).Table 1Demographics and Virologic Response (Not Directly Comparable)OMV/PTV/r + RBV (n = 122)LDV/SOF ± RBV (n = 130)Demographics, n (%) Sex, male91 (74.6)109 (83.8) Age, y, mean (range)52.7 (35–77)53.4 (21–79) Cirrhosis43 (35.2)73 (56.2)CTP A38 (88.4)61 (83.6)CTP B or C5 (11.6)12 (16.4) MELD score, mean (SD)aOnly in patients with cirrhosis.9 (3.1)9 (2.9)>18, n (%)3 (6.9)3 (4.1) Treatment historyNaive44 (36.1)70 (53.8)Non-responders48 (39.3)44 (33.8)Relapsers27 (22.1)16 (12.3) Treatment duration (wk)8—1 (0.8)1291 (74.6)99 (76.2)2431 (25.4)30 (23.1)Virologic response, n/N (%) Week 4 on-treatment107bUndetectable viral load (n = 85); detectable but unquantifiable viral load (n = 22)./116 (92.2)96cUndetectable viral load (n = 67); detectable but unquantifiable viral load (n = 29)./122 (78.2) EOT120/122 (98.4)129/130 (99.2) SVR4120/122 (98.4)125/130 (96.2) SVR12Overall100/104 (96.2)124/130 (95.4)Non-cirrhotic69/70 (98.6)54/55 (98.2)Cirrhotic31/34 (91.2)68/73 (93.2)NOTE. None of the patients included were human immunodeficiency virus co-infected.CTP, Child-Turcotte-Pugh; MELD, Model for End-Stage Liver Disease.a Only in patients with cirrhosis.b Undetectable viral load (n = 85); detectable but unquantifiable viral load (n = 22).c Undetectable viral load (n = 67); detectable but unquantifiable viral load (n = 29). Open table in a new tab NOTE. None of the patients included were human immunodeficiency virus co-infected. CTP, Child-Turcotte-Pugh; MELD, Model for End-Stage Liver Disease. Four patients (3.3%) discontinued treatment early, 3 because of an adverse event and 1 at patient request. SAEs were reported for 7 patients (5.7%). There were no deaths during treatment or follow-up. Baseline albumin <3.5 g/dL and platelets ≤70,000/mm3 (both P < .05) were significantly associated with development of SAEs on multivariate analysis. Data from 130 patients treated with LDV/SOF were included in the analysis (Table 1). Overall, 95.4% of those with available data achieved SVR12 (modified intent-to-treat). SVR12 was numerically lower in patients with cirrhosis, but overall there was no statistical difference in SVR12 according to degree of fibrosis (P = .244). The majority of patients without cirrhosis (68.3%) received LDV/SOF without RBV for 12 weeks, which achieved SVR12 of 100%. In patients with cirrhosis, the majority (83.9%) were treated with either LDV/SOF + RBV for 12 weeks (53.2%; SVR12, 87.9%) or with LDV/SOF for 24 weeks (30.6%; SVR12, 100%); 11.3% of patients were treated with LDV/SOF for 12 weeks and 4.8% LDV/SOF + RBV for 24 weeks. There was no significant difference in SVR12 between treatment arms for patients with cirrhosis. Among those with data, 78.2% had an on-treatment response at week 4, 99.2% had an EOT response, and 96.2% achieved SVR4. There was no significant difference between non-cirrhotic and cirrhotic patients in on-treatment response at week 4 (P = .265). Six patients experienced treatment failure, 4 patients relapsed (3 between EOT and post-treatment week 4 and 1 between weeks 4 and 12 after treatment), 1 patient withdrew early because of an adverse event, and 1 patient discontinued treatment voluntarily. Only baseline bilirubin >2 mg/dL was significantly associated with failure to achieve SVR on multivariate analysis (P < .05). SAEs were reported for 6 patients (4.6%) and led to treatment discontinuation in 1 patient. No patient died during treatment or follow-up. No baseline characteristics were significantly associated with SAEs. There were significant differences in baseline characteristics between the 2 treatment cohorts. More patients in the LDV/SOF group had cirrhosis (P < .001), mean elastography scores were higher (20.3 vs 13.2; P < .001), mean bilirubin levels were higher (1.01 vs 0.78 mg/dL; P = .01), and mean albumin levels were lower (4.1 vs 4.3 g/dL; P = .004). The LDV/SOF group included a significantly higher proportion of treatment-naive patients compared with the OMV/PTVr group (P = .006). A total of 116 patients with cirrhosis were included in the analysis (OMV/PTVr, n = 43; LDV/SOF, n = 73). SVR12 was achieved by 99 of 107 patients (92.5%) with available data (OMV/PTVr, 91.2%; LDV/SOF, 93.2%). A response at week 4 of treatment was achieved by 81.3% of cirrhotic patients overall (OMV/PTVr, 90.5%; LDV/SOF, 75.4%). EOT response (OMV/PTVr, 95.3%; LDV/SOF, 98.6%) and SVR4 (OMV/PTVr, 95.3%; LDV/SOF, 94.5%) were similar. Among cirrhotic patients only baseline albumin was significantly associated with failure to achieve SVR on multivariate analysis (P < .05). Overall, 8 patients experienced treatment failure (virologic failure, n = 4; withdrawal due to an adverse event, n = 3; voluntary discontinuation, n = 1). Eight patients (6.9%) developed SAEs. All these patients were Child-Pugh A at baseline, four (50%) with esophageal varices. Seven of the 8 patients who developed SAEs were also treated with RBV. SAEs were related to hepatic disease in 6 patients; 2 patients developed hepatocellular carcinoma (LDV/SOF group), 2 experienced hepatic decompensation (hepatic encephalopathy [OMV/PTVr group]; ascites [LDV/SOF group]), 1 patient had an infection (sepsis as a result of spontaneous bacterial peritonitis [LDV/SOF group]), and 1 patient developed hyperbilirubinemia (OMV/PTVr group). The majority of SAEs (5 of 8) arose at week 4 or week 12 of treatment. Platelet levels ≤70,000/mm3 were the only baseline factor associated with development of SAEs in multivariate analysis (P < .05). Our study is the largest to date to investigate the real-world effectiveness and safety of DAA therapy in HCV GT 4 patients. In our cohort of patients who were managed in routine clinical practice, both OMV/PTVr and LDV/SOF resulted in rapid virologic responses and high rates of SVR12 (overall, >95%). Virologic response at week 4 had no impact on SVR12. Rates of SVR12 in non-cirrhotic patients in our cohort were 99% with OMV/PTVr and 98% with LDV/SOF. These results compare favorably with the limited data available from controlled clinical trials evaluating these regimens, which have demonstrated SVR12 rates of 100% with OMV/PTVr in treatment-experienced and treatment-naive non-cirrhotic patients2Hézode C. Asselah T. Reddy K.R. et al.Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial.Lancet. 2015; 385: 2502-2509Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar and 100% with LDV/SOF in a small study in non-cirrhotic and cirrhotic patients.3Kohli A. Kapoor R. Sims Z. et al.Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label phase 2a cohort studyLancet Infect Dis. 2015; 15: 1049-1054Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar In our cohort, SVR12 data were available for 107 of a total of 116 cirrhotic patients, with overall SVR12 rate of 92.5% (91.2% with OMV/PTVr and 93.2% with LDV/SOF). At the time of writing, there are few published data for DAAs in GT 4 patients with cirrhosis. The ongoing AGATE studies are investigating OMV/PTVr in GT 4 patients including those with compensated cirrhosis. Preliminary data have shown SVR12 rates of 97% in cirrhotic patients treated with this regimen for 12 weeks (n = 31). Our study provides insight into clinician prescribing practice for GT 4 patients. Regimens prescribed varied, particularly for patients with cirrhosis. Although the majority of cirrhotic patients treated with OMV/PTVr + RBV received the recommended treatment of 24 weeks, 44% received treatment for only 12 weeks; however, there was no significant difference between SVR12 rates for 12 and 24 weeks. At the time patients included in the study were treated, the recommended treatment with LDV/SOF for GT 4 patients with cirrhosis was 24 weeks without RBV. Although around one-third of patients received this regimen, more than half were treated with LDV/SOF + RBV for 12 weeks; this is now also a recommended regimen. The LDV/SOF cohort included significantly more patients with more advanced liver disease. It is possible that because LDV/SOF is indicated for the treatment of decompensated cirrhosis whereas OMV/PTVr is not, it is perceived as a more appropriate choice for patients with more advanced disease. The fact that LDV/SOF can be used in an RBV-free regimen may also contribute. Safety and tolerability of both regimens were good in our real-world cohort. Overall, reported rates of SAEs in the current study (5.7% with OMV/PTVr ± RBV and 4.6% with LDV/SOF) were only slightly higher or similar to those reported in the pivotal clinical trials in HCV GT 1 patients (up to 5.5% for OMV/PTVr + dasabuvir and up to 3.8% for LDV/SOF).4Afdhal N. Reddy K.R. Nelson D.R. et al.Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection.N Engl J Med. 2014; 370: 1483-1493Crossref PubMed Scopus (1163) Google Scholar, 5Afdhal N. Zeuzem S. Kwo P. et al.Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection.N Engl J Med. 2014; 370: 1889-1898Crossref PubMed Scopus (1431) Google Scholar, 6Feld J.J. Kowdley K.V. Coakley E. et al.Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin.N Engl J Med. 2014; 370: 1594-1603Crossref PubMed Scopus (738) Google Scholar, 7Poordad F. Hezode C. Trinh R. et al.ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis.N Engl J Med. 2014; 370: 1973-1982Crossref PubMed Scopus (753) Google Scholar SAEs were reported in 6.9% of cirrhotic patients in our cohort and were largely experienced by patients receiving RBV. There have been post-marketing reports of decompensation in cirrhotic patients, generally with advanced disease, during early treatment with OMV/PTVr. Although causality has not been shown, treatment of Child-Pugh B patients with OMV/PTVr is no longer recommended in Europe and contraindicated in the United States, and additional monitoring is recommended for cirrhotic patients. In our cohort, decompensation occurred in 2 cirrhotic patients (1.7%) (one in each subcohort), both during post-treatment follow-up and both of whom were Child-Pugh A at baseline. Overall, the favorable safety findings in the current study are important because of the small number of studies in GT 4 patients, particularly those with cirrhosis. Because safety is generally expected to be poorer in real-world cohorts, which is related to factors such as a higher incidence of previously treated and severely affected patients and the presence of comorbidities and polypharmacy, these observations are encouraging. This study has the usual limitations related to its non-interventional/observational, real-world design, including the potential for bias because of prescribing and patient selection by physicians. Nevertheless, because of the current paucity of data with DAAs in HCV GT 4 patients, the relatively large number of patients included in the current study gives an important insight into the effectiveness and safety of 2 increasingly used oral combination antiviral therapies. The future is encouraging, with new DAA combinations becoming available. Recently the single tablet fixed-dose regimen of SOF/velpatasvir was approved for all genotypes on the basis of the results of the ASTRAL-1 trial in which SOF/velpatasvir demonstrated rates of SVR of 100% in 116 GT 4 patients.8Feld J.J. Jacobson I.M. Hezode C. et al.Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection.N Engl J Med. 2015; 373: 2599-2607Crossref PubMed Scopus (807) Google Scholar In summary, OMV/PTVr-based and LDV/SOF-based regimens yielded high rates of SVR12, comparable with the limited results from clinical trials, in both cirrhotic and non-cirrhotic HCV GT 4 patients managed in a real-world setting. The safety profiles of both regimens were good and comparable with those reported for other HCV genotypes. Silvia Montoliu (Department of Gastroenterology, Hospital Universitario Tarragona, Tarragona); Miguel Angel Serra (Department of Gastroenterology, Hospital Clinico de Valencia, Valencia); Raul Andrade (Department of Gastroenterology, Hospital Universitario Virgen de la Victoria, Malaga); Conrado Fernandez (Department of Gastroenterology, Hospital Universitario Fundación Alcorcón, Madrid); Miguel Fernández Bermejo (Department of Gastroenterology, Hospital San Pedro de Alcantara, Caceres); Miguel Angel Simon (Department of Gastroenterology, Hospital Clinico Universitario Lozano Blesa, Zaragoza); Lucia Bonet (Department of Gastroenterology, Hospital Universitario Son Espases, Palma de Mallorca); Juan de la Vega (Department of Gastroenterology, Hospital San Agustin, Aviles); Moises Diago (Department of Gastroenterology, Hospital Universitario General de Valencia, Valencia); José Ramón Fernández (Department of Gastroenterology, Hospital Universitario de Cruces, Bilbao); Gloria Sanchez Antolin (Department of Gastroenterology, Hospital Universitario Rio Hortega, Valladolid).