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
Summary Background Hepatitis C virus (HCV) genotype 4 accounts for about 13% of global HCV infections. Because interferon-containing treatments for genotype 4 infection have low efficacy and poor tolerability, an unmet need exists for effective all-oral regimens. We examined the efficacy and safety...
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| Veröffentlicht in: | The Lancet (British edition) 2015-06, Vol.385 (9986), p.2502-2509 |
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| creator | Hézode, Christophe, Dr Prof Asselah, Tarik, Prof Reddy, K Rajender, Prof Hassanein, Tarek, Prof Berenguer, Marina, MD Fleischer-Stepniewska, Katarzyna, MD Marcellin, Patrick, Prof Hall, Coleen, MS Schnell, Gretja, PhD Pilot-Matias, Tami, PhD Mobashery, Niloufar, MD Redman, Rebecca, MD Vilchez, Regis A, MD Pol, Stanislas, Prof |
| description | Summary Background Hepatitis C virus (HCV) genotype 4 accounts for about 13% of global HCV infections. Because interferon-containing treatments for genotype 4 infection have low efficacy and poor tolerability, an unmet need exists for effective all-oral regimens. We examined the efficacy and safety of an all-oral interferon-free regimen of ombitasvir, an NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (ombitasvir plus paritaprevir plus ritonavir), given with or without ribavirin. Methods In this multicentre ongoing phase 2b, randomised, open-label combination trial (PEARL-I), patients were recruited from academic, public, and private hospitals and clinics in France, Hungary, Italy, Poland, Romania, Spain, Turkey, and the USA. Eligible participants were aged 18–70 years with non-cirrhotic, chronic HCV genotype 4 infection (documented ≥6 months before screening) and plasma HCV RNA levels higher than 10 000 IU/mL. Previously untreated (treatment-naive) patients were randomly assigned (1:1) by computer-generated randomisation lists to receive once-daily ombitasvir (25 mg) plus paritaprevir (150 mg) plus ritonavir (100 mg) with or without weight-based ribavirin for 12 weeks. Previously treated (treatment-experienced) patients who had received pegylated interferon plus ribavirin all received the ribavirin-containing regimen. The primary endpoint was a sustained virological response (HCV RNA |
| doi_str_mv | 10.1016/S0140-6736(15)60159-3 |
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Because interferon-containing treatments for genotype 4 infection have low efficacy and poor tolerability, an unmet need exists for effective all-oral regimens. We examined the efficacy and safety of an all-oral interferon-free regimen of ombitasvir, an NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (ombitasvir plus paritaprevir plus ritonavir), given with or without ribavirin. Methods In this multicentre ongoing phase 2b, randomised, open-label combination trial (PEARL-I), patients were recruited from academic, public, and private hospitals and clinics in France, Hungary, Italy, Poland, Romania, Spain, Turkey, and the USA. Eligible participants were aged 18–70 years with non-cirrhotic, chronic HCV genotype 4 infection (documented ≥6 months before screening) and plasma HCV RNA levels higher than 10 000 IU/mL. Previously untreated (treatment-naive) patients were randomly assigned (1:1) by computer-generated randomisation lists to receive once-daily ombitasvir (25 mg) plus paritaprevir (150 mg) plus ritonavir (100 mg) with or without weight-based ribavirin for 12 weeks. Previously treated (treatment-experienced) patients who had received pegylated interferon plus ribavirin all received the ribavirin-containing regimen. The primary endpoint was a sustained virological response (HCV RNA <25 IU/mL) 12 weeks after the end of treatment (SVR12 ). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT01685203. Findings Between Aug 14, 2012, and Nov 19, 2013, 467 patients with HCV infection were screened, of whom 174 were infected with genotype 4. 135 patients were randomly assigned to treatment and received at least one dose of study medication; 86 patients were treatment-naive, of whom 44 received ombitasvir plus paritaprevir plus ritonavir and 42 received ombitasvir plus paritaprevir plus ritonavir with ribavirin, and 49 treatment-experienced patients received the ribavirin-containing regimen. In previously untreated patients, SVR12 rates were 100% (42/42 [95% CI 91·6–100]) in the ribavirin-containing regimen and 90·9% (40/44 [95% CI 78·3–97·5]) in the ribavirin-free regimen. No statistically significant differences in SVR12 rates were noted between the treatment-naive groups (mean difference −9·16% [95% CI −19·61 to 1·29]; p=0·086). All treatment-experienced patients achieved SVR12 (49/49; 100% [95% CI 92·7–100]). In the ribavirin-free group, two (5%) of 42 treatment-naive patients had virological relapse, and one (2%) of 44 had virological breakthrough; no virological failures were recorded in the ribavirin-containing regimen. The most common adverse event was headache (14 [29%] of 49 treatment-experienced patients and 14 [33%] of 42 treatment-naive patients). No adverse event-related discontinuations or dose interruptions of study medications, including ribavirin, were noted, and only four patients (4%) of 91 receiving ribavirin required dose modification for haemoglobin less than 100 g/L or anaemia. Interpretation An interferon-free regimen of ombitasvir plus paritaprevir plus ritonavir with or without ribavirin achieved high sustained virological response rates at 12 weeks after the end of treatment and was generally well tolerated, with low rates of anaemia and treatment discontinuation in non-cirrhotic previously untreated and previously treated patients with HCV genotype 4 infection. Funding AbbVie.</description><identifier>ISSN: 0140-6736</identifier><identifier>EISSN: 1474-547X</identifier><identifier>DOI: 10.1016/S0140-6736(15)60159-3</identifier><identifier>PMID: 25837829</identifier><identifier>CODEN: LANCAO</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject><![CDATA[Adolescent ; Adult ; Aged ; Alanine Transaminase - drug effects ; Anilides - administration & dosage ; Antiviral Agents - therapeutic use ; Aspartate Aminotransferases - drug effects ; Carbamates - administration & dosage ; Drug therapy ; Drug Therapy, Combination ; Female ; Genotype ; Genotype & phenotype ; Hepacivirus - genetics ; Hepatitis ; Hepatitis C virus ; Hepatitis C, Chronic - drug therapy ; Hepatitis C, Chronic - enzymology ; Hepatitis C, Chronic - virology ; Humans ; Infections ; Internal Medicine ; Liver cirrhosis ; Macrocyclic Compounds - administration & dosage ; Male ; Middle Aged ; Proteinase inhibitors ; Ribavirin - administration & dosage ; Ritonavir ; Ritonavir - administration & dosage ; Treatment Outcome ; Young Adult]]></subject><ispartof>The Lancet (British edition), 2015-06, Vol.385 (9986), p.2502-2509</ispartof><rights>Elsevier Ltd</rights><rights>2015 Elsevier Ltd</rights><rights>Copyright © 2015 Elsevier Ltd. All rights reserved.</rights><rights>Copyright Elsevier Limited Jun 20, 2015</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c551t-fa8c7903ca94388e2cc34877b66f71b13f94610ad556c4295e1c5259b25a62343</citedby><cites>FETCH-LOGICAL-c551t-fa8c7903ca94388e2cc34877b66f71b13f94610ad556c4295e1c5259b25a62343</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0140673615601593$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25837829$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hézode, Christophe, Dr Prof</creatorcontrib><creatorcontrib>Asselah, Tarik, Prof</creatorcontrib><creatorcontrib>Reddy, K Rajender, Prof</creatorcontrib><creatorcontrib>Hassanein, Tarek, Prof</creatorcontrib><creatorcontrib>Berenguer, Marina, MD</creatorcontrib><creatorcontrib>Fleischer-Stepniewska, Katarzyna, MD</creatorcontrib><creatorcontrib>Marcellin, Patrick, Prof</creatorcontrib><creatorcontrib>Hall, Coleen, MS</creatorcontrib><creatorcontrib>Schnell, Gretja, PhD</creatorcontrib><creatorcontrib>Pilot-Matias, Tami, PhD</creatorcontrib><creatorcontrib>Mobashery, Niloufar, MD</creatorcontrib><creatorcontrib>Redman, Rebecca, MD</creatorcontrib><creatorcontrib>Vilchez, Regis A, MD</creatorcontrib><creatorcontrib>Pol, Stanislas, Prof</creatorcontrib><title>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</title><title>The Lancet (British edition)</title><addtitle>Lancet</addtitle><description>Summary Background Hepatitis C virus (HCV) genotype 4 accounts for about 13% of global HCV infections. Because interferon-containing treatments for genotype 4 infection have low efficacy and poor tolerability, an unmet need exists for effective all-oral regimens. We examined the efficacy and safety of an all-oral interferon-free regimen of ombitasvir, an NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (ombitasvir plus paritaprevir plus ritonavir), given with or without ribavirin. Methods In this multicentre ongoing phase 2b, randomised, open-label combination trial (PEARL-I), patients were recruited from academic, public, and private hospitals and clinics in France, Hungary, Italy, Poland, Romania, Spain, Turkey, and the USA. Eligible participants were aged 18–70 years with non-cirrhotic, chronic HCV genotype 4 infection (documented ≥6 months before screening) and plasma HCV RNA levels higher than 10 000 IU/mL. Previously untreated (treatment-naive) patients were randomly assigned (1:1) by computer-generated randomisation lists to receive once-daily ombitasvir (25 mg) plus paritaprevir (150 mg) plus ritonavir (100 mg) with or without weight-based ribavirin for 12 weeks. Previously treated (treatment-experienced) patients who had received pegylated interferon plus ribavirin all received the ribavirin-containing regimen. The primary endpoint was a sustained virological response (HCV RNA <25 IU/mL) 12 weeks after the end of treatment (SVR12 ). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT01685203. Findings Between Aug 14, 2012, and Nov 19, 2013, 467 patients with HCV infection were screened, of whom 174 were infected with genotype 4. 135 patients were randomly assigned to treatment and received at least one dose of study medication; 86 patients were treatment-naive, of whom 44 received ombitasvir plus paritaprevir plus ritonavir and 42 received ombitasvir plus paritaprevir plus ritonavir with ribavirin, and 49 treatment-experienced patients received the ribavirin-containing regimen. In previously untreated patients, SVR12 rates were 100% (42/42 [95% CI 91·6–100]) in the ribavirin-containing regimen and 90·9% (40/44 [95% CI 78·3–97·5]) in the ribavirin-free regimen. No statistically significant differences in SVR12 rates were noted between the treatment-naive groups (mean difference −9·16% [95% CI −19·61 to 1·29]; p=0·086). All treatment-experienced patients achieved SVR12 (49/49; 100% [95% CI 92·7–100]). In the ribavirin-free group, two (5%) of 42 treatment-naive patients had virological relapse, and one (2%) of 44 had virological breakthrough; no virological failures were recorded in the ribavirin-containing regimen. The most common adverse event was headache (14 [29%] of 49 treatment-experienced patients and 14 [33%] of 42 treatment-naive patients). No adverse event-related discontinuations or dose interruptions of study medications, including ribavirin, were noted, and only four patients (4%) of 91 receiving ribavirin required dose modification for haemoglobin less than 100 g/L or anaemia. Interpretation An interferon-free regimen of ombitasvir plus paritaprevir plus ritonavir with or without ribavirin achieved high sustained virological response rates at 12 weeks after the end of treatment and was generally well tolerated, with low rates of anaemia and treatment discontinuation in non-cirrhotic previously untreated and previously treated patients with HCV genotype 4 infection. Funding AbbVie.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Alanine Transaminase - drug effects</subject><subject>Anilides - administration & dosage</subject><subject>Antiviral Agents - therapeutic use</subject><subject>Aspartate Aminotransferases - drug effects</subject><subject>Carbamates - administration & dosage</subject><subject>Drug therapy</subject><subject>Drug Therapy, Combination</subject><subject>Female</subject><subject>Genotype</subject><subject>Genotype & phenotype</subject><subject>Hepacivirus - genetics</subject><subject>Hepatitis</subject><subject>Hepatitis C virus</subject><subject>Hepatitis C, Chronic - drug therapy</subject><subject>Hepatitis C, Chronic - enzymology</subject><subject>Hepatitis C, Chronic - virology</subject><subject>Humans</subject><subject>Infections</subject><subject>Internal Medicine</subject><subject>Liver cirrhosis</subject><subject>Macrocyclic Compounds - administration & 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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</title><author>Hézode, Christophe, Dr Prof ; Asselah, Tarik, Prof ; Reddy, K Rajender, Prof ; Hassanein, Tarek, Prof ; Berenguer, Marina, MD ; Fleischer-Stepniewska, Katarzyna, MD ; Marcellin, Patrick, Prof ; Hall, Coleen, MS ; Schnell, Gretja, PhD ; Pilot-Matias, Tami, PhD ; Mobashery, Niloufar, MD ; Redman, Rebecca, MD ; Vilchez, Regis A, MD ; Pol, Stanislas, Prof</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c551t-fa8c7903ca94388e2cc34877b66f71b13f94610ad556c4295e1c5259b25a62343</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Alanine Transaminase - drug effects</topic><topic>Anilides - administration 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Central Basic</collection><collection>SIRS Editorial</collection><jtitle>The Lancet (British edition)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hézode, Christophe, Dr Prof</au><au>Asselah, Tarik, Prof</au><au>Reddy, K Rajender, Prof</au><au>Hassanein, Tarek, Prof</au><au>Berenguer, Marina, MD</au><au>Fleischer-Stepniewska, Katarzyna, MD</au><au>Marcellin, Patrick, Prof</au><au>Hall, Coleen, MS</au><au>Schnell, Gretja, PhD</au><au>Pilot-Matias, Tami, PhD</au><au>Mobashery, Niloufar, MD</au><au>Redman, Rebecca, MD</au><au>Vilchez, Regis A, MD</au><au>Pol, Stanislas, Prof</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>The Lancet (British edition)</jtitle><addtitle>Lancet</addtitle><date>2015-06-20</date><risdate>2015</risdate><volume>385</volume><issue>9986</issue><spage>2502</spage><epage>2509</epage><pages>2502-2509</pages><issn>0140-6736</issn><eissn>1474-547X</eissn><coden>LANCAO</coden><abstract>Summary Background Hepatitis C virus (HCV) genotype 4 accounts for about 13% of global HCV infections. Because interferon-containing treatments for genotype 4 infection have low efficacy and poor tolerability, an unmet need exists for effective all-oral regimens. We examined the efficacy and safety of an all-oral interferon-free regimen of ombitasvir, an NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (ombitasvir plus paritaprevir plus ritonavir), given with or without ribavirin. Methods In this multicentre ongoing phase 2b, randomised, open-label combination trial (PEARL-I), patients were recruited from academic, public, and private hospitals and clinics in France, Hungary, Italy, Poland, Romania, Spain, Turkey, and the USA. Eligible participants were aged 18–70 years with non-cirrhotic, chronic HCV genotype 4 infection (documented ≥6 months before screening) and plasma HCV RNA levels higher than 10 000 IU/mL. Previously untreated (treatment-naive) patients were randomly assigned (1:1) by computer-generated randomisation lists to receive once-daily ombitasvir (25 mg) plus paritaprevir (150 mg) plus ritonavir (100 mg) with or without weight-based ribavirin for 12 weeks. Previously treated (treatment-experienced) patients who had received pegylated interferon plus ribavirin all received the ribavirin-containing regimen. The primary endpoint was a sustained virological response (HCV RNA <25 IU/mL) 12 weeks after the end of treatment (SVR12 ). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT01685203. Findings Between Aug 14, 2012, and Nov 19, 2013, 467 patients with HCV infection were screened, of whom 174 were infected with genotype 4. 135 patients were randomly assigned to treatment and received at least one dose of study medication; 86 patients were treatment-naive, of whom 44 received ombitasvir plus paritaprevir plus ritonavir and 42 received ombitasvir plus paritaprevir plus ritonavir with ribavirin, and 49 treatment-experienced patients received the ribavirin-containing regimen. In previously untreated patients, SVR12 rates were 100% (42/42 [95% CI 91·6–100]) in the ribavirin-containing regimen and 90·9% (40/44 [95% CI 78·3–97·5]) in the ribavirin-free regimen. No statistically significant differences in SVR12 rates were noted between the treatment-naive groups (mean difference −9·16% [95% CI −19·61 to 1·29]; p=0·086). All treatment-experienced patients achieved SVR12 (49/49; 100% [95% CI 92·7–100]). In the ribavirin-free group, two (5%) of 42 treatment-naive patients had virological relapse, and one (2%) of 44 had virological breakthrough; no virological failures were recorded in the ribavirin-containing regimen. The most common adverse event was headache (14 [29%] of 49 treatment-experienced patients and 14 [33%] of 42 treatment-naive patients). No adverse event-related discontinuations or dose interruptions of study medications, including ribavirin, were noted, and only four patients (4%) of 91 receiving ribavirin required dose modification for haemoglobin less than 100 g/L or anaemia. Interpretation An interferon-free regimen of ombitasvir plus paritaprevir plus ritonavir with or without ribavirin achieved high sustained virological response rates at 12 weeks after the end of treatment and was generally well tolerated, with low rates of anaemia and treatment discontinuation in non-cirrhotic previously untreated and previously treated patients with HCV genotype 4 infection. Funding AbbVie.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>25837829</pmid><doi>10.1016/S0140-6736(15)60159-3</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0140-6736 |
| ispartof | The Lancet (British edition), 2015-06, Vol.385 (9986), p.2502-2509 |
| issn | 0140-6736 1474-547X |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1701485446 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Adolescent Adult Aged Alanine Transaminase - drug effects Anilides - administration & dosage Antiviral Agents - therapeutic use Aspartate Aminotransferases - drug effects Carbamates - administration & dosage Drug therapy Drug Therapy, Combination Female Genotype Genotype & phenotype Hepacivirus - genetics Hepatitis Hepatitis C virus Hepatitis C, Chronic - drug therapy Hepatitis C, Chronic - enzymology Hepatitis C, Chronic - virology Humans Infections Internal Medicine Liver cirrhosis Macrocyclic Compounds - administration & dosage Male Middle Aged Proteinase inhibitors Ribavirin - administration & dosage Ritonavir Ritonavir - administration & dosage Treatment Outcome Young Adult |
| title | 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 |
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