Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 30
Filter
1.
Dig Dis Sci ; 69(5): 1551-1561, 2024 May.
Article in English | MEDLINE | ID: mdl-38580885

ABSTRACT

Patients with chronic hepatitis C virus (HCV) infection and decompensated cirrhosis are an important population for antiviral therapy yet under-represented in clinical trials. HCV direct-acting antiviral (DAA) therapies, unlike interferon-containing regimens, can be safely utilized in decompensated patients. Per guidelines from the American Association for the Study of Liver Diseases (AASLD), therapy of choice in HCV and decompensated cirrhosis is sofosbuvir, an HCV polymerase inhibitor, combined with a replication complex inhibitor (NS5A inhibitor) with or without ribavirin. Combination therapy with a HCV protease inhibitor and an NS5A inhibitor is effective in this population but is specifically not recommended in AASLD guidelines due to safety concerns. Important risk factors for further decompensation during DAA therapy are serum albumin < 3.5 g/dL, MELD (Model for End-Stage Liver Disease) score > 14, or HCV genotype 3 infection. Although sustained virologic response (SVR) is achieved less often in patients with decompensated vs compensated cirrhosis, in clinical studies response rates are > 80%. Both Child-Turcotte-Pugh Class at baseline and viral genotype can affect these response rates. Achieving SVR lowers risk of mortality, but to a lesser extent than in individuals with compensated cirrhosis. Likewise, treating patients for HCV infection along with successful treatment for hepatocellular carcinoma improves risks of both liver-related and overall mortality. In fewer than one third of cases, treating transplant-eligible, HCV-infected patients pre-transplant enables their delisting from transplant wait lists.


Subject(s)
Antiviral Agents , Hepatitis C, Chronic , Liver Cirrhosis , Humans , Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/complications , Liver Cirrhosis/virology , Liver Cirrhosis/drug therapy , Drug Therapy, Combination , Hepacivirus/genetics , Hepacivirus/drug effects , Sustained Virologic Response , Sofosbuvir/therapeutic use
2.
JAMA ; 327(24): 2448-2449, 2022 06 28.
Article in English | MEDLINE | ID: mdl-35696255
4.
Gastroenterology ; 157(6): 1506-1517.e1, 2019 12.
Article in English | MEDLINE | ID: mdl-31401140

ABSTRACT

BACKGROUND & AIMS: Treatment options are limited for patients with hepatitis C (HCV) infection with treatment failure after sofosbuvir plus an NS5A inhibitor. There are some data for the efficacy of glecaprevir/pibrentasvir (G/P) in these patients. We performed a randomized trial of the safety and efficacy of 12 and 16 weeks of G/P, with or without ribavirin, in patients with HCV genotype 1 infection with treatment failure after sofosbuvir and an NS5A inhibitor. METHODS: We performed a phase 3b, open-label study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor. Patients without cirrhosis were randomly assigned to groups that received G/P for 12 weeks (n = 78, group A) or 16 weeks (n = 49, group B). Patients with compensated cirrhosis were randomly assigned to groups that received G/P and ribavirin for 12 weeks (n = 21, group C) or G/P for 16 weeks (n = 29, group D). The primary end point was a sustained virologic response 12 weeks after treatment. Samples collected at baseline and at time of treatment failure were sequenced for resistance-associated substitutions in NS3 and NS5A. RESULTS: Of the 177 patients in the 4 groups, 81% were men, 79% had HCV genotype 1a infection, and 44% were black. Proportions of patients with sustained virologic response 12 weeks after treatment in groups A, B, C, and D were 90%, 94%, 86%, and 97%, respectively. The treatment failed in 13 (7.3%) patients with HCV genotype 1a infection, 6 (7.9%) in group A, 3 (6.1%) in group B, 3 (6.1%) in group C (6.1%), and 1 (3.4%) in group D. Most patients had baseline resistance-associated substitutions in NS5A. Treatment-emergent resistance-associated substitutions in NS3 and NS5A were observed in 9 and 10 patients with treatment failure, respectively. G/P was well tolerated. Ribavirin increased adverse events but did not increase efficacy. CONCLUSIONS: In a randomized study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor, 16 weeks treatment with G/P produced sustained virologic response 12 weeks after treatment in >90% of patients, including those with compensated cirrhosis. ClinicalTrials.gov, Number: NCT03092375.


Subject(s)
Antiviral Agents/therapeutic use , Hepacivirus/genetics , Hepatitis C, Chronic/drug therapy , Adult , Aged , Aged, 80 and over , Antiviral Agents/pharmacology , Benzimidazoles/pharmacology , Benzimidazoles/therapeutic use , Drug Combinations , Drug Resistance, Multiple, Viral/genetics , Drug Therapy, Combination , Female , Genotype , Hepacivirus/isolation & purification , Hepatitis C, Chronic/virology , Humans , Male , Middle Aged , Pyrrolidines/pharmacology , Pyrrolidines/therapeutic use , Quinoxalines/pharmacology , Quinoxalines/therapeutic use , Ribavirin/pharmacology , Ribavirin/therapeutic use , Sofosbuvir/pharmacology , Sofosbuvir/therapeutic use , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Sustained Virologic Response , Treatment Failure , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/genetics
5.
Aliment Pharmacol Ther ; 48(9): 914-923, 2018 11.
Article in English | MEDLINE | ID: mdl-30288771

ABSTRACT

BACKGROUND: In 2017, the hepatitis C treatment regimens sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) and glecaprevir/pibrentasvir (G/P) received approval from the U.S. Food and Drug Administration. Although both SOF/VEL/VOX (NS5B polymerase inhibitor/NS5A inhibitor/NS3/4A protease inhibitor) and G/P (NS3/4A protease inhibitor/NS5A inhibitor) are pangenotypic regimens, they are indicated for distinct subsets of patients with hepatitis C. AIM: To compare and contrast available safety and efficacy data for SOF/VEL/VOX and G/P and outline their clinical utility. METHODS: For each of the regimens, this review outlines the indications, safety information, and the major clinical studies in which SOF/VEL/VOX and G/P were evaluated. RESULTS: SOF/VEL/VOX is positioned as a salvage regimen for patients previously treated with NS5A inhibitors and for genotype 1a- and 3-infected patients who had failed other sofosbuvir-containing regimens. G/P is the first pangenotypic regimen with an 8-week duration for treatment-naïve, non-cirrhotic patients, and it is indicated for patients with any genotype who have advanced kidney disease, including those on dialysis. CONCLUSION: The addition of SOF/VEL/VOX and G/P to existing hepatitis C treatment options will expand the number of patients who are eligible for and responsive to treatment, thus increasing the possibility of eliminating hepatitis C as a public health issue.


Subject(s)
Antiviral Agents/therapeutic use , Benzimidazoles/therapeutic use , Carbamates/therapeutic use , Hepatitis C, Chronic/drug therapy , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Macrocyclic Compounds/therapeutic use , Quinoxalines/therapeutic use , Sofosbuvir/therapeutic use , Sulfonamides/therapeutic use , Aminoisobutyric Acids , Clinical Trials, Phase III as Topic/methods , Cyclopropanes , Hepatitis C, Chronic/diagnosis , Hepatitis C, Chronic/epidemiology , Humans , Lactams, Macrocyclic , Leucine/analogs & derivatives , Proline/analogs & derivatives , Pyrrolidines
8.
Cell Mol Gastroenterol Hepatol ; 2(5): 676-684, 2016 Sep.
Article in English | MEDLINE | ID: mdl-28174739

ABSTRACT

BACKGROUND & AIMS: The host genetic environment contributes significantly to the outcomes of hepatitis C virus (HCV) infection and therapy response, but little is known about any effects of HCV infection on the host beyond any changes related to adaptive immune responses. HCV persistence is associated strongly with mitochondrial dysfunction, with liver mitochondrial DNA (mtDNA) genetic diversity linked to disease progression. METHODS: We evaluated the genetic diversity of 2 mtDNA genomic regions (hypervariable segments 1 and 2) obtained from sera of 116 persons using next-generation sequencing. RESULTS: Results were as follows: (1) the average diversity among cases with seronegative acute HCV infection was 4.2 times higher than among uninfected controls; (2) the diversity level among cases with chronic HCV infection was 96.1 times higher than among uninfected controls; and (3) the diversity was 23.1 times higher among chronic than acute cases. In 2 patients who were followed up during combined interferon and ribavirin therapy, mtDNA nucleotide diversity decreased dramatically after the completion of therapy in both patients: by 100% in patient A after 54 days and by 70.51% in patient B after 76 days. CONCLUSIONS: HCV infection strongly affects mtDNA genetic diversity. A rapid decrease in mtDNA genetic diversity observed after therapy-induced HCV clearance suggests that the effect is reversible, emphasizing dynamic genetic relationships between HCV and mitochondria. The level of mtDNA nucleotide diversity can be used to discriminate recent from past infections, which should facilitate the detection of recent transmission events and thus help identify modes of transmission.

9.
Gastroenterology ; 148(4): 762-70.e2; quiz e11-2, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25557952

ABSTRACT

BACKGROUND & AIMS: The efficacy and safety of interferon-free regimens for the treatment of chronic hepatitis C virus (HCV) infections require further evaluation and comparison with those of interferon-containing regimens. We compared a regimen of peginterferon, ribavirin, and sofosbuvir with a regimen of simeprevir and sofosbuvir in patients with HCV infection and unfavorable treatment features. METHODS: We performed a prospective open-label study of 82 patients with chronic HCV genotype 1a infection and Child's grade A cirrhosis enrolled from 2 clinics at a single center in Atlanta, Georgia, from December 2013 through January 2014. Fifty patients (61%) had not responded to treatment with peginterferon and ribavirin (null responders), and 32 (39%) were therapy naive; 39 (48%) were African American. Subjects were assigned randomly to groups given simeprevir (150 mg/day) and sofosbuvir (400 mg/day) (n = 58 in the final analysis) or peginterferon alfa 2b (1.5 mcg/kg/wk), ribavirin (1000-1200 mg/day), and sofosbuvir (400 mg/day) (n = 24 in the final analysis). Both regimens were given for 12 weeks. The primary trial end point was the proportion of patients with undetectable HCV-RNA levels 12 weeks after therapy completion (SVR12). RESULTS: A significantly greater percentage of patients (93%) given simeprevir and sofosbuvir achieved an SVR12 than those given the interferon-containing regimen (75%) (P = .02). Patients given the interferon-containing regimen had a significantly higher rate of virologic relapse than patients given simeprevir and sofosbuvir (P = .009), as well as worse self-reported outcomes and more side effects. Quality-of-life scores were higher in patients with SVR12 than those without, regardless of treatment regimen. CONCLUSIONS: In a prospective study of patients with chronic HCV genotype 1a infection and cirrhosis (48% African American and 61% prior null responders), a 12-week regimen of simeprevir and sofosbuvir produced a significantly higher rate of SVR12 and was better tolerated, with a lower viral relapse rate, than a 12-week regimen of peginterferon, ribavirin, and sofosbuvir. Clinicaltrials.gov no: NCT021683615.


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Heterocyclic Compounds, 3-Ring/therapeutic use , Interferon-alpha/therapeutic use , Liver Cirrhosis/etiology , Polyethylene Glycols/therapeutic use , RNA, Viral/blood , Ribavirin/therapeutic use , Sulfonamides/therapeutic use , Uridine Monophosphate/analogs & derivatives , Adult , Drug Therapy, Combination , Female , Genotype , Hepacivirus/genetics , Hepatitis C, Chronic/complications , Humans , Interferon alpha-2 , Liver Cirrhosis/classification , Male , Middle Aged , Recombinant Proteins/therapeutic use , Simeprevir , Sofosbuvir , Treatment Outcome , Uridine Monophosphate/therapeutic use , Viral Load
10.
Postgrad Med ; 126(7): 35-44, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25387212

ABSTRACT

The new American College of Cardiology/American Heart Association blood cholesterol guidelines of 2013 are the first major revision of cholesterol therapy guidance in over a decade. Commonly used low-density lipoprotein cholesterol (LDL-C) target goals have been abrogated in favor of intensity of statin therapy, more in line with data from randomized clinical trials. Four groups of adult patients have been identified from these studies who will most benefit from statins: patients with atherosclerotic cardiovascular disease (ASCVD); patients with primary elevations of LDL-C ≥ 190 mg/dL; diabetic patients between age 40 and 75 years without ASCVD whose LDL-C is between 70 and 189 mg/dL; and patients between age 40 and 75 years without ASCVD or diabetes with LDL-C between 70 and 189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher. This last primary prevention group has engendered the most controversy because the newly recommended risk calculator may overestimate risk or the 7.5% threshold may be too low, thereby subjecting too many patients to statins unnecessarily. This review summarizes the latest guidelines and pertinent evidence, and provides case examples to help clinicians familiarize themselves with the new recommendations.


Subject(s)
Cholesterol/blood , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Hyperlipidemias/drug therapy , Adult , Comorbidity , Diabetes Mellitus/blood , Diabetes Mellitus/epidemiology , Humans , Hypercholesterolemia/drug therapy , Hypercholesterolemia/epidemiology , Hyperlipidemias/etiology , Hypertriglyceridemia/drug therapy , Life Style , Primary Prevention , Risk Assessment
12.
Hepatology ; 59(1): 71-7, 2014 Jan.
Article in English | MEDLINE | ID: mdl-23873583

ABSTRACT

UNLABELLED: The new standard of care for treatment-naïve patients with hepatitis C virus (HCV) genotype 1 includes triple therapy with peginterferon, ribavirin, and a protease inhibitor. However, patients who achieve a rapid virologic response after 4 weeks of peginterferon and ribavirin therapy are likely to achieve a sustained virologic response (SVR), and we hypothesized that protease inhibitor therapy may be unnecessary in these patients. Treatment-naïve, noncirrhosis patients infected with genotype-1 HCV and a low viral load at baseline were considered for inclusion (n = 233). After 4 weeks of lead-in therapy with peginterferon α-2b and ribavirin, 101 patients (48%) had a rapid virologic response (defined as undetectable levels of hepatitis C virus RNA at 4 weeks) and were eligible to participate. Patients were randomized 1:1 to 20 weeks of additional therapy with peginterferon α-2b and ribavirin (double therapy) or to 24 weeks of peginterferon α-2b, ribavirin, and boceprevir (triple therapy). There was no significant difference in rates of SVR-12 in patients treated with double versus triple therapy. This similarity persisted regardless of viral subtype (genotype 1a or 1b), interleukin (IL)-28b genotype (CC or non-CC), or ethnicity (African American versus non-Hispanic white). CONCLUSION: Protease inhibitor therapy could be obviated in genotype 1-infected treatment-naïve patients with low viral load at baseline who achieve undetectable viremia after 4 weeks of peginterferon/ribavirin.


Subject(s)
Hepatitis C, Chronic/drug therapy , Proline/analogs & derivatives , Protease Inhibitors , Antiviral Agents/therapeutic use , Contraindications , Female , Genotype , Hepacivirus/genetics , Hepatitis C, Chronic/virology , Humans , Interferon alpha-2 , Interferon-alpha/therapeutic use , Male , Middle Aged , Polyethylene Glycols/therapeutic use , Recombinant Proteins/therapeutic use , Ribavirin/therapeutic use , Treatment Outcome , Viral Load
14.
Lancet Infect Dis ; 12(9): 717-28, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22647717

ABSTRACT

For the past decade, the standard treatment for chronic hepatitis C infection has been pegylated-interferon plus ribavirin. With US Food and Drug Administration approval of boceprevir and telaprevir--two protease inhibitors--the standard-of-care treatment for genotype-1 infection, the main genotype worldwide, is now peginterferon plus ribavirin and a protease inhibitor. Rates of sustained virological response or cure with triple combination treatment have improved substantially, both in patients who have had previous treatment and in those who have not. Improvements have been most substantial in populations regarded as difficult to treat, such as individuals with cirrhosis. However, despite improved response rates, protease inhibitors have incremental toxic effects, high costs, increased pill burden, and many drug interactions. Moreover, because new antiviral drugs directly inhibit hepatitis C virus, viral resistance has become an important issue, essentially precluding use of protease inhibitor monotherapy, and potentially restricting future treatment options for patients who consequently do not achieve sustained virological response. Protease inhibitors are the first of many antiviral medications that will probably be combined in future interferon-free regimens.


Subject(s)
Antiviral Agents/administration & dosage , Hepacivirus/classification , Hepacivirus/genetics , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Protease Inhibitors/administration & dosage , Standard of Care/trends , Antiviral Agents/adverse effects , Drug Resistance, Viral , Drug Therapy, Combination/adverse effects , Drug Therapy, Combination/methods , Genotype , Hepacivirus/isolation & purification , Humans , Interferon-alpha/administration & dosage , Oligopeptides/administration & dosage , Oligopeptides/adverse effects , Polyethylene Glycols/administration & dosage , Proline/administration & dosage , Proline/adverse effects , Proline/analogs & derivatives , Protease Inhibitors/adverse effects , Recombinant Proteins/administration & dosage , Ribavirin/administration & dosage , United States
17.
Clin Infect Dis ; 52(7): 889-900, 2011 Apr 01.
Article in English | MEDLINE | ID: mdl-21427396

ABSTRACT

Sustained virologic response (SVR) is defined as aviremia 24 weeks after completion of antiviral therapy for chronic hepatitis C virus (HCV) infection. In analyses of SVR durability, the incidence of late relapse is extremely low (<1%). Histologic regression of both necroinflammation and fibrosis has been demonstrated in paired liver biopsy samples in SVR-achieving patients. More noteworthy is the sustained responder's favorable prognosis even with baseline cirrhosis; despite mostly retrospective analyses, relative to nonresponders or to those untreated, patients with SVR have significantly fewer liver-related complications, less hepatocellular carcinoma, and fewer liver-related deaths. Although HCV is associated with insulin resistance, successful eradication of HCV appears to reduce the risk of impaired fasting glucose and diabetes development. In summary, chronic HCV infection is curable with SVR attainment, and with cure comes improved liver histology and more favorable clinical outcomes, in comparison with patients who do not achieve the same therapeutic milestone.


Subject(s)
Antiviral Agents/administration & dosage , Hepatitis C, Chronic/drug therapy , Carcinoma, Hepatocellular/epidemiology , Carcinoma, Hepatocellular/prevention & control , Humans , Liver Cirrhosis/epidemiology , Liver Cirrhosis/prevention & control , Liver Neoplasms/epidemiology , Liver Neoplasms/prevention & control , Treatment Outcome
18.
Curr Gastroenterol Rep ; 13(1): 78-86, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21080244

ABSTRACT

The hypothesis that host genetics play an essential role in the ability not only to clear acute hepatitis C infection but also to achieve sustained virologic response (SVR) to interferon (IFN)-based therapy has been proved with the recent discovery of two single-nucleotide polymorphisms on chromosome 19. Variants in the minor allele rs8099917 and the proximate polymorphism rs12979860, 3 kb upstream of the interleukin (IL)-28B gene, which encodes the endogenous antiviral cytokine IFN-λ, are associated with SVR and with natural viral clearance. The disparate frequencies of these alleles in ethnic groups worldwide may well explain differing rates of SVR among them. The test for one of these polymorphisms is now commercially available and can serve as a powerful predictor of a patient's chance of achieving SVR. Perhaps more importantly, the test can help the clinician personally tailor the duration and even the type of therapy that is most appropriate for an individual patient, newly or chronically infected with the hepatitis C virus.


Subject(s)
Hepatitis C/immunology , Interleukins/genetics , Antiviral Agents/therapeutic use , Genetic Testing , Genome-Wide Association Study , Genotype , Hepacivirus/isolation & purification , Hepatitis C/drug therapy , Hepatitis C/ethnology , Hepatitis C/virology , Humans , Interferons/therapeutic use , Interleukins/immunology , Polymorphism, Single Nucleotide , Viral Load
19.
In Silico Biol ; 11(5-6): 213-24, 2011.
Article in English | MEDLINE | ID: mdl-23202423

ABSTRACT

Machine-learning methods in the form of Bayesian networks (BN), linear projection (LP) and self-organizing tree (SOT) models were used to explore association among polymorphic sites within the HVR1 and NS5a regions of the HCV genome, host demographic factors (ethnicity, gender and age) and response to the combined interferon (IFN) and ribavirin (RBV) therapy. The BN models predicted therapy outcomes, gender and ethnicity with accuracy of 90%, 90% and 88.9%, respectively. The LP and SOT models strongly confirmed associations of the HVR1 and NS5A structures with response to therapy and demographic host factors identified by BN. The data indicate host specificity of HCV evolution and suggest the application of these models to predict outcomes of IFN/RBV therapy.


Subject(s)
Evolution, Molecular , Hepacivirus/genetics , Bayes Theorem , Genome, Viral/genetics , Hepacivirus/drug effects , Interferons/pharmacology , Ribavirin/pharmacology
SELECTION OF CITATIONS
SEARCH DETAIL
...